Physiological significance of the two isoforms of initiator tRNAs in .

Unlabelled: possesses four initiator tRNA (i-tRNA) genes, three of which are present together as and the fourth one as . In B, all four genes ( and ) encode i-tRNA, in which the G at position 46 is modified to mG46 by TrmB (mG methyltransferase). However, in K, because of a single-nucleotide polymorphism, encodes a variant, i-tRNA, having an A in place of mG46.

Extended pleurectomy decortication and chemotherapy versus chemotherapy alone for pleural mesothelioma (MARS 2): a phase 3 randomised controlled trial.

Background: Extended pleurectomy decortication for complete macroscopic resection for pleural mesothelioma has never been evaluated in a randomised trial. The aim of this study was to compare outcomes after extended pleurectomy decortication plus chemotherapy versus chemotherapy alone.

Methods: MARS 2 was a phase 3, national, multicentre, open-label, parallel two-group, pragmatic, superiority randomised controlled trial conducted in the UK.

Discordance in Recommendation Between Next-Generation Sequencing Test Reports and Molecular Tumor Boards in India.

Purpose: Accurate understanding of the genomic and transcriptomic data provided by next-generation sequencing (NGS) is essential for the effective utilization of precision oncology. Molecular tumor boards (MTBs) aim to translate the complex data in NGS reports into effective clinical interventions. Often, MTB treatment recommendations differ from those in the NGS reports.

Lamotrigine compromises the fidelity of initiator tRNA recruitment to the ribosomal P-site by IF2 and the RbfA release from 30S ribosomes in .

Lamotrigine (Ltg), an anticonvulsant drug, targets initiation factor 2 (IF2), compromises ribosome biogenesis and causes toxicity to . However, our understanding of Ltg toxicity in remains unclear. While our assays reveal no effects of Ltg on the ribosome-dependent GTPase activity of IF2 or its role in initiation as measured by dipeptide formation in a fast kinetics assay, the experiments show that Ltg causes accumulation of the 17S precursor of 16S rRNA and leads to a decrease in polysome levels in .

Nitric oxide-induced ribosome collision activates ribosomal surveillance mechanisms.

Impairment of protein translation can cause stalling and collision of ribosomes and is a signal for the activation of ribosomal surveillance and rescue pathways. Despite clear evidence that ribosome collision occurs stochastically at a cellular and organismal level, physiologically relevant sources of such aberrations are poorly understood. Here we show that a burst of the cellular signaling molecule nitric oxide (NO) reduces translational activity and causes ribosome collision in human cell lines.

Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With Mutations.

Purpose: The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against mutations. A phase II study of afatinib in mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS).

Patients And Methods: In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for mutations.

Candidate mechanisms of acquired resistance to first-line osimertinib in EGFR-mutated advanced non-small cell lung cancer.

Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR T790M resistance mutations. In the Phase III FLAURA study (NCT02296125), first-line osimertinib improved outcomes vs comparator EGFR-TKIs in EGFRm advanced non-small cell lung cancer. This analysis identifies acquired resistance mechanisms to first-line osimertinib.

Olaparib as maintenance treatment in patients with chemosensitive small cell lung cancer (STOMP): A randomised, double-blind, placebo-controlled phase II trial.

Objectives: Small cell lung cancer (SCLC) responds well to chemoradiotherapy but frequently relapses. Here, we evaluate activity and safety of the poly (adenosine diphosphate (ADP)-ribose) polymerase (PARP) inhibitor olaparib as maintenance treatment for patients with chemoresponsive SCLC.

Materials And Methods: Eligible patients had complete or partial response to first line chemotherapy or chemoradiotherapy for SCLC.

A prognostic score for patients with malignant pleural mesothelioma (MPM) receiving second-line immunotherapy or chemotherapy in the ETOP 9-15 PROMISE-meso phase III trial.

Introduction: Clinical and laboratory parameters associated with response for patients with advanced pre-treated malignant pleural mesothelioma (MPM) are lacking. We aimed to identify prognostic and predictive markers among patients with relapsed MPM who were randomised into the ETOP 9-15 PROMISE-meso phase III trial, evaluating pembrolizumab and chemotherapy.

Methods: Baseline clinical and laboratory parameters were investigated for prognostic or predictive value on progression-free survival (PFS) and overall survival (OS) in a retrospective analysis, based on the full cohort of 144 MPM patients.

An Alternative Role of RluD in the Fidelity of Translation Initiation in Escherichia coli.

The fidelity of initiator tRNA (i-tRNA) selection in the ribosomal P-site is a key step in translation initiation. The highly conserved three consecutive G:C base pairs (3GC pairs) in the i-tRNA anticodon stem play a crucial role in its selective binding in the P-site. Mutations in the 3GC pairs (3GC mutant) render the i-tRNA inactive in initiation.

European and US Real-World Treatment Patterns in Patients with Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer: A Retrospective Medical Record Review.

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the preferred first-line (1L) therapy for EGFR mutation-positive (EGFRm) advanced/metastatic non-small cell lung cancer (NSCLC).

Objective: Our objective was to describe real-world treatment patterns and T790M testing practices in patients with 1L disease progression (Europe/USA) following treatment with first- or second-generation EGFR-TKIs.

Methods: This was a retrospective, non-interventional medical record review of patients with EGFRm locally advanced/metastatic NSCLC from routine clinical practice (EGFR-TKI initiation: 1 January 2015 to 31 December 2017; follow-up: last available medical record).

Mesothelioma and Radical Surgery 2 (MARS 2): protocol for a multicentre randomised trial comparing (extended) pleurectomy decortication versus no (extended) pleurectomy decortication for patients with malignant pleural mesothelioma.

Introduction: Mesothelioma remains a lethal cancer. To date, systemic therapy with pemetrexed and a platinum drug remains the only licensed standard of care. As the median survival for patients with mesothelioma is 12.

Metabolic Flux of N-Formyltetrahydrofolate Plays a Critical Role in the Fidelity of Translation Initiation in Escherichia coli.

One-carbon metabolism produces methionine and N-formyl-tetrahydrofolate (N-fTHF) required for aminoacylation and formylation of initiator tRNA (i-tRNA), respectively. In Escherichia coli, N-fTHF is made from 5, 10-methylene-THF by a two-step reaction using 5,10-methylene-THF dehydrogenase/cyclohydrolase (FolD). The i-tRNAs from all domains of life possess a highly conserved sequence of three consecutive G-C base pairs (3GC pairs) in their anticodon stem.

Successful laparoscope-assisted orchiectomy in three cryptorchid sheep.

Three adult Corriedale cryptorchid sheep were subjected to laparoscopeassisted orchiectomy of the retained testicles. One ( = 2) or both ( = 1) the testicles were missing in their scrotal sac and inguinal regions. Ultrasonography was used to locate the retained testicles and their distance from the abdominal surface.

Pembrolizumab in patients with non-small-cell lung cancer of performance status 2 (PePS2): a single arm, phase 2 trial.

Background: Therapeutic blockade of the axis of programmed cell death 1 (PD-1) and its ligand (PD-L1) has transformed the management of non-small-cell lung cancer (NSCLC). Clinical trials with pembrolizumab have enrolled patients with performance status (PS) 0-1. However, around 18% of patients with NSCLC are PS2, and the activity and safety of pembrolizumab in these patients is unclear.

Tyrosine Kinase Inhibitors for the Treatment of EGFR Mutation-Positive Non-Small-Cell Lung Cancer: A Clash of the Generations.

The availability of 3 generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with different pharmacologic characteristics and clinical profiles has provided oncologists with a potentially confusing choice for the treatment of EGFR mutation-positive non-small-cell lung cancer. Although recent head-to-head clinical trials have demonstrated improved efficacy with second-generation (ie, afatinib, dacomitinib) and third-generation (ie, osimertinib) TKIs compared with the first-generation TKIs (eg, erlotinib, gefitinib), acquired resistance has been inevitable, regardless of which agent has been chosen as first-line therapy. Thus, the potential availability of subsequent treatment options is an important consideration.

Overall Survival with Osimertinib in Untreated, -Mutated Advanced NSCLC.

Background: Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and T790M resistance mutations. A phase 3 trial compared first-line osimertinib with other EGFR-TKIs in patients with mutation-positive advanced non-small-cell lung cancer (NSCLC). The trial showed longer progression-free survival with osimertinib than with the comparator EGFR-TKIs (hazard ratio for disease progression or death, 0.

SIRT6 transcriptionally regulates global protein synthesis through transcription factor Sp1 independent of its deacetylase activity.

Global protein synthesis is emerging as an important player in the context of aging and age-related diseases. However, the intricate molecular networks that regulate protein synthesis are poorly understood. Here, we report that SIRT6, a nuclear-localized histone deacetylase represses global protein synthesis by transcriptionally regulating mTOR signalling via the transcription factor Sp1, independent of its deacetylase activity.

Rapid formylation of the cellular initiator tRNA population makes a crucial contribution to its exclusive participation at the step of initiation.

Initiator tRNAs (i-tRNAs) possess highly conserved three consecutive GC base pairs (GC/GC/GC, 3GC pairs) in their anticodon stems. Additionally, in bacteria and eukaryotic organelles, the amino acid attached to i-tRNA is formylated by Fmt to facilitate its targeting to 30S ribosomes. Mutations in GC/GC/GC to UA/CG/AU in i-tRNACUA/3GC do not affect its formylation.

Deregulated AUF1 Assists BMP-EZH2-Mediated Delayed Wound Healing during Infection.

Tissue repair is a complex process that necessitates an interplay of cellular processes, now known to be dictated by epigenetics. Intriguingly, macrophages are testimony to a large repertoire of evolving functions in this process. We identified a role for BMP signaling in regulating macrophage responses to infection during wound repair in a murine model.

Utilisation of 10-formyldihydrofolate as substrate by dihydrofolate reductase (DHFR) and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) tranformylase/IMP cyclohydrolase (PurH) in .

Dihydrofolate reductase (DHFR) and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/IMP cyclohydrolase (PurH) play key roles in maintaining folate pools in cells, and are targets of antimicrobial and anticancer drugs. While the activities of bacterial DHFR and PurH on their classical substrates (DHF and 10-CHO-THF, respectively) are known, their activities and kinetic properties of utilisation of 10-CHO-DHF are unknown. We have determined the kinetic properties (/) of conversion of 10-CHO-DHF to 10-CHO-THF by DHFR, and to DHF by PurH.