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Background Epilepsy is a chronic neurologic condition with different risk factors and genetic predispositions. It is characterized by the occurrence of an epileptic seizure. To our knowledge, most studies have focused on revealing epilepsy prevalence in Saudi Arabia, but the etiological prevalence is still not well-studied in the region. Thus, this research aims to raise awareness and provide more insights into the etiological prevalence of this disorder. Methodology A cross-sectional study was performed among 431 adult patients diagnosed with epilepsy in the Neurology Department at King Abdulaziz Medical City in Jeddah, Saudi Arabia. Patients' data were retrospectively collected from electronic medical files covering the period between May 2016 and April 2021. Epilepsy etiologies were classified as suggested by the International League Against Epilepsy 2017. Results The most commonly identified seizures were generalized (25.3%) and focal (8.9%). However, 66.1% of seizure types were unidentifiable. The most common etiology was structural (42.9%), followed by genetic (7.2%), with strokes (24.3%) and tumors (23.8%) being the most prevalent structural etiologies. However, 47.6% of the patients were classified under unknown etiology. Conclusions This study suggested that epilepsy diagnosed as generalized was by far the most common seizure type in our cohort. Structural etiology was evident in most patients, with stroke being the highest presented etiology.
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Previous phase I DNA-vaccine based clinical trials using Mammaglobin-A (Mam-A), a human breast tumor associated antigen (TAA), demonstrated that this agent was safe and efficient at treating patients with stage IV breast cancer. The long-term success of cancer vaccines is limited by the diminished expression of human leukocyte antigen (HLA) class I molecules in the tumor microenvironment. The current study assessed the impact of various selenocompounds on the expression of HLA class I molecules in THP-1 cells, an apparent proficient antigen that presents a human monocyte-like cell line, and their eventual activation of MamA2.1 (HLA-A2 immunodominant epitope of Mam-A) specific cytotoxic CD8+ T lymphocytes (CTLs). The results revealed that, following treatment with methylselenol producing compounds [methylselenic acid (MSA) and dimethylselenide (DMDSe)], the expression of HLA class-I was increased and components involved with the antigen presentation machinery of THP-1 cells were upregulated. Furthermore, CTLs activated by MamA2.1 peptide presenting THP-1 cells, pre-treated with MSA and DMDSe, demonstrated an enhanced cytotoxicity in HLA-A2+/Mam-A+ AU565 and UACC-812 breast cancer cell lines when compared with CTLs activated by THP-1 cells without drug treatment. However, no significant cytotoxicity was observed under similar conditions in HLA-A2+/Mam-A- MCF-7 and MDA-MB-231 breast cancer cell lines. The results indicated that treatment with methylselenol producing compounds retained antigen-dependent activation of CD8+ T cells. The data of the current study demonstrated that MSA and DMDSe potentiated effector cytotoxic responses following TAA specific activation of CTLs, indicating their future role as vaccine adjuvants in cancer immunotherapy.
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Mammaglobin-A (MamA) is overexpressed in 40-80% of all human breast cancers. Recent phase I clinical trials of the MamA DNA vaccine showed encouraging safety outcomes. However, this vaccine elicited only a modest increase in MamA specific CD8+T lymphocyte (CTL) activation. As vaccine adjuvants play a critical role in enhancing the immunotherapeutic efficiency of vaccines, we tested the potential role of three synthetic CpG oligodeoxynucleotides (ODN2216-class A ODN, ODN2006-class B ODN, and ODN M362-class C ODN) to further enhance MamA specific CTL responses. Towards this, naïve CD8+T cells were obtained from healthy HLA-A2+ human donors. The HLA-A2 specific immunodominant epitope of MamA, MamA2.1 (LIYDSSLCDL), was utilized to activate naïve CD8+T cells. The THP-1 (HLA-A2+) cells were used as antigen presenting cells to stimulate naïve CD8+T cells along with (or without) co-treatment of various ODNs mentioned above. Activation of naïve CD8+T cells with the MamA2.1 peptide along with ODNs demonstrated enhanced MamA specific CTL mediated cytotoxicity on AU565 (HLA-A+/MamA+) breast cancer cells following co-treatment with ODN2006 and M362 compared to ODN2216 or MamA2.1 peptide alone. However, no significant cytotoxicity was noted upon treatment of MamA2.1 activated CTLs on MCF7 (HLA-A+/MamA-) cells, suggesting that the activation of CTLs is specific to the MamA antigen. Functional characterization studies demonstrated specific IL-12 mediated cross-talk between TLR-6 and -9 in THP-1 cells following stimulation with ODN2006 and M362, which was critical for the final cytotoxic activation of CD8+T lymphocytes. Based on these data, we conclude that ODN2006 and ODN M362 exerted a strong adjuvant effect through induction of the initial innate immune response through TLR9 upregulation followed by enhanced MamA specific CTL dependent adaptive immune responses. Our current data provide evidence for the application of Class-B/-C-CpG-ODNs as potential vaccine adjuvants towards enhancing the success of MamA based breast cancer vaccination.
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Recent evidence from our laboratory has demonstrated that high salt (Δ0.05 M NaCl) induced inflammatory response and cancer cell proliferation through salt inducible kinase-3 (SIK3) upregulation. As calcium influx is known to effect inflammatory response and drug resistance, we examined the impact of high salt on calcium influx in breast cancer cells. Treatment of MCF-7 and MDA-MB-231 cells with high salt induced an enhanced intracellular calcium intensity, which was significantly decreased by store operated calcium entry (SOCE) inhibitor co-treatment. Further, high salt induced P-glycoprotein (P-gp) mediated paclitaxel drug resistance in breast cancer cells. Murine tumor studies demonstrated that injection of MCF-7 cells cultured in high salt, exerted higher tumorigenicity compared to the basal cultured counterpart. Knock down of SIK3 by specific shRNA inhibited tumorigenicty, expression of SOCE regulators and P-gp activity, suggesting SIK3 is an upstream mediator of SOCE induced calcium influx. Furthermore, small molecule inhibitor, prostratin, exerted anti-tumor effect in murine models through SIK3 inhibition. Taken together, we conclude that SIK3 is an upstream regulator of store operated calcium entry proteins, Orai1 and STIM1, and mediates high salt induced inflammatory cytokine responses and P-gp mediated drug resistance. Therefore, small molecule inhibitors, such as prostratin, could offer novel anti-cancer approaches.
