BACKGROUND The Warburg effect is common in cancers.Lactate and its receptor GPR81 play an important role in cancer progression.It is widely accepted that membrane receptor nuclear translocation plays some novel role i...BACKGROUND The Warburg effect is common in cancers.Lactate and its receptor GPR81 play an important role in cancer progression.It is widely accepted that membrane receptor nuclear translocation plays some novel role in cancer pathology.The mechanism by which the lactate/GPR81 axis regulates cancer malignancy remains unclear.AIM To elucidate the mechanism of GPR81 nuclear transportation promoted by exogenous lactate.METHODS Lung cancer cells were stimulated with exogenous lactate and GPR81 levels were measured by immunofluoresence and western blot analysis in membrane,cytoplasmic,and nuclear fractions.Lung cancer cells were transduced with a mutant GPR81 nuclear localization signal(NLS)construct,wild type GPR81 or empty vector and used to examine how GPR81 nuclear transportation affects lung cancer cells malignancy in vitro and in vivo.Immunoprecipitation Proteomics analysis and Chromatin immunoprecipitation(ChIP)sequencing were used to determine GPR81 interacting proteins and genes.RESULTS In response to hypoxia/Lactate stimulation,GPR81 translocates and accumulates in the nucleus of lung cancer cells.Functionally,GPR81 nuclear translocation promotes cancer cell proliferation and motility.Depletion of the GPR81 NLS depletes GPR81 nuclear levels and decreases cancer cell growth and invasion in vitro,as well as cancer cell malignancy in vivo.Proteomics analysis revealed a set of proteins including SFPQ,that interact with GPR81 in the cancer cell nucleus.Notably,the interaction of GPR81 with SFPQ promotes cancer cell growth and motility.ChIP sequencing analysis discovered that there is a set of genes targeted by GPR81.CONCLUSION The interaction of GPR81 with SFPQ promotes cancer cell malignancy.GPR81 nuclear translocation is critical in conferring cancer progression and may be a potential therapeutic target for limiting cancer progression.展开更多
The major type of human liver cancer is hepatocellular carcinoma(HCC), and there are currently many risk factors that contribute to this deadly disease. The majority of HCC occurrences are associated with chronic hepa...The major type of human liver cancer is hepatocellular carcinoma(HCC), and there are currently many risk factors that contribute to this deadly disease. The majority of HCC occurrences are associated with chronic hepatitis viral infection, and hepatitis B viral(HBV) infection is currently a major health problem in Eastern Asia. Elucidating the genetic mechanisms associated with HBV-induced HCC has been difficult due to the heterogeneity and genetic complexity associated with this disease. A repertoire of animal models has been broadly used to study the pathophysiology and to develop potential treatment regimens for HBVassociated HCC. The use of these animal models has provided valuable genetic information and has been an important contributor to uncovering the factors involved in liver malignant transformation, invasion and metastasis. Recently, transposon-based mouse models are becoming more widely used in liver cancer research to interrogate the genome by forward genetics and also used to validate genes rapidly in a reverse genetic manner. Importantly, these transposon-based rapid reverse genetic mouse models could become crucial in testing potential therapeutic agents before proceeding to clinical trials in human. Therefore, this review will cover the use of transposon-based mouse models toaddress the problems of liver cancer, especially HBVassociated HCC occurrences in Asia.展开更多
Gene therapy has shown great potential to treat various diseases by repairing the abnormal gene function.However,a great challenge in bringing the nucleic acid formulations to the market is the safe and effective deli...Gene therapy has shown great potential to treat various diseases by repairing the abnormal gene function.However,a great challenge in bringing the nucleic acid formulations to the market is the safe and effective delivery to the specific tissues and cells.To be excited,the development of ionizable drug delivery systems(IDDSs)has promoted a great breakthrough as evidenced by the approval of the BNT162b2 vaccine for prevention of coronavirus disease 2019(COVID-19)in 2021.Compared with conventional cationic gene vectors,IDDSs can decrease the toxicity of carriers to cell membranes,and increase cellular uptake and endosomal escape of nucleic acids by their unique pH-responsive structures.Despite the progress,there remain necessary requirements for designing more efficient IDDSs for precise gene therapy.Herein,we systematically classify the IDDSs and summarize the characteristics and advantages of IDDSs in order to explore the underlying design mechanisms.The delivery mechanisms and therapeutic applications of IDDSs are comprehensively reviewed for the delivery of plasmid DNA(pDNA)and four kinds of RNA.In particular,organ selecting considerations and high-throughput screening are highlighted to explore efficiently multifunctional ionizable nanomaterials with superior gene delivery capacity.We anticipate providing references for researchers to rationally design more efficient and accurate targeted gene delivery systems in the future,and indicate ideas for developing next generation gene vectors.展开更多
The most common approaches to prevent and treat graft-versus-host disease (GVHD) are intended to deplete or suppress the T cells capable of mediating or supporting alloresponses;however, this renders the recipients fu...The most common approaches to prevent and treat graft-versus-host disease (GVHD) are intended to deplete or suppress the T cells capable of mediating or supporting alloresponses;however, this renders the recipients functionally T cell deficient and hence highly susceptible to infections and tumor recurrence. Depletion is often accomplished through the use of broadly reactive antibodies, while functional impairment is typically achieved by pharmacological agents that require long-term administration (usually six months or more), have significant side effects, and may not result in tolerance (i.e., nonresponsiveness) of donor T cells to conditioning regimen-resistant host alloantigen-bearing cells. As our knowledge of immune system homeostasis has increased, cell populations with immune regulatory function have been identified and characterized. Although such cell populations are typically present in low frequencies, methods to isolate and expand these cells have permitted their supplementation to the donor graft or infusion late post-transplant in order to stifle GVHD. This review discusses the biology and preclinical proof of concept of GVHD models, along with GVHD outcomes that focus exclusively on immune regulatory cell therapies that have progressed to clinical testing.展开更多
The androgen receptor(AR)is a member of the steroid receptor family of transcription factors.These ligandregulated transcription factors have C-terminal ligand binding domains with low nanomolar affinities for their c...The androgen receptor(AR)is a member of the steroid receptor family of transcription factors.These ligandregulated transcription factors have C-terminal ligand binding domains with low nanomolar affinities for their cognate steroid ligands.The steroid ligands for AR are the androgens testosterone and dihydrotestosterone(DHT),which are the most abundant sex hormones in the circulation of males.展开更多
Metastasis remains a critical challenge in cancer treatment and the leading cause of cancer-related mortality.Ongoing research has demonstrated the key role of extracellular vesicles(EVs)in facilitating communication ...Metastasis remains a critical challenge in cancer treatment and the leading cause of cancer-related mortality.Ongoing research has demonstrated the key role of extracellular vesicles(EVs)in facilitating communication between distant organs.Cancer cells release a substantial number of EVs that carry distinct cargo molecules,including oncogenic proteins,DNA fragments,and various RNA species.Upon uptake,these cargo molecules profoundly influence the biology of both normal and cancerous cells.This review consolidates the understanding of how EVs promote tumorigenesis by regulating processes such as proliferation,migration,metastasis,angiogenesis,stemness,and immunity.The exploration of EVs as a non-invasive method for cancer detection holds great promise,given that different cancer types exhibit unique protein and RNA signatures that can serve as valuable biomarkers for early diagnosis.Furthermore,growing interest exists in the potential bioengineering EVs for use as prospective therapeutic tools for cancer treatment.展开更多
Ovarian cancer has the highest mortality rate among gynecologic malignancies.The combination of cytoreductive surgery and chemotherapy is the standard regimen for the treatment of ovarian cancer.The initial treatment ...Ovarian cancer has the highest mortality rate among gynecologic malignancies.The combination of cytoreductive surgery and chemotherapy is the standard regimen for the treatment of ovarian cancer.The initial treatment is usually effective,but many patients with ovarian cancer experience recurrence,and treatment options for recurrent disease remain challenging.Cancer stem cells(CSCs)are suggested to play an essential role in cancer recurrence after initial chemotherapy.Furthermore,they are of great interest as CSCs may also be involved in chemotherapy susceptibility.Thus,understanding the characteristics and mechanisms by which CSCs display resistance to therapeutic agents is important to design effective cancer treatments.In this review,we describe and discuss current therapeutic regimens for ovarian cancer,as well as the various CSC markers,association between CSCs and disease progression,correlation of CSCs with poor prognosis,enrichment of CSCs in tumor tissues following repeated chemotherapy cycles,activation of major signaling pathways following chemotherapy,and potential inhibitors that suppress these signaling cascades.In addition,clinical trials evaluating novel targeted therapies to overcome chemotherapy resistance will be reviewed.The combination of traditional chemotherapy and CSC-targeted therapy could be an effective and promising anticancer treatment for ovarian cancer.Understanding the biological properties of CSCs and the mechanism of chemotherapy resistance are critical to design and develop new therapeutic strategies to overcome CSC-associated chemotherapy resistance.展开更多
The anticancer effect of chemotherapy has been historically attributed to directly inducing proliferating cancer cell death.1 Accumulating evidence suggests that chemotherapy also engages the immune system.Some chemot...The anticancer effect of chemotherapy has been historically attributed to directly inducing proliferating cancer cell death.1 Accumulating evidence suggests that chemotherapy also engages the immune system.Some chemotherapies can induce immunogenic cell death,leading to tumor antigen uptake and presentation by dendritic cells to activate tumor-reactive T cells.2 A new study by Wang et al.adds another dimension to this paradigm by demonstrating that chemotherapy pretreatment of cancer cells can directly activate virtual memory(VM)CD8^(+)T cells to mediate tumor cytotoxicity in an antigen-independent manner.展开更多
Liquid biopsies represent an attractive,minimally-invasive alternative to surgical sampling or complex imaging of breast cancer and breast cancer metastasis.Here we present a summary of the major biomarker components ...Liquid biopsies represent an attractive,minimally-invasive alternative to surgical sampling or complex imaging of breast cancer and breast cancer metastasis.Here we present a summary of the major biomarker components often evaluated in liquid biopsy samples from patients with breast cancer,including circulating tumor cells,circulating cell-free tumor DNA,and cancer-associated plasma proteins.We discuss recent advancements in methods of detection and use of these biomarkers in breast cancer.Finally,we highlight some of our own recent contributions to breast cancer liquid biopsy,including the identification and characterization of circulating Cancer Associated Fibroblasts.展开更多
Previous literature has well-established genetic factors as being associated with neuroblastoma(NB).About 1%–2%of NB cases are familial,with 85%of these cases predisposed to mutations in the PHOX2B and ALK genes.The ...Previous literature has well-established genetic factors as being associated with neuroblastoma(NB).About 1%–2%of NB cases are familial,with 85%of these cases predisposed to mutations in the PHOX2B and ALK genes.The genetic basis of sporadic NB has been studied through genome-wide association studies and next-generation sequencing approaches.Particularly,germline variants,as well as copy number variations,confer increased risks of NB,often with effect estimates≥1.5,underscoring the strong genetic contributions to NB.However,the strength of the association varied in non-genetic factors.Some risk factors,such as birth defects,maternal illicit drug use,and early infections,had relatively stronger associations(effect estimates≥1.5 or≤0.67),while some other factors remain inconclusive.This suggests that certain non-genetic factors may play a more prominent role in NB risk,while further research is needed to clarify the impact of others.We synthesized and critically evaluated existing literature on the risk factors of NB to provide an overview,analyze the current state of knowledge,and outline a research path to address the relative contributions of genetic and non-genetic factors in NB.Future epidemiologic studies should incorporate novel methods for measuring genetic and non-genetic factors to comprehensively assess the full extent of factors contributing to NB.Furthermore,the utilization of dried blood spots holds promise to overcome technical and recruitment challenges for future studies.These strategies will contribute to a more holistic understanding of NB etiology and potentially lead to improved prevention strategies.展开更多
Mucosal melanoma(MM)is a rare melanoma that affects the mucous membranes of the gastrointestinal,respiratory,and genitourinary tracts[1].In contrast to cutaneous melanoma(CM),MM occurs in body areas without sun exposu...Mucosal melanoma(MM)is a rare melanoma that affects the mucous membranes of the gastrointestinal,respiratory,and genitourinary tracts[1].In contrast to cutaneous melanoma(CM),MM occurs in body areas without sun exposure and is more difficult to detect,often overlooked until nodal or metastatic involvement[2].The molecular profile of MM is distinct,with a lower mutational burden and higher degree of chromosomal aberrations than CM,potentially affecting treatment strategies[3].Patients with MM typically receive the same immunotherapy as patients with CM and are not candidates for BRAF/MEK inhibition,an option for many patients with CM[1].However,standard-of-care therapies and immune checkpoint inhibitors(ICIs)are associated with poor outcomes in patients with MM[4–6].展开更多
MicroRNAs （miRNAs） are approximately 22-nucleotide-long non-coding RNAs that are important regulators of gene expression in eukaryotes, miRNAs are first transcribed as long primary transcripts, which then undergo a ...MicroRNAs （miRNAs） are approximately 22-nucleotide-long non-coding RNAs that are important regulators of gene expression in eukaryotes, miRNAs are first transcribed as long primary transcripts, which then undergo a series of processing steps to produce the single-stranded mature miRNAs. This article reviews our current knowledge of the mechanism and regulation of mammalian miRNA expression and points out areas of research that may enhance our understanding of how the specificity and efficiency of miRNA pro- duction is controlled in vivo.展开更多
A biological molecule,e.g.,an enzyme,tends to interact with its many cognate substrates,targets,or partners differentially.Such a property is termed relative specificity and has been proposed to regulate important phy...A biological molecule,e.g.,an enzyme,tends to interact with its many cognate substrates,targets,or partners differentially.Such a property is termed relative specificity and has been proposed to regulate important physiological functions,even though it has not been examined explicitly in most complex biochemical systems.This essay reviews several recent large-scale studies that investigate protein folding,signal transduction,RNA binding,translation and transcription in the context of relative specificity.These results and others support a pervasive role of relative specificity in diverse biological processes.It is becoming clear that relative specificity contributes fundamentally to the diversity and complexity of biological systems,which has significant implications in disease processes as well.展开更多
Glioma treatments are faced with challenges, including the inability to fully eliminate cancer stem cells, the immunosuppressive tumor microenvironment, and the blood brain barrier. Although progress has been made wit...Glioma treatments are faced with challenges, including the inability to fully eliminate cancer stem cells, the immunosuppressive tumor microenvironment, and the blood brain barrier. Although progress has been made with surgical, radiation, and chemotherapies, prognosis for patients remains poor. Rapidly emerging immunotherapies may be able to address the challenges that conventional techniques cannot. Immunotherapies manipulate the patient's immune system to selectively combat malignancies. Therapies often work to enhance T-cell and natural killer (NK) cell function, which can both eliminate tumor cells and enhance remission. Vaccines encourage in vivo development of anti-tumor T-cells and NK cells, while adoptive transfer techniques focus on engineering immune cells ex vivo before reintroducing them to patients. Vaccine and adoptive transfer therapies have been shown to induce enhanced immune responses in patients but have not always correlated with improved outcomes, likely because of the tumor immunosuppressive microenvironment. Checkpoint inhibitors can impair these tumor immunosuppressive capabilities. Although no one treatment has been able to consistently eliminate gliomas and maintain remission, combinations of vaccines or adoptive transfer techniques in conjunction with immune checkpoint inhibitors offers promise.展开更多
文摘BACKGROUND The Warburg effect is common in cancers.Lactate and its receptor GPR81 play an important role in cancer progression.It is widely accepted that membrane receptor nuclear translocation plays some novel role in cancer pathology.The mechanism by which the lactate/GPR81 axis regulates cancer malignancy remains unclear.AIM To elucidate the mechanism of GPR81 nuclear transportation promoted by exogenous lactate.METHODS Lung cancer cells were stimulated with exogenous lactate and GPR81 levels were measured by immunofluoresence and western blot analysis in membrane,cytoplasmic,and nuclear fractions.Lung cancer cells were transduced with a mutant GPR81 nuclear localization signal(NLS)construct,wild type GPR81 or empty vector and used to examine how GPR81 nuclear transportation affects lung cancer cells malignancy in vitro and in vivo.Immunoprecipitation Proteomics analysis and Chromatin immunoprecipitation(ChIP)sequencing were used to determine GPR81 interacting proteins and genes.RESULTS In response to hypoxia/Lactate stimulation,GPR81 translocates and accumulates in the nucleus of lung cancer cells.Functionally,GPR81 nuclear translocation promotes cancer cell proliferation and motility.Depletion of the GPR81 NLS depletes GPR81 nuclear levels and decreases cancer cell growth and invasion in vitro,as well as cancer cell malignancy in vivo.Proteomics analysis revealed a set of proteins including SFPQ,that interact with GPR81 in the cancer cell nucleus.Notably,the interaction of GPR81 with SFPQ promotes cancer cell growth and motility.ChIP sequencing analysis discovered that there is a set of genes targeted by GPR81.CONCLUSION The interaction of GPR81 with SFPQ promotes cancer cell malignancy.GPR81 nuclear translocation is critical in conferring cancer progression and may be a potential therapeutic target for limiting cancer progression.
基金Supported by Health Medical Research Fund No.11122171,the Food and Health Bureau,and the Hong Kong SAR Governmentthe Department of Applied Biology and Chemical Technology,The Hong Kong Polytechnic University,Hong Kong SAR(1-ZVAG,G-YBAY,G-UA94 and 1-ZE19)the NIH IMVTP grant No.T32 AI083196-04 to Tschida BR
文摘The major type of human liver cancer is hepatocellular carcinoma(HCC), and there are currently many risk factors that contribute to this deadly disease. The majority of HCC occurrences are associated with chronic hepatitis viral infection, and hepatitis B viral(HBV) infection is currently a major health problem in Eastern Asia. Elucidating the genetic mechanisms associated with HBV-induced HCC has been difficult due to the heterogeneity and genetic complexity associated with this disease. A repertoire of animal models has been broadly used to study the pathophysiology and to develop potential treatment regimens for HBVassociated HCC. The use of these animal models has provided valuable genetic information and has been an important contributor to uncovering the factors involved in liver malignant transformation, invasion and metastasis. Recently, transposon-based mouse models are becoming more widely used in liver cancer research to interrogate the genome by forward genetics and also used to validate genes rapidly in a reverse genetic manner. Importantly, these transposon-based rapid reverse genetic mouse models could become crucial in testing potential therapeutic agents before proceeding to clinical trials in human. Therefore, this review will cover the use of transposon-based mouse models toaddress the problems of liver cancer, especially HBVassociated HCC occurrences in Asia.
文摘Gene therapy has shown great potential to treat various diseases by repairing the abnormal gene function.However,a great challenge in bringing the nucleic acid formulations to the market is the safe and effective delivery to the specific tissues and cells.To be excited,the development of ionizable drug delivery systems(IDDSs)has promoted a great breakthrough as evidenced by the approval of the BNT162b2 vaccine for prevention of coronavirus disease 2019(COVID-19)in 2021.Compared with conventional cationic gene vectors,IDDSs can decrease the toxicity of carriers to cell membranes,and increase cellular uptake and endosomal escape of nucleic acids by their unique pH-responsive structures.Despite the progress,there remain necessary requirements for designing more efficient IDDSs for precise gene therapy.Herein,we systematically classify the IDDSs and summarize the characteristics and advantages of IDDSs in order to explore the underlying design mechanisms.The delivery mechanisms and therapeutic applications of IDDSs are comprehensively reviewed for the delivery of plasmid DNA(pDNA)and four kinds of RNA.In particular,organ selecting considerations and high-throughput screening are highlighted to explore efficiently multifunctional ionizable nanomaterials with superior gene delivery capacity.We anticipate providing references for researchers to rationally design more efficient and accurate targeted gene delivery systems in the future,and indicate ideas for developing next generation gene vectors.
基金supported by grants from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (R37 AI34495)National Heart, Lung, and Blood Institute, National Institutes of Health (R01 HL56067 and R01 HL11879)National Cancer Institute, National Institutes of Health (P01 CA142106 and P01 CA065493)
文摘The most common approaches to prevent and treat graft-versus-host disease (GVHD) are intended to deplete or suppress the T cells capable of mediating or supporting alloresponses;however, this renders the recipients functionally T cell deficient and hence highly susceptible to infections and tumor recurrence. Depletion is often accomplished through the use of broadly reactive antibodies, while functional impairment is typically achieved by pharmacological agents that require long-term administration (usually six months or more), have significant side effects, and may not result in tolerance (i.e., nonresponsiveness) of donor T cells to conditioning regimen-resistant host alloantigen-bearing cells. As our knowledge of immune system homeostasis has increased, cell populations with immune regulatory function have been identified and characterized. Although such cell populations are typically present in low frequencies, methods to isolate and expand these cells have permitted their supplementation to the donor graft or infusion late post-transplant in order to stifle GVHD. This review discusses the biology and preclinical proof of concept of GVHD models, along with GVHD outcomes that focus exclusively on immune regulatory cell therapies that have progressed to clinical testing.
文摘The androgen receptor(AR)is a member of the steroid receptor family of transcription factors.These ligandregulated transcription factors have C-terminal ligand binding domains with low nanomolar affinities for their cognate steroid ligands.The steroid ligands for AR are the androgens testosterone and dihydrotestosterone(DHT),which are the most abundant sex hormones in the circulation of males.
文摘Metastasis remains a critical challenge in cancer treatment and the leading cause of cancer-related mortality.Ongoing research has demonstrated the key role of extracellular vesicles(EVs)in facilitating communication between distant organs.Cancer cells release a substantial number of EVs that carry distinct cargo molecules,including oncogenic proteins,DNA fragments,and various RNA species.Upon uptake,these cargo molecules profoundly influence the biology of both normal and cancerous cells.This review consolidates the understanding of how EVs promote tumorigenesis by regulating processes such as proliferation,migration,metastasis,angiogenesis,stemness,and immunity.The exploration of EVs as a non-invasive method for cancer detection holds great promise,given that different cancer types exhibit unique protein and RNA signatures that can serve as valuable biomarkers for early diagnosis.Furthermore,growing interest exists in the potential bioengineering EVs for use as prospective therapeutic tools for cancer treatment.
基金The work was supported by the Liz Tilberis early career OCRA award,the Marsha Rivkin Ovarian Center pilot award,the WeRoc research grant from Foundation for Women’s Cancer,and the Elsa U.Pardee Foundation(awards to Chefetz I).
文摘Ovarian cancer has the highest mortality rate among gynecologic malignancies.The combination of cytoreductive surgery and chemotherapy is the standard regimen for the treatment of ovarian cancer.The initial treatment is usually effective,but many patients with ovarian cancer experience recurrence,and treatment options for recurrent disease remain challenging.Cancer stem cells(CSCs)are suggested to play an essential role in cancer recurrence after initial chemotherapy.Furthermore,they are of great interest as CSCs may also be involved in chemotherapy susceptibility.Thus,understanding the characteristics and mechanisms by which CSCs display resistance to therapeutic agents is important to design effective cancer treatments.In this review,we describe and discuss current therapeutic regimens for ovarian cancer,as well as the various CSC markers,association between CSCs and disease progression,correlation of CSCs with poor prognosis,enrichment of CSCs in tumor tissues following repeated chemotherapy cycles,activation of major signaling pathways following chemotherapy,and potential inhibitors that suppress these signaling cascades.In addition,clinical trials evaluating novel targeted therapies to overcome chemotherapy resistance will be reviewed.The combination of traditional chemotherapy and CSC-targeted therapy could be an effective and promising anticancer treatment for ovarian cancer.Understanding the biological properties of CSCs and the mechanism of chemotherapy resistance are critical to design and develop new therapeutic strategies to overcome CSC-associated chemotherapy resistance.
文摘The anticancer effect of chemotherapy has been historically attributed to directly inducing proliferating cancer cell death.1 Accumulating evidence suggests that chemotherapy also engages the immune system.Some chemotherapies can induce immunogenic cell death,leading to tumor antigen uptake and presentation by dendritic cells to activate tumor-reactive T cells.2 A new study by Wang et al.adds another dimension to this paradigm by demonstrating that chemotherapy pretreatment of cancer cells can directly activate virtual memory(VM)CD8^(+)T cells to mediate tumor cytotoxicity in an antigen-independent manner.
基金Our work referenced here was supported by funding from the Breast Cancer Research Foundation(BCRF16098),and by the Prevent Cancer Foundation(M1601095).
文摘Liquid biopsies represent an attractive,minimally-invasive alternative to surgical sampling or complex imaging of breast cancer and breast cancer metastasis.Here we present a summary of the major biomarker components often evaluated in liquid biopsy samples from patients with breast cancer,including circulating tumor cells,circulating cell-free tumor DNA,and cancer-associated plasma proteins.We discuss recent advancements in methods of detection and use of these biomarkers in breast cancer.Finally,we highlight some of our own recent contributions to breast cancer liquid biopsy,including the identification and characterization of circulating Cancer Associated Fibroblasts.
基金Children’s Cancer Research Fund(Minneapolis,MN)provided fellowship support for Eun Mi Jung’s training
文摘Previous literature has well-established genetic factors as being associated with neuroblastoma(NB).About 1%–2%of NB cases are familial,with 85%of these cases predisposed to mutations in the PHOX2B and ALK genes.The genetic basis of sporadic NB has been studied through genome-wide association studies and next-generation sequencing approaches.Particularly,germline variants,as well as copy number variations,confer increased risks of NB,often with effect estimates≥1.5,underscoring the strong genetic contributions to NB.However,the strength of the association varied in non-genetic factors.Some risk factors,such as birth defects,maternal illicit drug use,and early infections,had relatively stronger associations(effect estimates≥1.5 or≤0.67),while some other factors remain inconclusive.This suggests that certain non-genetic factors may play a more prominent role in NB risk,while further research is needed to clarify the impact of others.We synthesized and critically evaluated existing literature on the risk factors of NB to provide an overview,analyze the current state of knowledge,and outline a research path to address the relative contributions of genetic and non-genetic factors in NB.Future epidemiologic studies should incorporate novel methods for measuring genetic and non-genetic factors to comprehensively assess the full extent of factors contributing to NB.Furthermore,the utilization of dried blood spots holds promise to overcome technical and recruitment challenges for future studies.These strategies will contribute to a more holistic understanding of NB etiology and potentially lead to improved prevention strategies.
基金This study was sponsored by Iovance Biotherapeutics,Inc.(San Carlos,CA,USA).
文摘Mucosal melanoma(MM)is a rare melanoma that affects the mucous membranes of the gastrointestinal,respiratory,and genitourinary tracts[1].In contrast to cutaneous melanoma(CM),MM occurs in body areas without sun exposure and is more difficult to detect,often overlooked until nodal or metastatic involvement[2].The molecular profile of MM is distinct,with a lower mutational burden and higher degree of chromosomal aberrations than CM,potentially affecting treatment strategies[3].Patients with MM typically receive the same immunotherapy as patients with CM and are not candidates for BRAF/MEK inhibition,an option for many patients with CM[1].However,standard-of-care therapies and immune checkpoint inhibitors(ICIs)are associated with poor outcomes in patients with MM[4–6].
基金the support of the American Heart Association(Grant No. 0835471N)
文摘MicroRNAs （miRNAs） are approximately 22-nucleotide-long non-coding RNAs that are important regulators of gene expression in eukaryotes, miRNAs are first transcribed as long primary transcripts, which then undergo a series of processing steps to produce the single-stranded mature miRNAs. This article reviews our current knowledge of the mechanism and regulation of mammalian miRNA expression and points out areas of research that may enhance our understanding of how the specificity and efficiency of miRNA pro- duction is controlled in vivo.
基金partly supported by the National Institutes of Health(Grant Nos.5P50-DA011806-12 and R01DA031202)
文摘A biological molecule,e.g.,an enzyme,tends to interact with its many cognate substrates,targets,or partners differentially.Such a property is termed relative specificity and has been proposed to regulate important physiological functions,even though it has not been examined explicitly in most complex biochemical systems.This essay reviews several recent large-scale studies that investigate protein folding,signal transduction,RNA binding,translation and transcription in the context of relative specificity.These results and others support a pervasive role of relative specificity in diverse biological processes.It is becoming clear that relative specificity contributes fundamentally to the diversity and complexity of biological systems,which has significant implications in disease processes as well.
文摘Glioma treatments are faced with challenges, including the inability to fully eliminate cancer stem cells, the immunosuppressive tumor microenvironment, and the blood brain barrier. Although progress has been made with surgical, radiation, and chemotherapies, prognosis for patients remains poor. Rapidly emerging immunotherapies may be able to address the challenges that conventional techniques cannot. Immunotherapies manipulate the patient's immune system to selectively combat malignancies. Therapies often work to enhance T-cell and natural killer (NK) cell function, which can both eliminate tumor cells and enhance remission. Vaccines encourage in vivo development of anti-tumor T-cells and NK cells, while adoptive transfer techniques focus on engineering immune cells ex vivo before reintroducing them to patients. Vaccine and adoptive transfer therapies have been shown to induce enhanced immune responses in patients but have not always correlated with improved outcomes, likely because of the tumor immunosuppressive microenvironment. Checkpoint inhibitors can impair these tumor immunosuppressive capabilities. Although no one treatment has been able to consistently eliminate gliomas and maintain remission, combinations of vaccines or adoptive transfer techniques in conjunction with immune checkpoint inhibitors offers promise.
