BACKGROUND Hepatocellular carcinoma(HCC)has been a pervasive malignancy throughout the world with elevated mortality.Efficient therapeutic targets are beneficial to treat and predict the disease.Currently,the exact mo...BACKGROUND Hepatocellular carcinoma(HCC)has been a pervasive malignancy throughout the world with elevated mortality.Efficient therapeutic targets are beneficial to treat and predict the disease.Currently,the exact molecular mechanisms leading to the progression of HCC are still unclear.Research has shown that the microRNA-142-3p level decreases in HCC,whereas bioinformatics analysis of the cancer genome atlas database shows the ASH1L expression increased among liver tumor tissues.In this paper,we will explore the effects and mechanisms of microRNA-142-3p and ASH1L affect the prognosis of HCC patients and HCC cell bioactivity,and the association between them.AIM To investigate the effects and mechanisms of microRNA-142-3p and ASH1L on the HCC cell bioactivity and prognosis of HCC patients.METHODS In this study,we grouped HCC patients according to their immunohistochemistry results of ASH1L with pathological tissues,and retrospectively analyzed the prognosis of HCC patients.Furthermore,explored the roles and mechanisms of microRNA-142-3p and ASH1L by cellular and animal experiments,which involved the following experimental methods:Immunohistochemical staining,western blot,quantitative real-time-polymerase chain reaction,flow cytometric analysis,tumor xenografts in nude mice,etc.The statistical methods involved in this study contained t-test,one-way analysis of variance,theχ^(2)test,the Kaplan-Meier approach and the log-rank test.RESULTS In this study,we found that HCC patients with high expression of ASH1L possess a more recurrence rate as well as a decreased overall survival rate.ASH1L promotes the tumorigenicity of HCC and microRNA-142-3p exhibits reduced expression in HCC tissues and interacts with ASH1L through targeting the ASH1L 3′untranslated region.Furthermore,microRNA-142-3p promotes apoptosis and inhibits proliferation,invasion,and migration of HCC cell lines in vitro via ASH1L.For the exploration mechanism,we found ASH1L may promote an immunosuppressive microenvironment in HCC and ASH1L affects the expression of the cell junction protein zonula occludens-1,which is potentially relevant to the immune system.CONCLUSION Loss function of microRNA-142-3p induces cancer progression and immune evasion through upregulation of ASH1L in HCC.Both microRNA-142-3p and ASH1L can feature as new biomarker for HCC in the future.展开更多
Background:Individuals with diabetes have greater central arterial stiffness,wave reflections,and hemodynamics,all of which promote the accelerated cardiovascular pathology seen in this population.Acute aerobic exerci...Background:Individuals with diabetes have greater central arterial stiffness,wave reflections,and hemodynamics,all of which promote the accelerated cardiovascular pathology seen in this population.Acute aerobic exercise has been shown to be an effective strategy for reducing central arterial stiffness,wave reflections,and hemodynamics in healthy individuals;however,the effects of acute aerobic exercise in reducing these outcomes is not well established in people with diabetes.Recently,implementation of high-intensity interval exercise(HIIE)has shown superior improvements in cardiovascular health outcomes when compared to traditional aerobic exercise.Yet,the effect of HIIE on the aforementioned outcomes in people with diabetes is not known.The purpose of this study was to(i)describe the central arterial stiffness,wave reflections,and hemodynamic responses to a bout of HIIE and moderate-intensity continuous exercise(MICE)in adults with diabetes;and(ii)compare the effects of HIIE and MICE on the aforementioned outcomes.Methods:A total of 24 adult men and women(aged 29-59 years old)with type 1(n=12)and type 2(n=12)diabetes participated in a randomized cross-over study.All participants completed the following protocols:(i)HIIE:cycling for 4×4 min at 85%-95%of heart rate peak(HR_(peak)),interspersed with 3 min of active recovery at 60%-70%HR_(peak);(ii)MICE:33 min of continuous cycling at 60%-70%HR_(peak);and(iii)control(CON):lying quietly in a supine position for 30 min.Results:A significant group￡time effect was found for changes in central systolic blood pressure(F=3.20,p=0.01)with a transient reduction for the HIIE group but not for the MICE or CON groups.There was a significant group￡time effect for changes in augmentation index at a heart rate of 75 beats/min(F=2.32,p=0.04)with a decrease following for HIIE and MICE but not for CON.For all other measures of central arterial stiffness and hemodynamics,no significant changes were observed(p>0.05).Conclusion:A bout of HIIE appears to lead to a greater transient reduction in central systolic blood pressure than the reduction observed following MICE;however,both HIIE and MICE improved augmentation index at a heart rate of 75 beats/min in people with diabetes.There was no significant difference in response to HIIE and MICE in all outcomes.This provides preliminary evidence on the role of HIIE on such outcomes in people with diabetes.展开更多
BACKGROUND Management of single small hepatocellular carcinoma(HCC)is straightforward with curative outcomes achieved by locoregional therapy or resection.Liver transplantation is often considered for multiple small o...BACKGROUND Management of single small hepatocellular carcinoma(HCC)is straightforward with curative outcomes achieved by locoregional therapy or resection.Liver transplantation is often considered for multiple small or single large HCC.Management of two small HCC whether presenting synchronously or sequentially is less clear.AIM To define the outcomes of patients presenting with two small HCC.METHODS Retrospective review of HCC databases from multiple institutions of patients with either two synchronous or sequential HCC≤3 cm between January 2000 and March 2018.Primary outcomes were overall survival(OS)and transplant-free survival(TFS).RESULTS 104 patients were identified(male n=89).Median age was 63 years(interquartile range 58-67.75)and the most common aetiology of liver disease was hepatitis C(40.4%).59(56.7%)had synchronous HCC and 45(43.3%)had sequential.36 patients died(34.6%)and 25 were transplanted(24.0%).1,3 and 5-year OS was 93.0%,66.1% and 62.3% and 5-year post-transplant survival was 95.8%.1,3 and 5-year TFS was 82.1%,45.85% and 37.8%.When synchronous and sequential groups were compared,OS(1,3 and 5 year synchronous 91.3%,63.8%,61.1%,sequential 95.3%,69.5%,64.6%,P=0.41)was similar but TFS was higher in the sequential group(1,3 and 5 year synchronous 68.5%,37.3% and 29.7%,sequential 93.2%,56.6%,48.5%,P=0.02)though this difference did not remain during multivariate analysis.CONCLUSION TFS in patients presenting with two HCC≤3 cm is poor regardless of the timing of the second tumor.All patients presenting with two small HCC should be considered for transplantation.展开更多
BACKGROUND Patients with neurofibromatosis type 1(NF1)are exposed to a higher risk of developing neuroendocrine tumors(NETs).Periampullary neuroendocrine neoplasms(NENs)in NF1 patients primarily affect the duodenum an...BACKGROUND Patients with neurofibromatosis type 1(NF1)are exposed to a higher risk of developing neuroendocrine tumors(NETs).Periampullary neuroendocrine neoplasms(NENs)in NF1 patients primarily affect the duodenum and periampullary region.CASE SUMMARY A 50-year-old male patient was admitted to our hospital due to progressive skin and scleral yellowing for over 6 months.An abdominal contrast-enhanced computed tomography scan revealed a tumor in the periampullary region,which measured 1.2 cm×1.4 cm in size and showed a progressive enhancement.Magnetic resonance cholangiopancreatography indicated the dilation of intrahepatic and extrahepatic bile ducts.The patient was diagnosed with an ampullary tumor with the possibility of malignancy.A Whipple procedure was performed.Microscopically,the duodenum tumor was found to invade the mucosa,sphincter,and muscular layer of the duodenal papilla.Histologic hematoxylin and eosin staining confirmed the presence of duodenal G1 NET.Subsequently,a bibliometric analysis was performed to evaluate the state of NEN research.Publications about periampullary NENs showed an annual increase,with most of them focusing on the treatment and diagnosis of NENs.CONCLUSION This article reported a case of periampullary duodenal NET in a patient with NF1,and a bibliometric analysis was conducted.展开更多
Heart failure represents the end point of a variety of cardiovascular diseases.It is a growing health burden and a leading cause of death worldwide.To date,limited treatment options exist for the treatment of heart fa...Heart failure represents the end point of a variety of cardiovascular diseases.It is a growing health burden and a leading cause of death worldwide.To date,limited treatment options exist for the treatment of heart failure,but exercise has been well-established as one of the few safe and effective interventions,leading to improved outcomes in patients.However,a lack of patient adherence remains a significant barrier in the implementation of exercise-based therapy for the treatment of heart failure.The insulin-like growth factor 1(IGF1)phosphoinositide 3-kinase(PI3K)pathway has been recognized as perhaps the most critical pathway for mediating exercisedinduced heart growth and protection.Here,we discuss how modulating activity of the IGF1PI3K pathway may be a valuable approach for the development of therapies that mimic the protective effects of exercise on the heart.We outline some of the promising approaches being investigated that utilize PI3K-based therapy for the treatment of heart failure.We discuss the implications for cardiac pathology and cardiotoxicity that arise in a setting of reduced PI3K activity.Finally,we discuss the use of animal models of cardiac health and disease,and genetic mice with increased or decreased cardiac PI3K activity for the discovery of novel drug targets and biomarkers of cardiovascular disease.展开更多
AIM:To analyze the expression of kallikrein gene 10(KLK10)in gastric cancer and to determine whether KLK10 has independent prognostic value in gastric cancer.METHODS:We studied KLK10 expression in 80 histologically co...AIM:To analyze the expression of kallikrein gene 10(KLK10)in gastric cancer and to determine whether KLK10 has independent prognostic value in gastric cancer.METHODS:We studied KLK10 expression in 80 histologically confirmed gastric cancer samples using realtime quantitative reverse transcription-PCR and hK10expression using immunohistochemistry.Correlations with clinicopathological variables(lymph node metastasis,depth of invasion and histology)and with outcomes(disease-free survival and overall survival)during a median follow-up period of 31 mo were assessed.Gastric cancer tissues were then classified as KLK10 positive or negative.RESULTS:KLK10 was found to be highly expressed in 57/80(70%)of gastric cancer samples,while its expression was very low in normal gastric tissues.Positive relationships between KLK10 expression and lymph node metastasis(P=0.048),depth of invasion(P=0.034)and histology(P=0.015)were observed.Univariate survival analysis revealed that gastric cancer patients with positive KLK10 expression had an increased risk for relapse/metastasis and death(P=0.005 and0.002,respectively).Cox multivariate analysis indicated that KLK10 was an independent prognostic indicator of disease-free survival and overall survival in patients with gastric cancer.CONCLUSION:KLK10 expression is an independent biomarker of unfavorable prognosis in patients with gastric cancer.展开更多
Nasopharyngeal carcinoma （NPC） is a common cancer in Southern China and Southeast Asia. The disease is a poorly differentiated carcinoma without effective cure, and the mechanism underlying its development remains l...Nasopharyngeal carcinoma （NPC） is a common cancer in Southern China and Southeast Asia. The disease is a poorly differentiated carcinoma without effective cure, and the mechanism underlying its development remains largely unknown. Of several factors identified in NPC aetiology in recent years, Epstein-Barr virus （EBV） infection has emerged to be most important. In almost all NPC cells, EBV uses several intracellular mechanisms to cause oncogenic evolution of the infected cells. One such mechanism by which EBV infection induces cellular immortalization is believed to be through the activation of telomerase, an enzyme that is normally repressed but becomes activated during cancer development. Studies show that greater than 85% of primary NPC display high telomerase activity by mechanisms involving EBV infection, consistent with the notion that EBV is commonly involved in inducing cell immortalization. More recently, different EBV proteins have been shown to activate or inhibit the human telomerase reverse transcriptase gene, by modulating intracellular signalling pathways. These findings suggest a new model with a number of challenges towards our understanding, molecular targeting and therapeutic intervention in NPC.展开更多
Estrogen deficiency mediates aging, but the underlying mechanism remains to be fully determined. We report here that estrogen deficiency caused by targeted disruption of aromatase in mice results in significant inhibi...Estrogen deficiency mediates aging, but the underlying mechanism remains to be fully determined. We report here that estrogen deficiency caused by targeted disruption of aromatase in mice results in significant inhibition of telomerase activity in the adrenal gland in vivo. Gene expression analysis showed that, in the absence of estrogen, telomerase reverse transcriptase （TERT） gene expression is reduced in association with compromised cell proliferation in the adrenal gland cortex and adrenal atrophy. Stem cells positive in c-kit are identified to populate in the parenchyma of adrenal cortex. Analysis of telomeres revealed that estrogen deficiency results in significantly shorter teiomeres in the adrenal cortex than that in wild-type （WT） control mice. To further establish the causal effects of estrogen, we conducted an estrogen replacement therapy in these estrogen-deficient animals. Administration of estrogen for 3 weeks restores TERT gene expression, telomerase activity and cell proliferation in estrogen-deficient mice. Thus, our data show for the first time that estrogen deficiency causes inhibitions of TERT gene expression, telomerase activity, telomere maintenance, and cell proliferation in the adrenal gland of mice in vivo, suggesting that telomerase inhibition and telomere shortening may mediate cell proliferation arrest in the adrenal gland, thus contributing to estrogen deficiency-induced aging under physiological conditions.展开更多
AIM: To investigate over-expression of Osteopontin (OPN) pathway expression and mechanisms of action in human alcoholic liver disease (ALD), in vivo and in vitro acute alcohol models.
Metabolic associated fatty liver disease(MAFLD),previously termed nonalcoholic fatty liver disease,is the leading global cause of liver disease and is fast becoming the most common indication for liver transplantation...Metabolic associated fatty liver disease(MAFLD),previously termed nonalcoholic fatty liver disease,is the leading global cause of liver disease and is fast becoming the most common indication for liver transplantation.The recent change in nomenclature to MAFLD refocuses the conceptualisation of this disease entity to its metabolic underpinnings and may help to spur a paradigm shift in the approach to its management,including in the setting of liver transplantation.Patients with MAFLD present significant challenges in the pre-,peri-and posttransplant settings,largely due to the presence of medical comorbidities that include obesity,metabolic syndrome and cardiovascular risk factors.As the community prevalence of MAFLD increases concurrently with the obesity epidemic,donor liver steatosis is also a current and future concern.This review outlines current epidemiology,nomenclature,management issues and outcomes of liver transplantation in patients with MAFLD.展开更多
Myelin-associated inhibitory factors within the central nervous system（CNS） are considered to be one of the main obstacles for axonal regeneration following disease or injury. The nogo receptor 1（NgR1） has been we...Myelin-associated inhibitory factors within the central nervous system（CNS） are considered to be one of the main obstacles for axonal regeneration following disease or injury. The nogo receptor 1（NgR1） has been well documented to play a key role in limiting axonal regrowth in the injured and diseased mammalian CNS. However, the role of nogo receptor in immune cell activation during CNS inflammation is yet to be mechanistically elucidated. Microglia/macrophages are immune cells that are regarded as pathogenic contributors to inflammatory demyelinating lesions in multiple sclerosis（MS）. In this study, the animal model of MS, experimental autoimmune encephalomyelitis（EAE） was induced in ngr1^＋/＋ and ngr1^–/– female mice following injection with the myelin oligodendrocyte glycoprotein（MOG_（35–55）） peptide. A fatemap analysis of microglia/macrophages was performed throughout spinal cord sections of EAE-induced mice at clinical scores of 0, 1, 2 and 3, respectively（increasing locomotor disability） from both genotypes, using the CD11 b and Iba1 cell markers. Western immunoblotting using lysates from isolated spinal cord microglia/macrophages, along with immunohistochemistry and flow cytometric analysis, was performed to demonstrate the expression of nogo receptor and its two homologs during EAE progression. Myelin protein engulfment during EAE progression in ngr1^＋/＋ and ngr1^–/– mice was demonstrated by western immunblotting of lysates from isolated spinal cord microglia/macrophages, detecting levels of Nogo-A and MOG. The numbers of M1 and M2 microglia/macrophage phenotypes present in the spinal cords of EAE-induced ngr1^＋/＋ and ngr1^–/– mice, were assessed by flow cytometric analysis using CD38 and Erg-2 markers. A significant difference in microglia/macrophage numbers between ngr1^＋/＋ and ngr1^–/– mice was identified during the progression of the clinical symptoms of EAE, in the white versus gray matter regions of the spinal cord. This difference was unrelated to the expression of Ng R on these macrophage/microglial cells. We have identified that as EAE progresses, the phagocytic activity of microglia/macrophages with myelin debris, in ngr1^–/– mice, was enhanced. Moreover, we show a modulation from a predominant M1-pathogenic to the M2-neurotrophic cell phenotype in the ngr1^–/– mice during EAE progression. These findings suggest that CNS-specific macrophages and microglia of ngr1^–/– mice may exhibit an enhanced capacity to clear inhibitory molecules that are sequestered in inflammatory lesions.展开更多
AIM: To optimize the experimental protocols for a simple, sensitive and accurate bleeding assay.METHODS: Bleeding assay was performed in mice by tail tip amputation, immersing the tail in saline at 37 ℃, continuously...AIM: To optimize the experimental protocols for a simple, sensitive and accurate bleeding assay.METHODS: Bleeding assay was performed in mice by tail tip amputation, immersing the tail in saline at 37 ℃, continuously monitoring bleeding patterns and measuring bleeding volume from changes in the body weight. Sensitivity and extent of variation of bleeding time and bleeding volume were compared in mice treated with the P2 Y receptor inhibitor prasugrel at various doses or in mice deficient of Fc Rγ, a signaling protein of the glycoprotein VI receptor.RESULTS: We described details of the bleeding assay with the aim of standardizing this commonly used assay. The bleeding assay detailed here was simple to operate and permitted continuous monitoring of bleedingpattern and detection of re-bleeding. We also reported a simple and accurate way of quantifying bleeding volume from changes in the body weight, which correlated well with chemical assay of hemoglobin levels(r2 = 0.990, P < 0.0001). We determined by tail bleeding assay the dose-effect relation of the anti-platelet drug prasugrel from 0.015 to 5 mg/kg. Our results showed that the correlation of bleeding time and volume was unsatisfactory and that compared with the bleeding time, bleeding volume was more sensitive in detecting a partial inhibition of platelet's haemostatic activity(P < 0.01). Similarly, in mice with genetic disruption of Fc Rγ as a signaling molecule of P-selectin glycoprotein ligand-1 leading to platelet dysfunction, both increased bleeding volume and repeated bleeding pattern defined the phenotype of the knockout mice better than that of a prolonged bleeding time.CONCLUSION: Determination of bleeding pattern and bleeding volume, in addition to bleeding time, improved the sensitivity and accuracy of this assay, particularly when platelet function is partially inhibited.展开更多
Dear Editor,Severe Acute Respiratory Syndrome(SARS)has beendescribed as the first pandemic of the 21st century andbetween November 2002 and July 2003,over 8000 peo-ple were infected with the SARS-associated coronaviru...Dear Editor,Severe Acute Respiratory Syndrome(SARS)has beendescribed as the first pandemic of the 21st century andbetween November 2002 and July 2003,over 8000 peo-ple were infected with the SARS-associated coronavirus(SARS-CoV).Polymorphisms in the human leukocyteantigen(HLA)system have been shown to influencesusceptibility to SARS-CoV but here we were unable展开更多
AIM: Early calcification of atherosclerotic plaques are colocalized with macrophage and high mobility group box 1( HMGB1),a cytokine associated with biomineralizing process under physiological and pathological conditi...AIM: Early calcification of atherosclerotic plaques are colocalized with macrophage and high mobility group box 1( HMGB1),a cytokine associated with biomineralizing process under physiological and pathological conditions. Our study aims to evaluate whether HMGB1 induces ectopic mineralization via promoting the secretion of matrix vesicles( MVs) from macrophages. METHODS: HMGB1 was added to the medium of macrophages,the secretion of MVs in the supernatant was tested by flow cytometry analysis. The mineral deposition in calcifying medium was detected by Alizarin Red staining and von Kossa staining. Transmission electron microscopy showed the formation of hydroxyapatite crystals in MVs. Then we subcutaneous injection into mice with MVs to induce regional mineralization. RESULTS: HMGB1 significantly promoted secretion of MVs from macrophages as raveled by flow cytometry analysis. TNAP activity,considered as a marker of MVs maturation,was higher in HMGB1-induced MVs compared to the control-MVs. HMGB1-MVs also led to mineral deposition in an in vitro MVs-collagen mineralization model. Subcutaneous injection into mice with MVs derived from HMGB1-treated cells showed a greater potential to initiate regional mineralization. Mechanistic experiments revealed that HMGB1 activated neutral sphingomyelinase 2( n SMase2) that involved the receptor for advanced glycation end products( RAGE) and p38MAPK( upstream of n SMase2). Inhibition of n SMase2 with GW4869 or p38 MAPK with SB-239063 prevented MVs secretion and mineral deposition. CONCLUSIONS: HMGB1 induces MVs secretion from macrophages at least in part,via the RAGE / p38 MAPK /n SMase2 signaling pathway. Our findings thus reveal a novel mechanism by which HMGB1 may participated in the early calcification of atherosclerotic plaques.展开更多
Neurological heterotopic ossification(NHO)is a debilitating condition where bone forms in soft tissue,such as muscle surrounding the hip and knee,following an injury to the brain or spinal cord.This abnormal formation...Neurological heterotopic ossification(NHO)is a debilitating condition where bone forms in soft tissue,such as muscle surrounding the hip and knee,following an injury to the brain or spinal cord.This abnormal formation of bone can result in nerve impingement,pain,contractures and impaired movement.Patients are often diagnosed with NHO after the bone tissue has completely mineralised,leaving invasive surgical resection the only remaining treatment option.Surgical resection of NHO creates potential for added complications,particularly in patients with concomitant injury to the central nervous system(CNS).Although recent work has begun to shed light on the physiological mechanisms involved in NHO,there remains a significant knowledge gap related to the prognostic biomarkers and prophylactic treatments which are necessary to prevent NHO and optimise patient outcomes.This article reviews the current understanding pertaining to NHO epidemiology,pathobiology,biomarkers and treatment options.In particular,we focus on how concomitant CNS injury may drive ectopic bone formation and discuss considerations for treating polytrauma patients with NHO.We conclude that understanding of the pathogenesis of NHO is rapidly advancing,and as such,there is the strong potential for future research to unearth methods capable of identifying patients likely to develop NHO,and targeted treatments to prevent its manifestation.展开更多
Alzheimer’s disease（AD）is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles.Prior to the development of these characteristic pathological hallmarks of AD,ante...Alzheimer’s disease（AD）is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles.Prior to the development of these characteristic pathological hallmarks of AD,anterograde axonal transport is impaired.However,the key proteins that initiate these intracellular impairments remain elusive.The collapsin response mediator protein-2（CRMP-2）plays an integral role in kinesin-1-dependent axonal transport and there is evidence that phosphorylation of CRMP-2releases kinesin-1.Here,we tested the hypothesis that amyloid-beta（Aβ）-dependent phosphorylation of CRMP-2 disrupts its association with the kinesin-1（an anterograde axonal motor transport protein）in AD.We found that brain sections and lysates from AD patients demonstrated elevated phosphorylation of CRMP-2 at the T555 site.Additionally,in the transgenic Tg2576 mouse model of familial AD（FAD）that exhibits Aβaccumulation in the brain with age,we found substantial co-localization of p T555CRMP-2and dystrophic neurites.In SH-SY5Y differentiated neuronal cultures,Aβ-dependent phosphorylation of CRMP-2 at the T555 site was also elevated and this reduced the CRMP-2 association with kinesin-1.The overexpression of an unphosphorylatable form of CRMP-2 in neurons promoted the re-establishment of CRMP-2-kinesin association and axon elongation.These data suggest that Aβ-dependent phosphorylation of CRMP-2 at the T555 site may directly impair anterograde axonal transport protein function,leading to neuronal defects.展开更多
BACKGROUND Tumor necrosis factor-alpha inhibitors,including infliximab and adalimumab,are effective medical treatments for perianal fistulising Crohn’s disease(CD),but not all patients achieve fistula healing.AIM To ...BACKGROUND Tumor necrosis factor-alpha inhibitors,including infliximab and adalimumab,are effective medical treatments for perianal fistulising Crohn’s disease(CD),but not all patients achieve fistula healing.AIM To determine the correlation between perianal fistula healing and closure with infliximab and adalimumab trough levels.METHODS In this multicentre retrospective study conducted across four tertiary inflammatory bowel disease centres in Australia,we identified CD patients with perianal fistulae on maintenance infliximab or adalimumab who had a trough level within twelve weeks of clinical assessment.Data collected included demographics,serum infliximab and adalimumab trough levels(mg/L)within 12 wk before or after their most recent clinical assessment and concomitant medical or surgical therapy.The primary outcome was fistula healing,defined as cessation in fistula drainage.The secondary outcome was fistula closure,defined as healing and closure of all external fistula openings.Differences between patients who did or did not achieve fistula healing were compared using the chi-square test,t test or Mann-Whitney U test.RESULTS One hundred and fourteen patients(66 infliximab,48 adalimumab)were included.Forty-eight(72.7%)patients on maintenance infliximab achieved fistula healing and 18(27.3%)achieved fistula closure.Thirty-seven(77%)patients on maintenance adalimumab achieved fistula healing and 17(35.4%)achieved fistula closure.Patients who achieved fistula healing had significantly higher infliximab and adalimumab trough levels than patients who did not[infliximab:6.4(3.8-9.5)vs 3.0(0.3-6.2)mg/L,P=0.003;adalimumab:9.2(6.5-12.0)vs 5.4(2.5-8.3)mg/L,P=0.004].For patients on infliximab,fistula healing was associated with lower rates of detectable anti-infliximab antibodies and younger age.For patients on adalimumab,fistula healing was associated with higher rates of combination therapy with an immunomodulator.Serum trough levels for patients with and without fistula closure were not significantly different for infliximab[6.9(4.3-10.2)vs 5.5(2.5-8.3)mg/L,P=0.105]or adalimumab[10.0(6.6-12.0)vs 7.8(4.2-10.0)mg/L,P=0.083].CONCLUSION Higher maintenance infliximab and adalimumab trough levels are associated with perianal fistula healing in CD.展开更多
BACKGROUND Capecitabine(CAP)is a classic antimetabolic drug and has shown potential antirejection effects after liver transplantation(LT)in clinical studies.Our previous study showed that metronomic CAP can cause the ...BACKGROUND Capecitabine(CAP)is a classic antimetabolic drug and has shown potential antirejection effects after liver transplantation(LT)in clinical studies.Our previous study showed that metronomic CAP can cause the programmed death of T cells by inducing oxidative stress in healthy mice.Ferroptosis,a newly defined non-apoptotic cell death that occurs in response to iron overload and lethal levels of lipid peroxidation,is an important mechanism by which CAP induces cell death.Therefore,ferroptosis may also play an important role in CAP-induced T cell death and play an immunosuppressive role in acute rejection after transplantation.AIM To investigate the functions and underlying mechanisms of antirejection effects of metronomic CAP.METHODS A rat LT model of acute rejection was established,and the effect of metronomic CAP on splenic hematopoietic function and acute graft rejection was evaluated 7 d after LT.In vitro,primary CD3+T cells were sorted from rat spleens and human peripheral blood,and co-cultured with or without 5-fluorouracil(5-FU)(active agent of CAP).The levels of ferroptosis-related proteins,ferrous ion concentration,and oxidative stress-related indicators were observed.The changes in mitochondrial structure were observed using electron microscopy.RESULTS With no significant myelotoxicity,metronomic CAP alleviated graft injury(Banff score 9 vs 7.333,P<0.001),prolonged the survival time of the recipient rats(11.5 d vs 16 d,P<0.01),and reduced the infiltration rate of CD3+T cells in peripheral blood(6.859 vs 3.735,P<0.001),liver graft(7.459 vs 3.432,P<0.001),and spleen(26.92 vs 12.9,P<0.001),thereby inhibiting acute rejection after LT.In vitro,5-FU,an end product of CAP metabolism,induced the degradation of the ferritin heavy chain by upregulating nuclear receptor coactivator 4,which caused the accumulation of ferrous ions.It also inhibited nuclear erythroid 2 p45-related factor 2,heme oxygenase-1,and glutathione peroxidase 4,eventually leading to oxidative damage and ferroptosis of T cells.CONCLUSION Metronomic CAP can suppress acute allograft rejection in rats by triggering CD3+T cell ferroptosis,which makes it an effective immunosuppressive agent after LT.展开更多
基金Supported by the Haihe Laboratory of Cell Ecosystem Innovation Fund,No.22HHXBJC00001the Key Discipline Special Project of Tianjin Municipal Health Commission,No.TJWJ2022XK016.
文摘BACKGROUND Hepatocellular carcinoma(HCC)has been a pervasive malignancy throughout the world with elevated mortality.Efficient therapeutic targets are beneficial to treat and predict the disease.Currently,the exact molecular mechanisms leading to the progression of HCC are still unclear.Research has shown that the microRNA-142-3p level decreases in HCC,whereas bioinformatics analysis of the cancer genome atlas database shows the ASH1L expression increased among liver tumor tissues.In this paper,we will explore the effects and mechanisms of microRNA-142-3p and ASH1L affect the prognosis of HCC patients and HCC cell bioactivity,and the association between them.AIM To investigate the effects and mechanisms of microRNA-142-3p and ASH1L on the HCC cell bioactivity and prognosis of HCC patients.METHODS In this study,we grouped HCC patients according to their immunohistochemistry results of ASH1L with pathological tissues,and retrospectively analyzed the prognosis of HCC patients.Furthermore,explored the roles and mechanisms of microRNA-142-3p and ASH1L by cellular and animal experiments,which involved the following experimental methods:Immunohistochemical staining,western blot,quantitative real-time-polymerase chain reaction,flow cytometric analysis,tumor xenografts in nude mice,etc.The statistical methods involved in this study contained t-test,one-way analysis of variance,theχ^(2)test,the Kaplan-Meier approach and the log-rank test.RESULTS In this study,we found that HCC patients with high expression of ASH1L possess a more recurrence rate as well as a decreased overall survival rate.ASH1L promotes the tumorigenicity of HCC and microRNA-142-3p exhibits reduced expression in HCC tissues and interacts with ASH1L through targeting the ASH1L 3′untranslated region.Furthermore,microRNA-142-3p promotes apoptosis and inhibits proliferation,invasion,and migration of HCC cell lines in vitro via ASH1L.For the exploration mechanism,we found ASH1L may promote an immunosuppressive microenvironment in HCC and ASH1L affects the expression of the cell junction protein zonula occludens-1,which is potentially relevant to the immune system.CONCLUSION Loss function of microRNA-142-3p induces cancer progression and immune evasion through upregulation of ASH1L in HCC.Both microRNA-142-3p and ASH1L can feature as new biomarker for HCC in the future.
文摘Background:Individuals with diabetes have greater central arterial stiffness,wave reflections,and hemodynamics,all of which promote the accelerated cardiovascular pathology seen in this population.Acute aerobic exercise has been shown to be an effective strategy for reducing central arterial stiffness,wave reflections,and hemodynamics in healthy individuals;however,the effects of acute aerobic exercise in reducing these outcomes is not well established in people with diabetes.Recently,implementation of high-intensity interval exercise(HIIE)has shown superior improvements in cardiovascular health outcomes when compared to traditional aerobic exercise.Yet,the effect of HIIE on the aforementioned outcomes in people with diabetes is not known.The purpose of this study was to(i)describe the central arterial stiffness,wave reflections,and hemodynamic responses to a bout of HIIE and moderate-intensity continuous exercise(MICE)in adults with diabetes;and(ii)compare the effects of HIIE and MICE on the aforementioned outcomes.Methods:A total of 24 adult men and women(aged 29-59 years old)with type 1(n=12)and type 2(n=12)diabetes participated in a randomized cross-over study.All participants completed the following protocols:(i)HIIE:cycling for 4×4 min at 85%-95%of heart rate peak(HR_(peak)),interspersed with 3 min of active recovery at 60%-70%HR_(peak);(ii)MICE:33 min of continuous cycling at 60%-70%HR_(peak);and(iii)control(CON):lying quietly in a supine position for 30 min.Results:A significant group￡time effect was found for changes in central systolic blood pressure(F=3.20,p=0.01)with a transient reduction for the HIIE group but not for the MICE or CON groups.There was a significant group￡time effect for changes in augmentation index at a heart rate of 75 beats/min(F=2.32,p=0.04)with a decrease following for HIIE and MICE but not for CON.For all other measures of central arterial stiffness and hemodynamics,no significant changes were observed(p>0.05).Conclusion:A bout of HIIE appears to lead to a greater transient reduction in central systolic blood pressure than the reduction observed following MICE;however,both HIIE and MICE improved augmentation index at a heart rate of 75 beats/min in people with diabetes.There was no significant difference in response to HIIE and MICE in all outcomes.This provides preliminary evidence on the role of HIIE on such outcomes in people with diabetes.
文摘BACKGROUND Management of single small hepatocellular carcinoma(HCC)is straightforward with curative outcomes achieved by locoregional therapy or resection.Liver transplantation is often considered for multiple small or single large HCC.Management of two small HCC whether presenting synchronously or sequentially is less clear.AIM To define the outcomes of patients presenting with two small HCC.METHODS Retrospective review of HCC databases from multiple institutions of patients with either two synchronous or sequential HCC≤3 cm between January 2000 and March 2018.Primary outcomes were overall survival(OS)and transplant-free survival(TFS).RESULTS 104 patients were identified(male n=89).Median age was 63 years(interquartile range 58-67.75)and the most common aetiology of liver disease was hepatitis C(40.4%).59(56.7%)had synchronous HCC and 45(43.3%)had sequential.36 patients died(34.6%)and 25 were transplanted(24.0%).1,3 and 5-year OS was 93.0%,66.1% and 62.3% and 5-year post-transplant survival was 95.8%.1,3 and 5-year TFS was 82.1%,45.85% and 37.8%.When synchronous and sequential groups were compared,OS(1,3 and 5 year synchronous 91.3%,63.8%,61.1%,sequential 95.3%,69.5%,64.6%,P=0.41)was similar but TFS was higher in the sequential group(1,3 and 5 year synchronous 68.5%,37.3% and 29.7%,sequential 93.2%,56.6%,48.5%,P=0.02)though this difference did not remain during multivariate analysis.CONCLUSION TFS in patients presenting with two HCC≤3 cm is poor regardless of the timing of the second tumor.All patients presenting with two small HCC should be considered for transplantation.
文摘BACKGROUND Patients with neurofibromatosis type 1(NF1)are exposed to a higher risk of developing neuroendocrine tumors(NETs).Periampullary neuroendocrine neoplasms(NENs)in NF1 patients primarily affect the duodenum and periampullary region.CASE SUMMARY A 50-year-old male patient was admitted to our hospital due to progressive skin and scleral yellowing for over 6 months.An abdominal contrast-enhanced computed tomography scan revealed a tumor in the periampullary region,which measured 1.2 cm×1.4 cm in size and showed a progressive enhancement.Magnetic resonance cholangiopancreatography indicated the dilation of intrahepatic and extrahepatic bile ducts.The patient was diagnosed with an ampullary tumor with the possibility of malignancy.A Whipple procedure was performed.Microscopically,the duodenum tumor was found to invade the mucosa,sphincter,and muscular layer of the duodenal papilla.Histologic hematoxylin and eosin staining confirmed the presence of duodenal G1 NET.Subsequently,a bibliometric analysis was performed to evaluate the state of NEN research.Publications about periampullary NENs showed an annual increase,with most of them focusing on the treatment and diagnosis of NENs.CONCLUSION This article reported a case of periampullary duodenal NET in a patient with NF1,and a bibliometric analysis was conducted.
基金All authors are supported by the Victorian Government’s Operational Infrastructure Support ProgramSBS is supported by a joint Baker Heart and Diabetes Institute-La Trobe University doctoral scholarshipRM is supported by a National Health and Medical Research Council Senior Research Fellowship(Grant No.1078985).
文摘Heart failure represents the end point of a variety of cardiovascular diseases.It is a growing health burden and a leading cause of death worldwide.To date,limited treatment options exist for the treatment of heart failure,but exercise has been well-established as one of the few safe and effective interventions,leading to improved outcomes in patients.However,a lack of patient adherence remains a significant barrier in the implementation of exercise-based therapy for the treatment of heart failure.The insulin-like growth factor 1(IGF1)phosphoinositide 3-kinase(PI3K)pathway has been recognized as perhaps the most critical pathway for mediating exercisedinduced heart growth and protection.Here,we discuss how modulating activity of the IGF1PI3K pathway may be a valuable approach for the development of therapies that mimic the protective effects of exercise on the heart.We outline some of the promising approaches being investigated that utilize PI3K-based therapy for the treatment of heart failure.We discuss the implications for cardiac pathology and cardiotoxicity that arise in a setting of reduced PI3K activity.Finally,we discuss the use of animal models of cardiac health and disease,and genetic mice with increased or decreased cardiac PI3K activity for the discovery of novel drug targets and biomarkers of cardiovascular disease.
文摘AIM:To analyze the expression of kallikrein gene 10(KLK10)in gastric cancer and to determine whether KLK10 has independent prognostic value in gastric cancer.METHODS:We studied KLK10 expression in 80 histologically confirmed gastric cancer samples using realtime quantitative reverse transcription-PCR and hK10expression using immunohistochemistry.Correlations with clinicopathological variables(lymph node metastasis,depth of invasion and histology)and with outcomes(disease-free survival and overall survival)during a median follow-up period of 31 mo were assessed.Gastric cancer tissues were then classified as KLK10 positive or negative.RESULTS:KLK10 was found to be highly expressed in 57/80(70%)of gastric cancer samples,while its expression was very low in normal gastric tissues.Positive relationships between KLK10 expression and lymph node metastasis(P=0.048),depth of invasion(P=0.034)and histology(P=0.015)were observed.Univariate survival analysis revealed that gastric cancer patients with positive KLK10 expression had an increased risk for relapse/metastasis and death(P=0.005 and0.002,respectively).Cox multivariate analysis indicated that KLK10 was an independent prognostic indicator of disease-free survival and overall survival in patients with gastric cancer.CONCLUSION:KLK10 expression is an independent biomarker of unfavorable prognosis in patients with gastric cancer.
文摘Nasopharyngeal carcinoma （NPC） is a common cancer in Southern China and Southeast Asia. The disease is a poorly differentiated carcinoma without effective cure, and the mechanism underlying its development remains largely unknown. Of several factors identified in NPC aetiology in recent years, Epstein-Barr virus （EBV） infection has emerged to be most important. In almost all NPC cells, EBV uses several intracellular mechanisms to cause oncogenic evolution of the infected cells. One such mechanism by which EBV infection induces cellular immortalization is believed to be through the activation of telomerase, an enzyme that is normally repressed but becomes activated during cancer development. Studies show that greater than 85% of primary NPC display high telomerase activity by mechanisms involving EBV infection, consistent with the notion that EBV is commonly involved in inducing cell immortalization. More recently, different EBV proteins have been shown to activate or inhibit the human telomerase reverse transcriptase gene, by modulating intracellular signalling pathways. These findings suggest a new model with a number of challenges towards our understanding, molecular targeting and therapeutic intervention in NPC.
文摘Estrogen deficiency mediates aging, but the underlying mechanism remains to be fully determined. We report here that estrogen deficiency caused by targeted disruption of aromatase in mice results in significant inhibition of telomerase activity in the adrenal gland in vivo. Gene expression analysis showed that, in the absence of estrogen, telomerase reverse transcriptase （TERT） gene expression is reduced in association with compromised cell proliferation in the adrenal gland cortex and adrenal atrophy. Stem cells positive in c-kit are identified to populate in the parenchyma of adrenal cortex. Analysis of telomeres revealed that estrogen deficiency results in significantly shorter teiomeres in the adrenal cortex than that in wild-type （WT） control mice. To further establish the causal effects of estrogen, we conducted an estrogen replacement therapy in these estrogen-deficient animals. Administration of estrogen for 3 weeks restores TERT gene expression, telomerase activity and cell proliferation in estrogen-deficient mice. Thus, our data show for the first time that estrogen deficiency causes inhibitions of TERT gene expression, telomerase activity, telomere maintenance, and cell proliferation in the adrenal gland of mice in vivo, suggesting that telomerase inhibition and telomere shortening may mediate cell proliferation arrest in the adrenal gland, thus contributing to estrogen deficiency-induced aging under physiological conditions.
基金Supported by Philanthropic Anonymous Sourcethe University of Sydney Bridging Support Grant,in part for Honours ProjectSupported by the National Health and Medical Research Council,No.NHMRC Practitioner Research Fellowship for PH support
文摘AIM: To investigate over-expression of Osteopontin (OPN) pathway expression and mechanisms of action in human alcoholic liver disease (ALD), in vivo and in vitro acute alcohol models.
文摘Metabolic associated fatty liver disease(MAFLD),previously termed nonalcoholic fatty liver disease,is the leading global cause of liver disease and is fast becoming the most common indication for liver transplantation.The recent change in nomenclature to MAFLD refocuses the conceptualisation of this disease entity to its metabolic underpinnings and may help to spur a paradigm shift in the approach to its management,including in the setting of liver transplantation.Patients with MAFLD present significant challenges in the pre-,peri-and posttransplant settings,largely due to the presence of medical comorbidities that include obesity,metabolic syndrome and cardiovascular risk factors.As the community prevalence of MAFLD increases concurrently with the obesity epidemic,donor liver steatosis is also a current and future concern.This review outlines current epidemiology,nomenclature,management issues and outcomes of liver transplantation in patients with MAFLD.
基金supported by Multiple Sclerosis Research Australia and Trish Multiple Sclerosis Research Foundation Postgraduate Scholarship(to JYL)the National Multiple Sclerosis Society Project Grant#RG4398A1/1+2 种基金International Progressive Multiple Sclerosis Alliance Challenge Award#PA0065Multiple Sclerosis Research Australia and Trish Multiple Sclerosis Research Foundation#15-022Bethlehem Griffiths Research Foundation#BGRF1706(to SP)
文摘Myelin-associated inhibitory factors within the central nervous system（CNS） are considered to be one of the main obstacles for axonal regeneration following disease or injury. The nogo receptor 1（NgR1） has been well documented to play a key role in limiting axonal regrowth in the injured and diseased mammalian CNS. However, the role of nogo receptor in immune cell activation during CNS inflammation is yet to be mechanistically elucidated. Microglia/macrophages are immune cells that are regarded as pathogenic contributors to inflammatory demyelinating lesions in multiple sclerosis（MS）. In this study, the animal model of MS, experimental autoimmune encephalomyelitis（EAE） was induced in ngr1^＋/＋ and ngr1^–/– female mice following injection with the myelin oligodendrocyte glycoprotein（MOG_（35–55）） peptide. A fatemap analysis of microglia/macrophages was performed throughout spinal cord sections of EAE-induced mice at clinical scores of 0, 1, 2 and 3, respectively（increasing locomotor disability） from both genotypes, using the CD11 b and Iba1 cell markers. Western immunoblotting using lysates from isolated spinal cord microglia/macrophages, along with immunohistochemistry and flow cytometric analysis, was performed to demonstrate the expression of nogo receptor and its two homologs during EAE progression. Myelin protein engulfment during EAE progression in ngr1^＋/＋ and ngr1^–/– mice was demonstrated by western immunblotting of lysates from isolated spinal cord microglia/macrophages, detecting levels of Nogo-A and MOG. The numbers of M1 and M2 microglia/macrophage phenotypes present in the spinal cords of EAE-induced ngr1^＋/＋ and ngr1^–/– mice, were assessed by flow cytometric analysis using CD38 and Erg-2 markers. A significant difference in microglia/macrophage numbers between ngr1^＋/＋ and ngr1^–/– mice was identified during the progression of the clinical symptoms of EAE, in the white versus gray matter regions of the spinal cord. This difference was unrelated to the expression of Ng R on these macrophage/microglial cells. We have identified that as EAE progresses, the phagocytic activity of microglia/macrophages with myelin debris, in ngr1^–/– mice, was enhanced. Moreover, we show a modulation from a predominant M1-pathogenic to the M2-neurotrophic cell phenotype in the ngr1^–/– mice during EAE progression. These findings suggest that CNS-specific macrophages and microglia of ngr1^–/– mice may exhibit an enhanced capacity to clear inhibitory molecules that are sequestered in inflammatory lesions.
基金Supported by Project and Fellowship Grants from the National Health and Medical Research Council of Australia
文摘AIM: To optimize the experimental protocols for a simple, sensitive and accurate bleeding assay.METHODS: Bleeding assay was performed in mice by tail tip amputation, immersing the tail in saline at 37 ℃, continuously monitoring bleeding patterns and measuring bleeding volume from changes in the body weight. Sensitivity and extent of variation of bleeding time and bleeding volume were compared in mice treated with the P2 Y receptor inhibitor prasugrel at various doses or in mice deficient of Fc Rγ, a signaling protein of the glycoprotein VI receptor.RESULTS: We described details of the bleeding assay with the aim of standardizing this commonly used assay. The bleeding assay detailed here was simple to operate and permitted continuous monitoring of bleedingpattern and detection of re-bleeding. We also reported a simple and accurate way of quantifying bleeding volume from changes in the body weight, which correlated well with chemical assay of hemoglobin levels(r2 = 0.990, P < 0.0001). We determined by tail bleeding assay the dose-effect relation of the anti-platelet drug prasugrel from 0.015 to 5 mg/kg. Our results showed that the correlation of bleeding time and volume was unsatisfactory and that compared with the bleeding time, bleeding volume was more sensitive in detecting a partial inhibition of platelet's haemostatic activity(P < 0.01). Similarly, in mice with genetic disruption of Fc Rγ as a signaling molecule of P-selectin glycoprotein ligand-1 leading to platelet dysfunction, both increased bleeding volume and repeated bleeding pattern defined the phenotype of the knockout mice better than that of a prolonged bleeding time.CONCLUSION: Determination of bleeding pattern and bleeding volume, in addition to bleeding time, improved the sensitivity and accuracy of this assay, particularly when platelet function is partially inhibited.
文摘Dear Editor,Severe Acute Respiratory Syndrome(SARS)has beendescribed as the first pandemic of the 21st century andbetween November 2002 and July 2003,over 8000 peo-ple were infected with the SARS-associated coronavirus(SARS-CoV).Polymorphisms in the human leukocyteantigen(HLA)system have been shown to influencesusceptibility to SARS-CoV but here we were unable
基金Supported by the grants from the National Natural Science Foundation of China(No.81270362No.81470561)State Project For Essential Drug Research and Development(No.2013ZX09103003-001)
文摘AIM: Early calcification of atherosclerotic plaques are colocalized with macrophage and high mobility group box 1( HMGB1),a cytokine associated with biomineralizing process under physiological and pathological conditions. Our study aims to evaluate whether HMGB1 induces ectopic mineralization via promoting the secretion of matrix vesicles( MVs) from macrophages. METHODS: HMGB1 was added to the medium of macrophages,the secretion of MVs in the supernatant was tested by flow cytometry analysis. The mineral deposition in calcifying medium was detected by Alizarin Red staining and von Kossa staining. Transmission electron microscopy showed the formation of hydroxyapatite crystals in MVs. Then we subcutaneous injection into mice with MVs to induce regional mineralization. RESULTS: HMGB1 significantly promoted secretion of MVs from macrophages as raveled by flow cytometry analysis. TNAP activity,considered as a marker of MVs maturation,was higher in HMGB1-induced MVs compared to the control-MVs. HMGB1-MVs also led to mineral deposition in an in vitro MVs-collagen mineralization model. Subcutaneous injection into mice with MVs derived from HMGB1-treated cells showed a greater potential to initiate regional mineralization. Mechanistic experiments revealed that HMGB1 activated neutral sphingomyelinase 2( n SMase2) that involved the receptor for advanced glycation end products( RAGE) and p38MAPK( upstream of n SMase2). Inhibition of n SMase2 with GW4869 or p38 MAPK with SB-239063 prevented MVs secretion and mineral deposition. CONCLUSIONS: HMGB1 induces MVs secretion from macrophages at least in part,via the RAGE / p38 MAPK /n SMase2 signaling pathway. Our findings thus reveal a novel mechanism by which HMGB1 may participated in the early calcification of atherosclerotic plaques.
基金R.B.is supported by a grant from NINDS(NINDS RFA-NS-16-012)to T.O.B.and S.S.S.S.is supported by a fellowship from NHMRC.
文摘Neurological heterotopic ossification(NHO)is a debilitating condition where bone forms in soft tissue,such as muscle surrounding the hip and knee,following an injury to the brain or spinal cord.This abnormal formation of bone can result in nerve impingement,pain,contractures and impaired movement.Patients are often diagnosed with NHO after the bone tissue has completely mineralised,leaving invasive surgical resection the only remaining treatment option.Surgical resection of NHO creates potential for added complications,particularly in patients with concomitant injury to the central nervous system(CNS).Although recent work has begun to shed light on the physiological mechanisms involved in NHO,there remains a significant knowledge gap related to the prognostic biomarkers and prophylactic treatments which are necessary to prevent NHO and optimise patient outcomes.This article reviews the current understanding pertaining to NHO epidemiology,pathobiology,biomarkers and treatment options.In particular,we focus on how concomitant CNS injury may drive ectopic bone formation and discuss considerations for treating polytrauma patients with NHO.We conclude that understanding of the pathogenesis of NHO is rapidly advancing,and as such,there is the strong potential for future research to unearth methods capable of identifying patients likely to develop NHO,and targeted treatments to prevent its manifestation.
基金supported by King Abdul-Aziz University postgraduate scholarship(to SHM)the National Multiple Sclerosis Society(USA)Project Grant ID#RG43981/1(to SP)
文摘Alzheimer’s disease（AD）is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles.Prior to the development of these characteristic pathological hallmarks of AD,anterograde axonal transport is impaired.However,the key proteins that initiate these intracellular impairments remain elusive.The collapsin response mediator protein-2（CRMP-2）plays an integral role in kinesin-1-dependent axonal transport and there is evidence that phosphorylation of CRMP-2releases kinesin-1.Here,we tested the hypothesis that amyloid-beta（Aβ）-dependent phosphorylation of CRMP-2 disrupts its association with the kinesin-1（an anterograde axonal motor transport protein）in AD.We found that brain sections and lysates from AD patients demonstrated elevated phosphorylation of CRMP-2 at the T555 site.Additionally,in the transgenic Tg2576 mouse model of familial AD（FAD）that exhibits Aβaccumulation in the brain with age,we found substantial co-localization of p T555CRMP-2and dystrophic neurites.In SH-SY5Y differentiated neuronal cultures,Aβ-dependent phosphorylation of CRMP-2 at the T555 site was also elevated and this reduced the CRMP-2 association with kinesin-1.The overexpression of an unphosphorylatable form of CRMP-2 in neurons promoted the re-establishment of CRMP-2-kinesin association and axon elongation.These data suggest that Aβ-dependent phosphorylation of CRMP-2 at the T555 site may directly impair anterograde axonal transport protein function,leading to neuronal defects.
文摘BACKGROUND Tumor necrosis factor-alpha inhibitors,including infliximab and adalimumab,are effective medical treatments for perianal fistulising Crohn’s disease(CD),but not all patients achieve fistula healing.AIM To determine the correlation between perianal fistula healing and closure with infliximab and adalimumab trough levels.METHODS In this multicentre retrospective study conducted across four tertiary inflammatory bowel disease centres in Australia,we identified CD patients with perianal fistulae on maintenance infliximab or adalimumab who had a trough level within twelve weeks of clinical assessment.Data collected included demographics,serum infliximab and adalimumab trough levels(mg/L)within 12 wk before or after their most recent clinical assessment and concomitant medical or surgical therapy.The primary outcome was fistula healing,defined as cessation in fistula drainage.The secondary outcome was fistula closure,defined as healing and closure of all external fistula openings.Differences between patients who did or did not achieve fistula healing were compared using the chi-square test,t test or Mann-Whitney U test.RESULTS One hundred and fourteen patients(66 infliximab,48 adalimumab)were included.Forty-eight(72.7%)patients on maintenance infliximab achieved fistula healing and 18(27.3%)achieved fistula closure.Thirty-seven(77%)patients on maintenance adalimumab achieved fistula healing and 17(35.4%)achieved fistula closure.Patients who achieved fistula healing had significantly higher infliximab and adalimumab trough levels than patients who did not[infliximab:6.4(3.8-9.5)vs 3.0(0.3-6.2)mg/L,P=0.003;adalimumab:9.2(6.5-12.0)vs 5.4(2.5-8.3)mg/L,P=0.004].For patients on infliximab,fistula healing was associated with lower rates of detectable anti-infliximab antibodies and younger age.For patients on adalimumab,fistula healing was associated with higher rates of combination therapy with an immunomodulator.Serum trough levels for patients with and without fistula closure were not significantly different for infliximab[6.9(4.3-10.2)vs 5.5(2.5-8.3)mg/L,P=0.105]or adalimumab[10.0(6.6-12.0)vs 7.8(4.2-10.0)mg/L,P=0.083].CONCLUSION Higher maintenance infliximab and adalimumab trough levels are associated with perianal fistula healing in CD.
基金Supported by National Key Research and Development Program of China,No.2020YFA0710802The Youth Science Fund of the Nature Science Foundation of Tianjin,No.20JCQNJC01370+1 种基金The Key Projects of Tianjin Science and Technology Project,No.21JCZDJC00160The Science Foundation of Tianjin Health Commission,No.ZC20065 and No.ZC20089.
文摘BACKGROUND Capecitabine(CAP)is a classic antimetabolic drug and has shown potential antirejection effects after liver transplantation(LT)in clinical studies.Our previous study showed that metronomic CAP can cause the programmed death of T cells by inducing oxidative stress in healthy mice.Ferroptosis,a newly defined non-apoptotic cell death that occurs in response to iron overload and lethal levels of lipid peroxidation,is an important mechanism by which CAP induces cell death.Therefore,ferroptosis may also play an important role in CAP-induced T cell death and play an immunosuppressive role in acute rejection after transplantation.AIM To investigate the functions and underlying mechanisms of antirejection effects of metronomic CAP.METHODS A rat LT model of acute rejection was established,and the effect of metronomic CAP on splenic hematopoietic function and acute graft rejection was evaluated 7 d after LT.In vitro,primary CD3+T cells were sorted from rat spleens and human peripheral blood,and co-cultured with or without 5-fluorouracil(5-FU)(active agent of CAP).The levels of ferroptosis-related proteins,ferrous ion concentration,and oxidative stress-related indicators were observed.The changes in mitochondrial structure were observed using electron microscopy.RESULTS With no significant myelotoxicity,metronomic CAP alleviated graft injury(Banff score 9 vs 7.333,P<0.001),prolonged the survival time of the recipient rats(11.5 d vs 16 d,P<0.01),and reduced the infiltration rate of CD3+T cells in peripheral blood(6.859 vs 3.735,P<0.001),liver graft(7.459 vs 3.432,P<0.001),and spleen(26.92 vs 12.9,P<0.001),thereby inhibiting acute rejection after LT.In vitro,5-FU,an end product of CAP metabolism,induced the degradation of the ferritin heavy chain by upregulating nuclear receptor coactivator 4,which caused the accumulation of ferrous ions.It also inhibited nuclear erythroid 2 p45-related factor 2,heme oxygenase-1,and glutathione peroxidase 4,eventually leading to oxidative damage and ferroptosis of T cells.CONCLUSION Metronomic CAP can suppress acute allograft rejection in rats by triggering CD3+T cell ferroptosis,which makes it an effective immunosuppressive agent after LT.
