tbuckley/cabot-search huggingface dataset:
A Phamacoeconomic Analysis of Personalized Dosing vs Fixed Dosing of Pembrolizumab in Firstline PD-L1-Positive Non–Small Cell Lung Cancer
Authors: Daniel A Goldstein, Noa Gordon, Michal Davidescu, Moshe Leshno, Conor E Steuer, Nikita Patel, Salomon M Stemmer, Alona Zer
Journal: JNCI Journal of the National Cancer Institute (2017)

In October 2016, pembrolizumab became the new standard of care for firstline treatment of patients with metastatic non-small cell lung cancer (mNSCLC) whose tumors express programmed death ligand 1 in at least 50% of cells. The US Food and Drug Administration-recommended dose is 200 mg every three weeks. Multiple studies have demonstrated equivalent efficacy with weight-based doses between 2 mg/kg and 10 mg/kg. The objective of this study was to compare the economic impact of using personalized dosing (2 mg/kg) vs fixed dosing (200 mg) in the firstline setting of mNSCLC.We performed a budget impact analysis from the US societal perspective to compare fixed dosing with personalized dosing. We calculated the target population and weight of patients who would be treated with pembrolizumab annually in the firstline setting. Using survival curves from the KEYNOTE 024 trial with Weibull extrapolation, we estimated the mean number of cycles that patients would receive. Using the Medicare average sales price, we calculated the difference in cost between personalized and fixed dosing.Our base case model demonstrates that the total annual cost of pembrolizumab with fixed dosing is US $3 440 127 429, and with personalized dosing it is US $2 614 496 846. The use of personalized dosing would lead to a 24.0% annual savings of US $825 630 583 in the United States.Personalized dosing of pembrolizumab may have the potential to save approximately $0.825 billion annually in the United States, likely without impacting outcomes. This option should be considered for the firstline management of PD-L1-positive advanced lung cancer.
Identification and characterization of loop7 motif and its role in regulating biological function of human APOBEC3G through molecular modeling and biological assay
Authors: Congjie Zhai, Ling Ma, Zhixin Zhang, Jiwei Ding, Jing Wang, Yongxin Zhang, Xiaoyu Li, Fei Guo, Liyan Yu, Jinming Zhou, Shan Cen
Journal: Acta Pharmaceutica Sinica B (2017)

Human APOBEC3G (hA3G) is a cytidine deaminase which inhibits HIV-1 replication. The HIV-1 accessory protein viral infectivity factor (Vif) counteracts with hA3G by targeting it for proteasomal degradation. In this work, we constructed and optimized molecular models of the hA3G dimer and the hA3G-Vif complex. The molecular modeling study revealed that the loop7 motif of hA3G appears on the interfaces of both the hA3G-Vif complex and the hA3G dimer. Biochemical analysis provided evidence suggesting that binding of Vif to hA3G results in steric blocking of hA3G dimerization, implying that monomeric hA3G serves as a substrate for Vif-mediated degradation. Furthermore, we presented evidence for the important roles of the loop7 motif, especially the central residues within the region, in hA3G dimerization, hA3G--Vif interaction, Vif-mediated hA3G degradation as well as subcellular localization of hA3G. This work highlights a multiple-task interface formed by loop7 motif, which regulates biological function of hA3G, thus providing the feasibility of the strategy of blocking Vif-mediated A3G degradation by targeting the putative site around loop7.
The impact of racial disparity on outcomes of patients with early-stage uterine endometrioid carcinoma in an equal-access environment.
Authors: Jared R. Robbins, Benjamin S. Laser, Neal Bhat, Chad Cogan, Adnan Munkarah, Mohamed A. Elshaikh
Journal: Journal of Clinical Oncology (2012)

5088 Background: To determine if racial disparity exists between African American (AA) and non-African American (NAA) patients with early stage uterine endometrioid carcinoma who had similar multidisciplinary management. Methods: Our prospectively-maintained database of 1,450 uterine cancer patients was reviewed for this IRB-approved study. We identified 766 consecutive patients with endometrioid carcinoma 1988 FIGO stages I-II who underwent hysterectomy between 1987-2009. Patients with non-endometrioid carcinoma, mixed histologies and those who received preoperative treatments were excluded. For the purpose of data analysis, patients were divided into two groups; AA and NAA. Recurrence-free survival (RFS), disease specific (DSS) and overall survival (OS) was calculated from the date of hysterectomy using the Kaplan-Meier method. Cox regression modeling was used to explore the risks of various factors on recurrence. Results: Median follow-up was 5.1 years. 27% were AA and 73% were NAA. All patients underwent hysterectomy and oophorectomy. 80% had peritoneal cytology and 69% underwent lymphadenectomy. AA patients were more likely to have higher grade tumors, and more lymphovascular space involvement (LVSI). Although the two groups were balanced in regards to surgical staging and adjuvant treatment received, the five-year RFS and DSS were significantly lower in AA compared to NAA patients (91% vs 84%, p=0.030; 95% vs 88%, p=0.011, respectively). Between the two groups, OS was not significantly different. On multivariate analysis and after adjusting for other prognostic factors, race (AA vs NAA) was not a significant predictor of outcome. Grade 3 tumors and the presence of LVSI were the only two independent predictors of RFS and DSS with p=&lt;0.001 and p=&lt;0.001, respectively. Conclusions: In this large hospital-based study, AA race was associated with a higher incidence of adverse pathological features and worse recurrence-free and disease-specific survival. However, on multivariate analysis race was not an independent prognostic factor. Further studies are needed to elucidate possible underlying molecular mechanisms for these poorer outcomes.
The Authors' reply: Table 1
Authors: Loris Pironi, Alastair Forbes, André Van Gossum
Journal: Gut (2011)

The Authors' reply We thank Abu-Elmagd and Mazariegos1 for their comments and are pleased to have the opportunity to explain our work further.

Our study2 aimed to determine which indications for intestinal transplantation (ITx) were most closely associated with an increased risk of death on home parenteral nutrition (HPN), and whether deaths were due to causes that could be avoided by ITx. The indications for ITx we considered were those described by Medicare, USA, and the American Society of Transplantation; they include objective parameters which allow clear patient identification. Our results confirm that our baseline patient categorisation was appropriate. Ninety-five per cent of patients who were weaned off HPN belonged to the non-candidate group, and 95% of patients who underwent ITx belonged to the candidate group. Survival on HPN was significantly lower in candidates who had HPN failure. Death on HPN was mainly HPN related in candidates, and related to …
Obstructive sleep apnoea is not a risk factor for incident hospitalised depression: a historical cohort study
Authors: Tetyana Kendzerska, Andrea S. Gershon, Gillian A. Hawker, George A. Tomlinson, Richard S. Leung
Journal: European Respiratory Journal (2017)

We evaluated whether obstructive sleep apnoea (OSA) was related to the incidence of hospitalisation for depression, a robust end-point that is unlikely to result from misdiagnosis. All adults referred with suspected OSA who underwent a diagnostic sleep study at a large urban academic hospital between 1994 and 2010 and were linked to provincial health administrative data between 1991 and 2015 were included. Cox regression analysis was used to investigate the association between OSA symptoms and severity and incident hospitalised depression, the primary outcome. Over a median follow-up of 9.7 years, 136 (1.3%) out of 10 149 participants were hospitalised for depression. A significant crude effect of OSA symptoms (waking unrefreshed and impact on memory and concentration) on hospitalised depression became nonsignificant after controlling for confounders. Apnoea–hypopnoea index was not significantly associated with the outcome: adjusted hazard ratio (33 versus 6 events·h −1 ) 1.13 (95% CI 0.91–1.40). Factors associated with hospitalised depression were female sex, younger age, use of hypnotics, alcoholism and unemployment. In a large clinical cohort with suspected OSA, controlling for confounders, OSA symptoms and severity were not related to the risk of hospitalisation for depression, suggesting that previously reported links between OSA and depression may be due to overlapping diagnostic criteria. However, our findings cannot exclude a potential link between OSA and milder depression.
Современные достижения в оценке стеатоза печени
Authors: V.I. Didenko
Journal: GASTROENTEROLOGY (2020)

Статья посвящена обзору научных публикаций, посвященных проблеме верификации стеатоза печени. Сегодня все большее значение приобретает проблема своевременного выявления и лечения хронических диффузных заболеваний печени, в патогенезе которых ключевую роль играют фиброз и стеатоз печени. Считается, что стеатоз печени характеризуется накоплением липидов в гепатоцитах, превышающим 5 % массы печени. В последнее время особое внимание уделяется методам верификации стеатоза печени, которые можно разделить на инвазивные, малоинвазивные и неинвазивные. Не утратили актуальности инвазивные методы, к которым относится трепанбиопсия печени — золотой стандарт. Малоинвазивные методы верификации стеатоза печени основаны на биохимическом исследовании венозной крови. Малоинвазивные методы условно можно разделить на рутинные — триглицериды, общий холестерол, липопротеиды высокой плотности и др. — и расчетных коэффициентов: стеатотест и др., результат которых рассчитывается на основании нескольких показателей. К неинвазивным методам верификации относятся: УЗИ, КТ, МРТ, эластометрия с САРТМ-функцией (Фиброскан, модель 502). На наш взгляд, перспективным для верификации стеатоза печени является использование УЗИ с опцией измерения параметров жесткости артерий в режиме WТrack. Из неинвазивных методов верификации стеатоза печени в определенном смысле революцию произвела эластометрия печени при помощи аппарата FibroScan-502-touch с CAP™-функцией. Открывающиеся возможности ранней верификации стеатоза печени позволяют своевременно назначать комплекс лечебно-профилактических мероприятий и создавать предпосылки для остановки прогрессирования, а возможно, и для регресса стеатоза печени.
Abstract 17: Nuclear Calcium/Calmodulin-dependent Protein Kinase II Signaling Enhances Cardiac Progenitor Cell Survival and Cardiac Lineage Commitment
Authors: Pearl Quijada, Nirmala Hariharan, Jonathan Cubillo, Kristin M Bala, Lucia Ormachea, Donald M Bers, Mark A Sussman, Coralie Poizat
Journal: Circulation Research (2015)

Ca2+/Calmodulin-dependent protein kinase II (CaMKII) signaling in the heart regulates cardiomyocyte contractility and growth in response to elevated intracellular Ca2+. The δB isoform of CaMKII is the predominant nuclear splice variant in the adult heart and regulates cardiomyocyte hypertrophic gene expression by signaling to the histone deacetylase HDAC4. However, the role of CaMKIIδ in cardiac progenitor cells (CPCs) has not been explored. During developmental growth endogenous CPCs display primarily cytosolic CaMKIIδ, which localizes to the nuclear compartment of CPCs after myocardial infarction injury. CPCs undergoing early differentiation in vitro increase levels of CaMKIIδB in the nuclear compartment where the kinase may contribute to the regulation of CPC commitment. CPCs modified with an established lentiviral based constructs to overexpress CaMKIIδB (CPCeδB) have reduced proliferative rate compared to lentiviral transduction of CPCs with eGFP alone (CPCe). Additionally, stable expression of CaMKIIδB promotes distinct morphological changes such as increased cell surface area and increased length of cells compared to CPCe. CPCeδB are resistant to oxidative stress induced by H2O2 relative to CPCe, whereas a knockdown of CaMKIIδB using small hairpin RNA resulted in an up regulation of cell death compared to scrambled treated controls. Dexamethasone treatment to promote cardiac differentiation increased cardiomyogenic markers cardiac troponin T and α-smooth muscle actin measured by RT-PCR and immunoblot analyses in CPCeδB compared to control CPCe. Therefore, CaMKIIδB may serve as a novel modulatory protein to enhance CPC survival and commitment into the cardiac and smooth muscle lineage.
Abstract 2: Mesenchymal Stem Cell Therapy Prevented Doxorubicin Induced Cardiac Dysfunction in Diabetics Rats
Authors: Sanjiv Dhingra, Hania Ibrahim Ammar, Mira Barsoum Nashed, Rasha Ibrahim Ammar, Hala Gabr, Hany Elsebaee Elsayed, Glen Lester Sequiera, Ejlal Abu-El Rub, Niketa Sareen
Journal: Circulation Research (2015)

Background: It is now established that having diabetes not only increases the chances of cancer also it complicates cancer treatment therapy. Doxorubicin (DOX) is a well known anticancer drug, however the clinical use of DOX was limited due to its cardiotoxic effects. One of the major concerns with DOX therapy has been its toxicity in patients who are less robust and more prone to toxic side effects, particularly patients with comorbid diseases such as diabetes mellitus. Several studies have demonstrated that mesenchymal stem cell (MSC) therapy has the potential to restore cardiac function following DOX induced cardiac injury. However, there is no study available on the effects of MSC therapy on DOX induced cardiac dysfunction in diabetics. Methods and Results: Diabetes was induced in male Wistar rats by streptozotcin injection (STZ, 65mg/kg body weight, i.p.). After 4 weeks of STZ injection, blood glucose levels in STZ group (301.58±23.97mg/dl) were significantly greater than control group (83.51±7.91mg/dl). These diabetic rats were treated with adriamycin (2.5mg/kg body weight, i.p) 3 times/week for two weeks (AD group); or with adriamycin+bone marrow MSCs (BM-MSC; 2x106 cells, via tail vein) or with adriamycin+adipose tissue derived MSCs (AD-MSC; 2x106 cells, via tail vein). Echocardiographic measurements showed a significant decline in cardiac function (%EF) following adriamycin treatment. Both BM-MSC and AT-MSC treatment improved %EF at 4 weeks. After 4 weeks of MSC injection, hearts from all the groups were excised and subjected to retrograde Langendorff perfusion and baseline levels of left ventricular developed pressure (LVDP), maximum rate of pressure rise dp/dt max and rate pressure product (RPP) were recorded. AD treatment caused a significant decrease in LVDP, dp/dt max and RPP levels. Both BM-MSCs and AD-MSCs injection significantly improved all these parameters. Conclusion: Both BM-MSC and AT-MSC were equally effective in preventing deterioration of cardiac function following doxorubicin therapy in diabetic rats. Furthermore, these findings should act as a stimulus for further research on the benefits of MSC therapy for diabetic subjects suffering from cancer.
Abstract 15137: Detection of Diffuse Myocardial Fibrosis using Multi-slice T1 Mapping by Slice Interleaved T1 (STONE) Sequence in Patients With Hypertrophic Cardiomyopathy
Authors: Shingo Kato, Sébastien Roujol, Jihye Jang, Tamer Basha, Sophie Berg, Kraig V Kissinger, Beth Goddu, Evan Appelbaum, Martin Maron, Warren J Manning, Reza Nezafat
Journal: Circulation (2015)

Introduction: In hypertrophic cardiomyopathy (HCM), there are significant variations in left ventricular (LV) wall thickness and fibrosis, which necessitates a volumetric coverage. Slice-interleaved T1 (STONE) mapping sequence allows for the assessment of native T1 time with complete coverage of LV myocardium. Hypothesis: We hypothesized that STONE sequence is useful for the assessment of regional native T1 time abnormality in HCM patients. Methods: Twenty-four septal HCM patients (56±16 years) and 10 healthy adult control subjects (57±15 years) were studied. Native T1 mapping was performed using STONE sequence which enables acquisition of 5 slices in the short-axis plane within a 90 sec free-breathing scan. We measured LV native T1 time and maximum LV wall thickness in each 16 segments from 3 slices (basal-, mid- and apical-slice) and evaluated the relationship between LV native T1 time and wall thickness. Late gadolinium enhanced (LGE) MRI was acquired to assess presence of myocardial enhancement. Results: In HCM patients, LV native T1 time was significantly elevated compared to healthy controls, regardless of presence or absence of LGE (mean native T1 time; LGE (+) segments (n=27), 1139±55 msec; LGE (-) segments (n=351), 1118±55 msec; healthy control (n=160),1065±35 msec; p&lt;0.001 by one-way ANOVA, 6 segments were excluded from analysis due to artifacts). Among 351 segments without LGE, native LV T1 time was diffusely elevated over the 16 segments (Figure). Significant positive correlation was found between LV wall thickness and native LV T1 time (y=1013+8.7x, p&lt;0.001). Conclusions: In HCM, substantial number of segments without LGE showed elevated native T1 time, and native T1 time was correlated with LV wall thickness. Multi-slice T1 mapping by using STONE sequence could be advantageous to overcome limited cardiac coverage of conventional single-slice T1 mapping technique and to accurately detect the diffuse myocardial fibrosis in HCM patients.
PTU-020 Pre-Endoscopic Intravenous Proton Pump Inhibition and the outcomes of Acute upper Gastrointestinal Bleeding: Abstract PTU-020 Table 1
Authors: A S Taha, E Saffouri, C McCloskey, T Carigen, W J Angerson
Journal: Gut (2013)

<h3>Introduction</h3> Proton pump inhibitors (PPIs), when given following endoscopy for acute upper gastrointestinal bleeding (UGIB), can reduce the need for blood transfusion and surgery; little is known about their benefit when used in the period before endoscopy. We therefore aimed to investigate the outcomes of UGIB in patients given intravenous PPIs before their endoscopy. <h3>Methods</h3> A total of 404 patients with UGIB were included; 202 received intravenous omeprazole for a median of 1 day (IQR 0.25–2) before endoscopy and 202 did not, this treatment being at their physician’s discretion. Omeprazole was given either in bolus doses of 40-mg bid (n = 103; 51%), or as an infusion of 8-mg/hour after a loading dose of 80-mg (n = 99; 49%). After endoscopy, omeprazole was continued intravenously or orally in patients found to have ulcers/erosions in their oesophagus, stomach, or duodenum. Patients’ clinical details were noted including their Charlson comorbidity and Blatchford risk scores. Three major outcomes were measured: need for blood transfusion; hospital stay &gt; 6 days; and death within 30 days. The Mann-Whitney test, Chi-squared test and logistic regression were used as appropriate <h3>Results</h3> The two groups were comparable with respect to their gender, smoking, alcohol intake, and use of NSAIDs, aspirin, anti-thrombotic and other drugs. The treated group was older and had higher Blatchford and Charlson scores. However, when these factors were adjusted for, as shown in Table-1, below, no significant differences were noted between patients who received pre-endoscopic PPI and those who did not in terms of need for blood transfusion, length of hospital stay, or 30-day mortality. <h3>Conclusion</h3> The administration of intravenous PPI before endoscopy did not affect the outcomes of acute upper gastrointestinal bleeding in this retrospective study. This is relevant to the appropriate management of this common condition. <h3>Disclosure of Interest</h3> A. Taha Consultant for: Horizon Pharma USA; Vifor Pharma UK, E. Saffouri: None Declared, C. McCloskey: None Declared, T. Carigen: None Declared, W. Angerson: None Declared
Augmenting Amyloid PET Interpretations With Quantitative Information Improves Consistency of Early Amyloid Detection
Authors: Nicholas R. Harn, Suzanne L. Hunt, Jacqueline Hill, Eric Vidoni, Mark Perry, Jeffrey M. Burns
Journal: Clinical Nuclear Medicine (2017)

Establishing reliable methods for interpreting elevated cerebral amyloid-β plaque on PET scans is increasingly important for radiologists, as availability of PET imaging in clinical practice increases. We examined a 3-step method to detect plaque in cognitively normal older adults, focusing on the additive value of quantitative information during the PET scan interpretation process.Fifty-five F-florbetapir PET scans were evaluated by 3 experienced raters. Scans were first visually interpreted as having "elevated" or "nonelevated" plaque burden ("Visual Read"). Images were then processed using a standardized quantitative analysis software (MIMneuro) to generate whole brain and region of interest SUV ratios. This "Quantitative Read" was considered elevated if at least 2 of 6 regions of interest had an SUV ratio of more than 1.1. The final interpretation combined both visual and quantitative data together ("VisQ Read"). Cohen kappa values were assessed as a measure of interpretation agreement.Plaque was elevated in 25.5% to 29.1% of the 165 total Visual Reads. Interrater agreement was strong (kappa = 0.73-0.82) and consistent with reported values. Quantitative Reads were elevated in 45.5% of participants. Final VisQ Reads changed from initial Visual Reads in 16 interpretations (9.7%), with most changing from "nonelevated" Visual Reads to "elevated." These changed interpretations demonstrated lower plaque quantification than those initially read as "elevated" that remained unchanged. Interrater variability improved for VisQ Reads with the addition of quantitative information (kappa = 0.88-0.96).Inclusion of quantitative information increases consistency of PET scan interpretations for early detection of cerebral amyloid-β plaque accumulation.
Abstract 162: Hypoxia Inducible Factor Regulates Cardiac Ribonucleic Acid Splicing
Authors: Chad B Walton, Mark Khemmani, Brandyn Dunn, Ralph V Shohet
Journal: Circulation Research (2013)

Ischemic cardiomyopathy is associated with elevated levels of hypoxia inducible factor (HIF)-1, a transcription factor that plays a key role in the response to hypoxia. We have created a transgenic mouse model with inducible cardiomyocyte-specific expression of an oxygen-stable form of HIF-1α to better understand the role of HIF-1 in ischemic cardiomyopathy. We performed RNAseq on polyA selected cardiac RNA before and after three days of transgene expression, with 10 million processed reads per sample. Genes were considered possibly differentially expressed if, following adjustment for multiple testing, p-value for the comparison to uninduced was less than 0.05. Genes having evidence of alternative splicing (those with a q-value &lt;0.05 suggesting a change in the relative abundance of the different transcripts deriving from a single transcription start site) were identified. A total of 22 alternatively spliced genes were investigated. One transcript in particular, that for Calmodulin-dependent protein kinase II isoform gamma 2 (CaMKIIγ) was of particular interest because CaMKII homologs are involved in the phosphorylation of both RyR2 and PLB, and might thus be important in excitation-contraction coupling and cardiac contractility. The reference RNA sequence for CaMKIIγ was down regulated 11.7-fold, while variant 1 (missing Exons 7 and 8), and variant 2 (missing Exon 8) were up regulated 2.6-fold and 1.7-fold, respectively. Real-time PCR validation of the RNAseq data has been obtained in the transgenic hearts, and, to a lesser extent, in wild type mice subjected to LAD ligation. The cardiac effects of CaMKIIγ have been little studied in the response to hypoxia. Taken together with our prior observations of SERCA2a down-regulation and increased phosphorylation of PLB in the transgenic model, this new evidence suggests that another way in which HIF-1 may be modulating calcium flux is by reconfiguring the abundance of CaMKIIγ splice variants. The biochemical effect(s) of this variation in splice variants remains unknown, but seems likely to be connected to the decrement in cardiac contractility seen with HIF expression, and in ischemic cardiomyopathy. The surprising role of HIF in regulating splicing will also be a fertile area for further investigation.