Targeted Inhibition of Fibroblast Growth Factor Receptor 1-GLI Through AZD4547 and GANT61 Modulates Breast Cancer Progression.

The underlying mechanism of fibroblast growth factor receptor 1 (FGFR1) mediated carcinogenesis is still not fully understood. For instance, FGFR1 upregulation leads to endocrine therapy resistance in breast cancer patients. The current study aimed to identify FGFR1-linked genes to devise improved therapeutic strategies. RNA-seq and microarray expression data of 1,425 breast cancer patients from two independent cohorts were downloaded for the analysis. Gene Set Enrichment Analysis (GSEA) was performed to identify differentially expressed pathways associated with FGFR1 expression. Validation was done using 150 fresh tumor biopsy samples of breast cancer patients. The clinical relevance of mRNA and protein expression of FGFR1 and its associated genes were also evaluated in mouse embryonic fibroblasts (MEFs) and breast cancer cell line (MDA-MB-231). Furthermore, MDA-MB-231 cell line was treated with AZD4547 and GANT61 to identify the probable role of FGFR1 and its associated genes on cells motility and invasion. According to GSEA results, SHH pathway genes were significantly upregulated in FGFR1 patients in both discovery cohorts of breast cancer. Statistical analyses using both discovery cohorts and 150 fresh biopsy samples revealed strong association of FGFR1 and GLI1, a member of SHH pathway. The increase in the expression of these molecules was associated with poor prognosis, lymph node involvement, late stage, and metastasis. Combined exposures to AZD4547 (FGFR1 inhibitor) and GANT61 (GLI1 inhibitor) significantly reduced cell proliferation, cell motility, and invasion, suggesting molecular crosstalk in breast cancer progression and metastasis. A strong positive feedback mechanism between FGFR1-GLI1 axis was observed, which significantly increased cell proliferation and metastasis. Targeting FGFR1-GLI1 simultaneously will significantly improve the prognosis of breast cancer in patients.

Polycyclic Aromatic Hydrocarbon Levels in Wistar Rats Exposed to Ambient Air of Port Harcourt, Nigeria: An Indicator for Tissue Toxicity.

This study investigated the PAH levels in Wistar rats exposed to ambient air of the Port Harcourt metropolis. Twenty Wistar rats imported from a nonpolluted city (Enugu) were exposed to both indoor and outdoor air. Following the IACUC regulation, baseline data were obtained from 4 randomly selected rats, while the remaining 16 rats (8 each for indoor and outdoor) were left till day 90. Blood samples were obtained by cardiac puncture, and the PAH levels were determined using Gas Chromatography Flame-Ionization Detector (GC-FID). GraphPad Prism (version 8.0.2) Sidak's (for multiple data set) and unpaired t-tests (for two data sets) were used to evaluate the differences in group means. Seven of the PAHs found in indoor and outdoor rats were absent in baseline rats. The mean concentrations of PAH in indoor and outdoor animals were higher than those of baseline animals, except for Benzo(a)pyrene, which was found in baseline animals but absent in other animal groups. Additionally, Dibenz(a,h)anthracene, Indeno(1,2,3-c,d)pyrene, Pyrene, 2-methyl, and other carcinogenic PAHs were all significantly higher (p < 0.05) in outdoor groups. The vulnerable groups in Port Harcourt are at the greatest risk of such pollution. Therefore, urgent environmental and public health measures are necessary to mitigate the looming danger.

Substance Use, Highly Active Antiretroviral Therapy, and Liver Enzymes: Evidence From a Cross-Sectional Study of HIV-Infected Adult Patients Without Comorbidities on HAART in the University of Port Harcourt Teaching Hospital.

This study applied a structural equation modeling (SEM) to evaluate the role of substance use (alcohol, smoking, and trado-medicine use) to changes in the liver enzymes (AST, ALT, and ALP) levels in HIV-infected adult patients on a highly active antiretroviral treatment (HAART) for not <1 year. The study was a cross-sectional, part of a randomized comparative trial (Ref: UPH/CEREMAD/REC/19), involving 129 (46 males and 83 females) HIV-infected adult patients. Liver enzyme levels were determined from analyzed blood samples using the Clinical Chemistry Analyser (VS10) manufactured by Vitro Scient, while the study determined substance use using a reliable (Cronbach alpha = 0.805) rapid-exploratory survey questionnaire. Liver enzyme values were further categorized into: normal or abnormal using normal reference ranges (ALT = 7-55 U/L, AST = 8-48 U/L, and ALP = 40-129 U/L). STATGRAPHICS V16.1.11 (StatPoint Tech., Inc.) and SPSS (IBM® Amos V21.0.0, USA) were used to analyze the data. Among the HIV-HAART patients, 27.9% were alcohol users, 20.9% smokers, and 20.1% trado-medicine users. In addition, ALP (71.3%) abnormality was higher than ALT (34.9%) and AST (28.7%). The result from the SEM provided only a partial support for our hypotheses of direct substance use effects on the liver enzyme levels and abnormalities; with a direct association of alcohol with an elevated AST (b = 0.170, p = 0.05) and smoking with a higher AST (b = 0.484, p < 0.01) and ALT (b = 0.423, p < 0.01) values. Trado-medicine use was not directly associated with enzyme elevation and abnormality. In conclusion, ALP abnormality was the most common, and there is a close association between an elevated ALT and AST, with or without an elevated ALP. The study found that HIV-HAART patients who drink or smoke will have at least one or more abnormal transaminases. The possible explanation to the increased risk among HIV-HAART patients could be associated with the metabolic pressures and supra-additive effects on the livers.

Association between MDR1 polymorphisms and XELIRI and XELOX chemoresistance in Saudi patients with colorectal cancer.

Multidrug resistance member 1 (MDR1) is located on chromosome 7 and encodes P-glycoprotein, which is universally accepted as a drug resistance biomarker. MDR1 polymorphisms can alter protein expression or function, which has been previously reported to associate with various types of malignancies, such as colorectal cancer (CRC). Therefore, the present study aimed to determine the effects of MDR1 polymorphisms on drug responses of Saudi patients with CRC. DNA samples were obtained from 62 patients with CRC and 100 healthy controls. Genotypes and allele frequencies of MDR1 single nucleotide polymorphisms (SNPs) G2677T and T1236C were determined using the PCR-restriction fragment length polymorphism procedure. The results showed no significant differences in the genotype distribution and allele frequency of T1236C between patients with CRC and controls. However, G2677T was found to serve a highly significant role in protecting against the progression of CRC. In addition, none of the genotypes in SNPs T1236C and G2677T was found to affect chemoresistance to XELIRI and XELOX. In conclusion, although T1236C in the MDR1 gene is not associated with CRC risk, G2677T protects against the development of CRC. Neither of the MDR1 SNPs tested were associated with the risk of chemoresistance. Therefore, these two SNPs cannot be used as molecular markers for predicting drug response in patients with CRC.

Assessing Patient Confidence and Satisfaction about the Shared Decision-making Meetings for Planning Cancer Chemotherapy.

Background Patients increasingly express the desire to be involved in their treatment decisions, especially in critical situations, such as cancer chemotherapy that increase a doctor's responsibility toward fulfilling these needs. This process may require more than one meeting with the patient to meet their expectations and satisfaction levels. This study aimed to assess the satisfaction levels in cancer patients, who received chemotherapy, about their decision-making and if they were able to make this decision during the first meeting with their physicians. Methods A cross-sectional study was conducted in 2017 on 106 cancer patients aged 18 years or above who were receiving chemotherapy at the day-care unit of King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia. The data were collected by a direct or telephonic interview using a structured questionnaire. The variables were studied across two groups of patients based on the patient's ability to make decision in the first meeting with their physician. Data were expressed as frequencies (percentage) and Pearson Chi-Square test was used to assess the categorical variables. Results Out of the 106 patients, 42 (39.6%) of them were male. Ninety-one (85.8%) patients took the decision by themselves. Regarding the decision-making 90 (84.9%) patients were able to make the decision from the first meeting. Sixty-eight (64.2%) patients felt more satisfied if they had an additional session. There was a significant association between patients with the ability to make the decision during the first meeting and patients who took the decision by themselves (P = 0.033), patients with consideration of changing their decision if they had more meetings (P = 0.005), patients with consideration of withholding from chemotherapy in their mind (P = 0.019) and patients with thought that chemotherapy is affecting their life (P = 0.044). Conclusion The majority of the patients felt that more than one meeting with their doctors would be helpful in improving their satisfaction level during the decision-making process, consideration of withholding from chemotherapy in mind and that chemotherapy is affecting their life style. Future protocol in which the patients will be encouraged to have a confidence role on their treatment decision is recommended.

Frequent methylation of the KLOTHO gene and overexpression of the FGFR4 receptor in invasive ductal carcinoma of the breast.

Invasive ductal carcinoma of the breast is the most common cancer affecting women worldwide. The marked heterogeneity of breast cancer is matched only with the heterogeneity in its associated or causative factors. Breast cancer in Saudi Arabia is apparently an early onset with many of the affected females diagnosed before they reach the age of 50 years. One possible rationale underlying this observation is that consanguinity, which is widely spread in the Saudi community, is causing the accumulation of yet undetermined cancer susceptibility mutations. Another factor could be the accumulation of epigenetic aberrations caused by the shift toward a Western-like lifestyle in the past two decades. In order to shed some light into the molecular mechanisms underlying breast cancer in the Saudi community, we identified KLOTHO (KL) as a tumor-specific methylated gene using genome-wide methylation analysis of primary breast tumors utilizing the MBD-seq approach. KL methylation was frequent as it was detected in 55.3 % of breast cancer cases from Saudi Arabia (n = 179) using MethyLight assay. Furthermore, KL is downregulated in breast tumors with its expression induced following treatment with 5-azacytidine. The involvement of KL in breast cancer led us to investigate its relationship in the context of breast cancer, with one of the protagonists of its function, fibroblast growth factor receptor 4 (FGFR4). Overexpression of FGFR4 in breast cancer is frequent in our cohort and this overexpression is associated with poor overall survival. Interestingly, FGFR4 expression is higher in the absence of KL methylation and lower when KL is methylated and presumably silenced, which is suggestive of an intricate relationship between the two factors. In conclusion, our findings further implicate "metabolic" genes or pathways in breast cancer that are disrupted by epigenetic mechanisms and could provide new avenues for understanding this disease in a new context.

Uterine sarcoma. Clinico-pathological characteristics and outcome.

OBJECTIVES: To investigate the clinical and histopathological characteristics, with the prognostic factors, treatment outcome, pattern of relapse, and survival analysis of uterine sarcoma patients. METHODS: All patients with histologically proven uterine sarcoma were identified using the database at King Abdulaziz University Hospital, Jeddah, Saudi Arabia between January 2000 and December 2012. RESULTS: A total of 36 patients with uterine sarcoma were reviewed. The median age of all patients was 57 years, and the mean age was 57.72+/-13.17 years. Carcinosarcoma was reported in 21 patients (58%), leiomyosarcoma in 7 (19%), undifferentiated endometrial sarcoma in 6 (17%), and rhabdomyosarcoma in 2 (6%). Approximately half of the patients were stages III and IV (28% and 25%), while 15 patients (41%) were stage I; only 2 patients (6%) were stage II. The surgical treatment was hysterectomy and bilateral salpingoophorectomy (H+BSO) plus staging in 18 patients (50%), while in 4 patients (19%), H+BSO plus debulking was performed. Adjuvant chemotherapy was given in 24 (69%) and adjuvant radiotherapy in 5 (14%) cases, At a median follow-up period of 13.5 months, 8 patients (22%) relapsed. The 2-year disease-free survival (DFS) rate was 22% and the 5-year was 14%. In the multivariate analysis, the advanced stages  (p=0.015) and lymph vascular invasion (p=0.0001) were associated with poor DFS, while the use of chemotherapy significantly improved the DFS (p=0.027). CONCLUSIONS: The poor outcome of high-grade uterine sarcoma patients was identified, and only one third of patients (30%) survived for 2 years. This finding necessitates the need for more aggressive tools to fight this disease.