There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson’s disease after diagnosis.Given that preclinical and clinical studies suggest benefits of dietary n-3 poly...There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson’s disease after diagnosis.Given that preclinical and clinical studies suggest benefits of dietary n-3 polyunsaturated fatty acids,such as docosahexaenoic acid,and exercise in Parkinson’s disease,we investigated whether both could synergistically interact to induce recovery of the dopaminergic pathway.First,mice received a unilateral stereotactic injection of 6-hydroxydopamine into the striatum to establish an animal model of nigrostriatal denervation.Four weeks after lesion,animals were fed a docosahexaenoic acid-enriched or a control diet for the next 8 weeks.During this period,the animals had access to a running wheel,which they could use or not.Docosahexaenoic acid treatment,voluntary exercise,or the combination of both had no effect on(i)distance traveled in the open field test,(ii)the percentage of contraversive rotations in the apomorphine-induction test or(iii)the number of tyrosine-hydroxylase-positive cells in the substantia nigra pars compacta.However,the docosahexaenoic acid diet increased the number of tyrosine-hydroxylase-positive terminals and induced a rise in dopamine concentrations in the lesioned striatum.Compared to docosahexaenoic acid treatment or exercise alone,the combination of docosahexaenoic acid and exercise(i)improved forelimb balance in the stepping test,(ii)decreased the striatal DOPAC/dopamine ratio and(iii)led to increased dopamine transporter levels in the lesioned striatum.The present results suggest that the combination of exercise and docosahexaenoic acid may act synergistically in the striatum of mice with a unilateral lesion of the dopaminergic system and provide support for clinical trials combining nutrition and physical exercise in the treatment of Parkinson’s disease.展开更多
This study aimed to assess the therapeutic potential of nisin,5-fluorouracil(5FU)and selenium encapsulated in folate-conjugated thiolated chitosan nanoparticles(N/5FU/Se@FTCsNPs),combined with a probiotic cocktail of ...This study aimed to assess the therapeutic potential of nisin,5-fluorouracil(5FU)and selenium encapsulated in folate-conjugated thiolated chitosan nanoparticles(N/5FU/Se@FTCsNPs),combined with a probiotic cocktail of Lactobacillus acidophilus and Bifidobacterium bifidum,against colorectal cancer(CRC).The nanoparticles(277 nm,+9.2 mV)exhibited high drug loading efficiencies(5FU:89.11%,nisin:70.68%)and pH-responsive release,with minimal drug release under gastric conditions and∼60.7%release at colonic pH,facilitating targeted delivery.The formulation remained stable for over 40 d at−20°C and 4°C,demonstrating excellent biocompatibility(<2%hemolysis)and exhibiting strong mucoadhesive and mucus-penetrating abilities.In vitro,N/5FU/Se@FTCsNPs selectively targeted CT26 colon cancer cells(IC5n:1.57μg/ml)with minimal effects on healthy cells,enhanced cellular uptake,and induced ROS-mediated apoptosis.In vivo,oral administration-especially with probiotics-significantly reduced tumor volume,improved survival rates and alleviated chemotherapy-related side effects such as diarrhea and weight loss.Biodistribution studies confirmed increased tumor targeting and decreased off-target exposure.Mechanistically,the treatment downregulated oncogenes and inflammatory markers(2-to 12.5-fold),includingβ-catenin,mTOR,COX-2 and VEGF-α,while upregulating tumor suppressors and protective genes(4 to 14.8 fold),such as PTEN,CASP9 and Mucin 2(P<0.0001).This indicates inhibition of proliferation,metastasis,inflammation,and angiogenesis,along with improved gut barrier function.Cytokine profiling and histological analysis further confirmed reduced systemic inflammation and maintained hematological safety.These findings highlight N/5FU/Se@FTCsNPs combined with probiotics as a promising,safe and effective oral therapy for CRC,leveraging microbiota modulation and targeted delivery.展开更多
There are limited biosecurity measures directed at preventing airborne transmission of viruses in swine.The effectiveness of dust mitigation strategies such as oil sprinkling,to decrease risk of airborne virus transmi...There are limited biosecurity measures directed at preventing airborne transmission of viruses in swine.The effectiveness of dust mitigation strategies such as oil sprinkling,to decrease risk of airborne virus transmission are unknown.Metagenomics and qPCR for common fecal viruses were used to hunt for a ubiquitous virus to serve as a proxy when evaluating the efficiency of mitigation strategies against airborne viral infectious agents.Air particles were collected from swine buildings using high-volume air samplers.Extracted DNA and RNA were used to perform specific RT-qPCR and qPCR and analyzed by highthroughput sequencing.Porcine astroviruses group 2 were common(from 102 to 105 genomic copies per cubic meter of air or gc/m^(3),93%positivity)while no norovirus genogroup II was recovered from air samples.Porcine torque teno sus virus were detected by qPCR in low concentrations(from 101 to 102 gc/m^(3),47%positivity).Among the identified viral families by metagenomics analysis,Herelleviridae,Microviridae,Myoviridae,Podoviridae,and Siphoviridae were dominant.The phage vB_AviM_AVP of Aerococcus was present in all air samples and a newly designed qPCR revealed between 101 and 105 gc/m^(3) among the samples taken for the present study(97%positivity)and banked samples from5-and 15-year old studies(89%positivity).According to the present study,both the porcine astrovirus group 2 and the phage vB_AviM_AVP of Aerococcus could be proxy for airborne viruses of swine buildings.展开更多
Background: Prematurely-born individuals tend to exhibit higher resting oxidative stress, although evidence suggests they may be more resistant to acute hypoxia-induced redox balance alterations. We aimed to investiga...Background: Prematurely-born individuals tend to exhibit higher resting oxidative stress, although evidence suggests they may be more resistant to acute hypoxia-induced redox balance alterations. We aimed to investigate the redox balance changes across a 3-day hypobaric hypoxic exposure at 3375 m in healthy adults born preterm(gestational age ≤ 32 weeks) and their term-born(gestational age ≥ 38 weeks)counterparts.Methods: Resting venous blood was obtained in normoxia(prior to altitude exposure), immediately upon arrival to altitude, and the following 3mornings. Antioxidant(superoxide dismutase(SOD), catalase, glutathione peroxidase(GPx), and ferric reducing antioxidant power(FRAP)),pro-oxidant(xanthine oxidase(XO) and myeloperoxidase(MPO)) enzyme activity, oxidative stress markers(advanced oxidation protein product(AOPP) and malondialdehyde(MDA)), nitric oxide(NO) metabolites(nitrites, nitrates, and total nitrite and nitrate(NOx)), and nitrotyrosine were measured in plasma.Results: SOD increased only in the preterm group(p < 0.05). Catalase increased at arrival in preterm group(p < 0.05). XO activity increased at Day 3 for the preterm group, while it increased acutely(arrival and Day 1) in control group. MPO increased in both groups throughout the3 days(p < 0.05). AOPP only increased at arrival in the preterm(p < 0.05) whereas it decreased at arrival up to Day 3(p < 0.05) for control.MDA decreased in control group from arrival onward. Nitrotyrosine decreased in both groups(p < 0.05). Nitrites increased on Day 3(p < 0.05)in control group and decreased on Day 1(p < 0.05) in preterm group.Conclusion: These data indicate that antioxidant enzymes seem to increase immediately upon hypoxic exposure in preterm adults. Conversely, the blunted pro-oxidant enzyme response to prolonged hypoxia exposure suggests that these enzymes may be less sensitive in preterm individuals.These findings lend further support to the potential hypoxic preconditioning effect of preterm birth.展开更多
Objectives:Glioblastoma(GB)is a grade IV glial tumor characterized by high malignancy and dismal prognosis,primarily due to high recurrence rates and therapeutic resistance.The epidermal growth factor receptor(EGFR),a...Objectives:Glioblastoma(GB)is a grade IV glial tumor characterized by high malignancy and dismal prognosis,primarily due to high recurrence rates and therapeutic resistance.The epidermal growth factor receptor(EGFR),a receptor tyrosine kinase(RTK),regulates signaling pathways,including cell growth,proliferation,survival,migration,and cell death.Many cancers utilize immune checkpoints(ICs)to attenuate immune responses.CD73 is an enzyme that functions as an IC by hydrolyzing AMP to adenosine,suppressing immune cells in the tumor microenvironment.However,the role of CD73 in resistance to EGFR inhibitors is poorly understood.This study aims to elucidate the resistance mechanisms induced by anti-EGFR treatment and to evaluate an anti-CD73 approach to overcome resistance mediated by anti-EGFR monotherapy.Methods:The U251 GB cell line was treated with AG1478,an EGFR inhibitor,and the resistance markers MRP-1,PD-L1,and CD73 were evaluated using flow cytometry.Additionally,we assessed the combination effects of AG1478 and APCP(an EGFR and a CD73 inhibitor,respectively)on cell cycle progression,proliferation,apoptosis,and migration in vitro.Results:We observed high EGFR,PD-L1,and CD73 expression in human GB cells.The treatment with AG1478 increased the expression of resistance markers MRP-1,PD-L1,and CD73,whereas it decreased CTLA-4.The combination of AG1478 and APCP did not alter proliferation or apoptosis but interfered with cell cycling,arresting the cells in the G1 phase,decreasing cell motility and partially reversing MRP-1 overexpression.Conclusion:In summary,our findings indicate that CD73 inhibition has a modest effect in overcoming resistance to EGFR monotherapy in vitro.Thus,further in vivo studies are needed,as the inhibition of both EGFR and CD73 affects cells in the tumor microenvironment and could potentially enhance anti-tumor immunity.展开更多
AIM： To evaluate the results of sub total colectomy withI cecorectal anastomosis （STC-CRA） for isolated colonicinertia （CI）. METHODS： Fourteen patients （mean age 57.5±16.5 year） underwent surgery for isol...AIM： To evaluate the results of sub total colectomy withI cecorectal anastomosis （STC-CRA） for isolated colonicinertia （CI）. METHODS： Fourteen patients （mean age 57.5±16.5 year） underwent surgery for isolated CI between January 1986 and December 2002. The mean frequency of bowel motions with the aid of laxatives was 1.2±0.6 per week. All subjects underwent colonoscopy, anorectal manometry, cinedefaecography and colonic transit time （CTF）. CI was defined as diffuse markers delay on CTF without evidence of pelvic floor dysfunction. All patients underwent STC-CRA. Long-term follow-up was obtained prospectively by clinical visits between October 2005 and February 2006 at a mean of 10.5 ＋ 3.6 years （range 5-16 years） during which we considered the number of stool emissions, the presence of abdominal pain or digitations, the use of pain killers, laxatives and/or fibers. Patients were also asked if they were satisfied with the surgery. RESULTS： There was no postoperative mortality Postoperative complications occurred in 21.4% （3/14）. At the end of follow-up, bowel frequency was significantly （P〈0.05）increased to a mean of 4.8±7.5 per day （range 1-30）. One patient reported disabling diarrhea. Two patients used laxatives less than three times per month without complaining of what they called constipation Overall, 78.5% of patients would have chosen surgery again if necessary. CONCLUSION： STC-CRA is feasible and safe in patients with CI achieving 79% of success at a mean follow-up of 10.5 years. A prospective controlled evaluation is warranted to verify the advantages of this surgical approach in patients with CI.展开更多
Hepatocyte nuclear factor 4-alpha (HNF4-α) is a nuclear receptor regulating metabolism, cell junctions, differentiation and proliferation in liver and intestinal epithelial cells. Mutations within the HNF4...Hepatocyte nuclear factor 4-alpha (HNF4-α) is a nuclear receptor regulating metabolism, cell junctions, differentiation and proliferation in liver and intestinal epithelial cells. Mutations within the HNF4A gene are associated with human diseases such as maturity-onset diabetes of the young. Recently, HNF4A has also been described as a susceptibility gene for ulcerative colitis in genome-wide association studies. In addition, specific HNF4A genetic variants have been identified in pediatric cohorts of Crohn’s disease. Results obtained from knockout mice supported that HNF4-α can protect the intestinal mucosae against inflammation. However, the exact molecular links behind HNF4-α and inflammatory bowel diseases remains elusive. In this review, we will summarize the current knowledge about the role of HNF4-α and its isoforms in inflammation. Specific nature of HNF4-α P1 and P2 classes of isoforms will be summarized. HNF4-α role as a hepatocyte mediator for cytokines relays during liver inflammation will be integrated based on documented examples of the literature. Conclusions that can be made from these earlier liver studies will serve as a basis to extrapolate correlations and divergences applicable to intestinal inflammation. Finally, potential functional roles for HNF4-α isoforms in protecting the intestinal mucosae from chronic and pathological inflammation will be presented.展开更多
Development of the spine and thoracic cage consists of a complex series of events involving multiple metabolic processes, genes and signaling pathways. During growth, complex phenomena occur in rapid succession. This ...Development of the spine and thoracic cage consists of a complex series of events involving multiple metabolic processes, genes and signaling pathways. During growth, complex phenomena occur in rapid succession. This succession of events, this establishment of elements, is programmed according to a hierarchy. These events are well synchronized to maintain harmonious limb, spine and thoracic cage relationships, as growth in the various body segments does not occur simultaneously at the same magnitude or rate. In most severe cases of untreated progressive earlyonset spinal deformities, respiratory insufficiency and pulmonary and cardiac hypertension(cor pulmonale), which characterize thoracic insufficiency syndrome(TIS), can develop, sometimes leading to death. TIS is the inability of the thorax to ensure normal breathing. This clinical condition can be linked to costo-vertebral malformations(e.g., fused ribs, hemivertebrae, congenital bars), neuromuscular diseases(e.g., expiratory congenital hypotonia), Jeune or Jarcho-Levin syndromes or to 50% to 75% fusion of the thoracic spine before seven years of age. Complex spinal deformities alter normal growth plate development, and vertebral bodies become progressively distorted, perpetuating the disorder. Therefore, many scoliotic deformities can become growth plate disorders over time. This review aims to provide a comprehensive review of how spinal deformities can affect normal spine and thoracic cage growth. Previous conceptualizations are integrated with more recent scientific data to provide a better understanding of both normal and abnormal spine and thoracic cage growth.展开更多
Cell therapy has the potential to improve healing of ischemic heart, repopulate injured myocardium and restore cardiac function. The tremendous hope and potential of stem cell therapy is well understood, yet recent tr...Cell therapy has the potential to improve healing of ischemic heart, repopulate injured myocardium and restore cardiac function. The tremendous hope and potential of stem cell therapy is well understood, yet recent trials involving cell therapy for cardiovascular diseases have yielded mixed results with inconsistent data thereby readdressing controversies and unresolved questions regarding stem cell efficacy for ischemic cardiac disease treatment. These controversies are believed to arise by the lack of uniformity of the clinical trial methodologies, uncertainty regarding the underlying reparative mechanisms of stem cells, questions concerning the most appropriate cell population to use, the proper delivery method and timing in relation to the moment of infarction, as well as the poor stem cell survival and engraftment especially in a diseased microenvironment which is collectively acknowledged as a major hindrance to any form of cell therapy. Indeed, the microenvironment of the failing heart exhibits pathological hypoxic, oxidative and inflammatory stressors impairing the survival of transplanted cells. Therefore, in order to observe any significant therapeutic benefit there is a need to increase resilience of stem cells to death in the transplant microenvironment while preserving or better yet improving their reparative functionality. Although stem cell differentiation into cardiomyocytes has been observed in some instance, the prevailing reparative benefits are afforded through paracrine mechanisms that promote angiogenesis, cell survival, transdifferentiate host cells and modulate immune responses. Therefore, to maximize their reparative functionality, ex vivo manipulation of stem cells through physical, genetic and pharmacological means have shown promise to enable cells to thrive in the postischemic transplant microenvironment. In the present work, we will overview the current status of stem cell therapy for ischemic heart disease, discuss the most recurring cell populations employed, the mechanisms by which stem cells deliver a therapeutic benefit andstrategies that have been used to optimize and increase survival and functionality of stem cells including ex vivo preconditioning with drugs and a novel "pharmacooptimizer" as well as genetic modifications.展开更多
Foot ulcers are common in diabetic patients,have a cumulative lifetime incidence rate as high as 25%and frequently become infected.The spread of infection to soft tissue and bone is a major causal factor for lowerlimb...Foot ulcers are common in diabetic patients,have a cumulative lifetime incidence rate as high as 25%and frequently become infected.The spread of infection to soft tissue and bone is a major causal factor for lowerlimb amputation.For this reason,early diagnosis and appropriate treatment are essential,including treatment which is both local(of the foot)and systemic(metabolic),and this requires coordination by a multidisciplinary team.Optimal treatment also often involves extensive surgical debridement and management of the wound base,effective antibiotic therapy,consideration for revascularization and correction of metabolic abnormalities such as hyperglycemia.This article focuses on diagnosis and management of diabetic foot infections in the light of recently published data in order to help clinicians in identification,assessment and antibiotic therapy of diabetic foot infections.展开更多
The features of JAK-STAT signaling in liver cells are discussed in the current review. The role of this signaling cascade in carcinogenesis is accentuated. The possible involvement of this pathway and alteration of it...The features of JAK-STAT signaling in liver cells are discussed in the current review. The role of this signaling cascade in carcinogenesis is accentuated. The possible involvement of this pathway and alteration of its elements are compared for normal cholangiocytes, cholangiocarcinoma predisposition and development. Prolactin and interleukin-6 are described in detail as the best studied examples. In addition, the non-classical nuclear translocation of cytokine receptors is discussed in terms of its possible implication to cholangiocarcinoma development.展开更多
基金supported by funding from Parkinson Canadafunded by a scholarship from Parkinson Canadaa scholarship from Fonds d’Enseignement et de Recherche (FER) (Faculty of Pharmacy, Université Laval)
文摘There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson’s disease after diagnosis.Given that preclinical and clinical studies suggest benefits of dietary n-3 polyunsaturated fatty acids,such as docosahexaenoic acid,and exercise in Parkinson’s disease,we investigated whether both could synergistically interact to induce recovery of the dopaminergic pathway.First,mice received a unilateral stereotactic injection of 6-hydroxydopamine into the striatum to establish an animal model of nigrostriatal denervation.Four weeks after lesion,animals were fed a docosahexaenoic acid-enriched or a control diet for the next 8 weeks.During this period,the animals had access to a running wheel,which they could use or not.Docosahexaenoic acid treatment,voluntary exercise,or the combination of both had no effect on(i)distance traveled in the open field test,(ii)the percentage of contraversive rotations in the apomorphine-induction test or(iii)the number of tyrosine-hydroxylase-positive cells in the substantia nigra pars compacta.However,the docosahexaenoic acid diet increased the number of tyrosine-hydroxylase-positive terminals and induced a rise in dopamine concentrations in the lesioned striatum.Compared to docosahexaenoic acid treatment or exercise alone,the combination of docosahexaenoic acid and exercise(i)improved forelimb balance in the stepping test,(ii)decreased the striatal DOPAC/dopamine ratio and(iii)led to increased dopamine transporter levels in the lesioned striatum.The present results suggest that the combination of exercise and docosahexaenoic acid may act synergistically in the striatum of mice with a unilateral lesion of the dopaminergic system and provide support for clinical trials combining nutrition and physical exercise in the treatment of Parkinson’s disease.
基金supported by the Research Council of Tarbiat Modares University and the Iran National Science Foundation(INSF)(Grant Number:4043897).
文摘This study aimed to assess the therapeutic potential of nisin,5-fluorouracil(5FU)and selenium encapsulated in folate-conjugated thiolated chitosan nanoparticles(N/5FU/Se@FTCsNPs),combined with a probiotic cocktail of Lactobacillus acidophilus and Bifidobacterium bifidum,against colorectal cancer(CRC).The nanoparticles(277 nm,+9.2 mV)exhibited high drug loading efficiencies(5FU:89.11%,nisin:70.68%)and pH-responsive release,with minimal drug release under gastric conditions and∼60.7%release at colonic pH,facilitating targeted delivery.The formulation remained stable for over 40 d at−20°C and 4°C,demonstrating excellent biocompatibility(<2%hemolysis)and exhibiting strong mucoadhesive and mucus-penetrating abilities.In vitro,N/5FU/Se@FTCsNPs selectively targeted CT26 colon cancer cells(IC5n:1.57μg/ml)with minimal effects on healthy cells,enhanced cellular uptake,and induced ROS-mediated apoptosis.In vivo,oral administration-especially with probiotics-significantly reduced tumor volume,improved survival rates and alleviated chemotherapy-related side effects such as diarrhea and weight loss.Biodistribution studies confirmed increased tumor targeting and decreased off-target exposure.Mechanistically,the treatment downregulated oncogenes and inflammatory markers(2-to 12.5-fold),includingβ-catenin,mTOR,COX-2 and VEGF-α,while upregulating tumor suppressors and protective genes(4 to 14.8 fold),such as PTEN,CASP9 and Mucin 2(P<0.0001).This indicates inhibition of proliferation,metastasis,inflammation,and angiogenesis,along with improved gut barrier function.Cytokine profiling and histological analysis further confirmed reduced systemic inflammation and maintained hematological safety.These findings highlight N/5FU/Se@FTCsNPs combined with probiotics as a promising,safe and effective oral therapy for CRC,leveraging microbiota modulation and targeted delivery.
文摘There are limited biosecurity measures directed at preventing airborne transmission of viruses in swine.The effectiveness of dust mitigation strategies such as oil sprinkling,to decrease risk of airborne virus transmission are unknown.Metagenomics and qPCR for common fecal viruses were used to hunt for a ubiquitous virus to serve as a proxy when evaluating the efficiency of mitigation strategies against airborne viral infectious agents.Air particles were collected from swine buildings using high-volume air samplers.Extracted DNA and RNA were used to perform specific RT-qPCR and qPCR and analyzed by highthroughput sequencing.Porcine astroviruses group 2 were common(from 102 to 105 genomic copies per cubic meter of air or gc/m^(3),93%positivity)while no norovirus genogroup II was recovered from air samples.Porcine torque teno sus virus were detected by qPCR in low concentrations(from 101 to 102 gc/m^(3),47%positivity).Among the identified viral families by metagenomics analysis,Herelleviridae,Microviridae,Myoviridae,Podoviridae,and Siphoviridae were dominant.The phage vB_AviM_AVP of Aerococcus was present in all air samples and a newly designed qPCR revealed between 101 and 105 gc/m^(3) among the samples taken for the present study(97%positivity)and banked samples from5-and 15-year old studies(89%positivity).According to the present study,both the porcine astrovirus group 2 and the phage vB_AviM_AVP of Aerococcus could be proxy for airborne viruses of swine buildings.
基金funded by the Swiss National Science Foundation(SNSF Grant No.320030L_192073 to GM)the Slovenian Research Agency(ARRS Grant No.N5-0152 to TD).
文摘Background: Prematurely-born individuals tend to exhibit higher resting oxidative stress, although evidence suggests they may be more resistant to acute hypoxia-induced redox balance alterations. We aimed to investigate the redox balance changes across a 3-day hypobaric hypoxic exposure at 3375 m in healthy adults born preterm(gestational age ≤ 32 weeks) and their term-born(gestational age ≥ 38 weeks)counterparts.Methods: Resting venous blood was obtained in normoxia(prior to altitude exposure), immediately upon arrival to altitude, and the following 3mornings. Antioxidant(superoxide dismutase(SOD), catalase, glutathione peroxidase(GPx), and ferric reducing antioxidant power(FRAP)),pro-oxidant(xanthine oxidase(XO) and myeloperoxidase(MPO)) enzyme activity, oxidative stress markers(advanced oxidation protein product(AOPP) and malondialdehyde(MDA)), nitric oxide(NO) metabolites(nitrites, nitrates, and total nitrite and nitrate(NOx)), and nitrotyrosine were measured in plasma.Results: SOD increased only in the preterm group(p < 0.05). Catalase increased at arrival in preterm group(p < 0.05). XO activity increased at Day 3 for the preterm group, while it increased acutely(arrival and Day 1) in control group. MPO increased in both groups throughout the3 days(p < 0.05). AOPP only increased at arrival in the preterm(p < 0.05) whereas it decreased at arrival up to Day 3(p < 0.05) for control.MDA decreased in control group from arrival onward. Nitrotyrosine decreased in both groups(p < 0.05). Nitrites increased on Day 3(p < 0.05)in control group and decreased on Day 1(p < 0.05) in preterm group.Conclusion: These data indicate that antioxidant enzymes seem to increase immediately upon hypoxic exposure in preterm adults. Conversely, the blunted pro-oxidant enzyme response to prolonged hypoxia exposure suggests that these enzymes may be less sensitive in preterm individuals.These findings lend further support to the potential hypoxic preconditioning effect of preterm birth.
基金supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq,n°406035/2021-0 and PQ n°311580/2021-1,FigueiróF)Instituto Nacional de Ciência e Tecnologia-INCT/CNPq/CAPES/FAPERGS Grant no.465671/2014-4Jean Sévigny received support from the Natural Sciences and Engineering Research Council of Canada(NSERC,RGPIN-2023-05498).
文摘Objectives:Glioblastoma(GB)is a grade IV glial tumor characterized by high malignancy and dismal prognosis,primarily due to high recurrence rates and therapeutic resistance.The epidermal growth factor receptor(EGFR),a receptor tyrosine kinase(RTK),regulates signaling pathways,including cell growth,proliferation,survival,migration,and cell death.Many cancers utilize immune checkpoints(ICs)to attenuate immune responses.CD73 is an enzyme that functions as an IC by hydrolyzing AMP to adenosine,suppressing immune cells in the tumor microenvironment.However,the role of CD73 in resistance to EGFR inhibitors is poorly understood.This study aims to elucidate the resistance mechanisms induced by anti-EGFR treatment and to evaluate an anti-CD73 approach to overcome resistance mediated by anti-EGFR monotherapy.Methods:The U251 GB cell line was treated with AG1478,an EGFR inhibitor,and the resistance markers MRP-1,PD-L1,and CD73 were evaluated using flow cytometry.Additionally,we assessed the combination effects of AG1478 and APCP(an EGFR and a CD73 inhibitor,respectively)on cell cycle progression,proliferation,apoptosis,and migration in vitro.Results:We observed high EGFR,PD-L1,and CD73 expression in human GB cells.The treatment with AG1478 increased the expression of resistance markers MRP-1,PD-L1,and CD73,whereas it decreased CTLA-4.The combination of AG1478 and APCP did not alter proliferation or apoptosis but interfered with cell cycling,arresting the cells in the G1 phase,decreasing cell motility and partially reversing MRP-1 overexpression.Conclusion:In summary,our findings indicate that CD73 inhibition has a modest effect in overcoming resistance to EGFR monotherapy in vitro.Thus,further in vivo studies are needed,as the inhibition of both EGFR and CD73 affects cells in the tumor microenvironment and could potentially enhance anti-tumor immunity.
文摘AIM： To evaluate the results of sub total colectomy withI cecorectal anastomosis （STC-CRA） for isolated colonicinertia （CI）. METHODS： Fourteen patients （mean age 57.5±16.5 year） underwent surgery for isolated CI between January 1986 and December 2002. The mean frequency of bowel motions with the aid of laxatives was 1.2±0.6 per week. All subjects underwent colonoscopy, anorectal manometry, cinedefaecography and colonic transit time （CTF）. CI was defined as diffuse markers delay on CTF without evidence of pelvic floor dysfunction. All patients underwent STC-CRA. Long-term follow-up was obtained prospectively by clinical visits between October 2005 and February 2006 at a mean of 10.5 ＋ 3.6 years （range 5-16 years） during which we considered the number of stool emissions, the presence of abdominal pain or digitations, the use of pain killers, laxatives and/or fibers. Patients were also asked if they were satisfied with the surgery. RESULTS： There was no postoperative mortality Postoperative complications occurred in 21.4% （3/14）. At the end of follow-up, bowel frequency was significantly （P〈0.05）increased to a mean of 4.8±7.5 per day （range 1-30）. One patient reported disabling diarrhea. Two patients used laxatives less than three times per month without complaining of what they called constipation Overall, 78.5% of patients would have chosen surgery again if necessary. CONCLUSION： STC-CRA is feasible and safe in patients with CI achieving 79% of success at a mean follow-up of 10.5 years. A prospective controlled evaluation is warranted to verify the advantages of this surgical approach in patients with CI.
文摘Hepatocyte nuclear factor 4-alpha (HNF4-α) is a nuclear receptor regulating metabolism, cell junctions, differentiation and proliferation in liver and intestinal epithelial cells. Mutations within the HNF4A gene are associated with human diseases such as maturity-onset diabetes of the young. Recently, HNF4A has also been described as a susceptibility gene for ulcerative colitis in genome-wide association studies. In addition, specific HNF4A genetic variants have been identified in pediatric cohorts of Crohn’s disease. Results obtained from knockout mice supported that HNF4-α can protect the intestinal mucosae against inflammation. However, the exact molecular links behind HNF4-α and inflammatory bowel diseases remains elusive. In this review, we will summarize the current knowledge about the role of HNF4-α and its isoforms in inflammation. Specific nature of HNF4-α P1 and P2 classes of isoforms will be summarized. HNF4-α role as a hepatocyte mediator for cytokines relays during liver inflammation will be integrated based on documented examples of the literature. Conclusions that can be made from these earlier liver studies will serve as a basis to extrapolate correlations and divergences applicable to intestinal inflammation. Finally, potential functional roles for HNF4-α isoforms in protecting the intestinal mucosae from chronic and pathological inflammation will be presented.
文摘Development of the spine and thoracic cage consists of a complex series of events involving multiple metabolic processes, genes and signaling pathways. During growth, complex phenomena occur in rapid succession. This succession of events, this establishment of elements, is programmed according to a hierarchy. These events are well synchronized to maintain harmonious limb, spine and thoracic cage relationships, as growth in the various body segments does not occur simultaneously at the same magnitude or rate. In most severe cases of untreated progressive earlyonset spinal deformities, respiratory insufficiency and pulmonary and cardiac hypertension(cor pulmonale), which characterize thoracic insufficiency syndrome(TIS), can develop, sometimes leading to death. TIS is the inability of the thorax to ensure normal breathing. This clinical condition can be linked to costo-vertebral malformations(e.g., fused ribs, hemivertebrae, congenital bars), neuromuscular diseases(e.g., expiratory congenital hypotonia), Jeune or Jarcho-Levin syndromes or to 50% to 75% fusion of the thoracic spine before seven years of age. Complex spinal deformities alter normal growth plate development, and vertebral bodies become progressively distorted, perpetuating the disorder. Therefore, many scoliotic deformities can become growth plate disorders over time. This review aims to provide a comprehensive review of how spinal deformities can affect normal spine and thoracic cage growth. Previous conceptualizations are integrated with more recent scientific data to provide a better understanding of both normal and abnormal spine and thoracic cage growth.
文摘Cell therapy has the potential to improve healing of ischemic heart, repopulate injured myocardium and restore cardiac function. The tremendous hope and potential of stem cell therapy is well understood, yet recent trials involving cell therapy for cardiovascular diseases have yielded mixed results with inconsistent data thereby readdressing controversies and unresolved questions regarding stem cell efficacy for ischemic cardiac disease treatment. These controversies are believed to arise by the lack of uniformity of the clinical trial methodologies, uncertainty regarding the underlying reparative mechanisms of stem cells, questions concerning the most appropriate cell population to use, the proper delivery method and timing in relation to the moment of infarction, as well as the poor stem cell survival and engraftment especially in a diseased microenvironment which is collectively acknowledged as a major hindrance to any form of cell therapy. Indeed, the microenvironment of the failing heart exhibits pathological hypoxic, oxidative and inflammatory stressors impairing the survival of transplanted cells. Therefore, in order to observe any significant therapeutic benefit there is a need to increase resilience of stem cells to death in the transplant microenvironment while preserving or better yet improving their reparative functionality. Although stem cell differentiation into cardiomyocytes has been observed in some instance, the prevailing reparative benefits are afforded through paracrine mechanisms that promote angiogenesis, cell survival, transdifferentiate host cells and modulate immune responses. Therefore, to maximize their reparative functionality, ex vivo manipulation of stem cells through physical, genetic and pharmacological means have shown promise to enable cells to thrive in the postischemic transplant microenvironment. In the present work, we will overview the current status of stem cell therapy for ischemic heart disease, discuss the most recurring cell populations employed, the mechanisms by which stem cells deliver a therapeutic benefit andstrategies that have been used to optimize and increase survival and functionality of stem cells including ex vivo preconditioning with drugs and a novel "pharmacooptimizer" as well as genetic modifications.
基金Supported by Institut National de la SantéEt de la Recherche Médicale,the French Speaking Association for Diabetes and Metabolic Diseases(ALFEDIAM grant)the University of Montpellier 1,the Languedoc-Roussillon Area(Chercheur d'avenir Grant) and the City of Nmes
文摘Foot ulcers are common in diabetic patients,have a cumulative lifetime incidence rate as high as 25%and frequently become infected.The spread of infection to soft tissue and bone is a major causal factor for lowerlimb amputation.For this reason,early diagnosis and appropriate treatment are essential,including treatment which is both local(of the foot)and systemic(metabolic),and this requires coordination by a multidisciplinary team.Optimal treatment also often involves extensive surgical debridement and management of the wound base,effective antibiotic therapy,consideration for revascularization and correction of metabolic abnormalities such as hyperglycemia.This article focuses on diagnosis and management of diabetic foot infections in the light of recently published data in order to help clinicians in identification,assessment and antibiotic therapy of diabetic foot infections.
文摘The features of JAK-STAT signaling in liver cells are discussed in the current review. The role of this signaling cascade in carcinogenesis is accentuated. The possible involvement of this pathway and alteration of its elements are compared for normal cholangiocytes, cholangiocarcinoma predisposition and development. Prolactin and interleukin-6 are described in detail as the best studied examples. In addition, the non-classical nuclear translocation of cytokine receptors is discussed in terms of its possible implication to cholangiocarcinoma development.
