Recent trends in the surgical management of inflammatory bowel disease

Surgery is required in the vast majority of patients with Crohn’s disease (CD) and in approximately one-third of patients with ulcerative colitis (UC). Similar to medical treatments for IBD, significant advances have occurred in surgery. Advances in CD include an emphasis upon conservatism as exemplified by more limited resections, strictureplasties, and laparoscopic resections. The use of probiotics in selected patients has improved the outcome in patients with pouchitis following restorative proctocolectomy for UC. It is anticipated that ongoing discoveries in the molecular basis of IBD will in turn identify those patients who will best respond to surgery.

Amelioration of collagen-induced arthritis by CD95 (Apo-1/Fas)-ligand gene transfer

Both rheumatoid arthritis and animal models ofautoimmune arthritis are characterized by hyper-activation of synovial cells and hyperplasia of the synovialmembrane. The activated synovial cells produceinflammatory cytokines and degradative enzymes whichlead to destruction of cartilage and bones. Effectivetreatment of arthritis may require elimination of most orall activated synovial cells. The death factor

Genetic association and epistatic interaction of the interleukin-10 signaling pathway in pediatric inflammatory bowel disease

To study the genetic association and epistatic interaction of the interleukin (IL)-10 and IL-10/STAT3 pathways in pediatric inflammatory bowel disease (IBD). METHODSA total of 159 pediatric inflammatory IBD patients (Crohn’s disease, n = 136; ulcerative colitis, n = 23) and 129 matched controls were studied for genetic association of selected single nucleotide polymorphisms (SNPs) of the IL-10 gene and the genes IL10RA, IL10RB, STAT3, and HO1, from the IL-10/STAT3 signaling pathway. As interactions between SNPs from different loci may significantly affect the associated risk for disease, additive (a) and dominant (d) modeling of SNP interactions was also performed to examine high-order epistasis between combinations of the individual SNPs. RESULTSThe results showed that IL-10 rs304496 was associated with pediatric IBD (P = 0.022), but no association was found for two other IL-10 SNPs, rs1800872 and rs2034498, or for SNPs in genes IL10RA, IL10RB, STAT3, and HO1. However, analysis of epistatic interaction among these genes showed significant interactions: (1) between two IL-10 SNPs rs1800872 and rs3024496 (additive-additive P = 0.00015, Bonferroni P value (Bp) = 0.003); (2) between IL-10RB rs2834167 and HO1 rs2071746 (dominant-additive, P = 0.0018, Bp = 0.039); and (3) among IL-10 rs1800872, IL10RB rs2834167, and HO1 rs2071746 (additive-dominant-additive, P = 0.00015, Bp = 0.005), as well as weak interactions among IL-10 rs1800872, IL-10 rs3024496, and IL-10RA (additive-additive-additive, P = 0.003; Bp = 0.099), and among IL10RA, IL10RB, and HO1 genes (additive-dominant-additive, P = 0.008, Bp = 0.287). CONCLUSIONThese results indicate that both the IL-10 gene itself, and through epistatic interaction with genes within the IL-10/STAT3 signaling pathway, contribute to the risk of pediatric IBD.

The role of endoscopy in the management of hereditary diffuse gastric cancer syndrome

Hereditary diffuse gastric cancer(HDGC) syndrome is an inherited cancer risk syndrome associated with path-ogenic germline CDH1 variants. Given the high risk for developing diffuse gastric cancer, CDH1 carriers are recommended to undergo prophylactic total gastrectomy for cancer risk reduction. Current guidelines recommend upper endoscopy in CDH1 carriers prior to surgery and then annually for individuals deferring prophylactic total gastrectomy.Management of individuals from HDGC families without CDH1 pathogenic variants remains less clear, and management of families with CDH1 pathogenic variants in the absence of a family history of gastric cancer is particularly problematic at present. Despite adherence to surveillance protocols, endoscopic detection of cancer foci in HDGC is suboptimal and imperfect for facilitating decision-making. Alternative endoscopic modalities, such as chromoendoscopy,endoscopic ultrasound, and other non-white light methods have been utilized,but are of limited utility to further improve cancer detection and risk stratification in HDGC. Herein, we review what is known and what remains unclear about endoscopic surveillance for HDGC, among individuals with and without germline CDH1 pathogenic variants. Ultimately, the use of endoscopy in the management of HDGC remains a challenging arena, but one in which further research to improve surveillance is crucial.

Quick to remember, slow to forget： rapid recall responses of memory CD8^＋ T cells

The functional roles of memory B and T lymphocytes underlie the phenomenal success of prophylactic vaccinations, which have decreased morbidities and mortalities from infectious diseases globally over the last 50 years. However, it is becoming increasingly appreciated that memory cells are also capable of mediating the pathology associated with autoimmune disorders and transplant rejection, and may pose a significant barrier to future clinical advancement in immunoregulation. Therefore, understanding the unique properties of memory lymphocytes （as compared to their naive precursors） is a major area of investigation. Here, we focus on one of those singular properties of memory T cells （TM）-rapid recall. As will be discussed in more detail, rapid recall refers to the ability of quiescent TM cells to efficiently and robustly express‘effector functions＇ following stimulation. Studies that have advanced our understanding of TM cells＇ rapid recall using CD4^＋ T cells have been expertly reviewed elsewhere, so we will focus primarily on studies of CD8^＋ T cells. We will first review the different ways that CD8^＋ TM cells can be generated, followed by discussing how this influences their functional properties in the settings of immune protection and pathology. Then, rapid recall ability will be discussed, with emphasis placed on what is currently known about the mechanisms that underlie this unique property of TM cells.

History of the infantile hepatic hemangioma:From imaging to generating a differential diagnosis

We aim to provide an up-to-date summary of infantile hepatic hemangioma(IHH) and its misnomers and to dialectically present the differential diagnosis of these rare entities of the liver.Eligible peer-reviewed articles on hepatic infantile hemangiomas,published between 2000 and 2015,were reviewed for this study.IHH is the most common hepatic vascular tumor in children.Once a liver mass is identified in an infant,the differential diagnosis ranges from vascular malformations to benign and malignant tumors including mesenchymal hamartoma,hepatoblastoma,metastatic neuroblastoma,so careful physical examination,imaging studies,and,if indicated,tumor markers and biopsy,are of pivotal importance to ascertain the correct diagnosis.Despite the benign nature of IHHs,some of these lesions may demand medical and/or surgical intervention,especially for multiple and diffuse IHH.Complications can include hepatomegaly,hypothyroidism and cardiac failure.Therefore,a close follow-up is required until complete involution of the lesions.We propose an algorithm to guide the physicians towards the proper management of hepatic lesions.

Time Course of Age-dependent Changes in Intraocular Pressure and Retinal Ganglion Cell Death in DBA/2J Mouse

Purpose:To characterizes the progression of glaucoma in DBA/2J mice by measuring intraocular pressure(IOP) and retinal ganglion cells(RGCs) numbers in mice of various ages. Methods:A quantitative assessment of the pathophysiology of the DBA/2J mice was performed and the C57/BL6 mice was used as control. The IOP was measured by the servo-null micropipette system; the regional patterns of the loss of RGCs were determined by cell count of retrogradely-labeled RGCs. Results:The baseline IOP for DBA/2J mice at 7 weeks was (16.6 ± 1.2)mm Hg.Then IOP increased extend to 12 months, with the peak of (25.2 ± 1.2)mm Hg at 6 months of age. Retinal ganglion cell numbers did not decrease relative to control until 12 months of age(P=0.006), when the loss was proportionally higher in peripheral regions(P<0.05). Conclusion:The elevation in IOP precedes the loss of RGCs by several months. RGCs cell loss occurs particularly in peripheral regions of the retina. These findings expand our understanding of the changes in DBA/2J mice and provide information for experiments design when they are used as a glaucoma model for future studies of RGCs degeneration in glaucoma.

IgSF11-mediated phosphorylation of pyruvate kinase M2 regulates osteoclast differentiation and prevents pathological bone loss

Osteoclasts are primary bone-resorbing cells,and receptor-activated NF-k B ligand(RANKL)stimulation is the key driver of osteoclast differentiation.During late-stage differentiation,osteoclasts become multinucleated and enlarged(so-called“maturation”),suggesting their need to adapt to changing metabolic demands and a substantial increase in size.Here,we demonstrate that immunoglobulin superfamily 11(Ig SF11),which is required for osteoclast differentiation through an association with the postsynaptic scaffolding protein PSD-95,regulates osteoclast differentiation by controlling the activity of pyruvate kinase M isoform2(PKM2).By using a system that directly induces the activation of Ig SF11 in a controlled manner,we identified PKM2 as a major Ig SF11-induced tyrosine-phosphorylated protein.Ig SF11 activates multiple Src family tyrosine kinases(SFKs),including c-Src,Fyn,and Hc K,which phosphorylate PKM2 and thereby inhibit PKM2 activity.Consistently,Ig SF11-deficient cells show higher PKM2activity and defective osteoclast differentiation.Furthermore,inhibiting PKM2 activities with the specific inhibitor Shikonin rescues the impaired osteoclast differentiation in Ig SF11-deficient cells,and activating PKM2 with the specific activator TEPP46 suppresses osteoclast differentiation in wild-type cells.Moreover,PKM2 activation further suppresses osteoclastic bone loss without affecting bone formation in vivo.Taken together,these results show that Ig SF11 controls osteoclast differentiation through PKM2 activity,which is a metabolic switch necessary for optimal osteoclast maturation.

API2-MALT1 oncoprotein promotes lymphomagenesis via unique program of substrate ubiquitination and proteolysis

Lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is the most common extranodal B cell tumor and accounts for 8% of non-Hodgkin&#x02019;s lymphomas. Gastric MALT lymphoma is the best-studied example and is a prototypical neoplasm that occurs in the setting of chronic inflammation brought on by persistent infection or autoimmune disease. Cytogenetic abnormalities are commonly acquired during the course of disease and the most common is chromosomal translocation t(11;18)(q21;q21), which creates the API2-MALT1 fusion oncoprotein. t(11;18)-positive lymphomas can be clinically aggressive and have a higher rate of dissemination than t(11;18)-negative tumors. Many cancers, including MALT lymphomas, characteristically exhibit deregulated over-activation of cellular survival pathways, such as the nuclear factor-&#x003ba;B (NF-&#x003ba;B) pathway. Molecular characterization of API2-MALT1 has revealed it to be a potent activator of NF-&#x003ba;B, which is required for API2-MALT1-induced cellular transformation, however the mechanisms by which API2-MALT1 exerts these effects are only recently becoming apparent. The API2 moiety of the fusion binds tumor necrosis factor (TNF) receptor associated factor (TRAF) 2 and receptor interacting protein 1 (RIP1), two proteins essential for TNF receptor-induced NF-&#x003ba;B activation. By effectively mimicking ligand-bound TNF receptor, API2-MALT1 promotes TRAF2-dependent ubiquitination of RIP1, which then acts as a scaffold for nucleating and activating the canonical NF-&#x003ba;B machinery. Activation occurs, in part, through MALT1 moiety-dependent recruitment of TRAF6, which can directly modify NF-&#x003ba;B essential modulator, the principal downstream regulator of NF-&#x003ba;B. While the intrinsic MALT1 protease catalytic activity is dispensable for this canonical NF-&#x003ba;B signaling, it is critical for non-canonical NF-&#x003ba;B activation. In this regard, API2-MALT1 recognizes NF-&#x003ba;B inducing kinase (NIK), the essential upstream regulator of non-canonical NF-&#x003ba;B, and cleaves it to generate a stable, constitutively active fragment. Thus, API2-MALT1 harnesses multiple unique pathways to achieve deregulated NF-&#x003ba;B activation. Emerging data from our group and others have also detailed additional gain-of-function activities of API2-MALT1 that extend beyond NF-&#x003ba;B activation. Specifically, API2-MALT1 recruits and subverts multiple other signaling factors, including LIM domain and actin-binding protein 1 (LIMA1) and Smac/DIABLO. Like NIK, LIMA1 represents a unique substrate for API2-MALT1 protease activity, but unlike NIK, its cleavage sets in motion a major NF-&#x003ba;B-independent pathway for promoting oncogenesis. In this review, we highlight the most recent results characterizing these unique and diverse gain-of-function activities of API2-MALT1 and how they contribute to lymphomagenesis.

Regional disease characteristics and comorbidities of patients with schizophrenia in the Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC): Findings from an international large simple trial

Background: Using baseline data from the Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC), we assessed disease characteristics and prevalence of select comorbidities among subjects with schizophrenia in different clinical settings across 18 countries. ZODIAC was a randomized, open-label, one-year, large simple trial (LST) that enrolled 18,239 individuals with schizophrenia. Methods: Subjects were randomized to open-label treatment with ziprasidone (n = 9120) or olanzapine (n = 9119) in naturalistic (usual care) settings and followed for one year. Study sites (n = 749) applied minimal selection criteria in an attempt to make the study population as representative as possible of those receiving treatment in “real world” circumstances across the countries. Results: Mean patient age was 41 years, 55% were male, 34% were markedly ill or presented with more severe disease, and 66% of subjects had one or more select comorbid conditions [i.e. heart attack, stroke, hypertension, CAD/angina, high cholesterol/triglycerides, diabetes, or overweight (BMI ≥ 25)] at baseline. History of suicide attempt was greatest in the US (38%), compared with Sweden (34%), Brazil/South America (26%), Asia (23%), and Eastern Europe (20%). Overweight or obesity was the most prevalent comorbid risk factor, representing 60% of enrolled subjects, 70% of US subjects compared with 30% in Asia and 52% - 64% in the other regions studied. High cholesterol/triglycerides levels were found in 23% of US subjects compared with a relatively low prevalence in other countries (3% - 11%). History of cardiovascular or diabetes-related comorbidities was found in 31% of subjects. Current smoking (46.5%) and past smoking (11.8%) were common with men dominating the proportion of current smokers: US (61%);Asia (60%);Sweden (50%);Eastern Europe (49%);and Latin America (44%). Conclusions: Our findings indicate substantial baseline variations across countries in demographics, comorbid conditions, and psychiatric disease history. These data provide an international epidemiologic picture of schizophrenia and may help guide future research and treatment initiatives.

Evidence for the involvement of ActA in maturation of the Listeria monocytogenes phagosome

Dear Editor, Listeria monocytogenes （Lm）, a Gram-positive facultative bacterium, is the causative agent of listeriosis, a food-borne disease affecting humans. During infections, Lm enters phagosomes from which it escapes into the cytoplasm. Listeriolysin O （LLO） is essential, and two phospholipases play a role in this process. Actin polymerization provides the propulsive force that moves the bacteria through the cytoplasm and into adjacent cells. It is initiated by the interaction of the N-terminal domain of ActA,

Summary overview of human gene therapy trials in the U.S.

It has been approximately six and one-half yearssince the first patient was enrolled in a gene therapyclinical trial. Since that important begining, this typeof genetic intervention has grown into a worldwideinvestigative activity involving about 2100 patients asof December 1996. Although it was initially

Peripheral clonal deletion of MBP-specific T cells by intravenous au-toantigen: rapid reversal of ongoing, progressive experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis can be initiated spontaneously and developed progressively in TCR transgenic mice specific for myelin basic protein when exposed to non-sterile environment, thus more closely mimicking human multiple sclerosis. By intravenous administration of myelin basic protein, we succeeded in rapidly reversing the clinical and pathological signs of progressive spontaneous disease in these mice. The majority of transgenic T cells of MBP-injected mice was deleted, with dramatically increased numbers of apoptotic cells, in lymph nodes and spleen, but not in thymus. Proliferative responses of

Regulation of the subcellular localization of TRAF2 by TRAF1 reveals mechanisms of TRAF2 signaling

TRAF2 is a critical adaptor molecule for TNF receptors in inflammatory and immune signaling. Upon receptor engagement, TRAF2 is recruited to CD40 and translocates to lipid rafts in a RING finger-dependent process, which enables the activation of downstream kinases. TRAF1 can displace TRAF2 and CD40 from raft fractions, and it promotes the ability of TRAF2 to sustain signal activation. Replacement of the RING finger of TRAF2 with a raft-targeting signal restores JNK activation and association with the cytoskeletal protein Filamin, but not NF-KB activation. TRAF1-/-dendritic cells show attenuated

Uptake and outcomes of small intestinal and urinary tract cancer surveillance in Lynch syndrome

BACKGROUND Lynch syndrome(LS)is a hereditary cancer predisposition syndrome associated with increased risk of multiple cancers.While colorectal cancer surveillance decreases mortality in LS and is recommended by guidelines,there is lack of evidence for the efficacy of surveillance for extra-colonic cancers associated with LS,including small intestinal cancer(SIC)and urinary tract cancer(UTC).Given the limited evidence,guidelines do not consistently recommend surveillance for SIC and UTC,and it remains unclear how often individuals will choose to undergo and follow through with extra-colonic surveillance recommendations.AIM To study factors associated with SIC and UTC surveillance uptake and outcomes in LS.METHODS This is an IRB-approved retrospective analysis of individuals with LS seen at a tertiary care referral center.Included individuals had a pathogenic or likely pathogenic variant in MLH1,MSH2,MSH6,PMS2,or EPCAM,or were a confirmed obligate carrier,and had at least one documented visit to our center.Information regarding SIC and UTC surveillance was captured for each individual,and detailed personal and family history was obtained for individuals who had an initial LS management visit in our center’s dedicated high-risk LS clinic between January 1,2017 and October 29,2020.During these initial management visits,all patients had in-depth discussions of SIC and UTC surveillance with 1 of 3 providers experienced in LS management to promote informed decision-making about whether to pursue SIC and/or UTC surveillance.Statistical analysis using Pearson’s chi-squared test and Wilcoxon rank-sum test was completed to understand the factors associated with pursuit and completion of SIC and UTC surveillance,and a P value below 0.05 was deemed statistically significant.RESULTS Of 317 individuals with LS,86(27%)underwent a total of 105 SIC surveillance examinations,with 5 leading to additional work-up and no SICs diagnosed.Additionally,99(31%)patients underwent a total of 303 UTC surveillance examinations,with 19 requiring further evaluation and 1 UTC identified.Of 155 individuals who had an initial LS management visit between January 1,2017 and October 29,2020,63(41%)chose to undergo SIC surveillance and 58(37%)chose to undergo UTC surveillance.However,only 26(41%)and 32(55%)of those who initially chose to undergo SIC or UTC surveillance,respectively,successfully completed their surveillance examinations.Individuals with a pathogenic variant in MSH2 or EPCAM were more likely to initially choose to undergo SIC surveillance(P=0.034),and older individuals were more likely to complete SIC surveillance(P=0.007).Choosing to pursue UTC surveillance was more frequent among older individuals(P=0.018),and females more frequently completed UTC surveillance(P=0.002).Personal history of cancer and family history of SIC or UTC were not significantly associated with electing nor completing surveillance.Lastly,the provider discussing SIC/UTC surveillance was significantly associated with subsequent surveillance choices.CONCLUSION Pursuing and completing SIC/UTC surveillance in LS is influenced by several factors,however broad incorporation in LS management is likely unhelpful due to low yield and frequent false positive results.

Early Onset Post-Radiation Cutaneous Angiosarcoma of the Breast with Features of Atypical-Vascular Lesion: A Diagnostic Pitfall and Its Biologic Significance

Vascular proliferations may arise in the breast following radiation treatment for a primary breast adenocarcinoma. A post-radiation vascular proliferation can usually be classified as angiosarcoma or as an atypical vascular lesion (AVL). Angiosarcomas with a “low-grade” morphology, behave aggressively but exhibit substantial histomorphologic overlap with AVLs, which have a generally benign clinical course. We present a case of a post-radiation angiosarcoma of the breast with histologic features that mimic an atypical vascular lesion and discuss this challenging differential diagnosis. In addition to histologic mimicry, the lesion exhibited only patchy amplification of the avian myelocytomatosis viral oncogene homolog (MYC) gene by present fluorescence in-situ hybridization (FISH), and patchy MYC overexpression by immunohistochemistry. These features further complicate the distinction between AVL and angiosarcoma, and would be particularly problematic on a small biopsy. We believe that the morphologic and immunohistochemical overlap between these entities is suggestive of a biologic spectrum, and thus that, at least in some instances, angiosarcoma may arise from a pre-existing AVL or AVL-like lesion.

Effects of contact/collision sport history on gait in early-to mid-adulthood

Background:To determine the effect of contact/collision sport participation on measures of single-task(ST)and dual-task(DT)gait among early-to middle-aged adults.Methods:The study recruited 113 adults(34.88±11.80 years,(mean±SD);53.0%female)representing 4 groups.Groups included(a)former non-contact/collision athletes and non-athletes who are not physically active(n=28);(b)former non-contact/collision athletes who are physically active(n=29);(c)former contact/collision sport athletes who participated in high-risk sports and are physically active(n=29);and(d)former rugby players with prolonged repetitive head impact exposure history who are physically active(n=27).Gait parameters were collected using inertial measurement units during ST and DT gait.DT cost was calculated for all gait parameters(double support,gait speed,and stride length).Groups were compared first using one-way analysis of covariance.Then a multiple regression was performed for participants in the highrisk sport athletes and repetitive head impact exposure athletes groups only to predict gait outcomes from contact/collision sport career duration.Results:There were no significant differences between groups on any ST,DT,or DT cost outcomes(p>0.05).Contact/collision sport duration did not predict any ST,DT,or DT cost gait outcomes.Conclusion:Years and history of contact/collision sport participation does not appear to negatively affect or predict neurobehavioral function in early-to mid-adulthood among physically active individuals.

血管内皮靶向的药物投递系统

药物新剂型的开发已成为现代药剂学发展的一个方向,其中靶向药物投递系统（Targeted drug de-livery system,TDDS）的研究已经成为药剂学研究热点。TDDS指一类能使药物浓集定位于病变组织、器官、细胞或细胞内的新型给药系统.靶向制剂具有疗效高、药物用量少,毒副作用小等优点。

Complement and its role in innate and adaptive immune responses

The complement system plays a crucial role in the innate defense against common pathogens. Activation of complement leads to robust and efficient proteolytic cascades, which terminate in opsonization and lysis of the pathogen as well as in the generation of the classical inflammatory response through the production of potent proinflammatory molecules. More recently, however, the role of complement in the immune response has been expanded due to observations that link complement activation to adaptive immune responses. It is now appreciated that complement is a functional bridge between innate and adaptive immune responses that allows an integrated host defense to pathogenic challenges. As such, a study of its functions allows insight into the molecular underpinnings of host-pathogen interactions as well as the organization and orchestration of the host immune response. This review attempts to summarize the roles that complement plays in both innate and adaptive immune responses and the consequences of these interactions on host defense.

Regulation of inflammation and tumorigenesis by the FIPE family of phospholipid transfer proteins

The TIPE （tumor necrosis factor-a-induced protein 8-like） family are newly described regulators of immunity and tumorigenesis consisting of four highly homologous mammalian proteins： TNFAIP8 （tumor necrosis factor-a-induced protein 8）, TIPE1 （TNFAIP8-1ike 1, or TNFAIP8L1）, TIPE2 （TNFAIP8L2） and TIPE3 （TNFAIP8L3）. They are the only known transfer proteins of the lipid secondary messengers PIP2 （phosphatidylinositol 4,5-bisphosphate） and PIP3 （phosphatidylinositol 3,4,5-trisphosphate）. Cell-surface receptors, such as G-protein-coupled receptors and receptor tyrosine kinases, regulate inflammation and cancer via several signaling pathways, including the nuclear factor （NF）-KB and phosphoinositide-3 kinase （PI3K） pathways, the latter of which is upstream of both Akt and STAT3 activation. An expression analysis in humans demonstrated that the TIPE family is dysregulated in cancer and inflammation, and studies both in mice and in vitro have demonstrated that this family of proteins plays a critical role in tumorigenesis and inflammatory responses. In this review, we summarize the current literature for all four family members, with a special focus on the phenotypic manifestations present in the various knockout murine strains, as well as the related cell signalinR that has been elucidated to date.