Carcinoma of the stomach is still the second most common cause of cancer death worldwide, although the incidence and mortality have fallen dramatically over the last 50 years in many regions. The incidence of gastric ...Carcinoma of the stomach is still the second most common cause of cancer death worldwide, although the incidence and mortality have fallen dramatically over the last 50 years in many regions. The incidence of gastric cancer varies in different parts of the world and among various ethnic groups. Despite advances in diagnosis and treatment, the 5-year survival rate of stomach cancer is only 20 per cent. Stomach cancer can be classified into intestinal and diffuse types based on epidemiological and clinicopathological features. The etiology of gastric cancer is multifactorial and includes both dietary and nondietary factors. The major diet-related risk factors implicated in stomach cancer development include high content of nitrates and high salt intake. Accumulating evidence has implicated the role of Helicobacter pylori (H. pylori) infection in the pathogenesis of gastric cancer. The development of gastric cancer is a complex, multistep process involving multiple genetic and epigenetic alterations of oncogenes, tumor suppressor genes, DNA repair genes, cell cycle regulators, and signaling molecules. A plausible program for gastric cancer prevention involves intake of a balanced diet containing fruits and vegetables, improved sanitationand hygiene, screening and treatment of H. pylori infection, and follow-up of precancerous lesions. The fact that diet plays an important role in the etiology of gastric cancer offers scope for nutritional chemoprevention. Animal models have been extensively used to analyze the stepwise evolution of gastric carcinogenesis and to test dietary chemopreventive agents. Development of multitargeted preventive and therapeutic strategies for gastric cancer is a major challenge for the future.展开更多
Gastric cancer(GC) remains an important cause of cancer death worldwide with a high mortality rate due to the fact that the majority of GC cases are diagnosed at an advanced stage when the prognosis is poor and the tr...Gastric cancer(GC) remains an important cause of cancer death worldwide with a high mortality rate due to the fact that the majority of GC cases are diagnosed at an advanced stage when the prognosis is poor and the treatment options are limited. Unfortunately, the existing circulating biomarkers for GC diagnosis and prognosis display low sensitivity and specificity and the GC diagnosis is based only on the invasive procedures such as upper digestive endoscopy. There is a huge need for less invasive or non-invasive tests but also highly specific biomarkers in case of GC. Body fluids such as peripheral blood, urine or saliva,stomach wash/gastric juice could be a source of specific biomarkers, providing important data for screening and diagnosis in GC. This review summarized the recently discovered circulating molecules such as microRNAs, long non-coding RNAs, circular RNAs, which hold the promise to develop new strategies for early diagnosis of GC.展开更多
Asherman's syndrome(AS) is a common disease that presents endometrial regeneration disorder. However, little is known about its molecular features of this aregenerative endometrium in AS and how to reconstruct the...Asherman's syndrome(AS) is a common disease that presents endometrial regeneration disorder. However, little is known about its molecular features of this aregenerative endometrium in AS and how to reconstruct the functioning endometrium for the patients with AS. Here, we report that ΔNp63 is significantly upregulated in residual epithelial cells of the impaired endometrium in AS; the upregulated-ΔNp63 induces endometrial quiescence and alteration of stemness. Importantly, we demonstrate that engrafting high density of autologous bone marrow mononuclear cells(BMNCs) loaded in collagen scaffold onto the uterine lining of patients with AS downregulates ΔNp63 expression, reverses ΔNp63-induced pathological changes, normalizes the stemness alterations and restores endometrial regeneration. Finally, five patients achieved successful pregnancies and live births. Therefore, we conclude that ΔNp63 is a crucial therapeutic target for AS. This novel treatment significantly improves the outcome for the patients with severe AS.展开更多
As an evolutionarily conserved signalling network,the Hippo pathway plays a crucial role in the regulation of numerous biological processes.Thus,substantial efforts have been made to understand the upstream signals th...As an evolutionarily conserved signalling network,the Hippo pathway plays a crucial role in the regulation of numerous biological processes.Thus,substantial efforts have been made to understand the upstream signals that influence the activity of the Hippo pathway,as well as its physiological functions,such as cell proliferation and differentiation,organ growth,embryogenesis,and tissue regeneration/wound healing.However,dysregulation of the Hippo pathway can cause a variety of diseases,including cancer,eye diseases,cardiac diseases,pulmonary diseases,renal diseases,hepatic diseases,and immune dysfunction.Therefore,therapeutic strategies that target dysregulated Hippo components might be promising approaches for the treatment of a wide spectrum of diseases.Here,we review the key components and upstream signals of the Hippo pathway,as well as the critical physiological functions controlled by the Hippo pathway.Additionally,diseases associated with alterations in the Hippo pathway and potential therapies targeting Hippo components will be discussed.展开更多
Ferroptosis is a new form of programmed cell death characterized by the accumulation of iron-dependent lethal lipid peroxides.Recent discoveries have focused on alterations that occur in lipid metabolism during ferrop...Ferroptosis is a new form of programmed cell death characterized by the accumulation of iron-dependent lethal lipid peroxides.Recent discoveries have focused on alterations that occur in lipid metabolism during ferroptosis and have provided intriguing insights into the interplay between ferroptosis and lipid metabolism in cancer.Their interaction regulates the initiation,development,metastasis,therapy resistance of cancer,as well as the tumor immunity,which offers several potential strategies for cancer treatment.This review is a brief overview of the features characterizing the interaction between ferroptosis and lipid metabolism,and highlights the significance of this interaction in cancer.展开更多
Gastric cancer is believed to result in part from the accumulation of multiple genetic alterations leading to oncogeneoverexpression and tumor suppressor loss. Epigenetic alterations as a distinct and crucial mechanis...Gastric cancer is believed to result in part from the accumulation of multiple genetic alterations leading to oncogeneoverexpression and tumor suppressor loss. Epigenetic alterations as a distinct and crucial mechanism to silence a varietyof methylated tissue-specific and imprinted genes, have been extensively studied in gastric carcinoma and play impor-tant roles in gastric carcinogenesis. This review will briefly discuss the basic aspects of DNA methylation and CpGisland methylation, in particular the epigenetic alterations of certain critical genes implicated in gastric carcinogenesisand its relevance of clinical implications.展开更多
Advanced natural killer/T cell lymphoma(NKTL)has demonstrated poor prognosis with currently available therapies.Here,we report the efficacy of anti-programmed death 1(PD-1)antibody with the P-GEMOX(pegaspargase,gemcit...Advanced natural killer/T cell lymphoma(NKTL)has demonstrated poor prognosis with currently available therapies.Here,we report the efficacy of anti-programmed death 1(PD-1)antibody with the P-GEMOX(pegaspargase,gemcitabine,and oxaliplatin)regimen in advanced NKTL.Nine patients underwent six 21-day cycles of anti-PD-1 antibody(day 1),pegaspargase 2000 U/m2(day 1),gemcitabine 1 g/m2(days 1 and 8)and oxaliplatin 130 mg/m2(day 1),followed by anti-PD-1 antibody maintenance every 3 weeks.Programmed death-ligand 1(PD-L1)expression and genetic alterations were determined in paraffin-embedded pretreatment tissue samples using immunohistochemistry and next-generation sequencing(NGS)analysis.Responses were assessed using 18F-fluorodeoxyglucose positron emission tomography(18FDG-PET)and computed tomography or magnetic resonance imaging.Eight patients exhibited significant responses,comprising of seven complete remissions and one partial remission(overall response rate:88.9%).After a median follow-up of 10.6 months,6/9 patients(66.7%)remained in complete remission.The most common grade 3/4 adverse events were anemia(33.3%),neutropenia(33.3%),and thrombocytopenia(33.3%);all of which were manageable and resolved.Immunochemotherapy produced a high response rate in patients with positive PD-L1 expression(5/6,83.3%).NGS analysis suggested that STAT3/JAK3/PD-L1 alterations and ARID1A mutation were associated with immunochemotherapy efficacy.Mutation in DDX3X and alteration in epigenetic modifiers of KMT2D,TET2,and BCORL1 might indicate a poor response to immunochemotherapy.In conclusion,the anti-PD-1 antibody plus P-GEMOX regimen demonstrated promising efficacy in advanced NKTL.PD-L1 expression combined with specific genetic alterations could be used as potential biomarkers to predict therapeutic responses to immunochemotherapy.展开更多
Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies,including cancer vaccines,adoptive cell therapy and antibody-based therapies,especially for soli...Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies,including cancer vaccines,adoptive cell therapy and antibody-based therapies,especially for solid tumors.Neoantigens are newly formed antigens generated by tumor cells as a result of various tumor-specific alterations,such as genomic mutation,dysregulated RNA splicing,disordered post-translational modification,and integrated viral open reading frames.Neoantigens are recognized as non-self and trigger an immune response that is not subject to central and peripheral tolerance.The quick identification and prediction of tumor-specific neoantigens have been made possible by the advanced development of next-generation sequencing and bioinformatic technologies.Compared to tumor-associated antigens,the highly immunogenic and tumor-specific neoantigens provide emerging targets for personalized cancer immunotherapies,and serve as prospective predictors for tumor survival prognosis and immune checkpoint blockade responses.The development of cancer therapies will be aided by understanding the mechanism underlying neoantigen-induced anti-tumor immune response and by streamlining the process of neoantigen-based immunotherapies.This review provides an overview on the identification and characterization of neoantigens and outlines the clinical applications of prospective immunotherapeutic strategies based on neoantigens.We also explore their current status,inherent challenges,and clinical translation potential.展开更多
Gastric cancer is one of the leading causes of cancerrelated deaths worldwide, although the incidence has gradually decreased in many Western countries. Two main gastric cancer histotypes, intestinal and diffuse, are ...Gastric cancer is one of the leading causes of cancerrelated deaths worldwide, although the incidence has gradually decreased in many Western countries. Two main gastric cancer histotypes, intestinal and diffuse, are recognised. Although most of the described genetic alterations have been observed in both types, different genetic pathways have been hypothesized. Genetic and epigenetic events, including 1q loss of heterozygosity (LOH), microsatellite instability and hypermethylation, have mostly been reported in intestinal-type gastric carcinoma and its precursor lesions, whereas 17p LOH, mutation or loss of E-cadherin are more often implicated in the development of diffuse-type gastric cancer.In this review, we summarize the sometimes contradictory findings regarding those markers which influence the progression of gastric adenocarcinoma.展开更多
Aging is a gradual and irreversible pathophysiological process.It presents with declines in tissue and cell functions and significant increases in the risks of various aging-related diseases,including neurodegenerativ...Aging is a gradual and irreversible pathophysiological process.It presents with declines in tissue and cell functions and significant increases in the risks of various aging-related diseases,including neurodegenerative diseases,cardiovascular diseases,metabolic diseases,musculoskeletal diseases,and immune system diseases.Although the development of modern medicine has promoted human health and greatly extended life expectancy,with the aging of society,a variety of chronic diseases have gradually become the most important causes of disability and death in elderly individuals.Current research on aging focuses on elucidating how various endogenous and exogenous stresses(such as genomic instability,telomere dysfunction,epigenetic alterations,loss of proteostasis,compromise of autophagy,mitochondrial dysfunction,cellular senescence,stem cell exhaustion,altered intercellular communication,deregulated nutrient sensing)participate in the regulation of aging.Furthermore,thorough research on the pathogenesis of aging to identify interventions that promote health and longevity(such as caloric restriction,microbiota transplantation,and nutritional intervention)and clinical treatment methods for aging-related diseases(depletion of senescent cells,stem cell therapy,antioxidative and anti-inflammatory treatments,and hormone replacement therapy)could decrease the incidence and development of aging-related diseases and in turn promote healthy aging and longevity.展开更多
Infection susceptibility,poor vaccination efficacy,age-related disease onset,and neoplasms are linked to innate and adaptive immune dysfunction that accompanies aging(known as immunosenescence).During aging,organisms ...Infection susceptibility,poor vaccination efficacy,age-related disease onset,and neoplasms are linked to innate and adaptive immune dysfunction that accompanies aging(known as immunosenescence).During aging,organisms tend to develop a characteristic inflammatory state that expresses high levels of pro-inflammatory markers,termed inflammaging.This chronic inflammation is a typical phenomenon linked to immunosenescence and it is considered the major risk factor for age-related diseases.Thymic involution,naïve/memory cell ratio imbalance,dysregulated metabolism,and epigenetic alterations are striking features of immunosenescence.Disturbed T-cell pools and chronic antigen stimulation mediate premature senescence of immune cells,and senescent immune cells develop a proinflammatory senescence-associated secretory phenotype that exacerbates inflammaging.Although the underlying molecular mechanisms remain to be addressed,it is well documented that senescent T cells and inflammaging might be major driving forces in immunosenescence.Potential counteractive measures will be discussed,including intervention of cellular senescence and metabolic-epigenetic axes to mitigate immunosenescence.In recent years,immunosenescence has attracted increasing attention for its role in tumor development.As a result of the limited participation of elderly patients,the impact of immunosenescence on cancer immunotherapy is unclear.Despite some surprising results from clinical trials and drugs,it is necessary to investigate the role of immunosenescence in cancer and other age-related diseases.展开更多
Advanced natural killer/T cell lymphoma(NKTL)has demonstrated poor prognosis with currently available therapies.Here,we report the efficacy of anti-programmed death 1(PD-1)antibody with the P-GEMOX(pegaspargase,gemcit...Advanced natural killer/T cell lymphoma(NKTL)has demonstrated poor prognosis with currently available therapies.Here,we report the efficacy of anti-programmed death 1(PD-1)antibody with the P-GEMOX(pegaspargase,gemcitabine,and oxaliplatin)regimen in advanced NKTL.Nine patients underwent six 21-day cycles of anti-PD-1 antibody(day 1),pegaspargase 2000 U/m^(2)(day 1),gemcitabine 1 g/m^(2)(days 1 and 8)and oxaliplatin 130 mg/m^(2)(day 1),followed by anti-PD-1 antibody maintenance every 3 weeks.Programmed death-ligand 1(PD-L1)expression and genetic alterations were determined in paraffin-embedded pretreatment tissue samples using immunohistochemistry and next-generation sequencing(NGS)analysis.Responses were assessed using 18F-fluorodeoxyglucose positron emission tomography(18FDG-PET)and computed tomography or magnetic resonance imaging.Eight patients exhibited significant responses,comprising of seven complete remissions and one partial remission(overall response rate:88.9%).After a median follow-up of 10.6 months,6/9 patients(66.7%)remained in complete remission.The most common grade 3/4 adverse events were anemia(33.3%),neutropenia(33.3%),and thrombocytopenia(33.3%);all of which were manageable and resolved.Immunochemotherapy produced a high response rate in patients with positive PD-L1 expression(5/6,83.3%).NGS analysis suggested that STAT3/JAK3/PD-L1 alterations and ARID1A mutation were associated with immunochemotherapy efficacy.Mutation in DDX3X and alteration in epigenetic modifiers of KMT2D,TET2,and BCORL1 might indicate a poor response to immunochemotherapy.In conclusion,the anti-PD-1 antibody plus P-GEMOX regimen demonstrated promising efficacy in advanced NKTL.PD-L1 expression combined with specific genetic alterations could be used as potential biomarkers to predict therapeutic responses to immunochemotherapy.展开更多
Hepatocellular carcinoma(HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this...Hepatocellular carcinoma(HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC.展开更多
Prostate cancer is the most commonly diagnosed noncutaneous cancers in North American men.While androgen deprivation has remained as the cornerstone of prostate cancer treatment,resistance ensues leading to lethal dis...Prostate cancer is the most commonly diagnosed noncutaneous cancers in North American men.While androgen deprivation has remained as the cornerstone of prostate cancer treatment,resistance ensues leading to lethal disease.Forkhead box A1(FOXA1)encodes a pioneer factor that induces open chromatin conformation to allow the binding of other transcription factors.Through direct interactions with the Androgen Receptor(AR),FOXA1 helps to shape AR signaling that drives the growth and survival of normal prostate and prostate cancer cells.FOXA1 also possesses an AR-independent role of regulating epithelial-to-mesenchymal transition(EMT).In prostate cancer,mutations converge onto the coding sequence and c/s-regulatory elements(CREs)of FOXA1,leading to functional alterations.In addition,FOXA1 activity in prostate cancer can be modulated post-translationally through various mechanisms such as LSD1-mediated protein demethylation.In this review,we describe the latest discoveries related to the function and regulation of FOXA1 in prostate cancer,pointing to their relevance to guide future clinical interventions.展开更多
Inflammatory bowel diseases(IBDs)are characterized by a multifactorial partially unknown etiology that involves genetic,immunological and environmental factors.Up to 50%of IBD patients experience at least one extraint...Inflammatory bowel diseases(IBDs)are characterized by a multifactorial partially unknown etiology that involves genetic,immunological and environmental factors.Up to 50%of IBD patients experience at least one extraintestinal manifestation;among them is the involvement of bone density which is referred to as metabolic bone disease(MBD),including osteopenia and osteoporosis.Bone alterations in IBDs population appear to have a multifactorial etiology:Decreased physical activity,inflammation-related bone resorption,multiple intestinal resections,dietary malabsorption of minerals and vitamin D deficiency,genetic factors,gut-bone immune signaling interaction,steroid treatment,microbiota and pathogenic micro-organisms interaction,and dietary malabsorption of minerals,that,all together or individually,may contribute to the alteration of bone mineral density.This review aims to summarize the prevalence and pathophysiology of metabolic bone alterations in IBD subjects outlining the main risk factors of bone fragility.We also want to underline the role of the screening and prophylaxis of bone alterations in Crohn’s disease and ulcerative colitis patients and the importance of treating appropriately MBD.展开更多
Irritable bowel syndrome(IBS)is a commonly encountered chronic functional gastrointestinal(GI)disorder.Approximately 10%of IBS patients can trace the onset of their symptoms to a previous a bout of infectious dysenter...Irritable bowel syndrome(IBS)is a commonly encountered chronic functional gastrointestinal(GI)disorder.Approximately 10%of IBS patients can trace the onset of their symptoms to a previous a bout of infectious dysentery.The appearance of new IBS symptoms following an infectious event is defined as post-infectiousIBS.Indeed,with the World Health Organization estimating between 2 and 4 billion cases annually,infectious diarrheal disease represents an incredible international healthcare burden.Additionally,compounding evidence suggests many commonly encountered enteropathogens as unique triggers behind IBS symptom generation and underlying pathophysiological features.A growing body of work provides evidence supporting a role for pathogen-mediated modifications in the resident intestinal microbiota,epithelial barrier integrity,effector cell functions,and innate and adaptive immune features,all proposed physiological manifestations that can underlie GI abnormalities in IBS.Enteric pathogens must employ a vast array of machinery to evade host protective immune mechanisms,and illicit successful infections.Consequently,the impact of infectious events on host physiology can be multidimensional in terms of anatomical location,functional scope,and duration.This review offers a unique discussion of the mechanisms employed by many commonly encountered enteric pathogens that cause acute disease,but may also lead to the establishment of chronic GI dysfunction compatible with IBS.展开更多
AIM: To determine the features of microsatellite alterations and their association with clinicopathological characteristics of hepatocellular carcinoma (HCC). METHODS: Loss of heterozygosity (LOH) and microsatellite i...AIM: To determine the features of microsatellite alterations and their association with clinicopathological characteristics of hepatocellular carcinoma (HCC). METHODS: Loss of heterozygosity (LOH) and microsatellite instability (MSI) of 55 microsatellite loci were detected with PCR-based microsatellite polymorphism analyses in tumors and corresponding noncancerous liver tissues of 56 surgically resected HCCs using the MegaBACE 500 automatic DNA analysis system.RESULTS: LOH was found in 44 of 56 HCCs (78.6%) at one or several loci. Frequencies of LOH on 1p, 4q, 8p,16q, and 17p were 69.6% (39/56), 71.4% (40/56), 66.1% (37/56), 66.1% (37/56), and 64.3% (36/56), respectively. MSI was found in 18 of 56 HCCs (32.1%) at one or several loci. Ten of fifty-six (17.9%) HCCs had MSI-H. Serum HBV infection, alpha-fetoprotein concentration, tumor size, cirrhosis, histological grade, tumor capsule, as well as tumor intrahepatic metastasis, might be correlated with LOH on certain chromosome regions. CONCLUSION: Frequent microsatellite alterations exist in HCC. LOH, which represents a tumor suppressor gene pathway, plays a more important role in hepatocarcinogenesis. MSI, which represents a mismatch repair genepathway, is a rare event during liver carcinogenesis. Furthermore, LOH on certain chromosome regions may be correlated with clinicopathological characteristics in HCC.展开更多
Spinal cord injury(SCI)involves diverse injury responses in different cell types in a temporally and spatially specific manner.Here,using single-cell transcriptomic analyses combined with classic anatomical,behavioral...Spinal cord injury(SCI)involves diverse injury responses in different cell types in a temporally and spatially specific manner.Here,using single-cell transcriptomic analyses combined with classic anatomical,behavioral,electrophysiological analyses,we report,with single-cell resolution,temporal molecular and cellular changes in crush-injured adult mouse spinal cord.Data revealed pathological changes of 12 different major cell types,three of which infiltrated into the spinal cord at distinct times post-injury.We discovered novel microglia and astrocyte subtypes in the uninjured spinal cord,and their dynamic conversions into additional stage-specific subtypes/states.Most dynamic changes occur at 3-days post-injury and by day-14 the second wave of microglial activation emerged,accompanied with changes in various cell types including neurons,indicative of the second round of attacks.By day-38,major cell types are still substantially deviated from uninjured states,demonstrating prolonged alterations.This study provides a comprehensive mapping of cellular/molecular pathological changes along the temporal axis after SCI,which may facilitate the development of novel therapeutic strategies,including those targeting microglia.展开更多
基金Supported by A Grant from the Department of Biotechnology,New Delhi, India under the 7th FP of the Indo-EU Joint Collaborative Project on "FUNCFOOD"
文摘Carcinoma of the stomach is still the second most common cause of cancer death worldwide, although the incidence and mortality have fallen dramatically over the last 50 years in many regions. The incidence of gastric cancer varies in different parts of the world and among various ethnic groups. Despite advances in diagnosis and treatment, the 5-year survival rate of stomach cancer is only 20 per cent. Stomach cancer can be classified into intestinal and diffuse types based on epidemiological and clinicopathological features. The etiology of gastric cancer is multifactorial and includes both dietary and nondietary factors. The major diet-related risk factors implicated in stomach cancer development include high content of nitrates and high salt intake. Accumulating evidence has implicated the role of Helicobacter pylori (H. pylori) infection in the pathogenesis of gastric cancer. The development of gastric cancer is a complex, multistep process involving multiple genetic and epigenetic alterations of oncogenes, tumor suppressor genes, DNA repair genes, cell cycle regulators, and signaling molecules. A plausible program for gastric cancer prevention involves intake of a balanced diet containing fruits and vegetables, improved sanitationand hygiene, screening and treatment of H. pylori infection, and follow-up of precancerous lesions. The fact that diet plays an important role in the etiology of gastric cancer offers scope for nutritional chemoprevention. Animal models have been extensively used to analyze the stepwise evolution of gastric carcinogenesis and to test dietary chemopreventive agents. Development of multitargeted preventive and therapeutic strategies for gastric cancer is a major challenge for the future.
基金Supported by a grant of the Romanian National Authority for Scientific Research and Innovation,CNCS-UEFISCDI,No.PN-Ⅲ-P4-ID-PCCF2016-0158(contract PCCF17/2018)within PNCDI Ⅲ
文摘Gastric cancer(GC) remains an important cause of cancer death worldwide with a high mortality rate due to the fact that the majority of GC cases are diagnosed at an advanced stage when the prognosis is poor and the treatment options are limited. Unfortunately, the existing circulating biomarkers for GC diagnosis and prognosis display low sensitivity and specificity and the GC diagnosis is based only on the invasive procedures such as upper digestive endoscopy. There is a huge need for less invasive or non-invasive tests but also highly specific biomarkers in case of GC. Body fluids such as peripheral blood, urine or saliva,stomach wash/gastric juice could be a source of specific biomarkers, providing important data for screening and diagnosis in GC. This review summarized the recently discovered circulating molecules such as microRNAs, long non-coding RNAs, circular RNAs, which hold the promise to develop new strategies for early diagnosis of GC.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA01030505)Key research and development program of Jiangsu province (BE2016612), Jiangsu Biobank of Clinical Resources (BM2015004)+1 种基金the Key Laboratory for Maternal-Fetal Medicine from the Health Department of Jiangsu Province, China (XK201102)Project of Nanjing clinical medicine center and the National Natural Science Foundation of China (81401223)
文摘Asherman's syndrome(AS) is a common disease that presents endometrial regeneration disorder. However, little is known about its molecular features of this aregenerative endometrium in AS and how to reconstruct the functioning endometrium for the patients with AS. Here, we report that ΔNp63 is significantly upregulated in residual epithelial cells of the impaired endometrium in AS; the upregulated-ΔNp63 induces endometrial quiescence and alteration of stemness. Importantly, we demonstrate that engrafting high density of autologous bone marrow mononuclear cells(BMNCs) loaded in collagen scaffold onto the uterine lining of patients with AS downregulates ΔNp63 expression, reverses ΔNp63-induced pathological changes, normalizes the stemness alterations and restores endometrial regeneration. Finally, five patients achieved successful pregnancies and live births. Therefore, we conclude that ΔNp63 is a crucial therapeutic target for AS. This novel treatment significantly improves the outcome for the patients with severe AS.
基金National Natural Science Foundation of China(Grant No.82273297).
文摘As an evolutionarily conserved signalling network,the Hippo pathway plays a crucial role in the regulation of numerous biological processes.Thus,substantial efforts have been made to understand the upstream signals that influence the activity of the Hippo pathway,as well as its physiological functions,such as cell proliferation and differentiation,organ growth,embryogenesis,and tissue regeneration/wound healing.However,dysregulation of the Hippo pathway can cause a variety of diseases,including cancer,eye diseases,cardiac diseases,pulmonary diseases,renal diseases,hepatic diseases,and immune dysfunction.Therefore,therapeutic strategies that target dysregulated Hippo components might be promising approaches for the treatment of a wide spectrum of diseases.Here,we review the key components and upstream signals of the Hippo pathway,as well as the critical physiological functions controlled by the Hippo pathway.Additionally,diseases associated with alterations in the Hippo pathway and potential therapies targeting Hippo components will be discussed.
基金supported by National Natural Science Foundation of China(No.81920108027)Science and Technology Capability Enhancement Project of Army Medical University(No.2019XQY15).
文摘Ferroptosis is a new form of programmed cell death characterized by the accumulation of iron-dependent lethal lipid peroxides.Recent discoveries have focused on alterations that occur in lipid metabolism during ferroptosis and have provided intriguing insights into the interplay between ferroptosis and lipid metabolism in cancer.Their interaction regulates the initiation,development,metastasis,therapy resistance of cancer,as well as the tumor immunity,which offers several potential strategies for cancer treatment.This review is a brief overview of the features characterizing the interaction between ferroptosis and lipid metabolism,and highlights the significance of this interaction in cancer.
文摘Gastric cancer is believed to result in part from the accumulation of multiple genetic alterations leading to oncogeneoverexpression and tumor suppressor loss. Epigenetic alterations as a distinct and crucial mechanism to silence a varietyof methylated tissue-specific and imprinted genes, have been extensively studied in gastric carcinoma and play impor-tant roles in gastric carcinogenesis. This review will briefly discuss the basic aspects of DNA methylation and CpGisland methylation, in particular the epigenetic alterations of certain critical genes implicated in gastric carcinogenesisand its relevance of clinical implications.
基金supported by the Chinese National Natural Science Funds(82041009,31925013,31671457,91753139,and 31871405)Zhejiang University Joint Pingduoduo“Virus Infectious Disease Prevention and Control funds”,a special program from the Ministry of Science and Technology of China(2016YFA0502500)+2 种基金Jiangsu Provincial Distinguished Young Scholars award(BK20180043)the Zhejiang Natural Science Fund(LD19C070001),the Key Project of University Natural Science Foundation of Jiangsu Province(19KJA550003)A project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘Advanced natural killer/T cell lymphoma(NKTL)has demonstrated poor prognosis with currently available therapies.Here,we report the efficacy of anti-programmed death 1(PD-1)antibody with the P-GEMOX(pegaspargase,gemcitabine,and oxaliplatin)regimen in advanced NKTL.Nine patients underwent six 21-day cycles of anti-PD-1 antibody(day 1),pegaspargase 2000 U/m2(day 1),gemcitabine 1 g/m2(days 1 and 8)and oxaliplatin 130 mg/m2(day 1),followed by anti-PD-1 antibody maintenance every 3 weeks.Programmed death-ligand 1(PD-L1)expression and genetic alterations were determined in paraffin-embedded pretreatment tissue samples using immunohistochemistry and next-generation sequencing(NGS)analysis.Responses were assessed using 18F-fluorodeoxyglucose positron emission tomography(18FDG-PET)and computed tomography or magnetic resonance imaging.Eight patients exhibited significant responses,comprising of seven complete remissions and one partial remission(overall response rate:88.9%).After a median follow-up of 10.6 months,6/9 patients(66.7%)remained in complete remission.The most common grade 3/4 adverse events were anemia(33.3%),neutropenia(33.3%),and thrombocytopenia(33.3%);all of which were manageable and resolved.Immunochemotherapy produced a high response rate in patients with positive PD-L1 expression(5/6,83.3%).NGS analysis suggested that STAT3/JAK3/PD-L1 alterations and ARID1A mutation were associated with immunochemotherapy efficacy.Mutation in DDX3X and alteration in epigenetic modifiers of KMT2D,TET2,and BCORL1 might indicate a poor response to immunochemotherapy.In conclusion,the anti-PD-1 antibody plus P-GEMOX regimen demonstrated promising efficacy in advanced NKTL.PD-L1 expression combined with specific genetic alterations could be used as potential biomarkers to predict therapeutic responses to immunochemotherapy.
基金This work was supported by grants from the National Key R&D Program of China(2020YFA0509400)Guangdong Basic and Applied Basic Research Foundation(2019B030302012)+2 种基金the National Natural Science Foundation of China(81821002,82130082,81790251,81972665,82173003,82102738 and 82103168)1·3·5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYGD22007 and ZYJC21004)the Science and Technology Foundation of Shenzhen(JCYJ20200109113810154).BioRender was used to create the figures.
文摘Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies,including cancer vaccines,adoptive cell therapy and antibody-based therapies,especially for solid tumors.Neoantigens are newly formed antigens generated by tumor cells as a result of various tumor-specific alterations,such as genomic mutation,dysregulated RNA splicing,disordered post-translational modification,and integrated viral open reading frames.Neoantigens are recognized as non-self and trigger an immune response that is not subject to central and peripheral tolerance.The quick identification and prediction of tumor-specific neoantigens have been made possible by the advanced development of next-generation sequencing and bioinformatic technologies.Compared to tumor-associated antigens,the highly immunogenic and tumor-specific neoantigens provide emerging targets for personalized cancer immunotherapies,and serve as prospective predictors for tumor survival prognosis and immune checkpoint blockade responses.The development of cancer therapies will be aided by understanding the mechanism underlying neoantigen-induced anti-tumor immune response and by streamlining the process of neoantigen-based immunotherapies.This review provides an overview on the identification and characterization of neoantigens and outlines the clinical applications of prospective immunotherapeutic strategies based on neoantigens.We also explore their current status,inherent challenges,and clinical translation potential.
文摘Gastric cancer is one of the leading causes of cancerrelated deaths worldwide, although the incidence has gradually decreased in many Western countries. Two main gastric cancer histotypes, intestinal and diffuse, are recognised. Although most of the described genetic alterations have been observed in both types, different genetic pathways have been hypothesized. Genetic and epigenetic events, including 1q loss of heterozygosity (LOH), microsatellite instability and hypermethylation, have mostly been reported in intestinal-type gastric carcinoma and its precursor lesions, whereas 17p LOH, mutation or loss of E-cadherin are more often implicated in the development of diffuse-type gastric cancer.In this review, we summarize the sometimes contradictory findings regarding those markers which influence the progression of gastric adenocarcinoma.
基金supported by funds from the National Key R&D Program of China(2018YFC2000100 and 2021YFE0114200)the National Natural Science Foundation of China(81770228,81770858,81600618,and 82271597)+1 种基金the Beijing Natural Science Foundation(7212086)the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-I2M-1-050).
文摘Aging is a gradual and irreversible pathophysiological process.It presents with declines in tissue and cell functions and significant increases in the risks of various aging-related diseases,including neurodegenerative diseases,cardiovascular diseases,metabolic diseases,musculoskeletal diseases,and immune system diseases.Although the development of modern medicine has promoted human health and greatly extended life expectancy,with the aging of society,a variety of chronic diseases have gradually become the most important causes of disability and death in elderly individuals.Current research on aging focuses on elucidating how various endogenous and exogenous stresses(such as genomic instability,telomere dysfunction,epigenetic alterations,loss of proteostasis,compromise of autophagy,mitochondrial dysfunction,cellular senescence,stem cell exhaustion,altered intercellular communication,deregulated nutrient sensing)participate in the regulation of aging.Furthermore,thorough research on the pathogenesis of aging to identify interventions that promote health and longevity(such as caloric restriction,microbiota transplantation,and nutritional intervention)and clinical treatment methods for aging-related diseases(depletion of senescent cells,stem cell therapy,antioxidative and anti-inflammatory treatments,and hormone replacement therapy)could decrease the incidence and development of aging-related diseases and in turn promote healthy aging and longevity.
文摘Infection susceptibility,poor vaccination efficacy,age-related disease onset,and neoplasms are linked to innate and adaptive immune dysfunction that accompanies aging(known as immunosenescence).During aging,organisms tend to develop a characteristic inflammatory state that expresses high levels of pro-inflammatory markers,termed inflammaging.This chronic inflammation is a typical phenomenon linked to immunosenescence and it is considered the major risk factor for age-related diseases.Thymic involution,naïve/memory cell ratio imbalance,dysregulated metabolism,and epigenetic alterations are striking features of immunosenescence.Disturbed T-cell pools and chronic antigen stimulation mediate premature senescence of immune cells,and senescent immune cells develop a proinflammatory senescence-associated secretory phenotype that exacerbates inflammaging.Although the underlying molecular mechanisms remain to be addressed,it is well documented that senescent T cells and inflammaging might be major driving forces in immunosenescence.Potential counteractive measures will be discussed,including intervention of cellular senescence and metabolic-epigenetic axes to mitigate immunosenescence.In recent years,immunosenescence has attracted increasing attention for its role in tumor development.As a result of the limited participation of elderly patients,the impact of immunosenescence on cancer immunotherapy is unclear.Despite some surprising results from clinical trials and drugs,it is necessary to investigate the role of immunosenescence in cancer and other age-related diseases.
基金supported by the National Natural Science Foundation of China(81672686)Special Support Program of Sun Yat-sen University Cancer Center(PT19020401)+1 种基金Science and Technology Planning Project of Guangzhou,China(202002030205)Clinical Oncology Foundation of Chinese Society of Clinical Oncology(Y-XD2019-124).
文摘Advanced natural killer/T cell lymphoma(NKTL)has demonstrated poor prognosis with currently available therapies.Here,we report the efficacy of anti-programmed death 1(PD-1)antibody with the P-GEMOX(pegaspargase,gemcitabine,and oxaliplatin)regimen in advanced NKTL.Nine patients underwent six 21-day cycles of anti-PD-1 antibody(day 1),pegaspargase 2000 U/m^(2)(day 1),gemcitabine 1 g/m^(2)(days 1 and 8)and oxaliplatin 130 mg/m^(2)(day 1),followed by anti-PD-1 antibody maintenance every 3 weeks.Programmed death-ligand 1(PD-L1)expression and genetic alterations were determined in paraffin-embedded pretreatment tissue samples using immunohistochemistry and next-generation sequencing(NGS)analysis.Responses were assessed using 18F-fluorodeoxyglucose positron emission tomography(18FDG-PET)and computed tomography or magnetic resonance imaging.Eight patients exhibited significant responses,comprising of seven complete remissions and one partial remission(overall response rate:88.9%).After a median follow-up of 10.6 months,6/9 patients(66.7%)remained in complete remission.The most common grade 3/4 adverse events were anemia(33.3%),neutropenia(33.3%),and thrombocytopenia(33.3%);all of which were manageable and resolved.Immunochemotherapy produced a high response rate in patients with positive PD-L1 expression(5/6,83.3%).NGS analysis suggested that STAT3/JAK3/PD-L1 alterations and ARID1A mutation were associated with immunochemotherapy efficacy.Mutation in DDX3X and alteration in epigenetic modifiers of KMT2D,TET2,and BCORL1 might indicate a poor response to immunochemotherapy.In conclusion,the anti-PD-1 antibody plus P-GEMOX regimen demonstrated promising efficacy in advanced NKTL.PD-L1 expression combined with specific genetic alterations could be used as potential biomarkers to predict therapeutic responses to immunochemotherapy.
文摘Hepatocellular carcinoma(HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC.
文摘Prostate cancer is the most commonly diagnosed noncutaneous cancers in North American men.While androgen deprivation has remained as the cornerstone of prostate cancer treatment,resistance ensues leading to lethal disease.Forkhead box A1(FOXA1)encodes a pioneer factor that induces open chromatin conformation to allow the binding of other transcription factors.Through direct interactions with the Androgen Receptor(AR),FOXA1 helps to shape AR signaling that drives the growth and survival of normal prostate and prostate cancer cells.FOXA1 also possesses an AR-independent role of regulating epithelial-to-mesenchymal transition(EMT).In prostate cancer,mutations converge onto the coding sequence and c/s-regulatory elements(CREs)of FOXA1,leading to functional alterations.In addition,FOXA1 activity in prostate cancer can be modulated post-translationally through various mechanisms such as LSD1-mediated protein demethylation.In this review,we describe the latest discoveries related to the function and regulation of FOXA1 in prostate cancer,pointing to their relevance to guide future clinical interventions.
文摘Inflammatory bowel diseases(IBDs)are characterized by a multifactorial partially unknown etiology that involves genetic,immunological and environmental factors.Up to 50%of IBD patients experience at least one extraintestinal manifestation;among them is the involvement of bone density which is referred to as metabolic bone disease(MBD),including osteopenia and osteoporosis.Bone alterations in IBDs population appear to have a multifactorial etiology:Decreased physical activity,inflammation-related bone resorption,multiple intestinal resections,dietary malabsorption of minerals and vitamin D deficiency,genetic factors,gut-bone immune signaling interaction,steroid treatment,microbiota and pathogenic micro-organisms interaction,and dietary malabsorption of minerals,that,all together or individually,may contribute to the alteration of bone mineral density.This review aims to summarize the prevalence and pathophysiology of metabolic bone alterations in IBD subjects outlining the main risk factors of bone fragility.We also want to underline the role of the screening and prophylaxis of bone alterations in Crohn’s disease and ulcerative colitis patients and the importance of treating appropriately MBD.
基金Supported by Natural Sciences and Engineering Research Council of Canada(individual operating and CREATE)
文摘Irritable bowel syndrome(IBS)is a commonly encountered chronic functional gastrointestinal(GI)disorder.Approximately 10%of IBS patients can trace the onset of their symptoms to a previous a bout of infectious dysentery.The appearance of new IBS symptoms following an infectious event is defined as post-infectiousIBS.Indeed,with the World Health Organization estimating between 2 and 4 billion cases annually,infectious diarrheal disease represents an incredible international healthcare burden.Additionally,compounding evidence suggests many commonly encountered enteropathogens as unique triggers behind IBS symptom generation and underlying pathophysiological features.A growing body of work provides evidence supporting a role for pathogen-mediated modifications in the resident intestinal microbiota,epithelial barrier integrity,effector cell functions,and innate and adaptive immune features,all proposed physiological manifestations that can underlie GI abnormalities in IBS.Enteric pathogens must employ a vast array of machinery to evade host protective immune mechanisms,and illicit successful infections.Consequently,the impact of infectious events on host physiology can be multidimensional in terms of anatomical location,functional scope,and duration.This review offers a unique discussion of the mechanisms employed by many commonly encountered enteric pathogens that cause acute disease,but may also lead to the establishment of chronic GI dysfunction compatible with IBS.
基金Supported by the National Natural Science Foundation of China,No. 30370645the Hundred Leading Scientists Program of the Public Health Sector of Shanghai, No. 98BR007
文摘AIM: To determine the features of microsatellite alterations and their association with clinicopathological characteristics of hepatocellular carcinoma (HCC). METHODS: Loss of heterozygosity (LOH) and microsatellite instability (MSI) of 55 microsatellite loci were detected with PCR-based microsatellite polymorphism analyses in tumors and corresponding noncancerous liver tissues of 56 surgically resected HCCs using the MegaBACE 500 automatic DNA analysis system.RESULTS: LOH was found in 44 of 56 HCCs (78.6%) at one or several loci. Frequencies of LOH on 1p, 4q, 8p,16q, and 17p were 69.6% (39/56), 71.4% (40/56), 66.1% (37/56), 66.1% (37/56), and 64.3% (36/56), respectively. MSI was found in 18 of 56 HCCs (32.1%) at one or several loci. Ten of fifty-six (17.9%) HCCs had MSI-H. Serum HBV infection, alpha-fetoprotein concentration, tumor size, cirrhosis, histological grade, tumor capsule, as well as tumor intrahepatic metastasis, might be correlated with LOH on certain chromosome regions. CONCLUSION: Frequent microsatellite alterations exist in HCC. LOH, which represents a tumor suppressor gene pathway, plays a more important role in hepatocarcinogenesis. MSI, which represents a mismatch repair genepathway, is a rare event during liver carcinogenesis. Furthermore, LOH on certain chromosome regions may be correlated with clinicopathological characteristics in HCC.
基金grants from the National Key Research and Development Program of China(No.2016YFA0100800)the International(regional)cooperation and communication program of the National Natural Science Foundation of China(No.81820108013,31620103904,82030035)the State Key Program of the National Natural Science Foundation of China(No.81330030).
文摘Spinal cord injury(SCI)involves diverse injury responses in different cell types in a temporally and spatially specific manner.Here,using single-cell transcriptomic analyses combined with classic anatomical,behavioral,electrophysiological analyses,we report,with single-cell resolution,temporal molecular and cellular changes in crush-injured adult mouse spinal cord.Data revealed pathological changes of 12 different major cell types,three of which infiltrated into the spinal cord at distinct times post-injury.We discovered novel microglia and astrocyte subtypes in the uninjured spinal cord,and their dynamic conversions into additional stage-specific subtypes/states.Most dynamic changes occur at 3-days post-injury and by day-14 the second wave of microglial activation emerged,accompanied with changes in various cell types including neurons,indicative of the second round of attacks.By day-38,major cell types are still substantially deviated from uninjured states,demonstrating prolonged alterations.This study provides a comprehensive mapping of cellular/molecular pathological changes along the temporal axis after SCI,which may facilitate the development of novel therapeutic strategies,including those targeting microglia.
