The Bottom Rung of the Ladder: Battlefield Nuclear Weapons in Europe

A war in Europe would pit the heavily armored forces of the Warsaw Pact (WP) against the far more lightly equipped North Atlantic Treaty Organization (Nato) defenses. The Nato forces can expect to find themselves outnumbered and outgunned by those of the Pact

Highly Selective PTK2 Proteolysis Targeting Chimeras to Probe Focal Adhesion Kinase Scaffolding Functions

Focal adhesion tyrosine kinase (PTK2) is often overexpressed in human hepatocellular carcinoma (HCC), and several reports have linked PTK2 depletion and/or pharmacological inhibition to reduced tumorigenicity. However, the clinical relevance of targeting PTK2 still remains to be proven. Here, we present two highly selective and functional PTK2 proteolysis-targeting chimeras utilizing von Hippel–Lindau and cereblon ligands to hijack E3 ligases for PTK2 degradation. BI-3663 (cereblon-based) degrades PTK2 with a median DC₅₀ of 30 nM to >80% across a panel of 11 HCC cell lines. Despite effective PTK2 degradation, these compounds did not phenocopy the reported antiproliferative effects of PTK2 depletion in any of the cell lines tested. By disclosing these compounds, we hope to provide valuable tools for the study of PTK2 degradation across different biological systems

A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo

Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target protein and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. In the clinic, the oral route of administration is the option of choice but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed to achieve orally bioavailable molecules that selectively degrade the BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, to allow in vivo evaluation of the synthetic lethality concept of SMARCA2 dependency in SMARCA4-deficient cancers. Here we outline structure- and property-guided approaches that led to orally bioavailable VHL-recruiting degraders. Our tool compound, ACBI2, shows selective degradation of SMARCA2 over SMARCA4 in ex vivo human whole blood assays and in vivo efficacy in SMARCA4-deficient cancer models. This study demonstrates the feasibility for broadening the E3 ligase and physicochemical space that can be utilised for achieving oral efficacy with bifunctional molecules

GLORIA - A globally representative hyperspectral in situ dataset for optical sensing of water quality

The development of algorithms for remote sensing of water quality (RSWQ) requires a large amount of in situ data to account for the bio-geo-optical diversity of inland and coastal waters. The GLObal Reflectance community dataset for Imaging and optical sensing of Aquatic environments (GLORIA) includes 7,572 curated hyperspectral remote sensing reflectance measurements at 1 nm intervals within the 350 to 900 nm wavelength range. In addition, at least one co-located water quality measurement of chlorophyll a, total suspended solids, absorption by dissolved substances, and Secchi depth, is provided. The data were contributed by researchers affiliated with 59 institutions worldwide and come from 450 different water bodies, making GLORIA the de-facto state of knowledge of in situ coastal and inland aquatic optical diversity. Each measurement is documented with comprehensive methodological details, allowing users to evaluate fitness-for-purpose, and providing a reference for practitioners planning similar measurements. We provide open and free access to this dataset with the goal of enabling scientific and technological advancement towards operational regional and global RSWQ monitoring

Biological versus chronological ovarian age:implications for assisted reproductive technology

<p>Abstract</p> <p>Background</p> <p>Women have been able to delay childbearing since effective contraception became available in the 1960s. However, fertility decreases with increasing maternal age. A slow but steady decrease in fertility is observed in women aged between 30 and 35 years, which is followed by an accelerated decline among women aged over 35 years. A combination of delayed childbearing and reduced fecundity with increasing age has resulted in an increased number and proportion of women of greater than or equal to 35 years of age seeking assisted reproductive technology (ART) treatment.</p> <p>Methods</p> <p>Literature searches supplemented with the authors' knowledge.</p> <p>Results</p> <p>Despite major advances in medical technology, there is currently no ART treatment strategy that can fully compensate for the natural decline in fertility with increasing female age. Although chronological age is the most important predictor of ovarian response to follicle-stimulating hormone, the rate of reproductive ageing and ovarian sensitivity to gonadotrophins varies considerably among individuals. Both environmental and genetic factors contribute to depletion of the ovarian oocyte pool and reduction in oocyte quality. Thus, biological and chronological ovarian age are not always equivalent. Furthermore, biological age is more important than chronological age in predicting the outcome of ART. As older patients present increasingly for ART treatment, it will become more important to critically assess prognosis, counsel appropriately and optimize treatment strategies. Several genetic markers and biomarkers (such as anti-Müllerian hormone and the antral follicle count) are emerging that can identify women with accelerated biological ovarian ageing. Potential strategies for improving ovarian response include the use of luteinizing hormone (LH) and growth hormone (GH). When endogenous LH levels are heavily suppressed by gonadotrophin-releasing hormone analogues, LH supplementation may help to optimize treatment outcomes for women with biologically older ovaries. Exogenous GH may improve oocyte development and counteract the age-related decline of oocyte quality. The effects of GH may be mediated by insulin-like growth factor-I, which works synergistically with follicle-stimulating hormone on granulosa and theca cells.</p> <p>Conclusion</p> <p>Patients with biologically older ovaries may benefit from a tailored approach based on individual patient characteristics. Among the most promising adjuvant therapies for improving ART outcomes in women of advanced reproductive age are the administration of exogenous LH or GH.</p

First-line tandem high-dose chemotherapy and autologous stem cell transplantation versus single high-dose chemotherapy and autologous stem cell transplantation in multiple myeloma, a systematic review of controlled studies

Several clinical studies have compared single with tandem (also called double) autologous stem cell transplantation (ASCT) as first-line treatment in patients with symptomatic multiple myeloma (MM), one of the leading indications for ASCT worldwide

New high-resolution inductively coupled plasma mass spectrometry technology applied for the determination of V, Fe, Cu, Zn and Ag in human serum

Spectral interferences are a limiting factor in quadrupole inductively coupled plasma mass spectrometry (quadropole ICP-MS). Most of these interferences disappear when a high-resolution magnetic sector mass spectrometer is coupled to the ICP ion source. In this paper, results of the first analyses with a new type of a high resolution ICP-MS instrument are shown. The instrument is a commercially available machine (Finnigan MAT, Bremen, Germany) offering standard resolution settings of 300, 3000 and 7000 (M/DELTAM, 10% valley definition). With a resolution setting of 3000, V, Fe, Cu and Zn were determined in a second generation human serum reference material. Human serum diluted 4- to 8-fold was measured. The results, expressed as concentrations (mug g-1) [standard deviation (SD) in parentheses] in the freeze dried material for Fe, 23.6 (0.8); Cu, 10.7 (0.2); and Zn, 8.2 (0.8) are in good agreement with the certified values. The very low V content is not certified. In the high-resolution spectrum the V peak was measured next to an approximately 1000 times higher Cl35O16 peak and a concentration of 0.83 ng g-1, SD 0.09 ng g-1 was found, which confirms an earlier radiochemical neutron activation value of 0.67 ng g-1, SD 0.05 ng g-1. For the determination of Ag using the low resolution (300) setting a limit of detection (LOD) of 4.3 pg ml-1 in the solution was found. The instrumental LOD is 10-100 times lower and the experiments show that an investigation of blanks and methods of dealing with memory effects will be necessary before full use can be made of the sensitivity of high resolution ICP-MS