tbuckley/cabot-search huggingface dataset:
Predictors of Spontaneous and Systematically Assessed Suicidal Adverse Events in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) Study
Authors: David A. Brent, Graham J. Emslie, Greg N. Clarke, Joan Asarnow, Anthony Spirito, Louise Ritz, Benedetto Vitiello, Satish Iyengar, Boris Birmaher, Neal D. Ryan, Jamie Zelazny, Matthew Onorato, Betsy Kennard, Taryn L. Mayes, Lynn L. DeBar, James T. McCracken, Michael Strober, Robert Suddath, Henrietta Leonard, Giovanna Porta, Martin B. Keller
Journal: American Journal of Psychiatry (2009)

The authors sought to identify predictors of self-harm adverse events in treatment-resistant, depressed adolescents during the first 12 weeks of treatment.Depressed adolescents (N=334) who had not responded to a previous trial with an SSRI antidepressant were randomized to a switch to either another SSRI or venlafaxine, with or without cognitive behavior therapy. Self-harm events, i.e., suicidal and non-suicidal self-injury adverse events were assessed by spontaneous report for the first 181 participants, and by systematic weekly assessment for the last 153 participants.Higher rates of suicidal (20.8% vs. 8.8%) and nonsuicidal self-injury (17.6% vs. 2.2%), but not serious adverse events (8.4% vs. 7.3%) were detected with systematic monitoring. Median time to a suicidal event was 3 weeks, predicted by high baseline suicidal ideation, family conflict, and drug and alcohol use. Median time to nonsuicidal self-injury was 2 weeks, predicted by previous history of nonsuicidal self-injury. While there were no main effects of treatment, venlafaxine treatment was associated with a higher rate of self-harm adverse events in those with higher suicidal ideation. Adjunctive use of benzodiazepines, while in a small number of participants (N=10) was associated with higher rate of both suicidal and nonsuicidal self-injury adverse events.Since predictors of suicidal adverse events also predict poor response to treatment, and many of these events occurred early in treatment, improving the speed of response to depression, by targeting of family conflict, suicidal ideation, and drug use may help to reduce their incidence. The relationship of venlafaxine and of benzodiazepines to self-harm events requires further study and clinical caution.
Development of Eosinophilic Airway Inflammation and Airway Hyperresponsiveness in Mast Cell–deficient Mice
Authors: K. Takeda, E. Hamelmann, A. Joetham, L.D. Shultz, G.L. Larsen, C.G. Irvin, E.W. Gelfand
Journal: The Journal of Experimental Medicine (1997)

Mast cells are the main effector cells of immediate hypersensitivity and anaphylaxis. Their role in the development of allergen-induced airway hyperresponsiveness (AHR) is controversial and based on indirect evidence. To address these issues, mast cell–deficient mice (W/W v) and their congenic littermates were sensitized to ovalbumin (OVA) by intraperitoneal injection and subsequently challenged with OVA via the airways. Comparison of OVA-specific immunoglobulin E (IgE) levels in the serum and numbers of eosinophils in bronchoalveolar lavage fluid or lung digests showed no differences between the two groups of mice. Further, measurements of airway resistance and dynamic compliance at baseline and after inhalation of methacholine were similar. These data indicate that mast cells or IgE–mast cell activation is not required for the development of eosinophilic inflammation and AHR in mice sensitized to allergen via the intraperitoneal route and challenged via the airways.
Elevated Frequencies of Self-reactive CD8+ T Cells following Immunization with a Xenoantigen Are Due to the Presence of a Heteroclitic CD4+ T-Cell Helper Epitope
Authors: Korosh Kianizad, Laura A. Marshall, Natalie Grinshtein, Dannie Bernard, Renate Margl, Sheng Cheng, Friedrich Beermann, Yonghong Wan, Jonathan Bramson
Journal: Cancer Research (2007)

Abstract Immunization of mice with human dopachrome tautomerase (hDCT) provides greater protection against melanoma than immunization with the murine homologue (mDCT). We mapped the CD8+ and CD4+ T-cell epitopes in both proteins to better understand the mechanisms of the enhanced protection. The dominant CD8+ T-cell epitopes were fully conserved between both proteins, yet immunization with hDCT produced frequencies of CD8+ T cells that were 5- to 10-fold higher than immunization with mDCT. This difference was not intrinsic to the two proteins because comparable frequencies of CD8+ T cells were elicited by both antigens in DCT-deficient mice. Strikingly, only hDCT elicited a significant level of specific CD4+ T cells in wild-type (WT) mice. The murine protein was not devoid of CD4+ T-cell epitopes because immunization of DCT-deficient mice with mDCT resulted in robust CD4+ T-cell immunity directed against two epitopes that were not identified in WT mice. These results suggested that the reduced immunogenicity of mDCT in WT mice may be a function of insufficient CD4+ T-cell help. To address this possibility, the dominant CD4+ T-cell epitope from hDCT was introduced into mDCT. Immunization with the mutated mDCT evoked CD8+ T-cell frequencies and protective immunity comparable with hDCT. These results reveal a novel mechanism by which xenoantigens overcome tolerance. Our data also suggest that immunologic tolerance is more stringent for CD4+ T cells than CD8+ T cells, providing a mechanism of peripheral tolerance where autoreactive CD8+ T cells fail to be activated due to a lack of autoreactive CD4+ T cells specific for the same antigen. [Cancer Res 2007;67(13):6459–67]
Invasive Breast Cancer
Authors: Robert W. Carlson, D. Craig Allred, Benjamin O. Anderson, Harold J. Burstein, W. Bradford Carter, Stephen B. Edge, John K. Erban, William B. Farrar, Andres Forero, Sharon Hermes Giordano, Lori J. Goldstein, William J. Gradishar, Daniel F. Hayes, Clifford A. Hudis, Britt-Marie Ljung, David A. Mankoff, P. Kelly Marcom, Ingrid A. Mayer, Beryl McCormick, Lori J. Pierce, Elizabeth C. Reed, Jasgit Sachdev, Mary Lou Smith, George Somlo, John H. Ward, Antonio C. Wolff, Richard Zellars
Journal: Journal of the National Comprehensive Cancer Network (2011)

These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer are the work of the members of the NCCN Breast Cancer Panel.Categories of evidence and consensus were assessed and are noted in the algorithms and text.Although
Polymorphisms in <i>ERCC1</i> and Grade 3 or 4 Toxicity in Non–Small Cell Lung Cancer Patients
Authors: Rebecca Suk, Sarada Gurubhagavatula, Sohee Park, Wei Zhou, Li Su, Thomas J. Lynch, John C. Wain, Donna Neuberg, Geoffrey Liu, David C. Christiani
Journal: Clinical Cancer Research (2005)

Abstract Purpose: ERCC1 is a lead enzyme in the nucleotide excision repair pathway of DNA repair. Polymorphisms have been identified in the ERCC1 gene, the C8092A and codon 118 polymorphisms, which may lead to an altered capacity to regenerate damaged normal tissue and greater treatment-related toxicity. Experimental Design: Using logistic regression models, we evaluated the ERCC1 C8092A and codon 118 polymorphisms and their association with the occurrence of grade 3 or 4 toxicity in 214 stage III and IV non–small cell lung cancer patients treated first line with platinum-based chemotherapy. Adjusting covariates were performance status and type of treatment regimen. Results: There was no statistically significant association between either the C8092A or codon 118 polymorphism and overall or hematologic grade 3 or 4 toxicity. However, carrying at least one variant ERCC1 C8092A allele was associated with a significantly increased risk of grade 3 or 4 gastrointestinal toxicity (adjusted odds ratio, 2.33; 95% confidence interval, 1.07-5.05; P = 0.03). Conclusions: Adjusting for performance status and type of treatment regimen, carrying at least one ERCC1 8092A allele is associated with a &amp;gt;2-fold increase in grade 3 or 4 gastrointestinal toxicity among platinum-treated non–small cell lung cancer patients.
Cevimeline gargle for the treatment of xerostomia in patients with Sjogren's syndrome
Authors: Y Takagi
Journal: Annals of the Rheumatic Diseases (2004)

Figure 1 Active genital ulcer of the left labium majus together with genital scars.(A) Before the first infusion with infliximab; (B) 2 weeks after the first infusion; (C) 4 weeks after the second infusion.744 www.annrheumdis.com
Provisional diagnostic criteria for polymyalgia rheumatica: moving beyond clinical intuition?
Authors: Robert Spiera, Rene Westhovens
Journal: Annals of the Rheumatic Diseases (2012)

In 1964, US Supreme Court Justice Potter Stewart, a master of words, when trying to define hardcore pornography admitted, ‘I could never succeed in intelligibly doing so, but I know it when I see it…’. Polymyalgia rheumatica (PMR) has been in that sense the pornography of rheumatic diseases—a difficult to define syndrome of inflammatory pain and stiffness in older people, but one commonly encountered in practice, and not commonly missed by experienced clinicians.

The response to low doses of corticosteroids is often rapid, dramatic, and has been used by many clinicians as a feature that helps define the disease. No single clinical finding or laboratory abnormality is unique to this disorder, and although some aspects of cytokine abnormalities and histopathological findings in this disorder are understood, there is no single identifiable aetiopathogenesis. The rather recent history of PMR is one of many names and definitions, reflecting this uncertainty about the pathology and pathogenesis.1

In this issue of Annals of the Rheumatic Diseases , Dasgupta and colleagues2 report provisional classification criteria for PMR. In a study jointly sponsored by the European League Against Rheumatism and the American College of Rheumatology the authors propose a set of ‘provisional’ classification criteria. These emerged as the result of a multiphase effort in which they initially developed candidate criteria through a systemic literature review, then a consensus process and wider survey. These criteria were then assessed by experts, and those that emerged as most widely agreed upon were reviewed by both rheumatologists and non-rheumatologists in a wider survey generating a number of criteria most widely accepted. They then evaluated the performance of these proposed criteria in a 6-month prospective cohort study of 125 patients with new-onset PMR and 169 non-PMR control patients whose clinical presentation included features that can mimic PMR. They assessed …
Phase 1/2 Placebo-Controlled, Double-Blind, Dose-Escalating Trial of Myocardial Vascular Endothelial Growth Factor 2 Gene Transfer by Catheter Delivery in Patients With Chronic Myocardial Ischemia
Authors: Douglas W. Losordo, Peter R. Vale, Robert C. Hendel, Charles E. Milliken, F. David Fortuin, Nancie Cummings, Richard A. Schatz, Takayuki Asahara, Jeffrey M. Isner, Richard E. Kuntz
Journal: Circulation (2002)

Background — This phase 1/2 study investigated the safety of percutaneous catheter-based gene transfer of naked plasmid DNA encoding for vascular endothelial growth factor 2 (phVEGF2) to left ventricular (LV) myocardium in a prospective, randomized, double-blind, placebo-controlled, dose-escalating study of inoperable patients with class III or IV angina. Methods and Results — A steerable deflectable 8F catheter with a 27-gauge needle at its distal tip was advanced percutaneously to the endocardial surface of the LV in 19 patients (age, 61±2 years) with chronic myocardial ischemia who were not candidates for conventional revascularization. Patients were randomized in a double-blind fashion to receive 6 injections (total volume, 6.0 mL) of placebo or phVEGF2 in doses of 200 μg (n=9), 800 μg (n=9), or 2000 μg (n=1) guided by LV electromechanical (NOGA) mapping with a gene-to-placebo ratio of 2:1. A total of 114 LV injections were delivered and caused no hemodynamic alterations, sustained ventricular arrhythmias, ECG evidence of infarction, or ventricular perforation. End-point analysis at 12 weeks disclosed a statistically significant improvement in Canadian Cardiovascular Society (CCS) angina class in phVEGF2-treated versus placebo-treated patients (−1.3 versus −0.1, P =0.04). Remaining efficacy end points—including change in exercise duration (91.8 versus 3.9 seconds), functional improvement by ≥2 CCS classes (9 of 12 versus 1 of 6), and Seattle Angina Questionnaire data—all showed strong trends favoring efficacy of phVEGF2 versus placebo treatment. Conclusions — This phase 1/2, double-blind, randomized trial provides preliminary data that support safety of phVEGF2 catheter-mediated myocardial gene transfer. The statistically significant reduction in anginal class and strong positive trends for remaining end points suggest that a larger phase 2/3 trial is warranted.
Role of Oncogenic K-Ras in Cancer Stem Cell Activation by Aberrant Wnt/β-Catenin Signaling
Authors: Byoung-San Moon, Woo-Jeong Jeong, Jieun Park, Tae Il Kim, Do Sik Min, Kang-Yell Choi
Journal: JNCI Journal of the National Cancer Institute (2014)

Adenomatous polyposis coli ( APC ) loss-of-function mutations and K-Ras gain-of-function mutations are common abnormalities that occur during the initiation and intermediate adenoma stages of colorectal tumorigenesis, respectively. However, little is known about the role these mutations play in cancer stem cells (CSCs) associated with colorectal cancer (CRC) tumorigenesis. We analyzed tissue from CRC patients (n = 49) to determine whether K-Ras mutations contributed to CSC activation during colorectal tumorigenesis. DLD-1-K-Ras-WT and DLD-1-K-Ras-MT cells were cultured and evaluated for their ability to differentiate, form spheroids in vitro, and form tumors in vivo. Interaction between APC and K-Ras mutations in colorectal tumorigenesis was evaluated using APCMin/+ / K-RasLA2 mice and DLD-1-K-Ras-WT and DLD-1-K-Ras-MT cell xenografts. (n = 4) Group differences were determined by Student t test. All statistical tests were two-sided. The sphere-forming capability of DLD-1-K-Ras-MT cells was statistically significantly higher than that of DLD-1-K-Ras-WT cells (DLD-1-K-Ras-MT mean = 86.661 pixel, 95% confidence interval [CI] = 81.701 to 91.621 pixel; DLD-1-K-Ras-WT mean = 42.367 pixel, 95% CI = 36.467 to 48.267 pixel; P = .003). Moreover, both the size and weight of tumors from DLD-1-K-Ras-MT xenografts were markedly increased compared with tumors from DLD-1-K-Ras-WT cells. Expression of the CSC markers CD44, CD133, and CD166 was induced in intestinal tumors from APCMin/+ / K-RasLA2 mice, but not K-RasLA2 mice, indicating that APC mutation is required for CSC activation by oncogenic K-Ras mutation. K-Ras mutation activates CSCs, contributing to colorectal tumorigenesis and metastasis in CRC cells harboring APC mutations. Initial activation of β-catenin by APC loss and further enhancement through K-Ras mutation induces CD44, CD133, and CD166 expression.
From Mice to Humans
Authors: Yuhui Hu, Hongxia Sun, Jeffrey Drake, Frances Kittrell, Martin C. Abba, Li Deng, Sally Gaddis, Aysegul Sahin, Keith Baggerly, Daniel Medina, C. Marcelo Aldaz
Journal: Cancer Research (2004)

Abstract Genetically engineered mouse mammary cancer models have been used over the years as systems to study human breast cancer. However, much controversy exists on the utility of such models as valid equivalents to the human cancer condition. To perform an interspecies gene expression comparative study in breast cancer we used a mouse model that most closely resembles human breast carcinogenesis. This system relies on the transplant of p53 null mouse mammary epithelial cells into the cleared mammary fat pads of syngeneic hosts. Serial analysis of gene expression (SAGE) was used to obtain gene expression profiles of normal and tumor samples from this mouse mammary cancer model (&amp;gt;300,000 mouse mammary-specific tags). The resulting mouse data were compared with 25 of our human breast cancer SAGE libraries (&amp;gt;2.5 million human breast-specific tags). We observed significant similarities in the deregulation of specific genes and gene families when comparing mouse with human breast cancer SAGE data. A total of 72 transcripts were identified as commonly deregulated in both species. We observed a systematic and significant down-regulation in all of the tumors from both species of various cytokines, including CXCL1 (GRO1), LIF, interleukin 6, and CCL2. All of the mouse and most human mammary tumors also displayed decreased expression of genes known to inhibit cell proliferation, including NFKBIA (IKBα), GADD45B, and CDKN1A (p21); transcription-related genes such as CEBP, JUN, JUNB, and ELF1; and apoptosis-related transcripts such as IER3 and GADD34/PPP1R15A. Examples of overexpressed transcripts in tumors from both species include proliferation-related genes such as CCND1, CKS1B, and STMN1 (oncoprotein 18); and genes related to other functions such as SEPW1, SDFR1, DNCI2, and SP110. Importantly, abnormal expression of several of these genes has not been associated previously with breast cancer. The consistency of these observations was validated in independent mouse and human mammary cancer sets. This is the first interspecies comparison of mammary cancer gene expression profiles. The comparative analysis of mouse and human SAGE mammary cancer data validates this p53 null mouse tumor model as a useful system closely resembling human breast cancer development and progression. More importantly, these studies are allowing us to identify relevant biomarkers of potential use in human studies while leading to a better understanding of specific mechanisms of human breast carcinogenesis.
AN EXPERIMENTAL STUDY OF THE QUESTION OF ASPIRATION OF FOREIGN MATERIAL INTO THE AIR PASSAGES DURING INTRATRACHEAL INSUFFLATION
Authors: T. S. Githens, S. J. Meltzer
Journal: The Journal of Experimental Medicine (1911)

The foregoing experiments clearly justify the following conclusions :- Intratracheal insufflation protects the respiratory tract very efficiently against any invasion from the pharynx. The filling up of the pharynx with extraneous material, whether it be from the stomach or from the mouth, brings no danger to the trachea and bronchi. This holds true even if the animal is under deep anesthesia. On the other hand, the presence of a tube in the trachea or larynx without the protection of an effective recurrent air stream, definitely facilitates the entrance of foreign material from the pharynx into the trachea. Anesthesia, which removes the protective action of deglutition, greatly increases the danger from aspiration in these cases.
Abstract SY18-01: Alterations in metabolic pathways to support cancer cell proliferation
Authors: Matthew G. Vander Heiden
Journal: Cancer Research (2011)

Abstract Unlike the majority of differentiated cells, many cancer cells metabolize glucose by aerobic glycolysis even in the presence of sufficient oxygen to support mitochondrial respiration. This phenomenon, also known as the Warburg effect, is characterized by increased glycolysis with lactate production and decreased oxidative phosphorylation. We have argued that aerobic glycolysis may be selected for by cancer cells to meet the distinct metabolic needs of proliferation. Unlike metabolism in differentiated cells, which is geared toward efficient ATP generation, the aerobic glycolysis observed in cancer cells appears to be adapted to facilitate the accumulation of biomass. Our understanding of how cancer cells meet their metabolic needs is based primarily on studies of cultured cells, and nutrient conditions in vitro differ significantly from those seen by tumor cells in vivo. Our long-term objective is to develop a comprehensive understanding on how cell metabolism is altered to accommodate anabolic synthesis and support the growth of tumors in vivo. The M2 isoform of pyruvate kinase (PK-M2) promotes the metabolism of glucose by aerobic glycolysis, contributes to anabolic metabolism, and appears necessary for optimal tumor growth in vivo. Paradoxically, these consequences of PK-M2 isoform selection are associated with decreased pyruvate kinase enzyme activity. Experiments to test the hypothesis that decreased pyruvate kinase activity promotes anabolic metabolism and cell proliferation in vivo will be presented. This includes data generated using genetically engineered mouse cancer models and small molecule activators of PK-M2. Additionally, efforts to understand pyruvate kinase-mediated regulation of glycolysis in cancer cells will be discussed. Decreased pyruvate kinase activity in cancer cells is accompanied by an alternate regulation of glycolysis. This creates a branch point in glycolysis to divert 3-phosphoglycerate into the serine biosynthesis pathway, and this reorganization of metabolic flux appears to be is important for proliferation. In fact, in some cancers a substantial portion of the total glucose flux is directed to serine synthesis and additional genetic evidence will be presented to suggest that glucose flux into this pathway can promote cell transformation. Finally, the role of the tumor environment, and how this contributes to the reorganization of metabolic pathways to support anabolic metabolism will be discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY18-01. doi:10.1158/1538-7445.AM2011-SY18-01
Modulation of Thymic Selection by Expression of an Immediate-early Gene, Early Growth Response 1 (Egr-1)
Authors: Toru Miyazaki, François A. Lemonnier
Journal: The Journal of Experimental Medicine (1998)

The potential involvement of early growth response (Egr)-1, a zinc-finger transcription factor belonging to the immediate-early genes, in positive/negative selection of thymocytes has been implicated by its expression in the population of CD4+CD8+ double positive (DP) cells undergoing selection. To further investigate this possibility, transgenic mice overexpressing Egr-1 in thymocytes were bred with a transgenic mouse line expressing a T cell receptor (TCR) recognizing the H-Y male antigen in the context of H-2b class I major histocompatibility complex (MHC) molecules. In Egr-1/TCR H-Y double-transgenic mice, efficient positive selection of H-Y CD8+ T cells occurred, even in mice on either a nonselecting H-2d background or a β2-microglobulin (β2m)-deficient background in which the expression of class I MHC heavy chains is extremely low; no positive selection was observed on a Kb−/−Db−/−β2m−/− background where class I MHC expression is entirely absent. Similarly, when the Egr-1 transgene was introduced into a class II MHC–restricted TCR transgenic mouse line, Egr-1/TCR double-transgenic mice revealed increased numbers of CD4+ T cells selected by class II MHC, as well as significant numbers of CD8+ T cells selected by class I MHC (for which the transgenic TCR might have weak affinity). Thus, Egr-1 overexpression allows positive selection of thymocytes via TCR–MHC interactions of unusually low avidity, possibly by lowering the threshold of avidity required for positive selection. Supporting this possibility, increased numbers of alloreactive T cells were positively selected in Egr-1 transgenic mice, resulting in a strikingly enhanced response against allo-MHC. These results suggest that expression of Egr-1 and/or its target gene(s) may directly influence the thresholds required for thymocyte selection.
Dose-intensified weekly paclitaxel induces multiple nail disorders
Authors: D. Lüftner, B. Flath, C. Akrivakis, M. Schweigert, B. Prinz, H.G. Mergenthaler, P.E. Petrides, K.D. Wernecke, K. Possinger
Journal: Annals of Oncology (1998)