Search

The THINICE field campaign, based in Svalbard in August 2022, provided unique observations of summertime Arctic cyclones, their coupling with cloud cover, and their interactions with tropopause polar vortices and sea ice conditions. THINICE was motivated by the need to advance our understanding of these processes and to improve coupled models used to forecast weather and sea ice, as well as long-term projections of climate change in the Arctic. Two research aircraft were deployed with complementary instrumentation. The Service des Avions Frangais Instruments pour la Recherche en Environnement (Safire) Aerei da Trasporto Regionale 42 (ATR42) aircraft, equipped with the radar-lidar (RALI) remote sensing instrumentation and in situ cloud microphysics probes, flew in the midtroposphere to observe the wind and multiphase cloud structure of Arctic cyclones. The British Antarctic Survey Meteorological Airborne Science Instrumentation (MASIN) aircraft flew at low levels measuring sea ice properties, including surface brightness temperature, albedo and roughness, and the turbulent fluxes that mediate exchange of heat and momentum between the atmosphere and the surface. Long-duration instrumented balloons, operated by WindBorne Systems, sampled meteorological conditions within both cyclones and tropospheric polar vortices across the Arctic. Several novel findings are highlighted. Intense, shallow low-level jets along warm fronts were observed within three Arctic cyclones using the Doppler radar and turbulence probes. A detailed depiction of the interweaving layers of ice crystals and supercooled liquid water in mixed-phase clouds is revealed through the synergistic combination of the Doppler radar, the lidar, and in situ microphysical probes. Measurements of near-surface turbulent fluxes combined with remote sensing measurements of sea ice properties are being used to characterize atmosphere-sea ice interactions in the marginal ice zone. SIGNIFICANCE STATEMENT: Arctic cyclones can span several thousand kilometers and last several weeks, bringing strong winds, clouds, and precipitation across the remote Arctic and affecting the sea ice through wind stress, surface energy budget, and snow cover. Therefore, they play a key role in Arctic weather and climate. Motivated by the need to improve the coupled environmental prediction, the representation of cyclones, and their influence on the rapidly changing Arctic climate, the THINICE field campaign intensively observed several Arctic cyclones in August 2022 by operating two aircraft and launching steerable balloons. Key measurements of fine-scale features within Arctic cyclones are highlighted including low-level jets along fronts, mixed-phase clouds containing multiple layers of supercooled water, boundary layer turbulent fluxes, and sea ice properties beneath the cyclones. The ability of state-of-the-art numerical models, with and without coupling to dynamic sea ice models, in representing these cases and coupled processes is the focus of the ongoing work with an aim to improve prediction capabilities. KEYWORDS: Atmosphere; Arctic; Sea ice; Clouds; Jets; Aircraft observations, 1. Introduction The rapidly changing Arctic climate is one of the most alarming signals of global warming as it is having stark impacts on vulnerable ecological systems and indigenous people, [...]

Specific reactive oxygen species activate the GTPase Kirsten rat sarcoma virus (KRAS) by reacting with cysteine 118 (C118), leading to an electron transfer between C118 and nucleoside guanosine diphosphate (GDP), which causes the release of GDP. Here, we have mimicked permanent oxidation of human KRAS at C118 by replacing C118 with aspartic acid (C118D) in KRAS to show that oncogenic mutant KRAS is selectively inhibited via oxidation at C118, both in vitro and in vivo. Moreover, the combined treatment of hydrogen‐peroxide‐producing pro‐oxidant paraquat and nitric‐oxide‐producing inhibitor N(ω)‐nitro‐l‐arginine methyl ester selectively inhibits human mutant KRAS activity by inducing oxidization at C118. Our study shows for the first time the vulnerability of human mutant KRAS to oxidation, thereby paving the way to explore oxidation‐based anti‐KRAS treatments in humans.

Abstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are commonly used to treat non-small cell lung cancers with EGFR mutations, but drug resistance often emerges. Intratumor heterogeneity is a known cause of targeted therapy resistance and is considered a major factor in treatment failure. This study identifies clones of EGFR-mutant non-small cell lung tumors expressing low levels of both wild-type and mutant EGFR protein. These EGFR-low cells are intrinsically more tolerant to EGFR inhibitors, more invasive, and exhibit an epithelial-to-mesenchymal-like phenotype compared to their EGFR-high counterparts. The EGFR-low cells secrete Transforming growth factor beta (TGFβ) family cytokines, leading to increased recruitment of cancer-associated fibroblasts and immune suppression, thus contributing to the drug-tolerant tumor microenvironment. Notably, pharmacological induction of EGFR using epigenetic inhibitors sensitizes the resistant cells to EGFR inhibition. These findings suggest that intrinsic drug resistance can be prevented or reversed using combination therapies.

Purpose Internal cervical os (ICO) stiffness is related to menstrual pain, a key symptom of endometriosis. The study evaluated whether women with endometriosis have a stiffer ICO than unaffected women. Methods A retrospective cross-sectional analysis was conducted using prospectively collected data from women with and without endometriosis, spanning from June 2020 to September 2022. Endometriosis was diagnosed through clinical and ultrasound evaluations, with histological confirmation in a subset of participants. Strain elastography (SE) was employed to measure tissue elasticity in four cervical regions of interest: the ICO and the anterior, posterior, and middle cervical compartments (ACC, PCC, and MCC, respectively). Tissue elasticity was quantified using a color-based scoring system ranging from 0.1 (blue, indicating less elasticity) to 3.0 (red, indicating greater elasticity). Results Overall, 287 women were included, with 157 diagnosed with endometriosis and 130 controls. On SE, women with endometriosis exhibited a lower color score (mean±standard deviation), indicating lower elasticity, for the ICO (0.56±0.28 vs. 0.70±0.26, P=0.001) and PCC (0.69±0.30 vs. 0.80±0.27, P=0.002). Additionally, they had a lower ICO/MCC ratio (0.45±0.28 vs. 0.60±0.32, P=0.001) and ICO/ACC ratio (0.68±0.42 vs. 0.85±0.39, P=0.001). Multiple logistic regression analysis revealed that endometriosis was associated with the ICO color score (odds ratio, 0.053; 95% confidence interval, 0.014 to 0.202; R2=0.358; P=0.001), even after adjusting for confounding factors like the presence of myomas (P=0.040) and the use of hormonal therapy (P=0.001). The results were corroborated in women with histologically confirmed endometriosis (n=71). Conclusion The findings suggest a potential relationship between a stiffer ICO and endometriosis.

Neonatal meningitis and sepsis were diagnosed in a 32-day-old preterm-born infant. Streptococcus (S.) suis was isolated from cerebrospinal fluid and blood. Next-generation sequencing revealed that the strain was serotype 2 sequence type 1, and contained the ermB and tet(W) genes, which are responsible for resistance to macrolides and tetracycline, along with several pilus-associated genes and 20 virulence factors. High homology was observed with previously identified human and swine strains in the same area. S. suis meningitis and sepsis are mainly reported in adults, related to direct contact with pigs or contaminated pork meat consumption, while it is rarely reported in children. Herein, we describe the first case of S. suis in a newborn associated with meningitis and antimicrobial resistance. The rates of resistance to tetracyclines, lincosamides, and macrolides for this bacterium are increasing and are creating concern worldwide. Altogether, our findings highlight the importance of investigating S. suis in cases of neonatal meningitis, as well as the necessity of assessing the antimicrobial profile to obtain useful information for developing targeted therapies.

Abstract Intratumour heterogeneity significantly hinders the efficacy of anticancer therapies. Compared with drug perturbation experiments, which yield pharmacological data at the bulk cell level, single‐cell RNA sequencing (scRNA‐seq) technology provides a means to capture molecular heterogeneity at single‐cell resolution. Here, scPharm is introduced, a computational framework that integrates pharmacological profiles with scRNA‐seq data to identify pharmacological subpopulations of cells within a tumour and prioritize tailored drugs. scPharm uses the normalized enrichment scores (NESs) determined from gene set enrichment analysis to assess the distribution of cell identity genes in drug response‐determined gene lists. Based on the strong correlation between the NES and drug response at single‐cell resolution, scPharm successfully identified the sensitive subpopulations in ER‐positive and HER2‐positive human breast cancer tissues, revealed dynamic changes in the resistant subpopulation of human PC9 cells treated with erlotinib, and expanded its ability to a mouse model. Its superior performance and computational efficiency are confirmed through comparative evaluations with other single‐cell prediction tools. Additionally, scPharm predicted combination drug strategies by gauging compensation or booster effects between drugs and evaluated drug toxicity in healthy cells in the tumour microenvironment. Overall, scPharm provides a novel approach for precision medicine in cancers by revealing therapeutic heterogeneity at single‐cell resolution.

Background: The frontline management of non-oncogene addicted non-small cell lung cancer (NSCLC) involves immune-checkpoint inhibitors (ICI) alone or combined with chemotherapy (CT-ICI). The dynamic landscape of KRAS-positive NSCLC presents a spectrum of treatment options, including ICIs, targeted therapy and combination strategies currently under investigation. Methods: We conducted a prospective project to detect circulating tumor DNA (ctDNA) in patients with KRAS G12C, advanced NSCLC. We included patients undergoing upfront ICIs or subsequent line sotorasib. We planned three-time points: baseline (T0), after 3 months of treatment (T1) and at disease progression (T2). Results: 24 consecutive patients have been included. The most frequent baseline characteristics were: nonsquamous histology (95.8%), male gender (62.5%), ECOG PS 0–1 (79.2%), 3 metastatic sites (p ​= ​0.002) exhibited significantly elevated ctDNA. Median overall survival (OS) was 7.5 months, progression-free survival (PFS) was 4.0 months and the objective response rate (ORR) was 33.3%. Higher AF correlated with an increased risk of death (HR 1.04, p ​= ​0.03), though not progression. The mOS was 7.5 months (95% CI, 1.91-NR) in high-AF group and 11.3 months (95% CI, 6.6-NR) in low-AF group (p ​= ​0.38). Notably, a reduction in plasma DNA levels was significantly associated with objective response (p ​= ​0.01). Two patients received a T2 dosage showing increased ctDNA levels after a previous reduction associated with response. Conclusion: Early monitoring with ctDNA may offer potential benefits in the evolving scenario of KRAS G12C NSCLC treatment.