A new treatment paradigm for hepatitis C is that the treatment must include an existing direct-acting antiviral agent, namely, a protease inhibitor(PI) combined with PEGylated interferon-a and ribavirin. The currently...A new treatment paradigm for hepatitis C is that the treatment must include an existing direct-acting antiviral agent, namely, a protease inhibitor(PI) combined with PEGylated interferon-a and ribavirin. The currently mar-keted PIs and PIs in clinical trials have different mecha-nisms of action. The development of new PIs aims for an improved safety profile and higher effectiveness. This article reviews NS3/4A protease inhibitors, focusing on major criteria such as their effectiveness and safety. Specific attention is paid to dosing regimens and adverse event profiles of PIs administered in clinical settings.展开更多
<strong>Objective: </strong>The purpose of this study was to observe the factors related to T4 patients who underwent surgery for colorectal cancer (CRC) with peritoneal carcinomatosis. <strong>Metho...<strong>Objective: </strong>The purpose of this study was to observe the factors related to T4 patients who underwent surgery for colorectal cancer (CRC) with peritoneal carcinomatosis. <strong>Methods: </strong>154 T4 colorectal cancer patients who underwent surgery in the first Affiliated Hospital of Sun Yat-sen University were included in the study between August, 1994 and December, 2005. Some clinical variables were selected and statistically correlated with prognosis. <strong>Results:</strong> The overall survival time was 91.7 months at the end of December of 2010 or death. The complete cytoreduction had significant survival benefit than the palliative surgery group. The age, location, histological grade, complete cytoreduction and liver metastasis were associated with overall survival time (OS) according to the univariate analysis (P < 0.05). In addition, Cox multivariate analysis showed that the complete cytoreduction (CCR) and liver metastasis were independent factor influencing survival. <strong>Conclusion:</strong> Compared with palliative surgery, the incomplete cytoreduction fails to improve patient prognosis. Patients performed completed cytoreduction have a relative good prognosis.展开更多
<strong>Objective: </strong>To retrospectively analyze the prognostic differences between LCC and RCC, and to explore the occurrence of such differences in the relevant factors. Provide clinical basis for ...<strong>Objective: </strong>To retrospectively analyze the prognostic differences between LCC and RCC, and to explore the occurrence of such differences in the relevant factors. Provide clinical basis for the individualization and precise treatment of CRC. <strong>Methods: </strong>The clinical and follow-up data of 155 T4 CRC patients who underwent surgery in the first Affiliated Hospital of Sun Yat-sen University between August, 1994 and December, 2005. The age, sex, family history, staging, pathologic features, DFS, OS and other information were collected. The survival of the LCC (Left colon cancer) and RCC (Right colon cancer) patients was analyzed by Kaplan-Meier method. The survival curves of the LCC and RCC patients were compared by log-rank test. <strong>Results: </strong>There are statistically significant differences in N stage, CCR, family history and histological grade between two groups. Gender, histological grade and CCR were factors associated with OS and DFS of the T4 LCC according to the univariate and multivariate analyses. In addition, only the CCR was found to be the factor associated with OS and DFS of the T4 RCC. The mean survival of the patients was 104.23 years (range, 87.32 - 121.15 years) in the T4 RCC and 76.96 years (range, 61.32 - 92.60 years) in the T4 LCC groups. The complete cytoreduction had significant survival benefit than the palliative surgery group. <strong>Conclusion: </strong>The T4 RCC patients with CCR had a relatively better prognosis than LCC. Compared with palliative surgery, the incomplete cytoreduction fails to improve the prognosis of patient.展开更多
BACKGROUND: Viral replication in blood cells with nucleases may lead to the damage of lymphocytes genetic apparatus and the beginning of immunopathological reactions. AIM: Of this investigation is to reveal the damage...BACKGROUND: Viral replication in blood cells with nucleases may lead to the damage of lymphocytes genetic apparatus and the beginning of immunopathological reactions. AIM: Of this investigation is to reveal the damage to peripheral blood lymphocytes (PBL) DNA in the patients with chronic liver diseases. MATERIALS AND METHODS: Sixteen-nine patients with chronic liver diseases (37 patients with chronic viral hepatitis, 2 patients with liver cirrhosis of mixed etiology (alcohol+virus G), 30 women with primary biliary cirrhosis-PBC) were examined. The condition of DNA structure of PBL was measured by the fluorescence analysis of DNA unwinding (FADU) technique with modification. Changes of fluorescence (in %) reflected the DNA distractions degree (the presence of DNA single-stranded breaks and alkalinelabile sights). RESULTS AND CONCLUSION: The quantity of DNA single-stranded breaks and alkalinelabile sights in DNA in all patients with chronic viral hepatitis didn't differ from the control group, excluding the patients with chronic hepatitis (CH) C+G. Patients with HGV and TTV monoinfection had demonstrated the increase of the DNA single-stranded breaks PBL quantity. This fact may be connected with hypothesis about the viruses replication in white blood cells discussed in the literature. Tendency to increase quantity of DNA PBL damages in the patients with primary biliary cirrhosis (PBC) accordingly to the alkaline phosphatase activity increase was revealed. Significant decrease of the DNA single-stranded breaks and alkalinelabile sights in the PBC patients that were treated with prednisone was demonstrated. Probably, the tendency to increase the quantity of DNA single stranded breaks and alkalinelabile sights in lymphocytes of the PBC patients was depended on the surplus of the blood bile acid content.展开更多
Background:The tumor microenvironment plays an essential role in the therapeutic response to immunotherapy.It is necessary to identify immune cell infiltration(ICI)subtypes for evaluating prognosis and therapeutic ben...Background:The tumor microenvironment plays an essential role in the therapeutic response to immunotherapy.It is necessary to identify immune cell infiltration(ICI)subtypes for evaluating prognosis and therapeutic benefits.This study aimed to evaluate the ICI score as an effective prognostic biomarker for immune response.Methods:The cell-type identification by estimating relative subsets of RNA transcripts and the estimation of stromal and immune cells in malignant tumors using expression methods were used to analyse ICI landscapes in 161 colorectal cancer(CRC)samples with patients’clinical and prognostic data,RNA sequencing data,and whole-exome sequencing data from the Sixth Affiliated Hospital,Sun Yat-sen University(Guangzhou,China).Statistical analysis and data processing were conducted to calculate ICI scores,and to analyse the prognosis of CRC patients with different ICI scores and other features.A similar analysis with RNA sequencing and clinical data of colon adenocarcinoma(COAD)samples from The Cancer Genome Atlas(TCGA)database was conducted to confirm the correctness of the findings.Results:The high-ICI score group with a better prognosis(hazard ratio[HR],2.19;95%confidence interval[CI],1.03–4.64;logrank test,P=0.036)was characterized by the increased tumor mutational burden and interleukin-17(IL-17)signaling pathway.Significant differences in the prognosis and the expression levels of immune checkpoints and chemokine marker genes were found between the two ICI score groups.For COAD samples from TCGA,the results also showed a significant difference in patients’prognosis between the two ICI score groups(HR,1.72;95%CI,1.00–2.96;log-rank test,P=0.047).Conclusions:Tumor heterogeneity induced differences in identifying ICI subtypes of CRC patients.The ICI score may serve as an effective biomarker for predicting prognosis,help identify new therapeutic markers for CRC,and develop novel effective immune checkpoint blockade therapies.展开更多
Gastrointestinal microbiome,containing at least 100 trillion bacteria,resides in the mucosal surface of human intestine.Recent studies show that perturbations in the microbiota may influence physiology and link to a n...Gastrointestinal microbiome,containing at least 100 trillion bacteria,resides in the mucosal surface of human intestine.Recent studies show that perturbations in the microbiota may influence physiology and link to a number of diseases,including colon tumorigenesis.Colorectal cancer(CRC),the third most common cancer,is the disease resulting from multi-genes and multi-factors,but the mechanistic details between gut microenvironment and CRC remain poorly characterized.Thanks to new technologies such as metagenome sequencing,progress in large-scale analysis of the genetic and metabolic profile of gut microbial has been possible,which has facilitated studies about microbiota composition,taxonomic alterations and host interactions.Different bacterial species and their metabolites play critical roles in the development of CRC.Also,microbiota is important in the inflammatory response and immune processes deregulation during the development and progression of CRC.This review summarizes current studies regarding the association between gastrointestinalmicrobiota and the development of CRC,which provides insights into the therapeutic strategy of CRC.展开更多
It has been shown that gut microbiota dysbiosis leads to physiological changes and links to a number of diseases,including cancers.Thus,many cancer categories and treatment regimens should be investigated in the conte...It has been shown that gut microbiota dysbiosis leads to physiological changes and links to a number of diseases,including cancers.Thus,many cancer categories and treatment regimens should be investigated in the context of the microbiome.Owing to the availability of metagenome sequencing and multiomics studies,analyses of species characterization,host genetic changes,and metabolic profile of gut microbiota have become feasible,which has facilitated an exponential knowledge gain about microbiota composition,taxonomic alterations,and host interactions during tumorigenesis.However,the complexity of the gut microbiota,with a plethora of uncharacterized host-microbe,microbemicrobe,and environmental interactions,still contributes to the challenge of advancing our knowledge of the microbiota-cancer interactions.These interactions manifest in signaling relay,metabolism,immunity,tumor development,genetic instability,sensitivity to cancer chemotherapy and immunotherapy.This review summarizes current studies/molecular mechanisms regarding the association between the gut microbiota and the development of cancers,which provides insights into the therapeutic strategies that could be harnessed for cancer diagnosis,treatment,or prevention.展开更多
Background:Type Ⅱ diabetes mellitus(DM2)is a significant risk factor for cancers,including breast cancer.However,a proper diabetic breast cancer mouse model is notwell-established for treatment strategy design.Additi...Background:Type Ⅱ diabetes mellitus(DM2)is a significant risk factor for cancers,including breast cancer.However,a proper diabetic breast cancer mouse model is notwell-established for treatment strategy design.Additionally,the precise diabetic signaling pathways that regulate cancer growth remain unresolved.In the present study,we established a suitable mouse model and demonstrated the pathogenic role of diabetes on breast cancer progression.Methods:We successfully generated a transgenic mouse model of human epidermal growth factor receptor 2 positive(Her2^(+) or ERBB2)breast cancer with DM2 by crossing leptin receptor mutant(Lepr^(db/+))mice with (MMTV-ErbB2/neu)mice.Themousemodelswere administrated with antidiabetic drugs to assess the impacts of controlling DM2 in affecting tumor growth.Magnetic resonance spectroscopic imaging was employed to analyze the tumor metabolism.Results:Treatment with metformin/rosiglitazone in MMTV-ErbB2/Lepr^(db/db) mousemodel reduced serum insulin levels,prolonged overall survival,decreased cumulative tumor incidence,and inhibited tumor progression.Anti-insulin resistance medications also inhibited glycolytic metabolism in tumors in vivo as indicated by the reduced metabolic flux of hyperpolarized ^(13)C pyruvate-to-lactate reaction.The tumor cells from MMTV-ErbB2/Lepr^(db/db) transgenic mice treated with metformin had reprogrammed metabolism by reducing levels of both oxygen consumption and lactate production.Metformin decreased the expression of Myc and pyruvate kinase isozyme 2(PKM2),leading to metabolism reprogramming.Moreover,metformin attenuated the mTOR/AKT signaling pathway and altered adipokine profiles.Conclusions:MMTV-ErbB2/Lepr^(db/db) mouse model was able to recapitulate diabetic HER2^(+) human breast cancer.Additionally,our results defined the signaling pathways deregulated in HER2^(+) breast cancer under diabetic condition,which can be intervened by anti-insulin resistance therapy.展开更多
Background:Colorectal cancer(CRC)is one of the most common cancers in China.However,detailed clinical characteristics and survival information are limited.This study aimed to investigate the potential epidemiological ...Background:Colorectal cancer(CRC)is one of the most common cancers in China.However,detailed clinical characteristics and survival information are limited.This study aimed to investigate the potential epidemiological and clinical risk factors affecting the survival of CRC patients in southern China.Methods:Patients with primary CRC between 1994 and 2019 at the First and the Sixth Affiliated Hospitals of Sun Yat-sen University(Guangzhou,China)were included.Clinical characteristics and survival outcomes were collected from medical records.The Kaplan–Meier method was used to estimate overall survival(OS)and progression-free survival(PFS),and Cox’s proportional-hazards regression model was used to estimate hazard ratios and 95%confidence intervals.Results:Of all 13,328 patients,60.1%were men;the mean age was 61.3 years;53.5%had colon cancer.Among all patients,1,864(14.0%)were diagnosed with stage IV disease.The 3-and 5-year OS rates were 79.90%and 71.50%,respectively,whereas the 3-and 5-year PFS rates were 70.30%and 63.90%,respectively.The median OS and PFS times were 189 and 149 months,respectively.Among 13,328 patients,428(14.0%)patients with poor/undifferentiated cancer suffered recurrence.In patients with stageⅢand stageⅣdiseases,the median PFS times of the patients who received chemotherapy were significantly longer than those in patients who had not received chemotherapy(stageⅢ:147 vs 62 months,P<0.001;stageⅣ:14 vs 9.5 months,P<0.001).Conclusions:This retrospective cohort study illustrates the current status of the clinical characteristics of patients with CRC in southern China.Sex,age,family history,location of cancer occurrence,differentiation status,T status,N status,M status,clinical stage,operation,and surgical margin are independent factors associated with the OS of CRC patients.展开更多
Many microorganisms reside in the gastrointestinal tract and the dysbiosis of microorganisms can affect our health.Fungi have a relatively low level of presence(about 0.1%of the totalmicroorganisms)compared with bacte...Many microorganisms reside in the gastrointestinal tract and the dysbiosis of microorganisms can affect our health.Fungi have a relatively low level of presence(about 0.1%of the totalmicroorganisms)compared with bacteria,which makes it easier to underestimate their potential threat to health.However,fungal infections indeed participate in the onset and progression of many intestinal diseases,so they are crucially affecting our health[1,2].Recently,Li et al.described that C-type lectin receptors(CLRs)on myeloid cells,including Dectin-1,Dectin-2,Dectin-3,and Mincle,play an important role in the immune function induced by fungal pathogens of the intestinal microbiota[3].展开更多
Although VEGF-B was discovered as a VEGF-A homolog a long time ago,the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups.Notwithstanding,drugs that inhibit V...Although VEGF-B was discovered as a VEGF-A homolog a long time ago,the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups.Notwithstanding,drugs that inhibit VEGF-B together with other VEGF family members are being used to treat patients with various neovascular diseases.It is therefore critical to have a better understanding of the angiogenic effect of VEGF-B and the underlying mechanisms.Using comprehensive in vitro and in vivo methods and models,we reveal here for the first time an unexpected and surprising function of VEGF-B as an endogenous inhibitor of angiogenesis by inhibiting the FGF2/FGFR1 pathway when the latter is abundantly expressed.Mechanistically,we unveil that VEGF-B binds to FGFR1,induces FGFR1/VEGFR1 complex formation,and suppresses FGF2-induced Erk activation,and inhibits FGF2-driven angiogenesis and tumor growth.Our work uncovers a previously unrecognized novel function of VEGF-B in tethering the FGF2/FGFR1 pathway.Given the anti-angiogenic nature of VEGF-B under conditions of high FGF2/FGFR1 levels,caution is warranted when modulating VEGF-B activity to treat neovascular diseases.展开更多
Background:Diabetes mellitus type 2(DM2)is a modifiable risk factor associated with pancreatic carcinogenesis and tumor progression on the basis of epidemiology studies,but the biological mechanisms are not completely...Background:Diabetes mellitus type 2(DM2)is a modifiable risk factor associated with pancreatic carcinogenesis and tumor progression on the basis of epidemiology studies,but the biological mechanisms are not completely understood.The purpose of this study is to demonstrate direct evidence for the mechanisms mediating these epidemiologic phenomena.Our hypothesis is that DM2 accelerates pancreatic cancer growth and that metformin treatment has a beneficial impact.Methods:To determine the effect of glucose and insulin in pancreatic cancer proliferation,we used conditioned media to mimic DM2 conditions.Also,we studied the effect of anti-diabetic drugs,particularly metformin and rosiglitazone on pancreatic cancer growth.We established orthotopic/syngeneic(Leprdb/db)mouse cancer models to evaluate the effect of diabetes on pancreatic tumor growth and aggressiveness.Results:Our results showed that diabetes promotes pancreatic tumor growth.Furthermore,enhanced tumor growth and aggressiveness(e.g.epithelial-mesenchymal transition)can be explained by functional transcriptomic and metabolomic changes in the mice with diabetes,namely via activation of the AKT/mTOR pathway.Metformin treatment suppressed the diabetes-induced AKT/mTOR pathway activation and tumor growth.The metabolic profile determined by mass spectrum showed important changes of metabolites in the pancreatic cancer derived from diabetic mice treated with metformin.Conclusions:Diabetes mellitus type 2 has critical effects that promote pancreatic cancer progression via transcriptomic and metabolomic changes.Our animal models provide strong evidence for the causal relationship between diabetes and accelerated pancreatic cancers.This study sheds a new insight into the effects of metformin and its potential as part of therapeutic interventions for pancreatic cancer in diabetic patients.展开更多
The “seed and soil” concept has reformed paradigms for cancer treatment in the past decade. Accumulatingevidence indicates that the intimate crosstalk between cancer cells and stromal cells plays a tremendous role i...The “seed and soil” concept has reformed paradigms for cancer treatment in the past decade. Accumulatingevidence indicates that the intimate crosstalk between cancer cells and stromal cells plays a tremendous role intumor progression. Cancer-associated fibroblasts (CAFs), the largest population of stroma cells, influencetherapeutic effects through diverse mechanisms. Herein, we summarize the recent advances in the versatilefunctions of CAFs regarding their heterogeneity, and we mainly discuss the pro-tumorigenic functions of CAFswhich promote tumorigenesis and confer therapeutic resistance to tumors. Targeting CAFs is emerging as one ofthe most appealing strategies in anticancer therapies. The endeavors to target or reprogram the specific subtypesof CAFs provide great cancer treatment opportunities, which may provide a better clinical benefit to cancerpatients.展开更多
Human gut microbiota,containing at least 100 trillion bacteria,resides in the mucosal surface of the human intestine.Each individual is host to a distinct set of at least 160 species in the gut.The collective microbia...Human gut microbiota,containing at least 100 trillion bacteria,resides in the mucosal surface of the human intestine.Each individual is host to a distinct set of at least 160 species in the gut.The collective microbial genome encodes 500 times more genes than the human genome,and so it is tempting to consider human genes as noise in the storm of microbial signals[1].Recent data suggest that,while microbial signals modulate crucial functions of the healthy human body,there are also accumulating data suggesting that many human diseases have their origin in distorted gut microbiota composition[2].展开更多
文摘A new treatment paradigm for hepatitis C is that the treatment must include an existing direct-acting antiviral agent, namely, a protease inhibitor(PI) combined with PEGylated interferon-a and ribavirin. The currently mar-keted PIs and PIs in clinical trials have different mecha-nisms of action. The development of new PIs aims for an improved safety profile and higher effectiveness. This article reviews NS3/4A protease inhibitors, focusing on major criteria such as their effectiveness and safety. Specific attention is paid to dosing regimens and adverse event profiles of PIs administered in clinical settings.
文摘<strong>Objective: </strong>The purpose of this study was to observe the factors related to T4 patients who underwent surgery for colorectal cancer (CRC) with peritoneal carcinomatosis. <strong>Methods: </strong>154 T4 colorectal cancer patients who underwent surgery in the first Affiliated Hospital of Sun Yat-sen University were included in the study between August, 1994 and December, 2005. Some clinical variables were selected and statistically correlated with prognosis. <strong>Results:</strong> The overall survival time was 91.7 months at the end of December of 2010 or death. The complete cytoreduction had significant survival benefit than the palliative surgery group. The age, location, histological grade, complete cytoreduction and liver metastasis were associated with overall survival time (OS) according to the univariate analysis (P < 0.05). In addition, Cox multivariate analysis showed that the complete cytoreduction (CCR) and liver metastasis were independent factor influencing survival. <strong>Conclusion:</strong> Compared with palliative surgery, the incomplete cytoreduction fails to improve patient prognosis. Patients performed completed cytoreduction have a relative good prognosis.
文摘<strong>Objective: </strong>To retrospectively analyze the prognostic differences between LCC and RCC, and to explore the occurrence of such differences in the relevant factors. Provide clinical basis for the individualization and precise treatment of CRC. <strong>Methods: </strong>The clinical and follow-up data of 155 T4 CRC patients who underwent surgery in the first Affiliated Hospital of Sun Yat-sen University between August, 1994 and December, 2005. The age, sex, family history, staging, pathologic features, DFS, OS and other information were collected. The survival of the LCC (Left colon cancer) and RCC (Right colon cancer) patients was analyzed by Kaplan-Meier method. The survival curves of the LCC and RCC patients were compared by log-rank test. <strong>Results: </strong>There are statistically significant differences in N stage, CCR, family history and histological grade between two groups. Gender, histological grade and CCR were factors associated with OS and DFS of the T4 LCC according to the univariate and multivariate analyses. In addition, only the CCR was found to be the factor associated with OS and DFS of the T4 RCC. The mean survival of the patients was 104.23 years (range, 87.32 - 121.15 years) in the T4 RCC and 76.96 years (range, 61.32 - 92.60 years) in the T4 LCC groups. The complete cytoreduction had significant survival benefit than the palliative surgery group. <strong>Conclusion: </strong>The T4 RCC patients with CCR had a relatively better prognosis than LCC. Compared with palliative surgery, the incomplete cytoreduction fails to improve the prognosis of patient.
基金Grant source is the budget of the Central Research Institute of Gastroenterology that was supported by Department of Moscow Public Health.
文摘BACKGROUND: Viral replication in blood cells with nucleases may lead to the damage of lymphocytes genetic apparatus and the beginning of immunopathological reactions. AIM: Of this investigation is to reveal the damage to peripheral blood lymphocytes (PBL) DNA in the patients with chronic liver diseases. MATERIALS AND METHODS: Sixteen-nine patients with chronic liver diseases (37 patients with chronic viral hepatitis, 2 patients with liver cirrhosis of mixed etiology (alcohol+virus G), 30 women with primary biliary cirrhosis-PBC) were examined. The condition of DNA structure of PBL was measured by the fluorescence analysis of DNA unwinding (FADU) technique with modification. Changes of fluorescence (in %) reflected the DNA distractions degree (the presence of DNA single-stranded breaks and alkalinelabile sights). RESULTS AND CONCLUSION: The quantity of DNA single-stranded breaks and alkalinelabile sights in DNA in all patients with chronic viral hepatitis didn't differ from the control group, excluding the patients with chronic hepatitis (CH) C+G. Patients with HGV and TTV monoinfection had demonstrated the increase of the DNA single-stranded breaks PBL quantity. This fact may be connected with hypothesis about the viruses replication in white blood cells discussed in the literature. Tendency to increase quantity of DNA PBL damages in the patients with primary biliary cirrhosis (PBC) accordingly to the alkaline phosphatase activity increase was revealed. Significant decrease of the DNA single-stranded breaks and alkalinelabile sights in the PBC patients that were treated with prednisone was demonstrated. Probably, the tendency to increase the quantity of DNA single stranded breaks and alkalinelabile sights in lymphocytes of the PBC patients was depended on the surplus of the blood bile acid content.
基金approved by the Sixth Affiliated Hospital,Sun Yat-sen University,Guangzhou,China(No.2022ZSLYEC-227)Participants did not need informed consent to partici-pate in the study before taking part in this retrospective study.
文摘Background:The tumor microenvironment plays an essential role in the therapeutic response to immunotherapy.It is necessary to identify immune cell infiltration(ICI)subtypes for evaluating prognosis and therapeutic benefits.This study aimed to evaluate the ICI score as an effective prognostic biomarker for immune response.Methods:The cell-type identification by estimating relative subsets of RNA transcripts and the estimation of stromal and immune cells in malignant tumors using expression methods were used to analyse ICI landscapes in 161 colorectal cancer(CRC)samples with patients’clinical and prognostic data,RNA sequencing data,and whole-exome sequencing data from the Sixth Affiliated Hospital,Sun Yat-sen University(Guangzhou,China).Statistical analysis and data processing were conducted to calculate ICI scores,and to analyse the prognosis of CRC patients with different ICI scores and other features.A similar analysis with RNA sequencing and clinical data of colon adenocarcinoma(COAD)samples from The Cancer Genome Atlas(TCGA)database was conducted to confirm the correctness of the findings.Results:The high-ICI score group with a better prognosis(hazard ratio[HR],2.19;95%confidence interval[CI],1.03–4.64;logrank test,P=0.036)was characterized by the increased tumor mutational burden and interleukin-17(IL-17)signaling pathway.Significant differences in the prognosis and the expression levels of immune checkpoints and chemokine marker genes were found between the two ICI score groups.For COAD samples from TCGA,the results also showed a significant difference in patients’prognosis between the two ICI score groups(HR,1.72;95%CI,1.00–2.96;log-rank test,P=0.047).Conclusions:Tumor heterogeneity induced differences in identifying ICI subtypes of CRC patients.The ICI score may serve as an effective biomarker for predicting prognosis,help identify new therapeutic markers for CRC,and develop novel effective immune checkpoint blockade therapies.
文摘Gastrointestinal microbiome,containing at least 100 trillion bacteria,resides in the mucosal surface of human intestine.Recent studies show that perturbations in the microbiota may influence physiology and link to a number of diseases,including colon tumorigenesis.Colorectal cancer(CRC),the third most common cancer,is the disease resulting from multi-genes and multi-factors,but the mechanistic details between gut microenvironment and CRC remain poorly characterized.Thanks to new technologies such as metagenome sequencing,progress in large-scale analysis of the genetic and metabolic profile of gut microbial has been possible,which has facilitated studies about microbiota composition,taxonomic alterations and host interactions.Different bacterial species and their metabolites play critical roles in the development of CRC.Also,microbiota is important in the inflammatory response and immune processes deregulation during the development and progression of CRC.This review summarizes current studies regarding the association between gastrointestinalmicrobiota and the development of CRC,which provides insights into the therapeutic strategy of CRC.
基金National key research and development program,Grant/Award Numbers:2020YFA0803300,2018YFC0910300National Natural Science Foundation of China,Grant/Award Number:81630072+1 种基金Shenzhen Municipal Government of China,Grant/Award Number:KQTD20170810160226082China Association for Science and Technology,Grant/Award Numbers:2018YFC0910300,2020YFA0803300。
文摘It has been shown that gut microbiota dysbiosis leads to physiological changes and links to a number of diseases,including cancers.Thus,many cancer categories and treatment regimens should be investigated in the context of the microbiome.Owing to the availability of metagenome sequencing and multiomics studies,analyses of species characterization,host genetic changes,and metabolic profile of gut microbiota have become feasible,which has facilitated an exponential knowledge gain about microbiota composition,taxonomic alterations,and host interactions during tumorigenesis.However,the complexity of the gut microbiota,with a plethora of uncharacterized host-microbe,microbemicrobe,and environmental interactions,still contributes to the challenge of advancing our knowledge of the microbiota-cancer interactions.These interactions manifest in signaling relay,metabolism,immunity,tumor development,genetic instability,sensitivity to cancer chemotherapy and immunotherapy.This review summarizes current studies/molecular mechanisms regarding the association between the gut microbiota and the development of cancers,which provides insights into the therapeutic strategies that could be harnessed for cancer diagnosis,treatment,or prevention.
基金Fidelity Foundation,Grant/Award Number:2020YFA0803300Shenzhen Municipal GovernmentNationalNatural Science Foundation of China,Grant/Award Numbers:81702749,81630072,81773098,81803568,8160242.
文摘Background:Type Ⅱ diabetes mellitus(DM2)is a significant risk factor for cancers,including breast cancer.However,a proper diabetic breast cancer mouse model is notwell-established for treatment strategy design.Additionally,the precise diabetic signaling pathways that regulate cancer growth remain unresolved.In the present study,we established a suitable mouse model and demonstrated the pathogenic role of diabetes on breast cancer progression.Methods:We successfully generated a transgenic mouse model of human epidermal growth factor receptor 2 positive(Her2^(+) or ERBB2)breast cancer with DM2 by crossing leptin receptor mutant(Lepr^(db/+))mice with (MMTV-ErbB2/neu)mice.Themousemodelswere administrated with antidiabetic drugs to assess the impacts of controlling DM2 in affecting tumor growth.Magnetic resonance spectroscopic imaging was employed to analyze the tumor metabolism.Results:Treatment with metformin/rosiglitazone in MMTV-ErbB2/Lepr^(db/db) mousemodel reduced serum insulin levels,prolonged overall survival,decreased cumulative tumor incidence,and inhibited tumor progression.Anti-insulin resistance medications also inhibited glycolytic metabolism in tumors in vivo as indicated by the reduced metabolic flux of hyperpolarized ^(13)C pyruvate-to-lactate reaction.The tumor cells from MMTV-ErbB2/Lepr^(db/db) transgenic mice treated with metformin had reprogrammed metabolism by reducing levels of both oxygen consumption and lactate production.Metformin decreased the expression of Myc and pyruvate kinase isozyme 2(PKM2),leading to metabolism reprogramming.Moreover,metformin attenuated the mTOR/AKT signaling pathway and altered adipokine profiles.Conclusions:MMTV-ErbB2/Lepr^(db/db) mouse model was able to recapitulate diabetic HER2^(+) human breast cancer.Additionally,our results defined the signaling pathways deregulated in HER2^(+) breast cancer under diabetic condition,which can be intervened by anti-insulin resistance therapy.
基金supported by the National Natural Science Foundation of China[81773098,82111530099]Guangdong Special Young Talent Plan of Scientific and Technological Innovation[2019TQ05Y510]+2 种基金the Guangdong International Joint Research Program[2020A0505100027]Nature Science Foundation of Guangzhou[202102080387]Guangdong Public Health Project[2021-58]and National Key Clinical Discipline.
文摘Background:Colorectal cancer(CRC)is one of the most common cancers in China.However,detailed clinical characteristics and survival information are limited.This study aimed to investigate the potential epidemiological and clinical risk factors affecting the survival of CRC patients in southern China.Methods:Patients with primary CRC between 1994 and 2019 at the First and the Sixth Affiliated Hospitals of Sun Yat-sen University(Guangzhou,China)were included.Clinical characteristics and survival outcomes were collected from medical records.The Kaplan–Meier method was used to estimate overall survival(OS)and progression-free survival(PFS),and Cox’s proportional-hazards regression model was used to estimate hazard ratios and 95%confidence intervals.Results:Of all 13,328 patients,60.1%were men;the mean age was 61.3 years;53.5%had colon cancer.Among all patients,1,864(14.0%)were diagnosed with stage IV disease.The 3-and 5-year OS rates were 79.90%and 71.50%,respectively,whereas the 3-and 5-year PFS rates were 70.30%and 63.90%,respectively.The median OS and PFS times were 189 and 149 months,respectively.Among 13,328 patients,428(14.0%)patients with poor/undifferentiated cancer suffered recurrence.In patients with stageⅢand stageⅣdiseases,the median PFS times of the patients who received chemotherapy were significantly longer than those in patients who had not received chemotherapy(stageⅢ:147 vs 62 months,P<0.001;stageⅣ:14 vs 9.5 months,P<0.001).Conclusions:This retrospective cohort study illustrates the current status of the clinical characteristics of patients with CRC in southern China.Sex,age,family history,location of cancer occurrence,differentiation status,T status,N status,M status,clinical stage,operation,and surgical margin are independent factors associated with the OS of CRC patients.
文摘Many microorganisms reside in the gastrointestinal tract and the dysbiosis of microorganisms can affect our health.Fungi have a relatively low level of presence(about 0.1%of the totalmicroorganisms)compared with bacteria,which makes it easier to underestimate their potential threat to health.However,fungal infections indeed participate in the onset and progression of many intestinal diseases,so they are crucially affecting our health[1,2].Recently,Li et al.described that C-type lectin receptors(CLRs)on myeloid cells,including Dectin-1,Dectin-2,Dectin-3,and Mincle,play an important role in the immune function induced by fungal pathogens of the intestinal microbiota[3].
基金This study is supported by the State Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,and Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangzhou 510060,P.R.Chinathe National Natural Science Foundation of China(82150710555 and 82220108016 to X.Li,81970823 to Jin Yao and 81830013 to J.O.)+4 种基金a Key Research and Development Plan of Shandong Province(2016GSF201100)the Fundamental Research Funds for the Central Universities(19ykpy151)the long-term structural Methusalem funding by the Flemish Government,Belgiumthe Deutsche Forschungsge-meinschaft(Project No.:394046768-SFB1366)the DZHK partner site Mannheim/Heidelberg to H.F.L.,an ERA PerMed 2020 JTC grant“PROGRESS”.
文摘Although VEGF-B was discovered as a VEGF-A homolog a long time ago,the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups.Notwithstanding,drugs that inhibit VEGF-B together with other VEGF family members are being used to treat patients with various neovascular diseases.It is therefore critical to have a better understanding of the angiogenic effect of VEGF-B and the underlying mechanisms.Using comprehensive in vitro and in vivo methods and models,we reveal here for the first time an unexpected and surprising function of VEGF-B as an endogenous inhibitor of angiogenesis by inhibiting the FGF2/FGFR1 pathway when the latter is abundantly expressed.Mechanistically,we unveil that VEGF-B binds to FGFR1,induces FGFR1/VEGFR1 complex formation,and suppresses FGF2-induced Erk activation,and inhibits FGF2-driven angiogenesis and tumor growth.Our work uncovers a previously unrecognized novel function of VEGF-B in tethering the FGF2/FGFR1 pathway.Given the anti-angiogenic nature of VEGF-B under conditions of high FGF2/FGFR1 levels,caution is warranted when modulating VEGF-B activity to treat neovascular diseases.
基金supported in part by the National Key R&D Program of China[2018YFC0910303]Foundation,Fidelity Foundation,the National Natural Science Foundation of China[81630072]National Key Clinical Discipline.
文摘Background:Diabetes mellitus type 2(DM2)is a modifiable risk factor associated with pancreatic carcinogenesis and tumor progression on the basis of epidemiology studies,but the biological mechanisms are not completely understood.The purpose of this study is to demonstrate direct evidence for the mechanisms mediating these epidemiologic phenomena.Our hypothesis is that DM2 accelerates pancreatic cancer growth and that metformin treatment has a beneficial impact.Methods:To determine the effect of glucose and insulin in pancreatic cancer proliferation,we used conditioned media to mimic DM2 conditions.Also,we studied the effect of anti-diabetic drugs,particularly metformin and rosiglitazone on pancreatic cancer growth.We established orthotopic/syngeneic(Leprdb/db)mouse cancer models to evaluate the effect of diabetes on pancreatic tumor growth and aggressiveness.Results:Our results showed that diabetes promotes pancreatic tumor growth.Furthermore,enhanced tumor growth and aggressiveness(e.g.epithelial-mesenchymal transition)can be explained by functional transcriptomic and metabolomic changes in the mice with diabetes,namely via activation of the AKT/mTOR pathway.Metformin treatment suppressed the diabetes-induced AKT/mTOR pathway activation and tumor growth.The metabolic profile determined by mass spectrum showed important changes of metabolites in the pancreatic cancer derived from diabetic mice treated with metformin.Conclusions:Diabetes mellitus type 2 has critical effects that promote pancreatic cancer progression via transcriptomic and metabolomic changes.Our animal models provide strong evidence for the causal relationship between diabetes and accelerated pancreatic cancers.This study sheds a new insight into the effects of metformin and its potential as part of therapeutic interventions for pancreatic cancer in diabetic patients.
文摘The “seed and soil” concept has reformed paradigms for cancer treatment in the past decade. Accumulatingevidence indicates that the intimate crosstalk between cancer cells and stromal cells plays a tremendous role intumor progression. Cancer-associated fibroblasts (CAFs), the largest population of stroma cells, influencetherapeutic effects through diverse mechanisms. Herein, we summarize the recent advances in the versatilefunctions of CAFs regarding their heterogeneity, and we mainly discuss the pro-tumorigenic functions of CAFswhich promote tumorigenesis and confer therapeutic resistance to tumors. Targeting CAFs is emerging as one ofthe most appealing strategies in anticancer therapies. The endeavors to target or reprogram the specific subtypesof CAFs provide great cancer treatment opportunities, which may provide a better clinical benefit to cancerpatients.
文摘Human gut microbiota,containing at least 100 trillion bacteria,resides in the mucosal surface of the human intestine.Each individual is host to a distinct set of at least 160 species in the gut.The collective microbial genome encodes 500 times more genes than the human genome,and so it is tempting to consider human genes as noise in the storm of microbial signals[1].Recent data suggest that,while microbial signals modulate crucial functions of the healthy human body,there are also accumulating data suggesting that many human diseases have their origin in distorted gut microbiota composition[2].
