This editorial provides insights into the pivotal role of checkpoint kinase 1(CHEK1)as both a biomarker and therapeutic target in colorectal cancer(CRC),based on findings from a recent study by Pang et al.Using single...This editorial provides insights into the pivotal role of checkpoint kinase 1(CHEK1)as both a biomarker and therapeutic target in colorectal cancer(CRC),based on findings from a recent study by Pang et al.Using single-cell RNA sequencing and immunohistochemistry,the study demonstrates significant CHEK1 overexpression in CRC tissues and identifies nitidine chloride as a potent CHEK1 inhibitor that disrupts DNA damage repair pathways.These findings underscore the therapeutic potential of CHEK1 inhibition and highlight the need for further research to address gaps in CRC treatment.展开更多
Cluster of differentiation 47(CD47),an immune checkpoint commonly referred to as the“don’t eat me”signal,plays a pivotal role in tumor immune evasion by inhibiting phagocytosis through interaction with signal regul...Cluster of differentiation 47(CD47),an immune checkpoint commonly referred to as the“don’t eat me”signal,plays a pivotal role in tumor immune evasion by inhibiting phagocytosis through interaction with signal regulatory protein alpha(SIRPα)on macrophages and dendritic cells(DCs).Although early enthusiasm drove broad clinical development,recent discontinuations of major CD47-targeted programs have prompted re-evaluation of its therapeutic potential.The purpose of this commentary is to contextualize the setbacks observed with first-generation CD47 inhibitors and to highlight strategies aimed at overcoming their limitations.Clinical challenges,including anemia,thrombocytopenia,suboptimal pharmacokinetics,and limited single-agent efficacy,underscore the need to develop safer,more selective approaches.Emerging next-generation strategies,such as SIRPα-directed agents,bispecific antibodies,and conditionally active therapeutics,are designed to enhance safety and tumor selectivity and reduce systemic toxicity.In addition,spatial profiling and biomarker-driven patient selection are advancing toward guiding rational therapeutic combinations,including with“eat-me”signals(e.g.,calreticulin[CALR])orDNA damage response therapies(e.g.,poly(ADP-ribose)polymerase[PARP]inhibitors).Rather than signaling failure,these developments underscore the need for precision,context-specific applications,and adaptive trial designs to realize the durable therapeutic promise of CD47 blockade in cancer immunotherapy.展开更多
BACKGROUND The incidence of early-onset colorectal cancer(EOCRC,<45 years of age at onset)is on the rise among adults,including African Americans(AA).AIM To examine differences between EOCRC and late-onset colorect...BACKGROUND The incidence of early-onset colorectal cancer(EOCRC,<45 years of age at onset)is on the rise among adults,including African Americans(AA).AIM To examine differences between EOCRC and late-onset colorectal cancer(LOCRC)among AA patients and any effect during coronavirus disease(COVID)by comparing data during pre-COVID(2015-2019)and the COVID era(2020-2023).METHODS We conducted a retrospective review of Howard University Hospital records from 2015 to 2023 for colorectal cancer patients that included demographics,clinicals,pathology,and colonoscopy records.A three-year interval analysis was performed to compare post-COVID era(2020-2023)to preceding years to discern temporal trends.RESULTS The study included 138 LOCRC and 13 EOCRC cases of which>80%of patients were AA.Compared to pre-COVID,LOCRC cases increased in number from 55 to 83,and EOCRC cases increased from 6 to 7 during COVID.There was no change in mean age for LOCRC(64.7 years vs 65.3 years)but mean age increased for EOCRC(37.3 years vs 41.5 years).Males predominated in both groups particularly during the pandemic.More than 65%of LOCRC patient colonoscopies were for diagnostic purposes.Gastrointestinal bleeding as a colonoscopy indication and reduced bowel preparation quality were increased during the pandemic.EOCRC patients showed a shift from stage 4(49.2%)to stage 2(30%)and LOCRC patients staging trends changed from stage 4(40%)to stage 3(28.6%).CONCLUSION We report increase in colorectal cancer cases during the COVID-19 era,especially among young AA males.EOCRC and LOCRC patients showed distal location predominance,most commonly in recto-sigmoid region.The decrease in staging or metastasis,which might be due to growing awareness and earlier detection among patients.展开更多
Pancreatic cancer is the fourth leading cause of cancer death in the United States. While surgical resection remains the only curative option, more than 80% of patients present with unresectable disease. Unfortunately...Pancreatic cancer is the fourth leading cause of cancer death in the United States. While surgical resection remains the only curative option, more than 80% of patients present with unresectable disease. Unfortunately, even among those who undergo resection, the reported median survival is 15-23 mo, with a 5-year survival of approximately 20%. Disappointingly, over the past several decades, despite improvements in diagnostic imaging, surgical technique and chemotherapeutic options, only modest improvements in survival have been realized. Nevertheless, it remains clear that surgical resection is a prerequisite for achieving longterm survival and cure. There is now emerging consensus that a subgroup of patients, previously considered poor candidates for resection because of the relationship of their primary tumor to surrounding vasculature, may benefit from resection, particularly when preceded by neoadjuvant therapy. This stage of disease, termed borderline resectable pancreatic cancer, has become of increasing interest and is now the focus of a multiinstitutional clinical trial. Here we outline the history, progress, current treatment recommendations, and future directions for research in borderline resectable pancreatic cancer.展开更多
BACKGROUND Gastrointestinal cancer(GICA)is associated with a higher incidence of venous thromboembolism(VTE)compared to other solid tumors,moreover,recurrent VTE and major bleeding(MB)complications during anticoagulat...BACKGROUND Gastrointestinal cancer(GICA)is associated with a higher incidence of venous thromboembolism(VTE)compared to other solid tumors,moreover,recurrent VTE and major bleeding(MB)complications during anticoagulation treatment have an associated increase rate.GICA-VTE remains a challenging clinical scenario with MB concerns for utilization of direct oral anticoagulants(DOAC),especially with active cancer therapies.AIM To evaluate patient risk factors,effectiveness(VTE)and safety(MB)of DOACs and low molecular weight heparin(LMWH)in patients with active GICA-VTE.METHODS A retrospective chart review of patients receiving DOACs and LMWH with GICA and symptomatic or incidental VTE treated at comprehensive cancer center from November 2013 to February 2017 was performed.Inclusion criteria included active GI cancer diagnosed at any stage or treatment+/-6 mo of VTE diagnosis,whom were prescribed 6 mo or more of DOACs or LMWH.The Chi-squared test was used for overall and the Fisher exact test for pairwise comparisons of the proportions of patients experiencing recurrent VTE and MB events.Odds ratios were used to compare the relative odds of the occurrence of the outcome given exposure to the risk factor.RESULTS A total of 144 patients were prescribed anticoagulation,in which 106 fulfilled inclusion criteria apixaban(27.3%),rivaroxaban(34.9%)and enoxaparin(37.7%),and 38 were excluded.Patients median age was 66.5 years at GICA diagnosis and 67 years at CAVTE event,with 62%males,80%Caucasian,70%stage IV,pancreatic cancer(40.5%),30%Khorana Score(≥3 points),and 43.5%on active chemotherapy.Sixty-four percent of patients completed anticoagulation therapy(range 1 to 43 mo).Recurrent VTE at 6 mo was noted in 7.5%(n=3),6.8%(n=2)and 2.7%(n=1)of patients on enoxaparin,apixaban and rivaroxaban,respectively(all P=NS).MB at 6 mo were 5%(n=2)for enoxaparin,6.8%(n=2)for apixaban and 21.6%(n=8)for rivaroxaban(overall P=0.048;vs LMWH P=0.0423;all other P=NS).Significant predictors of a primary or secondary outcome for all anticoagulation therapies included:Active systemic treatment(OR=5.1,95%CI:1.3-19.3),high Khorana Score[≥3 points](OR=5.5,95%CI:1.7-17.1),active smoker(OR=6.7,95%CI:2.1-21.0),pancreatic cancer(OR=6.8,95%CI:1.9-23.2),and stage IV disease(OR=9.9,95%CI:1.2-79.1).CONCLUSION Rivaroxaban compared to apixaban and enoxaparin had a significantly higher risk of MB on GICA-VTE patients with equivocal efficacy.展开更多
Cancer immunotherapy has emerged as a promising strategy for the treatment of cancer,with the tumor microenvironment(TME)playing a pivotal role in modulating the immune response.CD47,a cell surface protein,has been id...Cancer immunotherapy has emerged as a promising strategy for the treatment of cancer,with the tumor microenvironment(TME)playing a pivotal role in modulating the immune response.CD47,a cell surface protein,has been identified as a crucial regulator of the TME and a potential therapeutic target for cancer therapy.However,the precise functions and implications of CD47 in the TME during immunotherapy for cancer patients remain incompletely understood.This comprehensive review aims to provide an overview of CD47’s multifaced role in TME regulation and immune evasion,elucidating its impact on various types of immunotherapy outcomes,including checkpoint inhibitors and CAR T-cell therapy.Notably,CD47-targeted therapies offer a promising avenue for improving cancer treatment outcomes,especially when combined with other immunotherapeutic approaches.The review also discusses current and potential CD47-targeted therapies being explored for cancer treatment and delves into the associated challenges and opportunities inherent in targeting CD47.Despite the demonstrated effectiveness of CD47-targeted therapies,there are potential problems,including unintended effects on healthy cells,hematological toxicities,and the development if resistance.Consequently,further research efforts are warranted to fully understand the underlying mechanisms of resistance and to optimize CD47-targeted therapies through innovative combination approaches,ultimately improving cancer treatment outcomes.Overall,this comprehensive review highlights the significance of CD47 as a promising target for cancer immunotherapy and provides valuable insight into the challenges and opportunities in developing effective CD47-targeted therapies for cancer treatment.展开更多
Objective:Cancer stem cell is one of the important causes of tumorigenesis as well as a drug target in the treatment of malignant tumor.However,at present,there is no immune vaccine targeting these cells.Octamer-bindi...Objective:Cancer stem cell is one of the important causes of tumorigenesis as well as a drug target in the treatment of malignant tumor.However,at present,there is no immune vaccine targeting these cells.Octamer-binding transcription factor 4(OCT4),a marker of embryonic stem cells and germ cells,often highly expresses in the early stages of tumorigenesis and is therefore a good candidate for cancer vaccine development.Methods:To identify the optimal carrier and adjuvant combination,we chemically synthesized and linked three different OCT4 epitope antigens to a carrier protein,keyhole limpet hemocyanin(KLH),combined with Toll-like receptor 9 agonist(TLR9).Results:Immunization with OCT4-3+TLR9 produced the strongest immune response in mice.In prevention assays,significant tumor growth inhibition was achieved in BABL/c mice treated with OCT4-3+TLR9(P<0.01).Importantly,the results showed that cytotoxic T lymphocyte activity and the inhibition of tumor growth were enhanced in mice immunized with OCT4-3 combined with TLR9.Meanwhile,multiple cytokines[such as interferon(IFN)-γ(P<0.05),interleukin(IL)-12(P<0.05),IL-2(P<0.01),and IL-6(P<0.05)]promoting cellular immune responses were shown to be greatly enhanced in mice immunized with OCT4-3+TLR9.Moreover,we considered safety considerations in terms of the composition of the vaccines to help facilitate the development of effective next-generation vaccines.Conclusions:Collectively,these experiments demonstrated that combination therapy with TLR9 agonist induced a tumor-specific adaptive immune response,leading to the suppression of primary tumor growth in testis embryonic carcinoma.展开更多
Objective:Bone metastasis occurs in up to 90%of men with advanced prostate cancer and leads to fractures,severe pain and therapy-resistance.Bone metastases induce a spectrum of types of bone lesions which can respond ...Objective:Bone metastasis occurs in up to 90%of men with advanced prostate cancer and leads to fractures,severe pain and therapy-resistance.Bone metastases induce a spectrum of types of bone lesions which can respond differently to therapy even within individual prostate cancer patients.Thus,the special environment of the bone makes the disease more complicated and incurable.A model in which bone lesions are reproducibly induced that mirrors the complexity seen in patients would be invaluable for pre-clinical testing of novel treatments.The microstructural changes in the femurs of mice implanted with PCSD1,a new patient-derived xenograft from a surgical prostate cancer bone metastasis specimen,were determined.Methods:Quantitative micro-computed tomography(micro-CT)and histological analyses were performed to evaluate the effects of direct injection of PCSD1 cells or media alone(Control)into the right femurs of Rag2/gc/male mice.Results:Bone lesions formed only in femurs of mice injected with PCSD1 cells.Bone volume(BV)was significantly decreased at the proximal and distal ends of the femurs(p<0.01)whereas BV(p<0.05)and bone shaft diameter(p<0.01)were significantly increased along the femur shaft.Conclusion:PCSD1 cells reproducibly induced bone loss leading to osteolytic lesions at the ends of the femur,and,in contrast,induced aberrant bone formation leading to osteoblastic lesions along the femur shaft.Therefore,the interaction of PCSD1 cells with different bone region-specific microenvironments specified the type of bone lesion.Our approach can be used to determine if different bone regions support more therapy resistant tumor growth,thus,requiring novel treatments.展开更多
OBJECTIVE Pancreatic ductal adenocarcinoma(PDAC),a lethal cancer in need of new,effective therapies,has a unique tumor microenvironment characterized by a dense fibrotic stroma(desmoplasia)that is generated by pancrea...OBJECTIVE Pancreatic ductal adenocarcinoma(PDAC),a lethal cancer in need of new,effective therapies,has a unique tumor microenvironment characterized by a dense fibrotic stroma(desmoplasia)that is generated by pancreatic cancer-associated fibroblasts(PCAFs)derived from pancreatic stellate cells(PSCs)and pancreatic fibroblasts(PFs).METHEDS and RESULTS Hypothesizing that G protein-coupled receptors(GPCRs)may regulate PCAFs,we used an unbiased GPCRomic array approach to compare GPCR expression in PCAFs,PFs and PSCs and identified 82 GPCRs commonly expressed by PCAFs derived from primary tumors of five PDAC patients.We discovered that PCAFs have increased expression of numerous GPCRs,in particular a GPCR with much higher expression in PCAFs compared to both PFs and PSCs.Immunohistochemistry revealed increased expression of this GPCR in PDAC tumors.Co-culture of PSCs with PDAC cells or incubation with TNFαinduced its expression.Activation of the GPCR in PCAF sincreased expression of interleukin-6(IL-6)via a cA MP/PKA/CREB signaling pathway.GPCR knockdown with siR NA diminished IL-6 production and secretionby PCAFs and ability of PCAF conditioned media to enhance proliferation of PDAC cells.CONCLUSION We conclude that PDAC cells induce expression by PCAFs of a novel GPCR,resulting in increased IL-6 production by PCAFs and promotion of PDAC cell proliferation.This PCAF-expressed GPCR thus contributes to PDAC cell-PCAF interaction and as such,may be a novel therapeutic target for PDAC tumors.展开更多
Objective:Immunotherapy that blocks inhibitory pathways in T lymphocytes,such as the PD-L1/PD-1 axis,is undergoing evaluation for various solid tumors.Notably,this emerging therapeutic approach is already in clinical ...Objective:Immunotherapy that blocks inhibitory pathways in T lymphocytes,such as the PD-L1/PD-1 axis,is undergoing evaluation for various solid tumors.Notably,this emerging therapeutic approach is already in clinical trials for advanced hepatocellular carcinoma(HCC).展开更多
Objectives:The Kirsten rat sarcoma virus(KRAS)G12D oncogenic mutation poses a significant challenge in treating solid tumors due to the lack of specific and effective therapeutic interventions.This study aims to explore...Objectives:The Kirsten rat sarcoma virus(KRAS)G12D oncogenic mutation poses a significant challenge in treating solid tumors due to the lack of specific and effective therapeutic interventions.This study aims to explore innovative approaches in T cell receptor(TCR)engineering and characterization to target the KRAS G12D7-16 mutation,providing potential strategies for overcoming this therapeutic challenge.Methods:In this innovative study,we engineered and characterized two T cell receptors(TCRs),KDA11-01 and KDA11-02 with high affinity for the KRAS G12D7-16 mutation.These TCRs were isolated from tumor-infiltrating lymphocytes(TILs)derived from tumor tissues of patients with the KRAS G12D mutation.We assessed their specificity and anti-tumor activity in vitro using various cancer cell lines.Results:KDA11-01 and KDA11-02 demonstrated exceptional specificity for the HLA-A*11:01-restricted KRAS G12D7-16 epitope,significantly inducing IFN-γrelease and eliminating tumor cells without cross-reactivity or alloreactivity.Conclusions:The successful development of KDA11-01 and KDA11-02 introduces a novel and precise TCR-based therapeutic strategy against KRAS G12D mutation,showing potential for significant advancements in cancer immunotherapy.展开更多
AIM To identify factors associated with Papanicolaou-smear(Pap-smear)cervical cancer screening rates in a safety net population.METHODS From January 2012 to May 2013,the use of Pap-smear was determined for all patient...AIM To identify factors associated with Papanicolaou-smear(Pap-smear)cervical cancer screening rates in a safety net population.METHODS From January 2012 to May 2013,the use of Pap-smear was determined for all patients seen at the breast clinic in a safety net hospital.Health literacy assessment was performed using the validated Newest Vital Sign.The records of patients were reviewed to determine if they had undergone Pap-smears for cervical cancer screening.Sociodemographic information was collected included age,education,monthly income,race/ethnicity,employment,insurance status,and primary care provider of the patient.Logistic regression analysis was then performed to determine factors associated with utilization of Papsmears.Crude and adjusted odds ratios derived from multivariate logistic regression models were calculated as well as the associated 95%CIs and P-values.RESULTS Overall,39%had Pap-smears in the prior 15 mo,1377 consecutive women were seen during the study period and their records were reviewed.Significantly more patients with adequate health literacy underwent Papsmears as compared to those with limited health literacy(59%vs 34%,P<0.0001).In multivariate analysis,patients with adequate health literacy,younger patients,and those with later age of first live birth were more likely to undergo Pap-smears.Patients whose primary care providers were gynecologists were also significantly more likely to have Pap-smears compared to other specialties(P<0.0001).Patients younger than 21 years or older than 65 years underwent screening less frequently(11%and 11%,respectively)than those 21-64 years(41%,P<0.0001).Race,ethnicity,language,and insurance status were not associated with Pap-smear screening rates.CONCLUSION Patient health literacy and primary care physician were associated with Pap-smear utilization.Development of interventions to target low health literacy populations could improve cervical cancer screening.展开更多
Clustered regulatory interspaced short palindromic repeats(CRISPR)has changed biomedical research and provided entirely new models to analyze every aspect of biomedical sciences during the last decade.In the study of ...Clustered regulatory interspaced short palindromic repeats(CRISPR)has changed biomedical research and provided entirely new models to analyze every aspect of biomedical sciences during the last decade.In the study of cancer,the CRISPR/CRISPR-associated protein(Cas)system opens new avenues into issues that were once unknown in our knowledge of the non-coding genome,tumor heterogeneity,and precision medicines.CRISPR/Cas-based geneediting technology now allows for the precise and permanent targeting of mutations and provides an opportunity to target small non-coding RNAs such as microRNAs(miRNAs).However,the development of effective and safe cancer gene editing therapy is highly dependent on proper design to be innocuous to normal cells and prevent introducing other abnormalities.This study aims to highlight the cutting-edge approaches in cancer-gene editing therapy based on the CRISPR/Cas technology to target miRNAs in cancer therapy.Furthermore,we highlight the potential challenges in CRISPR/Cas-mediated miRNA gene editing and offer advanced strategies to overcome them.展开更多
Esophageal squamous cell carcinoma(ESCC)remains a highly aggressive ma-lignancy with limited effective therapeutic options for patients with locally advanced unresectable disease.The study by Wei et al,featured in thi...Esophageal squamous cell carcinoma(ESCC)remains a highly aggressive ma-lignancy with limited effective therapeutic options for patients with locally advanced unresectable disease.The study by Wei et al,featured in this issue,highlights the potential of induction chemoimmunotherapy followed by definitive radiotherapy or concurrent chemoradiotherapy to improve treatment outcomes in this challenging patient population.This retrospective analysis of 132 patients demonstrates promising results,including a median progression-free survival of 14.2 months and overall survival of 19.9 months,alongside an acceptable safety profile.Notably,the study identifies the effectiveness of induction therapy and maintenance immunotherapy as key prognostic factors,emphasizing the syner-gistic potential of integrating immune checkpoint inhibitors with radiotherapy.While these findings are encouraging,they require further validation through prospective trials,along with biomarker-based and immune response studies,to refine patient selection and maximize therapeutic benefits.This editorial explores the implications of this research,its impact on clinical practice,and future di-rections for advancing the treatment landscape of ESCC.展开更多
DNA damage can, but does not always, induce cell death. While several pathways linking DNA damage signals to mitochondria-dependent and -independent death machineries have been elucidated, the connectivity of these pa...DNA damage can, but does not always, induce cell death. While several pathways linking DNA damage signals to mitochondria-dependent and -independent death machineries have been elucidated, the connectivity of these pathways is subject to regulation by multiple other factors that are not well understood. We have proposed two conceptual models to explain the delayed and variable cell death response to DNA damage： integrative surveillance versus autonomous pathways. In this review, we discuss how these two models may explain the in vivo regulation of cell death induced by ionizing radiation （IR） in the developing central nervous system, where the death response is regulated by radiation dose, cell cycle status and neuronal development.展开更多
Staphylococcus aureus(S.aureus)is a leading human pathogen capable of producing severe invasive infections such as bacteremia,sepsis,and endocarditis with high morbidity and mortality,exacerbated by the increasingly w...Staphylococcus aureus(S.aureus)is a leading human pathogen capable of producing severe invasive infections such as bacteremia,sepsis,and endocarditis with high morbidity and mortality,exacerbated by the increasingly widespread antibiotic resistance exemplified by methicillin-resistant strains(MRSA).S.aureus pathogenesis is fueled by the secretion of toxins—such as the membrane-damaging pore-forming atoxin,which have diverse cellular targets including the epithelium,endothelium,leukocytes,and platelets.Here,we examine the use of human platelet membrane-coated nanoparticles(PNPs)as a biomimetic decoy strategy to neutralize S.aureus toxins and preserve host cell defense functions.The PNPs blocked platelet damage induced by S.aureus secreted toxins,thereby supporting platelet activation and bactericidal activity.Likewise,the PNPs blocked macrophage damage induced by S.aureus secreted toxins,thus supporting macrophage oxidative burst,nitric oxide production,and bactericidal activity,and diminishing MRSA-induced neutrophil extracellular trap release.In a mouse model of MRSA systemic infection,PNP administration reduced bacterial counts in the blood and protected against mortality.Taken together,the results from the present work provide a proof of principle of the therapeutic benefit of PNPs in toxin neutralization,cytoprotection,and increased host resistance to invasive S.aureus infection.展开更多
Neuroblastoma (NBL) is one of the most common solid tumors and around 15% of cancer mortality in children. Amplification of the N-Myc proto-oncogene is strongly correlated with advanced disease and poor clinical outco...Neuroblastoma (NBL) is one of the most common solid tumors and around 15% of cancer mortality in children. Amplification of the N-Myc proto-oncogene is strongly correlated with advanced disease and poor clinical outcome in NBL. Recent studies described that ubiquitin-specific protease 7 (USP7;also known as HAUSP) interacts with N-Myc, induces deubiquitination and subsequent stabilization of N-Myc that in-turn potentiates N-Myc function, and treatment with the HAUSP inhibitor (P22077) blocked such effects.展开更多
Background:There exist few maximal oxygen uptake(VO_(2max))non-exercise-based prediction equations,fewer using machine learning(ML),and none specifically for older adults.Since direct measurement of VO_(2max)is infeas...Background:There exist few maximal oxygen uptake(VO_(2max))non-exercise-based prediction equations,fewer using machine learning(ML),and none specifically for older adults.Since direct measurement of VO_(2max)is infeasible in large epidemiologic cohort studies,we sought to develop,validate,compare,and assess the transportability of several ML VO_(2max)prediction algorithms.Methods:The Baltimore Longitudinal Study of Aging(BLSA)participants with valid VO2_(max)tests were included(n=1080).Least absolute shrinkage and selection operator,linear-and tree-boosted extreme gradient boosting,random forest,and support vector machine(SVM)algorithms were trained to predict VO_(2max)values.We developed these algorithms for:(a)the overall BLSA,(b)by sex,(c)using all BLSA variables,and(d)variables common in aging cohorts.Finally,we quantified the associations between measured and predicted VO_(2max)and mortality.Results:The age was 69.0±10.4 years(mean±SD)and the measured VO_(2max)was 21.6±5.9 mL/kg/min.Least absolute shrinkage and selection operator,linear-and tree-boosted extreme gradient boosting,random forest,and support vector machine yielded root mean squared errors of 3.4 mL/kg/min,3.6 mL/kg/min,3.4 mL/kg/min,3.6 mL/kg/min,and 3.5 mL/kg/min,respectively.Incremental quartiles of measured VO_(2max)showed an inverse gradient in mortality risk.Predicted VO_(2max)variables yielded similar effect estimates but were not robust to adjustment.Conclusion:Measured VO_(2max)is a strong predictor of mortality.Using ML can improve the accuracy of prediction as compared to simpler approaches but estimates of association with mortality remain sensitive to adjustment.Future studies should seek to reproduce these results so that VO_(2max),an important vital sign,can be more broadly studied as a modifiable target for promoting functional resiliency and healthy aging.展开更多
Genotoxic agents or inflammatory cytokines activate cellular stress responses and trigger programmed cell death. We have identified a signal transduction module, including three nuclear proteins that participate in th...Genotoxic agents or inflammatory cytokines activate cellular stress responses and trigger programmed cell death. We have identified a signal transduction module, including three nuclear proteins that participate in the regulation of cell death induced by chemotherapeutic agents and tumor necrosis factor (TNF). In this nuclear signaling module, retino- blastoma protein (Rb) functions as an inhibitor of apoptotic signal transduction. Inactivation of Rb by phosphorylation or caspase-dependent cleavage/degradation is required for cell death to occur. Rb inhibits the Abl tyrosine kinase. Thus, Rb inactivation is a pre-requisite for Abl activation by DNA damage or TNF. Activation of nuclear Abl and its down- stream effector p73 induces mitochondriadependent cell death. The involvement of these nuclear signal transducers in TNF induced apoptosis, which does not require new gene expression, indicates that nuclear events other than transcrip- tion can contribute to extrinsic apoptotic signal transduction.展开更多
Pioneered by a major cancer ge- nome sequencing project [1] and followed by numerous cancer genomic sequencing studies [2-4], the cytosolic isocitrate dehydrogenase （IDH1） gene and mitochondria isocitrate dehydrogen...Pioneered by a major cancer ge- nome sequencing project [1] and followed by numerous cancer genomic sequencing studies [2-4], the cytosolic isocitrate dehydrogenase （IDH1） gene and mitochondria isocitrate dehydrogenase （1DH2） gene are found to be frequently mutated in low grade gliomas and secondary glioblastoma multiforme （GBM）, acute myeloid leukemia （AML）, and to a much lower frequency in other types of tumors.展开更多
文摘This editorial provides insights into the pivotal role of checkpoint kinase 1(CHEK1)as both a biomarker and therapeutic target in colorectal cancer(CRC),based on findings from a recent study by Pang et al.Using single-cell RNA sequencing and immunohistochemistry,the study demonstrates significant CHEK1 overexpression in CRC tissues and identifies nitidine chloride as a potent CHEK1 inhibitor that disrupts DNA damage repair pathways.These findings underscore the therapeutic potential of CHEK1 inhibition and highlight the need for further research to address gaps in CRC treatment.
文摘Cluster of differentiation 47(CD47),an immune checkpoint commonly referred to as the“don’t eat me”signal,plays a pivotal role in tumor immune evasion by inhibiting phagocytosis through interaction with signal regulatory protein alpha(SIRPα)on macrophages and dendritic cells(DCs).Although early enthusiasm drove broad clinical development,recent discontinuations of major CD47-targeted programs have prompted re-evaluation of its therapeutic potential.The purpose of this commentary is to contextualize the setbacks observed with first-generation CD47 inhibitors and to highlight strategies aimed at overcoming their limitations.Clinical challenges,including anemia,thrombocytopenia,suboptimal pharmacokinetics,and limited single-agent efficacy,underscore the need to develop safer,more selective approaches.Emerging next-generation strategies,such as SIRPα-directed agents,bispecific antibodies,and conditionally active therapeutics,are designed to enhance safety and tumor selectivity and reduce systemic toxicity.In addition,spatial profiling and biomarker-driven patient selection are advancing toward guiding rational therapeutic combinations,including with“eat-me”signals(e.g.,calreticulin[CALR])orDNA damage response therapies(e.g.,poly(ADP-ribose)polymerase[PARP]inhibitors).Rather than signaling failure,these developments underscore the need for precision,context-specific applications,and adaptive trial designs to realize the durable therapeutic promise of CD47 blockade in cancer immunotherapy.
文摘BACKGROUND The incidence of early-onset colorectal cancer(EOCRC,<45 years of age at onset)is on the rise among adults,including African Americans(AA).AIM To examine differences between EOCRC and late-onset colorectal cancer(LOCRC)among AA patients and any effect during coronavirus disease(COVID)by comparing data during pre-COVID(2015-2019)and the COVID era(2020-2023).METHODS We conducted a retrospective review of Howard University Hospital records from 2015 to 2023 for colorectal cancer patients that included demographics,clinicals,pathology,and colonoscopy records.A three-year interval analysis was performed to compare post-COVID era(2020-2023)to preceding years to discern temporal trends.RESULTS The study included 138 LOCRC and 13 EOCRC cases of which>80%of patients were AA.Compared to pre-COVID,LOCRC cases increased in number from 55 to 83,and EOCRC cases increased from 6 to 7 during COVID.There was no change in mean age for LOCRC(64.7 years vs 65.3 years)but mean age increased for EOCRC(37.3 years vs 41.5 years).Males predominated in both groups particularly during the pandemic.More than 65%of LOCRC patient colonoscopies were for diagnostic purposes.Gastrointestinal bleeding as a colonoscopy indication and reduced bowel preparation quality were increased during the pandemic.EOCRC patients showed a shift from stage 4(49.2%)to stage 2(30%)and LOCRC patients staging trends changed from stage 4(40%)to stage 3(28.6%).CONCLUSION We report increase in colorectal cancer cases during the COVID-19 era,especially among young AA males.EOCRC and LOCRC patients showed distal location predominance,most commonly in recto-sigmoid region.The decrease in staging or metastasis,which might be due to growing awareness and earlier detection among patients.
文摘Pancreatic cancer is the fourth leading cause of cancer death in the United States. While surgical resection remains the only curative option, more than 80% of patients present with unresectable disease. Unfortunately, even among those who undergo resection, the reported median survival is 15-23 mo, with a 5-year survival of approximately 20%. Disappointingly, over the past several decades, despite improvements in diagnostic imaging, surgical technique and chemotherapeutic options, only modest improvements in survival have been realized. Nevertheless, it remains clear that surgical resection is a prerequisite for achieving longterm survival and cure. There is now emerging consensus that a subgroup of patients, previously considered poor candidates for resection because of the relationship of their primary tumor to surrounding vasculature, may benefit from resection, particularly when preceded by neoadjuvant therapy. This stage of disease, termed borderline resectable pancreatic cancer, has become of increasing interest and is now the focus of a multiinstitutional clinical trial. Here we outline the history, progress, current treatment recommendations, and future directions for research in borderline resectable pancreatic cancer.
基金The University of Arizona Hematology and Medical Oncology Fellowship program
文摘BACKGROUND Gastrointestinal cancer(GICA)is associated with a higher incidence of venous thromboembolism(VTE)compared to other solid tumors,moreover,recurrent VTE and major bleeding(MB)complications during anticoagulation treatment have an associated increase rate.GICA-VTE remains a challenging clinical scenario with MB concerns for utilization of direct oral anticoagulants(DOAC),especially with active cancer therapies.AIM To evaluate patient risk factors,effectiveness(VTE)and safety(MB)of DOACs and low molecular weight heparin(LMWH)in patients with active GICA-VTE.METHODS A retrospective chart review of patients receiving DOACs and LMWH with GICA and symptomatic or incidental VTE treated at comprehensive cancer center from November 2013 to February 2017 was performed.Inclusion criteria included active GI cancer diagnosed at any stage or treatment+/-6 mo of VTE diagnosis,whom were prescribed 6 mo or more of DOACs or LMWH.The Chi-squared test was used for overall and the Fisher exact test for pairwise comparisons of the proportions of patients experiencing recurrent VTE and MB events.Odds ratios were used to compare the relative odds of the occurrence of the outcome given exposure to the risk factor.RESULTS A total of 144 patients were prescribed anticoagulation,in which 106 fulfilled inclusion criteria apixaban(27.3%),rivaroxaban(34.9%)and enoxaparin(37.7%),and 38 were excluded.Patients median age was 66.5 years at GICA diagnosis and 67 years at CAVTE event,with 62%males,80%Caucasian,70%stage IV,pancreatic cancer(40.5%),30%Khorana Score(≥3 points),and 43.5%on active chemotherapy.Sixty-four percent of patients completed anticoagulation therapy(range 1 to 43 mo).Recurrent VTE at 6 mo was noted in 7.5%(n=3),6.8%(n=2)and 2.7%(n=1)of patients on enoxaparin,apixaban and rivaroxaban,respectively(all P=NS).MB at 6 mo were 5%(n=2)for enoxaparin,6.8%(n=2)for apixaban and 21.6%(n=8)for rivaroxaban(overall P=0.048;vs LMWH P=0.0423;all other P=NS).Significant predictors of a primary or secondary outcome for all anticoagulation therapies included:Active systemic treatment(OR=5.1,95%CI:1.3-19.3),high Khorana Score[≥3 points](OR=5.5,95%CI:1.7-17.1),active smoker(OR=6.7,95%CI:2.1-21.0),pancreatic cancer(OR=6.8,95%CI:1.9-23.2),and stage IV disease(OR=9.9,95%CI:1.2-79.1).CONCLUSION Rivaroxaban compared to apixaban and enoxaparin had a significantly higher risk of MB on GICA-VTE patients with equivocal efficacy.
基金the Huzhou Science and Technology Bureau,Zhejiang Province,China(2020GZ41).
文摘Cancer immunotherapy has emerged as a promising strategy for the treatment of cancer,with the tumor microenvironment(TME)playing a pivotal role in modulating the immune response.CD47,a cell surface protein,has been identified as a crucial regulator of the TME and a potential therapeutic target for cancer therapy.However,the precise functions and implications of CD47 in the TME during immunotherapy for cancer patients remain incompletely understood.This comprehensive review aims to provide an overview of CD47’s multifaced role in TME regulation and immune evasion,elucidating its impact on various types of immunotherapy outcomes,including checkpoint inhibitors and CAR T-cell therapy.Notably,CD47-targeted therapies offer a promising avenue for improving cancer treatment outcomes,especially when combined with other immunotherapeutic approaches.The review also discusses current and potential CD47-targeted therapies being explored for cancer treatment and delves into the associated challenges and opportunities inherent in targeting CD47.Despite the demonstrated effectiveness of CD47-targeted therapies,there are potential problems,including unintended effects on healthy cells,hematological toxicities,and the development if resistance.Consequently,further research efforts are warranted to fully understand the underlying mechanisms of resistance and to optimize CD47-targeted therapies through innovative combination approaches,ultimately improving cancer treatment outcomes.Overall,this comprehensive review highlights the significance of CD47 as a promising target for cancer immunotherapy and provides valuable insight into the challenges and opportunities in developing effective CD47-targeted therapies for cancer treatment.
基金supported by the National Natural Science Foundation of China(NSFC)(Grant Nos.81803081,81703050,and 21677102)Shenzhen Basic Research Project(Grant Nos.JCYJ20170303160906960,JCYJ20170307100703967,and JCYJ20160331114230843)+2 种基金the Shenzhen International Cooperation Research Project(Grant No.GJHZ20170313111237888)the Subject Layout Project of Shenzhen Science and Technology Creation Commission(Grant Nos.JCYJ20170818092553608 and JCYJ20160331114230843)the China Shenzhen Peacock Innovation Team Project(Grant No.KQTD20140630100658078)。
文摘Objective:Cancer stem cell is one of the important causes of tumorigenesis as well as a drug target in the treatment of malignant tumor.However,at present,there is no immune vaccine targeting these cells.Octamer-binding transcription factor 4(OCT4),a marker of embryonic stem cells and germ cells,often highly expresses in the early stages of tumorigenesis and is therefore a good candidate for cancer vaccine development.Methods:To identify the optimal carrier and adjuvant combination,we chemically synthesized and linked three different OCT4 epitope antigens to a carrier protein,keyhole limpet hemocyanin(KLH),combined with Toll-like receptor 9 agonist(TLR9).Results:Immunization with OCT4-3+TLR9 produced the strongest immune response in mice.In prevention assays,significant tumor growth inhibition was achieved in BABL/c mice treated with OCT4-3+TLR9(P<0.01).Importantly,the results showed that cytotoxic T lymphocyte activity and the inhibition of tumor growth were enhanced in mice immunized with OCT4-3 combined with TLR9.Meanwhile,multiple cytokines[such as interferon(IFN)-γ(P<0.05),interleukin(IL)-12(P<0.05),IL-2(P<0.01),and IL-6(P<0.05)]promoting cellular immune responses were shown to be greatly enhanced in mice immunized with OCT4-3+TLR9.Moreover,we considered safety considerations in terms of the composition of the vaccines to help facilitate the development of effective next-generation vaccines.Conclusions:Collectively,these experiments demonstrated that combination therapy with TLR9 agonist induced a tumor-specific adaptive immune response,leading to the suppression of primary tumor growth in testis embryonic carcinoma.
基金We are grateful for the funding support for this work from the Leo and Anne Albert Charitable Foundation and the Phi Beta Psi Sorority.We deeply appreciate the invaluable contributions of Dr.Nissi Varki,Director,and Laarni Gapuz,Manager,Moores Cancer Center Histology Core.
文摘Objective:Bone metastasis occurs in up to 90%of men with advanced prostate cancer and leads to fractures,severe pain and therapy-resistance.Bone metastases induce a spectrum of types of bone lesions which can respond differently to therapy even within individual prostate cancer patients.Thus,the special environment of the bone makes the disease more complicated and incurable.A model in which bone lesions are reproducibly induced that mirrors the complexity seen in patients would be invaluable for pre-clinical testing of novel treatments.The microstructural changes in the femurs of mice implanted with PCSD1,a new patient-derived xenograft from a surgical prostate cancer bone metastasis specimen,were determined.Methods:Quantitative micro-computed tomography(micro-CT)and histological analyses were performed to evaluate the effects of direct injection of PCSD1 cells or media alone(Control)into the right femurs of Rag2/gc/male mice.Results:Bone lesions formed only in femurs of mice injected with PCSD1 cells.Bone volume(BV)was significantly decreased at the proximal and distal ends of the femurs(p<0.01)whereas BV(p<0.05)and bone shaft diameter(p<0.01)were significantly increased along the femur shaft.Conclusion:PCSD1 cells reproducibly induced bone loss leading to osteolytic lesions at the ends of the femur,and,in contrast,induced aberrant bone formation leading to osteoblastic lesions along the femur shaft.Therefore,the interaction of PCSD1 cells with different bone region-specific microenvironments specified the type of bone lesion.Our approach can be used to determine if different bone regions support more therapy resistant tumor growth,thus,requiring novel treatments.
文摘OBJECTIVE Pancreatic ductal adenocarcinoma(PDAC),a lethal cancer in need of new,effective therapies,has a unique tumor microenvironment characterized by a dense fibrotic stroma(desmoplasia)that is generated by pancreatic cancer-associated fibroblasts(PCAFs)derived from pancreatic stellate cells(PSCs)and pancreatic fibroblasts(PFs).METHEDS and RESULTS Hypothesizing that G protein-coupled receptors(GPCRs)may regulate PCAFs,we used an unbiased GPCRomic array approach to compare GPCR expression in PCAFs,PFs and PSCs and identified 82 GPCRs commonly expressed by PCAFs derived from primary tumors of five PDAC patients.We discovered that PCAFs have increased expression of numerous GPCRs,in particular a GPCR with much higher expression in PCAFs compared to both PFs and PSCs.Immunohistochemistry revealed increased expression of this GPCR in PDAC tumors.Co-culture of PSCs with PDAC cells or incubation with TNFαinduced its expression.Activation of the GPCR in PCAF sincreased expression of interleukin-6(IL-6)via a cA MP/PKA/CREB signaling pathway.GPCR knockdown with siR NA diminished IL-6 production and secretionby PCAFs and ability of PCAF conditioned media to enhance proliferation of PDAC cells.CONCLUSION We conclude that PDAC cells induce expression by PCAFs of a novel GPCR,resulting in increased IL-6 production by PCAFs and promotion of PDAC cell proliferation.This PCAF-expressed GPCR thus contributes to PDAC cell-PCAF interaction and as such,may be a novel therapeutic target for PDAC tumors.
文摘Objective:Immunotherapy that blocks inhibitory pathways in T lymphocytes,such as the PD-L1/PD-1 axis,is undergoing evaluation for various solid tumors.Notably,this emerging therapeutic approach is already in clinical trials for advanced hepatocellular carcinoma(HCC).
基金funded by the key R&D Project of Hubei Province(Social Development),China(2022BCA018)the Cooperative Innovation Center of Industrial Fermentation(Ministry of Education&Hubei Province),China(2022KF16)to Kanghong Hu.
文摘Objectives:The Kirsten rat sarcoma virus(KRAS)G12D oncogenic mutation poses a significant challenge in treating solid tumors due to the lack of specific and effective therapeutic interventions.This study aims to explore innovative approaches in T cell receptor(TCR)engineering and characterization to target the KRAS G12D7-16 mutation,providing potential strategies for overcoming this therapeutic challenge.Methods:In this innovative study,we engineered and characterized two T cell receptors(TCRs),KDA11-01 and KDA11-02 with high affinity for the KRAS G12D7-16 mutation.These TCRs were isolated from tumor-infiltrating lymphocytes(TILs)derived from tumor tissues of patients with the KRAS G12D mutation.We assessed their specificity and anti-tumor activity in vitro using various cancer cell lines.Results:KDA11-01 and KDA11-02 demonstrated exceptional specificity for the HLA-A*11:01-restricted KRAS G12D7-16 epitope,significantly inducing IFN-γrelease and eliminating tumor cells without cross-reactivity or alloreactivity.Conclusions:The successful development of KDA11-01 and KDA11-02 introduces a novel and precise TCR-based therapeutic strategy against KRAS G12D mutation,showing potential for significant advancements in cancer immunotherapy.
文摘AIM To identify factors associated with Papanicolaou-smear(Pap-smear)cervical cancer screening rates in a safety net population.METHODS From January 2012 to May 2013,the use of Pap-smear was determined for all patients seen at the breast clinic in a safety net hospital.Health literacy assessment was performed using the validated Newest Vital Sign.The records of patients were reviewed to determine if they had undergone Pap-smears for cervical cancer screening.Sociodemographic information was collected included age,education,monthly income,race/ethnicity,employment,insurance status,and primary care provider of the patient.Logistic regression analysis was then performed to determine factors associated with utilization of Papsmears.Crude and adjusted odds ratios derived from multivariate logistic regression models were calculated as well as the associated 95%CIs and P-values.RESULTS Overall,39%had Pap-smears in the prior 15 mo,1377 consecutive women were seen during the study period and their records were reviewed.Significantly more patients with adequate health literacy underwent Papsmears as compared to those with limited health literacy(59%vs 34%,P<0.0001).In multivariate analysis,patients with adequate health literacy,younger patients,and those with later age of first live birth were more likely to undergo Pap-smears.Patients whose primary care providers were gynecologists were also significantly more likely to have Pap-smears compared to other specialties(P<0.0001).Patients younger than 21 years or older than 65 years underwent screening less frequently(11%and 11%,respectively)than those 21-64 years(41%,P<0.0001).Race,ethnicity,language,and insurance status were not associated with Pap-smear screening rates.CONCLUSION Patient health literacy and primary care physician were associated with Pap-smear utilization.Development of interventions to target low health literacy populations could improve cervical cancer screening.
文摘Clustered regulatory interspaced short palindromic repeats(CRISPR)has changed biomedical research and provided entirely new models to analyze every aspect of biomedical sciences during the last decade.In the study of cancer,the CRISPR/CRISPR-associated protein(Cas)system opens new avenues into issues that were once unknown in our knowledge of the non-coding genome,tumor heterogeneity,and precision medicines.CRISPR/Cas-based geneediting technology now allows for the precise and permanent targeting of mutations and provides an opportunity to target small non-coding RNAs such as microRNAs(miRNAs).However,the development of effective and safe cancer gene editing therapy is highly dependent on proper design to be innocuous to normal cells and prevent introducing other abnormalities.This study aims to highlight the cutting-edge approaches in cancer-gene editing therapy based on the CRISPR/Cas technology to target miRNAs in cancer therapy.Furthermore,we highlight the potential challenges in CRISPR/Cas-mediated miRNA gene editing and offer advanced strategies to overcome them.
基金Supported by National Science Centre,Poland,No.2021/43/B/NZ5/03345.
文摘Esophageal squamous cell carcinoma(ESCC)remains a highly aggressive ma-lignancy with limited effective therapeutic options for patients with locally advanced unresectable disease.The study by Wei et al,featured in this issue,highlights the potential of induction chemoimmunotherapy followed by definitive radiotherapy or concurrent chemoradiotherapy to improve treatment outcomes in this challenging patient population.This retrospective analysis of 132 patients demonstrates promising results,including a median progression-free survival of 14.2 months and overall survival of 19.9 months,alongside an acceptable safety profile.Notably,the study identifies the effectiveness of induction therapy and maintenance immunotherapy as key prognostic factors,emphasizing the syner-gistic potential of integrating immune checkpoint inhibitors with radiotherapy.While these findings are encouraging,they require further validation through prospective trials,along with biomarker-based and immune response studies,to refine patient selection and maximize therapeutic benefits.This editorial explores the implications of this research,its impact on clinical practice,and future di-rections for advancing the treatment landscape of ESCC.
文摘DNA damage can, but does not always, induce cell death. While several pathways linking DNA damage signals to mitochondria-dependent and -independent death machineries have been elucidated, the connectivity of these pathways is subject to regulation by multiple other factors that are not well understood. We have proposed two conceptual models to explain the delayed and variable cell death response to DNA damage： integrative surveillance versus autonomous pathways. In this review, we discuss how these two models may explain the in vivo regulation of cell death induced by ionizing radiation （IR） in the developing central nervous system, where the death response is regulated by radiation dose, cell cycle status and neuronal development.
基金This work was supported by National Institutes of Health grants HL125352 and U01AI124316(VN).
文摘Staphylococcus aureus(S.aureus)is a leading human pathogen capable of producing severe invasive infections such as bacteremia,sepsis,and endocarditis with high morbidity and mortality,exacerbated by the increasingly widespread antibiotic resistance exemplified by methicillin-resistant strains(MRSA).S.aureus pathogenesis is fueled by the secretion of toxins—such as the membrane-damaging pore-forming atoxin,which have diverse cellular targets including the epithelium,endothelium,leukocytes,and platelets.Here,we examine the use of human platelet membrane-coated nanoparticles(PNPs)as a biomimetic decoy strategy to neutralize S.aureus toxins and preserve host cell defense functions.The PNPs blocked platelet damage induced by S.aureus secreted toxins,thereby supporting platelet activation and bactericidal activity.Likewise,the PNPs blocked macrophage damage induced by S.aureus secreted toxins,thus supporting macrophage oxidative burst,nitric oxide production,and bactericidal activity,and diminishing MRSA-induced neutrophil extracellular trap release.In a mouse model of MRSA systemic infection,PNP administration reduced bacterial counts in the blood and protected against mortality.Taken together,the results from the present work provide a proof of principle of the therapeutic benefit of PNPs in toxin neutralization,cytoprotection,and increased host resistance to invasive S.aureus infection.
文摘Neuroblastoma (NBL) is one of the most common solid tumors and around 15% of cancer mortality in children. Amplification of the N-Myc proto-oncogene is strongly correlated with advanced disease and poor clinical outcome in NBL. Recent studies described that ubiquitin-specific protease 7 (USP7;also known as HAUSP) interacts with N-Myc, induces deubiquitination and subsequent stabilization of N-Myc that in-turn potentiates N-Myc function, and treatment with the HAUSP inhibitor (P22077) blocked such effects.
基金supported in part by the Intramural Research Program of the National Institute on Agingsupported by the National Cancer Institute(K01 CA234317)+1 种基金the San Diego State University/UC San Diego Comprehensive Cancer Center Partnership(U54 CA132384 and U54 CA132379)the Alzheimer's Disease Resource Center for Minority Aging Research at the University of California San Diego(P30 AG059299)。
文摘Background:There exist few maximal oxygen uptake(VO_(2max))non-exercise-based prediction equations,fewer using machine learning(ML),and none specifically for older adults.Since direct measurement of VO_(2max)is infeasible in large epidemiologic cohort studies,we sought to develop,validate,compare,and assess the transportability of several ML VO_(2max)prediction algorithms.Methods:The Baltimore Longitudinal Study of Aging(BLSA)participants with valid VO2_(max)tests were included(n=1080).Least absolute shrinkage and selection operator,linear-and tree-boosted extreme gradient boosting,random forest,and support vector machine(SVM)algorithms were trained to predict VO_(2max)values.We developed these algorithms for:(a)the overall BLSA,(b)by sex,(c)using all BLSA variables,and(d)variables common in aging cohorts.Finally,we quantified the associations between measured and predicted VO_(2max)and mortality.Results:The age was 69.0±10.4 years(mean±SD)and the measured VO_(2max)was 21.6±5.9 mL/kg/min.Least absolute shrinkage and selection operator,linear-and tree-boosted extreme gradient boosting,random forest,and support vector machine yielded root mean squared errors of 3.4 mL/kg/min,3.6 mL/kg/min,3.4 mL/kg/min,3.6 mL/kg/min,and 3.5 mL/kg/min,respectively.Incremental quartiles of measured VO_(2max)showed an inverse gradient in mortality risk.Predicted VO_(2max)variables yielded similar effect estimates but were not robust to adjustment.Conclusion:Measured VO_(2max)is a strong predictor of mortality.Using ML can improve the accuracy of prediction as compared to simpler approaches but estimates of association with mortality remain sensitive to adjustment.Future studies should seek to reproduce these results so that VO_(2max),an important vital sign,can be more broadly studied as a modifiable target for promoting functional resiliency and healthy aging.
文摘Genotoxic agents or inflammatory cytokines activate cellular stress responses and trigger programmed cell death. We have identified a signal transduction module, including three nuclear proteins that participate in the regulation of cell death induced by chemotherapeutic agents and tumor necrosis factor (TNF). In this nuclear signaling module, retino- blastoma protein (Rb) functions as an inhibitor of apoptotic signal transduction. Inactivation of Rb by phosphorylation or caspase-dependent cleavage/degradation is required for cell death to occur. Rb inhibits the Abl tyrosine kinase. Thus, Rb inactivation is a pre-requisite for Abl activation by DNA damage or TNF. Activation of nuclear Abl and its down- stream effector p73 induces mitochondriadependent cell death. The involvement of these nuclear signal transducers in TNF induced apoptosis, which does not require new gene expression, indicates that nuclear events other than transcrip- tion can contribute to extrinsic apoptotic signal transduction.
文摘Pioneered by a major cancer ge- nome sequencing project [1] and followed by numerous cancer genomic sequencing studies [2-4], the cytosolic isocitrate dehydrogenase （IDH1） gene and mitochondria isocitrate dehydrogenase （1DH2） gene are found to be frequently mutated in low grade gliomas and secondary glioblastoma multiforme （GBM）, acute myeloid leukemia （AML）, and to a much lower frequency in other types of tumors.
