Until very recently, treatment for chronic hepatitis C virus(HCV) infection has been based on the combination of two non-viral specific drugs: pegylated interferon-α and ribavirin, which is effective in, overall, abo...Until very recently, treatment for chronic hepatitis C virus(HCV) infection has been based on the combination of two non-viral specific drugs: pegylated interferon-α and ribavirin, which is effective in, overall, about 40%-50% of cases. To improve the response to treatment, novel drugs have been designed to specifically block viral proteins. Multiple compounds are under development, and the approval for clinical use of the first of such direct-acting antivirals in 2011(Telaprevir and Boceprevir), represents a milestone in HCV treatment. HCV therapeutics is entering a new expanding era, and a highly-effective cure is envisioned for the first timesince the discovery of the virus in 1989. However, any antiviral treatment may be limited by the capacity of the virus to overcome the selective pressure of new drugs, generating antiviral resistance. Here, we try to provide a basic overview of new treatments, HCV resistance to new antivirals and some considerations derived from a Public Health perspective, using HCV resistance to protease and polymerase inhibitors as examples.展开更多
Bone is a dynamic tissue that is constantly renewed by the coordinated action of two cell types, i.e., the bone-resorbing osteoclasts and the bone-forming osteoblasts. However, in some circumstances, bone regeneration...Bone is a dynamic tissue that is constantly renewed by the coordinated action of two cell types, i.e., the bone-resorbing osteoclasts and the bone-forming osteoblasts. However, in some circumstances, bone regeneration exceeds bone self repair capacities. This is notably often the case after bone fractures, osteolytic bone tumor surgery, or osteonecrosis. In this regard,bone tissue engineering with autologous or allogenic mesenchymal stem cells(MSCs) is been widely developed. MSCs can be isolated from bone marrow or other tissues such as adipose tissue or umbilical cord, and can be implanted in bone defects with or without prior amplification and stimulation. However, the outcome of most pre-clinical studies remains relatively disappointing. A better understanding of the successive steps and molecular mechanisms involved in MSC-osteoblastic differentiation appears to be crucial to optimize MSC-bone therapy. In this review, we first present the important growth factors that stimulate osteoblastogenesis. Then we review the main transcription factors that modulate osteoblast differentiation, and the microRNAs(miRs)that inhibit their expression. Finally, we also discuss articles dealing with the use of these factors and miRs in the development of new bone MSC therapy strategies. We particularly focus on the studies using human MSCs, since significant differences exist between osteoblast differentiation mechanisms in humans and mice for instance.展开更多
The reduction of nitrate to nitrite by the oral microbiota has been proposed to be important for oral health and results in nitric oxide formation that can improve cardiometabolic conditions. Studies of bacterial comp...The reduction of nitrate to nitrite by the oral microbiota has been proposed to be important for oral health and results in nitric oxide formation that can improve cardiometabolic conditions. Studies of bacterial composition in subgingival plaque suggest that nitrate-reducing bacteria are associated with periodontal health, but the impact of periodontitis on nitrate-reducing capacity(NRC)and, therefore, nitric oxide availability has not been evaluated. The current study aimed to evaluate how periodontitis affects the NRC of the oral microbiota. First, 16S rRNA sequencing data from five different countries were analyzed, revealing that nitratereducing bacteria were significantly lower in subgingival plaque of periodontitis patients compared with healthy individuals(P < 0.05 in all five datasets with n = 20–82 samples per dataset). Secondly, subgingival plaque, saliva, and plasma samples were obtained from 42 periodontitis patients before and after periodontal treatment. The oral NRC was determined in vitro by incubating saliva with 8 mmol/L nitrate(a concentration found in saliva after nitrate-rich vegetable intake) and compared with the NRC of 15healthy individuals. Salivary NRC was found to be diminished in periodontal patients before treatment(P < 0.05) but recovered to healthy levels 90 days post-treatment. Additionally, the subgingival levels of nitrate-reducing bacteria increased after treatment and correlated negatively with periodontitis-associated bacteria(P < 0.01). No significant effect of periodontal treatment on the baseline saliva and plasma nitrate and nitrite levels was found, indicating that differences in the NRC may only be revealed after nitrate intake. Our results suggest that an impaired NRC in periodontitis could limit dietary nitrate-derived nitric oxide levels, and the effect on systemic health should be explored in future studies.展开更多
Background The utility of routine extensive molecular profiling of pediatric tumors is a matter of debate due to the high number of genetic alterations of unknown significance or low evidence and the lack of standardi...Background The utility of routine extensive molecular profiling of pediatric tumors is a matter of debate due to the high number of genetic alterations of unknown significance or low evidence and the lack of standardized and personalized decision support methods.Digital drug assignment(DDA)is a novel computational method to prioritize treatment options by aggregating numerous evidence-based associations between multiple drivers,targets,and targeted agents.DDA has been validated to improve personalized treatment decisions based on the outcome data of adult patients treated in the SHIVA01 clinical trial.The aim of this study was to evaluate the utility of DDA in pediatric oncology.Methods Between 2017 and 2020,103 high-risk pediatric cancer patients(<21 years)were involved in our precision oncology program,and samples from 100 patients were eligible for further analysis.Tissue or blood samples were analyzed by whole-exome(WES)or targeted panel sequencing and other molecular diagnostic modalities and processed by a software system using the DDA algorithm for therapeutic decision support.Finally,a molecular tumor board(MTB)evaluated the results to provide therapy recommendations.Results Of the 100 cases with comprehensive molecular diagnostic data,88 yielded WES and 12 panel sequencing results.DDA identified matching off-label targeted treatment options(actionability)in 72/100 cases(72%),while 57/100(57%)showed potential drug resistance.Actionability reached 88%(29/33)by 2020 due to the continuous updates of the evidence database.MTB approved the clinical use of a DDA-top-listed treatment in 56 of 72 actionable cases(78%).The approved therapies had significantly higher aggregated evidence levels(AELs)than dismissed therapies.Filtering of WES results for targeted panels missed important mutations affecting therapy selection.Conclusions DDA is a promising approach to overcome challenges associated with the interpretation of extensive molecular profiling in the routine care of high-risk pediatric cancers.Knowledgebase updates enable automatic interpretation of a continuously expanding gene set,a“virtual”panel,filtered out from genome-wide analysis to always maximize the performance of precision treatment planning.展开更多
Hepatocellular carcinoma(HCC)is the most common cancer associated with chronic liver disease and cirrhosis.The most common cause of HCC is chronic hepatitis C virus infection and many studies in Europe,Asia and North ...Hepatocellular carcinoma(HCC)is the most common cancer associated with chronic liver disease and cirrhosis.The most common cause of HCC is chronic hepatitis C virus infection and many studies in Europe,Asia and North America have focused on its etiology,epidemiology,diagnostic tools,and therapeutic options.However,little is known about these issues in Latin America.The aim of this review is to address these aspects of HCC in Latin America.The main risk factors associated with developing HCC in this region are:age,concomitant cirrhosis,hepatitis C infection,obesity and hereditary disease such as hemochromatosis.On the other hand,screening tests and diagnostic methods of HCC are mostly serum alpha fetoprotein quantification,liver ultrasound,computed tomography,magnetic resonance,and histopathology.Novel diagnostic methods include gut microbiota analysis and the use of nanotechnology and they continue to be tested.Finally,according to the Barcelona Clinic Liver Cancer,curative treatments used in HCC patients are mainly liver resection,liver transplantation,and local ablation,each with advantages and disadvantages.In conclusion,clear strategies are urgently needed to understand the extent of HCC and related problems in this part of the world.This review provides greater knowledge of HCC for the proper design of preventive programs by taking into consideration specific characteristics of our population.Also,this review allows for an understanding of individualizing treatments according to the patient’s needs.展开更多
Chemoresistance is a primary cause of treatment failure in pancreatic cancer.Identifying cell surface markers specifically expressed in chemoresistant cancer cells(CCCs)could facilitate targeted therapies to overcome ...Chemoresistance is a primary cause of treatment failure in pancreatic cancer.Identifying cell surface markers specifically expressed in chemoresistant cancer cells(CCCs)could facilitate targeted therapies to overcome chemoresistance.We performed an antibody-based screen and found that TRA-1-60 and TRA-1-81,two‘stemness’cell surface markers,are highly enriched in CCCs.Further-more,TRA-1-60^(+)/TRA-1-81^(+)cells are chemoresistant compared to TRA-1-60^(-)/TRA-1-81^(-)cells.Transcriptome profiling identified UGT1A10,shown to be both necessary and sufficient to maintain TRA-1-60/TRA-1-81 expression and chemoresistance.From a high-content chemical screen,we identified Cymarin,which downregulates UGT1A10,eliminates TRA-1-60/TRA-1-81 expression,and increases chemosensitivity both in vitro and in vivo.Finally,TRA-1-60/TRA-1-81 expression is highly specific in primary cancer tissue and positively correlated with chemoresistance and short survival,which highlights their potentiality for targeted therapy.Therefore,we discovered a novel CCC surface marker regulated by a pathway that promotes chemoresistance,as well as a leading drug candidate to target this pathway.展开更多
Drug administration customized to individual cells could intrinsically address cancer heterogeneity and provide a safe and effective method for delivering personalized treatment. To accomplish this, we developed a sma...Drug administration customized to individual cells could intrinsically address cancer heterogeneity and provide a safe and effective method for delivering personalized treatment. To accomplish this, we developed a smart nanodrug delivery system characterized by cancer cell-targeted drug delivery and intracellular biomarker-responsive drug activation. This system was composed of a long-nicked DNA duplex formed by tandem hybridization of two extended antisense oligonucleotides whose ends were separately blocked with a cancer cell-specific aptamer, AS1411,and a replaceable anti-biomarker probe(ABP). We demonstrated that this DNA nanodrug was directed to cancer cells with the guidance power of AS 1411 and then activated by the presence of a given intracellular biomarker. By using such a belt-and-braces strategy, this DNA nanodrug system could safely and efficiently accelerate apoptosis of target cancer cells. Moreover, since the expression level of biomarkers tends to indicate the specific physiological state of individual cells, biomarker-responsive activation of the nanodrug is expected to enable customized drug administration at the cellular level.展开更多
基金Supported by The Fondo de Investigación Sanitaria,Instituto de Salud Carlos III,Spanish Ministry of Economy,Directorate of Science(PI10/00512 and CIBER-ESP)supported by the Fondo de Investigación Sanitaria,Instituto de Salud Carlos III,Spain
文摘Until very recently, treatment for chronic hepatitis C virus(HCV) infection has been based on the combination of two non-viral specific drugs: pegylated interferon-α and ribavirin, which is effective in, overall, about 40%-50% of cases. To improve the response to treatment, novel drugs have been designed to specifically block viral proteins. Multiple compounds are under development, and the approval for clinical use of the first of such direct-acting antivirals in 2011(Telaprevir and Boceprevir), represents a milestone in HCV treatment. HCV therapeutics is entering a new expanding era, and a highly-effective cure is envisioned for the first timesince the discovery of the virus in 1989. However, any antiviral treatment may be limited by the capacity of the virus to overcome the selective pressure of new drugs, generating antiviral resistance. Here, we try to provide a basic overview of new treatments, HCV resistance to new antivirals and some considerations derived from a Public Health perspective, using HCV resistance to protease and polymerase inhibitors as examples.
文摘Bone is a dynamic tissue that is constantly renewed by the coordinated action of two cell types, i.e., the bone-resorbing osteoclasts and the bone-forming osteoblasts. However, in some circumstances, bone regeneration exceeds bone self repair capacities. This is notably often the case after bone fractures, osteolytic bone tumor surgery, or osteonecrosis. In this regard,bone tissue engineering with autologous or allogenic mesenchymal stem cells(MSCs) is been widely developed. MSCs can be isolated from bone marrow or other tissues such as adipose tissue or umbilical cord, and can be implanted in bone defects with or without prior amplification and stimulation. However, the outcome of most pre-clinical studies remains relatively disappointing. A better understanding of the successive steps and molecular mechanisms involved in MSC-osteoblastic differentiation appears to be crucial to optimize MSC-bone therapy. In this review, we first present the important growth factors that stimulate osteoblastogenesis. Then we review the main transcription factors that modulate osteoblast differentiation, and the microRNAs(miRs)that inhibit their expression. Finally, we also discuss articles dealing with the use of these factors and miRs in the development of new bone MSC therapy strategies. We particularly focus on the studies using human MSCs, since significant differences exist between osteoblast differentiation mechanisms in humans and mice for instance.
基金funded by grants from EU Marie Curie ITN RAPID(grant number 290246)Versus Arthritis(Grant Number 20823)+4 种基金the BBSRC(BB/P504567/1)supported by a student stipend from the University of Glasgow and Dentsply Sirona(Project Number 300881)supported by a grant from the European Regional Development Fund and the Spanish Ministry of Science,Innovation and Universities with the reference RTI2018-102032-B-I00the Valencian Innovation Agency with the reference INNVAL20/19/006supported by an FPI fellowship from the Spanish Ministry of Science,Innovation,and Universities with the reference Bio2015-68711-R。
文摘The reduction of nitrate to nitrite by the oral microbiota has been proposed to be important for oral health and results in nitric oxide formation that can improve cardiometabolic conditions. Studies of bacterial composition in subgingival plaque suggest that nitrate-reducing bacteria are associated with periodontal health, but the impact of periodontitis on nitrate-reducing capacity(NRC)and, therefore, nitric oxide availability has not been evaluated. The current study aimed to evaluate how periodontitis affects the NRC of the oral microbiota. First, 16S rRNA sequencing data from five different countries were analyzed, revealing that nitratereducing bacteria were significantly lower in subgingival plaque of periodontitis patients compared with healthy individuals(P < 0.05 in all five datasets with n = 20–82 samples per dataset). Secondly, subgingival plaque, saliva, and plasma samples were obtained from 42 periodontitis patients before and after periodontal treatment. The oral NRC was determined in vitro by incubating saliva with 8 mmol/L nitrate(a concentration found in saliva after nitrate-rich vegetable intake) and compared with the NRC of 15healthy individuals. Salivary NRC was found to be diminished in periodontal patients before treatment(P < 0.05) but recovered to healthy levels 90 days post-treatment. Additionally, the subgingival levels of nitrate-reducing bacteria increased after treatment and correlated negatively with periodontitis-associated bacteria(P < 0.01). No significant effect of periodontal treatment on the baseline saliva and plasma nitrate and nitrite levels was found, indicating that differences in the NRC may only be revealed after nitrate intake. Our results suggest that an impaired NRC in periodontitis could limit dietary nitrate-derived nitric oxide levels, and the effect on systemic health should be explored in future studies.
基金Open access funding provided by Semmelweis UniversityHungarian Innovation Agency under NVKP_16-1-2016-0005,KFI_16-1-2016-0048,NKFIH K_22143021 and 2019-1.1.1-PIACI-KFI-2019-00367 projects,K_143021.
文摘Background The utility of routine extensive molecular profiling of pediatric tumors is a matter of debate due to the high number of genetic alterations of unknown significance or low evidence and the lack of standardized and personalized decision support methods.Digital drug assignment(DDA)is a novel computational method to prioritize treatment options by aggregating numerous evidence-based associations between multiple drivers,targets,and targeted agents.DDA has been validated to improve personalized treatment decisions based on the outcome data of adult patients treated in the SHIVA01 clinical trial.The aim of this study was to evaluate the utility of DDA in pediatric oncology.Methods Between 2017 and 2020,103 high-risk pediatric cancer patients(<21 years)were involved in our precision oncology program,and samples from 100 patients were eligible for further analysis.Tissue or blood samples were analyzed by whole-exome(WES)or targeted panel sequencing and other molecular diagnostic modalities and processed by a software system using the DDA algorithm for therapeutic decision support.Finally,a molecular tumor board(MTB)evaluated the results to provide therapy recommendations.Results Of the 100 cases with comprehensive molecular diagnostic data,88 yielded WES and 12 panel sequencing results.DDA identified matching off-label targeted treatment options(actionability)in 72/100 cases(72%),while 57/100(57%)showed potential drug resistance.Actionability reached 88%(29/33)by 2020 due to the continuous updates of the evidence database.MTB approved the clinical use of a DDA-top-listed treatment in 56 of 72 actionable cases(78%).The approved therapies had significantly higher aggregated evidence levels(AELs)than dismissed therapies.Filtering of WES results for targeted panels missed important mutations affecting therapy selection.Conclusions DDA is a promising approach to overcome challenges associated with the interpretation of extensive molecular profiling in the routine care of high-risk pediatric cancers.Knowledgebase updates enable automatic interpretation of a continuously expanding gene set,a“virtual”panel,filtered out from genome-wide analysis to always maximize the performance of precision treatment planning.
文摘Hepatocellular carcinoma(HCC)is the most common cancer associated with chronic liver disease and cirrhosis.The most common cause of HCC is chronic hepatitis C virus infection and many studies in Europe,Asia and North America have focused on its etiology,epidemiology,diagnostic tools,and therapeutic options.However,little is known about these issues in Latin America.The aim of this review is to address these aspects of HCC in Latin America.The main risk factors associated with developing HCC in this region are:age,concomitant cirrhosis,hepatitis C infection,obesity and hereditary disease such as hemochromatosis.On the other hand,screening tests and diagnostic methods of HCC are mostly serum alpha fetoprotein quantification,liver ultrasound,computed tomography,magnetic resonance,and histopathology.Novel diagnostic methods include gut microbiota analysis and the use of nanotechnology and they continue to be tested.Finally,according to the Barcelona Clinic Liver Cancer,curative treatments used in HCC patients are mainly liver resection,liver transplantation,and local ablation,each with advantages and disadvantages.In conclusion,clear strategies are urgently needed to understand the extent of HCC and related problems in this part of the world.This review provides greater knowledge of HCC for the proper design of preventive programs by taking into consideration specific characteristics of our population.Also,this review allows for an understanding of individualizing treatments according to the patient’s needs.
基金supported by a Shared Facility contract from the New York State Department of Health(NYSTEM C029156)Weill Cornell Medicine Department of Surgery,two pilot grants from Center for Advanced Digestive Care and Clinical and Transitional Science Center of Weill Cornell Medical College(to T.E.and S.C.),Alice Bohmfalk Charitable Trust(to F.M.),and National Institutes of Health(R01 CA204228 to S.D.L.).
文摘Chemoresistance is a primary cause of treatment failure in pancreatic cancer.Identifying cell surface markers specifically expressed in chemoresistant cancer cells(CCCs)could facilitate targeted therapies to overcome chemoresistance.We performed an antibody-based screen and found that TRA-1-60 and TRA-1-81,two‘stemness’cell surface markers,are highly enriched in CCCs.Further-more,TRA-1-60^(+)/TRA-1-81^(+)cells are chemoresistant compared to TRA-1-60^(-)/TRA-1-81^(-)cells.Transcriptome profiling identified UGT1A10,shown to be both necessary and sufficient to maintain TRA-1-60/TRA-1-81 expression and chemoresistance.From a high-content chemical screen,we identified Cymarin,which downregulates UGT1A10,eliminates TRA-1-60/TRA-1-81 expression,and increases chemosensitivity both in vitro and in vivo.Finally,TRA-1-60/TRA-1-81 expression is highly specific in primary cancer tissue and positively correlated with chemoresistance and short survival,which highlights their potentiality for targeted therapy.Therefore,we discovered a novel CCC surface marker regulated by a pathway that promotes chemoresistance,as well as a leading drug candidate to target this pathway.
基金supported by the National Natural Science Foundation of China(21505039,2013CB932702)the China National Instrumentation Program(2011YQ03012412)the National Institutes of Health grants(GM079359,CA133086)
文摘Drug administration customized to individual cells could intrinsically address cancer heterogeneity and provide a safe and effective method for delivering personalized treatment. To accomplish this, we developed a smart nanodrug delivery system characterized by cancer cell-targeted drug delivery and intracellular biomarker-responsive drug activation. This system was composed of a long-nicked DNA duplex formed by tandem hybridization of two extended antisense oligonucleotides whose ends were separately blocked with a cancer cell-specific aptamer, AS1411,and a replaceable anti-biomarker probe(ABP). We demonstrated that this DNA nanodrug was directed to cancer cells with the guidance power of AS 1411 and then activated by the presence of a given intracellular biomarker. By using such a belt-and-braces strategy, this DNA nanodrug system could safely and efficiently accelerate apoptosis of target cancer cells. Moreover, since the expression level of biomarkers tends to indicate the specific physiological state of individual cells, biomarker-responsive activation of the nanodrug is expected to enable customized drug administration at the cellular level.
