Hepatocellular carcinoma(HCC)is currently the sixth most common type of cancer with a high mortality rate and an increasing incidence worldwide.Its etiology is usually linked to environmental,dietary or lifestyle fact...Hepatocellular carcinoma(HCC)is currently the sixth most common type of cancer with a high mortality rate and an increasing incidence worldwide.Its etiology is usually linked to environmental,dietary or lifestyle factors.HCC most commonly arises in a cirrhotic liver but interestingly an increasing proportion of HCCs develop in the non-fibrotic or minimal fibrotic liver and a shift in the underlying etiology can be observed.Although this process is yet to be completely understood,this changing scenario also has impact on the material seen by pathologists,presenting them with new diagnostic dilemmas.Histopathologic criteria for diagnosing classical,progressed HCC are well established and known,but with an increase in detection of small and early HCCs due to routine screening programs,the diagnosis of these small lesions in core needle biopsies poses a difficult challenge.These lesions can be far more difficult to distinguish from one another than progressed HCC,which is usually a clear cut hematoxylin and eosin diagnosis.Furthermore lesions thought to derive from progenitor cells have recently been reclassified in the WHO.This review summarizes recent developments and tries to put new HCC biomarkers in context with the WHOs reclassification.Furthermore it also addresses the group of tumors known as combined hepatocellular-cholangiocellular carcinomas.展开更多
New frontiers about retinal cell transplantation for retinal degenerative diseases start from the idea that acting on stem cells can help regenerate retinal layers and establish new synapses among retinal cells.Defici...New frontiers about retinal cell transplantation for retinal degenerative diseases start from the idea that acting on stem cells can help regenerate retinal layers and establish new synapses among retinal cells.Deficiency or alterations of synaptic input and neurotrophic factors result in trans-neuronal degeneration of the inner retinal cells.Thus,the disruption of photoreceptors takes place.However,even in advanced forms of retinal degeneration,a good percentage of the ganglion cells and the inner nuclear layer neurons remain intact.This phenomenon provides evidence for obtaining retinal circuitry through the transplantation of photoreceptors into the subretinal region.The eye is regarded as an optimal organ for cell transplantation because of its immunological privilege and the relatively small number of cells collaborating to carry out visual activities.The eyeball's immunological privilege,characterized by the suppression of delayed-type hypersensitivity responses in ocular tissues,is responsible for the low rate of graft rejection in transplant patients.The main discoveries highlight the capacity of embryonic stem cells(ESCs)and induced pluripotent stem cells to regenerate damaged retinal regions.Recent progress has shown significant enhancements in transplant procedures and results.The research also explores the ethical ramifications linked to the utilization of stem cells,emphasizing the ongoing issue surrounding ESCs.The analysis centers on recent breakthroughs,including the fabrication of three-dimensional retinal organoids and the innovation of scaffolding for cell transportation.Moreover,researchers are currently assessing the possibility of CRISPR and other advanced gene editing technologies to enhance the outcomes of retinal transplantation.The widespread use of universally recognized safe surgical and imaging methods enables retinal transplantation and monitoring of transplanted cell growth toward the correct location.Currently,most therapy approaches are in the first phases of development and neces展开更多
Uveal melanoma(UM)is the most common primary intraocular cancer in adults.The incidence in Europe and the United States is 6-7 per million population per year.Although most primary UMs can be successfully treated and ...Uveal melanoma(UM)is the most common primary intraocular cancer in adults.The incidence in Europe and the United States is 6-7 per million population per year.Although most primary UMs can be successfully treated and locally controlled by irradiation therapy or local tumor resection,up to 50%of UM patients develop metastases that usually involve the liver and are fatal within 1 year.To date,chemotherapy and targeted treatments only obtain minimal responses in patients with metastatic UM,which is still characterized by poor prognosis.No standard therapeutic approaches for its prevention or treatment have been established.The application of immunotherapy agents,such as immune checkpoint inhibitors that are effective in cutaneous melanoma,has shown limited effects in the treatment of ocular disease.This is due to UM’s distinct genetics,natural history,and complex interaction with the immune system.Unlike cutaneous melanomas characterized mainly by BRAF or NRAS mutations,UMs are usually triggered by a mutation in GNAQ or GNA11.As a result,more effective immunotherapeutic approaches,such as cancer vaccines,adoptive cell transfer,and other new molecules are currently being studied.In this review,we examine novel immunotherapeutic strategies in clinical and preclinical studies and highlight the latest insight in immunotherapy and the development of tailored treatment of UM.展开更多
AIM: To assess the evolution of duodenal lymphocytosis(DL), a condition characterized by increased intraepithelial lymphocytes(IELs), over 2 years of follow-up.METHODS: Consecutive patients undergoing upper endoscopy/...AIM: To assess the evolution of duodenal lymphocytosis(DL), a condition characterized by increased intraepithelial lymphocytes(IELs), over 2 years of follow-up.METHODS: Consecutive patients undergoing upper endoscopy/histology for abdominal pain, diarrhea, weight loss, weakness or other extraintestinal features compatible with celiac disease(CD) were included. Evaluation of IELs infiltrate in duodenal biopsy sampleswas carried out by CD3-immunohistochemistry and expressed as number of positive cells/100 enterocytes. Diagnostic agreement on the IELs count was tested by calculating the weighted k coefficient. All patients underwent serological detection of autoantibodies associated with CD: Ig G and Ig A anti-tissue transglutaminase and endomysium. Each patient underwent further investigations to clarify the origin of DL at baseline and/or in the course of 2 years of follow-up every six months. Autoimmune thyroiditis, intestinal infections, parasitic diseases, bacterial intestinal overgrowth, hypolactasia and wheat allergy were detected. Colonoscopy and enteric magnetic resonance i m a g i n g w e r e p e r f o r m e d w h e n n e c e s s a r y. R i s k factors affecting the final diagnosis were detected by multinomial logistic regression and expressed as OR.RESULTS: Eighty-five patients(16 males, 69 females, aged 34.1 ± 12.5 years) were followed up for a mean period of 21.7 ± 11.7 mo. At baseline, endoscopy/duodenal biopsy, CD3 immunohistochemistry revealed: > 25 IELs/100 enterocytes in 22 subjects, 15-25 IELs in 37 and < 15 IELs in 26. They all had negative serum anti-transglutaminase and anti-endomysium, whilst 5 showed Ig G anti-gliadin positivity. In the course of follow-up, 23 developed CD seropositivity and gluten sensitivity(GS) was identified in 19. Other diagnoses were: 5 Helicobacter pylori infections, 4 jejunal Crohn's disease, 1 lymphocytic colitis and 1 systemic sclerosis. The disease in the remaining 32 patients was classified as irritable bowel syndrome because of the lack of diagnostic evidence. 展开更多
Hepatitis B virus(HBV) is responsible for 50%-80% of cases of hepatocellular carcinoma(HCC) worldwide.Entecavir(ET) is a potent inhibitor of chronic HBV-DNA polymerase,inhibiting both the priming and elongation steps ...Hepatitis B virus(HBV) is responsible for 50%-80% of cases of hepatocellular carcinoma(HCC) worldwide.Entecavir(ET) is a potent inhibitor of chronic HBV-DNA polymerase,inhibiting both the priming and elongation steps of viral DNA replication.Sorafenib(SO) has proven efficacy in prolonging survival in patients with advanced HCC.In this frontier report we discuss a possible way to optimize treatment outcomes in patients with HBV and HCC by treatment with ET and SO,on the basis of our practice and published evidence from the literature.展开更多
Background:Traumatic pancreatic injuries are rare,and guidelines specifying management are controversial and difficult to apply in the acute clinical setting.Due to sparse data on these injuries,we carried out a retro...Background:Traumatic pancreatic injuries are rare,and guidelines specifying management are controversial and difficult to apply in the acute clinical setting.Due to sparse data on these injuries,we carried out a retrospective review to determine outcomes following surgical or non-surgical management of traumatic pancreatic injuries.We hypothesize a higher morbidity and mortality rate in patients treated surgically when compared to patients treated non-surgically.Methods:We performed a retrospective review of data from four trauma centers in New York from 1990–2014,comparing patients who had blunt traumatic pancreatic injuries who were managed operatively to those managed non-operatively.We compared continuous variables using the Mann-Whitney U test and categorical variables using the chi-square and Fisher’s exact tests.Univariate analysis was performed to determine the possible confounding factors associated with mortality in both treatment groups.Results:Twenty nine patients were managed operatively and 32 non-operatively.There was a significant difference between the operative and non-operative groups in median age(37.0 vs.16.2 years,P=0.016),grade of pancreatic injury(grade I;30.8 vs.85.2%,P value for all comparisons<0.0001),median injury severity score(ISS)(16.0 vs.4.0,P=0.002),blood transfusion(55.2 vs.15.6%,P=0.0012),other abdominal injuries(79.3 vs.38.7%,P=0.0014),pelvic fractures(17.2 vs.0.00%,P=0.020),intensive care unit(ICU)admission(86.2 vs.50.0%,P=0.003),median length of stay(LOS)(16.0 vs.4.0 days,P<0.0001),and mortality(27.6 vs.3.1%,P=0.010).Conclusions:Patients with traumatic pancreatic injuries treated operatively were more severely injured and suffered greater complications than those treated non-operatively.The greater morbidity and mortality associated with these patients warrants further study to determine optimal triage strategies and which subset of patients is likely to benefit from surgery.展开更多
Hepatitis B virus(HBV)is the leading cause of liver disease and infects an estimated 240 million people worldwide.It is characterised by a high degree of genetic heterogeneity because of the use of a reverse transcrip...Hepatitis B virus(HBV)is the leading cause of liver disease and infects an estimated 240 million people worldwide.It is characterised by a high degree of genetic heterogeneity because of the use of a reverse transcriptase during viral replication.The ten genotypes(A-J)that have been described so far further segregate into a number of subgenotypes which have distinct ethno-geographic distribution.Genotypes A and D are ubiquitous and the most prevalent genotypes in Europe(mainly represented by subgenotypes D1-3 and A2);genotypes B and C are restricted to eastern Asia and Oceania;genotype E to central and western Africa;and genotypes H and F(classified into 4 subgenotypes)to Latin America and Alaska.This review summarises the data obtained by studying the global phylodynamics and phylogeography of HBV genotypes,particularly those concerning the origin and dispersion histories of genotypes A,D,E and F and their subgenotypes.The lack of any consensus concerning the HBV substitution rate and the conflicting data obtained using different calibration approaches make the time of origin and divergence of the various genotypes and subgenotypes largely uncertain.It is hypothesised that HBV evolutionary rates are time dependent,and that the changes depend on the main transmission routes of the genotypes and the dynamics of the infected populations.展开更多
Reporter genes produce a protein product in transfected cells that can be easily measured in intact or lysed cells and they have been extensively used in numerous basic and applied research applications.Over the past ...Reporter genes produce a protein product in transfected cells that can be easily measured in intact or lysed cells and they have been extensively used in numerous basic and applied research applications.Over the past 10 years,reporter gene assays have been widely accepted and used for analysis of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related dioxin-like compounds in various types of matrices,such as biological,environmental,food and feed samples,given that high-resolution instrumental analysis techniques are impractical for large-scale screening analysis.The most sensitive cell-based reporter gene bioassay systems developed are the mechanism-based CALUX(Chemically Activated Luciferase Expression) and CAFLUX(Chemically Activated Fluorescent Expression) bioassays,which utilize recombinant cell lines containing stably transfected dioxin(AhR) responsive firefly luciferase or enhanced green fluorescent protein(EGFP) reporter genes,respectively.While the current CALUX and CAFLUX bioassays are very sensitive,increasing their lower limit of sensitivity,magnitude of response and dynamic range for chemical detection would significantly increase their utility,particularly for those samples that contain low levels of dioxin-like HAHs(i.e.,serum) .In this study,we report that the addition of modulators of cell signaling pathways or modification of cell culture conditions results in significant improvement in the magnitude and overall responsiveness of the existing CALUX and CAFLUX cell bioassays.展开更多
Symptomatic hepato-diaphragmatic interposition of a bowel loop or Chilaiditi's syndrome is a peculiar anatomical condition most often found by chance. Its described symptoms range from intermittent, mild abdominal...Symptomatic hepato-diaphragmatic interposition of a bowel loop or Chilaiditi's syndrome is a peculiar anatomical condition most often found by chance. Its described symptoms range from intermittent, mild abdominal pain and dyspepsia to acute intestinal obstruction. We report a case of hepato-diaphragmatic migration of the hepatic flexure of the colon associated to an unusual, heretofore unreported, angina-like pain exclusively evoked by the left lateral decubitus. To maximize the chance of observing anatomical changes in different postures, computed tomography of the chest and abdomen was performed after air insufflation into the colon. While frank herniation into the chest was excluded, the scan showed that the hepatic flexure-with the interposition of the diaphragm-came in contact with the right side of the heart in the left lateral, but not in the supine, decubitus. This finding was reproduced by echocardiography which also showed virtually unaltered hemodynamics after the change of posture. ECG, left and right ventricular global and regional function as well as cardiac injury markers also remained unchanged during the maneuver, indicating that the pain evoked by the latter was unlikely due to myocardial ischemia. This case suggests that Chilaiditi's syndrome should be included among the possible, although rare,causes of unexplained angina-like symptoms.展开更多
AIM： To asses the expression of myeloid dendritic cells （CD11c＋） subset during acute HCV hepatitis and its possible involvement in natural history of the infection.METHODS： We enrolled 11 patients with acute hepa...AIM： To asses the expression of myeloid dendritic cells （CD11c＋） subset during acute HCV hepatitis and its possible involvement in natural history of the infection.METHODS： We enrolled 11 patients with acute hepatitis C （AHC） （Group A）, 10 patients with acute hepatitis A （AHA） （as infective control-Group B） and 10 healthy donors （group C） in this study. All patients underwent selective flow cytometry gating strategies to assess the peripheral number of the myeloid dendritic cells （mDCs） to understand the possible role and differences during acute hepatitis.RESULTS： Eight of 11 patients with acute HCV hepatitis did not show any increase of mDCs compared to healthy individuals, while a significant decrease of mDCs was found in absolute cell count （z=-2.37, P〈0.05） and percentage （z=-2.30; P〈 0.05） as compared with AHA. On the contrary, The remaining three patients of the group A had a higher mDCs number and percentage as occur in group B. Interestingly, after six months, those patients did not show any increase of mDCs subset were chronically infected, while the three subjects with an increase of peripheral mDCs, as in HAV acute infection, resolved the illness.CONCLUSION： The lack of increase of mDCs during acute hepatitis C might be an important factor involved in chronicization of the infection.展开更多
Vein of Galen malformation(VOGM) is a rare congenital vascular malformation caused by the maldevelopment of its embryonic precursor,the median prosencephalic vein of Markowski.VOGM results in neonatal morbidity and mo...Vein of Galen malformation(VOGM) is a rare congenital vascular malformation caused by the maldevelopment of its embryonic precursor,the median prosencephalic vein of Markowski.VOGM results in neonatal morbidity and mortality,and premature delivery does not improve the outcome.We report a term female neonate in whom a vein of Galen malformation was diagnosed prenatally at 37 wk of gestation during a growth ultrasound and confirmed by fetal magnetic resonance imaging.Signs of cardiac decompensation were evident in the fetus.Multiple interventional radiology embolizations of the feeding vessels were performed successfully on days 7,10,12,14 and 19.A review of the literature on the endovascular management of neonates with these malformations is presented herein.展开更多
This paper summarizes some useful concepts about the coordination of directional overcurrent protections.The following key topics are described:the analysis of systems in a ring configuration and only one source of sh...This paper summarizes some useful concepts about the coordination of directional overcurrent protections.The following key topics are described:the analysis of systems in a ring configuration and only one source of short-circuit currents;the impossibility of obtaining selectivity for all the possible system configurations with multiple sources;the need for inverse functions in order to obtain selectivity in systems with multiple sources;the coordination with protections for radial loads;the coordination between instantaneous and delayed functions;the considerations to select the pickup values;the influence of contributions from motors to short circuit currents;the transient configurations due to sequential trips at both line ends;the influence of dynamic behavior of overcurrent functions;the influence of stability constraints;other specific considerations for ground functions;some specific considerations for systems with distributed generation.A summary of these points and their effect on the coordination of directional overcurrent protections is not available in the current literature.This novel description should facilitate the inclusion of these key points in research and coordination studies related to these protective functions.展开更多
The organism Caenorhabditis elegans is a performant model system for studying human biological processes and diseases,but until now all phenome data are produced as population-averaged read-outs.Monitoring of individu...The organism Caenorhabditis elegans is a performant model system for studying human biological processes and diseases,but until now all phenome data are produced as population-averaged read-outs.Monitoring of individual responses to drug treatments would however be more informative.Here,a new strategy to track different phenotypic traits of individual C.elegans nematodes throughout their full life-cycle-i.e.,embryonic and post-embryonic development,until adulthood onset,differently from life-span-is presented.In an automated fashion,single worms were synchronized,isolated,and cultured from egg to adulthood in a microfluidic device,where their identity was preserved during their whole development.Several phenotypes were monitored and quantified for each animal,resulting in high-content phenome data.Specifically,the method was validated by analyzing the response of C.elegans to doxycycline,an antibiotic fairly well-known to prolong the development and activate mitochondrial stress-response pathways in different species.Interestingly,the obtained extensive single-worm phenome not only confirmed the dramatic doxycycline effect on the worm developmental delay,but more importantly revealed subtle yet severe treatment-dependent phenotypes that are representative of minority subgroups and would have otherwise stayed hidden in an averaged dataset.Such heterogeneous response started during the embryonic development,which makes essential having a dedicated chip that allows including this early developmental stage in the drug assay.Our approach would therefore allow elucidating pharmaceutical or therapeutic responses that so far were still being overlooked.展开更多
We studied the prevalence of non-alcoholic fatty liver disease and non-alcoholic-steatohepatitis in patients with metabolicsyndrome but normal liver enzymes. The histological findings of patients with normal liver enz...We studied the prevalence of non-alcoholic fatty liver disease and non-alcoholic-steatohepatitis in patients with metabolicsyndrome but normal liver enzymes. The histological findings of patients with normal liver enzymes and non-alcoholic-steatohepatitis were compared with those of a control-group with persistently abnormal liver enzymes. Patients presenting with normal liver enzymes were enrolled in the study and underwent liver biopsy. Prevalence of non-alcoholic-steatohepatitis and risk factors for fibrosis and cirrhosis were evaluated. Data from a control-group with non-alcoholic-steatohepatitis and abnormal liver enzymes were used to compare the histological findings. Fifty-eight of the 80 patients enrolled had varying degrees of non-alcoholic steatohepatitis, of these 26 had fibrosis and 8 silent cirrhosis. The association of metabolic-syndrome, female-sex, a long-history of obesity and body mass index > 45 were considered to be independent risk-factors for fibrosis. Comparing the histological findings of cases and controls we found a similar severity of steatosis and fibrosis, with a greater prevalence of ballooning degeneration and glycogenated-nuclei rather than lobular-inflammation. In the subjects selected according to our criteria, liver enzyme levels could not be used as surrogate markers of non-alcoholic-steatohepatitis. Histological hallmarks of patients with metabolic-syndrome, normal liver enzymes and non-alcoholic-steatohepatitis consist to a lesser degree of lobular-inflammation and a more severe ballooning and glycogenated-nuclei.展开更多
In recent decades,designers have increasingly focused on the stability of assemblies in composite materials over time,particularly when used in structural applications.The use of structural adhesives allows for realis...In recent decades,designers have increasingly focused on the stability of assemblies in composite materials over time,particularly when used in structural applications.The use of structural adhesives allows for realising assemblies without mechanical fasteners.In fact,bonding is an assembly technique that prevent corrosion,ensures uniform stresses in the joint,and grows the specific resistance of the assembly.The knowledge of the behaviour of bonded joint is necessary to ensure the reliability of this technique over time,especially in aggressive environments.The aim of this wo rk consists in investigating the combined effect of hydrothermal ageing and temperature test on the lap shear strength of single lap joints realised in CFRP.The results showed a higher influence of the ageing on paste adhesive compared to film adhesive.However,the ageing,combined with the operating temperature,played a fundamental role on the shear strength of the bonded joints.展开更多
Abstract： In HIV-1 management, eradication of the virus from sanctuaries represents a major and challenging goal. The genital tract, gut associated lymphoid tissue, lymph nodes, central nervous system, macrophages an...Abstract： In HIV-1 management, eradication of the virus from sanctuaries represents a major and challenging goal. The genital tract, gut associated lymphoid tissue, lymph nodes, central nervous system, macrophages and latently infected CD4＋ T lymphocytes are typical sites where H1V-1 compartmentalizes. To circumvent this problem, a consistent number of studies have focused on improving ARVs （antiretroviral drugs） delivery into sanctuary sites and different nanoteehnological approaches have been developed. Cellular HIV-1 sanctuaries （i.e. macrophages） can be reached by nanoformulation of ARVs or by activation of latently infected cells. Anatomical sanctuaries （i.e. brain or male genital tract） can be addressed by increasing the permeation of ARVs across tissue barriers, such as the blood-brain barrier or the blood-testis barrier, while ARVs concentration in lymph nodes can be enhanced by drug encapsulation in CD4-targeted nanoparticles.展开更多
It has become clear that inflammation is an important component of coronary heart disease. Atherosclerotic disease usually begins with injury to endothelial cells.……
About 30% of human breast cancers are human epidermal growth factor receptor 2 （HER2）＋. This particular biological portrait is characterized by the overexpression of HER2 receptor with the subsequent deregulation o...About 30% of human breast cancers are human epidermal growth factor receptor 2 （HER2）＋. This particular biological portrait is characterized by the overexpression of HER2 receptor with the subsequent deregulation of downstream pathways, which control cellular survival and proliferation. The most effective treatment for HER2＋ cancer is represented by therapy with HER2-targeted agents. Anti-HER2 therapy dramatically improves clini-cal outcomes, although it shows some limitations in achieving a proper treatment. These drawbacks of HER2-targeted therapy may be overcome with the develop-ment of HER2-targeted drug delivery nanodevices. These nanoparticles possess an internal three-dimensional com-partimentalization, which allows to combine the specifc target recognition with their capability to act as a drug reservoir for the selective delivery of chemotherapics to tumor sites. Moreover, nanoparticles useful in photo-thermal ablation or in photodynamic therapy have been functionalized in order to match specifcity in tumor cell recognition and suitable chemical properties. Here, we summarize the state of the art concerning the HER2＋ breast cancer and anti-HER2 therapy, in particular deep-ening the contribution of the nanomedicine. Description of preclinical studies performed with HER2-targeted nanoparticles for HER2＋ breast cancer therapy will be preceded by an overview on HER2-targeting molecules and nano-conjugation strategies. Further investigation will be necessary to introduce these nano-drugs in clinical prac-tice; however promising results encourage an upcoming translation of this research for the next future.展开更多
文摘Hepatocellular carcinoma(HCC)is currently the sixth most common type of cancer with a high mortality rate and an increasing incidence worldwide.Its etiology is usually linked to environmental,dietary or lifestyle factors.HCC most commonly arises in a cirrhotic liver but interestingly an increasing proportion of HCCs develop in the non-fibrotic or minimal fibrotic liver and a shift in the underlying etiology can be observed.Although this process is yet to be completely understood,this changing scenario also has impact on the material seen by pathologists,presenting them with new diagnostic dilemmas.Histopathologic criteria for diagnosing classical,progressed HCC are well established and known,but with an increase in detection of small and early HCCs due to routine screening programs,the diagnosis of these small lesions in core needle biopsies poses a difficult challenge.These lesions can be far more difficult to distinguish from one another than progressed HCC,which is usually a clear cut hematoxylin and eosin diagnosis.Furthermore lesions thought to derive from progenitor cells have recently been reclassified in the WHO.This review summarizes recent developments and tries to put new HCC biomarkers in context with the WHOs reclassification.Furthermore it also addresses the group of tumors known as combined hepatocellular-cholangiocellular carcinomas.
文摘New frontiers about retinal cell transplantation for retinal degenerative diseases start from the idea that acting on stem cells can help regenerate retinal layers and establish new synapses among retinal cells.Deficiency or alterations of synaptic input and neurotrophic factors result in trans-neuronal degeneration of the inner retinal cells.Thus,the disruption of photoreceptors takes place.However,even in advanced forms of retinal degeneration,a good percentage of the ganglion cells and the inner nuclear layer neurons remain intact.This phenomenon provides evidence for obtaining retinal circuitry through the transplantation of photoreceptors into the subretinal region.The eye is regarded as an optimal organ for cell transplantation because of its immunological privilege and the relatively small number of cells collaborating to carry out visual activities.The eyeball's immunological privilege,characterized by the suppression of delayed-type hypersensitivity responses in ocular tissues,is responsible for the low rate of graft rejection in transplant patients.The main discoveries highlight the capacity of embryonic stem cells(ESCs)and induced pluripotent stem cells to regenerate damaged retinal regions.Recent progress has shown significant enhancements in transplant procedures and results.The research also explores the ethical ramifications linked to the utilization of stem cells,emphasizing the ongoing issue surrounding ESCs.The analysis centers on recent breakthroughs,including the fabrication of three-dimensional retinal organoids and the innovation of scaffolding for cell transportation.Moreover,researchers are currently assessing the possibility of CRISPR and other advanced gene editing technologies to enhance the outcomes of retinal transplantation.The widespread use of universally recognized safe surgical and imaging methods enables retinal transplantation and monitoring of transplanted cell growth toward the correct location.Currently,most therapy approaches are in the first phases of development and neces
文摘Uveal melanoma(UM)is the most common primary intraocular cancer in adults.The incidence in Europe and the United States is 6-7 per million population per year.Although most primary UMs can be successfully treated and locally controlled by irradiation therapy or local tumor resection,up to 50%of UM patients develop metastases that usually involve the liver and are fatal within 1 year.To date,chemotherapy and targeted treatments only obtain minimal responses in patients with metastatic UM,which is still characterized by poor prognosis.No standard therapeutic approaches for its prevention or treatment have been established.The application of immunotherapy agents,such as immune checkpoint inhibitors that are effective in cutaneous melanoma,has shown limited effects in the treatment of ocular disease.This is due to UM’s distinct genetics,natural history,and complex interaction with the immune system.Unlike cutaneous melanomas characterized mainly by BRAF or NRAS mutations,UMs are usually triggered by a mutation in GNAQ or GNA11.As a result,more effective immunotherapeutic approaches,such as cancer vaccines,adoptive cell transfer,and other new molecules are currently being studied.In this review,we examine novel immunotherapeutic strategies in clinical and preclinical studies and highlight the latest insight in immunotherapy and the development of tailored treatment of UM.
文摘AIM: To assess the evolution of duodenal lymphocytosis(DL), a condition characterized by increased intraepithelial lymphocytes(IELs), over 2 years of follow-up.METHODS: Consecutive patients undergoing upper endoscopy/histology for abdominal pain, diarrhea, weight loss, weakness or other extraintestinal features compatible with celiac disease(CD) were included. Evaluation of IELs infiltrate in duodenal biopsy sampleswas carried out by CD3-immunohistochemistry and expressed as number of positive cells/100 enterocytes. Diagnostic agreement on the IELs count was tested by calculating the weighted k coefficient. All patients underwent serological detection of autoantibodies associated with CD: Ig G and Ig A anti-tissue transglutaminase and endomysium. Each patient underwent further investigations to clarify the origin of DL at baseline and/or in the course of 2 years of follow-up every six months. Autoimmune thyroiditis, intestinal infections, parasitic diseases, bacterial intestinal overgrowth, hypolactasia and wheat allergy were detected. Colonoscopy and enteric magnetic resonance i m a g i n g w e r e p e r f o r m e d w h e n n e c e s s a r y. R i s k factors affecting the final diagnosis were detected by multinomial logistic regression and expressed as OR.RESULTS: Eighty-five patients(16 males, 69 females, aged 34.1 ± 12.5 years) were followed up for a mean period of 21.7 ± 11.7 mo. At baseline, endoscopy/duodenal biopsy, CD3 immunohistochemistry revealed: > 25 IELs/100 enterocytes in 22 subjects, 15-25 IELs in 37 and < 15 IELs in 26. They all had negative serum anti-transglutaminase and anti-endomysium, whilst 5 showed Ig G anti-gliadin positivity. In the course of follow-up, 23 developed CD seropositivity and gluten sensitivity(GS) was identified in 19. Other diagnoses were: 5 Helicobacter pylori infections, 4 jejunal Crohn's disease, 1 lymphocytic colitis and 1 systemic sclerosis. The disease in the remaining 32 patients was classified as irritable bowel syndrome because of the lack of diagnostic evidence.
文摘Hepatitis B virus(HBV) is responsible for 50%-80% of cases of hepatocellular carcinoma(HCC) worldwide.Entecavir(ET) is a potent inhibitor of chronic HBV-DNA polymerase,inhibiting both the priming and elongation steps of viral DNA replication.Sorafenib(SO) has proven efficacy in prolonging survival in patients with advanced HCC.In this frontier report we discuss a possible way to optimize treatment outcomes in patients with HBV and HCC by treatment with ET and SO,on the basis of our practice and published evidence from the literature.
文摘Background:Traumatic pancreatic injuries are rare,and guidelines specifying management are controversial and difficult to apply in the acute clinical setting.Due to sparse data on these injuries,we carried out a retrospective review to determine outcomes following surgical or non-surgical management of traumatic pancreatic injuries.We hypothesize a higher morbidity and mortality rate in patients treated surgically when compared to patients treated non-surgically.Methods:We performed a retrospective review of data from four trauma centers in New York from 1990–2014,comparing patients who had blunt traumatic pancreatic injuries who were managed operatively to those managed non-operatively.We compared continuous variables using the Mann-Whitney U test and categorical variables using the chi-square and Fisher’s exact tests.Univariate analysis was performed to determine the possible confounding factors associated with mortality in both treatment groups.Results:Twenty nine patients were managed operatively and 32 non-operatively.There was a significant difference between the operative and non-operative groups in median age(37.0 vs.16.2 years,P=0.016),grade of pancreatic injury(grade I;30.8 vs.85.2%,P value for all comparisons<0.0001),median injury severity score(ISS)(16.0 vs.4.0,P=0.002),blood transfusion(55.2 vs.15.6%,P=0.0012),other abdominal injuries(79.3 vs.38.7%,P=0.0014),pelvic fractures(17.2 vs.0.00%,P=0.020),intensive care unit(ICU)admission(86.2 vs.50.0%,P=0.003),median length of stay(LOS)(16.0 vs.4.0 days,P<0.0001),and mortality(27.6 vs.3.1%,P=0.010).Conclusions:Patients with traumatic pancreatic injuries treated operatively were more severely injured and suffered greater complications than those treated non-operatively.The greater morbidity and mortality associated with these patients warrants further study to determine optimal triage strategies and which subset of patients is likely to benefit from surgery.
文摘Hepatitis B virus(HBV)is the leading cause of liver disease and infects an estimated 240 million people worldwide.It is characterised by a high degree of genetic heterogeneity because of the use of a reverse transcriptase during viral replication.The ten genotypes(A-J)that have been described so far further segregate into a number of subgenotypes which have distinct ethno-geographic distribution.Genotypes A and D are ubiquitous and the most prevalent genotypes in Europe(mainly represented by subgenotypes D1-3 and A2);genotypes B and C are restricted to eastern Asia and Oceania;genotype E to central and western Africa;and genotypes H and F(classified into 4 subgenotypes)to Latin America and Alaska.This review summarises the data obtained by studying the global phylodynamics and phylogeography of HBV genotypes,particularly those concerning the origin and dispersion histories of genotypes A,D,E and F and their subgenotypes.The lack of any consensus concerning the HBV substitution rate and the conflicting data obtained using different calibration approaches make the time of origin and divergence of the various genotypes and subgenotypes largely uncertain.It is hypothesised that HBV evolutionary rates are time dependent,and that the changes depend on the main transmission routes of the genotypes and the dynamics of the infected populations.
基金support from the National Institutes of Environmental Health Sciences Superfund Basic Research Grant(ES004699(MSD))the California Agricultural Experiment Station,the Startup Fund of 100 Talents Program of Chinese Academy of Sciences+1 种基金the National Natural Science Foundation of China (20921063)the National Basic Research Program(2010CB933500)
文摘Reporter genes produce a protein product in transfected cells that can be easily measured in intact or lysed cells and they have been extensively used in numerous basic and applied research applications.Over the past 10 years,reporter gene assays have been widely accepted and used for analysis of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related dioxin-like compounds in various types of matrices,such as biological,environmental,food and feed samples,given that high-resolution instrumental analysis techniques are impractical for large-scale screening analysis.The most sensitive cell-based reporter gene bioassay systems developed are the mechanism-based CALUX(Chemically Activated Luciferase Expression) and CAFLUX(Chemically Activated Fluorescent Expression) bioassays,which utilize recombinant cell lines containing stably transfected dioxin(AhR) responsive firefly luciferase or enhanced green fluorescent protein(EGFP) reporter genes,respectively.While the current CALUX and CAFLUX bioassays are very sensitive,increasing their lower limit of sensitivity,magnitude of response and dynamic range for chemical detection would significantly increase their utility,particularly for those samples that contain low levels of dioxin-like HAHs(i.e.,serum) .In this study,we report that the addition of modulators of cell signaling pathways or modification of cell culture conditions results in significant improvement in the magnitude and overall responsiveness of the existing CALUX and CAFLUX cell bioassays.
文摘Symptomatic hepato-diaphragmatic interposition of a bowel loop or Chilaiditi's syndrome is a peculiar anatomical condition most often found by chance. Its described symptoms range from intermittent, mild abdominal pain and dyspepsia to acute intestinal obstruction. We report a case of hepato-diaphragmatic migration of the hepatic flexure of the colon associated to an unusual, heretofore unreported, angina-like pain exclusively evoked by the left lateral decubitus. To maximize the chance of observing anatomical changes in different postures, computed tomography of the chest and abdomen was performed after air insufflation into the colon. While frank herniation into the chest was excluded, the scan showed that the hepatic flexure-with the interposition of the diaphragm-came in contact with the right side of the heart in the left lateral, but not in the supine, decubitus. This finding was reproduced by echocardiography which also showed virtually unaltered hemodynamics after the change of posture. ECG, left and right ventricular global and regional function as well as cardiac injury markers also remained unchanged during the maneuver, indicating that the pain evoked by the latter was unlikely due to myocardial ischemia. This case suggests that Chilaiditi's syndrome should be included among the possible, although rare,causes of unexplained angina-like symptoms.
文摘AIM： To asses the expression of myeloid dendritic cells （CD11c＋） subset during acute HCV hepatitis and its possible involvement in natural history of the infection.METHODS： We enrolled 11 patients with acute hepatitis C （AHC） （Group A）, 10 patients with acute hepatitis A （AHA） （as infective control-Group B） and 10 healthy donors （group C） in this study. All patients underwent selective flow cytometry gating strategies to assess the peripheral number of the myeloid dendritic cells （mDCs） to understand the possible role and differences during acute hepatitis.RESULTS： Eight of 11 patients with acute HCV hepatitis did not show any increase of mDCs compared to healthy individuals, while a significant decrease of mDCs was found in absolute cell count （z=-2.37, P〈0.05） and percentage （z=-2.30; P〈 0.05） as compared with AHA. On the contrary, The remaining three patients of the group A had a higher mDCs number and percentage as occur in group B. Interestingly, after six months, those patients did not show any increase of mDCs subset were chronically infected, while the three subjects with an increase of peripheral mDCs, as in HAV acute infection, resolved the illness.CONCLUSION： The lack of increase of mDCs during acute hepatitis C might be an important factor involved in chronicization of the infection.
文摘Vein of Galen malformation(VOGM) is a rare congenital vascular malformation caused by the maldevelopment of its embryonic precursor,the median prosencephalic vein of Markowski.VOGM results in neonatal morbidity and mortality,and premature delivery does not improve the outcome.We report a term female neonate in whom a vein of Galen malformation was diagnosed prenatally at 37 wk of gestation during a growth ultrasound and confirmed by fetal magnetic resonance imaging.Signs of cardiac decompensation were evident in the fetus.Multiple interventional radiology embolizations of the feeding vessels were performed successfully on days 7,10,12,14 and 19.A review of the literature on the endovascular management of neonates with these malformations is presented herein.
文摘This paper summarizes some useful concepts about the coordination of directional overcurrent protections.The following key topics are described:the analysis of systems in a ring configuration and only one source of short-circuit currents;the impossibility of obtaining selectivity for all the possible system configurations with multiple sources;the need for inverse functions in order to obtain selectivity in systems with multiple sources;the coordination with protections for radial loads;the coordination between instantaneous and delayed functions;the considerations to select the pickup values;the influence of contributions from motors to short circuit currents;the transient configurations due to sequential trips at both line ends;the influence of dynamic behavior of overcurrent functions;the influence of stability constraints;other specific considerations for ground functions;some specific considerations for systems with distributed generation.A summary of these points and their effect on the coordination of directional overcurrent protections is not available in the current literature.This novel description should facilitate the inclusion of these key points in research and coordination studies related to these protective functions.
基金This work in the M.A.G.laboratory was supported by the Ecole Polytechnique Fédérale de Lausanne and the EU Ideas program(ERC-2012-AdG-320404)V.S.was supported by the‘EPFL Fellows’program co-funded by Marie Skłodowska-Curie,Horizon 2020 Grant agreement(665667)+4 种基金M.C.and L.M.were supported by the Gebert Rüf Stiftung(GRS-025/16).The work in the J.A.laboratory is supported by the EPFL,NIH(R01AG043930)Systems X(SySX.ch 2013/153)Velux Stiftung(1019)the Swiss National Science Foundation(31003A-140780).
文摘The organism Caenorhabditis elegans is a performant model system for studying human biological processes and diseases,but until now all phenome data are produced as population-averaged read-outs.Monitoring of individual responses to drug treatments would however be more informative.Here,a new strategy to track different phenotypic traits of individual C.elegans nematodes throughout their full life-cycle-i.e.,embryonic and post-embryonic development,until adulthood onset,differently from life-span-is presented.In an automated fashion,single worms were synchronized,isolated,and cultured from egg to adulthood in a microfluidic device,where their identity was preserved during their whole development.Several phenotypes were monitored and quantified for each animal,resulting in high-content phenome data.Specifically,the method was validated by analyzing the response of C.elegans to doxycycline,an antibiotic fairly well-known to prolong the development and activate mitochondrial stress-response pathways in different species.Interestingly,the obtained extensive single-worm phenome not only confirmed the dramatic doxycycline effect on the worm developmental delay,but more importantly revealed subtle yet severe treatment-dependent phenotypes that are representative of minority subgroups and would have otherwise stayed hidden in an averaged dataset.Such heterogeneous response started during the embryonic development,which makes essential having a dedicated chip that allows including this early developmental stage in the drug assay.Our approach would therefore allow elucidating pharmaceutical or therapeutic responses that so far were still being overlooked.
文摘We studied the prevalence of non-alcoholic fatty liver disease and non-alcoholic-steatohepatitis in patients with metabolicsyndrome but normal liver enzymes. The histological findings of patients with normal liver enzymes and non-alcoholic-steatohepatitis were compared with those of a control-group with persistently abnormal liver enzymes. Patients presenting with normal liver enzymes were enrolled in the study and underwent liver biopsy. Prevalence of non-alcoholic-steatohepatitis and risk factors for fibrosis and cirrhosis were evaluated. Data from a control-group with non-alcoholic-steatohepatitis and abnormal liver enzymes were used to compare the histological findings. Fifty-eight of the 80 patients enrolled had varying degrees of non-alcoholic steatohepatitis, of these 26 had fibrosis and 8 silent cirrhosis. The association of metabolic-syndrome, female-sex, a long-history of obesity and body mass index > 45 were considered to be independent risk-factors for fibrosis. Comparing the histological findings of cases and controls we found a similar severity of steatosis and fibrosis, with a greater prevalence of ballooning degeneration and glycogenated-nuclei rather than lobular-inflammation. In the subjects selected according to our criteria, liver enzyme levels could not be used as surrogate markers of non-alcoholic-steatohepatitis. Histological hallmarks of patients with metabolic-syndrome, normal liver enzymes and non-alcoholic-steatohepatitis consist to a lesser degree of lobular-inflammation and a more severe ballooning and glycogenated-nuclei.
基金the funding of the Italian M.I.U.R.(Ministry of Instruction,University and Technological Research)。
文摘In recent decades,designers have increasingly focused on the stability of assemblies in composite materials over time,particularly when used in structural applications.The use of structural adhesives allows for realising assemblies without mechanical fasteners.In fact,bonding is an assembly technique that prevent corrosion,ensures uniform stresses in the joint,and grows the specific resistance of the assembly.The knowledge of the behaviour of bonded joint is necessary to ensure the reliability of this technique over time,especially in aggressive environments.The aim of this wo rk consists in investigating the combined effect of hydrothermal ageing and temperature test on the lap shear strength of single lap joints realised in CFRP.The results showed a higher influence of the ageing on paste adhesive compared to film adhesive.However,the ageing,combined with the operating temperature,played a fundamental role on the shear strength of the bonded joints.
文摘Abstract： In HIV-1 management, eradication of the virus from sanctuaries represents a major and challenging goal. The genital tract, gut associated lymphoid tissue, lymph nodes, central nervous system, macrophages and latently infected CD4＋ T lymphocytes are typical sites where H1V-1 compartmentalizes. To circumvent this problem, a consistent number of studies have focused on improving ARVs （antiretroviral drugs） delivery into sanctuary sites and different nanoteehnological approaches have been developed. Cellular HIV-1 sanctuaries （i.e. macrophages） can be reached by nanoformulation of ARVs or by activation of latently infected cells. Anatomical sanctuaries （i.e. brain or male genital tract） can be addressed by increasing the permeation of ARVs across tissue barriers, such as the blood-brain barrier or the blood-testis barrier, while ARVs concentration in lymph nodes can be enhanced by drug encapsulation in CD4-targeted nanoparticles.
文摘 It has become clear that inflammation is an important component of coronary heart disease. Atherosclerotic disease usually begins with injury to endothelial cells.……
文摘About 30% of human breast cancers are human epidermal growth factor receptor 2 （HER2）＋. This particular biological portrait is characterized by the overexpression of HER2 receptor with the subsequent deregulation of downstream pathways, which control cellular survival and proliferation. The most effective treatment for HER2＋ cancer is represented by therapy with HER2-targeted agents. Anti-HER2 therapy dramatically improves clini-cal outcomes, although it shows some limitations in achieving a proper treatment. These drawbacks of HER2-targeted therapy may be overcome with the develop-ment of HER2-targeted drug delivery nanodevices. These nanoparticles possess an internal three-dimensional com-partimentalization, which allows to combine the specifc target recognition with their capability to act as a drug reservoir for the selective delivery of chemotherapics to tumor sites. Moreover, nanoparticles useful in photo-thermal ablation or in photodynamic therapy have been functionalized in order to match specifcity in tumor cell recognition and suitable chemical properties. Here, we summarize the state of the art concerning the HER2＋ breast cancer and anti-HER2 therapy, in particular deep-ening the contribution of the nanomedicine. Description of preclinical studies performed with HER2-targeted nanoparticles for HER2＋ breast cancer therapy will be preceded by an overview on HER2-targeting molecules and nano-conjugation strategies. Further investigation will be necessary to introduce these nano-drugs in clinical prac-tice; however promising results encourage an upcoming translation of this research for the next future.
