tbuckley/cabot-search huggingface dataset:
The Novel Organic Arsenical Darinaparsin Induces MAPK-Mediated and SHP1-Dependent Cell Death in T-cell Lymphoma and Hodgkin Lymphoma Cells and Human Xenograft Models
Authors: Dashnamoorthy Ravi, Savita Bhalla, Ronald B. Gartenhaus, Jennifer Crombie, Irawati Kandela, Jaya Sharma, Andrew Mazar, Andrew M. Evens
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Darinaparsin (Zio-101) is a novel organic arsenical compound with encouraging clinical activity in relapsed/refractory T-cell lymphoma (TCL) and Hodgkin lymphoma (HL); however, little is known about its mechanism of action. Experimental Design: TCL cell lines (Jurkat, Hut78, and HH) and HL cell lines (L428, L540, and L1236) were examined for in vitro cell death by MTT assay and Annexin V–based flow cytometry. Jurkat and L540-derived xenografts in SCID mice were examined for in vivo tumor inhibition and survival. Biologic effects of darinaparsin on the MAPK pathway were investigated using pharmacologic inhibitors, RNAi and transient transfection for overexpression for SHP1 and MEK. Results: Darinaparsin treatment resulted in time- and dose-dependent cytotoxicity and apoptosis in all TCL and HL cell lines. In addition, darinaparsin had more rapid, higher, and sustained intracellular arsenic levels compared with arsenic trioxide via mass spectrometry. In vivo experiments with Jurkat (TCL) and L540 (HL)-derived lymphoma xenografts showed significant inhibition of tumor growth and improved survival in darinaparsin-treated SCID mice. Biologically, darinaparsin caused phosphorylation of ERK (and relevant downstream substrates) primarily by decreasing the inhibitory SHP1 phosphatase and coimmunoprecipitation showed significant ERK/SHP1 interaction. Furthermore, ERK shRNA knockdown or constitutive overexpression of SHP1 resulted in increased apoptosis, whereas cotreatment with pharmacologic MEK inhibitors resulted in synergistic cell death. Conversely, SHP1 blockade (via pharmacologic inhibition or RNAi) and MEK constitutive activation decreased darinaparsin-related cell death. Conclusions: Altogether, these data show that darinaparsin is highly active in HL and TCL and its activity is dependent primarily on MAPK mechanisms. Clin Cancer Res; 20(23); 6023–33. ©2014 AACR.
Disturbed Coronary Hemodynamics in Vessels With Intermediate Stenoses Evaluated With Fractional Flow Reserve
Authors: Mauro Echavarria-Pinto, Javier Escaned, Enrico Macías, Miguel Medina, Nieves Gonzalo, Ricardo Petraco, Sayan Sen, Pilar Jimenez-Quevedo, Rosana Hernandez, Rafael Mila, Borja Ibañez, Ivan J. Nuñez-Gil, Cristina Fernández, Fernando Alfonso, Camino Bañuelos, Eulogio García, Justin Davies, Antonio Fernández-Ortiz, Carlos Macaya
Journal: Circulation (2013)

In chronic ischemic heart disease, focal stenosis, diffuse atherosclerotic narrowings, and microcirculatory dysfunction (MCD) contribute to limit myocardial flow. The prevalence of these ischemic heart disease levels in fractional flow reserve (FFR) interrogated vessels remains largely unknown.Using intracoronary measurements, 91 coronaries (78 patients) with intermediate stenoses were classified in 4 FFR and coronary flow reserve (CFR) agreement groups, using FFR>0.80 and CFR<2 as cutoffs. Index of microcirculatory resistance (IMR) and atherosclerotic burden (Gensini score) were also assessed. MCD was assumed when IMR≥29.1 (75(th) percentile). Fifty-four (59.3%) vessels had normal FFR, from which only 20 (37%) presented both normal CFR and IMR. Among vessels with FFR>0.80, most (63%) presented disturbed hemodynamics: abnormal CFR in 28 (52%) and MCD in 18 (33%). Vessels with FFR>0.80 presented higher IMR [adjusted mean 27.6 (95% confidence interval, 23.4-31.8)] than those with FFR≤0.80 [17.3 (95% confidence interval, 13.0-21.7), p=0.001]. Atherosclerotic burden was inversely correlated with CFR (r=-0.207, P=0.055), and in vessels with FFR>0.80 and CFR<2 (n=28, 39%), IMR had a wide dispersion (7-72.7 U), suggesting a combination of diffuse atherosclerotic narrowings and MCD. Vessels with FFR≤0.80 and normal CFR presented the lowest IMR, suggesting a preserved microcirculation.A substantial number of coronary arteries with stenoses showing an FFR>0.80 present disturbed hemodynamics. Integration of FFR, CFR, and IMR supports the existence of differentiated patterns of ischemic heart disease that combine focal and diffuse coronary narrowings with variable degrees of MCD.
The C/C-13910 genotype of adult-type hypolactasia is associated with an increased risk of colorectal cancer in the Finnish population
Authors: H. Rasinperä, C. Forsblom, N. S. Enattah, P. Halonen, K. Salo, M. Victorzon, J. P. Mecklin, H. Järvinen, S. Enholm, G. Sellick, H. Alazzouzi, R. Houlston, J. Robinson, P. H. Groop, I. Tomlinson, S. Schwartz, L. A. Aaltonen, I. Järvelä
Journal: Gut (2005)

<b>Background and aims:</b> The role of nutrition in the pathogenesis of colorectal cancer is not fully understood. Milk products are an essential part of human nutrition in Western countries. Absorption of lactose, the main sugar of milk, is regulated by the activity of the lactase enzyme in the gut wall. The activity of lactase is genetically determined and is associated with a C/T single nucleotide polymorphism residing 13910 bp upstream of the lactase coding sequence. Here we have studied the relationship between the C/T<sub>−13910</sub> polymorphism and colorectal cancer in Finnish, British, and Spanish populations. <b>Patients and methods:</b> A total of 2766 subjects, including 963 Finnish, 283 British, and 163 Spanish subjects with colorectal cancer, and 773 Finnish, 363 British, and 221 Spanish control subjects, were genotyped for the C/T<sub>−13910</sub> variant by polymerase chain reaction minisequencing. <b>Results:</b> The C/C<sub>−13910</sub> genotype, which is a robust molecular marker of low lactase activity (lactase non-persistence), was found to significantly associate with the risk of colorectal cancer (p = 0.015) in the Finnish subjects, with an odds ratio of 1.40 (95% confidence interval 1.07–1.85). No association was found with site, histology, or stage of the tumour. No significant risk was detected in the British or Spanish populations. <b>Conclusion:</b> Low lactase enzyme activity, defined by genotyping of the C/T<sub>−13910</sub> variant, may increase the risk of colorectal cancer. Further studies are warranted to investigate the role of milk and other dairy products in the pathogenesis of colon cancer in different populations.
Non-alcoholic fatty liver disease as a risk factor for hepatocellular carcinoma: mechanisms and implications
Authors: F. Stickel, C. Hellerbrand
Journal: Gut (2010)

The pathophysiological significance of hepatic lipid accumulation in the absence of significant alcohol consumption is increasingly recognised. Thus, non-alcoholic fatty liver disease (NAFLD) is now considered the most common cause of liver enzyme elevation in Western countries.1 It is regarded as the hepatic manifestation of the metabolic syndrome (MS), characterised by central obesity and insulin resistance (IR), and resulting diabetes type 2, dyslipidaemia and hypertension.2 NAFLD encompasses mild hepatic steatosis to steatohepatitis (non-alcoholic steatohepatitis (NASH)) with significant necroinflammation and progressive fibrosis. NAFLD is believed to account for a large fraction, if not entirely for what was previously termed ‘cryptogenic cirrhosis’.3

Since cirrhosis is the main risk factor for hepatocellular carcinoma (HCC), liver cancer could be simply a complication of end-stage NAFLD, similar to the situation encountered in other chronic fibrosing liver diseases. However, accumulating evidence suggests that hepatocarcinogenesis may also be related to earlier stages of NAFLD. Case series of patients with HCC and NAFLD as the only identified risk factor strongly suggest that hepatocarcinogenesis is part of the natural history of NAFLD. Based on the known association of NAFLD with IR and MS, approximately two-thirds of the patients were obese and/or diabetic,4 and a remarkable 25% of these patients had no cirrhosis. Considering the rapidly increasing prevalence of both conditions in affluent societies, and their significance in the pathophysiology of NAFLD, a rising incidence of NAFLD and its complications—including HCC—can be expected in the mid-term future. Therefore, it is particularly worrying that the most persuasive evidence for an association between NAFLD and HCC derives from studies on the risk of HCC in patients with MS. In a large prospective cohort study HCC mortality was significantly higher in obese subjects than in those with normal body mass index.5 The most comprehensive data underlining the significance …
Medical Expenditures Associated With Diabetes Acute Complications in Privately Insured U.S. Youth
Authors: Sundar S. Shrestha, Ping Zhang, Lawrence Barker, Giuseppina Imperatore
Journal: Diabetes Care (2010)

OBJECTIVE To estimate medical expenditures attributable to diabetes ketoacidosis (DKA) and severe hypoglycemia among privately insured insulin-treated U.S. youth with diabetes. RESEARCH DESIGN AND METHODS We analyzed the insurance claims of 7,556 youth, age ≤19 years, with insulin-treated diabetes. The youth were continuously enrolled in fee-for-service health plans, and claims were obtained from the 2007 U.S. MarketScan Commercial Claims and Encounter database. We used regression models to estimate total medical expenditures and their subcomponents: outpatient, inpatient, and drug expenditures. The excess expenditures associated with DKA and severe hypoglycemia were estimated as the difference between predicted medical expenditures for youth who did/did not experience either DKA or severe hypoglycemia. RESULTS For youth with and without DKA, respectively, predicted mean annual total medical expenditures were $14,236 and $8,398 (an excess of $5,837 for those with DKA). The excess was statistically greater for those with one or more episodes of DKA ($8,455) than among those with only one episode ($3,554). Predicted mean annual total medical expenditures were $12,850 and $8,970 for youth with and without severe hypoglycemia, respectively (an excess of $3,880 for those with severe hypoglycemia). The excess was greater among those with one or more episodes ($5,929) than among those with only one ($2,888). CONCLUSIONS Medical expenditures for potentially preventable DKA and severe hypoglycemia in U.S. youth with insulin-treated diabetes are substantial. Improving the quality of care for these youth to prevent the development of these two complications could avert substantial U.S. health care expenditures.
The Corepressor Silencing Mediator for Retinoid and Thyroid Hormone Receptor Facilitates Cellular Recovery from DNA Double-Strand Breaks
Authors: Jiujiu Yu, Christine Palmer, Theresa Alenghat, Yun Li, Gary Kao, Mitchell A. Lazar
Journal: Cancer Research (2006)

Abstract Cells are frequently challenged by DNA double-strand breaks (DSB) that threaten their normal function and survival. In mammalian cells, the repair of DSBs is predominantly mediated by the DNA-dependent protein kinase (DNA-PK) complex. We unexpectedly found that the corepressor silencing mediator for retinoid and thyroid hormone receptor (SMRT) associates with the DNA-PK repair complex. The SMRT/histone deacetylase 3 complex is required for the transcriptional repressive property of the Ku70 subunit of the repair complex. Moreover, SMRT, but not the related Nuclear Receptor Corepressor, is required for cellular recovery from DNA DSBs induced by ionizing radiation or DNA damage–inducing drugs. Thus, the corepressor SMRT plays a novel and critical role in the cellular response to DSBs. (Cancer Res 2006; 66(18): 9316-22)
Azathioprine and diffuse alveolar haemorrhage: the pharmacogenetics of thiopurine methyltransferase
Authors: D. Perri, D. E. C. Cole, O. Friedman, E. Piliotis, S. Mintz, N. K. J. Adhikari
Journal: European Respiratory Journal (2007)

Current guidelines support the use of corticosteroids and azathioprine as one possible treatment strategy for idiopathic pulmonary fibrosis (IPF). However, some patients with genetic polymorphisms of thiopurine methyltransferase (TPMT) are at risk of severe azathioprine myelotoxicity. The current authors present the case of an 85-yr-old Caucasian male with IPF who developed diffuse alveolar haemorrhage as a complication of azathioprine-induced myelosuppression. Leukocyte genetic TPMT testing revealed that the patient had homozygous polymorphisms associated with the absence of TPMT activity and severe azathioprine-induced myelotoxicity. Thiopurine methyltransferase deficiency should be considered in patients who develop leukopenia early in treatment with azathiopurine, or who present with severe marrow suppression at usual doses. For centres with equipped laboratories, a dosing suggestion is provided based on thiopurine methyltransferase testing. Even with screening strategies, frequent monitoring of complete blood count and liver biochemistry should remain the mainstay of surveillance for azathioprine toxicity.
Clinimetric properties of bronchoalveolar lavage inflammatory markers in cystic fibrosis
Authors: M. Fayon, L. Kent, S. Bui, L. Dupont, I. Sermet
Journal: European Respiratory Journal (2013)

The Standardisation Committee of the European Cystic Fibrosis Society Clinical Trial Network has undertaken the evaluation of clinical end-points for therapeutic interventions regarding their use in multicentre clinical trials in cystic fibrosis (CF). This review of biomarkers in bronchoalveolar lavage (BAL) is part of the group's work. The aims of this project were: 1) to review the literature on reliability, validity and responsiveness of BAL in patients with CF; 2) to gain consensus of the group on the feasibility of BAL; and 3) to gain consensus on answers to key questions regarding the promotion of BAL to surrogate end-point status. Assessment of BAL inflammatory markers in the literature indicates that their reliability, validity and responsiveness are adequate for clinical trials. After discussion of the practical characteristics it was concluded that BAL has an attractive validity profile, albeit with limited feasibility. It is particularly applicable to multicentre trials in preschool children with CF and early or mild lung disease. This is the first article to collate the literature in this manner. This provides a rationale to support the use of BAL in early clinical trials in preschool children with CF.
Amassing the masses
Authors: Scott Hall
Journal: Behavioral and Brain Sciences (2000)

Nevin &amp; Grace (N&amp;G) buttress their metaphor with some good props. However, it is still not clear what momentum is analogous to. If momentum is a measure of strength, then the authors should say so and tell us how to calculate it. Furthermore, if “other” behavior can be introduced into the equation (and N&amp;G's foray into the applied world suggests that it can), it is unclear when the masses are accrued and how much is accrued to each behavior.
Molecular genetics and clinical features of Chinese idiopathic and heritable pulmonary arterial hypertension patients
Authors: D. Liu, Q-Q. Liu, M. Eyries, W-H. Wu, P. Yuan, R. Zhang, F. Soubrier, Z-C. Jing
Journal: European Respiratory Journal (2011)

Mutations of the bone morphogenetic protein type II receptor ( BMPR2 ) gene predispose to pulmonary arterial hypertension (PAH). 290 idiopathic (I)PAH patients and 15 heritable (H)PAH were screened to determine the spectrum and rate of BMPR2 mutations in a large Chinese patient group. Gene sequencing and multiplex ligation-dependent probe amplification (MLPA®) were used to detect sequence mutations and large rearrangements (RGTs). Total mutation rate was 14.5% (n=42 out of 290) in Chinese IPAH patients, and 53.3% (n=8 out of 15) in HPAH patients. RGT mutation rate was 3.1% (n=7 out of 229) and represented 14% (n=7 out of 50) of all identified mutations. 25 BMPR2 mutations were newly identified. Patients in this study were younger than other reported PAH subjects. BMPR2 mutation carriers were ∼6 yrs younger at diagnosis than noncarriers (p=0.002), but this relationship was significant only in the female group, which was larger. The proportion of females carrying a BMPR2 mutation was half that of males (12.8% versus 25.3%; p=0.008). Our results indicate that the overall genetics of Chinese PAH patients is similar to that of other populations, but the clinical picture differs by the precocity of the disease in the whole patient group, and the lower proportion of females found to carry a BMPR2 mutation.
Gestational Diabetes Mellitus Diagnosed With a 2-h 75-g Oral Glucose Tolerance Test and Adverse Pregnancy Outcomes
Authors: Maria I. Schmidt, Bruce B. Duncan, Angela J. Reichelt, Leandro Branchtein, Maria C. Matos, Adriana Costa e Forti, Ethel R. Spichler, Judith M.D.C. Pousada, Margareth M. Teixeira, Tsuyoshi Yamashita
Journal: Diabetes Care (2001)

OBJECTIVE—To evaluate American Diabetes Association (ADA) and World Health Organization (WHO) diagnostic criteria for gestational diabetes mellitus (GDM) against pregnancy outcomes. RESEARCH DESIGN AND METHODS—This cohort study consecutively enrolled Brazilian adult women attending general prenatal clinics. All women were requested to undertake a standardized 2-h 75-g oral glucose tolerance test (OGTT) between their estimated 24th and 28th gestational weeks and were then followed to delivery. New ADA criteria for GDM require two plasma glucose values ≥5.3 mmol/l (fasting), ≥10 mmol/l (1 h), and ≥8.6 mmol/l (2 h). WHO criteria require a plasma glucose ≥7.0 mmol/l (fasting) or ≥7.8 mmol/l (2 h). Individuals with hyperglycemia indicative of diabetes outside of pregnancy were excluded. RESULTS—Among the 4,977 women studied, 2.4% (95% CI 2.0–2.9) presented with GDM by ADA criteria and 7.2% (6.5–7.9) by WHO criteria. After adjustment for the effects of age, obesity, and other risk factors, GDM by ADA criteria predicted an increased risk of macrosomia (RR 1.29, 95% CI 0.73–2.18), preeclampsia (2.28, 1.22–4.16), and perinatal death (3.10, 1.42–6.47). Similarly, GDM by WHO criteria predicted increased risk for macrosomia (1.45, 1.06–1.95), preeclampsia (1.94, 1.22–3.03), and perinatal death (1.59, 0.86–2.90). Of women positive by WHO criteria, 260 (73%) were negative by ADA criteria. Conversely, 22 (18%) women positive by ADA criteria were negative by WHO criteria. CONCLUSIONS—GDM based on a 2-h 75-g OGTT defined by either WHO or ADA criteria predicts adverse pregnancy outcomes.
Getting a peace of the action: measures of post traumatic stress in UK military peacekeepers
Authors: Neil Greenberg, Amy Iversen, Lisa Hull, Duncan Bland, Simon Wessely
Journal: Journal of the Royal Society of Medicine (2008)

Objectives This study aimed to measure prevalence of post traumatic stress disorder (PTSD) in a sample of UK Armed Forces peacekeepers. The study also aimed to explore the influence of deploying without an established peer group (deployment status) upon health outcomes using an accepted diagnostic tool for PTSD (PCL-M) and an alternative measure of post-traumatic distress. Design Using a sub-sample of the King's military cohort we surveyed personnel that deployed on peacekeeping operations between 1991 and 2000 ( n=1198). Setting Respondents' mean age was 36 years (min, 23 to max, 60) and 81% ( n=964) were serving in the Armed Forces at the time of participation. Main outcome measures PTSD prevalence was determined in British military peacekeepers using the PLC-M (cut-offs 44 and 50), the General Health Questionnaire (GHQ-12) and a composite brief measure of potential post traumatic symptomology, ‘PostTraumatic Stress Reaction’ (PTSR) for comparison. Results PTSD prevalence varied from 3.6 to 5.5%. Officers and married personnel were less likely to be cases. Neither gender, age or deployment status influenced PTSD prevalence. Conclusions PTSD was an uncommon disorder in this sample of British military peacekeepers, with prevalence rates being lower than those reported by other nations. Deploying without an established peer group was not associated with developing PTSD. We postulate that differences in culture and operational practices may account for the lower rates of PTSD.
Elevated A1C in Adults Without a History of Diabetes in the U.S.
Authors: Elizabeth Selvin, Hong Zhu, Frederick L. Brancati
Journal: Diabetes Care (2009)

OBJECTIVE The purpose of this study was to examine the prevalence and correlates of elevated A1C in a large, nationally representative sample of adults without diabetes in the U.S. RESEARCH DESIGN AND METHODS We analyzed data from 15,934 participants aged ≥20 years without diagnosed diabetes who had A1C measurements in the 1999–2006 National Health and Nutrition Examination Survey, a cross-sectional and nationally representative sample of the U.S. population. RESULTS The overall prevalence of A1C &amp;gt;6% was 3.8%, corresponding to 7.1 million adults without diabetes in the U.S. population. Approximately 90% of these individuals had fasting glucose ≥100 mg/dl. Older age, male sex, non-Hispanic black race/ethnicity, hypercholesterolemia, higher BMI, and lower attained education were significantly associated with having a higher A1C level even among individuals with normal fasting glucose (&amp;lt;100 mg/dl) and after multivariable adjustment. CONCLUSIONS A single elevated A1C level (A1C &amp;gt;6%) is common in the general population of adults without a history of diabetes and is highly reliable for the detection of elevated fasting glucose. Nondiabetic adults with elevated A1C are likely to have impaired fasting glucose and an array of other risk factors for type 2 diabetes and cardiovascular disease.
Influence of Ethical Safeguards on Research Participation: Comparison of Perspectives of People With Schizophrenia and Psychiatrists
Authors: Laura W. Roberts, Katherine A. Green Hammond, Teddy D. Warner, Rae Lewis
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: Several safeguards have been developed to protect research volunteers, but little is known about how the people involved in this research—the stakeholders—view these efforts to assure participant rights and well-being. The authors' goal was to examine these perspectives. METHOD: As part of a larger study, 60 people with schizophrenia and 69 psychiatrists rated the protectiveness and influence on patients' willingness to participate in research of five safeguards: informed consent, alternative decision makers, institutional review boards, data safety monitoring boards, and confidentiality measures. RESULTS: All safeguards were perceived by both the participants with schizophrenia and by the psychiatrists as protective: on a scale of 1–5 on which 1=not protective at all and 5=very much protects, the mean scores ranged from 3.54 to 4.07. Four of the five safeguards were perceived by both the people with schizophrenia and by the psychiatrists as positively influencing patients' participation decisions. On a scale of 1–5 on which 1=much less willing and 5=much more willing to participate, the mean scores for these four safeguards ranged from 3.86 to 4.30. The mean score for the safeguard of an alternative decision maker, however, was 3.09. The ratings of protectiveness made by both the people with schizophrenia and the psychiatrists were correlated with their ratings of patients' willingness to participate in studies. CONCLUSIONS: Ethical commitment to research volunteers is expressed in safeguards. These efforts appear to be viewed positively by key stakeholders and may influence research participation decision making.