Grain and phase stress criteria for behaviour and cleavage in duplex and bainitic steels

Stress analyses by X-ray diffraction are performed on a cast duplex (32% ferrite) stainless steel elbow and a bainitic (95% ferrite) pressure vessel steel. During an in situ tensile test, micrographic observations are made (visible glides and microcracks) and related to the stress state determined in the individual ferritic grains (aged duplex) and the ferritic phase (bainite loaded at low temperatures). Several material parameters have been identified at different scales, as for example, the critical resolved shear stress of 245 MPa for the aged ferritic grain (duplex) or 275 MPa for bainite (–60 ◦C), a crystallographic cleavage propagation criterion of 465 MPa (stress normal to {100} planes), and a fracture stress of approximately 700 MPa in the ferritic phase. Even though the two steels are different in many respects, the macroscopic fracture strains and stresses are well predicted by the polycrystalline model developed for bainite, whatever the temperatures tested (considering 7% of the grains reaching the local criterion)

Clinical trials in pregnancy and the “shadows of thalidomide”: Revisiting the legacy of Frances Kelsey

Despite great need for improved understanding of the use of drugs and biological products in pregnancy, clinical trials in pregnancy are rare, therapeutics in pregnancy are woefully understudied, and pregnant individuals are routinely excluded as trial participants. Recently, however, the U.S. Food and Drug Administration (FDA) has signaled strong support for advancing scientific research with pregnant populations, marking a significant shift from the past. Over the last sixty years, precaution and fear have largely characterized clinical research in pregnancy, deriving in large part from a protectionist ethic that materialized after the thalidomide drug disaster. FDA reviewer Frances Kelsey courageously prevented thalidomide from being marketed in the United States, and her work guided and solidified the FDA's image as protector of the general population from unsafe and ineffective drugs. Yet, when it comes to protection, pregnant persons have been left behind, and experts refer to the "shadows of thalidomide" that hamper clinical trials in pregnancy. Drawing on analysis of Frances Kelsey's archived papers in addition to focused media coverage of Kelsey and thalidomide, we discuss the durable cultural narrative surrounding Kelsey's important work. We argue that revisiting Kelsey's legacy with attention to themes that have characterized her achievement-staying vigilant, prioritizing safety, and mitigating pharmaceutical-based harm-in fact facilitates progress toward the ethical obligation to protect pregnant people through research, toward the generation of pregnancy-specific data for evidence-based care, and toward realizing Kelsey's legacy of safeguarding pregnant people and their offspring from the harms of untested drugs

Another Consequence of Overturning Roe: Imperiling Progress on Clinical Research in Pregnancy

In recent years, tremendous progress has been made toward recognizing the need for improved medical knowledge for pregnant people, a population group that has long been excluded from clinical trials and suffered the harms that result from a poor evidence base to inform care (Lyerly, Little, and Faden 2008). From the National Institutes of Health (NIH) to the Food and Drug Administration (FDA), federal agencies have signaled strong support for closing knowledge gaps in pregnancy, in part through advancing responsible inclusion of pregnant individuals in clinical research (e.g., FDA 2018; PRGLAC 2018). As evidence of progress, a new National Academies report on improving representation in clinical trials emphasizes that a more equitable research enterprise would be responsive to the clinical needs of pregnant people (NASEM 2022)

Tumor-Targeted Synergistic Blockade of MAPK and PI3K from a Layer-by-Layer Nanoparticle

Purpose: Cross-talk and feedback between the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR cell signaling pathways is critical for tumor initiation, maintenance, and adaptive resistance to targeted therapy in a variety of solid tumors. Combined blockade of these pathways—horizontal blockade—is a promising therapeutic strategy; however, compounded dose-limiting toxicity of free small molecule inhibitor combinations is a significant barrier to its clinical application. Experimental Design: AZD6244 (selumetinib), an allosteric inhibitor of Mek1/2, and PX-866, a covalent inhibitor of PI3K, were co-encapsulated in a tumor-targeting nanoscale drug formulation—layer-by-layer (LbL) nanoparticles. Structure, size, and surface charge of the nanoscale formulations were characterized, in addition to in vitro cell entry, synergistic cell killing, and combined signal blockade. In vivo tumor targeting and therapy was investigated in breast tumor xenograft-bearing NCR nude mice by live animal fluorescence/bioluminescence imaging, Western blotting, serum cytokine analysis, and immunohistochemistry. Results: Combined MAPK and PI3K axis blockade from the nanoscale formulations (160 ± 20 nm, −40 ± 1 mV) was synergistically toxic toward triple-negative breast (MDA-MB-231) and RAS-mutant lung tumor cells (KP7B) in vitro, effects that were further enhanced upon encapsulation. In vivo, systemically administered LbL nanoparticles preferentially targeted subcutaneous MDA-MB-231 tumor xenografts, simultaneously blocked tumor-specific phosphorylation of the terminal kinases Erk and Akt, and elicited significant disease stabilization in the absence of dose-limiting hepatotoxic effects observed from the free drug combination. Mice receiving untargeted, but dual drug-loaded nanoparticles exhibited progressive disease. Conclusions: Tumor-targeting nanoscale drug formulations could provide a more safe and effective means to synergistically block MAPK and PI3K in the clinic.United States. Department of Defense (OCRP Teal Innovator Award)National Institutes of Health (U.S.) (Grant NIBIB 1F32EB017614-02)Misrock FoundationNational Science Foundation (U.S.)Swiss National Science FoundationDavid H. Koch Institute for Integrative Cancer Research at MIT (Support Grant P30-CA14051)National Cancer Institute (U.S.)National Science Foundation (U.S.) (Massachusetts Institute of Technology. Materials Research Science and Engineering Center. Shared Experimental Facilities Grant DMR-0819762)Breast Cancer Alliance (Exceptional Project Grant

Targeting NaPi2b in ovarian cancer.

Novel biomarkers are needed to direct new treatments for ovarian cancer, a disease for which the standard of care remains heavily focused on platinum-based chemotherapy. Despite the success of PARP inhibitors, treatment options are limited, particularly in the platinum-resistant setting. NaPi2b is a cell surface sodium-dependent phosphate transporter that regulates phosphate homeostasis under normal physiological conditions and is a lineage marker that is expressed in select cancers, including ovarian, lung, thyroid, and breast cancers, with limited expression in normal tissues. Based on its increased expression in ovarian tumors, NaPi2b is a promising candidate to be studied as a biomarker for treatment and patient selection in ovarian cancer. In preclinical studies, the use of antibodies against NaPi2b showed that this protein can be exploited for tumor mapping and therapeutic targeting. Emerging data from phase 1 and 2 clinical trials in ovarian cancer have suggested that NaPi2b can be successfully detected in patient biopsy samples using immunohistochemistry, and the NaPi2b-targeting antibody-drug conjugate under evaluation appeared to elicit therapeutic responses. The aim of this review is to examine literature supporting NaPi2b as a novel biomarker for potential treatment and patient selection in ovarian cancer and to discuss the critical next steps and future analyses necessary to drive the study of this biomarker and therapeutic targeting forward

Targeting transcription regulation in cancer with a covalent CDK7 inhibitor

Tumour oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state, but direct pharmacological inhibition of transcription factors has so far proven difficult. However, the transcriptional machinery contains various enzymatic cofactors that can be targeted for the development of new therapeutic candidates, including cyclin-dependent kinases (CDKs). Here we present the discovery and characterization of a covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell-line profiling indicates that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukaemia (T-ALL), have exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL cells shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and the key role of RUNX1 in the core transcriptional regulatory circuitry of these tumour cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumour types that are dependent on transcription for maintenance of the oncogenic state.National Institutes of Health (U.S.) (Grant HG002668)National Institutes of Health (U.S.) (Grant CA109901

An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations

Protein-protein interactions govern almost all cellular functions. These complex networks of stable and transient associations can be mapped by affinity purification mass spectrometry (AP-MS) and complementary proximity-based labeling methods such as BioID. To exploit the advantages of both strategies, we here design and optimize an integrated approach combining AP-MS and BioID in a single construct, which we term MAC-tag. We systematically apply the MAC-tag approach to 18 subcellular and 3 sub-organelle localization markers, generating a molecular context database, which can be used to define a protein's molecular location. In addition, we show that combining the AP-MS and BioID results makes it possible to obtain interaction distances within a protein complex. Taken together, our integrated strategy enables the comprehensive mapping of the physical and functional interactions of proteins, defining their molecular context and improving our understanding of the cellular interactome.Peer reviewe