tbuckley/cabot-search huggingface dataset:
Natural History of Asymptomatic Severe Aortic Stenosis and the Association of Early Intervention With Outcomes
Authors: Brigitta Gahl, Mevlüt Çelik, Stuart J. Head, Jean-Louis Vanoverschelde, Philippe Pibarot, Michael J. Reardon, Nicolas M. van Mieghem, A. Pieter Kappetein, Peter Jüni, Bruno R. da Costa
Journal: JAMA Cardiology (2020)

<h3>Importance</h3> Whether intervention should be performed in patients with asymptomatic severe aortic stenosis (AS) remains debated. <h3>Objective</h3> To meta-analyze the natural history of asymptomatic severe AS and examine the association of early intervention with survival. <h3>Data Sources</h3> PubMed, Embase, and Cochrane databases were searched from inception to February 1, 2020. <h3>Study Selection</h3> Observational studies of adult patients with asymptomatic severe AS. <h3>Data Extraction and Synthesis</h3> Two investigators independently extracted study and patient characteristics, follow-up time, events, and prognostic indicators of events. Random-effects models were used to derive pooled estimates. <h3>Main Outcomes and Measures</h3> The meta-analysis on natural history was performed on the primary end point of all-cause death occurring during a conservative treatment period, with secondary end points consisting of cardiac death, death due to heart failure, sudden death, development of symptoms, development of an indication for aortic valve intervention, and aortic valve intervention. The primary end point for the meta-analysis of early intervention vs a conservative strategy was all-cause death during long-term follow-up. Finally, meta-analysis was performed on the association of prognostic indicators with the composite of death or aortic valve intervention found in multivariable models. <h3>Results</h3> A total of 29 studies with 4075 patients with 11 901 years of follow-up were included. Pooled rates per 100 patients per year were 4.8 (95% CI, 3.6-6.4) for all-cause death, 3.0 (95% CI, 2.2-4.1) for cardiac death, 2.0 (95% CI, 1.3-3.1) for death due to heart failure, 1.1 (95% CI, 0.6-2.1) for sudden death, 18.1 (95% CI, 12.8-25.4) for an indication for aortic valve intervention, 18.5 (95% CI, 13.4-25.5) for development of symptoms, and 19.2 (95% CI, 15.5-23.8) for aortic valve intervention. Early intervention was associated with a significant reduction in long-term mortality (hazard ratio, 0.38; 95% CI, 0.25-0.58). Factors associated with worse prognosis were severity of AS, low-flow AS, left ventricular damage, and atherosclerotic risk factors. <h3>Conclusions and Relevance</h3> Data from observational studies and a recent randomized clinical trial suggest that many patients with asymptomatic severe AS develop an indication for aortic valve intervention, and their deaths are mostly cardiac but not only sudden. Other end points besides sudden death should be considered during the decision to perform early intervention that are associated with improved survival.
Coronavirus Disease 2019 (COVID-19) and Cardiac Injury
Authors: Kevin S. Heffernan, Erin D. Michos, Brooks B. Gump
Journal: JAMA Cardiology (2020)

Shaobo Shi, MD; Mu Qin, MD; Bo Shen, MD; Yuli Cai, MD; Tao Liu, MD; Fan Yang, MD; Wei Gong, MMSC; Xu Liu, MD, PhD; Jinjun Liang, MD, PhD; Qinyan Zhao, MD, PhD; He Huang, MD, PhD; Bo Yang, MD, PhD; Congxin Huang, MD, PhD
Cancer stromal targeting therapy to overcome the pitfall of EPR effect
Authors: Yasuhiro Matsumura
Journal: Advanced Drug Delivery Reviews (2020)

Many animal experiments performed worldwide have proven EPR effects However, it is hard to say that the EPR effect works in clinical practice. In the case of hematological malignancies, the administered anticancer agents (ACA) can physically interact with the malignant cells, making it easier to reflect in vitro data. In solid tumors, however, the extravasated ACAs must diffuse evenly within the whole tumor mass. Therefore, the cancer stroma and the tumor mass itself can be obstacles to drug delivery systems (DDS) including antibody therapeutics. We have demonstrated that hypercoagulability caused by cancer forms cancer stroma. We further showed that the more aggressive the cancer, the greater the deposition of insoluble fibrin (IF) in cancer tissue. In this background, we decided to create monoclonal antibody (mAb) that specifically binds to IF. After a long effort, a new and unique IF-specific mAb was developed. Subsequently, anti-IF mAb conjugated with an ACA using a V-L-K linker which can be cut by plasmin. Because plasmin is activated only during IF formation, the ACA is released from the ADC only when the conjugate is bound to the IF. The released ACA may readily get to cancer cells through the stromal obstacle because of its small size. The ACA also damages the capillary that nourish cancer cells. We have named this strategy cancer (CA) stroma (S) targeting (T) therapy, or CAST therapy.
Leveraging Systematic Functional Analysis to Benchmark an <i>In Silico</i> Framework Distinguishes Driver from Passenger MEK Mutants in Cancer
Authors: Aphrothiti J. Hanrahan, Brooke E. Sylvester, Matthew T. Chang, Arijh Elzein, Jianjiong Gao, Weiwei Han, Ye Liu, Dong Xu, Sizhi P. Gao, Alexander N. Gorelick, Alexis M. Jones, Amber J. Kiliti, Moriah H. Nissan, Clare A. Nimura, Abigail N. Poteshman, Zhan Yao, Yijun Gao, Wenhuo Hu, Hannah C. Wise, Elena I. Gavrila, Alexander N. Shoushtari, Shakuntala Tiwari, Agnes Viale, Omar Abdel-Wahab, Taha Merghoub, Michael F. Berger, Neal Rosen, Barry S. Taylor, David B. Solit
Journal: Cancer Research (2020)

Abstract Despite significant advances in cancer precision medicine, a significant hurdle to its broader adoption remains the multitude of variants of unknown significance identified by clinical tumor sequencing and the lack of biologically validated methods to distinguish between functional and benign variants. Here we used functional data on MAP2K1 and MAP2K2 mutations generated in real-time within a co-clinical trial framework to benchmark the predictive value of a three-part in silico methodology. Our computational approach to variant classification incorporated hotspot analysis, three-dimensional molecular dynamics simulation, and sequence paralogy. In silico prediction accurately distinguished functional from benign MAP2K1 and MAP2K2 mutants, yet drug sensitivity varied widely among activating mutant alleles. These results suggest that multifaceted in silico modeling can inform patient accrual to MEK/ERK inhibitor clinical trials, but computational methods need to be paired with laboratory- and clinic-based efforts designed to unravel variabilities in drug response. Significance: Leveraging prospective functional characterization of MEK1/2 mutants, it was found that hotspot analysis, molecular dynamics simulation, and sequence paralogy are complementary tools that can robustly prioritize variants for biologic, therapeutic, and clinical validation. See related commentary by Whitehead and Sebolt-Leopold, p. 4042
Harnessing endophenotypes and network medicine for Alzheimer's drug repurposing
Authors: Jiansong Fang, Andrew A. Pieper, Ruth Nussinov, Garam Lee, Lynn Bekris, James B. Leverenz, Jeffrey Cummings, Feixiong Cheng
Journal: Medicinal Research Reviews (2020)

Abstract Following two decades of more than 400 clinical trials centered on the “one drug, one target, one disease” paradigm, there is still no effective disease‐modifying therapy for Alzheimer's disease (AD). The inherent complexity of AD may challenge this reductionist strategy. Recent observations and advances in network medicine further indicate that AD likely shares common underlying mechanisms and intermediate pathophenotypes, or endophenotypes, with other diseases. In this review, we consider AD pathobiology, disease comorbidity, pleiotropy, and therapeutic development, and construct relevant endophenotype networks to guide future therapeutic development. Specifically, we discuss six main endophenotype hypotheses in AD: amyloidosis, tauopathy, neuroinflammation, mitochondrial dysfunction, vascular dysfunction, and lysosomal dysfunction. We further consider how this endophenotype network framework can provide advances in computational and experimental strategies for drug‐repurposing and identification of new candidate therapeutic strategies for patients suffering from or at risk for AD. We highlight new opportunities for endophenotype‐informed, drug discovery in AD, by exploiting multi‐omics data. Integration of genomics, transcriptomics, radiomics, pharmacogenomics, and interactomics (protein–protein interactions) are essential for successful drug discovery. We describe experimental technologies for AD drug discovery including human induced pluripotent stem cells, transgenic mouse/rat models, and population‐based retrospective case–control studies that may be integrated with multi‐omics in a network medicine methodology. In summary, endophenotype‐based network medicine methodologies will promote AD therapeutic development that will optimize the usefulness of available data and support deep phenotyping of the patient heterogeneity for personalized medicine in AD.
The association of the serum levels of myostatin, follistatin, and interleukin-6 with sarcopenia, and their impacts on survival in patients with hepatocellular carcinoma
Authors: Kanghyug Choi, Hee Yoon Jang, Joong Mo Ahn, Sung Ho Hwang, Jung Wha Chung, Yun Suk Choi, Jin-Wook Kim, Eun Sun Jang, Gwang Hyeon Choi, Sook-Hyang Jeong
Journal: Clinical and Molecular Hepatology (2020)

The role of serum myokine levels in sarcopenia and the outcome of hepatocellular carcinoma (HCC) patients are not clear. This study investigated the serum levels of myostatin, follistatin, and interleukin-6 (IL-6) in HCC patients and their association with sarcopenia and survival.Using prospectively collected pretreatment samples from 238 HCC patients in a hospital from 2012 to 2015, the serum levels of 3 myokines were determined and compared to 50 samples from age and sex-matched healthy controls. Sarcopenia was evaluated using the psoas muscle index (PMI) measured at the third lumbar level in the computed tomography, and clinical data were collected until 2017.The median levels of the 3 myokines for the male and female HCC patients were as follow: myostatin (3,979.3 and 2,976.3 pg/mL), follistatin (2,118.5 and 2,174.6 pg/mL), and IL-6 (2.5 and 2.7 pg/mL), respectively. Those in the HCC patients were all significantly higher than in the healthy controls. In the HCC patient, the median PMI was 4.43 (males) and 2.17 cm2/m2 (females) with a sarcopenic prevalence of 56.4%. The serum levels of myostatin, IL-6 and follistatin in the HCC patients showed a positive, negative, and no correlation with PMI, respectively. The serum follistatin level was an independent factor for poor survival in HCC patients.The serum levels of myostatin, follistatin, and IL-6 and their correlation with sarcopenia and survival were presented in HCC patients for the first time. The role of the serum follistatin level as a poor prognostic biomarker warrants further study.
Pan-RAF inhibition induces apoptosis in acute myeloid leukemia cells and synergizes with BCL2 inhibition
Authors: Mahesh Tambe, Ella Karjalainen, Markus Vähä-Koskela, Daria Bulanova, Bjørn T. Gjertsen, Mika Kontro, Kimmo Porkka, Caroline A. Heckman, Krister Wennerberg
Journal: Leukemia (2020)
P-217 Value of liquid biopsy using high-affinity plasma DNA binding magnetic beads and qualitative real-time PCR for KRAS, NRAS and BRAF mutations in metastatic colorectal cancer patients
Authors: J. Lucchetti, V. Formica, E. Doldo, C. Morelli, L. Vergilii, D. Nitti, A. Nardecchia, N. Renzi, E. Dell'Aquila, G. Perrone, G. Palmieri, A. Orlandi, M. Roselli
Journal: Annals of Oncology (2020)
Myocarditis in Relation to Angiographic Findings in Patients With Provisional Diagnoses of MINOCA
Authors: Anaïs Hausvater, Nathaniel R Smilowitz, Boyangzi Li, Gabriel Redel-Traub, Mary Quien, Yingzhi Qian, Judy Zhong, Joseph M Nicholson, Giovanni Camastra, Loïc Bière, Roman Panovský, Montenegro Sá, Edouard Gerbaud, Joseph B Selvanayagam, Mouaz H Al-Mallah, Tilman Emrich, Harmony R Reynolds
Journal: JACC. Cardiovascular imaging (2020)
Arterial Stiffness Predicts Mortality in Individuals With Type 1 Diabetes
Authors: Anniina Tynjälä, Carol Forsblom, Valma Harjutsalo, Per-Henrik Groop, Daniel Gordin
Journal: Diabetes Care (2020)

OBJECTIVE Type 1 diabetes is accompanied by a significant burden of cardiovascular disease (CVD), which is poorly explained by traditional risk factors. We therefore aimed to explore whether arterial stiffness estimated by the augmentation index (AIx) predicts mortality in individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS After baseline examination comprising pulse wave analysis by applanation tonometry alongside assessment of traditional cardiovascular risk factors, 906 individuals with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study were followed up for a median of 8.2 years (interquartile range 5.7–9.7). Associations between baseline hemodynamics, including AIx, and all-cause mortality as well as a composite of cardiovascular and/or diabetes-related mortality were investigated using multivariable Cox regression models. RESULTS The 67 individuals who died during follow-up had higher baseline AIx (median 28% [interquartile range 21–33] vs. 19% [9–27]; P &amp;lt; 0.001) compared with those alive. This association was independent of conventional risk factors (age, sex, BMI, HbA1c, estimated glomerular filtration rate [eGFR], and previous CVD event) in Cox regression analysis (standardized hazard ratio 1.71 [95% CI 1.10–2.65]; P = 0.017) and sustained in a subanalysis of individuals with chronic kidney disease. Similarly, higher AIx was associated with the composite secondary end point of cardiovascular and diabetes-related death (N = 53) after adjustments for sex, BMI, eGFR, previous CVD event, and height (standardized hazard ratio 2.30 [1.38–3.83]; P = 0.001). CONCLUSIONS AIx predicts all-cause mortality as well as a composite cardiovascular and/or diabetes-related cause of death in individuals with type 1 diabetes, independent of established cardiovascular risk factors.
New compounds: Structure of antitumor activity relationship study of B- and D-ring modified and non-modified steroidal esters of chlorambucil's active metabolite
Authors: Athanasios Papageorgiou, Eleni Stergiou, Ioannis Stergiou, George Geromichalos, George Fountzilas
Journal: Cancer Research (2006)

547  Introduction: Nitrogen mustards are among the oldest and most extensively studied agents in human cancer chemotherapy. These drugs exert their biological activity by inducing interstrand cross-links in the major groove of DNA, which represents the most toxic of all alkylation events. Despite that only a small fraction forms effective cross-links due to their high inner chemical activity which results in their covalent binding to the nucleophilic sites of other biomolecules. Alternatively, simple mustards undergo rapid hydrolysis before reaching the DNA target. We have studied the effect of modification of the B-steroidal ring to lactamic on the antitumor potency of D-modified and D-non-modified steroidal esters of chlorambucil9s active metabolites. Materials and methods: In this study the pancreatic ductal adenocarcinoma PAN-02 was used. It was purchased from the NCI (USA). Tumor was grown in C57BL. The tumor was implanted subcutaneously with puncture in the inguinal region. The amount of the transplanted graft was 40-50 mg fragment. The acute toxicity of the compounds was determined and the lethal dose LD10 was used as a therapeutic dose. The antitumor activity was assessed from the inhibition of tumor growth by volume in cm3 and T/C%. Results and discussion: The toxicities of the compounds tested (PHE, 1A, 1B, 1C, 2A, 2B, 2C) are reported. The LD50 values of the steroidal esteric derivatives are higher than those of nitrogen mustard, showing that this conjugation reduces the cytotoxicity of the alkylating agent. From the results we can estimate that all esteric derivatives tested gave better TI% and T/C% values than the nitrogen mustard itself. Although the introduction of the allylic 7-keto group in the B-steroidal ring had impressive influence on the antitumor potency of the compounds tested (T/C% equal or higher of 70 % for all the oxidized compounds), similar results were not observed in the case of B-lactamic steroidal derivatives. The presence of the -NHCO moiety in the B-steroidal ring produced derivatives marginally active but at the same time were more toxic. This type of behavior offers additional support for the concept that this molecules produce their antitumor activity by binding at specific sites and that the steroidal moiety is not only a simple carrier for the nitrogen mustard.
Topical siRNA delivery to the cornea and anterior eye by hybrid silicon-lipid nanoparticles
Authors: Paulina Baran-Rachwalska, Nissim Torabi-Pour, Flavia Maria Sutera, Mukhtar Ahmed, Keith Thomas, M. Andrew Nesbit, Michael Welsh, C.B. Tara Moore, Suzanne R. Saffie-Siebert
Journal: Journal of Controlled Release (2020)

The major unmet need and crucial challenge hampering the exciting potential of RNAi therapeutics in ophthalmology is to find an effective, safe and non-invasive means of delivering siRNA to the cornea. Although all tissues of the eye are accessible by injection, topical application is preferable for the frequent treatment regimen that would be necessary for siRNA-induced gene silencing. However, the ocular surface is one of the more complex biological barriers for drug delivery due to the combined effect of short contact time, tear dilution and poor corneal cell penetration. Using nanotechnology to overcome the challenges, we developed a unique silicon-based delivery platform for ocular delivery of siRNA. This biocompatible hybrid of porous silicon nanoparticles and lipids has demonstrated an ability to bind nucleic acid and deliver functional siRNA to corneal cells both in vitro and in vivo. Potent transfection of human corneal epithelial cells with siRNA-ProSilic® formulation was followed by a successful downregulation of reporter protein expression. Moreover, siRNA complexed with this silicon-based hybrid and applied in vivo topically to mice eyes penetrated across all cornea layers and resulted in a significant reduction of the targeted protein expression in corneal epithelium. In terms of siRNA loading capacity, system versatility, and potency of action, ProSilic provides unique attributes as a biodegradable delivery platform for therapeutic oligonucleotides.
アレルギー感作の予防におけるフラゲリンA抱合体によるIL-10樹状細胞誘導に対するラパマイシンの哺乳類標的の重要な役割【JST・京大機械翻訳】
Authors: Schuelke Stefan, Fiedler Anna-Helena, Junker Ann-Christine, Flaczyk Adam, Wolfheimer Sonja, Wangorsch Andrea, Heinz Anke, Beckert Hendrik, Nagl Birgit, Bohle Barbara, Vieths Stefan, Toda Masako, Scheurer Stephan
Journal: Journal of Allergy and Clinical Immunology (2018)
P-209 Multicenter real life experience of biological agents in patients with metastatic colorectal cancer
Authors: U. Demirci, I. Ertürk, Ç. Arslan, A. Bilici, D. Çevik, I. Cicin, F. Dane, B. Dölek, M. Kaplan, N. Karadurmuş, F. Kose, M. Şendur, Y. Ürün, S. Kılıçkap
Journal: Annals of Oncology (2020)
Computed tomography of covid-19 pneumonia
Authors: Han Ma, Yaqin Zhang
Journal: BMJ (2020)

On 23 January 2020, a man in his late 60s presented to hospital in Zhuhai, China, with a four day history of fever (~38°C) and no other symptoms.His wife, who was in her early 70s, also had a fever and was admitted to hospital at the same time.His blood pressure was 130/75 mm Hg, pulse 62 beats/min, respiratory rate 20 breaths/min, and oxygen saturation 95-98% on air.On auscultation, slightly coarse chest sounds were heard.Unenhanced chest computed tomography showed multifocal ground glass opacity in the bilateral subpleural area (fig 1) and he was admitted.He was given intravenous antibiotics (the standard local treatment for bilateral pneumonia), and covid-19 reverse transcriptase polymerase chain reaction (RT-PCR) assay was performed on nasal and pharyngeal swabs, in accordance with World Health Organization protocol. 1 The results were available on day 2 after presentation (table 1).
Progression of Coronary Artery Stenosis during 6 Months was Associated with the Number of Yellow Plaques Detected by Baseline Angioscopy
Authors: Ohmori Yosuke, Ueda Yasunori, Komatsu Sei, Kashiwase Kazunori, Ohyabu Jota, Hirayama Atsushi, Kodama Kazuhisa
Journal: Circulation (2006)
Pat Beresford West
Authors: Murray Fletcher, Anne Francis
Journal: BMJ (2020)

Pat Beresford West (nee Bagley) was raised in Thurso, the northernmost town on the mainland of Britain, and she remained fiercely proud of her Scottish heritage throughout her life.

Pat’s early career did not follow a conventional path, in no small part a reflection of her free spirit and sense of fun. She made a big impression wherever she went, and a friend described the impact of her “hippie dresses, bare feet, wild hair, and disarming style” on some of her more conservative colleagues, when she was working as a junior doctor.

After house jobs in Truro, Pat embarked on the first of many adventures. She joined an ocean going yacht headed for the Caribbean, combining her crewing duties with those of on-board doctor. There were many who urged caution about interrupting her career at such an early stage, but the lure of sun and adventure was too much.

Although at the end of the voyage she returned to the south-west of England, working again for a period in Cornwall (where she met her future husband), followed by north Devon, it was not long before the next adventure. This time she headed to the Outer Hebrides, to work for a while as a locum GP in Stornoway.

A move to South-east Asia followed later, and this was where she got married. However, by her own admission, Pat found the role of a dutiful colonial wife hard, and she quickly became bored and restless. On discovering she was pregnant, she insisted on returning to Edinburgh for the birth of her son, Ben.

The family eventually settled in north Devon, and over …
Abstract 15838: Enough Already With Chest Pain Severity Ratings to Confirm a ST Segment Elevation Myocardial Infarction Diagnosis ST Segment Elevation Myocardial Infarction in Males or Females
Authors: Richard Mullvain, Catherine Benziger, Daniel M Saman
Journal: Circulation (2018)

Introduction: A positive 12-Lead electrocardiogram is required to diagnose ST segment elevation myocardial infarction (STEMI), but also requires evaluation of signs and symptoms, including a chest ...
The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of multiple myeloma
Authors: Nina Shah, Jack Aiello, David E Avigan, Jesus G Berdeja, Ivan M Borrello, Ajai Chari, Adam D Cohen, Karthik Ganapathi, Lissa Gray, Damian Green, Amrita Krishnan, Yi Lin, Elisabet Manasanch, Nikhil C Munshi, Ajay K Nooka, Aaron P Rapoport, Eric L Smith, Ravi Vij, Madhav Dhodapkar
Journal: Journal for ImmunoTherapy of Cancer (2020)

Outcomes in multiple myeloma (MM) have improved dramatically in the last two decades with the advent of novel therapies including immunomodulatory agents (IMiDs), proteasome inhibitors and monoclonal antibodies. In recent years, immunotherapy for the treatment of MM has advanced rapidly, with the approval of new targeted agents and monoclonal antibodies directed against myeloma cell-surface antigens, as well as maturing data from late stage trials of chimeric antigen receptor (CAR) T cells. Therapies that engage the immune system to treat myeloma offer significant clinical benefits with durable responses and manageable toxicity profiles, however, the appropriate use of these immunotherapy agents can present unique challenges for practicing physicians. Therefore, the Society for Immunotherapy of Cancer convened an expert panel, which met to consider the current role of approved and emerging immunotherapy agents in MM and provide guidance to the oncology community by developing consensus recommendations. As immunotherapy evolves as a therapeutic option for the treatment of MM, these guidelines will be updated.