Citations

Background Cancers persist despite expression of immunogenic neoantigens and ongoing antitumor immune responses. While some occult tumors likely are cleared by effective antitumor immune responses, the targeted antigens are not easily identifiable as those tumors spontaneously disappear. Methods We used mouse models with a defined antigenic protein mimicking tumor-specific neoantigens to address the nature of these spontaneous anti-tumor immune responses. Results BALB/c (H-2d ) mice challenged with BALB/c breast tumors expressing the rat-erbB2 oncoprotein succumb to their tumors despite ongoing immune responses targeting tumor-specific model antigens. Meanwhile, congenic BALB.B (H-2b ) and H-2d/H-2b F1 hybrid mice spontaneously eliminate genetically matched tumors in a major histocompatibility complex (MHC)-II dependent manner. Adoptive transfer and immune cell depletion strategies revealed CD4+ T cells and CD20+ B cells are crucial mediators of the protective response in H-2b mice. Furthermore, passive transfer of immune serum from mice rejecting their tumors confers resistance in tumor antigen-tolerant animals with an inversely proportional relationship between tumor outgrowth and the amount of rat-erbB2 specific antibody present in tumor-bearing mice. Introduction of the rat-erb2 ectodomain into other H-2b tumor models also promotes their spontaneous tumor rejection. Notably, the tumor microenvironments differ in rat-erbB2+ tumor-bearing BALB.B and BALB/c mice at the time of fate decision in the models reflecting the differences between effective and ineffective tumor immune responses. Conclusions We find that the effective antitumor immunity targeting neoantigens in these breast cancer models is determined by MHC-II-restricted presentation of optimal cancer-associated antigens. These responses are dependent on CD4+ T cells, B cells, and antigen-specific antibodies.

Abstract Chronically elevated circulating excess free fatty acids (ie, lipotoxicity) is a pathological process implicated in several metabolic disorders, including obesity-driven type 2 diabetes (T2D). Lipotoxicity exerts detrimental effects on pancreatic islet β-cells by reducing glucose-stimulated insulin secretion (GSIS), altering β-cell transcriptional identity, and promoting apoptosis. While β-cell-derived small extracellular vesicles (sEV) have been shown to contribute to β-cell failure in T2D, their specific role in lipotoxicity-mediated β-cell failure remains to be elucidated. In this work, we demonstrate that lipotoxicity enhances the release of sEVs from β-cells, which exhibit altered proteomic and lipidomic profiles. These palmitate (PAL)-exposed extracellular vesicles (EVs) induce β-cell dysfunction in healthy mouse and human islets and trigger significant islet transcriptional changes, including the upregulation of genes associated with the TGFβ/Smad3 pathway, as noted by RNA sequencing. Importantly, pharmacological inhibition of the TGFβI/II receptor improved PAL EV-induced β-cell dysfunction, underscoring their involvement in activating the TGFβ/Smad3 pathway during this process. We have comprehensively characterized lipotoxic β-cell sEVs and implicated their role in inducing β-cell functional failure in T2D. These findings highlight potential avenues for therapeutic interventions targeting sEV-mediated pathways to preserve β-cell health in metabolic disorders.

Abstract Background: Intra-articular corticosteroid injections (ICSI) have been shown to be an effective symptomatic non-operative treatment for hip osteoarthritis (OA) and other joint-related pain. There has been recent dispute over the true risk of complications from ICSI specifically when injected into the hip. Avascular necrosis (AVN) of the femoral head has been reported to occur in up to 30.5% of patients after undergoing hip ICSI, and up to 50.6% of patients experiencing osteoarthritis progression in as little as 3 months following injection. Purpose: To analyze the current protocol of hip ICSIs performed by two fellowship-trained non-operative sports medicine physicians and assess the rate of femoral head avascular necrosis. We hypothesized that the rate of AVN will be less than what has been recently reported in the literature. Study Design: Retrospective chart review Methods: Patients that underwent at least one intra-articular corticosteroid hip injection by two fellowship trained non-operative sports medicine physicians at this institution were identified using an institutional database. Exclusion criteria included injections with contrast dye used for imaging, injections that administered orthobiologics to the intra-articular, and non-intra-articular injections. Procedure notes were reviewed for anesthetic and steroid type, dosage, and needle size. Each chart was screened for demographic information, post-injection infections, AVN diagnosis, and subsequent hip replacement. 10 patients were identified with an AVN diagnosis. Their MRNs were sent to a board-certified radiologist at the same medical institution. The radiologist was blinded to the patient’s chart and instructed to identify the first radiograph with evidence of AVN. Patients were excluded if the reviewer did not agree with the diagnosis as it appeared in the medical chart or the AVN developed post-traumatically. Results: 449 patients, 530 hips, underwent 1.8 ± 1.4 ICSIs and 16.3% underwent THA at an average of 2.2 ± 2.3 years following their first injection. Of the 530 hips that underwent ICSI, only 1 hip demonstrated findings of AVN on radiographs following the first injection, and this patient had been taking oral prednisone for over 20 years. Conclusions: Intra-articular corticosteroid injections are a relatively safe symptomatic treatment option for hip pain secondary to both OA and non-OA pathology to be considered when other non-operative treatment options have failed. While the use of steroids comes with an inherent risk of osteonecrosis and cartilage damage, these results demonstrate that, when performed properly with ultrasound guidance and sterile technique, the risk of femoral head avascular necrosis is minimal.

Abstract Introduction: Periacetabular osteotomy (PAO) is a complex procedure historically requiring inpatient stay. There is increased emphasis for these to be performed on an outpatient basis by insurance companies. The purpose of this study was to investigate the proportion of various surgical listing classifications (outpatient, outpatient-overnight, inpatient), the incidence of subsequent denial/request for additional documentation for approval of inpatient stay, and to characterize the average length of stay (LOS) following PAO. Methods: A retrospective chart review was performed to identify all PAOs, performed by four participating surgeons, at a single academic institution over a two-year period. The initial listing status as an outpatient-overnight or inpatient procedure was identified. Whether a preoperative peer review was required for approval of inpatient listings as well as if additional documentation was necessary to convert outpatient-overnight listings to inpatient stays were also recorded. Results: A total of 140 PAOs amongst 117 patients were performed with 25 (17.9%) initially listed as an inpatient stay and 115 (82.1%) listed as outpatient-overnight. Of the 25 PAOs listed as inpatient, 2 (8.0%) required a preoperative peer review process to justify or clarify listing status. The average LOS was 1.9 ± 1.4 days with 55.7% (78/140) of PAOs staying two or more nights in the hospital. Only 6 PAOs (4.3%) went home the same day as surgery. Of the 115 PAOs listed as an outpatient-overnight, 53 (46.1%) converted to an inpatient stay. Conclusion: Over half of PAOs performed required inpatient stay beyond outpatient-overnight status. Preoperative peer-to-peer review for inpatient stay approval was modestly frequent (8% of inpatient listings), and all conversions to inpatient required additional service documentation to support status conversion. Understanding trends in postoperative hospitalizations and LOS might allow for better informed partnerships between surgeons and insurance companies creating more efficient pre-authorizations, billing practices, and expected patterns of patient care and discharge.