A novel siphon-based divide-and-conquer(SbDaC)policy is presented in this paper for the synthesis of Petri net(PN)based liveness-enforcing supervisors(LES)for flexible manufacturing systems(FMS)prone to deadlocks or l...A novel siphon-based divide-and-conquer(SbDaC)policy is presented in this paper for the synthesis of Petri net(PN)based liveness-enforcing supervisors(LES)for flexible manufacturing systems(FMS)prone to deadlocks or livelocks.The proposed method takes an uncontrolled and bounded PN model(UPNM)of the FMS.Firstly,the reduced PNM(RPNM)is obtained from the UPNM by using PN reduction rules to reduce the computation burden.Then,the set of strict minimal siphons(SMSs)of the RPNM is computed.Next,the complementary set of SMSs is computed from the set of SMSs.By the union of these two sets,the superset of SMSs is computed.Finally,the set of subnets of the RPNM is obtained by applying the PN reduction rules to the superset of SMSs.All these subnets suffer from deadlocks.These subnets are then ordered from the smallest one to the largest one based on a criterion.To enforce liveness on these subnets,a set of control places(CPs)is computed starting from the smallest subnet to the largest one.Once all subnets are live,this process provides the LES,consisting of a set of CPs to be used for the UPNM.The live controlled PN model(CPNM)is constructed by merging the LES with the UPNM.The SbDaC policy is applicable to all classes of PNs related to FMS prone to deadlocks or livelocks.Several FMS examples are considered from the literature to highlight the applicability of the SbDaC policy.In particular,three examples are utilized to emphasize the importance,applicability and effectiveness of the SbDaC policy to realistic FMS with very large state spaces.展开更多
With the rapid evolution of artificial intelligence(AI)technologies,the medical industry is undergoing a profound transformation driven by data intelligence.As the foundational element for intelligent diagnosis,precis...With the rapid evolution of artificial intelligence(AI)technologies,the medical industry is undergoing a profound transformation driven by data intelligence.As the foundational element for intelligent diagnosis,precision prevention,and public health governance,medical data is characterized by massive volume,complex structure,diverse sources,high dimensionality,strong privacy,and high timeliness.Traditional data analysis methods are no longer sufficient to meet the comprehensive requirements of data security,intelligent processing,and decision support.Through techniques such as machine learning,deep learning,natural language processing,and multimodal fusion,AI provides robust technical support for medical data cleaning,governance,mining,and application.At the data level,intelligent algorithms enable the standardization,structuring,and interoperability of medical data,promoting information sharing across medical systems.At the model level,AI supports auxiliary diagnosis and precision treatment through image recognition,medical record analysis,and knowledge graph construction.At the system level,intelligent decision-support platforms continuously enhance the efficiency and accuracy of healthcare services.However,the widespread adoption of AI in medicine still faces challenges such as privacy protection,data security,model interpretability,and the lack of unified industry standards.Based on a systematic review of AI’s key supporting technologies in medical data processing and application,this paper focuses on the compliance challenges and adaptation strategies during industry integration and proposes an adaptation framework centered on“technological trustworthiness,data security,and industry collaboration.”The study provides theoretical and practical insights for promoting the standardized and sustainable development of AI in the healthcare industry.展开更多
Monoacylglycerol lipase(MAGL)constitutes a crucial serine hydrolase within the endocannabinoid system,which has been suggested as a potential therapeutic target for the treatment of various neurodegenerative disorders...Monoacylglycerol lipase(MAGL)constitutes a crucial serine hydrolase within the endocannabinoid system,which has been suggested as a potential therapeutic target for the treatment of various neurodegenerative disorders.While MAGL inhibitors have entered the clinical arena,a highly selective and MAGL-specific positron emission tomography(PET)ligand holds promise to significantly facilitate clinical drug development by allowing the quantification of MAGL levels and the assessment of target occupancy in patients.Accordingly,this study aimed to develop a new series of reversible MAGL inhibitor candidates,based on a piperazinyl azetidine diamide scaffold.Compound 3 demonstrated the most promising performance characteristics in pharmacological evaluations compared to other MAGL inhibitor candidates.Subsequently,it was labeled with fluorine-18 and further assessed through autoradiography and PET imaging,as well as ex vivo biodistribution and metabolite analysis experiments in rodents.Compound 3 exhibited a heterogeneous radioactivity distribution,favorable brain uptake,and excellent in vivo binding specificity.Target occupancy studies with a therapeutic MAGL inhibitor demonstrated a dose-dependent PET signal reduction of[^(18)F]3 in rat brains.In conclusion,[^(18)F]3([^(18)F]MAGL-2011)has the potential to serve as an effective MAGL PET ligand.展开更多
Diffuse large B-cell lymphoma(DLBCL),the most common subtype of non-Hodgkin’s lymphoma(NHL)worldwide,accounts for 39% and 44% of nodal and extranodal NHL cases in China,respectively1.Standard first-line treatment for...Diffuse large B-cell lymphoma(DLBCL),the most common subtype of non-Hodgkin’s lymphoma(NHL)worldwide,accounts for 39% and 44% of nodal and extranodal NHL cases in China,respectively1.Standard first-line treatment for DLBCL is chemo-immunotherapy with rituximab,cyclophos-phamide,doxorubicin,vincristine,and prednisone,which cures 50%-60% of patients2.展开更多
BACKGROUND: The availability of novel direct-acting antivirals (DAAs) represents a new era of curative hepatitis C virus (HCV) treatment, with over 95% of patients infected with HCV genotype 1 achieving sustained viro...BACKGROUND: The availability of novel direct-acting antivirals (DAAs) represents a new era of curative hepatitis C virus (HCV) treatment, with over 95% of patients infected with HCV genotype 1 achieving sustained virological response (SVR). Nevertheless, the majority of patients globally are unable to access these treatments because of cost and infrastructure constraints and, thus, remain untreated and uncured. DATA SOURCE: Relevant articles of peginterferon (PegIFN)-based treatments in HCV and sofosbuvir-based treatments, simeprevir, daclatasvir/asunaprevir, ritonavir-boosted paritaprevir/ombitasvir/dasabuvir, and grazoprevir/elbasvir, were searched in PubMed database, including general population and special population. RESULTS: PegIFN in combination with ribavirin remains an important and relevant option for some patients, achieving SVR rates of up to 79% in genotype 1 and 89% in genotype 2 or 3 infections, which increases for patients with favorable IL28B genotypes. Triple therapy of DAA plus PegIFN/ribavirin is effective in treating difficult-to-cure patients infected with HCV genotype 3 or with resistance-associated variants. Owing to its long history in HCV management, the efficacy, tolerability and long-term outcomes associated with PegIFN alfa-2a are well established and have been validated in large-scale studies and in clinical practice for many populations. Furthermore, emerging data show that IFN-induced SVR is associated with lower incidences of hepatocellular carcinoma compared with DAAs. On the contrary, novel DAAs have yet to be studied in special populations, and long-term outcomes, particularly tumor development and recurrence in patients with cirrhosis and/or hepatocellular carcinoma, and reactivation of HBV in dually infected patients, are still unclear. CONCLUSION: In this interferon-free era, PegIFN-based regimens remain a safe and effective option for selected HCV patients.展开更多
Tumor necrosis factor-alpha (TNF-α) is an important cytokine in generating an immune response against infection with hepatitis C virus (HCV). The functions of TNF-α may be altered by single-nucleotide polymorphisms ...Tumor necrosis factor-alpha (TNF-α) is an important cytokine in generating an immune response against infection with hepatitis C virus (HCV). The functions of TNF-α may be altered by single-nucleotide polymorphisms (SNPs) in its gene structure. We hypothesized that SNPs in TNF-α may be important in determining the outcome of an HCV infection. To test this hypothesis, we investigated the role of the polymorphism -308G/A, which is located in the promoter region of the TNF-α gene, in the progression of HCV infection in Egyptian patients using a quantitative real-time polymerase chain reaction (qRT-PCR). The distribution of this polymorphism and its impact on the serum level of TNF-α was compared between 90 HCV-infected patients [45 with HCV-induced cirrhosis and 45 with HCV-related hepatocellular carcinoma (HCC)] and 45 healthy Egyptian volunteers without any history of liver disease. Our results showed that at the TNF-α -308 position, the G/G allele was most common (78.5% ) in the study population, with the G/A and A/A alleles occurring less frequently (13.3% and 8.1% , respectively). Frequencies of G/G, G/A, and A/A genotypes were 87%, 7%, and 6% in patients with liver cirrhosis and were 94% , 4% , and 2% in patients with HCC, respectively. Serum levels of TNF-α were significantly higher in HCV-infected patients than in healthy controls, indicating that the TNF-α -308 polymorphism does not influence the production of TNF-α. The serum level of TNF-α was positively correlated with HCV infection. Taken together, these findings suggest that the TNF-α -308 polymorphism may not be a host genetic factor associated with the severity of HCV infection, but may be an independent risk factor for HCC.展开更多
AIM： To assess the use of capecitabine-based therapy and associated complication rates in patients with gastroesophageal cancer （GEC） in a real-world treat- ment setting. METHODS： Patients with claims between 2004...AIM： To assess the use of capecitabine-based therapy and associated complication rates in patients with gastroesophageal cancer （GEC） in a real-world treat- ment setting. METHODS： Patients with claims between 2004 and 2005 were identified from the Thomson Reuters MarketScan databases. Capecitabine regimens were compared with 5-fluorouracU （5-FU） and other chemotherapy regimens, and were stratified by treatment setting. RESULTS： We identified 1013 patients with GEC： approximately half had treatment initiated with a 5-FU regimen, whereas 11% had therapy initiated with a capecitabine regimen. The mean capecitabine dose overall was 2382 ± 1118 mg/d, and capecitabine was used as monotherapy more often than in combination. Overall, 5-FU regimens were the most common treat- ment option in neoadjuvant and adjuvant settings, while other non-capecitabine regimens were used more widely in first- and second-line settings. The overall unadjusted complication rate for capecitabine regimens was about half of that seen with 5-FU regimens. In multivariate analyses, capecitabine recipients had a 51% （95% CI： 26%-81%） lower risk of developing any complication than 5-FU recipients did. The risk of developing bone marrow, constitutional, gastrointestinal tract, infectious, or skin complications was lower with capecitabine therapy than with 5-FU.CONCLUSION： Capecitabine appeared to have a favorable side effect profile compared with 5-FU, which indicates that it may be a treatment option for GEC.展开更多
AIM To detect hyper-conserved regions in the hepatitis B virus(HBV) X gene(HBX) 5' region that could be candidates for gene therapy.METHODS The study included 27 chronic hepatitis B treatmentnaive patients in vari...AIM To detect hyper-conserved regions in the hepatitis B virus(HBV) X gene(HBX) 5' region that could be candidates for gene therapy.METHODS The study included 27 chronic hepatitis B treatmentnaive patients in various clinical stages(from chronic infection to cirrhosis and hepatocellular carcinoma, both HBeA g-negative and HBeA g-positive), and infected with HBV genotypes A-F and H. In a serum sample from each patient with viremia > 3.5 log IU/m L, the HBX 5' end region [nucleotide(nt) 1255-1611] was PCRamplified and submitted to next-generation sequencing(NGS). We assessed genotype variants by phylogenetic analysis, and evaluated conservation of this region by calculating the information content of each nucleotide position in a multiple alignment of all unique sequences(haplotypes) obtained by NGS. Conservation at the HBx protein amino acid(aa) level was also analyzed.RESULTS NGS yielded 1333069 sequences from the 27 samples, with a median of 4578 sequences/sample(2487-9279, IQR 2817). In 14/27 patients(51.8%), phylogenetic analysis of viral nucleotide haplotypes showed a complex mixture of genotypic variants. Analysis of the information content in the haplotype multiple alignments detected 2 hyper-conserved nucleotide regions, one in the HBX upstream non-coding region(nt 1255-1286) and the other in the 5' end coding region(nt 1519-1603). This last region coded for a conserved amino acid region(aa 63-76) that partially overlaps a Kunitz-like domain.CONCLUSION Two hyper-conserved regions detected in the HBX 5' end may be of value for targeted gene therapy, regardless of the patients' clinical stage or HBV genotype.展开更多
Gastric cancer and liver cancer are among the most common malignancies and the leading causes of death worldwide,due to late detection and high recurrence rates.Today,these cancers have a heavy socioeconomic burden,fo...Gastric cancer and liver cancer are among the most common malignancies and the leading causes of death worldwide,due to late detection and high recurrence rates.Today,these cancers have a heavy socioeconomic burden,for which a full understanding of their pathophysiological features is warranted to search for promising biomarkers and therapeutic targets.Osteopontin (OPN) is overexpressed in most patients with gastric and liver cancers.Over the past decade,emerging evidence has revealed a correlation of OPN level and clinicopathological features and prognosis in gastric and liver cancers,indicating its potential as an independent prognostic indicator in such patients.Functional studies have verified the potential of OPN knockdown as a therapeutic approach in vitro and in vivo .Furthermore,OPN mediates multifaceted roles in the interaction between cancer cells and the tumor microenvironment,in which many details need further exploration.OPN signaling results in various functions,including prevention of apoptosis,modulation of angiogenesis,malfunction of tumor-associated macrophages,degradation of extracellular matrix,activation of phosphoinositide 3-kinase-Akt and nuclear factor-κB pathways,which lead to tumor formation and progression,particularly in gastric and liver cancers.This editorial aims to review recent findings on alteration in OPN expression and its clinicopathological associations with tumor progression,its potential as a therapeutic target,and putative mechanisms in gastric and liver cancers.Better understanding of the implications of OPN in tumorigenesis might facilitate development of therapeutic regimens to benefit patients with these deadly malignancies.展开更多
AIM To determine the variability/conservation of the domain of hepatitis B virus(HBV) pre S1 region that interacts with sodium-taurocholate cotransporting polypeptide(hereafter, NTCP-interacting domain) and the preval...AIM To determine the variability/conservation of the domain of hepatitis B virus(HBV) pre S1 region that interacts with sodium-taurocholate cotransporting polypeptide(hereafter, NTCP-interacting domain) and the prevalence of the rs2296651 polymorphism(S267 F, NTCP variant) in a Spanish population. METHODS Serum samples from 246 individuals were included and divided into 3 groups: patients with chronic HBV infection(CHB)(n = 41, 73% Caucasians), patients with resolved HBV infection(n = 100, 100% Caucasians) and an HBV-uninfected control group(n = 105, 100% Caucasians). Variability/conservation of the amino acid(aa) sequences of the NTCPinteracting domain,(aa 2-48 in viral genotype D) and a highly conserved pre S1 domain associated with virion morphogenesis(aa 92-103 in viral genotype D) were analyzed by next-generation sequencing and compared in 18 CHB patients with viremia > 4 log IU/mL. The rs2296651 polymorphism was determined in all individuals in all 3 groups using an in-house real-time PCR melting curve analysis.RESULTS The HBV pre S1 NTCP-interacting domain showed a high degree of conservation among the examined viral genomes especially between aa 9 and 21(in the genotype D consensus sequence). As compared with the virion morphogenesis domain, the NTCPinteracting domain had a smaller proportion of HBV genotype-unrelated changes comprising > 1% of the quasispecies(25.5% vs 31.8%), but a larger proportion of genotype-associated viral polymorphisms(34% vs 27.3%), according to consensus sequences from Gen Bank patterns of HBV genotypes A to H. Variation/conservation in both domains depended on viral genotype, with genotype C being the most highly conserved and genotype E the most variable(limited finding, only 2 genotype E included). Of note, proline residues were highly conserved in both domains, and serine residues showed changes only to threonine or tyrosine in the virion morphogenesis domain. The rs2296651 polymorphism was not detected in any participant.CONCLUSION In our CHB population, the NTCP-interacting domain was highly conserved, particularly the proline residues and essential amino acids related with the NTCP interaction, and the prevalence of rs2296651 was low/null.展开更多
Hepatitis delta virus(HDV)seems to strongly suppress hepatitis B virus(HBV)replication,although little is known about the mechanism of this interaction.Both these viruses show a dynamic distribution of mutants,resulti...Hepatitis delta virus(HDV)seems to strongly suppress hepatitis B virus(HBV)replication,although little is known about the mechanism of this interaction.Both these viruses show a dynamic distribution of mutants,resulting in viral quasispecies.Next-generation sequencing is a viable approach for analyzing the composition of these mutant spectra.As the regulatory hepatitis B X protein(HBx)is essential for HBV replication,determination of HBV X gene(HBX)quasispecies complexity in HBV/HDV infection compared to HBV monoinfection may provide information on the interactions between these two viruses.AIM To compare HBV quasispecies complexity in the HBX 5'region between chronic hepatitis delta(CHD)and chronic HBV mono-infected patients.METHODS Twenty-four untreated patients were included:7/24(29.2%)with HBeAgnegative chronic HBV infection(CI,previously termed inactive carriers),8/24(33.3%)with HBeAg-negative chronic hepatitis B(CHB)and 9/24(37.5%)with CHD.A serum sample from each patient was first tested for HBV DNA levels.The HBX 5'region[nucleotides(nt)1255-1611]was then PCR-amplified for subsequent next-generation sequencing(MiSeq,Illumina,United States).HBV quasispecies complexity in the region analyzed was evaluated using incidencebased indices(number of haplotypes and number of mutations),abundancebased indices(Hill numbers of order 1 and 2),and functional indices(mutation frequency and nucleotide diversity).We also evaluated the pattern of nucleotide changes to investigate which of them could be the cause of the quasispecies complexity.RESULTS CHB patients showed higher median HBV-DNA levels[5.4 logIU/mL,interquartile range(IQR)3.5-7.9]than CHD(3.4 logIU/mL,IQR 3-7.6)(P=n.s.)or CI(3.2 logIU/mL,IQR 2.3-3.5)(P<0.01)patients.The incidence and abundance indices indicated that HBV quasispecies complexity was significantly greater in CI than CHB.A similar trend was observed in CHD patients,although only Hill numbers of order 2 showed statistically significant differences(CHB2.81,IQR 1.11-4.57 vs CHD 8.87,6.56-11.18,P=0.038).There were no significant differences in the functional indices,but CI and CHD patients also showed a trend towards greater complexity than CHB.No differences were found for any HBV quasispecies complexity indices between CHD and CI patients.G-to-A and C-to-T nucleotide changes,characteristic of APOBEC3 G,were higher in CHD and CI than in CHB in genotype A haplotypes,but not in genotype D.The proportion of nt G-to-A vs A-to-G changes and C-to-T vs T-to-C changes in genotype A and D haplotypes in CHD patients showed no significant differences.In CHB and CI the results of these comparisons were dependent on HBV genotype.CONCLUSION The lower-replication CHD and CI groups show a trend to higher quasispecies complexity than the higher-replication CHB group.The mechanisms associated with this greater complexity require elucidation.展开更多
AIM: To present an approach for selectively killing retrovirus-infected cells that combines the toxicity of Pseudomonas exotoxin (PE) and the presence of reverse transcriptase (RT) in infected cells. METHODS: PE antis...AIM: To present an approach for selectively killing retrovirus-infected cells that combines the toxicity of Pseudomonas exotoxin (PE) and the presence of reverse transcriptase (RT) in infected cells. METHODS: PE antisense toxin RNA has palindromic stem loops at its 5' and 3' ends enabling self-primed generation of cDNA in the presence of RT. The RT activity expressed in retrovirus-infected cells converts "antisense-toxin-RNA" into a lethal toxin gene exclusively in these cells. RESULTS: Using cotransfection studies with PE-expressing RNAs and β-gal expressing reporter plasmids, we show that, in HepG2 and HepG2.2.15 hepatoma cells as well as in duck hepatitis B virus (DHBV) infected cells, HBV or DHBV-polymerase reverse transcribe a lethal cDNA copy of an antisense toxin RNA, which is composed of sequences complementary to a PE gene and eukaryotic transcription and translation signals. CONCLUSION: This finding may have important implications as a novel therapeutic strategy aimed at the elimination of HBV infection.展开更多
基金The authors extend their appreciation to King Saud University,Saudi Arabia for funding this work through the Ongoing Research Funding Program(ORF-2025-704),King Saud University,Riyadh,Saudi Arabia.
文摘A novel siphon-based divide-and-conquer(SbDaC)policy is presented in this paper for the synthesis of Petri net(PN)based liveness-enforcing supervisors(LES)for flexible manufacturing systems(FMS)prone to deadlocks or livelocks.The proposed method takes an uncontrolled and bounded PN model(UPNM)of the FMS.Firstly,the reduced PNM(RPNM)is obtained from the UPNM by using PN reduction rules to reduce the computation burden.Then,the set of strict minimal siphons(SMSs)of the RPNM is computed.Next,the complementary set of SMSs is computed from the set of SMSs.By the union of these two sets,the superset of SMSs is computed.Finally,the set of subnets of the RPNM is obtained by applying the PN reduction rules to the superset of SMSs.All these subnets suffer from deadlocks.These subnets are then ordered from the smallest one to the largest one based on a criterion.To enforce liveness on these subnets,a set of control places(CPs)is computed starting from the smallest subnet to the largest one.Once all subnets are live,this process provides the LES,consisting of a set of CPs to be used for the UPNM.The live controlled PN model(CPNM)is constructed by merging the LES with the UPNM.The SbDaC policy is applicable to all classes of PNs related to FMS prone to deadlocks or livelocks.Several FMS examples are considered from the literature to highlight the applicability of the SbDaC policy.In particular,three examples are utilized to emphasize the importance,applicability and effectiveness of the SbDaC policy to realistic FMS with very large state spaces.
文摘With the rapid evolution of artificial intelligence(AI)technologies,the medical industry is undergoing a profound transformation driven by data intelligence.As the foundational element for intelligent diagnosis,precision prevention,and public health governance,medical data is characterized by massive volume,complex structure,diverse sources,high dimensionality,strong privacy,and high timeliness.Traditional data analysis methods are no longer sufficient to meet the comprehensive requirements of data security,intelligent processing,and decision support.Through techniques such as machine learning,deep learning,natural language processing,and multimodal fusion,AI provides robust technical support for medical data cleaning,governance,mining,and application.At the data level,intelligent algorithms enable the standardization,structuring,and interoperability of medical data,promoting information sharing across medical systems.At the model level,AI supports auxiliary diagnosis and precision treatment through image recognition,medical record analysis,and knowledge graph construction.At the system level,intelligent decision-support platforms continuously enhance the efficiency and accuracy of healthcare services.However,the widespread adoption of AI in medicine still faces challenges such as privacy protection,data security,model interpretability,and the lack of unified industry standards.Based on a systematic review of AI’s key supporting technologies in medical data processing and application,this paper focuses on the compliance challenges and adaptation strategies during industry integration and proposes an adaptation framework centered on“technological trustworthiness,data security,and industry collaboration.”The study provides theoretical and practical insights for promoting the standardized and sustainable development of AI in the healthcare industry.
基金supported by NCI T32CA275777support provided,in part,by the NIH grants(S10OD034326,DA038000 and DA043507,USA)+1 种基金Emory Radiology Startup and Chair FundEmory School of Medicine Endowed Directorship.
文摘Monoacylglycerol lipase(MAGL)constitutes a crucial serine hydrolase within the endocannabinoid system,which has been suggested as a potential therapeutic target for the treatment of various neurodegenerative disorders.While MAGL inhibitors have entered the clinical arena,a highly selective and MAGL-specific positron emission tomography(PET)ligand holds promise to significantly facilitate clinical drug development by allowing the quantification of MAGL levels and the assessment of target occupancy in patients.Accordingly,this study aimed to develop a new series of reversible MAGL inhibitor candidates,based on a piperazinyl azetidine diamide scaffold.Compound 3 demonstrated the most promising performance characteristics in pharmacological evaluations compared to other MAGL inhibitor candidates.Subsequently,it was labeled with fluorine-18 and further assessed through autoradiography and PET imaging,as well as ex vivo biodistribution and metabolite analysis experiments in rodents.Compound 3 exhibited a heterogeneous radioactivity distribution,favorable brain uptake,and excellent in vivo binding specificity.Target occupancy studies with a therapeutic MAGL inhibitor demonstrated a dose-dependent PET signal reduction of[^(18)F]3 in rat brains.In conclusion,[^(18)F]3([^(18)F]MAGL-2011)has the potential to serve as an effective MAGL PET ligand.
基金sponsored by Shanghai Roche Pharmaceuticals Ltd.
文摘Diffuse large B-cell lymphoma(DLBCL),the most common subtype of non-Hodgkin’s lymphoma(NHL)worldwide,accounts for 39% and 44% of nodal and extranodal NHL cases in China,respectively1.Standard first-line treatment for DLBCL is chemo-immunotherapy with rituximab,cyclophos-phamide,doxorubicin,vincristine,and prednisone,which cures 50%-60% of patients2.
文摘BACKGROUND: The availability of novel direct-acting antivirals (DAAs) represents a new era of curative hepatitis C virus (HCV) treatment, with over 95% of patients infected with HCV genotype 1 achieving sustained virological response (SVR). Nevertheless, the majority of patients globally are unable to access these treatments because of cost and infrastructure constraints and, thus, remain untreated and uncured. DATA SOURCE: Relevant articles of peginterferon (PegIFN)-based treatments in HCV and sofosbuvir-based treatments, simeprevir, daclatasvir/asunaprevir, ritonavir-boosted paritaprevir/ombitasvir/dasabuvir, and grazoprevir/elbasvir, were searched in PubMed database, including general population and special population. RESULTS: PegIFN in combination with ribavirin remains an important and relevant option for some patients, achieving SVR rates of up to 79% in genotype 1 and 89% in genotype 2 or 3 infections, which increases for patients with favorable IL28B genotypes. Triple therapy of DAA plus PegIFN/ribavirin is effective in treating difficult-to-cure patients infected with HCV genotype 3 or with resistance-associated variants. Owing to its long history in HCV management, the efficacy, tolerability and long-term outcomes associated with PegIFN alfa-2a are well established and have been validated in large-scale studies and in clinical practice for many populations. Furthermore, emerging data show that IFN-induced SVR is associated with lower incidences of hepatocellular carcinoma compared with DAAs. On the contrary, novel DAAs have yet to be studied in special populations, and long-term outcomes, particularly tumor development and recurrence in patients with cirrhosis and/or hepatocellular carcinoma, and reactivation of HBV in dually infected patients, are still unclear. CONCLUSION: In this interferon-free era, PegIFN-based regimens remain a safe and effective option for selected HCV patients.
文摘Tumor necrosis factor-alpha (TNF-α) is an important cytokine in generating an immune response against infection with hepatitis C virus (HCV). The functions of TNF-α may be altered by single-nucleotide polymorphisms (SNPs) in its gene structure. We hypothesized that SNPs in TNF-α may be important in determining the outcome of an HCV infection. To test this hypothesis, we investigated the role of the polymorphism -308G/A, which is located in the promoter region of the TNF-α gene, in the progression of HCV infection in Egyptian patients using a quantitative real-time polymerase chain reaction (qRT-PCR). The distribution of this polymorphism and its impact on the serum level of TNF-α was compared between 90 HCV-infected patients [45 with HCV-induced cirrhosis and 45 with HCV-related hepatocellular carcinoma (HCC)] and 45 healthy Egyptian volunteers without any history of liver disease. Our results showed that at the TNF-α -308 position, the G/G allele was most common (78.5% ) in the study population, with the G/A and A/A alleles occurring less frequently (13.3% and 8.1% , respectively). Frequencies of G/G, G/A, and A/A genotypes were 87%, 7%, and 6% in patients with liver cirrhosis and were 94% , 4% , and 2% in patients with HCC, respectively. Serum levels of TNF-α were significantly higher in HCV-infected patients than in healthy controls, indicating that the TNF-α -308 polymorphism does not influence the production of TNF-α. The serum level of TNF-α was positively correlated with HCV infection. Taken together, these findings suggest that the TNF-α -308 polymorphism may not be a host genetic factor associated with the severity of HCV infection, but may be an independent risk factor for HCC.
文摘AIM： To assess the use of capecitabine-based therapy and associated complication rates in patients with gastroesophageal cancer （GEC） in a real-world treat- ment setting. METHODS： Patients with claims between 2004 and 2005 were identified from the Thomson Reuters MarketScan databases. Capecitabine regimens were compared with 5-fluorouracU （5-FU） and other chemotherapy regimens, and were stratified by treatment setting. RESULTS： We identified 1013 patients with GEC： approximately half had treatment initiated with a 5-FU regimen, whereas 11% had therapy initiated with a capecitabine regimen. The mean capecitabine dose overall was 2382 ± 1118 mg/d, and capecitabine was used as monotherapy more often than in combination. Overall, 5-FU regimens were the most common treat- ment option in neoadjuvant and adjuvant settings, while other non-capecitabine regimens were used more widely in first- and second-line settings. The overall unadjusted complication rate for capecitabine regimens was about half of that seen with 5-FU regimens. In multivariate analyses, capecitabine recipients had a 51% （95% CI： 26%-81%） lower risk of developing any complication than 5-FU recipients did. The risk of developing bone marrow, constitutional, gastrointestinal tract, infectious, or skin complications was lower with capecitabine therapy than with 5-FU.CONCLUSION： Capecitabine appeared to have a favorable side effect profile compared with 5-FU, which indicates that it may be a treatment option for GEC.
基金Supported by the Instituto de Salud Carlos III,No.PI15/00856the European Regional Development Fund(ERDF),No.PI15/00856
文摘AIM To detect hyper-conserved regions in the hepatitis B virus(HBV) X gene(HBX) 5' region that could be candidates for gene therapy.METHODS The study included 27 chronic hepatitis B treatmentnaive patients in various clinical stages(from chronic infection to cirrhosis and hepatocellular carcinoma, both HBeA g-negative and HBeA g-positive), and infected with HBV genotypes A-F and H. In a serum sample from each patient with viremia > 3.5 log IU/m L, the HBX 5' end region [nucleotide(nt) 1255-1611] was PCRamplified and submitted to next-generation sequencing(NGS). We assessed genotype variants by phylogenetic analysis, and evaluated conservation of this region by calculating the information content of each nucleotide position in a multiple alignment of all unique sequences(haplotypes) obtained by NGS. Conservation at the HBx protein amino acid(aa) level was also analyzed.RESULTS NGS yielded 1333069 sequences from the 27 samples, with a median of 4578 sequences/sample(2487-9279, IQR 2817). In 14/27 patients(51.8%), phylogenetic analysis of viral nucleotide haplotypes showed a complex mixture of genotypic variants. Analysis of the information content in the haplotype multiple alignments detected 2 hyper-conserved nucleotide regions, one in the HBX upstream non-coding region(nt 1255-1286) and the other in the 5' end coding region(nt 1519-1603). This last region coded for a conserved amino acid region(aa 63-76) that partially overlaps a Kunitz-like domain.CONCLUSION Two hyper-conserved regions detected in the HBX 5' end may be of value for targeted gene therapy, regardless of the patients' clinical stage or HBV genotype.
文摘Gastric cancer and liver cancer are among the most common malignancies and the leading causes of death worldwide,due to late detection and high recurrence rates.Today,these cancers have a heavy socioeconomic burden,for which a full understanding of their pathophysiological features is warranted to search for promising biomarkers and therapeutic targets.Osteopontin (OPN) is overexpressed in most patients with gastric and liver cancers.Over the past decade,emerging evidence has revealed a correlation of OPN level and clinicopathological features and prognosis in gastric and liver cancers,indicating its potential as an independent prognostic indicator in such patients.Functional studies have verified the potential of OPN knockdown as a therapeutic approach in vitro and in vivo .Furthermore,OPN mediates multifaceted roles in the interaction between cancer cells and the tumor microenvironment,in which many details need further exploration.OPN signaling results in various functions,including prevention of apoptosis,modulation of angiogenesis,malfunction of tumor-associated macrophages,degradation of extracellular matrix,activation of phosphoinositide 3-kinase-Akt and nuclear factor-κB pathways,which lead to tumor formation and progression,particularly in gastric and liver cancers.This editorial aims to review recent findings on alteration in OPN expression and its clinicopathological associations with tumor progression,its potential as a therapeutic target,and putative mechanisms in gastric and liver cancers.Better understanding of the implications of OPN in tumorigenesis might facilitate development of therapeutic regimens to benefit patients with these deadly malignancies.
基金Supported by Instituto de Salud Carlos Ⅲ,No.PI14/01416 and No.PI15/00856cofinanced by the European Regional Development Fund(ERDF)the Gilead Fellowship Program,No.GLD14-00296
文摘AIM To determine the variability/conservation of the domain of hepatitis B virus(HBV) pre S1 region that interacts with sodium-taurocholate cotransporting polypeptide(hereafter, NTCP-interacting domain) and the prevalence of the rs2296651 polymorphism(S267 F, NTCP variant) in a Spanish population. METHODS Serum samples from 246 individuals were included and divided into 3 groups: patients with chronic HBV infection(CHB)(n = 41, 73% Caucasians), patients with resolved HBV infection(n = 100, 100% Caucasians) and an HBV-uninfected control group(n = 105, 100% Caucasians). Variability/conservation of the amino acid(aa) sequences of the NTCPinteracting domain,(aa 2-48 in viral genotype D) and a highly conserved pre S1 domain associated with virion morphogenesis(aa 92-103 in viral genotype D) were analyzed by next-generation sequencing and compared in 18 CHB patients with viremia > 4 log IU/mL. The rs2296651 polymorphism was determined in all individuals in all 3 groups using an in-house real-time PCR melting curve analysis.RESULTS The HBV pre S1 NTCP-interacting domain showed a high degree of conservation among the examined viral genomes especially between aa 9 and 21(in the genotype D consensus sequence). As compared with the virion morphogenesis domain, the NTCPinteracting domain had a smaller proportion of HBV genotype-unrelated changes comprising > 1% of the quasispecies(25.5% vs 31.8%), but a larger proportion of genotype-associated viral polymorphisms(34% vs 27.3%), according to consensus sequences from Gen Bank patterns of HBV genotypes A to H. Variation/conservation in both domains depended on viral genotype, with genotype C being the most highly conserved and genotype E the most variable(limited finding, only 2 genotype E included). Of note, proline residues were highly conserved in both domains, and serine residues showed changes only to threonine or tyrosine in the virion morphogenesis domain. The rs2296651 polymorphism was not detected in any participant.CONCLUSION In our CHB population, the NTCP-interacting domain was highly conserved, particularly the proline residues and essential amino acids related with the NTCP interaction, and the prevalence of rs2296651 was low/null.
基金Supported by the Instituto de Salud CarlosⅢ,grants PI15/00856 and PI17/02233co-financed by the European Regional Development Fund(ERDF)
文摘Hepatitis delta virus(HDV)seems to strongly suppress hepatitis B virus(HBV)replication,although little is known about the mechanism of this interaction.Both these viruses show a dynamic distribution of mutants,resulting in viral quasispecies.Next-generation sequencing is a viable approach for analyzing the composition of these mutant spectra.As the regulatory hepatitis B X protein(HBx)is essential for HBV replication,determination of HBV X gene(HBX)quasispecies complexity in HBV/HDV infection compared to HBV monoinfection may provide information on the interactions between these two viruses.AIM To compare HBV quasispecies complexity in the HBX 5'region between chronic hepatitis delta(CHD)and chronic HBV mono-infected patients.METHODS Twenty-four untreated patients were included:7/24(29.2%)with HBeAgnegative chronic HBV infection(CI,previously termed inactive carriers),8/24(33.3%)with HBeAg-negative chronic hepatitis B(CHB)and 9/24(37.5%)with CHD.A serum sample from each patient was first tested for HBV DNA levels.The HBX 5'region[nucleotides(nt)1255-1611]was then PCR-amplified for subsequent next-generation sequencing(MiSeq,Illumina,United States).HBV quasispecies complexity in the region analyzed was evaluated using incidencebased indices(number of haplotypes and number of mutations),abundancebased indices(Hill numbers of order 1 and 2),and functional indices(mutation frequency and nucleotide diversity).We also evaluated the pattern of nucleotide changes to investigate which of them could be the cause of the quasispecies complexity.RESULTS CHB patients showed higher median HBV-DNA levels[5.4 logIU/mL,interquartile range(IQR)3.5-7.9]than CHD(3.4 logIU/mL,IQR 3-7.6)(P=n.s.)or CI(3.2 logIU/mL,IQR 2.3-3.5)(P<0.01)patients.The incidence and abundance indices indicated that HBV quasispecies complexity was significantly greater in CI than CHB.A similar trend was observed in CHD patients,although only Hill numbers of order 2 showed statistically significant differences(CHB2.81,IQR 1.11-4.57 vs CHD 8.87,6.56-11.18,P=0.038).There were no significant differences in the functional indices,but CI and CHD patients also showed a trend towards greater complexity than CHB.No differences were found for any HBV quasispecies complexity indices between CHD and CI patients.G-to-A and C-to-T nucleotide changes,characteristic of APOBEC3 G,were higher in CHD and CI than in CHB in genotype A haplotypes,but not in genotype D.The proportion of nt G-to-A vs A-to-G changes and C-to-T vs T-to-C changes in genotype A and D haplotypes in CHD patients showed no significant differences.In CHB and CI the results of these comparisons were dependent on HBV genotype.CONCLUSION The lower-replication CHD and CI groups show a trend to higher quasispecies complexity than the higher-replication CHB group.The mechanisms associated with this greater complexity require elucidation.
文摘AIM: To present an approach for selectively killing retrovirus-infected cells that combines the toxicity of Pseudomonas exotoxin (PE) and the presence of reverse transcriptase (RT) in infected cells. METHODS: PE antisense toxin RNA has palindromic stem loops at its 5' and 3' ends enabling self-primed generation of cDNA in the presence of RT. The RT activity expressed in retrovirus-infected cells converts "antisense-toxin-RNA" into a lethal toxin gene exclusively in these cells. RESULTS: Using cotransfection studies with PE-expressing RNAs and β-gal expressing reporter plasmids, we show that, in HepG2 and HepG2.2.15 hepatoma cells as well as in duck hepatitis B virus (DHBV) infected cells, HBV or DHBV-polymerase reverse transcribe a lethal cDNA copy of an antisense toxin RNA, which is composed of sequences complementary to a PE gene and eukaryotic transcription and translation signals. CONCLUSION: This finding may have important implications as a novel therapeutic strategy aimed at the elimination of HBV infection.
