tbuckley/cabot-search huggingface dataset:
Trastuzumab-Related Cardiotoxicity: Calling Into Question the Concept of Reversibility
Authors: Melinda L. Telli, Sharon A. Hunt, Robert W. Carlson, Alice E. Guardino
Journal: Journal of Clinical Oncology (2007)

Purpose To assess the spectrum and reversibility of the cardiotoxicity observed in the adjuvant trastuzumab trials. Design The design and efficacy of the major adjuvant trastuzumab trials was assessed, including the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31, North Central Cancer Treatment Group N9831, Herceptin Adjuvant, Breast Cancer International Research Group 006, and Finland Herceptin trials. The cardiotoxicity data were evaluated with a focus on the follow-up cardiac evaluations of women who were diagnosed with cardiotoxicity. Proposed mechanisms of trastuzumab-related cardiotoxicity were considered. The natural history of congestive heart failure (CHF) was reviewed with the goal of placing the trastuzumab experience in context. Results Up to 4% of patients enrolled onto the adjuvant trastuzumab trials experienced severe CHF during treatment. In these trials, early stopping rules that identified an unacceptable level of cardiotoxicity were never reached. Despite this, a large number of patients on these trials experienced some form of cardiotoxicity that ultimately required discontinuation of trastuzumab. Approximately 14% of patients in the NSABP B-31 trial discontinued trastuzumab because of asymptomatic decreases in left ventricular ejection fraction (LVEF). Results of follow-up cardiac evaluations of patients diagnosed with any degree of cardiotoxicity in the NSABP B-31 trial document that a clinically significant proportion of patients have sustained decrements in their LVEF to less than 50%. Conclusion Adjuvant trastuzumab provides substantial benefits to patients with human epidermal growth factor receptor 2–positive breast cancer, however, competing immediate and long-term cardiovascular risks are a great concern. Continued cardiac follow-up of these women is of critical importance.
Intratumoral Expression of Mature Human Neutrophil Peptide-1 Mediates Antitumor Immunity in Mice
Authors: Yong-sheng Wang, Dan Li, Hua-shan Shi, Yan-jun Wen, Li Yang, Ning Xu, Xian-cheng Chen, Xiang Chen, Ping Chen, Jiong Li, Hong-xin Deng, Chun-ting Wang, Gang Xie, Shan Huang, Yong-qiu Mao, Li-juan Chen, Xia Zhao, Yu-quan Wei
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Human neutrophil peptides (HNP1-3), small molecular antimicrobial peptides, are expressed within tumors and associated with tumor necrosis and inhibition of angiogenesis. Recent investigations have suggested that HNP1-3 are likely to be involved in the host immune responses to tumors. Experimental Design: We used recombinant pSec-HNP1, which expresses a secretable form of HNP1, to obtain expression of HNP1 in the tumor milieu in immunocompetent mice to explore the possible roles of HNP1 in tumor immunity. The antitumor effects were investigated in established CT26 colon cancer and 4T1 breast cancer models. Results: HNP1-mediated chemotactic and activating effects on immature dendritic cells were detected both in vitro and in vivo. Intratumoral expression of HNP1 resulted in not only significant tumor growth inhibition but also increased CTL infiltration within tumors. Adoptive transfer of splenocytes and a 51Cr release assay revealed specific cellular immune responses. Furthermore, increased antibodies were also found in sera from pSec-HNP1treated mice supporting specific humoral immune responses. Increased apoptosis and decreased angiogenesis were also shown in treated tumors. Conclusions: These findings indicate that HNP1 can exert multiple antitumor effects through different mechanisms; more importantly, HNP1 mediates host immune responses to tumors in situ through the recruitment and subsequent activation of immature dendritic cells and thus shows promising potential in cancer therapy. (Clin Cancer Res 2009;15(22):690111)
A Young Woman With Heart Failure and Altered Mental Status—The Answer in the Electrocardiogram
Authors: Christopher L. Brown, JoAnn Lindenfeld, Marat Fudim
Journal: JAMA Internal Medicine (2015)

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 Internal Medicine 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 Internal Medicine journal
Reduced Mitochondrial Oxidative Capacity and Increased Mitochondrial Uncoupling Impair Myocardial Energetics in Obesity
Authors: Sihem Boudina, Sandra Sena, Brian T. O’Neill, Prakash Tathireddy, Martin E. Young, E. Dale Abel
Journal: Circulation (2005)

Background— Obesity is a risk factor for cardiovascular disease and is strongly associated with insulin resistance and type 2 diabetes. Recent studies in obese humans and animals demonstrated increased myocardial oxygen consumption (MV̇ o 2 ) and reduced cardiac efficiency (CE); however, the underlying mechanisms remain unclear. The present study was performed to determine whether mitochondrial dysfunction and uncoupling are responsible for reduced cardiac performance and efficiency in ob/ob mice. Methods and Results— Cardiac function, MV̇ o 2 , mitochondrial respiration, and ATP synthesis were measured in 9-week-old ob/ob and control mouse hearts. Contractile function and MV̇ o 2 in glucose-perfused ob/ob hearts were similar to controls under basal conditions but were reduced under high workload. Perfusion of ob/ob hearts with glucose and palmitate increased MV̇ o 2 and reduced CE by 23% under basal conditions, and CE remained impaired at high workload. In glucose-perfused ob/ob hearts, mitochondrial state 3 respirations were reduced but ATP/O ratios were unchanged. In contrast, state 3 respiration rates were similar in ob/ob and control mitochondria from hearts perfused with palmitate and glucose, but ATP synthesis rates and ATP/O ratios were significantly reduced in ob/ob , which suggests increased mitochondrial uncoupling. Pyruvate dehydrogenase activity and protein levels of complexes I, III, and V were reduced in obese mice. Conclusions— These data indicate that reduced mitochondrial oxidative capacity may contribute to cardiac dysfunction in ob/ob mice. Moreover, fatty acid but not glucose-induced mitochondrial uncoupling reduces CE in obese mice by limiting ATP production and increasing MV̇ o 2 .
Age-related phenotypic and oncogenic differences in T-cell acute lymphoblastic leukemias may reflect thymic atrophy
Authors: Vahid Asnafi, Kheira Beldjord, Marta Libura, Patrick Villarese, Corrine Millien, Paola Ballerini, Emilienne Kuhlein, Marina Lafage-Pochitaloff, Eric Delabesse, Olivier Bernard, Elizabeth Macintyre
Journal: Blood (2004)
Laryngeal ultrasound: a useful method in predicting post-extubation stridor. A pilot study
Authors: L-W Ding, H-C Wang, H-D Wu, C-J Chang, P-C Yang
Journal: European Respiratory Journal (2006)

The cuff-leak test was widely used for the prediction of post-extubation stridor, but controversial results limit its clinical application. The current study used real-time ultrasonography to evaluate the air-leak and hypothesised that the air-column width, measured by ultrasonography, may be correlated to the development of post-extubation stridor. From June 1, 2001 to March 1, 2002, a total of 51 planned extubations in 51 consecutively intubated patients were included. All of the patients received ultrasonographical examinations of their vocal cords and larynx in addition to an air-column width measurement within 24 h prior to extubation. The overall post-extubation stridor rate was 7.8%. The air-leak volume presented as median (interquartile range) were 300 (350) mL and 25 (20) mL, respectively, for the nonstridor and stridor groups. The air-column width during cuff deflation was 6.4 (2) mm and 4.5 (0.8) mm, respectively. They were found to be statistically significant. In conclusion, the authors demonstrated that laryngeal ultrasonography could be a reliable, noninvasive method, in the evaluation of vocal cords, laryngeal morphology and the ease of airflow, which passed through vocal cords or subglottic area due to laryngeal oedema. The air-column width during cuff deflation was a potential predictor of post-extubation stridor.
Reliability of a commercially available threshold loading device in healthy subjects and in patients with chronic obstructive pulmonary disease.
Authors: R Gosselink, R C Wagenaar, M Decramer
Journal: Thorax (1996)

BACKGROUND: Threshold loading with the Nickerson and Keens9 device is frequently applied in the training and assessment of inspiratory muscles. However, this equipment is not easily applied in clinical practice and training. A study was therefore designed to investigate the accuracy and reliability of the Threshold, a commercially available threshold loading device. METHODS: The resolution (accuracy) of the system was determined by measuring variation of pressure and flow during one minute in an experimental setup. The reproducibility and flow independence were then determined during threshold loading at six different inspiratory loads between 25% and 50% maximal inspiratory pressure (PImax) in 10 patients with chronic obstructive pulmonary disease (COPD) and eight healthy subjects. RESULTS: In the first experiment the mean variation of the sustained pressure for all loads was 1.7%. The mean coefficients of variation for pressure and flow measurements were 0.2% and 3%, respectively. In the second experiment the healthy subjects showed mean coefficients of variation for pressure and flow of 0.8% and 20.5%, respectively, and the patients showed mean coefficients of variation of 0.6% and 14.5%, respectively. CONCLUSIONS: During the in vitro experiment as well as during the experiments in patients with COPD and in healthy subjects only small variations in pressure were observed despite large variations in flow. The Threshold is a reliable and reproducible device for loading inspiratory muscles in patients with COPD as well as in healthy subjects.
Association of Stromal Tumor-Infiltrating Lymphocytes With Recurrence-Free Survival in the N9831 Adjuvant Trial in Patients With Early-Stage HER2-Positive Breast Cancer
Authors: Edith A. Perez, Karla V. Ballman, Kathy S. Tenner, E. Aubrey Thompson, Sunil S. Badve, Helen Bailey, Frederick L. Baehner
Journal: JAMA Oncology (2015)

<h3>Importance</h3> The presence of tumor-infiltrating lymphocytes at diagnosis is reported to be prognostic in triple-negative breast cancer. <h3>Objective</h3> To evaluate the association of stromal tumor-infiltrating lymphocytes (STILs) with recurrence-free survival (RFS) in women with human epidermal growth factor receptor 2 (HER2)–positive breast cancer treated with chemotherapy or chemotherapy plus trastuzumab in the N9831 trial. <h3>Design, Setting, and Participants</h3> Hematoxylin-eosin–stained tumor slides from patients with early-stage HER2-positive breast cancer in 2 of the 3 arms of the N9831 trial were assessed for STILs at an academic medical center. The amounts of STILs were quantitated in deciles, and a level of at least 60% STILs was used for the prespecified categorical cutoff. The association between STILs and RFS was evaluated with Cox models. <h3>Exposure</h3> Standard chemotherapy consisting of doxorubicin-cyclophosphamide followed by weekly paclitaxel (arm A) or doxorubicin-cyclophosphamide followed by weekly paclitaxel plus trastuzumab followed by trastuzumab alone (arm C). <h3>Main Outcomes and Measures</h3> Stromal tumor-infiltrating lymphocytes and their association with RFS. <h3>Results</h3> A total of 489 patients from arm A and 456 patients from arm C were assessed with a median (range) follow-up of 4.4 (0-13.6) years. The 10-year Kaplan-Meier estimates for RFS in arm A were 90.9% and 64.5% for patients with high and low levels of STILs, respectively (hazard ratio [HR], 0.23 [95% CI, 0.07-0.73];<i>P</i> = .01). The 10-year estimates for RFS in arm C were 80.0% and 80.1% for patients with high and low levels of STILs, respectively (HR, 1.26 [95% CI, 0.50-3.17];<i>P</i> = .63). The test for interaction between trastuzumab treatment and STIL status was statistically significant (<i>P</i> = .03). In a multivariable analysis, STIL status remained significantly associated with RFS in arm A and not significantly associated in arm C (HR, 1.01 [95% CI, 0.89-1.15]; interaction<i>P</i> = .04). <h3>Conclusions and Relevance</h3> This analysis of participants in the N9831 trial found that the presence of STILs was prognostically associated with RFS in patients treated with chemotherapy alone but not in patients treated with chemotherapy plus trastuzumab. High levels of STILs were associated with lack of trastuzumab therapy benefit, in contrast to a previously reported association between increased levels of STILs and increased trastuzumab benefit in HER2-positive patients. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT00005970
Characteristics of attenders and non-attenders at an asthma education programme.
Authors: R Yoon, D K McKenzie, D A Miles, A Bauman
Journal: Thorax (1991)

A controlled trial of asthma education was conducted but only 51 out of 164 eligible patients participated.Differences between subjects who participated in the trial and those who expressed initial interest but subsequently declined were studied.Women, non-smokers, and those whose attending physician was concerned in the study were significantly more likely to attend the programme. Higher socioeconomic status was associated with greater attendance, but this did not reach significance. Psychosocial malfunctioning due to asthma was also associated with attendance, but this was not significant when sex and education level were taken into account. There was no difference between attenders and non-attenders with respect to age, number of previous admissions, airway function, self reported asthma severity, knowledge about asthma, and self management practices.The results suggest that many asthmatic patients recovering from a severe exacerbation of airflow obstruction will not participate in hospital based health education programmes. Alternative strategies may be required to improve the self management behaviour of these patients.
Identification of a three-gene expression signature of poor-prognosis breast carcinoma.
Authors: Ivan Bièche, Sengül Tozlu, Igor Girault, Rosette Lidereau
Journal: Molecular Cancer (2004)

The clinical course of breast cancer is difficult to predict on the basis of established clinical and pathological prognostic criteria. Given the genetic complexity of breast carcinomas, it is not surprising that correlations with individual genetic abnormalities have also been disappointing. The use of gene expression profiles could result in more accurate and objective prognostication. To this end, we used real-time quantitative RT-PCR assays to quantify the mRNA expression of a large panel (n = 47) of genes previously identified as candidate prognostic molecular markers in a series of 100 ERα-positive breast tumor samples from patients with known long-term follow-up. We identified a three-gene expression signature (BRCA2, DNMT3B and CCNE1) as an independent prognostic marker (P = 0.007 by univariate analysis; P = 0.006 by multivariate analysis). This "poor prognosis" signature was then tested on an independent panel of ERα-positive breast tumors from a well-defined cohort of 104 postmenopausal breast cancer patients treated with primary surgery followed by adjuvant tamoxifen alone: although this "poor prognosis" signature was associated with shorter relapse-free survival in univariate analysis (P = 0.029), it did not persist as an independent prognostic factor in multivariate analysis (P = 0.27). Our results confirm the value of gene expression signatures in predicting the outcome of breast cancer.
Identification of improved IL28B SNPs and haplotypes for prediction of drug response in treatment of hepatitis C using massively parallel sequencing in a cross-sectional European cohort
Authors: Katherine R Smith, Vijayaprakash Suppiah, Kate O'Connor, Thomas Berg, Martin Weltman, Maria Abate, Ulrich Spengler, Margaret Bassendine, Gail Matthews, William L Irving, Elizabeth Powell, Stephen Riordan, Golo Ahlenstiel, Graeme J Stewart, Melanie Bahlo, Jacob George, David R Booth
Journal: Genome Medicine (2011)

The hepatitis C virus (HCV) infects nearly 3% of the World's population, causing severe liver disease in many. Standard of care therapy is currently pegylated interferon alpha and ribavirin (PegIFN/R), which is effective in less than half of those infected with the most common viral genotype. Two IL28B single nucleotide polymorphisms (SNPs), rs8099917 and rs12979860, predict response to (PegIFN/R) therapy in treatment of HCV infection. These SNPs were identified in genome wide analyses using Illumina genotyping chips. In people of European ancestry, there are 6 common (more than 1%) haplotypes for IL28B, one tagged by the rs8099917 minor allele, four tagged by rs12979860. We used massively parallel sequencing of the IL28B and IL28A gene regions generated by polymerase chain reaction (PCR) from pooled DNA samples from 100 responders and 99 non-responders to therapy, to identify common variants. Variants that had high odds ratios and were validated were then genotyped in a cohort of 905 responders and non-responders. Their predictive power was assessed, alone and in combination with HLA-C. Only SNPs in the IL28B linkage disequilibrium block predicted drug response. Eighteen SNPs were identified with evidence for association with drug response, and with a high degree of confidence in the sequence call. We found that two SNPs, rs4803221 (homozygote minor allele positive predictive value (PPV) of 77%) and rs7248668 (PPV 78%), predicted failure to respond better than the current best, rs8099917 (PPV 73%) and rs12979860 (PPV 68%) in this cross-sectional cohort. The best SNPs tagged a single common haplotype, haplotype 2. Genotypes predicted lack of response better than alleles. However, combination of IL28B haplotype 2 carrier status with the HLA-C C2C2 genotype, which has previously been reported to improve prediction in combination with IL28B, provides the highest PPV (80%). The haplotypes present alternative putative transcription factor binding and methylation sites. Massively parallel sequencing allowed identification and comparison of the best common SNPs for identifying treatment failure in therapy for HCV. SNPs tagging a single haplotype have the highest PPV, especially in combination with HLA-C. The functional basis for the association may be due to altered regulation of the gene. These approaches have utility in improving diagnostic testing and identifying causal haplotypes or SNPs.
Therapeutic Synergy of Human Papillomavirus E7 Subunit Vaccines plus Cisplatin in an Animal Tumor Model: Causal Involvement of Increased Sensitivity of Cisplatin-Treated Tumors to CTL-Mediated Killing in Therapeutic Synergy
Authors: Sung Hwa Bae, Young-Ja Park, Jae-Bok Park, Youn Seok Choi, Mi Suk Kim, Jeong-Im Sin
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The goal of this study was to investigate the therapeutic potentials of combining chemotherapy with human papillomavirus (HPV) E7 subunit vaccines in an animal tumor model and to determine the underlying therapeutic mechanisms. Experimental Design: Animals bearing HPV E6/E7–expressing tumors were treated intratumorally with a selected cytotoxic drug, cisplatin, twice at 1-week interval and s.c. with E7 subunit vaccines thrice at 1-week interval. Tumor chemoimmunoresponse was measured by tumor size. Ag-specific CTL activities and tumor histology were checked in mice under treatments. Apoptosis, in vivo T-cell subset depletion, adoptive CTL transfer, and tumor regression were used to determine the mechanisms for antitumor therapeutic effects. Results: Combined therapy using cisplatin plus E7 subunit vaccines improved cure and recurrence rates of tumors and long-term antitumor immunity dramatically more than single therapy alone. In particular, both components of E7 subunit vaccines were required for induction of Ag-specific CTL as well as therapeutic synergy when combined with cisplatin. This therapeutic synergy was abrogated by depletion of CD8+ T cells in vivo and was concomitant with histologic changes (such as heavy infiltration of lymphocytes and reduced tumor cell density). Finally, the increased sensitivity of cisplatin-treated tumors to CTL-mediated killing was found to be responsible for therapeutic synergy. Conclusions: E7 subunit vaccines plus cisplatin mediate antitumor therapeutic synergy through the increased sensitivity of cisplatin-treated tumors to CTL-mediated killing. Moreover, E7-based therapeutic vaccines have the potential to improve chemotherapy in patients with cervical cancer.
Resveratrol Exerts Antiproliferative Activity and Induces Apoptosis in Waldenström's Macroglobulinemia
Authors: Aldo M. Roccaro, Xavier Leleu, Antonio Sacco, Anne-Sophie Moreau, Evdoxia Hatjiharissi, Xiaoying Jia, Lian Xu, Bryan Ciccarelli, Christopher J. Patterson, Hai T. Ngo, Domenico Russo, Angelo Vacca, Franco Dammacco, Kenneth C. Anderson, Irene M. Ghobrial, Steven P. Treon
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Resveratrol (3,4',5-tri-hydroxy-trans-stilbene) is an antioxidant constituent of a wide variety of plant species including grapes. It has gained considerable attention because of its anticancer properties, as shown in solid and hematologic malignancies. Whether resveratrol could inhibit proliferation or induce cytotoxicity in Waldenström's macroglobulinemia (WM) was investigated. Experimental Design: We studied resveratrol-induced inhibition of proliferation and induction of cytotoxicity in WM cell lines, WM primary tumor cells, IgM-secreting cells, and peripheral blood mononuclear cells. The mechanisms of action and different signaling pathways involved were studied using Western blot and gene expression profile analysis. Resveratrol activity was also evaluated in the bone marrow microenvironment. We finally investigated whether or not resveratrol could have any synergistic effect if used in combination with other drugs widely used in the treatment of WM. Results: Resveratrol inhibited proliferation and induced cytotoxicity against WM cells, IgM-secreting cells, as well as primary WM cells, without affecting peripheral blood mononuclear cells; down-regulated Akt, extracellular signal-regulated kinase mitogen-activated protein kinases, and Wnt signaling pathways, as well as Akt activity; induced cell cycle arrest and apoptosis; and triggered c-Jun-NH2-terminal-kinase activation, followed by the activation of intrinsic and extrinsic caspase pathways. Lastly, adherence to bone marrow stromal cells did not confer protection to WM cells against resveratrol-induced cytotoxicity. Furthermore, resveratrol showed synergistic cytotoxicity when combined with dexamethasone, fludarabine, and bortezomib. Conclusion: Our data show that resveratrol has significant antitumor activity in WM, providing the framework for clinical trials in this disease.