tbuckley/cabot-search huggingface dataset:
Management of Germ Cell Cancer: Lessons Learned From a National Database
Authors: Ronald de Wit
Journal: Journal of Clinical Oncology (2015)

The treatment of metastatic germ cell cancer (GCC) with cisplatin-based chemotherapy results in a cure in well over 90% of patients with good-prognosis disease according to the International GermCellCancerCollaborativeGroup. 1 Recentdataindicatethatthe eventual cure rate is also improving in intermediate- and poor-risk disease and may be approaching 90% in expert centers. 2 Managing treatmentofyoungmaleswithcurativeintentisagratifyingopportunity for every medical oncologist. Young oncologists who have often been involved in the treatment of patients with GCC during their fellowships at academic sites and who continue their career in community hospitals may wish to continue managing this type of patient. The pitfall, though, is that they are no longer working in an environmentwheretheycanengageinexpertteamdiscussionsand,withrare exceptions, they work without a surgeon experienced in postchemotherapy(post-CT)resectionsandoftenwithoutdedicatedradiologists and pathologists. Consequently, the proper place for managing these patients remains controversial, and there is a continuing debate in both Europe and the United States on whether treatment of these patients in low-volume centers is appropriate. Two previous studies from leading expert centers in the United States are relevant in this regard. 3-5 Both studies contained data on post-CT histology findings after treatment, either at the expert center from the very beginning or after having the chemotherapy administered in community hospitals and referral only at the time of the post-CT surgery. The authors felt thatthehigherratesofunfavorablehistology(viablecancerofmature
Transposable elements modulate human RNA abundance and splicing via specific RNA-protein interactions
Authors: David R Kelley, David G Hendrickson, Danielle Tenen, John L Rinn
Journal: Genome biology (2014)

Transposable elements (TEs) have significantly influenced the evolution of transcriptional regulatory networks in the human genome. Post-transcriptional regulation of human genes by TE-derived sequences has been observed in specific contexts, but has yet to be systematically and comprehensively investigated. Here, we study a collection of 75 CLIP-Seq experiments mapping the RNA binding sites for a diverse set of 51 human proteins to explore the role of TEs in post-transcriptional regulation of human mRNAs and lncRNAs via RNA-protein interactions. We detect widespread interactions between RNA binding proteins (RBPs) and many families of TE-derived sequence in the CLIP-Seq data. Further, alignment coverage peaks on specific positions of the TE consensus sequences, illuminating a diversity of TE-specific RBP binding motifs. Evidence of binding and conservation of these motifs in the nonrepetitive transcriptome suggests that TEs have generally appropriated existing sequence preferences of the RBPs. Depletion assays for numerous RBPs show that TE-derived binding sites affect transcript abundance and splicing similarly to nonrepetitive sites. However, in a few cases the effect of RBP binding depends on the specific TE family bound; for example, the ubiquitously expressed RBP HuR confers transcript stability unless bound to an Alu element. Our meta-analysis suggests a widespread role for TEs in shaping RNA-protein regulatory networks in the human genome.
Deficiency of pRb Family Proteins and p53 in Invasive Urothelial Tumorigenesis
Authors: Feng He, Lan Mo, Xiao-Yong Zheng, Changkun Hu, Herbert Lepor, Eva Y-H.P. Lee, Tung-Tien Sun, Xue-Ru Wu
Journal: Cancer Research (2009)

Defects in pRb tumor suppressor pathway occur in approximately 50% of the deadly muscle-invasive urothelial carcinomas in humans and urothelial carcinoma is the most prevalent epithelial cancer in long-term survivors of hereditary retinoblastomas caused by loss-of-function RB1 mutations. Here, we show that conditional inactivation of both RB1 alleles in mouse urothelium failed to accelerate urothelial proliferation. Instead, it profoundly activated the p53 pathway, leading to extensive apoptosis, and selectively induced pRb family member p107. Thus, pRb loss triggered multiple fail-safe mechanisms whereby urothelial cells evade tumorigenesis. Additional loss of p53 in pRb-deficient urothelial cells removed these p53-dependent tumor barriers, resulting in late-onset hyperplasia, umbrella cell nuclear atypia, and rare-occurring low-grade, superficial papillary bladder tumors, without eliciting invasive carcinomas. Importantly, mice deficient in both pRb and p53, but not those deficient in either protein alone, were highly susceptible to subthreshold carcinogen exposure and developed invasive urothelial carcinomas that strongly resembled the human counterparts. The invasive lesions had a marked reduction of p107 but not p130 of the pRb family. Our data provide compelling evidence, indicating that urothelium, one of the slowest cycling epithelia, is remarkably resistant to transformation by pRb or p53 deficiency; that concurrent loss of these two tumor suppressors is necessary but insufficient to initiate urothelial tumorigenesis along the invasive pathway; that p107 may play a critical role in suppressing invasive urothelial tumor formation; and that replacing/restoring the function of pRb, p107, or p53 could be explored as a potential therapeutic strategy to block urothelial tumor progression.
Changes in Pyruvate Metabolism Detected by Magnetic Resonance Imaging Are Linked to DNA Damage and Serve as a Sensor of Temozolomide Response in Glioblastoma Cells
Authors: Ilwoo Park, Joydeep Mukherjee, Motokazu Ito, Myriam M. Chaumeil, Llewellyn E. Jalbert, Karin Gaensler, Sabrina M. Ronen, Sarah J. Nelson, Russell O. Pieper
Journal: Cancer Research (2014)

Recent findings show that exposure to temozolomide (TMZ), a DNA-damaging drug used to treat glioblastoma (GBM), can suppress the conversion of pyruvate to lactate. To understand the mechanistic basis for this effect and its potential utility as a TMZ response biomarker, we compared the response of isogenic GBM cell populations differing only in expression of the DNA repair protein methyltransferase (MGMT), a TMZ-sensitivity determinant, after exposure to TMZ in vitro and in vivo. Hyperpolarized [1-((13))C]-pyruvate-based MRI was used to monitor temporal effects on pyruvate metabolism in parallel with DNA-damage responses and tumor cell growth. TMZ exposure decreased conversion of pyruvate to lactate only in MGMT-deficient cells. This effect coincided temporally with TMZ-induced increases in levels of the DNA-damage response protein pChk1. Changes in pyruvate to lactate conversion triggered by TMZ preceded tumor growth suppression and were not associated with changes in levels of NADH or lactate dehydrogenase activity in tumors. Instead, they were associated with a TMZ-induced decrease in the expression and activity of pyruvate kinase PKM2, a glycolytic enzyme that indirectly controls pyruvate metabolism. PKM2 silencing decreased PK activity, intracellular lactate levels, and conversion of pyruvate to lactate in the same manner as TMZ, and Chk1 silencing blocked the TMZ-induced decrease in PKM2 expression. Overall, our findings showed how TMZ-induced DNA damage is linked through PKM2 to changes in pyruvate metabolism, and how these changes can be exploited by MRI methods as an early sensor of TMZ therapeutic response.
"Winter Vomiting" and Collapse
Authors: M. D. Bull
Journal: BMJ (1965)

Epidemic CollapseSIR,-Referring to the mysterious illness among pupils at a girls' school reported in the B.M.7.for 16 October (p.950) the fact that laboratory investigations so far have proved negative prompts me to relate an incident with which I was concerned at a mixed secondary modern school some years ago.I was called to this school one morning by the head teacher as a number of pupils had been taken ill.When I arrived I found that some of the children had already been sent home not feeling well.Others were lying in classrooms and corridors exhibiting various stages of " collapse."Among those I examined some had
Time-Dependent Prognostic Scoring System for Predicting Survival and Leukemic Evolution in Myelodysplastic Syndromes
Authors: Luca Malcovati, Ulrich Germing, Andrea Kuendgen, Matteo G. Della Porta, Cristiana Pascutto, Rosangela Invernizzi, Aristoteles Giagounidis, Barbara Hildebrandt, Paolo Bernasconi, Sabine Knipp, Corinna Strupp, Mario Lazzarino, Carlo Aul, Mario Cazzola
Journal: Journal of Clinical Oncology (2007)

Purpose The aims of this study were to identify the most significant prognostic factors in myelodysplastic syndromes (MDS) taking into account both their values at clinical onset and their changes in time and to develop a dynamic model for predicting survival and leukemic evolution that can be applied at any time during the course of the disease. Patients and Methods We studied a learning cohort of 426 MDS patients diagnosed at the Department of Hematology, San Matteo Hospital, Pavia, Italy, between 1992 and 2004, and a validation cohort of 739 patients diagnosed at the Heinrich-Heine-University Hospital, Düsseldorf, Germany, between 1982 and 2003. All patients were reclassified according to WHO criteria. Univariable and multivariable analyses were performed using Cox models with time-dependent covariates. Results The most important variables for the prognostic model were WHO subgroups, karyotype, and transfusion requirement. We defined a WHO classification–based prognostic scoring system (WPSS) that was able to classify patients into five risk groups showing different survivals (median survival from 12 to 103 months) and probabilities of leukemic evolution (P &lt; .001). WPSS was shown to predict survival and leukemia progression at any time during follow-up (P &lt; .001), and its prognostic value was confirmed in the validation cohort. Conclusion WPSS is a dynamic prognostic scoring system that provides an accurate prediction of survival and risk of leukemic evolution in MDS patients at any time during the course of their disease. This time-dependent system seems particularly useful in lower risk patients and may be used for implementing risk-adapted treatment strategies.
Clioquinol, a Therapeutic Agent for Alzheimer's Disease, Has Proteasome-Inhibitory, Androgen Receptor–Suppressing, Apoptosis-Inducing, and Antitumor Activities in Human Prostate Cancer Cells and Xenografts
Authors: Di Chen, Qiuzhi Cindy Cui, Huanjie Yang, Raul A. Barrea, Fazlul H. Sarkar, Shijie Sheng, Bing Yan, G. Prem Veer Reddy, Q. Ping Dou
Journal: Cancer Research (2007)

Tumor growth and metastasis depend on angiogenesis that requires the cofactor copper. Consistently, high levels of copper have been found in many types of human cancers, including prostate, breast, colon, and lung. Recent studies suggest that copper could be used as a novel selective target for cancer therapies. Clioquinol is capable of forming stable complexes with copper and currently used in clinics for treatment of Alzheimer's disease. Most recently, it has been reported that clioquinol possesses antitumor effects. However, the underlying molecular mechanism is unclear. We report here that after binding to copper, clioquinol can inhibit the proteasomal chymotrypsin-like activity, repress androgen receptor (AR) protein expression, and induce apoptotic cell death in human prostate cancer LNCaP and C4-2B cells. In addition, clioquinol alone exhibits similar effects in prostate cancer cell lines with elevated copper at concentrations similar to those found in patients. Addition of dihydrotestosterone did not affect clioquinol-mediated proteasome inhibition in both prostate cancer cell lines. However, dihydrotestosterone partially inhibited clioquinol-induced AR suppression and apoptosis only in androgen-dependent LNCaP cells. Animal studies show that clioquinol treatment significantly inhibits the growth of human prostate tumor C4-2B xenografts (by 66%), associated with in vivo proteasome inhibition, AR protein repression, angiogenesis suppression, and apoptosis induction. Our study provides strong evidence that clioquinol is able to target tumor proteasome in vivo in a copper-dependent manner, resulting in formation of an active AR inhibitor and apoptosis inducer that is responsible for its observed antiprostate tumor effect.
Uterine Inflammatory Myofibroblastic Tumor in a 10-Year-Old Girl Presenting As Polypoid Mass
Authors: Filippo Fraggetta, Claudio Doglioni, Paolo Scollo, Lorenza Pecciarini, Massimo Ippolito, Paolo Amico, Giuseppe Pelosi, Maurilio Ponzoni
Journal: Journal of Clinical Oncology (2014)
Population-Level Impact of the Bivalent, Quadrivalent, and Nonavalent Human Papillomavirus Vaccines: A Model–Based Analysis
Authors: Nicolas Van de Velde, Marie-Claude Boily, Mélanie Drolet, Eduardo L. Franco, Marie-Hélène Mayrand, Erich V. Kliewer, François Coutlée, Jean-François Laprise, Talía Malagón, Marc Brisson
Journal: JNCI Journal of the National Cancer Institute (2012)

Bivalent and quadrivalent human papillomavirus (HPV) vaccines are now licensed in several countries. Furthermore, clinical trials examining the efficacy of a nonavalent vaccine are underway. We aimed to compare the potential population-level effectiveness of the bivalent, quadrivalent, and candidate nonavalent HPV vaccines. We developed an individual-based, transmission-dynamic model of HPV infection and disease in a population stratified by age, gender, sexual activity, and screening behavior. The model was calibrated to highly stratified sexual behavior, HPV epidemiology, and cervical screening data from Canada. Under base case assumptions, vaccinating 12-year-old girls (70% coverage) with the bivalent (quadrivalent) vaccine is predicted to reduce the cumulative incidence of anogenital warts (AGWs) by 0.0% (72.1%), diagnosed cervical intraepithelial neoplasia lesions 2 and 3 (CIN2 and -3) by 51.0% (46.1%), and cervical squamous cell carcinoma (SCC) by 31.9% (30.5%), over 70 years. Changing from a bivalent (quadrivalent) to a nonavalent vaccine is predicted to reduce the cumulative number of AGW episodes by an additional 66.7% (0.0%), CIN2 and -3 episodes by an additional 9.3% (12.5%), and SCC cases by an additional 4.8% (6.6%) over 70 years. Differences in predicted population-level effectiveness between the vaccines were most sensitive to duration of protection and the time horizon of analysis. The vaccines produced similar effectiveness at preventing noncervical HPV-related cancers. The bivalent vaccine is expected to be slightly more effective at preventing CIN2 and -3 and SCC in the longer term, whereas the quadrivalent vaccine is expected to substantially reduce AGW cases shortly after the start of vaccination programs. Switching to a nonavalent vaccine has the potential to further reduce precancerous lesions and cervical cancer.
Specific Macrophage Subtypes Influence the Progression of Rhabdomyolysis-Induced Kidney Injury
Authors: Julie Belliere, Audrey Casemayou, Laure Ducasse, Alexia Zakaroff-Girard, Frédéric Martins, Jason S. Iacovoni, Céline Guilbeau-Frugier, Bénédicte Buffin-Meyer, Bernard Pipy, Dominique Chauveau, Joost P. Schanstra, Jean-Loup Bascands
Journal: Journal of the American Society of Nephrology (2014)

Rhabdomyolysis can be life threatening if complicated by AKI. Macrophage infiltration has been observed in rat kidneys after glycerol-induced rhabdomyolysis, but the role of macrophages in rhabdomyolysis-induced AKI remains unknown. Here, in a patient diagnosed with rhabdomyolysis, we detected substantial macrophage infiltration in the kidney. In a mouse model of rhabdomyolysis-induced AKI, diverse renal macrophage phenotypes were observed depending on the stage of the disease. Two days after rhabdomyolysis, F4/80(low)CD11b(high)Ly6b(high)CD206(low) kidney macrophages were dominant, whereas by day 8, F4/80(high)CD11b(+)Ly6b(low)CD206(high) cells became the most abundant. Single-cell gene expression analyses of FACS-sorted macrophages revealed that these subpopulations were heterogeneous and that individual cells simultaneously expressed both M1 and M2 markers. Liposomal clodronate-mediated macrophage depletion significantly reduced the early infiltration of F4/80(low)CD11b(high)Ly6b(high)CD206(low) macrophages. Furthermore, transcriptionally regulated targets potentially involved in disease progression, including fibronectin, collagen III, and chemoattractants that were identified via single-cell analysis, were verified as macrophage-dependent in situ. In vitro, myoglobin treatment induced proximal tubular cells to secrete chemoattractants and macrophages to express proinflammatory markers. At day 30, liposomal clodronate-mediated macrophage depletion reduced fibrosis and improved both kidney repair and mouse survival. Seven months after rhabdomyolysis, histologic lesions were still present but were substantially reduced with prior depletion of macrophages. These results suggest an important role for macrophages in rhabdomyolysis-induced AKI progression and advocate the utility of long-term follow-up for patients with this disease.
Brain-tethered T cells
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

Brain-tethered T cellsOn page 1805, Kawakami et al. show that antigen-specific CD4 ϩ T cells that attack the brain become stationary within brain tissue, whereas nonspecific T cells cruise through without stopping.These intravital images-the first to capture T cells launching an autoimmune attack on the brain-suggest that antigenspecific T cells behave similarly in dense brain tissue as they do in lymph nodes.Activated CD4 ϩ T cells specific for the endogenous brain protein myelin basic protein (MBP) trigger fatal encephalomyelitis in a rat model of multiple sclerosis.These cells migrate into the central nervous system (CNS) where they become reactivated.Previous studies by this group showed that both antigen-specific and nonspecific T cells gain access to the CNS, but only specific cells become reactivated once there.Kawakami et al. now show that a subset of MBP-specific T cells-likely those that have encountered antigen-stopped moving inside the brain, appearing tethered to a fixed point.T cells specific for a control antigen kept moving, suggesting that the presence of antigen was required for T cells to stop moving and to trigger disease.The authors were surprised to find that T cells move as rapidly through the dense brain tissue as in the more aqueous environment of the lymph nodes.How they do this is not known but the authors suggest that the T cells may produce proteases that help clear a path through the compact tissue.
Cigarette Smoke Induces Systemic Defects in Cystic Fibrosis Transmembrane Conductance Regulator Function
Authors: S. Vamsee Raju, Patricia L. Jackson, Clifford A. Courville, Carmel M. McNicholas, Peter A. Sloane, Gina Sabbatini, Sherry Tidwell, Li Ping Tang, Bo Liu, James A. Fortenberry, Caleb W. Jones, Jeremy A. Boydston, J. P. Clancy, Larry E. Bowen, Frank J. Accurso, J. Edwin Blalock, Mark T. Dransfield, Steven M. Rowe
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

Several extrapulmonary disorders have been linked to cigarette smoking. Smoking is reported to cause cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction in the airway, and is also associated with pancreatitis, male infertility, and cachexia, features characteristic of cystic fibrosis and suggestive of an etiological role for CFTR.To study the effect of cigarette smoke on extrapulmonary CFTR function.Demographics, spirometry, exercise tolerance, symptom questionnaires, CFTR genetics, and sweat chloride analysis were obtained in smokers with and without chronic obstructive pulmonary disease (COPD). CFTR activity was measured by nasal potential difference in mice and by Ussing chamber electrophysiology in vitro. Serum acrolein levels were estimated with mass spectroscopy.Healthy smokers (29.45 ± 13.90 mEq), smokers with COPD (31.89 ± 13.9 mEq), and former smokers with COPD (25.07 ± 10.92 mEq) had elevated sweat chloride levels compared with normal control subjects (14.5 ± 7.77 mEq), indicating reduced CFTR activity in a nonrespiratory organ. Intestinal current measurements also demonstrated a 65% decrease in CFTR function in smokers compared with never smokers. CFTR activity was decreased by 68% in normal human bronchial epithelial cells exposed to plasma from smokers, suggesting that one or more circulating agents could confer CFTR dysfunction. Cigarette smoke-exposed mice had decreased CFTR activity in intestinal epithelium (84.3 and 45%, after 5 and 17 wk, respectively). Acrolein, a component of cigarette smoke, was higher in smokers, blocked CFTR by inhibiting channel gating, and was attenuated by antioxidant N-acetylcysteine, a known scavenger of acrolein.Smoking causes systemic CFTR dysfunction. Acrolein present in cigarette smoke mediates CFTR defects in extrapulmonary tissues in smokers.
Patients' perception of the informed consent process for neurooncology clinical trials
Authors: Eva Knifed, Nir Lipsman, Warren Mason, Mark Bernstein
Journal: Neuro-Oncology (2008)

The informed consent process is a cornerstone of modern medical research. This study was conducted to explore the process in the context of neurooncology clinical trials. Qualitative methodology and analysis were used on open-ended, face-to-face interviews conducted with 21 patients. Six comprehensive themes emerged: (1) general understanding of the objectives and purpose of clinical trials was good, (2) recall of risks was low, (3) patients did not believe that their care would be compromised by forgoing the clinical trial, (4) patients felt participation was voluntary and free of coercion, (5) patients would not have withdrawn from the trial in the event of complications, and (6) patients were satisfied with the informed consent process. Informed consent is a dynamic process; when appropriately executed, it can be a powerful safeguard protecting patient autonomy. If sufficient time is allowed to deliberate participation and ample opportunity is provided for information sharing and disclosure, researchers can be confident that participants are knowledgeable about the trial and aware of their rights.