tbuckley/cabot-search huggingface dataset:
Cabozantinib in Patients With Advanced Prostate Cancer: Results of a Phase II Randomized Discontinuation Trial
Authors: David C. Smith, Matthew R. Smith, Christopher Sweeney, Aymen A. Elfiky, Christopher Logothetis, Paul G. Corn, Nicholas J. Vogelzang, Eric J. Small, Andrea L. Harzstark, Michael S. Gordon, Ulka N. Vaishampayan, Naomi B. Haas, Alexander I. Spira, Primo N. Lara, Chia-Chi Lin, Sandy Srinivas, Avishay Sella, Patrick Schöffski, Christian Scheffold, Aaron L. Weitzman, Maha Hussain
Journal: Journal of Clinical Oncology (2012)

Cabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2. We evaluated the activity of cabozantinib in patients with castration-resistant prostate cancer (CRPC) in a phase II randomized discontinuation trial with an expansion cohort.Patients received 100 mg of cabozantinib daily. Those with stable disease per RECIST at 12 weeks were randomly assigned to cabozantinib or placebo. Primary end points were objective response rate at 12 weeks and progression-free survival (PFS) after random assignment.One hundred seventy-one men with CRPC were enrolled. Random assignment was halted early based on the observed activity of cabozantinib. Seventy-two percent of patients had regression in soft tissue lesions, whereas 68% of evaluable patients had improvement on bone scan, including complete resolution in 12%. The objective response rate at 12 weeks was 5%, with stable disease in 75% of patients. Thirty-one patients with stable disease at week 12 were randomly assigned. Median PFS was 23.9 weeks (95% CI, 10.7 to 62.4 weeks) with cabozantinib and 5.9 weeks (95% CI, 5.4 to 6.6 weeks) with placebo (hazard ratio, 0.12; P < .001). Serum total alkaline phosphatase and plasma cross-linked C-terminal telopeptide of type I collagen were reduced by ≥ 50% in 57% of evaluable patients. On retrospective review, bone pain improved in 67% of evaluable patients, with a decrease in narcotic use in 56%. The most common grade 3 adverse events were fatigue (16%), hypertension (12%), and hand-foot syndrome (8%).Cabozantinib has clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in bone turnover markers, pain, and narcotic use.
Aztreonam vs. cefotaxime in the treatment of gram-negative spontaneous peritonitis in cirrhotic patients
Authors: Javier Ariza, Xavier Xiol, Maria Esteve, Fernando Fernández Bañeres, Josefina Liñares, Teresa Alonso, Francisco Gudiol
Journal: Hepatology (1991)

Aztreonam and cefotaxime were compared in 44 cirrhotic patients who had 52 episodes of gramnegative spontaneous peritonitis. Patients were randomized into two therapeutic groups of similar characteristics. Group A (28 episodes) received 0.5 gm of aztreonam every 8 hr, and group B (24 episodes) received 1 gm of cefotaxime every 6 hr, for a planned 14-day period. Peak and trough serum and ascitic fluid levels of both antibiotics were several times higher than the minimum inhibitory concentrations of causative microorganisms. Eleven patients (21%) died within the first 48 hr after beginning therapy, which included seven in the aztreonam group and four in the cefotaxime group. In the remaining patients, signs and symptoms of infection were promptly controlled, and ascitic fluid cultures became negative after 48 hr in all cases, except in one patient from the aztreonam group, who was a clinical failure. Two patients from the aztreonam group and one from the cefotaxime group relapsed after treatment. The overall mortality rate was 50%, which was lower than classically reported: 12 patients (43%) died in the aztreonam group, and 14 (58%) died in the cefotaxime group (p = 0.265, NS). Hepatorenal syndrome and digestive tract hemorrhage were the most frequent causes of death occurring after the first 48 hr of treatment. Streptococcal superinfections developed in three patients (14.2%) in the aztreonam group. We conclude that both antibiotics at the low doses used in this study are similarly well tolerated and effective in controlling this infection. Because the use of aztreonam as the initial empirical treatment requires a concomitant antibiotic against gram-positive infections and the possibility of streptococcal superinfections, cefotaxime seems to be a more advantageous therapeutic alternative for this patient population. (HEPATOLOGY1991;14:91–98.)
The contribution of cross-cultural study to dynamic systems modeling of emotions
Authors: Greg Downey
Journal: Behavioral and Brain Sciences (2005)

Lewis neglects cross-cultural data in his dynamic systems model of emotion, probably because appraisal theory disregards behavior and because anthropologists have not engaged discussions of neural plasticity in the brain sciences. Considering cultural variation in emotion-related behavior, such as grieving, indigenous descriptions of emotions, and alternative developmental regimens, such as sport, opens up avenues to test dynamic systems models.
Activating Transcription Factor 3 Constitutes a Negative Feedback Mechanism That Attenuates Saturated Fatty Acid/Toll-Like Receptor 4 Signaling and Macrophage Activation in Obese Adipose Tissue
Authors: Takayoshi Suganami, Xunmei Yuan, Yuri Shimoda, Kozue Uchio-Yamada, Nobutaka Nakagawa, Ibuki Shirakawa, Takako Usami, Takamitsu Tsukahara, Keizo Nakayama, Yoshihiro Miyamoto, Kazuki Yasuda, Junichiro Matsuda, Yasutomi Kamei, Shigetaka Kitajima, Yoshihiro Ogawa
Journal: Circulation Research (2009)

Obese adipose tissue is markedly infiltrated by macrophages, suggesting that they may participate in the inflammatory pathways that are activated in obese adipose tissue. Evidence has suggested that saturated fatty acids released via adipocyte lipolysis serve as a naturally occurring ligand that stimulates Toll-like receptor (TLR)4 signaling, thereby inducing the inflammatory responses in macrophages in obese adipose tissue. Through a combination of cDNA microarray analyses of saturated fatty acid-stimulated macrophages in vitro and obese adipose tissue in vivo, here we identified activating transcription factor (ATF)3, a member of the ATF/cAMP response element-binding protein family of basic leucine zipper-type transcription factors, as a target gene of saturated fatty acids/TLR4 signaling in macrophages in obese adipose tissue. Importantly, ATF3, when induced by saturated fatty acids, can transcriptionally repress tumor necrosis factor-alpha production in macrophages in vitro. Chromatin immunoprecipitation assay revealed that ATF3 is recruited to the region containing the activator protein-1 site of the endogenous tumor necrosis factor-alpha promoter. Furthermore, transgenic overexpression of ATF3 specifically in macrophages results in the marked attenuation of proinflammatory M1 macrophage activation in the adipose tissue from genetically obese KKA(y) mice fed high-fat diet. This study provides evidence that ATF3, which is induced in obese adipose tissue, acts as a transcriptional repressor of saturated fatty acids/TLR4 signaling, thereby revealing the negative feedback mechanism that attenuates obesity-induced macrophage activation. Our data also suggest that activation of ATF3 in macrophages offers a novel therapeutic strategy to prevent or treat obesity-induced adipose tissue inflammation.
Probing the Interaction Between Inactivation Gating and <scp>d</scp> d-Sotalol Block of <i>HERG</i>
Authors: Hirotaka Numaguchi, Franklin M. Mullins, J. P. Johnson, David C. Johns, Sunny S. Po, Iris C.-H. Yang, Gordon F. Tomaselli, Jeffrey R. Balser
Journal: Circulation Research (2000)

Potassium channels encoded by HERG underlie I:(Kr), a sensitive target for most class III antiarrhythmic drugs, including methanesulfonanilides such as Dd-sotalol. Recently it was shown that these drugs are trapped in the channel as it closes during hyperpolarization. At the same time, HERG channels rapidly open and inactivate when depolarized, and methanesulfonanilide block is known to develop in a use-dependent manner, suggesting a potential role for inactivation in drug binding. However, the role of HERG inactivation in class III drug action is uncertain: pore mutations that remove inactivation reduce block, yet many of these mutations also modify the channel permeation properties and could alter drug affinity through gating-independent mechanisms. In the present study, we identify a definitive role for inactivation gating in Dd-sotalol block of HERG, using interventions complementary to mutagenesis. These interventions (addition of extracellular Cd(2+), removal of extracellular Na(+)) modify the voltage dependence of inactivation but not activation. In normal extracellular solutions, block of HERG current by 300 micromol/L Dd-sotalol reached 80% after a 10-minute period of repetitive depolarization to +20 mV. Maneuvers that impeded steady-state inactivation also reduced Dd-sotalol block of HERG: 100 micromol/L Cd(2+) reduced steady-state block to 55% at +20 mV (P:<0.05); removing extracellular Na(+) reduced block to 44% (P:<0.05). An inactivation-disabling mutation (G628C-S631C) reduced Dd-sotalol block to only 11% (P:<0.05 versus wild type). However, increasing the rate of channel inactivation by depolarizing to +60 mV reduced Dd-sotalol block to 49% (P:<0.05 versus +20 mV), suggesting that the drug does not primarily bind to the inactivated state. Coexpression of MiRP1 with HERG had no effect on inactivation gating and did not modify Dd-sotalol block. We postulate that Dd-sotalol accesses its receptor in the open pore, and the drug-receptor interaction is then stabilized by inactivation. Whereas deactivation traps the bound methanesulfonanilide during hyperpolarization, we propose that HERG inactivation stabilizes the drug-receptor interaction during membrane depolarization.
Influence of School Competitive Food and Beverage Policies on Obesity, Consumption, and Availability
Authors: Jamie F. Chriqui, Margaret Pickel, Mary Story
Journal: JAMA Pediatrics (2014)

The US Department of Agriculture recently issued an interim final rule governing the sale of foods and beverages sold outside of the school meal programs ("competitive foods and beverages" [CF&Bs]).To examine the potential influence that the federal rule may have based on peer-reviewed published studies examining the relationship between state laws and/or school district policies and student body mass index (BMI) and weight outcomes, consumption, and availability of CF&Bs.Keyword searches of peer-reviewed literature published between January 2005 and March 2013 were conducted using multiple databases. Titles and abstracts for 1160 nonduplicate articles were reviewed, with a full review conducted on 64 of those articles to determine their relevancy. Qualitative studies, studies of self-reported policies, or studies examining broad policies without a specific CF&B element were excluded.Twenty-four studies were selected for inclusion. Studies focused on state laws (n = 14), district policies (n = 8), or both (n = 2), with the majority of studies (n = 18) examining foods and beverages (as opposed to food-only or beverage-only policies). Sixteen studies examined prepolicy/postpolicy changes, and 8 studies examined postpolicy changes. Study designs were cross-sectional (n = 20), longitudinal (n = 3), or a combination (n = 1). Outcomes examined included change in BMI, weight, probability of overweight or obesity (n = 4), consumption (n = 10), and availability (n = 13); 3 studies examined more than 1 outcome. The majority of studies primarily reported results in the expected direction (n = 15), with the remaining studies (n = 9) reporting primarily mixed or nonsignificant results.In most cases, CF&B policies are associated with changes in consumption and/or availability in the expected direction; however, caution should be exercised, given that nearly all were cross-sectional. The influence of such policies on overall student consumption and BMI and weight outcomes was mixed. The findings hold promise for the likely influence of federal CF&B regulations on changes in student in-school consumption and in-school competitive food availability. Further research is needed to truly understand the association between these policies and overall consumption and weight outcomes.
Shortening velocity and myosin and myofibrillar ATPase activity related to myosin isoenzyme composition during postnatal development in rat myocardium.
Authors: V Cappelli, R Bottinelli, C Poggesi, R Moggio, C Reggiani
Journal: Circulation Research (1989)

The relation between functional properties of the contractile apparatus, such as shortening velocity and ATPase activity, and myosin isoenzyme composition was studied in ventricular myocardium of adult (60-90-day-old) rats and of newborn (3-day-old) and young (10- and 20-day-old) rats. In adult animals, variations of isomyosin pattern were produced by reducing food intake and by changing the thyroid state. Hyperthyroidism was induced with triiodothyronine daily injection for 15 days; hypothyroidism was induced with iodine-free diet and KClO4 in drinking water for 50-60 days. The following parameters were studied: 1) calcium-magnesium-activated and magnesium-activated ATPase activity of washed and purified myofibrils, 2) calcium-activated ATPase activity of purified myosin, 3) isomyosin composition and relative content of alpha-myosin heavy chains (alpha-MHCs), and 4) force-velocity curve of left and right ventricle papillary muscles. To take into account the difference in excitation-contraction coupling between newborn and adult myocardium, the determination of the force-velocity curve was repeated in Krebs' solution with normal [CaCl2] (2.5 mM) and in Krebs' solution with high [CaCl2] (10 mM). During postnatal growth, the relative content of alpha-MHC increased and reached a maximum at about 20 days. Pronounced increases of myofibrillar and myosin ATPase activity and in shortening velocity occurred during the same period. In adult hyperthyroid rats, alpha-MHC content as well as enzymatic activity and shortening velocity were higher than in control adult animals. Hypothyroidism and food deprivation caused a decrease of alpha-MHC content and a reduction of both enzymatic activities and shortening velocity. The study of the relations between alpha-MHC relative content and functional parameters showed that 1) in ventricular myocardium of adult rats a linear relation existed between alpha-MHC content and myosin and myofibrillar ATPase activity and shortening velocity, and 2) in newborn and young rat ventricular myocardium, both enzymatic activities and shortening velocity were lower than would have been expected on the basis of the linear relation described above. This latter observation could be accounted for by a variation in specific activity of myosin during postnatal development or by the presence of peculiar isomyosins that cannot be detected with usual electrophoretic techniques.
ADDRESS ON THE PREVENTION OF MORTALITY FROM PELVIC OPERATIONS
Authors: H. M. Jones
Journal: BMJ (1910)

PELVIC OPERATIONS. [THErcBJRIsAL 77 culos1is give also clinical manifestations of disease, older children overcome the primary tuberculous infection, the more probably the older they are at the time of the infection, without showing more pronounced symptoms of disease.The prognosis of tuberculosis developed in the several years becomes better from year to year.According to an approximate calculation, the mortality from fresh tuber- culosis in the several periods is as follows:
Prevalence of cardiovascular diseases in psoriatic arthritis resembles that of rheumatoid arthritis
Authors: A. Jamnitski, I. M. Visman, M. J. L. Peters, M. Boers, B. A. C. Dijkmans, M. T. Nurmohamed
Journal: Annals of the Rheumatic Diseases (2010)

The increased risk for cardiovascular disease (CVD) in rheumatoid arthritis (RA) is well known and inflammation appears to play a pivotal aetiological role. There is now substantial interest in whether or not psoriatic arthritis (PsA) is also associated with an enhanced cardiovascular (CV) risk. However, data on CVD in PsA is limited.1,–,3 The aim of this comparative study was to determine the prevalence of non-fatal CVD in patients with PsA compared with patients with RA and to investigate the risk factors of CVD in PsA.

In 2008 a CV questionnaire was sent to all 753 patients with PsA aged 50–75 years registered at our centre.4 As a comparator group, data from 353 randomly selected patients with RA aged 50–75 years (the CARdiovascular research and RhEumatoid arthritis study) were …
Human muscle–derived stem/progenitor cells promote functional murine peripheral nerve regeneration
Authors: Mitra Lavasani, Seth D. Thompson, Jonathan B. Pollett, Arvydas Usas, Aiping Lu, Donna B. Stolz, Katherine A. Clark, Bin Sun, Bruno Péault, Johnny Huard
Journal: Journal of Clinical Investigation (2014)

Peripheral nerve injuries and neuropathies lead to profound functional deficits. Here, we have demonstrated that muscle-derived stem/progenitor cells (MDSPCs) isolated from adult human skeletal muscle (hMDSPCs) can adopt neuronal and glial phenotypes in vitro and ameliorate a critical-sized sciatic nerve injury and its associated defects in a murine model. Transplanted hMDSPCs surrounded the axonal growth cone, while hMDSPCs infiltrating the regenerating nerve differentiated into myelinating Schwann cells. Engraftment of hMDSPCs into the area of the damaged nerve promoted axonal regeneration, which led to functional recovery as measured by sustained gait improvement. Furthermore, no adverse effects were observed in these animals up to 18 months after transplantation. Following hMDSPC therapy, gastrocnemius muscles from mice exhibited substantially less muscle atrophy, an increase in muscle mass after denervation, and reorganization of motor endplates at the postsynaptic sites compared with those from PBS-treated mice. Evaluation of nerve defects in animals transplanted with vehicle-only or myoblast-like cells did not reveal histological or functional recovery. These data demonstrate the efficacy of hMDSPC-based therapy for peripheral nerve injury and suggest that hMDSPC transplantation has potential to be translated for use in human neuropathies.
The structural and functional polarity of the hepatic human/rat hybrid WIF-B is a stable and dominant trait
Authors: Virginie Bender, Pilar Bravo, Catherine Decaens, Doris Cassio
Journal: Hepatology (1999)

WIF-B cells were generated previously to obtain a good in vitro model expressing the structural and functional polarity of hepatocytes. Here we tested the stability and the strength of the WIF-B polarized phenotype. WIF-B cells stayed polarized and formed functional bile canaliculi even after 3 months in culture or after injection in nude mice and culture of the resulting tumors. WIF-B was subcloned and 10,000 colonies were examined; all (except for 3) were composed of bile canaliculi forming cells. Some subclones were characterized; the polarized ones presented the same properties and karyotype as the WIF-B cells; the 3 unpolarized subclones had a lower level of E-cadherin and different karyotypes. WIF-B cells were fused with their nonpolarized hepatic parental cells. The polarity state of the resulting FWIF hybrids was studied from day 11 to day 38 after fusion, by immunolocalization of hepatocyte domain-specific plasma membrane proteins. Most FWIF colonies (>80%) were composed of polarized cells. Soon after fusion these cells were exclusively polarized as simple epithelial cells. The percent of colonies containing cells expressing the typical hepatocyte polarity increased with time and reached 80% at day 38. This result confirms the two-step polarization process previously described for WIF-B. Chromosomally complete FWIF hybrids were examined several months after fusion. As shown by the study of bile acid transport and by confocal analysis of the localization of membrane domain markers, FWIF cells expressed a functional and fully polarized hepatic phenotype. In conclusion, polarity is a stable and dominant trait of WIF-B.
Bacillary dysentery as a causative factor of irritable bowel syndrome and its pathogenesis
Authors: L-H Wang
Journal: Gut (2004)

The incidence of irritable bowel syndrome (IBS) or functional bowel disorders (FBD) after bacillary dysentery (BD) has not been extensively evaluated, and little is known of the pathogenesis of post-infective (PI) IBS. Therefore, we investigated the incidence of IBS and FBD in a Chinese patient population who had recovered from BD. To further elucidate its pathogenesis, neuroimmunological changes, including interleukins (IL), mast cells, neuropeptides, and the relationship between mast cells and intestinal nerves, were investigated.A cohort study of 295 patients who had recovered from BD (shigella identified from stool in 71.4%) and 243 control subjects consisting of patient siblings or spouses who had not been infected with BD were included in the study. All subjects were followed up using questionnaires for 1-2 years to explore the incidence of FBD and IBS, as defined by the Rome II criteria. In 56 cases of IBS (PI and non-PI) from another source, the number of mast cells in biopsy specimens from the intestinal mucosa were stained with antitryptase antibody and counted under light microscopy. Also, the relationship of mast cells to neurone specific enolase (NSE), substance P (SP), 5-hydroxytryptamine (5-HT), or calcitonin gene related peptide positive nerve fibres was observed using double staining with alcian blue and neuropeptide antibodies. In 30 cases of IBS (PI-IBS, n = 15) taken at random from the 56 cases, expression of interleukin (IL)-1alpha, IL-1beta, and IL-1 receptor antagonist (IL-1ra) mRNAs in intestinal mucosa were identified using reverse transcription-polymerase chain reaction. The above results were compared with 12 non-IBS controls.In the BD infected cohort, the incidences of FBD and IBS were 22.4% and 8.1% (in total)-10.2% (among those in who shigella were identified) respectively, which were significantly higher (p<0.01) than the incidences of FBD (7.4%) and IBS (0.8%) in the control cohort. A longer duration of diarrhoea (>or=7 days) was associated with a higher risk of developing FBD (odds ratio 3.49 (95% confidence interval 1.71-7.13)). Expression of IL-1beta mRNA in terminal ileum and rectosigmoid mucosa was significantly higher in PI-IBS patients (p<0.01). The number of mast cells in the terminal ileum mucosa in PI-IBS (11.19 (2.83)) and non-PI-IBS patients (10.78 (1.23)) was significantly increased compared with that (6.05 (0.51)) in control subjects (p<0.01). Also, in the terminal ileum and rectosigmoid mucosa of IBS patients, the density of NSE, SP, and 5-HT positively stained nerve fibres increased (p<0.05) and appeared in clusters, surrounding an increased number of mast cells (p<0.01 compared with controls).BD is a causative factor in PI-IBS. The immune and nervous system may both play important roles in the pathogenesis of PI-IBS.