Alternative Lengthening of Telomeres in Pediatric High-Grade Glioma and Therapeutic Implications.

Pediatric high-grade gliomas (pHGGs), including diffuse intrinsic pontine glioma (DIPG), are highly aggressive tumors with dismal prognoses despite multimodal therapy including surgery, radiation therapy, and chemotherapy. To achieve cellular immortality cancer cells must overcome replicative senescence and apoptosis by activating telomere maintenance mechanisms (TMMs) through the reactivation of telomerase activity or using alternative lengthening of telomere (ALT) pathways. Although the ALT phenotype is more prevalent in pHGGs compared to adult HGGs, the molecular pathway and the prognostic significance of ALT activation are not well understood in pHGGs. Here, we report the heterogeneity of TMM in pHGGs and their association with genetic alterations. Additionally, we show that sensitivity to the protein kinase ataxia telangiectasia- and RAD3-related protein (ATR) inhibitor and the ATR downstream target CHK1 is not specific to pHGG ALT-positive cells. Together, these findings underscore the need for novel therapeutic strategies to target ALT in pHGG tumors.

Vitamin D deficiency in adult patients with ulcerative colitis: Prevalence and relationship with disease severity, extent, and duration.

BACKGROUND: Vitamin D plays a key role in gut immunity and maintenance of the mucosal barrier. Vitamin D deficiency (VDD) worsens ulcerative colitis (UC) and its supplementation ameliorates the disease in mouse models. The prevalence and predictors of VDD in UC are not known. METHODS: Consecutive patients with UC (n = 80) underwent clinical, endoscopic, and histological evaluation to assess the extent, severity using UC disease activity index (UCDAI) score, and duration of illness. An equal number of age and gender-matched healthy adults without any features of inflammatory bowel disease (IBD) living in the same latitude were identified as controls. The serum 25-hydroxy vitamin D3 level was estimated. The subjects were classified as deficient (< 20 ng/mL), insufficient (20-32 ng/mL), sufficient (32-80 ng/mL), and optimal (> 80 ng/mL) based on vitamin D levels. Chi-square test and Mann-Whitney U test were done to identify factors associated with vitamin D deficiency. RESULTS: The patients and controls were similar in age and gender (40 ± 11.4 years, 51% male vs. 40 ± 12 years, 51% male; p = 1.000). Median vitamin D levels among patients were lower than the controls (18.1 ng/mL [IQR 14] vs. 32.5 ng/mL [IQR 36]; p < 0.001). Patients were more often VDD (56% vs. 40%) or insufficient (34% vs. 9%) and less often sufficient (9% vs. 40%) or optimal (1% vs. 11%), in contrast to controls (p < 0.001). Median vitamin D levels were lower in those with UCDAI > 6 (15 vs. 21 ng/mL; p = 0.01), having pancolitis (13 vs. 21 ng/mL, p = 0.01), and longer duration of illness > 2 years (13.8 vs. 20.8; p = 0.025). Vitamin D levels showed a negative correlation with frequency of stools (rho = - 0.244, p = 0.05), disease duration (rho = - 0.244, p = 0.007) and UCDAI score (r = - 0.348, p = 0.002). CONCLUSION: VDD is highly prevalent among patients with UC. Patients with longer disease duration, more severe symptoms, and pancolitis are likely to have lower vitamin D levels.

Leucaena leucocephala pod seed protein as an alternate to animal protein in fish feed and evaluation of its role to fight against infection caused by Vibrio harveyi and Pseudomonas aeruginosa.

The laboratory acclimatized Clarias gariepinus (80 ±â€¯10 g) were divided into six groups and five subgroups each containing 10 fish. A fish feed was reconstituted by adding 33% powder of Leucaena leucocephala seed in place of fish trash. Group B, C and E were fed on reconstituted feed and group A, D and F were fed on artificial feed containing animal protein for 7 days prior to start of experiments. Then Group B was challenged with BSA while other groups were challenged with Vibrio harveyi (Group C, D) and Pseudomonas aeruginosa (Group E, F). Group A was used as negative control (not challenged with antigen). The fish were challenged on weekly intervals till 28th day. Blood was collected from one subgroup of each group on day 7, 14, 21 & 28 and finally sacrificed on day 35. Change in body weight, liver function tests (SGOT, SGPT) and serum ALP levels were monitored. The phagocytic index, percentage phagocytosis and nitric oxide levels were measured in macrophages isolated from spleen and head kidney. The levels of total fish immunoglobulin were also measured following indirect ELISA. The results showed improved immune response in fish fed on 33% L. leucocephala pod seed reconstituted feed; however their specific growth rate was low.

Effectiveness of flipped classroom with Poll Everywhere as a teaching-learning method for pharmacy students.

OBJECTIVES: Flipped classroom (FC) is a pedagogical model to engage students in learning process by replacing the didactic lectures. Using technology, lectures are moved out of the classroom and delivered online as means to provide interaction and collaboration. Poll Everywhere is an audience response system (ARS) which can be used in an FC to make the activities more interesting, engaging, and interactive. This study aims to study the perception of undergraduate pharmacy students on FC activity using Poll Everywhere ARS and to study the effectiveness of FC activity as a teaching-learning tool for delivering complementary medicine module in the undergraduate pharmacy program. MATERIALS AND METHODS: In this nonrandomized trial on interrupted time series study, flipped class was conducted on group of 112 students of bachelor of pharmacy semester V. The topic selected was popular herbal remedies of the complementary medicine module. Flipped class was conducted with audio and video presentation in the form of a quiz using ten one-best-answer type of multiple-choice questions covering the learning objectives. Audience response was captured using web-based interaction with Poll Everywhere. Feedback was obtained from participants at the end of FC activity and debriefing was done. RESULTS: Randomly selected 112 complete responses were included in the final analysis. There were 47 (42%) male and 65 (58%) female respondents. The overall Cronbach's alpha of feedback questionnaire was 0.912. The central tendencies and dispersions of items in the questionnaire indicated the effectiveness of FC. The low or middle achievers of quiz session (pretest) during the FC activity were three times (95% confidence interval [CI] = 1.1-8.9) at the risk of providing neutral or negative feedback than high achievers (P = 0.040). Those who gave neutral or negative feedback on FC activity were 3.9 times (95% CI = 1.3-11.8) at the risk of becoming low or middle achievers during the end of semester examination (P = 0.013). The multivariate analysis of "Agree" or "Disagree" and "Agree" or "Strongly Agree" was statistically significant. CONCLUSION: This study provides insight on how the pharmacy students learn and develop their cognitive functions. The results revealed that the FC activity with Poll Everywhere is an effective teaching-learning method.

1-Triacontanol cerotate; isolated from Marsilea quadrifolia Linn. ameliorates reactive oxidative damage in the frontal cortex and hippocampus of chronic epileptic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Marsilea quadrifolia Linn. (MQ) has been used for insomnia and epileptic disorders in traditional Indian medicine. The present study is to isolate the active component responsible for antiepileptic property of MQ by evaluating its ability to minimize the reactive oxidative damage in brain due to chronic epilepsy in rat. MATERIALS AND METHODS: 1-Triacontanol cerotate (1TAC) was isolated after chromatography on a silica gel from dried petroleum ether fraction of methanolic extract of MQ. Acute oral toxicity studies of 1TAC were carried out and efficacy of 1TAC on malondialdehyde (MDA) and reduced glutathione (GSH) production in different brain areas of chronic pentylenetetrazole (PTZ) induced epileptic rats were evaluated. RESULTS: Our results showed that PTZ-kindled chronic epileptic rats had an increase MDA and decreased GSH concentration in the frontal cortex as well as hippocampus, compared to the normal control. MDA and GSH concentrations in those brain areas were normalized after treatment with sodium valproate (SV) in 200 mg kg(-1)bw; as well as 1TAC in 40 and 80 mg kg(-1)bw doses. CONCLUSION: Production of reactive oxygen species (ROS) is known to worsen epileptogenesis. The isolated component 1TAC which reduced the reactive oxidative damage in hippocampus and frontal cortex of PTZ kindled rats could be responsible for antiepileptic property of MQ. Its action is found to be dose dependent, with 80 mg kg(-1)bw showing even better efficacy than 200 mg kg(-1)bw of SV.

Distinct metabolic effects following short-term exposure of different high-fat diets in male and female mice.

Obesity-associated hepatic lipid accumulation and chronic low-grade inflammation lead to metabolic defects. Saturated fatty acids (SFA) are a risk factor for, whereas unsaturated fatty acids (UFA) are thought to be protective against, developing metabolic diseases. Sex differences exist in the regulation of metabolism. We tested the hypothesis that diets high in SFA, mono-UFA (MUFA), or poly-UFA (PUFA) had early, sex-distinct effects that differentially contribute to long-term metabolic disturbance such as fatty liver and insulin resistance. Metabolic changes including body and fat mass, circulating leptin and glucose levels, plasma lipid profile, hepatic lipid accumulation, expression levels of genes related to lipid metabolism and low-grade inflammation, and tissue insulin sensitivity were compared between male and female mice fed with a low-fat chow, or high-fat SFA, MUFA, or PUFA for a short period of four days. SFA and MUFA males increased adiposity associated with increased liver lipid accumulation and rapid activation of inflammation in adipose and muscle tissues, whereas PUFA males did not show lipid accumulation or tissue inflammation compared to chow males. All SFA and UFA males displayed tissue insulin resistance. In contrast, female high-fat diet groups had normal liver lipid content and maintained tissue insulin sensitivity without showing tissue inflammation. Therefore, sex differences existed during early phase of development of metabolic dysfunction. The beneficial effects of PUFA, but not MUFA, were corroborated in protection of obesity, hyperlipidemia, fatty liver, and low-grade inflammation. The benefit of MUFA and PUFA in maintaining tissue insulin sensitivity in males, however, was questioned.