Shannonkaspersen8005

lantschouensis) and honey bees (Apis mellifera L.) begin laying eggs. Overall, based on the expression of IRP30 during development and egg laying in female bumble bees, this protein not only responds to immune challenge but also may play an important role in metamorphosis and reproduction. © The Author(s) 2020. Published by Oxford University Press on behalf of Entomological Society of America.The house crickets, Acheta domesticus, are sustainable and nutritious future sources of food, due to their nutritional benefits, particular high protein content and potential in solving global malnutrition. Different diets, particularly protein content, can influence the growth and nutritional value of crickets. The aim of this present study was to evaluate the effects of commercial diets and other formulated diets on the nutritional composition and growth parameters of the house crickets, being a major challenge to cricket's farmers in Thailand. Feed conversion ratio were 1.50, 1.50, and 1.51 for fed crickets on a blend of 22% protein and dry pulp pumpkin powder, fed 22% protein plus fresh pumpkin pulp, and fed 22% protein alone, indicated that these groups are high feed convertors and represented the quality of these diets compared to 1.73 and 1.81 for fed crickets on a blend of 22% and 16% protein, and those fed on 16% protein alone. Fed crickets on 22% protein had the highest amount of protein (76%), the lowest (48%) in those fed on 22% protein and fresh pumpkin pulp inclusion. The group on 22% protein diet also had the highest amount of phosphorus, potassium, calcium, and sodium. Fed 22% protein and either dry pulp pumpkin powder or fresh pumpkin pulp condition have shown improvement in vitamin B content. Crickets can effectively be produced on 22% protein diet to improve yield output and several minerals such as phosphorus, potassium, calcium, and sodium. Syk inhibitor In contrast, the supplementation of 22% protein diet with pumpkin (Cucurbita maxima) will improve vitamin B content. © The Author(s) 2020. Published by Oxford University Press on behalf of Entomological Society of America.Acute myeloid leukemia (AML) with inv(3)/t(3;3)(q21q26) is a distinct WHO recognized entity, characterized by its aggressive course and poor prognosis. In this subtype of AML, the translocation of a GATA2 enhancer (3q21) to MECOM (3q26) results in overexpression of the MECOM isoform EVI1 and monoallelic expression of GATA2 from the unaffected allele. The full-length MECOM transcript, MDS1-EVI1, is not expressed as the result of the 3q26 rearrangement. Besides the classical inv(3)/t(3;3), a number of other 3q26/MECOM rearrangements with poor treatment response have been reported in AML. Here we demonstrate, in a group of 33 AML patients with atypical 3q26 rearrangements, MECOM involvement with EVI1 overexpression, but no or low MDS1-EVI1 levels. Moreover, the 3q26 translocations in these AML patients often involve super-enhancers of genes active in myeloid development (e.g. CD164, PROM1, CDK6 or MYC). In more than 50% of these cases allele specific GATA2 expression was observed, either by copy number loss or by an unexplained allelic imbalance. Altogether, atypical 3q26 recapitulate the main leukemic mechanism of inv(3)/t(3;3) AML, namely EVI1 overexpression driven by enhancer hijacking, absent MDS1-EVI1 expression and potential GATA2 involvement. Therefore, we conclude that both atypical 3q26/MECOM and inv(3)/t(3;3) can be classified as a single entity of 3q26-rearranged AMLs. Routine analyses determining MECOM rearrangements, EVI1 and MDS1-EVI1 expression are required to recognize 3q-rearranged AML cases. Copyright © 2020 American Society of Hematology.Oncogenic RAS mutations pose substantial challenges for rational drug discovery. Sequence variations within the hypervariable region (HVR) of Ras isoforms underlie differential post-translational modification and subcellular trafficking, potentially resulting in selective vulnerabilities. Specifically, inhibiting the palmitoylation/depalmitoylation cycle is an appealing strategy for treating NRAS mutant cancers, particularly as normal tissues would retain K-Ras4b function for physiologic signaling. The role of endogenous N-RasG12D palmitoylation in signal transduction, hematopoietic differentiation, and myeloid transformation are unknown and addressing these key questions will inform efforts to develop mechanism-based therapies. To evaluate the palmitoylation/depalmitoylation cycle as a candidate drug target in an in vivo disease-relevant model system, we introduced a C181S mutation into a conditional NrasG12D "knock-in" allele. The C181S second site amino acid substitution abrogated myeloid transformation by NrasG12D, which was associated with mislocalization of the non-palmitoylated N-Ras mutant protein, reduced Raf/MEK/ERK signaling, and alterations in hematopoietic stem and progenitor populations. Furthermore, hematologic malignancies arising in NrasG12D/G12D,C181S compound heterozygous mice invariably acquired revertant mutations that restored cysteine 181. Together, these studies validate the palmitoylation cycle as a promising therapeutic target in NRAS mutant cancers. Copyright © 2020 American Society of Hematology.Mutations in JAK2, MPL, or CALR are detected in more than 80% of myeloproliferative neoplasm (MPN) patients and are thought to play a driver role in MPN pathogenesis via autosomal activation of the JAK-STAT signaling cascade. Mutant CALR binds to MPL, activates downstream MPL signaling cascades, and induces essential thrombocythemia in mice. However, embryonic lethality of Calr-deficient mice precludes determination of a role for CALR in hematopoiesis. To clarify the role of CALR in normal hematopoiesis and MPN pathogenesis, we generated hematopoietic cell-specific Calr-deficient mice. CALR deficiency had little effect on the leukocyte count, hemoglobin levels, or platelet count in peripheral blood. However, Calr-deficient mice showed some hematopoietic properties of MPN, including decreased erythropoiesis and increased myeloid progenitor cells in the bone marrow, and extramedullary hematopoiesis in the spleen. Transplantation experiments revealed that Calr haploinsufficiency promoted the self-renewal capacity of hematopoietic stem cells. We generated CALRdel52 mutant transgenic mice with Calr haploinsufficiency as a model that mimics human MPN patients and found that Calr haploinsufficiency restored the self-renewal capacity of hematopoietic stem cells damaged by CALR mutations. Only recipient mice transplanted with Lineage－Sca1+c-kit+ cells harboring both CALR mutation and Calr haploinsufficiency developed MPN in competitive conditions, showing that CALR haploinsufficiency was required for the onset of CALR-mutated MPNs. Copyright © 2020 American Society of Hematology.Resistance to multimodal chemotherapy continues to limit the prognosis of acute lymphoblastic leukemia (ALL). This occurs in part through a process called adhesion-mediated drug resistance, which depends on ALL cell adhesion to the stroma through adhesion molecules, including integrins. Integrin α6 has been implicated in minimal residual disease in ALL and in the migration of ALL cells to the central nervous system. However, it has not been evaluated in the context of chemotherapeutic resistance. Here, we show that the anti-human α6-blocking antibody P5G10 induces apoptosis in primary ALL in vitro and sensitizes primary ALL cells to chemotherapy or tyrosine kinase inhibition in vitro and in vivo. We further analyzed the underlying mechanism of α6-associated apoptosis using a conditional knockout model of α6 in murine BCR-ABL1+ B-ALL cells and showed that α6-deficient ALL cells underwent apoptosis. In vivo deletion of α6 in combination with tyrosine kinase inhibitor (TKI) treatment was more effective in eradicating ALL than treatment with a TKI (nilotinib) alone. Proteomic analysis revealed that α6 deletion in murine ALL was associated with changes in Src signaling, including the upregulation of phosphorylated Lyn (pTyr507) and Fyn (pTyr530). Thus, our data support α6 as a novel therapeutic target for ALL. Copyright © 2020 American Society of Hematology.Immunomodulatory drugs (IMiDs) are key agents for the treatment of multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the recruitment of neo-substrates to cereblon, a substrate receptor of the E3 ubiquitin ligase complex; therefore, identification of cell specific neo-substrates is important to understand the effects of IMiDs. In clinical practice, IMiDs induce thrombocytopenia that frequently results in the discontinuation of IMiDs treatment. In the current study, we sought to identify the molecular mechanism underlying thrombocytopenia induced by IMiDs treatment. We found that IMiDs strongly impaired proplatelet formation, a critical step in functional platelet production, through the inhibition of autocrine estradiol signaling in human megakaryocytes. Furthermore, we identified aromatase, an indispensable enzyme for estradiol biosynthesis, as a novel neo-substrate of cereblon. IMiDs promoted the recruitment of aromatase to cereblon, resulting in the degradation of aromatase in a proteasome-dependent manner. Finally, aromatase was significantly degraded in the bone marrow of patients with multiple myeloma who developed thrombocytopenia with IMiDs treatment. These data suggest that aromatase is a neo-substrate of cereblon that is responsible for IMiDs-induced thrombocytopenia. Copyright © 2020 American Society of Hematology.BACKGROUND Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. METHODS Adults ≥18 years with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in this international Phase 3 randomized, double-blind, placebo-controlled trial. Patients (N=211) were randomized 21 to either venetoclax (N=143) or placebo (N=68) in 28-day cycles, plus low-dose cytarabine (LDAC) on days 1-10. The primary endpoint was overall survival (OS); secondary endpoints included response rates, transfusion independence, and event-free survival. RESULTS Median age was 76 years (range 36-93), 38% had secondary AML, and 20% had prior hypomethylating agent (HMA) treatment. The planned primary analysis showed that the venetoclax arm provided a benefit of 25% reduction in the risk-of-death over the LDAC-alone arm (hazard ratio [HR] 0.75 [95% CI 0.52-1.07], p=0.11), although it was not statistically significant; with median OS of 7.2 months and 4.1 months, respectively. An unplanned analysis with an additional 6 months of follow up demonstrated a median OS of 8.4 months for the venetoclax arm (HR 0.70; 95% CI 0.50-0.98; p=0.04). The CR/CRi rates were 48% and 13% for the Venetoclax plus LDAC arm and LDAC-alone arm, respectively. Key grade ≥3 adverse events (Ven vs. LDAC-alone) were febrile neutropenia (32% vs 29%), neutropenia (47% vs. 16%), and thrombocytopenia (45% vs 37%). CONCLUSION Venetoclax plus LDAC demonstrates a clinically meaningful improvement in remission rates and OS compared to LDAC alone, in the context of a manageable safety profile. These results confirm venetoclax plus LDAC is an important frontline AML treatment option for patients unfit for intensive chemotherapy. Copyright © 2020 American Society of Hematology.