Background:Posttraumatic stress disorder(PTSD)has been associated with volumetric and white matter microstructural changes among general and veteran populations.However,regions implicated have greatly varied and often...Background:Posttraumatic stress disorder(PTSD)has been associated with volumetric and white matter microstructural changes among general and veteran populations.However,regions implicated have greatly varied and often conflict between studies,potentially due to confounding comorbidities within samples.This study compared grey matter volume and white matter microstructure among Australian combat veterans with and without a lifetime diagnosis of PTSD,in a homogenous sample assessed for known confounding comorbidities.Methods:Sixty-eight male trauma-exposed veterans(16 PTSD-diagnosed;mean age 69 years)completed a battery of psychometric assessments and underwent magnetic resonance and diffusion tensor imaging.Analyses included tractbased spatial statistics,voxel-wise analyses,diffusion connectome-based group-wise analysis,and volumetric analysis.Results:Significantly smaller grey matter volumes were observed in the left prefrontal cortex(P=0.026),bilateral middle frontal gyrus(P=0.021),and left anterior insula(P=0.048)in the PTSD group compared to controls.Significant negative correlations were found between PTSD symptom severity and fractional anisotropy values in the left corticospinal tract(R^(2)=0.34,P=0.024)and left inferior cerebellar peduncle(R^(2)=0.62,P=0.016).No connectome-based differences in white matter properties were observed.Conclusions:Findings from this study reinforce reports of white matter alterations,as indicated by reduced fractional anisotropy values,in relation to PTSD symptom severity,as well as patterns of reduced volume in the prefrontal cortex.These results contribute to the developing profile of neuroanatomical differences uniquely attributable to veterans who suffer from chronic PTSD.展开更多
The goals of global vaccination are to control,eliminate,or eradicate infectious diseases in a sustainable way that strengthens public health systems.Although the use of vaccines is essential for the control of epidem...The goals of global vaccination are to control,eliminate,or eradicate infectious diseases in a sustainable way that strengthens public health systems.Although the use of vaccines is essential for the control of epidemics,the vaccines against coronavirus disease 2019(COVID-19)proved to be inadequate to end the pandemic and thus are considered incomplete.These vaccines failed to prevent infection,so their primary purpose has been shifted to prevent severe disease and reduce hospitalizations and deaths.Therefore,we believe that all the strategies available to reduce transmission,hospitalizations and deaths due to COVID-19 will be put in place.It is reported that uncontrolled inflammation and thrombosis are the principal mechanisms for aggravation and death in patients with COVID-19.Unlike corticosteroids that should not be administered at the beginning of the symptoms for their immunosuppressive action,which could worsen the evolution of the disease,the usefulness of non-steroidal anti-inflammatory drugs in the early at-home treatment of the disease is becoming evident.展开更多
The mechanisms that promote liver injury in non-alcoholic fatty liver disease(NAFLD) are yet to be thoroughly elucidated. As such, effective treatment strategies are lacking and novel therapeutic targets are required....The mechanisms that promote liver injury in non-alcoholic fatty liver disease(NAFLD) are yet to be thoroughly elucidated. As such, effective treatment strategies are lacking and novel therapeutic targets are required. Iron has been widely implicated in the pathogenesis of NAFLD and represents a potential target for treatment. Relationships between serum ferritin concentration and NAFLD are noted in a majority of studies, although serum ferritin is an imprecise measure of iron loading. Numerous mechanisms for a pathogenic role of hepatic iron in NAFLD have been demonstrated in animal and cell culture models. However, the human data linking hepatic iron to liver injury in NAFLD is less clear, with seemingly conflicting evidence, supporting either an effect of iron in hepatocytes or within reticulo-endothelial cells. Adipose tissue has emerged as a key site at which iron may have a pathogenic role in NAFLD. Evidence for this comes indirectly from studies that have evaluated the role of adipose tissue iron with respect to insulin resistance. Adding further complexity, multiple strands of evidence support an effect of NAFLD itself on iron metabolism. In this review, we summarise the human and basic science data that has evaluated the role of iron in NAFLD pathogenesis.展开更多
AIM To establish a model to enrich and characterize stemlike cells from murine normal liver and hepatocellular carcinoma(HCC) cell lines and to further investigate stem-like cell association with epithelial-to-mesench...AIM To establish a model to enrich and characterize stemlike cells from murine normal liver and hepatocellular carcinoma(HCC) cell lines and to further investigate stem-like cell association with epithelial-to-mesenchymal transition(EMT).METHODS In this study,we utilized a stem cell conditioned serumfree medium to enrich stem-like cells from mouse HCC and normal liver cell lines,Hepa 1-6 and AML12,respectively.We isolated the 3-dimensional spheres and assessed their stemness characteristics by evaluating theRNA levels of stemness genes and a cell surface stem cell marker by quantitative reverse transcriptase-PCR(q RTPCR).Next,we examined the relationship between stem cells and EMT using q RT-PCR.RESULTS Three-dimensional spheres were enriched by culturing murine HCC and normal hepatocyte cell lines in stem cell conditioned serum-free medium supplemented with epidermal growth factor,basic fibroblast growth factor and heparin sulfate.The 3-dimensional spheres had enhanced stemness markers such as Klf4 and Bmi1 and hepatic cancer stem cell(CSC) marker Cd44 compared to parental cells grown as adherent cultures.We report that epithelial markers E-cadherin and ZO-1 were downregulated,while mesenchymal markers Vimentin and Fibronectin were upregulated in 3-dimensional spheres.The 3-dimensional spheres also exhibited changes in expression of Snai,Zeb and Twist family of EMT transcription factors.CONCLUSION Our novel method successfully enriched stem-like cells which possessed an EMT phenotype.The isolation and characterization of murine hepatic CSCs could establish a precise target for the development of more effective therapies for HCC.展开更多
Purpose:This systematic review and meta-analysis aimed to evaluate the effect of wearable devices for improving physical activity and healthrelated outcomes in cancer survivors.Methods:CINAHL,Cochrane,Ebscohost,MEDLIN...Purpose:This systematic review and meta-analysis aimed to evaluate the effect of wearable devices for improving physical activity and healthrelated outcomes in cancer survivors.Methods:CINAHL,Cochrane,Ebscohost,MEDLINE,Pubmed,ProQuest Health and Medical Complete,ProQuest Nursing and Allied Health Source,ScienceDirect,and SPORTDiscus databases were searched for randomized controlled trials published before September 1,2020,that evaluated interventions involving wearable devices in cancer survivors.Standardized mean differences(SMDs)were calculated to assess effects on physical activity and health-related outcomes.Subgroup analyses were conducted to assess whether the effects differed by interventions and cancer characteristics.Risk of bias was assessed using the Cochrane risk of bias tool.Results:Thirty-five trials were included(breast cancer,n=15,43%).Intervention durations ranged between 4 weeks and 1 year.Most trials(n=25,71%)involved pedometer-based physical activity interventions.Seven(20%)involved Fitbit-based interventions,and 3(9%)involved other wearable physical activity trackers(e.g.,Polar,Garmin).Compared to usual care,wearable devices had moderate-to-large effects(SMD range 0.54-0.87,p<0.001)on moderate-intensity physical activity,moderate-to-vigorous-intensity physical activity,total physical activity,and daily steps.Compared to usual care,those in the intervention had higher quality of life,aerobic fitness,physical function,and reduced fatigue(SMD range=0.18-0.66,all p<0.05).Conclusion:Wearable physical activity trackers and pedometers are effective tools that increase physical activity and improve health-related outcomes in individuals with cancer.Identifying how these devices can be implemented for longer-term use with other intervention components remains an area for future research.展开更多
AIM To identify risk factors associated with the formation of biliary strictures post liver transplantation over a period of 10-year in Queensland.METHODS Data on liver donors and recipients in Queensland between 2005...AIM To identify risk factors associated with the formation of biliary strictures post liver transplantation over a period of 10-year in Queensland.METHODS Data on liver donors and recipients in Queensland between 2005 and 2014 was obtained from an electronic patient data system.In addition,intra-operative and post-operative characteristics were collected and a logistical regression analysis was performed to evaluate their association with the development of biliary strictures.RESULTS Of 296 liver transplants performed,285(96.3%) were from brain dead donors.Biliary strictures developed in 45(15.2%) recipients.Anastomotic stricture formation(n = 25,48.1%) was the commonest complication,with 14(58.3%) of these occurred within 6-mo of transplant.A percutaneous approach or endoscopic retrograde cholangiography was used to treat 17(37.8%) patients with biliary strictures.Biliary reconstruction was initially or ultimately required in 22(48.9%) patients.In recipients developing biliary strictures,bilirubin was significantly increased within the first postoperative week(Day 7 total bilirubin 74 μmol/L vs 49 μmol/L,P = 0.012).In both univariate and multivariate regression analysis,Day 7 total bilirubin > 55 μmol/L was associated with the development of biliary stricture formation.In addition,hepatic artery thrombosis and primary sclerosing cholangitis were identified as independent risk factors.CONCLUSION In addition to known risk factors,bilirubin levels in the early post-operative period could be used as a clinical indicator for biliary stricture formation.展开更多
We report the clinical case of a 40-year-old Italian woman, who soon after her booster vaccination with mRNA-1273 after the two previous vaccinations with BNT162b2, developed severe headache, high fever, and Musculo-s...We report the clinical case of a 40-year-old Italian woman, who soon after her booster vaccination with mRNA-1273 after the two previous vaccinations with BNT162b2, developed severe headache, high fever, and Musculo-skeletal pain. She went to the emergency department, where computerized tomography (CT) scans of chest and brain were performed, resulting in both negative for pathologic findings. On the contrary, white blood count was strongly lowered and D-dimer severely elevated. She improved after treatment with enoxaparin and the blood analyses returned in the normal range after ten days. This case supports the hypothesis that COVID-19 vaccines could increase blood clotting in some predisposed subjects. Therefore, we believe that robust and well-designed clinical trials, considering the evaluation of D-dimer levels, should be performed to eliminate any doubts on this issue.展开更多
AIM To investigate the synergistic hepato-protective properties of curcumin and vitamin E in an Hfe^(-/-)high calorie diet model of steatohepatitis.METHODS Hfe^(-/-)C57BL/6J mice were fed either a high calorie diet or...AIM To investigate the synergistic hepato-protective properties of curcumin and vitamin E in an Hfe^(-/-)high calorie diet model of steatohepatitis.METHODS Hfe^(-/-)C57BL/6J mice were fed either a high calorie diet or a high calorie diet with 1 mg/g curcumin; 1.5 mg/g vitamin E; or combination of 1 mg/g curcumin + 1.5 mg/g vitamin E for 20 wk. Serum and liver tissue were collected at the completion of the experiment. Liver histology was graded by a pathologist for steatosis, inflammation and fibrosis. RNA and protein was extracted from liver tissue to examine gene and protein expression associated with fatty acid oxidation, mitochondrial biogenesis and oxidative stress pathways.RESULTS Hfe^(-/-)mice fed the high calorie diet developed steatohepatitis and pericentral fibrosis. Combination treatment with curcumin and vitamin E resulted in a greater reduction of percent steatosis than either vitamin E or curcumin therapy alone. Serum alanine aminotransferase and non-alcoholic fatty liver disease(NAFLD) activity score were decreased following combination therapy with curcumin and vitamin E compared with high calorie diet alone. No changes were observed in inflammatory or fibrosis markers following treatment. Epididymal fat pad weights were significantly reduced following combination therapy, however total body weight and liver weight were unchanged. Combination therapy increased the m RNA expression of Adipo R2, Ppar-α, Cpt1 a, Nrf-1 and Tfb2 m suggesting enhanced fatty acid oxidation and mitochondrial biogenesis. In addition, combination treatment resulted in increased catalase activity in Hfe^(-/-)mice. CONCLUSION Combination curcumin and vitamin E treatment decreases liver injury in this steatohepatitis model, indicating that combination therapy may be of value in NAFLD.展开更多
Hepatocellular carcinoma(HCC)is the most lethal and common type of liver cancer with limited treatment options at the advanced stage.The use of immune checkpoint inhibitor(ICI)based immunotherapy is exponentially incr...Hepatocellular carcinoma(HCC)is the most lethal and common type of liver cancer with limited treatment options at the advanced stage.The use of immune checkpoint inhibitor(ICI)based immunotherapy is exponentially increasing in the treatment of patients with advanced solid tumors.The expression of immune checkpoints on tumor cells leading to lower activity of T-cells is one of the major mechanisms of immune escape.Checkpoint blockade immunotherapies with antibodies against PD-1,PD-L1 or CTLA-4 are being investigated in clinical trials in HCC patients.ICIs have improved survival in patients with inoperable advanced stage HCC where other curative treatments are not applicable.However,the response rates remain low with only a small subset of patients responding to this therapy.There is an unmet need to identify predictive markers to select those HCC patients who would benefit from ICI therapies.Importantly,epithelial-to-mesenchymal transition(EMT),a major process driving HCC invasion and metastasis by regulating the phenotypic cellular switching from epithelial to mesenchymal state,has been implicated as a resistance mechanism associated with ICI therapies.The role of EMT as a regulator of immune checkpoint molecule in HCC is just emerging.However,the consequence of EMT as a resistance mechanism in HCC patients undergoing ICI treatments remains unexplored.In this review,we summarize the recent clinical studies with ICIs in HCC and highlight the trials underway featuring novel monotherapies and combinatorial approaches based on immune and non-immune therapies.We will discuss the ongoing efforts to discover new immune checkpoint molecules in HCC as potential drug targets.We also highlight the role of EMT in facilitating therapy resistance in HCC treated with ICIs and discuss potential strategies to circumvent resistance in ICI treated HCC patients.展开更多
Hepatocellular carcinoma(HCC)is a significant global health problem with high morbidity and mortality.Its incidence is increasing exponentially worldwide with a close overlap between annual incidence and death rates.E...Hepatocellular carcinoma(HCC)is a significant global health problem with high morbidity and mortality.Its incidence is increasing exponentially worldwide with a close overlap between annual incidence and death rates.Even though significant advances have been made in HCC treatment,fewer than 20%of patients with HCC are suitable for potentially curative treatment.Hereditary hemochromatosis(HH)is an important genetic risk factor for HCC.HH is an autosomal recessive disorder of iron metabolism,characterised by elevated iron deposition in most organs including the liver,leading to progressive organ dysfunction.HCC is a complication of HH,nearly always occurring in patients with cirrhosis and contributes to increased mortality rates.Identifying the susceptibility of development of HCC in HH patients has gained much traction.This review summarises the current knowledge with regard to the association of HH and HCC in order to encourage further research.In this review,we focus particularly on HFE gene-related HH.Herein,we highlight and discuss emerging clinical research which addresses the prevalence of HCC in HH patients and the coincidence of HH with other risk factors for HCC development.We also focus on the therapeutic tools in the management of HCC associated with HH.展开更多
Hepatocellular carcinoma (HCC) commonly presents at an advanced stage due to the lack of efficient early screening tools. Early, non-invasive biomarkers useful in the diagnosis and prognosis of HCC would be of signifi...Hepatocellular carcinoma (HCC) commonly presents at an advanced stage due to the lack of efficient early screening tools. Early, non-invasive biomarkers useful in the diagnosis and prognosis of HCC would be of significant benefit for HCC management. Development of exosome-based liquid biopsy as a non-invasive method for the management of HCC has gained much traction. Exosomes are small membranous vesicles secreted by most cell types including HCC cells. Exosomes serve as couriers for the intercellular transfer of important biomolecules, including, protein, nucleic acids and lipids to nearby and distant cells in the body. The molecular cargos carried by exosome have been described to play significant roles in cancer progression. Herein, we will dissect how HCC-derived exosomes confer aggressive traits such as tumour growth, invasion, immune remodelling and drug resistance to HCC cells. We review the current literature concerning exosomes as biomarkers in a diagnostic setting, evaluating their prognostic, predictive and monitoring capabilities. This review will highlight and discuss emerging research in the utility of exosome-based liquid biopsies therapeutic tools in HCC management. Here we will also focus on advances in exosome biology in preclinical studies.展开更多
基金RSL Queensland funded this study as part of the PTSD Initiative at the Gallipoli Medical Research Foundation.The Australian Government Department of Veterans’Affairs provided transport for eligible participants。
文摘Background:Posttraumatic stress disorder(PTSD)has been associated with volumetric and white matter microstructural changes among general and veteran populations.However,regions implicated have greatly varied and often conflict between studies,potentially due to confounding comorbidities within samples.This study compared grey matter volume and white matter microstructure among Australian combat veterans with and without a lifetime diagnosis of PTSD,in a homogenous sample assessed for known confounding comorbidities.Methods:Sixty-eight male trauma-exposed veterans(16 PTSD-diagnosed;mean age 69 years)completed a battery of psychometric assessments and underwent magnetic resonance and diffusion tensor imaging.Analyses included tractbased spatial statistics,voxel-wise analyses,diffusion connectome-based group-wise analysis,and volumetric analysis.Results:Significantly smaller grey matter volumes were observed in the left prefrontal cortex(P=0.026),bilateral middle frontal gyrus(P=0.021),and left anterior insula(P=0.048)in the PTSD group compared to controls.Significant negative correlations were found between PTSD symptom severity and fractional anisotropy values in the left corticospinal tract(R^(2)=0.34,P=0.024)and left inferior cerebellar peduncle(R^(2)=0.62,P=0.016).No connectome-based differences in white matter properties were observed.Conclusions:Findings from this study reinforce reports of white matter alterations,as indicated by reduced fractional anisotropy values,in relation to PTSD symptom severity,as well as patterns of reduced volume in the prefrontal cortex.These results contribute to the developing profile of neuroanatomical differences uniquely attributable to veterans who suffer from chronic PTSD.
文摘The goals of global vaccination are to control,eliminate,or eradicate infectious diseases in a sustainable way that strengthens public health systems.Although the use of vaccines is essential for the control of epidemics,the vaccines against coronavirus disease 2019(COVID-19)proved to be inadequate to end the pandemic and thus are considered incomplete.These vaccines failed to prevent infection,so their primary purpose has been shifted to prevent severe disease and reduce hospitalizations and deaths.Therefore,we believe that all the strategies available to reduce transmission,hospitalizations and deaths due to COVID-19 will be put in place.It is reported that uncontrolled inflammation and thrombosis are the principal mechanisms for aggravation and death in patients with COVID-19.Unlike corticosteroids that should not be administered at the beginning of the symptoms for their immunosuppressive action,which could worsen the evolution of the disease,the usefulness of non-steroidal anti-inflammatory drugs in the early at-home treatment of the disease is becoming evident.
文摘The mechanisms that promote liver injury in non-alcoholic fatty liver disease(NAFLD) are yet to be thoroughly elucidated. As such, effective treatment strategies are lacking and novel therapeutic targets are required. Iron has been widely implicated in the pathogenesis of NAFLD and represents a potential target for treatment. Relationships between serum ferritin concentration and NAFLD are noted in a majority of studies, although serum ferritin is an imprecise measure of iron loading. Numerous mechanisms for a pathogenic role of hepatic iron in NAFLD have been demonstrated in animal and cell culture models. However, the human data linking hepatic iron to liver injury in NAFLD is less clear, with seemingly conflicting evidence, supporting either an effect of iron in hepatocytes or within reticulo-endothelial cells. Adipose tissue has emerged as a key site at which iron may have a pathogenic role in NAFLD. Evidence for this comes indirectly from studies that have evaluated the role of adipose tissue iron with respect to insulin resistance. Adding further complexity, multiple strands of evidence support an effect of NAFLD itself on iron metabolism. In this review, we summarise the human and basic science data that has evaluated the role of iron in NAFLD pathogenesis.
基金Supported by The Gallipoli Medical Research Foundation,Australia,No.016092the Cyril Gilbert Foundation,Australia,No.017348
文摘AIM To establish a model to enrich and characterize stemlike cells from murine normal liver and hepatocellular carcinoma(HCC) cell lines and to further investigate stem-like cell association with epithelial-to-mesenchymal transition(EMT).METHODS In this study,we utilized a stem cell conditioned serumfree medium to enrich stem-like cells from mouse HCC and normal liver cell lines,Hepa 1-6 and AML12,respectively.We isolated the 3-dimensional spheres and assessed their stemness characteristics by evaluating theRNA levels of stemness genes and a cell surface stem cell marker by quantitative reverse transcriptase-PCR(q RTPCR).Next,we examined the relationship between stem cells and EMT using q RT-PCR.RESULTS Three-dimensional spheres were enriched by culturing murine HCC and normal hepatocyte cell lines in stem cell conditioned serum-free medium supplemented with epidermal growth factor,basic fibroblast growth factor and heparin sulfate.The 3-dimensional spheres had enhanced stemness markers such as Klf4 and Bmi1 and hepatic cancer stem cell(CSC) marker Cd44 compared to parental cells grown as adherent cultures.We report that epithelial markers E-cadherin and ZO-1 were downregulated,while mesenchymal markers Vimentin and Fibronectin were upregulated in 3-dimensional spheres.The 3-dimensional spheres also exhibited changes in expression of Snai,Zeb and Twist family of EMT transcription factors.CONCLUSION Our novel method successfully enriched stem-like cells which possessed an EMT phenotype.The isolation and characterization of murine hepatic CSCs could establish a precise target for the development of more effective therapies for HCC.
文摘Purpose:This systematic review and meta-analysis aimed to evaluate the effect of wearable devices for improving physical activity and healthrelated outcomes in cancer survivors.Methods:CINAHL,Cochrane,Ebscohost,MEDLINE,Pubmed,ProQuest Health and Medical Complete,ProQuest Nursing and Allied Health Source,ScienceDirect,and SPORTDiscus databases were searched for randomized controlled trials published before September 1,2020,that evaluated interventions involving wearable devices in cancer survivors.Standardized mean differences(SMDs)were calculated to assess effects on physical activity and health-related outcomes.Subgroup analyses were conducted to assess whether the effects differed by interventions and cancer characteristics.Risk of bias was assessed using the Cochrane risk of bias tool.Results:Thirty-five trials were included(breast cancer,n=15,43%).Intervention durations ranged between 4 weeks and 1 year.Most trials(n=25,71%)involved pedometer-based physical activity interventions.Seven(20%)involved Fitbit-based interventions,and 3(9%)involved other wearable physical activity trackers(e.g.,Polar,Garmin).Compared to usual care,wearable devices had moderate-to-large effects(SMD range 0.54-0.87,p<0.001)on moderate-intensity physical activity,moderate-to-vigorous-intensity physical activity,total physical activity,and daily steps.Compared to usual care,those in the intervention had higher quality of life,aerobic fitness,physical function,and reduced fatigue(SMD range=0.18-0.66,all p<0.05).Conclusion:Wearable physical activity trackers and pedometers are effective tools that increase physical activity and improve health-related outcomes in individuals with cancer.Identifying how these devices can be implemented for longer-term use with other intervention components remains an area for future research.
文摘AIM To identify risk factors associated with the formation of biliary strictures post liver transplantation over a period of 10-year in Queensland.METHODS Data on liver donors and recipients in Queensland between 2005 and 2014 was obtained from an electronic patient data system.In addition,intra-operative and post-operative characteristics were collected and a logistical regression analysis was performed to evaluate their association with the development of biliary strictures.RESULTS Of 296 liver transplants performed,285(96.3%) were from brain dead donors.Biliary strictures developed in 45(15.2%) recipients.Anastomotic stricture formation(n = 25,48.1%) was the commonest complication,with 14(58.3%) of these occurred within 6-mo of transplant.A percutaneous approach or endoscopic retrograde cholangiography was used to treat 17(37.8%) patients with biliary strictures.Biliary reconstruction was initially or ultimately required in 22(48.9%) patients.In recipients developing biliary strictures,bilirubin was significantly increased within the first postoperative week(Day 7 total bilirubin 74 μmol/L vs 49 μmol/L,P = 0.012).In both univariate and multivariate regression analysis,Day 7 total bilirubin > 55 μmol/L was associated with the development of biliary stricture formation.In addition,hepatic artery thrombosis and primary sclerosing cholangitis were identified as independent risk factors.CONCLUSION In addition to known risk factors,bilirubin levels in the early post-operative period could be used as a clinical indicator for biliary stricture formation.
文摘We report the clinical case of a 40-year-old Italian woman, who soon after her booster vaccination with mRNA-1273 after the two previous vaccinations with BNT162b2, developed severe headache, high fever, and Musculo-skeletal pain. She went to the emergency department, where computerized tomography (CT) scans of chest and brain were performed, resulting in both negative for pathologic findings. On the contrary, white blood count was strongly lowered and D-dimer severely elevated. She improved after treatment with enoxaparin and the blood analyses returned in the normal range after ten days. This case supports the hypothesis that COVID-19 vaccines could increase blood clotting in some predisposed subjects. Therefore, we believe that robust and well-designed clinical trials, considering the evaluation of D-dimer levels, should be performed to eliminate any doubts on this issue.
文摘AIM To investigate the synergistic hepato-protective properties of curcumin and vitamin E in an Hfe^(-/-)high calorie diet model of steatohepatitis.METHODS Hfe^(-/-)C57BL/6J mice were fed either a high calorie diet or a high calorie diet with 1 mg/g curcumin; 1.5 mg/g vitamin E; or combination of 1 mg/g curcumin + 1.5 mg/g vitamin E for 20 wk. Serum and liver tissue were collected at the completion of the experiment. Liver histology was graded by a pathologist for steatosis, inflammation and fibrosis. RNA and protein was extracted from liver tissue to examine gene and protein expression associated with fatty acid oxidation, mitochondrial biogenesis and oxidative stress pathways.RESULTS Hfe^(-/-)mice fed the high calorie diet developed steatohepatitis and pericentral fibrosis. Combination treatment with curcumin and vitamin E resulted in a greater reduction of percent steatosis than either vitamin E or curcumin therapy alone. Serum alanine aminotransferase and non-alcoholic fatty liver disease(NAFLD) activity score were decreased following combination therapy with curcumin and vitamin E compared with high calorie diet alone. No changes were observed in inflammatory or fibrosis markers following treatment. Epididymal fat pad weights were significantly reduced following combination therapy, however total body weight and liver weight were unchanged. Combination therapy increased the m RNA expression of Adipo R2, Ppar-α, Cpt1 a, Nrf-1 and Tfb2 m suggesting enhanced fatty acid oxidation and mitochondrial biogenesis. In addition, combination treatment resulted in increased catalase activity in Hfe^(-/-)mice. CONCLUSION Combination curcumin and vitamin E treatment decreases liver injury in this steatohepatitis model, indicating that combination therapy may be of value in NAFLD.
基金This manuscript publication is funded by Gallipoli Medical Research Foundation.
文摘Hepatocellular carcinoma(HCC)is the most lethal and common type of liver cancer with limited treatment options at the advanced stage.The use of immune checkpoint inhibitor(ICI)based immunotherapy is exponentially increasing in the treatment of patients with advanced solid tumors.The expression of immune checkpoints on tumor cells leading to lower activity of T-cells is one of the major mechanisms of immune escape.Checkpoint blockade immunotherapies with antibodies against PD-1,PD-L1 or CTLA-4 are being investigated in clinical trials in HCC patients.ICIs have improved survival in patients with inoperable advanced stage HCC where other curative treatments are not applicable.However,the response rates remain low with only a small subset of patients responding to this therapy.There is an unmet need to identify predictive markers to select those HCC patients who would benefit from ICI therapies.Importantly,epithelial-to-mesenchymal transition(EMT),a major process driving HCC invasion and metastasis by regulating the phenotypic cellular switching from epithelial to mesenchymal state,has been implicated as a resistance mechanism associated with ICI therapies.The role of EMT as a regulator of immune checkpoint molecule in HCC is just emerging.However,the consequence of EMT as a resistance mechanism in HCC patients undergoing ICI treatments remains unexplored.In this review,we summarize the recent clinical studies with ICIs in HCC and highlight the trials underway featuring novel monotherapies and combinatorial approaches based on immune and non-immune therapies.We will discuss the ongoing efforts to discover new immune checkpoint molecules in HCC as potential drug targets.We also highlight the role of EMT in facilitating therapy resistance in HCC treated with ICIs and discuss potential strategies to circumvent resistance in ICI treated HCC patients.
文摘Hepatocellular carcinoma(HCC)is a significant global health problem with high morbidity and mortality.Its incidence is increasing exponentially worldwide with a close overlap between annual incidence and death rates.Even though significant advances have been made in HCC treatment,fewer than 20%of patients with HCC are suitable for potentially curative treatment.Hereditary hemochromatosis(HH)is an important genetic risk factor for HCC.HH is an autosomal recessive disorder of iron metabolism,characterised by elevated iron deposition in most organs including the liver,leading to progressive organ dysfunction.HCC is a complication of HH,nearly always occurring in patients with cirrhosis and contributes to increased mortality rates.Identifying the susceptibility of development of HCC in HH patients has gained much traction.This review summarises the current knowledge with regard to the association of HH and HCC in order to encourage further research.In this review,we focus particularly on HFE gene-related HH.Herein,we highlight and discuss emerging clinical research which addresses the prevalence of HCC in HH patients and the coincidence of HH with other risk factors for HCC development.We also focus on the therapeutic tools in the management of HCC associated with HH.
文摘Hepatocellular carcinoma (HCC) commonly presents at an advanced stage due to the lack of efficient early screening tools. Early, non-invasive biomarkers useful in the diagnosis and prognosis of HCC would be of significant benefit for HCC management. Development of exosome-based liquid biopsy as a non-invasive method for the management of HCC has gained much traction. Exosomes are small membranous vesicles secreted by most cell types including HCC cells. Exosomes serve as couriers for the intercellular transfer of important biomolecules, including, protein, nucleic acids and lipids to nearby and distant cells in the body. The molecular cargos carried by exosome have been described to play significant roles in cancer progression. Herein, we will dissect how HCC-derived exosomes confer aggressive traits such as tumour growth, invasion, immune remodelling and drug resistance to HCC cells. We review the current literature concerning exosomes as biomarkers in a diagnostic setting, evaluating their prognostic, predictive and monitoring capabilities. This review will highlight and discuss emerging research in the utility of exosome-based liquid biopsies therapeutic tools in HCC management. Here we will also focus on advances in exosome biology in preclinical studies.
