Biomedical subjects

Debajyoti Sinha

Publications and source records attributed to Debajyoti Sinha.

7 recordsLinked to original sources

PubMed2006

Potent antitumor activity of a novel cationic pyridinium-ceramide alone or in combination with gemcitabine against human head and neck squamous cell carcinomas in vitro and in vivo.

In this study, a cationic water-soluble ceramide analog L-threo-C6-pyridinium-ceramide-bromide (L-t-C6-Pyr-Cer), which exhibits high solubility and bioavailability, inhibited the growth of various human head and neck squamous cell carcinoma (HNSCC) cell lines at low IC50 concentrations, independent of their p53 status. Consistent with its design to target negatively charged intracellular compartments, L-t-C6-Pyr-Cer accumulated mainly in mitochondria-, and nuclei-enriched fractions upon treatment of human UM-SCC-22A cells [human squamous cell carcinoma (SCC) of the hypopharynx] at 1 to 6 h. In addition to its growth-inhibitory function as a single agent, the supra-additive interaction of L-t-C6-Pyr-Cer with gemcitabine (GMZ), a chemotherapeutic agent used in HNSCC, was determined using isobologram studies. Then, the effects of this ceramide, alone or in combination with GMZ, on the growth of UM-SCC-22A xenografts in SCID mice was assessed following the determination of preclinical parameters, such as maximum tolerated dose, clearance from the blood, and bioaccumulation. Results demonstrated that treatment with L-t-C6-Pyr-Cer in combination with GMZ significantly prevented the growth of HNSCC tumors in vivo. The therapeutic efficacy of L-t-C6-Pyr-Cer/GMZ combination against HNSCC tumors was approximately 2.5-fold better than that of the combination of 5-fluorouracil/cis-platin. In addition, liquid chromatography/mass spectroscopy analysis showed that the levels of L-t-C6-Pyr-Cer in HNSCC tumors were significantly higher than its levels in the liver and intestines; interestingly, the combination with GMZ increased the sustained accumulation of this ceramide by approximately 40%. Moreover, treatment with L-t-C6-Pyr-Cer/GMZ combination resulted in a significant inhibition of telomerase activity and decrease in telomere length in vivo, which are among downstream targets of ceramide.

Animals↗

PubMed2006

Fresh frozen plasma and platelet concentrates may increase plasma anti-diphtheria toxin IgG concentrations: Implications for diphtheria fusion protein therapy.

We are developing two fusion proteins consisting of a diphtheria toxin (DT) linked to either granulocyte macrophage colony stimulating factor (DT388-GMCSF) or interleukin-3 (DT388-IL3). In trials, patients with anti-DT IgG concentrations >2.5 microg/ml had significantly lower concentrations of either fusion protein. DT389-IL2 is currently FDA approved for the treatment of cutaneous T-cell lymphomas. We noted increased concentrations of anti-DT IgG after administration of platelet concentrates (PC). Because many of these patients require transfusions, we measured the anti-DT IgG content of FFP and PC. We assayed 14 bags of FFP and 12 bags of single-donor PCs for anti-DT IgG by an enzymoimmunoassay against DT389-IL2, DT388-IL3, DT388-GMCSF. The median (percent of samples positive) of anti-DT IgG concentrations in PC against DT388-GMCSF, DT388-IL3, DT389-IL2 was 0.8 microg/ml (83%), 0.7 microg/ml (83%), and 0.3 microg/ml (58%), respectively. The median (percent of samples positive) anti-DT IgG concentration in FFP against DT388-GMCSF, DT388-IL3, and DT389-IL2 was 2.1 microg/ml (86%), 1.9 microg/ml (93%), and 1.4 microg/ml (86%), respectively. There was a strong association between anti-DT389IL2 IgG, anti-DT388IL3 IgG, and anti-DT388GMCSF IgG concentrations in both the FFP (95.6%) and PC (76.3%). Assuming a plasma volume of 3 l in a 70 kg patient, a single FFP unit would increase the plasma anti-DT389IL2 IgG, anti-DT388IL3 IgG, and anti-DT388GMCSF IgG by 0.13 microg/ml, 0.17 microg/ml, and 0.19 microg/ml, respectively. For PC, a single unit would increase plasma anti-DT389-IL2 IgG, anti-DT388-IL3 IgG, and anti-DT388-GMCSF IgG by 0.03 microg/ml, 0.06 microg/ml, and 0.07 microg/ml, respectively. In conclusion, a single FFP or PC appears to minimally increase anti-DT IgG concentrations, but multiple units may significantly do such.

Blood Platelets↗

PubMed2005

Prognostic and functional significance of thromboxane synthase gene overexpression in invasive bladder cancer.

Thromboxane synthase (TXAS) is one of the enzymes downstream from cyclooxygenase-2 and catalyzes the synthesis of thromboxane A(2) (TXA(2)). TXAS was among the genes we identified based on its overexpression in invasive bladder tumors. TXAS is overexpressed in common forms of bladder tumors: 69 of 97 (71.1%) transitional cell carcinoma (TCC), 38 of 53 (71.6%) squamous cell carcinoma, and 5 of 11 (45.5%) adenocarcinoma relative to nontumor tissue. Overall, 112 of 161 (69.5%) invasive tumors exhibited elevated expression. Significantly, patients with tumors having >4-fold levels of TXAS expression showed significant statistical evidence of lower overall survival expressed by the estimated hazard ratio of 2.74 with P = 0.009 in Cox's regression analysis. TXAS mRNA expression was found to be an independent prognostic marker for patients with bladder cancer. Treatment of bladder cancer cell lines (T24 and TCC-SUP) with TXAS inhibitors and TXA(2) (TP) receptor antagonists reduced cell growth, migration, and invasion, whereas TP agonists stimulated cell migration and invasion. The positive correlation between elevated TXAS expression and shorter patient survival supports a potential role for TXAS-regulated pathways in tumor invasion and metastases and suggests that modulation of the TXAS pathway may offer a novel therapeutic approach.

Adenocarcinoma↗

PubMed2005

Sex differences in the effect of diabetes duration on coronary heart disease mortality.

BACKGROUND: It is not known whether the coronary heart disease (CHD) mortality risk associated with recent (RDM; <10 years) or long-standing diabetes mellitus (LDM; > or =10 years) varies by sex. METHODS: The relationship between diabetes duration and CHD mortality was evaluated among 10 871 adults (aged 35-74 years at baseline) using the 1971-1992 National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. RESULTS: The CHD mortality rates per 1000 person-years in men with no myocardial infarction (MI) or diabetes, MI only, RDM only, LDM only, MI and RDM, and MI and LDM were 5.5 (95% confidence interval, 4.8-6.2), 15.2 (11.6-20.0), 13.2 (7.9-22.1), 11.4 (6.4-20.3), 36.0 (16.7-77.7), and 35.4 (14.0-89.7), respectively. The corresponding rates in women were 2.9 (2.5-3.3), 7.3 (5.0-10.8), 5.2 (3.5-7.7), 10.7 (7.5-15.5), 9.3 (4.3-19.9), and 21.6 (6.1-76.0), respectively. Compared with MI, the multivariate hazard ratios and their 95% confidence intervals (adjusted for age, race, smoking, hypertension, total cholesterol level, and body mass index) for fatal CHD in men with RDM, LDM, MI and RDM, and MI and LDM were 0.7 (0.3-1.3), 0.8 (0.4-1.4), 3.2 (1.4-7.4), and 2.4 (0.8-6.7), respectively. The corresponding ratios in women were 0.9 (0.6-1.3), 1.8 (1.1-3.2), 1.3 (0.5-3.5), and 1.6 (0.2-10.9), respectively. CONCLUSIONS: In men, RDM and LDM were associated with as high a risk for CHD death as MI. In women, although RDM had a CHD mortality risk similar to MI, LDM had an even greater risk. Because women with LDM are at very high risk for CHD mortality, current guidelines may need to be further refined to match intensity of treatment to risk in these women.

Adult↗

PubMed2004

A Bayesian approach for the analysis of panel-count data with dependent termination.

We consider modeling and Bayesian analysis for panel-count data when the termination time for each subject may depend on its history of the recurrent events. We propose a fully specified semiparametric model for the joint distribution of the recurrent events and the termination time. For this model, we provide a natural motivation, derive several novel properties, and develop a Bayesian analysis based on a Markov chain Monte Carlo algorithm. Comparisons are made to other existing models and methods for panel-count data. We demonstrate the usefulness of our new models and methodologies through the reanalysis of a data set from a clinical trial.

Algorithms↗

PubMed2004

Family-focused smoking cessation:enhanced efficacy by the addition of partner support and group therapy.

While partner support has been found to be an important factor in smoking cessation, programs with partner training have not demonstrated improved efficacy. The goal of this project was to evaluate the effectiveness of a smoking cessation treatment program that included partner support in an innovative education/therapy model similar to alcohol and drug treatment programs. Subjects included 23 smokers, 71% with a support partner. The program consisted of a smoking cessation curriculum, combined with facilitated group therapy for participants and partners, and individualized medication evaluation. Smoking abstinence was 87% at program completion and 80% at one month follow up, 100% abstinence in participants with support and 50% in participants without support (p < 0.05). Smoking Stage of Change at enrollment was: contemplation 22%, preparation 70%, and action 8%, with 87% movement toward action stage. In the present study, partner support enhanced short-term abstinence from smoking.

Adolescent↗

PubMed2003

Influence of celiac axis lymph nodes in the definitive treatment of esophageal cancer.

The management of patients with cancer of the distal thoracic esophagus is often made difficult by the presence of disease in the celiac axis lymph nodes. We investigated the outcome of such patients treated for cure in an attempt to better define the best treatment. The charts of all patients with esophageal cancer treated at the Department of Radiation Oncology at the Medical University of South Carolina between 1990 and 1998 were reviewed. Three groups of patients were analyzed: NoMo, N1Mo, and patients with positive celiac axis lymph nodes (M1a). Among 217 patients, 56 patients received radiotherapy with intent to cure, along with surgery, chemotherapy, or some combination of these modalities. Of these, 14 had disease of the distal esophagus with the celiac axis as their only site of distant disease. Comparison of survival curves in the three analyzed groups revealed no statistically significant differences in terms of overall survival (p = 0.3458 by the log-rank test) or disease-free survival (p = 0.5509 by the log-rank test). Patients with positive celiac axis lymph nodes as their only site of "M1" disease experienced a 2-year survival rate similar to "Mo" patients when treated with curative intent.

Combined Modality Therapy↗