Calorimetry probe for runaway electron heat load measurement at COMPASS.

Runaway electrons, accelerated in a tokamak discharge to high energies (tens of MeV), can cause serious damage to plasma facing components. Therefore, it is important to develop effective mitigation strategies to reduce the risk of tokamak damage. To study the effects of various mitigation strategies, a dedicated diagnostic, the calorimetry probe, was developed at the COMPASS tokamak.

CDK9 inhibition as an effective therapy for small cell lung cancer.

Treatment-naïve small cell lung cancer (SCLC) is typically susceptible to standard-of-care chemotherapy consisting of cisplatin and etoposide recently combined with PD-L1 inhibitors. Yet, in most cases, SCLC patients develop resistance to first-line therapy and alternative therapies are urgently required to overcome this resistance. In this study, we tested the efficacy of dinaciclib, an FDA-orphan drug and inhibitor of the cyclin-dependent kinase (CDK) 9, among other CDKs, in SCLC.

Characterizing Evolutionary Dynamics Reveals Strategies to Exhaust the Spectrum of Subclonal Resistance in EGFR-Mutant Lung Cancer.

Unlabelled: The emergence of resistance to targeted therapies restrains their efficacy. The development of rationally guided drug combinations could overcome this currently insurmountable clinical challenge. However, our limited understanding of the trajectories that drive the outgrowth of resistant clones in cancer cell populations precludes design of drug combinations to forestall resistance.

Resistance to MET inhibition in MET-dependent NSCLC and therapeutic activity after switching from type I to type II MET inhibitors.

Objectives: Resistance to MET inhibition occurs inevitably in MET-dependent non-small cell lung cancer and the underlying mechanisms are insufficiently understood. We describe resistance mechanisms in patients with MET exon 14 skipping mutation (METΔ), MET amplification, and MET fusion and report treatment outcomes after switching therapy from type I to type II MET inhibitors.

Materials And Methods: Pre- and post-treatment biopsies were analysed by NGS (next generation sequencing), digital droplet PCR (polymerase chain reaction), and FISH (fluorescense in situ hybridization).

A Cross-Sectional Assessment of HIV Self-Testing Preferences and Uptake Among Key Populations in Phnom Penh, Cambodia.

Background: HIV self-testing (HIVST) is recommended by the World Health Organization, but implementation remains limited. This cross-sectional study evaluated HIVST uptake among female entertainment workers (EWs), men who have sex with men (MSM), and transgender women in Phnom Penh, Cambodia, to inform national implementation.

Methods: Between December 2018 and September 2019, individuals reached through community outreach or via online advertising were offered HIVST or referrals to facility-based testing.

Cloaca-Like Anomalies in the Male: A Report on Two Cases.

"Cloaca" is a term used to describe an anomaly in the female where a single orifice is located in the perineum draining both urogenital and gastrointestinal tracts. Few reports used the same term "cloaca" to describe the counterpart anomaly in the male. We present two "male" cases of anorectal anomalies associated with significant penile deformity (caudally displaced penis) that were managed during the period between January 2010 and September 2021.

Report of the First International Symposium on NUT Carcinoma.

NUT carcinoma is a rare, aggressive cancer defined by rearrangements of the NUTM1 gene. No routinely effective treatments of NUT carcinoma exist, despite harboring a targetable oncoprotein, most commonly BRD4-NUT. The vast majority of cases are fatal.

CD74-NRG1 Fusions Are Oncogenic In Vivo and Induce Therapeutically Tractable ERBB2:ERBB3 Heterodimerization.

NRG1 fusions are recurrent somatic genome alterations occurring across several tumor types, including invasive mucinous lung adenocarcinomas and pancreatic ductal adenocarcinomas and are potentially actionable genetic alterations in these cancers. We initially discovered CD74-NRG1 as the first NRG1 fusion in lung adenocarcinomas, and many additional fusion partners have since been identified. Here, we present the first CD74-NRG1 transgenic mouse model and provide evidence that ubiquitous expression of the CD74-NRG1 fusion protein in vivo leads to tumor development at high frequency.

Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer.

Activation of MAPK signaling via BRAF mutations may limit the activity of EGFR inhibitors in EGFR-mutant lung cancer patients. However, the impact of BRAF mutations on the selection and fitness of emerging resistant clones during anti-EGFR therapy remains elusive. We tracked the evolution of subclonal mutations by whole-exome sequencing and performed clonal analyses of individual metastases during therapy.

MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I.

Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming.

Conceptual design of Thomson scattering diagnostics for the COMPASS-U tokamak.

The Thomson scattering (TS) diagnostic, one of the key diagnostics used on the tokamaks around the world, is planned for the COMPASS-U tokamak, which is recently under design and construction in the Institute of Plasma Physics in Prague, Czech Republic. This tokamak is supposed to be a world-unique, high magnetic field device with hot walls, allowing for the study of the plasma exhaust in advanced operational scenarios and testing cutting-edge technologies relevant to future fusion reactors, e.g.

Thomson scattering synthetic diagnostic module for the Cherab framework.

This contribution presents a Thomson scattering module developed for the Raysect and Cherab framework. Detailed models of spectroscopic diagnostic systems can be created in the framework, which deliver synthetic data with high precision due to accurate physical treatment of ray propagation and radiation phenomena. The addition of the presented module will allow us to model Thomson scattering systems that can aid both data validation and design.

Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes.

Loss of TP53 and RB1 in treatment-naïve small cell lung cancer (SCLC) suggests selective pressure to inactivate cell death pathways prior to therapy. Yet, which of these pathways remain available in treatment-naïve SCLC is unknown. Here, through systemic analysis of cell death pathway availability in treatment-naïve SCLC, we identify non-neuroendocrine (NE) SCLC to be vulnerable to ferroptosis through subtype-specific lipidome remodeling.

The next tier of EGFR resistance mutations in lung cancer.

EGFR mutations account for the majority of druggable targets in lung adenocarcinoma. Over the past decades the optimization of EGFR inhibitors revolutionized the treatment options for patients suffering from this disease. The pace of this development was largely dictated by the inevitable emergence of resistance mutations during drug treatment.

Sorafenib and everolimus in patients with advanced solid tumors and KRAS-mutated NSCLC: A phase I trial with early pharmacodynamic FDG-PET assessment.

Background: Treatment of patients with solid tumors and KRAS mutations remains disappointing. One option is the combined inhibition of pathways involved in RAF-MEK-ERK and PI3K-AKT-mTOR.

Methods: Patients with relapsed solid tumors were treated with escalating doses of everolimus (E) 2.

New Approaches to SCLC Therapy: From the Laboratory to the Clinic.

The outcomes of patients with SCLC have not yet been substantially impacted by the revolution in precision oncology, primarily owing to a paucity of genetic alterations in actionable driver oncogenes. Nevertheless, systemic therapies that include immunotherapy are beginning to show promise in the clinic. Although, these results are encouraging, many patients do not respond to, or rapidly recur after, current regimens, necessitating alternative or complementary therapeutic strategies.

MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer.

MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a.

Genomic Profiling Identifies Outcome-Relevant Mechanisms of Innate and Acquired Resistance to Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Lung Cancer.

Purpose: Third-generation epidermal growth factor receptor () tyrosine kinase inhibitors (TKIs) are effective in acquired resistance (AR) to early-generation EGFR TKIs in EGFR-mutant lung cancer. However, efficacy is marked by interindividual heterogeneity. We present the molecular profiles of pretreatment and post-treatment samples from patients treated with third-generation EGFR TKIs and their impact on treatment outcomes.

K-ras Mutation Subtypes in NSCLC and Associated Co-occuring Mutations in Other Oncogenic Pathways.

Introduction: Although KRAS mutations in NSCLC have been considered mutually exclusive driver mutations for a long time, there is now growing evidence that KRAS-mutated NSCLC represents a genetically heterogeneous subgroup. We sought to determine genetic heterogeneity with respect to cancer-related co-mutations and their correlation with different KRAS mutation subtypes.

Methods: Diagnostic samples from 4507 patients with NSCLC were analyzed by next-generation sequencing by using a panel of 14 genes and, in a subset of patients, fluorescence in situ hybridization.

Overcoming EGFR-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors.

The emergence of acquired resistance against targeted drugs remains a major clinical challenge in lung adenocarcinoma patients. In a subgroup of these patients we identified an association between selection of EGFR-negative but EGFR-positive subclones and osimertinib resistance. We demonstrate that EGFR limits the activity of third-generation EGFR inhibitors both in vitro and in vivo.

Observation and evaluation of the alignment of Thomson scattering systems.

Concerning plasma diagnostics based on Thomson scattering (TS), precise adjustment and proper alignment is of great importance in order to provide reliable and accurate measurements. Any misalignment could result in an incorrectly determined plasma density or prevent the measurement with this type of diagnostic altogether. Suitable means of alignment monitoring should be integrated into each TS diagnostic system.

Structural Alterations of MET Trigger Response to MET Kinase Inhibition in Lung Adenocarcinoma Patients.

We sought to investigate the clinical response to MET inhibition in patients diagnosed with structural MET alterations and to characterize their functional relevance in cellular models. Patients were selected for treatment with crizotinib upon results of hybrid capture-based next-generation sequencing. To confirm the clinical observations, we analyzed cellular models that express these MET kinase alterations.

Systematic Kinase Inhibitor Profiling Identifies CDK9 as a Synthetic Lethal Target in NUT Midline Carcinoma.

Kinase inhibitors represent the backbone of targeted cancer therapy, yet only a limited number of oncogenic drivers are directly druggable. By interrogating the activity of 1,505 kinase inhibitors, we found that BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells are specifically killed by CDK9 inhibition (CDK9i) and depend on CDK9 and Cyclin-T1 expression. We show that CDK9i leads to robust induction of apoptosis and of markers of DNA damage response in NMC cells.