TPX-0131, a Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and ALK-resistant Mutations.

Since 2011, with the approval of crizotinib and subsequent approval of four additional targeted therapies, anaplastic lymphoma kinase (ALK) inhibitors have become important treatments for a subset of patients with lung cancer. Each generation of ALK inhibitor showed improvements in terms of central nervous system (CNS) penetration and potency against wild-type (WT) ALK, yet a key continued limitation is their susceptibility to resistance from ALK active-site mutations. The solvent front mutation (G1202R) and gatekeeper mutation (L1196M) are major resistance mechanisms to the first two generations of inhibitors while patients treated with the third-generation ALK inhibitor lorlatinib often experience progressive disease with multiple mutations on the same allele (mutations in cis, compound mutations). TPX-0131 is a compact macrocyclic molecule designed to fit within the ATP-binding boundary to inhibit ALK fusion proteins. In cellular assays, TPX-0131 was more potent than all five approved ALK inhibitors against WT ALK and many types of ALK resistance mutations, e.g., G1202R, L1196M, and compound mutations. In biochemical assays, TPX-0131 potently inhibited (IC50 <10 nmol/L) WT ALK and 26 ALK mutants (single and compound mutations). TPX-0131, but not lorlatinib, caused complete tumor regression in ALK (G1202R) and ALK compound mutation-dependent xenograft models. Following repeat oral administration of TPX-0131 to rats, brain levels of TPX-0131 were approximately 66% of those observed in plasma. Taken together, preclinical studies show that TPX-0131 is a CNS-penetrant, next-generation ALK inhibitor that has potency against WT ALK and a spectrum of acquired resistance mutations, especially the G1202R solvent front mutation and compound mutations, for which there are currently no effective therapies.

Tunable UV-visible absorption of SnS2 layered quantum dots produced by liquid phase exfoliation.

4H-SnS2 layered crystals synthesized by a hydrothermal method were used to obtain via liquid phase exfoliation quantum dots (QDs), consisting of a single layer (SLQDs) or multiple layers (MLQDs). Systematic downshift of the peaks in the Raman spectra of crystals with a decrease in size was observed. The bandgap of layered QDs, estimated by UV-visible absorption spectroscopy and the tunneling current measurements using graphene probes, increases from 2.25 eV to 3.50 eV with decreasing size. 2-4 nm SLQDs, which are transparent in the visible region, show selective absorption and photosensitivity at wavelengths in the ultraviolet region of the spectrum while larger MLQDs (5-90 nm) exhibit a broad band absorption in the visible spectral region and the photoresponse under white light. The results show that the layered quantum dots obtained by liquid phase exfoliation exhibit well-controlled and regulated bandgap absorption in a wide tunable wavelength range. These novel layered quantum dots prepared using an inexpensive method of exfoliation and deposition from solution onto various substrates at room temperature can be used to create highly efficient visible-blind ultraviolet photodetectors and multiple bandgap solar cells.

A novel pepper (Capsicum annuum) receptor-like kinase functions as a negative regulator of plant cell death via accumulation of superoxide anions.

Plant receptor-like kinases belong to a large gene family. The Capsicum annuum receptor-like kinase 1 (CaRLK1) gene encodes a transmembrane protein with a cytoplasmic kinase domain and an extracellular domain. The CaRLK1 extracellular domain (ECD)-green fluorescent protein (GFP) fusion protein was targeted to the plasma membrane, and the kinase domain of the CaRLK1 protein exhibited autophosphorylation activity. CaRLK1 transcripts were more strongly induced in treatment with Xag8ra than in treatment with Xag8-13. Furthermore, infection with incompatible Xanthomonas campestris pv. vesicatoria race 3 induced expression of CaRLK1 more strongly than in the compatible interaction. Cell death caused by both a disease-forming and an HR-inducing pathogen was delayed in the CaRLK1-transgenic plants. Ectopic expression of CaRLK1 also induced transcripts of the lesion stimulating disease (LSD) gene, a negative regulator of cell death. Respiratory burst oxidase homolog (RBOH) genes were up-regulated in the transgenic plants compared with the wild type, as the concentration of the superoxide anion was increased. In contrast, the concentration of H(2)O(2) did not differ between the transgenic and wild-type plants. These results support the theory that the suppression of plant cell death by CaRLK1 is associated with consistent production of the superoxide anion and induction of the RBOH genes and the LSD gene, but not with the concentration of H(2)O(2). Thus, CaRLK1 may be a receptor of an as yet unidentified pathogen molecular pattern and may function as a negative regulator of plant cell death.

Isolation and functional characterization of the Arabidopsis salt-tolerance 32 (AtSAT32) gene associated with salt tolerance and ABA signaling.

Recently, we have isolated salt-tolerance genes (SATs) on the basis of the overexpression screening of yeast with a maize cDNA library from kernels. One of the selected genes [salt-tolerance 32 (SAT32)] appears to be a key determinant for salt stress tolerance in yeast cells. Maize SAT32 cDNA encodes for a 49-kDa protein, which is 41% identity with the Arabidopsis salt-tolerance 32 (AtSAT32) unknown gene. Arabidopsis Transfer-DNA (T-DNA) knockout AtSAT32 (atsat32) altered root elongation, including reduced silique length and reduced seed number. In an effort to further assess salinity tolerance in Arabidopsis, we have functionally characterized the AtSAT32 gene and determined that salinity and the plant hormone ABA induced the expression of AtSAT32. The atsat32 mutant was more sensitive to salinity than the wild-type plant. On the contrary, Arabidopsis overexpressing AtSAT32 (35S::AtSAT32) showed enhanced salt tolerance and increased activity of vacuolar H(+)-pyrophosphatase (V-PPase, EC 3.6.1.1) under high-salt conditions. Consistent with these observations, 35S::AtSAT32 plants exhibited increased expression of salt-responsive and ABA-responsive genes, including the Rd29A, Erd15, Rd29B, Rd22 and RAB18 genes. Therefore, our results indicate that AtSAT32 is involved in both salinity tolerance and ABA signaling as a positive regulator in Arabidopsis.

Effects of exercise training on pathological cardiac hypertrophy related gene expression and apoptosis.

This study determined whether exercise training prevents pathological hypertrophy in the left ventricle by modulation of myocardial and apoptosis-associated genes. We used spontaneously hypertensive rats (n=15, non-exercise SHR), exercise-trained SHR (n=15, treadmill exercise for 12 weeks), and sedentary Wistar-Kyoto (WKY) rats (n=15). Exercise-trained SHR expressed adaptive changes such as reduced body weight, heart rate, blood pressures, left ventricle wall thickness, lipid profiles, and homocysteine level. The mRNA expression of angiotensin converting enzyme, endothelin-1, and brain natriuretic peptides in the heart was lower in the exercise-trained SHR and in the WKY than in the non-exercise SHR, whereas mRNA expression of caveolin-3 and eNOS in the heart was higher. Bcl-2 protein was higher in the exercise-trained SHR than in the WKY and the non-exercise SHR. In contrast, Bax protein levels were lower in the exercise-trained SHR and in the WKY than in the non-exercise SHR. Furthermore, the levels of the active forms of caspase-3 (20 kDa) were lower in the exercise-trained SHR and in the WKY than in the non-exercise SHR. These findings suggest that exercise training prevents pathological hypertrophy in the left ventricle by modulation of myocardial genes and that it interferes with a signal transduction pathway of apoptosis secondary to the pathological cardiac hypertrophy.

Complex oscillations in a simple model for the Briggs-Rauscher reaction.

Complex oscillations in a simple model of the Briggs-Rauscher reaction mechanism in a continuously stirred tank reactor proposed by Kim et al. [J. Chem. Phys. 117, 2710 (2002)] are investigated numerically. The k(0)-[CH(2)(COOH)(2)](0) phase diagram is constructed first where k(0) is the flow rate and [...](0) is the input concentration. Within the region surrounded by the Hopf bifurcation curve, we find complex oscillation regions which are again separated from the regular oscillation region by the secondary Hopf bifurcation curves. Mixed mode oscillations with an incomplete Farey sequence, periodic-chaotic (or nonperiodic) sequence, and various types of burst oscillations are observed in complex oscillation regions. Also, chaotic burst oscillations, which are due to the transition from one kind of burst to another kind, are reported.