Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution

Ghrelin acts in opposition to leptin to downregulate feeding behavior via vagal afferent pathways by inducing cAMP-mediated increase in SOCS3 expression, which negatively affects leptin-induced pY-STAT3 and blocks neuronal firing in nodose ganglia neurons.

“The orexigenic hormone ghrelin acts in opposition to leptin to downregulate feeding behavior via the vagal afferent pathways by inducing exchange protein activated by cAMP–mediated increase in SOCS3 expression, which negatively affects leptin-induced pY-STAT3 and blocks neuronal firing in nodose ganglia neurons”

• cites Heldsinger et al., 2014 sourceDisputed

  Split into 2 atoms — 1 confirmed, 0 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

STAT3 inhibitors-SF-1-066, BP-1-102, and MM206-may, in addition to binding to the SH2 domain, affect the function of the SH2 domain by binding to and perturbing the structure of domains of STAT3 at a distance from the SH2 domain, suggesting an allosteric destabilizing effect on the SH2 domain.

“For example, hydrogen–deuterium exchange experiments and other studies show that STAT3 inhibitors—SF-1-066, BP-1-102, and MM206—may, in addition to binding to the SH2 domain, affect the function of the SH2 domain by binding to and perturbing the structure of domains of STAT3 at a distance from the SH2 domain, suggesting an allosteric destabilizing effect on the SH2 domain (Resetca et al., 2014;”

• cites Resetca et al., 2014 sourceDisputed

  Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites Minus et al., 2015 sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

The human genome encodes four JAKs: JAK1, JAK2, JAK3, and TYK2.

“The human genome encodes four JAKs—JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2)—that associate selectively (Fig. 1) with different receptors (Wilks, 1989; Firmbach-Kraft et al., 1990; Wilks et al., 1991; Harpur et al., 1992).”

• cites Wilks, 1989 sourceNot checked — no full text of the source
• cites Firmbach-Kraft et al., 1990Not checked — no full text of the source
• cites Wilks et al., 1991 sourcePartly supported

  The abstract (p. 2057) identifies JAK1 and says JAK2 is a second member of the family. The indexed passages do not identify JAK3 or TYK2 or state that the human genome encodes exactly four JAKs, so this paper supports only part of the attributed list. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Respiratory epithelium-specific STAT3 knockout impairs injury tolerance.

“Impaired injury tolerance”

• cites Hokuto et al., 2004 sourceSupported

Intestinal epithelium-specific STAT3 knockout impairs epithelial wound healing.

“Impaired epithelial wound healing”

• cites Pickert et al., 2009 sourceSupported

Generally, S727 phosphorylation is suggested to work with Y705 phosphorylation to activate STAT3-mediated transcription, most likely through recruiting coactivator proteins.

“Generally, pS is suggested to work with pY to activate STAT3-mediated transcription (Wen et al., 1995; Abe et al., 2001; Shen et al., 2004) most likely through recruiting coactivator proteins (Schuringa et al., 2001; Lufei et al., 2007; Lee et al., 2009a), e.g., JNK1/2-mediated pS-STAT3 following UVA irradiation, enhanced STAT3–DNA binding in epidermal JB6 cells (Zhang et al., 2001; Liu et al., 2”

• cites Wen et al., 1995 sourceNot checked — no full text of the source
• cites Abe et al., 2001 sourceNot checked — no full text of the source
• cites Shen et al., 2004 sourceSupported

STAT3 undergoes post-translational modifications including methylation, acetylation, ubiquitination, ISGylation, and SUMOylation.

“In addition to tyrosine phosphorylation, STAT3 also undergoes a variety of other post-translational modifications, including methylation, acetylation, ubiquitination, IFN-stimulated gene (ISG)-ylation, and small ubiquitin-related modifiers (SUMOs)-conjugation (SUMOylation) (Kojima et al., 2013; You et al., 2015; Zouein et al., 2015; Avalle and Poli, 2018; Hu et al., 2018) with various effects on”

• cites Kojima et al., 2013 sourcePartly supported

  The IL-6 Receptor System and Its Signaling Pathways section (page not supplied) describes STAT3 methylation at Lys140, and its Figure 2 caption states that STAT3 is acetylated at multiple lysines. Our copy does not substantiate the other listed modifications—ubiquitination, ISGylation, or SUMOylation—of STAT3. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites You et al., 2015 sourceCould not verify

  The sections on tyrosine and serine phosphorylation of STAT3 discuss those modifications, but do not address any of the five modifications named in the claim. Searches for methylation, acetylation, ubiquitination, ISGylation, and SUMOylation found no supporting passage in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites Zouein et al., 2015 sourcePartly supported

  The Introduction’s “Posttranslational Modifications of STAT3” section (page unavailable) identifies methylation, acetylation, and mono-ubiquitination of STAT3. It does not identify ISGylation or SUMOylation, so this source supports only part of the attributed list. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Canonical STAT3 signaling is regulated by several feedback-inhibitory loops.

“Canonical STAT3 signaling is regulated by several feedback-inhibitory loops (Schmitz et al., 2000).”

• cites Schmitz et al., 2000 sourcePartly supported

  The Discussion (page unavailable) says that SHP2 binds gp130 Tyr 759 and negatively regulates STAT activation; it also reports that MAPK activation reduces STAT phosphorylation. This supports inhibitory regulation in the IL-6/gp130 pathway, but the paper does not establish several feedback-inhibitory loops governing canonical STAT3 signaling generally. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

S727 phosphorylation of STAT3 is mediated by various serine/threonine kinases depending on the stimulus, upstream signaling pathway, and cell type.

“In addition to phosphorylation on Y705, STAT3 can be phosphorylated on Ser727 within its TAD (Wen et al., 1995) by various serine/threonine kinases, e.g., mitogen-activated protein kinase (MAPK) like MAPK kinase/ERK (Chung et al., 1997; Stephens et al., 1998; Ng et al., 2011), c-Jun N-terminal kinase (JNK) (Zhang et al., 2001; Liu et al., 2012), p38 (Gollob et al., 1999; Lim and Cao, 1999; Turkson”

• cites Wen et al., 1995 sourceNot checked — no full text of the source
• cites Chung et al., 1997 sourceSupported
• cites Zhang et al., 2001 sourceSupported

The SH2 domain is required for docking of STAT3 to tyrosine-phosphorylated receptors.

“The SH2 domain is also required for docking to tyrosine-phosphorylated receptors (Vogt et al., 2011).”

• cites Vogt et al., 2011 sourceSupported

The effect of S727 phosphorylation on STAT3 gene transcription is varied and depends on the phosphorylating kinase and cell type.

“The effect of S727 phosphorylation (pS) on STAT3 gene transcription is varied and depends on the phosphorylating kinase, as well as the cell type, which likely dictates the availability of other transcription factors and proteins that help STAT3 bind to kinase (Avalle and Poli, 2018).”

• cites Avalle and Poli, 2018 sourcePartly supported

  Section 3.3 says S727 phosphorylation can be carried out by several kinases and can affect transcriptional induction or STAT3 activation dynamics. Section 3 also says STAT3 activates different genes across cell types, partly through differences in binding-site accessibility and interactions with transcription factors and cofactors. The paper does not establish that the transcriptional effect of S727 phosphorylation depends on which kinase phosphorylates it, or that those proteins help STAT3 bind to a kinase. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

Keratinocyte-specific STAT3 knockout impairs the hair cycle and skin wound healing.

“Impaired hair cycle and skin wound healing”

• cites Sano et al., 1999 sourceSupported

G-CSF-mediated activation of STAT3 induces granulocytic progenitor proliferation through transcriptional upregulation of C/EBPβ and c-Myc.

“granulocyte cell-stimulating factor–mediated activation of STAT3 induces granulocytic progenitor proliferation through transcriptional upregulation of CCAAT/enhancer-binding protein (C/EBP)β and c-Myc”

• cites Johansen et al., 2001 sourcePartly supported

  The Discussion (page unavailable) says that maintaining c-Myc expression keeps myeloblasts proliferative, supporting c-Myc’s role in proliferation. It does not establish that G-CSF activates STAT3 to transcriptionally upregulate C/EBPβ and c-Myc; the mechanism it examines is C/EBPα-mediated downregulation of c-Myc. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites Hirai et al., 2006 sourceNot checked — no full text of the source
• cites Zhang et al., 2010 sourceSupported

Neural cell-specific STAT3 knockout causes obesity, diabetes, infertility, and thermal dysregulation.

“Obesity, diabetes, infertility, and thermal dysregulation”

• cites Gao et al., 2004 sourceSupported

In AD-HIES, patient cells have diminished STAT3 activity due to an autosomal-dominant loss-of-function STAT3 mutation.

“patient’s cells have diminished STAT3 activity due to an autosomal-dominant, loss-of-function STAT3 mutation”

• cites Bocchini et al., 2016 sourceSupported

Adipocyte-specific STAT3 knockout increases body weight and adiposity.

“Increased body weight and adiposity”

• cites Cernkovich et al., 2008 sourceSupported

STAT3 regulates critical steps in emergency granulopoiesis.

“STAT3 was shown to regulate critical steps in emergency granulopoiesis”

• cites Hillmer et al., 2016 sourceSupported

STAT3 is not required for basal granulopoiesis.

“STAT3 was found not to be required for basal granulopoiesis”

• cites Lee et al., 2002 sourceSupported

AD-HIES patients do not demonstrate quantitative defects in basal or stress hematopoiesis, including production of neutrophils, total lymphocyte numbers, red blood cells, or platelets.

“AD-HIES patients do not demonstrate quantitative defects in basal or stress hematopoiesis, including the production of neutrophils, total lymphocyte numbers, red blood cells, or platelets”

• cites Zhang et al., 2010 sourceCould not verify

  The Discussion (page not provided) mentions patients with hyper-IgE syndrome but says their emergency granulopoiesis and neutrophil function have not been investigated extensively. The reported blood-cell and progenitor findings concern mice, not AD-HIES patients. Searches for AD-HIES blood-cell counts and hematopoiesis found no passage establishing the claimed absence of quantitative defects in patients. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

U-STAT3, not pY-STAT3 or pS-STAT3, transcriptionally activates Fanconi C during early phases of granulopoiesis.

“U-STAT3 and not pY-STAT3 (or pS-STAT3) recently was found to transcriptionally activate Fanconi C, a DNA repair protein that is expressed during early phases of granulopoiesis”

• cites Shah et al., 2018 sourcePartly supported

  The Introduction says Stat3 increases FANCC transcription during initiation of emergency granulopoiesis. But the Results report equivalent FANCC promoter activation by wild-type Stat3 and mutants lacking either the tyrosine or serine phosphorylation site; the Discussion concludes that phosphorylation does not enhance activation. These passages support phosphorylation being unnecessary, not the claim that phosphorylated Stat3 does not activate FANCC. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

AD-HIES primary immune defects include intrinsic impairments in neutrophil chemotaxis.

“intrinsic impairments in neutrophil chemotaxis”

• cites Hill and Quie, 1974Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Hill et al., 1974Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Panopoulos et al., 2006 sourcePartly supported

  The Results (page not provided) show a cell-autonomous chemotaxis defect in STAT3-deficient mouse neutrophils, specifically in responses to the CXCR2 ligands MIP-2 and KC; migration toward fMLP was similar to controls. The paper does not establish that impaired neutrophil chemotaxis is a primary immune defect in people with AD-HIES. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

B cell-specific STAT3 knockout reduces B cell compartments and plasma cells.

“Reduced B cell compartments and plasma cells”

• cites Chou et al., 2006 sourceNot checked — no full text of the source
• cites Fornek et al., 2006 sourcePartly supported

  The discussion reports a profound decrease in T-dependent IgG antibody-secreting cells after B-cell-specific Stat3 deletion, supporting a reduction in that plasma-cell subset. It also states that B-cell numbers in the bone marrow, spleen, and lymph nodes were equivalent to controls and that B-cell development was intact, contrary to the claimed reduction in B-cell compartments. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Flt3L activates STAT3 to stimulate dendritic cell progenitor proliferation.

“Fms-related tyrosine kinase 3 ligand, the major DC growth factor, activates STAT3 to stimulate DC progenitor proliferation”

• cites Esashi et al., 2008 sourceSupported
• cites Li et al., 2012Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

IL-21/JAK3/STAT3 signaling promotes generation of megakaryocytes from CD34+ cells.

“the IL-21/JAK3/STAT3 signaling pathway promotes generation of megakaryocytes from CD34+ cells”

• cites Benbarche et al., 2017 sourceSupported

STAT3-deficient macrophages, neutrophils, and dendritic cells and hematopoietic-specific STAT3-KO mice have increased production of inflammatory cytokines.

“STAT3-deficient macrophages, neutrophils, and DCs”

• cites Takeda et al., 1999 sourceNot checked — no full text of the source
• cites Melillo et al., 2010 sourcePartly supported

  The Results (Functional characterization of Stat3 CKO DCs; page unavailable) report significantly increased IL-12 and IL-23 secretion by stimulated Stat3-deficient dendritic cells. The Discussion describes macrophage-predominant IL-12 secretion in a myeloid-specific deletion model, but does not establish increased cytokine production by STAT3-deficient neutrophils. It describes inflammation after broader hematopoietic deletion without establishing the claimed cytokine increase for those mice. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites Welte et al., 2003 sourceNot checked — no full text of the source

STAT3 suppresses TLR signaling in mature phagocytes by suppressing NF-κB and MAPK through direct transcriptional repression of an E2 ubiquitin-conjugating enzyme required for TLR signaling.

“STAT3 suppresses TLR signaling in mature phagocytes”

• cites Takeda et al., 1999 sourceNot checked — no full text of the source
• cites Melillo et al., 2010 sourcePartly supported

  The Discussion reports increased TLR-dependent IL-12 and IL-23 secretion in Stat3-deficient dendritic cells, supporting a negative regulatory role for STAT3 in those cells. It does not establish the claim across mature phagocytes generally, or the proposed mechanism involving NF-κB, MAPK, and direct repression of an E2 ubiquitin-conjugating enzyme. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites El Kasmi et al., 2007 sourceNot checked — no full text of the source

T cell-secreted IL-21 activates STAT3, which facilitates differentiation of later-stage B-lineage-committed CD19+ precursors to IgG-secreting plasma cells.

“T cell–secreted IL-21 activates STAT3, which facilitates differentiation of later-stage B-lineage–committed CD19+ precursors to IgG-secreting plasma cells”

• cites Fornek et al., 2006 sourcePartly supported

  The Introduction (page not supplied) says IL-21 activates STAT3, and the Discussion proposes that STAT3 activation helps drive T-dependent IgG plasma-cell formation. But the Discussion names IL-21 as one of several possible cytokines, rather than establishing that T-cell-secreted IL-21 drives this process. The paper studies CD19-lineage B cells, not specifically later-stage CD19+ precursors. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Leptin activates the JAK2/STAT3 signaling pathway in human B cells to induce IL-6 and TNF-α.

“Leptin activates the JAK2/STAT3 signaling pathway in human B cells to induce IL-6 and TNF-α”

• cites Esashi et al., 2008 sourceCould not verify

  The signaling-results passage (Immunity section; page not specified) reports STAT3 activation by Flt3L and GM-CSF in dendritic-cell progenitors, not by leptin in human B cells. Searches for leptin, JAK2/STAT3 in human B cells, and IL-6 and TNF-α induction found no passage addressing the claim. (LLM, conf=0.77)

  Experimental — accuracy not yet measured

STAT3 forms a complex with Syk and PLCγ2 to mediate platelet activation and aggregation.

“STAT3 forms a complex with Syk and PLCγ2 to mediate platelet activation and aggregation”

• cites Zhou et al., 2013 sourcePartly supported

  The Discussion reports that STAT3 interacts with Syk and PLCγ2, likely forming a three-molecule complex that enhances collagen-induced platelet activation and aggregation. The claim omits the collagen-specific condition and states complex formation more definitively than the Discussion does; the Abstract’s Methods and Results also reports no inhibition of ADP- or TRAP-induced aggregation. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

STAT3 plays major roles in immature dendritic cell development and function, affecting both plasmacytoid DCs and conventional DCs.

“STAT3 also plays major roles in immature DC development and function”

• cites Laouar et al., 2003 sourceNot checked — no full text of the source
• cites Merad and Manz, 2009 sourcePartly supported

  The ‘Transcription factors in DC development’ section reports that STAT3 affects Flt3L-mediated development of both plasmacytoid DCs and other DCs. It does not establish a role in immature DC function, and it specifies that STAT3 deficiency does not block GM-CSF-mediated DC development. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites Merad et al., 2013 sourcePartly supported

  The STATs section reports that STAT3 has a nonredundant role in DC development and that mice lacking it have profound reductions in DCs and pDCs. It does not establish a role for STAT3 in immature DC function or specifically identify immature DCs as the affected population; no page number is available in our copy. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

T lymphocyte lineage-specific STAT3-KO mice studies revealed a crucial role of IL-6/STAT3-mediated T cell survival independent of Bcl-2.

“T lymphocyte lineage-specific STAT3-KO mice studies revealed the crucial role of IL-6/STAT3-mediated T cell survival, independent of Bcl-2”

• cites Schindler et al., 1992 sourceNot checked — no full text of the source
• cites Takeda et al., 1998 sourceSupported

IL-6-activated pY-STAT3 transcriptionally induces early production of IL-4 and IL-21 in CD4+ T cells.

“IL-6–activated pY-STAT3 transcriptionally induces early production of IL-4 and IL-21 in CD4+ T cells”

• cites Yang and Rincon, 2016 sourcePartly supported

  Section 3.3 (page not provided) says that IL-6 promotes IL-4 and IL-21 production in CD4 cells, but attributes transcription-factor STAT3 induction of early expression specifically to IL-21. It does not say that pY-STAT3 transcriptionally induces early IL-4 production; instead, it describes STAT3 sustaining later IL-4 production independently of transcriptional activity. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Leptin/LepRb/JAK2/STAT3 signaling plays major roles in energy homeostasis and neuroendocrine function through upregulation of POMC and downregulation of AgRP.

“Leptin/LepRb/JAK2/STAT3 signaling plays major roles in energy homeostasis and neuroendocrine function”

• cites Millington, 2007 sourcePartly supported

  The Background section (“Leptin and hypothalamic regulation”; page unavailable) describes leptin acting through LEPRB on feeding-related neurons and activating POMC neurons. The AgRP section also reports higher agrp and lower pomc expression in leptin-deficient mice, supporting the proposed directions of regulation. Our copy does not establish the full LepRb/JAK2/STAT3 pathway or attribute a major role in neuroendocrine function to that pathway. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Use of an HDAC inhibitor enabled effective T cell priming and antitumor response.

“use of a HDAC inhibitor enabled effective T cell priming and antitumor response”

• cites Wang et al., 2011aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Cheng et al., 2014 sourcePartly supported

  The Results section reports that the HDAC6 inhibitor Tubastatin A enhanced antigen-specific CD4+ T-cell activation and priming, including in vaccinated mice. It also restored responsiveness of T cells isolated from tumor-bearing mice, but does not report an antitumor response such as reduced tumor growth or rejection (page numbers unavailable). (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Human mast cell function in Job's syndrome patients was affected somewhat by reduced STAT3 signaling.

“human mast cell function in Job’s syndrome patients was affected somewhat by the reduced STAT3 signaling”

• cites Siegel et al., 2013 sourceSupported

STAT3 inhibits generation of CD4+ Tregs from naive CD4+ precursors by suppressing the Treg-specifying transcription factor Foxp3 in mature Tregs.

“STAT3 inhibits generation of CD4+ Tregs from naive CD4+ precursors by suppressing the Treg-specifying transcription factor Foxp3 in mature Tregs”

• cites Yang et al., 2008aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Laurence et al., 2012 sourcePartly supported

  The Results section on iTreg generation reports that STAT3 inhibits FoxP3 induction in naïve T cells during allogeneic transplantation. The Discussion separately describes STAT3-dependent loss of FoxP3 in existing natural Tregs. The claim conflates these findings: the paper does not show that suppressing FoxP3 in mature Tregs is how STAT3 inhibits Treg generation from naïve precursors. No page numbers were provided in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Clinical food allergy and anaphylaxis are decreased in patients with Job's or AD-HIES despite a significant burden of eczematous skin disease and increased IgE.

“clinical food allergy and anaphylaxis are decreased in patients with Job’s or AD-HIES, despite a significant burden of eczematous skin disease and increased levels of IgE”

• cites Siegel et al., 2013 sourceSupported

STAT3 activated by IL-6, IL-21, and IL-23 upregulates RORγt, RORα, IL-21, IL-23R, and IL-17, helping development and stabilization of Th17 cells.

“STAT3 activated by several proinflammatory cytokines, e.g., IL-6, IL-21, and IL-23, upregulates RORγt, RORα, IL-21, IL-23R, and IL-17, thereby helping in the development and stabilization of Th17 cells”

• cites Laurence et al., 2007 sourceNot checked — no full text of the source
• cites Nishihara et al., 2007 sourcePartly supported

  The Introduction and the section on gp130 STAT3-binding residues report that IL-6–gp130–STAT3 signaling promotes RORγt expression and Th17 development. The latter section only suggests that STAT3 might induce IL-17 mRNA; our copy does not establish the claimed STAT3-mediated upregulation of RORα, IL-21, or IL-23R, activation by IL-21 or IL-23, or stabilization of Th17 cells. Page numbers were not provided. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Yang et al., 2007bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

STAT3-HDAC6 transcriptionally upregulates IL-10, preventing effective antigen-specific CD4+ T cell activation in tumor-bearing mice.

“STAT3–HDAC6 transcriptionally upregulates IL-10, preventing effective Ag-specific CD4+ T cell activation in tumor-bearing mice”

• cites Cheng et al., 2014 sourcePartly supported

  The Discussion describes HDAC6 and STAT3 as regulators of Il10 transcription in APCs, and the Results show that disrupting HDAC6 improves antigen-specific CD4+ T-cell activation. In the tumor-bearing-mouse model, however, the paper tested re-isolated tolerant T cells with HDAC6-deficient APCs in vitro; it does not show that the STAT3–HDAC6–IL-10 pathway prevented their activation within tumor-bearing mice. Page numbers are unavailable in our copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

IL-10- and IL-21-mediated STAT3 activation helps generate stable, long-lived memory CD8+ T cells through regulating Eomes, BCL6, and Blimp1.

“IL-10– and IL-21–mediated STAT3 activation”

• cites Cui et al., 2011 sourceSupported
• cites Kaech and Cui, 2012 sourcePartly supported

  The ‘effector to memory T cell transition’ section links IL-10 and IL-21 to STAT3-dependent maturation of memory CD8+ T cells, and the ‘STAT3, STAT4 and STAT5’ section says STAT3 sustains EOMES and BCL-6 expression. The ‘BLIMP1 and BCL-6’ section says BLIMP1 declines as memory cells mature, but does not establish that STAT3 promotes long-lived memory cells by regulating BLIMP1; it also describes the proposed cytokine effect on BCL-6 as likely rather than established. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

STAT3-dependent transcriptional activity within endothelial cells regulating microRNA17-92, PTEN, Src, E2F, and β-catenin is a more important contributor to reduced endothelial cell permeability and anaphylaxis protection in Job's syndrome patients.

“the STAT3-dependent transcriptional activity within endothelial cells that regulates critical components involved in the architecture and functional dynamics of endothelial junctions, i.e., microRNA17-92, PTEN, Src, E2F, and β-catenin, is a more important contributor to reduced endothelial cell permeability and anaphylaxis protection in these patients”

• cites Hox et al., 2016 sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

mtSTAT3 contributes to maintaining late expression of IL-4 and IL-21 through increases in mitochondrial calcium levels and ATP.

“mtSTAT3 contributes to maintaining their late expression through increases in mitochondrial calcium levels and ATP”

• cites Yang et al., 2015 sourcePartly supported

  The Results section on mitochondrial Ca2+ and late cytokine production links Stat3 and mitochondrial Ca2+ to sustained IL-21 and IL-4 production in activated CD4 cells. But the Results section on mitochondrial hyperpolarization reports that IL-6 did not increase intracellular or extracellular ATP, contrary to the claimed ATP increase. Page numbers are unavailable in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

STAT3 itself can be subject to direct modification by oxidative stress, as 9 of the 14 cysteine residues within STAT3 are redox sensitive.

“STAT3 itself can be subject to direct modification by oxidative stress, as 9 of the 14 cysteine residues within STAT3 have been reported to be redox sensitive.”

• cites Li and Shaw, 2004 sourceNot checked — no full text of the source
• cites Xie et al., 2009 sourcePartly supported

  The section ‘STAT3 protein contains cysteine residues that are targets for S-glutathionylation’ reports that STAT3 has reactive thiols and that its cysteines can undergo oxidative modification. The Discussion says it remains unclear which cysteines are particularly reactive; our copy does not report that 9 of STAT3’s 14 cysteine residues are redox sensitive. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Li et al., 2010aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

STAT3 plays a key role in amino acid-mediated dampening of insulin signaling in hepatic cells, primarily through a mTOR-mediated pS-STAT3 pathway that is independent of pY-STAT3.

“STAT3 also plays a key role in amino acid–mediated dampening of insulin signaling in hepatic cells, primarily through a mTOR-mediated pS-STAT3 pathway that is independent of pY-STAT3 (Kim et al., 2009).”

• cites Kim et al., 2009 sourceSupported

pS-STAT3 is important in radioresistance in glioblastoma multiforme.

“Recently, the importance of pS-STAT3 in radioresistance in glioblastoma multiforme also has been suggested (Ouédraogo et al., 2016).”

• cites Ouédraogo et al., 2016 sourceSupported

CLL cells modify their metabolism to oxidize free fatty acids with the help of constitutively activated STAT3 (mostly pS-STAT3) through transcriptional upregulation of lipoprotein lipase.

“CLL cells modify their metabolism to oxidize free fatty acids with the help of constitutively activated STAT3 (mostly pS-STAT3) through transcriptional upregulation of lipoprotein lipase, which catalyzes the hydrolysis of triglycerides into free fatty acids (Rozovski et al., 2015).”

• cites Rozovski et al., 2015 sourceSupported

Persistently elevated pY-STAT3 levels mediated by chronic UV exposure are a key step in UV-induced skin cancer.

“persistently elevated pY-STAT3 levels mediated by chronic UV exposure are a key step in UV-induced skin cancer (Chan et al., 2004a,b; Aziz et al., 2007a,b; Barry et al., 2010).”

• cites Chan et al., 2004a,bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Aziz et al., 2007a,bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Barry et al., 2010 sourcePartly supported

  The Results report that STAT3 levels correlate with repair of UV-damaged DNA in mouse embryonic fibroblasts, and the Discussion considers a possible role for elevated STAT3 in cancer-cell DNA repair (page numbers unavailable). The paper does not establish that chronic UV exposure persistently elevates pY-STAT3 or that this is a key step in UV-induced skin cancer. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

STAT3 activation seems to be protective against UV.

“STAT3 activation seems to be protective (Shen et al., 2001; Chan et al., 2004b; Sano et al., 2005; Aziz et al., 2007a; Barry et al., 2010; Bito et al., 2010a,b).”

• cites Shen et al., 2001 sourceSupported
• cites Chan et al., 2004bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Sano et al., 2005 sourceNot checked — no full text of the source

The leptin/JAK2/STAT3 pathway inhibits insulin synthesis.

“The leptin/JAK2/STAT3 pathway inhibits insulin synthesis, whereas SOCS3 blocks the STAT3-dependent regulation of the preproinsulin 1 gene promoter (Laubner et al., 2005).”

• cites Laubner et al., 2005 sourceSupported

SOCS3 blocks STAT3-dependent regulation of the preproinsulin 1 gene promoter.

“whereas SOCS3 blocks the STAT3-dependent regulation of the preproinsulin 1 gene promoter (Laubner et al., 2005).”

• cites Laubner et al., 2005 sourceSupported

Thiol-targeting agents inhibit IL-6-induced STAT3 activation by S-glutathionylation in HepG2 cells, human endothelial cells, neonatal rat cardiomyocytes, and adult mouse cardiac myocytes.

“thiol-targeting agents also inhibited IL-6–induced STAT3 activation by S-glutathionylation in HepG2 cells (Xie et al., 2009), human endothelial cells, neonatal rat cardiomyocytes, and adult mouse cardiac myocytes (Zgheib et al., 2012)”

• cites Xie et al., 2009 sourceSupported
• cites Zgheib et al., 2012 sourcePartly supported

  The Results and Figures 2–3 report that thiol-reactive compounds inhibited LIF-induced, not IL-6-induced, STAT3 activation in human endothelial cells and neonatal rat and adult-phenotype mouse cardiac myocytes. The Results section “NCP Enhances STAT3 Glutathionylation and Dimerization” reports glutathionylation in HL-1 cells only when NCP and diamide were combined; it does not establish S-glutathionylation as the cause of the inhibition across the cited cell types. The HepG2 finding is separately attributed to Xie et al. in the citing sentence. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

STAT3 in hepatocytes regulates glucose homeostasis by transcriptionally suppressing expression of gluconeogenic genes, e.g., glucose-6-phosphatase and phosphoenolpyruvate carboxykinase.

“which in turn regulates glucose homeostasis by transcriptionally suppressing (Ramadoss et al., 2009) expression of gluconeogenic genes, e.g., glucose-6-phosphatase and phosphoenolpyruvate carboxykinase (Inoue et al., 2004).”

• cites Ramadoss et al., 2009 sourceSupported
• cites Inoue et al., 2004 sourceNot checked — no full text of the source

STAT3 is activated by UV through DNA damage and reactive oxygen species.

“STAT3 also is activated by UV through DNA damage and reactive oxygen species (Shen et al., 2001; Aziz et al., 2007a; Barry et al., 2010; Bito et al., 2010b).”

• cites Shen et al., 2001 sourceCould not verify

  The Results section on fibroblasts transformed by Stat3-C reports that cells expressing constitutively activated Stat3 were relatively resistant to UV-induced apoptosis. It does not report that UV activates Stat3, or that DNA damage or reactive oxygen species mediate such activation; searches for those mechanisms found no supporting passage in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites Aziz et al., 2007aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Barry et al., 2010 sourcePartly supported

  The Abstract (page unavailable) reports STAT3 activation in rat myocardium after ischemia–reperfusion injury, which generates reactive oxygen species. The Results and Abstract link STAT3 to repair of UV-damaged DNA, but do not show that UV activates STAT3 through DNA damage or reactive oxygen species. (LLM, conf=0.81)

  Experimental — accuracy not yet measured

Levels of pY-STAT3 are increased in in vitro models and in patients with ionizing radiation-resistant tumors by IR at doses used for radiotherapy (≥2 Gy), contributing to selection of IR-resistant cells in many different cancers.

“Levels of pY-STAT3 also are increased in in vitro models, as well as in patients with ionizing radiation (IR)–resistant tumors, by IR at doses used for radiotherapy (≥2 Gy), contributing to selection of IR-resistant cells in many different cancers (Ho et al., 2010; Liu et al., 2013; Pan et al., 2013; Yan et al., 2013; Gao et al., 2014; Klein et al., 2014; Lau et al., 2015; Zang et al., 2017; Lu et”

• cites Ho et al., 2010Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Liu et al., 2013 sourcePartly supported

  The Figure 4 results (p. 7) show that LIF activates STAT3 Tyr705 in nasopharyngeal carcinoma cells, and the Figure 5 results (p. 9) show that LIF-treated cells survive irradiation doses including 2 and 4 Gy better than controls. The discussion (Figure 8, p. 13) links IR-induced cytokines and STAT3 signaling to acquired radioresistance. The paper does not show that irradiation itself raises pY-STAT3 in patients with resistant tumors, or establish that this mechanism selects resistant cells across many cancers. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Pan et al., 2013 sourcePartly supported

  The Results section, “Stattic Sensitize NPC Cells to Radiotherapy” (page unavailable), reports that inhibiting STAT3 increased the sensitivity of nasopharyngeal carcinoma cells to 10 Gy irradiation. The paper does not show that irradiation increases pY-STAT3, or establish that such an increase selects resistant cells in patients or across many cancers; its reported increase in STAT3 phosphorylation followed IL-6 treatment, not irradiation. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Sorafenib activates autophagy in multiple liver cancer cell lines through targeting STAT3 and reducing MCL1 expression.

“Sorafenib, a small-molecule kinase insert domain receptor inhibitor, activates autophagy in multiple liver cancer cell lines through targeting STAT3 and reducing MCL1 expression (Tai et al., 2013).”

• cites Tai et al., 2013 sourceSupported

IL-6 and pY-STAT3 induced by chemotherapy promote premature senescence in lymphoma cells in a paracrine manner, maintaining a minimal residual number of chemoresistant cells that could lead to relapse.

“IL-6 and pY-STAT3 induced by chemotherapy promoted premature senescence in lymphoma cells in a paracrine manner, which maintained a minimal residual number of chemoresistant cells that could lead to relapse.”

• cites Gilbert and Hemann, 2010 sourcePartly supported

  The Abstract and Results support chemotherapy-induced, paracrine IL-6 protection of residual lymphoma cells that can fuel relapse. They do not support the claim that IL-6 and pY-STAT3 induce premature senescence in lymphoma cells: the Abstract and the Results section on senescence place senescence in thymic stromal cells, while the Discussion says acute IL-6 release precedes it. The Results discuss Jak/Stat3 signaling but do not establish the claimed pY-STAT3–senescence mechanism. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

S-nitrosylation is a redox-related post-translational modification that inhibits STAT3 activation.

“S-nitrosylation is another redox-related post-translational modification that inhibits STAT3 activation.”

• cites Kim et al., 2014 sourceSupported

STAT3 promotes autophagy, e.g., LIF/STAT3 and OSM/STAT3 signaling promote autophagy in mammary gland cells by upregulating both p55 and p50 isoforms of PI3K regulatory subunit 1, PIK3R1.

“STAT3 also promotes autophagy, e.g., leukemia inhibitory factor/STAT3 and oncostatin M/STAT3 signaling promote autophagy in mammary gland cells by upregulating both the p55 and p50 isoforms of PI3K regulatory subunit 1, PIK3R1 (Pensa et al., 2014).”

• cites Pensa et al., 2014 sourcePartly supported

  The Results section reports that OSM activates Stat3, increases p55α and p50α expression in mammary epithelial cells, and appears to induce autophagy. It identifies LIF as an inducer of these isoforms in the mammary gland, but does not show that LIF promotes autophagy. The authors also say they could not isolate the isoforms’ direct contribution to the OSM response, so the claimed mechanism is stronger than their evidence. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

In microglial cells, endogenous NO produced by iNOS or treatment with s-nitrosoglutathione leads to s-nitrosylation of STAT3 on C259, which inhibits JAK2-STAT3-induced gene expression and cell proliferation.

“In microglial cells, endogenous nitric oxide (NO) produced by inducible NO synthase (iNOS) or by treatment with s-nitrosoglutathione led to s-nitrosylation of STAT3 on C259, which inhibited JAK2-STAT3–induced gene expression and cell proliferation (Kim et al., 2014).”

• cites Kim et al., 2014 sourceSupported

Resuscitation from hemorrhagic shock results in apoptosis of lung type I alveolar endothelial cells, liver hepatocytes, and cardiomyocytes.

“Importantly, resuscitation from hemorrhagic shock also resulted in apoptosis of lung type I alveolar endothelial cells (Moran et al., 2009), liver hepatocytes (Moran et al., 2008), and cardiomyocytes (Thacker et al., 2013)”

• cites Moran et al., 2009 sourceNot checked — no full text of the source
• cites Moran et al., 2008Not checked — no full text of the source
• cites Thacker et al., 2013 sourceSupported

IL-6 treatment reduces endothelial disruption and neutrophil sequestration in lung and alveolar spaces, resulting in improved oxygenation after I/R.

“IL-6 treatment also reduced endothelial disruption and neutrophil sequestration in lung and alveolar spaces, resulting in improved oxygenation after I/R (Zhang et al., 2016).”

• cites Zhang et al., 2016 sourceCould not verify

  The Results section on β-adrenergic STAT3 activation mentions an IL-6-family cytokine only as a laboratory positive control. The Results on chronic β-adrenergic stimulation concern cardiac injury, not lung injury. Searches for neutrophil sequestration, endothelial disruption, oxygenation, and lung ischemia/reperfusion found no passage addressing the attributed claim. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Cells lacking STAT3 are less efficient in repairing damaged DNA due to reduced activity of ATM-Chk2 and ATR-Chk1.

“cells lacking STAT3 are less efficient in repairing damaged DNA due to reduced activity of ataxia-telangiectasia mutated (ATM)-Chk2 and ATM and RAD3‐related (ATR)-Chk1, two major pathways involved in sensing DNA damage (Barry et al., 2010).”

• cites Barry et al., 2010 sourceSupported

STAT3 negatively regulates both PIK3C3 and BECN1 through recruitment of HDAC3 on its promoter.

“STAT3 also negatively regulates both PIK3C3 (Yamada et al., 2012) and BECN1 (Miao et al., 2014) through recruitment of HDAC3 on its promoter (Miao et al., 2014).”

• cites Yamada et al., 2012 sourceSupported
• cites Miao et al., 2014 sourceNot checked — no full text of the source

There is a close relationship between elevated proinflammatory factors e.g., IL-1α, IL-6, TNF, and NF-κB, which tend to increase in tissues with senescence and age.

“There is a close relationship between elevated proinflammatory factors e.g., IL-1α, IL-6, TNF, and NF-κB, which tend to increase in tissues with senescence and age (McHugh and Gil, 2018).”

• cites McHugh and Gil, 2018 sourceSupported

STAT3 transcriptionally regulates mediator of DNA damage checkpoint 1, the master regulator of the ATM-chk2 pathway.

“STAT3 transcriptionally regulates mediator of DNA damage checkpoint 1, the master regulator of the ATM-chk2 pathway (Barry et al., 2010).”

• cites Barry et al., 2010 sourcePartly supported

  The Abstract and Discussion (page not specified) state that STAT3 modulates MDC1 expression at the transcriptional level and that MDC1 is a regulator of the ATM–Chk2 pathway. They call MDC1 a key mediator, not the singular “master regulator”; the Results instead identify ATM as the pathway’s apical kinase. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Studies investigating the impact of disease-causing mutations on STAT3 suggest that there are long-range communications between domains of STAT3, implying that STAT3 activity may be subject to allosteric modulation.

“Studies investigating the impact of disease-causing mutations on STAT3 suggest that there are long-range communications between domains of STAT3, implying that STAT3 activity may be subject to allosteric modulation (Zhang et al., 2000; Mertens et al., 2015; Namanja et al., 2016).”

• cites Zhang et al., 2000 sourcePartly supported

  The Results and Discussion (page not available in our copy) show that mutations in STAT3’s coiled-coil domain affect SH2-mediated receptor binding, and propose an intramolecular interaction between the domains. This supports the suggested long-range communication and possible modulation of activity. The mutations studied were experimentally introduced; the paper does not identify them as disease-causing. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Mertens et al., 2015 sourcePartly supported

  The paper’s opening summary and Discussion report functional interactions between STAT3 domains and propose that altering those interactions could inhibit STAT3 activity. However, the mutations tested in this study were introduced experimentally; the paper does not establish that they are disease-causing mutations. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Namanja et al., 2016 sourceSupported

In IgE/antigen anaphylaxis model and to histamine alone, hematocrit levels and local plasma transudate are significantly lower in TTI-101-treated mice compared with untreated mice.

“Similar to findings in mut-Stat3 mice, Hox et al. (2016) found that hematocrit levels and local plasma transudate in response to the IgE/antigen anaphylaxis model and to histamine alone were significantly lower in TTI-101–treated mice compared with untreated mice.”

• cites Hox et al., 2016 sourcePartly supported

  The Discussion reports significantly lower hematocrit levels and local plasma transudate after IgE/antigen or histamine exposure, but identifies the treated mice as receiving C188–9, not TTI-101. The Methods section on STAT3 inhibition likewise identifies C188–9 as the injected drug. Page numbers are unavailable in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

STAT3 forms proteotoxic aggregates in mitochondria when tumor cells are treated with OPB-51602, STA21, or WP1066.

“For instance, it has been reported that STAT3 forms proteotoxic aggregates in mitochondria when tumor cells are treated with OPB-51602, STA21, or WP1066 (Genini et al., 2017).”

• cites Genini et al., 2017 sourcePartly supported

  The sections “STAT3 Forms Proteotoxic Aggregates in the Presence of OPB-51602” and “Mitochondrial Dysfunction and Proteotoxic Aggregate Formation” report STAT3 aggregates after treatment with OPB-51602 and other inhibitors, including STA21 and WP1066. But the claimed location is wrong: fractionation found STAT3 depleted from mitochondria after OPB-51602 treatment and shifted into an insoluble protein fraction, not aggregated in mitochondria. No page numbers are available in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Each of these small-molecule inhibitors binds in the ATP-binding cleft located between the β-sheet-rich N-lobe and α-helix-rich C-lobe of the JH1 domain.

“Each of these small-molecule inhibitors has been shown to bind in the ATP-binding cleft located between the β-sheet–rich N-lobe and α-helix–rich C-lobe of the JH1 domain (Alicea-Velázquez and Boggon, 2011).”

• cites Alicea-Velázquez and Boggon, 2011 sourceSupported

Some STAT3 inhibitors, such as Stattic and some members of the S3I-201 family, inhibit STAT3 by covalently reacting with residues (largely cysteines) at key locations within STAT3, as well as other off-target proteins.

“Some, such as Stattic and some members of the S3I-201 family of compounds, inhibit STAT3 by covalently reacting with residues (largely cysteines) at key locations within STAT3, as well as other off-target proteins (Heidelberger et al., 2013; Ball et al., 2016).”

• cites Heidelberger et al., 2013 sourceNot checked — no full text of the source
• cites Ball et al., 2016 sourcePartly supported

  The Results show that S3I-201 covalently modifies five STAT3 cysteines, and the Discussion reports cysteine modification by Stattic. The paper also reports widespread alkylation of other cellular proteins by S3I-201. It does not establish that covalent modification is the mechanism by which these compounds inhibit STAT3, or show STAT3 protein modification by other S3I-201-family members. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Other approaches currently underway involve modulation of autoregulators of STAT3 activity, such as strategies to activate protein phosphatases, members of the protein inhibitors of activated STAT family, or SOCS protein members.

“Other approaches currently underway involve modulation of autoregulators of STAT3 activity, such as strategies to activate protein phosphatases, members of the protein inhibitors of activated STAT family, or suppressor of cytokine signaling (SOCS) protein members (Heppler and Frank, 2017; Durham et al., 2019).”

• cites Heppler and Frank, 2017 sourcePartly supported

  The Therapeutic Implications of Endogenous STAT Inhibitors section (page unavailable) describes efforts to restore SOCS and PIAS expression and mimic SOCS1 activity. The Concluding Remarks (page unavailable) instead treat investigation of STAT phosphatases as a potential route to future therapies; they do not describe strategies to activate phosphatases as currently underway. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Durham et al., 2019 sourcePartly supported

  The section “Exploiting SOCS interactions as new therapeutic targets” (pp. 11, 13) discusses strategies to enhance SOCS3 function and use SOCS3 mimetics to reduce STAT3 activation. The cited paper supports the SOCS approach, but the passages do not support the sentence’s separate approaches involving activation of protein phosphatases or protein inhibitors of activated STAT. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Ruxolitinib increases body weight in patients with primary myelofibrosis and metastatic pancreatic adenocarcinoma.

“A Phase II trial of the JAK1/2 inhibitor, ruxolitinib, has been shown to increase body weight, in patients with primary myelofibrosis (PMF) and metastatic pancreatic adenocarcinoma”

• cites Jatoi, 2013 sourceNot checked — no full text of the source
• cites Cerchione et al., 2017 sourcePartly supported

  In the case description (page not available), a patient with primary myelofibrosis gained weight to 55 kg after ruxolitinib was restarted in combination with hydroxyurea. The paper is a single-patient case report, not a Phase II trial, and our copy reports no patients with metastatic pancreatic adenocarcinoma. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Activation of STAT3 in pathogenic T cells contributes to colitis by increasing their survival.

“Studies undertaken to tease out the role played by CD4+ cells in IBD determined that activation of STAT3 in pathogenic T cells contributes to colitis by increasing their survival (Kasembeli et al., 2018).”

• cites Kasembeli et al., 2018 sourceSupported

Genetic deletion of STAT3 in innate immune cells, such as myeloid cells (neutrophils and macrophages), and enterocytes results in chronic colitis.

“In contrast, genetic deletion of STAT3 in innate immune cells, such as myeloid cells (neutrophils and macrophages), and enterocytes resulted in chronic colitis (Takeda et al., 1999; Atreya et al., 2000; Yamamoto et al., 2000; Suzuki et al., 2001; Pickert et al., 2009).”

• cites Takeda et al., 1999 sourceNot checked — no full text of the source
• cites Atreya et al., 2000 sourceNot checked — no full text of the source
• cites Yamamoto et al., 2000 sourceCould not verify

  The ‘Anti-IL-6R mAb treatment prevents the development of colitis’ section reports antibody treatment in mice given CD4+ T cells, not genetic deletion of STAT3. Searches for STAT3 deletion in myeloid cells and enterocytes found no passage addressing whether those deletions cause chronic colitis; the paper’s different intervention is not a contradiction. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Jakinibs may increase the risk of secondary malignancy, e.g., lymphoma, in PMF.

“there is a word of caution regarding the use of Jakinibs in PMF as they may increase the risk of secondary malignancy, e.g., lymphoma”

• cites Porpaczy et al., 2018 sourceSupported

IL-6 signaling through STAT3 controls accelerated loss of white adipose tissue, as shown by inhibition of white adipose tissue lipolysis in mice treated with anti-IL-6R antibody.

“IL-6 signaling through STAT3 has been shown to control this process, as evidenced by inhibition of white adipose tissue lipolysis in mice treated with anti–IL-6R antibody”

• cites Babaei et al., 2018 sourcePartly supported

  The section on transient IL-6 family activation reports that lipolytic stimulation raises IL-6 and IL-11, activating Jak/Stat3 in adipocyte progenitors. The Discussion says Stat3 activation depended on lipolysis in this model, rather than showing that IL-6–STAT3 signaling controlled white adipose tissue loss. Our copy does not report inhibition of lipolysis in mice treated with anti–IL-6R antibody. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Wang et al., 2018aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Among the genes linked to IBD susceptibility are some related to intestinal mucosal immune responses, including STAT3.

“Among these genes are included some related to intestinal mucosal immune responses, including STAT3 (Lees et al., 2011; Kasembeli et al., 2018).”

• cites Lees et al., 2011 sourceNot checked — no full text of the source
• cites Kasembeli et al., 2018 sourceSupported

TGF-β1 signaling can induce STAT3-dependent fibrotic responses by phosphorylation and activation of JAK2.

“TGF-β1 signaling can induce STAT3-dependent fibrotic responses by phosphorylation and activation of JAK2”

• cites Zhang et al., 2015 sourceSupported

Inhibition of STAT3 with TTI-101 reverses muscle loss in cachexia models by suppressing MAFbx/Atrogin-1 and MuRF1 expression and reducing caspase-3 activity.

“Inhibition of STAT3 with TTI-101 reversed muscle loss in both cachexia models by suppressing the expression of MAFbx/Atrogin-1 and MuRF1 and reducing caspase-3 activity”

• cites Silva et al., 2015 sourcePartly supported

  The Experimental Procedures and Discussion identify the inhibitor used as C188-9, not TTI-101; our copy does not establish that the names refer to the same compound. The paper reports that C188-9 preserved muscle mass in C26 tumor-bearing mice, reduced MAFbx/Atrogin-1 and MuRF-1 expression, and blocked a marker of caspase-3 proteolytic activity. The LLC model used muscle-specific Stat3 knockout rather than inhibitor treatment, so the claim that the named drug reversed muscle loss in both models is not supported. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

STAT3 plays a major role in cellular processes driving fibrosis, including fibroblast and myofibroblast proliferation, cell survival, angiogenesis, and cell plasticity.

“STAT3 plays a major role in many of the cellular processes that drive the development and progression of fibrosis, including fibroblast and myofibroblast cell proliferation, cell survival, induction of angiogenesis, and cell plasticity”

• cites Kasembeli et al., 2018 sourceSupported

Mutations in JAK2 are found in 50% to 95% of patients with PV, ET, and PMF, with activating V617F mutation.

“Mutations in JAK2 have been found in a large proportion of patients with chronic MPNs, with estimates ranging from 50% to 95% of patients with PV, ET, and PMF having activating V617F mutation in JAK2.”

• cites Chen et al., 2012 sourceSupported
• cites Vainchenker and Constantinescu, 2013 sourceNot checked — no full text of the source

Proinflammatory cytokines TNF-α, IL-6, and IFN-γ drive catabolic signaling associated with cachexia.

“Proinflammatory cytokines, such as TNF-α, IL-6, and IFN-γ, drive catabolic signaling associated with cachexia”

• cites Mantovani et al., 2000 sourceNot checked — no full text of the source
• cites Miyamoto et al., 2016 sourcePartly supported

  The Background sections on cachexia pathways and cytokine-driven protein degradation link TNF-α and IL-6 to muscle-wasting signaling. They name IL-1, rather than IFN-γ, alongside those cytokines; a search for IFN-γ found no passage supporting that part of the claim. The indexed passages provide no page numbers. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Porporato, 2016 sourceSupported

TTI-101 administration to hepatocyte-specific Pten KO mice, a model of NASH progressing to cirrhosis, reduced liver injury and fibrosis.

“We demonstrated that TTI-101 administration to hepatocyte-specific Pten KO (HepPten-) mice, a model of nonalcoholic steatohepatitis (NASH) progressing to cirrhosis, reduced liver injury and fibrosis”

• cites Jung et al., 2017 sourcePartly supported

  The Results section, “C188-9 Treatment Improves NASH and Liver Function” (page unavailable), reports reduced fibrosis and lower ALT and AST levels in hepatocyte-specific Pten knockout mice. The paper calls the administered compound C188-9, not TTI-101, and describes the mice as developing NASH before HCC; our copy does not establish that this model progresses to cirrhosis or identify the two drug names as equivalent. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Levels of pY-STAT3 are increased in skeletal muscle in mouse models of cachexia, including chronic kidney disease and cancer.

“Levels of pY-STAT3 are increased in skeletal muscle in mouse models of cachexia, including models of chronic kidney disease (Zhang et al., 2013a) and cancer (Silva et al., 2015).”

• cites Zhang et al., 2013aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Silva et al., 2015 sourceSupported

In clinical trials, CDDO-Me showed therapeutic activities against several types of cancers.

“In clinical trials, CDDO-Me showed therapeutic activities against several types of cancers.”

• cites Wang et al., 2014Not checked — no full text of the source
• cites Hong et al., 2012 sourceSupported

CDDO-Me has a slow and saturable oral absorption.

“Pharmacokinetic parameters suggest that CDDO-Me has a slow and saturable oral absorption, long terminal-phase half-life (39 hours at 900 mg/day), nonlinear dose-dependent exposures at high doses (600–1300 mg/day), and high interpatient variability.”

• cites Hong et al., 2012 sourceSupported

CDDO-Me has nonlinear dose-dependent exposures at high doses (600-1300 mg/day).

“Pharmacokinetic parameters suggest that CDDO-Me has a slow and saturable oral absorption, long terminal-phase half-life (39 hours at 900 mg/day), nonlinear dose-dependent exposures at high doses (600–1300 mg/day), and high interpatient variability.”

• cites Hong et al., 2012 sourceSupported

Dose-limiting toxicities of CDDO-Me were grade 3 liver transaminase elevations that were reversible.

“Dose-limiting toxicities were grade 3 liver transaminase elevations that were reversible.”

• cites Hong et al., 2012 sourceSupported

CDDO-Me has high interpatient variability.

“Pharmacokinetic parameters suggest that CDDO-Me has a slow and saturable oral absorption, long terminal-phase half-life (39 hours at 900 mg/day), nonlinear dose-dependent exposures at high doses (600–1300 mg/day), and high interpatient variability.”

• cites Hong et al., 2012 sourceSupported

OPB-111077 demonstrated only modest responses against unselected tumors with objective responses in only two patients with diffuse large B-cell lymphoma.

“OPB-OPB‐111077 demonstrated only modest responses against unselected tumors with objective responses observed in only two patients with diffuse large B‐cell lymphoma.”

• cites Tolcher et al., 2018 sourcePartly supported

  The Discussion says OPB-111077 had minimal clinical activity against unselected tumors overall, supporting the claim of modest responses. But it reports a partial response in one subject with diffuse large B-cell lymphoma, not objective responses in two. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

The overall data appeared encouraging enough to support continued development of other synthetic triterpenoids as anticancer agents.

“Overall, the data appeared encouraging enough to support continued development of other synthetic triterpenoids as anticancer agents (Hong et al., 2012).”

• cites Hong et al., 2012 sourceSupported

Nrf2 plays a prominent role in kidney function.

“Because targeting of Keap1 with CDDO-Me can induce nuclear factor erythroid 2–related factor 2, which plays a prominent role in kidney function (Tanaka et al., 2008), it has been evaluated in Phase I/II trials for clinical activity in patients with moderate to severe chronic kidney disease.”

• cites Tanaka et al., 2008 sourcePartly supported

  The Discussion (page not provided) concludes that Nrf2 target-gene induction protects kidneys from FeNTA-induced oxidative damage. That supports an important role in renal protection, but the paper does not establish the broader claim that Nrf2 plays a prominent role in kidney function generally. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

CDDO-Me has a long terminal-phase half-life (39 hours at 900 mg/day).

“Pharmacokinetic parameters suggest that CDDO-Me has a slow and saturable oral absorption, long terminal-phase half-life (39 hours at 900 mg/day), nonlinear dose-dependent exposures at high doses (600–1300 mg/day), and high interpatient variability.”

• cites Hong et al., 2012 sourceSupported

Subsequent studies by Khan et al. (2018) showed that GLG-801 has direct antitumor activity in two breast cancer mouse models.

“Subsequent studies published recently by Khan et al. (2018) showed that GLG-801 has direct antitumor activity in two breast cancer mouse models.”

• cites Khan et al., 2018 sourcePartly supported

  The Discussion (page unavailable) reports that pyrimethamine (PYR) inhibited tumor growth in mouse models of transplanted and spontaneous breast cancer, including a direct effect on cancer cells. The paper does not identify PYR as GLG-801, so our copy cannot verify the claim under that drug name. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Studies performed in parallel with other STAT3 inhibitors previously shown to target mtSTAT3 were confirmatory.

“Our studies showed that TTI-101 did not affect mitochondrial ATP generation or oxygen consumption, whereas studies performed in parallel with other STAT3 inhibitors previously shown to target mtSTAT3 (Genini et al., 2017) were confirmatory (data not shown).”

• cites Genini et al., 2017 sourceSupported

TTI-101 demonstrated potent antitumor activity in several preclinical cancer models, including NSCLC, head and neck squamous cell carcinoma, hepatocellular carcinoma, and ER-positive breast cancer resistant to inhibitors of cyclin-dependent kinases.

“TTI-101 demonstrated potent antitumor activity in several preclinical cancer models, including NSCLC (Lewis et al., 2015), head and neck squamous cell carcinoma (Bharadwaj et al., 2016a), hepatocellular carcinoma (Jung et al., 2017), and ER-positive breast cancer resistant to inhibitors of cyclin-dependent kinases (Kettner et al., 2019).”

• cites Lewis et al., 2015 sourcePartly supported

  The Abstract Results and Discussion (page numbers unavailable) report that C188-9 inhibited NSCLC cell growth and reduced tumor growth in A549 mouse xenografts. Lewis et al. do not identify C188-9 as TTI-101, so our copy does not establish the compound-name link. The other cancer models have separate citations in the citing sentence and are not attributed to Lewis et al. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites Bharadwaj et al., 2016aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Jung et al., 2017 sourcePartly supported

  The Results section ('C188-9 Treatment Resulted in Tumor Growth Arrest'; page unavailable) reports significantly slower tumor growth in the HCC mouse model. This supports the HCC portion of the citing sentence, but our copy calls the compound C188-9 and does not establish that it is TTI-101. The other cancer models have separate citations in the citing sentence and are not attributed to this paper. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

Toxicities observed in Phase I/II studies of OPB-31121 that halted its further development resulted from its targeting of mtSTAT3.

“The toxicities observed in Phase I/II studies of OPB-31121 that halted its further development resulted from its targeting of mtSTAT3 (Genini et al., 2017).”

• cites Genini et al., 2017 sourcePartly supported

  In the section “OPB-51602 Inhibits STAT3 by Binding to the SH2D” (page not supplied), the paper includes OPB-31121 in a cell-based mitochondrial membrane-potential assay, but establishes mSTAT3-dependent cytotoxicity specifically for OPB-51602. The References list Phase I studies of OPB-31121; our copy does not establish that mtSTAT3 targeting caused toxicities in those patients or that toxicities halted the drug’s development. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

Daily administration of TTI-101 for 14 days skewed T cell development away from Th17 cells toward Th1 cells, phenocopying mice that transgenically express a dominant-negative STAT3 mutation.

“Specifically, daily administration of TTI-101 for 14 days skewed T cell development away from Th17 cells toward Th1 cells, thereby phenocopying mice that transgenically express a dominant-negative STAT3 mutation (Steward-Tharp et al., 2014).”

• cites Steward-Tharp et al., 2014 sourcePartly supported

  The section ‘Mut-Stat3 mice recapitulate biochemical and functional features of human HIES’ (page not provided) reports impaired IL-17 expression in the mutant mice, supporting the Th17 part of the comparison. It says Th1 polarization was unchanged and IFN-γ-positive Th-cell numbers were similar to controls, so it does not support a shift toward Th1. The TTI-101 treatment result is the citing authors’ finding, not a result attributed to this source. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Pyrimethamine was identified as a STAT3 inhibitor using a cell-based functional screen of a Preswick library of compounds.

“It was identified as a STAT3 inhibitor using a cell-based functional screen of a Preswick library of compounds.”

• cites Takakura et al., 2011 sourceSupported

Early studies demonstrated that GLG-801 inhibited STAT3 activation and renal cyst formation in a mouse model of polycystic kidney.

“Early studies demonstrated that GLG-801 inhibited STAT3 activation and renal cyst formation in a mouse model of polycystic kidney (Takakura et al., 2011).”

• cites Takakura et al., 2011 sourcePartly supported

  The Introduction reports that pyrimethamine and S3I-201 inhibited cyst formation and growth in adult-onset and neonatal PKD mouse models, respectively. The S3I-201 results also report reduced pSTAT3-positive kidney cells. The paper does not identify either compound as GLG-801 or report these effects for GLG-801, so the named-drug attribution is unsupported. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Modestly increased numbers of peripheral blood mononuclear cells with myeloid markers were seen in TTI-101-treated animals, which phenocopied mice with myeloid-lineage-specific deletion of STAT3.

“In addition, modestly increased numbers of peripheral blood mononuclear cells with myeloid markers were seen in treated animals, which phenocopied mice with myeloid-lineage–specific deletion of STAT3 (Lee et al., 2002).”

• cites Lee et al., 2002 sourcePartly supported

  In “Granulopoiesis in the Absence of STAT3” (page unavailable), Lee et al. report an increased percentage of peripheral-blood neutrophils in STAT3-deficient mice, supporting the claimed resemblance in myeloid-cell phenotype. However, they studied Mx-Cre-mediated STAT3 deletion in hematopoietic progenitors, not myeloid-lineage-specific deletion, and did not report increased numbers of peripheral blood mononuclear cells bearing myeloid markers. The treated animals’ result belongs to the citing study, not Lee et al. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Exposure of mice to TTI-101 has modest and expected effects on T cell subsets and myeloid cells.

“Exposure of mice to TTI-101 has modest and expected effects on T cell subsets and myeloid cells.”

• cites Steward-Tharp et al., 2014 sourceCould not verify

  The C. rodentium infection and Discussion passages examine T cells and myeloid cells in mice with mutant STAT3, not mice exposed to TTI-101. Searches for TTI-101 and drug-treatment effects found no passage in our copy assessing whether its effects on those cells are modest or expected. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites Lee et al., 2002 sourceCould not verify

  The Granulopoiesis in the Absence of STAT3 section (Table 1; page unavailable) reports neutrophil and lymphocyte counts after induced STAT3 deletion in mice, not after TTI-101 exposure. Searches for TTI-101 and T-cell subsets found no passage addressing the claimed treatment effects. (LLM, conf=0.77)

  Experimental — accuracy not yet measured

No serious active pharmaceutical ingredient-attributable AEs have been observed to date in the Phase I study of TTI-101.

“No serious active pharmaceutical ingredient–attributable AEs have been observed to date.”

TTI-101 did not affect mitochondrial ATP generation or oxygen consumption in DU145 and HS358 cells.

“Our studies showed that TTI-101 did not affect mitochondrial ATP generation or oxygen consumption, whereas studies performed in parallel with other STAT3 inhibitors previously shown to target mtSTAT3 (Genini et al., 2017) were confirmatory (data not shown).”

Persistent or dysregulated JAK/STAT3 signaling is maladaptive and contributes to many diseases, including chronic inflammation, fibrosis, and cancer.

“Persistent or dysregulated JAK/STAT3 signaling, however, is maladaptive and contributes to many diseases, including diseases characterized by chronic inflammation and fibrosis, and cancer.”

STAT3 knockout in all cells causes embryonic lethality at 7 days.

“Embryonic lethal at 7 days”

• cites Takeda et al., 1997 sourceNot checked — no full text of the source

Multiple growth factors also signal via activation of STAT3.

“Similarly, multiple growth factors also signal via activation of STAT3 (Bharadwaj et al., 2016b).”

• cites Bharadwaj et al., 2016bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

STAT3 knockout in hematopoietic-derived cells impairs dendritic cell function with defective transition of CMP/CLP to common DC precursors.

“Impaired DC function: defective transition of CMP/CLP to common DC precursors”

• cites Laouar et al., 2003 sourceNot checked — no full text of the source

AD-HIES primary immune defects include impaired barrier functions, especially of the skin and respiratory tract, due to delayed wound healing.

“impaired barrier functions, especially of the skin and respiratory tract, due to delayed wound healing”

• cites Table 1Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

JAK3 is constitutively active in human platelets.

“JAK3, which is constitutively active in human platelets”

• cites Rodriguez-Linares and Watson, 1994 sourceNot checked — no full text of the source
• cites Witthuhn et al., 1999 sourceNot checked — no full text of the source
• cites Imada and Leonard, 2000 sourceNot checked — no full text of the source

Thrombin treatment activates STAT1 and STAT3.

“Thrombin treatment activates STAT1 and STAT3”

• cites Tibbles et al., 2001 sourceNot checked — no full text of the source

Bone marrow cell-specific STAT3 knockout impairs myeloid cells resulting in Crohn's disease-like pathology.

“Impaired myeloid cells resulting in Crohn’s disease-like pathology”

• cites Welte et al., 2003 sourceNot checked — no full text of the source

Attenuating STAT3 and NF-κB signaling in immature dendritic cells leads to systemic dendritic cell dysfunction in non-small cell lung cancer.

“attenuating STAT3 and NF-κB signaling in immature DCs leads to systemic DC dysfunction in non-small cell lung cancer (NSCLC)”

• cites Li et al., 2017Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Platelets from JAK3-deficient mice display reduced thrombin-induced increases in pY-STAT1 and pY-STAT3.

“platelets from JAK3-deficient mice displayed reduced thrombin-induced increases in pY-STAT1 and pY-STAT3”

• cites Tibbles et al., 2001 sourceNot checked — no full text of the source

SOCS3 regulates leptin/pY-Jak2/pY-STAT3 signaling in the hypothalamus, causing leptin resistance.

“SOCS3 also regulates leptin/pY-Jak2/pY-STAT3 signaling in the hypothalamus, causing leptin resistance”

• cites Bjorbaek et al., 1999Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Howard et al., 2004 sourceNot checked — no full text of the source
• cites Mori et al., 2004 sourceNot checked — no full text of the source

Jak2/STAT3-mediated lipolysis is mediated through reduced levels of fatty acid synthase, acetyl-CoA carboxylase, and acyl-CoA oxidase.

“and reduced levels of fatty acid synthase, acetyl-CoA carboxylase, and acyl-CoA ocxidase (Xu et al., 2013).”

• cites Xu et al., 2013Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

STAT3 has a role in lipolysis.

“suggesting a role of STAT3 in lipolysis”

Th17 cells are perturbed by ghrelin through its antagonization of leptin/STAT3 signaling.

“Th17 cells were shown to be perturbed by the orexigenic adipocyte-derived hormone, Ghrelin”

• cites Xu et al., 2015Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

JAK2, STAT1, and STAT3 are activated by oxidized low-density lipoprotein.

“JAK2, STAT1, and STAT3 are activated by oxidized low-density lipoprotein (Maziere et al., 2001)”

• cites Maziere et al., 2001 sourceNot checked — no full text of the source

Jak2/STAT3-mediated lipolysis is mediated through upregulation of adipose triglyceride lipase expression.

“Jak2/STAT3-mediated lipolysis is mediated through its ability to upregulate adipose triglyceride lipase expression (Li et al., 2010b)”

• cites Li et al., 2010bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

STAT3 is involved in liver maintenance of glucose homeostasis by adjusting glucose production to achieve energy balance.

“STAT3 is involved in liver maintenance of glucose homeostasis by adjusting glucose production to achieve energy balance.”

The STAT3 pathway is essential for glucose homeostasis.

“The STAT3 pathway, thus, is essential for glucose homeostasis and may provide a novel therapeutic target for obesity.”

STAT3 transcriptionally activates genes of several anti-autophagy-related proteins e.g., BCL2, BCL2L1, and MCL1.

“STAT3 transcriptionally activates genes of several anti-autophagy–related proteins e.g., BCL2, BCL2L1, and MCL1 (Fukada et al., 1996; Bromberg et al., 1999; Bowman et al., 2000).”

• cites Fukada et al., 1996 sourceNot checked — no full text of the source
• cites Bromberg et al., 1999 sourceNot checked — no full text of the source
• cites Bowman et al., 2000 sourceNot checked — no full text of the source

Peroxide treatment induces homodimerization of STAT3 through disulfide bonding of cysteines within the amino terminus of STAT3.

“Peroxide treatment induced homodimerization of STAT3 formation through a disulfide bonding of cysteines within the amino terminus of STAT3 (Li and Shaw, 2004).”

• cites Li and Shaw, 2004 sourceNot checked — no full text of the source

In hemorrhagic shock, both NF-κB and STAT3 are activated in lungs and livers in an iNOS-dependent manner.

“Examination of hemorrhagic shock in induced iNOS-KO mice or following administration of an iNOS inhibitor demonstrated that both NF-κB and STAT3 were activated in the lungs and livers in an iNOS-dependent manner (Hierholzer et al., 1998a)”

• cites Hierholzer et al., 1998aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

JAK2-mediated Y705 phosphorylation is blocked by S-glutathionylation of C328 and C542 within the DNA binding domain and Linker domain of STAT3.

“JAK2-mediated Y705 phosphorylation also was blocked (Butturini et al., 2014) by S-glutathionylation of C328 and C542 within the DNA binding domain and Linker domain of STAT3, respectively.”

• cites Butturini et al., 2014 sourceNot checked — no full text of the source

Targeting IL-6/STAT3 signaling may be a viable strategy for bypassing senescence-induced chemoresistance.

“indicating that targeting IL-6/STAT3 signaling may be a viable strategy for bypassing senescence-induced chemoresistance.”

Ischemia followed by 15 minutes of reperfusion in the lung induces STAT3 and NF-κB nuclear translocation.

“Ischemia followed by 15 minutes of reperfusion in the lung induces STAT3 and NF-κB nuclear translocation (Farivar et al., 2006).”

• cites Farivar et al., 2006 sourceNot checked — no full text of the source

STAT3 is essential for both the early ROS increase and the later senescence-associated-β-galactosidase activity through STAT3-regulated soluble factor IGFBP5 in human fibroblasts and vascular endothelial cells.

“STAT3 was similarly described to be essential for both the early ROS increase, as well as the later senescence-associated-β-galactosidase activity, through STAT3-regulated soluble factor insulin-like growth factor binding protein 5 in both human fibroblasts (Udono et al., 2012) and vascular endothelial cells (Kim et al., 2007).”

• cites Udono et al., 2012 sourceNot checked — no full text of the source
• cites Kim et al., 2007 sourceNot checked — no full text of the source

Cytoplasmic STAT3 inhibits autophagy by inhibiting eukaryotic translation initiation factor 2-α kinase 2 activity, by binding to its catalytic domain, thereby preventing formation of phosphorylated eIF2α.

“In contrast to nuclear STAT3, cytoplasmic STAT3 inhibits autophagy by inhibiting eukaryotic translation initiation factor 2-α kinase 2 activity, by binding to its catalytic domain, thereby inhibiting its enzymatic activity, thereby preventing formation of phosphorylated eukaryotic translation initiation factor 2-α, a known autophagy activator (Shen et al., 2012).”

• cites Shen et al., 2012 sourceNot checked — no full text of the source

iNOS inhibition results in marked reduction of lung and liver injury.

“and that iNOS inhibition resulted in a marked reduction of lung and liver injury.”

• cites Hierholzer et al., 1998aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

STAT3 is essential for the protective effects of heme oxygenase-1 in oxidant-induced lung injury.

“STAT3 also is essential for the protective effects of heme oxygenase-1 in oxidant-induced lung injury (Zhang et al., 2006).”

• cites Zhang et al., 2006 sourceNot checked — no full text of the source

In lung models of in vitro anoxia-reoxygenation and in vivo I/R, carbon monoxide attenuates endothelial cell apoptosis through enhanced STAT3 activation via PI3K/Akt and p38 MAPK pathways.

“In studies of lung models of in vitro anoxia–reoxygenation and in vivo I/R, carbon monoxide attenuated endothelial cell apoptosis presumably through enhanced STAT3 activation via PI3K/Akt and p38 MAPK pathways (Zhang et al., 2003, 2005).”

• cites Zhang et al., 2003 sourceNot checked — no full text of the source
• cites Zhang et al., 2005 sourceNot checked — no full text of the source

Each of these STAT3 inhibitors demonstrates the ability to inhibit the growth of one or more cancer cell lines owing in some instances to their inhibition of STAT3 binding to its pY-peptide ligands and blocking IL-6-induced STAT3 activation, nuclear translocation, and transcriptional gene activation.

“Each demonstrates the ability to inhibit the growth of one or more cancer cell lines owing in some instances to their inhibition of STAT3 binding to its pY-peptide ligands and blocking IL-6–induced STAT3 activation, nuclear translocation, and transcriptional gene activation (Zhang et al., 2013c).”

• cites Zhang et al., 2013cNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Administration of STAT1/3 decoy oligonucleotides or the Jakinib Tyr1A mitigates airway inflammation and airway hyper-responsiveness in lungs of mice challenged with HDM.

“Administration of STAT1/3 decoy oligonucleotides or the Jakinib, Tyr1A, was shown to mitigate airway inflammation and airway hyper-responsiveness in lungs of mice challenged with HDM (Simeone-Penney, 2008).”

• cites Simeone-Penney, 2008Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

All Jakinibs in use or undergoing clinical trials to this point in time are ATP analogs that target the kinase (JH1) domain.

“All Jakinibs in use or undergoing clinical trials to this point in time are ATP analogs that target the kinase (JH1) domain (Fig. 1).”

Targeting JAK/STAT3 signaling may be of benefit in the treatment of neutrophilic, steroid-resistant asthma.

“Targeting JAK/STAT3 signaling may be of benefit in the treatment of neutrophilic, steroid-resistant asthma.”

The Jakinib ruxolitinib reduces food allergy manifestations in mice through prevention of mast cell hyperplasia and inhibition of mast cell activation.

“The Jakinib, ruxolitinib, was shown to reduce food allergy manifestations in mice through prevention of mast cell hyperplasia and inhibition of mast cell activation (Yamaki and Yoshino, 2014).”

• cites Yamaki and Yoshino, 2014 sourceNot checked — no full text of the source

Diseases may result from both diminished and aberrantly augmented STAT3 activity in various cells, tissues, and organs.

“As is evident from the above discussions and Table 2, diseases may result from both diminished and aberrantly augmented STAT3 activity in various cells, tissues, and organs.”

JAK/STAT3 inhibition may prevent anaphylaxis in those suffering from severe allergies to peanuts or other allergens.

“raises the possibility of using JAK/STAT3 inhibition to prevent anaphylaxis in those suffering from severe allergies to peanuts or other allergens that are low-level contaminates of many foods.”

STAT3 inhibition interferes with a common pathway regulating vascular permeability.

“Together with the findings in the mut-Stat3 mice described above, these results suggest that STAT3 inhibition interferes with a common pathway regulating vascular permeability”

Pharmacological blockade of STAT3 in HDM-challenged mice with TTI-101 (C188-9) inhibits allergen-induced STAT3 phosphorylation, resulting in reduction in airway inflammation and remodeling.

“Pharmacological blockade of STAT3 in HDM-challenged mice with TTI-101 (C188-9) inhibited allergen-induced STAT3 phosphorylation, resulting in concomitant reduction in airway inflammation and remodeling.”

• cites Gavino et al., 2016 sourceNot checked — no full text of the source

Approaches based on siRNA and short hairpin RNA targeting of STAT3 activity have resulted in development of a naked antisense oligonucleotide-based drug, AZD9150 (IONIS-STAT3-2.5Rx or danvatirsen), which has entered Phase II clinical trials in cancer patients.

“Approaches based on siRNA and short hairpin RNA targeting of STAT3 activity have resulted in the development of a naked antisense oligonucleotide–based drug, AZD9150 (IONIS-STAT3-2.5Rx or danvatirsen), which has entered Phase II clinical trials in cancer patients (see below).”

Persistently activated STAT3 within cardiomyocytes results in a worse outcome following MI due, in part, to increased inflammation.

“However, persistently activated STAT3 within cardiomyocytes resulted in a worse outcome following MI due, in part, to increased inflammation (Hilfiker-Kleiner et al., 2010).”

• cites Hilfiker-Kleiner et al., 2010 sourceNot checked — no full text of the source

Targeting JAK and STAT3 with small-molecule inhibitors may provide a superior anti-asthma treatment approach compared with standard therapies as they would target both Th2- and Th17-associated asthmas.

“The data summarized above suggest that targeting JAK and STAT3 with small-molecule inhibitors may provide a superior anti-asthma treatment approach compared with standard therapies as, they would target both Th2- and Th17-associated asthmas (Choy et al., 2015).”

• cites Choy et al., 2015 sourceNot checked — no full text of the source

STAT3 inhibitors identified by structure-based high-throughput virtual screening include STA-21, Stattic, S3I-201/NSC74859, BP-1-102, OPB-31121, TTI-101 (C188-9), and their analogs.

“STAT3 inhibitors identified by structure-based high-throughput virtual screening include STA-21, Stattic (Stat three-inhibitory compound), S3I-201/NSC74859, BP-1-102, OPB-31121, TTI-101 (C188-9), and their analogs.”

Treatment of mice in a chronic-binge ethanol feeding model with STAT3-inducing cytokines IL-6/IL-22 ameliorates fat accumulation in hepatocytes.

“Treatment of mice in a murine model of chronic-binge ethanol feeding with STAT3-inducing cytokines, e.g., IL-6/IL-22, ameliorates fat accumulation in hepatocytes”

• cites Wang et al., 2004aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Ki et al., 2010Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Hepatocyte-specific gp130- or STAT3-KO mice exhibit exacerbated steatosis induced by choline-deficient, methionine-supplemented diet, alcohol-containing diet, or high-fat diet.

“hepatocyte-specific gp130- or STAT3-KO mice exhibit exacerbated steatosis induced by a choline-deficient, methionine-supplemented diet; alcohol-containing diet; or a high-fat diet”

• cites Kroy et al., 2010 sourceNot checked — no full text of the source

The IL-6/JAK2/STAT3 signaling pathway is a valid target to treat NASH, non-alcoholic fatty liver disease, and insulin resistance, especially in the setting of obesity and type 2 diabetes.

“Thus, the IL-6/JAK2/STAT3 signaling pathway is a valid target to treat NASH, non-alcoholic fatty liver disease, and insulin resistance, especially in the setting of obesity and type 2 diabetes.”

Activated IL-6/STAT3 in non-alcoholic fatty liver disease is associated with increased insulin resistance.

“Activated IL-6/STAT3 in non-alcoholic fatty liver disease is associated with increased insulin resistance”

• cites Min et al., 2015 sourceNot checked — no full text of the source

JAK activity contributes to cellular transformation and tumorigenesis through mechanisms including increased constitutive activation of upstream receptors, increased receptor expression or genetic alterations in cytokine receptors, disruption of negative regulators, and JAK mutations.

“There are several ways in which JAK activity contributes to cellular transformation and tumorigenesis. These include the following: 1) increased constitutive activation of upstream receptors due to overproduction of stimulating ligands; 2) increased receptor expression, or genetic alterations in cytokine receptors that constitutively induce JAK activation; 3) disruption of negative regulators of J”

Fibrotic tissue samples from patients often show elevated levels of pY-STAT3.

“Fibrotic tissue samples from patients often show elevated levels of pY-STAT3”

• cites Ogata et al., 2006 sourceNot checked — no full text of the source

CDDO-Me may be beneficial in patients with moderate to severe chronic kidney disease.

“Data from these studies demonstrated a significant increase from baseline in estimated glomerular filtration rate, a measure of improved kidney function, which suggested that CDDO-Me may be beneficial in these patients.”

• AssumptionRests on an assumption: In Phase I/II trials of CDDO-Me in patients with moderate to severe chronic kidney disease, data demonstrated a significant increase from baseline in estimated glomerular filtration rate.

Screening experiments show that CDDO-Me inhibits a wide range of targets in addition to STAT3, including PPARγ, Keap1, and inhibitory NF-κB kinase.

“Screening experiments show that CDDO-Me inhibits a wide range of targets in addition to STAT3, including PPARγ, kelch-like ECH-associated protein 1 (Keap1), and inhibitory NF-κB kinase.”

• cites Wang et al., 2014Not checked — no full text of the source

A subsequent Phase III trial of CDDO-Me was terminated in chronic kidney disease patients due to a high rate of cardiovascular events when compared with placebo.

“However, a subsequent Phase III trial was terminated in chronic kidney disease patients due to a high rate of cardiovascular events when compared with placebo (Nezu et al., 2017).”

• cites Nezu et al., 2017 sourceNot checked — no full text of the source

Limited effectiveness and toxicities of Jakinibs have provided impetus to develop inhibitors of molecular targets downstream of JAK, such as STAT3.

“The limited effectiveness and toxicities of Jakinibs have provided an impetus to develop inhibitors of molecular targets downstream of JAK, such as STAT3.”

Napabucasin may have activity toward targets other than STAT3.

“Napabucasin treatment also appeared to inhibit multiple self-renewal pathways, suggesting that it may have activity toward targets other than STAT3 (Li et al., 2015).”

• cites Li et al., 2015Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Inhibition of Keap1 leads to activation of Nrf2.

“Inhibition of Keap1 leads to activation of the nuclear factor erythroid 2–related factor 2, an oxidative stress response transcription factor known to activate a variety of cytoprotective genes (Wang et al., 2014).”

• cites Wang et al., 2014Not checked — no full text of the source

Napabucasin treatment inhibits multiple self-renewal pathways.

“Napabucasin treatment also appeared to inhibit multiple self-renewal pathways, suggesting that it may have activity toward targets other than STAT3 (Li et al., 2015).”

• cites Li et al., 2015Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

No toxicity attributed to CDDO-Me administration was observed in a Phase I clinical trial RTA 402-C-0702 for pancreatic adenocarcinomas in which gemcitabine was combined with oral CDDO-Me at doses of 150 to 300 mg/day.

“Of note, no toxicity attributed to CDDO-Me administration was observed in a Phase I clinical trial RTA 402-C-0702 for pancreatic adenocarcinomas in which gemcitabine was combined with oral administration of CDDO-Me at different doses ranging from 150 to 300 mg/day (Wang et al., 2014).”

• cites Wang et al., 2014Not checked — no full text of the source

Hyperactivation of STAT3 is a salient attribute of many cancers.

“Hyperactivation of STAT3 is a salient attribute of many cancers”

• cites Bromberg et al., 1999 sourceNot checked — no full text of the source
• cites Sriuranpong et al., 2003Not checked — no full text of the source
• cites Bharadwaj et al., 2016bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

JAK/STAT signaling pathway contributes to development and progression of a wide range of both hematologic and solid cancers.

“Taken all together, it is clear that JAK/STAT signaling pathway contributes to the development and progression of a wide range of both hematologic and solid cancers.”

Napabucasin was first identified by its ability to inhibit properties of cancer stemness and STAT3 activity in gel-shift assays.

“It was first identified by its ability to inhibit properties of cancer stemness and STAT3 activity in gel-shift assays (US patent 8,877,803).”

• cites US patent 8,877,803Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In Phase I and II trials, TEAE related to the administration of napabucasin were generally mild and included predominantly grades 1 and 2 GI TEAE.

“Phase I and II trials showed that TEAE related to the administration of the napabucasin were generally mild and included predominantly grades 1 and 2 GI TEAE.”

• cites Jonker et al., 2014 sourceNot checked — no full text of the source
• cites Laurie et al., 2014 sourceNot checked — no full text of the source

Patients with pY-STAT3-positive disease demonstrated significantly improved overall survival when treated with napabucasin (median oxidative stress = 5.1 months) compared with placebo-treated patients (median oxidative stress = 3.0 months).

“However, patients with pY-STAT3–positive disease demonstrated significantly improved overall survival when treated with napabucasin (median oxidative stress = 5.1 months) compared with placebo-treated patients (median oxidative stress = 3.0 months), even though patients with pY-STAT3–positive tumors had a poorer prognosis.”

• cites Hubbard and Grothey, 2017 sourceNot checked — no full text of the source

These inhibitors would not be expected to reduce platelet activity early in hemostasis involving traumatically damaged vessels.

“Importantly, however, these inhibitors would not be expected to reduce platelet activity early in hemostasis involving traumatically damaged vessels.”

• AssumptionRests on an assumption: The scaffold function of STAT3 in platelet activation is mediated by homodimers of pY-STAT3.

TTI-101 potently inhibits STAT3 binding to its pY-peptide ligand [Ki = 12.4 nM].

“TTI-101 potently inhibits STAT3 binding to its pY-peptide ligand [Ki = 12.4 nM (Bharadwaj et al., 2016a)].”

• cites Bharadwaj et al., 2016aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

TTI-101 (C188-9) emerged from a structure-based, drug-design program that began with computer-based docking of 920,000 compounds into the SH2 domain of STAT3 and identified three hits (C3, C30, and C188).

“TTI-101 (C188-9) emerged from a structure-based, drug-design program that began with computer-based docking of 920,000 compounds into the SH2 domain of STAT3 and identified three hits (C3, C30, and C188) (Xu et al., 2009); each hit inhibited STAT3 binding to its pY-peptide ligand, thereby blocking two steps in STAT3 activation—recruitment to activated receptor complexes and homodimerization.”

• cites Xu et al., 2009Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

STAT3 inhibitors that reduce levels of pY-STAT3 would be expected to have similar effects on the levels and activities of other post-translationally modified forms of STAT3.

“Consequently, STAT3 inhibitors that reduce levels of pY-STAT3 would be expected to have similar effects on the levels and activities of these other post-translationally modified forms of STAT3.”

• AssumptionRests on an assumption: Most forms of post-translationally modified STAT3 proteins are modified after their phosphorylation at key tyrosine sites.

Targeting mtSTAT3 to modify aberrant oxidative phosphorylation in cancer cells may have contributed to the anticancer effects of OPB-31121, similar to other agents undergoing clinical study that target this cancer cell vulnerability.

“It is of interest to note that targeting of mtSTAT3 to modify aberrant oxidative phosphorylation in cancer cells may have contributed to the anticancer effects of OPB-31121, similar to other agents undergoing clinical study that target this cancer cell vulnerability (Zhang et al., 2019).”

• cites Zhang et al., 2019 sourceNot checked — no full text of the source

Hit-to-lead strategies focused on the most potent initial hit, C188, and led to TTI-101.

“Hit-to-lead strategies performed in collaboration with Tvardi Therapeutics (formerly StemMed), a clinical-stage drug-development company, focused on the most potent initial hit, C188 (Xu et al., 2009), and led to TTI-101 (Bharadwaj et al., 2016a).”

• cites Xu et al., 2009Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Bharadwaj et al., 2016aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

This may not be the case based on the more limited clinical manifestations observed in patients with Job's syndrome or AD-HIES.

“However, this may not be the case based on the more limited clinical manifestations observed in patients with Job’s syndrome or AD-HIES, as discussed above.”

Pharmacokinetic studies in mice demonstrated tumor levels 2.6 times simultaneously measured plasma levels.

“Pharmacokinetic studies in mice demonstrated tumor levels 2.6 times simultaneously measured plasma levels (Bharadwaj et al., 2016a).”

• cites Bharadwaj et al., 2016aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

A Phase III clinical trial of napabucasin versus placebo in patients with advanced CRC showed no significant difference in unselected patients, with regard to overall survival, progression-free survival, or disease control rate.

“A Phase III clinical trial of napabucasin versus placebo in patients with advanced CRC showed no significant difference in unselected patients, with regard to overall survival, progression-free survival, or disease control rate.”

• cites Hubbard and Grothey, 2017 sourceNot checked — no full text of the source

STAT3 inhibitors that reduce pY-STAT3 could potentially reduce platelet function in inflamed tissue, such as a ruptured atherosclerotic plaque.

“Similarly, because the scaffold function of STAT3 in platelet activation is mediated by homodimers of pY-STAT3, STAT3 inhibitors that reduce pY-STAT3 could potentially reduce platelet function in inflamed tissue, such as a ruptured atherosclerotic plaque.”

• AssumptionRests on an assumption: The scaffold function of STAT3 in platelet activation is mediated by homodimers of pY-STAT3.

There currently are three ongoing Phase III clinical trials involving napabucasin in combination with other standard chemotherapy agents in metastatic CRC, metastatic pancreatic ductal adenocarcinoma, and other advanced malignancies.

“There currently are three ongoing Phase III clinical trials involving napabucasin in combination with other standard chemotherapy agents in metastatic CRC, metastatic pancreatic ductal adenocarcinoma, and other advanced malignancies (Hubbard and Grothey, 2017).”

• cites Hubbard and Grothey, 2017 sourceNot checked — no full text of the source

The impact of reduced pY-STAT3 on the ER function of STAT3 is expected to be minimal.

“Similarly, because the activity of STAT3 in the ER does not require STAT3 to be phosphorylated at Y705, the impact of reduced pY-STAT3 on the ER function of STAT3 is expected to be minimal.”

• AssumptionRests on an assumption: The activity of STAT3 in the ER does not require STAT3 to be phosphorylated at Y705.

Patients with pY-STAT3-positive tumors had a poorer prognosis.

“However, patients with pY-STAT3–positive disease demonstrated significantly improved overall survival when treated with napabucasin (median oxidative stress = 5.1 months) compared with placebo-treated patients (median oxidative stress = 3.0 months), even though patients with pY-STAT3–positive tumors had a poorer prognosis.”

• cites Hubbard and Grothey, 2017 sourceNot checked — no full text of the source

At a daily dose of 400 mg, plasma levels of napabucasin were over its half-maximal inhibitory concentration (1.5 μM) for 8 hours.

“At daily dose of 400 mg, plasma levels of napabucasin were over its half-maximal inhibitory concentration (1.5 µM) for 8 hours (Jonker et al., 2014; Laurie et al., 2014).”

• cites Jonker et al., 2014 sourceNot checked — no full text of the source
• cites Laurie et al., 2014 sourceNot checked — no full text of the source

The mechanism by which GLG-801 inhibits STAT3 activation is not clear.

“While demonstrating efficacy and the ability to block STAT3 activation in preclinical models, the mechanism by which GLG-801 inhibits STAT3 activation is not clear.”

Phase I and II clinical studies demonstrated promising antitumor efficacy when napabucasin was combined with standard chemotherapy agents.

“Phase I and II clinical studies demonstrated promising antitumor efficacy when napabucasin was combined with standard chemotherapy agents (Garcia et al., 2016).”

• cites Garcia et al., 2016 sourceNot checked — no full text of the source

A Phase I/II clinical study is underway in patients with metastatic triple-negative breast cancer.

“A Phase I/II clinical study is underway in patients with metastatic triple-negative breast cancer (EU Clinical Trials Register, 2017).”

• cites EU Clinical Trials Register, 2017Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The above review suggests that targeting STAT3 in adults might result in unacceptable toxicity, including hematopoietic and immune deficiencies, bleeding disorders, metabolic disorders, and a variety of impairments in stress responses.

“The above review of the important contributions of canonical STAT3 signaling in basal and stress conditions suggests that targeting STAT3 in adults might result in unacceptable toxicity, including hematopoietic and immune deficiencies, bleeding disorders, metabolic disorders, and a variety of impairments in stress responses.”

A Phase I trial of WP-1066 in patients with glioblastoma multiforme and melanoma that has metastasized to the brain is currently underway at MD Anderson Cancer Center.

“A Phase I trial of WP-1066 in patients with glioblastoma multiforme and melanoma that has metastasized to the brain is currently underway at MD Anderson Cancer Center (Bharadwaj et al., 2016b).”

• cites Bharadwaj et al., 2016bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.