Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibi...Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.展开更多
It was in the 1980s that research on somatostatin(SST)in Alzheimer’s disease(AD)truly gained traction,demonstrating consistent colocalization with amyloid-β(Aβ),along with massive SST/SST cell losses(Almeida,2024)....It was in the 1980s that research on somatostatin(SST)in Alzheimer’s disease(AD)truly gained traction,demonstrating consistent colocalization with amyloid-β(Aβ),along with massive SST/SST cell losses(Almeida,2024).Although the field already had some grasp over the neuroendocrine and hypothalamic functions of the peptide,very little was known about the GABAergic interneurons(SST-INs)that synthesize it in cortical/hippocampal regions.Quite excitingly,over 40 years later,research has grown effervescent.展开更多
Different forms of programmed cell death have been described to participate in the degeneration of dopaminergic neurons in Parkinson’s disease(PD).Given the critical role that disturbance of mitochondrial homeostasis...Different forms of programmed cell death have been described to participate in the degeneration of dopaminergic neurons in Parkinson’s disease(PD).Given the critical role that disturbance of mitochondrial homeostasis plays in the pathogenesis of PD,apoptosis can be reasonably considered as one of the cell death pathways involved in neuronal loss(Schon and Przedborski,2011).Multiple lines of evidence support that proposal such as the observations in postmortem human brain samples of PD patients including mitochondrial complex I deficiency,reactive oxygen species generation,and oxidative damage to lipids,proteins,and DNA,among others.展开更多
The visual system of teleost fish grows continuously,which is a useful model for studying regeneration of the central nervous system.Glial cells are key for this process,but their contribution is still not well define...The visual system of teleost fish grows continuously,which is a useful model for studying regeneration of the central nervous system.Glial cells are key for this process,but their contribution is still not well defined.We followed oligodendrocytes in the visual system of adult zebrafish during regeneration of the optic nerve at 6,24,and 72 hours post-lesion and at 7 and 14 days post-lesion via the sox10:tagRFP transgenic line and confocal microscopy.To understand the changes that these oligodendrocytes undergo during regeneration,we used Sox2 immunohistochemistry,a stem cell marker involved in oligodendrocyte differentiation.We also used the Click-iT™ Plus TUNEL assay to study cell death and a BrdU assay to determine cell proliferation.Before optic nerve crush,sox10:tagRFP oligodendrocytes are located in the retina,in the optic nerve head,and through all the entire optic nerve.Sox2-positive cells are present in the peripheral germinal zone,the mature retina,and the optic nerve.After optic nerve crush,sox10:tagRFP cells disappeared from the optic nerve crush zone,suggesting that they died,although they were not TUNEL positive.Concomitantly,the number of Sox2-positive cells increased around the crushed area,the optic nerve head,and the retina.Then,between 24 hours post-lesion and 14 days post-lesion,double sox10:tagRFP/Sox2-positive cells were detected in the retina,optic nerve head,and whole optic nerve,together with a proliferation response at 72 hours post-lesion.Our results confirm that a degenerating process may occur prior to regeneration.First,sox10:tagRFP oligodendrocytes that surround the degenerated axons stop wrapping them,change their“myelinating oligodendrocyte”morphology to a“nonmyelinating oligodendrocyte”morphology,and die.Then,residual oligodendrocyte progenitor cells in the optic nerve and retina proliferate and differentiate for the purpose of remyelination.As new axons arise from the surviving retinal ganglion cells,new sox10:tagRFP oligodendrocytes arise from residual oligodendrocyte progenitor cells to guide,nourish and myelinate them.Thus,oligodendrocytes play an active role in zebrafish axon regeneration and remyelination.展开更多
Objective:To assess the distribution of ABO blood group and their relationship with Plasmodium falciparum(P.falciparum) malaria among febrile outpatients who sought medical attention at Dore Bafeno Health Center,South...Objective:To assess the distribution of ABO blood group and their relationship with Plasmodium falciparum(P.falciparum) malaria among febrile outpatients who sought medical attention at Dore Bafeno Health Center,Southern Ethiopia.Methods:A total of 269 febrile outpatients who visited Dore Bafeno Health Center,Southern Ethiopia,were examined for malaria and also tested for ABO blood groups in January 2010.The blood specimens were collected by finger pricking,stained with Geimsa,and examined microscopically.Positive cases of the parasitemia were counted.CareStart^(TM) Malaria PflPv Combo was also used to test the blood specimens for malaria.ABO blood groups were determined by agglutination test using ERYCLONE antisera.Data on socio-demographic characteristics and treatment status of the participants were also collected.Chi-square and ANOVA tests were used to assess the difference between frequencies and means,respectively.Results:Out of a total of 269 participants,178(66.2%) febrile patients were found to be infected with Plasmodium parasites,among which 146(54.3%),28(10.4%),and 4(1.5%) belonged to P.falciparum,P.vivax,and mixed infections,respectively.All febrile patients were also tested for ABO blood groups and 51.3%,23.5%,21.9%and 3.3%were found to be blood types of 0,A,B and AB,respectively.Both total malaria infection and P.falciparum infection showed significant association with blood types(P<0.05).The proportion of A or B but not 0 phenotypes was higher(P<0.05) in individuals with P.falciparum as compared with non-infected individuals.The chance of having P.falciparum infection in patients with blood groups A,B and AB was 2.5,2.5 and 3.3times more than individuals showing blood 0 phenotypes,respectively.The mean P.falciparum malaria parasitemia for blood groups A,B,AB,and 0 were 3 744/μ L,1 805/ μ L,5 331/μ L,and1 515/μ L,respectively(P<0.01).Conclusions:The present findings indicate that individuals of blood groups A,B and AB are more susceptible to P.falciparum infection as compared with individuals of blood group O.Nevertheless,further in depth studies are required to clearly establish the role that ABO blood group plays in P.falciparum malaria.展开更多
Stroke is classified as ischemic or hemorrhagic,and there are few effective treatments for either type.Immunologic mechanisms play a critical role in secondary brain injury following a stroke,which manifests as cytoki...Stroke is classified as ischemic or hemorrhagic,and there are few effective treatments for either type.Immunologic mechanisms play a critical role in secondary brain injury following a stroke,which manifests as cytokine release,blood–brain barrier disruption,neuronal cell death,and ultimately behavioral impairment.Suppressing the inflammatory response has been shown to mitigate this cascade of events in experimental stroke models.However,in clinical trials of anti-inflammatory agents,longterm immunosuppression has not demonstrated significant clinical benefits for patients.This may be attributable to the dichotomous roles of inflammation in both tissue injury and repair,as well as the complex pathophysiologic inflammatory processes in stroke.Inhibiting acute harmful inflammatory responses or inducing a phenotypic shift from a pro-inflammatory to an anti-inflammatory state at specific time points after a stroke are alternative and promising therapeutic strategies.Identifying agents that can modulate inflammation requires a detailed understanding of the inflammatory processes of stroke.Furthermore,epigenetic reprogramming plays a crucial role in modulating post-stroke inflammation and can potentially be exploited for stroke management.In this review,we summarize current findings on the epigenetic regulation of the inflammatory response in stroke,focusing on key signaling pathways including nuclear factor-kappa B,Janus kinase/signal transducer and activator of transcription,and mitogen-activated protein kinase as well as inflammasome activation.We also discuss promising molecular targets for stroke treatment.The evidence to date indicates that therapeutic targeting of the epigenetic regulation of inflammation can shift the balance from inflammation-induced tissue injury to repair following stroke,leading to improved post-stroke outcomes.展开更多
The intricate landscape of neurodegenerative diseases complicates the search for effective therapeutic approaches.Photoreceptor degeneration,the common endpoint in various retinal diseases,including retinitis pigmento...The intricate landscape of neurodegenerative diseases complicates the search for effective therapeutic approaches.Photoreceptor degeneration,the common endpoint in various retinal diseases,including retinitis pigmentosa and age-related macular degeneration,leads to vision loss or blindness.While primary cell death is driven by genetic mutations,oxidative stress,and neuroinflammation,additional mechanisms contribute to disease progression.In retinitis pigmentosa,a multitude of genetic alterations can trigger the degeneration of photoreceptors,while other retinopathies,such as agerelated macular degeneration,are initiated by combinations of environmental factors,such as diet,smoking,and hypertension,with genetic predispositions.Nutraceutical therapies,which blend the principles of nutrition and pharmaceuticals,aim to harness the health benefits of bioactive compounds for therapeutic applications.These compounds generally possess multi-target effects.Polyphenols and flavonoids,secondary plant metabolites abundant in plant-based foods,are known for their antioxidant,neuroprotective,and anti-inflammatory properties.This review focuses on the potential of polyphenols and flavonoids as nutraceuticals to treat neurodegenerative diseases such as retinitis pigmentosa.Furthermore,the importance of developing reliable delivery methods to enhance the bioavailability and therapeutic efficacy of these compounds will be discussed.By combining nutraceuticals with other emerging therapies,such as genetic and cell-based treatments,it is possible to offer a more comprehensive approach to treating retinal degenerative diseases.These advancements could lead to a viable and accessible option,improving the quality of life for patients with retinal diseases.展开更多
Rheumatoid arthritis(RA)is a chronic systemic autoimmune disease that extends beyond joint inflammation,affecting pulmonary and metabolic pathways.Interstitial lung disease(ILD)is one of its most serious extra-articul...Rheumatoid arthritis(RA)is a chronic systemic autoimmune disease that extends beyond joint inflammation,affecting pulmonary and metabolic pathways.Interstitial lung disease(ILD)is one of its most serious extra-articular complications,while type 2 diabetes mellitus(T2DM)frequently coexists with RA and may exacerbate inflammatory and fibrotic processes.This editorial discusses the study by Sutton et al,the largest population-based analysis to date exploring the link between T2DM and ILD in patients with RA,and reflects on its mechanistic and clinical implications.In a nationwide cohort of more than 120000 hospitalized RA patients,Sutton et al demonstrated that the coexistence of T2DM nearly doubles the odds of developing ILD(odds ratio=2.02;95%confidence interval:1.84-2.22),with additional increases in pulmonary hypertension,pneumothorax,and length of stay.These findings reinforce the concept of a metabolic-pulmonary-autoimmune axis,in which chronic inflammation promotes insulin resistance and metabolic dysfunction,while hyperglycaemia and advanced glycation end-products amplify oxidative stress and fibrogenesis.This reciprocal interaction may induce a self-perpetuating cycle of“metaflammation”,fibrosis,and organ damage.Conclusion:Recognizing diabetes as a silent amplifier of RA-associated ILD redefines the interface between rheumatology,pulmonology,and endocrinology.Early detection and integrated management of metabolic and pulmonary comorbidities should be prioritized,while future studies must determine whether optimizing glycemic control can attenuate pulmonary fibrosis and improve longterm outcomes.展开更多
The development of neurodegenerative diseases is closely related to the disruption of central nervous system homeostasis.Microglia,as innate immune cells,play important roles in the maintenance of central nervous syst...The development of neurodegenerative diseases is closely related to the disruption of central nervous system homeostasis.Microglia,as innate immune cells,play important roles in the maintenance of central nervous system homeostasis,injury response,and neurodegenerative diseases.Lactate has been considered a metabolic waste product,but recent studies are revealing ever more of the physiological functions of lactate.Lactylation is an important pathway in lactate function and is involved in glycolysis-related functions,macrophage polarization,neuromodulation,and angiogenesis and has also been implicated in the development of various diseases.This review provides an overview of the lactate metabolic and homeostatic regulatory processes involved in microglia lactylation,histone versus non-histone lactylation,and therapeutic approaches targeting lactate.Finally,we summarize the current research on microglia lactylation in central nervous system diseases.A deeper understanding of the metabolic regulatory mechanisms of microglia lactylation will provide more options for the treatment of central nervous system diseases.展开更多
Cloud computing has become an essential technology for the management and processing of large datasets,offering scalability,high availability,and fault tolerance.However,optimizing data replication across multiple dat...Cloud computing has become an essential technology for the management and processing of large datasets,offering scalability,high availability,and fault tolerance.However,optimizing data replication across multiple data centers poses a significant challenge,especially when balancing opposing goals such as latency,storage costs,energy consumption,and network efficiency.This study introduces a novel Dynamic Optimization Algorithm called Dynamic Multi-Objective Gannet Optimization(DMGO),designed to enhance data replication efficiency in cloud environments.Unlike traditional static replication systems,DMGO adapts dynamically to variations in network conditions,system demand,and resource availability.The approach utilizes multi-objective optimization approaches to efficiently balance data access latency,storage efficiency,and operational costs.DMGO consistently evaluates data center performance and adjusts replication algorithms in real time to guarantee optimal system efficiency.Experimental evaluations conducted in a simulated cloud environment demonstrate that DMGO significantly outperforms conventional static algorithms,achieving faster data access,lower storage overhead,reduced energy consumption,and improved scalability.The proposed methodology offers a robust and adaptable solution for modern cloud systems,ensuring efficient resource consumption while maintaining high performance.展开更多
Most studies assessing urine biochemistry for acute kidney injury(AKI)monitoring rely on paradigms from the 1970s.It was proposed that a single measurement of urinary parameters in the presence of increased serum crea...Most studies assessing urine biochemistry for acute kidney injury(AKI)monitoring rely on paradigms from the 1970s.It was proposed that a single measurement of urinary parameters in the presence of increased serum creatinine(sCr)could help understand AKI pathophysiology and predict its duration.However,those studies produced variable and controversial results.Recently,an alternative“urine biochemical approach”has been proposed.In contrast with the traditional approach,it includes sequential urine electrolyte assessment,evaluation before AKI diagnosis,and interpretation of avid sodium retention as a marker of renal microcirculatory stress instead of low renal perfusion.This review highlights the rationale of this alternative approach,which is focused on early urinary biochemical changes that precede increases in sCr as well as signs of renal recovery before decreases in sCr.The relevance of urine composition in conjunction with urine volume for a proper evaluation of renal function is emphasized.This new approach aims to enhance the utility of urinary biochemical parameters in AKI monitoring,particularly in patients who are critically ill.展开更多
Soil organic amendments(OAs)are used to replenish carbon(C)and nutrients in the soil to prevent its degradation and increase its fertility.While soil can be an important C sink,it can also release significant amounts ...Soil organic amendments(OAs)are used to replenish carbon(C)and nutrients in the soil to prevent its degradation and increase its fertility.While soil can be an important C sink,it can also release significant amounts of greenhouse gases(GHGs).Different OA pretreatment technologies indirectly affect soil aggregate formation and C stabilization even when the same initial substrate is used.However,little is known about the long-term effect of OA pretreatment on the soil C and nitrogen(N)associated with macroaggregates,which are known to disintegrate faster than microaggregates.In this study,we studied the effect of OA pretreatment on soil C and N in relation to aggregate formation and GHG emissions using five differently pretreated OAs from the same original OA,i.e.,composted,digested,and fermented OA,a 1:1 mix of the composted and fermented OAs,and the unpretreated original OA.We monitored the changes in a soil column experiment after 6 and 12 months of incubation.Our results indicated that OA pretreatment indirectly affected GHG emissions from soil.The composted and mixed OAs released less GHGs(i.e.,carbon dioxide,nitrous oxide,and methane)but had no positive impact on macroaggregates,while the digested OA induced long-lasting macroaggregation and occluded particulate organic matter formation,emitting intermediate levels of GHGs.The unpretreated OA exhibited the highest GHG emissions,similar to the fermented OA,albeit without benefiting macroaggregation.These demonstrated that OA pretreatment had a long-lasting indirect effect on soil C and N,influencing total GHG emissions,nitrous oxide formation mechanisms,and soil macroaggregate formation.展开更多
The purpose of this work was to examine the interaction of graphene-like nanoclusters with fragments of polymers of the same nature, but somewhat different structure, for example, polyethylene (PE) and polypropylene (...The purpose of this work was to examine the interaction of graphene-like nanoclusters with fragments of polymers of the same nature, but somewhat different structure, for example, polyethylene (PE) and polypropylene (PP) by means of quantum chemistry. By method of density functional theory with the exchange-correlation functional B3LYP, the basis set 6 - 31 G (d, p) and the Grimme’s dispersion correction, the energy values have been calculated of interaction between nanocarbon fragments and oligomers of PE and PP, the most probable structures of their intermolecular complexes being optimized. A graphene-like plane of 40 carbon atoms and 16 atoms of hydrogen was chosen as a model for the surface of the graphene and carbon nanotubes (CNT). In order to take into account the dimensional effect of the surface of the nanotube fragment model on the interaction energy, in addition to the above described, two larger models were used, with the general formula C54H18 and C96N24. It has been found that the interaction energy of nanocarbon fragment with an oligomer of PP is greater, compared with PE, which is consistent with the experimental data on melting temperatures of pure polymers and nanotube-polymer composites. The polymer with a surface of nanocarbon fragment forms an intermolecular complex not bound covalently and retained by intermolecular dispersion forces. Oligomers of polymeric matters and carbon surfaces in formed nanocomplex are placed closer to each other than separate polymeric links between them.展开更多
Esophageal squamous cell carcinoma continues to heavily burden clinicians worldwide. Researchers have discovered the genomic landscape of esophageal squamous cell carcinoma, which holds promise for an era of personali...Esophageal squamous cell carcinoma continues to heavily burden clinicians worldwide. Researchers have discovered the genomic landscape of esophageal squamous cell carcinoma, which holds promise for an era of personalized oncology care. One of the most pressing problems facing this issue is to improve the understanding of the newly available genomic data, and identify the driver-gene mutations, pathways, and networks. The emergence of a legion of novel targeted agents has generated much hope and hype regarding more potent treatment regimens, but the accuracy of drug selection is still arguable. Other problems, such as cancer heterogeneity, drug resistance, exceptional responders, and side effects, have to be surmounted. Evolving topics in personalized oncology, such as interpretation of genomics data, issues in targeted therapy, research approaches for targeted therapy, and future perspectives, will be discussed in this editorial.展开更多
BACKGROUND Hepatic encephalopathy(HE)is a poorly understood complication in hepatosplenic schistosomiasis(HSS),a neglected cause of non-cirrhotic portal hypertension.Although portosystemic shunts(PSS)are commonly obse...BACKGROUND Hepatic encephalopathy(HE)is a poorly understood complication in hepatosplenic schistosomiasis(HSS),a neglected cause of non-cirrhotic portal hypertension.Although portosystemic shunts(PSS)are commonly observed in HSS patients,the prevalence and clinical impact of overt HE(OHE)and minimal HE(MHE)remain understudied,particularly in resource-limited settings.AIM To determine OHE/MHE prevalence in HSS and its associations with PSS,clinical,and laboratory characteristics.METHODS This cross-sectional study included 200 HSS patients undergoing treatment at the Hospital of Universidade Federal de Pernambuco in Brazil between 2021 and 2023.Cognitive function was assessed using the animal naming test(ANT)and Mini-Mental State Examination(MMSE),while psychological status was evaluated with the Hospital Anxiety and Depression Scale.PSS was identified via ultrasound,and fibrosis severity was quantified using the Coutinho index(CI).Analyses were adjusted for education level and the presence of comorbidities.Statistical analyses were performed using R software.RESULTS The prevalence of OHE was 0.5%,while MHE,diagnosed via ANT,affected 24%of patients.ANT positivity was significantly associated with the presence of PSS(35.1%vs 15.1%;P=0.0018)and higher CI scores(1.79±0.26 vs 1.30±0.84;P=0.045).Patients with MHE demonstrated notably lower MMSE scores(24.06±1.17 vs 26.04±0.63;P=0.0003),independent of education level.The ANT showed high diagnostic robustness,even among patients with limited formal education.CONCLUSION MHE is prevalent in HSS,especially with PSS,and is associated with portal hypertension severity.The ANT enables practical screening,underscoring the need for routine assessment to improve outcomes.展开更多
Microwave thermochemotherapy(MTC)has been applied to treat lip squamous cell carcinoma(LSCC),but a deeper understanding of its therapeutic mechanisms and molecular biology is needed.To address this,we used single-cell...Microwave thermochemotherapy(MTC)has been applied to treat lip squamous cell carcinoma(LSCC),but a deeper understanding of its therapeutic mechanisms and molecular biology is needed.To address this,we used single-cell transcriptomics(scRNA-seq)and spatial transcriptomics(ST)to highlight the pivotal role of tumor-associated neutrophils(TANs)among tumor-infiltrating immune cells and their therapeutic response to MTC.MNDA+TANs with anti-tumor activity(N1-phenotype)are found to be abundantly infiltrated by MTC with benefit of increased blood perfusion,and these TANs are characterized by enhanced cytotoxicity,ameliorated hypoxia,and upregulated IL1B,activating T&NK cells and fibroblasts via IL1B-IL1R.In this highly anti-tumor immunogenic and hypoxia-reversed microenvironment under MTC,fibroblasts accumulated in the tumor front(TF)can recruit N1-TANs via CXCL2-CXCR2 and clear N2-TANs(pro-tumor phenotype)via CXCL12-CXCR4,which results in the aggregation of N1-TANs and extracellular matrix(ECM)deposition.In addition,we construct an N1-TANs marker,MX2,which positively correlates with better prognosis in LSCC patients,and employ deep learning techniques to predict expression of MX2 from hematoxylin-eosin(H&E)-stained images so as to conveniently guide decision making in clinical practice.Collectively,our findings demonstrate that the N1-TANs/fibroblasts defense wall formed in response to MTC effectively combat LSCC.展开更多
The rapid advancement of nanotechnology has sparked much interest in applying nanoscale perovskite materials for photodetection applications.These materials are promising candidates for next-generation photodetectors(...The rapid advancement of nanotechnology has sparked much interest in applying nanoscale perovskite materials for photodetection applications.These materials are promising candidates for next-generation photodetectors(PDs)due to their unique optoelectronic properties and flexible synthesis routes.This review explores the approaches used in the development and use of optoelectronic devices made of different nanoscale perovskite architectures,including quantum dots,nanosheets,nanorods,nanowires,and nanocrystals.Through a thorough analysis of recent literature,the review also addresses common issues like the mechanisms underlying the degradation of perovskite PDs and offers perspectives on potential solutions to improve stability and scalability that impede widespread implementation.In addition,it highlights that photodetection encompasses the detection of light fields in dimensions other than light intensity and suggests potential avenues for future research to overcome these obstacles and fully realize the potential of nanoscale perovskite materials in state-of-the-art photodetection systems.This review provides a comprehensive overview of nanoscale perovskite PDs and guides future research efforts towards improved performance and wider applicability,making it a valuable resource for researchers.展开更多
BACKGROUND External gastrointestinal fistulas(EGIFs)are serious postoperative complications associated with prolonged hospital stays,sepsis,malnutrition,and high mortality rates.Reducing gastrointestinal secretions wi...BACKGROUND External gastrointestinal fistulas(EGIFs)are serious postoperative complications associated with prolonged hospital stays,sepsis,malnutrition,and high mortality rates.Reducing gastrointestinal secretions with somatostatin or its analogues may facilitate fistula closure.The clinical effectiveness of these therapies,however,remains uncertain.AIM To investigate the effectiveness of somatostatin-based therapy for EGIFs.METHODS A systematic review and meta-analysis(Prospero CRD420251054344)of nine randomized controlled trials(442 patients)compared somatostatin-based therapies with standard care in tertiary care settings.Protocols included somatostatin,octreotide,or lanreotide,administered at various dosages(250 micrograms/hour intravenous infusion or 100 micrograms subcutaneous injection three times daily)for 7 to 56 days.Primary outcomes were fistula closure rates and time to closure.Secondary outcomes were hospital length of stay,complications,need for surgical intervention,and mortality.Mean differences and risk ratios(RRs)with 95%confidence intervals(CIs)were calculated using random-effects models.Risk of bias was assessed with the Cochrane RoB 2 tool.RESULTS There was no statistically significant difference in closure rate(RR:1.11,95%CI:0.95-1.28,P=0.19,I^(2)=0%)between 134/193 patients receiving somatostatin-based therapy and 99/170 control patients.Time to closure was reduced by 6.16 days(mean difference-6.16,95%CI:-7.44 to-4.88,P<0.001,I^(2)=0%)in 126 patients in intervention group vs 114 in control group.Hospital stay was shortened by 4.00 days(mean difference-4.00,95%CI:-7.99 to-0.01,P=0.05,I^(2)=0%)in 56 vs 62 patients.There were no differences in complications(RRs:0.76,95%CI:0.55-1.05),need for surgical intervention(RRs:0.67,95%CI:0.38-1.19),or mortality(RRs:0.77,95%CI:0.44-1.35).Limitations include small sample sizes,heterogeneity in treatment regimens,and inconsistent outcome definitions,which may affect generalizability.Limited data for some outcomes,such as hospital stay,and exclusion of some datasets for methodological reasons reduced statistical power.CONCLUSION Somatostatin-based therapies did not significantly improve fistula closure rates but were associated with shorter time to closure and hospital stay.Mortality,complications,and surgical intervention requirements remained unchanged,suggesting that these therapies may serve only as an adjunctive option in selected patients.展开更多
4-Aminopyridine(4-AP), an FDA-approved drug for the symptomatic treatment of multiple sclerosis, is used to improve neuromuscular function in patients with diverse demyelinating disorders. We recently demonstrated tha...4-Aminopyridine(4-AP), an FDA-approved drug for the symptomatic treatment of multiple sclerosis, is used to improve neuromuscular function in patients with diverse demyelinating disorders. We recently demonstrated that local, transdermal or injectable forms of 4-AP improve myelination, nerve conduction velocity, muscle atrophy, and motor function after traumatic peripheral nerve injury in mice. While oral 4-AP is most commonly used in the clinic, it is unknown whether human equivalent oral doses of 4-AP have effects on traumatic peripheral nerve injury differentiation, myelination, muscle atrophy, functional recovery, and post-injury inflammatory processes in animals. Mice with sciatic nerve crush or denervation injury received oral or intraperitoneal 4-AP(10 μg) or vehicle alone and were examined for pharmacokinetics, motor function, muscle mass, intrinsic muscle force, nerve morphological and gene expression profiles. 4-AP showed linear pharmacokinetics and the maximum plasma 4-AP concentrations were proportional to 4-AP dose. Acute single dose of oral 4-AP administration induced a rapid transient improvement in motor function that was different in traumatic peripheral nerve injury with or without nerve continuity, chronic daily oral 4-AP treatment significantly enhanced post crush injury motor function recovery and this effect was associated with improved myelination, muscle mass, and ex vivo muscle force. Polymerase chain reaction array analysis with crushed nerve revealed significant alterations in gene involved in axonal inflammation and regeneration. These findings provide convincing evidence that regardless of the route of administration, 4-AP can acutely differentiate traumatic peripheral nerve injury with or without nerve continuity and can enhance in vivo functional recovery with better preservation of myelin sheaths, muscle mass, and muscle force. The animal experiments were approved by the University Committee on Animal Research(UCAR) at the University of Rochester(UCAR-2009-019) on March 31, 2017.展开更多
基金a Ph D fellowship by FCT-Fundacao para a Ciência Tecnologia (SFRH/BD/135868/2018)(to SSC)。
文摘Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.
文摘It was in the 1980s that research on somatostatin(SST)in Alzheimer’s disease(AD)truly gained traction,demonstrating consistent colocalization with amyloid-β(Aβ),along with massive SST/SST cell losses(Almeida,2024).Although the field already had some grasp over the neuroendocrine and hypothalamic functions of the peptide,very little was known about the GABAergic interneurons(SST-INs)that synthesize it in cortical/hippocampal regions.Quite excitingly,over 40 years later,research has grown effervescent.
基金supported by the Spanish Ministerio de Ciencia e Innovación/Agencia Española de Investigación(PID2021-124096OB-I00)(to JLV)JGR was granted by Demensfonden,The Royal Physiografic Society of Lund,Neurofonden,The Greta och Johan Kocks stiftelser,and Bertil och Ebon Norlins stiftelse.
文摘Different forms of programmed cell death have been described to participate in the degeneration of dopaminergic neurons in Parkinson’s disease(PD).Given the critical role that disturbance of mitochondrial homeostasis plays in the pathogenesis of PD,apoptosis can be reasonably considered as one of the cell death pathways involved in neuronal loss(Schon and Przedborski,2011).Multiple lines of evidence support that proposal such as the observations in postmortem human brain samples of PD patients including mitochondrial complex I deficiency,reactive oxygen species generation,and oxidative damage to lipids,proteins,and DNA,among others.
基金supported by the Lanzadera TCUE and C2 program(Universidad de Salamanca)(to ASL)the Spanish National Research Council(CSIC)funded by the Junta de Castilla y León and co-financed by the European Regional Development Fund(ERDF“Europe drives our growth”):Internationalization Project“CL-EI-2021-08-IBFG Unit of Excellence”,Grant(PID2022-138478OA-100)funded by MICIU/AEI/10.13039/501100011033 and,by FEDER,UE(to MGM)+3 种基金Junta de Castilla y León(SA225P23)Gerencia Regional de Salud(2701/A1/2023)(to AV)the Plan Especial Grado Medicina(USAL)(to CPM)a Ramón y Cajal researcher:Grant RYC2021-033684-I funded by MICIU/AEI/10.13039/501100011033 and,by European Union NextGenerationEU/PRTR.
文摘The visual system of teleost fish grows continuously,which is a useful model for studying regeneration of the central nervous system.Glial cells are key for this process,but their contribution is still not well defined.We followed oligodendrocytes in the visual system of adult zebrafish during regeneration of the optic nerve at 6,24,and 72 hours post-lesion and at 7 and 14 days post-lesion via the sox10:tagRFP transgenic line and confocal microscopy.To understand the changes that these oligodendrocytes undergo during regeneration,we used Sox2 immunohistochemistry,a stem cell marker involved in oligodendrocyte differentiation.We also used the Click-iT™ Plus TUNEL assay to study cell death and a BrdU assay to determine cell proliferation.Before optic nerve crush,sox10:tagRFP oligodendrocytes are located in the retina,in the optic nerve head,and through all the entire optic nerve.Sox2-positive cells are present in the peripheral germinal zone,the mature retina,and the optic nerve.After optic nerve crush,sox10:tagRFP cells disappeared from the optic nerve crush zone,suggesting that they died,although they were not TUNEL positive.Concomitantly,the number of Sox2-positive cells increased around the crushed area,the optic nerve head,and the retina.Then,between 24 hours post-lesion and 14 days post-lesion,double sox10:tagRFP/Sox2-positive cells were detected in the retina,optic nerve head,and whole optic nerve,together with a proliferation response at 72 hours post-lesion.Our results confirm that a degenerating process may occur prior to regeneration.First,sox10:tagRFP oligodendrocytes that surround the degenerated axons stop wrapping them,change their“myelinating oligodendrocyte”morphology to a“nonmyelinating oligodendrocyte”morphology,and die.Then,residual oligodendrocyte progenitor cells in the optic nerve and retina proliferate and differentiate for the purpose of remyelination.As new axons arise from the surviving retinal ganglion cells,new sox10:tagRFP oligodendrocytes arise from residual oligodendrocyte progenitor cells to guide,nourish and myelinate them.Thus,oligodendrocytes play an active role in zebrafish axon regeneration and remyelination.
基金supported by a grant from NIH(R01AI132695)to RM。
文摘Chronic wasting disease—a prion disease affecting cervids:Many neurological conditions,including Alzheimer's and Parkinson's diseases,amyotrophic lateral sclerosis,frontotemporal dementias,among others,are caused by the accumulation of misfolded proteins in the brain.These diseases affect not only humans,but also animals.
基金Supported by School of Graduate Studies through Aklilu LemmaInstitute of Pathobiology,Addis Ababa University(No:RDP/Py-014/09)
文摘Objective:To assess the distribution of ABO blood group and their relationship with Plasmodium falciparum(P.falciparum) malaria among febrile outpatients who sought medical attention at Dore Bafeno Health Center,Southern Ethiopia.Methods:A total of 269 febrile outpatients who visited Dore Bafeno Health Center,Southern Ethiopia,were examined for malaria and also tested for ABO blood groups in January 2010.The blood specimens were collected by finger pricking,stained with Geimsa,and examined microscopically.Positive cases of the parasitemia were counted.CareStart^(TM) Malaria PflPv Combo was also used to test the blood specimens for malaria.ABO blood groups were determined by agglutination test using ERYCLONE antisera.Data on socio-demographic characteristics and treatment status of the participants were also collected.Chi-square and ANOVA tests were used to assess the difference between frequencies and means,respectively.Results:Out of a total of 269 participants,178(66.2%) febrile patients were found to be infected with Plasmodium parasites,among which 146(54.3%),28(10.4%),and 4(1.5%) belonged to P.falciparum,P.vivax,and mixed infections,respectively.All febrile patients were also tested for ABO blood groups and 51.3%,23.5%,21.9%and 3.3%were found to be blood types of 0,A,B and AB,respectively.Both total malaria infection and P.falciparum infection showed significant association with blood types(P<0.05).The proportion of A or B but not 0 phenotypes was higher(P<0.05) in individuals with P.falciparum as compared with non-infected individuals.The chance of having P.falciparum infection in patients with blood groups A,B and AB was 2.5,2.5 and 3.3times more than individuals showing blood 0 phenotypes,respectively.The mean P.falciparum malaria parasitemia for blood groups A,B,AB,and 0 were 3 744/μ L,1 805/ μ L,5 331/μ L,and1 515/μ L,respectively(P<0.01).Conclusions:The present findings indicate that individuals of blood groups A,B and AB are more susceptible to P.falciparum infection as compared with individuals of blood group O.Nevertheless,further in depth studies are required to clearly establish the role that ABO blood group plays in P.falciparum malaria.
基金supported by the National Natural Science Foundation of China,Nos.32070735(to QL),82371321(to QL),82171270(to ZL)Public Service Platform for Artificial Intelligence Screening and Auxiliary Diagnosis for the Medical and Health Industry,Ministry of Industry and Information Technology of the People's Republic of China,No.2020-0103-3-1(to ZL)+2 种基金the Natural Science Foundation of Beijing,No.Z200016(to ZL)Beijing Talents Project,No.2018000021223ZK03(to ZL)Beijing Municipal Committee of Science and Technology,No.Z201100005620010(to ZL)。
文摘Stroke is classified as ischemic or hemorrhagic,and there are few effective treatments for either type.Immunologic mechanisms play a critical role in secondary brain injury following a stroke,which manifests as cytokine release,blood–brain barrier disruption,neuronal cell death,and ultimately behavioral impairment.Suppressing the inflammatory response has been shown to mitigate this cascade of events in experimental stroke models.However,in clinical trials of anti-inflammatory agents,longterm immunosuppression has not demonstrated significant clinical benefits for patients.This may be attributable to the dichotomous roles of inflammation in both tissue injury and repair,as well as the complex pathophysiologic inflammatory processes in stroke.Inhibiting acute harmful inflammatory responses or inducing a phenotypic shift from a pro-inflammatory to an anti-inflammatory state at specific time points after a stroke are alternative and promising therapeutic strategies.Identifying agents that can modulate inflammation requires a detailed understanding of the inflammatory processes of stroke.Furthermore,epigenetic reprogramming plays a crucial role in modulating post-stroke inflammation and can potentially be exploited for stroke management.In this review,we summarize current findings on the epigenetic regulation of the inflammatory response in stroke,focusing on key signaling pathways including nuclear factor-kappa B,Janus kinase/signal transducer and activator of transcription,and mitogen-activated protein kinase as well as inflammasome activation.We also discuss promising molecular targets for stroke treatment.The evidence to date indicates that therapeutic targeting of the epigenetic regulation of inflammation can shift the balance from inflammation-induced tissue injury to repair following stroke,leading to improved post-stroke outcomes.
基金Fundação de AmparoàPesquisa do Estado de São Paulo(FAPESP,Brazil,#2020/11667-0)and Universidade Federal do ABC(UFABC,Brazil)were recipients of fellowships from FAPESP:THLV(#2021/11969-9 and#2024/00828-3),GBS(#2021/14227-3),and GMB(#2024/10858-7)+1 种基金recipients of fellowships from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior(CAPES,Brazil):MIM(Finance Code 001,#88887.597402/2021-00)recipients of fellowships from Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq,Brazil.):GKD(#145164/2024-1),and DRA(#308819/2022-5).
文摘The intricate landscape of neurodegenerative diseases complicates the search for effective therapeutic approaches.Photoreceptor degeneration,the common endpoint in various retinal diseases,including retinitis pigmentosa and age-related macular degeneration,leads to vision loss or blindness.While primary cell death is driven by genetic mutations,oxidative stress,and neuroinflammation,additional mechanisms contribute to disease progression.In retinitis pigmentosa,a multitude of genetic alterations can trigger the degeneration of photoreceptors,while other retinopathies,such as agerelated macular degeneration,are initiated by combinations of environmental factors,such as diet,smoking,and hypertension,with genetic predispositions.Nutraceutical therapies,which blend the principles of nutrition and pharmaceuticals,aim to harness the health benefits of bioactive compounds for therapeutic applications.These compounds generally possess multi-target effects.Polyphenols and flavonoids,secondary plant metabolites abundant in plant-based foods,are known for their antioxidant,neuroprotective,and anti-inflammatory properties.This review focuses on the potential of polyphenols and flavonoids as nutraceuticals to treat neurodegenerative diseases such as retinitis pigmentosa.Furthermore,the importance of developing reliable delivery methods to enhance the bioavailability and therapeutic efficacy of these compounds will be discussed.By combining nutraceuticals with other emerging therapies,such as genetic and cell-based treatments,it is possible to offer a more comprehensive approach to treating retinal degenerative diseases.These advancements could lead to a viable and accessible option,improving the quality of life for patients with retinal diseases.
文摘Rheumatoid arthritis(RA)is a chronic systemic autoimmune disease that extends beyond joint inflammation,affecting pulmonary and metabolic pathways.Interstitial lung disease(ILD)is one of its most serious extra-articular complications,while type 2 diabetes mellitus(T2DM)frequently coexists with RA and may exacerbate inflammatory and fibrotic processes.This editorial discusses the study by Sutton et al,the largest population-based analysis to date exploring the link between T2DM and ILD in patients with RA,and reflects on its mechanistic and clinical implications.In a nationwide cohort of more than 120000 hospitalized RA patients,Sutton et al demonstrated that the coexistence of T2DM nearly doubles the odds of developing ILD(odds ratio=2.02;95%confidence interval:1.84-2.22),with additional increases in pulmonary hypertension,pneumothorax,and length of stay.These findings reinforce the concept of a metabolic-pulmonary-autoimmune axis,in which chronic inflammation promotes insulin resistance and metabolic dysfunction,while hyperglycaemia and advanced glycation end-products amplify oxidative stress and fibrogenesis.This reciprocal interaction may induce a self-perpetuating cycle of“metaflammation”,fibrosis,and organ damage.Conclusion:Recognizing diabetes as a silent amplifier of RA-associated ILD redefines the interface between rheumatology,pulmonology,and endocrinology.Early detection and integrated management of metabolic and pulmonary comorbidities should be prioritized,while future studies must determine whether optimizing glycemic control can attenuate pulmonary fibrosis and improve longterm outcomes.
文摘The development of neurodegenerative diseases is closely related to the disruption of central nervous system homeostasis.Microglia,as innate immune cells,play important roles in the maintenance of central nervous system homeostasis,injury response,and neurodegenerative diseases.Lactate has been considered a metabolic waste product,but recent studies are revealing ever more of the physiological functions of lactate.Lactylation is an important pathway in lactate function and is involved in glycolysis-related functions,macrophage polarization,neuromodulation,and angiogenesis and has also been implicated in the development of various diseases.This review provides an overview of the lactate metabolic and homeostatic regulatory processes involved in microglia lactylation,histone versus non-histone lactylation,and therapeutic approaches targeting lactate.Finally,we summarize the current research on microglia lactylation in central nervous system diseases.A deeper understanding of the metabolic regulatory mechanisms of microglia lactylation will provide more options for the treatment of central nervous system diseases.
文摘Cloud computing has become an essential technology for the management and processing of large datasets,offering scalability,high availability,and fault tolerance.However,optimizing data replication across multiple data centers poses a significant challenge,especially when balancing opposing goals such as latency,storage costs,energy consumption,and network efficiency.This study introduces a novel Dynamic Optimization Algorithm called Dynamic Multi-Objective Gannet Optimization(DMGO),designed to enhance data replication efficiency in cloud environments.Unlike traditional static replication systems,DMGO adapts dynamically to variations in network conditions,system demand,and resource availability.The approach utilizes multi-objective optimization approaches to efficiently balance data access latency,storage efficiency,and operational costs.DMGO consistently evaluates data center performance and adjusts replication algorithms in real time to guarantee optimal system efficiency.Experimental evaluations conducted in a simulated cloud environment demonstrate that DMGO significantly outperforms conventional static algorithms,achieving faster data access,lower storage overhead,reduced energy consumption,and improved scalability.The proposed methodology offers a robust and adaptable solution for modern cloud systems,ensuring efficient resource consumption while maintaining high performance.
文摘Most studies assessing urine biochemistry for acute kidney injury(AKI)monitoring rely on paradigms from the 1970s.It was proposed that a single measurement of urinary parameters in the presence of increased serum creatinine(sCr)could help understand AKI pathophysiology and predict its duration.However,those studies produced variable and controversial results.Recently,an alternative“urine biochemical approach”has been proposed.In contrast with the traditional approach,it includes sequential urine electrolyte assessment,evaluation before AKI diagnosis,and interpretation of avid sodium retention as a marker of renal microcirculatory stress instead of low renal perfusion.This review highlights the rationale of this alternative approach,which is focused on early urinary biochemical changes that precede increases in sCr as well as signs of renal recovery before decreases in sCr.The relevance of urine composition in conjunction with urine volume for a proper evaluation of renal function is emphasized.This new approach aims to enhance the utility of urinary biochemical parameters in AKI monitoring,particularly in patients who are critically ill.
基金funded by the Dutch Ministry of Economic Affairs and Climate Policy,the European Union Regional Development Fund,the City of Leeuwarden,the Province of Fryslân,the Northern Netherlands Provinces and The Netherlands Organization for Scientific Research.Wetsus also coordinates the WaterSEED project,which received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement(No.665874)。
文摘Soil organic amendments(OAs)are used to replenish carbon(C)and nutrients in the soil to prevent its degradation and increase its fertility.While soil can be an important C sink,it can also release significant amounts of greenhouse gases(GHGs).Different OA pretreatment technologies indirectly affect soil aggregate formation and C stabilization even when the same initial substrate is used.However,little is known about the long-term effect of OA pretreatment on the soil C and nitrogen(N)associated with macroaggregates,which are known to disintegrate faster than microaggregates.In this study,we studied the effect of OA pretreatment on soil C and N in relation to aggregate formation and GHG emissions using five differently pretreated OAs from the same original OA,i.e.,composted,digested,and fermented OA,a 1:1 mix of the composted and fermented OAs,and the unpretreated original OA.We monitored the changes in a soil column experiment after 6 and 12 months of incubation.Our results indicated that OA pretreatment indirectly affected GHG emissions from soil.The composted and mixed OAs released less GHGs(i.e.,carbon dioxide,nitrous oxide,and methane)but had no positive impact on macroaggregates,while the digested OA induced long-lasting macroaggregation and occluded particulate organic matter formation,emitting intermediate levels of GHGs.The unpretreated OA exhibited the highest GHG emissions,similar to the fermented OA,albeit without benefiting macroaggregation.These demonstrated that OA pretreatment had a long-lasting indirect effect on soil C and N,influencing total GHG emissions,nitrous oxide formation mechanisms,and soil macroaggregate formation.
文摘The purpose of this work was to examine the interaction of graphene-like nanoclusters with fragments of polymers of the same nature, but somewhat different structure, for example, polyethylene (PE) and polypropylene (PP) by means of quantum chemistry. By method of density functional theory with the exchange-correlation functional B3LYP, the basis set 6 - 31 G (d, p) and the Grimme’s dispersion correction, the energy values have been calculated of interaction between nanocarbon fragments and oligomers of PE and PP, the most probable structures of their intermolecular complexes being optimized. A graphene-like plane of 40 carbon atoms and 16 atoms of hydrogen was chosen as a model for the surface of the graphene and carbon nanotubes (CNT). In order to take into account the dimensional effect of the surface of the nanotube fragment model on the interaction energy, in addition to the above described, two larger models were used, with the general formula C54H18 and C96N24. It has been found that the interaction energy of nanocarbon fragment with an oligomer of PP is greater, compared with PE, which is consistent with the experimental data on melting temperatures of pure polymers and nanotube-polymer composites. The polymer with a surface of nanocarbon fragment forms an intermolecular complex not bound covalently and retained by intermolecular dispersion forces. Oligomers of polymeric matters and carbon surfaces in formed nanocomplex are placed closer to each other than separate polymeric links between them.
基金Supported by Grants from Beijing Academic Leaders Program,NO.2009-2-17Beijing Natural Science Foundation,No.7102029+5 种基金Capital Medical Developed Research Fund,No.2007-1023New Scholar Star Program of Ministry of EducationNational Basic Research Program of China,No.2011CB504300Specialized Research Fund for the Doctoral Program of Higher Education,No.20130001110108National Natural Science Foundation for Distinguished Young Scholars,No.81301748Science Fund for Creative Research Groups of the National Natural Science Foundation of China,No.IRT13003 and No.NIH/NCI U54 CA156735
文摘Esophageal squamous cell carcinoma continues to heavily burden clinicians worldwide. Researchers have discovered the genomic landscape of esophageal squamous cell carcinoma, which holds promise for an era of personalized oncology care. One of the most pressing problems facing this issue is to improve the understanding of the newly available genomic data, and identify the driver-gene mutations, pathways, and networks. The emergence of a legion of novel targeted agents has generated much hope and hype regarding more potent treatment regimens, but the accuracy of drug selection is still arguable. Other problems, such as cancer heterogeneity, drug resistance, exceptional responders, and side effects, have to be surmounted. Evolving topics in personalized oncology, such as interpretation of genomics data, issues in targeted therapy, research approaches for targeted therapy, and future perspectives, will be discussed in this editorial.
文摘BACKGROUND Hepatic encephalopathy(HE)is a poorly understood complication in hepatosplenic schistosomiasis(HSS),a neglected cause of non-cirrhotic portal hypertension.Although portosystemic shunts(PSS)are commonly observed in HSS patients,the prevalence and clinical impact of overt HE(OHE)and minimal HE(MHE)remain understudied,particularly in resource-limited settings.AIM To determine OHE/MHE prevalence in HSS and its associations with PSS,clinical,and laboratory characteristics.METHODS This cross-sectional study included 200 HSS patients undergoing treatment at the Hospital of Universidade Federal de Pernambuco in Brazil between 2021 and 2023.Cognitive function was assessed using the animal naming test(ANT)and Mini-Mental State Examination(MMSE),while psychological status was evaluated with the Hospital Anxiety and Depression Scale.PSS was identified via ultrasound,and fibrosis severity was quantified using the Coutinho index(CI).Analyses were adjusted for education level and the presence of comorbidities.Statistical analyses were performed using R software.RESULTS The prevalence of OHE was 0.5%,while MHE,diagnosed via ANT,affected 24%of patients.ANT positivity was significantly associated with the presence of PSS(35.1%vs 15.1%;P=0.0018)and higher CI scores(1.79±0.26 vs 1.30±0.84;P=0.045).Patients with MHE demonstrated notably lower MMSE scores(24.06±1.17 vs 26.04±0.63;P=0.0003),independent of education level.The ANT showed high diagnostic robustness,even among patients with limited formal education.CONCLUSION MHE is prevalent in HSS,especially with PSS,and is associated with portal hypertension severity.The ANT enables practical screening,underscoring the need for routine assessment to improve outcomes.
基金supported by National Natural Science Foundation of China grants(Nos.82173326 and 82473058)Key Research and Development Project of Sichuan Province(Nos.2024YFFK0374 and 2024YFFK0198)Interdisciplinary Innovation Project of West China College of Stomatology,Sichuan University(RD-03-202004).
文摘Microwave thermochemotherapy(MTC)has been applied to treat lip squamous cell carcinoma(LSCC),but a deeper understanding of its therapeutic mechanisms and molecular biology is needed.To address this,we used single-cell transcriptomics(scRNA-seq)and spatial transcriptomics(ST)to highlight the pivotal role of tumor-associated neutrophils(TANs)among tumor-infiltrating immune cells and their therapeutic response to MTC.MNDA+TANs with anti-tumor activity(N1-phenotype)are found to be abundantly infiltrated by MTC with benefit of increased blood perfusion,and these TANs are characterized by enhanced cytotoxicity,ameliorated hypoxia,and upregulated IL1B,activating T&NK cells and fibroblasts via IL1B-IL1R.In this highly anti-tumor immunogenic and hypoxia-reversed microenvironment under MTC,fibroblasts accumulated in the tumor front(TF)can recruit N1-TANs via CXCL2-CXCR2 and clear N2-TANs(pro-tumor phenotype)via CXCL12-CXCR4,which results in the aggregation of N1-TANs and extracellular matrix(ECM)deposition.In addition,we construct an N1-TANs marker,MX2,which positively correlates with better prognosis in LSCC patients,and employ deep learning techniques to predict expression of MX2 from hematoxylin-eosin(H&E)-stained images so as to conveniently guide decision making in clinical practice.Collectively,our findings demonstrate that the N1-TANs/fibroblasts defense wall formed in response to MTC effectively combat LSCC.
基金supported by the National Research Foundation of Korea(NRF)grant funded by the Korean government(MSIT)(No.RS-2022–00165798)Anhui Natural Science Foundation(No.2308085MF211)The authors extend their appreciation to the Deanship of Research and Graduate Studies at King Khalid University for funding this work through Large Research Project under Grant Number(R.G.P.2/491/45).
文摘The rapid advancement of nanotechnology has sparked much interest in applying nanoscale perovskite materials for photodetection applications.These materials are promising candidates for next-generation photodetectors(PDs)due to their unique optoelectronic properties and flexible synthesis routes.This review explores the approaches used in the development and use of optoelectronic devices made of different nanoscale perovskite architectures,including quantum dots,nanosheets,nanorods,nanowires,and nanocrystals.Through a thorough analysis of recent literature,the review also addresses common issues like the mechanisms underlying the degradation of perovskite PDs and offers perspectives on potential solutions to improve stability and scalability that impede widespread implementation.In addition,it highlights that photodetection encompasses the detection of light fields in dimensions other than light intensity and suggests potential avenues for future research to overcome these obstacles and fully realize the potential of nanoscale perovskite materials in state-of-the-art photodetection systems.This review provides a comprehensive overview of nanoscale perovskite PDs and guides future research efforts towards improved performance and wider applicability,making it a valuable resource for researchers.
文摘BACKGROUND External gastrointestinal fistulas(EGIFs)are serious postoperative complications associated with prolonged hospital stays,sepsis,malnutrition,and high mortality rates.Reducing gastrointestinal secretions with somatostatin or its analogues may facilitate fistula closure.The clinical effectiveness of these therapies,however,remains uncertain.AIM To investigate the effectiveness of somatostatin-based therapy for EGIFs.METHODS A systematic review and meta-analysis(Prospero CRD420251054344)of nine randomized controlled trials(442 patients)compared somatostatin-based therapies with standard care in tertiary care settings.Protocols included somatostatin,octreotide,or lanreotide,administered at various dosages(250 micrograms/hour intravenous infusion or 100 micrograms subcutaneous injection three times daily)for 7 to 56 days.Primary outcomes were fistula closure rates and time to closure.Secondary outcomes were hospital length of stay,complications,need for surgical intervention,and mortality.Mean differences and risk ratios(RRs)with 95%confidence intervals(CIs)were calculated using random-effects models.Risk of bias was assessed with the Cochrane RoB 2 tool.RESULTS There was no statistically significant difference in closure rate(RR:1.11,95%CI:0.95-1.28,P=0.19,I^(2)=0%)between 134/193 patients receiving somatostatin-based therapy and 99/170 control patients.Time to closure was reduced by 6.16 days(mean difference-6.16,95%CI:-7.44 to-4.88,P<0.001,I^(2)=0%)in 126 patients in intervention group vs 114 in control group.Hospital stay was shortened by 4.00 days(mean difference-4.00,95%CI:-7.99 to-0.01,P=0.05,I^(2)=0%)in 56 vs 62 patients.There were no differences in complications(RRs:0.76,95%CI:0.55-1.05),need for surgical intervention(RRs:0.67,95%CI:0.38-1.19),or mortality(RRs:0.77,95%CI:0.44-1.35).Limitations include small sample sizes,heterogeneity in treatment regimens,and inconsistent outcome definitions,which may affect generalizability.Limited data for some outcomes,such as hospital stay,and exclusion of some datasets for methodological reasons reduced statistical power.CONCLUSION Somatostatin-based therapies did not significantly improve fistula closure rates but were associated with shorter time to closure and hospital stay.Mortality,complications,and surgical intervention requirements remained unchanged,suggesting that these therapies may serve only as an adjunctive option in selected patients.
基金supported by grants from the National Institutes of Health(NIHK08 AR060164-01A)+2 种基金the Department of Defense(DoDW81XWH-16-1-0725)to JCEinstitutional support from the University of Rochester and Pennsylvania State University Medical Centers。
文摘4-Aminopyridine(4-AP), an FDA-approved drug for the symptomatic treatment of multiple sclerosis, is used to improve neuromuscular function in patients with diverse demyelinating disorders. We recently demonstrated that local, transdermal or injectable forms of 4-AP improve myelination, nerve conduction velocity, muscle atrophy, and motor function after traumatic peripheral nerve injury in mice. While oral 4-AP is most commonly used in the clinic, it is unknown whether human equivalent oral doses of 4-AP have effects on traumatic peripheral nerve injury differentiation, myelination, muscle atrophy, functional recovery, and post-injury inflammatory processes in animals. Mice with sciatic nerve crush or denervation injury received oral or intraperitoneal 4-AP(10 μg) or vehicle alone and were examined for pharmacokinetics, motor function, muscle mass, intrinsic muscle force, nerve morphological and gene expression profiles. 4-AP showed linear pharmacokinetics and the maximum plasma 4-AP concentrations were proportional to 4-AP dose. Acute single dose of oral 4-AP administration induced a rapid transient improvement in motor function that was different in traumatic peripheral nerve injury with or without nerve continuity, chronic daily oral 4-AP treatment significantly enhanced post crush injury motor function recovery and this effect was associated with improved myelination, muscle mass, and ex vivo muscle force. Polymerase chain reaction array analysis with crushed nerve revealed significant alterations in gene involved in axonal inflammation and regeneration. These findings provide convincing evidence that regardless of the route of administration, 4-AP can acutely differentiate traumatic peripheral nerve injury with or without nerve continuity and can enhance in vivo functional recovery with better preservation of myelin sheaths, muscle mass, and muscle force. The animal experiments were approved by the University Committee on Animal Research(UCAR) at the University of Rochester(UCAR-2009-019) on March 31, 2017.
