O1 Regulation of genes by telomere length over long distances

PURPOSE: Breast cancer (BC) is the leading malignancy among Sudanese women. Yet, data on survival are limited. This study aimed to determine 5-year overall survival (OS) of BC in Sudanese women, and identify prognostic demographic and clinicopathologic factors. PATIENTS AND METHODS: A hospital-based retrospective study was conducted by reviewing data of women with BC diagnosed and treated at the National Cancer Institute—University of Gezira during 2012, and followed up to end of August 2018. Data were retrieved from medical records and analyzed, OS was determined, and the prognostic factors were explored. RESULTS: A total of 225 cases were recruited. The median age at presentation was 45 years (range, 22-85 years). Clinical stage I, II, III, and IV represented 3.1%, 31.6%, 48%, and 17.3%, respectively. Most women (81.3%) were treated with curative intent. Of those, 25.1% received neoadjuvant chemotherapy. Mastectomy was the commonest (61.7%) type of surgery. The median follow-up period was 59.8 months with mean OS time of 55.7 months. The 5-year cumulative survival rate was 58%. The 5-year OS rates for stages I, II, III, and IV were 71.5%, 82.4%, 56.5%, and 8.4%, respectively. For lymph node (LN)-positive cases, 5-year OS rate was 63% and for LN-negative was 83.5%. Presenting with advanced-stage disease and positive LN status associated with short OS times ( P < .005). CONCLUSION: OS of women with BC in Central Sudan is worse than in the developed world, but similar to African countries. Our findings indicate that advanced stage at diagnosis and lymph nodal involvement are strong predictors of short survival times. Raising awareness and introducing early detection programs are critical for better survival of these patients.

According to Globocan 2020, breast cancer is considered one of the most common cancers affecting women and is one of the leading causes of death in over 100 countries. The available classical treatment options do not always give satisfactory outcomes, and some patients develop resistance to these treatments. This study aims to investigate the combination of nanovectorized siRNA directed against anti-apoptotic protein Survivin (siSurvivin) by targeted stealth magnetic siRNA nanovectors (TS-MSN), designed in our lab, with Doxorubicin (DOX), as an option for HER2+ breast cancer treatment. The hypothesis is that the pretreatment of the HER2+ breast cancer cell line SK-BR-3 with siSurvivin will induce apoptosis in the cancer cells and enhance the therapeutic efficacy of DOX, allowing a dose reduction of DOX and hence a reduction of potential side effects. TS-MSN are based on superparamagnetic iron oxide nanoparticles (SPIONs) covalently coupled with a fluorophore sulfocyanine-5 and polyethylene glycol 5000 (PEG₅₀₀₀) and functionalized with single-chain variable fragments (scFv) of an antibody targeting the HER2 membrane receptor. These covalently functionalized SPIONs are then complexed via electrostatic interactions with therapeutic siRNA and the cationic polymers, chitosan, and poly-L-arginine. TS-MSN_siSurvivin had an average size of 144 ± 30 nm, a PDI of 0.3, and a slightly positive zeta potential value of 10.56 ± 05.70 mV. The agarose gel electrophoresis assay confirmed that the siRNA is well-complexed into TS-MSN without leakage, as no free siRNA was detected. Moreover, siRNA in TS-MSN was protected from RNAse A degradation for up to 6 h at 37 °C. Formulations of TS-MSN with siSurvivin demonstrated in vitro gene knockdown up to 89% in the HER2+ breast cancer cell line SK-BR-3. Furthermore, qRT-PCR confirmed a significant Survivin mRNA relative expression inhibition (about 50%) compared to control siRNA or untreated cells. A combination protocol was evaluated between TS-MSN and Doxorubicin (DOX) for the first time. Therefore, SK-BR-3 cells were pretreated with TS-MSN formulated with siSurvivin at 50 nM for 24 h alone, before a DOX treatment at a concentration of 0.5 µM (corresponding to the IC₅₀) was added for 48 h. The MTT cytotoxicity tests, performed after 72 h of treatment, revealed that the combination had a significant synergistic cytotoxic effect on SK-BR-3 cells compared to monotherapies or untreated cells. We confirmed that pretreatment of cells with siSurvivin potentializes the cytotoxic effect of DOX as an alternative approach for treating HER2+ breast cancer. In conclusion, a combination of anti-Survivin siRNA and DOX would be a good alternative in HER2+ breast cancer therapy.

Background: Type 2 diabetes is emerging in Sudan and is associated with obesity. Deregulated lipid metabolism and inflammatory states are suggested risk factors for cardiovascular disease, which is a leading cause of diabetic death. This study aimed to investigate C-reactive protein (CRP) levels and the lipid profile in type 2 diabetic adult Sudanese compared with nondiabetics, and to test their associations with other characteristics. Methods: A cross-sectional study including 70 diabetics and 40 nondiabetics was conducted. Anthropometric measurements were assessed, and demographic and medical data were obtained using a structured questionnaire. Blood specimens were collected and biochemical parameters were analyzed applying standard methods. Results: CRP and triglycerides were significantly higher in the diabetic group (P<0.001 and P=0.01, respectively). Differences in total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were not statistically significant between the diabetic and nondiabetic groups. In the diabetic group, correlation analysis revealed that the CRP level had a significant positive correlation with LDL-C (r=0.255, P=0.034) and body mass index (r=0.29, P=0.016). Body mass index showed a significant positive correlation with triglycerides (r=0.386, P=0.001). Within the lipid parameters, a number of significant correlations were observed. Elevated levels of CRP, LDL-C, and triglycerides were markedly more prevalent in the diabetic group of patients. Diabetics showed significantly higher CRP levels compared with nondiabetics (odds ratio 5.56, P=0.001). Conclusion: The high prevalence of obesity among diabetics, together with elevated levels of triglycerides and CRP, suggest coexistence of dyslipidemia and inflammation in diabetes. Our findings emphasize that diabetics were 5.6 times more likely to have high CRP levels than nondiabetics; as CRP is a predictor of cardiovascular disease risk, it can be recognized that diabetics are at more risk of cardiovascular disease than nondiabetics. Considering evaluation of CRP together with the lipid profile in prediction of cardiovascular disease risk in Sudanese diabetics should be further tested in large-scale studies.

In this work, lipid-based nanoparticles (LBNP) were designed to combine tyrosine kinase inhibitor (TKI) Lapatinib (LAPA) with siRNA directed against apoptosis inhibitor protein Survivin (siSurvivin) in an injectable form. This nanosystem is based on lipid nanocapsules (LNCs) coated with a cationic polymeric shell composed of chitosan grafted through a transacylation reaction. The hydrophobic LAPA is solubilized in the inner oily core, while hydrophilic siRNA is associated electrostatically onto the nanocarrier’s surface. The co-loaded LBNP showed a narrow size distribution (polydispersity index (PDI) < 0.3), a size of 130 nm, and a slightly positive zeta potential (+21 mV). LAPA and siRNA were loaded in LBNP at a high rate of >90% (10.6 mM) and 100% (4.6 µM), respectively. The siRNA-LAPA_LBNP was readily uptaken by the human epidermal growth factor receptor 2 overexpressed (HER2+) breast cancer cell line SK-BR-3. Moreover, the cytotoxicity studies confirmed that the blank chitosan decorated LBNP is not toxic to the cells with the tested concentrations, which correspond to LAPA concentrations from 1 to 10 µM, at different incubation times up to 96 h. Furthermore, siCtrl.-LAPA_LBNP had a more cytotoxic effect than Lapatinib salt, while siSurvivin-LAPA_LBNP had a significant synergistic cytotoxic effect compared to siCtrl.-LAPA_LBNP. All these findings suggested that the developed modified LBNP could potentiate anti-Survivin siRNA and LAPA anti-cancer activity.