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Biomedical subjects

D Sarkar

Publications and source records attributed to D Sarkar.

At least 19 recordsLinked to original sources
PubMed2006

Effect of soil properties on arsenic fractionation and bioaccessibility in cattle and sheep dipping vat sites.

Historical use of high arsenic (As) concentrations in cattle/sheep dipping vat sites to treat ticks has resulted in severe contamination of soil and groundwater with this Group-A human carcinogen. In the absence of a universally applicable soil As bioaccessibility model, baseline risk assessment studies have traditionally used the extremely conservative estimate of 100% soil As bioaccessibility. Several in-vitro, as well as, in-vivo animal studies suggest that As bioaccessibility in soil can be lower than that in water. Arsenic in soils exists in several geochemical forms with varying degree of dissolution in the human digestive system, and thus, with highly varying As bioaccessibility. Earlier batch incubation studies with As-spiked soils have shown that As bioaccessibility is a function of soil physicochemical properties. We selected 12 dipping vat soils collected from USA and Australia to test the hypothesis that soil properties exert a significant effect on As bioaccessibility in As-contaminated sites. The 12 soils varied widely in terms of soil physico-chemical properties. They were subject to an As sequential fractionation scheme and two in-vitro tests (IVGS and IVGIA) to simulate soil As bioavailability in the human gastrointestinal system. Sequential As fractionation results showed that the majority of the As measured in the dipping vat soils resided either in the Fe/Al hydroxide fraction, or the Ca/Mg fractions, or in the residual fraction. Water-extractable As fraction of the 12 soils was typically <10% of the total, reaching values up to 23%, indicating minimal leaching potential, and hence, lower risk of As-contamination from exposure to groundwater, typically used as drinking water in many parts of the world. Partial individual correlations and subsequent multiple regression analyses suggested that the most significant soil factors influencing As bioaccessibility were total Ca+Mg, total P, clay content and EC. Collectively, these soil properties were able to explain 85 and 86% of the variability associated with the prediction of bioaccessible As, using IVGS and IVGIA in-vitro tests, respectively. This study showed that specific soil properties influenced the magnitude of soil As bioaccessibility, which was typically much lower than total soil-As concentrations, challenging the traditional risk assessment guideline, which assumes that soil As is 100% bioaccessible. Our study showed that total soil As concentration is unlikely to provide an accurate estimate of human health risk from exposure to dipping vat site soils.

Animals↗
PubMed2006

Targeting inhibition of K-ras enhances Ad.mda-7-induced growth suppression and apoptosis in mutant K-ras colorectal cancer cells.

Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a cancer-specific, growth-suppressing and apoptosis-inducing gene with broad-spectrum antitumor activity. However, when administered by means of a replication-incompetent adenovirus, Ad.mda-7, several colorectal carcinoma cell lines are resistant to its antiproliferative and antisurvival effects. We have presently endeavored to determine if K-ras mutations, present in approximately 40-50% of colorectal cancers and which may mediate resistance to chemotherapy and radiotherapy, represent a predisposing genetic factor mitigating reduced sensitivity to Ad.mda-7. To suppress ras expression, three structurally different replication-incompetent adenoviral vectors were engineered that express (1) an intracellular, neutralizing single-chain antibody (scAb) to p21 ras (Ad.K-ras scAb), (2) an antisense (AS) K-ras gene (Ad.K-ras AS) or (3) both mda-7/IL-24 and a K-ras AS gene in a single bipartite virus (Ad.m7.KAS). Simultaneous inhibition of K-ras and expression of mda-7/IL-24 enhanced killing of colorectal carcinoma cells with mutated K-ras, but not with wild-type K-ras. The extent of killing depended on the degree of K-ras downregulation, with Ad.K-ras AS being generally more efficient than Ad.K-ras scAb in combination with Ad.mda-7. These findings support an effective dual-combinatorial approach for the therapy of colorectal cancers that employs a unique cancer-specific suppressor gene (mda-7/IL-24) with targeted inhibition of oncogene (ras) expression.

Adenoviridae↗
PubMed2006

A phase I study of intravenous TZT-1027 administered on day 1 and day 8 of a three-weekly cycle in combination with carboplatin given on day 1 alone in patients with advanced solid tumours.

BACKGROUND: TZT-1027 is a tubulin-binding drug and synthetic derivative of dolastatin-10 with cytotoxic and antivascular activity in vitro and in vivo. Studies have demonstrated anti-tumour activity in several tumour types. METHODS: Patients were treated with escalating doses of TZT-1027 and carboplatin at doses from 1.6 to 2.0 mg/m2 and AUC 4 and 5 respectively. For pharmacokinetic analysis, plasma sampling was done during the first course using a high-performance liquid chromatographic assay. RESULTS: 14 patients received a total of 55 cycles at three dose levels. Dose limiting toxicities (DLTs) were first observed with 1.6 mg/m2 TZT-1027 and carboplatin AUC 5; 1 patient had grade 4 neutropenia and a delay in day 8 treatment occurred in two patients (gr 2 fatigue, gr 3 diarrhoea). At TZT-1027 2 mg/m2 and carboplatin AUC 5, one patient experienced grade 3 paralytic ileus. The most frequent toxicities were neutropenia, anaemia, fatigue, constipation, infection and vomiting. Peripheral neuropathy was reported in 36% of patients. One patient (pancreatic adenocarcinoma) achieved a partial response lasting 181 days. Pharmacokinetic analysis did not demonstrate any interaction between TZT-1027 and carboplatin. CONCLUSIONS: The recommended phase II dose is TZT-1027 1.6 mg/m2 and carboplatin AUC 5. No evidence of a PK interaction between these agents was observed.

Adult↗
PubMed2006

Ionizing radiation enhances therapeutic activity of mda-7/IL-24: overcoming radiation- and mda-7/IL-24-resistance in prostate cancer cells overexpressing the antiapoptotic proteins bcl-xL or bcl-2.

Subtraction hybridization applied to terminally differentiating human melanoma cells identified mda-7/IL-24, a cytokine belonging to the IL-10 gene superfamily. Adenoviral-mediated delivery of mda-7/IL-24 (Ad.mda-7) provokes apoptosis selectively in a wide spectrum of cancers in vitro in cell culture, in vivo in human tumor xenograft animal models and in patients with advanced carcinomas and melanomas. In human prostate cancer cells, a role for mitochondrial dysfunction and induction of reactive oxygen species in the apoptotic process has been established. Ectopic overexpression of bcl-xL and bcl-2 prevents these changes including apoptosis induction in prostate tumor cells by Ad.mda-7. We now document that this resistance to apoptosis can be reversed by treating bcl-2 family overexpressing prostate tumor cells with ionizing radiation in combination with Ad.mda-7 or purified GST-MDA-7 protein. Additionally, radiation augments apoptosis induction by mda-7/IL-24 in parental and neomycin-resistant prostate tumor cells. Radiosensitization to mda-7/IL-24 is dependent on JNK signaling, as treatment with the JNK 1/2/3 inhibitor SP600125 abolishes this effect. Considering that elevated expression of bcl-xL and bcl-2 are frequent events in prostate cancer development and progression, the present studies support the use of ionizing radiation in combination with mda-7/IL-24 as a means of augmenting the therapeutic benefit of this gene in prostate cancer, particularly in the context of tumors displaying resistance to radiation therapy owing to bcl-2 family member overexpression.

Apoptosis↗
PubMed2006

Activation of Ras/Raf protects cells from melanoma differentiation-associated gene-5-induced apoptosis.

Melanoma differentiation-associated gene-5 (mda-5) was the first molecule identified in nature whose encoded protein embodied the unique structural combination of an N-terminal caspase recruitment domain and a C-terminal DExD/H RNA helicase domain. As suggested by its structure, cumulative evidences documented that ectopic expression of mda-5 leads to growth inhibition and/or apoptosis in various cell lines. However, the signaling pathways involved in mda-5-mediated killing have not been elucidated. In this study, we utilized either genetically modified cloned rat embryo fibroblast cells overexpressing different functionally and structurally distinct oncogenes or human pancreatic and colorectal carcinoma cells containing mutant active ras to resolve the role of the Ras/Raf signaling pathway in mda-5-mediated growth inhibition/apoptosis induction. Rodent and human tumor cells containing constitutively activated Raf/Raf/MEK/ERK pathways were resistant to mda-5-induced killing and this protection was antagonized by intervening in this signal transduction cascade either by directly inhibiting ras activity using an antisense strategy or by targeting ras-downstream factors, such as MEK1/2, with the pharmacological inhibitor PD98059. The present findings provide a further example of potential cross-talk between growth-inhibitory and growth-promoting pathways in which the ultimate balance of these factors defines cellular homeostasis, leading to survival or induction of programmed cell death.

Adenoviridae↗
PubMed2006

Defining the mechanism by which IFN-beta dowregulates c-myc expression in human melanoma cells: pivotal role for human polynucleotide phosphorylase (hPNPaseold-35).

Type I interferons (IFN-alpha/-beta) are capable of suppressing c-myc mRNA expression by modulating post-transcriptional processing. However, the molecular mechanism of this phenomenon is poorly understood. We previously established that human polynucleotide phosphorylase (hPNPase(old-35)), a type I IFN-inducible 3',5' exoribonuclease involved in mRNA degradation, induces G1 cell cycle arrest and eventually apoptosis by specifically degrading c-myc mRNA. We now demonstrate a close association between IFN-beta-induced hPNPase(old-35) upregulation and c-myc downregulation in human melanoma cells. Employing stable melanoma cell clones expressing hPNPase(old-35) small inhibitory RNA, we demonstrate that hPNPase(old-35) is a key molecule coupled with IFN-beta-mediated downregulation of c-myc mRNA. Inhibition of hPNPase(old-35) or overexpression of c-myc protects melanoma cells from IFN-beta-mediated growth inhibition, emphasizing the importance of hPNPase(old-35) upregulation and consequent c-myc downregulation in IFN-beta-induced growth inhibition and apoptosis induction. In these contexts, targeted overexpression of hPNPase(old-35) might be a novel therapeutic strategy for c-myc-overexpressing and IFN-resistant tumors, such as melanomas.

Apoptosis↗
PubMed2006

Targeted yield concept and a framework of fertilizer recommendation in irrigated rice domains of subtropical India.

Soil test crop response (STCR) correlation studies were carried out in Vindhyan alluvial plain during 2001 to 2004 taking IR-36 as test crop to quantify rice production in the context of the variability of soil properties and use of balanced fertilizers based on targeted yield concept. The soils were developed on gently sloping alluvial plain with different physiographic settings and notable variation in drainage condition. Soil properties show moderate variation in texture (loamy to clay), organic carbon content (4.4 to 9.8 g/kg), cation exchange capacity (10.2 to 22.4 cmol (p+)/kg) and pH (5.3 to 6.4). Soil fertility status for N is low to medium (224 to 348 kg/ha), P is medium to high (87 to 320 kg/ha) and K ranges from medium to high (158 to 678 kg/ha). Database regarding nutrient requirement in kg/t of grain produce (NR), the percent contribution from the soil available nutrients [CS (%)] and the percent contribution from the applied fertilizer nutrients [CF (%)] were computed for calibrating and formulating fertilizer recommendations. Validity of the yield target for 7 and 8 t/ha was tested in farmers' fields and yields targets varied at less than 10%. The percent achievement of targets aimed at different level was more than 90%, indicating soil test based fertilizer recommendation approach was economically viable within the agro-ecological zone with relatively uniform cropping practices and socio-economic conditions.

Crops, Agricultural↗
PubMed2005

Primary neurological manifestations of lung cancer--a retrospective analysis of 8 patients.

Neurological manifestations are reported in 5 to 10% of cases of lung cancer. We present a series of 216 consecutive patients of lung cancer of which 8 patients presented first with neurological manifestations without overt respiratory symptoms. The present study aimed to identify the number of patients of lung cancer presenting with primary neurological symptoms, the nature of the presentations, and the outcome of these patients among 216 patients who presented over a 2 year period in the Institute of Postgraduate Medical Education and Research, Kolkata. Out of 8 patients, 3 patients presented with seizures, 3 patients with hemiparesis and 2 patients with paraparesis. Thus, 3.7% (8/216) of patients in our series presented with a neurological manifestation. We concluded that primary neurological manifestations are rare in lung cancer. The lungs should be the first site of evaluation in a case of a cerebral metastasis with an unknown primary.

Adult↗
PubMed2004

Coronary angiography using a portable super-C-arm imaging system in a district general hospital.

BACKGROUND: New generation portable super-C-arm imaging systems may offer an alternative means of performing coronary angiography at a lower cost compared with a fixed laboratory. We evaluated the use of one such system (GE-OEC 9800) in a district hospital setting. METHODS: The demographics, procedure and screening times, emitted radiation dose and diagnoses of the first 200 consecutive patients were obtained from a prospective database. Comparison between the portable and fixed systems were made by analysing results from similar cohorts of patients who underwent angiography by the same operators. Image quality was assessed in 23 patients, by an independent cardiologist, comparing the GE-OEC 9800 angiograms with repeat images using a fixed laboratory Philips (HM 3000) system within 3 months of the first study. RESULTS: The procedure time (mean (S.D.)) was 18.9 (0.8) min for the 200 cases. The screening time was 255 (15) s with an emitted radiation of 22.8 (1.4) Gy/cm(2). Comparison between the C-arm and fixed systems revealed significantly longer screening time (230.6 (14.6) vs. 157 (12.9) s, p<0.001), whilst the total radiation doses were not significantly different (21.1 (1.5) vs. 18.6 (1.11) Gy/cm(2)). Independently assessed image quality was satisfactory. The main variance in 57 lesions seen in the 23 patients using the angiograms obtained from the fixed laboratory as reference included overestimated stenosis (two lesions), underestimated stenosis (or subsequent disease progression) (four lesions), lack of appreciation of side-branch ostial involvement (two lesions) and vessel calcification (one lesion). CONCLUSIONS: Portable imaging systems can offer a reliable and cost-effective diagnostic coronary angiography service in a district hospital.

Coronary Angiography↗
PubMed2003

Azithromycin in the treatment of cholera in children.

AIM: To evaluate the efficacy of azithromycin in the treatment of cholera in children. METHODS: A double-blind, randomized, controlled clinical trial on 80 children with acute watery diarrhoea and moderate to severe dehydration compared the efficacy of azithromycin and erythromycin in treating cholera. Data were analysed for 56 patients who were stool culture positive for Vibrio cholerae. In conjunction with rehydration therapy, 29 patients received azithromycin and 27 patients received erythromycin. Patients in the two treatment groups had comparable clinical and blood biochemical characteristics on admission. RESULTS: Patients who received azithromycin had significantly less stool output, shorter duration of diarrhoea and lower fluid intake compared with patients who received erythromycin. CONCLUSION: Azithromycin appears to be superior to erythromycin for treating cholera in children.

Anti-Bacterial Agents↗