BACKGROUND Chronic intestinal pseudo-obstruction(CIPO)is a rare and debilitating disorder,characterized by severe impairments in gastrointestinal motility.The affected sites include the enteric/intrinsic autonomic ner...BACKGROUND Chronic intestinal pseudo-obstruction(CIPO)is a rare and debilitating disorder,characterized by severe impairments in gastrointestinal motility.The affected sites include the enteric/intrinsic autonomic nerves(neuropathy),intestinal smooth muscle cells(myopathy),and interstitial cells of Cajal(mesenchymopathy).The etiology can be genetic,idiopathic,or acquired.Owing to its nonspecific clinical presentation and lack of definitive diagnostic methods,misdiagnosis of CIPO is common.CASE SUMMARY This case involved an older male with insidious onset in adolescence who presented with postprandial bloating,intermittent diarrhea,and weight loss.During the disease course,the patient experienced two episodes of intestinal obstruction.Imaging revealed multisegmental digestive tract abnormalities(gastric emptying disorder,significant duodenal dilatation,and segmental jejunal dilatation).Whole-exome sequencing revealed a rare MYH11 mutation[NM_0010-40113.2:C.5819del(p.Pro1940HisfsTer91)],confirming hereditary myopathic CIPO.CONCLUSION This report adds to our current understanding of CIPO etiology by reinforcing the role of MYH11 variants in the pathogenesis of the CIPO phenotype.展开更多
Different newborn screening(NBS) programs have been practiced in many countries since the 1960 s. It is of considerable interest whether next-generation sequencing is applicable in NBS. We have developed a panel of 46...Different newborn screening(NBS) programs have been practiced in many countries since the 1960 s. It is of considerable interest whether next-generation sequencing is applicable in NBS. We have developed a panel of 465 causative genes for 596 early-onset, relatively high incidence, and potentially actionable severe inherited diseases in our Newborn Screening with Targeted Sequencing(NESTS) program to screen 11,484 babies in 8 Women and Children’s hospitals nationwide in China retrospectively. The positive rate from preliminary screening of NESTS was 7.85%(902/11,484). With 45.89%(414/902) follow-up of preliminary positive cases, the overall clinically confirmative diagnosis rate of monogenic disorders was 12.07%(50/414), estimating an average of 0.95%(7.85% × 12.07%) clinical diagnosis rate, suggesting that monogenic disorders account for a considerable proportion of birth defects. The disease/gene spectrum varied in different regions of China. NESTS was implemented in a hospital by screening 3923 newborns to evaluate its clinical application. The turn-around time of a primary report, including the sequencing period of < 7 days, was within 11 days by our automatic interpretation pipeline. Our results suggest that NESTS is feasible and cost-effective as a first-tier NBS program, which will change the status of current clinical practice of NBS in China.展开更多
In China,an estimated 48.42-82.11 million individuals are affected by rare diseases.This estimate is derived from the Orphanet database,based on the global population of 7.55 billion and China's population of 1.39...In China,an estimated 48.42-82.11 million individuals are affected by rare diseases.This estimate is derived from the Orphanet database,based on the global population of 7.55 billion and China's population of 1.39 billion in 2017(source:National Bureau of Statistics of China)[1,2].展开更多
Menopause is characterized by the cessation of menstruation and a decline in reproductive function,which is an intrinsic component of the aging process.However,it has been a frequently overlooked field of women’s hea...Menopause is characterized by the cessation of menstruation and a decline in reproductive function,which is an intrinsic component of the aging process.However,it has been a frequently overlooked field of women’s health.The oral and gut microbiota,constituting the largest ecosystem within the human body,are important for maintaining human health and notably contribute to the healthy aging of menopausal women.Therefore,a comprehensive review elucidating the impact of the gut and oral microbiota on menopause for healthy aging is of paramount importance.This paper presents the current understanding of the microbiome during menopause,with a particular focus on alterations in the oral and gut microbiota.Our study elucidates the complex interplay between the microbiome and sex hormone levels,explores microbial crosstalk dynamics,and investigates the associations between the microbiome and diseases linked to menopause.Additionally,this review explores the potential of microbiome-targeting therapies for managing menopause-related diseases.Given that menopause can last for approximately 30 years,gaining insights into how the microbiome and menopause interact could pave the way for innovative interventions,which may result in symptomatic relief from menopause and an increase in quality of life in women.展开更多
Although the spatial characteristics within the tumor microenvironment of lung adenocarcinoma(LUAD)have been identified,the mechanisms by which these factors promote LUAD progression and immune evasion remain unclear....Although the spatial characteristics within the tumor microenvironment of lung adenocarcinoma(LUAD)have been identified,the mechanisms by which these factors promote LUAD progression and immune evasion remain unclear.Using spatial transcriptomics and single-cell RNA-sequencing data from multi-regional LUAD biopsies consisting of tumor core,tumor edge,and normal area,we sought to delineate the spatial heterogeneity and driving factors of cell colocalization.Two cancer cell sub-clusters(Cancer_c1 and Cancer_c2),associated with LUAD initiation and metastasis,respectively,exhibit distinct spatial distributions and immune cell colocalizations.In particular,Cancer_c1,enriched within the tumor core,could directly interact with B cells or indirectly recruit B cells through macrophages.Conversely,Cancer_c2 enriched within the tumor edge exhibits colocalization with CD8^(+)T cells.Collectively,our work elucidates the spatial distribution of cancer cell subtypes and their interaction with immune cells in the core and edge of LUAD,providing insights for developing therapeutic strategies for cancer intervention.展开更多
Spinocerebellar ataxia(SCA)type 51 is a neurodegenerative disease caused by CAG repeat expansions in exon 1 of the THAP11 gene.These repeats are translated into a glutamine-rich protein,THAP11-polyQ,which forms protei...Spinocerebellar ataxia(SCA)type 51 is a neurodegenerative disease caused by CAG repeat expansions in exon 1 of the THAP11 gene.These repeats are translated into a glutamine-rich protein,THAP11-polyQ,which forms protein aggregates and exhibits toxicity in cell models;however,the underlying mechanism remains unclear.In this study,we generate transgenic Drosophila models expressing varying lengths of THAP11-polyQ using the UAS-GAL4 system and assess neurodegeneration through pathological and behavioral analyses.Our results demonstrate that expression of THAP11-polyQ in transgenic flies leads to progressive neuronal cell loss,locomotor deficiency,and reduced survival.RNA sequencing of patient-derived skin fibroblasts reveals significant enrichment of the PI3K–Akt–mTOR pathway,and electron microscopy of transgenic flies shows an increase in multilamellar bodies,suggesting involvement of autophagy in SCA51.Consequently,we treat the fly model with rapamycin,an mTOR inhibitor known to enhance autophagy.This treatment reduces toxic THAP11-polyQ protein aggregates,significantly alleviates neuronal degeneration,and improves locomotor function,consistent with the rescue effects observed upon overexpression of Atg8a.Overall,these findings suggest that the Drosophila model,which recapitulates the neurodegenerative features of SCA51,can be used to investigate pathogenic mechanisms and that rapamycin holds promising potential as a therapeutic approach for this disease.展开更多
BACKGROUND Familial partial lipodystrophy disease(FPLD)is a collection of rare genetic diseases featuring partial loss of adipose tissue.However,metabolic difficulties,such as severe insulin resistance,diabetes,hypert...BACKGROUND Familial partial lipodystrophy disease(FPLD)is a collection of rare genetic diseases featuring partial loss of adipose tissue.However,metabolic difficulties,such as severe insulin resistance,diabetes,hypertriglyceridemia,and hyperte-nsion frequently occur alongside adipose tissue loss,making it susceptible misdiagnosis and delaying effective treatment.Numerous genes are implicated the occurrence of FPLD,and genetic testing has been for conditions linked single gene mutation related to FPLD.Reviewing recent reports,treatment of the disease is limited to preventing and improving complications in patients.In 2017,a 31-year-old woman with diabetes,hypertension and hypertriglyceri-demia was hospitalized.We identified a mutation in her peroxisome proliferator-activated receptor gamma(PPARG)gene,Y151C(p.Tyr151Cys),which results in a nucleotide substitution residue 452 in the DNA-binding domain(DBD)of PPARG.The unaffected family member did not carry this mutation.Pioglitazone,a PPARG agonist,improved the patient’s responsiveness to hypoglycemic and antihyper-tensive therapy.After one year of treatment in our hospital,the fasting blood glucose and glycosylated hemoglobin of the patient were close to normal.展开更多
BACKGROUND Late infantile ceroid lipofuscinosis is a rare neurodegenerative disorder that appears between the ages of 2 and 4 years and is difficult to diagnose. In this report we present two sisters with this conditi...BACKGROUND Late infantile ceroid lipofuscinosis is a rare neurodegenerative disorder that appears between the ages of 2 and 4 years and is difficult to diagnose. In this report we present two sisters with this condition, and the clinical course consisted of delayed developmental skills initially and later regression of previously acquired skills. The cases were initially considered as childhood disintegrative disorder(CDD); however, when whole exome sequencing(WES) genetic testing was done, they proved to be variant late infantile ceroid lipofuscinosis. This is the first report from Jordan.CASE SUMMARY Clinical presentation included developmental delay and initially speech delay,followed by lose of sphincter control. Motor development was normal until 4 years of age, then they developed ataxia(fear of going downstairs) and weakness while walking. Atonic and myoclonic seizures become intractable, and this was followed by inability to stand or sit and loss of expressive language. In addition to complete blood count test, liver function test, kidney function test, serum electrolyte test, and blood sugar test, serum amino acid profile, B12 level test,thyroid function test, and a brain computed tomography scan were also normal.An electroencephalogram showed a generalized spike and wave pattern, and magnetic resonance imaging showed little to no abnormalities. After dealing with the cases as CDD, WES testing proved a final diagnosis of variant late infantile ceroid lipofuscinosis. Current treatment is anti-epileptic drugs and supportive care at home, and they are now in vegetative state.CONCLUSION This report highlights the importance of WES for the identification of genetic diseases, especially neurodegenerative disorders.展开更多
Staphylococcal enterotoxin A(SEA)derived from Staphylococcus aureus,as a superantigen,shows potential for cancer immunotherapy,but systemic immunotoxicity restricts its clinical application.Targeted delivery of SEA to...Staphylococcal enterotoxin A(SEA)derived from Staphylococcus aureus,as a superantigen,shows potential for cancer immunotherapy,but systemic immunotoxicity restricts its clinical application.Targeted delivery of SEA to tumor site provides a promising option for reducing the systemic toxicity.Here,we constructed an iRGD peptide(H-[Cys-Arg-Gly-Asp-Lys-Gly-Pro-Asp-Cys]-NH_(2))modified nanoparticle(iDPP)to deliver plasmids encoding SEA for melanoma treatment.The iDPP/SEA nanocomplexes efficiently mediated SEA expression in B16-F10 cells in vivo and in vitro and induced the activation of lymphocytes and maturation of murine bone marrow-derived dendritic cells(BMDCs)in vitro.In the subcutaneous B16-F10 melanoma model,the iDPP/SEA nanocomplexes could effectively enhance immune response and T lymphocytes infiltration in tumor site after intravenous administration,thereby considerably decreased melanoma growth.Meanwhile,no obvious adverse effect was observed after intravenous administration of the iDPP/SEA nanocomplexes in vivo.Our findings demonstrated that gene therapy of SEA is a potential candidate for melanoma treatment.展开更多
BACKGROUND Congenital analbuminemia(CAA) is a very rare disorder. Our data describes the clinical features and laboratory results of a new case established by mutation analysis of the albumin gene in a 39-year-old wom...BACKGROUND Congenital analbuminemia(CAA) is a very rare disorder. Our data describes the clinical features and laboratory results of a new case established by mutation analysis of the albumin gene in a 39-year-old woman presenting with hypercholesterolemia. Our findings contribute to shed light on the molecular genetics of the disorder and confirm that safe and well tolerated hypocholesterolemic treatment with atorvastatin may be administered in dislipidemic patient with CAA in order to reduce their cardiovascular risk.CASE SUMMARY Our patient presented with a history of hypercholesterolemia and referred asthenia and heaviness in both legs. She was born from healthy and nonconsanguineous parents and her development was normal. She had not familiarity for early cardiovascular disease, and did not report personal history of hypertension, chronic kidney or liver diseases. Clinical laboratories results showed critically reduced value of albumin whereas other serum proteins were elevated. Main causes of hypoalbuminemia(proteinuria, inflammatory state and insufficient hepatic synthesis) were ruled out by normal procedures and laboratory tests. So the hypothesis of a CAA was tested through mutation analysis of the albumin gene that revealed a homozygous CA deletion in exon 12,at nucleotide positions c1614-1615. This finding brought to the diagnosis of CAA.Currently the patient receives Atorvastatin 20 mg od and undergoes clinical and laboratory follow-up every six months. She never needed albumin infusions.CONCLUSION Our experience shows how treatment with atorvastatin may be safely administered and well tolerated in patients affected by CAA.展开更多
BACKGROUND Pyogenic arthritis,pyoderma gangrenosum,and acne(PAPA)syndrome is a rare autosomal dominant genetic disease characterized by severe autoimmune inflammation,caused by mutations in the PSTPIP1 gene.Due to PAP...BACKGROUND Pyogenic arthritis,pyoderma gangrenosum,and acne(PAPA)syndrome is a rare autosomal dominant genetic disease characterized by severe autoimmune inflammation,caused by mutations in the PSTPIP1 gene.Due to PAPA heterogeneous clinical manifestation,misdiagnosis or delayed diagnoses are difficult to avoid.With the use of whole-exome sequencing,we identified a missense mutation in the PSTPIP1 gene in a Chinese family.To the best of our knowledge,this is the first case of PAPA reported in China.CASE SUMMARY A 9-year-old boy suffered from recurrent aseptic pyogenic arthritis triggered by minor trauma or few obvious predisposing causes for more than 3 years.Pyogenic arthritis occurred every 3-5 mo,affecting his knees,elbows,and ankle joints.Treatments,such as glucocorticoids,antibiotics,even surgeries could alleviate joints pain and swelling to some extent but could not inhibit the recurrence of arthritis.Similar symptoms were present in his younger brother but not in his parents.According to the whole-exome sequencing,a missense mutation in exon 11 of the PSTPIP1 gene(c.748G>C;p.E250Q)was detected in the boy,his young-er brother and his father.Taking into account the similar phenotypic features with PAPA syndrome reported previously,we confirmed a diagnosis of PAPA syndrome for the family.CONCLUSION In this case,a missense mutation(c.748G>C;p.E250Q)in PSTPIP1 gene was identified in a Chinese family with PAPA syndrome.Previous studies emphasize the fact that PAPA syndrome is hard to diagnose just through the clinical manifestations owing to its heterogeneous expression.Genetic testing is an effectual auxiliary diagnostic method,especially in the early stages of pyogenic arthritis.Only if we have a deep understanding and rich experience of this rare disease can we make a prompt diagnosis,develop the best clinical treatment plan,and give good fertility guidance.展开更多
A growing amount of evidence has indicated contributions of variants in causative genes of Parkinson’s disease (PD) to the development of sleep disturbance in PD and prodromal PD stages. In this article, we aimed to ...A growing amount of evidence has indicated contributions of variants in causative genes of Parkinson’s disease (PD) to the development of sleep disturbance in PD and prodromal PD stages. In this article, we aimed to investigate the role of genetics in sleep disorders in PD patients and asymptomatic carriers at prodromal stage of PD. A systematic review and meta-analysis of observational studies was conducted based on the MEDLINE, EMBASE and PsychINFO databases. A pooled effect size was calculated by odds ratio (OR) and standard mean difference (SMD). Forty studies were selected for quantitative analysis, including 17 studies on glucocerebrosidase (GBA), 25 studies on Leucine-rich repeat kinase 2 (LRRK2) and 7 on parkin (PRKN) genes, and 3 studies on alpha-synuclein gene (SNCA) were used for qualitative analysis. Patients with PD carrying GBA variants had a significantly higher risk for rapid-eye-movement behavior disorders (RBD) (OR, 1.82) and higher RBD Screening Questionnaire scores (SMD, 0.33). Asymptomatic carriers of GBA variants had higher severity of RBD during follow-up. Patients with PD carrying the LRRK2 G2019S variant had lower risk and severity of RBD compared with those without LRRK2 G2019S. Variants of GBA, LRRK2 and PRKN did not increase or decrease the risk and severity of excessive daytime sleepiness and restless legs syndrome in PD. Our findings suggest that the genetic heterogeneity plays a role in the development of sleep disorders, mainly RBD, in PD and the prodromal stage of PD.展开更多
Objective:Immunoglobulin G4-related disease(IgG4-RD)is a systemic immune-mediated fibroinflammatory condition.Previous studies have indicated relationships between malignancy and autoimmunity.This retrospective cohort...Objective:Immunoglobulin G4-related disease(IgG4-RD)is a systemic immune-mediated fibroinflammatory condition.Previous studies have indicated relationships between malignancy and autoimmunity.This retrospective cohort study aimed to determine IgG4-RD incidence and clinical features in patients with a family history of malignancy.Methods:To analyze the relationship between IgG4-RD and family history of malignancy,we reviewed IgG4-RD patients with a family history of malignancy diagnosed in various departments in West China Hospital,Sichuan University from December 2012 to September 2019.Clinical data and laboratory features were compared between IgG4-RD patients with and without a family history of malignancy.Results:Among 168 enrolled patients with IgG4-RD,22(13.1%)had a family history of malignancy.The most frequently involved system in family members with malignancy was the digestive system(38.5%).Among patients with a family history of malignancy,the most frequently involved organs in IgG4-RD were the pancreas(31.9%)and lymph nodes(31.9%).Age at symptom onset was older in IgG4-RD patients with a family history of malignancy than in patients without a family history of malignancy(50–59 years:36.3%vs.16.4%,p=0.0393).Hemoglobin(p=0.0172)and albumin(p=0.0247)levels were higher and globulin(p=0.0232)levels were lower in patients with a family history of malignancy.Conclusions:Our findings suggest that a family history of malignancy may be associated with IgG4-RD development.We hypothesize that genetic susceptibility may be involved in the pathogenesis of IgG4-RD.展开更多
To the Editor:A 7-year-old boy underwent surgery at the West China Hospital in Chengdu,China,because of developing a mass in the left distal forearm over 1 month.A biopsy from the surgery resulted in a diagnosis of hi...To the Editor:A 7-year-old boy underwent surgery at the West China Hospital in Chengdu,China,because of developing a mass in the left distal forearm over 1 month.A biopsy from the surgery resulted in a diagnosis of histiocytosis,with suspected yellow granulomas.The patient also suffered from poor wound healing with purulent secretions.Two months post-operation,the patient was re-admitted to the hospital due to suffer a painful swelling in the left ankle over 10 days.Color Doppler ultrasound examination revealed a left ankle joint synovitis and a left posterior tibialis fasciitis.The patient had a history of recurrent respiratory infections since infancy,for which he had received anti-tuberculosis therapy.However,there was no record of acid-fast bacilli being isolated from the patient.There was also no family history of a similar illness among his siblings or parents.In addition to the respiratory infections,the patient also underwent open drainage of abscesses in the posterior ears and posterior cervical lymph nodes at the age of 5 and the perianus at the age of 6.He was frequently prescribed two-or three-fold antibiotics,such as oxycefazid,vancomycin,and imipenem,because of his recurring multi-site infectious lesions.展开更多
Hirschsprung's disease(HsCR)is the most common type of developmental gastrointestinal malformation causing intestinal obstruction in children,with an incidence of 1/5000 in live births.1 it is characterized by the...Hirschsprung's disease(HsCR)is the most common type of developmental gastrointestinal malformation causing intestinal obstruction in children,with an incidence of 1/5000 in live births.1 it is characterized by the absence of intrinsic ganglion cells in the myenteric and submucosal plexuses of the distal gastrointestinal tract,leading to the dysregulation of smooth muscle contraction/relaxation and resulting in intestinal obstruction.Depending on the length of the aganglionic intestine,HSCR can be categorized into short-segmental HSCR(S-HSCR),which affects up to the sigmoid colon from the anus,and long-segmental HSCR(LHSCR),which affects beyond the sigmoid colon.1 In some rare conditions,aganglionic lesions can affect the full length of the colon or even the whole intestine.展开更多
Main text The levodopa-induced dyskinesias(LIDs)in Parkinson’disease(PD)patients during levodopa treatment can lead to significant disability.Accumulative evidence has suggested that the younger the age of onset,the ...Main text The levodopa-induced dyskinesias(LIDs)in Parkinson’disease(PD)patients during levodopa treatment can lead to significant disability.Accumulative evidence has suggested that the younger the age of onset,the more likely the development of LIDs[1].Till now,most of the studies on clinical or genetic risk factors for LIDs were cross-sectional[2],or included limited sample size[3],or mainly included late-onset PD patients[4].Here,we investigated the incidence of LIDs in the early stage of early-onset PD(EOPD),including the first 5 years of duration and the first 5 years of dopamine replacement therapy(DRT),and established and validated clinicalgenetic models for LID prediction.Detailed methods are provided in Supplementary File 1.展开更多
Neuroendocrine tumours(NETs)are rare cancers with positive somatostatin receptor 2(SSTR2)expression,and treatment strategies for NETs are not satisfactory.Nanomaterial-mediated therapy targeting SSTR2 in NETs is very ...Neuroendocrine tumours(NETs)are rare cancers with positive somatostatin receptor 2(SSTR2)expression,and treatment strategies for NETs are not satisfactory.Nanomaterial-mediated therapy targeting SSTR2 in NETs is very promising.This study firstly combined mesoporous silica-coated gold nanorods(AuNRs@mSiO_(2))and targeting-SSTR2 dodecane tetraacetic acidtyrosine3-octreotate(DOTA-TATE)into AuNRs@mSiO_(2)@DOTA-TATE to investigate NETs inhibition under near-infrared light.AuNRs@mSiO_(2)@DOTA-TATE showed good photothermal conversion efficiency.In vitro,under light irradiation,the cell viability significantly decreased with increasing AuNR@mSiO_(2)@DOTA-TATE concentration;in two successfully established neuroendocrine tumour organoids with SSTR2 expression,AuNRs@mSiO_(2)@DOTA-TATE with light inhibited tumours significantly better than AuNRs@mSiO_(2) with light.In vivo,the SSTR2-targeting ability and biodistribution of AuNRs@mSiO_(2)@DOTA-TATE were confirmed with AuNRs@mSiO_(2)@64Cu-DOTA-TATE under micro-positron emission tomography/computed tomography(micro-PET/CT);in the AuNRs@mSiO_(2)@DOTA-TATE with laser group,the tumour surface temperature increased rapidly,with tumour volumes similar to those in the octreotide group and significantly lower than those in other groups.There was no significant difference in mice body weight between the AuNRs@mSiO_(2)@DOTA-TATE with laser group and other groups.No significant inflammatory lesions or cell necrosis was found in the main organs.In summary,we presented a feasible strategy to construct AuNRs@mSiO_(2)@DOTA-TATE with good photothermal conversion efficiency,targetingSSTR2 ability,significant antitumour effects,and good biocompatibility,warranting further explorations of AuNRs@mSiO_(2)@DOTA-TATE for NETs therapy applications.展开更多
Decompensated liver cirrhosis(DLC)is characterized by severe liver dysfunction and immune dysregulation,posing significant treatment challenges.Mesenchymal stromal cell(MSC)therapy has shown promise in DLC treatment,b...Decompensated liver cirrhosis(DLC)is characterized by severe liver dysfunction and immune dysregulation,posing significant treatment challenges.Mesenchymal stromal cell(MSC)therapy has shown promise in DLC treatment,but the optimal dosing strategies and dose-dependent therapeutic mechanisms in humans remain unclear,limiting its clinical application.We conducted sequential Phase Ia/Ib trials using a single-arm,dose-escalation design to evaluate the safety and tolerability of MSC therapy in DLC patients while also exploring its immunomodulatory effects and gathering preliminary therapeutic signals.展开更多
Most genome-wide association studies(GWAS)of Venous Thromboembolism(VTE)have used data from individuals of European descent,however,genetic factors for VTE have not been fully identified in Chinese populations,which c...Most genome-wide association studies(GWAS)of Venous Thromboembolism(VTE)have used data from individuals of European descent,however,genetic factors for VTE have not been fully identified in Chinese populations,which causes the limited use of existing polygenic risk scores(PRS)to identify subpopulations at high risk of VTE for prevention.We,therefore,aimed to curate all the potential VTE-related single-nucleotide polymorphisms(SNPs)for the construction of a new improved PRS model based on the self-adapting method,and then evaluate its utility and effectiveness in the stratification of VTE risk in Chinese populations.We comprehensively analyzed the mutation spectrum of VTE-associated SNPs in the Chinese cohort,and ranked their individual risk effects independently using risk ratio,logistic regression coefficient,and penalty regression coefficient as evaluation criteria.By integrating various algorithms and evaluating their performance,we trained the optimal prediction model of VTE risk in the Chinese population with the least SNP features,established an adaptive PRS model with progressive SNP overlay,and tested it on an independent Chinese population cohort.Self-adaptive polygenic risk score model based on all 318 SNPs or on the 44 most strongly associated SNPs performed similarly(areas under receiver-operating characteristic curves(AUCs)of 0.739 and 0.709,respectively)on the testing dataset of the Chinese VTE cohort,and that achieve the overall best level of the AUC from a conventional PRS model based on known genetic risk factors(0.620–0.718).In addition,we observed the self-adaptive PRS model was an independent effective risk stratification indicator beyond other clinical characteristics including age and smoking status.Our data revealed that only 44 SNPs-derived PRS model can be effectively used in discriminating subpopulations at high risk of VTE.To become clinically useful,our model could benefit from a practically feasible VTE screening program for precision prevention in Chinese populations.展开更多
Adenosine,a critical molecule regulating cellular function both inside and outside cells,is controlled by two human adenosine deaminases:ADA1 and ADA2.While ADA1 primarily resides in the cytoplasm,ADA2 can be transpor...Adenosine,a critical molecule regulating cellular function both inside and outside cells,is controlled by two human adenosine deaminases:ADA1 and ADA2.While ADA1 primarily resides in the cytoplasm,ADA2 can be transported to lysosomes within cells or secreted outside the cell.Patients with ADA2 deficiency(DADA2)often suffer from systemic vasculitis due to elevated levels of TNF-α in their blood.Monocytes from DADA2 patients exhibit excessive TNF-α secretion and differentiate into pro-inflammatory M1-type macrophages.Our findings demonstrate that ADA2 localizes to endolysosomes within macrophages,and its intracellular concentration decreases in cells secreting TNF-α.This suggests that ADA2 may function as a lysosomal adenosine deaminase,regulating TNF-α expression by the cells.Interestingly,pneumonia patients exhibit higher ADA2 concentrations in their bronchoalveolar lavage(BAL),correlating with elevated pro-inflammatory cytokine levels.Conversely,cord blood has low ADA2 levels,creating a more immunosuppressive environment.Additionally,secreted ADA2 can bind to apoptotic cells,activating immune cells by reducing extracellular adenosine levels.These findings imply that ADA2 release from monocytes during inflammation,triggered by growth factors,may be crucial for cell activation.Targeting intracellular and extracellular ADA2 activities could pave the way for novel therapies in inflammatory and autoimmune disorders.展开更多
基金Supported by The National High Level Hospital Clinical Research Funding,No.2022-PUMCH-B-129.
文摘BACKGROUND Chronic intestinal pseudo-obstruction(CIPO)is a rare and debilitating disorder,characterized by severe impairments in gastrointestinal motility.The affected sites include the enteric/intrinsic autonomic nerves(neuropathy),intestinal smooth muscle cells(myopathy),and interstitial cells of Cajal(mesenchymopathy).The etiology can be genetic,idiopathic,or acquired.Owing to its nonspecific clinical presentation and lack of definitive diagnostic methods,misdiagnosis of CIPO is common.CASE SUMMARY This case involved an older male with insidious onset in adolescence who presented with postprandial bloating,intermittent diarrhea,and weight loss.During the disease course,the patient experienced two episodes of intestinal obstruction.Imaging revealed multisegmental digestive tract abnormalities(gastric emptying disorder,significant duodenal dilatation,and segmental jejunal dilatation).Whole-exome sequencing revealed a rare MYH11 mutation[NM_0010-40113.2:C.5819del(p.Pro1940HisfsTer91)],confirming hereditary myopathic CIPO.CONCLUSION This report adds to our current understanding of CIPO etiology by reinforcing the role of MYH11 variants in the pathogenesis of the CIPO phenotype.
基金partially supported by grants from the Ministry of Science and Technology of China(2016YFC1000306)the Beijing Municipal Science and Technology Commission Foundation(Z181100001918003)+1 种基金the Beijing Municipal Commission of Health and Family Planning Foundation(2018-21141,2020-4-1144)Beihang University&Capital Medical University Advanced Innovation Center for Big Data-Based Precision Medicine Plan(BHME-201905)。
文摘Different newborn screening(NBS) programs have been practiced in many countries since the 1960 s. It is of considerable interest whether next-generation sequencing is applicable in NBS. We have developed a panel of 465 causative genes for 596 early-onset, relatively high incidence, and potentially actionable severe inherited diseases in our Newborn Screening with Targeted Sequencing(NESTS) program to screen 11,484 babies in 8 Women and Children’s hospitals nationwide in China retrospectively. The positive rate from preliminary screening of NESTS was 7.85%(902/11,484). With 45.89%(414/902) follow-up of preliminary positive cases, the overall clinically confirmative diagnosis rate of monogenic disorders was 12.07%(50/414), estimating an average of 0.95%(7.85% × 12.07%) clinical diagnosis rate, suggesting that monogenic disorders account for a considerable proportion of birth defects. The disease/gene spectrum varied in different regions of China. NESTS was implemented in a hospital by screening 3923 newborns to evaluate its clinical application. The turn-around time of a primary report, including the sequencing period of < 7 days, was within 11 days by our automatic interpretation pipeline. Our results suggest that NESTS is feasible and cost-effective as a first-tier NBS program, which will change the status of current clinical practice of NBS in China.
基金supported by the National Key Research and Development Program of China(2022YFC2703100)The Ministry of Finance of the People's Republic of China funded the UPWARDS projectthe National Health Commission of the People's Republic of China(NHC)for supporting this study。
文摘In China,an estimated 48.42-82.11 million individuals are affected by rare diseases.This estimate is derived from the Orphanet database,based on the global population of 7.55 billion and China's population of 1.39 billion in 2017(source:National Bureau of Statistics of China)[1,2].
基金supported by Science&Technology Fundamental Resources Investigation Program(2022FY100800)the CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-12M-1-023/2023-12M-C&T-B-005)+1 种基金Funding for Reform and Development of Beijing Municipal Health Commissionthe National High Level Hospital Clinical Research Funding(2022-PUMCH-B-094).
文摘Menopause is characterized by the cessation of menstruation and a decline in reproductive function,which is an intrinsic component of the aging process.However,it has been a frequently overlooked field of women’s health.The oral and gut microbiota,constituting the largest ecosystem within the human body,are important for maintaining human health and notably contribute to the healthy aging of menopausal women.Therefore,a comprehensive review elucidating the impact of the gut and oral microbiota on menopause for healthy aging is of paramount importance.This paper presents the current understanding of the microbiome during menopause,with a particular focus on alterations in the oral and gut microbiota.Our study elucidates the complex interplay between the microbiome and sex hormone levels,explores microbial crosstalk dynamics,and investigates the associations between the microbiome and diseases linked to menopause.Additionally,this review explores the potential of microbiome-targeting therapies for managing menopause-related diseases.Given that menopause can last for approximately 30 years,gaining insights into how the microbiome and menopause interact could pave the way for innovative interventions,which may result in symptomatic relief from menopause and an increase in quality of life in women.
基金supported by the National Natural Science Foundation of China(82002432 to J.W.,82302068 to M.Z.,and 32300568 to T.W.)the Natural Science Foundation of Shandong Province(ZR2024MH159 to Y.Z.,ZR2020QH179 to J.W.,ZR2022QH057 to M.Z.,and ZR2021QH005 to T.W.)the China Postdoctoral Science Foundation(2024M752006 to S.M.)。
文摘Although the spatial characteristics within the tumor microenvironment of lung adenocarcinoma(LUAD)have been identified,the mechanisms by which these factors promote LUAD progression and immune evasion remain unclear.Using spatial transcriptomics and single-cell RNA-sequencing data from multi-regional LUAD biopsies consisting of tumor core,tumor edge,and normal area,we sought to delineate the spatial heterogeneity and driving factors of cell colocalization.Two cancer cell sub-clusters(Cancer_c1 and Cancer_c2),associated with LUAD initiation and metastasis,respectively,exhibit distinct spatial distributions and immune cell colocalizations.In particular,Cancer_c1,enriched within the tumor core,could directly interact with B cells or indirectly recruit B cells through macrophages.Conversely,Cancer_c2 enriched within the tumor edge exhibits colocalization with CD8^(+)T cells.Collectively,our work elucidates the spatial distribution of cancer cell subtypes and their interaction with immune cells in the core and edge of LUAD,providing insights for developing therapeutic strategies for cancer intervention.
基金financially supported by the National Natural Science Foundation of China(82402177,82171846,82422025,82471430)Clinical Medicine Plus X-Young Scholars Project of Peking University(PKU2025PKULCXQ026)+1 种基金National High Level Hospital Clinical Research Funding(Interdepartmental Research Project of Peking University First Hospital,2023IR51,High Quality Clinical Research Project of Peking University First Hospital,2022CR69)Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases(BZ0317).
文摘Spinocerebellar ataxia(SCA)type 51 is a neurodegenerative disease caused by CAG repeat expansions in exon 1 of the THAP11 gene.These repeats are translated into a glutamine-rich protein,THAP11-polyQ,which forms protein aggregates and exhibits toxicity in cell models;however,the underlying mechanism remains unclear.In this study,we generate transgenic Drosophila models expressing varying lengths of THAP11-polyQ using the UAS-GAL4 system and assess neurodegeneration through pathological and behavioral analyses.Our results demonstrate that expression of THAP11-polyQ in transgenic flies leads to progressive neuronal cell loss,locomotor deficiency,and reduced survival.RNA sequencing of patient-derived skin fibroblasts reveals significant enrichment of the PI3K–Akt–mTOR pathway,and electron microscopy of transgenic flies shows an increase in multilamellar bodies,suggesting involvement of autophagy in SCA51.Consequently,we treat the fly model with rapamycin,an mTOR inhibitor known to enhance autophagy.This treatment reduces toxic THAP11-polyQ protein aggregates,significantly alleviates neuronal degeneration,and improves locomotor function,consistent with the rescue effects observed upon overexpression of Atg8a.Overall,these findings suggest that the Drosophila model,which recapitulates the neurodegenerative features of SCA51,can be used to investigate pathogenic mechanisms and that rapamycin holds promising potential as a therapeutic approach for this disease.
文摘BACKGROUND Familial partial lipodystrophy disease(FPLD)is a collection of rare genetic diseases featuring partial loss of adipose tissue.However,metabolic difficulties,such as severe insulin resistance,diabetes,hypertriglyceridemia,and hyperte-nsion frequently occur alongside adipose tissue loss,making it susceptible misdiagnosis and delaying effective treatment.Numerous genes are implicated the occurrence of FPLD,and genetic testing has been for conditions linked single gene mutation related to FPLD.Reviewing recent reports,treatment of the disease is limited to preventing and improving complications in patients.In 2017,a 31-year-old woman with diabetes,hypertension and hypertriglyceri-demia was hospitalized.We identified a mutation in her peroxisome proliferator-activated receptor gamma(PPARG)gene,Y151C(p.Tyr151Cys),which results in a nucleotide substitution residue 452 in the DNA-binding domain(DBD)of PPARG.The unaffected family member did not carry this mutation.Pioglitazone,a PPARG agonist,improved the patient’s responsiveness to hypoglycemic and antihyper-tensive therapy.After one year of treatment in our hospital,the fasting blood glucose and glycosylated hemoglobin of the patient were close to normal.
文摘BACKGROUND Late infantile ceroid lipofuscinosis is a rare neurodegenerative disorder that appears between the ages of 2 and 4 years and is difficult to diagnose. In this report we present two sisters with this condition, and the clinical course consisted of delayed developmental skills initially and later regression of previously acquired skills. The cases were initially considered as childhood disintegrative disorder(CDD); however, when whole exome sequencing(WES) genetic testing was done, they proved to be variant late infantile ceroid lipofuscinosis. This is the first report from Jordan.CASE SUMMARY Clinical presentation included developmental delay and initially speech delay,followed by lose of sphincter control. Motor development was normal until 4 years of age, then they developed ataxia(fear of going downstairs) and weakness while walking. Atonic and myoclonic seizures become intractable, and this was followed by inability to stand or sit and loss of expressive language. In addition to complete blood count test, liver function test, kidney function test, serum electrolyte test, and blood sugar test, serum amino acid profile, B12 level test,thyroid function test, and a brain computed tomography scan were also normal.An electroencephalogram showed a generalized spike and wave pattern, and magnetic resonance imaging showed little to no abnormalities. After dealing with the cases as CDD, WES testing proved a final diagnosis of variant late infantile ceroid lipofuscinosis. Current treatment is anti-epileptic drugs and supportive care at home, and they are now in vegetative state.CONCLUSION This report highlights the importance of WES for the identification of genetic diseases, especially neurodegenerative disorders.
基金supported by the National Natural Science Foundation(No.82073363)the Sichuan Science and Technology Program(Nos.2020YFQ0059,2022YFQ0004)the Natural Science Foundation of Sichuan Province(No.2022NSFSC1304).
文摘Staphylococcal enterotoxin A(SEA)derived from Staphylococcus aureus,as a superantigen,shows potential for cancer immunotherapy,but systemic immunotoxicity restricts its clinical application.Targeted delivery of SEA to tumor site provides a promising option for reducing the systemic toxicity.Here,we constructed an iRGD peptide(H-[Cys-Arg-Gly-Asp-Lys-Gly-Pro-Asp-Cys]-NH_(2))modified nanoparticle(iDPP)to deliver plasmids encoding SEA for melanoma treatment.The iDPP/SEA nanocomplexes efficiently mediated SEA expression in B16-F10 cells in vivo and in vitro and induced the activation of lymphocytes and maturation of murine bone marrow-derived dendritic cells(BMDCs)in vitro.In the subcutaneous B16-F10 melanoma model,the iDPP/SEA nanocomplexes could effectively enhance immune response and T lymphocytes infiltration in tumor site after intravenous administration,thereby considerably decreased melanoma growth.Meanwhile,no obvious adverse effect was observed after intravenous administration of the iDPP/SEA nanocomplexes in vivo.Our findings demonstrated that gene therapy of SEA is a potential candidate for melanoma treatment.
基金Supported by a Grant of the Italian Ministry of Education,University and Research to the Department of Molecular Medicine of the University of Pavia under the initiative "Dipartimenti di Eccellenza(2018-2022)",and Compagnia di S.Paolo,No.ROL9849
文摘BACKGROUND Congenital analbuminemia(CAA) is a very rare disorder. Our data describes the clinical features and laboratory results of a new case established by mutation analysis of the albumin gene in a 39-year-old woman presenting with hypercholesterolemia. Our findings contribute to shed light on the molecular genetics of the disorder and confirm that safe and well tolerated hypocholesterolemic treatment with atorvastatin may be administered in dislipidemic patient with CAA in order to reduce their cardiovascular risk.CASE SUMMARY Our patient presented with a history of hypercholesterolemia and referred asthenia and heaviness in both legs. She was born from healthy and nonconsanguineous parents and her development was normal. She had not familiarity for early cardiovascular disease, and did not report personal history of hypertension, chronic kidney or liver diseases. Clinical laboratories results showed critically reduced value of albumin whereas other serum proteins were elevated. Main causes of hypoalbuminemia(proteinuria, inflammatory state and insufficient hepatic synthesis) were ruled out by normal procedures and laboratory tests. So the hypothesis of a CAA was tested through mutation analysis of the albumin gene that revealed a homozygous CA deletion in exon 12,at nucleotide positions c1614-1615. This finding brought to the diagnosis of CAA.Currently the patient receives Atorvastatin 20 mg od and undergoes clinical and laboratory follow-up every six months. She never needed albumin infusions.CONCLUSION Our experience shows how treatment with atorvastatin may be safely administered and well tolerated in patients affected by CAA.
基金Supported by the National Natural Science Foundation of China,No.81770875the Post-Doctor Research Project,West China Hospital,Sichuan University,No.19HXBH053+1 种基金the Health and Family Planning Commission of Sichuan Province,No.19PJ096the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University,No.2020HXFH008 and No.ZYJC18003.
文摘BACKGROUND Pyogenic arthritis,pyoderma gangrenosum,and acne(PAPA)syndrome is a rare autosomal dominant genetic disease characterized by severe autoimmune inflammation,caused by mutations in the PSTPIP1 gene.Due to PAPA heterogeneous clinical manifestation,misdiagnosis or delayed diagnoses are difficult to avoid.With the use of whole-exome sequencing,we identified a missense mutation in the PSTPIP1 gene in a Chinese family.To the best of our knowledge,this is the first case of PAPA reported in China.CASE SUMMARY A 9-year-old boy suffered from recurrent aseptic pyogenic arthritis triggered by minor trauma or few obvious predisposing causes for more than 3 years.Pyogenic arthritis occurred every 3-5 mo,affecting his knees,elbows,and ankle joints.Treatments,such as glucocorticoids,antibiotics,even surgeries could alleviate joints pain and swelling to some extent but could not inhibit the recurrence of arthritis.Similar symptoms were present in his younger brother but not in his parents.According to the whole-exome sequencing,a missense mutation in exon 11 of the PSTPIP1 gene(c.748G>C;p.E250Q)was detected in the boy,his young-er brother and his father.Taking into account the similar phenotypic features with PAPA syndrome reported previously,we confirmed a diagnosis of PAPA syndrome for the family.CONCLUSION In this case,a missense mutation(c.748G>C;p.E250Q)in PSTPIP1 gene was identified in a Chinese family with PAPA syndrome.Previous studies emphasize the fact that PAPA syndrome is hard to diagnose just through the clinical manifestations owing to its heterogeneous expression.Genetic testing is an effectual auxiliary diagnostic method,especially in the early stages of pyogenic arthritis.Only if we have a deep understanding and rich experience of this rare disease can we make a prompt diagnosis,develop the best clinical treatment plan,and give good fertility guidance.
基金the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(No.ZYJC18038)the Sichuan Science and Technology Program(Grant No.2021YJ0415)the Science Foundation of Chengdu Science and Technology Bureau(Grant No.2019-YF05-00307-SN).
文摘A growing amount of evidence has indicated contributions of variants in causative genes of Parkinson’s disease (PD) to the development of sleep disturbance in PD and prodromal PD stages. In this article, we aimed to investigate the role of genetics in sleep disorders in PD patients and asymptomatic carriers at prodromal stage of PD. A systematic review and meta-analysis of observational studies was conducted based on the MEDLINE, EMBASE and PsychINFO databases. A pooled effect size was calculated by odds ratio (OR) and standard mean difference (SMD). Forty studies were selected for quantitative analysis, including 17 studies on glucocerebrosidase (GBA), 25 studies on Leucine-rich repeat kinase 2 (LRRK2) and 7 on parkin (PRKN) genes, and 3 studies on alpha-synuclein gene (SNCA) were used for qualitative analysis. Patients with PD carrying GBA variants had a significantly higher risk for rapid-eye-movement behavior disorders (RBD) (OR, 1.82) and higher RBD Screening Questionnaire scores (SMD, 0.33). Asymptomatic carriers of GBA variants had higher severity of RBD during follow-up. Patients with PD carrying the LRRK2 G2019S variant had lower risk and severity of RBD compared with those without LRRK2 G2019S. Variants of GBA, LRRK2 and PRKN did not increase or decrease the risk and severity of excessive daytime sleepiness and restless legs syndrome in PD. Our findings suggest that the genetic heterogeneity plays a role in the development of sleep disorders, mainly RBD, in PD and the prodromal stage of PD.
基金National Natural Science Foundation of China,Grant/Award Numbers:81403041,81770101,81771742,82001728National Key Research and Development Program of China,Grant/Award Number:2016YFC0906201+2 种基金Department of Science and Technology of Sichuan Province,Grant/Award Numbers:2019YJ0099,2019YJ0139China Postdoctoral Science Foundation,Grant/Award Number:2019M6635221·3·5 project for Outstanding interdisciplinary project of West China Hospital,Sichuan University,Grant/Award Numbers:ZYGD18015,ZYJC18003,ZYJC18024。
文摘Objective:Immunoglobulin G4-related disease(IgG4-RD)is a systemic immune-mediated fibroinflammatory condition.Previous studies have indicated relationships between malignancy and autoimmunity.This retrospective cohort study aimed to determine IgG4-RD incidence and clinical features in patients with a family history of malignancy.Methods:To analyze the relationship between IgG4-RD and family history of malignancy,we reviewed IgG4-RD patients with a family history of malignancy diagnosed in various departments in West China Hospital,Sichuan University from December 2012 to September 2019.Clinical data and laboratory features were compared between IgG4-RD patients with and without a family history of malignancy.Results:Among 168 enrolled patients with IgG4-RD,22(13.1%)had a family history of malignancy.The most frequently involved system in family members with malignancy was the digestive system(38.5%).Among patients with a family history of malignancy,the most frequently involved organs in IgG4-RD were the pancreas(31.9%)and lymph nodes(31.9%).Age at symptom onset was older in IgG4-RD patients with a family history of malignancy than in patients without a family history of malignancy(50–59 years:36.3%vs.16.4%,p=0.0393).Hemoglobin(p=0.0172)and albumin(p=0.0247)levels were higher and globulin(p=0.0232)levels were lower in patients with a family history of malignancy.Conclusions:Our findings suggest that a family history of malignancy may be associated with IgG4-RD development.We hypothesize that genetic susceptibility may be involved in the pathogenesis of IgG4-RD.
基金supported by grants from the National Natural Science Foundation of China(No.81770875)1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(Nos.2020HXFH008,ZYJC18003)。
文摘To the Editor:A 7-year-old boy underwent surgery at the West China Hospital in Chengdu,China,because of developing a mass in the left distal forearm over 1 month.A biopsy from the surgery resulted in a diagnosis of histiocytosis,with suspected yellow granulomas.The patient also suffered from poor wound healing with purulent secretions.Two months post-operation,the patient was re-admitted to the hospital due to suffer a painful swelling in the left ankle over 10 days.Color Doppler ultrasound examination revealed a left ankle joint synovitis and a left posterior tibialis fasciitis.The patient had a history of recurrent respiratory infections since infancy,for which he had received anti-tuberculosis therapy.However,there was no record of acid-fast bacilli being isolated from the patient.There was also no family history of a similar illness among his siblings or parents.In addition to the respiratory infections,the patient also underwent open drainage of abscesses in the posterior ears and posterior cervical lymph nodes at the age of 5 and the perianus at the age of 6.He was frequently prescribed two-or three-fold antibiotics,such as oxycefazid,vancomycin,and imipenem,because of his recurring multi-site infectious lesions.
基金supported by the Scientific Research Starting Foundation for Introduced Talents,West China Hospital,Sichuan University,China(to Jing Chen)Natural Science Foundation of Sichuan Province,China(No.2022NSFSC1436 to Qi Wang and No.2022NSFSC1301 to Jing Chen)1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University,China(No.ZYJC18003 to Yi Liu and No.2021HXFH020 to Bo Xiang).
文摘Hirschsprung's disease(HsCR)is the most common type of developmental gastrointestinal malformation causing intestinal obstruction in children,with an incidence of 1/5000 in live births.1 it is characterized by the absence of intrinsic ganglion cells in the myenteric and submucosal plexuses of the distal gastrointestinal tract,leading to the dysregulation of smooth muscle contraction/relaxation and resulting in intestinal obstruction.Depending on the length of the aganglionic intestine,HSCR can be categorized into short-segmental HSCR(S-HSCR),which affects up to the sigmoid colon from the anus,and long-segmental HSCR(LHSCR),which affects beyond the sigmoid colon.1 In some rare conditions,aganglionic lesions can affect the full length of the colon or even the whole intestine.
基金This study was supported by the National Key Research and Development Program of China(2018YFC1312001 and 2016YFC0901504)the National Natural Science Foundation of China(81971188)the 1.3.5 project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYJC18038,ZYJC18003 and 2019HXFH046).
文摘Main text The levodopa-induced dyskinesias(LIDs)in Parkinson’disease(PD)patients during levodopa treatment can lead to significant disability.Accumulative evidence has suggested that the younger the age of onset,the more likely the development of LIDs[1].Till now,most of the studies on clinical or genetic risk factors for LIDs were cross-sectional[2],or included limited sample size[3],or mainly included late-onset PD patients[4].Here,we investigated the incidence of LIDs in the early stage of early-onset PD(EOPD),including the first 5 years of duration and the first 5 years of dopamine replacement therapy(DRT),and established and validated clinicalgenetic models for LID prediction.Detailed methods are provided in Supplementary File 1.
基金supported by CAMS Innovation Fund for Medical Sciences(CIFMS)(Nos.2021-I2M-1-066,2017-I2M-4-002,and 2021-I2M1-019)the National Natural Science Foundation of China(Nos.81972311,82141127,and 31970794)+3 种基金the State Key Project on Infection Diseases of China(No.2017ZX10201021-007-003)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(No.2019PT310026)Sanming Project of Medicine in Shenzhen(No.SZSM202011010)Independent research project of the State Key Laboratory of Tribology,and the State Key Laboratory Special fund from the Ministry of Science(No.2060204).
文摘Neuroendocrine tumours(NETs)are rare cancers with positive somatostatin receptor 2(SSTR2)expression,and treatment strategies for NETs are not satisfactory.Nanomaterial-mediated therapy targeting SSTR2 in NETs is very promising.This study firstly combined mesoporous silica-coated gold nanorods(AuNRs@mSiO_(2))and targeting-SSTR2 dodecane tetraacetic acidtyrosine3-octreotate(DOTA-TATE)into AuNRs@mSiO_(2)@DOTA-TATE to investigate NETs inhibition under near-infrared light.AuNRs@mSiO_(2)@DOTA-TATE showed good photothermal conversion efficiency.In vitro,under light irradiation,the cell viability significantly decreased with increasing AuNR@mSiO_(2)@DOTA-TATE concentration;in two successfully established neuroendocrine tumour organoids with SSTR2 expression,AuNRs@mSiO_(2)@DOTA-TATE with light inhibited tumours significantly better than AuNRs@mSiO_(2) with light.In vivo,the SSTR2-targeting ability and biodistribution of AuNRs@mSiO_(2)@DOTA-TATE were confirmed with AuNRs@mSiO_(2)@64Cu-DOTA-TATE under micro-positron emission tomography/computed tomography(micro-PET/CT);in the AuNRs@mSiO_(2)@DOTA-TATE with laser group,the tumour surface temperature increased rapidly,with tumour volumes similar to those in the octreotide group and significantly lower than those in other groups.There was no significant difference in mice body weight between the AuNRs@mSiO_(2)@DOTA-TATE with laser group and other groups.No significant inflammatory lesions or cell necrosis was found in the main organs.In summary,we presented a feasible strategy to construct AuNRs@mSiO_(2)@DOTA-TATE with good photothermal conversion efficiency,targetingSSTR2 ability,significant antitumour effects,and good biocompatibility,warranting further explorations of AuNRs@mSiO_(2)@DOTA-TATE for NETs therapy applications.
基金supported by the National Key R&D Program of China(2022YFA1105604,2022YFC2304400)the Innovation Platform for Academicians of Hainan Province(YSPTZX202216)the National Clinical Center for Infectious Diseases,PLA General Hospital(NCRC-ID202105,413FZT6).
文摘Decompensated liver cirrhosis(DLC)is characterized by severe liver dysfunction and immune dysregulation,posing significant treatment challenges.Mesenchymal stromal cell(MSC)therapy has shown promise in DLC treatment,but the optimal dosing strategies and dose-dependent therapeutic mechanisms in humans remain unclear,limiting its clinical application.We conducted sequential Phase Ia/Ib trials using a single-arm,dose-escalation design to evaluate the safety and tolerability of MSC therapy in DLC patients while also exploring its immunomodulatory effects and gathering preliminary therapeutic signals.
基金National High Level Hospital Clinical Research Funding 2023-NHLHCRF-YGJH-03.
文摘Most genome-wide association studies(GWAS)of Venous Thromboembolism(VTE)have used data from individuals of European descent,however,genetic factors for VTE have not been fully identified in Chinese populations,which causes the limited use of existing polygenic risk scores(PRS)to identify subpopulations at high risk of VTE for prevention.We,therefore,aimed to curate all the potential VTE-related single-nucleotide polymorphisms(SNPs)for the construction of a new improved PRS model based on the self-adapting method,and then evaluate its utility and effectiveness in the stratification of VTE risk in Chinese populations.We comprehensively analyzed the mutation spectrum of VTE-associated SNPs in the Chinese cohort,and ranked their individual risk effects independently using risk ratio,logistic regression coefficient,and penalty regression coefficient as evaluation criteria.By integrating various algorithms and evaluating their performance,we trained the optimal prediction model of VTE risk in the Chinese population with the least SNP features,established an adaptive PRS model with progressive SNP overlay,and tested it on an independent Chinese population cohort.Self-adaptive polygenic risk score model based on all 318 SNPs or on the 44 most strongly associated SNPs performed similarly(areas under receiver-operating characteristic curves(AUCs)of 0.739 and 0.709,respectively)on the testing dataset of the Chinese VTE cohort,and that achieve the overall best level of the AUC from a conventional PRS model based on known genetic risk factors(0.620–0.718).In addition,we observed the self-adaptive PRS model was an independent effective risk stratification indicator beyond other clinical characteristics including age and smoking status.Our data revealed that only 44 SNPs-derived PRS model can be effectively used in discriminating subpopulations at high risk of VTE.To become clinically useful,our model could benefit from a practically feasible VTE screening program for precision prevention in Chinese populations.
基金supported by Guangzhou Women and Children’s Hospital,Guangzhou Science and Technology Project(No.202201011494 to Liang Dong),and a grant(No.256053 to Andrey V.Zavialov)from the Finnish Academy.
文摘Adenosine,a critical molecule regulating cellular function both inside and outside cells,is controlled by two human adenosine deaminases:ADA1 and ADA2.While ADA1 primarily resides in the cytoplasm,ADA2 can be transported to lysosomes within cells or secreted outside the cell.Patients with ADA2 deficiency(DADA2)often suffer from systemic vasculitis due to elevated levels of TNF-α in their blood.Monocytes from DADA2 patients exhibit excessive TNF-α secretion and differentiate into pro-inflammatory M1-type macrophages.Our findings demonstrate that ADA2 localizes to endolysosomes within macrophages,and its intracellular concentration decreases in cells secreting TNF-α.This suggests that ADA2 may function as a lysosomal adenosine deaminase,regulating TNF-α expression by the cells.Interestingly,pneumonia patients exhibit higher ADA2 concentrations in their bronchoalveolar lavage(BAL),correlating with elevated pro-inflammatory cytokine levels.Conversely,cord blood has low ADA2 levels,creating a more immunosuppressive environment.Additionally,secreted ADA2 can bind to apoptotic cells,activating immune cells by reducing extracellular adenosine levels.These findings imply that ADA2 release from monocytes during inflammation,triggered by growth factors,may be crucial for cell activation.Targeting intracellular and extracellular ADA2 activities could pave the way for novel therapies in inflammatory and autoimmune disorders.
