Fully adaptive fluorescence enhanced optical tomography using tetrahedral dual-mesh has been developed. The proposed method has been enabled by the efficient intersection algorithm developed for 8-subtetrahedron subdivision scheme. Using the synthetic data, we demonstrate that the tetrahedredron-based adaptive dual-mesh scheme can provide at reasonable cost, high resolution imaging of small fluorescent targets simulated in the breast-shaped phantoms.
Bacillus coagulans RCS3 isolated from hot water springs secreted five isozymes i.e. beta-gal I-V of beta-galactosidase. beta-gal III isozyme was purified using DEAE cellulose and Sephadex G 100 column chromatography. Its molecular weight characterization showed a single band at 315 kD in Native PAGE, while two subunits of 50.1 and 53.7 kD in SDS PAGE. beta-Cal III had pH optima in the range of 6-7 and temperature optima at 65 degrees C. It preferred nitro-aryl-beta-D-galactoside as substrate having K-m of 4.16 mM with ONPG. More than 85% and 80% hydrolysis of lactose (1-5%, w/v) was recorded within 48 h of incubation at 55 degrees C and 50 degrees C respectively and pH range of 6-7. About 78-86% hydrolysis of lactose in various brands of standardized milk was recorded at incubation temperature of 50 degrees C. These results marked the applications of beta-gal III in processing of milk/whey industry. (C) 2011 Elsevier B.V. All rights reserved.
Background Nonadherence of antiemetic prescriptions to evidence-based antiemetic guidelines is associated with an increased proportion of chemotherapy-induced nausea and vomiting. The current project was carried out to improve the quality of antiemetic prescriptions at our institute. Methods We initially performed a retrospective analysis of 1,211 consecutive antiemetic prescription records of adult patients with solid tumors who received outpatient chemotherapy regimens. The antiemetic prescription records were classified as either ASCO-guideline adherent or nonadherent, and the impact on emesis was studied. These data were used to educate clinicians regarding the importance of adherence to guidelines. We then revised our antiemetic prescription policies and made their use mandatory. In addition, a double-check system was introduced to ensure implementation. A reaudit was performed to study the impact of these interventions. Results ASCO-guideline-adherent prescriptions in the initial part of our study were associated with a lower rate of vomiting (6.6% v 21.9%; P < .001), emergency visits (2.6% v 5.8%; P =3D .006), and hospitalization for emesis (0.9% v 4.9%; P < .001). The proportion of prescriptions classified as ASCO-guideline adherent in the initial audit and the reaudit were 63.6% and 98.5%, respectively (P < .001). The proportion of patients for whom antiemetic prescriptions were overused was significantly lower on the reaudit (41.3% v 68.3% before the interventions; P =3D .001). Conclusion Mandatory, semirigid corrective steps as carried out in this audit led to an improvement in antiemetic-guideline adherence rate.
Su, Yu-Ru
Di, Chongzhi
Bien, Stephanie
Huang, Licai
Dong, Xinyuan
Abecasis, Goncalo
Berndt, Sonja
Bezieau, Stephane
Brenner, Hermann
Caan, Bette
Casey, Graham
Chang-Claude, Jenny
Chanock, Stephen
Chen, Sai
Connolly, Charles
Curtis, Keith
Figueiredo, Jane
Gala, Manish
Gallinger, Steven
Harrison, Tabitha
Hoffmeister, Michael
Hopper, John
Huyghe, Jeroen R.
Jenkins, Mark
Joshi, Amit
Le Marchand, Loic
Newcomb, Polly
Nickerson, Deborah
Potter, John
Schoen, Robert
Slattery, Martha
White, Emily
Zanke, Brent
Peters, Ulrike
Hsu, Li
Genome-wide association studies (GWASs) have successfully identified thousands of genetic variants for many complex diseases; however, these variants explain only a small fraction of the heritability. Recently, genetic association studies that leverage external transcriptome data have received much attention and shown promise for discovering novel variants. One such approach, PrediXcan, is to use predicted gene expression through genetic regulation. However, there are limitations in this approach. The predicted gene expression may be biased, resulting from regularized regression applied to moderately sample-sized reference studies. Further, some variants can individually influence disease risk through alternative functional mechanisms besides expression. Thus, testing only the association of predicted gene expression as proposed in PrediXcan will potentially lose power. To tackle these challenges, we consider a unified mixed effects model that formulates the association of intermediate phenotypes such as imputed gene expression through fixed effects, while allowing residual effects of individual variants to be random. We consider a set-based score testing framework, MiST (mixed effects score test), and propose two data-driven combination approaches to jointly test for the fixed and random effects. We establish the asymptotic distributions, which enable rapid calculation of p values for genome-wide analyses, and provide p values for fixed and random effects separately to enhance interpretability over GWASs. Extensive simulations demonstrate that our approaches are more powerful than existing ones. We apply our approach to a large-scale GWAS of colorectal cancer and identify two genes, POU5FIB and ATF1, which would have otherwise been missed by PrediXcan, after adjusting for all known loci.
Objectives: Cancer is frequently complicated by thromboembolic events (TEs). We aimed to determine the incidence of TEs in lung cancer patients treated with platinum-based chemotherapy and study patients' baseline and treatment attributes correlating with its onset. Materials and methods: Advanced lung cancer patients started on platinum-based chemotherapy were evaluated at baseline and during routine visits for the development of TEs. The duration of follow-up was 4 weeks from the last chemotherapy. A TE occurring between the first dose of chemotherapy and 4 weeks after the last dose was considered to be chemotherapy associated. Results: Of the 165 patients on platinum chemotherapy who completed follow-up, TEs occurred in 4.8% (8 out of 165) patients. Among these, three patients had developed venous pulmonary thromboembolism and five patients had developed cerebral infarction, out of which four had arterial cerebral infarction and one patient had a superior sagittal sinus thrombosis. The majority of events (7 out of 8) occurred within 100 days of starting platinum chemotherapy. Overall, the median time until occurrence of TE was 48 days (range, 10-130 days). None of the presumed risk factors were found be associated with the occurrence of TEs on univariate analysis. Conclusions: Advanced lung cancer patients on platinum chemotherapy are predisposed to thromboembolism due to many factors. Despite its lower incidence in our study, exclusion of patients with prior thrombosis suggests the incidence of de novo thrombosis, and hence raises a valid question of the need of thromboprophylaxis in a selected group of patients.
Fu, Xiaoyong
Creighton, Chad J
Biswal, Nrusingh C
Kumar, Vijetha
Shea, Martin
Herrera, Sabrina
Contreras, Alejandro
Gutierrez, Carolina
Wang, Tao
Nanda, Sarmistha
Giuliano, Mario
Morrison, Gladys
Nardone, Agostina
Karlin, Kristen L
Westbrook, Thomas F
Heiser, Laura M
Anur, Pavana
Spellman, Paul
Guichard, Sylvie M
Smith, Paul D
Davies, Barry R
Klinowska, Teresa
Lee, Adrian V
Mills, Gordon B
Rimawi, Mothaffar F
Hilsenbeck, Susan G
Gray, Joe W
Joshi, Amit
Osborne, C Kent
Schiff, Rachel
INTRODUCTION: Activation of the phosphatidylinositol 3-kinase (PI3K) pathway in estrogen receptor alpha (ER)-positive breast cancer is associated with reduced ER expression and activity, luminal B subtype, and poor outcome. Phosphatase and tensin homolog (PTEN), a negative regulator of this pathway, is typically lost in ER-negative breast cancer. We set out to clarify the role of reduced PTEN levels in endocrine resistance, and to explore the combination of newly developed PI3K downstream kinase inhibitors to overcome this resistance.; METHODS: Altered cellular signaling, gene expression, and endocrine sensitivity were determined in inducible PTEN-knockdown ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer cell and/or xenograft models. Single or two-agent combinations of kinase inhibitors were examined to improve endocrine therapy.; RESULTS: Moderate PTEN reduction was sufficient to enhance PI3K signaling, generate a gene signature associated with the luminal B subtype of breast cancer, and cause endocrine resistance in vitro and in vivo. The mammalian target of rapamycin (mTOR), protein kinase B (AKT), or mitogen-activated protein kinase kinase (MEK) inhibitors, alone or in combination, improved endocrine therapy, but the efficacy varied by PTEN levels, type of endocrine therapy, and the specific inhibitor(s). A single-agent AKT inhibitor combined with fulvestrant conferred superior efficacy in overcoming resistance, inducing apoptosis and tumor regression.; CONCLUSIONS: Moderate reduction in PTEN, without complete loss, can activate the PI3K pathway to cause endocrine resistance in ER-positive breast cancer, which can be overcome by combining endocrine therapy with inhibitors of the PI3K pathway. Our data suggests that the ER degrader fulvestrant, to block both ligand-dependent and -independent ER signaling, combined with an AKT inhibitor is an effective strategy to test in patients.=20
Goswami, Akshra
Shah, Bhahwal Ali
Kumar, Ajay
Rizvi, Masood Ahmad
Kumar, Suresh
Bhushan, Shashi
Malik, Fayaz Ahmed
Batra, Navneet
Joshi, Amit
Singh, Jagtar
Leukemia is one of the deadliest types of cancer. Lack of effective treatment strategies has resulted in an extensive quest for new therapeutic molecules against it. This study explores the molecular mechanism of anticancer activity of P16, a semisynthetic analog of parthenin, against the human acute lymphoblastic leukemia MOLT-4 cells. P16 displayed antiproliferative activity in different cancer cell lines; however, MOLT-4 cells showed highest sensitivity for P16 with IC50 value of 0.6muM. Further studies revealed that P16 induced cell death by apoptosis. It caused mitochondrial stress, which was mediated by the translocation of Bax from cytosol to mitochondria and release of cytochrome c into the cytosol and consequent activation of caspase-9. However, P16 was also able to activate caspase-8, thus involving both extrinsic and intrinsic pathways of apoptosis. Further, activation of caspase-3 led to cleavage of its target proteins PARP-1 and ICAD, which resulted in apoptotic DNA damage. P16 induced apoptosis was accompanied by the down-regulation of important leukemic cell survival proteins like pAKT (S473), pAKT (T308), pP70S6K, pCRAF, and pERK1/2. However, inhibition of caspases by Z-VAD-FMK reversed the down-regulatory effect of P16 on pAKT (S473) and pP70S6K, as evident by the cell viability assay and flow cytometric analysis but this inhibition did not completely reverse the antiproliferative effect of P16, thereby indicating the role of additional factors apart from caspases in P16 induced apoptosis in MOLT-4 cells. Owing to its antiproliferative potential against leukemia cells, P16 can further be explored as an effective therapeutics against leukemia. Copyright =C2=A9 2014 Elsevier Ireland Ltd. All rights reserved.
Singh, Jagtar
Behal, Arvind
Singla, Neha
Joshi, Amit
Birbian, Niti
Singh, Sukhdeep
Bali, Vandana
Batra, Navneet
Microorganisms constitute two third of the Earth's biological diversity. As many as 99% of the microorganisms present in certain environments cannot be cultured by standard techniques. Culture-independent methods are required to understand the genetic diversity, population structure and ecological roles of the majority of organisms. Metagenomics is the genomic analysis of microorganisms by direct extraction and cloning of DNA from their natural environment. Protocols have been developed to capture unexplored microbial diversity to overcome the existing barriers in estimation of diversity. New screening methods have been designed to select specific functional genes within metagenomic libraries to detect novel biocatalysts as well as bioactive molecules applicable to mankind. To study the complete gene or operon clusters, various vectors including cosmid, fosmid or bacterial artificial chromosomes are being developed. Bioinformatics tools and databases have added much to the study of microbial diversity. This review describes the various methodologies and tools developed to understand the biology of uncultured microbes including bacteria, archaea and viruses through metagenomic analysis.
Haramagatti, Chandrashekara R.
Dhande, Priya
Bhavsar, Ritesh
Umbarkar, Ajinkya
Joshi, Amit
Iron oxide yellow pigment (PY42) dispersion was prepared using the mixture of dispersing agents (surfactants) alkyl aryl sulphonates (S1), lecithin (mixture of phospholipids) (S2), alkoxylated fatty alcohols (S3), and polyoxyethylene tri-decyl ether phosphate (S4). Evaluation of this pigment dispersion in an aqueous paint resulted in acceptable coloristic properties. However, stability of the dispersion with respect to a significant increase in viscosity and settling behaviors when subjected to accelerated stability test (at 55 degrees C for 30 days) was observed. Rheology profiles have been used to characterize the pigment dispersions. Role of various combinations of surfactants on rheology of pigment dispersion was studied. It was found that, certain surfactants played a crucial role on stability of pigment dispersions during accelerated stability. Elimination of surfactant S3 or S4 resulted in an acceptable viscosity at ambient conditions. However, in the accelerated stability test pigment dispersion without S3 showed significantly high viscosity whereas, dispersion without S4 showed no increase in viscosity. From the physical examination, viscosity measurements and analysis of rheology profiles it can be concluded that polyoxyethylene tri-decyl ether phosphate (S4) is the key contributor for the viscosity pickup and settling behavior during the accelerated stability test. Moreover, the rheology study is of great help in predicting the relative stability of the samples.
Joshi, Amit
Rajput, Sandeep
Wang, Chun
Ma, Jun
Cao, Deliang
Aldo-keto reductase family 1 member B10 (AKR1B10), over-expressed in multiple human cancers, might be implicated in cancer development and progression via detoxifying cytotoxic carbonyls and regulating fatty acid synthesis. In the present study, we investigated the ortholog of AKR1B10 in mice, an ideal modeling organism greatly contributing to human disease investigations. In the mouse, there are three aldo-keto reductase family 1 subfamily B (AKR1B) members, i.e., AKR1B3, AKR1B7, and AKR1B8. Among them, AKR1B8 has the highest similarity to human AKR1B10 in terms of amino acid sequence, computer-modeled structures, substrate spectra and specificity, and tissue distribution. More importantly, similar to human AKR1B10, mouse AKR1B8 associates with murine acetyl-CoA carboxylase-a and mediates fatty acid synthesis in colon cancer cells. Taken together, our data suggest that murine AKR1B8 is the ortholog of human AKR1B10.
Plasterer, Cody
Tsaih, Shirng-Wern
Peck, Amy R.
Chervoneva, Inna
O’Meara, Caitlin
Sun, Yunguang
Lemke, Angela
Murphy, Dana
Smith, Jennifer
Ran, Sophia
Kovatich, Albert J.
Hooke, Jeffrey A.
Shriver, Craig D.
Hu, Hai
Mitchell, Edith P.
Bergom, Carmen
Joshi, Amit
Auer, Paul
Prokop, Jeremy
Rui, Hallgeir
Flister, Michael J.