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Biomedical subjects

Kirti Shetty

Publications and source records attributed to Kirti Shetty.

8 recordsLinked to original sources
PubMed2006

TGF-beta signaling pathway inactivation and cell cycle deregulation in the development of gastric cancer: role of the beta-spectrin, ELF.

We have shown that loss of ELF, a stem cell adaptor protein, disrupts TGF-beta signaling through Smad3 and Smad4 localization. Notably elf(+/-)/smad4(+/-) mice develop gastric cancer presenting this as an important model for analyzing molecular event in gastric carcinogenesis. To gain further insight into the functional role of ELF in gastric cancer suppression, we carried out a detailed characterization of cell cycle events leading to gastric tumorigenesis. elf(-/-) cells and elf(+/-)/smad4(+/-) mice demonstrate a marked alteration of cell cycle regulators, such as Cdk4, K-Ras, and p21. Levels of Cdk4 increased compared to normal controls, suggesting loss of ELF results in functional abnormalities in cell cycle regulation. We further demonstrate that the elf(-/-) MEFs show a disruption of G1/S cell cycle transition and a significant reduction in senescence. Thus, in response to ELF deficiency, the abnormalities of G1/S checkpoint and senescence contribute their increment of susceptibility to malignant transformation.

Aging↗
PubMed2005

The role of TGF-beta and Wnt signaling in gastrointestinal stem cells and cancer.

The past three decades have seen an unremitting quest to identify and understand gastrointestinal stem cells, their plasticity in differentiating across cell types, as well as their role in normal, regenerative, and cancer cells. A fascinating hallmark of stem cells is their ability to undergo assymetric cell division, which entails replication of the DNA followed by division of the nucleus and partitioning of the cytoplasm to yield two different daughter cells: a stem cell as well as a committed progenitor cell, the latter proliferating into differentiated progeny. We are only just beginning to understand how normally quiescent, tissue-specific stem cells interpret a vast array of signals to develop into the gastrointestinal system. These signaling pathways include the transforming growth factor-beta (TGF-beta) superfamily, Wnt, FGFs, Hedgehog, Hox proteins that originate from surrounding mesodermal/stromal tissue as well as endodermal/epithelial tissue. TGF-beta and wnt proteins are key morphogens that ultimately influence cell division and cell fate, so that gut endodermal stem cells enter the cell cycle, and undergo cell division that ultimately leads to differentiated cells such as functional hepatocytes, gastric parietal cells, or gut epithelial cells. Disruptions and errors in this process usually lead to tissue-specific gastrointestinal cancers such as hepatocellular cancers, gastric adenocarcinomas, and colonic adenocarcinomas. An increasingly complex and coherent view of stem/progenitor cell signaling networks, which coordinate cell growth, proliferation, stress management, and survival, is helping to define the fragile areas where malignancies are likely to develop and shows promise for the development of better cancer therapies.

Animals↗
PubMed2005

T-cell response relative to genotype and ethnicity during antiviral therapy for chronic hepatitis C.

Viral genotype and host ethnicity are important predictors of viral clearance during antiviral therapy for chronic hepatitis C virus (HCV) infection. Based on the role of T cells in natural HCV clearance, we hypothesized that T cells may contribute to the genotypic and ethnic difference in treatment outcome. To test this hypothesis, T-cell response to HCV antigens (core, nonstructural NS3/4 and NS5) and control phytohemagglutinin (PHA) was monitored prospectively and was correlated with virological outcome in 41 patients chronically infected with HCV (27 genotype 1, 14 genotype 2 or 3; 19 black persons, 22 white persons) undergoing combined interferon alfa and ribavirin therapy. Interestingly, in patients with genotype 2 or 3 infection, enhanced virological response coincided with a greater T-cell response to HCV NS3/4 antigen at baseline (50% vs. 15%; P = .026) that augmented further during therapy (29% vs. 4%; P = .035) compared with genotype 1-infected patients. However, HCV-specific T-cell response remained weak in genotype 1-infected patients regardless of virological outcome or ethnicity. Furthermore, virological outcome was associated with a suppressed baseline proliferative response to phytohemagglutinin (P < .03) that increased during therapy (P < .003) independent of ethnicity or genotype. In conclusion, HCV-specific T-cell response was associated with HCV genotype but not with therapeutic clearance of HCV infection. The association between treatment outcome and phytohemagglutinin response suggests more global and antigen-nonspecific mechanisms for therapeutic HCV clearance.

Antiviral Agents↗
PubMed2005

Renal function after orthotopic liver transplantation is predicted by duration of pretransplantation creatinine elevation.

In patients with recent onset renal insufficiency, the decision to perform combined kidney/liver transplantation (CKLT) vs. orthotopic liver transplantation alone (OLTa) can be difficult. We hypothesized that duration of renal dysfunction may correlate with creatinine elevation after liver transplantation. We retrospectively identified 69 liver transplantation patients with pretransplantation creatinine > or =1.5 mg/dL (53 OLTa, 13 CKLT). Variables analyzed were presence of hepatorenal syndrome, creatinine, Model for End-Stage Liver Disease score, albumin, age, race, gender, cause of liver disease, diabetes mellitus, hypertension, and history of ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatic encephalopathy, renal replacement therapy (RRT), and transjugular intrahepatic portosystemic shunting. Duration of pretransplantation renal dysfunction was predictive of 6- and 12-month creatinine post-OLTa. Area under the receiver operating characteristic (ROC) curve for prediction of 12-month renal insufficiency by renal dysfunction duration was 0.71; optimal duration cutoff was 3.6 weeks. We applied a multivariable model, derived from OLTa patients, to CKLT subjects with definite or possible hepatorenal syndrome. Predicted 12-month creatinine without renal transplantation was >2.0 mg/dL for each patient. CKLT patients as opposed to OLTa patients had longer duration of renal dysfunction (median, 18.1 vs. 2.7 weeks, P < 0.001), higher creatinine (median 4.0 versus 1.7 mg/dL, P < 0.001), and higher rate of pretransplantation RRT (62% vs. 7%, P < 0.001). Adjusting for baseline characteristics, CKLT patients had lower creatinine than OLTa patients at 6 months (P =0.15) and 12 months (P =0.01) after transplantation. In conclusion, duration, but not cause, of renal dysfunction predicts renal outcome in OLTa recipients. Prospective studies may use duration of renal dysfunction to help identify CKLT candidates.

Cohort Studies↗
PubMed2005

A comparison of tacrolimus and cyclosporine in liver transplantation: effects on renal function and cardiovascular risk status.

A retrospective chart review of 1065 consecutive liver allograft recipients in 11 centers from January 1997 to September 1998 was performed. Patients were followed for 3 years or until graft loss. Patients received either tacrolimus (n = 594), cyclosporine (n = 450) or no calcineurin inhibitor (n = 21). Model for end-stage liver disease (MELD) scores at time of transplant were similar between the two groups. During follow-up, more patients switched from cyclosporine to tacrolimus (26.7%) than from tacrolimus to cyclosporine (12.8%; p < 0.0001). Patient and graft survival were equivalent. Corticosteroid use was more common in cyclosporine-treated patients (p < 0.00001). Patients receiving tacrolimus experienced lower serum creatinine levels at months 3 through 36 (p < 0.0001). Systolic blood pressure was lower in patients receiving tacrolimus (p < 0.001) despite a reduced requirement for anti-hypertensive agents (p < 0.0001). In addition, tacrolimus was associated with lower total cholesterol and triglyceride levels for months 3 through 24 and 3 through 12, respectively (p < 0.01), despite a reduced requirement for anti-hyperlipidemic agents. The incidence of new-onset diabetes mellitus was similar in both groups. While both calcineurin inhibitors were associated with excellent patient and graft survival, renal function, blood pressure and serum lipid levels were significantly better with tacrolimus treatment.

Adolescent↗
PubMed2004

Liver transplantation for hepatocellular carcinoma validation of present selection criteria in predicting outcome.

Appropriate patient selection is crucial in ensuring acceptable outcomes from orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). The United Network for Organ Sharing (UNOS) has elected to prioritize HCC patients for OLT based on criteria of tumor burden. However, it is unclear whether these criteria correlate with outcome, or with the pathobiological features associated with tumor recurrence. Therefore, we analyzed 109 consecutive patients undergoing OLT for HCC at our center, to determine the utility of present selection criteria in predicting outcome. Pathologic tumor staging of the explanted liver was based on the American Tumor Study Group modified tumor node metastases (pTNM) classification system. Multifocality was defined as >4 tumor nodules on explant. Survival analysis was performed using Kaplan-Meier and Cox proportional hazards regression methods. At a median follow-up of 18.9 months, the overall mortality was 19% with 15 patients (14%) dying of recurrent HCC. Kaplan-Meier 1, 3 and 5-year survival rates were 89.5%, 68%, and 65%, respectively. Recurrence-free rates of 1, 3, and 5 years were 89%, 75%, and 65%, respectively. On univariate analysis, the factors found to be significantly associated with recurrence of HCC were explant features of macrovascular invasion, tumor size (per centimeter increase), pTNM stage (per 1-stage increase), and pre-transplant serum alphafetoprotein (AFP) >300 ng/mL. In defining a threshold level, we found that explant tumor diameter > or =3 cm, and those tumors classified as at least pT3 on pathological examination, were significantly associated with recurrence (P =.01 and.03, respectively). Tumor size on explant was found to be strongly correlated with multifocality (P =.017) and vascular invasion (P =.02). Patients exceeding pathological UNOS criteria were 3.1 times more likely to have recurrence of HCC (P =.03). In conclusion, we found that tumor size appears to be a surrogate marker for negative pathobiological predictors of outcome, i.e., vascular invasion and multifocality. Present UNOS selection criteria for HCC based on tumor burden appear to provide adequate discriminatory power in predicting outcome of OLT.

Adult↗
PubMed2004

Endoscopic management of biliary complications after adult living donor liver transplantation.

OBJECTIVES: Biliary complications and their treatment in adult cadaveric liver transplantation (CLT) are well described. However, biliary complications and their management in living donor liver transplantation (LDLT) are not well characterized. We assessed the role of endoscopic retrograde cholangiopancreatography (ERCP) in the diagnosis and management of biliary complications following LDLT. METHODS: We performed a retrospective cohort analysis of all LDLT recipients with duct-to-duct anastomoses (n = 15). Specific data included referral for ERCP, diagnosis, and therapy. Comparisons were made to a 260 CLT recipient cohort. RESULTS: Greater percentage of LDLT recipients underwent ERCP (73%) compared to CLT recipients (25%; p= 0.001). Biliary complications diagnosed by ERCP in LDLT recipients consisted of bile leaks and strictures, and were more frequent than in CLT recipients (leaks: 53%vs 12%; p= 0.001; strictures: 27%vs 5%; p= 0.01). Most leaks occurred at T-tube sites (LDLT: 87%; CLT: 65%). Diagnosis and therapy of leaks required a median of 2 ERCP procedures in both groups. Bile leaks were successfully treated endoscopically in 100% and 84% of LDLT and CLT recipients, respectively (p= 0.56). Most biliary strictures were anastomotic (LDLT: 100%; CLT: 64%). Strictures were diagnosed and treated with a median of 1.5 and 2 ERCP procedures in the LDLT and CLT groups, respectively. The duration of endoscopic therapy was a median of 10 and 14 wk, and success rates were 75% and 62% (p= 1.0) in LDLT and CLT groups, respectively. CONCLUSIONS: LDLT is associated with increased biliary complications as compared to CLT. ERCP is useful for diagnosis, can successfully treat most LDLT-related biliary complications, and should be attempted prior to more invasive interventions.

Adolescent↗