Alzheimer’s disease(AD)and other tauopathies are characterized by the accumulation of misfolded tau protein,which forms toxic oligomers that contribute to synaptic dysfunction and neuronal loss.Here,we briefly discus...Alzheimer’s disease(AD)and other tauopathies are characterized by the accumulation of misfolded tau protein,which forms toxic oligomers that contribute to synaptic dysfunction and neuronal loss.Here,we briefly discuss recent findings indicating that the cellular prion protein(PrPC)plays a critical role in mediating the synaptotoxic effects of tau oligomers(TauOs),offering new insights into disease pathogenesis and potential therapeutic strategies.展开更多
PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals.PrPSccan adopt different patho...PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals.PrPSccan adopt different pathogenic conformations(prion strains),which can be resistant to potential drugs,or acquire drug resistance,posing challenges for the development of effective therapies.Since PrPCis the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity,it represents an attractive therapeutic target fo r prion diseases.In this minireview,we briefly outline the approaches to target PrPCand discuss our recent identification of Zn(Ⅱ)-Bn PyP,a PrPC-targeting porphyrin with an unprecedented bimodal mechanism of action.We argue that in-depth understanding of the molecular mechanism by which Zn(Ⅱ)-Bn PyP targets PrPCmay lead toward the development of a new class of dual mechanism anti-prion compounds.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
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
Pamiparib is a potent and selective oral poly(adenosine diphosphate(ADP)-ribose)-polymerase(PARP)1/2inhibitor(PARPi).Pamiparib has good bioavailability and shows greater cytotoxic potency and similar DNA-trapping capa...Pamiparib is a potent and selective oral poly(adenosine diphosphate(ADP)-ribose)-polymerase(PARP)1/2inhibitor(PARPi).Pamiparib has good bioavailability and shows greater cytotoxic potency and similar DNA-trapping capacity compared to olaparib.It is not affected by adenosine triphosphate(ATP)-binding cassette transporters.展开更多
Background Mitophagy is an essential cellular autophagic process which maintains mitochondrial homeostasis,but its role in high fat diet(HFD)-induced lipid accumulation is unclear in the yellow catfish.Thus,this study...Background Mitophagy is an essential cellular autophagic process which maintains mitochondrial homeostasis,but its role in high fat diet(HFD)-induced lipid accumulation is unclear in the yellow catfish.Thus,this study aimed to elucidate mechanism of mitochondria mediating HFD-induced hepatic fat accumulation.Results In the present study,yellow catfish were fed three diets with dietary fat at 6.31%(low fat;LFD,control),12.03%(middle fat;MFD)and 15.32%(high fat;HFD),respectively,for 8 weeks.High dietary fat addition raised hepatic lipid accumulation,and declined mRNA and protein levels of Parkin-dependent mitophagy,down-regulated the Parkin protein expression and the estrogen-related receptor alpha(Errα)ubiquitination,and induced Errαprotein levels;fatty acid(FA)incubation reduced Parkin-dependent mitophagy,inhibited Errαubiquitination and increased Errαprotein expression,and raised TG accumulation.Furthermore,yellow catfish hepatocytes were isolated and cultured.Nicotinamide mononucleotide,N-acetyl-L-cysteine,Parkin and errαsiRNA knockdown were used under FA incubation,respectively.Parkin downregulation mediated FA incubation-induced TG accumulation and mitoautophagic inhibition;Parkin ubiquitinated Errα,and K63 was an important ubiquitination site for deubiquitinating Parkin activity;Errαtargets fas,acca and pparγgenes,whose activation contributed to FA-induced lipogenesis and lipid accumulation.Thus,high fat diet(HFD)and FA incubation inhibited Parkin activity,suppressed mitophagy and activated Errαpathway,and induced hepatic lipogenic metabolism and lipotoxicity.Conclusions Overall,our study provided new targets against HFD-induced hepatic lipid accumulation and nonalcoholic fatty liver disease in the vertebrates.展开更多
Objective The aim of this study was to investigate the value of the 8th American Joint Committee on Cancer(AJCC)anatomic and prognostic stage groups for penile cancer patients and explore whether there is room for imp...Objective The aim of this study was to investigate the value of the 8th American Joint Committee on Cancer(AJCC)anatomic and prognostic stage groups for penile cancer patients and explore whether there is room for improvement.Methods The clinical and histopathologic data from 16 centers between January 2000 and December 2021 were assessed according to the 8th AJCC anatomic and prognostic stage groups.Kaplan–Meier plots were used to estimate the disease-specific survival(DSS)of the patients.The accuracy of the staging systems was investigated using the Harrell's concordance index(C-index).Results According to the 8th AJCC anatomic and prognostic stage groups,the 5-year DSS rates for patients with stages 0is/a,I,IIA,IIB,IIIA,IIIB,and IV disease were 100%,99%,86%,81%,66%,34%,and 23%,respectively(p_(0is/a–I)=0.8,p_(I–IIA)<0.001,p_(IIA–IIB)=0.5,p_(IIB–IIIA)<0.001,p_(IIIA–IIIB)<0.001,p_(IIIB–IV)=0.004,and p_(Total)<0.001).According to the modified model 1 system,the 5-year DSS rates without survivorship overlap for patients with stages 0is/a,I,II,IIIA,IIIB,and IV disease were 100%,99%,88%,66%,34%,and 23%,respectively(p_(0is/a–I)=0.8,p_(I–II)<0.001,p_(II–IIIA)=0.002,p_(IIIA–IIIB)<0.001,p_(IIIB–IV)=0.004,and p_(Total)<0.001).Similarly,according to the modified model 2 system,the 5-year DSS rates without survivorship overlap for patients with stages 0is/a,I,II,IIIA,IIIB,and IV disease were 100%,99%,86%,66%,34%,and 23%,respectively(p_(0is/a–I)=0.8,p_(I–II)<0.001,p_(II–IIIA)=0.008,p_(IIIA–IIIB)<0.001,p_(IIIB–IV)=0.004,and p_(Total)<0.001).The C-index scores of the simple modified staging systems were not inferior to those of the AJCC anatomic and prognostic stage groups.These results were confirmed by the bootstrap internal validation.Conclusion There is still room for improvement about the 8th AJCC anatomic and prognostic stage groups.The improved models,which are more concise and convenient,have similar prediction accuracy.展开更多
Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer death with an overall survival of 5% at five years. The development of PDAC is characteristically associated to the accumulation of distinctive gen...Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer death with an overall survival of 5% at five years. The development of PDAC is characteristically associated to the accumulation of distinctive genetic mutations and is preceded by the exposure to several risk factors. Epidemiology has demonstrated that PDAC risk factors may be non-modifiable risks (sex, age, presence of genetic mutations, ethnicity) and modifiable and co-morbidity factors related to the specific habits and lifestyle. Recently it has become evident that obesity and diabetes are two important modifiable risk factors for PDAC. Obesity and diabetes are complex systemic and intertwined diseases and, over the years, experimental evidence indicate that insulin-resistance, alteration of adipokines, especially leptin and adiponectin, oxidative stress and inflammation may play a role in PDAC. Peroxisome proliferator activated receptor-γ (PPARγ) is a nuclear receptor transcription factor that is implicated in the regulation of metabolism, differentiation and inflammation. PPARγ is a key regulator of adipocytes differentiation, regulates insulin and adipokines production and secretion, may modulate inflammation, and it is implicated in PDAC. PPARγ agonists are used in the treatment of diabetes and oxidative stress-associated diseases and have been evaluated for the treatment of PDAC. PPARγ is at the cross-road of diabetes, obesity, and PDAC and it is an interesting target to pharmacologically prevent PDAC in obese and diabetic patients.展开更多
Islet cell transplantation has therapeutic potential to treat type 1 diabetes,which is characterized by autoimmune destruction of insulin-producing pancreatic isletβcells.It represents a minimal invasive approach for...Islet cell transplantation has therapeutic potential to treat type 1 diabetes,which is characterized by autoimmune destruction of insulin-producing pancreatic isletβcells.It represents a minimal invasive approach forβcell replacement,but long-term blood control is still largely unachievable.This phenomenon can be attributed to the lack of islet vasculature and hypoxic environment in the immediate post-transplantation period that contributes to the acute loss of islets by ischemia.Moreover,graft failures continue to occur because of immunological rejection,despite the use of potent immunosuppressive agents.Mesenchymal stem cells(MSCs)have the potential to enhance islet transplantation by suppressing inflammatory damage and immune mediated rejection.In this review we discuss the impact of MSCs on islet transplantation and focus on the potential role of MSCs in protecting islet grafts from early graft failure and from autoimmune attack.展开更多
Hepatocellular carcinoma(HCC) is the most common primary tumor of the liver. Its relationship to chronic liver diseases, in particular cirrhosis, develops on a background of viral hepatitis, excessive alcohol intake o...Hepatocellular carcinoma(HCC) is the most common primary tumor of the liver. Its relationship to chronic liver diseases, in particular cirrhosis, develops on a background of viral hepatitis, excessive alcohol intake or metabolic steatohepatitis, leads to a high incidence and prevalence of this neoplasia worldwide. Despite the spread of HCC, its treatment it's still a hard challenge, due to high rate of late diagnosis and to lack of therapeutic options for advanced disease. In fact radical surgery and liver transplantation, the most radical therapeutic approaches, are indicated only in case of early diagnosis. Even local therapies, such as transarterial chemoembolization, find limited indications, leading to an important problem regarding treatment of advanced disease. In this situation, until terminal HCC occurs, systemic therapy is the only possible approach, with sorafenib as the only standard treatment available. Anyway, the efficacy of this drug is limited and many efforts are necessary to understand who could benefit more with this treatment. Therefore, other molecules for a targeted therapy were evaluated, but only regorafenib showed promising results. Beside molecular target therapy, also cytotoxic drugs, in particular oxaliplatinand gemcitabine-based regimens, and immune-checkpoint inhibitors were tested with interesting results. The future of the treatment of this neoplasia is linked to our ability to understand its mechanisms of resistance and to find novel therapeutic targets, with the objective to purpose individualized approaches to patients affected by advanced HCC.展开更多
Colorectal cancer (CRC) remains one of the most common malignancies in the world. Although surgical resection combined with adjuvant therapy is effective at the early stages of the disease, resistance to conventional ...Colorectal cancer (CRC) remains one of the most common malignancies in the world. Although surgical resection combined with adjuvant therapy is effective at the early stages of the disease, resistance to conventional therapies is frequently observed in advanced stages, where treatments become ineffective. Resistance to cisplatin, irinotecan and 5-fluorouracil chemotherapy has been shown to involve mitogen-activated protein kinase (MAPK) signaling and recent studies identified p38α MAPK as a mediator of resistance to various agents in CRC patients. Studies published in the last decade showed a dual role for the p38α pathway in mammals. Its role as a negative regulator of proliferation has been reported in both normal (including cardiomyocytes, hepatocytes, fibroblasts, hematopoietic and lung cells) and cancer cells (colon, prostate, breast, lung tumor cells). This function is mediated by the negative regulation of cell cycle progression and the transduction of some apoptotic stimuli. However, despite its anti-proliferative and tumor suppressor activity in some tissues, the p38α pathway may also acquire an oncogenic role involving cancer related-processes such as cell metabolism, invasion, inflammation and angiogenesis. In this review, we summarize current knowledge about the predominant role of the p38α MAPK pathway in CRC development and chemoresistance. In our view, this might help establish the therapeutic potential of the targeted manipulation of this pathway in clinical settings.展开更多
The liver is the major drug-metabolizing and drug-detoxifying organ.Many drugs can cause liver damage through various mechanisms;however,the liver response to injury includes a relatively narrow spectrum of alteration...The liver is the major drug-metabolizing and drug-detoxifying organ.Many drugs can cause liver damage through various mechanisms;however,the liver response to injury includes a relatively narrow spectrum of alterations that,regardless of the cause,are represented by phlogosis,oxidative stress and necrosis.The combination of these alterations mainly results in three radiological findings:vascular alterations,structural changes and metabolic function reduction.Chemotherapy has changed in recent decades in terms of the drugs,protocols and duration,allowing patients a longer life expectancy.As a consequence,we are currently observing an increase in chemotherapy-associated liver injury patterns once considered unusual.Recognizing this form of damage in an early stage is crucial for reconsidering the therapy regimen and thus avoiding severe complications.In this frontier article,we analyze the role of imaging in detecting some of these pathological patterns,such as pseudocirrhosis,“yellow liver”due to chemotherapy-associated steatosis-steatohepatitis,and“blue liver”,including sinusoidal obstruction syndrome,veno-occlusive disease and peliosis.展开更多
Our previous studies revealed that etomidate, a non-barbiturate intravenous anesthetic agent, has protective effects on retinal ganglion cells within 7 days after optic nerve transection. Whether this process is relat...Our previous studies revealed that etomidate, a non-barbiturate intravenous anesthetic agent, has protective effects on retinal ganglion cells within 7 days after optic nerve transection. Whether this process is related to anti-oxidative stress is not clear. To reveal its mechanism, we established the optic nerve transection injury model by transecting 1 mm behind the left eyeball of adult male Sprague-Dawley rats. The rats received an intraperitoneal injection of etomidate(4 mg/kg) once per day for 7 days. The results showed that etomidate significantly enhanced the number of retinal ganglion cells retrogradely labeled with Fluorogold at 7 days after optic nerve transection. Etomidate also significantly reduced the levels of nitric oxide and malonaldehyde in the retina and increased the level of glutathione at 12 hours after optic nerve transection. Thus, etomidate can protect retinal ganglion cells after optic nerve transection in adult rats by activating an anti-oxidative stress response. The study was approved by the Animal Ethics Committee at Air Force Medical University, China(approval No. 20180305) on March 5, 2018.展开更多
Eleven grape cultivars were analysed to explore the variety differences of fresh grape phenolic profiles.The results showed that free phenolics were predominant in grape skins and pulps,and showed the higher antioxida...Eleven grape cultivars were analysed to explore the variety differences of fresh grape phenolic profiles.The results showed that free phenolics were predominant in grape skins and pulps,and showed the higher antioxidant activities than bound.In 11 cultivars,Muscat Kyoho extracts had the highest total phenolic content in skins(10.525 mg GAE g^(–1)FW)and pulps(1.134 mg GAE g^(–1)FW),and exhibited the highest DPPH radical scavening capacity(EC_(50)=11.7μg mL^(–1))and oxygen radical absorbance capacity(ORAC)value(190.57μmol TE g^(–1)FW)of free phenolic in skin.In addition,the most abundant phenolics in grape skins were found to be flavonoids such as kaempferol in Kyoho skin(541.2μg g^(–1)FW),rutin,catechin and epicatechin in Muscat Kyoho skin(262.3,86.3 and 70.0μg g^(–1)FW,respectively).Furthermore,the principal component analysis showed a strong difference of phenolic profiles with the cultivars,existing forms and distributions.Pearson correlation coefficient analysis showed a significant linear correlation between total phenolic content and antioxidant activity(P<0.05).Therefore,both skins and pulps were rich sources of bioactive phenolic compounds,and Muscat Kyoho was the ideal source among all samples.展开更多
AIM: To prospectively assess the impact of time of endoscopy and endoscopist's experience on the outcome of non-variceal acute upper gastrointestinal (GI) bleeding patients in a large teaching hospital.METHODS: Al...AIM: To prospectively assess the impact of time of endoscopy and endoscopist's experience on the outcome of non-variceal acute upper gastrointestinal (GI) bleeding patients in a large teaching hospital.METHODS: All patients admitted for non-variceal acute upper GI bleeding for over a 2-year period were potentially eligible for this study. They were managed by a team of seven endoscopists on 24-h call whose experience was categorized into two levels (high and low) according to the number of endoscopic hemostatic procedures undertaken before the study. Endoscopic treatment was standardized according to Forrest classification of lesions as well as the subsequent medical therapy. Time of endoscopy was subdivided into two time periods: routine (8 a.m.-5 p.m.) and on-call (5 p.m.-8 a.m.). For each category of experience and time periods rebleeding rate, transfusion requirement, need for surgery, length of hospital stay and mortality we compared. Multivariate analysis was used to discriminate the impact of different variables on the outcomes that were considered.RESULTS: Study population consisted of 272 patients (mean age 67.3 years) with endoscopic stigmata of hemorrhage. The patients were equally distributed among the endoscopists, whereas only 19% of procedures were done out of working hours. Rockall score and Forrest classification at admission did not differ between time periods and degree of experience.Univariate analysis showed that higher endoscopist's experience was associated with significant reduction in rebleeding rate (14% vs 37%), transfusion requirements (1.8±0.6 vs 3.0±1.7 units) as well as surgery (4% vs 10%), but not associated with the length of hospital stay nor mortality. By contrast, outcomes did not significantly differ between the two time periods of endoscopy.On multivariate analysis, endoscopist's experience was independently associated with rebleeding rate and transfusion requirements. Odds ratios for low experienced endoscopist were 4.47 for rebleeding and 6.90 for need of transfusion after the endoscopy.CONCLUSION: Endoscopist's experience is an important independent prognostic factor for non-variceal acute upper GI bleeding. Urgent endoscopy should be undertaken preferentially by a skilled endoscopist as less expert staff tends to underestimate some risk lesions with a negative influence on hemostasis.展开更多
基金supported by the Italian Ministry of Health grant RF-2021-12372337(to GF and CB).
文摘Alzheimer’s disease(AD)and other tauopathies are characterized by the accumulation of misfolded tau protein,which forms toxic oligomers that contribute to synaptic dysfunction and neuronal loss.Here,we briefly discuss recent findings indicating that the cellular prion protein(PrPC)plays a critical role in mediating the synaptotoxic effects of tau oligomers(TauOs),offering new insights into disease pathogenesis and potential therapeutic strategies.
基金supported by Telethon Italy award GGP15225(to RC and GM)Italian Ministry of Health award RF-2016-02362950(to RC and CZ)+1 种基金the CJD Foundation USA(to RC)the Associazione Italiana Encefalopatie da Prioni(AIEnP)(to RC).
文摘PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals.PrPSccan adopt different pathogenic conformations(prion strains),which can be resistant to potential drugs,or acquire drug resistance,posing challenges for the development of effective therapies.Since PrPCis the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity,it represents an attractive therapeutic target fo r prion diseases.In this minireview,we briefly outline the approaches to target PrPCand discuss our recent identification of Zn(Ⅱ)-Bn PyP,a PrPC-targeting porphyrin with an unprecedented bimodal mechanism of action.We argue that in-depth understanding of the molecular mechanism by which Zn(Ⅱ)-Bn PyP targets PrPCmay lead toward the development of a new class of dual mechanism anti-prion compounds.
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 in part by funding from BeiGene,Ltd.,USA(Grant No.:KPR081)with additional support from the Alessandra Bono Foundation,Italy.
文摘Pamiparib is a potent and selective oral poly(adenosine diphosphate(ADP)-ribose)-polymerase(PARP)1/2inhibitor(PARPi).Pamiparib has good bioavailability and shows greater cytotoxic potency and similar DNA-trapping capacity compared to olaparib.It is not affected by adenosine triphosphate(ATP)-binding cassette transporters.
基金funded by National Key R&D Program of China(2024YFD2402000)。
文摘Background Mitophagy is an essential cellular autophagic process which maintains mitochondrial homeostasis,but its role in high fat diet(HFD)-induced lipid accumulation is unclear in the yellow catfish.Thus,this study aimed to elucidate mechanism of mitochondria mediating HFD-induced hepatic fat accumulation.Results In the present study,yellow catfish were fed three diets with dietary fat at 6.31%(low fat;LFD,control),12.03%(middle fat;MFD)and 15.32%(high fat;HFD),respectively,for 8 weeks.High dietary fat addition raised hepatic lipid accumulation,and declined mRNA and protein levels of Parkin-dependent mitophagy,down-regulated the Parkin protein expression and the estrogen-related receptor alpha(Errα)ubiquitination,and induced Errαprotein levels;fatty acid(FA)incubation reduced Parkin-dependent mitophagy,inhibited Errαubiquitination and increased Errαprotein expression,and raised TG accumulation.Furthermore,yellow catfish hepatocytes were isolated and cultured.Nicotinamide mononucleotide,N-acetyl-L-cysteine,Parkin and errαsiRNA knockdown were used under FA incubation,respectively.Parkin downregulation mediated FA incubation-induced TG accumulation and mitoautophagic inhibition;Parkin ubiquitinated Errα,and K63 was an important ubiquitination site for deubiquitinating Parkin activity;Errαtargets fas,acca and pparγgenes,whose activation contributed to FA-induced lipogenesis and lipid accumulation.Thus,high fat diet(HFD)and FA incubation inhibited Parkin activity,suppressed mitophagy and activated Errαpathway,and induced hepatic lipogenic metabolism and lipotoxicity.Conclusions Overall,our study provided new targets against HFD-induced hepatic lipid accumulation and nonalcoholic fatty liver disease in the vertebrates.
基金supported by the Guangdong Province Nature Foundation of China Project (No. 2022A1515012200 to Li Z)Shenzhen Science and Technology Program (No. RCYX20221008093032008 to Li Z)Shenzhen People's Hospital Clinician Scientist Training Program (No. SYWGSJCYJ202405 to Li Z).
文摘Objective The aim of this study was to investigate the value of the 8th American Joint Committee on Cancer(AJCC)anatomic and prognostic stage groups for penile cancer patients and explore whether there is room for improvement.Methods The clinical and histopathologic data from 16 centers between January 2000 and December 2021 were assessed according to the 8th AJCC anatomic and prognostic stage groups.Kaplan–Meier plots were used to estimate the disease-specific survival(DSS)of the patients.The accuracy of the staging systems was investigated using the Harrell's concordance index(C-index).Results According to the 8th AJCC anatomic and prognostic stage groups,the 5-year DSS rates for patients with stages 0is/a,I,IIA,IIB,IIIA,IIIB,and IV disease were 100%,99%,86%,81%,66%,34%,and 23%,respectively(p_(0is/a–I)=0.8,p_(I–IIA)<0.001,p_(IIA–IIB)=0.5,p_(IIB–IIIA)<0.001,p_(IIIA–IIIB)<0.001,p_(IIIB–IV)=0.004,and p_(Total)<0.001).According to the modified model 1 system,the 5-year DSS rates without survivorship overlap for patients with stages 0is/a,I,II,IIIA,IIIB,and IV disease were 100%,99%,88%,66%,34%,and 23%,respectively(p_(0is/a–I)=0.8,p_(I–II)<0.001,p_(II–IIIA)=0.002,p_(IIIA–IIIB)<0.001,p_(IIIB–IV)=0.004,and p_(Total)<0.001).Similarly,according to the modified model 2 system,the 5-year DSS rates without survivorship overlap for patients with stages 0is/a,I,II,IIIA,IIIB,and IV disease were 100%,99%,86%,66%,34%,and 23%,respectively(p_(0is/a–I)=0.8,p_(I–II)<0.001,p_(II–IIIA)=0.008,p_(IIIA–IIIB)<0.001,p_(IIIB–IV)=0.004,and p_(Total)<0.001).The C-index scores of the simple modified staging systems were not inferior to those of the AJCC anatomic and prognostic stage groups.These results were confirmed by the bootstrap internal validation.Conclusion There is still room for improvement about the 8th AJCC anatomic and prognostic stage groups.The improved models,which are more concise and convenient,have similar prediction accuracy.
基金Supported by Fondo per gli Investimenti della Ricerca di BaseNo.RBAP10MY35_002+1 种基金Ente Cassa di Risparmio di Firenzeand Fior Gen ONLUS to Galli A
文摘Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer death with an overall survival of 5% at five years. The development of PDAC is characteristically associated to the accumulation of distinctive genetic mutations and is preceded by the exposure to several risk factors. Epidemiology has demonstrated that PDAC risk factors may be non-modifiable risks (sex, age, presence of genetic mutations, ethnicity) and modifiable and co-morbidity factors related to the specific habits and lifestyle. Recently it has become evident that obesity and diabetes are two important modifiable risk factors for PDAC. Obesity and diabetes are complex systemic and intertwined diseases and, over the years, experimental evidence indicate that insulin-resistance, alteration of adipokines, especially leptin and adiponectin, oxidative stress and inflammation may play a role in PDAC. Peroxisome proliferator activated receptor-γ (PPARγ) is a nuclear receptor transcription factor that is implicated in the regulation of metabolism, differentiation and inflammation. PPARγ is a key regulator of adipocytes differentiation, regulates insulin and adipokines production and secretion, may modulate inflammation, and it is implicated in PDAC. PPARγ agonists are used in the treatment of diabetes and oxidative stress-associated diseases and have been evaluated for the treatment of PDAC. PPARγ is at the cross-road of diabetes, obesity, and PDAC and it is an interesting target to pharmacologically prevent PDAC in obese and diabetic patients.
文摘Islet cell transplantation has therapeutic potential to treat type 1 diabetes,which is characterized by autoimmune destruction of insulin-producing pancreatic isletβcells.It represents a minimal invasive approach forβcell replacement,but long-term blood control is still largely unachievable.This phenomenon can be attributed to the lack of islet vasculature and hypoxic environment in the immediate post-transplantation period that contributes to the acute loss of islets by ischemia.Moreover,graft failures continue to occur because of immunological rejection,despite the use of potent immunosuppressive agents.Mesenchymal stem cells(MSCs)have the potential to enhance islet transplantation by suppressing inflammatory damage and immune mediated rejection.In this review we discuss the impact of MSCs on islet transplantation and focus on the potential role of MSCs in protecting islet grafts from early graft failure and from autoimmune attack.
文摘Hepatocellular carcinoma(HCC) is the most common primary tumor of the liver. Its relationship to chronic liver diseases, in particular cirrhosis, develops on a background of viral hepatitis, excessive alcohol intake or metabolic steatohepatitis, leads to a high incidence and prevalence of this neoplasia worldwide. Despite the spread of HCC, its treatment it's still a hard challenge, due to high rate of late diagnosis and to lack of therapeutic options for advanced disease. In fact radical surgery and liver transplantation, the most radical therapeutic approaches, are indicated only in case of early diagnosis. Even local therapies, such as transarterial chemoembolization, find limited indications, leading to an important problem regarding treatment of advanced disease. In this situation, until terminal HCC occurs, systemic therapy is the only possible approach, with sorafenib as the only standard treatment available. Anyway, the efficacy of this drug is limited and many efforts are necessary to understand who could benefit more with this treatment. Therefore, other molecules for a targeted therapy were evaluated, but only regorafenib showed promising results. Beside molecular target therapy, also cytotoxic drugs, in particular oxaliplatinand gemcitabine-based regimens, and immune-checkpoint inhibitors were tested with interesting results. The future of the treatment of this neoplasia is linked to our ability to understand its mechanisms of resistance and to find novel therapeutic targets, with the objective to purpose individualized approaches to patients affected by advanced HCC.
基金Supported by Italian Association for Cancer Research(AIRC)fellowship(to Grossi V)Italian Foundation for Cancer Research(FIRC)fellowships(to Peserico A and Tezil T)+1 种基金Investigator Grant 2010 No.IG10177 to Simone C from the Italian Association for Cancer Research(AIRC)FIRB"Futuro in Ricerca"RBFR12VP3Q_003(to Simone C)from the Italian MIUR
文摘Colorectal cancer (CRC) remains one of the most common malignancies in the world. Although surgical resection combined with adjuvant therapy is effective at the early stages of the disease, resistance to conventional therapies is frequently observed in advanced stages, where treatments become ineffective. Resistance to cisplatin, irinotecan and 5-fluorouracil chemotherapy has been shown to involve mitogen-activated protein kinase (MAPK) signaling and recent studies identified p38α MAPK as a mediator of resistance to various agents in CRC patients. Studies published in the last decade showed a dual role for the p38α pathway in mammals. Its role as a negative regulator of proliferation has been reported in both normal (including cardiomyocytes, hepatocytes, fibroblasts, hematopoietic and lung cells) and cancer cells (colon, prostate, breast, lung tumor cells). This function is mediated by the negative regulation of cell cycle progression and the transduction of some apoptotic stimuli. However, despite its anti-proliferative and tumor suppressor activity in some tissues, the p38α pathway may also acquire an oncogenic role involving cancer related-processes such as cell metabolism, invasion, inflammation and angiogenesis. In this review, we summarize current knowledge about the predominant role of the p38α MAPK pathway in CRC development and chemoresistance. In our view, this might help establish the therapeutic potential of the targeted manipulation of this pathway in clinical settings.
文摘The liver is the major drug-metabolizing and drug-detoxifying organ.Many drugs can cause liver damage through various mechanisms;however,the liver response to injury includes a relatively narrow spectrum of alterations that,regardless of the cause,are represented by phlogosis,oxidative stress and necrosis.The combination of these alterations mainly results in three radiological findings:vascular alterations,structural changes and metabolic function reduction.Chemotherapy has changed in recent decades in terms of the drugs,protocols and duration,allowing patients a longer life expectancy.As a consequence,we are currently observing an increase in chemotherapy-associated liver injury patterns once considered unusual.Recognizing this form of damage in an early stage is crucial for reconsidering the therapy regimen and thus avoiding severe complications.In this frontier article,we analyze the role of imaging in detecting some of these pathological patterns,such as pseudocirrhosis,“yellow liver”due to chemotherapy-associated steatosis-steatohepatitis,and“blue liver”,including sinusoidal obstruction syndrome,veno-occlusive disease and peliosis.
基金supported by the National Natural Science Foundation of China,No.81670846(to MMW)and 81470631(to SWY)the Natural Science Foundation of Shaanxi Province of China,No.2016SF-171(to MMW)the National Basic Research Program of China,No.2014CB542202(to SWY)
文摘Our previous studies revealed that etomidate, a non-barbiturate intravenous anesthetic agent, has protective effects on retinal ganglion cells within 7 days after optic nerve transection. Whether this process is related to anti-oxidative stress is not clear. To reveal its mechanism, we established the optic nerve transection injury model by transecting 1 mm behind the left eyeball of adult male Sprague-Dawley rats. The rats received an intraperitoneal injection of etomidate(4 mg/kg) once per day for 7 days. The results showed that etomidate significantly enhanced the number of retinal ganglion cells retrogradely labeled with Fluorogold at 7 days after optic nerve transection. Etomidate also significantly reduced the levels of nitric oxide and malonaldehyde in the retina and increased the level of glutathione at 12 hours after optic nerve transection. Thus, etomidate can protect retinal ganglion cells after optic nerve transection in adult rats by activating an anti-oxidative stress response. The study was approved by the Animal Ethics Committee at Air Force Medical University, China(approval No. 20180305) on March 5, 2018.
基金supported by the National Key R&D Program of China(2016YFD0400203)the National Natural Science Foundation of China(31471576)
文摘Eleven grape cultivars were analysed to explore the variety differences of fresh grape phenolic profiles.The results showed that free phenolics were predominant in grape skins and pulps,and showed the higher antioxidant activities than bound.In 11 cultivars,Muscat Kyoho extracts had the highest total phenolic content in skins(10.525 mg GAE g^(–1)FW)and pulps(1.134 mg GAE g^(–1)FW),and exhibited the highest DPPH radical scavening capacity(EC_(50)=11.7μg mL^(–1))and oxygen radical absorbance capacity(ORAC)value(190.57μmol TE g^(–1)FW)of free phenolic in skin.In addition,the most abundant phenolics in grape skins were found to be flavonoids such as kaempferol in Kyoho skin(541.2μg g^(–1)FW),rutin,catechin and epicatechin in Muscat Kyoho skin(262.3,86.3 and 70.0μg g^(–1)FW,respectively).Furthermore,the principal component analysis showed a strong difference of phenolic profiles with the cultivars,existing forms and distributions.Pearson correlation coefficient analysis showed a significant linear correlation between total phenolic content and antioxidant activity(P<0.05).Therefore,both skins and pulps were rich sources of bioactive phenolic compounds,and Muscat Kyoho was the ideal source among all samples.
文摘AIM: To prospectively assess the impact of time of endoscopy and endoscopist's experience on the outcome of non-variceal acute upper gastrointestinal (GI) bleeding patients in a large teaching hospital.METHODS: All patients admitted for non-variceal acute upper GI bleeding for over a 2-year period were potentially eligible for this study. They were managed by a team of seven endoscopists on 24-h call whose experience was categorized into two levels (high and low) according to the number of endoscopic hemostatic procedures undertaken before the study. Endoscopic treatment was standardized according to Forrest classification of lesions as well as the subsequent medical therapy. Time of endoscopy was subdivided into two time periods: routine (8 a.m.-5 p.m.) and on-call (5 p.m.-8 a.m.). For each category of experience and time periods rebleeding rate, transfusion requirement, need for surgery, length of hospital stay and mortality we compared. Multivariate analysis was used to discriminate the impact of different variables on the outcomes that were considered.RESULTS: Study population consisted of 272 patients (mean age 67.3 years) with endoscopic stigmata of hemorrhage. The patients were equally distributed among the endoscopists, whereas only 19% of procedures were done out of working hours. Rockall score and Forrest classification at admission did not differ between time periods and degree of experience.Univariate analysis showed that higher endoscopist's experience was associated with significant reduction in rebleeding rate (14% vs 37%), transfusion requirements (1.8±0.6 vs 3.0±1.7 units) as well as surgery (4% vs 10%), but not associated with the length of hospital stay nor mortality. By contrast, outcomes did not significantly differ between the two time periods of endoscopy.On multivariate analysis, endoscopist's experience was independently associated with rebleeding rate and transfusion requirements. Odds ratios for low experienced endoscopist were 4.47 for rebleeding and 6.90 for need of transfusion after the endoscopy.CONCLUSION: Endoscopist's experience is an important independent prognostic factor for non-variceal acute upper GI bleeding. Urgent endoscopy should be undertaken preferentially by a skilled endoscopist as less expert staff tends to underestimate some risk lesions with a negative influence on hemostasis.
