tbuckley/cabot-search huggingface dataset:
Risk Stratification of Genetic, Dilated Cardiomyopathies Associated With Neuromuscular Disorders
Authors: Pieter van der Bijl, Victoria Delgado, Marianne Bootsma, Jeroen J. Bax
Journal: Circulation (2018)

The etiology of dilated cardiomyopathy (DCM) can be grouped as either genetic or nongenetic. More than 50 pathogenic genes have been described, with sarcomeric and lamin A/C mutations being the most common. Mutation carriers for genetic DCM are often asymptomatic until cardiac disease manifests with heart failure, arrhythmias, or sudden cardiac death. Preventive strategies are promising but can only be applied and tested adequately if genetic DCM can be diagnosed at an early stage. Early diagnosis of mutation carriers that may develop overt DCM requires advanced imaging techniques that can detect subtle structural and functional abnormalities. Advanced echocardiographic techniques such as tissue Doppler imaging and speckle tracking strain analysis permit early detection of functional abnormalities, whereas cardiovascular magnetic resonance techniques provide information on tissue characterization and myocardial energetics that may be altered at an early stage. Furthermore, nuclear imaging techniques provide information on cellular function (metabolism, perfusion). Once the diagnosis of overt DCM has been established, various imaging parameters such as echocardiography-based myocardial mechanics and cardiovascular magnetic resonance-based tissue characterization have shown incremental benefit to left ventricular ejection fraction in risk stratification. Further research is required to understand how imaging techniques may help to choose management strategies that could delay progression when instituted early in the course of the disease. The present article reviews the role of imaging in the risk stratification of genetic DCM in general, with specific emphasis on DCM associated with neuromuscular disorders.
SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling
Authors: Jakob Voelkl, Trang T.D. Luong, Rashad Tuffaha, Katharina Musculus, Tilman Auer, Xiaoming Lian, Christoph Daniel, Daniel Zickler, Beate Boehme, Michael Sacherer, Bernhard Metzler, Dietmar Kuhl, Maik Gollasch, Kerstin Amann, Dominik N. Müller, Burkert Pieske, Florian Lang, Ioana Alesutan
Journal: Journal of Clinical Investigation (2018)

Medial vascular calcification, associated with enhanced mortality in chronic kidney disease (CKD), is fostered by osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Here, we describe that serum- and glucocorticoid-inducible kinase 1 (SGK1) was upregulated in VSMCs under calcifying conditions. In primary human aortic VSMCs, overexpression of constitutively active SGK1S422D, but not inactive SGK1K127N, upregulated osteo-/chondrogenic marker expression and activity, effects pointing to increased osteo-/chondrogenic transdifferentiation. SGK1S422D induced nuclear translocation and increased transcriptional activity of NF-κB. Silencing or pharmacological inhibition of IKK abrogated the osteoinductive effects of SGK1S422D. Genetic deficiency, silencing, and pharmacological inhibition of SGK1 dissipated phosphate-induced calcification and osteo-/chondrogenic transdifferentiation of VSMCs. Aortic calcification, stiffness, and osteo-/chondrogenic transdifferentiation in mice following cholecalciferol overload were strongly reduced by genetic knockout or pharmacological inhibition of Sgk1 by EMD638683. Similarly, Sgk1 deficiency blunted vascular calcification in apolipoprotein E-deficient mice after subtotal nephrectomy. Treatment of human aortic smooth muscle cells with serum from uremic patients induced osteo-/chondrogenic transdifferentiation, effects ameliorated by EMD638683. These observations identified SGK1 as a key regulator of vascular calcification. SGK1 promoted vascular calcification, at least partly, via NF-κB activation. Inhibition of SGK1 may, thus, reduce the burden of vascular calcification in CKD.
Correlation with invasive left ventricular filling pressures and prognostic relevance of the echocardiographic diastolic parameters used in the 2016 ESC heart failure guidelines and in the 2016 ASE/EACVI recommendations: a systematic review in patients wi
Authors: Jan F. Nauta, Yoran M. Hummel, Peter van der Meer, Carolyn S.P. Lam, Adriaan A. Voors, Joost P. van Melle
Journal: European Journal of Heart Failure (2018)
Association of Cannabis Use With Adolescent Psychotic Symptoms
Authors: Josiane Bourque, Mohammad H. Afzali, Patricia J. Conrod
Journal: JAMA Psychiatry (2018)

Heroin overdose death rates climbed after 2010. 1 We specified random-effects meta-analysis comparisons of 2 intervals and found that, from 2006 to 2010, risk of dependence was 23.7% (95% CI, 16.8%-30.6%)vs 41.7% (95% CI, 35.3%-48.0%)from 2011 to 2016.We then explored 2002 to 2010 and derived an estimate of 20.1% (95% CI, 15.5%-24.7%).We compared the estimate of 20.3% (95% CI, 14.6%-25.
Computing the cost of care per day of breast cancer survivor care.
Authors: Douglas W. Blayney, Craig Lindquist, Tina Seto, Nhat Minh Hoang, Allison W. Kurian
Journal: Journal of Clinical Oncology (2018)

10 Background: Cost of breast cancer survivor surveillance, of survivorship care and of variation in care practices are unknown. Furthermore, it is not known whether intense surveillance care adds value. We developed a method to measure the cost of surveillance to account for varying follow-up duration [cost of care per day (CCPD)], and explored the impact of surveillance cost on survival. Methods: We queried the Oncoshare database {Kurian et al Cancer 2014}, which amalgamates data from Stanford Health Care’s (SHC) electronic health record (EHR) (imaging, infused drugs, inpatient and outpatient facility and professional services), from the California Cancer Registry, and the Social Security Death Index. We included breast cancer patients diagnosed 2000-2014, Stages 0-III who had surgery, chemotherapy or radiation treatment at SHC, and who had more than two visits at SHC within 3 years of their treatment completion. We tallied Common Procedural Terminology (CPT©) codes assigned to each service, and mapped each CPT code to the corresponding code and date in the CMS Medicare fee schedule. For patients with breast cancer relapse, we explored the post-relapse survival of the costliest 20% compared with the other patients. Results: CCPD was $2.45 for care delivered at SHC. Among the three breast cancer subtypes (luminal, Her-2 over-expressed and triple negative) there was no difference in cost. Among patients who relapsed, those in the most expensive 20% CCPD had significantly shorter survival than other patients. The high-cost patients had more co-morbidity [cerebrovascular disease (4% for low cost vs 7% for high), chronic pulmonary disease (5% vs 10%), CHF (2% vs 7%), diabetes (4% vs 7%), liver disease (4% vs 9%)]. Conclusions: Cost of care per day (CCPD) is a useful metric to assess value of surveillance and survivorship care, and is also applicable to initial treatment and post-relapse care, to identify “positive deviants” ( those who have developed best practices) in high value care delivery. We captured only costs for treatment at SHC, and merging our data with claims data from 3 rd party carriers could increase the accuracy and validity of the CCPD. We identified a model for further testing to reduce total spending for high-quality oncology care.
PanDrugs: a novel method to prioritize anticancer drug treatments according to individual genomic data
Authors: Elena Piñeiro-Yáñez, Miguel Reboiro-Jato, Gonzalo Gómez-López, Javier Perales-Patón, Kevin Troulé, José Manuel Rodríguez, Héctor Tejero, Takeshi Shimamura, Pedro Pablo López-Casas, Julián Carretero, Alfonso Valencia, Manuel Hidalgo, Daniel Glez-Peña, Fátima Al-Shahrour
Journal: Genome Medicine (2018)

Large-sequencing cancer genome projects have shown that tumors have thousands of molecular alterations and their frequency is highly heterogeneous. In such scenarios, physicians and oncologists routinely face lists of cancer genomic alterations where only a minority of them are relevant biomarkers to drive clinical decision-making. For this reason, the medical community agrees on the urgent need of methodologies to establish the relevance of tumor alterations, assisting in genomic profile interpretation, and, more importantly, to prioritize those that could be clinically actionable for cancer therapy. We present PanDrugs, a new computational methodology to guide the selection of personalized treatments in cancer patients using the variant lists provided by genome-wide sequencing analyses. PanDrugs offers the largest database of drug-target associations available from well-known targeted therapies to preclinical drugs. Scoring data-driven gene cancer relevance and drug feasibility PanDrugs interprets genomic alterations and provides a prioritized evidence-based list of anticancer therapies. Our tool represents the first drug prescription strategy applying a rational based on pathway context, multi-gene markers impact and information provided by functional experiments. Our approach has been systematically applied to TCGA patients and successfully validated in a cancer case study with a xenograft mouse model demonstrating its utility. PanDrugs is a feasible method to identify potentially druggable molecular alterations and prioritize drugs to facilitate the interpretation of genomic landscape and clinical decision-making in cancer patients. Our approach expands the search of druggable genomic alterations from the concept of cancer driver genes to the druggable pathway context extending anticancer therapeutic options beyond already known cancer genes. The methodology is public and easily integratable with custom pipelines through its programmatic API or its docker image. The PanDrugs webtool is freely accessible at http://www.pandrugs.org .
Assessing perceptions of transition readiness in the adolescent and young adult oncology population.
Authors: Vaibhav Agrawal, Kristina K. Blessing, Andrea Berger, Amanda Schleicher, Mike Styer, Vicki Seel, Sharif S. Khan, Michal A. Miller
Journal: Journal of Clinical Oncology (2018)

73 Background: Childhood cancer patients have distinct health-related needs as they transition from patient to survivor and from pediatric to adult-based care. This study used the Transition Readiness Assessment Questionnaire (TRAQ) to assess transition readiness and compare variation in readiness perceptions between patients, parents, and physicians. Methods: The TRAQ was completed by patients between ages 12 to 26 and their parent and oncologist at Geisinger Medical Center from Sept. 2015 to Dec. 2016. Surveys were scored according to validated methods (min. 1, max. 5). Statistical analysis was completed using SAS 9.4. Results: The study enrolled 49 patients, including 6 patients (12.2%) and 43 survivors (87.8%). There were 29 males (59.2%). The patient’s mean age at the time of survey was 18.4 years. Cancer types included: acute lymphoblastic leukemia (n = 17), lymphoma (n = 12), and sarcoma (n = 7). There were no significant differences in overall TRAQ scores between parents, patients, and physicians (mean 3.2, 3.5, and 3.7, respectively). The highest interobserver agreement was seen between patients and parents; the lowest was seen between physicians and patients. The greatest competency was assessed in the activity of talking with providers, and the lowest was measured in appointment keeping. In the domain of tracking health issues, providers assigned higher scores than patients (p = 0.003) and parents (p = 0.001). In the skill of talking with providers, patients ranked themselves higher than providers (p = 0.003). There was no significant variation in scores based on disease type, length of therapy, or insurance type. Patient age at diagnosis, patient age at therapy completion, and patient age at survey were correlated with higher patient (p = 0.004, p = 0.002, p = 0.0001, respectively), parent (p = 0.017, p = 0.019, p = 0.0001, respectively), and physician (p = 0.027, p = 0.03, p = 0.0001, respectively) scores. Conclusions: This study demonstrated that the overall assessment of transition readiness in the adolescent and young adult oncology population was similar between patients, parents, and physicians. The TRAQ is a tool that can be effectively used to guide healthcare transition in this population.
NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis
Authors: Alena Grebe, Florian Hoss, Eicke Latz
Journal: Circulation Research (2018)

Inflammation is an important driver of atherosclerosis, the underlying pathology of cardiovascular diseases. Therefore, therapeutic targeting of inflammatory pathways is suggested to improve cardiovascular outcomes in patients with cardiovascular diseases. This concept was recently proven by CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study), which demonstrated the therapeutic potential of the monoclonal IL (interleukin)-1β-neutralizing antibody canakinumab. IL-1β and other IL-1 family cytokines are important vascular and systemic inflammatory mediators, which contribute to atherogenesis. The NLRP3 (NOD [nucleotide oligomerization domain]-, LRR [leucine-rich repeat]-, and PYD [pyrin domain]-containing protein 3) inflammasome, an innate immune signaling complex, is the key mediator of IL-1 family cytokine production in atherosclerosis. NLRP3 is activated by various endogenous danger signals abundantly present in atherosclerotic lesions, such as oxidized low-density lipoprotein and cholesterol crystals. Consequently, NLRP3 inflammasome activation contributes to the vascular inflammatory response driving atherosclerosis development and progression. Here, we review the mechanisms of NLRP3 inflammasome activation and proinflammatory IL-1 family cytokine production in the context of atherosclerosis and discuss treatment possibilities in light of the positive outcomes of the CANTOS trial.
USP22 deficiency leads to myeloid leukemia upon oncogenic Kras activation through a PU.1-dependent mechanism
Authors: Johanna Melo-Cardenas, Yuanming Xu, Juncheng Wei, Can Tan, Sinyi Kong, Beixue Gao, Elena Montauti, Gina Kirsammer, Jonathan D. Licht, Jindan Yu, Peng Ji, John D. Crispino, Deyu Fang
Journal: Blood (2018)
Neuronatin regulates pancreatic β cell insulin content and secretion
Authors: Steven J. Millership, Gabriela Da Silva Xavier, Agharul I. Choudhury, Sergio Bertazzo, Pauline Chabosseau, Silvia M.A. Pedroni, Elaine E. Irvine, Alex Montoya, Peter Faull, William R. Taylor, Julie Kerr-Conte, Francois Pattou, Jorge Ferrer, Mark Christian, Rosalind M. John, Mathieu Latreille, Ming Liu, Guy A. Rutter, James Scott, Dominic J. Withers
Journal: Journal of Clinical Investigation (2018)

Neuronatin (Nnat) is an imprinted gene implicated in human obesity and widely expressed in neuroendocrine and metabolic tissues in a hormone- and nutrient-sensitive manner. However, its molecular and cellular functions and precise role in organismal physiology remain only partly defined. Here we demonstrate that mice lacking Nnat globally or specifically in β cells display impaired glucose-stimulated insulin secretion leading to defective glucose handling under conditions of nutrient excess. In contrast, we report no evidence for any feeding or body weight phenotypes in global Nnat-null mice. At the molecular level neuronatin augments insulin signal peptide cleavage by binding to the signal peptidase complex and facilitates translocation of the nascent preprohormone. Loss of neuronatin expression in β cells therefore reduces insulin content and blunts glucose-stimulated insulin secretion. Nnat expression, in turn, is glucose-regulated. This mechanism therefore represents a novel site of nutrient-sensitive control of β cell function and whole-animal glucose homeostasis. These data also suggest a potential wider role for Nnat in the regulation of metabolism through the modulation of peptide processing events.
CA15-3/MUC1 in CCTG MA-32 (NCT01101438): A phase III RCT of the effect of metformin vs. placebo on invasive disease free and overall survival in early stage breast cancer (BC).
Authors: Ryan JO Dowling, Wendy R. Parulekar, Karen A. Gelmon, Lois E. Shepherd, Shakeel Virk, Marguerite Ennis, Fangya Mao, Jennifer A. Ligibel, Dawn L. Hershman, Priya Rastogi, Ingrid A. Mayer, Timothy J. Hobday, Julie Lemieux, Alastair Mark Thompson, Manuela Rabaglio-Poretti, Timothy Joseph Whelan, Vuk Stambolic, Bingshu E. Chen, Pamela Jean Goodwin
Journal: Journal of Clinical Oncology (2018)

557 Background: The diabetes drug metformin may improve BC outcomes through enhanced obesity-related physiology or direct anti-tumor effects. We studied the effect of metformin on CA15-3 (the soluble moiety of the MUC1 protein), a marker associated with BC prognosis that also has mitogenic and metabolic effects that favor tumorigenesis. Methods: 3,256 women with T1-3, N0-3, M0 BC who had completed standard therapy (ongoing hormone therapy permitted) provided fasting blood (stored at -80C) at baseline and 6 months. CA15-3 and insulin were measured by Roche ECLIA; leptin, and hs-CRP by Luminex Milliplex MAP and Roche ITA. Spearman coefficients were calculated and comparisons analyzed using Wilcoxon signed rank test and multivariable linear regression models. Tests were two-sided. Results: Mean age was 52.3 and BMI 28.6 kg/m2. Tumor and treatment characteristics were balanced between arms (overall: T2/3 in 59.8%, N +ve in 52.9%, grade 1/2/3 in 9.1%/35.3%/54.4%, ER+ in 69.6%, HER2+ in 17.1%; 50.4% underwent mastectomy, 74.0% received radiation, 89.2% chemotherapy, 17% trastuzumab, and 64.4% hormones). Baseline values and 6 month changes are shown below. In multi-variable analyses (including age, BMI, tumor characteristics, treatment), metformin (vs placebo) led to a greater relative reduction in CA15-3 (-5.81%; 95% CI: -3.94% to -7.64%, p < 0.0001). CA15-3 change at 6 months significantly correlated with change in BMI (r=0.10, p<0.0001), glucose (r=0.05, p=0.011) and hsCRP (r=0.05, p=0.022). Conclusions: Metformin significantly lowered CA15-3; change in CA15-3 was associated with improved obesity-associated physiology and BMI, consistent with hypothesized beneficial actions of metformin. Clinical trial information: NCT01101438.Variable Baseline 6 Months Change Metformin Placebo Metformin Placebo Metformin Placebo CA15-3 (U/ml) 17.8 18.0 16.5 18.9* -1.2. 0.8* BMI (kg/m2) 28.8 28.5 28.1 28.7* -0.58 0.21* Insulin (pM) 83.4 81.0 74.1 85.5* -7.4 5.3* Glucose (mM) 5.2 5.2 5.1 5.2* -0.09 0.06* Leptin (ng/ml) 19.3 18.9 18.2 20.9* -1.2 2.2* hs-CRP (ug/ml) 3.1 2.7 3.4 3.3* 0.52 0.57* Mean values. *significant difference between metformin and placebo, p < 0.05
Northern Ireland abortion law breaches human rights, say judges
Authors: Clare Dyer
Journal: BMJ (2018)

Pressure is growing for reform of the strict abortion law in Northern Ireland after a majority of the seven judges considering the issue in the UK Supreme Court decided that it breached the European Convention on Human Rights.

However, a majority of the justices also held that they were unable to make a binding decision that the law needed changing because the Northern Ireland Human Rights Commission, which had brought the case to court, had no standing to bring it. Technically, therefore, they had to dismiss the appeal.

Lord Mance, Lord Reed, Lady Black, and Lord Lloyd-Jones concluded that the commission had no standing because it had not …
Optimizing Oxygen Saturation Targets in Extremely Preterm Infants
Authors: Matthew J. Bizzarro
Journal: JAMA (2018)

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Comparison of efficacy and safety of biosimilar filgrastim in a RCT (PIONEER) and real-world practice (MONITOR-GCSF).
Authors: Nadia Harbeck, Lillian Yau, Nicola Mathieson, Andriy Krendyukov
Journal: Journal of Clinical Oncology (2018)

111 Background: Sandoz biosimilar filgrastim has been approved in the US since 2015 for several indications including prevention of chemotherapy-induced neutropenia. US approval was based on results from PIONEER, a phase III confirmatory trial in breast cancer (BC) patients receiving chemotherapy randomized to either Sandoz biosimilar or reference filgrastim (Blackwell et al. Ann Oncol 2015;26:1948-53). BC is considered a sensitive indication to demonstrate filgrastim biosimilarity. Post-approval, safety of Sandoz biosimilar filgrastim has been monitored in MONITOR-GSCF, an observational study in patients with solid or hematological malignancies undergoing chemotherapy (Gascon et al. Support Care Cancer 2016;24:911-25). The results from PIONEER were compared to the MONITOR-GCSF BC cohort to evaluate Sandoz biosimilar filgrastim in a RCT and a real-world practice setting in BC. Methods: Results were compared for corresponding endpoints. Patient- and cycle-level comparisons were made between patients in PIONEER, and all BC patients receiving biosimilar filgrastim in MONITOR-GCSF. Results: There were 217 evaluable patients in PIONEER and 466 in MONITOR-GCSF. Patients were generally younger in PIONEER (mean age, years ± SD: 48.9 ± 11.3 vs 56.2 ± 11.7). Patient level results are reported. Febrile neutropenia (FN) was reported in 5.1% (PIONEER) vs 6.2% (MONITOR-GCSF). All grade adverse events (AEs) were generally reported at a higher level in PIONEER than MONITOR-GCSF, including musculoskeletal/connective tissue disorders (PIONEER: 261, MONITOR-GCSF: 20 [absolute numbers]); infections/infestations (PIONEER: 31, MONITOR-GCSF: 3); skin/subcutaneous tissue disorders (PIONEER: 258, MONITOR-GCSF: 5) and general disorders/administration site conditions (PIONEER: 673, MONITOR-GCSF: 7). Cycle level results were generally similar between studies. Conclusions: Sandoz biosimilar filgrastim prevented FN in a RCT and in real-world practice in BC patients receiving (neo-)adjuvant chemotherapy. In real-world practice, experiencing AEs may be perceived as unavoidable in order to achieve clinical efficacy. Thus Phase III RCTs remain an effective tool to assess and monitor AEs.