Copines, a Family of Calcium Sensor Proteins and Their Role in Brain Function.

The Copines are a family of evolutionary conserved calcium-binding proteins found in most eukaryotic organisms from protists to humans. They share a unique architecture and contain tandem C2 domains and a Von Willebrand factor type A (VWA) domain. C2 domains in Copines bind calcium, phospholipids, and other proteins and mediate the transient association of these proteins with biological membranes at elevated calcium levels.

M9657 Is a Bispecific Tumor-Targeted Anti-CD137 Agonist That Induces MSLN-Dependent Antitumor Immunity without Liver Inflammation.

The costimulatory receptor CD137 (also known as TNFRSF9 or 4-1BB) sustains effective cytotoxic T-cell responses. Agonistic anti-CD137 cancer immunotherapies are being investigated in clinical trials. Development of the first-generation CD137-agonist monotherapies utomilumab and urelumab was unsuccessful due to low antitumor efficacy mediated by the epitope recognized on CD137 or hepatotoxicity mediated by Fcγ receptors (FcγR) ligand-dependent CD137 activation, respectively.

SNARE Modulators and SNARE Mimetic Peptides.

The soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptor (SNARE) proteins play a central role in most forms of intracellular membrane trafficking, a key process that allows for membrane and biocargo shuffling between multiple compartments within the cell and extracellular environment. The structural organization of SNARE proteins is relatively simple, with several intrinsically disordered and folded elements (e.g.

Therapeutic Antibodies in Cancer Treatment in the UK.

The growing understanding of the molecular mechanisms of carcinogenesis accelerated the development of monoclonal therapeutic antibodies to specifically target multiple cancer pathways. Recombinant protein therapeutics now constitute a large proportion of yearly approved medicines. Oncology, autoimmune diseases and to a smaller degree the prophylaxis of organ transplant rejection are their main application areas.

AC/DC Thermal Nano-Analyzer Compatible with Bulk Liquid Measurements.

Nanocalorimetry, or thermal nano-analysis, is a powerful tool for fast thermal processing and thermodynamic analysis of materials at the nanoscale. Despite multiple reports of successful applications in the material sciences to study phase transitions in metals and polymers, thermodynamic analysis of biological systems in their natural microenvironment has not been achieved yet. Simply scaling down traditional calorimetric techniques, although beneficial for material sciences, is not always appropriate for biological objects, which cannot be removed out of their native biological environment or be miniaturized to suit instrument limitations.

Peptides and Anti-peptide Antibodies for Small- and Medium-Scale Peptide and Anti-peptide Affinity Microarrays.

This chapter describes the principles for selection of antigenic peptides for the development of anti-peptide antibodies suitable for microarray-based multiplex affinity assays and optional mass spectrometry detection. The methods described here are mostly applicable to small- and medium-scale multiplex affinity assay and microarrays. Although the same principles of peptide selection may also be applied to larger-scale arrays (with 100+ features), informatics software and printing methods may well differ.

Fast Protocols for Characterizing Antibody-Peptide Binding.

Microarray assay formats gained popularity in the 1990s, first implemented in DNA-based arrays but later adopted for use with proteins, namely antibodies, peptides, low molecular weight (LMW) molecules, such as lipids, and even tissues. In nucleic acid-based affinity assays and arrays, but not in protein or peptide arrays, the specificity and affinity of complementary strand interactions can be deduced from or adjusted through modifications to the nucleotide sequence. Arrays of LMW molecules are characterized by largely uniform but low binding affinities.

Rational Approach to Finding Genes Encoding Molecular Biomarkers: Focus on Breast Cancer.

Early detection of cancer facilitates treatment and improves patient survival. We hypothesized that molecular biomarkers of cancer could be rationally predicted based on even partial knowledge of transcriptional regulation, functional pathways and gene co-expression networks. To test our data mining approach, we focused on breast cancer, as one of the best-studied models of this disease.

Colocalized targeting of TGF-β and PD-L1 by bintrafusp alfa elicits distinct antitumor responses.

Background: Bintrafusp alfa (BA) is a bifunctional fusion protein designed for colocalized, simultaneous inhibition of two immunosuppressive pathways, transforming growth factor-β (TGF-β) and programmed death-ligand 1 (PD-L1), within the tumor microenvironment (TME). We hypothesized that targeting PD-L1 to the tumor by BA colocalizes the TGF-β trap (TGF-βRII) to the TME, enabling it to sequester TGF-β in the tumor more effectively than systemic TGF-β blockade, thereby enhancing antitumor activity.

Methods: Multiple technologies were used to characterize the TGF-β trap binding avidity.

Bottom-Up Approach to the Discovery of Clinically Relevant Biomarker Genes: The Case of Colorectal Cancer.

Traditional approaches to genome-wide marker discovery often follow a common top-down strategy, where a large scale 'omics' investigation is followed by the analysis of functional pathways involved, to narrow down the list of identified putative biomarkers, and to deconvolute gene expression networks, or to obtain an insight into genetic alterations observed in cancer. We set out to investigate whether a reverse approach would allow full or partial reconstruction of the transcriptional programs and biological pathways specific to a given cancer and whether the full or substantially expanded list of putative markers could thus be identified by starting with the partial knowledge of a few disease-specific markers. To this end, we used 10 well-documented differentially expressed markers of colorectal cancer (CRC), analyzed their transcription factor networks and biological pathways, and predicted the existence of 193 new putative markers.

Environmentally Acquired and Their Role in Colonization Resistance.

is an environmentally acquired, anaerobic, spore-forming bacterium which ordinarily causes disease following antibiotic-mediated dysbiosis of the intestinal microbiota. Although much is understood regarding the life cycle of , the fate of spores upon ingestion remains unclear, and the underlying factors that predispose an individual to colonization and subsequent development of infection (CDI) are not fully understood. Here, we show that , a ubiquitous and environmentally acquired, spore-forming bacterium is associated with colonization resistance to .

Colorectal Cancer Diagnosis: The Obstacles We Face in Determining a Non-Invasive Test and Current Advances in Biomarker Detection.

Globally, colorectal cancer (CRC) is the third most common cancer, with 1.4 million new cases and over 700,000 deaths per annum. Despite being one of the most common cancers, few molecular approaches to detect CRC exist.

Assessing Fast Structure Formation Processes in Isotactic Polypropylene with a Combination of Nanofocus X-ray Diffraction and In Situ Nanocalorimetry.

A combination of in situ nanocalorimetry with simultaneous nanofocus 2D Wide-Angle X-ray Scattering (WAXS) was used to study polymorphic behaviour and structure formation in a single micro-drop of isotactic polypropylene (iPP) with defined thermal history. We were able to generate, detect, and characterize a number of different iPP morphologies using our custom-built ultrafast chip-based nanocalorimetry instrument designed for use with the European Synchrotron Radiation Facility (ESRF) high intensity nanofocus X-ray beamline facility. The detected iPP morphologies included monoclinic alpha-phase crystals, mesophase, and mixed morphologies with different mesophase/crystalline compositional ratios.

Micellar Antibiotics of .

Members of the genus, particularly the " group", are known to produce amphipathic lipopeptides with biosurfactant activity. This includes the surfactins, fengycins and iturins that have been associated with antibacterial, antifungal, and anti-viral properties. We have screened a large collection of , isolated from human, animal, estuarine water and soil samples and found that the most potent lipopeptide producers are members of the species .

Modelling the adsorption of proteins to nanoparticles at the solid-liquid interface.

Hypothesis: We developed a geometrical model to determine the theoretical maximum number of proteins that can pack as a monolayer surrounding a spherical nanoparticle. We applied our new model to study the adsorption of receptor binding domain (RBD) of the SARS-CoV-2 spike protein to silica nanoparticles. Due to its abundance and extensive use in manufacturing, silica represents a reservoir where the virus can accumulate.

Discovery of Pemigatinib: A Potent and Selective Fibroblast Growth Factor Receptor (FGFR) Inhibitor.

Aberrant activation of FGFR has been linked to the pathogenesis of many tumor types. Selective inhibition of FGFR has emerged as a promising approach for cancer treatment. Herein, we describe the discovery of compound (INCB054828, pemigatinib), a highly potent and selective inhibitor of FGFR1, FGFR2, and FGFR3 with excellent physiochemical properties and pharmacokinetic profiles.

The Urban River Syndrome: Achieving Sustainability Against a Backdrop of Accelerating Change.

Human activities have been affecting rivers and other natural systems for millennia. Anthropogenic changes to rivers over the last few centuries led to the accelerating state of decline of coastal and estuarine regions globally. Urban rivers are parts of larger catchment ecosystems, which in turn form parts of wider nested, interconnected systems.

Kinetic model of polyunsaturated fatty acids oxidation in micelles.

A kinetic model of polyunsaturated fatty acids (PUFAs) radical chain oxidation in micelles is presented, taking into account the diffusion of active intermediates between aqueous and organic phases, and its effect on the detailed mechanism of the process. The model made it possible to indirectly involve the structural changes of micelles and their kinetic characteristics by varying the actual values of the reactions rate constants. The modeling results are in good agreement with experimental data for the oxidation of methyl linoleate and linoleic acid.

Insulin-Like Growth Factor-1 (IGF-1) and Its Monitoring in Medical Diagnostic and in Sports.

Insulin-like growth factor-1 (IGF-1) is the principal mediator of growth hormone (GH), plays a crucial role in promoting cell growth and differentiation in childhood and continues to have an anabolic effect in adults. IGF-1 is part of a wide network of growth factors, receptors and binding proteins involved in mediating cellular proliferation, differentiation and apoptosis. Bioavailability of IGF-1 is affected by insulin-like growth factor binding proteins (IGFBPs) which bind IGF-1 in circulation with an affinity equal to or greater than that of the IGF-1 receptor (IGF-1R).

Parsaclisib Is a Next-Generation Phosphoinositide 3-Kinase Inhibitor with Reduced Hepatotoxicity and Potent Antitumor and Immunomodulatory Activities in Models of B-Cell Malignancy.

The clinical use of first-generation phosphoinositide 3-kinase (PI3K) inhibitors in B-cell malignancies is hampered by hepatotoxicity, requiring dose reduction, treatment interruption, and/or discontinuation of therapy. In addition, potential molecular mechanisms by which resistance to this class of drugs occurs have not been investigated. Parsaclisib (INCB050465) is a potent and selective next-generation PI3K inhibitor that differs in structure from first-generation PI3K inhibitors and has shown encouraging anti-B-cell tumor activity and reduced hepatotoxicity in phase 1/2 clinical studies.

INCB054828 (pemigatinib), a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays activity against genetically defined tumor models.

Alterations in fibroblast growth factor receptor (FGFR) genes have been identified as potential driver oncogenes. Pharmacological targeting of FGFRs may therefore provide therapeutic benefit to selected cancer patients, and proof-of-concept has been established in early clinical trials of FGFR inhibitors. Here, we present the molecular structure and preclinical characterization of INCB054828 (pemigatinib), a novel, selective inhibitor of FGFR 1, 2, and 3, currently in phase 2 clinical trials.

A thermo-responsive, self-assembling biointerface for on demand release of surface-immobilised proteins.

Dedicated chemistries for on-demand capture and release of biomolecules at the solid-liquid interface are required for applications in drug delivery, for the synthesis of switchable surfaces used in analytical devices and for the assembly of next-generation biomaterials with complex architectures and functions. Here we report the engineering of a binary self-assembling polypeptide system for reversible protein capture, immobilisation and controlled thermo-responsive release from a solid surface. The first element of the binary system is a universal protein substrate immobilised on a solid surface.