tbuckley/cabot-search huggingface dataset:
Altered Serotonin 2A Receptor Activity in Women Who Have Recovered From Bulimia Nervosa
Authors: Walter H. Kaye, Guido K. Frank, Carolyn C. Meltzer, Julie C. Price, Claire W. McConaha, Penelope J. Crossan, Kelly L. Klump, Leigh Rhodes
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: The authors' goal was to confirm that brain serotonin (5-HT) alterations are present in patients who have recovered from bulimia nervosa. Positron emission tomography imaging with [18F]altanserin was used to characterize binding of the 5-HT2A receptor, which might contribute to altered feeding, mood, or impulse control. METHOD: Nine women who had recovered from bulimia nervosa (they had no episodes of binge eating or purging, were at normal weight, and had regular menstrual cycles for more than 1 year) were compared with 12 female volunteers who had never had bulimia. RESULTS: The healthy volunteers, but not the women who had recovered from bulimia nervosa, had an age-related decline in 5-HT2A binding. Women who had recovered from bulimia nervosa had a reduction of medial orbital frontal cortex 5-HT2A binding. CONCLUSIONS: The lack of age-related changes in 5-HT activity is further evidence of 5-HT alterations in subjects who have recovered from bulimia nervosa. In addition, vulnerabilities for eating disorders, impulse dyscontrol, and mood disturbances may involve 5-HT and frontal lobe activity.
Deep Sequencing in Conjunction with Expression and Functional Analyses Reveals Activation of FGFR1 in Ewing Sarcoma
Authors: Konstantin Agelopoulos, Günther H.S. Richter, Eva Schmidt, Uta Dirksen, Kristina von Heyking, Benjamin Moser, Hans-Ulrich Klein, Udo Kontny, Martin Dugas, Kathrin Poos, Eberhard Korsching, Thorsten Buch, Matthias Weckesser, Isabell Schulze, Regina Besoke, Anika Witten, Monika Stoll, Gabriele Köhler, Wolfgang Hartmann, Eva Wardelmann, Claudia Rossig, Daniel Baumhoer, Heribert Jürgens, Stefan Burdach, Wolfgang E. Berdel, Carsten Müller-Tidow
Journal: Clinical Cancer Research (2015)

A low mutation rate seems to be a general feature of pediatric cancers, in particular in oncofusion gene-driven tumors. Genetically, Ewing sarcoma is defined by balanced chromosomal EWS/ETS translocations, which give rise to oncogenic chimeric proteins (EWS-ETS). Other contributing somatic mutations involved in disease development have only been observed at low frequency.Tumor samples of 116 Ewing sarcoma patients were analyzed here. Whole-genome sequencing was performed on two patients with normal, primary, and relapsed tissue. Whole-exome sequencing was performed on 50 Ewing sarcoma and 22 matched normal tissues. A discovery dataset of 14 of these tumor/normal pairs identified 232 somatic mutations. Recurrent nonsynonymous mutations were validated in the 36 remaining exomes. Transcriptome analysis was performed in a subset of 14 of 50 Ewing sarcomas and DNA copy number gain and expression of FGFR1 in 63 of 116 Ewing sarcomas.Relapsed tumors consistently showed a 2- to 3-fold increased number of mutations. We identified several recurrently mutated genes at low frequency (ANKRD30A, CCDC19, KIAA0319, KIAA1522, LAMB4, SLFN11, STAG2, TP53, UNC80, ZNF98). An oncogenic fibroblast growth factor receptor 1 (FGFR1) mutation (N546K) was detected, and the FGFR1 locus frequently showed copy number gain (31.7%) in primary tumors. Furthermore, high-level FGFR1 expression was noted as a characteristic feature of Ewing sarcoma. RNA interference of FGFR1 expression in Ewing sarcoma lines blocked proliferation and completely suppressed xenograft tumor growth. FGFR1 tyrosine kinase inhibitor (TKI) therapy in a patient with Ewing sarcoma relapse significantly reduced 18-FDG-PET activity.FGFR1 may constitute a promising target for novel therapeutic approaches in Ewing sarcoma.
Encapsulated in silica: genome, proteome and physiology of the thermophilic bacterium Anoxybacillus flavithermus WK1
Authors: Jimmy H Saw, Bruce W Mountain, Lu Feng, Marina V Omelchenko, Shaobin Hou, Jennifer A Saito, Matthew B Stott, Dan Li, Guang Zhao, Junli Wu, Michael Y Galperin, Eugene V Koonin, Kira S Makarova, Yuri I Wolf, Daniel J Rigden, Peter F Dunfield, Lei Wang, Maqsudul Alam
Journal: Genome biology (2008)

Abstract Background Gram-positive bacteria of the genus Anoxybacillus have been found in diverse thermophilic habitats, such as geothermal hot springs and manure, and in processed foods such as gelatin and milk powder. Anoxybacillus flavithermus is a facultatively anaerobic bacterium found in super-saturated silica solutions and in opaline silica sinter. The ability of A. flavithermus to grow in super-saturated silica solutions makes it an ideal subject to study the processes of sinter formation, which might be similar to the biomineralization processes that occurred at the dawn of life. Results We report here the complete genome sequence of A. flavithermus strain WK1, isolated from the waste water drain at the Wairakei geothermal power station in New Zealand. It consists of a single chromosome of 2,846,746 base pairs and is predicted to encode 2,863 proteins. In silico genome analysis identified several enzymes that could be involved in silica adaptation and biofilm formation, and their predicted functions were experimentally validated in vitro . Proteomic analysis confirmed the regulation of biofilm-related proteins and crucial enzymes for the synthesis of long-chain polyamines as constituents of silica nanospheres. Conclusions Microbial fossils preserved in silica and silica sinters are excellent objects for studying ancient life, a new paleobiological frontier. An integrated analysis of the A. flavithermus genome and proteome provides the first glimpse of metabolic adaptation during silicification and sinter formation. Comparative genome analysis suggests an extensive gene loss in the Anoxybacillus / Geobacillus branch after its divergence from other bacilli.
Harnessing the Immune System for the Treatment of Non–Small-Cell Lung Cancer
Authors: Julie R. Brahmer
Journal: Journal of Clinical Oncology (2013)

Over the last several years, new therapeutic targets have emerged in immunotherapy, particularly the immune checkpoint pathways. Blocking inhibitory pathways via monoclonal antibodies, such as the anti-cytotoxic T-lymphocyte antigen-4 antibody (ipilimumab), anti-programmed cell death-1 antibody (BMS-936558), and anti-programmed cell death-1 ligand antibody (BMS-936559), has the ability to break down the shield that tumors co-opt for their defense. Vaccines are able to help the immune system develop immune memory that can have long-lasting, tumor-specific effects. Newer vaccines, particularly the tumor cell vaccine, belagenpumatucel-L, and the antigen-specific vaccines, melanoma-associated antigen-A3, liposomal BLP-25, TG4010, and recombinant human epidermal growth factor, are being evaluated in some of the largest trials ever attempted in lung cancer therapy. These therapies alone or in combination may hold the key to making immunotherapy a reality in the treatment of lung cancer.
FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3
Authors: Liqing Wang, Yujie Liu, Rongxiang Han, Ulf H. Beier, Tricia R. Bhatti, Tatiana Akimova, Mark I. Greene, Scott W. Hiebert, Wayne W. Hancock
Journal: Journal of Clinical Investigation (2015)

Treg dysfunction is associated with a variety of inflammatory diseases. Treg populations are defined by expression of the oligomeric transcription factor FOXP3 and inability to produce IL-2, a cytokine required for T cell maintenance and survival. FOXP3 activity is regulated post-translationally by histone/protein acetyltransferases and histone/protein deacetylases (HDACs). Here, we determined that HDAC3 mediates both the development and function of the two main Treg subsets, thymus-derived Tregs and induced Tregs (iTregs). We determined that HDAC3 and FOXP3 physically interact and that HDAC3 expression markedly reduces Il2 promoter activity. In murine models, conditional deletion of Hdac3 during thymic Treg development restored Treg production of IL-2 and blocked the suppressive function of Tregs. HDAC3-deficient mice died from autoimmunity by 4–6 weeks of age; however, injection of WT FOXP3+ Tregs prolonged survival. Adoptive transfer of Hdac3-deficient Tregs, unlike WT Tregs, did not control T cell proliferation in naive mice and did not prevent allograft rejection or colitis. HDAC3 also regulated the development of iTregs, as HDAC3-deficient conventional T cells were not converted into iTregs under polarizing conditions and produced large amounts of IL-2, IL-6, and IL-17. We conclude that HDAC3 is essential for the normal development and suppressive functions of thymic and peripheral FOXP3+ Tregs.
Increased Heparanase Expression Is Caused by Promoter Hypomethylation and Up-Regulation of Transcriptional Factor Early Growth Response-1 in Human Prostate Cancer
Authors: Tatsuya Ogishima, Hiroaki Shiina, Julia E. Breault, Laura Tabatabai, William W. Bassett, Hideki Enokida, Long-Cheng Li, Toshifumi Kawakami, Shinji Urakami, Leopoldo A. Ribeiro-Filho, Masaharu Terashima, Makoto Fujime, Mikio Igawa, Rajvir Dahiya
Journal: Clinical Cancer Research (2005)

Heparanase degrades heparan sulfate and has been implicated in tumor invasion and metastasis. The transcription factor, early growth response 1 (EGR1), is associated with the inducible transcription of the heparanase gene. We hypothesize that CpG hypomethylation in the heparanase promoter coupled with up-regulation of EGR1 levels may induce heparanase expression in human prostate cancer.Cultured prostate cancer cell lines (Du145, DuPro, LNCaP, and PC-3) with and without 5'-aza-2-deoxycytidine treatment, 177 prostate cancer samples, and 69 benign prostatic hyperplasia (BPH) samples were used. The frequency and level of heparanase promoter methylation were analyzed by methylation-specific primers which covered the core binding motif of EGR1 (GGCG) or SP1 (GGGCGG) or both.In cultured Du145, DuPro, LNCaP, and PC-3 cell lines, mRNA transcripts of heparanase were significantly increased after 5'-aza-2-deoxycytidine treatment, suggesting that promoter methylation was involved in the regulation of heparanase mRNA transcript. Significantly higher methylation was found in BPH samples than in prostate cancer samples (P < 0.0001), whereas mRNA transcripts of the heparanase gene were inversely lower in BPH samples than in prostate cancer samples (P < 0.01). EGR1 expression in prostate cancer tissues was significantly higher than in BPH tissues (P < 0.001) and correlated with heparanase expression (P < 0.0001). Moreover, multiple regression analysis revealed that up-regulation of EGR1 contributed significantly more to heparanase expression than did promoter CpG hypomethylation in prostate cancer samples (P < 0.0001).To our knowledge this is the first comprehensive study demonstrating that increased heparanase expression in prostate cancer tissues is due to promoter hypomethylation and up-regulation of transcription factor EGR1.
Supplemental Perioperative Oxygen and the Risk of Surgical Wound Infection&lt;SUBTITLE&gt;A Randomized Controlled Trial&lt;/SUBTITLE&gt;
Authors: F. Javier Belda, Luciano Aguilera, José García de la Asunción, Javier Alberti, Rosario Vicente, Lucía Ferrándiz, Rafael Rodríguez, Daniel I. Sessler, Gerardo Aguilar, Stephanie García Botello, Rafael Ortí
Journal: JAMA (2005)

ContextSupplemental perioperative oxygen has been variously reported to halve or double the risk of surgical wound infection.ObjectiveTo test the hypothesis that supplemental oxygen reduces infection risk in patients following colorectal surgery.Design, Setting, and PatientsA double-blind, randomized controlled trial of 300 patients aged 18 to 80 years who underwent elective colorectal surgery in 14 Spanish hospitals from March 1, 2003, to October 31, 2004. Wound infections were diagnosed by blinded investigators using Centers for Disease Control and Prevention criteria. Baseline patient characteristics, anesthetic treatment, and potential confounding factors were recorded.InterventionsPatients were randomly assigned to either 30% or 80% fraction of inspired oxygen (FIO2) intraoperatively and for 6 hours after surgery. Anesthetic treatment and antibiotic administration were standardized.Main Outcome MeasuresAny surgical site infection (SSI); secondary outcomes included return of bowel function and ability to tolerate solid food, ambulation, suture removal, and duration of hospitalization.ResultsA total of 143 patients received 30% perioperative oxygen and 148 received 80% perioperative oxygen. Surgical site infection occurred in 35 patients (24.4%) administered 30% FIO2 and in 22 patients (14.9%) administered 80% FIO2 (P=.04). The risk of SSI was 39% lower in the 80% FIO2 group (relative risk [RR], 0.61; 95% confidence interval [CI], 0.38-0.98) vs the 30% FIO2 group. After adjustment for important covariates, the RR of infection in patients administered supplemental oxygen was 0.46 (95% CI, 0.22-0.95; P = .04). None of the secondary outcomes varied significantly between the 2 treatment groups.ConclusionsPatients receiving supplemental inspired oxygen had a significant reduction in the risk of wound infection. Supplemental oxygen appears to be an effective intervention to reduce SSI in patients undergoing colon or rectal surgery.Trial RegistrationClinicalTrials.gov Identifier: NCT00235456
Impact of a controlled heated breathing tube humidifier on sleep quality during CPAP therapy in a cool sleeping environment
Authors: G. Nilius, U. Domanski, K-J. Franke, K-H. Ruhle
Journal: European Respiratory Journal (2008)

There are conflicting data on the effect of adding a heated humidifier to nasal continuous positive airway pressure (CPAP) therapy for patients with obstructive sleep apnoea syndrome (OSAS). The effects of heated humidification on sleep quality and treatment side-effects for patients who prefer a cold bedroom environment have not been studied. A randomised, controlled crossover trial involving 19 patients with a first-ever diagnosis of OSAS measured the effect of conventional heated humidification added to CPAP compared with a controlled heated breathing tube humidifier (ThermoSmart®; Fisher and Paykel Healthcare, Auckland, New Zealand) on sleep quality. During the night in the sleep laboratory at a mean room temperature of 14°C, less condensation formed with the controlled heated breathing tube humidifier (1.9 mL versus 35.3 mL) in the delivery system. In addition, the total sleep time, time spent in sleep stages 3 and 4, and rapid eye movement sleep phases were significantly longer and the overall side-effect score was lower than with conventional heated humidification. Patients on nasal continuous positive airway pressure desiring a cool bedroom temperature could benefit from controlled heated breathing tube humidification technology (with inputs from ambient temperature, set pressure and flow).
Definition and Impact of Pathologic Complete Response on Prognosis After Neoadjuvant Chemotherapy in Various Intrinsic Breast Cancer Subtypes
Authors: Gunter von Minckwitz, Michael Untch, Jens-Uwe Blohmer, Serban D. Costa, Holger Eidtmann, Peter A. Fasching, Bernd Gerber, Wolfgang Eiermann, Jörn Hilfrich, Jens Huober, Christian Jackisch, Manfred Kaufmann, Gottfried E. Konecny, Carsten Denkert, Valentina Nekljudova, Keyur Mehta, Sibylle Loibl
Journal: Journal of Clinical Oncology (2012)

Purpose The exact definition of pathologic complete response (pCR) and its prognostic impact on survival in intrinsic breast cancer subtypes is uncertain. Methods Tumor response at surgery and its association with long-term outcome of 6,377 patients with primary breast cancer receiving neoadjuvant anthracycline-taxane–based chemotherapy in seven randomized trials were analyzed. Results Disease-free survival (DFS) was significantly superior in patients with no invasive and no in situ residuals in breast or nodes (n = 955) compared with patients with residual ductal carcinoma in situ only (n = 309), no invasive residuals in breast but involved nodes (n = 186), only focal-invasive disease in the breast (n = 478), and gross invasive residual disease (n = 4,449; P &lt; .001). Hazard ratios for DFS comparing patients with or without pCR were lowest when defined as no invasive and no in situ residuals (0.446) and increased monotonously when in situ residuals (0.523), no invasive breast residuals but involved nodes (0.623), and focal-invasive disease (0.727) were included in the definition. pCR was associated with improved DFS in luminal B/human epidermal growth factor receptor 2 (HER2) –negative (P = .005), HER2-positive/nonluminal (P &lt; .001), and triple-negative (P &lt; .001) tumors but not in luminal A (P = .39) or luminal B/HER2-positive (P = .45) breast cancer. pCR in HER2-positive (nonluminal) and triple-negative tumors was associated with excellent prognosis. Conclusion pCR defined as no invasive and no in situ residuals in breast and nodes can best discriminate between patients with favorable and unfavorable outcomes. Patients with noninvasive or focal-invasive residues or involved lymph nodes should not be considered as having achieved pCR. pCR is a suitable surrogate end point for patients with luminal B/HER2-negative, HER2-positive (nonluminal), and triple-negative disease but not for those with luminal B/HER2-positive or luminal A tumors.
Clinically Applicable Models to Characterize<i>BRCA1</i>and<i>BRCA2</i>Variants of Uncertain Significance
Authors: Andrew D. Spearman, Kevin Sweet, Xiao-Ping Zhou, Jane McLennan, Fergus J. Couch, Amanda Ewart Toland
Journal: Journal of Clinical Oncology (2008)

Purpose Twenty percent of individuals with a strong family and/or personal history of breast and ovarian cancer carry a deleterious mutation in BRCA1 or BRCA2. Identification of mutations in these genes is extremely beneficial for patients pursuing risk reduction strategies. Approximately 7% of individuals who have genetic testing of BRCA1 and BRCA2 carry a variant of uncertain significance (VUS), making clinical management less certain. The majority of identified VUS occur only in one to two individuals; these variants are not able to be classified using current classification models with segregation analysis components. Methods To develop a clinically applicable method that can predict the pathogenicity of VUS that does not require familial information or segregation analysis, we identified characteristics of breast or ovarian tumors that distinguished sporadic tumors from tumors with BRCA1 or BRCA2 mutations. Study participants included individuals with known deleterious mutations in BRCA1 or BRCA2 and individuals with classified or unclassified BRCA variants. Results We applied the models to 57 tumors with 43 different deleterious BRCA mutations and 57 tumors with 54 unique classified and unclassified BRCA variants. Of the 33 previously unclassified VUS studied, we found evidence of neutrality for 21. Conclusion Our models showed 98% sensitivity and 76% specificity for predicting classified DNA changes. We classified 64% of unknown variants as neutral. Classification of VUS as neutral will have immediate benefit for those individuals and their family members. These models are adaptable for the clinic and will be useful for individuals with limited available family history.
A105: Late Cardiac Assessment in Children Who Were Diagnosed With Post Streptococcal Reactive Arthritis-A Long Term Study
Authors: Liat Perl, Ifat Kvint, Avraham Matityahu, Alex Levi, Yosef Uziel, Judit Barash
Journal: Arthritis & Rheumatology (2014)

Background/Purpose:

In different from rheumatic fever (RF), the association of post streptococcal reactive arthritis (PSRA) and carditis is controversial. Currently the American Heart Association recommends anti-streptococcal prophylaxis for PSRA for one year, repeat echocardiogram and discontinuation of prophylaxis if normal (level 2, C evidence).



Aim—To examine whether there is late cardiac involvement in a cohort of children with PSRA.



Methods:

Children with defined PSRA who were followed at the pediatric rheumatology units in Meir and Kaplan hospitals had echocardiography, done by pediatric cardiologists, at least 1 year following diagnosis.



Results:

146 PSRA patients fulfilled the study criteria. Of these, 69 had undergone echocardiography 1–6.9 years from diagnosis. All had normal major parameters. 20 patients had minimal findings: 5 (7.2%) mild mitral insufficiency; 12 (17.4%) minimal mitral insufficiency; 2 (2.9%) mild tricuspid insufficiency and one patient (1.4%) had very mild aortic insufficiency. All were consistent as non significant findings. Of the 77 patients who did not complete echocardiography, 31 were randomly excluded from the study, 26 refused to undergo echocardiography, and 20 were lost to followup, all were asymptomatic according to their medical record or telephone questionnaire. There were no statistically significant differences between the group that had completed echocardiography to the group that had not.



Conclusion:

No late cardiac involvement was found in our pediatric PSRA patients. Therefore, different approaches to antibiotic prophylaxis for PSRA and RF are probably justified. A prospective, double blind placebo controlled study is needed to definitively assess the necessity of prophylaxis in PSRA.
Elevations in Troponin T and I Are Associated With Abnormal Tissue Level Perfusion
Authors: Graham C. Wong, David A. Morrow, Sabina Murphy, Nicole Kraimer, Rupal Pai, David James, Debbie H. Robertson, Laura A. Demopoulos, Peter DiBattiste, Christopher P. Cannon, C.Michael Gibson
Journal: Circulation (2002)

Background — Cardiac troponin T (cTnT) and I elevations are associated with a higher risk of adverse events, a higher incidence of multivessel disease, complex lesions, and visible thrombus in the setting of non-ST elevation (NSTE) acute coronary syndromes (ACS). Other pathophysiological mechanisms underlying troponin elevation remain unclear. Methods and Results — We evaluated the relationship between troponin elevation and tissue level perfusion using the TIMI myocardial perfusion grade (TMPG) in 310 patients with NSTE-ACS in the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction (TACTICS-TIMI) 18 trial. TMPG 0/1 (“closed” microvasculature) was observed more frequently in cTnT-positive patients both before (58.1% versus 42.1%; P =0.007) and after percutaneous coronary intervention (55.4% versus 35.6%; P =0.004). cTnT levels were higher among patients with TMPG 0/1 versus patients with TMPG 2/3 (0.50 versus 0.31 ng/mL; P =0.006). cTnT-positive patients were more likely to have thrombus (42.5% versus 29.3%), tighter stenoses (72.0% versus 64.8%), and higher rates of TIMI flow grade 0/1 (15.6% versus 7.0%; all P &lt;0.05). TMPG 0/1 remained independently associated with cTnT elevation (odds ratio, 1.81; P =0.02), even after adjusting for epicardial TIMI flow grade, presence of thrombus, and prior myocardial infarction. TMPG 0/1 flow both before and after intervention was associated with increased risk of death or myocardial infarction at 6 months. Conclusions — Similar to what has been observed in the setting of ST-elevation myocardial infarction, abnormal tissue level perfusion is also associated with adverse outcomes in the NSTE-ACS setting. Independent of the presence of thrombus and abnormal flow in the epicardial artery, impaired tissue level perfusion is associated with a 1.8-fold increased risk of cTnT elevation.