tbuckley/cabot-search huggingface dataset:
T-bet is not required for the generation of T cells with antitumor effector activity.
Authors: Poornima B. Rao, Hallie J. Graor, Julian A. Kim
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

5569 

INTRODUCTION: T-helper-1 cells have been postulated to be the key effectors responsible for specific antitumor immunity. Precursor T cell differentiation is dependent upon the activation of the transcription factor t-bet (T-box expressed in T cells), and the resultant transcription of Th-1 specific cytokines, with the suppression of Th-2 type cytokine expression. The purpose of this study was to determine whether t-bet protein expression and function was an absolute requirement for T cell mediated regression of established tumors in an in vivo model of adoptive therapy for cancer. METHODS: Previous studies have demonstrated that lymphocytes derived from tumor draining lymph nodes (TDLNs) can be activated with anti-CD3/IL-2 in vitro and mediate the regression of established tumor on adoptive transfer in vivo . TDLN derived from wild-type and t-bet deficient mice were compared for t-bet protein expression, cell surface phenotype, cytokine secretion, and therapeutic efficacy on adoptive transfer in vivo . RESULTS: 4T1 TDLNs from wild-type and t-bet deficient mice demonstrate similar expression of CD4/CD8, CD62L, CD30, B220, and Thy1.2. TDLN from both wild-type and t-bet deficient mice demonstrate similar tumor-stimulated cytokine release in vitro . When subfractionated on the basis of CD4 and CD8 expression, wild-type TDLN effectors exhibited similar tumor stimulated cytokine secretion, whereas t-bet deficient TDLN exhibited significantly greater CD8+ derived interferon gamma secretion relative to CD4+ cells. Finally, on adoptive transfer, TDLN from wild-type and t-bet deficient mice were able to mediate regression of 3-day established 4T1 subcutaneous tumors whether in wild-type or t-bet deficient hosts, though TDLN from t-bet deficient mice did so with diminished efficacy in wild-type animals. CONCLUSIONS: These results confirm that t-bet expression and function is not essential to the generation of therapeutic effector T cells in the adoptive therapy for cancer. t-bet does not appear to be required for the generation of T cell mediated antitumor immunity, suggesting the presence of a Th-1 independent mechanism for the generation of specific T cell based antitumor effector activity.
Abstract P114: Evidence of Transplacental Antibody Transfer in Proposed Animal Model for Hypoplastic Left Heart Syndrome
Authors: Charles R Cole, Mitali Basu, R Scott Baker, Chris Lam, Adita Blanco, Madeleine Cunningham, Pirooz Eghtesady
Journal: Circulation Research (2011)

Background: The pathogenesis of Hypoplastic Left Heart Syndrome (HLHS), a congenital heart disease with significant morbidity and mortality, remains unknown. We previously proposed a hypothesis wherein HLHS represents a type of rheumatic heart disease in the fetus; trans-placental passage of maternal anti-strep or anti-cardiac myosin (CM) antibodies are postulated to play a key role in the pathogenesis of disease. This is a first report of an animal model that we have developed to assess our hypothesis. Methods: Female Lewis rats (∼ 8 weeks old) were immunized with either streptococcal antigen M type 5 S. pyogenes (PepM5; n=6), rat CM (n=8) or saline (controls; n=5) with three booster injections administered at 2-week intervals. Serum titers of acquired PepM5 or CM antibodies were determined by ELISA assays every 7–14 days. No boosters were administered during gestation. Trans-uterine echocardiography was performed near term (E19-21) to determine fetal number and viability then cesarean section was performed under anesthesia to deliver the progeny. Maternal and fetal serum and hearts were harvested for analysis. Results: All rats immunized with PepM5 had elevated serum anti-PepM5 antibody titers (&gt;1:12800) and two of these animals also had elevated anti-CM titers (1:800). The offspring of these PepM5 immunized animals had elevated anti-PepM5 antibody titers (≥1:6400), but no CM elevation. Rats immunized with CM had a variable response ranging from anti-CM titers of 1:1600 to &gt;1:12800; there were two non-responders. Their fetuses had anti-CM titers that ranged from 1:100 to 1:800. None of the controls had detectable serum titers. Fetal CM titers of ≥1:200 correlate with maternal peak CM titers of ≥1:6400 and/or maternal harvest titers of ≥1:800. Thus far, 6 of the CM treated fetuses have evidence of left-sided morphologic abnormalities along a variable spectrum; all of these fetuses had CM titers of ≥1:200. Conclusion: We have documented maternal antibody response and trans-placental antibody transfer from maternal rats immunized with CM or PepM5 prior to pregnancy. Anti-CM antibody does not cross the placental as readily as PepM5. Preliminary histologic findings demonstrate probable HLHS phenotype, which appears to correlate with fetal antibody titer.
Concomitant Suppression of IKZF1, IRF4 and MYC Contribute to the Anti-Tumor Activity of the BET Inhibitor, Cpi-0610, in Disease Models of Multiple Myeloma
Authors: Ka Tat Siu, Janani Ramachandran, Andrew J. Yee, Homare Eda, Loredana Santo, Elizabeth K. O'Donnell, Cristina Panaroni, Jennifer Mertz, Robert J. Sims, Michael Cooper, Noopur Raje
Journal: Blood (2016)
Modified submucosal tunneling endoscopic resection for submucosal tumors in the esophagus and gastric fundus near the cardia
Authors: Qiang Zhang, Jian-Qun Cai, Li Xiang, Zhen Wang, Si de Liu, Yang Bai
Journal: Endoscopy (2017)

Background and study aims Submucosal tunneling endoscopic resection with double opening (DO-STER) was developed by our group for the resection of submucosal tumors in the esophagus and gastric fundus near the cardia. This study aimed to provide a preliminary evaluation of feasibility and safety of DO-STER. Methods The key to DO-STER is the creation of a tunnel opening in the mucosa over the inferior border of the tumor. During resection, the tumor can be gradually pushed out of the submucosal tunnel through the opening, leaving enough space for operation within the tunnel. A total of 10 tumors resected by DO-STER were retrospectively reviewed. Results All tumors were successfully resected by DO-STER. One tumor was located at the lower esophagus, four at the esophagogastric junction, and five at the gastric fundus near the cardia. Tumor size ranged from 1.0 × 1.2 cm to 3.5 × 5.0 cm, and all tumors originated from the muscularis propria. Operative times ranged from 45 to 150 minutes. No delayed bleeding or perforation occurred. Conclusion DO-STER seems to provide an alternative approach for resection of tumors in the esophagus and gastric fundus near the cardia.
Durable radiologic and clinical disease stability beyond PSA progression in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA).
Authors: Diletta Bianchini, Shahneen Kaur Sandhu, Amy Mulick Cassidy, Andrea Zivi, Janusz Mezynski, Deborah Mukherji, Carmel Jo Pezaro, Alison Helen Reid, Nikhil Babu Oommen, David Olmos, Aurelius Gabriel Omlin, Ajit Sarvadikar, Emilda Thompson, Joanne Hunt, Elizabeth Sheridan, Gerhardt Attard, Johann Sebastian De Bono
Journal: Journal of Clinical Oncology (2012)

4553 Background: AA, a potent oral CYP17A1 inhibitor is approved for treatment of mCRPC with a survival advantage of 4.9 months. In clinical practice, response evaluation remains challenging for pts with mCRPC. CTC conversion from CTC ≥ 5 to CTC &lt; 5 with treatment predicts for improved overall survival in mCRPC. We hypothesized that pts continue to have durable disease stability beyond PSA progression on AA. Methods: Prostate Specific Antigen (PSA) responses, radiological responses and CTC conversion rates were retrospectively analysed in pts treated on AA at our institution. CTCs, PSA and imaging were obtained at predefined time points during these studies. Radiological and PSA progression were defined by standard Prostate Cancer Working Group Criteria II. Clinical progression consisted of worsening disease related pain, skeletal events or declining performance status.Pearson’s chi-squared test and the Kaplan-Meier method were used for this analysis. Results: 141 patients [ECOG Performance Status 0-2; Median Age: 69.7 (range 44.7-87.1); 85 post-docetaxel, 56 pre-docetaxel] received AA. The median duration of clinical and radiological stable disease (SD) was 16.8 months (n=55) and 5.6 months (n=75) in patients with a baseline CTCs count of ≤ 5 cells/7.5mls and ≥ 5 cells/7.5 mls respectively. In the 105 patients with documented PSA progression on AA there was a median 5.7-month delay in detecting radiological and/or clinical progression (95% CI: 4.2, 8.4; range 0.3, 35.6 months). Radiological and clinical SD of ≥ 1 year, ≥ 2 years and ≥ 3 years on AA was observed in 43/141 (30.5%), 21/141 (14.9%) and 12/141 (8.5%) respectively. Conclusions: Radiological and clinical disease stabilization beyond PSA progression is maintained in a high proportion of mCRPC patients treated with AA. Future studies should evaluate whether continued AA treatment beyond PSA and radiological progression can impact outcome.
Cardiovascular Testing and Clinical Outcomes in Emergency Department Patients With Chest Pain
Authors: Alexander T. Sandhu, Paul A. Heidenreich, Jay Bhattacharya, M. Kate Bundorf
Journal: JAMA Internal Medicine (2017)

Noninvasive testing and coronary angiography are used to evaluate patients who present to the emergency department (ED) with chest pain, but their effects on outcomes are uncertain.To determine whether cardiovascular testing-noninvasive imaging or coronary angiography-is associated with changes in the rates of coronary revascularization or acute myocardial infarction (AMI) admission in patients who present to the ED with chest pain without initial findings of ischemia.This retrospective cohort analysis used weekday (Monday-Thursday) vs weekend (Friday-Sunday) presentation as an instrument to adjust for unobserved case-mix variation (selection bias) between 2011 and 2012. National claims data (Truven MarketScan) was used. The data included a total of 926 633 privately insured patients ages 18 to 64 years who presented to the ED with chest pain without initial diagnosis consistent with acute ischemia.Noninvasive testing or coronary angiography within 2 days or 30 days of presentation.The primary end points were coronary revascularization (percutaneous coronary intervention or coronary artery bypass graft surgery) and AMI admission at 7, 30, 180, and 365 days. The secondary end points were coronary angiography and coronary artery bypass grafting in those who underwent angiography.The patients were ages 18 to 64 years with an average age of 44.4 years. A total of 536 197 patients (57.9%) were women. Patients who received testing (224 973) had increased risk at baseline and had greater risk of AMI admission than those who did not receive testing (701 660) (0.35% vs 0.14% at 30 days). Weekday patients (571 988) had similar baseline comorbidities to weekend patients (354 645) but were more likely to receive testing. After risk factor adjustment, testing within 30 days was associated with a significant increase in coronary angiography (36.5 per 1000 patients tested; 95% CI, 21.0-52.0) and revascularization (22.8 per 1000 patients tested; 95% CI, 10.6-35.0) at 1 year but no significant change in AMI admissions (7.8 per 1000 patients tested; 95% CI, -1.4 to 17.0). Testing within 2 days was also associated with a significant increase in coronary revascularization but no difference in AMI admissions.Cardiac testing in patients with chest pain was associated with increased downstream testing and treatment without a reduction in AMI admissions, suggesting that routine testing may not be warranted. Further research into whether specific high-risk subgroups benefit from testing is needed.
Construction of versatile multilayered composite nanoparticles from a customized nanogel template
Authors: Jian Zhang, Jinpeng Jia, Jimin P. Kim, Fei Yang, Xing Wang, Hong Shen, Sijia Xu, Jian Yang, Decheng Wu
Journal: Bioactive Materials (2017)

We present a highly adaptable design platform for multi-responsive, multilayered composite nanoparticles (MC-NPs) with fine-tunable functional layers. A flexible disulfide-linked nanogel template is obtained by a controlled in-situ gelation method, enabling a high degree of control over each successive layer. From this template, we optimize "smart" biomaterials with biofunctional surfaces, tunable drug release kinetics, and magnetic or pH-responsive functionality, fabricated into MC-NPs for targeted drug release and periosteum-mimetic structures for controlled rhBMP-2 release towards bone tissue formation in-vivo. Such a versatile platform for the design of MC-NPs is a powerful tool that shows considerable therapeutic potential in clinical fields such as oncology and orthopedics.
Health, Wealth, and the U.S. Senate
Authors: Debra Malina, Stephen Morrissey, Mary Beth Hamel, Caren G. Solomon, Arnold M. Epstein, Edward W. Campion, Jeffrey M. Drazen
Journal: New England Journal of Medicine (2017)

The Better Care Reconciliation Act (BCRA), as the U.S. Senate calls the health care bill released by a small working group of Republican senators last week, is not designed to lead to better care for Americans. Like the House bill that was passed in early May, the American Health Care Act (AHCA), it would actually do the opposite: reduce the number of people with health insurance by about 22 million, raise insurance costs for millions more, and give states the option to allow insurers to omit coverage for many critical health care services so that patients with costly illnesses, preexisting . . .
Evaluation of the combination antiemetic therapy on chemotherapy-induced nausea and vomiting in patients with colorectal cancer receiving FOLFOX regimen: A pooled analysis
Authors: Mototsugu Shimokawa, Junichi Nishimura, Toshinobu Hayashi, Toshihiro Kudo, Takahiro Kogawa, Yoshihito Ide, Reiko Matsui, Keisuke Aiba, Kazuo Tamura
Journal: Annals of Oncology (2017)
Home monitoring improves endpoint efficiency in idiopathic pulmonary fibrosis
Authors: Kerri A. Johannson, Eric Vittinghoff, Julie Morisset, Joyce S. Lee, John R. Balmes, Harold R. Collard
Journal: European Respiratory Journal (2017)

The objective of this study was to investigate the reliability, feasibility and analytical impact of home-based measurement of forced vital capacity (FVC) and dyspnoea as clinical endpoints in idiopathic pulmonary fibrosis (IPF). Patients with IPF performed weekly home-based assessment of FVC and dyspnoea using a mobile hand-held spirometer and self-administered dyspnoea questionnaires. Weekly variability in FVC and dyspnoea was estimated, and sample sizes were simulated for a hypothetical 24-week clinical trial using either traditional office-based interval measurement or mobile weekly assessment. In total, 25 patients were enrolled. Mean adherence to weekly assessments over 24 weeks was greater than 90%. Compared with change assessment using baseline and 24-week measurements only, weekly assessment of FVC resulted in enhanced precision and power. For example, a hypothetical 24-week clinical trial with FVC as the primary endpoint would require 951 patients using weekly home spirometry compared with 3840 patients using office spirometry measures at weeks 1 and 24 only. The ability of repeated measures to reduce clinical trial sample size was influenced by the correlation structure of the data. Home monitoring can improve the precision of endpoint assessments, allowing for greater efficiency in clinical trials of therapeutics for IPF.
Early Infection Attenuates Hematologic Malignant Disease Relapse Following Initial Allogeneic Hematopoietic Cell Transplantation
Authors: Jeffery J Auletta, Monica I Ardura, Sumithira Vasu, Ying Huang, Qiuhong Zhao, Amy S. Ruppert, Abigail Shoben, Patrick Elder, Anissa Bingman, Rhonda Kitzler, Gerard Lozanski, Rolla Abu-Arja, Hemalatha G. Rangarajan, Rajinder Bajwa, Edwin M Horwitz, Lynn O'Donnell, Samantha Jaglowski, Rebecca B Klisovic, Sam Penza, Yvonne A Efebera, Craig C Hofmeister, Ashley E Rosko, Don M Benson, Leslie A. Andritsos, William Blum, Steven M Devine
Journal: Blood (2016)
Thiopurine Methyltransferase Genotype Distribution in Irish Patients with Crohn's and Ulcerative Colitis: A Frequency Study
Authors: B Crowley, E Bairead, F Shanahan, LJ Fanning
Journal: Endoscopy (2006)

Aims: The aim of this study was to determine the frequency of TMPT polymorphisms in a population of Crohns and Ulcerative Colitis patients and whether or not this was different to the frequency reported in other Caucasian populations. Source material This was a blinded randomized study. The DNA used in this study was selected from a biobank of specimens used to previously to identify genetic associations with Crohns and Ulcerative Colitis.
Detection of ErbB dimers in cell lines and breast cancer tissue using DNA programmed chemistry
Authors: David Livingston, Tanya Landsman, Richard Martinelli, Lawrence Haff, Yumei Huang, Benjamin Seigal, Dingxue Yan, James Coull
Journal: Clinical Cancer Research (2008)

B20  ErbB receptors, including EGFR and Her2, are involved in an array of combinatorial interactions which can form homo- or heterodimers. Currently, there are no approved clinical diagnostics that can directly visualize ErbB dimers in FFPE tissue sections using fluorescence microscopy. Such a diagnostic would prove valuable in predicting drug treatment failures for ErbB-targeted agents. We have developed a fluorescence microscope-based assay for identifying ErbB family dimeric forms in breast cancer tissue. Our technology is based on Ensemble’s DNA programmed chemistry (DPC). We introduced two separate ErbB-specific DNA-linked non-fluorescent probe precursors into permeabilized cells or sectioned tissue that subsequently react in situ to produce a fluorophore at the site of a receptor dimer in cell monolayers or tissue sections. Using this technology, we have quantified ErbB homo- and heterodimers in human ErbB-expressing cell lines that express Erb1, 2 or 3, and the response of these dimer levels to ligands such as EGFR or Heregulin. Biochemical analysis of these cell lines under the same treatment conditions have allowed us to correlate our DPC-based readout with the presence of dimers as detected by cross-linking and Western blot. Further, we have detected and quantified ErbB2 dimer levels in FFPE human breast cancer tissue sections. We conclude that this new technique will be useful in translational studies of resistance to ErbB-directed targeted therapies.
THERE'S AN APP FOR THAT: RELIABILITY OF AN IPHONE APP TO ASSESS UPPER EXTREMITY PROPRIOCEPTION AND STABILITY
Authors: James Lynch, Keeley Smith, Vrund Patel, Kayla Luchan
Journal: British Journal of Sports Medicine (2017)

Background The ability to maintain joint stability and motion control of the extremities is important in injury prevention and recovery. Quantitative measurement of proprioception, especially the upper extremity, is difficult and requires expensive equipment. Objective We investigated the reliability of a custom iPhone app to compile accelerometer data and calculate a path length of movement during 20 second trials. Design This study used a prospective test-retest design. Subjects completed three trials on each upper extremity (RA and LA) 48 hours apart (MWF). A convenience sample of subjects was used. Setting The study was conducted at a small liberal arts undergraduate institution. Patients (or Participants) Subjects were students associated with exercise science or athletic training programs. The activity level ranged from recreational athlete to NCAA Division II athletes. Twenty-three subjects started with 15 completing all upper extremity trials. Exclusion criterion was an upper extremity injury in the last month. Interventions (or Assessment of Risk Factors) An iPhone 6 app was developed to utilize accelerometer data in a Cartesian grid. Data was obtained at 20 Hz to calculate a path length of motion for each trial. Each subject stood, holding the iPhone in the palm of the hand directly in front of the shoulder with palm up, attempting to minimize motion for 20 seconds. Main Outcome Measurements Reliability measures were calculated between trials using the path length of motion in each trial. Results The mean path length for RA was 2669 with a standard error of 372, with LA being 2774 and 424. The intraclass correlation coefficient was 0.86 for the right arm and 0.74 for the left across three trials. Conclusions The accelerometer in an iPhone 6 is a moderately reliable instrument for assessing motion control stability in the upper extremity. We plan to add additional data filtering to the app.
Abstract 144: An Intact NEDD8 Pathway Protects Cardiomyocytes against Proteotoxic Stress
Authors: Huabo Su, Jie Li, Wenxia Ma
Journal: Circulation Research (2013)

NEDD8 is a ubiquitin (Ub)-like protein whose modification on cellular proteins is crucial to various cellular processes. Conjugation of NEDD8 to target proteins (neddylation) is mediated by its unique set of E1, E2 and E3, and can be reversed by the actions of deneddylase such as the COP9 signalosome (CSN) and NEDP1, a process termed deneddylation. Canonical neddylation involves NEDD8 E1 (NAE1) and directly attaches NEDD8 to the substrate, whereas atypical neddylation utilizes a Ub activating enzyme (UBE1) to incorporate NEDD8 to the Ub chain of target proteins. The physiological significance of such atypical neddylation remains unknown in any cell types. Here we report a protective role of atypical neddylation to proteotoxic stress in cardiomyocytes. Proteasome inhibitor Bortezomib (BZM) increases high molecular weight species of neddylated proteins in a dose- and time- dependent manner. Immunoprecipitation analysis reveals mixed modification of these proteins by Ub and NEDD8. Silencing of UBE1, but not inhibition of NAE1, diminishes BZM-induced neddylation response and aggravates the BZM-induced cell death. Interestingly, forced expression of deneddylase NEDP1 also reduces BZM-induced neddylation but surprisingly attenuates cell injury. The protective effect of NEDP1 is dependent on its deneddylation activity. We thus propose that atypical neddylation is an adaptive response and that dynamic cycling of neddylation and deneddylation is essential to cardiomyocytes to antagonize proteotoxic stress, possibly through preventing depletion of ubiquitin. Additionally, imposing proteotoxic stress by H2O2, simulated ischemia reperfusion or expression of misfolded proteins all elicits such atypical neddylation in cardiomyocytes. Furthermore, increased neddylated proteins are also evident in mouse hearts suffering from proteotoxic stress, which is caused by either expression of misfolded proteins or deficiency of a 19S proteasome subunit. These findings, combined with our previous reports that the CSN regulates proteasomal and autophagic proteolysis in the heart, strongly suggest that a fine-tuned NEDD8 system is critical to protein quality control and is essential to cardiomyocyte survival and functioning.