Objective:This study aimed to assess the global,regional,and national burden of early-onset gastric cancer(EOGC)and the attributable risk factors from 1990-2021 with projections extending to 2040.Methods:The EOGC burd...Objective:This study aimed to assess the global,regional,and national burden of early-onset gastric cancer(EOGC)and the attributable risk factors from 1990-2021 with projections extending to 2040.Methods:The EOGC burden was quantified using incidence,prevalence,mortality,and disability-adjusted life years(DALYs)with calculation of age-standardized rates.The risk factor contributions were analyzed and disparities were evaluated using the slope index of inequality.Future trends for 2021-2040 were estimated using a Bayesian age-period-cohort model.Results:There were approximately 125,000 new cases of EOGC globally in 2021 with an estimated 336,000 individuals living with EOGC and 78,000 associated deaths,contributing to 3.86 million DALYs.The highest EOGC incidence rates existed among individuals 45-49 years of age.The global age-standardized incidence,prevalence,mortality,and DALY rates demonstrated an overall decline between 1990 and 2021.Smoking and high-salt dietary intake were the leading risk factors for DALYs with regional and gender-based variations.Smoking accounted for>10% of DALYs in Central Europe and East Asia,while high-salt dietary intake accounted for approximately 8% of DALYs.Despite the overall decline in the EOGC burden,disparities across geographic regions widened.Projections indicated a continued gradual reduction in EOGC burden through 2040.Conclusion:Although the global burden of EOGC has decreased,significant disparities persist across geographic regions,age groups,and genders.Public health interventions should combine smoking prevention strategies(e.g.,youth education and tobacco taxation)with cessation programs with dietary salt reduction initiatives.展开更多
BACKGROUND Hereditary factors are more prevalent in early-onset colorectal cancers(EOCRC)etiology.Lynch syndrome(LS)is the most common hereditary colorectal cancer(CRC)syndrome that results from mutations in DNA misma...BACKGROUND Hereditary factors are more prevalent in early-onset colorectal cancers(EOCRC)etiology.Lynch syndrome(LS)is the most common hereditary colorectal cancer(CRC)syndrome that results from mutations in DNA mismatch repair(MMR)genes.This phenomenon is defined as microsatellite instability(MSI).Immunohistochemistry(IHC)is a widely used,practical,and cost-effective method for the screening of MSI.However,using IHC alone may be insufficient to identify patients with MSI and LS.AIM To determine the clinicopathological features in EOCRC,IHC performance,and the frequency of genetic testing for EOCRC patients.METHODS A retrospective review was conducted on patients with CRC aged≤50 years who underwent surgery at our center between January 2014 and July 2021.MMR proteins were screened using IHC.Of the 131 patients included,IHC was performed on 130.Patients were classified as MSI or microsatellite-stable(MSS),and their features were compared.Additionally,data from patients who received genetic counseling were analyzed.RESULTS Thirty patients with MSI were designated as group 1,whereas 100 with MSS were defined as group 2.The mean age in group 1 was the lowest(median age:42 vs 46,P<0.05).Group 1 exhibited a higher frequency of tumors in the right colon and a lower frequency in the rectum.Lymph node involvement and distant metastases were less common in group 1,and in group 2,tumors were generally diagnosed at a more advanced stage.Genetic testing was performed in 53 patients(40%),with a definitive LS diagnosis established in 13/17 patients(76.4%)in group 1 and 1/36(2.7%)patients in group 2,resulting in a total of 14 patients(26.4%)with confirmed LS.CONCLUSION MSI tumors show a better prognosis.IHC is very effective for screening MSI,but may not be sufficient alone.Low genetic counseling rates highlight the need for hospital-based surveillance programs.展开更多
Background The molecular mechanisms of early-onset multigenerational diabetes remain unknown.This study aimed to investigate the clinical and genetic characteristics of early-onset diabetes involving at least two cons...Background The molecular mechanisms of early-onset multigenerational diabetes remain unknown.This study aimed to investigate the clinical and genetic characteristics of early-onset diabetes involving at least two consecutive generations.Methods From 1296 inpatients with diabetes,we selected individuals who were≤30 years of age and who were clinically suspected of having familial monogenic diabetes.Clinical data were collected from the probands and their family members.Whole-exome sequencing(WES)was used to identify possible causal variants for diabetes.Candidate pathogenic variants were verified by Sanger sequencing,assessed for cosegregation in family members,and evaluated on the basis of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology(ACMG/AMP)guidelines.Moreover,missense and synonymous variants were subjected to in silico pathogenicity prediction via MutationTaster and PolyPhen-2.RNAfold was used to predict RNA structural alterations for synonymous variants.Results Twenty-five early-onset diabetes patients with a history of familial diabetes were enrolled.Pathogenic/likely pathogenic variants(p.Gly292fs in HNF1A,p.Gly245Argfs*22 in PDX1,p.Asp329His in KCNJ11,p.Leu734Phe and p.Val606Gly in WFS1)were detected in four patients,who were diagnosed accurately and treated with reasonable hypoglycemic agents based on genetic testing results.The variants of uncertain significance(ABCC8 c.3039 G>A(p.Ser1013=Ser),MAPK8IP1 p.Gln144_Gly145insSerGln,and TBC1D4 p.Arg1249Trp)were identified in three probands.Conclusion Patients with early-onset diabetes involving at least two consecutive generations may harbor genetic variants.Genetic testing in this population enables precision diagnosis,informs individualized treatment,and facilitates genetic counseling.展开更多
BACKGROUND Colorectal cancer(CRC)is the second leading cause of cancer-related deaths worldwide with an alarming rise in early-onset CRC(eoCRC)over the past several decades.Unlike late-onset CRC,the drivers behind eoC...BACKGROUND Colorectal cancer(CRC)is the second leading cause of cancer-related deaths worldwide with an alarming rise in early-onset CRC(eoCRC)over the past several decades.Unlike late-onset CRC,the drivers behind eoCRC remain less clear.While certain risk factors such as obesity and smoking have demonstrated a relatively strong association with eoCRC in the literature,some studies have challenged these associations,emphasizing the need for additional studies.METHODS This cross-sectional study used de-identified data from the National Health and Nutrition Examination Survey(1999-2023),including 30321 United States adults aged 18 to 49 years.Participants with missing key variables were excluded.Standardized protocols were used to collect demographic,lifestyle,anthropo-metric[body mass index(BMI),body roundness index(BRI),waist circumference(WC)],and self-reported CRC data.Logistic regression and propensity score matching assessed associations between obesity-related parameters and eoCRC.Statistical analyses were performed in R and Stata,with P<0.05 defined as significant.RESULTS Of 30321 participants,48 received a diagnosis of eoCRC.Patients with eoCRC were older(mean age 39.96 years vs 34.36 years;P<0.001)and had higher WC and BRI.None of the eoCRC patients were heavy drinkers(P=0.006).Unadjusted models demonstrated significant associations of eoCRC with BRI quartiles,as well as BMI-defined obesity,WC,and smoking.In unadjusted models,BRI remained the strongest independent predictor;those in the highest BRI quartiles had over 10-fold greater odds of eoCRC.In fully adjusted models,BRI remained significant,but BMI-and waist-based obesity were not.CONCLUSION BRI is a stronger predictor of eoCRC risk compared to other obesity indices and is a superior tool for identifying young individuals at higher risk of CRC.展开更多
BACKGROUND The incidence of oesophageal adenocarcinoma(OAC)has been reported to be increasing in many countries.Alongside this trend,an increase in incidence of early-onset OAC,defined as OAC in adults aged under 50 y...BACKGROUND The incidence of oesophageal adenocarcinoma(OAC)has been reported to be increasing in many countries.Alongside this trend,an increase in incidence of early-onset OAC,defined as OAC in adults aged under 50 years,has been observed.It is unclear whether survival outcomes for early-onset OAC patients differ from older age groups.AIM To investigate survival outcomes in early-onset OAC patients.METHODS Ovid Medline and Embase were searched from inception to January 2022 for relevant studies relating to early-onset OAC and survival outcomes.Results regarding the overall five-year survival and risk of death of younger and older patients with OAC were extracted and pooled using meta-analyses to produce pooled estimates and 95%CIs where possible.RESULTS Eleven studies which compared survival of early-onset OAC,defined as age at diagnosis of<50 years,with older patients were included.A narrative review of median and mean survival demonstrated conflicting results,with studies showing early-onset OAC patients having both better and worse outcomes compared to older age groups.A meta-analysis of five-year survival demonstrated similar outcomes across age groups,with 22%-25%of patients in the young,middle and older age groups alive after five years.A meta-analysis of four studies demon-strated that early-onset OAC patients did not have a significantly increased risk of death compared to middle-aged patients(hazard ratio 1.12,95%CI:0.85-1.47).INTRODUCTION There is concern that the incidence of oesophageal adenocarcinoma(OAC)in patients under 50,described as early-onset OAC,is increasing.However,data regarding survival of younger patients with OAC is sparse.Globally,while increasing age remains a major non-modifiable risk factor for cancer,the incidence of early-onset cancers,largely accepted to be in adults aged under 50 years,is increasing[1].This includes an observed increase in the incidence of gastrointestinal malignancies such as colorectal,oesophageal,gastric and hepatobiliary cancers[2-4].Despite oesophageal squamous cell carcinoma(OSCC)being more common globally(88%of cases)[5],a striking increase in oesophageal OAC incidence has been reported in developed countries,such as the United States and Europe[6,7].Worryingly,the United Kingdom has the highest incidence of OAC cases in the world[8].In addition to the increase in OAC,an increase in incidence of early-onset OAC,defined as OAC in adults aged under 50 years,has been observed[9,10].A population-based cohort in the Netherlands,consisting of 59584 patients,demonstrated the incidence of early-onset OAC to have tripled from 1989 to 2018,while OSCC cases declined in this age group[7].OAC usually develops in the lower third of the oesophagus and the gastro-oesophageal junction,with risk factors including obesity and gastro-oesophageal reflux disease[11].A poor prognosis is observed,with the overall five-year survival rate for oesophageal cancer between 15%-20%,even with treatment[12,13].These low survival rates are likely due to a combination of late diagnosis,intrinsic resistance to systemic therapy and the limited efficacy of surgical resection.Younger patients tend to present at a more advanced stage at diagnosis compared to those diagnosed later in life.A single centre,retrospective study found that 33.3%of patients in the younger age category(<50 years old)presented with stage IV OAC,compared to the 20.6%of the oldest age category(>70 years old)[14].Another population-based study in the Netherlands observed that OAC patients under 50 years old also presented with distant metastasis more often in comparison to older patients(50.5%vs 44.7%),and that tumour differentiation also varied between age groups[15].Reports of survival estimates in patients with early-onset OAC compared with older patients have resulted in contrasting findings to date.Some studies report that due to the advanced stage and aggressiveness of the tumours seen that the prognosis of these patients is almost always worse than their older counterparts[16].In contrast,another study found that the overall survival,as well as stage-specific survival was higher in those who were younger[17].A Dutch study which included only resectable cases found no difference in 5-year disease specific survival[18].Given the conflicting evidence to date,the aim of this systematic review was to investigate survival in OAC patients according to age at diagnosis.A protocol was composed,and the reporting of this systematic review designed,using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines[19].The protocol included:The review question,search strategy,inclusion criteria,type of quality assessment,the strategy for data analysis,and the‘population,intervention,comparator,and outcome’criteria.These are expanded below.展开更多
The aim of this research was to study the clinical features and microvascular complications risk factors of early-onset type 2 diabetes mellitus(T2DM).We analyzed the clinical data from 1421 T2DM inpatients at Wuhan U...The aim of this research was to study the clinical features and microvascular complications risk factors of early-onset type 2 diabetes mellitus(T2DM).We analyzed the clinical data from 1421 T2DM inpatients at Wuhan Union Hospital.Subjects were divided into early-onset T2DM group(diagnostic age<40 years)and late-onset T2DM group(diagnostic age>40 years).All subjects underwent a standardized assessment of microvascular complications.Data were compared with independent-samples t test or Chi-square test.Multiple logistic regression was used to determine the risk factors of microvascular complications.Patients with early-onset T2DM were more inclined to have a lower systolic blood pressure(SBP),a longer duration of diabetes and higher levels of body mass index(BM1),uric acid(UA),fasting plasma glucose(FPG),total cholesterol(TC),triglyceride(TG)and glycosylated hemoglobin(HbAlc)than those with lateonset T2DM(P<0.05).The prevalence of diabetic retinopathy(DR)was significantly higher and that of diabetic peripheral neuropathy(DPN)was significantly lower in early-onset group than in late-onset group(P<0.05).For DN,UA was an independent risk factor in early-onset T2DM.SBP and TG were independent risk factors in late-onset T2DM.For DR,duration of diabetes and SBP were independent risk factors in early-onset T2DM.Duration of diabetes,SBP and HbAlc were independent risk factors in late-onset T2DM.This study demonstrated that the clinical characteristics of early-onset T2DM were metabolic disorders,including glucose metabolism,lipid metabolism and amino acid metabolism.Early-onset T2DM was more likely to be associated with DR.The potential pathogenesis of early and late-onset T2DM might be different.The management of metabolic risk factors especially HbA1c,SBP,TG and UA is advised to be performed in the early stage of diabetes.展开更多
Colorectal cancer is the third most common cancer diagnosed worldwide. Although epidemiology data show a marked variability around the world, its overall incidence rate shows a slow but steady decrease, mainly in deve...Colorectal cancer is the third most common cancer diagnosed worldwide. Although epidemiology data show a marked variability around the world, its overall incidence rate shows a slow but steady decrease, mainly in developed countries. Conversely, early-onset colorectal cancer appears to display an opposite trend with an overall prevalence in United States and European Union ranging from 3.0% and 8.6%. Colorectal cancer has a substantial proportion of familial cases. In particular, early age at onset is especially suggestive of hereditary predisposition. The clinicopathological and molecular features of colorectal cancer cases show a marked heterogeneity not only between early- and late-onset cases but also within the early-onset group. Two distinct subtypes of early-onset colorectal cancers can be identified: a “sporadic” subtype, usually without family history, and an inherited subtype arising in the context of well defined hereditary syndromes. The pathogenesis of the early-onset disease is substantially well characterized in the inherited subtype, which is mainly associated to the Lynch syndrome and occasionally to other rare mendelian diseases, whereas in the “sporadic” subtype the origin of the disease may be attributed to the presence of various common/rare genetic variants, so far largely unidentified, displaying variable penetrance. These variants are thought to act cumulatively to increase the risk of colorectal cancer, and presumably to also anticipate its onset. Efforts are ongoing in the attempt to unravel the intricate genetic basis of this “sporadic” early-onset disease. A better knowledge of molecular entities and pathways may impact on family-tailored prevention and clinical management strategies.展开更多
Colorectal cancer(CRC)is one of the most prevalent malignancies worldwide.Although most prevalent among older people,its incidence above 50 years old has been decreasing globally in the last decades,probably as a resu...Colorectal cancer(CRC)is one of the most prevalent malignancies worldwide.Although most prevalent among older people,its incidence above 50 years old has been decreasing globally in the last decades,probably as a result of better screening.Paradoxically,its incidence in patients below 50 years old[early-onset CRC(EO-CRC)]has been increasing,for reasons not yet fully understood.EOCRC’s increasing incidence is genre independent but shows racial disparities and has been described to occur worldwide.It follows a birth-cohort effect which probably reflects a change in exposure to CRC risk factors.Its incidence is predicted to double until 2030,which makes EO-CRC a serious public health issue.Both modifiable and non-modifiable risk factors have been identified-some are potential targets for preventive measures.EO-CRC is often diagnosed at advanced stages and histological features associated with poor prognosis have been described.EO-CRC presents some distinctive features:Microsatellite instability is common,but another subtype of tumours,both microsatellite and chromosome stable also seems relevant.There are no age-specific treatment protocols and studies on EO-CRC survival rates have shown conflicting data.Due to the higher germline pathological mutations found in EO-CRC patients,an accurate genetic risk evaluation should be performed.In this review,we summarize the current evidence on epidemiological,clinical,histopathological and molecular features of EO-CRC and discuss the contribution of genetics and lifestyle risk factors.We further comment on screening strategies and specific dimensions to consider when dealing with a younger cancer patient.展开更多
Colorectal cancer(CRC) is the third most frequent cancer type and the incidence of this disease is increasing gradually per year in individuals younger than 50 years old. The current knowledge is that early-onset CRC(...Colorectal cancer(CRC) is the third most frequent cancer type and the incidence of this disease is increasing gradually per year in individuals younger than 50 years old. The current knowledge is that early-onset CRC(EOCRC) cases are heterogeneous population that includes both hereditary and sporadic forms of the CRC. Although EOCRC cases have some distinguishing clinical and pathological features than elder age CRC, the molecular mechanism underlying the EOCRC is poorly clarified. Given the significance of CRC in the world of medicine, the present review will focus on the recent knowledge in the molecular basis of genetic and epigenetic mechanism of the hereditary forms of EOCRC, which includes Lynch syndrome, Familial CRC type X, Familial adenomatous polyposis, Mut YH-associated polyposis, Juvenile polyposis syndrome, Peutz-Jeghers Syndrome and sporadic forms of EOCRC. Recent findings about molecular genetics and epigenetic basis of EOCRC gave rise to new alternative therapy protocols. Although exact diagnosis of these cases still remains complicated, the present review paves way for better predictions and contributes to more accurate diagnostic and therapeutic strategies into clinical approach.展开更多
Currently, gastric cancer(GC) is one of the most frequently diagnosed neoplasms, with a global burden of 723000 deaths in 2012. It is the third leading cause of cancer-related death worldwide. There are numerous possi...Currently, gastric cancer(GC) is one of the most frequently diagnosed neoplasms, with a global burden of 723000 deaths in 2012. It is the third leading cause of cancer-related death worldwide. There are numerous possible factors that stimulate the procarcinogenic activity of important genes. These factors include genetic susceptibility expressed in a singlenucleotide polymorphism, various acquired mutations(chromosomal instability, microsatellite instability, somatic gene mutations, epigenetic alterations) and environmental circumstances(e.g., helicobcter pylori infection, EBV infection, diet, and smoking). Most of the aforementioned pathways overlap, and authors agree that a clear-cut pathway for GC may not exist. Thus, the categorization of carcinogenic events is complicated. Lately, it has been claimed that research on early-onset gastric carcinoma(EOGC) and hereditary GC may contribute towards unravelling some part of the mystery of the GC molecular pattern because young patients are less exposed to environmental carcinogens and because carcinogenesis in this setting may be more dependent on genetic factors. The comparison of various aspects that differ and coexist in EOGCs and conventional GCs might enable scientists to: distinguish which features in the pathway of gastric carcinogenesisare modifiable, discover specific GC markers and identify a specific target. This review provides a summary of the data published thus far concerning the molecular characteristics of GC and highlights the outstanding features of EOGC.展开更多
Colorectal cancer(CRC)has a great impact on the world population.With increasing frequency,CRC is described according to the presenting phenotype,based on its molecular characteristics.Classification of CRC tumors acc...Colorectal cancer(CRC)has a great impact on the world population.With increasing frequency,CRC is described according to the presenting phenotype,based on its molecular characteristics.Classification of CRC tumors according to their genetic and/or epigenetic alterations is not only important for establishing the molecular bases of the disease,but also for predicting patient outcomes and developing more individualized treatments.Early-onset CRC is a heterogeneous disease,with a strong familial component,although the disease is sporadic in an important proportion of cases.Different molecular alterations appear to contribute to the apparent heterogeneity of the early-onset population and subgroups can be distinguished with distinct histopathologic and familial characteristics.Moreover,compared with late-onset CRC,there are characteristicsthat suggest that early-onset CRC may have a different molecular basis.The purpose of this review was to analyze the current state of knowledge about earlyonset CRC with respect to clinicopathologic,familial and molecular features.Together,these features make it increasingly clear that this subset of CRC may be a separate disease,although it has much in common with late-onset CRC.展开更多
Objective Very early-onset coronary artery disease （CAD） is a great challenge in cardiovascular medicine throughout the world, especially regarding its early diagnosis. This study explored whether circulating microR...Objective Very early-onset coronary artery disease （CAD） is a great challenge in cardiovascular medicine throughout the world, especially regarding its early diagnosis. This study explored whether circulating microRNAs （miRNAs） could be used as potential biomarkers for patients with very early-onset CAD. Methods We performed an initial screening of miRNA expression using RNA isolated from 20 patients with angiographically documented very early-onset CAD and 20 age- and sex-matched normal controls. For further confirmation, we prospectively examined the miRNAs selected from 40 patients with very early-onset CAD and 40 angiography-normal controls. Results A total of 22 overexpressed miRNAs and 22 underexpressed miRNAs were detected in the initial screening. RT-qPCR analysis of the miRNAs obtained from the initial screening revealed that four miRNAs including miR-196-5p, miR-3163-3p, miR-145-3p, and miR-190a-5p exhibited significantly decreased expression in patients compared with that in controls （P〈0.05）. The areas under the receiver operating characteristic curve for these miRNAs were 0.824 （95% CI, 0.731-0.917; P〈0.001）, 0.758 （95% CI, 0.651-0.864; P〈0.001）, 0.753 （95% CI, 0.643-0.863; P〈0.001）, and 0.782 （95% CI, 0.680-0.884; P〈0.001）, respectively, in the validation set. Conclusion To our knowledge, this is an advanced study to report about four serum miRNAs （miR-196-5p, miR-3163-3p, miR-145-3p, and miR-190a-5p） that could be used as novel biomarkers for the diagnosis of very early-onset CAD.展开更多
Early-onset epilepsy is a neurological abnormality in childhood, and it is especially common in the first2 years after birth. Seizures in early life mostly result from structural or metabolic disorders in the brain, a...Early-onset epilepsy is a neurological abnormality in childhood, and it is especially common in the first2 years after birth. Seizures in early life mostly result from structural or metabolic disorders in the brain, and the genetic causes of idiopathic seizures have been extensively investigated. In this study, we identified four missense mutations in the SETD1 A gene(SET domain-containing 1 A, histone lysine methyltransferase): three de novo mutations in three individuals and one inherited mutation in a four-generation family. Whole-exome sequencing indicated that all four of these mutations were responsible for the seizures. Mutations of SETD1 A have been implicated in schizophrenia and developmental disorders, so we examined the role of the four mutations(R913 C, Q269 R, G1369 R, and R1392 H) in neural development. We found that their expression in mouse primary cortical neurons affected excitatory synapse development. Moreover, expression of the R913 C mutation also affected the migration of cortical neurons in the mouse brain.We further identified two common genes(Neurl4 and Usp39) affected by mutations of SETD1 A. These results suggested that the mutations of SETD1 A play a fundamental role in abnormal synaptic function and the development of neurons, so they may be pathogenic factors for neurodevelopmental disorders.展开更多
There is by no means a clear-cut pattern of mutations contributing to gastric cancers,and gastric cancer research can be hampered by the diversity of factors that can induce gastric cancer,such as Helicobacter pylori ...There is by no means a clear-cut pattern of mutations contributing to gastric cancers,and gastric cancer research can be hampered by the diversity of factors that can induce gastric cancer,such as Helicobacter pylori infection,diet,ageing and other environmental factors.Tumours are unquestionably riddled with genetic changes yet we are faced with an unsolvable puzzle with respect to a temporal relationship.It is postulated that inherited genetic factors may be more important in early-onset gastric cancer (EOGC) than in gastric cancers found in older patients as they have less exposure to environmental carcinogens.EOGC,therefore,could provide a key to unravelling the genetic changes in gastric carcinogenesis.Gastric cancers occurring in young patients provide an ideal background on which to try and uncover the initiating stages of gastric carcinogenesis.This review summarizes the literature regarding EOGC and also presents evidence that these cancers have a unique molecular-genetic phenotype,distinct from conventional gastric cancer.展开更多
Various early-onset spinal deformities, particularly infantile and juvenile scoliosis(JS), still pose challenges to pediatric orthopedic surgeons. The ideal treatment of these deformities has yet to emerge, as both cl...Various early-onset spinal deformities, particularly infantile and juvenile scoliosis(JS), still pose challenges to pediatric orthopedic surgeons. The ideal treatment of these deformities has yet to emerge, as both clinicians and surgeons still face multiple challenges including preservation of thoracic motion, spine and cage, and protection of cardiac and lung growth and function. Elongation-derotation-flexion(EDF) casting is a technique that uses a custom-made thoracolumbar cast based on a three-dimensional correction concept. EDF can control progression of the deformity and- in some cases-coax the initially-curved spine to grow straighter by acting simultaneously in the frontal, sagittal and coronal planes. Here we provide a comprehensive review of how infantile and JS can affect normal spine and thorax and how serial EDF casting can be used to manage these spinal deformities. A fresh review of the literature helps fully understand the principles of the serial EDF casting technique and the effectiveness of conservative treatment in patients with early-onset spinal deformities, particularly infantile and juvenile scolisois.展开更多
Mutation of the DYT1 gene has been reported to cause early-onset primary torsion dystonia （DYT1） Due to DYT1 gene mutation, defective wild torsinA and the accumulation of mutant torsinA （GAG-deleted DYT1 gene encod...Mutation of the DYT1 gene has been reported to cause early-onset primary torsion dystonia （DYT1） Due to DYT1 gene mutation, defective wild torsinA and the accumulation of mutant torsinA （GAG-deleted DYT1 gene encoded the mutant torsinA, torsinA＆E） play an important role in DYT1 pathogenesis. Intracellular inclusion bodies are formed, and dopamine transport and release are disturbed by interfering functions of endoplasmic reticulum, nuclear membrane, and cytoskeleton of neural cells, resulting in DYT1 onset. Small interfering RNA could serve as a potential therapy for DYT1. However, the exact function of wild torsinA and the pathological effects of torsinAAE require further studies.展开更多
BACKGROUND The incidence of patients with early-onset pancreatic cancer(EOPC;age≤50 years at diagnosis)is on the rise,placing a heavy burden on individuals,families,and society.The role of combination therapy includi...BACKGROUND The incidence of patients with early-onset pancreatic cancer(EOPC;age≤50 years at diagnosis)is on the rise,placing a heavy burden on individuals,families,and society.The role of combination therapy including surgery,radiotherapy,and chemotherapy in non-metastatic EOPC is not well-defined.AIM To investigate the treatment patterns and survival outcomes in patients with non-metastatic EOPC.METHODS A total of 277 patients with non-metastatic EOPC who were treated at our institution between 2017 and 2021 were investigated retrospectively.Overall survival(OS),disease-free survival,and progression-free survival were estimated using the Kaplan-Meier method.Univariate and multivariate analyses with the Cox proportional hazards model were used to identify prognostic factors.RESULTS With a median follow-up time of 34.6 months,the 1-year,2-year,and 3-year OS rates for the entire cohort were 84.3%,51.5%,and 27.6%,respectively.The median OS of patients with localized disease who received surgery alone and adjuvant therapy(AT)were 21.2 months and 28.8 months,respectively(P=0.007).The median OS of patients with locally advanced disease who received radiotherapy-based combination therapy(RCT),surgery after neoadjuvant therapy(NAT),and chemotherapy were 28.5 months,25.6 months,and 14.0 months,respectively(P=0.002).The median OS after regional recurrence were 16.0 months,13.4 months,and 8.9 months in the RCT,chemotherapy,and supportive therapy groups,respectively(P=0.035).Multivariate analysis demonstrated that carbohydrate antigen 19-9 level,pathological grade,T-stage,N-stage,and resection were independent prognostic factors for non-metastatic EOPC.CONCLUSION AT improves postoperative survival in localized patients.Surgery after NAT and RCT are the preferred therapeutic options for patients with locally advanced EOPC.展开更多
BACKGROUND Interleukin 10 receptor alpha subunit(IL10RA)dysfunction is the main cause of very early-onset inflammatory bowel disease(VEO-IBD)in East Asians.AIM To identify disease-causing gene mutations in four patien...BACKGROUND Interleukin 10 receptor alpha subunit(IL10RA)dysfunction is the main cause of very early-onset inflammatory bowel disease(VEO-IBD)in East Asians.AIM To identify disease-causing gene mutations in four patients with VEO-IBD and verify functional changes related to the disease-causing mutations.METHODS From May 2016 to September 2020,four young patients with clinically diagnosed VEO-IBD were recruited.Before hospitalization,using targeted gene panel sequencing and trio-whole-exome sequencing(WES),three patients were found to harbor a IL10RA mutation(c.301C>T,p.R101W in one patient;c.537G>A,p.T179T in two patients),but WES results of the fourth patient were not conclusive.We performed whole-genome sequencing(WGS)on patients A and B and reanalyzed the data from patients C and D.Peripheral blood mononuclear cells(PBMCs)from patient D were isolated and stimulated with lipopolysaccharide(LPS),interleukin 10(IL-10),and LPS+IL-10.Serum IL-10 levels in four patients and tumor necrosis factor-α(TNF-α)in the cell supernatant were determined by enzyme-linked immunosorbent assay.Phosphorylation of signal transducer and activator of transcription 3(STAT3)at Tyr705 and Ser727 in PBMCs was determined by western blot analysis.RESULTS The four children in our study consisted of two males and two females.The age at disease onset ranged from 18 d to 9 mo.After hospitalization,a novel 333-bp deletion encompassing exon 1 of IL10RA was found in patients A and B using WGS and was found in patients C and D after reanalysis of their WES data.Patient D was homozygous for the 333 bp deletion.All four patients had elevated serum IL-10 levels.In vitro,IL-10-stimulated PBMCs from patient D failed to induce STAT3 phosphorylation at Tyr705 and only minimally suppressed TNF-αproduction induced by LPS.Phosphorylation at Ser727 in PBMCs was not affected by LPS or LPS+IL-10 in both healthy subjects and in patient D.CONCLUSION WGS revealed a novel 333-bp deletion of IL10RA in four patients with VEO-IBD,whereas the WES results were inconclusive.展开更多
BACKGROUND The incidence of early-onset colorectal cancer(EO-CRC)is rising in the United States,and is often diagnosed at advanced stages.Low serum ferritin is often incidentally discovered in young adults,however,the...BACKGROUND The incidence of early-onset colorectal cancer(EO-CRC)is rising in the United States,and is often diagnosed at advanced stages.Low serum ferritin is often incidentally discovered in young adults,however,the indication for endoscopy in EO-CRC is unclear.AIM To compare serum ferritin between patients with EO-CRC and healthy controls(HCs),and examine the association of serum ferritin in EO-CRC with patient-and disease-specific characteristics.METHODS A retrospective study of patients<50 years with newly-diagnosed EO-CRC was conducted from 1/2013-12/2023.Patients were included if serum ferritin was measured within 2 years prior to 1 year following CRC histologic diagnosis.To supplement the analysis,a cohort of HCs meeting similar inclusion and exclusion criteria were identified for comparison.A sensitivity analysis including only patients with serum ferritin obtained at or before diagnosis was separately performed to minimize risk of confounding.RESULTS Among 85 patients identified with EO-CRC(48 females),the median serum ferritin level was 26 ng/mL(range<1-2759 ng/mL).Compared to HCs(n=80211),there were a higher proportion of individuals with EO-CRC with serum ferritin<20 ng/mL(female 65%,male 40%)versus HCs(female 32.1%,male 7.2%)age 29-39 years(P=0.002 and P<0.00001,respectively).Stage IV disease was associated with significantly higher serum ferritin compared to less advanced stages(P<0.001).Serum ferritin obtained before or at the time of diagnosis was lower than levels obtained after diagnosis.Similar findings were confirmed in the sensitivity analysis.CONCLUSION Severe iron deficiency may indicate an increased risk of EO-CRC,particularly at earlier stages.Further studies defining the optimal serum ferritin threshold and routine incorporation of serum ferritin in screening algorithms is essential to develop more effective screening strategies for EO-CRC.展开更多
Early-onset colorectal cancer(EOCRC)has seen an alarming rise worldwide over the past two decades.The reason for this global trend is poorly understood.EOCRC appears to have its own unique clinical and molecular featu...Early-onset colorectal cancer(EOCRC)has seen an alarming rise worldwide over the past two decades.The reason for this global trend is poorly understood.EOCRC appears to have its own unique clinical and molecular features when compared with late-onset colorectal cancer.Younger patients appear to have more distal or rectal disease,a more advanced stage of disease at presentation,and more unfavorable histological features.Identifying risk factors for EOCRC is the first step in mitigating the rising burden of this disease.Here we summarize several noteworthy biological factors and environmental exposures that are postulated to be responsible culprits.This can hopefully translate in clinical practice to the development of better risk stratification tool for identifying highrisk individuals for early colorectal cancer screening,and identifying areas needed for further research to curb this rising trend.展开更多
基金funded Chongqing Science and Health Joint Research Project in TCM(Grant No.2024ZYDB002).
文摘Objective:This study aimed to assess the global,regional,and national burden of early-onset gastric cancer(EOGC)and the attributable risk factors from 1990-2021 with projections extending to 2040.Methods:The EOGC burden was quantified using incidence,prevalence,mortality,and disability-adjusted life years(DALYs)with calculation of age-standardized rates.The risk factor contributions were analyzed and disparities were evaluated using the slope index of inequality.Future trends for 2021-2040 were estimated using a Bayesian age-period-cohort model.Results:There were approximately 125,000 new cases of EOGC globally in 2021 with an estimated 336,000 individuals living with EOGC and 78,000 associated deaths,contributing to 3.86 million DALYs.The highest EOGC incidence rates existed among individuals 45-49 years of age.The global age-standardized incidence,prevalence,mortality,and DALY rates demonstrated an overall decline between 1990 and 2021.Smoking and high-salt dietary intake were the leading risk factors for DALYs with regional and gender-based variations.Smoking accounted for>10% of DALYs in Central Europe and East Asia,while high-salt dietary intake accounted for approximately 8% of DALYs.Despite the overall decline in the EOGC burden,disparities across geographic regions widened.Projections indicated a continued gradual reduction in EOGC burden through 2040.Conclusion:Although the global burden of EOGC has decreased,significant disparities persist across geographic regions,age groups,and genders.Public health interventions should combine smoking prevention strategies(e.g.,youth education and tobacco taxation)with cessation programs with dietary salt reduction initiatives.
文摘BACKGROUND Hereditary factors are more prevalent in early-onset colorectal cancers(EOCRC)etiology.Lynch syndrome(LS)is the most common hereditary colorectal cancer(CRC)syndrome that results from mutations in DNA mismatch repair(MMR)genes.This phenomenon is defined as microsatellite instability(MSI).Immunohistochemistry(IHC)is a widely used,practical,and cost-effective method for the screening of MSI.However,using IHC alone may be insufficient to identify patients with MSI and LS.AIM To determine the clinicopathological features in EOCRC,IHC performance,and the frequency of genetic testing for EOCRC patients.METHODS A retrospective review was conducted on patients with CRC aged≤50 years who underwent surgery at our center between January 2014 and July 2021.MMR proteins were screened using IHC.Of the 131 patients included,IHC was performed on 130.Patients were classified as MSI or microsatellite-stable(MSS),and their features were compared.Additionally,data from patients who received genetic counseling were analyzed.RESULTS Thirty patients with MSI were designated as group 1,whereas 100 with MSS were defined as group 2.The mean age in group 1 was the lowest(median age:42 vs 46,P<0.05).Group 1 exhibited a higher frequency of tumors in the right colon and a lower frequency in the rectum.Lymph node involvement and distant metastases were less common in group 1,and in group 2,tumors were generally diagnosed at a more advanced stage.Genetic testing was performed in 53 patients(40%),with a definitive LS diagnosis established in 13/17 patients(76.4%)in group 1 and 1/36(2.7%)patients in group 2,resulting in a total of 14 patients(26.4%)with confirmed LS.CONCLUSION MSI tumors show a better prognosis.IHC is very effective for screening MSI,but may not be sufficient alone.Low genetic counseling rates highlight the need for hospital-based surveillance programs.
基金supported by Diabetes Talent Research Project of China,International Medical Foundation 2019(No.2018-N-1).
文摘Background The molecular mechanisms of early-onset multigenerational diabetes remain unknown.This study aimed to investigate the clinical and genetic characteristics of early-onset diabetes involving at least two consecutive generations.Methods From 1296 inpatients with diabetes,we selected individuals who were≤30 years of age and who were clinically suspected of having familial monogenic diabetes.Clinical data were collected from the probands and their family members.Whole-exome sequencing(WES)was used to identify possible causal variants for diabetes.Candidate pathogenic variants were verified by Sanger sequencing,assessed for cosegregation in family members,and evaluated on the basis of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology(ACMG/AMP)guidelines.Moreover,missense and synonymous variants were subjected to in silico pathogenicity prediction via MutationTaster and PolyPhen-2.RNAfold was used to predict RNA structural alterations for synonymous variants.Results Twenty-five early-onset diabetes patients with a history of familial diabetes were enrolled.Pathogenic/likely pathogenic variants(p.Gly292fs in HNF1A,p.Gly245Argfs*22 in PDX1,p.Asp329His in KCNJ11,p.Leu734Phe and p.Val606Gly in WFS1)were detected in four patients,who were diagnosed accurately and treated with reasonable hypoglycemic agents based on genetic testing results.The variants of uncertain significance(ABCC8 c.3039 G>A(p.Ser1013=Ser),MAPK8IP1 p.Gln144_Gly145insSerGln,and TBC1D4 p.Arg1249Trp)were identified in three probands.Conclusion Patients with early-onset diabetes involving at least two consecutive generations may harbor genetic variants.Genetic testing in this population enables precision diagnosis,informs individualized treatment,and facilitates genetic counseling.
文摘BACKGROUND Colorectal cancer(CRC)is the second leading cause of cancer-related deaths worldwide with an alarming rise in early-onset CRC(eoCRC)over the past several decades.Unlike late-onset CRC,the drivers behind eoCRC remain less clear.While certain risk factors such as obesity and smoking have demonstrated a relatively strong association with eoCRC in the literature,some studies have challenged these associations,emphasizing the need for additional studies.METHODS This cross-sectional study used de-identified data from the National Health and Nutrition Examination Survey(1999-2023),including 30321 United States adults aged 18 to 49 years.Participants with missing key variables were excluded.Standardized protocols were used to collect demographic,lifestyle,anthropo-metric[body mass index(BMI),body roundness index(BRI),waist circumference(WC)],and self-reported CRC data.Logistic regression and propensity score matching assessed associations between obesity-related parameters and eoCRC.Statistical analyses were performed in R and Stata,with P<0.05 defined as significant.RESULTS Of 30321 participants,48 received a diagnosis of eoCRC.Patients with eoCRC were older(mean age 39.96 years vs 34.36 years;P<0.001)and had higher WC and BRI.None of the eoCRC patients were heavy drinkers(P=0.006).Unadjusted models demonstrated significant associations of eoCRC with BRI quartiles,as well as BMI-defined obesity,WC,and smoking.In unadjusted models,BRI remained the strongest independent predictor;those in the highest BRI quartiles had over 10-fold greater odds of eoCRC.In fully adjusted models,BRI remained significant,but BMI-and waist-based obesity were not.CONCLUSION BRI is a stronger predictor of eoCRC risk compared to other obesity indices and is a superior tool for identifying young individuals at higher risk of CRC.
文摘BACKGROUND The incidence of oesophageal adenocarcinoma(OAC)has been reported to be increasing in many countries.Alongside this trend,an increase in incidence of early-onset OAC,defined as OAC in adults aged under 50 years,has been observed.It is unclear whether survival outcomes for early-onset OAC patients differ from older age groups.AIM To investigate survival outcomes in early-onset OAC patients.METHODS Ovid Medline and Embase were searched from inception to January 2022 for relevant studies relating to early-onset OAC and survival outcomes.Results regarding the overall five-year survival and risk of death of younger and older patients with OAC were extracted and pooled using meta-analyses to produce pooled estimates and 95%CIs where possible.RESULTS Eleven studies which compared survival of early-onset OAC,defined as age at diagnosis of<50 years,with older patients were included.A narrative review of median and mean survival demonstrated conflicting results,with studies showing early-onset OAC patients having both better and worse outcomes compared to older age groups.A meta-analysis of five-year survival demonstrated similar outcomes across age groups,with 22%-25%of patients in the young,middle and older age groups alive after five years.A meta-analysis of four studies demon-strated that early-onset OAC patients did not have a significantly increased risk of death compared to middle-aged patients(hazard ratio 1.12,95%CI:0.85-1.47).INTRODUCTION There is concern that the incidence of oesophageal adenocarcinoma(OAC)in patients under 50,described as early-onset OAC,is increasing.However,data regarding survival of younger patients with OAC is sparse.Globally,while increasing age remains a major non-modifiable risk factor for cancer,the incidence of early-onset cancers,largely accepted to be in adults aged under 50 years,is increasing[1].This includes an observed increase in the incidence of gastrointestinal malignancies such as colorectal,oesophageal,gastric and hepatobiliary cancers[2-4].Despite oesophageal squamous cell carcinoma(OSCC)being more common globally(88%of cases)[5],a striking increase in oesophageal OAC incidence has been reported in developed countries,such as the United States and Europe[6,7].Worryingly,the United Kingdom has the highest incidence of OAC cases in the world[8].In addition to the increase in OAC,an increase in incidence of early-onset OAC,defined as OAC in adults aged under 50 years,has been observed[9,10].A population-based cohort in the Netherlands,consisting of 59584 patients,demonstrated the incidence of early-onset OAC to have tripled from 1989 to 2018,while OSCC cases declined in this age group[7].OAC usually develops in the lower third of the oesophagus and the gastro-oesophageal junction,with risk factors including obesity and gastro-oesophageal reflux disease[11].A poor prognosis is observed,with the overall five-year survival rate for oesophageal cancer between 15%-20%,even with treatment[12,13].These low survival rates are likely due to a combination of late diagnosis,intrinsic resistance to systemic therapy and the limited efficacy of surgical resection.Younger patients tend to present at a more advanced stage at diagnosis compared to those diagnosed later in life.A single centre,retrospective study found that 33.3%of patients in the younger age category(<50 years old)presented with stage IV OAC,compared to the 20.6%of the oldest age category(>70 years old)[14].Another population-based study in the Netherlands observed that OAC patients under 50 years old also presented with distant metastasis more often in comparison to older patients(50.5%vs 44.7%),and that tumour differentiation also varied between age groups[15].Reports of survival estimates in patients with early-onset OAC compared with older patients have resulted in contrasting findings to date.Some studies report that due to the advanced stage and aggressiveness of the tumours seen that the prognosis of these patients is almost always worse than their older counterparts[16].In contrast,another study found that the overall survival,as well as stage-specific survival was higher in those who were younger[17].A Dutch study which included only resectable cases found no difference in 5-year disease specific survival[18].Given the conflicting evidence to date,the aim of this systematic review was to investigate survival in OAC patients according to age at diagnosis.A protocol was composed,and the reporting of this systematic review designed,using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines[19].The protocol included:The review question,search strategy,inclusion criteria,type of quality assessment,the strategy for data analysis,and the‘population,intervention,comparator,and outcome’criteria.These are expanded below.
文摘The aim of this research was to study the clinical features and microvascular complications risk factors of early-onset type 2 diabetes mellitus(T2DM).We analyzed the clinical data from 1421 T2DM inpatients at Wuhan Union Hospital.Subjects were divided into early-onset T2DM group(diagnostic age<40 years)and late-onset T2DM group(diagnostic age>40 years).All subjects underwent a standardized assessment of microvascular complications.Data were compared with independent-samples t test or Chi-square test.Multiple logistic regression was used to determine the risk factors of microvascular complications.Patients with early-onset T2DM were more inclined to have a lower systolic blood pressure(SBP),a longer duration of diabetes and higher levels of body mass index(BM1),uric acid(UA),fasting plasma glucose(FPG),total cholesterol(TC),triglyceride(TG)and glycosylated hemoglobin(HbAlc)than those with lateonset T2DM(P<0.05).The prevalence of diabetic retinopathy(DR)was significantly higher and that of diabetic peripheral neuropathy(DPN)was significantly lower in early-onset group than in late-onset group(P<0.05).For DN,UA was an independent risk factor in early-onset T2DM.SBP and TG were independent risk factors in late-onset T2DM.For DR,duration of diabetes and SBP were independent risk factors in early-onset T2DM.Duration of diabetes,SBP and HbAlc were independent risk factors in late-onset T2DM.This study demonstrated that the clinical characteristics of early-onset T2DM were metabolic disorders,including glucose metabolism,lipid metabolism and amino acid metabolism.Early-onset T2DM was more likely to be associated with DR.The potential pathogenesis of early and late-onset T2DM might be different.The management of metabolic risk factors especially HbA1c,SBP,TG and UA is advised to be performed in the early stage of diabetes.
文摘Colorectal cancer is the third most common cancer diagnosed worldwide. Although epidemiology data show a marked variability around the world, its overall incidence rate shows a slow but steady decrease, mainly in developed countries. Conversely, early-onset colorectal cancer appears to display an opposite trend with an overall prevalence in United States and European Union ranging from 3.0% and 8.6%. Colorectal cancer has a substantial proportion of familial cases. In particular, early age at onset is especially suggestive of hereditary predisposition. The clinicopathological and molecular features of colorectal cancer cases show a marked heterogeneity not only between early- and late-onset cases but also within the early-onset group. Two distinct subtypes of early-onset colorectal cancers can be identified: a “sporadic” subtype, usually without family history, and an inherited subtype arising in the context of well defined hereditary syndromes. The pathogenesis of the early-onset disease is substantially well characterized in the inherited subtype, which is mainly associated to the Lynch syndrome and occasionally to other rare mendelian diseases, whereas in the “sporadic” subtype the origin of the disease may be attributed to the presence of various common/rare genetic variants, so far largely unidentified, displaying variable penetrance. These variants are thought to act cumulatively to increase the risk of colorectal cancer, and presumably to also anticipate its onset. Efforts are ongoing in the attempt to unravel the intricate genetic basis of this “sporadic” early-onset disease. A better knowledge of molecular entities and pathways may impact on family-tailored prevention and clinical management strategies.
文摘Colorectal cancer(CRC)is one of the most prevalent malignancies worldwide.Although most prevalent among older people,its incidence above 50 years old has been decreasing globally in the last decades,probably as a result of better screening.Paradoxically,its incidence in patients below 50 years old[early-onset CRC(EO-CRC)]has been increasing,for reasons not yet fully understood.EOCRC’s increasing incidence is genre independent but shows racial disparities and has been described to occur worldwide.It follows a birth-cohort effect which probably reflects a change in exposure to CRC risk factors.Its incidence is predicted to double until 2030,which makes EO-CRC a serious public health issue.Both modifiable and non-modifiable risk factors have been identified-some are potential targets for preventive measures.EO-CRC is often diagnosed at advanced stages and histological features associated with poor prognosis have been described.EO-CRC presents some distinctive features:Microsatellite instability is common,but another subtype of tumours,both microsatellite and chromosome stable also seems relevant.There are no age-specific treatment protocols and studies on EO-CRC survival rates have shown conflicting data.Due to the higher germline pathological mutations found in EO-CRC patients,an accurate genetic risk evaluation should be performed.In this review,we summarize the current evidence on epidemiological,clinical,histopathological and molecular features of EO-CRC and discuss the contribution of genetics and lifestyle risk factors.We further comment on screening strategies and specific dimensions to consider when dealing with a younger cancer patient.
文摘Colorectal cancer(CRC) is the third most frequent cancer type and the incidence of this disease is increasing gradually per year in individuals younger than 50 years old. The current knowledge is that early-onset CRC(EOCRC) cases are heterogeneous population that includes both hereditary and sporadic forms of the CRC. Although EOCRC cases have some distinguishing clinical and pathological features than elder age CRC, the molecular mechanism underlying the EOCRC is poorly clarified. Given the significance of CRC in the world of medicine, the present review will focus on the recent knowledge in the molecular basis of genetic and epigenetic mechanism of the hereditary forms of EOCRC, which includes Lynch syndrome, Familial CRC type X, Familial adenomatous polyposis, Mut YH-associated polyposis, Juvenile polyposis syndrome, Peutz-Jeghers Syndrome and sporadic forms of EOCRC. Recent findings about molecular genetics and epigenetic basis of EOCRC gave rise to new alternative therapy protocols. Although exact diagnosis of these cases still remains complicated, the present review paves way for better predictions and contributes to more accurate diagnostic and therapeutic strategies into clinical approach.
基金Supported by A grant from the Polish Ministry of Science and Higher EducationNo.N N402 423838
文摘Currently, gastric cancer(GC) is one of the most frequently diagnosed neoplasms, with a global burden of 723000 deaths in 2012. It is the third leading cause of cancer-related death worldwide. There are numerous possible factors that stimulate the procarcinogenic activity of important genes. These factors include genetic susceptibility expressed in a singlenucleotide polymorphism, various acquired mutations(chromosomal instability, microsatellite instability, somatic gene mutations, epigenetic alterations) and environmental circumstances(e.g., helicobcter pylori infection, EBV infection, diet, and smoking). Most of the aforementioned pathways overlap, and authors agree that a clear-cut pathway for GC may not exist. Thus, the categorization of carcinogenic events is complicated. Lately, it has been claimed that research on early-onset gastric carcinoma(EOGC) and hereditary GC may contribute towards unravelling some part of the mystery of the GC molecular pattern because young patients are less exposed to environmental carcinogens and because carcinogenesis in this setting may be more dependent on genetic factors. The comparison of various aspects that differ and coexist in EOGCs and conventional GCs might enable scientists to: distinguish which features in the pathway of gastric carcinogenesisare modifiable, discover specific GC markers and identify a specific target. This review provides a summary of the data published thus far concerning the molecular characteristics of GC and highlights the outstanding features of EOGC.
基金Supported by Project PI10/0683 from the Spanish Ministry of Health and Consumer Affairs
文摘Colorectal cancer(CRC)has a great impact on the world population.With increasing frequency,CRC is described according to the presenting phenotype,based on its molecular characteristics.Classification of CRC tumors according to their genetic and/or epigenetic alterations is not only important for establishing the molecular bases of the disease,but also for predicting patient outcomes and developing more individualized treatments.Early-onset CRC is a heterogeneous disease,with a strong familial component,although the disease is sporadic in an important proportion of cases.Different molecular alterations appear to contribute to the apparent heterogeneity of the early-onset population and subgroups can be distinguished with distinct histopathologic and familial characteristics.Moreover,compared with late-onset CRC,there are characteristicsthat suggest that early-onset CRC may have a different molecular basis.The purpose of this review was to analyze the current state of knowledge about earlyonset CRC with respect to clinicopathologic,familial and molecular features.Together,these features make it increasingly clear that this subset of CRC may be a separate disease,although it has much in common with late-onset CRC.
基金partially supported by the National Natural Science Foundation of China(81070171,81241121)the Specialized Research Fund for the Doctoral Program of Higher Education of China(20111106110013)+2 种基金the Capital Special Foundation of Clinical Application Research(Z121107001012015)the Capital Health Development Fund(2011400302)the Beijing Natural Science Foundation(7131014)
文摘Objective Very early-onset coronary artery disease （CAD） is a great challenge in cardiovascular medicine throughout the world, especially regarding its early diagnosis. This study explored whether circulating microRNAs （miRNAs） could be used as potential biomarkers for patients with very early-onset CAD. Methods We performed an initial screening of miRNA expression using RNA isolated from 20 patients with angiographically documented very early-onset CAD and 20 age- and sex-matched normal controls. For further confirmation, we prospectively examined the miRNAs selected from 40 patients with very early-onset CAD and 40 angiography-normal controls. Results A total of 22 overexpressed miRNAs and 22 underexpressed miRNAs were detected in the initial screening. RT-qPCR analysis of the miRNAs obtained from the initial screening revealed that four miRNAs including miR-196-5p, miR-3163-3p, miR-145-3p, and miR-190a-5p exhibited significantly decreased expression in patients compared with that in controls （P〈0.05）. The areas under the receiver operating characteristic curve for these miRNAs were 0.824 （95% CI, 0.731-0.917; P〈0.001）, 0.758 （95% CI, 0.651-0.864; P〈0.001）, 0.753 （95% CI, 0.643-0.863; P〈0.001）, and 0.782 （95% CI, 0.680-0.884; P〈0.001）, respectively, in the validation set. Conclusion To our knowledge, this is an advanced study to report about four serum miRNAs （miR-196-5p, miR-3163-3p, miR-145-3p, and miR-190a-5p） that could be used as novel biomarkers for the diagnosis of very early-onset CAD.
基金supported by the National Natural Science Foundation of China (81741087, 91432111, 31625013, and 81471484)the Science and Technology Commission of Shanghai Municipality, China (14411950402)+1 种基金a Shanghai Municipal Science and Technology Major Project (#018SHZDZX05)the Postdoctoral Science Foundation of China (2017M621361)
文摘Early-onset epilepsy is a neurological abnormality in childhood, and it is especially common in the first2 years after birth. Seizures in early life mostly result from structural or metabolic disorders in the brain, and the genetic causes of idiopathic seizures have been extensively investigated. In this study, we identified four missense mutations in the SETD1 A gene(SET domain-containing 1 A, histone lysine methyltransferase): three de novo mutations in three individuals and one inherited mutation in a four-generation family. Whole-exome sequencing indicated that all four of these mutations were responsible for the seizures. Mutations of SETD1 A have been implicated in schizophrenia and developmental disorders, so we examined the role of the four mutations(R913 C, Q269 R, G1369 R, and R1392 H) in neural development. We found that their expression in mouse primary cortical neurons affected excitatory synapse development. Moreover, expression of the R913 C mutation also affected the migration of cortical neurons in the mouse brain.We further identified two common genes(Neurl4 and Usp39) affected by mutations of SETD1 A. These results suggested that the mutations of SETD1 A play a fundamental role in abnormal synaptic function and the development of neurons, so they may be pathogenic factors for neurodevelopmental disorders.
文摘There is by no means a clear-cut pattern of mutations contributing to gastric cancers,and gastric cancer research can be hampered by the diversity of factors that can induce gastric cancer,such as Helicobacter pylori infection,diet,ageing and other environmental factors.Tumours are unquestionably riddled with genetic changes yet we are faced with an unsolvable puzzle with respect to a temporal relationship.It is postulated that inherited genetic factors may be more important in early-onset gastric cancer (EOGC) than in gastric cancers found in older patients as they have less exposure to environmental carcinogens.EOGC,therefore,could provide a key to unravelling the genetic changes in gastric carcinogenesis.Gastric cancers occurring in young patients provide an ideal background on which to try and uncover the initiating stages of gastric carcinogenesis.This review summarizes the literature regarding EOGC and also presents evidence that these cancers have a unique molecular-genetic phenotype,distinct from conventional gastric cancer.
文摘Various early-onset spinal deformities, particularly infantile and juvenile scoliosis(JS), still pose challenges to pediatric orthopedic surgeons. The ideal treatment of these deformities has yet to emerge, as both clinicians and surgeons still face multiple challenges including preservation of thoracic motion, spine and cage, and protection of cardiac and lung growth and function. Elongation-derotation-flexion(EDF) casting is a technique that uses a custom-made thoracolumbar cast based on a three-dimensional correction concept. EDF can control progression of the deformity and- in some cases-coax the initially-curved spine to grow straighter by acting simultaneously in the frontal, sagittal and coronal planes. Here we provide a comprehensive review of how infantile and JS can affect normal spine and thorax and how serial EDF casting can be used to manage these spinal deformities. A fresh review of the literature helps fully understand the principles of the serial EDF casting technique and the effectiveness of conservative treatment in patients with early-onset spinal deformities, particularly infantile and juvenile scolisois.
基金the National Natural Science Foundation of China,No.30400144
文摘Mutation of the DYT1 gene has been reported to cause early-onset primary torsion dystonia （DYT1） Due to DYT1 gene mutation, defective wild torsinA and the accumulation of mutant torsinA （GAG-deleted DYT1 gene encoded the mutant torsinA, torsinA＆E） play an important role in DYT1 pathogenesis. Intracellular inclusion bodies are formed, and dopamine transport and release are disturbed by interfering functions of endoplasmic reticulum, nuclear membrane, and cytoskeleton of neural cells, resulting in DYT1 onset. Small interfering RNA could serve as a potential therapy for DYT1. However, the exact function of wild torsinA and the pathological effects of torsinAAE require further studies.
文摘BACKGROUND The incidence of patients with early-onset pancreatic cancer(EOPC;age≤50 years at diagnosis)is on the rise,placing a heavy burden on individuals,families,and society.The role of combination therapy including surgery,radiotherapy,and chemotherapy in non-metastatic EOPC is not well-defined.AIM To investigate the treatment patterns and survival outcomes in patients with non-metastatic EOPC.METHODS A total of 277 patients with non-metastatic EOPC who were treated at our institution between 2017 and 2021 were investigated retrospectively.Overall survival(OS),disease-free survival,and progression-free survival were estimated using the Kaplan-Meier method.Univariate and multivariate analyses with the Cox proportional hazards model were used to identify prognostic factors.RESULTS With a median follow-up time of 34.6 months,the 1-year,2-year,and 3-year OS rates for the entire cohort were 84.3%,51.5%,and 27.6%,respectively.The median OS of patients with localized disease who received surgery alone and adjuvant therapy(AT)were 21.2 months and 28.8 months,respectively(P=0.007).The median OS of patients with locally advanced disease who received radiotherapy-based combination therapy(RCT),surgery after neoadjuvant therapy(NAT),and chemotherapy were 28.5 months,25.6 months,and 14.0 months,respectively(P=0.002).The median OS after regional recurrence were 16.0 months,13.4 months,and 8.9 months in the RCT,chemotherapy,and supportive therapy groups,respectively(P=0.035).Multivariate analysis demonstrated that carbohydrate antigen 19-9 level,pathological grade,T-stage,N-stage,and resection were independent prognostic factors for non-metastatic EOPC.CONCLUSION AT improves postoperative survival in localized patients.Surgery after NAT and RCT are the preferred therapeutic options for patients with locally advanced EOPC.
基金the National Natural Science Foundation of China,No.81741103.
文摘BACKGROUND Interleukin 10 receptor alpha subunit(IL10RA)dysfunction is the main cause of very early-onset inflammatory bowel disease(VEO-IBD)in East Asians.AIM To identify disease-causing gene mutations in four patients with VEO-IBD and verify functional changes related to the disease-causing mutations.METHODS From May 2016 to September 2020,four young patients with clinically diagnosed VEO-IBD were recruited.Before hospitalization,using targeted gene panel sequencing and trio-whole-exome sequencing(WES),three patients were found to harbor a IL10RA mutation(c.301C>T,p.R101W in one patient;c.537G>A,p.T179T in two patients),but WES results of the fourth patient were not conclusive.We performed whole-genome sequencing(WGS)on patients A and B and reanalyzed the data from patients C and D.Peripheral blood mononuclear cells(PBMCs)from patient D were isolated and stimulated with lipopolysaccharide(LPS),interleukin 10(IL-10),and LPS+IL-10.Serum IL-10 levels in four patients and tumor necrosis factor-α(TNF-α)in the cell supernatant were determined by enzyme-linked immunosorbent assay.Phosphorylation of signal transducer and activator of transcription 3(STAT3)at Tyr705 and Ser727 in PBMCs was determined by western blot analysis.RESULTS The four children in our study consisted of two males and two females.The age at disease onset ranged from 18 d to 9 mo.After hospitalization,a novel 333-bp deletion encompassing exon 1 of IL10RA was found in patients A and B using WGS and was found in patients C and D after reanalysis of their WES data.Patient D was homozygous for the 333 bp deletion.All four patients had elevated serum IL-10 levels.In vitro,IL-10-stimulated PBMCs from patient D failed to induce STAT3 phosphorylation at Tyr705 and only minimally suppressed TNF-αproduction induced by LPS.Phosphorylation at Ser727 in PBMCs was not affected by LPS or LPS+IL-10 in both healthy subjects and in patient D.CONCLUSION WGS revealed a novel 333-bp deletion of IL10RA in four patients with VEO-IBD,whereas the WES results were inconclusive.
基金Supported by the Oregon Health&Sciences(OHSU)Institutional Review Board,No.STUDY00026428.
文摘BACKGROUND The incidence of early-onset colorectal cancer(EO-CRC)is rising in the United States,and is often diagnosed at advanced stages.Low serum ferritin is often incidentally discovered in young adults,however,the indication for endoscopy in EO-CRC is unclear.AIM To compare serum ferritin between patients with EO-CRC and healthy controls(HCs),and examine the association of serum ferritin in EO-CRC with patient-and disease-specific characteristics.METHODS A retrospective study of patients<50 years with newly-diagnosed EO-CRC was conducted from 1/2013-12/2023.Patients were included if serum ferritin was measured within 2 years prior to 1 year following CRC histologic diagnosis.To supplement the analysis,a cohort of HCs meeting similar inclusion and exclusion criteria were identified for comparison.A sensitivity analysis including only patients with serum ferritin obtained at or before diagnosis was separately performed to minimize risk of confounding.RESULTS Among 85 patients identified with EO-CRC(48 females),the median serum ferritin level was 26 ng/mL(range<1-2759 ng/mL).Compared to HCs(n=80211),there were a higher proportion of individuals with EO-CRC with serum ferritin<20 ng/mL(female 65%,male 40%)versus HCs(female 32.1%,male 7.2%)age 29-39 years(P=0.002 and P<0.00001,respectively).Stage IV disease was associated with significantly higher serum ferritin compared to less advanced stages(P<0.001).Serum ferritin obtained before or at the time of diagnosis was lower than levels obtained after diagnosis.Similar findings were confirmed in the sensitivity analysis.CONCLUSION Severe iron deficiency may indicate an increased risk of EO-CRC,particularly at earlier stages.Further studies defining the optimal serum ferritin threshold and routine incorporation of serum ferritin in screening algorithms is essential to develop more effective screening strategies for EO-CRC.
文摘Early-onset colorectal cancer(EOCRC)has seen an alarming rise worldwide over the past two decades.The reason for this global trend is poorly understood.EOCRC appears to have its own unique clinical and molecular features when compared with late-onset colorectal cancer.Younger patients appear to have more distal or rectal disease,a more advanced stage of disease at presentation,and more unfavorable histological features.Identifying risk factors for EOCRC is the first step in mitigating the rising burden of this disease.Here we summarize several noteworthy biological factors and environmental exposures that are postulated to be responsible culprits.This can hopefully translate in clinical practice to the development of better risk stratification tool for identifying highrisk individuals for early colorectal cancer screening,and identifying areas needed for further research to curb this rising trend.
