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التغيير الاستراتيجي في الكليات والجامعات : التخطيط من أجل البقاء والازدهار
يقوم المؤلفون في هذا الكتاب بدراسة عملية التخطيط الاستراتيجي من وجهات نظر متعددة، يعرضون من خلالها النظريات و النماذج الإدارية ويقدمون نصائحهم في التخطيط الاستراتيجي بناء على دراسة متعمقة، للوصول إلى إدارة استراتيجية فعالة تواكب التطور والتغير في العالم من حولنا وهذه الإرشادات والملاحظات بمنزلة منارة تضيء الطريق لمن يقتحم مجال العمل في سلك التعليم العالي.
BOOK
Analysis of DNA methylation in cancer: location revisited
Changes in DNA methylation in cancer have been heralded as promising targets for the development of powerful diagnostic, prognostic, and predictive biomarkers. Despite the existence of more than 14,000 scientific publications describing DNA methylation-based biomarkers and their clinical associations in cancer, only 14 of these biomarkers have been translated into a commercially available clinical test. Methodological and experimental obstacles are both major causes of this disparity, but the genomic location of a DNA methylation-based biomarker is an intrinsic and essential property that also has an important and often overlooked role. Here, we examine the importance of the location of DNA methylation for the development of cancer biomarkers, and take a detailed look at the genomic location and other relevant characteristics of the various biomarkers with commercially available tests. We also emphasize the value of publicly available databases for the development of DNA methylation-based biomarkers and the importance of accurate reporting of the full methodological details of research findings.
Journal Article
Epigenetic heterogeneity in cancer
Phenotypic and functional heterogeneity is one of the hallmarks of human cancers. Tumor genotype variations among tumors within different patients are known as interpatient heterogeneity, and variability among multiple tumors of the same type arising in the same patient is referred to as intra-patient heterogeneity. Subpopulations of cancer cells with distinct phenotypic and molecular features within a tumor are called intratumor heterogeneity (ITH). Since Nowell proposed the clonal evolution of tumor cell populations in 1976, tumor heterogeneity, especially ITH, was actively studied. Research has focused on the genetic basis of cancer, particularly mutational activation of oncogenes or inactivation of tumor-suppressor genes (TSGs). The phenomenon of ITH is commonly explained by Darwinian-like clonal evolution of a single tumor. Despite the monoclonal origin of most cancers, new clones arise during tumor progression due to the continuous acquisition of mutations. It is clear that disruption of the \"epigenetic machinery\" plays an important role in cancer development. Aberrant epigenetic changes occur more frequently than gene mutations in human cancers. The epigenome is at the intersection of the environment and genome. Epigenetic dysregulation occurs in the earliest stage of cancer. The current trend of epigenetic therapy is to use epigenetic drugs to reverse and/or delay future resistance to cancer therapies. A majority of cancer therapies fail to achieve durable responses, which is often attributed to ITH. Epigenetic therapy may reverse drug resistance in heterogeneous cancer. Complete understanding of genetic and epigenetic heterogeneity may assist in designing combinations of targeted therapies based on molecular information extracted from individual tumors.
Journal Article
Methylation of NRN1 is a novel synthetic lethal marker of PI3K‐Akt‐mTOR and ATR inhibitors in esophageal cancer
Wnt, PI3K‐Akt‐mTOR, and NF‐κB pathways were reported to be involved in DNA damage repair (DDR). DDR‐deficient cancers become critically dependent on backup DNA repair pathways. Neuritin 1 (NRN1) is reported to be involved in PI3K‐Akt‐mTOR, and its role in DDR remains unclear. Methylation‐specific PCR, siRNA, flow cytometry, esophageal cancer cell lines, and xenograft mouse models were used to examine the role of NRN1 in esophageal cancer. The expression of NRN1 is frequently repressed by promoter region methylation in human esophageal cancer cells. NRN1 was methylated in 50.4% (510/1012) of primary esophageal cancer samples. NRN1 methylation is associated significantly with age (P < .001), tumor size (P < .01), TNM stage (P < .001), differentiation (P < .001) and alcohol consumption (P < .05). We found that NRN1 methylation is an independent prognostic factor for poor 5‐y overall survival (P < .001). NRN1 inhibits colony formation, cell proliferation, migration, and invasion, and induces apoptosis and G1/S arrest in esophageal cancer cells. NRN1 suppresses KYSE150 and KYSE30 cells xenografts growth in nude mice. PI3K signaling is reported to activate ATR signaling by targeting CHK1, the downstream component of ATR. By analyzing the synthetic efficiency of NVP‐BEZ235 (PI3K inhibitor) and VE‐822 (an ATR inhibitor), we found that the combination of NVP‐BEZ235 and VE‐822 increased cytotoxicity in NRN1 methylated esophageal cancer cells, as well as KYSE150 cell xenografts. In conclusion, NRN1 suppresses esophageal cancer growth both in vitro and in vivo by inhibiting PI3K‐Akt‐mTOR signaling. Methylation of NRN1 is a novel synthetic lethal marker for PI3K‐Akt‐mTOR and ATR inhibitors in human esophageal cancer. The combination of NVP‐BEZ235 and VE‐822 increased cytotoxicity in NRN1 methylated esophageal cancer cells. Methylation of NRN1 is a novel synthetic lethal marker for PI3K‐Akt‐mTOR and ATR inhibitors in human esophageal cancer.
Journal Article
Multiplex Digital Methylation‐Specific PCR for Noninvasive Screening of Lung Cancer
There remains tremendous interest in developing liquid biopsy assays for detection of cancer‐specific alterations, such as mutations and DNA methylation, in cell‐free DNA (cfDNA) obtained through noninvasive blood draws. However, liquid biopsy analysis is often challenging due to exceedingly low fractions of circulating tumor DNA (ctDNA), necessitating the use of extended tumor biomarker panels. While multiplexed PCR strategies provide advantages such as higher throughput, their implementation is often hindered by challenges such as primer‐dimers and PCR competition. Alternatively, digital PCR (dPCR) approaches generally offer superior performance, but with constrained multiplexing capability. This paper describes development and validation of the first multiplex digital methylation‐specific PCR (mdMSP) platform for simultaneous analysis of four methylation biomarkers for liquid‐biopsy‐based detection of non‐small cell lung cancer (NSCLC). mdMSP employs a microfluidic device containing four independent, but identical modules, housing a total of 40 160 nanowells. Analytical validation of the mdMSP platform demonstrates multiplex detection at analytical specificities as low as 0.0005%. The clinical utility of mdMSP is also demonstrated in a cohort of 72 clinical samples of low‐volume liquid biopsy specimens from patients with computed tomography (CT)‐scan indeterminant pulmonary nodules, exhibiting superior clinical performance when compared to traditional MSP assays for noninvasive detection of early‐stage NSCLC. This paper describes the development and analytical/clinical validation of the first mdMSP platform for the simultaneous analysis of four DNA methylation biomarkers for liquid‐biopsy‐based detection of early‐stage NSCLC. The demonstrated analytical sensitivity/specificity and clinical utility indicate the potential of mdMSP platform to be a complementary method for improved CT screening of lung cancer.
Journal Article
Dysfunctional KEAP1–NRF2 Interaction in Non-Small-Cell Lung Cancer
Nuclear factor erythroid-2 related factor 2 (NRF2) is a redox-sensitive transcription factor that positively regulates the expression of genes encoding antioxidants, xenobiotic detoxification enzymes, and drug efflux pumps, and confers cytoprotection against oxidative stress and xenobiotics in normal cells. Kelch-like ECH-associated protein 1 (KEAP1) negatively regulates NRF2 activity by targeting it to proteasomal degradation. Increased expression of cellular antioxidants and xenobiotic detoxification enzymes has been implicated in resistance of tumor cells against chemotherapeutic drugs.
Here we report a systematic analysis of the KEAP1 genomic locus in lung cancer patients and cell lines that revealed deletion, insertion, and missense mutations in functionally important domains of KEAP1 and a very high percentage of loss of heterozygosity at 19p13.2, suggesting that biallelic inactivation of KEAP1 in lung cancer is a common event. Sequencing of KEAP1 in 12 cell lines and 54 non-small-cell lung cancer (NSCLC) samples revealed somatic mutations in KEAP1 in a total of six cell lines and ten tumors at a frequency of 50% and 19%, respectively. All the mutations were within highly conserved amino acid residues located in the Kelch or intervening region domain of the KEAP1 protein, suggesting that these mutations would likely abolish KEAP1 repressor activity. Evaluation of loss of heterozygosity at 19p13.2 revealed allelic losses in 61% of the NSCLC cell lines and 41% of the tumor samples. Decreased KEAP1 activity in cancer cells induced greater nuclear accumulation of NRF2, causing enhanced transcriptional induction of antioxidants, xenobiotic metabolism enzymes, and drug efflux pumps.
This is the first study to our knowledge to demonstrate that biallelic inactivation of KEAP1 is a frequent genetic alteration in NSCLC. Loss of KEAP1 function leading to constitutive activation of NRF2-mediated gene expression in cancer suggests that tumor cells manipulate the NRF2 pathway for their survival against chemotherapeutic agents.
Journal Article
Epigenetic silencing of JAM3 promotes esophageal cancer development by activating Wnt signaling
Background
The role of JAM3 in different tumors is controversial. The epigenetic regulation and the mechanism of JAM3 remain to be elucidated in human esophageal cancer (EC).
Methods
Eleven EC cell lines, 49 cases of esophageal intraepithelial neoplasia (EIN) and 760 cases of primary EC samples were employed. Methylation-specific polymerase chain reaction, immunohistochemistry, MTT, western blot and xenograft mouse models were applied in this study.
Results
The inverse association between RNA expression and promoter region methylation of JAM3 was found by analyzing 185 cases of EC samples extracted from the TCGA database (
p
< 0.05). JAM3 was highly expressed in KYSE450, KYSE520, TE1 and YES2 cells, low level expressed in KYSE70 cells and unexpressed in KYSE30, KYSE150, KYSE410, KYSE510, TE13 and BIC1 cells. JAM3 was unmethylated in KYSE450, KYSE520, TE1 and YES2 cells, partial methylated in KYSE70 cells and completely methylated in KYSE30, KYSE150, KYSE410, KYSE510, TE13 and BIC1 cells. The expression of JAM3 is correlated with methylation status. The levels of JAM3 were unchanged in KYSE450, KYSE520, TE1 and YES2 cells, increased in KYSE70 cells and restored expression in KYSE30, KYSE150, KYSE410, KYSE510, TE13 and BIC1 cells after 5-aza-2′-deoxycytidine treatment, suggesting that the expression of JAM3 is regulated by promoter region methylation. JAM3 was methylated in 26.5% (13/49) of EIN and 51.1% (388/760) of primary EC, and methylation of JAM3 was associated significantly with tumor differentiation and family history (all
p
< 0.05). Methylation of JAM3 is an independent prognostic factor of poor 5-year overall survival (
p
< 0.05). JAM3 suppresses cell proliferation, colony formation, migration and invasion and induces G1/S arrest and apoptosis in EC. Further study demonstrated that JAM3 suppressed EC cells and xenograft tumor growth by inhibiting Wnt/β-catenin signaling.
Conclusion
JAM3 is frequently methylated in human EC, and the expression of JAM3 is regulated by promoter region methylation. JAM3 methylation is an early detection and prognostic marker of EC. JAM3 suppresses EC growth both in vitro and in vivo by inhibiting Wnt signaling.
Journal Article
DNA Methylation Markers and Early Recurrence in Stage I Lung Cancer
Methylation of the promoter region of a gene is a mechanism that influences gene expression. In this study of patients with stage I non–small-cell lung cancer (NSCLC), methylation of seven genes —
p16, CDH13, APC, RASSF1A, MGMT, ASC,
and
DAPK
— from tumor and lymph-node specimens was studied. Four genes (
p16, CDH13, RASSF1A,
and
APC
), when methylated, were associated with recurrence after surgery with curative intent.
In this study of patients with stage I non–small-cell lung cancer, methylation of seven genes from tumor and lymph-node specimens was studied. Four genes, when methylated, were associated with recurrence after surgery with curative intent.
Surgery with curative intent is the standard of care for patients with stage I non–small-cell lung cancer (NSCLC), yet notwithstanding advances in treatment, the dissemination of tumor cells outside the area of curative resection is a leading cause of relapse.
1
–
3
Despite surgery, approximately 30 to 40% of patients with NSCLC who have discrete lesions and histologically negative lymph nodes (stage I cancer; T1–2N0, according to the tumor–node–metastasis [TNM] classification criteria) die of recurrent disease.
4
–
6
Many of these recurrences are systemic, making it likely that such patients had occult micrometastases beyond the margins of surgical resection.
4
Epigenetic gene silencing . . .
Journal Article
Predictive value of CHFR and MLH1 methylation in human gastric cancer
Background
Gastric carcinoma (GC) has one of the highest mortality rates of cancer diseases and has a high incidence rate in China. Palliative chemotherapy is the main treatment for advanced gastric cancer. It is necessary to compare the effectiveness and toxicities of different regimens. This study explores the possibility of methylation of DNA damage repair genes serving as a prognostic and chemo-sensitive marker in human gastric cancer.
Methods
The methylation status of five DNA damage repair genes (CHFR, FANCF, MGMT, MLH1, and RASSF1A) was detected by nested methylation-specific PCR in 102 paraffin-embedded gastric cancer samples. Chi-square or Fisher’s exact tests were used to evaluate the association of methylation status and clinic-pathological factors. The Kaplan–Meier method and Cox proportional hazards models were employed to analyze the association of methylation status and chemo-sensitivity.
Results
The results indicate that CHFR, MLH1, RASSF1A, MGMT, and FANCF were methylated in 34.3 % (35/102), 21.6 % (22/102), 12.7 % (13/102), 9.8 % (10/102), and 0 % (0/102) of samples, respectively. No association was found between methylation of CHFR, MLH1, RASSF1A, MGMT, or FANCF with gender, age, tumor size, tumor differentiation, lymph node metastasis, and TNM stage. In docetaxel-treated gastric cancer patients, resistance to docetaxel was found in CHFR unmethylated patients by Cox proportional hazards model (HR 0.243, 95 % CI, 0.069–0.859,
p
= 0.028), and overall survival is longer in the CHFR methylated group compared with the CHFR unmethylated group (log-rank,
p
= 0.036). In oxaliplatin-treated gastric cancer patients, resistance to oxaliplatin was found in MLH1 methylated patients (HR 2.988, 95 % CI, 1.064–8.394,
p
= 0.038), and overall survival was longer in the MLH1 unmethylated group compared with the MLH1 methylated group (log-rank,
p
= 0.046).
Conclusions
CHFR is frequently methylated in human gastric cancer, and CHFR methylation may serve as a docetaxel-sensitive marker. MLH1 methylation was related to oxaliplatin resistance in gastric cancer patients.
Journal Article
Neighborhood-level deprivation and survival in lung cancer
Background
Despite recent advances in lung cancer therapeutics and improving overall survival, disparities persist among socially disadvantaged populations. This study aims to determine the effects of neighborhood deprivation indices (NDI) on lung cancer mortality. This is a multicenter retrospective cohort study assessing the relationship between NDI and overall survival adjusted for age, disease stage, and DNA methylation among biopsy-proven lung cancer patients. State-specific NDI for each year of sample collection were computed at the U.S. census tract level and dichotomized into low- and high-deprivation.
Results
A total of 173 non small lung cancer patients were included, with
n
= 85 (49%) and
n
= 88 (51%) in the low and high-deprivation groups, respectively. NDI was significantly higher among Black patients when compared with White patients (
p
= 0.003). There was a significant correlation between DNA methylation and stage for HOXA7, SOX17, ZFP42, HOXA9, CDO1 and TAC1. Only
HOXA7
DNA methylation was positively correlated with NDI. The high-deprivation group had a statistically significant shorter survival than the low-deprivation group (
p
= 0.02). After adjusting for age, race, stage, and DNA methylation status, belonging to the high-deprivation group was associated with higher mortality with a hazard ratio of 1.81 (95%CI: 1.03–3.19).
Conclusions
Increased neighborhood-level deprivation may be associated with liquid biopsy DNA methylation, shorter survival, and increased mortality. Changes in health care policies that consider neighborhood-level indices of socioeconomic deprivation may enable a more equitable increase in lung cancer survival.
Journal Article