Experimental therapies targeting immune and stromal cells,such as mast cells,cancer-associated fibroblasts,dendritic cells,and tumor endothelial cells,in the treatment of gastrointestinal solid tumors pose new and com...Experimental therapies targeting immune and stromal cells,such as mast cells,cancer-associated fibroblasts,dendritic cells,and tumor endothelial cells,in the treatment of gastrointestinal solid tumors pose new and complex surgical and medico-legal challenges.These innovative treatments require that informed consent not be limited to simple acceptance of the medical procedure,but instead reflect a true relational and cognitive process grounded in understanding,free choice,and the ability to revoke consent at any time.In particular,it is essential that the patient understands the experimental nature of the therapy,its development stage,potential benefits and risks,as well as the implications for their health and personal dignity.In the case of stromal cell-based treatments,which may exert complex immunomodulatory effects or activate angiogenic pathways that are not yet fully understood,patients must be made fully aware that they are participating in a non-standardized therapy whose outcomes,whether beneficial or harmful,cannot yet be predicted with certainty.This requires particularly careful medical communication,using simple yet scientifically accurate explanations delivered in appropriate language,along with a final verification of the patient’s actual understanding.展开更多
A recently published prospective study marks a breakthrough for congenital olfactory disorders in children.The study provides the first long-term,three-year follow-up data,robustly demonstrating the durable efficacy a...A recently published prospective study marks a breakthrough for congenital olfactory disorders in children.The study provides the first long-term,three-year follow-up data,robustly demonstrating the durable efficacy and safety of autologous nasal epithelial stem cell transplantation.This work reveals immense therapeutic potential for a condition traditionally considered untreatable.However,this milestone achievement also presents new challenges.To translate this pioneering therapy from a single-center success to a global standard,multicenter,controlled clinical trials must be initiated immediately.Only through rigorous validation can we ensure its widespread adoption and ultimately bring hope to millions of children worldwide.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
AIM: To investigate the in vivo effects of type Ⅰdiabetes on the mechanical strength of tibial bone in a rodent model.METHODS: The biomechanical effect of diabetes on the structural integrity of the tibia in streptoz...AIM: To investigate the in vivo effects of type Ⅰdiabetes on the mechanical strength of tibial bone in a rodent model.METHODS: The biomechanical effect of diabetes on the structural integrity of the tibia in streptozotocin induced diabetic Wistar rats was analysed. Induction of diabetes was achieved by an intra-peritoneal injection and confirmed by measuring serial blood glucose levels(> 150 mg/d L). After 8 wk the tibiae were harvested and compared to a control group. Biomechanical analysis of harvested tibiae was performed using a threepoint bending technique on a servo hydraulic MTS 858 MiniB ionix frame. Maximum force applied to failure(N), stiffness(N × mm) and energy absorbed(N/mm) were recorded and plotted on load displacement curves. A displacement control loading mode of 1 mm/min was selected to simulate quasi-static loading conditions. Measurements from load-displacement curves were directly compared between groups.RESULTS: Fourteen streptozotocin induced diabetic Wistar rats were compared against nineteen non-diabetic controls. An average increase of 155.2 g in body weight was observed in the control group compared with only 5 g in the diabetic group during the experimental study period. Levels of blood glucose increased to 440.25 mg/d L in the diabetic group compared to 116.62 mg/d L in the control group.The biomechanical results demonstrate a highly significant reduction in the maximum load to failure from 69.5 N to 58 N in diabetic group compared to control(P = 0.011). Energy absorption to fracture was reduced from 28.2 N in the control group to 23.5 N in the diabetic group(P = 0.082). No significant differences were observed between the groups for bending stiffness.CONCLUSION: Streptozotocin-induced diabetes in rodents reduces the maximum force and energy absorption to failure of bone, suggesting a predisposition for fracture risk.展开更多
Objective:To investigate the effects and possible mechanisms of the combination of DMDD(2-dodecyl-6-methoxycyclohexa-2-5-diene-1-4-dione),a traditional Chinese medicine monomer,and sorafenib on the malignant biologica...Objective:To investigate the effects and possible mechanisms of the combination of DMDD(2-dodecyl-6-methoxycyclohexa-2-5-diene-1-4-dione),a traditional Chinese medicine monomer,and sorafenib on the malignant biological behavior of human hepatocellular carcinoma Huh7 cells.Methods:The experiment was divided into four groups:Huh7 cells control group,DMDD group,sorafenib group and DMDD and sorafenib combination group.The CCK-8 assay was used to measure the viability of Huh7 cells,and the Kim's formula was used to determine the synergistic effect.The plate cloning experiment was conducted to test colony formation ability of Huh7 cells.The scratch and Transwell experiments were performed to evaluate the migration ability and the invasion ability of Huh7 cells.The cell cycle of Huh7 cells was detected by flow cytometry.RT-qPCR and Western blot were used to measure the mRNA transcription level and protein expression level of PHGDH in the serine synthesis pathway.Results:The plate cloning experiment,scratch experiment,and Transwell migration experiment showed that the combined application of DMDD and Sorafenib significantly enhanced the inhibitory effect on the proliferation,migration,and invasion ability of Huh7 cells compared to the control group,DMDD group,and Sorafenib group(P<0.05).According to the Kim's formula,the combination of DMDD(final concentrations of 2,4,8μmol/L)and Sorafenib(final concentrations of 1,2,4μmol/L)had a synergistic inhibitory effect on the proliferation of Huh7 cells(Q>1.15).6,10μmol/L DMDD combined with 3,5μmol/L Sorafenib showed additive effect.The cell cycle of Huh7 cells was detected by flow cytometry,and the results showed that after 48 hours of drug intervention,the proportion of G2/M phase cells in the control group,DMDD group,Sorafenib group,and combination group were(10.63±0.32)%,(35.77±1.22)%,(30.03±2.22)%,and(38.97±0.60)%,respectively.Compared with the control group,the proportion of G2/M phase cells in the three groups significantly increased(P<0.0001).Compared with the Sorafenib group,the proportion of G2/M phase cells in the combination group significantly increased(P<0.0001).RT-qPCR and Western blot results showed that the combined application of DMDD and Sorafenib significantly inhibited the mRNA transcription level and protein expression level of PHGDH(P<0.05).Conclusion:The combined application of DMDD and Sorafenib has a synergistic effect that can enhance the inhibitory effect on the proliferation,invasion,and migration ability of Huh7 cells.The mechanism of this effect is related to the synergistic inhibition of the gene transcription and protein expression of PHGDH in the serine synthesis pathway.展开更多
Vulvodynia,a chronic pain disorder affecting the vulvar region,represents a significant challenge in both diagnosis and treatment within the field of women’s health.This condition is characterized by chronic pain tha...Vulvodynia,a chronic pain disorder affecting the vulvar region,represents a significant challenge in both diagnosis and treatment within the field of women’s health.This condition is characterized by chronic pain that significantly affects the quality of life of afflicted women.The present perspective paper examines the role of spinal sensitization and microglial activation in vulvodynia.展开更多
Background:Platinum chemotherapy(CT)remains the backbone of systemic therapy for patients with smallcell lung cancer(SCLC).The nucleotide excision repair(NER)pathway plays a central role in the repair of the DNA damag...Background:Platinum chemotherapy(CT)remains the backbone of systemic therapy for patients with smallcell lung cancer(SCLC).The nucleotide excision repair(NER)pathway plays a central role in the repair of the DNA damage exerted by platinum agents.Alteration in this repair mechanism may affect patients’survival.Materials and Methods:We conducted a retrospective analysis of data from 38 patients with extensive disease(ED)-SCLC who underwent platinum-CT at the Clinical Oncology Unit,Careggi University Hospital,Florence(Italy),from 2015 to 2020.mRNA expression analysis and single nucleotide polymorphism(SNP)characterization of three NER pathway genes—namely ERCC1,ERCC2,and ERCC5—were performed on patient tumor samples.Results:Overall,elevated expression of ERCC genes was observed in SCLC patients compared to healthy controls.Patients with low ERCC1 and ERCC5 expression levels exhibited a better median progression-free survival(mPFS=7.1 vs.4.9 months,p=0.39 for ERCC1 and mPFS=6.9 vs.4.8 months,p=0.093 for ERCC5)and overall survival(mOS=8.7 vs.6.0 months,p=0.4 for ERCC1 and mOS=7.2 vs.6.2 months,p=0.13 for ERCC5).Genotyping analysis of five SNPs of ERCC genes showed a longer survival in patients harboring the wild-type genotype or the heterozygous variant of the ERCC1 rs11615 SNP(p=0.24 for PFS and p=0.14 for OS)and of the rs13181 and rs1799793 ERCC2 SNPs(p=0.43 and p=0.26 for PFS and p=0.21 and p=0.16 for OS,respectively)compared to patients with homozygous mutant genotypes.Conclusions:The comprehensive analysis of ERCC gene expression and SNP variants appears to identify patients who derive greater survival benefits from platinum-CT.展开更多
Despite decades of dedicated resea rch,Alzheimer's disease (AD) is an age-related and progressive neurodegenerative disorder for which the mechanisms of onset are sti unc ear.AD is cha racterized by featured histo...Despite decades of dedicated resea rch,Alzheimer's disease (AD) is an age-related and progressive neurodegenerative disorder for which the mechanisms of onset are sti unc ear.AD is cha racterized by featured histological alterations including amyloid-beta (AB) plaque deposition,accumulation of neurofibrillary to ngles of hyperphosphorylated-tau,and neuronal loss,accompanied by progressive cognitive decline and behavioral changes.展开更多
Primary biliary cholangitis is a chronic cholestatic autoimmune liver disease that progressively damages the bile ducts,leading to cholestasis and,in advanced stages,cirrhosis.While it primarily affects middle-aged wo...Primary biliary cholangitis is a chronic cholestatic autoimmune liver disease that progressively damages the bile ducts,leading to cholestasis and,in advanced stages,cirrhosis.While it primarily affects middle-aged women,recent data indicate a rising incidence in men.The interplay between genetic susceptibility,environmental exposures,and gut microbiome alterations is thought to drive disease onset.Diagnosis relies on persistent cholestatic enzyme elevation,diseasespecific autoantibodies,and,in select cases,liver biopsy.Ursodeoxycholic acid remains the cornerstone of treatment,but many patients show an incomplete response.The recent withdrawal of obeticholic acid from the market,due to insufficient evidence of long-term benefit,has highlighted the urgent need for effective second-line therapies.Agonists of peroxisome proliferator-activated receptors,such as elafibranor and seladelpar,have demonstrated promising biochemical improvements and may reshape the therapeutic landscape.Future research is focused on refining risk assessment,optimizing treatment combinations,and addressing symptoms such as fatigue and pruritus to enhance patient well-being.A shift toward early intervention and personalized treatment strategies may further improve long-term outcomes in primary biliary cholangitis.展开更多
Objective:Nowadays robot-assisted partial nephrectomy(RAPN)represents the standard of care for clinical T1(cT1)renal masses,providing similar oncological outcomes when compared to open or laparoscopic PN with advantag...Objective:Nowadays robot-assisted partial nephrectomy(RAPN)represents the standard of care for clinical T1(cT1)renal masses,providing similar oncological outcomes when compared to open or laparoscopic PN with advantages in terms of functional outcomes and lower perioperative comorbidity,when compared to radical nephrectomy.Methods:We performed an extensive literature review of studies regarding RAPN,its evolution,technical aspects and applications,and new technological tools using different combinations of Medical Subject Headings terms“RAPN”,“partial nephrectomy”,“robot-assisted”,“nephron-sparing surgery”,“renal cell carcinoma”,“complex renal masses”,“endophytic renal masses”,and“bilateral renal tumors”.Results:A consistent body of evidence was selected,including original articles,systematic reviews,meta-analyses,and clinical trials having RAPN as the central focus in adult patients,with all its technical nuances.We started our narrative review with a background on PN and its evolution toward the robotic era with a special spotlight on the extending indications for PN in large and highly complex renal masses.Our review continued with an overview of nephron-sparing surgery in bilateral and recurrent masses.RAPN for bilateral synchronous renal masses represents a challenging scenario with no formal recommendations provided by international guidelines and controversial management and decision-making.Additionally,we reported evidence on redo RAPN which seems to be safe and effective.A final overview of the available technological tools,and in particular on three-dimensional reconstruction was provided.Conclusion:RAPN has been established as the standard of care for cT1 renal masses with an expanding spectrum of applications in different scenarios,including large(cT2),highly complex,and bilateral renal masses,as well as the surgical treatment of local recurrences after nephron-sparing surgery with acknowledged advantages in terms of functional outcomes and perioperative risk profiles while maintaining similar oncological outcomes when compared to open or laparoscopic PN and radical treatment.展开更多
Background:The surgical management of patients with benign prostatic hyperplasia(BPH)has considerably evolved through recent years.Nonetheless,benefits and harms of several laser procedures are still to be determined....Background:The surgical management of patients with benign prostatic hyperplasia(BPH)has considerably evolved through recent years.Nonetheless,benefits and harms of several laser procedures are still to be determined.The study aimed to report perioperative and early functional results of patients treated with anatomical photo vaporization of the prostate(aPVP).Methods:Data from consecutive patients treated with aPVP by using a 180-W XPS GreenLight laser were prospectively collected in a single tertiary center between 2020 and 2023.The surgical procedure was divided into a modular step-by-step fashion.Patients were asked to complete self-administered questionnaires at baseline and during follow-up visits.Results:Overall,176 consecutive patients were enrolled.Median age was 65[interquartile range(IQR)63–72]years.The baseline median prostate volume was 61.2(IQR 52.5–71.0)mL,and the median max flow rate(Qmax)was 9.3(IQR 7.8–11.5)mL/s.Median preoperative International Prostate Symptom Score(IPSS)was 25(IQR 22–29).Overall,the median operative time was 42(IQR 31–47)minutes with a median energy/mL of tissue delivered of 2447 kJ/mL.At 3 month-evaluation,significant improvements were observed,with a median Qmax of 28(IQR:24–32)mL/s and a median IPSS reduction of 15(IQR:11–18)points.A strong inverse correlation was identified between energy delivery during initial procedural steps and the severity of postoperative storage symptoms(all p<0.05),underscoring the importance of precise energy modulation.Multivariate analysis identified increased prostate volume(odds ratio[OR]:1.02;95%confidence interval[CI]1.01–1.11;p=0.001)and higher prostate width-to-length ratio(OR:1.28;95%CI 1.04–1.78;p=0.03)as independent predictors of increased energy requirements.Conclusions:aPVP with 180-W XPS GreenLight laser is a safe and effective technique showing worthy early functional results.The limitation of the energy delivered in some key phases of the procedure may be associated with a significant reduction in postoperative irritative symptoms.The shape and dimensions of the prostate also play a critical role in determining the total energy required for complete adenoma removal.展开更多
BACKGROUND Barrett esophagus(BE),a metaplastic adaptive process to gastrointestinal reflux,is associated with a higher risk of developing esophageal adenocarcinoma.However,the factors and mechanism that drive the mali...BACKGROUND Barrett esophagus(BE),a metaplastic adaptive process to gastrointestinal reflux,is associated with a higher risk of developing esophageal adenocarcinoma.However,the factors and mechanism that drive the malignant progression of BE is not well understood.AIM To investigate the role of bile acids,a component of the reflux fluid,in the malignant progression of BE.METHODS Using engineered green fluorescent protein-labeled adult tissue-resident stem cells isolated from BE clinical biopsies(BE-ASCs)as the target,we studied the effect of hydrophobic deoxycholic acid(DCA)and hydrophilic tetrahydroxylated bile acids(THBA)on cell viability by fluorescence intensity analysis,mucin production by dark density measurement,tissue structure by pathology analysis,expression of different pro-inflammatory factors gene by quantitative polymerase chain reaction and proteins by Western blot.RESULTS We found that hydrophobic DCA has cytotoxic and proinflammatory effects through activation of interleukin-1β(IL-1β)-nuclear factor kappa-B(NF-κB)inflammatory pathway on BE-ASCs.This action results in impaired cell viability,tissue intactness,reduced mucin production,and increased transition to disorganized atypical cells without intestinal features.In contrast,co-culture with hydrophilic THBA inhibited the IL-1β-NF-κB inflammatory pathway with maintenance of mature intestinal type cellular and histomorphology.CONCLUSION Our data indicates that the hydrophilic bile acid THBA can counteract the cytotoxic and proinflammatory effect of hydrophobic DCA and prevent the malignant progression of BE by inhibiting the IL-1β-NF-κB pathway.展开更多
Background Non-suicidal self-injury(NSSI)is a significant health concern among adolescents and young adults,often resulting from adverse childhood experiences(ACEs).Dissociation,post-traumatic symptoms and attachment ...Background Non-suicidal self-injury(NSSI)is a significant health concern among adolescents and young adults,often resulting from adverse childhood experiences(ACEs).Dissociation,post-traumatic symptoms and attachment style may have a role in shaping such associations.Aims This study aims to provide a unified model of the impact of ACEs on NSSI,exploring complex post-traumatic stress disorder(cPTSD)symptoms and dissociation as potential mediators and the role of the predominant attachment style in affecting such associations.Methods 1010 young individuals attending the last year of high school participated in this cross-sectional study.ACEs,cPTSD,dissociation and NSSI were evaluated using self-report questionnaires.We fitted a path model of NSSI,with ACEs as exogenous variables and cPTSD and dissociation as sequential mediators.Secure,fearful and preoccupied attachment styles were modelled as grouping variables.Results Our findings showed that dissociation mediated the impact of ACEs on NSSI in subjects with a fearful attachment style,as opposed to those with a preoccupied attachment for whom cPTSD symptoms mediated the ACEs-NSSI association.Conclusions Attachment styles moderate the relationship between ACEs and NSSI,with either dissociation or post-traumatic symptomatology mediating the impact of ACEs on NSSI,depending on the predominant attachment style.Our results highlight the importance of attachment as a pathway modifier in the relationships between different psychopathology dimensions,providing a useful framework to better conceptualise the ACEs-NSSI association.展开更多
1 MHC-I Loss in the Immune Evasion of Cancer Cells Pancreatic ductal adenocarcinoma(PDAC)is a lethal cancer with a poor prognosis due to its aggressive nature and late detection.Recently,new discoveries in PDAC demons...1 MHC-I Loss in the Immune Evasion of Cancer Cells Pancreatic ductal adenocarcinoma(PDAC)is a lethal cancer with a poor prognosis due to its aggressive nature and late detection.Recently,new discoveries in PDAC demonstrated receptor-interacting protein kinase 2(RIPK2)triggering immune evasion.Mechanistically,RIPK2 drives the desmoplastic tumor microenvironment(TME)and restricts the activation and density of tumor-infiltrating effector T cells by impairing the expression of major histocompatibility complex class I(MHC-I)[1].This process might be relevant in different solid cancer entities as illustrated by analyzing publicly available databases.展开更多
Post-traumatic stress disorder(PTSD)is a severe neuropsychiatric disorder characterised by reexperiencing,avoidance and hyperarousal.Memory abnormalities manifested as intrusive thoughts and prolonged distressful emot...Post-traumatic stress disorder(PTSD)is a severe neuropsychiatric disorder characterised by reexperiencing,avoidance and hyperarousal.Memory abnormalities manifested as intrusive thoughts and prolonged distressful emotions are postulated as key roles in PTSD development and persistence.Over the past decades,convergent results from human and animal studies have systematically investigated contributions of the amygdala,hippocampus and medial prefrontal cortex(mPFC)in fear memory processes,including fear acquisition,storage,reconsolidation and extinction.These findings provide mechanistic insights for cognitive-behavioural therapy and aid in developing pathological region-targeted neuromodulation treatment for PTSD.Taking advantage of advances in cell-type selective labelling and manipulation technologies,recent studies have focused on the spatiotemporal regulation of neural circuits underlying distinct phases of fear memory processes.These findings have revealed that multiple distributed brain areas participate in the fear memory encoding network.Moreover,the functional role of distinct neuronal ensembles within the amygdala-hippocampus-mPFC pathway,identified by genetic markers and projection profiles,has been assigned to temporally separate features of fear processing,demonstrating the sophistication of the fear encoding circuit.These results provide mechanistic insights into PTSD pathology and might shed light on aetiology-based clinical interventions for PTSD.Therefore,the present review will mainly focus on the recent progress in elucidating neural circuit mechanisms underlying the dynamic regulation of fear memory,with an emphasis on the spatial distribution of fear memory encoding neural networks and the temporal coherence between neuronal ensemble activity and fear expression.展开更多
BACKGROUND Colorectal cancer(CRC)is a prevalent gastrointestinal malignancy with a typi-cally unfavorable prognosis following the onset of liver metastases.AIM To develop and validate a new clinical prediction model t...BACKGROUND Colorectal cancer(CRC)is a prevalent gastrointestinal malignancy with a typi-cally unfavorable prognosis following the onset of liver metastases.AIM To develop and validate a new clinical prediction model to accurately forecast overall survival(OS)in CRC patients following surgical treatment for liver metastasis.METHODS This study included 1059 patients diagnosed with CRC liver metastases(CRLM)at the Xijing Hospital between 2010 and 2022.The patients were randomly divided into training and validation cohorts at a 7:3 ratio.Key clinical predictors were identified using least absolute shrinkage and selection operator(LASSO)regression combined with a Cox proportional hazards model,leading to the establishment of a prediction model and preparation of a nomogram to enhance its clinical utility.Decision curve analysis(DCA)and Kaplan-Meier survival analysis were employed to evaluate the precision and predictive performance of the model.RESULTS The LASSO-Cox regression analysis revealed multiple pivotal clinical biomarkers significantly linked to CRLM,including gamma-glutamyl transferase levels,blood chloride concentration,activated partial thromboplastin time,N stage,and vascular invasion.The model's receiver operating characteristic curve area under the curve exceeded 0.7 for both the training and validation groups with moderate-to-good predictive accuracy.Furthermore,DCA validated the nomogram's effectiveness for OS prediction.Kaplan-Meier risk stratification demonstrated markedly improved OS among patients classified as low-risk compared to those categorized as high-risk(P<0.001),highlighting its clinical utility for risk assessment and treatment guidance.CONCLUSION The nomogram prediction model constructed in this study has good predictive value and can effectively assess the survival rate of patients with CRLM.展开更多
Food allergies are abnormal immune responses triggered by specific foods,affecting the quality of life of millions of people worldwide.In recent years,the prevalence of food allergies has increased significantly,espec...Food allergies are abnormal immune responses triggered by specific foods,affecting the quality of life of millions of people worldwide.In recent years,the prevalence of food allergies has increased significantly,especially in Westernized countries,prompting the scientific community to explore the complex mechanisms behind them.Dietary patterns and specific dietary components are important factors related to the occurrence,development,and prevention of food allergies.Studies have shown that the Mediterranean diet,which is high in fiber,rich in antioxidants,and healthy fats,shows potential protective effects by promoting the balance of intestinal flora,maintaining the intestinal barrier,and regulating immunity.In contrast,a high-fat,high-sugar,low-fiber Western diet is associated with an increased risk of allergies.Key dietary components such as omega-3 fatty acids,dietary fiber,vitamins A,D,and E,and bioactive substances such as quercetin and curcumin can regulate immune tolerance through multiple pathways,including epigenetic regulation and affecting mitochondrial function.However,advanced glycation end products(AGEs),emulsifiers,artificial sweeteners produced by food processing,and pesticide residues(such as glyphosate)may damage the intestinal barrier,disrupt the flora,and increase the risk of allergies.This review explored the risk and protective factors for food allergies from a dietary perspective,thus benefiting the progress of intervention and therapy of food allergy.展开更多
Esophageal cancer is an aggressive malignancy often diagnosed at advanced stages,with esophageal squamous cell carcinoma being the predominant subtype worldwide.Standard first-line chemotherapy provides limited surviv...Esophageal cancer is an aggressive malignancy often diagnosed at advanced stages,with esophageal squamous cell carcinoma being the predominant subtype worldwide.Standard first-line chemotherapy provides limited survival benefits,with a median overall survival of less than 1 year.Recent advancements in immunotherapy,particularly immune checkpoint inhibitors(ICIs),have trans-formed the treatment landscape,improving overall survival and progression-free survival.However,response rates remain variable,with programmed death ligand 1(PD-L1)expression being the primary predictive biomarker.The variability in PD-L1 testing methods and immune microenvironment alterations after prior treatments complicate patient selection for ICIs.Several phase 3 trials,including KEYNOTE-590 and CheckMate 648,have demonstrated the efficacy of ICIs combined with chemotherapy,particularly in patients positive for PD-L1.Despite these advances,long-term survival remains low,emphasizing the need for better biomarkers and novel therapeutic strategies.This review explored current first-line treatment options for esophageal squamous cell carcinoma,challenges in biomarker-based patient selection,and emerging therapeutic approaches.展开更多
Background:Developing a granulomatous liver injury preclinical model may pave the way to understanding hepatic-TB(tuberculosis)and autoimmune granulomatous liver diseases.Antitubercular(ATT)and other drugs'metabol...Background:Developing a granulomatous liver injury preclinical model may pave the way to understanding hepatic-TB(tuberculosis)and autoimmune granulomatous liver diseases.Antitubercular(ATT)and other drugs'metabolism in the presence of a specific type of liver injury is not well understood.The present study aimed to establish a preclinical model of granulomatous hepatitis by using the BCG(Bacillus CalmetteGuérin)vaccine,further studying it in the presence of ATT dosing,and analyze the pharmacokinetics of isoniazid,rifampicin,and their respective primary metabolites.Methods:We used 56 rats in seven equal groups.Group I functioned as a normal control(NC)receiving normal saline only.Groups II-IV received intravenous injections of low-,medium-,and high-dose BCG vaccine daily for 21 days.Groups V,VI,and VII received isoniazid(H)alone,rifampicin(R)alone,and isoniazid+rifampicin(HR)for a subsequent 15 days in addition to high dose BCG for the first 21 days,respectively.Liver function tests(LFT)were monitored on days 0,21,28,and 36.Rats were sacrificed later for oxidative stress and histopathological examination.Results:The study observed BCG dose-specific LFT derangements in groups II-IV compared to group I on day 21(p<0.05).Isoniazid,rifampicin,and combination intervention groups demonstrated normalization of the BCG-led LFT changes.Histology and oxidative stress parameters confirmed model development and biochemical changes.Isoniazid area under the curve(AUC)showed a reduction of 16.9%in BCG+HR group in comparison to the BCG+H group(p=0.01).Des-acetyl-rifampicin AUC and maximum-concentration value demonstrated a significant rise in BCG+HR group in comparison to the BCG+R group(p=0.001).Conclusion:A novel preclinical model of granulomatous liver injury was developed using the BCG vaccine strain and validated with ATT response.展开更多
Cancer is a global health problem and one of the leading causes of mortality.Immune checkpoint inhibitors have revolutionized the field of oncology,emerging as a powerful treatment strategy.A key pathway that has garn...Cancer is a global health problem and one of the leading causes of mortality.Immune checkpoint inhibitors have revolutionized the field of oncology,emerging as a powerful treatment strategy.A key pathway that has garnered considerable attention is programmed cell death-1(PD-1)/programmed cell death-ligand 1(PD-L1).The interaction between PD-L1 expressed on tumor cells and PD-1 reduces the innate immune response and thus compromises the capability of the body’s immune system.Furthermore,it controls the phenotype and functionality of innate and adaptive immune components.A range of monoclonal antibodies,including avelumab,atezolizumab,camrelizumab,dostarlimab,durvalumab,sinitilimab,toripalimab,and zimberelimab,have been developed for targeting the interaction between PD-1 and PD-L1.These agents can induce a broad spectrum of autoimmune-like complications that may affect any organ system.Recent studies have focused on the effect of various natural compounds that inhibit immune checkpoints.This could contribute to the existing arsenal of anticancer drugs.Several bioactive natural agents have been shown to affect the PD-1/PD-L1 signaling axis,promoting tumor cell apoptosis,influencing cell proliferation,and eventually leading to tumor cell death and inhibiting cancer progression.However,there is a substantial knowledge gap regarding the role of different natural compounds targeting PD-1 in the context of cancer.Hence,this review aims to provide a common connection between PD-1/PD-L1 blockade and the anticancer effects of distinct natural molecules.Moreover,the primary focus will be on the underlying mechanism of action as well as the clinical efficacy of bioactive molecules.Current challenges along with the scope of future research directions targeting PD-1/PD-L1 interactions through natural substances are also discussed.展开更多
文摘Experimental therapies targeting immune and stromal cells,such as mast cells,cancer-associated fibroblasts,dendritic cells,and tumor endothelial cells,in the treatment of gastrointestinal solid tumors pose new and complex surgical and medico-legal challenges.These innovative treatments require that informed consent not be limited to simple acceptance of the medical procedure,but instead reflect a true relational and cognitive process grounded in understanding,free choice,and the ability to revoke consent at any time.In particular,it is essential that the patient understands the experimental nature of the therapy,its development stage,potential benefits and risks,as well as the implications for their health and personal dignity.In the case of stromal cell-based treatments,which may exert complex immunomodulatory effects or activate angiogenic pathways that are not yet fully understood,patients must be made fully aware that they are participating in a non-standardized therapy whose outcomes,whether beneficial or harmful,cannot yet be predicted with certainty.This requires particularly careful medical communication,using simple yet scientifically accurate explanations delivered in appropriate language,along with a final verification of the patient’s actual understanding.
文摘A recently published prospective study marks a breakthrough for congenital olfactory disorders in children.The study provides the first long-term,three-year follow-up data,robustly demonstrating the durable efficacy and safety of autologous nasal epithelial stem cell transplantation.This work reveals immense therapeutic potential for a condition traditionally considered untreatable.However,this milestone achievement also presents new challenges.To translate this pioneering therapy from a single-center success to a global standard,multicenter,controlled clinical trials must be initiated immediately.Only through rigorous validation can we ensure its widespread adoption and ultimately bring hope to millions of children worldwide.
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.
文摘AIM: To investigate the in vivo effects of type Ⅰdiabetes on the mechanical strength of tibial bone in a rodent model.METHODS: The biomechanical effect of diabetes on the structural integrity of the tibia in streptozotocin induced diabetic Wistar rats was analysed. Induction of diabetes was achieved by an intra-peritoneal injection and confirmed by measuring serial blood glucose levels(> 150 mg/d L). After 8 wk the tibiae were harvested and compared to a control group. Biomechanical analysis of harvested tibiae was performed using a threepoint bending technique on a servo hydraulic MTS 858 MiniB ionix frame. Maximum force applied to failure(N), stiffness(N × mm) and energy absorbed(N/mm) were recorded and plotted on load displacement curves. A displacement control loading mode of 1 mm/min was selected to simulate quasi-static loading conditions. Measurements from load-displacement curves were directly compared between groups.RESULTS: Fourteen streptozotocin induced diabetic Wistar rats were compared against nineteen non-diabetic controls. An average increase of 155.2 g in body weight was observed in the control group compared with only 5 g in the diabetic group during the experimental study period. Levels of blood glucose increased to 440.25 mg/d L in the diabetic group compared to 116.62 mg/d L in the control group.The biomechanical results demonstrate a highly significant reduction in the maximum load to failure from 69.5 N to 58 N in diabetic group compared to control(P = 0.011). Energy absorption to fracture was reduced from 28.2 N in the control group to 23.5 N in the diabetic group(P = 0.082). No significant differences were observed between the groups for bending stiffness.CONCLUSION: Streptozotocin-induced diabetes in rodents reduces the maximum force and energy absorption to failure of bone, suggesting a predisposition for fracture risk.
基金This study was supported by National Natural Foundation Project of China(81860504)。
文摘Objective:To investigate the effects and possible mechanisms of the combination of DMDD(2-dodecyl-6-methoxycyclohexa-2-5-diene-1-4-dione),a traditional Chinese medicine monomer,and sorafenib on the malignant biological behavior of human hepatocellular carcinoma Huh7 cells.Methods:The experiment was divided into four groups:Huh7 cells control group,DMDD group,sorafenib group and DMDD and sorafenib combination group.The CCK-8 assay was used to measure the viability of Huh7 cells,and the Kim's formula was used to determine the synergistic effect.The plate cloning experiment was conducted to test colony formation ability of Huh7 cells.The scratch and Transwell experiments were performed to evaluate the migration ability and the invasion ability of Huh7 cells.The cell cycle of Huh7 cells was detected by flow cytometry.RT-qPCR and Western blot were used to measure the mRNA transcription level and protein expression level of PHGDH in the serine synthesis pathway.Results:The plate cloning experiment,scratch experiment,and Transwell migration experiment showed that the combined application of DMDD and Sorafenib significantly enhanced the inhibitory effect on the proliferation,migration,and invasion ability of Huh7 cells compared to the control group,DMDD group,and Sorafenib group(P<0.05).According to the Kim's formula,the combination of DMDD(final concentrations of 2,4,8μmol/L)and Sorafenib(final concentrations of 1,2,4μmol/L)had a synergistic inhibitory effect on the proliferation of Huh7 cells(Q>1.15).6,10μmol/L DMDD combined with 3,5μmol/L Sorafenib showed additive effect.The cell cycle of Huh7 cells was detected by flow cytometry,and the results showed that after 48 hours of drug intervention,the proportion of G2/M phase cells in the control group,DMDD group,Sorafenib group,and combination group were(10.63±0.32)%,(35.77±1.22)%,(30.03±2.22)%,and(38.97±0.60)%,respectively.Compared with the control group,the proportion of G2/M phase cells in the three groups significantly increased(P<0.0001).Compared with the Sorafenib group,the proportion of G2/M phase cells in the combination group significantly increased(P<0.0001).RT-qPCR and Western blot results showed that the combined application of DMDD and Sorafenib significantly inhibited the mRNA transcription level and protein expression level of PHGDH(P<0.05).Conclusion:The combined application of DMDD and Sorafenib has a synergistic effect that can enhance the inhibitory effect on the proliferation,invasion,and migration ability of Huh7 cells.The mechanism of this effect is related to the synergistic inhibition of the gene transcription and protein expression of PHGDH in the serine synthesis pathway.
文摘Vulvodynia,a chronic pain disorder affecting the vulvar region,represents a significant challenge in both diagnosis and treatment within the field of women’s health.This condition is characterized by chronic pain that significantly affects the quality of life of afflicted women.The present perspective paper examines the role of spinal sensitization and microglial activation in vulvodynia.
文摘Background:Platinum chemotherapy(CT)remains the backbone of systemic therapy for patients with smallcell lung cancer(SCLC).The nucleotide excision repair(NER)pathway plays a central role in the repair of the DNA damage exerted by platinum agents.Alteration in this repair mechanism may affect patients’survival.Materials and Methods:We conducted a retrospective analysis of data from 38 patients with extensive disease(ED)-SCLC who underwent platinum-CT at the Clinical Oncology Unit,Careggi University Hospital,Florence(Italy),from 2015 to 2020.mRNA expression analysis and single nucleotide polymorphism(SNP)characterization of three NER pathway genes—namely ERCC1,ERCC2,and ERCC5—were performed on patient tumor samples.Results:Overall,elevated expression of ERCC genes was observed in SCLC patients compared to healthy controls.Patients with low ERCC1 and ERCC5 expression levels exhibited a better median progression-free survival(mPFS=7.1 vs.4.9 months,p=0.39 for ERCC1 and mPFS=6.9 vs.4.8 months,p=0.093 for ERCC5)and overall survival(mOS=8.7 vs.6.0 months,p=0.4 for ERCC1 and mOS=7.2 vs.6.2 months,p=0.13 for ERCC5).Genotyping analysis of five SNPs of ERCC genes showed a longer survival in patients harboring the wild-type genotype or the heterozygous variant of the ERCC1 rs11615 SNP(p=0.24 for PFS and p=0.14 for OS)and of the rs13181 and rs1799793 ERCC2 SNPs(p=0.43 and p=0.26 for PFS and p=0.21 and p=0.16 for OS,respectively)compared to patients with homozygous mutant genotypes.Conclusions:The comprehensive analysis of ERCC gene expression and SNP variants appears to identify patients who derive greater survival benefits from platinum-CT.
基金supported by an under-40 grant from the Italian Association for Alzheimer’s Research [AIRALZH AGYR2021]the Strategic University Projects–Young Researcher Independence grant [YRG2021] from the Università Campus Bio-Medico di Roma (Rome, Italy)(to LLB)+1 种基金Italian Ministry of Health [Research Grant:GR-2019-12370446]the American Alzheimer’s Association [AARG-22-922961](to PK)。
文摘Despite decades of dedicated resea rch,Alzheimer's disease (AD) is an age-related and progressive neurodegenerative disorder for which the mechanisms of onset are sti unc ear.AD is cha racterized by featured histological alterations including amyloid-beta (AB) plaque deposition,accumulation of neurofibrillary to ngles of hyperphosphorylated-tau,and neuronal loss,accompanied by progressive cognitive decline and behavioral changes.
文摘Primary biliary cholangitis is a chronic cholestatic autoimmune liver disease that progressively damages the bile ducts,leading to cholestasis and,in advanced stages,cirrhosis.While it primarily affects middle-aged women,recent data indicate a rising incidence in men.The interplay between genetic susceptibility,environmental exposures,and gut microbiome alterations is thought to drive disease onset.Diagnosis relies on persistent cholestatic enzyme elevation,diseasespecific autoantibodies,and,in select cases,liver biopsy.Ursodeoxycholic acid remains the cornerstone of treatment,but many patients show an incomplete response.The recent withdrawal of obeticholic acid from the market,due to insufficient evidence of long-term benefit,has highlighted the urgent need for effective second-line therapies.Agonists of peroxisome proliferator-activated receptors,such as elafibranor and seladelpar,have demonstrated promising biochemical improvements and may reshape the therapeutic landscape.Future research is focused on refining risk assessment,optimizing treatment combinations,and addressing symptoms such as fatigue and pruritus to enhance patient well-being.A shift toward early intervention and personalized treatment strategies may further improve long-term outcomes in primary biliary cholangitis.
文摘Objective:Nowadays robot-assisted partial nephrectomy(RAPN)represents the standard of care for clinical T1(cT1)renal masses,providing similar oncological outcomes when compared to open or laparoscopic PN with advantages in terms of functional outcomes and lower perioperative comorbidity,when compared to radical nephrectomy.Methods:We performed an extensive literature review of studies regarding RAPN,its evolution,technical aspects and applications,and new technological tools using different combinations of Medical Subject Headings terms“RAPN”,“partial nephrectomy”,“robot-assisted”,“nephron-sparing surgery”,“renal cell carcinoma”,“complex renal masses”,“endophytic renal masses”,and“bilateral renal tumors”.Results:A consistent body of evidence was selected,including original articles,systematic reviews,meta-analyses,and clinical trials having RAPN as the central focus in adult patients,with all its technical nuances.We started our narrative review with a background on PN and its evolution toward the robotic era with a special spotlight on the extending indications for PN in large and highly complex renal masses.Our review continued with an overview of nephron-sparing surgery in bilateral and recurrent masses.RAPN for bilateral synchronous renal masses represents a challenging scenario with no formal recommendations provided by international guidelines and controversial management and decision-making.Additionally,we reported evidence on redo RAPN which seems to be safe and effective.A final overview of the available technological tools,and in particular on three-dimensional reconstruction was provided.Conclusion:RAPN has been established as the standard of care for cT1 renal masses with an expanding spectrum of applications in different scenarios,including large(cT2),highly complex,and bilateral renal masses,as well as the surgical treatment of local recurrences after nephron-sparing surgery with acknowledged advantages in terms of functional outcomes and perioperative risk profiles while maintaining similar oncological outcomes when compared to open or laparoscopic PN and radical treatment.
文摘Background:The surgical management of patients with benign prostatic hyperplasia(BPH)has considerably evolved through recent years.Nonetheless,benefits and harms of several laser procedures are still to be determined.The study aimed to report perioperative and early functional results of patients treated with anatomical photo vaporization of the prostate(aPVP).Methods:Data from consecutive patients treated with aPVP by using a 180-W XPS GreenLight laser were prospectively collected in a single tertiary center between 2020 and 2023.The surgical procedure was divided into a modular step-by-step fashion.Patients were asked to complete self-administered questionnaires at baseline and during follow-up visits.Results:Overall,176 consecutive patients were enrolled.Median age was 65[interquartile range(IQR)63–72]years.The baseline median prostate volume was 61.2(IQR 52.5–71.0)mL,and the median max flow rate(Qmax)was 9.3(IQR 7.8–11.5)mL/s.Median preoperative International Prostate Symptom Score(IPSS)was 25(IQR 22–29).Overall,the median operative time was 42(IQR 31–47)minutes with a median energy/mL of tissue delivered of 2447 kJ/mL.At 3 month-evaluation,significant improvements were observed,with a median Qmax of 28(IQR:24–32)mL/s and a median IPSS reduction of 15(IQR:11–18)points.A strong inverse correlation was identified between energy delivery during initial procedural steps and the severity of postoperative storage symptoms(all p<0.05),underscoring the importance of precise energy modulation.Multivariate analysis identified increased prostate volume(odds ratio[OR]:1.02;95%confidence interval[CI]1.01–1.11;p=0.001)and higher prostate width-to-length ratio(OR:1.28;95%CI 1.04–1.78;p=0.03)as independent predictors of increased energy requirements.Conclusions:aPVP with 180-W XPS GreenLight laser is a safe and effective technique showing worthy early functional results.The limitation of the energy delivered in some key phases of the procedure may be associated with a significant reduction in postoperative irritative symptoms.The shape and dimensions of the prostate also play a critical role in determining the total energy required for complete adenoma removal.
文摘BACKGROUND Barrett esophagus(BE),a metaplastic adaptive process to gastrointestinal reflux,is associated with a higher risk of developing esophageal adenocarcinoma.However,the factors and mechanism that drive the malignant progression of BE is not well understood.AIM To investigate the role of bile acids,a component of the reflux fluid,in the malignant progression of BE.METHODS Using engineered green fluorescent protein-labeled adult tissue-resident stem cells isolated from BE clinical biopsies(BE-ASCs)as the target,we studied the effect of hydrophobic deoxycholic acid(DCA)and hydrophilic tetrahydroxylated bile acids(THBA)on cell viability by fluorescence intensity analysis,mucin production by dark density measurement,tissue structure by pathology analysis,expression of different pro-inflammatory factors gene by quantitative polymerase chain reaction and proteins by Western blot.RESULTS We found that hydrophobic DCA has cytotoxic and proinflammatory effects through activation of interleukin-1β(IL-1β)-nuclear factor kappa-B(NF-κB)inflammatory pathway on BE-ASCs.This action results in impaired cell viability,tissue intactness,reduced mucin production,and increased transition to disorganized atypical cells without intestinal features.In contrast,co-culture with hydrophilic THBA inhibited the IL-1β-NF-κB inflammatory pathway with maintenance of mature intestinal type cellular and histomorphology.CONCLUSION Our data indicates that the hydrophilic bile acid THBA can counteract the cytotoxic and proinflammatory effect of hydrophobic DCA and prevent the malignant progression of BE by inhibiting the IL-1β-NF-κB pathway.
基金supported by #NEXTGENERATIONEU(NGEU)and funded by the Ministry of University and Research(MUR),National Recovery and Resilience Plan(NRRP),project MNESYS(PE0000006)-(DN.155311.10.2022)supported by Sapienza Grant 2021(RM12117A60BDF685).
文摘Background Non-suicidal self-injury(NSSI)is a significant health concern among adolescents and young adults,often resulting from adverse childhood experiences(ACEs).Dissociation,post-traumatic symptoms and attachment style may have a role in shaping such associations.Aims This study aims to provide a unified model of the impact of ACEs on NSSI,exploring complex post-traumatic stress disorder(cPTSD)symptoms and dissociation as potential mediators and the role of the predominant attachment style in affecting such associations.Methods 1010 young individuals attending the last year of high school participated in this cross-sectional study.ACEs,cPTSD,dissociation and NSSI were evaluated using self-report questionnaires.We fitted a path model of NSSI,with ACEs as exogenous variables and cPTSD and dissociation as sequential mediators.Secure,fearful and preoccupied attachment styles were modelled as grouping variables.Results Our findings showed that dissociation mediated the impact of ACEs on NSSI in subjects with a fearful attachment style,as opposed to those with a preoccupied attachment for whom cPTSD symptoms mediated the ACEs-NSSI association.Conclusions Attachment styles moderate the relationship between ACEs and NSSI,with either dissociation or post-traumatic symptomatology mediating the impact of ACEs on NSSI,depending on the predominant attachment style.Our results highlight the importance of attachment as a pathway modifier in the relationships between different psychopathology dimensions,providing a useful framework to better conceptualise the ACEs-NSSI association.
文摘1 MHC-I Loss in the Immune Evasion of Cancer Cells Pancreatic ductal adenocarcinoma(PDAC)is a lethal cancer with a poor prognosis due to its aggressive nature and late detection.Recently,new discoveries in PDAC demonstrated receptor-interacting protein kinase 2(RIPK2)triggering immune evasion.Mechanistically,RIPK2 drives the desmoplastic tumor microenvironment(TME)and restricts the activation and density of tumor-infiltrating effector T cells by impairing the expression of major histocompatibility complex class I(MHC-I)[1].This process might be relevant in different solid cancer entities as illustrated by analyzing publicly available databases.
基金supported by the National Natural Science Foundation of China(82401772)the Shanghai Municipal Education Commission(2021-01-07-00-02-E0086).
文摘Post-traumatic stress disorder(PTSD)is a severe neuropsychiatric disorder characterised by reexperiencing,avoidance and hyperarousal.Memory abnormalities manifested as intrusive thoughts and prolonged distressful emotions are postulated as key roles in PTSD development and persistence.Over the past decades,convergent results from human and animal studies have systematically investigated contributions of the amygdala,hippocampus and medial prefrontal cortex(mPFC)in fear memory processes,including fear acquisition,storage,reconsolidation and extinction.These findings provide mechanistic insights for cognitive-behavioural therapy and aid in developing pathological region-targeted neuromodulation treatment for PTSD.Taking advantage of advances in cell-type selective labelling and manipulation technologies,recent studies have focused on the spatiotemporal regulation of neural circuits underlying distinct phases of fear memory processes.These findings have revealed that multiple distributed brain areas participate in the fear memory encoding network.Moreover,the functional role of distinct neuronal ensembles within the amygdala-hippocampus-mPFC pathway,identified by genetic markers and projection profiles,has been assigned to temporally separate features of fear processing,demonstrating the sophistication of the fear encoding circuit.These results provide mechanistic insights into PTSD pathology and might shed light on aetiology-based clinical interventions for PTSD.Therefore,the present review will mainly focus on the recent progress in elucidating neural circuit mechanisms underlying the dynamic regulation of fear memory,with an emphasis on the spatial distribution of fear memory encoding neural networks and the temporal coherence between neuronal ensemble activity and fear expression.
文摘BACKGROUND Colorectal cancer(CRC)is a prevalent gastrointestinal malignancy with a typi-cally unfavorable prognosis following the onset of liver metastases.AIM To develop and validate a new clinical prediction model to accurately forecast overall survival(OS)in CRC patients following surgical treatment for liver metastasis.METHODS This study included 1059 patients diagnosed with CRC liver metastases(CRLM)at the Xijing Hospital between 2010 and 2022.The patients were randomly divided into training and validation cohorts at a 7:3 ratio.Key clinical predictors were identified using least absolute shrinkage and selection operator(LASSO)regression combined with a Cox proportional hazards model,leading to the establishment of a prediction model and preparation of a nomogram to enhance its clinical utility.Decision curve analysis(DCA)and Kaplan-Meier survival analysis were employed to evaluate the precision and predictive performance of the model.RESULTS The LASSO-Cox regression analysis revealed multiple pivotal clinical biomarkers significantly linked to CRLM,including gamma-glutamyl transferase levels,blood chloride concentration,activated partial thromboplastin time,N stage,and vascular invasion.The model's receiver operating characteristic curve area under the curve exceeded 0.7 for both the training and validation groups with moderate-to-good predictive accuracy.Furthermore,DCA validated the nomogram's effectiveness for OS prediction.Kaplan-Meier risk stratification demonstrated markedly improved OS among patients classified as low-risk compared to those categorized as high-risk(P<0.001),highlighting its clinical utility for risk assessment and treatment guidance.CONCLUSION The nomogram prediction model constructed in this study has good predictive value and can effectively assess the survival rate of patients with CRLM.
基金the financial support received from the Open Project of National Center of Technology Innovation for Dairy(No.2024-KFKT-009)the Key R&D Program of Zhejiang Provincial Administration for Market Regulation(No.ZD2024001).
文摘Food allergies are abnormal immune responses triggered by specific foods,affecting the quality of life of millions of people worldwide.In recent years,the prevalence of food allergies has increased significantly,especially in Westernized countries,prompting the scientific community to explore the complex mechanisms behind them.Dietary patterns and specific dietary components are important factors related to the occurrence,development,and prevention of food allergies.Studies have shown that the Mediterranean diet,which is high in fiber,rich in antioxidants,and healthy fats,shows potential protective effects by promoting the balance of intestinal flora,maintaining the intestinal barrier,and regulating immunity.In contrast,a high-fat,high-sugar,low-fiber Western diet is associated with an increased risk of allergies.Key dietary components such as omega-3 fatty acids,dietary fiber,vitamins A,D,and E,and bioactive substances such as quercetin and curcumin can regulate immune tolerance through multiple pathways,including epigenetic regulation and affecting mitochondrial function.However,advanced glycation end products(AGEs),emulsifiers,artificial sweeteners produced by food processing,and pesticide residues(such as glyphosate)may damage the intestinal barrier,disrupt the flora,and increase the risk of allergies.This review explored the risk and protective factors for food allergies from a dietary perspective,thus benefiting the progress of intervention and therapy of food allergy.
文摘Esophageal cancer is an aggressive malignancy often diagnosed at advanced stages,with esophageal squamous cell carcinoma being the predominant subtype worldwide.Standard first-line chemotherapy provides limited survival benefits,with a median overall survival of less than 1 year.Recent advancements in immunotherapy,particularly immune checkpoint inhibitors(ICIs),have trans-formed the treatment landscape,improving overall survival and progression-free survival.However,response rates remain variable,with programmed death ligand 1(PD-L1)expression being the primary predictive biomarker.The variability in PD-L1 testing methods and immune microenvironment alterations after prior treatments complicate patient selection for ICIs.Several phase 3 trials,including KEYNOTE-590 and CheckMate 648,have demonstrated the efficacy of ICIs combined with chemotherapy,particularly in patients positive for PD-L1.Despite these advances,long-term survival remains low,emphasizing the need for better biomarkers and novel therapeutic strategies.This review explored current first-line treatment options for esophageal squamous cell carcinoma,challenges in biomarker-based patient selection,and emerging therapeutic approaches.
文摘Background:Developing a granulomatous liver injury preclinical model may pave the way to understanding hepatic-TB(tuberculosis)and autoimmune granulomatous liver diseases.Antitubercular(ATT)and other drugs'metabolism in the presence of a specific type of liver injury is not well understood.The present study aimed to establish a preclinical model of granulomatous hepatitis by using the BCG(Bacillus CalmetteGuérin)vaccine,further studying it in the presence of ATT dosing,and analyze the pharmacokinetics of isoniazid,rifampicin,and their respective primary metabolites.Methods:We used 56 rats in seven equal groups.Group I functioned as a normal control(NC)receiving normal saline only.Groups II-IV received intravenous injections of low-,medium-,and high-dose BCG vaccine daily for 21 days.Groups V,VI,and VII received isoniazid(H)alone,rifampicin(R)alone,and isoniazid+rifampicin(HR)for a subsequent 15 days in addition to high dose BCG for the first 21 days,respectively.Liver function tests(LFT)were monitored on days 0,21,28,and 36.Rats were sacrificed later for oxidative stress and histopathological examination.Results:The study observed BCG dose-specific LFT derangements in groups II-IV compared to group I on day 21(p<0.05).Isoniazid,rifampicin,and combination intervention groups demonstrated normalization of the BCG-led LFT changes.Histology and oxidative stress parameters confirmed model development and biochemical changes.Isoniazid area under the curve(AUC)showed a reduction of 16.9%in BCG+HR group in comparison to the BCG+H group(p=0.01).Des-acetyl-rifampicin AUC and maximum-concentration value demonstrated a significant rise in BCG+HR group in comparison to the BCG+R group(p=0.001).Conclusion:A novel preclinical model of granulomatous liver injury was developed using the BCG vaccine strain and validated with ATT response.
基金support provided by the Department of Science and Technology,Science and Engineering Research Board(DST-SERB),the Anusandhan National Research Foundation(ANRF),State University Research Excellence(SERB-SURE),Ministry of Science and Technology,Govt.of India(SUR/2022/001353).
文摘Cancer is a global health problem and one of the leading causes of mortality.Immune checkpoint inhibitors have revolutionized the field of oncology,emerging as a powerful treatment strategy.A key pathway that has garnered considerable attention is programmed cell death-1(PD-1)/programmed cell death-ligand 1(PD-L1).The interaction between PD-L1 expressed on tumor cells and PD-1 reduces the innate immune response and thus compromises the capability of the body’s immune system.Furthermore,it controls the phenotype and functionality of innate and adaptive immune components.A range of monoclonal antibodies,including avelumab,atezolizumab,camrelizumab,dostarlimab,durvalumab,sinitilimab,toripalimab,and zimberelimab,have been developed for targeting the interaction between PD-1 and PD-L1.These agents can induce a broad spectrum of autoimmune-like complications that may affect any organ system.Recent studies have focused on the effect of various natural compounds that inhibit immune checkpoints.This could contribute to the existing arsenal of anticancer drugs.Several bioactive natural agents have been shown to affect the PD-1/PD-L1 signaling axis,promoting tumor cell apoptosis,influencing cell proliferation,and eventually leading to tumor cell death and inhibiting cancer progression.However,there is a substantial knowledge gap regarding the role of different natural compounds targeting PD-1 in the context of cancer.Hence,this review aims to provide a common connection between PD-1/PD-L1 blockade and the anticancer effects of distinct natural molecules.Moreover,the primary focus will be on the underlying mechanism of action as well as the clinical efficacy of bioactive molecules.Current challenges along with the scope of future research directions targeting PD-1/PD-L1 interactions through natural substances are also discussed.
