tbuckley/cabot-search huggingface dataset:
Abstract #96: Confirmation of a set of genetic susceptibility variants for chronic lymphocytic leukemia (CLL)
Authors: Susan Slager, Lynn Goldin, Sara Strom, Mark Lanasa, Logan Spector, Laura Rassenti, Jose Leis, Nicola Camp, Neil Kay, Celine Vachon, J. Weinberg, Kari Rabe, Sara Achenbach, Curtis Hanson, Gerald Marti, Timothy Call, Neil Caporaso, James Cerhan
Journal: Cancer Research (2009)

Background: CLL is the most common adult leukemia in the United States, and there is strong and consistent evidence that a genetic component contributes to its etiology. A recent genome-wide association study (GWAS) of CLL identified 7 genetic variants located on 2q13 (rs17483466, ACOXL), 2q37 (rs17483466, SP140),6p25 (rs872071, rs9378805, IRF4/MUM1), 11q24 (rs735665, GRAMD1B), 15q23 (rs7176508), 19q13 (rs11083846, PRKD2) that increased the risk of CLL within a European population. Using genotype data from our Affymetrix Genome-Wide Human SNP Array 6.0 and Affymetrix Immune-Inflammation panel, we evaluated the association of these 7 variants, or variants in linkage disequilibrium (LD) with these variants, with risk of CLL in an independent sample of U.S. Caucasians. Methods: Peripheral blood samples were collected from 399 CLL cases and 632 controls. Of the 399 CLL cases, 99 patients were from high-risk CLL families (i.e., families with two or more relatives with CLL) that were collected as part of the Genetic Epidemiology of CLL (GEC) Consortium. The remaining cases and controls were obtained from the Mayo Clinic NHL case-control study. Using the data from two large genotyping projects, we selected 11 single nucleotide polymorphisms (SNPs) for evaluation. These included the exact SNPs identified in the recent GWAS or, if not available, SNPs that were in tight LD (r2> 0.9). The most prevalent homozygous genotype was used as the reference group, and each SNP was modeled individually as having a log-additive effect (expressed as ordinal odds ratios (ORs) per variant allele and 95% confidence intervals) in a logistic regression analysis. Results. The mean age at diagnosis was 61.8 years for cases and 64% were male; among controls, the mean age at enrollment was 61.7 years and 57% were men. Of the 7 SNPs identified in the previous GWAS, we had genotyped 5 (rs17483466, rs13397985, rs872071, rs9378805, and rs735665) of them across the two larger genotyping projects. All 5 of these SNPs were statistically significant (p-trend   Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 96.
Survival analysis of treatment with S-1, alone or in combination with CDDP (SP), in elderly patients with advanced gastric cancer: A 10-year retrospective cohort study.
Authors: Akitaka Makiyama, Tatsuhiro Kajitani, Hisanobu Oda, Chinatsu Fujimoto, Taito Esaki
Journal: Journal of Clinical Oncology (2013)

e15170 Background: In Japan, the elderly population is increasing, and steadily increase the number of deaths in the elderly gastric cancer patients. However, the standard treatment of elderly gastric cancer has not been established, either treatment of S-1 or SP is carried out in the clinical practice, while SP is considered as standard therapy in the young people. Now, we investigated the impact of S-1 and SP on survival time in clinical practice. Methods: Between 2003 and 2012, advanced gastric cancer patients over 70 years of age received S-1 or SP as first line therapy were retrospectively reviewed to investigate clinical outcomes. Patient characteristics analyzed included age, gender, performance status (PS), tumor histology, renal function and metastatic site. In addition, we have analyzed prognostic factors in multivariate analysis. Results: Among 93 patients (pts), 67 pts (72%) received S-1 and 26 pts (28%) received SP. Patient characteristics between the two groups showed no significant differences in gender, histology, metastatic site, or creatinine clearance level, but did show an imbalance in PS (tended with better at SP group) and age (tended with younger at SP group), significantly. Even though the background factors were favorable results in SP group, there were no significant differences in median progression-free survival (median 139 vs. 102 days; p = 0.96) and overall survival (median 330 vs. 263 days; p = 0.55) between S-1 and SP group, respectively. Grade 3-4 neutropenia (10 vs. 27%, p &lt; 0.05) , fatigue (3 vs. 15%, p &lt; 0.05) and Grade 1-2 creatinine increased (9 vs. 31%, p &lt; 0.01) were more frequent in the SP group than in the S-1 group, respectively. According to the multivariate analysis, exposure to CDDP was not independently associated with a better prognosis. Conclusions: Despite the obvious limitations of this analysis, there does not appear to be a benefit for the addition of CDDP in the elderly gastric cancer patients due to the increase of toxicity. A randomized controlled trial in this age group is warranted. We will also report the results of clinically meaningful prognostic factors associated with the primary treatment at annual meeting.
Effects of over-expressed truncated Hoxa-1 protein on the expression of Hoxa-1 and its target genes
Authors: Cristina C. Fernandez, Lorraine J. Gudas
Journal: Cancer Research (2004)

1584  Retinoic acid plays an important role in development by transcriptionally regulating the expression of Hox genes. Hox genes are a group of transcription factors that bind to DNA through a helix-turn-helix motif termed the homeodomain. These genes are involved in establishing anterior to posterior pattern formation during vertebrate development. Aberrant expression of Hox genes has been implicated in carcinogenesis. For example, the Nup98-HoxA9 fusion protein inhibits differentiation and promotes transformation of haematopoietic progenitor cells. Cervical and lumbro-sacral HOX gene expression is altered in primary human breast cancers when compared to normal tissue. Also, Hoxa-1 expression has been detected in carcinomas of the mouse mammary gland but not in normal mammary tissue. Previously our lab has shown that RA directly regulates the expression of Hoxa-1 (previously termed ERA-1) in F9 teratocarcinoma cells. The Hoxa-1 gene encodes two alternatively spliced mRNAs that can direct the synthesis of two distinct proteins, one that contains the homeobox, Hoxa-1-993, and another truncated protein that lacks the DNA binding domain, Hoxa-1-399. Additionally, a third alternatively spliced transcript of HOXA1 (also lacking the conserved DNA binding domain) has been reported in MCF7 human breast cancer cells. The functions of the Hox proteins that lack the homeodomain are not known. Therefore, a major question in the field concerns the function of the smaller Hoxa-1 protein, which lacks the DNA binding domain. We have employed wild type and EW-F9 mutant embryonic stem cells, which over-express the Hoxa-1-399 transcript in the presence of zinc, to examine the effects of the shorter Hoxa-1 protein on the expression of Hoxa-1 target genes. Northern blot analysis shows that over-expression of Hoxa-1-399 in EW-F9 cells enhances expression of endogenous Hoxa-1, Hoxb-1 (a known Hoxa-1 target), and Hox cofactors, Meis and Pbx1. Therefore, these results may indicate that the function of the truncated Hoxa-1 protein is to up-regulate the expression of Hoxa-1 target genes, possibly by stabilizing the Hoxa-1-993 message or enhancing the transcription of the Hoxa-1 gene.
CERTAIN ASPECTS OF THE PHARMACOLOGY OF THE SALICYLATES
Authors: PAUL K. SMITH
Journal: Pharmacological Reviews (1949)

The many intensive studies on the pharmacology of salicylates have revealed the principal features of their actions and physiological disposition. They are rapidly absorbed from all portions of the gastrointestinal tract, absorption being most rapid in the small intestine from slightly acid solutions. Distribution is throughout the body, appreciable amounts being within the cells. Degradation includes partial oxidation or conjugation with glycine or glycuronic acid. Excretion is moderately rapid, the free salicylate being excreted more rapidly when the urinary pH is high.  The salicylates are among the least toxic of commonly used drugs; but rarely, even in moderate doses, they produce severe reactions, particularly in asthmatic patients. Large doses may produce a transient fall in plasma prothrombin, but there is seldom a hemorrhagic tendency. Nausea and vomiting are usually associated with high plasma levels and are primarily central in origin. Large doses of salicylates stimulate the respiration; this produces an alkalosis which may continue until a ketosis develops.  Several decades of research on the salicylates have left many problems still unsolved. One of the most important is whether the salicylates act  per se  or through the degradation product, gentisic acid. In favor of the latter hypothesis is the beneficial action of gentisic acid in rheumatic fever (196). But there is some question whether the compound inhibits hyaluronidase (180, 197, 234), and the dose required in therapy is larger than would be expected on the basis of the fraction of salicylate known to be converted to gentisate (154); also the drug fails to prevent anaphylactic shock (166) whereas the salicylates are effective (50, 166).  The metabolism of methyl salicylate has not been studied as intensively as that of salicylic acid and acetylsalicylic acid. It may be that it differs appreciably.  The failure to demonstrate consistently an analgesic effect of salicylates may be due to inadequate methods of studying analgesia.  The demonstration that salicylates prevent anaphylactic shock raises the question of the possible relation of this phenomenon to the mechanism of salicylate action in rheumatic fever.
Impact of the third and subsequent lines of chemotherapy in the cure rate of patients with high-risk gestational trophoblastic neoplasia (HR-GTN).
Authors: Gustavo Jankilevich, Maria Ines Bianconi, Silvina Otero, Lucia Alvarez, Claudio Storino
Journal: Journal of Clinical Oncology (2012)

e15521 Background: Successful chemotherapy is the backbone of the treatment of patients with HR-GTN. However a percentage of this patients will recur to first treatment attempt. It is not defined how many lines of chemotherapy are required to achieve complete reponse and wether to continue with different chemotherapy regimens is beneficial for achieving the cure. Methods: We performed a review of medical records of consecutive patients with diagnosis of gestational trophoblastic disease (GTD) and HR-GTN by FIGO-OMS criteria between 1990-2011. All were treated in our hospital. Results: 365 patients were registrated with GTD diagnosis. Thirty-four patients had HRNTG, 23 patients (67.6%) had complete reponse with first and second line chemotherapy (EMA PE and EMA CO). Eight of eleven patients had complete reponse with additional regimens. Three patients died, one due toxicity. The reponse rate of third and more lines was 72%. Overall disease free survival was 91%. Conclusions: In patients with HRNTG three or more lines of treatment achieves the cure in a high percentage of patients. In this setting the therapy should always be with curative intent, regardless of the number of lines required to achieve this objective.
A phase I study of testosterone in patients (pts) with early castrate resistant prostate cancer (CRPC)
Authors: D. A. Knight, S. G. Mohile, E. M. Posadas, E. A. Manchen, W. M. Stadler
Journal: Journal of Clinical Oncology (2007)

15584 Background: Transition to the castrate resistant state may be due, in part, to the development of a more sensitive and promiscuous androgen receptor (AR) pathway. Androgen therapy of CRPC leads to growth arrest and tumor shrinkage in preclinical models. Historical studies of exogenous testosterone in pts is limited. This study was designed to determine toxicity of a transdermal testosterone therapy (Androderm [A]) in early CRPC. Methods: Pts with progressive PSA increases following androgen ablation and antiandrogen therapy with minimal or no bone metastases (Bone Scan Index of &lt; 1.4%) and no visceral metastases were eligible. Pts were randomized to treatment with 2.5, 5.0, or 7.5mg/day of A and LHRH agonist treatment was maintained. Toxicity was evaluated every 2 weeks and all subjects underwent laboratory, quality of life (UCLA Prostate Cancer Index), and hand grip strength testing at baseline and week 6. Treatment was discontinued for severe toxicity, radiologic progression, or a 3-fold increase in PSA. Results: To date fourteen men were enrolled. Median baseline PSA was 10.9ng/mL (Range:5.3–63.6). Eight pts had no radiologic evidence of disease. Median on therapy testosterone levels (ng/dL) were 216 (n=4), 308 (n=5), 325 (n=5) for 2.5, 5.0, 7.5mg/day dose levels, respectively. Toxicities included grade 2 rash (n=1, dose 7.5), grade 2 hypertension (n=1, dose 7.5), grade 2 hypoglycemia (n=1, dose 5), and grade 2 anorexia (n=1, dose 5). In 29% of pts (n=4), there was a decrease in PSA (max decrease = 43%) from baseline lasting from 4 - 36 weeks; two sustained an initial rise before PSA decline. All other subjects required discontinuation of therapy due to PSA increase and/or radiological progression within 2–13 weeks; none of these patients sustained symptomatic progression of disease and PSA decreased in 8/11 pts with available data after therapy discontinuation. In this small sample, there were no significant differences between baseline and 6-week QOL and hand-grip scores. Conclusion: Testosterone treatment in early CRPC is feasible and safe, although use of PSA to assess anti-tumor effects is difficult. Further evaluation would require a randomized trial to evaluate time to progression and QOL endpoints. No significant financial relationships to disclose.
Mechanisms for hemodynamic instability related to renal replacement therapy: a narrative review
Authors: Adrianna Douvris, Khalid Zeid, Swapnil Hiremath, Sean M. Bagshaw, Ron Wald, William Beaubien-Souligny, Jennifer Kong, Claudio Ronco, Edward G. Clark
Journal: Intensive Care Medicine (2019)

Hemodynamic instability related to renal replacement therapy (HIRRT) is a frequent complication of all renal replacement therapy (RRT) modalities commonly used in the intensive care unit. HIRRT is associated with increased mortality and may impair kidney recovery. Our current understanding of the physiologic basis for HIRRT comes primarily from studies of end-stage kidney disease patients on maintenance hemodialysis in whom HIRRT is referred to as ‘intradialytic hypotension’. Nonetheless, there are many studies that provide additional insights into the underlying mechanisms for HIRRT specifically in critically ill patients. In particular, recent evidence challenges the notion that HIRRT is almost entirely related to excessive ultrafiltration. Although excessive ultrafiltration is a key mechanism, multiple other RRT-related mechanisms may precipitate HIRRT and this could have implications for how HIRRT should be managed (e.g., the appropriate response might not always be to reduce ultrafiltration, particularly in the context of significant fluid overload). This review briefly summarizes the incidence and adverse effects of HIRRT and reviews what is currently known regarding the mechanisms underpinning it. This includes consideration of the evidence that exists for various RRT-related interventions to prevent or limit HIRRT. An enhanced understanding of the mechanisms that underlie HIRRT, beyond just excessive ultrafiltration, may lead to more effective RRT-related interventions to mitigate its occurrence and consequences.
Dynamic Chromatin Targeting of BRD4 Stimulates Cardiac Fibroblast Activation
Authors: Matthew S. Stratton, Rushita A. Bagchi, Marina B. Felisbino, Rachel A. Hirsch, Harrison E. Smith, Andrew S. Riching, Blake Y. Enyart, Keith A. Koch, Maria A. Cavasin, Michael Alexanian, Kunhua Song, Jun Qi, Madeleine E. Lemieux, Deepak Srivastava, Maggie P.Y. Lam, Saptarsi M. Haldar, Charles Y. Lin, Timothy A. McKinsey
Journal: Circulation Research (2019)

Rationale: Small molecule inhibitors of the acetyl-histone binding protein BRD4 have been shown to block cardiac fibrosis in preclinical models of heart failure (HF). However, since the inhibitors target BRD4 ubiquitously, it is unclear whether this chromatin reader protein functions in cell type-specific manner to control pathological myocardial fibrosis. Furthermore, the molecular mechanisms by which BRD4 stimulates the transcriptional program for cardiac fibrosis remain unknown. Objective: We sought to test the hypothesis that BRD4 functions in a cell-autonomous and signal-responsive manner to control activation of cardiac fibroblasts, which are the major extracellular matrix-producing cells of the heart. Methods and Results: RNA-sequencing, mass spectrometry, and cell-based assays employing primary adult rat ventricular fibroblasts demonstrated that BRD4 functions as an effector of TGF-β (transforming growth factor-β) signaling to stimulate conversion of quiescent cardiac fibroblasts into Periostin ( Postn )-positive cells that express high levels of extracellular matrix. These findings were confirmed in vivo through whole-transcriptome analysis of cardiac fibroblasts from mice subjected to transverse aortic constriction and treated with the small molecule BRD4 inhibitor, JQ1. Chromatin immunoprecipitation-sequencing revealed that BRD4 undergoes stimulus-dependent, genome-wide redistribution in cardiac fibroblasts, becoming enriched on a subset of enhancers and super-enhancers, and leading to RNA polymerase II activation and expression of downstream target genes. Employing the Sertad4 (SERTA domain-containing protein 4) locus as a prototype, we demonstrate that dynamic chromatin targeting of BRD4 is controlled, in part, by p38 MAPK (mitogen-activated protein kinase) and provide evidence of a critical function for Sertad4 in TGF-β-mediated cardiac fibroblast activation. Conclusions: These findings define BRD4 as a central regulator of the pro-fibrotic cardiac fibroblast phenotype, establish a p38-dependent signaling circuit for epigenetic reprogramming in heart failure, and uncover a novel role for Sertad4 . The work provides a mechanistic foundation for the development of BRD4 inhibitors as targeted anti-fibrotic therapies for the heart.
Hypothalamic dopamine signalling regulates brown fat thermogenesis
Authors: Cintia Folgueira, Daniel Beiroa, Begoña Porteiro, Manon Duquenne, Emma Puighermanal, Marcos F. Fondevila, Silvia Barja-Fernández, Rosalia Gallego, René Hernández-Bautista, Cecilia Castelao, Ana Senra, Patricia Seoane-Collazo, Noemi Gómez-Lado, Pablo Aguiar, Diana Guallar, Miguel Fidalgo, Amparo Romero-Pico, Roger Adan, Clemence Blouet, Jose Luís Labandeira-García, Françoise Jeanrenaud, Imre Kallo, Zsolt Liposits, Javier Salvador, Vincent Prevot, Carlos Dieguez, Miguel López, Emmanuel Valjent, Gema Frühbeck, Luisa M. Seoane, Ruben Nogueiras
Journal: Nature Metabolism (2019)
Targeting virulence factors as an antimicrobial approach: Pigment inhibitors
Authors: Shuaishuai Ni, Baoli Li, Yixiang Xu, Fei Mao, Xiaokang Li, Lefu Lan, Jin Zhu, Jian Li
Journal: Medicinal Research Reviews (2019)

Abstract The fascinating and dangerous colored pathogens contain unique chemically pigmented molecules, which give varied and efficient assistance as virulence factors to the crucial reproduction and growth of microbes. Therefore, multiple novel strategies and inhibitors have been developed in recent years that target virulence factor pigments. However, despite the importance and significance of this topic, it has not yet been comprehensively reviewed. Moreover, research groups around the world have made successful progress against antibacterial infections by targeting pigment production, including our serial works on the discovery of CrtN inhibitors against staphyloxanthin production in Staphylococcus aureus . On the basis of the previous achievements and recent progress of our group in this field, this article will be the first comprehensive review of pigment inhibitors against colored pathogens, especially S. aureus infections, and this article includes design strategies, representative case studies, advantages, limitations, and perspectives to guide future research.
The Alpha Emitter Astatine-211 Targeted to CD38 Can Eradicate Multiple Myeloma in Minimal Residual Disease Models
Authors: Shyril O'Steen, Melissa C. Comstock, Johnnie J. Orozco, Donald K. Hamlin, D. Scott Wilbur, Jon Jones, Aimee Kenoyer, Margaret E. Nartea, Yukang Lin, Brian W. Miller, Sherilyn A. Tuazon, Brian G. Till, Ajay K. Gopal, Brenda M. Sandmaier, Oliver W. Press, Damian J. Green
Journal: Blood (2018)
Mediastinal lymph node staging in patients with non-small cell lung cancer (NSCLC) with F18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT).
Authors: Miriam Mendez, Constanza Maximiano, Miriam Huelves, Bernard Gaston Doger de Speville, Patricia Ibeas, Andrea Ruiz-Valdepeñas, Magda Palka, Gema Diaz, David Gomez, Mariano Provencio
Journal: Journal of Clinical Oncology (2012)

e17503 Background: Lung cancer is the leading cause of cancer-related deaths in the Western world. CT and mediastinoscopy are the standard for staging modalities in recent years; PET has emerged as a complement to other techniques. Mediastinal lymph node (MLN) staging is important because it establishes subsequent treatment. The aim of the present study is to analyze the relationship between mediastinal staging by endobronchial ultrasound-guided transbronchial needle aspiration, mediastinoscopy, lymphadenectomy and PET. It also analyzes the patient characteristics like age, sex, histology. Methods: The study prospectively evaluated 42 patients from August 2009 to March 2011. All of them had MLN staging by PET and pathology (tumor resection with systematic lymph node dissection, transbronchial needle aspiration or mediastinoscopy). Univariable date analysis was conducted using Pearson's chi-square test. P values were considered statistically significant if &lt;0.05. Results: The study group comprised 42 patients, 83% men and 17% female, mean age of 66 years. The primary tumor cell type: 45% squamous cell, 33% adenocarcinoma and 19% large cells. 40 patients were smoking. The most frequent location of tumor was upper lobes (58%). The most common stage found after surgery was stage I (42%), stage II (19%), stage III (A: 29%, B: 5%) and stage IV (5%). The kappa statistic for diagnostic agreement between CT and PET was 0.53 (p&lt;0.001). About MLN staging, PET has a sensitivity of 61% and specificity of 53% , positive predictive value 61% and negative 53%. Conclusions: The present study attempts to find the relationship between tumor involvement found in PET and resected tumor specimens obtained from the mediastinum. Our sensitivity and specificity were not concordant with those previously reported; this may be due to the learning curve at our center or the shortness of our series. In contrast we conducted histological examination of all involved MLNs, supporting our data and shows that this confirmation can lead to a change of therapeutic strategy in some cases.