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1.  Roles of sensory nerves in the regulation of radiation-induced structural and functional changes in the heart 
International journal of radiation oncology, biology, physics  2014;88(1):10.1016/j.ijrobp.2013.10.014.
Purpose
Radiation-induced heart disease (RIHD) is a chronic severe side effect of radiotherapy of intrathoracic and chest wall tumors. The heart contains a dense network of sensory neurons that are not only involved in monitoring of cardiac events such as ischemia/reperfusion, but also play a role in cardiac tissue homeostasis, preconditioning, and repair. The purpose of this study was to examine the role of sensory nerves in RIHD.
Methods and Materials
Male Sprague-Dawley rats were administered capsaicin to permanently ablate sensory nerves, two weeks before local image-guided heart X-ray irradiation with a single dose of 21 Gy. During the 6-months follow up time, heart function was assessed with high resolution echocardiography. At 6 months after irradiation, cardiac structural and molecular changes were examined with histology, immunohistochemistry, and Western-Blots.
Results
Capsaicin-pretreatment blunted the effects of radiation on myocardial fibrosis and mast cell infiltration and activity. On the other hand, capsaicin-pretreatment caused a small but significant reduction in cardiac output at 6 months after irradiation. Capsaicin did not alter the effects of radiation on cardiac macrophage number or indicators of autophagy and apoptosis.
Conclusions
These results suggest that sensory nerves, while playing a predominantly protective role in radiation-induced cardiac function changes, may eventually enhance radiation-induced myocardial fibrosis and mast cell activity.
doi:10.1016/j.ijrobp.2013.10.014
PMCID: PMC3868013  PMID: 24331664
2.  A Novel Technique for Image-Guided Local Heart Irradiation in the Rat 
In radiotherapy treatment of thoracic, breast and chest wall tumors, the heart may be included (partially or fully) in the radiation field. As a result, patients may develop radiation-induced heart disease (RIHD) several years after exposure to radiation. There are few methods available to prevent or reverse RIHD and the biological mechanisms remain poorly understood. In order to further study the effects of radiation on the heart, we developed a model of local heart irradiation in rats using an image-guided small animal conformal radiation therapy device (SACRTD) developed at our institution. First, Monte Carlo based simulations were used to design an appropriate collimator. EBT-2 films were used to measure relative dosimetry, and the absolute dose rate at the isocenter was measured using the AAPM protocol TG-61. The hearts of adult male Sprague-Dawley rats were irradiated with a total dose of 21 Gy. For this purpose, rats were anesthetized with isoflurane and placed in a custom-made vertical rat holder. Each heart was irradiated with a 3-beam technique (one AP field and 2 lateral fields), with each beam delivering 7 Gy. For each field, the heart was visualized with a digital flat panel x-ray imager and placed at the isocenter of the 1.8 cm diameter beam. In biological analysis of radiation exposure, immunohistochemistry showed γH2Ax foci and nitrotyrosine throughout the irradiated hearts but not in the lungs. Long-term follow-up of animals revealed histopathological manifestations of RIHD, including myocardial degeneration and fibrosis. The results demonstrate that the rat heart irradiation technique using the SACRTD was successful and that surrounding untargeted tissues were spared, making this approach a powerful tool for in vivo radiobiological studies of RIHD. Functional and structural changes in the rat heart after local irradiation are ongoing.
doi:10.7785/tcrtexpress.2013.600256
PMCID: PMC3951712  PMID: 24000983
Radiation-induced heart disease; animal model; local heart irradiation; SACRTD
3.  Comparison of Dexmedetomidine, Propofol and Midazolam for Short-Term Sedation in Postoperatively Mechanically Ventilated Neurosurgical Patients 
Background: Effective management of analgesia and sedation in the intensive care unit depends on the needs of the patient, subjective and/or objective measurement and drug titration to achieve specific endpoints.
Aim: The present study compared the efficacy of dexmedetomidine, propofol and midazolam for sedation in neurosurgical patients for postoperative mechanical ventilation.
Materials and Methods: Ninety patients aged 20-65 years, ASA physical status I to III, undergoing neurosurgery and requiring postoperative ventilation were included. The patients were randomly divided into three groups of 30 each. Group D received dexmedetomidine 1 mcg/kg over 15 minutes as a loading dose, followed by 0.4-0.7 mcg/kg/h. Group P received propofol 1 mg/kg over 15 minutes as a loading dose, followed by 1-3 mg/kg/h. Group M received midazolam 0.04 mg/kg over 15 minutes as a loading dose, followed by 0.08 mg/kg/h.
Measurements: Heart rate, mean arterial pressure, sedation level, fentanyl requirement, ventilation and extubation time were recorded.
Results: Adequate sedation level was achieved with all three agents. Dexmedetomidine group required less fentanyl for postoperative analgesia. In group D there was a decrease in HR after dexmedetomidine infusion (p<0.05), but there was no significant difference in HR between group P and group M. After administration of study drug there was a significant decrease in MAP comparison to baseline value in all groups at all time intervals (p<0.05), except postextubation period (p>0.05). Extubation time was lowest in group P (p<0.05).
Conclusion: Dexmedetomidine is safer and equally effective agent compared to propofol and midazolam for sedation of neurosurgical mechanically ventilated patients with good hemodynamic stability and extubation time as rapid as propofol. Dexmedetomidine also reduced postoperative fentanyl requirements.
doi:10.7860/JCDR/2014/8797.4817
PMCID: PMC4225903  PMID: 25386451
Hemodynamic changes; Neuroprotection; Opioids
4.  Single Junction Inverted Polymer Solar Cell Reaching Power Conversion Efficiency 10.31% by Employing Dual-Doped Zinc Oxide Nano-Film as Cathode Interlayer 
Scientific Reports  2014;4:6813.
We present high efficiency and stable inverted PSCs (i-PSC) by employing sol-gel processed simultaneously doped ZnO by Indium and fullerene derivative (BisNPC60-OH) (denoted as InZnO-BisC60) film as cathode interlayer and PTB7-Th:PC71BM as the active layer (where PTB7-Th is a low bandgap polymer we proposed previously). This dual-doped ZnO, InZnO-BisC60, film shows dual and opposite gradient dopant concentration profiles, being rich in fullerene derivative at the cathode surface in contact with active layer and rich in In at the cathode surface in contact with the ITO surface. Such doping in ZnO not only gives improved surface conductivity by a factor of 270 (from 0.015 to 4.06 S cm−1) but also provides enhanced electron mobility by a factor of 132 (from 8.25*10−5 to 1.09*10−2 cm2 V−1 s−1). The resulting i-PSC exhibits the improved PCE 10.31% relative to that with ZnO without doping 8.25%. This PCE 10.31% is the best result among the reported values so far for single junction PSC.
doi:10.1038/srep06813
PMCID: PMC4212227  PMID: 25351472
5.  Reversible inhibition of lysine specific demethylase 1 is a novel anti-tumor strategy for poorly differentiated endometrial carcinoma 
BMC Cancer  2014;14(1):752.
Background
Endometrial cancer is the most common gynecologic malignancy. Type II endometrial carcinoma is often poorly differentiated and patients diagnosed with Type II disease (~11%) are disproportionately represented in annual endometrial cancer deaths (48%). Recent genomic studies highlight mutations in chromatin regulators as drivers in Type II endometrial carcinoma tumorigenesis, suggesting the use of epigenetic targeted therapies could provide clinical benefit to these patients. We investigated the anti-tumor efficacy of the LSD1 inhibitor HCI2509 in two poorly differentiated Type II endometrial cancer cell lines AN3CA and KLE.
Methods
The effects of HCI2509 on viability, proliferation, anchorage-independent growth, global histone methylation, LSD1 target gene induction, cell cycle, caspase activation and TUNEL were assayed. KLE cells were used in an orthotopic xenograft model to assess the anti-tumor activity of HCI2509.
Results
Both AN3CA and KLE cells were sensitive to HCI2509 treatment with IC50s near 500 nM for cell viability. Inhibition of LSD1 with HCI2509 caused decreased proliferation and anchorage independent growth in soft agar, elevated global histone methylation, and perturbed the cell cycle in both cell lines. These effects were largely dose-dependent. HCI2509 treatment also caused apoptotic cell death. Orthotopic implantation of KLE cells resulted in slow-growing and diffuse tumors throughout the abdomen. Tumor burden was distributed log-normally. Treatment with HCI2509 resulted 5/9 tumor regressions such that treatment and regressions were significantly associated (p = 0.034).
Conclusions
Our findings demonstrate the anti-cancer properties of the LSD1 inhibitor HCI2509 on poorly differentiated endometrial carcinoma cell lines, AN3CA and KLE. HCI2509 showed single-agent efficacy in orthotopic xenograft studies. Continued studies are needed to preclinically validate LSD1 inhibition as a therapeutic strategy for endometrial carcinoma.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-752) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2407-14-752
PMCID: PMC4197342  PMID: 25300887
6.  Ceritinib in ALK-Rearranged Non–Small-Cell Lung Cancer 
The New England journal of medicine  2014;370(13):1189-1197.
BACKGROUND
Non–small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies.
METHODS
In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib.
RESULTS
A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5).
CONCLUSIONS
Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT01283516.)
doi:10.1056/NEJMoa1311107
PMCID: PMC4079055  PMID: 24670165
7.  Inhibition of Nek2 by Small Molecules Affects Proteasome Activity 
BioMed Research International  2014;2014:273180.
Background. Nek2 is a serine/threonine kinase localized to the centrosome. It promotes cell cycle progression from G2 to M by inducing centrosome separation. Recent studies have shown that high Nek2 expression is correlated with drug resistance in multiple myeloma patients. Materials and Methods. To investigate the role of Nek2 in bortezomib resistance, we ectopically overexpressed Nek2 in several cancer cell lines, including multiple myeloma lines. Small-molecule inhibitors of Nek2 were discovered using an in-house library of compounds. We tested the inhibitors on proteasome and cell cycle activity in several cell lines. Results. Proteasome activity was elevated in Nek2-overexpressing cell lines. The Nek2 inhibitors inhibited proteasome activity in these cancer cell lines. Treatment with these inhibitors resulted in inhibition of proteasome-mediated degradation of several cell cycle regulators in HeLa cells, leaving them arrested in G2/M. Combining these Nek2 inhibitors with bortezomib increased the efficacy of bortezomib in decreasing proteasome activity in vitro. Treatment with these novel Nek2 inhibitors successfully mitigated drug resistance in bortezomib-resistant multiple myeloma. Conclusion. Nek2 plays a central role in proteasome-mediated cell cycle regulation and in conferring resistance to bortezomib in cancer cells. Taken together, our results introduce Nek2 as a therapeutic target in bortezomib-resistant multiple myeloma.
doi:10.1155/2014/273180
PMCID: PMC4182079  PMID: 25313354
8.  In Vivo Efficacy of a Synthetic Coumarin Derivative in a Murine Model of Aspergillosis 
PLoS ONE  2014;9(8):e103039.
Despite advances in therapeutic modalities, aspergillosis remains a leading cause of mortality. This has necessitated the identification of effective and safe antifungal molecules. In the present study, in vivo safety and antifungal efficacy of a coumarin derivative, N, N, N-Triethyl-11-(4-methyl-2-oxo-2H-benzopyran-7-yloxy)-11-oxoundecan-1-aminium bromide (SCD-1), was investigated. The maximum tolerable dose of compound was determined according to OECD 423 guidelines. The compound could be assigned to category IV of the Globally Harmonized System and its LD50 cut-off was found to be 2000 mg/kg body weight. The survival increased in Aspergillus fumigatus-infected mice treated with a dose of 200 mg/kg, orally or 100 mg/kg body weight, intraperitoneally, of SCD-1 in comparison to infected-untreated animals. The SCD-1 treatment resulted in significant reduction in colony counts in vital organs of the animals. Its protective effect was also observed on day 14 as there was marked reduction in fungal colonies. The treatment with SCD-1 also reduced the levels of serum biochemical parameters with respect to infected-untreated animals. It could be concluded that SCD-1 is a quite safe antifungal compound, which conferred dose dependent protection against experimental aspergillosis. Therefore, SCD-1 holds potential for developing new formulations for aspergillosis.
doi:10.1371/journal.pone.0103039
PMCID: PMC4139195  PMID: 25140804
9.  Phase II Study of Everolimus in Patients With Metastatic Colorectal Adenocarcinoma Previously Treated With Bevacizumab-, Fluoropyrimidine-, Oxaliplatin-, and Irinotecan-Based Regimens 
Purpose
Dysregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is seen in 40–60% of colorectal cancer (CRC) patients. Everolimus, an oral inhibitor of mTOR, demonstrated efficacy in metastatic CRC (mCRC) patients in phase I studies.
Experimental Design
In sequential phase II studies assessing 2 dosing schedules, mCRC patients refractory to bevacizumab-, fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens received everolimus 70 mg/week (N=99) or 10 mg/d (N=100). Primary endpoints were disease control rate (DCR) and objective response rate; secondary endpoints included progression-free survival (PFS), overall survival (OS), and duration of response or stable disease (SD). Tumor tissue was collected from all patients for predefined exploratory biomarker analyses.
Results
71 patients were included in the per protocol set for each cohort. DCRs of 31.0% and 32.4% (all SD) were seen in the weekly and daily schedules, respectively. Median duration of SD was 3.9 months in each cohort. Median PFS and OS were 1.8 months and 4.9 months and 1.8 months and 5.9 months, respectively, for the weekly and daily schedules. Among patients receiving daily everolimus, those with a KRAS mutation experienced significantly shorter median OS (P = .008) and lower DCR (P = .035) compared with those with wild-type KRAS in exploratory biomarker analyses.
Conclusions
Everolimus 70 mg/week or 10 mg/day was well tolerated but did not confer meaningful efficacy in heavily pretreated mCRC patients. Future studies may consider evaluating everolimus in combination with other agents or in patients with dysregulation of the PI3K/Akt/mTOR pathway.
doi:10.1158/1078-0432.CCR-13-0027
PMCID: PMC3725595  PMID: 23743569
Clinical trial; Colorectal cancer; Everolimus; mTOR; Phase II
10.  Effects of radiation on the epidermal growth factor receptor pathway in the heart 
Purpose
Radiation-induced heart disease (RIHD) is a serious side effect of thoracic radiotherapy. The epidermal growth factor receptor (EGFR) pathway is essential for the function and survival of cardiomyocytes. Hence, agents that target the EGFR pathway are cardiotoxic. Tocotrienols protect from radiation injury, but may also enhance the therapeutic effects of EGFR pathway inhibitors in cancer treatment. This study investigates the effects of local irradiation on the EGFR pathway in the heart and tests whether tocotrienols may modify radiation-induced changes in this pathway.
Methods
Male Sprague-Dawley rats received image-guided localized heart irradiation with 21 Gy. Twenty four hours before irradiation, rats received a single dose of tocotrienol-enriched formulation or vehicle by oral gavage. At time points from 2 hours to 9 months after irradiation, left ventricular expression of EGFR pathway mediators was studied.
Results
Irradiation caused a decrease in the expression of epidermal growth factor (EGF) and neuregulin-1 (Nrg-1) mRNA from 6 hours up to 10 weeks, followed by an upregulation of these ligands and the receptor erythroblastic leukemia viral oncogene homolog (ErbB)4 at 6 months. In addition, the upregulation of Nrg-1 was statistically significant up to 9 months after irradiation. A long-term upregulation of ErbB2 protein did not coincide with changes in transcription or post-translational interaction with the chaperone heat shock protein 90 (HSP90). Pretreatment with tocotrienols prevented radiation-induced changes at 2 weeks.
Conclusions
Local heart irradiation causes long-term changes in the EGFR pathway. Studies have to address how radiation may interact with cardiotoxic effects of EGFR inhibitors.
doi:10.3109/09553002.2013.782110
PMCID: PMC3700655  PMID: 23488537
Radiation-induced heart disease; Epidermal Growth Factor Receptor pathway; Neuregulin-1; Tocotrienols
11.  Histone deacetylase inhibitor treatment induces ‘BRCAness’ and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells 
Oncotarget  2014;5(14):5637-5650.
There is an unmet need to develop new, more effective and safe therapies for the aggressive forms of triple negative breast cancers (TNBCs). While up to 20% of women under 50 years of age with TNBC harbor germline mutations in BRCA1, and these tumors are sensitive to treatment with poly(ADP) ribose polymerase inhibitors, a majority of TNBCs lack BRCA1 mutations or loss of expression. Findings presented here demonstrate that by attenuating the levels of DNA damage response and homologous recombination proteins, pan-histone deacetylase inhibitor (HDI) treatment induces ‘BRCAness’ and sensitizes TNBC cells lacking BRCA1 to lethal effects of PARP inhibitor or cisplatin. Treatment with HDI also induced hyperacetylation of nuclear hsp90. Similar effects were observed following shRNA-mediated depletion of HDAC3, confirming its role as the deacetylase for nuclear HSP90. Furthermore, cotreatment with HDI and ABT-888 induced significantly more DNA strand breaks than either agent alone, and synergistically induced apoptosis of TNBC cells. Notably, co-treatment with HDI and ABT-888 significantly reduced in vivo tumor growth and markedly improved the survival of mice bearing TNBC cell xenografts. These findings support the rationale to interrogate the clinical activity of this novel combination against human TNBC, irrespective of its expression of mutant BRCA1.
PMCID: PMC4170637  PMID: 25026298
HDAC inhibitor; Triple Negative Breast Cancer; PARP inhibitor; BRCAness
12.  Neuro-cognitive functioning in unaffected siblings of patients with bipolar disorder: Comparison with bipolar patients and healthy controls 
Indian Journal of Psychiatry  2014;56(3):283-288.
Aim:
Neurocognitive tests can provide reliable endophenotypes for bipolar disorder (BD). The aim of this study was to compare the neurocognitive functioning of unaffected siblings of patients of bipolar affective disorder (BPAD) with that of patients with BD and a group of healthy controls.
Materials and Methods:
A total of 20 unaffected siblings of patients with BD-I, 20 patients of BD-I who were currently in remission and a group of 20 healthy control subjects were assessed for neurocognitive functions using Wisconsin Card Sorting Test, Brief Visuospatial Memory Test-Revised, Hopkins Verbal Learning Test-Revised and Wechsler Adult Intelligence Scale Digit Symbol Test.
Results:
Compared to healthy controls, unaffected siblings of patients with BD performed poorly on tests of verbal learning, but no significant differences were seen between the two groups for executive functions, visual learning and psychomotor speed, concentration and graphomotor abilities. Compared to unaffected siblings, patients with BD performed poorly on the tests of executive functions, visual memory, verbal memory, psychomotor speed, concentration, and graphomotor abilities.
Conclusion:
Verbal memory can serve as an endophenotype of bipolar disorder.
doi:10.4103/0019-5545.140645
PMCID: PMC4181184  PMID: 25316940
Bipolar disorder; cognitive functions; endophenotype; unaffected siblings
13.  Mechanism and relevance of EWS/FLI-mediated transcriptional repression in Ewing sarcoma 
Oncogene  2012;32(42):5089-5100.
Ewing sarcoma provides an important model for transcription-factor mediated oncogenic transformation because of its reliance on the ETS-type fusion oncoprotein EWS/FLI. EWS/FLI functions as a transcriptional activator and transcriptional activation is required for its oncogenic activity. Here we demonstrate that a previously less-well characterized transcriptional repressive function of the EWS/FLI fusion is also required for the transformed phenotype of Ewing sarcoma. Through comparison of EWS/FLI transcriptional profiling and genome-wide localization data, we define the complement of EWS/FLI direct downregulated target genes. We demonstrate that LOX is a previously undescribed EWS/FLI-repressed target that inhibits the transformed phenotype of Ewing sarcoma cells. Mechanistic studies demonstrate that the NuRD co-repressor complex interacts with EWS/FLI, and that its associated histone deacetylase and LSD1 activities contribute to the repressive function. Taken together, these data reveal a previously unknown molecular function for EWS/FLI, demonstrate a more highly coordinated oncogenic transcriptional hierarchy mediated by EWS/FLI than previously suspected, and implicate a new paradigm for therapeutic intervention aimed at controlling NuRD activity in Ewing sarcoma tumors.
doi:10.1038/onc.2012.525
PMCID: PMC3899696  PMID: 23178492
Ewing sarcoma; EWS/FLI; NuRD; transcription; repression
14.  Mechanistic studies of FosB: a divalent-metal-dependent bacillithiol-S-transferase that mediates fosfomycin resistance in Staphylococcus aureus 
The Biochemical journal  2013;451(1):69-79.
FosB is a divalent-metal-dependent thiol-S-transferase implicated in fosfomycin resistance among many pathogenic Gram-positive bacteria. In the present paper, we describe detailed kinetic studies of FosB from Staphylococcus aureus (SaFosB) that confirm that bacillithiol (BSH) is its preferred physiological thiol substrate. SaFosB is the first to be characterized among a new class of enzyme (bacillithiol-S-transferases), which, unlike glutathione transferases, are distributed among many low-G + C Gram-positive bacteria that use BSH instead of glutathione as their major low-molecular-mass thiol. The Km values for BSH and fosfomycin are 4.2 and 17.8 mM respectively. Substrate specificity assays revealed that the thiol and amino groups of BSH are essential for activity, whereas malate is important for SaFosB recognition and catalytic efficiency. Metal activity assays indicated that Mn2+ and Mg2+ are likely to be the relevant cofactors under physiological conditions. The serine analogue of BSH (BOH) is an effective competitive inhibitor of SaFosB with respect to BSH, but uncompetitive with respect to fosfomycin. Coupled with NMR characterization of the reaction product (BS– fosfomycin), this demonstrates that the SaFosB-catalysed reaction pathway involves a compulsory ordered binding mechanism with fosfomycin binding first followed by BSH which then attacks the more sterically hindered C-1 carbon of the fosfomycin epoxide. Disruption of BSH biosynthesis in S. aureus increases sensitivity to fosfomycin. Together, these results indicate that SaFosB is a divalent-metal-dependent bacillithiol-S-transferase that confers fosfomycin resistance on S. aureus.
doi:10.1042/BJ20121541
PMCID: PMC3960972  PMID: 23256780
antibiotic detoxification; bacillithiol; metalloenzyme; substrate mimic
15.  Heavy Metal Levels in Adolescent and Maternal Blood: Association with Risk of Hypospadias 
ISRN Pediatrics  2014;2014:714234.
Background. Hypospadias is a part of testicular digenesis syndrome (TDS) which includes infertility, cryptorchidism, and spermatogenesis. Heavy metals act as endocrine disrupting compounds. Heavy metals such as cadmium, chromium, arsenic, and lead have been associated with male infertility, cryptorchidism, spermatogenesis, cancer, reproductive disorder, and neurological disorder. However, it remains an important issue to corroborate or refute the hypothesis that the role of heavy metals in male reproductive tract disorders. Hence, the present study was designed to investigate the possible association of heavy metal and risk of hypospadias by estimating the blood heavy metal levels. Methods. In this case control study, 50 hypospadias boys diagnosed and confirmed by a pediatric urologist and 50 randomly selected age-matched (1–5 years) healthy control boys not suffering from any clinically detectible illness and their mothers have been included and heavy metal levels in the blood of these subjects have been estimated by Atomic Absorption Spectrophotometer (AAS). Result. Significantly high levels of cadmium and lead have been observed in hypospadias cases; however, all heavy metal levels were present in higher concentration. Conclusion. Higher blood levels of cadmium and lead may be associated with the increased risk of hypospadias.
doi:10.1155/2014/714234
PMCID: PMC3960776  PMID: 24729887
16.  Unusual presentation of a culture-positive right atrial mass 
We report a patient with a mass in the right atrium which led to pulmonary embolism. Postoperatively the mass was identified as a tuberculoma and it was culture-positive for Mycobacterium tuberculosis. Patient responded to modified antitubercular treatment and discharged from hospital in satisfactory condition.
doi:10.1016/j.jcdr.2013.02.009
PMCID: PMC3758083  PMID: 24023479
Antemortem diagnosis; Mycobacterium tuberculosis; Myocardial tuberculosis; Right atrial tuberculoma
17.  Spaces of Ideal Convergent Sequences 
The Scientific World Journal  2014;2014:134534.
In the present paper, we introduce some sequence spaces using ideal convergence and Musielak-Orlicz function ℳ = (Mk). We also examine some topological properties of the resulting sequence spaces.
doi:10.1155/2014/134534
PMCID: PMC3925588  PMID: 24592143
18.  Patient Aesthetic Satisfaction with Timing of Nasal Fracture Manipulation 
Surgery Research and Practice  2014;2014:238520.
Introduction. To determine patient cosmetic satisfaction following nasal fracture manipulation under general anaesthetic when offered at different time intervals after injury. Materials and Methods. Prospective chart review of adult patients with nasal fractures treated by closed reduction at a busy district general hospital in Greater London over a 10-month period. Patients were asked by a standardised telephone interview about satisfaction with nasal cosmesis pre- and postoperatively using a Likert scale. Results. Seventy-six of 106 patients presented for nasal manipulation at up to 9 weeks after injury and were successfully contacted (72%) postoperatively. Forty-nine patients (64%) reported that they still would have had the surgery in retrospect. Those done within 1-2 weeks after injury resulted in the highest mean satisfaction score (4.56 ± 0.25). There was a negative correlation between patient satisfaction and timing of surgery (ρ = −0.37, P = 0.001). Of the patients satisfied or very satisfied with their procedure, 96% had it done within 4 weeks. Conclusion. The majority of patients treated with closed reduction of nasal fractures under general anaesthetic are satisfied with the cosmetic outcome and would still have undergone surgery in retrospect. Increasing time of surgery after 2 weeks resulted in lower patient satisfaction.
doi:10.1155/2014/238520
PMCID: PMC4208588  PMID: 25374948
19.  A Group Intervention for HIV/STI Risk Reduction among Indian Couples 
Health Promotion Perspectives  2013;3(2):137-146.
Background: HIV in India is transmitted primarily by heterosexual contact. The present study sought to test the feasibility of a group HIV/STI risk re­duction intervention among heterosexual couples in India.
Methods: Focus groups and key informant interviews were used in 2008 to cul­turally tailor the intervention. Thirty sexually active and HIV/STI negative cou­ples were enrolled and assessed regarding risk behavior and sexual barrier accept­ability. Gender-concordant group sessions used cognitive behavioral strategies for HIV/STI prevention.
Results: At baseline, male condom use was low (36%); no participants re­ported use of female condoms or vaginal gels. HIV knowledge was low; women had more HIV knowledge and more positive attitudes towards con­dom use than men. Post-intervention, willingness to use all barrier products (t = 10.0, P< .001) and intentions to avoid risk behavior increased (t = 5.62, P< .001).
Conclusion: This study illustrates the feasibility of utilizing a group interven­tion to enhance HIV/STI risk reduction among Indian couples.
doi:10.5681/hpp.2013.017
PMCID: PMC3963661  PMID: 24688963
Sexual barrier; HIV; STI; Intervention; India
20.  In Vivo Assessment of Antihyperglycemic and Antioxidant Activity from Oil of Seeds of Brassica Nigra in Streptozotocin Induced Diabetic Rats 
Advanced Pharmaceutical Bulletin  2013;3(2):359-365.
Purpose: This study was made to investigate the antihyperglycemic and antioxidant potential of oil of seeds of Brassica nigra (BNO) in streptozotocin -nicotinamide (STZ) induced type 2 diabetic rats. Methods: BNO was orally administered to diabetic rats to study its effect in both acute and chronic antihyperglycemic study. The body weight, oral glucose tolerance test and biochemical parameters viz. glucose level, insulin level, liver glycogen content, glycosylated hemoglobin and antioxidant parameters were estimated for all treated groups and compared against diabetic control group. Results: Administration of BNO at a dose 500 mg/kg and 1000 mg/kg body weight p.o. to STZ diabetic rats showed reduction in blood glucose level from 335 mg/dl to 280 mg/dl at 4th h and from 330 mg/dl to 265 mg/dl respectively which was found significant (p<0.01) as compared with diabetic control. BNO (500 mg/kg and 1000 mg/kg) and glibenclamide (0.6 mg/kg) in respective groups of diabetic animals administered for 28 days reduced the blood glucose level in streptozotocin-nicotinamide induced diabetic rats. There was significant increase in body weight, liver glycogen content, plasma insulin level and decrease in glycosylated hemoglobin in test groups as compared to control group. In vivo antioxidant studies on STZ-nicotinamide induced diabetic rat’s revealed decreased malondialdehyde (MDA) and increased reduced glutathione (GSH). Conclusion: Thus the results showed that the oil of seeds of Brassica nigra has significant antihyperglycemic and antioxidant activity.
doi:10.5681/apb.2013.058
PMCID: PMC3848242  PMID: 24312861
Brassica nigra; Seeds; Streptozotocin; Essential oil; MDA
21.  Cardiac inflammation after local irradiation is influenced by the kallikrein-kinin system 
Cancer research  2012;72(19):4984-4992.
Radiotherapy of intrathoracic and chest wall tumors may lead to exposure of the heart to ionizing radiation, resulting in radiation-induced heart diseases (RIHD). The main manifestations of RIHD become apparent many years after treatment and include cardiomyopathy and accelerated atherosclerosis. This study examines the role of the kallikrein-kinin system (KKS) in RIHD by investigating the cardiac radiation response in a kininogen-deficient Brown Norway Katholiek (BN/Ka) rat model. BN/Ka rats and wild-type Brown Norway (BN) rats were exposed to local heart irradiation with a single dose of 18 Gy or 24 Gy and were observed for 3-6 months. Examinations included in vivo and ex vivo cardiac function, histopathology, gene and protein expression measurements, and mitochondrial swelling assays. Upon local heart irradiation, changes in in vivo cardiac function were significantly less in BN/Ka rats. For instance, a single dose of 24 Gy caused a 35% increase in fractional shortening in BN rats compared to a 16% increase in BN/Ka rats. BN rats, but not BN/Ka rats, showed a 56% reduction in cardiac numbers of CD2-positive cells, and a 57% increase in CD68-positive cells, together with a 52% increase in phosphorylation of Erk1/2. Local heart irradiation had similar effects on histopathology, mitochondrial changes, and left ventricular mRNA levels of NADPH oxidases in the two genotypes. These results suggest that the KKS plays a role in the effects of radiation on cardiac function and recruitment of inflammatory cells. The KKS may have these effects at least in part by altering Erk1/2 signaling.
doi:10.1158/0008-5472.CAN-12-1831
PMCID: PMC3463770  PMID: 22865451
Radiation-induced heart disease; Kallikrein-kinin system; Bradykinin
22.  Comparison of Shear Bond Strength and Estimation of Adhesive Remnant Index between Light-cure Composite and Dual-cure Composite: An in vitro Study 
ABSTRACT
Aims and objectives: To measure and compare the shear bond strength and adhesive remnant index of light-cure composite. (Enlight, Ormco.) and dual-cure composite (Phase II dual cure, Reliance Ortho).
Materials and methods: Sixty extracted human premolar teeth were divided into two groups: group I (blue): conventional light cure composite resin. (Enlight, Ormco.) and group II (green): dual cure composite resin. (Phase II dual cure, Reliance Ortho.) with 30 teeth in each group. These samples were tested on the universal testing machine to measure the shear bond strength.
Results: Student t-test showed that the mean shear bond strength of the conventional light cure group (8.54 MPa - 10.42 MPa) was significantly lower than dual cure group (10.45 MPa -12.17 MPa).
Conclusion: These findings indicate that the shear bond strength of dual-cure composite resin (Phase II dual cure, Reliance Ortho) is comparatively higher than conventional light-cure composite resin (Enlight, Ormco). In the majority of the samples, adhesive remnant index (ARI) scores were 4 and 5 in both the groups whereas score 1 is attained by the least number of samples in both the groups.
How to cite this article: Verma G, Trehan M, Sharma S. Comparison of Shear Bond Strength and Estimation of Adhesive Remnant Index between Light-cure Composite and Dual-cure Composite: An in vitro Study. Int J Clin Pediatr Dent 2013;6(3):166-170.
doi:10.5005/jp-journals-10005-1212
PMCID: PMC4086599  PMID: 25206216
Light-cure; Dual-cure; Shear bond strength; Adhesive remnant index
23.  SS18-SSX2 and the mitochondrial apoptosis pathway in mouse and human synovial sarcomas 
Oncogene  2012;32(18):2365-2375.e5.
Synovial sarcoma is a deadly malignancy with limited sensitivity to traditional cytotoxic chemotherapy. SS18-SSX fusion oncogene expression characterizes human synovial sarcomas and drives oncogenesis in a mouse model. Elevated expression of BCL2 is considered a consistent feature of the synovial sarcoma expression profile. Our objective was to evaluate the expression of apoptotic pathway members in synovial sarcomas and interrogate the impact of modulating SS18-SSX expression on this pathway. We show in human and murine synovial sarcoma cells that SS18-SSX increases BCL2 expression, but represses other anti-apoptotic genes, including MCL1 and BCL2A1. This repression is achieved by directly suppressing expression via binding through ATF2 to the cyclic AMP response element in the promoters of these genes and recruiting TLE1/Groucho. The suppression of these two anti-apoptotic pathways silences the typical routes by which other tumors evade BH3-domain peptidomimetic pharmacotherapy. We show that mouse and human synovial sarcoma cells are sensitive in vitro to ABT-263, a BH3-peptidomimetic, much more so than are other tested cancer cell lines. ABT-263 also enhances the sensitivity of these cells to doxorubicin, a traditional cytotoxic chemotherapy used for synovial sarcoma. We also demonstrate the capacity of ABT-263 to stunt synovial sarcomagenesis in vivo in a genetic mouse model. These data recommend pursuit of BH3-peptidomimetic pharmacotherapy in human synovial sarcomas.
doi:10.1038/onc.2012.247
PMCID: PMC3756901  PMID: 22797074
synovial sarcoma; apoptosis; chemotherapy; targeted therapy; mouse model
24.  Effects of Late Administration of Pentoxifylline and Tocotrienols in an Image-Guided Rat Model of Localized Heart Irradiation 
PLoS ONE  2013;8(7):e68762.
Radiation-induced heart disease (RIHD) is a long-term side effect of radiotherapy of intrathoracic, chest wall and breast tumors when radiation fields encompass all or part of the heart. Previous studies have shown that pentoxifylline (PTX) in combination with α-tocopherol reduced manifestations of RIHD in rat models of local heart irradiation. The relative contribution of PTX and α-tocopherol to these beneficial effects are not known. This study examined the effects of PTX alone or in combination with tocotrienols, forms of vitamin E with potential potent radiation mitigation properties. Rats received localized X-irradiation of the heart with an image-guided irradiation technique. At 3 months after irradiation rats received oral treatment with vehicle, PTX, or PTX in combination with a tocotrienol-enriched formulation. At 6 months after irradiation, PTX-treated rats showed arrhythmia in 5 out of 14 animals. PTX alone or in combination with tocotrienols did not alter cardiac radiation fibrosis, left ventricular protein expression of the endothelial markers von Willebrand factor and neuregulin-1, or phosphorylation of the signal mediators Akt, Erk1/2, or PKCα. On the other hand, tocotrienols reduced cardiac numbers of mast cells and macrophages, but enhanced the expression of tissue factor. While this new rat model of localized heart irradiation does not support the use of PTX alone, the effects of tocotrienols on chronic manifestations of RIHD deserve further investigation.
doi:10.1371/journal.pone.0068762
PMCID: PMC3718790  PMID: 23894340
25.  Spatially Fractionated Radiation Induces Cytotoxicity and Changes in Gene Expression in Bystander and Radiation Adjacent Murine Carcinoma Cells 
Radiation Research  2012;177(6):751-765.
Radiation-induced bystander effects have been extensively studied at low doses, since evidence of bystander induced cell killing and other effects on unirradiated cells were found to be predominant at doses up to 0.5 Gy. Therefore, few studies have examined bystander effects induced by exposure to higher doses of radiation, such as spatially fractionated radiation (GRID) treatment. In the present study, we evaluate the ability of GRID treatment to induce changes in GRID adjacent (bystander) regions, in two different murine carcinoma cell lines following exposure to a single irradiation dose of 10 Gy. Murine SCK mammary carcinoma cells and SCCVII squamous carcinoma cells were irradiated using a brass collimator to create a GRID pattern of nine circular fields 12 mm in diameter with a center-to-center distance of 18 mm. Similar to the typical clinical implementation of GRID, this is approximately a 50:50 ratio of direct and bystander exposure. We also performed experiments by irradiating separate cultures and transferring the medium to unirradiated bystander cultures. Clonogenic survival was evaluated in both cell lines to determine the occurrence of radiation-induced bystander effects. For the purpose of our study, we have defined bystander cells as GRID adjacent cells that received approximately 1 Gy scatter dose or unirradiated cells receiving conditioned medium from irradiated cells. We observed significant bystander killing of cells adjacent to the GRID irradiated regions compared to sham treated controls. We also observed bystander killing of SCK and SCCVII cells cultured in conditioned medium obtained from cells irradiated with 10 Gy. Therefore, our results confirm the occurrence of bystander effects following exposure to a high-dose of radiation and suggest that cell-to-cell contact is not required for these effects. In addition, the gene expression profile for DNA damage and cellular stress response signaling in SCCVII cells after GRID exposure was studied. The occurrence of GRID-induced bystander gene expression changes in significant numbers of DNA damage and cellular stress response signaling genes, providing molecular evidence for possible mechanisms of bystander cell killing.
PMCID: PMC3395590  PMID: 22559204

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