Browsing by Author "Skill, Nicholas"

Now showing 1 - 6 of 6
  • Thumbnail Image
    Item
    Contemporary paradigm for the evaluation and treatment of hereditary gastric cancer
    (AME Publishing Company, 2019-02-25) Skill, Nicholas; Maluccio, Mary; Surgery, School of Medicine
    Gastric cancer is the third leading cause of cancer mortality worldwide. Survival is linked to stage at diagnosis and tolerance to surgery and adjuvant therapy. The emergence of sophisticated methods to identify patients at high risk for the development of gastric cancer has given us an opportunity to eliminate a lethal disease in an identifiable patient population. Guidelines and recommendations have been established and prophylactic total gastrectomy is considered the most effective treatment. However, this requires substantial physical and emotional investment. It is imperative that patients and families are supported by genetic counseling, ongoing surveillance, and survivorship studies.
  • Thumbnail Image
    Item
    Detection of Hepatocellular Carcinoma in Hepatitis C Patients: Biomarker Discovery by LC-MS
    (Elsevier, 2014-09-01) Bowers, Jeremiah; Hughes, Emma; Skill, Nicholas; Maluccio, Mary; Raftery, Daniel; Department of Surgery, IU School of Medicine
    Hepatocellular carcinoma (HCC) accounts for most cases of liver cancer worldwide; contraction of hepatitis C (HCV) is considered a major risk factor for liver cancer even when individuals have not developed formal cirrhosis. Global, untargeted metabolic profiling methods were applied to serum samples from patients with either HCV alone or HCC (with underlying HCV). The main objective of the study was to identify metabolite based biomarkers associated with cancer risk, with the long term goal of ultimately improving early detection and prognosis. Serum global metabolite profiles from patients with HCC (n=37) and HCV (n=21) were obtained using high performance liquid chromatography-mass spectrometry (HPLC-MS) methods. The selection of statistically significant metabolites for partial least-squares discriminant analysis (PLS-DA) model creation based on biological and statistical significance was contrasted to that of a traditional approach utilizing p-values alone. A PLS-DA model created using the former approach resulted in a model with 92% sensitivity, 95% specificity, and an AUROC of 0.93. A series of PLS-DA models iteratively utilizing three to seven metabolites that were altered significantly (p<0.05) and sufficiently (FC≤0.7 or FC≥1.3) showed the best performance using p-values alone, the PLS-DA model was capable of generating 73% sensitivity, 95% specificity, and an AUROC of 0.92. Metabolic profiles derived from LC-MS readily distinguish patients with HCC and HCV from those with HCV only. Differences in the metabolic profiles between highrisk individuals and HCC indicate the possibility of identifying the early development of liver cancer in at risk patients. The use of biological significance as a selection process prior to PLSDA modeling may offer improved probabilities for translation of newly discovered biomarkers to clinical application.
  • Thumbnail Image
    Item
    Differentiating Hepatocellular Carcinoma from Hepatitis C Using Metabolite Profiling
    (MDPI, 2012-10-10) Wei, Siwei; Suryani, Yuliana; Gowda, G. A. Nagana; Skill, Nicholas; Maluccio, Mary; Raftery, Daniel; Surgery, School of Medicine
    Hepatocellular carcinoma (HCC) accounts for most liver cancer cases worldwide. Contraction of the hepatitis C virus (HCV) is considered a major risk factor for liver cancer. In order to identify the risk of cancer, metabolic profiling of serum samples from patients with HCC (n=40) and HCV (n=22) was performed by 1H nuclear magnetic resonance spectroscopy. Multivariate statistical analysis showed a distinct separation of the two patient cohorts, indicating a distinct metabolic difference between HCC and HCV patient groups based on signals from lipids and other individual metabolites. Univariate analysis showed that three metabolites (choline, valine and creatinine) were significantly altered in HCC. A PLS-DA model based on these three metabolites showed a sensitivity of 80%, specificity of 71% and an area under the receiver operating curve of 0.83, outperforming the clinical marker alpha-fetoprotein (AFP). The robustness of the model was tested using Monte-Carlo cross validation (MCCV). This study showed that metabolite profiling could provide an alternative approach for HCC screening in HCV patients, many of whom have high risk for developing liver cancer.
  • Thumbnail Image
    Item
    Murine study of portal hypertension associated endothelin-1 hypo-response
    (Baishideng Publishing Group, 2015-04-28) Theodorakis, Nicholas; Maluccio, Mary; Skill, Nicholas; Department of Medicine, IU School of Medicine
    AIM: To investigate endothelin-1 hypo-responsive associated with portal hypertension in order to improve patient treatment outcomes. METHODS: Wild type, eNOS(-/-) and iNOS(-/-) mice received partial portal vein ligation surgery to induce portal hypertension or sham surgery. Development of portal hypertension was determined by measuring the splenic pulp pressure, abdominal aortic flow and portal systemic shunting. To measure splenic pulp pressure, a microtip pressure transducer was inserted into the spleen pulp. Abdominal aortic flow was measured by placing an ultrasonic Doppler flow probe around the abdominal aorta between the diaphragm and celiac artery. Portal systemic shunting was calculated by injection of fluorescent microspheres in to the splenic vein and determining the percentage accumulation of spheres in liver and pulmonary beds. Endothelin-1 hypo-response was evaluated by measuring the change in abdominal aortic flow in response to endothelin-1 intravenous administration. In addition, thoracic aorta endothelin-1 contraction was measured in 5 mm isolated thoracic aorta rings ex-vivo using an ADI small vessel myograph. RESULTS: In wild type and iNOS(-/-) mice splenic pulp pressure increased from 7.5 ± 1.1 mmHg and 7.2 ± 1 mmHg to 25.4 ± 3.1 mmHg and 22 ± 4 mmHg respectively. In eNOS(-/-) mice splenic pulp pressure was increased after 1 d (P = NS), after which it decreased and by 7 d was not significantly elevated when compared to 7 d sham operated controls (6.9 ± 0.6 mmHg and 7.3 ± 0.8 mmHg respectively, P = 0.3). Abdominal aortic flow was increased by 80% and 73% in 7 d portal vein ligated wild type and iNOS when compared to shams, whereas there was no significant difference in 7 d portal vein ligated eNOS(-/-) mice when compared to shams. Endothelin-1 induced a rapid reduction in abdominal aortic blood flow in wild type, eNOS(-/-) and iNOS(-/-) sham mice (50% ± 8%, 73% ± 9% and 47% ± 9% respectively). Following portal vein ligation endothelin-1 reduction in blood flow was significantly diminished in each mouse group. Abdominal aortic flow was reduced by 19% ± 9%, 32% ± 10% and 9% ± 9% in wild type, eNOS(-/-) and iNOS(-/-) mice respectively. CONCLUSION: Aberrant endothelin-1 response in murine portal hypertension is NOS isoform independent. Moreover, portal hypertension in the portal vein ligation model is independent of ET-1 function.
  • Thumbnail Image
    Item
    Specific Lowering of Asymmetric Dimethylarginine by Pharmacological Dimethylarginine Dimethylaminohydrolase Improves Endothelial Function, Reduces Blood Pressure and Ischemia-Reperfusion Injury
    (American Society for Pharmacology and Experimental Therapeutics, 2021) Lee, Young; Mehrotra, Purvi; Basile, David; Ullah, Mahbub; Singh, Arshnoor; Skill, Nicholas; Younes, Subhi Talal; Sasser, Jennifer; Shekhar, Anantha; Singh, Jaipal; Cellular and Integrative Physiology, School of Medicine
    Multiple clinical and preclinical studies have demonstrated that plasma levels of asymmetric dimethylarginine (ADMA) are strongly associated with hypertension, diabetes, and cardiovascular and renal disease. Genetic studies in rodents have provided evidence that ADMA metabolizing dimethylarginine dimethylaminohydrolase (DDAH)-1 plays a role in hypertension and cardiovascular disease. However, it remains to be established whether ADMA is a bystander, biomarker, or sufficient contributor to the pathogenesis of hypertension and cardiovascular and renal disease. The goal of the present investigation was to develop a pharmacological molecule to specifically lower ADMA and determine the physiologic consequences of ADMA lowering in animal models. Further, we sought to determine whether ADMA lowering will produce therapeutic benefits in vascular disease in which high ADMA levels are produced. A novel long-acting recombinant DDAH (M-DDAH) was produced by post-translational modification, which effectively lowered ADMA in vitro and in vivo. Treatment with M-DDAH improved endothelial function as measured by increase in cGMP and in vitro angiogenesis. In a rat model of hypertension, M-DDAH significantly reduced blood pressure (vehicle: 187 ± 19 mm Hg vs. M-DDAH: 157 ± 23 mm Hg; P < 0.05). Similarly, in a rat model of ischemia-reperfusion injury, M-DDAH significantly improved renal function as measured by reduction in serum creatinine (vehicle: 3.14 ± 0.74 mg/dl vs. M-DDAH: 1.1 ± 0.75 mg/dl; P < 0.01), inflammation, and injured tubules (vehicle: 73.1 ± 11.1% vs. M-DDAH: 22.1 ± 18.4%; P < 0.001). These pharmacological studies have provided direct evidence for a pathologic role of ADMA and the therapeutic benefits of ADMA lowering in preclinical models of endothelial dysfunction, hypertension, and ischemia-reperfusion injury. SIGNIFICANCE STATEMENT: High levels of ADMA occur in patients with cardiovascular and renal disease. A novel modified dimethylarginine dimethylaminohydrolase by PEGylation effectively lowers ADMA, improves endothelial function, reduces blood pressure and protects from ischemia-reperfusion renal injury.
  • Thumbnail Image
    Item
    Targeted Metabolic Profiling of Hepatocellular Carcinoma and Hepatitis C using LC-MS/MS
    (Wiley, 2013) Baniasadi, Hamid; Gowda, G. A. Nagana; Gu, Haiwei; Zeng, Ao; Zhuang, Shui; Skill, Nicholas; Maluccio, Mary; Raftery, Daniel; Surgery, School of Medicine
    Hepatitis C virus (HCV) infection of the liver is a global health problem and a major risk factor for the development of hepatocellular carcinoma (HCC). Sensitive methods are needed for the improved and earlier detection of HCC, which would provide better therapy options. Metabolic profiling of the high-risk population (HCV patients) and those with HCC provides insights into the process of liver carcinogenesis and possible biomarkers for earlier cancer detection. Seventy-three blood metabolites were quantitatively profiled in HCC (n = 30) and cirrhotic HCV (n = 22) patients using a targeted approach based on LC-MS/MS. Sixteen of 73 targeted metabolites differed significantly (p < 0.05) and their levels varied up to a factor of 3.3 between HCC and HCV. Four of these 16 metabolites (methionine, 5-hydroxymethyl-2'-deoxyuridine, N2,N2-dimethylguanosine, and uric acid) that showed the lowest p values were used to develop and internally validate a classification model using partial least squares discriminant analysis. The model exhibited high classification accuracy for distinguishing the two groups with sensitivity, specificity, and area under the receiver operating characteristic curve of 97%, 95%, and 0.98, respectively. A number of perturbed metabolic pathways, including amino acid, purine, and nucleotide metabolism, were identified based on the 16 biomarker candidates. These results provide a promising methodology to distinguish cirrhotic HCV patients, who are at high risk to develop HCC, from those who have already progressed to HCC. The results also provide insights into the altered metabolism between HCC and HCV.