tbuckley/cabot-search huggingface dataset:
A role for the gut microbiota in energy harvesting?
Authors: Valentina Tremaroli, Petia Kovatcheva-Datchary, Fredrik Bäckhed
Journal: Gut (2010)

The amount of energy that is stored in the body depends on the balance between energy intake and expenditure: when energy intake exceeds expenditure, excess energy is stored as fat, which leads to weight gain and eventually obesity. A number of factors are associated with the obesity epidemic that is spreading worldwide, such as individual genetic predisposition, diet and lifestyle. Recently, the community of microbes colonising the gastrointestinal tract, the gut microbiota, has been recognised as one such factor.1–3 Studies on mice maintained under germ-free conditions have shown that the gut microbiota promotes increased adiposity by enhancing energy extraction from food and modulating host genes that regulate fat storage.1

Culture independent analyses of the composition of the gut microbiota have revealed that obese individuals harboured a varied proportion of two prevailing phyla, Firmicutes and Bacteroidetes, in comparison to lean subjects.4 Furthermore, the obese metagenome, which is the set of all genes present in the genomes of gut microbes, was enriched in gene functions associated with carbohydrate and lipid metabolism.5 Both in animal and human studies, obesity has been linked to a different composition of the gut microbiota. However, results from different studies are not concordant as to the contribution of specific components of the gut microbiota to the pathogenesis of obesity …
Rare Copy Number Variation Discovery and Cross-Disorder Comparisons Identify Risk Genes for ADHD
Authors: Anath C. Lionel, Jennifer Crosbie, Nicole Barbosa, Tara Goodale, Bhooma Thiruvahindrapuram, Jessica Rickaby, Matthew Gazzellone, Andrew R. Carson, Jennifer L. Howe, Zhuozhi Wang, John Wei, Alexandre F. R. Stewart, Robert Roberts, Ruth McPherson, Andreas Fiebig, Andre Franke, Stefan Schreiber, Lonnie Zwaigenbaum, Bridget A. Fernandez, Wendy Roberts, Paul D. Arnold, Peter Szatmari, Christian R. Marshall, Russell Schachar, Stephen W. Scherer
Journal: Science Translational Medicine (2011)

A high-resolution analysis of copy number variation in patients with ADHD reveals new gene associations, few de novo mutations, and overlap with genes implicated in other disorders such as autism.
Identification of Human Neutrophil-derived Cathepsin G and Azurocidin/CAP37 as Chemoattractants for Mononuclear Cells and Neutrophils
Authors: Oleg Chertov, Hirotsugu Ueda, Luo Ling Xu, Kenji Tani, William J. Murphy, Ji Ming Wang, O.M. Zack Howard, Thomas J. Sayers, Joost J. Oppenheim
Journal: The Journal of Experimental Medicine (1997)

Macrophage infiltration into inflammatory sites is generally preceded by neutrophils. This suggests neutrophils may be the source of chemotactic factors for monocytes. To identify these putative monocyte attractants, we have systematically prepared neutrophil granules, lysed them, and sequentially purified the released proteins by several reverse phase chromatography procedures. Assays for monocyte chemotactic activity of the chromatography fractions yielded a major peak of activity associated with a protein of 30 kD, according to SDS-PAGE analysis. NH2-terminal sequence of the protein revealed this to be identical to cathepsin G. The monocyte chemotactic activity of human cathepsin G was dose dependent with optimal concentration at 0.5–1 μg/ml. Cathepsin G is chemotactic rather than chemokinetic for monocytes, as demonstrated by checkerboard analysis. Cathepsin G–induced monocyte chemotaxis is partially pertussis toxin sensitive implying the involvement of a G protein–coupled receptor. Enzymatic activity of cathepsin G is associated with its monocyte chemotactic activity, since DFP- or PMSF-inactivated cathepsin G no longer induced monocyte migration. The chemotactic activity of cathepsin G can also be completely blocked by α1 antichymotrypsin, a specific inhibitor of chymotrypsin-like proteinases present in human plasma. In addition, cathepsin G is also a potent chemoattractant for neutrophils and a chemokinetic stimulant for T cells. In the course of pursuing these in vitro studies, we established that the T cell chemoattractant, azurocidin/CAP37 from human neutrophil granules, at doses of 0.05 to 5 μg/ml, was chemotactic for monocytes and neutrophils. As predicted from the in vitro chemotactic activity, subcutaneous injection of cathepsin G into BALB/c mice led to infiltration of both mononuclear cells and neutrophils. Thus, the transition of inflammatory exudate from neutrophil to mononuclear cells can be mediated, at least in part, by extracellular release of neutrophil granule proteins such as cathepsin G and azurocidin/CAP37.
Revised Staging Classification Improves Outcome Prediction for Small Intestinal Neuroendocrine Tumors
Authors: Michelle Kang Kim, Richard R.P. Warner, Sasan Roayaie, Noam Harpaz, Stephen C. Ward, Steven Itzkowitz, Juan P. Wisnivesky
Journal: Journal of Clinical Oncology (2013)

Small intestinal (SI) neuroendocrine tumors (NETs) have heterogeneous outcomes. The NET societies have recently proposed a TNM staging classification. In this study, we used population-based data to assess the validity of the staging system.We identified patients with SI-NETS diagnosed between 1988 and 2009 from the Surveillance, Epidemiology, and End Results registry. We used Kaplan-Meier analysis to assess disease-specific survival according to TNM status. Cox models were constructed to evaluate differences in prognosis after controlling for potential confounders.We identified 6,792 patients with SI-NET. Although the current staging system was predictive of prognosis, there was overlap among some groups (stage I/IIA, P = .36; stage IIB/IIIB, P = .70). Additionally, stage IIIB patients had better survival than stage IIIA patients (P < .001). Adjusted analyses showed similar outcomes for T1 versus T2 disease (hazard ratio [HR], 1.02; 95% CI, 0.63 to 1.66). Patients with T3 (HR, 3.60; 95% CI, 2.28 to 5.69) and T4 (HR, 5.50; 95% CI, 3.42 to 8.86) tumors had significantly worse survival than patients with T1 disease. N1 involvement conferred worse survival in T1 (HR, 3.08; 95% CI, 1.75 to 5.44) and T2 disease (HR, 2.73; 95% CI, 1.84 to 4.07) but not in T3 (HR, 0.99; 95% CI, 0.76 to 1.30) or T4 (HR, 0.98; 95% CI, 0.71 to 1.35) disease. A revised classification showed no overlap in survival across groups.Progressively more advanced T status is associated with worse SI-NET prognosis. Regional lymph node involvement is a marker of worse survival only among patients with T1 or T2 status. These results suggest that revisions to the current staging classification may be helpful.
Factors affecting the potassium concentration at the mucosal surface of the proximal and the distal colon of guinea pig.
Authors: U Kuck-Biere, W von Engelhardt
Journal: Gut (1990)

K+ concentrations were measured in vitro with K+ sensitive microelectrodes in the microclimate at the luminal cell surface of the colon of guinea pigs. The serosal K+ concentration was mostly 5.4 mmol/1, the mucosal K+ concentrations were changed (0, 5, 50, or 70 mmol/l). Under control conditions K+ concentrations in the microclimate of the proximal colon were also low (6-9 mmol/l) and rather independent from K+ concentrations in the bulk luminal solution. In the distal colon K+ concentrations in the microclimate increased from 3.7 mmol/l when no K+ was in the luminal solution, up to 22 mmol/l when the mucosal K+ concentrations was 70 mmol/l. Attempts to decrease K+ conductance of the apical membrane with Ba++, to impair K+ transport with ouabain and to increase the paracellular shunt with deoxycholic acid did not affect K+ concentrations in the microclimate of the proximal colon but decreased K+ concentrations in the distal colon. When valinomycin or triaminopyrimidine were added to the mucosal solution at high K+ concentrations in the luminal solutions the K+ concentration in the microclimate was raised. At low luminal K+ concentrations valinomycin had no effect, triaminopyrimidine significantly diminished K+ concentrations at the cell surface. Regional differences in paracellular shunt conductance and in the preepithelial diffusion barrier are thought to be responsible for the observed differences between the proximal and the distal colon. Obviously, however, further unknown mechanisms have to be involved.
Group a streptococcal antigens cross-reactive with myocardium. Purification of heart-reactive antibody and isolation and characterization of the streptococcal antigen
Authors: I Van De Rijn, JB Sabriskie, M McCarty
Journal: The Journal of Experimental Medicine (1977)

Heart-reactive antibody (HRA) appears in the sera of experimental animals inoculated with group A streptococci as well as patients with acute rheumatic fever. Adsorption of either serum with group A streptococcal membranes will remove the HRA. Blocking experiments between these two types of HRAs have demonstrated that the antibodies are directed towards different antigenic determinants on either the same or different molecules. To isolate and purify the antigen from the group A streptococcus cross-reactive with sarcolemmal sheaths of cardiac myofibers, it became necessary to purify the HRA from rheumatic fever patients' sera. Isolated gamma globulin containing all of the HRA was adsorbed onto human sarcolemmal sheaths. The specific HRA was released by using potassium iodide. Over 99 percent of the purified HRA was shown to bind the sarcolemmal sheath whereas less than 1 percent of the antibody would bind nonspecifically to other material. Preparations of group A streptococcal membrane will bind HRA purified from the sera of acute rheumatic patients at levels of 97 percent or greater. The cross-reactive antigen solubilized by nonionic detergent was purified 120-fold by column chromatography. On sodium dodecyl sulfate polyacrylamide electrophoresis, the antigen was demonstrated to be composed of four polypeptides with mol wt of 32,000, 28,000, 26,000, and 22,000 daltons, respectively. Only proteolytic enzymes could destroy the antigenic determinant whereas glycosidases and lipases had no effect. The purified antigen blocked the binding of purified HRA to normal human heart sections.
Prospective evaluation of fine needle aspiration in the diagnosis of lung cancer.
Authors: D Veale, J J Gilmartin, M D Sumerling, V Wadehra, G J Gibson
Journal: Thorax (1988)

The role of fine needle aspiration biopsy has been assessed prospectively in the diagnosis of discrete lung shadows. A questionnaire was completed before each of 100 biopsies (in 97 patients) to determine the clinician's pretest diagnosis and the likelihood of malignancy. The latter estimates were combined with the previously established sensitivity (71%) and specificity (100%) of the procedure for diagnosing malignancy in the unit to allow calculation in each case of the change in certainty of malignancy as a result of the investigation. Among the 100 biopsies there were 73 true positive and 13 true negative results. There were no false positive results but there were 14 false negatives (cases where malignancy was later proved but where the biopsy did not show unequivocal evidence of malignancy). Among the 27 negative biopsy results the clinician had estimated the likelihood of malignancy as 80% or more in 13 cases. In 11 of these 13 patients the eventual diagnosis proved to be a malignant tumour; on the other hand, six of the 10 patients given a less than 50% chance of malignancy had a benign outcome. A positive biopsy result was therefore quantitively of greatest value when the prior estimate of malignancy was low. In the case of the false negative results the prior probability of malignancy was usually sufficiently high to merit further investigation. It is estimated that the procedure led to the avoidance of thoracotomy in up to 14 of 97 patients.
Outcomes in obese and overweight acute myeloid leukemia patients receiving chemotherapy dosed according to actual body weight
Authors: Candice M. Wenzell, Erika M. Gallagher, Marc Earl, Jun‐Yen Yeh, Karissa N. Kusick, Anjali S. Advani, Matt E. Kalaycio, Sudipto Mukherjee, Ramon V. Tiu, Jaroslaw P. Maciejewski, Mikkael A. Sekeres
Journal: American Journal of Hematology (2013)

Cytotoxic chemotherapy dosages are traditionally calculated according to body surface area (BSA). No guidelines exist for chemotherapy dosing of acute myeloid leukemia (AML) patients at extremes of weight. We investigated the efficacy and safety of chemotherapy dosed according to BSA based on actual body weight (ABW) among under/normal weight, overweight, and obese AML patients. AML patients (excluding acute promyelocytic leukemia) treated with anthracycline and cytarabine-based remission induction chemotherapy from 2002 to 2009 at Cleveland Clinic were divided into three body mass index (BMI) groups: under/normal weight (BMI ≤ 24.9), overweight (BMI 25.0-29.9), and obese (BMI ≥ 30.0). Among 247 AML patients, 81 (33%) were under/normal weight, 81 (33%) were overweight, and 85 (34%) were obese. Complete remission (CR) rates were similar among these groups (69.1, 79.0, and 76.5%, respectively; P = 0.321), as was median survival (10.7, 16.7, and 14.2 months, respectively, P = 0.352) and 30-day mortality (3.7, 2.5, 7.1%, respectively, P = 0.331). There was no difference among groups in days to neutrophil or platelet recovery, hospitalization days for induction chemotherapy, and bacteremia. After adjustment for confounders (age, sex, BMI, white blood cells, cytogenetic risk, etiology, and bacteremia), overall survival was significantly shorter for normal weight compared to overweight (P = 0.006) and obese (0.038) patients. Response rates and adverse events were not significantly different among AML patients of all weight classes when induction chemotherapy was dosed according to ABW. Induction chemotherapy in these patients can be safely dosed using ABW.
Posttranslational modification and mutation of histidine 50 trigger alpha synuclein aggregation and toxicity
Authors: Wei Xiang, Stefanie Menges, Johannes Cm Schlachetzki, Holger Meixner, Anna-Carin Hoffmann, Ursula Schlötzer-Schrehardt, Cord-Michael Becker, Jürgen Winkler, Jochen Klucken
Journal: Molecular Neurodegeneration (2015)

Aggregation and aggregation-mediated formation of toxic alpha synuclein (aSyn) species have been linked to the pathogenesis of sporadic and monogenic Parkinson's disease (PD). A novel H50Q mutation of aSyn, resulting in the substitution of histidine by glutamine, has recently been identified in PD patients. We have previously shown that the lipid peroxidation product 4-hydroxy-2-nonenal (HNE) induces the formation of HNE-aSyn adducts, thereby promoting aSyn oligomerization and increasing its extracellular toxicity to human dopaminergic neurons. Intriguingly, we identified histidine 50 (H50) of aSyn as one of the HNE modification target residues. These converging lines of evidence support the hypothesis that changes in H50 via posttranslational modification (PTM) and mutation trigger the formation of aggregated, toxic aSyn species, which interfere with cellular homeostasis. In the present study, we aim to elucidate 1) the role of H50 in HNE-mediated aSyn aggregation and toxicity, and 2) the impact of H50 mutation on aSyn pathology. Besides the PD-related H50Q, we analyze a PD-unrelated control mutation, in which H50 is replaced by an arginine residue (H50R).Analysis of HNE-treated aSyn revealed that H50 is the most susceptible residue of aSyn to HNE modification and is crucial for HNE-mediated aSyn oligomerization. Overexpression of aSyn with substituted H50 in H4 neuroglioma cells reduced HNE-induced cell damage, indicating a pivotal role of H50 in HNE modification-induced aSyn toxicity. Furthermore, we showed in vitro that H50Q/R mutations substantially increase the formation of high density and fibrillar aSyn species, and potentiate the oligomerization propensity of aSyn in the presence of a nitrating agent. Cell-based experiments also revealed that overexpression of H50Q aSyn in H4 cells promotes aSyn oligomerization. Importantly, overexpression of both H50Q/R aSyn mutants in H4 cells significantly increased cell death when compared to wild type aSyn. This increase in cell death was further exacerbated by the application of H2O2.A dual approach addressing alterations of H50 showed that either H50 PTM or mutation trigger aSyn aggregation and toxicity, suggesting an important role of aSyn H50 in the pathogenesis of both sporadic and monogenic PD.
Imaging a Genetically Engineered Oncolytic Vaccinia Virus (GLV-1h99) Using a Human Norepinephrine Transporter Reporter Gene
Authors: Peter Brader, Kaitlyn J. Kelly, Nanhai Chen, Yong A. Yu, Qian Zhang, Pat Zanzonico, Eva M. Burnazi, Rashid E. Ghani, Inna Serganova, Hedvig Hricak, Aladar A. Szalay, Yuman Fong, Ronald G. Blasberg
Journal: Clinical Cancer Research (2009)

Oncolytic viral therapy continues to be investigated for the treatment of cancer, and future studies in patients would benefit greatly from a noninvasive modality for assessing virus dissemination, targeting, and persistence. The purpose of this study was to determine if a genetically modified vaccinia virus, GLV-1h99, containing a human norepinephrine transporter (hNET) reporter gene, could be sequentially monitored by [(123)I]metaiodobenzylguanidine (MIBG) gamma-camera and [(124)I]MIBG positron emission tomography (PET) imaging.GLV-1h99 was tested in human malignant mesothelioma and pancreatic cancer cell lines for cytotoxicity, expression of the hNET protein using immunoblot analysis, and [(123)I]MIBG uptake in cell culture assays. In vivo [(123)I]MIBG gamma-camera and serial [(124)I]MIBG PET imaging was done in MSTO-211H orthotopic pleural mesothelioma tumors.GLV-1h99 successfully infected and provided dose-dependent levels of transgene hNET expression in human malignant mesothelioma and pancreatic cancer cells. The time course of [(123)I]MIBG accumulation showed a peak of radiotracer uptake at 48 hours after virus infection in vitro. In vivo hNET expression in MSTO-211H pleural tumors could be imaged by [(123)I]MIBG scintigraphy and [(124)I]MIBG PET 48 and 72 hours after GLV-1h99 virus administration. Histologic analysis confirmed the presence of GLV-1h99 in tumors.GLV-1h99 shows high mesothelioma tumor cell infectivity and cytotoxic efficacy. The feasibility of imaging virus-targeted tumor using the hNET reporter system with [(123)I]MIBG gamma-camera and [(124)I]MIBG PET was shown in an orthotopic pleural mesothelioma tumor model. The inclusion of human reporter genes into recombinant oncolytic viruses enhances the potential for translation to clinical monitoring of oncolytic viral therapy.
THE INEFFICIENCY OF THE PRESENT METHODS OF SALINE INFUSION: A DESCRIPTION OF A NEW METHOD
Authors: N. S. Carruthers
Journal: BMJ (1911)

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Prediction of acute left main coronary artery obstruction by 12-lead electrocardiography
Authors: Hirosuke Yamaji, Kohichiro Iwasaki, Shozo Kusachi, Takashi Murakami, Ryouichi Hirami, Hiromi Hamamoto, Kazuyoshi Hina, Toshimasa Kita, Noburu Sakakibara, Takao Tsuji
Journal: Journal of the American College of Cardiology (2001)
Genetic variation in the hypothalamic–pituitary–adrenal stress axis influences susceptibility to musculoskeletal pain: results from the EPIFUND study
Authors: Kate L Holliday, Barbara I Nicholl, Gary J Macfarlane, Wendy Thomson, Kelly A Davies, John McBeth
Journal: Annals of the Rheumatic Diseases (2009)

Objectives To determine if genetic variation in genes in the hypothalamic–pituitary–adrenal (HPA) axis, the primary stress response system, influences susceptibility to developing musculoskeletal pain. Methods Pain and comorbidity data was collected at three time points in a prospective population-based cohort study. Pairwise tagging single nucleotide polymorphisms (SNPs) were selected and genotyped for seven genes. Genetic association analysis was carried out using zero-inflated negative binomial regression to test for association between SNPs and the maximum number of pain sites across the three time points in participants reporting pain, reported as proportional changes with 95% CIs. SNPs were also tested for association with chronic widespread pain (CWP) using logistic regression reporting odds ratios and 95% CI. Results A total of 75 SNPs were successfully genotyped in 994 participants including 164 cases with persistent CWP and 172 pain-free controls. Multiple SNPs in SERPINA6 were associated with the maximum number of pain sites; for example, each copy of the T allele of rs941601 was associated with having 16% (proportional change=1.16, 95% CI 1.04 to 1.28, p=0.006) more pain sites compared to participants with the CC genotype. SERPINA6 gene SNPs were also associated with CWP. Significant associations between the maximum number of pain sites and SNPs in the CRHBP and POMC genes were also observed and a SNP in MC2R was also associated with CWP. Associations between SNPs and comorbidity of poor sleep quality and depression explained some of the associations observed. Conclusions Genetic variation in HPA axis genes was associated with musculoskeletal pain; however, some of the associations were explained by comorbidities. Replication of these findings is required in independent cohorts.
Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL)
Authors: Barbara Wassmann, Heike Pfeifer, Nicola Goekbuget, Dietrich W. Beelen, Joachim Beck, Matthias Stelljes, Martin Bornhäuser, Albrecht Reichle, Jolanta Perz, Rainer Haas, Arnold Ganser, Mathias Schmid, Lothar Kanz, Georg Lenz, Martin Kaufmann, Anja Binckebanck, Patrick Brück, Regina Reutzel, Harald Gschaidmeier, Stefan Schwartz, Dieter Hoelzer, Oliver G. Ottmann
Journal: Blood (2006)
Microphthalmia transcription factor immunohistochemistry: A useful diagnostic marker in the diagnosis and detection of cutaneous melanoma, sentinel lymph node metastases, and extracutaneous melanocytic neoplasms
Authors: Fiona M. O'Reilly, Daniel J. Brat, Barbara E. McAlpine, Hans E. Grossniklaus, Andrew L. Folpe, Jack L. Arbiser
Journal: Journal of the American Academy of Dermatology (2001)