Intratumoral delivery of lipid nanoparticle-formulated mRNA encoding IL-21, IL-7, and 4-1BBL induces systemic anti-tumor immunity.

Local delivery of mRNA-based immunotherapy offers a promising avenue as it enables the production of specific immunomodulatory proteins that can stimulate the immune system to recognize and eliminate cancer cells while limiting systemic exposure and toxicities. Here, we develop and employ lipid-based nanoparticles (LNPs) to intratumorally deliver an mRNA mixture encoding the cytokines interleukin (IL)-21 and IL-7 and the immunostimulatory molecule 4-1BB ligand (Triplet LNP). IL-21 synergy with IL-7 and 4-1BBL leads to a profound increase in the frequency of tumor-infiltrating CD8 T cells and their capacity to produce granzyme B and IFN-γ, leading to tumor eradication and the development of long-term immunological memory.

Flt3L therapy increases the abundance of Treg-promoting CCR7 cDCs in preclinical cancer models.

Conventional dendritic cells (cDCs) are at the forefront of activating the immune system to mount an anti-tumor immune response. Flt3L is a cytokine required for DC development that can increase DC abundance in the tumor when administered therapeutically. However, the impact of Flt3L on the phenotype of distinct cDC subsets in the tumor microenvironment is still largely undetermined.

Hapten/Myristoyl Functionalized Poly(propyleneimine) Dendrimers as Potent Cell Surface Recruiters of Antibodies for Mediating Innate Immune Killing.

Recruiting endogenous antibodies to the surface of cancer cells using antibody-recruiting molecules has the potential to unleash innate immune effector killing mechanisms against antibody-bound cancer cells. The affinity of endogenous antibodies is relatively low, and many currently explored antibody-recruiting strategies rely on targeting over-expressed receptors, which have not yet been identified in most solid tumors. Here, both challenges are addressed by functionalizing poly(propyleneimine) (PPI) dendrimers with both multiple dinitrophenyl (DNP) motifs, as anti-hapten antibody-recruiting motifs, and myristoyl motifs, as universal phospholipid cell membrane anchoring motifs, to recruit anti-hapten antibodies to cell surfaces.

Met-Signaling Controls Dendritic Cell Migration in Skin by Regulating Podosome Formation and Function.

Signaling through the HGF receptor/Met in skin-resident Langerhans cells (LCs) and dermal dendritic cells (DCs) is essential for their emigration toward draining lymph nodes upon inflammation-induced activation. In this study, we addressed the role of Met signaling in distinct steps of LC/dermal DC emigration from the skin by employing a conditionally Met-deficient mouse model (Met). We found that Met deficiency severely impaired podosome formation in DCs and concomitantly decreased the proteolytic degradation of gelatin.

Guidelines for mouse and human DC functional assays.

This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs and various non-lymphoid tissues. Recent studies have provided evidence for an increasing number of phenotypically distinct conventional DC (cDC) subsets that on one hand exhibit a certain functional plasticity, but on the other hand are characterized by their tissue- and context-dependent functional specialization. Here, we describe a selection of assays for the functional characterization of mouse and human cDC.

IFN-α/β Signaling Is Required for CDG-Mediated CTL Generation and B Lymphocyte Activation.

Among cyclic di-nucleotides (CDN), both cyclic di-AMP (CDA) and di-GMP (CDG) are promising adjuvants and immune modulators. These molecules are not only able to induce profuse antibody production but also predominant T helper 1 and cytotoxic CD8 T lymphocytes (CTL) responses, which enable their use for vaccination against intracellular pathogens as well as in cancer immunotherapy. However, for their successful translation into the clinic, a comprehensive understanding of CDN mode of action is still essential.

Efficacy of CD40 Agonists Is Mediated by Distinct cDC Subsets and Subverted by Suppressive Macrophages.

Unlabelled: Agonistic αCD40 therapy has been shown to inhibit cancer progression in only a fraction of patients. Understanding the cancer cell-intrinsic and microenvironmental determinants of αCD40 therapy response is therefore crucial to identify responsive patient populations and to design efficient combinatorial treatments. Here, we show that the therapeutic efficacy of αCD40 in subcutaneous melanoma relies on preexisting, type 1 classical dendritic cell (cDC1)-primed CD8+ T cells.

Sequence Analysis, Antibiogram Profile, Virulence and Antibiotic Resistance Genes of XDR and MDR Isolated from Layer Chickens in Egypt.

Background: is incriminated frequently in severe economic losses and mortalities in the poultry industry. This study aimed to detect the prevalence of in layer chickens, sequence analysis, the antibiogram profiles, and PCR screening of virulence determinants and antibiotic resistance genes.

Methods: Accordingly, 300 samples (tracheal swabs, ovary and oviduct, and lung) were randomly collected from 100 diseased layer chickens from private commercial layer farms at Elsharkia Governorate, Egypt.

Acinetobacter baumannii Sampled from Cattle and Pigs Represent Novel Clones.

Acinetobacter baumannii is a very important human pathogen. Nonetheless, we know very little about nonhuman isolates of A. baumannii.

PLA/Hydroxyapatite scaffolds exhibit in vitro immunological inertness and promote robust osteogenic differentiation of human mesenchymal stem cells without osteogenic stimuli.

Bone defects stand out as one of the greatest challenges of reconstructive surgery. Fused deposition modelling (FDM) allows for the printing of 3D scaffolds tailored to the morphology and size of bone damage in a patient-specific and high-precision manner. However, FDM still suffers from the lack of materials capable of efficiently supporting osteogenesis.

Nintedanib targets KIT D816V neoplastic cells derived from induced pluripotent stem cells of systemic mastocytosis.

The KIT D816V mutation is found in >80% of patients with systemic mastocytosis (SM) and is key to neoplastic mast cell (MC) expansion and accumulation in affected organs. Therefore, KIT D816V represents a prime therapeutic target for SM. Here, we generated a panel of patient-specific KIT D816V induced pluripotent stem cells (iPSCs) from patients with aggressive SM and mast cell leukemia to develop a patient-specific SM disease model for mechanistic and drug-discovery studies.

Functionalized Cellulose Nanocrystals for Cellular Labeling and Bioimaging.

Cellulose nanocrystals (CNCs) are unique and promising natural nanomaterials that can be extracted from native cellulose fibers by acid hydrolysis. In this study, we developed chemically modified CNC derivatives by covalent tethering of PEGylated biotin and perylenediimide (PDI)-based near-infrared organic dye and evaluated their suitability for labeling and imaging of different cell lines including J774A.1 macrophages, NIH-3T3 fibroblasts, HeLa adenocarcinoma cells, and primary murine dendritic cells.

Identification of Acinetobacter baumannii of Human and Animal Origins by a Gene-Specific PCR.

Acinetobacter baumannii is a notorious nosocomial pathogen known for its ability to cause severe infections, especially in intensive care units. The identification of a conserved gene encoding a hypothetical protein in A. baumannii isolates but not in other Acinetobacter species during a comparative genomic analysis was reported.

Dealing with time-varying recruitment and length in Hill-type muscle models.

Hill-type muscle models are often used in muscle simulation studies and also in the design and virtual prototyping of functional electrical stimulation systems. These models have to behave in a sufficiently realistic manner when recruitment level and contractile element (CE) length change continuously. For this reason, most previous models have used instantaneous CE length in the muscle׳s force vs.

Black necrotic oesophagus following the use of biodegradable stent for benign oesophageal stricture.

Biodegradable stents are increasingly being used for benign oesophageal conditions that include refractory strictures and perforations. Acute oesophageal necrosis has been reported with various other conditions but none due to the insertion of biodegradable stents. A 58-year-old male presented as an acute emergency in severe haemodynamic shock.

The rise of carbapenem-resistant Acinetobacter baumannii.

Acinetobacter spp. are Gram-negative bacteria that have become one of the most difficult pathogens to treat. The species A.

Plasmid-encoded PER-7 β-lactamase responsible for ceftazidime resistance in Acinetobacter baumannii isolated in the United Arab Emirates.

Objectives: To investigate the mechanism of ceftazidime resistance in two isogenic Acinetobacter baumannii strains from the United Arab Emirates.

Methods: Two A. baumannii strains, NM55 and NM128, were isolated 4 months apart from a 6-year-old patient in the United Arab Emirates.

Molecular epidemiology and antimicrobial resistance pattern of extended-spectrum-β-lactamase-producing Enterobacteriaceae in Glasgow, Scotland.

Objectives: To establish the molecular epidemiology and antimicrobial resistance pattern of extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae harbouring bla(CTX-M) in Glasgow, Scotland.

Methods: During a 12 week period, Enterobacteriaceae isolates obtained from urine samples were collected and susceptibility testing performed. Isolates were screened for the presence of bla(CTX-M) by multiplex PCR and selected Escherichia coli genes were subsequently sequenced.

Epidemiology of Acinetobacter baumannii of animal origin.

Acinetobacter baumannii is an opportunistic pathogen responsible for nosocomial infections, however the origins of these bacteria remain unclear. Sixteen A. baumannii strains collected from animals slaughtered for human consumption were investigated for their susceptibility profiles, resistance islands (RIs), class 1 integrons, insertion sequence ISAba1, and bla(OXA-51)-like and bla(AmpC) genes.

Analysis of residual pancreatic bed necrosis using computed tomography following minimally invasive necrosectomy.

Purpose: In a unit practicing minimally invasive pancreatic necrosectomy (MIPN), our aim was to assess whether tomographic residual necrotic volume was an objective indicator for repeat necrosectomy.

Methods: Prospective study of acute pancreatitis admissions. Patients with infected pancreatic necrosis or deteriorating sepsis had MIPN.

Distribution of intrinsic plasmid replicase genes and their association with carbapenem-hydrolyzing class D beta-lactamase genes in European clinical isolates of Acinetobacter baumannii.

Ninety-six genetically diverse multidrug-resistant clinical isolates of Acinetobacter baumannii from 25 hospitals in 17 European countries were screened by PCR for specific carbapenemase-hydrolyzing class D β-lactamase (CHDL) genes and by PCR-based replicon typing for the presence of 19 different plasmid replicase (rep) gene homology groups (GRs). Results were confirmed by DNA sequencing where necessary. All 96 isolates contained at least 1 (with a maximum of 4) of the 19 groups of rep genes.

Characterization of epidemiologically unrelated Acinetobacter baumannii isolates from four continents by use of multilocus sequence typing, pulsed-field gel electrophoresis, and sequence-based typing of bla(OXA-51-like) genes.

This study used a diverse collection of epidemiologically unrelated Acinetobacter baumannii isolates to compare the robustness of a multilocus sequence typing (MLST) scheme, based on conserved regions of seven housekeeping genes, gltA, gdhB, recA, cpn60, rpoD, gyrB, and gpi, with that of sequence-based typing of bla(OXA-51-like) genes (SBT-bla(OXA-51-like) genes). The data obtained by analysis of MLST and SBT-bla(OXA-51-like) genes were compared to the data generated by pulsed-field gel electrophoresis (PFGE). The topologies of the phylogenetic trees generated for the gyrB and gpi genes showed evidence of recombination and were inconsistent with those of the trees generated for the other five genes.