Prostate cancer （PCa） results from a multistep process. This process includes initiation, which occurs through various aging events and multiple insults （such as chronic infection, inflammation and genetic instabil...Prostate cancer （PCa） results from a multistep process. This process includes initiation, which occurs through various aging events and multiple insults （such as chronic infection, inflammation and genetic instability through reactive oxygen species causing DNA double-strand breaks）, followed by a multistep process of progression. These steps include several genetic and epigenetic alterations, as well as alterations to the chromatin structure, which occur in response to the carcinogenic stress-related events that sustain proliferative signaling. Events such as evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis are readily observed. In addition, in conjunction with these critical drivers of carcinogenesis, other factors related to the etiopathogenesis of PCa, involving energy metabolism and evasion of the immune surveillance system, appear to be involved. In addition, when cancer spread and metastasis occur, the ＇tumor microenvironment＇ in the bone of PCa patients may provide a way to sustain dormancy or senescence and eventually establish a ＇seed and soil＇ site where PCa proliferation and growth may occur over time. When PCa is initiated and progression ensues, significant alterations in nuclear size, shape and heterochromatin （DNA transcription） organization are found, and key nuclear transcriptional and structural proteins, as well as multiple nuclear bodies can lead to precancerous and malignant changes. These series of cellular and tissue-related malignancy-associated events can be quantified to assess disease progression and management.展开更多
BACKGROUND The prognosis of gastric cancer continues to remain poor,and epigenetic drugs like histone deacetylase inhibitors(HDACi)have been envisaged as potential therapeutic agents.Nevertheless,clinical trials are f...BACKGROUND The prognosis of gastric cancer continues to remain poor,and epigenetic drugs like histone deacetylase inhibitors(HDACi)have been envisaged as potential therapeutic agents.Nevertheless,clinical trials are facing issues with toxicity and efficacy against solid tumors,which may be partly due to the lack of patient stratification for effective treatments.To study the need of patient stratification before HDACi treatment,and the efficacy of pre-treatment of HDACi as a chemotherapeutic drug sensitizer.METHODS The expression activity of class 1 HDACs and histone acetylation was examined in human gastric cancer cells and tissues.The potential combinatorial regime of HDACi and chemotherapy drugs was defined on the basis of observed drug binding assays,chromatin remodeling and cell death.RESULTS In the present study,the data suggest that the differential increase in HDAC activity and the expression of class 1 HDACs are associated with hypoacetylation of histone proteins in tumors compared to normal adjacent mucosa tissue samples of gastric cancer.The data highlights for the first time that pretreatment of HDACi results in an increased amount of DNA-bound drugs associated with enhanced histone acetylation,chromatin relaxation and cell cycle arrest.Fraction-affected plots and combination index-based analysis show that pre-HDACi chemo drug combinatorial regimes,including valproic acid with cisplatin or oxaliplatin and trichostatin A with epirubicin,exhibit synergism with maximum cytotoxic potential due to higher cell death at low combined doses in gastric cancer cell lines.CONCLUSION Expression or activity of class 1 HDACs among gastric cancer patients present an effective approach for patient stratification.Furthermore,HDACi therapy in pretreatment regimes is more effective with chemotherapy drugs,and may aid in predicting individual patient prognosis.展开更多
Stromal cells provide a crucial microenvironment for overlying epithelium. Here we investigated the expression and function of a stromal cell-specific protein, stromal cell-derived factor-1 （SDF-1）, in normal human ...Stromal cells provide a crucial microenvironment for overlying epithelium. Here we investigated the expression and function of a stromal cell-specific protein, stromal cell-derived factor-1 （SDF-1）, in normal human skin and in the tissues of diseased skin. Immunohistology and laser capture microdissection （LCM）-coupled quantitative real- time RT-PCR revealed that SDF-1 is constitutively and predominantly expressed in dermal stromal cells in nor- mal human skin in vivo. To our surprise, an extremely high level of SDF-1 transcription was observed in the dermis of normal human skin in vivo, evidenced by much higher mRNA expression level than type I collagen, the most abundant and highly expressed protein in human skin. SDF-1 was also upregulated in the tissues of many human skin disorders including psoriasis, basal cell carcinoma （BCC）, and squamous cell carcinoma （SCC）. Double immunostaining for SDF-1 and HSP47 （heat shock protein 47）, a marker of fibroblasts, revealed that fibroblasts were the major source of stroma-cell-derived SDF-1 in both normal and diseased skin. Functionally, SDF-1 activates the ERK （extracellular-signal-regulated kinases） pathway and functions as a mitogen to stimulate epidermalkeratinocyte proliferation. Both overexpression of SDF-1 in dermal fibroblasts and treatment with rhSDF-1 to the skin equivalent cultures significantly increased the number of keratinocyte layers and epidermal thickness. Con- versely, the stimulative function of SDF-1 on keratinocyte proliferation was nearly completely eliminated by inter- fering with CXCR4, a specific receptor of SDF-1, or by knock-down of SDF-1 in fibroblasts. Our data reveal that extremely high levels of SDF-1 provide a crucial microenvironment for epidermal keratinocyte proliferation in both physiologic and pathologic skin conditions.展开更多
The high risk of postoperative mortality in lung adenocarcinoma(LUAD)patients is principally driven by cancer recurrence and low response rates to adjuvant treatment.Here,A combined cohort containing 1,026 stageⅠ-Ⅲp...The high risk of postoperative mortality in lung adenocarcinoma(LUAD)patients is principally driven by cancer recurrence and low response rates to adjuvant treatment.Here,A combined cohort containing 1,026 stageⅠ-Ⅲpatients was divided into the learning(n Z 678)and validation datasets(n Z 348).The former was used to establish a 16-mRNA risk signature for recurrence prediction with multiple statistical algorithms,which was verified in the valida-tion set.Univariate and multivariate analyses confirmed it as an independent indicator for both recurrence-free survival(RFS)and overall survival(OS).Distinct molecular characteristics between the two groups including genomic alterations,and hallmark pathways were compre-hensively analyzed.Remarkably,the classifier was tightly linked to immune infiltrations,high-lighting the critical role of immune surveillance in prolonging survival for LUAD.Moreover,the classifier was a valuable predictor for therapeutic responses in patients,and the low-risk group was more likely to yield clinical benefits from immunotherapy.A transcription factor regulato-ry proteineprotein interaction network(TF-PPI-network)was constructed via weighted gene co-expression network analysis(WGCNA)concerning the hub genes of the signature.The con-structed multidimensional nomogram dramatically increased the predictive accuracy.There-fore,our signature provides a forceful basis for individualized LUAD management with promising potential implications.展开更多
BACKGROUND： The ＂Era of Big Data＂ and ＂Precision Medicine＂ is now upon us. That is, interrogation of large data sets obtained from groups of similar patients or from the patient themselves over time will now hypo...BACKGROUND： The ＂Era of Big Data＂ and ＂Precision Medicine＂ is now upon us. That is, interrogation of large data sets obtained from groups of similar patients or from the patient themselves over time will now hypothetically permit therapies to be designed to provide maximal efficacy with minimal side effects. However, such discoveries depend upon recruitment of very large numbers of subjects （tens of thousands） along with their associated biospecimens and medical records. When considering the establishment of a biobank or the refocusing of an existing repository for the purpose of＂omics＂ research （i.e., genomics, metabolomics, proteomics, microbiomics, etc.） and/or precision medicine, there are a number of considerations to ponder. Each of these facets is discussed. OBJECTIVE： The objective of this review is to describe best practices for the establishment and operations ofa biobank that will be used for omics （genomics, proteomics, metabolomics, microbiomics） analyses based on published literature and our own practical experiences. METHODS： We describe the most commonly described approaches to a variety of biobanking issues, including our own practical experiences over the past 5 years. RESULTS： Based on the particular biobanking situation and downstream application, we have described best practices based on the literature and own experience, taking into consideration ease of application and costs. CONCLUSIONS： The banking of various types of clinical biospecimens has many valuable uses but often depends on overall costs versus sample utility. In addition, specimen flexibility is important but is influenced by the ease or difficulty of the application. It is always preferable to collect and stored a biospecimen in a format that allows for multiple types of downstream analyses, but that often requires additional expertise, equipment and reagents that can increase overall costs. We have described the methodologies most successfully applied to many situations.展开更多
The high recurrence and low responsiveness to immunotherapy make ovarian cancer(OC)the most lethal gynecological malignancy.Tumor microenvironment is critical in risk stratification and the discovery of molecular targ...The high recurrence and low responsiveness to immunotherapy make ovarian cancer(OC)the most lethal gynecological malignancy.Tumor microenvironment is critical in risk stratification and the discovery of molecular targets.We developed a prognostic classification for OC,which could also predict the prognosis of other gynecological cancers including breast cancer,endometrial cancer,and cervical cancer.Somatic mutation,hallmark pathways,and immune landscapes were characterized.Integrative analysis of immune checkpoints and multiple immune signatures revealed the low-risk group responds better to immune checkpoint inhibitors,which was validated by an external immunotherapeutic cohort(IMvigor210).Singlecell RNA sequencing(scRNA-seq)confirmed the high expression of SERPINB1 and SERPINB9 in dendritic cells,and AlphaFold2 was used to infer their 3D protein structures.Putative molecular compounds binding to SERPINB1/SERPINB9 were predicted by virtual screening.展开更多
Chronic exposure to herbicides,weedicides,and pesticides is associated with the onset and progress of neurodegenerative disorders such as Parkinson's disease(PD),Alzheimer's disease(AD),and Amyotrophic Lateral...Chronic exposure to herbicides,weedicides,and pesticides is associated with the onset and progress of neurodegenerative disorders such as Parkinson's disease(PD),Alzheimer's disease(AD),and Amyotrophic Lateral Sclerosis(ALS).Here,we have investigated whether quinic-and chlorogenic-acid-derived Carbon Quantum Dots(QACQDs and ChACQDs,respectively)pro-tect against a(pesticide)paraquat-insult model of PD.Our results indicated that both types of CQDs intervened in the soluble-to-toxic transformation of the amyloid-forming model protein Hen Egg White Lysozyme(HEWL).Furthermore,QACQDs and ChACQDs demonstrated antioxidant activity while remaining biocompatible in a human neuroblastoma-derived cell line(SH-SY5Y)up to 5 mg/ml and protected the cell line from the environmental neurotoxicant(paraquat).Importantly,both CQDs were found to protect dopaminergic neuronal ablation in a paraquat model of Parkinson's disease using the nematode C.elegans.Our results are significant because both plant-derived organic acids cross the blood–brain barrier,making them attractive for developing CQD architectures.Furthermore,since the synthesis of these CQDs was performed using green chemistry methods from precursor acids that cross the BBB,these engineered bionanomaterial platforms are tantalizing candidates for preventing neurodegenerative disorders associated with expo-sure to environmental neurotoxicants.展开更多
基金funded by the Special Research Project for the Non-profit Public Service of the Ministry of Health(Grant 201202022)the National ‘‘Twelfth Five-Year Plan’’ for Science&Technology supported by the Ministry of Science and Technology(Grant 2012BAI01B01)
文摘Prostate cancer （PCa） results from a multistep process. This process includes initiation, which occurs through various aging events and multiple insults （such as chronic infection, inflammation and genetic instability through reactive oxygen species causing DNA double-strand breaks）, followed by a multistep process of progression. These steps include several genetic and epigenetic alterations, as well as alterations to the chromatin structure, which occur in response to the carcinogenic stress-related events that sustain proliferative signaling. Events such as evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis are readily observed. In addition, in conjunction with these critical drivers of carcinogenesis, other factors related to the etiopathogenesis of PCa, involving energy metabolism and evasion of the immune surveillance system, appear to be involved. In addition, when cancer spread and metastasis occur, the ＇tumor microenvironment＇ in the bone of PCa patients may provide a way to sustain dormancy or senescence and eventually establish a ＇seed and soil＇ site where PCa proliferation and growth may occur over time. When PCa is initiated and progression ensues, significant alterations in nuclear size, shape and heterochromatin （DNA transcription） organization are found, and key nuclear transcriptional and structural proteins, as well as multiple nuclear bodies can lead to precancerous and malignant changes. These series of cellular and tissue-related malignancy-associated events can be quantified to assess disease progression and management.
基金Supported by TMH-IRG(account number-466/2012 and 164/2016)LTMT grant for project funding+1 种基金ACTREC-TMC for funding to Gupta labsupported by ACTREC fellowships
文摘BACKGROUND The prognosis of gastric cancer continues to remain poor,and epigenetic drugs like histone deacetylase inhibitors(HDACi)have been envisaged as potential therapeutic agents.Nevertheless,clinical trials are facing issues with toxicity and efficacy against solid tumors,which may be partly due to the lack of patient stratification for effective treatments.To study the need of patient stratification before HDACi treatment,and the efficacy of pre-treatment of HDACi as a chemotherapeutic drug sensitizer.METHODS The expression activity of class 1 HDACs and histone acetylation was examined in human gastric cancer cells and tissues.The potential combinatorial regime of HDACi and chemotherapy drugs was defined on the basis of observed drug binding assays,chromatin remodeling and cell death.RESULTS In the present study,the data suggest that the differential increase in HDAC activity and the expression of class 1 HDACs are associated with hypoacetylation of histone proteins in tumors compared to normal adjacent mucosa tissue samples of gastric cancer.The data highlights for the first time that pretreatment of HDACi results in an increased amount of DNA-bound drugs associated with enhanced histone acetylation,chromatin relaxation and cell cycle arrest.Fraction-affected plots and combination index-based analysis show that pre-HDACi chemo drug combinatorial regimes,including valproic acid with cisplatin or oxaliplatin and trichostatin A with epirubicin,exhibit synergism with maximum cytotoxic potential due to higher cell death at low combined doses in gastric cancer cell lines.CONCLUSION Expression or activity of class 1 HDACs among gastric cancer patients present an effective approach for patient stratification.Furthermore,HDACi therapy in pretreatment regimes is more effective with chemotherapy drugs,and may aid in predicting individual patient prognosis.
文摘Stromal cells provide a crucial microenvironment for overlying epithelium. Here we investigated the expression and function of a stromal cell-specific protein, stromal cell-derived factor-1 （SDF-1）, in normal human skin and in the tissues of diseased skin. Immunohistology and laser capture microdissection （LCM）-coupled quantitative real- time RT-PCR revealed that SDF-1 is constitutively and predominantly expressed in dermal stromal cells in nor- mal human skin in vivo. To our surprise, an extremely high level of SDF-1 transcription was observed in the dermis of normal human skin in vivo, evidenced by much higher mRNA expression level than type I collagen, the most abundant and highly expressed protein in human skin. SDF-1 was also upregulated in the tissues of many human skin disorders including psoriasis, basal cell carcinoma （BCC）, and squamous cell carcinoma （SCC）. Double immunostaining for SDF-1 and HSP47 （heat shock protein 47）, a marker of fibroblasts, revealed that fibroblasts were the major source of stroma-cell-derived SDF-1 in both normal and diseased skin. Functionally, SDF-1 activates the ERK （extracellular-signal-regulated kinases） pathway and functions as a mitogen to stimulate epidermalkeratinocyte proliferation. Both overexpression of SDF-1 in dermal fibroblasts and treatment with rhSDF-1 to the skin equivalent cultures significantly increased the number of keratinocyte layers and epidermal thickness. Con- versely, the stimulative function of SDF-1 on keratinocyte proliferation was nearly completely eliminated by inter- fering with CXCR4, a specific receptor of SDF-1, or by knock-down of SDF-1 in fibroblasts. Our data reveal that extremely high levels of SDF-1 provide a crucial microenvironment for epidermal keratinocyte proliferation in both physiologic and pathologic skin conditions.
文摘The high risk of postoperative mortality in lung adenocarcinoma(LUAD)patients is principally driven by cancer recurrence and low response rates to adjuvant treatment.Here,A combined cohort containing 1,026 stageⅠ-Ⅲpatients was divided into the learning(n Z 678)and validation datasets(n Z 348).The former was used to establish a 16-mRNA risk signature for recurrence prediction with multiple statistical algorithms,which was verified in the valida-tion set.Univariate and multivariate analyses confirmed it as an independent indicator for both recurrence-free survival(RFS)and overall survival(OS).Distinct molecular characteristics between the two groups including genomic alterations,and hallmark pathways were compre-hensively analyzed.Remarkably,the classifier was tightly linked to immune infiltrations,high-lighting the critical role of immune surveillance in prolonging survival for LUAD.Moreover,the classifier was a valuable predictor for therapeutic responses in patients,and the low-risk group was more likely to yield clinical benefits from immunotherapy.A transcription factor regulato-ry proteineprotein interaction network(TF-PPI-network)was constructed via weighted gene co-expression network analysis(WGCNA)concerning the hub genes of the signature.The con-structed multidimensional nomogram dramatically increased the predictive accuracy.There-fore,our signature provides a forceful basis for individualized LUAD management with promising potential implications.
文摘BACKGROUND： The ＂Era of Big Data＂ and ＂Precision Medicine＂ is now upon us. That is, interrogation of large data sets obtained from groups of similar patients or from the patient themselves over time will now hypothetically permit therapies to be designed to provide maximal efficacy with minimal side effects. However, such discoveries depend upon recruitment of very large numbers of subjects （tens of thousands） along with their associated biospecimens and medical records. When considering the establishment of a biobank or the refocusing of an existing repository for the purpose of＂omics＂ research （i.e., genomics, metabolomics, proteomics, microbiomics, etc.） and/or precision medicine, there are a number of considerations to ponder. Each of these facets is discussed. OBJECTIVE： The objective of this review is to describe best practices for the establishment and operations ofa biobank that will be used for omics （genomics, proteomics, metabolomics, microbiomics） analyses based on published literature and our own practical experiences. METHODS： We describe the most commonly described approaches to a variety of biobanking issues, including our own practical experiences over the past 5 years. RESULTS： Based on the particular biobanking situation and downstream application, we have described best practices based on the literature and own experience, taking into consideration ease of application and costs. CONCLUSIONS： The banking of various types of clinical biospecimens has many valuable uses but often depends on overall costs versus sample utility. In addition, specimen flexibility is important but is influenced by the ease or difficulty of the application. It is always preferable to collect and stored a biospecimen in a format that allows for multiple types of downstream analyses, but that often requires additional expertise, equipment and reagents that can increase overall costs. We have described the methodologies most successfully applied to many situations.
基金the China Postdoctoral Science Foundation(No.2022M720896).
文摘The high recurrence and low responsiveness to immunotherapy make ovarian cancer(OC)the most lethal gynecological malignancy.Tumor microenvironment is critical in risk stratification and the discovery of molecular targets.We developed a prognostic classification for OC,which could also predict the prognosis of other gynecological cancers including breast cancer,endometrial cancer,and cervical cancer.Somatic mutation,hallmark pathways,and immune landscapes were characterized.Integrative analysis of immune checkpoints and multiple immune signatures revealed the low-risk group responds better to immune checkpoint inhibitors,which was validated by an external immunotherapeutic cohort(IMvigor210).Singlecell RNA sequencing(scRNA-seq)confirmed the high expression of SERPINB1 and SERPINB9 in dendritic cells,and AlphaFold2 was used to infer their 3D protein structures.Putative molecular compounds binding to SERPINB1/SERPINB9 were predicted by virtual screening.
文摘Chronic exposure to herbicides,weedicides,and pesticides is associated with the onset and progress of neurodegenerative disorders such as Parkinson's disease(PD),Alzheimer's disease(AD),and Amyotrophic Lateral Sclerosis(ALS).Here,we have investigated whether quinic-and chlorogenic-acid-derived Carbon Quantum Dots(QACQDs and ChACQDs,respectively)pro-tect against a(pesticide)paraquat-insult model of PD.Our results indicated that both types of CQDs intervened in the soluble-to-toxic transformation of the amyloid-forming model protein Hen Egg White Lysozyme(HEWL).Furthermore,QACQDs and ChACQDs demonstrated antioxidant activity while remaining biocompatible in a human neuroblastoma-derived cell line(SH-SY5Y)up to 5 mg/ml and protected the cell line from the environmental neurotoxicant(paraquat).Importantly,both CQDs were found to protect dopaminergic neuronal ablation in a paraquat model of Parkinson's disease using the nematode C.elegans.Our results are significant because both plant-derived organic acids cross the blood–brain barrier,making them attractive for developing CQD architectures.Furthermore,since the synthesis of these CQDs was performed using green chemistry methods from precursor acids that cross the BBB,these engineered bionanomaterial platforms are tantalizing candidates for preventing neurodegenerative disorders associated with expo-sure to environmental neurotoxicants.
