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

In the paper

“Studies in the mut-Stat3 bearing two copies of the V463del STAT3 mutation frequently found in Job’s syndrome patients demonstrated both defective mast cell degranulation and reduced endothelial cell permeability”

What the sources say

• Partly supported

  The Methods (mut-Stat3 mice; page unavailable) describe mice carrying two copies of a transgene encoding the V463 deletion. The Results (page unavailable) report a reduced anaphylactic response and infer impaired in vivo mast cell degranulation. The paper does not report reduced endothelial cell permeability; its mouse anaphylaxis assay measured body temperature, not permeability. (LLM, conf=0.88)

  cites Siegel et al., 2013 sourceExperimental — accuracy not yet measured
• Disputed

  The Results section reports reduced anaphylaxis in Stat3-mutant mice, and the Conclusions attribute reduced vascular permeability to impaired STAT3 signaling. But the Results explicitly say the mutant mice showed no significant difference in histamine release after challenge, contrary to the claim that their mast cell degranulation was defective. The cited passages do not specify the V463del genotype (page numbers unavailable). (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

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

In the paper

“This pathway is activated in response to many protein ligands, including cytokines, growth factors, interferons (IFNs), and peptide hormones, where it regulates a wide range of cellular processes, including cell growth, proliferation, differentiation, and apoptosis (Rawlings et al., 2004; O’Shea et al., 2013).”

What the sources say

• ?Not checked — no full text of the sourcecites Rawlings et al., 2004 source
• Partly supported

  The CYTOKINES AND JAK–STAT SIGNALING section identifies interferons, colony-stimulating factors, growth hormone, and other peptide hormones as ligands whose receptors use JAK–STAT signaling, and links these signals to growth and differentiation. The CANCER section links STAT activation to proliferation and cell survival. The source does not support the implication that growth factors generally activate this pathway, and it does not explicitly describe apoptosis as a process the pathway regulates. (LLM, conf=0.86)

  cites O’Shea et al., 2013 sourceExperimental — accuracy not yet measured

In the paper

“Their essential role in developmental biology is underscored by the fact that deficiency in JAK1 and JAK2 is embryonically lethal due to neurologic defects and deficiencies in erythropoiesis, respectively, whereas deficiencies in JAK3 and TYK2 are associated with a variety of severe immunodeficiency syndromes in animal models and humans (Ghoreschi et al., 2009).”

What the sources say

• Partly supported

  The Jak1 deficiency section describes Jak1-knockout mice as perinatally lethal, probably due to neurological deficits—not embryonically lethal. The Jak2 deficiency section reports embryonic lethality from defective erythropoiesis, while the sections on Jak3 and Tyk2 describe immunodeficiency in humans and mouse models. (LLM, conf=0.90)

  cites Ghoreschi et al., 2009 sourceExperimental — accuracy not yet measured

In the paper

“Recent X-ray crystal structural studies have provided a clearer delineation of JAK structural architecture, with four distinct domains: 1) N-terminal band 4.1, ezrin, radixin, moesin (FERM) domain; 2) SH2 domain; 3) the catalytically active JH1 kinase domain located at the C-terminal end; and 4) the pseudo-kinase domain (JH2), located adjacent to it, which is enzymatically inactive but has a cruc”

What the sources say

• Partly supported

  The introductory passage describes four JAK domains in the stated order, and the Results show that the TYK2 pseudokinase inhibits kinase activity. But the introduction also reports weak catalytic activity in the JAK2 pseudokinase, so the categorical claim that JH2 is enzymatically inactive is not supported. Our copy provides no page number for these passages. (LLM, conf=0.90)

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

In the paper

“Many cytokines bind to receptors composed of heterologous polypeptide chains, and several of the polypeptide chains are common or shared. In addition, a single or combination of two to three JAKs selectively associates with each receptor (Lin et al., 1995; Baker et al., 2007; Kiu and Nicholson, 2012) (Fig. 2). The consequence is that a combination of different STATs can be activated by a single cy”

What the sources say

• ?Not checked — no full text of the sourcecites Lin et al., 1995 source
• ?Not checked — no full text of the sourcecites Baker et al., 2007 source
• 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 Kiu and Nicholson, 2012 sourceExperimental — accuracy not yet measured

In the paper

“The phosphatase tyrosine–protein phosphatase nonreceptor type 11, also known as protein–tyrosine phosphatase 1D or Src homology protein tyrosine phosphatase (SHP)-2, is recruited to the pYSTV motif of gp130 and phosphorylated on tyrosine residues by JAKs, which increases its tyrosine phosphatase activity for STAT3, which reduces pY-STAT3 levels (Schmitz et al., 2000).”

What the sources say

• Partly supported

  The Discussion (page unavailable) says SHP2 binds gp130 Tyr759, is phosphorylated after IL-6 stimulation, and negatively regulates STAT activation. It does not establish that JAKs directly phosphorylate SHP2 or that phosphorylation increases SHP2’s phosphatase activity toward STAT3. Instead, it discusses MAPK pathway activation as a possible route to reduced STAT phosphorylation. (LLM, conf=0.87)

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

In the paper

“Another inhibitory loop is mediated by suppressor of cytokine signaling (SOCS)3 (Yoshimura et al., 2007). SOCS3 mRNA is rapidly induced by activated STAT3 and STAT1, and SOCS3 protein interacts with pYSTV motif of gp130 through its SH2 domain and inhibits JAK activity through its kinase-inhibitory region, thereby restricting further STAT3 activation (Babon et al., 2012; Kershaw et al., 2013).”

What the sources say

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

  The Results describe an SH2-domain ligand containing the gp130 pYSTV sequence, show that the kinase-inhibitory region is required for JAK inhibition, and demonstrate that SOCS3 inhibits JAK2 substrate phosphorylation (page not available in our copy). The Introduction describes SOCS expression as induced by JAK–STAT activation, but does not establish rapid SOCS3 mRNA induction specifically by activated STAT3 and STAT1. (LLM, conf=0.87)

  cites Babon et al., 2012 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section identifies the gp130 pYSTV-containing binding site and shows the gp130 fragment in SOCS3’s SH2-domain binding groove. The Introduction describes direct JAK inhibition by SOCS3’s kinase-inhibitory region, supporting the proposed restraint on JAK/STAT signaling. Our copy does not establish that activated STAT3 and STAT1 rapidly induce SOCS3 mRNA, or specifically demonstrate reduced further STAT3 activation. (LLM, conf=0.88)

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

In the paper

“Other phosphatases have been implicated in the modulation of STAT3 signaling, for example, phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which has both lipid and protein phosphatase activity, has been shown to act as a negative regulator of STAT3 (Sun and Steinberg, 2002; Mukhopadhyay et al., 2010), where its protein phosphatase activity negatively affects phosphorylation of”

What the sources say

• ?Not checked — no full text of the sourcecites Sun and Steinberg, 2002 source
• ?Not checked — no full text of the sourcecites Mukhopadhyay et al., 2010 source
• Partly supported

  The Discussion (page unavailable) supports positive regulation in this context: PTEN loss reduces LIFRβ expression and STAT3 Tyr705 phosphorylation in astrocytes, and correlates with STAT3 inactivation in human glioblastomas. It does not support the attributed negative regulation through PTEN’s protein phosphatase activity; the mechanism it describes runs through Akt–FOXO and LIFRβ. (LLM, conf=0.88)

  cites de la Iglesia et al., 2008 sourceExperimental — accuracy not yet measured

In the paper

“Mechanistically, pS727 in the nucleus is required for the recruitment of histone lysine methyltransferase SET9, which dimethylates STAT3 at Lys140, leading to pY705 inhibition (Yang et al., 2010).”

What the sources say

• Partly supported

  The Results show that nuclear, DNA-bound STAT3 requires S727 phosphorylation for K140 dimethylation, and that SET9 is required for that modification. They also report greater and more sustained Y705 phosphorylation when K140 cannot be methylated. But the Discussion presents recruitment of SET9 by phosphorylated S727 only as a possibility, and the Results say the mechanistic link between K140 methylation and Y705 phosphorylation is unclear. (LLM, conf=0.90)

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

In the paper

“However, there are instances when pS727 appears to counteract pY705 function. e.g., cdk5-mediated pS727 repressed FoxP3 upregulation, thereby limiting T regulatory cell (Treg) development (Lam et al., 2015), and reduction in pS727 by CK2–protein phosphatase 2A enhanced pY-STAT3–induced tumorigenic potential of glioma cells (Mandal et al., 2014).”

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 Lam et al., 2015 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Mandal et al., 2014 source

In the paper

“STAT3 can also be activated independent of pY705 phosphorylation by simultaneous phosphorylation of Thr-714 and Ser727 (Waitkus et al., 2014) and upon engagement of CD44 through Lys-685 acetylation (Lee et al., 2009b).”

What the sources say

• Supported

  The Discussion reports that STAT3 modified at both Thr-714 and Ser-727 drives gene induction, likely without Tyr-705 phosphorylation, during simultaneous EGFR/PAR-1 signaling. The CD44/Lys-685 clause is attributed to Lee et al., not to Waitkus et al., and is not part of this verdict. (LLM, conf=0.93)

  cites Waitkus et al., 2014 source
• ?Not matched

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

  cites Lee et al., 2009b

In the paper

“STAT3 activation mediates neutrophil mobilization in the bone marrow”

What the sources say

• Partly supported

  The Results and Discussion support a role for STAT3 in acute G-CSF–induced neutrophil mobilization from bone marrow into circulation and in chemotaxis toward MIP-2. They do not support the quoted mechanism of upregulating CXCR2/Il8rb and MIP-2/Cxcl2: the Results explicitly state that CXCR2 expression is independent of STAT3 and describe MIP-2 as a chemoattractant used to test the response. The Discussion also cautions that STAT3 is not necessary for all neutrophil mobilization. (LLM, conf=0.88)

  cites Panopoulos et al., 2006 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Nguyen-Jackson et al., 2010 source
• ?Not matched

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

  cites Nguyen-Jackson et al., 2010, 2012

In the paper

“Insulin resistance; impaired liver regeneration”

What the sources say

• ?Not checked — no full text of the sourcecites Inoue et al., 2004 source
• Partly supported

  The Abstract and the section on liver-mass restoration report higher early mortality and a slight, temporary decrease in hepatocyte DNA synthesis after liver-specific STAT3 deletion. They also report complete liver-mass recovery, so they do not support a general claim of impaired regeneration. Our copy does not report insulin resistance (searched: “insulin resistance”). Page numbers were unavailable. (LLM, conf=0.87)

  cites Moh et al., 2007 sourceExperimental — accuracy not yet measured

In the paper

“Unaltered basal hematopoiesis; impaired stem cell regeneration after 5-FU”

What the sources say

• Partly supported

  The Introduction describes STAT3 deletion in hematopoietic progenitors, and the granulopoiesis results report similar total white-cell counts and numbers of general precursors in controls and knockout mice. But basal hematopoiesis was not wholly unaltered: the mutants had increased neutrophils. The paper describes treating mice with 5-fluorouracil, but the located passage does not report impaired stem-cell regeneration afterward (page unavailable in our copy). (LLM, conf=0.85)

  cites Lee et al., 2002 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Chung et al., 2006 source

In the paper

“leads to STAT3 protein instability and reduced half-life”

What the sources say

• Partly supported

  The Results report that most AD-HIES STAT3 mutations are predicted to destabilize the protein, and the STAT3 protein half-life section reports a 79% reduction in patient cells with structural or structural-functional mutations. The claim is unqualified: that same section reports a normal half-life for cells with the functional mutation R382W. (LLM, conf=0.87)

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

In the paper

“Increased apoptosis and impaired Th17 development”

What the sources say

• Partly supported

  The section ‘IL-6 does not prevent apoptosis of Stat3-deficient T cells’ (page not specified) reports that IL-6 failed to reduce apoptosis in T cell-specific Stat3-deficient cells, supporting the apoptosis portion under that condition. Our copy does not report impaired Th17 development; the Discussion instead reports no apparent abnormality in general T cell development, which does not settle the Th17-specific claim. (LLM, conf=0.89)

  cites Takeda et al., 1998b 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

“decreased generation of Th17 cells and production of IL-17 and IL-22, which reduces epithelial production of chemokines and defensins”

What the sources say

• Supported

  The Pathogenesis section states that STAT3 mutations in AD-HIES cause failure of Th17 differentiation and subsequent IL-17 secretion. Its Figure 2 explanation says Th17 cells secrete IL-17 and IL-22, which stimulate epithelial production of chemokines and defensins, respectively; the same section reports reduced antimicrobial-peptide production from epithelial cells in AD-HIES. (LLM, conf=0.92)

  cites Yong et al., 2012 source
• Partly supported

  The Job’s syndrome section (page unavailable) reports low Th17-cell levels and defective Th17 differentiation in patients with AD STAT3 deficiency, and links IL-17 activity to neutrophil recruitment. It does not state that these patients produce less IL-22 or that reduced IL-17 and IL-22 decrease epithelial chemokine and defensin production. (LLM, conf=0.86)

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

In the paper

“AD-HIES is a rare multisystem disorder classified as a primary immunodeficiency disease, usually of children”

What the sources say

• Partly supported

  The Introduction classifies HIES, including its autosomal dominant form, as a primary immunodeficiency and describes the condition as rare. The AD-HIES Clinical features section calls it a multisystem disease and says its rash usually appears within weeks of birth, but it does not establish that AD-HIES is usually a disease of children rather than adults. (LLM, conf=0.86)

  cites Yong et al., 2012 sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract identifies HIES as a primary immunodeficiency, and the Job’s syndrome section describes its immune, skeletal, dental, joint, and vascular manifestations and reports more than 200 patients worldwide. That section describes neonatal and other early signs, but it does not characterize AD-HIES as usually a disorder of children; it also reports that around 80% of patients live to at least age 50. (LLM, conf=0.83)

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

In the paper

“Increased presbycardia and MI susceptibility”

What the sources say

• Partly supported

  The Results (page not provided) show greater age-related cardiac fibrosis and declining systolic function in mice with cardiomyocyte-specific STAT3 knockout, supporting the presbycardia portion. The paper reports greater susceptibility to doxorubicin-induced injury, not myocardial infarction. Its introductory mention of STAT3 activation during acute myocardial infarction does not establish increased infarction susceptibility after knockout. (LLM, conf=0.89)

  cites Jacoby et al., 2003 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Hilfiker-Kleiner et al., 2004 source

In the paper

“Thrombopoietin activates the JAK/STAT3 pathway in megakaryocytes”

What the sources say

• ?Not checked — no full text of the sourcecites Broudy and Kaushansky, 1995 source
• Partly supported

  The In Vitro Activities of ML section says thrombopoietin supports megakaryocyte maturation and fragmentation into platelets, and The Successful Search Begins describes signaling through its receptor. Neither passage establishes activation of JAK/STAT3 in megakaryocytes; searches for “JAK” and “STAT3” found no such passage. The supplied claim’s additional assertion about upregulated platelet-production genes is also not established by these passages. (LLM, conf=0.82)

  cites Kaushansky, 1995 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Drachman and Kaushansky, 1997 source

In the paper

“IL-6– and IL-10–stimulated STAT3 is also known to suppress DC maturation and activation and promote immune tolerance”

What the sources say

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

  The sections on STAT3 activity in DCs and decreased DC differentiation report that tumor-derived factors maintain STAT3 activity, impair DC maturation and reduce their ability to stimulate T cells. The paper identifies IL-10 as a STAT3 activator and finds that blocking it has a modest effect on tumor-conditioned STAT3 activity, but it does not establish the claimed IL-6– and IL-10–stimulated mechanism or show that it promotes immune tolerance. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  cites Nefedova et al., 2004 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., 2004b

In the paper

“inhibition of JAK/STAT3 signaling improves mature DC function and augments antitumor immunity”

What the sources say

• Partly supported

  In “Increased STAT3 activity is directly involved in accumulation of ImCs and decreased DC differentiation,” blocking STAT3 in progenitor cells restored their differentiation into mature DCs. The “Discussion” proposes that STAT3 inhibition may improve immune responses in cancer, but does not demonstrate augmented antitumor immunity. It also reports that reducing STAT3 activity in activated DCs did not improve their function, so the claim about improved mature DC function is not supported. (LLM, conf=0.90)

  cites Nefedova et al., 2004 sourceExperimental — accuracy not yet measured
• ?Not matched

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

  cites Nefedova et al., 2005a
• ?Not matched

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

  cites Nefedova et al., 2005b

In the paper

“Thrombopoietin synthesis in the liver is regulated by Jak2/STAT3”

What the sources say

• Supported

  The section ‘The aging (senescence) induced platelet clearance’ states that removal of aged, desialylated platelets drives hepatic thrombopoietin mRNA expression via JAK2 and STAT3. This supports the claim that the pathway regulates liver thrombopoietin synthesis; the paper describes it as a response to platelet clearance, not the only regulatory pathway. (LLM, conf=0.91)

  cites Grozovsky et al., 2015 source
• Supported

  The “AMR-IL-6R connection” section states that the hepatic AMR pathway involves JAK2 and STAT3 and leads to STAT3-mediated hepatic thrombopoietin (TPO) mRNA expression. It also reports that inhibiting this pathway reduces hepatic TPO expression and secretion. Page numbers are not available in our copy. (LLM, conf=0.92)

  cites Hoffmeister and Falet, 2016 source

In the paper

“Tcf4/E2-2, another transcriptional regulator of plasmacytoid DC development, is also transcriptionally upregulated by STAT3”

What the sources say

• ?Could not verify

  The Discussion describes STAT3-dependent induction of PU.1 and the myeloid integrin αMβ2, not Tcf4/E2-2. Searches for Tcf4/E2-2 and plasmacytoid dendritic cells found no passage addressing whether STAT3 transcriptionally upregulates Tcf4/E2-2. Page numbers were unavailable in our copy. (LLM, conf=0.76)

  cites Panopoulos et al., 2002 sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Results and Discussion passages (page unavailable) examine Flt3 expression in bone-marrow progenitors and their capacity to produce dendritic cells. A search for Tcf4/E2-2 and STAT3 found no passage addressing whether STAT3 transcriptionally upregulates Tcf4/E2-2. (LLM, conf=0.76)

  cites D’Amico and Wu, 2003 sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Results section reports that enforced STAT3 expression increased Flt3 mRNA in MEPs, not Tcf4/E2-2. Searches for Tcf4 and E2-2 found no passage in our copy addressing whether STAT3 upregulates that gene. Page numbers were not available in the indexed passages. (LLM, conf=0.78)

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

In the paper

“IL-9 through a JAK2/STAT3 signaling pathway facilitated platelet function and promoted development of deep venous thrombosis”

What the sources say

• Supported

  The Discussion (p. 1891) concludes that IL-9 facilitated platelet aggregation and activation through the JAK2/STAT3 pathway, promoting DVT development. It also reports increased thrombus size in an IL-9-treated mouse model; the mechanistic conclusion is based on platelet and mouse-model findings. (LLM, conf=0.94)

  cites Feng et al., 2018 source

In the paper

“STAT3 also controls development of CXC chemokine receptor 5–expressing T follicular helper cells, their localization to the B cell follicle within germinal centers of secondary lymphoid organs, and their IL-21 secretion, which mediates B cell help in germinal centers by stimulating proliferation and antibody affinity maturation”

What the sources say

• ?Not checked — no full text of the sourcecites Leonard et al., 2008 source
• 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 Ding et al., 2013 sourceExperimental — accuracy not yet measured

In the paper

“Overall, STAT3 is indispensable for physiologic leptin actions, and STAT3 dysfunction in any direction could cause pathophysiological alterations in mice and humans”

What the sources say

• ?Not checked — no full text of the sourcecites Akira et al., 1994 source
• ?Not checked — no full text of the sourcecites Wang et al., 2012 source
• Partly supported

  The Introduction reports that constitutive STAT3 activation is associated with malignant tumors and that disruption of the mouse Stat3 gene causes embryonic lethality. These examples support a narrower claim that altered STAT3 function can have pathological consequences, but the paper does not address whether STAT3 is indispensable for physiological leptin actions or establish the claimed effects of dysfunction in any direction across mice and humans (searched: leptin actions, leptin receptor, pathophysiological alterations). (LLM, conf=0.78)

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

In the paper

“In the setting of graft-versus-host disease (GVHD), STAT3 deficiency promotes inducible Treg generation, restrains GVHD, and improves mouse survival”

What the sources say

• Supported

  The Results section (‘STAT3 in T cells is required for the development of acute GvHD’) reports reduced GVHD and survival of mice receiving STAT3-deficient donor T cells. The Results section on iTreg generation and the Discussion link increased iTreg development from STAT3-deficient naïve T cells to protection against lethal GVHD. The finding concerns STAT3 deficiency in transferred T cells, not STAT3 deficiency throughout the mouse. (LLM, conf=0.93)

  cites Laurence et al., 2012 source

In the paper

“STAT3 deletion in neurons decreases POMC and increases AgRP and neuropeptide Y levels, leading to hyperphagia, obesity, infertility, and thermal dysregulation”

What the sources say

• Supported

  The Abstract (page not provided) reports that mice with neural-specific STAT3 disruption were hyperphagic, obese, infertile, and hypothermic after fasting or cold stress. It also reports reduced POMC and increased NPY and AgRP; the Results link the neuropeptide imbalance to hyperphagia. (LLM, conf=0.90)

  cites Gao et al., 2004 source

In the paper

“STAT3 and Foxp3 appear to coregulate IL10 in T-regs”

What the sources say

• Partly supported

  The supplied passage labeled Abstract reports that Foxp3 associates with active Stat3 in Tregs and that Il10 is among the genes dependent on both, supporting the hedged coregulation statement in the verbatim citing sentence. The copy does not establish histone acetyltransferase-1–mediated modification of the Il10 promoter or show that this particular mechanism maintains Th17 suppression; its promoter-binding experiments concern Il6 and Tgfb1 instead. (LLM, conf=0.88)

  cites Chaudhry et al., 2009 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section (“IL-10R signaling facilitates IL-10 production by Treg cells”; page unavailable) shows that STAT3 binds the Il10 locus and links IL-10R signaling to IL-10 expression in Tregs. The Introduction says STAT3 and Foxp3 cooperatively regulate a subset of genes, but our copy does not establish that IL10 is one of those jointly regulated genes. (LLM, conf=0.84)

  cites Chaudhry et al., 2011 sourceExperimental — accuracy not yet measured
• Partly supported

  In “Treg-mediated control of inflammatory responses” (page unavailable), the paper says STAT3 binds Foxp3 and modulates gene expression, and that STAT3 is needed to control Th17 responses. It does not identify IL-10 as a gene they coregulate. The “Overriding inhibitions” section instead describes IL-10-mediated STAT3 activation in Tregs; neither passage supports the claimed acetyltransferase-mediated modification of the IL-10 promoter. (LLM, conf=0.87)

  cites Chaudhry and Rudensky, 2013 sourceExperimental — accuracy not yet measured

In the paper

“AD-HIES patients demonstrate reduced numbers of memory CD8+ T cells, as well as fewer memory CD4+ T cells, relative to healthy controls”

What the sources say

• ?Could not verify

  The Results discuss reduced memory B-cell frequency and impaired T follicular helper-cell generation in AD-HIES, but do not report numbers of memory CD8+ or memory CD4+ T cells. Searches for those subsets and for reduced T-cell memory populations yielded no supporting passage in our copy. (LLM, conf=0.75)

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

In the paper

“STAT3 also transcriptionally upregulates anti-inflammatory transforming growth factor (TGF)-β1 and IL-10 in CD4+ T cells”

What the sources say

• Partly supported

  The Results section reports that active STAT3 increased both TGF-β1 and IL-10 production in CD4+ T cells, and shows STAT3 binding to the TGF-β1 promoter. The Discussion says STAT3 may promote Th3 induction and that IL-10 is usually necessary for Th3 induction in vitro. The copy does not establish direct transcriptional upregulation of IL-10 by STAT3 in these cells or demonstrate that STAT3's effect on Th3 induction depends on IL-10. Page numbers were not available in the supplied copy. (LLM, conf=0.83)

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

In the paper

“Leptin binds to its specific receptor, LepRb, on cells in the central nervous system (CNS) and peripheral tissues, including skeletal muscle, placenta, ovary, pituitary gland, and lymphoid tissue”

What the sources say

• Partly supported

  The Physiology of leptin section says leptin binds to LepRs in the brain and peripheral tissues, and that LepRb is the isoform primarily responsible for signaling. It lists skeletal muscle, placenta, ovary, pituitary gland, and lymphoid tissue as sites of leptin expression—not specifically as sites of LepRb expression. No page number is provided in our copy. (LLM, conf=0.90)

  cites Park and Ahima, 2014 sourceExperimental — accuracy not yet measured

In the paper

“STAT3 facilitates adipogenesis from preadipocytes”

What the sources say

• ?Not checked — no full text of the sourcecites Wang et al., 2009 source
• Partly supported

  The Introduction (page not available) says that STAT3 regulates adipogenesis in 3T3-L1 preadipocytes through PPARγ and C/EBPβ, and reports regulation of C/EBPβ transcription. It does not describe epigenetic activation of PPARγ, so that mechanism in the quoted claim is unsupported; the shorter citing sentence is supported. (LLM, conf=0.86)

  cites Kang et al., 2013 sourceExperimental — accuracy not yet measured
• Partly supported

  The ‘C/EBP activation by adipogenic stimuli’ section says that a JAK2–STAT3 cascade directly promotes C/EBPβ expression in committed preadipocytes, supporting the printed sentence. The ‘Epigenomics provides insights into early PPARγ activation’ section discusses epigenetic regulation of PPARγ but does not attribute that regulation to STAT3, so the fuller quoted mechanism is not fully supported. No page numbers are available in our copy. (LLM, conf=0.86)

  cites Cristancho and Lazar, 2011 sourceExperimental — accuracy not yet measured

In the paper

“IL-10 protects against high-fat diet–induced inflammation and improves glucose tolerance through the activation of STAT3 (Grant et al., 2014).”

What the sources say

• Partly supported

  The glucose-homeostasis Results report improved glucose tolerance and reduced adipose inflammation in high-fat-fed mice lacking myeloid PTP1B. The Discussion proposes a STAT3-dependent expansion of IL-10-secreting cells as the mechanism, but presents that mechanism as postulated; it does not establish that IL-10 itself caused the improved glucose tolerance through STAT3 activation. Page numbers are unavailable in our copy. (LLM, conf=0.86)

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

In the paper

“The importance of the leptin/STAT3 pathway in immune aging, tumor progression, and T cell dysfunction in cancer is suggested by recent findings that obese cancer patients respond better than nonobese patients to checkpoint therapy, especially therapy directed against the programmed cell death protein 1 (PD1)/programmed death-ligand 1 (PD-L1) axis perhaps due to increased leptin signaling”

What the sources say

• Supported

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

  cites Wang et al., 2019 source

In the paper

“Insulin increases IL-6 expression in Kupffer cells and activates STAT3 in hepatocytes (Inoue, 2016)”

What the sources say

• Partly supported

  The section “Central insulin action regulates HGP” (page not provided) says central insulin action increases IL-6 secretion by Kupffer cells, which activates STAT3 in hepatocytes. It supports the pathway, but the body passage does not establish the claim’s more specific point that IL-6 expression increases. (LLM, conf=0.82)

  cites Inoue, 2016 sourceExperimental — accuracy not yet measured

In the paper

“Adipocyte-specific Stat3-KO mice have increased body weight and more adipose tissue mass due to adipocyte hypertrophy, but do not show evidence of adipocyte hyperplasia, hyperphagia, or reduced energy expenditure (Cernkovich et al., 2008), suggesting a role of STAT3 in lipolysis.”

What the sources say

• Partly supported

  The Discussion reports increased body weight and adiposity associated with adipocyte hypertrophy, not hyperplasia, hyperphagia, or reduced energy expenditure, in male ASKO mice fed standard chow. The claim omits that restriction: the Results report normal growth curves in female ASKO mice. (LLM, conf=0.88)

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

In the paper

“These modifications affect the transcriptional activity of STAT3 through inhibiting Y705 phosphorylation and/or DNA binding, as well as inducing formation of higher order complexes and interfering with the function of the TAD (Li and Shaw, 2004; Xie et al., 2009; Li et al., 2010a; Kurdi et al., 2012; Butturini et al., 2014; Sobotta et al., 2015).”

What the sources say

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

  The Discussion reports that STAT3 S-glutathionylation reduces IL-6-induced tyrosine phosphorylation and transcriptional activation, and that S-thiolation reduces DNA binding. Our copy does not support attributing higher-order complex formation or interference with the transactivation domain (TAD) to this paper. (LLM, conf=0.87)

  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

“Peroxide treatment leads to phosphorylation of STAT3 (pY-STAT3) and its nuclear translocation in human lymphocytes (Carballo et al., 1999)”

What the sources say

• Supported

  The Results section reports increased STAT3 tyrosine phosphorylation in H₂O₂-treated peripheral blood lymphocytes and detects STAT3 in the nucleus after treatment. The Discussion likewise states that H₂O₂ promotes STAT3 tyrosine phosphorylation in human lymphocytes, followed by nuclear translocation. (LLM, conf=0.95)

  cites Carballo et al., 1999 source

In the paper

“Antibody against IL-6, gp130 siRNA, or dominant-negative STAT3 enhanced chemo-induced death in lymphoma (Gilbert and Hemann, 2010), as well as colon cancer (Yun et al., 2012)”

What the sources say

• Partly supported

  The Results section on Jak2 signaling (page unavailable) reports that Jak2/Jak3 inhibition removed protection against doxorubicin in lymphoma cells and improved outcomes in lymphoma-bearing mice. The cited paper does not report testing an anti-IL-6 antibody, gp130 siRNA, or dominant-negative STAT3 for this effect. The colon-cancer portion is attached to a different citation and is not attributed to Gilbert and Hemann. (LLM, conf=0.88)

  cites Gilbert and Hemann, 2010 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Yun et al., 2012 source

In the paper

“Both normal and tumor cells undergo senescence in response to various insults that cause persistent DNA damage (Kuilman et al., 2010; Rodier and Campisi, 2011; Sikora et al., 2011; Ohtani and Hara, 2013)”

What the sources say

• Supported

  The DNA damage-induced senescence section (page unavailable) reports senescence-like arrest in normal human fibroblasts after ionizing radiation and senescence of tumor cells after DNA-damaging drugs. The Replicative cellular senescence section adds that the duration of DNA-damage signaling can affect whether cells undergo senescence. (LLM, conf=0.88)

  cites Kuilman et al., 2010 source
• Supported

  In “What causes cellular senescence?” (page not provided), the paper describes several senescence-inducing insults, including telomere erosion, DNA double-strand breaks, and oncogenic signals that can produce a persistent DNA damage response. In “Cellular senescence and tumor suppression” (page not provided), it says that some tumor cells also senesce, including in response to chemotherapy. The claim is consistent with those passages, provided “tumor cells” is read as some tumor cells, not all. (LLM, conf=0.88)

  cites Rodier and Campisi, 2011 source
• ?Not checked — no full text of the sourcecites Sikora et al., 2011 source

In the paper

“Respiratory epithelial cell–specific STAT3-KO mice progressed more rapidly than STAT3 wild-type mice to lung injury after exposure to 95% oxygen (Hokuto et al., 2004), indicating a hyperoxia-protective role for STAT3.”

What the sources say

• Supported

  The Results report that respiratory epithelial Stat-3–deleted mice exposed to 95% oxygen developed symptoms sooner and had more severe lung injury than nondeleted controls. The Discussion states that STAT-3 is required to maintain lung function during hyperoxia, supporting the protective-role interpretation. (LLM, conf=0.94)

  cites Hokuto et al., 2004 source

In the paper

“Population-based, genome-wide–association studies followed by subsequent meta-analysis of population-based, genome-wide–association studies and immunochip data have identified more than 160 loci linked to IBD susceptibility (Jostins et al., 2012).”

What the sources say

• Supported

  The Abstract reports 163 IBD loci meeting genome-wide significance thresholds. It also describes a meta-analysis of GWAS data with Immunochip validation genotypes from cases and controls; the Methods Summary confirms this approach. (LLM, conf=0.94)

  cites Jostins et al., 2012 source

In the paper

“In mammalian cells, sorbitol-induced hyperosmolarity resulted in phosphorylation of JAK1, JAK2, and TYK2 and led to activation of STAT1 and STAT3, independent of gp130, leading to formation of STAT1/STAT3 heterodimer complexes and increased DNA binding (Gatsios et al., 1998).”

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 Gatsios et al., 1998 sourceExperimental — accuracy not yet measured

In the paper

“Other small-molecule inhibitors besides platinum-based compounds also have been identified, including InS3-54 and HO-3867, which specifically target the DNA-binding domain of STAT3, inhibit its binding to DNA, and block STAT3-mediated gene activation (Rath et al., 2014).”

What the sources say

• Partly supported

  In Results (‘DAPs target STAT3’; page not provided), the paper reports that HO-3867 is predicted to interact with STAT3’s DNA-binding domain, inhibits STAT3 DNA binding, and reduces a transcriptional reporter signal. The cited paper does not establish these claims for InS3-54; its experiments here concern HO-3867 and H-4073. (LLM, conf=0.90)

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

In the paper

“Both are idiopathic chronic inflammatory diseases of the gastrointestinal (GI) tract that cause substantial morbidity, occasional mortality, and a 20- to 30-fold increased risk of developing colorectal cancer (CRC) (Kasembeli et al., 2018).”

What the sources say

• Partly supported

  Section 3.1 (Overview; page unavailable) identifies UC and CD as forms of idiopathic gastrointestinal inflammatory bowel disease, lists symptoms consistent with substantial morbidity, and reports a 20- to 30-fold higher colorectal-cancer risk than in the general population. It does not state that UC and CD cause occasional mortality in patients; the mortality discussed in section 3.2 concerns mice with experimentally induced colitis. (LLM, conf=0.87)

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

In the paper

“Platinum IV compounds—CPA-1, CPA-7, IS3 295, and platinum (IV) tetrachloride—also can inhibit STAT3 DNA-binding activity and inhibit cancer cell line growth (Turkson et al., 2004).”

What the sources say

• Partly supported

  The Introduction and the section on inhibition of in vitro Stat3 DNA-binding activity report that CPA-1, CPA-7, and platinum(IV) tetrachloride inhibit Stat3 DNA binding; the Introduction also reports growth inhibition in malignant cell lines. Our copy does not identify IS3 295 among the compounds tested (searched: “IS3 295” and “IS3-295”), so the claim is unsupported for that compound. Page numbers were not provided. (LLM, conf=0.88)

  cites Turkson et al., 2004 sourceExperimental — accuracy not yet measured

In the paper

“Nucleic acid–based drugs, including decoy oligonucleotides and, perhaps, G-quartet oligonucleotides, have been identified that inhibit STAT3-mediated gene expression and inhibit growth of different cancer cell lines (Leong et al., 2003; Lewis et al., 2008; Sun et al., 2008; Shen et al., 2009; Zhang et al., 2013b; Liu et al., 2014; Sen et al., 2014).”

What the sources say

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

  The Abstract reports that STAT3-binding-sequence oligonucleotides induced apoptosis in prostate and pancreatic cancer cell lines. The section ‘Anti-STAT3 Oligonucleotides Inhibited Expression of a STAT3-Regulated Gene, CD46’ reports reduced CD46 expression, supporting the gene-expression part of the claim. This paper does not establish the claim about G-quartet oligonucleotides. (LLM, conf=0.86)

  cites Lewis et al., 2008 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Sun et al., 2008 source

In the paper

“Of note, pS-STAT3 optimizes mitochondrial respiration and limits ROS formation from complex I following cardiac ischemia (Szczepanek et al., 2012).”

What the sources say

• Partly supported

  Section 3.4 reports that mitochondria-targeted STAT3 modulates respiration and prevents the ischemia-induced rise in complex I–associated ROS; section 4 describes reduced ROS during ischemia. The passages do not establish that the STAT3 responsible is specifically serine-phosphorylated (pS-STAT3), and the reported ROS effect is during ischemia rather than specifically following it. (LLM, conf=0.84)

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

In the paper

“STAT3 is known to regulate both Th2 cell recruitment during allergic inflammation and the production of Th17 cells and the expansion and recruitment of neutrophils (Chen et al., 2007; Ma et al., 2008; Milner et al., 2008).”

What the sources say

• Partly supported

  The Introduction identifies STAT3 as a critical regulator of Th17 differentiation. It also links enhanced STAT3 activity after SOCS3 deletion to inflammatory disease with neutrophil infiltration, but does not establish that STAT3 regulates neutrophil expansion or recruitment. Its discussion of Th2 cells does not address STAT3-dependent recruitment during allergic inflammation. (LLM, conf=0.88)

  cites Chen 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 Ma et al., 2008
• Partly supported

  The Abstract supports a crucial role for STAT3 signalling in TH17-cell generation and links loss of TH17 cells to impaired neutrophil recruitment, mobilization and influx. It does not establish that STAT3 regulates Th2-cell recruitment during allergic inflammation or neutrophil expansion. (LLM, conf=0.87)

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

In the paper

“Genetic and pharmacological inhibition of STAT3 signaling has been shown to suppress fibrosis in many animal models, including models of lung fibrosis, in which haploinsufficiency of STAT3 eliminated the increase in lung collagen (hydroxproline) content in bleomycin-treated mice”

What the sources say

• Partly supported

  The Results section, ‘Genetic restriction of Stat3 signalling ameliorates the fibrotic response in bleomycin-challenged mice’ (page unavailable), reports that Stat3+/− mice were completely protected from bleomycin-induced lung collagen deposition; Figure 6 identifies the collagen measure as lung hydroxyproline content. The paper supports this genetic lung-fibrosis example, but the cited passages do not establish that pharmacological STAT3 inhibition suppresses fibrosis across many animal models. (LLM, conf=0.86)

  cites O’Donoghue et al., 2012 sourceExperimental — accuracy not yet measured

In the paper

“Ruxolitinib, a JAK1/JAK2 inhibitor, has demonstrated promising activity in PMF patients, showing increased benefit across several end points, e.g., reduction in splenomegaly, improvement in disease-related symptoms, and increased overall survival, when compared with placebo or best available therapy”

What the sources say

• Partly supported

  The Conclusions report reduced splenomegaly and disease-related symptoms versus best available therapy, but state that an effect on overall survival had not been shown. The Discussion likewise says no overall-survival benefit was observed. This study included patients with primary and other forms of myelofibrosis; it did not compare ruxolitinib with placebo. (LLM, conf=0.90)

  cites Harrison et al., 2012 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (Efficacy, page unavailable) report reduced spleen volume and improved symptoms in the PMF subgroup versus placebo. The Abstract (Results, page unavailable) reports better overall survival for the combined myelofibrosis population, not specifically for PMF. This trial compared ruxolitinib with placebo, not best available therapy. (LLM, conf=0.88)

  cites Verstovsek et al., 2012 sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract (p. 1) reports reduced splenomegaly, improved disease-related symptoms, and prolonged survival with ruxolitinib compared with placebo or best available therapy. The Methods (p. 2) show that the trials included patients with primary myelofibrosis, but also patients with secondary myelofibrosis; the cited results are not reported specifically for the PMF subgroup. (LLM, conf=0.82)

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

In the paper

“the JAK2 gain-of-function mutation (V617F) has been suggested to play a prominent role in MPNs (Baxter et al., 2005; Levine et al., 2005), being present in in ∼95% of PV, 50% to 60% of ET, and ∼50% of all PMF patients and associated with increased risk of mortality and splenomegaly”

What the sources say

• ?Not checked — no full text of the sourcecites Baxter et al., 2005 source
• ?Not checked — no full text of the sourcecites Levine et al., 2005 source
• Supported

  The “Clinical Relevance of JAK2V617F in Myelofibrosis” section reports the mutation in approximately 95% of PV patients and 50% of ET and MF patients; another passage says more than 50% of ET patients. It also reports significantly increased all-cause mortality and splenomegaly among patients with JAK2V617F compared with JAK2-wild-type patients in a PMF analysis. (LLM, conf=0.91)

  cites Verstovsek, 2010 source

In the paper

“Both TTI-101 and S3I-201 have been tested in several mouse models of fibrosis, including bleomycin-induced lung and skin fibrosis (scleroderma) and genetically-engineered models of scleroderma, as well as a model mouse of interstitial kidney fibrosis induced by unilateral ureteral obstruction, in which inhibition of STAT3 phosphorylation by these compounds blocks the development of organ fibrosis”

What the sources say

• ?Not checked — no full text of the sourcecites Pang et al., 2010 source
• ?Not checked — no full text of the sourcecites Pedroza et al., 2016 source
• Partly supported

  The Results section (page unavailable) reports that S3I-201 reduces skin fibrosis in two mouse models, along with myofibroblast differentiation and mRNA levels of fibrosis-related genes. The paper does not report testing TTI-101 or either compound in mouse models of lung or kidney fibrosis, so those parts of the attribution are unsupported. (LLM, conf=0.89)

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

In the paper

“The link between IL-6/STAT3 signaling and muscle and adipose tissue wasting is well established in mouse models of cachexia (White et al., 2011; Silva et al., 2015) and has been reinforced preliminarily in clinical studies.”

What the sources say

• Partly supported

  The Results section reports increased muscle STAT3 activation in cachectic ApcMin/+ mice and reduced activation after IL-6 receptor blockade; the Introduction also links IL-6 to muscle wasting. The paper does not establish a link to adipose tissue wasting. Its human evidence concerns reduced muscle protein synthesis after IL-6 administration, not clinical confirmation of the combined muscle-and-adipose claim. (LLM, conf=0.85)

  cites White et al., 2011 sourceExperimental — accuracy not yet measured
• Partly supported

  The mouse experiments and Discussion support a link between STAT3 signaling and muscle wasting in cancer cachexia; the Discussion proposes IL-6 as one possible activator. The introductory passage reports mouse studies of IL-6-associated muscle and fat loss, but also calls those results controversial. It does not establish STAT3-mediated adipose wasting, and the cited paper provides no clinical evidence for the separate clause about clinical studies. (LLM, conf=0.85)

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

In the paper

“whereas transient IL-6/STAT3 seems to be helping maintain glucose homeostasis, chronic IL-6/STAT3 signaling impairs insulin action, leading to insulin resistance and inflammation-associated glucose intolerance, probably through an increase in basal SOCS3 levels”

What the sources say

• Partly supported

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

  cites Yang et al., 2012 sourceExperimental — accuracy not yet measured
• Supported

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

  cites Wunderlich et al., 2013 source

In the paper

“The IL-6/JAK/STAT3 signaling pathway has also been implicated in many solid tumors, where it has been shown to promote tumor growth and progression while hindering antitumor immunity.”

What the sources say

• Supported

  The Abstract says the IL-6/JAK/STAT3 pathway has a key role in many human cancers and notes elevated IL-6 in patients with solid tumours. The STAT3 subsection describes its effects on tumour proliferation, invasion and metastasis, as well as its suppression of antitumour immunity. (LLM, conf=0.94)

  cites Johnson et al., 2018 source

In the paper

“In another Phase I trial of CDDO-Me in patients with advanced solid tumors and lymphomas, a complete tumor response occurred in one mantle cell lymphoma patient and a partial response was observed in an anaplastic thyroid carcinoma patient at a dose of 900 mg/day.”

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 Hong et al., 2012 sourceExperimental — accuracy not yet measured

In the paper

“Elevated levels of STAT3 have been observed in a large number of both solid and hematologic tumors, where its signaling underpins a majority of all known cardinal features of cancer (Yuan et al., 2015b), including growth and proliferation (Banerjee and Resat, 2016), antiapoptosis (Gritsko et al., 2006), cell transformation (Bromberg et al., 1999), angiogenesis (Doucette et al., 2012), metastasis (”

What the sources say

• ?Not matched

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

  cites Yuan et al., 2015b
• Supported

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

  cites Banerjee and Resat, 2016 source
• Supported

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

  cites Gritsko et al., 2006 source

In the paper

“Jakinibs are associated with immunosuppression, and common early adverse effects include diarrhea, nasopharyngitis, headache, and urinary tract infection, whereas prolonged treatment has been associated with upper respiratory tract infections, nasopharyngitis, and bronchitis.”

What the sources say

• ?Not checked — no full text of the sourcecites Bose et al., 2017 source
• 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 Kotyla, 2018 sourceExperimental — accuracy not yet measured

In the paper

“The naked, antisense, modified oligonucleotide, AZD9150 (danvatirsen), targets STAT3 and demonstrated antitumor activity in a Phase 1 dose-escalation study in patients with highly treatment-refractory lymphoma and NSCLC”

What the sources say

• Supported

  The Discussion states that AZD9150 is an antisense oligonucleotide that decreased STAT3 expression and demonstrated antitumor activity in patients with highly treatment-refractory lymphoma and non-small cell lung cancer in a phase I dose-escalation study. The Results describe responses in both patient groups. (LLM, conf=0.95)

  cites Hong et al., 2015 source

In the paper

“CDDO-Me inhibits constitutive and IL-6–induced JAK1 activity by directly binding to Cys1077 in the JAK1 kinase domain, thereby blocking its ability to phosphorylate STAT3 at Y705.”

What the sources say

• Partly supported

  The Discussion (page unavailable) says CDDO-Me inhibits IL-6-induced and constitutive JAK1 activity and supports a model in which binding at Cys1077 blocks JAK1 as an upstream effector of STAT3 phosphorylation. The ‘CDDO-Me interacts directly with JAK1’ section reports reduced binding after Cys1077 mutation and blocked JAK1-mediated STAT3 phosphorylation. Our copy does not specify Y705 as the phosphorylation site, so that detail is unsupported. (LLM, conf=0.86)

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

In the paper

“STAT3 has been implicated in chemotherapy resistance; there is a strong correlation between STAT3 activation and chemoresistance, and STAT3 inhibition has been shown to restore sensitivity of tumors to chemotherapeutic drugs”

What the sources say

• ?Not checked — no full text of the sourcecites Real et al., 2002 source
• ?Not checked — no full text of the sourcecites Huang et al., 2012 source
• Partly supported

  The Results section (‘Imatinib potentiates doxorubicin-induced apoptosis by inhibiting STAT3-dependent survival pathways’; page unavailable) says STAT3 is implicated in chemoresistance and reports that silencing STAT3 enhanced doxorubicin-induced apoptosis in cancer cells. It does not establish a strong correlation between STAT3 activation and chemoresistance, and its cell-based doxorubicin findings do not demonstrate restored sensitivity of tumors to chemotherapeutic drugs generally. (LLM, conf=0.85)

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

In the paper

“This molecule developed by Otsuka Pharmaceutical (Tokyo, Japan) showed a good pharmacokinetic profile (Hayakawa et al., 2013; Kim et al., 2013b; Bendell et al., 2014; Brambilla et al., 2015), but demonstrated limited antitumor activity in patients with HCC (Bendell et al., 2014). Furthermore, long-term dosing resulted in a high incidence of peripheral neuropathy”

What the sources say

• ?Could not verify

  Hayakawa et al. is cited for the good pharmacokinetic profile; the HCC activity claim is cited to Bendell et al., and the neuropathy statement has no citation attached in the supplied sentence. The Results discuss oral dosing and common toxicities, while the Discussion says the HCC study was ongoing, but neither section reports pharmacokinetic measurements or assesses the drug's pharmacokinetic profile (searched: pharmacokinetics, exposure, bioavailability and half-life). (LLM, conf=0.75)

  cites Hayakawa et al., 2013 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Bendell et al., 2014 source

In the paper

“Importantly, 5 of 10 patients demonstrated clinical benefit, with one patient experiencing a partial clinical response (40% reduction in tumor sizes according to response evaluation criteria in solid tumors) for 12 months.”

In the paper

“Key biological functions of Janus kinase (JAK)/signal transducer and activator of transcription (STAT)3 signaling can be delineated into two broad categories: those essential for normal cell and organ development and those activated in response to stress that are adaptive.”

In the paper

“The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signal transduction pathway is an evolutionarily conserved pathway present in Drosophila melanogaster through Homo sapiens (Hou et al., 2002).”

What the sources say

• ?Not checked — no full text of the sourcecites Hou et al., 2002 source

In the paper

“Not surprisingly, the majority of disease-causing mutations in JAKs are located in the JH2 domain.”

In the paper

“Latent STAT3 is predominantly localized in the cytoplasm as homotypic N-terminal domain (NTD)-to-NTD dimers.”

In the paper

“The N-terminal and SH2 domains are essential for the dimerization that, respectively, stabilizes the inactive and active conformations of STAT3.”

In the paper

“STAT3 activation is achieved when cytokines or peptide hormones bind to cell surface receptors, orchestrating a series of events, including phosphorylation at key sites, primarily tyrosine (Y) 705,which leads to activation or rearrangement of the dimer from NTD-to-NTD to SH2-to-SH2, nuclear localization, and transcriptional activation of specific genes by binding to respective DNA elements at the”

In the paper

“This domain is missing in the major alternative isoform of STAT3, STAT3β, due to alternative mRNA splicing that shifts the reading frame and replaces the 55-amino-acid residue TAD with seven distinct residues that confer prolonged nuclear retention to STAT3β compared with STAT3βΔ (Shao et al., 2001).”

What the sources say

• ?Not checked — no full text of the sourcecites Shao et al., 2001 source

In the paper

“More than 30 different cytokines in various tissue and cell systems have been implicated in the canonical signaling pathways of STAT3, involving nuclear translocation and activation of transcription of its target genes (Bharadwaj et al., 2016b).”

What the sources say

• ?Not matched

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

  cites Bharadwaj et al., 2016b

In the paper

“Furthermore, pS727 increases STAT3 binding to nuclear tyrosine phosphatase TC45 (Wakahara et al., 2012), leading to rapid dephosphorylation of pY705, thereby shortening the duration of STAT3 activity.”

What the sources say

• ?Not checked — no full text of the sourcecites Wakahara et al., 2012 source

In the paper

“STAT3 is a member of a family of seven proteins known to play critical roles in cytokine and growth factor signaling (Darnell, 2002).”

What the sources say

• ?Not checked — no full text of the sourcecites Darnell, 2002 source

In the paper

“STAT3 is structured into seven functional domains (Fig. 3): 1) the globular N-terminal domain, 2) coil-coiled domain, 3) DNA-binding domain, 4) linker domain, 5) SH2 domain, 6) loop domain, and 7) transactivation domain, all of which play a role in STAT3 function (Shao et al., 2004).”

What the sources say

• ?Not checked — no full text of the sourcecites Shao et al., 2004 source

In the paper

“High susceptibility to endotoxin shock, ↑ TNF-α, IL-1, and IFN-γ”

What the sources say

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

In the paper

“SOCS3 blocks IL-6 signaling by binding to gp130, thus limiting the IL-6/pY-STAT3 activation, but it does not inhibit IL-10/pY-STAT3 axis, inducing prolonged STAT3 activation”

What the sources say

• ?Not checked — no full text of the sourcecites Nakata et al., 2016 source

In the paper

“STAT3 is required for developmental transition of pre-pro-B cell progenitors to subsequent precursor populations and their survival”

What the sources say

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

In the paper

“Although both IL-6 and IL-10 activate STAT3, they confer opposite effects because of differential effects of SOCS3, induced by each”

What the sources say

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

In the paper

“Pretreatment of human platelets with the JAK3 inhibitor, WHI-P131, markedly diminished pY-STAT1 and pY-STAT3 levels and diminished all markers of platelet activation, including shape change, pseudopod formation, degranulation, serotonin release, as well as platelet aggregation”

What the sources say

• ?Not checked — no full text of the sourcecites Tibbles et al., 2001 source

In the paper

“treatment of mice with WHI-P131 prolonged bleeding time and improved event-free survival”

What the sources say

• ?Not checked — no full text of the sourcecites Tibbles et al., 2001 source

In the paper

“Activation of STAT3 also promotes transcription of IL-2 and perforin genes, thereby promoting natural killer cell activation”

What the sources say

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

In the paper

“STAT3 is also essential for Th17 differentiation mediated by IL-6/transforming growth factor (TGF)-β/IL-21”

What the sources say

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

“IL-6/TGF-β combination, in contrast, helps Th17 differentiation through upregulating the ectonucleotidases, CD39 and CD73 (IL-6/STAT3 action), which cleave extracellular ATP to produce immunosuppressive adenosine production and TGF-β–mediated downregulation of the transcriptional repressor growth factor independent-1”

What the sources say

• ?Not matched

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

  cites Rébé et al., 2013

In the paper

“Mice with homozygous knock-in substitution of LepRb tyrosine residue Tyr1138”

What the sources say

• ?Not checked — no full text of the sourcecites Bates et al., 2003 source
• ?Not checked — no full text of the sourcecites Bates and Myers, 2004 source

In the paper

“CD39-pos Th17 cells promotes tumor growth, suggesting their immunosuppressive role in cancer”

What the sources say

• ?Not checked — no full text of the sourcecites Chalmin et al., 2012 source

In the paper

“leptin, secreted by adipose tissue, regulates energy homeostasis, glucose and lipid metabolism, immune function, and other systems”

What the sources say

• ?Not matched

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

  cites Hu et al., 2018

In the paper

“adipocyte-specific JAK2-KO mice have impaired lipolysis and increased body weight through decreased STAT3 activation, which results in insulin resistance with ageing (Shi et al., 2014).”

What the sources say

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

In the paper

“following induction of differentiation, relative levels of pS-mtSTAT3 are markedly reduced in contrast to elevated levels of total cellular pS-STAT3”

What the sources say

• ?Not checked — no full text of the sourcecites Kramer et al., 2015 source

In the paper

“Cigarette smoke extract (CSE) induced IL-6 expression and increased levels of pY-STAT3 and STAT3-DNA binding in human bronchial epithelial cells (HBECs) (Liu, 2007), which protected these cells from apoptosis.”

What the sources say

• ?Not checked — no full text of the sourcecites Liu, 2007 source

In the paper

“Thus, STAT3 augmentation may be a viable strategy to prevent hemorrhagic shock–mediated pathologies, resulting in decrease in mortality”

In the paper

“Leukemia inhibitory factor binding to its receptor and gp130 activates Akt, STAT3, and ERK1/2 and protects cardiomyocytes from oxidative and ischemic stress by acting on mitochondria and inducing gene transcription (Zouein et al., 2013b).”

What the sources say

• ?Not matched

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

  cites Zouein et al., 2013b

In the paper

“Anti–IL-6 neutralizing antibody, as well as STAT3 small interfering RNA (siRNA), rendered HBECs sensitive to CSE-induced DNA damage, suggesting that STAT3 mediates HBEC survival in response to CSE-induced DNA damage (Liu, 2007).”

What the sources say

• ?Not checked — no full text of the sourcecites Liu, 2007 source

In the paper

“overexpressing of STAT3C (a constitutively active form of STAT3) in respiratory epithelial cells (Lian et al., 2005) improved animal survival following hyperoxia and protected the lung from inflammation and injury through reducing mRNA levels of matrix metalloproteases, e.g., matrix metalloproteinases (MMP)9 and MMP12, and levels of adhesion molecules”

What the sources say

• ?Not checked — no full text of the sourcecites Lian et al., 2005 source

In the paper

“Increased production of IL-6 and granulocyte cell–stimulating factor and activation of STAT3 was found to occur early in rat lungs following resuscitation from hemorrhagic shock, a whole-body ischemia–reperfusion injury (Hierholzer et al., 1998b,c; Meng et al., 2000, 2001).”

What the sources say

• ?Not matched

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

  cites Hierholzer et al., 1998b,c
• ?Not checked — no full text of the sourcecites Meng et al., 2000 source
• ?Not checked — no full text of the sourcecites Meng et al., 2001 source

In the paper

“Following DNA damage induced by topoisomerase I inhibition, STAT3 is phosphorylated by cdk5 at S727, but not Y705; pS-STAT3 transcriptionally upregulates Eme1, the endonuclease involved in DNA repair, which reduces DNA damage (Courapied et al., 2010).”

What the sources say

• ?Not checked — no full text of the sourcecites Courapied et al., 2010 source

In the paper

“Excessive JAK activity has been linked to numerous disorders, including inflammatory diseases such as psoriasis and inflammatory bowel disease; myeloproliferative diseases, e.g., polycythemia vera (PV); and hematologic malignancies, including myeloid leukemia and multiple myeloma.”

In the paper

“Following I/R injury (Hilfiker-Kleiner et al., 2004), cardiomyocyte-specific STAT3-KO mice had greater infarct size and cardiomyocyte apoptosis”

What the sources say

• ?Not checked — no full text of the sourcecites Hilfiker-Kleiner et al., 2004 source

In the paper

“Studies with cardiomyocyte-targeted STAT3-KO mice reveal that although cardiac STAT3 depletion did not affect infarct size, STAT3 is crucial for cardiac preconditioning (Smith et al., 2004).”

What the sources say

• ?Not checked — no full text of the sourcecites Smith et al., 2004 source

In the paper

“Several approaches to reduce STAT3 activity have been proposed and include targeting of specific receptors or receptor-associated kinases, especially JAKs, upstream of STAT3, in addition to strategies to directly interfere with STAT3 activity by preventing its recruitment to receptors, dimerization, nuclear localization, and DNA binding [see Bharadwaj et al. (2016b)].”

What the sources say

• ?Not matched

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

  cites Bharadwaj et al. (2016b)

In the paper

“Prolonged elevated glucose could also signal as a cell stressor through multiple pathways, including hyperosmolarity (McGinn et al., 2003), protein kinase C (PKC) activation (Mandarino, 1992), and oxidative damage (Nishikawa et al., 2000), likely involving pS-STAT3, as well as pY-STAT3.”

What the sources say

• ?Not checked — no full text of the sourcecites McGinn et al., 2003 source
• ?Not checked — no full text of the sourcecites Mandarino, 1992 source
• ?Not checked — no full text of the sourcecites Nishikawa et al., 2000 source

In the paper

“Manifestations of dextran sulfate sodium–induced colitis were more severe in STAT3Δβ/Δβ transgenic mice, which express only STAT3α (Maritano et al., 2004; Marino et al., 2014), indicating that a STAT3 activity globally contributes to dextran sulfate sodium–induced colitis.”

What the sources say

• ?Not checked — no full text of the sourcecites Maritano et al., 2004 source
• ?Not checked — no full text of the sourcecites Marino et al., 2014

In the paper

“whereas JAK-STAT inhibitor treatment leads to improvement in constitutional symptoms and reduced splenomegaly, they show only modest benefit in reduction of clonal burden (Deininger et al., 2015), suggesting that the bulk of the observed clinical benefit of these inhibitors may arise from modulation of JAK-STAT signaling not associated with the expanded mutant clone(s).”

What the sources say

• ?Not checked — no full text of the sourcecites Deininger et al., 2015 source

In the paper

“bardoxolone has been found to be toxic to mitochondria, as it inhibits mitochondrial electron transport via perturbations in inner mitochondrial membrane integrity (Samudio et al., 2006), which, as with the Otsuka compounds described above, has implications for toxicity of this agent in patients.”

What the sources say

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

In the paper

“Grade 3 TEAE were GI-related (7.3%) and fatigue (2.4%).”

What the sources say

• ?Not checked — no full text of the sourcecites Jonker et al., 2014 source
• ?Not checked — no full text of the sourcecites Laurie et al., 2014 source

In the paper

“It has been shown to downregulate expression of genes associated with cancer cell stemness and to kill cells exhibiting properties of cancer cell stemness in various types of cancers.”

What the sources say

• ?Not matched

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

  cites Li et al., 2015

In the paper

“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).”

What the sources say

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

In the paper

“Dose escalation was stopped because of pill burden, and no maximum tolerated dose was established.”

What the sources say

• ?Not checked — no full text of the sourcecites Jonker et al., 2014 source
• ?Not checked — no full text of the sourcecites Laurie et al., 2014 source

In the paper

“Preclinical studies in mouse models of several cancers show that napabucasin was effective both as monotherapy and in combination with other agents, particularly paclitaxel where synergy was observed.”

What the sources say

• ?Not checked — no full text of the sourcecites Garcia et al., 2016 source

In the paper

“Notably, no new AE or pharmacokinetic interactions were observed when napabucasin was combined with paclitaxel.”

What the sources say

• ?Not checked — no full text of the sourcecites Garcia et al., 2016 source

In the paper

“In contrast, STAT3 inhibitors that reduced levels of pY-STAT3 would be expected to increase U-STAT3 levels, if only slightly, and would be expected to have minimal impact on the activity of U-STAT3.”

In the paper

“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.”

What the sources say

• ?Not matched

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

  cites Xu et al., 2009

In the paper

“Pyrimethamine currently is marketed for the treatment of parasitic diseases and is under evaluation in Phase I/II clinical trials in Europe for a number of cancer indications, including CLL and triple-negative breast cancer.”

What the sources say

• ?Not matched

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

  cites EU Clinical Trials Register, 2017

In the paper

“Jakinibs have been successfully introduced into the clinic, as described above, and, for the foreseeable future, they will continue to be useful in the treatment of several inflammatory and neoplastic conditions.”

In the paper

“WP-1066 is a potent inhibitor of JAK2 and downstream STAT3 signaling.”

What the sources say

• ?Not matched

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

  cites Bharadwaj et al., 2016b

In the paper

“Their toxicities, although for the most part manageable, are the major impediment to their broader use, however.”

In the paper

“The future of STAT3 inhibitors as therapies for inflammatory and fibrotic disorders and for cancer is promising, but caution is urged especially with regard to achieving sufficient target engagement, especially in the setting of cancer, and the avoidance of toxicity, especially in noncancer indications.”