tbuckley/cabot-search huggingface dataset:
A2.26 JAK-STAT signalling regulates pro-inflammatory mediators and fibroblast invasion in RA
Authors: C Orr, E Linehan, W Gao, K McCreevy, T McGarry, U Fearon, DJ Veale
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background/Objectives</h3> Rheumatoid Arthritis (RA) is a common, chronic immune-mediated inflammatory disease, characterised by synovitis and progressive destruction of articular cartilage and bone. Janus Kinase and Signal Transducer and Activator of Transcription (JAK/STAT), a critical signalling pathway involved in inflammatory mechanisms, has been implicated in the pathogenesis of RA. In this study we examine the effect of Tofacitinib (JAK inhibitor CP-690,550) on pro-inflammatory pathways in RA using in vitro and ex-vivo culture models. <h3>Methods</h3> Primary RA synovial fibroblasts (RASFC) and whole tissue <i>ex vivo</i> RA synovial explant cultures were established from RA biopsies obtained at arthroscopy. Phospho-STAT3 (p-STAT3), phospho-STAT1 (p-STAT1), Suppressor of Cytokine Signalling 3 (SOCS3) and Protein Inhibitor of Activated Stat 3 (PIAS3) expression were quantified by Western Blot in RASFC following culture in the presence of IL-17, OSM and IL-6. RASFC were cultured with IL-17, OSM and IL-6 in the presence or absence of Tofacitinib (1 uM) and cytokine secretion in supernatants were measured by ELISA. Ex-vivo RA synovial explants were cultured with Tofacitinib (1 uM) and spontaneous secretion of IL-6, IL-8, MMP3, Tie2, PIGF and bFGF were quantified in supernatants by ELISA or MSD multiplex. Finally conditioned media from control and Tofacitinib treated RA explants were cultured with RASFC and cell invasion assessed by Transwell Matrigel<sup>TM</sup> invasion chambers. <h3>Results</h3> IL-17, OSM and IL-6 induced p-STAT3, p-STAT1 expression and inhibited SOCS3 and PIAS3 expression in RASFC. Tofacitinib decreased IL-17, OSM and IL-6 induced cytokine production from RASFC. Tofacitinib inhibited spontaneous release of IL-6, IL-8, MMP3 and soluble Tie2 receptor from RA synovial explant cultures, with no effect observed for PIGF and bFGF. Finally, conditioned media from Tofacitinib treated RA explants inhibited RASFC invasion. <h3>Conclusion</h3> This study demonstrates inverse expression of pSTATs and their negative regulators SOCS3/PIAS3 in response to pro-inflammatory mediators in RA. In addition Tofacitinib inhibits pro-inflammatory mediators and RASFC invasion, further confirming a role for JAK-STAT inhibition in the treatment of RA.
In vitro studies on peripheral blood leucocytes in rheumatoid arthritis.
Authors: H A Menard, T Haim, A P Peltier
Journal: Annals of the Rheumatic Diseases (1974)

Current concepts onthepathogenesis ofrheumatoid arthritis (RA)centre oninflammation induced by immunecomplexes. These complexes consist mainly ofIgGandIgG-rheumatoid factor present locally or sometimes systemically. Thismechanism explains thesuperimposable deposition ofimmunoglobulins andcomplement inthesynovial membrane andalso manyfeatures oftherheumatoid synovial fluid: low complement levels, anticomplementary
A Continuous-State Coalescent and the Impact of Weak Selection on the Structure of Gene Genealogies
Authors: B. D. O'Fallon, J. Seger, F. R. Adler
Journal: Molecular Biology and Evolution (2010)

Coalescent theory provides an elegant and powerful method for understanding the shape of gene genealogies and resulting patterns of genetic diversity. However, the coalescent does not naturally accommodate the effects of heritable variation in fitness. Although some methods are available for studying the effects of strong selection (Ns ≫ 1), few tools beyond forward simulation are available for quantifying the impact of weak selection at many sites. Here, we introduce a continuous-state coalescent capable of accurately describing the distortions to genealogies caused by moderate to weak natural selection affecting many linked sites. We calculate approximately the full distribution of pairwise coalescent times, the lengths of coalescent intervals, and the time to the most recent common ancestor of a sample. Weak selection (Ns ≈ 1) is found to substantially decrease the tree depth, primarily through a shortening of the lengths of the basal coalescent intervals. Additionally, we demonstrate that only two parameters, population size and the variance of the distribution describing fitness heritability, are sufficient to describe most changes.
Endogenous Toll-Like Receptor 9 Regulates AKI by Promoting Regulatory T Cell Recruitment
Authors: Maliha A. Alikhan, Shaun A. Summers, Poh Y. Gan, Amy J. Chan, Mary B. Khouri, Joshua D. Ooi, Joanna R. Ghali, Dragana Odobasic, Michael J. Hickey, A. Richard Kitching, Stephen R. Holdsworth
Journal: Journal of the American Society of Nephrology (2015)

Toll-like receptor 9 (TLR9) enhances proinflammatory responses, but whether it can act in a regulatory capacity remains to be established. In experimental murine AKI induced by cisplatin, Tlr9(-/-) mice developed enhanced renal injury and exhibited fewer intrarenal regulatory T cells (Tregs) compared with genetically intact mice. A series of reconstitution and depletion studies defined a role for TLR9 in maintaining Treg-mediated homeostasis in cisplatin-induced AKI. When Rag1(-/-) mice were reconstituted with nonregulatory CD25(-) splenocytes from wild-type (WT) or Tlr9(-/-) mice, AKI was similarly enhanced. However, when Rag1(-/-) mice were reconstituted with CD4(+)CD25(+) regulatory cells, WT CD4(+)CD25(+) cells were more renoprotective and localized to the kidney more efficiently than Tlr9(-/-) CD4(+)CD25(+) cells. In Treg-depleted Foxp3(DTR) mice, reconstitution with naive WT CD4(+)CD25(+) cells resulted in less severe AKI than did reconstitution with Tlr9(-/-) Tregs. Tlr9(-/-) mice were not deficient in CD4(+)CD25(+) cells, and WT and TLR9-deficient Tregs had similar suppressive function ex vivo. However, expression of adhesion molecules important in Treg trafficking was reduced on peripheral CD4(+)CD25(+) cells from Tlr9(-/-) mice. In conclusion, we identified a pathway by which TLR9 promotes renal Treg accumulation in AKI.
Progress with Chronic Myelogenous Leukemia: A Personal Perspective over Four Decades
Authors: Peter C. Nowell
Journal: Annual Review of Medicine (2002)

Our understanding and treatment of chronic myelogenous leukemia (CML) has progressed since 1960 in parallel with work on cancer in general. CML provided the first evidence of a specific genetic change associated with a human cancer (the Philadelphia chromosome) and the clonal nature of these disorders. With improved cytogenetic and molecular techniques over subsequent decades, the specific genetic rearrangements of CML and many other tumors were defined and the complex mechanisms of carcinogenesis gradually unraveled. During this period, improved treatments for CML (chemotherapy, interferon, bone marrow transplantation) were implemented, and therapy targeted to the specific genetic change in the leukemic cells has recently been brought to promising clinical trials. Similar efforts are under way for other human cancers, and although the problem is enormously complex, there is real hope for major improvements in controlling these disorders.
Phase II Clinical Trial of Neoadjuvant Alternating Doublet Chemotherapy With Ifosfamide/Doxorubicin and Etoposide/Cisplatin in Small-Cell Urothelial Cancer
Authors: Arlene O. Siefker-Radtke, Ashish M. Kamat, H. Barton Grossman, Dallas L. Williams, Wei Qiao, Peter F. Thall, Colin P. Dinney, Randall E. Millikan
Journal: Journal of Clinical Oncology (2009)

Currently, treatment recommendations for small-cell urothelial cancer (SCUC) are based on anecdotal case reports and small retrospective series. We now report results from the first phase II clinical trial developed exclusively for SCUC, to our knowledge.From 2001 to 2006, 30 patients with SCUC provided consent and were treated with alternating doublet chemotherapy. Patients with surgically resectable disease (< or = cT4aN0M0) received a total of four cycles of neoadjuvant chemotherapy, whereas those with unresectable disease (> or = cT4b, N+, or M+) received two cycles beyond maximal response.Eighteen patients with surgically resectable SCUC received neoadjuvant treatment with a median overall survival (OS) of 58 months; 13 of these patients remain alive and cancer free. For patients with cT2N0M0 SCUC, the 5-year OS rate is 80%; only one of four patients with cT3b-4aN0M0 remains alive (median OS, 37.8 months). For 12 patients with unresectable or metastatic SCUC, the median OS was 13.3 months. Chemotherapy was well tolerated, with transfusion, neutropenic fever, and infection remaining the most frequent grade 3 and 4 toxicities. There was only one postsurgical death. Brain metastases were strongly associated with more advanced-stage disease, developing in eight of 16 patients with either bulky tumors (> or = cT3b) or metastatic disease (P = .004).These clinical trial results are consistent with previously reported retrospective data demonstrating long-term survival with four cycles of neoadjuvant chemotherapy for surgically resectable SCUC. Once metastases develop, the prognosis remains poor. The strong positive association between disease stage and brain metastases highlights a patient subset that may potentially benefit from prophylactic cranial irradiation.
Prognostic factors in pathological stage IB nonsmall cell lung cancer greater than 3 cm
Authors: J-J. Hung, W-J. Jeng, W-H. Hsu, S-F. Lin, C-C. Hsieh, B-S. Huang, M-H. Huang, J-S. Liu, T-Y. Chou, Y-C.i Wu
Journal: European Respiratory Journal (2010)

Significant heterogenity of stage IB (sixth edition of the TNM staging system) nonsmall cell lung cancer (NSCLC) has been identified, and further subclassification according to tumour size has been proposed. The aim of this study is to evaluate the prognostic factors in patients with resected stage IB NSCLC > 3 cm. From January 1980 to December 2000, 525 patients underwent surgical resection for stage IB NSCLC > 3 cm at Taipei Veterans General Hospital, Taipei, Taiwan. The clinicopathological characteristics of these patients were retrospectively reviewed. The 5- and 10-yr overall survival rates were 44.9% and 27.3%, respectively. Age (p < 0.001), tumour size (p = 0.002), extent of pulmonary resection (p = 0.002), histological type (p = 0.005) and number of mediastinal lymph nodes dissected/sampled (p = 0.004) were significant predictors for overall survival in multivariate analysis. Patients with tumour size >7 cm, or > 5 to ≤ 7 cm, had a worse survival than those with tumour size > 3 to ≤ 5 cm. However, visceral pleural invasion did not influence overall survival. Stage IB NSCLC with a diameter > 3 cm may be subclassified according to tumour size regardless of visceral pleural invasion.
Role of CCR8 and Other Chemokine Pathways in the Migration of Monocyte-derived Dendritic Cells to Lymph Nodes
Authors: Chunfeng Qu, Emmerson W. Edwards, Frank Tacke, Véronique Angeli, Jaime Llodrá, Guzman Sanchez-Schmitz, Alexandre Garin, Nasreen S. Haque, Wendy Peters, Nico van Rooijen, Carmen Sanchez-Torres, Jonathan Bromberg, Israel F. Charo, Steffen Jung, Sergio A. Lira, Gwendalyn J. Randolph
Journal: The Journal of Experimental Medicine (2004)

Studying the influence of chemokine receptors (CCRs) on monocyte fate may reveal information about which subpopulations of monocytes convert to dendritic cells (DCs) and the migration pathways that they use. First, we examined whether prominent CCRs on different monocyte subsets, CCR2 or CX3CR1, mediated migration events upstream of the accumulation of monocyte-derived DCs in lymph nodes (LNs). Monocytes were labeled and traced by uptake of latex microspheres in skin. Unexpectedly, neither CCR2 nor CX3CR1 were required. However, absence of CCR2 led to an increased labeling of the minor Gr-1int monocyte population, and the number of latex+ DCs that emigrated to LNs was correspondingly increased. Characterization of Gr-1int monocytes revealed that they selectively expressed CCR7 and CCR8 mRNA in blood. CCR7 and CCR8 pathways were used by monocyte-derived DCs during mobilization from skin to LNs. The role of CCR8 in emigration from tissues also applied to human monocyte-derived cells in a model of transendothelial trafficking. Collectively, the data suggest that Gr-1int monocytes may be most disposed to become a lymphatic-migrating DCs. When these monocyte-derived DCs exit skin to emigrate to LNs, they use not only CCR7 but also CCR8, which was not previously recognized to participate in migration to LNs.
Early Versus Delayed Endocrine Treatment of T2-T3 pN1-3 M0 Prostate Cancer Without Local Treatment of the Primary Tumour: Final Results of European Organisation for the Research and Treatment of Cancer Protocol 30846 After 13 Years of Follow-up (A Randomised Controlled Trial)
Authors: Fritz H. Schröder, Karl-Heinz Kurth, Sophie D. Fossa, Wytse Hoekstra, Peter P. Karthaus, Linda De Prijck, Laurence Collette
Journal: European Urology (2008)
Alemtuzumab Compared With Chlorambucil As First-Line Therapy for Chronic Lymphocytic Leukemia
Authors: Peter Hillmen, Aleksander B. Skotnicki, Tadeusz Robak, Branimir Jaksic, Anna Dmoszynska, Jingyang Wu, Cynthia Sirard, Jiri Mayer
Journal: Journal of Clinical Oncology (2007)

Purpose We conducted a randomized trial to evaluate the efficacy and safety of intravenous alemtuzumab compared with chlorambucil in first-line treatment of chronic lymphocytic leukemia (CLL). Patients and Methods Patients received alemtuzumab (30 mg three times per week, for up to 12 weeks) or chlorambucil (40 mg/m 2 every 28 days, for up to 12 months). The primary end point was progression-free survival (PFS). Secondary end points included overall response rate (ORR), complete response (CR), time to alternative therapy, safety, and overall survival. Results We randomly assigned 297 patients, 149 to alemtuzumab and 148 to chlorambucil. Alemtuzumab had superior PFS, with a 42% reduction in risk of progression or death (hazard ratio [HR] = 0.58; P = .0001), and a median time to alternative treatment of 23.3 versus 14.7 months for chlorambucil (HR = 0.54; P = .0001). The ORR was 83% with alemtuzumab (24% CR) versus 55% with chlorambucil (2% CR); differences in ORR and CR were highly statistically significant (P &lt; .0001). Elimination of minimal residual disease occurred in 11 of 36 complete responders to alemtuzumab versus none to chlorambucil. Adverse events profiles were similar, except for more infusion-related and cytomegalovirus (CMV) events with alemtuzumab and more nausea and vomiting with chlorambucil. CMV events had no apparent impact on efficacy. Conclusion As first-line treatment for patients with CLL, alemtuzumab demonstrated significantly improved PFS, time to alternative treatment, ORR and CR, and minimal residual disease–negative remissions compared with chlorambucil, with predictable and manageable toxicity.
THE RELATIONSHIP BETWEEN ANTIGENIC STRUCTURE AND THE REQUIREMENT FOR THYMUS-DERIVED CELLS IN THE IMMUNE RESPONSE
Authors: Marc Feldmann, Antony Basten
Journal: The Journal of Experimental Medicine (1971)

Certain antigens such as polymerized flagellin are capable of producing relatively normal antibody levels in thymectomized mice, whereas others, including heterologous erythrocytes require the presence of T cells in a helper capacity. The mechanism of thymus-independent antibody production was investigated by comparing the primary IgM responses of spleen cells from ATXBM, XBM, and normal mice to various physical forms of the flagellar antigens of Salmonella adelaide in vitro. No reduction in antibody-forming cell levels to polymerized flagellin over a wide dose range was observed in ATXBM cultures, although the same spleen cells did not respond to an optimal dose of sheep red cells. In contrast, when flagellar determinants were presented in a monomeric form or as flagellin-coated donkey red cells, a highly significant difference was observed between the antibody responses of spleen cells from ATXBM mice and XBM or normal controls. The results suggested that the requirement for T cells in antibody production is not a property of specific antigenic determinants, but depends on the mode of antigenic presentation. The validity of this conclusion was confirmed by using another antigenic determinant (DNP) coupled either to the thymus-independent carrier, POL, or to the thymus-dependent carrier, DRC. Spleen cells from XBM mice produced comparable AFC levels to both forms of DNP, but the results from ATXBM cultures showed a marked difference. The anti-DNP response to DNP-DRC was greatly reduced compared to controls, whereas that to DNP-POL was normal even after prolonged thoracic duct drainage of the ATXBM donors and pretreatment of their spleen cells with anti-theta-serum and complement. The data presented here imply that the role of T cells in humoral immunity is the presentation of antigen to B cells in such a manner as to initiate optimal antibody synthesis.
Objective Responses in Patients with Malignant Melanoma or Renal Cell Cancer in Early Clinical Studies Do Not Predict Regulatory Approval
Authors: John Goffin, Stefan Baral, Dongsheng Tu, Dora Nomikos, Lesley Seymour
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Tumor responses in early-phase trials are used to determine whether new agents warrant further study. Given that spontaneous regressions are observed in melanoma and renal cell carcinoma, this study assessed whether tumor responses, particularly in these two tumor types, predict for future regulatory drug approval. Experimental Design: The literature was reviewed to assess tumor response rates to cytotoxic agents in phase I and II trials in the following solid tumors: melanoma, renal cell carcinoma, non–small-cell lung cancer, breast cancer, ovarian cancer, colorectal cancer, and other solid tumors. Response rates were categorized and the relationship of these categories to the end point of regulatory drug approval was determined. Results: Fifty-eight drugs were assessed in 100 phase I trials, and 46 of these drugs were also studied in 499 phase II trials. Higher overall response rates in both phase I trials (P = 0.03) and phase II trials (P &amp;lt; 0.0001) were predictive of regulatory approval. However, response in melanoma or renal cell carcinoma was not predictive for either phase I or phase II studies. Conclusions: For cytotoxic agents, although overall objective response rates reliably predict subsequent marketing approval, isolated responses in melanoma and renal cell carcinoma are not predictive.
X-ray-Induced Changes in Gene lt Expression in Normal and r, Oncogene-Transformed Rat Cell Lines
Authors: M. Lambert, C. Borek
Journal: JNCI Journal of the National Cancer Institute (1988)

As an approach to identifying specific cellular markers for the cyto-toxic action of x rays in mammalian cells, we used the QUEST system of high-resolution, two-dimensional protein gel electrophoresis and a computerized data base on proteins to score quantitative changes in patterns of protein synthesis. We measured the responses elicited after x irradiation of cells from the normal rat cell line REF52 as well as two oncogene-transformed REF52 cell lines with Ela or Ela plus the mutated c-Harvey-ras T24 (HRAS1 T24) allele. The transformed cell lines differed substantially in the patterns of changes in protein synthesis seen immediately after DNA damage. In addition, we identified a specific subset of growth-regulated cellular polypeptides that are correlated with the observed increase in x-ray-induced cell killing hi the transformed cell lines. One of these polypeptides was cyclin (proliferating-cell nuclear antigen), a cell-cycle-specific DNA polym-erase delta auxiliary factor. Synthesis of this set of coregulated polypeptides was rapidly suppressed by x irradiation in normal REF52 cells only. The inability of x irradiation to induce suppression of protein synthesis in cells from the transformed cell lines correlated with the increased susceptibility to x-ray-induced cell killing. This finding suggests that the cellular processes that underlie regulation of DNA-damage-induced growth arrest at the level of replicative elongation plays a role hi determining the survival of x-irradiated cells. [J Natl Cancer Inst 1988:80:1402–14071
Sporadic desmoid-type fibromatosis: a stepwise approach to a non-metastasising neoplasm—a position paper from the Italian and the French Sarcoma Group
Authors: A. Gronchi, C. Colombo, C. Le Péchoux, A.P. Dei Tos, A. Le Cesne, A. Marrari, N. Penel, G. Grignani, J.Y. Blay, P.G. Casali, E. Stoeckle, F. Gherlinzoni, P. Meeus, C. Mussi, F. Gouin, F. Duffaud, M. Fiore, S. Bonvalot
Journal: Annals of Oncology (2013)
Virus–host interactions in HBV-related hepatocellular carcinoma: more to be revealed?
Authors: Wanlu Cao, Maikel P Peppelenbosch, Qiuwei Pan
Journal: Gut (2014)

Sir,

We read with interest the paper by Amaddeo et al 1 describing a comprehensive and integrative study to understand the molecular characteristics of HBV-related hepatocellular carcinoma (HCC). Chronic HBV infection is one of the most common causes of HCC. Although integration of viral gene into host genome has been implicated as an important oncogenic mechanism, a series of studies have reported that both direct and indirect hepatocarcinogenic actions of HBV infection exist. Amaddeo et al 1 found a frequent inactivation of p53 and overexpression of stem cell-related genes in HBV-infected HCC tumours. Most importantly, TP53 mutations were shown to be associated with poor prognosis exclusively in HBV-related patients. This is probably an indirect oncogenic mechanism resulting from HBV infection.

In parallel, in a very recent Cancer Cell paper, …
Noninvasive Versus Histologic Detection of Gastric Atrophy in a Hispanic Population in North America
Authors: David Y. Graham, Zhannat Z. Nurgalieva, Hala M.T. El-Zimaity, Antone R. Opekun, Armando Campos, Leoncio Guerrero, Alfredo Chavez, Victor Cardenas
Journal: Clinical Gastroenterology and Hepatology (2006)
Survival in Bladder and Renal Cell Cancers Is Familial
Authors: Jianguang Ji, Asta Fo[Combining Diaeresis]rsti, Jan Sundquist, Per Lenner, Kari Hemminki
Journal: Journal of the American Society of Nephrology (2008)

Having family members with cancer has been associated with increased risk for bladder and renal cell cancers, but its association with survival has not been examined. This study was an analysis of the nationwide Swedish Family-Cancer Database and revealed that survival for bladder and renal cell cancers was similar whether the cancer was familial or sporadic; however, when survival in offspring was analyzed according to the affected parents' length of survival, prognosis was concordant. Cox proportional hazard regression models revealed that for bladder cancer, the risk for death among offspring whose parents survived > or =5 yr was approximately one third that of offspring whose parents survived <5 yr, after adjustment for gender, age at diagnosis, time period of diagnosis, socioeconomic status, and geographic region (adjusted hazard ratio 0.34; 95% confidence interval 0.15 to 0.80, for overall mortality). A risk of similar magnitude was found for renal cell cancer (adjusted hazard ratio 0.38; 95% confidence interval 0.16 to 0.87, for overall mortality). These population-level findings suggest heritability of prognosis for bladder and renal cell cancers. Genetic factors likely contribute to the mechanism underlying this observation.