tbuckley/cabot-search huggingface dataset:
Chromosome 3p Loss–Orchestrated VHL, HIF, and Epigenetic Deregulation in Clear Cell Renal Cell Carcinoma
Authors: James J. Hsieh, Valerie H. Le, Toshinao Oyama, Christopher J. Ricketts, Thai Huu Ho, Emily H. Cheng
Journal: Journal of Clinical Oncology (2018)

Clear cell renal cell carcinoma (ccRCC) is the most common renal cell carcinoma subtype, and metastatic ccRCC is associated with 5-year survival rates of 10% to 20%. Genetically, ccRCC originates from sequential losses of multiple tumor suppressor genes. Remarkably, chromosome 3p loss occurs in more than 90% of sporadic ccRCCs. This results in concurrent one-copy loss of four tumor suppressor genes that are also mutated individually at high frequency in ccRCC (ie, VHL, 80%; PBRM1, 29% to 46%; BAP1, 6% to 19%; and SETD2, 8% to 30%). Pathogenically, 3p loss probably represents the first genetic event that occurs in sporadic ccRCC and the second genetic event in VHL-mutated hereditary ccRCC. VHL constitutes the substrate recognition module of the VCB-Cul2 E3 ligase that degrades HIF1/2α, whereas PBRM1, BAP1, and SETD2 are epigenetic modulators that regulate gene transcription. Because 3p loss and VHL inactivation are nearly universal truncal events in ccRCC, the resulting HIF1/2 signaling overdrive and accompanied tumor hypervascularization probably underlie the therapeutic benefits observed with vascular endothelial growth factor receptor inhibitors, including sorafenib, sunitinib, pazopanib, axitinib, bevacizumab, cabozantinib, and lenvatinib. Furthermore, recent marked advances in ccRCC genomics, transcriptomics, proteomics, metabolomics, molecular mechanisms, mouse models, prognostic and predictive biomarkers, and clinical trials have rendered invaluable translational insights concerning precision kidney cancer therapeutics. With an armamentarium encompassing 13 drugs that exploit seven unique therapeutic mechanisms (ie, cytokines, vascular endothelial growth factor receptor, mTORC1, cMET/AXL, fibroblast growth factor receptor, programmed cell death-1 and programmed death-ligand 1, and cytotoxic T-cell lymphocyte associated-4) to treat metastatic renal cell carcinoma, one of the imminent clinical questions concerning care of patients with metastatic ccRCC is how a personalized treatment strategy, through rationally combining and sequencing different therapeutic modalities, can be formulated to offer the best clinical outcome for individual patients. Here, we attempt to integrate recent discoveries of immediate translational impacts and discuss future translational challenges and opportunities.
Abstract 17955: Reduction in 30-day Rehospitalization After Discharge From a Heart Failure Admission in Patients Receiving LCZ696 versus Enalapril: PARADIGM-HF
Authors: Scott D Solomon, Milton Packer, Michael Zile, Jean Rouleau, Karl Swedberg, Akshay Desai, Victor Shi, Martin Lefkowitz, John J McMurray
Journal: Circulation (2015)

Introduction: The angiotensin receptor neprilysin inhibitor LCZ696 reduced cardiovascular death, heart failure hospitalization and all-cause mortality in patients with heart failure and reduced ejection fraction compared with enalapril. Hypothesis: We hypothesized that LCZ696 would reduce 30-day readmission after a heart failure hospitalization. Methods: PARADIGM-HF randomized 8399 patients with HF and reduced ejection fraction to either LCZ696 200mg bid or Enalapril 10mg bid. We assessed the risk of 30-day readmission for any cause following investigator reported and adjudicated hospitalization for heart failure. Admission and discharge dates were available for 2800 hospitalizations (95%) in 1638 patients. Results: Of 2800 HF hospitalizations, 1545 occurred in 871 patients in the enalapril group and 1255 occurred in 767 patients in the LCZ arm. Overall, 10.5% of these HF hospitalizations were followed by a repeat hospitalization for any cause within 30 days of discharge, and this occurred significantly less frequently in the LCZ arm (8.7%) relative to the enalapril arm (12.0%), in both unadjusted models and a random-effects logistic regression model accounting for the repeated HF hospitalizations experienced by some patients. We observed similar results in a sensitivity analysis restricted only to the first HF hospitalization for each patient. Further adjustment for baseline characteristics did not alter these findings. Similar effect sizes were observed for adjudicated heart failure hospitalizations. Conclusion: In patients admitted with heart failure in PARADIGM-HF, LCZ reduced 30-day readmissions for any-cause.
Abstract 16571: The Potential Impact of Expanding Cardiac Rehabilitation Coverage in Heart Failure: Insights From Get With the Guidelines Heart Failure
Authors: Jacob P Kelly, Brad G Hammill, Jacob A Doll, G. Michael Felker, Paul A Heidenreich, Clyde W Yancy, Deepak L Bhatt, Greg C Fonarow, Adrian F Hernandez
Journal: Circulation (2015)

Background: In February 2014, coverage for cardiac rehabilitation (CR) was expanded by Centers for Medicare &amp; Medicaid to include patients with chronic symptomatic heart failure (HF) on optimal medical therapy with ejection fraction &lt;35%. Thus, we sought to characterize the patient population newly eligible for CR based on the expanded criteria and their associated outcomes. Methods: We analyzed the Get With The Guidelines-HF registry linked to Medicare claims data from 2008-2012 to assess three groups of patients age 65 or older: previously eligible (due to prior MI, CABG, stable angina, heart valve surgery, or PCI in the previous 12 months), newly eligible, and ineligible for CR. Ineligible patients met neither criteria. Incidence rate was calculated with Kaplan-Meier estimates and Cox proportional hazard models were used to determine the association of events. Results: Among 51,665 HF patients discharged alive, 27.2% (n=14,053) were newly eligible and 14.5% were previously eligible for CR (n=7477). Newly eligible patients were more likely to be black, have atrial fibrillation and EF &lt; 35%, while having fewer previous hospitalizations than patients previously eligible for CR. Newly eligible and ineligible patients had similar risk for 1-year mortality compared with those previously eligible (adjusted Hazard Ratio [HR] 0.95, 95% Confidence Interval [CI] 0.88-1.02, p-value=0.13 and [HR] 1.05, 95% [CI] 0.98-1.13, p-value=0.17, respectively). However, newly eligible and ineligible patients had lower risk for 1-year readmission compared with those previously eligible (adjusted [HR] 0.89, 95% [CI] 0.85-0.93, p-value&lt;0.001 and [HR] 0.94, 95% [CI] 0.90- 0.98, p-value&lt;0.001). Conclusions: The extension of coverage for cardiac rehabilitation has tripled the potentially eligible HF population. As these newly eligible patients are at high risk for adverse outcomes, cardiac rehabilitation should be considered.
Scottish mesh review had serious failings
Authors: Bryan Christie
Journal: BMJ (2018)

A heavily criticised official review into the use of transvaginal mesh implants in Scotland in 2017 has been found to have serious failings.

The report,1 which recommended that mesh implants should continue to be made available in Scotland, was branded a whitewash by women who have suffered life changing complications as a result of surgery. Such was the level of opposition that the Scottish government ordered an inquiry into the way the review was conducted.

That has now reported and concluded …
Abstract P352: Trends in the Type of Coronary Heart Disease Hospitalizations: Increasing Proportions of Chronic Forms, Especially among the Elderly
Authors: Carla Koopman, Michiel L Bots, Ineke van Dis, Ilonca Vaartjes
Journal: Circulation (2013)

Background: Time trends in event rates of acute myocardial infarction (AMI) show encouraging declines. We studied trends in rates and characteristics of coronary heart disease (CHD) hospital admiss...
Incidence of Atrial Fibrillation in Elite Athletes
Authors: Araceli Boraita, Alejandro Santos-Lozano, María E. Heras, Florencia González-Amigo, Susana López-Ortiz, Julián P. Villacastín, Alejandro Lucia
Journal: JAMA Cardiology (2018)

Vigorous exercise (particularly endurance sports) might increase the risk of atrial fibrillation (AF), but there is variability in the reported frequency of this condition among elite athletes. The underlying pathophysiologic source remains unclear.To determine AF incidence in a large cohort of elite athletes and its association with potential risk factors.Retrospective observational cohort of all Spanish athletes (N = 6813) referred to a single center was used to determine AF incidence from January 1, 1997, to December 31, 2017, and cross-sectional analysis was conducted to compare athletes with and without reported AF. The cohort covered most sports disciplines, and the studied athletes were on national teams and competed in major international events. Cardiologists responsible for echocardiographic assessment were not blinded to the condition (AF or no AF) of the athletes.All participants underwent at least 1 cardiologic evaluation, including assessment at time of AF diagnosis in those with this condition.Diagnosis of AF based on resting and/or exercise electrocardiogram, and/or 24-hour Holter monitoring and echocardiography-assessed atrial dimensions.A total of 6813 Spanish elite athletes (2385 [35.0%] women) were referred for cardiac evaluation during the study period. Mean (SD) age was 22 (7) years, and mean (SD) time of competition was 8 (5) years. Only 21 athletes (1 woman), participating in different types of sports, had AF (ie, paroxysmal [n = 18], persistent [n = 1], or long-standing persistent [n = 2]) during the 20-year study. In multivariate analysis, increasing values of age (odds ratio [OR], 1.07; 95% CI, 1.00-1.14), years of competition (OR, 1.14; 95% CI, 1.07-1.22), and left atrial anteroposterior diameter (OR, 1.21; 95% CI, 1.10-1.32) were associated with higher AF risk.The incidence of AF is low among young Spanish elite athletes, even when considering only endurance athletes. Yet, potential contributors (particularly atrial remodeling) need to be monitored.
Non–Clear Cell Renal Cell Carcinomas: From Shadow to Light
Authors: Laurence Albiges, Ronan Flippot, Nathalie Rioux-Leclercq, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2018)

Non-clear cell renal cell carcinomas (RCCs) account for up to 25% of kidney cancers and encompass distinct diseases with distinct pathologic features, different molecular alterations, and various patterns of response to systemic therapies. Recent advances in molecular biology and large collaborative efforts helped to better define the oncogenic mechanisms at play in papillary, chromophobe, collecting duct, medullary, translocation, and sarcomatoid RCCs. Papillary RCCs are divided into several subsets of tumors characterized by distinct gene expression profiles, chromatin remodeling genes, cell cycle changes, and alterations of the MET pathway. Chromophobe RCC genomic analysis revealed mostly metabolic pathway alterations with mitochondrial dysfunctions. Translocation RCCs are characterized by MITF fusions and wide genomic reprogramming. Collecting duct carcinomas are distinct entities from upper tract urothelial carcinomas associated with high T-cell infiltration and metabolic alterations. Medullary RCCs present alterations of the INI1 gene and rhabdoid features at pathologic analysis. Finally, sarcomatoid RCCs represent sarcomatoid differentiation for any subsets of RCCs with specific alterations associated with mesenchymal dedifferentiation. From the standpoint of systemic therapy, more than a decade of using VEGF and mTOR inhibitors showed that they generally had limited efficacy in non-clear cell RCCs compared with clear cell RCCs. MET inhibitors are actively being developed for papillary RCC with a specific focus on MET-driven tumors. Other strategies under investigation include CDK4/6 inhibitors in tumors with cell cycle alterations and EZH2 inhibitors in RCCs with INI1 loss. The emergence of immune checkpoint inhibitors and combination strategies enlarges the spectrum of investigational treatments. Better understanding of driver and passenger alterations and better patient stratification along with dedicated clinical networks will be key to improving the management of these rare tumors.
TLR-stimulated IRAKM activates caspase-8 inflammasome in microglia and promotes neuroinflammation
Authors: Cun-Jin Zhang, Meiling Jiang, Hao Zhou, Weiwei Liu, Chenhui Wang, Zizhen Kang, Bing Han, Quanri Zhang, Xing Chen, Jianxin Xiao, Amanda Fisher, William J. Kaiser, Masanori A. Murayama, Yoichiro Iwakura, Ji Gao, Julie Carman, Ashok Dongre, George Dubyak, Derek W. Abbott, Fu-Dong Shi, Richard M. Ransohoff, Xiaoxia Li
Journal: Journal of Clinical Investigation (2018)

NLRP3 inflammasome plays a critical spatiotemporal role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). This study reports a mechanistic insight into noncanonical NLRP3 inflammasome activation in microglia for the effector stage of EAE. Microglia-specific deficiency of ASC (apoptosis-associated speck-like protein containing a C-terminal caspase-activation and recruitment [CARD] domain) attenuated T cell expansion and neutrophil recruitment during EAE pathogenesis. Mechanistically, TLR stimulation led to IRAKM–caspase-8–ASC complex formation, resulting in the activation of caspase-8 and IL-1β release in microglia. Noncanonical inflammasome-derived IL-1β produced by microglia in the CNS helped to expand the microglia population in an autocrine manner and amplified the production of inflammatory cytokines/chemokines. Furthermore, active caspase-8 was markedly increased in the microglia in the brain tissue from patients with multiple sclerosis. Taken together, our study suggests that microglia-derived IL-1β via noncanonical caspase-8–dependent inflammasome is necessary for microglia to exert their pathogenic role during CNS inflammation.
Vibration-Controlled Transient Elastography for Diagnosing Cirrhosis and Staging Hepatic Fibrosis
Authors: Julius Wilder, Steve S. Choi, Cynthia A. Moylan
Journal: JAMA (2018)

A 68-year-old man has an undetectable hepatitis C (HCV) viral load, normal liver function tests, and an elevated vibration-controlled transient elastography (VCTE) measure after 12 weeks of antiviral treatment for HCV with stage 2 fibrosis by biopsy. How do you interpret the results?
Neuronal PAS domain 2 (Npas2) facilitated osseointegration of titanium implant with rough surface through a neuroskeletal mechanism
Authors: Kenzo Morinaga, Hodaka Sasaki, Sil Park, Akishige Hokugo, Hiroko Okawa, Yu Tahara, Christopher S. Colwell, Ichiro Nishimura
Journal: Biomaterials (2018)
Bullying in the workplace: almost 40% of doctors think it is a problem, BMA finds
Authors: Abi Rimmer
Journal: BMJ (2018)

Over a third of doctors think that bullying, undermining, or harassment is a problem at their main place of work, which some say seriously affects their personal and working lives, a BMA survey has found.1

In the survey of 7887 UK doctors 10% said that there was “often” a problem with bullying, undermining, or harassment in their workplace, and 29% thought that these were an issue “sometimes.”

Over two thirds (65%) of respondents said that pressure of work was the main cause of bullying, and over half (58%) thought that it was difficult to …
Abstract 11257: Physiologic Quantification of the Diastolic Pressure Difference Re-classifies Pulmonary Hypertension in Patients With Advanced Heart Failure
Authors: Stephen P Wright, Geraldine Paradero, Suhail Agarwal, Yas Moayedi, Farid Foroutan, Ana Carolina Alba, Jay Baumwol, Susanna Mak
Journal: Circulation (2016)

Introduction: Assessment of pulmonary hypertension (PH) by right heart catheterization remains important in the evaluation of advanced heart failure (HF) patients being considered for cardiac transplant. Delineating ‘isolated’ post-capillary PH (Ipc-PH) and ‘combined’ pre- and post-capillary PH (Cpc-PH) remains a challenge in hemodynamic assessment, as the usual practice of calculating the diastolic pressure difference (DPD) has limitations pre-disposing it to underestimation. Hypothesis: QRS-gated calculation of the DPD (QRS-DPD), specific to late diastole when the DPD is expected to be small, will reduce the frequency of negative DPD values, and re-classify a subset of patients as Cpc-PH. Methods: Advanced HF patients (n = 136, median age = 56 years) referred for right heart catheterization within the clinical evaluation for cardiac transplant candidacy were studied. Hemodynamics were analyzed offline and measurements were averaged over 8-10 beat intervals. Automated measurements of systolic/diastolic/mean pulmonary artery pressure (sPAP/dPAP/mPAP), and mean pulmonary artery wedge pressure (mPAWP) were generated as per usual practice. Usual practice DPD (UP-DPD) was calculated as [dPAP – mPAWP]. Within the same intervals, pulmonary artery pressure (QRS-PAP) and pulmonary artery wedge pressure (QRS-PAWP) gated to the QRS-onset were manually measured for each beat and averaged. QRS-DPD was calculated as [QRS-PAP – QRS-PAWP]. Results: The mean UP-DPD was 0 ± 5 mmHg, and was &lt;0 mmHg in 61/136 cases (45%). The mean QRS-DPD was 5 ± 4 mmHg, and was &lt;0 mmHg in 10/136 cases (7%) (p &lt; 0.05). Of 136 cases, 67 (49%) demonstrated mPAP ≥25 mmHg and mPAWP &gt;15 mmHg. Using the UP-DPD classified 4/67 as Cpc-PH (DPD ≥7 mmHg), while the QRS-DPD classified 22/67 as Cpc-PH (p &lt; 0.05). Conclusions: QRS-gated measurements increase the calculated DPD, and reduce the frequency of negative values. In advanced HF patients with PH, up to 25% of Ipc-PH cases may be re-classified as Cpc-PH.
Lyra: A Phase 2 Study of Daratumumab (Dara) Plus Cyclophosphamide, Bortezomib, and Dexamethasone (Cybord) in Newly Diagnosed and Relapsed Patients (Pts) with Multiple Myeloma (MM)
Authors: Habte Yimer, Jason Melear, Edward Faber, William Bensinger, John M Burke, Mohit Narang, Don Stevens, Sriya W. Gunawardena, Yana Lutska, Keqin Qi, Jon Ukropec, Ming Qi, Thomas Lin, Robert M Rifkin
Journal: Blood (2018)
Enhancement of antitumor potency of extracellular vesicles derived from natural killer cells by IL-15 priming
Authors: Liya Zhu, Senthilkumar Kalimuthu, Ji Min Oh, Prakash Gangadaran, Se Hwan Baek, Shin Young Jeong, Sang-Woo Lee, Jaetae Lee, Byeong-Cheol Ahn
Journal: Biomaterials (2018)
Abstract 16953: Role of the Fast Transient Outward Current Ito,f in Shaping Action Potential Waveforms in Human iPSC-derived Cardiomyocytes
Authors: Scott Marrus, Steven Springer, Rita Martinez, Edward Dranoff, Rebecca Mellor, Anna Zhang, Evelyn Kanter, Kathryn Yamada, Jeanne Nerbonne
Journal: Circulation (2014)

Abnormalities of a key repolarizing cardiac potassium current, the fast transient outward potassium current, I to,f , are associated with both heart failure and congenital arrhythmia syndromes. However, the precise role of I to,f in shaping action potential waveforms remains unclear. This study was designed to define the functional role of the fast transient outward potassium current, I to,f , in shaping action potentials in human iPSC-derived cardiomyocytes (iPSC-CMs). Most iPSC-CMs (29 of 43 cells) demonstrated spontaneous electrical activity, slow upstroke velocity (63±71 V/s), a wide range of action potential durations (APD90 = 860±722 ms) and heterogeneous action potential waveforms. Using dynamic current clamp, a modeled human ventricular inwardly rectifying K + current, I K1 , was introduced into iPSC-CMs, resulting in silencing of spontaneous activity, hyperpolarization of the resting membrane potential (RMP = -90±3 mV), increased peak upstroke velocity (dV/dt = 346±71 V/s) and decreased APD90 (420±211 ms) to values similar to those recorded in isolated adult human ventricular myocytes (RMP = -84±3 mV, dV/dt = 348±101 V/s and APD90 = 468±133 ms, all p&gt;0.05). Importantly, a ventricular-like action potential waveform was observed in 25 of the 26 cells studied following the dynamic clamp addition of I K1 . Using these cells as a model of human ventricular myocytes, further dynamic current clamp experiments introduced a modeled human fast transient outward K + current, I to,f , and revealed that increasing in the amplitude of I to,f results in an increase in the phase 1 notch and a progressive shortening of the action potential duration in iPSC-CMs. Together, the experiments here demonstrate that combining human iPSC-CMs with the power of the dynamic current clamp technique to modulate directly and precisely the “expression” of individual ionic currents provides a novel and quantitative approach to defining the roles of specific ionic conductances in regulating the excitability of human cardiomyocytes.
Response to: ‘Knee osteoarthritis and bisphosphonates: Could BCP crystals be the missing link?’ by Murphy <i>et al</i>
Authors: Willem Lems
Journal: Annals of the Rheumatic Diseases (2018)

Response to: 'Knee osteoarthritis and bisphosphonates: Could BCP crystals be the missing link?' by Murphy et al I read with great interest the letter from Murphy and McCarthy 1 : 'knee osteoarthritis and bisphosphonates: could BCP crystals be the missing link?'. 1 I recently gave comments on two case-control studies, 2 in which the need for a total knee prosthesis was around 25% lower in bisphosphonate (BP) users than in controls. 3 4What could be the explanation?It could be related to epidemiology: BP-users have a healthier lifestyle than non-users, by doing more exercise therapy, preventing overweight and so on.The other option is a biological effect, for example, an effect of BPs on the underlying subchondral bone in patients with osteoarthritis (OA). 5urphy and McCarthy bring in that BPs have a strong affinity for basic crystal phosphates (BCPs) and that this might inhibit inflammatory reactions in the synovial fluid. 1 They argued that BCPs have been found in the cartilage of 100% of patients with OA at the time of joint replacement and that BCPs might contribute to inflammation in OA.Although this is certainly a valuable suggestion, the incidence of clinically manifest knee-osteoarthritis based on BCP-crystals is low in patients with OA.Since knee-OA is a whole joint disease, cartilage, bone, synovial inflammation and muscular weakness all play a role, 6 it is very likely that other factors are among the mean determinants of inflammation and pain in patients with knee-OA.So, BCP-crystals are probably not 'the' missing link, but might be a' missing link.Nevertheless, since the pathogenesis of OA is not fully elucidated and therapeutic options are scarce, further research in the direction of BCPs and BPs in patients with knee-OA is very welcome.
Combined Hepatocellular–Cholangiocarcinoma in a Patient With Cirrhosis Due to Cholesteryl Ester Storage Disease
Authors: Graciela Elia Castro Narro, Armando Gamboa Domínguez, Alejandra Consuelo Sánchez, Abel Salazar Martínez, Jose Agramonte Hevia, J.J. Cebolla, Miguel Enrique Cuellar Mendoza, Héctor Adrián Díaz Hernández
Journal: Hepatology (2018)

Castro Narro, Graciela Elia; Gamboa Domínguez, Armando; Consuelo Sánchez, Alejandra; Salazar Martínez, Abel; Agramonte Hevia, Jose; Cebolla, J.J.; Cuellar Mendoza, Miguel Enrique; Díaz Hernández, Héctor Adrián Author Information