Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127.

Increasing use of covalent and noncovalent inhibitors of Bruton's tyrosine kinase (BTK) has elucidated a series of acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance mutations in BTK with distinct enzymatic activities, including some that impair BTK enzymatic activity while imparting novel protein-protein interactions that sustain B cell receptor (BCR) signaling. Furthermore, we describe a clinical-stage BTK and IKZF1/3 degrader, NX-2127, that can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling.

Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton's Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies.

Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, is an essential effector of B-cell receptor (BCR) signaling. Chronic activation of BTK-mediated BCR signaling is a hallmark of many hematological malignancies, which makes it an attractive therapeutic target. Pharmacological inhibition of BTK enzymatic function is now a well-proven strategy for the treatment of patients with these malignancies.

NRX-0492 degrades wild-type and C481 mutant BTK and demonstrates in vivo activity in CLL patient-derived xenografts.

Bruton tyrosine kinase (BTK) is essential for B-cell receptor (BCR) signaling, a driver of chronic lymphocytic leukemia (CLL). Covalent inhibitors bind C481 in the active site of BTK and have become a preferred CLL therapy. Disease progression on covalent BTK inhibitors is commonly associated with C481 mutations.

TB-PRACTECAL: study protocol for a randomised, controlled, open-label, phase II-III trial to evaluate the safety and efficacy of regimens containing bedaquiline and pretomanid for the treatment of adult patients with pulmonary multidrug-resistant tuberculosis.

Background: Globally rifampicin-resistant tuberculosis disease affects around 460,000 people each year. Currently recommended regimens are 9-24 months duration, have poor efficacy and carry significant toxicity. A shorter, less toxic and more efficacious regimen would improve outcomes for people with rifampicin-resistant tuberculosis.

Researching, co-creating and testing innovations in paper-based health information systems (PHISICC) to support health workers' decision-making: protocol of a multi-country, transdisciplinary, mixed-methods research programme in three sub-Saharan countries.

Background: Health information systems are crucial to provide data for decision-making and demand for data is constantly growing. However, the link between data and decisions is not always rational or linear and the management of data ends up overloading frontline health workers, which may compromise quality of healthcare delivery. Despite limited evidence, there is an increasing push for the digitalization of health information systems, which poses enormous challenges, particularly in remote, rural settings in low- and middle-income countries.

Does an innovative paper-based health information system (PHISICC) improve data quality and use in primary healthcare? Protocol of a multicountry, cluster randomised controlled trial in sub-Saharan African rural settings.

Introduction: Front-line health workers in remote health facilities are the first contact of the formal health sector and are confronted with life-saving decisions. Health information systems (HIS) support the collection and use of health related data. However, HIS focus on reporting and are unfit to support decisions.

Comparative Study of the Mode of Action of Clinically Approved Platinum-Based Chemotherapeutics.

Platinum drugs are among the most effective anticancer agents, but their mode of action is still not fully understood. We therefore carried out a systematic investigation on the cellular activities of cisplatin, carboplatin and oxaliplatin in A498 kidney cancer cells. Cytotoxicity was higher for cisplatin and oxaliplatin compared to carboplatin, with induction of apoptosis as the preferred mode of cell death.

PARP1 Is Required for ATM-Mediated p53 Activation and p53-Mediated Gene Expression after Ionizing Radiation.

PARP1 and p53 are key players in maintaining genomic stability, but their interplay is still not fully understood. We investigated the impact of PARP1 knockout on the DNA damage response after ionizing radiation (IR) by comparing a U2OS-based PARP1-knockout cell line, established by using the genome-editing system CRISPR/Cas9, with its wild-type counterpart. We intended to gain more insight into the impact of PARP1 on the transcriptional level under basal conditions, after low dose (1 Gy) and high dose (10 Gy) DNA damage induced by IR, aiming to reveal the potential connections between the involved pathways.

Activity profile of the cisplatin analogue PN149 in different tumor cell lines.

The efficacy of the anticancer drug cisplatin is restricted by tumor cell resistance and occurrence of severe side effects. One strategy to overcome these limitations is the development of new, improved platinum drugs. Previous investigations showed that platinum(IV)-nitroxyl complexes are able to circumvent cisplatin resistance in bladder cancer cells.

The Structural and Functional Basis for Recurring Sulfa Drug Resistance Mutations in Dihydropteroate Synthase.

Staphylococcal species are a leading cause of bacterial drug-resistant infections and associated mortality. One strategy to combat bacterial drug resistance is to revisit compromised targets, and to circumvent resistance mechanisms using structure-assisted drug discovery. The folate pathway is an ideal candidate for this approach.

A two-helix motif positions the lysophosphatidic acid acyltransferase active site for catalysis within the membrane bilayer.

Phosphatidic acid (PA), the central intermediate in membrane phospholipid synthesis, is generated by two acyltransferases in a pathway conserved in all life forms. The second step in this pathway is catalyzed by 1-acyl-sn-glycerol-3-phosphate acyltransferase, called PlsC in bacteria. Here we present the crystal structure of PlsC from Thermotoga maritima, revealing an unusual hydrophobic/aromatic N-terminal two-helix motif linked to an acyltransferase αβ-domain that contains the catalytic HXD motif.

Structure and mechanism of the phage T4 recombination mediator protein UvsY.

The UvsY recombination mediator protein is critical for efficient homologous recombination in bacteriophage T4 and is the functional analog of the eukaryotic Rad52 protein. During T4 homologous recombination, the UvsX recombinase has to compete with the prebound gp32 single-stranded binding protein for DNA-binding sites and UvsY stimulates this filament nucleation event. We report here the crystal structure of UvsY in four similar open-barrel heptameric assemblies and provide structural and biophysical insights into its function.

A randomized trial comparing in person and electronic interventions for improving adherence to oral medications in schizophrenia.

Poor adherence to medication leads to symptom exacerbation and interferes with the recovery process for patients with schizophrenia. Following baseline assessment, 142 patients in medication maintenance at a community mental health center were randomized to one of 3 treatments for 9 months: (1) PharmCAT, supports including pill containers, signs, alarms, checklists and the organization of belongings established in weekly home visits from a PharmCAT therapist; (2) Med-eMonitor (MM), an electronic medication monitor that prompts use of medication, cues the taking of medication, warns patients when they are taking the wrong medication or taking it at the wrong time, record complaints, and, through modem hookup, alerts treatment staff of failures to take medication as prescribed; (3) Treatment as Usual (TAU). All patients received the Med-eMonitor device to record medication adherence.

Analysis of the active-site mechanism of tyrosyl-DNA phosphodiesterase I: a member of the phospholipase D superfamily.

Tyrosyl-DNA phosphodiesterase I (Tdp1) is a member of the phospholipase D superfamily that hydrolyzes 3'-phospho-DNA adducts via two conserved catalytic histidines-one acting as the lead nucleophile and the second acting as a general acid/base. Substitution of the second histidine specifically to arginine contributes to the neurodegenerative disease spinocerebellar ataxia with axonal neuropathy (SCAN1). We investigated the catalytic role of this histidine in the yeast protein (His432) using a combination of X-ray crystallography, biochemistry, yeast genetics, and theoretical chemistry.

Crystal structure of the phage T4 recombinase UvsX and its functional interaction with the T4 SF2 helicase UvsW.

Bacteriophage T4 provides an important model system for studying the mechanism of homologous recombination. We have determined the crystal structure of the T4 UvsX recombinase, and the overall architecture and fold closely resemble those of RecA, including a highly conserved ATP binding site. Based on this new structure, we reanalyzed electron microscopy reconstructions of UvsX-DNA filaments and docked the UvsX crystal structure into two different filament forms: a compressed filament generated in the presence of ADP and an elongated filament generated in the presence of ATP and aluminum fluoride.

Screening workers for genetic hypersusceptibility: potential ethical, legal, and social implications from the Human Genome Project.

One of the potential outcomes of the Human Genome Project will be the ability to identify individuals who are at increased risk of adverse health effects following exposure to hazardous substances in the workplace because of genetic hypersusceptibility. The ability to identify such individuals is likely to lead to the inclusion of genetic screening in worker protection programs. This technology and its applications will have a number of potential ethical, legal, and social implications.