Objective The aim of this study was to investigate the value of the 8th American Joint Committee on Cancer(AJCC)anatomic and prognostic stage groups for penile cancer patients and explore whether there is room for imp...Objective The aim of this study was to investigate the value of the 8th American Joint Committee on Cancer(AJCC)anatomic and prognostic stage groups for penile cancer patients and explore whether there is room for improvement.Methods The clinical and histopathologic data from 16 centers between January 2000 and December 2021 were assessed according to the 8th AJCC anatomic and prognostic stage groups.Kaplan–Meier plots were used to estimate the disease-specific survival(DSS)of the patients.The accuracy of the staging systems was investigated using the Harrell's concordance index(C-index).Results According to the 8th AJCC anatomic and prognostic stage groups,the 5-year DSS rates for patients with stages 0is/a,I,IIA,IIB,IIIA,IIIB,and IV disease were 100%,99%,86%,81%,66%,34%,and 23%,respectively(p_(0is/a–I)=0.8,p_(I–IIA)<0.001,p_(IIA–IIB)=0.5,p_(IIB–IIIA)<0.001,p_(IIIA–IIIB)<0.001,p_(IIIB–IV)=0.004,and p_(Total)<0.001).According to the modified model 1 system,the 5-year DSS rates without survivorship overlap for patients with stages 0is/a,I,II,IIIA,IIIB,and IV disease were 100%,99%,88%,66%,34%,and 23%,respectively(p_(0is/a–I)=0.8,p_(I–II)<0.001,p_(II–IIIA)=0.002,p_(IIIA–IIIB)<0.001,p_(IIIB–IV)=0.004,and p_(Total)<0.001).Similarly,according to the modified model 2 system,the 5-year DSS rates without survivorship overlap for patients with stages 0is/a,I,II,IIIA,IIIB,and IV disease were 100%,99%,86%,66%,34%,and 23%,respectively(p_(0is/a–I)=0.8,p_(I–II)<0.001,p_(II–IIIA)=0.008,p_(IIIA–IIIB)<0.001,p_(IIIB–IV)=0.004,and p_(Total)<0.001).The C-index scores of the simple modified staging systems were not inferior to those of the AJCC anatomic and prognostic stage groups.These results were confirmed by the bootstrap internal validation.Conclusion There is still room for improvement about the 8th AJCC anatomic and prognostic stage groups.The improved models,which are more concise and convenient,have similar prediction accuracy.展开更多
Ischemic heart disease(IHD)remains a leading contributor to cardiovascular disease(CVD)worldwide.Despite advances in diagnostic and therapeutic approaches,translational research demands robust large animal models to b...Ischemic heart disease(IHD)remains a leading contributor to cardiovascular disease(CVD)worldwide.Despite advances in diagnostic and therapeutic approaches,translational research demands robust large animal models to bridge the gap between experimental interventions and clinical application.Among these,porcine models have gained prominence due to their anatomical,physiological,immunological,and genomic similarities to humans.This review provides a comprehensive overview of current methodologies for establishing porcine IHD models,critically assesses emerging rehabilitative strategies,and outlines innovative therapeutic technologies,with the goal of guiding model selection and fostering the development of novel treatment strategies.展开更多
The ambiguity of etiology makes temporomandibular joint osteoarthritis(TMJOA)“difficult-to-treat”.Emerging evidence underscores the therapeutic promise of exosomes in osteoarthritis management.Nonetheless,challenges...The ambiguity of etiology makes temporomandibular joint osteoarthritis(TMJOA)“difficult-to-treat”.Emerging evidence underscores the therapeutic promise of exosomes in osteoarthritis management.Nonetheless,challenges such as low yields and insignificant efficacy of current exosome therapies necessitate significant advances.Addressing lower strontium(Sr)levels in arthritic synovial microenvironment,we studied the effect of Sr element on exosomes and miRNA selectively loading in synovial mesenchymal stem cells(SMSCs).Here,we developed an optimized system that boosts the yield of SMSC-derived exosomes(SMSCEXOs)and improves their miRNA profiles with an elevated proportion of beneficial miRNAs,while reducing harmful ones by pretreating SMSCs with Sr.Compared to untreated SMSC-EXOs,Sr-pretreated SMSC-derived exosomes(Sr-SMSC-EXOs)demonstrated superior therapeutic efficacy by mitigating chondrocyte ferroptosis and reducing osteoclast-mediated joint pain in TMJOA.Our results illustrate Alix’s crucial role in Sr-triggered miRNA loading,identifying miR-143-3p as a key anti-TMJOA exosomal component.Interestingly,this system is specifically oriented towards synovium-derived stem cells.The insight into trace elementdriven,site-specific miRNA selectively loading in SMSC-EXOs proposes a promising therapeutic enhancement strategy for TMJOA.展开更多
Cancer immunotherapy harnesses the immune system to attack tumors and has received extensive attention in recent years.Cancer vaccines as an important branch of immunotherapy are designed for delivering tumor antigens...Cancer immunotherapy harnesses the immune system to attack tumors and has received extensive attention in recent years.Cancer vaccines as an important branch of immunotherapy are designed for delivering tumor antigens to antigen-presenting cells(APCs)to stimulate a strong immune response to against tumors,representing a potentially therapeutic and prophylactic effect with the long-term anticancer benefits.Nevertheless,the disappointing outcomes of their clinical use might be attributed to dilemma in antigen selection,immunogenicity,lymph nodes(LNs)targeting ability,lysosomal escape ability,immune evasion,etc.Nanotechnology,aiming to overcome these barriers,has been utilized in cancer vaccine development for decades.Numerous preclinical and clinical studies demonstrate positive results in nanomaterials-based cancer vaccines with considerable improvement in the vaccine efficacy.In this review,we systematically introduced the characteristics of nanovaccines and highlighted the different types of nanomaterials used for cancer vaccine design.In addition,the opportunities and challenges of the emerging nanotechnology-based cancer vaccines were discussed.展开更多
Aim: A new concept of locomotive syndrome has been proposed by the Japanese Orthopaedic Association. The aim of this study is to clarify the utility of its self-checklist, “loco-check,” as a tool for estimating the ...Aim: A new concept of locomotive syndrome has been proposed by the Japanese Orthopaedic Association. The aim of this study is to clarify the utility of its self-checklist, “loco-check,” as a tool for estimating the physical dysfunction of elderly people. Methods: Subjects were 1124 community-dwelling Japanese people, 557 men and 567 women, aged 40-89 years. Information about the seven “loco-check” items was obtained from present inquiry sheets. Physical functions were examined by grip strength, knee extension strength, walking speed and one-leg standing time with open eyes. The averages of these test values, controlled for age and BMI, were compared between the “loco-check” (+) group and the “loco-check” (-) group. Also we examined about the trend of decline of physical function, together with SF36 physical function subscale score, as the number of the items chosen increased. Results: Adjusted average values of all four physical function examinations in the “lococheck” (+) group were significantly lower than those of the “loco-check” (-) group (all, p . Also the adjusted average values of the majority of four tests were significantly lower in those who checked each of the “loco-check” items than those who did not, for most of the items. It was also revealed that the more items subjects checked, the lower the adjusted average values were, except for one-leg standing time. It was also the case with SF36 physical function subscale score. Conclusion: We showed the utility of “loco-check” as a simple tool not only for noticing the physical dysfunction of elderly people, but also for estimating the extent of it, except for balancing ability, particularly by counting the number of checked items.展开更多
Dendron-polymer-based nanoscale and stimuli-responsive drug delivery systems have shown great promise in tumor-targeting accumulation without significant toxicity.Here we report a dendronized polymer-doxorubicin(DOX)h...Dendron-polymer-based nanoscale and stimuli-responsive drug delivery systems have shown great promise in tumor-targeting accumulation without significant toxicity.Here we report a dendronized polymer-doxorubicin(DOX)hybrid(DPDH)with an improved in vivo drug delivery efficiency for cancer therapy compared with a linear polymer-DOX conjugate(LPDC).The in vitro drug release profile of DOX indicates that DPDH displays pH-responsive drug release due to cleavage of hydrazone bonds since a greater amount of DOX is released at pH 5.2 at a faster rate than at pH 7.4.DPDH efficiently enters 4 T1 cells and releases DOX to induce cytotoxicity and apoptosis.Owing to the dendronzied structure,DPDH has a significantly longer blood circulation time than LPDC.DPDH substantially enhances the therapeutic efficacy to suppress tumor growth in a 4 T1 mammary cancer model than LPDC as well as free drug,evidenced from tumor growth inhibition,TUNEL assessment and histological analysis.Biosafety of DPDH is also confirmed from hemolysis,body weight shifts during treatment and pathological analysis.This study demonstrates the use of dendronized polymer-DOX hybrids for specific drug molecules is a promising approach for drug delivery.展开更多
The insulating nature of sulfur species,sluggish reaction kinetics,and uncontrolled dissolution of lithium polysulfide(LiPS)intermediates during the complex and multiphase sulfur redox process,have severely inhibited ...The insulating nature of sulfur species,sluggish reaction kinetics,and uncontrolled dissolution of lithium polysulfide(LiPS)intermediates during the complex and multiphase sulfur redox process,have severely inhibited the applications of Li-S batteries.In this study,we report a rational strategy to accelerate the polysulfide catalysis via constructing phosphorus modulated porous CeO_(2)(P-CeO_(2))for advanced Li-S batteries.The morphology and surface analysis demonstrate that the P-CeO_(2)consists of abundant Pmodulated porous CeO_(2)nanocrystallines.The battery performance reveals that the introduction of P will lead to an improved initial capacity of 1027 mA hg^(-1)than that of bare CeO_(2)(895.7 mA hg^(-1))at 0.2 C.In addition,the P-CeO_(2)cathode can maintain a low capacity decay ratio of 0.10%per cycle after 500 cycles at 1.0 C.The coin battery tests suggest that the P-CeO_(2)cathode presents faster oxidation-reduction kinetics of LiPS and quick diffusion of Li^+ions.Meanwhile,the studies of redox processes and chemical interactions of LiPS have demonstrated the P-CeO_(2)cathode displays stronger adsorption of Li_(2)S_(6),higher redox peak current,and earlier precipitation of Li_(2)S than the bare CeO_(2).This study demonstrates for the first time that the P-modulation of metal oxide surface can simultaneously promote the catalytic reaction kinetics and chemical interaction of LiPS.We anticipate that this P-modulation method can be extended to many other nanostructured metal catalytic sites for developing affordable advanced Li-S batteries.展开更多
A 64-year-old man was admitted to our hospital with hematemesis and melena.Six years ago,he had undergone total gastrectomy with Roux-en-Y esophagojejunostomy for gastric cancer.Endoscopic examination revealed varicos...A 64-year-old man was admitted to our hospital with hematemesis and melena.Six years ago,he had undergone total gastrectomy with Roux-en-Y esophagojejunostomy for gastric cancer.Endoscopic examination revealed varicose veins at the anastomotic sites with cherry-red spots and hemorrhage.Abdominal computed tomography showed that the varices were supplied by a dilated jejunal vein.Transjugular intrahepatic portosystemic shunt(TIPS)and variceal embolization were performed.There were no major complications or episodes of bleeding during the three-month follow-up.We conclude that TIPS in combination with varices obliteration is an effective alternative method for treatment of ruptured esophagojejunal varices after total gastrectomy.展开更多
BACKGROUND Surgical site infections(SSIs)increase mortality,hospital stays,additional medical treatment,and medical costs.Subcutaneous drains prevent SSIs in gynecological and breast surgeries;however,their clinical i...BACKGROUND Surgical site infections(SSIs)increase mortality,hospital stays,additional medical treatment,and medical costs.Subcutaneous drains prevent SSIs in gynecological and breast surgeries;however,their clinical impact in abdominal surgery remains unclear.AIM To investigate whether subcutaneous drains were beneficial in abdominal surgery using a systematic review and meta-analysis.METHODS The database search used PubMed,MEDLINE,and the Cochrane Library.The following inclusion criteria were set for the systematic review:(1)Randomized controlled trial studies comparing SSIs after abdominal surgery with or without subcutaneous drains;and(2)Studies that described clinical outcomes,such as SSIs,seroma formation,the length of hospital stays,and mortality.RESULTS Eight studies were included in this meta-analysis.The rate of total SSIs was significantly lower in the drained group(54/771,7.0%)than in the control group(89/759,11.7%),particularly in gastrointestinal surgery.Furthermore,the rate of superficial SSIs was slightly lower in the drained group(31/517,6.0%)than in the control group(49/521,9.4%).No significant differences were observed in seroma formation between the groups.Hospital stays were shorter in the drained group than in the control group.CONCLUSION Subcutaneous drains after abdominal surgery prevented SSIs and reduced hospital stays but did not significantly affect seroma formation.The timing of drain removal needs to be reconsidered in future studies.展开更多
Dear Editor,The mpox(formerly known as monkeypox)disease caused by the mpox virus(MPXV)has infected more than 89,700 people and is linked to 157 deaths in 114 countries worldwide as of September 2023(www.who.int).Mpox...Dear Editor,The mpox(formerly known as monkeypox)disease caused by the mpox virus(MPXV)has infected more than 89,700 people and is linked to 157 deaths in 114 countries worldwide as of September 2023(www.who.int).Mpox is a zoonotic disease,the first human case of which was reported in 1970(Breman et al.,1980).Common symptoms in mpox-infected individuals include fever,myalgia,fatigue,headache,and a characteristic rash(Isidro et al.,2022).Current treatments for mpox remain limited,and an in-depth investigation of essential viral protein(s)will help to explore novel drug targets.展开更多
Inhaled drug-containing nanocarriers have been well applied as an important strategy in pulmonary dis-eases.Acute lung injury(ALI)is characterized by abnormal lung tension and complex pathogenesis,with high mortality ...Inhaled drug-containing nanocarriers have been well applied as an important strategy in pulmonary dis-eases.Acute lung injury(ALI)is characterized by abnormal lung tension and complex pathogenesis,with high mortality because of the limitations of targeted intervention.Accordingly,in the present study,we first identified that the mechanosensitive ion channel Piezo1 participated in the ALI-associated processes induced by lipopolysaccharide(LPS)in vitro and in vivo.Then,chitosan-stabilized bovine serum albu-min nanoparticles(NCs)emulsified with the Piezo1 inhibitor GsMTx4(NC-GsMTx4)were generated and exhibited excellent biocompatibility and biological function.Through aerosol inhalation,NC-GsMTx4 im-proved lung injury and inhibited cell apoptosis in LPS-stressed ALI mice and alleviated pulmonary fibrosis during the later stage of ALI.Mechanistically,GsMTx4 could regulate inflammation and apoptosis in lung epithelial cells via NF-κB and ERK1/2 signaling.In summary,our findings provide new insights into the pathological mechanisms of Piezo1 in ALI progression,and nebulized inhalation of NC-GsMTx4 offers a prospective platform for targeting Piezo1 to treat ALI efficiently and conveniently.展开更多
The use of thallium(I) hydroxide (TlOH) as a base is known to extremely accelerate the Suzuki-Miyaura cross-coupling reaction using organoboronic acid or organoboronic acid ester as a substrate. Here, we investigated ...The use of thallium(I) hydroxide (TlOH) as a base is known to extremely accelerate the Suzuki-Miyaura cross-coupling reaction using organoboronic acid or organoboronic acid ester as a substrate. Here, we investigated the effects of TlOH by comparing with other conventional bases such as KOH, K2CO3, and CsF for Pd0-mediated rapid cross-coupling reactions between CH3I and organoborane reagents, such as phenyl-, (Z)-4-benzyloxy-2-butenyl-, and benzylboronic acid pinacol esters under the conditions CH3I/borane/Pd0/base (1:40:1:3) in THF/H2O or DMF/H2O for 5 min with an aim to fabricate a PET tracer efficiently. Consequently, however, the use of TlOH was much less efficient than the other bases for the acceleration of cross-coupling reactions. Thus, it was reconfirmed that the milder and non-toxic conditions using K2CO3 or CsF so far developed by our group were most appropriate for the rapid C-methylations.展开更多
11C-labeled C1-C10 partial structure of kulokekahilide-2 (1) was successfully synthesized based on Pd0-mediated rapid C-[11C]methylation using [11C]methyl iodide and pinacol alkenylboronate. The preparation of organob...11C-labeled C1-C10 partial structure of kulokekahilide-2 (1) was successfully synthesized based on Pd0-mediated rapid C-[11C]methylation using [11C]methyl iodide and pinacol alkenylboronate. The preparation of organoboron intermediate via olefin cross-metathesis is also a crucial procedure for the synthesis of 11C-labeling C1-C10 dihy-droxy acid moiety of 1.展开更多
Dear Editor,Autism is a neurodevelopmental disorder that poses a significant threat to human health,with its primary manifestations including social disability,impairments in verbal and non-verbal communication,and th...Dear Editor,Autism is a neurodevelopmental disorder that poses a significant threat to human health,with its primary manifestations including social disability,impairments in verbal and non-verbal communication,and the presence of narrow interests along with stereotypical repetitive behaviors.Recent research has shown that the Sox5 transcription factor plays a significant role in the axonal projection,migration,localization,and communication of newly generated neurons[1].Defects in the Sox5 gene are known to increase the risk of autism.A clinical study on 16 patients with Sox5 gene defects found that Sox5 haploinsufficiency is closely linked to key traits like developmental delay,language delay,behavioral problems,and minor deformities such as a protruding forehead and a wide,flat nasal bridge[2].展开更多
Dear Editor,Oculo-facio-cardio-dental(OFCD)syndrome is a rare X chromosome-linked dominant genetic disease with multiple system and site abnormalities.The typical traits shown in this disease are:1)eye abnormalities,n...Dear Editor,Oculo-facio-cardio-dental(OFCD)syndrome is a rare X chromosome-linked dominant genetic disease with multiple system and site abnormalities.The typical traits shown in this disease are:1)eye abnormalities,notably congenital cataracts,microphthalmia,and secondary glaucoma;2)facial deformities,in particular long and narrow face,high nasal bridge,nasal tip cartilage division,and cleft palate.展开更多
In the realm of drug discovery,recent advancements have paved the way for innovative approaches and methodologies.This comprehensive review encapsulates six distinct yet interrelated mini-reviews,each shedding light o...In the realm of drug discovery,recent advancements have paved the way for innovative approaches and methodologies.This comprehensive review encapsulates six distinct yet interrelated mini-reviews,each shedding light on novel strategies in drug development.(a)The resurgence of covalent drugs is highlighted,focusing on the targeted covalent inhibitors(TCIs)and their role in enhancing selectivity and affinity.(b)The potential of the quantum mechanics-based computational aid drug design(CADD)tool,Cov_DOX,is introduced for predicting protein-covalent ligand binding structures and affinities.(c)The scaffolding function of proteins is proposed as a new avenue for drug design,with a focus on modulating protein-protein interactions through small molecules and proteolysis targeting chimeras(PROTACs).(d)The concept of pro-PROTACs is explored as a promising strategy for cancer therapy,combining the principles of prodrugs and PROTACs to enhance specificity and reduce toxicity.(e)The design of prodrugs through carbon-carbon bond cleavage is discussed,offering a new perspective for the activation of drugs with limited modifiable functional groups.(f)The targeting of programmed cell death pathways in cancer therapies with small molecules is reviewed,emphasizing the induction of autophagy-dependent cell death,ferroptosis,and cuproptosis.These insights collectively contribute to a deeper understanding of the dynamic landscape of drug discovery.展开更多
BACKGROUND There are only a few studies on the influence of economic inequalities on youngonset type 2 diabetes(T2D).AIM To examine the impact of different family incomes on the development of youngonset T2D.METHODS W...BACKGROUND There are only a few studies on the influence of economic inequalities on youngonset type 2 diabetes(T2D).AIM To examine the impact of different family incomes on the development of youngonset T2D.METHODS We identified 7505336 young adults aged 20-39 years from the 2008 Taiwan region Health Insurance Research Database,China.The young adults were divided into low-income,middle-income,and high-income groups.Cox proportional hazards models were used to determine the risks of young-onset T2D and all-cause mortality in low-income and middle-income groups compared with the highincome group.RESULTS With a mean follow-up of 8.0 years,the incidence rates of young-onset T2D were 3.39,3.10,and 2.88 per 1000 person-years in the low-income,middle-income,and high-income groups,respectively.Compared with the high-income group,the risk of young-onset T2D was significantly higher in the low-income[adjusted hazard ratio(aHR)(95%CI):1.46(1.44–1.48)]and middle-income[aHR(95%CI):1.29(1.27–1.31)]groups.All-cause mortality was also higher in the low-income[aHR(95%CI):2.79(2.70–2.88)]and middle-income[aHR(95%CI):1.59(1.53–1.65)]groups.Older age,male sex,obesity,smoking,alcohol-related disorders,hypertension,dyslipidemia,gout,and psychotic disorders were significantly associated with increased risks of both young-onset T2D and mortality.CONCLUSION This nationwide cohort study demonstrated that young people from low-income and middle-income groups had a higher risk of youth-onset T2D and mortality than those from the high-income group.展开更多
Osteoarthritis(OA)is a degenerative joint disease accompanied with the loss of cartilage and consequent nociceptive symptoms.Normal articular cartilage maintains at aneural state.Neuron guidance factor Semaphorin 3A(S...Osteoarthritis(OA)is a degenerative joint disease accompanied with the loss of cartilage and consequent nociceptive symptoms.Normal articular cartilage maintains at aneural state.Neuron guidance factor Semaphorin 3A(Sema3A)is a membrane-associated secreted protein with chemorepulsive properties for axons.However,the role of Sema3A in articular cartilage is still not clear.In the present studies,we investigated the functions of Sema3A in OA development in mice,non-human primates,and patients with OA.Sema3A has a protective effect on cartilage degradation,validated by the organoid culture in vitro and confirmed in chondrocyte-specific Sema3A conditional knockout mice.We demonstrated that Sema3A is a key molecule in maintaining cartilage homeostasis from chondrocyte hypertrophy via activating the PI3K pathway.The potential usage of Sema3A for OA treatment was validated in mouse and Rhesus macaque OA models through intra-articular injection of Sema3A,and also in patients by administering Sema3A containing platelet-rich plasma into the knee joints.Our studies demonstrated that Sema3A exerts a critical role in inhibiting neurite ingrowth and preventing chondrocyte hypertrophy in cartilage,and could be potentially used for OA treatment.展开更多
Type 2 diabetes一associated with impaired insulin/insulin-like growth factor-1 (IGF1) signaling (IIS)一is a risk factor for cognitive impairment and dementia including Alzheimer's disease (AD). The insulin recepto...Type 2 diabetes一associated with impaired insulin/insulin-like growth factor-1 (IGF1) signaling (IIS)一is a risk factor for cognitive impairment and dementia including Alzheimer's disease (AD). The insulin receptor substrate (IRS) proteins are major components of IIS, which transmit upstream signals via the insulin receptor and/or IGF1 receptor to multiple intracellular signaling pathways, including AKT/protein kinase B and extracellular-signal-regulated kinase cascades. Of the four IRS proteins in mammals, IRS1 and IRS2 play key roles in regulating growth and survival, metabolism, and aging. Meanwhile, the roles of IRS1 and IRS2 in the central nervous system with respect to cognitive abilities remain to be clarified. In contrast to IRS2 in peripheral tissues, inactivation of neural IRS2 exerts beneficial effects, resulting in the reduction of amyloid p accumulation and premature mortality in AD mouse models. On the other hand, the increased phosphorylation of IRS 1 at several serine sites is observed in the brains from patients with AD and animal models of AD or cognitive impairment induced by type 2 diabetes. However, these serine sites are also activated in a mouse model of type 2 diabetes, in which the diabetes drug metformin improves memory impairment. Because IRS1 and IRS2 signaling pathways are regulated through complex mechanisms including positive and negative feedback loops, whether the elevated phosphorylation of IRS1 at specific serine sites found in AD brains is a primary response to cognitive dysfunction remains unknown. Here, we examine the associations between IRS 1 /1 RS2-mediated signaling in the central nervous system and cognitive decline.展开更多
基金supported by the Guangdong Province Nature Foundation of China Project (No. 2022A1515012200 to Li Z)Shenzhen Science and Technology Program (No. RCYX20221008093032008 to Li Z)Shenzhen People's Hospital Clinician Scientist Training Program (No. SYWGSJCYJ202405 to Li Z).
文摘Objective The aim of this study was to investigate the value of the 8th American Joint Committee on Cancer(AJCC)anatomic and prognostic stage groups for penile cancer patients and explore whether there is room for improvement.Methods The clinical and histopathologic data from 16 centers between January 2000 and December 2021 were assessed according to the 8th AJCC anatomic and prognostic stage groups.Kaplan–Meier plots were used to estimate the disease-specific survival(DSS)of the patients.The accuracy of the staging systems was investigated using the Harrell's concordance index(C-index).Results According to the 8th AJCC anatomic and prognostic stage groups,the 5-year DSS rates for patients with stages 0is/a,I,IIA,IIB,IIIA,IIIB,and IV disease were 100%,99%,86%,81%,66%,34%,and 23%,respectively(p_(0is/a–I)=0.8,p_(I–IIA)<0.001,p_(IIA–IIB)=0.5,p_(IIB–IIIA)<0.001,p_(IIIA–IIIB)<0.001,p_(IIIB–IV)=0.004,and p_(Total)<0.001).According to the modified model 1 system,the 5-year DSS rates without survivorship overlap for patients with stages 0is/a,I,II,IIIA,IIIB,and IV disease were 100%,99%,88%,66%,34%,and 23%,respectively(p_(0is/a–I)=0.8,p_(I–II)<0.001,p_(II–IIIA)=0.002,p_(IIIA–IIIB)<0.001,p_(IIIB–IV)=0.004,and p_(Total)<0.001).Similarly,according to the modified model 2 system,the 5-year DSS rates without survivorship overlap for patients with stages 0is/a,I,II,IIIA,IIIB,and IV disease were 100%,99%,86%,66%,34%,and 23%,respectively(p_(0is/a–I)=0.8,p_(I–II)<0.001,p_(II–IIIA)=0.008,p_(IIIA–IIIB)<0.001,p_(IIIB–IV)=0.004,and p_(Total)<0.001).The C-index scores of the simple modified staging systems were not inferior to those of the AJCC anatomic and prognostic stage groups.These results were confirmed by the bootstrap internal validation.Conclusion There is still room for improvement about the 8th AJCC anatomic and prognostic stage groups.The improved models,which are more concise and convenient,have similar prediction accuracy.
基金supported by the National Key R&D Program of China(2023YFC3603800,2023YFC3603801)National Natural Science Foundation of China(82202793,82172534,82372574)+3 种基金Natural Science Foundation of Sichuan Province(2023NSFSC1999,2023NSFSC1495)Young and Middle-Aged Leading Talent Cultivation Project of Sichuan University(JH20231160)Noncommunicable Chronic Diseases-National Science and Technology Major Project(2024ZD0526000)1·3·5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYJC21038)。
文摘Ischemic heart disease(IHD)remains a leading contributor to cardiovascular disease(CVD)worldwide.Despite advances in diagnostic and therapeutic approaches,translational research demands robust large animal models to bridge the gap between experimental interventions and clinical application.Among these,porcine models have gained prominence due to their anatomical,physiological,immunological,and genomic similarities to humans.This review provides a comprehensive overview of current methodologies for establishing porcine IHD models,critically assesses emerging rehabilitative strategies,and outlines innovative therapeutic technologies,with the goal of guiding model selection and fostering the development of novel treatment strategies.
基金supported by National Natural Science Foundation of China(Nos.82271019,82472149,82471024)Sichuan Science and Technology Program(No.24ZDYF0099)Research and Develop Program,West China Hospital of Stomatology Sichuan University(RD-03-202101)to J.W.
文摘The ambiguity of etiology makes temporomandibular joint osteoarthritis(TMJOA)“difficult-to-treat”.Emerging evidence underscores the therapeutic promise of exosomes in osteoarthritis management.Nonetheless,challenges such as low yields and insignificant efficacy of current exosome therapies necessitate significant advances.Addressing lower strontium(Sr)levels in arthritic synovial microenvironment,we studied the effect of Sr element on exosomes and miRNA selectively loading in synovial mesenchymal stem cells(SMSCs).Here,we developed an optimized system that boosts the yield of SMSC-derived exosomes(SMSCEXOs)and improves their miRNA profiles with an elevated proportion of beneficial miRNAs,while reducing harmful ones by pretreating SMSCs with Sr.Compared to untreated SMSC-EXOs,Sr-pretreated SMSC-derived exosomes(Sr-SMSC-EXOs)demonstrated superior therapeutic efficacy by mitigating chondrocyte ferroptosis and reducing osteoclast-mediated joint pain in TMJOA.Our results illustrate Alix’s crucial role in Sr-triggered miRNA loading,identifying miR-143-3p as a key anti-TMJOA exosomal component.Interestingly,this system is specifically oriented towards synovium-derived stem cells.The insight into trace elementdriven,site-specific miRNA selectively loading in SMSC-EXOs proposes a promising therapeutic enhancement strategy for TMJOA.
基金supported by the National Science Foundation for Excellent Young Scholars(No.32122052)National Natural Science Foundation Regional Innovation and Development(No.U19A2003).
文摘Cancer immunotherapy harnesses the immune system to attack tumors and has received extensive attention in recent years.Cancer vaccines as an important branch of immunotherapy are designed for delivering tumor antigens to antigen-presenting cells(APCs)to stimulate a strong immune response to against tumors,representing a potentially therapeutic and prophylactic effect with the long-term anticancer benefits.Nevertheless,the disappointing outcomes of their clinical use might be attributed to dilemma in antigen selection,immunogenicity,lymph nodes(LNs)targeting ability,lysosomal escape ability,immune evasion,etc.Nanotechnology,aiming to overcome these barriers,has been utilized in cancer vaccine development for decades.Numerous preclinical and clinical studies demonstrate positive results in nanomaterials-based cancer vaccines with considerable improvement in the vaccine efficacy.In this review,we systematically introduced the characteristics of nanovaccines and highlighted the different types of nanomaterials used for cancer vaccine design.In addition,the opportunities and challenges of the emerging nanotechnology-based cancer vaccines were discussed.
文摘Aim: A new concept of locomotive syndrome has been proposed by the Japanese Orthopaedic Association. The aim of this study is to clarify the utility of its self-checklist, “loco-check,” as a tool for estimating the physical dysfunction of elderly people. Methods: Subjects were 1124 community-dwelling Japanese people, 557 men and 567 women, aged 40-89 years. Information about the seven “loco-check” items was obtained from present inquiry sheets. Physical functions were examined by grip strength, knee extension strength, walking speed and one-leg standing time with open eyes. The averages of these test values, controlled for age and BMI, were compared between the “loco-check” (+) group and the “loco-check” (-) group. Also we examined about the trend of decline of physical function, together with SF36 physical function subscale score, as the number of the items chosen increased. Results: Adjusted average values of all four physical function examinations in the “lococheck” (+) group were significantly lower than those of the “loco-check” (-) group (all, p . Also the adjusted average values of the majority of four tests were significantly lower in those who checked each of the “loco-check” items than those who did not, for most of the items. It was also revealed that the more items subjects checked, the lower the adjusted average values were, except for one-leg standing time. It was also the case with SF36 physical function subscale score. Conclusion: We showed the utility of “loco-check” as a simple tool not only for noticing the physical dysfunction of elderly people, but also for estimating the extent of it, except for balancing ability, particularly by counting the number of checked items.
基金supported financially by National Natural Science Foundation of China(51673127,51873120,81621003,81801820)Department of Science and Technology of Sichuan Province(2018HH0006)+3 种基金Ministry of Science and Technology of the People’s Republic of China(2015DFE52780)China Postdoctoral Science Foundation(2018M643493)1·3·5 Research Funds in West China Hospital of Sichuan University(ZYGD18028)the Fundamental Research Funds for the Central Universities(2018SCU12032)。
文摘Dendron-polymer-based nanoscale and stimuli-responsive drug delivery systems have shown great promise in tumor-targeting accumulation without significant toxicity.Here we report a dendronized polymer-doxorubicin(DOX)hybrid(DPDH)with an improved in vivo drug delivery efficiency for cancer therapy compared with a linear polymer-DOX conjugate(LPDC).The in vitro drug release profile of DOX indicates that DPDH displays pH-responsive drug release due to cleavage of hydrazone bonds since a greater amount of DOX is released at pH 5.2 at a faster rate than at pH 7.4.DPDH efficiently enters 4 T1 cells and releases DOX to induce cytotoxicity and apoptosis.Owing to the dendronzied structure,DPDH has a significantly longer blood circulation time than LPDC.DPDH substantially enhances the therapeutic efficacy to suppress tumor growth in a 4 T1 mammary cancer model than LPDC as well as free drug,evidenced from tumor growth inhibition,TUNEL assessment and histological analysis.Biosafety of DPDH is also confirmed from hemolysis,body weight shifts during treatment and pathological analysis.This study demonstrates the use of dendronized polymer-DOX hybrids for specific drug molecules is a promising approach for drug delivery.
基金financially supported by the National Key R&D Program of China(2021YFE0205000)the National Natural Science Foundation of China(No.52173133)+5 种基金the Science and Technology Project of Sichuan Province(Nos.2021YFH0135 and 2020YFH0087)the China Postdoctoral Science Foundation(2021M692303)the full-time Postdoctoral Foundation of Sichuan University(2021SCU12013)the support of the State Key Laboratory of Polymer Materials Engineering(No.sklpme 2021-4-02)the Fundamental Research Funds for the Central Universitiesthe Alexander von Humboldt Fellowship。
文摘The insulating nature of sulfur species,sluggish reaction kinetics,and uncontrolled dissolution of lithium polysulfide(LiPS)intermediates during the complex and multiphase sulfur redox process,have severely inhibited the applications of Li-S batteries.In this study,we report a rational strategy to accelerate the polysulfide catalysis via constructing phosphorus modulated porous CeO_(2)(P-CeO_(2))for advanced Li-S batteries.The morphology and surface analysis demonstrate that the P-CeO_(2)consists of abundant Pmodulated porous CeO_(2)nanocrystallines.The battery performance reveals that the introduction of P will lead to an improved initial capacity of 1027 mA hg^(-1)than that of bare CeO_(2)(895.7 mA hg^(-1))at 0.2 C.In addition,the P-CeO_(2)cathode can maintain a low capacity decay ratio of 0.10%per cycle after 500 cycles at 1.0 C.The coin battery tests suggest that the P-CeO_(2)cathode presents faster oxidation-reduction kinetics of LiPS and quick diffusion of Li^+ions.Meanwhile,the studies of redox processes and chemical interactions of LiPS have demonstrated the P-CeO_(2)cathode displays stronger adsorption of Li_(2)S_(6),higher redox peak current,and earlier precipitation of Li_(2)S than the bare CeO_(2).This study demonstrates for the first time that the P-modulation of metal oxide surface can simultaneously promote the catalytic reaction kinetics and chemical interaction of LiPS.We anticipate that this P-modulation method can be extended to many other nanostructured metal catalytic sites for developing affordable advanced Li-S batteries.
文摘A 64-year-old man was admitted to our hospital with hematemesis and melena.Six years ago,he had undergone total gastrectomy with Roux-en-Y esophagojejunostomy for gastric cancer.Endoscopic examination revealed varicose veins at the anastomotic sites with cherry-red spots and hemorrhage.Abdominal computed tomography showed that the varices were supplied by a dilated jejunal vein.Transjugular intrahepatic portosystemic shunt(TIPS)and variceal embolization were performed.There were no major complications or episodes of bleeding during the three-month follow-up.We conclude that TIPS in combination with varices obliteration is an effective alternative method for treatment of ruptured esophagojejunal varices after total gastrectomy.
基金Supported by Grants-in-Aid from JSPS KAKENHI,No.JP 21K10715 and No.JP 20K10404Northern Advancement Center for Science&Technology,No.T-2-2+9 种基金the Yasuda Medical Foundation,No.31010316the Okawa Foundation for Information and Telecommunications,No.41111042Taiju Life Social Welfare Foundation,No.50811490Japan Keirin Autorace Foundation,No.2023M-378Project Mirai Cancer Research Grants,No.31010269Takahashi Industrial and Economic Research Foundation,No.50411278Sapporo Doto Hospital,No.50311211Noguchi Hospital,No.40310551Doki-kai Tomakomai Hospital,No.40710739Tsuchida Hospital,No.50811478.
文摘BACKGROUND Surgical site infections(SSIs)increase mortality,hospital stays,additional medical treatment,and medical costs.Subcutaneous drains prevent SSIs in gynecological and breast surgeries;however,their clinical impact in abdominal surgery remains unclear.AIM To investigate whether subcutaneous drains were beneficial in abdominal surgery using a systematic review and meta-analysis.METHODS The database search used PubMed,MEDLINE,and the Cochrane Library.The following inclusion criteria were set for the systematic review:(1)Randomized controlled trial studies comparing SSIs after abdominal surgery with or without subcutaneous drains;and(2)Studies that described clinical outcomes,such as SSIs,seroma formation,the length of hospital stays,and mortality.RESULTS Eight studies were included in this meta-analysis.The rate of total SSIs was significantly lower in the drained group(54/771,7.0%)than in the control group(89/759,11.7%),particularly in gastrointestinal surgery.Furthermore,the rate of superficial SSIs was slightly lower in the drained group(31/517,6.0%)than in the control group(49/521,9.4%).No significant differences were observed in seroma formation between the groups.Hospital stays were shorter in the drained group than in the control group.CONCLUSION Subcutaneous drains after abdominal surgery prevented SSIs and reduced hospital stays but did not significantly affect seroma formation.The timing of drain removal needs to be reconsidered in future studies.
基金supported by the National Key R&D Program of China(2021YFF0702004)Additionally,we received the grants of the 1.3.5 project for disciplines of excellence(ZYYC21008)+1 种基金the National Clinical Research Center for Geriatrics(Z2021JC008)West China Hospital,Sichuan University.
文摘Dear Editor,The mpox(formerly known as monkeypox)disease caused by the mpox virus(MPXV)has infected more than 89,700 people and is linked to 157 deaths in 114 countries worldwide as of September 2023(www.who.int).Mpox is a zoonotic disease,the first human case of which was reported in 1970(Breman et al.,1980).Common symptoms in mpox-infected individuals include fever,myalgia,fatigue,headache,and a characteristic rash(Isidro et al.,2022).Current treatments for mpox remain limited,and an in-depth investigation of essential viral protein(s)will help to explore novel drug targets.
基金supported by the Science and Technology Plan of Jiangxi Provincial Health Commission(No.SKJP220201115)Live Science and Technology of Suzhou(No.SS201862)the Prior-ity Academic Program Development of Jiangsu Higher Education Institutions(PAPD).Translational Research Grant of NCRCH(No.2020WSB08).
文摘Inhaled drug-containing nanocarriers have been well applied as an important strategy in pulmonary dis-eases.Acute lung injury(ALI)is characterized by abnormal lung tension and complex pathogenesis,with high mortality because of the limitations of targeted intervention.Accordingly,in the present study,we first identified that the mechanosensitive ion channel Piezo1 participated in the ALI-associated processes induced by lipopolysaccharide(LPS)in vitro and in vivo.Then,chitosan-stabilized bovine serum albu-min nanoparticles(NCs)emulsified with the Piezo1 inhibitor GsMTx4(NC-GsMTx4)were generated and exhibited excellent biocompatibility and biological function.Through aerosol inhalation,NC-GsMTx4 im-proved lung injury and inhibited cell apoptosis in LPS-stressed ALI mice and alleviated pulmonary fibrosis during the later stage of ALI.Mechanistically,GsMTx4 could regulate inflammation and apoptosis in lung epithelial cells via NF-κB and ERK1/2 signaling.In summary,our findings provide new insights into the pathological mechanisms of Piezo1 in ALI progression,and nebulized inhalation of NC-GsMTx4 offers a prospective platform for targeting Piezo1 to treat ALI efficiently and conveniently.
文摘The use of thallium(I) hydroxide (TlOH) as a base is known to extremely accelerate the Suzuki-Miyaura cross-coupling reaction using organoboronic acid or organoboronic acid ester as a substrate. Here, we investigated the effects of TlOH by comparing with other conventional bases such as KOH, K2CO3, and CsF for Pd0-mediated rapid cross-coupling reactions between CH3I and organoborane reagents, such as phenyl-, (Z)-4-benzyloxy-2-butenyl-, and benzylboronic acid pinacol esters under the conditions CH3I/borane/Pd0/base (1:40:1:3) in THF/H2O or DMF/H2O for 5 min with an aim to fabricate a PET tracer efficiently. Consequently, however, the use of TlOH was much less efficient than the other bases for the acceleration of cross-coupling reactions. Thus, it was reconfirmed that the milder and non-toxic conditions using K2CO3 or CsF so far developed by our group were most appropriate for the rapid C-methylations.
文摘11C-labeled C1-C10 partial structure of kulokekahilide-2 (1) was successfully synthesized based on Pd0-mediated rapid C-[11C]methylation using [11C]methyl iodide and pinacol alkenylboronate. The preparation of organoboron intermediate via olefin cross-metathesis is also a crucial procedure for the synthesis of 11C-labeling C1-C10 dihy-droxy acid moiety of 1.
基金supported by the Fujian Provincial Science and Technology Youth Project(2021111)the Technology Innovation Joint Funding Project(2023Y9289)the National Natural Science Foundation of China(82401643).
文摘Dear Editor,Autism is a neurodevelopmental disorder that poses a significant threat to human health,with its primary manifestations including social disability,impairments in verbal and non-verbal communication,and the presence of narrow interests along with stereotypical repetitive behaviors.Recent research has shown that the Sox5 transcription factor plays a significant role in the axonal projection,migration,localization,and communication of newly generated neurons[1].Defects in the Sox5 gene are known to increase the risk of autism.A clinical study on 16 patients with Sox5 gene defects found that Sox5 haploinsufficiency is closely linked to key traits like developmental delay,language delay,behavioral problems,and minor deformities such as a protruding forehead and a wide,flat nasal bridge[2].
基金Supported by National Natural Science Foundation of China(No.82171026).
文摘Dear Editor,Oculo-facio-cardio-dental(OFCD)syndrome is a rare X chromosome-linked dominant genetic disease with multiple system and site abnormalities.The typical traits shown in this disease are:1)eye abnormalities,notably congenital cataracts,microphthalmia,and secondary glaucoma;2)facial deformities,in particular long and narrow face,high nasal bridge,nasal tip cartilage division,and cleft palate.
基金supported by grants from the National Natural Science Foundation of China(No.82273770)the Foundation for Innovative Research Groups of the National Natural Science Foundation of Sichuan Province(No.24NSFTD0051).
文摘In the realm of drug discovery,recent advancements have paved the way for innovative approaches and methodologies.This comprehensive review encapsulates six distinct yet interrelated mini-reviews,each shedding light on novel strategies in drug development.(a)The resurgence of covalent drugs is highlighted,focusing on the targeted covalent inhibitors(TCIs)and their role in enhancing selectivity and affinity.(b)The potential of the quantum mechanics-based computational aid drug design(CADD)tool,Cov_DOX,is introduced for predicting protein-covalent ligand binding structures and affinities.(c)The scaffolding function of proteins is proposed as a new avenue for drug design,with a focus on modulating protein-protein interactions through small molecules and proteolysis targeting chimeras(PROTACs).(d)The concept of pro-PROTACs is explored as a promising strategy for cancer therapy,combining the principles of prodrugs and PROTACs to enhance specificity and reduce toxicity.(e)The design of prodrugs through carbon-carbon bond cleavage is discussed,offering a new perspective for the activation of drugs with limited modifiable functional groups.(f)The targeting of programmed cell death pathways in cancer therapies with small molecules is reviewed,emphasizing the induction of autophagy-dependent cell death,ferroptosis,and cuproptosis.These insights collectively contribute to a deeper understanding of the dynamic landscape of drug discovery.
基金Supported by Taipei Veterans General Hospital,No.V113C-166 and No.V114C-177National Science and Technology Council,R.O.C,No.NSTC113-2314-B-075-007-.
文摘BACKGROUND There are only a few studies on the influence of economic inequalities on youngonset type 2 diabetes(T2D).AIM To examine the impact of different family incomes on the development of youngonset T2D.METHODS We identified 7505336 young adults aged 20-39 years from the 2008 Taiwan region Health Insurance Research Database,China.The young adults were divided into low-income,middle-income,and high-income groups.Cox proportional hazards models were used to determine the risks of young-onset T2D and all-cause mortality in low-income and middle-income groups compared with the highincome group.RESULTS With a mean follow-up of 8.0 years,the incidence rates of young-onset T2D were 3.39,3.10,and 2.88 per 1000 person-years in the low-income,middle-income,and high-income groups,respectively.Compared with the high-income group,the risk of young-onset T2D was significantly higher in the low-income[adjusted hazard ratio(aHR)(95%CI):1.46(1.44–1.48)]and middle-income[aHR(95%CI):1.29(1.27–1.31)]groups.All-cause mortality was also higher in the low-income[aHR(95%CI):2.79(2.70–2.88)]and middle-income[aHR(95%CI):1.59(1.53–1.65)]groups.Older age,male sex,obesity,smoking,alcohol-related disorders,hypertension,dyslipidemia,gout,and psychotic disorders were significantly associated with increased risks of both young-onset T2D and mortality.CONCLUSION This nationwide cohort study demonstrated that young people from low-income and middle-income groups had a higher risk of youth-onset T2D and mortality than those from the high-income group.
基金partly National Key R&D Program of China(2023YFA1801200,2023YFA1801202)Major Program of the National Natural Science Foundation of China(T2394532)+6 种基金National Natural Science Foundation of China(82072489)The Foundation of Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions(NYKFKT2019007)Shenzhen Medical Research Fund(B2302011)The Sanming Project of Medicine in Shenzhen(SZZYSM202311013)The China Postdoctoral Science Foundational,2023M743679Shenzhen Science and Technology Research Funding(JCYJ20220818101414032)Key Research Project of Science&Technology Department of Sichuan Province,China(2024YFFK0041)。
文摘Osteoarthritis(OA)is a degenerative joint disease accompanied with the loss of cartilage and consequent nociceptive symptoms.Normal articular cartilage maintains at aneural state.Neuron guidance factor Semaphorin 3A(Sema3A)is a membrane-associated secreted protein with chemorepulsive properties for axons.However,the role of Sema3A in articular cartilage is still not clear.In the present studies,we investigated the functions of Sema3A in OA development in mice,non-human primates,and patients with OA.Sema3A has a protective effect on cartilage degradation,validated by the organoid culture in vitro and confirmed in chondrocyte-specific Sema3A conditional knockout mice.We demonstrated that Sema3A is a key molecule in maintaining cartilage homeostasis from chondrocyte hypertrophy via activating the PI3K pathway.The potential usage of Sema3A for OA treatment was validated in mouse and Rhesus macaque OA models through intra-articular injection of Sema3A,and also in patients by administering Sema3A containing platelet-rich plasma into the knee joints.Our studies demonstrated that Sema3A exerts a critical role in inhibiting neurite ingrowth and preventing chondrocyte hypertrophy in cartilage,and could be potentially used for OA treatment.
基金supported by a MEXTGrant-in-Aid for Scientific Research on Innovative Areas(brain environment)(JP24111536 to AT)+3 种基金JSPS KAKENHI(JP24650201,JP26282026,JP17K19951,JP17H02188 to AT)grants from the Mitsubishi Foundation(to AT)NOVARTIS Foundation Japan for the Promotion of Science(to AT)
文摘Type 2 diabetes一associated with impaired insulin/insulin-like growth factor-1 (IGF1) signaling (IIS)一is a risk factor for cognitive impairment and dementia including Alzheimer's disease (AD). The insulin receptor substrate (IRS) proteins are major components of IIS, which transmit upstream signals via the insulin receptor and/or IGF1 receptor to multiple intracellular signaling pathways, including AKT/protein kinase B and extracellular-signal-regulated kinase cascades. Of the four IRS proteins in mammals, IRS1 and IRS2 play key roles in regulating growth and survival, metabolism, and aging. Meanwhile, the roles of IRS1 and IRS2 in the central nervous system with respect to cognitive abilities remain to be clarified. In contrast to IRS2 in peripheral tissues, inactivation of neural IRS2 exerts beneficial effects, resulting in the reduction of amyloid p accumulation and premature mortality in AD mouse models. On the other hand, the increased phosphorylation of IRS 1 at several serine sites is observed in the brains from patients with AD and animal models of AD or cognitive impairment induced by type 2 diabetes. However, these serine sites are also activated in a mouse model of type 2 diabetes, in which the diabetes drug metformin improves memory impairment. Because IRS1 and IRS2 signaling pathways are regulated through complex mechanisms including positive and negative feedback loops, whether the elevated phosphorylation of IRS1 at specific serine sites found in AD brains is a primary response to cognitive dysfunction remains unknown. Here, we examine the associations between IRS 1 /1 RS2-mediated signaling in the central nervous system and cognitive decline.
