The visual system of teleost fish grows continuously,which is a useful model for studying regeneration of the central nervous system.Glial cells are key for this process,but their contribution is still not well define...The visual system of teleost fish grows continuously,which is a useful model for studying regeneration of the central nervous system.Glial cells are key for this process,but their contribution is still not well defined.We followed oligodendrocytes in the visual system of adult zebrafish during regeneration of the optic nerve at 6,24,and 72 hours post-lesion and at 7 and 14 days post-lesion via the sox10:tagRFP transgenic line and confocal microscopy.To understand the changes that these oligodendrocytes undergo during regeneration,we used Sox2 immunohistochemistry,a stem cell marker involved in oligodendrocyte differentiation.We also used the Click-iT™ Plus TUNEL assay to study cell death and a BrdU assay to determine cell proliferation.Before optic nerve crush,sox10:tagRFP oligodendrocytes are located in the retina,in the optic nerve head,and through all the entire optic nerve.Sox2-positive cells are present in the peripheral germinal zone,the mature retina,and the optic nerve.After optic nerve crush,sox10:tagRFP cells disappeared from the optic nerve crush zone,suggesting that they died,although they were not TUNEL positive.Concomitantly,the number of Sox2-positive cells increased around the crushed area,the optic nerve head,and the retina.Then,between 24 hours post-lesion and 14 days post-lesion,double sox10:tagRFP/Sox2-positive cells were detected in the retina,optic nerve head,and whole optic nerve,together with a proliferation response at 72 hours post-lesion.Our results confirm that a degenerating process may occur prior to regeneration.First,sox10:tagRFP oligodendrocytes that surround the degenerated axons stop wrapping them,change their“myelinating oligodendrocyte”morphology to a“nonmyelinating oligodendrocyte”morphology,and die.Then,residual oligodendrocyte progenitor cells in the optic nerve and retina proliferate and differentiate for the purpose of remyelination.As new axons arise from the surviving retinal ganglion cells,new sox10:tagRFP oligodendrocytes arise from residual oligodendrocyte progenitor cells to guide,nourish and myelinate them.Thus,oligodendrocytes play an active role in zebrafish axon regeneration and remyelination.展开更多
Background Transcatheter Aortic Valve Implantation(TAVI)has changed the treatment paradigm of the aortic stenosis(AS).It has become the treatment of choice in patients with symptomatic AS and surgical high risk,and a ...Background Transcatheter Aortic Valve Implantation(TAVI)has changed the treatment paradigm of the aortic stenosis(AS).It has become the treatment of choice in patients with symptomatic AS and surgical high risk,and a valid alternative to surgical aortic valve replacement in patients with low and medium surgical risk.Despite numerous evidence on clinical results,indications and benefits,only a few studies analyse it from patient's perspective and the impact of TAVI on them.The objective of this study is to evaluate the experience of patients undergoing TAVI.Methods Cross-sectional,descriptive observational study in two Spanish hospitals,with a establish Nurse TAVI program,with100 patients undergoing TAVI.A specific questionnaire was designed(VALVEX questionnaire)and a pilot study was conducted by a multidisciplinary team of doctors,nurses and patients.The questionnaire was given to patients at 30 days after TAVI procedure during the follow up at the TAVI nurse clinic.Results The study demonstrated a mean satisfaction of 9 for the TAVI program,with 96%of patients that would recommend TAVI to other patients.Patients scored a high satisfaction on the information received prior to the procedure.During the procedure and admission,the satisfaction was high in relation to the care received.During the follow up,satisfaction was high in relation to the role of the TAVI nurse,for the information and continuation of care during the procedure,in reducing anxiety,organising their admission and understanding the process.However,questions with less scores were related to hospital catering,delay between diagnosed and treatment,and patient decision-making process.Conclusion The evaluation of patient experience allows us to improve the information given to the patient during their TAVI process and it can also allow patients to be more relax,aware and prepared for the procedure.Continuous follow up enables monitoring of patient recovery and helps to discuss any doubts improving patient's satisfaction.The use of PREMs and PROMs associated to TAVI pathway combined with an active participation of the patient on the design of the questionnaire is essential for keeping the patient in the centre of the TAVI pathway.展开更多
Intravesical bacillus Calmette-Guerin(BCG) instillation has been adopted for the treatment of patients with superficial bladder cancer. Severe adverse events due to local instillation of BCG are uncommon, with an over...Intravesical bacillus Calmette-Guerin(BCG) instillation has been adopted for the treatment of patients with superficial bladder cancer. Severe adverse events due to local instillation of BCG are uncommon, with an overall rate of serious complications of less than 5%. We report the case of an immunocompetent adult patient with multi-system effects, namely pneumonitis, granulomatous hepatitis and meningitis, who responded well to standard treatment for Mycobacterium bovis. This case highlights the importance of a thorough assessment of this type of patient.展开更多
Introduction: Abdominal angiostrongyliasis is an infrequently diagnosed disease because it is little known and is usually well tolerated. Methods: We carried out a systematic review with PubMed as a search engine for ...Introduction: Abdominal angiostrongyliasis is an infrequently diagnosed disease because it is little known and is usually well tolerated. Methods: We carried out a systematic review with PubMed as a search engine for the MedLine database, and we analysed the clinical, epidemiological and analytical parameters of this disease. Results: In total, reports of 27 case have been found, together with a series of 116 patients, which were later augmented up to 194 patients. In the results, we have observed a predominance of male patients, and Costa Rica, Brazil and the United States as the main countries of origin. Typical symptoms include abdominal pain on the right iliac fossa, with leukocytosis and eosinophilia. Discussion: There are some serological diagnostic methods, although lack of standardization leads to most of the diagnoses being reached via pathology. Surgery is the usual treatment approach. Although there are medical options, this is a controversial subject because of the low number of cases published in the literature, which implies an absence of solid studies.展开更多
The aim of the work was to analyze and expose the donor and recipient riskfactors in pancreas transplantation.In the following paper,we exposed the 2018Spanish Consensus Document on Donor and Recipient Selection Crite...The aim of the work was to analyze and expose the donor and recipient riskfactors in pancreas transplantation.In the following paper,we exposed the 2018Spanish Consensus Document on Donor and Recipient Selection Criteria forPancreas Transplantation.An assessment of the previous Selection Criteria forDonors and Recipients of Pancreas Transplantation,published in 2005 by theSpanish Pancreas Transplant Group(GETP)and the National TransplantOrganization(ONT)was performed.A literature review was performed usingCochrane Library,PubMed and Google Scholar databases.Some of the followingterms were used for the literature search:“Diabetes Mellitus,”“PancreasTransplantation,”“Insulin-Secreting Cells,”“Pancreas Allograft Thrombosis,”“Allograft Pancreatitis,”“Donors’Risk Factors,”“Recipients’Risk Factors,”“Pancreas Allograft Rejection”and“Pancreas Allograft Survival.”After anextended search,different inclusion criteria were established.Articles anddocuments with abstracts of full text and in English or Spanish language wereselected.Subsequently,different scientific meetings took place during 2015 and2016 by the GETP.Finally,the updated criteria were published by the GETP andONT in 2018.Several risk factors have been described in pancreas transplantationthat can be divided into donor risk factors:Advanced age(>50 years);high bodymass index(BMI)(>30 kg/m2);cause of death(e.g.,stroke);previoushyperglycemia;hyperamylasemia;cold ischemia time(greater than 8 or 12 h,depending on the type of donation);the use of vasopressors in the intensive careunit or cardiac arrest;and the macroscopic aspect of the pancreas allograft.Thefollowing are recipient risk factors:Advanced age(>50 years);active smoking;high BMI(>30 kg/m2);and peripheral artery disease or sensorimotorpolyneuropathy.Based on the aforementioned parameters,different selectioncriteria have been established for the recipients depending on the type of pancreastransplantation.Knowledge of the risk factors for pancreas transplantation allowsthe establishment of reliable selection criteria for choosing donors and recipients.展开更多
Cholangiopathies are a group of diseases primarily or secondarily affecting bile duct cells, and result in cholangiocyte proliferation, regression, and/or transformation. Their etiopathogenesis may be associated with ...Cholangiopathies are a group of diseases primarily or secondarily affecting bile duct cells, and result in cholangiocyte proliferation, regression, and/or transformation. Their etiopathogenesis may be associated with a broad variety of causes of different nature, which includes genetic, neoplastic, immune-associated, infectious, vascular, and drug-induced alterations, or being idiopathic. miRNAs, small non-coding endogenous RNAs that post-transcriptionally regulate gene expres sion, have been associated with pathophysiological processes in different organs and cell types, and are postulated as potential targets for diagnosis and therapy. In the current manuscript, knowledge regarding the role of miRNAs in the development and/or progression of cholangiopathies has been reviewed and the most relevant findings in this promising field of hepatology have been highlighted.展开更多
The serotonergic system in the brain plays a major role in mood and anxiety regulation when exposed to stress. The aim of the present study was to evaluate the effects of Sertraline administration in coping with stres...The serotonergic system in the brain plays a major role in mood and anxiety regulation when exposed to stress. The aim of the present study was to evaluate the effects of Sertraline administration in coping with stress using the behavioural paradigms of the acoustic startle reflex (ASR) and its prepulse inhibition (PPI) in both sexes. Wistar rats were divided into two groups: intact animals and exposed to restraint stress (RS) 3 times per day during 7 days, which were then subdivided into three other groups: injected with Sertraline (5 mg/kg/day) or the drug vehicle saline for 8 consecutive days, and non-injected. ASR and PPI values were analyzed along 4 sessions to determine behavioral changes. Upon it, we also determine the effects of acute immobilization stress analyzing physiological stress indicators in blood. Our data show sex differences in response to stress paradigms. RS affected more intensely males than females, disturbing the males’ growth and the long-term startle habituation that were not affected in females. PPI increased in the vehicle-injected animals when compared to baseline in both sexes, and Sertraline reversed more efficiently it in females. Moreover, despite both sexes exposed to stressful paradigms exhibited a significant increase in serum glutamic-oxaloacetic transaminase and lactate dehydrogenase enzymes when compared with intact controls, as well as leucopenia, some differences according to sex were found in the haemostatic response to stress. Notably, the repeated injections procedure disturbed the early response to stress, which Sertraline only attenuated in both sexes. Our data suggest that 8-day Sertraline administration is effective in reversing stress-induced changes in some physio-logical parameters, but insufficient to return immunological values to normality.展开更多
Understanding of the cellular signaling pathways involved in cancer disease is of great importance.These complex biological mechanisms can be thoroughly revealed by their structure,dynamics,and control methods.Artific...Understanding of the cellular signaling pathways involved in cancer disease is of great importance.These complex biological mechanisms can be thoroughly revealed by their structure,dynamics,and control methods.Artificial intelligence offers rule-based models that favor the research of human signaling processes.In this paper,we give an overview of the advantages of the formalism of symbolic models in medical biology and cell biology of the uveal melanoma.A language is described that allows us:(1)To define the system states and elements with their alterations;(2)To model the dynamics of the cellular system;and(3)To perform inference-based analysis with the logical tools of the language.展开更多
Identifying the factors that contribute to individual susceptibility to cancer is essential for both prevention and treatment.The advancement of biotechnologies,particularly next-generation sequencing,has accelerated ...Identifying the factors that contribute to individual susceptibility to cancer is essential for both prevention and treatment.The advancement of biotechnologies,particularly next-generation sequencing,has accelerated the discovery of genetic variants linked to cancer susceptibility.While hundreds of cancer-susceptibility genes have been identified,they only explain a small fraction of the overall cancer risk,a phenomenon known as"missing heritability".Despite progress,even considering factors such as epistasis,epigenetics,and gene-environment interactions,the missing heritability remains unresolved.Recent research has revealed that an individual's microbiome composition plays a significant role in cancer susceptibility through several mechanisms,such as modulating immune cell activity and influencing the presence or removal of environmental carcinogens.In this review,we examine the multifaceted roles of the microbiome in cancer risk and explore gene-microbiome and environment-microbiome interactions that may contribute to cancer susceptibility.Additionally,we highlight the importance of experimental models,such as collaborative cross mice,and advanced analytical tools,like artificial intelligence,in identifying microbial factors associated with cancer risk.Understanding these microbial determinants can open new avenues for interventions aimed at reducing cancer risk and guide the development of more effective cancer treatments.展开更多
Cancer drug resistance constitutes a severe limitation for the satisfactory outcome of these patients.This is a complex problem due to the co-existence in cancer cells of multiple and synergistic mechanisms of chemore...Cancer drug resistance constitutes a severe limitation for the satisfactory outcome of these patients.This is a complex problem due to the co-existence in cancer cells of multiple and synergistic mechanisms of chemoresistance(MOC).These mechanisms are accounted for by the expression of a set of genes included in the so-called resistome,whose effectiveness often leads to a lack of response to pharmacological treatment.Additionally,genetic variants affecting these genes further increase the complexity of the question.This review focuses on a set of genes encoding members of the transportome involved in drug uptake,which have been classified into the MOC-1A subgroup of the resistome.These proteins belong to the solute carrier(SLC)superfamily.More precisely,we have considered here several members of families SLC2,SLC7,SLC19,SLC22,SLCO,SLC28,SLC29,SLC31,SLC46,and SLC47 due to the impact of their expression and genetic variants in anticancer drug uptake by tumor cells or,in some cases,general bioavailability.Changes in their expression levels and the appearance of genetic variants can contribute to the Darwinian selection of more resistant clones and,hence,to the development of a more malignant phenotype.Accordingly,to address this issue in future personalized medicine,it is necessary to characterize both changes in resistome genes that can affect their function.It is also essential to consider the time-dependent dimension of these features,as the genetic expression and the appearance of genetic variants can change during tumor progression and in response to treatment.展开更多
Although only 10-15%of liver cancers are cholangiocarcinomas(CCAs),which derive from the epithelial cells of the biliary tree,these cancers constitute a serious and growing health problem worldwide.The rate of mortali...Although only 10-15%of liver cancers are cholangiocarcinomas(CCAs),which derive from the epithelial cells of the biliary tree,these cancers constitute a serious and growing health problem worldwide.The rate of mortality due to this tumor is very high because CCA usually appears in aged people and very often,in more than 70%of cases,are diagnosed late because of:(I)their anatomical localization in a big organ like the liver;(II)the lack of specific symptoms during most time of their development;and(III)the absence of available accurate,specific and sensitive biomarkers(1).These characteristics reduce the rate of success of surgical resection,which is the only curative option for CCA patients,because the response of this aggressive cancer to the available pharmacological armamentarium is extremely feeble(2).This justifies the interest of many groups to identify non-invasive markers to achieve early diagnosis that also permit to distinguish CCA from non-malignant biliary diseases and from hepatocellular carcinoma(HCC),the most frequent liver cancer,which derives from hepatocytes(3).展开更多
Background:Loiasis is an uncommon and poorly understood parasitic disease outside endemic areas of Africa.The aim of this study was to describe the clinical and biological patterns and treatment of imported loiasis by...Background:Loiasis is an uncommon and poorly understood parasitic disease outside endemic areas of Africa.The aim of this study was to describe the clinical and biological patterns and treatment of imported loiasis by sub-Saharan migrants diagnosed in Madrid,Spain.Methods:A retrospective study was conducted with sub-Saharan immigrants seen at the Tropical Medicine Unit of the Carlos III Hospital in Madrid,Spain,a reference center,over 19 years.Categorical variables were expressed as frequency counts and percentages.Continuous variables were expressed as the mean and standard deviation(SD)or median and interquartile range(IQR:Q3–Q1).Chi-square tests were used to assess the association between categorical variables.The measured outcomes were expressed as the odds ratio(OR)with a 95%confidential interval.Continuous variables were compared by Student’s t-tests or Mann-Whitney U tests.Binary logistic regression models were used.P<0.05 was considered a statistically significant difference.Results:One hundred thirty-one migrants from tropical and subtropical areas with loiasis were identified.Forty-nine patients were male(37.4%).The migrants’mean age(±SD)was 42.3±17.3 years,and 124(94.7%)were from Equatorial Guinea.The median time(IQR)between arrival in Spain and the first consultation was 2(1–7)months.One hundred fifteen migrants had eosinophilia,and one hundred thirteen had hyper-IgE syndrome.Fifty-seven patients had pruritus(43.5%),and thirty patients had Calabar swelling(22.9%).Seventy-three patients had coinfections with other filarial nematodes(54.2%),and 58 migrants had only Loa loa infections(45.8%).One hundred two patients(77.9%)were treated;45.1%(46/102)patients were treated with one drug,and 54.9%(56/102)patients were treated with combined therapy.Adverse reactions were described in 14(10.7%)migrants.Conclusions:Our patients presented early clinical manifestations and few atypical features.Thus,physicians should systematically consider loiasis in migrants with a typical presentation.However,considering that 72.5%of the patients had only positive microfilaremia without any symptoms,we suggest searching for microfilaremia in every migrant from endemic countries for loiasis presenting with eosinophilia.展开更多
Primary liver cancers constitute the fourth most deadly group of cancers.Their poor prognosis is due in part to the pre-existence and/or development,often during treatment,of powerful mechanisms accounting for the poo...Primary liver cancers constitute the fourth most deadly group of cancers.Their poor prognosis is due in part to the pre-existence and/or development,often during treatment,of powerful mechanisms accounting for the poor response of cancer cells to antitumor drugs.These include both impaired gene expression and the appearance of spliced variants,polymorphisms and mutations,affecting the function of genes leading to the reduction in intracellular concentrations of active agents,changes in molecular targets and survival pathways,altered tumor microenvironment and phenotypic transition.The present review summarizes available information regarding the role of germline and somatic mutations affecting drug transporters,enzymes involved in drug metabolism,organelles and signaling molecules related to liver cancer chemoresistance.A more complete picture of the actual complexity of this problem is urgently needed for carrying out further pharmacogenomic studies aimed to improve the management of patients suffering from hepatocellular carcinoma or cholangiocarcinoma.展开更多
The interest of Western medicine in Traditional Chinese Medicine(TCM) as a source of drug leads/new drugs to treat diseases without available efficient therapies has been dramatically augmented in the last decades by ...The interest of Western medicine in Traditional Chinese Medicine(TCM) as a source of drug leads/new drugs to treat diseases without available efficient therapies has been dramatically augmented in the last decades by the extensive work and the outstanding findings achieved within this kind of medicine. The practice of TCM over thousands of years has equipped scientists with substantial experience with hundreds of plants that led to the discovery of artemisinin(qinghaosu), which is extracted from the medicinal plant Artemisia annua L.(qinghao). The unexpected success of artemisinin in combating malaria has drawn strong attention from the scientific community towards TCM. Artemisinin was discovered by Youyou Tu in 1972. Since then, several novel pharmacological activities based on the well-known properties of the sesquiterpene lactone structure with the oxepane ring and an endoperoxide bridge have been unravelled. Beyond malaria, artemisinin and its derivatives(artemisinins) exert profound activities towards other protozoans(Leishmania, Trypanosoma, amoebas, Neospora caninum, and Eimeria tenella), trematodes(Schistosoma, liver flukes), and viruses(human cytomegalovirus, hepatitis B and C viruses). Less clear is the effect against bacteria and fungi. Based on the promising results of artemisinin and the first generation derivatives(artesunate, artemether, arteether), novel drug development strategies have been pursued.These included the synthesis of acetal-and non-acetal-type artemisinin dimeric molecules as well as developing nanotechnological approaches, e.g.artemisinin-based liposomes, niosomes, micelles, solid lipid nanocarriers, nanostructured lipid carriers, nanoparticles, fullerenes and nanotubes. The current review presents an overview on different aspects of artemisinins, including sources, chemistry, biological/pharmacological properties, types of infectious pathogens that are susceptible to artemisinins in vitro and in vivo, in addition to the advancement in their drug delivery systems utilizing pharmaceutical technology. It would be expected that different therapeutic strategies based on the second and third generation artemisinin derivatives and artemisinin-based drug technologies would be available in the near future to treat specific infectious diseases.展开更多
Cholangiocarcinoma(CCA)is the second most frequent primary malignant neoplasm of the hepatobiliary system.Unfortunately,CCA is often diagnosed at an advanced stage,when potentially curative surgical treatments are not...Cholangiocarcinoma(CCA)is the second most frequent primary malignant neoplasm of the hepatobiliary system.Unfortunately,CCA is often diagnosed at an advanced stage,when potentially curative surgical treatments are not recommended.The probability of achieving complete resection in patients who undergo surgery is about 25%(1)and even when complete tumor removal is achieved,the risk of recurrence is greater than 50%.Identification and validation of reliable biomarkers is crucial for the early detection,accurate diagnosis,appropriate staging/prognosis,therapy selection and effective monitoring of patients with biliary tract cancers(BTCs)(Figure 1).Achieving early diagnosis remains a challenge to improve survival and,although many promising biomarkers have been identified(2),to date none have reached clinical practice.展开更多
Background Mansonella perstans infection can be considered one of the most neglected tropical infectious diseases.Very few studies have reported on the clinical picture caused by infection with this nematode.Therefore...Background Mansonella perstans infection can be considered one of the most neglected tropical infectious diseases.Very few studies have reported on the clinical picture caused by infection with this nematode.Therefore,our study was aimed to describe the clinical patterns and treatment of imported M.perstans infection by migrants from Africa.Methods The present study evaluated a large cohort of migrants who have been diagnosed,examined and treated for imported M.perstans infection at a Spanish reference center(Hospital Carlos III Tropical Medicine Unit,Madrid,Spain)over a 19-year period.Most patients voluntarily attend the emergency unit or are referred from primary care or general hospitals in Madrid.Chi-square test was used to compare the association between categorical variables.The continuous variables were compared by Student’s t-test or the Mann–Whitney test.The corresponding regression models were used for multivariate analysis.Results Five hundred three cases of migrants from tropical and subtropical areas with M.perstans infection were identified.Two hundred sixty-four patients were female(52.5%).The mean age(±SD)was 44.6±18.2 years(range:16–93 years).The mean time(±SD)between the arrival in Spain and the first consultation was 8.6±18.0 months.The major origin of the patients was Equatorial Guinea(97.6%).Regarding the clinical picture,257 patients were asymptomatic(54.7%)and 228 were symptomatic(45.3%);190 patients had pruritus(37.8%),50(9.9%)had arthralgia,18 patients had Calabar-like swelling(3.6%),and 15(3%)had abdominal pain.Four hundred forty-two(87.9%)migrants had hyper-IgE,and 340(67.6%)had eosinophilia.One hundred ninety-five patients had coinfections with other filarial nematodes(38.8%),and 308 migrants had only M.perstans infection(61.2%).Four hundred thirty-seven cases(86.9%)had been treated with anti-filarial drugs;292 cases were treated with one anti-filarial drug,and 145 cases were treated with combined anti-filarial therapy.Additionally,20(4%)cases received steroids and 38(7.6%)cases received antihistamines.Conclusions A long series of M.perstans infections is presented in sub-Saharan immigrants whose data indicate that it should be included in the differential diagnosis in patients with pruritus or analytical alterations such as eosinophilia or hyper-IgE presentation,and they also have a high number of coinfections with other microorganisms whose treatment needs to be protocolized.展开更多
C3G is a GEF(guanine nucleotide exchange factor)for Rap GTPases,among which the isoform Rap1b is an essential protein in platelet biology.Using transgenic mouse models with platelet-specific overexpression of C3G or m...C3G is a GEF(guanine nucleotide exchange factor)for Rap GTPases,among which the isoform Rap1b is an essential protein in platelet biology.Using transgenic mouse models with platelet-specific overexpression of C3G or mutant C3GΔCat,we have unveiled a new function of C3G in regulating the hemostatic function of platelets through its participation in the thrombin-PKCRap1b pathway.C3G also plays important roles in angiogenesis,tumor growth,and metastasis through its regulation of the platelet secretome.In addition,C3G contributes to megakaryopoiesis and thrombopoiesis.Here,we used a platelet-specific C3G-KO mouse model to further support the role of C3G in hemostasis.C3G-KO platelets showed a significant delay in platelet activation and aggregation as a consequence of the defective activation of Rap1,which resulted in decreased thrombus formation in vivo.Additionally,we explored the contribution of C3G-Rap1b to platelet signaling pathways triggered by thrombin,PMA or ADP,in the referenced transgenic mouse model,through the use of a battery of specific inhibitors.We found that platelet C3G is phosphorylated at Tyr504 by a mechanism involving PKC-Src.This phosphorylation was shown to be positively regulated by ERKs through their inhibition of the tyrosine phosphatase Shp2.Moreover,C3G participates in the ADP-P2Y12-PI3K-Rap1b pathway and is a mediator of thrombin-TXA2 activities.However,it inhibits the synthesis of TXA2 through cPLA2 regulation.Taken together,our data reveal the critical role of C3G in the main pathways leading to platelet activation and aggregation through the regulation of Rap1b.展开更多
Aim:Previous studies suggest that circulating tumor cells(CTC)are present at very low frequencies in blood of pancreatic cancer(PC)patients.However,no technique has proven efficient for their detection,in part due to ...Aim:Previous studies suggest that circulating tumor cells(CTC)are present at very low frequencies in blood of pancreatic cancer(PC)patients.However,no technique has proven efficient for their detection,in part due to the lack of accurate tumor markers.Here,we evaluated the potential utility of two marker candidates-Mucin 16(MUC16)and Tetraspanin 1(TSPAN1)-identified through a detailed review of the literature.Methods:To evaluate the pattern of expression of both markers in pancreatic tumor cells vs.normal blood,we used cell lines derived from pancreatic cancer patients and blood from healthy adults.Results:Antibodies against both MUC16 and TSPAN1 showed expression in three pancreatic cancer(PC)cell lines while they were absent in blood cells.To evaluate the efficiency of isolating tumor cells from blood,PC cell lines were spiked at different frequencies in blood,sequentially stained with biotin-conjugated TSPAN1 and MUC16 antibodies and a streptavidin ferrofluids,followed by immunomagnetic enrichment.The recovery of spiked TSPAN1+tumor cells was high with limited contamination by leukocytes.In contrast,no PC cells were isolated when the biotin MUC16 reagent was used because the biotin-conjugated clone did not recognize PC cells.Conclusion:The combination of MUC16,TSPAN1,and epithelial cell adhesion molecule(EpCAM)antibodies will likely increase the efficiency of capturing circulating tumor cell in blood of pancreatic ductal adenocarcinoma.To further develop a protocol for isolation of circulating tumor cell in blood of PC patients,high amounts of antibodies(5-10 mg)against EpCAM,MUC16,and TSPAN1 will be needed.展开更多
Primary liver cancers constitute the fourth leading cause of cancer mortality worldwide,due to their high morbidity,late diagnosis and lack of effective treatments.Hepatocellular carcinoma(HCC)represents 80%and cholan...Primary liver cancers constitute the fourth leading cause of cancer mortality worldwide,due to their high morbidity,late diagnosis and lack of effective treatments.Hepatocellular carcinoma(HCC)represents 80%and cholangiocarcinoma(CCA)15%of liver cancers.Several genetic and epigenetic gene alterations(e.g.,TERT,TP53 or CTNNB1)are HCC drivers,although many additional gene alterations contribute to HCC initiation and/or progression.Rho and Ras GTPases have been widely implicated in tumorigenesis and their activators(GEFs)have recently emerged as putative key players in liver cancer.The Ras GEF,C3G(RAPGEF1),a GEF mainly for Rap proteins,has recently been uncovered as a relevant gene in HCC.Its upregulation promotes tumor growth,although a decrease in C3G levels favors migration/invasion and lung metastasis.Rap1A/1B/2A/2B are overexpressed in HCC tumors,but their effects are controversial and not equivalent to those of C3G.The C3G partner,CRKL,is also overexpressed in HCC,promoting proliferation,migration and invasion.Various Rho GEFs are also deregulated in liver cancer.Tiam1 and Tiam2 expression is upregulated in HCC,promoting proliferation,migration and metastasis.In addition,ARHGEF-10L/9/19/39 are overexpressed in HCC tumors,facilitating migration,invasion,metastasis and proliferation.Another Rho GEF,Vav2,is also involved in metastasis.Little is known about the participation of these GEFs and GTPases in CCA.However,analysis of cancer databases uncovered deregulations or genetic alterations in several of these genes,in both CCA and HCC.Hence,GEFs function appear essential for liver homeostasis,although future studies are needed to define their precise function in liver cancer.展开更多
基金supported by the Lanzadera TCUE and C2 program(Universidad de Salamanca)(to ASL)the Spanish National Research Council(CSIC)funded by the Junta de Castilla y León and co-financed by the European Regional Development Fund(ERDF“Europe drives our growth”):Internationalization Project“CL-EI-2021-08-IBFG Unit of Excellence”,Grant(PID2022-138478OA-100)funded by MICIU/AEI/10.13039/501100011033 and,by FEDER,UE(to MGM)+3 种基金Junta de Castilla y León(SA225P23)Gerencia Regional de Salud(2701/A1/2023)(to AV)the Plan Especial Grado Medicina(USAL)(to CPM)a Ramón y Cajal researcher:Grant RYC2021-033684-I funded by MICIU/AEI/10.13039/501100011033 and,by European Union NextGenerationEU/PRTR.
文摘The visual system of teleost fish grows continuously,which is a useful model for studying regeneration of the central nervous system.Glial cells are key for this process,but their contribution is still not well defined.We followed oligodendrocytes in the visual system of adult zebrafish during regeneration of the optic nerve at 6,24,and 72 hours post-lesion and at 7 and 14 days post-lesion via the sox10:tagRFP transgenic line and confocal microscopy.To understand the changes that these oligodendrocytes undergo during regeneration,we used Sox2 immunohistochemistry,a stem cell marker involved in oligodendrocyte differentiation.We also used the Click-iT™ Plus TUNEL assay to study cell death and a BrdU assay to determine cell proliferation.Before optic nerve crush,sox10:tagRFP oligodendrocytes are located in the retina,in the optic nerve head,and through all the entire optic nerve.Sox2-positive cells are present in the peripheral germinal zone,the mature retina,and the optic nerve.After optic nerve crush,sox10:tagRFP cells disappeared from the optic nerve crush zone,suggesting that they died,although they were not TUNEL positive.Concomitantly,the number of Sox2-positive cells increased around the crushed area,the optic nerve head,and the retina.Then,between 24 hours post-lesion and 14 days post-lesion,double sox10:tagRFP/Sox2-positive cells were detected in the retina,optic nerve head,and whole optic nerve,together with a proliferation response at 72 hours post-lesion.Our results confirm that a degenerating process may occur prior to regeneration.First,sox10:tagRFP oligodendrocytes that surround the degenerated axons stop wrapping them,change their“myelinating oligodendrocyte”morphology to a“nonmyelinating oligodendrocyte”morphology,and die.Then,residual oligodendrocyte progenitor cells in the optic nerve and retina proliferate and differentiate for the purpose of remyelination.As new axons arise from the surviving retinal ganglion cells,new sox10:tagRFP oligodendrocytes arise from residual oligodendrocyte progenitor cells to guide,nourish and myelinate them.Thus,oligodendrocytes play an active role in zebrafish axon regeneration and remyelination.
基金funded by a IBYE23_0002 grant supported by Instituto de investigación biom-édica de Salamanca IBSAL,Castilla y León (Spain) and by a GRS 2860/A1/2023 by Gerencia Regional de Salud o f Castilla y León (Spain)。
文摘Background Transcatheter Aortic Valve Implantation(TAVI)has changed the treatment paradigm of the aortic stenosis(AS).It has become the treatment of choice in patients with symptomatic AS and surgical high risk,and a valid alternative to surgical aortic valve replacement in patients with low and medium surgical risk.Despite numerous evidence on clinical results,indications and benefits,only a few studies analyse it from patient's perspective and the impact of TAVI on them.The objective of this study is to evaluate the experience of patients undergoing TAVI.Methods Cross-sectional,descriptive observational study in two Spanish hospitals,with a establish Nurse TAVI program,with100 patients undergoing TAVI.A specific questionnaire was designed(VALVEX questionnaire)and a pilot study was conducted by a multidisciplinary team of doctors,nurses and patients.The questionnaire was given to patients at 30 days after TAVI procedure during the follow up at the TAVI nurse clinic.Results The study demonstrated a mean satisfaction of 9 for the TAVI program,with 96%of patients that would recommend TAVI to other patients.Patients scored a high satisfaction on the information received prior to the procedure.During the procedure and admission,the satisfaction was high in relation to the care received.During the follow up,satisfaction was high in relation to the role of the TAVI nurse,for the information and continuation of care during the procedure,in reducing anxiety,organising their admission and understanding the process.However,questions with less scores were related to hospital catering,delay between diagnosed and treatment,and patient decision-making process.Conclusion The evaluation of patient experience allows us to improve the information given to the patient during their TAVI process and it can also allow patients to be more relax,aware and prepared for the procedure.Continuous follow up enables monitoring of patient recovery and helps to discuss any doubts improving patient's satisfaction.The use of PREMs and PROMs associated to TAVI pathway combined with an active participation of the patient on the design of the questionnaire is essential for keeping the patient in the centre of the TAVI pathway.
文摘Intravesical bacillus Calmette-Guerin(BCG) instillation has been adopted for the treatment of patients with superficial bladder cancer. Severe adverse events due to local instillation of BCG are uncommon, with an overall rate of serious complications of less than 5%. We report the case of an immunocompetent adult patient with multi-system effects, namely pneumonitis, granulomatous hepatitis and meningitis, who responded well to standard treatment for Mycobacterium bovis. This case highlights the importance of a thorough assessment of this type of patient.
文摘Introduction: Abdominal angiostrongyliasis is an infrequently diagnosed disease because it is little known and is usually well tolerated. Methods: We carried out a systematic review with PubMed as a search engine for the MedLine database, and we analysed the clinical, epidemiological and analytical parameters of this disease. Results: In total, reports of 27 case have been found, together with a series of 116 patients, which were later augmented up to 194 patients. In the results, we have observed a predominance of male patients, and Costa Rica, Brazil and the United States as the main countries of origin. Typical symptoms include abdominal pain on the right iliac fossa, with leukocytosis and eosinophilia. Discussion: There are some serological diagnostic methods, although lack of standardization leads to most of the diagnoses being reached via pathology. Surgery is the usual treatment approach. Although there are medical options, this is a controversial subject because of the low number of cases published in the literature, which implies an absence of solid studies.
文摘The aim of the work was to analyze and expose the donor and recipient riskfactors in pancreas transplantation.In the following paper,we exposed the 2018Spanish Consensus Document on Donor and Recipient Selection Criteria forPancreas Transplantation.An assessment of the previous Selection Criteria forDonors and Recipients of Pancreas Transplantation,published in 2005 by theSpanish Pancreas Transplant Group(GETP)and the National TransplantOrganization(ONT)was performed.A literature review was performed usingCochrane Library,PubMed and Google Scholar databases.Some of the followingterms were used for the literature search:“Diabetes Mellitus,”“PancreasTransplantation,”“Insulin-Secreting Cells,”“Pancreas Allograft Thrombosis,”“Allograft Pancreatitis,”“Donors’Risk Factors,”“Recipients’Risk Factors,”“Pancreas Allograft Rejection”and“Pancreas Allograft Survival.”After anextended search,different inclusion criteria were established.Articles anddocuments with abstracts of full text and in English or Spanish language wereselected.Subsequently,different scientific meetings took place during 2015 and2016 by the GETP.Finally,the updated criteria were published by the GETP andONT in 2018.Several risk factors have been described in pancreas transplantationthat can be divided into donor risk factors:Advanced age(>50 years);high bodymass index(BMI)(>30 kg/m2);cause of death(e.g.,stroke);previoushyperglycemia;hyperamylasemia;cold ischemia time(greater than 8 or 12 h,depending on the type of donation);the use of vasopressors in the intensive careunit or cardiac arrest;and the macroscopic aspect of the pancreas allograft.Thefollowing are recipient risk factors:Advanced age(>50 years);active smoking;high BMI(>30 kg/m2);and peripheral artery disease or sensorimotorpolyneuropathy.Based on the aforementioned parameters,different selectioncriteria have been established for the recipients depending on the type of pancreastransplantation.Knowledge of the risk factors for pancreas transplantation allowsthe establishment of reliable selection criteria for choosing donors and recipients.
文摘Cholangiopathies are a group of diseases primarily or secondarily affecting bile duct cells, and result in cholangiocyte proliferation, regression, and/or transformation. Their etiopathogenesis may be associated with a broad variety of causes of different nature, which includes genetic, neoplastic, immune-associated, infectious, vascular, and drug-induced alterations, or being idiopathic. miRNAs, small non-coding endogenous RNAs that post-transcriptionally regulate gene expres sion, have been associated with pathophysiological processes in different organs and cell types, and are postulated as potential targets for diagnosis and therapy. In the current manuscript, knowledge regarding the role of miRNAs in the development and/or progression of cholangiopathies has been reviewed and the most relevant findings in this promising field of hepatology have been highlighted.
基金supported by the University of Salamanca Research Support Grant 2015 to Dr.Dolores E.Lopez
文摘The serotonergic system in the brain plays a major role in mood and anxiety regulation when exposed to stress. The aim of the present study was to evaluate the effects of Sertraline administration in coping with stress using the behavioural paradigms of the acoustic startle reflex (ASR) and its prepulse inhibition (PPI) in both sexes. Wistar rats were divided into two groups: intact animals and exposed to restraint stress (RS) 3 times per day during 7 days, which were then subdivided into three other groups: injected with Sertraline (5 mg/kg/day) or the drug vehicle saline for 8 consecutive days, and non-injected. ASR and PPI values were analyzed along 4 sessions to determine behavioral changes. Upon it, we also determine the effects of acute immobilization stress analyzing physiological stress indicators in blood. Our data show sex differences in response to stress paradigms. RS affected more intensely males than females, disturbing the males’ growth and the long-term startle habituation that were not affected in females. PPI increased in the vehicle-injected animals when compared to baseline in both sexes, and Sertraline reversed more efficiently it in females. Moreover, despite both sexes exposed to stressful paradigms exhibited a significant increase in serum glutamic-oxaloacetic transaminase and lactate dehydrogenase enzymes when compared with intact controls, as well as leucopenia, some differences according to sex were found in the haemostatic response to stress. Notably, the repeated injections procedure disturbed the early response to stress, which Sertraline only attenuated in both sexes. Our data suggest that 8-day Sertraline administration is effective in reversing stress-induced changes in some physio-logical parameters, but insufficient to return immunological values to normality.
文摘Understanding of the cellular signaling pathways involved in cancer disease is of great importance.These complex biological mechanisms can be thoroughly revealed by their structure,dynamics,and control methods.Artificial intelligence offers rule-based models that favor the research of human signaling processes.In this paper,we give an overview of the advantages of the formalism of symbolic models in medical biology and cell biology of the uveal melanoma.A language is described that allows us:(1)To define the system states and elements with their alterations;(2)To model the dynamics of the cellular system;and(3)To perform inference-based analysis with the logical tools of the language.
基金Supported by The United States Department of Defense Breast Cancer Research Program,No.BC190820the National Institutes of Health,No.R01ES031322.
文摘Identifying the factors that contribute to individual susceptibility to cancer is essential for both prevention and treatment.The advancement of biotechnologies,particularly next-generation sequencing,has accelerated the discovery of genetic variants linked to cancer susceptibility.While hundreds of cancer-susceptibility genes have been identified,they only explain a small fraction of the overall cancer risk,a phenomenon known as"missing heritability".Despite progress,even considering factors such as epistasis,epigenetics,and gene-environment interactions,the missing heritability remains unresolved.Recent research has revealed that an individual's microbiome composition plays a significant role in cancer susceptibility through several mechanisms,such as modulating immune cell activity and influencing the presence or removal of environmental carcinogens.In this review,we examine the multifaceted roles of the microbiome in cancer risk and explore gene-microbiome and environment-microbiome interactions that may contribute to cancer susceptibility.Additionally,we highlight the importance of experimental models,such as collaborative cross mice,and advanced analytical tools,like artificial intelligence,in identifying microbial factors associated with cancer risk.Understanding these microbial determinants can open new avenues for interventions aimed at reducing cancer risk and guide the development of more effective cancer treatments.
基金funding from CIBEREHD,Fondo de Investigaciones Sanitarias,Instituto de Salud Carlos Ⅲ co-funded by European Regional Development Fund/European Social Fund,“Investing in your future”)(PI19/00819,PI20/00189,PI23/00681,and PI22/00526)Junta de Castilla y León(SA074P20,GRS 2322/A/21,and SA113P23)+2 种基金FundacióMarato TV3(Ref.201916-31),Fundación AECC(AECC2023/2027)University of Salamanca(PC_TCUE21-23_011)Spain.Reviejo M was supported by a postdoctoral contract funded by the“Junta de Castilla y Leon”(SA113P23).
文摘Cancer drug resistance constitutes a severe limitation for the satisfactory outcome of these patients.This is a complex problem due to the co-existence in cancer cells of multiple and synergistic mechanisms of chemoresistance(MOC).These mechanisms are accounted for by the expression of a set of genes included in the so-called resistome,whose effectiveness often leads to a lack of response to pharmacological treatment.Additionally,genetic variants affecting these genes further increase the complexity of the question.This review focuses on a set of genes encoding members of the transportome involved in drug uptake,which have been classified into the MOC-1A subgroup of the resistome.These proteins belong to the solute carrier(SLC)superfamily.More precisely,we have considered here several members of families SLC2,SLC7,SLC19,SLC22,SLCO,SLC28,SLC29,SLC31,SLC46,and SLC47 due to the impact of their expression and genetic variants in anticancer drug uptake by tumor cells or,in some cases,general bioavailability.Changes in their expression levels and the appearance of genetic variants can contribute to the Darwinian selection of more resistant clones and,hence,to the development of a more malignant phenotype.Accordingly,to address this issue in future personalized medicine,it is necessary to characterize both changes in resistome genes that can affect their function.It is also essential to consider the time-dependent dimension of these features,as the genetic expression and the appearance of genetic variants can change during tumor progression and in response to treatment.
基金Carlos III Institute of Health,Spain(PI16/00598 and PI19/00819)co-financed by European Regional Development FundMinistry of Science and Innovation,Spain(SAF2016-75197-R)Asociación Espanola Contra el Cancer,Spain(AECC-Cancer raros 2017/2020)and Centro Internacional sobre el Envejecimiento,Spain(OLD-HEPAMARKER,0348_CIE_6_E)co-financed with European Union ERDF funds.
文摘Although only 10-15%of liver cancers are cholangiocarcinomas(CCAs),which derive from the epithelial cells of the biliary tree,these cancers constitute a serious and growing health problem worldwide.The rate of mortality due to this tumor is very high because CCA usually appears in aged people and very often,in more than 70%of cases,are diagnosed late because of:(I)their anatomical localization in a big organ like the liver;(II)the lack of specific symptoms during most time of their development;and(III)the absence of available accurate,specific and sensitive biomarkers(1).These characteristics reduce the rate of success of surgical resection,which is the only curative option for CCA patients,because the response of this aggressive cancer to the available pharmacological armamentarium is extremely feeble(2).This justifies the interest of many groups to identify non-invasive markers to achieve early diagnosis that also permit to distinguish CCA from non-malignant biliary diseases and from hepatocellular carcinoma(HCC),the most frequent liver cancer,which derives from hepatocytes(3).
文摘Background:Loiasis is an uncommon and poorly understood parasitic disease outside endemic areas of Africa.The aim of this study was to describe the clinical and biological patterns and treatment of imported loiasis by sub-Saharan migrants diagnosed in Madrid,Spain.Methods:A retrospective study was conducted with sub-Saharan immigrants seen at the Tropical Medicine Unit of the Carlos III Hospital in Madrid,Spain,a reference center,over 19 years.Categorical variables were expressed as frequency counts and percentages.Continuous variables were expressed as the mean and standard deviation(SD)or median and interquartile range(IQR:Q3–Q1).Chi-square tests were used to assess the association between categorical variables.The measured outcomes were expressed as the odds ratio(OR)with a 95%confidential interval.Continuous variables were compared by Student’s t-tests or Mann-Whitney U tests.Binary logistic regression models were used.P<0.05 was considered a statistically significant difference.Results:One hundred thirty-one migrants from tropical and subtropical areas with loiasis were identified.Forty-nine patients were male(37.4%).The migrants’mean age(±SD)was 42.3±17.3 years,and 124(94.7%)were from Equatorial Guinea.The median time(IQR)between arrival in Spain and the first consultation was 2(1–7)months.One hundred fifteen migrants had eosinophilia,and one hundred thirteen had hyper-IgE syndrome.Fifty-seven patients had pruritus(43.5%),and thirty patients had Calabar swelling(22.9%).Seventy-three patients had coinfections with other filarial nematodes(54.2%),and 58 migrants had only Loa loa infections(45.8%).One hundred two patients(77.9%)were treated;45.1%(46/102)patients were treated with one drug,and 54.9%(56/102)patients were treated with combined therapy.Adverse reactions were described in 14(10.7%)migrants.Conclusions:Our patients presented early clinical manifestations and few atypical features.Thus,physicians should systematically consider loiasis in migrants with a typical presentation.However,considering that 72.5%of the patients had only positive microfilaremia without any symptoms,we suggest searching for microfilaremia in every migrant from endemic countries for loiasis presenting with eosinophilia.
基金This study was supported by the Biomedical Research Networking Center in Hepatic and Digestive Diseases-CIBERehd(EHD15PI05/2016)the Health Research Fund,Institute of Health Carlos III,Spain(PI16/00598,co-funded by the European Regional Development Fund/European Social Fund,"Investing in your future")+4 种基金the Spanish Ministry of Economy,Industry and Competitiveness(SAF2016-75197-R)the Regional Government of Castile and Leon(SA063P17)and the AECC Scientific Foundation(2017/2020)Spain.MAP,ASM and PSS were supported by a pre-doctoral contract by“Ministry of Education,Culture and Sports”,Spain(BOE-A-2015-9456 and BOE-B-2017-72875)REE was supported by a pre-doctoral contract funded by the“Junta de Castilla y León,Fondo Social Europeo”(EDU/574/2018).
文摘Primary liver cancers constitute the fourth most deadly group of cancers.Their poor prognosis is due in part to the pre-existence and/or development,often during treatment,of powerful mechanisms accounting for the poor response of cancer cells to antitumor drugs.These include both impaired gene expression and the appearance of spliced variants,polymorphisms and mutations,affecting the function of genes leading to the reduction in intracellular concentrations of active agents,changes in molecular targets and survival pathways,altered tumor microenvironment and phenotypic transition.The present review summarizes available information regarding the role of germline and somatic mutations affecting drug transporters,enzymes involved in drug metabolism,organelles and signaling molecules related to liver cancer chemoresistance.A more complete picture of the actual complexity of this problem is urgently needed for carrying out further pharmacogenomic studies aimed to improve the management of patients suffering from hepatocellular carcinoma or cholangiocarcinoma.
文摘The interest of Western medicine in Traditional Chinese Medicine(TCM) as a source of drug leads/new drugs to treat diseases without available efficient therapies has been dramatically augmented in the last decades by the extensive work and the outstanding findings achieved within this kind of medicine. The practice of TCM over thousands of years has equipped scientists with substantial experience with hundreds of plants that led to the discovery of artemisinin(qinghaosu), which is extracted from the medicinal plant Artemisia annua L.(qinghao). The unexpected success of artemisinin in combating malaria has drawn strong attention from the scientific community towards TCM. Artemisinin was discovered by Youyou Tu in 1972. Since then, several novel pharmacological activities based on the well-known properties of the sesquiterpene lactone structure with the oxepane ring and an endoperoxide bridge have been unravelled. Beyond malaria, artemisinin and its derivatives(artemisinins) exert profound activities towards other protozoans(Leishmania, Trypanosoma, amoebas, Neospora caninum, and Eimeria tenella), trematodes(Schistosoma, liver flukes), and viruses(human cytomegalovirus, hepatitis B and C viruses). Less clear is the effect against bacteria and fungi. Based on the promising results of artemisinin and the first generation derivatives(artesunate, artemether, arteether), novel drug development strategies have been pursued.These included the synthesis of acetal-and non-acetal-type artemisinin dimeric molecules as well as developing nanotechnological approaches, e.g.artemisinin-based liposomes, niosomes, micelles, solid lipid nanocarriers, nanostructured lipid carriers, nanoparticles, fullerenes and nanotubes. The current review presents an overview on different aspects of artemisinins, including sources, chemistry, biological/pharmacological properties, types of infectious pathogens that are susceptible to artemisinins in vitro and in vivo, in addition to the advancement in their drug delivery systems utilizing pharmaceutical technology. It would be expected that different therapeutic strategies based on the second and third generation artemisinin derivatives and artemisinin-based drug technologies would be available in the near future to treat specific infectious diseases.
文摘Cholangiocarcinoma(CCA)is the second most frequent primary malignant neoplasm of the hepatobiliary system.Unfortunately,CCA is often diagnosed at an advanced stage,when potentially curative surgical treatments are not recommended.The probability of achieving complete resection in patients who undergo surgery is about 25%(1)and even when complete tumor removal is achieved,the risk of recurrence is greater than 50%.Identification and validation of reliable biomarkers is crucial for the early detection,accurate diagnosis,appropriate staging/prognosis,therapy selection and effective monitoring of patients with biliary tract cancers(BTCs)(Figure 1).Achieving early diagnosis remains a challenge to improve survival and,although many promising biomarkers have been identified(2),to date none have reached clinical practice.
文摘Background Mansonella perstans infection can be considered one of the most neglected tropical infectious diseases.Very few studies have reported on the clinical picture caused by infection with this nematode.Therefore,our study was aimed to describe the clinical patterns and treatment of imported M.perstans infection by migrants from Africa.Methods The present study evaluated a large cohort of migrants who have been diagnosed,examined and treated for imported M.perstans infection at a Spanish reference center(Hospital Carlos III Tropical Medicine Unit,Madrid,Spain)over a 19-year period.Most patients voluntarily attend the emergency unit or are referred from primary care or general hospitals in Madrid.Chi-square test was used to compare the association between categorical variables.The continuous variables were compared by Student’s t-test or the Mann–Whitney test.The corresponding regression models were used for multivariate analysis.Results Five hundred three cases of migrants from tropical and subtropical areas with M.perstans infection were identified.Two hundred sixty-four patients were female(52.5%).The mean age(±SD)was 44.6±18.2 years(range:16–93 years).The mean time(±SD)between the arrival in Spain and the first consultation was 8.6±18.0 months.The major origin of the patients was Equatorial Guinea(97.6%).Regarding the clinical picture,257 patients were asymptomatic(54.7%)and 228 were symptomatic(45.3%);190 patients had pruritus(37.8%),50(9.9%)had arthralgia,18 patients had Calabar-like swelling(3.6%),and 15(3%)had abdominal pain.Four hundred forty-two(87.9%)migrants had hyper-IgE,and 340(67.6%)had eosinophilia.One hundred ninety-five patients had coinfections with other filarial nematodes(38.8%),and 308 migrants had only M.perstans infection(61.2%).Four hundred thirty-seven cases(86.9%)had been treated with anti-filarial drugs;292 cases were treated with one anti-filarial drug,and 145 cases were treated with combined anti-filarial therapy.Additionally,20(4%)cases received steroids and 38(7.6%)cases received antihistamines.Conclusions A long series of M.perstans infections is presented in sub-Saharan immigrants whose data indicate that it should be included in the differential diagnosis in patients with pruritus or analytical alterations such as eosinophilia or hyper-IgE presentation,and they also have a high number of coinfections with other microorganisms whose treatment needs to be protocolized.
基金supported by grants from the Spanish Ministry of Economy and Competitiveness[SAF2013-48210-C2-1-R,SAF2016-76588-C2-2-R to C.Guerrero,SAF2013-48210-C2-2-R,SAF2016-76588-C2-1-R to A.P.]by two grants from the Council of Education of Junta de Castilla y León,Spain[SA157A12-1,SA017U16 to C.Guerrero].All funding was cosponsored by the European FEDER Program.
文摘C3G is a GEF(guanine nucleotide exchange factor)for Rap GTPases,among which the isoform Rap1b is an essential protein in platelet biology.Using transgenic mouse models with platelet-specific overexpression of C3G or mutant C3GΔCat,we have unveiled a new function of C3G in regulating the hemostatic function of platelets through its participation in the thrombin-PKCRap1b pathway.C3G also plays important roles in angiogenesis,tumor growth,and metastasis through its regulation of the platelet secretome.In addition,C3G contributes to megakaryopoiesis and thrombopoiesis.Here,we used a platelet-specific C3G-KO mouse model to further support the role of C3G in hemostasis.C3G-KO platelets showed a significant delay in platelet activation and aggregation as a consequence of the defective activation of Rap1,which resulted in decreased thrombus formation in vivo.Additionally,we explored the contribution of C3G-Rap1b to platelet signaling pathways triggered by thrombin,PMA or ADP,in the referenced transgenic mouse model,through the use of a battery of specific inhibitors.We found that platelet C3G is phosphorylated at Tyr504 by a mechanism involving PKC-Src.This phosphorylation was shown to be positively regulated by ERKs through their inhibition of the tyrosine phosphatase Shp2.Moreover,C3G participates in the ADP-P2Y12-PI3K-Rap1b pathway and is a mediator of thrombin-TXA2 activities.However,it inhibits the synthesis of TXA2 through cPLA2 regulation.Taken together,our data reveal the critical role of C3G in the main pathways leading to platelet activation and aggregation through the regulation of Rap1b.
基金This work was supported by Biomedical Research Networking Centre Consortium-CIBER-CIBERONC(CB16/12/00400)of the Instituto de Salud Carlos III,Madrid,Spain.Mayado A was supported by the JoséCastillejo Mobility Grant for young doctors funded by the Spanish Ministry of Education and Vocational Training(CAS18/00388).
文摘Aim:Previous studies suggest that circulating tumor cells(CTC)are present at very low frequencies in blood of pancreatic cancer(PC)patients.However,no technique has proven efficient for their detection,in part due to the lack of accurate tumor markers.Here,we evaluated the potential utility of two marker candidates-Mucin 16(MUC16)and Tetraspanin 1(TSPAN1)-identified through a detailed review of the literature.Methods:To evaluate the pattern of expression of both markers in pancreatic tumor cells vs.normal blood,we used cell lines derived from pancreatic cancer patients and blood from healthy adults.Results:Antibodies against both MUC16 and TSPAN1 showed expression in three pancreatic cancer(PC)cell lines while they were absent in blood cells.To evaluate the efficiency of isolating tumor cells from blood,PC cell lines were spiked at different frequencies in blood,sequentially stained with biotin-conjugated TSPAN1 and MUC16 antibodies and a streptavidin ferrofluids,followed by immunomagnetic enrichment.The recovery of spiked TSPAN1+tumor cells was high with limited contamination by leukocytes.In contrast,no PC cells were isolated when the biotin MUC16 reagent was used because the biotin-conjugated clone did not recognize PC cells.Conclusion:The combination of MUC16,TSPAN1,and epithelial cell adhesion molecule(EpCAM)antibodies will likely increase the efficiency of capturing circulating tumor cell in blood of pancreatic ductal adenocarcinoma.To further develop a protocol for isolation of circulating tumor cell in blood of PC patients,high amounts of antibodies(5-10 mg)against EpCAM,MUC16,and TSPAN1 will be needed.
基金supported by grants from the Spanish Ministry of Economy and Competitiveness(SAF2016-76588-C2-1-R and PID2019-104143RB-C22 to Porras A,SAF2016-76588-C2-2-R and PID2019-104143RB-C21 to Guerrero G and PID2019-104991RB-I00 to Bragado P)by two grants from the Council of Education of Junta de Castilla y León,Spain(SA017U16 and SA078P20 to Guerrero C)+2 种基金cosponsored by the European FEDER ProgramSequera C was supported by a fellowship from Complutense University from Madrid.Gutierrez-Uzquiza A is supported by Madrid Community Program for Talent Attraction(MRF 2017-T1/BMD-5468)Bragado P received support from BBVA(Becas Leonardo 2018,BBM-TRA-0041).
文摘Primary liver cancers constitute the fourth leading cause of cancer mortality worldwide,due to their high morbidity,late diagnosis and lack of effective treatments.Hepatocellular carcinoma(HCC)represents 80%and cholangiocarcinoma(CCA)15%of liver cancers.Several genetic and epigenetic gene alterations(e.g.,TERT,TP53 or CTNNB1)are HCC drivers,although many additional gene alterations contribute to HCC initiation and/or progression.Rho and Ras GTPases have been widely implicated in tumorigenesis and their activators(GEFs)have recently emerged as putative key players in liver cancer.The Ras GEF,C3G(RAPGEF1),a GEF mainly for Rap proteins,has recently been uncovered as a relevant gene in HCC.Its upregulation promotes tumor growth,although a decrease in C3G levels favors migration/invasion and lung metastasis.Rap1A/1B/2A/2B are overexpressed in HCC tumors,but their effects are controversial and not equivalent to those of C3G.The C3G partner,CRKL,is also overexpressed in HCC,promoting proliferation,migration and invasion.Various Rho GEFs are also deregulated in liver cancer.Tiam1 and Tiam2 expression is upregulated in HCC,promoting proliferation,migration and metastasis.In addition,ARHGEF-10L/9/19/39 are overexpressed in HCC tumors,facilitating migration,invasion,metastasis and proliferation.Another Rho GEF,Vav2,is also involved in metastasis.Little is known about the participation of these GEFs and GTPases in CCA.However,analysis of cancer databases uncovered deregulations or genetic alterations in several of these genes,in both CCA and HCC.Hence,GEFs function appear essential for liver homeostasis,although future studies are needed to define their precise function in liver cancer.
