Although the identification of B cell subsets with negative regulatory functions and the definition of their mechanisms of action are recent events, the important negative regulatory roles of B cells in immune respons...Although the identification of B cell subsets with negative regulatory functions and the definition of their mechanisms of action are recent events, the important negative regulatory roles of B cells in immune responses are now broadly recognized. There is an emerging appreciation for the pivotal role played by B cells in several areas of human diseases including autoimmune diseases and non-autoimmune diseases such as parasite infections and cancer. The recent research advancement of regulatory B cells in human disease coincides with the vastly accelerated pace of research on the bridging of innate and adaptive immune system. Current study and our continued research may provide better understanding of the mechanisms that promote regulatory B10 cell function to counteract exaggerated immune activation in autoimmune as well as non-autoimmune conditions. This review is focused on the current knowledge of BREG functions studied in animal models of autoimmune and non-autoimmune diseases.展开更多
Medical journals and scientific journals in general,have been our community’s way of reporting scientific findings for the past three-hundred years.During this time,they have been in continuous evolution,undergoing m...Medical journals and scientific journals in general,have been our community’s way of reporting scientific findings for the past three-hundred years.During this time,they have been in continuous evolution,undergoing many changes,with the aim to better and more efficiently communicate research to other specialists and thewider public.Here,the hLife’s co-Editor-in-Chief Dr.Chen Dong speaks with Dr.Eric Rubin and Dr.Rui-Ping Xiao from The New England Journal of Medicine(NJEM)on the history and development of medical journals,a dialogue which took place immediately following the launch ceremony of hLife.They reflect on how reporting of medical discoveries has changed over time,the future medical challenges that society faces and how journals can address these issues,and they also give their views on how new technologies,including the use of artificial intelligence(AI),will be incorporated into the medical research and publishing.展开更多
Monocytes are effector immune cells but a precise anal-ysis of their role in immune response has been preclud-ed by their heterogeneity. Indeed, human monocytesare composed of at least three different subsets withdiff...Monocytes are effector immune cells but a precise anal-ysis of their role in immune response has been preclud-ed by their heterogeneity. Indeed, human monocytesare composed of at least three different subsets withdifferent phenotypic characteristics and functional prop-erties, the so-called classical, intermediate and non-classical monocytes. A review of the literature showsthat these monocyte subsets are differently affectedduring viral, bacterial, parasitic and fungal infections.The expansion of the CD16＋ compartment （intermedi-ate and non-classical monocytes） is typically observedin the majority of infectious diseases and the increasedproportion of CD16＋ monocytes is likely related totheir activation through their direct interaction with thepathogen or the infammatory context. In contrast, thenumber of non-classical and intermediate monocytesis decreased in Q fever endocarditis, suggesting thatcomplex mechanisms govern the equilibrium among monocyte subsets. The measurement of monocyte sub-sets would be useful in better understanding of the role of monocyte activation in the pathophysiology of infec-tious diseases.展开更多
Nuclear erythroid 2-related factor 2(Nrf2) is a central regulator of antioxidative response elements-mediated gene expression. It has a significant role in adaptive responses to oxidative stress by interacting with th...Nuclear erythroid 2-related factor 2(Nrf2) is a central regulator of antioxidative response elements-mediated gene expression. It has a significant role in adaptive responses to oxidative stress by interacting with the antioxidant response element, which induces the expression of a variety of downstream targets aimed at cytoprotection. Previous studies suggested oxidative stress and associated damage could represent a common link between different forms of diseases. Oxidative stress has been implicated in various liver diseases, including viral hepatitis, nonalcoholic fatty liver disease/steatohepatitis, alcoholic liver disease and drug-induced liver injury. Nrf2 activation is initiated by oxidative or electrophilic stress, and aids in the detoxification and elimination of potentially harmful exogenous chemicals and their metabolites. The expression of Nrf2 has been observed throughout human tissue, with high expression in detoxification organs, especially the liver. Thus, Nrf2 may serve as a major regulator of several cellular defense associated pathways by which hepatic cells combat oxidative stress. We review the relevant literature concerning the crucial role of Nrf2 and its signaling pathways against oxidative stress to protect hepatic cell from oxidative damage during development of common chronic liver diseases. We also review the use of Nrf2 as a therapeutic target to prevent and treat liver diseases.展开更多
Hypoxia（low oxygen level） is an important feature during infections and affects the host defence mechanisms. The host has evolved specific responses to address hypoxia, which are strongly dependent on the activation...Hypoxia（low oxygen level） is an important feature during infections and affects the host defence mechanisms. The host has evolved specific responses to address hypoxia, which are strongly dependent on the activation of hypoxia-inducible factor 1（HIF-1）.Hypoxia interferes degradation of HIF-1 alpha subunit（HIF-1α）, leading to stabilisation of HIF-1α, heterodimerization with HIF-1 beta subunit（HIF-1β） and subsequent activation of HIF-1 pathway. Apical periodontitis（periapical lesion） is a consequence of endodontic infection and ultimately results in destruction of tooth-supporting tissue, including alveolar bone. Thus far, the role of HIF-1 in periapical lesions has not been systematically examined. In the present study, we determined the role of HIF-1 in a wellcharacterised mouse periapical lesion model using two HIF-1α-activating strategies, dimethyloxalylglycine（DMOG） and adenovirusinduced constitutively active HIF-1α（CA-HIF1 A）. Both DMOG and CA-HIF1 A attenuated periapical inflammation and tissue destruction. The attenuation in vivo was associated with downregulation of nuclear factor-κappa B（NF-κB） and osteoclastic gene expressions. These two agents also suppressed NF-κB activation and subsequent production of proinflammatory cytokines by macrophages. Furthermore, activation of HIF-1α by DMOG specifically suppressed lipopolysaccharide-stimulated macrophage differentiation into M1 cells, increasing the ratio of M2 macrophages against M1 cells. Taken together, our data indicated that activation of HIF-1 plays a protective role in the development of apical periodontitis via downregulation of NF-κB, proinflammatory cytokines, M1 macrophages and osteoclastogenesis.展开更多
Parkinson’s disease（PD）is the second most common neurodegenerative disease affecting 1%of the population over 60 years of age.The progressive degeneration of dopaminergic neurons at the substantia nigra pars compa...Parkinson’s disease（PD）is the second most common neurodegenerative disease affecting 1%of the population over 60 years of age.The progressive degeneration of dopaminergic neurons at the substantia nigra pars compacta（SNpc）results in a severe and gradual depletion of dopamine content in the striatum,a phenomena that is responsible for the characteristic motor symptoms of this disease.展开更多
BACKGROUND Recent studies in non-colorectal malignancy have associated T resident memory(T_(RM)) cells with improved patient survival. It is unknown if T_(RM) plays a role in colorectal cancer(CRC).AIM To examine the ...BACKGROUND Recent studies in non-colorectal malignancy have associated T resident memory(T_(RM)) cells with improved patient survival. It is unknown if T_(RM) plays a role in colorectal cancer(CRC).AIM To examine the potential role of T_(RM) cells in providing immunogenicity in CRC stratified by microsatellite instability(MSI) and BRAF status.METHODS Patients with known MSI and BRAF mutation status were eligible for inclusion in this study. CRC tumour sections stained with haematoxylin and eosin were microscopically reviewed and the images scanned prior to assessment for location of invading edge and core of tumour. Sequential sections were prepared for quantitative multiplex immunohistochemistry(IHC) staining. Opal Multiplex IHC staining was performed with appropriate positive and negative controls and imaged using a standard fluorescent microscope fitted with a spectral scanning camera(Mantra) in conjunction with Mantra snap software. Images were unmixed and annotated in in Form 2.2.0. Statistical analysis was performed using Graphpad Prism Version 7 and Stata Version 15.RESULTS Seventy-two patients with known MSI and BRAF status were included in the study. All patients were assessed for MSI by IHC and high resolution capillary electrophoresis testing and 44 of these patients successfully underwent quantitative multiplex IHC staining. Overall, there was a statistically significant increase in CD8+ T_(RM) cells in the MSI(BRAF mutant and wild type) group over the microsatellite stable(MSS) group. There was a statistically significant difference in CD8+ T_(RM) between high level MSI(MSI-H):BRAF mutant [22.57, 95% confidence interval(CI): 14.31-30.84] vs MSS [8.031(95%CI: 4.698-11.36)], P = 0.0076 and MSI-H:BRAF wild type [16.18(95%CI: 10.44-21.93)] vs MSS [8.031(95%CI: 4.698-11.36)], P = 0.0279. There was no statistically significant difference in CD8 T cells(both CD8+CD103-and CD8+CD103+T_(RM)) between MSI-H: BRAF mutant and wild type CRC.CONCLUSION This study has shown that CD8+ T_(RM) are found in greater abundance in MSI-H CRC, both BRAF mutant and MSI-H:BRAF wild type, when compared with their MSS counterpart. CD8+ T_(RM) may play a role in the immunogenicity in MSI-H CRC(BRAF mutant and BRAF wild type). Further studies should focus on the potential immunogenic qualities of T_(RM) cells and investigate potential immunotherapeutic approaches to improve treatment and survival associated with CRC.展开更多
AIM To determine whether recent evidence-based United States polices on male circumcision(MC) apply to comparable Anglophone countries,Australia and New Zealand.METHODS Articles in 2005 through 2015 were retrieved fro...AIM To determine whether recent evidence-based United States polices on male circumcision(MC) apply to comparable Anglophone countries,Australia and New Zealand.METHODS Articles in 2005 through 2015 were retrieved from PubM ed using the keyword "circumcision" together with 36 relevant subtopics.A further PubM ed search was performed for articles published in 2016.Searches of the EMBASE and Cochrane databases did not yield additional citable articles.Articles were assessed for quality and those rated 2+ and above according to the Scottish Intercollegiate Grading System were studied further.The most relevant andrepresentative of the topic were included.Bibliographies were examined to retrieve further key references.Randomized controlled trials,recent high quality systematic reviews or meta-analyses(level 1++ or 1+ evidence) were prioritized for inclusion.A risk-benefit analysis of articles rated for quality was performed.For efficiency and reliability,recent randomized controlled trials,metaanalyses,high quality systematic reviews and large welldesigned studies were used if available.Internet searches were conducted for other relevant information,including policies and Australian data on claims under Medicare for MC.RESULTS Evidence-based policy statements by the American Academy of Pediatrics(AAP) and the Centers for Disease Control and Prevention(CDC) support infant and later age male circumcision(MC) as a desirable public health measure.Our systematic review of relevant literature over the past decade yielded 140 journal articles that met our inclusion criteria.Together,these showed that early infant MC confers immediate and lifelong benefits by protecting against urinary tract infections having potential adverse long-term renal effects,phimosis that causes difficult and painful erections and "ballooning" during urination,inflammatory skin conditions,inferior penile hygiene,candidiasis,various sexually transmissible infections in both sexes,genital ulcers,and penile,prostate and cervical cancer.Our risk-benefit analysis showed that benefits exceeded procedural risks,which are predominantly minor,by up to 200 to 1.We estimated that more than 1 in 2 uncircumcised males will experience an adverse foreskin-related medical condition over their lifetime.Wide-ranging evidence from surveys,physiological measurements,and the anatomical location of penile sensory receptors responsible for sexual sensation strongly and consistently suggested that MC has no detrimental effect on sexual function,sensitivity or pleasure.United States studies showed that early infant MC is cost saving.The evidence supporting early infant MC has further strengthened since the positive AAP and CDC reviews.CONCLUSION Affirmative MC policies are needed in Australia and New Zealand.Routine provision of accurate,unbiased education,and access in public hospitals,will maximize health and financial benefits.展开更多
The protein disulfide isomerases（PDIs）family has a central function in the folding of proteins synthetized through the secretory pathway.ERp57,also known as Grp58 or PDIA3,is one of the main studied members of this ...The protein disulfide isomerases（PDIs）family has a central function in the folding of proteins synthetized through the secretory pathway.ERp57,also known as Grp58 or PDIA3,is one of the main studied members of this family.展开更多
Toll-like receptors (TLRs) play a key role in B cell-mediated innate and adaptive immunity. It has been shown that interleukin 10 (IL-10)-producing regulatory B cells (B10 cells) can negatively regulate cellular immun...Toll-like receptors (TLRs) play a key role in B cell-mediated innate and adaptive immunity. It has been shown that interleukin 10 (IL-10)-producing regulatory B cells (B10 cells) can negatively regulate cellular immune responses and inflammation in autoimmune diseases. In this study, we determined the effect of TLR4 signaling on the CD40-activated B10 cell competency. The results demonstrated that LPS and CD40L synergistically stimulated proliferation of mouse splenocytes. The percentage of B10 cells in cultured splenocytes was significantly increased after CD40L stimulation but such increase was diminished by the addition of LPS. Such effects by LPS were only observed in cells from WT but not TLR4−/−mice. IL-10 mRNA expression and protein production in B10 cells from cultured splenocytes were significantly up-regulated by CD40L stimulation but were inhibited after the addition of LPS in a TLR4-dependent manner. This study suggests that LPS-induced TLR4 signaling attenuate CD40L-activated regulatory B10 cell competency.展开更多
Although the transcription factor, nudear factor-κB （NF-κB） is known to regulate cell death and survival, its precise role in cell death within the central nervous system （CNS） remains unknown. We previously rep...Although the transcription factor, nudear factor-κB （NF-κB） is known to regulate cell death and survival, its precise role in cell death within the central nervous system （CNS） remains unknown. We previously reported that mice with a homozygous deficiency for NF-κBp50 spon- taneously developed optic neuropathy. We examined the expression and activation of pro-apoptotic factor（s） that mediate optic neuropathy in p50-/- mice. Recombination activating gene 1 （Ragl） is known to regulate the recombination of immunoglobulin V（D）J.展开更多
Human uterine leiomyosarcoma (LMS) develops more often in the muscle tissue layer of the uterine body than in the uterine cervix. The development of gynecologic tumors is often correlated with female hormone secretion...Human uterine leiomyosarcoma (LMS) develops more often in the muscle tissue layer of the uterine body than in the uterine cervix. The development of gynecologic tumors is often correlated with female hormone secretion;however, the development of uterine LMS is not substantially correlated with hormonal conditions, and the risk factors are not yet known. Importantly, a diagnostic-biomarker, which distinguishes malignant uterine LMS from benign tumor leiomyoma (LMA), is yet to be established. Accordingly, it is necessary to analyze risk factors associated with uterine LMS, to establish a clinical treatment method. Protea some β-ring subunit LMP2/β1i-deficient mice spontaneously develop uterine LMS, with a disease prevalence of ~40% by 14 months of age. We found LMP2/β1i expression to be absent in human uterine LMS, but present in human LMA. Therefore, defective-LMP2/β1i expression may be one of the risk factors for human uterine LMS. LMP2/β1i is a potential diagnostic-biomarker under the combination of candidate molecules, for instance cyclin B1, cyclin E and calponin h1 and ki-67/MIB1 counts for uterine mesenchymal tumors, especially human uterine LMS, and may be a targeted-molecule for a new therapeutic approach.展开更多
Background: Antibiotics are a key part of modern healthcare,but their use has downsides,including selecting for antibiotic resistance,both in the individuals treated with antibiotics and in the community at large.When...Background: Antibiotics are a key part of modern healthcare,but their use has downsides,including selecting for antibiotic resistance,both in the individuals treated with antibiotics and in the community at large.When evaluating the benefits and costs of mass administration of azithromycin to reduce childhood mortality,effects of antibiotic use on antibiotic resistance are important but difficult to measure,especially when evaluating resistance that“spills over”from antibiotic-treated individuals to other members of their community.The aim of this scoping review was to identify how the existing literature on antibiotic resistance modeling could be better leveraged to understand the effect of mass drug administration(MDA)on antibiotic resistance.Main text: Mathematical models of antibiotic use and resistance may be useful for estimating the expected effects of different MDA implementations on different populations,as well as aiding interpretation of existing data and guiding future experimental design.Here,strengths and limitations of models of antibiotic resistance are reviewed,and possible applications of those models in the context of mass drug administration with azithromycin are discussed.Conclusions: Statistical models of antibiotic use and resistance may provide robust and relevant estimates of the possible effects of MDA on resistance.Mechanistic models of resistance,while able to more precisely estimate the effects of different implementations of MDA on resistance,may require more data from MDA trials to be accurately parameterized.展开更多
Systemic lupus erythematosus(SLE)is a systemic autoimmune disease characterized by extraordinary heterogeneity,due to the complex pathogenesis and diverse manifestations.Stratification of patients for therapy and prog...Systemic lupus erythematosus(SLE)is a systemic autoimmune disease characterized by extraordinary heterogeneity,due to the complex pathogenesis and diverse manifestations.Stratification of patients for therapy and prognosis represents a major challenge to manage SLE.Conventional biomarkers for disease diagnosis and activity assessment provide very limited insight into immunological pathogenesis and therapeutic response rates.The advancement of“omics”technologies including genomics,transcriptomics,proteomics,and metabolomics has constituted an unprecedented opportunity to characterize the immunopathological landscape in individual patients with SLE.Indeed,genomic studies reveal a subset of SLE patients carrying one or more functional single nucleotide polymorphisms(SNPs)underlying immune dysregulation while transcriptomic studies have revealed subgroups in SLE patients showing distinct signatures for Type I interferon(TI-IFN)pathway activation or aberrant differentiation of B cells into plasma cells.This review will summarize results from the latest studies using omics technology to understand SLE heterogeneity.In addition,we propose that the application of artificial intelligence,such as by machine learning-based nonlinear dimensionality reduction method uniform manifold approximation and projection(UMAP)can further strengthen the analysis of omics big data.The combination of new technology and novel analysis pipeline can lead to breakthroughs in stratifying SLE patients for a better monitoring of disease activity and more precise design of treatment regime,not only for conventional immunosuppression but also novel immunotherapies targeting B-cell activating factor(BAFF),TI-IFN,and interleukin 2(IL-2).展开更多
The discovery and utilization of RNA-guided surveillance complexes,such as CRISPR-Cas9,for sequencespecific DNA or RNA cleavage,has revolutionised the process of gene modification or knockdown.To optimise the use of t...The discovery and utilization of RNA-guided surveillance complexes,such as CRISPR-Cas9,for sequencespecific DNA or RNA cleavage,has revolutionised the process of gene modification or knockdown.To optimise the use of this technology,an exploratory race has ensued to discover or develop new RNA-guided endonucleases with the most flexible sequence targeting requirements,coupled with high cleavage efficacy and specificity.Here we review the constraints of existing gene editing and assess the merits of exploiting the diversity of CRISPR-Cas effectors as a methodology for surmounting these limitations.展开更多
Peripheral neuropathies refer to a group of conditions in which the peripheral nervous system(PNS)is damaged.These pathological state are are associated with weakness,pain,and loss of motor and sensory control.More th...Peripheral neuropathies refer to a group of conditions in which the peripheral nervous system(PNS)is damaged.These pathological state are are associated with weakness,pain,and loss of motor and sensory control.More than 100 types of peripheral neuropathies have been identified,with distinct symptoms and prognosis classified according to the type of damage to the nerves.Injury to peripheral nerves results in disabling loss of sensory and motor func-展开更多
To study the epidemiology of early onset neonatal bacterial meningitis (EONBM) in Australasia. Design: Prospective surveillance study, 1992- 2002, in 20 neonatal units in Australia and New Zealand. EONBM was defined a...To study the epidemiology of early onset neonatal bacterial meningitis (EONBM) in Australasia. Design: Prospective surveillance study, 1992- 2002, in 20 neonatal units in Australia and New Zealand. EONBM was defined as meningitis occurring within 48 hours of delivery. Results: There were 852 babies with early onset sepsis, of whom 78 (9.2% ) had EONBM. The incidence of early onset group B streptococcal meningitis fell significantly froma peak of 0.24/1000 live births in 1993 to 0.03/1000 in 2002 (p trend = 0.002). There was no significant change over time in the incidence of Escherichia coli meningitis. The rate of EONBM in very low birthweight babies was 1.09/1000 compared with the rate in all infants of 0.11/1000. The overall rate of EONBM was 0.41/1000 in 1992 and 0.06 in 2001, but this trend was not significant (p trend = 0.07). Case-fatality rates for EO-NBM did not change signifi cantly with time. Birth weight < 1500 g (odds ratio (OR) 7.2 (95% confidence interval (CI) 4.8 to 10.9)) and Gram negative bacillary meningitis (OR 3.3 (95% CI 2.2 to 4.9)) were significant risk factors for mortality. Sixty two percent of the 129 babies who died from early onset sepsis or suspected sepsis did not have a lumbar puncture performed. Conclusion: The incidence of early onset group B streptococcal meningitis has fallen, probably because of maternal intrapartum antibiotic prophylaxis, without a corresponding change in E coli meningitis. Gram negative bacillary meningitis still carries a worse prognosis than meningitis with a Gram positive organism.展开更多
Context: Postnatal transmission of human immunodeficiency virus-1 (HIV) via breastfeeding reverses gains achieved by perinatal antiretroviral interventions. Objective: To compare the efficacy and safety of 2 infant fe...Context: Postnatal transmission of human immunodeficiency virus-1 (HIV) via breastfeeding reverses gains achieved by perinatal antiretroviral interventions. Objective: To compare the efficacy and safety of 2 infant feeding strategies for the prevention of postnatal mother-to-child HIV transmission. Design, Setting, and Patients: A 2×2 factorial randomized clinical trial with peripartum (single-dose nevirapine vs placebo) and postpartum infant feeding (formula vs breastfeeding with infant zidovudine prophylaxis) interventions. In Botswana between March 27, 2001, and October 29, 2003, 1200 HIV-positive pregnant women were randomized from 4 district hospitals. Infants were evaluated at birth, monthly until age 7 months, at age 9 months, then every third month through age 18 months. Intervention: All of the mothers received zidovudine 300 mg orally twice daily from 34 weeksgestation and during labor. Mothers and infants were randomized to receive single-dose nevirapine or placebo. Infants were randomized to 6 months of breastfeeding plus prophylactic infant zidovudine (breastfed plus zidovudine), or formula feeding plus 1 month of infant zidovudine (formula fed). Main Outcome Measures: Primary efficacy (HIV infection by age 7 months and HIV-free survival by age 18 months) and safety (occurrence of infant adverse events by 7 months of age) end points were evaluated in 1179 infants. Results: The 7-month HIV infection rates were 5.6%(32 infants in the formula-fed group) vs 9.0%(51 infants in the breastfed plus zidovudine group) (P=.04; 95%confidence interval for difference,-6.4%to-0.4%). Cumulative mortality or HIV infection rates at 18 months were 80 infants (13.9%, formula fed)-vs 86 infants (15.1%breastfed plus zidovudine) (P=.60; 95%confidence interval for difference,-5.3%to 2.9%). Cumulative infant mortality at 7 months was significantly higher for the formulafed group than for the breastfed plus zidovudine group (9.3%vs 4.9%; P=.003), but this difference diminished beyond month 7 such that the time-to-mortality distributions through age 18 months were not significantly different (P=.21). Conclusions: Breastfeeding with zidovudine prophylaxis was not as effective as formula feeding in preventing postnatal HIV transmission, but was associated with a lower mortality rate at 7 months. Both strategies had comparable HIV-free survival at 18 months. These results demonstrate the risk of formula feeding to infants in sub-Saharan Africa, and the need for studies of alternative strategies. Trial Registration: clinical trials. gov Identifier:展开更多
Background:Systemic lupus erythematosus(SLE)is a complex systemic autoimmune disease characterized by development of autoantibodies and multiorgan involvement.Kidney involvement,termed lupus nephritis,has major impact...Background:Systemic lupus erythematosus(SLE)is a complex systemic autoimmune disease characterized by development of autoantibodies and multiorgan involvement.Kidney involvement,termed lupus nephritis,has major impact on life expectancy.It is increasingly recognized that SLE is likely a common clinical manifestation of pathophysiologically diverse processes,and lupus nephritis has similarly been associated with several distinct immunological processes.We compared the immune cell phenotypes of individuals with SLE in the presence or absence of nephritis.Methods:Cryopreserved peripheral blood mononuclear cells from SLE patients with and without kidney involvement underwent flow cytometric analysis to identify major populations in T cells,B cells and myeloid lineages.Results:We compared the frequencies of lymphocyte populations in 69 SLE patients without nephritis,20 SLE patients with nephritis,and 92 healthy blood donors.Patients with SLE and lupus nephritis(LN)had reduced marginal zone B cells(P<0.0001 in SLE;P=0.001 in LN),memory B cells(P=0.002 in SLE;P=0.001 in LN)and circulating T follicular helper(Tfh)memory cells(P<0.0001 in SLE and LN)compared to healthy donors.Patients with lupus nephritis had increase Th2(P<0.0001)and T regulatory cells(P<0.0001)compared to both SLE patients without nephritis and healthy donors.Conclusion:SLE patients with and without lupus nephritis have distinct immunologic differences that may reflect the unique pathophysiological processes contributing to disease manifestations.展开更多
Uterine tumors are the most common type of gynecologic neoplasm.Uterine leiomyosarcoma(LMS)is rare,accounting for 2%to 5%of tumors of the uterine body.Uterine LMS develops more often in the muscle tissue layer of the ...Uterine tumors are the most common type of gynecologic neoplasm.Uterine leiomyosarcoma(LMS)is rare,accounting for 2%to 5%of tumors of the uterine body.Uterine LMS develops more often in the muscle tissue layer of the uterine body than in the uterine cervix.The development of gynecologic tumors is often correlated with female hormone secretion;however,the development of uterine LMS is not substantially correlated with hormonal conditions,and the risk factors are not yet known.Radiographic evaluation combined with PET/CT can be useless in the diagnosis and surveillance of uterine LMS.Importantly,a diagnostic biomarker,which distinguishes malignant LMS and benign tumor leiomyoma(LMA)is yet to be established.Accordingly,it is necessary to analyze risk factors associated with uterine LMS in order to establish a method of treatment.LMP2-deficient mice spontaneously develop uterine LMS,with a disease prevalence of~40%by 14 months of age.It is therefore of interest whether human uterine LMS shows a loss of LMP2 expression.We found LMP2 expression is absent in human LMS,but present in human LMA.Therefore,defective LMP2 expression may be one of the risk factors for LMS.LMP2 is potentially a diagnostic biomarker for uterine LMS,and gene therapy with LMP2-encording DNA may be a new therapeutic approach.展开更多
文摘Although the identification of B cell subsets with negative regulatory functions and the definition of their mechanisms of action are recent events, the important negative regulatory roles of B cells in immune responses are now broadly recognized. There is an emerging appreciation for the pivotal role played by B cells in several areas of human diseases including autoimmune diseases and non-autoimmune diseases such as parasite infections and cancer. The recent research advancement of regulatory B cells in human disease coincides with the vastly accelerated pace of research on the bridging of innate and adaptive immune system. Current study and our continued research may provide better understanding of the mechanisms that promote regulatory B10 cell function to counteract exaggerated immune activation in autoimmune as well as non-autoimmune conditions. This review is focused on the current knowledge of BREG functions studied in animal models of autoimmune and non-autoimmune diseases.
文摘Medical journals and scientific journals in general,have been our community’s way of reporting scientific findings for the past three-hundred years.During this time,they have been in continuous evolution,undergoing many changes,with the aim to better and more efficiently communicate research to other specialists and thewider public.Here,the hLife’s co-Editor-in-Chief Dr.Chen Dong speaks with Dr.Eric Rubin and Dr.Rui-Ping Xiao from The New England Journal of Medicine(NJEM)on the history and development of medical journals,a dialogue which took place immediately following the launch ceremony of hLife.They reflect on how reporting of medical discoveries has changed over time,the future medical challenges that society faces and how journals can address these issues,and they also give their views on how new technologies,including the use of artificial intelligence(AI),will be incorporated into the medical research and publishing.
文摘Monocytes are effector immune cells but a precise anal-ysis of their role in immune response has been preclud-ed by their heterogeneity. Indeed, human monocytesare composed of at least three different subsets withdifferent phenotypic characteristics and functional prop-erties, the so-called classical, intermediate and non-classical monocytes. A review of the literature showsthat these monocyte subsets are differently affectedduring viral, bacterial, parasitic and fungal infections.The expansion of the CD16＋ compartment （intermedi-ate and non-classical monocytes） is typically observedin the majority of infectious diseases and the increasedproportion of CD16＋ monocytes is likely related totheir activation through their direct interaction with thepathogen or the infammatory context. In contrast, thenumber of non-classical and intermediate monocytesis decreased in Q fever endocarditis, suggesting thatcomplex mechanisms govern the equilibrium among monocyte subsets. The measurement of monocyte sub-sets would be useful in better understanding of the role of monocyte activation in the pathophysiology of infec-tious diseases.
基金Supported by The Scientific Research Projects from the Development and Reform Commission of Hunan Province,China,No.2011(1318),No.2012(1493)and No.2013(1132)
文摘Nuclear erythroid 2-related factor 2(Nrf2) is a central regulator of antioxidative response elements-mediated gene expression. It has a significant role in adaptive responses to oxidative stress by interacting with the antioxidant response element, which induces the expression of a variety of downstream targets aimed at cytoprotection. Previous studies suggested oxidative stress and associated damage could represent a common link between different forms of diseases. Oxidative stress has been implicated in various liver diseases, including viral hepatitis, nonalcoholic fatty liver disease/steatohepatitis, alcoholic liver disease and drug-induced liver injury. Nrf2 activation is initiated by oxidative or electrophilic stress, and aids in the detoxification and elimination of potentially harmful exogenous chemicals and their metabolites. The expression of Nrf2 has been observed throughout human tissue, with high expression in detoxification organs, especially the liver. Thus, Nrf2 may serve as a major regulator of several cellular defense associated pathways by which hepatic cells combat oxidative stress. We review the relevant literature concerning the crucial role of Nrf2 and its signaling pathways against oxidative stress to protect hepatic cell from oxidative damage during development of common chronic liver diseases. We also review the use of Nrf2 as a therapeutic target to prevent and treat liver diseases.
基金supported by the National Institute of Dental and Craniofacial Research(NIDCR)the National Center for Research Resources(NCRR)of the National Institutes of Health(NIH)under award numbers R21DE023178,R01DE024796,and S10RR027553
文摘Hypoxia（low oxygen level） is an important feature during infections and affects the host defence mechanisms. The host has evolved specific responses to address hypoxia, which are strongly dependent on the activation of hypoxia-inducible factor 1（HIF-1）.Hypoxia interferes degradation of HIF-1 alpha subunit（HIF-1α）, leading to stabilisation of HIF-1α, heterodimerization with HIF-1 beta subunit（HIF-1β） and subsequent activation of HIF-1 pathway. Apical periodontitis（periapical lesion） is a consequence of endodontic infection and ultimately results in destruction of tooth-supporting tissue, including alveolar bone. Thus far, the role of HIF-1 in periapical lesions has not been systematically examined. In the present study, we determined the role of HIF-1 in a wellcharacterised mouse periapical lesion model using two HIF-1α-activating strategies, dimethyloxalylglycine（DMOG） and adenovirusinduced constitutively active HIF-1α（CA-HIF1 A）. Both DMOG and CA-HIF1 A attenuated periapical inflammation and tissue destruction. The attenuation in vivo was associated with downregulation of nuclear factor-κappa B（NF-κB） and osteoclastic gene expressions. These two agents also suppressed NF-κB activation and subsequent production of proinflammatory cytokines by macrophages. Furthermore, activation of HIF-1α by DMOG specifically suppressed lipopolysaccharide-stimulated macrophage differentiation into M1 cells, increasing the ratio of M2 macrophages against M1 cells. Taken together, our data indicated that activation of HIF-1 plays a protective role in the development of apical periodontitis via downregulation of NF-κB, proinflammatory cytokines, M1 macrophages and osteoclastogenesis.
基金supported by FONDECYT-11140738 (G.M.).Michael J. Fox Foundation for Parkinson Research, Ring Initiative ACT1109+1 种基金FONDEF D11I1007 (C.H.). We also thank, FONDECYT-1140549Millennium Institute P09-015-F, COPEC-UC, and Frick Foundation (C.H.). V.C. is supported by CONICYT fellowship
文摘Parkinson’s disease（PD）is the second most common neurodegenerative disease affecting 1%of the population over 60 years of age.The progressive degeneration of dopaminergic neurons at the substantia nigra pars compacta（SNpc）results in a severe and gradual depletion of dopamine content in the striatum,a phenomena that is responsible for the characteristic motor symptoms of this disease.
文摘BACKGROUND Recent studies in non-colorectal malignancy have associated T resident memory(T_(RM)) cells with improved patient survival. It is unknown if T_(RM) plays a role in colorectal cancer(CRC).AIM To examine the potential role of T_(RM) cells in providing immunogenicity in CRC stratified by microsatellite instability(MSI) and BRAF status.METHODS Patients with known MSI and BRAF mutation status were eligible for inclusion in this study. CRC tumour sections stained with haematoxylin and eosin were microscopically reviewed and the images scanned prior to assessment for location of invading edge and core of tumour. Sequential sections were prepared for quantitative multiplex immunohistochemistry(IHC) staining. Opal Multiplex IHC staining was performed with appropriate positive and negative controls and imaged using a standard fluorescent microscope fitted with a spectral scanning camera(Mantra) in conjunction with Mantra snap software. Images were unmixed and annotated in in Form 2.2.0. Statistical analysis was performed using Graphpad Prism Version 7 and Stata Version 15.RESULTS Seventy-two patients with known MSI and BRAF status were included in the study. All patients were assessed for MSI by IHC and high resolution capillary electrophoresis testing and 44 of these patients successfully underwent quantitative multiplex IHC staining. Overall, there was a statistically significant increase in CD8+ T_(RM) cells in the MSI(BRAF mutant and wild type) group over the microsatellite stable(MSS) group. There was a statistically significant difference in CD8+ T_(RM) between high level MSI(MSI-H):BRAF mutant [22.57, 95% confidence interval(CI): 14.31-30.84] vs MSS [8.031(95%CI: 4.698-11.36)], P = 0.0076 and MSI-H:BRAF wild type [16.18(95%CI: 10.44-21.93)] vs MSS [8.031(95%CI: 4.698-11.36)], P = 0.0279. There was no statistically significant difference in CD8 T cells(both CD8+CD103-and CD8+CD103+T_(RM)) between MSI-H: BRAF mutant and wild type CRC.CONCLUSION This study has shown that CD8+ T_(RM) are found in greater abundance in MSI-H CRC, both BRAF mutant and MSI-H:BRAF wild type, when compared with their MSS counterpart. CD8+ T_(RM) may play a role in the immunogenicity in MSI-H CRC(BRAF mutant and BRAF wild type). Further studies should focus on the potential immunogenic qualities of T_(RM) cells and investigate potential immunotherapeutic approaches to improve treatment and survival associated with CRC.
文摘AIM To determine whether recent evidence-based United States polices on male circumcision(MC) apply to comparable Anglophone countries,Australia and New Zealand.METHODS Articles in 2005 through 2015 were retrieved from PubM ed using the keyword "circumcision" together with 36 relevant subtopics.A further PubM ed search was performed for articles published in 2016.Searches of the EMBASE and Cochrane databases did not yield additional citable articles.Articles were assessed for quality and those rated 2+ and above according to the Scottish Intercollegiate Grading System were studied further.The most relevant andrepresentative of the topic were included.Bibliographies were examined to retrieve further key references.Randomized controlled trials,recent high quality systematic reviews or meta-analyses(level 1++ or 1+ evidence) were prioritized for inclusion.A risk-benefit analysis of articles rated for quality was performed.For efficiency and reliability,recent randomized controlled trials,metaanalyses,high quality systematic reviews and large welldesigned studies were used if available.Internet searches were conducted for other relevant information,including policies and Australian data on claims under Medicare for MC.RESULTS Evidence-based policy statements by the American Academy of Pediatrics(AAP) and the Centers for Disease Control and Prevention(CDC) support infant and later age male circumcision(MC) as a desirable public health measure.Our systematic review of relevant literature over the past decade yielded 140 journal articles that met our inclusion criteria.Together,these showed that early infant MC confers immediate and lifelong benefits by protecting against urinary tract infections having potential adverse long-term renal effects,phimosis that causes difficult and painful erections and "ballooning" during urination,inflammatory skin conditions,inferior penile hygiene,candidiasis,various sexually transmissible infections in both sexes,genital ulcers,and penile,prostate and cervical cancer.Our risk-benefit analysis showed that benefits exceeded procedural risks,which are predominantly minor,by up to 200 to 1.We estimated that more than 1 in 2 uncircumcised males will experience an adverse foreskin-related medical condition over their lifetime.Wide-ranging evidence from surveys,physiological measurements,and the anatomical location of penile sensory receptors responsible for sexual sensation strongly and consistently suggested that MC has no detrimental effect on sexual function,sensitivity or pleasure.United States studies showed that early infant MC is cost saving.The evidence supporting early infant MC has further strengthened since the positive AAP and CDC reviews.CONCLUSION Affirmative MC policies are needed in Australia and New Zealand.Routine provision of accurate,unbiased education,and access in public hospitals,will maximize health and financial benefits.
基金FONDECYT 1161284(SM),Millennium Institute No.P09-015-F,Fondo de Financiamiento de Centros de Investigación enáreas Prioritarias(FONDAP)15150012(CHSM)+3 种基金the Frick Foundation No.20014-15,ALS Therapy Alliance 2014-F-059,Muscular Dystrophy Association 382453,Comisión Nacional de Investigación Científica y Tecnológica(CONICYT)CONICYTUSA2013-0003the Michael J.Fox Foundation for Parkinson’s Research No.9277,Fundación Copec–Universidad Católica No.2013.R.40,Ecos-Conicyt C13S02,FONDECYT 1140549,Office of Naval Research–Global(ONR-G)N62909-16-1-2003Amyotrophic Lateral Sclerosis Research Program Therapeutic Idea Award AL150111(C.H.)LB is supported by a CONICYT fellowship
文摘The protein disulfide isomerases（PDIs）family has a central function in the folding of proteins synthetized through the secretory pathway.ERp57,also known as Grp58 or PDIA3,is one of the main studied members of this family.
文摘Toll-like receptors (TLRs) play a key role in B cell-mediated innate and adaptive immunity. It has been shown that interleukin 10 (IL-10)-producing regulatory B cells (B10 cells) can negatively regulate cellular immune responses and inflammation in autoimmune diseases. In this study, we determined the effect of TLR4 signaling on the CD40-activated B10 cell competency. The results demonstrated that LPS and CD40L synergistically stimulated proliferation of mouse splenocytes. The percentage of B10 cells in cultured splenocytes was significantly increased after CD40L stimulation but such increase was diminished by the addition of LPS. Such effects by LPS were only observed in cells from WT but not TLR4−/−mice. IL-10 mRNA expression and protein production in B10 cells from cultured splenocytes were significantly up-regulated by CD40L stimulation but were inhibited after the addition of LPS in a TLR4-dependent manner. This study suggests that LPS-induced TLR4 signaling attenuate CD40L-activated regulatory B10 cell competency.
文摘Although the transcription factor, nudear factor-κB （NF-κB） is known to regulate cell death and survival, its precise role in cell death within the central nervous system （CNS） remains unknown. We previously reported that mice with a homozygous deficiency for NF-κBp50 spon- taneously developed optic neuropathy. We examined the expression and activation of pro-apoptotic factor（s） that mediate optic neuropathy in p50-/- mice. Recombination activating gene 1 （Ragl） is known to regulate the recombination of immunoglobulin V（D）J.
文摘Human uterine leiomyosarcoma (LMS) develops more often in the muscle tissue layer of the uterine body than in the uterine cervix. The development of gynecologic tumors is often correlated with female hormone secretion;however, the development of uterine LMS is not substantially correlated with hormonal conditions, and the risk factors are not yet known. Importantly, a diagnostic-biomarker, which distinguishes malignant uterine LMS from benign tumor leiomyoma (LMA), is yet to be established. Accordingly, it is necessary to analyze risk factors associated with uterine LMS, to establish a clinical treatment method. Protea some β-ring subunit LMP2/β1i-deficient mice spontaneously develop uterine LMS, with a disease prevalence of ~40% by 14 months of age. We found LMP2/β1i expression to be absent in human uterine LMS, but present in human LMA. Therefore, defective-LMP2/β1i expression may be one of the risk factors for human uterine LMS. LMP2/β1i is a potential diagnostic-biomarker under the combination of candidate molecules, for instance cyclin B1, cyclin E and calponin h1 and ki-67/MIB1 counts for uterine mesenchymal tumors, especially human uterine LMS, and may be a targeted-molecule for a new therapeutic approach.
文摘Background: Antibiotics are a key part of modern healthcare,but their use has downsides,including selecting for antibiotic resistance,both in the individuals treated with antibiotics and in the community at large.When evaluating the benefits and costs of mass administration of azithromycin to reduce childhood mortality,effects of antibiotic use on antibiotic resistance are important but difficult to measure,especially when evaluating resistance that“spills over”from antibiotic-treated individuals to other members of their community.The aim of this scoping review was to identify how the existing literature on antibiotic resistance modeling could be better leveraged to understand the effect of mass drug administration(MDA)on antibiotic resistance.Main text: Mathematical models of antibiotic use and resistance may be useful for estimating the expected effects of different MDA implementations on different populations,as well as aiding interpretation of existing data and guiding future experimental design.Here,strengths and limitations of models of antibiotic resistance are reviewed,and possible applications of those models in the context of mass drug administration with azithromycin are discussed.Conclusions: Statistical models of antibiotic use and resistance may provide robust and relevant estimates of the possible effects of MDA on resistance.Mechanistic models of resistance,while able to more precisely estimate the effects of different implementations of MDA on resistance,may require more data from MDA trials to be accurately parameterized.
基金Bellberry Limited and The Viertel Charitable Foundation,Grant/Award Number:Bellberry Limited and The Viertel Charitable Foundation。
文摘Systemic lupus erythematosus(SLE)is a systemic autoimmune disease characterized by extraordinary heterogeneity,due to the complex pathogenesis and diverse manifestations.Stratification of patients for therapy and prognosis represents a major challenge to manage SLE.Conventional biomarkers for disease diagnosis and activity assessment provide very limited insight into immunological pathogenesis and therapeutic response rates.The advancement of“omics”technologies including genomics,transcriptomics,proteomics,and metabolomics has constituted an unprecedented opportunity to characterize the immunopathological landscape in individual patients with SLE.Indeed,genomic studies reveal a subset of SLE patients carrying one or more functional single nucleotide polymorphisms(SNPs)underlying immune dysregulation while transcriptomic studies have revealed subgroups in SLE patients showing distinct signatures for Type I interferon(TI-IFN)pathway activation or aberrant differentiation of B cells into plasma cells.This review will summarize results from the latest studies using omics technology to understand SLE heterogeneity.In addition,we propose that the application of artificial intelligence,such as by machine learning-based nonlinear dimensionality reduction method uniform manifold approximation and projection(UMAP)can further strengthen the analysis of omics big data.The combination of new technology and novel analysis pipeline can lead to breakthroughs in stratifying SLE patients for a better monitoring of disease activity and more precise design of treatment regime,not only for conventional immunosuppression but also novel immunotherapies targeting B-cell activating factor(BAFF),TI-IFN,and interleukin 2(IL-2).
基金the National Health and Medical Research Council of Australia(Grant No.APP1143008)the Australian Research Council(Grant No.DP180101494)the National Natural Science Foundation of China(Grant No.81772214).
文摘The discovery and utilization of RNA-guided surveillance complexes,such as CRISPR-Cas9,for sequencespecific DNA or RNA cleavage,has revolutionised the process of gene modification or knockdown.To optimise the use of this technology,an exploratory race has ensued to discover or develop new RNA-guided endonucleases with the most flexible sequence targeting requirements,coupled with high cleavage efficacy and specificity.Here we review the constraints of existing gene editing and assess the merits of exploiting the diversity of CRISPR-Cas effectors as a methodology for surmounting these limitations.
基金funded by FONDAP program 15150012(to CH and FAC)Millennium Institute,No.P09-015-F+12 种基金the Frick Foundation 20014-15ALS Therapy Alliance 2014-F-059Muscular Dystrophy Association 382453CONICYT-USA 2013-0003Michael J Fox Foundation for Parkinson′s Research–Target Validation grant No.9277COPEC-UC Foundation 2013.R.40Ecos-Conicyt C13S02FONDECYT No.1140549Office of Naval Research-Global(ONR-G)N62909-16-1-2003ALSRP Therapeutic Idea Award AL150111(to CH)Millennium Nucleus-P-07-011-FFONDECYT,No.1110987(to FAC)PhD fellow supported by CONICYT,No.21130843(to MO)
文摘Peripheral neuropathies refer to a group of conditions in which the peripheral nervous system(PNS)is damaged.These pathological state are are associated with weakness,pain,and loss of motor and sensory control.More than 100 types of peripheral neuropathies have been identified,with distinct symptoms and prognosis classified according to the type of damage to the nerves.Injury to peripheral nerves results in disabling loss of sensory and motor func-
文摘To study the epidemiology of early onset neonatal bacterial meningitis (EONBM) in Australasia. Design: Prospective surveillance study, 1992- 2002, in 20 neonatal units in Australia and New Zealand. EONBM was defined as meningitis occurring within 48 hours of delivery. Results: There were 852 babies with early onset sepsis, of whom 78 (9.2% ) had EONBM. The incidence of early onset group B streptococcal meningitis fell significantly froma peak of 0.24/1000 live births in 1993 to 0.03/1000 in 2002 (p trend = 0.002). There was no significant change over time in the incidence of Escherichia coli meningitis. The rate of EONBM in very low birthweight babies was 1.09/1000 compared with the rate in all infants of 0.11/1000. The overall rate of EONBM was 0.41/1000 in 1992 and 0.06 in 2001, but this trend was not significant (p trend = 0.07). Case-fatality rates for EO-NBM did not change signifi cantly with time. Birth weight < 1500 g (odds ratio (OR) 7.2 (95% confidence interval (CI) 4.8 to 10.9)) and Gram negative bacillary meningitis (OR 3.3 (95% CI 2.2 to 4.9)) were significant risk factors for mortality. Sixty two percent of the 129 babies who died from early onset sepsis or suspected sepsis did not have a lumbar puncture performed. Conclusion: The incidence of early onset group B streptococcal meningitis has fallen, probably because of maternal intrapartum antibiotic prophylaxis, without a corresponding change in E coli meningitis. Gram negative bacillary meningitis still carries a worse prognosis than meningitis with a Gram positive organism.
文摘Context: Postnatal transmission of human immunodeficiency virus-1 (HIV) via breastfeeding reverses gains achieved by perinatal antiretroviral interventions. Objective: To compare the efficacy and safety of 2 infant feeding strategies for the prevention of postnatal mother-to-child HIV transmission. Design, Setting, and Patients: A 2×2 factorial randomized clinical trial with peripartum (single-dose nevirapine vs placebo) and postpartum infant feeding (formula vs breastfeeding with infant zidovudine prophylaxis) interventions. In Botswana between March 27, 2001, and October 29, 2003, 1200 HIV-positive pregnant women were randomized from 4 district hospitals. Infants were evaluated at birth, monthly until age 7 months, at age 9 months, then every third month through age 18 months. Intervention: All of the mothers received zidovudine 300 mg orally twice daily from 34 weeksgestation and during labor. Mothers and infants were randomized to receive single-dose nevirapine or placebo. Infants were randomized to 6 months of breastfeeding plus prophylactic infant zidovudine (breastfed plus zidovudine), or formula feeding plus 1 month of infant zidovudine (formula fed). Main Outcome Measures: Primary efficacy (HIV infection by age 7 months and HIV-free survival by age 18 months) and safety (occurrence of infant adverse events by 7 months of age) end points were evaluated in 1179 infants. Results: The 7-month HIV infection rates were 5.6%(32 infants in the formula-fed group) vs 9.0%(51 infants in the breastfed plus zidovudine group) (P=.04; 95%confidence interval for difference,-6.4%to-0.4%). Cumulative mortality or HIV infection rates at 18 months were 80 infants (13.9%, formula fed)-vs 86 infants (15.1%breastfed plus zidovudine) (P=.60; 95%confidence interval for difference,-5.3%to 2.9%). Cumulative infant mortality at 7 months was significantly higher for the formulafed group than for the breastfed plus zidovudine group (9.3%vs 4.9%; P=.003), but this difference diminished beyond month 7 such that the time-to-mortality distributions through age 18 months were not significantly different (P=.21). Conclusions: Breastfeeding with zidovudine prophylaxis was not as effective as formula feeding in preventing postnatal HIV transmission, but was associated with a lower mortality rate at 7 months. Both strategies had comparable HIV-free survival at 18 months. These results demonstrate the risk of formula feeding to infants in sub-Saharan Africa, and the need for studies of alternative strategies. Trial Registration: clinical trials. gov Identifier:
基金The Canberra Hospital Private Practice FundNational Health and Medical Research CouncilThe Jacquot Foundation。
文摘Background:Systemic lupus erythematosus(SLE)is a complex systemic autoimmune disease characterized by development of autoantibodies and multiorgan involvement.Kidney involvement,termed lupus nephritis,has major impact on life expectancy.It is increasingly recognized that SLE is likely a common clinical manifestation of pathophysiologically diverse processes,and lupus nephritis has similarly been associated with several distinct immunological processes.We compared the immune cell phenotypes of individuals with SLE in the presence or absence of nephritis.Methods:Cryopreserved peripheral blood mononuclear cells from SLE patients with and without kidney involvement underwent flow cytometric analysis to identify major populations in T cells,B cells and myeloid lineages.Results:We compared the frequencies of lymphocyte populations in 69 SLE patients without nephritis,20 SLE patients with nephritis,and 92 healthy blood donors.Patients with SLE and lupus nephritis(LN)had reduced marginal zone B cells(P<0.0001 in SLE;P=0.001 in LN),memory B cells(P=0.002 in SLE;P=0.001 in LN)and circulating T follicular helper(Tfh)memory cells(P<0.0001 in SLE and LN)compared to healthy donors.Patients with lupus nephritis had increase Th2(P<0.0001)and T regulatory cells(P<0.0001)compared to both SLE patients without nephritis and healthy donors.Conclusion:SLE patients with and without lupus nephritis have distinct immunologic differences that may reflect the unique pathophysiological processes contributing to disease manifestations.
基金supported in part by grants from the Ministry of Education,Culture,Science and Technology,and The Foundation of Osaka Cancer Research,The Ichiro Kanehara Foundation of the Promotion of Medical Science and Medical Care,Foundation for Promotion of Cancer Research,Kanzawa Medical Research Foundation,The Shinshu Medical Foundation,and Takeda Science Foundation.
文摘Uterine tumors are the most common type of gynecologic neoplasm.Uterine leiomyosarcoma(LMS)is rare,accounting for 2%to 5%of tumors of the uterine body.Uterine LMS develops more often in the muscle tissue layer of the uterine body than in the uterine cervix.The development of gynecologic tumors is often correlated with female hormone secretion;however,the development of uterine LMS is not substantially correlated with hormonal conditions,and the risk factors are not yet known.Radiographic evaluation combined with PET/CT can be useless in the diagnosis and surveillance of uterine LMS.Importantly,a diagnostic biomarker,which distinguishes malignant LMS and benign tumor leiomyoma(LMA)is yet to be established.Accordingly,it is necessary to analyze risk factors associated with uterine LMS in order to establish a method of treatment.LMP2-deficient mice spontaneously develop uterine LMS,with a disease prevalence of~40%by 14 months of age.It is therefore of interest whether human uterine LMS shows a loss of LMP2 expression.We found LMP2 expression is absent in human LMS,but present in human LMA.Therefore,defective LMP2 expression may be one of the risk factors for LMS.LMP2 is potentially a diagnostic biomarker for uterine LMS,and gene therapy with LMP2-encording DNA may be a new therapeutic approach.
