tbuckley/cabot-search huggingface dataset:
Capsiate, a Nonpungent Capsaicin-Like Compound, Inhibits Angiogenesis and Vascular Permeability via a Direct Inhibition of Src Kinase Activity
Authors: Bo-Jeong Pyun, Sun Choi, Yoonji Lee, Tae-Woong Kim, Jeong-Ki Min, Yonghak Kim, Byung-Dong Kim, Jeong-Han Kim, Tae-Yoon Kim, Young-Myeong Kim, Young-Guen Kwon
Journal: Cancer Research (2008)

Abstract Capsiate, a nonpungent capsaicin analogue, and its dihydroderivative dihydrocapsiate are the major capsaicinoids of the nonpungent red pepper cultivar CH-19 Sweet. In this study, we report the biological actions and underlying molecular mechanisms of capsiate on angiogenesis and vascular permeability. In vitro, capsiate and dihydrocapsiate inhibited vascular endothelial growth factor (VEGF)–induced proliferation, chemotactic motility, and capillary-like tube formation of primary cultured human endothelial cells. They also inhibited sprouting of endothelial cells in the rat aorta and formation of new blood vessels in the mouse Matrigel plug assay in response to VEGF. Moreover, both compounds blocked VEGF-induced endothelial permeability and loss of vascular endothelial (VE)–cadherin–facilitated endothelial cell-cell junctions. Importantly, capsiate suppressed VEGF-induced activation of Src kinase and phosphorylation of its downstream substrates, such as p125FAK and VE-cadherin, without affecting autophosphorylation of the VEGF receptor KDR/Flk-1. In vitro kinase assay and molecular modeling studies revealed that capsiate inhibits Src kinase activity via its preferential docking to the ATP-binding site of Src kinase. Taken together, these results suggest that capsiate could be useful for blocking pathologic angiogenesis and vascular permeability caused by VEGF. [Cancer Res 2008;68(1):227–35]
Heat Shock Protein 90 and ErbB2 in the Cardiac Response to Doxorubicin Injury
Authors: Kathleen Gabrielson, Djahida Bedja, Scott Pin, Allison Tsao, Lucio Gama, Bibo Yuan, Nicole Muratore
Journal: Cancer Research (2007)

Abstract A major drawback to doxorubicin as a cancer-treating drug is cardiac toxicity. To understand the mechanism of doxorubicin cardiac toxicity and the potent synergic effect seen when doxorubicin is combined with anti-ErbB2 (trastuzumab), we developed an in vivo rat model that exhibits progressive dose-dependent cardiac damage and loss of cardiac function after doxorubicin treatment. The hearts of these animals respond to doxorubicin damage by increasing levels of ErbB2 and the ErbB family ligand, neuregulin 1β, and by activating the downstream Akt signaling pathway. These increases in ErbB2 protein levels are not due to increased ErbB2 mRNA, however, suggesting post-transcriptional mechanisms for regulating this protein in the heart. Accordingly, levels of heat shock protein 90 (HSP90), a known ErbB2 protein stabilizer and chaperone, are increased by doxorubicin treatment, and coimmunoprecipitation reveals binding of HSP90 to ErbB2. Isolated cardiomyocytes are more susceptible to doxorubicin after treatment with HSP90 inhibitor, 17-(allylamino)-17-demethoxygeldanamycin, suggesting that the HSP90 is protective during doxorubicin treatment. Thus, our results provide one plausible mechanism for the susceptibility of the heart to anti-ErbB2 therapy post-doxorubicin therapy in subclinical and clinical conditions. Additionally, these results suggest that further testing is needed for HSP90 inhibitors under various conditions in the heart. [Cancer Res 2007;67(4):1436–41]
N<scp>aturally</scp>A<scp>rising</scp>CD4<sup>+</sup>R<scp>egulatory</scp>T C<scp>ells for</scp>I<scp>mmunologic</scp>S<scp>elf</scp>-T<scp>olerance and</scp>N<scp>egative</scp>C<scp>ontrol of</scp>I<scp>mmune</scp>R<scp>esponses</scp>
Authors: Shimon Sakaguchi
Journal: Annual Review of Immunology (2003)

▪ Abstract Naturally occurring CD4 + regulatory T cells, the majority of which express CD25, are engaged in dominant control of self-reactive T cells, contributing to the maintenance of immunologic self-tolerance. Their depletion or functional alteration leads to the development of autoimmune disease in otherwise normal animals. The majority, if not all, of such CD25 + CD4 + regulatory T cells are produced by the normal thymus as a functionally distinct and mature subpopulation of T cells. Their repertoire of antigen specificities is as broad as that of naive T cells, and they are capable of recognizing both self and nonself antigens, thus enabling them to control various immune responses. In addition to antigen recognition, signals through various accessory molecules and via cytokines control their activation, expansion, and survival, and tune their suppressive activity. Furthermore, the generation of CD25 + CD4 + regulatory T cells in the immune system is at least in part developmentally and genetically controlled. Genetic defects that primarily affect their development or function can indeed be a primary cause of autoimmune and other inflammatory disorders in humans. Based on recent advances in our understanding of the cellular and molecular basis of this T cell–mediated immune regulation, this review discusses how naturally arising CD25 + CD4 + regulatory T cells contribute to the maintenance of immunologic self-tolerance and negative control of various immune responses, and how they can be exploited to prevent and treat autoimmune disease, allergy, cancer, and chronic infection, or establish donor-specific transplantation tolerance.
One week triple therapy for <i>Helicobacter pylori</i>: a multicentre comparative study
Authors: J J Misiewicz, A W Harris, K D Bardhan, S Levi, C O’Morain, B T Cooper, G D Kerr, M F Dixon, H Langworthy, D Piper
Journal: Gut (1997)

Background— Eradication of Helicobacter pylori cures and prevents the relapse of duodenal ulceration and also results in histological resolution of chronic active gastritis. Aim —To compare four treatment regimens lasting seven days of a proton pump inhibitor and two antibiotics in the eradication of H pylori . Patients —Men or women with H pylori positive duodenal ulceration or gastritis, or both. Methods —A single blind, prospectively randomised, parallel group, comparative, multicentre study. After a positive CLO test, patients underwent histology, H pylori culture, and a 13 C urea breath test to confirm H pylori status. Treatment with one of four regimens: LAC, LAM, LCM, or OAM, where L is 30 mg of lansoprazole twice daily, A is 1 g of amoxycillin twice daily, M is 400 mg of metronidazole twice daily, C is 250 mg of clarithromycin twice daily, and O is 20 mg of omeprazole twice daily, was assigned randomly. A follow up breath test was done at least 28 days after completing treatment. Results — H pylori eradication (intention to treat) was 104/121 (86.0%) with LAC, 87/131 (66.4%) with LAM, 103/118 (87.3%) with LCM, and 94/126 (74.6%) with OAM. There was a significant difference (p &lt; 0.001) in the proportion of patients in whom eradication was successful between LAC and LCM when compared with LAM, but no significant difference (p = 0.15) between LAM and OAM. Metronidazole resistance before treatment was identified as a significant prognostic factor with regard to eradication of H pylori . The regimens which contained metronidazole were significantly less effective than those without metronidazole in the presence of pretreatment resistant H pylori . There was no difference among the treatment groups with regard to the incidence and severity of adverse events reported. Conclusions —All four treatment regimens were safe and effective in eradicating H pylori in the patient population studied. LAC was the most efficacious treatment in patients with pretreatment metronidazole resistant H pylori , and was significantly better than LAM and OAM in this group of patients.
BAL lymphocyte activation antigens and diffusing capacity are related in mild to moderate pulmonary sarcoidosis
Authors: A Xaubet, C Agusti, J Roca, C Picado, R Rodriguez-Roisin
Journal: European Respiratory Journal (1993)

To investigate the relationship [corrected] between immunocytological features of bronchoalveolar lavage (BAL) and clinical indices in sarcoidosis, we studied the lymphocyte subsets, as well as the expression of human leucocyte antigen-DR (HLA-DR) and interleukin 2 receptor (IL-2R) antigens in BAL lymphocytes. We studied 16 patients with untreated sarcoidosis and 12 control subjects. We found significantly higher absolute numbers of lymphocytes bearing the IL-2R antigen in sarcoidosis. A stronger difference between groups was observed in both the percentage and absolute numbers of HLA-DR+ lymphocytes. We also found a moderate but significant correlation between the number of lymphocytes expressing the activation antigens and single breath carbon monoxide diffusing capacity in patients with sarcoidosis: DLCO vs HLA-DR+ lymphocytes (r = -0.60); DLCO vs IL-2R+ lymphocytes (r = -0.62); carbon monoxide transfer coefficient (KCO vs HLA-DR+ lymphocytes (r = -0.53); and KCO vs IL-2R+ lymphocytes (r = -0.58). Our results suggest that the reduction in diffusing capacity, expressed as either DLCO or KCO, results from the severity of alveolitis in mild to moderate sarcoidosis.
Cytokine therapy reverses NK cell anergy in MHC-deficient tumors
Authors: Michele Ardolino, Camillia S. Azimi, Alexandre Iannello, Troy N. Trevino, Lucas Horan, Lily Zhang, Weiwen Deng, Aaron M. Ring, Suzanne Fischer, K. Christopher Garcia, David H. Raulet
Journal: Journal of Clinical Investigation (2014)

Various cytokines have been evaluated as potential anticancer drugs; however, most cytokine trials have shown relatively low efficacy. Here, we found that treatments with IL-12 and IL-18 or with a mutant form of IL-2 (the "superkine" called H9) provided substantial therapeutic benefit for mice specifically bearing MHC class I-deficient tumors, but these treatments were ineffective for mice with matched MHC class I+ tumors. Cytokine efficacy was linked to the reversal of the anergic state of NK cells that specifically occurred in MHC class I-deficient tumors, but not MHC class I+ tumors. NK cell anergy was accompanied by impaired early signal transduction and was locally imparted by the presence of MHC class I-deficient tumor cells, even when such cells were a minor population in a tumor mixture. These results demonstrate that MHC class I-deficient tumor cells can escape from the immune response by functionally inactivating NK cells, and suggest cytokine-based immunotherapy as a potential strategy for MHC class I-deficient tumors. These results suggest that such cytokine therapies would be optimized by stratification of patients. Moreover, our results suggest that such treatments may be highly beneficial in the context of therapies to enhance NK cell functions in cancer patients.
Physicians as caretakers and collaborators
Authors: M Gregg Bloche
Journal: The Lancet (1998)

On a winters night in Istanbul 3 years ago, American pathologist Robert Kirschner told an audience of forensic physicians what most did not want to hear. The setting was a conference on medical complicity in the torture and murder of Kurdish people by Turkish forces. Kirschner, who had led Physicians for Human Rights' investigations of mass killings in Bosnia and Rwanda for the UN War Crimes Tribunal, contended that the Turkish necropsy practice of examining only the body, without probing the circumstances of death, yields reports that help to cover up murder and torture.
Adaptation of Hepatic Mitochondrial Function in Humans with Non-Alcoholic Fatty Liver Is Lost in Steatohepatitis
Authors: Chrysi Koliaki, Julia Szendroedi, Kirti Kaul, Tomas Jelenik, Peter Nowotny, Frank Jankowiak, Christian Herder, Maren Carstensen, Markus Krausch, Wolfram Trudo Knoefel, Matthias Schlensak, Michael Roden
Journal: Cell Metabolism (2015)
A Founder Mutation of the &lt;EMPH TYPE="ITAL"&gt;MSH2&lt;/EMPH&gt; Gene and Hereditary Nonpolyposis Colorectal Cancer in the United States
Authors: Henry T. Lynch
Journal: JAMA (2004)

ContextHereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is caused by mutations in the mismatch repair genes and confers an extraordinarily high risk of colorectal, endometrial, and other cancers. However, while carriers of these mutations should be identified, counseled, and offered clinical surveillance, at present the mutations are not tested for in mutation analyses.ObjectiveTo describe the prevalence of a large genomic deletion encompassing exons 1 to 6 of the MSH2 gene that is widespread in the US population as a result of a founder effect.Design, Setting, and PatientsOngoing genealogical and historical study conducted to assess the origin and spread of an MSH2 mutation previously identified in 9 apparently unrelated families with putative HNPCC and living in widely different geographic locations in the United States.Main Outcome MeasuresClassification of family members as carriers or noncarriers of the MSH2 mutation; spread of the mutation across the continental United States.ResultsTo date, 566 family members of the 9 probands have been identified to be at risk and counseled; 137 of these have been tested, and 61 carry the founder mutation. Three families have been genealogically shown to descend from a German immigrant family that arrived and first settled in Pennsylvania in the early 1700s. Movements of branches of the family from Pennsylvania through North Carolina, Alabama, Kentucky, Missouri, Iowa, Nebraska, Utah, Texas, and California have been documented, and carriers of the mutation have already been diagnosed in 14 states. In contrast, the deletion was not found among 407 European and Australian families with HNPCC.ConclusionThe postulated high frequency and continent-wide geographic distribution of a cancer-predisposing founder mutation of the MSH2 gene in a large, outbred (as opposed to genetically isolated) population, and the ease with which the mutation can be detected, suggest that the routine testing of individuals at risk for HNPCC in the United States should include an assay for this mutation until more is learned about its occurrence.
Cervical Dorsal Column Stimulation Relieves Pain of Brachial Plexus Avulsion
Authors: M I Bennett, Y M A Tai
Journal: Journal of the Royal Society of Medicine (1994)

Five patients with deafferentation pain due to brachial plexus avulsion injuries were treated with cervical dorsal column stimulation (DCS). This has produced a clinically useful improvement in pain relief and mood scores during a mean follow-up period of 13.5 months. No complications have been encountered and the advantages of DCS are discussed.
A Mutational Analysis of the Binding of Staphylococcal Enterotoxins B and C3 to the T Cell Receptor β Chain and Major Histocompatibility Complex Class II
Authors: Lukas Leder, Andrea Llera, Pascal M. Lavoie, Marina I. Lebedeva, Hongmin Li, Rafick-Pierre Sékaly, Gregory A. Bohach, Pamala J. Gahr, Patrick M. Schlievert, Klaus Karjalainen, Roy A. Mariuzza
Journal: The Journal of Experimental Medicine (1998)

The three-dimensional structure of the complex between a T cell receptor (TCR) β chain (mouse Vβ8.2Jβ2.1Cβ1) and the superantigen (SAG) staphylococcal enterotoxin C3 (SEC3) has been recently determined to 3.5 Å resolution. To evaluate the actual contribution of individual SAG residues to stabilizing the β–SEC3 complex, as well as to investigate the relationship between the affinity of SAGs for TCR and MHC and their ability to activate T cells, we measured the binding of a set of SEC3 and staphylococcal enterotoxin B (SEB) mutants to soluble recombinant TCR β chain and to the human MHC class II molecule HLA-DR1. Affinities were determined by sedimentation equilibrium and/or surface plasmon detection, while mitogenic potency was assessed using T cells from rearrangement-deficient TCR transgenic mice. We show that there is a clear and simple relationship between the affinity of SAGs for the TCR and their biological activity: the tighter the binding of a particular mutant of SEC3 or SEB to the TCR β chain, the greater its ability to stimulate T cells. We also find that there is an interplay between TCR–SAG and SAG–MHC interactions in determining mitogenic potency, such that a small increase in the affinity of a SAG for MHC can overcome a large decrease in the SAG's affinity for the TCR. Finally, we observe that those SEC3 residues that make the greatest energetic contribution to stabilizing the β–SEC3 complex (“hot spot” residues) are strictly conserved among enterotoxins reactive with mouse Vβ8.2, thereby providing a basis for understanding why SAGs having other residues at these positions show different Vβ-binding specificities.
Death receptors in cervical cancer
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

Death-prone T cells might increase the risk of developing cervical cancer, according to a study on page 967. Sun and colleagues show that women with cervical cancer are more likely to have T cells that are genetically programmed to express high levels of the death-inducing molecule FAS ligand (FASL).Most cervical cancers are associated with human papillomavirus (HPV) infection. But not all HPV-infected women develop cervical cancer, suggesting that other factors contribute to cancer progression. A recent study linked cervical cancer with a genetic polymorphism in the gene encoding the death receptor FAS, which triggers apoptosis when bound by its ligand FASL. However, these findings are controversial as other studies failed to confirm this association.






Figure 

T cells homozygous for the −844C FASL polymorphism express more FASL when activated.




Sun and colleagues now find that a naturally occurring polymorphism in the FASL promoter was three times more prevalent in Chinese women with cervical cancer than in cancer-free controls. T cells with this single nucleotide polymorphism (−844C) expressed more FASL and were more prone to cell death after stimulation with cervical cancer cells than T cells without the polymorphism (−844T). Although the mechanism remains obscure, the authors suggest that an increased propensity for cell death might limit the ability of tumor-specific T cells to eradicate tumor cells.

The −844C polymorphism was recently found to improve the binding of a transcription factor that helps drive FASL gene expression, and to increase FASL protein levels on fibroblasts. In that study, the polymorphism was linked to the autoimmune disease systemic lupus erythematosus (SLE). The link to SLE was postulated to result from increased FAS-mediated cell death, which might facilitate the release of nuclear antigens that are then targeted by the immune response.
An Intact Immune System Is Required for the Anticancer Activities of Histone Deacetylase Inhibitors
Authors: Alison C. West, Stephen R. Mattarollo, Jake Shortt, Leonie A. Cluse, Ailsa J. Christiansen, Mark J. Smyth, Ricky W. Johnstone
Journal: Cancer Research (2013)

Abstract Cell-intrinsic effects such as induction of apoptosis and/or inhibition of cell proliferation have been proposed as the major antitumor responses to histone deacetylase inhibitors (HDACi). These compounds can also mediate immune-modulatory effects that may contribute to their anticancer effects. However, HDACi can also induce anti-inflammatory, and potentially immunosuppressive, outcomes. We therefore sought to clarify the role of the immune system in mediating the efficacy of HDACi in a physiologic setting, using preclinical, syngeneic murine models of hematologic malignancies and solid tumors. We showed an intact immune system was required for the robust anticancer effects of the HDACi vorinostat and panobinostat against a colon adenocarcinoma and two aggressive models of leukemia/lymphoma. Importantly, although HDACi-treated immunocompromised mice bearing established lymphoma succumbed to disease significantly earlier than tumor bearing, HDACi-treated wild-type (WT) mice, treatment with the conventional chemotherapeutic etoposide equivalently enhanced the survival of both strains. IFN-γ and tumor cell signaling through IFN-γR were particularly important for the anticancer effects of HDACi, and vorinostat and IFN-γ acted in concert to enhance the immunogenicity of tumor cells. Furthermore, we show that a combination of vorinostat with α-galactosylceramide (α-GalCer), an IFN-γ–inducing agent, was significantly more potent against established lymphoma than vorinostat treatment alone. Intriguingly, B cells, but not natural killer cells or CD8+ T cells, were implicated as effectors of the vorinostat antitumor immune response. Together, our data suggest HDACi are immunostimulatory during cancer treatment and that combinatorial therapeutic regimes with immunotherapies should be considered in the clinic. Cancer Res; 73(24); 7265–76. ©2013 AACR.
Prediagnostic Body Mass Index and Pancreatic Cancer Survival
Authors: Chen Yuan, Ying Bao, Chen Wu, Peter Kraft, Shuji Ogino, Kimmie Ng, Zhi Rong Qian, Douglas A. Rubinson, Meir J. Stampfer, Edward L. Giovannucci, Brian M. Wolpin
Journal: Journal of Clinical Oncology (2013)

Purpose Although obesity is associated with increased incidence of pancreatic cancer, studies have not prospectively evaluated prediagnostic body mass index (BMI) and survival. Patients and Methods We analyzed survival by prediagnostic BMI assessed in 1986 among 902 patients from two large prospective cohorts diagnosed from 1988 to 2010. We estimated hazard ratios (HRs) for death using Cox proportional hazards models, with adjustment for age, sex, race/ethnicity, smoking, diagnosis year, and stage. We evaluated the temporal association of BMI with survival by grouping reported BMI by 2-year lag-time intervals before diagnosis. Results The multivariable-adjusted HR for death was 1.53 (95% CI, 1.11 to 2.09) comparing patients with BMI ≥ 35 kg/m 2 with those with BMI &lt; 25 kg/m 2 (P trend = .001), which was similar after adjustment for stage. The association of BMI with survival was stronger with longer lag times between reported BMI and cancer diagnosis. Among patients with BMI collected 18 to 20 years before diagnosis, HR for death was 2.31 (95% CI, 1.48 to 3.61; P trend &lt; .001), comparing obese with healthy-weight patients. No statistically significant differences were seen by cohort, smoking status, or stage, although the association was stronger among never-smokers (HR, 1.61; 95% CI, 1.01 to 2.57; P trend = .002) than ever-smokers (HR, 1.36; 95% CI, 0.86 to 2.15; P trend = .63), comparing BMI ≥ 35 kg/m 2 with BMI &lt; 25 kg/m 2 . Higher prediagnostic BMI was associated with more advanced stage at diagnosis, with 72.5% of obese patients presenting with metastatic disease versus 59.4% of healthy-weight patients (P = .02). Conclusion Higher prediagnostic BMI was associated with statistically significantly decreased survival among patients with pancreatic cancer from two large prospective cohorts.