Newbury College

In chickens and humans, classical class I molecules of the major histocompatibility complex (MHC) can have a hierarchy of correlated properties, including cell surface expression and peptide repertoire. Chicken BF2 alleles that are less well-expressed on the cell surface and bind a very wide range of peptides are expressed by MHC haplotypes that confer protection from a variety of economically-important infectious diseases, while certain human HLA-B alleles that are well-expressed and bind a narrow range of peptides lead to slow progression from HIV infection to AIDS. Understanding the impact of these promiscuous generalists and fastidious specialists is of considerable interest. The promiscuous BF2 molecule from the chicken B21 haplotype, BF2*21:01, binds a wide range of peptides by remodelling the peptide-binding site, allowing co-variation of the anchor residues at peptide positions P2 and Pc-2, and binding of an anchor residue at Pc. By using in vitro refolding assays with peptides and peptide libraries, determining thermostability and crystal structures, and analysing a chicken B21 cell line by immunopeptidomics, we found that BF2*21:01 will accommodate many possible combinations at P2 and Pc-2, as well as several hydrophobic amino acids at Pc. However, marked preferences for particular peptide lengths, particular amino acids at the three anchor residues, combinations of amino acids at P2 and Pc-2, and amino acids at P3 and Pc-3 affecting stability lead to high frequencies of major peptides while still allowing the possibility of presenting a wide peptide repertoire. These simplifying principles may eventually allow predictions of pathogen peptides with stable binding for this iconic promiscuous class I molecule, as well as providing the data for more sophisticated peptide prediction methods.

Summary Subepiglottic cysts (SECs) form within the aryepiglottic tissue of the equine upper airway and are thought to arise from remnants of the embryonic thyroglossal duct, craniopharyngeal duct or Ranke's pouch. The clinical presentation of affected horses can vary, with larger cysts usually associated with signs such as dysphasia, exercise intolerance and epiglottic entrapment. Incidental recognition of asymptomatic cases can occur during routine endoscopic examination. Various surgical approaches and techniques for cyst excision have been described and are most commonly performed under general anaesthesia. This case report describes an alternative surgical technique in two horses where cyst excision was performed under standing sedation using a transoral approach with endoscopic guidance. A four‐wire electrocautery polypectomy snare was used to encircle and excise the cyst(s) in toto. The technique offers advantages including improved visualisation of the surgical field and reduced complications usually associated with general anaesthesia. In both cases, the surgery was well tolerated, the cysts were successfully removed without complication, and recoveries were uneventful.

12007 Background: CIT is a common consequence of antineoplastic regimens for gastrointestinal (GI) cancers, occurring in >60% of colorectal cancer patients receiving multiagent chemotherapy. CIT can lead to chemotherapy dose reduction, delay, omission, and discontinuation, potentially worsening outcomes. There are no widely available licensed therapies for this unmet need. Aim: To evaluate the safety and efficacy of the thrombopoietin receptor agonist romiplostim (ROMI) in patients with GI cancers to limit chemotherapy dose modifications from CIT. Methods: This was a phase 3, placebo (PBO)-controlled RCT of patients receiving oxaliplatin-based multiagent regimens for GI cancers with persistent CIT, ie platelets (Plt) ≤85×10 9 /L on day 1 of a scheduled chemotherapy cycle (NCT03362177). Patients from 55 sites in 14 countries were randomized 2:1 to ROMI or PBO for 3 chemotherapy cycles, stratified by baseline Plt (< or ≥50×10 9 /L) and cancer type. Study drug started at 2 μg/kg subcutaneous weekly, adjusted weekly by 1 μg/kg up to 10 μg/kg to target Plt ≥100×10 9 /L in 12 weeks (≤4 weeks at 10 μg/kg). Chemotherapy started when Plt ≥100×10 9 /L (Plt response) or after week 4 per investigator. The primary endpoint was no CIT-induced dose modification of any myelosuppressive agent in either the second or third chemotherapy cycle per independent adjudication committee. Results: Patients (N=165; 109 ROMI, 56 PBO) had colorectal (75%), gastroesophageal (13%), or pancreatic (12%) cancer; 60% were male, 90% White, 4% Black, and 24% Hispanic, with mean (SD) age of 61.4 (11.1) years. Baseline median (range) Plt was 69 (8–85)×10 9 /L; 11% had Plt <50×10 9 /L. Stage IV disease rates were ROMI 65%, PBO 55%. Most (75%) patients completed study drug; 3% discontinued due to adverse events (AEs). The primary endpoint was achieved in 92/109 (84%) patients receiving ROMI vs 20/56 (36%) receiving PBO (odds ratio 10.2; 95% CI 4.6-22.5; P<0.001). Median (range) Plt nadirs were ROMI 87 (14–167)×10 9 /L, PBO 58 (22–95)×10 9 /L; P=0.005. For those with Plt responses (ROMI 97%, PBO 77%), median (95% CI) time to first Plt response was ROMI 1.1 (not estimable) weeks, PBO 2.1 (1.1-3.0) weeks; P<0.001. Treatment-related (TR) AE rates were ROMI: 12%, PBO: 7%, most frequently nausea (2%, 2%) and headache (2%, 0%). TR serious AEs and TRAEs leading to death or discontinuation of study drug or chemotherapy were not observed in either arm. Conclusions: In this first global phase 3 RCT of ROMI vs PBO for CIT, ROMI was well tolerated and efficacious in the treatment and prevention of CIT in GI cancers. These results are potentially practice-changing for a common serious condition encountered routinely in clinical practice worldwide that prevents delivery of on-time, full-dose anticancer therapy. Final results from long-term follow-up will be presented. Clinical trial information: NCT03362177 .

Between March and August 2024, three species of Fundulus topminnows, including two northern studfish, Fundulus catenatus, six blackspotted topminnows, Fundulus olivaceus, and eleven blackstriped topminnows, Fundulus notatus, were collected from various Ouachita River drainage watersheds in Arkansas, USA. They were examined for myxozoans by having their gill, gallbladder, fins, integument, mesenteries, musculature, and other major organs examined. The mesenteries of two (33%) F. olivaceus from Town Creek (Fulton County, Arkansas, USA) were infected with a new myxozoan, Myxobolus storeri sp. n. Molecular data consisted of a 1726 base pair sequence of the partial small subunit ribosomal RNA gene for M. storeri sp. n. Histologically, plasmodia were limited to mesenteric adipose and hepatic parenchyma, causing slight compression of neighboring tissue but producing no associated inflammatory response in the examined histosections. This is the first time a myxozoan has been described from F. olivaceus and is the seventh species recorded from any member of the fish family Fundulidae.

is the world's largest gathering and industry exhibition for MHz through THz professionals, annually organized by the IEEE MTT-S as the society's premier flagship conference. The conference represents a unique opportunity to bring together researchers and practitioners with diverse technical backgrounds to share the most recent advances in MHz-to-THz technologies and systems. The in-person-only conference was held on June 19-24, 2023, at the San Diego Convention Center and it's a pleasure to report that the number of conference paper submissions and attendance were back to prepandemic levels. This Special Issue of IEEE TMTT is filled with significantly extended versions of the highly rated and attended, papers that these authors presented at the 2023 conference. The extended IEEE TMTT papers go through the same rigorous review process as regular IEEE TMTT submissions (with the added challenge of extending their already excellent conference submissions).

Focal hyperintense lesions within the navicular bursa emanating from the dorsal border of the deep digital flexor tendon (DDFT) can be recognised on T1-weighted magnetic resonance images (MRI) and have been attributed to lameness in horses. Removal of these lesions, also referred to as synovial masses, by navicular bursoscopy is currently recommended. To investigate the correlation between MRI and navicular bursoscopic findings. It is hypothesised that the prognosis following surgery is proportional to the size of the DDFT lesion. Retrospective analysis of clinical records. Horses undergoing standing low-field MRI and navicular bursoscopy with >1 year follow-up were included. A grading system was developed to classify the size of synovial mass(es) and lesion(s) of the DDFT on MRI and at surgery. Generalised estimating equations were used to evaluate the association between MRI findings and surgery and between outcome and severity of the tendon injury. Fifty-nine horses presenting over a 15-year period (2006-2021) fulfilled inclusion criteria. Ninety navicular bursae were examined both on MRI and endoscopically. There was strong correlation between the size of synovial masses and tendon lesions on MRI and bursoscopy (p < 0.001, OR: 25.61, 95% CI 8.71-75.29 and p < 0.001, OR: 7.34, 95% CI 2.70-19.92, respectively). Size of tendon lesion and synovial mass had no impact on prognosis (p = 0.3, OR: 1, 95% CI 1-1 and p = 0.1, OR: 1, 95% CI 1-1, respectively), which was guarded (30.5% return to previous level of exercise). Performance data for conservatively treated horses with MRI-detected synovial masses was not considered, nor was the effect of navicular bursal effusion. Horses were not randomly assigned to treatment protocols. There is good correlation between MRI and bursoscopic findings of DDFT lesions and synovial masses within the navicular bursa, with no false positives. Size of the synovial masses and DDFT lesions does not influence prognosis following navicular bursoscopy.

6041 Background: This study was proposed to elucidate the impact of combining anti-platelet therapy with an immune checkpoint inhibitor (ICI) in altering the CD8+ T cell function in patients with head and neck squamous cell carcinoma (HNSCC). With a total enrollment of 15 of out an expected 20 patients, this report characterizes the findings thus far from the ongoing study. Methods: This crossover trial consisted of two different treatment regimens for two groups. Regimen A involved treatment with a PD-1 inhibitor pembrolizumab (200 mg iv over 30 min) every 3 weeks in combination of daily aspirin (81 mg orally) and clopidogrel (75 mg orally) for a total of 6 weeks. Regimen B involved pembrolizumab monotherapy (200 mg iv over 30 min) every 3 weeks for two cycles. Thus far, 15 patients with recurrent or metastatic HNSCC were randomized into the two groups, with Group 1 receiving Regimen A followed by Regimen B, while Group 2 received Regimen B followed by Regimen A. In addition to clinical endpoint, in depth analysis of the peripheral blood mononuclear cells (PBMCs) was also implemented using samples obtained prior to treatment, in between regimens, and at the end of treatment. These samples were then analyzed using a spectral flow cytometer panel specific for human CD8+ T cells. Given the 75 percent accrual, we performed analysis with the obtained clinical samples and data. Results: Of the 15 patients enrolled into the study, 14 remained on study and completed the trial till endpoint. All 14 patients presented with no overtly significant adverse events (AEs). In terms of clinical response, we observed in Group 1 patients (n=7) a total of 1 CR (complete response), 1 PR (partial response), 2 SD (stable disease), and 3 PD (progressive disease), while Group 2 (n=7) presented with 2 PR, 2 SD, and 3 PD. Spectral flow analysis performed on Group 1 patient samples revealed an increase in the Ki67+PD1+ proliferative subset post combination treatment (p value &lt; 0.05, paired Student’s t-test). This finding indicates a potential increase in proliferation among CD8+ T cells after antigen stimulation that may pertain to the combination of anti-PD-1 and anti-platelet therapy. In addition, a higher frequency of Ki67+TIGIT+ CD8+ population (p value &lt; 0.05, paired Student’s t-test) was also observed after combination therapy compared to pre-treatment; however, this level was not sustained after combination therapy was ceased, implying that ongoing anti-platelet therapy may be necessary for augmenting ICI. Conclusions: Combination of anti-PD1 and anti-platelet therapy demonstrates potential for remodeling the immune compartment pertaining to CD8+ T cells without resulting in overt toxicity. Further analysis of the effects of this combination regimen will be essential to better characterize tumor specific impact. Clinical trial information: NCT03245489 .

1092 Background: ORIN1001 is a first-in-class small molecule targeting a novel enzyme with a unique mode of inhibition that selectively blocks the Inositol Requiring Enzyme 1α (IRE1) RNAse and blocks X-Box Binding Protein 1 (XBP1) activation in the endoplasmic reticulum. ORIN1001 is now undergoing Phase 1/2 clinical testing in advanced solid tumors. Methods: In a Phase 1 dose escalation trial (3+3 design), ORIN1001 was administered PO daily as a single agent in patients (pts) with advanced solid tumors and in combination with Abraxane in pts with relapsed, refractory breast cancer. Safety, tolerability, pharmacokinetics, and preliminary efficacy of ORIN1001 was evaluated and a RP2D determined. Results: As of Jan, 2023, 30 patients with advanced cancer have received ORIN1001 as a single agent at doses up to 650 mg per day in 21-day continuous cycles and 13 patients with breast cancer have received ORIN1001 at doses up to 400 mg in combination with Abraxane in 28-day continuous cycles. For single agent, DLTs consisting of thrombocytopenia were observed at 200 mg (2 pts) and 650 mg (2 pts) and, rash was observed at 200 mg (1 pt) and 500 mg (1 pt). For combination treatment, DLTs consisting of thrombocytopenia were observed at 300 mg (1 pt), fatigue/ rash at 400 mg (1 pt), febrile neutropenia/low WBC at 400/500 mg (1 pt at each dose). Common ( &gt; 15%) adverse events were predominantly nausea and/or vomiting (Grade 1-2 in severity). ORIN1001 exposure increased in a dose proportional manner with a mean T1/2 at steady state of approximately 20 hours. For single agent, best response per RECIST 1.1 was partial response (PR) in 2 of 30 pts. These PRs included a stage IV colon cancer pt exceeding 44 months on treatment at 100 mg, and stage IV ER-/PR-/HER2+ breast cancer pt with 5 months on treatment at 500 mg. Stable disease (SD) was observed in a total of 16 of 30 pts with breast, colorectal, mesothelioma, liver, prostate, kidney or ovarian cancer. For combination therapy with Abraxane, a PR was observed in one ER+/PR-/HER2- breast cancer pt at 300 mg ORIN1001 and SD was observed in 5 of 13 pts. SD included both triple negative and ER+/HER2- breast cancer pts at 300 or 400 mg with ongoing treatment exceeding 5 months. Of note, in a separate Phase 1 oncology basket trial in China, there were 2 PRs; 1 pt with stage IV NSCLC at 300 mg and 1 pt with metastatic castrate resistant prostate cancer at 100 mg exceeding 9 and 5 months of treatment with ORIN1001 in combination with Abraxane, respectively. Conclusions: Phase 1 clinical evaluation of ORIN1001 has demonstrated tolerability and dose proportional PK. The proposed RP2D is estimated to be 500 mg and 300 mg ORIN1001 for single agent and in combination with Abraxane, respectively. Early efficacy data with ORIN1001 demonstrate clinical responses (SD and PR) in multiple pts with heavily-pretreated advanced solid tumors as a single agent or in combination with Abraxane in breast cancer patients. Clinical trial information: NCT03950570 .

VOC emissions from asphalt pavements at service temperature contribute significantly to SOA formation in urban areas.