Drug-sensitive FGFR3 mutations in lung adenocarcinoma.

Background: Lung cancer is the leading cause of cancer-related deaths across the world. In this study, we present therapeutically relevant genetic alterations in lung adenocarcinoma of Indian origin. Materials and methods: Forty-five primary lung adenocarcinoma tumors were sequenced for 676 amplicons using RainDance cancer panel at an average coverage of 1500 × (reads per million mapped reads). To validate the findings, 49 mutations across 23 genes were genotyped in an additional set of 363 primary lung adenocarcinoma tumors using mass spectrometry. NIH/3T3 cells over expressing mutant and wild-type FGFR3 constructs were characterized for anchorage independent growth, constitutive activation, tumor formation and sensitivity to FGFR inhibitors using in vitro and xenograft mouse models. Results: We present the first spectrum of actionable alterations in lung adenocarcinoma tumors of Indian origin, and shows that mutations of FGFR3 are present in 20 of 363 (5.5%) patients. These FGFR3 mutations are constitutively active and oncogenic when ectopically expressed in NIH/3T3 cells and using a xenograft model in NOD/SCID mice. Inhibition of FGFR3 kinase activity inhibits transformation of NIH/3T3 overexpressing FGFR3 constructs and growth of tumors driven by FGFR3 in the xenograft models. The reduction in tumor size in the mouse is paralleled by a reduction in the amounts of phospho-ERK, validating the in vitro findings. Interestingly, the FGFR3 mutations are significantly higher in a proportion of younger patients and show a trend toward better overall survival, compared with patients lacking actionable alterations or those harboring KRAS mutations. Conclusion: We present the first actionable mutation spectrum in Indian lung cancer genome. These findings implicate FGFR3 as a novel therapeutic in lung adenocarcinoma.

Comparison of alogliptin and glipizide for composite endpoint of glycated haemoglobin reduction, no hypoglycaemia and no weight gain in type 2 diabetes mellitus.

This was a post hoc analysis of a 2-year, double-blind study of 2639 patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin monotherapy, which assessed achievement of a composite endpoint of sustained glycated haemoglobin (HbA1c) reduction (≤7.0% at week 104 or ≥0.5% decrease from baseline) with no weight gain and no hypoglycaemic events with alogliptin 12.5 and 25 mg daily or glipizide (≤20 mg daily), each added to metformin. With an HbA1c target of ≤7.0%, 24.2 and 26.9% of patients treated with alogliptin 12.5 and 25 mg, respectively, achieved the composite endpoint versus 10.7% of patients treated with glipizide (both p < 0.001). With a criterion of ≥0.5% decrease in HbA1c, the composite endpoint was reached in 22.5, 25.2 and 10.4% of patients treated with alogliptin 12.5 mg, alogliptin 25 mg and glipizide, respectively. Odds ratios for achieving the composite endpoint favoured alogliptin in the primary analysis set and in all subgroups of patients. Patients with T2DM failing metformin monotherapy were more likely to achieve sustained glycaemic control with no hypoglycaemia or weight gain at 2 years with alogliptin than with glipizide.

Six-year analysis of compliance to weekly concurrent chemoradiotherapy in head and neck carcinomas.

OBJECTIVES: To evaluate treatment compliance to weekly concurrent chemoradiotherapy (CRT) in head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN: Retrospective analysis. SETTING: Tertiary care hospital. MAIN OUTCOME MEASURES: Overall treatment time (OTT), acute radiation morbidity and treatment completion rate without prolongation of overall treatment time of more than 2 days. RESULTS: Three hundred and seventy-eight head and neck carcinoma patients treated with radical CRT with 70 Gy/35 fractions of radiotherapy with weekly cisplatin 40 mg/m(2) were included in the study. Median age was 52 years (range 22-77 years), oropharynx was most commonly (54%) involved site, and 55% were in stage IV disease. Majority (86%) of patients were able to complete cancer-directed therapy, median OTT was 52 days (46-140 days). Nineteen per cent of patients completed treatment without prolongation of OTT beyond 2 days and 68% of patients there completed treatment prolongation of OTT beyond 7 days. Nearly, sixty-six of the patients experienced grade II or higher acute radiation morbidities. CONCLUSIONS: Delivery of weekly low-dose concurrent CRT is safe and feasible. Two-thirds of the patients experienced treatment prolongation of more than 2 days and 14% could not complete treatment. Results within in the study suggest to a greater need to lay emphasis on continuity of a course of radical CRT for HNSCC.

MACROBID INDUCED HEPATITIS.

More than 900 drugs, toxins and herbs have been reported to cause liver injury. Drugs account for 20-40 percent of all instances of fulminant hepatic failure.

Polysaccharide and monosaccharide guided liver delivery of Sorafenib Tosylate - A nano-strategic approach and comparative assessment of hepatospecificity.

Hepatospecific delivery by ligand based receptor targeting is an established strategy to augment therapy associated with liver diseases and disorders. Previously, we have investigated the effect of ligand headgroup on cellular uptake mediated by the asialoglycoprotein receptor by in silico and in vitro approach. In this paper, we report the design of agarose based liposomes for delivery to liver cancer cells and provide a proof of concept of the targeting efficiency against galactose liposomes using an in vivo approach. Sorafenib Tosylate loaded targeting liposomes were developed and optimized using factorial design. Comparative evaluation including cell cytotoxicity, pharmacokinetics and biodistribution and hepatospecific uptake was performed for both the liposomal systems. The formulations possessed a particle size of 150 - 180 nm and a zeta potential of 30 - 60 mV depending on the amount of ligand and drug loading, with more than 90% entrapment efficiency. A two-fold increase in cytotoxicity was observed with agarose-based liposomes as compared to galactose based liposomes. In vivo PK evaluation indicated a reduction in half life of drug when loaded in agarose ligand loaded system, probably due to greater uptake in the liver as evidenced in biodistribution study. Intrahepatic disposition revealed a higher PC/NPC uptake ratio with the targeted systems as compared to conventional liposomes, although the agarose-based system resulted in highest uptake ratio. A biocompatible platform for specific delivery of drugs to hepatocytes was established validating a rational approach to design liver targeting systems.

Toxicity assessment of free form of heavy metals in aqueous media on earthworm Eudrillus eugeniae.

Metals are found in free and also in combined forms. In order to get information on the effect of free forms of heavy metals on earthworms the aqueous extracts of metals were tested on earthworms both in individual form and also in combined form. Different concentrations, i.e. 1 ppm, 5 ppm, and 10 ppm, were selected arbitrarily and were used in the experiments. Metals like copper, cadmium, chromium, zinc and lead were used. Earthworms' Eudrillus eugeniae activity, i.e. their response to the toxicity of metals, was monitored continuously for 5 h. It can be concluded that free form/ionic form/dissolved form of heavy metals are more toxic for earthworms, concurrent with findings of workers who have drawn same inference during studies on aquatic organisms. Earthworms can serve as biomarkers for wastewater and sludge treatment studies as they have shown typical adverse body reactions and symptoms altogether different in reaction to each of the metals during aqueous medium studies. It can be inferred that, if earthworms are utilised for treating wastewater and sludges containing these five heavy metals, one can ascertain the presence of individual metal concentrations in the wastewaters and sludges by studying the typical body reactions of earthworms during the treatment.

Association of glutathione S-transferase (GSTM1, T1 and P1) gene polymorphisms with type 2 diabetes mellitus in north Indian population.

BACKGROUND: Diabetes mellitus is associated with an increased production of reactive oxygen species (ROS) and a reduction in antioxidant defense. The oxidative stress becomes evident as a result of accumulation of ROS in conditions of inflammation and Type 2 diabetes mellitus (T2DM). The genes involved in redox balance, which determines the susceptibility to T2DM remain unclear. In humans, the glutathione S-transferase (GST) family comprises several classes of GST isozymes, the polymorphic variants of GSTM1, T1 and P1 genes result in decreased or loss of enzyme activity. AIMS: The present study evaluated the effect of genetic polymorphisms of the GST gene family on the risk of developing T2DM in the North Indian population. SETTINGS AND DESIGN: GSTM1, T1 and P1 polymorphisms were genotyped in 100 T2DM patients and 200 healthy controls from North India to analyze their association with T2DM susceptibility. MATERIALS AND METHODS: Analysis of GSTM1 and GSTT1 gene polymorphisms was performed by multiplex polymerase chain reaction (PCR) and GSTP1 by PCR-Restriction Fragment Length Polymorphism (RFLP). STATISTICAL ANALYSIS: Fisher's exact test and chi2 statistics using SPSS software (Version-15.0). RESULTS: We observed significant association of GSTM1 null (P=0.004, OR= 2.042, 95%CI= 1.254-3.325) and GSTP1 (I/V) (P=0.001, OR= 0.397, 95%CI=0.225-0.701) with T2DM and no significant association with GSTT1 (P=0.493). The combined analysis of the three genotypes GSTM1 null, T1 present and P1 (I/I) demonstrated an increase in T2DM risk (P= 0.005, OR= 2.431 95% CI=1.315-4.496). CONCLUSIONS: This is the first study showing the association of a combined effect of GSTM1, T1 and P1 genotypes in a representative cohort of Indian patients with T2DM. Since significant association was seen in GSTM1 null and GSTP1 (I/V) and multiple association in GSTM1 null, T1 present and P1 (I/I), these polymorphisms can be screened in the population to determine the diabetic risk.

Assessing analytical variability of measurement of vitamin A in corn-soy blend.

Two multilaboratory investigations were conducted by SUSTAIN to assess variability in the measurement of vitamin A, the marker used to verify levels of vitamin premix addition to enriched/fortified food aid products, including the widely distributed corn-soy blend (CSB). CSB specifications identify AACC Approved Method 86-06 or equivalent methods for vitamin A analysis, however there is no requirement to demonstrate equivalency. CSB samples with known and blinded levels of vitamin A and a reference standard were analyzed by 16 laboratories using their respective methods. Calculated coefficients of variation across all laboratories and methods for unknown samples and reference standard were 35 and 7.1%, respectively, suggesting the largest source of variation is the vitamin extraction procedure. Laboratories generally overestimated low levels and underestimated high levels of vitamin A within the range of 6000 and 16 000 IU/lb. Only two laboratories demonstrated excellent internal precision (+/- 300 IU vitamin A/lb) and reported values within 95% confidence interval for all blinded samples. Results of this study have implications both for quality control in food aid products (due to the use of vitamin A as a marker) and for regulatory oversight of vitamin A content in commercial food products.

Vermifilters: a tool for aerobic biological treatment of herbal pharmaceutical wastewater.

Herbal pharmaceutical wastewater possesses high chemical oxygen demand (COD) (21,960-26,000 mg/l) and biochemical oxygen demand (BOD) (11,200-15,660 mg/l) and suspended solids (SS) (5,460-7,370 mg/l). It cannot be directly discharged into surface water bodies, due to its highly biodegradable nature. Herbal pharmaceutical wastewater has been treated by using vermifilter, which is an ecosystem consisting of biosoil with bacteria and earthworms producing vermicastings. In the present studies a cost-effective, eco-friendly and sustainable method has been applied for the treatment of herbal pharmaceutical wastewater using earthworms. Studies were carried out at different organic loadings, ranging between 0.8 and 3.2 kg COD/m(3)day at three different hydraulic loadings of 1, 2 and 4 days. Vermifilters packed with 1:1:1 ratio of soil, sand and vermicast as media matrix along with the twenty adult earthworms in each reactor was used for the experiments. Treated effluent was colour and odour free. Efficient COD/BOD removals in the range of 85.44%-94.48% and 89.77%-96.26% were obtained respectively at 2 days hydraulic retention time (HRT). Heavy metal removals were also observed and no sludge production problem was encountered, only nutrient rich vermicast from the filters were removed and analysed after the experiments. It showed higher manurial value than control in terms of available nitrogen, phosphorus and potassium (NPK) and were in the range of 178.75-278.75 Kg/hectare available nitrogen, 16.128-50.4 kg/hectare of available phosphorus and 19.3-28.6 kg/hectare of available potassium at maximum HRT and at different organic loadings. This paper discusses in detail the feasibility of vermifilters in herbal pharmaceutical wastewater treatment at different organic and hydraulic loadings.

Dataset on statistical reduction of COD by electrocoagulation process using RSM.

Viable and low treatment cost is a challenge for municipal wastewater, therefore, an efficient and cost effective electrocoagulation (EC) process was studied to treat domestic sewage (DS) in laboratory batch process using SS-304 as electrode material. Effects of various parameters like pH, current density (CD), electrode configuration in numbers and treatment time (tR) were tested to find optimum operating condition for COD and other pollutants removal. The experiments were also planned to optimize the operating parameters through response surface methodology (RSM) based central composite design (CCD) which gave 77.78% COD reduction at CD = 27.78 A/m2 and tR = 20 min respectively.

Smartphones and tooth brushing: content analysis of the current available mobile health apps for motivation and training.

INTRODUCTION: Smartphone mobile app is an innovative concept for health behaviour-based interventions. AIM: The present study aimed to analyse apps developed for smartphones that promote tooth brushing amongst children using the Coventry, Aberdeen, and London-Refined (CALO-RE) taxonomy for behaviour change. MATERIALS AND METHODS: Tooth brushing apps available in English and free to download that purported to assist with brushing were searched on the Apple app store using search terms based on Boolean logic and included AND combinations for keywords tooth brushing, children, toothbrush and motivation in the health and fitness category; six apps met the inclusion criteria and were downloaded. The behaviour change taxonomies were assessed individually for each app and scored as per coding and analysed for presence or absence. RESULTS: Only three of the behaviour change taxonomies were present in all apps, i.e. information provision (general), goal setting (behaviour) and prompt practice. Setting graded tasks, self-monitoring of behavioural outcome, demonstration of behaviour, prompt use of imagery and time management were included in four out of six apps. CONCLUSION: The present study explores a new arena for oral healthcare motivation and prevention in children through the use of mobile phone apps.

Structure and properties of metallic glasses.

Recent experience has shown that certain metal alloys can be put into glass form by rapid melt-quenching or by various condensation processes. Models for the nature and structure of these glasses are surveyed and shown to be quite parallel to those already developed for the more common nonmetallic glasses. The rather unique magnetic, superconducting, and mechanical properties and the technical potential of metallic glasses are also discussed.

The microstructure of high--critical current superconducting films.

The microstructure of superconducting films that have shown high-critical current densities has been studied. The films are shown to be epitaxial and contain twins and precipitates. The main difference between these films and low current carrying samples is the absence of grain boundaries. These boundaries are therefore identified as the cause of the lower critical current in ceramic samples.

Improved detail in biological soft X-ray microscopy: study of blood platelets.

Improved image quality in soft x-ray contact microscopy can be obtained by examining the resist with transmission rather than scanning electron microscopy. Application of the new technique to air-dried preparations of human blood platelets reveals structures not visible in the same cells with transmission electron microscopy or when the resist is examined by scanning electron microscopy. As seen by the new technique, platelet pseudopods contain a central structure connected to a network in the platelet and dense bodies exhibit a lamellar structure.

Spatially Resolved Observation of Supercurrents Across Grain Boundaries in YBaCuO Films.

Spatially resolved resistivity measurements of current transport across individual grain boundaries have been made on superconducting YBa(2)Cu(3)O(7). These experiments were done by low-temperature scanning electron microscopy with a resolution of 1 to 2 micrometers, and they show directly the limitation of the critical current density caused by grain boundaries in YBa(2)Cu(3)O(7). Furthermore, complex spatial patterns of the current transport across grain boundaries were observed. These patterns reflect self-excited resonances of the grain boundaries and are closely correlated to the unexplained "sub-gap structure" in the current-voltage characteristics of polycrystalline YBa(2)Cu(3)O(7).

Liquid crystal alignment on carbonaceous surfaces with orientational order.

We used near-edge x-ray absorption fine structure (NEXAFS) spectroscopy to link the orientational bond order at three carbonaceous surfaces-rubbed polyimide, ion beam-irradiated polyimide, and ion beam-irradiated diamondlike carbon films-with the direction of liquid crystal (LC) alignment on these surfaces. We show that, in general, LC alignment can be created on any carbonaceous substrate by inducing orientational order at its surface. Our results form the scientific basis for LC alignment layers consisting of amorphous carbon films in which orientational order near the surface is induced by a directional low-energy ion beam.

Ultrasound assisted synthesis of polyacrylic acid-nanoclay nanocomposite and its application in sonosorption studies of malachite green dye.

Synthesis of nanoclay nanocomposite has been undertaken by using polyacryalic acid (PAA) in aqueous medium and ultrasound environment and its application in dye removal has been investigated. The synthesized product was characterized by using FTIR and XRD techniques. The sonosorption capacity of the product namely PAA-nanoclay composite was determined by choosing malachite green (MG) dye as a model pollutant. The effects of various parameters such as nanocomposite loading, pH, various process conditions etc. have been studied. On comparing the results obtained with that of nanoclay as an adsorbent, it was found for an initial concentration of 500mg/l, the PAA-nanoclay nanocomposite exhibited higher percentage of pollutant removal (68%) and for nanoclay it was 54%. The adsorption data has been correlated using Langmuir and Freundlich models. The fit of the Freundlich isotherm model was found to be good in the entire range of concentration for the experimental sorption data obtained on the nanoclay nanocomposite. A plausible reaction mechanism for use of PAA-nanoclay nanocomposite as an adsorbent is also proposed.

Diversity of birds at Panipat refinery, Haryana (India).

Avifaunal study was carried out in Panipat refinery area before and after commissioning. A total of 63 birds were observed during the study, of which 39 and 49 birds were present during 1992 and 2001 respectively. Of these, 25 birds were common during both the study period. Blue rock pigeon was most dominant during 1992 whereas house sparrow was dominant during 2001. Species diversity index was found to be 5.26 and 6.64 in respective years. Jaccard's and Sorenson similarity indices were 0.40 and 0.57 respectively. Majority of birds were insectivorous in habits followed by granivorous birds in 1992 and piscivorous birds in 2001. The study reveals that less diversity was observed in 1992 when Panipat refinery was commissioned, but more birds especially aquatic ones were observed after the commissioning of the refinery. This has been attributed to increase in birds habitats due to developments of wetlands in and outside refinery, development of green belt around refinery and increase in green cover of area due to boosting of agroforestry and social forestry.

Oral administration of 3,3'-diselenodipropionic acid prevents thoracic radiation induced pneumonitis in mice by suppressing NF-kB/IL-17/G-CSF/neutrophil axis.

The incidence of symptomatic radiation induced lung pneumonitis (RILP), a major dose limiting side effect of thoracic radiotherapy, is in the range of 15-40%. Therapeutic options for the prevention and treatment of RILP are limited. Hence there is a need for developing novel radioprotectors to prevent RILP which can be patient compliant. This study sought to evaluate the efficacy of oral 3,3'-diselenodipropionic acid (DSePA), a novel selenocystine derivative to prevent RILP. C3H/HeJ (pneumonitis responding) mice received a single dose of 18 Gy, whole thorax irradiation and a subset were treated with DSePA orally (2.5 mg/kg), three times per week beginning 2 h post irradiation and continued till 6 months. DSePA delayed onset of grade ≥ 2 RILP by 45 days compared to radiation control (~105 versus ~60 days). It also reversed the severity of pneumonitis in 3/10 radiation treated mice leading to significant improvement in asymptomatic survival compared to radiation control (~180 versus ~102 days). DSePA significantly (p < 0.05) reduced the radiation-mediated infiltration of polymorphonuclear neutrophils (PMN) and elevation in levels of cytokines such as IL1-ß, ICAM-1, E-selectin, IL-17 and TGF-ß in the bronchoalveolar lavage fluid. Moreover DSePA lowered PMN-induced oxidants, maintained glutathione peroxidase activity and suppressed NF-kB/IL-17/G-CSF/neutrophil axis in the lung of irradiated mice. Additionally, this compound did not protect A549 (lung cancer) derived xenograft tumor from radiation exposure in SCID mice. DSePA offers protection to normal lung against RILP without affecting radiation sensitivity of tumors. It has the potential to be developed as an oral agent for preventing RILP.

Development of a melting tablet containing promethazine HCl against motion sickness.

The purpose of this study was to design a 'Traveller Friendly Drug Delivery System' for PM-HCl. Conventional promethazine (PM-HCl) tablets are bitter, need to be taken 1 h before symptoms and water is also needed. Taste-masked granules were produced with Eudragit E100 by extrusion, and analyzed with FTIR, DSC, and XRD. Tablets formulated from granules by direct compression using Ac-Di-Sol, Polyplasdone-XL, Primojel and ion-exchanger Tulsion339 and evaluated for mass uniformity, friability, tensile strength, drug content uniformity, water absorption ratio, in-vitro and in-vivo disintegration time and in-vitro dissolution studies. The observed drug-polymer interactions and reduced crystallinity may be reasons for increased dissolution rates. The formulated tablets were disintegrated within 15 s. Tablets (25 mg PM-HCl) with Ac-Di-Sol (4%) showed complete release within 1 min, while marketed conventional tablets (Phenergan; Rhone-Poulec) release 25% during the same period. A preliminary stability studies for the prepared tablets carried at 30 +/- 2 degrees C/60 +/- 5% RH, and 40 +/- 2 degrees C/75 +/- 5%RH for 3 months showed no significant changes in the tablets quality at 30 +/- 2 degrees C/60 +/- 5% RH. However, at 40 +/- 2 degrees C/75 +/- 5%RH marked increase in in-vitro disintegration time, tensile strength and decrease in friability and water absorption ratio was found. The present studies indicate the abilities of Eudragit E 100 for taste masking and improving the dissolution profile of PM-HCl after complexation. In addition, by employing cost effective direct compression method, fast-dissolving tablets of 400 mg total weight with an acceptable quality could be prepared.