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

In the paper

“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”

What the sources say

• Disputed

  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.

  cites Heldsinger et al., 2014 sourceExperimental — accuracy not yet measured

In the paper

“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;”

What the sources say

• Disputed

  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.

  cites Resetca et al., 2014 sourceExperimental — accuracy not yet measured
• Partly supported

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

  cites Minus et al., 2015 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Wilks, 1989 source
• ?Not checked — no full text of the sourcecites Firmbach-Kraft et al., 1990
• Partly 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)

  cites Wilks et al., 1991 sourceExperimental — accuracy not yet measured

In the paper

“Impaired injury tolerance”

What the sources say

• Supported

  The Results report that mice with respiratory epithelium-specific Stat-3 deletion were more susceptible to oxygen-induced lung injury and had significantly reduced survival during hyperoxia. The claim is supported for the hyperoxic injury tested in this study. (LLM, conf=0.92)

  cites Hokuto et al., 2004 source

In the paper

“Impaired epithelial wound healing”

What the sources say

• Supported

  In Results and Discussion (page not supplied), the paper identifies STAT3IEC-KO mice as having an intestinal epithelial cell-specific STAT3 deletion. Its in vivo wound-healing experiment found that their colonic wounds healed significantly more slowly than those of controls and remained open at day 6. (LLM, conf=0.95)

  cites Pickert et al., 2009 source

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites Wen et al., 1995 source
• ?Not checked — no full text of the sourcecites Abe et al., 2001 source
• Supported

  The Abstract states that tyrosine phosphorylation activates STAT3 and that serine 727 phosphorylation provides supplemental activation. It also says serine phosphorylation is required for full transcriptional activation. The coactivator mechanism is attached to other citations in the citing sentence, not to Shen et al. (LLM, conf=0.93)

  cites Shen et al., 2004 source

In the paper

“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”

What the sources say

• Partly 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)

  cites Kojima et al., 2013 sourceExperimental — accuracy not yet measured
• ?Could 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)

  cites You et al., 2015 sourceExperimental — accuracy not yet measured
• Partly 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)

  cites Zouein et al., 2015 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Partly 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)

  cites Schmitz et al., 2000 sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites Wen et al., 1995 source
• Supported

  The cited paper reports that ERK-family MAP kinases phosphorylate STAT3 at Ser727 in response to growth factors (Abstract). That supports the ERK/MAPK example to which the Chung et al. citation is attached; this citation is not offered for the sentence’s separate JNK or p38 examples. (LLM, conf=0.93)

  cites Chung et al., 1997 source
• Supported

  The citation to Zhang et al. is attached to JNK as an example of a kinase involved in STAT3 Ser727 phosphorylation. In “Induction of Ser 727,” the paper reports that JNK1 and JNK2 phosphorylated Ser727 in its kinase experiments; the Discussion identifies JNKs as mediators in the UVA response in JB6 cells. The citation does not need to establish the other kinases listed with separate citations. (LLM, conf=0.93)

  cites Zhang et al., 2001 source

In the paper

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

What the sources say

• Supported

  The Introduction states that phosphorylated tyrosine residues on cytokine receptors serve as docking sites for SH2-domain proteins such as STAT transcription factors, which are then recruited to the receptor. This supports the claim about STAT3 docking; the supplied passage has no page number. (LLM, conf=0.91)

  cites Vogt et al., 2011 source

In the paper

“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).”

What the sources say

• Partly 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)

  cites Avalle and Poli, 2018 sourceExperimental — accuracy not yet measured

In the paper

“Impaired hair cycle and skin wound healing”

What the sources say

• Supported

  The Results section reports that Stat3-disrupted mice did not enter the second anagen hair-cycle stage, unlike controls, and that wound healing was retarded in keratinocyte-specific Stat3-disrupted mice. The Discussion likewise describes retarded wound healing in vivo and in vitro. Page numbers were not provided in the supplied passages. (LLM, conf=0.94)

  cites Sano et al., 1999 source

In the paper

“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”

What the sources say

• Partly 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)

  cites Johansen et al., 2001 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Hirai et al., 2006 source
• Supported

  The Introduction reports that STAT3 promotes G-CSF-responsive proliferation of immature granulocytes, directly induces C/EBPβ expression, and regulates G-CSF-dependent c-myc transcription. The Discussion describes STAT3-driven Cebpb transcription and sustained c-myc expression as mechanisms supporting progenitor growth. (LLM, conf=0.94)

  cites Zhang et al., 2010 source

In the paper

“Obesity, diabetes, infertility, and thermal dysregulation”

What the sources say

• Supported

  The Results describe a neural-specific STAT3 deletion in mice. The Abstract reports that surviving mutants were obese, diabetic, and infertile, and became hypothermic after fasting or cold stress; the Results also document impaired temperature maintenance during a cold challenge. (LLM, conf=0.95)

  cites Gao et al., 2004 source

In the paper

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

What the sources say

• Supported

  The Introduction states that AD-HIES is caused by dominant-negative STAT3 mutations and explains that these mutations produce dysfunctional dimers that dilute functional ones. The Discussion likewise describes impaired STAT3 activity in patient cells, supporting the claim’s description of diminished activity from an autosomal-dominant mutation. (LLM, conf=0.91)

  cites Bocchini et al., 2016 source

In the paper

“Increased body weight and adiposity”

What the sources say

• Supported

  The Abstract reports that mice with adipocyte-specific STAT3 disruption weighed more than littermate controls and had increased adipose tissue mass. The Discussion likewise states that loss of STAT3 in mature adipocytes in male mice caused higher body weight and increased adiposity. (LLM, conf=0.95)

  cites Cernkovich et al., 2008 source

In the paper

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

What the sources say

• Supported

  The ‘Emergency and steady state granulopoiesis’ section states directly that STAT3 regulates critical steps during emergency granulopoiesis. It identifies neutrophil release, chemotaxis, and granulocytic progenitor proliferation as examples. (LLM, conf=0.95)

  cites Hillmer et al., 2016 source

In the paper

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

What the sources say

• Supported

  The Abstract (page unavailable) reports that granulocytes developed from STAT3-null bone marrow progenitors and that mice lacking STAT3 in hematopoietic progenitors developed neutrophilia rather than a deficit in granulopoiesis. This supports the claim in the paper’s mouse model. (LLM, conf=0.91)

  cites Lee et al., 2002 source

In the paper

“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”

What the sources say

• ?Could 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)

  cites Zhang et al., 2010 sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Partly 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)

  cites Shah et al., 2018 sourceExperimental — accuracy not yet measured

In the paper

“intrinsic impairments in neutrophil chemotaxis”

What the sources say

• ?Not matched

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

  cites Hill and Quie, 1974
• ?Not matched

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

  cites Hill et al., 1974
• Partly 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)

  cites Panopoulos et al., 2006 sourceExperimental — accuracy not yet measured

In the paper

“Reduced B cell compartments and plasma cells”

What the sources say

• ?Not checked — no full text of the sourcecites Chou et al., 2006 source
• Partly 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)

  cites Fornek et al., 2006 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Supported

  The section “STAT3 Controls Flt3L-Dependent Proliferation” reports that STAT3 was crucial for Flt3L-dependent proliferation and had an important role in DC progenitor proliferation. The Discussion likewise states that STAT3 was necessary for bone-marrow progenitors to proliferate in response to Flt3L. Page numbers are not provided in our copy. (LLM, conf=0.91)

  cites Esashi et al., 2008 source
• ?Not matched

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

  cites Li et al., 2012

In the paper

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

What the sources say

• Supported

  The Results section reports that IL-21 increased megakaryocyte generation from cultured CD34+ progenitors. In the same section, JAK3 and STAT3 inhibitors abolished the IL-21-associated increase, supporting the pathway attribution. The supplied passages do not specify page numbers. (LLM, conf=0.94)

  cites Benbarche et al., 2017 source

In the paper

“STAT3-deficient macrophages, neutrophils, and DCs”

What the sources say

• ?Not checked — no full text of the sourcecites Takeda et al., 1999 source
• Partly 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)

  cites Melillo et al., 2010 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Welte et al., 2003 source

In the paper

“STAT3 suppresses TLR signaling in mature phagocytes”

What the sources say

• ?Not checked — no full text of the sourcecites Takeda et al., 1999 source
• Partly 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)

  cites Melillo et al., 2010 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites El Kasmi et al., 2007 source

In the paper

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

What the sources say

• Partly 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)

  cites Fornek et al., 2006 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• ?Could 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)

  cites Esashi et al., 2008 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Partly 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)

  cites Zhou et al., 2013 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Laouar et al., 2003 source
• Partly 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)

  cites Merad and Manz, 2009 sourceExperimental — accuracy not yet measured
• Partly 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)

  cites Merad et al., 2013 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Schindler et al., 1992 source
• Supported

  The paper describes generating T-cell-specific Stat3-deficient mice and reports that IL-6 failed to prevent apoptosis in their T cells (passage 5). The ‘IL-6 induced Bcl-2 expression in Stat3-deficient T cells’ section reports that Bcl-2 was still up-regulated and concludes that the IL-6/Stat3 antiapoptotic signal acts independently of Bcl-2 (passages 1 and 4). (LLM, conf=0.94)

  cites Takeda et al., 1998 source

In the paper

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

What the sources say

• Partly 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)

  cites Yang and Rincon, 2016 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Partly 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)

  cites Millington, 2007 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• ?Not matched

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

  cites Wang et al., 2011a
• Partly 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)

  cites Cheng et al., 2014 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Supported

  The Results report reduced morphine-induced skin wheals in patients with AD-HIES, a test the paper uses to probe mast cell degranulation. They also report that silencing STAT3 reduced degranulation in primary human mast cells. Together, these findings support the claim, though the cultured mast-cell experiments did not use cells from the patients. (LLM, conf=0.87)

  cites Siegel et al., 2013 source

In the paper

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

What the sources say

• ?Not matched

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

  cites Yang et al., 2008a
• Partly 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)

  cites Laurence et al., 2012 sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Supported

  The paper states that patients with AD-HIES almost all have an eczematous rash and markedly elevated serum IgE. Its Results report lower rates of food hypersensitivity and food anaphylaxis in patients with AD-HIES than in atopic controls with comparably elevated IgE. (LLM, conf=0.94)

  cites Siegel et al., 2013 source

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites Laurence et al., 2007 source
• Partly 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)

  cites Nishihara et al., 2007 sourceExperimental — accuracy not yet measured
• ?Not matched

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

  cites Yang et al., 2007b

In the paper

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

What the sources say

• Partly 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)

  cites Cheng et al., 2014 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Supported

  The Introduction (page not provided) says IL-10 and IL-21 act together to promote mature, self-renewing memory CD8+ T cells, and that the pathway sustains BCL-6, Eomes, and Blimp-1 during the effector-to-memory transition. The Results section (page not provided) also reports reduced levels of all three factors in memory CD8+ T cells lacking STAT3. (LLM, conf=0.94)

  cites Cui et al., 2011 source
• Partly 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)

  cites Kaech and Cui, 2012 sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Partly supported

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

  cites Hox et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Partly 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)

  cites Yang et al., 2015 sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites Li and Shaw, 2004 source
• Partly 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)

  cites Xie et al., 2009 sourceExperimental — accuracy not yet measured
• ?Not matched

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

  cites Li et al., 2010a

In the paper

“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).”

What the sources say

• Supported

  The Discussion describes STAT3-mediated suppression of insulin signaling by amino acids as dependent on Ser 727 phosphorylation and independent of tyrosine phosphorylation. The section on mTOR-dependent Ser 727 phosphorylation reports that rapamycin abolished amino acid–stimulated phosphorylation in mouse primary hepatocytes. Page numbers are unavailable in our copy. (LLM, conf=0.93)

  cites Kim et al., 2009 source

In the paper

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

What the sources say

• Supported

  The Results report that pSTAT3-S727 levels positively correlated with intrinsic radioresistance in 15 human glioma cell lines. The Abstract also reports radiosensitization accompanied by reduced pSTAT3-S727 in certain GBM cell lines, supporting the citing sentence’s hedged claim. (LLM, conf=0.93)

  cites Ouédraogo et al., 2016 source

In the paper

“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).”

What the sources say

• Supported

  The Discussion states that STAT3 activates LPL transcription and that CLL cells use stored lipids for energy in an LPL-dependent process driven by STAT3. The Introduction identifies constitutive serine phosphorylation of STAT3 in CLL and says LPL hydrolyzes triglycerides into free fatty acids. (LLM, conf=0.94)

  cites Rozovski et al., 2015 source

In the paper

“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).”

What the sources say

• ?Not matched

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

  cites Chan et al., 2004a,b
• ?Not matched

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

  cites Aziz et al., 2007a,b
• Partly 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)

  cites Barry et al., 2010 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Supported

  The Discussion reports that constitutively activated Stat3 protected fibroblasts from apoptosis induced by UV irradiation. This supports the hedged claim, specifically as protection from UV-induced apoptosis in the cells studied. (LLM, conf=0.92)

  cites Shen et al., 2001 source
• ?Not matched

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

  cites Chan et al., 2004b
• ?Not checked — no full text of the sourcecites Sano et al., 2005 source

In the paper

“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).”

What the sources say

• Supported

  The Abstract reports that leptin induces SOCS3 through JAK–STAT3/5b signaling and that SOCS3 inhibits STAT3/5b-dependent preproinsulin 1 promoter activity. The Discussion clarifies that STAT3 itself activates the promoter; the inhibitory effect attributed to the leptin pathway is mediated downstream, rather than by STAT3 acting alone. (LLM, conf=0.90)

  cites Laubner et al., 2005 source

In the paper

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

What the sources say

• Supported

  The section on SOCS3 inhibition of the rINS-1 promoter reports that SOCS3 overexpression inhibits STAT3-dependent transactivation of the rat preproinsulin 1 promoter in INS-1 cells. The Discussion reiterates that SOCS3 inhibits promoter activity stimulated by STAT3. (LLM, conf=0.94)

  cites Laubner et al., 2005 source

In the paper

“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)”

What the sources say

• Supported

  The citation to Xie et al. is attached to the HepG2-cell finding, not the findings in endothelial or cardiac cells. The Discussion reports that diamide, oxidized glutathione, and PDTC increased STAT3 S-glutathionylation while reducing IL-6-induced STAT3 phosphorylation; the STAT3 S-glutathionylation section identifies the treated cells as HepG2 cells. No page numbers are available in our copy. (LLM, conf=0.94)

  cites Xie et al., 2009 source
• Partly 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)

  cites Zgheib et al., 2012 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Supported

  The Discussion states that STAT3 directly targets the regulatory regions of G6Pase and PEPCK to regulate their expression and describes negative regulation of both genes. The paper also links controlled expression of these gluconeogenic genes to glucose homeostasis. Page numbers are not provided in the supplied passages. (LLM, conf=0.93)

  cites Ramadoss et al., 2009 source
• ?Not checked — no full text of the sourcecites Inoue et al., 2004 source

In the paper

“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).”

What the sources say

• ?Could 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)

  cites Shen et al., 2001 sourceExperimental — accuracy not yet measured
• ?Not matched

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

  cites Aziz et al., 2007a
• Partly 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)

  cites Barry et al., 2010 sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• ?Not matched

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

  cites Ho et al., 2010
• Partly 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)

  cites Liu et al., 2013 sourceExperimental — accuracy not yet measured
• Partly 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)

  cites Pan et al., 2013 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Supported

  The Results section, “Sorafenib induces autophagy in HCC cell lines” (page not specified), reports increased autophagosome formation in four tested liver cancer cell lines. The Results sections on p-STAT3 signaling and SHP-1-dependent inhibition of STAT3 (pages not specified) report that sorafenib inhibits STAT3 signaling, reduces Mcl-1 expression, and induces autophagy through that pathway. (LLM, conf=0.93)

  cites Tai et al., 2013 source

In the paper

“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.”

What the sources say

• Partly 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)

  cites Gilbert and Hemann, 2010 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Supported

  The Abstract identifies S-nitrosylation as a redox-based modification of protein thiols and reports that it inhibits STAT3 activation by inhibiting Tyr 705 phosphorylation. The Discussion likewise states that S-nitrosylation inhibits STAT3 activation. (LLM, conf=0.94)

  cites Kim et al., 2014 source

In the paper

“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).”

What the sources say

• Partly 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)

  cites Pensa et al., 2014 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Supported

  The Discussion reports that iNOS-produced NO and GSNO inhibit STAT3-dependent gene expression and microglial proliferation. The Innovation section links this inhibition to STAT3 S-nitrosylation and identifies Cys 259 as the site modified by GSNO. (LLM, conf=0.93)

  cites Kim et al., 2014 source

In the paper

“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)”

What the sources say

• ?Not checked — no full text of the sourcecites Moran et al., 2009 source
• ?Not checked — no full text of the sourcecites Moran et al., 2008
• Supported

  Thacker et al. is cited for cardiomyocyte apoptosis, not the lung or liver findings assigned to the other citations. The Abstract states that trauma with hemorrhagic shock results in heart failure marked by cardiomyocyte apoptosis and describes resuscitation as part of the experimental context. (LLM, conf=0.92)

  cites Thacker et al., 2013 source

In the paper

“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).”

What the sources say

• ?Could 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)

  cites Zhang et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Supported

  The Abstract states that STAT3-deficient cells repair damaged DNA less efficiently and show reduced ATM–Chk2 and ATR–Chk1 activity. It concludes that STAT3 supports efficient repair partly by modulating those pathways. The experiments described in the Results and Discussion used mouse embryonic fibroblasts. (LLM, conf=0.93)

  cites Barry et al., 2010 source

In the paper

“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).”

What the sources say

• Supported

  Yamada et al. are cited for the PIK3C3 part of the sentence, not for BECN1 or HDAC3 recruitment, which are separately attributed to Miao et al. In the Results (‘Blockade of STAT3 signaling reverses FynT inhibition of macroautophagy’), inhibiting STAT3 increased Vps34—the PIK3C3 protein—and the Discussion reports that it reversed the Fyn-dependent decrease in Vps34. (LLM, conf=0.91)

  cites Yamada et al., 2012 source
• ?Not checked — no full text of the sourcecites Miao et al., 2014 source

In the paper

“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).”

What the sources say

• Supported

  The section “Senescence, the SASP, and age-related inflammation” explicitly reports that IL-1α, IL-6, TNF, and NF-κB activity increase in tissues with age. It also discusses senescence as a possible contributor to this age-related inflammation. The paper specifies NF-κB activity, rather than NF-κB levels; no page number is provided in our copy. (LLM, conf=0.90)

  cites McHugh and Gil, 2018 source

In the paper

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

What the sources say

• Partly 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)

  cites Barry et al., 2010 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Partly 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)

  cites Zhang et al., 2000 sourceExperimental — accuracy not yet measured
• Partly 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)

  cites Mertens et al., 2015 sourceExperimental — accuracy not yet measured
• Supported

  The Introduction reports allosteric communication between STAT3 domains and says the disease-associated I568F mutation affects distant domains and SH2 activity. The Discussion concludes that inter-domain allosteric communication controls STAT3 function and changes caused by disease-inducing mutations. (LLM, conf=0.94)

  cites Namanja et al., 2016 source

In the paper

“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.”

What the sources say

• Partly 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)

  cites Hox et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Partly 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)

  cites Genini et al., 2017 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Supported

  The ‘Targeted inhibition of Jak activity’ section states that, in all the Jak kinase-domain structures discussed, a small-molecule inhibitor binds in the ATP cleft between a β-sheet-rich N-lobe and an α-helix-rich C-lobe. The ‘Overview of cytokine signaling through Jak kinases’ section identifies JH1 as the kinase domain. (LLM, conf=0.94)

  cites Alicea-Velázquez and Boggon, 2011 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Heidelberger et al., 2013 source
• Partly 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)

  cites Ball et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Partly 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)

  cites Heppler and Frank, 2017 sourceExperimental — accuracy not yet measured
• Partly 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)

  cites Durham et al., 2019 sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites Jatoi, 2013 source
• Partly 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)

  cites Cerchione et al., 2017 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Supported

  Section 3.2 states that STAT3 activation by IL-6 prolongs the survival of pathogenic T cells in the lamina propria and that STAT3 activation in T cells contributes to colitis. This directly supports the attributed mechanism. (LLM, conf=0.93)

  cites Kasembeli et al., 2018 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Takeda et al., 1999 source
• ?Not checked — no full text of the sourcecites Atreya et al., 2000 source
• ?Could 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)

  cites Yamamoto et al., 2000 sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Supported

  The Discussion states that JAK1/2 inhibition is associated with a risk of aggressive B-cell lymphoma, which it describes as a second malignancy. The Results report three lymphomas among 31 inhibitor-treated patients with primary myelofibrosis, versus one among 185 conventionally treated patients. (LLM, conf=0.94)

  cites Porpaczy et al., 2018 source

In the paper

“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”

What the sources say

• Partly 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)

  cites Babaei et al., 2018 sourceExperimental — accuracy not yet measured
• ?Not matched

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

  cites Wang et al., 2018a

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Lees et al., 2011 source
• Supported

  Section 3.2, “Contribution of STAT3 to IBD,” states that genome-wide association studies identified loci linked to IBD susceptibility, including genes related to intestinal mucosal immune responses such as STAT3. This directly supports the attributed paraphrase. (LLM, conf=0.95)

  cites Kasembeli et al., 2018 source

In the paper

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

What the sources say

• Supported

  The section “Inhibition of CK2 suppresses TGFβ-induced JAK2-STAT3 activation” (page not specified) reports that TGFβ induced JAK2 phosphorylation and increased phosphorylated, activated STAT3 in fibroblasts. It also identifies JAK2 and STAT3 as mediators of TGFβ’s pro-fibrotic effects. (LLM, conf=0.88)

  cites Zhang et al., 2015 source

In the paper

“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”

What the sources say

• Partly 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)

  cites Silva et al., 2015 sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Supported

  Section 5.2 identifies STAT3’s roles in proliferation, prevention of apoptosis, angiogenesis, and cell plasticity as processes involved in fibrosis. Sections 5.4 and 5.5 specifically discuss myofibroblast proliferation and fibroblast plasticity. The provided passages do not give page numbers. (LLM, conf=0.93)

  cites Kasembeli et al., 2018 source

In the paper

“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.”

What the sources say

• Supported

  The “JAK2 Mutations in Chronic Myeloid Malignancies” section reports JAK2-V617F in approximately 95% of patients with PV and 50%–60% of those with ET or PMF. The “Cell of Origin and Mutation Timing” section describes mutant JAK2 activity and JAK2 activation, supporting the characterization of V617F as activating. (LLM, conf=0.94)

  cites Chen et al., 2012 source
• ?Not checked — no full text of the sourcecites Vainchenker and Constantinescu, 2013 source

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Mantovani et al., 2000 source
• Partly 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)

  cites Miyamoto et al., 2016 sourceExperimental — accuracy not yet measured
• Supported

  The Introduction’s “Immune system” section identifies TNFα, IL-6, and interferon gamma as pro-inflammatory cytokines that promote cachexia. The “Skeletal muscle wasting” section also lists all three among factors promoting catabolism in cachectic mouse models and patients. (LLM, conf=0.94)

  cites Porporato, 2016 source

In the paper

“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”

What the sources say

• Partly 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)

  cites Jung et al., 2017 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Not matched

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

  cites Zhang et al., 2013a
• Supported

  Silva et al. supports the cancer-model portion of the sentence: the results report increased p-Stat3 in muscles of mice bearing Lewis lung carcinoma tumors, and the Discussion concludes that cancer activates Stat3 in muscle. The chronic kidney disease portion is attributed to Zhang et al., not to this source. Page numbers are unavailable in our copy. (LLM, conf=0.92)

  cites Silva et al., 2015 source

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Wang et al., 2014
• Supported

  The Discussion states that clinical activity was observed in a variety of tumor types. The Abstract Results report a complete response in mantle cell lymphoma and a partial response in anaplastic thyroid carcinoma, supporting the claim of activity against multiple cancers. (LLM, conf=0.90)

  cites Hong et al., 2012 source

In the paper

“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.”

What the sources say

• Supported

  The Introduction identifies CDDO-Me as bardoxolone methyl. The Discussion describes slow oral absorption, and the Results > Pharmacokinetics section says the dose–exposure pattern is suggestive of saturable absorption. Page numbers are not available in our copy. (LLM, conf=0.95)

  cites Hong et al., 2012 source

In the paper

“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.”

What the sources say

• Supported

  The Discussion (page unavailable) explicitly describes nonlinearity at high doses. The Results > Pharmacokinetics section reports less-than-proportionate increases in plasma exposure as dose increased, and Results > Safety documents the 600, 900, and 1,300 mg/day dose levels. (LLM, conf=0.90)

  cites Hong et al., 2012 source

In the paper

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

What the sources say

• Supported

  The Abstract (Results) explicitly identifies the dose-limiting toxicities as grade 3 reversible liver transaminase elevations. The Results (Safety) and Discussion specify that these were ALT elevations at 1,300 mg/d and describe their resolution. (LLM, conf=0.95)

  cites Hong et al., 2012 source

In the paper

“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.”

What the sources say

• Supported

  The Discussion explicitly characterizes bardoxolone methyl’s pharmacokinetics as having high interpatient variability. The Results (Pharmacokinetics) also report variability of 64%–77% after the first dose and 39%–54% after the last dose among patients at the 900 mg dose level. (LLM, conf=0.95)

  cites Hong et al., 2012 source

In the paper

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

What the sources say

• Partly 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)

  cites Tolcher et al., 2018 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Supported

  The Abstract Conclusions state that objective tumor responses and pharmacodynamic effects supported continued development of other synthetic triterpenoids in cancer. That directly supports the citing sentence’s assessment. (LLM, conf=0.94)

  cites Hong et al., 2012 source

In the paper

“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.”

What the sources say

• Partly 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)

  cites Tanaka et al., 2008 sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

  The Results > Pharmacokinetics passage reports an apparent terminal-phase half-life of 39 ± 20 hours in patients receiving 900 mg/day. The authors caution that monitoring after the final dose may have been too short to estimate it accurately. (LLM, conf=0.94)

  cites Hong et al., 2012 source

In the paper

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

What the sources say

• Partly 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)

  cites Khan et al., 2018 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Supported

  In the section on OPB-51602 and mitochondrial function, the paper identifies mitochondrial STAT3 (mSTAT3) as a key target of OPB-51602 and reports suppression of mitochondrial oxygen consumption and ATP production. Its section on other STAT3 inhibitors reports that those compounds also impaired mitochondrial membrane potential and ATP production. The parallel confirmatory experiments described as “data not shown” are the citing authors’ own work, not a result attributed to Genini et al. (LLM, conf=0.88)

  cites Genini et al., 2017 source

In the paper

“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).”

What the sources say

• Partly 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)

  cites Lewis et al., 2015 sourceExperimental — accuracy not yet measured
• ?Not matched

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

  cites Bharadwaj et al., 2016a
• Partly 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)

  cites Jung et al., 2017 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Partly 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)

  cites Genini et al., 2017 sourceExperimental — accuracy not yet measured