tbuckley/cabot-search huggingface dataset:
FDA Approval Summary: Atezolizumab Plus Paclitaxel Protein-bound for the Treatment of Patients with Advanced or Metastatic TNBC Whose Tumors Express PD-L1
Authors: Preeti Narayan, Sakar Wahby, Jennifer J. Gao, Laleh Amiri-Kordestani, Amna Ibrahim, Erik Bloomquist, Shenghui Tang, Yuan Xu, Jiang Liu, Wentao Fu, Pengfei Song, Bellinda L. King-Kallimanis, Sherry Hou, Yutao Gong, Shyam Kalavar, Soma Ghosh, Reena Philip, Kirsten B. Goldberg, Marc R. Theoret, Gideon M. Blumenthal, Paul G. Kluetz, Rajeshwari Sridhara, Richard Pazdur, Julia A. Beaver
Journal: Clinical Cancer Research (2020)

On March 8, 2019, the FDA granted accelerated approval to atezolizumab in combination with paclitaxel protein-bound for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 [PD-L1 stained tumor-infiltrating immune cells (IC) of any intensity covering ≥1% of the tumor area], as determined by an FDA-approved test. Approval was based on data from IMpassion130, which randomized patients to receive atezolizumab or placebo in combination with paclitaxel protein-bound. Investigator-assessed progression-free survival (PFS) in the intent-to-treat (ITT) and PD-L1-positive populations were coprimary endpoints. After 13-month median follow-up, the estimated median PFS in the PD-L1-positive population was 7.4 months in the atezolizumab arm and 4.8 months in the placebo arm [HR = 0.60; 95% confidence interval (CI), 0.48-0.77]. Overall survival (OS) results were immature with 43% deaths in the ITT population, representing 59% of the OS events required to perform the final OS analysis. Adverse reactions occurring in ≥20% of patients receiving atezolizumab with paclitaxel protein-bound were alopecia, peripheral neuropathies, fatigue, nausea, diarrhea, anemia, constipation, cough, headache, neutropenia, vomiting, and decreased appetite. Accelerated approval was appropriate taking into account the unmet medical need along with the immaturity of the OS results and potential for PFS in the PD-L1-expressing population to predict clinical benefit.
Role of Low‐Density Lipoprotein in Early Vascular Aging Associated With Systemic Lupus Erythematosus
Authors: Hua‐Chen Chan, Hsiu‐Chuan Chan, Chan‐Jung Liang, Hsiang‐Chun Lee, Hung Su, An‐Sheng Lee, Jentaie Shiea, Wen‐Chan Tsai, Tsan‐Teng Ou, Cheng‐Chin Wu, Chih‐Sheng Chu, Richard A. Dixon, Liang‐Yin Ke, Jeng‐Hsien Yen, Chu‐Huang Chen
Journal: Arthritis & Rheumatology (2020)

Patients with systemic lupus erythematosus (SLE) often have atherosclerotic complications at a young age but normal low-density lipoprotein (LDL) levels. This study was undertaken to investigate the role of LDL composition in promoting early vascular aging in SLE patients.Plasma LDL from 45 SLE patients (SLE-LDL) and from 37 normal healthy controls (N-LDL) was chromatographically divided into 5 subfractions (L1-L5), and the subfraction composition was analyzed. Correlations between subfraction levels and signs of early vascular aging were assessed. Mechanisms of lipid-mediated endothelial dysfunction were explored using in vitro assays and experiments in apoE-/- mice.The L5 percentage was increased 3.4 times in the plasma of SLE patients compared with normal controls. This increased percentage of SLE-L5 was positively correlated with the mean blood pressure (r = 0.27, P = 0.04), carotid intima-media thickness (IMT) (right carotid IMT, r = 0.4, P = 0.004; left carotid IMT, r = 0.36, P = 0.01), pulse wave velocity (r = 0.29, P = 0.04), and blood levels of CD16+ monocytes (r = 0.35, P = 0.004) and CX3CL1 cytokines (r = 0.43, P < 0.001) in SLE patients. Matrix-assisted laser desorption ionization-time-of-flight mass spectrometry analysis revealed that plasma levels of lysophosphatidylcholine (LPC) and platelet-activating factor (PAF) were increased in SLE-LDL and in the SLE-L5 plasma subfraction. Injecting SLE-LDL, SLE-L5, or LPC into young, male apoE-/- mice caused increases in plasma CX3CL1 levels, aortic fatty-streak areas, aortic vascular aging, and macrophage infiltration into the aortic wall, whereas injection of N-LDL or SLE-L1 had negligible effects (n = 3-8 mice per group). In vitro, SLE-L5 lipid extracts induced increases in CX3CR1 and CD16 expression in human monocytes; synthetic PAF and LPC had similar effects. Furthermore, lipid extracts of SLE-LDL and SLE-L5 induced the expression of CX3CL1 and enhanced monocyte-endothelial cell adhesion in assays with bovine aortic endothelial cells.An increase in plasma L5 levels, not total LDL concentration, may promote early vascular aging in SLE patients, leading to premature atherosclerosis.
Probing and Enhancing Ligand-Mediated Active Targeting of Tumors Using Sub-5 nm Ultrafine Iron Oxide Nanoparticles
Authors: Yaolin Xu, Hui Wu, Jing Huang, Weiping Qian, Deborah E. Martinson, Bing Ji, Yuancheng Li, Yongqiang A. Wang, Lily Yang, Hui Mao
Journal: Theranostics (2020)

Rationale: "Active targeting" based on the ligand-target affinity is a common strategy to precisely deliver nanoparticle (NP) imaging probes or drug carriers to the diseased tissue.However, such ligand-mediated active targeting inevitably takes place with prerequisite "passive targeting", driven by the enhanced permeability and retention (EPR) effect.Thus, the efficiency of active targeting in relation to off-targeted unbound NPs is of great importance in quantitative imaging of tumor biomarkers and delivery.With the notion that easy clearance of off-targeted uIONPs may lead to enhanced active targeting and tumor accumulation, we examined the NP size effect on "active targeting" of the transferrin receptor (TfR) using transferrin (Tf)-conjugated sub-5 nm (3 nm core) ultrafine iron oxide NPs (uIONPs) and larger IONPs (30 nm core).Methods: Green fluorescent dye (FITC)-labeled active targeting uIONPs (FITC-Tf-uIONPs) and red fluorescent dye (TRITC)-labeled passive targeting uIONPs (TRITC-uIONPs) were prepared.FITC-Tf-IONPs and TRITC-IONPs were used as comparison for the NP size effect.Multiphoton imaging, confocal fluorescence imaging, histological staining and computational analysis were applied to track different types of NPs in tumors at 1, 3 and 24 hours after co-injection of equal amounts of paired NPs, e.g., active targeting FITC-Tf-uIONPs and non-targeting TRITC-uIONPs, or FITC-Tf-IONPs and TRITC-IONPs into the same mice bearing 4T1 mouse mammary tumors.Results: Active targeting uIONPs exhibited an almost 6-fold higher level of tumor retention with deeper penetration comparing to non-targeting uIONPs at 24 hours after co-injection.However, accumulation of active targeting IONPs with a 30-nm core is only about 1.15-fold higher than non-targeting IONPs.The enhanced active targeting by uIONPs can be attributed to the size dependent clearance of unbound off-targeted NPs, as majority off-targeted uIONPs were readily cleared from the tumor by intravasation back into tumor blood vessels likely due to high interstitial pressure, even though they are not favorable for macrophage uptake.Conclusion: Ligand-mediated active targeting improves the delivery and accumulation of the sub-5 nm NPs.The improvement on active targeting is size-dependent and facilitated by NPs with sub-5 nm core sizes.Thus, sub-5 nm NPs may serve as favorable platforms for development of NP-based molecular imaging probes and targeted drug carriers.
Protein expression of EZH2 significantly increased in colorectal cancer compared with adjacent normal epithelium: A manual and quantitative image analyses
Authors: Andrey Khramtsov, Dezheng Huo, Brooke Sylvester, Tatyana Grushko, Maria Tretiakova, Can Gong, Lise Sveen, Semira Yassin, Jerome Scarborough, Olufunmilayo Olopade
Journal: Cancer Research (2007)

5438  Background: The enhancer of zeste homologue 2 (EZH2) is a member of the polycomb group of genes and is involved in cell cycle regulation. Strong EZH2 protein expression has been documented as a marker of invasion and proliferation in a variety of malignant tumors. In colorectal cancer (CRC), however, the status of EZH2 is not clear. In this pilot study, for the first time the immunohistochemical expression of EZH2 protein in invasive colorectal carcinomas has been evaluated.   Design: We generated a tissue microarray (TMA) with 85 specimens from 38 cases that included CRC and adjacent histologically normal epithelium. Immunohistochemical staining wasperformed using a DAKO immunostainer with the rabbit anti-EZH2 antibody (18-7395; 1:200, Zymed). The manual semiquantitative analysis was based on the evaluation of the intensity of nuclearreaction for EZH2 and the percentage of tumor cells stained positive and categorized in 4-tier system as negative (0), weakly positive (1+), moderatelypositive (2+) or strongly positive (3+). Two quantitative types of scores were generated using Automated Cellular Imaging System (ACIS, Clarient): an automated score (ACIS-Auto) and an ACIS-assisted score. Aperio ScanScope and TMALab software for nuclear algorithm were applied as an additional type of quantification. Automatically generated measurements were then translated into the 4-tier system to compare with semiquantitative analysis. Scores were compared between CRC and normal epithelium using sign-rank test. Receivers operating characteristic (ROC) analyses were performed to quantify the accuracy of 4 methods to discriminate tumor and normal tissue.  Results: Normal colorectal epithelium was moderately and weakly positive for EZH2 expression in 61% (22/36) and 33% (12/36) specimens, respectively. No strongly positive staining has been detected. In contrast, CRC showed strong EZH2 immunostaining in 55% (21/38) of cases and moderate expression in 42% (16/38) cases. Moreover, higher EZH2 expression in CRC specimens versus normal epithelium was significant by all 4 scoring methods (p≤0.0001). According to ROC analysis, semiquantitative and ACIS-assisted methods were the most accurate.  Conclusions: Significant increase in EZH2 expression in CRC versus to adjacent normal colonic epithelium detected in our study suggests the involvement of EZH2 in CRC tumor progression. Interactions between the EZH2 and otherpredictive and prognostic markers will be investigated on larger cohort. The most effective way for the evaluation of novel biomarkers in cancer on TMAs is the combination of computer-assisted methods with pathologist-based verification of each image.
Abstract 276: TAT-PTEN9c Targets Heart Directly to Improve Survival From Cardiac Arrest
Authors: Xiangdong Zhu, Filip Gasior, Jing Li, Huashan Wang, Zhiyi Zhu, J M Odonnell, Terry L Vanden Hoek
Journal: Circulation (2019)

Introduction: It is well established that hypothermia enhances cardiac arrest (CA) survival due, in part, to a mechanism of enhanced Akt activation. In this study we investigate whether the biosynthetic PTEN inhibitor (TAT-PTEN9c) provides therapeutic protection on survival due to direct effects on heart. Hypothesis: We hypothesized that TAT-PTEN9c interferes with endogenous PTEN binding at its cell membrane adaptor and leads to enhanced Akt activation, mouse survival and cardiac functional recovery. The improved CA survival is due in part to the improved contractile functional recovery of heart by TAT-PTEN9c. We also tested if the treatment targets the heart directly to enhanced recovery in isolated perfused rat heart after a period of global arrest. Methods: TAT-PTEN9c (7.5 mg/kg) was given intravenously (IV) after CA in mouse to determine protective effects of the treatment on survival and heart function. Western blot was used to determine the efficacy of TAT-PTEN9c for Akt activation. In the isolated rat heart, direct effect of treatment (1-10 μm) on cardiac function (HR, LVDP, RPP) were measured for 20 min following 20 min global ischemia. Results: In the mouse model of cardiac arrest, survival was significantly increased in the TAT-PTEN9c treated group compared to saline controls at 4 h (10/15, 67% vs. 6/15, 40%, P &lt; 0.05) after CPR. TAT-PTEN9c improved MAP at both R30 min and R2h. The treated mice had increased Akt phosphorylation at R15 min in both heart and brain tissues with significantly decreased sorbitol content and reduced release of taurine and glutamate into blood, suggesting improved metabolic recovery and glucose utilization. For the isolated heart model, RPP was reduced by 25% for both TAT vehicle and non-treatment groups following arrest. With TAT-PTEN9c treatment, cardiac contractile function was completely recovered (pre-arrest RPP 29.1k+/- 4.8; post-arrest 28.0K +/- 5.0). Conclusion: TAT-PTEN9c enhances Akt activation and decrease glucose shunting to the polyol pathway in critical organs, preventing osmotic injury and early cardiovascular collapse and death. The improved survival by this treatment is in part due to its direct effect on heart functional recovery.
Across-Site Differences in the Mechanism of Alcohol-Induced Digestive Tract Carcinogenesis: An Evaluation by Mediation Analysis
Authors: Yuriko N. Koyanagi, Etsuji Suzuki, Issei Imoto, Yumiko Kasugai, Isao Oze, Tomotaka Ugai, Madoka Iwase, Yoshiaki Usui, Yukino Kawakatsu, Michi Sawabe, Yutaka Hirayama, Tsutomu Tanaka, Tetsuya Abe, Seiji Ito, Koji Komori, Nobuhiro Hanai, Masahiro Tajika, Yasuhiro Shimizu, Yasumasa Niwa, Hidemi Ito, Keitaro Matsuo
Journal: Cancer Research (2020)

A genetic variant on aldehyde dehydrogenase 2 (ALDH2 rs671, Glu504Lys) contributes to carcinogenesis after alcohol consumption. Somewhat conversely, the ALDH2 Lys allele also confers a protective effect against alcohol-induced carcinogenesis by decreasing alcohol consumption due to acetaldehyde-related adverse effects. Here, we applied a mediation analysis to five case-control studies for head and neck, esophageal, stomach, small intestine, and colorectal cancers, with 4,099 cases and 6,065 controls, and explored the potentially heterogeneous impact of alcohol drinking on digestive tract carcinogenesis by decomposing the total effect of the ALDH2 Lys allele on digestive tract cancer risk into the two opposing effects of the carcinogenic effect (direct effect) and the protective effect (indirect effect mediated by drinking behavior). Alcohol was associated with an increased risk of most digestive tract cancers, but significant direct effects were observed only for upper gastrointestinal tract cancer risk, and varied substantially by site, with ORs (95% confidence interval) of 1.83 (1.43-2.36) for head and neck cancer, 21.15 (9.11-49.12) for esophageal cancer, and 1.65 (1.38-1.96) for stomach cancer. In contrast, a significant protective indirect effect was observed on risk for all cancers, except small intestine cancer. These findings suggest that alcohol is a major risk factor for digestive tract cancers, but its impact as a surrogate for acetaldehyde exposure appears heterogeneous by site. Meanwhile, the behavior-related effect of the ALDH2 Lys allele results in a decreased risk of most digestive tract cancers. SIGNIFICANCE: These findings support that genetic alcohol avoidance is a factor against alcohol-induced cancers.
Safety, tolerability, pharmacokinetics, and immunogenicity of a human monoclonal antibody targeting the G glycoprotein of henipaviruses in healthy adults: a first-in-human, randomised, controlled, phase 1 study
Authors: Elliott Geoffrey Playford, Trent Munro, Stephen M Mahler, Suzanne Elliott, Michael Gerometta, Kym L Hoger, Martina L Jones, Paul Griffin, Kathleen D Lynch, Heidi Carroll, Debra El Saadi, Margaret E Gilmour, Benjamin Hughes, Karen Hughes, Edwin Huang, Christopher de Bakker, Reuben Klein, Mark G Scher, Ina L Smith, Lin-Fa Wang, Stephen B Lambert, Dimiter S Dimitrov, Peter P Gray, Christopher C Broder
Journal: The Lancet Infectious Diseases (2020)
The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial.[summary for patients in Ann Intern Med. 2005 Apr 19;142(8):I46; PMID: 15838061]
Authors: T.J. Orchard, M. Temprosa, R. Goldberg, S. Haffner, R. Ratner
Journal: Annals of Internal Medicine (2005)
Association of Work Environment With Missed and Rushed Care Tasks Among Care Aides in Nursing Homes
Authors: Yuting Song, Matthias Hoben, Peter Norton, Carole A. Estabrooks
Journal: JAMA Network Open (2020)

In Canada, approximately 81% of residents of nursing homes live with mild to severe cognitive impairment. Care needs of this population are increasingly complex, but resources, such as staffing, for nursing homes continue to be limited. Staff risk missing or rushing care tasks and interfering with quality of care and life.To assess the association of work environment with missing and rushing essential care tasks in nursing homes.This cross-sectional study used survey data collected from a random sample of 93 urban nursing homes in Western Canada, stratified by health region, owner-operator model, and facility size, between May and December 2017. All 5411 eligible care aides were invited to participate, and 4016 care aides agreed and completed structured, computer-assisted interviews in person. Analyses were conducted from July 4, 2018, to February 27, 2019.Self-reported number of essential care tasks missed (range, 0-8) or rushed (range, 0-7) in the most recent shift. Two-level random intercept hurdle regressions controlled for care aide, care unit, and nursing home characteristics.Of 4016 care aides, 2757 (68.7%) were 40 years or older, 3574 (89.1%) were women, and 1353 (66.3%) spoke English as an additional language. For their most recent shift, 2306 care aides (57.4%) reported missing at least 1 essential care task and 2628 care aides (65.4%) reported rushing at least 1 essential care task. Care aides on units with more favorable work environments (eg, more effective leadership, better work culture, higher levels of buffering resources) were less likely to miss any care tasks (odds ratio, 1.59; 95% CI, 1.34-1.90; P < .001) and less likely to rush any care task (odds ratio, 1.66; 95% CI, 1.38-1.99; P < .001).This study found that rates of missed and rushed essential care in Canadian nursing homes were high and were higher in units with less favorable work environments. This finding suggests that work environment should be added to the list of modifiable factors associated with improving nursing home care, as it may be an important pathway for improving quality of care. Further research is needed to understand associations of missed and rushed care and of improving work environments with outcomes among residents of nursing homes.
Characterization of Disease Phenotype in Very Preterm Infants with Severe Bronchopulmonary Dysplasia
Authors: Katherine Y. Wu, Erik A. Jensen, Ammie M. White, Yan Wang, David M. Biko, Kathleen Nilan, María V. Fraga, Laura Mercer-Rosa, Huayan Zhang, Haresh Kirpalani
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Bronchopulmonary dysplasia (BPD) is a heterogenous condition with poorly characterized disease subgroups.Objectives: To define the frequency of three disease components: moderate–severe parenchymal disease, pulmonary hypertension (PH), or large airway disease, in a referral cohort of preterm infants with severe BPD. The association between each component and a primary composite outcome of death before hospital discharge, tracheostomy, or home pulmonary vasodilator therapy was assessed.Methods: This was a retrospective, single-center cohort study of infants born at <32 weeks’ gestation with severe BPD who underwent both chest computed tomography with angiography (CTA) and echocardiography between 40 and 50 weeks postmenstrual age between 2011 and 2015. Moderate–severe parenchymal lung disease was defined as an Ochiai score ≥8 on CTA. PH was diagnosed by echocardiogram using standard criteria. Large airway disease was defined as tracheomalacia or bronchomalacia on bronchoscopy and/or tracheoscopy or CTA.Measurements and Main Results: Of 76 evaluated infants, 73 (96%) were classifiable into phenotypic subgroups: 57 with moderate–severe parenchymal disease, 48 with PH, and 44 with large airway disease. The presence of all three disease components was most common (n = 23). Individually, PH and large airway disease, but not moderate–severe parenchymal disease, were associated with increased risk for the primary study outcome. Having more disease components was associated with an incremental increase in the risk for the primary outcome (2 vs. 1: odds ratio, 4.9; 95% confidence interval, 1.4–17.2 and 3 vs. 1: odds ratio, 12.8; 95% confidence interval, 2.4–70.0).Conclusions: Infants with severe BPD are variable in their predominant pathophysiology. Disease phenotyping may enable better risk stratification and targeted therapeutic intervention.
25P A Novel Serum Thymidine Kinase Activity (S-TK) Assay for Quantification of Total Cell Division in Man, with Special Reference to Breast Carcinoma
Authors: S. Gronowitz, B. Nisman, T. Allweis, L. Kadouri, B. Mali, T. Hamburger, T. Peretz
Journal: Annals of Oncology (2012)
Antibodies to hepatitis B virus and hepatitis C virus in alcoholic hepatitis and cirrhosis: Their prevalence and clinical relevance
Authors: C MENDENHALL
Journal: Hepatology (1991)

Patients with overt alcoholic liver disease who had participated in a multicenter therapeutic trial and subgroups of controls (i.e., alcoholic patients without liver disease and patients with neither alcoholism nor liver disease) were tested for hepatitis B virus and hepatitis C virus antibodies to determine the prevalence of these antibodies to determine the prevalence of these antibodies and any clinical association in the progression and outcome of alcoholic liver disease. Antibodies to hepatitis B (anti-HBs and/or anti-HBc) were found in 29.2% of patients with alcoholic liver disease, in 26.1% of hospitalized alcoholic patients without liver disease and in 24.2% of hospitalized nonalcoholic patients without liver disease; frequencies were not significantly different from one another. HBsAg was not evaluated because HBsAg+ patients had been excluded from the original trial. The presence of these antibody markers correlated with ethnic origin of and immunoglobulin levels in the patients. In contrast, antibody to hepatitis C, as detected by enzyme immunoassay, was positive in 27.1%, 4.8% and 3.0% of the three groups, respectively, the first differing significantly from the other two. Antibody to hepatitis C virus positivity correlated significantly with clinical severity of the disease and with the presence of histological features that imply chronic viral infection (periportal inflammation, cirrhosis), despite the fact that the supplementary assay for antibody to hepatitis C virus, using recombinant immunoblot assay, reduced the positive rate by 79%.(ABSTRACT TRUNCATED AT 250 WORDS)