Excess non-COVID-19-related mortality among inflammatory bowel disease decedents during the COVID-19 pandemic

BACKGROUND The coronavirus disease 2019(COVID-19)pandemic disrupted healthcare in the United States.AIM To investigate COVID-19-related and non-COVID-19-related death and characteristics associated with excess death among inflammatory bowel disease(IBD)decedents.METHODS We performed a register-based study using data from the National Vital Statistics System,which reports death data from over 99%of the United States population,from January 1,2006 through December 31,2021.IBD-related deaths among adults 25 years and older were stratified by age,sex,race/ethnicity,place of death,and primary cause of death.Predicted and actual age-standardized mortality rates(ASMRs)per 100000 persons were compared.RESULTS 49782 IBD-related deaths occurred during the study period.Non-COVID-19-related deaths increased by 13.14%in 2020 and 18.12%in 2021[2020 ASMR:1.55 actual vs 1.37 predicted,95%confidence interval(CI):1.26-1.49;2021 ASMR:1.63 actual vs 1.38 predicted,95%CI:1.26-1.49].In 2020,non-COVID-19-related mortality increased by 17.65%in ulcerative colitis(UC)patients between the ages of 25 and 65 and 36.36%in non-Hispanic black(NHB)Crohn’s disease(CD)patients.During the pandemic,deaths at home or on arrival and at medical facilities as well as deaths due to neoplasms also increased.CONCLUSION IBD patients suffered excess non-COVID-19-related death during the pandemic.Excess death was associated with younger age among UC patients,and with NHB race among CD patients.Increased death at home or on arrival and due to neoplasms suggests that delayed presentation and difficulty accessing healthcare may have led to increased IBD mortality.

Pre-operative visceral adipose tissue radiodensity is a potentially novel prognostic biomarker for early endoscopic post-operative recurrence in Crohn’s disease

BACKGROUND Evidence suggests inflammatory mesenteric fat is involved in post-operative recurrence(POR)of Crohn’s disease(CD).However,its prognostic value is INTRODUCTION Crohn’s disease(CD)is a debilitating chronic immune-mediated inflammatory disease(IMID)of the gastrointestinal tract that is increasing in incidence and prevalence globally[1].CD patients often undergo surgery for disease-related complic-ations and/or medically refractory disease.Unfortunately,surgery is not curative,and many patients develop post-operative recurrence(POR)of CD with a significant proportion eventually requiring additional surgeries.With advances in early detection and therapeutics,the contemporary 10-year risk of surgery has improved from 50%to 26%,but the risk of recurrent surgery has remained unchanged at 30%,suggesting a need to improve post-operative management strategies[2].Presently,there are two accepted strategies to mitigate POR,but each have potential limitations.Firstly,patients start early post-operative pharmacologic prophylaxis within 4-6 wk after surgery.This strategy can potentially overtreat a subset of patient who may not develop long-term disease recurrence off therapy.Consequently,these patients are at risk of medication-related adverse events and the direct and indirect costs associated with therapy with little or no benefit[3].The second strategy is performing early colonoscopy within 6-12 months after surgery and escalating therapy based on FOOTNOTES Author contributions:Gu P is the guarantor of the article and was involved in concept and design,data collection,statistical analysis,drafting of manuscript,and final approval of manuscript;Dube S and Choi SY were involved in statistical analysis,drafting of the manuscript,and final approval of manuscript;Gellada N,Win S,Lee YJ and Yang S were involved in the data collection,drafting of the manuscript,and final approval of manuscript;Haritunians T and Li D were involved in data analysis and interpretation,drafting of manuscript and final approval of manuscript;Melmed GY,Yarur AJ,Fleshner P,Kallman C and Devkota S were involved in study concept and design,data interpretation,drafting of manuscript and final approval of manuscript;Vasiliauskas EA,Bonthala N,Syal G,Ziring D and Targan SR were involved in data interpretation,drafting of manuscript and final approval of manuscript;Rabizadeh S was involved in study concept and design,drafting of manuscript and final approval of manuscript;McGovern DPB was involved in concept and design,statistical analysis,drafting of manuscript and final approval of manuscript.

Phenformin activates ER stress to promote autophagic cell death via NIBAN1 and DDIT4 in oral squamous cell carcinoma independent of AMPK

The efficient clinical treatment of oral squamous cell carcinoma(OSCC)is still a challenge that demands the development of effective new drugs.Phenformin has been shown to produce more potent anti-tumor activities than metformin on different tumors,however,not much is known about the influence of phenformin on OSCC cells.We found that phenformin suppresses OSCC cell proliferation,and promotes OSCC cell autophagy and apoptosis to significantly inhibit OSCC cell growth both in vivo and in vitro.RNA-seq analysis revealed that autophagy pathways were the main targets of phenformin and identified two new targets DDIT4(DNA damage inducible transcript 4)and NIBAN1(niban apoptosis regulator 1).We found that phenformin significantly induces the expression of both DDIT4 and NIBAN1 to promote OSCC autophagy.Further,the enhanced expression of DDIT4 and NIBAN1 elicited by phenformin was not blocked by the knockdown of AMPK but was suppressed by the knockdown of transcription factor ATF4(activation transcription factor 4),which was induced by phenformin treatment in OSCC cells.Mechanistically,these results revealed that phenformin triggers endoplasmic reticulum(ER)stress to activate PERK(protein kinase R-like ER kinase),which phosphorylates the transitional initial factor eIF2,and the increased phosphorylation of eIF2 leads to the increased translation of ATF4.In summary,we discovered that phenformin induces its new targets DDIT4 and especially NIBAN1 to promote autophagic and apoptotic cell death to suppress OSCC cell growth.Our study supports the potential clinical utility of phenformin for OSCC treatment in the future.

Impact of an oligosaccharide-based polymer on the metabolic profiles and microbial ecology of weanling pigs experimentally infected with a pathogenic E.coli

Background Our previous study has reported that supplementation of oligosaccharide-based polymer enhances gut health and disease resistance of pigs infected with enterotoxigenic E.coli(ETEC)F18 in a manner similar to carbadox.The objective of this study was to investigate the impacts of oligosaccharide-based polymer or antibiotic on the host metabolic profiles and colon microbiota of weaned pigs experimentally infected with ETEC F18.Results Multivariate analysis highlighted the differences in the metabolic profiles of serum and colon digesta which were predominantly found between pigs supplemented with oligosaccharide-based polymer and antibiotic.The relative abundance of metabolic markers of immune responses and nutrient metabolisms,such as amino acids and carbohydrates,were significantly differentiated between the oligosaccharide-based polymer and antibiotic groups(q<0.2 and fold change>2.0).In addition,pigs in antibiotic had a reduced(P<0.05)relative abundance of Lachnospiraceae and Lactobacillaceae,whereas had greater(P<0.05)Clostridiaceae and Streptococcaceae in the colon digesta on d 11 post-inoculation(PI)compared with d 5 PI.Conclusions The impact of oligosaccharide-based polymer on the metabolic and microbial profiles of pigs is not fully understood,and further exploration is needed.However,current research suggest that various mechanisms are involved in the enhanced disease resistance and performance in ETEC-challenged pigs by supplementing this polymer.

Pan-cancer analysis of RNA 5-methylcytosine reader (ALYREF)

The incre asing interest in RNA modifications has signifcantly advanced epigenomic and epitranscriptomic technologies.This study focuses on the immuno oncological impact of ALYREF in human cancer through a pan-cancer analysis,enhancing understanding of this gene's role in cancer.We observed differential ALYREF expression between tumor and normal samples,correl ating strongly with prognosis in various cancers,particularly kidney renal papillary cell carcinoma(KIRP)and liver hepatocellular carcinoma(LIHC).ALYREF showed a negative correlation with most tumor-infitrating cells in lung squamous cell carcinoma(LUSC)and lymphoid neoplasm difuse large B-cell lymphoma(DLBC),while positive correlations were noted in IIHC,kidney chromophobe(KICH),mesothelioma(MESO),KIRP,pheochromocytoma and paraganglioma(PARD),and glioma(GBMLGG).Aditionally,ALYREF expression was closely associated with tumor heterogeneity,stemness indices,and a high mutation rate in TP53 across these cancers.In conclusion,ALYREF may serve as an oncogenic biomarker in numerous cancers,meriting further research attention.

Evaluating the accuracy and reproducibility of ChatGPT-4 in answering patient questions related to small intestinal bacterial overgrowth

BACKGROUND Small intestinal bacterial overgrowth(SIBO)poses diagnostic and treatment challenges due to its complex management and evolving guidelines.Patients often seek online information related to their health,prompting interest in large language models,like GPT-4,as potential sources of patient education.AIM To investigate ChatGPT-4's accuracy and reproducibility in responding to patient questions related to SIBO.METHODS A total of 27 patient questions related to SIBO were curated from professional societies,Facebook groups,and Reddit threads.Each question was entered into GPT-4 twice on separate days to examine reproducibility of accuracy on separate occasions.GPT-4 generated responses were independently evaluated for accuracy and reproducibility by two motility fellowship-trained gastroenterologists.A third senior fellowship-trained gastroenterologist resolved disagreements.Accuracy of responses were graded using the scale:(1)Comprehensive;(2)Correct but inadequate;(3)Some correct and some incorrect;or(4)Completely incorrect.Two responses were generated for every question to evaluate reproducibility in accuracy.RESULTS In evaluating GPT-4's effectiveness at answering SIBO-related questions,it provided responses with correct information to 18/27(66.7%)of questions,with 16/27(59.3%)of responses graded as comprehensive and 2/27(7.4%)responses graded as correct but inadequate.The model provided responses with incorrect information to 9/27(33.3%)of questions,with 4/27(14.8%)of responses graded as completely incorrect and 5/27(18.5%)of responses graded as mixed correct and incorrect data.Accuracy varied by question category,with questions related to“basic knowledge”achieving the highest proportion of comprehensive responses(90%)and no incorrect responses.On the other hand,the“treatment”related questions yielded the lowest proportion of comprehensive responses(33.3%)and highest percent of completely incorrect responses(33.3%).A total of 77.8%of questions yielded reproducible responses.CONCLUSION Though GPT-4 shows promise as a supplementary tool for SIBO-related patient education,the model requires further refinement and validation in subsequent iterations prior to its integration into patient care.

Ultrasound shear wave elastography and liver fibrosis: A Prospective Multicenter Study

AIM To assess the accuracy of shear wave elastography(SWE) alone and in combination with aminotransferase platelet ratio index(APRI) score in the staging of liver fibrosis.METHODS A multicenter prospective study was conducted to assess the accuracy of SWE(medians) and APRI to predict biopsy results. The analysis focused on distinguishing the different stages of liver disease, namely, F0 from F1-4, F0-1 from F2-4, F0-2 from F3-4 and F0-3 from F4; F0-F1 from F2-F4 being of primary interest. The area under the receiver operating characteristic(AUROC) curve was computed using logistic regression model. The role of age, gender and steatosis was also assessed.RESULTS SWE alone accurately distinguished F0-1 from F2-4 with a high probability. The AUROC using SWE alone was 0.91 compared to 0.78 for using the APRI score alone.The APRI score, when used in conjunction with SWE, did not make a significant contribution to the AUROC. SWE and steatosis were the only significant predictors that differentiated F0-1 from F2-4 with an AUROC of 0.944.CONCLUSION Our study validates the use of SWE in the diagnosis and staging of liver fibrosis. Furthermore, the probability of a correct diagnosis is significantly enhanced with the addition of steatosis as a prognostic factor.

Genomics in personalized cancer medicine and its impact on earlydrug development in China: report from the 6th Annual Meeting of the US Chinese Anti-Cancer Association(USCACA) at the 50th ASCOAnnual Meeting

The 6th Annual Meeting of the United States Chinese Anti-Cancer Association(USCACA) was held in conjunction with the 50 th Annual Meeting of American Society of Clinical Oncology(ASCO) on May 30, 2014 in Chicago, Illinois, the United States of America. With a focus on personalized medicine, the conference featured novel approaches to investigate genomic aberrations in cancer cells and innovative clinical trial designs to expedite cancer drug development in biomarker-defined patient populations. A panel discussion further provided in-depth advice on advancing development of personalized cancer medicines in China. The conference also summarized USCACA key initiatives and accomplishments, including two awards designated to recognize young investigators from China for their achievements and to support their training in the United States. As an effort to promote international collaboration, USCACA will team up with Chinese Society of Clinical Oncology(CSCO) to host a joint session on "Breakthrough Cancer Medicines" at the upcoming CSCO Annual Meeting on September 20 th, 2014 in Xiamen, China.

Trapezial Resection Arthroplasty: More Is Not Necessarily Better

Introduction: Thumb carpometacarpal joint arthritis can cause significant pain and limitation in activity. Patients who are unable to obtain symptomatic relief from anti-inflammatories, splinting, and cortisone injections may be indicated for surgical treatment. The earliest form of surgical intervention was trapeziectomy alone;since, numerous adjunctive procedures have evolved. In this study, we conduct a literature review comparing outcomes of simple trapeziectomy to other interventions for thumb carpometacarpal arthritis. Methods: A literature search using the PubMed/Medline database was conducted. Inclusion criteria were the following: 1) the study was a primary study written in English, 2) treatment options were surgical and compared trapeziectomy with other forms of surgical treatment for thumb carpometacarpal arthritis, 3) the study was a randomized controlled trial, 4) the study included outcomes such as pain, physical function, range of motion, and/or strength. Included studies were then compiled into a table for further review. Results: 11 studies met inclusion criteria. All studies were randomized controlled trials and demonstrated level II evidence. Surgical procedures in these studies included ligament reconstruction and tendon interposition (LRTI), flexor carpi radialis suspension, carpometacarpal joint denervation, and carpometacarpal joint arthroplasty. No significant differences were found between trapeziectomy alone versus adjunctive surgical procedures when comparing patient-reported outcomes, patient satisfaction, range of motion, grip strength, and key/tip pinch strength with follow-up ranging from 1 year to 18 years post-operative. Discussion/Conclusions: In our review of the evidence, we find no significant differences in patient-reported outcomes, patient satisfaction, range of motion, grip strength, and key/tip pinch strength both in the short- and long-term post-operative periods. This raises the question of whether adjunctive procedures are necessary for the treatment of thumb carpometacarpal arthritis, as they may lead to increased operative time, costs, and complications compared to trapeziectomy alone.

Exploratory therapy for brainstem gliomas

Brainstem gliomas comprise both slow-growing and highly aggressive tumors,the latter carrying a dismal prognosis of approximately 10 months in children.Given their common locations along the brainstem,they are often not amenable to surgical resection.There are currently a host of exploratory therapies under investigation ranging from immunotherapy,small molecular inhibitors,epigenetic-modifying agents,and radiation protocols to combat these difficult-to-treat tumors.Recent discoveries highlighting the role of H3 histone mutations in diffuse midline glioma oncogenesis have yielded a variety of new targetable antigens and aberrant signaling pathways.Although many of these studies have shown promise in terms of inhibiting tumor growth and disease progression,results to date have been modest in their ability to translate into meaningful clinical benefit.This review will serve as an updated report on the current state of literature concerning pre-clinical and clinical therapies being investigated for brainstem glioma.In addition,this review will serve as a guide for clinicians as we review the evolving nomenclature of brainstem gliomas,commonly presenting symptoms,diagnostic tools,and standard therapies.

Exploring the interplay of lncRNA,senescence and urinary tumors:opportunities and challenges

Introduction About 72%of human genome is transcribed to non-coding RNAs,which have captivated researchers a lot for shedding light on their pivotal roles in regulating the initiation and progression of various diseases,including cancers[1].Among these,long non-coding RNAs(lncRNAs)have emerged as key players in the complex landscape of gene regulation.LncRNAs perform a variety of roles,including scaffolding to encourage the interaction of related proteins,decoys to thwart transcriptional factors from the target gene’s promoter,sponges of linked miRNA to prevent target gene destruction,and guide molecules to recruit components for chromatin remodeling[1].Many cancers are closely related to age[2-5]and such patients are expected be increased gradually as almost 20%of the world’s population will be 65 or older by 2030[6]and those over the age of 65 have an 11-fold higher incidence of cancer than people under that age[7].As one of the typical hallmarks of aging[8],cellular senescence is Cellular senescence is induced by stressful insults and certain physiological processes and is characterized by a prolonged and essentially irreversible cell-cycle arrest with secretory features,macromolecular damage,and altered metabolism[9].Here,we aim to provide insights of the intersection between lncRNAs,cellular senescence,and urinary tumors,unraveling the potential implications and therapeutic avenues within this multifaceted network.

Epidural Blood Patches Performed with Miethke Sensor Reservoir for Continuous Intracranial Pressure Monitoring

An epidural blood patch (EBP) is a procedure performed by injecting autologous blood into a patient’s epidural space, usually at the site of a suspected CSF leak. It is typically performed in patients with characteristic postural headaches due to low intracranial pressure. We report a case of a young female with an implanted Miethke Sensor Reservoir, which was used for continuous intracranial pressure (ICP) monitoring during a two-level epidural blood patch. ICP increased only with thoracic injection, suggesting thoracic EBP may have greater efficacy than lumbar EBP in treating SIH and PDPH when the site of CSF leak is unknown.

新型冠状病毒感染相关疼痛

目前研究表明,有相当一部分病人在感染新型冠状病毒同时或后期出现头痛、腹痛、关节痛、肌痛、骨痛和或神经病理性疼痛等相关症状。为了加强疼痛科医师对新型冠状病毒感染相关疼痛的认识,提高新型冠状病毒感染相关疼痛的诊断水平和完善相关治疗方案,本文将对新型冠状病毒感染相关疼痛的发病率、可能机制和影像学表现等方面进行综述,以期为临床有效预防和治疗新型冠状病毒感染相关疼痛提供参考。

微管相关蛋白2在胰腺神经内分泌肿瘤组织中的表达及预后意义

目的:探索微管相关蛋白2(microtubule-associated protein 2,MAP2)与微管相关蛋白1B(microtubule-associated protein 1B,MAP1B)在预测胰腺神经内分泌肿瘤(pancreatic neuroendocrine tumors,PNETs)患者预后中的意义。方法:收集1999年12月至2016年12月来自于北京协和医院、中山大学附属第一医院、复旦大学上海癌症中心和Cedars-Sinai医学中心(洛杉矶)193例患者的193个原发肿瘤标本。免疫组织化学染色法分别检测193例、120例PNETs组织中MAP2、MAP1B的表达,随后分析蛋白表达与患者临床病理特征及预后的关系。结果:MAP2和MAP1B在PNETs患者中的阳性率分别为45.6%(88/193)和64.2%(77/120)。MAP2表达阳性的患者的总生存好于阴性患者(P=0.012)。另外,MAP2阳性Ⅱ、Ⅲ期患者的总生存也优于阴性者(P=0.017)。然而,MAP1B的表达与肿瘤大小、转移、肿瘤组织学分级、临床分期、总生存、无病生存均无相关性(P>0.05)。结论:MAP2为潜在的预测PNETs患者预后的指标。

Pancreatic neuroendocrine tumors: biology, diagnosis, and treatment

Pancreatic neuroendocrine tumors (PNETs), a group of endocrine tumors arising in the pancreas, are among the most common neuroendocrine tumors. The genetic causes of familial and sporadic PNETs are somewhat understood, but their molecular pathogenesis remains unknown. Most PNETs are indolent but have malignant potential. The biological behavior of an individual PNET is unpredictable; higher tumor grade, lymph node and liver metastasis, and larger tumor size generally indicate a less favorable prognosis. Endocrine testing, imaging, and histological evidence are necessary to accurately diagnose PNETs. A 4-pronged aggressive treatment approach consisting of surgery, locoregional therapy, systemic therapy, and complication control has become popular in academic centers around the world. The optimal application of the multiple systemic therapeutic modalities is under development; efficacy, safety, availability, and cost should be considered when treating a specific patient. The clinical presentation, diagnosis, and treatment of specific types of PNETs and familial PNET syndromes, including the novel Mahvash disease, are summarized.

Fatty liver in hepatitis C patients post-sustained virological response with direct-acting antivirals

AIM To determine steatosis and fibrosis prevalence in hepatitis C patients after a sustained virological response achieved with direct-acting antivirals.METHODS Transient elastography with controlled attenuation parameter(CAP) was used to assess hepatic steatosis post-sustained virological response(SVR);the CAP technology was not available in the United States at study initiation.Liver stiffness/fibrosis was measured before and 47 wk after treatment completion.Patients with genotype 3 and patients with cirrhosis were excluded.RESULTS One hundred and one patients were included in the study.Post-SVR there were decreases from baseline in alanine aminotransferase(ALT)(63.1 to 17.8 U/L),aspartate aminotransferase(51.8 to 21.5 U/L) and fibrosis score(7.4 to 6.1 k Pa)(P < 0.05).Post-SVR,48 patients(47.5%) had steatosis on CAP;of these,6.25% had advanced fibrosis.Patients with steatosis had higher body mass index(29.0 vs 26.1 kg/m2),glucose(107.8 vs 96.6 mg/d L),ALT(20.4 vs 15.3 mg/d L),CAP score(296.3 vs 212.4 d B/m) and fibrosis score(7.0 vs 5.3 k Pa);P < 0.05.Interestingly,compared to baseline,both patients with and without steatosis had change in fibrosis score post-SVR(7.7 k Pa vs 7.0 k Pa and 7.0 k Pa vs 5.3 k Pa);alternatively,(P < 0.05) and therefore patients with steatosis continued to have clinically significant stiffness(≥ 7 k Pa).CONCLUSION Fatty liver is very common in hepatitis C virus(HCV) patients post-SVR.These patients continue to have elevated mean fibrosis score(≥ 7 k Pa) compared to those without fatty liver;some have advanced fibrosis.Long term follow up is needed to assess steatosis and fibrosis in HCV patients post-SVR.

Biomarkers and subtypes of deranged lipid metabolism in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD)is a heterogeneous and complex disease that is imprecisely diagnosed by liver biopsy.NAFLD covers a spectrum that ranges from simple steatosis,nonalcoholic steatohepatitis(NASH)with varying degrees of fibrosis,to cirrhosis,which is a major risk factor for hepatocellular carcinoma.Lifestyle and eating habit changes during the last century have made NAFLD the most common liver disease linked to obesity,type 2 diabetes mellitus and dyslipidemia,with a global prevalence of 25%.NAFLD arises when the uptake of fatty acids(FA)and triglycerides(TG)from circulation and de novo lipogenesis saturate the rate of FAβ-oxidation and verylow density lipoprotein(VLDL)-TG export.Deranged lipid metabolism is also associated with NAFLD progression from steatosis to NASH,and therefore,alterations in liver and serum lipidomic signatures are good indicators of the disease’s development and progression.This review focuses on the importance of the classification of NAFLD patients into different subtypes,corresponding to the main alteration(s)in the major pathways that regulate FA homeostasis leading,in each case,to the initiation and progression of NASH.This concept also supports the targeted intervention as a key approach to maximize therapeutic efficacy and opens the door to the development of precise NASH treatments.

COVID-19 in cancer patients:risk,clinical features,and management

A novel coronavirus known as severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has spread across the world,prompting the World Health Organization to declare the coronavirus disease of 2019(COVID-19)a public health emergency of international concern.Cancer patients are regarded as a highly vulnerable population to SARS-CoV-2 infection and development of more severe COVID-19 symptoms,which is possibly due to the systemic immunosuppressive state caused directly by tumor growth and indirectly by effects of anticancer treatment.Currently,much effort has been directed toward studying the pathogenesis and treatment of COVID-19,but the risk profiles,prognoses,and treatment outcomes in cancer patients remain unclear.Based on the current literature,we summarize the risk profiles,clinical and biochemical characteristics,and therapy outcomes of COVID-19 infections in cancer patients.The challenges in the clinical care of cancer patients with COVID-19 are discussed.The goal of this review is to stimulate research to better understand the biological impact and prognoses of COVID-19 infections in cancer patients,thus facilitating improvement of the clinical management of these patients.

Immunopathology of inflammatory bowel disease

Inflammatory bowel disease (IBD) results from a complex series of interactions between susceptibility genes, the environment, and the immune system. The host microbiome, as well as viruses and fungi, play important roles in the development of IBD either by causing inflammation directly or indirectly through an altered immune system. New technologies have allowed researchers to be able to quantify the various components of the microbiome, which will allow for future developments in the etiology of IBD. Various components of the mucosal immune system are implicated in the pathogenesis of IBD and include intestinal epithelial cells, innate lymphoid cells, cells of the innate (macrophages/monocytes, neutrophils, and dendritic cells) and adaptive (T-cells and B-cells) immune system, and their secreted mediators (cytokines and chemokines). Either a mucosal susceptibility or defect in sampling of gut luminal antigen, possibly through the process of autophagy, leads to activation of innate immune response that may be mediated by enhanced toll-like receptor activity. The antigen presenting cells then mediate the differentiation of na&#x000ef;ve T-cells into effector T helper (Th) cells, including Th1, Th2, and Th17, which alter gut homeostasis and lead to IBD. In this review, the effects of these components in the immunopathogenesis of IBD will be discussed.

Methionine adenosyltransferases in liver cancer

Methionine adenosyltransferases(MATs)are essential enzymes for life as they produce S-adenosylmethionine(SAMe),the biological methyl donor required for a plethora of reactions within the cell.Mammalian systems express two genes,MAT1A and MAT2A,which encode for MATα1 and MATα2,the catalytic subunits of the MAT isoenzymes,respectively.A third gene MAT2B,encodes a regulatory subunit known as MATβwhich controls the activity of MATα2.MAT1A,which is mainly expressed in hepatocytes,maintains the differentiated state of these cells,whilst MAT2A and MAT2B are expressed in extrahepatic tissues as well as non-parenchymal cells of the liver(e.g.,hepatic stellate and Kupffer cells).The biosynthesis of SAMe is impaired in patients with chronic liver disease and liver cancer due to decreased expression and inactivation of MATα1.A switch from MAT1A to MAT2A/MAT2B occurs in multiple liver diseases and during liver growth and dedifferentiation,but this change in the expression pattern of MATs results in reduced hepatic SAMe level.Decades of study have utilized the Mat1a-knockout(KO)mouse that spontaneously develops non-alcoholic steatohepatitis(NASH)and hepatocellular carcinoma(HCC)to elucidate a variety of mechanisms by which MAT proteins dysregulation contributes to liver carcinogenesis.An increasing volume of work indicates that MATs have SAMe-independent functions,distinct interactomes and multiple subcellular localizations.Here we aim to provide an overview of MAT biology including genes,isoenzymes and their regulation to provide the context for understanding consequences of their dysregulation.We will highlight recent breakthroughs in the field and underscore the importance of MAT’s in liver tumorigenesis as well as their potential as targets for cancer therapy.