tbuckley/cabot-search huggingface dataset:
Hsp90 Promotes Kinase Evolution
Authors: Jennifer Lachowiec, Tzitziki Lemus, Elhanan Borenstein, Christine Queitsch
Journal: Molecular Biology and Evolution (2014)

Heat-shock protein 90 (Hsp90) promotes the maturation and stability of its client proteins, including many kinases. In doing so, Hsp90 may allow its clients to accumulate mutations as previously proposed by the capacitor hypothesis. If true, Hsp90 clients should show increased evolutionary rate compared with nonclients; however, other factors, such as gene expression and protein connectivity, may confound or obscure the chaperone’s putative contribution. Here, we compared the evolutionary rates of many Hsp90 clients and nonclients in the human protein kinase superfamily. We show that Hsp90 client status promotes evolutionary rate independently of, but in a small magnitude similar to that of gene expression and protein connectivity. Hsp90’s effect on kinase evolutionary rate was detected across mammals, specifically relaxing purifying selection. Hsp90 clients also showed increased nucleotide diversity and harbored more damaging variation than nonclient kinases across humans. These results are consistent with the central argument of the capacitor hypothesis that interaction with the chaperone allows its clients to harbor genetic variation. Hsp90 client status is thought to be highly dynamic with as few as one amino acid change rendering a protein dependent on the chaperone. Contrary to this expectation, we found that across protein kinase phylogeny Hsp90 client status tends to be gained, maintained, and shared among closely related kinases. We also infer that the ancestral protein kinase was not an Hsp90 client. Taken together, our results suggest that Hsp90 played an important role in shaping the kinase superfamily.
Overexpression and knockout of miR-126 both promote leukemogenesis
Authors: Zejuan Li, Ping Chen, Rui Su, Yuanyuan Li, Chao Hu, Yungui Wang, Stephen Arnovitz, Miao He, Sandeep Gurbuxani, Zhixiang Zuo, Abdel G. Elkahloun, Shenglai Li, Hengyou Weng, Hao Huang, Mary Beth Neilly, Shusheng Wang, Eric N. Olson, Richard A. Larson, Michelle M. Le Beau, Jiwang Zhang, Xi Jiang, Minjie Wei, Jie Jin, Paul P. Liu, Jianjun Chen
Journal: Blood (2015)
Defining Rates and Risk Factors for Readmissions Following Emergency General Surgery
Authors: Joaquim M. Havens, Olubode A. Olufajo, Zara R. Cooper, Adil H. Haider, Adil A. Shah, Ali Salim
Journal: JAMA Surgery (2015)

Hospital readmission rates following surgery are increasingly being used as a marker of quality of care and are used in pay-for-performance metrics. To our knowledge, comprehensive data on readmissions to the initial hospital or a different hospital after emergency general surgery (EGS) procedures do not exist.To define readmission rates and identify risk factors for readmission after common EGS procedures.Patients undergoing EGS, as defined by the American Association for the Surgery of Trauma, were identified in the California State Inpatient Database (2007-2011) on January 15, 2015. Patients were 18 years and older. We identified the 5 most commonly performed EGS procedures in each of 11 EGS diagnosis groups. Patient demographics (sex, age, race/ethnicity, and insurance type) as well as Charlson Comorbidity Index score, length of stay, complications, and discharge disposition were collected. Factors associated with readmission were determined using multivariate logistic regression models analysis.Thirty-day hospital readmission.Among 177,511 patients meeting inclusion criteria, 57.1% were white, 48.8% were privately insured, and most were 45 years and older (51.3%). Laparoscopic appendectomy (35.2%) and laparoscopic cholecystectomy (19.3%) were the most common procedures. The overall 30-day readmission rate was 5.91%. Readmission rates ranged from 4.1% (upper gastrointestinal) to 16.8% (cardiothoracic). Of readmitted patients, 16.8% were readmitted at a different hospital. Predictors of readmission included Charlson Comorbidity Index score of 2 or greater (adjusted odds ratio: 2.26 [95% CI, 2.14-2.39]), leaving against medical advice (adjusted odds ratio: 2.24 [95% CI, 1.89-2.66]), and public insurance (adjusted odds ratio: 1.55 [95% CI, 1.47-1.64]). The most common reasons for readmission were surgical site infections (16.9%), gastrointestinal complications (11.3%), and pulmonary complications (3.6%).Readmission after EGS procedures is common and varies widely depending on patient factors and diagnosis categories. One in 5 readmitted patients will go to a different hospital, causing fragmentation of care and potentially obscuring the utility of readmission as a quality metric. Assisting socially vulnerable patients and reducing postoperative complications, including infections, are targets to reduce readmissions.
Gut to lung
Authors: Sylvia Knapp
Journal: Gut (2015)

Over the last few years, microbiome-focused studies have propelled our understanding of the importance and contribution of several species of gut microbes to immunity and tissue homeostasis.1 Certain microbiota were discovered to essentially shape the intestinal immune system, and changes in the composition of the gut microbiome were found associated with a wide range of diseases, including IBD, metabolic diseases such as diabetes or even neurological disorders like autism.1 These studies laid the foundation for novel therapeutic interventions like microbiome-tailored treatments. As a first, seemingly simple but nevertheless effective step, faecal microbiota transplantation (FMT) is increasingly recognised as a powerful means to treat conditions associated with dysbiosis, most notably Clostridium difficile enteritis.2

In a parallel attempt, the lungs moved into the focus of microbe-interested scientists and clinicians alike. As a result, the lung microbiome as its own unique habitat was explored, ending the century-old misconception that lungs are sterile sites. Empowered by more sophisticated technical tools like pyrosequencing, a number of studies established the composition of the lung microbiome in healthy people and discovered various degrees of alterations in …
A Review of: “Jing-Bao Nie. Behind the Silence: Chinese Voices on Abortion”
Authors: Grant Gillett
Journal: The American Journal of Bioethics (2006)

When one thinks of the abortion debate in bioethics, one thinks of the hoary old standoff between the sanctity of the life of the child and the rights of the woman over her own body. Jing-Bao Nie's...
Targeting LGR5 <sup>+</sup> cells with an antibody-drug conjugate for the treatment of colon cancer
Authors: Melissa R. Junttila, Weiguang Mao, Xi Wang, Bu-Er Wang, Thinh Pham, John Flygare, Shang-Fan Yu, Sharon Yee, David Goldenberg, Carter Fields, Jeffrey Eastham-Anderson, Mallika Singh, Rajesh Vij, Jo-Anne Hongo, Ron Firestein, Melissa Schutten, Kelly Flagella, Paul Polakis, Andrew G. Polson
Journal: Science Translational Medicine (2015)

Cancer stem cells (CSCs) are hypothesized to actively maintain tumors similarly to how their normal counterparts replenish differentiated cell types within tissues, making them an attractive therapeutic target for the treatment of cancer. Because most CSC markers also label normal tissue stem cells, it is unclear how to selectively target them without compromising normal tissue homeostasis. We evaluated a strategy that targets the cell surface leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), a well-characterized tissue stem cell and CSC marker, with an antibody conjugated to distinct cytotoxic drugs. One antibody-drug conjugate (ADC) demonstrated potent tumor efficacy and safety in vivo. Furthermore, the ADC decreased tumor size and proliferation, translating to improved survival in a genetically engineered model of intestinal tumorigenesis. These data demonstrate that ADCs can be leveraged to exploit differences between normal and cancer stem cells to successfully target gastrointestinal cancers.
MINDful polypectomy: a quality improvement initiative to improve complete resection of colorectal polyps
Authors: Shireena Desai, Beacher Schneider, Samuel Ho, Samir Gupta
Journal: Endoscopy (2015)

Incomplete resection of colon polyps is common, and the rate is significantly higher for 1- to 2-cm polyps (17.3 %) than for smaller, 5- to 9-mm polyps (6.8 %) [1]. We instituted a quality improvement measure to evaluate whether a "MINDful polypectomy" mnemonic summarizing a standardized approach for the resection of polyps ≥ 1 cm in size would decrease the rates of incomplete resection among outpatients undergoing routine colonoscopy. This earlier version of the mnemonic was: "Move polyp to 6-o'clock position; Inspect carefully, consider NBI (narrow-band imaging); Note whether borders are completely removed; Due diligence with biopsies of polypectomy edges to ensure complete resection." The mnemonic was presented to all endoscopists, with a reminder poster placed in each endoscopy room. We measured compliance with the mnemonic based on whether biopsy of the polypectomy edge was completed for polyps ≥ 1 cm.
We are not in kansas anymore: The unfamiliar landscape of NASH
Authors: Wajahat Z. Mehal
Journal: Hepatology (2015)

1Section of Digestive DiseasesYale UniversityNew HavenCT *Address reprint requests to: Wajahat Z. Mehal, M.D., D.Phil., Section of Digestive Diseases, Yale University, New Haven, CT, 06520‐8019. E‐mail: [email protected]; fax: 1‐203‐785‐7273.
Peripheral Type Benzodiazepine Receptors
Authors: A Verma, S H Snyder
Journal: The Annual Review of Pharmacology and Toxicology (1989)

Over the past two decades, deadly coronaviruses, with the most recent being the severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) 2019 pandemic, have majorly challenged public health. The path for virus invasion into humans and other ...Read More
How are depression and bulimia related?
Authors: A B Levy, K N Dixon, S L Stern
Journal: American Journal of Psychiatry (1989)

The idea that bulimia may be related to affective illness was encouraged by early reports of a high prevalence of clinical depression in bulimic patients as well as a high lifetime prevalence of depression in the families of these patients. More recent evidence suggests, however, that bulimia and major depression are distinct entities. The authors review clinical data, family studies, pharmacotherapy, and the neurobiology of bulimia and discuss the nature of the relationship between depression and bulimia.
Aberrant sodium influx causes cardiomyopathy and atrial fibrillation in mice
Authors: Elaine Wan, Jeffrey Abrams, Richard L. Weinberg, Alexander N. Katchman, Joseph Bayne, Sergey I. Zakharov, Lin Yang, John P. Morrow, Hasan Garan, Steven O. Marx
Journal: Journal of Clinical Investigation (2015)

Increased sodium influx via incomplete inactivation of the major cardiac sodium channel Na(V)1.5 is correlated with an increased incidence of atrial fibrillation (AF) in humans. Here, we sought to determine whether increased sodium entry is sufficient to cause the structural and electrophysiological perturbations that are required to initiate and sustain AF. We used mice expressing a human Na(V)1.5 variant with a mutation in the anesthetic-binding site (F1759A-Na(V)1.5) and demonstrated that incomplete Na+ channel inactivation is sufficient to drive structural alterations, including atrial and ventricular enlargement, myofibril disarray, fibrosis and mitochondrial injury, and electrophysiological dysfunctions that together lead to spontaneous and prolonged episodes of AF in these mice. Using this model, we determined that the increase in a persistent sodium current causes heterogeneously prolonged action potential duration and rotors, as well as wave and wavelets in the atria, and thereby mimics mechanistic theories that have been proposed for AF in humans. Acute inhibition of the sodium-calcium exchanger, which targets the downstream effects of enhanced sodium entry, markedly reduced the burden of AF and ventricular arrhythmias in this model, suggesting a potential therapeutic approach for AF. Together, our results indicate that these mice will be important for assessing the cellular mechanisms and potential effectiveness of antiarrhythmic therapies.
In vitro cytotoxicity of docetaxel in childhood acute leukemias.
Authors: R Consolini, C H Pui, F G Behm, S C Raimondi, D Campana
Journal: Journal of Clinical Oncology (1998)

PURPOSE In seeking to identify novel effective antileukemic agents, we assessed the in vitro activity of the taxoid docetaxel (Taxotere; Rhone-Poulenc Rorer, Antony, France) in primary leukemic cells supported in culture by bone marrow-derived stromal layers. MATERIALS AND METHODS Bone marrow samples from children with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) were cultured on allogeneic bone marrow-derived stromal layers and exposed to various concentrations of docetaxel. After 7 days of culture, the number of viable leukemic cells were counted by flow cytometry and compared with that in parallel cultures without drugs. RESULTS In 20 samples tested (15 B-lineage ALL, one T-lineage ALL, and four AML), the median cytotoxicity was 78% after a 7-day culture in the presence of 100 ng/mL docetaxel (range, 54% to 95%). The effects were dose-dependent and extended to all five ALL samples with the t(9;22)(q34;q11) (Philadelphia chromosome) or 11q23 abnormalities, karyotypes associated with an unfavorable outcome. Studies with continuously growing cell lines demonstrated that docetaxel exerted its cytotoxic effect by inducing apoptosis, and was consistently more effective than paclitaxel (Taxol; Bristol-Myers Squibb, Wallingford, CT) (mean 50% cell kill [LC50], 6.93 v 12.86 ng/mL in six leukemic cell lines). The antileukemic activities of docetaxel and vincristine were synergistic. While the mean (+/- SD) cytotoxicity of vincristine (0.1 ng/mL) was 11.2% +/- 7.3% and that of docetaxel (10 ng/mL) was 19.3% +/- 17.5% in CEM-C7 cells after 24 hours, combining the two agents increased the cytotoxicity to 62.5% +/- 20.7% (P = .003). CONCLUSION Docetaxel, at concentrations achievable in vivo, is cytotoxic to ALL and AML cells. These results provide a rationale for clinical trials of docetaxel in patients with acute leukemia.
A Novel Gaussian Extrapolation Approach for 2D Gel Electrophoresis Saturated Protein Spots
Authors: Massimo Natale, Alfonso Caiazzo, Enrico M. Bucci, Elisa Ficarra
Journal: Genomics Proteomics & Bioinformatics (2012)

Abstract Analysis of images obtained from two-dimensional gel electrophoresis (2D-GE) is a topic of utmost importance in bioinformatics research, since commercial and academic software available currently has proven to be neither completely effective nor fully automatic, often requiring manual revision and refinement of computer generated matches. In this work, we present an effective technique for the detection and the reconstruction of over-saturated protein spots. Firstly, the algorithm reveals overexposed areas, where spots may be truncated, and plateau regions caused by smeared and overlapping spots. Next, it reconstructs the correct distribution of pixel values in these overexposed areas and plateau regions, using a two-dimensional least-squares fitting based on a generalized Gaussian distribution. Pixel correction in saturated and smeared spots allows more accurate quantification, providing more reliable image analysis results. The method is validated for processing highly exposed 2D-GE images, comparing reconstructed spots with the corresponding non-saturated image, demonstrating that the algorithm enables correct spot quantification.
Role of Bacterial Cytotoxins in Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura
Authors: Shai Ashkenazi
Journal: Annual Review of Medicine (1993)

Bacterial cytotoxins, which are produced by Shigella dysenteriae 1 and certain E. coli serotypes, kill mammalian cells by inhibiting protein synthesis. They have been related to hemolytic uremic syndrome and thrombotic thrombocytopenic purpura, probably by initial insult to vascular endothelial cells. This insight opened new avenues of research and possible interventions.
Learning and Courtship in <i>Drosophila</i>: Two Stories with Mutants
Authors: William G. Quinn, Ralph J. Greenspan
Journal: Annual Review of Neuroscience (1984)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Small bowel posters 326-335
Authors: S Parry, J Barton, M Welfare, I Mohammed, L Cherkas, S Riley, T Spector, N Trudgill, S Lal, J Mclaughlin, G Giampaolo, G Dockray, A Varro, D Thompson, J Jones, D Kendall, P Millns, C Hawkey, S Dunlop, D Jenkins, R Spiller, L Gregory, L Yaguez, S Coen, E Amaro, S Smale, A Hobson, S Williams, Q Aziz, V Chudleigh, E Brennan, S Tarry, S Myers, S Lewis, G Smith, K Palmer, Z Khan, E Simpson, A Cole, I Macdonald, D Pye, A Austin, J Freeman
Journal: Gut (2002)

Introduction: Previous studies, many uncontrolled, suggest 4 to 32% of people develop irritable bowel syndrome (IBS) after ID.Little information is available on the development of other FGIDs after ID.Aim: To determine if patients with stool culture confirmed bacterial diarrhoea were more likely to develop gut symptoms consistent with a diagnosis of IBS, functional dyspepsia or functional diarrhoea at 3 and 6 month follow up compared with community controls.Methods: A prospective community-based case-control study over one year.Subjects with stool positive bacterial infectious diarrhoea and control subjects from the same primary care practice were invited to participate.The presence or not of IBS, functional dyspepsia or functional diarrhoea was diagnosed at the start and at follow up using self-complete Rome II modular questionnaires.The diagnosis of a baseline FGID excluded subjects from continuing.There were 128 cases and 219 community controls eligible and who consented to participate.Results: At follow up there was a higher incidence of FGIDs in the cases compared with controls, mainly due to a higher incidence of IBS (see table ).There was no difference in the incidence of functional dyspepsia between cases and controls.Conclusions: IBS and functional diarrhoea is diagnosed more frequently in people at three and six-month follow up after an episode of stool positive bacterial diarrhoea compared with community controls despite careful exclusion of people with pre-existing FGIDS and adds further support for the concept of post-infectious IBS.
Patient-reported short-term and long-term physical and psychologic symptoms: results of the continuous hyperfractionated accelerated [correction of acclerated] radiotherapy (CHART) randomized trial in non-small-cell lung cancer. CHART Steering Committee.
Authors: A J Bailey, M K Parmar, R J Stephens
Journal: Journal of Clinical Oncology (1998)

The randomized multicenter trial of continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy for patients with non-small-cell lung cancer (NSCLC) showed a significant survival benefit to CHART (29% v 20% at 2 years, P=.004). However, an assessment of the effect on physical and psychologic symptoms is vital to balance the costs and benefits of the two treatments.A total of 356 patients in the United Kingdom completed the Rotterdam Symptom Checklist (RSCL) and the Hospital Anxiety and Depression Scale (HADS) at 10 time points. The principal aim of the analyses was to keep the methods simple, so as to allow the presentation and interpretation of the results to be as clear as possible. This was achieved by (1) considering individual symptoms rather than symptom subscales or domains, (2) assessing short-term effects (up to 3 months) and long-term effects (at 1 and 2 years) separately, and (3) for the short-term analyses, (a) splitting the data randomly into an exploratory data set and a confirmatory data set, and (b) using two different methods of analysis: a subject-specific approach, which used the area under the curve (AUC) as a summary measure, and a group-based method, which plotted the percent of patients with moderate or severe symptoms over time.The results indicate that apart from CHART causing transient pain on swallowing and heartburn, there was little difference between the regimens in the short or long-term.Combining the results of the patient-assessed symptom comparisons with the clinical results indicates that CHART confers a major benefit without serious morbidity.
Competitive Binding Between Id1 and E2F1 to Cdc20 Regulates E2F1 Degradation and Thymidylate Synthase Expression to Promote Esophageal Cancer Chemoresistance
Authors: Bin Li, Wen Wen Xu, Xin Yuan Guan, Yan Ru Qin, Simon Law, Nikki Pui Yue Lee, Kin Tak Chan, Pui Ying Tam, Yuk Yin Li, Kwok Wah Chan, Hiu Fung Yuen, Sai Wah Tsao, Qing Yu He, Annie L.M. Cheung
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Chemoresistance is a major obstacle in cancer therapy. We found that fluorouracil (5-FU)-resistant esophageal squamous cell carcinoma cell lines, established through exposure to increasing concentrations of 5-FU, showed upregulation of Id1, IGF2, and E2F1. We hypothesized that these genes may play an important role in cancer chemoresistance. Experimental Design: In vitro and in vivo functional assays were performed to study the effects of Id1–E2F1–IGF2 signaling in chemoresistance. Quantitative real-time PCR, Western blotting, immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter assays were used to investigate the molecular mechanisms by which Id1 regulates E2F1 and by which E2F1 regulates IGF2. Clinical specimens, tumor tissue microarray, and Gene Expression Omnibus datasets were used to analyze the correlations between gene expressions and the relationships between expression profiles and patient survival outcomes. Results: Id1 conferred 5-FU chemoresistance through E2F1-dependent induction of thymidylate synthase expression in esophageal cancer cells and tumor xenografts. Mechanistically, Id1 protects E2F1 protein from degradation and increases its expression by binding competitively to Cdc20, whereas E2F1 mediates Id1-induced upregulation of IGF2 by binding directly to the IGF2 promoter and activating its transcription. The expression level of E2F1 was positively correlated with that of Id1 and IGF2 in human cancers. More importantly, concurrent high expression of Id1 and IGF2 was associated with unfavorable patient survival in multiple cancer types. Conclusions: Our findings define an intricate E2F1-dependent mechanism by which Id1 increases thymidylate synthase and IGF2 expressions to promote cancer chemoresistance. The Id1–E2F1–IGF2 regulatory axis has important implications for cancer prognosis and treatment. Clin Cancer Res; 22(5); 1243–55. ©2015 AACR.
Applications of Antigen Receptor Gene Rearrangements to the Diagnosis and Characterization of Lymphoid Neoplasms
Authors: J Sklar, L M Weiss
Journal: Annual Review of Medicine (1988)

During early stages of lymphocyte development, genes for antigen receptors (immunoglobulin and T-cell receptor proteins) undergo rearrangements of their DNA sequences. The resulting configurations of rearranged DNA are highly variable from cell to cell and serve as genetic markers for individual lymphocytes. These markers can be utilized to detect clonal lymphocytic proliferations, as seen in lymphoid malignancies, and to identify the lineage of lymphoid neoplasms. Chromosomal rearrangements involving recombination between the DNA of antigen receptor genes and other sites in the genome also occur in lymphoid neoplasms, and molecular analysis of such rearrangements is potentially useful in the diagnosis of lymphomas and leukemias.