The FMS-like tyrosine kinase 3 (FLT3) gene, belonging to the receptor tyrosine kinase (TK) subclass III family, plays an important role in normal hematopoiesis and is one of the most frequently mutated genes in hematologic malignancies as well as an attractive target for directed inhibition. Activating mutations of this gene, including internal tandem duplication in the juxtamembrane (JM) domain and point mutations in the TK domain, are found in approximately one-third of patients with acute myeloid leukemia and in a smaller subset of patients with acute lymphoblastic leukemia. We report here that FLT3 may contribute to leukemogenesis in a patient with myeloproliferative disorder and a t(12;13)(p13;q12) translocation through generating a fusion gene with the ETS variant gene 6 (ETV6) gene. ETV6 has been reported to fuse to various partner genes, including TK and transcription factors. Both ETV6/FLT3 and reciprocal FLT3/ETV6 transcripts were detected in the patient mRNA by reverse transcriptase-polymerase chain reaction. At the protein level, however, only ETV6/FLT3 products were expressed. Among them, one retains the helix-loop-helix (HLH) oligomerization domain of ETV6 and the JM as well as TK domain of FLT3. FLT3 receptor in leukemic cells might be inappropriately activated through dimerization by HLH domain of ETV6, which consequently interfered with proliferation and differentiation of hematopoietic cells.

Human leukocyte antigen (HLA) genotyping displays the particular characteristics of HLA alleles and haplotype frequencies in each population. Although it is considered the current gold standard for HLA typing, high-resolution sequence-based HLA typing is currently unavailable in Kinh Vietnamese populations. In this study, high-resolution sequence-based HLA typing (3-field) was performed using an amplicon-based nextgeneration sequencing platform to identify the HLA-A,-B,-C,-DRB1, and-DQB1 alleles of 101 unrelated healthy Kinh Vietnamese individuals from southern Vietnam. A total of 28 HLA-A, 41 HLA-B, 21 HLA-C, 26 HLA-DRB1, and 25 HLA-DQB1 alleles were identified. The most frequently occurring HLA alleles were A *

FMS-like tyrosine kinase-3 (FLT3) is a new therapeutic target for acute myelocytic leukemia (AML), because FLT3 mutations are the most common genetic alterations in AML and are directly related to leukemogenesis. We studied cytotoxic interactions of a FLT3 inhibitor, PKC412, with eight conventional antileukemic agents (cytarabine, doxorubicin, idarubicin, mitoxantrone, etoposide, 4-hydroperoxy-cyclophosphamide, methotrexate and vincristine) using three leukemia cell lines carrying FLT3 mutations (MOLM13, MOLM14 and MV4-11) and five leukemia cell lines without FLT3 mutations (KOPB-26, THP-1, BALL-1, KG-1 and U937). PKC412 showed synergistic effects with all agents studied except methotrexate for FLT3-mutated cell lines in isobologram analysis. In contrast, PKC412 was rather antagonistic to most drugs, except for 4-hydroperoxy-cyclophosphamide and vincristine, in leukemia cell lines without FLT3 mutations. Cell-cycle analysis revealed that PKC412 induced G1 arrest in leukemia cell lines carrying FLT3 mutations, whereas it arrested cells in G2/M phase in the absence of FLT3 mutations, which may underlie the divergent cytotoxic interactions. These results suggest that the simultaneous administration of PKC412 and other agents except methotrexate is clinically effective against FLT3 mutationpositive leukemias, whereas it would be of little benefit for FLT3 mutation-negative leukemias. Our findings may be of help for the design of PKC412-based combination chemotherapy.

The exact molecular mechanism by which epigallocatechin gallate (EGCG) suppresses human pancreatic cancer cell proliferation is unclear. We show here that EGCG-treated pancreatic cancer cells AsPC-1 and BxPC-3 decrease cell adhesion ability on micro-pattern dots, accompanied by dephosphorylations of both focal adhesion kinase (FAK) and insulin-like growth factor-1 receptor (IGF-1R) whereas retained the activations of mitogen-activated protein kinase and mammalian target of rapamycin. The growth of AsPC-1 and BxPC-3 cells can be significantly suppressed by EGCG treatment alone in a dose-dependent manner. At a dose of 100 μM which completely abolishes activations of FAK and IGF-1R, EGCG suppresses more than 50% of cell proliferation without evidence of apoptosis analyzed by PARP cleavage. Finally, the MEK1/2 inhibitor U0126 enhances growth-suppressive effect of EGCG. Our data suggests that blocking FAK and IGF-1R by EGCG could prove valuable for targeted therapy, which can be used in combination with other therapies, for pancreatic cancer.

We investigate the radiative decay of the cosmic neutrino background, and its impact on the spectrum of the cosmic microwave background (CMB) that is known to be a nearly perfect black body. We derive exact formulae for the decay of a heavier neutrino into a lighter neutrino and a photon, νj → νi + γ, and of absorption as its inverse, νi + γ → νj, by accounting for the precise form of the neutrino momentum distribution. Our calculations show that if the neutrinos are heavier than O(0.1) eV, the exact formulae give results that differ by ∼50%, compared with approximate ones where neutrinos are assumed to be at rest. We also find that spectral distortion due to absorption is more important for heavy neutrino masses (by a factor of ∼10 going from a neutrino mass of 0.01 eV to 0.1 eV). By analyzing the CMB spectral data measured with COBE-FIRAS, we obtain lower limits on the neutrino lifetime of τ12 4 × 10 21 s (95% C.L.) for the smaller mass splitting and τ13 ∼ τ23 10 19 s for the larger mass splitting. These represent up to one order of magnitude improvement over previous CMB constraints. With future CMB experiments such as PIXIE, these limits will improve by roughly 4 orders of magnitude. This translates to a projected upper limit on the neutrino magnetic moment (for certain neutrino masses and decay modes) of µν < 3 × 10 −11 µB, where µB is the Bohr magneton. Such constraints would make future precision CMB measurements competitive with lab-based constraints on neutrino magnetic moments. PACS numbers: 13.35.Hb, 95.30.Cq, 98.70.Vc, 98.80.-k arXiv:1803.00588v2 [astro-ph.CO]

The mutational spectrum of deafness in Indochina Peninsula, including Vietnam, remains mostly undetermined. This significantly hampers the progress toward establishing an effective genetic screening method and early customized rehabilitation modalities for hearing loss. In this study, we evaluated the genetic profile of severe-to-profound hearing loss in a Vietnamese pediatric population using a hierarchical genetic analysis protocol that screened 11 known deafness-causing variants, followed by massively parallel sequencing targeting 129 deafness-associated genes. Eighty-seven children with isolated severe-to-profound non-syndromic hearing loss without family history were included. The overall molecular diagnostic yield was estimated to be 31.7%. The mutational spectrum for severe-to-profound non-syndromic hearing loss in our Vietnamese population was unique: The most prevalent variants resided in the MYO15A gene (7.2%), followed by GJB2 (6.9%), MYO7A (5.5%), SLC26A4 (4.6%), TMC1 (1.8%), ESPN (1.8%), POU3F4 (1.8%), MYH14 (1.8%), EYA1 (1.8%), and MR-RNR1 (1.1%). The unique spectrum of causative genes in the Vietnamese deaf population was similar to that in the southern Chinese deaf population. It is our hope that the mutation spectrum provided here could aid in establishing an efficient protocol for genetic analysis of severe-to-profound hearing loss and a customized screening kit for the Vietnamese population.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal tract. Most GISTs patients respond to imatinib, yet will eventually exhibit resistance, and the mechanisms of imatinib resistance have not yet been fully elucidated. To clarify the mechanisms of secondary imatinib-resistant gastrointestinal stromal tumors, we generated resistant cells from the imatinib-sensitive GIST-T1 cells by exposing them to increasing concentrations of imatinib for 6 m. GIST-T1 IR (imatinib-resistant) cells showing an IC50 of imatinib 5-7 microM were generated. In GIST-T1 IR cells, KIT and its downstream signaling molecules remained phosphorylated with the presence of 1 microM imatinib, and no new mutations were found in KIT, PDGFRA, PKCtheta and JAK2. DNA micro-array analysis showed the overexpression of Cas-L in the resistant cells with 513 fold higher than that in the parental cells. Cas-L overexpression and SRC hyper-activation were also observed in the resistant cells at protein level and they were markedly decreased in KIT siRNA transfected GIST-T1 IR cells. Interestingly, GIST-T1 IR cells transfected with Cas-L siRNA turned out to become again sensitive to imatinib. Imatinib or PP1, a SRC inhibitor, alone was not enough to suppress the activation of KIT and its downstream signaling molecules, but the combination of them showed strong inhibitory effects on those in the resistant cells. We report for the first time that the mechanism of imatinib-resistant GISTs, at least in one cell line, involves KIT/Cas-L/SRC signaling. Cas-L depletion sensitized the resistant GIST-T1 IR cells to imatinib.

Background HLA-B∗38:02 has been shown to be associated with antithyroid drug-induced agranulocytosis in Asian patients. Methods HLA-B∗38:02 was analyzed by sequence-based typing in 21 patients who developed antithyroid drug-induced agranulocytosis and in 81 controls. Results Frequency of HLA-B∗38:02 was 52.4% in agranulocytosis patients compared to 3.7% in controls (OR = 28.6, 95% CI = 6.8–120.2). Conclusions HLA-B∗38:02 is a significant risk factor for agranulocytosis in Kinh Vietnamese patients treated with antithyroid drug.