Modelling the impact of organic molecules and phosphate ions on biosilica pattern formation in diatoms.

The rapid and complex patterning of biosilica in diatom frustules is of great interest in nanotechnology, although it remains incompletely understood. Specific organic molecules, including long-chain polyamines, silaffins and silacidins, are essential in this process. The molecular structure of synthesized polyamines significantly affects the quantity, size and shape of silica precipitates.

Efficacy and Safety of Zimlovisertib, Ritlecitinib, and Tofacitinib, Alone and in Combination, in Patients With Moderate to Severe Rheumatoid Arthritis and an Inadequate Response to Methotrexate.

Objective: We aimed to evaluate the efficacy and safety of zimlovisertib (interleukin-1 receptor-associated kinase 4 inhibitor) in combination with ritlecitinib (a JAK3 and tyrosine kinase expressed in hepatocellular carcinoma [TEC] kinase family inhibitors) or tofacitinib (a JAK inhibitor) versus tofacitinib alone.

Methods: This phase 2 study randomized patients with moderate to severe active rheumatoid arthritis to zimlovisertib 400 mg + tofacitinib 11 mg, zimlovisertib 400 mg + ritlecitinib 100 mg, zimlovisertib 400 mg, ritlecitinib 100 mg, or tofacitinib 11 mg (4:4:3:3:4) for 24 weeks. The primary endpoint was change from baseline (CFB) in Disease Activity Score in 28 joints, C-reactive protein (DAS28-CRP) at week 12.

Efficacy, safety, and target engagement of dazukibart, an IFNβ specific monoclonal antibody, in adults with dermatomyositis: a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial.

Background: Dermatomyositis is a chronic autoimmune disease with distinctive cutaneous eruptions and muscle weakness, and the pathophysiology is characterised by type I interferon (IFN) dysregulation. This study aims to assess the efficacy, safety, and target engagement of dazukibart, a potent, selective, humanised IgG1 neutralising monoclonal antibody directed against IFNβ, in adults with moderate-to-severe dermatomyositis.

Methods: This multicentre, double-blind, randomised, placebo-controlled, phase 2 trial was conducted at 25 university-based hospitals and outpatient sites in Germany, Hungary, Poland, Spain, and the USA.

Dynamics of positional information in the vertebrate neural tube.

In developing embryos, cells acquire distinct identities depending on their position in a tissue. Secreted signalling molecules, known as morphogens, act as long-range cues to provide the spatial information that controls these cell fate decisions. In several tissues, both the level and the duration of morphogen signalling appear to be important for determining cell fates.

Exploratory pharmacodynamics and efficacy of PF-06817024 in a Phase 1 study of patients with chronic rhinosinusitis and atopic dermatitis.

PF-06817024 is a humanized antibody against interleukin-33 that has the potential to inhibit type 2 inflammation. An exploratory analysis of the pharmacodynamics and clinical effects of single and repeat doses of PF-06817024 was assessed in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and patients with moderate-to-severe atopic dermatitis (AD), respectively, as part of a Phase 1, first-in-human study. Rhinosinusitis symptoms were improved, and nasal polyps were decreased in size following treatment with PF-06817024 in patients with CRSwNP.

An agent-based modelling framework to study growth mechanisms in mutant cell alveolar type II cells.

Mutations in the epidermal growth factor receptor (EGFR) are common in non-small cell lung cancer (NSCLC), particularly in never-smoker patients. However, these mutations are not always carcinogenic, and have recently been reported in histologically normal lung tissue from patients with and without lung cancer. To investigate the outcome of EGFR mutation in healthy lung stem cells, we grow murine alveolar type II organoids monoclonally in a three-dimensional Matrigel.

Qualified kidney injury biomarkers demonstrate value during early clinical drug development.

Drug-induced kidney injury (DIKI) is of significant concern, both during drug development and in clinical practice. We report a patient-centric approach for clinical implementation of the FDA-qualified kidney safety biomarker panel, highlighting Phase 1 and 2 trials for candidate therapeutics in Pfizer's portfolio (PFE-1 and PFE-2, respectively) that induced kidney tubular injury in rat toxicity studies. Clusterin (CLU), cystatin-C (CysC), kidney injury molecule-1 (KIM-1), N-acetyl-beta-d-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin (OPN) were measured in urine samples from (i) Phase 1 healthy volunteers (HVs; n = 12) dosed with PFE-1, (ii) Phase 2 rheumatoid arthritis (RA) patients (n = 266) dosed with PFE-2, (iii) lupus patients on standard-of-care therapies (n = 121), and (iv) healthy volunteers (n = 60).

Serial Postoperative Circulating Tumor DNA Assessment Has Strong Prognostic Value During Long-Term Follow-Up in Patients With Breast Cancer.

Purpose: Here, we report the sensitivity of a personalized, tumor-informed circulating tumor DNA (ctDNA) assay (Signatera) for detection of molecular relapse during long-term follow-up of patients with breast cancer.

Methods: A total of 156 patients with primary breast cancer were monitored clinically for up to 12 years after surgery and adjuvant chemotherapy. Semiannual blood samples were prospectively collected, and analyzed retrospectively to detect residual disease by ultradeep sequencing using ctDNA assays, developed from primary tumor whole-exome sequencing data.

Circulating tumour DNA dynamics during alternating chemotherapy and hormonal therapy in metastatic breast cancer: the ALERT study.

Purpose: Although changes in circulating tumour DNA (ctDNA) in breast cancer are well described, the kinetics of their fluctuations has not been described over short timescales. We investigated ctDNA dynamics during alternating cycles of chemotherapy and hormonal treatment in pre-treated patients with oestrogen receptor-positive metastatic breast cancer.

Methods: Patients received alternating, 9-week cycles of eribulin and aromatase inhibitors (AIs).

Regulation of long-range BMP gradients and embryonic polarity by propagation of local calcium-firing activity.

Many amniote vertebrate species including humans can form identical twins from a single embryo, but this only occurs rarely. It has been suggested that the primitive-streak-forming embryonic region emits signals that inhibit streak formation elsewhere but the signals involved, how they are transmitted and how they act has not been elucidated. Here we show that short tracks of calcium firing activity propagate through extraembryonic tissue via gap junctions and prevent ectopic primitive streak formation in chick embryos.

Meta-Analysis of Circulating Tumor Cell PD-L1 Expression and the Association with Clinical Outcomes in Non-Small Cell Lung Cancer.

Background: Programmed death ligand-1 (PD-L1) expression on circulating tumor cells (CTCs) has been suggested to provide prognostic information in non-small cell lung cancer (NSCLC), but consensus relative to treatment outcomes is lacking. We conducted the first comprehensive meta-analysis exploring its potential as a prognostic and predictive marker, and assessed the concordance between PD-L1 + CTCs and paired tumor tissue in NSCLC patients.

Method: A comprehensive search was applied to PubMed and EMBASE to identify 26 studies that evaluated PD-L1 + CTCs and their association with survival outcomes in 1236 NSCLC patients.

Effect of abrocitinib on skin biomarkers in patients with moderate-to-severe atopic dermatitis.

Background: This is the first report on the effects of abrocitinib, a Janus kinase 1-selective inhibitor, on the expression of skin biomarkers in patients with moderate-to-severe atopic dermatitis (AD).

Methods: JADE MOA (NCT03915496) was a double-blind Phase 2a trial. Adults were randomly assigned 1:1:1 to receive monotherapy with once-daily abrocitinib 200 mg, abrocitinib 100 mg, or placebo for 12 weeks.

The Interplay Between Splicing of Two Exon Combinations Differentially Affects Membrane Targeting and Function of Human Ca2.2.

N-type calcium channels (Ca2.2) are predominantly localized in presynaptic terminals, and are particularly important for pain transmission in the spinal cord. Furthermore, they have multiple isoforms, conferred by alternatively spliced or cassette exons, which are differentially expressed.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PF-06817024 in Healthy Participants, Participants with Chronic Rhinosinusitis with Nasal Polyps, and Participants with Atopic Dermatitis: A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study.

PF-06817024 is a high affinity, humanized antibody that binds interleukin-33, a proinflammatory type 2 cytokine, and thereby has the potential to inhibit downstream type 2 inflammation. This Phase 1, randomized, placebo-controlled study was conducted in 3 parts to evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics of escalating single and limited repeat PF-06817024 doses in healthy participants (Part 1), a single dose of PF-06817024 in participants with chronic rhinosinusitis with nasal polyps (Part 2), and repeat doses of PF-06817024 in participants with moderate to severe atopic dermatitis (atoptic dermatitis; Part 3). PF-06817024 was generally well tolerated in all participant populations.

Coupling dynamics of 2D Notch-Delta signalling.

Understanding pattern formation driven by cell-cell interactions has been a significant theme in cellular biology for many years. In particular, due to their implications within many biological contexts, lateral-inhibition mechanisms present in the Notch-Delta signalling pathway led to an extensive discussion between biologists and mathematicians. Deterministic and stochastic models have been developed as a consequence of this discussion, some of which address long-range signalling by considering cell protrusions reaching non-neighbouring cells.

The Type I Interferon Signature Reflects Multiple Phenotypic and Activity Measures in Dermatomyositis.

Objective: The type 1 interferon (IFN) pathway is up-regulated in dermatomyositis (DM). We sought to define how organ-specific disease activity as well as autoantibodies and other clinical factors are independently associated with systemic type I IFN activity in adult patients with DM.

Methods: RNA sequencing was performed on 355 whole blood samples collected from 202 well-phenotyped DM patients followed up during the course of their clinical care.

A Rapid, Shallow Whole Genome Sequencing Workflow Applicable to Limiting Amounts of Cell-Free DNA.

Background: Somatic copy number alterations (sCNAs) acquired during the evolution of breast cancer provide valuable prognostic and therapeutic information. Here we present a workflow for screening sCNAs using picogram amounts of cell-free DNA (cfDNA) and single circulating tumor cells (CTCs).

Methods: We repurposed the Ion ReproSeq PGS™ preimplantation genetic testing kit to perform shallow whole genome sequencing on 178 cfDNA samples (300 pg) and individual CTCs from 10 MBC patients with metastatic breast cancer (MBC) recovered by CellSearch®/DEPArray™.

The importance of cache domains in αδ proteins and the basis for their gabapentinoid selectivity.

In this hybrid review, we have first collected and reviewed available information on the structure and function of the enigmatic cache domains in αδ proteins. These are organized into two double cache (dCache_1) domains, and they are present in all αδ proteins. We have also included new data on the key function of these domains with respect to amino acid and gabapentinoid binding to the universal amino acid-binding pocket, which is present in αδ-1 and αδ-2.

Comparison of phenomics and cfDNA in a large breast screening population: the Breast Screening and Monitoring Study (BSMS).

To assess their roles in breast cancer diagnostics, we aimed to compare plasma cell-free DNA (cfDNA) levels with the circulating metabolome in a large breast screening cohort of women recalled for mammography, including healthy women and women with mammographically detected breast diseases, ductal carcinoma in situ and invasive breast cancer: the Breast Screening and Monitoring Study (BSMS). In 999 women, plasma was analyzed by nuclear magnetic resonance (NMR) and Ultra-Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS) and then processed to isolate and quantify total cfDNA. NMR and UPLC-MS results were compared with data for 186 healthy women derived from the AIRWAVE cohort.

Shallow WGS of individual CTCs identifies actionable targets for informing treatment decisions in metastatic breast cancer.

Background: We report copy-number profiling by low-pass WGS (LP-WGS) in individual circulating tumour cells (CTCs) for guiding treatment in patients with metastatic breast cancer (MBC), comparing CTC results with mutations detected in circulating tumour DNA (ctDNA) in the same blood samples.

Methods: Across 10 patients with MBC who were progressing at the time of blood sampling and that had >20 CTCs detected by CellSearch, 63 single cells (50 CTCs and 13 WBCs) and 16 cell pools (8 CTC pools and 8 WBC pools) were recovered from peripheral blood by CellSearch/DEPArray™ and sequenced with Ampli1 LowPass technology (Menarini Silicon Biosystems). Copy-number aberrations were identified using the MSBiosuite software platform, and results were compared with mutations detected in matched plasma cfDNA analysed by targeted next-generation sequencing using the Oncomine™ Breast cfDNA Assay (Thermo Fisher).

The role of evolutionary game theory in spatial and non-spatial models of the survival of cooperation in cancer: a review.

Evolutionary game theory (EGT) is a branch of mathematics which considers populations of individuals interacting with each other to receive pay-offs. An individual's pay-off is dependent on the strategy of its opponent(s) as well as on its own, and the higher its pay-off, the higher its reproductive fitness. Its offspring generally inherit its interaction strategy, subject to random mutation.

Dying to cooperate: the role of environmental harshness in human collaboration.

It has been proposed that environmental stress acted as a selection pressure on the evolution of human cooperation. Through agent-based evolutionary modelling, mathematical analysis, and human experimental data we illuminate the mechanisms by which the environment influences cooperative success and decision making in a Stag Hunt game. The modelling and mathematical results show that only cooperative foraging phenotypes survive the harshest of environments but pay a penalty for miscoordination in favourable environments.

Structure modeling hints at a granular organization of the Golgi ribbon.

Background: In vertebrate cells, the Golgi functional subunits, mini-stacks, are linked into a tri-dimensional network. How this "ribbon" architecture relates to Golgi functions remains unclear. Are all connections between mini-stacks equal? Is the local structure of the ribbon of functional importance? These are difficult questions to address, without a quantifiable readout of the output of ribbon-embedded mini-stacks.

ADAM17 Mediates Proteolytic Maturation of Voltage-Gated Calcium Channel Auxiliary αδ Subunits, and Enables Calcium Current Enhancement.

The auxiliary αδ subunits of voltage-gated calcium (Ca) channels are key to augmenting expression and function of Ca1 and Ca2 channels, and are also important drug targets in several therapeutic areas, including neuropathic pain. The αδ proteins are translated as preproteins encoding both α and δ, and post-translationally proteolyzed into α and δ subunits, which remain associated as a complex. In this study, we have identified ADAM17 as a key protease involved in proteolytic processing of pro-αδ-1 and αδ-3 subunits.

'Neighbourhood watch' model: embryonic epiblast cells assess positional information in relation to their neighbours.

In many developing and regenerating systems, tissue pattern is established through gradients of informative morphogens, but we know little about how cells interpret these. Using experimental manipulation of early chick embryos, including misexpression of an inducer (VG1 or ACTIVIN) and an inhibitor (BMP4), we test two alternative models for their ability to explain how the site of primitive streak formation is positioned relative to the rest of the embryo. In one model, cells read morphogen concentrations cell-autonomously.