Citations

Abstract A series of seven I-Ab-reactive monoclonal antibodies (mAb) has been derived from a BALB/c anti-C57BL/6 immunization. Analysis of the reactivity patterns of these mAb with spleen cells of mice from the independent haplotypes has revealed three groups of mAb: group I mAb react with all haplotypes except d, group II with all except d and k, and group III with all except d, k, and j. In addition, the group I and group II mAb also react with human class II-expressing cells. We have used these mAb to isolate one mutant I-Ab-expressing cell line and three additional I-Ak mutant cell lines. These antibodies have been used, in conjunction with a large panel of I-A-reactive mAb available from others, to extensively characterize our collection of mutant I-A-expressing cell lines. Analysis of the mutant cell lines has allowed us to assign the reactivity of each mAb to either the A alpha- or the A beta-polypeptide. All seven newly isolated mAb appear to react with determinants on the A alpha-polypeptide. Furthermore, analysis of the panel of A alpha k- and A beta k-mutants has allowed us to discriminate at least five epitopes that are separable by mutation on the A beta k-polypeptide, and two epitopes on the A alpha k-polypeptide.

Abstract A segment of the murine immune response-associated (Ia) antigen A beta chain mRNA has been cloned, and this cDNA clone has been used to examine the organization of the genes encoding these highly polymorphic cell surface proteins. To isolate this clone, pIA beta-1, we screened 5000 cDNA clones by a filter hybridization-selection assay using a rabbit heteroantiserum to identify the A beta chain produced in in vitro translation reactions. This clone corresponds to a segment of the mRNA encoding the beta chain of the murine I-A antigen. The 464 bp nucleotide sequence of the insert is consistent with a cDNA clone encoding the carboxyl end of the murine A beta chain. Comparison of this nucleotide sequence to a human Ia beta chain-derived cDNA clone suggests that the two clones could encode proteins that are about 90% homologous in this region. Southern blot analysis using pIA beta-1 as a probe to investigate the structure of the A beta chain gene in inbred strains of mice allows two conclusions. First, there is only one A beta chain gene homologous to this cDNA clone in each haploid mouse genome. Second, the restriction fragments encoding this gene are highly polymorphic. We postulate that the mechanism which generates polymorphic variation of the A beta chain may be involved in generating the restriction site polymorphism within or near the A beta chain gene.

Abstract Small amounts of a 22,000-dalton (22Kd) Ia polypeptide were immunoprecipitated with monoclonal anti-Ia antibodies from murine B lymphocyte tumor cells and from splenocytes that express the I-Ad subregion. HPLC peptide map comparisons of A alpha d, A beta d and the 22Kd polypeptides demonstrated that the 22Kd polypeptide has extensive homology with A alpha d. Amino terminal sequence analysis of the 3H-tyrosine 22Kd polypeptide indicates this polypeptide has tyrosines at residues 16, 17, 30, and 32. Unexpectedly, this amino terminal 22Kd sequence is homologous with A beta d rather than A alpha d. These results suggest that the 22Kd polypeptide is a hybrid molecule containing both A alpha d and A beta d-like sequences. The 22Kd polypeptide has provisionally been designated A delta d.

Abstract The endoplasmic reticulum resident protein calnexin interacts with several glycoproteins including class I MHC molecules. Calnexin is thought to retain free class I heavy chains and/or promote their folding and assembly with beta 2-microglobulin and peptide ligand. Whereas with other glycoproteins, Asn-linked glycans seem to be involved in calnexin association, with class I molecules the transmembrane region has been implicated. To critically define the structures on class I molecules that determine their interaction with calnexin, we have studied carbohydrate-deficient and transmembrane-variant class I molecules. Carbohydrate-deficient class I molecules were found to accumulate intracellularly in an open, non-beta 2-microglobulin-associated conformation. However, open as well as conformed class I molecules showed significant calnexin association whether they were aglycosylated or fully glycosylated. Thus, carbohydrate moieties may be necessary for efficient class I folding, but are not required for calnexin association. Calnexin was also found associated with a soluble class I molecule that has a truncated transmembrane segment, demonstrating that membrane attachment of class I is not required for interaction with calnexin. Finally, two isoforms of the class Ib molecule Q7b were compared. Unexpectedly, the glycosylphosphatidylinositol-anchored Q7b isoform was found associated with calnexin, whereas the soluble Q7b isoform was not calnexin associated. These comparisons of Q7b isoforms implicate the class I-connecting peptide segment and not the transmembrane region as a site of interaction with calnexin.

AbstractHospitals, payors, and patients increasingly expect us to report our outcomes in more detail and to justify our treatment decisions and costs. Although there are many stakeholders in surgical outcomes, physicians must take the lead role in defining how outcomes are assessed. Skull base lesions interact with surrounding anatomy to produce a complex spectrum of presentations and surgical challenges, requiring a wide variety of surgical approaches. Moreover, many skull base lesions are relatively rare. These factors and others often preclude the use of prospective randomized clinical trials, thus necessitating alternate methods of scientific inquiry. In this paper, we propose a roadmap for implementing a skull base registry, along with expected benefits and challenges.

TPS3172 Background: Ulixertinib (BVD-523) is a small molecule inhibitor of extracellular signal-regulated kinases 1/2 (ERK1/2) in development as a novel anti-cancer drug. Early clinical data demonstrated anti-tumor activity, especially for patients with tumors harboring atypical BRAF or MEK1/2 alterations (Sullivan et al., Cancer Discov. 2018;8(2):184-195). Atypical BRAF (non-V600) alterations can be categorized according to characteristics of molecular signaling (Class II or III), are seen in approximately 3% of all human cancers, and there are currently no approved therapies for this indication. Similar to atypical BRAF alterations, the incidence of MEK1/2 alterations are rare in human tumors (< 1 %). Preclinical data have demonstrated activity of ulixertinib in MEK mutant models. Ulixertinib has FDA fast-track designation for patients with solid tumors, other than CRC, with specific BRAF mutations (G469A, L485W, or L597Q). Designed with intent to register, the BVD-523-ABC clinical trial will continue evaluation of ulixertinib in patients with tumors harboring any atypical BRAF or MEK1/2 alteration (NCT04488003). Methods: This multi-center, phase II study, will be conducted in two parts and assess the clinical benefit, safety, pharmacokinetics, and pharmacodynamics of ulixertinib in patients with advanced malignancies. Ulixertinib will be administered at the RP2D of 600 mg BID for 28-day treatment cycles. Eligible patients will have locally advanced or metastatic cancer which progressed following standard systemic therapies, or for which the patient is not a candidate or refused systemic therapy. Planned correlative analyses include reverse phase protein array and transcriptomics of tumor tissue. Part A is open-label and tumor agnostic, except for group 4 and 6 (CRC patients only). Patients will enroll into one of six groups based on BRAF (groups 1-4) or MEK1/2 (groups 5-6) tumor alteration (38 patients per group). Overall response rate (ORR) is the primary endpoint for Part A, with secondary endpoints including duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Part B is tumor histology specific. Patients will be randomized to receive either ulixertinib or physician's choice of treatment in a 2:1 ratio. Up to three specified tumor histologies will be defined, guided by available Part A data (n = 80-100 per histology). The primary endpoint of Part B is PFS, and secondary endpoints include OS, ORR, and DOR. This study has enrolled 43 patients of the planned 228 in Part A at the time of abstract submission. Clinical trial information: NCT04488003.

2651 Background: Etigilimab (etig), a humanized IgG1 monoclonal antibody, blocks TIGIT interaction with PVR (poliovirus receptor) and inhibits downstream signalling with target cell killing. Etig +/- nivolumab (nivo) showed acceptable safety and preliminary activity in a FIH Phase 1a/b study in solid tumors. ACTIVATE, an open-label Phase 1b/2 basket study is evaluating further efficacy, safety, tolerability and PK/PD of etig+nivo. This is a preliminary efficacy and safety analysis from ACTIVATE. Methods: Subjects with advanced/metastatic solid tumors without curative/standard of care therapies are given IV etig+nivo Q2W until disease progression or intolerable toxicity. Six open cohorts are enrolling in parallel: endometrial cancer (post-front-line platinum), endometrial cancer (2-3 prior lines), PD-L1+ checkpoint-inhibitor-naïve (CPI-n) cervical cancer, rare cancers (germ cell tumor (GCT), sarcoma, uveal melanoma), ovarian cancer (post-front-line platinum) and TMB-h/MSS, (TMB >10mut/mb) tumors. Tumor assessments are done every 8 weeks following baseline scan. Primary endpoint is investigator-assessed ORR by RECIST 1.1. Secondary endpoints include duration of response and safety. Results: Of 27 efficacy-evaluable subjects enrolled in the 6 open cohorts with minimum 1 staging scan or radiological/clinical progression at data cut-off of 02/10/22, 12 had clinical benefit with 1 complete response (CR), 2 partial responses (PRs) and 9 stable diseases (SDs) and 15 had radiological/clinical progressive disease (PD), with an overall response rate (ORR) of 11% and disease control rate (DCR) of 44%. Conclusions: Etig+nivo is safe and well tolerated with no new safety signals. Early efficacy was noted in cervical cancer (1CR, 1PR and 1SD) and uveal melanoma (3 SDs >20 weeks). Encouraging activity was also noted in ovarian cancer and post-CPI treated TMB-H/MSS NSCLC. These early data support continued evaluation of the combination of etig+nivo. Clinical activity was notable as below. Clinical trial information: NCT04761198. [Table: see text]

Abstract Introduction Transnasal access to the anterior skull base provides a minimally invasive approach for sellar and parasellar masses compared with its open counterparts. The unique microbiome of the sinonasal mucosa provides distinct challenges not encountered with other cranial approaches. The use of antibiotics in these cases has not been standardized, and data remain scarce regarding infectious outcomes. Methods We conducted a multicenter retrospective analysis of shared quality data points for the endoscopic endonasal approach (EEA) for pituitary adenomas, along with other sellar and parasellar region masses that were included by participating institutions. Patient and operative characteristics, perioperative and postoperative antibiotic regimens and their durations, intraoperative and postoperative cerebrospinal fluid leak, and onset of postoperative meningitis and sinusitis were compared. Results Fifteen institutions participated and provided 6 consecutive months' worth of case data. Five hundred ninety-three cases were included in the study, of which 564 were pituitary adenomectomies. The incidences of postoperative meningitis and sinusitis were low (0.67 and 2.87% for all pathologies, respectively; 0.35% meningitis for pituitary adenomas) and did not correlate with any specific antibiotic regimen. Immunocompromised status posed an increased odds of meningitis in pituitary adenomectomies (28.6, 95% confidence interval [1.72–474.4]). Conclusions The results show no clear benefit to postoperative antimicrobial use in EEA, with further larger studies needed.

Background The treatment of depression in children and adolescents is a substantial public health challenge. This study examined artificial intelligence tools for the prediction of early outcomes in depressed children and adolescents treated with fluoxetine, duloxetine, or placebo. Methods The study samples included training datasets ( N = 271) from patients with major depressive disorder (MDD) treated with fluoxetine and testing datasets from patients with MDD treated with duloxetine ( N = 255) or placebo ( N = 265). Treatment trajectories were generated using probabilistic graphical models (PGMs). Unsupervised machine learning identified specific depressive symptom profiles and related thresholds of improvement during acute treatment. Results Variation in six depressive symptoms (difficulty having fun, social withdrawal, excessive fatigue, irritability, low self‐esteem, and depressed feelings) assessed with the Children’s Depression Rating Scale‐Revised at 4–6 weeks predicted treatment outcomes with fluoxetine at 10–12 weeks with an average accuracy of 73% in the training dataset. The same six symptoms predicted 10–12 week outcomes at 4–6 weeks in (a) duloxetine testing datasets with an average accuracy of 76% and (b) placebo‐treated patients with accuracies of 67%. In placebo‐treated patients, the accuracies of predicting response and remission were similar to antidepressants. Accuracies for predicting nonresponse to placebo treatment were significantly lower than antidepressants. Conclusions PGMs provided clinically meaningful predictions in samples of depressed children and adolescents treated with fluoxetine or duloxetine. Future work should augment PGMs with biological data for refined predictions to guide the selection of pharmacological and psychotherapeutic treatment in children and adolescents with depression.