Transforming growth factor-beta(TGF-β)is a multifunctional cytokine that performs a dual role as a tumor suppressor and tumor promoter during cancer progression.Among different ligands of the TGF-βfamily,TGF-β1 mod...Transforming growth factor-beta(TGF-β)is a multifunctional cytokine that performs a dual role as a tumor suppressor and tumor promoter during cancer progression.Among different ligands of the TGF-βfamily,TGF-β1 modulates most of its biological outcomes.Despite the abundant expression of TGF-β1 in the liver,steatosis to hepatocellular carcinoma(HCC)progression triggers elevated TGF-β1 levels,contributing to poor prognosis and survival.Additionally,elevated TGF-β1 levels in the tumor microenvironment create an immunosuppressive stage via various mechanisms.TGF-β1 has a prime role as a diagnostic and prognostic biomarker in HCC.Moreover,TGF-β1 is widely studied as a therapeutic target either as monotherapy or combined with immune checkpoint inhibitors.This review provides clinical relevance and up-to-date information regarding the potential of TGF-β1 in diagnosis,prognosis,and therapy against HCC.展开更多
AIM: To assess the utility and safety of single-operator cholangiopancreatoscopy(SOCPS) using the Spy Glass system in widespread clinical application for biliary and pancreatic diseases.METHODS: This study was a prosp...AIM: To assess the utility and safety of single-operator cholangiopancreatoscopy(SOCPS) using the Spy Glass system in widespread clinical application for biliary and pancreatic diseases.METHODS: This study was a prospective case series conducted in 20 referral centers in Japan. There were 148 patients who underwent SOCPS; 124 for biliary diseases and 24 for pancreatic diseases. The attempted interventions were SOCPS examination, SOCPS-directed tissue sampling, and therapy for stone removal, among others. The main outcomes were related to the procedure success rate in terms of visualizing the target lesions, SOCPS-directed adequate tissue sampling, and complete stone removal. RESULTS: A total of 148 patients were enrolled for the diagnosis of indeterminate biliary and pancreatic lesions or treatment of biliary and pancreatic disease. The overall procedure success rate of visualizing the target lesions was 91.2%(135/148). The overall procedural success rates of visualizing the target lesions of diagnostic SOCPS in the bile duct and pancreatic duct were 95.5%(84/89) and 88.2%(15/17), respectively. Diagnosis: the overall adequate tissue for histologic examination was secured in 81.4% of the 86 patients who underwent biopsy under SOCPS(bile duct, 60/75, 80.0%; pancreatic duct, 10/11, 90.9%). The accuracy of histologic diagnosis using SOCPS-directed biopsies in indeterminate bile duct lesions was 70.7%(53/75). In the pancreatic duct, the accuracy of SOCPS visual impression of intraductal papillary mucinous neoplasm was 87.5%(14/16). Stone therapy: complete biliary and pancreatic stone clearance combined with SOCPS-directed stone therapy using electrohydraulic lithotripsy or laser lithotripsy was achieved in 74.2%(23/31) and 42.9%(3/7) of the patients, respectively. Others: SOCPS using the Spy Glass system was used in cannulation of the cystic duct in two patients and for passing across the obstructed self-expandable metallic stent for a malignant biliary stricture in two patients. All procedures were successful in both SOCPS-guided therapies. The incidence of procedure-related adverse events was 5.4%(8/148). CONCLUSION: SOCPS with direct visualization and biopsy for diagnosis and SOCPS-directed therapy for biliary and pancreatic diseases can be safely performed with a high success rate.展开更多
The therapeutic options for hepatocellular carcinoma (HCC) have been so far rather inadequate.Sorafenib has shown an overall survival benefit and has become the new standard of care for advanced HCC.Nevertheless,in cl...The therapeutic options for hepatocellular carcinoma (HCC) have been so far rather inadequate.Sorafenib has shown an overall survival benefit and has become the new standard of care for advanced HCC.Nevertheless,in clinical practice,some patients are discontinuing this drug because of side effects,and misinterpretation of radiographic response may contribute to this.We highlight the importance of prolonged sorafenib ad-ministration,even at reduced dose,and of qualitative and careful radiographic evaluation.We observed two partial and two complete responses,one histologically confirmed,with progression-free survival ranging from 12 to 62 mo.Three of the responses were achieved following substantial dose reductions,and a gradual change in lesion density preceded or paralleled tumor shrinkage,as seen by computed tomography.This report supports the feasibility of dose adjustments to allow prolonged administration of sorafenib,and highlights the need for new imaging criteria for a more appropriate characterization of response in HCC.展开更多
Oxidative stress has been investigated in the context of alcoholic liver injury for many years and shown to be a causal factor of chronic hepatitis C(CHC), nonalcoholic steatohepatitis(NASH), drug-induced liver injury...Oxidative stress has been investigated in the context of alcoholic liver injury for many years and shown to be a causal factor of chronic hepatitis C(CHC), nonalcoholic steatohepatitis(NASH), drug-induced liver injury, Wilson's disease, and hemochromatosis. In CHC, it has been demonstrated that oxidative stress plays an important role in hepatocarcinogenesis. In cases with persistent hepatitis due to failure of hepatitis C virus eradication,or chronic liver disease, such as NASH, the treatment of which remains unestablished, it is important to reduce serum alanine aminotransferase levels and prevent liver fibrosis and development of hepatocellular carcinoma. This also suggests the importance of antioxidant therapy. Among treatment options where it would be expected that anti-inflammatory activity plays a role in their confirmed efficacy for chronic hepatitis, iron depletion therapy, glycyrrhizin, ursodeoxycholic acid, Sho-Saiko-To, and vitamin E can all be considered antioxidant therapies. To date, however, the ability of these treatments to prevent cancer has been confirmed only in CHC. Nevertheless, anti-inflammatory and antifibrotic effects have been demonstrated in other liver diseases and these therapies may potentially be effective for cancer prevention.展开更多
OBJECTIVE: To focus a new chemoprevention approach that uses nanotechnology to deliver luteolin to human breast cancer cells(MCF-7), and its underlying mechanism.METHODS: Water-soluble copolymer-encapsulated nanoparti...OBJECTIVE: To focus a new chemoprevention approach that uses nanotechnology to deliver luteolin to human breast cancer cells(MCF-7), and its underlying mechanism.METHODS: Water-soluble copolymer-encapsulated nanoparticle-luteolin(CENL) was formulated using the hydrophobic drug luteolin. The ability to load and release he anticancer drug into/from the synthesized hyperbranched polyester was evaluated by high-performance liquid chromatography.The successful synthesis of CENL was supported by analytical techniques including fourier transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, gel permeation chromatography,and dynamic light scattering. Cell viability was measured using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide color method. Reactive oxygen species(ROS) were measured using a dichlorofluorescein probe and intracellular calcium(Cai2+) was evaluated with a flu3-AM probe.RESULTS: The results showed that the drug delivery system is stable and that the loading capacity is high. Treatment with nanoparticles containing luteolin and free luteolin resulted in cell death in breast cancer cells at high concentrations (IC50(33 ± 4) and(48 ± 6) μM, respectively)At high concentrations,CENL reduced cell viability and increased ROS and Cai2+ production.CONCLUSION: Our results demonstrate that CENL has potential for human breast cancer treatment.展开更多
KRAS is the most frequently mutated oncogene in human malignancies,observed in approximately two in five colorectal cancers(CRC).KRAS mutations were historically considered“undruggable”ten years ago and associated w...KRAS is the most frequently mutated oncogene in human malignancies,observed in approximately two in five colorectal cancers(CRC).KRAS mutations were historically considered“undruggable”ten years ago and associated with resistance to EGFR targeted therapy.The success of finding allele-specific covalent KRASG12C inhibitors recently has made markedly breakthrough in KRAS targeted therapy,and has accelerated the discovery of agents targeting other KRAS mutants,such as G12D and G12V.Evidence in preclinical and clinical settings has proved excellent efficacy of several inhibitors in KRAS mutant CRC.Sotorasib and Adagrasib are currently changing the treatment paradigm for patients with metastatic CRC harboring KRASG12C mutation.The phenomenon that KRASG12C inhibition shows inferior efficacy in patients with CRC compared with non-small cell lung cancer has been observed in clinic due to drug resistance,and combination strategies to overcome the resistance are now being investigated in clinical trials.Here,we review the development of KRAS targeted treatment in CRC,mechanisms of resistance and potential combination strategies to improve efficacy.展开更多
Radiological imaging has a critical role in the diagnosis of sarcomas and in evaluating therapy response assessment.The current gold standard for response assessment in solid tumors is the Response Evaluation Criteria...Radiological imaging has a critical role in the diagnosis of sarcomas and in evaluating therapy response assessment.The current gold standard for response assessment in solid tumors is the Response Evaluation Criteria in Solid Tumors,which evaluates changes in tumor size as a surrogate endpoint for therapeutic efficacy.However,tumors may undergo necrosis,changes in vascularization or become cystic in response to therapy,with no significant volume changes;thus,size assessments alone may not be adequate.Such morphological changes may give rise to radiographic phenotypes that are not easily detected by human operators.Fortunately,recent advances in high-performance computing and machine learning algorithms have enabled deep analysis of radiological images to extract features that can provide richer information about intensity,shape,size or volume,and texture of tumor phenotypes.There is growing evidence to suggest that these image-derived or“radiomic features”are sensitive to biological processes such as necrosis and glucose metabolism.Thus,radiomics could prove to be a critical tool for assessing treatment response and may present an integral complement to existing response criteria,opening new avenues for patient assessment in sarcoma trials.展开更多
基金Supported by the Amrita Vishwa Vidyapeetham SEED grant (K-PHAR-22-662)
文摘Transforming growth factor-beta(TGF-β)is a multifunctional cytokine that performs a dual role as a tumor suppressor and tumor promoter during cancer progression.Among different ligands of the TGF-βfamily,TGF-β1 modulates most of its biological outcomes.Despite the abundant expression of TGF-β1 in the liver,steatosis to hepatocellular carcinoma(HCC)progression triggers elevated TGF-β1 levels,contributing to poor prognosis and survival.Additionally,elevated TGF-β1 levels in the tumor microenvironment create an immunosuppressive stage via various mechanisms.TGF-β1 has a prime role as a diagnostic and prognostic biomarker in HCC.Moreover,TGF-β1 is widely studied as a therapeutic target either as monotherapy or combined with immune checkpoint inhibitors.This review provides clinical relevance and up-to-date information regarding the potential of TGF-β1 in diagnosis,prognosis,and therapy against HCC.
文摘AIM: To assess the utility and safety of single-operator cholangiopancreatoscopy(SOCPS) using the Spy Glass system in widespread clinical application for biliary and pancreatic diseases.METHODS: This study was a prospective case series conducted in 20 referral centers in Japan. There were 148 patients who underwent SOCPS; 124 for biliary diseases and 24 for pancreatic diseases. The attempted interventions were SOCPS examination, SOCPS-directed tissue sampling, and therapy for stone removal, among others. The main outcomes were related to the procedure success rate in terms of visualizing the target lesions, SOCPS-directed adequate tissue sampling, and complete stone removal. RESULTS: A total of 148 patients were enrolled for the diagnosis of indeterminate biliary and pancreatic lesions or treatment of biliary and pancreatic disease. The overall procedure success rate of visualizing the target lesions was 91.2%(135/148). The overall procedural success rates of visualizing the target lesions of diagnostic SOCPS in the bile duct and pancreatic duct were 95.5%(84/89) and 88.2%(15/17), respectively. Diagnosis: the overall adequate tissue for histologic examination was secured in 81.4% of the 86 patients who underwent biopsy under SOCPS(bile duct, 60/75, 80.0%; pancreatic duct, 10/11, 90.9%). The accuracy of histologic diagnosis using SOCPS-directed biopsies in indeterminate bile duct lesions was 70.7%(53/75). In the pancreatic duct, the accuracy of SOCPS visual impression of intraductal papillary mucinous neoplasm was 87.5%(14/16). Stone therapy: complete biliary and pancreatic stone clearance combined with SOCPS-directed stone therapy using electrohydraulic lithotripsy or laser lithotripsy was achieved in 74.2%(23/31) and 42.9%(3/7) of the patients, respectively. Others: SOCPS using the Spy Glass system was used in cannulation of the cystic duct in two patients and for passing across the obstructed self-expandable metallic stent for a malignant biliary stricture in two patients. All procedures were successful in both SOCPS-guided therapies. The incidence of procedure-related adverse events was 5.4%(8/148). CONCLUSION: SOCPS with direct visualization and biopsy for diagnosis and SOCPS-directed therapy for biliary and pancreatic diseases can be safely performed with a high success rate.
文摘The therapeutic options for hepatocellular carcinoma (HCC) have been so far rather inadequate.Sorafenib has shown an overall survival benefit and has become the new standard of care for advanced HCC.Nevertheless,in clinical practice,some patients are discontinuing this drug because of side effects,and misinterpretation of radiographic response may contribute to this.We highlight the importance of prolonged sorafenib ad-ministration,even at reduced dose,and of qualitative and careful radiographic evaluation.We observed two partial and two complete responses,one histologically confirmed,with progression-free survival ranging from 12 to 62 mo.Three of the responses were achieved following substantial dose reductions,and a gradual change in lesion density preceded or paralleled tumor shrinkage,as seen by computed tomography.This report supports the feasibility of dose adjustments to allow prolonged administration of sorafenib,and highlights the need for new imaging criteria for a more appropriate characterization of response in HCC.
文摘Oxidative stress has been investigated in the context of alcoholic liver injury for many years and shown to be a causal factor of chronic hepatitis C(CHC), nonalcoholic steatohepatitis(NASH), drug-induced liver injury, Wilson's disease, and hemochromatosis. In CHC, it has been demonstrated that oxidative stress plays an important role in hepatocarcinogenesis. In cases with persistent hepatitis due to failure of hepatitis C virus eradication,or chronic liver disease, such as NASH, the treatment of which remains unestablished, it is important to reduce serum alanine aminotransferase levels and prevent liver fibrosis and development of hepatocellular carcinoma. This also suggests the importance of antioxidant therapy. Among treatment options where it would be expected that anti-inflammatory activity plays a role in their confirmed efficacy for chronic hepatitis, iron depletion therapy, glycyrrhizin, ursodeoxycholic acid, Sho-Saiko-To, and vitamin E can all be considered antioxidant therapies. To date, however, the ability of these treatments to prevent cancer has been confirmed only in CHC. Nevertheless, anti-inflammatory and antifibrotic effects have been demonstrated in other liver diseases and these therapies may potentially be effective for cancer prevention.
基金the financial and technical support of Ilam University of Medical Science
文摘OBJECTIVE: To focus a new chemoprevention approach that uses nanotechnology to deliver luteolin to human breast cancer cells(MCF-7), and its underlying mechanism.METHODS: Water-soluble copolymer-encapsulated nanoparticle-luteolin(CENL) was formulated using the hydrophobic drug luteolin. The ability to load and release he anticancer drug into/from the synthesized hyperbranched polyester was evaluated by high-performance liquid chromatography.The successful synthesis of CENL was supported by analytical techniques including fourier transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, gel permeation chromatography,and dynamic light scattering. Cell viability was measured using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide color method. Reactive oxygen species(ROS) were measured using a dichlorofluorescein probe and intracellular calcium(Cai2+) was evaluated with a flu3-AM probe.RESULTS: The results showed that the drug delivery system is stable and that the loading capacity is high. Treatment with nanoparticles containing luteolin and free luteolin resulted in cell death in breast cancer cells at high concentrations (IC50(33 ± 4) and(48 ± 6) μM, respectively)At high concentrations,CENL reduced cell viability and increased ROS and Cai2+ production.CONCLUSION: Our results demonstrate that CENL has potential for human breast cancer treatment.
文摘KRAS is the most frequently mutated oncogene in human malignancies,observed in approximately two in five colorectal cancers(CRC).KRAS mutations were historically considered“undruggable”ten years ago and associated with resistance to EGFR targeted therapy.The success of finding allele-specific covalent KRASG12C inhibitors recently has made markedly breakthrough in KRAS targeted therapy,and has accelerated the discovery of agents targeting other KRAS mutants,such as G12D and G12V.Evidence in preclinical and clinical settings has proved excellent efficacy of several inhibitors in KRAS mutant CRC.Sotorasib and Adagrasib are currently changing the treatment paradigm for patients with metastatic CRC harboring KRASG12C mutation.The phenomenon that KRASG12C inhibition shows inferior efficacy in patients with CRC compared with non-small cell lung cancer has been observed in clinic due to drug resistance,and combination strategies to overcome the resistance are now being investigated in clinical trials.Here,we review the development of KRAS targeted treatment in CRC,mechanisms of resistance and potential combination strategies to improve efficacy.
基金This research was supported by the Sarcoma Alliance for Research through Collaboration LMSARC research fundthe philanthropic LMS360 research fund from the University of Michigan LMS360.
文摘Radiological imaging has a critical role in the diagnosis of sarcomas and in evaluating therapy response assessment.The current gold standard for response assessment in solid tumors is the Response Evaluation Criteria in Solid Tumors,which evaluates changes in tumor size as a surrogate endpoint for therapeutic efficacy.However,tumors may undergo necrosis,changes in vascularization or become cystic in response to therapy,with no significant volume changes;thus,size assessments alone may not be adequate.Such morphological changes may give rise to radiographic phenotypes that are not easily detected by human operators.Fortunately,recent advances in high-performance computing and machine learning algorithms have enabled deep analysis of radiological images to extract features that can provide richer information about intensity,shape,size or volume,and texture of tumor phenotypes.There is growing evidence to suggest that these image-derived or“radiomic features”are sensitive to biological processes such as necrosis and glucose metabolism.Thus,radiomics could prove to be a critical tool for assessing treatment response and may present an integral complement to existing response criteria,opening new avenues for patient assessment in sarcoma trials.
