tbuckley/cabot-search huggingface dataset:
Functional consequences of microbial shifts in the human gastrointestinal tract linked to antibiotic treatment and obesity
Authors: Ester Hernández, Rafael Bargiela, María Suárez Diez, Anette Friedrichs, Ana Elena Pérez-Cobas, María José Gosalbes, Henrik Knecht, Mónica Martínez-Martínez, Jana Seifert, Martin von Bergen, Alejandro Artacho, Alicia Ruiz, Cristina Campoy, Amparo Latorre, Stephan J Ott, Andrés Moya, Antonio Suárez, Vitor A.P. Martins dos Santos, Manuel Ferrer
Journal: Gut Microbes (2013)

The microbiomes in the gastrointestinal tract (GIT) of individuals receiving antibiotics and those in obese subjects undergo compositional shifts, the metabolic effects and linkages of which are not clearly understood. Herein, we set to gain insight into these effects, particularly with regard to carbohydrate metabolism, and to contribute to unravel the underlying mechanisms and consequences for health conditions. We measured the activity level of GIT carbohydrate-active enzymes toward 23 distinct sugars in adults patients (n = 2) receiving 14-d β-lactam therapy and in obese (n = 7) and lean (n = 5) adolescents. We observed that both 14 d antibiotic-treated and obese subjects showed higher and less balanced sugar anabolic capacities, with 40% carbohydrates being preferentially processed as compared with non-treated and lean patients. Metaproteome-wide metabolic reconstructions confirmed that the impaired utilization of sugars propagated throughout the pentose phosphate metabolism, which had adverse consequences for the metabolic status of the GIT microbiota. The results point to an age-independent positive association between GIT glycosidase activity and the body mass index, fasting blood glucose and insulin resistance (r ( 2) ≥ 0.95). Moreover, antibiotics altered the active fraction of enzymes controlling the thickness, composition and consistency of the mucin glycans. Our data and analyses provide biochemical insights into the effects of antibiotic usage on the dynamics of the GIT microbiota and pin-point presumptive links to obesity. The knowledge and the hypotheses generated herein lay a foundation for subsequent, systematic research that will be paramount for the design of "smart" dietary and therapeutic interventions to modulate host-microbe metabolic co-regulation in intestinal homeostasis.
Calcium Regulates Key Components of Vascular Smooth Muscle Cell–Derived Matrix Vesicles to Enhance Mineralization
Authors: Alexander N. Kapustin, John D. Davies, Joanne L. Reynolds, Rosamund McNair, Gregory T. Jones, Anissa Sidibe, Leon J. Schurgers, Jeremy N. Skepper, Diane Proudfoot, Manuel Mayr, Catherine M. Shanahan
Journal: Circulation Research (2011)

Matrix vesicles (MVs) are specialized structures that initiate mineral nucleation during physiological skeletogenesis. Similar vesicular structures are deposited at sites of pathological vascular calcification, and studies in vitro have shown that elevated levels of extracellular calcium (Ca) can induce mineralization of vascular smooth muscle cell (VSMC)-derived MVs.To determine the mechanisms that promote mineralization of VSMC-MVs in response to calcium stress.Transmission electron microscopy showed that both nonmineralized and mineralized MVs were abundantly deposited in the extracellular matrix at sites of calcification. Using cultured human VSMCs, we showed that MV mineralization is calcium dependent and can be inhibited by BAPTA-AM. MVs released by VSMCs in response to extracellular calcium lacked the key mineralization inhibitor matrix Gla protein and showed enhanced matrix metalloproteinase-2 activity. Proteomics revealed that VSMC-MVs share similarities with chondrocyte-derived MVs, including enrichment of the calcium-binding proteins annexins (Anx) A2, A5, and A6. Biotin cross-linking and flow cytometry demonstrated that in response to calcium, AnxA6 shuttled to the plasma membrane and was selectively enriched in MVs. AnxA6 was also abundant at sites of vascular calcification in vivo, and small interfering RNA depletion of AnxA6 reduced VSMC mineralization. Flow cytometry showed that in addition to AnxA6, calcium induced phosphatidylserine exposure on the MV surface, thus providing hydroxyapatite nucleation sites.In contrast to the coordinated signaling response observed in chondrocyte MVs, mineralization of VSMC-MVs is a pathological response to disturbed intracellular calcium homeostasis that leads to inhibitor depletion and the formation of AnxA6/phosphatidylserine nucleation complexes.
Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy.
Authors: J Cuzick, H Stewart, L Rutqvist, J Houghton, R Edwards, C Redmond, R Peto, M Baum, B Fisher, H Host
Journal: Journal of Clinical Oncology (1994)

PURPOSE To examine long-term cause-specific mortality in patients irradiated for breast cancer as part of a randomized clinical trial. PATIENTS AND METHODS We studied all available information from randomized trials initiated before 1975 in which radiotherapy was the randomized option and surgery was the same for both treatment arms. Eight such trials were identified. RESULTS The increased all-cause mortality rate in 10-year survivors previously reported is no longer significant, although a numerical difference in favor of non-irradiated patients remains. This result was strongly influenced by the earliest trials, and more recent trials have found a nonsignificant net benefit in overall mortality associated with radiation therapy. An excess of cardiac deaths was apparent in both early and more recent trials (P &lt; .001), but this was offset by a reduced number of deaths due to breast cancer, especially in more recent trials. CONCLUSION The reduction of breast cancer deaths suggests that radiation therapy may have a value beyond the clearly established improvements obtainable for local control. Use of techniques that minimize cardiac dose is important in reducing the risks of adjuvant radiotherapy, especially in good-prognosis patients.
Altered immunosuppressive activity of alveolar macrophages in farmer's lung disease
Authors: A. Dakhama, E. Israël-Assayag, Y. Cormier
Journal: European Respiratory Journal (1996)

Since normal alveolar macrophages (AMs) can suppress T-cell proliferation to mitogenic and antigenic stimuli both in vitro and in vivo, we questioned whether an altered AM immunosuppressive activity could account for the alveolar lymphocytosis observed in farmer9s lung (FL) and whether granulocyte/macrophage colony-stimulating factor (GM-CSF), a cytokine able to abrogate AM-induced immunosuppression, is involved in the process. The ability of different concentrations of AMs to inhibit lymphocyte proliferation in response to the T-cell-specific mitogen phytohaemagglutin (PHA) after in vitro culture was tested in three groups of subjects: 12 patients with FL; four asymptomatic farmers (AS); and six normal volunteers (N). Release of GM-CSF by AMs was also measured. At all ratios tested, AMs from patients with FL did not suppress the lymphoproliferation but instead had an enhancing effect. In AS, AMs enhanced the proliferation at a lower ratio but inhibited it at high ratios. In N subjects, as described previously, AMs increasingly inhibited the blastogenesis of lymphocytes (L) at increasing ratios of AM:L. In some patients with FL, AMs spontaneously released more GM-CSF than in normal volunteers (206 +/- 84 versus 29 +/- 14 pg.mL-1, respectively). In AS, GM-CSF release was intermediate (74 +/- 36 pg.mL-1). In conclusion, a defect in the ability of alveolar macrophages to suppress the proliferation of lymphocytes in the lung of patients with farmer9s lung is a major factor accounting for the development of the observed lymphocytic alveolitis. Granulocyte/macrophage colony-stimulating factor could be one factor which may contribute to this alteration.
A meta-analysis of gemcitabine containing chemotherapy for locally advanced and metastatic pancreatic adenocarcinoma
Authors: Jing Hu, Gang Zhao, Hong-Xia Wang, Lei Tang, Ying-Chun Xu, Yue Ma, Feng-Chun Zhang
Journal: Journal of Hematology & Oncology (2011)

Abstract Background The objectives of the present study are to investigate the efficacy and safety profile of gemcitabine-based combinations in the treatment of locally advanced and metastatic pancreatic adenocarcinoma (LA/MPC). Methods We performed a computerized search using combinations of the following keywords: "chemotherapy", "gemcitabine", "trial", and "pancreatic cancer". Results Thirty-five trials were included in the present analysis, with a total of 9,979 patients accrued. The analysis showed that the gemcitabine-based combination therapy was associated with significantly better overall survival (OS) (ORs, 1.15; p = 0.011), progression-free survival (PFS) (ORs, 1.27; p &lt; 0.001), and overall response rate (ORR) (ORs, 1.58; p &lt; 0.001) than gemcitabine monotherapy. Similar results were obtained when the gemcitabine-fluoropyrimidine combination was compared with gemcitabine, with the OS (ORs, 1.33; p = 0.007), PFS (ORs, 1.53; p &lt; 0.001), and ORR (ORs 1.47, p = 0.03) being better in the case of the former. The OS (ORs, 1.33; p = 0.019), PFS (ORs, 1.38; p = 0.011), and one-year survival (ORs, 1.40; p = 0.04) achieved with the gemcitabine-oxaliplatin combination were significantly greater than those achieved with gemcitabine alone. However, no survival benefit (OS: ORs, 1.01, p = 0.93; PFS: ORs, 1.19, p = 0.17) was noted when the gemcitabine-cisplatin combination was compared to gemcitabine monotherapy. The combinations of gemcitabine and other cytotoxic agents also afforded disappointing results. Our analysis indicated that the ORR improved when patients were treated with the gemcitabine-camptothecin combination rather than gemcitabine alone (ORs, 2.03; p = 0.003); however, there were no differences in the OS (ORs, 1.03; p = 0.82) and PFS (ORs, 0.97; p = 0.78) in this case. Conclusions Gemcitabine in combination with capecitabine or oxaliplatin was associated with enhanced OS and ORR as compared with gemcitabine in monotherapy, which are likely to become the preferred standard first-line treatment of LA/MPC.
Oxidative burst in lipopolysaccharide-activated human alveolar macrophages is inhibited by interleukin-9
Authors: C. Pilette, Y. Ouadrhiri, J. Van Snick, J-C. Renauld, P. Staquet, J-P. Vaerman, Y. Sibille
Journal: European Respiratory Journal (2002)

Interleukin (IL)-9 is known to regulate many cell types involved in T-helper type 2 responses classically associated with asthma, including B- and T-lymphocytes, mast cells, eosinophils and epithelial cells. In contrast, target cells mediating the effects of IL-9 in the lower respiratory tract remain to be identified. Therefore, the authors evaluated the activity of IL-9 on human alveolar macrophages (AM) from healthy volunteers. AM preincubated with IL-9 before lipopolysaccharide (LPS) stimulation exhibited a decreased oxidative burst, as previously shown with IL-4. The inhibitory effect of IL-9 was abolished by anti-hIL-9Rα monoclonal antibody, and presence of IL-9 receptors on AM was demonstrated by immunofluorescence. Both IL-4 and IL-9 failed to modulate tumour necrosis factor-α, IL-8 and IL-10 release by LPS-stimulated AM. However, several observations suggested that IL-9 and IL-4 act through different mechanisms: 1) interferon-γ antagonised the IL-4- but not the IL-9-mediated inhibition of AM oxidative burst; 2) expression of CD14 was downregulated by IL-4 but not by IL-9 and 3) production of tumour growth factor-β by activated AM was potentiated by IL-9 and not by IL-4, and was required for the IL-9-mediated inhibition of AM oxidative burst. These observations provide additional information concerning the activity of interleukin-9 in the lung, related to inflammatory or fibrosing lung processes.
Toward Molecular Imaging–Driven Drug Development in Oncology
Authors: Elisabeth G.E. de Vries, Thijs H. Oude Munnink, Marcel A.T.M. van Vugt, Wouter B. Nagengast
Journal: Cancer Discovery (2011)

With current testing strategies, the number of novel targeted anticancer agents will exceed our drug selection capacity. Molecular imaging is a powerful additional tool that can assist us in selecting effective drugs and help patients benefit from targeted agents. Moreover, measurement of the functional effects of such targeted agents could permit dynamic tuning of treatment selection at the earliest time point at which loss of functional effects is observed.
Carbohydrate malabsorption. Its measurement and its contribution to diarrhea.
Authors: H F Hammer, K D Fine, C A Santa Ana, J L Porter, L R Schiller, J S Fordtran
Journal: Journal of Clinical Investigation (1990)

The major purpose of this research was to gain insight into the effect of carbohydrate malabsorption on fecal water output. To do this we measured daily fecal output of total carbohydrate, reducing sugars, and organic acids (a product of bacterial fermentation). Normal subjects were studied in their native state and when diarrhea was induced by mechanisms that did and did not involve carbohydrate malabsorption. Patients with malabsorption syndrome were also studied. We concluded that: (a) Excretion of carbohydrate and its breakdown products can be expressed as a single number by converting organic acids to their monosaccharide equivalents. (b) Diarrhea per se causes only a trivial increase in fecal carbohydrate excretion. (c) The molar output of osmotic moieties in feces due to unabsorbed carbohydrate can be determined by adding fecal reducing sugars to organic acids and their obligated cations. This expression parallels almost exactly the effect of increasing doses of lactulose (a nonabsorbable sugar) on fecal water output; one excreted millimole obligates 3.5 g of stool water. This relationship can be used to predict the effect of carbohydrate malabsorption on stool water output in patients with diarrhea. (d) 12 of 19 patients with malabsorption syndrome due to various diseases had excessive fecal excretion of carbohydrate and its breakdown products; of the diseases that cause malabsorption syndrome, combined small and large bowel resection is most likely to result in excessive fecal excretion of carbohydrate and monosaccharide equivalents. In 6 of these 19 patients carbohydrate malabsorption appeared to be the major cause of diarrhea.
Cellular Regulation of RGS Proteins: Modulators and Integrators of G Protein Signaling
Authors: S. Hollinger
Journal: Pharmacological Reviews (2002)

Regulators of G protein signaling (RGS) and RGS-like proteins are a family (&gt;30 members) of highly diverse, multifunctional signaling proteins that bind directly to activated Gα subunits. Family members are defined by a shared RGS domain, which is responsible for Gα binding and markedly stimulates the GTPase activity of Gα subunits leading to their deactivation and termination of downstream signals. Although much has been learned in recent years about the biochemistry of RGS/Gα interactions, considerably less is known about the broader cellular roles and regulation of RGS proteins. Recent findings indicate that cellular mechanisms such as covalent modification, alternative gene splicing, and protein processing can dictate the activity and subcellular localization of RGS proteins. Many family members also directly link G proteins to a growing list of signaling proteins with diverse cellular roles. New findings indicate that RGS proteins act not as dedicated inhibitors but, rather, as tightly regulated modulators and integrators of G protein signaling. In some cases, RGS proteins modulate the lifetime and kinetics of both slow-acting (e.g., Ca<sup>2+</sup> oscillations) and fast-acting (e.g., ion conductances, phototransduction) signaling responses. In other cases, RGS proteins integrate G proteins with signaling pathways linked to such diverse cellular responses as cell growth and differentiation, cell motility, and intracellular trafficking. These and other recent studies with animal model systems indicate that RGS proteins play important roles in both physiology and disease. Recognition of the central functions these proteins play in vital cellular processes has focused our attention on RGS proteins as exciting new candidates for therapeutic intervention and drug development.
Regulation of proximal T cell receptor signaling and tolerance induction by deubiquitinase Usp9X
Authors: Edwina Naik, Joshua D. Webster, Jason DeVoss, Jinfeng Liu, Rowena Suriben, Vishva M. Dixit
Journal: The Journal of Experimental Medicine (2014)

The T cell hyperproliferation and autoimmune phenotypes that manifest in mice lacking E3 ubiquitin ligases such as Cbl, ITCH, or GRAIL highlight the importance of ubiquitination for the maintenance of peripheral T cell tolerance. Less is known, however, about the deubiquitinating enzymes that regulate T cell proliferation and effector function. Here, we define a cell intrinsic role for the deubiquitinase Usp9X during proximal TCR signaling. Usp9X-deficient T cells were hypoproliferative, yet mice with T cell-specific Usp9x deletion had elevated numbers of antigen-experienced T cells and expanded PD-1 and OX40-expressing populations consistent with immune hyperactivity. Aged Usp9x KO mice developed lupus-like autoimmunity and lymphoproliferative disease, indicating that ubiquitin ligases and deubiquitinases maintain the delicate balance between effective immunity and self-tolerance.
Age at Onset, Childhood Psychopathology, and 2-Year Outcome in Psychotic Bipolar Disorder
Authors: Gabrielle A Carlson, Evelyn J Bromet, Corine Driessens, Ramin Mojtabai, Joseph E Schwartz
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: The relationships of age at onset and childhood psychopathology to 2-year clinical and functional outcomes in first-admission patients with bipolar I disorder were examined. METHOD: Patients with bipolar I disorder (N=123) presenting with psychotic symptoms were followed over a 2-year period. Age at onset was stratified into <19 and ≥19 years. Childhood psychopathology was categorized as behavior problems, other psychopathology, and none. Functional and clinical outcomes were rated with standard measures. RESULTS: Childhood psychopathology and age at onset were independently related to poorer functional and clinical outcome. In the multivariate models that included psychopathology, age at onset, sex, and education, early age at onset was related to incomplete remission, and childhood psychopathology was related to functional outcome. CONCLUSIONS: Childhood psychopathology and age at onset contribute independently to outcomes of bipolar disorder. Childhood psychopathology is a much stronger predictor of functioning than age at onset.
Safety and efficacy of ledipasvir‐sofosbuvir in black patients with hepatitis C virus infection: A retrospective analysis of phase 3 data
Authors: Julius M. Wilder, Lennox J. Jeffers, Natarajan Ravendhran, Mitchell L. Shiffman, John Poulos, Mark S. Sulkowski, Norman Gitlin, Kimberly Workowski, Yanni Zhu, Jenny C. Yang, Phillip S. Pang, John G. McHutchison, Andrew J. Muir, Charles Howell, Kris Kowdley, Nezam Afdhal, K. Rajender Reddy
Journal: Hepatology (2015)

Black patients chronically infected with genotype 1 hepatitis C virus (HCV) have historically had lower rates of response to interferon‐based treatment than patients of other races. In the phase 3 ION program, the single‐tablet regimen of the NS5A inhibitor ledipasvir and NS5B nucleotide polymerase inhibitor sofosbuvir was shown to be safe and highly effective in the general population. The aim of this study was to evaluate the safety and efficacy of ledipasvir/sofosbuvir in black patients using data from the three open‐label ION clinical trials, which evaluated the safety and efficacy of 8, 12, and 24 weeks of ledipasvir/sofosbuvir with or without ribavirin for the treatment of treatment‐naïve and treatment‐experienced patients with genotype 1 HCV, including those with compensated cirrhosis. The primary endpoint was sustained virologic response at 12 weeks after the end of therapy (SVR12). For our analysis, rates of SVR12, treatment‐emergent adverse events, and graded laboratory abnormalities were analyzed in black versus non‐black patients. Of the 1949 patients evaluated, 308 (16%) were black. On average, black patients were older, had higher body mass index, were more likely to be IL28B non‐CC, and had a lower serum alanine aminotransferase at baseline than non‐black patients. Overall, 95% of black and 97% of non‐black patients achieved SVR12. The rate of relapse was 3% in black patients as compared with 2% in non‐black patients. The most common adverse events included fatigue, headache, nausea, and insomnia. The majority of adverse events occurred more frequently in the ribavirin‐containing arms of the studies. No differences were observed in overall safety by race. Conclusion : A once‐daily dosage of ledipasvir/sofosbuvir was similarly effective in black and non‐black patients with genotype 1 HCV infection. The addition of ribavirin did not appear to increase SVR12 but was associated with higher rates of adverse events. (H epatology 2016;63:437–444)
Glutathione Reverses Endothelial Damage From Peroxynitrite, the Byproduct of Nitric Oxide Degradation, in Crystalloid Cardioplegia
Authors: M Nakamura, V H Thourani, R S Ronson, D A Velez, X L Ma, S Katzmark, J Robinson, L S Schmarkey, Z Q Zhao, N P Wang, R A Guyton, J Vinten-Johansen
Journal: Circulation (2000)

NO has been advocated as an adjunct to cardioplegia solutions. However, NO undergoes a rapid biradical reaction with superoxide anions to produce peroxynitrite (ONOO(-)). ONOO(-) in crystalloid cardioplegia solution induces injury to coronary endothelium and to systolic function after cardioplegia and reperfusion. However, ONOO(-) may be degraded to less lethal or cardioprotective intermediates with glutathione (GSH) in reactions separate from its well known antioxidant effects. We hypothesized that GSH detoxifies ONOO(-) and reverses defects in endothelial function and systolic function when present in crystalloid cardioplegia.In anesthetized dogs on cardiopulmonary bypass, a 45-minute period of global normothermic ischemia was followed by 60 minutes of intermittent cold crystalloid cardioplegia (Plegisol) and 2 hours of reperfusion. The cardioplegia solution contained 5 micromol/L authentic ONOO(-); catalase was included to attenuate the potential antioxidant effects of GSH and to unmask the effects on ONOO(-). In 1 group (CP+GSH, n=5), the cardioplegia contained 500 micromol/L GSH, whereas 1 group received crystalloid cardioplegia without GSH (CCP, n=6). There were no group differences in postcardioplegia left ventricular systolic function (end-systolic pressure-volume relation, impedance catheter: CCP 10.0+/-2.4 versus CP+GSH 10.6+/-1.3 mm Hg/mL) or diastolic chamber stiffness (ss-coefficient: CCP 0.35+/-0.2 versus CP+GSH 0.31+/-0.18). Myocardial neutrophil accumulation (myeloperoxidase activity) was attenuated in CP+GSH versus CCP (2.2+/-0.7 versus 5.4+/-1.2, P:<0.05). In postexperimental coronary arteries, maximal endothelium-dependent relaxation was greater in CP+GSH than in CCP (118+/-6% versus 92+/-5%, P:<0.05), with a smaller EC(50) value (-7. 10+/-0.05 versus -6.98+/-0.03, respectively, P:<0.05). Smooth muscle relaxation was complete in both groups. The adherence of neutrophils to postexperimental coronary arteries as a measure of endothelial function was less in CP+GSH than in CCP (98+/-18 versus 234+/-36 neutrophils/mm(2), P:<0.05). Nitrosoglutathione, a byproduct of the reaction between ONOO(-) and GSH, was greater in CP+GSH than in CCP (4.1+/-2.3 versus 0.4+/-0.2 microg/mL, P:<0.05).GSH in crystalloid cardioplegia detoxifies ONOO(-) and forms cardioprotective nitrosoglutathione, resulting in attenuated neutrophil adherence and selective endothelial protection through the inhibition of neutrophil-mediated damage.