Objective:Oxaliplatin(OXA)and 5-fluorouracil(5-FU)are 2 commonly used chemotherapeutic agents for colorectal cancer(CRC).MicroRNAs(miRNAs,miRs)play crucial roles in the development of chemoresistance in various cancer...Objective:Oxaliplatin(OXA)and 5-fluorouracil(5-FU)are 2 commonly used chemotherapeutic agents for colorectal cancer(CRC).MicroRNAs(miRNAs,miRs)play crucial roles in the development of chemoresistance in various cancers.However,the role and mechanism of miR-224-5p in regulating CRC chemoresistance remain unclear.This study aims to investigate the function of miR-224-5p in chemoresistant CRC cells and the underlying mechanisms.Methods:CRC datasets GSE28702 and GSE69657 were downloaded from the Gene Expression Omnibus(GEO)database.Differentially expressed miRNAs between drug sensitive and resistant groups(OXA or 5-FU)were analyzed,and miR-224-5p was identified as the target miRNA.Chemoresistant cell lines HCT15-OXR,HCT15-5-FU,SW480-OXR,and SW480-5-FU were established.Transient transfections were performed using miR-224-5p mimics,inhibitors,and their respective negative controls(control mimic,control inhibitor)in these cell lines.Cells were treated with different concentrations of OXA or 5-FU post-transfection,and the half-maximal inhibitory concentration(IC_(50))was determined using the cell counting kit-8(CCK-8)assay.Cell proliferation was assessed by CCK-8 and colony formation assays.The expression levels of miR-224-5p,LC3,and P62 were measured by real-time polymerase chain reaction(real-time PCR)and/or Western blotting.Autophagic flux was assessed using a tandem fluorescent-tagged LC3 reporter assay.TargetScan 8.0,miRTarBase,miRPathDB,and HADb were used to predict B-cell lymphoma-2(Bcl-2)as a potential miR-244-5p target,which was further validated by dual luciferase reporter assays.Results:Chemoresistant CRC cells exhibited down-regulated miR-224-5p expression,whereas up-regulation of miR-224-5p enhanced chemotherapy sensitivity.Exposure to OXA or 5-FU significantly increased autophagic activity in chemoresistant CRC cells,which was reversed by miR-224-5p overexpression.Dual-luciferase assays verified Bcl-2 as a direct target of miR-224-5p.Conclusion:MiR-224-5p regulates chemoresistance in CRC by modulating autophagy through direct targeting of Bcl-2.展开更多
BACKGROUND Cytomegalovirus(CMV)infections can cause significant morbidity and mortality in immunocompromised individuals.CMV targets dysfunctional lymphocytes.Chronic rituximab(RTX)therapy can cause B-lymphocyte dysfu...BACKGROUND Cytomegalovirus(CMV)infections can cause significant morbidity and mortality in immunocompromised individuals.CMV targets dysfunctional lymphocytes.Chronic rituximab(RTX)therapy can cause B-lymphocyte dysfunction,increasing CMV risk.Rarely,CMV infections present with critical illness such as septic shock.CASE SUMMARY A 64-year-old African American woman presented with generalized weakness and non-bloody watery diarrhea of 4-6 weeks duration.She did not have nausea,vomiting or,abdominal pain.She had been on monthly RTX infusions for neuromyelitis optica.She was admitted for septic shock due to pancolitis.Blood investigations suggested pancytopenia and serology detected significantly elevated CMV DNA.Valganciclovir treatment led to disease resolution.CONCLUSION This case illustrates an extremely rare case of CMV colitis associated with RTX use presenting with septic shock.High suspicion for rare opportunistic infections is imperative in individuals with long-term RTX use.展开更多
Background:Immune checkpoint inhibitors play an important role in the treatment of solid tumors,but the currently used immune checkpoint inhibitors targeting programmed cell death-1(PD-1),programmed cell death ligand-...Background:Immune checkpoint inhibitors play an important role in the treatment of solid tumors,but the currently used immune checkpoint inhibitors targeting programmed cell death-1(PD-1),programmed cell death ligand-1(PD-L1),and cytotoxic T-lymphocyte antigen-4(CTLA-4)show limited clinical efficacy in many breast cancers.B7H3 has been widely reported as an immunosuppressive molecule,but its immunological function in breast cancer patients remains unclear.Methods:We analyzed the expression of B7H3 in breast cancer samples using data from the Cancer Genome Atlas Program(TCGA)and the Gene Expression Omnibus(GEO)databases.MicroRNAs were selected using the TarBase,miRTarBase,and miRBase databases.The regulatory role of the microRNA hsa-miR-214-3p on B7H3 was investigated through dual-luciferase reporter assays,which identified the specific action sites of interaction.The expression levels of B7H3 and hsa-miR-214-3p in human breast cancer tissues and adjacent normal tissues were quantified using Western blotting and quantitative PCR(qPCR).In vitro experiments were performed to observe the effects of modulating the expression of B7H3 or hsa-miR-214-3p on breast cancer cell proliferation and apoptosis.Additionally,the regulatory impact of hsa-miR-214-3p on B7H3 was examined.Enzyme-linked immunosorbent assays(ELISA)and flow cytometry were employed to assess the effects of co-cultured breast cancer cells and normal human peripheral blood mononuclear cells(PBMCs)on immune cells and associated cytokines.Results:In breast cancer tissues,the expression level of B7H3 is inversely correlated with that of hsa-miR-214-3p,as well as with the regulatory effects on breast cancercell behavior.Hsa-miR-214-3p was found to inhibit breast cancer cell growth by downregulating B7H3.Importantly,our research identified,for the first time,two binding sites for hsa-miR-214-3p on the 3’UTR of B7H3,both of which exert similar effects independently.Co-culture experiments revealed that hsamiR-214-3p obstructs the suppressive function of B7H3 on CD8^(+)T cells and natural killer cells.Conclusions:This study confirms the existence of two hsa-miR-214-3p binding sites on the 3’UTR of B7H3,reinforcing the role of hsamiR-214-3p as a regulatory factor for B7H3.In breast cancer,hsa-miR-214-3p reduces tumor cell proliferation and enhances the tumor immune microenvironment by downregulating B7H3.These findings suggest new potential targets for the clinical treatment of breast cancer.展开更多
Introduction:Non–muscle-invasive bladder cancer(NMIBC)is a common malignancy worldwide.While Bacillus Calmette-Guérin(BCG)is standard of care for treatment for most patients with high-risk NMIBC,many will either...Introduction:Non–muscle-invasive bladder cancer(NMIBC)is a common malignancy worldwide.While Bacillus Calmette-Guérin(BCG)is standard of care for treatment for most patients with high-risk NMIBC,many will either not respond to BCG initially or will eventually develop BCG-unresponsive disease.A treatment option in BCG-unresponsive disease is nadofaragene firadenovec-vncg(Adstiladrin),a nonreplicating adenoviral vector–based gene therapy approved by the US Food and Drug Administration(FDA)for the treatment of adults with high-risk BCGunresponsive NMIBC with carcinoma in situ with or without papillary tumors.Objective:To review safety outcomes of participants who received the FDA-approved dose of nadofaragene firadenovec(3×10^(11)vp/mL)across phase 2(NCT01687244)and phase 3(NCT02773849)studies.Methods:Data from the phase 2 and phase 3 studies were collected and analyzed.The findings were reported using descriptive statistics to summarize the key outcomes observed across studies.Results:Common adverse events(AEs)among nadofaragene firadenovec recipients were leakage of fluid around the urinary catheter,fatigue,bladder spasm,chills,dysuria,and micturition urgency.Most study drug–related AEs were mild and localized,with no grade 4 or 5 study drug–related AEs observed in either study.Study drug–related AEs were generally transient,with most study drug–related AEs having a median duration of≤2.0 days in the phase 3 study.Discontinuation rates due to study drug–related AEs were low,with none(0%)in the phase 2 study and three(1.9%)in the phase 3 study.No specific postmarketing surveillance was required by the FDA besides routine pharmacovigilance monitoring;no new real-world safety signals have been observed.Conclusion:Nadofaragene firadenovec demonstrated a favorable and tolerable safety profile across its clinical study program,allowing for broad patient selection among those with high-risk BCG-unresponsive NMIBC.展开更多
This editorial provides insights into the pivotal role of checkpoint kinase 1(CHEK1)as both a biomarker and therapeutic target in colorectal cancer(CRC),based on findings from a recent study by Pang et al.Using single...This editorial provides insights into the pivotal role of checkpoint kinase 1(CHEK1)as both a biomarker and therapeutic target in colorectal cancer(CRC),based on findings from a recent study by Pang et al.Using single-cell RNA sequencing and immunohistochemistry,the study demonstrates significant CHEK1 overexpression in CRC tissues and identifies nitidine chloride as a potent CHEK1 inhibitor that disrupts DNA damage repair pathways.These findings underscore the therapeutic potential of CHEK1 inhibition and highlight the need for further research to address gaps in CRC treatment.展开更多
Objective:This study investigated the outcomes of microsurgical subinguinal varicocelectomy(MSV)on semen and hormonal parameters in cases with isolated sperm defects(oligozoospermia,asthenozoospermia,or teratozoosperm...Objective:This study investigated the outcomes of microsurgical subinguinal varicocelectomy(MSV)on semen and hormonal parameters in cases with isolated sperm defects(oligozoospermia,asthenozoospermia,or teratozoospermia).Methods:A retrospective review of charts of patients who underwent MSV for clinically palpable varicocele between January 1,2011 and January 1,2019 at Hamad Medical Corporation was undertaken.All patients diagnosed with isolated oligozoospermia,asthenozoospermia,or teratozoospermia in the preoperative semen analysis were included.Men with multiple sperm defects,genetic abnormalities,azoospermia,history of genitourinary infection,exposure to chemotherapy or radiotherapy,or prior use of peri-operative fertility treatment were excluded.Data extracted from the electronic medical records included(collected before MSV and up to 6 months postoperatively):demographics(age),clinical data(fertility-related medical history and surgical interventions),family history(consanguinity and infertility),physical examination findings from general and local genital exam(varicocele side and grade),laboratory data such as semen analysis,sperm DNA fragmentation tests,and hormone levels(follicle-stimulating hormone,luteinizing hormone,total testosterone,estradiol,and prolactin),and imaging(scrotal color Doppler ultrasound).Results:A total of 331 patients with isolated sperm defects were included.Postoperatively,83.3%of patients showed an improvement in sperm concentration with a median increase of 7 millions/mL.Postoperatively,76.7%of isolated asthenozoospermic patients showed an improvement in total motility and 66.0%had an improvement in progressive motility with median increases of 15.0%and 7.5%,respectively.Postoperatively,70.0%of the teratozoospermic patients showed an improvement in normal sperm morphology with a median increase of 6%.No changes were observed in other semen or hormone parameters that were examined.Conclusion:MSV is a valid and effective treatment modality for patients with isolated sperm defects that significantly corrects their respective semen abnormality and improves their chances of natural conception.展开更多
Objectives Retinal ischemia-reperfusion(RIR)injury results in irreversible visual impairments.The disruption of the outer blood-retinal barrier(OBRB)is a major ocular pathogenic process that RIR injury affects.Current...Objectives Retinal ischemia-reperfusion(RIR)injury results in irreversible visual impairments.The disruption of the outer blood-retinal barrier(OBRB)is a major ocular pathogenic process that RIR injury affects.Current clinical strategies are limited.This study aimed to elucidate how electroacupuncture(EA)protects the OBRB against RIR injury.Methods Male Wistar rats(7 weeks old,250 g to 280 g)were used in this study.Three independent experiments were conducted.First,Opioid peptide levels were quantified using enzyme-linked immunosorbent assay(ELISA).42 rats were randomly divided into 7 groups(n=6/group):Control:No treatment;high intraocular pressure(HIOP):Acute intraocular pressure elevation-induced RIR injury;HIOP+SHAM EA:RIR injury+sham EA at Xinming(Extra acupoint)and Jingming(BL1)for 30 min(shallow needle insertion but without electric stimulation);HIOP+2 Hz EA:RIR injury+2 Hz EA at Xinming and BL1 for 30 min;HIOP+100 Hz:RIR injury+100 Hz EA at Xinming and BL1 for 30 min;HIOP+2/100 Hz EA:RIR injury+2/100 Hz EA at Xinming and BL1 for 30 min;HIOP+4/20 Hz EA:RIR injury+4/20 Hz EA at Xinming and BL1 for 30 min.Second,retinal morphology was assessed by hematoxylin and eosin(HE)staining.20 rats were randomly allocated into 4 groups(n=5/group):Control:No treatment;HIOP:Acute intraocular pressure elevation-induced RIR injury;HIOP+SHAM EA:RIR injury+sham EA at Xinming and BL1 for 30 min(shallow needle insertion but without electric stimulation);HIOP+2 Hz EA:RIR injury+2 Hz EA at Xinming and BL1 for 30 min.Third,the permeability of OBRB was evaluated using the fluorescein isothiocyanate(FITC)-dextran leakage assay.15 rats were randomly divided into 5 groups(n=3/group):Control:No treatment;HIOP:Acute intraocular pressure elevation-induced RIR injury;HIOP+SHAM EA:RIR injury+sham EA at Xinming and BL1 for 30 min(shallow needle insertion but without electric stimulation);HIOP+2 Hz EA:RIR injury+2 Hz EA at Xinming and BL1 for 30 min;Nal+HIOP+2 Hz EA:Intravitreal injection ofδ-opioid receptor antagonist Naltridole(10µl,100 nM)30 min before RIR injury induction,followed by 2 Hz EA treatment at Xinming and BL1 for 30 min.In vitro studies examined enkephalins'effects on oxygen–glucose deprivation/reperfusion(OGD/R)induced injury in ARPE‐19 cells.Cell viability was evaluated by cell counting kit-8(CCK-8)assay,and morphological changes were recorded by Molecular Devices.Apoptosis was detected by Annexin V-FITC flow cytometry.Delta opioid receptor(DOR)expression in total protein and membrane protein were analyzed by western blotting(WB).Immunofluorescence(IF)staining and WB assessed ZO-1 and Claudin-19.For cell-based assays,n indicates the number of biologically independent replicates.Results It was found that 2 Hz EA treatment increased enkephalins(methionine-enkephalin and leucine-enkephalin)levels(P<0.01),restoring the increased retinal thickness(P<0.05)and mitigating RGCs loss(P<0.05)post-RIR injury.FITC-dextran leakage in the outer retina was ameliorated by 2 Hz EA(P<0.05),reversibly countered by Naltrindole(P<0.05),a DOR antagonist.Treatment with 30µM enkephalins enhanced ARPE-19 cell viability(P<0.001,P<0.0001)and inhibited apoptosis(P<0.0001).Enkephalins elevated DOR levels in total protein(P<0.05)and membrane protein fractions(P<0.001,P<0.0001),as well as elevated ZO-1(P<0.001,P<0.01)and Claudin-19(P<0.0001,P<0.001)levels following OGD/R,counteracted by Naltrindole.Conclusion It was found that 2 Hz EA inhibits the breakdown of OBRB via enkephalins activate DOR in RIR injury.展开更多
背景与目的:华蟾素目前广泛应用于肿瘤的治疗中,由于在80年代上市,未进行临床Ⅰ期研究,无法确定其最大耐受剂量。因此本文旨在观察华蟾素治疗肝细胞癌、肺癌和胰腺癌的最大耐受剂量和不良反应,同时评价治疗疗效。方法:Ⅲ、Ⅳ期肝细胞癌...背景与目的:华蟾素目前广泛应用于肿瘤的治疗中,由于在80年代上市,未进行临床Ⅰ期研究,无法确定其最大耐受剂量。因此本文旨在观察华蟾素治疗肝细胞癌、肺癌和胰腺癌的最大耐受剂量和不良反应,同时评价治疗疗效。方法:Ⅲ、Ⅳ期肝细胞癌、非小细胞肺癌和胰腺癌接受华蟾素治疗,采用静脉滴注,连续14 d,21 d为一疗程。如果没有出现剂量限制性毒性,治疗将持续2个疗程。剂量递增的方案为:10、20、40、60、90和120 m l/(m2.d)。结果:入组15例患者(每个剂量组为3例)中,11例为肝癌,2例胰腺癌和2例肺癌。第五剂量组结束时没有发现剂量限制性毒性(DLT)。其中14例患者可评价疗效,6例(42.9%)为SD,8例(57.1%)为PD。在第一剂量组中,1例肝癌患者肿瘤缩小20%并维持11个月。结论:本研究最高剂量达到常规剂量的8倍,尚未出现剂量限制性毒性。部分患者获得了肿瘤缩小或稳定的疗效。展开更多
基金supported by the National Natural Science Foundation(82072729)Wuhan Municipal Health Commission Medical Research Project(WX19Q30),China。
文摘Objective:Oxaliplatin(OXA)and 5-fluorouracil(5-FU)are 2 commonly used chemotherapeutic agents for colorectal cancer(CRC).MicroRNAs(miRNAs,miRs)play crucial roles in the development of chemoresistance in various cancers.However,the role and mechanism of miR-224-5p in regulating CRC chemoresistance remain unclear.This study aims to investigate the function of miR-224-5p in chemoresistant CRC cells and the underlying mechanisms.Methods:CRC datasets GSE28702 and GSE69657 were downloaded from the Gene Expression Omnibus(GEO)database.Differentially expressed miRNAs between drug sensitive and resistant groups(OXA or 5-FU)were analyzed,and miR-224-5p was identified as the target miRNA.Chemoresistant cell lines HCT15-OXR,HCT15-5-FU,SW480-OXR,and SW480-5-FU were established.Transient transfections were performed using miR-224-5p mimics,inhibitors,and their respective negative controls(control mimic,control inhibitor)in these cell lines.Cells were treated with different concentrations of OXA or 5-FU post-transfection,and the half-maximal inhibitory concentration(IC_(50))was determined using the cell counting kit-8(CCK-8)assay.Cell proliferation was assessed by CCK-8 and colony formation assays.The expression levels of miR-224-5p,LC3,and P62 were measured by real-time polymerase chain reaction(real-time PCR)and/or Western blotting.Autophagic flux was assessed using a tandem fluorescent-tagged LC3 reporter assay.TargetScan 8.0,miRTarBase,miRPathDB,and HADb were used to predict B-cell lymphoma-2(Bcl-2)as a potential miR-244-5p target,which was further validated by dual luciferase reporter assays.Results:Chemoresistant CRC cells exhibited down-regulated miR-224-5p expression,whereas up-regulation of miR-224-5p enhanced chemotherapy sensitivity.Exposure to OXA or 5-FU significantly increased autophagic activity in chemoresistant CRC cells,which was reversed by miR-224-5p overexpression.Dual-luciferase assays verified Bcl-2 as a direct target of miR-224-5p.Conclusion:MiR-224-5p regulates chemoresistance in CRC by modulating autophagy through direct targeting of Bcl-2.
文摘BACKGROUND Cytomegalovirus(CMV)infections can cause significant morbidity and mortality in immunocompromised individuals.CMV targets dysfunctional lymphocytes.Chronic rituximab(RTX)therapy can cause B-lymphocyte dysfunction,increasing CMV risk.Rarely,CMV infections present with critical illness such as septic shock.CASE SUMMARY A 64-year-old African American woman presented with generalized weakness and non-bloody watery diarrhea of 4-6 weeks duration.She did not have nausea,vomiting or,abdominal pain.She had been on monthly RTX infusions for neuromyelitis optica.She was admitted for septic shock due to pancolitis.Blood investigations suggested pancytopenia and serology detected significantly elevated CMV DNA.Valganciclovir treatment led to disease resolution.CONCLUSION This case illustrates an extremely rare case of CMV colitis associated with RTX use presenting with septic shock.High suspicion for rare opportunistic infections is imperative in individuals with long-term RTX use.
基金funded by the Natural Science Foundation of Guangdong Province(grant number 2022A1515012315)Guangdong Medical Science and Technology Research Fund Project(grant number A2023185)+2 种基金the Discipline Construction Project of Guangdong Medical University(grant number 4SG22005G)the 2023 Provincial Basic and Applied Basic Research Fund Enterprise Joint Fund Project(grant number 2023A1515220149)Southern Medical University Shunde Hospital 2023 Research Initiation Programme Project(SRSP2023016).
文摘Background:Immune checkpoint inhibitors play an important role in the treatment of solid tumors,but the currently used immune checkpoint inhibitors targeting programmed cell death-1(PD-1),programmed cell death ligand-1(PD-L1),and cytotoxic T-lymphocyte antigen-4(CTLA-4)show limited clinical efficacy in many breast cancers.B7H3 has been widely reported as an immunosuppressive molecule,but its immunological function in breast cancer patients remains unclear.Methods:We analyzed the expression of B7H3 in breast cancer samples using data from the Cancer Genome Atlas Program(TCGA)and the Gene Expression Omnibus(GEO)databases.MicroRNAs were selected using the TarBase,miRTarBase,and miRBase databases.The regulatory role of the microRNA hsa-miR-214-3p on B7H3 was investigated through dual-luciferase reporter assays,which identified the specific action sites of interaction.The expression levels of B7H3 and hsa-miR-214-3p in human breast cancer tissues and adjacent normal tissues were quantified using Western blotting and quantitative PCR(qPCR).In vitro experiments were performed to observe the effects of modulating the expression of B7H3 or hsa-miR-214-3p on breast cancer cell proliferation and apoptosis.Additionally,the regulatory impact of hsa-miR-214-3p on B7H3 was examined.Enzyme-linked immunosorbent assays(ELISA)and flow cytometry were employed to assess the effects of co-cultured breast cancer cells and normal human peripheral blood mononuclear cells(PBMCs)on immune cells and associated cytokines.Results:In breast cancer tissues,the expression level of B7H3 is inversely correlated with that of hsa-miR-214-3p,as well as with the regulatory effects on breast cancercell behavior.Hsa-miR-214-3p was found to inhibit breast cancer cell growth by downregulating B7H3.Importantly,our research identified,for the first time,two binding sites for hsa-miR-214-3p on the 3’UTR of B7H3,both of which exert similar effects independently.Co-culture experiments revealed that hsamiR-214-3p obstructs the suppressive function of B7H3 on CD8^(+)T cells and natural killer cells.Conclusions:This study confirms the existence of two hsa-miR-214-3p binding sites on the 3’UTR of B7H3,reinforcing the role of hsamiR-214-3p as a regulatory factor for B7H3.In breast cancer,hsa-miR-214-3p reduces tumor cell proliferation and enhances the tumor immune microenvironment by downregulating B7H3.These findings suggest new potential targets for the clinical treatment of breast cancer.
基金This work was supported by Ferring Pharmaceuticals Inc.
文摘Introduction:Non–muscle-invasive bladder cancer(NMIBC)is a common malignancy worldwide.While Bacillus Calmette-Guérin(BCG)is standard of care for treatment for most patients with high-risk NMIBC,many will either not respond to BCG initially or will eventually develop BCG-unresponsive disease.A treatment option in BCG-unresponsive disease is nadofaragene firadenovec-vncg(Adstiladrin),a nonreplicating adenoviral vector–based gene therapy approved by the US Food and Drug Administration(FDA)for the treatment of adults with high-risk BCGunresponsive NMIBC with carcinoma in situ with or without papillary tumors.Objective:To review safety outcomes of participants who received the FDA-approved dose of nadofaragene firadenovec(3×10^(11)vp/mL)across phase 2(NCT01687244)and phase 3(NCT02773849)studies.Methods:Data from the phase 2 and phase 3 studies were collected and analyzed.The findings were reported using descriptive statistics to summarize the key outcomes observed across studies.Results:Common adverse events(AEs)among nadofaragene firadenovec recipients were leakage of fluid around the urinary catheter,fatigue,bladder spasm,chills,dysuria,and micturition urgency.Most study drug–related AEs were mild and localized,with no grade 4 or 5 study drug–related AEs observed in either study.Study drug–related AEs were generally transient,with most study drug–related AEs having a median duration of≤2.0 days in the phase 3 study.Discontinuation rates due to study drug–related AEs were low,with none(0%)in the phase 2 study and three(1.9%)in the phase 3 study.No specific postmarketing surveillance was required by the FDA besides routine pharmacovigilance monitoring;no new real-world safety signals have been observed.Conclusion:Nadofaragene firadenovec demonstrated a favorable and tolerable safety profile across its clinical study program,allowing for broad patient selection among those with high-risk BCG-unresponsive NMIBC.
文摘This editorial provides insights into the pivotal role of checkpoint kinase 1(CHEK1)as both a biomarker and therapeutic target in colorectal cancer(CRC),based on findings from a recent study by Pang et al.Using single-cell RNA sequencing and immunohistochemistry,the study demonstrates significant CHEK1 overexpression in CRC tissues and identifies nitidine chloride as a potent CHEK1 inhibitor that disrupts DNA damage repair pathways.These findings underscore the therapeutic potential of CHEK1 inhibition and highlight the need for further research to address gaps in CRC treatment.
文摘Objective:This study investigated the outcomes of microsurgical subinguinal varicocelectomy(MSV)on semen and hormonal parameters in cases with isolated sperm defects(oligozoospermia,asthenozoospermia,or teratozoospermia).Methods:A retrospective review of charts of patients who underwent MSV for clinically palpable varicocele between January 1,2011 and January 1,2019 at Hamad Medical Corporation was undertaken.All patients diagnosed with isolated oligozoospermia,asthenozoospermia,or teratozoospermia in the preoperative semen analysis were included.Men with multiple sperm defects,genetic abnormalities,azoospermia,history of genitourinary infection,exposure to chemotherapy or radiotherapy,or prior use of peri-operative fertility treatment were excluded.Data extracted from the electronic medical records included(collected before MSV and up to 6 months postoperatively):demographics(age),clinical data(fertility-related medical history and surgical interventions),family history(consanguinity and infertility),physical examination findings from general and local genital exam(varicocele side and grade),laboratory data such as semen analysis,sperm DNA fragmentation tests,and hormone levels(follicle-stimulating hormone,luteinizing hormone,total testosterone,estradiol,and prolactin),and imaging(scrotal color Doppler ultrasound).Results:A total of 331 patients with isolated sperm defects were included.Postoperatively,83.3%of patients showed an improvement in sperm concentration with a median increase of 7 millions/mL.Postoperatively,76.7%of isolated asthenozoospermic patients showed an improvement in total motility and 66.0%had an improvement in progressive motility with median increases of 15.0%and 7.5%,respectively.Postoperatively,70.0%of the teratozoospermic patients showed an improvement in normal sperm morphology with a median increase of 6%.No changes were observed in other semen or hormone parameters that were examined.Conclusion:MSV is a valid and effective treatment modality for patients with isolated sperm defects that significantly corrects their respective semen abnormality and improves their chances of natural conception.
基金Supported by the National Natural Science Foundation of China:81574078。
文摘Objectives Retinal ischemia-reperfusion(RIR)injury results in irreversible visual impairments.The disruption of the outer blood-retinal barrier(OBRB)is a major ocular pathogenic process that RIR injury affects.Current clinical strategies are limited.This study aimed to elucidate how electroacupuncture(EA)protects the OBRB against RIR injury.Methods Male Wistar rats(7 weeks old,250 g to 280 g)were used in this study.Three independent experiments were conducted.First,Opioid peptide levels were quantified using enzyme-linked immunosorbent assay(ELISA).42 rats were randomly divided into 7 groups(n=6/group):Control:No treatment;high intraocular pressure(HIOP):Acute intraocular pressure elevation-induced RIR injury;HIOP+SHAM EA:RIR injury+sham EA at Xinming(Extra acupoint)and Jingming(BL1)for 30 min(shallow needle insertion but without electric stimulation);HIOP+2 Hz EA:RIR injury+2 Hz EA at Xinming and BL1 for 30 min;HIOP+100 Hz:RIR injury+100 Hz EA at Xinming and BL1 for 30 min;HIOP+2/100 Hz EA:RIR injury+2/100 Hz EA at Xinming and BL1 for 30 min;HIOP+4/20 Hz EA:RIR injury+4/20 Hz EA at Xinming and BL1 for 30 min.Second,retinal morphology was assessed by hematoxylin and eosin(HE)staining.20 rats were randomly allocated into 4 groups(n=5/group):Control:No treatment;HIOP:Acute intraocular pressure elevation-induced RIR injury;HIOP+SHAM EA:RIR injury+sham EA at Xinming and BL1 for 30 min(shallow needle insertion but without electric stimulation);HIOP+2 Hz EA:RIR injury+2 Hz EA at Xinming and BL1 for 30 min.Third,the permeability of OBRB was evaluated using the fluorescein isothiocyanate(FITC)-dextran leakage assay.15 rats were randomly divided into 5 groups(n=3/group):Control:No treatment;HIOP:Acute intraocular pressure elevation-induced RIR injury;HIOP+SHAM EA:RIR injury+sham EA at Xinming and BL1 for 30 min(shallow needle insertion but without electric stimulation);HIOP+2 Hz EA:RIR injury+2 Hz EA at Xinming and BL1 for 30 min;Nal+HIOP+2 Hz EA:Intravitreal injection ofδ-opioid receptor antagonist Naltridole(10µl,100 nM)30 min before RIR injury induction,followed by 2 Hz EA treatment at Xinming and BL1 for 30 min.In vitro studies examined enkephalins'effects on oxygen–glucose deprivation/reperfusion(OGD/R)induced injury in ARPE‐19 cells.Cell viability was evaluated by cell counting kit-8(CCK-8)assay,and morphological changes were recorded by Molecular Devices.Apoptosis was detected by Annexin V-FITC flow cytometry.Delta opioid receptor(DOR)expression in total protein and membrane protein were analyzed by western blotting(WB).Immunofluorescence(IF)staining and WB assessed ZO-1 and Claudin-19.For cell-based assays,n indicates the number of biologically independent replicates.Results It was found that 2 Hz EA treatment increased enkephalins(methionine-enkephalin and leucine-enkephalin)levels(P<0.01),restoring the increased retinal thickness(P<0.05)and mitigating RGCs loss(P<0.05)post-RIR injury.FITC-dextran leakage in the outer retina was ameliorated by 2 Hz EA(P<0.05),reversibly countered by Naltrindole(P<0.05),a DOR antagonist.Treatment with 30µM enkephalins enhanced ARPE-19 cell viability(P<0.001,P<0.0001)and inhibited apoptosis(P<0.0001).Enkephalins elevated DOR levels in total protein(P<0.05)and membrane protein fractions(P<0.001,P<0.0001),as well as elevated ZO-1(P<0.001,P<0.01)and Claudin-19(P<0.0001,P<0.001)levels following OGD/R,counteracted by Naltrindole.Conclusion It was found that 2 Hz EA inhibits the breakdown of OBRB via enkephalins activate DOR in RIR injury.
文摘背景与目的:华蟾素目前广泛应用于肿瘤的治疗中,由于在80年代上市,未进行临床Ⅰ期研究,无法确定其最大耐受剂量。因此本文旨在观察华蟾素治疗肝细胞癌、肺癌和胰腺癌的最大耐受剂量和不良反应,同时评价治疗疗效。方法:Ⅲ、Ⅳ期肝细胞癌、非小细胞肺癌和胰腺癌接受华蟾素治疗,采用静脉滴注,连续14 d,21 d为一疗程。如果没有出现剂量限制性毒性,治疗将持续2个疗程。剂量递增的方案为:10、20、40、60、90和120 m l/(m2.d)。结果:入组15例患者(每个剂量组为3例)中,11例为肝癌,2例胰腺癌和2例肺癌。第五剂量组结束时没有发现剂量限制性毒性(DLT)。其中14例患者可评价疗效,6例(42.9%)为SD,8例(57.1%)为PD。在第一剂量组中,1例肝癌患者肿瘤缩小20%并维持11个月。结论:本研究最高剂量达到常规剂量的8倍,尚未出现剂量限制性毒性。部分患者获得了肿瘤缩小或稳定的疗效。
