tbuckley/cabot-search huggingface dataset:
Abstract 17278: Concomitant Use of Ivabradine in the Setting of Cardiogenic Shock: A Case Series
Authors: Michael H Chiu, Jonathan G Howlett, Nakul C Sharma
Journal: Circulation (2018)

Background: Ivabradine, a selective sinus node inhibitor, is indicated for patients with chronic heart failure with reduced ejection fraction (HFrEF). Use in cardiogenic shock is currently contraindicated. However, studies have suggested increasing heart rate may be deleterious for patients with HFrEF due to an inverted Bowditch-Treppe response. Limited case series have suggested use of Ivabradine in decompensated HFrEF may be beneficial. We present a case series of patients who presented with severely decompensated HFrEF and received inotropic support and concomitant ivabradine. Methods: We selected four patients with HFrEF presenting with elevated sinus heart rate and cardiogenic shock (cardiac index &lt;2.0L/min*m2with pulmonary artery wedge pressure &gt; 20 mmHg by invasive hemodynamic monitoring) while on inotropic therapy and were intolerant of beta blockade due to hypotension. Ivabradine 2.5 mg 12 h was initiated and subsequently titrated with continued monitoring with baseline, 24 h and latest obtained parameters recorded. Other treatments occurred at the discretion of the attending physician. Results: Four male patients (mean age 44 years) with non-ischemic cardiomyopathy (mean EF 17%, mean NT-pro-BNP 5104 pg/ml) were included. Ivabradine was tolerated in all cases, with a mean dose of 6 mg q12h. Mean heart rate and pulmonary wedge pressure fell 20% and 32% respectively from baseline to last measurement, while stroke volume increased with an overall improvement in cardiac index. (Table 1) There were no changes noted in mean arterial blood pressure. All patients underwent successful wean of inotropic support within 48 hours and were discharged alive on beta blocker and ACE inhibitor therapy. No adverse events attributed to use of Ivabradine were observed. Conclusion: In our small series of patients with cardiogenic shock, beta blocker intolerance and elevated sinus heart rate, Ivabradine was added without any deleterious hemodynamic effect and associated with early clinical improvement. Further studies are needed to better assess its potential use in this population.
Abstract A26: Molecular analysis of short- vs. long-term ovarian cancer survivors
Authors: Elaine Stur, Graziela Zibetti Dal Molin, Sherry Wu, Keith Baggerly, Shelley Tworoger, Douglas Levine, Beth Karlan, Kathleen Moore, Susan Lutgendorf, Anil Sood
Journal: Clinical Cancer Research (2020)

Abstract Background: High-grade serous ovarian carcinomas (HGSOC) comprise the majority of ovarian cancer cases and usually present at diagnosis with late stages of disease. Despite having similar histology, patients with HGSOC often experience highly variable outcomes. The underlying determinants for long-term (LT- ≥10 years) versus short-term (ST- &amp;lt;3 years) survival are largely unknown. The present study sought to identify molecular predictors of LT survival for women with HGSOC. To achieve this, we used deep molecular analysis of tumors from LT and ST survival patients of HGSOC. Methods: For the discovery tumor cohort, RNA sequencing was conducted on twenty-four (24) frozen samples HGSOC tumors (12 from LT and 12 from ST survivors). A validation cohort included 29 samples (15 from LT and 14 from ST survivors). In vitro studies were carried out using OVCAR8 and SKOV3 cell lines. Results: From RNAseq analysis, a total of 11 genes were differentially expressed between ST and LT survivors (fold change &amp;gt;2, p &amp;lt; 1 × 10-5, FDR &amp;lt;0.01). A secondary screen was used to eliminate genes that were expressed below threshold levels (fold change &amp;gt;2). Three genes were overexpressed in LT survivors; one had sufficient expression for future therapeutic benefit—TMEM62. In the subsequent validation cohort, TMEM62 had the most significant result of the initial genes of interest, with qRT-PCR data demonstrating an average 3.0-fold higher expression of TMEM62 mRNA in LT versus ST survivors. Next, OVCAR8 and SKOV3 ovarian cancer cells were transfected with TMEM62 using a bacterial plasmid; increased expression of TMEM62 led to decreased proliferation (OVCAR8 73%; SKOV3: 33%), invasion (OVCAR8: 73%; SKOV3: 33%), and a slight decrease in migration (about 2%) in both cell lines. Using a protein array, a decrease in chemokines in SKOV3 cells (MIF, Serpin E1, IL6, CXCL7, IL8, Midkine, and CXCL1) was observed, suggesting that increased TMEM62 expression may lead to reduced tumor inflammatory markers. Conclusion: Our results demonstrate that TMEM62 may be a novel treatment target for HGSOC given its much higher expression in those patients who achieve long-term survival. These findings may have implications for biomarker and intervention strategies to help improve patient outcomes. Citation Format: Elaine Stur, Graziela Zibetti Dal Molin, Sherry Wu, Keith Baggerly, Shelley Tworoger, Douglas Levine, Beth Karlan, Kathleen Moore, Susan Lutgendorf, Anil Sood. Molecular analysis of short- vs. long-term ovarian cancer survivors [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A26.
Systemic Amyloidosis Recognition, Prognosis, and Therapy
Authors: Morie A. Gertz, Angela Dispenzieri
Journal: JAMA (2020)

Many patients with systemic amyloidosis are underdiagnosed. Overall, 25% of patients with immunoglobulin light chain (AL) amyloidosis die within 6 months of diagnosis and 25% of patients with amyloid transthyretin (ATTR) amyloidosis die within 24 months of diagnosis. Effective therapy exists but is ineffective if end-organ damage is severe.To provide evidence-based recommendations that could allow clinicians to diagnose this rare set of diseases earlier and enable accurate staging and counseling about prognosis.A comprehensive literature search was conducted by a reference librarian with publication dates from January 1, 2000, to December 31, 2019. Key search terms included amyloid, amyloidosis, nephrotic syndrome, heart failure preserved ejection fraction, and peripheral neuropathy. Exclusion criteria included case reports, non-English-language text, and case series of fewer than 10 patients. The authors independently selected and appraised relevant literature.There was a total of 1769 studies in the final data set. Eighty-one articles were included in this review, of which 12 were randomized clinical trials of therapy that included 3074 patients, 9 were case series, and 3 were cohort studies. The incidence of AL amyloidosis is approximately 12 cases per million persons per year and there is an estimated prevalence of 30 000 to 45 000 cases in the US and European Union. The incidence of variant ATTR amyloidosis is estimated to be 0.3 cases per year per million persons with a prevalence estimate of 5.2 cases per million persons. Wild-type ATTR is estimated to have a prevalence of 155 to 191 cases per million persons. Amyloidosis should be considered in the differential diagnosis of adult nondiabetic nephrotic syndrome; heart failure with preserved ejection fraction, particularly if restrictive features are present; unexplained hepatomegaly without imaging abnormalities; peripheral neuropathy with distal sensory symptoms, such as numbness, paresthesia, and dysesthesias (although the autonomic manifestations occasionally may be the presenting feature); and monoclonal gammopathy of undetermined significance with atypical clinical features. Staging can be performed using blood testing only. Therapeutic decision-making for AL amyloidosis involves choosing between high-dose chemotherapy and stem cell transplant or bortezomib-based chemotherapy. There are 3 therapies approved by the US Food and Drug Administration for managing ATTR amyloidosis, depending on clinical phenotype.All forms of amyloidosis are underdiagnosed. All forms now have approved therapies that have been demonstrated to improve either survival or disability and quality of life. The diagnosis should be considered in patients that have a multisystem disorder involving the heart, kidney, liver, or nervous system.
Non-adherence in non-inferiority trials: pitfalls and recommendations
Authors: Yin Mo, Cherry Lim, James A Watson, Nicholas J White, Ben S Cooper
Journal: BMJ (2020)

Non-adherence in non-inferiority trials can affect treatment effect estimates and often increases the chance of claiming non-inferiority under the standard intention-to-treat analysis. This article discusses the implications of different patterns of non-adherence in non-inferiority trials and offers practical recommendations for trial design, alternative analysis strategies, and outcome reporting to reduce bias in treatment estimates and improve transparency in reporting.
Association of SPOP Mutations with Outcomes in Men with De Novo Metastatic Castration-sensitive Prostate Cancer
Authors: Umang Swami, Pedro Isaacsson Velho, Roberto Nussenzveig, Jonathan Chipman, Victor Sacristan Santos, Stephanie Erickson, Divya Dharmaraj, Ajjai Shivaram Alva, Ulka N. Vaishampayan, John Esther, Andrew W. Hahn, Benjamin Louis Maughan, Emmanuel S. Antonarakis, Neeraj Agarwal
Journal: European Urology (2020)
Government’s “new deal” does not erase years of underinvestment in NHS buildings, say leaders
Authors: Gareth Iacobucci
Journal: BMJ (2020)

The UK prime minister, Boris Johnson, has promised to accelerate £1.5bn (€1.66bn; $1.86bn) of funding for new buildings in the NHS as part of his “new deal” to help the country recover from covid-19.

He said that the money would accelerate hospital maintenance, eradicating mental health dormitories, enabling hospital building, and improving emergency department capacity.1

Healthcare leaders welcomed the announcement but warned that the government faced an uphill challenge to deliver, given the years of underinvestment that had left …
Basic and Therapeutic Aspects of Angiogenesis Updated
Authors: Guy Eelen, Lucas Treps, Xuri Li, Peter Carmeliet
Journal: Circulation Research (2020)

All organisms growing beyond the oxygen diffusion limit critically depend on a functional vasculature for survival. Yet blood vessels are far more than passive, uniform conduits for oxygen and nutrient supply. A remarkable organotypic heterogeneity is brought about by tissue-specific differentiated endothelial cells (lining the blood vessels’ lumen) and allows blood vessels to deal with organ-specific demands for homeostasis. On the flip side, when blood vessels go awry, they promote life-threatening diseases characterized by endothelial cells inappropriately adopting an angiogenic state (eg, tumor vascularization) or becoming dysfunctional (eg, diabetic microvasculopathies), calling respectively for antiangiogenic therapies and proangiogenic/vascular regenerative strategies. In solid tumors, despite initial enthusiasm, growth factor–based (mostly anti-VEGF [vascular endothelial growth factor]) antiangiogenic therapies do not sufficiently live up to the expectations in terms of efficiency and patient survival, in part, due to intrinsic and acquired therapy resistance. Tumors cunningly deploy alternative growth factors than the ones targeted by the antiangiogenic therapies to reinstigate angiogenesis or revert to other ways of securing blood flow, independently of the targeted growth factors. In trying to alleviate tissue ischemia and to repair dysfunctional or damaged endothelium, local in-tissue administration of (genes encoding) proangiogenic factors or endothelial (stem) cells harnessing regenerative potential have been explored. Notwithstanding evaluation in clinical trials, these approaches are often hampered by dosing issues and limited half-life or local retention of the administered agents. Here, without intending to provide an all-encompassing historical overview, we focus on some recent advances in understanding endothelial cell behavior in health and disease and identify novel molecular players and concepts that could eventually be considered for therapeutic targeting.
Identification of cell type-specific methylation signals in bulk whole genome bisulfite sequencing data
Authors: C. Anthony Scott, Jack D. Duryea, Harry MacKay, Maria S. Baker, Eleonora Laritsky, Chathura J. Gunasekara, Cristian Coarfa, Robert A. Waterland
Journal: Genome biology (2020)

The traditional approach to studying the epigenetic mechanism CpG methylation in tissue samples is to identify regions of concordant differential methylation spanning multiple CpG sites (differentially methylated regions). Variation limited to single or small numbers of CpGs has been assumed to reflect stochastic processes. To test this, we developed software, Cluster-Based analysis of CpG methylation (CluBCpG), and explored variation in read-level CpG methylation patterns in whole genome bisulfite sequencing data.Analysis of both human and mouse whole genome bisulfite sequencing datasets reveals read-level signatures associated with cell type and cell type-specific biological processes. These signatures, which are mostly orthogonal to classical differentially methylated regions, are enriched at cell type-specific enhancers and allow estimation of proportional cell composition in synthetic mixtures and improved prediction of gene expression. In tandem, we developed a machine learning algorithm, Precise Read-Level Imputation of Methylation (PReLIM), to increase coverage of existing whole genome bisulfite sequencing datasets by imputing CpG methylation states on individual sequencing reads. PReLIM both improves CluBCpG coverage and performance and enables identification of novel differentially methylated regions, which we independently validate.Our data indicate that, rather than stochastic variation, read-level CpG methylation patterns in tissue whole genome bisulfite sequencing libraries reflect cell type. Accordingly, these new computational tools should lead to an improved understanding of epigenetic regulation by DNA methylation.
Lean Americans With Nonalcoholic Fatty Liver Disease Have Lower Rates of Cirrhosis and Comorbid Diseases
Authors: Ethan M. Weinberg, Huy N. Trinh, Roberto J. Firpi, Kalyan Ram Bhamidimarri, Samuel Klein, Jonathan Durlam, Stephanie Watkins, K. Rajender Reddy, Michael Weiss, Richard C. Zink, Anna S. Lok
Journal: Clinical Gastroenterology and Hepatology (2020)
FDG PET/CT Suggesting Pulmonary Artery Involvement of Takayasu Arteritis
Authors: Yong Liu, Guansheng Tong, Zhe Wen
Journal: Clinical Nuclear Medicine (2020)

Abstract Pulmonary artery involvement can occur in about half of the patients suffering Takayasu arteritis. Increased FDG activity in the aorta and its main branches in patients with Takayasu arteritis on PET/CT had been well-reported. However, the FDG PET/CT appearance of pulmonary artery involvement in Takayasu arteritis is less known. We present FDG PET/CT findings in a 37-year-old patient with known Takayasu arteritis. The images showed rim-like FDG activity in opacities in the left lung, which was later proven due to narrowed left main pulmonary artery.
Survival outcome of palliative primary tumor resection for colorectal cancer patients with synchronous liver and/or lung metastases: A retrospective cohort study in the SEER database by propensity score matching analysis
Authors: Xianzhe Chen, Weixian Hu, Chengzhi Huang, Weijun Liang, Jie Zhang, Deqing Wu, Zejian Lv, Yong Li, Yuwen Luo, Zongyu Liang, Minjia Wang, Junjiang Wang, Xueqing Yao
Journal: International Journal of Surgery (2020)
Haploidentical transplants for patients with relapse after the first allograft
Authors: Samer A. Srour, Piyanuch Kongtim, Gabriela Rondon, Julianne Chen, Demetrios Petropoulos, Jeremy Ramdial, Uday Popat, Partow Kebriaei, Muzaffar Qazilbash, Elizabeth J. Shpall, Richard E. Champlin, Stefan O. Ciurea
Journal: American Journal of Hematology (2020)

Relapse after allogeneic hematopoietic stem-cell transplantation (AHSCT) is associated with very poor outcomes. A second transplant offers the possibility of long-term disease control. We analyzed outcomes with haploidentical donors for second allograft at our institution. All consecutive patients with hematological malignancies (N = 29) who relapsed after AHSCT and underwent a haploidentical transplant (haploSCT) as second transplant between February 2009 and October 2018 were included. Median age was 36 years (interquartile range (IQR) 24-60); 83% of patients had high/very high disease risk index; 61% of AML/MDS patients had high-risk cytogenetics; and only 24% were in complete remission at transplant. With a median follow-up of 46.9 months, the 3-year relapse, non-relapse mortality (NRM), progression-free survival (PFS) and overall survival (OS) were 30%, 39%, 31% and 40%, respectively. In multivariable analysis (MVA), comorbidity index (HCT-CI) and detectable donor-specific anti-HLA antibodies (DSA) prior to second transplant were significantly associated with worse outcomes. Patients with HCT-CI <3 and without DSA had 3-year PFS and OS of 53% and 60.3%, respectively. Our findings suggest that haploSCT as second AHSCT is feasible and potentially curative. Lower HCT-CI and no DSA were associated with lower NRM and improved survival. Haploidentical grafts might be a preferred donor source for second AHSCT as these are high-risk patients who frequently need to proceed urgently to transplant.
Decoding the evolutionary response to prostate cancer therapy by plasma genome sequencing
Authors: Naveen Ramesh, Emi Sei, Pei Ching Tsai, Shanshan Bai, Yuehui Zhao, Patricia Troncoso, Paul G. Corn, Christopher Logothetis, Amado J. Zurita, Nicholas E. Navin
Journal: Genome biology (2020)

Investigating genome evolution in response to therapy is difficult in human tissue samples. To address this challenge, we develop an unbiased whole-genome plasma DNA sequencing approach that concurrently measures genomic copy number and exome mutations from archival cryostored plasma samples. This approach is applied to study longitudinal blood plasma samples from prostate cancer patients, where longitudinal tissue biopsies from the bone and other metastatic sites have been challenging to collect. A molecular characterization of archival plasma DNA from 233 patients and genomic profiling of 101 patients identifies clinical correlations of aneuploid plasma DNA profiles with poor survival, increased plasma DNA concentrations, and lower plasma DNA size distributions. Deep-exome sequencing and genomic copy number profiling are performed on 23 patients, including 9 patients with matched metastatic tissues and 12 patients with serial plasma samples. These data show a high concordance in genomic alterations between the plasma DNA and metastatic tissue samples, suggesting the plasma DNA is highly representative of the tissue alterations. Longitudinal sequencing of 12 patients with 2–5 serial plasma samples reveals clonal dynamics and genome evolution in response to hormonal and chemotherapy. By performing an integrated evolutionary analysis, minor subclones are identified in 9 patients that expanded in response to therapy and harbored mutations associated with resistance. This study provides an unbiased evolutionary approach to non-invasively delineate clonal dynamics and identify clones with mutations associated with resistance in prostate cancer.
Novel ultrasmall multifunctional nanodots for dual-modal MR/NIR-II imaging-guided photothermal therapy
Authors: Fenfen Li, Tuanwei Li, Debo Zhi, Pengping Xu, Wenshen Wang, Yi Hu, Yuanyuan Zhang, Shaozhen Wang, J. Matula Thomas, J. Beauchamp Norman, Weiping Ding, Lifeng Yan, Bensheng Qiu
Journal: Biomaterials (2020)
KRASQ61H Preferentially Signals through MAPK in a RAF Dimer-Dependent Manner in Non–Small Cell Lung Cancer
Authors: Zhi-Wei Zhou, Chiara Ambrogio, Asim K. Bera, Qing Li, Xing-Xiao Li, Lianbo Li, Jieun Son, Sudershan Gondi, Jiaqi Li, Emily Campbell, Hua Jin, Jeffrey J. Okoro, Cheng-Xiong Xu, Pasi A. Janne, Kenneth D. Westover
Journal: Cancer Research (2020)

Abstract Assembly of RAS molecules into complexes at the cell membrane is critical for RAS signaling. We previously showed that oncogenic KRAS codon 61 mutations increase its affinity for RAF, raising the possibility that KRASQ61H, the most common KRAS mutation at codon 61, upregulates RAS signaling through mechanisms at the level of RAS assemblies. We show here that KRASQ61H exhibits preferential binding to RAF relative to PI3K in cells, leading to enhanced MAPK signaling in in vitro models and human NSCLC tumors. X-ray crystallography of KRASQ61H:GTP revealed that a hyperdynamic switch 2 allows for a more stable interaction with switch 1, suggesting that enhanced RAF activity arises from a combination of absent intrinsic GTP hydrolysis activity and increased affinity for RAF. Disruption of KRASQ61H assemblies by the RAS oligomer–disrupting D154Q mutation impaired RAF dimerization and altered MAPK signaling but had little effect on PI3K signaling. However, KRASQ61H oligomers but not KRASG12D oligomers were disrupted by RAF mutations that disrupt RAF–RAF interactions. KRASQ61H cells show enhanced sensitivity to RAF and MEK inhibitors individually, whereas combined treatment elicited synergistic growth inhibition. Furthermore, KRASQ61H tumors in mice exhibited high vulnerability to MEK inhibitor, consistent with cooperativity between KRASQ61H and RAF oligomerization and dependence on MAPK signaling. These findings support the notion that KRASQ61H and functionally similar mutations may serve as predictive biomarkers for targeted therapies against the MAPK pathway. Significance: These findings show that oncogenic KRASQ61H forms a cooperative RAS–RAF ternary complex, which renders RAS-driven tumors vulnerable to MEKi and RAFi, thus establishing a framework for evaluating RAS biomarker-driven targeted therapies.
Abstract 11999: Effect of Ticagrelor With or Without Aspirin on Saphenous Vein Graft Patency One Year After Coronary-Artery Bypass Surgery Under Different Baseline Levels of Low-Density Lipoprotein Cholesterol: A Post-Hoc Analysis of the DACAB Trial (DACAB-LDL)
Authors: Jiaxi Zhu, Yunpeng Zhu, Minlu Zhang, Qiang Zhao
Journal: Circulation (2018)

Objective: The post-hoc analysis aimed to explore the effect of ticagrelor plus aspirin (T+A) or ticagrelor alone (T) vs aspirin alone (A) on saphenous vein (SV) graft patency 1 year after coronary...