👤 Paras Gaur

Genetic alterations activating the MAPK pathway are common in non-small cell lung cancer (NSCLC). Patients with NSCLC may benefit from treatment with the pan-RAF inhibitor naporafenib (LXH254) plus the ERK1/2 inhibitor rineterkib (LTT462) or MEK1/2 inhibitor trametinib. This first-in-human phase 1b dose-escalation/dose-expansion study investigated the combinations of naporafenib (50-350 mg once daily [QD] or 300-600 mg twice daily [BID]) with rineterkib (100-300 mg QD) in patients with KRAS-/BRAF-mutant NSCLC and naporafenib (200 mg BID or 400 mg BID) with trametinib (0.5 mg QD, 1 mg QD or 1 mg QD 2 weeks on/2 weeks off) in patients with KRAS-/BRAF-mutant NSCLC and NRAS-mutant melanoma. The primary objectives were to identify the recommended dose for expansion (RDE) and evaluate tolerability and safety. Secondary objectives included antitumor activity and pharmacodynamics. Overall, 216 patients were treated with naporafenib plus rineterkib (NSCLC: n = 101) or naporafenib plus trametinib (NSCLC: n = 79; melanoma: n = 36). In total, 10 of 62 (16%) patients experienced at least one dose-limiting toxicity. The RDEs were established as naporafenib 400 mg BID plus rineterkib 200 mg QD, naporafenib 200 mg BID plus trametinib 1 mg QD and naporafenib 400 mg BID plus trametinib 0.5 mg QD. The most frequent grade ≥ 3 treatment-related adverse event was increased lipase (8/101 [7.9%] patients) for naporafenib plus rineterkib and rash (22/115 [19.1%] patients) for naporafenib plus trametinib. Among patients with NSCLC, partial response was observed in three patients (one with KRAS-mutant, two with BRAF Both naporafenib combinations had acceptable safety profiles. Antitumor activity was limited in patients with NSCLC, despite the observed on-target pharmacodynamic effect. gov identifier: NCT02974725. Show less

As many as 700,000 unique sequences in the human genome are predicted to fold into G-quadruplexes (G4s), non-canonical structures formed by Hoogsteen guanine-guanine pairing within G-rich nucleic acids. G4s play both physiological and pathological roles in many vital cellular processes including DNA replication, DNA repair and RNA transcription. Several reagents have been developed to visualize G4s in vitro and in cells. Recently, Zhen et al. synthesized a small protein G4P based on the G4 recognition motif from RHAU (DHX36) helicase (RHAU specific motif, RSM). G4P was reported to bind the G4 structures in cells and in vitro, and to display better selectivity toward G4s than the previously published BG4 antibody. To get insight into G4P- G4 interaction kinetics and selectivity, we purified G4P and its expanded variants, and analyzed their G4 binding using single-molecule total internal reflection fluorescence microscopy and mass photometry. We found that G4P binds to various G4s with affinities defined mostly by the association rate. Doubling the number of the RSM units in the G4P increases the protein's affinity for telomeric G4s and its ability to interact with sequences folding into multiple G4s. Show less

As many as 700,000 unique sequences in the human genome are predicted to fold into G-quadruplexes (G4s), non-canonical structures formed by Hoogsteen guanine-guanine pairing within G-rich nucleic acids. G4s play both physiological and pathological roles in many vital cellular processes including DNA replication, DNA repair and RNA transcription. Several reagents have been developed to visualize G4s Show less

This investigation was undertaken to assess the population of indigenous (Bareilly local) pigs for meat quality genes (RYR1, PRKAG3, HFABP, MYF-5, and MC4R). The results showed that indigenous pigs were monomorphic at RYR1locus (100% NN genotype), HFABP locus (100% HH genotype), and MYF-5 locus (100% DD genotype). Homozygote RR and heterozygote QR genotypes were observed at PRKAG3 (c.599 G>A) SNP locus with 89 and 11% frequency. The frequency of wild (R) and mutant (Q) allele at the said locus was 95 and 5%. The MC4R SNP had three genotypes; homozygote AA with 5% frequency, heterozygote AG with 53% frequency, and homozygote GG with 42% frequency. Corresponding frequency of A and G allele was 32 and 68%, respectively. Monomorphic status at RYR1locus for NN genotype, HFABP locus for HH genotype, and MYF-5 locus for DD genotype indicated that favorable genes for quality pork production have been fixed in the population. The higher frequency of RR genotype (89%) at PRKAG3 and GG genotype (42%) at MC4R locus further explained the existence of favorable genotypes in indigenous pigs. Show less

This study was designed to screen the crossbred pigs for SNPs in five candidate genes, associated with pork quality traits and to differentiate their genotypes by PCR-RFLP. The results indicated that genotypes of crossbred pigs were NN (90%) and Nn (10%) for RYR1; RR (83%) and QR (17%) for PRKAG3; HH (98%), Hh (1%) and hh (1%) for HFABP; DD (99%) and CD (1%) for MYF-5; and AG (57%), GG (26%) and AA (17%) for MC4R SNPs, respectively. Allelic frequencies for five SNPs {RYR1 (1843C>T), PRKAG3 (c.599G>A), HFABP (c.1322C>T), MYF-5 (c.1205A>C) and MC4R (c.1426A>G)} were 0.95 and 0.05 (N/n), 0.08 and 0.92 (Q/R), 0.99 and 0.01 (H/h), 0.00 and 1.00 (C/D) and 0.45 and 0.55 (A/G), respectively. The effect of RYR1 (1843C>T) SNP was significant on pH Show less

The liver X receptors (LXRs) are a family of nuclear receptor transcription factors that are activated by oxysterols and have defined roles in both lipid metabolism and cholesterol regulation. LXRs also affect antimicrobial responses and have anti-inflammatory effects in macrophages. As mice lacking LXRs are more susceptible to infection by intracellular bacteria Listeria monocytogenes and Mycobacterium tuberculosis, we hypothesized that LXR might also influence macrophage responses to the intracellular protozoan parasite Leishmania chagasi/infantum, a causative agent of visceral leishmaniasis. Surprisingly, both LXRα knock-out and LXRα/LXRβ double-knock-out (DKO) mice were markedly resistant to systemic L. chagasi/infantum infection compared to wild-type mice. Parasite loads in the livers and spleens of these animals were significantly lower than in wild-type mice 28 days after challenge. Bone marrow-derived macrophages from LXR-DKO mice infected with L. chagasi/infantum in vitro in the presence of IFN-γ were able to kill parasites more efficiently than wild-type macrophages. This enhanced killing by LXR-deficient macrophages correlated with higher levels of nitric oxide produced, as well as increased gene expression of IL-1β. Additionally, LXR ligands abrogated nitric oxide production in wild-type macrophages in response to infection. These observations suggest that LXR-deficient mice and macrophages mount antimicrobial responses to Leishmania infection that are distinct from those mounted by wild-type mice and macrophages. Furthermore, comparison of these findings to other intracellular infection models suggests that LXR signaling pathways modulate host antimicrobial responses in a complex and pathogen-specific manner. The LXR pathway thus represents a potential therapeutic target for modulating immunity against Leishmania or other intracellular parasites. Show less

The present study investigated genetic variation in the 3' flanking region of ApoA-I (PstI), the 3' untranslated region of ApoC-III (SstI) and intron 2 of ApoA-IV (XbaI) in 435 type 2 diabetes mellitus patients, divided according to the presence or absence of coronary heart disease (CHD). Uncommon allele frequencies (P2, S2, X2) were 17.5%, 32.5%, 16.2% and 29.5%, 17.9%, 13.8% in patients with and without CHD, respectively. Linkage disequilibrium (D' = 0.31-0.73, p<0.01) was observed in all diallelic pairs except XbaI/PstI and XbaI/SstI in patients having CHD. Haplotype analysis revealed that P1-S2-X1 is a susceptibility haplotype that increases the risk of CHD in diabetes (OR 2.85, CI 1.51-5.61), exacerbating risk (OR 3.57, CI 1.81-7.45) even after adjustment for confounders. The findings in the present study suggest that each unit of P1-S2-X1 in diabetes increases the risk of CHD by a factor of 1.37+/-0.307 (beta + SE), which is manifest in its multiplicative mode. Show less