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1.  Determination of 17 Organophosphate Pesticide Residues in Mango by Modified QuEChERS Extraction Method Using GC-NPD/GC-MS and Hazard Index Estimation in Lucknow, India 
PLoS ONE  2014;9(5):e96493.
A total of 162 samples of different varieties of mango: Deshehari, Langra, Safeda in three growing stages (Pre-mature, Unripe and Ripe) were collected from Lucknow, India, and analyzed for the presence of seventeen organophosphate pesticide residues. The QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) method of extraction coupled with gas chromatography was validated for pesticides and qualitatively confirmed by gas chromatography- mass spectrometry. The method was validated with different concentrations of mixture of seventeen organophosphate pesticides (0.05, 0.10, 0.50 mg kg−1) in mango. The average recovery varied from 70.20% to 95.25% with less than 10% relative standard deviation. The limit of quantification of different pesticides ranged from 0.007 to 0.033 mg kg−1. Out of seventeen organophosphate pesticides only malathion and chlorpyriphos were detected. Approximately 20% of the mango samples have shown the presence of these two pesticides. The malathion residues ranged from ND-1.407 mg kg−1 and chlorpyriphos ND-0.313 mg kg−1 which is well below the maximum residues limit (PFA-1954). In three varieties of mango at different stages from unpeeled to peeled sample reduction of malathion and chlorpyriphos ranged from 35.48%–100% and 46.66%–100% respectively. The estimated daily intake of malathion ranged from 0.032 to 0.121 µg kg−1 and chlorpyriphos ranged from zero to 0.022 µg kg−1 body weight from three different stages of mango. The hazard indices ranged from 0.0015 to 0.0060 for malathion and zero to 0.0022 for chlorpyriphos. It is therefore indicated that seasonal consumption of these three varieties of mango may not pose any health hazards for the population of Lucknow, city, India because the hazard indices for malathion and chlorpyriphos residues were below to one.
PMCID: PMC4014508  PMID: 24809911
2.  Structural Changes in the Insular Cortex in Alcohol Dependence: A cross sectional study 
Iranian Journal of Psychiatry  2011;6(4):133-137.
This study was conducted to determine the changes in the insular cortex in alcohol dependent subjects, and to compare the same with controls, the associated clinical findings.
The study group consisted of 30 subjects with alcohol dependence syndrome (ADS) selected randomly from the out patient services of the department of psychiatry of a tertiary care hospital. The control group consisted of 30 matched subjects selected randomly from the out patient department and from patients screened for uncomplicated headache. Both groups were examined by a computerized scan (CT), and Mini Mental Status Examination (MMSE).
Chi square, and ‘t’ test were done after calculating the Evan's ratio. The two groups were compared to assess the cortical atrophy and ventricular enlargement. Cognitive functions were tested by MMSE, and the scores were compared. Atrophy was significantly higher in the experimental group; however, it was not significant. Cognitive functioning was found to be significantly impaired in the experimental group.
The study showed that alcohol dependence leads to cortical atrophy which is age independent. The statistically significant disturbance in the MMSE scores along with the frontal and parietal cortical atrophy is also indicative of the insular cortex involvement in the experimental group.
Alcohol dependence leads to cerebral atrophy along with the involvement of the insular cortex.
PMCID: PMC3395958  PMID: 22952538
Alcohol related disorders; Cerebral cortex; Cognition; Computed tomography
3.  Effect of Genetic Variant (rs11887534) in ABCG8 Gene in Coronary Artery Disease and Response to Atorvastatin Therapy 
Disease markers  2010;28(5):307-313.
Background: ATP-binding cassette transporter ABCG8 plays an important role in excretion of cholesterol from liver. Common genetic polymorphisms in ABCG8 gene may genetically predispose an individual to coronary artery disease (CAD) along with response to atorvastatin therapy. Thus, we aimed to examine the role of ABCG8 D19H polymorphism (rs11887534) in susceptibility to CAD and its influence on atorvastatin response.
Methodology: The study included 213 CAD patients and 220 controls. Genotyping of ABCG8 D19H polymorphism was done by PCR-RFLP.
Results: Our results showed that ABCG8 ‘H’ allele was conferring significant risk for CAD in a dominant model (OR = 2.54; p = 0.014). This increased risk for CAD was more pronounced in males (OR = 2.69; p = 0.030). No correlation of ABCG8 genotypes with the risk factors (diabetes, hypertension and smoking) of CAD was observed. On atorvastatin treatment there was a significant decrease in the LDL-C levels (p = 0.021). However, stepwise multiple regression analysis showed that this decease was not associated with ABCG8 genetic variant (p = 0.845). Observed determinants of variation in interindividual response to atorvastatin therapy were pre-treatment LDL-C (p = 0.024) and TC (p = 0.017).
Conclusion: Although the genetic variant 19H of ABCG8 confers risk for CAD in North Indian population, it is not associated with interindividual response to atorvastatin therapy.
PMCID: PMC3833422  PMID: 20592455
Coronary artery disease; polymorphism; ABCG8; Atorvastatin therapy; PCR-RFLP
4.  Plasma Prolidase Activity and Oxidative Stress in Patients with Parkinson's Disease 
Parkinson's Disease  2015;2015:598028.
Prolidase deficiency has been related to mental retardation and oxidative stress. The study aimed to observe plasma prolidase activity (PPA), total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI) in patients with Parkinson's disease (PD). 240 subjects with PD and 150 healthy volunteers were considered as cases and controls, respectively. PPA, TOS, TAS, and OSI were measured spectrophotometrically. PPA and TAS in cases were more significantly decreased than controls (P < 0.01), while TOS and OSI were significantly increased (P < 0.001). In cases, nonsignificant, positive correlation was observed between PPA and TOS and OSI while significant, negative correlation was observed between PPA and TAS (P = 0.047). PPA in cases was nonsignificantly decreased with increased duration of PD (P = 0.747) while TAS was significantly decreased (P < 0.001) and TOS and OSI were significantly increased (P < 0.001). It was observed that higher age groups had decreased PPA, and TAS and increased TOS and OSI compared to lower age groups in cases. In summary, patients with PD have decreased PPA and increased oxidative stress compared to healthy volunteers. PPA was associated with oxidative stress markers in patients with PD. Decreased PPA and TAS and increased TOS and OSI were associated with progression of disease and higher age.
PMCID: PMC4546767  PMID: 26347150
5.  A comparative clinico-radiographic study of guided tissue regeneration with bioresorbable membrane and a composite synthetic bone graft for the treatment of periodontal osseous defects 
The aim was to evaluate the bonefill in periodontal osseous defects with the help of guided tissue regeneration, bioresorbable membrane (PerioCol) + bone graft (Grabio Glascera) in combination and with bonegraft (Grabio Glascera) alone.
Materials and Methods:
The study involved total 30 sites in systemically healthy 19 patients. The parameters for evaluation includes plaque index sulcus bleeding index with one or more periodontal osseous defects having (i) probing depth (PD) of ≥ 5 mm (ii) clinical attachment loss (CAL) of ≥ 5 mm and (iii) ≥3 mm of radiographic periodontal osseous defect (iv) bonefill (v) crestal bone loss (vi) defect resolution. The study involved the three wall and two wall defects which should be either located interproximally or involving the furcation area. The statistical analysis was done using Statistical Package for Social Sciences, the Wilcoxon signed rank statistic W + for Mann–Whitney U-test.
The net gain in PD and CAL after 6 months for Group I ([PerioCol] + [Grabio Glascera]) and Group II (Grabio Glascera) was 3.94 ± 1.81 mm, 3.57 ± 2.21 mm and 3.94 ± 1.81, 3.57 ± 2.21 mm, respectively. The results of the study for Group I and Group II with regards to mean net bonefill, was 3.25 ± 2.32 (58%) mm and 5.14 ± 3.84 (40.26 ± 19.14%) mm, crestal bone loss − 0.25 ± 0.68 mm and − 0.79 ± 1.19 mm. Defect resolution 3.50 ± 2.34 mm and 5.93 ± 4.01 mm, respectively.
On comparing both the groups together after 6 months of therapy, the results were equally effective for combination of graft and membrane versus bone graft alone since no statistical significant difference was seen between above parameters for both the groups. Thus, both the treatment modalities are comparable and equally effective.
PMCID: PMC4555800  PMID: 26392691
Bioresorbable membrane; guided tissue regeneration; periodontal regeneration; synthetic bone graft
6.  ERG rearrangement and protein expression in the progression to castration-resistant prostate cancer 
Approximately half of the prostate carcinomas are characterized by a chromosomal rearrangement fusing the androgen-regulated gene TMPRSS2 to the oncogenic ETS transcription factor ERG. Aim of this study was to comprehensively analyze the role and impact of the ERG rearrangement and protein expression on the progression to castration-resistant (CR) disease.
We used a tissue microarray (TMA) constructed from 114 hormone naive (HN) and 117 CR PCs. We analyzed the ERG rearrangement status by fluorescence in situ hybridization and the expression profiles of ERG, androgen receptor (AR) and the proliferation marker Ki67 by immunohistochemistry.
Nearly half of the PC tissue specimens (HN: 38%, CR: 46%) harbored a TMPRSS2-ERG gene fusion. HN PCs with positive translocation status showed increased tumor cell proliferation (P<0.05). As expected, TMPRSS2-ERG gene fusion was strongly associated with increased ERG protein expression in HN and CR PCs (both P<0.0001). Remarkably, the study revealed a subgroup (26%) of CR PCs with ERG rearrangement but without any detectable ERG protein expression. This subgroup showed significantly lower levels of AR protein expression and androgen-regulated serum PSA (both P< 0.05).
In this study, we identified a subgroup of ERG-rearranged CR PCs without detectable ERG protein expression. Our results suggest that this subgroup could represent CR PCs with a dispensed AR pathway. These tumors might represent a thus far unrecognized subset of patients with AR-independent CR PC who may not benefit from conventional therapy directed against the AR pathway.
PMCID: PMC4097053  PMID: 24469092
castration resistance; TMPRSS2-ERG; ERG
7.  Differential Alterations in the Expression of Neurotransmitter Receptors in Inner Retina following Loss of Photoreceptors in rd1 Mouse 
PLoS ONE  2015;10(4):e0123896.
Loss of photoreceptors leads to significant remodeling in inner retina of rd1 mouse, a widely used model of retinal degeneration. Several morphological and physiological alterations occur in the second- and third-order retinal neurons. Synaptic activity in the excitatory bipolar cells and the predominantly inhibitory amacrine cells is enhanced. Retinal ganglion cells (RGCs) exhibit hyperactivity and aberrant spiking pattern, which adversely affects the quality of signals they can carry to the brain. To further understand the pathophysiology of retinal degeneration, and how it may lead to aberrant spiking in RGCs, we asked how loss of photoreceptors affects some of the neurotransmitter receptors in rd1 mouse. Using Western blotting, we measured the levels of several neurotransmitter receptors in adult rd1 mouse retina. We found significantly higher levels of AMPA, glycine and GABAa receptors, but lower levels of GABAc receptors in rd1 mouse than in wild-type. Since GABAa receptor is expressed in several retinal layers, we employed quantitative immunohistochemistry to measure GABAa receptor levels in specific retinal layers. We found that the levels of GABAa receptors in inner plexiform layer of wild-type and rd1 mice were similar, whereas those in outer plexiform layer and inner nuclear layer combined were higher in rd1 mouse. Specifically, we found that the number of GABAa-immunoreactive somas in the inner nuclear layer of rd1 mouse retina was significantly higher than in wild-type. These findings provide further insights into neurochemical remodeling in the inner retina of rd1 mouse, and how it might lead to oscillatory activity in RGCs.
PMCID: PMC4383516  PMID: 25835503
8.  Molecular Mechanism of Formation of Cortical Opacity in CRYAAN101D Transgenic Mice 
The CRYAAN101D transgenic mouse model expressing deamidated αA-crystallin (deamidation at N101 position to D) develops cortical cataract at the age of 7 to 9 months. The present study was carried out to explore the molecular mechanism that leads to the development of cortical opacity in CRYAAN101D lenses.
RNA sequence analysis was carried out on 2- and 4-month-old αA-N101D and wild type (WT) lenses. To understand the biologic relevance and function of significantly altered genes, Ingenuity Pathway Analysis (IPA) was done. To elucidate terminal differentiation defects, immunohistochemical, and Western blot analyses were carried out.
RNA sequence and IPA data suggested that the genes belonging to gene expression, cellular assembly and organization, and cell cycle and apoptosis networks were altered in N101D lenses. In addition, the tight junction signaling and Rho A signaling were among the top three canonical pathways that were affected in N101D mutant. Immunohistochemical analysis identified a series of terminal differentiation defects in N101D lenses, specifically, increased proliferation and decreased differentiation of lens epithelial cells (LEC) and decreased denucleation of lens fiber cells (LFC). The expression of Rho A was reduced in different-aged N101D lenses, and, conversely, Cdc42 and Rac1 expressions were increased in the N101D mutants. Moreover, earlier in development, the expression of major membrane-bound molecular transporter Na,K-ATPase was drastically reduced in N101D lenses.
The results suggest that the terminal differentiation defects, specifically, increased proliferation and decreased denucleation are responsible for the development of lens opacity in N101D lenses.
Previously we have shown that the lenses of mice expressing CRYAAN101D transgene develop mild cortical lens opacity at the age of 7 months. In continuation of that work, the present study elucidates a potential molecular mechanism of formation of cortical opacity in CRYAAN101D transgenic mice (N101D mutant).
PMCID: PMC4197685  PMID: 25146988
alpha A crystallin; denucleation; cortical opacity; deamidation
9.  Persistent Post-radiotherapy Pain and Locoregional Recurrence in Head and Neck Cancer-Is There a Hidden Link? 
The Korean Journal of Pain  2015;28(2):116-121.
To explore the relationship between persistent post-radiotherapy pain and locoregional recurrence in head and neck cancer patients.
Five year retrospective data was reviewed of 86 patients of head and neck cancer treated with radiotherapy who continued to have pain at 6 weeks after completion of treatment. At follow-up after 3 months, these patients were stratified into: Group A (n = 39) constituted of patients whose pain subsided and Group B (n = 47) were patients who continued to have persistent pain.
At median follow-up time of 25 months (range: 8-47), one patient (2.6%) and 18 (38.3%) patients in group A and group B had locoregional recurrence respectively (P < 0.0001). Furthermore, group B patients had higher mean pain score levels as compared to group A (P = 0.03). Patients in whom pain subsided within 3 months had statistically much greater disease-free survival in comparison to those with persistent pain (P < 0.0001).
Pain in head and neck cancer is an important symptom and should be considered a poor prognostic factor. In the current study, the majority of the patients with persistent pain had recurrent disease as compared to those in whom pain subsided within 3 months of post-treatment. It is suggested that patients with persistent pain need more intense follow-up and should be investigated thoroughly to detect recurrence at an early stage to provide a better quality of life.
PMCID: PMC4387456  PMID: 25852833
Disease-free survival; Follow-up studies; Head and neck neoplasms; Local recurrence; Pain; Quality of life
10.  Comparison of Newly Diagnosed and Relapsed Patients with Acute Promyelocytic Leukemia Treated with Arsenic Trioxide: Insight into Mechanisms of Resistance 
PLoS ONE  2015;10(3):e0121912.
There is limited data on the clinical, cellular and molecular changes in relapsed acute promyeloytic leukemia (RAPL) in comparison with newly diagnosed cases (NAPL). We undertook a prospective study to compare NAPL and RAPL patients treated with arsenic trioxide (ATO) based regimens. 98 NAPL and 28 RAPL were enrolled in this study. RAPL patients had a significantly lower WBC count and higher platelet count at diagnosis. IC bleeds was significantly lower in RAPL cases (P=0.022). The ability of malignant promyelocytes to concentrate ATO intracellularly and their in-vitro IC50 to ATO was not significantly different between the two groups. Targeted NGS revealed PML B2 domain mutations in 4 (15.38%) of the RAPL subset and none were associated with secondary resistance to ATO. A microarray GEP revealed 1744 genes were 2 fold and above differentially expressed between the two groups. The most prominent differentially regulated pathways were cell adhesion (n=92), cell survival (n=50), immune regulation (n=74) and stem cell regulation (n=51). Consistent with the GEP data, immunophenotyping revealed significantly increased CD34 expression (P=0.001) in RAPL cases and there was in-vitro evidence of significant microenvironment mediated innate resistance (EM-DR) to ATO. Resistance and relapse following treatment with ATO is probably multi-factorial, mutations in PML B2 domain while seen only in RAPL may not be the major clinically relevant cause of subsequent relapses. In RAPL additional factors such as expansion of the leukemia initiating compartment along with EM-DR may contribute significantly to relapse following treatment with ATO based regimens.
PMCID: PMC4378855  PMID: 25822503
11.  SELDI-TOF MS Whole Serum Proteomic Profiling with IMAC Surface Does Not Reliably Detect Prostate Cancer 
Clinical chemistry  2007;54(1):53-60.
The analysis of bodily fluids using SELDI-TOF MS has been reported to identify signatures of spectral peaks that can be used to differentiate patients with a specific disease from normal or control patients. This report is the 2nd of 2 companion articles describing a validation study of a SELDI-TOF MS approach with IMAC surface sample processing to identify prostatic adenocarcinoma.
We sought to derive a decision algorithm for classification of prostate cancer from SELDI-TOF MS spectral data from a new retrospective sample cohort of 400 specimens. This new cohort was selected to minimize possible confounders identified in the previous study described in the companion paper.
The resulting new classifier failed to separate patients with prostate cancer from biopsy-negative controls; nor did it separate patients with prostate cancer with Gleason scores <7 from those with Gleason scores ≥7.
In this, the 2nd stage of our planned validation process, the SELDI-TOF MS– based protein expression profiling approach did not perform well enough to advance to the 3rd (prospective study) stage. We conclude that the results from our previous studies—in which differentiation between prostate cancer and noncancer was demonstrated—are not generalizable. Earlier study samples likely had biases in sample selection that upon removal, as in the present study, resulted in inability of the technique to discriminate cancer from non-cancer cases.
PMCID: PMC4332515  PMID: 18024530
12.  Analytical platform evaluation for quantification of ERG in prostate cancer using protein and mRNA detection methods 
The established methods for detecting prostate cancer (CaP) are based on tests using PSA (blood), PCA3 (urine), and AMACR (tissue) as biomarkers in patient samples. The demonstration of ERG oncoprotein overexpression due to gene fusion in CaP has thus provided ERG as an additional biomarker. Based on this, we hypothesized that ERG protein quantification methods can be of use in the diagnosis of prostate cancer.
An antibody-free assay for ERG3 protein detection was developed based on PRISM (high-pressure high-resolution separations with intelligent selection and multiplexing)-SRM (selected reaction monitoring) mass spectrometry. We utilized TMPRSS2-ERG positive VCaP and TMPRSS2-ERG negative LNCaP cells to simulate three different sample types (cells, tissue, and post-DRE urine sediment). Enzyme-linked immunosorbent assay (ELISA), western blot, NanoString, and qRT-PCR were also used in the analysis of these samples.
Recombinant ERG3 protein spiked into LNCaP cell lysates could be detected at levels as low as 20 pg by PRISM-SRM analysis. The sensitivity of the PRISM-SRM assay was approximately 10,000 VCaP cells in a mixed cell population model of VCaP and LNCaP cells. Interestingly, ERG protein could be detected in as few as 600 VCaP cells spiked into female urine. The sensitivity of the in-house ELISA was similar to the PRISM-SRM assay, with detection of 30 pg of purified recombinant ERG3 protein and 10,000 VCaP cells. On the other hand, qRT-PCR exhibited a higher sensitivity, as TMPRSS2-ERG transcripts were detected in as few as 100 VCaP cells, in comparison to NanoString methodologies which detected ERG from 10,000 cells.
Based on this data, we propose that the detection of both ERG transcriptional products with RNA-based assays, as well as protein products of ERG using PRISM-SRM assays, may be of clinical value in developing diagnostic and prognostic assays for prostate cancer given their sensitivity, specificity, and reproducibility.
PMCID: PMC4342100  PMID: 25889691
ERG; Quantification; Biomarker; PRISM-SRM; MRM; Mass spectrometry; ELISA; Prostate cancer; Diagnosis
13.  Oxidative Stress and Major Depression 
Background: Major causative factor for major depression is inflammation, autoimmune tissue damage and prolonged psychological stress, which leads to oxidative stress. The aim of this study was to know the association of free radicals and antioxidant status in subjects suffering from major depression.
Materials and Methods: Sixty patients diagnosed as a case of unipolar depression as per DSM IV, fulfilling the inclusion and exclusion criteria were compared with 40 healthy age and sex matched controls. The sera of both the groups were collected taking aseptic precautions and were evaluated for the markers of oxidative stress and for the antioxidants. The age group of the sample and the controls was between 18-60 y, both males and females were equally represented in the groups.
Results: A significantly high level of malondialdehyde (MDA) was found in the patients with major depression (1.95 ± 1.04 mmol/L) as compared to healthy controls (0.366 ± 0.175 mmol/L) (p < 0.0001). The serum level of nitrite was found to be lower in cases (23.18 ± 12.08 μmol/L) in comparison to controls (26.18 ± 8.68 μmol/L) (p = 0.1789). Similarly the serum level of ascorbic acid and superoxide dismutase (SOD) were significantly below as compared to healthy controls (all p < 0.0001). Ceruloplasmin levels were also depressed in cases (p = 0.3943).
Conclusion: The study concluded that in the absence of known oxidative injury causative agents, the lowered levels of antioxidants and higher levels of MDA implicate the high degree of oxidative stress in unipolar depression.
PMCID: PMC4316245  PMID: 25653939
Malondialdehyde; Major depression; Nitric oxide; Reactive oxygen Species; Super oxide dismutase
14.  Transcriptomics profiling of Indian mustard (Brassica juncea) under arsenate stress identifies key candidate genes and regulatory pathways 
Arsenic (As) is a non-essential element, a groundwater pollutant, whose uptake by plants produces toxic effects. The use of As-contaminated groundwater for irrigation can affect the crop productivity. Realizing the importance of the Brassica juncea as a crop plant in terms of oil-yield, there is a need to unravel mechanistic details of response to As stress and identify key functional genes and pathways. In this research, we studied time-dependent (4–96 h) transcriptome changes in roots and shoots of B. juncea under arsenate [As(V)] stress using Agilent platform. Among the whole transcriptome profiled genes, a total of 1,285 genes showed significant change in expression pattern upon As(V) exposure. The differentially expressed genes were categorized to various signaling pathways including hormones (jasmonate, abscisic acid, auxin, and ethylene) and kinases. Significant effects were also noticed on genes related to sulfur, nitrogen, CHO, and lipid metabolisms along with photosynthesis. Biochemical assays were conducted using specific inhibitors of glutathione and jasmonate biosynthesis, and kinases. The inhibitor studies revealed interconnection among sulfur metabolism, jasmonate, and kinase signaling pathways. In addition, various transposons also constituted a part of the altered transcriptome. Lastly, we profiled a set of key functional up- and down-regulated genes using real-time RT-PCR, which could act as an early indicators of the As stress.
PMCID: PMC4541038  PMID: 26347763
arsenic; Brassica juncea; microarray; phytohormones; transporters; transposons
15.  Functionalized Graphene Sheets As Immobilization Matrix for Fenugreek β-Amylase: Enzyme Kinetics and Stability Studies 
PLoS ONE  2014;9(11):e113408.
β-Amylase finds application in food and pharmaceutical industries. Functionalized graphene sheets were customised as a matrix for covalent immobilization of Fenugreek β-amylase using glutaraldehyde as a cross-linker. The factors affecting the process were optimized using Response Surface Methodology based Box-Behnken design of experiment which resulted in 84% immobilization efficiency. Scanning and Transmission Electron Microscopy (SEM, TEM) and Fourier Tansform Infrared (FTIR) spectroscopy were employed for the purpose of characterization of attachment of enzyme on the graphene. The enzyme kinetic studies were carried out for obtaining best catalytic performance and enhanced reusability. Optimum temperature remained unchanged, whereas optimum pH showed shift towards acidic range for immobilized enzyme. Increase in thermal stability of immobilized enzyme and non-toxic nature of functionalized graphene can be exploited for production of maltose in food and pharmaceutical industries.
PMCID: PMC4239066  PMID: 25412079
16.  Coryphoid Palm Leaf Fossils from the Maastrichtian–Danian of Central India with Remarks on Phytogeography of the Coryphoideae (Arecaceae) 
PLoS ONE  2014;9(11):e111738.
Premise of research
A large number of fossil coryphoid palm wood and fruits have been reported from the Deccan Intertrappean beds of India. We document the oldest well-preserved and very rare costapalmate palm leaves and inflorescence like structures from the same horizon.
A number of specimens were collected from Maastrichtian–Danian sediments of the Deccan Intertrappean beds, Ghughua, near Umaria, Dindori District, Madhya Pradesh, India. The specimens are compared with modern and fossil taxa of the family Arecaceae.
Pivotal results
Sabalites dindoriensis sp. nov. is described based on fossil leaf specimens including basal to apical parts. These are the oldest coryphoid fossil palm leaves from India as well as, at the time of deposition, from the Gondwana- derived continents.
The fossil record of coryphoid palm leaves presented here and reported from the Eurasian localities suggests that this is the oldest record of coryphoid palm leaves from India and also from the Gondwana- derived continents suggesting that the coryphoid palms were well established and wide spread on both northern and southern hemispheres by the Maastrichtian–Danian. The coryphoid palms probably dispersed into India from Europe via Africa during the latest Cretaceous long before the Indian Plate collided with the Eurasian Plate.
PMCID: PMC4230940  PMID: 25394208
17.  In Vitro, In Silico and In Vivo Studies of Ursolic Acid as an Anti-Filarial Agent 
PLoS ONE  2014;9(11):e111244.
As part of our drug discovery program for anti-filarial agents from Indian medicinal plants, leaves of Eucalyptus tereticornis were chemically investigated, which resulted in the isolation and characterization of an anti-filarial agent, ursolic acid (UA) as a major constituent. Antifilarial activity of UA against the human lymphatic filarial parasite Brugia malayi using in vitro and in vivo assays, and in silico docking search on glutathione-s-transferase (GST) parasitic enzyme were carried out. The UA was lethal to microfilariae (mf; LC100: 50; IC50: 8.84 µM) and female adult worms (LC100: 100; IC50: 35.36 µM) as observed by motility assay; it exerted 86% inhibition in MTT reduction potential of the adult parasites. The selectivity index (SI) of UA for the parasites was found safe. This was supported by the molecular docking studies, which showed adequate docking (LibDock) scores for UA (−8.6) with respect to the standard antifilarial drugs, ivermectin (IVM −8.4) and diethylcarbamazine (DEC-C −4.6) on glutathione-s-transferase enzyme. Further, in silico pharmacokinetic and drug-likeness studies showed that UA possesses drug-like properties. Furthermore, UA was evaluated in vivo in B. malayi-M. coucha model (natural infection), which showed 54% macrofilaricidal activity, 56% female worm sterility and almost unchanged microfilaraemia maintained throughout observation period with no adverse effect on the host. Thus, in conclusion in vitro, in silico and in vivo results indicate that UA is a promising, inexpensive, widely available natural lead, which can be designed and developed into a macrofilaricidal drug. To the best of our knowledge this is the first ever report on the anti-filarial potential of UA from E. tereticornis, which is in full agreement with the Thomson Reuter's ‘Metadrug’ tool screening predictions.
PMCID: PMC4222910  PMID: 25375886
18.  Serum Prolidase Activity and Oxidative Stress in Diabetic Nephropathy and End Stage Renal Disease: A Correlative Study with Glucose and Creatinine 
Association of oxidative stress and serum prolidase activity (SPA) has been reported in many chronic diseases. The study was aimed at evaluating the correlation of glucose and creatinine to SPA and oxidative stress in patients with diabetic nephropathy (DN) and end stage renal disease (ESRD) concerned with T2DM. 50 healthy volunteers, 50 patients with T2DM, 86 patients with DN, and 43 patients with ESRD were considered as control-1, control-2, case-1, and case-2, respectively. Blood glucose, creatinine, SPA, total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI) were measured by colorimetric tests. SPA, TOS, and OSI were significantly increased in case-1 and case-2 than control-1 and control-2, while TAS was significantly decreased (P < 0.001). Blood glucose was linearly correlated to SPA, TOS, TAS, and OSI in control-2, case-1 and case-2 (P < 0.001). Serum creatinine was linearly correlated with SPA, TOS, TAS and OSI in control-2 and case-1 (P < 0.001). In case-2, serum creatinine was significantly correlated with SPA only (P < 0.001). Thus, the study concluded that SPA and oxidative stress significantly correlated with blood glucose and creatinine. SPA, TOS, TAS, and OSI can be used as biomarkers for diagnosis of kidney damage.
PMCID: PMC4172940  PMID: 25276429
19.  Predominance of ERG-negative high-grade prostate cancers in African American men 
Molecular and Clinical Oncology  2014;2(6):982-986.
Erythroblast transformation-specific-related gene (ERG) fusions, the most common and validated prostate cancer (CaP) genome alteration, result in alterations in the expression of the ERG oncoprotein. Significantly lower frequencies of ERG have been reported in tumors of African American (AA) in comparison to Caucasian American (CA) men. Building on our preliminary observations, this study has focused on the increased association of the ERG-negative status with higher-grade prostate tumors in AA men. Representative whole-mount prostate sections from a matched cohort of 63 AA and 63 CA men with Gleason scores of 4+3 and those with Gleason scores of 8–10 were analyzed for ERG oncoprotein by immunohistochemistry. The striking finding of this study was that ERG expression was 3 times more likely to be present in the higher-grade index tumors of CA men compared to AA men (31 of 63 vs. 10 of 63 patients, respectively; P<0.0001). Although the mechanisms underlying these differences have not been elucidated, the present study along with our previous observations underscores that ERG typing may enhance the understanding of ethnic differences and future targeted therapy of CaP.
PMCID: PMC4179793  PMID: 25279185
prostate cancer; erythroblast transformation-specific-related gene; transmembrane protease serine 2 gene fusion; race; ethnicity
20.  Impact of CCL2 and Its Receptor CCR2 Gene Polymorphism in North Indian Population: A Comparative Study in Different Ethnic Groups Worldwide 
Chemokine are small, inducible pro-inflammatory cytokines involved in many biological processes, such as migration of leukocytes, atherosclerosis, angiogenesis, tumor growth, and metastasis. Chemokine are also known to influence tumor cell’s activity. Specifically, tumor cells express chemokine receptors in a non random manner suggesting a role of chemokine in metastatic destination of tumor cells. The present study was conducted to determine distribution of (Chemokine receptor 2) CCR2 V64I, Chemokine ligand 2 CCL2 I/D, and CCL2 2518 A>G gene polymorphisms in North Indian population and compare with different populations globally. Polymerase chain reaction (PCR)-based analysis was conducted in 200 normal healthy individuals of similar ethnicity. Allelic frequencies in wild type (GG) of CCR2 V64I G>A were 63 % G; CCL2 I/D 42 % II; CCL2 2518 A>G 40.5 % A. The minor variant allele frequency in our population was as follows: 19.5 % for CCR2 V64I, 35.5 % for CCL2 I/D, 35.3 % for CCL2 2518 A>G. We further compared frequency distribution for these genes with various published studies in different ethnicity. Our results suggested that frequency in chemokine genes exhibit distinctive pattern in India that could be attributed to ethnicity variation. This could assist in high-risk screening of human exposed to environmental carcinogens and cancer predisposition in different ethnic groups. Thus, they signify an impact of ethnicity and provide a basis for future epidemiological and clinical studies.
PMCID: PMC3689333  PMID: 24426221
Chemokine gene; SNPs; Bladder cancer; PCR–RFLP; North India
21.  The significance of TNFAIP8 in prostate cancer response to radiation and docetaxel and disease recurrence 
TNFAIP8 is a NF-κB-inducible, oncogenic molecule. Previous “promoter array” studies have identified differential methylation and regulation of TNFAIP8 in prostate epithelial and cancer cell lines. Here we demonstrate that TNFAIP8 expression is induced by androgen in hormone-responsive LNCaP prostate cancer cells. In athymic mice bearing hormone-refractory PC-3 prostate tumor xenografts, intravenous treatment with a liposomal formulation of TNFAIP8 antisense oligonucleotide (LE-AS5) caused reduced expression of TNFAIP8 in tumor tissues, and a combination of LE-AS5 and radiation or docetaxel treatment resulted in significant inhibition of PC-3 tumor growth as compared to single agents. The immunohistochemical evaluation of TNFAIP8 expression revealed correlation of both cytoplasmic and nuclear TNFAIP8 overexpression with high grade prostatic adenocarcinomas, while nuclear overexpression was found to be an independent predictor of disease recurrence controlling for tumor grade. Increased nuclear TNFAIP8 expression was statistically significantly associated with a 2.44 fold (95 % confidence interval: 1.01–5.91) higher risk of prostate cancer recurrence. Mechanistically, TNFAIP8 seems to function as a scaffold (or adaptor) protein. In the antibody microarray analysis of proteins associated with the TNFAIP8 immune-complex, we have identified Karyopherin alpha2 as a novel binding partner of nuclear TNFAIP8 in PC-3 cells. The Ingenuity Pathway Analysis of the TNFAIP8 interacting proteins suggested that TNFAIP8 influences cancer progression pathways and networks involving integrins and matrix metalloproteinases. Taken together, present studies demonstrate that TNFAIP8 is a novel therapeutic target in prostate cancer, and indicate a potential relationship of the nuclear trafficking of TNFAIP8 with adverse outcomes in a subset of prostate cancer patients.
PMCID: PMC3620960  PMID: 23280553
prostate cancer; therapy response; prognosis; TNFAIP8; KPNA2
22.  A combined approach for the enhancement and segmentation of mammograms using modified fuzzy C-means method in wavelet domain 
In this paper, a combined approach for enhancement and segmentation of mammograms is proposed. In preprocessing stage, a contrast limited adaptive histogram equalization (CLAHE) method is applied to obtain the better contrast mammograms. After this, the proposed combined methods are applied. In the first step of the proposed approach, a two dimensional (2D) discrete wavelet transform (DWT) is applied to all the input images. In the second step, a proposed nonlinear complex diffusion based unsharp masking and crispening method is applied on the approximation coefficients of the wavelet transformed images to further highlight the abnormalities such as micro-calcifications, tumours, etc., to reduce the false positives (FPs). Thirdly, a modified fuzzy c-means (FCM) segmentation method is applied on the output of the second step. In the modified FCM method, the mutual information is proposed as a similarity measure in place of conventional Euclidian distance based dissimilarity measure for FCM segmentation. Finally, the inverse 2D-DWT is applied. The efficacy of the proposed unsharp masking and crispening method for image enhancement is evaluated in terms of signal-to-noise ratio (SNR) and that of the proposed segmentation method is evaluated in terms of random index (RI), global consistency error (GCE), and variation of information (VoI). The performance of the proposed segmentation approach is compared with the other commonly used segmentation approaches such as Otsu's thresholding, texture based, k-means, and FCM clustering as well as thresholding. From the obtained results, it is observed that the proposed segmentation approach performs better and takes lesser processing time in comparison to the standard FCM and other segmentation methods in consideration.
PMCID: PMC4154185  PMID: 25190996
Mammogram segmentation; mammogram enhancement; modified fuzzy c-means segmentation; mutual information; performance evaluation; wavelet based segmentation
23.  Functional antagonism of TMPRSS2-ERG splice variants in prostate cancer 
Genes & Cancer  2014;5(7-8):273-284.
The fusion between ERG coding sequences and the TMPRSS2 promoter is the most prevalent in prostate cancer (CaP). The presence of two main types of TMPRSS2-ERG fusion transcripts in CaP specimens, Type I and Type II, prompted us to hypothesize that the cumulative actions of different ERG variants may impact CaP development/progression. Using TMPRSS2-ERG3 (Type I) and TMPRSS2-ERG8 (Type II) expression vectors, we determined that the TMPRSS2- ERG8 encoded protein is deficient in transcriptional regulation compared to TMPRSS2-ERG3. Co-transfection of vectors resulted in decreased transcriptional regulation compared to TMPRSS2-ERG3 alone, suggesting transdominance of ERG8. Expression of exogenous ERG8 protein resulted in a decrease in endogenous ERG3 protein levels in TMPRSS2-ERG positive VCaP cells, with a concomitant decrease in C-MYC. Further, we showed a physical association between ERG3 and ERG8 in live cells by the bimolecular fluorescence complementation assay, providing a basis for the observed effects. Inhibitory effects of TMPRSS2-ERG8 on TMPRSS2- ERG3 were also corroborated by gene expression data from human prostate cancers, which showed a positive correlation between C-MYC expression and TMPRSS2-ERG3/TMPRSS2- ERG8 ratio. We propose that an elevated TMPRSS2-ERG3/TMPRSS2-ERG8 ratio results in elevated C-MYC in CaP, providing a strong rationale for the biomarker and therapeutic utility of ERG splice variants, along with C-MYC.
PMCID: PMC4162137  PMID: 25221645
ERG; Splice variants; Prostate cancer; Dominant negative; C-MYC
24.  Basal Expression of Pluripotency-Associated Genes Can Contribute to Stemness Property and Differentiation Potential 
Stem Cells and Development  2013;22(12):1802-1817.
Pluripotency and stemness is believed to be associated with high Oct-3/4, Nanog, and Sox-2 (ONS) expression. Similar to embryonic stem cells (ESCs), high ONS expression eventually became the measure of pluripotency in any cell. The threshold expression of ONS genes that underscores pluripotency, stemness, and differentiation potential is still unclear. Therefore, we raised a question as to whether pluripotency and stemness is a function of basal ONS gene expression. To prove this, we carried out a comparative study between basal ONS expressing NIH3T3 cells with pluripotent mouse bone marrow mesenchymal stem cells (mBMSC) and mouse ESC. Our studies on cellular, molecular, and immunological biomarkers between NIH3T3 and mBMSC demonstrated stemness property of undifferentiated NIH3T3 cells that was similar to mBMSC and somewhat close to ESC as well. In vivo teratoma formation with all three germ layer derivatives strengthen the fact that these cells in spite of basal ONS gene expression can differentiate into cells of multiple lineages without any genetic modification. Conclusively, our novel findings suggested that the phenomenon of pluripotency which imparts ability for multilineage cell differentiation is not necessarily a function of high ONS gene expression.
PMCID: PMC3668502  PMID: 23343006
25.  Pharmacognostical study and establishment of quality parameters of aerial parts of Costus speciosus-a well known tropical folklore medicine 
To evaluate the diagnostic pharmacognostical characters of Costus speciosus (aerial parts) along with their physico-chemical parameters and fluorosence analysis.
The pharmacognostical characters were determined in terms of macroscopy, microscopy, powder microscopy, leaf constant, fluorescence analysis and preliminary phytochemical investigation.
The findings of macroscopy revealed that leaves elliptic to oblong or oblong-lancoelate, thick, spirally arranged, with stem clasping sheaths up to 4 cm, flowers large, white, cone-like terminal spikes, with bright red bracts. Transverse section of leaflet showed the presence of cuticularised epidermis with polygonal cells on adaxial surface and bluntly angled cells on abaxial surface of lamina, mesophyll cells differentiated in to single layered palisade cells on each surface and 2-3 layered spongy parenchyma, unicellular and uniseriate multicellular covering trichomes, paracytic stomata and vascular bundles surrounded by sclerenchymatous multicellular sheath. Preliminary phytochemical screening exhibited the presence of various phytochemical groups like alkaloids, glycosides, steroids, phenolic constituents. Further, the leaf constants, powder microscopy and fluorescence characteristics indicated outstanding results from this investigation
Various pharmacognostical and physico-chemical parameters have pivotal roles in identification, authentication and establishment of quality parameters of the species.
PMCID: PMC3994359  PMID: 25182951
Costus speciosus; Quality control; Physico-chemical parameters; Microscopy; Fluorescence analysis

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