AIM:To report a meta-analysis of the studies that compared the laparoscopic with the open approach for colon cancer resection.METHODS:Forty-seven manuscripts were reviewed,33 of which employed for meta-analysis accord...AIM:To report a meta-analysis of the studies that compared the laparoscopic with the open approach for colon cancer resection.METHODS:Forty-seven manuscripts were reviewed,33 of which employed for meta-analysis according to the PRISMA guidelines.The results were differentiated according to the study design(prospective randomized trials vs case-control series)and according to the tu-mor’s location.Outcome measures included:(1)shortterm results(operating times,blood losses,bowel function recovery,post-operative pain,return to the oral intake,complications and hospital stay);(2)oncological adequateness(number of nodes harvested in the surgical specimens);and(3)long-term results(including the survivals’rates and incidence of incisional hernias)and(4)costs.RESULTS:Meta-analysis of trials provided evidences in support of the laparoscopic procedures for a several short-term outcomes including:a lower blood loss,an earlier recovery of the bowel function,an earlier return to the oral intake,a shorter hospital stay and a lower morbidity rate.Opposite the operating time has been confirmed shorter in open surgery.The same trend has been reported investigating case-control series and cancer by sites,even though there are some concerns regarding the power of the studies in this latter field due to the small number of trials and the small sample of patients enrolled.The two approaches were comparable regarding the mean number of nodes harvested and long-term results,even though these variables were documented reviewing the literature but were not computable for meta-analysis.The analysis of the costs documented lower costs for the open surgery,however just few studies investigated the incidence of postoperative hernias.CONCLUSION:Laparoscopy is superior for the majority of short-term results.Future studies should better differentiate these approaches on the basis of tumors’location and the post-operative hernias.展开更多
In the current landscape of endothelial cell isolation for building in vitro models of the blood-brain barrier,our work moves towards reproducing the features of the neurovascular unit to achieve glial compliance thro...In the current landscape of endothelial cell isolation for building in vitro models of the blood-brain barrier,our work moves towards reproducing the features of the neurovascular unit to achieve glial compliance through an innovative biomimetic coating technology for brain chronic implants.We hypothesized that the autologous origin of human brain mic rovascular endothelial cells(hBMECs)is the first requirement for the suitable coating to prevent the glial inflammato ry response trigge red by foreign neuroprosthetics.Therefo re,this study established a new procedure to preserve the in vitro viability of hBMECs isolated from gray and white matter specimens taken from neurosurge ry patients.Culturing adult hBMECs is generally considered a challenging task due to the difficult survival ex vivo and progressive reduction in proliferation of these cells.The addition of 10 nMβ-estradiol 17-acetate to the hBMEC culture medium was found to be an essential and discriminating factor promoting adhesion and proliferation both after isolation and thawing,suppo rting the well-known protective role played by estrogens on microvessels.In particular,β-estradiol 17-acetate was critical for both freshly isolated and thawed female-derived hBMECs,while it was not necessary for freshly isolated male-derived hBMECs;however,it did countera ct the decay in the viability of the latter after thawing.The tumo r-free hBMECs were thus cultured for up to 2 months and their growth efficiency was assessed befo re and after two periods of cryopreservation.Des pite the thermal stress,the hBMECs remained viable and suitable for re-freezing and storage for several months.This approach increasing in vitro viability of hBMECs opens new perspectives for the use of cryopreserved autologous hBMECs as biomimetic therapeutic tools,offering the potential to avoid additional surgical sampling for each patient.展开更多
AIM To investigate survival rate and incidence of hepatocellular carcinoma(HCC) in patients with decompensated cirrhosis in the antiviral era.METHODS We used the Korean Health Insurance Review and Assessment. Korea...AIM To investigate survival rate and incidence of hepatocellular carcinoma(HCC) in patients with decompensated cirrhosis in the antiviral era.METHODS We used the Korean Health Insurance Review and Assessment. Korea's health insurance system is a public single-payer system. The study population consisted of 286871 patients who were prescribed hepatitis B antiviral therapy for the first time between 2007 and 2014 in accordance with the insurance guidelines.Overall, 48365 antiviral treatment-na?ve patients treated between 2008 and 2009 were included, and each had a follow-up period ≥ 5 years. Data were analyzed for the 1 st decompensated chronic hepatitis B(CHB) and treatment-na?ve patients(n = 7166). RESULTS The mean patient age was 43.5 years. The annual mortality rates were 2.4%-19.1%, and 5-year cumulative mortality rate was 32.6% in 1^(st) decompensated CHB treatment-na?ve subjects. But the annual mortality rates sharply decreased to 3.4%(2.4%-4.9%, 2-5 year) after one year of antiviral treatment. Incidence of HCC at first year was 14.3%, the annual incidence of HCC decreased to 2.5%(1.8%-3.7%, 2-5 year) after one year. 5-year cumulative incidence of HCC was 24.1%. Recurrence rate of decompensated event was 46.9% at first year, but the annual incidence of second decompensation events in decompensated CHB treatment-na?ve patients was 3.4%(2.1%-5.4%, 2-5 year) after one year antiviral treatment. 5-year cumulative recurrence rate of decompensated events was 60.6%. Meanwhile, 5-year cumulative mortality rate was 3.1%, and 5-year cumulative incidence of HCC was 11.5% in compensated CHB treatment-na?ve patients.CONCLUSION Long term outcome of decompensated cirrhosis treated with antiviral agent improved much, and incidence of hepatocellular carcinoma and mortality sharply decreased after one year treatment.展开更多
AIM To validate the effects of receptor interacting protein kinase-3(RIP3) deletion in non-alcoholic fatty liver disease(NAFLD) and to clarify the mechanism of action.METHODS Wild-type(WT) and RIP3 knockout(KO) mice w...AIM To validate the effects of receptor interacting protein kinase-3(RIP3) deletion in non-alcoholic fatty liver disease(NAFLD) and to clarify the mechanism of action.METHODS Wild-type(WT) and RIP3 knockout(KO) mice werefed normal chow and high fat(HF) diets for 12 wk. The body weight was assessed once weekly. After 12 wk, the liver and serum samples were extracted. The liver tissue expression levels of RIP3, microsomal triglyceride transfer protein, protein disulfide isomerase, apolipoprotein-B, X-box binding protein-1, sterol regulatory element-binding protein-1c, fatty acid synthase, cluster of differentiation-36, diglyceride acyltransferase, peroxisome proliferator-activated receptor alpha, tumor necrosis factor-alpha(TNF-α), and interleukin-6 were assessed. Oleic acid treated primary hepatocytes from WT and RIP3 KO mice were stained with Nile red. The expression of inflammatory cytokines, including chemokine(C-X-C motif) ligand(CXCL) 1, CXCL2, and TNF-α, in monocytes was evaluated.RESULTS RIP3 KO HF diet fed mice showed a significant gain in body weight, and liver weight, liver to body weight ratio, and liver triglycerides were increased in HF diet fed RIP3 KO mice compared to HF diet fed WT mice. RIP3 KO primary hepatocytes also had increased intracellular fat droplets compared to WT primary hepatocytes after oleic acid treatment. RIP3 overexpression decreased hepatic fat content. Quantitative real-time polymerase chain reaction analysis showed that the expression of very-low-density lipoproteins secretion markers(microsomal triglyceride transfer protein, protein disulfide isomerase, and apolipoprotein-B) was significantly suppressed in RIP3 KO mice. The overall NAFLD Activity Score was the same between WT and RIP3 KO mice; however, RIP3 KO mice had increased fatty change and decreased lobular inflammation compared to WT mice. Inflammatory signals(CXCL1/2, TNF-α, and interleukin-6) increased after lipopolysaccharide and pancaspase inhibitor(necroptotic condition) treatment in monocytes. Neutrophil chemokines(CXCL1, and CXCL2) were decreased, and TNF-α was increased after RIP3 inhibitor treatment in monocytes.CONCLUSION RIP3 deletion exacerbates steatosis, and partially inhibits inflammation in the HF diet induced NAFLD model.展开更多
To investigate a possible therapeutic mechanism of cell therapy in the field of cerebral palsy using granulocyte-colony stimulating factor(G-CSF)-mobilized peripheral blood mononuclear cells(m PBMCs),we compared the e...To investigate a possible therapeutic mechanism of cell therapy in the field of cerebral palsy using granulocyte-colony stimulating factor(G-CSF)-mobilized peripheral blood mononuclear cells(m PBMCs),we compared the expression of inflammatory cytokines and neurotrophic factors in PBMCs and m PBMCs from children with cerebral palsy to those from healthy adult donors and to cord blood mononuclear cells donated from healthy newborns.No significant differences in expression of neurotrophic factors were found between PBMCs and m PBMCs.However,in cerebral palsy children,the expression of interleukin-6 was significantly increased in m PBMCs as compared to PBMCs,and the expression of interleukin-3 was significantly decreased in m PBMCs as compared to PBMCs.In healthy adults,the expression levels of both interleukin-1βand interleukin-6 were significantly increased in m PBMCs as compared to PBMCs.The expression of brain-derived neurotrophic factors in m PBMC from cerebral palsy children was significantly higher than that in the cord blood or m PBMCs from healthy adults.The expression of G-CSF in m PBMCs from cerebral palsy children was comparable to that in the cord blood but significantly higher than that in m PBMCs from healthy adults.Lower expression of pro-inflammatory cytokines(interleukin-1β,interleukin-3,and-6)and higher expression of anti-inflammatory cytokines(interleukin-8 and interleukin-9)were observed from the cord blood and m PBMCs from cerebral palsy children rather than from healthy adults.These findings indicate that m PBMCs from cerebral palsy and cord blood mononuclear cells from healthy newborns have the potential to become seed cells for treatment of cerebral palsy.展开更多
Acute pancreatitis (AP) is a serious inflammatory disease with rising incidence both in the adult and pediatric populations. It has been shown that mitochondrial injury and energy depletion are the earliest intracellu...Acute pancreatitis (AP) is a serious inflammatory disease with rising incidence both in the adult and pediatric populations. It has been shown that mitochondrial injury and energy depletion are the earliest intracellular events in the early phase of AP. Moreover, it has been revealed that restoration of intracellular ATP level restores cellular functions and defends the cells from death. We have recently shown in a systematic review and meta-analysis that early enteral feeding is beneficial in adults; however, no reviews are available concerning the effect of early enteral feeding in pediatric AP. In this minireview, our aim was to systematically analyse the literature on the treatmentof acute pediatric pancreatitis. The preferred reporting items for systematic review(PRISMA-P) were followed, and the question was drafted based on participants, intervention, comparison and outcomes: P: patients under the age of twenty-one suffering from acute pancreatitis; I: early enteral nutrition (per os and nasogastric- or nasojejunal tube started within 48 h); C: nil per os therapy; O: length of hospitalization, need for treatment at an intensive care unit, development of severe AP, lung injury (including lung oedema and pleural effusion), white blood cell count and pain score on admission. Altogether, 632 articles (Pub Med: 131; EMBASE: 501) were found. After detailed screening of eligible papers, five of them met inclusion criteria. Only retrospective clinical trials were available. Due to insufficient information from the authors, it was only possible to address length of hospitalization as an outcome of the study. Our mini-meta-analysis showed that early enteral nutrition significantly(SD = 0.806, P = 0.034) decreases length of hospitalization compared with nil per os diet in acute pediatric pancreatitis. In this minireview, we clearly show that early enteral nutrition, started within 24-48 h, is beneficial in acute pediatric pancreatitis. Prospective studies and better presentation of research are crucially needed to achieve a higher level of evidence.展开更多
Autoimmune cholangitis would be the appropriate name to define the immune-mediated bile duct injury following the breakdown of tolerance to mitochondrial proteins and the appearance of serum autoantibodies and autorea...Autoimmune cholangitis would be the appropriate name to define the immune-mediated bile duct injury following the breakdown of tolerance to mitochondrial proteins and the appearance of serum autoantibodies and autoreactive T cells.Nevertheless,the conditionis universally named primary biliary cirrhosis(PBC).The disease etiology and pathogenesis remain largely unknown despite the proposed lines of evidence.One twin study and numerous epidemiology reportssuggest that both a susceptible genetic background and environmental factors determine disease onsetwhile a recent genome-wide association study proposed highly significant associations with several commongenetic polymorphisms in subgroups of patients.Specific infectious agents and chemicals may contribute to the disease onset and perpetuation in a geneticallysusceptible host,possibly through molecular mimicry.Importantly,several murine models have been proposed and include strains in which PBC is genetically determined or induced by immunization with chemicals and bacteria.From a pathogenetic standpoint,new exciting data have demonstrated the unique apoptotic features of bile duct cells that allow the mitochondrial autoantigens to be taken up in their intact form within apoptotic blebs.We are convinced that the application of the most recent molecular techniques will soon pro-vide developments in PBC etiology and pathogenesis with likely implications in diagnostics and therapeutics.展开更多
Colorectal cancer(CRC) remains one of the major public health problems throughout the world.Originally depicted as a multi-step dynamical disease,CRC develops slowly over several years and progresses through cytologic...Colorectal cancer(CRC) remains one of the major public health problems throughout the world.Originally depicted as a multi-step dynamical disease,CRC develops slowly over several years and progresses through cytologically distinct benign and malignant states,from single crypt lesions through adenoma,to malignant carcinoma with the potential for invasion and metastasis.Moving from histological observations since a long time,it has been recognized that inflammation and immunity actively participate in the pathogenesis,surveillance and progression of CRC.The advent of immunohistochemical techniques and of animal models has improved our understanding of the immune dynamical system in CRC.It is well known that immune cells have variable behavior controlled by complex interactions in the tumor microenvironment.Advances in immunology and molecular biology have shown that CRC is immunogenic and that host immune responses influence survival.Several lines of evidence support the concept that tumor stromal cells,are not merely a scaffold,but rather they influence growth,survival,and invasiveness of cancer cells,dynamically contributing to the tumor microenvironment,together with immune cells.Different types of immune cells infiltrate CRC,comprising cells of both the innate and adaptive immune system.A relevant issue is to unravel the discrepancy between the inhibitory effects on cancer growth exerted by the local immune response and the promoting effects on cancer proliferation,invasion,and dissemination induced by some types of inflammatory cells.Here,we sought to discuss the role played by innate and adaptive immune system in the local progression and metastasis of CRC,and the prognostic information that we can currently understand and exploit.展开更多
The immune system(IS)is set to provide protection against pathogens,surveillance against tumor cells and promotion of healing.Such functions can be efficiently performed thanks to the presence of a large network of ce...The immune system(IS)is set to provide protection against pathogens,surveillance against tumor cells and promotion of healing.Such functions can be efficiently performed thanks to the presence of a large network of cells with variable degrees of specialization,which are traditionally divided into two functional branches:the in-展开更多
Osteopontin is a broadly expressed pleiotropic protein,and is attracting increased attention because of its role in the pathophysiology of several inflammatory,degenerative,autoimmune,and oncologic diseases.In fact,in...Osteopontin is a broadly expressed pleiotropic protein,and is attracting increased attention because of its role in the pathophysiology of several inflammatory,degenerative,autoimmune,and oncologic diseases.In fact,in the last decade,several studies have shown that osteopontin contributes to tissue damage not only by recruiting harmful inflammatory cells to the site of lesion,but also increasing their survival.The detrimental role of osteopontin has been indeed well documented in the context of different neurological conditions(i.e.,multiple sclerosis,Parkinson’s,and Alzheimer’s diseases).Intriguingly,recent findings show that osteopontin is involved not only in promoting tissue damage(the Yin),but also in repair/regenerative mechanisms(the Yang),mostly triggered by the inflammatory response.These two apparently discordant roles are partly related to the presence of different functional domains in the osteopontin molecule,which are exposed after thrombin or metalloproteases cleavages.Such functional domains may in turn activate intracellular signaling pathways and mediate cell-cell and cell-matrix interactions.This review describes the current knowledge on the Yin and Yang features of osteopontin in nervous system diseases.Understanding the mechanisms behind the Yin/Yang would be relevant to develop highly specific tools targeting this multifunctional protein.展开更多
Growing evidence has highlighted that angiotensin-converting enzyme(ACE)-inhibitors(ACEi)/AT1 receptor blockers(ARBs)may influence the complex interplay between dopamine and the renin-angiotensin system in the nigrost...Growing evidence has highlighted that angiotensin-converting enzyme(ACE)-inhibitors(ACEi)/AT1 receptor blockers(ARBs)may influence the complex interplay between dopamine and the renin-angiotensin system in the nigrostriatal pathway,thus affecting the development of levodopa-induced dyskinesia in Parkinson’s disease(PD).In the present study,we analyzed whether the use of this class of medication was associated with a reduced occurrence of levodopa-induced dyskinesia,using electronically-stored information of idiopathic PD patients enrolled at Novara University Hospital“Maggiore della Carità”.We conducted a retrospective case-control study identifying PD patients with dyskinesias(PwD;n=47)as cases.For each PwD we selected a non-dyskinetic control(NoD),nearly perfectly matched according to sex,Unified Parkinson’s Disease Rating Scale(UPDRS)part III score,and duration of antiparkinsonian treatment.Binary logistic regression was used to evaluate whether dyskinesias were associated with ACEi/ARBs use.Ninety-four PD patients were included,aged 72.18±9 years,with an average disease duration of 10.20±4.8 years and 9.04±4.9 years of antiparkinsonian treatment.The mean UPDRS part III score was 18.87±7.6 and the median HY stage was 2.In the NoD group,25(53.2%)were users and 22(46.8%)non-users of ACEi/ARBs.Conversely,in the PwD group,11(23.4%)were users and 36 non-users(76.6%)of this drug class(Pearson chi-square=8.824,P=0.003).Concerning general medication,there were no other statistically significant differences between groups.After controlling for tremor dominant phenotype,levodopa equivalent daily dose,HY 3-4,and disease duration,ACEi/ARBs use was a significant predictor of a lower occurrence of dyskinesia(OR=0.226,95%CI:0.080-0.636,P=0.005).Therefore,our study suggests that ACEi/ARBs may reduce levodopa-induced dyskinesia occurrence and,thanks to good tolerability and easy management,represent a feasible choice when dealing with the treatment of hypertension in PD patients.The study was approved by the Ethics Committee of Novara University Hospital“Maggiore della Carità”(CE 65/16)on July 27,2016.展开更多
It is generally believed that serious events are unlikely to result from atherosclerotic disease of a non-dominant hypoplastic right coronary artery (RCA). Left dominant coronary artery system are usually associated w...It is generally believed that serious events are unlikely to result from atherosclerotic disease of a non-dominant hypoplastic right coronary artery (RCA). Left dominant coronary artery system are usually associated with higher in-hospital mortality among patients undergoing percutaneous coronary intervention.[1,2] Nevertheless, clinical series or reports of right ventricle infarction, malignat arrhythmias and sudden death correlated to non-dominant RCA have been reported in the literature in the past years.[3,4] The specific contribute of non-dominant RCA disease on long-term follow-up in patients aged over 65 years has not been yet clarified.展开更多
AIM:To evaluate the hospitalization rate of femoralneck fractures in the elderly Italian population over ten years.METHODS:We analyzed national hospitalizations records collected at central level by the Ministry of He...AIM:To evaluate the hospitalization rate of femoralneck fractures in the elderly Italian population over ten years.METHODS:We analyzed national hospitalizations records collected at central level by the Ministry of Health from 2000 to 2009.Age-and sex-specific rates of fractures occurred at femoral neck in people≥65 years old.We performed a sub-analysis over a three-year period(2007-2009),presenting data per five-year age groups,in order to evaluate the incidence of the hip fracture in the oldest population.RESULTS:We estimated a total of 839008 hospitalizations due to femoral neck fractures between 2000 and2009 in people≥65,with an overall increase of 29.8%over 10 years.The incidence per 10000 inhabitants remarkably increased in people≥75,passing from158.5 to 166.8(+5.2%)and from 72.6 to 77.5(+6.8%)over the ten-year period in women and men,respectively.The oldest age group(people>85 years old)accounted for more than 42%of total hospital admissions in 2009(n=39000),despite representing only 2.5%of the Italian population.Particularly,women aged>85accounted for 30.8%of total fractures,although they represented just 1.8%of the general population.The results of this analysis indicate that the incidence of hip fractures progressively increased from 2000 to 2009,but a reduction can be observed for the first time in women≤75(-7.9%between 2004 and 2009).CONCLUSION:Incidence of hip fractures in Italy are continuously increasing,although women aged 65-74years old started showing a decreasing trend.展开更多
Alkaline phosphatase(ALP)is widely expressed in human tissues.ALP plays an important role in the dephosphorylation of proteins and nucleic acids.Therefore,quantitative analysis of ALP plays a vital role in disease dia...Alkaline phosphatase(ALP)is widely expressed in human tissues.ALP plays an important role in the dephosphorylation of proteins and nucleic acids.Therefore,quantitative analysis of ALP plays a vital role in disease diagnosis and the development of biological detection methods.Terminal deoxynucleotidyl transferase(TdT)catalyzes continuous polymerization of deoxynucleotide triphosphates at the 30-OH end of single-stranded DNA in the absence of a template.In this study,we developed a highly sensitive and selective method based on TdT and endonuclease Ⅳ(Endo Ⅳ)to quantify ALP activity.After ALP hydrolyzes the 30-PO_(4) end of the substrate and generates 30-OH,TdT can effectively elongate the 30-OH end with deoxynucleotide adenine triphosphate(dATP)and produce a poly A tail,which can be detected by the poly T probes.Endo Ⅳ digests the AP site in poly T probes to generate a fluorescent signal and a new 30-OH end,leading to the generation of exponential fluorescence signal amplification.The substrate for TdT elongation was optimized,and a limit of detection of 4.3×10^(-3) U/L was achieved for ALP by the optimized substrate structure.This method can also detect ALP in the cell lysate of a single cell.This work has potential applications in disease diagnosis and biomedical detection.展开更多
The treatment for hepatocellular carcinoma(HCC)relies on liver resection,which is,however,burdened by a high rate of recurrence after surgery,up to 60%at 5 years.No pre-operative tools are currently available to asses...The treatment for hepatocellular carcinoma(HCC)relies on liver resection,which is,however,burdened by a high rate of recurrence after surgery,up to 60%at 5 years.No pre-operative tools are currently available to assess the recurrence risk tailored to every single patient.Recently liquid biopsy has shown interesting results in diagnosis,prognosis and treatment allocation strategies in other types of cancers,since its ability to identify circulating tumor cells(CTCs)derived from the primary tumor.Those cells were advocated to be responsible for the majority of cases of recurrence and cancer-related deaths for HCC.In fact,after being modified by the epithelial-mesenchymal transition,CTCs circulate as“seeds”in peripheral blood,then reach the target organ as dormant cells which could be subsequently“awakened”and activated,and then initiate metastasis.Their presence may justify the disagreement registered in terms of efficacy of anatomic vs non-anatomic resections,particularly in the case of microvascular invasion,which has been recently pointed as a histological sign of the spread of those cells.Thus,their presence,also in the early stages,may justify the recurrence event also in the contest of liver transplant.Understanding the mechanism behind the tumor progression may allow improving the treatment selection according to the biological patient-based characteristics.Moreover,it may drive the development of novel biological tailored tests which could address a specific patient to neoadjuvant or adjuvant strategies,and in perspective,it could also become a new method to allocate organs for transplantation,according to the risk of relapse after liver transplant.The present paper will describe the most recent evidence on the role of CTCs in determining the relapse of HCC,highlighting their potential clinical implication as novel tumor behavior biomarkers able to influence the surgical choice.展开更多
BACKGROUND Approximately half of all new cases of gastric cancer(GC)and related deaths occur in China.More than 80%of patients with GC are diagnosed at an advanced stage,which results in poor prognosis.Although HER2-d...BACKGROUND Approximately half of all new cases of gastric cancer(GC)and related deaths occur in China.More than 80%of patients with GC are diagnosed at an advanced stage,which results in poor prognosis.Although HER2-directed therapy and immune checkpoint inhibitors have been somewhat successful,new drugs are still needed for the treatment of GC.Notably,several gene fusion-targeted drugs have been approved by the United States Food and Drug Administration for solid tumors,including GC,such as larotrectinib for NTRK fusion-positive cancers and zenocutuzumab for NRG1 fusion-positive cancers.However,gene fusions involving targetable genes have not been well characterized in Chinese patients with GC.AIM To identify the profile of fusions involving targetable genes in Chinese patients with GC using clinical specimens and determine the distribution of patients with gene fusion variants among the molecular subtypes of GC.METHODS We retrospectively analyzed gene fusion events in tumor tissue samples from 954 Chinese patients with GC.Clinicopathological characteristics were obtained from their medical records.Genetic alterations,such as single nucleotide variants,indels,amplifications,and gene fusions,were identified using a targeted sequencing panel containing 825 genes.Fusions were validated by fluorescence in situ hybridization(FISH)using break-apart probes.The microsatellite instability(MSI)status was evaluated using MSIsensor from the targeted sequencing panel data.Tumor mutational burden(TMB)was calculated using the total number of nonsynonymous mutations divided by the total genomic targeted region.Chi-square analysis was used to determine the enrichment of gene fusions associated with the molecular subtypes of GC.RESULTS We found that 1.68%(16/954)of patients harbored 20 fusion events involving targetable genes.RARA fusions(n=5)were the most common,followed by FGFR2,BRAF,MET,FGFR3,RET,ALK,EGFR,NTRK2,and NRG1 fusions.Two of the RARA fusions,EML4-ALK(E6:E20)and EGFRSEPTIN14(E7:E10),have been identified in other tumors but not in GC.Surprisingly,18 gene fusion events were previously not reported in any cancer types.Twelve of the eighteen novel gene fusions included complete exons encoding functional domains of targetable genes,such as the tyrosine kinase domain of receptor tyrosine kinases and the DNA-and ligand-binding domains of RARA.Consistent with the results of detection using the targeted sequencing fusion panel,the results of FISH(fluorescence in situ hybridization)confirmed the rearrangement of FGFR2 and BRAF in tumors from patients 04 and 09,respectively.Genetic analysis indicated that the fusion genes were significantly enriched in patients with ERBB2 amplification(P=0.02);however,there were no significant differences between fusion-positive and fusion-negative patients in age,sex,MSI status,and TMB.CONCLUSION We characterized the landscape of fusions involving targetable genes in a Chinese GC cohort and found that 1.68%of patients with GC harbor potential targetable gene fusions,which were enriched in patients with ERBB2 amplification.Gene fusion detection may provide a potential treatment strategy for patients with GC with disease progression following standard therapy.展开更多
With advances in targeted and personalized treatment for lung cancer, molecular analysis of tumors is routinely performed for sequencing of treatment options in patients with advanced non-small-cell lung cancer (NSCLC...With advances in targeted and personalized treatment for lung cancer, molecular analysis of tumors is routinely performed for sequencing of treatment options in patients with advanced non-small-cell lung cancer (NSCLC). Oncogene addiction due to driver mutations includes EGFR exon 20 insertion mutations, MET amplification, EML4-AL, KRAS G12C point mutations, RET rearrangements, HER2 amplification and mutations, and FGFR amplification and translocations. A re-biopsy at the time of tumor recurrence or progression after first-line treatment failure is important for further molecular assessment and personalized therapy. However, repeat tumor biopsies are fraught with challenges including access to the tumor, sample inadequacy, patient consent, patient performance status, safety, or physician’s choice or assessment. Cytological specimens are gaining importance but are limited due to validation difficulties. Liquid biopsies, which are minimally invasive have shown promise to assess dynamic biomarkers using ctDNA analysis and are thus frequently considered in routine clinical practice in advanced NSCLC patients to guide further targeted treatment. Here we present a comprehensive review that emphasizes the significance of performing tumor re-biopsy in advanced stage NSCLC patients following resistance to first-line treatment and simultaneously highlights the current challenges in performing the same and the current status and future perspectives of liquid biopsy in NSCLC.展开更多
Iron is one of the essential trace elements in human body,which plays a critical role in electron respiratory chain,DNA synthesis,and oxygen utilization.The iron content in adult body is about 40 mg/kg[1].When iron co...Iron is one of the essential trace elements in human body,which plays a critical role in electron respiratory chain,DNA synthesis,and oxygen utilization.The iron content in adult body is about 40 mg/kg[1].When iron content in human body decreases,the normal physiological functions are affected,which causes series of iron deficiency diseases,such as iron deficiency anemia.Iron deficiency is a common nutritional deficiency that affects over 2 billion people worldwide[2].Iron deficiency leads to immune,neurological,respiratory,and other disorders.There is a dynamic balance of iron metabolism in human body,which includes three main processes:iron uptake,storage,and output.It is absorbed by small intestinal epithelial cells,stored in red blood cells,liver,and muscle fibers,and exported by excrement or shedding of small intestinal epithelial cells.展开更多
Lung adenocarcinoma(LUAD)is the leading cause of cancer-related deaths,accounting for over a million deaths worldwide annually.Immunogenic cell death(ICD)elicits an adaptive immune response.However,the role of ICD-rel...Lung adenocarcinoma(LUAD)is the leading cause of cancer-related deaths,accounting for over a million deaths worldwide annually.Immunogenic cell death(ICD)elicits an adaptive immune response.However,the role of ICD-related long noncoding RNAs(lncRNAs)in LUAD is unknown.In this study,we investigated the characteristics of the tumor microenvironment in LUAD,the prognostic significance of ICD-related lncRNAs,and the half-maximal inhibitory concentration(IC50)of possible chemotherapeutic drugs.We sorted prognostic lncRNAs using univariate Cox regression and constructed a risk signature based on them.We then confirmed the model’s accuracy and generated a nomogram.Additionally,we performed immune microenvironment analysis,somatic mutation calculation,Tumor Immune Dysfunction and Exclusion(TIDE)analysis,and anticancer pharmaceutical IC50 prediction.Least absolute shrinkage and selection operator Cox regression identified 27 prognostic lncRNAs related to ICD,and a unique risk signature using 10 ICD-related lncRNAs was constructed.The risk score was confirmed to be a reliable predictor of survival,with the highest c-index score.The signature had a remarkable predictive performance with clinical applicability and could accurately predict the overall survival in LUAD.Furthermore,the lncRNA signature was closely associated with immunocyte invasion.We also analyzed the correlation between the risk score,tumor-infiltrating immune cells,and prognosis and identified high immune and ESTIMATE scores in low-risk patients.Moreover,we observed elevated checkpoint gene expression and low TIDE scores in high-risk patients,indicating a good immunotherapy response.Finally,high-risk patients were shown to be susceptible to anticancer medications.Therefore,our unique risk signature comprising 10 ICD-related lncRNAs was demonstrated to indicate the characteristics of the tumor-immune microenvironment in LUAD,predict patients’overall survival,and guide individualized treatment.展开更多
Oxlnflammation:definition and role in disease:Oxlnflammation has been introduced as a new term in the biomedical field to highlight the deep and mutual relationship between the dysregulation of redox and immune homeos...Oxlnflammation:definition and role in disease:Oxlnflammation has been introduced as a new term in the biomedical field to highlight the deep and mutual relationship between the dysregulation of redox and immune homeostasis(Valacchi et al.,2018).Regardless of which is the initial spark,inflammation cannot take place without a concomitant oxidative stress response and vice-versa.In other words,they are sides of the same coin.展开更多
基金Supported by The PhD University Grant program"Clinical and Experimental Research Methodologies in Oncology"provided by the Faculty of Medicine and Psychology University of Rome"La Sapienza"to La Torre M
文摘AIM:To report a meta-analysis of the studies that compared the laparoscopic with the open approach for colon cancer resection.METHODS:Forty-seven manuscripts were reviewed,33 of which employed for meta-analysis according to the PRISMA guidelines.The results were differentiated according to the study design(prospective randomized trials vs case-control series)and according to the tu-mor’s location.Outcome measures included:(1)shortterm results(operating times,blood losses,bowel function recovery,post-operative pain,return to the oral intake,complications and hospital stay);(2)oncological adequateness(number of nodes harvested in the surgical specimens);and(3)long-term results(including the survivals’rates and incidence of incisional hernias)and(4)costs.RESULTS:Meta-analysis of trials provided evidences in support of the laparoscopic procedures for a several short-term outcomes including:a lower blood loss,an earlier recovery of the bowel function,an earlier return to the oral intake,a shorter hospital stay and a lower morbidity rate.Opposite the operating time has been confirmed shorter in open surgery.The same trend has been reported investigating case-control series and cancer by sites,even though there are some concerns regarding the power of the studies in this latter field due to the small number of trials and the small sample of patients enrolled.The two approaches were comparable regarding the mean number of nodes harvested and long-term results,even though these variables were documented reviewing the literature but were not computable for meta-analysis.The analysis of the costs documented lower costs for the open surgery,however just few studies investigated the incidence of postoperative hernias.CONCLUSION:Laparoscopy is superior for the majority of short-term results.Future studies should better differentiate these approaches on the basis of tumors’location and the post-operative hernias.
基金supported by EnTimeMent H2020-FETPROACT-824160(to LF)。
文摘In the current landscape of endothelial cell isolation for building in vitro models of the blood-brain barrier,our work moves towards reproducing the features of the neurovascular unit to achieve glial compliance through an innovative biomimetic coating technology for brain chronic implants.We hypothesized that the autologous origin of human brain mic rovascular endothelial cells(hBMECs)is the first requirement for the suitable coating to prevent the glial inflammato ry response trigge red by foreign neuroprosthetics.Therefo re,this study established a new procedure to preserve the in vitro viability of hBMECs isolated from gray and white matter specimens taken from neurosurge ry patients.Culturing adult hBMECs is generally considered a challenging task due to the difficult survival ex vivo and progressive reduction in proliferation of these cells.The addition of 10 nMβ-estradiol 17-acetate to the hBMEC culture medium was found to be an essential and discriminating factor promoting adhesion and proliferation both after isolation and thawing,suppo rting the well-known protective role played by estrogens on microvessels.In particular,β-estradiol 17-acetate was critical for both freshly isolated and thawed female-derived hBMECs,while it was not necessary for freshly isolated male-derived hBMECs;however,it did countera ct the decay in the viability of the latter after thawing.The tumo r-free hBMECs were thus cultured for up to 2 months and their growth efficiency was assessed befo re and after two periods of cryopreservation.Des pite the thermal stress,the hBMECs remained viable and suitable for re-freezing and storage for several months.This approach increasing in vitro viability of hBMECs opens new perspectives for the use of cryopreserved autologous hBMECs as biomimetic therapeutic tools,offering the potential to avoid additional surgical sampling for each patient.
基金Supported by The Research Supporting Program of The Korean Association for the Study of the Liver and The Korean Liver Foundation
文摘AIM To investigate survival rate and incidence of hepatocellular carcinoma(HCC) in patients with decompensated cirrhosis in the antiviral era.METHODS We used the Korean Health Insurance Review and Assessment. Korea's health insurance system is a public single-payer system. The study population consisted of 286871 patients who were prescribed hepatitis B antiviral therapy for the first time between 2007 and 2014 in accordance with the insurance guidelines.Overall, 48365 antiviral treatment-na?ve patients treated between 2008 and 2009 were included, and each had a follow-up period ≥ 5 years. Data were analyzed for the 1 st decompensated chronic hepatitis B(CHB) and treatment-na?ve patients(n = 7166). RESULTS The mean patient age was 43.5 years. The annual mortality rates were 2.4%-19.1%, and 5-year cumulative mortality rate was 32.6% in 1^(st) decompensated CHB treatment-na?ve subjects. But the annual mortality rates sharply decreased to 3.4%(2.4%-4.9%, 2-5 year) after one year of antiviral treatment. Incidence of HCC at first year was 14.3%, the annual incidence of HCC decreased to 2.5%(1.8%-3.7%, 2-5 year) after one year. 5-year cumulative incidence of HCC was 24.1%. Recurrence rate of decompensated event was 46.9% at first year, but the annual incidence of second decompensation events in decompensated CHB treatment-na?ve patients was 3.4%(2.1%-5.4%, 2-5 year) after one year antiviral treatment. 5-year cumulative recurrence rate of decompensated events was 60.6%. Meanwhile, 5-year cumulative mortality rate was 3.1%, and 5-year cumulative incidence of HCC was 11.5% in compensated CHB treatment-na?ve patients.CONCLUSION Long term outcome of decompensated cirrhosis treated with antiviral agent improved much, and incidence of hepatocellular carcinoma and mortality sharply decreased after one year treatment.
基金Supported by National Research Foundation of Korea(NRF)funded by the South Korean Government,No.NRF-2017M3A9C8028794
文摘AIM To validate the effects of receptor interacting protein kinase-3(RIP3) deletion in non-alcoholic fatty liver disease(NAFLD) and to clarify the mechanism of action.METHODS Wild-type(WT) and RIP3 knockout(KO) mice werefed normal chow and high fat(HF) diets for 12 wk. The body weight was assessed once weekly. After 12 wk, the liver and serum samples were extracted. The liver tissue expression levels of RIP3, microsomal triglyceride transfer protein, protein disulfide isomerase, apolipoprotein-B, X-box binding protein-1, sterol regulatory element-binding protein-1c, fatty acid synthase, cluster of differentiation-36, diglyceride acyltransferase, peroxisome proliferator-activated receptor alpha, tumor necrosis factor-alpha(TNF-α), and interleukin-6 were assessed. Oleic acid treated primary hepatocytes from WT and RIP3 KO mice were stained with Nile red. The expression of inflammatory cytokines, including chemokine(C-X-C motif) ligand(CXCL) 1, CXCL2, and TNF-α, in monocytes was evaluated.RESULTS RIP3 KO HF diet fed mice showed a significant gain in body weight, and liver weight, liver to body weight ratio, and liver triglycerides were increased in HF diet fed RIP3 KO mice compared to HF diet fed WT mice. RIP3 KO primary hepatocytes also had increased intracellular fat droplets compared to WT primary hepatocytes after oleic acid treatment. RIP3 overexpression decreased hepatic fat content. Quantitative real-time polymerase chain reaction analysis showed that the expression of very-low-density lipoproteins secretion markers(microsomal triglyceride transfer protein, protein disulfide isomerase, and apolipoprotein-B) was significantly suppressed in RIP3 KO mice. The overall NAFLD Activity Score was the same between WT and RIP3 KO mice; however, RIP3 KO mice had increased fatty change and decreased lobular inflammation compared to WT mice. Inflammatory signals(CXCL1/2, TNF-α, and interleukin-6) increased after lipopolysaccharide and pancaspase inhibitor(necroptotic condition) treatment in monocytes. Neutrophil chemokines(CXCL1, and CXCL2) were decreased, and TNF-α was increased after RIP3 inhibitor treatment in monocytes.CONCLUSION RIP3 deletion exacerbates steatosis, and partially inhibits inflammation in the HF diet induced NAFLD model.
基金supported by the Research Fund of Hanyang University(HY-2012)
文摘To investigate a possible therapeutic mechanism of cell therapy in the field of cerebral palsy using granulocyte-colony stimulating factor(G-CSF)-mobilized peripheral blood mononuclear cells(m PBMCs),we compared the expression of inflammatory cytokines and neurotrophic factors in PBMCs and m PBMCs from children with cerebral palsy to those from healthy adult donors and to cord blood mononuclear cells donated from healthy newborns.No significant differences in expression of neurotrophic factors were found between PBMCs and m PBMCs.However,in cerebral palsy children,the expression of interleukin-6 was significantly increased in m PBMCs as compared to PBMCs,and the expression of interleukin-3 was significantly decreased in m PBMCs as compared to PBMCs.In healthy adults,the expression levels of both interleukin-1βand interleukin-6 were significantly increased in m PBMCs as compared to PBMCs.The expression of brain-derived neurotrophic factors in m PBMC from cerebral palsy children was significantly higher than that in the cord blood or m PBMCs from healthy adults.The expression of G-CSF in m PBMCs from cerebral palsy children was comparable to that in the cord blood but significantly higher than that in m PBMCs from healthy adults.Lower expression of pro-inflammatory cytokines(interleukin-1β,interleukin-3,and-6)and higher expression of anti-inflammatory cytokines(interleukin-8 and interleukin-9)were observed from the cord blood and m PBMCs from cerebral palsy children rather than from healthy adults.These findings indicate that m PBMCs from cerebral palsy and cord blood mononuclear cells from healthy newborns have the potential to become seed cells for treatment of cerebral palsy.
基金the Hungarian Scientific Research Fund,No.K116634 to Hegyi Pthe Momentum Grant of the Hungarian Academy of Sciences,No.LP2014-10/2014 to Hegyi P
文摘Acute pancreatitis (AP) is a serious inflammatory disease with rising incidence both in the adult and pediatric populations. It has been shown that mitochondrial injury and energy depletion are the earliest intracellular events in the early phase of AP. Moreover, it has been revealed that restoration of intracellular ATP level restores cellular functions and defends the cells from death. We have recently shown in a systematic review and meta-analysis that early enteral feeding is beneficial in adults; however, no reviews are available concerning the effect of early enteral feeding in pediatric AP. In this minireview, our aim was to systematically analyse the literature on the treatmentof acute pediatric pancreatitis. The preferred reporting items for systematic review(PRISMA-P) were followed, and the question was drafted based on participants, intervention, comparison and outcomes: P: patients under the age of twenty-one suffering from acute pancreatitis; I: early enteral nutrition (per os and nasogastric- or nasojejunal tube started within 48 h); C: nil per os therapy; O: length of hospitalization, need for treatment at an intensive care unit, development of severe AP, lung injury (including lung oedema and pleural effusion), white blood cell count and pain score on admission. Altogether, 632 articles (Pub Med: 131; EMBASE: 501) were found. After detailed screening of eligible papers, five of them met inclusion criteria. Only retrospective clinical trials were available. Due to insufficient information from the authors, it was only possible to address length of hospitalization as an outcome of the study. Our mini-meta-analysis showed that early enteral nutrition significantly(SD = 0.806, P = 0.034) decreases length of hospitalization compared with nil per os diet in acute pediatric pancreatitis. In this minireview, we clearly show that early enteral nutrition, started within 24-48 h, is beneficial in acute pediatric pancreatitis. Prospective studies and better presentation of research are crucially needed to achieve a higher level of evidence.
文摘Autoimmune cholangitis would be the appropriate name to define the immune-mediated bile duct injury following the breakdown of tolerance to mitochondrial proteins and the appearance of serum autoantibodies and autoreactive T cells.Nevertheless,the conditionis universally named primary biliary cirrhosis(PBC).The disease etiology and pathogenesis remain largely unknown despite the proposed lines of evidence.One twin study and numerous epidemiology reportssuggest that both a susceptible genetic background and environmental factors determine disease onsetwhile a recent genome-wide association study proposed highly significant associations with several commongenetic polymorphisms in subgroups of patients.Specific infectious agents and chemicals may contribute to the disease onset and perpetuation in a geneticallysusceptible host,possibly through molecular mimicry.Importantly,several murine models have been proposed and include strains in which PBC is genetically determined or induced by immunization with chemicals and bacteria.From a pathogenetic standpoint,new exciting data have demonstrated the unique apoptotic features of bile duct cells that allow the mitochondrial autoantigens to be taken up in their intact form within apoptotic blebs.We are convinced that the application of the most recent molecular techniques will soon pro-vide developments in PBC etiology and pathogenesis with likely implications in diagnostics and therapeutics.
基金Supported by Ministry of Education,University and Research (MIUR),Target Project Oncologia 2006Alliance Against Cancerthe Italian Association for Cancer Research Grant Project,No. IG5256
文摘Colorectal cancer(CRC) remains one of the major public health problems throughout the world.Originally depicted as a multi-step dynamical disease,CRC develops slowly over several years and progresses through cytologically distinct benign and malignant states,from single crypt lesions through adenoma,to malignant carcinoma with the potential for invasion and metastasis.Moving from histological observations since a long time,it has been recognized that inflammation and immunity actively participate in the pathogenesis,surveillance and progression of CRC.The advent of immunohistochemical techniques and of animal models has improved our understanding of the immune dynamical system in CRC.It is well known that immune cells have variable behavior controlled by complex interactions in the tumor microenvironment.Advances in immunology and molecular biology have shown that CRC is immunogenic and that host immune responses influence survival.Several lines of evidence support the concept that tumor stromal cells,are not merely a scaffold,but rather they influence growth,survival,and invasiveness of cancer cells,dynamically contributing to the tumor microenvironment,together with immune cells.Different types of immune cells infiltrate CRC,comprising cells of both the innate and adaptive immune system.A relevant issue is to unravel the discrepancy between the inhibitory effects on cancer growth exerted by the local immune response and the promoting effects on cancer proliferation,invasion,and dissemination induced by some types of inflammatory cells.Here,we sought to discuss the role played by innate and adaptive immune system in the local progression and metastasis of CRC,and the prognostic information that we can currently understand and exploit.
文摘The immune system(IS)is set to provide protection against pathogens,surveillance against tumor cells and promotion of healing.Such functions can be efficiently performed thanks to the presence of a large network of cells with variable degrees of specialization,which are traditionally divided into two functional branches:the in-
基金funded by the Italian Ministry of Education,University and Research(MIUR)Program“Departments of Excellence 2018-2022”,AGING and FOHN Projects,Fondazione Cariplo 2019-3277 and Associazione Ricerca sul Cancro(IG 20714,AIRC,Milano).
文摘Osteopontin is a broadly expressed pleiotropic protein,and is attracting increased attention because of its role in the pathophysiology of several inflammatory,degenerative,autoimmune,and oncologic diseases.In fact,in the last decade,several studies have shown that osteopontin contributes to tissue damage not only by recruiting harmful inflammatory cells to the site of lesion,but also increasing their survival.The detrimental role of osteopontin has been indeed well documented in the context of different neurological conditions(i.e.,multiple sclerosis,Parkinson’s,and Alzheimer’s diseases).Intriguingly,recent findings show that osteopontin is involved not only in promoting tissue damage(the Yin),but also in repair/regenerative mechanisms(the Yang),mostly triggered by the inflammatory response.These two apparently discordant roles are partly related to the presence of different functional domains in the osteopontin molecule,which are exposed after thrombin or metalloproteases cleavages.Such functional domains may in turn activate intracellular signaling pathways and mediate cell-cell and cell-matrix interactions.This review describes the current knowledge on the Yin and Yang features of osteopontin in nervous system diseases.Understanding the mechanisms behind the Yin/Yang would be relevant to develop highly specific tools targeting this multifunctional protein.
文摘Growing evidence has highlighted that angiotensin-converting enzyme(ACE)-inhibitors(ACEi)/AT1 receptor blockers(ARBs)may influence the complex interplay between dopamine and the renin-angiotensin system in the nigrostriatal pathway,thus affecting the development of levodopa-induced dyskinesia in Parkinson’s disease(PD).In the present study,we analyzed whether the use of this class of medication was associated with a reduced occurrence of levodopa-induced dyskinesia,using electronically-stored information of idiopathic PD patients enrolled at Novara University Hospital“Maggiore della Carità”.We conducted a retrospective case-control study identifying PD patients with dyskinesias(PwD;n=47)as cases.For each PwD we selected a non-dyskinetic control(NoD),nearly perfectly matched according to sex,Unified Parkinson’s Disease Rating Scale(UPDRS)part III score,and duration of antiparkinsonian treatment.Binary logistic regression was used to evaluate whether dyskinesias were associated with ACEi/ARBs use.Ninety-four PD patients were included,aged 72.18±9 years,with an average disease duration of 10.20±4.8 years and 9.04±4.9 years of antiparkinsonian treatment.The mean UPDRS part III score was 18.87±7.6 and the median HY stage was 2.In the NoD group,25(53.2%)were users and 22(46.8%)non-users of ACEi/ARBs.Conversely,in the PwD group,11(23.4%)were users and 36 non-users(76.6%)of this drug class(Pearson chi-square=8.824,P=0.003).Concerning general medication,there were no other statistically significant differences between groups.After controlling for tremor dominant phenotype,levodopa equivalent daily dose,HY 3-4,and disease duration,ACEi/ARBs use was a significant predictor of a lower occurrence of dyskinesia(OR=0.226,95%CI:0.080-0.636,P=0.005).Therefore,our study suggests that ACEi/ARBs may reduce levodopa-induced dyskinesia occurrence and,thanks to good tolerability and easy management,represent a feasible choice when dealing with the treatment of hypertension in PD patients.The study was approved by the Ethics Committee of Novara University Hospital“Maggiore della Carità”(CE 65/16)on July 27,2016.
文摘It is generally believed that serious events are unlikely to result from atherosclerotic disease of a non-dominant hypoplastic right coronary artery (RCA). Left dominant coronary artery system are usually associated with higher in-hospital mortality among patients undergoing percutaneous coronary intervention.[1,2] Nevertheless, clinical series or reports of right ventricle infarction, malignat arrhythmias and sudden death correlated to non-dominant RCA have been reported in the literature in the past years.[3,4] The specific contribute of non-dominant RCA disease on long-term follow-up in patients aged over 65 years has not been yet clarified.
基金Supported by Consulting/speaking by Sanofi-Aventis,AMGEN,Servier,Eli-Lilly,Abiogen to Piscitelli PResearch grant and funding for consulting/speaking by Merck,Sanofi-Aventis,Novartis,Stroder-Servier,Procter and Gamble,Ely Lilly,Roche,Glaxo to Brandi ML and Tarantino U
文摘AIM:To evaluate the hospitalization rate of femoralneck fractures in the elderly Italian population over ten years.METHODS:We analyzed national hospitalizations records collected at central level by the Ministry of Health from 2000 to 2009.Age-and sex-specific rates of fractures occurred at femoral neck in people≥65 years old.We performed a sub-analysis over a three-year period(2007-2009),presenting data per five-year age groups,in order to evaluate the incidence of the hip fracture in the oldest population.RESULTS:We estimated a total of 839008 hospitalizations due to femoral neck fractures between 2000 and2009 in people≥65,with an overall increase of 29.8%over 10 years.The incidence per 10000 inhabitants remarkably increased in people≥75,passing from158.5 to 166.8(+5.2%)and from 72.6 to 77.5(+6.8%)over the ten-year period in women and men,respectively.The oldest age group(people>85 years old)accounted for more than 42%of total hospital admissions in 2009(n=39000),despite representing only 2.5%of the Italian population.Particularly,women aged>85accounted for 30.8%of total fractures,although they represented just 1.8%of the general population.The results of this analysis indicate that the incidence of hip fractures progressively increased from 2000 to 2009,but a reduction can be observed for the first time in women≤75(-7.9%between 2004 and 2009).CONCLUSION:Incidence of hip fractures in Italy are continuously increasing,although women aged 65-74years old started showing a decreasing trend.
基金financially supported by the National Natural Science Foundation of China(Grant No.:21904045)the Fundamental Research Funds for the Central Universities(HUST:Grant No.:2019kfyXJJS169)Training Program of Innovation and Entrepreneurship for Undergraduates of Hubei Province(Grant No.:S202010487225).
文摘Alkaline phosphatase(ALP)is widely expressed in human tissues.ALP plays an important role in the dephosphorylation of proteins and nucleic acids.Therefore,quantitative analysis of ALP plays a vital role in disease diagnosis and the development of biological detection methods.Terminal deoxynucleotidyl transferase(TdT)catalyzes continuous polymerization of deoxynucleotide triphosphates at the 30-OH end of single-stranded DNA in the absence of a template.In this study,we developed a highly sensitive and selective method based on TdT and endonuclease Ⅳ(Endo Ⅳ)to quantify ALP activity.After ALP hydrolyzes the 30-PO_(4) end of the substrate and generates 30-OH,TdT can effectively elongate the 30-OH end with deoxynucleotide adenine triphosphate(dATP)and produce a poly A tail,which can be detected by the poly T probes.Endo Ⅳ digests the AP site in poly T probes to generate a fluorescent signal and a new 30-OH end,leading to the generation of exponential fluorescence signal amplification.The substrate for TdT elongation was optimized,and a limit of detection of 4.3×10^(-3) U/L was achieved for ALP by the optimized substrate structure.This method can also detect ALP in the cell lysate of a single cell.This work has potential applications in disease diagnosis and biomedical detection.
文摘The treatment for hepatocellular carcinoma(HCC)relies on liver resection,which is,however,burdened by a high rate of recurrence after surgery,up to 60%at 5 years.No pre-operative tools are currently available to assess the recurrence risk tailored to every single patient.Recently liquid biopsy has shown interesting results in diagnosis,prognosis and treatment allocation strategies in other types of cancers,since its ability to identify circulating tumor cells(CTCs)derived from the primary tumor.Those cells were advocated to be responsible for the majority of cases of recurrence and cancer-related deaths for HCC.In fact,after being modified by the epithelial-mesenchymal transition,CTCs circulate as“seeds”in peripheral blood,then reach the target organ as dormant cells which could be subsequently“awakened”and activated,and then initiate metastasis.Their presence may justify the disagreement registered in terms of efficacy of anatomic vs non-anatomic resections,particularly in the case of microvascular invasion,which has been recently pointed as a histological sign of the spread of those cells.Thus,their presence,also in the early stages,may justify the recurrence event also in the contest of liver transplant.Understanding the mechanism behind the tumor progression may allow improving the treatment selection according to the biological patient-based characteristics.Moreover,it may drive the development of novel biological tailored tests which could address a specific patient to neoadjuvant or adjuvant strategies,and in perspective,it could also become a new method to allocate organs for transplantation,according to the risk of relapse after liver transplant.The present paper will describe the most recent evidence on the role of CTCs in determining the relapse of HCC,highlighting their potential clinical implication as novel tumor behavior biomarkers able to influence the surgical choice.
文摘BACKGROUND Approximately half of all new cases of gastric cancer(GC)and related deaths occur in China.More than 80%of patients with GC are diagnosed at an advanced stage,which results in poor prognosis.Although HER2-directed therapy and immune checkpoint inhibitors have been somewhat successful,new drugs are still needed for the treatment of GC.Notably,several gene fusion-targeted drugs have been approved by the United States Food and Drug Administration for solid tumors,including GC,such as larotrectinib for NTRK fusion-positive cancers and zenocutuzumab for NRG1 fusion-positive cancers.However,gene fusions involving targetable genes have not been well characterized in Chinese patients with GC.AIM To identify the profile of fusions involving targetable genes in Chinese patients with GC using clinical specimens and determine the distribution of patients with gene fusion variants among the molecular subtypes of GC.METHODS We retrospectively analyzed gene fusion events in tumor tissue samples from 954 Chinese patients with GC.Clinicopathological characteristics were obtained from their medical records.Genetic alterations,such as single nucleotide variants,indels,amplifications,and gene fusions,were identified using a targeted sequencing panel containing 825 genes.Fusions were validated by fluorescence in situ hybridization(FISH)using break-apart probes.The microsatellite instability(MSI)status was evaluated using MSIsensor from the targeted sequencing panel data.Tumor mutational burden(TMB)was calculated using the total number of nonsynonymous mutations divided by the total genomic targeted region.Chi-square analysis was used to determine the enrichment of gene fusions associated with the molecular subtypes of GC.RESULTS We found that 1.68%(16/954)of patients harbored 20 fusion events involving targetable genes.RARA fusions(n=5)were the most common,followed by FGFR2,BRAF,MET,FGFR3,RET,ALK,EGFR,NTRK2,and NRG1 fusions.Two of the RARA fusions,EML4-ALK(E6:E20)and EGFRSEPTIN14(E7:E10),have been identified in other tumors but not in GC.Surprisingly,18 gene fusion events were previously not reported in any cancer types.Twelve of the eighteen novel gene fusions included complete exons encoding functional domains of targetable genes,such as the tyrosine kinase domain of receptor tyrosine kinases and the DNA-and ligand-binding domains of RARA.Consistent with the results of detection using the targeted sequencing fusion panel,the results of FISH(fluorescence in situ hybridization)confirmed the rearrangement of FGFR2 and BRAF in tumors from patients 04 and 09,respectively.Genetic analysis indicated that the fusion genes were significantly enriched in patients with ERBB2 amplification(P=0.02);however,there were no significant differences between fusion-positive and fusion-negative patients in age,sex,MSI status,and TMB.CONCLUSION We characterized the landscape of fusions involving targetable genes in a Chinese GC cohort and found that 1.68%of patients with GC harbor potential targetable gene fusions,which were enriched in patients with ERBB2 amplification.Gene fusion detection may provide a potential treatment strategy for patients with GC with disease progression following standard therapy.
文摘With advances in targeted and personalized treatment for lung cancer, molecular analysis of tumors is routinely performed for sequencing of treatment options in patients with advanced non-small-cell lung cancer (NSCLC). Oncogene addiction due to driver mutations includes EGFR exon 20 insertion mutations, MET amplification, EML4-AL, KRAS G12C point mutations, RET rearrangements, HER2 amplification and mutations, and FGFR amplification and translocations. A re-biopsy at the time of tumor recurrence or progression after first-line treatment failure is important for further molecular assessment and personalized therapy. However, repeat tumor biopsies are fraught with challenges including access to the tumor, sample inadequacy, patient consent, patient performance status, safety, or physician’s choice or assessment. Cytological specimens are gaining importance but are limited due to validation difficulties. Liquid biopsies, which are minimally invasive have shown promise to assess dynamic biomarkers using ctDNA analysis and are thus frequently considered in routine clinical practice in advanced NSCLC patients to guide further targeted treatment. Here we present a comprehensive review that emphasizes the significance of performing tumor re-biopsy in advanced stage NSCLC patients following resistance to first-line treatment and simultaneously highlights the current challenges in performing the same and the current status and future perspectives of liquid biopsy in NSCLC.
文摘Iron is one of the essential trace elements in human body,which plays a critical role in electron respiratory chain,DNA synthesis,and oxygen utilization.The iron content in adult body is about 40 mg/kg[1].When iron content in human body decreases,the normal physiological functions are affected,which causes series of iron deficiency diseases,such as iron deficiency anemia.Iron deficiency is a common nutritional deficiency that affects over 2 billion people worldwide[2].Iron deficiency leads to immune,neurological,respiratory,and other disorders.There is a dynamic balance of iron metabolism in human body,which includes three main processes:iron uptake,storage,and output.It is absorbed by small intestinal epithelial cells,stored in red blood cells,liver,and muscle fibers,and exported by excrement or shedding of small intestinal epithelial cells.
文摘Lung adenocarcinoma(LUAD)is the leading cause of cancer-related deaths,accounting for over a million deaths worldwide annually.Immunogenic cell death(ICD)elicits an adaptive immune response.However,the role of ICD-related long noncoding RNAs(lncRNAs)in LUAD is unknown.In this study,we investigated the characteristics of the tumor microenvironment in LUAD,the prognostic significance of ICD-related lncRNAs,and the half-maximal inhibitory concentration(IC50)of possible chemotherapeutic drugs.We sorted prognostic lncRNAs using univariate Cox regression and constructed a risk signature based on them.We then confirmed the model’s accuracy and generated a nomogram.Additionally,we performed immune microenvironment analysis,somatic mutation calculation,Tumor Immune Dysfunction and Exclusion(TIDE)analysis,and anticancer pharmaceutical IC50 prediction.Least absolute shrinkage and selection operator Cox regression identified 27 prognostic lncRNAs related to ICD,and a unique risk signature using 10 ICD-related lncRNAs was constructed.The risk score was confirmed to be a reliable predictor of survival,with the highest c-index score.The signature had a remarkable predictive performance with clinical applicability and could accurately predict the overall survival in LUAD.Furthermore,the lncRNA signature was closely associated with immunocyte invasion.We also analyzed the correlation between the risk score,tumor-infiltrating immune cells,and prognosis and identified high immune and ESTIMATE scores in low-risk patients.Moreover,we observed elevated checkpoint gene expression and low TIDE scores in high-risk patients,indicating a good immunotherapy response.Finally,high-risk patients were shown to be susceptible to anticancer medications.Therefore,our unique risk signature comprising 10 ICD-related lncRNAs was demonstrated to indicate the characteristics of the tumor-immune microenvironment in LUAD,predict patients’overall survival,and guide individualized treatment.
文摘Oxlnflammation:definition and role in disease:Oxlnflammation has been introduced as a new term in the biomedical field to highlight the deep and mutual relationship between the dysregulation of redox and immune homeostasis(Valacchi et al.,2018).Regardless of which is the initial spark,inflammation cannot take place without a concomitant oxidative stress response and vice-versa.In other words,they are sides of the same coin.
