tbuckley/cabot-search huggingface dataset:
Presentation of splice variants of 1-alpha-hydroxylase in MCF-7 breast cancer cells
Authors: T. Cordes, D. Diesing, S. Becker, D. Fischer, K. Diedrich, M. Friedrich
Journal: Journal of Clinical Oncology (2006)

20097 Background: Calcitriol (1,25-dihydroxyvitamin D 3 ) is the most active metabolite of vitamin D. It is known for its antiproliferative and differentiating effects on many cell populations including MCF-7 and other breast cancer cells. 1α-hydroxylase (CYP27B1) one of the key enzymes has been found in breast cancer cells suggesting an autocrine regulation of producing calcitriol. An alternative splicing of the encoding genes for the1α-hydroxylase might play a role in regulating enzyme levels and can explain tissue specific variations of the enzyme activity. Splice variants containing intron 1 may encode for truncated proteins with deletion of protein domains which are essential for its enzymatic activity. Methods: In order to obtain more information on the abundance of 1α-hydroxylase splice variants, we performed a highly specific nested touchdown PCR in MCF-7 cells. The protein products of the full length enzyme and its slice variants were confirmed by Western Blot. Results: The full length sequence of 1α-hydroxylase and two different splice variants including intron 1 were isolated. Conclusion: We hypothesize that the expression of the splice variants can lead to a quantitatively lower expression the mRNA of the full length enzyme. The abundance of less active 1α-hydroxylase protein products can alter the local synthesis of calcitriol in the cells and may explain variations of enzymatic activity in different cells and tissues. No significant financial relationships to disclose.
Peripheral blood Th17 / Treg ratio increases in late asthmatic response
Authors: Masatsugu Yamamoto, Amrit Singh, Jian Ruan, Gail M. Gauvreau, Sven Olek, Ulrich Hoffmueller, Paul M. O'Byrne, Christopher R. Carlsten, J. Mark FitzGerald, Louis-Philippe Boulet, Scott J. Tebbutt
Journal: European Respiratory Journal (2013)

Background   The late asthmatic response follows the early asthmatic response to allergen inhalation challenge (AIC) in half of atopic asthmatics (dual responder, DR). DRs develop airway hyperresponsiveness (AHR) and more prominent and sustained airway inflammation after AIC. While Th17 and regulatory T (Treg) cells have been studied in asthma, their roles have not been fully understood in isolated early responders (ERs) and DRs. A new method has been utilized to quantify immune cell subsets based on DNA methylation.   Aims   We aimed to measure immune cells and gene expression profiles in blood cells pre and post AIC, comparing ERs and DRs.   Methods   Eight ERs and 6 DRs underwent AIC. Blood cells were collected pre- and 2 hours post-challenge. DNA was used for epigenetic cell counting (Epiontis, Germany). Th17 and Treg cells were counted as percentage of demethylation of the cell-specific gene region; IL17A gene and FOXP3 Treg-specific demethylated regions, respectively, and the Th17/Treg ratio was compared between ERs and DRs using t-test. Gene expression was measured with Affymetrix Human Gene 1.0 ST array (Affymetrix, USA). After normalization, identified genes significantly correlated to each cell-type. GeneGo network analysis was performed for biological functions.   Results   The genes significantly correlated to Th17 and Treg counts were enriched in GeneGo analyses for Th17 functions and regulatory cellular functions, respectively. Th17/Treg was significantly higher at baseline in ERs compared to DRs (p 0.002). Th17/Treg significantly increased in DRs compared to ERs (p 0.023).   Conclusion   Th17/Treg imbalance may contribute to development of late phase bronchoconstriction and the associated AHR and inflammation.
Chemotherapy-induced tumor necrosis as a prognostic factor in localized Ewing's sarcoma of the extremities.
Authors: P Picci, T Böhling, G Bacci, S Ferrari, L Sangiorgi, M Mercuri, P Ruggieri, M Manfrini, A Ferraro, R Casadei, M S Benassi, A F Mancini, P Rosito, A Cazzola, E Barbieri, A Tienghi, A Brach del Prever, A Comandone, P Bacchini, F Bertoni
Journal: Journal of Clinical Oncology (1997)

PURPOSE This study was performed to assess the prognostic value of the proposed histopathologic method to evaluate the response of the primary tumor to preoperative chemotherapy in Ewing's sarcoma. PATIENTS AND METHODS The response to chemotherapy was evaluated from the specimens of 118 Ewing's sarcoma patients, who were preoperatively treated by chemotherapy alone. Responses were graded I to III (macroscopic viable tumor, microscopic viable tumor, and no viable tumor cells, respectively). Follow-up data were available for all patients, with a mean follow-up duration of 86 months (range, 30 to 158). RESULTS A statistically highly significant difference was observed in outcome among the three groups of patients. For patients with total necrosis (grade III response), the estimated 5-year disease-free survival rate was 95%, in contrast to 68% for grade II responders and 34% for grade III responders (P &lt; .0001). This difference was also confirmed when any single group was compared with the other groups. Among the parameters tested, patient age and the size of tumor had some prognostic value. CONCLUSION The proposed histopathologic grading, to evaluate the effect of chemotherapy on the primary tumor, had the strongest correlation to clinical outcome. This method could therefore be used to identify patients with a high risk of recurrent disease. These patients could be randomized to receive alternative postoperative treatments to investigate whether more aggressive therapies will improve outcome.
Cost-Effectiveness of Adding Cardiac Resynchronization Therapy to an Implantable Cardioverter-Defibrillator Among Patients With Mild Heart Failure
Authors: Christopher Y. Woo, Erika J. Strandberg, Michelle D. Schmiegelow, Allison L. Pitt, Mark A. Hlatky, Douglas K. Owens, Jeremy D. Goldhaber-Fiebert
Journal: Annals of Internal Medicine (2015)

Background: Cardiac resynchronization therapy (CRT) reduces mortality and heart failure hospitalizations in patients with mild heart failure. Objective: To estimate the cost-effectiveness of adding CRT to an implantable cardioverter-defibrillator (CRT-D) compared with implantable cardioverter-defibrillator (ICD) alone among patients with left ventricular systolic dysfunction, prolonged intraventricular conduction, and mild heart failure. Design: Markov decision model. Data Sources: Clinical trials, clinical registries, claims data from Centers for Medicare & Medicaid Services, and Centers for Disease Control and Prevention life tables. Target Population: Patients aged 65 years or older with a left ventricular ejection fraction (LVEF) of 30% or less, QRS duration of 120 milliseconds or more, and New York Heart Association (NYHA) class I or II symptoms. Time Horizon: Lifetime. Perspective: Societal. Intervention: CRT-D or ICD alone. Outcome Measures: Life-years, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). Results of Base-Case Analysis: Use of CRT-D increased life expectancy (9.8 years versus 8.8 years), QALYs (8.6 years versus 7.6 years), and costs ($286 500 versus $228 600), yielding a cost per QALY gained of $61 700. Results of Sensitivity Analyses: The cost-effectiveness of CRT-D was most dependent on the degree of mortality reduction: When the risk ratio for death was 0.95, the ICER increased to $119 600 per QALY. More expensive CRT-D devices, shorter CRT-D battery life, and older age also made the cost-effectiveness of CRT-D less favorable. Limitations: The estimated mortality reduction for CRT-D was largely based on a single trial. Data on patients with NYHA class I symptoms were limited. The cost-effectiveness of CRT-D in patients with NYHA class I symptoms remains uncertain. Conclusion: In patients with an LVEF of 30% or less, QRS duration of 120 milliseconds or more, and NYHA class II symptoms, CRT-D appears to be economically attractive relative to ICD alone when a reduction in mortality is expected. Primary Funding Source: National Institutes of Health, University of Copenhagen, U.S. Department of Veterans Affairs.
Long-term follow-up and prognostic factor analysis in advanced ovarian carcinoma: the Gynecologic Oncology Group experience.
Authors: G A Omura, M F Brady, H D Homesley, E Yordan, F J Major, H J Buchsbaum, R C Park
Journal: Journal of Clinical Oncology (1991)

Long-term follow-up was obtained on 726 women with advanced ovarian carcinoma (suboptimal stage III and stage IV) who had received primary chemotherapy on two Gynecologic Oncology Group (GOG) protocols between 1976 and 1982. The first study compared melphalan alone versus melphalan plus hexamethylmelamine versus cyclophosphamide plus doxorubicin (CA). The second study evaluated the same CA regimen with or without cisplatin. Eligibility for the two studies was the same. At last contact, 76 patients were alive. In a multivariate analysis, cell type other than clear cell or mucinous, cisplatin-based treatment, good performance status, younger age, lower stage, clinically nonmeasurable disease, smaller residual tumor volume, and absence of ascites were favorable characteristics for overall survival (P less than .05). Second-look laparotomy was negative significantly more often among those with endometrioid tumors; there were no negative second-look laparotomies among those with mucinous or clear cell tumors. There were 30 patients with suboptimal stage III disease who had a negative second-look laparotomy; 18 (60%) have experienced recurrence, and 13 (43%) have died. Although cisplatin treatment was beneficial, new treatments are clearly needed.
N-myc genomic content and DNA ploidy in stage IVS neuroblastoma.
Authors: J Bourhis, C Dominici, H McDowell, G Raschella, G Wilson, M A Castello, E Plouvier, J Lemerle, G Riou, J Bénard
Journal: Journal of Clinical Oncology (1991)

DNA ploidy and N-myc genomic content were analyzed in a series of stage IVS neuroblastomas by flow cytometry and Southern blot hybridization, respectively. Of the 12 stage IVS neuroblastomas studied, nine were aneuploid (DNA index [DI] greater than 1), two were diploid (DI = 1), and one was not assessable for DNA content due to insufficient tumor material. N-myc gene amplification was present in two of 12 tumors. None of the aneuploid tumors exhibited N-myc amplification. Among the aneuploid neuroblastomas, the DIs were between 1.27 and 1.60, ie, in the near-triploid range. The follow-up from diagnosis ranged from 1 to 41 months (mean, 20 months). The nine neuroblastomas with near-triploid DNA content were free of disease at the end of the follow-up period. In contrast, a rapid and fatal tumor progression was observed for the three neuroblastomas with N-myc amplification and/or diploidy. Although involving only a limited series, these results strongly suggest that the combined analysis of DNA ploidy and N-myc genomic content could predict clinical outcome in stage IVS neuroblastoma and should help to identify patients for whom a more aggressive therapy is required.
Mucocutaneous pyoderma gangrenosum due to trisomy 8 neutrophilic infiltrates in a patient with myelodysplastic syndrome
Authors: N. Haga, H. Iwata, Y. Yamaguchi, T. Shirato, K. Nishimura, N. Yamane, S. Shinkuma, K. Natsuga, T. Kondo, H. Shimizu
Journal: British Journal of Dermatology (2015)

Funding sources: none. Conflicts of interest: none declared. Dear Editor, Myelodysplastic syndromes (MDSs) are heterogeneous clonal haematopoietic disorders that mostly affect older people. Trisomy 8 is one of the most frequent aberrant karyotypes in MDS. Myeloid neoplasms including MDS, especially those with trisomy 8, are occasionally associated with neutrophilic dermatoses, such as Behçet disease, Sweet syndrome and pyoderma gangrenosum.1 2 It is hypothesized that infiltrating neutrophils in neutrophilic dermatoses originate from the MDS cells in these cases. However, no previous studies have identified the origin of the infiltrating neutrophils associated with MDS in lesional skin. Here we report a case of MDS with trisomy 8 showing genital and oral ulcers accompanied by neutrophilic dermatosis. Remarkably, infiltrating neutrophils in the involved skin demonstrated trisomy 8, as identified by a combination of fluorescence in situ hybridization (FISH) and immunohistochemistry. An 87‐year‐old Japanese man presented with a 5‐month history of painful ulcers on the oral cavity and scrotum. Physical examination revealed painful scrotal ulcers of up to 2 cm (Fig. 1a). Ulcers with necrotic tissue were seen on the tip of the tongue, the right upper lip and the left buccal mucosa (Fig. 1b). A skin biopsy was taken from the scrotal ulcer. Histologically, the lesions showed ulceration accompanied by marked neutrophilic infiltrates, the proliferation of blood vessels and fibrosis in the dermis (Fig. 1c). High‐power magnification demonstrated that many neutrophils had infiltrated in the dermis.
A nosocomial outbreak of KPC-2-producing Klebsiella pneumoniae in a Chinese hospital: dissemination of ST11 and emergence of ST37, ST392 and ST395
Authors: J. Yang, L. Ye, L. Guo, Q. Zhao, R. Chen, Y. Luo, Y. Chen, S. Tian, J. Zhao, D. Shen, L. Han
Journal: Clinical Microbiology and Infection (2013)
Multiple atypical nevi: a cutaneous marker of germ cell tumors.
Authors: D Raghavan, J R Zalcberg, J J Grygiel, N Teriana, K M Cox, W McCarthy, M Flynn
Journal: Journal of Clinical Oncology (1994)

This study assessed whether a specific association exists between atypical nevi and germ cell tumors (GCT).A prospective comparison was performed on a cohort of 129 unselected patients with GCT and a series of 153 healthy men. Three or more of the following criteria were required for diagnosis of multiple atypical nevi: greater than 5 mm in diameter; variegated color, often speckled black/brown, with irregularly distributed pigmentation; irregular outline or indistinct border; and at least three such lesions.Prevalences for multiple atypical nevi in patients with GCT and in healthy controls were 37% and 15%, respectively (P < .01). Two patients with these lesions also had documented malignant melanoma. In contrast, 16% of patients with GCT had a history of testicular maldescent (the most common known risk factor), compared with 5% of healthy controls (P < .01).Multiple atypical nevi occur with a statistically significant increased prevalence in patients with GCT as compared with healthy controls, and constitute one of the most common known clinical associations with this malignancy. These data may be of relevance for our understanding of the biology of GCT and of malignant melanoma, in the design of screening programs for testis cancer, and in the follow-up evaluation of patients with each of these disorders.
A Global Biomedical R&amp;D Fund and Mechanism for Innovations of Public Health Importance
Authors: Manica Balasegaram, Christian Bréchot, Jeremy Farrar, David Heymann, Nirmal Ganguly, Martin Khor, Yves Lévy, Precious Matsoso, Ren Minghui, Bernard Pécoul, Liu Peilong, Marcel Tanner, John-Arne Røttingen
Journal: PLoS Medicine (2015)

Over the last few years, there have been significant challenges in and increased concerns around anti-microbial resistance (AMR), emerging infectious diseases, and neglected diseases (NDs).Both AMR and emerging infectious diseases, specifically Ebola, have recently been elevated to the level of public health concerns affecting global security.All these areas have identifiable prevention and management strategies that can and should be scaled up.However, an additional consistent thread that runs throughout all these global health concerns is the deficit in innovation of new tools in relation to the identified needs.Therapeutics and vaccines for Summary Points• Anti-microbial resistance, emerging infectious diseases, and neglected diseases are all important public health concerns and priorities with serious market failures, deficits, and identified needs in biomedical innovation.
Independent Association Between Improvement of Nonalcoholic Fatty Liver Disease and Reduced Incidence of Type 2 Diabetes
Authors: Hajime Yamazaki, Toru Tsuboya, Kunihiko Tsuji, Mitsuru Dohke, Hiroyuki Maguchi
Journal: Diabetes Care (2015)

Only a few studies have evaluated the long-term effects of nonalcoholic fatty liver disease (NAFLD) on type 2 diabetes mellitus (T2DM), and none have examined whether NAFLD improvement reduces T2DM incidence. We investigated the association between NAFLD improvement and T2DM incidence.Between 2000 and 2012, 4,604 participants who underwent a health check twice with >10 years between were enrolled. Exclusion criteria were positive hepatitis B surface antigen, positive hepatitis C antibody, ethanol intake >20 g/day, and diabetes. The 3,074 eligible participants were divided into an NAFLD group (n = 728) and a non-NAFLD group (n = 2,346) according to ultrasonography-detected fatty liver. The NAFLD group was categorized into an improved group (n = 110) and a sustained NAFLD group (n = 618) based on fatty liver disappearance at the second visit. Incident T2DM odds ratios (ORs) were estimated by logistic regression models adjusted for age, sex, BMI, impaired fasting glucose, family history of diabetes, dyslipidemia, hypertension, and physical exercise.T2DM occurred in 117 participants (16.1%) in the NAFLD group and 72 (3.1%) in the non-NAFLD group. NAFLD at baseline was associated with T2DM incidence (multivariate OR 2.37 [95% CI 1.60-3.52]). T2DM occurred in 7 participants (6.4%) in the improved group and in 110 (17.8%) in the sustained NAFLD group. NAFLD improvement was associated with reduced T2DM incidence (multivariate OR 0.27 [95% CI 0.12-0.61]).NAFLD improvement is associated with T2DM incidence reduction.
Estimation of the role of the test GeneXpert MTB-RIF in the diagnosis of pulmonary tuberculosis
Authors: Zhanna Laushkina, Andrey Cherednichenko
Journal: European Respiratory Journal (2014)

Delay in diagnosis of pulmonary tuberculosis worsens results of treatment, increased severity, mortality and transmission.  Purpose: To define the sensitivity and specificity of the test GeneXpert MBT-RIF.  Materials and methods: The study included 69 patients with suspected pulmonary tuberculosis were in therapeutic clinic of Novosibirsk Research TB Institute in 2013. To all patients were performed the necessary diagnostic tests and the diagnosis was established. Patients passed the three sputum samples: three fluorescence microscopy, solid (egg-based Lowenstein–Jensenand) and liquid (BACTEC) culture and the GeneXpert MBT-RIF test were carried out.  Results: 13 (18.8%) had smear- and culture-positive tuberculosis, 1 (1.4%) had smear-negative, culture-positive tuberculosis, 48 (69.6%) had smear- and culture-negative tuberculosisand had clinical and radiographical defined tuberculosis, and 7 (10.1%) had no clinical evidence of tuberculosis. Among culture-positive patients, a single direct the GeneXpert MBT-RIF test identified 13 (100%) of 13 patients with smear-positive tuberculosis and 16 (32.7%) of 49 with smear-negative tuberculosis. The test was negative in 7 of 7 patients without tuberculosis (100%). GeneXpert MBT-RIF testing identified 15 (46.9%) patients with rifampicin-resistant bacteria of 32cases of positive the GeneXpert MBT-RIF test.  Conclusion: The GeneXpert MBT-RIF has a high sensitivity and specificity, may reduce the time of diagnosis of TB, as well as the identification of resistance to rifampicin. Identification of resistance to rifampicin allows assigning in the early periods of corresponding chemotherapy.
Asymptomatic Worsening of Airway Inflammation during Low-Dose Allergen Exposure in Asthma
Authors: Josephine de Kluijver, Christine E. Evertse, Jasmijn A. Schrumpf, Hilly van der Veen, Aeilko H. Zwinderman, Pieter S. Hiemstra, Klaus F. Rabe, Peter J. Sterk
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Asthma is a chronic inflammatory disease that persists even during adequate therapy and asymptomatic episodes. We questioned whether “silent” chronic allergen exposure can induce and maintain airway inflammation and whether this still occurs during regular treatment with inhaled steroids. Twenty-six patients with house dust mite allergy and mild asthma (dual responders) participated in a parallel, double-blind study. All patients inhaled a low-dose of allergen on 10 subsequent working days (Days 1–5, 8–12). They were treated with 400 μg budesonide once daily (n = 13) or placebo (n = 13) from Days −3 to 19. At baseline (Day −6) and on Days 5, 12, and 19 we measured the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20), and percent eosinophils, interleukin (IL)-5/interferon-γ messenger RNA ratio (in sputum cells by real-time reverse transcription-polymerase chain reaction [RT-PCR]), and eosinophilic cationic protein (ECP) in induced sputum. Symptoms, peak expiratory flow (PEF), FEV1, and exhaled nitric oxide (NO) were recorded repeatedly during the study. In the placebo group, repeated low-dose allergen exposure resulted in a significant increase in sputum eosinophils (p = 0.043), ECP (p = 0.011), IL-5/IFN-γ messenger RNA ratio (p = 0.04), and in exhaled NO (p = 0.001), without worsening of symptoms, PEF, or baseline FEV1 (p > 0.07). In the budesonide group, the changes in PC20, sputum ECP, and exhaled NO were significantly different as compared with the placebo group (p < 0.03). We conclude that repeated low-dose allergen exposure in asthma can lead to airway inflammation without worsening of symptoms, which can be prevented by inhaled steroid treatment. This suggests that antiinflammatory therapy is beneficial during allergen exposure, even during asymptomatic episodes.