Background:Despite advances in the diagnosis of patients with hepatocellular carcinoma(HCC),70%-80%of patients are diagnosed with advanced stage disease.Portal vein tumor thrombus(PVTT)is among the most ominous signs ...Background:Despite advances in the diagnosis of patients with hepatocellular carcinoma(HCC),70%-80%of patients are diagnosed with advanced stage disease.Portal vein tumor thrombus(PVTT)is among the most ominous signs of advanced stage disease and has been associated with poor survival if untreated.Data sources:A systematic search of MEDLINE(PubMed),Embase,Cochrane Library and Database for Systematic Reviews(CDSR),Google Scholar,and National Institute for Health and Clinical Excellence(NICE)databases until December 2022 was conducted using free text and MeSH terms:hepatocellular carcinoma,portal vein tumor thrombus,portal vein thrombosis,vascular invasion,liver and/or hepatic resection,liver transplantation,and systematic review.Results:Centers of surgical excellence have reported promising results related to the individualized surgical management of portal thrombus versus arterial chemoembolization or systemic chemotherapy.Critical elements to the individualized surgical management of HCC and portal thrombus include precise classification of the portal vein tumor thrombus,accurate identification of the subgroups of patients who may benefit from resection,as well as meticulous surgical technique.This review addressed five specific areas:(a)formation of PVTT;(b)classifications of PVTT;(c)controversies related to clinical guidelines;(d)surgical treatments versus non-surgical approaches;and(e)characterization of surgical techniques correlated with classifications of PVTT.Conclusions:Current evidence from Chinese and Japanese high-volume centers demonstrated that patients with HCC and associated PVTT can be managed with surgical resection with acceptable results.展开更多
Liposarcoma is one of the most common soft tissue sarcomas,however,its occurrence rate is still rare compared to other cancers.Due to its rarity,in vitro experiments are an essential approach to elucidate liposarcoma ...Liposarcoma is one of the most common soft tissue sarcomas,however,its occurrence rate is still rare compared to other cancers.Due to its rarity,in vitro experiments are an essential approach to elucidate liposarcoma pathobiology.Conventional cell culture-based research(2D cell culture)is still playing a pivotal role,while several shortcomings have been recently under discussion.In vivo,mouse models are usually adopted for pre-clinical analyses with expectations to overcome the issues of 2D cell culture.However,they do not fully recapitulate human dedifferentiated liposarcoma(DDLPS)characteristics.Therefore,three-dimensional(3D)culture systems have been the recent research focus in the cell biology field with the expectation to overcome at the same time the disadvantages of 2D cell culture and in vivo animal models and fill in the gap between them.Given the liposarcoma rarity,we believe that 3D cell culture techniques,including 3D cell cultures/co-cultures,and Patient-Derived tumor Organoids(PDOs),represent a promising approach to facilitate liposarcoma investigation and elucidate its molecular mechanisms and effective therapy development.In this review,we first provide a general overview of 3D cell cultures compared to 2D cell cultures.We then focus on one of the recent 3D cell culture applications,Patient-Derived Organoids(PDOs),summarizing and discussing several PDO methodologies.Finally,we discuss the current and future applications of PDOs to sarcoma,particularly in the field of liposarcoma.展开更多
BACKGROUND Although surgical resection is associated with the best long-term outcomes for neuroendocrine liver metastases(NELM),the current indications for and outcomes of surgery for NELM from a population perspectiv...BACKGROUND Although surgical resection is associated with the best long-term outcomes for neuroendocrine liver metastases(NELM),the current indications for and outcomes of surgery for NELM from a population perspective are not well understood.AIM To determine the current indications for and outcomes of liver resection(LR)for NELM using a population-based cohort.METHODS A retrospective review of the 2014-2017 American College of Surgeons National Surgical Quality Improvement Program and targeted hepatectomy databases was performed to identify patients who underwent LR for NELM.Perioperative characteristics and 30-d morbidity and mortality were analyzed.RESULTS Among 669 patients who underwent LR for NELM,the median age was 60(interquartile range:51-67)and 51%were male.While the number of metastases resected ranged from 1 to 9,the most common(45%)number of tumors resected was one.The majority(68%)of patients had a largest tumor size of<5 cm.Most patients underwent partial hepatectomy(71%)while fewer underwent a right or left hepatectomy or trisectionectomy.The majority of operations were open(82%)versus laparoscopic(17%)or robotic(1%).In addition,30%of patients underwent intraoperative ablation while 45%had another concomitant operation including cholecystectomy(28.8%),bowel resection(20.2%),or partial pancreatectomy(3.4%).Overall 30-d morbidity and mortality was 29%and 1.3%,respectively.On multivariate analysis,American Society of Anesthesiologists class≥3[odds ratios(OR),OR=2.089,95%confidence intervals(CI):1.197-3.645],open approach(OR=1.867,95%CI:1.148-3.036),right hepatectomy(OR=1.618,95%CI:1.014-2.582),and prolonged operative time of>230 min(OR=1.731,95%CI:1.168-2.565)were associated with higher 30-d morbidity while intraoperative ablation and concomitant procedures were not.CONCLUSION LR for NELM was performed with relatively low postoperative morbidity and mortality.Concomitant procedures performed at the time of LR did not increase morbidity.展开更多
PURPOSE: To determine the safety and efficacy of gefitinib,an epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor,in combination with radiation for newly diagnosed glioblastoma(GBM) patients.METHODS AND M...PURPOSE: To determine the safety and efficacy of gefitinib,an epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor,in combination with radiation for newly diagnosed glioblastoma(GBM) patients.METHODS AND MATERIALS: Between March 21,2002,and May 3,2004,Radiation Therapy Oncology Group(RTOG) 0211 enrolled 31 and 147GBM patients in the phase 1 and 2 arms,respectively.Treatment consisted of daily oral gefinitnib started at the time of conventional cranial radiation therapy(RT) and continued post RT for 18 months or until progression.Tissue microarrays from 68 cases were analyzed for EGFR expression.RESULTS: The maximum tolerated dose(MTD) of gefitinib was determined to be 500 mg in patients on non-enzyme-inducing anticonvulsant drugs(non-EIAEDs).All patients in the phase 2 component were treated at a gefitinib dose of 500 mg;patients receiving EIADSs could be escalated to 750 mg.The most common side effects of gefitinib in combination with radiation were dermatologic and gastrointestinal.Median survival was 11.5 months for patients treated per protocol.There was no overall survival benefit for patients treated with gefitinib + RT when compared with a historical cohort of patients treated with RT alone,matched by RTOG recursive partitioning analysis(RPA) class distribution.Younger age was significantly associated with better outcome.Per protocol stratification,EGFR expression was not found to be of prognostic value for gefitinib + RT-treated patients.CONCLUSIONS: The addition of gefitinib to RT is well tolerated.Median survival of RTOG 0211 patients treated with RT with concurrent and adjuvant gefitinib was similar to that in a historical control cohort treated with radiation alone.展开更多
AIM To evaluate disparities in the treatment of hepatocellular carcinoma(HCC) based on gender.METHODS A retrospective database analysis using the Nationwide Inpatient Sample(NIS) was performed between 2010 and 2013. A...AIM To evaluate disparities in the treatment of hepatocellular carcinoma(HCC) based on gender.METHODS A retrospective database analysis using the Nationwide Inpatient Sample(NIS) was performed between 2010 and 2013. Adult patients with a primary diagnosis of hepatocellular carcinoma determined by International Classification of Disease 9(ICD-9) codes were included. Univariate analysis and multivariate logistic regressions were performed to analyze differences in treatment, mortality, features of decompensation, and metastatic disease based on the patient's gender.RESULTS The analysis included 62582 patients with 45908 men and 16674 women. Women were less likely to present with decompensated liver disease(OR = 0.84, P < 0.001) and had less risk of inpatient mortality when compared to men(OR = 0.75, P < 0.001). Women were more likely to receive inpatient resection(OR = 1.31, P < 0.001) or an ablation(OR = 1.22, P = 0.028) than men. There was no significant difference between men and women in regard to liver transplantation and transcatheter arterial chemoembolization(TACE).CONCLUSION Gender impacts treatment for hepatocellular carcinoma. Women are more likely to undergo an ablation or resection then men. Gender disparities in transplantation have resolved.展开更多
Reprogramming of lipid metabolism is a newly recognized hallmark of malignancy.Increased lipid uptake,storage and lipogenesis occur in a variety of cancers and contribute to rapid tumor growth.Lipids constitute the ba...Reprogramming of lipid metabolism is a newly recognized hallmark of malignancy.Increased lipid uptake,storage and lipogenesis occur in a variety of cancers and contribute to rapid tumor growth.Lipids constitute the basic struc-ture of membranes and also function as signaling molecules and energy sources.Sterol regulatory element-binding proteins(SREBPs),a family of membrane-bound transcription factors in the endoplasmic reticulum,play a central role in the regulation of lipid metabolism.Recent studies have revealed that SREBPs are highly up-regulated in various cancers and promote tumor growth.SREBP cleavage-activating protein is a key transporter in the trafficking and activation of SREBPs as well as a critical glucose sensor,thus linking glucose metabolism and de novo lipid synthesis.Targeting altered lipid metabolic pathways has become a promising anti-cancer strategy.This review summarizes recent progress in our understanding of lipid metabolism regulation in malignancy,and highlights potential molecu-lar targets and their inhibitors for cancer treatment.展开更多
Background: Patients with advanced hepatobiliary cancer (HBC) have a dismal prognosis and limited treatment options. Immunotherapy has been considered as a promising treatment, especially for cancers not amenable to s...Background: Patients with advanced hepatobiliary cancer (HBC) have a dismal prognosis and limited treatment options. Immunotherapy has been considered as a promising treatment, especially for cancers not amenable to surgery. Methods: Between 2004, and 2015, patients diagnosed with hepatocellular carcinoma (HCC), intra- and extrahepatic cholangiocarcinoma and gallbladder cancer (GBC) were identified in the National Cancer Database. Results: Among 249,913 patients with HBC, only 585 (0.2%) patients received immunotherapy. Among patients who received immunotherapy, most patients were diagnosed between 2012 and 2015, had private insurance, as well as an income ≥$46,000 and were treated at an academic facility. The use of immunotherapy among HBC patients varied by diagnosis (HCC, 67.7%;bile duct cancer, 14%). On multivariable analysis, a more recent period of diagnosis (OR 1.80, 95% CI: 1.44-2.25), median income >$46,000 (OR 1.43, 95% CI: 1.11-1.87), and higher tumor stage (stage III, OR 2.22, 95% CI: 1.65-3.01;stage IV, OR 3.24, 95% CI:2.41-4.34) were associated with greater odds of receiving immunotherapy. Conclusions: Overall utilization of immunotherapy in the US among patients with HBC was very low, yet has increased over time. Certain socioeconomic factors were associated with an increased likely of receiving immunotherapy, suggesting disparities in access of patients with lower socioeconomic status.展开更多
Exosome is an excellent vesicle for in vivo delivery of therapeutics,including RNAi and chemical drugs.The extremely high efficiency in cancer regression can partly be attributed to its fusion mechanism in delivering ...Exosome is an excellent vesicle for in vivo delivery of therapeutics,including RNAi and chemical drugs.The extremely high efficiency in cancer regression can partly be attributed to its fusion mechanism in delivering therapeutics to cytosol without endosome trapping.However,being composed of a lipidbilayer membrane without specific recognition capacity for aimed-cells,the entry into nonspecific cells can lead to potential side-effects and toxicity.Applying engineering approaches for targeting-capacity to deliver therapeutics to specific cells is desirable.Techniques with chemical modification in vitro and genetic engineering in cells have been reported to decorate exosomes with targeting ligands.RNA nanoparticles have been used to harbor tumor-specific ligands displayed on exosome surface.The negative charge reduces nonspecific binding to vital cells with negatively charged lipid-membrane due to the electrostatic repulsion,thus lowering the side-effect and toxicity.In this review,we focus on the uniqueness of RNA nanoparticles for exosome surface display of chemical ligands,small peptides or RNA aptamers,for specific cancer targeting to deliver anticancer therapeutics,highlighting recent advances in targeted delivery of siRNA and miRNA that overcomes the previous RNAi delivery roadblocks.Proper understanding of exosome engineering with RNA nanotechnology promises efficient therapies for a wide range of cancer subtypes.展开更多
Non-small cell lung cancer(NSCLC)remains the leading cause of cancer-related deaths in the Western world.Despite progress made with targeted therapies and immune checkpoint inhibitors,the vast majority of patients hav...Non-small cell lung cancer(NSCLC)remains the leading cause of cancer-related deaths in the Western world.Despite progress made with targeted therapies and immune checkpoint inhibitors,the vast majority of patients have to undergo chemotherapy with platinum-based drugs.To increase efficacy and reduce potential side effects,a more comprehensive understanding of the mechanisms of the DNA damage response(DDR)is required.We have shown that overexpressby live cell imaging Incuyion of the scaffold protein RAN binding protein 9(RANBP9)is pervasive in NSCLC.More importantly,patients with higher levels of RANBP9 exhibit a worse outcome from treatment with platinum-based drugs.Mechanistically,RANBP9 exists as a target and an enabler of the ataxia telangiectasia mutated(ATM)kinase signaling.Indeed,the depletion of RANBP9 in NSCLC cells abates ATM activation and its downstream targets such as pby live cell imaging Incuy53 signaling.RANBP9 knockout cells are more sensitive than controls to the inhibition of the ataxia and telangiectasia-related(ATR)kinase but not to ATM inhibition.The absence of RANBP9 renders cells more sensitive to drugs inhibiting the Poly(ADP-ribose)-Polymerase(PARP)resulting in a“BRCAness-like”phenotype.In summary,as a result of increased sensitivity to DNA damaging drugs conferred by its ablation in vitro and in vivo,RANBP9 may be considered as a potential target for the treatment of NSCLC.This article aims to report the results from past and ongoing investigations focused on the role of RANBP9 in the response to DNA damage,particularly in the context of NSCLC.This review concludes with future directions and speculative remarks which will need to be addressed in the coming years.展开更多
Background:Although offering the best chance of potential cure for patients with localized perihilar cholangiocarcinoma(pCCA),resection has been associated with high morbidity and sometimes poor long-term outcomes due...Background:Although offering the best chance of potential cure for patients with localized perihilar cholangiocarcinoma(pCCA),resection has been associated with high morbidity and sometimes poor long-term outcomes due to recurrence.We sought to develop a predictive model to identify individuals at high risk for very early recurrence(VER)after curative-intent surgery for pCCA.Methods:Patients who underwent curative-intent surgery for pCCA between 2000-2023 were identified from a multi-institutional database.An eXtreme Gradient Boosting(XGBoost)model was developed to estimate the risk of VER,defined as recurrence within 6 months after resection.The relative importance of clinicopathologic factors was determined using SHapley Additive exPlanations(SHAP)values.Results:Among 434 patients undergoing curative-intent resection for pCCA,65(15.0%)patients developed VER.Median overall survival(OS)among patients with and without VER was 8.4[interquartile range(IQR)6.6-11.3]versus 38.5(IQR 31.9-45.7)months(P<0.001).An XGBoost model was able to stratify patients relative to the risk of VER[low-risk:6-month recurrence-free survival(RFS)94.6%vs.intermediate-risk:6-month RFS 88.3%vs.high-risk:6-month RFS 40.0%;P<0.001].Similarly,3-year OS incrementally worsened based on VER risk(low-risk:75.3%vs.intermediate-risk:19.5%vs.high-risk:4.6%;P<0.001).The SHAP algorithm identified age,preoperative carbohydrate antigen 19-9(CA19-9)levels,tumor size and differentiation/grade,as well as lymph node metastasis as the five most important predictors of VER.The predictive accuracy of the model was good in the training[c-index:0.74,95%confidence interval(CI):0.67-0.81]and internal validation(c-index:0.77,95%CI:0.71-0.83)cohorts.An easy-to-use risk calculator for VER was developed and made available online at:https://junkawashima.shinyapps.io/VER_hilar/.Conclusions:A novel,machine learning based model was able to predict accurately the chance of VER after curative-intent resection of pCCA.In turn,the tool may help surgeons in the selection of patients likely to benefit the most from resection,as well as counsel individuals about the anticipated risk of recurrence in the early post-operative period.展开更多
Cellular plasticity enables cells to dynamically adapt to environmental changes by altering their phenotype.This plasticity plays a crucial role in tissue repair and regeneration and contributes to pathological proces...Cellular plasticity enables cells to dynamically adapt to environmental changes by altering their phenotype.This plasticity plays a crucial role in tissue repair and regeneration and contributes to pathological processes such as cancer metastasis.Advances in single-cell omics have significantly advanced the study of cellular states and provided new opportunities for accurate cell classification and uncovering cellular transitions.In this perspective,we emphasize integrating chromatin accessibility data and extrinsic factors,such as microenvironmental cues,with single-cell transcriptomic data to develop holistic models for identifying plastic cell states.Additionally,coupling artificial intelligence with single-cell omics offers transformative potential to address existing challenges and fill gaps in identifying and characterizing plastic cells.We envision the development of a universal plasticity metric,a standardized metric for quantifying cellular plasticity.This metric would enable consistent measurement across diverse studies,creating a unified framework that bridges fields such as developmental biology,cancer research,and regenerative medicine.Fostering innovative approaches to identifying and analyzing cellular plasticity promises not only to deepen our understanding of cellular plasticity but also to accelerate therapeutic advancements,paving the way for novel precision medicine strategies to treat complex diseases such as cancer.展开更多
We read with great interest the article by Fuster-Anglada et al.recently published in the Journal of Hepatology reporting a single-center experience on histological predictors of aggressive recurrence following liver ...We read with great interest the article by Fuster-Anglada et al.recently published in the Journal of Hepatology reporting a single-center experience on histological predictors of aggressive recurrence following liver resection of hepatocellular carcinoma(HCC)(1).The study analyzed a total of 218 patients with Barcelona Clinic Liver Cancer(BCLC)0 or A HCC who underwent liver resection over the course of two decades[2000-2020](1).展开更多
Objectives:Racial disparities persist despite attempts to establish an egalitarian framework for surgical care.This study aimed to investigate racioethnic disparities in comorbidities and outcomes following surgery fo...Objectives:Racial disparities persist despite attempts to establish an egalitarian framework for surgical care.This study aimed to investigate racioethnic disparities in comorbidities and outcomes following surgery for head and neck tumors.Methods:This retrospective study included adult patients who underwent head and neck oncologic surgery between 2008 and 2020 from the National Surgical Quality Improvement Program.Multivariable regression analyses were conducted to explore the association of the following racioethnic categories with postoperative outcomes:White,Black,Hispanic,and Asian.Results:A total of 113,234 patients were included in the study,comprising 78.3%White,8.7%Black,6.9%Hispanic,and 6.0%Asian patients.Black patients had higher rates of pre-existing comorbidities compared to White patients.Specifically,the rates of comorbidities such as diabetes mellitus(19.8%vs.12.4%),hypertension(57.5%vs.41.5%),smoking history(18.8%vs.15.0%),dyspnea(7.4%vs.5.7%),and preoperative anemia(43.6%vs.36.5%)were higher among Black patients.On regression analyses,Black race was not associated with major morbidity following head and neck oncologic surgeries(odds ratio,1.098,95%confidence interval,0.935–1.289)when compared to White patients.However,there were significant associations between the comorbidities associated with the Black race and an increased risk of major morbidity.Conclusions:Black patients undergoing head and neck oncologic surgery face a significant challenge due to a higher burden of comorbidities.These comorbidities,in turn,have been found to be associated with postoperative major morbidity.展开更多
Stimuli-resp on sive release of drugs from a nano carrier in spatial-,temporal-,and dosage-controlled fashi ons is of great interest in the pharmaceutical industry.Paclitaxel is one of the most effective and popular c...Stimuli-resp on sive release of drugs from a nano carrier in spatial-,temporal-,and dosage-controlled fashi ons is of great interest in the pharmaceutical industry.Paclitaxel is one of the most effective and popular chemotherapeutic drugs against a number of cancers such as metastatic or non metastatic breast can cer,non-small cell lung can cer,refractory ovaria n cancer,AIDS-related Kaposi's sarcoma,and head and neck can cers.Here,by taki ng the adva ntage of RNA nanotechno logy in biomedical and material scie nee,we developed a three-dime nsional pyramid-shaped RNA nanocage for a photocontrolled release of cargo,using paclitaxel as a model drug.The light-triggered release of paclitaxel or fluorophore Cy5 was achieved by incorporation of photocleavable spacers into the RNA nanoparticles.Upon irradiation with ultraviolet light,cargos were rapidly released(within 5 min).In vitro treatment of breast can cer cells with the RNA nano particles harbori ng photocleavable paclitaxel showed higher cytotoxicity as compared to RNA nanoparticles without the photocleavable spacer.The methodology provides proof of con cept for the applicati on of the light-triggered con trolled release of drugs from RNA nano cages.展开更多
Background:Machine learning to predict morbidity and mortality-especially in a population traditionally considered low risk-has not been previously examined.We sought to characterize the incidence of death among patie...Background:Machine learning to predict morbidity and mortality-especially in a population traditionally considered low risk-has not been previously examined.We sought to characterize the incidence of death among patients with a low estimated morbidity and mortality risk based on the National Surgical Quality Improvement Program(NSQIP)estimated probability(EP),as well as develop a machine learning model to identify individuals at risk for“unpredicted death”(UD)among patients undergoing hepatopancreatic(HP)procedures.Methods:The NSQIP database was used to identify patients who underwent elective HP surgery between 2012-2017.The risk of morbidity and mortality was stratified into three tiers(low,intermediate,or high estimated)using a k-means clustering method with bin sorting.A machine learning classification tree and multivariable regression analyses were used to predict 30-day mortality with a 10-fold cross validation.C statistics were used to compare model performance.Results:Among 63,507 patients who underwent an HP procedure,median patient age was 63(IQR:54-71)years.Patients underwent either pancreatectomy(n=38,209,60.2%)or hepatic resection(n=25,298,39.8%).Patients were stratified into three tiers of predicted morbidity and mortality risk based on the NSQIP EP:low(n=36,923,58.1%),intermediate(n=23,609,37.2%)and high risk(n=2,975,4.7%).Among 36,923 patients with low estimated risk of morbidity and mortality,237 patients(0.6%)experienced a UD.According to the classification tree analysis,age was the most important factor to predict UD(importance 16.9)followed by preoperative albumin level(importance:10.8),disseminated cancer(importance:6.5),preoperative platelet count(importance:6.5),and sex(importance 5.9).Among patients deemed to be low risk,the c-statistic for the machine learning derived prediction model was 0.807 compared with an AUC of only 0.662 for the NSQIP EP.Conclusions:A prognostic model derived using machine learning methodology performed better than the NSQIP EP in predicting 30-day UD among low risk patients undergoing HP surgery.展开更多
Nanotubes are miniature materials with significant potential applications in nanotechnological, medical, biological and material sciences. The quest for manufacturing methods of nano-mechanical modules is in progress....Nanotubes are miniature materials with significant potential applications in nanotechnological, medical, biological and material sciences. The quest for manufacturing methods of nano-mechanical modules is in progress. For example, the application of carbon nanotubes has been extensively investigated due to the precise width control, but the precise length control remains challenging. Here we report two approaches for the one-pot self-assembly of RNA nanotubes. For the first approach, six RNA strands were used to assemble the nanotube by forming a 11 nm long hollow channel with the inner diameter of 1.7 nm and the outside diameter of 6.3 nm. For the second approach, six RNA strands were designed to hybridize with their neighboring strands by complementary base pairing and formed a nanotube with a six-helix hollow channel similar to the nanotube assembled by the first approach. The fabricated RNA nanotubes were characterized by gel electrophoresis and atomic force microscopy (AFM), confirming the formation of nanotube-shaped RNA nanostructures. Cholesterol molecules were introduced into RNA nanotubes to facilitate their incorporation into lipid bilayer. Incubation of RNA nanotube complex with the free-standing lipid bilayer membrane under applied voltage led to discrete current signatures. Addition of peptides into the sensing chamber revealed discrete steps of current blockage. Polyarginine peptides with different lengths can be detected by current signatures, suggesting that the RNA-cholesterol complex holds the promise of achieving single molecule sensing of peptides.展开更多
In healthy humans, ammonia circulates in the bloodstream at a concentration around 11–32 μmol/L. Whether ammonia plays any physiological role has been unknown until a recent report published in Nature Metabolism.1 A...In healthy humans, ammonia circulates in the bloodstream at a concentration around 11–32 μmol/L. Whether ammonia plays any physiological role has been unknown until a recent report published in Nature Metabolism.1 Ammonia, long thought to be a toxic waste product of amino acid metabolism, needs to be excreted from the human body as urea. Intriguingly, in this paper, Cheng et al1 for the first time reported that ammonia is not a waste product;rather, it is an unprecedented signaling molecule tying glucose and glutamine to lipid production in human cells. This study revealed that ammonia released from glutamine triggers a cascade of cellular processes leading to the activation of lipogenesis machinery for lipid production (Fig. 1). This discovery has major implications for developing treatments for human diseases such as cancers and metabolic syndromes, as dysregulated metabolism is a hallmark of these diseases.展开更多
文摘Background:Despite advances in the diagnosis of patients with hepatocellular carcinoma(HCC),70%-80%of patients are diagnosed with advanced stage disease.Portal vein tumor thrombus(PVTT)is among the most ominous signs of advanced stage disease and has been associated with poor survival if untreated.Data sources:A systematic search of MEDLINE(PubMed),Embase,Cochrane Library and Database for Systematic Reviews(CDSR),Google Scholar,and National Institute for Health and Clinical Excellence(NICE)databases until December 2022 was conducted using free text and MeSH terms:hepatocellular carcinoma,portal vein tumor thrombus,portal vein thrombosis,vascular invasion,liver and/or hepatic resection,liver transplantation,and systematic review.Results:Centers of surgical excellence have reported promising results related to the individualized surgical management of portal thrombus versus arterial chemoembolization or systemic chemotherapy.Critical elements to the individualized surgical management of HCC and portal thrombus include precise classification of the portal vein tumor thrombus,accurate identification of the subgroups of patients who may benefit from resection,as well as meticulous surgical technique.This review addressed five specific areas:(a)formation of PVTT;(b)classifications of PVTT;(c)controversies related to clinical guidelines;(d)surgical treatments versus non-surgical approaches;and(e)characterization of surgical techniques correlated with classifications of PVTT.Conclusions:Current evidence from Chinese and Japanese high-volume centers demonstrated that patients with HCC and associated PVTT can be managed with surgical resection with acceptable results.
文摘Liposarcoma is one of the most common soft tissue sarcomas,however,its occurrence rate is still rare compared to other cancers.Due to its rarity,in vitro experiments are an essential approach to elucidate liposarcoma pathobiology.Conventional cell culture-based research(2D cell culture)is still playing a pivotal role,while several shortcomings have been recently under discussion.In vivo,mouse models are usually adopted for pre-clinical analyses with expectations to overcome the issues of 2D cell culture.However,they do not fully recapitulate human dedifferentiated liposarcoma(DDLPS)characteristics.Therefore,three-dimensional(3D)culture systems have been the recent research focus in the cell biology field with the expectation to overcome at the same time the disadvantages of 2D cell culture and in vivo animal models and fill in the gap between them.Given the liposarcoma rarity,we believe that 3D cell culture techniques,including 3D cell cultures/co-cultures,and Patient-Derived tumor Organoids(PDOs),represent a promising approach to facilitate liposarcoma investigation and elucidate its molecular mechanisms and effective therapy development.In this review,we first provide a general overview of 3D cell cultures compared to 2D cell cultures.We then focus on one of the recent 3D cell culture applications,Patient-Derived Organoids(PDOs),summarizing and discussing several PDO methodologies.Finally,we discuss the current and future applications of PDOs to sarcoma,particularly in the field of liposarcoma.
基金NIH Grant NS079701(DG)American Cancer Society Research Scholar Grant RSG-14-228-01-CSM(DG)OSUCCC Idea Grant(DG)+2 种基金OSUCCC Translational Therapeutic Program seed grant(DG)Pelotonia Postdoc Fellowship(CC)OSU Department of Radiation-Oncology Basic Research seed Grant(CC)的资助
文摘BACKGROUND Although surgical resection is associated with the best long-term outcomes for neuroendocrine liver metastases(NELM),the current indications for and outcomes of surgery for NELM from a population perspective are not well understood.AIM To determine the current indications for and outcomes of liver resection(LR)for NELM using a population-based cohort.METHODS A retrospective review of the 2014-2017 American College of Surgeons National Surgical Quality Improvement Program and targeted hepatectomy databases was performed to identify patients who underwent LR for NELM.Perioperative characteristics and 30-d morbidity and mortality were analyzed.RESULTS Among 669 patients who underwent LR for NELM,the median age was 60(interquartile range:51-67)and 51%were male.While the number of metastases resected ranged from 1 to 9,the most common(45%)number of tumors resected was one.The majority(68%)of patients had a largest tumor size of<5 cm.Most patients underwent partial hepatectomy(71%)while fewer underwent a right or left hepatectomy or trisectionectomy.The majority of operations were open(82%)versus laparoscopic(17%)or robotic(1%).In addition,30%of patients underwent intraoperative ablation while 45%had another concomitant operation including cholecystectomy(28.8%),bowel resection(20.2%),or partial pancreatectomy(3.4%).Overall 30-d morbidity and mortality was 29%and 1.3%,respectively.On multivariate analysis,American Society of Anesthesiologists class≥3[odds ratios(OR),OR=2.089,95%confidence intervals(CI):1.197-3.645],open approach(OR=1.867,95%CI:1.148-3.036),right hepatectomy(OR=1.618,95%CI:1.014-2.582),and prolonged operative time of>230 min(OR=1.731,95%CI:1.168-2.565)were associated with higher 30-d morbidity while intraoperative ablation and concomitant procedures were not.CONCLUSION LR for NELM was performed with relatively low postoperative morbidity and mortality.Concomitant procedures performed at the time of LR did not increase morbidity.
文摘PURPOSE: To determine the safety and efficacy of gefitinib,an epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor,in combination with radiation for newly diagnosed glioblastoma(GBM) patients.METHODS AND MATERIALS: Between March 21,2002,and May 3,2004,Radiation Therapy Oncology Group(RTOG) 0211 enrolled 31 and 147GBM patients in the phase 1 and 2 arms,respectively.Treatment consisted of daily oral gefinitnib started at the time of conventional cranial radiation therapy(RT) and continued post RT for 18 months or until progression.Tissue microarrays from 68 cases were analyzed for EGFR expression.RESULTS: The maximum tolerated dose(MTD) of gefitinib was determined to be 500 mg in patients on non-enzyme-inducing anticonvulsant drugs(non-EIAEDs).All patients in the phase 2 component were treated at a gefitinib dose of 500 mg;patients receiving EIADSs could be escalated to 750 mg.The most common side effects of gefitinib in combination with radiation were dermatologic and gastrointestinal.Median survival was 11.5 months for patients treated per protocol.There was no overall survival benefit for patients treated with gefitinib + RT when compared with a historical cohort of patients treated with RT alone,matched by RTOG recursive partitioning analysis(RPA) class distribution.Younger age was significantly associated with better outcome.Per protocol stratification,EGFR expression was not found to be of prognostic value for gefitinib + RT-treated patients.CONCLUSIONS: The addition of gefitinib to RT is well tolerated.Median survival of RTOG 0211 patients treated with RT with concurrent and adjuvant gefitinib was similar to that in a historical control cohort treated with radiation alone.
文摘AIM To evaluate disparities in the treatment of hepatocellular carcinoma(HCC) based on gender.METHODS A retrospective database analysis using the Nationwide Inpatient Sample(NIS) was performed between 2010 and 2013. Adult patients with a primary diagnosis of hepatocellular carcinoma determined by International Classification of Disease 9(ICD-9) codes were included. Univariate analysis and multivariate logistic regressions were performed to analyze differences in treatment, mortality, features of decompensation, and metastatic disease based on the patient's gender.RESULTS The analysis included 62582 patients with 45908 men and 16674 women. Women were less likely to present with decompensated liver disease(OR = 0.84, P < 0.001) and had less risk of inpatient mortality when compared to men(OR = 0.75, P < 0.001). Women were more likely to receive inpatient resection(OR = 1.31, P < 0.001) or an ablation(OR = 1.22, P = 0.028) than men. There was no significant difference between men and women in regard to liver transplantation and transcatheter arterial chemoembolization(TACE).CONCLUSION Gender impacts treatment for hepatocellular carcinoma. Women are more likely to undergo an ablation or resection then men. Gender disparities in transplantation have resolved.
基金supported by NIH Grant NS079701(DG)American Cancer Society Research Scholar Grant RSG-14-228-01-CSM(DG)+3 种基金OSUCCC Idea Grant(DG)an OSUCCC Translational Therapeutic Program seed grant(DG)a Pelotonia Postdoc Fellowship(CC)an OSU Department of Radiation-Oncology Basic Research seed Grant(CC).
文摘Reprogramming of lipid metabolism is a newly recognized hallmark of malignancy.Increased lipid uptake,storage and lipogenesis occur in a variety of cancers and contribute to rapid tumor growth.Lipids constitute the basic struc-ture of membranes and also function as signaling molecules and energy sources.Sterol regulatory element-binding proteins(SREBPs),a family of membrane-bound transcription factors in the endoplasmic reticulum,play a central role in the regulation of lipid metabolism.Recent studies have revealed that SREBPs are highly up-regulated in various cancers and promote tumor growth.SREBP cleavage-activating protein is a key transporter in the trafficking and activation of SREBPs as well as a critical glucose sensor,thus linking glucose metabolism and de novo lipid synthesis.Targeting altered lipid metabolic pathways has become a promising anti-cancer strategy.This review summarizes recent progress in our understanding of lipid metabolism regulation in malignancy,and highlights potential molecu-lar targets and their inhibitors for cancer treatment.
文摘Background: Patients with advanced hepatobiliary cancer (HBC) have a dismal prognosis and limited treatment options. Immunotherapy has been considered as a promising treatment, especially for cancers not amenable to surgery. Methods: Between 2004, and 2015, patients diagnosed with hepatocellular carcinoma (HCC), intra- and extrahepatic cholangiocarcinoma and gallbladder cancer (GBC) were identified in the National Cancer Database. Results: Among 249,913 patients with HBC, only 585 (0.2%) patients received immunotherapy. Among patients who received immunotherapy, most patients were diagnosed between 2012 and 2015, had private insurance, as well as an income ≥$46,000 and were treated at an academic facility. The use of immunotherapy among HBC patients varied by diagnosis (HCC, 67.7%;bile duct cancer, 14%). On multivariable analysis, a more recent period of diagnosis (OR 1.80, 95% CI: 1.44-2.25), median income >$46,000 (OR 1.43, 95% CI: 1.11-1.87), and higher tumor stage (stage III, OR 2.22, 95% CI: 1.65-3.01;stage IV, OR 3.24, 95% CI:2.41-4.34) were associated with greater odds of receiving immunotherapy. Conclusions: Overall utilization of immunotherapy in the US among patients with HBC was very low, yet has increased over time. Certain socioeconomic factors were associated with an increased likely of receiving immunotherapy, suggesting disparities in access of patients with lower socioeconomic status.
基金supported in part by NIH grants U01CA207946 and R01EB019036 to Peixuan Guo and NIH grant R01CA257961 to Dan Shu and Daniel W.Binzelfunded by the CM Chen Foundationsupported in part by Grant P30CA016058,National Cancer Institute,Bethesda,MD。
文摘Exosome is an excellent vesicle for in vivo delivery of therapeutics,including RNAi and chemical drugs.The extremely high efficiency in cancer regression can partly be attributed to its fusion mechanism in delivering therapeutics to cytosol without endosome trapping.However,being composed of a lipidbilayer membrane without specific recognition capacity for aimed-cells,the entry into nonspecific cells can lead to potential side-effects and toxicity.Applying engineering approaches for targeting-capacity to deliver therapeutics to specific cells is desirable.Techniques with chemical modification in vitro and genetic engineering in cells have been reported to decorate exosomes with targeting ligands.RNA nanoparticles have been used to harbor tumor-specific ligands displayed on exosome surface.The negative charge reduces nonspecific binding to vital cells with negatively charged lipid-membrane due to the electrostatic repulsion,thus lowering the side-effect and toxicity.In this review,we focus on the uniqueness of RNA nanoparticles for exosome surface display of chemical ligands,small peptides or RNA aptamers,for specific cancer targeting to deliver anticancer therapeutics,highlighting recent advances in targeted delivery of siRNA and miRNA that overcomes the previous RNAi delivery roadblocks.Proper understanding of exosome engineering with RNA nanotechnology promises efficient therapies for a wide range of cancer subtypes.
基金the Ohio State University Comprehensive Cancer Center(P30 CA016058).
文摘Non-small cell lung cancer(NSCLC)remains the leading cause of cancer-related deaths in the Western world.Despite progress made with targeted therapies and immune checkpoint inhibitors,the vast majority of patients have to undergo chemotherapy with platinum-based drugs.To increase efficacy and reduce potential side effects,a more comprehensive understanding of the mechanisms of the DNA damage response(DDR)is required.We have shown that overexpressby live cell imaging Incuyion of the scaffold protein RAN binding protein 9(RANBP9)is pervasive in NSCLC.More importantly,patients with higher levels of RANBP9 exhibit a worse outcome from treatment with platinum-based drugs.Mechanistically,RANBP9 exists as a target and an enabler of the ataxia telangiectasia mutated(ATM)kinase signaling.Indeed,the depletion of RANBP9 in NSCLC cells abates ATM activation and its downstream targets such as pby live cell imaging Incuy53 signaling.RANBP9 knockout cells are more sensitive than controls to the inhibition of the ataxia and telangiectasia-related(ATR)kinase but not to ATM inhibition.The absence of RANBP9 renders cells more sensitive to drugs inhibiting the Poly(ADP-ribose)-Polymerase(PARP)resulting in a“BRCAness-like”phenotype.In summary,as a result of increased sensitivity to DNA damaging drugs conferred by its ablation in vitro and in vivo,RANBP9 may be considered as a potential target for the treatment of NSCLC.This article aims to report the results from past and ongoing investigations focused on the role of RANBP9 in the response to DNA damage,particularly in the context of NSCLC.This review concludes with future directions and speculative remarks which will need to be addressed in the coming years.
文摘Background:Although offering the best chance of potential cure for patients with localized perihilar cholangiocarcinoma(pCCA),resection has been associated with high morbidity and sometimes poor long-term outcomes due to recurrence.We sought to develop a predictive model to identify individuals at high risk for very early recurrence(VER)after curative-intent surgery for pCCA.Methods:Patients who underwent curative-intent surgery for pCCA between 2000-2023 were identified from a multi-institutional database.An eXtreme Gradient Boosting(XGBoost)model was developed to estimate the risk of VER,defined as recurrence within 6 months after resection.The relative importance of clinicopathologic factors was determined using SHapley Additive exPlanations(SHAP)values.Results:Among 434 patients undergoing curative-intent resection for pCCA,65(15.0%)patients developed VER.Median overall survival(OS)among patients with and without VER was 8.4[interquartile range(IQR)6.6-11.3]versus 38.5(IQR 31.9-45.7)months(P<0.001).An XGBoost model was able to stratify patients relative to the risk of VER[low-risk:6-month recurrence-free survival(RFS)94.6%vs.intermediate-risk:6-month RFS 88.3%vs.high-risk:6-month RFS 40.0%;P<0.001].Similarly,3-year OS incrementally worsened based on VER risk(low-risk:75.3%vs.intermediate-risk:19.5%vs.high-risk:4.6%;P<0.001).The SHAP algorithm identified age,preoperative carbohydrate antigen 19-9(CA19-9)levels,tumor size and differentiation/grade,as well as lymph node metastasis as the five most important predictors of VER.The predictive accuracy of the model was good in the training[c-index:0.74,95%confidence interval(CI):0.67-0.81]and internal validation(c-index:0.77,95%CI:0.71-0.83)cohorts.An easy-to-use risk calculator for VER was developed and made available online at:https://junkawashima.shinyapps.io/VER_hilar/.Conclusions:A novel,machine learning based model was able to predict accurately the chance of VER after curative-intent resection of pCCA.In turn,the tool may help surgeons in the selection of patients likely to benefit the most from resection,as well as counsel individuals about the anticipated risk of recurrence in the early post-operative period.
基金The TriState SenNet,Grant/Award Number:U54AG075931the Pelotonia Institute of Immuno-Oncology(PlIO).
文摘Cellular plasticity enables cells to dynamically adapt to environmental changes by altering their phenotype.This plasticity plays a crucial role in tissue repair and regeneration and contributes to pathological processes such as cancer metastasis.Advances in single-cell omics have significantly advanced the study of cellular states and provided new opportunities for accurate cell classification and uncovering cellular transitions.In this perspective,we emphasize integrating chromatin accessibility data and extrinsic factors,such as microenvironmental cues,with single-cell transcriptomic data to develop holistic models for identifying plastic cell states.Additionally,coupling artificial intelligence with single-cell omics offers transformative potential to address existing challenges and fill gaps in identifying and characterizing plastic cells.We envision the development of a universal plasticity metric,a standardized metric for quantifying cellular plasticity.This metric would enable consistent measurement across diverse studies,creating a unified framework that bridges fields such as developmental biology,cancer research,and regenerative medicine.Fostering innovative approaches to identifying and analyzing cellular plasticity promises not only to deepen our understanding of cellular plasticity but also to accelerate therapeutic advancements,paving the way for novel precision medicine strategies to treat complex diseases such as cancer.
文摘We read with great interest the article by Fuster-Anglada et al.recently published in the Journal of Hepatology reporting a single-center experience on histological predictors of aggressive recurrence following liver resection of hepatocellular carcinoma(HCC)(1).The study analyzed a total of 218 patients with Barcelona Clinic Liver Cancer(BCLC)0 or A HCC who underwent liver resection over the course of two decades[2000-2020](1).
文摘Objectives:Racial disparities persist despite attempts to establish an egalitarian framework for surgical care.This study aimed to investigate racioethnic disparities in comorbidities and outcomes following surgery for head and neck tumors.Methods:This retrospective study included adult patients who underwent head and neck oncologic surgery between 2008 and 2020 from the National Surgical Quality Improvement Program.Multivariable regression analyses were conducted to explore the association of the following racioethnic categories with postoperative outcomes:White,Black,Hispanic,and Asian.Results:A total of 113,234 patients were included in the study,comprising 78.3%White,8.7%Black,6.9%Hispanic,and 6.0%Asian patients.Black patients had higher rates of pre-existing comorbidities compared to White patients.Specifically,the rates of comorbidities such as diabetes mellitus(19.8%vs.12.4%),hypertension(57.5%vs.41.5%),smoking history(18.8%vs.15.0%),dyspnea(7.4%vs.5.7%),and preoperative anemia(43.6%vs.36.5%)were higher among Black patients.On regression analyses,Black race was not associated with major morbidity following head and neck oncologic surgeries(odds ratio,1.098,95%confidence interval,0.935–1.289)when compared to White patients.However,there were significant associations between the comorbidities associated with the Black race and an increased risk of major morbidity.Conclusions:Black patients undergoing head and neck oncologic surgery face a significant challenge due to a higher burden of comorbidities.These comorbidities,in turn,have been found to be associated with postoperative major morbidity.
文摘Stimuli-resp on sive release of drugs from a nano carrier in spatial-,temporal-,and dosage-controlled fashi ons is of great interest in the pharmaceutical industry.Paclitaxel is one of the most effective and popular chemotherapeutic drugs against a number of cancers such as metastatic or non metastatic breast can cer,non-small cell lung can cer,refractory ovaria n cancer,AIDS-related Kaposi's sarcoma,and head and neck can cers.Here,by taki ng the adva ntage of RNA nanotechno logy in biomedical and material scie nee,we developed a three-dime nsional pyramid-shaped RNA nanocage for a photocontrolled release of cargo,using paclitaxel as a model drug.The light-triggered release of paclitaxel or fluorophore Cy5 was achieved by incorporation of photocleavable spacers into the RNA nanoparticles.Upon irradiation with ultraviolet light,cargos were rapidly released(within 5 min).In vitro treatment of breast can cer cells with the RNA nano particles harbori ng photocleavable paclitaxel showed higher cytotoxicity as compared to RNA nanoparticles without the photocleavable spacer.The methodology provides proof of con cept for the applicati on of the light-triggered con trolled release of drugs from RNA nano cages.
文摘Background:Machine learning to predict morbidity and mortality-especially in a population traditionally considered low risk-has not been previously examined.We sought to characterize the incidence of death among patients with a low estimated morbidity and mortality risk based on the National Surgical Quality Improvement Program(NSQIP)estimated probability(EP),as well as develop a machine learning model to identify individuals at risk for“unpredicted death”(UD)among patients undergoing hepatopancreatic(HP)procedures.Methods:The NSQIP database was used to identify patients who underwent elective HP surgery between 2012-2017.The risk of morbidity and mortality was stratified into three tiers(low,intermediate,or high estimated)using a k-means clustering method with bin sorting.A machine learning classification tree and multivariable regression analyses were used to predict 30-day mortality with a 10-fold cross validation.C statistics were used to compare model performance.Results:Among 63,507 patients who underwent an HP procedure,median patient age was 63(IQR:54-71)years.Patients underwent either pancreatectomy(n=38,209,60.2%)or hepatic resection(n=25,298,39.8%).Patients were stratified into three tiers of predicted morbidity and mortality risk based on the NSQIP EP:low(n=36,923,58.1%),intermediate(n=23,609,37.2%)and high risk(n=2,975,4.7%).Among 36,923 patients with low estimated risk of morbidity and mortality,237 patients(0.6%)experienced a UD.According to the classification tree analysis,age was the most important factor to predict UD(importance 16.9)followed by preoperative albumin level(importance:10.8),disseminated cancer(importance:6.5),preoperative platelet count(importance:6.5),and sex(importance 5.9).Among patients deemed to be low risk,the c-statistic for the machine learning derived prediction model was 0.807 compared with an AUC of only 0.662 for the NSQIP EP.Conclusions:A prognostic model derived using machine learning methodology performed better than the NSQIP EP in predicting 30-day UD among low risk patients undergoing HP surgery.
文摘Nanotubes are miniature materials with significant potential applications in nanotechnological, medical, biological and material sciences. The quest for manufacturing methods of nano-mechanical modules is in progress. For example, the application of carbon nanotubes has been extensively investigated due to the precise width control, but the precise length control remains challenging. Here we report two approaches for the one-pot self-assembly of RNA nanotubes. For the first approach, six RNA strands were used to assemble the nanotube by forming a 11 nm long hollow channel with the inner diameter of 1.7 nm and the outside diameter of 6.3 nm. For the second approach, six RNA strands were designed to hybridize with their neighboring strands by complementary base pairing and formed a nanotube with a six-helix hollow channel similar to the nanotube assembled by the first approach. The fabricated RNA nanotubes were characterized by gel electrophoresis and atomic force microscopy (AFM), confirming the formation of nanotube-shaped RNA nanostructures. Cholesterol molecules were introduced into RNA nanotubes to facilitate their incorporation into lipid bilayer. Incubation of RNA nanotube complex with the free-standing lipid bilayer membrane under applied voltage led to discrete current signatures. Addition of peptides into the sensing chamber revealed discrete steps of current blockage. Polyarginine peptides with different lengths can be detected by current signatures, suggesting that the RNA-cholesterol complex holds the promise of achieving single molecule sensing of peptides.
基金supported by the National Institute of Neurological Disorders and Stroke and the National Cancer Institute grants(USA)(No.NS104332,NS112935,CA227874 and CA240726 to D.Guo)。
文摘In healthy humans, ammonia circulates in the bloodstream at a concentration around 11–32 μmol/L. Whether ammonia plays any physiological role has been unknown until a recent report published in Nature Metabolism.1 Ammonia, long thought to be a toxic waste product of amino acid metabolism, needs to be excreted from the human body as urea. Intriguingly, in this paper, Cheng et al1 for the first time reported that ammonia is not a waste product;rather, it is an unprecedented signaling molecule tying glucose and glutamine to lipid production in human cells. This study revealed that ammonia released from glutamine triggers a cascade of cellular processes leading to the activation of lipogenesis machinery for lipid production (Fig. 1). This discovery has major implications for developing treatments for human diseases such as cancers and metabolic syndromes, as dysregulated metabolism is a hallmark of these diseases.
