tbuckley/cabot-search huggingface dataset:
Bifidobacterium strains from resident infant human gastrointestinal microflora exert antimicrobial activity
Authors: V Lievin
Journal: Gut (2000)

<h3>Abstract</h3> A SARS-CoV-2 Alpha outbreak was detected in a nursing home after residents and staff had completed vaccination with BNT162b. In a retrospective cohort study, we estimated an age-adjusted vaccine effectiveness of 88% [95% confidence interval (95%CI) 41-98%] against hospitalization/death. Ct values at diagnosis were higher with longer intervals since the second vaccination [&gt;21 vs. ≤21 days: 4.82 cycles, 95%CI: 0.06-9.58]. Secondary attack rates were 67% lower in households of vaccinated [2/9 (22.2%)] than unvaccinated infected staff [12/18 (66.7%); p=0.046]. Vaccination reduced the risk of severe outcomes, Ct values and transmission, but not fully. Non-pharmaceutical interventions remain important for vaccinated individuals.
Neurotensin serum levels and skin gene expression are increased in atopic dermatitis
Authors: M. Vasiadi, A.P. Mondolfi, K.-D. Alysandratos, A. Therianou, A. Katsarou-Katsari, T. Petrakopoulou, A. Theoharidis, A. Miniati, T.C. Theoharides
Journal: British Journal of Dermatology (2013)

Background Neurotensin (NT) participates in immune responses, but the mechanisms are not known. We have previously shown that NT augments the ability of corticotropin-releasing hormone (CRH) to increase mast-cell-dependent vascular permeability in rodents. We also showed that NT stimulates human mastcell release of vascular endothelial growth factor, and that CRH is increased in the serum of patients with atopic dermatitis (AD), an inflammatory skin condition involving mast cells. Objectives To measure serum levels of NT, and lesional skin expression of NT and the main NT receptor (NTR-1) in AD, and to compare it with skin expression in chronic urticaria (CU) and urticaria pigmentosa (UP). Methods Serum NT was measured with a Milliplex microbead array. Skin NT and NTR-1 gene expression was determined with quantitative polymerase chain reaction. Immunohistochemistry was performed using a mouse monoclonal antibody for NT, and a rabbit polyclonal antibody for NTR-1. Mast cells were counterstained with Leder dye. Results Neurotensin is significantly elevated in the serum of patients with AD compared with healthy controls (P = 0.0001). NT gene expression is also significantly increased in lesional skin of patients with AD compared with controls (P = 0.0194). Moreover, immunohistochemistry of AD lesions shows NT > NTR-1 staining of perivascular cells, many of which are identified as mast cells after staining with Leder dye. There was no statistically significant difference in NT and NTR-1 lesional skin gene expression in patients with either CU or UP. Conclusions These results suggest that interactions between NT and mast cells may occur and contribute to AD pathogenesis.
Nuclear Estrogen Receptor β in Lung Cancer: Expression and Survival Differences by Sex
Authors: Ann G. Schwartz, Geoffrey M. Prysak, Valerie Murphy, Fulvio Lonardo, Harvey Pass, Jan Schwartz, Sam Brooks
Journal: Clinical Cancer Research (2005)

Abstract Purpose: A role for estrogens in determining lung cancer risk and prognosis is suggested by reported sex differences in susceptibility and survival. Archival lung tissue was evaluated for the presence of nuclear estrogen receptor (ER)-α and ER-β and the relationship between ER status, subject characteristics, and survival. Experimental Design: Paraffin-embedded lung tumor samples were obtained from 214 women and 64 men from two population-based, case-control studies as were 10 normal lung autopsy samples from patients without cancer. Nuclear ER-α and ER-β expression was determined by immunohistochemistry. Logistic regression was used to identify factors associated with ER positivity and Cox proportional hazards models were used to measure survival differences by ER status. Results: Neither tumor (0 of 94) nor normal (0 of 10) lung tissue stained positive for ER-α. Nuclear ER-β positivity was present in 61% of tumor tissue samples (170 of 278; 70.3% in men and 58.3% in women) and 20% of normal tissue samples (2 of 10; P = 0.01). In multivariate analyses, females were 46% less likely to have ER-β–positive tumors than males (odds ratio, 0.54; 95% confidence interval, 0.27-1.08). This relationship was stronger and statistically significant in adenocarcinomas (odds ratio, 0.40; 95% confidence interval, 0.18-0.89). Women with ER-β–positive tumors had a nonsignificant 73% (P = 0.1) increase in mortality, whereas men with ER-β–positive tumors had a significant 55% (P = 0.04) reduction in mortality compared with those with ER-β–negative tumors. Conclusions: This study suggests differential expression by sex and influence on survival in men of nuclear ER-β in lung cancer, particularly in adenocarcinomas.
Androgen Receptor Splice Variants Mediate Enzalutamide Resistance in Castration-Resistant Prostate Cancer Cell Lines
Authors: Yingming Li, Siu Chiu Chan, Lucas J. Brand, Tae Hyun Hwang, Kevin A.T. Silverstein, Scott M. Dehm
Journal: Cancer Research (2012)

Persistent androgen receptor (AR) transcriptional activity underlies resistance to AR-targeted therapy and progression to lethal castration-resistant prostate cancer (CRPC). Recent success in retargeting persistent AR activity with next generation androgen/AR axis inhibitors such as enzalutamide (MDV3100) has validated AR as a master regulator during all stages of disease progression. However, resistance to next generation AR inhibitors limits therapeutic efficacy for many patients. One emerging mechanism of CRPC progression is AR gene rearrangement, promoting synthesis of constitutively active truncated AR splice variants (AR-V) that lack the AR ligand-binding domain. In this study, we show that cells with AR gene rearrangements expressing both full-length and AR-Vs are androgen independent and enzalutamide resistant. However, selective knock-down of AR-V expression inhibited androgen-independent growth and restored responsiveness to androgens and antiandrogens. In heterogeneous cell populations, AR gene rearrangements marked individual AR-V-dependent cells that were resistant to enzalutamide. Gene expression profiling following knock-down of full-length AR or AR-Vs showed that AR-Vs drive resistance to AR-targeted therapy by functioning as constitutive and independent effectors of the androgen/AR transcriptional program. Further, mitotic genes deemed previously to be unique AR-V targets were found to be biphasic targets associated with a proliferative level of signaling output from either AR-Vs or androgen-stimulated AR. Overall, these studies highlight AR-Vs as key mediators of persistent AR signaling and resistance to the current arsenal of conventional and next generation AR-directed therapies, advancing the concept of AR-Vs as therapeutic targets in advanced disease.
Content and quality of 2000 controlled trials in schizophrenia over 50 years
Authors: B. Thornley, C. Adams
Journal: BMJ (1998)

<h3>Abstract</h3> <b>Objective</b> To provide a comprehensive survey of the content and quality of intervention studies relevant to the treatment of schizophrenia. <b>Design</b> Data were extracted from 2000 trials on the Cochrane Schizophrenia Group9s register. <b>Main outcome measures</b> Type and date of publication, country of origin, language, size of study, treatment setting, participant group, interventions, outcomes, and quality of study. <b>Results</b> Hospital based drug trials undertaken in the United States were dominant in the sample (54%). Generally, studies were short (54%&lt;6 weeks), small (mean number of patients 65), and poorly reported (64% had a quality score of ≤2 (maximum score 5)). Over 600 different interventions were studied in these trials, and 640 different rating scales were used to measure outcome. <b>Conclusions</b> Half a century of studies of limited quality, duration, and clinical utility leave much scope for well planned, conducted, and reported trials. The drug regulatory authorities should stipulate that the results of both explanatory and pragmatic trials are necessary before a compound is given a licence for everyday use.
PF00299804, an Irreversible Pan-ERBB Inhibitor, Is Effective in Lung Cancer Models with<i>EGFR</i>and<i>ERBB2</i>Mutations that Are Resistant to Gefitinib
Authors: Jeffrey A. Engelman, Kreshnik Zejnullahu, Christopher-Michael Gale, Eugene Lifshits, Andrea J. Gonzales, Takeshi Shimamura, Feng Zhao, Patrick W. Vincent, George N. Naumov, James E. Bradner, Irene W. Althaus, Leena Gandhi, Geoffrey I. Shapiro, James M. Nelson, John V. Heymach, Matthew Meyerson, Kwok-Kin Wong, Pasi A. Jänne
Journal: Cancer Research (2007)

Abstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib are effective treatments for a subset of non–small cell lung cancers. In particular, cancers with specific EGFR-activating mutations seem to be the most sensitive to these agents. However, despite their initial response, such cancers almost invariably develop resistance. In 50% of such cancers, a secondary EGFR mutation, T790M, has been identified that renders gefitinib and erlotinib ineffective inhibitors of EGFR kinase activity. Thus, there is a clinical need to develop novel EGFR inhibitors that can effectively inactivate T790M-containing EGFR proteins. In this study, we evaluate the effectiveness of a novel compound, PF00299804, an irreversible pan-ERBB inhibitor. The results from these studies show that PF00299804 is a potent inhibitor of EGFR-activating mutations as well as the EGFR T790M resistance mutation both in vitro and in vivo. Additionally, PF00299804 is a highly effective inhibitor of both the wild-type ERBB2 and the gefitinib-resistant oncogenic ERBB2 mutation identified in lung cancers. These preclinical evaluations support further clinical development of PF00299804 for cancers with mutations and/or amplifications of ERBB family members. [Cancer Res 2007;67(24):11924–32]
Reliability of Human Epidermal Growth Factor Receptor 2 Immunohistochemistry in Breast Core Needle Biopsies
Authors: Annette Lebeau, Andreas Turzynski, Susanne Braun, Wera Behrhof, Barbara Fleige, Wolfgang D. Schmitt, Tobias J. Grob, Lia Burkhardt, Dieter Hölzel, Christian Jackisch, Christoph Thomssen, Volkmar Müller, Michael Untch
Journal: Journal of Clinical Oncology (2010)

Purpose Core needle biopsies (CNBs) are widely used to determine human epidermal growth factor receptor 2 (HER2) status in breast cancer. Recent publications reported up to 20% false-positive results on CNBs if immunohistochemistry (IHC) is compared with fluorescent in situ hybridization (FISH). To clarify, if confirmation of IHC positivity by FISH is generally required, we analyzed the reliability of IHC positivity on CNBs versus surgical specimens in a multi-institutional study. Patients and Methods Five pathologic laboratories contributed to this study by performing IHC on 500 CNBs and the corresponding surgical specimens overall. If IHC revealed score 2+ or 3+, HER2 status was confirmed by FISH in a central laboratory. We compared evaluation according to US Food and Drug Administration–approved scoring criteria and recently published American Society of Clinical Oncology (ASCO)–College of American Pathologists (CAP) guidelines. Results CNBs scored 3+ revealed five false-positive results if scoring followed the US Food and Drug Administration criteria (five of 40; 12.5%) and two false-positives in terms of the ASCO-CAP criteria (two of 33; 6.1%). IHC was false negative in one CNB only. By contrast, IHC on surgical specimens revealed five false-negative results, but only one false-positive result (one of 35; 2.9%) if scored following US Food and Drug Administration–approved criteria. With the aid of the ASCO-CAP criteria, false-positive IHC results were obtained in only one of the five participating institutions. Conclusion IHC 3+ scores on CNBs proved to be reliable in four of the five participating institutions if scoring followed the ASCO-CAP criteria. Therefore, accurate determination of HER2 status in breast cancer is possible on CNB using the common strategy to screen all cases by IHC and retest only 2+ scores by FISH. Prerequisites are quality assurance and the application of the new ASCO-CAP criteria.
Infectious Hepatitis C Virus Pseudo-particles Containing Functional E1–E2 Envelope Protein Complexes
Authors: Birke Bartosch, Jean Dubuisson, François-Loïc Cosset
Journal: The Journal of Experimental Medicine (2003)

The study of hepatitis C virus (HCV), a major cause of chronic liver disease, has been hampered by the lack of a cell culture system supporting its replication. Here, we have successfully generated infectious pseudo-particles that were assembled by displaying unmodified and functional HCV glycoproteins onto retroviral and lentiviral core particles. The presence of a green fluorescent protein marker gene packaged within these HCV pseudo-particles allowed reliable and fast determination of infectivity mediated by the HCV glycoproteins. Primary hepatocytes as well as hepato-carcinoma cells were found to be the major targets of infection in vitro. High infectivity of the pseudo-particles required both E1 and E2 HCV glycoproteins, and was neutralized by sera from HCV-infected patients and by some anti-E2 monoclonal antibodies. In addition, these pseudo-particles allowed investigation of the role of putative HCV receptors. Although our results tend to confirm their involvement, they provide evidence that neither LDLr nor CD81 is sufficient to mediate HCV cell entry. Altogether, these studies indicate that these pseudo-particles may mimic the early infection steps of parental HCV and will be suitable for the development of much needed new antiviral therapies.
Derivation and Prospective Validation of a Simple Index for Prediction of Cardiac Risk of Major Noncardiac Surgery
Authors: Thomas H. Lee, Edward R. Marcantonio, Carol M. Mangione, Eric J. Thomas, Carisi A. Polanczyk, E. Francis Cook, David J. Sugarbaker, Magruder C. Donaldson, Robert Poss, Kalon K. L. Ho, Lynn E. Ludwig, Alex Pedan, Lee Goldman
Journal: Circulation (1999)

Background —Cardiac complications are important causes of morbidity after noncardiac surgery. The purpose of this prospective cohort study was to develop and validate an index for risk of cardiac complications. Methods and Results —We studied 4315 patients aged ≥50 years undergoing elective major noncardiac procedures in a tertiary-care teaching hospital. The main outcome measures were major cardiac complications. Major cardiac complications occurred in 56 (2%) of 2893 patients assigned to the derivation cohort. Six independent predictors of complications were identified and included in a Revised Cardiac Risk Index: high-risk type of surgery, history of ischemic heart disease, history of congestive heart failure, history of cerebrovascular disease, preoperative treatment with insulin, and preoperative serum creatinine &gt;2.0 mg/dL. Rates of major cardiac complication with 0, 1, 2, or ≥3 of these factors were 0.5%, 1.3%, 4%, and 9%, respectively, in the derivation cohort and 0.4%, 0.9%, 7%, and 11%, respectively, among 1422 patients in the validation cohort. Receiver operating characteristic curve analysis in the validation cohort indicated that the diagnostic performance of the Revised Cardiac Risk Index was superior to other published risk-prediction indexes. Conclusions —In stable patients undergoing nonurgent major noncardiac surgery, this index can identify patients at higher risk for complications. This index may be useful for identification of candidates for further risk stratification with noninvasive technologies or other management strategies, as well as low-risk patients in whom additional evaluation is unlikely to be helpful.
Altered metabolic homeostasis is associated with appetite regulation during and following 48-h of severe energy deprivation in adults
Authors: J Philip Karl, Tracey J Smith, Marques A Wilson, Asma S Bukhari, Stefan M Pasiakos, Holly L McClung, James P McClung, Harris R Lieberman
Journal: Metabolism (2015)

Military personnel frequently endure intermittent periods of severe energy deficit which can compromise health and performance. Physiologic factors contributing to underconsumption, and the subsequent drive to overeat, are not fully characterized. This study aimed to identify associations between appetite, metabolic homeostasis and endocrine responses during and following severe, short-term energy deprivation.Twenty-three young adults (17M/6F, 21±3years, BMI 25±3kg/m(2)) participated in a randomized, controlled, crossover trial. During separate 48-h periods, participants increased habitual energy expenditure by 1647±345kcal/d (mean±SD) through prescribed exercise at 40-65% VO2peak, and consumed provided isovolumetric diets designed to maintain energy balance at the elevated energy expenditure (EB; 36±93kcal/d energy deficit) or to produce a severe energy deficit (ED; 3681±716kcal/d energy deficit). Appetite, markers of metabolic homeostasis and endocrine mediators of appetite and substrate availability were periodically measured. Ad libitum energy intake was measured over 36h following both experimental periods.Appetite increased during ED and was greater than during EB despite maintenance of diet volume (P=0.004). Ad libitum energy intake was 907kcal/36h [95% CI: 321, 1493kcal/36h, P=0.004] higher following ED compared to following EB. Serum beta-hydroxybutyrate, free fatty acids, branched-chain amino acids, dehydroepiandrosterone-sulfate (DHEA-S) and cortisol concentrations were higher (P<0.001 for all), whereas whole-body protein balance was more negative (P<0.001), and serum glucose, insulin, and leptin concentrations were lower (P<0.001 for all) during ED relative to during EB. Cortisol concentrations, but not any other hormone or metabolic substrate, were inversely associated with satiety during EB (R(2)=0.23, P=0.04). In contrast, serum glucose and DHEA-S concentrations were inversely associated with satiety during ED (R(2)=0.68, P<0.001). No associations between physiologic variables measured during EB and ad libitum energy intake following EB were observed. However, serum leptin and net protein balance measured during ED were inversely associated with ad libitum energy intake following ED (R(2)=0.48, P=0.01).These findings suggest that changes in metabolic homeostasis during energy deprivation modulate appetite independent of reductions in diet volume. Following energy deprivation, physiologic signals of adipose and lean tissue loss may drive restoration of energy balance.www.clinicaltrials.gov #NCT01603550.
Phase II Study of Ganitumab, a Fully Human Anti–Type-1 Insulin-Like Growth Factor Receptor Antibody, in Patients With Metastatic Ewing Family Tumors or Desmoplastic Small Round Cell Tumors
Authors: William D. Tap, George Demetri, Phillip Barnette, Jayesh Desai, Petr Kavan, Richard Tozer, Pasquale W. Benedetto, Gregory Friberg, Hongjie Deng, Ian McCaffery, Ian Leitch, Sunita Badola, Sung Chang, Min Zhu, Anthony Tolcher
Journal: Journal of Clinical Oncology (2012)

Ganitumab is a fully human monoclonal antibody against type-1 insulin-like growth factor receptor (IGF1R). An open-label phase II study was conducted to evaluate the efficacy and safety of ganitumab monotherapy in patients with metastatic Ewing family tumors (EFT) or desmoplastic small round cell tumors (DSRCT).Patients ≥16 years of age with relapsed or refractory EFT or DSRCT received 12 mg/kg of ganitumab every 2 weeks. Objective response rate (ORR) was the primary end point. Secondary end points included clinical benefit rate (CBR = complete + partial responses + stable disease [SD] ≥ 24 weeks) and safety and pharmacokinetic profiles of ganitumab. The relationship between tumor response and EWS gene translocation status and IGF-1 levels was evaluated.Thirty-eight patients (22 with EFT; 16 with DSRCT) received one or more doses of ganitumab. Twenty-four patients (63%) experienced ganitumab-related adverse events. Grade 3 related events included hyperglycemia (n = 2), thrombocytopenia (n = 5), neutropenia (n = 2), leukopenia (n = 1), and transient ischemic attack (n = 1). There were no grade 4 or 5 treatment-related events. Of 35 patients assessed for response, two had partial responses (ORR, 6%) and 17 (49%) had SD. Four patients had SD ≥ 24 weeks, contributing to a CBR of 17%. The pharmacokinetic profile of ganitumab was similar to that observed in the first-in-human trial. Elevation of IGF-1 levels was observed postdose. EWS-Fli1 translocations were analyzed by RNA sequencing and fluorescent in situ hybridization, and novel translocations were observed in EFT and DSCRT. No apparent relationship between tumor response and IGF-1 levels or EWS gene translocations was observed.Ganitumab was well tolerated and demonstrated antitumor activity in patients with advanced recurrent EFT or DSRCT.
Surgery followed by Persistence of High-Grade Squamous Intraepithelial Lesions Is Associated with the Induction of a Dysfunctional HPV16-Specific T-Cell Response
Authors: Peggy J. de Vos van Steenwijk, Sytse J. Piersma, Marij J.P. Welters, Jeanette M. van der Hulst, Gertjan Fleuren, Bart W.J. Hellebrekers, Gemma G. Kenter, Sjoerd H. van der Burg
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To characterize HPV16 E6- and E7-specific T-cell immunity in patients with high-grade squamous intraepithelial lesions (HSIL). Experimental Design: Peripheral blood mononuclear cells isolated from 38 patients with HPV16+ HSIL were used to determine the magnitude, breadth, and polarization of HPV16-specific T-cell responses by proliferation assays and cytokine assays. Furthermore, HSIL-infiltrating T cells isolated from 7 cases were analyzed for the presence of HPV16 E6- and/or E7-specific T cells, phenotyped, and tested for the specific production of IFN-γ and interleukin-10 as well as for their capacity to suppress immune responses. Results: HPV16-specific T-cell responses were absent in the circulation of the majority (∼60%) of patients who visit the clinic for treatment of a HPV16+ HSIL lesion. Notably, HPV16-specific T-cell reactivity was predominantly detected in patients returning to the clinic for repetitive treatment of a persistent or recurrent HPV16+ HSIL lesion after initial destructive treatment. The majority (&amp;gt;70%) of these HPV16-specific T-cell responses did not secrete proinflammatory cytokines, indicating that most of the subjects, although in principle able to mount a HPV16-specific immune response, fail to develop protective cellular immunity. This notion is sustained by our observation that only three HSIL-infiltrating T-cell cultures contained HPV16-specific T cells, one of which clearly consisted of HPV16 E7-specific regulatory T cells. Conclusions: The presence of HPV16-specific T cells with a non-Th1/Th2 cytokine and even suppressive signature in patients with HSIL may affect the outcome of vaccine approaches aiming at reinforcing human papillomavirus-specific immunity to attack human papillomavirus-induced lesions.