tbuckley/cabot-search huggingface dataset:
Chromosomal Instability and Supernumerary Centrosomes Represent Precursor Defects in a Mouse Model of T-Cell Lymphoma
Authors: Christopher I. van de Wetering, C. Michael Knudson
Journal: Cancer Research (2007)

Abstract A hallmark of carcinogenesis is resistance to cell death. However, recent studies indicate that Bax expression increased apoptosis and promoted oncogenesis. In this study, we hypothesized that Bax promotes tumor formation by increasing chromosomal instability (CIN). Consistent with this hypothesis, spectral karyotype analysis (SKY) of lymphomas derived from Lck-Bax38/1 mice were consistently aneuploid. To determine if CIN precedes tumor formation, quantitative cytogenetic analysis, SKY analysis, and quantitative centrosome staining were done on thymocytes from young premalignant mice. Between 6 and 10 weeks of age, thymi from Bax-expressing mice (either p53+/+ or p53−/−) had an increased percentage of aneuploid cells as well as an increase in cells with supernumerary centrosomes. For 3- to 6-week-old mice, Bax expression increased aneuploidy and supernumerary centrosomes in p53−/− mice but not in p53+/+ animals. Importantly, both aneuploidy and supernumerary centrosomes were attenuated by Bcl-2. Remarkably, SKY analysis showed multiple independent aneuploid populations in the p53−/− Bax-expressing mice between 3 and 6 weeks of age. These results indicate that oligoclonal aneuploidy and supernumerary centrosomes are early hallmarks of Bax-induced lymphoma formation and support a novel link between the Bcl-2 family and CIN. The data provide an attractive model for the paradoxical effects of the Bcl-2 family on carcinogenesis that have been observed in multiple studies of both humans and mice. [Cancer Res 2007;67(17):8081–8]
Cholesterol Lowering in 2015
Authors: Philip Greenland, Michael S. Lauer
Journal: JAMA (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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Abstract 3490: Topotecan synergizes with CHEK1 inhibitor to induce apoptosis in ovarian cancer cells
Authors: Marianne K. H. Kim, Jana James, Christina Annunziata
Journal: Cancer Research (2015)

Abstract Background Topotecan is a therapeutic option for women with platinum-resistant or -refractory ovarian cancer. However, the dose-limiting toxicity of topotecan is myelosuppression. This led us to seek a combination treatment to augment topotecan anti-cancer activity in a cancer-targeted manner. Ovarian serous cancers, a major subtype, show dysregulated DNA repair pathway and often display a high level of CHEK1, a cell cycle regulator and DNA damage sensor. CHEK1 inhibitors are a novel approach to treatment, and have been used as single agents or in combination chemotherapy in many cancers. Methods We evaluated the cellular effects of topotecan in a panel of high grade serous (HGS) and non-HGS ovarian cancer cells. We then determined IC50s of topotecan in the absence and presence of suboptimal concentrations of CHEK1 inhibitor, PF477736. Synergism between topotecan and PF477736 was calculated based on cellular viability assays. Cytotoxic effect of the combined treatment was compared with apoptotic activities by Caspase3/7 activity assay and Western blotting of cleaved-PARP1 and γH2A.X. Results Non-HGS ovarian cancer cells were generally more sensitive to topotecan treatment compared to HGS ovarian cancer cells. When combined with suboptimal concentrations of CHEK1 inhibitor, topotecan potently and synergistically inhibited the proliferation of HGS ovarian cancer cells. This dramatic synergism in cellular toxicity was consistent with increases in markers of apoptosis. Conclusions Our findings suggest that the addition of CHEK1 inhibitor increases the response of ovarian cancer cells to topotecan. Furthermore, reduced dosages of both drugs achieved maximal cytotoxic effects by combining topotecan with CHEK1 inhibitor. This strategy would potentially minimize side effects of the drugs for extended clinical benefit. Citation Format: Marianne K. H. Kim, Jana James, Christina Annunziata. Topotecan synergizes with CHEK1 inhibitor to induce apoptosis in ovarian cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3490. doi:10.1158/1538-7445.AM2015-3490
Relentless increase of resistance to fluoroquinolones and expanded-spectrum cephalosporins in Escherichia coli: 20 years of surveillance in resource-limited settings from Latin America
Authors: A. Bartoloni, L. Pallecchi, E. Riccobono, A. Mantella, D. Magnelli, T. Di Maggio, A.L. Villagran, Y. Lara, C. Saavedra, M. Strohmeyer, F. Bartalesi, C. Trigoso, G.M. Rossolini
Journal: Clinical Microbiology and Infection (2012)
T-cell clonality assessment by next-generation sequencing improves detection sensitivity in mycosis fungoides
Authors: Kari E. Sufficool, Christina M. Lockwood, Haley J. Abel, Ian S. Hagemann, Jonathan A. Schumacher, Todd W. Kelley, Eric J. Duncavage
Journal: Journal of the American Academy of Dermatology (2015)

T-cell receptor (TCR) clonality assessment is a principal diagnostic test in the management of mycosis fungoides (MF). However, current polymerase chain reaction-based methods may produce ambiguous results, often because of low abundance of clonal T lymphocytes, resulting in weak clonal peaks that cannot be size-resolved by contemporary capillary electrophoresis (CE).We sought to determine if next-generation sequencing (NGS)-based detection has increased sensitivity for T-cell clonality over CE-based detection in MF.Clonality was determined by an NGS-based method in which the TCR-γ variable region was polymerase chain reaction amplified and the products sequenced to establish the identity of rearranged variable and joining regions.Of the 35 MF cases tested, 29 (85%) showed a clonal T-cell rearrangement by NGS, compared with 15 (44%) by standard CE detection. Three patients with MF had follow-up testing that showed identical, clonal TCR sequences in subsequent skin biopsy specimens.Clonal T-cell populations have been described in benign conditions; evidence of clonality alone, by any method, is not sufficient for diagnosis.TCR clonality assessment by NGS has superior sensitivity compared with CE-based detection. Further, NGS enables tracking of specific clones across multiple time points for more accurate identification of recurrent MF.
Function of Twist-2 as an antigen presentation attenuator and effect on potency of dendritic cells for immunotherapy
Authors: A. Sharabi, M. Aldrich, S. Chen
Journal: Journal of Clinical Oncology (2008)

3019 Background: One goal of dendritic cell (DC) based immunotherapy is to induce an effective antitumor immune response, but clinical successes have been limited. Recently, negative regulators present in many signal transduction pathways have been shown to inhibit the ability of DCs to induce a potent immune response. Blocking these inhibitors may be key to unlocking the full potential of DCs for immunotherapy. Twist-1 and Twist-2 are negative feedback regulators of NFkB. Twist-2 binds to promoters of cytokines, such as TNF-alpha and IL-1, and blocks NFkB dependent transcription. Thus, we hypothesized that silencing Twist-2 would enhance the potency of DC based antitumor therapies. Methods: We performed preclinical experiments to evaluate the safety and efficacy of Twist-2 silenced DCs. Mice were separated into three groups: a PBS treated mock group; a group which received peptide pulsed GFP shRNA transduced DCs; and a group which received peptide pulsed Twist-2 shRNA transduced DCs. Mice received 1x106 DCs and 30ug TLR4 ligand on days 1, 2, and 3 post immunization. Two weeks after immunization Pentamer analysis, Elispot, and intracellular cytokine flow cytometry were performed. Experiments were repeated three times. Results: We observed no adverse events in any group. Mice which received Twist-2 silenced DCs had significant increases in pentamer-specific T-cells, and Elispot counts as compared to control DCs indicating an enhanced magnitude of immune response. Antigen-specific CD8 T-cells from mice which received Twist-2 silenced DCs had significant increases in intracellular IFNgamma, perforin and granzyme, indicating an increased cytotoxic response. Antigen-specific CD4 T-cells from mice which received Twist-2 silenced DCs had significant increases in intracellular TNFalpha and IL-2. Furthermore, memory markers including CD44, CD62L, and CCR7 were upregulated on T-cells from mice which received Twist-2 silenced DCs, signifying a potent and lasting immune response generated in these mice. Conclusions: These results identify Twist-2 as a critical negative regulator of DC function and immuno-stimulatory capacity. Furthermore, silencing Twist-2 shows promise as a strategy for enhancing the potency of DC-based cancer immunotherapy. No significant financial relationships to disclose.
Severe Herpes Zoster Infection in the United Kingdom: Experience in a Regional Infectious Disease Unit
Authors: P Bannister, B Crosse
Journal: Journal of the Royal Society of Medicine (1989)

Seventy-three cases of severe herpes zoster infection admitted to a regional infectious disease unit over a 3-year period were reviewed. Complications were common. Elderly patients were in the majority (55%), were hospitalized for longer and accounted for 78% of all complications. Acyclovir therapy was used in 44 cases with a reduction in both the duration of hospital stay and complication rate.
Estimation of the exercise ventilatory compensation point by the analysis of the relationship between minute ventilation and heart rate in patients with pulmonary hypertension
Authors: Paolo Marinelli, Roberto Badagliacca, Matteo Bonini, Roberto Poscia, Mattia Internullo, Simone Pascale, Gabriele Valli, Paolo Palange, Carmine Dario Vizza
Journal: European Respiratory Journal (2012)

Background: Incremental cardio-pulmonary exercise test with gas exchange measurement is the gold standard for the identification of the ventilatory compensation point (VCP). It has previously been demonstrated that the change in the slope of increment of minute ventilation over heart rate (ΔV9E/ΔHR) can be utilized alternatively to the ventilatory equivalent for CO2 (V9E /V9CO2) method for detection of VCP in healthy subjects. The reliability of this parameter in patients affected by cardiac and pulmonary diseases is still not well elucidated. Aim: To evaluate the efficacy and reliability of the ΔV9E/ΔHR in patients with pulmonary hypertension. Methods: Twenty subjects (11F – 9M; mean age 44±15.8 SD) with a diagnosis of pulmonary hypertension underwent an incremental maximal exercise test on a cycle-ergometer. V9O2, V9CO2, V9E were measured breath-by-breath. Heart rate was also registered. Results are expressed as mean±SD. Results: All patients reached the VCP showing a mean VO2 max % predicted of 55±15%. As in healthy subjects it was possible to identify two different slopes (S1 – S2) of increment in the ΔV9E/ΔHR in 14 out of the 20 patients tested (0.78±0.2 vs 1.83±1.0 p=0.002). The remaining 6 patients in whom was not detected a significant difference between the two slopes interestingly showed an altered cardiac function, as shown by the O2 pulse in the final phase of exercise. Conclusions: ΔV9E/ΔHR as a predictor of the VCP, appears to be a useful and reliable method to identify more severe IP patients with an altered cardiac function.
Contribution of nonignorable environmental factor to impairing liver disease mortality reduction target in China
Authors: Chao Dong, Shifang Peng
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. To the Editor: We read with great interest the featured article by Wang et al.,1 in which the authors elegantly demonstrated the epidemiology and characteristics of tremendous liver disease burden in China. However, while explaining why China contributes to 51% of the global deaths from liver cancer with less than one fifth of the world‐wide population base and why incidence of liver cirrhosis and HCC has increased during recent years, the authors attributed the increase of morbidity and mortality to low patient awareness and treatment rate. Over the past three decades, with China's rapid economic rise, environmental pollution problems have become noticeably worse. It would be essential for global readers to discuss and to understand, to a large extent, that this epidemiological discrepancy results from environmental factors. Based on the report2 shown in National Underground Water Pollution Control Programs 2011‐2020 from China's Ministry of Environmental Protection, more than 90% of the underground water as a drinking water source suffers from varying levels of pollution. The major water and soil pollutants are nitrite nitrogen, amino nitrogen, chloride, and heavy metals, such as iron, manganese, lead, arsenic, cadmium, and mercury. Some areas were even polluted by microorganisms.3 Many studies4 on environmental etiology of high‐incidence areas of liver cancer in China have demonstrated the association of toxin exposure from water pollution with liver cancer mortality. The increased risk of liver cancer was corroborated by a case‐control study, in which male residents in the exposed village had an increased mortality odds ratio for liver cancer of 2.57 (95% confidence interval: 1.21‐5.46), compared with those in the unexposed area after adjustment for age and period.6 Similarly, other toxins, such as nitrite,4 iron,5 and inorganic arsenic7 exposure, are significant risk factors for clustered HCC mortality in China as well. Thus, in order to reverse this disturbing trend, as the authors mentioned, many challenges need to be tackled "collaboratively." But this collaboration is not a simple one merely between clinicians and researchers, but a real non‐neglectable approach of the entire society, involving multidisciplinary work of hepatologists, surgeons, industrialists, and environmentalists and, especially, effective and visionary governance, as well as enlightenment of patients' awareness and public participation.
Role of molecular and cellular techniques applied to EBUS-TBNA of mediastinal lymph nodes for lung cancer staging
Authors: Antonio Bugalho, Gloria Nunes, Manuela Correia, Catarina Martins, Sara S. Dias, Paula A. Videira, Maria João Marques Gomes
Journal: European Respiratory Journal (2012)

Introduction: Accurate NSCLC staging is of major importance since it dictates the choice of treatment and prognosis. EBUS-TBNA is a minimally invasive method to sample mediastinal lymph nodes. The concomitant identification of cancer biomarkers is important to improve EBUS-TBNA staging.  Aim: Assess the feasibility and role of EBUS-TBNA combined to the identification of tumour-associated antigens and tumour-associated immune responses to diagnose lymph node metastases and pathological characteristics in lymph node aspirates.  Methods: In a prospective study, EBUS-TBNA samples from 57 patients with confirmed or suspected lung cancer were analysed by cytopathology, flow cytometry (FACS) and reverse-transcriptase polymerase chain reaction (RT-PCR). Results: All samples were adequately processed by the 3 different techniques. Among the 47 samples diagnosed with tumour cell by cytopathology, 70% showed the presence of cytokeratin-19 (CK-19) cells by FACS and 83% of the SCLC were CK-19 negative. CK-19 phenotype and gene expression were significantly correlated (r= 0.901) and cells with this phenotype also expressed CEA, sialyl Lewis X and CD44+ in 22.2%, 25.0% and 18.7% of cases. The expression of the  EPCAM  gene was significantly higher in the cytopathologically diagnosed cases (p=0.03). The analysis of immune cells profile in the aspirates of these patients revealed a decrease in total leukocytes (p=0.022) and a increase in monocytes (p= 0.039).  Conclusions: The combination of molecular and cellular biology techniques with EBUS-TBNA might be a feasible option to improve NSCLC staging and offer an individualized diagnostic and therapeutic approach to lung cancer patients.
Phase II trial of vinorelbine in metastatic squamous cell esophageal carcinoma. European Organization for Research and Treatment of Cancer Gastrointestinal Treat Cancer Cooperative Group.
Authors: T Conroy, P L Etienne, A Adenis, D J Wagener, B Paillot, E François, L Bedenne, J H Jacob, J F Seitz, H Bleiberg, C Van Pottelsberghe, M Van Glabbeke, F M Delgado, S Merle, J Wils
Journal: Journal of Clinical Oncology (1996)

PURPOSE To evaluate the response rate and toxic effects of vinorelbine (VNB) administered as a single agent in metastatic squamous cell esophageal carcinoma. PATIENTS AND METHODS Forty-six eligible patients with measurable lesions were included and were stratified according to previous chemotherapy. Thirty patients without prior chemotherapy and 16 pretreated with cisplatin-based chemotherapy were assessable for toxicity and response. VNB was administered weekly as a 25-mg/m2 short intravenous (i.v.) infusion. RESULTS Six of 30 patients (20%) without prior chemotherapy achieved a partial response (PR) (95% confidence interval [CI], 8% to 39%). The median duration of response was 21 weeks (range, 17 to 28). One of 16 patients (6%) with prior chemotherapy had a complete response (CR) of 31 weeks' duration (95% CI, 0% to 30%). The overall response rate (World Health Organization [WHO] criteria) was 15% (CR, 2%; PR 13%; 95% CI, 6% to 29%). The median dose-intensity (DI) was 20 mg/m2/wk. VNB was well tolerated and zero instances of WHO grade 4 nonhematologic toxicity occurred. At least one episode of grade 3 or 4 granulocytopenia was seen in 59% of patients. A grade 2 or 3 infection occurred in 16% of patients, but no toxic deaths occurred. Other side effects were rare, and peripheral neurotoxicity has been minor (26% grade 1). CONCLUSION These data indicate that VNB is an active agent in metastatic esophageal squamous cell carcinoma. Given its excellent tolerance profile and low toxicity, further evaluation of VNB in combination therapy is warranted.
PSYCHOSOMATIC DERMATOLOGICAL SYNDROMES IN MILITARY SERVICE
Authors: DANIEL J. SULLIVAN, EUGENE S. BERESTON
Journal: American Journal of Psychiatry (1946)

1. Psychosomatic dermatological syndromes (neurodermatitis, psychogenic urticaria, pruritus and hyperhidrosis) should be excluded from induction just as much as chronic asthma, peptic ulcer, functional hypertension, and chronic psychoneurosis whether expressed purely in psychological symptoms or as other psychosomatic syndromes. 2. Psychosomatic dermatological syndromes are produced or aggravated by the environmental stress of military service. 3. Predisposition is a common and important characteristic. 4. In predisposed individuals faced with situations which are frustrating, potentially threatening or distasteful, an initial attack or new attack or aggravation of a psychosomatic dermatological syndrome can be expected. Specific examples of such situations are rebellion against authority, distasteful duty assignment, and return to combat. 5. Prognosis is poor as far as continued military service is concerned, even on limited duty. These patients react like chronic asthmatics, having recurrent disabling attacks under even minimal environmental stress.
Comparing three different forms of interprofessional education on health professional inhaler technique and maintenance of correct technique
Authors: Sinthia Bosnic-Anticevich, Margaret Williamson, Biljana Cvetkovski, Sofia Mavritsakis, Pippa Travsers-Mason, Gosia Mendrela, Erica Sainsbury, Meg Stuart, Judith Mackson, Carol Armour
Journal: European Respiratory Journal (2013)

Aim: To compare the effect of three education interventions, on the ability of health professionals (HPs) to achieve and maintain correct inhaler technique (IT).  Method: A parallel group, three arm, repeated measure design was used to implement and evaluate three educational interventions: traditional face-to-face workshop(1) (Model 1), online learning module (Model 2) and a collaborative face-to-face workshop(Model 3). HPs’ IT was assessed within a fortnight of competing the modules. If HP IT was not correct, the assessor would provide immediate personal training and assessment until correct IT was achieved. HPs then delivered the Collaborations in Asthma Management in the Community (CAMCOM), protocol, involving optimisation of patient’s IT over 6 months. HPs IT was then re-assessed.  Results: A total of 81 HP (27 GPs, 11 practice nurses and 43 pharmacists) participated in the study (28, 17 and 36 HPs in Models 1, 2, and 3 respectively). There was a statistically significant difference in the mean proportion of HPs with correct technique between Modules 1, 2, and 3 initially (72%, 27.4% and 47.8% respectively, Pearson’s Chi-Squared, n=81, p  Conclusion: Different forms of HP education have had differing effects on inhaler technique of participating HPs. After 6 months this technique had generally deteriorated which has implications for what patients might receive in practice. Reasons for non-maintenance of HP IT need to be further explored.