tbuckley/cabot-search huggingface dataset:
Bcl-xl does not have to bind Bax to protect T cells from death
Authors: Xinqi Liu, Yanan Zhu, Shaodong Dai, Janice White, Fred Peyerl, John W. Kappler, Philippa Marrack
Journal: The Journal of Experimental Medicine (2006)

Activated T cells die when antigen disappears from animals. This death is caused by proteins related to Bcl-2. Two hypotheses have been suggested to explain the actions of the different types of Bcl-2 proteins. One hypothesis suggests that, when T cells prepare to die, Bak and Bax, the proteins that actually kill activated T cells, are released from antiapoptotic proteins such as Bcl-2 and Bcl-xl. Another hypothesis suggests that Bak and Bax are normally free and are triggered to kill cells by release of messenger proteins, such as Bim, from Bcl-2 and Bcl-xl. Here, a form of Bcl-xl, which lacks a long unstructured loop, is used to show that the first hypothesis is not correct. Bcl-xl without its loop protects activated T cells from death, yet Bcl-xl without its loop cannot bind any form of Bak and Bax. Thus, binding of Bcl-xl to Bak or Bax is not involved in T cell life or death. The loop of Bcl-xl is also somewhat involved in Bcl-xl's binding of Bim because Bcl-xl without its loop binds Bim less well than wild-type Bcl-xl. Moreover, the loop may have additional, as yet unknown, functions because it changes its shape when Bcl-xl binds Bim.
Histone Lysine Methyltransferase SETD8 Promotes Carcinogenesis by Deregulating PCNA Expression
Authors: Masashi Takawa, Hyun-Soo Cho, Shinya Hayami, Gouji Toyokawa, Masaharu Kogure, Yuka Yamane, Yukiko Iwai, Kazuhiro Maejima, Koji Ueda, Akiko Masuda, Naoshi Dohmae, Helen I. Field, Tatsuhiko Tsunoda, Takaaki Kobayashi, Takayuki Akasu, Masanori Sugiyama, Shin-ichi Ohnuma, Yutaka Atomi, Bruce A.J. Ponder, Yusuke Nakamura, Ryuji Hamamoto
Journal: Cancer Research (2012)

Although the physiologic significance of lysine methylation of histones is well known, whether lysine methylation plays a role in the regulation of nonhistone proteins has not yet been examined. The histone lysine methyltransferase SETD8 is overexpressed in various types of cancer and seems to play a crucial role in S-phase progression. Here, we show that SETD8 regulates the function of proliferating cell nuclear antigen (PCNA) protein through lysine methylation. We found that SETD8 methylated PCNA on lysine 248, and either depletion of SETD8 or substitution of lysine 248 destabilized PCNA expression. Mechanistically, lysine methylation significantly enhanced the interaction between PCNA and the flap endonuclease FEN1. Loss of PCNA methylation retarded the maturation of Okazaki fragments, slowed DNA replication, and induced DNA damage, and cells expressing a methylation-inactive PCNA mutant were more susceptible to DNA damage. An increase of methylated PCNA was found in cancer cells, and the expression levels of SETD8 and PCNA were correlated in cancer tissue samples. Together, our findings reveal a function for lysine methylation on a nonhistone protein and suggest that aberrant lysine methylation of PCNA may play a role in human carcinogenesis.
Hepatitis B Virus Screening Before Chemotherapy for Lymphoma: A Cost-Effectiveness Analysis
Authors: Urszula Zurawska, Lisa K. Hicks, Gloria Woo, Chaim M. Bell, Murray Krahn, Kelvin K. Chan, Jordan J. Feld
Journal: Journal of Clinical Oncology (2012)

Hepatitis B virus (HBV) reactivation is a potentially fatal complication of chemotherapy that can be largely prevented with antiviral prophylaxis. It remains unclear whether HBV screening is cost effective.A decision model was developed to compare the clinical outcomes, costs, and cost effectiveness of three HBV screening strategies for patients with lymphoma before R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy: screen all patients for hepatitis B surface antigen (HBsAg; Screen-All), screen patients identified as being at high risk for HBV infection (Screen-HR), and screen no one (Screen-None). Patients testing positive were administered antiviral therapy until 6 months after completion of chemotherapy. Those not screened were initiated on antiviral therapy only if HBV hepatitis occurred. Probabilities of HBV and lymphoma outcomes were derived from systematic literature review. A third-party payer perspective was adopted, costs were expressed in 2011 Canadian dollars, and a 1-year time horizon was used.Screen-All was the dominant strategy. It was least costly at $32,589, compared with $32,598 for Screen-HR and $32,657 for Screen-None. It was also associated with the highest 1-year survival rate at 84.99%, compared with 84.96% for Screen-HR and 84.86% for Screen-None. The analysis was sensitive to the prevalence of HBsAg positivity in the low-risk population, with Screen-HR becoming least costly when this value was ≤ 0.20%.In patients receiving R-CHOP for lymphoma, screening all patients for HBV reduces the rate of HBV reactivation (10-fold) and is less costly than screening only high-risk patients or screening no patients.
Phenothiazine Intake and Staff Attitudes
Authors: DAVID S. IRWIN, WILLIAM D. WEITZEL, DONALD W. MORGAN
Journal: American Journal of Psychiatry (1971)

The authors report the percentages of patients who failed to adhere minimally to prescribed phenothiazine medication schedules in closed-ward, open-ward, and chronic outpatient treatment situations within a single hospital. An unexpected finding was that significantly more outpatients on thioridazine (55 percent) than on chlorpromazine (15 percent) were not taking minimal amounts of medication. Staff attitudes regarding the usefulness of antipsychotic medications were also studied. The principal factor governing patient intake of medication appeared to be the amount of direct patient supervision.
Medulloblastoma: Clinical and biologic aspects
Authors: R. J. Packer, P. Cogen, G. Vezina, L. B. Rorke
Journal: Neuro-Oncology (1999)

Medulloblastoma is the most common childhood primary CNS tumor, and treatment approaches have evolved over the past three decades. The biologic underpinnings of medulloblastoma are not fully characterized, but recent work has identified new, important directions for research. Stratification of patients with medulloblastoma into risk groups is the backbone of most ongoing therapeutic studies. Patients are usually characterized as being either average risk or poor risk, although an intermediate risk group may exist. Standard treatment for older children with medulloblastoma consists of radiation and, for most, chemotherapy. Children with nondisseminated disease at the time of diagnosis have been reported to have as high as an 80% five-year disease-free survival rate after treatment with reduced dose (2340 cGy) craniospinal irradiation, local boost radiation therapy (5500 cGy), and chemotherapy, given during and after radiation therapy. Preradiation chemotherapy has yet to be shown to be of benefit for children with medulloblastoma. Children with disseminated disease are a highly problematic subgroup of patients to treat. A variety of new approaches are being studied, most of which are intensifying chemotherapy either prior to or after radiation. Long-term survivors of medulloblastoma are at significant risk for permanent endocrinologic, cognitive, and psychological sequelae. Infants and very young children with medulloblastoma remain a difficult therapeutic challenge because they have the most virulent form of the disease and are at highest risk for treatment-related sequelae.
Asthma and Suicide Mortality in Young People: A 12-Year Follow-Up Study
Authors: Chian-Jue Kuo, Vincent Chin-Hung Chen, Wen-Chung Lee, Wei J. Chen, Cleusa P. Ferri, Robert Stewart, Te-Jen Lai, Chiao-Chicy Chen, Tsu-Nai Wang, Ying-Chin Ko
Journal: American Journal of Psychiatry (2010)

Objective: Mortality risk is relatively high in young people with asthma, and the risk may include causes of death other than those directly linked to respiratory disease. The authors investigated the association between asthma and suicide mortality in a large population-based cohort of young people. Method: A total of 162,766 high school students 11 to 16 years of age living in a catchment area in Taiwan from October 1995 to June 1996 were enrolled in a study of asthma and allergy. Each student and his or her parents completed structured questionnaires. Participants were classified into three groups at baseline: current asthma (symptoms present in the past year), previous asthma (history of asthma but no symptoms in the past year), and no asthma. Participants were followed to December 2007 by record linkage to the national Death Certification System. Cox proportional hazards models were used to study the association between asthma and cause of death. Results: The incidence rate of suicide mortality in participants with current asthma at baseline was more than twice that of those without asthma (11.0 compared with 4.3 per 100,000 person-years), but there was no significant difference in the incidence of natural deaths. The adjusted hazard ratio for suicide was 2.26 (95% CI=1.43–3.58) in the current asthma group and 1.76 (95% CI=0.90–3.43) in the previous asthma group. Having a greater number of asthma symptoms at baseline was associated with a higher risk of subsequent suicide. The population attributable fraction was 7.0%. Conclusions: These results highlight evidence of excess suicide mortality in young people with asthma. There is a need to improve mental health care for young people, particularly those with more severe and persistent asthma symptoms.
DNA methylation profiling of ovarian carcinomas and their in vitro models identifies HOXA9, HOXB5, SCGB3A1, and CRABP1 as novel targets
Authors: Qinghua Wu, Ragnhild A Lothe, Terje Ahlquist, Ilvars Silins, Claes G Tropé, Francesca Micci, Jahn M Nesland, Zhenhe Suo, Guro E Lind
Journal: Molecular Cancer (2007)

Abstract Background The epigenetics of ovarian carcinogenesis remains poorly described. We have in the present study investigated the promoter methylation status of 13 genes in primary ovarian carcinomas (n = 52) and their in vitro models (n = 4; ES-2, OV-90, OVCAR-3, and SKOV-3) by methylation-specific polymerase chain reaction (MSP). Direct bisulphite sequencing analysis was used to confirm the methylation status of individual genes. The MSP results were compared with clinico- pathological features. Results Eight out of the 13 genes were hypermethylated among the ovarian carcinomas, and altogether 40 of 52 tumours were methylated in one or more genes. Promoter hypermethylation of HOXA9 , RASSF1A , APC , CDH13 , HOXB5 , SCGB3A1 (HIN-1) , CRABP1 , and MLH1 was found in 51% (26/51), 49% (23/47), 24% (12/51), 20% (10/51), 12% (6/52), 10% (5/52), 4% (2/48), and 2% (1/51) of the carcinomas, respectively, whereas ADAMTS1 , MGMT , NR3C1 , p14 ARF , and p16 INK 4 a were unmethylated in all samples. The methylation frequencies of HOXA9 and SCGB3A1 were higher among relatively early-stage carcinomas (FIGO I-II) than among carcinomas of later stages (FIGO III-IV; P = 0.002, P = 0.020, respectively). The majority of the early-stage carcinomas were of the endometrioid histotype. Additionally, HOXA9 hypermethylation was more common in tumours from patients older than 60 years of age (15/21) than among those of younger age (11/30; P = 0.023). Finally, there was a significant difference in HOXA9 methylation frequency among the histological types ( P = 0.007). Conclusion DNA hypermethylation of tumour suppressor genes seems to play an important role in ovarian carcinogenesis and HOXA9 , HOXB5 , SCGB3A1 , and CRABP1 are identified as novel hypermethylated target genes in this tumour type.
Common Sodium Channel Promoter Haplotype in Asian Subjects Underlies Variability in Cardiac Conduction
Authors: Connie R. Bezzina, Wataru Shimizu, Ping Yang, Tamara T. Koopmann, Michael W.T. Tanck, Yoshihiro Miyamoto, Shiro Kamakura, Dan M. Roden, Arthur A.M. Wilde
Journal: Circulation (2006)

Background— Reduced cardiac sodium current slows conduction and renders the heart susceptible to ventricular fibrillation. Loss of function mutations in SCN5A , encoding the cardiac sodium channel, are one cause of the Brugada syndrome, associated with slow conduction and a high incidence of ventricular fibrillation, especially in Asians. In this study, we tested the hypothesis that an SCN5A promoter polymorphism common in Asians modulates variability in cardiac conduction. Methods and Results— Resequencing 2.8 kb of SCN5A promoter identified a haplotype variant consisting of 6 polymorphisms in near-complete linkage disequilibrium that occurred at an allele frequency of 22% in Asian subjects and was absent in whites and blacks. Reporter activity of this variant haplotype, designated HapB, in cardiomyocytes was reduced 62% compared with wild-type haplotype ( P =0.006). The relationship between SCN5A promoter haplotype and PR and QRS durations, indexes of conduction velocity, was then analyzed in a cohort of 71 Japanese Brugada syndrome subjects without SCN5A mutations and in 102 Japanese control subjects. In both groups, PR and QRS durations were significantly longer in HapB individuals ( P ≤0.002) with a gene-dose effect. In addition, up to 28% and 48% of variability in PR and QRS durations, respectively, were attributable to this haplotype. The extent of QRS widening during challenge with sodium channel blockers, known to be arrhythmogenic in Brugada syndrome and other settings, was also genotype dependent ( P =0.002). Conclusions— These data demonstrate that genetically determined variable sodium channel transcription occurs in the human heart and is associated with variable conduction velocity, an important contributor to arrhythmia susceptibility.
Relationship of Circulating Tumor Cells to Tumor Response, Progression-Free Survival, and Overall Survival in Patients With Metastatic Colorectal Cancer
Authors: Steven J. Cohen, Cornelis J.A. Punt, Nicholas Iannotti, Bruce H. Saidman, Kert D. Sabbath, Nashat Y. Gabrail, Joel Picus, Michael Morse, Edith Mitchell, M. Craig Miller, Gerald V. Doyle, Henk Tissing, Leon W.M.M. Terstappen, Neal J. Meropol
Journal: Journal of Clinical Oncology (2008)

As treatment options expand for metastatic colorectal cancer (mCRC), a blood marker with a prognostic and predictive role could guide treatment. We tested the hypothesis that circulating tumor cells (CTCs) could predict clinical outcome in patients with mCRC.In a prospective multicenter study, CTCs were enumerated in the peripheral blood of 430 patients with mCRC at baseline and after starting first-, second-, or third-line therapy. CTCs were measured using an immunomagnetic separation technique.Patients were stratified into unfavorable and favorable prognostic groups based on CTC levels of three or more or less than three CTCs/7.5 mL, respectively. Patients with unfavorable compared with favorable baseline CTCs had shorter median progression-free survival (PFS; 4.5 v 7.9 months; P = .0002) and overall survival (OS; 9.4 v 18.5 months; P < .0001). Differences persisted at 1 to 2, 3 to 5, 6 to 12, and 13 to 20 weeks after therapy. Conversion of baseline unfavorable CTCs to favorable at 3 to 5 weeks was associated with significantly longer PFS and OS compared with patients with unfavorable CTCs at both time points (PFS, 6.2 v 1.6 months; P = .02; OS, 11.0 v 3.7 months; P = .0002). Among nonprogressing patients, favorable compared with unfavorable CTCs within 1 month of imaging was associated with longer survival (18.8 v 7.1 months; P < .0001). Baseline and follow-up CTC levels remained strong predictors of PFS and OS after adjustment for clinically significant factors.The number of CTCs before and during treatment is an independent predictor of PFS and OS in patients with metastatic colorectal cancer. CTCs provide prognostic information in addition to that of imaging studies.
Production of Thymus and Activation-Regulated Chemokine and Macrophage-Derived Chemokine by CCR4+ Adult T-Cell Leukemia Cells
Authors: Takatoshi Shimauchi, Satoshi Imai, Ryosuke Hino, Yoshiki Tokura
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Adult T-cell leukemia/lymphoma (ATL) is a peripheral CD4+CD25+ T-cell malignancy caused by human T-cell leukemia virus type I. The tumor cells frequently infiltrate in the skin, lymph nodes and other organs and especially form prominent cutaneous masses. Recently, ATL cells have been shown to express Th2 chemokine receptor CCR4. The aim of this study is to investigate the possibility that CCR4 ligands, thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC), are produced by CCR4+ ATL cells per se. Experimental Design: CD4+ or CD4+CD14− cells were purified from peripheral blood mononuclear cells of 11 ATL patients with cutaneous involvement and normal healthy volunteers. Tissue-infiltrating cells were isolated from skin tumors. The expression of chemokine receptors on these cells were analyzed by flow cytometry. The production of chemokines and cytokines by the neoplastic cells was assessed by ELISA and reverse transcription-PCR after cultivation for 96 hours in the presence or absence of anti-CD3/CD28 monoclonal antibodies. Finally, TARC and CCR4 expressions were examined by immunohistochemistry. Results: ATL cells highly expressed CCR4 but did not necessarily exhibit the Th2 cytokine profile. The cells also produced TARC and MDC. The production level of MDC was higher in the skin tumor formation group than that in the nontumor group. Immunohistochemically, both CCR4 and TARC were expressed by the tumor cells in the lesional skin. Conclusions: ATL cells not only express CCR4 but also produce TARC and MDC. The skin tumor formation as well as the monoclonal integration of proviral DNA are the factors that are associated with the high production of Th2 chemokines by ATL cells.
Hepatopulmonary syndrome: prevalence and predictive value of various cut offs for arterial oxygenation and their clinical consequences
Authors: P Schenk
Journal: Gut (2002)

<b>Background:</b> The hepatopulmonary syndrome (HPS) is defined as the triad of liver disease, arterial deoxygenation, and pulmonary vascular dilatation. The reported prevalence of HPS in cirrhotic patients varies between 4% and 19%, and various threshold values defining arterial deoxygenation have been used and recommended previously. However, it is not known how the prevalence of HPS differs using different cut off values for arterial deoxygenation. <b>Methods:</b> We studied 127 patients for the presence of HPS using transthoracic contrast echocardiography for detection of pulmonary vasodilation, pulmonary function tests, and blood gas analysis. <b>Results:</b> Ninety eight patients were included in the study, of whom 33 (34%) had a positive contrast echocardiography. Using an increased alveolar-arterial difference for the partial pressure of oxygen (AaDO<sub>2</sub>) as an indication of hypoxaemia, the prevalence of HPS was considerably higher (&gt;15 mm Hg, 32%; &gt;20 mm Hg, 31%; and &gt;age related threshold, 28%) than using reduced partial pressure of arterial oxygen (PaO<sub>2</sub>) as a threshold (&lt;80 mm Hg, 19%; &lt;70 mm Hg, 15%; and &lt;age related threshold, 15%). For AaDO<sub>2</sub> as the cut off, the positive predictive value for a diagnosis of HPS was low (34%, 37%, and 53%, respectively). In contrast, PaO<sub>2</sub> as a cut off had considerably higher positive predictive values (44%, 93%, and 94%, respectively). Introducing PaO<sub>2</sub> &lt;65 mm Hg as the cut off, the positive predictive value increased to 100%. Dyspnoea was more often present in patients with “clinically significant” HPS (57%) compared with “subclinical HPS” (8%), and patients without HPS (6%). The Child-Pugh score correlated significantly with the severity of HPS. Two of five liver transplanted patients with “subclinical HPS” had embolic brain infarcts, possibly induced by venous emboli passing through dilated intrapulmonary vessels. <b>Conclusions:</b> Defining arterial hypoxaemia in HPS by different, previously used, cut off values for arterial oxygenation leads to a wide variation in the prevalence of HPS in the same sample of cirrhotic patients.
Frequency of thromboembolic events in patients with lung cancer at the time of diagnosis and in the course of disease
Authors: Markus Samulowski, Catharina Crolow, Torsten Blum, Jens Kollmeier, Wolfram Grüning, Nicolas Schönfeld, Roland C. Bittner, Torsten T. Bauer
Journal: European Respiratory Journal (2011)

Background:  Clinicians are frequently confronted by thromboembolic events (TEE) in patients with lung cancer. Early pulmonary embolism (within the first 3 months after primary diagnosis) is regarded as a negative prognostic factor. However, the benefit of a prophylactic anticoagulation has not been evaluated so far. Lung cancer itself as well as certain chemotherapeutic agents are considered to be independent risk factors for TEE.   Methods:  All patients with a primary diagnosis of lung cancer between January 2008 and December 2010 were prospectively recorded within our tumour registry and retrospectively evaluated with regard to TEE. A pulmonary embolism (PE) was diagnosed with CT pulmonary angiography or alternatively with a ventilation-perfusion scintigraphy in patients with known contraindications to radiocontrast agents. A deep venous thrombosis (DVT) was diagnosed with colour-coded duplex sonography.   Results:  Within the 33 months 1722 patients (1077 men, 645 women) were diagnosed with lung cancer. SCLCand NSCLC in 185 (11%) and 1537 cases (89%), respectively. TEE were documented in 132 patients (7.7%). 75 of those had proven DVT and 75 PE. At the time of primary diagnosis DVT and/or PE was detectable in 33 patients (1.9%) (DVT: n=11, PE: n=13, DVT+PE n=9). Within the observed course of the disease 99 patients (5.7%) developed TEE (DVT: n=46, PE: n=44, DVT+PE n=9).   Conclusions:  According to our data, about every 50th patient with lung cancer has already proven TEE at the time of primary diagnosis. In the further course of the disease more than 5.7% develop TEE. Thus, the benefit of a prophylactic anticoagulation should be prospectively evaluated.
Insect and Scorpion Sting
Authors: W. Peter Horen
Journal: JAMA (1972)

Some arthropods of the orders Hymenoptera and Scorpionida inflict medically significant bites. About 20% of Americans are believed to be hypersensitive to venoms of hymenopteran insects (including honeybees, bumblebees, wasps, hornets, and fire ants), which often sting with little provocation. From 1950 through 1959, of 460 deaths due to venomous animals, 50% were caused by stings of Hymenoptera, especially the honeybee, and 1.7% by stings of scorpions.<sup>1</sup>One person reportedly died in 1964 from the sting of fire ants. This article reports recent findings about stings of such arthropods and suggests a rationale for treatment. <h3>Hymenoptera</h3> With rare exceptions, members of this order are social insects that build nests or hives above or under the ground, occasionally in tree stumps or hollows of live trees. Most species, except for the "velvet ants" (mutillid wasps) and true ants, have two pairs of membranous wings. The thorax and abdomen are distinctly