Rational design of multifunctional nanoplatforms capable of combining therapeutic effects with real-time monitoring of drug distribution and tumor status is emerging as a promising approach in cancer nanomedicine.Here...Rational design of multifunctional nanoplatforms capable of combining therapeutic effects with real-time monitoring of drug distribution and tumor status is emerging as a promising approach in cancer nanomedicine.Here,we introduce pyropheophorbide a-bisaminoquinoline conjugate lipid nanoparticles(PPBC LNPs)as a bimodal system for image-guided phototherapy in bladder cancer treatment.PPBC LNPs not only demonstrate both powerful photodynamic and photothermal effects upon light activation,but also exhibit potent autophagy blockage,effectively inducing bladder cancer cell death.Furthermore,PPBC LNPs possess remarkable photoacoustic(PA)and fluorescence(FL)imaging capabilities,enabling imaging with high-resolution,deep tissue penetration and high sensitivity for tracking drug biodistribution and phototherapy efficacy.Specifically,PA imaging confirms the efficient accumulation of PPBC LNPs within tumor and predicts therapeutic outcomes of photodynamic therapy,while FL imaging confirms their prolonged retention at the tumor site for up to 6 days.PPBC LNPs significantly suppress bladder tumor growth,with several tumors completely ablated following just two doses of the nanoparticles and laser treatment.Additionally,PPBC LNPs were formulated with lipid-based excipients and assembled using microfluidic technology to enhance biocompatibility,stability,and scalability,showing potential for clinical translation.This versatile nanoparticle represents a promising candidate for further development in bladder cancer therapy.展开更多
Esophageal cancer(EC),a common malignant tumor of the digestive tract,requires early diagnosis and timely treatment to improve patient prognosis.Automated detection of EC using medical imaging has the potential to inc...Esophageal cancer(EC),a common malignant tumor of the digestive tract,requires early diagnosis and timely treatment to improve patient prognosis.Automated detection of EC using medical imaging has the potential to increase screening efficiency and diagnostic accuracy,thereby significantly improving long-term survival rates and the quality of life of patients.Recent advances in deep learning(DL),particularly convolutional neural networks,have demons-trated remarkable performance in medical imaging analysis.These techniques have shown significant progress in the automated identification of malignant tumors,quantitative analysis of lesions,and improvement in diagnostic accuracy and efficiency.This article comprehensively examines the research progress of DL in medical imaging for EC,covering various imaging modalities such as digital pathology,endoscopy,computed tomography,etc.It explores the clinical value and application prospects of DL in EC screening and diagnosis.Additionally,the article addresses several critical challenges that must be overcome for the clinical translation of DL techniques,including constructing high-quality datasets,promoting multimodal feature fusion,and optimizing artificial intelligence-clinical workflow integration.By providing a detailed overview of the current state of DL in EC imaging and highlighting the key challenges and future directions,this article aims to guide future research and facilitate the clinical implementation of DL technologies in EC management,ultimately contributing to better patient outcomes.展开更多
Objective:To determine the safety and the role of modulating cytokines and proteases in the immune response to intravesical Bacillus Calmette-Guérin(BCG)when primed with systemic intradermal BCG.Methods:Phase 1 a...Objective:To determine the safety and the role of modulating cytokines and proteases in the immune response to intravesical Bacillus Calmette-Guérin(BCG)when primed with systemic intradermal BCG.Methods:Phase 1 and mechanistic longitudinal,prospective,single-blind randomized study(NCT04806178).Twenty-one non-muscle invasive urothelial bladder cancer patients undergoing intravesical adjuvant BCG after transurethral resection of bladder tumor(TURBT)in a teaching hospital between September 2021 and April 2023 were randomized to 0.1 mL of intradermal BCG vaccine or placebo(0.9%saline)administered 15 days before the start of intravesical BCG therapy.Blood samples were evaluated mechanistically regarding eight cytokines serum levels interferon-induced transmembrane protein 3 Gene(IFITM3),Interleukin 1 beta(IL1-BETA),interleukin-2 receptor alpha chain(IL2 RA),Interleukin 6(IL 6),Interleukin 10(IL 10),Tumor necrosis factor alpha(TNF-α),Interferon-β,AXL,and one protease CASPASE 8.Results:After 1 exclusion,twenty patients were randomized to intradermal BCG(n=11)and intradermal placebo(n=9).There was no difference in adverse effects emerging from the intravesical Onco-BCG therapy,and no difference in the expression of the cytokines and proteases analyzed between control and intervention,and over time.Conclusions:Intradermal BCG administration before intravesical application was safe,with no increase in adverse effects.It also does not seem to change the analyzed targets during the intravesical induction-phase BCG.Other immune targets should be explored in the future.The Brazilian tuberculosis-endemic status,where BCG vaccination is mandatory,might have affected the results.展开更多
Background:Despite advances in the diagnosis of patients with hepatocellular carcinoma(HCC),70%-80%of patients are diagnosed with advanced stage disease.Portal vein tumor thrombus(PVTT)is among the most ominous signs ...Background:Despite advances in the diagnosis of patients with hepatocellular carcinoma(HCC),70%-80%of patients are diagnosed with advanced stage disease.Portal vein tumor thrombus(PVTT)is among the most ominous signs of advanced stage disease and has been associated with poor survival if untreated.Data sources:A systematic search of MEDLINE(PubMed),Embase,Cochrane Library and Database for Systematic Reviews(CDSR),Google Scholar,and National Institute for Health and Clinical Excellence(NICE)databases until December 2022 was conducted using free text and MeSH terms:hepatocellular carcinoma,portal vein tumor thrombus,portal vein thrombosis,vascular invasion,liver and/or hepatic resection,liver transplantation,and systematic review.Results:Centers of surgical excellence have reported promising results related to the individualized surgical management of portal thrombus versus arterial chemoembolization or systemic chemotherapy.Critical elements to the individualized surgical management of HCC and portal thrombus include precise classification of the portal vein tumor thrombus,accurate identification of the subgroups of patients who may benefit from resection,as well as meticulous surgical technique.This review addressed five specific areas:(a)formation of PVTT;(b)classifications of PVTT;(c)controversies related to clinical guidelines;(d)surgical treatments versus non-surgical approaches;and(e)characterization of surgical techniques correlated with classifications of PVTT.Conclusions:Current evidence from Chinese and Japanese high-volume centers demonstrated that patients with HCC and associated PVTT can be managed with surgical resection with acceptable results.展开更多
Recently, a novel comprehensive treatment consisting of cytoreductive surgery(CRS) and perioperative chemotherapy(POC) was developed for the treatment of peritoneal metastasis(PM) with a curative intent. In the treatm...Recently, a novel comprehensive treatment consisting of cytoreductive surgery(CRS) and perioperative chemotherapy(POC) was developed for the treatment of peritoneal metastasis(PM) with a curative intent. In the treatment, the macroscopic disease is completely removed by the peritonectomy techniques in combination with POC. This article reviews the results of the comprehensive treatment for PM from gastric cancer, and verifies the effects of CRS and POC, including neoadjuvant chemotherapy(NAC) and hyperthermic intraoperative intraperitoneal chemotherapy(HIPEC). Completeness of cytoreduction, peritoneal carcinomatosis index(PCI) less than the threshold levels after NAC,absence of ascites, cytologic status, pathologic response after NAC are the independent prognostic factors. Among these prognostic factors, PCI threshold level is the most valuable independent prognostic factor. After staging laparoscopy, patients with PM from gastric cancer are recommended to treat with NAC before CRS. After NAC, indication for CRS is determined by laparoscopy. The indications of the comprehensive treatment are patients with PCI less than the threshold levels, negative cytology, and responders after NAC. Patients satisfy these factors are the candidates for the CRS and HIPEC.展开更多
Rarely,scientific developments centered around the patient as a whole arepublished.Our multidisciplinary group,headed by gastrointestinal surgeons,applied this research philosophy considering the most important aspect...Rarely,scientific developments centered around the patient as a whole arepublished.Our multidisciplinary group,headed by gastrointestinal surgeons,applied this research philosophy considering the most important aspects of thediseases“colon-and rectal cancer”in the long-term developments.Good expertcooperation/knowledge at the Comprehensive Cancer Center Ulm(CCCU)wereapplied in several phase III trials for multimodal treatments of primary tumors(MMT)and metastatic diseases(involving nearly 2000 patients and 64 centers),fortreatment individualization of MMT and of metastatic disease,for psychooncology/quality of life involving the patients’wishes,and for disease prevention.Most of the targets initially were heavily rejected/discussed in thescientific communities,but now have become standards in treatments andnational guidelines or are topics in modern translational research protocolsinvolving molecular biology for e.g.,“patient centered individualized treatment”.In this context we also describe the paths we had to tread in order to realize ournew goals,which at the end were highly beneficial for the patients from manypoints of view.This description is also important for students and youngresearchers who,with an actual view on our recent developments,might want toknow how medical progress was achieved.展开更多
Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical outcomes.Despite considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of adv...Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical outcomes.Despite considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of advanced stage metastatic CRC(mCRC).In particular,the five-year survival rate is very low since mCRC is currently rarely curable.Over the past decade,cancer treatment has significantly improved with the introduction of cancer immunotherapies,specifically immune checkpoint inhibitors.Therapies aimed at blocking immune checkpoints such as PD-1,PD-L1,and CTLA-4 target inhibitory pathways of the immune system,and thereby enhance anti-tumor immunity.These therapies thus have shown promising results in many clinical trials alone or in combination.The efficacy and safety of immunotherapy,either alone or in combination with CRC,have been investigated in several clinical trials.Clinical trials,including KEYNOTE-164 and CheckMate 142,have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab,respectively,for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC.Unfortunately,these drugs benefit only a small percentage of patients,with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients.To this end,primary and secondary resistance to immunotherapy remains a significant issue,and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response.This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC.The underlying rationale,challenges faced,and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.展开更多
Our recent breakthrough discovery demonstrated that the anticancer drug FL118 tightly binds to and then dephosphorylates and degrades the oncogenic protein DEAD-box helicase 5(DDX5),leading to the inhibition of DDX5 d...Our recent breakthrough discovery demonstrated that the anticancer drug FL118 tightly binds to and then dephosphorylates and degrades the oncogenic protein DEAD-box helicase 5(DDX5),leading to the inhibition of DDX5 downstream targets(e.g.,survivin,myeloid cell leukemia 1(Mcl-1),X-linked inhibitor of apoptosis(XIAP),c-Myc,mutant Kras,etc.)[1].FL118 is a molecular glue(MG)that can alter the interactomes of two or more non-interacting proteins[2].Thus,FL118 exhibits high efficacy against colorectal and pancreatic cancer xenograft tumors[1,3].However,moving FL118 into clinical trials requires a clinically compatible FL118 drug product(DP)that possesses high antitumor efficacy and low toxicity via oral(ideal)or intravenous(iv)administration.Here,we report the development and characterization of a clinically and orally compatible FL118 DP.We show that(1)FL118 drug substances(DS)exhibit high chemical stability under various test conditions;(2)a clinically and orally compatible FL118 DP can be manufactured through the formulation of FL118 DS with 2-hydroxypropyl-bcyclodextrin(HPbCD)using mixed solvents of glacial acetic acid(GAA)with ethanol through microfluidizer-mediated spray dried dispersion(M-SDD).展开更多
1.Double-sided role of vibration and shaking Removing vibration and shaking is a pivotal engineering task,which is showcased,for instance,in spacecraft attitude control systems that ensure a precise three-dimensional ...1.Double-sided role of vibration and shaking Removing vibration and shaking is a pivotal engineering task,which is showcased,for instance,in spacecraft attitude control systems that ensure a precise three-dimensional orientation.Vibration or shaking,such as precession caused by external torque,nutation stemming from off-axis angular momentum,and wobbling due to geometric misalignment,necessitate active and passive damping mechanisms.This principle extends beyond spacecraft to centrifugation techniques,pivotal not only in washing machines but also in a spectrum of biomedical apparatuses used for isolating cells and organelles and separating DNA and proteins.展开更多
Objective:Several studies have been conducted on the effects and toxicity of adding oxaliplatin to fluorouracilbased or capecitabine-based chemoradiotherapy(CRT)regimens as significantly increasing the toxic response ...Objective:Several studies have been conducted on the effects and toxicity of adding oxaliplatin to fluorouracilbased or capecitabine-based chemoradiotherapy(CRT)regimens as significantly increasing the toxic response without benefit to survival.In this study,we further explored the role of these two postoperative CRT regimens in patients with pathological stage N2 rectal cancer.Methods:This study was a subgroup analysis of a randomized clinical trial.A total of 180 patients with pathological stage N2 rectal cancer were eligible,85 received capecitabine with radiotherapy(RT),and 95 received capecitabine and oxaliplatin with RT.Patients in both groups received adjuvant chemotherapy[capecitabine and oxaliplatin(XELOX);or fluorouracil,leucovorin,and oxaliplatin(FOLFOX)]after CRT.Results:At a median follow-up of 59.2[interquartile range(IQR),34.0−96.8]months,the three-year diseasefree survival(DFS)was 53.3%and 64.9%in the control group and the experimental group,respectively[hazard ratio(HR),0.63;95%confidence interval(95%CI),0.41−0.98;P=0.04].There was no significant difference between the groups in overall survival(OS)(HR,0.62;95%CI,0.37−1.05;P=0.07),the incidence of locoregional recurrence(HR,0.62;95%CI,0.24−1.64;P=0.33),the incidence of distant metastasis(HR,0.67;95%CI,0.42−1.06;P=0.09)and grade 3−4 acute toxicities(P=0.78).For patients with survival longer than 3 years,the conditional overall survival(COS)was significantly better in the experimental group(HR,0.39;95%CI,0.16−0.96;P=0.03).Conclusions:Our results indicated that adding oxaliplatin to capecitabine-based postoperative CRT is safe and effective in patients with pathological stage N2 rectal cancer.展开更多
Liposarcoma is one of the most common soft tissue sarcomas,however,its occurrence rate is still rare compared to other cancers.Due to its rarity,in vitro experiments are an essential approach to elucidate liposarcoma ...Liposarcoma is one of the most common soft tissue sarcomas,however,its occurrence rate is still rare compared to other cancers.Due to its rarity,in vitro experiments are an essential approach to elucidate liposarcoma pathobiology.Conventional cell culture-based research(2D cell culture)is still playing a pivotal role,while several shortcomings have been recently under discussion.In vivo,mouse models are usually adopted for pre-clinical analyses with expectations to overcome the issues of 2D cell culture.However,they do not fully recapitulate human dedifferentiated liposarcoma(DDLPS)characteristics.Therefore,three-dimensional(3D)culture systems have been the recent research focus in the cell biology field with the expectation to overcome at the same time the disadvantages of 2D cell culture and in vivo animal models and fill in the gap between them.Given the liposarcoma rarity,we believe that 3D cell culture techniques,including 3D cell cultures/co-cultures,and Patient-Derived tumor Organoids(PDOs),represent a promising approach to facilitate liposarcoma investigation and elucidate its molecular mechanisms and effective therapy development.In this review,we first provide a general overview of 3D cell cultures compared to 2D cell cultures.We then focus on one of the recent 3D cell culture applications,Patient-Derived Organoids(PDOs),summarizing and discussing several PDO methodologies.Finally,we discuss the current and future applications of PDOs to sarcoma,particularly in the field of liposarcoma.展开更多
Hepatocellular carcinoma(HCC),which is essentially primary liver cancer,is closely related to CD8^(+)T cell immune infiltration and immune suppression.We constructed a CD8^(+)T cells related risk score model to predic...Hepatocellular carcinoma(HCC),which is essentially primary liver cancer,is closely related to CD8^(+)T cell immune infiltration and immune suppression.We constructed a CD8^(+)T cells related risk score model to predict the prognosis of HCC patients and provided therapeutic guidance based on the risk score.Using integrated bulk RNA sequencing(RNA-seq)and single-cell RNA sequencing(scRNA-seq)datasets,we identified stable CD8^(+)T cell signatures.Based on these signatures,a 3-gene risk score model,comprised of KLRB1,RGS 2,and TNFRSF1B was constructed.The risk score model was well validated through an independent external validation cohort.We divided patients into high-risk and low-risk groups according to the risk score and compared the differences in immune microenvironment between these two groups.Compared with low-risk patients,high-risk patients have higher M2-type macrophage content(P<0.0001)and lower CD8^(+)T cells infiltration(P<0.0001).High-risk patients predict worse response to immunotherapy treatment than low-risk patients(P<0.01).Drug sensitivity analysis shows that PI3K-β inhibitor AZD6482 and TGFβRII inhibitor SB505124 may be suitable therapies for high-risk patients,while the IGF-1R inhibitor BMS-754807 or the novel pyrimidine-based anti-tumor metabolic drug Gemcitabine could be potential therapeutic choices for low-risk patients.Moreover,expression of these 3-gene model was verified by immunohistochemistry.In summary,the establishment and validation of a CD8^(+)T cell-derived risk model can more accurately predict the prognosis of HCC patients and guide the construction of personalized treatment plans.展开更多
Soft tissue sarcomas(STS)are rare malignant tumors originating from mesoder-mal tissues with a poor prognosis,accounting for approximately 1%of all malig-nancies and comprising around 50 distinct subtypes.Conventional...Soft tissue sarcomas(STS)are rare malignant tumors originating from mesoder-mal tissues with a poor prognosis,accounting for approximately 1%of all malig-nancies and comprising around 50 distinct subtypes.Conventional imaging mo-dalities,such as computed tomography(CT)and magnetic resonance imaging(MRI),primarily provide anatomical information,whereas 18F-fluorodeoxyglucose positron emission tomography/CT(18F-FDG PET/CT)integrates functional metabolic and anatomical imaging,serving as a critical complementary tool in the diagnosis and management of STS.This article reviews recent advances in the application of 18F-FDG PET/CT for STS.The advantages of 18F-FDG PET/CT in STS include:(1)Early detection of metabolic activity changes in tumors,partic-ularly when morphological alterations are insignificant;(2)Effective differen-tiation between benign and malignant soft tissue tumors,as well as aiding in distinguishing high-grade from low-grade sarcomas;(3)Identification of occult metastatic lesions,improving staging accuracy,and facilitating restaging in cases of recurrence or metastasis;(4)Utilization of parameters such as maximum stan-dardized uptake value and metabolic tumor volume to assist in tumor grading and prognostic evaluation;and(5)Monitoring treatment response to guide adjust-ments in personalized therapeutic strategies.However,18F-FDG PET/CT has limitations in diagnosis of certain STS subtypes(e.g.,myxoid liposarcoma),detection and biopsy of metastatic lymph nodes,necessitating integration with clinical evaluation and other imaging techniques.18F-FDG PET/CT is poised to play an increasingly vital role in the precision diagnosis and treatment of STS.展开更多
BACKGROUND Advancements in immunosuppressive therapies have improved graft survival by enhancing graft tolerance and preventing organ rejection.However,the risk of malignancy associated with prolonged immunosuppressio...BACKGROUND Advancements in immunosuppressive therapies have improved graft survival by enhancing graft tolerance and preventing organ rejection.However,the risk of malignancy associated with prolonged immunosuppression remains a concern,as it can adversely affect recipients’quality of life and survival.While the link be-tween immunosuppression and increased cancer risk is well-documented,the specific interactions between graft rejection and post-transplant malignancy(PTM)remain poorly understood.Addressing this knowledge gap is crucial for devising immunosuppressive strategies that balance rejection prevention with cancer risk reduction.AIM To investigate whether immunosuppression in PTM reduces rejection risk,while immune activation during rejection protects against malignancy.METHODS We analyzed data from the United Network for Organ Sharing’s Organ Procurewith no prior history of malignancy(in donors or recipients).Landmark analyses at 1,2,3,5,10,15,and 20 years post-transplant,Kaplan–Meier analyses,and time-dependent Cox proportional hazards regression models,each incorporating the temporal dimension of outcomes,assessed the association between rejection-induced graft failure(RGF)and PTM.Multivariate models were adjusted for clinical and immunological factors,including immunosuppression regimens.RESULTS The cohort included 579905 recipients(kidney:386878;liver:108390;heart:45046;lung:37643;pancreas:1948)with a mean follow-up of 7.3 years and a median age of 50.6±13.2 years.RGF was associated with a reduction in PTM risk across all time points[hazard ratio(HR)=0.07-0.20,P<0.001],even after excluding mortality cases.Kidney transplant recipients exhibited the most pronounced reduction(HR=0.22,P<0.001).Conversely,among recipients with PTM,RGF risk decreased across all time points up to 15 years after excluding mortality cases(HR=0.49–0.80,P<0.001).This risk reduction was observed in kidney,liver,heart,and lung transplants(HRs=0.90,0.21,0.21,and 0.18,respectively;P<0.001)but not in pancreas transplants.CONCLUSION RGF reduces PTM risk,particularly in kidney transplants,while PTM decreases RGF risk in kidney,liver,heart,and lung transplants.展开更多
Objective:Soluble epoxide hydrolase(sEH)emerges as a target of interest for inflammatory diseases.Piperine is a natural amide alkaloid from Piper nigrum and displays an inhibitory effect toward sEH,its chemical struct...Objective:Soluble epoxide hydrolase(sEH)emerges as a target of interest for inflammatory diseases.Piperine is a natural amide alkaloid from Piper nigrum and displays an inhibitory effect toward sEH,its chemical structural transformation was carried out in order to obtain a library of sEH inhibitors based on its skeleton.Methods:Structural transformation of piperine was carried out by chemical methods,and piperine derivatives were assayed for their sEH potentials.A mouse acute lung injury model was constructed by lipopolysaccharide(LPS).Hematoxylin and eosin(H&E)staining,immunofluorescence staining,Western Blot,and enzyme-linked immunosorbent assay were used for investigating the protective potential of sEH inhibitor 11h.Results:Piperine derivatives 11e,11h,11j,and 11o showed inhibitory potentials toward sEH with values of half maximal inhibitory concentration(IC50)from 20 to 70 nM.Compound 11h attenuated the pathological course of LPS-mediated acute lung injury(ALI)in vivo.Furthermore,levels of cytokines tumor necrosis factor alpha(TNF-α),interleukin 6(IL-6),myeloperoxidase(MPO),and lactate dehydrogenase(LDH)were decreased after administration of 11h.The LPS-mediated inflammation and redox unbalance,including expressions of cyclooxygenase-2(COX-2),heme oxygenase-1(HO-1),intercellular cell adhesion molecule-1(ICAM-1),vascular cell adhesion molecule-1(VCAM-1),p-p65/p65,glutamate-cysteine ligase modifier subunit(GCLM),and nuclear factor erythroid-2-related factor 2(Nrf2),were ameliorated through nuclear factor kappa B(NF-κB)and Nrf2 pathways via enhancing levels of epoxyeicosatrienoic acids(EETs)in LPS-exposed ALI mice after compound 11h treatment.Molecular docking demonstrated that the aromatic unsaturated group of 11h occupied a hydrophobic pocket and its urea group formed three hydrogen bonds with Asp333,Tyr381,and Tyr465,which stabilized the active conformation of the ligand.Conclusions:These findings demonstrated that compound 11h may serve as a lead compound for developing sEH inhibitors and treating inflammation related to diseases,such as ALI.展开更多
The increasing aging population and aging-associated diseases have become a global issue for decades.People over 65 show an increased prevalence and greater severity of periodontitis,which poses threats to overall hea...The increasing aging population and aging-associated diseases have become a global issue for decades.People over 65 show an increased prevalence and greater severity of periodontitis,which poses threats to overall health.Studies have demonstrated a significant association between aging and the dysfunction of neutrophils,critical cells in the early stages of periodontitis,and their crosstalk with macrophages and T and B lymphocytes to establish the periodontal lesion.Neutrophils differentiate and mature in the bone marrow before entering the circulation;during an infection,they are recruited to infected tissues guided by the signal from chemokines and cytokines to eliminate invading pathogens.Neutrophils are crucial in maintaining a balanced response between host and microbes to prevent periodontal diseases in periodontal tissues.The impacts of aging on neutrophils'chemotaxis,anti-microbial function,cell activation,and lifespan result in impaired neutrophil functions and excessive neutrophil activation,which could influence periodontitis course.We summarize the roles of neutrophils in periodontal diseases and the aging-related impacts on neutrophil functional responses.We also explore the underlying mechanisms that can contribute to periodontitis manifestation in aging.This review could help us better understand the pathogenesis of periodontitis,which could offer novel therapeutic targets for periodontitis.展开更多
Calvarial nerves,along with vasculature,influence skull formation during development and following injury,but it remains unclear how calvarial nerves are spatially distributed during postnatal growth and aging.Studyin...Calvarial nerves,along with vasculature,influence skull formation during development and following injury,but it remains unclear how calvarial nerves are spatially distributed during postnatal growth and aging.Studying the spatial distribution of nerves in the skull remains a challenge due to a lack of methods to quantify 3D structures in intact bone.To visualize calvarial 3D neurovascular architecture,we imaged nerves and endothelial cells with lightsheet microscopy.展开更多
BACKGROUND Genetic disorders affecting hepatobiliary transporters can be triggered by various factors,resulting in marked cholestasis.CASE SUMMARY We report two patients who experienced a severe episode of intrahepati...BACKGROUND Genetic disorders affecting hepatobiliary transporters can be triggered by various factors,resulting in marked cholestasis.CASE SUMMARY We report two patients who experienced a severe episode of intrahepatic cholestasis triggered by an acute hepatitis E virus infection.Following an extensive clinical examination that ruled out common causes of cholestatic liver damage,we conducted next-generation sequencing to determine the genetic profiles of the patients.The analysis revealed several known and unknown variants in genes associated with hepatobiliary transporters and bile salt regulation,including ATP8B1,ABCB11,ABCB4,MYO5B,and FXR.For a comprehensive understanding of the pathophysiology,we performed ClinVar analysis and utilized PolyPhen for bioinformatic prediction of functional impact.Both patients exhibited rapid symptom improvement and a decrease in hyperbilirubinemia when treated with either rifampicin or bezafibrate.CONCLUSION Our findings introduce hepatitis E viral infection as a novel trigger for intrahepatic cholestasis,and we categorize the significance of the various genetic variants based on the current state of research.展开更多
Objective:Radical nephroureterectomy(RNU)is considered the standard of care for patients with high-risk upper tract urothelial carcinoma.Current literature reveals a deficit in direct comparative studies evaluating th...Objective:Radical nephroureterectomy(RNU)is considered the standard of care for patients with high-risk upper tract urothelial carcinoma.Current literature reveals a deficit in direct comparative studies evaluating the efficacy of different chemotherapeutic agents administered in single postoperative instillation following RNU.The primary aim of this study was to compare the bladder recurrence(BR)rates between patients receiving a single instillation of mitomycin C(MMC)versus gemcitabine(Gem)after RNU.Methods:The ROBUUST(ROBotic surgery for Upper tract Urothelial cancer STudy)2.0 is an international,multicenter registry that aggregates data on patients who have undergone curative surgery for upper tract urothelial carcinoma across participating centers from January 2015 to December 2022.Data including primary baseline variables of the patients,characteristics of the tumors,surgical management,and definitive histopathological characterizations were collected and stratified based on the type of postoperative bladder instillation:MMC(the MMC group)and Gem(the Gem group).We selected variables correlated with our primary outcome to conduct a propensity-score match analysis.Results:One hundred patients in the MMC group were matched 1:1 with 100 patients in the Gem group.At 36 months of follow-up,30 patients in the MMC group and 39 patients in the Gem group experienced BR,representing recurrence rates of 30%and 39%,respectively(p=0.2).The Cox proportional hazards model comparing BR between the groups revealed a hazard ratio of 1.58(95%confidence interval:0.98-2.55)with a non-statistically significant increased risk of BR in the Gem group compared with the MMC group(p=0.059).Conclusion:A single perioperative instillation of Gem or MMC seems to offer similar efficacy in reducing the risk of BR in patients undergoing RNU.Further research,ideally within the framework of prospective studies,is warranted to elucidate the optimal chemotherapeutic approach in this setting.展开更多
The incidence and mortality of gastric cancer have fallen dramatically in US and elsewhere over the past several decades. Nonetheless, gastric cancer remains a major public health issue as the fourth most common cance...The incidence and mortality of gastric cancer have fallen dramatically in US and elsewhere over the past several decades. Nonetheless, gastric cancer remains a major public health issue as the fourth most common cancer and the second leading cause of cancer death worldwide. Demographic trends differ by tumor location and histology. While there has been a marked decline in distal, intestinal type gastric cancers, the incidence of proximal, diffuse type adenocarcinomas of the gastric cardia has been increasing, particularly in the Western countries. Incidence by tumor sub-site also varies widely based on geographic location, race, and socioeconomic status. Distal gastric cancer predominates in developing countries, among blacks, and in lower socioeconomic groups, whereas proximal tumors are more common in developed countries, among whites, and in higher socio-economic classes. Diverging trends in the incidence of gastric cancer by tumor location suggest that they may represent two diseases with different etiologies. The main risk factors for distal gastric cancer include Helicobacter pylori （H pylori） infection and dietary factors, whereas gastroesophageal reflux disease and obesity play important roles in the development of proximal stomach cancer. The purpose of this review is to examine the epidemiology and risk factors of gastric cancer, and to discuss strategies for primary prevention.展开更多
文摘Rational design of multifunctional nanoplatforms capable of combining therapeutic effects with real-time monitoring of drug distribution and tumor status is emerging as a promising approach in cancer nanomedicine.Here,we introduce pyropheophorbide a-bisaminoquinoline conjugate lipid nanoparticles(PPBC LNPs)as a bimodal system for image-guided phototherapy in bladder cancer treatment.PPBC LNPs not only demonstrate both powerful photodynamic and photothermal effects upon light activation,but also exhibit potent autophagy blockage,effectively inducing bladder cancer cell death.Furthermore,PPBC LNPs possess remarkable photoacoustic(PA)and fluorescence(FL)imaging capabilities,enabling imaging with high-resolution,deep tissue penetration and high sensitivity for tracking drug biodistribution and phototherapy efficacy.Specifically,PA imaging confirms the efficient accumulation of PPBC LNPs within tumor and predicts therapeutic outcomes of photodynamic therapy,while FL imaging confirms their prolonged retention at the tumor site for up to 6 days.PPBC LNPs significantly suppress bladder tumor growth,with several tumors completely ablated following just two doses of the nanoparticles and laser treatment.Additionally,PPBC LNPs were formulated with lipid-based excipients and assembled using microfluidic technology to enhance biocompatibility,stability,and scalability,showing potential for clinical translation.This versatile nanoparticle represents a promising candidate for further development in bladder cancer therapy.
基金Supported by Funding for Clinical Trials from the Nanjing Drum Tower Hospital,Affiliated Hospital of Medical School,Nanjing University,No.2021-LCYJ-MS-11.
文摘Esophageal cancer(EC),a common malignant tumor of the digestive tract,requires early diagnosis and timely treatment to improve patient prognosis.Automated detection of EC using medical imaging has the potential to increase screening efficiency and diagnostic accuracy,thereby significantly improving long-term survival rates and the quality of life of patients.Recent advances in deep learning(DL),particularly convolutional neural networks,have demons-trated remarkable performance in medical imaging analysis.These techniques have shown significant progress in the automated identification of malignant tumors,quantitative analysis of lesions,and improvement in diagnostic accuracy and efficiency.This article comprehensively examines the research progress of DL in medical imaging for EC,covering various imaging modalities such as digital pathology,endoscopy,computed tomography,etc.It explores the clinical value and application prospects of DL in EC screening and diagnosis.Additionally,the article addresses several critical challenges that must be overcome for the clinical translation of DL techniques,including constructing high-quality datasets,promoting multimodal feature fusion,and optimizing artificial intelligence-clinical workflow integration.By providing a detailed overview of the current state of DL in EC imaging and highlighting the key challenges and future directions,this article aims to guide future research and facilitate the clinical implementation of DL technologies in EC management,ultimately contributing to better patient outcomes.
基金National Council for Scientific and Technological Development,CNPq,Research Productivity,grant numbers:304747/2018-1/310135/2022-2(Reis LO).
文摘Objective:To determine the safety and the role of modulating cytokines and proteases in the immune response to intravesical Bacillus Calmette-Guérin(BCG)when primed with systemic intradermal BCG.Methods:Phase 1 and mechanistic longitudinal,prospective,single-blind randomized study(NCT04806178).Twenty-one non-muscle invasive urothelial bladder cancer patients undergoing intravesical adjuvant BCG after transurethral resection of bladder tumor(TURBT)in a teaching hospital between September 2021 and April 2023 were randomized to 0.1 mL of intradermal BCG vaccine or placebo(0.9%saline)administered 15 days before the start of intravesical BCG therapy.Blood samples were evaluated mechanistically regarding eight cytokines serum levels interferon-induced transmembrane protein 3 Gene(IFITM3),Interleukin 1 beta(IL1-BETA),interleukin-2 receptor alpha chain(IL2 RA),Interleukin 6(IL 6),Interleukin 10(IL 10),Tumor necrosis factor alpha(TNF-α),Interferon-β,AXL,and one protease CASPASE 8.Results:After 1 exclusion,twenty patients were randomized to intradermal BCG(n=11)and intradermal placebo(n=9).There was no difference in adverse effects emerging from the intravesical Onco-BCG therapy,and no difference in the expression of the cytokines and proteases analyzed between control and intervention,and over time.Conclusions:Intradermal BCG administration before intravesical application was safe,with no increase in adverse effects.It also does not seem to change the analyzed targets during the intravesical induction-phase BCG.Other immune targets should be explored in the future.The Brazilian tuberculosis-endemic status,where BCG vaccination is mandatory,might have affected the results.
文摘Background:Despite advances in the diagnosis of patients with hepatocellular carcinoma(HCC),70%-80%of patients are diagnosed with advanced stage disease.Portal vein tumor thrombus(PVTT)is among the most ominous signs of advanced stage disease and has been associated with poor survival if untreated.Data sources:A systematic search of MEDLINE(PubMed),Embase,Cochrane Library and Database for Systematic Reviews(CDSR),Google Scholar,and National Institute for Health and Clinical Excellence(NICE)databases until December 2022 was conducted using free text and MeSH terms:hepatocellular carcinoma,portal vein tumor thrombus,portal vein thrombosis,vascular invasion,liver and/or hepatic resection,liver transplantation,and systematic review.Results:Centers of surgical excellence have reported promising results related to the individualized surgical management of portal thrombus versus arterial chemoembolization or systemic chemotherapy.Critical elements to the individualized surgical management of HCC and portal thrombus include precise classification of the portal vein tumor thrombus,accurate identification of the subgroups of patients who may benefit from resection,as well as meticulous surgical technique.This review addressed five specific areas:(a)formation of PVTT;(b)classifications of PVTT;(c)controversies related to clinical guidelines;(d)surgical treatments versus non-surgical approaches;and(e)characterization of surgical techniques correlated with classifications of PVTT.Conclusions:Current evidence from Chinese and Japanese high-volume centers demonstrated that patients with HCC and associated PVTT can be managed with surgical resection with acceptable results.
文摘Recently, a novel comprehensive treatment consisting of cytoreductive surgery(CRS) and perioperative chemotherapy(POC) was developed for the treatment of peritoneal metastasis(PM) with a curative intent. In the treatment, the macroscopic disease is completely removed by the peritonectomy techniques in combination with POC. This article reviews the results of the comprehensive treatment for PM from gastric cancer, and verifies the effects of CRS and POC, including neoadjuvant chemotherapy(NAC) and hyperthermic intraoperative intraperitoneal chemotherapy(HIPEC). Completeness of cytoreduction, peritoneal carcinomatosis index(PCI) less than the threshold levels after NAC,absence of ascites, cytologic status, pathologic response after NAC are the independent prognostic factors. Among these prognostic factors, PCI threshold level is the most valuable independent prognostic factor. After staging laparoscopy, patients with PM from gastric cancer are recommended to treat with NAC before CRS. After NAC, indication for CRS is determined by laparoscopy. The indications of the comprehensive treatment are patients with PCI less than the threshold levels, negative cytology, and responders after NAC. Patients satisfy these factors are the candidates for the CRS and HIPEC.
文摘Rarely,scientific developments centered around the patient as a whole arepublished.Our multidisciplinary group,headed by gastrointestinal surgeons,applied this research philosophy considering the most important aspects of thediseases“colon-and rectal cancer”in the long-term developments.Good expertcooperation/knowledge at the Comprehensive Cancer Center Ulm(CCCU)wereapplied in several phase III trials for multimodal treatments of primary tumors(MMT)and metastatic diseases(involving nearly 2000 patients and 64 centers),fortreatment individualization of MMT and of metastatic disease,for psychooncology/quality of life involving the patients’wishes,and for disease prevention.Most of the targets initially were heavily rejected/discussed in thescientific communities,but now have become standards in treatments andnational guidelines or are topics in modern translational research protocolsinvolving molecular biology for e.g.,“patient centered individualized treatment”.In this context we also describe the paths we had to tread in order to realize ournew goals,which at the end were highly beneficial for the patients from manypoints of view.This description is also important for students and youngresearchers who,with an actual view on our recent developments,might want toknow how medical progress was achieved.
基金Supported by IU Simon Comprehensive Cancer Center grant,No.5P30CA082709-24.
文摘Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical outcomes.Despite considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of advanced stage metastatic CRC(mCRC).In particular,the five-year survival rate is very low since mCRC is currently rarely curable.Over the past decade,cancer treatment has significantly improved with the introduction of cancer immunotherapies,specifically immune checkpoint inhibitors.Therapies aimed at blocking immune checkpoints such as PD-1,PD-L1,and CTLA-4 target inhibitory pathways of the immune system,and thereby enhance anti-tumor immunity.These therapies thus have shown promising results in many clinical trials alone or in combination.The efficacy and safety of immunotherapy,either alone or in combination with CRC,have been investigated in several clinical trials.Clinical trials,including KEYNOTE-164 and CheckMate 142,have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab,respectively,for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC.Unfortunately,these drugs benefit only a small percentage of patients,with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients.To this end,primary and secondary resistance to immunotherapy remains a significant issue,and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response.This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC.The underlying rationale,challenges faced,and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.
文摘Our recent breakthrough discovery demonstrated that the anticancer drug FL118 tightly binds to and then dephosphorylates and degrades the oncogenic protein DEAD-box helicase 5(DDX5),leading to the inhibition of DDX5 downstream targets(e.g.,survivin,myeloid cell leukemia 1(Mcl-1),X-linked inhibitor of apoptosis(XIAP),c-Myc,mutant Kras,etc.)[1].FL118 is a molecular glue(MG)that can alter the interactomes of two or more non-interacting proteins[2].Thus,FL118 exhibits high efficacy against colorectal and pancreatic cancer xenograft tumors[1,3].However,moving FL118 into clinical trials requires a clinically compatible FL118 drug product(DP)that possesses high antitumor efficacy and low toxicity via oral(ideal)or intravenous(iv)administration.Here,we report the development and characterization of a clinically and orally compatible FL118 DP.We show that(1)FL118 drug substances(DS)exhibit high chemical stability under various test conditions;(2)a clinically and orally compatible FL118 DP can be manufactured through the formulation of FL118 DS with 2-hydroxypropyl-bcyclodextrin(HPbCD)using mixed solvents of glacial acetic acid(GAA)with ethanol through microfluidizer-mediated spray dried dispersion(M-SDD).
文摘1.Double-sided role of vibration and shaking Removing vibration and shaking is a pivotal engineering task,which is showcased,for instance,in spacecraft attitude control systems that ensure a precise three-dimensional orientation.Vibration or shaking,such as precession caused by external torque,nutation stemming from off-axis angular momentum,and wobbling due to geometric misalignment,necessitate active and passive damping mechanisms.This principle extends beyond spacecraft to centrifugation techniques,pivotal not only in washing machines but also in a spectrum of biomedical apparatuses used for isolating cells and organelles and separating DNA and proteins.
基金supported by grants from Sanming Project of Medicine in Shenzhen(No.SZSM202211030)the Science and Technology Department Basic Research Project of Shanxi(No.202203021221284)。
文摘Objective:Several studies have been conducted on the effects and toxicity of adding oxaliplatin to fluorouracilbased or capecitabine-based chemoradiotherapy(CRT)regimens as significantly increasing the toxic response without benefit to survival.In this study,we further explored the role of these two postoperative CRT regimens in patients with pathological stage N2 rectal cancer.Methods:This study was a subgroup analysis of a randomized clinical trial.A total of 180 patients with pathological stage N2 rectal cancer were eligible,85 received capecitabine with radiotherapy(RT),and 95 received capecitabine and oxaliplatin with RT.Patients in both groups received adjuvant chemotherapy[capecitabine and oxaliplatin(XELOX);or fluorouracil,leucovorin,and oxaliplatin(FOLFOX)]after CRT.Results:At a median follow-up of 59.2[interquartile range(IQR),34.0−96.8]months,the three-year diseasefree survival(DFS)was 53.3%and 64.9%in the control group and the experimental group,respectively[hazard ratio(HR),0.63;95%confidence interval(95%CI),0.41−0.98;P=0.04].There was no significant difference between the groups in overall survival(OS)(HR,0.62;95%CI,0.37−1.05;P=0.07),the incidence of locoregional recurrence(HR,0.62;95%CI,0.24−1.64;P=0.33),the incidence of distant metastasis(HR,0.67;95%CI,0.42−1.06;P=0.09)and grade 3−4 acute toxicities(P=0.78).For patients with survival longer than 3 years,the conditional overall survival(COS)was significantly better in the experimental group(HR,0.39;95%CI,0.16−0.96;P=0.03).Conclusions:Our results indicated that adding oxaliplatin to capecitabine-based postoperative CRT is safe and effective in patients with pathological stage N2 rectal cancer.
文摘Liposarcoma is one of the most common soft tissue sarcomas,however,its occurrence rate is still rare compared to other cancers.Due to its rarity,in vitro experiments are an essential approach to elucidate liposarcoma pathobiology.Conventional cell culture-based research(2D cell culture)is still playing a pivotal role,while several shortcomings have been recently under discussion.In vivo,mouse models are usually adopted for pre-clinical analyses with expectations to overcome the issues of 2D cell culture.However,they do not fully recapitulate human dedifferentiated liposarcoma(DDLPS)characteristics.Therefore,three-dimensional(3D)culture systems have been the recent research focus in the cell biology field with the expectation to overcome at the same time the disadvantages of 2D cell culture and in vivo animal models and fill in the gap between them.Given the liposarcoma rarity,we believe that 3D cell culture techniques,including 3D cell cultures/co-cultures,and Patient-Derived tumor Organoids(PDOs),represent a promising approach to facilitate liposarcoma investigation and elucidate its molecular mechanisms and effective therapy development.In this review,we first provide a general overview of 3D cell cultures compared to 2D cell cultures.We then focus on one of the recent 3D cell culture applications,Patient-Derived Organoids(PDOs),summarizing and discussing several PDO methodologies.Finally,we discuss the current and future applications of PDOs to sarcoma,particularly in the field of liposarcoma.
基金国家自然科学基金项目(No.81902513)山西省应用基础研究计划项目(No.202303021211114 and 202103021224228)山西省高等教育百亿工程“科技引导”专项(No.BYJL047)资助。
文摘Hepatocellular carcinoma(HCC),which is essentially primary liver cancer,is closely related to CD8^(+)T cell immune infiltration and immune suppression.We constructed a CD8^(+)T cells related risk score model to predict the prognosis of HCC patients and provided therapeutic guidance based on the risk score.Using integrated bulk RNA sequencing(RNA-seq)and single-cell RNA sequencing(scRNA-seq)datasets,we identified stable CD8^(+)T cell signatures.Based on these signatures,a 3-gene risk score model,comprised of KLRB1,RGS 2,and TNFRSF1B was constructed.The risk score model was well validated through an independent external validation cohort.We divided patients into high-risk and low-risk groups according to the risk score and compared the differences in immune microenvironment between these two groups.Compared with low-risk patients,high-risk patients have higher M2-type macrophage content(P<0.0001)and lower CD8^(+)T cells infiltration(P<0.0001).High-risk patients predict worse response to immunotherapy treatment than low-risk patients(P<0.01).Drug sensitivity analysis shows that PI3K-β inhibitor AZD6482 and TGFβRII inhibitor SB505124 may be suitable therapies for high-risk patients,while the IGF-1R inhibitor BMS-754807 or the novel pyrimidine-based anti-tumor metabolic drug Gemcitabine could be potential therapeutic choices for low-risk patients.Moreover,expression of these 3-gene model was verified by immunohistochemistry.In summary,the establishment and validation of a CD8^(+)T cell-derived risk model can more accurately predict the prognosis of HCC patients and guide the construction of personalized treatment plans.
文摘Soft tissue sarcomas(STS)are rare malignant tumors originating from mesoder-mal tissues with a poor prognosis,accounting for approximately 1%of all malig-nancies and comprising around 50 distinct subtypes.Conventional imaging mo-dalities,such as computed tomography(CT)and magnetic resonance imaging(MRI),primarily provide anatomical information,whereas 18F-fluorodeoxyglucose positron emission tomography/CT(18F-FDG PET/CT)integrates functional metabolic and anatomical imaging,serving as a critical complementary tool in the diagnosis and management of STS.This article reviews recent advances in the application of 18F-FDG PET/CT for STS.The advantages of 18F-FDG PET/CT in STS include:(1)Early detection of metabolic activity changes in tumors,partic-ularly when morphological alterations are insignificant;(2)Effective differen-tiation between benign and malignant soft tissue tumors,as well as aiding in distinguishing high-grade from low-grade sarcomas;(3)Identification of occult metastatic lesions,improving staging accuracy,and facilitating restaging in cases of recurrence or metastasis;(4)Utilization of parameters such as maximum stan-dardized uptake value and metabolic tumor volume to assist in tumor grading and prognostic evaluation;and(5)Monitoring treatment response to guide adjust-ments in personalized therapeutic strategies.However,18F-FDG PET/CT has limitations in diagnosis of certain STS subtypes(e.g.,myxoid liposarcoma),detection and biopsy of metastatic lymph nodes,necessitating integration with clinical evaluation and other imaging techniques.18F-FDG PET/CT is poised to play an increasingly vital role in the precision diagnosis and treatment of STS.
文摘BACKGROUND Advancements in immunosuppressive therapies have improved graft survival by enhancing graft tolerance and preventing organ rejection.However,the risk of malignancy associated with prolonged immunosuppression remains a concern,as it can adversely affect recipients’quality of life and survival.While the link be-tween immunosuppression and increased cancer risk is well-documented,the specific interactions between graft rejection and post-transplant malignancy(PTM)remain poorly understood.Addressing this knowledge gap is crucial for devising immunosuppressive strategies that balance rejection prevention with cancer risk reduction.AIM To investigate whether immunosuppression in PTM reduces rejection risk,while immune activation during rejection protects against malignancy.METHODS We analyzed data from the United Network for Organ Sharing’s Organ Procurewith no prior history of malignancy(in donors or recipients).Landmark analyses at 1,2,3,5,10,15,and 20 years post-transplant,Kaplan–Meier analyses,and time-dependent Cox proportional hazards regression models,each incorporating the temporal dimension of outcomes,assessed the association between rejection-induced graft failure(RGF)and PTM.Multivariate models were adjusted for clinical and immunological factors,including immunosuppression regimens.RESULTS The cohort included 579905 recipients(kidney:386878;liver:108390;heart:45046;lung:37643;pancreas:1948)with a mean follow-up of 7.3 years and a median age of 50.6±13.2 years.RGF was associated with a reduction in PTM risk across all time points[hazard ratio(HR)=0.07-0.20,P<0.001],even after excluding mortality cases.Kidney transplant recipients exhibited the most pronounced reduction(HR=0.22,P<0.001).Conversely,among recipients with PTM,RGF risk decreased across all time points up to 15 years after excluding mortality cases(HR=0.49–0.80,P<0.001).This risk reduction was observed in kidney,liver,heart,and lung transplants(HRs=0.90,0.21,0.21,and 0.18,respectively;P<0.001)but not in pancreas transplants.CONCLUSION RGF reduces PTM risk,particularly in kidney transplants,while PTM decreases RGF risk in kidney,liver,heart,and lung transplants.
基金supported by the National Natural Science Foundation of China(82274069 and 82003580)Shenzhen science and technology research and development funds(JCYJ20190808171803553 and 2022071718149001)+4 种基金Young Scientific and Technological Talents(Level Two)in Tianjin(QN20230212)Tianjin Education Commission Research Program Project(2024KJ004)Young Elite Scientists Sponsorship Program by China Association of Chinese Medicine(2022-QNRC2-B09)“1+X”Research Project of the Second Hospital of Dalian Medical University(2024JJ11PT005)Eaglet Plan Project of Tianjin University of Traditional Chinese Medicine(XJS2024101)。
文摘Objective:Soluble epoxide hydrolase(sEH)emerges as a target of interest for inflammatory diseases.Piperine is a natural amide alkaloid from Piper nigrum and displays an inhibitory effect toward sEH,its chemical structural transformation was carried out in order to obtain a library of sEH inhibitors based on its skeleton.Methods:Structural transformation of piperine was carried out by chemical methods,and piperine derivatives were assayed for their sEH potentials.A mouse acute lung injury model was constructed by lipopolysaccharide(LPS).Hematoxylin and eosin(H&E)staining,immunofluorescence staining,Western Blot,and enzyme-linked immunosorbent assay were used for investigating the protective potential of sEH inhibitor 11h.Results:Piperine derivatives 11e,11h,11j,and 11o showed inhibitory potentials toward sEH with values of half maximal inhibitory concentration(IC50)from 20 to 70 nM.Compound 11h attenuated the pathological course of LPS-mediated acute lung injury(ALI)in vivo.Furthermore,levels of cytokines tumor necrosis factor alpha(TNF-α),interleukin 6(IL-6),myeloperoxidase(MPO),and lactate dehydrogenase(LDH)were decreased after administration of 11h.The LPS-mediated inflammation and redox unbalance,including expressions of cyclooxygenase-2(COX-2),heme oxygenase-1(HO-1),intercellular cell adhesion molecule-1(ICAM-1),vascular cell adhesion molecule-1(VCAM-1),p-p65/p65,glutamate-cysteine ligase modifier subunit(GCLM),and nuclear factor erythroid-2-related factor 2(Nrf2),were ameliorated through nuclear factor kappa B(NF-κB)and Nrf2 pathways via enhancing levels of epoxyeicosatrienoic acids(EETs)in LPS-exposed ALI mice after compound 11h treatment.Molecular docking demonstrated that the aromatic unsaturated group of 11h occupied a hydrophobic pocket and its urea group formed three hydrogen bonds with Asp333,Tyr381,and Tyr465,which stabilized the active conformation of the ligand.Conclusions:These findings demonstrated that compound 11h may serve as a lead compound for developing sEH inhibitors and treating inflammation related to diseases,such as ALI.
文摘The increasing aging population and aging-associated diseases have become a global issue for decades.People over 65 show an increased prevalence and greater severity of periodontitis,which poses threats to overall health.Studies have demonstrated a significant association between aging and the dysfunction of neutrophils,critical cells in the early stages of periodontitis,and their crosstalk with macrophages and T and B lymphocytes to establish the periodontal lesion.Neutrophils differentiate and mature in the bone marrow before entering the circulation;during an infection,they are recruited to infected tissues guided by the signal from chemokines and cytokines to eliminate invading pathogens.Neutrophils are crucial in maintaining a balanced response between host and microbes to prevent periodontal diseases in periodontal tissues.The impacts of aging on neutrophils'chemotaxis,anti-microbial function,cell activation,and lifespan result in impaired neutrophil functions and excessive neutrophil activation,which could influence periodontitis course.We summarize the roles of neutrophils in periodontal diseases and the aging-related impacts on neutrophil functional responses.We also explore the underlying mechanisms that can contribute to periodontitis manifestation in aging.This review could help us better understand the pathogenesis of periodontitis,which could offer novel therapeutic targets for periodontitis.
基金supported by funding from NIDCR(1R01DE027957)Maryland Stem Cell Research Fund(2022-MSCRFV-5782)the NSF GRFP and NCI(5R01CA237597-05,2R01CA196701-06A1).
文摘Calvarial nerves,along with vasculature,influence skull formation during development and following injury,but it remains unclear how calvarial nerves are spatially distributed during postnatal growth and aging.Studying the spatial distribution of nerves in the skull remains a challenge due to a lack of methods to quantify 3D structures in intact bone.To visualize calvarial 3D neurovascular architecture,we imaged nerves and endothelial cells with lightsheet microscopy.
文摘BACKGROUND Genetic disorders affecting hepatobiliary transporters can be triggered by various factors,resulting in marked cholestasis.CASE SUMMARY We report two patients who experienced a severe episode of intrahepatic cholestasis triggered by an acute hepatitis E virus infection.Following an extensive clinical examination that ruled out common causes of cholestatic liver damage,we conducted next-generation sequencing to determine the genetic profiles of the patients.The analysis revealed several known and unknown variants in genes associated with hepatobiliary transporters and bile salt regulation,including ATP8B1,ABCB11,ABCB4,MYO5B,and FXR.For a comprehensive understanding of the pathophysiology,we performed ClinVar analysis and utilized PolyPhen for bioinformatic prediction of functional impact.Both patients exhibited rapid symptom improvement and a decrease in hyperbilirubinemia when treated with either rifampicin or bezafibrate.CONCLUSION Our findings introduce hepatitis E viral infection as a novel trigger for intrahepatic cholestasis,and we categorize the significance of the various genetic variants based on the current state of research.
文摘Objective:Radical nephroureterectomy(RNU)is considered the standard of care for patients with high-risk upper tract urothelial carcinoma.Current literature reveals a deficit in direct comparative studies evaluating the efficacy of different chemotherapeutic agents administered in single postoperative instillation following RNU.The primary aim of this study was to compare the bladder recurrence(BR)rates between patients receiving a single instillation of mitomycin C(MMC)versus gemcitabine(Gem)after RNU.Methods:The ROBUUST(ROBotic surgery for Upper tract Urothelial cancer STudy)2.0 is an international,multicenter registry that aggregates data on patients who have undergone curative surgery for upper tract urothelial carcinoma across participating centers from January 2015 to December 2022.Data including primary baseline variables of the patients,characteristics of the tumors,surgical management,and definitive histopathological characterizations were collected and stratified based on the type of postoperative bladder instillation:MMC(the MMC group)and Gem(the Gem group).We selected variables correlated with our primary outcome to conduct a propensity-score match analysis.Results:One hundred patients in the MMC group were matched 1:1 with 100 patients in the Gem group.At 36 months of follow-up,30 patients in the MMC group and 39 patients in the Gem group experienced BR,representing recurrence rates of 30%and 39%,respectively(p=0.2).The Cox proportional hazards model comparing BR between the groups revealed a hazard ratio of 1.58(95%confidence interval:0.98-2.55)with a non-statistically significant increased risk of BR in the Gem group compared with the MMC group(p=0.059).Conclusion:A single perioperative instillation of Gem or MMC seems to offer similar efficacy in reducing the risk of BR in patients undergoing RNU.Further research,ideally within the framework of prospective studies,is warranted to elucidate the optimal chemotherapeutic approach in this setting.
文摘The incidence and mortality of gastric cancer have fallen dramatically in US and elsewhere over the past several decades. Nonetheless, gastric cancer remains a major public health issue as the fourth most common cancer and the second leading cause of cancer death worldwide. Demographic trends differ by tumor location and histology. While there has been a marked decline in distal, intestinal type gastric cancers, the incidence of proximal, diffuse type adenocarcinomas of the gastric cardia has been increasing, particularly in the Western countries. Incidence by tumor sub-site also varies widely based on geographic location, race, and socioeconomic status. Distal gastric cancer predominates in developing countries, among blacks, and in lower socioeconomic groups, whereas proximal tumors are more common in developed countries, among whites, and in higher socio-economic classes. Diverging trends in the incidence of gastric cancer by tumor location suggest that they may represent two diseases with different etiologies. The main risk factors for distal gastric cancer include Helicobacter pylori （H pylori） infection and dietary factors, whereas gastroesophageal reflux disease and obesity play important roles in the development of proximal stomach cancer. The purpose of this review is to examine the epidemiology and risk factors of gastric cancer, and to discuss strategies for primary prevention.
