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Several tyrosine kinase inhibitors have activity in Ph-positive chronic and acute leukemia, but resistant disease and unacceptable side effects may limit efficacy. Ponatinib showed a high level of activity in a phase 2 study of tyrosine kinase inhibitor–resistant disease but was associated with arterial thrombosis. Patients with newly diagnosed chronic myeloid leukemia (CML) frequently receive imatinib. Although initial response rates are high, imatinib fails in up to 40% of patients because of disease resistance, frequently because of BCR-ABL kinase domain mutations or unacceptable side effects. 1 , 2 Patients who discontinue imatinib may have a response to second-generation tyrosine kinase inhibitors. However, 37 to 52% of patients do not have a response, 3 – 8 and 23 to 26% of patients have an initial major cytogenetic response that is lost by 2 years. 3 , 9 The prognosis for these patients is very poor. With the exception of the small number . . .

Samarium hexaboride has recently come under examination as a possible topological insulator. Transport measurements investigating the effects of magnetic impurities on this system uncover characteristics that are consistent with topologically insulating behaviour, and reveal a strongly suppressed bulk conductivity. Topological invariants of electron wavefunctions in condensed matter reveal many intriguing phenomena 1 , 2 . A notable example is provided by topological insulators, which are characterized by an insulating bulk coexisting with a metallic boundary state 3 , 4 . Although there has been intense interest in Bi-based topological insulators 5 , 6 , their behaviour is complicated by the presence of a considerable residual bulk conductivity 7 , 8 , 9 , 10 . Theories predict 11 , 12 that the Kondo insulator system SmB 6 , which is known to undergo a transition from a Kondo lattice metal to a small-gap insulator state with decreasing temperature, could be a topological insulator. Although the insulating bulk and metallic surface separation has been demonstrated in recent transport measurements 13 , 14 , 15 , these have not demonstrated the topologically protected nature of the metallic surface state. Here we report thickness-dependent transport measurements on doped SmB 6 , and show that magnetic and non-magnetic doping results in contrasting behaviour that supports the conclusion that SmB 6 shows virtually no residual bulk conductivity.

A genetic variant conferring a loss of function on the enzyme hydroxysteroid 17-beta dehydrogenase 13, expressed in the membrane surrounding the hepatic lipid droplet, was associated with a reduced risk of chronic liver disease.

In a large randomized trial that compares regimens in which brentuximab vedotin replaced bleomycin, the group receiving the brentuximab had a 4.9 percentage-point improvement in modified progression-free survival, less pulmonary toxicity, and more myelotoxicity and neurotoxicity.

Vascular endothelial growth factor-A (VEGF), a potent angiogenic factor, is also implicated in self-renewal in several normal tissue types. VEGF has been shown to drive malignant stem cells but mechanisms thereof and tumor types affected are not fully characterized. Here, we show VEGF promotes breast and lung cancer stem cell (CSC) self-renewal via VEGF receptor-2 (VEGFR-2)/STAT3-mediated upregulation of Myc and Sox2. VEGF increased tumor spheres and aldehyde dehydrogenase activity, both proxies for stem cell function in vitro, in triple-negative breast cancer (TNBC) lines and dissociated primary cancers, and in lung cancer lines. VEGF exposure before injection increased breast cancer-initiating cell abundance in vivo yielding increased orthotopic tumors, and increased metastasis from orthotopic primaries and following tail vein injection without further VEGF treatment. VEGF rapidly stimulated VEGFR-2/JAK2/STAT3 binding and activated STAT3 to bind MYC and SOX2 promoters and induce their expression. VEGFR-2 knockdown or inhibition abrogated VEGF-mediated STAT3 activation, MYC and SOX2 induction and sphere formation. Notably, knockdown of either STAT3 , MYC or SOX2 impaired VEGF-upregulation of pSTAT3, MYC and SOX2 expression and sphere formation. Each transcription factor, once upregulated, appears to promote sustained activation of the others, creating a feed-forward loop to drive self-renewal. Thus, in addition to angiogenic effects, VEGF promotes tumor-initiating cell self-renewal through VEGFR-2/STAT3 signaling. Analysis of primary breast and lung cancers (>1300 each) showed high VEGF expression, was prognostic of poor outcome and strongly associated with STAT3 and MYC expression, supporting the link between VEGF and CSC self-renewal. High-VEGF tumors may be most likely to escape anti-angiogenics by upregulating VEGF, driving CSC self-renewal to re-populate post-treatment. Our work highlights the need to better define VEGF-driven cancer subsets and supports further investigation of combined therapeutic blockade of VEGF or VEGFR-2 and JAK2/STAT3.

Solar ultraviolet (UV) light is a major etiological factor in skin carcinogenesis, with solar UV-stimulated signal transduction inducing pathological changes and skin damage. The primary sensor of solar UV-induced cellular signaling has not been identified. We use an experimental system of solar simulated light (SSL) to mimic solar UV and we demonstrate that Fyn is a primary redox sensor involved in SSL-induced signal transduction. Reactive oxygen species (ROS) generated by SSL exposure directly oxidize Cys488 of Fyn, resulting in increased Fyn kinase activity. Fyn oxidation was increased in mouse skin after SSL exposure and Fyn-knockout mice formed larger and more tumors compared with Fyn wild-type mice when exposed to SSL for an extended period of time. Murine embryonic fibroblasts (MEFs) lacking Fyn and cells in which Fyn expression was knocked down were resistant to SSL-induced apoptosis. Furthermore, cells expressing mutant Fyn (C448A) were resistant to SSL-induced apoptosis. These findings suggest that Fyn acts as a regulatory nexus between solar UV, ROS and signal transduction during skin carcinogenesis.

Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic virus and the culprit behind the human disease Kaposi sarcoma (KS), an AIDS-defining malignancy. KSHV encodes a viral G-protein-coupled receptor (vGPCR) critical for the initiation and progression of KS. In this study, we identified that YAP/TAZ, two homologous oncoproteins inhibited by the Hippo tumor suppressor pathway, are activated in KSHV-infected cells in vitro, KS-like mouse tumors and clinical human KS specimens. The KSHV-encoded vGPCR acts through Gq/11 and G12/13 to inhibit the Hippo pathway kinases Lats1/2, promoting the activation of YAP/TAZ. Furthermore, depletion of YAP/TAZ blocks vGPCR-induced cell proliferation and tumorigenesis in a xenograft mouse model. The vGPCR-transformed cells are sensitive to pharmacologic inhibition of YAP. Our study establishes a pivotal role of the Hippo pathway in mediating the oncogenic activity of KSHV and development of KS, and also suggests a potential of using YAP inhibitors for KS intervention.

BiFeO 3 –BaTiO 3 lead-free piezoelectric ceramics have been studied for their application to sensors and actuators. The high strain and piezoelectric actuator coefficient ( d 33 *) are observed in tetragonal 0.60BiFeO 3 –0.40BaTiO 3 ceramic with heat-treated single-phase rutile titanium dioxide (TiO 2 ) powders than in ceramic with commercial mixed-phase with rutile and anatase TiO 2 . The optimized sintering temperature is 1010 °C with the quenching process. The increase of the grain size in microstructure, higher tetragonal phase volume fraction, and higher tetragonality are observed in ceramic with rutile TiO 2 than in ceramic with commercial TiO 2 . The maximum strain is 0.316%, and d 33 * is 576 pm/V. A high Curie phase transition temperature of 355 °C is measured with the maximum dielectric constant (ε r , max ) about 30% higher than that of ceramic with commercial TiO 2 . It is found that the single-phase starting material is important to improve piezoelectric, ferroelectric, and dielectric properties in lead-free piezoelectric ceramics.