Hepatic steatosis is often seen in patients with chronic hepatitis C (CH-C). It is still unclear whether these patients have an impaired mitochondrial β-oxidation. In this study we assessed mitochondrial β-oxidation in CH-C patients by investigating ketogenesis during fasting.
Post-diagnosis hemoglobin change associates with overall survival of multiple...Enrique Moreno Gonzalez
Anemia refers to low hemoglobin (Hb) level and is a risk factor of cancer patient survival. The National Comprehensive Cancer Network recently suggested that post-diagnosis Hb change, regardless of baseline Hb level, indicates the potential presence of anemia. However, there is no epidemiological study evaluating whether Hb change has direct prognostic values for cancer patients at the population level.
Abnormal expression of Pygopus 2 correlates with a malignant phenotype in hum...Enrique Moreno Gonzalez
Pygopus 2 (Pygo2) is a Pygo family member and an important component of the Wnt signaling transcriptional complex. Despite this data, no clinical studies investigating Pygo2 expression in lung cancer have yet been reported.
Ohio State's 2016 ASH Review Blood and Marrow Trasplantation (with Turning Po...OSUCCC - James
Ohio State’s 2016 ASH Review
Blood and Marrow Transplantation
Basem M. William, MD, MRCP(UK), FACP
Assistant Professor of Internal Medicine
Blood and Marrow Transplant Program
Ohio States 2016 ASH Review Blood and Marrow TransplantationOSUCCC - James
Ohio State’s 2016 ASH Review
Blood and Marrow Transplantation
Basem M. William, MD, MRCP(UK), FACP
Assistant Professor of Internal Medicine
Blood and Marrow Transplant Program
Post-diagnosis hemoglobin change associates with overall survival of multiple...Enrique Moreno Gonzalez
Anemia refers to low hemoglobin (Hb) level and is a risk factor of cancer patient survival. The National Comprehensive Cancer Network recently suggested that post-diagnosis Hb change, regardless of baseline Hb level, indicates the potential presence of anemia. However, there is no epidemiological study evaluating whether Hb change has direct prognostic values for cancer patients at the population level.
Abnormal expression of Pygopus 2 correlates with a malignant phenotype in hum...Enrique Moreno Gonzalez
Pygopus 2 (Pygo2) is a Pygo family member and an important component of the Wnt signaling transcriptional complex. Despite this data, no clinical studies investigating Pygo2 expression in lung cancer have yet been reported.
Ohio State's 2016 ASH Review Blood and Marrow Trasplantation (with Turning Po...OSUCCC - James
Ohio State’s 2016 ASH Review
Blood and Marrow Transplantation
Basem M. William, MD, MRCP(UK), FACP
Assistant Professor of Internal Medicine
Blood and Marrow Transplant Program
Ohio States 2016 ASH Review Blood and Marrow TransplantationOSUCCC - James
Ohio State’s 2016 ASH Review
Blood and Marrow Transplantation
Basem M. William, MD, MRCP(UK), FACP
Assistant Professor of Internal Medicine
Blood and Marrow Transplant Program
Expanding treatment platform in m crc bayer - asyut 2018Mohamed Abdulla
Describes the different therapeutic approach to patients with metastatic colorectal cancer in the 3rd subsequent treatment line with especial emphasis on the role of regorafenib and how to manipulate the adverse events while not compromise the outcome.
Hepatitis B infection in Stem cell transplant patients and role of lamivudine...Alok Gupta
The presentation describes Hepatitis B infection in Stem cell transplant patients and role of lamivudine prophylaxis in prevention.
The presentation was made at annual meeting of Mumbai Hematology Group held at ACTREC, Mumbai in 2014.
hMSH2 Gly322Asp (rs4987188) Single nucleotide polymorphism and the risk of br...Agriculture Journal IJOEAR
Aim: Breast cancer is the most common cancer in women both in the developed and less developed world. The reported study was designed to explore associations between hMSH2 - Gly322Asp (1032G>A, rs4987188) single nucleotide polymorphism (SNP) and the risk of breast carcinoma in the Polish women.
Material and methods: Blood samples were obtained from women with breast cancer (n=225), treated at the Department of Oncological Surgery and Breast Diseases, Polish Mother’s Memorial Hospital – Research Institute between the years 2005 and 2012. A control group included 220 cancer-free women. Genomic DNA was isolated and the SNP Gly322Asp of hMSH2 was determined by High-Resolution Melter method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each genotype and allele.
Results: This study revealed that single nucleotide polymorphism Gly322Asp of hMSH2 is associated with both breast cancer risk and grading. Moreover, it can be linked with breast carcinoma tumor size and lymph node status. The Asp allele in patients may be a risk factor for breast carcinoma (OR 5.12; 95% CI 3.77 –6.97, p<.0001).
Conclusions: Gly322Asp single nucleotide polymorphism of hMSH2 may be a risk factor of breast cancer in the Polish women.
Connexin-43 can delay early recurrence and metastasis in patients with hepati...Enrique Moreno Gonzalez
We studied the relationships among Cx43, CD105, and VEGF in specimens of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) with different serum AFP levels with respect to recurrence and metastasis.
Prostate cancer the androgenic fortified dogmaMohamed Abdulla
It describes the androgenic nature of prostate cancer and the androgenic axis should be tackled in all phases of prostate cancer. Also a special emphasis on recent data on management of metastatic hormone sensitive prostate cancer.
Functional p53 is required for rapid restoration of daunorubicin-induced lesi...Enrique Moreno Gonzalez
The tumour suppressor and transcription factor p53 is a major determinant of the therapeutic response to anthracyclines. In healthy tissue, p53 is also considered pivotal for side effects of anthracycline treatment such as lesions in haematopoietic tissues like the spleen. We used a Trp53null mouse to explore the significance of p53 in anthracycline (daunorubicin) induced lesions in the spleen.
Expanding treatment platform in m crc bayer - asyut 2018Mohamed Abdulla
Describes the different therapeutic approach to patients with metastatic colorectal cancer in the 3rd subsequent treatment line with especial emphasis on the role of regorafenib and how to manipulate the adverse events while not compromise the outcome.
Hepatitis B infection in Stem cell transplant patients and role of lamivudine...Alok Gupta
The presentation describes Hepatitis B infection in Stem cell transplant patients and role of lamivudine prophylaxis in prevention.
The presentation was made at annual meeting of Mumbai Hematology Group held at ACTREC, Mumbai in 2014.
hMSH2 Gly322Asp (rs4987188) Single nucleotide polymorphism and the risk of br...Agriculture Journal IJOEAR
Aim: Breast cancer is the most common cancer in women both in the developed and less developed world. The reported study was designed to explore associations between hMSH2 - Gly322Asp (1032G>A, rs4987188) single nucleotide polymorphism (SNP) and the risk of breast carcinoma in the Polish women.
Material and methods: Blood samples were obtained from women with breast cancer (n=225), treated at the Department of Oncological Surgery and Breast Diseases, Polish Mother’s Memorial Hospital – Research Institute between the years 2005 and 2012. A control group included 220 cancer-free women. Genomic DNA was isolated and the SNP Gly322Asp of hMSH2 was determined by High-Resolution Melter method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each genotype and allele.
Results: This study revealed that single nucleotide polymorphism Gly322Asp of hMSH2 is associated with both breast cancer risk and grading. Moreover, it can be linked with breast carcinoma tumor size and lymph node status. The Asp allele in patients may be a risk factor for breast carcinoma (OR 5.12; 95% CI 3.77 –6.97, p<.0001).
Conclusions: Gly322Asp single nucleotide polymorphism of hMSH2 may be a risk factor of breast cancer in the Polish women.
Connexin-43 can delay early recurrence and metastasis in patients with hepati...Enrique Moreno Gonzalez
We studied the relationships among Cx43, CD105, and VEGF in specimens of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) with different serum AFP levels with respect to recurrence and metastasis.
Prostate cancer the androgenic fortified dogmaMohamed Abdulla
It describes the androgenic nature of prostate cancer and the androgenic axis should be tackled in all phases of prostate cancer. Also a special emphasis on recent data on management of metastatic hormone sensitive prostate cancer.
Functional p53 is required for rapid restoration of daunorubicin-induced lesi...Enrique Moreno Gonzalez
The tumour suppressor and transcription factor p53 is a major determinant of the therapeutic response to anthracyclines. In healthy tissue, p53 is also considered pivotal for side effects of anthracycline treatment such as lesions in haematopoietic tissues like the spleen. We used a Trp53null mouse to explore the significance of p53 in anthracycline (daunorubicin) induced lesions in the spleen.
Differentiation of irradiation and cetuximab induced skin reactions in patien...Enrique Moreno Gonzalez
In order to improve the clinical outcome of patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) not being capable to receive platinum-based chemoradiation, radiotherapy can be intensified by addition of cetuximab, a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR). The radioimmunotherapy with cetuximab is a feasible treatment option showing a favourable toxicity profile. The most frequent side effect of radiotherapy is radiation dermatitis, the most common side effect of treatment with cetuximab is acneiform rash. Incidence and severity of these frequent, often overlapping and sometimes limiting skin reactions, however, are not well explored. A clinical and molecular differentiation between radiogenic skin reactions and skin reactions caused by cetuximab which may correlate with outcome, have never been described before.
Cost-effectiveness of MRI for breast cancer screening in BRCA1/2 mutation car...Enrique Moreno Gonzalez
Women with mutations in BRCA1 or BRCA2 are at high risk of developing breast cancer and, in British Columbia, Canada, are offered screening with both magnetic resonance imaging (MRI) and mammography to facilitate early detection. MRI is more sensitive than mammography but is more costly and produces more false positive results. The purpose of this study was to calculate the cost-effectiveness of MRI screening for breast cancer in BRCA1/2 mutation carriers in a Canadian setting.
Overexpression of YAP 1 contributes to progressive features and poor prognosi...Enrique Moreno Gonzalez
Yes-associated protein 1 (YAP 1), the nuclear effector of the Hippo pathway, is a key regulator of organ size and a candidate human oncogene in multiple tumors. However, the expression dynamics of YAP 1 in urothelial carcinoma of the bladder (UCB) and its clinical/prognostic significance are unclear.
Cholestasis induces reversible accumulation of periplakin in mouse liverEnrique Moreno Gonzalez
Periplakin (PPL) is a rod-shaped cytolinker protein thought to connect cellular adhesion junctional complexes to cytoskeletal filaments. PPL serves as a structural component of the cornified envelope in the skin and interacts with various types of proteins in cultured cells; its level decreases dramatically during tumorigenic progression in human epithelial tissues. Despite these intriguing observations, the physiological roles of PPL, especially in noncutaneous tissues, are still largely unknown. Because we observed a marked fluctuation of PPL expression in mouse liver in association with the bile acid receptor farnesoid X receptor (FXR) and cholestasis, we sought to characterize the role of PPL in the liver and determine its contributions to the etiology and pathogenesis of cholestasis.
CXCR7 is induced by hypoxia and mediates glioma cell migration towards SDF-1a...Enrique Moreno Gonzalez
Glioblastomas, the most common and malignant brain tumors of the central nervous system, exhibit high invasive capacity, which hinders effective therapy. Therefore, intense efforts aimed at improved therapeutics are ongoing to delineate the molecular mechanisms governing glioma cell migration and invasion.
Transglucosidase improves the gut microbiota profile of type 2 diabetes melli...Enrique Moreno Gonzalez
Recently, the relationship between gut microbiota and obesity has been highlighted. The
present randomized, double-blind, placebo-controlled study aimed to evaluate the efficacy of
transglucosidase (TGD) in modulating blood glucose levels and body weight gain in patients
with type 2 diabetes mellitus (T2DM) and to clarify the underlying mechanism by analyzing
the gut microbiota of T2DM patients.
Cystatin C as a marker of Cardio metabolic disorder in obese South Indian ind...iosrjce
Human obesity is strongly associated with cardio metabolic disease. Cystatin C is a
naturally occurring protease inhibitor and marker of cardiovascular disease. The main objective of present
study was to estimate the serum levels of Cystatin C in individuals with normal BMI, and obese, aged between
18-39 Yrs and to compare the levels of serum Cystatin C among these individuals and to correlate the levels of
serum Cystatin C with cardio metabolic risk factors.
Material & Methods: The study population was taken from healthy volunteers of Mysore city, aged between 18-
39 years of either sex. The study population was divided into 2 groups based on BMI. Each group contains
sample size of 45. Fasting serum sample was analyzed for Blood glucose, Total cholesterol, Total Triglycerides,
Direct HDL cholesterol, Direct LDL Cholesterol by enzymatic method and serum Cystatin-C by
immunoturbidimetric method using auto analyser.
Results: The serum Cystatin C levels was significantly increased in obese groups, p value<0.001. The mean
serum Cystatin C levels in normal BMI group was 0.78±0.03, and in Obese group is 1.15±0.09. In the study
serum Cystatin C showed a positive correlation with serum glucose(r=0.61) serum triglycerides (r=0.7),
Atherogenic index of plasma (AIP) (r=0.80), TCHOL: HDL (r=0.71), HDL: LDL (r=0.70) respectively and
negative correlation with serum HDL (r=-0.52)
Transplantation of Autologous Bone Marrow- Derived Stromal Cells in Type 2 Di...CrimsonpublishersITERM
Type 2 Diabetes is a debilitating metabolic disorder which is also the seventh leading cause of death worldwide. Current therapeutic regimes to date have failed to achieve significant long-term glycemic control even with intensive insulin therapy as revealed by deregulated Hb1Ac and C-peptides levels. In the current study, we have evaluated the effect of regenerative cellular therapy for functional recovery from Diabetic pathophysiology. 10 patients with a median age of 51 years were selected for the study and subjected to bone marrow isolation. These samples were processed under sterile conditions for the enrichment of mononuclear cells (BM MNCs) from bone marrow. After strict quality control and characterization of cells, 2 x 106 cells/kg of BM MNCs were infused back into the patient through the anterior pancreaticoduodenal artery. We performed an evaluation of clinical parameters like Body Mass Index, Fasting Plasma Glucose, Fasting Plasma Insulin, HbA1c and C-peptide levels, and followed up the patients for 12 months. Our study showed a reduction in insulin dependency by ≥ 50%.
The aim of this work is to illustrate a difficult diagnostic in vitamin B12 deficiency because of using of multivitamin preparations to a patient with unknown etiology of anemia. History Patient: a 70 year old engineer, following 8 years vegetable – dietary, was admitted to the county hospital, in neurology department, with diagnostic of poli-radiculonevrites, received in ward the treatment with milgama (containing 250 micro-gram multivitamin). After a lipotimia status the patient was transferred to cardiology department. Laboratory examinations showed in peripheral blood: Hb = 6 3 g/dl; Ht = 18.8%; RBC= 290.000/mm³; PLT. = 214000/mm³; WBC = 5300/³mm; Ret. = 3, 7%; Erythrocytes indices = normal values; ESR = 38 mm/h, moderate increase and serum iron decreased, 36 microgram/dl value. On blood smear in optic microscopy was registered: Band = 5% (with nucleus in ring!!!), differential count being normally with aspect flags on Coulter HMX Analyzer with 22 parameters: neutrophilia, lymphopenia, anemia. To microscopic examination of slide from bone morrow, have occurred the hyperplasic series of erythrocytes ~ 45%, deficiency of erythropoiesis, poly-cromathopil and acidophil erythroblasts with megaloblastic character, large metamielocytes and giant band forms. Macrocytes and ovalocytes where also presented. Biopsy results from gastric mucosa showed lesions of chronic gastritis, non-atrophic epithelium. Conclusions: Megaloblastosis appears in some time with vitamin B12 deficiently in bone morrow but no in peripheral blood because of administration of multivitamin drugs, deleting haematological shape of megaloblastic anemia.
Intake of Black Vinegar on Anthropometric Measures, Cardiometabolic Profiles,...mahendrareddychirra
Obesity and type 2 diabetes mellitus are the most important chronic diseases around the world. They are associated with huge medical expenditure and with increasing morbidity and mortality among related cardio-metabolic diseases in developing and developed countries [1,2].
Vinegar was first reported to have anti-glycemic effects since 1988 in animal and human studies [3]. Vinegar may be associated with improved insulin sensitivity and delayed gastric emptying that accompanied improved glycemic control and reduced body weight [4,5].
Alterations of Mitochondrial Functions and DNA in Diabetic Cardiomyopathy of ...CrimsonPublishersIOD
Alterations of Mitochondrial Functions and DNA in Diabetic Cardiomyopathy of CCK1 Receptors-Deficient Rats by Abdelbary Prince, Magdy A Ghoneim, Abdallah M El-Ebidi, Hala A Mousa and Jin Han in Interventions in Obesity & Diabetes
П. Сутерс "Проявления инсулинорезистентности и гликемический контроль в интен...rnw-aspen
Доклад с 15 Межрегиональной научно-практической конференции "Искусственное питание и инфузионная терапия больных в медицине критических состояний" 21-22 мая 2015 г
Similar to Impaired mitochondrial beta-oxidation in patients with chronic hepatitis C: relation with viral load and insulin resistance (20)
Incidence of pneumonia and risk factors among patients with head and neck can...Enrique Moreno Gonzalez
This study investigated the incidence and patient- and treatment-related risk factors related to pneumonia acquired during radiotherapy (PNRT) in head and neck cancer (HNC) patients.
Gene expression analysis of a Helicobacter pyloriinfected and high-salt diet-...Enrique Moreno Gonzalez
Helicobacter pylori (H. pylori) infection and excessive salt intake are known as important risk factors for stomach cancer in humans. However, interactions of these two factors with gene expression profiles during gastric carcinogenesis remain unclear. In the present study, we investigated the global gene expression associated with stomach carcinogenesis and prognosis of human gastric cancer using a mouse model.
Acute myeloid leukemia (AML) is a hematopoietic malignancy with a dismal outcome in the majority of cases. A detailed understanding of the genetic alterations and gene expression changes that contribute to its pathogenesis is important to improve prognostication, disease monitoring, and therapy. In this context, leukemia-associated misexpression of microRNAs (miRNAs) has been studied, but no coherent picture has emerged yet, thus warranting further investigations.
Recently, a phase II clinical trial in hepatocellular carcinoma (HCC) has suggested that the combination of sorafenib and 5-fluorouracil (5-FU) is feasible and side effects are manageable. However, preclinical experimental data explaining the interaction mechanism(s) are lacking. Our objective is to investigate the anticancer efficacy and mechanism of combined sorafenib and 5-FU therapy in vitro in HCC cell lines MHCC97H and SMMC-7721.
Differences in microRNA expression during tumor development in the transition...Enrique Moreno Gonzalez
The prostate is divided into three glandular zones, the peripheral zone (PZ), the transition zone (TZ), and the central zone. Most prostate tumors arise in the peripheral zone (70-75%) and in the transition zone (20-25%) while only 10% arise in the central zone. The aim of this study was to investigate if differences in miRNA expression could be a possible explanation for the difference in propensity of tumors in the zones of the prostate.
Multicentric and multifocal versus unifocal breast cancer: differences in the...Enrique Moreno Gonzalez
The aim of this study was to evaluate the expression of the cell adhesion-related glycoproteins MUC-1, β-catenin and E-cadherin in multicentric/multifocal breast cancer in comparison to unifocal disease in order to identify potential differences in the biology of these tumor types.
The life in sight application study (LISA): design of a randomized controlled...Enrique Moreno Gonzalez
It is widely recognized that spiritual care plays an important role in physical and psychosocial well-being of cancer patients, but there is little evidence based research on the effects of spiritual care. We will conduct a randomized controlled trial on spiritual care using a brief structured interview scheme supported by an e-application. The aim is to examine whether an assisted reflection on life events and ultimate life goals can improve quality of life of cancer patients.
Clinical and experimental studies regarding the expression and diagnostic val...Enrique Moreno Gonzalez
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a multifunctional Ig-like cell adhesion molecule that has a wide range of biological functions. According to previous reports, serum CEACAM1 is dysregulated in different malignant tumours and associated with tumour progression. However, the serum CEACAM1 expression in nonsmall-cell lung carcinomas (NSCLC) is unclear. The different expression ratio of CEACAM1-S and CEACAM1-L isoform has seldom been investigated in NSCLC. This research is intended to study the serum CEACAM1 and the ratio of CEACAM1-S/L isoforms in NSCLC.
Assessment of preoperative exercise capacity in hepatocellular carcinoma pati...Enrique Moreno Gonzalez
Cardiopulmonary exercise testing measures oxygen uptake at increasing levels of work and predicts cardiopulmonary performance under conditions of stress, such as after abdominal surgery. Dynamic assessment of preoperative exercise capacity may be a useful predictor of postoperative prognosis. This study examined the relationship between preoperative exercise capacity and event-free survival in hepatocellular carcinoma (HCC) patients with chronic liver injury who underwent hepatectomy.
Intraepithelial lymphocyte distribution differs between the bulb and the seco...Enrique Moreno Gonzalez
Evaluation of intraepithelial duodenal lymphocytosis (IDL) is important in celiac disease (CD). There is no established cut-off value for increased number of IELs in the bulb. We therefore investigated the relation between IEL counts in the bulb and duodenal specimens in non-celiac subjects.
Sticky siRNAs targeting survivin and cyclin B1 exert an antitumoral effect on...Enrique Moreno Gonzalez
Melanoma represents one of the most aggressive and therapeutically challenging malignancies as it often gives rise to metastases and develops resistance to classical chemotherapeutic agents. Although diverse therapies have been generated, no major improvement of the patient prognosis has been noticed. One promising alternative to the conventional therapeutic approaches currently available is the inactivation of proteins essential for survival and/or progression of melanomas by means of RNA interference. Survivin and cyclin B1, both involved in cell survival and proliferation and frequently deregulated in human cancers, are good candidate target genes for siRNA mediated therapeutics.
Association between variations in the fat mass and obesity-associated gene an...Enrique Moreno Gonzalez
It is clear that genetic variations in the fat mass and obesity-associated (FTO) gene affect body mass index and the risk of obesity. Given the mounting evidence showing a positive association between obesity and pancreatic cancer, this study aimed to investigate the relation between variants in the FTO gene, obesity and pancreatic cancer risk.
The cysteinyl leukotriene 2 receptor contributes to all-trans retinoic acid-i...Enrique Moreno Gonzalez
Cysteinyl leukotrienes (CysLTs) are potent pro-inflammatory mediators that are increased in samples from patients with inflammatory bowel diseases (IBDs). Individuals with IBDs have enhanced susceptibility to colon carcinogenesis. In colorectal cancer, the balance between the pro-mitogenic cysteinyl leukotriene 1 receptor (CysLT1R) and the differentiation-promoting cysteinyl leukotriene 2 receptor (CysLT2R) is lost. Further, our previous data indicate that patients with high CysLT1R and low CysLT2R expression have a poor prognosis. In this study, we examined whether the balance between CysLT1R and CysLT2R could be restored by treatment with the cancer chemopreventive agent all-trans retinoic acid (ATRA).
Clinical features and outcome of cryptogenic hepatocellular carcinoma compare...Enrique Moreno Gonzalez
Cryptogenic hepatocellular carcinoma (HCC) is thought to arise due to non-alcoholic fatty liver disease (NAFLD). This study investigated the prevalence, clinical features, and outcomes of cryptogenic HCC and compared them with those of HCC related to hepatitis B virus infection (HBV-HCC), hepatitis C virus infection (HCV-HCC), and alcohol (ALCHCC) in Korea.
Fatty liver index correlates with non-alcoholic fatty liver disease, but not ...Enrique Moreno Gonzalez
Fatty liver index (FLI) was recently established to predict non-alcoholic fatty liver disease (NAFLD) in general population, which is known to be associated with coronary artery atherosclerotic disease (CAD).
This study aims to investigate whether FLI correlates with NAFLD and with newly diagnosed CAD in a special Chinese population who underwent coronary angiography.
Antibiotic exposure and the development of coeliac disease: a nationwide case...Enrique Moreno Gonzalez
The intestinal microbiota has been proposed to play a pathogenic role in coeliac disease (CD). Although antibiotics are common environmental factors with a profound impact on intestinal microbiota, data on antibiotic use as a risk factor for subsequent CD development are scarce.
Implication from thyroid function decreasing during chemotherapy in breast ca...Enrique Moreno Gonzalez
Thyroid hormones have been shown to regulate breast cancer cells growth, the absence or reduction of thyroid hormones in cells could provoke a proliferation arrest in G0-G1 or weak mitochondrial activity, which makes cells insensitive to therapies for cancers through transforming into low metabolism status. This biological phenomenon may help explain why treatment efficacy and prognosis vary among breast cancer patients having hypothyroid, hyperthyroid and normal function. Nevertheless, the abnormal thyroid function in breast cancer patients has been considered being mainly caused by thyroid diseases, few studied influence of chemotherapy on thyroid function and whether its alteration during chemotherapy can influence the respose to chemotherapy is still unclear. So, we aimed to find the alterations of thyroid function and non-thyroidal illness syndrome (NTIS) prevalence druing chemotherapy in breast cancer patients, and investigate the influence of thyroid hormones on chemotherapeutic efficacy.
Optimal schedule of Bacillus Calmette-Guerin for non-muscle-invasive bladder ...Enrique Moreno Gonzalez
To explore the necessity of maintenance, efficacy of low-dose and superiority of various combination therapies of Bacillus Calmette-Guérin (BCG) in treatment of superficial bladder cancer (BCa).
Environment inside even a small tumor is characterized by total (anoxia) or partial oxygen deprivation, hypoxia. It has been shown that radiotherapy and some conventional chemotherapies may be less effective in hypoxia, and therefore it is important to investigate how different drugs act in different microenvironments. In this study we perform a large screening of the effects of 19 clinically used or experimental chemotherapeutic drugs on four different cell lines in conditions of normoxia, hypoxia and anoxia.
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
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TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
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Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
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2. Impaired mitochondrial β-oxidation in patients with
chronic hepatitis C: relation with viral load and
insulin resistance
Chikako Sato1*
*
Corresponding author
Email: s.chikako@med.id.yamagata-u.ac.jp
Takafumi Saito1
Email: tasaitoh@med.id.yamagata-u.ac.jp
Keiko Misawa1
Email: k-misawa@miyuki.or.jp
Tomohiro Katsumi1
Email: t-katsumi@med.id.yamagata-u.ac.jp
Kyoko Tomita1
Email: to.kyoko@med.id.yamagata-u.ac.jp
Rika Ishii1
Email: rika-i@med.id.yamagata-u.ac.jp
Hiroaki Haga1
Email: hihaga@med.id.yamagata-u.ac.jp
Kazuo Okumoto1
Email: okumoto@med.id.yamagata-u.ac.jp
Yuko Nishise1
Email: ynishise@med.id.yamagata-u.ac.jp
Hisayoshi Watanabe1
Email: h-watanabe@med.id.yamagata-u.ac.jp
Yoshiyuki Ueno1
Email: y-ueno@med.id.yamagata-u.ac.jp
Sumio Kawata2
Email: Sumio_Kawata@pref.hyogo.lg.jp
1
Department of Gastroenterology, Faculty of Medicine, Yamagata University,
Yamagata 990-9585, Japan
2
Nishinomiya Hyogo Prefectural Hospital, Hyogo 662-0918, Japan
3. Abstract
Background
Hepatic steatosis is often seen in patients with chronic hepatitis C (CH-C). It is still unclear
whether these patients have an impaired mitochondrial β-oxidation. In this study we assessed
mitochondrial β-oxidation in CH-C patients by investigating ketogenesis during fasting.
Methods
This study consisted of thirty patients with CH-C. Serum levels of insulin and hepatitis C
virus (HCV) core protein were measured by chemiluminescence enzyme immunoassay. The
subjects were then fasted, and venous blood samples were drawn 12 h and 15 h after the start
of fasting. The levels of blood ketone bodies were measured by an enzymatic cycling method.
The rate of change in total ketone body concentration was compared with that in eight
healthy volunteers.
Results
The rate of change in total ketone body concentration between 12 h and 15 h after the start of
fasting was significantly lower in CH-C patients than in healthy volunteers (129.9% (8.5-
577.3%) vs. 321.6% (139.6-405.4%); P <0.01). The rate of change in total ketone body
concentration in patients with a serum level of HCV core protein of 10000 fmol/L or higher
was significantly lower than in patients with a level of less than 10000 fmol/L (54.8% (8.5-
304.3%) vs. 153.6% (17.1-577.3%); P <0.05). The rate of change in total ketone body
concentration in patients with a homeostasis model assessment of insulin resistance (HOMA-
IR) of 2.5 or higher was significantly lower than in patients with a HOMA-IR of less than 2.5
(56.7% (8.5-186.7%) vs. 156.4% (33.3-577.3%); P <0.01).
Conclusions
These results suggest that mitochondrial β-oxidation is impaired, possibly due to HCV
infection in patients with CH-C.
Keywords
Ketogenesis, Fasting test, Hepatic steatosis, HCV
Background
Hepatitis C virus (HCV) infection is a major cause of chronic liver injury. Hepatic steatosis is
one of histologic features of chronic HCV infection with a risk of progression of liver
diseases [1]. Hepatic steatosis is caused by some mechanisms, which include an increase of
fatty acids uptake and synthesis, a decrease of fatty acids β-oxidation, or low level of
secretion of very-low density lipoprotein. HCV core protein-transgenic mice develop hepatic
steatosis due to impaired β-oxidation caused by mitochondrial damage [2]. However, there
has been no evidence of impaired β-oxidation in patients with chronic hepatitis C (CH-C) in
vivo.
4. During starvation, mitochondria produces acetyl CoA, which is converted into ketone bodies
by fatty acids β-oxidation. In patients with impaired hepatic mitochondrial β-oxidation,
ketogenesis is expected to be inadequate. Adult-onset type 2 citrullinemia (CTLN2) has been
demonstrated to present as non-alcoholic fatty liver disease (NAFLD) [3]. CTLN 2 is
associated with mutations in the SLC25A13 gene encoding citrin, which is a component of
the mitochondrial malate-aspartate shuttle. Functional defectiveness of citrin impairs not only
transport of aspartate from mitochondria but that of NADH into mitochondria. This induces
activation of the citrate-malate shuttle with compensatory production of acetyl CoA, which in
turn stimulates fatty acid synthesis. In addition, mitochondrial accumulation of malonyl CoA
in a high NADH/NAD+
environment suppresses fatty acid oxidation. These circumstances
lead to hepatic steatosis in patients with CTLN 2 [4]. Inui et al. have demonstrated that
suppression of fatty acid oxidation is accompanied by impaired ketogenesis in such patients
[5].
Based on this background, we measured the concentration of blood ketone bodies during
fasting in order to evaluate mitochondrial β-oxidation in patients with CH-C, and thus to
investigate a mechanism of steatosis associated with HCV infection. Here, we report for the
first time that mitochondrial β-oxidation is impaired in patients with CH-C.
Methods
Patients
Thirty patients (14 male and 16 female, the mean age 54.2, ranging from 22 to 74 years old)
with CH-C were studied. The patients were admitted to Yamagata University Hospital for
treatment between March 2006 and May 2009. All of the patients had been positive for both
serum anti-HCV and HCV RNA for more than 6 months, and had elevated levels of serum
alanine aminotransferase (ALT). They were all negative for hepatocellular carcinoma,
hepatitis B, autoimmune hepatitis, primary biliary cirrhosis, heart failure, renal insufficiency,
a history of diabetes mellitus, excess alcohol intake (daily ethanol consumption >20 g) or
drug abuse. None of the patients fulfilled the criteria for Metabolic Syndrome in Japan [6,7],
i.e. the presence of at least two of the following three abnormalities in addition to visceral
obesity (waist circumference: 85 cm or more in men, 90 cm or more in women): 1)
triglycerides ≥150 mg/dl and/or HDL-cholesterol <40 mg/dl, or receiving treatment for this
type of dyslipidemia; 2) systolic blood pressure ≥130 and/or diastolic blood pressure ≥85, or
receiving treatment for hypertension; 3) fasting glucose ≥110 mg/dl or receiving treatment for
diabetes. As a control group, eight volunteers (4 male and 4 female) were included (the mean
age 30.5, ranging from 26 to 39 years old). All of them were healthy, with a BMI of <25
kg/m2
, without medication or severe disease. Written informed consent to participate was
obtained from all subjects, and the study protocol was approved by The Yamagata University
Hospital Ethics Committee.
Methods
Clinical and laboratory data
Body height, weight and waist circumference were measured at the time of admission. Body
mass index (BMI) was calculated as: BMI = body weight (kg)/body height (m)2
. Venous
blood samples were collected after a 12-h overnight fast for standard biochemical testing and
determination of serum insulin levels, HCV genotype and HCV core protein. Serum insulin
5. was determined by chemiluminescence enzyme immunoassay (Lumipulseprestoinsulin®,
Fujirebio Inc., Tokyo, Japan). Insulin resistance was determined based on the homeostasis
model assessment of insulin resistance (HOMA-IR). HOMA-IR was calculated using the
formula: [fasting glucose (mg/dl) × fasting insulin (µU/ml)] / 405 [8]. Insulin resistance was
defined as HOMA-IR >2.5. The amount of HCV core antigen and HCV RNA in serum were
measured by a chemiluminescence enzyme immunoassay (Lumispot Eiken HCV antigen®,
Eiken Chemical Co., Ltd., Tokyo, Japan) and an amplicor HCV RNA detection kit (Amplicor
HCV v2.0®, Roche Diagnostics, Tokyo, Japan) or a real-time PCR assay (COBAS®
TaqMan® HCV Test, Roche Diagnostics, Tokyo, Japan), respectively.
Fasting test
In general, ketone bodies are not detected during periods of feeding, but after the onset of
fasting, glycogen is gradually consumed and ketone bodies are produced rapidly after about
12 hours of fasting. The rate of change in ketone body production between 12 and 15 hours
represented the initial increase, and was interpreted as the initial velocity of ketogenesis.
Fasting tests were performed in both subjects and volunteers. They were permitted to drink
water after their last meal, and blood samples were drawn to measure the proportion of
ketone bodies, glucose, insulin, free fatty acid and triglyceride levels at 12 and 15 h after the
last meal. Carnitine fractionation was also measured at 12 after the last meal, using an
enzymatic cycling method (Total Carnitine Kainos®, Free Carnitine Kainos®, Kainos
Laboratories, Inc., Tokyo, Japan). During fasting, urine organic acids were measured by gas
chromatograph-mass spectrometry and then analyzed using software to determine the
presence of disorders of organic acid metabolism. Serum ketone bodies were measured by an
enzymatic cycling method (3-hydroxybutyrate Kainos®, Total ketone body Kainos®, ketone
body standard reagent 2®, Kainos Laboratories, Inc. Tokyo, Japan). These measurements
were performed by SRL Inc. (Tokyo, Japan). The rate of change in total ketone body
concentration from 12 h to 15 h was calculated using the equation: (total ketone bodies at 15
h – total ketone bodies at 12 h)/ total ketone bodies at 12 h × 100.
Histological assessment
Liver biopsies were performed under sonographic guidance in 25 patients who provided
informed consent. The liver tissues were fixed in 10% formalin, embedded in paraffin and
stained with hematoxylin-eosin and silver stain. Liver histology was graded and staged by a
pathologist based on the international classification [9]. The grade of steatosis was modified
as follows: grade 0 = no steatosis and between 0% and 5% of hepatocytes containing visible
macrovesicular steatosis, grade 1 = between 5% and 33%, grade 2 = between 33% and 66%,
and grade 3 = more than 66% according to the non-alcoholic fatty liver disease Activity
Score [10].
Statistical analysis
Results are expressed as the mean ± standard deviation (SD) or the median and range (in
parenthesis). Student’s t test was used for normally distributed non-paired continuous
variables. The rate of change in total ketone body concentration was assessed as a parametric
value because the value was distributed parametrically after logarithmic transformation.
Wilcoxon’s signed-ranks test was used for paired continuous variables. Comparisons between
more than two groups were made by one-way analysis of variance. All P-values were based
6. on a two-sided test of statistical significance. Differences at P <0.05 were considered to be
statistically significant.
Results
Subject characteristics
The characteristics of thirty patients with chronic hepatitis C were shown in Table 1. The
mean level of BMI was less than 25 kg/m2
, and that of fasting plasma glucose was within
normal range. The mean level of ALT was greater than the upper limit of normal range. Nine
patients had a status of insulin resistance in whom HOMA-IR showed a level of 2.5 or
greater. All patients were positive for HCV RNA in whom the mean level of serum HCV
core antigen showed a 6505 fmol/L. Of the 30 patients, 20 (66.7%) were infected with the
HCV genotype 1b, 6 (20.0%) with genotype 2a, and 4 (13.3%) with genotype 2b. Fifteen
(60%) had a liver fibrosis grade of F1, 7 (28%) had F2, and 3 (12%) had F3. Six (24%) had a
liver steatosis grade of 0, 18 (72%) had grade 1, 1 (4%) had grade 2, and none had grade 3.
Table 1 Patient characteristics
Patients Reference value
Age (yr) b
54.2 ± 10.6
Male/Female (ratio) 14/16 (0.47)
BMI (kg/m2
) b
23.7 ± 2.7 18.5 - 25
ALT (IU/L) a
47.5 (17–167) 8 - 42
γGTP (IU/L) a
41 (13–152) 10 - 47
ChE (IU/L) b
312.9 ± 88.2 185 - 431
Fasting plasma glucose (mg/dL) b
95.5 ± 9.7 70 - 109
Insulin (µIU/mL) a
8.7 (4.5 - 20.4) 1.84 - 12.2
HOMA-IR a
2.0 (1.2 - 5.1)
HOMA-IR > 2.5 (%) 9 (30)
Triglyceride (mg/dL) b
91.4 ± 31.1 30 - 149
Total cholesterol (mg/dL) b
175.2 ± 25.4 129 - 219
Acylcarnitine (µmol/L) a
9.25 (5.7 - 21.1) 6 - 23
HCV RNA (LogIU/mL) b
6.1 ± 0.9
HCV core antigen (fmol/L) a
6505 (<20–23200)
HCV Genotype 1b / 2a / 2b 20 / 6 / 4
Inflammation A0 / A1 / A2 / A3 0 / 15 / 10 / 0
Fibrosis F0 / F1 / F2 / F3 / F4 0 / 15 / 7 / 3 / 0
Steatosis G0 / G1 / G2 / G3 6 /18 / 1 / 0
BMI, body mass index; ALT, alanine aminotransferase; γGTP, gamma-
glutamyltranspeptidase; ChE, cholinesterase; HOMA-IR, homeostasis model assessment of
insulin resistance.
Data are a
medians (min-max), b
the means ± standard deviation.
Free fatty acids concentration during fasting in CH-C patients and healthy
volunteers
The concentration of free fatty acids increased by fasting in CH-C patients and healthy
volunteers. The rate of change in free fatty acids concentration between 12 h and 15 h was
7. similar in both groups (CH-C patients 48.6% ± 45.0 vs. healthy volunteers 70.3% ± 95.2; ns),
as shown in Figure 1.
Figure 1 Free fatty acids concentration during fasting in patients with chronic hepatitis
C and healthy volunteers. The rate of change in free fatty acid concentration between 12 h
and 15 h after fasting was similar in both groups. The line represents a mean value. Welch’s
t-test.
Ketone body concentration during fasting in CH-C patients and healthy
volunteers
The levels of total blood ketone bodies were elevated in both CH-C patients and healthy
volunteers 15 h after the start of fasting, but the rate of change between 12 h and 15 h after
fasting was significantly different between them. The rate of change in total ketone body
concentration between 12 h and 15 h was shown in Figure 2. It was significantly lower in
CH-C patients than in healthy volunteers (129.9% (8.5-577.3%) vs. 321.6% (139.6-405.4%);
P <0.01). The rates of change in both acetoacetate (Figure 3A) and 3-hydroxybutyrate (Figure
3B) between 12 h and 15 h after fasting were also significantly lower in CH-C patients than
in healthy volunteers (acetoacetate : 109.5% (−5.8-514.3%) vs. 254.8% (145.5-341.7%) , 3-
hydroxybutyrate : 130.8% (−3.8-606.7%) vs. 337% (135.5-495%) ; P <0.01).
Figure 2 Total ketone body concentration during fasting in patients with chronic
hepatitis C and healthy volunteers. The rate of change in total ketone body concentration
between 12 h and 15 h after fasting was significantly lower in patients than in healthy
volunteers (** denotes P <0.01). The line represents a median value. Log transformation was
performed. Student’s t test.
Figure 3 Ketone body fraction concentration during fasting in patients with chronic
hepatitis C and healthy volunteers. The rates of change in both acetoacetate (A) and 3-
hydroxybutyrate (B) between 12 h and 15 h after fasting were significantly lower in patients
than in healthy volunteers (** denotes P <0.01). The line represents a median value. Log
transformation was performed. Student’s t test.
There was a significant positive correlation between the concentration of total ketone body
and the levels of acylcarnitine (rs 0.56, P <0.01) at 12 h after fasting, as shown in Figure 4A,
similar to the pattern of free fatty acids (rs 0.54, P <0.01, Figure 4B). The level of
acylcarnitine was significantly lower in CH-C patients than in healthy volunteers (9.25
µmol/L (5.7-21.1 µmol/L) vs. 11.65 µmol/L (9.3-17 µmol/L); P <0.05).
Figure 4 Ketone body concentration are related with acylcarnitine and free fatty acid in
patients with chronic hepatitis C. There is a significant positive correlation between the
concentration of total ketone body and the levels of acylcarnitine (rs 0.56, P <0.01),(A), as
well as free fatty acids (rs 0.54, P <0.01), (B).
Relationship between the rate of change in total ketone body concentration
and clinical parameters in CH-C patients
We stratified CH-C patients into two groups based on the clinical parameters. The rate of
change in total ketone body concentration between 12 h and 15 h in patients with a serum
HCV core protein level of 10000 fmol/L or higher was significantly lower than that in
8. patients with a level of less than 10000 fmol/L (54.8% (8.5-304.3%) vs. 153.6% (17.1-
577.3%); P <0.05) (Figure 5). In addition, the rate of change in total ketone body
concentration in patients with a higher HOMA-IR value (2.5 or greater) was significantly
lower than that in patients with a value of less than 2.5 (56.7% (8.5-186.7%) vs. 156.4%
(33.3-577.3%); P <0.01) (Figure 6). The patients with biopsy-proven steatosis had a relatively
low rate of change in total ketone body concentration between 12 h and 15 h in comparison
with those without steatosis, although the rate was not significantly different between them
(Figure 7). There was no significant difference in the rate of change in total ketone body
concentration among the HCV genotypes (1b 120.2% (8.5-577.3%), 2a 129.9% (91.7-
304.3%), 2b 135.8% (56.7-253.3%)). No significant difference in the rate of change in total
ketone body concentration was demonstrated among the stages of fibrosis (F1 91.7% (17.1-
436%), F2 133% (8.5-283.3%), F3 88.6% (34.2-577.3%)).
Figure 5 HCV core protein and the change in total ketone body concentration during
fasting. The rate of change in total ketone body concentration between 12 h and 15 h after
fasting in patients with a serum HCV core protein level of 10000 fmol/L or higher was
significantly lower than that in patients with a level of less than 10000 fmol/L (* denotes P
<0.05). The line represents a median value. Log transformation was performed. Student’s t
test.
Figure 6 Insulin resistance and the change in total ketone body concentration during
fasting. The rate of change in total ketone body concentration in patients with a higher
HOMA-IR value (2.5 or greater) was significantly lower than that in patients with a value of
less than 2.5 (** denotes P <0.01). The line represents a median value. Log transformation
was performed. Student’s t test.
Figure 7 Hepatic steatosis and the change in total ketone body concentration during
fasting. The patients with steatosis had a relatively low rate of change in total ketone body
concentration between 12 h and 15 h after fasting in comparison with those without steatosis,
although it was not significant. The line represents a median value. Log transformation was
performed. Student’s t test.
Discussion
Hepatitis C virus (HCV) is the leading cause of chronic hepatitis, subsequent liver cirrhosis
and hepatocellular carcinoma. Hepatic steatosis is commonly seen in patients with chronic
HCV infection having a high viral load, and it is in part associated with the development of
insulin resistance [1], hepatic fibrosis [11] and hepatocarcinogenesis [12] during infection.
Steatosis is also associated with a lower rate of sustained response to anti-viral therapy [13],
and shows improvement after successful eradication of HCV by anti-viral therapy [14].
In general, fat accumulation in hepatocytes can result from several causes; increase of fatty
acid uptake by hepatocyte, increase of fatty acid synthesis in hepatocyte, decrease of hepatic
fatty acid oxidation, decrease of very-low density lipoprotein secretion. The mechanisms of
steatosis in HCV infection are not fully understood. In the previous study using liver biopsy
specimens of patients with HCV infection, it is shown that expression of peroxisome
proliferator-activated receptor (PPAR)-α is impaired, which is an important factor in the
regulation of mitochondrial β-oxidation [15]. Therefore, impaired mitochondrial β-oxidation
is supposed to be a mechanism of hepatic steatosis observed in the state of HCV infection.
9. However, there is no previous study which investigated whether mitochondrial β-oxidation is
impaired in patients with CH-C in vivo. In the present study, therefore, we focused on the
mechanism of ketogenesis in humans by investigating ketogenic capacity during fasting. The
rate of change in total ketone body concentration between 12 h and 15 h after the start of
fasting was significantly lower in CH-C patients than in healthy volunteers, while the rate of
change in free fatty acids concentration was similar in both groups. Therefore there is a
possibility that steps from acetyl-CoA to ketone bodies are impaired in patients with CH-C.
In addition, Hoppel et al. reported that acylcarnitine increased during fasting and ketone
bodies correlated with short-chain acylcarnitines. It is speculated that the increase in short-
chain acylcarnitines may be a by-product of fatty acid β-oxidation [16]. In our patients, the
level of acylcarnitine was significantly lower in CH-C patients than in healthy volunteers.
Thus, these support that mitochondrial β-oxidation is impaired in patients with CH-C. Further
studies are needed to assess which step is involved in the impairment of ketone bodies
formation in HCV infection.
During starvation, ketone bodies increase in the body under conditions of normal
mitochondrial β-oxidation. Since insulin secretion decreases during fasting, synthesis of
triglyceride from acyl CoA is suppressed. Therefore, acyl CoA is β-oxidized to acetyl CoA in
mitochondria. Oxaloacetate is used for gluconeogenesis during fasting. Under this condition,
acetyl CoA cannot conjugate oxaloacetate, and the tricarboxylic acid (TCA) cycle is
inhibited. Inhibition of the TCA cycle also occurs through consumption of nicotinamide
adenine dinucleotide (NAD+
) and the production of reduced nicotinamide adenine
dinucleotide (NADH) via β-oxidation. Consequently, acetyl CoA shifts towards ketogenesis.
Acetyl CoA enters the TCA cycle and is used as fuel in muscle. Thus, the liver is the only
organ that produces ketone bodies and secretes them into blood. In individuals with impaired
hepatic mitochondrial β-oxidation, it is expected that ketogenesis would not be adequate. This
is a reason why measurement of blood ketone body concentration in a fasting state facilitates
assessment of mitochondrial β-oxidation in vivo [5].
In the present study, the rate of change in total ketone body concentration in patients with a
serum level of HCV core protein of 10,000 fmol/L or higher was significantly lower than in
patients with a level of less than 10,000 fmol/L, showing that patients with a higher level of
serum HCV core protein had lower ketogenic capacity. HCV core protein induces hepatic
steatosis with disappearance of the double structure of mitochondrial membranes in HCV
core transgenic mice [2]. HCV core protein is largely associated with mitochondrial
dysfunction [17]. Moreover, recent studies have reported that HCV core protein
downregulates the expression of PPAR-α, which is abundant in hepatocytes and is an
important factor in the regulation of mitochondrial β-oxidation [15,18]. Our data suggest an
impairment of mitochondrial β-oxidation by HCV infection.
Although no significant relationship between fatty acid oxidation and the grade of steatosis
was demonstrated in this study (Figure 7), this issue would be worth investigating in a larger
cohort of patients. HCV infection induces mitochondrial dysfunction as a result of oxidative
stress, which is closely related to liver inflammation and hepatocarcinogenesis [19].
Oxidative stress is associated with impairment of fatty acid oxidation, and thus impaired
ketogenesis seems to represent the increased oxidative stress in CH-C patients.
Insulin resistance in patients with CH-C has been reported [20]. At this study, insulin
resistance, HOMA-IR >2.5, was observed in 9 of 30 patients. In this study, a significant
positive correlation was evident between the concentration of total ketone bodies and that of
free fatty acids. However, in some patients with insulin resistance, the concentrations of both
10. free fatty acids and ketone bodies were not so high. The rate of change in the concentrations
of total ketone bodies was significantly lower in patients with a higher HOMA-IR value (2.5
or greater) than in those with a value of less than 2.5. Many other factors may influence the
level of fatty acid. Further studies are needed to elucidate the mechanism of insulin resistance
in CH-C patients.
Our CH-C patients were significantly older than the healthy volunteers. However, we did not
observe any significant correlation between the age of our subjects and the rate of change in
total ketone body concentration within the age range investigated (data not shown). Elderly
people in good health have a similar capacity to produce ketones to middle-aged or young
adults [21].
Conclusions
The results of our study suggest that mitochondrial β-oxidation is impaired, possibly due to
HCV infection. Further studies are needed to elucidate the detailed pathophysiology of
impaired fatty acid metabolism in CH-C and its clinical significance.
Abbreviations
CH-C, Chronic hepatitis C; HCV, Hepatitis C virus; HOMA-IR, Homeostasis model
assessment of insulin resistance; CTLN2, Adult-onset type 2 citrullinemia; NAFLD, Non-
alcoholic fatty liver disease; ALT, Alanine aminotransferase; BMI, Body mass index; SD,
Standard deviation; PPAR, Peroxisome proliferator-activated receptor; TCA, Tricarboxylic
acid; NAD, Nicotinamide adenine dinucleotide; NADH, Reduced nicotinamide adenine
dinucleotide; SREBP, Sterol regulatory element-binding protein
Competing interests
No financial interests to disclosure that related to this study.
Authors’ contributions
SC, MK, KT, TK, IR, HH, OK and NY contributed to data collection and data analysis. SC,
ST, WH and UY contributed to data interpretation and manuscript writing. KS contributed to
the design and conduct of the study. All authors read and approved the final manuscript.
Acknowledgements
This study was supported in part by a grant from the Global Center of Excellence (COE)
program of the Japan Society for the Promotion of Science.
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