Major advances have been made over the last decade in our understanding of the molecular basis ofseveral cardiac conditions. Hypertrophic cardiomyopathy (HCM) was the first cardiac disorder in whicha genetic basis was...Major advances have been made over the last decade in our understanding of the molecular basis ofseveral cardiac conditions. Hypertrophic cardiomyopathy (HCM) was the first cardiac disorder in whicha genetic basis was identified and as such, has acted as a paradigm for the study of an inherited cardiacdisorder. HCM can result in clinical symptoms ranging from no symptoms to severe heart failure andpremature sudden death. HCM is the commonest cause of sudden death in those aged less than 35 years,including competitive athletes. At least ten genes have now been identified, defects in which cause HCM.All of these genes encode proteins which comprise the basic contractile unit of the heart, i.e. the sarcomere.While much is now known about which genes cause disease and the various clinical presentations, very littleis known about how these gene defects cause disease, and what factors modify the expression of the mutantgenes. Studies in both cell culture and animal models of HCM are now beginning to shed light on thesignalling pathways involved in HCM, and the role of both environmental and genetic modifying factors.Understanding these mechanisms will ultimately improve our knowledge of the basic biology of heart musclefunction, and will therefore provide new avenues for treating cardiovascular disease in man.展开更多
N^6-methyladenosine(m^6 A) is an essential RNA modification that regulates key cellular processes, including stem cell renewal,cellular differentiation, and response to DNA damage. Unsurprisingly, aberrant m^6 A methy...N^6-methyladenosine(m^6 A) is an essential RNA modification that regulates key cellular processes, including stem cell renewal,cellular differentiation, and response to DNA damage. Unsurprisingly, aberrant m^6 A methylation has been implicated in the development and maintenance of diverse human cancers. Altered m^6 A levels affect RNA processing, mRNA degradation, and translation of mRNAs into proteins, thereby disrupting gene expression regulation and promoting tumorigenesis. Recent studies have reported that the abnormal expression of m^6 A regulatory enzymes affects m^6 A abundance and consequently dysregulates the expression of tumor suppressor genes and oncogenes, including MYC, SOCS2, ADAM19, and PTEN. In this review, we discuss the specific roles of m^6 A missing space "writers", "erasers", and "readers" in normal physiology and how their altered expression promotes tumorigenesis. We also describe the potential of exploiting the aberrant expression of these enzymes for cancer diagnosis, prognosis, and the development of novel therapies.展开更多
Chimeric antigen receptor T(CAR T)cell therapy has demonstrated efficacy in the treatment of haematologic malignancies.However,the accompanying adverse events,the most common of which is cytokine release syndrome(CRS)...Chimeric antigen receptor T(CAR T)cell therapy has demonstrated efficacy in the treatment of haematologic malignancies.However,the accompanying adverse events,the most common of which is cytokine release syndrome(CRS),substantially limit its wide application.Due to its unique physiological characteristics,CRS in CAR T-cell treatment for B-cell non-Hodgkin lymphoma(BNHL)may exhibit some special features.Although existing guidelines had greatly promoted the recognition and management of CRS,many recommendations are not fully applicable to B-NHL.Therefore,it is imperative to identify responses that are specific to CRS observed following CAR T treatment for B-NHL.Based on underlying biological processes and known pathophysiological mechanisms,we tentatively propose a new model to illustrate the occurrence and evolution of CAR T-cell-therapy-related CRS in BNHL.In this model,tumour burden and bone marrow suppression are considered determinants of CRS.Novel phenomena after CAR T-cell infusion(such as local inflammatory response)are further identified.The proposed model will help us better understand the basic biology of CRS and recognize and manage it more rationally.展开更多
Tumor vasculature is characterized by aberrant structure and function,resulting in immune suppressive profiles of tumor microenvironment through limiting immune cell infiltration into tumors,endogenous immune surveill...Tumor vasculature is characterized by aberrant structure and function,resulting in immune suppressive profiles of tumor microenvironment through limiting immune cell infiltration into tumors,endogenous immune surveillance and immune cell function.Vascular normalization as a novel therapeutic strategy tends to prune some of the immature blood vessels and fortify the structure and function of the remaining vessels,thus improving immune stimulation and the efficacy of immunotherapy.Interestingly,the presence of"immune-vascular crosstalk"enables the formation of a positive feedback loop between vascular normalization and immune reprogramming,providing the possibility to develop new cancer therapeutic strategies.The applications of nanomedicine in vascular-targeting therapy in cancer have gained increasing attention due to its specific physical and chemical properties.Here,we reviewed the recent advances of effective routes,especially nanomedicine,for normalizing tumor vasculature.We also summarized the development of enhancing nanoparticle-based anticancer drug delivery via the employment of transcytosis and mimicking immune cell extravasation.This review explores the potential to optimize nanomedicine-based therapeutic strategies as an alternative option for cancer treatment.展开更多
The incidence of lymphoma has gradually increased over previous decades,and it ranks among the ten most prevalent cancers worldwide.With the development of targeted therapeutic strategies,though a subset of lymphoma p...The incidence of lymphoma has gradually increased over previous decades,and it ranks among the ten most prevalent cancers worldwide.With the development of targeted therapeutic strategies,though a subset of lymphoma patients has become curable,the treatment of refractory and relapsed diseases remains challenging.Many efforts have been made to explore new targets and to develop corresponding therapies.In addition to novel antibodies targeting surface antigens and small molecular inhibitors targeting oncogenic signaling pathways and tumor suppressors,immune checkpoint inhibitors and chimeric antigen receptor T-cells have been rapidly developed to target the tumor microenvironment.Although these targeted agents have shown great success in treating lymphoma patients,adverse events should be noted.The selection of the most suitable candidates,optimal dosage,and effective combinations warrant further investigation.In this review,we systematically outlined the advances in targeted therapy for malignant lymphoma,providing a clinical rationale for mechanism-based lymphoma treatment in the era of precision medicine.展开更多
Elucidating the exact contribution of microglia to central nervous system(CNS)pathology has historically been extremely challenging.These resident parenchymal myeloid cells are considered to have critical roles as fro...Elucidating the exact contribution of microglia to central nervous system(CNS)pathology has historically been extremely challenging.These resident parenchymal myeloid cells are considered to have critical roles as frontline responders during pathogen invasion and CNS perturbation.Thus,understanding the precise temporal kinetics of microglial function is central to the evolution of novel therapeutics for disease intervention and/or resolution(Spiteri et al.,2022a).The development of PLX5622,a colony-stimulating factor 1 receptor(CSF-1R)inhibitor typically formulated into a rodent chow for simple oral administration has facilitated exploration of microglial functions in disease(Spangenberg et al.,2019).展开更多
Aberrant tumor blood vessels are prone to propel the malignant progression of tumors,and targeting abnormal metabolism of tumor endothelial cells emerges as a promising option to achieve vascular normalization and ant...Aberrant tumor blood vessels are prone to propel the malignant progression of tumors,and targeting abnormal metabolism of tumor endothelial cells emerges as a promising option to achieve vascular normalization and antagonize tumor progression.Herein,we demonstrated that salvianic acid A(SAA)played a pivotal role in contributing to vascular normalization in the tumor-bearing mice,thereby improving delivery and effectiveness of the chemotherapeutic agent.SAA was capable of inhibiting glycolysis and strengthening endothelial junctions in the human umbilical vein endothelial cells(HUVECs)exposed to hypoxia.Mechanistically,SAA was inclined to directly bind to the glycolytic enzyme PKM2,leading to a dramatic decrease in endothelial glycolysis.More importantly,SAA improved the endothelial integrity via activating theβ-Catenin/Claudin-5 signaling axis in a PKM2-dependent manner.Our findings suggest that SAA may serve as a potent agent for inducing tumor vascular normalization.展开更多
Of over 170 types of RNA modifications discovered,N^(6)-methyladenosine(m^(6)A)is the most actively studied.m6A confers oncogenic potential,maintains cancer stem cells,and is associated with cancer-related outcomes.^(...Of over 170 types of RNA modifications discovered,N^(6)-methyladenosine(m^(6)A)is the most actively studied.m6A confers oncogenic potential,maintains cancer stem cells,and is associated with cancer-related outcomes.^(1) The role of RNA modifications including m^(1)A is poorly understood.展开更多
BACKGROUND Recent studies in non-colorectal malignancy have associated T resident memory(T_(RM)) cells with improved patient survival. It is unknown if T_(RM) plays a role in colorectal cancer(CRC).AIM To examine the ...BACKGROUND Recent studies in non-colorectal malignancy have associated T resident memory(T_(RM)) cells with improved patient survival. It is unknown if T_(RM) plays a role in colorectal cancer(CRC).AIM To examine the potential role of T_(RM) cells in providing immunogenicity in CRC stratified by microsatellite instability(MSI) and BRAF status.METHODS Patients with known MSI and BRAF mutation status were eligible for inclusion in this study. CRC tumour sections stained with haematoxylin and eosin were microscopically reviewed and the images scanned prior to assessment for location of invading edge and core of tumour. Sequential sections were prepared for quantitative multiplex immunohistochemistry(IHC) staining. Opal Multiplex IHC staining was performed with appropriate positive and negative controls and imaged using a standard fluorescent microscope fitted with a spectral scanning camera(Mantra) in conjunction with Mantra snap software. Images were unmixed and annotated in in Form 2.2.0. Statistical analysis was performed using Graphpad Prism Version 7 and Stata Version 15.RESULTS Seventy-two patients with known MSI and BRAF status were included in the study. All patients were assessed for MSI by IHC and high resolution capillary electrophoresis testing and 44 of these patients successfully underwent quantitative multiplex IHC staining. Overall, there was a statistically significant increase in CD8+ T_(RM) cells in the MSI(BRAF mutant and wild type) group over the microsatellite stable(MSS) group. There was a statistically significant difference in CD8+ T_(RM) between high level MSI(MSI-H):BRAF mutant [22.57, 95% confidence interval(CI): 14.31-30.84] vs MSS [8.031(95%CI: 4.698-11.36)], P = 0.0076 and MSI-H:BRAF wild type [16.18(95%CI: 10.44-21.93)] vs MSS [8.031(95%CI: 4.698-11.36)], P = 0.0279. There was no statistically significant difference in CD8 T cells(both CD8+CD103-and CD8+CD103+T_(RM)) between MSI-H: BRAF mutant and wild type CRC.CONCLUSION This study has shown that CD8+ T_(RM) are found in greater abun展开更多
Balanced sphingolipid signaling is important for the maintenance of homeostasis. Sphingolipids were demonstrated to function as structural components, second messengers, and regulators of cell growth and survival in n...Balanced sphingolipid signaling is important for the maintenance of homeostasis. Sphingolipids were demonstrated to function as structural components, second messengers, and regulators of cell growth and survival in normal and disease-affected tissues. Particularly, sphingosine kinase 1 (SphK1) and its product sphingosine-1-phosphate (S1P) operate as mediators and facilitators of proliferation-linked signaling. Unlimited proliferation (selfrenewal) within the regulated environment is a hallmark of progenitor/stem cells that was recently associated with the S1P signaling network in vasculature, nervous,muscular, and immune systems. S1P was shown to regulate progenitor-related characteristics in normal and cancerstemcells(CSCs) viaG-protein coupled receptorsS1Pn(n=1 to 5). The SphK/S1P axis is crucially involved in the regulation of embryonic development of vasculature and the nervous system, hematopoietic stem cell migration, regeneration of skeletal muscle, and development of multiple sclerosis. The ratio of the S1P receptor expression, localization, and specific S1P receptoractivated downstream effectors influenced the rate of selfrenewal and should be further explored as regeneration related targets. Considering malignant transformation,it is essential to control the level of self-renewal capacity.Proliferation of the progenitor cell should be synchronized with differentiation to provide healthy lifelong function of blood, immune systems, and replacement of damaged ordead cells. The differentiation-related role of SphK/S1P remains poorly assessed. A few pioneering investigations exploredpharmacologicaltoolsthattargetsphingolipid signaling and can potentially confine and direct self-renewal towards normal differentiation. Further investigation is required to test the role of the SphK/S1P axis in regulation of self-renewal and differentiation.展开更多
AIM:To investigate the expression of dipeptidyl peptidase(DPP) 8 and DPP9 in lymphocytes and various models of liver fibrosis.METHODS:DPP8 and DPP9 expression were measured in mouse splenic CD4 + T-cells,CD8 + T-cells...AIM:To investigate the expression of dipeptidyl peptidase(DPP) 8 and DPP9 in lymphocytes and various models of liver fibrosis.METHODS:DPP8 and DPP9 expression were measured in mouse splenic CD4 + T-cells,CD8 + T-cells and B-cells(B220 +),human lymphoma cell lines and mouse splenocytes stimulated with pokeweed mitogen(PWM) or lipopolysaccharide(LPS),and in dithiothreitol(DTT) and mitomycin-C treated Raji cells.DPP8 and DPP9 expression were measured in epidermal growth factor(EGF) treated Huh7 hepatoma cells,in fibrotic liver samples from mice treated with carbon tetrachloride(CCl 4) and from multidrug resistance gene 2(Mdr2 /Abcb4) gene knockout(gko) mice with biliary fibrosis,and in human end stage primary biliary cirrhosis(PBC).RESULTS:All three lymphocyte subsets expressed DPP8 and DPP9 mRNA.DPP8 and DPP9 expression were upregulated in both PWM and LPS stimulated mouse splenocytes and in both Jurkat T-and Raji B-cell lines.DPP8 and DPP9 were downregulated in DTT treated and upregulated in mitomycin-C treated Raji cells.DPP9transfected Raji cells exhibited more annexin V + cells and associated apoptosis.DPP8 and DPP9 mRNA were upregulated in CCl 4 induced fibrotic livers but not in the lymphocytes isolated from such livers,while DPP9 was upregulated in EGF stimulated Huh7 cells.In contrast,intrahepatic DPP8 and DPP9 mRNA expression levels were low in the Mdr2 gko mouse and in human PBC compared to non-diseased livers.CONCLUSION:These expression patterns point to biological roles for DPP8 and DPP9 in lymphocyte activation and apoptosis and in hepatocytes during liver disease pathogenesis.展开更多
Hemipteran insects are the most devastating pest for different crops of high economic value. Colocasia esculenta tuber agglutinin (CEA), a mannose binding monocot lectin from araceae family was previously reported by ...Hemipteran insects are the most devastating pest for different crops of high economic value. Colocasia esculenta tuber agglutinin (CEA), a mannose binding monocot lectin from araceae family was previously reported by the present group to be effective against some members of this class of pests. In the present study, efficacy of this potent lectin has been extended to cotton aphid (Aphis gossypii) which is becoming a highly damaging pest of cotton in recent days. Because, like other aphids, A. gossypii not only extracts the phloem fluid but also transmit disease causing viruses and add to the high degree of yield loss. Efficacy of the lectin on cotton aphid as well as other hemipteran insects prompted us further to clone the protein coding gene. Very little sequence information of this gene was available in the database. Hence, attempt had been made to study the protein through liquid chromatography-tandem mass spectrometry (LC-MS/MS) to have the detailed peptide information. On the basis of the peptide homology information obtained from LC-MS/MS the complete coding sequence of CEA was determined. The coding sequence corresponding to CEA was cloned further using primers designed on the basis of above information and genome walk technology for its potential utilisation in insect management programme.展开更多
To investigate the relationship between 25-hydroxyvitamin D (25-OHD) deficiency and hepatic encephalopathy (HE) in patients with chronic liver disease (CLD). METHODSA retrospective analysis of the results of 392 adult...To investigate the relationship between 25-hydroxyvitamin D (25-OHD) deficiency and hepatic encephalopathy (HE) in patients with chronic liver disease (CLD). METHODSA retrospective analysis of the results of 392 adult patients with chronic liver disease who were assessed for liver transplantation between 2006 and 2010 was undertaken. HE, severity of CLD, nutritional status and 25-OHD were analysed in patients assessed for liver transplantation between 2006 and 2010. Patients who presented with acute, fulminant or subacute disease, with a primary diagnosis of liver cancer, were assessed for re-transplantation or who did not have a 25-OHD measurement were excluded from the analysis. RESULTSOne hundred and sixty-five patients were included in this analysis. The mean age of all patients was 53 ± 8 years. Moderate to severe 25-OHD deficiency was identified in 49 patients of whom 36 had grade 2-3 HE compared with 13 patients who were not encephalopathic (P ≤ 0.0001). Mild 25-OHD deficiency was not associated with HE. There was a significant correlation between the severity of 25-OHD deficiency and the severity of liver disease (r = 0.39, P ≤ 0.0001) and disease severity and the presence of HE (P ≤ 0.0001). Importantly, individuals with 25-OHD deficiency were more likely to have a diagnosis of overt HE (OHE) at a significantly lower model for end stage liver disease (MELD) score than individuals without OHE (P ≤ 0.0001). This significant difference was observed with MELD scores from 10 to 38. CONCLUSION25-OHD deficiency was observed in the majority of patients with CLD and for the first time was found to be significantly worse in patients with OHE.展开更多
Hemipteran group of sap sucking insect pests cause worldwide crop destruction. The role of mannose specific monocot lectins have recently been worked out in hemipteran pest management. The present article demonstrates...Hemipteran group of sap sucking insect pests cause worldwide crop destruction. The role of mannose specific monocot lectins have recently been worked out in hemipteran pest management. The present article demonstrates the insecticidal efficacy of a new mannose specific agglutinin, isolated from tubers of Amorphophallus paeonifolius (AMTL) against a wide range of hemipteran insects. The 25 kDa dimeric protein was found to inhibit the survivability of hemipteran insects namely, Lipaphis erysimi, Aphis gossypii and Dysdercus cingulatus quite efficiently, as analysed by synthetic diet based bioassay experiments. Surface Plasmon Resonance study detected binding of insecticidal AMTL to insect gut brush border membrane vesicle (BBMV) protein, an absolute prerequisite for conferring toxicity against target insects. Further ligand blot analysis spotted a ~74 kDa glycoprotein as putative receptor of AMTL from the total BBMV protein fraction of Lipaphis erysimi. Phylogenetic analysis showed a significant relatedness of AMTL to the previously established monocot lectin Galanthus nivalis agglutinin (GNA) in terms of their conserved mannose binding domains, agglutinating ability of rabbit erythrocytes and insecticidal efficacies. These information project AMTL as a promising candidate in preventing crop loss caused due to hemipteran insect attack.展开更多
Hepatocellular carcinoma(HCC)is the most common primary liver malignancy,with increasing incidence worldwide.Alcohol-related cirrhosis(AC)accounts for 30%of the global incidence of HCC and HCC-related deaths.With the ...Hepatocellular carcinoma(HCC)is the most common primary liver malignancy,with increasing incidence worldwide.Alcohol-related cirrhosis(AC)accounts for 30%of the global incidence of HCC and HCC-related deaths.With the decline of hepatitis C virus(HCV)and decreasing HCV-related HCC,AC will soon become the leading cause of HCC.Excess alcohol consumption(>80 g per day for>10 years)increases the risk of HCC by 5-fold.However,only up to 35%of excessive drinkers develop cirrhosis and its associated HCC risk.Individual variation in susceptibility to HCC is known,but there is limited information to predict who among the patients is at high risk of progressing to HCC.Clinical risk factors for HCC include male gender,older age,severity of cirrhosis,obesity and presence of type 2 diabetes.In addition to ethnic variability in HCC risk,genetic variants are known to alter the risk of alcohol-related HCC.For example,single nucleotide polymorphisms in PNPLA3(rs738409,C>G)and TM6SF2(rs58542926,C>T)increase the risk of AC-related HCC,whereas HSD17B13(T>A)reduces the risk for HCC.Studies have also confirmed PNPLA3 and TM6SF2 to be independent risk factors for AC-related(but not HCV-related)HCC.Combining genetic risk factors with phenotypic/clinical risk factors has been explored for stratification of patients for HCC development.Risk allele rs378409-G in PNPLA3 when combined with phenotypic/clinical risk factors(BMI,age,sex)has enabled HCC risk stratification of AC patients into low-,intermediate-and high-risk subgroups.Similarly,a combination of the two genetic variants PNPLA3-G and TM6SF2-T has been independently associated with risk of HCC onset.Using a polygenic risk score approach of incorporating several genetic variants,prognostic performance of polygenic risk score that included PNPLA3 rs378409 and TM6SF2 rs58542926 improved HCC prediction better than with either variant alone.Incorporating new variants and risk factors has the potential to build better algorithms/models to predict onset,early diagnosis and treatments for AC展开更多
BACKGROUND Apical hypertrophic cardiomyopathy(HCM)is considered to have a benign prognosis in terms of cardiovascular mortality.This serial case report aimed to raise awareness of ventricular fibrillation(VF)and sudde...BACKGROUND Apical hypertrophic cardiomyopathy(HCM)is considered to have a benign prognosis in terms of cardiovascular mortality.This serial case report aimed to raise awareness of ventricular fibrillation(VF)and sudden cardiac death(SCD)in apical HCM.CASE SUMMARY Here we describe two rare cases of apical HCM that presented with documented VF and sudden cardiac collapse.These patients were previously not recommended for primary prevention using implantable cardioverter-defibrillator(ICD)therapy based on current guidelines.However,both received ICD therapy for the secondary prevention of SCD.CONCLUSION These cases illustrate serious complications including VF and aborted sudden cardiac arrest in apical HCM patients who are initially not candidates for primary prevention using ICD implantation based on current guidelines.展开更多
OBJECTIVE Our previous studies demonstrated that various ingredients from the traditional Chinese medicine(TCM)for promoting blood circulation and removing blood stasis,as exemplified by cryptotanshinone and salvianol...OBJECTIVE Our previous studies demonstrated that various ingredients from the traditional Chinese medicine(TCM)for promoting blood circulation and removing blood stasis,as exemplified by cryptotanshinone and salvianolic acid B,exerted striking effects on modulating angiogenesis and vascular permeability,which suggests that they may be effective in treating vascular leak-driven diseases(e.g.tumor,cerebral cavernous malformation and diabetic retinopathy).However,the lack of reliable and advanced technologies and models sets up difficult hurdles for better understanding the role of TCM for promoting blood circulation and removing blood stasis.To this end,this study is to outline numerous cutting-edge platforms that can be utilized for exploring the function of TCM for promoting blood circulation and removing blood stasis in vascular leak-driven diseases.METHODS Two-photon laser scanning fluorescence microscopy was used to observe the interactions between neutrophils and blood vessels in a real-time manner.Dynamic flow system was employed to mimic the in vivo behaviors of neutrophils.RIP1-Tag5 spontaneous pancreatic cancer model was used to study the function of tumor blood vessels.CCM2ECKO(deletion of CCM2 in endothelial cells)mice were employed to establish the cerebral cavernous malformation(CCM)animal model.Micro-computed tomography(micro-CT)was utilized to assess the CCM lesion.Müller cell-knockout mouse model was used to study the progression of diabetic retinopathy.Vascular permeability in this model was assessed by fluorescein angiography.RESULTS The interactions between neutrophils and endothelial cells involve a series of complicated processes,including rolling,adhesion,intraluminal crawling and transmigration,which were all monitored in vivo by two-photon laser scanning fluorescence microscopy in a real-time manner.Dynamic flow system was capable of recapitulating the biological behaviors of neutrophils in vitro.Tumor vascular function in particular vascular perfusion could be assessed in the RIP1-Tag5 sp展开更多
Hepatocellular carcinoma (HCC) is a major and increasing cause of clinical and economic burden worldwide. Now that there are effective therapies to control or eradicate viral aetiologies, the landscape of HCC is chang...Hepatocellular carcinoma (HCC) is a major and increasing cause of clinical and economic burden worldwide. Now that there are effective therapies to control or eradicate viral aetiologies, the landscape of HCC is changing with alcoholic and metabolic liver diseases becoming major catalysts. The pathogenesis of HCC is complex and incompletely understood, hampering improvements in therapy. Animal models are essential tools for advancing study on the cellular and molecular processes in HCC and for screening potential novel therapies. Many models of hepatocarcinogenesis have been established using various methods including genetic engineering, chemotoxic agents and dietary manipulation to direct implantation of tumour cells. However, none of these can accurately replicate all features found in human diseases. In this review, we provide an overview of different mouse models of HCC with a particular focus on cancer arising from alcoholic liver disease, non-alcoholic fatty liver disease and hereditary haemochromatosis. We also highlight their strengths and limitations and provide perspectives for future study.展开更多
文摘Major advances have been made over the last decade in our understanding of the molecular basis ofseveral cardiac conditions. Hypertrophic cardiomyopathy (HCM) was the first cardiac disorder in whicha genetic basis was identified and as such, has acted as a paradigm for the study of an inherited cardiacdisorder. HCM can result in clinical symptoms ranging from no symptoms to severe heart failure andpremature sudden death. HCM is the commonest cause of sudden death in those aged less than 35 years,including competitive athletes. At least ten genes have now been identified, defects in which cause HCM.All of these genes encode proteins which comprise the basic contractile unit of the heart, i.e. the sarcomere.While much is now known about which genes cause disease and the various clinical presentations, very littleis known about how these gene defects cause disease, and what factors modify the expression of the mutantgenes. Studies in both cell culture and animal models of HCM are now beginning to shed light on thesignalling pathways involved in HCM, and the role of both environmental and genetic modifying factors.Understanding these mechanisms will ultimately improve our knowledge of the basic biology of heart musclefunction, and will therefore provide new avenues for treating cardiovascular disease in man.
基金Justin Jong-Leong Wong holds a Fellowship from the Cancer Institute of NSW and receives funding from the National Health and Medical Research Council of Australia (Grant No 1128175, 1129901 and 1126306)
文摘N^6-methyladenosine(m^6 A) is an essential RNA modification that regulates key cellular processes, including stem cell renewal,cellular differentiation, and response to DNA damage. Unsurprisingly, aberrant m^6 A methylation has been implicated in the development and maintenance of diverse human cancers. Altered m^6 A levels affect RNA processing, mRNA degradation, and translation of mRNAs into proteins, thereby disrupting gene expression regulation and promoting tumorigenesis. Recent studies have reported that the abnormal expression of m^6 A regulatory enzymes affects m^6 A abundance and consequently dysregulates the expression of tumor suppressor genes and oncogenes, including MYC, SOCS2, ADAM19, and PTEN. In this review, we discuss the specific roles of m^6 A missing space "writers", "erasers", and "readers" in normal physiology and how their altered expression promotes tumorigenesis. We also describe the potential of exploiting the aberrant expression of these enzymes for cancer diagnosis, prognosis, and the development of novel therapies.
基金supported by grants from the National Natural Science Foundation of China(No.81830002 and 31991171 to W.D.H.,No.81703044 to J.S.W.,No.81830006 to W.B.Q.and No.8183004 to A.B.L.)a Leading Talents Grant of Science&Technology from Beijing(No.Z181100006318004 to W.D.H.)a grant from the Science Technology Department of Zhejiang Province(No.2018C03016-1 to W.B.Q.).
文摘Chimeric antigen receptor T(CAR T)cell therapy has demonstrated efficacy in the treatment of haematologic malignancies.However,the accompanying adverse events,the most common of which is cytokine release syndrome(CRS),substantially limit its wide application.Due to its unique physiological characteristics,CRS in CAR T-cell treatment for B-cell non-Hodgkin lymphoma(BNHL)may exhibit some special features.Although existing guidelines had greatly promoted the recognition and management of CRS,many recommendations are not fully applicable to B-NHL.Therefore,it is imperative to identify responses that are specific to CRS observed following CAR T treatment for B-NHL.Based on underlying biological processes and known pathophysiological mechanisms,we tentatively propose a new model to illustrate the occurrence and evolution of CAR T-cell-therapy-related CRS in BNHL.In this model,tumour burden and bone marrow suppression are considered determinants of CRS.Novel phenomena after CAR T-cell infusion(such as local inflammatory response)are further identified.The proposed model will help us better understand the basic biology of CRS and recognize and manage it more rationally.
文摘Tumor vasculature is characterized by aberrant structure and function,resulting in immune suppressive profiles of tumor microenvironment through limiting immune cell infiltration into tumors,endogenous immune surveillance and immune cell function.Vascular normalization as a novel therapeutic strategy tends to prune some of the immature blood vessels and fortify the structure and function of the remaining vessels,thus improving immune stimulation and the efficacy of immunotherapy.Interestingly,the presence of"immune-vascular crosstalk"enables the formation of a positive feedback loop between vascular normalization and immune reprogramming,providing the possibility to develop new cancer therapeutic strategies.The applications of nanomedicine in vascular-targeting therapy in cancer have gained increasing attention due to its specific physical and chemical properties.Here,we reviewed the recent advances of effective routes,especially nanomedicine,for normalizing tumor vasculature.We also summarized the development of enhancing nanoparticle-based anticancer drug delivery via the employment of transcytosis and mimicking immune cell extravasation.This review explores the potential to optimize nanomedicine-based therapeutic strategies as an alternative option for cancer treatment.
基金supported,in part,by research funding from the National Natural Science Foundation of China(81520108003,81830007,and 81670176)the Chang Jiang Scholars Program,the Shanghai Commission of Science and Technology(16JC1405800)+3 种基金the Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support(20152206 and 20152208)the Clinical Research Plan of Shanghai Hospital Development Center(SHDC,16CR2017A)the Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine(DLY201601)the Collaborative Innovation Center of Systems Biomedicine,the Samuel Waxman Cancer Research Foundation,the innovative research team of high-level local universities in Shanghai,and the shared Research Project Grants,University of Sydney and SJTU.
文摘The incidence of lymphoma has gradually increased over previous decades,and it ranks among the ten most prevalent cancers worldwide.With the development of targeted therapeutic strategies,though a subset of lymphoma patients has become curable,the treatment of refractory and relapsed diseases remains challenging.Many efforts have been made to explore new targets and to develop corresponding therapies.In addition to novel antibodies targeting surface antigens and small molecular inhibitors targeting oncogenic signaling pathways and tumor suppressors,immune checkpoint inhibitors and chimeric antigen receptor T-cells have been rapidly developed to target the tumor microenvironment.Although these targeted agents have shown great success in treating lymphoma patients,adverse events should be noted.The selection of the most suitable candidates,optimal dosage,and effective combinations warrant further investigation.In this review,we systematically outlined the advances in targeted therapy for malignant lymphoma,providing a clinical rationale for mechanism-based lymphoma treatment in the era of precision medicine.
基金supported by a grant from the Merridew Foundation and NH&MRC ProjectNo.1088242 (to NJCK)+1 种基金supported by the Australian Government Research Training Stipend ScholarshipThe University of Sydney Postgraduate Merit Award
文摘Elucidating the exact contribution of microglia to central nervous system(CNS)pathology has historically been extremely challenging.These resident parenchymal myeloid cells are considered to have critical roles as frontline responders during pathogen invasion and CNS perturbation.Thus,understanding the precise temporal kinetics of microglial function is central to the evolution of novel therapeutics for disease intervention and/or resolution(Spiteri et al.,2022a).The development of PLX5622,a colony-stimulating factor 1 receptor(CSF-1R)inhibitor typically formulated into a rodent chow for simple oral administration has facilitated exploration of microglial functions in disease(Spangenberg et al.,2019).
基金This work was financially supported by the projects of National Natural Science Foundation of China(82003991,82101844,and 82304953)Natural Science Foundation of Jiangsu Province(BK20230744,China)+1 种基金Jiangsu Specially Appointed Professorship Foundation(013038021001,China)Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX22-2045 and KYCX23-2038,China).
文摘Aberrant tumor blood vessels are prone to propel the malignant progression of tumors,and targeting abnormal metabolism of tumor endothelial cells emerges as a promising option to achieve vascular normalization and antagonize tumor progression.Herein,we demonstrated that salvianic acid A(SAA)played a pivotal role in contributing to vascular normalization in the tumor-bearing mice,thereby improving delivery and effectiveness of the chemotherapeutic agent.SAA was capable of inhibiting glycolysis and strengthening endothelial junctions in the human umbilical vein endothelial cells(HUVECs)exposed to hypoxia.Mechanistically,SAA was inclined to directly bind to the glycolytic enzyme PKM2,leading to a dramatic decrease in endothelial glycolysis.More importantly,SAA improved the endothelial integrity via activating theβ-Catenin/Claudin-5 signaling axis in a PKM2-dependent manner.Our findings suggest that SAA may serve as a potent agent for inducing tumor vascular normalization.
基金supported by the National Health and Medical Research Council of Australia(No.1128175,1158998&2010647)the Cancer Council NSW(No.RG 19-05).
文摘Of over 170 types of RNA modifications discovered,N^(6)-methyladenosine(m^(6)A)is the most actively studied.m6A confers oncogenic potential,maintains cancer stem cells,and is associated with cancer-related outcomes.^(1) The role of RNA modifications including m^(1)A is poorly understood.
文摘BACKGROUND Recent studies in non-colorectal malignancy have associated T resident memory(T_(RM)) cells with improved patient survival. It is unknown if T_(RM) plays a role in colorectal cancer(CRC).AIM To examine the potential role of T_(RM) cells in providing immunogenicity in CRC stratified by microsatellite instability(MSI) and BRAF status.METHODS Patients with known MSI and BRAF mutation status were eligible for inclusion in this study. CRC tumour sections stained with haematoxylin and eosin were microscopically reviewed and the images scanned prior to assessment for location of invading edge and core of tumour. Sequential sections were prepared for quantitative multiplex immunohistochemistry(IHC) staining. Opal Multiplex IHC staining was performed with appropriate positive and negative controls and imaged using a standard fluorescent microscope fitted with a spectral scanning camera(Mantra) in conjunction with Mantra snap software. Images were unmixed and annotated in in Form 2.2.0. Statistical analysis was performed using Graphpad Prism Version 7 and Stata Version 15.RESULTS Seventy-two patients with known MSI and BRAF status were included in the study. All patients were assessed for MSI by IHC and high resolution capillary electrophoresis testing and 44 of these patients successfully underwent quantitative multiplex IHC staining. Overall, there was a statistically significant increase in CD8+ T_(RM) cells in the MSI(BRAF mutant and wild type) group over the microsatellite stable(MSS) group. There was a statistically significant difference in CD8+ T_(RM) between high level MSI(MSI-H):BRAF mutant [22.57, 95% confidence interval(CI): 14.31-30.84] vs MSS [8.031(95%CI: 4.698-11.36)], P = 0.0076 and MSI-H:BRAF wild type [16.18(95%CI: 10.44-21.93)] vs MSS [8.031(95%CI: 4.698-11.36)], P = 0.0279. There was no statistically significant difference in CD8 T cells(both CD8+CD103-and CD8+CD103+T_(RM)) between MSI-H: BRAF mutant and wild type CRC.CONCLUSION This study has shown that CD8+ T_(RM) are found in greater abun
文摘Balanced sphingolipid signaling is important for the maintenance of homeostasis. Sphingolipids were demonstrated to function as structural components, second messengers, and regulators of cell growth and survival in normal and disease-affected tissues. Particularly, sphingosine kinase 1 (SphK1) and its product sphingosine-1-phosphate (S1P) operate as mediators and facilitators of proliferation-linked signaling. Unlimited proliferation (selfrenewal) within the regulated environment is a hallmark of progenitor/stem cells that was recently associated with the S1P signaling network in vasculature, nervous,muscular, and immune systems. S1P was shown to regulate progenitor-related characteristics in normal and cancerstemcells(CSCs) viaG-protein coupled receptorsS1Pn(n=1 to 5). The SphK/S1P axis is crucially involved in the regulation of embryonic development of vasculature and the nervous system, hematopoietic stem cell migration, regeneration of skeletal muscle, and development of multiple sclerosis. The ratio of the S1P receptor expression, localization, and specific S1P receptoractivated downstream effectors influenced the rate of selfrenewal and should be further explored as regeneration related targets. Considering malignant transformation,it is essential to control the level of self-renewal capacity.Proliferation of the progenitor cell should be synchronized with differentiation to provide healthy lifelong function of blood, immune systems, and replacement of damaged ordead cells. The differentiation-related role of SphK/S1P remains poorly assessed. A few pioneering investigations exploredpharmacologicaltoolsthattargetsphingolipid signaling and can potentially confine and direct self-renewal towards normal differentiation. Further investigation is required to test the role of the SphK/S1P axis in regulation of self-renewal and differentiation.
基金Supported by Australian National Health and Medical Research Council Grant 512282 (to Gorrell MD)Rebecca L Cooper Foundation Equipment Grants (to Gorrell MD)+2 种基金University of Sydney International Scholarship (to Chen Y)Australian Postgraduate Scholarship (to Yao TW)Grant NIH U19AI066313 (to Schuppan D)
文摘AIM:To investigate the expression of dipeptidyl peptidase(DPP) 8 and DPP9 in lymphocytes and various models of liver fibrosis.METHODS:DPP8 and DPP9 expression were measured in mouse splenic CD4 + T-cells,CD8 + T-cells and B-cells(B220 +),human lymphoma cell lines and mouse splenocytes stimulated with pokeweed mitogen(PWM) or lipopolysaccharide(LPS),and in dithiothreitol(DTT) and mitomycin-C treated Raji cells.DPP8 and DPP9 expression were measured in epidermal growth factor(EGF) treated Huh7 hepatoma cells,in fibrotic liver samples from mice treated with carbon tetrachloride(CCl 4) and from multidrug resistance gene 2(Mdr2 /Abcb4) gene knockout(gko) mice with biliary fibrosis,and in human end stage primary biliary cirrhosis(PBC).RESULTS:All three lymphocyte subsets expressed DPP8 and DPP9 mRNA.DPP8 and DPP9 expression were upregulated in both PWM and LPS stimulated mouse splenocytes and in both Jurkat T-and Raji B-cell lines.DPP8 and DPP9 were downregulated in DTT treated and upregulated in mitomycin-C treated Raji cells.DPP9transfected Raji cells exhibited more annexin V + cells and associated apoptosis.DPP8 and DPP9 mRNA were upregulated in CCl 4 induced fibrotic livers but not in the lymphocytes isolated from such livers,while DPP9 was upregulated in EGF stimulated Huh7 cells.In contrast,intrahepatic DPP8 and DPP9 mRNA expression levels were low in the Mdr2 gko mouse and in human PBC compared to non-diseased livers.CONCLUSION:These expression patterns point to biological roles for DPP8 and DPP9 in lymphocyte activation and apoptosis and in hepatocytes during liver disease pathogenesis.
文摘Hemipteran insects are the most devastating pest for different crops of high economic value. Colocasia esculenta tuber agglutinin (CEA), a mannose binding monocot lectin from araceae family was previously reported by the present group to be effective against some members of this class of pests. In the present study, efficacy of this potent lectin has been extended to cotton aphid (Aphis gossypii) which is becoming a highly damaging pest of cotton in recent days. Because, like other aphids, A. gossypii not only extracts the phloem fluid but also transmit disease causing viruses and add to the high degree of yield loss. Efficacy of the lectin on cotton aphid as well as other hemipteran insects prompted us further to clone the protein coding gene. Very little sequence information of this gene was available in the database. Hence, attempt had been made to study the protein through liquid chromatography-tandem mass spectrometry (LC-MS/MS) to have the detailed peptide information. On the basis of the peptide homology information obtained from LC-MS/MS the complete coding sequence of CEA was determined. The coding sequence corresponding to CEA was cloned further using primers designed on the basis of above information and genome walk technology for its potential utilisation in insect management programme.
文摘To investigate the relationship between 25-hydroxyvitamin D (25-OHD) deficiency and hepatic encephalopathy (HE) in patients with chronic liver disease (CLD). METHODSA retrospective analysis of the results of 392 adult patients with chronic liver disease who were assessed for liver transplantation between 2006 and 2010 was undertaken. HE, severity of CLD, nutritional status and 25-OHD were analysed in patients assessed for liver transplantation between 2006 and 2010. Patients who presented with acute, fulminant or subacute disease, with a primary diagnosis of liver cancer, were assessed for re-transplantation or who did not have a 25-OHD measurement were excluded from the analysis. RESULTSOne hundred and sixty-five patients were included in this analysis. The mean age of all patients was 53 ± 8 years. Moderate to severe 25-OHD deficiency was identified in 49 patients of whom 36 had grade 2-3 HE compared with 13 patients who were not encephalopathic (P ≤ 0.0001). Mild 25-OHD deficiency was not associated with HE. There was a significant correlation between the severity of 25-OHD deficiency and the severity of liver disease (r = 0.39, P ≤ 0.0001) and disease severity and the presence of HE (P ≤ 0.0001). Importantly, individuals with 25-OHD deficiency were more likely to have a diagnosis of overt HE (OHE) at a significantly lower model for end stage liver disease (MELD) score than individuals without OHE (P ≤ 0.0001). This significant difference was observed with MELD scores from 10 to 38. CONCLUSION25-OHD deficiency was observed in the majority of patients with CLD and for the first time was found to be significantly worse in patients with OHE.
文摘Hemipteran group of sap sucking insect pests cause worldwide crop destruction. The role of mannose specific monocot lectins have recently been worked out in hemipteran pest management. The present article demonstrates the insecticidal efficacy of a new mannose specific agglutinin, isolated from tubers of Amorphophallus paeonifolius (AMTL) against a wide range of hemipteran insects. The 25 kDa dimeric protein was found to inhibit the survivability of hemipteran insects namely, Lipaphis erysimi, Aphis gossypii and Dysdercus cingulatus quite efficiently, as analysed by synthetic diet based bioassay experiments. Surface Plasmon Resonance study detected binding of insecticidal AMTL to insect gut brush border membrane vesicle (BBMV) protein, an absolute prerequisite for conferring toxicity against target insects. Further ligand blot analysis spotted a ~74 kDa glycoprotein as putative receptor of AMTL from the total BBMV protein fraction of Lipaphis erysimi. Phylogenetic analysis showed a significant relatedness of AMTL to the previously established monocot lectin Galanthus nivalis agglutinin (GNA) in terms of their conserved mannose binding domains, agglutinating ability of rabbit erythrocytes and insecticidal efficacies. These information project AMTL as a promising candidate in preventing crop loss caused due to hemipteran insect attack.
文摘Hepatocellular carcinoma(HCC)is the most common primary liver malignancy,with increasing incidence worldwide.Alcohol-related cirrhosis(AC)accounts for 30%of the global incidence of HCC and HCC-related deaths.With the decline of hepatitis C virus(HCV)and decreasing HCV-related HCC,AC will soon become the leading cause of HCC.Excess alcohol consumption(>80 g per day for>10 years)increases the risk of HCC by 5-fold.However,only up to 35%of excessive drinkers develop cirrhosis and its associated HCC risk.Individual variation in susceptibility to HCC is known,but there is limited information to predict who among the patients is at high risk of progressing to HCC.Clinical risk factors for HCC include male gender,older age,severity of cirrhosis,obesity and presence of type 2 diabetes.In addition to ethnic variability in HCC risk,genetic variants are known to alter the risk of alcohol-related HCC.For example,single nucleotide polymorphisms in PNPLA3(rs738409,C>G)and TM6SF2(rs58542926,C>T)increase the risk of AC-related HCC,whereas HSD17B13(T>A)reduces the risk for HCC.Studies have also confirmed PNPLA3 and TM6SF2 to be independent risk factors for AC-related(but not HCV-related)HCC.Combining genetic risk factors with phenotypic/clinical risk factors has been explored for stratification of patients for HCC development.Risk allele rs378409-G in PNPLA3 when combined with phenotypic/clinical risk factors(BMI,age,sex)has enabled HCC risk stratification of AC patients into low-,intermediate-and high-risk subgroups.Similarly,a combination of the two genetic variants PNPLA3-G and TM6SF2-T has been independently associated with risk of HCC onset.Using a polygenic risk score approach of incorporating several genetic variants,prognostic performance of polygenic risk score that included PNPLA3 rs378409 and TM6SF2 rs58542926 improved HCC prediction better than with either variant alone.Incorporating new variants and risk factors has the potential to build better algorithms/models to predict onset,early diagnosis and treatments for AC
文摘BACKGROUND Apical hypertrophic cardiomyopathy(HCM)is considered to have a benign prognosis in terms of cardiovascular mortality.This serial case report aimed to raise awareness of ventricular fibrillation(VF)and sudden cardiac death(SCD)in apical HCM.CASE SUMMARY Here we describe two rare cases of apical HCM that presented with documented VF and sudden cardiac collapse.These patients were previously not recommended for primary prevention using implantable cardioverter-defibrillator(ICD)therapy based on current guidelines.However,both received ICD therapy for the secondary prevention of SCD.CONCLUSION These cases illustrate serious complications including VF and aborted sudden cardiac arrest in apical HCM patients who are initially not candidates for primary prevention using ICD implantation based on current guidelines.
文摘OBJECTIVE Our previous studies demonstrated that various ingredients from the traditional Chinese medicine(TCM)for promoting blood circulation and removing blood stasis,as exemplified by cryptotanshinone and salvianolic acid B,exerted striking effects on modulating angiogenesis and vascular permeability,which suggests that they may be effective in treating vascular leak-driven diseases(e.g.tumor,cerebral cavernous malformation and diabetic retinopathy).However,the lack of reliable and advanced technologies and models sets up difficult hurdles for better understanding the role of TCM for promoting blood circulation and removing blood stasis.To this end,this study is to outline numerous cutting-edge platforms that can be utilized for exploring the function of TCM for promoting blood circulation and removing blood stasis in vascular leak-driven diseases.METHODS Two-photon laser scanning fluorescence microscopy was used to observe the interactions between neutrophils and blood vessels in a real-time manner.Dynamic flow system was employed to mimic the in vivo behaviors of neutrophils.RIP1-Tag5 spontaneous pancreatic cancer model was used to study the function of tumor blood vessels.CCM2ECKO(deletion of CCM2 in endothelial cells)mice were employed to establish the cerebral cavernous malformation(CCM)animal model.Micro-computed tomography(micro-CT)was utilized to assess the CCM lesion.Müller cell-knockout mouse model was used to study the progression of diabetic retinopathy.Vascular permeability in this model was assessed by fluorescein angiography.RESULTS The interactions between neutrophils and endothelial cells involve a series of complicated processes,including rolling,adhesion,intraluminal crawling and transmigration,which were all monitored in vivo by two-photon laser scanning fluorescence microscopy in a real-time manner.Dynamic flow system was capable of recapitulating the biological behaviors of neutrophils in vitro.Tumor vascular function in particular vascular perfusion could be assessed in the RIP1-Tag5 sp
文摘Hepatocellular carcinoma (HCC) is a major and increasing cause of clinical and economic burden worldwide. Now that there are effective therapies to control or eradicate viral aetiologies, the landscape of HCC is changing with alcoholic and metabolic liver diseases becoming major catalysts. The pathogenesis of HCC is complex and incompletely understood, hampering improvements in therapy. Animal models are essential tools for advancing study on the cellular and molecular processes in HCC and for screening potential novel therapies. Many models of hepatocarcinogenesis have been established using various methods including genetic engineering, chemotoxic agents and dietary manipulation to direct implantation of tumour cells. However, none of these can accurately replicate all features found in human diseases. In this review, we provide an overview of different mouse models of HCC with a particular focus on cancer arising from alcoholic liver disease, non-alcoholic fatty liver disease and hereditary haemochromatosis. We also highlight their strengths and limitations and provide perspectives for future study.
