tbuckley/cabot-search huggingface dataset:
Unmet need in chronic hepatitis B management
Authors: Lilian Yan Liang, Grace Lai-Hung Wong
Journal: Clinical and Molecular Hepatology (2019)

Despite all these exciting developments, there remain some unmet needs in the management for patients with chronic hepatitis B (CHB). As majority of CHB patients are going to use oral nucleos(t)ide analogues (NAs) for decades, Safety profile of NAs is of no doubt an important issue. The newest nucleotide analogue tenofovir alafenamide is potent in terms of viral suppression, together with favourable renal and bone safety profile. Biochemical response as reflected by alanine aminotransferase (ALT) normalization is recently found to be prognostically important. Patients who achieved ALT normalization have reduced the risk of hepatic events by 49%. Functional cure as reflected by hepatitis B surface antigen seroclearance not only implies patients may stop NA treatment, it also confers to a reduced risk of hepatocellular carcinoma and other hepatic events. Hence functional cure should be the ultimate treatment goal in CHB patients. Preemptive antiviral treatment may reduce mother-to-child transmission of hepatitis B virus, especially if birth dose of vaccination cannot be given in the first two hours after delivery. Lastly, despite the currently first-line NAs have high-genetic barrier to drug resistance mutations, there are still are many patients who were previously treated with low barrier of resistance including lamivudine, telbivudine or adefovir dipivoxil which could lead to antiviral resistance and affecting the choice of NAs. Keywords: Hepatitis B; Cirrhosis; Hepatocellular carcinoma; Mortality; Tenofovir alafenamide
Rapid Hematologic and Organ Responses with Daratumumab, Bortezomib and Dexamethasone in Patients with Relapsed/Refractory AL Amyloidosis
Authors: Sarah S Lee, Nathaniel Rosko, Bhumika J. Patel, Madeline Waldron, Jackie Tomer, Roman Goldman, Mary Ann Karam, Janice Reed, Beth M. Faiman, Kimberly Hamilton, Saveta Mathur, Christy J. Samaras, Jason Valent
Journal: Blood (2018)
Clinical Characteristics and Outcomes of Chronic Lymphocytic Leukemia Patients with Richter Transformation
Authors: Yucai Wang, Marcella Tschautscher, Kari G. Chaffee, Timothy G. Call, Jose F. Leis, Saad S. Kenderian, Neil E. Kay, Eli Muchtar, Daniel L. Van Dyke, Susan M. Schwager, Susan L. Slager, Sameer A. Parikh, Wei Ding
Journal: Blood (2018)
Health-Related Quality of Life in KEYNOTE-010: a Phase II/III Study of Pembrolizumab Versus Docetaxel in Patients With Previously Treated Advanced, Programmed Death Ligand 1–Expressing NSCLC
Authors: Fabrice Barlesi, Edward B. Garon, Dong-Wan Kim, Enriqueta Felip, Ji-Youn Han, Joo-Hang Kim, Myung-Ju Ahn, Mary Jo Fidler, Matthew A. Gubens, Gilberto de Castro, Veerle Surmont, Qiao Li, Anne C. Deitz, Gregory M. Lubiniecki, Roy S. Herbst
Journal: Journal of Thoracic Oncology (2019)
Immunoscore clinical utility to identify good prognostic colon cancer stage II patients with high-risk clinico-pathological features for whom adjuvant treatment may be avoided.
Authors: Jerome Galon, Fabienne Hermitte, Bernhard Mlecnik, Florence Marliot, Carlo Bruno Bifulco, Alessandro Lugli, Iris D. Nagtegaal, Arndt Hartmann, Marc Van Den Eynde, Michael H. A. Roehrl, Pamela S Ohashi, Eva Zavadova, Toshihiko Torigoe, Prabhudas S. Patel, Yili Wang, Yutaka Kawakami, Francesco Marincola, Paolo Antonio Ascierto, Bernard A. Fox, Franck Pages
Journal: Journal of Clinical Oncology (2019)

487 Background: Immunoscore Colon is an IVD test predicting the risk of relapse in early-stage colon cancer (CC) patients, by measuring the host immune response at the tumor site. It is a risk-assessment tool providing independent and superior prognostic value than the usual tumor risk parameters and is intended to be used as an adjunct to the TNM classification. Risk assessment is particularly important to decide when to propose an adjuvant (adj.) treatment for stage (St) II CC patients. High-risk stage II patients defined as those with poor prognostic features including T4, lymph nodes &lt; 12, poor differentiation, VELIPI, bowel obstruction/perforation can be considered for adj. chemotherapy (CT). However, additional risk factors are needed to guide treatment decisions. Methods: A subgroup analysis was performed on the St II untreated patients (n = 1130) from the Immunoscore international validation study (Pagès The Lancet 2018). The high-risk patients (with at least 1 clinico-pathological high-risk feature) were classified in 2 categories using pre-defined cutoffs: Low Immunoscore versus High Immunoscore and their five-year time to recurrence (5Y TTR) was compared to the TTR of the low-risk patients (without any clinico-pathological high-risk feature). Results: Among the patients with high-risk features (n = 630), 438 (69.5%) had a High Immunoscore with a corresponding 5Y TTR of 87.4 (95% CI 83.9-91.0), statistically similar (logrank pv not stratified p &gt; 0.42, wald pv stratified by center p &gt; 0.20) to the TTR 89.1 (95% CI 86.1-92.1) observed for the 500 low-risk patients (with no clinico-pathological feature). Furthermore, 5Y TTR for these patients were statistically similar to those of St II patients with high-risk features and a High Immunoscore (n = 438), who received adj. CT (n = 162) (5Y TTR of 83.4 (95% CI 77.6-89.9). Conclusions: These data show that despite the presence of high-risk features that usually trigger adj. treatment, when not treated with CT, a significant part of these patients (69.5%) have a recurrence risk similar to the low risk patients. Therefore, the Immunoscore test could be a good tool for adj. treatment decision in St II patients.
Abstract B045: Gene expression pathways associated with vigorous physical activity in prostate cancer
Authors: Claire H. Pernar, Giovanni Parmigiani, Edward L. Giovannucci, Eric B. Rimm, Stephen Finn, Michelangelo Fiorentino, Ericka M. Ebot, Lorelei A. Mucci
Journal: Cancer Research (2018)

Abstract Background: Epidemiologic studies have consistently shown that men engaged in high levels of physical activity have lower risks of advanced and fatal prostate cancer. The mechanisms underlying this association are not well understood but may include changes in hormonal and anti-inflammatory pathways. Our objective was to investigate the link between prediagnostic physical activity and gene expression alterations in prostate tumor and adjacent normal tissue. Methods: We performed whole-gene expression profiling on tumor (N=248) and adjacent normal tissue (N=117) among a subset of men diagnosed with indolent and lethal prostate cancer between 1986 and 2005 in the prospective Health Professionals Follow-up Study. Men were followed prospectively for prostate cancer outcomes through 2011. Physical activity was ascertained by self-report of the average number of hours per week spent engaged in various forms of recreational physical activity at baseline and every two years thereafter. We examined cumulative average physical activity of vigorous intensity in units of metabolic equivalent of task (MET)-hours/week updated from baseline to the time prostate cancer diagnosis. Gene set enrichment analysis was performed among KEGG and hallmark gene sets to identify pathways with differential expression by vigorous activity. Results: We identified 33 KEGG and four Hallmark gene sets enriched in the adjacent normal tissue comparing men in the highest compared to the lowest quintile of vigorous activity (false-discovery rate &amp;lt; 0.25). Among the significant gene sets identified were cancer-related pathways as well as vascular smooth muscle contraction, angiogenesis, and insulin-signaling pathways. No gene sets were significantly enriched in the tumor tissue. Conclusions: These findings suggest that physical activity may influence prostate cancer development through epigenetic alterations in the prostate tissue. Future studies are needed to confirm these findings and further investigate potential mechanisms linking physical activity to risk of lethal prostate cancer. Citation Format: Claire H. Pernar, Giovanni Parmigiani, Edward L. Giovannucci, Eric B. Rimm, Stephen Finn, Michelangelo Fiorentino, Ericka M. Ebot, Lorelei A. Mucci. Gene expression pathways associated with vigorous physical activity in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B045.
Abstract #3714: In vitro and in vivo antitumor activities of MK-2206, a new allosteric Akt inhibitor
Authors: Wei Lu, Debbie Defeo-Jones, Lenora Davis, Gaozhen Hang, Jennifer Tammam, Harold Hatch, Bart Lutterbach, Christopher Ware, Kathleen Haskell, Bob Drakas, Karen Leander, Craig Cherrin, Aubrey Watkins, Kelly Hamilton, Philip Sanderson, Hans Huber, Pradip Majumder, Bo-Sheng Pan
Journal: Cancer Research (2009)

Aberrant activation of the serine/threonine kinase Akt, a central node of the PI3K pathway, has been found in a significant proportion of human solid tumors, making Akt an attractive target for therapeutic intervention. MK-2206 is a potent inhibitor of Akt isozymes 1, 2, and 3 with in vitro IC50 values of 8, 12, and 65 nM, respectively. The compound is an allosteric inhibitor of Akt, requiring the presence of the Pleckstrin homology domain for activity. As a consequence, MK-2206 is highly selective against Akt, exhibiting no inhibitory activities against over 250 protein kinases when tested at 1\#956;M. In several cancer cell lines, MK-2206 potently inhibited Akt1 kinase activity (IC50 \#8776; 20 nM), and blocked Akt2 and Akt3 activities 2- to 6-fold less potently. MK-2206 potently inhibited phosphorylation of T308 and S473 of Akt in these cell lines and prevented Akt-mediated phosphorylation of down-stream signaling molecules, including TSC2, PRAS40 and ribosomal S6 proteins. MK-2206 exhibited potent anti-proliferative activity against a number of cancer cell lines harboring one or more of the following genetic defects: 1) constitutive activation of receptor tyrosine kinases such as HER2; 2) PTEN mutation, 3) PI3KCA mutation, and 4) Akt2 amplification. In nude mice bearing A2780 ovarian cancer xenografts, a single oral dose of MK-2206 at 240 mg/kg caused sustained inhibition (>70 %) of phospho-Akt1/2 (T308 and S473) in the tumors. In the same tumor model, MK-2206 inhibited tumor growth by \#8776; 60% when administrated orally at 240 mg/kg per day three times a week. These preclinical results support further clinical development of MK-2206.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3714.
Abstract MP29: Kidney Function, Bone-mineral Metabolism Markers, and Peripheral Artery Disease: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Chao Yang, Lucia Kwak, Shoshana Ballew, Bernard Jaar, Aaron Folsom, Gerardo Heiss, Elizabeth Selvin, Pamela Lutsey, Josef Coresh, Kunihiro Matsushita
Journal: Circulation (2016)

Introduction: Impaired kidney function is a known risk factor for lower-extremity peripheral artery disease (PAD). Whether novel markers of kidney filtration like cystatin C and beta-2-microglobulin (B2M) differ in their associations with PAD risk compared to creatinine-based estimated glomerular filtration rate (eGFRcr) is unclear. Also, bone-mineral metabolism (BMM) disorders are commonly complicated with impaired kidney function, but it is not known whether BMM markers influenced by kidney function are associated with PAD. Hypothesis: Novel filtration markers are more strongly associated with PAD risk than eGFRcr, and BMM markers are associated with PAD risk beyond kidney function. Methods: Using data from 13215 ARIC Study participants free of clinical history of PAD at baseline (1990-1992), we applied Cox proportional hazards model to quantify the associations of biomarkers and eGFR equations incorporating these biomarkers (cystatin C, B2M, eGFRcr, and eGFR based on cystatin C and cr [eGFRcr-cys]) with PAD risk. We also evaluated whether BMM markers (fibroblast growth factor 23, parathyroid hormone, calcium and phosphorus) were associated with PAD after adjustment for eGFR. PAD was defined as hospitalizations with ICD-9 code of 440.2x and 440.3. Results: During a median follow-up of 21 years, 587 participants had at least one hospitalization with a discharge code for PAD. The novel markers cystatin C and B2M showed stronger associations with PAD compared to eGFRcr (Table). When examining BMM markers, only elevated phosphorus level was associated with PAD risk and the association remained significant after adjustment for eGFRcr-cys (Table). Conclusions: The novel filtration markers cystatin C and B2M are stronger in their association with PAD compared to eGFRcr. Moreover, higher phosphorus level was related to future PAD risk beyond kidney function. Our results suggest novel filtration markers may improve PAD risk assessment, and there is a possible role for phosphorus metabolism in the pathophysiology of PAD.
TP53 Mutations in Myeloid Neoplasm Patients with and without Significant Personal and Family History of Cancer
Authors: Sophia Colombari Figueroa, Bhumika J. Patel, Shimoli Vipul Barot, Teodora Kuzmanovic, Aziz Nazha, Eric D. Hsi, James R. Cook, Sudipto Mukherjee, Aaron T. Gerds, Mikkael A. Sekeres, Matt Kalaycio, Anjali S. Advani, Jaroslaw P. Maciejewski, Hetty E. Carraway
Journal: Blood (2018)
Detection of methylated <i>BCAT1</i> and <i>IKZF1</i> in stage II/III rectal cancer receiving chemoradiation.
Authors: Chin-Tung Chen, Lauren Tufts, Piyush Aggarwal, Frederick Heller, Martin R. Weiser
Journal: Journal of Clinical Oncology (2019)

602 Background: In liquid biopsy, analyses of circulating tumor DNA (ctDNA) in blood have been used as a tool in cancer screening, identifying tumor mutations and monitoring treatment responses/recurrences. Aberrant methylation of some genes have been associated with cancer. Two genes, BCAT1 and IKZF1, are highly methylated and specific to colorectal cancer (CRC) in blood. Detection of these two methylated genes in post-surgery samples also correlates with higher chance of recurrence. Here we investigated the presence of methylated BCAT1 and IKZF1 at multiple time-points for each patient. Methods: Plasma was extracted from blood within 4 hours of the blood collection. ctDNA were extracted from plasma and bisulphite converted using commercially available kits. Real-time qPCR was used to analyze the converted DNA in three replicates and deemed positive if at least one replicate detected either methylated BCAT1 or IKZF1. Quantification of both genes were determined using separate gene-specific standard curves. Results: Nine Stage II/III rectal cancer (RC) patients was enrolled into the study, with one pre-treatment blood draw and several subsequent draws collected throughout the treatment cycles. five patients tested positive for at least one of the methylated genes prior to treatment. Four of these five patients showed an immediate drop in detection for the assayed genes after one cycle of chemotherapy and either remains at low concentration or is undetectable through the rest of the treatment cycles. These patients either have partial or complete response to the treatment regimen. One patient with continuous high levels of methylated BCAT1 and IKZF1 post-treatment have recurred two months after surgery. Conclusions: Methylated BCAT1 and/or IKZF1 were detected in over 50% of the Stage II/III RC patients pre-treatment. This assay is sensitive to the effect of chemotherapy regimen. A significant number of these patients showed a partial/complete response to their treatment regimen and/or reduction in tumor burden, which is reflected in the loss of detection of these two genes. This study shows that this assay may be a viable tool to pair with Imaging for assessment of patient response to treatment regimen.
Cancer-Associated Thrombosis and Bleeding Risk in Gastrointestinal Malignancies with Apixaban and Rivaroxaban Compared to Low Molecular Weight Heparin
Authors: Damon E. Houghton, Dalene M. Bott-Kitslaar, Emily Vargas, David O. Hodge, Teresa R Lang, Lisa Peterson, Ana I Casanegra, Robert D. McBane, Waldemar E. Wysokinski, David A Froehling
Journal: Blood (2018)
Abstract 17145: Non-invasive Tracking of Endogenous Bone Marrow Cell Recruitment After Myocardial Infarction in Mice
Authors: James T Thackeray, Mortimer Korf-Klingebiel, Yong Wang, Olga S Kustikova, Jens P Bankstahl, Kai C Wollert, Frank M Bengel
Journal: Circulation (2015)

Limited clinical benefit of exogenous stem cell therapy has renewed interest in strategies to enhance endogenous cell recruitment after myocardial infarction (MI). Nuclear imaging of stem cell trafficking has been restricted to exogenous stem cells, and may be compromised by low cell retention and continuous expression of reporter genes. We evaluated the feasibility of transplanting reporter gene-labeled endogenous bone marrow under an inducible promoter as a platform for imaging endogenous cell recruitment in MI. Sodium iodide symporter (NIS) was cloned into a lentiviral vector under constitutive (c-NIS) or doxycycline-inducible (i-NIS) promoter. Hematopoetic stem cells (HSCs) were transduced with c-NIS, i-NIS, or a null lentivirus. C57Bl/6 mice (n=57) underwent bone marrow ablation by irradiation and bone marrow was replaced with transduced HSCs (5x105). After 8 weeks, mice underwent coronary artery ligation. Doxycycline (dox) was provided to a subset of i-NIS mice 4d before surgery. Serial SPECT imaging demonstrated increased radioiodine uptake in the perfusion defect of c-NIS compared to NIS-null mice (TBR infarct: MI+3d, 3.0±0.3 v 1.6±0.1 p&lt;0.001; MI+7d, 3.1±0.9 v 1.4±0.3 p&lt;0.01), and comparable uptake in i-NIS transplanted mice. Infarct-to-remote-myocardium radioiodine uptake ratio was 6.5±0.2% higher in c-NIS versus NIS null (p&lt;0.05). Dox-induced i-NIS mice exhibited increased radioiodine uptake in whole myocardium compared to non-induced i-NIS at 1d post-MI (TBR: 2.0±0.3 v 1.6±0.3, p=0.04). This difference dissipated at 7d (TBR 1.5±0.5 v 1.3±0.1, p=0.27). Multi-isotope autoradiography confirmed the presence of radioiodine within the infarct region, associated with histologic markers of inflammation. Bone marrow transplant with NIS reporter gene-labeled HSCs enabled tracking of cell homing post-MI. The inducible construct has the advantage for delivery and/or monitoring of a therapeutic agent with exquisite temporal control.
Abstract 17721: A Distinctively Adverse Pattern of Left Atrial Myopathy is Observed Among Aged Adults With Diabetes Mellitus
Authors: Vivian J Chow, Hannah H Chew, Shuang Leng, Xiaodan Zhao, Liang Zhong, Ru San Tan, Woon-Puay Koh, Angela S Koh
Journal: Circulation (2017)

Introduction: Left atrial (LA) phasic function is emerging as a sensitive marker of preclinical disease among cohorts without cardiovascular disease (CVD). LA myopathy is a phenomenon common to both diabetes mellitus (DM) and chronological aging. However, it is not known which phase of left atrial function is distinctly associated with DM before clinical CVD, particularly among aged adults susceptible to left atrial aging. Methods: We studied community based participants without known diagnoses of cardiovascular disease. Longitudinal LA strain comprising reservoir strain (es), conduit strain (ee) and booster strain (ea) and their corresponding peak strain rates (SRs, SRe, SRa) were measured using cardiac magnetic resonance feature tracking technique. Associations between age, DM, clinical covariates and left atrial phasic function were studied in adjusted models. Results: We studied 249 eligible participants (mean age 70.4±8.9 years; 110 (44%) females; 131 (53%) had hypertension, 119 (48%) had dyslipidemi...
Genetic or Pharmacological Inhibition of the Polycomb Group Protein BMI1 Impairs Leukemic Transformation Mediated By the CALM-AF10 Fusion Oncoprotein
Authors: Karina O. Barbosa, Anwesha Ghosh, Anagha Deshpande, Sayantanee Dutta, Scott A. Armstrong, Stefan K. Bohlander, Aniruddha J. Deshpande
Journal: Blood (2018)
SPECT/CT Findings in Scapular Notching After Reverse Shoulder Arthroplasty
Authors: Matthaeus Cieciera, Ralf Schoeniger, Ujwal Bhure, Klaus Strobel
Journal: Clinical Nuclear Medicine (2019)

Scapular notching (SN) is a unique complication in reverse shoulder arthroplasty, caused by repetitive impingement of the humeral polyethylene liner against the inferior scapular neck. It occurs in up to 96% of cases, with bone loss beneath the glenoid baseplate and polyethylene wear. SN can be associated with pain, decreased range of motion, and might result in glenoid implant failure. Modification of glenosphere design and humeral neck angle showed substantially less SN. SPECT/CT is a promising tool providing combined morphologic and metabolic information in symptomatic SN. We present SPECT/CT findings in 7 cases of symptomatic SN in reverse shoulder arthroplasty patients.
Talin-Dependent Integrin Activation Regulates VE-Cadherin Localization and Endothelial Cell Barrier Function
Authors: Fadi E. Pulous, Cynthia M. Grimsley-Myers, Shevali Kansal, Andrew P. Kowalczyk, Brian G. Petrich
Journal: Circulation Research (2019)

Rationale: Endothelial barrier function depends on the proper localization and function of the adherens junction protein VE (vascular endothelial)-cadherin. Previous studies have suggested a functional relationship between integrin-mediated adhesion complexes and VE-cadherin yet the underlying molecular links are unclear. Binding of the cytoskeletal adaptor protein talin to the β-integrin cytoplasmic domain is a key final step in regulating the affinity of integrins for extracellular ligands (activation) but the role of integrin activation in VE-cadherin mediated endothelial barrier function is unknown. Objective: To test the requirement of talin-dependent activation of β1 integrin in VE-cadherin organization and endothelial cell (EC) barrier function. Methods and Results: EC-specific deletion of talin in adult mice resulted in impaired stability of intestinal microvascular blood vessels, hemorrhage, and death. Talin-deficient endothelium showed altered VE-cadherin organization at EC junctions in vivo. shRNA (short hairpin RNA)-mediated knockdown of talin1 expression in cultured ECs led to increased radial actin stress fibers, increased adherens junction width and increased endothelial monolayer permeability measured by electrical cell-substrate impedance sensing. Restoring β1-integrin activation in talin-deficient cells with a β1-integrin activating antibody normalized both VE-cadherin organization and EC barrier function. In addition, VE-cadherin organization was normalized by reexpression of talin or integrin activating talin head domain but not a talin head domain mutant that is selectively deficient in activating integrins. Conclusions: Talin-dependent activation of EC β1-integrin stabilizes VE-cadherin at endothelial junctions and promotes endothelial barrier function.
Serum Erythropoietin Levels in Essential Thrombocythemia: Phenotypic and Prognostic Correlates
Authors: Natasha Szuber, Sravanthi Lavu, Mythri Mudireddy, Maura Nicolosi, Domenico Penna, Rangit Vallapureddy, Terra L. Lasho, Christy Finke, Curtis A. Hanson, Rhett P. Ketterling, Animesh Pardanani, Naseema Gangat, Ayalew Tefferi
Journal: Blood (2018)
Untargeted metabolomic profiling identifies disease-specific signatures in food allergy and asthma
Authors: Elena Crestani, Hani Harb, Louis-Marie Charbonnier, Jonathan Leirer, Alison Motsinger-Reif, Rima Rachid, Wanda Phipatanakul, Rima Kaddurah-Daouk, Talal A. Chatila
Journal: Journal of Allergy and Clinical Immunology (2019)
HDAC1 and HDAC2 Regulate Intermediate Progenitor Positioning to Safeguard Neocortical Development
Authors: Tianxiang Tang, Yandong Zhang, Yafei Wang, Zheping Cai, Zhiheng Lu, Leiting Li, Ru Huang, Astrid Hagelkruys, Patrick Matthias, Heng Zhang, Christian Seiser, Yunli Xie
Journal: Neuron (2019)