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Biomedical subjects

Sanjay Bansal

Publications and source records attributed to Sanjay Bansal.

9 recordsLinked to original sources
PubMed2006

Estrogen receptor-alpha binds p53 tumor suppressor protein directly and represses its function.

Estrogen receptor-alpha (ERalpha) promotes proliferation of breast cancer cells, whereas tumor suppressor protein p53 impedes proliferation of cells with genomic damage. Whether there is a direct link between these two antagonistic pathways has remained unclear. Here we report that ERalpha binds directly to p53 and represses its function. The activation function-2 (AF-2) domain of ERalpha and the C-terminal regulatory domain of p53 are necessary for the interaction. Knocking down p53 and ERalpha by small interfering RNA elicits opposite effects on p53-target gene expression and cell cycle progression. Remarkably, ionizing radiation that causes genomic damage disrupts the interaction between ERalpha and p53. Ionizing radiation together with ERalpha knock down results in additive effect on transcription of endogenous p53-target gene p21 (CDKN1) in human breast cancer cells. Our findings reveal a novel mechanism for regulating p53 and suggest that suppressing p53 function is an important component in the pro-proliferative role of ERalpha.

Breast Neoplasms↗
PubMed2006

Acute liver failure.

Acute liver failure in children is a rare but potentially fatal disease. Causes of ALF in neonatal period are different from those in early or late childhood. Despite the improvement in the paediatric intensive care, liver transplantation remains the only effective treatment. Use of newer treatment modalities (liver assist devices and hepatocyte transplantation) is still in experimental phase. Management requires early recognition, prompt diagnosis of treatable condition, supportive therapy and prevention of complications hence these children should ideally be treated in a specialist unit.

Child↗
PubMed2006

Oral clindamycin 300 mg BID compared with oral amoxicillin/clavulanic acid 1 g BID in the outpatient treatment of acute recurrent pharyngotonsillitis caused by group a beta-hemolytic streptococci: an international, multicenter, randomized, investigator-blinded, prospective trial in patients between the ages of 12 and 60 years.

BACKGROUND: The increasing rate of treatment failure with penicillin and other beta-lactam antibiotics in pharyngotonsillitis caused by group A beta-hemolytic streptococci (GABHS) has prompted the search for alternative antimicrobials. Both clindamycin and amoxicillin/clavulanic acid have excellent clinical activity in pharyngotonsillitis. OBJECTIVE: This study compared the clinical and bacteriologic efficacy and tolerability of oral clindamycin with those of oral amoxicillin/clavulanic acid in the outpatient treatment of acute recurrent GABHS pharyngotonsillitis. METHODS: This was an international, multicenter, randomized, investigator-blinded, prospective study in patients with acute recurrent pharyngotonsillitis. Recurrence was defined as > or =2 episodes of documented pharyngeal and/or tonsillar infection within the 12 months before the study. A rapid diagnostic test for GABHS was performed before initiating therapy, and positive results were confirmed by pharyngotonsillar culture. Patients were randomly assigned to receive oral clindamycin 300 mg BID or oral amoxicillin/clavulanic acid 1 g BID for 10 days. Culture was repeated on day 12. The primary study end points were clinical and bacteriologic efficacy assessed on day 12, and clinical and bacteriologic recurrence rates assessed at a visit taking place up to 3 months after the completion of treatment. Tolerability was the secondary end point. RESULTS: Seven hundred seventy-four patients with acute, recurrent GABHS pharyngotonsillitis were enrolled in the study (mean age, 28 years; age range, 12-60 years). Five hundred forty-two patients (272 clindamycin, 270 amoxicillin/clavulanic acid) were clinically evaluable at day 12. Four hundred ninety-four patients were bacteriologically evaluable, and the safety population included 772 patients. There were no significant differences between groups at baseline. In terms of clinical efficacy at day 12, 252/272 (92.6%) patients in the clindamycin group and 230/270 (85.2%) patients in the amoxicillin/clavulanic acid group were considered cured (P < 0.003). At day 12, bacteriologic eradication was achieved in 237/242 (97.9%) and 238/252 (94.4%) patients in the respective treatment groups (P = NS). No clinical response was observed in the absence of bacteriologic eradication. At 3-month follow-up, clinical cure was achieved in 267/280 (95.4%) patients in the clindamycin group and 267/280 (95.7%) patients in the amoxicillin/clavulanic acid group (P = NS); bacteriologic eradication was observed in 235 (99.2%) and 237 (99.6%) of the respective treatment groups (P = NS). Both treatments were well tolerated. Adverse events were reported in 53/384 (13.8%) patients in the clindamycin group and 41/390 (10.5%) patients in the amoxicillin/clavulanic acid group. The most commonly reported adverse events involved the digestive system (mainly diarrhea), occurring in 33 (8.6%) and 22 (5.6%) patients in the respective treatment groups. CONCLUSIONS: In this study in patients with acute recurrent GABHS pharyngotonsillitis, oral clindamycin 300 mg BID and oral amoxicillin/clavulanic acid 1 g BID achieved comparable rates of bacteriologic eradication at 12 days and 3 months and comparable clinical cure rates at 3 months. Patients who received clindamycin had significantly greater clinical cure rates at 12 days. Both regimens were well tolerated.

Acute Disease↗
PubMed2006

Polyclonal T-cell responses to cytochrome P450IID6 are associated with disease activity in autoimmune hepatitis type 2.

BACKGROUND & AIMS: Autoimmune hepatitis type 2 (AIH-2), a severe juvenile liver disorder of unknown etiology and pathogenesis, is characterized by liver-kidney microsomal antibody type 1 targeting cytochrome P450IID6 (CYP2D6) and is associated to HLA DRB1*07. Although CYP2D6 B-cell reactivity has been extensively characterized, little is known about CYP2D6-specific T-cell responses. The aim of the present study was to characterize anti-CYP2D6 cellular immune responses and their possible pathogenic role in patients with AIH-2. METHODS: We investigated T-cell reactivity against 61 overlapping peptides spanning the full CYP2D6 protein using ex vivo cultures obtained at diagnosis, remission, and relapse. Moreover, CYP2D6-specific T-cell reactivity was investigated in the context of HLA restriction, peptide-binding affinity to HLA DRB1*07, cytokine profile, disease specificity, and clinical course. RESULTS: Proliferative responses to CYP2D6 cluster to 7 antigenic regions in DRB1*07 and to 4 regions in non-DRB1*07 patients. Whereas distinct peptides induce production of interferon gamma, interleukin-4, or interleukin-10, peptides inducing interferon-gamma and proliferation overlap. There is also an overlap between sequences inducing T- and B-cell responses. The breadth (number of epitopes) and intensity (quantity of cytokine produced) of the T-cell response are directly correlated to disease activity (biochemical and histologic markers). CONCLUSIONS: These data imply that the T-cell response to CYP2D6 in AIH-2 is polyclonal, involves multiple effector types targeting different epitopes, and is associated with hepatocyte damage, knowledge that should form the basis for a more refined therapeutic approach.

Adolescent↗
PubMed2005

Cross talk between mitochondria and superoxide generating NADPH oxidase in breast and ovarian tumors.

Reactive oxygen species (ROS) signal cascades involved in cell growth, cell death, mitogenesis, angiogenesis and carcinogenesis. ROS are produced as a byproduct of oxidative phosphorylation (OXPHOS) in the mitochondria. It is estimated that 2-4% of the oxygen consumed during OXPHOS is converted to ROS. Besides mitochondria, NADPH-oxidase 1 (Nox1) also generates a significant amount of ROS in the cell. In this paper, we tested the hypothesis that mitochondria control Nox 1 redox signaling and the loss of control of this signaling contributes to tumorigenesis. We analyzed Nox1 expression in a mitochondrial gene knockout (rho(0)) cell line and in the isogenic cybrid cell line in which mitochondrial genes were restored by transfer of wild type mitochondria into rho(0) cells. Our study revealed, for the first time, that the inactivation of mitochondrial genes leads to down-regulation of Nox1 and that the transfer of wild type mitochondrial genes restored the Nox1 expression to a level comparable to that in the parental cell line. Consistent with Nox1 down-regulation, we found that rho(0) cells contained low levels of superoxide anion and that superoxide levels reversed to parental levels in cybrid cells when Nox1 expression was restored by transfer of wild type mitochondria. Increasing mitochondrial superoxide levels also increased the expression of Nox1 in parental cells. Confocal microscopy studies revealed that Nox1 localizes in the mitochondria. Nox1 was highly expressed in breast (86%) and ovarian (71%) tumors and that its expression positively correlated with expression of cytochrome C oxidase encoded by mtDNA. Our study, described in this paper demonstrates the existence of cross talk between the mitochondria and NADPH oxidase. Furthermore, our studies suggest that mitochondria control Nox1 redox signaling and the loss of control of this signaling contributes to breast and ovarian tumorigenesis.

Breast Neoplasms↗
PubMed2005

Chronic liver disease related to 6-thioguanine in children with acute lymphoblastic leukaemia.

BACKGROUND/AIMS: The United Kingdom (UK) acute lymphoblastic leukaemia (ALL) 97/99 clinical trial compared 6-mercaptopurine (6MP) with 6-thioguanine (6TG) as maintenance therapy for childhood ALL. Review of interim results has led to discontinuation of the 6TG arm. METHODS: We report six children with ALL, who presented with splenomegaly after a median (range) treatment duration of 12 (6-22) months. All these children were treated in the 6TG-arm. RESULTS: The median (range) age at presentation was 6.6 (3.2-11.5) years. There were five boys. The presenting features were splenomegaly in all and hepatomegaly in four. AST was abnormal in one (80 IU/l, normal range 10-50). Abdominal sonography showed an altered texture of the liver parenchyma and confirmed splenomegaly. Microscopy showed findings within the spectrum of occlusive venopathy and nodular regenerative hyperplasia (NRH). After a median (range) follow-up of 23 (4-36) months splenomegaly and thrombocytopenia, suggestive of progressive portal hypertension, continue to worsen in all children. CONCLUSIONS: 6TG is associated with chronic hepatic toxicity and progressive portal hypertension on follow-up. Microscopy showed NRH in all patients with features in keeping with an intrahepatic occlusive venopathy and variable parenchymal atrophy and loss.

Antimetabolites, Antineoplastic↗
PubMed2004

Hepatocyte transplantation for inherited factor VII deficiency.

Hepatocyte transplantation has been investigated in patients with liver-based metabolic disorders and acute liver failure. We report the first use of hepatocyte transplantation in two brothers with severe inherited coagulation factor VII deficiency. Patient 1 received a total of 1.09x10(9) cryopreserved hepatocytes, and patient received 2.18x10(9) fresh and cryopreserved hepatocytes through a Hickman line inserted in the inferior mesenteric vein. Infusion of isolated human hepatocytes improved the coagulation defect and markedly decreased the requirement for exogenous recombinant factor VII (rFVIIa) to approximately 20% of that before cell transplantation. In both patients, episodes of line sepsis were associated with an increase in rFVIIa requirement. Six months posthepatocyte transplantation, higher rFVIIa doses were required, suggesting loss of transplanted hepatocyte function. Because of increasing problems with venous access and long-term uncertainty of the efficacy of hepatocyte transplantation, orthotopic liver transplantation was performed successfully in both cases.

Adolescent↗
PubMed2004

One liver, three recipients: segment IV from split-liver procedures as a source of hepatocytes for cell transplantation.

Hepatocyte transplantation is emerging as a possible treatment for patients with acute liver failure and liver-based metabolic disorders. With the limited availability of donor tissue, it is important to find new sources of liver tissue for isolation of high-quality hepatocytes. Segment IV with or without the caudate lobe was removed during three split-liver procedures. Hepatocytes were isolated from the tissues using a collagenase perfusion technique under strict sterile conditions. The mean number of hepatocytes that were isolated was 5.14 x 10(8) cells with a mean cell viability of 89%. Two of the hepatocyte preparations were used for cell transplantation in a 1-day-old boy with an antenatal diagnosis of a severe urea cycle defect caused by ornithine transcarbamylase deficiency. The six recipients of split-liver grafts demonstrated no complications related to the removal of segment IV. Segment IV with or without the caudate lobe obtained from split-liver procedures is potentially a good source of high-quality hepatocytes for cell transplantation.

Adolescent↗