tbuckley/cabot-search huggingface dataset:
Low mutation burden and frequent loss of CDKN2A/B and SMARCA2, but not PRC2, define premalignant neurofibromatosis type 1–associated atypical neurofibromas
Authors: Alexander Pemov, Nancy F Hansen, Sivasish Sindiri, Rajesh Patidar, Christine S Higham, Eva Dombi, Markku M Miettinen, Patricia Fetsch, Hilde Brems, Settara C Chandrasekharappa, Kristine Jones, Bin Zhu, Jun S Wei, James C Mullikin, Margaret R Wallace, Javed Khan, Eric Legius, Brigitte C Widemann, Douglas R Stewart
Journal: Neuro-Oncology (2019)

Abstract Background Neurofibromatosis type 1 (NF1) is a tumor-predisposition disorder caused by germline mutations in NF1. NF1 patients have an 8–16% lifetime risk of developing a malignant peripheral nerve sheath tumor (MPNST), a highly aggressive soft-tissue sarcoma, often arising from preexisting benign plexiform neurofibromas (PNs) and atypical neurofibromas (ANFs). ANFs are distinct from both PN and MPNST, representing an intermediate step in malignant transformation. Methods In the first comprehensive genomic analysis of ANF originating from multiple patients, we performed tumor/normal whole-exome sequencing (WES) of 16 ANFs. In addition, we conducted WES of 3 MPNSTs, copy-number meta-analysis of 26 ANFs and 28 MPNSTs, and whole transcriptome sequencing analysis of 5 ANFs and 5 MPNSTs. Results We identified a low number of mutations (median 1, range 0–5) in the exomes of ANFs (only NF1 somatic mutations were recurrent), and frequent deletions of CDKN2A/B (69%) and SMARCA2 (42%). We determined that polycomb repressor complex 2 (PRC2) genes EED and SUZ12 were frequently mutated, deleted, or downregulated in MPNSTs but not in ANFs. Our pilot gene expression study revealed upregulated NRAS, MDM2, CCND1/2/3, and CDK4/6 in ANFs and MPNSTs, and overexpression of EZH2 in MPNSTs only. Conclusions The PN-ANF transition is primarily driven by the deletion of CDKN2A/B. Further progression from ANF to MPNST likely involves broad chromosomal rearrangements and frequent inactivation of the PRC2 genes, loss of the DNA repair genes, and copy-number increase of signal transduction and cell-cycle and pluripotency self-renewal genes.
The importance of environmental threats and ideology in explaining extreme self-sacrifice
Authors: Abdo Elnakouri, Ian McGregor, Igor Grossmann
Journal: Behavioral and Brain Sciences (2018)

Abstract We argue that Whitehouse's group-based model neglects two key contextual variables: environmental threats and ideology. Environmental threats lead to extremism outside of group settings and predispose individuals toward joining ideologically zealous groups. Ideologies and environmental threats can also explain why certain groups adopt norms that encourage violent self-sacrifice.
Abstract 17954: Deficiency of CD40-CD40L Signaling in T Cells and Dcs Attenuates Atherosclerosis
Authors: Christina Bürger, Holger Winkels, Dorothee Atzler, Christian Weber, Norbert Gerdes, Esther Lutgens
Journal: Circulation (2017)

Introduction: The co-stimulatory molecule CD40L-CD40 dyad is a major driver of atherosclerosis. CD40L and CD40 are expressed on a wide variety of cell types including T cells and mature dendritic c...
18F-FDG PET/CT for Prognostic Stratification of Patients With Extranodal Natural Killer/T-Cell Lymphoma
Authors: Chunxia Qin, Shirui Yang, Xun Sun, Xiaotian Xia, Chunyan Li, Xiaoli Lan
Journal: Clinical Nuclear Medicine (2019)

The prognostic value of PET/CT for extranodal natural killer/T-cell lymphoma (ENKTL) patients is controversial. We sought to investigate the use of pretreatment and interim PET/CT in this disease.Sixty-five patients diagnosed with ENKTL who underwent pretreatment (n = 53) and/or interim PET/CT scans (after 2-4 cycles of chemotherapy and/or radiotherapy, n = 33) were retrospectively enrolled. Interim PET/CT images were interpreted according to the Deauville 5-point scale. PET/CT results were assessed for their predictive value of progression-free survival (PFS) and overall survival (OS). Kaplan-Meier estimates were generated to evaluate the predictive value of clinical parameters and PET/CT scans for prognosis evaluation. The Cox proportional hazards model was performed to assess the potential independent predictors for PFS and OS.Patients with a high score (4/5) according to the Deauville scale had heavier tumor burdens and tended to have elevated serum LDH and β2-microglobulin (β2-MG). In univariate analysis, the following parameters were predictive of PFS: age (≤60 vs > 60 years), stage (I/II vs III/IV), lesion location (nasal vs extranasal), LDH (normal vs elevated), β2-MG (normal vs elevated), SUVmax before treatment (≤8.3 vs > 8.3), and interim PET/CT results. For OS, the predictive factors were composed of stage, lesion location, LDH, β2-MG, and interim PET/CT results. However, in multivariate analysis, only interim PET/CT scan interpreted by the Deauville scale remained as an independent predictor for both PFS and OS.Interim PET/CT scan displayed potential predictive value for ENKTL patients. Response assessment according to the Deauville 5-point scale may help to improve the accuracy of prediction. Patients with advanced stage (III/IV), elevated LDH or β2-MG, and a high Deauville score of 4 to 5 on the interim PET/CT scan were more likely to have reduced PFS and OS.
Abstract 18389: A Three-dimensional Cardiac Simulator Could Simulate Hypothetical Pressure-Volume Loop and Energy Metabolism
Authors: Hirotada Masuda, Shigeru Miyagawa, Takumi Washio, Seiryo Sugiura, Toshiaki Hisada, Yoshiki Sawa
Journal: Circulation (2017)

Introduction: Although Pressure-Volume (PV) loop may be golden standard to evaluate true cardiac function, clinically it may be difficult to get detailed data about PV loop because of some risks for severe heart failure patients. We developed a three-dimensional cardiac simulator “UT-Heart”, which can analyze both cross-bridge system kinetics and left ventricular kinetics, can simulate hemodynamics containing metabolisms or PV loop in failing heart. Hypothesis: UT-Heart can estimate the hypothetical PV loop from simple clinical data in severe heart failure patient having dilated cardiomyopathy-related mitral regurgitation (DCM-MR). Method: To simulate hemodynamics including PV loop and metabolisms, cardiac morphology such as LV end diastolic volume, end systolic volume, and stroke volumes was extracted from preoperative and postoperative (Mitral valve replacement) cardiac CT in DCM-MR patients and cardiac pressure by heart catheter examination and ECG were obtained. The ATP consumption of myocardium was e...
Household contact investigation for the detection of tuberculosis in Vietnam: economic evaluation of a cluster-randomised trial
Authors: Thomas Lung, Guy B Marks, Nguyen Viet Nhung, Nguyen Thu Anh, Nghiem Le Phuong Hoa, Le Thi Ngoc Anh, Nguyen Binh Hoa, Warwick John Britton, Jessica Bestrashniy, Stephen Jan, Gregory J Fox
Journal: The Lancet Global Health (2019)

BackgroundActive case finding is recommended as an important strategy to control tuberculosis, particularly in low-income and middle-income countries with a high prevalence of the disease. However, the costs and cost-effectiveness of active case finding are unclear due to the absence of evidence from randomised trials. We assessed the costs and cost-effectiveness of an active case finding strategy in Vietnam, where there is a high prevalence of tuberculosis.MethodsWe conducted an economic evaluation alongside the Active Case Finding in Tuberculosis (ACT2) trial—a pragmatic cluster-randomised controlled trial in 70 districts across eight provinces of Vietnam. Patients aged 15 years and older with smear-positive pulmonary tuberculosis were recruited to the trial if they lived with one or more other household members. Household contacts were verbally invited to the clinic by the index patient with tuberculosis. ACT2 compared a combination of active and passive case finding with usual care (passive case finding) of household contacts of patients with tuberculosis from a health system perspective. Clustering occurred at the district and household level. Districts were the unit of randomisation, and we used minimisation to ensure balance of intervention and control districts within each province. In the intervention group, participants were invited to attend screening at baseline, 6 months, 12 months, and 24 months. We determined health-care costs with a standardised national costing survey and reported results in 2017 $US. The primary outcome of our study was disability-adjusted life years (DALYs) averted over a 24-month period. ACT2 was registered prospectively with the Australian and New Zealand Clinical Trials Registry, number ACTRN126.100.00600044.FindingsBetween Aug 11, 2010, and Aug 11, 2015, 10 964 index patients and 25 707 household contacts completed the ACT2 study. There were 10 069 household contacts in the intervention group and 15 638 household contacts in the control group. The incremental cost-effectiveness ratio per DALY averted was $544 (330–1375).InterpretationActive case finding was shown to be highly cost-effective in a setting with a high prevalence of tuberculosis. Investment in the wide-scale implementation of this programme in Vietnam should be strongly supported.FundingAustralian National Health and Medical Research Council.
Patients’ and doctors’ perspectives on allergen specific immunotherapy in Korea
Authors: Yoo Seob Shin, Jae-Woo Kwon, Jae-Woo Jung, Sang Min Lee, Ji Hye Kim, Jeong-Hee Choi, Young Min Ahn, Soo-Young Lee, Jung-Won Park, Man Yong Han
Journal: Journal of Allergy and Clinical Immunology (2019)
Feasibility of endoscopic resection in early gastric cancer with lymphovascular invasion.
Authors: Jun Haeng Lee, Hyuk Lee, Jae J Kim
Journal: Journal of Clinical Oncology (2019)

87 Background: Lymphovascular invasion (LVI) is associated with the risk of lymph node metastasis (LNM) and poor survival in gastric cancer patients. However, it is unclear whether LVI is a noncurative criteria component in all patients. We evaluated the risk factors of LNM in LVI-positive early gastric cancer (EGC) patients and identified a subgroup with a negligible LNM risk to assess the feasibility of endoscopic resection in these patients. Methods: The clinicopathologic and survival data of patients undergoing surgery for gastric cancer were reviewed; LVI-positive EGC patients were selected. Logistic regression analysis was used to test the associations of potential risk factors with LNM; Kaplan-Meier analysis was used to compare survival curves. Results: LVI was detected in 1,243 (15.5%) patients. In the multivariate logistic analysis, larger tumor size (odds ratio [OR], 1.23; 95% confidence interval [CI], 1.16-1.31; P &lt; 0.001), presence of ulcer (OR, 1.80; 95% CI, 1.15-2.82, P = 0.010), undifferentiated histology (OR, 1.64; 95% CI, 1.25-2.16; P &lt; 0.001), submucosal invasion (OR, 2.28, 95% CI, 1.38-3.76, P = 0.001), middle (OR, 2.12; 95% CI, 1.26-3.55, P = 0.004) or lower third location (OR, 2.28; 95% CI, 1.32-3.60, P = 0.002), and younger age (OR, 0.98; 95% CI, 0.97-0.99; P = 0.002) independently predicted LNM in LVI-positive EGC patients. LVI-positive patients fulfilling the absolute endoscopic resection criteria did not have LNM, and there was no significant difference in the overall (P = 0.928) and disease-specific survival (P = 0.821) between these patients and those with LVI-negative EGC. Conclusions: Additional surgery after endoscopic resection might be unnecessary in LVI-positive patients meeting the absolute criteria for endoscopic resection.
Prevalence of pancreaticobiliary cancer in Irish families with BRCA1 and BRCA2 mutations.
Authors: Robert Power, Cristin Leavy, C. Nolan, Niamh White, R. M. Clarke, David James Gallagher, Maeve Aine Lowery
Journal: Journal of Clinical Oncology (2019)

210 Background: Germline mutations in BRCA1 and BRCA2 genes are associated with pancreatic ductal adenocarcinoma (PDAC), and more recently associated with increased risk of biliary tract cancers (BTC). This study assessed the prevalence, age and gender distribution of PDAC/BTC in BRCA1/2 positive families; compared to those of the Irish population. Methods: A review of all families referred to a national genetics clinic from 09/11/1997-01/06/2018 was performed following institutional ethics board approval. Demographics including age, sex and BRCA mutation status was collected in each case of PDAC/BTC. The BOADICEA algorithm was used to estimate the probability that an untested relative of a known BRCA1/2 mutation carrier with PDAC was a carrier. Results: 3252 distinct family pedigrees were reviewed, of which 1193 contained a proband who underwent testing for BRCA1/2 based on Manchester score ≥ 15. Among 128 BRCA2 positive families, 27 (21%) contained a 1 st /2 nd or 3 rd degree relative with PDAC, of 116 BRCA1 positive families, 11 (9%) contained a 1 st / 2 nd or 3 rd degree relative with PDAC (male: female (m:f) = 1:0.9). Of these 38 families, 25 pts with PDAC had ≥ 50% likelihood of being a mutation carrier by BODICEA analysis. This cohort had a median age at diagnosis of 55 (33-75), with a mean (55) significantly lower than that of 8364 unselected patients with PDAC identified through the National Cancer Registry Ireland (71, p &lt; 0.0001). Six BRCA2 positive (5%) and 2 BRCA1 positive pedigrees (2%) contained an individual with BTC; median age at diagnosis was 65 (33-99, m:f = 1:7). Additional pedigrees with Lynch Syndrome (n = 3), FAP (n = 1) and ATM (n = 2) and PDAC were identified. Conclusions: PDAC and BTC are prevalent in Irish families with a BRCA1/2 mutation and are associated with early onset malignancy. This consolidates evidence of PDAC and BTC as BRCA- associated cancers in the Irish population and supports current guidelines recommending universal germline testing for PDAC patients. [Table: see text]
EBS generalized severe is an inflammatory disease
Authors: E. Castela, M.K. Tulic, A. Rozières, E. Bourrat, J.‐F. Nicolas, J. Kanitakis, P. Vabres, D. Bessis, J. Mazereeuw, F. Morice‐Picard, D. Baty, F. Berard, J.‐P. Lacour, T. Passeron, C. Chiaverini
Journal: British Journal of Dermatology (2019)

Epidermolysis bullosa (EB) is a group of genetic disorders in which the skin is abnormally fragile. In EB simplex, the skin cells tend to fall apart because their internal scaffolding of keratin fibres is defective, due to mutations in the genes encoding keratins type 5 or 14 (KRT5 and KRT14). But people with the generalised, severe type of EB simplex (EBS‐GS) are sometimes more ill than would be expected just from a mechanical problem with the skin; some even die in infancy, usually from infection. This group from France and Scotland explored the possibility that EBS‐GS patients also have a faulty immune system. They re‐examined skin specimens taken previously for diagnostic purposes from 17 patients with EBS‐GS and also tested fresh skin biopsies and blister fluid from a further 10 patients. They consistently found more inflammatory cells and higher levels of chemicals which promote inflammation (cytokines) than normal. The findings were the same regardless of whether the sample was from blistered or normal‐looking skin and whether the fault was in KRT5 or KRT14. Markers for the cytokine Th17 were particularly high, encouraging them to treat three EBS‐GS patients with the anti‐Th17 drug Apremilast as used in psoriasis. All three reported a dramatic reduction in blisters within the first month, which lasted throughout treatment for up to 10 months, with minimal side‐effects. One patient stopped the Apremilast after 7 months because of nausea and the blistering came back 2 days later. This appears to be a promising new approach to treating EBS‐GS.
Social media: end self regulation, say MPs in report on children’s health
Authors: Jacqui Wise
Journal: BMJ (2019)

Social media companies must be subject to a formal legal duty of care to help protect young people’s health and wellbeing, a group of MPs has concluded.1

The Science and Technology Committee called on the UK government to create a comprehensive regulatory framework clearly setting out the responsibilities of social media companies towards their users.

In a report on the impact of social media and screen use on young people’s health the committee also called for a regulator to be appointed by the end of October 2019 to provide guidance on how to spot and minimise harms, monitor compliance with a code of practice, and take enforcement action when necessary. The regulator must be backed by a strong sanctions regime, the committee said.

The government …
Efficacy of Community-Based Exercise Therapy Among African American Patients With Peripheral Artery Disease
Authors: Tracie C. Collins, Liuqiang Lu, Jasjit S. Ahluwalia, Nicole L. Nollen, John Sirard, Robert Marcotte, Spencer Post, Rosey Zackula
Journal: JAMA Network Open (2019)

<h3>Importance</h3> African American individuals are 2 times more likely than non-Hispanic white individuals to have peripheral artery disease (PAD). Structured community-based exercise therapy improves walking distance among patients with PAD, but these patients require motivation to adhere to therapy. <h3>Objective</h3> To assess whether motivational interviewing (MI) is more efficacious than Patient-Centered Assessment and Counseling for Exercise (PACE) or control to improve walking distance in African American patients with PAD. <h3>Design, Setting, and Participants</h3> In this 3-group randomized clinical trial, 174 African American patients with PAD were studied from May 1, 2012, to November 30, 2016, at health care centers, churches, and health fairs in Wichita, Kansas; Kansas City, Kansas, and Kansas City, Missouri. <h3>Interventions</h3> Patients were randomized in a 1:1:1 fashion to 1 of 3 groups (57 to MI, 57 to PACE, and 60 to control). The 2 counseling interventions were delivered biweekly for 3 months and monthly for 3 months followed by a 6-month maintenance phase with limited contact. Control participants received a mailing at 3 and 9 months. <h3>Main Outcomes and Measures</h3> The primary outcome was 6-month change in 6-minute walking performance. Secondary outcomes included 12-month change in walking performance and 6- and 12-month changes in quality of life. <h3>Results</h3> A total of 174 African American patients (mean [SD] age, 64.2 [11.2] years; 128 [74.0%] female) were studied. At 6 months, mean (SE) change in walking distance by group was as follows: MI, −3.42 (4.55) m; PACE, 2.74 (6.00) m; and control, −0.18 (4.40) m. At 12 months, mean (SE) change in walking distance by group was as follows: MI, −7.75 (5.50) m; PACE, 13.75 (6.13) m; and control, −1.08 (5.73) m. Comparing each of the intervention arms (MI and PACE) with the control arm, no statistically significant increases in walking distance at 6 months (MI: change, −2.10 m; 95% CI, −16.54 to 12.35 m; PACE: change, 2.31 m; 95% CI, −11.36 to 15.97 m) or 12 months (MI: change, −5.56 m; 95% CI, −21.18 to 10.06 m; PACE: change, 14.24 m; 95% CI, −1.85 to 30.34 m) were found. Compared with MI, PACE resulted in a statistically significant increase in walking distance at 12 months of 19.80 m (95% CI, 3.33-36.28 m). <h3>Conclusions and Relevance</h3> In a cohort of African American patients with PAD, MI was not efficacious in improving walking distance at 6 or 12 months. The results of this study do not support the use of MI to improve walking performance in African American patients with PAD. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT01321086
FoxO1 inhibits autophagosome-lysosome fusion leading to endothelial autophagic-apoptosis in diabetes
Authors: Hui Zhang, Song Ge, Kesuai He, Xin Zhao, Ya Wu, Yongfeng Shao, Xiaohong Wu
Journal: Cardiovascular Research (2019)

Abstract Aims Inadequate autophagy contributed to endothelial dysfunction in diabetic patients. We aimed to investigate the relationship between inadequate autophagy and endothelial cells (ECs) apoptosis in diabetes and its underlying mechanism. Methods and results Aortic intima and ECs were isolated from diabetic patients. Cultured human aortic endothelial cells (HAECs) were stimulated with advanced glycation end products (AGEs). The expression of autophagy and apoptosis-related proteins were determined by western blotting. Autophagosomes were observed by electron microscopy. The fusion of autophagosome and lysosomes was detected by immunofluorescence. Compared with non-diabetic subjects, the levels of LC3-II, p62, FoxO1, and Ac-FoxO1 were increased in ECs from diabetic patients, accompanied by the decreased expressions of Atg14, STX17, and co-localization of LC3-II/LAMP2 and Atg14/STX17. Long-term stimulation with AGEs up-regulated LC3-II and p62 expression and the number of autophagosomes with decreased level of Atg14, STX17, Ras-related protein 7 (Rab7), and co-localization of LC3-II/LAMP2 and Atg14/STX17 in HAECs. The apoptosis rates were increased with elevated cleaved-caspase-3 and declined Bcl-2 expression. Inhibition of autophagy with 3-methyladenine could reduce long-term AGEs-induced apoptosis. Higher levels of FoxO1, Ac-FoxO1, and Ac-FoxO1 binding to Atg7 were detected in AGEs-treated HAECs. AGEs-induced FoxO1 enhanced Akt activity, decreased SIRT1-deacetylase activity by phosphorylation and elevated Ac-FoxO1. Knockout of FoxO1 reduced AGEs-induced autophagy and promoted the expression of Atg14 and the co-localization of LC3-II/LAMP 2 and Atg14/STX17. Conclusion Inadequate autophagy with impaired autophagosome-lysosomal fusion exists in aortic intima and ECs from diabetic patients. FoxO1 mediates AGEs-induced ECs autophagic apoptosis through impairing autophagosome-lysosomes fusion by inhibiting Atg14 expression.
Regulation of microbiota–GLP1 axis by sennoside A in diet-induced obese mice
Authors: Jiamei Le, Xiaoying Zhang, Weiping Jia, Yong Zhang, Juntao Luo, Yongning Sun, Jianping Ye
Journal: Acta Pharmaceutica Sinica B (2019)

Sennoside A (SA) is a bioactive component of Chinese herbal medicines with an activity of irritant laxative, which is often used in the treatment of constipation and obesity. However, its activity remains unknown in the regulation of insulin sensitivity. In this study, the impact of SA on insulin sensitivity was tested in high fat diet (HFD)-induced obese mice through dietary supplementation. At a dosage of 30 mg/kg/day, SA improved insulin sensitivity in the mice after 8-week treatment as indicated by HOMA-IR (homeostatic model assessment for insulin resistance) and glucose tolerance test (GTT). SA restored plasma level of glucagon-like peptide 1 (GLP1) by 90% and mRNA expression of Glp1 by 80% in the large intestine of HFD mice. In the mechanism, SA restored the gut microbiota profile, short chain fatty acids (SCFAs), and mucosal structure in the colon. A mitochondrial stress was observed in the enterocytes of HFD mice with ATP elevation, structural damage, and complex dysfunction. The mitochondrial response was induced in enterocytes by the dietary fat as the same responses were induced by palmitic acid in the cell culture. The mitochondrial response was inhibited in HFD mice by SA treatment. These data suggest that SA may restore the function of microbiota-GLP1 axis to improve glucose metabolism in the obese mice.