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1.  Suitability of self-collected vaginal samples for cervical cancer screening in peri-urban villages in Andhra Pradesh, India 
Objectives:
Our aim was to determine if (1) Hybrid Capture 2 and a PCR-based method were comparable for detection of high-risk HPVs, (2) clinician-collected and self-collected samples were equally efficient to detect HPV and cervical cancer precursor lesions and (3) if participation rates improved with home-based vs. clinic-based self collection.
Methods:
Samples were selected from women participating in a cervical cancer screening study according to human papillomavirus (HPV), visual inspection with acetic acid (VIA), or Pap smear screening results. From 432 of 892 selected women, split sample aliquots were tested for HPV DNA using both the Hybrid Capture 2 assay and the Roche prototype line blot assay. Women from a subset of villages were recruited at two separate time points for clinic-based self-collection and home-based self-collection, and participation rates were compared.
Results:
Pairwise agreement between self- and clinician-collected samples was high by both hc2 (90.8% agreement, kappa=0.7) and PCR (92.6% agreement, kappa=0.8), with significantly increased high-risk HPV detection in clinician-collected specimens (McNemar's p<0.01). Ability to detect precursor lesions was highest by PCR testing of clinician-collected samples and lowest by Hybrid Capture 2 testing of self-collected samples (11/11 and 9/11 cases of cervical intraepithelial neoplasia grade 2/3 and cancer detected, respectively). Participation in home-based screening was significantly higher than clinic-based screening (71.5% and 53.8%, respectively; p<0.001) among women 30-45 years old.
Conclusion:
The combination of improved screening coverage and a high single test sensitivity afforded by HPV DNA testing of home-based self-collected swabs may have a greater programmatic impact on cervical cancer mortality reduction compared to programs requiring a pelvic exam.
doi:10.1158/1055-9965.EPI-08-1171
PMCID: PMC2762740  PMID: 19423518
2.  Purification and characterization of cysteine protease from germinating cotyledons of horse gram 
BMC Biochemistry  2009;10:28.
Background
Proteolytic enzymes play central role in the biochemical mechanism of germination and intricately involved in many aspects of plant physiology and development. To study the mechanism of protein mobilization, undertaken the task of purifying and characterizing proteases, which occur transiently in germinating seeds of horse gram.
Results
Cysteine protease (CPRHG) was purified to homogeneity with 118 fold by four step procedure comprising Crude extract, (NH4)2SO4 fractionation, DEAE-Cellulose and CM-sephacel chromatography from the 2 day germinating cotyledons of horse gram (Macrotyloma uniflorum (Lam.) Verdc.). CPRHG is a monomer with molecular mass of 30 k Da, was determined by SDS-PAGE and gel filtration. The purified enzyme on IEF showed two isoforms having pI values of 5.85 and 6.1. CPRHG composed of high content of aspartic acid, glutamic acid and serine. The enzyme activity was completely inhibited by pCMB, iodoacetate and DEPC indicating cysteine and histidine residues at the active site. However, on addition of sulfhydryl reagents (cysteine, dithiothreitol, glutathione and beta-ME) reverse the strong inhibition by pCMB. The enzyme is fairly stable toward pH and temperature. Immunoblot analysis shows that the enzyme synthesized as zymogen (preproenzyme with 81 kDa) and processed to a 40 kDa proenzyme which was further degraded to give 30 kDa active enzyme.
Conclusion
It appears that the newly synthesized protease is inactive, and activation takes place during germination. CPRHG has a broad substrate specificity and stability in pH, temperature, etc. therefore, this protease may turn out to be an efficient choice for the pharmaceutical, medicinal, food, and biotechnology industry.
doi:10.1186/1471-2091-10-28
PMCID: PMC2784799  PMID: 19919695
3.  Hyperkalemia masking left ventricular hypertrophy in electrocardiogram in a patient with end-stage renal disease 
Indian Journal of Nephrology  2008;18(1):22-23.
A patient of severe chronic renal failure presented with hyperkalemic electrocardiographic (ECG) changes and hyperkalemia. Following a session of hemodialysis, when he reverted to normokalemia, the repeat ECG revealed left ventricular hypertrophy (LVH). Thus we confronted with a situation of hyperkalemia, masking the LVH on ECG initially and when the hyperkalemia was corrected with dialysis the LVH showed in ECG. The plausible explanation for this electrophysiological behaviour was offered.
doi:10.4103/0971-4065.41284
PMCID: PMC2847725  PMID: 20368916
Electrocardiography; end stage renal disease; hyperkalemia; left ventricular enlargement
5.  Interleukin 22 Inhibits Intracellular Growth of Mycobacterium tuberculosis by Enhancing Calgranulin A Expression 
The Journal of Infectious Diseases  2013;209(4):578-587.
Previously, we found that interleukin 22 (IL-22) inhibits intracellular growth of Mycobacterium tuberculosis in human monocyte–derived macrophages (MDMs). In the current study, we determined the mechanisms underlying these effects. We found that W7, a phagolysosomal fusion inhibitor, abrogates IL-22–dependent M. tuberculosis growth inhibition in MDMs, suggesting that IL-22 acts through enhanced phagolysosomal fusion. Our microarray analysis indicated that recombinant IL-22 (rIL-22) enhances the expression of an intracellular signaling molecule, calgranulin A. This was confirmed by real-time polymerase chain reaction, Western blot, and confocal microscopy. Calgranulin A small interfering RNA (siRNA) abrogated rIL-22–dependent growth inhibition of M. tuberculosis in MDMs. IL-22 enhanced Rab7 expression and downregulated Rab14 expression of M. tuberculosis–infected MDMs, and these effects were reversed by calgranulin A siRNA. These results suggest that M. tuberculosis growth inhibition by IL-22 depends on calgranulin A and enhanced phagolysosomal fusion, which is associated with increased Rab7 and reduced Rab14 expression.
doi:10.1093/infdis/jit495
PMCID: PMC3903372  PMID: 24041785
tuberculosis; Human; Cytokine; IL-22
6.  Draft Genome Sequence of the Extremely Halophilic Bacterium Halomonas salina Strain CIFRI1, Isolated from the East Coast of India 
Genome Announcements  2015;3(1):e01321-14.
Halomonas salina strain CIFRI1 is an extremely salt-stress-tolerant bacterium isolated from the salt crystals of the east coast of India. Here we report the annotated 3.45-Mb draft genome sequence of strain CIFRI1 having 86 contigs with 3,139 protein coding loci, including 62 RNA genes.
doi:10.1128/genomeA.01321-14
PMCID: PMC4290979  PMID: 25573926
7.  Processing, physico-chemical, sensory and nutritional evaluation of protein, mineral and vitamin enriched peanut chikki - an Indian traditional sweet 
Chikki, a popular Indian traditional sweet snack prepared from peanut was enriched with protein, minerals and vitamins by incorporating soy protein isolate, calcium carbonate, ferrous fumerate, vitamin A and folic acid to meet the growing demand for health foods. The enriched nutra chikki was evaluated for physico-chemical characteristics such as moisture, texture, peroxide value (PV), fatty acid composition in comparison with control peanut chikki. Nutra chikki, which had initial moisture content of 2–3%, did not alter much up to 60 days of storage at 27 °C and 37 °C. PV increased gradually at 27 °C, whereas at 37 °C, it was higher. Hardness of nutra chikki did not change significantly when stored at 27 °C up to 105 days, but at 37 °C a gradual increase in hardness was observed after 45 days. These results of nutra chikki were similar and comparable with those of control chikki. Nutra chikki had 18% protein, 20% fat, 6.42% Ca, 1.7% Fe, 4000 μg vitamin A and 2660 μg folic acid. Protein digestibility corrected amino acid score of nutra chikki was 0.78 whereas that of control chikki was 0.73. The fatty acid composition of control and nutra chikki was same as both contain peanuts as oil source. The formulation and process parameters for preparation of protein, mineral and vitamin enriched peanut chikki, were standardized. The storage stability and quality parameters of enriched chikki were comparable with those of control chikki.
doi:10.1007/s13197-011-0467-0
PMCID: PMC3857401  PMID: 24426063
Peanut chikki; Fortified chikki; Protein enriched chikki; Processing; Sensory evaluation
8.  Physico-chemical characteristics of burfi prepared by using medium chain triglyceride rich margarines 
Medium chain triglyceride rich margarines were prepared using palm, coconut oil blends in the ratio of 80:20 (Margarine 1) and 60:40 (Margarine 2). The margarines were used to prepare burfi and compared with products prepared using commercial margarine, ghee and butter. The physicochemical characteristics such as texture, color, free fatty acid, peroxide value, saponification value, unsaponifiable matter and fatty acid composition of oils, fats and margarines were carried out. Results showed that 11.0 and 21.9% of medium chain triglycerides were present in margarine 1 and 2 respectively. The texture, colour, moisture content, peroxide value and sensory evaluation were carried out for the burfi samples. Laboratory prepared margarines improved the textural quality of burfi compared to commercial margarine, ghee and butter. The sensory analyses of the burfi samples revealed that burfi prepared from margarine 1 was more acceptable compared to commercial margarine.
doi:10.1007/s13197-011-0478-x
PMCID: PMC3857410  PMID: 24426059
Margarine; Burfi; Medium chain triglyceride
9.  The Relevance of the Colon to Zinc Nutrition 
Nutrients  2015;7(1):572-583.
Globally, zinc deficiency is widespread, despite decades of research highlighting its negative effects on health, and in particular upon child health in low-income countries. Apart from inadequate dietary intake of bioavailable zinc, other significant contributors to zinc deficiency include the excessive intestinal loss of endogenously secreted zinc and impairment in small intestinal absorptive function. Such changes are likely to occur in children suffering from environmental (or tropical) enteropathy (EE)—an almost universal condition among inhabitants of developing countries characterized by morphologic and functional changes in the small intestine. Changes to the proximal gut in environmental enteropathy will likely influence the nature and amount of zinc delivered into the large intestine. Consequently, we reviewed the current literature to determine if colonic absorption of endogenous or exogenous (dietary) zinc could contribute to overall zinc nutriture. Whilst we found evidence that significant zinc absorption occurs in the rodent colon, and is favoured when microbially-fermentable carbohydrates (specifically resistant starch) are consumed, it is unclear whether this process occur in humans and/or to what degree. Constraints in study design in the few available studies may well have masked a possible colonic contribution to zinc nutrition. Furthermore these few available human studies have failed to include the actual target population that would benefit, namely infants affected by EE where zinc delivery to the colon may be increased and who are also at risk of zinc deficiency. In conducting this review we have not been able to confirm a colonic contribution to zinc absorption in humans. However, given the observations in rodents and that feeding resistant starch to children is feasible, definitive studies utilising the dual stable isotope method in children with EE should be undertaken.
doi:10.3390/nu7010572
PMCID: PMC4303854  PMID: 25594440
colon; zinc; mineral absorption; fermentation
10.  Protective Association of Tumor Necrosis Factor Superfamily 15 (TNFSF15) Polymorphic Haplotype with Ulcerative Colitis and Crohn's Disease in an Indian Population 
PLoS ONE  2014;9(12):e114665.
Background
Tumor necrosis factor superfamily (TNFSF) proteins are involved in the genesis of inflammatory bowel disease (IBD). We examined the association of seven single nucleotide polymorphisms (SNP) in the TNFSF15 gene with Crohn's disease (CD) and ulcerative colitis (UC) in the Indian population.
Methods
Seven SNPs in the TNFSF15 gene (rs10114470, rs3810936, rs6478108, rs4263839, rs6478109, rs7848647 and rs7869487) were genotyped in 309 CD patients, 330 UC patients and 437 healthy controls using the Sequenom iPLEX MassArray platform. Disease associations were evaluated for allelotypes and for genotypes.
Results
The minor T alleles and the TT genotypes of rs10114470 and rs3810936 were significantly protectively associated with both CD and UC. The CC genotype of rs6478108, AA genotype of rs4263839, the AA genotype of rs6478109, the TT genotype of rs7848647 and the CC genotype of rs7869487 were all protectively associated with CD but not with UC. Two haplotype blocks could be discerned, one where SNPs rs10114470 and rs3810936 were in tight LD (D′ = 0.8) and the other where rs6478108, rs4263839, rs6478109, rs7848647 and rs7869487 were in tight LD (D′ 0.92–1.00). The second block of haplotypes were not associated with CD or with UC. The first block of haplotypes was very significantly associated with both CD and UC.
Conclusions
Strong associations exist between TNFSF15 gene polymorphisms and IBD (both CD and UC) in the Indian population.
doi:10.1371/journal.pone.0114665
PMCID: PMC4264777  PMID: 25501099
11.  Novel application of digital microfluidics for the detection of biotinidase deficiency in newborns 
Clinical biochemistry  2013;46(18):1889-1891.
Objective
Newborn screening for biotinidase deficiency can be performed using a fluorometric enzyme assay on dried blood spot specimens. As a pre-requisite to the consolidation of different enzymatic assays onto a single platform, we describe here a novel analytical method for detecting biotinidase deficiency using the same digital microfluidic cartridge that has already been demonstrated to screen for five lysosomal storage diseases (Pompe, Fabry, Gaucher, Hurler and Hunter) in a multiplex format.
Methods
A novel assay to quantify biotinidase concentration in dried blood spots (DBS) was developed and optimized on the digital microfluidic platform using proficiency testing samples from the Centers for Disease Control and Prevention. The enzymatic assay uses 4-methylumbelliferyl biotin as the fluorogenic substrate. Biotinidase deficiency assays were performed on normal (n=200) and deficient (n=7) newborn DBS specimens.
Results
Enzymatic activity analysis of biotinidase deficiency revealed distinct separation between normal and affected DBS specimens using digital microfluidics and these results matched the expected activity.
Conclusions
This study has demonstrated performance of biotinidase deficiency assays by measurement of 4-methylumbelliferyl product on a digital microfluidic platform. Due to the inherent ease in multiplexing on such a platform, consolidation of other fluorimetric assays onto a single cartridge may be realized.
doi:10.1016/j.clinbiochem.2013.09.003
PMCID: PMC3926755  PMID: 24036022
Newborn screening; biotinidase deficiency; digital microfluidics; dried blood spot; multiplex assay
12.  Desmoid Tumours: Our Experience of Six Cases and Review of Literature 
Desmoid tumours represent aggressive fibroblastic proliferation of the musculoaponeurotic structures commonly from the anterior abdominal wall. These tumours infiltrate locally, recur frequently but do not metastasize. Antecedent trauma, pregnancy and estrogens play a role in the etiopathogenesis of these tumours. In familial adenomatous polyposis (FAP) genetic history associated with chromosomal abnormality and familial incidence as in Gardner's syndrome is reported and most of these tumours are intraperitoneal either in the mesentery or pelvis and may be multiple and they carry poor prognosis. Surgery is the most preferred treatment and requires wide excision with 1 cm margin followed by reconstruction of the defect in the anterior abdominal wall either with local musculoaponeurotic layers or with synthetic mesh. In intra-abdominal cases associated with FAP in addition to surgery, hormonal treatment, chemotherapy and Radiotherapy are also advised depending upon the particular condition but usually prognosis is not encouraging.
In this article we present our personal experience in the successful treatment of six cases of sporadic desmoids, five in females of child bearing age, and all in the anterior abdominal wall and one extra abdominal in a child aged 13 y in the gluteal region (Case 6). It is very interesting and unique to see two desmoid tumours developing in the same patient (Case2)one in each of the Rectus abdominal muscles (Right & Left).
doi:10.7860/JCDR/2014/9610.5032
PMCID: PMC4253223  PMID: 25478405
Abdominal fibromatosis; Desmoids; Surgery
13.  A Comprehensive Assessment of Lymphatic Filariasis in Sri Lanka Six Years after Cessation of Mass Drug Administration 
Background
The Sri Lankan Anti-Filariasis Campaign conducted 5 rounds of mass drug administration (MDA) with diethycarbamazine plus albendazole between 2002 and 2006. We now report results of a comprehensive surveillance program that assessed the lymphatic filariasis (LF) situation in Sri Lanka 6 years after cessation of MDA.
Methodology and Principal Findings
Transmission assessment surveys (TAS) were performed per WHO guidelines in primary school children in 11 evaluation units (EUs) in all 8 formerly endemic districts. All EUs easily satisfied WHO criteria for stopping MDA. Comprehensive surveillance was performed in 19 Public Health Inspector (PHI) areas (subdistrict health administrative units). The surveillance package included cross-sectional community surveys for microfilaremia (Mf) and circulating filarial antigenemia (CFA), school surveys for CFA and anti-filarial antibodies, and collection of Culex mosquitoes with gravid traps for detection of filarial DNA (molecular xenomonitoring, MX). Provisional target rates for interruption of LF transmission were community CFA <2%, antibody in school children <2%, and filarial DNA in mosquitoes <0.25%. Community Mf and CFA prevalence rates ranged from 0–0.9% and 0–3.4%, respectively. Infection rates were significantly higher in males and lower in people who denied prior treatment. Antibody rates in school children exceeded 2% in 10 study sites; the area that had the highest community and school CFA rates also had the highest school antibody rate (6.9%). Filarial DNA rates in mosquitoes exceeded 0.25% in 10 PHI areas.
Conclusions
Comprehensive surveillance is feasible for some national filariasis elimination programs. Low-level persistence of LF was present in all study sites; several sites failed to meet provisional endpoint criteria for LF elimination, and follow-up testing will be needed in these areas. TAS was not sensitive for detecting low-level persistence of filariasis in Sri Lanka. We recommend use of antibody and MX testing as tools to complement TAS for post-MDA surveillance.
Author Summary
Lymphatic Filariasis (LF, also known as “elephantiasis”) is a disabling and deforming disease that is caused by parasitic worms that are transmitted by mosquitoes. The Sri Lankan Anti-Filariasis Campaign provided five annual rounds of mass drug administration (MDA) with diethylcarbamazine and albendazole between 2002 and 2006 in all endemic areas (districts or implementation units), and this reduced infection rates to very low levels in all sentinel and spot check sites. Transmission Assessment Surveys (TAS, surveys for filarial antigenemia in primary school children) performed in 2012–2013 (about 6 years after the last round of MDA) showed that all 11 evaluation units in formerly endemic areas easily satisfied a key World Health Organization target for LF elimination programs. More comprehensive surveillance was performed with other tests to assess LF parameters in 19 study sites in the same eight districts. We detected evidence of persistent LF in all districts and evidence of ongoing transmission in several areas. Exposure monitoring (screening for anti-filarial antibodies in primary school children) and molecular xenomonitoring (detecting filarial DNA in mosquito vectors) were much more sensitive than TAS for detecting low level persistence of filariasis in Sri Lanka. These methods are complementary to TAS, and they are feasible for use by some national filariasis elimination programs. Results from this study suggest that TAS alone may not be sufficient for assessing the success of filariasis elimination programs.
doi:10.1371/journal.pntd.0003281
PMCID: PMC4230885  PMID: 25393404
15.  Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer 
Nature genetics  2014;46(5):487-491.
Introduction
The somatic mutations in a cancer genome are the aggregate outcome of one or more mutational processes operative through the life of the cancer patient1-3. Each mutational process leaves a characteristic mutational signature determined by the mechanisms of DNA damage and repair that constitute it. A role was recently proposed for the APOBEC family of cytidine deaminases in generating particular genome-wide mutational signatures1,4 and a signature of localized hypermutation called kataegis1,4. A germline copy number polymorphism involving APOBEC3A and APOBEC3B, which effectively deletes APOBEC3B5, has been associated with a modest increased risk of breast cancer6-8. Here, we show that breast cancers in carriers of the deletion show more mutations of the putative APOBEC-dependent genome-wide signatures than cancers in non-carriers. The results suggest that the APOBEC3A/3B germline deletion allele confers cancer susceptibility through increased activity of APOBEC-dependent mutational processes, although the mechanism by which this occurs remains unknown.
doi:10.1038/ng.2955
PMCID: PMC4137149  PMID: 24728294
16.  Identification of 1-[4-Benzyloxyphenyl)-but-3-enyl]-1H-azoles as New Class of Antitubercular and Antimicrobial Agents 
ACS Medicinal Chemistry Letters  2013;4(10):958-963.
A series of 1-[(4-benzyloxyphenyl)-but-3-enyl]-1H-azoles has been identified as potent antitubercular agents against Mycobacterium tuberculosis. Synthesis of compounds involved acid catalyzed ring-opening of cyclopropyl ring of phenyl cyclopropyl methanols followed by nucleophilic attack of the azoles on the carbocation intermediates. Several of the compounds 26, 34, and 36 exhibited significant antitubercular activities with MIC value as low as 1.56, 1.56, and 0.61 μg/mL, respectively, comparable to many standard drugs. These compounds were also screened against other strains of bacteria and fungi, and few of them showed good antifungal activity against A. fumigatus, responsible for lung infection.
doi:10.1021/ml4002248
PMCID: PMC4027561  PMID: 24900592
Antitubercular agents; azoles; cyclopropyl methanols; Mycobacterium tuberculosis
17.  Biocomposite nanofibrous strategies for the controlled release of biomolecules for skin tissue regeneration 
Nanotechnology and tissue engineering have enabled engineering of nanostructured strategies to meet the current challenges in skin tissue regeneration. Electrospinning technology creates porous nanofibrous scaffolds to mimic extracellular matrix of the native tissues. The present study was performed to gain some insights into the applications of poly(l-lactic acid)-co-poly-(ε-caprolactone) (PLACL)/silk fibroin (SF)/vitamin E (VE)/curcumin (Cur) nanofibrous scaffolds and to assess their potential for being used as substrates for the culture of human dermal fibroblasts for skin tissue engineering. PLACL/SF/VE/Cur nanofibrous scaffolds were fabricated by electrospinning and characterized by fiber morphology, membrane porosity, wettability, mechanical strength, and chemical properties by Fourier transform infrared (FTIR) analysis. Human dermal fibroblasts were cultured on these scaffolds, and the cell scaffold interactions were analyzed by cell proliferation, cell morphology, secretion of collagen, expression of F-actin, and 5-chloromethylfluorescein diacetate (CMFDA) dye. The electrospun nanofiber diameter was obtained between 198±4 nm and 332±13 nm for PLACL, PLACL/SF, PLACL/SF/VE, and PLACL/SF/VE/Cur nanofibrous scaffolds. FTIR analysis showed the presence of the amide groups I, II, and III, and a porosity of up to 92% obtained on these nanofibrous scaffolds. The results showed that the fibroblast proliferation, cell morphology, F-actin, CMFDA dye expression, and secretion of collagen were significantly increased in PLACL/SF/VE/Cur when compared to PLACL nanofibrous scaffolds. The accessibility of human dermal fibroblasts cultured on PLACL/SF/VE/Cur nanofibrous scaffolds proved to be a potential scaffold for skin tissue regeneration.
doi:10.2147/IJN.S65335
PMCID: PMC4200034  PMID: 25336949
poly(l-lactic acid)-co-poly-(ε-caprolactone); silk fibroin; fibroblast; Sirius red staining; curcumin release; skin tissue regeneration
18.  Dual Primary Malignancy: A Rare Organ Combination 
Case Reports in Pulmonology  2014;2014:760631.
A 63-year-old female smoker was evaluated for lump over the right breast, fine needle aspiration cytology of which showed infiltrating ductal carcinoma. Investigations also revealed the presence of left upper lobe mass lesion, the biopsy of which suggested small cell carcinoma. The existence of two malignancies having different histopathologies at anatomically distinct sites suggests the diagnosis of dual primary malignancy involving the breast and the lung which, being a rare combination, prompted us to report the case.
doi:10.1155/2014/760631
PMCID: PMC4220575  PMID: 25400968
19.  Intra Peritoneal Polypropylene Mesh and Newer Meshes in Ventral Hernia Repair: What EBM Says? 
The Indian Journal of Surgery  2012;75(5):346-351.
Incisional hernias and other ventral hernias are common surgical problems. It is estimated that incisional hernia complicates about 2 % to 10 % of laparotomies. Ventral and incisional hernia repairs are among the common surgeries done by a general surgeon. It is proven beyond any doubt that suture repair of these hernias should not be done as recurrence rates are unacceptably high, some series reporting as high as 54 % on long-term follow-up. A prosthetic mesh should always be used in ventral hernia repair (VHR). Now, the polypropylene mesh (PPM) has become the prosthetic mesh of choice in the repair of hernias, including inguinal hernia. However, with the advent of laparoscopic repair where the mesh is placed intraperitoneally, concerns regarding safety of PPM are raised. Newer meshes are introduced, claiming lesser complication rate. Many types of newer meshes are available now. Newer meshes are invariably costlier than PPM by 15–20 times. Is this extra cost worth? We looked in to available literature for an answer.
doi:10.1007/s12262-012-0743-x
PMCID: PMC3824771  PMID: 24426474
Ventral hernia repair; Incisional hernia repair; Intraperitoneal mesh; Laparoscopic hernia repair; Open hernia repair; Polypropylene mesh (PPM); Newer meshes; PTFE mesh; ePTFE mesh; Composite mesh; PCO mesh
20.  Recurrent PTPRB and PLCG1 mutations in angiosarcoma 
Nature genetics  2014;46(4):376-379.
Angiosarcoma is an aggressive malignancy that arises spontaneously or secondarily to ionising radiation or chronic lymphoedema1. Previous work has identified aberrant angiogenesis, including occasional somatic mutations in angiogenesis signalling genes, as a key driver of angiosarcoma1. Here, we employed whole genome, exome, and targeted sequencing to study the somatic changes underpinning primary and secondary angiosarcoma. We identified recurrent mutations in two genes, PTPRB and PLCG1, which are intimately linked to angiogenesis. The endothelial phosphatase PTPRB, a negative regulator of vascular growth factor tyrosine kinases, harboured predominantly truncating mutations in 10/39 (26%) tumours. PLCG1, a signal transducer of tyrosine kinases, presented with a recurrent, likely activating R707Q missense variant in 3/34 cases (9%). Overall, 15/39 (38%) tumours harboured at least one driver mutation in angiogenesis signalling genes. Our findings inform and reinforce current therapeutic efforts to target angiogenesis signalling in angiosarcoma.
doi:10.1038/ng.2921
PMCID: PMC4032873  PMID: 24633157
22.  Multiplex Newborn Screening for Pompe, Fabry, Hunter, Gaucher, and Hurler Diseases Using a Digital Microfluidic Platform 
Purpose
New therapies for lysosomal storage diseases (LSDs) have generated interest in screening newborns for these conditions. We present performance validation data on a digital microfluidic platform that performs multiplex enzymatic assays for Pompe, Fabry, Hunter, Gaucher, and Hurler diseases.
Methods
We developed an investigational disposable digital microfluidic cartridge that uses a single dried blood spot (DBS) punch for performing a 5-plex fluorometric enzymatic assay on up to 44 DBS samples. Precision and linearity of the assays were determined by analyzing quality control DBS samples; clinical performance was determined by analyzing 600 presumed normal and known affected samples (12 for Pompe, 7 for Fabry and 10 each for Hunter, Gaucher and Hurler).
Results
Overall coefficient of variation (CV) values between cartridges, days, instruments, and operators ranged from 2 to 21%; linearity correlation coefficients were ≥ 0.98 for all assays. The multiplex enzymatic assay performed from a single DBS punch was able to discriminate presumed normal from known affected samples for 5 LSDs.
Conclusions
Digital microfluidic technology shows potential for rapid, high-throughput screening for 5 LSDs in a newborn screening laboratory environment. Sample preparation to enzymatic activity on each cartridge is less than 3 hours.
doi:10.1016/j.cca.2013.05.001
PMCID: PMC3926752  PMID: 23660237
Newborn screening; lysosomal storage disease; digital microfluidics; dried blood spot; high throughput; multiplex enzymatic assay
23.  SRA/SET domain-containing proteins link RNA polymerase V occupancy to DNA methylation 
Nature  2014;507(7490):124-128.
RNA-directed DNA methylation (RdDM) in Arabidopsis thaliana depends on the upstream synthesis of 24-nucleotide small interfering RNAs (siRNAs) by RNA POLYMERASE IV (Pol IV)1,2 and downstream synthesis of non-coding transcripts by Pol V. Pol V transcripts are thought to interact with siRNAs which then recruit DOMAINS REARRANGED METHYLTRANSFERASE 2 (DRM2) to methylate DNA3-7. The SU(VAR)3-9 homologs SUVH2 and SUVH9 act in this downstream step but the mechanism of their action is unknown8,9. Here we show that genome-wide Pol V association with chromatin redundantly requires, SUVH2 and SUVH9. Although SUVH2 and SUVH9 resemble histone methyltransferases a crystal structure reveals that SUVH9 lacks a peptide-substrate binding cleft and lacks a properly formed S-adenosyl methionine (SAM) binding pocket necessary for normal catalysis, consistent with a lack of methyltransferase activity for these proteins8. SUVH2 and SUVH9 both contain SET- and RING-ASSOCIATED (SRA) domains capable of binding methylated DNA8, suggesting that they function to recruit Pol V through DNA methylation. Consistent with this model, mutation of DNA METHYLTRANSFERASE 1 (MET1) causes loss of DNA methylation, a nearly complete loss of Pol V at its normal locations, and redistribution of Pol V to sites that become hypermethylated. Furthermore, tethering SUVH2 with a zinc finger to an unmethylated site is sufficient to recruit Pol V and establish DNA methylation and gene silencing. These results suggest that Pol V is recruited to DNA methylation through the methyl-DNA binding SUVH2 and SUVH9 proteins, and our mechanistic findings suggest a means for selectively targeting regions of plant genomes for epigenetic silencing.
doi:10.1038/nature12931
PMCID: PMC3963826  PMID: 24463519
24.  Association of IRGM Gene Mutations with Inflammatory Bowel Disease in the Indian Population 
PLoS ONE  2014;9(9):e106863.
Background
Mutations in the IRGM gene have been associated with Crohn's disease in several populations but have not been explored in Indian patients with this disease. This study examined the association of IRGM mutations with ulcerative colitis and Crohn's disease in Indian patients with inflammatory bowel disease.
Methods
The IRGM gene was amplified in four segments and Sanger-sequenced in 101 participants (42 Crohn's disease, 39 ulcerative colitis, and 20 healthy controls). Ten single nucleotide polymorphisms (SNP) were genotyped in 1200 participants (352 Crohn's disease, 400 ulcerative colitis, and 448 healthy controls) using Sequenom MassARRAY iPLEX. Disease associations were evaluated for each of the ten SNPs.
Results
Thirty one mutations were identified in the IRGM gene, of which two had not hitherto been reported (150226250- ss947429272 & 150227858- ss947429273). Ten SNPs (6 from the above and 4 from the literature) were evaluated. Significant associations with Crohn's disease were noted with the T allele of rs1000113 (OR 1.46, 95% CI 1.12–1.90), T allele of rs9637876 (OR 1.25, 95% CI 1.005–1.561) and C allele of rs 13361189 (OR 1.33, 95% CI 1.07–1.669). Two SNPs – rs11747270 and rs180802994 – did not exhibit Hardy-Weinberg equilibrium but were associated with both Crohn's disease and ulcerative colitis in this population. The remaining SNPs did not show significant associations with either Crohn's disease or ulcerative colitis.
Conclusions
Association of IRGM gene SNPs with Crohn's disease is reported for the first time in Indian patients. We also report, for the first time, an association of rs 9637876 in the IRGM gene with Crohn's disease.
doi:10.1371/journal.pone.0106863
PMCID: PMC4156415  PMID: 25191865
25.  Ameliorative Effect of Fisetin on Cisplatin-Induced Nephrotoxicity in Rats via Modulation of NF-κB Activation and Antioxidant Defence 
PLoS ONE  2014;9(9):e105070.
Nephrotoxicity is a dose-dependent side effect of cisplatin limiting its clinical usage in the field of cancer chemotherapy. Fisetin is a bioactive flavonoid with recognized antioxidant and anti-inflammatory properties. In the present study, we investigated the potential renoprotective effect and underlying mechanism of fisetin using rat model of cisplatin-induced nephrotoxicity. The elevation in serum biomarkers of renal damage (blood urea nitrogen and creatinine); degree of histopathological alterations and oxidative stress were significantly restored towards normal in fisetin treated, cisplatin challenged animals. Fisetin treatment also significantly attenuated the cisplatin-induced IκBα degradation and phosphorylation and blocked the NF-κB (p65) nuclear translocation, with subsequent elevation of pro-inflammatory cytokine, TNF-α, protein expression of iNOS and myeloperoxidase activities. Furthermore, fisetin markedly attenuated the translocation of cytochrome c protein from the mitochondria to the cytosol; decreased the expression of pro-apoptotic proteins including Bax, cleaved caspase-3, cleaved caspase-9 and p53; and prevented the decline of anti-apoptotic protein, Bcl-2. The cisplatin-induced mRNA expression of NOX2/gp91phox and NOX4/RENOX and the NADPH oxidase enzyme activity were also significantly lowered by fisetin treatment. Moreover, the evaluated mitochondrial respiratory enzyme activities and mitochondrial antioxidants were restored by fisetin treatment. Estimation of platinum concentration in kidney tissues revealed that fisetin treatment along with cisplatin did not alter the cisplatin uptake in kidney tissues. In conclusion, these findings suggest that fisetin may be used as a promising adjunct candidate for cisplatin use.
doi:10.1371/journal.pone.0105070
PMCID: PMC4153571  PMID: 25184746

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