tbuckley/cabot-search huggingface dataset:
BRCA1 and BRCA2 mutations/variations in African Americans
Authors: Carolyn W. Broome, Desta Beyene, Meseret Ashenafi, Yasmine Kanaan, Marina Ganpat, Georgia Dunston, Lawrence Brody
Journal: Cancer Research (2005)

1322   BRCA1/2 mutations were investigated in 99 independent families at elevated risk of germline mutations. Of the 99 high-risk families, 71 were families with multiple cases of breast cancer, 14 with multiple cases of breast and ovarian cancers, 8 with only early onset breast cancer (40 years or less), 3 with only bilateral breast cancer, 2 with male breast cancer, and 1 individual with breast and ovarian cancer. In this study, families were screened by denaturing high performance liquid chromatography (DHPLC). One deleterious BRCA1 mutation (5296delGAAA) was detected in two unrelated families. One of these families had 12 cases of breast cancer and 3 ovarian cancers, and the proband (tested individual) was diagnosed at age 32. The other family had 3 cases of breast cancer, 1 case of ovarian cancer, 2 cases of prostate cancer; and the proband was diagnosed at age 30 with estrogen/progesterone receptor-negative (ER-PR-) cancer. Early age of onset and ER-PR- tumors are characteristic of BRCA1 carriers. This protein truncating mutation deletes important functional regions of BRCA1, has previously been reported in African Americans, Africans, and other ethnic groups, and may represent a founder mutation arising hundreds of years ago. Two missense variations (Ile379Met and Glu1210Lys) may affect BRCA1 function. The Ile379Met variation, which has been previously reported in African Americans and Caucasians, is predicted to affect function by SIFT analysis (Ng & Henikoff, 2001) and by comparison of human, ancestral eutherian, and marsupial protein sequences (Ramirez et al., 2004). Ile379Met was detected in a woman diagnosed with ER-PR- breast cancer at ages 41 and 46; her mother also had breast cancer. The Glu1210Lys variation, which has not been previously noted in the breast cancer information core (BIC), is predicted to affect function by SIFT analysis. However, the proband was diagnosed at age 79 with ER+PR+ breast cancer and has 2 affected sisters. The BRCA1 884G>A rare variation (silent Glu255) is located in an alternative exon 11 splicing enhancer (ESE) sequence and is expected to delete most of exon 11 (Orban and Olah, 2001). This ESE variation, which has not been previously reported in the BIC, was observed in a family with 3 cases of breast cancer and the proband was age 56 at diagnosis. Numerous coding and non-coding unclassified variations and polymorphisms were detected with BRCA1 and BRCA2 analysis. Several of these variations have not been previously reported. Frequently, the same group of polymorphisms were observed in linkage disequilibrium in different families. Previously, we detected 2 deleterious BRCA1 mutations and 8 pathogenic BRCA2 mutations in this cohort of high-risk families (Panguluri et al., 1999; Kanaan et al., 2003).
Adding care to cure for patients with liver disease: A cultural shift
Authors: Alain Braillon
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. TO THE EDITOR: Innes et al.1 must be commended for showing robust evidence that “at least half (in other term, more than half) the excess mortality risk for individuals with chronic hepatitis C in the US may be due to health risk behaviours rather than chronic hepatitis C.” This deserves comment, as I fear Innes et al. may be blowing in the wind. Indeed, this study confirms previous findings.2 For example, among health risk behaviors, smoking ranks first as an independent and dose‐related cause of hepatocellular carcinoma. In a large European cohort, the population‐attributable percentage for tobacco use for hepatocellular carcinoma (48%) was more than twice that of the second‐most attributed risk factor, hepatitis C (21%).3 This is also a concern elsewhere; for example, 50% of Chinese males are smokers, and smoking prevalence increases in developing countries. Sadly, raising concerns about health risk behaviors seems futile.5 First, there is enduring denial within the scientific community. Some editors, fearing scientific debate, reject comments challenging the relevance of studies of hepatocellular carcinoma that ignore smoking and conclude that screening improves survival despite raw data analysis. However, this notion is demonstrated by two recent reports by Cucchetti and Singal, in which the age of those screened was 60.3 years with a 14.6‐month survival versus 61.6 years and 6.0 months for patients who were not screened.5 Accordingly, screened patients died at a younger age than those who were not screened, despite previous warnings.8 Second is the rise of “sciensationalism” (i.e., sensationalism in science).8 The list of sciensationalist publications is too long to list here, even in journals that are not tabloids, but two recent examples are “The 8‐Week Cure for Hepatitis C”9 and “The Discovery of Sofosbuvir: A Revolution for Therapy of Chronic Hepatitis C.”8 A search of all PubMed data since 2015 obtained 19 hits for “revolution” and “hepatitis” in the same article title. Industrial epidemics and the liver The epidemics of modern times are industrial epidemics, not viral epidemics. The agents are tobacco, alcohol, processed foods (with salt, fat, or sugar), the host is the industry, and the vector for transmission is brilliant but devastating social marketing. I do not want to shame my colleagues for bypassing health risk behaviors, however. Scapegoating is pointless, and the wisest attitude may simply be to have a concern for curing a disease. In contrast, being concerned only on an individual patient level may be absurd. I often feel like the Danaids, trying to fill a barrel with a sieve, because there are virtually no comprehensive and robust policies regarding the regulation of tobacco, alcohol, and junk foods due to deliberate inertia of most politicians. Worse, there are not enough resources and time to care for unhealthy behaviors, given that long‐term multiprofessional intervention is required but is not provided.9
136PD_PR 3-year survival and duration of response in randomized phase II study of atezolizumab (atezo) vs docetaxel (doc) in 2L+ NSCLC (POPLAR)
Authors: J. Mazières, K. Park, C. Lewanski, S. Gadgeel, L. Fehrenbacher, A. Rittmeyer, J-Y. Han, A. Artal-Cortes, F. Braiteh, J. Vansteenkiste
Journal: Journal of Thoracic Oncology (2018)
Abstract 17344: Serial Quantitative Cellular MRI of Macrophage Infiltration in the Post-Infarct Heart Using T1-Mapping and Gd-Liposomes
Authors: Nivedita K Naresh, Moriel H Vandsburger, Alexander L Klibanov, Ronald J Beyers, Patrick A Antkowiak, Yaqin Xu, Robert S Smith, Brent A French, Frederick H Epstein
Journal: Circulation (2010)

Introduction: Following myocardial infarction (MI), macrophages infiltrate the infarct zone to clear necrotic debris and modulate angiogenesis and infarct healing. Previously, in vivo MRI of post-M...
Abstract 14206: The Ryanodine Receptor Calcium Leak Does Not Contribute to the Development of Heart Failure
Authors: Belal A Mohamed, Stefan Neef, Dawid Lbik, Sara Khadjeh, Samuel Sossalla, Stephan Lehnart, Gerd Hasenfuss, Karl Toischer
Journal: Circulation (2015)

Rationale: Increased sarcoplasmic reticulum (SR) Ca2+ leak via cardiac ryanodine receptor (RyR2) is thought to play a role in heart failure (HF) development. Inhibition of this leak has been suggested to be an emerging therapeutic strategy. However, some studies have raised controversy as to the importance of SR Ca2+ leak in HF development. Previously, we and others have shown that pressure overload (PO) and myocardial infarction (MI) models result in an increased SR Ca2+ leak and maladaptive cardiac remodeling. Objective: We sought to determine whether inhibiting SR Ca2+ leak in PO or MI could avert HF progression. Methods and Results: Wild-type C57BL/6J mice treated with or without RyR2 stabilizer, Rycal S36, were exposed to two model of chronic cardiac stress, transaortic constriction (TAC)-induced PO or permanent coronary artery occlusion-induced MI. Left ventricular structural and functional remodeling were determined after surgeries. SR Ca2+ leak was significantly reduced in S36-treated mice versus placebo controls after surgeries. However, both placebo- and S36-treated mice developed pathological cardiac remodeling and systolic dysfunction nearly to the same extent in both experimental models. Interestingly, there was a trend, but not significant, toward improved survival in S36-treated mice compared to that in placebo (P = 0.12 and 0.13 in TAC-S36 and MI-S36, respectively). Conclusion: These results strongly support the idea that SR Ca2+ leak is irrelevant to the development of cardiac dysfunction after TAC or MI. The minimal reduced mortality after TAC or MI suggests a possible antiarrhythmic effect of the Rycal S36, which needs further investigations.
21P Influence of delayed and prolonged fixation on the evaluation of immunohistochemical staining on pulmonary resection specimen
Authors: M. Van Seijen, L. Brcic, A. Navarro, I. Sansano, M. Béndek, B. Witte, I. Brcic, R. Kammler, R.A. Stahel, E. Thunnissen
Journal: Journal of Thoracic Oncology (2018)
Adiponectin determines farnesoid X receptor agonism-mediated cardioprotection against post-infarction remodelling and dysfunction
Authors: Yunlong Xia, Fuyang Zhang, Shihao Zhao, Yueyang Li, Xiyao Chen, Erhe Gao, Xinyue Xu, Zhenyu Xiong, Xiaomeng Zhang, Jinglong Zhang, Huishou Zhao, Wei Wang, Helin Wang, Yanjie Guo, Yi Liu, Congye Li, Shan Wang, Ling Zhang, Wenjun Yan, Ling Tao
Journal: Cardiovascular Research (2018)

The farnesoid X receptor (FXR) is a member of the metabolic nuclear receptor superfamily that plays a critical regulatory role in cardiovascular physiology/pathology. However, the role of systemic FXR activation in the chronic phase in myocardial infarction (MI)-induced cardiac remodelling and dysfunction remains unclear. In this study, we aimed to elucidate the role of long-term FXR activation on post-MI cardiac remodelling and dysfunction.Mice underwent either MI surgery or sham operation. At 1 week after MI, both sham and MI mice were gavaged with 25 mg/kg/d of a synthetic FXR agonist (GW4064) or a vehicle control for 7 weeks, and cardiac performance was assessed by consecutive echocardiography studies. Administration of GW4064 significantly increased left ventricular ejection fraction at 4 weeks and 8 weeks after MI (both P < 0.01). Moreover, GW4064 treatment increased angiogenesis and mitochondrial biogenesis, reduced cardiomyocyte loss and inflammation, and ameliorated cardiac remodelling as evidenced by heart weight, lung weight, atrial natriuretic peptide/brain natriuretic peptide levels, and myocardial fibrosis at 8 weeks post-MI. At the molecular level, GW4064 significantly increased FXR mRNA expression and transcriptional activity in heart tissue. Moreover, over-expression of myocardial FXR failed to exert significant cardioprotection in vivo, indicating that GW4064 improved post-MI heart remodelling and function independent of myocardial FXR expression/activity. Among the four down-stream soluble molecules of FXR, plasma adiponectin was most significantly increased by GW4064. In cultured adipocytes, GW4064 increased mRNA levels and protein expression of adiponectin. Conditioned medium of GW4064-treated adipocytes activated AMPK-PGC-1α signalling and reduced hypoxia-induced cardiomyocyte apoptosis, all of which were attenuated by an adiponectin neutralizing anti-body. More importantly, when knocking-out adiponectin in mice, the cardioprotective effects of GW4064 were attenuated.We are the first to show that FXR agonism ameliorated post-MI cardiac dysfunction and remodelling by stimulating adiponectin secretion. Thus, we demonstrated that FXR agonism is a potential therapeutic strategy in post-MI heart failure.
Use of CMV gB/pp65 eVLPs to harness the immunogenicity of foreign viral antigens to target solid tumors.
Authors: David E Anderson, Tanvir Ahmed, Catalina Soare, Anne-Catherine Fluckiger, Barthelemy Ontsouka, Abebaw Diress, Jasminka Bozic, Matthew Yorke, Allen Waziri, Marc Kirchmeier, Francisco Diaz-Mitoma
Journal: Journal of Clinical Oncology (2017)

165 Background: Human cytomegalovirus (CMV) is a ubiquitous, generally asymptomatic virus that is present in over 90% of GBM and breast cancer tumors which have comparatively low mutational burdens and predicted neoantigens relative to melanoma or lung cancer. Memory CD4 + and CD8 + T cells are most frequently directed against the gB and pp65 antigens, respectively. Thus, CMV gB and pp65 represent highly immunogenic “foreign” antigen components of a vaccine against GBM and breast cancer. Methods: Enveloped virus-like particles (eVLPs) are produced after transfection of HEK 293 cells with a plasmid encoding murine leukemia virus Gag plasmid fused in-frame with CMV pp65 antigen, which gives rise to particles. Co-transfected CMV gB plasmid enables particles budding from the cell surface to incorporate the gB protein into the lipid bilayer. Surface expression of gB and internal expression of pp65 have been confirmed by CryoEM and immunogold labelling. Production and purification of multiple batches at a GMP-compliant manufacturer has demonstrated consistent purity and yields that meet regulatory requirements. Results: eVLPs restimulate IFN-g secreting CD4 + and CD8 + T cells in ex vivo PBMCs from healthy subjects (n=8) at mean frequencies of 0.27% and 1.28%, respectively. eVLP formulation with GM-CSF augments IFN-g and CCL3 secretion in stimulated PBMCs from healthy subjects (n=5), GBM patients (n=5), and breast cancer (n=1) patients to comparable levels. This vaccine candidate also induces de novo CD4 + and CD8 + responses in mice. The vaccine induces high titer antibody responses against CMV gB, and the potential for ADCC activity against gB-expressing GBM tumor cells is currently being investigated. Conclusions: CMV gB/pp65 eVLPs address several shortcomings of past theraeputic vaccines, including: 1) the poor immunogenicity of "self" tumor-associated antigens, 2) failure to induce robust CD4 + responses that support CD8 + tumor-specific responses, 3) inclusion of only one or a few epitopes that rapidly encourage tumor cell immunoselection of variants that no longer express the target(s). An IND submission to FDA for a phase I/IIa trial in GBM patients is planned for H1 2017.
Second primary cancers and recurrence in patients after resection of colorectal cancer: An integrated analysis of trials by Japan Clinical Oncology Group: JCOG0205, JCOG0212, JCOG0404 (JCOG1702A).
Authors: Kiyo Tanaka, Gakuto Ogawa, Junki Mizusawa, Junko Eba, Hiroshi Katayama, Kenichi Nakamura, Yasuhiro Shimada, Tetsuya Hamaguchi, Yoshihiro Moriya, Shin Fujita, Seigo Kitano, Masafumi Inomata, Yukihide Kanemitsu, Haruhiko Fukuda
Journal: Journal of Clinical Oncology (2018)

561 Background: Improvements in early detection and treatment have resulted in an increasing number of long-term survivors of colorectal cancer (CRC). For the survivors, Second primary cancers and recurrence are important issues, but the evidence for appropriate surveillance strategy is limited. The aim of this study was to investigate the frequency and the timing of second primary cancers and recurrence in patients (pts) after surgery using 3 randomized trials (J0205, J0212 and J0404) conducted by Colorectal Cancer Study Group of JCOG. Methods: Eligibility criteria included histologically proven CRC and having received surgery. The timing, site and frequency of second primary cancer and recurrence were investigated. Risk factors associated with the events were explored. Standardized incidence ratio (SIR) about second primary cancer compared with national database of Japan Cancer Registry was estimated. Results: A total of 2,824 pts with a median follow-up time of 6 years were included. Median age was 62 years old (23-75), male/female was 58%/42%, and stage 0/I/II/III/IV was 0.2%/8.7%/25.4%/64.8%/0.9%. Pts with 5-FU based adjuvant chemotherapy were 63%. Cumulative incidence of second primary cancer increased constantly over time (Table). Among 240 pts, the most common site was lung (37), stomach (35) and colon (32). In multivariable analysis, age (over 64 years old) and sex (male) were risk factors (age HR: 1.60 (95% CI: 1.24-2.07), sex HR: 1.36 (95% CI: 1.04-1.78)). The SIR of any second primary cancers was 1.07 (95% CI: 0.94-1.21). The SIR for second primary cancers of colon was 1.09 (95% CI: 0.79-1.47). On the other hand, cumulative incidence of recurrence almost reached at 3 years. Conclusions: Common surveillance strategy can be applied even for curatively resected CRC pts after 3 years from surgery, because the risk of second primary cancer was almost same as general population over time. The necessity of intensive follow-up to detect recurrence decreases after 3 years. [Table: see text]
Full alignment of some but not all representations in dialogue
Authors: Holly P. Branigan
Journal: Behavioral and Brain Sciences (2004)

I argue that alignment of linguistic representations and situation models in dialogue are qualitatively distinct. By virtue of the isomorphy between interlocutors' linguistic representations, interlocutors align their linguistic representations fully. However, evidence about situation models is indirect and mediated through language, with the result that alignment of situation models is only partial.
Abstract 16745: It Would be Possible to Rescue Traumatic Hemorrhagic Shock Patients Who Failed to Fluid Resuscitation (Fluid Non-responder) but Succeed in REBOA Resuscitation (REBOA/IABO Responder)
Authors: Tomohiko Orita, Tomohiro Funabiki, Motoyasu Yamazaki, Masayuki Shimizu, Tomohiro Sato, Taku Akashi, Yousuke Kobayashi, Kousuke Yoshida, Yoshimi Nakamichi, Saori Kurata, Mitsuhide Kitano
Journal: Circulation (2015)

Introduction: Fluid resuscitation (FR) and massive transfusion protocol (MTP) are important initial strategies for traumatic hemorrhagic shock cases. But poor responded patients to them are difficult to rescue. In such cases, open aortic cross clamping or intra-aortic balloon occlusion (IABO) would be performed as a temporary hemostasis treatment. Recently, IABO for severe trauma has been named resuscitative endovascular balloon occlusion of the aorta (REBOA). But it is still unclear which case can be rescued with REBOA. So we studied the relationship between the responsiveness to FR and REBOA. Methods: Consecutive 46 traumatic hemorrhagic shock patients underwent REBOA at our ER for last 86 months were included. All of their FAST were positive and done FR and MTP as a first-line resuscitation. 10Fr or 7Fr IABO devices were inserted at supraphrenic level (zone I) and underwent fundamental hemostasis by operative management (OM) and/or transcatheter arterial embolization (TAE). They were sorted into responded group or non-responded group for REBOA. The primary end point was a recovery rate from the shock state within 48 hours. Secondary end points were a survival rate in 30th days and a rate of complications. Results: 26 transient or non-responded patients (Fluid Non-responder) responded for REBOA (REBOA Responder group). 20 Fluid Non-responders did not respond for REBOA (REBOA Non-responder group). There were no significant differences in ISS (REBOA Responder vs. Non-responder: 45.8+/-15.2 vs. 54.8+/-22.3), amount of total fluid (7187+/-5782ml vs. 6772+/-4851) and total blood transfusion (4816+/-3006ml vs. 5080+/-3330), required time to occlude after arriving ER (25.3+/-12.6min vs. 19.4+/-9.8) and total occlusion time (76.4+/-66.5min vs. 92.7+/-34.4). There was significant difference in the changes of systolic blood pressure before and after of REBOA (59.3+/-25.7mmHg vs. 38.3+/-39.4, p=0.04). A recovery rate from shock state was 65%(12/26) vs. 0%(0/20) (p&lt;0.01) and a survival rate was 14/26(54%) vs. 0/20(0%) (p&lt;0.01). One complication occurred in REBOA Responder group but was not lethal. Conclusions: It would be necessary to recognize that Fluid Non-responder but REBOA Responder with traumatic hemorrhagic shock could be possible to rescue.
Abstract 18892: Variations of Drug Responses in Induced Pluripotent Stem Cell-Derived Cardiomyocytes From Healthy Japanese Volunteers
Authors: Masamichi Ito, Issei Komuro, Atsuhiko Naito
Journal: Circulation (2016)

Introduction: Cardiac safety assessment is an important process during drug discovery in order to prevent retractions of the new drugs from the market. Cardiac safety assessment using human induced...
Mini-incision versus hand-assisted laparoscopic donor nephrectomy in living-donor kidney transplantation: A retrospective cohort study
Authors: Tanvi Subramanian, Leigh Anne Dageforde, Neeta Vachharajani, Jason Wellen, M.B. Majella Doyle, Yiing Lin, Adeel Khan, Michael Senter-Zapata, William Chapman, Surendra Shenoy
Journal: International Journal of Surgery (2018)
Hydrogels for Advanced Stem Cell Therapies: A Biomimetic Materials Approach for Enhancing Natural Tissue Function
Authors: Wissam Farhat, Anwarul Hasan, Lucian Lucia, Frederic Becquart, Ali Ayoub, Firas Kobeissy
Journal: IEEE Reviews in Biomedical Engineering (2018)

Stem-cell-based therapy is a promising approach for the treatment of a myriad of diseases and injuries. However, the low rate of cell survival and the uncontrolled differentiation of the injected stem cells currently remain key challenges in advancing stem cell therapeutics. Hydrogels are biomaterials that are potentially highly effective candidates for scaffold systems for stem cells and other molecular encapsulation approaches to target in vivo delivery. Hydrogel-based strategies can potentially address several current challenges in stem cell therapy. We present a concise overview of the recent advances in applications of hydrogels in stem cell therapies, with a focus particularly on the recent advances in the design and approaches for application of hydrogels in tissue engineering. The capability of hydrogels to either enhance the function of the transplanted stem cells by promoting their controlled differentiation or enhance the recruitment of endogenous adult stem cells to the injury site for repair is also reviewed. Finally, the importance of impacts and the desired relationship between the scaffold system and the encapsulated stem cells are discussed.