Oligomeric cystatin C supports the immunosuppressive activity of myeloid cells through interaction with inhibitory receptors
Open accessAbstract
Amyloid proteins are linked to various diseases; however, their functional roles in immunity and cancer remain unclear. Here, we establish a direct link between oligomeric cystatin C—a cysteine cathepsin inhibitor and a well-characterized amyloidogenic protein—within the tumor microenvironment and the immune inhibitory receptors LILRB2 and LILRB5 on myeloid cells. We demonstrated that human LILRB2 and LILRB5, along with their murine counterpart PIRB, serve as functional receptors for cystatin C oligomers. Engagement of these inhibitory receptors by oligomeric cystatin C enhances the immunosuppressive activity of myeloid cells, leading to T-cell suppression and tumor progression. Deletion of the CST3 gene, which encodes cystatin C, in host mice and tumor cells impaired tumor growth, whereas its overexpression accelerated cancer progression in LILRB2 and LILRB5 transgenic mice. Mechanistically, cystatin C–LILRB2 signaling is driven by both canonical phosphatases and the enhanced TGF-β pathway. Additionally, we identified interactions between LILRB receptors and transthyretin oligomers, another amyloid linked to transthyretin amyloidosis, suggesting a broader paradigm of amyloid–LILRB interactions. Our findings reveal an unexpected role of oligomeric cystatin C in enhancing myeloid cell immunosuppression, expand the functional spectrum of amyloid proteins and underscore the importance of these proteins in immune evasion and cancer development.
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TL;DR
Oligomeric cystatin C acts as a ligand for the inhibitory receptors LILRB2 and LILRB5, enhancing myeloid cell immunosuppression and promoting tumor progression. The cystatin C–LILRB2 axis signals through ITIM/SHP and enhanced TGF-β signaling, and oligomeric transthyretin shows similar LILRB2/LILRB5 binding.
Key findings
- In 16 melanoma tumor tissues, cystatin C was detected as both monomeric and oligomeric forms in 56.25% (9/16), predominantly monomeric in 31.25% (5/16), and predominantly oligomeric in 12.50% (2/16); oligomeric cystatin C bound monocytes and neutrophils and selectively bound LILRB2, LILRB5, and murine PIRB.
- Binding affinities of purified cystatin CEX to LILRB2 and LILRB5 were EC50 ~22.76 nM and 1.18 μM, respectively; LILRB2 binding required the N-terminal D1D2 domain, whereas LILRB5 binding required the C-terminal D3D4 domain.
- Cystatin C oligomers activated LILRB2/LILRB5 reporter cells, induced LILRB2/LILRB5 tyrosine phosphorylation and SHP-1 recruitment, inhibited M1 macrophage and dendritic cell differentiation, promoted N2-like neutrophils, and enhanced monocyte- and MDSC-mediated T-cell suppression; these effects were reversed or partially reversed by anti-LILRB2 blockade.
- CST3 deletion in host mice and tumor cells impaired B16-F10 tumor growth and shifted the tumor microenvironment toward antitumor immunity, whereas CST3 overexpression accelerated B16-F10 and CT-2A tumor growth in LILRB2KI and LILRB5KI mice and in hCD34+ humanized mice; anti-LILRB2 delayed SK-MEL-5-hcystatin C tumor growth.
Methods
- Binding and signaling were assessed using recombinant cystatin C, conditioned media, flow cytometry, co-IP, pull-down, ELISA, biolayer interferometry, LILRB chimeric reporter cells, and THP-1 cells expressing LILRB2 or LILRB5.
- Primary human CD14+ monocytes, CD15+ neutrophils, MDSCs, and autologous T cells were used for differentiation, polarization, endocytosis, migration, CFSE proliferation, and IFN-γ ELISA assays, with anti-LILRB2 blocking antibodies.
- In vivo work used CST3−/− and PIRB−/− mice, myeloid-specific LILRB2KI and LILRB5KI mice, NSG-SGM3 mice, and hCD34+ humanized mice bearing B16-F10, CT-2A, or SK-MEL-5 tumors; TCGA/GEPIA and TIMER 2.0 were used for survival and CST3–LILRB2 correlation analyses.
Limitations
- The paper states that targeting cystatin C faces challenges including rarity of cystatin C-related disease, limited drug delivery across the blood–brain barrier, and absence of robust animal models; it also notes that further studies are needed to clarify cystatin C oligomer effects on B cells.
- The text makes evident that some in vitro effects were only partially reversed by anti-LILRB2 blockade, and TCGA analyses showed weak positive correlations between CST3 and LILRB2/LILRB5 and a nonsignificant trend for CST3 and overall survival across all cancers (P > 0.05).
- The text also makes evident that cystatin C did not show a statistically significant interaction with TGF-β receptors in the authors’ analyses, and the in vivo evidence relies heavily on transgenic or humanized mouse models rather than spontaneous human tumors.
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Claims the paper makes
28 of 41 cited sources checked · 12 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Accumulation and activation of immunosuppressive myeloid cells are strongly correlated with reduced efficacy of immunotherapies and poor prognosis across various cancers.
“Their accumulation and activation are strongly correlated with reduced efficacy of immunotherapies and poor prognosis across various cancers, such as colorectal cancer, pancreatic cancer, glioblastoma, breast cancer, liver cancer, head and neck cancer, lung cancer, and prostate cancer13.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [13] Barry, S. T., Gabrilovich, D. I., Sansom, O. J., Campbell, A. D. & Morton, J. P. Therapeutic targeting of tumour myeloid cells. Nat. Rev. Cancer 23, 216–237 (2023). source
The available passages (Dosing Strategy > M-MDSC; page not given) list myeloid-cell markers and treatment trials in several cancers, but do not link myeloid-cell accumulation or activation to immunotherapy efficacy or prognosis. Searches for “poor prognosis,” “immunotherapy resistance,” and the named cancer types did not find a passage establishing the claimed correlation. (LLM, conf=0.72)
Experimental — accuracy not yet measured
- Findingown data
Patient-derived MDSCs suppressed the proliferation and function of autologous T cells in a coculture system.
“As expected, patient-derived MDSCs suppressed the proliferation and function of autologous T cells in a coculture system (Fig. 3c–e and Supplementary Fig. 5b), which is consistent with their known immunosuppressive activity31,32.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [31] Xie, J. et al. Blocking LAIR1 signaling in immune cells inhibits tumor development. Front. Immunol. 13, 996026 (2022). source
The Results section ('LAIR1 inhibition restored T cell proliferation in coculture'; page unavailable) reports that patient-derived MDSCs inhibited autologous T-cell proliferation and describes this as immunosuppressive activity. It does not report a separate measure of T-cell function in that coculture, so the additional claim about suppressed function is not independently supported. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [32] Huang, R. et al. LILRB3 supports immunosuppressive activity of myeloid cells and tumor development. Cancer Immunol. Res. 12, 350–362 (2024). source
- Findingown data
PIRB−/− mice presented a significant reduction in cystatin C oligomer binding to monocytes and neutrophils compared with wild-type mice.
“Moreover, compared with wild-type mice, PIRB−/− mice presented a significant reduction in cystatin C oligomer binding to monocytes and neutrophils, suggesting that PIRB is a receptor for cystatin C oligomers on myeloid cells (Supplementary Fig. 3d).”
Quote in the paperSubstantial claim - Findingown data
Cystatin C from DMEM-conditioned medium did not bind immune cells.
“While cystatin C from DMEM-conditioned medium did not bind immune cells, EX-CELL-derived cystatin C exhibited significant binding to monocytes and neutrophils, with moderate binding to B cells (Fig. 1b).”
Quote in the paperSubstantial claim - Findingown data
Oligomeric cystatin C within the tumor microenvironment directly links to the immune inhibitory receptors LILRB2 and LILRB5 on myeloid cells.
“Here, we establish a direct link between oligomeric cystatin C—a cysteine cathepsin inhibitor and a well-characterized amyloidogenic protein—within the tumor microenvironment and the immune inhibitory receptors LILRB2 and LILRB5 on myeloid cells.”
Quote in the paperSubstantial claim
- Findingown data
For LILRB5, the C-terminal D3D4 domain, rather than the N-terminal D1D2 domain, is essential for cystatin C binding.
“In contrast, for LILRB5, the C-terminal D3D4 domain—rather than the NK-terminal D1D2 domain—was essential for cystatin C binding (Supplementary Fig. 2l).”
Quote in the paperSubstantial claim - Findingown data
Human LILRB2 and LILRB5, along with their murine counterpart PIRB, serve as functional receptors for cystatin C oligomers.
“We demonstrated that human LILRB2 and LILRB5, along with their murine counterpart PIRB, serve as functional receptors for cystatin C oligomers.”
Quote in the paperSubstantial claim - Findingown data
Deletion of the CST3 gene in host mice and tumor cells impairs tumor growth.
“Deletion of the CST3 gene, which encodes cystatin C, in host mice and tumor cells impaired tumor growth, whereas its overexpression accelerated cancer progression in LILRB2 and LILRB5 transgenic mice.”
Quote in the paperSubstantial claim - Findingown data
EX-CELL-derived cystatin C exhibited stronger binding to LILRB2- and LILRB5-expressing cells than monomeric cystatin C in DMEM.
“Compared with monomeric cystatin C in DMEM, EX-CELL-derived cystatin C exhibited stronger binding to LILRB2- and LILRB5-expressing cells (Fig. 1c).”
Quote in the paperSubstantial claim - Findingown data
Cystatin C oligomers bound to the extracellular domains of LILRB2 and LILRB5 fused to IgG-Fc.
“Additionally, the cystatin C oligomers bound to the extracellular domains (ECDs) of LILRB2 and LILRB5 fused to IgG-Fc, reinforcing their direct interaction (Fig. 1f and Supplementary Fig. 2f).”
Quote in the paperSubstantial claim - Findingown data
ELISA binding affinities of cystatin CEX to LILRB2 and LILRB5 have EC50 values of approximately 22.76 nM and 1.18 μM, respectively.
“ELISAs were used to determine the binding affinities, with EC50 values of ~22.76 nM and 1.18 μM for LILRB2 and LILRB5, respectively (Fig. 1h and Supplementary Fig. 2j).”
Quote in the paperSubstantial claim - Findingown data
LILRB receptors interact with transthyretin oligomers.
“Additionally, we identified interactions between LILRB receptors and transthyretin oligomers, another amyloid linked to transthyretin amyloidosis, suggesting a broader paradigm of amyloid–LILRB interactions.”
Quote in the paperNot a substantial claim - Findingown data
In vitro pull-down assays using purified cystatin CEX and LILRB2-Fc or LILRB5-Fc validated the interaction.
“In vitro pull-down assays using purified cystatin CEX and LILRB2-Fc or LILRB5-Fc further validated this interaction (Fig. 1g and Supplementary Fig. 2i).”
Quote in the paperSubstantial claim - Findingown data
Overexpression of cystatin C accelerates cancer progression in LILRB2 and LILRB5 transgenic mice.
“Deletion of the CST3 gene, which encodes cystatin C, in host mice and tumor cells impaired tumor growth, whereas its overexpression accelerated cancer progression in LILRB2 and LILRB5 transgenic mice.”
Quote in the paperSubstantial claim - Findingown data
Commercial recombinant cystatin C (SinoBiological) exists only as a monomer under nonreducing conditions.
“we analyzed the aggregation states of commercial recombinant cystatin C (SinoBiological, hereafter referred to as cystatin CSino) under nonreducing conditions and found that it exists only as a monomer (Supplementary Fig. 2a).”
Quote in the paperSubstantial claim - Findingown data
The majority of cancer patients surveyed presented elevated serum cystatin C levels compared with healthy controls.
“Among the cancer patients surveyed, the majority presented elevated serum cystatin C levels compared with those of healthy controls (Supplementary Fig. 1a).”
Quote in the paperNot a substantial claim - Findingown data
In the CT-2A-hcystatin C tumor model, immune cell subsets with antitumor activity, such as T cells and NK cells, were significantly reduced.
“In contrast, immune cell subsets with antitumor activity, such as T cells and NK cells, were significantly reduced (Supplementary Fig. 7e).”
Quote in the paperSubstantial claim - Findingown data
Blockade of LILRB2 significantly delayed SK-MEL-5-hcystatin C tumor growth in hCD34+ humanized mice.
“Compared with isotype control treatment, blockade of LILRB2 significantly delayed SK-MEL-5-hcystatin C tumor growth (Fig. 6d).”
Quote in the paperSubstantial claim- Rests on an assumption: The hCD34+ humanized mouse model's immune system is sufficiently human-like to reveal the human immune cell-dependent effects of cystatin C.
- Rests on an assumption: The anti-LILRB2 blocking antibody specifically inhibits LILRB2 without affecting other receptors.
- Findingown data
Cystatin C deficiency had no detectable effect on immune cell populations in the peripheral blood.
“Furthermore, cystatin C deficiency had no detectable effect on immune cell populations in the peripheral blood (Supplementary Fig. 6f).”
Quote in the paperNot a substantial claim - Findingown data
High CST3 expression was significantly associated with poor disease-free survival across all cancer patients.
“High CST3 expression was also significantly associated with poor disease-free survival across all cancer patients (Supplementary Fig. 8b), further implicating cystatin C in adverse clinical outcomes.”
Quote in the paperNot a substantial claim - Findingown data
mRNA expression levels of IL-10 and NOS2 were consistent with the observed effects of cystatin CEX on M1 macrophage differentiation.
“Additionally, the mRNA expression levels of the immunosuppressive genes IL-10 and NOS2 were also consistent with these findings (Supplementary Fig. 4f).”
Quote in the paperNot a substantial claim - Findingown data
Forced expression of CST3 promotes tumor growth in LILRB2KI mice.
“Fig. 5 Forced expression of CST3 promotes tumor growth in LILRB2KI mice.”
Quote in the paperSubstantial claim - Findingown data
Cystatin CEX significantly increased MDSC viability in vitro.
“Cystatin CEX significantly increased MDSC viability in vitro (Fig. 3f).”
Quote in the paperSubstantial claim - Findingown data
B16-F10-hcystatin C overexpression significantly increased the proportion of LILRB2+ myeloid cells among total myeloid cells in LILRB2KI mice.
“Consistent with this tumor-promoting phenotype, flow cytometry analysis revealed that B16-F10-hcystatin C overexpression significantly increased the proportion of LILRB2⁺ myeloid cells among total myeloid cells in LILRB2KI mice (Fig. 5c), indicating a more immunosuppressive TME.”
Quote in the paperSubstantial claim- Rests on an assumption: LILRB2KI and LILRB5KI transgenic mice recapitulate human LILRB2 and LILRB5 function in cancer.
- Findingown data
The interaction between LILRB2 and TGF-βRI was markedly increased following TGF-β1 stimulation.
“Additionally, the interaction between LILRB2 and TGF-βRI was markedly increased following TGF-β1 stimulation (Fig. 7f), indicating that LILRB2 enhances SMAD2-dependent canonical TGF-β signaling.”
Quote in the paperSubstantial claim - Findingown data
Percentages of IFN-γ+, perforin+, and granzyme+ CD8+ T cells were significantly greater in the TME of cystatin C−/− mice than in that of WT mice.
“Consistent with increased CD8⁺ T-cell infiltration, the percentages of IFN-γ⁺, perforin⁺, and granzyme⁺ CD8⁺ T cells were significantly greater in the TME of cystatin C−/− mice than in that of WT mice, suggesting enhanced T-cell cytotoxicity (Fig. 4d).”
Quote in the paperSubstantial claim - Findingown data
In the B16-F10-hcystatin C model, myeloid cells showed significant downregulation of CD80 and upregulation of CD14 and CD206, indicative of a tolerogenic myeloid phenotype.
“Further analysis of myeloid cells in the B16-F10-hcystatin C model revealed significant downregulation of CD80 expression and upregulation of CD14 and CD206 expression, indicative of a tolerogenic myeloid phenotype (Fig. 5e).”
Quote in the paperSubstantial claim - Findingown data
Similar results were observed in the HEK293T-LILRB5 system.
“Similar results were observed in the HEK293T-LILRB5 system (Supplementary Fig. 4c).”
Quote in the paperSubstantial claim - Findingown data
In the B16-F10-hcystatin C model, intracellular staining revealed significantly elevated levels of phosphorylated STAT3 in myeloid cells.
“Additionally, intracellular staining revealed significantly elevated levels of phosphorylated STAT3, a key regulator of MDSC differentiation and immunosuppressive function (Fig. 5e).”
Quote in the paperSubstantial claim - Findingown data
Only soluble cystatin CEX, but not cystatin CSino, effectively induced LILRB2 and LILRB5 reporter cell activation.
“However, only soluble cystatin CEX, but not cystatin CSino, effectively induced LILRB2 and LILRB5 reporter cell activation, further suggesting that oligomeric cystatin C binds and activates LILRB2 and LILRB5 (Fig. 2a and Supplementary Fig. 4b).”
Quote in the paperSubstantial claim - Findingown data
In WT mice, tumor growth kinetics were similar between sgScramble and sgCST3 B16-F10 clones.
“While tumor growth kinetics were similar between sgScramble and sgCST3 B16-F10 clones in WT mice, cystatin C−/− mice presented significantly reduced tumor growth and lower endpoint tumor weights for sgCST3, but not sgScramble, B16-F10 tumors (Fig. 4a, b).”
Quote in the paperSubstantial claim - Findingown data
The extracellular domain of TGF-βRI is required for its interaction with LILRB2.
“Co-IP analysis revealed that the extracellular domain of TGF-βRI is required for its interaction with LILRB2 (Fig. 7c), suggesting that LILRB2 may facilitate the recruitment of TGF-βRI to TGF-βRII.”
Quote in the paperSubstantial claim - Findingown data
LILRB2 promoted the recruitment of TGF-βRI to TGF-βRII in a dose-dependent manner.
“As expected, LILRB2 promoted the recruitment of TGF-βRI to TGF-βRII in a dose-dependent manner (Fig. 7d).”
Quote in the paperSubstantial claim - Findingown data
Surface expression of CD14 and CD163 was increased following cystatin CEX treatment, which was partially reversed by anti-LILRB2 blockade.
“In addition, the surface expression of the immunosuppressive markers CD14 and CD163 was increased following cystatin CEX treatment, which was partially reversed by anti-LILRB2 blockade (Fig. 3g).”
Quote in the paperSubstantial claim- Rests on an assumption: Anti-LILRB2 and anti-LILRB5 blocking antibodies specifically block the cystatin C–LILRB interaction without off-target effects.
- Findingown data
Cystatin CEX further enhanced the MDSC-mediated suppression of T-cell proliferation and function.
“Notably, cystatin CEX further enhanced the MDSC-mediated suppression of T-cell proliferation and function (Fig. 3c–e and Supplementary Fig. 5b).”
Quote in the paperSubstantial claim - Findingown data
Forced expression of human cystatin C in B16-F10 or CT-2A cells significantly accelerated tumor growth in LILRB2KI mice but not in WT mice.
“As expected, forced expression of human cystatin C in B16-F10 or CT-2A cells significantly accelerated tumor growth in LILRB2KI mice but not in WT mice (Fig. 5a, b).”
Quote in the paperSubstantial claim- Rests on an assumption: LILRB2KI and LILRB5KI transgenic mice recapitulate human LILRB2 and LILRB5 function in cancer.
- Findingown data
B16-F10-hcystatin C tumor growth was accelerated in LILRB5KI mice.
“Furthermore, B16-F10-hcystatin C tumor growth was accelerated in LILRB5KI mice (Supplementary Fig. 7g, h).”
Quote in the paperSubstantial claim - Findingown data
The immunosuppressive effect of cystatin CEX on MDSC-mediated T-cell suppression was partially reversed by anti-LILRB2 treatment.
“This immunosuppressive effect was partially reversed by anti-LILRB2 treatment, reinforcing the role of cystatin C oligomers in promoting MDSC function (Fig. 3c–e).”
Quote in the paperSubstantial claim- Rests on an assumption: Anti-LILRB2 and anti-LILRB5 blocking antibodies specifically block the cystatin C–LILRB interaction without off-target effects.
- Findingown data
Activation of LILRB2 and LILRB5 reporter cells by cystatin C was abrogated by anti-LILRB2 and anti-LILRB5 blocking antibodies.
“This activation was abrogated by anti-LILRB2 and anti-LILRB5 blocking antibodies, confirming the specificity of the interaction between cystatin C and its receptors (Fig. 2a and Supplementary Fig. 4b).”
Quote in the paperSubstantial claim- Rests on an assumption: Anti-LILRB2 and anti-LILRB5 blocking antibodies specifically block the cystatin C–LILRB interaction without off-target effects.
- Findingown data
Cystatin C-coated plates consistently induced tyrosine phosphorylation of LILRB2 and LILRB5 in THP-1-derived monocyte cell lines stably expressing LILRB2 or LILRB5.
“cystatin C-coated plates consistently induced tyrosine phosphorylation of LILRB2 and LILRB5 in these cells (Fig. 2c and Supplementary Fig. 4d).”
Quote in the paperSubstantial claim - Findingown data
Cystatin CEX did not alter the elongated, loosely adherent morphology of M2a macrophages induced by M-CSF and IL-4.
“Compared with BSA-treated controls, cystatin CEX did not alter the elongated, loosely adherent morphology of M2a macrophages induced by M-CSF and IL-4 (Supplementary Fig. 4g).”
Quote in the paperNot a substantial claim - Findingown data
In the CT-2A-hcystatin C tumor model, immune profiling revealed increased accumulation of immunosuppressive myeloid cell populations, including TAMs, PMN-MDSCs, M-MDSCs, and Treg cells, compared with the CT-2A-vec control model.
“Similarly, in the CT-2A-hcystatin C tumor model, immune profiling revealed increased accumulation of immunosuppressive myeloid cell populations, including TAMs, PMN-MDSCs, M-MDSCs, and Treg cells, compared with those in the CT-2A-vec control model.”
Quote in the paperSubstantial claim - Findingown data
In the B16-F10 melanoma model, cystatin C underwent moderate oligomerization during tumor progression compared with adjacent normal skin tissue.
“In the B16-F10 melanoma model, compared with adjacent normal skin tissue, cystatin C underwent moderate oligomerization during tumor progression (Supplementary Fig. 6a, b).”
Quote in the paperSubstantial claim - Findingown data
Cystatin CEX significantly inhibited the GM-CSF-induced round and flattened morphology characteristic of M1 macrophages after six days of differentiation, an effect reversed by LILRB2 blockade.
“Compared with BSA-treated controls, cystatin CEX significantly inhibited the GM-CSF-induced round and flattened morphology characteristic of M1 macrophages after six days of differentiation, an effect reversed by LILRB2 blockade (Fig. 2d).”
Quote in the paperSubstantial claim- Rests on an assumption: Anti-LILRB2 and anti-LILRB5 blocking antibodies specifically block the cystatin C–LILRB interaction without off-target effects.
- Findingown data
Substantial oligomerization of human cystatin C was observed in the TME of B16-F10-hcystatin C and CT-2A-hcystatin C tumors in LILRB2KI mice.
“Additionally, substantial oligomerization of human cystatin C was observed in the TME of B16-F10-hcystatin C and CT-2A-hcystatin C tumors in LILRB2KI mice (Supplementary Fig. 7c).”
Quote in the paperSubstantial claim - Findingown data
Anti-LILRB2 treatment significantly delayed B16-F10-hcystatin C tumor progression in LILRB2KI mice.
“Importantly, anti-LILRB2 treatment significantly delayed B16-F10-hcystatin C tumor progression in LILRB2KI mice (Supplementary Fig. 7f).”
Quote in the paperSubstantial claim- Rests on an assumption: The anti-LILRB2 blocking antibody specifically inhibits LILRB2 without affecting other receptors.
- Findingown data
CST3 knockout (cystatin C−/−) mice on the C57BL/6 background lack cystatin C protein in brain, lung, muscle, heart, spleen, kidney, liver, and plasma.
“In contrast, western blot and dot blot assays confirmed the absence of cystatin C protein in the brain, lung, muscle, heart, spleen, kidney, liver, and plasma of cystatin C−/− mice (Supplementary Fig. 6d, e).”
Quote in the paperSubstantial claim - Findingown data
sgScramble and sgCST3 B16-F10 clones had equivalent proliferative activities in vitro.
“MTS assays revealed that sgScramble and sgCST3 B16-F10 clones had equivalent proliferative activities in vitro (Supplementary Fig. 6h).”
Quote in the paperSubstantial claim - Findingown data
The interaction between LILRBs and TGF-β receptors was partially inhibited by anti-LILRB2 blocking antibodies.
“Notably, this interaction was partially inhibited by anti-LILRB2 blocking antibodies, suggesting a specific and regulatable association (Supplementary Fig. 9b).”
Quote in the paperSubstantial claim- Rests on an assumption: The anti-LILRB2 blocking antibody specifically inhibits LILRB2 without affecting other receptors.
- Findingown data
Bioinformatic analysis of TCGA data revealed a modest correlation between high CST3 expression and poor overall survival across all cancer patients, with a trend toward significance (P > 0.05).
“Bioinformatic analysis of data from The Cancer Genome Atlas (TCGA) revealed a modest correlation between high CST3 expression and poor overall survival across all cancer patients (P > 0.05, but with a trend toward significance; Supplementary Fig. 8b).”
Quote in the paperNot a substantial claim - Findingown data
Cystatin C deletion significantly increased expression of proinflammatory cytokines TNF-α, IL-1β, and IL-12 in sorted splenic Mac1+Gr-1+ myeloid cells from tumor-bearing mice.
“Additionally, cytokine analysis of sorted splenic Mac1⁺Gr-1⁺ myeloid cells from tumor-bearing mice revealed that compared with WT controls, cystatin C deletion significantly increased the expression of proinflammatory cytokines, including TNF-α, IL-1β, and IL-12 (Fig. 4e).”
Quote in the paperSubstantial claim - Findingown data
Cystatin CEX treatment significantly upregulated the expression of CXCR2 (CD182), a marker of N2 neutrophils.
“Additionally, cystatin CEX treatment significantly upregulated the expression of CXCR2 (CD182), a marker of N2 neutrophils, further supporting its role in promoting an immunosuppressive neutrophil phenotype (Fig. 2f).”
Quote in the paperSubstantial claim - Findingown data
LILRB2-TGF-βRI binding was validated in primary neutrophils.
“This interaction was further validated in primary neutrophils, where Co-IP assays confirmed LILRB2–TGF-βRI binding (Supplementary Fig. 9c).”
Quote in the paperSubstantial claim - Findingown data
The increases in SMAD2/SMAD3 phosphorylation were partially reversed upon LILRB2 blockade.
“Notably, these increases were partially reversed upon LILRB2 blockade (Fig. 7h), indicating that cystatin C modulates TGF-β signaling in a LILRB2-dependent manner.”
Quote in the paperSubstantial claim- Rests on an assumption: The anti-LILRB2 blocking antibody specifically inhibits LILRB2 without affecting other receptors.
- Findingown data
The predominant binding form of TTR detected was its oligomeric state.
“Notably, the predominant binding form of TTR detected was its oligomeric state (Fig. 8c).”
Quote in the paperSubstantial claim - Findingown data
Plates coated with TTR and SAA4, but not PrP or α-synuclein, significantly activated LILRB2 and LILRB5 reporter cells.
“Consistent with our findings for cystatin C, plates coated with TTR and SAA4, but not PrP or α-synuclein, significantly activated LILRB2 and LILRB5 reporter cells (Supplementary Fig. 10).”
Quote in the paperSubstantial claim - Findingown data
The degree of cystatin C oligomer formation may not be directly proportional to high protein levels.
“However, the degree of cystatin C oligomer formation may not be directly proportional to high protein levels (Supplementary Fig. 1b).”
Quote in the paperNot a substantial claim - Findingown data
Incubation of LILRB2-transfected HEK293T cells with TTRF87M/L110M-containing DMEM validated the cell-surface interaction between oligomeric TTR and LILRB2.
“Additionally, incubation of LILRB2-transfected HEK293T cells with TTRF87M/L110M-containing DMEM further validated the cell–surface interaction between oligomeric TTR and LILRB2 (Fig. 8e).”
Quote in the paperNot a substantial claim - Findingown data
The oligomeric TTRF87M/L110M variant exhibited a stronger interaction with LILRB2 than the WT and other TTR mutants did.
“Cotransfection of TTR or TTR variants with LILRB2-Flag in HEK293T cells followed by co-IP and western blotting demonstrated that the oligomeric TTRF87M/L110M variant exhibited a stronger interaction with LILRB2 than the WT and other TTR mutants did.”
Quote in the paperSubstantial claim- Rests on an assumption: The F87M/L110M TTR mutant is a valid model for studying oligomeric TTR interactions.
- Findingown data
Oligomeric cystatin C significantly enhanced both the cis- and trans-interactions between LILRB2 and TGF-βRI.
“Oligomeric cystatin C significantly enhanced both the cis- and trans-interactions between LILRB2 and TGF-βRI (Fig. 7g).”
Quote in the paperSubstantial claim - Findingown data
Our analyses did not reveal a statistically significant interaction between cystatin C (either monomeric or oligomeric) and TGF-β receptors.
“Regrettably, our analyses did not reveal a statistically significant interaction between cystatin C (either in its monomeric or oligomeric form) and TGF-β receptors (Supplementary Fig. 9d).”
Quote in the paperSubstantial claim - Findingown data
SMAD2/SMAD3 phosphorylation was markedly increased in primary neutrophils and monocytes following cystatin CEX treatment.
“Consistent with these findings, SMAD2/SMAD3 phosphorylation was markedly increased in primary neutrophils and monocytes following cystatin CEX treatment (Fig. 7h).”
Quote in the paperSubstantial claim - Findingown data
TTRF87M/L110M oligomers strongly bound to the LILRB2 ECD.
“Similar to our previous results, TTRF87M/L110M oligomers strongly bound to the LILRB2 ECD (Fig. 8d).”
Quote in the paperSubstantial claim - Findingown data
SMAD2 phosphorylation was significantly greater in THP-1 sgCST3 cells than in THP-1 sgScramble cells.
“Unexpectedly, SMAD2 phosphorylation was significantly greater in THP-1 sgCST3 cells than in THP-1 sgScramble cells (Supplementary Fig. 9e), indicating that physiological cystatin C functions as a negative regulator of TGF-β signaling.”
Quote in the paperSubstantial claim- Rests on an assumption: The CST3 knockout in THP-1 cells specifically eliminates cystatin C without off-target effects.
- Interpretationnone given
Cystatin C-LILRB2 signaling is driven by both canonical phosphatases and the enhanced TGF-β pathway.
“Mechanistically, cystatin C–LILRB2 signaling is driven by both canonical phosphatases and the enhanced TGF-β pathway.”
Quote in the paperSubstantial claim - Interpretationown data
The L1 loop plays a critical role in the recognition of the LILRB2 and LILRB5 receptors.
“These findings suggest that the L1 loop plays a critical role in the recognition of the LILRB2 and LILRB5 receptors.”
Quote in the paperSubstantial claim - Interpretationown data
Oligomeric cystatin C plays an unexpected role in enhancing myeloid cell immunosuppression.
“Our findings reveal an unexpected role of oligomeric cystatin C in enhancing myeloid cell immunosuppression, expand the functional spectrum of amyloid proteins and underscore the importance of these proteins in immune evasion and cancer development.”
Quote in the paperSubstantial claim - Interpretationown data
The findings suggest a broader paradigm of amyloid-LILRB interactions.
“Additionally, we identified interactions between LILRB receptors and transthyretin oligomers, another amyloid linked to transthyretin amyloidosis, suggesting a broader paradigm of amyloid–LILRB interactions.”
Quote in the paperSubstantial claim - Interpretationown data
Engagement of these inhibitory receptors by oligomeric cystatin C leads to T-cell suppression.
“Engagement of these inhibitory receptors by oligomeric cystatin C enhances the immunosuppressive activity of myeloid cells, leading to T-cell suppression and tumor progression.”
Quote in the paperSubstantial claim - Interpretationown data
Engagement of LILRB2, LILRB5, or PIRB by oligomeric cystatin C enhances the immunosuppressive activity of myeloid cells.
“Engagement of these inhibitory receptors by oligomeric cystatin C enhances the immunosuppressive activity of myeloid cells, leading to T-cell suppression and tumor progression.”
Quote in the paperSubstantial claim - Interpretationown data
Oligomeric cystatin C exists in tumor tissues, albeit with variable abundance across samples.
“suggesting that oligomeric cystatin C exists in tumor tissues, albeit with variable abundance across samples.”
Quote in the paperSubstantial claim - Interpretationreasoning
Engagement of these inhibitory receptors by oligomeric cystatin C leads to tumor progression.
“Engagement of these inhibitory receptors by oligomeric cystatin C enhances the immunosuppressive activity of myeloid cells, leading to T-cell suppression and tumor progression.”
Quote in the paperSubstantial claim - Interpretationown data
Cystatin C undergoes dimerization and oligomerization in the EX-CELL environment.
“However, in EX-CELL-conditioned medium, monomeric cystatin C levels were reduced, whereas dimer and oligomer levels were increased, suggesting that cystatin C undergoes dimerization and oligomerization in this environment (Fig. 1a).”
Quote in the paperSubstantial claim - Interpretationown data
Mouse cystatin C displayed similar binding patterns to human cystatin C, indicating a conserved interaction mechanism across species.
“Notably, mouse cystatin C displayed similar binding patterns, indicating a conserved interaction mechanism across species (Supplementary Fig. 2b, c).”
Quote in the paperNot a substantial claim - Interpretationown data
The shift in immune composition indicates that cystatin C depletion transforms the TME from protumor to antitumor.
“This shift in immune composition indicates that cystatin C depletion transforms the TME from protumor to antitumor.”
Quote in the paperSubstantial claim - Interpretationown data
LILRB2 enhances SMAD2-dependent canonical TGF-β signaling.
“indicating that LILRB2 enhances SMAD2-dependent canonical TGF-β signaling.”
Quote in the paperSubstantial claim - Interpretationown data
Cystatin C oligomers impair DC differentiation through LILRB2.
“These inhibitory effects were reversed by anti-LILRB2, confirming that cystatin C oligomers impair DC differentiation through LILRB2 (Fig. 2e).”
Quote in the paperSubstantial claim - Interpretationown data
Cystatin C oligomers support the immunosuppressive activities of primary myeloid cells in vitro through the LILRB interaction.
“Together, these results indicate that cystatin C oligomers support the immunosuppressive activities of primary myeloid cells in vitro through the LILRB interaction.”
Quote in the paperSubstantial claim - Interpretationown data
Cystatin C enhances the immunosuppressive functions of tumor-associated myeloid cells through interaction with the LILRB2 and LILRB5 receptors in vivo.
“These findings suggest that cystatin C enhances the immunosuppressive functions of tumor-associated myeloid cells through interaction with the LILRB2 and LILRB5 receptors in vivo.”
Quote in the paperSubstantial claim- Rests on an assumption: LILRB2 and LILRB5 are inhibitory receptors whose engagement suppresses myeloid cell function.
- Interpretationown data
The tumor-promoting effects of cystatin C depend on human immune cells.
“suggesting that the tumor-promoting effects of cystatin C depend on human immune cells.”
Quote in the paperSubstantial claim- Rests on an assumption: The hCD34+ humanized mouse model's immune system is sufficiently human-like to reveal the human immune cell-dependent effects of cystatin C.
- Interpretationown data
Cystatin C oligomers inhibit M1 macrophage differentiation via LILRB2.
“These results indicate that cystatin C oligomers inhibit M1 macrophage differentiation via LILRB2.”
Quote in the paperSubstantial claim - Interpretationown data
PIRB is a receptor for cystatin C oligomers on myeloid cells.
“Moreover, compared with wild-type mice, PIRB−/− mice presented a significant reduction in cystatin C oligomer binding to monocytes and neutrophils, suggesting that PIRB is a receptor for cystatin C oligomers on myeloid cells (Supplementary Fig. 3d).”
Quote in the paperSubstantial claim - Study design and conductown data
Cystatin CEX has minimal endotoxin content.
“To ensure the suitability of cystatin CEX for use in primary cell assays, we first assessed and confirmed its minimal endotoxin content (Supplementary Fig. 4e).”
Quote in the paperNot a substantial claim - Premisecitation
Acidic conditions disrupt three salt bridges between β2 and β3, facilitating the release of the N-terminal β1-α-β2-L1 loop motifs and subsequent domain swapping.
“Studies on cystatin C have shown that acidic conditions disrupt three salt bridges between β2 and β3, facilitating the release of the N-terminal β1-α-β2-L1 loop motifs and subsequent domain swapping69.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [69] Liu, H. et al. Molecular dynamics simulations of human cystatin C and its L68Q varient to investigate the domain swapping mechanism. J. Biomol. Struct. Dyn. 25, 135–144 (2007). source
- Interpretationown data
Physiological cystatin C functions as a negative regulator of TGF-β signaling.
“indicating that physiological cystatin C functions as a negative regulator of TGF-β signaling.”
Quote in the paperSubstantial claim- Rests on an assumption: The CST3 knockout in THP-1 cells specifically eliminates cystatin C without off-target effects.
- Interpretationcitation
Prolonged exposure to an acidic environment likely contributes to cystatin C oligomerization within the TME.
“Given that both myeloid and tumor cells are major sources of cystatin C within the TME, prolonged exposure to an acidic environment likely contributes to its oligomerization.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Our findings establish an unexpected molecular link between specific amyloid proteins, immunity, and cancer development.
“Importantly, our findings establish an unexpected molecular link between specific amyloid proteins, immunity, and cancer development, opening new avenues for therapeutic intervention.”
Quote in the paperSubstantial claim - Interpretationown data
TTR and SAA4 are potential extracellular ligands for the inhibitory receptors LILRB2 and LILRB5.
“These results suggest that TTR and SAA4 are potential extracellular ligands for the inhibitory receptors LILRB2 and LILRB5.”
Quote in the paperSubstantial claim - Premisecitation
In a TTR V30M mouse model, following nerve injury, mice exhibit reduced expression of cytokines and chemokines essential for recruiting immune cells such as macrophages and neutrophils.
“Studies using a TTR V30M mouse model have shown that, following nerve injury, these mice exhibit reduced expression of cytokines and chemokines essential for recruiting immune cells, such as macrophages and neutrophils, both of which are critical for nerve regeneration71.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [71] Goncalves, N. P., Teixeira-Coelho, M. & Saraiva, M. J. The inflammatory response to sciatic nerve injury in a familial amyloidotic polyneuropathy mouse model. Exp. Neurol. 257, 76–87 (2014). source
- Interpretationown data
The immune inhibitory receptors LILRB2 and LILRB5 are receptors for cystatin C.
“Here, we identified the immune inhibitory receptors LILRB2 and LILRB5 as receptors for cystatin C, a cysteine cathepsin inhibitor, which defines a novel function for this secreted protein.”
Quote in the paperSubstantial claim - Interpretationown data
Cystatin C modulates TGF-β signaling in a LILRB2-dependent manner.
“indicating that cystatin C modulates TGF-β signaling in a LILRB2-dependent manner.”
Quote in the paperSubstantial claim- Rests on an assumption: The anti-LILRB2 blocking antibody specifically inhibits LILRB2 without affecting other receptors.
- Classified as probably not a substantial claim. 42
- May combine two claims. 63
Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.
PremisecitationCystatin C promotes tumor growth and therapy resistance by enhancing cancer cell survival during radiotherapy and facilitating tumor repopulation.
“While cystatin C has been reported to promote tumor growth and therapy resistance by enhancing cancer cell survival during radiotherapy and facilitating tumor repopulation11”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [11] Zhao, Y. et al. Cancer cells enter an adaptive persistence to survive radiotherapy and repopulate tumor. Adv. Sci. 10, e2204177 (2023). source
Classified as probably not a substantial claim.
PremisecitationAmyloid proteins can regulate immune responses by interacting with different immune receptors.
“Researches revealed that amyloid proteins can regulate immune responses by interacting with different immune receptors.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [2] Gambuzza, M. E. et al. Toll-like receptors in Alzheimer’s disease: a therapeutic perspective. CNS Neurol. Disord. Drug Targets 13, 1542–1558 (2014). source
- cites [3] Kim, T. et al. Human LilrB2 is a beta-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer’s model. Science 341, 1399–1404 (2013). source
The paper’s Abstract (page unavailable in our copy) reports that β-amyloid oligomers bind PirB and LilrB2, receptors associated with the immune system. It links that interaction to synaptic loss and impaired plasticity, not to regulation of immune responses. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSome amyloid proteins, including amyloid-β, islet amyloid polypeptide, and calcitonin, can suppress pancreatic cancer cell proliferation in a sequence-, concentration-, and aggregation-dependent manner.
“Some amyloid proteins, including amyloid-β (Aβ), islet amyloid polypeptide (IAPP), and calcitonin (CT), can suppress pancreatic cancer cell proliferation in a sequence-, concentration-, and aggregation-dependent manner7.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [7] Tang, Y., Zhang, D., Robinson, S. & Zheng, J. Inhibition of pancreatic cancer cells by different amyloid proteins reveals an inverse relationship between neurodegenerative diseases and cancer. Adv. Biol. 7, e2300070 (2023). source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationLILRBs are expressed predominantly on myeloid cells and their murine relatives PirB and gp49B1 differ in expression patterns and ligand specificity.
“LILRBs are expressed predominantly on myeloid cells and their murine relatives—PirB and gp49B121,22—differ in both expression patterns and ligand specificity.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [21] Kubagawa, H., Burrows, P. D. & Cooper, M. D. A novel pair of immunoglobulin-like receptors expressed by B cells and myeloid cells. Proc. Natl. Acad. Sci. USA 94, 5261–5266 (1997). source
The Discussion reports PIR-B expression in B and myeloid lineages and describes gp49B1 expression in mast and NK cells, supporting a difference in expression patterns. But its “Potential Ligands for PIR-A and PIR-B” section says PIR ligand identity was unknown; it does not establish a difference in ligand specificity between PIR-B and gp49B1. The cited paper also does not establish that human LILRBs are predominantly myeloid. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [22] Katz, H. R. et al. Mouse mast cell gp49B1 contains two immunoreceptor tyrosine-based inhibition motifs and suppresses mast cell activation when coligated with the high-affinity Fc receptor for IgE. Proc. Natl. Acad. Sci. USA 93, 10809–10814 (1996). source
The opening passage (section and page not supplied) identifies gp49B1 as a mouse mast-cell receptor in a family that includes human myeloid receptors, supporting its identification as a murine relative. It does not discuss PirB or compare PirB and gp49B1 expression patterns or ligand specificity. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationLILRB proteins are type I transmembrane receptors predominantly expressed on hematopoietic cells.
“The LILRB proteins are type I transmembrane receptors predominantly expressed on hematopoietic cells14–20.”
Quote in the paperNot a substantial claim5 of 7 sources checked- cites [14] Dietrich, J., Nakajima, H. & Colonna, M. Human inhibitory and activating Ig-like receptors which modulate the function of myeloid cells. Microbes Infect. 2, 323–329 (2000). source
- cites [15] Hirayasu, K. & Arase, H. Functional and genetic diversity of leukocyte immunoglobulin-like receptor and implication for disease associations. J. Hum. Genet. 60, 703–708 (2015). source
- cites [16] Takai, T., Nakamura, A. & Endo, S. Role of PIR-B in autoimmune glomerulonephritis. J. Biomed. Biotechnol. 2011, 275302 (2011). source
Section 2.1 identifies LILRB1 and LILRB2 as human receptors associated with B cells and myeloid-lineage cells, supporting their expression on hematopoietic cells. Section 2.2 describes PIR-B—not LILRB proteins—as a type I transmembrane receptor. The paper does not establish that LILRB proteins as a group have that structure or are predominantly expressed on hematopoietic cells. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [17] van der Touw, W., Chen, H. M., Pan, P. Y. & Chen, S. H. LILRB receptor-mediated regulation of myeloid cell maturation and function. Cancer Immunol. Immunother. 66, 1079–1087 (2017). source
The Introduction (page unavailable) says LILRB expression is enriched in myeloid cells and also occurs in other immune cells, supporting predominant expression on hematopoietic cells. It describes LILRBs as receptors with cytoplasmic signaling domains, but does not identify them as type I transmembrane receptors. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [18] Lewis Marffy, A. L. & McCarthy, A. J. Leukocyte Immunoglobulin-Like receptors (LILRs) on human neutrophils: modulators of infection and immunity. Front. Immunol. 11, 857 (2020). source
- cites [19] Redondo-Garcia, S. et al. Human leukocyte immunoglobulin-like receptors in health and disease. Front. Immunol. 14, 1282874 (2023). source
- cites [20] Deng, M. et al. Leukocyte immunoglobulin-like receptor subfamily B: therapeutic targets in cancer. Antib. Ther. 4, 16–33 (2021). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationElevated cystatin C expression is linked to increased all-cause and cancer-specific mortality across diverse populations.
“Epidemiological studies and large-scale data analyses have linked elevated cystatin C expression to increased all-cause and cancer-specific mortality across diverse populations9,10.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [9] Kleeman, S. O. et al. Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapye. Cell Genom. 3, 100347 (2023). source
The Results section (“CyC production is associated with accelerated onset of disease”; page unavailable) links a blood-test-derived cystatin C production proxy to increased all-cause mortality in UK Biobank and cancer-specific mortality in patients with cancer; it also reports an association between a production-related genetic score and cancer-specific mortality in two cohorts. The claim overstates the evidence by calling these measures cystatin C expression and extending the mortality findings to diverse populations: the reported genetic analyses used European-ancestry cohorts. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [10] Wu, J. et al. Association of plasma cystatin C with all-cause and cause-specific mortality among middle-aged and elderly individuals: a prospective community-based cohort study. Sci. Rep. 12, 22265 (2022). source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationExtracellular amyloid fibrils modulate mechanosignaling and influence the physical and biochemical properties of tumor niches in melanoma and pancreatic ductal adenocarcinoma cells, thereby promoting tumor cell migration and invasion.
“These fibrils have been shown to modulate mechanosignaling and influence the physical and biochemical properties of tumor niches in both melanoma and pancreatic ductal adenocarcinoma cells, thereby promoting tumor cells migration and invasion6.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [6] Farris, F. et al. Unveiling the mechanistic link between extracellular amyloid fibrils, mechano-signaling and YAP activation in cancer. Cell Death. Dis. 15, 28 (2024). source
The Results section reports that amyloid fibrils activate YAP through a glycocalyx–HIPPO signaling axis in melanoma and pancreatic cancer, promoting cell migration and invasion. The Discussion describes the fibrils as a mechanical stimulus in the tumor microenvironment, but does not establish that they change the physical and biochemical properties of tumor niches; it says the basis of their mechanical recognition remains unclear. No page numbers are available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAmyloid β interacts with immune inhibitory receptors, leading to suppression of immune cell activity.
“Conversely, Aβ has also been reported to interact with immune inhibitory receptors, leading to suppression of immune cell activity and highlighting its context-dependent immunomodulatory capacity3.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [3] Kim, T. et al. Human LilrB2 is a beta-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer’s model. Science 341, 1399–1404 (2013). source
The indexed paper reports that Aβ oligomers bind PirB and LilrB2, receptors associated with inhibitory signaling in the immune system. Its reported consequences of Aβ binding concern neuronal signaling and synaptic plasticity, not suppression of immune cell activity. The passages are indexed under “Abstract”; no page number is provided. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAmyloid precursor protein is upregulated in advanced breast cancer and is associated with increased cancer cell proliferation, migration, and invasion.
“Amyloid precursor protein (APP), for example, is upregulated in advanced breast cancer and has been associated with increased cancer cell proliferation, migration, and invasion4.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [4] Lim, S. et al. Amyloid-beta precursor protein promotes cell proliferation and motility of advanced breast cancer. BMC Cancer 14, 928 (2014). source
May combine two claims.
FindingcitationSingle-cell RNA sequencing data from 12 melanoma patients confirmed high CST3 expression within the myeloid cell compartment, as well as ectopic expression in the tumor compartment.
“Single-cell RNA sequencing (scRNA-seq) data from 12 melanoma patients confirmed high CST3 expression within the myeloid cell compartment, as well as ectopic expression in the tumor compartment9.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [9] Kleeman, S. O. et al. Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapye. Cell Genom. 3, 100347 (2023). source
May combine two claims.
PremisecitationIn lung squamous cell carcinoma, elevated expression of the CST3 gene in tumor-associated fibroblasts is associated with reduced responsiveness to immunotherapy and worse clinical outcomes.
“In lung squamous cell carcinoma, elevated expression of the CST3 gene in tumor-associated fibroblasts, an alternative source of cystatin C, is also associated with reduced responsiveness to immunotherapy and worse clinical outcomes39.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [39] Zhang, X., Xiao, Q., Zhang, C., Zhou, Q. & Xu, T. Construction of a prognostic model with CAFs for predicting the prognosis and immunotherapeutic response of lung squamous cell carcinoma. J. Cell. Mol. Med. 28, e18262 (2024). source
The Results (Construction and validation of prognostic model; no page given) report CST3 overexpression in LUSC tumour tissue, and the Discussion identifies CST3 as one of nine genes in a prognostic CAF-related signature. The Results (Exploration of the immune landscape; no page given) associate immunotherapy responsiveness with the composite risk groups, not with CST3 expression in tumour-associated fibroblasts specifically. The paper therefore does not establish that elevated fibroblast CST3 itself predicts reduced responsiveness or worse outcomes. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe pan-caspase inhibitor Q-VD-Oph inhibits spontaneous neutrophil apoptosis and consequently increases neutrophil lifespan.
“the cultivation of neutrophils in the polarization experiments was carried out in the presence of 3 mM pan-caspase inhibitor Q-VD-Oph (Selleckchem, cat. no. S7311) to inhibit spontaneous neutrophil apoptosis and, consequently, increase their lifespan82.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [82] Fan, Y. et al. Targeting multiple cell death pathways extends the shelf life and preserves the function of human and mouse neutrophils for transfusion. Sci. Transl. Med. 13, eabb1069 (2021). source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationRAGE is a well-known mediator of inflammation and is recognized for interacting with soluble oligomers of various amyloid proteins, including TTR and SAA.
“The receptor for advanced glycation end products (RAGE) is a well-known mediator of inflammation and is recognized for interacting with soluble oligomers of various amyloid proteins, including TTR and SAA73,74.”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [73] Sousa, M. M. et al. Familial amyloid polyneuropathy: receptor for advanced glycation end products-dependent triggering of neuronal inflammatory and apoptotic pathways. J. Neurosci. 21, 7576–7586 (2001). source
The section on TTR fibrils inducing cell stress reports RAGE-dependent inflammatory cytokine expression, and the introductory passage says RAGE binds fibrillar TTR and amyloid A (page numbers unavailable). The paper does not establish binding to soluble oligomers of TTR or SAA; its cell experiments distinguish fibrillar TTR from soluble TTR, which did not induce the reported responses. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [74] Yan, S. D. et al. Receptor-dependent cell stress and amyloid accumulation in systemic amyloidosis. Nat. Med. 6, 643–651 (2000). source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAsymptomatic FAP patients already exhibit elevated levels of the anti-inflammatory cytokines IL-33 and IL-10, suggesting that an anti-inflammatory response may precede fibril deposition.
“Interestingly, asymptomatic FAP patients already exhibit elevated levels of the anti-inflammatory cytokines IL-33 and IL-10, suggesting that an anti-inflammatory response may precede fibril deposition72.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [72] Azevedo, E. P. et al. Inflammatory profiling of patients with familial amyloid polyneuropathy. BMC Neurol. 19, 146 (2019). source
The Results section on asymptomatic patients reports significantly elevated IL-33 and IL-10 and suggests that immune changes might precede amyloid deposition. However, the Results section comparing patients with healthy subjects describes IL-33 as associated with promoting inflammation; it identifies IL-10, not IL-33, as anti-inflammatory. The claimed early anti-inflammatory response therefore overstates what these findings show. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSynchrotron radiation can induce domain swapping of human cystatin C.
“Research has shown that synchrotron radiation can induce domain swapping of human cystatin C66, a mechanism implicated in oligomerization and amyloid fibril formation.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [66] Taube, M. et al. The domain swapping of human cystatin C induced by synchrotron radiation. Sci. Rep. 9, 8548 (2019). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationInflammation is a hallmark of several neurodegenerative disorders, including FAP.
“Inflammation is a hallmark of several neurodegenerative disorders, including FAP70.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [70] Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C. & Gage, F. H. Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918–934 (2010). source
The Alzheimer's Disease section describes an inflammatory response in AD, and the Amyotrophic Lateral Sclerosis section reports prominent neuroinflammation in ALS. Those passages support the general point about several neurodegenerative disorders, but the passages in our copy do not establish it for FAP. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim. May combine two claims.
PremisecitationNeutrophils have a short life span and undergo apoptosis within a few hours.
“Since neutrophils have a short life span and undergo apoptosis within a few hours”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [82] Fan, Y. et al. Targeting multiple cell death pathways extends the shelf life and preserves the function of human and mouse neutrophils for transfusion. Sci. Transl. Med. 13, eabb1069 (2021). source
The Discussion describes neutrophils as short-lived, and the Introduction identifies apoptosis as one of their death pathways. But the Results report an untreated half-life of less than 24 hours in culture, not that neutrophils undergo apoptosis within a few hours; they also distinguish apoptotic from lytic death. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCystatin C plays a critical role in enabling cancer cells to enter a radiation-tolerant state, allowing them to evade radiation and repopulate the tumor.
“Importantly, cystatin C plays a critical role in enabling cancer cells to enter a radiation-tolerant state, allowing them to evade radiation and repopulate the tumor11.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [11] Zhao, Y. et al. Cancer cells enter an adaptive persistence to survive radiotherapy and repopulate tumor. Adv. Sci. 10, e2204177 (2023). source
The Results (‘Gene Profiling Verified by 10× scRNA-seq and Functional Studies’; page not provided) report that CST3 knockout reduced progeny production and radiation survival. But knockout did not prevent formation of radiation-tolerant persister cells, so the claim that cystatin C enables cancer cells to enter that state is not supported. The Abstract likewise links CST3 depletion to reduced budding and tumor repopulation, not reduced entry into the state. (LLM, conf=0.91)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGlucocorticoids have been reported to increase cystatin C production under pathological conditions.
“Additionally, glucocorticoids, which are commonly used as adjuvants during chemotherapy and radiotherapy, have been reported to increase cystatin C production under pathological conditions9.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [9] Kleeman, S. O. et al. Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapye. Cell Genom. 3, 100347 (2023). source
May combine two claims.
Findingown dataV57P and G59P substitutions significantly reduced LILRB2 and LILRB5 binding, whereas A58P had a minimal impact.
“While these mutations modestly accelerated oligomerization, the V57P and G59P substitutions significantly reduced LILRB2 and LILRB5 binding, whereas A58P had a minimal impact (Fig. 1i).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe N-terminal D1D2 domain of LILRB2 is critical for cystatin C binding, whereas the D3D4 domain has minimal affinity.
“our flow cytometry analysis confirmed that the N-terminal D1D2 domain of LILRB2 is critical for cystatin C binding, whereas the D3D4 domain has minimal affinity (Fig. 1j).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataTotal soluble amyloid oligomers were detected in the serum samples of eight cancer patients.
“Additionally, total soluble amyloid oligomers were detected in the serum samples of eight cancer patients (Supplementary Fig. 1b).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataBiolayer interferometry verified direct interactions between cystatin CEX, but not cystatin CSino, and LILRB2 and LILRB5.
“Biolayer interferometry also verified the direction interactions between cystatin CEX, but not cystatin CSino, and LILRB2 and LILRB5 (Supplementary Fig. 2k).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataL68Q cystatin C interacts more strongly with LILRB2 and LILRB5 than wild-type cystatin C, with oligomers being the predominant binding form.
“Cotransfection of HEK293T cells with cystatin C or the amyloidogenic L68Q mutant (associated with hereditary cystatin C amyloid angiopathy (HCCAA)) revealed that L68Q cystatin C interacts more strongly with LILRB2 and LILRB5 than wild-type cystatin C does, with oligomers being the predominant binding form (Fig. 1d and Supplementary Fig. 2d).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBoth human and mouse EX-CELL-derived cystatin C bound robustly to PIRB-expressing HEK293T cells but not to gp49B1-expressing cells.
“Both human and mouse EX-CELL-derived cystatin C bound robustly to PIRB-expressing HEK293T cells but not to gp49B1-expressing cells (Supplementary Fig. 3a, b).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn EX-CELL-conditioned medium, monomeric cystatin C levels were reduced, whereas dimer and oligomer levels were increased.
“However, in EX-CELL-conditioned medium, monomeric cystatin C levels were reduced, whereas dimer and oligomer levels were increased, suggesting that cystatin C undergoes dimerization and oligomerization in this environment (Fig. 1a).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPurified cystatin CEX, but not cystatin CSino, bound to LILRB2- and LILRB5-expressing cells.
“we purified cystatin C from EX-CELL medium (cystatin CEX; Supplementary Fig. 2g) and observed that cystatin CEX, but not cystatin CSino, bound to LILRB2- and LILRB5-expressing cells (Supplementary Fig. 2h).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataEX-CELL-derived cystatin C exhibited significant binding to monocytes and neutrophils, with moderate binding to B cells.
“While cystatin C from DMEM-conditioned medium did not bind immune cells, EX-CELL-derived cystatin C exhibited significant binding to monocytes and neutrophils, with moderate binding to B cells (Fig. 1b).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn sixteen melanoma tumor tissues, 56.25% had both monomeric and oligomeric cystatin C, 31.25% had predominantly monomeric cystatin C, and 12.50% had oligomeric forms as the major species.
“Distinct patterns were observed: in 56.25% of the samples (9 out of 16), both monomeric and oligomeric forms of cystatin C were detected; in 31.25% of the samples (5 out of 16), the monomeric form predominated; and in the remaining 12.50% (2 out of 16), oligomeric forms were the major species (Supplementary Fig. 1c)”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn DMEM, cystatin C is predominantly monomeric, with a small fraction existing as dimers but no detectable oligomers.
“In Dulbecco’s modified Eagle’s medium (DMEM), cystatin C is predominantly monomeric, with a small fraction existing as dimers but no detectable oligomers.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBoth LILRB2 and LILRB5 reporter cells were activated by immobilized commercial cystatin CSino or cystatin CEX.
“Both LILRB2 and LILRB5 reporter cells were activated by immobilized commercial cystatin CSino or cystatin CEX (which promotes protein clustering on the plastic surface through tethering).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCST3 expression was negatively correlated with overall survival in patients with esophageal cancer, glioblastoma, kidney clear cell carcinoma, lower-grade glioma, liver cancer, lung squamous cell carcinoma, stomach cancer, and ocular melanoma.
“Notably, CST3 expression was negatively correlated with overall survival in patients with esophageal cancer, glioblastoma, kidney clear cell carcinoma, lower-grade glioma, liver cancer, lung squamous cell carcinoma, stomach cancer, and ocular melanoma (Fig. 6a).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCystatin C−/− mice presented significantly reduced tumor growth and lower endpoint tumor weights for sgCST3, but not sgScramble, B16-F10 tumors.
“While tumor growth kinetics were similar between sgScramble and sgCST3 B16-F10 clones in WT mice, cystatin C−/− mice presented significantly reduced tumor growth and lower endpoint tumor weights for sgCST3, but not sgScramble, B16-F10 tumors (Fig. 4a, b).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe combined presence of monocytes and cystatin CEX significantly suppressed T-cell proliferation, an effect partially reversed by LILRB2 blockade.
“While neither monocytes nor cystatin CEX alone affected T-cell proliferation (Fig. 3a and Supplementary Fig. 5a), their combined presence significantly suppressed T-cell proliferation, an effect that was partially reversed by LILRB2 blockade (Fig. 3a, b).”
Quote in the paperSubstantial claim- Rests on an assumption: Anti-LILRB2 and anti-LILRB5 blocking antibodies specifically block the cystatin C–LILRB interaction without off-target effects.
May combine two claims.
Findingown dataCystatin C depletion led to a substantial reduction in tumor-associated macrophages, polymorphonuclear myeloid-derived suppressor cells, and regulatory T cells but significantly increased infiltration of CD8+ T cells and natural killer cells.
“In the B16-F10 tumor model, cystatin C depletion led to a substantial reduction in tumor-associated macrophages (TAMs), polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), and regulatory T cells (Tregs) but significantly increased the infiltration of CD8⁺ T cells and natural killer (NK) cells (Fig. 4c and Supplementary Fig. 6i).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCystatin CEX suppressed CD86 expression, maintained CD14 expression, and prevented the downregulation of CD163 in M1 macrophage differentiation; these effects were reversed by anti-LILRB2 treatment.
“Surface marker expression analysis further supported these observations, as cystatin CEX suppressed CD86 expression, maintained CD14 expression, and prevented the downregulation of CD163, which are hallmarks of M1 macrophage differentiation. These effects were also reversed by anti-LILRB2 treatment (Fig. 2d).”
Quote in the paperSubstantial claim- Rests on an assumption: Anti-LILRB2 and anti-LILRB5 blocking antibodies specifically block the cystatin C–LILRB interaction without off-target effects.
May combine two claims.
Findingown dataN1 polarization, characterized by CD62Lneg/low expression and CD16 downregulation, was significantly inhibited by cystatin CEX, and this effect was reversed by LILRB2 blockade.
“Flow cytometry analysis revealed that N1 polarization, which is characterized by CD62Lneg/low expression and CD16 downregulation, was significantly inhibited by cystatin CEX, and this effect was reversed by LILRB2 blockade (Fig. 2f).”
Quote in the paperSubstantial claim- Rests on an assumption: Anti-LILRB2 and anti-LILRB5 blocking antibodies specifically block the cystatin C–LILRB interaction without off-target effects.
May combine two claims.
Findingown dataCystatin CEX treatment inhibited the downregulation of CD14 and suppressed the upregulation of CD40 and CD86 during monocyte-derived DC differentiation; these inhibitory effects were reversed by anti-LILRB2.
“However, cystatin CEX treatment inhibited the downregulation of CD14 and suppressed the upregulation of CD40 and CD86 (Fig. 2e). These inhibitory effects were reversed by anti-LILRB2, confirming that cystatin C oligomers impair DC differentiation through LILRB2 (Fig. 2e).”
Quote in the paperSubstantial claim- Rests on an assumption: Anti-LILRB2 and anti-LILRB5 blocking antibodies specifically block the cystatin C–LILRB interaction without off-target effects.
May combine two claims.
Findingown dataNeither monocytes nor cystatin CEX alone affected T-cell proliferation.
“While neither monocytes nor cystatin CEX alone affected T-cell proliferation (Fig. 3a and Supplementary Fig. 5a), their combined presence significantly suppressed T-cell proliferation, an effect that was partially reversed by LILRB2 blockade (Fig. 3a, b).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataB16-F10-hcystatin C overexpression increased the presence of immunosuppressive tumor-associated macrophages and PMN-MDSCs, accompanied by a reduction in immunostimulatory T cells.
“This finding was further supported by the increased presence of immunosuppressive tumor-associated macrophages (TAMs) and PMN-MDSCs, accompanied by a reduction in immunostimulatory T cells (Fig. 5d and Supplementary Fig. 7d).”
Quote in the paperSubstantial claim- Rests on an assumption: LILRB2KI and LILRB5KI transgenic mice recapitulate human LILRB2 and LILRB5 function in cancer.
May combine two claims.
Findingown dataUpon TGF-β1 stimulation, phosphorylation of SMAD2 was significantly greater in THP-1-LILRB2 cells than in parental THP-1 cells, whereas activation of noncanonical signaling pathways remained unchanged.
“Upon TGF-β1 stimulation, the phosphorylation of SMAD2 was significantly greater in THP-1-LILRB2 cells than in parental THP-1 cells, whereas the activation of noncanonical signaling pathways remained unchanged (Fig. 7e).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataLILRBs interacted with both TGF-βRI and TGF-βRII, with a preferential association with TGF-βRI after normalization to expression levels.
“LILRBs interacted with both TGF-βRI and TGF-βRII, with a preferential association with TGF-βRI after normalization to the expression levels (Fig. 7a and Supplementary Fig. 9a).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCo-IP confirmed a trans interaction between LILRB2 and TGF-βRI, which was partially inhibited by anti-LILRB2 blocking antibodies.
“Co-IP confirmed a trans interaction between LILRB2 and TGF-βRI, which was also partially inhibited by anti-LILRB2 blocking antibodies (Fig. 7b).”
Quote in the paperSubstantial claim- Rests on an assumption: The anti-LILRB2 blocking antibody specifically inhibits LILRB2 without affecting other receptors.
May combine two claims.
Findingown dataCystatin CEX significantly inhibited neutrophil degranulation and endocytosis while promoting neutrophil migration.
“Consistent with these findings, functional assays demonstrated that cystatin CEX significantly inhibited neutrophil degranulation and endocytosis while promoting neutrophil migration (Fig. 2g–i).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataUpon further polarization with LPS, cystatin CEX did not change CD163 or CD206 surface expression levels but significantly inhibited expression of the M1 markers CD80 and CD86; this suppression was reversed by LILRB2 blockade.
“Additionally, upon further polarization with LPS, cystatin CEX did not change CD163 or CD206 surface expression levels, but it significantly inhibited the expression of the M1 markers CD80 and CD86, indicating reduced M1 functional output. This suppression was reversed by LILRB2 blockade, further supporting the role of LILRB2 in mediating the effects of cystatin C (Supplementary Fig. 4g).”
Quote in the paperSubstantial claim- Rests on an assumption: Anti-LILRB2 and anti-LILRB5 blocking antibodies specifically block the cystatin C–LILRB interaction without off-target effects.
May combine two claims.
Findingown dataHuman CST3 mRNA and protein are ubiquitously expressed across normal tissues, with myeloid-derived cells identified as the primary contributors to extracellular cystatin C levels in healthy individuals.
“Human CST3 mRNA and protein are ubiquitously expressed across normal tissues, with myeloid-derived cells identified as the primary contributors to extracellular cystatin C levels in healthy individuals, according to BioGPS tissue microarray and proteome analysis (Supplementary Fig. 8a).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataForced expression of human cystatin C significantly accelerated tumor growth in hCD34+ humanized mice but not in NSG-SGM3 mice.
“Forced expression of human cystatin C significantly accelerated tumor growth in hCD34⁺ humanized mice but not in NSG-SGM3 mice (Fig. 6c and Supplementary Fig. 8f), suggesting that the tumor-promoting effects of cystatin C depend on human immune cells.”
Quote in the paperSubstantial claim- Rests on an assumption: The hCD34+ humanized mouse model's immune system is sufficiently human-like to reveal the human immune cell-dependent effects of cystatin C.
May combine two claims.
Findingown dataCystatin C oligomers induce LILRB2-specific tyrosine phosphorylation and promote SHP-1 recruitment, which is reversed by anti-LILRB2 blocking antibodies.
“Cotransfection of HEK293T cells with LILRB2-Flag, Lyn kinase, and SHP-1/SHP-2, followed by incubation with EX-CELL-conditioned cystatin C medium, revealed that cystatin C oligomers induce LILRB2-specific tyrosine phosphorylation and promote SHP-1 recruitment. This activation was effectively reversed by anti-LILRB2 blocking antibodies (Fig. 2b).”
Quote in the paperSubstantial claim- Rests on an assumption: Anti-LILRB2 and anti-LILRB5 blocking antibodies specifically block the cystatin C–LILRB interaction without off-target effects.
May combine two claims.
Findingown dataDMEM-conditioned medium containing TTRF87M/L110M strongly bound to LILRB2- and LILRB5-transfected HEK293T cells, whereas the other TTR variants did not interact.
“Flow cytometry analysis revealed that DMEM-conditioned medium containing TTRF87M/L110M strongly bound to LILRB2- and LILRB5-transfected HEK293T cells, whereas the other TTR variants did not interact (Fig. 8b).”
Quote in the paperSubstantial claim- Rests on an assumption: The F87M/L110M TTR mutant is a valid model for studying oligomeric TTR interactions.
May combine two claims.
Findingown dataThe F87M/L110M mutation, but not the V30M, L55P, or V122I mutations, promoted dramatic TTR oligomerization.
“Western blot analysis of DMEM-conditioned medium collected from HEK293T cells expressing these TTR variants revealed that the F87M/L110M mutation, but not the V30M, L55P, or V122I mutations, promoted dramatic TTR oligomerization (Fig. 8a).”
Quote in the paperSubstantial claim- Rests on an assumption: The F87M/L110M TTR mutant is a valid model for studying oligomeric TTR interactions.
May combine two claims.
Findingown dataTafamidis treatment suppressed TTRF87M/L110M oligomerization and reduced TTRF87M/L110M binding to LILRB2 and LILRB5 in a dose-dependent manner.
“Tafamidis treatment suppressed TTRF87M/L110M oligomerization and reduced TTRF87M/L110M binding to LILRB2 and LILRB5 in a dose-dependent manner (Fig. 8h, i).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe T119M mutation significantly inhibited TTRF87M/L110M oligomerization and reduced its binding affinity to LILRB2 and LILRB5.
“As expected, the T119M mutation significantly inhibited TTRF87M/L110M oligomerization and reduced its binding affinity to LILRB2 and LILRB5 (Fig. 8f, g).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataWe observed moderate binding of cystatin C oligomers to the surface of B cells.
“Additionally, we observed moderate binding of cystatin C oligomers to the surface of B cells.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationLILRBs contain immunoreceptor tyrosine-based inhibitory motifs that recruit SHP-1, SHP-2, or SHIP and function as immune checkpoint molecules with immunosuppressive roles in human immunity and cancer.
“They contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that can recruit the tyrosine phosphatases SHP-1 and SHP-2 or the inositol phosphatase SHIP, and function as immune checkpoint molecules, playing immunosuppressive roles in human immunity and cancer development20.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Deng, M. et al. Leukocyte immunoglobulin-like receptor subfamily B: therapeutic targets in cancer. Antib. Ther. 4, 16–33 (2021).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCystatin C, encoded by CST3, is a potent cysteine cathepsin inhibitor and a well-characterized amyloidogenic protein associated with hereditary cystatin C amyloid angiopathy.
“Cystatin C, encoded by the CST3 gene, is a potent cysteine cathepsin inhibitor and a well-characterized amyloidogenic protein associated with hereditary cystatin C amyloid angiopathy (HCCAA), an autosomal dominant disorder caused by amyloid deposition in cerebral vasculature8.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8] Palsdottir, A. et al. Mutation in cystatin C gene causes hereditary brain haemorrhage. Lancet 2, 603–604 (1988). source
Probably not a substantial claim: may not pass S2 (checkable).
PremisereasoningKnockout mouse models may not be optimal for elucidating the biological significance of LILRBs.
“Consequently, knockout mouse models may not be optimal for elucidating the biological significance of LILRBs.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAmyloid β activates innate immune sensors Toll-like receptors and NOD-like receptors, leading to inflammatory cascades and microglial activation.
“amyloid β (Aβ), which is associated with Alzheimer’s disease pathology, has been shown to activate innate immune sensors Toll-like receptors (TLRs) and NOD-like receptors (NLRs), thereby leading to inflammatory cascades and microglial activation2.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [2] Gambuzza, M. E. et al. Toll-like receptors in Alzheimer’s disease: a therapeutic perspective. CNS Neurol. Disord. Drug Targets 13, 1542–1558 (2014). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCystatin C has tumor-suppressive properties mainly through its inhibitory action on cysteine cathepsins, thereby inhibiting tumor cell invasion and metastasis.
“it has also demonstrated tumor-suppressive properties, mainly through its inhibitory action on cysteine cathepsins, enzymes that regulate extracellular matrix (ECM) degradation and remodeling, thereby inhibiting tumor cells invasion and metastasis12.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Leto, G., Crescimanno, M. & Flandina, C. On the role of Cystatin C in cancer progression. Life Sci. 202, 152–160 (2018). source
May combine two claims.
Interpretationown dataLILRB2 and LILRB5 share a common ligand, but their ligand-binding mechanisms differ.
“These results suggest that LILRB2 and LILRB5 share a common ligand, but their ligand-binding mechanisms differ.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataCystatin C plays a key role in shaping an immunosuppressive TME by promoting the accumulation of immunosuppressive myeloid cells while inhibiting antitumor immune responses.
“These findings demonstrate that cystatin C plays a key role in shaping an immunosuppressive TME by promoting the accumulation of immunosuppressive myeloid cells while inhibiting antitumor immune responses.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Interpretationown dataCystatin C−/− mice presented a normal appearance, organ size, and litter frequency, suggesting that cystatin C is not essential for overall development and growth.
“Despite this depletion, cystatin C−/− mice presented a normal appearance, organ size, and litter frequency, suggesting that cystatin C is not essential for overall development and growth.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataCystatin C oligomers reprogram monocytes into an immunosuppressive state via LILRB2, ultimately inhibiting T-cell proliferation.
“These results suggest that cystatin C oligomers reprogram monocytes into an immunosuppressive state via LILRB2, ultimately inhibiting T-cell proliferation.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataOligomeric cystatin C is a functional extracellular ligand that binds and activates the inhibitory receptors LILRB2 and LILRB5, promoting downstream immunosuppressive signaling.
“Together, these results establish oligomeric cystatin C as a functional extracellular ligand that binds and activates the inhibitory receptors LILRB2 and LILRB5, promoting downstream immunosuppressive signaling.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataCST3 silencing disrupts these immunosuppressive effects, leading to enhanced T-cell cytotoxicity and suppressed tumor growth in vivo.
“CST3 silencing disrupts these immunosuppressive effects, leading to enhanced T-cell cytotoxicity and suppressed tumor growth in vivo.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataOligomeric cystatin C selectively binds to human LILRB2 and LILRB5, as well as mouse PIRB, establishing a conserved mechanism of immunosuppressive receptor engagement.
“Collectively, these results demonstrate that oligomeric cystatin C selectively binds to human LILRB2 and LILRB5, as well as mouse PIRB, establishing a conserved mechanism of immunosuppressive receptor engagement.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe cystatin C-LILRB2 axis supports the immunosuppressive capacity of myeloid cells through both the classical ITIM-SHP pathway and the enhancement of TGF-β signaling.
“Taken together, our results suggest that the cystatin C–LILRB2 axis supports the immunosuppressive capacity of myeloid cells through both the classical ITIM–SHP pathway and the enhancement of TGF-β signaling.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataCystatin C facilitates LILRB2-TGF-βRI interactions, leading to increased SMAD2/SMAD3 activation, ultimately promoting a more immunosuppressive TME.
“Cystatin C facilitates LILRB2–TGF-βRI interactions, leading to increased SMAD2/SMAD3 activation, ultimately promoting a more immunosuppressive TME.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenExperimenters were blinded to treatment conditions for tumor size measurement.
“For tumor size measurement, the experimenters were blinded to the treatment conditions of the mice.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductreasoningTo ensure consistent levels of human immune cell engraftment, only mice with ≥25% human CD45+ chimerism (with human myeloid and T cells) in the peripheral blood, as determined by flow cytometry 6 weeks post-transplantation, were included in the humanized mouse study.
“To ensure consistent levels of human immune cell engraftment, only mice with ≥25% human CD45⁺ chimerism (with human myeloid and T cells) in the peripheral blood, as determined by flow cytometry 6 weeks post-transplantation, were included in the study.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenDouble referencing, using both the reference well and reference sensor, was used in Octet binding kinetics to account for nonspecific binding.
“Double referencing, which uses both the reference well and reference sensor, was used to account for nonspecific binding.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIncreased serum concentrations of cystatin C have been reported in patients with various cancers, such as melanoma and colorectal cancer, compared with healthy individuals.
“Consistent with our findings, increased serum concentrations of cystatin C have been reported in patients with various cancers, such as melanoma and colorectal cancer, compared with healthy individuals63.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [63] Kos, J. et al. Cysteine proteinase inhibitors stefin A, stefin B, and cystatin C in sera from patients with colorectal cancer: relation to prognosis. Clin. Cancer Res. 6, 505–511 (2000).
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCystatin C has been reported to antagonize TGF-β signaling through interaction with TGF-βRII.
“Cystatin C has been reported to antagonize TGF-β signaling through interaction with TGF-βRII49.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [49] Sokol, J. P. & Schiemann, W. P. Cystatin C antagonizes transforming growth factor beta signaling in normal and cancer cells. Mol. Cancer Res. 2, 183–195 (2004). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGlucocorticoids are linked to increased cancer metastasis.
“Glucocorticoids are also linked to increased cancer metastasis67.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [67] Obradovic, M. M. S. et al. Glucocorticoids promote breast cancer metastasis. Nature 567, 540–544 (2019). source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenMice were randomly allocated to each group.
“For each experiment, the same sex- and age-matched (6–8 weeks) mice were used and randomly allocated to each group.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenIn the neutrophil endocytosis assay, a parallel group was incubated with FITC-dextran at 4 °C to control for nonspecific binding and passive uptake.
“To control for nonspecific binding and passive uptake, a parallel group was incubated with FITC-dextran at 4 °C.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Premisenone givenThrough these interactions, RAGE contributes to chronic inflammation, driving the pathogenesis of neurodegenerative diseases and systemic amyloidosis.
“Through these interactions, RAGE contributes to chronic inflammation, driving the pathogenesis of neurodegenerative diseases and systemic amyloidosis.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductreasoningMice meeting the ≥25% human CD45+ chimerism criteria were stratified on the basis of the percentage of human CD45+ cells and then randomly assigned to experimental groups via a stratified randomization strategy to minimize variability in human immune cell reconstitution across groups.
“Mice meeting these criteria were stratified on the basis of the percentage of human CD45⁺ cells and then randomly assigned to experimental groups via a stratified randomization strategy to minimize variability in human immune cell reconstitution across groups.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataIn the indicated antibody experiments, mice were randomized into two groups on the basis of tumor size.
“For the indicated antibody experiments, the mice were randomized into two groups on the basis of tumor size, followed by intraperitoneal injection of 200 μg of isotype or anti-LILRB2 at days 4, 7, and 10.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenPropidium iodide staining after primary antibody staining or zombie yellow staining before primary antibody staining was used to exclude dead cells from flow cytometry analysis.
“Propidium iodide (Sigma, cat. no. P4864) staining after primary antibody staining or zombie yellow (Biolegend, cat. no. 423104) staining before primary antibody staining was used to exclude dead cells from analysis.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningOligomeric cystatin C binds to the inhibitory receptors LILRB2 and LILRB5 on myeloid cells, thereby increasing their immunosuppressive activity and contributing to tumor progression.
“Simultaneously, oligomeric cystatin C binds to the inhibitory receptors LILRB2 and LILRB5 on myeloid cells, thereby increasing their immunosuppressive activity and contributing to tumor progression.”
Quote in the paperSubstantial claim- Rests on an assumption: Oligomeric cystatin C is present and functional in the tumor microenvironment.
May combine two claims.
Interpretationown dataOligomeric TTR interacts with the LILRB2 and LILRB5 receptors in a manner similar to that of cystatin C, suggesting a conserved mechanism of amyloid-LILRB interactions.
“These findings demonstrate that oligomeric TTR interacts with the LILRB2 and LILRB5 receptors in a manner similar to that of cystatin C, suggesting a conserved mechanism of amyloid–LILRB interactions.”
Quote in the paperSubstantial claim- Rests on an assumption: TTR oligomers are the pathologically relevant form in TTR amyloidosis.
May combine two claims.
Interpretationnone givenThe immunosuppressive effects induced by the cystatin C-LILRB2 axis are mediated through the classical ITIM-SHP pathway and the upregulation of TGF-β signaling within these cells.
“Mechanistically, the immunosuppressive effects induced by the cystatin C–LILRB2 axis are mediated through the classical ITIM-SHP pathway and the upregulation of TGF-β signaling within these cells.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenAlbumin levels were determined with an anti-albumin antibody and served as an internal control in the dot blot.
“Albumin levels were determined with an anti-albumin antibody (Millipore, cat. no. SAB4200711), which served as an internal control.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataOligomeric cystatin C enhances the immunosuppressive activity of myeloid cells by engaging LILRB2/5 inhibitory receptors, thereby suppressing T-cell function and promoting cancer progression.
“We demonstrated that oligomeric cystatin C enhances the immunosuppressive activity of myeloid cells by engaging LILRB2/5 inhibitory receptors, thereby suppressing T-cell function and promoting cancer progression (Supplementary Fig. 11).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenCell lines were routinely tested for mycoplasma contamination.
“All the cell lines were routinely tested via a mycoplasma contamination kit (R&D Systems, cat. no. CUL001B).”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataWithin the TME, cystatin C undergoes oligomerization, disrupting the conformation of the N/L1/L2 motif and abrogating its inhibitory activity against cysteine cathepsins.
“Our findings provide mechanistic insight into this paradox: within the TME, cystatin C undergoes oligomerization, disrupting the conformation of the N/L1/L2 motif and abrogating its inhibitory activity against cysteine cathepsins.”
Quote in the paperSubstantial claim- Rests on an assumption: Oligomeric cystatin C is present and functional in the tumor microenvironment.
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationown dataStrong interactions exist between TTR oligomers and the LILRB2 and LILRB5 receptors.
“Moreover, we identified strong interactions between transthyretin (TTR) oligomers—another well-characterized amyloid protein associated with systemic amyloidosis—and the LILRB2 and LILRB5 receptors.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataAll plasmids used in the study were sequence-verified via whole-plasmid sequencing.
“All the plasmids were sequence-verified via whole-plasmid sequencing (Eurofins Genomics).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenEndotoxin levels of cystatin CEX were quantified via the Pierce Chromogenic Endotoxin Quant Kit according to the manufacturer's instructions.
“Endotoxin levels of cystatin CEX were quantified via the Pierce™ Chromogenic Endotoxin Quant Kit (Thermo Fisher, cat. no. A39553) according to the manufacturer’s instructions.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Oligomeric cystatin C generated in EX-CELL-conditioned medium is representative of cystatin C oligomers in the tumor microenvironment.
“However, in EX-CELL-conditioned medium, monomeric cystatin C levels were reduced, whereas dimer and oligomer levels were increased, suggesting that cystatin C undergoes dimerization and oligomerization in this environment (Fig. 1a).”
The paper relies on this without support.
LILRB2KI and LILRB5KI transgenic mice recapitulate human LILRB2 and LILRB5 function in cancer.
“Given that LILRB family members are specific to primates, we employed myeloid-specific (LysM-Cre) LILRB2-transgenic (LILRB2KI) and LILRB5-transgenic (LILRB5KI) C57BL/6 mice to investigate the functional role of human cystatin C in activating LILRB2 and LILRB5 in vivo.”
The paper relies on this without support.
Anti-LILRB2 and anti-LILRB5 blocking antibodies specifically block the cystatin C–LILRB interaction without off-target effects.
“This activation was abrogated by anti-LILRB2 and anti-LILRB5 blocking antibodies, confirming the specificity of the interaction between cystatin C and its receptors (Fig. 2a and Supplementary Fig. 4b).”
The paper relies on this without support.
MDSCs isolated from peripheral blood of cancer patients are representative of tumor-associated MDSCs in the tumor microenvironment.
“we isolated myeloid-derived suppressor cells (MDSCs) and autologous T cells from peripheral blood samples of patients with prostate, kidney, and lung cancer.”
The paper relies on this without support.
The hCD34+ humanized mouse model's immune system is sufficiently human-like to reveal the human immune cell-dependent effects of cystatin C.
“To investigate the role of cystatin C in human tumor development, we established a humanized mouse model by transplanting human cord blood-derived CD34⁺ cells into NSG-SGM3 mice, as described previously23,31.”
The paper relies on this without support.
LILRB2 and LILRB5 are inhibitory receptors whose engagement suppresses myeloid cell function.
“Given the well-established immunosuppressive role of LILRBs in myeloid cells, we investigated whether LILRBs interact with and modulate the TGF-β signaling pathway.”
The paper relies on this without support.
Oligomeric cystatin C is present and functional in the tumor microenvironment.
“Our findings provide mechanistic insight into this paradox: within the TME, cystatin C undergoes oligomerization, disrupting the conformation of the N/L1/L2 motif and abrogating its inhibitory activity against cysteine cathepsins.”
The paper relies on this without support.
TTR oligomers are the pathologically relevant form in TTR amyloidosis.
“These findings demonstrate that oligomeric TTR interacts with the LILRB2 and LILRB5 receptors in a manner similar to that of cystatin C, suggesting a conserved mechanism of amyloid–LILRB interactions.”
The paper relies on this without support.
The F87M/L110M TTR mutant is a valid model for studying oligomeric TTR interactions.
“To determine the binding form of TTR, we introduced three common amyloidogenic mutations—V30M, L55P, and V122I—along with a monomeric engineered F87M/L110M mutation52,53.”
The paper relies on this without support.
The anti-LILRB2 blocking antibody specifically inhibits LILRB2 without affecting other receptors.
“Notably, this interaction was partially inhibited by anti-LILRB2 blocking antibodies, suggesting a specific and regulatable association (Supplementary Fig. 9b).”
The paper relies on this without support.
The CST3 knockout in THP-1 cells specifically eliminates cystatin C without off-target effects.
“To assess whether cystatin C affects TGF-β signaling, we generated CST3-knockout THP-1 cells (THP-1 sgCST3).”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Conflicting anti-LILRB2 concentration in the reporter assay
MajorThe Fig. 2 caption specifies 20 μg/mL anti-LILRB2 antibody, while the reporter-assay method specifies 10 μg/mL.
“in the presence or absence of an anti-LILRB2 (20 μg/mL) blocking antibody”
“the indicated isotype (10 μg/mL), anti-LILRB2 blocking (10 μg/mL) or anti-LILRB5 blocking antibodies were added to the culture medium.”
Neutrophil polarization method specifies CD14+ cells
MinorThe method says it isolates CD15+ neutrophils but then describes polarizing CD14+ cells, leaving the identity of the cells used in that assay inconsistent.
“Normal human CD15+ neutrophils were isolated via the AutoMACS Pro separation system from the granulocyte fraction of normal peripheral blood.”
“Polarization of neutrophils toward an N1-like phenotype was conducted in a 96-well plate with 1 × 105 CD14+ cells per well”
Cites
Smad-dependent and Smad-independent pathways in TGF-β family signalling
Derynck, R., & Zhang, Y. E. (2003) · Nature · doi:10.1038/nature02006 · Cited by 5,370 · see citing works
Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis
Kayed, R., Head, E., Thompson, J. L., McIntire, T. M., Milton, S. C., Cotman, C. W., & Glabe, C. G. (2003) · Science · doi:10.1126/science.1079469 · Cited by 4,064 · see citing works
Mechanisms underlying inflammation in neurodegeneration
Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C., & Gage, F. H. (2010) · Cell · doi:10.1016/j.cell.2010.02.016 · Cited by 3,580 · see citing works
Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade
Chiti, F., & Dobson, C. M. (2017) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-061516-045115 · Cited by 2,629 · see citing works
TGFβ signals through a heteromeric protein kinase receptor complex
Wrana, J. L., Attisano, L., Cárcamo, J. M., Zentella‐Dehesa, A., Doody, J. F., Laiho, M., Wang, X.-F., & Massagué, J. (1992) · Cell · doi:10.1016/0092-8674(92)90395-s · Cited by 1,528 · see citing works
TGF-ß Signaling in Fibroblasts Modulates the Oncogenic Potential of Adjacent Epithelia
Bhowmick, N. A., Chytil, A., Plieth, D., Gorska, A. E., Dumont, N., Shappell, S., Washington, M. K., Neilson, E. G., & Moses, H. L. (2004) · Science · doi:10.1126/science.1090922 · Cited by 1,401 · see citing works
Yang, L., Huang, J., Ren, X., Gorska, A. E., Chytil, A., Aakre, M., Carbone, D. P., Matrisian, L. M., Richmond, A., Lin, P. C., et al. (2008) · Cancer Cell · doi:10.1016/j.ccr.2007.12.004 · Cited by 918 · see citing works
Barkal, A. A., Weiskopf, K., Kao, K. S., Gordon, S. R., Rosental, B., Yiu, Y. Y., George, B. M., Markovic, M., Ring, N. G., Tsai, J. M., et al. (2017) · Nature Immunology · doi:10.1038/s41590-017-0004-z · Cited by 560 · see citing works
The type I TGF-β receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner
Sorrentino, A., Thakur, N., Grimsby, S., Marcusson, A., von Bülow, V., Schuster, N., Zhang, S., Heldin, C., & Landström, M. (2008) · Nature Cell Biology · doi:10.1038/ncb1780 · Cited by 553 · see citing works
Glucocorticoids promote breast cancer metastasis
Obradović, M. M. S., Hamelin, B., Manevski, N., Couto, J. P., Sethi, A., Coissieux, M.-M., Münst, S., Okamoto, R., Kohler, H., Schmidt, A., et al. (2019) · Nature · doi:10.1038/s41586-019-1019-4 · Cited by 462 · see citing works
Kim, T., Vidal, G. S., Djurisic, M., William, C. M., Birnbaum, M. E., Garcia, K. C., Hyman, B. T., & Shatz, C. J. (2013) · Science · doi:10.1126/science.1242077 · Cited by 410 · see citing works
Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping.
Janowski, R., Kozak, M., Jankowska, E., Grzonka, Z., GRUBB, A. O., Abrahamson, M., & Jaskólski, M. (2001) · Nature Structural Biology · doi:10.1038/86188 · Cited by 395 · see citing works
A clinical overview of WT1 gene mutations
Little, M. H., & Wells, C. A. (1997) · Human Mutation · doi:10.1002/(sici)1098-1004(1997)9:3 · Cited by 392 · see citing works
Quintas, A., Vaz, D. C., Cardoso, I., Saraiva, M. J., & Brito, R. M. M. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m101024200 · Cited by 344 · see citing works
Receptor-dependent cell stress and amyloid accumulation in systemic amyloidosis
Yan, S. D., Zhu, H., Zhu, A., Golabek, A., Du, H., Roher, A., Yu, J., Soto, C., Schmidt, A. M., Stern, D., et al. (2000) · Nature Medicine · doi:10.1038/76216 · Cited by 343 · see citing works
Smad4 signalling in T cells is required for suppression of gastrointestinal cancer
Kim, B., Li, C., Qiao, W., Mamura, M., Kasperczak, B., Anver, M. R., Wolfraim, L. A., Hong, S., Mushinski, E. B., Potter, M., et al. (2006) · Nature · doi:10.1038/nature04846 · Cited by 320 · see citing works
A novel pair of immunoglobulin-like receptors expressed by B cells and myeloid cells
Kubagawa, H., Burrows, P. D., & Cooper, M. D. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.10.5261 · Cited by 319 · see citing works
LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration
Deng, M., Gui, X., Kim, J., Xie, L., Chen, W., Li, Z., He, L., Chen, Y., Chen, H., Luo, W., et al. (2018) · Nature · doi:10.1038/s41586-018-0615-z · Cited by 305 · see citing works
Self-citationTherapeutic targeting of tumour myeloid cells
Barry, S. T., Gabrilovich, D. I., Sansom, O. J., Campbell, A. D., & Morton, J. P. (2023) · Nature Reviews Cancer · doi:10.1038/s41568-022-00546-2 · Cited by 305 · see citing works
An Attempt to Polarize Human Neutrophils Toward N1 and N2 Phenotypes in vitro
Ohms, M., Möller, S., & Laskay, T. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00532 · Cited by 299 · see citing works
Groppe, J. C., Hinck, C. S., Samavarchi‐Tehrani, P., Zubieta, C., Schuermann, J. P., Taylor, A. B., Schwarz, P. M., Wrana, J. L., & Hinck, A. P. (2008) · Molecular Cell · doi:10.1016/j.molcel.2007.11.039 · Cited by 284 · see citing works
Inhibitory receptors bind Angptls and support blood stem cells and leukemia development
Zheng, J., Umikawa, M., Cui, C., Li, J., Chen, X., Zhang, C.-Z., Hyunh, H., Kang, X., Silvany, R., Wan, X., et al. (2012) · Nature · doi:10.1038/nature11095 · Cited by 267 · see citing works
Self-citationGu, Y., Liu, Y., Fu, L., Zhai, L., Zhu, J., Han, Y., Jiang, Y., Zhang, Y., Zhang, P., Jiang, Z., et al. (2019) · Nature Medicine · doi:10.1038/s41591-018-0309-y · Cited by 267 · see citing works
Chen, H.-M., van der Touw, W., Wang, Y. S., Kang, K., Mai, S., Zhang, J., Alsina‐Beauchamp, D., Duty, J. A., Mungamuri, S. K., Zhang, B., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci97570 · Cited by 254 · see citing works
An Engineered Transthyretin Monomer that Is Nonamyloidogenic, Unless It Is Partially Denatured
Jiang, X., Smith, C. S., Petrassi, H. M., et al. (2001) · Biochemistry · doi:10.1021/bi011194d · Cited by 239 · see citing works
MUTATION IN CYSTATIN C GENE CAUSES HEREDITARY BRAIN HAEMORRHAGE
Palsdottir, A., Thorsteinsson, L., Olafsson, I., Abrahamson, M., Arnason, A., Grubb, A., & Jensson, O. (1988) · The Lancet · doi:10.1016/s0140-6736(88)90641-1 · Cited by 212 · see citing works
Sousa, M. M., Du Yan, S., Fernandes, R., Guimarães, A., Stern, D., & Saraiva, M. J. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-19-07576.2001 · Cited by 212 · see citing works
Therapeutic B-cell depletion reverses progression of Alzheimer’s disease
Kim, K., Wang, X., Ragonnaud, E., Bodogai, M., Illouz, T., DeLuca, M., McDevitt, R. A., Gusev, F., Okun, E., Rogaev, E., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22479-4 · Cited by 206 · see citing works
(2000) · PubMed · Cited by 184 · see citing works
LILRB receptor-mediated regulation of myeloid cell maturation and function
van der Touw, W., Chen, H.-M., Pan, P.-Y., & Chen, S.-H. (2017) · Cancer Immunology, Immunotherapy · doi:10.1007/s00262-017-2023-x · Cited by 167 · see citing works
Cystatin C antagonizes transforming growth factor beta signaling in normal and cancer cells.
Sokol, J. P., & Schiemann, W. P. (2004) · PubMed · Cited by 156 · see citing works
Katz, H. R., Vivier, E., Castells, M. C., McCormick, M. J., Chambers, J. M., & Austen, K. F. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.20.10809 · Cited by 155 · see citing works
TGF-β Signaling in Myeloid Cells Is Required for Tumor Metastasis
Pang, Y., Gara, S. K., Achyut, B. R., Li, Z., Yan, H. H., Day, C., Weiss, J. M., Trinchieri, G., Morris, J. C., & Li, Y. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0527 · Cited by 155 · see citing works
A Novel Anti-LILRB4 CAR-T Cell for the Treatment of Monocytic AML
John, S., Chen, H., Deng, M., Gui, X., Wu, G., Chen, W., Li, Z., Zhang, N., An, Z., & Zhang, C. C. (2018) · Molecular Therapy · doi:10.1016/j.ymthe.2018.08.001 · Cited by 139 · see citing works
Self-citationFolding-related Dimerization of Human Cystatin C
Ekiel, I. H., & Abrahamson, M. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.3.1314 · Cited by 132 · see citing works
Toll-Like Receptors in Alzheimer’s Disease: A Therapeutic Perspective
Gambuzza, M., Sofo, V., Salmeri, F., Soraci, L., Marino, S., & Bramanti, P. (2014) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527313666140806124850 · Cited by 131 · see citing works
LILRB4 suppresses immunity in solid tumors and is a potential target for immunotherapy
Sharma, N., Atolagbe, O. T., Ge, Z., & Allison, J. P. (2021) · The Journal of Experimental Medicine · doi:10.1084/jem.20201811 · Cited by 131 · see citing works
Hirayasu, K., & Arase, H. (2015) · Journal of Human Genetics · doi:10.1038/jhg.2015.64 · Cited by 129 · see citing works
Cystatin C Antagonizes Transforming Growth Factor β Signaling in Normal and Cancer Cells
Sokol, J. P., & Schiemann, W. P. (2004) · Molecular Cancer Research · doi:10.1158/1541-7786.183.2.3 · Cited by 121 · see citing works
Increased Melanoma Risk in Parkinson Disease
Bertoni, J. M. (2010) · Archives of Neurology · doi:10.1001/archneurol.2010.1 · Cited by 119 · see citing works
Huh, C. G., Håkansson, K., Nathanson, C. M., Thorgeirsson, U. P., Jonsson, N., Grubb, A., Abrahamson, M., & Karlsson, S. (1999) · Molecular Pathology · doi:10.1136/mp.52.6.332 · Cited by 119 · see citing works
NMR structural studies of human cystatin C dimers and monomers
Ekiel, I. H., Abrahamson, M., Fulton, D. B., et al. (1997) · Journal of Molecular Biology · doi:10.1006/jmbi.1997.1150 · Cited by 111 · see citing works
Madan, S., Dispenzieri, A. A., Lacy, M. Q., Buadi, F. K., Hayman, S. R., Zeldenrust, S. R., Rajkumar, S. V., Gertz, M. A., & Kumar, S. K. (2010) · Mayo Clinic Proceedings · doi:10.4065/mcp.2009.0547 · Cited by 110 · see citing works
Amyloid-β precursor protein promotes cell proliferation and motility of advanced breast cancer
Lim, S., Yoo, B. K., Kim, H.-S., Gilmore, H. L., Lee, Y., Lee, H.-P., Kim, S.-J., Letterio, J., & Lee, H.-G. (2014) · BMC Cancer · doi:10.1186/1471-2407-14-928 · Cited by 100 · see citing works
Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis
Kleffman, K., Levinson, G., Rose, I. V. L., Blumenberg, L. M., Shadaloey, S. A. A., Dhabaria, A., Wong, E., Galán-Echevarría, F., Karz, A., Argibay, D., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1006 · Cited by 100 · see citing works
Saïd, G., Grippon, S., & Kirkpatrick, P. N. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3675 · Cited by 86 · see citing works
On the role of cystatin C in cancer progression
Leto, G., Crescimanno, M., & Flandina, C. (2018) · Life Sciences · doi:10.1016/j.lfs.2018.04.013 · Cited by 84 · see citing works
Achyut, B. R., Bader, D. A., Robles, A. I., Wangsa, D., Harris, C. C., Ried, T., & Yang, H. H. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003251 · Cited by 77 · see citing works
Wu, G., Xu, Y., Schultz, R. D., Chen, H., Xie, J., Deng, M., Liu, X., Gui, X., John, S., Lu, Z., et al. (2021) · Nature Cancer · doi:10.1038/s43018-021-00262-0 · Cited by 75 · see citing works
Self-citationSingh, L., Muise, E. S., Bhattacharya, A., Grein, J., Javaid, S., Stivers, P., Zhang, J., Qu, Y., Joyce-Shaikh, B., Loboda, A. P., et al. (2020) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-20-0622 · Cited by 70 · see citing works
Self-citationThe Fibronectin–ILT3 Interaction Functions as a Stromal Checkpoint that Suppresses Myeloid Cells
Paavola, K. J., Roda, J. M., Lin, V. Y., Chen, P., O'Hollaren, K. P., Ventura, R., Crawley, S., Li, B., Chen, H.-I. H., Malmersjö, S., et al. (2021) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-21-0240 · Cited by 68 · see citing works
Self-citationInflammatory profiling of patients with familial amyloid polyneuropathy
Azevedo, E. P., Guimaraes-Costa, A. B., Bandeira-Melo, C., Chimelli, L., Waddington-Cruz, M., Saraiva, E. M., Palhano, F. L., & Foguel, D. (2019) · BMC Neurology · doi:10.1186/s12883-019-1369-4 · Cited by 66 · see citing works
Lewis Marffy, A. L., & McCarthy, A. J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00857 · Cited by 63 · see citing works
LILRB4-targeting Antibody–Drug Conjugates for the Treatment of Acute Myeloid Leukemia
Anami, Y., Deng, M., Gui, X., Yamaguchi, A., Yamazaki, C. M., Zhang, N., Zhang, C. C., An, Z., & Tsuchikama, K. (2020) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-0407 · Cited by 61 · see citing works
Self-citationAntagonistic anti-LILRB1 monoclonal antibody regulates antitumor functions of natural killer cells
Chen, H., Chen, Y., Deng, M., John, S., Gui, X., Kansagra, A. J., Chen, W., Kim, J., Lewis, C. M., Wu, G., et al. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2019-000515 · Cited by 60 · see citing works
Self-citationTransthyretin: Its function and amyloid formation
Ueda, M. (2022) · Neurochemistry International · doi:10.1016/j.neuint.2022.105313 · Cited by 59 · see citing works
Human inhibitory and activating Ig-like receptors which modulate the function of myeloid cells
Dietrich, J., Nakajima, H., & Colonna, M. (2000) · Microbes and Infection · doi:10.1016/s1286-4579(00)00294-x · Cited by 53 · see citing works
Human leukocyte immunoglobulin-like receptors in health and disease
Redondo-García, S., Barritt, C., Papagregoriou, C., Yeboah, M., Frendeus, B., Cragg, M. S., & Roghanian, A. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1282874 · Cited by 53 · see citing works
Leukocyte immunoglobulin-like receptor subfamily B: therapeutic targets in cancer
Deng, M., Chen, H., Liu, X., Huang, R., He, Y., Yoo, B., Xie, J., John, S., Zhang, N., An, Z., et al. (2021) · Antibody Therapeutics · doi:10.1093/abt/tbab002 · Cited by 53 · see citing works
Self-citationKleeman, S. O., Thakir, T. M., Demestichas, B., Mourikis, N., Loiero, D., Ferrer, M., Bankier, S., Riazat-Kesh, Y. J. R. A., Lee, H., Chantzichristos, D., et al. (2023) · Cell Genomics · doi:10.1016/j.xgen.2023.100347 · Cited by 37 · see citing works
Fan, Y., Teng, Y., Loison, F., Pang, A., Kasorn, A., Shao, X., Zhang, C., Ren, Q., Yu, H., Zheng, Y., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abb1069 · Cited by 36 · see citing works
Self-citationBlocking LAIR1 signaling in immune cells inhibits tumor development
Xie, J., Gui, X., Deng, M., Chen, H., Chen, Y., Liu, X., Ku, Z., Tan, L., Huang, R., He, Y., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.996026 · Cited by 36 · see citing works
Self-citationZavršnik, J., Butinar, M., Prebanda, M. T., Krajnc, A., Vidmar, R., Fonovič, M., GRUBB, A. O., Türk, V., Turk, B., & Vasiljeva, O. S. (2017) · Oncotarget · doi:10.18632/oncotarget.17379 · Cited by 32 · see citing works
A perspective on LILRBs and LAIR1 as immune checkpoint targets for cancer treatment
Zhang, C. C. (2022) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2022.09.019 · Cited by 32 · see citing works
Self-citationRole of PIR‐B in Autoimmune Glomerulonephritis
Takai, T., Nakamura, A., & Endo, S. (2011) · BioMed Research International · doi:10.1155/2011/275302 · Cited by 32 · see citing works
Cancer Cells Enter an Adaptive Persistence to Survive Radiotherapy and Repopulate Tumor
Zhao, Y., Lu, T., Song, Y., Wen, Y., Deng, Z., Fan, J., Zhao, M., Zhao, R., Luo, Y., xie, J., et al. (2023) · Advanced Science · doi:10.1002/advs.202204177 · Cited by 29 · see citing works
Self-citationGonçalves, N. P., Teixeira-Coelho, M., & Saraiva, M. J. (2014) · Experimental Neurology · doi:10.1016/j.expneurol.2014.04.030 · Cited by 27 · see citing works
LILRB3 Supports Immunosuppressive Activity of Myeloid Cells and Tumor Development
Huang, R., Liu, X., Kim, J., Deng, H., Deng, M., Gui, X., Chen, H., Wu, G., Xiong, W., Xie, J., et al. (2024) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-23-0496 · Cited by 24 · see citing works
Self-citationFrequency and profile of Parkinson's disease prodromi in patients with malignant melanoma
Walter, U., Heilmann, E., Voss, J., et al. (2015) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2014-310239 · Cited by 23 · see citing works
The domain swapping of human cystatin C induced by synchrotron radiation
Taube, M., Pietralik, Z., Szymanska, A., Szutkowski, K., Clemens, D., Grubb, A., & Kozak, M. (2019) · Scientific Reports · doi:10.1038/s41598-019-44811-1 · Cited by 20 · see citing works
Noshita, S., Kubo, Y., Kajiwara, K., Okuzaki, D., Nada, S., & Okada, M. (2023) · Journal of Cell Science · doi:10.1242/jcs.261001 · Cited by 20 · see citing works
Yakymovych, I., Yakymovych, M., Hamidi, A., Landström, M., & Heldin, C. (2022) · Science Signaling · doi:10.1126/scisignal.abp9521 · Cited by 18 · see citing works
Zhang, X., Xiao, Q., Zhang, C., Zhou, Q., & Xu, T. (2024) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.18262 · Cited by 14 · see citing works
Self-citationSecretogranin 2 binds LILRB4 resulting in immunosuppression
Yang, X., Huang, R. Y., Fang, M., He, Y., Xie, J., Liu, X., Zhang, C. C., Lou, Q., Deng, M., Xiong, W., et al. (2025) · Nature Immunology · doi:10.1038/s41590-025-02233-4 · Cited by 14 · see citing works
Self-citationAmir, A. R. A., & Sheikh, S. S. (2006) · Journal of Nephrology · doi:10.1093/joneph/19.3.361 · Cited by 12 · see citing works
Liu, H.-L., Lin, Y.-M., Zhao, J.-H., Hsieh, M.-C., Lin, H.-Y., Huang, C.-H., Fang, H.-W., Ho, Y., & Chen, W.-Y. (2007) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2007.10507162 · Cited by 12 · see citing works
Serum amyloid A protein in cancer prognosis: a meta-analysis and systematic review
Lai, Y., Li, Y., & Gao, L. (2021) · Translational Cancer Research · doi:10.21037/tcr-20-3417 · Cited by 12 · see citing works
Advanced systemic amyloidosis secondary to metastatic renal cell carcinoma
Algarra, M. A., Juan-Fita, M. J., Sandiego, S., et al. (2020) · ecancermedicalscience · doi:10.3332/ecancer.2020.1156 · Cited by 11 · see citing works
Wu, J., Liang, Y., Chen, R., Xu, L., Ou, Z., Liang, H., & Zhao, L. (2022) · Scientific Reports · doi:10.1038/s41598-022-24722-4 · Cited by 10 · see citing works
Tang, Y., Zhang, D., Robinson, S., & Zheng, J. (2023) · Advanced Biology · doi:10.1002/adbi.202300070 · Cited by 9 · see citing works
Farris, F., Elhagh, A., Vigorito, I., Alongi, N., Pisati, F., Giannattasio, M., Casagrande, F., Veghini, L., Corbo, V., Tripodo, C., et al. (2024) · Cell Death & Disease · doi:10.1038/s41419-024-06424-z · Cited by 8 · see citing works
Eph Receptors Activate Myeloid Checkpoint Receptor LILRB5 to Support Tumor Development
He, Y., Zhang, C. C., Tan, L., Deng, M., Liu, X., Huang, R. B., Yang, X., Xie, J., Lou, Q., Fang, M., et al. (2025) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-24-0737 · Cited by 6 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Deng, P., Yan, S., & Lu, J. (2026) · Clinical Medicine · doi:10.1016/j.clinme.2026.100598
Zong, X., Zhu, Z., Zhang, X., et al. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.117494
- Authors
- Zhang, C., He, Y., Liu, X., Xie, J., Fang, M., Yang, X., Huang, R., Lou, Q., Li, B., Gupta, A., Lewis, C., Diamond, M. I., Zhang, N., An, Z., & Zhang, C. C.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Harold C. Simmons Comprehensive Cancer Center
- Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (US)
- ORCID
- Venue
- Signal Transduction and Targeted Therapy
- Published
- 2025-11-14
- Volume
- 10
- Issue
- 1
- Pages
- 368-368
- ISSN
- 2059-3635 (ISSN-L)
- PMC
- PMC12615798
- OpenAlex
- W4416235851
- Cited by
- 2
- References
- 81
- Citations by year
- 2026: 2
- FWCI
- 0.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Signal Transduction and Targeted Therapy (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion, cc-by)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Division of Cancer Prevention, National Cancer Institute (5P30CA142543, Lung Cancer SPORE Development Research Program, R01CA248736, R01CA263079)
- Cancer Prevention and Research Institute of Texas (RP220032, RP15150551, RP190561)
- Welch Foundation (AU-0042-20030616)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Keywords
- cystatin C, LILRB2, PirB, inhibitory receptors, myeloid cells, immunosuppression, T cell suppression, tumor microenvironment, amyloid proteins, TGF-beta signaling, phosphatase, CST3, tumor progression, immune evasion
- MeSH terms
- Animals, Humans, Membrane Glycoproteins, Mice, Transgenic, Receptors, Immunologic, Signal Transduction, Myeloid Cells, Mice, Cystatin C, Tumor Microenvironment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-19.
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