tbuckley/cabot-search huggingface dataset:
A novel spontaneous hepatocellular carcinoma mouse model for studying T-cell exhaustion in the tumor microenvironment
Authors: Yu-Tzu Liu, Tai-Chung Tseng, Ruey-Shyang Soong, Chun-Yi Peng, Yu-Hsing Cheng, Shiu-Feng Huang, Tsung-Hsien Chuang, Jia-Horng Kao, Li-Rung Huang
Journal: Journal for ImmunoTherapy of Cancer (2018)

Immunotherapy has ushered in a new era of cancer therapy, and this is also applicable to therapy of hepatocellular carcinoma (HCC). In this context, effective development of therapeutic strategies requires an HCC mouse model with known tumor-associated antigens (TAAs) and an HCC growth reporter. We created such a model using hydrodynamic injection and a transposon system to introduce <i>AKT</i> and <i>NRAS</i> and open reading frames (ORFs) encoding surrogate tumor antigens and luciferase into chromosomes of hepatocytes to induce nodular and diffuse tumors in the liver. TAA-specific CD8<sup>+</sup> T cells were detected during HCC progression; however, these showed exhausted-like phenotypes and were unable to control tumor growth. Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAM) from the tumor microenvironment were found to contribute to the suppression of the CD8<sup>+</sup> T-cell response. The transposon-based Akt/N-Ras-induced HCC mouse model we developed enables researchers to monitor tumor growth non-invasively and to quantify and characterize endogenous or adoptively transferred TAA-specific CD8<sup>+</sup> T-cell responses. These features make it a suitable preclinical model for exploration and evaluation of immune checkpoint inhibitors and cell-based immunotherapies for HCC treatment.
Overall survival of transplant eligible patients with newly diagnosed multiple myeloma: comparative effectiveness analysis of modern induction regimens on outcome
Authors: Ashley R. Paquin, Shaji K. Kumar, Francis K. Buadi, Morie A. Gertz, Martha Q. Lacy, Angela Dispenzieri, David Dingli, Lisa Hwa, Amie Fonder, Miriam Hobbs, Suzanne R. Hayman, Steven R. Zeldenrust, John A. Lust, Stephen J. Russell, Nelson Leung, Prashant Kapoor, Ronald S. Go, Yi Lin, Wilson I. Gonsalves, Taxiarchis Kourelis, Rahma Warsame, Robert A. Kyle, S. Vincent Rajkumar
Journal: Blood Cancer Journal (2018)

Abstract Overall survival (OS) of multiple myeloma has improved remarkably over time, with the recent Intergroupe Francophone du Myelome (IFM) 2009 randomized trial reporting a 4-year OS rate of approximately 82% in patients receiving modern therapy. However, survival estimates from clinical trials may overestimate outcomes seen in clinical practice even with the adjustment for age and other key characteristics. The purpose of this study was to determine the OS of myeloma patients seen in routine clinical practice who resembled the cohort studied in the IFM 2009 trial. A second goal was to conduct a brief comparative effectiveness analysis of bortezomib, lenalidomide, dexamethasone, and other major induction regimens used during the study period. We studied all patients with myeloma 65 years of age and younger, seen at the Mayo Clinic between January 1, 2010 and August 31, 2015, who had a stem cell harvest performed within 12 months of initial diagnosis. Patients with baseline serum creatinine &gt;2 mg/dL were excluded. Five hundred and eighteen patients were studied. The 4-year OS rate was 82.3%, comparable to results achieved in the contemporaneous IFM randomized trial. The 4-year OS rates for standard and high-risk myeloma were 86.3% and 68.2%, respectively.
Use of Combination Systemic-Intratumoral HPV Vaccine to Treat Cutaneous Basaloid Squamous Cell Carcinomas
Authors: Florence Brunet-Possenti, Lydia Deschamps, Charlotte Charpentier
Journal: JAMA Dermatology (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Abstract 21230: Mortality in Coronary Disease Following Cardiac Rehabilitation: Focus on Weight Loss or Lean Mass?
Authors: Sergey Kachur, Michael Morledge, Carl J Lavie, De Schutter Alban, Ross Arena, Richard Milani
Journal: Circulation (2017)

Introduction: Cardiac rehabilitation (CR) in stable coronary heart disease (CHD) has been shown to improve mortality commensurate with levels of improvement in cardiorespiratory fitness (CRF) and lean mass. The current study examines the effects of changes in LM in determining mortality outcomes after CR. Hypothesis: Effects of weight changes on mortality are influenced by the obesity paradox; stratifying weight changes by lean mass (LM) will help differentiate healthy from unhealthy weight loss. Methods: 1110 subjects with stable CHD referred for CR between 01/2000 and 06/2013 with a mean follow-up of 6.3 years were stratified according to median change in peak oxygen consumption (VO 2 ) measured during maximal cardiopulmonary exercise testing and median change in LM index (LMI). Mortality differences were adjusted for age, sex, baseline VO 2 , ejection fraction, and body mass index. Results: Changes in weight following CR were not a significant predictor of mortality. Likewise, changes in waist circumference and LMI were not significant independent predictors of mortality. However, change in LMI when combined with change in peak VO 2 yielded significant prognostic information between those in the top and bottom 50 th percentile of peak VO 2 changes (HR 2.58; 95% CI 1.54-4.33; p &lt; 0.001) and a strong trend toward significance for lower mortality in individuals who gain LMI (HR 1.72; 95% CI 0.99-2.97; p = 0.05). ( Figure 1 ) Conclusions: In patients with CHD, stratifying changes in LM by peak VO 2 has the potential to gauge the response to exercise training and associated mortality benefits than each measure alone. Further study is needed to determine if targeting both increases in VO 2 and LMI can lead to better outcomes in patients enrolling into CR.
Strategies for improving diabetic therapy via alternative administration routes that involve stimuli-responsive insulin-delivering systems
Authors: Yu-Jung Lin, Fwu-Long Mi, Po-Yen Lin, Yang-Bao Miao, Tringyo Huang, Kuan-Hung Chen, Chiung-Tong Chen, Yen Chang, Hsing-Wen Sung
Journal: Advanced Drug Delivery Reviews (2018)
Preliminary results from a phase 1 study of AB122, a programmed cell death-1 (PD-1) inhibitor, in patients with advanced solid malignancies
Authors: L.C. Seitz, A. Rieger, W. Berry, D. Ashok, D. Direnzo, L. Jin, S.J. Lee, A. Park, D. Piovesan, J.B.L. Tan, M.J. Walters, J. Karakunnel
Journal: Annals of Oncology (2018)

Background: AB122 is a fully human monoclonal antibody targeting PD-1. It binds tightly to a different PD-1 epitope than other currently approved antibodies in this class. Here we report preliminary data from an ongoing, open-label, dose-escalation (3 + 3 design) study evaluating the safety, tolerability, immunogenicity, pharmacokinetics, pharmacodynamics, and antitumor activity of AB122 monotherapy in patients (pts) with select advanced solid tumors. Methods: Eligible pts had pathologically confirmed select advanced solid tumors, received ≤5 prior lines of systemic therapies, and had measurable disease per RECIST v1.1. AB122 was administered intravenously (IV) every 2 wks (Q2W) at escalating doses (80, 240, 720 mg). Intermediate Q2W doses and other schedules (every 3 wks [Q3W] or 4 wks [Q4W]) were also evaluated. Adverse events (AEs) were graded according to NCI CTCAE v4.03 and antitumor activity was assessed using RECIST v1.1. Results: As of 15Aug2018, 19 pts with advanced ovarian (n = 7), endometrial (n = 3), colorectal (n = 3), gastroesophageal (n = 2), head and neck, breast, prostate, and lung (n = 1 each) cancer were treated at doses of 80 mg Q2W (n = 3), 240 mg Q2W (n = 6), 360 mg Q2W (n = 1), 360 mg Q3W (n = 4), and 480 mg Q4W (n = 5). Most pts were female (74%) and White (89%); median age was 68 yrs (51-80). The number of doses received ranged from 1 to 18; 8 pts remain on study. The most common treatment-emergent AEs were fatigue (42%), diarrhea (21%), urinary tract infection, back pain, nausea, and anemia (16% each). 16% of pts each had ≥Grade 3 AEs and serious AEs but none were considered treatment-related by investigators. There were no dose-limiting toxicities or discontinuations due to AEs. Data from pts in the 80 and 240 mg Q2W cohorts showed that AB122 serum concentrations ≥1.5 μg/mL (equivalent to 10 nM) are associated with full receptor occupancy. Among 12 efficacy-evaluable pts, the disease control rate was 42%. Conclusions: These preliminary results indicate that AB122 monotherapy was well tolerated and active in various advanced solid tumor types. The dose and schedule of 240 mg IV Q2W were selected for further evaluation as monotherapy and in combination with other agents. Legal entity responsible for the study: Arcus Biosciences, Inc. Funding: Arcus Biosciences, Inc. Disclosure: L.C. Seitz, W. Berry, D. Ashok, D. Direnzo, L. Jin, S.J. Lee, A. Park, D. Piovesan, J. Karakunnel: Employee of Arcus Biosciences, Inc. A. Rieger, J.B.L. Tan, M.J. Walters: Employee of Arcus Biosciences, Inc.
Correlative analysis of gene expression changes and PD-L1 immunoexpression in non-small cell lung cancer
Authors: I.M.C. Guerreiro, D. Barros-Silva, P. Lopes, A.L. Cunha, J. Lobo, A. Rodrigues, M. Soares, L. Antunes, R. Henrique, C. Jerónimo
Journal: Annals of Oncology (2018)

Background: Lung cancer (LC) cells frequently express programmed death-ligand 1 (PD-L1). Although this expression grossly correlates with likelihood of response to checkpoint inhibitors, prediction of response is rather imperfect and, thus, more accurate predictive biomarkers are mandatory. The aim of this study was to investigate the association of immune checkpoint PD-L1 and DNA methylation status of DNA repair genes (RAD51B and XXRC3) as well as vimentin (VIM) expression in non-small cell lung cancer (NSCLC), correlating with patients' outcome. Methods: A cohort of NSCLC patients diagnosed between August 2014 and June 2017 were enrolled after informed consent. Expression of PD-L1 was determined by IHQ. Evaluation of the methylation status of DNA repair genes (RAD51B and XRCC3) and VIM expression was performed by quantitative methylation-specific PCR (qMSP) using SybrGreen methodology. Predictors of PD-L1 expression were determined using logistic regression multivariable models. Impact on overall survival was determined using Cox analysis. Results: A total of 75 patients with NSCLC were assessed for PD-L1 immunoexpression, 60 (80%) were male and the median age was 64 years old (range: 29-88). Fifty patients (66.7%) presented adenocarcinoma, 24 (32%) squamous cell carcinoma and one NSCLC NOS. Thirty-nine (52%) cases depicted positivity for PD-L1. RAD51B promoter methylation levels and VIM expression were significantly higher in PD-L1 positive cases compared to negative group (p = 0.01). This significant association was maintained in multivariable analyses: per each unit increase in RAD51B promoter methylation level and VIM expression, the OR for PD-L1 expression was 20.4 (CI95%: 1.5-275.2) and 1.23 (CI95%: 1-1.4), respectively. Association between XXRC3 promoter methylation and PD-L1 expression was not found. None of the analyzed markers associated with patients' overall survival. Conclusions: Herein, higher RAD51B methylation levels and VIM expression are independently associated with PD-L1 immunoexpression. Further studies with an extended cohort and follow-up period are warranted to validate these results. Legal entity responsible for the study: Instituto Português de Oncologia do Porto. Funding: Instituto Português de Oncologia do Porto. Disclosure: All authors have declared no conflicts of interest.
Differential Subcellular Localization Regulates Oncogenic Signaling by ROS1 Kinase Fusion Proteins
Authors: Dana S. Neel, David V. Allegakoen, Victor Olivas, Manasi K. Mayekar, Golzar Hemmati, Nilanjana Chatterjee, Collin M. Blakely, Caroline E. McCoach, Julia K. Rotow, Anh Le, Niki Karachaliou, Rafael Rosell, Jonathan W. Riess, Robert Nichols, Robert C. Doebele, Trever G. Bivona
Journal: Cancer Research (2018)

Abstract Chromosomal rearrangements involving receptor tyrosine kinases (RTK) are a clinically relevant oncogenic mechanism in human cancers. These chimeric oncoproteins often contain the C-terminal kinase domain of the RTK joined in cis to various N-terminal, nonkinase fusion partners. The functional role of the N-terminal fusion partner in RTK fusion oncoproteins is poorly understood. Here, we show that distinct N-terminal fusion partners drive differential subcellular localization, which imparts distinct cell signaling and oncogenic properties of different, clinically relevant ROS1 RTK fusion oncoproteins. SDC4-ROS1 and SLC34A2-ROS1 fusion oncoproteins resided on endosomes and activated the MAPK pathway. CD74-ROS1 variants that localized instead to the endoplasmic reticulum (ER) showed compromised activation of MAPK. Forced relocalization of CD74-ROS1 from the ER to endosomes restored MAPK signaling. ROS1 fusion oncoproteins that better activate MAPK formed more aggressive tumors. Thus, differential subcellular localization controlled by the N-terminal fusion partner regulates the oncogenic mechanisms and output of certain RTK fusion oncoproteins. Significance: ROS1 fusion oncoproteins exhibit differential activation of MAPK signaling according to subcellular localization, with ROS1 fusions localized to endosomes, the strongest activators of MAPK signaling.
Risk of Atrial Fibrillation with Ibrutinib in Patients with B-Cell Malignancies: An Updated Meta-Analysis of Phase III Randomized Controlled Trials
Authors: Somedeb Ball, Wasawat Vutthikraivit, Avash Das, Peggy J Edwards, Lukman Tijani, Nicholas J Short, Abhishek Maiti
Journal: Blood (2018)
B-cell lymphomas present immunoglobulin neoantigens
Authors: Michael S. Khodadoust, Niclas Olsson, Binbin Chen, Brian Sworder, Tanaya Shree, Chih Long Liu, Lichao Zhang, Debra K. Czerwinski, Mark M. Davis, Ronald Levy, Joshua E. Elias, Ash A. Alizadeh
Journal: Blood (2018)
Human sgo1 down-regulation leads to chromosomal instability in human colorectal cancer cells
Authors: Moriya Iwaizumi, Kazuya Shinmura, Hidetaka Yamada, Haruhiko Sugimura
Journal: Cancer Research (2008)

5074  Chromosomal instability (CIN) is recognized as a hallmark of cancer and is caused by a spindle assembly checkpoint disorder or chromosome mis-segregation during mitosis. Although the recent identification of human shugoshin (hSgo1), an important player in proper chromosome segregation, has suggested involvement of hSgo1 in tumorigenesis, little is known about how it is involved. To obtain information about the status of hSgo1 in human colorectal cancer, we studied the alterations of hSgo1 in colorectal cancer cases. Among the 30 colorectal cancer cases, five of the 16 (31.2%) informative cases had loss of heterozygosity at the hSgo1 locus on 3p24, but there was no mutation in the other allele. In 10 of 24 (41.7%) cases, hSgo1 mRNA expression was decreased in the tumor tissue in comparison with the corresponding normal tissue (P=0.032). Interestingly, in addition to the down-regulation of full-length hSgo1 protein in the tumor in 40% of the cases, the cleavage pattern in the tumor and corresponding non-tumor tissues differed in 73%. To assess the effects of hSgo1 down-regulation, we performed hSgo1 knockdown by transfecting the diploid HCT116 cell line with a short hairpin RNA expression vector. Human Sgo1 knockdown cells proliferated slowly because of both G2/M arrest and apoptosis, and marked of CIN in the form of aneuploidy and micronuclei were later observed in hSgo1 knockdown cells. Increased centrosome amplification, the presence of binucleated cells, and mitotic catastrophes were also noted in hSgo1 knockdown cells. Taken together, these findings suggest that hSgo1 down-regulation leads to CIN in colorectal cancer.
Acute Kidney Injury in Patients Receiving Systemic Treatment for Cancer: A Population-Based Cohort Study
Authors: Abhijat Kitchlu, Eric McArthur, Eitan Amir, Christopher M Booth, Rinku Sutradhar, Habeeb Majeed, Danielle M Nash, Samuel A Silver, Amit X Garg, Christopher T Chan, S Joseph Kim, Ron Wald
Journal: JNCI Journal of the National Cancer Institute (2018)

Patients undergoing treatment for cancer are at increased risk of acute kidney injury (AKI). There are few data on AKI incidence and risk factors in the current era of cancer treatment.We conducted a population-based study of all patients initiating systemic therapy (chemotherapy or targeted agents) for a new cancer diagnosis in Ontario, Canada (2007-2014). The primary outcome was hospitalization with AKI or acute dialysis. We estimated the cumulative incidence of AKI and fitted Fine and Gray models, adjusting for demographics, cancer characteristics, comorbidities, and coprescriptions. We modeled exposure to systemic therapy (the 90-day period following treatments) as a time-varying covariate. We also assessed temporal trends in annual AKI incidence.We identified 163 071 patients initiating systemic therapy of whom 10 880 experienced AKI. The rate of AKI was 27 per 1000 person-years, with overall cumulative incidence of 9.3% (95% CI = 9.1% to 9.6%). Malignancies with the highest 5-year AKI incidence were myeloma (26.0%, 95% CI = 24.4% to 27.7%), bladder (19.0%, 95% CI = 17.6% to 20.5%), and leukemia (15.4%, 95% CI = 14.3% to 16.5%). Advanced cancer stage, chronic kidney disease, and diabetes were associated with increased risk of AKI (adjusted hazard ratios [aHR] = 1.41, 95% CI = 1.28 to 1.54; 1.80, 95% CI = 1.67 to 1.93; and 1.43, 95% CI = 1.37 to 1.50, respectively). In patients aged 66 years or older with universal drug benefits, diuretic, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker coprescription was associated with higher AKI risk (aHR = 1.20, 95% CI = 1.14 to 1.28; 1.30, 95% CI = 1.23 to 1.38). AKI risk was further accentuated during the 90-day period following systemic therapy (aHR = 2.34, 95% CI = 2.24 to 2.45). The annual incidence of AKI increased from 18 to 52 per 1000 person-years between 2007 and 2014.Cancer-related AKI is common and associated with advanced stage, chronic kidney disease, diabetes, and concomitant receipt of diuretics or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. Risk is heightened in the 90 days after systemic therapy. Preventive strategies are needed to address the increasing burden of AKI in this population.
Mechanisms of Adaptation to Ibrutinib in High Risk Chronic Lymphocytic Leukemia
Authors: Valeria Spina, Gabriela Forestieri, Antonella Zucchetto, Alessio Bruscaggin, Tamara Bittolo, Lodovico Terzi di Bergamo, Eva Szenes, Adalgisa Condoluci, Erika Tissino, Lorenzo De Paoli, Clara Deambrogi, Anna Maria Frustaci, Francesco Autore, Michele Merli, Lydia Scarfo, Claudia Cirillo Sanchez, Francesca Guidetti, Simone Favini, Fary Diop, Renzo Lucchini, Tanja N. Hartmann, Giovanni Del Poeta, Roberto Marasca, Francesco Zaja, Bernhard Gerber, Emanuele Zucca, Georg Stussi, Jakob R. Passweg, Paolo Ghia, Francesco Passamonti, Michael Gregor, Luca Laurenti, Marco Montillo, Alessandra Tedeschi, Franco Cavalli, Gianluca Gaidano, Valter Gattei, Davide Rossi
Journal: Blood (2018)
Abstract 13165: Median Household Income and Rural Location Associated With Sudden Unexpected Death in Wake County, NC
Authors: Louisa A Mounsey, Feng-Chang Lin, Mary Elizabeth Lewis, Parin Nanavati, Neil Mehta, Anthony Nwosu, Chani J Hodonsky, Irion Pursell, Eugene H Chung, Ross J Simpson, John P Mounsey
Journal: Circulation (2015)

Introduction: The incidence of sudden unexpected death (SUD) in a racially and socioeconomically diverse population has been inadequately studied. We collated all SUDs among the 18 to 64 year population over a 12-month period in Wake County, North Carolina, a racially and socioeconomically diverse predominantly urban county, population c1 million. We investigated the socioeconomic differences in incidence of SUD to assist in future development of targeted interventions. Methods: Cases of possible SUD were identified from the Wake County EMS. Expected deaths were excluded and determination for cohort inclusion was made by independent cardiologists from review of medical records and medical examiner’s reports. SUD cases were geocoded to the level of census tract using death certificate residence address and the U.S Census Geocoder. Wake County includes 185 census tracts, population 5022 ± 2285 (M±SD). Median household income and other demographic data were obtained from the 2013 American Community Survey and 2010 U.S Census. Univariate and multivariable analysis were used to identify associates of SUD. Results: The 2013 incidence of SUD in Wake County was 19.5/100,000. A majority (107 of 185) of census tracts had at least one SUD, with 190 total. Census tracts with ≥1 SUD had a higher population of African Americans, a greater proportion unmarried, and a lower median household income than those with no SUDs (figure, p≤.001). After multivariable analysis, only median household income and rural tract location remained significantly associated with sudden death. Conclusion: This examination exemplifies the importance of studying sudden unexpected death in a racially and socioeconomically diverse population. Multivariable analysis suggests that low household income and rural location are important potential contributing factors to sudden death. Educational interventions to reduce the incidence of sudden death should be developed with these populations in mind.