Johansenmcdowell0236

We further identified a discovery set of 26 upregulated genes at stringent cut-off (FDR less then 0.05) that appeared as a unified signature across the IBMF subtypes. Subsequent transcriptomic analysis on genetically uncharacterised BMF cases revealed a striking overlap of genes, including 22 from the discovery set indicating a unified transcriptional drive across the classic (FA, DC and SDS) and uncharacterised BMF subtypes. This study has relevance in disease pathogenesis, for example in explaining the features (including the BMF) common to all IBMF cases and suggests harnessing this "transcriptional signature" for patient benefit.Bone marrow (BM) niche-derived signals are critical for facilitating engraftment after hematopoietic stem cell (HSC) transplantation (HSCT). HSCT is required for restoration of hematopoiesis in patients with inherited bone marrow failure syndromes (iBMFS). Shwachman-Diamond syndrome (SDS) is a rare iBMFS associated with mutations in SBDS. Previous studies have demonstrated that SBDS deficiency in osteolineage niche cells causes bone marrow dysfunction that promotes leukemia development. However, it is unknown whether BM niche defects caused by SBDS deficiency also impair efficient engraftment of healthy donor HSC following HSCT, a hypothesis that could explain morbidity seen after clinical HSCT for patients with SDS. Here, we report a mouse model with inducible Sbds deletion in hematopoietic and osteolineage cells. Primary and secondary BM transplantation (BMT) studies demonstrated that SBDS deficiency within BM niches caused poor donor hematopoietic recovery and specifically poor HSC engraftment after myeloablative BMT. We have additionally identified multiple molecular and cellular defects within niche populations that are driven by SBDS deficiency and that are accentuated or develop specifically following myeloablative conditioning. These abnormalities include altered frequencies of multiple niche cell subsets including mesenchymal lineage cells, macrophages and endothelial cells; disruption of growth factor signaling, chemokine pathway activation, and adhesion molecule expression; and p53 pathway activation, and signals involved in cell cycle arrest. Taken together, this study demonstrates that SBDS deficiency profoundly impacts recipient hematopoietic niche function in the setting of HSCT, suggesting that novel therapeutic strategies targeting host niches could improve clinical HSCT outcomes for patients with SDS.Acquired genetic mutations can confer resistance to arsenic trioxide (ATO) in the treatment of acute promyelocytic leukemia (APL). However, such resistance-conferring mutations are rare and do not explain most disease recurrence seen in the clinic. We have generated stable ATO-resistant promyelocytic cell lines that are also less sensitive to ATRA and the combination of ATO and ATRA compared to the sensitive cell line. Characterization of these in-house generated resistant cell lines showed significant differences in immunophenotype, drug transporter expression, anti-apoptotic protein dependence, and PML-RARA mutation. Gene expression profiling revealed prominent dysregulation of the cellular metabolic pathways in these ATO resistant APL cell lines. Glycolytic inhibition by 2-DG was sufficient and comparable to the standard of care (ATO) in targeting the sensitive APL cell line. 2-DG was also effective in the in vivo transplantable APL mouse model; however, it did not affect the ATO resistant cell lines. In contrast, the resistant cell lines were significantly affected by compounds targeting the mitochondrial respiration when combined with ATO, irrespective of the ATO resistance-conferring genetic mutations or the pattern of their anti-apoptotic protein dependency. Our data demonstrate that the addition of mitocans in combination with ATO can overcome ATO resistance. We further show that this combination has the potential in the treatment of non-M3 AML and relapsed APL. The translation of this approach in the clinic needs to be explored further.We attempted to develop an efficient method for producing isomaltose, a disaccharide consisting of an α-(1→6)-linkage, from starch by combining enzymes of known activity. We found that the combination of 1,4-α-glucan 6-α-glucosyltransferase from Bacillus globisporus N75 and isopullulanase from Aspergillus brasiliensis ATCC 9642 led to the efficient synthesis of isomaltose. Inclusion of isoamylase and cyclomaltodextrin glucanotransferase resulted in increased efficiency, with production yields exceeding 70%. Furthermore, we considered that isomaltooligosaccharides could be synthesized from starch by combining 1,4-α-glucan 6-α-glucosyltransferase from Paenibacillus sp. PP710 and isopullulanase. In reactions that additionally utilized isoamylase and α-amylase, the total concentration of product, which included a series of isomaltooligosaccharides from isomaltose to isomaltodecaose, was 131 mM, and the ratio of 6-linked glucopyranosyl bonds to all bonds was 91.7% at a substrate concentration of 10%. The development of these manufacturing methods will accelerate the industrial production of isomaltose and isomaltooligosaccharides.The expression of BCL6 in B cell lymphoma can be deregulated by chromosomal translocations, somatic mutations in the promoter regulatory regions or reduced proteasome-mediated degradation. FBXO11 was recently identified as a ubiquitin ligase involved in the degradation of BCL6 and is frequently inactivated in lymphoma or other tumors. Here, we show that FBXO11 mutations are found in 23% of Burkitt lymphoma (BL) patients. FBXO11 mutations impaired BCL6 degradation and the deletion of FBXO11 protein completely stabilized BCL6 levels in human BL cell lines. Conditional deletion of either one or two copies of the FBXO11 gene in mice cooperated with oncogenic MYC and accelerated B cell lymphoma onset, providing experimental evidence that FBXO11 is a haplo-insufficient oncosuppressor in B cell lymphoma. In WT and FBXO11-deficient BL mouse and human cell lines, targeting BCL6 via specific degrader or inhibitors partially impaired lymphoma growth in vitro and in vivo. Inhibition of MYC by the Omomyc mini-protein blocked cell proliferation and increased apoptosis, effects further increased by combined BCL6 targeting. Thus, by validating the functional role of FBXO11 mutations in BL we further highlight the key role of BCL6 in BL biology and provide evidence that innovative therapeutic approaches such as BCL6 degraders and direct MYC inhibition could be exploited as a targeted therapy for BL.The efficacy of daratumumab is partially dependent on CD38 expression on multiple myeloma (MM) cells. this website We have previously shown that ATRA upregulates CD38 expression and reverts daratumumab-resistance ex vivo. We therefore evaluated the optimal dose, efficacy and safety of daratumumab combined with ATRA in daratumumab-refractory MM patients in a phase 1/2 study (NCT02751255). In part A of the study, 63 patients were treated with daratumumab monotherapy. Fifty daratumumab-refractory patients were subsequently enrolled in part B, and treated with daratumumab (re-intensified schedule) combined with ATRA until disease progression. The recommended phase 2 dose of ATRA in combination with daratumumab was defined as 45 mg/m2. At this dose, the overall response rate (ORR) was 5%, indicating that the primary endpoint (ORR≥15%) was not met. However, the majority of patients (66%) achieved at least stable disease. After a median follow-up of 43 months, the median PFS for all patients was 2.8 months. Patients who previously achieved at least a partial response or minimal response/stable disease with prior daratumumab monotherapy had a significantly longer PFS, compared to those who immediately progressed during daratumumab as single agent (median PFS 3.4 and 2.8 versus 1.3 months). The median OS was 19.1 months. The addition of ATRA did not increase the incidence of adverse events. Flow cytometric analysis revealed that ATRA temporarily increased CD38 expression on immune cell subsets. In conclusion, the addition of ATRA and re-intensification of daratumumab had limited activity in daratumumab-refractory patients, which may be explained by the transient upregulation of CD38 expression.We compared candidemia due to Candida auris and other non-C.auris cases in hospitalized COVID-19 patients over a period of nine months at our institution. Candidemia cases in all admitted patients (with or without COVID-19) from April-December 2020 were identified. Electronic records were accessed to record clinical data of COVID-19 patients with candidemia. For statistical analysis, independent samples Mann-Whitney U test was used for continuous and Fisher's exact test was used for categorical variables.A total of 26 candidemia cases (four C.auris, 22 non-C.auris) in 2438 admitted COVID-19 (10.7 per 1000 admissions) and 59 candidemia cases (six C.auris, 53 non-C.auris) in admitted non-COVID patients (8.2 per 1000 admission) were identified. The proportion of C.auris candidemia in COVID-19 and non-COVID-19 patients was 15.4% and 10% respectively. 4/26 of COVID-19 candidemia patients were aged ≤ 15 years (10 months-15 years). Comparison of C.auris and non-C.auris candidemia cases reveal significant difference (4 Candida auris;22 non-C.auris) in COVID-19 patients (April-December 2020) are reported from Pakistan. Compared to non-C.auris, C.auris candidemia patients had higher prior antifungal exposure, longer hospital stay, higher MDR bacteria and increased rate of Candida colonization.

Dicarbonyls are highly reactive compounds and major precursors of advanced glycation endproducts (AGEs). Both dicarbonyls and AGEs are associated with development of age-related diseases. Dicarbonyls are formed endogenously, but also during food processing. To what extent dicarbonyls from the diet contribute to circulating dicarbonyls and AGEs in tissues is unknown.

To examine cross-sectional associations of dietary dicarbonyl intake with plasma dicarbonyl concentrations and skin AGEs.

In 2566 individuals of the population based Maastricht Study (age 60±8 yrs, 50% males, 26% type 2 diabetes), we estimated habitual intake of the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG), by combining Food Frequency Questionnaires with our dietary dicarbonyl database of MGO, GO, and 3-DG concentrations in >200 commonly-consumed food products. Fasting plasma concentrations of MGO, GO, and 3-DG were measured by UPLC-MS/MS. Skin AGEs were measured as skin autofluorescence (SAF), using the ed to be determined.Clinical Trial Registry number The study has been approved by the institutional medical ethical committee (NL31329.068.10) and the Minister of Health, Welfare and Sports of the Netherlands (Permit 131088-105234-PG).

Higher habitual intake of dietary MGO and GO, but not 3-DG, was associated with higher corresponding plasma concentrations. Higher intake of MGO was also associated with higher SAF. These results suggest dietary absorption of MGO and GO. Biological implications of dietary absorption of MGO and GO need to be determined.Clinical Trial Registry number The study has been approved by the institutional medical ethical committee (NL31329.068.10) and the Minister of Health, Welfare and Sports of the Netherlands (Permit 131088-105234-PG).