The human intestinal microbiome plays a major role in human health and diseases, including colorectal cancer. Colorectal carcinogenesis represents a heterogeneous process with a differing set of somatic molecular alte...The human intestinal microbiome plays a major role in human health and diseases, including colorectal cancer. Colorectal carcinogenesis represents a heterogeneous process with a differing set of somatic molecular alterations, influenced by diet, environmental and microbial exposures, and host immunity. Fusobacterium species are part of the human oral and intestinal microbiota. Metagenomic analyses have shown an enrichment of Fusobacterium nucleatum(F. nucleatum) in colorectal carcinoma tissue. Using 511 colorectal carcinomas from Japanese patients, we assessed the presence of F. nucleatum. Our results showed that the frequency of F. nucleatum positivity in the Japanese colorectal cancer was 8.6%(44/511), which was lower than that in United States cohort studies(13%). Similar to the United States studies, F. nucleatum positivityin Japanese colorectal cancers was significantly associated with microsatellite instability(MSI)-high status. Regarding the immune response in colorectal cancer, high levels of infiltrating T-cell subsets(i.e., CD3+, CD8+, CD45RO+, and FOXP3+ cells) have been associated with better patient prognosis. There is also evidence to indicate that molecular features of colorectal cancer, especially MSI, influence T-cell-mediated adaptive immunity. Concerning the association between the gut microbiome and immunity, F. nucleatum has been shown to expand myeloid-derived immune cells, which inhibit T-cell proliferation and induce T-cell apoptosis in colorectal cancer. This finding indicates that F. nucleatum possesses immunosuppressive activities by inhibiting human T-cell responses. Certain micro RNAs are induced during the macrophage inflammatory response and have the ability to regulate host-cell responses to pathogens. Micro RNA-21 increases the levels of IL-10 and prostaglandin E2, which suppress antitumor T-cell-mediated adaptive immunity through the inhibition of the antigen-presenting capacities of dendritic cells and T-cell proliferation in colorectal cancer cells. Thus, emerging evidence may provide insights for strategies to target microbiota, immune cells and tumor molecular alterations for colorectal cancer prevention and treatment. Further investigation is needed to clarify the association of Fusobacterium with T-cells and micro RNA expressions in colorectal cancer.展开更多
Gastric cancer(GC)is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide.There is an increasing understanding of the roles that genetic and epigenetic alterations...Gastric cancer(GC)is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide.There is an increasing understanding of the roles that genetic and epigenetic alterations play in GCs.Recent studies using nextgeneration sequencing(NGS)have revealed a number of potential cancer-driving genes in GC.Whole-exome sequencing of GC has identified recurrent somatic mutations in the chromatin remodeling gene ARID1A and alterations in the cell adhesion gene FAT4,a member of the cadherin gene family.Mutations in chromatin remodeling genes(ARID1A,MLL3 and MLL)have been found in 47%of GCs.Whole-genome sequencing and whole-transcriptome sequencing analyses have also discovered novel alterations in GC.Recent studies of cancer epigenetics have revealed widespread alterations in genes involved in the epigenetic machinery,such as DNA methylation,histone modifications,nucleosome positioning,noncoding RNAs and microRNAs.Recent advances in molecular research on GC have resulted in the introduction of new diagnostic and therapeutic strategies into clinical settings.The antihuman epidermal growth receptor 2(HER2)antibody trastuzumab has led to an era of personalized therapy in GC.In addition,ramucirumab,a monoclonal antibody targeting vascular endothelial growth factor receptor(VEGFR)-2,is the first biological treatment that showed survival benefits as a single-agent therapy in patients with advanced GC who progressed after firstline chemotherapy.Using NGS to systematically identify gene alterations in GC is a promising approach with remarkable potential for investigating the pathogenesis of GC and identifying novel therapeutic targets,as well as useful biomarkers.In this review,we will summarize the recent advances in the understanding of the molecular pathogenesis of GC,focusing on the potential use of these genetic and epigenetic alterations as diagnostic biomarkers and novel therapeutic targets.展开更多
Obesity-associated cancers, including colon cancer and breast cancer, are increasing in Asian countries with Westernized lifestyles as exemplified by reduced physical activity and increased fat/sugar consumption. An e...Obesity-associated cancers, including colon cancer and breast cancer, are increasing in Asian countries with Westernized lifestyles as exemplified by reduced physical activity and increased fat/sugar consumption. An excessive accumulation of visceral adipose tissue causes insulin resistance, dyslipidemia and adipocytokine imbalance, and these factors are suggested to be involved in cancer promotion. To prevent obesityassociated cancers, researcher attention is increasing on the so-called "functional foods". In addition, new approaches to cancer control are in high demand, and using "functional foods" as supplemental or adjuvant agents in chemotherapy is thought to be a promising approach. One of these functional ingredients is xanthophylls, which are natural fat-soluble pigments found in fruits, vegetables, algae and other plants. Xanthophylls belong to the carotenoid class and have struc-tures containing oxygen. Some studies have revealed that xanthophylls improve the inflammation status, serum triglyceride levels, blood pressure levels and liver function test values. Furthermore, recent studies show that xanthophylls possess high anti-cancer, antidiabetic, anti-obesity and anti-oxidant properties. In this review, we highlight the recent findings for five xanthophylls, namely astaxanthin, β-cryptoxanthin, fucoxanthin, neoxanthin and zeaxanthin/lutein, and their relevance to cancer prevention.展开更多
There is an increasing understanding of the roles that microsatellite instability (MSI) plays in Lynch syndrome (by mutations) and sporadic (by mainly epigenetic changes) gastrointestinal (GI) and other cancers. Defic...There is an increasing understanding of the roles that microsatellite instability (MSI) plays in Lynch syndrome (by mutations) and sporadic (by mainly epigenetic changes) gastrointestinal (GI) and other cancers. Deficient DNA mismatch repair (MMR) results in the strong mutator phenotype known as MSI, which is the hallmark of cancers arising within Lynch syndrome. MSI is characterized by length alterations within simple repeated sequences called microsatellites. Lynch syndrome occurs primarily because of germline mutations in one of the MMR genes, mainly MLH1 or MSH2 , less frequently MSH6 , and rarely PMS2 . MSI is also observed in about 15% of sporadic colorectal, gastric, and endometrial cancers and in lower frequencies in a minority of other cancers where it is often associated with the hypermethylation of the MLH1 gene. miRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level and are critical in many biological processes and cellular pathways. There is accumulating evidence to support the notion that the interrelationship between MSI and miRNA plays a key role in the pathogenesis of GI cancer. As a possible new mechanism underlying MSI, overexpression of miR-155 has been shown to downregulate expression of MLH1, MSH2, and MSH6. Thus, a subset of MSI-positive (MSI+) cancers without known MMR defects may result from miR-155 overexpression. Target genes of frameshift mutation for MSI are involved in various cellular functions, such as DNA repair, cell signaling, and apoptosis. A novel class of target genes that included not only epigenetic modifier genes, such as HDAC2 , but also miRNA processing machinery genes, including TARBP2 and XPO5 , were found to be mutated in MSI+ GI cancers. Thus, a subset of MSI+ colorectal cancers (CRCs) has been proposed to exhibit a mutated miRNA machinery phenotype. Genetic, epigenetic, and transcriptomic differences exist between MSI+ and MSI cancers. Molecular signatures of miRNA expression apparently have the potential to distinguish between MSI+ and MSI CRCs. In this review, we summarize recent advances in the MSI pathogenesis of GI cancer, with the focus on its relationship with miRNA as well as on the potential to use MSI and related alterations as biomarkers and novel therapeutic targets.展开更多
AIM:To investigate human epidermal growth factor receptor 2(HER2)-phosphatidylinositol 3-kinase(PI3K)-vAkt murine thymoma viral oncogene homolog signaling pathway.METHODS:We analyzed 231 formalin-fixed,paraffinembedde...AIM:To investigate human epidermal growth factor receptor 2(HER2)-phosphatidylinositol 3-kinase(PI3K)-vAkt murine thymoma viral oncogene homolog signaling pathway.METHODS:We analyzed 231 formalin-fixed,paraffinembedded gastric cancer tissue specimens from Japanese patients who had undergone surgical treatment.The patients' age,sex,tumor location,depth of invasion,pathological type,lymph node metastasis,and pathological stage were determined by a review of the medical records.Expression of HER2 was analyzed by immunohistochemistry(IHC) using the HercepTest TM kit.Standard criteria for HER2 positivity(0,1+,2+,and 3+) were used.Tumors that scored 3+ were considered HER2-positive.Expression of phospho Akt(pAkt) was also analyzed by IHC.Tumors were considered pAkt-positive when the percentage of positive tumor cells was 10% or more.PI3K,catalytic,alpha polypeptide(PIK3CA) mutations in exons 1,9 and 20 were analyzed by pyrosequencing.Epstein-Barr virus(EBV) infection was analyzed by in situ hybridization targeting EBV-encoded small RNA(EBER) with an EBER-RNA probe.Microsatellite instability(MSI) was analyzed by polymerase chain reaction using the mononucleotide markers BAT25 and BAT26.RESULTS:HER2 expression levels of 0,1+,2+ and 3+ were found in 167(72%),32(14%),12(5%) and 20(8.7%) samples,respectively.HER2 overexpression(IHC 3+) significantly correlated with intestinal histological type(15/20 vs 98 /205,P = 0.05).PIK3CA mutations were present in 20 cases(8.7%) and significantly correlated with MSI(10/20 vs 9/211,P < 0.01).The mutation frequency was high(21%) in T4 cancers and very low(6%) in T2 cancers.Mutations in exons 1,9 and 20 were detected in 5(2%),9(4%) and 7(3%) cases,respectively.Two new types of PIK3CA mutation,R88Q and R108H,were found in exon1.All PIK3CA mutations were heterozygous missense singlebase substitutions,the most common being H1047R(6/20,30%) in exon20.Eighteen cancers(8%) were EBV-positive and this positivity significantly correlated with a diffuse histological type(13/18 vs 93/198,P = 0.04).There were 7 cases of lymphoepithelioma-like carcinomas(LELC) and 6 of those cases were EBV-positive(percent/EBV:6/18,33%;percent/all LELC:6/7,86%).pAkt expression was positive in 119(53%) cases but showed no correlation with clinicopathological characteristics.pAkt expression was significantly correlated with HER2 overexpression(16/20 vs 103/211,P < 0.01) but not with PIK3CA mutations(12/20 vs 107/211,P = 0.37) or EBV infection(8/18 vs 103/211,P = 0.69).The frequency of pAkt expression was higher in cancers with exon20 mutations(100%) than in those with exon1(40%) or exon9(56%) mutations.One case showed both HER2 overexpression and EBV infection and 3 cases showed both PIK3CA mutations and EBV infection.However,no cases showed both PIK3CA mutations and HER2 overexpression.One EBVpositive cancer with PIK3CA mutation(H1047R) was MSI-positive.Three of these 4 cases were positive for pAkt expression.In survival analysis,pAkt expression significantly correlated with a poor prognosis(hazard ratio 1.75;95%CI:1.12-2.80,P = 0.02).CONCLUSION:HER2 expression,PIK3CA mutations and EBV infection in gastric cancer were characterized.pAkt expression significantly correlates with HER2 expression and with a poor prognosis.展开更多
OBJECTIVE: Deoxyelephantopin, a sesquiterpene lactone from Elephantopus scaber, showed inhibition of the growth of various tumor cells in vitro. In the present study, we investigated the cytotoxicity and apoptosis-in...OBJECTIVE: Deoxyelephantopin, a sesquiterpene lactone from Elephantopus scaber, showed inhibition of the growth of various tumor cells in vitro. In the present study, we investigated the cytotoxicity and apoptosis-inducing capacity of deoxyelephantopin on lung adenocarcinoma (A549) cells. METHODS: The cytotoxic effect of deoxyelephantopin on A549 cells and normal lymphocytes was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and 50% inhibitory concentration (IC50) value was determined. The self-renewal and proliferating potential of A549 cells after treatment with deoxyelephantopin were examined by colony formation assay. Cellular morphology of deoxyelephantopin-treated cells was observed using phase- contrast microscopy. The induction of apoptosis was evaluated using acddine orange and ethidium bromide staining, Hoechst 33342 staining, terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end-labeling (TUNEL) assay, DNA fragmentation analysis and Annexin V-fluorescein isothiocyanate staining by flow cytometry. Activation of caspases was detected using fluorogenic substrate specific to caspases 2, 3, 8 and 9 and flow cytometric analysis. The total cellular DNA content and expression of cleaved poly (ADP-ribose) polymerase was also analyzed. RESULTS: Deoxyelephantopin exhibited cytotoxicity to A549 cells (IC50 = 12.287 μg/mL), however, there was no toxicity towards normal human lymphocytes. Deoxyelephantopin suppressed the colony-forming ability of A549 cells in a dose-dependent manner. Acridine orange, ethidium bromide and Hoechst 33342 staining showed cell shrinkage, chromosomal condensation and nuclear fragmentation, indicating induction of apoptosis. Deoxyelephantopin increased apoptosis of A549 cells, as evidenced by more TUNEL-positive cells. DNA fragmentation and Annexin V staining revealed late-stage apoptotic cell population. Deoxyelephantopin inhibited A549 cell growth by cell cycle arrest at G2/M phase and induced apoptosis through both extrinsic and intrinsic pathways. CONCLUSION: These results suggest that deoxyelephantopin has great potential as a new chemotherapeutic agent to be developed further for the treatment of lung cancer.展开更多
AIM: To investigate the long-term consequences of chemotherapy-related HBV reactivation in patients with lymphoma.METHODS: This study was based on the database of published prospective study evaluating HBV reactivatio...AIM: To investigate the long-term consequences of chemotherapy-related HBV reactivation in patients with lymphoma.METHODS: This study was based on the database of published prospective study evaluating HBV reactivation in HBV lymphoma patients during chemotherapy.Deteriorated liver reserve (DLR) was defined as development of either one of the following conditions during follow-up: (1) newly onset parenchyma liver disease, splenomegaly or ascites without evidence of lymphoma involvement; (2) decrease of the ratio (albumin/globulin ratio) to less than 0.8 or increase of the ratio of INR of prothrombin time to larger than 1.2 without evidence of malnutrition or infection. Liver cirrhosis was diagnosed by imaging studies.RESULTS: A total of 49 patients were included. The median follow-up was 6.2 years (range, 3.9-8.1 years).There were 31 patients with and 18 patients without HBV reactivation. Although there was no difference of overall survival (OS) and chemotherapy response rate between the two groups, DLR developed more frequently in patients with HBV reactivation (48.4% vs 16.7%; P= 0.0342). Among the HBV reactivators, HBV genotype C was associated with a higher risk of developing DLR (P = 0.0768) and liver cirrhosis (P = 0.003). Four of five patients with sustained high titer of HBV DNA and two of three patients with multiple HBV reactivation developed DLR. Further, patients with a sustained high titer of HBV DNA had the shortest OS among the HBV reactivators (P= 0.0000). No patients in the non-HBV reactivation group developed hepatic failure or liver cirrhosis.CONCLUSION: Chemotherapy-related HBV reactivation is associated with the long-term effect of deterioration of hepatic function.展开更多
AIM: A high percentage of early-stage high-grade gastric mucosa-associated lymphoid tissue (MALT) lymphomas remain Helicobacter pylori(H pylori)-dependent. However,unlike their low-grade counterparts, high-grade gastr...AIM: A high percentage of early-stage high-grade gastric mucosa-associated lymphoid tissue (MALT) lymphomas remain Helicobacter pylori(H pylori)-dependent. However,unlike their low-grade counterparts, high-grade gastric MALT lymphomas may progress rapidly if unresponsive to H pylori eradication. It is mandatory to identify markers that may predict the H pylori-dependent status of these tumors. Proliferation of MALT lymphoma cells depends on cognate help and cell-to-cell contact of H pylori-specific intratumoral T-cells. To examine whether the expression of co-stimulatory marker CD86 (B7.2) and the infiltration of CD56 (+) natural killer (NK) cells can be useful markers to predict Hpylori-dependent status of high-grade gastric MALT lymphoma.METHODS: Lymphoma biopsies from 26 patients who had participated in a prospective study of H pylori-eradication for stage IE high-grade gastric MALT lymphomas were evaluated. Tumors that resolved to Wotherspoon grade Ⅱ or less after H pylorieradication were classified as H pyloridependent; others were classified as H pylori-independent.The infiltration of NK cells and the expression of CD86 in pre-treatment paraffin-embedded lymphoma tissues were determined by immunohistochemistry.RESULTS: There were 16 H pylori-dependent and 10H pylori-independent cases. CD86 expression was detected in 11 (68.8%) of 16 Hpyiori-dependent cases but in none of 10 Hpylori-independent cases (P = 0.001).H pylori-dependent high-grade gastric MALT lymphomas contained significantly higher numbers of CD56 (+) NK cells than H pylori-independent cases (2.8±1.4% vs 1.1±0.8%; P = 0.003). CD86 positive MALT lymphomas also showed significantly increased infiltration of CD56 (+)NK cells compared to CD86-negative cases (2.9±1.1% vs1.4±1.3%; P= 0.005).CONCLUSION: These results suggest that the expression of co-stimulatory marker CD86 and the increased infiltration of NK cells are associated with H pylori-dependent state of early-stage high-grade gastric MALT lymphomas.展开更多
Acute myeloid leukemia (AML) is a phenotypically heterogeneous disorder. The M4 subtype of AML is frequently associated with the cytogenetic marker inversion 16 and/or the presence of eosinophilia. Blast crisis is the...Acute myeloid leukemia (AML) is a phenotypically heterogeneous disorder. The M4 subtype of AML is frequently associated with the cytogenetic marker inversion 16 and/or the presence of eosinophilia. Blast crisis is the aggressive phase of the triphasic chronic myeloid leukemia (CML), which is a disease with Philadelphia (Ph) chromosome as the major abnormality. In the present study, we report a 76-year-old patient suspected of having AML with eosinophilic differentiation (AML-M4), which in clinical tests resembles CML blast crisis with multiple chromosomal abnormalities. Isochromosome 21 [i(21)(q10)] was the most recurrent feature noted in metaphases with 46 chromosomes. Ring chromosome, tetraploid endoreduplication, recurrent aneuploid clones with loss of X chromosome, monosomy 17, monosomy 7, and structural variation translocation (9;14) were also observed in this patient. Fluorescent in situ hybridization (FISH) confirmed the absence of Ph chromosome. This report shows how cytogenetic analyses revealed atypical structural aberrations in the M4 subtype of AML.展开更多
AIM:To investigate insulin-like growth factor 2(IGF2)differentially methylated region(DMR)0 hypomethylation in relation to clinicopathological and molecular features in colorectal serrated lesions.METHODS:To accuratel...AIM:To investigate insulin-like growth factor 2(IGF2)differentially methylated region(DMR)0 hypomethylation in relation to clinicopathological and molecular features in colorectal serrated lesions.METHODS:To accurately analyze the association between the histological types and molecular features of each type of serrated lesion,we consecutively collected1386 formalin-fixed paraffin-embedded tissue specimens that comprised all histological types[hyperplastic polyps(HPs,n=121),sessile serrated adenomas(SSAs,n=132),traditional serrated adenomas(TSAs,n=111),non-serrated adenomas(n=195),and colorectal cancers(n=827)].We evaluated the methylation levels of IGF2 DMR0 and long interspersed nucleotide element-1(LINE-1)in HPs(n=115),SSAs(n=120),SSAs with cytological dysplasia(n=10),TSAs(n=91),TSAs with high-grade dysplasia(HGD)(n=15),non-serrated adenomas(n=80),non-serrated adenomas with HGD(n=105),and CRCs(n=794).For the accurate quantification of the relative methylation levels(scale 0%-100%)of IGF2 DMR0 and LINE-1,we used bisulfite pyrosequencing method.Tumor specimens were analyzed for microsatellite instability,KRAS(codons 12 and 13),BRAF(V600E),and PIK3CA(exons 9and 20)mutations;MLH1 and MGMT methylation;and IGF2 expression by immunohistochemistry.RESULTS:The distribution of the IGF2 DMR0 methylation level in 351 serrated lesions and 185 non-serrated adenomas(with or without HGD)was as follows:mean61.7,median 62.5,SD 18.0,range 5.0-99.0,interquartile range 49.5-74.4.The IGF2 DMR0 methylation level was divided into quartiles(Q1≥74.5,Q2 62.6-74.4,Q3 49.6-62.5,Q4≤49.5)for further analysis.With regard to the histological type,the IGF2 DMR0 methylation levels of SSAs(mean±SD,73.1±12.3)were significantly higher than those of HPs(61.9±20.5),TSAs(61.6±19.6),and non-serrated adenomas(59.0±15.8)(P<0.0001).The IGF2 DMR0 methylation level was inversely correlated with the IGF2 expression level(r=-0.21,P=0.0051).IGF2 DMR0 hypomethylation was less frequently detected in SSAs compared with HPs,TSAs,and non-serrated adenomas(P<0.0001).Multivariate logistic regression analysis also showed that IGF2 DMR0 hypomethylation was inversely associated with SSAs(P<0.0001).The methylation levels of IGF2 DMR0 and LINE-1 in TSAs with HGD(50.2±18.7and 55.7±5.4,respectively)were significantly lower than those in TSAs(61.6±19.6 and 58.8±4.7,respectively)(IGF2 DMR0,P=0.038;LINE-1,P=0.024).CONCLUSION:IGF2 DMR0 hypomethylation may be an infrequent epigenetic alteration in the SSA pathway.Hypomethylation of IGF2 DMR0 and LINE-1 may play a role in TSA pathway progression.展开更多
AIM To assess dietary myo-inositol in reducing stem cell activation in colitis,and validate pβ-cateninS^(552) as a biomarker of recurrent dysplasia.METHODS We examined the effects of dietary myo-inositol treatment on...AIM To assess dietary myo-inositol in reducing stem cell activation in colitis,and validate pβ-cateninS^(552) as a biomarker of recurrent dysplasia.METHODS We examined the effects of dietary myo-inositol treatment on inflammation,pβ-cateninS^(552) and p Akt levels by histology and western blot in IL-10-/-and dextran sodium sulfate-treated colitic mice. Additionally,we assessed nuclear pβ-cateninS^(552) in patients treated with myo-inositol in a clinical trial,and in patients with and without a history of colitis-induced dysplasia.RESULTS In mice,pβ-cateninS^(552) staining faithfully reported the effects of myo-inositol in reducing inflammation and intestinal stem cell activation. In a pilot clinical trial of myo-inositol administration in patients with a history of low grade dysplasia(LGD),two patients had reduced numbers of intestinal stem cell activation compared to the placebo control patient. In humans,pβ-cateninS^(552) staining discriminated ulcerative colitis patients with a history of LGD from those with benign disease.CONCLUSION Enumerating crypts with increased numbers of pβ-cateninS^(552)-positive cells can be utilized as a biomarker in colitis-associated cancer chemoprevention trials.展开更多
Background:Aberrant activation of anaplastic lymphoma kinase(ALK)signaling has been found to be involved in the tumorigenesis of multiple types of cancer.The aim of this study was to determine the role of this pathway...Background:Aberrant activation of anaplastic lymphoma kinase(ALK)signaling has been found to be involved in the tumorigenesis of multiple types of cancer.The aim of this study was to determine the role of this pathway in the pathogenesis of breast cancer.Methods:An ALK pathway signature that we generated previously was used to compute the ALK pathway activity in 6381 breast cancer samples from 42 microarray datasets,and the associations between ALK pathway signature score and clinical variables were examined using logistic regression and survival analyses.Results:Our results indicated that high ALK pathway activity was a significant risk factor for hormone receptor-negative,high-grade breast cancer in the 42 datasets.ALK pathway activity was positively associated with pathological complete response(pCR)in 15 datasets annotated with patient’s neoadjuvant chemotherapy response information(overall odds ratio=1.67,P<0.01),and this association was more significant in HER2-negative and grade 1&2 tumors than in HER2-positive and grade 3 tumors.ALK pathway activity was also positively associated with recurrence risk in breast cancer patients from 30 datasets annotated with survival information(overall hazard ratio=1.21,P<0.01),particularly in patients with age>50 years old,with positive lymph nodes,or with residual disease after neoadjuvant chemotherapy.Conclusions:ALK may be involved in breast cancer tumorigenesis,and ALK pathway signature score may serve as a prognostic biomarker for breast cancer.展开更多
The control of cell proliferation is an essential feature in development and tissue homeostasis and is prominently deregulated in tumors.Three publications in Nature now uncover the mechanism underlying the degradatio...The control of cell proliferation is an essential feature in development and tissue homeostasis and is prominently deregulated in tumors.Three publications in Nature now uncover the mechanism underlying the degradation of cyclin D1-3 and provide important insights for the targeted therapy of the cancer cell cycle.展开更多
Dear Editor,The molecular pathogenesis of estrogen receptor(ER)-negative,especially triple-negative breast cancer(TNBC),is unclear,thus,the treatment of these types of cancers is still a great challenge[1].Chemotherap...Dear Editor,The molecular pathogenesis of estrogen receptor(ER)-negative,especially triple-negative breast cancer(TNBC),is unclear,thus,the treatment of these types of cancers is still a great challenge[1].Chemotherapy remains the primary adjuvant treatment choice for TNBC patients[2],but a large number of these tumors are resistant to chemotherapy and relapse ormetastasize quickly after adjuvant therapy[3].展开更多
Objective: To define the prevalence, pattern, and clinical course of arthritis presenting at the time of diagnosis of Kawasaki disease. Study design: A single-center, retrospective study of 414 consecutive patients di...Objective: To define the prevalence, pattern, and clinical course of arthritis presenting at the time of diagnosis of Kawasaki disease. Study design: A single-center, retrospective study of 414 consecutive patients diagnosed with Kawasaki disease between January 1997 and December 2002 was performed. Standardized clinical assessments, laboratory and imaging test results, and treatment regimens were reviewed. The clinical, laboratory, treatment response,and coronary outcome data were analyzed for children with and without arthritis. Results: The prevalence of arthritis was 7.5%(31/414). In the 31 children with arthritis,55%had oligoarticular involvement and 45%had polyarticular involvement. In both of these groups, the large joints were predominantly involved. Some 88%of the children with arthritis responded to standard intravenous immunoglobulin therapy for acute Kawasaki disease and did not require additional medications. The children with arthritis had significantly increased levels of inflammatory markers, but their demographical and clinical features were otherwise similar to those of the children without arthritis, including coronary outcome, with the same proportion(13%) of children from each group having coronaryartery lesions (z-score ≥2.5). Conclusions: Arthritisis a short-lived phenomenon included in the clinical spectrum of acute Kawasaki disease. Children with arthritis have evidence of increased systemic inflammation but otherwise share the same clinical features, response to treatment, and coronary outcomes as patients without arthritis.Most cases of arthritis resolve without additional therapeutic intervention.展开更多
Ribosome biogenesis and protein synthesis are fundamental rate-limiting steps for cell growth and proliferation.The ribosomal proteins(RPs),comprising the structural parts of the ribosome,are essential for ribosome as...Ribosome biogenesis and protein synthesis are fundamental rate-limiting steps for cell growth and proliferation.The ribosomal proteins(RPs),comprising the structural parts of the ribosome,are essential for ribosome assembly and function.In addition to their canonical ribosomal functions,multiple RPs have extra-ribosomal functions including activation of p53-dependent or p53-independent pathways in response to stress,resulting in cell cycle arrest and apoptosis.Defects in ribosome biogenesis,translation,and the functions of individual RPs,including mutations in RPs have been linked to a diverse range of human congenital disorders termed ribosomopathies.Ribosomopathies are characterized by tissue-specific phenotypic abnormalities and higher cancer risk later in life.Recent discoveries of somatic mutations in RPs in multiple tumor types reinforce the connections between ribosomal defects and cancer.In this article,we review the most recent advances in understanding the molecular consequences of RP mutations and ribosomal defects in ribosomopathies and cancer.We particularly discuss the molecular basis of the transition from hypo-to hyper-proliferation in ribosomopathies with elevated cancer risk,a paradox termed"Dameshek's riddle."Furthermore,we review the current treatments for ribosomopathies and prospective therapies targeting ribosomal defects.We also highlight recent advances in ribosome stress-based cancer therapeutics.Importantly,insights into the mechanisms of resistance to therapies targeting ribosome biogenesis bring new perspectives into the molecular basis of cancer susceptibility in ribosomopathies and new clinical implications for cancer therapy.展开更多
基金Supported by Japanese Society of Gastroenterology Research Foundation(to Nosho K)Pancreas Research Foundation of Japan(to Nosho K)+4 种基金Medical Research Encouragement Prize of The Japan Medical Association(to Nosho K)The Japan Society for the Promotion of Science Challenging Exploratory Researchgrant No.25670371(to Shinomura Y)Ono Cancer Research Foundation(to Ito M)
文摘The human intestinal microbiome plays a major role in human health and diseases, including colorectal cancer. Colorectal carcinogenesis represents a heterogeneous process with a differing set of somatic molecular alterations, influenced by diet, environmental and microbial exposures, and host immunity. Fusobacterium species are part of the human oral and intestinal microbiota. Metagenomic analyses have shown an enrichment of Fusobacterium nucleatum(F. nucleatum) in colorectal carcinoma tissue. Using 511 colorectal carcinomas from Japanese patients, we assessed the presence of F. nucleatum. Our results showed that the frequency of F. nucleatum positivity in the Japanese colorectal cancer was 8.6%(44/511), which was lower than that in United States cohort studies(13%). Similar to the United States studies, F. nucleatum positivityin Japanese colorectal cancers was significantly associated with microsatellite instability(MSI)-high status. Regarding the immune response in colorectal cancer, high levels of infiltrating T-cell subsets(i.e., CD3+, CD8+, CD45RO+, and FOXP3+ cells) have been associated with better patient prognosis. There is also evidence to indicate that molecular features of colorectal cancer, especially MSI, influence T-cell-mediated adaptive immunity. Concerning the association between the gut microbiome and immunity, F. nucleatum has been shown to expand myeloid-derived immune cells, which inhibit T-cell proliferation and induce T-cell apoptosis in colorectal cancer. This finding indicates that F. nucleatum possesses immunosuppressive activities by inhibiting human T-cell responses. Certain micro RNAs are induced during the macrophage inflammatory response and have the ability to regulate host-cell responses to pathogens. Micro RNA-21 increases the levels of IL-10 and prostaglandin E2, which suppress antitumor T-cell-mediated adaptive immunity through the inhibition of the antigen-presenting capacities of dendritic cells and T-cell proliferation in colorectal cancer cells. Thus, emerging evidence may provide insights for strategies to target microbiota, immune cells and tumor molecular alterations for colorectal cancer prevention and treatment. Further investigation is needed to clarify the association of Fusobacterium with T-cells and micro RNA expressions in colorectal cancer.
基金Supported by Grants-in-Aid for Scientific Research from the Ministry of Education,Culture,Sports,Science and Technology of Japan
文摘Gastric cancer(GC)is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide.There is an increasing understanding of the roles that genetic and epigenetic alterations play in GCs.Recent studies using nextgeneration sequencing(NGS)have revealed a number of potential cancer-driving genes in GC.Whole-exome sequencing of GC has identified recurrent somatic mutations in the chromatin remodeling gene ARID1A and alterations in the cell adhesion gene FAT4,a member of the cadherin gene family.Mutations in chromatin remodeling genes(ARID1A,MLL3 and MLL)have been found in 47%of GCs.Whole-genome sequencing and whole-transcriptome sequencing analyses have also discovered novel alterations in GC.Recent studies of cancer epigenetics have revealed widespread alterations in genes involved in the epigenetic machinery,such as DNA methylation,histone modifications,nucleosome positioning,noncoding RNAs and microRNAs.Recent advances in molecular research on GC have resulted in the introduction of new diagnostic and therapeutic strategies into clinical settings.The antihuman epidermal growth receptor 2(HER2)antibody trastuzumab has led to an era of personalized therapy in GC.In addition,ramucirumab,a monoclonal antibody targeting vascular endothelial growth factor receptor(VEGFR)-2,is the first biological treatment that showed survival benefits as a single-agent therapy in patients with advanced GC who progressed after firstline chemotherapy.Using NGS to systematically identify gene alterations in GC is a promising approach with remarkable potential for investigating the pathogenesis of GC and identifying novel therapeutic targets,as well as useful biomarkers.In this review,we will summarize the recent advances in the understanding of the molecular pathogenesis of GC,focusing on the potential use of these genetic and epigenetic alterations as diagnostic biomarkers and novel therapeutic targets.
基金Supported by National Cancer Center Research and Development Fund No.25-A-15The Research Grant of the Princess Takamatsu Cancer Research Fund
文摘Obesity-associated cancers, including colon cancer and breast cancer, are increasing in Asian countries with Westernized lifestyles as exemplified by reduced physical activity and increased fat/sugar consumption. An excessive accumulation of visceral adipose tissue causes insulin resistance, dyslipidemia and adipocytokine imbalance, and these factors are suggested to be involved in cancer promotion. To prevent obesityassociated cancers, researcher attention is increasing on the so-called "functional foods". In addition, new approaches to cancer control are in high demand, and using "functional foods" as supplemental or adjuvant agents in chemotherapy is thought to be a promising approach. One of these functional ingredients is xanthophylls, which are natural fat-soluble pigments found in fruits, vegetables, algae and other plants. Xanthophylls belong to the carotenoid class and have struc-tures containing oxygen. Some studies have revealed that xanthophylls improve the inflammation status, serum triglyceride levels, blood pressure levels and liver function test values. Furthermore, recent studies show that xanthophylls possess high anti-cancer, antidiabetic, anti-obesity and anti-oxidant properties. In this review, we highlight the recent findings for five xanthophylls, namely astaxanthin, β-cryptoxanthin, fucoxanthin, neoxanthin and zeaxanthin/lutein, and their relevance to cancer prevention.
基金Supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan
文摘There is an increasing understanding of the roles that microsatellite instability (MSI) plays in Lynch syndrome (by mutations) and sporadic (by mainly epigenetic changes) gastrointestinal (GI) and other cancers. Deficient DNA mismatch repair (MMR) results in the strong mutator phenotype known as MSI, which is the hallmark of cancers arising within Lynch syndrome. MSI is characterized by length alterations within simple repeated sequences called microsatellites. Lynch syndrome occurs primarily because of germline mutations in one of the MMR genes, mainly MLH1 or MSH2 , less frequently MSH6 , and rarely PMS2 . MSI is also observed in about 15% of sporadic colorectal, gastric, and endometrial cancers and in lower frequencies in a minority of other cancers where it is often associated with the hypermethylation of the MLH1 gene. miRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level and are critical in many biological processes and cellular pathways. There is accumulating evidence to support the notion that the interrelationship between MSI and miRNA plays a key role in the pathogenesis of GI cancer. As a possible new mechanism underlying MSI, overexpression of miR-155 has been shown to downregulate expression of MLH1, MSH2, and MSH6. Thus, a subset of MSI-positive (MSI+) cancers without known MMR defects may result from miR-155 overexpression. Target genes of frameshift mutation for MSI are involved in various cellular functions, such as DNA repair, cell signaling, and apoptosis. A novel class of target genes that included not only epigenetic modifier genes, such as HDAC2 , but also miRNA processing machinery genes, including TARBP2 and XPO5 , were found to be mutated in MSI+ GI cancers. Thus, a subset of MSI+ colorectal cancers (CRCs) has been proposed to exhibit a mutated miRNA machinery phenotype. Genetic, epigenetic, and transcriptomic differences exist between MSI+ and MSI cancers. Molecular signatures of miRNA expression apparently have the potential to distinguish between MSI+ and MSI CRCs. In this review, we summarize recent advances in the MSI pathogenesis of GI cancer, with the focus on its relationship with miRNA as well as on the potential to use MSI and related alterations as biomarkers and novel therapeutic targets.
基金Supported by Grants-in-Aid for Scientific Research from the Ministry of Education,Culture,Sports,Science and Technology of Japan,to Yamamoto H and Shinomura Y
文摘AIM:To investigate human epidermal growth factor receptor 2(HER2)-phosphatidylinositol 3-kinase(PI3K)-vAkt murine thymoma viral oncogene homolog signaling pathway.METHODS:We analyzed 231 formalin-fixed,paraffinembedded gastric cancer tissue specimens from Japanese patients who had undergone surgical treatment.The patients' age,sex,tumor location,depth of invasion,pathological type,lymph node metastasis,and pathological stage were determined by a review of the medical records.Expression of HER2 was analyzed by immunohistochemistry(IHC) using the HercepTest TM kit.Standard criteria for HER2 positivity(0,1+,2+,and 3+) were used.Tumors that scored 3+ were considered HER2-positive.Expression of phospho Akt(pAkt) was also analyzed by IHC.Tumors were considered pAkt-positive when the percentage of positive tumor cells was 10% or more.PI3K,catalytic,alpha polypeptide(PIK3CA) mutations in exons 1,9 and 20 were analyzed by pyrosequencing.Epstein-Barr virus(EBV) infection was analyzed by in situ hybridization targeting EBV-encoded small RNA(EBER) with an EBER-RNA probe.Microsatellite instability(MSI) was analyzed by polymerase chain reaction using the mononucleotide markers BAT25 and BAT26.RESULTS:HER2 expression levels of 0,1+,2+ and 3+ were found in 167(72%),32(14%),12(5%) and 20(8.7%) samples,respectively.HER2 overexpression(IHC 3+) significantly correlated with intestinal histological type(15/20 vs 98 /205,P = 0.05).PIK3CA mutations were present in 20 cases(8.7%) and significantly correlated with MSI(10/20 vs 9/211,P < 0.01).The mutation frequency was high(21%) in T4 cancers and very low(6%) in T2 cancers.Mutations in exons 1,9 and 20 were detected in 5(2%),9(4%) and 7(3%) cases,respectively.Two new types of PIK3CA mutation,R88Q and R108H,were found in exon1.All PIK3CA mutations were heterozygous missense singlebase substitutions,the most common being H1047R(6/20,30%) in exon20.Eighteen cancers(8%) were EBV-positive and this positivity significantly correlated with a diffuse histological type(13/18 vs 93/198,P = 0.04).There were 7 cases of lymphoepithelioma-like carcinomas(LELC) and 6 of those cases were EBV-positive(percent/EBV:6/18,33%;percent/all LELC:6/7,86%).pAkt expression was positive in 119(53%) cases but showed no correlation with clinicopathological characteristics.pAkt expression was significantly correlated with HER2 overexpression(16/20 vs 103/211,P < 0.01) but not with PIK3CA mutations(12/20 vs 107/211,P = 0.37) or EBV infection(8/18 vs 103/211,P = 0.69).The frequency of pAkt expression was higher in cancers with exon20 mutations(100%) than in those with exon1(40%) or exon9(56%) mutations.One case showed both HER2 overexpression and EBV infection and 3 cases showed both PIK3CA mutations and EBV infection.However,no cases showed both PIK3CA mutations and HER2 overexpression.One EBVpositive cancer with PIK3CA mutation(H1047R) was MSI-positive.Three of these 4 cases were positive for pAkt expression.In survival analysis,pAkt expression significantly correlated with a poor prognosis(hazard ratio 1.75;95%CI:1.12-2.80,P = 0.02).CONCLUSION:HER2 expression,PIK3CA mutations and EBV infection in gastric cancer were characterized.pAkt expression significantly correlates with HER2 expression and with a poor prognosis.
基金Kerala State Council for Science Technology and Environment (KSCSTE) and University Grant Commission for financial support
文摘OBJECTIVE: Deoxyelephantopin, a sesquiterpene lactone from Elephantopus scaber, showed inhibition of the growth of various tumor cells in vitro. In the present study, we investigated the cytotoxicity and apoptosis-inducing capacity of deoxyelephantopin on lung adenocarcinoma (A549) cells. METHODS: The cytotoxic effect of deoxyelephantopin on A549 cells and normal lymphocytes was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and 50% inhibitory concentration (IC50) value was determined. The self-renewal and proliferating potential of A549 cells after treatment with deoxyelephantopin were examined by colony formation assay. Cellular morphology of deoxyelephantopin-treated cells was observed using phase- contrast microscopy. The induction of apoptosis was evaluated using acddine orange and ethidium bromide staining, Hoechst 33342 staining, terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end-labeling (TUNEL) assay, DNA fragmentation analysis and Annexin V-fluorescein isothiocyanate staining by flow cytometry. Activation of caspases was detected using fluorogenic substrate specific to caspases 2, 3, 8 and 9 and flow cytometric analysis. The total cellular DNA content and expression of cleaved poly (ADP-ribose) polymerase was also analyzed. RESULTS: Deoxyelephantopin exhibited cytotoxicity to A549 cells (IC50 = 12.287 μg/mL), however, there was no toxicity towards normal human lymphocytes. Deoxyelephantopin suppressed the colony-forming ability of A549 cells in a dose-dependent manner. Acridine orange, ethidium bromide and Hoechst 33342 staining showed cell shrinkage, chromosomal condensation and nuclear fragmentation, indicating induction of apoptosis. Deoxyelephantopin increased apoptosis of A549 cells, as evidenced by more TUNEL-positive cells. DNA fragmentation and Annexin V staining revealed late-stage apoptotic cell population. Deoxyelephantopin inhibited A549 cell growth by cell cycle arrest at G2/M phase and induced apoptosis through both extrinsic and intrinsic pathways. CONCLUSION: These results suggest that deoxyelephantopin has great potential as a new chemotherapeutic agent to be developed further for the treatment of lung cancer.
基金Supported by the National Health Research Institute, Taiwan, China
文摘AIM: To investigate the long-term consequences of chemotherapy-related HBV reactivation in patients with lymphoma.METHODS: This study was based on the database of published prospective study evaluating HBV reactivation in HBV lymphoma patients during chemotherapy.Deteriorated liver reserve (DLR) was defined as development of either one of the following conditions during follow-up: (1) newly onset parenchyma liver disease, splenomegaly or ascites without evidence of lymphoma involvement; (2) decrease of the ratio (albumin/globulin ratio) to less than 0.8 or increase of the ratio of INR of prothrombin time to larger than 1.2 without evidence of malnutrition or infection. Liver cirrhosis was diagnosed by imaging studies.RESULTS: A total of 49 patients were included. The median follow-up was 6.2 years (range, 3.9-8.1 years).There were 31 patients with and 18 patients without HBV reactivation. Although there was no difference of overall survival (OS) and chemotherapy response rate between the two groups, DLR developed more frequently in patients with HBV reactivation (48.4% vs 16.7%; P= 0.0342). Among the HBV reactivators, HBV genotype C was associated with a higher risk of developing DLR (P = 0.0768) and liver cirrhosis (P = 0.003). Four of five patients with sustained high titer of HBV DNA and two of three patients with multiple HBV reactivation developed DLR. Further, patients with a sustained high titer of HBV DNA had the shortest OS among the HBV reactivators (P= 0.0000). No patients in the non-HBV reactivation group developed hepatic failure or liver cirrhosis.CONCLUSION: Chemotherapy-related HBV reactivation is associated with the long-term effect of deterioration of hepatic function.
基金Supported by the Research Grants, No. NSC91-3112-B-002-009No. NSC92-3112-B-002-027,No. NSC93-3112-B-002-007from the National Science Council, No. NHRI-CN-CA9201S(92A084, and 93A059) from the National Health Research Institutes,and No. NTUH 93-N012 No. NTUH 94S155 from National Taiwan University Hospital, Taiwan, China
文摘AIM: A high percentage of early-stage high-grade gastric mucosa-associated lymphoid tissue (MALT) lymphomas remain Helicobacter pylori(H pylori)-dependent. However,unlike their low-grade counterparts, high-grade gastric MALT lymphomas may progress rapidly if unresponsive to H pylori eradication. It is mandatory to identify markers that may predict the H pylori-dependent status of these tumors. Proliferation of MALT lymphoma cells depends on cognate help and cell-to-cell contact of H pylori-specific intratumoral T-cells. To examine whether the expression of co-stimulatory marker CD86 (B7.2) and the infiltration of CD56 (+) natural killer (NK) cells can be useful markers to predict Hpylori-dependent status of high-grade gastric MALT lymphoma.METHODS: Lymphoma biopsies from 26 patients who had participated in a prospective study of H pylori-eradication for stage IE high-grade gastric MALT lymphomas were evaluated. Tumors that resolved to Wotherspoon grade Ⅱ or less after H pylorieradication were classified as H pyloridependent; others were classified as H pylori-independent.The infiltration of NK cells and the expression of CD86 in pre-treatment paraffin-embedded lymphoma tissues were determined by immunohistochemistry.RESULTS: There were 16 H pylori-dependent and 10H pylori-independent cases. CD86 expression was detected in 11 (68.8%) of 16 Hpyiori-dependent cases but in none of 10 Hpylori-independent cases (P = 0.001).H pylori-dependent high-grade gastric MALT lymphomas contained significantly higher numbers of CD56 (+) NK cells than H pylori-independent cases (2.8±1.4% vs 1.1±0.8%; P = 0.003). CD86 positive MALT lymphomas also showed significantly increased infiltration of CD56 (+)NK cells compared to CD86-negative cases (2.9±1.1% vs1.4±1.3%; P= 0.005).CONCLUSION: These results suggest that the expression of co-stimulatory marker CD86 and the increased infiltration of NK cells are associated with H pylori-dependent state of early-stage high-grade gastric MALT lymphomas.
基金supported by a grant from Kerala State Council for Science, Technology and Environment(KSCSTE), Govt. of Kerala, India
文摘Acute myeloid leukemia (AML) is a phenotypically heterogeneous disorder. The M4 subtype of AML is frequently associated with the cytogenetic marker inversion 16 and/or the presence of eosinophilia. Blast crisis is the aggressive phase of the triphasic chronic myeloid leukemia (CML), which is a disease with Philadelphia (Ph) chromosome as the major abnormality. In the present study, we report a 76-year-old patient suspected of having AML with eosinophilic differentiation (AML-M4), which in clinical tests resembles CML blast crisis with multiple chromosomal abnormalities. Isochromosome 21 [i(21)(q10)] was the most recurrent feature noted in metaphases with 46 chromosomes. Ring chromosome, tetraploid endoreduplication, recurrent aneuploid clones with loss of X chromosome, monosomy 17, monosomy 7, and structural variation translocation (9;14) were also observed in this patient. Fluorescent in situ hybridization (FISH) confirmed the absence of Ph chromosome. This report shows how cytogenetic analyses revealed atypical structural aberrations in the M4 subtype of AML.
基金Supported by The Japan Society for the Promotion of Science(JSPS)Grant-in-Aid for Scientific Research,grant No.23790800(to Nosho K)and 23390200(to Shinomura Y)A-STEP(Adaptable and Seamless Technology Transfer Program through Targetdriven R and D)(to Nosho K)+4 种基金Daiwa Securities Health Foundation(to Nosho K)Kobayashi Foundation for Cancer Research(to Nosho K)Sagawa Foundation for Promotion of Cancer Research(to Nosho K)Suzuken Memorial Foundation(to Nosho K),and Takeda Science Foundation(to Nosho K)USA National Institute of Health,grant number R01 CA151993(to Ogino S)
文摘AIM:To investigate insulin-like growth factor 2(IGF2)differentially methylated region(DMR)0 hypomethylation in relation to clinicopathological and molecular features in colorectal serrated lesions.METHODS:To accurately analyze the association between the histological types and molecular features of each type of serrated lesion,we consecutively collected1386 formalin-fixed paraffin-embedded tissue specimens that comprised all histological types[hyperplastic polyps(HPs,n=121),sessile serrated adenomas(SSAs,n=132),traditional serrated adenomas(TSAs,n=111),non-serrated adenomas(n=195),and colorectal cancers(n=827)].We evaluated the methylation levels of IGF2 DMR0 and long interspersed nucleotide element-1(LINE-1)in HPs(n=115),SSAs(n=120),SSAs with cytological dysplasia(n=10),TSAs(n=91),TSAs with high-grade dysplasia(HGD)(n=15),non-serrated adenomas(n=80),non-serrated adenomas with HGD(n=105),and CRCs(n=794).For the accurate quantification of the relative methylation levels(scale 0%-100%)of IGF2 DMR0 and LINE-1,we used bisulfite pyrosequencing method.Tumor specimens were analyzed for microsatellite instability,KRAS(codons 12 and 13),BRAF(V600E),and PIK3CA(exons 9and 20)mutations;MLH1 and MGMT methylation;and IGF2 expression by immunohistochemistry.RESULTS:The distribution of the IGF2 DMR0 methylation level in 351 serrated lesions and 185 non-serrated adenomas(with or without HGD)was as follows:mean61.7,median 62.5,SD 18.0,range 5.0-99.0,interquartile range 49.5-74.4.The IGF2 DMR0 methylation level was divided into quartiles(Q1≥74.5,Q2 62.6-74.4,Q3 49.6-62.5,Q4≤49.5)for further analysis.With regard to the histological type,the IGF2 DMR0 methylation levels of SSAs(mean±SD,73.1±12.3)were significantly higher than those of HPs(61.9±20.5),TSAs(61.6±19.6),and non-serrated adenomas(59.0±15.8)(P<0.0001).The IGF2 DMR0 methylation level was inversely correlated with the IGF2 expression level(r=-0.21,P=0.0051).IGF2 DMR0 hypomethylation was less frequently detected in SSAs compared with HPs,TSAs,and non-serrated adenomas(P<0.0001).Multivariate logistic regression analysis also showed that IGF2 DMR0 hypomethylation was inversely associated with SSAs(P<0.0001).The methylation levels of IGF2 DMR0 and LINE-1 in TSAs with HGD(50.2±18.7and 55.7±5.4,respectively)were significantly lower than those in TSAs(61.6±19.6 and 58.8±4.7,respectively)(IGF2 DMR0,P=0.038;LINE-1,P=0.024).CONCLUSION:IGF2 DMR0 hypomethylation may be an infrequent epigenetic alteration in the SSA pathway.Hypomethylation of IGF2 DMR0 and LINE-1 may play a role in TSA pathway progression.
基金Supported by Veterans Affairs Merit Award,No.IO1CX001353(to Barrett TA)National Institutes of Health,No.2R01DK095662-06A1(to Barrett TA)+3 种基金the National Cancer Institute at the National Institutes of Health,No.N01-CN-35157(to Bergan R)the Training Program in Oncogenesis and Developmental Biology through the National Cancer Institute,No.NCI T32 CA080621(to Bradford EM)an Institutional Development Award from the National Institute of General Medical Sciences of the National Institutes of Health,No.8 P20GM103527-05American Physiological Society STEP-UP Fellowship(to Thompson CA)
文摘AIM To assess dietary myo-inositol in reducing stem cell activation in colitis,and validate pβ-cateninS^(552) as a biomarker of recurrent dysplasia.METHODS We examined the effects of dietary myo-inositol treatment on inflammation,pβ-cateninS^(552) and p Akt levels by histology and western blot in IL-10-/-and dextran sodium sulfate-treated colitic mice. Additionally,we assessed nuclear pβ-cateninS^(552) in patients treated with myo-inositol in a clinical trial,and in patients with and without a history of colitis-induced dysplasia.RESULTS In mice,pβ-cateninS^(552) staining faithfully reported the effects of myo-inositol in reducing inflammation and intestinal stem cell activation. In a pilot clinical trial of myo-inositol administration in patients with a history of low grade dysplasia(LGD),two patients had reduced numbers of intestinal stem cell activation compared to the placebo control patient. In humans,pβ-cateninS^(552) staining discriminated ulcerative colitis patients with a history of LGD from those with benign disease.CONCLUSION Enumerating crypts with increased numbers of pβ-cateninS^(552)-positive cells can be utilized as a biomarker in colitis-associated cancer chemoprevention trials.
基金This work was supported in part by Accelerating Excel-lence in Translational Science Pilot Grants G0812D05,a pilot project award from the National Institutes of Health(NCI,NIMHD)Grants:U54 CA143931 and U54MD0075984,and NIH/NCI SC1CA200517 to Y.Wu.
文摘Background:Aberrant activation of anaplastic lymphoma kinase(ALK)signaling has been found to be involved in the tumorigenesis of multiple types of cancer.The aim of this study was to determine the role of this pathway in the pathogenesis of breast cancer.Methods:An ALK pathway signature that we generated previously was used to compute the ALK pathway activity in 6381 breast cancer samples from 42 microarray datasets,and the associations between ALK pathway signature score and clinical variables were examined using logistic regression and survival analyses.Results:Our results indicated that high ALK pathway activity was a significant risk factor for hormone receptor-negative,high-grade breast cancer in the 42 datasets.ALK pathway activity was positively associated with pathological complete response(pCR)in 15 datasets annotated with patient’s neoadjuvant chemotherapy response information(overall odds ratio=1.67,P<0.01),and this association was more significant in HER2-negative and grade 1&2 tumors than in HER2-positive and grade 3 tumors.ALK pathway activity was also positively associated with recurrence risk in breast cancer patients from 30 datasets annotated with survival information(overall hazard ratio=1.21,P<0.01),particularly in patients with age>50 years old,with positive lymph nodes,or with residual disease after neoadjuvant chemotherapy.Conclusions:ALK may be involved in breast cancer tumorigenesis,and ALK pathway signature score may serve as a prognostic biomarker for breast cancer.
基金Research on cell cycle in our lab is funded by the Baden-Wurttemberg Foundation(BWSTJSF2019-027,to M.C.-H.)the German Cancer Aid(70113919 to S.D.)the German Cancer Consortium DKTK(FR04 to S.D.).
文摘The control of cell proliferation is an essential feature in development and tissue homeostasis and is prominently deregulated in tumors.Three publications in Nature now uncover the mechanism underlying the degradation of cyclin D1-3 and provide important insights for the targeted therapy of the cancer cell cycle.
基金supported in part by NIH-NIMHD U54MD007598,U54CA143931,NIH/NCI1U54CA14393,U56 CA101599-01Department-of-Defense Breast Cancer Research Program grant BC043180,NIH/NCATS CTSI UL1TR000124 to J.V.Vadgama+1 种基金Accelerating Excellence in Translational Science(AXIS)Pilot Grants G0812D05,NIH/NCI SC1CA200517 and 9 SC1 GM135050-05 to Y.WuNIH/NIMHD Accelerating Excellence in Translational Science(AXIS)Pilot Grants G0814C01(Q.Hao).
文摘Dear Editor,The molecular pathogenesis of estrogen receptor(ER)-negative,especially triple-negative breast cancer(TNBC),is unclear,thus,the treatment of these types of cancers is still a great challenge[1].Chemotherapy remains the primary adjuvant treatment choice for TNBC patients[2],but a large number of these tumors are resistant to chemotherapy and relapse ormetastasize quickly after adjuvant therapy[3].
文摘Objective: To define the prevalence, pattern, and clinical course of arthritis presenting at the time of diagnosis of Kawasaki disease. Study design: A single-center, retrospective study of 414 consecutive patients diagnosed with Kawasaki disease between January 1997 and December 2002 was performed. Standardized clinical assessments, laboratory and imaging test results, and treatment regimens were reviewed. The clinical, laboratory, treatment response,and coronary outcome data were analyzed for children with and without arthritis. Results: The prevalence of arthritis was 7.5%(31/414). In the 31 children with arthritis,55%had oligoarticular involvement and 45%had polyarticular involvement. In both of these groups, the large joints were predominantly involved. Some 88%of the children with arthritis responded to standard intravenous immunoglobulin therapy for acute Kawasaki disease and did not require additional medications. The children with arthritis had significantly increased levels of inflammatory markers, but their demographical and clinical features were otherwise similar to those of the children without arthritis, including coronary outcome, with the same proportion(13%) of children from each group having coronaryartery lesions (z-score ≥2.5). Conclusions: Arthritisis a short-lived phenomenon included in the clinical spectrum of acute Kawasaki disease. Children with arthritis have evidence of increased systemic inflammation but otherwise share the same clinical features, response to treatment, and coronary outcomes as patients without arthritis.Most cases of arthritis resolve without additional therapeutic intervention.
基金This work was supported by the National Health and Medical Research Council(NHMRC)of Australia(Project grants#1053792 and#1162052)Cancer Council Victoria Project Grant#1184873+1 种基金R.B.P was supported by Senior Research NHMRC Fellowship#1058586E.S.is supported by a Victorian Cancer Agency Mid-Career Research Fellowship(MCRF19007).
文摘Ribosome biogenesis and protein synthesis are fundamental rate-limiting steps for cell growth and proliferation.The ribosomal proteins(RPs),comprising the structural parts of the ribosome,are essential for ribosome assembly and function.In addition to their canonical ribosomal functions,multiple RPs have extra-ribosomal functions including activation of p53-dependent or p53-independent pathways in response to stress,resulting in cell cycle arrest and apoptosis.Defects in ribosome biogenesis,translation,and the functions of individual RPs,including mutations in RPs have been linked to a diverse range of human congenital disorders termed ribosomopathies.Ribosomopathies are characterized by tissue-specific phenotypic abnormalities and higher cancer risk later in life.Recent discoveries of somatic mutations in RPs in multiple tumor types reinforce the connections between ribosomal defects and cancer.In this article,we review the most recent advances in understanding the molecular consequences of RP mutations and ribosomal defects in ribosomopathies and cancer.We particularly discuss the molecular basis of the transition from hypo-to hyper-proliferation in ribosomopathies with elevated cancer risk,a paradox termed"Dameshek's riddle."Furthermore,we review the current treatments for ribosomopathies and prospective therapies targeting ribosomal defects.We also highlight recent advances in ribosome stress-based cancer therapeutics.Importantly,insights into the mechanisms of resistance to therapies targeting ribosome biogenesis bring new perspectives into the molecular basis of cancer susceptibility in ribosomopathies and new clinical implications for cancer therapy.