Pan-KRAS inhibitors BI-2493 and BI-2865 display potent anti-tumor activity in tumors with KRAS wild-type allele amplification.

KRASG12C selective inhibitors, such as sotorasib and adagrasib, have raised hopes of targeting other KRAS mutant alleles in cancer patients. We report that KRAS wild-type amplified tumor models are sensitive to treatment with the small molecule KRAS inhibitors BI-2493 and BI-2865. These pan-KRAS inhibitors directly target the "OFF" state of KRAS and result in potent anti-tumor activity in pre-clinical models of cancers driven by KRAS mutant proteins.

A Comparative Pharmacokinetics Study of Orally and Intranasally Administered 8-Nitro-1,3-benzothiazin-4-one (BTZ043) Amorphous Drug Nanoparticles.

BTZ043 is an 8-nitro-1,3-benzothiazin-4-one with potency against multidrug-resistant . Low solubility and hepatic metabolism are linked to poor oral bioavailability. Amorphous drug nanoparticles (ADN) were formulated to improve the bioavailability.

SHIV remission in macaques with early treatment initiation and ultra long-lasting antiviral activity.

Studies in SIV-infected macaques show that the virus reservoir is particularly refractory to conventional suppressive antiretroviral therapy (ART). We posit that optimized ART regimens designed to have robust penetration in tissue reservoirs and long-lasting antiviral activity may be advantageous for HIV or SIV remission. Here we treat macaques infected with RT-SHIV with oral emtricitabine/tenofovir alafenamide and long-acting cabotegravir/rilpivirine without (n = 4) or with (n = 4) the immune activator vesatolimod after the initial onset of viremia.

Adherence to CDC Guidelines for mpox Evaluation: Practice Patterns Across an Academic Medical System During the 2022 Epidemic.

Background: Patients with suspected mpox presented to different venues for evaluation during the 2022 outbreak. We hypothesized that practice patterns may differ across venue of care.

Methods: We conducted an observational study of patients undergoing mpox testing between 1 June 2022 and 15 December 2022.

Discovery of a Myeloid Cell Leukemia 1 (Mcl-1) Inhibitor That Demonstrates Potent Activities in Mouse Models of Hematological and Solid Tumors.

Myeloid cell leukemia 1 (Mcl-1) is a key regulator of the intrinsic apoptosis pathway. Overexpression of Mcl-1 is correlated with high tumor grade, poor survival, and both intrinsic and acquired resistance to cancer therapies. Herein, we disclose the structure-guided design of a small molecule Mcl-1 inhibitor, compound , that binds to Mcl-1 with subnanomolar affinity, inhibits growth in cell culture assays, and possesses low clearance in mouse and dog pharmacokinetic (PK) experiments.

Cocktail of lipophilic and hydrophilic chemotherapeutics in high-load core@shell nanocarriers to treat pancreatic tumours.

ITC/Toc@Gd(FLP) core@shell nanocarriers with a chemotherapeutic cocktail of lipophilic irinotecan (ITC) as the particle core and hydrophilic fludarabine phosphate (FLP) in the particle shell are realized. They are prepared a microemulsion approach with ITC dissolved in tocopherol (Toc) as droplet phase and stabilized by water-insoluble Gd(FLP). The synthesis can be followed by zeta-potential analysis.

Short anesthesia without intravenous fluid therapy in children: Results of a prospective non-interventional multicenter observational study.

Background: The German guidelines recommend that intravenous fluid therapy should not be mandatorily performed in children with short fasting times undergoing short anesthesia, but there is a lack of clinical studies including a large number of pediatric patients. Therefore, we performed a prospective non-interventional multicenter observational study to evaluate the perioperative hemodynamic and metabolic stability of children undergoing short anesthesia without intravenous fluid therapy.

Aims: The primary aim was to assess the incidence of hypotension and the secondary aim was to assess the real preoperative fasting times, the incidence of hypoglycemia and the impact on ketone bodies and acid-base balance.

Highly Transparent, Yet Photoluminescent: 2D CdSe/CdS Nanoplatelet-Zeolitic Imidazolate Framework Composites Sensitive to Gas Adsorption.

In this work, thin composite films of zeolitic imidazolate frameworks (ZIFs) and colloidal two-dimensional (2D) core-crown CdSe/CdS nanoplatelet (NPL) emitters with minimal scattering are formed by a cycled growth method and yield highly transparent coatings with strong and narrow photoluminescence of the NPLs at 546 nm (FWHM: 25 nm) in a solid-state composite structure. The porous ZIF matrix acts as functional encapsulation for the emitters and enables the adsorption of the guest molecules water and ethanol. The adsorption and desorption of the guest molecules is then characterized by a reversable photoluminescence change of the embedded NPLs.

Risk Factors for Hospitalization and Effect of Immunosuppression on Clinical Outcomes Among an Urban Cohort of Patients With Mpox.

Background: During the 2022 mpox outbreak most patients were managed as outpatients, but some required hospitalization. Uncontrolled human immunodeficiency virus (HIV) has been identified as a risk factor for severe mpox.

Methods: Patients with mpox diagnosed or treated within the Johns Hopkins Health System between 1 June and 15 December 2022 were included.

Synthesis and Crystal Structure of the Europium(II) Hydride Oxide Iodide EuHOI Showing Blue-Green Luminescence.

As the first europium(II) hydride oxide iodide, dark red single crystals of EuHOI could be synthesized from oxygen-contaminated mixtures of EuH and EuI. Its orthorhombic crystal structure ( = 1636.97(9) pm, = 1369.

Updates to the Autism Intervention Research Network on Physical Health (AIR-P) Research Agenda.

Introduction: Autistic individuals, now representing one in 36 individuals in the U.S., experience disproportionate physical health challenges relative to non-autistic individuals.

Elucidating the nature of the proton radioactivity and branching ratio on the first proton emitter discovered Co.

The observation of a weak proton-emission branch in the decay of the 3174-keV Co isomeric state marked the discovery of proton radioactivity in atomic nuclei in 1970. Here we show, based on the partial half-lives and the decay energies of the possible proton-emission branches, that the exceptionally high angular momentum barriers, [Formula: see text] and [Formula: see text], play a key role in hindering the proton radioactivity from Co, making them very challenging to observe and calculate. Indeed, experiments had to wait decades for significant advances in accelerator facilities and multi-faceted state-of-the-art decay stations to gain full access to all observables.

Efficacy of urban road salt reduction strategies on public supply well quality.

Long-term road salt application has increased chloride (Cl) concentrations in public drinking water wells in many cold climate communities. A range of Best Management Practices (BMPs) have been adopted to mitigate the impact of road deicing compounds on groundwater quality. Chronic increases in chloride levels have been observed in several municipal well fields within the southern Ontario Regional Municipality of Waterloo (RMOW).

Evaluation of Hydraulic Conductivity Estimates from Various Approaches with Groundwater Flow Models.

Significant efforts have been expended for improved characterization of hydraulic conductivity (K) and specific storage (S) to better understand groundwater flow and contaminant transport processes. Conventional methods including grain size analyses (GSA), permeameter, slug, and pumping tests have been utilized extensively, while Direct Push-based Hydraulic Profiling Tool (HPT) surveys have been developed to obtain high-resolution K estimates. Moreover, inverse modeling approaches based on geology-based zonations, and highly parameterized Hydraulic Tomography (HT) have also been advanced to map spatial variations of K and S between and beyond boreholes.

Pan-KRAS inhibitor disables oncogenic signalling and tumour growth.

KRAS is one of the most commonly mutated proteins in cancer, and efforts to directly inhibit its function have been continuing for decades. The most successful of these has been the development of covalent allele-specific inhibitors that trap KRAS G12C in its inactive conformation and suppress tumour growth in patients. Whether inactive-state selective inhibition can be used to therapeutically target non-G12C KRAS mutants remains under investigation.

SMART RHESINs-Superparamagnetic Magnetite Architecture Made of Phenolic Resin Hollow Spheres Coated with Eu(III) Containing Silica Nanoparticles for Future Quantitative Magnetic Particle Imaging Applications.

Magnetic particle imaging (MPI) is a powerful and rapidly growing tomographic imaging technique that allows for the non-invasive visualization of superparamagnetic nanoparticles (NPs) in living matter. Despite its potential for a wide range of applications, the intrinsic quantitative nature of MPI has not been fully exploited in biological environments. In this study, a novel NP architecture that overcomes this limitation by maintaining a virtually unchanged effective relaxation (Brownian plus Néel) even when immobilized is presented.

Extended pilot test of a cross-injection in situ denitrification system for pre-emptive treatment of municipal well water.

Elevated groundwater nitrate concentrations have been linked to deleterious health and environmental effects. A significant source of the nitrate is nitrogen fertilizers applied to agricultural landscapes. Beneficial Management Practices (BMPs), including the optimization of fertilizer use and selective crop rotations, have proven to be effective in some cases.

Amorphous Drug Nanoparticles for Inhalation Therapy of Multidrug-Resistant Tuberculosis.

Tuberculosis (TB) is one of the most prevalent infectious diseases. The global TB situation is further complicated by increasing patient numbers infected with strains resistant to either one or two of the first-line therapeutics, promoted by insufficient treatment length and/or drug levels due to adverse reactions and reduced patient compliance. An intriguing approach to improve anti-TB therapy relates to nanocarrier-based drug-delivery systems, which enhance local drug concentrations at infection sites without systemic toxicity.

Untangling the intertwined: metallic to semiconducting phase transition of colloidal MoS nanoplatelets and nanosheets.

2D semiconducting transition metal dichalcogenides (TMDCs) are highly promising materials for future spin- and valleytronic applications and exhibit an ultrafast response to external (optical) stimuli which is essential for optoelectronics. Colloidal nanochemistry on the other hand is an emerging alternative for the synthesis of 2D TMDC nanosheet (NS) ensembles, allowing for the control of the reaction tunable precursor and ligand chemistry. Up to now, wet-chemical colloidal syntheses yielded intertwined/agglomerated NSs with a large lateral size.

BI-907828, a novel potent MDM2 inhibitor, inhibits glioblastoma brain tumor stem cells in vitro and prolongs survival in orthotopic xenograft mouse models.

Background: The tumor suppressor TP53 (p53) is frequently mutated, and its downstream effectors inactivated in many cancers, including glioblastoma (GBM). In tumors with wild-type status, p53 function is frequently attenuated by alternate mechanisms including amplification and overexpression of its key negative regulator, MDM2. We investigated the efficacy of the MDM2 inhibitor, BI-907828, in GBM patient-derived brain tumor stem cells (BTSCs) with different amplification statuses of MDM2, in vitro and in orthotopic xenograft models.

Subsurface mobility of land applied greenhouse nutrient feed water and environmental implications.

Greenhouse nutrient feedwater (GNF) discharge is considered a potential contributor to eutrophication issues in Lake Erie, Ontario. Land application of GNF is an accepted legislated management response to mitigate the impact of such nutrient loads. To assess the potential environmental impacts of this management practice, field infiltration experiments were conducted at four different greenhouse operations near Leamington, Ontario.

Fragment Optimization of Reversible Binding to the Switch II Pocket on KRAS Leads to a Potent, In Vivo Active KRAS Inhibitor.

Activating mutations in KRAS are the most frequent oncogenic alterations in cancer. The oncogenic hotspot position 12, located at the lip of the switch II pocket, offers a covalent attachment point for KRAS inhibitors. To date, KRAS inhibitors have been discovered by first covalently binding to the cysteine at position 12 and then optimizing pocket binding.