In this study, mortality from colorectal cancer was reduced by about 80% in a subgroup of patients with tumors that expressed a mutated, activated form of phosphatidylinositol 3-kinase (17% of all ...tumors) when the patients took aspirin regularly after the diagnosis.
Numerous observational and randomized, controlled studies have suggested a protective effect of regular use of aspirin on colorectal neoplasias.
1
–
7
The favorable outcome that has been associated with aspirin use after colorectal cancer is diagnosed
8
–
10
suggests that aspirin is a promising agent for adjuvant therapy. Accumulating data suggest that colorectal cancers are a heterogeneous group of diseases that potentially have differential responses to treatment.
11
The effect of postdiagnosis aspirin use on survival appears to differ according to tumor expression of PTGS2 (HGNC:9605, the official symbol for prostaglandin-endoperoxide synthase 2, also known as cyclooxygenase-2) as assessed by immunohistochemical techniques.
8
Considering . . .
In cancer cells, the nuclear transport system is often disrupted, leading to abnormal localization of nuclear proteins and altered gene expression. This disruption can arise from various mechanisms ...such as mutations in genes that regulate nuclear transport, altered expression of transport proteins, and changes in nuclear envelope structure. Oncogenic protein build-up in the nucleus due to the disturbance in nuclear transport can also boost tumor growth and cell proliferation. In this study, we performed bioinformatic analyses of 23 key nuclear transport receptors using genomic and transcriptomic data from pancancer and head and neck squamous cell carcinoma (HNSCC) datasets from The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia and found that the total alteration frequency of 23 nuclear transport receptors in 2691 samples of the PCAWG Consortium was 42.1% and a high levels of genetic alterations was significantly associated with poor overall survival. Amplification was the most common type of genetic alterations, and results in the overexpression of nuclear transport receptors in HNSCC compared to normal tissues. Furthermore, our study revealed that seven out of eight cell cycle genes (CDK1, CDK2, CDK4, CDK6, CCNA1, CCNB1, and CCNE2) were significantly and positively correlated with nuclear transport receptor genes in TCGA pancancer and CCLE datasets. Additionally, functional enrichment analysis showed that nuclear transport receptor genes were mainly enriched in the adhesion junction, cell cycle, ERBB, MAPK, MTOR and WNT signaling pathways.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Osteopontin (OPN) is an osteogenic marker protein. Osteoblast functions are affected by inflammatory cytokines and pathological conditions. OPN is highly expressed in bone lesions such as those in ...rheumatoid arthritis. However, local regulatory effects of OPN on osteoblasts remain ambiguous. Here we examined how OPN influences osteoblast responses to mechanical stress and growth factors. Expression of NO synthase 1 (
) and
was increased by low-intensity pulsed ultrasound (LIPUS) in MC3T3-E1 cells and primary osteoblasts. The increase of
expression was abrogated by both exogenous OPN overexpression and recombinant OPN treatment, whereas it was promoted by OPN-specific siRNA and OPN antibody. Moreover, LIPUS-induced phosphorylation of focal adhesion kinase (FAK), a crucial regulator of mechanoresponses, was down-regulated by OPN treatments. OPN also attenuated hepatocyte growth factor-induced vitamin D receptor (
) expression and platelet-derived growth factor-induced cell mobility through the repression of FAK activity. Of note, the expression of low-molecular weight protein tyrosine phosphatase (LMW-PTP), a FAK phosphatase, was increased in both OPN-treated and differentiated osteoblasts. CD44 was a specific OPN receptor for LWW-PTP induction. Consistently, the suppressive influence of OPN on osteoblast responsiveness was abrogated by LMW-PTP knockdown. Taken together, these results reveal novel functions of OPN in osteoblast physiology.
Purpose: Host immune response to tumor may be an important prognostic factor for colon cancer patients. However, little is known on
prognostic significance of histopathologic lymphoid reaction to ...tumor, independent of the number of lymph nodes examined and
tumoral molecular alterations, including microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP),
both of which are associated with lymphocytic reaction and clinical outcome.
Experimental Design: Using 843 colorectal cancer patients in two independent prospective cohorts, we examined patient prognosis in relation to
four components of lymphocytic reaction (i.e., Crohn's-like reaction, peritumoral reaction, intratumoral periglandular reaction,
and tumor-infiltrating lymphocytes) and overall lymphocytic score (0-12). CIMP was determined using eight markers including
CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 , and SOCS1 . Cox proportional hazard models computed hazard ratio for mortality, adjusted for covariates including tumor stage, body
mass index, lymph node count, KRAS, BRAF , p53, cyclooxygenase-2 ( PTGS2 ), MSI, CIMP, and LINE-1 methylation.
Results: Increasing overall lymphocytic reaction score including tumor-infiltrating lymphocytes was associated with a significant
improvement in colorectal cancerâspecific and overall survival (log-rank P < 0.003). These findings remained significant (adjusted hazard ratio estimates, 0.49-0.71; P trend < 0.009) in multivariate models that adjusted for covariates, including body mass index, MSI, CIMP, LINE-1 hypomethylation,
and cyclooxygenase-2. The beneficial effect of tumoral lymphocytic reaction was consistent across strata of clinical, pathologic,
and molecular characteristics.
Conclusions: Lymphocytic reactions to tumor were associated with improved prognosis among colorectal cancer patients, independent of lymph
node count and other clinical, pathologic, and molecular characteristics. (Clin Cancer Res 2009;15(20):6412â20)
CONTEXT Alterations of the WNT signaling pathway and cadherin-associated protein β 1 (CTNNB1 or β-catenin) have been implicated in colorectal carcinogenesis and metabolic diseases. OBJECTIVE To test ...the hypothesis that CTNNB1 activation in colorectal cancer modifies prognostic associations of body mass index (BMI) and level of postdiagnosis physical activity. DESIGN, SETTING, AND PATIENTS Two US prospective cohort studies (Nurses' Health Study and the Health Professionals Follow-up Study) were used to evaluate CTNNB1 localization by immunohistochemistry in 955 patients with stage I, II, III, or IV colon and rectal cancer from 1980 through 2004. A Cox proportional hazards model was used to compute the hazard ratio (HR) for mortality, adjusting for clinical and tumor features, including microsatellite instability, CpG island methylator phenotype, level of long interspersed nucleotide element 1 methylation, mutations in KRAS, BRAF, or PIK3CA, and tumor protein p53. MAIN OUTCOME MEASURES Colorectal cancer–specific mortality and overall mortality through June 30, 2009. RESULTS In obese patients (BMI ≥30), positive status for nuclear CTNNB1 was associated with significantly better colorectal cancer–specific survival (adjusted HR, 0.24 95% confidence interval {CI}, 0.12-0.49, P <.001 for interaction; 5-year survival: 0.85 for patients with positive nuclear CTNNB1 status vs 0.78 for those with negative status) and overall survival (adjusted HR, 0.56 95% CI, 0.35-0.90, P = .03 for interaction; 5-year survival: 0.77 for patients with positive nuclear CTNNB1 status vs 0.74 for those with negative status), while CTNNB1 status was not associated with prognosis among nonobese patients (BMI <30). Among patients with negative status for nuclear CTNNB1 and cancer in stages I, II, or III, postdiagnosis physical activity was associated with better colorectal cancer–specific survival (adjusted HR, 0.33 95% CI, 0.13-0.81, P = .05 for interaction; 5-year survival: 0.97 for ≥18 vs 0.89 for <18 metabolic equivalent task hours/week), while postdiagnosis physical activity was not associated with colorectal cancer–specific survival among patients with positive status for nuclear CTNNB1 (adjusted HR, 1.07 95% CI, 0.50-2.30). CONCLUSIONS Among obese patients only, activation of CTNNB1 was associated with better colorectal cancer–specific survival and overall survival. Postdiagnosis physical activity was associated with better colorectal cancer–specific survival only among patients with negative status for nuclear CTNNB1. These molecular pathological epidemiology findings suggest that the effects of alterations in the WNT-CTNNB1 pathway on outcome are modified by BMI and physical activity.
STAT3 is a transcription factor that is constitutively activated in some cancers. It seems to play crucial roles in cell proliferation and survival, angiogenesis, tumor-promoting inflammation, and ...suppression of antitumor host immune response in the tumor microenvironment. Although the STAT3 signaling pathway is a potential drug target, clinical, pathologic, molecular, or prognostic features of STAT3-activated colorectal cancer remain uncertain.
Utilizing a database of 724 colon and rectal cancer cases, we evaluated phosphorylated STAT3 (p-STAT3) expression by immunohistochemistry. The Cox proportional hazards model was used to compute mortality HR, adjusting for clinical, pathologic, and molecular features, including microsatellite instability (MSI), the CpG island methylator phenotype (CIMP), LINE-1 methylation, 18q LOH, TP53 (p53), CTNNB1 (β-catenin), JC virus T-antigen, and KRAS, BRAF, and PIK3CA mutations.
Among the 724 tumors, 131 (18%) showed high-level p-STAT3 expression (p-STAT3-high), 244 (34%) showed low-level expression (p-STAT3-low), and the remaining 349 (48%) were negative for p-STAT3. p-STAT3 overexpression was associated with significantly higher colorectal cancer-specific mortality log-rank P = 0.0020; univariate HR (p-STAT3-high vs. p-STAT3-negative): 1.85, 95% CI: 1.30-2.63, P(trend) = 0.0005; multivariate HR: 1.61, 95% CI: 1.11-2.34, P(trend) = 0.015. p-STAT3 expression was positively associated with peritumoral lymphocytic reaction (multivariate OR: 3.23; 95% CI: 1.89-5.53, P < 0.0001). p-STAT3 expression was not associated with MSI, CIMP, or LINE-1 hypomethylation.
STAT3 activation in colorectal cancer is associated with adverse clinical outcome, supporting its potential roles as a prognostic biomarker and a chemoprevention and/or therapeutic target.
PIK3CA mutation and subsequent activation of the AKT pathway play an important role in colorectal carcinogenesis. However, little is known about the prognostic role of PIK3CA mutation in colon ...cancer.
Using 450 resectable colon cancers (stage I to III) in two independent prospective cohorts, we detected PIK3CA mutation in 82 tumors (18%) by pyrosequencing. Cox proportional hazards models were used to calculate hazard ratios (HRs) of colon cancer-specific and overall mortalities, adjusted for patient characteristics and tumoral molecular features, including the CpG island methylation phenotype, microsatellite instability (MSI), LINE-1 hypomethylation, and p53, CIMP, KRAS and BRAF mutation.
Compared with patients with PIK3CA wild-type tumors, those with PIK3CA-mutated tumors experienced an increase in colon cancer-specific mortality according to univariate analysis (HR = 1.64; 95% CI, 0.95 to 2.86), which persisted after adjusting for other known or potential risk factors for cancer recurrence (including MSI; multivariate HR = 2.23; 95% CI, 1.21 to 4.11). The effect of PIK3CA mutation on cancer survival seemed to differ according to KRAS mutational status. Among patients with KRAS wild-type tumors, the presence of PIK3CA mutation was associated with a significant increase in colon cancer-specific mortality (HR = 3.80; 95% CI, 1.56 to 9.27). In contrast, PIK3CA mutation conferred no significant effect on mortality among patients with KRAS-mutated tumors (HR = 1.25; 95% CI, 0.52 to 2.96).
Among patients who undergo a curative resection of colon cancer, PIK3CA mutation is associated with shorter cancer-specific survival. The adverse effect of PIK3CA mutation may be potentially limited to patients with KRAS wild-type tumors.
The oral cavity is one of the main entry sites for SARS-CoV-2. Gingival keratinocytes express transmembrane serine protease 2 (TMPRSS2), responsible for priming the SARS-CoV-2 spike protein. We ...investigated whether periodontitis increased the expression of TMPRSS2.
To investigate gene expression in periodontitis, we analyzed the expression of specific genes from (1) the Gene Expression Omnibus (GEO) dataset of 247 human gingival tissues and (2) an experimentally-induced periodontitis mouse model. Human gingival tissues with or without periodontitis were immunohistochemically stained using an anti-TMPRSS2 antibody. Analysis of the TMPRSS2 promoter was performed using a ChIP-Atlas dataset. TMPRSS2 expression was detected in cultured human keratinocytes using quantitative reverse transcription (qRT)-PCR and Western blot analysis.
GEO dataset analysis and an experimentally-induced periodontitis model revealed increased expression of TMPRSS2 in periodontitis gingiva. The keratinocyte cell membrane in periodontitis gingiva was strongly immunohistochemically stained for TMPRSS2. Using ChIP-Atlas and GEO datasets, we screened for transcription factors that bind to the TMPRSS2 promoter region. We found one candidate, estrogen receptor 1 (ESR1), highly expressed in periodontitis gingiva. Analysis of the GEO dataset revealed a correlation between ESR1 and TMPRSS2 expression in gingival tissues. An ESR1 ligand induced TMPRSS2 expression in cultured keratinocytes.
Periodontitis increases TMPRSS2 expression in the cell membrane of gingival keratinocytes.
•Expression of COVID-19 essential TMPRSS2 was increased in periodontitis gingiva.•Keratinocytes in periodontitis gingiva were immunochemically stained for TMPRSS2.•Estrogen signal was associated with increased TMPRSS2 expression.
Amidst the fourth COVID-19 wave in Viet Nam, national lockdowns necessitated the closure of numerous dental schools. To assess DDS (Doctor of Dental Surgery) graduation exams, this study analyzed ...their 2021 implementation in comparison to onsite exams conducted in 2020 and 2022 at the Faculty of Odonto-Stomatology, University of Medicine and Pharmacy at Ho Chi Minh City, Viet Nam (FOS-UMPH). The final online examination comprises two main sessions: a synchronous online examination using FOS-UMPH e-Learning for theories (consisting of 200 MCQs and 3 written tests with 3 clinical situations needed be solved) and a synchronous online examination using Microsoft Teams for practicum (comprising of 12 online OSCE stations). The final grades were evaluated using the same metrics in face-to-face final examinations in 2022 and 2020. A total of 114, 112 and 95 students were recruited for the first-time exams in 2020, 2021 and 2022, respectively. In order to analyze the reliability, histogram and k-mean clustering were employed. The histograms from 2020, 2021 and 2022 showed a striking similarity. However, fewer students failed in 2021 and 2022 (13% and 12.6%, respectively) compared to 2020 (28%), with clinical problem-solving part grades (belonging to theory session) being notably higher in 2021 and 2022. Intriguingly, the MCQ Score results showed the identical patterns. The courses of orthodontics, dental public health, and pediatrics subjects (in the group of prevention and development dentistry) stood out for their exceptional accuracy across both sessions. After examining data gathered over three years, we identified three distinct clusters: the first comprised of scattered average and low scores, the second characterized by high scores but unstable and scattered and the third cluster boasting consistently high and centered scores. According to our study, online and onsite traditional graduation exam results are relatively equivalent, but additional measures are necessary to standardize the final examination and adapt to the new normal trend in dental education.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genome-wide DNA hypomethylation plays a role in genomic instability and carcinogenesis. LINE-1 (L1 retrotransposon) constitutes a substantial portion of the human genome, and LINE-1 methylation ...correlates with global DNA methylation status. LINE-1 hypomethylation in colon cancer has been strongly associated with poor prognosis. However, whether LINE-1 hypomethylators constitute a distinct cancer subtype remains uncertain. Recent evidence for concordant LINE-1 hypomethylation within synchronous colorectal cancer pairs suggests the presence of a non-stochastic mechanism influencing tumor LINE-1 methylation level. Thus, it is of particular interest to examine whether its wide variation can be attributed to clinical, pathologic or molecular features.
Utilizing a database of 869 colorectal cancers in two prospective cohort studies, we constructed multivariate linear and logistic regression models for LINE-1 methylation (quantified by Pyrosequencing). Variables included age, sex, body mass index, family history of colorectal cancer, smoking status, tumor location, stage, grade, mucinous component, signet ring cells, tumor infiltrating lymphocytes, CpG island methylator phenotype (CIMP), microsatellite instability, expression of TP53 (p53), CDKN1A (p21), CTNNB1 (beta-catenin), PTGS2 (cyclooxygenase-2), and FASN, and mutations in KRAS, BRAF, and PIK3CA.
Tumoral LINE-1 methylation ranged from 23.1 to 90.3 of 0-100 scale (mean 61.4; median 62.3; standard deviation 9.6), and distributed approximately normally except for extreme hypomethylators LINE-1 methylation < 40; N = 22 (2.5%), which were far more than what could be expected by normal distribution. LINE-1 extreme hypomethylators were significantly associated with younger patients (p = 0.0058). Residual plot by multivariate linear regression showed that LINE-1 extreme hypomethylators clustered as one distinct group, separate from the main tumor group. The multivariate linear regression model could explain 8.4% of the total variability of LINE-1 methylation (R-square = 0.084). Multivariate logistic regression models for binary LINE-1 hypomethylation outcomes (cutoffs of 40, 50 and 60) showed at most fair predictive ability (area under receiver operator characteristics curve < 0.63).
LINE-1 extreme hypomethylators appear to constitute a previously-unrecognized, distinct subtype of colorectal cancers, which needs to be confirmed by additional studies. Our tumor LINE-1 methylation data indicate enormous epigenomic diversity of individual colorectal cancers.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
