Miracle-dz/UniFAR-FTUs huggingface dataset:
Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Most small cell lung cancer (SCLC) patients are initially responsive to cytotoxic chemotherapy, but almost all undergo fatal relapse with progressive disease, highlighting an urgent need for improved therapies and better patient outcomes in this disease. The proapoptotic BH3 mimetic ABT-737 that targets BCL-2 family proteins demonstrated good single-agent efficacy in preclinical SCLC models. However, so far clinical trials of the BH3 mimetic Navitoclax have been disappointing. We previously demonstrated that inhibition of a PI3K/BMX cell survival signaling pathway sensitized colorectal cancer cells to ABT-737. Here, we show that SCLC cell lines, which express high levels of BMX, become sensitized to ABT-737 upon inhibition of PI3K in vitro, and this is dependent on inhibition of the PI3K-BMX-AKT/mTOR signaling pathway. Consistent with these cell line data, when combined with Navitoclax, PI3K inhibition suppressed tumor growth in both an established SCLC xenograft model and in a newly established circulating tumor cell–derived explant (CDX) model generated from a blood sample obtained at presentation from a chemorefractory SCLC patient. These data show for the first time that a PI3K/BMX signaling pathway plays a role in SCLC cell survival and that a BH3 mimetic plus PI3K inhibition causes prolonged tumor regression in a chemorefractory SCLC patient–derived model in vivo. These data add to a body of evidence that this combination should move toward the clinic. Mol Cancer Ther; 15(6); 1248–60. ©2016 AACR.
Recent Clinical Experience with Famciclovir — A ‘Third Generation’ Nucleoside Prodrug

The herpesviruses continue to produce considerable morbidity in man. Once infected with herpes simplex (HSV), the virus remains dormant within the nervous system and may reactivate if provoked by stress, trauma and/or other factors. To date, there is no cure, but antiviral medication can reduce duration and severity of symptoms and prophylaxis can suppress recurrent episodes of disease. The second-generation guanosine nucleosides, acyclovir and penciclovir, are effective inhibitors with low toxicity; both, however, have relatively low oral bioavailability. Subsequently, the orally bioavailable prodrugs valaciclovir and famciclovir have been introduced. These compounds offer high oral bioavailabilty and deliver acyclovir and penciclovir, respectively, to the target cells by means of more convenient dosing schedules. This short review points to recent experience with famciclovir in the management of HSV and varicella-zoster virus.
Helicobacter pylori eradication therapy: a discrepancy between current guidelines and clinical practice

Background Consensus guidelines recommend that patients with peptic ulcer disease, and other causes of dyspepsia, should be treated with Helicobacter pylori eradication regimens. However, it has not been firmly established whether physicians have adapted their practice accordingly. Objectives (1) To establish the proportion of ulcer‐healing prescriptions that H. pylori eradication regimens accounted for, (2) to evaluate the composition of the eradication regimens used, and (3) to compare the prescribing patterns of specialist and primary care practitioners. Methods Seven community pharmacy practices were identified, and all prescriptions for individual acid‐suppressing agents and eradication regimens were prospectively evaluated over an initial one‐month period. Prospective documentation and evaluation of eradication regimens only was then continued for a further three‐month period. Results The prescriptions for 585 patients were evaluated. Proton‐pump inhibitors and H2‐receptor antagonists accounted for 261 (44.5%) and 307 (52.5%) of prescriptions respectively. H. pylori eradication therapy was prescribed for 17 (2.9%) patients in this initial period. Sixty‐six eradication regimens were evaluated over four months: 48/66 (73%) of these were initiated by primary care practitioners and 18/66 (27%) by specialists. Thirteen different combinations of antibiotics and acid‐suppressing agents were identified — many of undocumented efficacy. Dual, triple and quadruple regimens accounted for 15 (23%), 48 (72.5%) and 3 (4.5%) of patient prescriptions respectively. Conclusion H. pylori eradication therapy currently accounts for a very small proportion of ulcer‐healing medication in clinical practice. Most eradication regimens are initiated by primary care practitioners. In comparison with specialist practices, prescriptions from this source are more likely to be of undocumented efficacy. Eur J Gastroenterol Hepatol 12:433‐437 © 2000 Lippincott Williams & Wilkins European Journal of Gastroenterology & Hepatology 2000, 12:433‐437
Treatment of Helicobacter gastritis with IL-4 requires somatostatin

Fifty percent of the world's population is infected with Helicobacter pylori; however, treatment has been insufficient to eradicate the organisms due to rising antibiotic resistance. Helicobacter infection is characterized by induction of a T helper 1 lymphocyte (Th1) immune response, hypergastrinemia, and suppressed tissue somatostatin (SOM) levels. However, the mechanism by which the immune response regulates acid secretion is not known. We show here that treatment with IFN-γ, a Th1 cytokine, was sufficient to induce gastritis, increase gastrin, and decrease SOM levels within 7 days. In contrast, the T helper 2 lymphocyte cytokine IL-4 increased SOM levels and effectively suppressed gastrin expression and secretion. This result demonstrated reciprocal regulation of acid regulatory peptides by immune modulators. IL-4 pretreatment prevented gastritis in infected wild-type but not in SOM null mice. Thus, the ability of IL-4 to oppose a Th1-mediated infection required SOM. Immunofluorescence was used to document the presence of IL-4 receptors on the gastric SOM-secreting cell (D cell). Moreover, IL-4 stimulated SOM release from primary D cell cultures. Treatment of mice chronically infected with Helicobacter felis for 2 mo with the SOM analogue octreotide resolved the inflammation. Thus, a mechanism by which IL-4 resolves inflammation in the stomach is by stimulating the release of SOM from gastric D cells.
Study on the Eco-Environmental Water Requirements in Mid and Downstream Region of the Yellow River

Based on the definition and the classification of the eco-environmental water requirements, the minimum eco-environmental water requirements in the typical county at the mid and downstream of the Yellow River are computed. In the process, Penman-Monteith method and the method based on the theory of hydrological cycle are used. The results show that the water consumed by the eco-environment reaches 6.097 times 10 8 m 3 and 7.018 times 10 8 m 3 , the average being 6.56 times 10 8 m 3 . The difference between the two methods is about 13%. Comparison with other researches shows that the result is rational. The methods are reasonable and can be used in other semiarid and semi-wet region.
Structure and Generation of Turbulence at Interfaces Strained by Internal Solitary Waves Propagating Shoreward over the Continental Shelf

Abstract Detailed observations of the structure within internal solitary waves propagating shoreward over Oregon's continental shelf reveal the evolving nature of interfaces as they become unstable and break, creating turbulent flow. A persistent feature is high acoustic backscatter beginning in the vicinity of the wave trough and continuing through its trailing edge and wake. This is demonstrated to be due to enhanced density microstructure. Increased small-scale strain ahead of the wave trough compresses select density interfaces, thereby locally increasing stratification. This is followed by a sequence of overturning, high-density microstructure, and turbulence at the interface, which is coincident with the high acoustic backscatter. The Richardson number estimated from observations is larger than 1/4, indicating that the interface is stable. However, density profiles reveal these preturbulent interfaces to be O(10 cm) thick, much thinner than can be resolved with shipboard velocity measurements. By as.
Influence of Seasonal Variations of Temperature and Light on the Growth Rate of Cultures and Natural Populations of Intertidal Diatoms

Cultures of four benthic diatom species (Navicula salinarum, Amphiprora cf, paludosa, N. arenaria, Gyrosigma spenceni) were kept at the surface of a mudflat in order to measure division rates. During incubations in the period of December to June the mean temperature was the predominant factor regulating cell division rate. Immersion of the mudflat with very turbid tidal water was an important factor only at a low-level mudflat station during winter and early spring. Strong temperature fluctuations during incubations, with periods of frost in winter and periods of insolation during hot summer weather, did not interrupt growth of the cultures. Hence high temperatures and high irradiance values are unlikely to be the direct cause of the summer minimum in population density that is frequently observed in the estuary. After the winter minimum the increase in population density was measured at three levels of the mudflat. At the high-level station the density increased in January at still very low temperatures, whereas at the mid- and low-level stations this increase started in March. This observation indicates that the emersion time of the mudflat and hence its exposure to full daylight is an important factor in the development of the spring bloom. The density of the diatom populations in the 0.5 cm top layer of the sediment increased only at a very low rate (with maximum rates of ca. 0.1 doublings d-l). Low photosynthetic rates of natural diatom populations in the sediment core are the cause of these low doubling rates of natural populations on the mudflat. Dispersal of diatom cells into the sediment is probably responsible for the decreased photosynthetic rates and, consequently, for the low doubling rates of sediment-inhabiting diatoms.
An investigation of dentists' and dental students' estimates of diagnostic probabilities.

BACKGROUND Research in medicine has shown that physicians have difficulty estimating the probability that a patient has a condition on the basis of available diagnostic evidence. They consistently undervalue baseline information about the patient relative to test information and are poor intuitive calculators of probability. The authors could not locate in the literature any studies of diagnostic probability estimates from baseline information and test data for dentists. METHODS Using two vignettes that contained different baseline information, dental students and clinical faculty members estimated the probability that the described hypothetical patient had the condition in question. Respondents also commented on the project. CONCLUSIONS Both groups of respondents overemphasized the importance of test evidence relative to baseline information, although experienced practitioners did so to a lesser extent than did students. Respondents, especially practitioners, expressed resistance to performing a diagnostic task that required precise estimates of probability. CLINICAL IMPLICATIONS Dentists appear to estimate diagnostic probabilities in an intuitive fashion, but they do so imprecisely. Clinical experience provides some protection against the bias of overestimating test evidence compared with baseline information. These findings raise questions about how practitioners use probability estimates and whether other models also may play a role. The incorporation of information from evidence-based dentistry into practice requires better understanding.
A comparison of skilled nursing facility rehabilitation treatment and outcomes under Medicare managed care and Medicare fee-for-service reimbursement.

PURPOSE This article compares the rehabilitation treatment and outcomes of Medicare managed care organization (MCO) and fee-for-service (FFS) patients in skilled nursing facilities (SNFs). DESIGN AND METHODS Data on 514 MCO patients and 420 FFS patients treated in four for-profit Southern California-based SNFs between June 1996 and September 1998 were analyzed with bivariate and multivariate regression models. RESULTS After controlling for time since onset and other sociodemographic and health status characteristics, Medicare MCO patients were found to receive significantly fewer therapy units and have significantly shorter lengths of stay in rehabilitation programs. IMPLICATIONS The findings may be the result of more global differences in the trajectories of care among MCO and FFS patients treated in SNFs, yet they highlight critical issues related to the spread of Medicare managed care in nursing homes and the dynamic between MCO and FFS reimbursement systems.
Prevalence of bronchial asthma and factors associated with it among higher secondary school children in Ernakulam district, Kerala, Southern India

Context: Bronchial asthma is one of the leading causes of hospitalization and cause of frequent absenteeism among children and adolescents. Studies reporting the prevalence of bronchial asthma among adolescents from India are limited and the available studies report wide geographic variations in the prevalence of bronchial asthma. Aims: The current study was aimed to estimate the prevalence of bronchial asthma among higher secondary school children and to identify various factors associated with it in Ernakulam district, Kerala, Southern India. Settings and Design: The study was conducted in Ernakulam district, the industrial capital of Kerala. A school-based cross-sectional study was conducted. Subjects and Methods: Data were collected from 629 students from 4 randomly selected higher secondary schools using a structured questionnaire. Section on details of respiratory symptoms was adapted from International Union Against Tuberculosis and Lung Disease bronchial symptoms questionnaire. Statistical Analysis Used: Descriptive statistics was done with frequencies and percentages and confidence intervals (CIs) were calculated. Univariate and multivariate analysis was done for factors associated with bronchial asthma generating odds ratios (ORs) and 95% CIs. Results: A total of 629 students participated in this study. The prevalence of bronchial asthma was estimated to be 9.9% (95% CI = 7.53%–12.27%). Students residing in a rural area (adjusted OR = 1.95, 95% CI = 1.10–3.46) having family history of bronchial asthma (adjusted OR = 2.84, 95% CI = 1.57–5.11) and usual exposure to friend's smoke (adjusted OR = 2.16, 95% CI = 1.17–3.97) were significantly associated with bronchial asthma. Conclusions: The prevalence of bronchial asthma was higher among higher secondary school students of Ernakulam district. Considering high prevalence and its contributions to morbidity and mortality, a comprehensive program to tackle the issue of chronic respiratory diseases may be needed. The issue of active and passive smoking at schools exists and need to be resolved.
Polymorphism in the gene regulatory region of MCP-1 is associated with asthma susceptibility and severity.

BACKGROUND Chemokines play an important role in the pathophysiology of asthma and allergy. Recently, polymorphisms in the gene regulatory region of monocyte chemoattractant protein 1 (MCP-1) and in the promoter region of RANTES have been found; these polymorphisms increase the expression of the chemokines. OBJECTIVE We investigated whether the presence of the polymorphisms was associated with atopy or asthma and whether these alleles influenced the severity of asthma in affected individuals. METHODS Three groups of subjects-160 children with asthma (disease severity being classified according to the Global Initiative for Asthma guidelines, modified for children), 151 children with nonasthmatic but allergic phenotype, and 303 children without allergic or asthmatic disorders-were screened with a PCR-based assay for genotyping. RESULTS The frequency of the -2518G polymorphism in the gene regulatory region of MCP-1 was significantly higher in asthmatic children than in controls (P <.001; odds ratio [OR] = 2.0 [1.4-2.6]) and nonasthmatic atopic children (P <.001; OR = 2.0 [1.4-2.9]). The MCP-1 G/G genotype correlated with asthma severity. In asthmatic children, the MCP-1 -2518G allele was also associated with an increased blood eosinophil level. The promoter polymorphisms in the RANTES gene did not have a detectable effect on the susceptibility to asthma or allergy or on the blood eosinophil count. CONCLUSION In this cohort of children, there are associations between carrying G at -2518 of the MCP-1 gene regulatory region and the presence of asthma as well as between asthma severity and homozygosity for the G allele. In asthmatic children, the MCP-1 -2518G polymorphism correlated with increased eosinophil levels. This variant of MCP-1 might belong to the predictor gene set for asthma.
Fragmentation of a drop as it falls in a lighter miscible fluid.

We report an experimental investigation of the fragmentation process of a heavy drop falling in a lighter miscible fluid. For fixed liquid composition and for different drop sizes, we observe that the fragmentation cascade stops after a few breakups, once each individual droplet has reduced below a critical volume for further splitting. Since each fragmentation is the outcome of a hydrodynamic instability, we expect fluctuations in the size of the fragmented droplets. The main experimental outcomes are the following: ~1! the first breakup time scales with the size separation from the critical volume in a universal way independent of the fluid composition; ~2! in the region intermediate between the first and the last fragmentation, the droplet sizes display multifractal properties, with the average dimension D0 decreasing to a minimum and then increasing again once diffusion prevails; and ~3! the droplet height scales with time with an exponent independent of the drop volume and composition. @S1063-651X~96! 00607-1#
Theoretical investigation of the effect of sugar substitution on the antioxidant properties of flavonoids

Natural flavonoids are secondary phenolic plant metabolites known for their bioactivity as antioxidants. The evaluation of this property is generally done by the estimation of their direct free radical-scavenging activity as hydrogen or electron donating compounds. This paper reviews experimental results available in the literature for a selection of flavonoids and compares them with calculated quantities characteristic of the hydrogen or electron donation. For that purpose, bond dissociation energies, ionization potentials and electron transfer enthalpies are computed by using DFT methods and the ONIOM procedure implemented in the ab initio program Gaussian. This process has been chosen because it can be extended to the study of large molecules. When acid dissociation and interaction with the solvent are taken into account, the results present very good concordance with experimental results, enlightening the complexity of the processes involved in the classical assays which measure the ability of compounds to scavenge the (2,2′-azinobis-(3-ethylbenzthiazoline-6-sulfonic acid) diammonium salt) radical cation (ABTS +) or the 2,2-diphenyl-1-picryl-hydrazyl radical (DPPH·). This study demonstrates the good accuracy of theoretical calculations in obtaining the relative energies involved in free radical scavenging abilities and its capacity for predictive behaviour. It also highlights the necessity to take into account the pKa of the compounds and the solvent interaction. The ability of the method to calculate the antioxidant properties of larger molecules are tested on glycosylated flavonoids and the effects of sugar substitution on the antioxidant properties of flavonoids are investigated, pointing out the importance of the charges on the oxygen atoms.
Insulin Induces Progressive Insulin Resistance in Cultured Rat Adipocytes: Sequential Effects at Receptor and Multiple Postreceptor Sites

We have examined the ability of insulin to regulate insulin action in primary cultured adipocytes, and found that insulin induces progressive insulin resistance in this target tissue. To assess effects at both receptor and postreceptor sites, we cultured cells in the absence (control) and presence of 100 ng/ml insulin, and, after various times, measured the dose response of insulin's ability to bind cell-surface receptors and stimulate 2-deoxyglucose transport. In control cells, insulin binding (0.2 ng/ml) was increased 10–13% due to an apparent increase in receptor affinity (6–24 h). A comparable increase in affinity was also observed in treated cells; however, concomitantly, insulin decreased the number of cell-surface receptors causing a slowly progressive net decrease in binding after a 6– 10-h lag (maximal 30% at 24 h). When insulin action was assessed in control cells, the functional consequence of increased receptor binding was hypersensitization (i.e., increased insulin sensitivity) manifested by a leftward shift in the 2-deoxyglucose dose-response curve. On the other hand, in the treated cells, insulin produced insulin resistance initially by decreasing insulin sensitivity. The ED50 for insulin stimulation of glucose transport increased 84% from 0.31 to 0.57 ng/ml at 6 h without a net change in insulin binding; this was the result of a decrease in coupling efficiency between occupied receptors and the insulin effect. Receptor uncoupling progressively increased in severity, but before the full effect was reached insulin also caused a rapid decline in maximally stimulated glucose transport rates (between 6 and 10 h). This decrease in insulin responsiveness (maximal 52%) exacerbated overall insulin resistance, and was indicative of a postreceptor defect in the glucose transport system. Finally, insulin-induced receptor downregulation contributed, along with uncoupling, to a further decrease in insulin sensitivity, and constituted a more long-term regulatory mechanism. We also observed that insulin could regulate the basal glucose transport system by preventing a progressive rise in basal transport observed in control cells. In conclusion, primary cultured adipocytes can be used to study long-term regulation of insulin action. We found that insulin induces progressive insulin resistance with sequential effects at multiple sites in the insulin action pathway, including decreased coupling efficiency between occupied receptors and stimulated glucose transport, a postreceptor defect in insulin responsiveness of the glucose transport system, and receptor downregulation. These mechanisms may be relevant to the cellular defects in insulin action present in clinical states of insulin resistance and hyperinsulinemia.