Thin channel β-Ga2O3 MOSFETs with self-aligned refractory metal gates

We report the first demonstration of self-aligned gate (SAG) β-Ga2O3 metal-oxide-semiconductor field-effect transistors (MOSFETs) as a path toward eliminating source access resistance for low-loss power applications. The SAG process is implemented with a subtractively defined and etched refractory metal, such as Tungsten, combined with ion-implantation. We report experimental and modeled DC performance of a representative SAG device that achieved a maximum transconductance of 35 mS mm-1 and an on-resistance of ∼30 Ω mm with a 2.5 μm gate length. These results highlight the advantage of implant technology for SAG β-Ga2O3 MOSFETs enabling future power switching and RF devices with low parasitic resistance. © Not subject to copyright in the USA. Contribution of Wright-Patterson AFB

Using routine inpatient data to identify patients at risk of hospital readmission

Background: A relatively small percentage of patients with chronic medical conditions account for a much larger percentage of inpatient costs. There is some evidence that case-management can improve health and quality-of-life and reduce the number of times these patients are readmitted. To assess whether a statistical algorithm, based on routine inpatient data, can be used to identify patients at risk of readmission and who would therefore benefit from case-management

Specificity of bispecific T cell receptors and antibodies targeting peptide-HLA

Tumor-associated peptide–human leukocyte antigen complexes (pHLAs) represent the largest pool of cell surface–expressed cancer-specific epitopes, making them attractive targets for cancer therapies. Soluble bispecific molecules that incorporate an anti-CD3 effector function are being developed to redirect T cells against these targets using 2 different approaches. The first achieves pHLA recognition via affinity-enhanced versions of natural TCRs (e.g., immune-mobilizing monoclonal T cell receptors against cancer [ImmTAC] molecules), whereas the second harnesses an antibody-based format (TCR-mimic antibodies). For both classes of reagent, target specificity is vital, considering the vast universe of potential pHLA molecules that can be presented on healthy cells. Here, we made use of structural, biochemical, and computational approaches to investigate the molecular rules underpinning the reactivity patterns of pHLA-targeting bispecifics. We demonstrate that affinity-enhanced TCRs engage pHLA using a comparatively broad and balanced energetic footprint, with interactions distributed over several HLA and peptide side chains. As ImmTAC molecules, these TCRs also retained a greater degree of pHLA selectivity, with less off-target activity in cellular assays. Conversely, TCR-mimic antibodies tended to exhibit binding modes focused more toward hot spots on the HLA surface and exhibited a greater degree of crossreactivity. Our findings extend our understanding of the basic principles that underpin pHLA selectivity and exemplify a number of molecular approaches that can be used to probe the specificity of pHLA-targeting molecules, aiding the development of future reagents

TCR‐induced alteration of primary MHC peptide anchor residue

The HLA‐A*02:01‐restricted decapeptide EAAGIGILTV, derived from melanoma antigen recognized by T‐cells‐1 (MART‐1) protein, represents one of the best‐studied tumor associated T‐cell epitopes, but clinical results targeting this peptide have been disappointing. This limitation may reflect the dominance of the nonapeptide, AAGIGILTV, at the melanoma cell surface. The decapeptide and nonapeptide are presented in distinct conformations by HLA‐A*02:01 and TCRs from clinically relevant T‐cell clones recognize the nonapeptide poorly. Here, we studied the MEL5 TCR that potently recognizes the nonapeptide. The structure of the MEL5‐HLA‐A*02:01‐AAGIGILTV complex revealed an induced fit mechanism of antigen recognition involving altered peptide–MHC anchoring. This “flexing” at the TCR–peptide–MHC interface to accommodate the peptide antigen explains previously observed incongruences in this well‐studied system and has important implications for future therapeutic approaches. Finally, this study expands upon the mechanisms by which molecular plasticity can influence antigen recognition by T cells

Vascular findings on FDG PET/CT:a pictorial review

Since its introduction into clinical practice, 2-deoxy-2-[(18)F]flu-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) has become firmly established in the field of oncological imaging, with a growing body of evidence demonstrating its use in infectious and inflammatory vascular pathologies. This pictorial review illustrates the utility of FDG PET/CT as a diagnostic tool in the investigation of vascular disease and highlights some of the more common incidental vascular findings that PET reporters may encounter on standard oncology FDG PET/CTs, including atherosclerosis, large vessel vasculitis, complications of vascular grafts, infectious aortitis and acute aortic syndromes

Geotemporal Fluorophore Biodistribution Mapping of Colorectal Cancer: Micro and Macroscopic Insights

Fluorescence-guided oncology promises to improve both the detection and treatment of malignancy. We sought to investigate the temporal distribution of indocyanine green (ICG), an exogenous fluorophore in human colorectal cancer. This analysis aims to enhance our understanding of ICG’s effectiveness in current tumour detection and inform potential future diagnostic and therapeutic enhancements. Methods: Fifty consenting patients undergoing treatment for suspected/confirmed colorectal neoplasia provided near infrared (NIR) video and imagery of transanally recorded and ex vivo resected rectal lesions following intravenous ICG administration (0.25 mg/kg), with a subgroup providing tissue samples for microscopic (including near infrared) analysis. Computer vision techniques detailed macroscopic ‘early’ (2 h) tissue fluorescence appearances from surgical imagery with digital NIR scanning (Licor, Lincoln, NE, USA) and from microscopic analysis (Nikon, Tokyo, Japan) undertaken by a consultant pathologist detailing tissue-level fluorescence distribution over the same time. Results: Significant intra-tumoural fluorescence heterogeneity was seen ‘early’ in malignant versus benign lesions. In all ‘early’ samples, fluorescence was predominantly within the tissue stroma, with uptake within plasma cells, blood vessels and lymphatics, but not within malignant or healthy glands. At ‘late’ stage observation, fluorescence was visualised non-uniformly within the intracellular cytoplasm of malignant tissue but not retained in benign glands. Fluorescence also accumulated within any present peritumoural inflammatory tissue. Conclusion: This study demonstrates the time course diffusion patterns of ICG through both benign and malignant tumours in vivo in human patients at both macroscopic and microscopic levels, demonstrating important cellular drivers and features of geolocalisation and how they differ longitudinally after exposure to ICG

Effect of serial infusions of CER-001, a pre-β High-density lipoprotein mimetic, on coronary atherosclerosis in patients following acute coronary syndromes in the CER-001 atherosclerosis regression acute coronary syndrome trial: A randomized clinical trial

IMPORTANCE CER-001 is a negatively charged, engineered pre-β high-density lipoprotein (HDL) mimetic containing apolipoproteinA-I and sphingomyelin. Preliminary studies demonstrated favorable effects ofCER-001oncholesterol effluxandvascular inflammation.Aposthocreanalysis of a previously completed study of intravenous infusion of CER-001, 3mg/k, showed that the intravenousinfusioninpatientswithahighcoronaryplaqueburdenpromotedregressionasassessed by intravascular ultrasonography. OBJECTIVE To determine the effect of infusing CER-001 on coronary atherosclerosis progression in statin-treated patients. DESIGN, SETTING, AND PARTICIPANTS A double-blind, randomized, multicenter trial evaluating the effect of 10weekly intravenous infusions of CER-001, 3mg/kg, (n = 135) or placebo (n = 137) in patients with an acute coronary syndrome (ACS) and baseline percent atheroma volume (PAV) greater than30%in the proximal segment of an epicardial artery by intravascular ultrasonography. The study included 34 academic and community hospitals in Australia, Hungary, the Netherlands, and the United States in patients with ACS presenting for coronary angiography. Patientswere enrolled from August 15, 2015, to November 19, 2016. INTERVENTIONS Participants were randomized to receive weekly CER-001, 3mg/kg, or placebo for 10 weeks in addition to statins. MAIN OUTCOMES AND MEASURES The primary efficacy measure was the nominal change in PAV from baseline today 78 measured by serial intravascular ultrasonography imaging. These condary efficacy measureswere nominal change in normalized total atheroma volume and percentage of patients demonstrating plaque regression. Safety and tolerabilitywere also evaluated. RESULTS Among 293 patients (mean [SD] age, 59.8 [9.4] years; 217 men[79.8%]and 261 white race/ethnicity [96.0%]),86(29%) had statin prior use prior to the indexACS and 272 (92.8%)had evaluable imagingat follow-up. The place boand CER-001 groups had similar post treatment median levels of low-density lipoprotein cholesterol (74mg/dL vs 79mg/dL; P = .15) and high-density lipoproteincholesterol(43mg/dLvs44mg/dL;P = .66). The primary efficacy measure, PAV, decreased 0.41% with placebo (P = .005 compared with baseline), but not with CER-001 (-0.09%; P = .67 compared with baseline; between group differences, 0.32%; P = .15). Similar percentages of patients in the placebo and CER-001 groups demonstrated regression of PAV(57.7%vs 53.3%; P = .49). Infusions were well tolerated, with no differences in clinical and laboratory adverse events observed between treatment groups. CONCLUSIONS AND RELEVANCE Infusion of CER-001 did not promote regression of coronary atherosclerosis in statin-treated patients with ACS and high plaque burden