CKIα ablation induces p53 activation, and CKIα degradation underlies the therapeutic effect of lenalidomide in a pre-leukemia syndrome. Here we describe the development of CKIα inhibitors, which co-target the transcriptional kinases CDK7 and CDK9, thereby augmenting CKIα-induced p53 activation and its anti-leukemic activity. Oncogene-driving super-enhancers (SEs) are highly sensitive to CDK7/9 inhibition. We identified multiple newly gained SEs in primary mouse acute myeloid leukemia (AML) cells and demonstrate that the inhibitors abolish many SEs and preferentially suppress the transcription elongation of SE-driven oncogenes. We show that blocking CKIα together with CDK7 and/or CDK9 synergistically stabilize p53, deprive leukemia cells of survival and proliferation-maintaining SE-driven oncogenes, and induce apoptosis. Leukemia progenitors are selectively eliminated by the inhibitors, explaining their therapeutic efficacy with preserved hematopoiesis and leukemia cure potential; they eradicate leukemia in MLL-AF9 and Tet2;Flt3 AML mouse models and in several patient-derived AML xenograft models, supporting their potential efficacy in curing human leukemia.

Introduction:This study aimed to design an immunogenic epitope for Cryptococcus neoformans the etiological agent of cryptococcosis using in silico simulations, for epitope prediction, we selected the mannoprotein antigen MP88 which it's known to induce protective immunity. Material &method:A total of 39 sequences of MP88 protein with length 378 amino acids were retrieved from the National Center for Biotechnology Information database (NCBI) in the FASTA format were used to predict antigenic B-cell and T cell epitopes via different bioinformatics tools at Immune Epitope Database and Analysis Resource (IEDB). The tertiary structure prediction of MP88 was created in RaptorX, and visualized by UCSF Chimera software. Result:A Conserved B-cell epitopes AYSTPA, AYSTPAS, PASSNCK, and DSAYPP have displayed the most promising B cell epitopes. While the YMAADQFCL, VSYEEWMNY and FQQRYTGTF they represent the best candidates T-cell conserved epitopes, the 9-mer epitope YMAADQFCL display the greater interact with 9 MHC-I alleles and HLA-A*02:01 alleles have the best interaction with an epitope. The VSYEEWMNY and FQQRYTGTF they are nonallergen while YMAADQFCL was an allergen. For MHC class II peptide binding prediction, the YARLLSLNA, ISYGTAMAV and INQTSYARL represent the most Three highly binding affinity core epitopes. The core epitope INQTSYARL was found to interact with 14 MHC-II. The allergenicity prediction reveals ISYGTAMAV, INQTSYARL were non-allergen and YARLLSLNA was an allergen. Regarding population coverage the YMAADQFCL exhibit, a higher percentage among the world (69.75%) and the average population coverage was 93.01%. In MHC-II, ISYGTAMAV epitope reveal a higher percentage (74.39%) and the average population coverage was (81.94%). This successfully designed a peptide vaccine against Cryptococcus neoformans open up a new horizon in Cryptococcus neoformans research; the results require validation by in vitro and in vivo experiments.

Background: Influenza A (H3N2) clade 3C.3a was the predominant influenza virus in Israel throughout the 2018-2019 season, constituting a drift from the influenza A (H3N2) vaccine. We estimated the end-of season vaccine effectiveness (VE) by age, among community patients with influenza-like illness (ILI), considering the hemagglutinin (HA) gene mutations and amino acid substitutions of influenza A (H3N2) viruses detected. Methods: Nose-throat samples were analyzed for the presence of influenza virus, type/subtype, and HA gene sequence. HA gene sequences and amino acid substitutions were compared to the influenza A/Singapore/INFIMH-16-0019/2016 (H3N2)-like 2018-2019 vaccine virus, and a phylogenetic tree was generated. Influenza VE against influenza A (H3N2) was estimated using the test-negative design. VE was estimated by age group and by 15 year moving age intervals. Results: In total, 90% of the influenza A (H3N2) viruses belonged to the 3C.3a clade, constituting a unique situation in the northern hemisphere. Adjusted all-age influenza A (H3N2) VE was −3.5% (95% CI: −51.2 to 29.1). Although adjusted VEs were very low among infants, children, and young adults, a VE of 45% (95% CI: −19.2 to 74.6) was estimated among adults aged ≥45 years old. Conclusions: The higher VE point estimates among older adults may be related to previous exposure to similar influenza viruses.

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