No abstract

Compelling evidences indicate a key role for regulatory T cells (T reg ) on the host response to cancer. The Wilms' tumor antigen (WT1) is overexpressed in several human leukemias and thus considered as promising target for development of leukemia vaccine. However, recent studies indicated that the generation of effective WT1-specific cytotoxic T cells can be largely affected by the presence of T regs . We have generated T-cell lines and clones that specifically recognized a WT1-84 (RYFKLSHLQMHSRKH) peptide in an HLA-DRB1*0402-restricted manner. Importantly, they recognized HLA-DRB1*04-matched fresh leukemic cells expressing the WT1 antigen. These clones exerted a T helper 2 cytokine profile, had a CD4 + CD25 + Foxp3 + GITR + CD127 À T reg phenotype, and significantly inhibited the proliferative activity of allogeneic T cells independently of cell contact. Priming of alloreactive T cells in the presence of T regs strongly inhibited the expansion of natural killer (NK), NK T, and CD8 + T cells and had an inhibitory effect on NK/NK T cytotoxic activity but not on CD8 + T cells. Furthermore, priming of T cells with the WT1-126 HLA-A0201-restricted peptide in the presence of T regs strongly inhibited the induction of anti-WT1-126 CD8 + CTL responses as evidenced by both very low cytotoxic activity and IFN-; production. Moreover, these T reg clones specifically produced granzyme B and selectively induced apoptosis in WT1-84-pulsed autologous antigen-presenting cells but not in apoptotic-resistant DR4-matched leukemic cells. Importantly, we have also detected anti-WT1-84 interleukin-5 + /granzyme B + / Foxp3 + CD4 + T regs in five of eight HLA-DR4 + acute myeloid leukemia patients. Collectively, our in vitro and in vivo findings strongly suggest important implications for the clinical manipulation of T regs in cancer patients. [Cancer Res 2008;68(15):6350-9]

Objectives: This study aimed to determine the relationship between glycaemic control and carotid atherosclerotic disease among patients with acute ischaemic stroke (AIS). Methods: This retrospective cross-sectional study took place in the Neurology Department of King Fahad Hospital of University, Khobar, Saudi Arabia, from April to October 2017. Data were collected from the medical records of 244 patients with a diagnosis of AIS confirmed by computed tomography. Doppler ultrasounds of the carotid artery were performed to determine the presence of increased carotid intima media thickness (CIMT) and plaques. Results: Significantly higher mean glycated haemoglobin (HbA1c) levels were noted in cases with high CIMT values (P = 0.002), but not in cases with carotid plaques (P = 0.360). In addition, there was a significant association between diabetes mellitus (DM) and high CIMT (P = 0.045), but not with carotid plaques (P = 0.075). Finally, while dyslipidaemia and age were independently correlated with high CIMT values (P = 0.034 and <0.001, respectively) and carotid plaques (P <0.001 each), no independent relationships were noted in terms of gender and other risk factors like DM, hypertension and smoking (P >0.050 each). Conclusion: High HbA1c levels were associated with high CIMT values, but not with carotid plaques. Therefore, HbA1c levels may be useful as an indirect marker of the initial stages of carotid artery atherosclerosis.Keywords: Glycated Hemoglobin A1c; Diabetes Mellitus; Carotid Intima-Media Thickness; Atherosclerotic Plaque; Stroke.

To determine relationship between fatigue, depression with the registration in multiple sclerosis (MS) society activity, and stress with the risk developing a new attack in patients with Relapsing remitting MS (RRMS) in the Kingdom of Saudi Arabia (KSA). Methods: This was a cohort retrospective study conducted in the KSA between July 2018 and July 2019 which included a total of 465 RRMS patients. Data were collected during interviews using the Beck Depression Inventory (BDI) and Modified Fatigue Impacts Scale (MFIS). Demographic and clinical data were also collected. Original Article Results: Of 465 participants, 317 expressed psychological stress before the last attack, 67 of whom developed an attack within 4 weeks, and 250 of whom developed an attack after 4 weeks. Significantly lower BDI scores were associated with registration in MS associations (p=0.003, df = 5). Significantly lower MFIS scores were associated with registration in MS associations (p=0.001, df = 5). Conclusion: The majority of RRMS patients have a significant fatigue and depression, and there are significant relationships between registration in the MS society and MFIS and BDI scores where patients who officially registered in MS society have lower score in MFIS and BDI. we recommend regular follow-ups with a psychologist and/or registration with MS societies.

CD24 confers features of stemness and enhances cell motility in colorectal cancer (CRC). It is heavily glycosylated and contains numerous O-glycosylation sites but just two N-glycosylation sites (N36, N52). Since N-glycosylation is thought to be important in mediating the function of glycoproteins, we hypothesized that CD24 might be dependent on N-glycosylation for its activities. To test this hypothesis, site-directed mutagenesis was used to remove N-glycosylation sites by converting the target asparagine residues to glutamine. Each site was removed individually (CD24N36Q and CD24N52Q) and in combination (CD24N[36,52]Q), and the mutant CD24 clones were ectopically expressed in HCT116 and SW480 cells (CRC cell lines with low endogenous CD24 expression). The effect of the mutant CD24 on cell viability, cell motility and induction of downstream targets was compared to wild-type CD24 (CD24WT) and empty vector controls (EVC). Ectopic expression of the individually mutated clones CD24N36Q and CD24N52Q resulted in increased cell motility compared to EVC but was significantly less than that induced by CD24WT. Ectopic expression of the double mutant clone CD24N[36,52]Q resulted in near-complete abrogation in the induction of cell motility. Unexpectedly, the expression of mutant clones (both single and double mutants) led to increased cell viability. Analysis of downstream targets and F-actin staining demonstrated reduced induction of known CD24 targets by the mutant vectors and a reduced cadherin-switch (a surrogate marker for Epithelial-Mesenchymal Transition (EMT). We conclude that each N-glycosylation sites contribute partially to the motility inducing activities of CD24 and that these are additive. Loss of the N-glycosylation results in an unexpected gain of proliferative function. Further studies are necessary to elucidate the exact mechanisms behind these activities.