High-affinity T cell receptor ImmTAC® bispecific efficiently redirects T cells to kill tumor cells expressing the cancer-testis antigen PRAME.

Background: PRAME (eferentially expressed ntigen in lanoma) is a cancer-testis antigen expressed in several tumor indications, representing an attractive anticancer target. However, its intracellular location limits targeting by traditional methods. PRAME peptides are presented on the surface of tumor cells by human leukocyte antigen (HLA) molecules, indicating that a T cell receptor (TCR)-based strategy that redirects T cells to kill PRAME tumors could be a novel immunotherapeutic option.

Protection against Clostridioides difficile disease by a naturally avirulent strain.

Clostridioides difficile is a leading cause of healthcare infections. Gut dysbiosis promotes C. difficile infection (CDI) and CDIs promote gut dysbiosis, leading to frequent CDI recurrence.

Benchmarking Bulb Yield, Medicinal Sulfur Compounds, and Mineral Nutrition of Garlic Varieties.

Garlic is widely cultivated for both its culinary and medicinal properties. Bulb yield, organosulfur compounds, and plant mineral nutrition of 32 garlic varieties were characterized. Across genotypes, there was large variability in bulb weight and alliin and allicin concentrations.

Broadening alloselectivity of T cell receptors by structure guided engineering.

Specificity of a T cell receptor (TCR) is determined by the combination of its interactions to the peptide and human leukocyte antigen (HLA). TCR-based therapeutic molecules have to date targeted a single peptide in the context of a single HLA allele. Some peptides are presented on multiple HLA alleles, and by engineering TCRs for specific recognition of more than one allele, there is potential to expand the targetable patient population.

Prehospital Whole Blood Administration for Pediatric Gastrointestinal Hemorrhage: A Case Report.

The management of gastrointestinal (GI) hemorrhage in a prehospital setting presents significant challenges, particularly in arresting the hemorrhage and initiating resuscitation. This case report introduces a novel instance of prehospital whole blood transfusion to an 8-year-old male with severe lower GI hemorrhage, marking a shift in prehospital pediatric care. The patient, with no previous significant medical history, presented with acute rectal bleeding, severe hypotension (systolic/diastolic blood pressure [BP] 50/30 mmHg), and tachycardia (148 bpm).

Protection against disease by a naturally avirulent strain.

strains belonging to the epidemic BI/NAP1/027 (RT027) group have been associated with increased transmissibility and disease severity. In addition to the major toxin A and toxin B virulence factors, RT027 strains also encode the CDT binary toxin. Our lab previously identified a toxigenic RT027 isolate, ST1-75, that is avirulent in mice despite densely colonizing the colon.

Tuning the potency and selectivity of ImmTAC molecules by affinity modulation.

T-cell-engaging bispecifics have great clinical potential for the treatment of cancer and infectious diseases. The binding affinity and kinetics of a bispecific molecule for both target and T-cell CD3 have substantial effects on potency and specificity, but the rules governing these relationships are not fully understood. Using immune mobilizing monoclonal TCRs against cancer (ImmTAC) molecules as a model, we explored the impact of altering affinity for target and CD3 on the potency and specificity of the redirected T-cell response.

Sulfur Nutrition Affects Garlic Bulb Yield and Allicin Concentration.

Improving bulb yield and allicin content of garlic is important in meeting fresh and pharmaceutical market demands. Garlic plants have a high demand for sulfur (S) since allicin contains S atoms. Two experiments were conducted to identify the effect of S application rate on garlic yield and quality.

Therapeutic high affinity T cell receptor targeting a KRAS cancer neoantigen.

Neoantigens derived from somatic mutations are specific to cancer cells and are ideal targets for cancer immunotherapy. KRAS is the most frequently mutated oncogene and drives the pathogenesis of several cancers. Here we show the identification and development of an affinity-enhanced T cell receptor (TCR) that recognizes a peptide derived from the most common KRAS mutant, KRAS, presented in the context of HLA-A*11:01.

Unconventional modes of peptide-HLA-I presentation change the rules of TCR engagement.

The intracellular proteome of virtually every nucleated cell in the body is continuously presented at the cell surface the human leukocyte antigen class I (HLA-I) antigen processing pathway. This pathway classically involves proteasomal degradation of intracellular proteins into short peptides that can be presented by HLA-I molecules for interrogation by T-cell receptors (TCRs) expressed on the surface of CD8 T cells. During the initiation of a T-cell immune response, the TCR acts as the T cell's primary sensor, using flexible loops to mould around the surface of the pHLA-I molecule to identify foreign or dysregulated antigens.

Detection and Distribution of Viruses Infecting Garlic Crops in Australia.

The distribution of viruses in eastern Australian field garlic was evaluated. Detection assays were developed that involved generic RT-PCR for viruses in the , and genera followed by virus-specific colorimetric dot-blot hybridization. Assays targeted the potyviruses (onion yellow dwarf virus (OYDV), shallot yellow stripe virus (SYSV), and leek yellow stripe virus (LYSV)), the carlaviruses (garlic common latent virus (GCLV) and shallot latent virus (SLV)), and the allexiviruses (garlic viruses A, B, C, X (GarVA, -B, -C, -X) and shallot virus X (ShVX)).

Comparison of Air Force, Army, and Navy Emergency Medical Technician Candidates' Performance on the National Registry Cognitive Examination.

Introduction: Military medics function similarly to civilian emergency medical technicians (EMTs); however, they perform their emergency medical care in combat zones and military treatment facilities. Both civilian and military EMTs must take and pass the National Registry of EMT's cognitive examination to be certified as a Nationally Registered EMT; however, there is a discrepancy in requirements for obtaining and maintaining National EMT Certification between the military branches of the DoD. In our study, we aimed to compare the performance of the U.

Molecular Rules Underpinning Enhanced Affinity Binding of Human T Cell Receptors Engineered for Immunotherapy.

Immuno-oncology approaches that utilize T cell receptors (TCRs) are becoming highly attractive because of their potential to target virtually all cellular proteins, including cancer-specific epitopes, via the recognition of peptide-human leukocyte antigen (pHLA) complexes presented at the cell surface. However, because natural TCRs generally recognize cancer-derived pHLAs with very weak affinities, efforts have been made to enhance their binding strength, in some cases by several million-fold. In this study, we investigated the mechanisms underpinning human TCR affinity enhancement by comparing the crystal structures of engineered enhanced affinity TCRs with those of their wild-type progenitors.

T cell receptor interactions with human leukocyte antigen govern indirect peptide selectivity for the cancer testis antigen MAGE-A4.

T cell-mediated immunity is governed primarily by T cell receptor (TCR) recognition of peptide-human leukocyte antigen (pHLA) complexes and is essential for immunosurveillance and disease control. This interaction is generally stabilized by interactions between the HLA surface and TCR germline-encoded complementarity-determining region (CDR) loops 1 and 2, whereas peptide selectivity is guided by direct interactions with the TCR CDR3 loops. Here, we solved the structure of a newly identified TCR in complex with a clinically relevant peptide derived from the cancer testis antigen melanoma antigen-A4 (MAGE-A4).

Variation in zinc concentration of sweetcorn kernels reflects source-sink dynamics influenced by kernel number.

Grain yield and mineral nutrient concentration in cereal crops are usually inversely correlated, undermining biofortification efforts. Here, sink size, expressed as kernel number per cob, was manipulated by controlling the time when the silks of sweetcorn (Zea mays) cv. Hybrix 5 and var.

TCRs with Distinct Specificity Profiles Use Different Binding Modes to Engage an Identical Peptide-HLA Complex.

The molecular rules driving TCR cross-reactivity are poorly understood and, consequently, it is unclear the extent to which TCRs targeting the same Ag recognize the same off-target peptides. We determined TCR-peptide-HLA crystal structures and, using a single-chain peptide-HLA phage library, we generated peptide specificity profiles for three newly identified human TCRs specific for the cancer testis Ag NY-ESO-1-HLA-A2. Two TCRs engaged the same central peptide feature, although were more permissive at peripheral peptide positions and, accordingly, possessed partially overlapping peptide specificity profiles.

Dispatcher Identification of Out-of-Hospital Cardiac Arrest and Neurologically Intact Survival: A Retrospective Cohort Study.

Introduction: To date, there are no published data on the association of patient-centered outcomes and accurate public-safety answering point (PSAP) dispatch in an American population. The goal of this study is to determine if PSAP dispatcher recognition of out-of-hospital cardiac arrest (OHCA) is associated with neurologically intact survival to hospital discharge.

Methods: This retrospective cohort study is an analysis of prospectively collected Quality Assurance/Quality Improvement (QA/QI) data from the San Antonio Fire Department (SAFD; San Antonio, Texas USA) OHCA registry from January 2013 through December 2015.

Acute Flares of Knee Osteoarthritis (the ACT-FLARE Study): Protocol for a Web-Based Case-Crossover Study in Community-Dwelling Adults.

Background: The cardinal feature of osteoarthritis (OA) is pain. Although heterogeneity in pain and function have been demonstrated in the long-term course of OA, the more proximate determinants of acute flare-ups remain less clear. How short-term intermittent or transient exposures trigger acute flare-ups has important implications for effective and sustainable self-management strategies.

Speciation and accumulation of Zn in sweetcorn kernels for genetic and agronomic biofortification programs.

In sweetcorn (Zea mays L.), embryo Zn is accumulated mainly as Zn-phytate, whereas endosperm Zn is complexed with a N- or S-containing ligand. Understanding the speciation of Zn in crop plants helps improve the effectiveness of biofortification efforts.

Prehospital Double Sequential Defibrillation: A Matched Case-Control Study.

Objectives: The goal of our study was to determine whether prehospital double sequential defibrillation (DSD) is associated with improved survival to hospital admission in the setting of refractory ventricular fibrillation/pulseless ventricular tachycardia (VF/pVT).

Methods: This project is a matched case-control study derived from prospectively collected quality assurance/quality improvement data obtained from the San Antonio Fire Department out-of-hospital cardiac arrest (OHCA) database between January 2013 and December 2015. The cases were defined as OHCA patients with refractory VF/pVT who survived to hospital admission.

In situ analyses of inorganic nutrient distribution in sweetcorn and maize kernels using synchrotron-based X-ray fluorescence microscopy.

Background And Aims: Understanding the spatial distribution of inorganic nutrients within edible parts of plant products helps biofortification efforts to identify and focus on specific uptake pathways and storage mechanisms.

Methods: Kernels of sweetcorn (Zea mays) variety 'High zeaxanthin 103146' and maize inbred line 'Thai Floury 2' were harvested at two different maturity stages, and the distributions of K, P, S, Ca, Zn, Fe and Mn were examined in situ using synchrotron-based X-ray fluorescence microscopy.

Key Results: The distribution of inorganic nutrients was largely similar between maize and sweetcorn, but differed markedly depending upon the maturity stage after further embryonic development.

Airway Management for Trauma Patients.

Trauma airway management is a critical skill for medical providers supporting combat casualties since it is an integral component of damage control resuscitation and surgery. This clinical practice guideline presents methods for optimizing the airway management of patients with traumatic injury in the operational medical treatment facility environment. The guidelines represent the knowledge and experience of 10 co-authors from 3 allied countries representing Emergency Medicine, Surgery and Anesthesia.

Does Experience Matter? Paramedic Cardiac Resuscitation Experience Effect on Out-of-Hospital Cardiac Arrest Outcomes.

Objective: Outcomes of Out-of-Hospital Cardiac Arrest (OHCA) are influenced by many factors. We postulate that paramedics who have participated in a greater number of OHCA resuscitations will have improved patient outcomes when compared to paramedics who participated in fewer resuscitations.

Methods: We conducted a retrospective analysis of prospectively collected data abstracted from the cardiac arrest database of a large urban EMS system.

An Assessment of National EMT Certification Among Enlisted Military Medics.

Background: Navy Hospital Corpsmen (HMs) are the Navy equivalent to Emergency Medical Technicians (EMTs) both in-garrison and on the battlefield. In 2000, the Emergency Medical Services (EMS) Education Agenda for the Future highlighted the need for a single certification agency to provide consistent evaluation of entry level competence for each nationally recognized EMS provider level. Administered by the National Registry of EMTs (NREMT), National EMT Certification is currently utilized by 46 states, the District of Columbia, four territories, and six federal organizations as part of their processes for granting licensure.