tbuckley/cabot-search huggingface dataset:
Liver function test abnormalities and their clinical relevance in primary myelofibrosis
Authors: D Barraco, M Mudireddy, S Shah, C A Hanson, R P Ketterling, N Gangat, A Pardanani, A Tefferi
Journal: Blood Cancer Journal (2017)

Hepatomegaly is a common finding in primary myelofibrosis (PMF), 1 mostly due to extramedullary hematopoiesis, as demonstrated by liver biopsies in previous studies, 2 and high serum alkaline phosphatase (ALP) is usually the most frequent associated biochemical abnormality.In the current study, we examined the clinical, prognostic and molecular correlates of increased ALP and aspartate aminotransferase (AST) in PMF.Table 1.Presenting clinical and laboratory of 398 patients with primary myelofibrosis stratified by the presence or absence of alkaline phosphatase ⩾ grade 2 elevation per CTCAE Variables All patients (n = 398) Patients with alkaline phosphatase ⩾ grade 2 (n = 29, 7%) Patients with alkaline phosphatase ograde 2 (n = 369, 93%) P-value Age at referall in years median (range) 63 (30-88) 61 (35-81) 62 (28-88) 0.4 Male (%) 249 (63) 21 (72) 228 (62) 0.26 Hemoglobin, g/dl median (range) 10.7 (6.8-16.3)10.3 (7.4-14.4)10.7 (6.8-16.3)0.56 Leukocytes, × 10 9 /l median (range) 8.7 (1.4-146.6)9.2 (3.7-75) 8.7 (1.4-146.6)0.06 WBC 425 × 10 9 /l, n (%) 52 (13) 10 (34) 42 (11) 0.0004 Platelets, × 10 9 /l median (range) 219 (12-1921) 218 (52-662) 219 (12-1921) 0.36 Circulating blasts % median (range) 0 (0-14) 1 (0-10) 0 (0-14) 0.5 LDH, UI/l median (range) 'N' evaluable = 346 (87%) 515 (136-2263) 557 (171-1901) 513 (136-2263) 0.71 Total bilirubin, mg/dl median (range) 'N' evaluable = 393 (99%) 0.7 (0.1-29) 0.8 (0.2-2.4) 0.7 (0.1-29) 0.5 AST, U/l median (range) 'N' evaluable = 397 (99%) 29 (8-145) 33 (14-145) 28 (8-81) 0.045 ALT, U/l median (range) 'N' evaluable = 96 (24%) 22 (8-209) 35 (12-209) 22 (8-62) 0.22 Presence of palpable splenomegaly 'N' evaluable = 396 (99%), n (%) 278 (70) 20 (69) (70) 0.9 Presence of non-hepatosplenic extramedullary hematopoiesis 'N' evaluable = 393 (99%), n (%) 23 (6) 2 (7) 21 (6) 0.8 Presence of constitutional symptoms 'N' evaluable = 392 (98%), n (%) 115 (29) 10 (34) 105 (29) 0.
Abstract P069: Interplay Between the Ubiquitin-Proteasome System and Autophagy in the Heart
Authors: Changhua Wang, Zongwen Tian, Qingwen Zheng, Huabo Su, Jie Li, Xuejun (XJ) Wang
Journal: Circulation Research (2011)

The ubiquitin-proteasome system (UPS) and autophagy are responsible for the degradation of most cellular proteins. Dysfunctions in the UPS and autophagy are both implicated in cardiac pathogenesis. The UPS and autophagy, thought to be two parallel pathways, seem to interact. Pharmacologically induced proteasome inhibition (PSMI) was shown to increase autophagosomes in cultured cardiomyocytes (CMs) but this observation remains to be demonstrated in intact animals and it is unclear whether the increased autophagosomes are caused by an increased autophagic flux. A recent report shows that chronic autophagic inhibition (AI) impairs the degradation of proteasomal substrates in a p62-dependent manner in cultured cells but this has not been tested in intact animals or CMs. Here we sought to address these important issues. Using the GFP-LC3 reporter, we demonstrate in both cell cultures and intact mice that PSMI upregulates p62 and increases autophagic flux in CMs. This is consistent with the increased autophagic flux in proteinopathic mouse hearts in which proteasome function is inadequate. We then tested the effect of AI on the degradation of a surrogate proteasome substrate (GFPu) in cultured CMs. GFPu was expressed in cultured n eonatal r at ventricular myocytes (NRVMs) via adenoviral delivery. Compared with the vehicle treatment, a 24-hr treatment but not 6-hr treatment of autophagy inhibitor 3-methyladenine (3-MA) or lysosome inhibitor bafilomycin A1 (BFA) significantly increased GFPu and p62 proteins in cultured NRVMs. Next, we tested the effect of AI on UPS-mediated protein degradation in intact mice. Transgenic mice overexpressing GFPdgn, a previously validated surrogate proteasome substrate, were treated with BFA (1.6 mg/kg/12hr, i. p. ). BFA induced lysosome inhibition was verified by a significant increase in LC3-II and p62. Myocardial GFPdgn protein levels were significantly increased 24hrs but not 3hrs after the first BFA injection. The protein level of representative proteasome subunits was not affected by AI. Our data demonstrate that PSMI activates autophagy while chronic AI impairs the degradation of proteasome substrates in the heart. It will be interesting and important to test the role of p62 in the interplay.
Rigor and Reproducibility in Analysis of Vascular Calcification
Authors: Linda L. Demer, Yin Tintut, Kim-Lien Nguyen, Tzung Hsiai, Jason T. Lee
Journal: Circulation Research (2017)

Clinical and pre-clinical studies of cardiovascular calcification often require interpretation of images from histopathology, CT scans, intravascular ultrasound, and positron emission tomography.To avoid potential pitfalls in biological inferences, investigators should know what happens to data in image processing algorithms, the limitations of cross-sectional images in studying mechanostability, and how smoothing algorithms can mask partial-volume artifacts in PET images.
Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden
Authors: Zachary R. Chalmers, Caitlin F. Connelly, David Fabrizio, Laurie Gay, Siraj M. Ali, Riley Ennis, Alexa Schrock, Brittany Campbell, Adam Shlien, Juliann Chmielecki, Franklin Huang, Yuting He, James Sun, Uri Tabori, Mark Kennedy, Daniel S. Lieber, Steven Roels, Jared White, Geoffrey A. Otto, Jeffrey S. Ross, Levi Garraway, Vincent A. Miller, Phillip J. Stephens, Garrett M. Frampton
Journal: Genome Medicine (2017)

High tumor mutational burden (TMB) is an emerging biomarker of sensitivity to immune checkpoint inhibitors and has been shown to be more significantly associated with response to PD-1 and PD-L1 blockade immunotherapy than PD-1 or PD-L1 expression, as measured by immunohistochemistry (IHC). The distribution of TMB and the subset of patients with high TMB has not been well characterized in the majority of cancer types. In this study, we compare TMB measured by a targeted comprehensive genomic profiling (CGP) assay to TMB measured by exome sequencing and simulate the expected variance in TMB when sequencing less than the whole exome. We then describe the distribution of TMB across a diverse cohort of 100,000 cancer cases and test for association between somatic alterations and TMB in over 100 tumor types. We demonstrate that measurements of TMB from comprehensive genomic profiling are strongly reflective of measurements from whole exome sequencing and model that below 0.5 Mb the variance in measurement increases significantly. We find that a subset of patients exhibits high TMB across almost all types of cancer, including many rare tumor types, and characterize the relationship between high TMB and microsatellite instability status. We find that TMB increases significantly with age, showing a 2.4-fold difference between age 10 and age 90 years. Finally, we investigate the molecular basis of TMB and identify genes and mutations associated with TMB level. We identify a cluster of somatic mutations in the promoter of the gene PMS2, which occur in 10% of skin cancers and are highly associated with increased TMB. These results show that a CGP assay targeting ~1.1 Mb of coding genome can accurately assess TMB compared with sequencing the whole exome. Using this method, we find that many disease types have a substantial portion of patients with high TMB who might benefit from immunotherapy. Finally, we identify novel, recurrent promoter mutations in PMS2, which may be another example of regulatory mutations contributing to tumorigenesis.
LANDING WITH LESS HIP FLEXION IS ASSOCIATED WITH INCREASED RISK OF ACL INJURIES IN YOUNG FEMALE TEAM SPORTS PLAYERS
Authors: Mari Leppänen, Kati Pasanen, Tron Krosshaug, Pekka Kannus, Tommi Vasankari, Jari Parkkari
Journal: British Journal of Sports Medicine (2017)

Background Stiff landings with less knee flexion and high vertical ground reaction force have shown to be associated with increased risk of ACL injuries (Leppänen et al . 2016). The association between other sagittal plane measures and the risk of ACL injuries is less studied in prospective study designs. Objective To investigate the relationship between selected sagittal plane hip, knee, and ankle biomechanics and the risk of ACL injuries in young female team sport players. Design Prospective cohort study. Setting Female youth team sports. Participants A total of 171 female basketball and floorball players (aged 12–21) participated in a VDJ test using 3D motion analysis. All new ACL injuries, as well as match and training exposure, were recorded for 1 to 3 years. Assessment of Risk Factors The following biomechanical variables were analysed: 1) peak knee extension moment, 2) peak hip flexion angle, 3) peak hip extension moment, and 4) peak ankle dorsiflexion angle. Cox regression models were used to calculate hazard ratios (HRs, adjusted for 10 unit change) and 95% confidence intervals (CIs). Main Outcome Measurements Non-contact ACL injuries. Results Subjects suffered a total of 15 ACL injuries during the follow-up (0.2 injuries per 1 000 player hours). Of the investigated variables, landing with decreased hip flexion was significantly associated with increased risk of ACL injury (HR 0.60; 95% CI 0.37 to 0.97, P =0.038). Peak knee extension moment (HR 1.13; 95% CI 0.79 to 1.62, P =0.490), peak hip extension moment (HR 0.88; 95% CI 0.77 to 1.01, P =0.065), and peak ankle dorsiflexion angle (HR 0.70; 95% CI 0.33 to 1.51, P =0.360) were not significantly associated with ACL injuries. Conclusions Landing with less hip flexion may increase the risk of ACL injury in young female team sport players. More studies with large study populations are needed to confirm these findings.
Improving the specificity of prostate cancer screening for early detection of lethal disease.
Authors: Hans Lilja, Andrew J. Vickers, Daniel Sjoberg, Robert Johansson, Torvald Granfors, Mattias Johansson, Kim Pettersson, Peter T. Scardino, Göran Hallmans, Pär Stattin
Journal: Journal of Clinical Oncology (2014)

5081 Background: PSA is used to detect prostate cancer, but many men need to be screened, biopsied, and diagnosed to prevent one cancer death. We sought to increase the specificity of screening for lethal prostate cancer. Methods: We conducted a nested case-control study to determine the relationship between four kallikrein markers (kallikrein related peptidase 2, total, free, and intact PSA) and long-term risk of metastasis. Of the 40,379 men providing blood at age 40, 50, and 60 during 1986-2009 for the Västerbotten Intervention Project, 12,561 were followed for over 15 years. Using the Swedish Cancer Registry, 1,423 incident prostate cancer cases and 235 men with evidence of distant metastases were identified. Kallikrein markers were measured in cryopreserved blood from cases and controls. Results: Risk of prostate cancer metastasis at 20 years was higher (16-fold at age 60, 7-fold at age 50, 3-fold at age 40) among men with PSA in top quartile than men with PSA below median. Most metastatic cases occurred in men with PSA in top quartile at age 50 (69%) or 60 (73%). Among men with PSA levels above median, a pre-specified model based on four kallikrein markers improved prediction of distant metastasis documented 10-20 years later compared to PSA alone. Among men with PSA ≥2 ng/ml at age 50, discrimination increased from 0.77 (PSA alone) to 0.88 (kallikrein panel); for men with PSA ≥2 ng/ml at age 60, discrimination increased from 0.81 to 0.87. We also conducted a decision analysis evaluating hypothetical outcomes had the panel been used to aid decisions about biopsy in this cohort. Using the biopsy cutoff used in the European randomized prostate cancer screening trial (PSA ≥3 ng/ml) would have resulted in biopsies performed on 15.5% of men with blood drawn at age 60. This rate would have been reduced by 38% if biopsy were restricted to those with ≥7.5% risk of high-grade cancer according to the panel. However, 10 to 15-year risk of distant metastases was only 0.18% to 1.16% in this group; a 15-year risk of metastases less than an eighth of that for those with PSA ≥3 ng/ml and ≥7.5% risk score. Conclusions: The specificity of PSA screening can be improved by focusing on men with modestly elevated PSA at age 50-60 and by reflex testing of four kallikrein markers.
What’s the point of happiness research?
Authors: Sophie Arie
Journal: BMJ (2017)

Paul Litchfield runs the What Works Centre for Wellness, which rates evidence in an effort to influence government and corporate policy. Sophie Arie asks him about the centre’s work

The former UK prime minister David Cameron announced in 2010 that making people happy should be one of government’s main goals.1 It began measuring the nation’s happiness in 2012 and later set up the What Works Centre for Wellness to gather evidence to inform policy decisions. Paul Litchfield is the organisation’s chair.

“The centre is one of seven in the What Works Network, which the government created in 2013 in what it said was ‘the first time any government has taken a national approach to prioritising the use of evidence in decision-making.’2 The centres look at evidence and try to use it to inform policy at all levels, from central government to third sector organisations and companies.

“The centre works with 50 institutions—universities, think tanks, and charities—carrying out research on wellness. We collate, synthesise, and rate the research. And then we aim to translate it into a useful form that people can apply.”

“We are independent but most of our funding comes from government and …
Comparative Trends in Payment Adjustments Between Safety-Net and Other Hospitals Since the Introduction of the Hospital Readmission Reduction Program and Value-Based Purchasing
Authors: Nathan Favini, Jason M. Hockenberry, Matlin Gilman, Sanjula Jain, Michael K. Ong, E. Kathleen Adams, Edmund R. Becker
Journal: JAMA (2017)

This study compares trends in Medicare payment adjustments to safety-net vs non–safety-net hospitals under Hospital Readmission Reduction Program (HRRP) and Value-Based Purchasing programs, intended to incentivize higher-quality health care.
Analyses of Heme-Regulated Genes during Erythoid Differentiation.
Authors: Tohru Fujiwara, Yoko Okitsu, Tsuyoshi Ikura, Shinichiro Takahashi, Kazumichi Furuyama, Kazuhiko Igarashi, Masayuki Yamamoto, Shigeru Sassa, Hideo Harigae
Journal: Blood (2007)
Methotrexate-Cytarabine-Dexamethasone Combination Chemotherapy with or without Rituximab in Patients with Primary Central Nervous System Lymphoma
Authors: Jing Liu, Xuefei Sun, Xueyan Bai, Yuedan Chen, Jun Qian, Hong Zhu, Yaming Wang, Nan Ji, Shengjun Sun, Yajie Wang, Yuanbo Liu
Journal: Blood (2016)
<i>KIT</i> and <i>PDGFRA</i> mutations of gastrointestinal stromal tumor
Authors: T. Nishida, T. Takahashi, K. Nakajima, T. Tsujinaka, S. Hirota
Journal: Journal of Clinical Oncology (2009)

10560 Background: KIT or PDGFRA mutations are found in gastrointestinal stromal tumors (GIST) and are correlated with imatinib (IM) effects. Most reports studied only hot-spots of each gene using paraffin sections and extracted DNA. Here we examined full sequence of the genes using frozen section of GI mesenchymal tumors. Methods: Histologic Dx was done with HE and immunohistochemistory (IH). Using RNA obtained from fresh samples of serial 209 pts with GIST (n=174), myogenic (21), neurogenic tumors (11), or GI sarcoma (3), KIT or PDGFRA cDNA was amplified by RT-PCR and fully sequenced. Results: Tumors other than GIST showed no KIT-immunoreactivity, and had no-PCR-products of KIT (32) or wild type (WT) (3). PDGFRA of these tumors is WT. In IH, KIT was positive in 94% of GIST and CD34 in 84%. 7 GIST showed no-PCR-products of KIT, 8 WT of the genes, 142 KIT, or 17 PDGFRA mutations. Mutations are mutually exclusive. No-PCR was associated with IM-responded GIST (6 out of 15 IM-treated pts), in which KIT expression in IH was scarcely seen. WT are found in 3 juvenile GIST or 4 NF-1, and only 1 adult GIST showed WT. KIT mutations are found in exon (Ex) 9 (10 pts), Ex 11 (125), Ex 13 (3), or Ex 17 (4). All Ex 9 mutations are typical insertion mutations, found in small intestine (8) or colon (2), and associated with poor prognosis. Ex 13 and 17 mutations are missense and Ex 11 showed various type of mutations including deletion, insertion and missense mutations. These mutations distributed throughout GI tract. Deletion mutations in Ex 11 are associated with high recurrence rates (38/64 pts) and poor prognosis. 7 pts showed insertion mutation in the distal part of Ex 11. PDGFRA mutations found in Ex 12 (4 pts) or Ex18 (13) are missense mutations and associated with gastric location, epithelioid histology (10/16), low mitotic activity and relatively indolent clinical features. Conclusions: KIT mRNA and protein are sometimes depressed in IM-responded lesions, which causes difficulty in mutation research. Mutations in KIT and PDGFRA are specific for GIST and WT GIST is extremely rare in adult pts except NF-1. No significant financial relationships to disclose.
Glycosaminoglycan-based hydrogels capture inflammatory chemokines and rescue defective wound healing in mice
Authors: Nadine Lohmann, Lucas Schirmer, Passant Atallah, Elke Wandel, Ruben A. Ferrer, Carsten Werner, Jan C. Simon, Sandra Franz, Uwe Freudenberg
Journal: Science Translational Medicine (2017)

Glycosaminoglycan-based hydrogels scavenge proinflammatory chemokines, reduce the influx of immune cells, and improve the healing of chronic wounds.
Elevated Hypothalamic TCPTP in Obesity Contributes to Cellular Leptin Resistance
Authors: Kim Loh, Atsushi Fukushima, Xinmei Zhang, Sandra Galic, Dana Briggs, Pablo J. Enriori, Stephanie Simonds, Florian Wiede, Alexander Reichenbach, Christine Hauser, Natalie A. Sims, Kendra K. Bence, Sheng Zhang, Zhong-Yin Zhang, Barbara B. Kahn, Benjamin G. Neel, Zane B. Andrews, Michael A. Cowley, Tony Tiganis
Journal: Cell Metabolism (2012)
Abstract 230: Cartilage Intermediate Layer Protein-1 Attenuates Pressure Overload-induced Cardiac Fibrosis by Targeting Transforming Growth Factor-β1
Authors: Li Li, Cheng-Lin Zhang, Dan Wu, Li-Ling Wu
Journal: Circulation Research (2015)

Background: Cartilage intermediate layer protein-1 (CILP-1), a monomeric extracellular matrix glycoprotein expressed mainly in the middle zones of articular cartilage, interacts directly with transforming growth factor-β1 (TGF-β1). Recent studies showed that CILP-1 was upregulated in the heart tissue following cardiac ischemia reperfusion injury. However, the role of CILP-1 in pathological cardiac remodeling is poorly defined. Aims: To explore the effect of CILP-1 on myocardial interstitial fibrosis and reveal the possible molecular mechanism. Methods and Results: We found that CILP-1 was mainly expressed in mouse cardiac fibroblasts (CFs) by using western blot analysis and immunofluorescence. Myocardial expression of CILP-1 was upregulated in mice subjected to transverse aortic constriction (TAC) for 2, 4, and 8 weeks. AAV-9-mediated delivery of CILP-1 into mice increased the binding of CILP-1 with TGF-β1, attenuated interstitial fibrosis, and improved cardiac function. In cultured adult mouse CFs, CILP-1 overexpression inhibited myofibroblast differentiation and expression of profibrotic molecules induced by TGF-β1. Furthermore, CILP-1 attenuated TGF-β1-induced Smad3 phosphorylation and nuclear translocation. Conclusions: CILP-1 alleviates pressure overload-induced cardiac fibrosis and dysfunction. CILP-1 exerts its anti-fibrotic effect through targeting TGF-β1 signaling. This study will offer a new therapeutic strategy for preventing and treating myocardial interstitial remodeling.
Randomized Phase II Study Investigating Pazopanib Versus Weekly Paclitaxel in Relapsed or Progressive Urothelial Cancer
Authors: Robert J. Jones, Syed A. Hussain, Andrew S. Protheroe, Alison Birtle, Prabir Chakraborti, Robert A. Huddart, Satinder Jagdev, Amit Bahl, Andrew Stockdale, Santhanam Sundar, Simon J. Crabb, Judith Dixon-Hughes, Laura Alexander, Anna Morris, Caroline Kelly, Jon Stobo, James Paul, Thomas Powles
Journal: Journal of Clinical Oncology (2017)

Purpose Two previous single-arm trials have drawn conflicting conclusions regarding the activity of pazopanib in urothelial cancers after failure of platinum-based chemotherapy. Patients and Methods This randomized (1:1) open-label phase II trial compared the efficacy of pazopanib 800 mg orally with paclitaxel (80 mg/m
Increased collagen within the transverse tubules in human heart failure
Authors: David J. Crossman, Xin Shen, Mia Jüllig, Michelle Munro, Yufeng Hou, Martin Middleditch, Darshan Shrestha, Amy Li, Sean Lal, Cristobal G. dos Remedios, David Baddeley, Peter N. Ruygrok, Christian Soeller
Journal: Cardiovascular Research (2017)

In heart failure transverse-tubule (t-tubule) remodelling disrupts calcium release, and contraction. T-tubules in human failing hearts exhibit increased labelling by wheat germ agglutinin (WGA), a lectin that binds to the dystrophin-associated glycoprotein complex. We hypothesized changes in this complex may explain the increased WGA labelling and contribute to t-tubule remodelling in the failing human heart. In this study we sought to identify the molecules responsible for this increased WGA labelling.Confocal and super-resolution fluorescence microscopy and proteomic analyses were used to quantify left ventricle samples from healthy donors and patients with idiopathic dilated cardiomyopathy (IDCM). Confocal microscopy demonstrated both WGA and dystrophin were located at t-tubules. Super-resolution microscopy revealed that WGA labelling of t-tubules is largely located within the lumen while dystrophin was restricted to near the sarcolemma. Western blots probed with WGA reveal a 5.7-fold increase in a 140 kDa band in IDCM. Mass spectrometry identified this band as type VI collagen (Col-VI) comprised of α1(VI), α2(VI), and α3(VI) chains. Pertinently, mutations in Col-VI cause muscular dystrophy. Western blotting identified a 2.4-fold increased expression and 3.2-fold increased WGA binding of Col-VI in IDCM. Confocal images showed that Col-VI is located in the t-tubules and that their diameter increased in the IDCM samples. Super-resolution imaging revealed Col-VI was restricted to the t-tubule lumen where increases were associated with displacement in the sarcolemma as identified from dystrophin labelling. Samples were also labelled for type I, III, and IV collagen. Both confocal and super-resolution imaging identified that these collagens were also present within t-tubule lumen.Increased expression and labelling of collagen in IDCM samples indicates fibrosis may contribute to t-tubule remodelling in human heart failure.
Insulitis in Autoantibody-Positive Pancreatic Donor With History of Gestational Diabetes Mellitus
Authors: Jessica Jackson, Amanda Posgai, Martha Campbell-Thompson, Irina Kusmartseva
Journal: Diabetes Care (2017)

The patient (nPOD 6310) was a 28-year-old female, 32 days postoperative from a cesarean delivery. Her past medical history was significant for chronic hypertension, severe preeclampsia, acute renal failure, and gestational diabetes mellitus (GDM). She was brought to the emergency department after collapsing, with total downtime of 20–30 min. On arrival, she was admitted to the intensive care unit and found to be in hypertensive crisis. Her hospital course was complicated by renal failure requiring four rounds of hemodialysis, hypertension requiring multiple agents for control, and a degree of hyperglycemia requiring insulin. Computed tomography of the head demonstrated anoxic encephalopathy with multiple infarcts within the brain. The patient was declared brain-dead and, with authorization obtained from next of kin, became an organ donor. The pancreas, along with blood, was recovered for research through the Network for Pancreatic Organ …