KRAS inhibitors: resistance drivers and combinatorial strategies.

In 1982, the RAS genes HRAS and KRAS were discovered as the first human cancer genes, with KRAS later identified as one of the most frequently mutated oncogenes. Yet, it took nearly 40 years to develop clinically effective inhibitors for RAS-mutant cancers. The discovery in 2013 by Shokat and colleagues of a druggable pocket in KRAS paved the way to FDA approval of the first covalently binding KRAS inhibitors, sotorasib and adagrasib, in 2021 and 2022, respectively.

Phylogeny, evolution and a re-classification of the .

The is an independent lichenized lineage within the comprising . 390 species and 50 genera. Very few studies have dealt with family and genus classification using molecular data and many groups are in need of thorough revision.

snRNA-seq stratifies multiple sclerosis patients into distinct white matter glial responses.

Poor understanding of the cellular and molecular basis of clinical and genetic heterogeneity in progressive multiple sclerosis (MS) has hindered the search for new effective therapies. To address this gap, we analyzed 632,000 single-nucleus RNA sequencing profiles from 156 brain tissue samples of MS and control donors to examine inter- and intra-donor heterogeneity. We found distinct cell type-specific gene expression changes between MS gray and white matter, highlighting clear pathology differences.

Scalable production of ultraflat and ultraflexible diamond membrane.

Diamond is an exceptional material with great potential across various fields owing to its interesting properties. However, despite extensive efforts over the past decades, producing large quantities of desired ultrathin diamond membranes for widespread use remains challenging. Here we demonstrate that edge-exposed exfoliation using sticky tape is a simple, scalable and reliable method for producing ultrathin and transferable polycrystalline diamond membranes.

Pregnancy and Infant Outcomes in Women With Multiple Sclerosis Treated With Ocrelizumab.

Background And Objectives: Ocrelizumab labeling advises contraception for women during treatment and for 6-12 months thereafter. Because pregnancies may occur during this time, it is critical to understand pregnancy and infant outcomes in women with multiple sclerosis (MS) after ocrelizumab exposure.

Methods: Pregnancy cases reported to Roche global pharmacovigilance until 12 July 2023 were analyzed.

Relationship Between Severity of Ischemia and Coronary Artery Disease for Different Stress Test Modalities in the ISCHEMIA Trial.

Background: The relationship between the extent and severity of stress-induced ischemia and the extent and severity of anatomic coronary artery disease (CAD) in patients with obstructive CAD is multifactorial and includes the intensity of stress achieved, type of testing used, presence and extent of prior infarction, collateral blood flow, plaque characteristics, microvascular disease, coronary vasomotor tone, and genetic factors. Among chronic coronary disease participants with site-determined moderate or severe ischemia, we investigated associations between ischemia severity on stress testing and the extent of CAD on coronary computed tomography angiography.

Methods: Clinically indicated stress testing included nuclear imaging, echocardiography, cardiac magnetic resonance imaging, or nonimaging exercise tolerance test.

Formation of Apoplastic Barriers to Radial O₂ Loss in Rice Roots: Effects of Low-O₂ and High-Fe Conditions, and the Roles of Suberin, Glycerol Esters, and Iron Plaques.

Lack of O and high concentrations of iron (Fe) are common in flooded soils where Rice (Oryza sativa L.) is cultivated. We tested the hypothesis that growing in stagnant or high Fe conditions might induce the formation of apoplastic barriers in roots with different properties and chemical compositions.

Role and Safety of Tirofiban in Peri-Interventional Antiplatelet Management for Aneurysm Treatment.

Background: Tirofiban is administered for the treatment of aneurysms in cases of thromboembolic complications, as well as in cases of acute stenting or flow-diverter implantation required within the scope of aneurysm treatment. We aimed to investigate the efficacy and safety of tirofiban in this group of patients.

Methods: We conducted a retrospective analysis of all patients undergoing aneurysm treatment and receiving peri-interventional tirofiban administration at our institution between 2009 and 2019.

Impact of personalized response-directed surgery and adjuvant therapy on survival after neoadjuvant immunotherapy in stage III melanoma: Comparison of 3-year data from PRADO and OpACIN-neo.

Background: Pathologic response following neoadjuvant immune checkpoint blockade (ICB) in stage III melanoma serves as a surrogate marker for long-term outcomes. This may support more personalized, response-directed treatment strategies.

Methods: The OpACIN-neo and PRADO trials were phase 2 studies evaluating neoadjuvant treatment with ipilimumab and nivolumab in stage III melanoma.

Development and in vitro testing of an orthodontic miniscrew for use in the mandible.

Objective: Temporary anchorage devices (TADs) have been successfully used in the maxilla. However, in the mandible, lower success rates present a challenge in everyday clinical practice. A new TAD design will be presented that is intended to demonstrate optimization of the coupling structure as well as in the thread area for use in the mandible.

Molecular adaptation to neoadjuvant immunotherapy in triple-negative breast cancer.

Therapy-induced molecular adaptation of triple-negative breast cancer is crucial for immunotherapy response and resistance. We analyze tumor biopsies from three different time points in the randomized neoadjuvant GeparNuevo trial (NCT02685059), evaluating the combination of durvalumab with chemotherapy, for longitudinal alterations of gene expression. Durvalumab induces an activation of immune and stromal gene expression as well as a reduction of proliferation-related gene expression.

Amyloid-β positivity is less prevalent in cognitively unimpaired KL-VS heterozygotes.

Background: Klotho, encoded by the gene, is an anti-aging and neuroprotective protein. KL-VS heterozygosity (KL-VS) is hypothesized to be protective against the accumulation of Alzheimer's disease (AD) neuropathological hallmarks (amyloid-β (Aβ) and tau).

Objective: We examine whether being positive for Aβ (A+) or tau (T+), or A/T joint status [positive for Aβ (A + T-), tau (A-T+), both (A + T+) or neither (A-T-)] vary by KL-VS and whether serum klotho protein levels vary based on A+, T+, or A/T status in a cohort enriched for AD risk.

Association of Changes in Cerebral and Hypothalamic Structure With Sleep Dysfunction in Patients With Genetic Frontotemporal Dementia.

Background And Objectives: Sleep dysfunction is common in patients with neurodegenerative disorders; however, its neural underpinnings remain poorly characterized in genetic frontotemporal dementia (FTD). Hypothalamic nuclei important for sleep regulation may be related to this dysfunction. Thus, we examined changes in hypothalamic structure across the lifespan in patients with genetic FTD and whether these changes related to sleep dysfunction.

Association of Initial Side of Brain Atrophy With Clinical Features and Disease Progression in Patients With Frontotemporal Dementia.

Background And Objectives: Pathogenic variants in the gene cause frontotemporal dementia (FTD-) with marked brain asymmetry. This study aims to assess whether the disease progression of FTD- depends on the initial side of the atrophy. We also investigated the potential use of brain asymmetry as a biomarker of the disease.

Liver cyst penetration of antibiotics at the target site of infection: a randomized pharmacokinetic trial.

Background: The EASL cystic liver disease guideline states that drug penetration at the site of infection (liver cyst) is essential for successful treatment, but pharmacokinetic (PK) data on cyst penetration are limited.

Objectives: This study aims to investigate tissue penetration of four antibiotics in non-infected liver cysts and explores influencing factors.

Methods: We performed a prospective, randomized single-dose PK-study.

Synthetic studies on the tetrasubstituted D-ring of cystobactamids lead to potent terephthalic acid antibiotics.

Novel scaffolds for broad-spectrum antibiotics are rare and in strong demand because of the increase in antimicrobial resistance. The cystobactamids, discovered from myxobacterial sources, have a unique hexapeptidic scaffold with five arylamides and possess potent, resistance-breaking properties. This study investigates the role of the central D-ring pharmacophore in cystobactamids, a para-aminobenzoic acid (PABA) moiety that is additionally substituted by hydroxy and isopropoxy functions.

Identification of late-stage tau accumulation using plasma phospho-tau217.

Background: Blood-based disease staging across the Alzheimer's disease (AD) continuum holds the promise to identify individuals that profit from disease-modifying therapies. We set out to identify Braak V (Braak V and/or VI) tau PET-positive individuals within amyloid-β (Aβ)-positive individuals using plasma biomarkers.

Methods: In this cross-sectional study, we assessed 289 individuals from the TRIAD cohort and 306 individuals from the WRAP study across the AD continuum.

[Systemic therapy for head and neck cancer-highlights of the 2024 ASCO Annual Meeting].

Background: Systemic therapy of head and neck squamous cell carcinoma (HNSCC), in contrast to local therapy, is a very general term for the use of drugs that affect the entire organism. Immunotherapy is a subtype of systemic therapy, although the boundaries are hard to define, since the immune system is likely to play an essential role in all treatments. This article focuses on systemic therapy.

Microaxial Flow Pump Use and Renal Outcomes in Infarct-Related Cardiogenic Shock: A Secondary Analysis of the DanGer Shock Trial.

Background: In DanGer Shock (the Danish-German Cardiogenic Shock trial), use of a microaxial flow pump (mAFP) in patients with ST-segment-elevation myocardial infarction-related cardiogenic shock led to lower all-cause mortality but higher rates of renal replacement therapy (RRT). In this prespecified analysis, rates and predictors of acute kidney injury (AKI) and RRT were assessed.

Methods: In this international, randomized, open-label, multicenter trial, 355 adult patients with ST-segment-elevation myocardial infarction-related cardiogenic shock were randomized to mAFP (n=179) or standard care alone (n=176).