Evidence of a Hardening in the Cosmic Ray Proton Spectrum at around 166 TeV Observed by the GRAPES-3 Experiment.

We present the measurement of the cosmic ray proton spectrum from 50 TeV to 1.3 PeV using 7.81×10^{6} extensive air shower events recorded by the ground-based GRAPES-3 experiment between 1 January 2014 and 26 October 2015 with a live time of 460 day. Our measurements provide an overlap with direct observations by satellite and balloon-based experiments. The electromagnetic and muon components in the shower were measured by a dense array of plastic scintillator detectors and a tracking muon telescope, respectively. The relative composition of the proton primary from the air shower data containing all primary particles was extracted using the multiplicity distribution of muons which is a sensitive observable for mass composition. The observed proton spectrum suggests a spectral hardening at ∼166 TeV and disfavors a single power law description of the spectrum up to the Knee energy (∼3 PeV).

Development and evaluation of herbal formulation AKIGTU01 and AKIGCL03 against acne producing microbes.

Acne vulgaris is a common global skin disease affecting teenagers and adults and exerting serious psychological impacts which includes everlasting scarring, reduced self-image, depression and anxiety. One of the suspected causative agent of acne is Propionibacterium acnes; a Gram positive anaerobic organism which lives in skin hair follicle and openings. Treatments currently available for acne include use of oral antibiotics, hormones, isotretinoin and also physical treatments like lesion removal and photo-therapy. All these are associated with risks and none is completely satisfactory.Therefore, natural alternatives are gaining greater research support but lacks sufficient studies. In our study we have isolated Propionibacterium acnes from infected individuals and tested the effect of certain chemicals and herbs/ vegetable extracts against it. There anti-acne property was studied and compared with commercially used antibiotics including Clinagel (Clindamycin phosphate), Vibramycin (Doxycycline), Erythromycin, Novidat (Ciprofloxacin) and Amoxil (Amoxicillin). Results indicate that some of the selected herbs and chemicals showed good activity against Propionibacterium acnes synergistic to the antibiotics when used alone or in combination. Findings of this research can play an important role in natural product based drug discovery for the treatment of Acne vulgaris.

Measurement of the Electrical Properties of a Thundercloud Through Muon Imaging by the GRAPES-3 Experiment.

The GRAPES-3 muon telescope located in Ooty, India records rapid (∼10 min) variations in the muon intensity during major thunderstorms. Out of a total of 184 thunderstorms recorded during the interval of April 2011-December 2014, the one on December 1, 2014 produced a massive potential of 1.3 GV. The electric field measured by four well-separated (up to 6 km) monitors on the ground was used to help estimate some of the properties of this thundercloud, including its altitude and area that were found to be 11.4 km above mean sea level and ≥380 km^{2}, respectively. A charging time of 6 min to reach 1.3 GV implied the delivery of a power of ≥2 GW by this thundercloud that was moving at a speed of ∼60 km h^{-1}. This work possibly provides the first direct evidence for the generation of gigavolt potentials in thunderclouds that could also possibly explain the production of highest-energy (100 MeV) gamma rays in the terrestrial gamma-ray flashes.

Clinical significance of TP53 (R72P) and MDM2 (T309G) polymorphisms in breast cancer patients

Introduction: TP53 gene is the most frequently altered tumor suppressor gene in breast cancer. It has been observed that MDM2 plays a central role in regulating the TP53 pathway. This study aimed to investigate the role of TP53 Arg72Pro and MDM2 T309G polymorphisms in breast cancer patients. Material and method: The TP53 (Arg72Pro) and MDM2 (T309G) polymorphisms were studied in a hospital-based case control study by AS-PCR in 100 breast cancer patients and 100 healthy control subjects. Results: It was observed that TP53 Arg72Pro polymorphism was significantly associated with breast cancer (v2 = 9.92, p = 0.007). A significantly increased breast cancer risk was associated with the Proline allele [odds ratio 1.84 (95 % CI: 1.22-2.77), risk ratio 1.34 (95 % CI: 1.11-1.63), p value 0.003], HER2/neu status (p = 0.01) and distant metastasis (p = 0.05). On the other hand, we have found a significant correlation between MDM2 (T309G) polymorphism with HER2/neu status (v2 = 11.14, p = 0.003) and distant metastasis (p value = 0.04). Conclusion: Our finding suggests that TP53 (Arg72Pro) polymorphism may play a significant role as risk factor for breast cancer in north Indian breast cancer patients. While MDM2 (T309G) polymorphism may not be directly associated with the risk of breast cancer occurrence in the same population, but it may play role in disease progression by triggering TP53 (AU)

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Potential impact of (rs 4645878) BAX promoter -248G > A and (rs 1042522) TP53 72Arg > pro polymorphisms on epithelial ovarian cancer patients

Background. In India, Epithelial ovarian cancer has emerged as one of the most common malignancies affecting women. Tumor protein 53 (TP53) induces expression of the B cell lymphoma 2-associated X protein (BAX) gene by directly binding to the TP53-binding element in the BAX promoter. Therefore, we hypothesized that single-nucleotide polymorphism of BAX promoter −248G>A and TP53 72Arg>Pro gene may jointly contribute to ovarian cancer risk. Objectives. This study aimed at exploring the association of BAX promoter −248G>A and TP53 72Arg>Pro gene polymorphism with risk of developing EOC and its clinicopathological features and to evaluate gene-gene interaction of these two polymorphisms with risk of developing EOC. Materials. The study was conducted on 70 Epithelial ovarian cancer patients and 70 healthy controls. Genotyping of p53 codon 72 and BAX promoter gene was examined by ASO-PCR and PICA-PCR, respectively. Odds ratios and 95 % confidence intervals were calculated. Results. We found an increased cancer risk associated with the BAX AA (ORs = 4.1, 95 %, CI = 1.23-13.97) genotype. An increased risk was also associated with the TP53 Pro/Pro (OR = 4.4, 95 % CI = 1.40-13.99) and Arg/Pro genotype (OR = 2.3, 95 % CI = 1.13-4.86). The gene-gene interaction of these polymorphisms increased EOC risk in a more than additive manner (ORs for the presence of both BAX AA and TP53 Arg/Pro genotypes = 8.7, 95 % CI = 1.66-45.48). BAX GG genotype was associated with adverse staging of cancer (P = 0.01). Conclusions. The findings suggest that polymorphism of BAX and TP53 genes may be potential genetic modifiers for developing ovarian cancer (AU)

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Clinical significance of TP53 (R72P) and MDM2 (T309G) polymorphisms in breast cancer patients.

INTRODUCTION: TP53 gene is the most frequently altered tumor suppressor gene in breast cancer. It has been observed that MDM2 plays a central role in regulating the TP53 pathway. This study aimed to investigate the role of TP53 Arg72Pro and MDM2 T309G polymorphisms in breast cancer patients. MATERIAL AND METHOD: The TP53 (Arg72Pro) and MDM2 (T309G) polymorphisms were studied in a hospital-based case control study by AS-PCR in 100 breast cancer patients and 100 healthy control subjects. RESULTS: It was observed that TP53 Arg72Pro polymorphism was significantly associated with breast cancer (χ (2) = 9.92, p = 0.007). A significantly increased breast cancer risk was associated with the Proline allele [odds ratio 1.84 (95 % CI: 1.22-2.77), risk ratio 1.34 (95 % CI: 1.11-1.63), p value 0.003], HER2/neu status (p = 0.01) and distant metastasis (p = 0.05). On the other hand, we have found a significant correlation between MDM2 (T309G) polymorphism with HER2/neu status (χ (2) = 11.14, p = 0.003) and distant metastasis (p value = 0.04). CONCLUSION: Our finding suggests that TP53 (Arg72Pro) polymorphism may play a significant role as risk factor for breast cancer in north Indian breast cancer patients. While MDM2 (T309G) polymorphism may not be directly associated with the risk of breast cancer occurrence in the same population, but it may play role in disease progression by triggering TP53.

Potential impact of (rs 4645878) BAX promoter -248G>A and (rs 1042522) TP53 72Arg>pro polymorphisms on epithelial ovarian cancer patients.

BACKGROUND: In India, Epithelial ovarian cancer has emerged as one of the most common malignancies affecting women. Tumor protein 53 (TP53) induces expression of the B cell lymphoma 2-associated X protein (BAX) gene by directly binding to the TP53-binding element in the BAX promoter. Therefore, we hypothesized that single-nucleotide polymorphism of BAX promoter -248G>A and TP53 72Arg>Pro gene may jointly contribute to ovarian cancer risk. OBJECTIVES: This study aimed at exploring the association of BAX promoter -248G>A and TP53 72Arg>Pro gene polymorphism with risk of developing EOC and its clinicopathological features and to evaluate gene-gene interaction of these two polymorphisms with risk of developing EOC. MATERIALS: The study was conducted on 70 Epithelial ovarian cancer patients and 70 healthy controls. Genotyping of p53 codon 72 and BAX promoter gene was examined by ASO-PCR and PICA-PCR, respectively. Odds ratios and 95 % confidence intervals were calculated. RESULTS: We found an increased cancer risk associated with the BAX AA (ORs = 4.1, 95 %, CI = 1.23-13.97) genotype. An increased risk was also associated with the TP53 Pro/Pro (OR = 4.4, 95 % CI = 1.40-13.99) and Arg/Pro genotype (OR = 2.3, 95 % CI = 1.13-4.86). The gene-gene interaction of these polymorphisms increased EOC risk in a more than additive manner (ORs for the presence of both BAX AA and TP53 Arg/Pro genotypes = 8.7, 95 % CI = 1.66-45.48). BAX GG genotype was associated with adverse staging of cancer (P = 0.01). CONCLUSIONS: The findings suggest that polymorphism of BAX and TP53 genes may be potential genetic modifiers for developing ovarian cancer.

Expression of serum miR-200a, miR-200b, and miR-200c as candidate biomarkers in epithelial ovarian cancer and their association with clinicopathological features

Background. MicroRNAs (miRs) have been implicated in the etiology of various human cancers. The aim of this study was to investigate the association of the expression of three members - miR 200a, miR 200b, and miR 200c belonging to the miR-200 family with clinicopathological characteristics and their impact on the progression of epithelial ovarian cancer (EOC). Materials and methods. Total RNA from serum was isolated by Trizol method, polyadenylated, and reverse transcribed into cDNA. Expression levels of miR-200a, miR-200b, and miR-200c were detected by using miRNA qRT-PCR. We measured miR expression in 70 serum samples of EOC patients with matched controls using U6 snRNA as a reference. Levels of miR expression was compared with distinct clinicopathological features. Results. Expression of miR-200a was found to be greater than six-fold (p = 0.01), miR-200b and miR-200c greater than three-fold (p = 0.01) in comparison with matched normal controls. Association of miRNA expression with clinicopathological factors and progression was statistically evaluated. The expression levels of miR-200a and miR-200c were found to be significantly associated with disease progression (p = 0.04 and p < 0.001, respectively). miR-200a overexpression was found be associated with tumor histology and stage. Patients with lymph node metastasis showed significant elevation of miR-200c (p = 0.006). The AUC in ROC curve also indicated that serum levels of miR-200a and miR-200c might be worthwhile as a diagnostic tool in the near future. Conclusion. Our findings suggest that miR-200a, miR-200b, and miR-200c overexpressions are associated with the aggressive tumor progression and be recognized as reliable markers to predict the prognosis and survival in EOC patients (AU)

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Expression of serum miR-200a, miR-200b, and miR-200c as candidate biomarkers in epithelial ovarian cancer and their association with clinicopathological features.

BACKGROUND: MicroRNAs (miRs) have been implicated in the etiology of various human cancers. The aim of this study was to investigate the association of the expression of three members--miR 200a, miR 200b, and miR 200c belonging to the miR-200 family with clinicopathological characteristics and their impact on the progression of epithelial ovarian cancer (EOC). MATERIALS AND METHODS: Total RNA from serum was isolated by Trizol method, polyadenylated, and reverse transcribed into cDNA. Expression levels of miR-200a, miR-200b, and miR-200c were detected by using miRNA qRT-PCR. We measured miR expression in 70 serum samples of EOC patients with matched controls using U6 snRNA as a reference. Levels of miR expression was compared with distinct clinicopathological features. RESULTS: Expression of miR-200a was found to be greater than six-fold (p = 0.01), miR-200b and miR-200c greater than three-fold (p = 0.01) in comparison with matched normal controls. Association of miRNA expression with clinicopathological factors and progression was statistically evaluated. The expression levels of miR-200a and miR-200c were found to be significantly associated with disease progression (p = 0.04 and p < 0.001, respectively). miR-200a overexpression was found be associated with tumor histology and stage. Patients with lymph node metastasis showed significant elevation of miR-200c (p = 0.006). The AUC in ROC curve also indicated that serum levels of miR-200a and miR-200c might be worthwhile as a diagnostic tool in the near future. CONCLUSION: Our findings suggest that miR-200a, miR-200b, and miR-200c overexpressions are associated with the aggressive tumor progression and be recognized as reliable markers to predict the prognosis and survival in EOC patients.

Simple multiplex RT-PCR for identifying common fusion BCR-ABL transcript types and evaluation of molecular response of the a2b2 and a2b3 transcripts to Imatinib resistance in north Indian chronic myeloid leukemia patients.

INTRODUCTION: Chronic myeloid leukemia (CML) is characterized by the Philadelphia chromosome, an abnormally shortened chromosome 22. It is the result of a reciprocal translocation of chromosomes 9 and 22, creating BCR-ABL fusion transcripts, b3a2, b2a2, and e1a2. The aim of our study was to determine the type of BCR-ABL fusion transcripts for molecular diagnosis and investigate the frequency of BCR-ABL fusion transcripts in CML patients by multiplex RT-PCR in CML. MATERIALS AND METHODS: A single reaction with multiple primers multiplex PCR was used to detect and investigate the type and frequency in 200 CML patients among which 116, 33, and 51 were in CP, AP, and BC phase, respectively. RESULTS: The study included 200 CML patients, among whom breakpoints in b3a2, b2a2 transcripts were detected in 68% and 24%, respectively, while 8% of the patients showed both b3a2/b2a2. A statistically significant difference was seen between frequency of BCR-ABL fusion transcripts and gender (P = 0.03), molecular response (P = 0.04), and hematological response (P = 0.05). However, there was no correlation found between frequencies of BCR-/ABL fusion transcripts and other clinicopathological parameters like age, type of therapy, thrombocytopenia, and white blood cell count. CONCLUSION: Multiplex reverse transcriptase-polymerase chain reaction is useful and saves time in the detection of BCR-ABL variants; the occurrence of these transcripts associated with CML can assist in prognosis and treatment of disease.

Development of microsatellite loci in Artocarpus altilis (Moraceae) and cross-amplification in congeneric species.

PREMISE OF THE STUDY: Microsatellite loci were isolated and characterized from enriched genomic libraries of Artocarpus altilis (breadfruit) and tested in four Artocarpus species and one hybrid. The microsatellite markers provide new tools for further studies in Artocarpus. • METHODS AND RESULTS: A total of 25 microsatellite loci were evaluated across four Artocarpus species and one hybrid. Twenty-one microsatellite loci were evaluated on A. altilis (241), A. camansi (34), A. mariannensis (15), and A. altilis × mariannensis (64) samples. Nine of those loci plus four additional loci were evaluated on A. heterophyllus (jackfruit, 426) samples. All loci are polymorphic for at least one species. The average number of alleles ranges from two to nine within taxa. • CONCLUSIONS: These microsatellite primers will facilitate further studies on the genetic structure and evolutionary and domestication history of Artocarpus species. They will aid in cultivar identification and establishing germplasm conservation strategies for breadfruit and jackfruit.

Using real-time alerts for clinical trials: Identifying potential study subjects.

BACKGROUND: Clinical trials are widely accepted as a necessary step in evaluating the safety and efficacy of new pharmaceutical products. In order for a sufficiently powered study, a clinical trial depends on the effective and unbiased recruitment of eligible patients. Trials involving seasonal diseases like influenza pose additional challenges. OBJECTIVE: This is a feasibility study of a mobile real-time alerting system to systematically identify potential study subjects for a randomized controlled trial evaluating the safety and efficacy of early intervention with interferon alfacon-1 for patients hospitalized for influenza virus infection. METHODS: The alerting system was setup in a 471-bed acute care teaching hospital, enabled with computerized physician order entry (CPOE) and a rules-based alerting system. Patients were identified from the entire hospital using two alerts types: pharmacy prescription records for antiviral drugs, and positive influenza laboratory results. Email alerts were generated and sent to BlackBerry(®) devices carried by the study personnel for a 6 month period. The alerts were archived automatically on a secure server and were exported for analysis in Microsoft Access. RESULTS: Over a period of 21 weeks, 779 total alerts were received. The study team was alerted to 241 patients, of whom 85 were potential study subjects. The alert system identified all but one of the patients independently identified by infection control. CONCLUSIONS: Real-time identification of potential study subjects is possible with the integration of computerized physician order entry and BlackBerry(®) technology. It is a viable method for the systematic identification of patients throughout a hospital, particularly for trials investigating time-sensitive disease progression.

Synthesis, characterization and biological activity of a series of carboxamide derivatives of ofloxacin.

The present study was designed to help develop new agents with better antimicrobial profiles. Specifically, we focused on modification of the basic structure of ofloxacin by introducing new functionality at its C3 position. For this purpose, the carboxylic group at the C3 position of ofloxacin was replaced by an amide group through an ester aminolysis reaction. The structure of these derivatives was established by various analytical techniques i.e., IR, (1)H-NMR, (13)C-NMR CHNS elemental analysis and mass spectrometry. The antibacterial activity of ofloxacin and its derivatives against ten different Gram-positive and Gram-negative microorganisms was studied using a disk susceptibility method. These compounds were further tested for their activity against various fungi and compared to ofloxacin. The synthesized compounds showed diverse antimicrobial profiles. Among them, a few compounds possessed a comparable or better activity in comparison to the reference drug.

Simultaneous determination of piracetam and its four impurities by RP-HPLC with UV detection.

A simple and rapid high-performance liquid chromatographic method for the separation and determination of piracetam and its four impurities, 2-oxopyrrolidin-1-yl)acetic acid, pyrrolidin-2-one, methyl (2-oxopyrrolidin-1-yl)acetate, and ethyl (2-oxopyrrolidin-1-yl)acetate, was developed. The separation was achieved on a reversed-phase C(18) Nucleosil column (25 cm x 0.46 cm, 10 microm). The mobile phase is composed of an aqueous solution containing 0.2 g/L of triethyl amine-acetonitrile (85:15, v/v). The pH of the mobile phase was adjusted to 6.5 with phosphoric acid at a flow rate of 1 mL/min at ambient temperature and UV detection at 205 nm. The developed method was found to give good separation between the pure drug and its four related substance. The polynomial regression data for the calibration plots showed good linear relationship in the concentration range of 50-10,000 ng/mL, 25-10,000 ng/mL, 45-10,000 ng/mL, 34-10,000 ng/mL, and 55-10,000 ng/mL, respectively, with r(2) = 0.9999. The method was validated for precision, accuracy, ruggedness, and recovery. The minimum quantifiable amounts were found to be 50 ng/mL of piracetam, 25 ng/mL of 2-oxopyrrolidin-1-yl)acetic acid, 45 ng/mL of pyrrolidin-2-one, 34 ng/mL of methyl (2-oxopyrrolidin-1-yl)acetate, and 55 ng/mL of ethyl (2-oxopyrrolidin-1-yl)acetate. Statistical analysis proves that the method is reproducible and selective for the estimation of piracetam as well as its related substance. As the method could effectively separate the drug from the related substances, it can be employed as a stability-indicating one. The proposed method shows high efficiency, allowing the separation of the main component piracetam from other impurities.

Simultaneous determination of metformin, cimetidine, famotidine, and ranitidine in human serum and dosage formulations using HPLC with UV detection.

A new, simple, and reliable reversed-phase high-performance liquid chromatographic method has been developed and validated for the simultaneous determination of metformin (Metf), cimetidine (Cimt), famotidine (Famt), and ranitidine (Rant) in their synthetic mixtures and tablet formulations. These drugs were separated on a Purospher Star RP18 endcapped (250 mm × 4.6 mm i.d.) column packed with 5-µm particles. The mobile phase, optimized through an experimental design, consisted of methanol-water-triethylamine (20:80:0.05), whose pH was adjusted to 3.0 with phosphoric acid (85%) pumped at a flow rate of 1.0 mL/min. UV detection was performed at 229 nm. The method was validated in the sample concentration range of 5-25 µg/mL for all the drugs, where it demonstrated good linearity with r = 0.9998, 0.9979, 0.9997, and 0.9987 (n = 6), respectively. For independent 100% level samples, the intra-day and inter-day precision was in the range i.e. < 2.0 for all the drugs. The method demonstrated robustness, resisting to small deliberate changes in pH, flow rate, and composition (organic:aqueous ratio) of the mobile phase. The limit of detection values were 0.071, 0.116, 0.134, and 0.110 µg/mL, while the limit of quantitation were 0.217, 0.352, 0.405, and 0.368 µg/mL for Metf, Cimt, Famt, and Rant, respectively. The applicability of the method was demonstrated by determining the drug content in pharmaceutical formulations, where it exhibited good performance.

Postharvest hardness and color evolution of white button mushrooms (Agaricus bisporus).

UNLABELLED: The quality evaluation of mushrooms was studied by storing fresh white button mushrooms (Agaricus bisporus) for 6 to 8 d, at various controlled temperature conditions (3.5 to 15 degrees C) and measuring the instrumental textural hardness and color of the mushroom cap for different product batches. A nonlinear mixed effect Weibull model was used to describe mushroom cap texture and color kinetics during storage considering the batch variability into account. Storage temperature was found to play a significant role in controlling texture and color degradation. On lowering storage temperature (i) the extent of the final browning extent in the mushroom after storage was reduced and (ii) the rate textural hardness losses was slowed down. A linear dependence of the final browning index with temperature was found. An Arrhenius type relationship was found to exist between the temperature of storage and storage time with respect to textural hardness. The average batch energy of activation was calculated to be 207 +/- 42 kJ/mol in a temperature range of 3.5 to 20 degrees C. PRACTICAL APPLICATION: This article evaluates how temperature abuse affects mushroom texture and color, applying methods that allow for the consideration of the natural product variability that is inherent in mushrooms. Its results apply to mushroom producers, retail distribution, and supermarkets for effective storage management.

Spectrophotometric determination of gabapentin in pharmaceutical formulations using ninhydrin and pi-acceptors.

Simple, rapid and sensitive spectrophotometric procedures are developed for the analysis of gabapentin in pure form as well as in their pharmaceutical formulations. The methods are based on the reaction of gabapentin as n-electron donor with ninhydrin and pi-acceptors namely, 2,3,5,6-tetrachloro-1,4-benzoquinone, chloranilic acid, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, tetracyanoethylene and 7,7,8,8-tetracyanoquinodimethane. The obtained complexes were measured at 568, 230, 314, 304, 335 and 439 nm for ninhydrin, chloranil, Chloranilic acid, DDQ, TCNE and TCNQ respectively. The proposed procedures could be successfully applied to the determination of gabepentin with good recovery; percent ranged from 99.3 to 100.7 The association constants and free energy changes using Benesi-Hildebrand plots are also studied.

Spectrophotometric Quantitation of Metformin in Bulk Drug and Pharmaceutical Formulations using Multivariate Technique.

A sensitive and accurate UV spectrophotometric method with multivariate calibration technique for the determination of metformin hydrochloride in bulk drug and different pharmaceutical formulations has been described. This technique is based on the use of the linear regression equations by using relationship between concentration and absorbance at five different wavelength. The results were treated statistically and were found highly accurate, precise and reproducible. The method is accurate, precise (% recovery 102.50+/-0.063, CV

In vitro hypoglycemic activity of methanolic extract of some indigenous plants.

Pakistan is rich in medicinally important plants and has ancient herbal treatment methods. Present work is based on the study of six indigenous plants Eugenia jambolana, Lawsonia inermis, Momordica charantia, Morus alba, Nigella sativa and Trigonella foenum graecum which show the inhibitory effect of glucose utilization, and are in use as hypoglycemic agents of varying degree in traditional system of medicine. The glucose uptake activity of (methanolic extracts) of these plants was tested in vitro and glucose was estimated by glucose oxidase method. The results in three different media revealed that, hypoglycemic activity is more prominent in neutral and basic media as compared to acidic medium.