A biologic-device combination product delivering tumor-derived antigens elicits immunogenic cell death-associated immune responses against glioblastoma.

BACKGROUND: IGV-001 is a personalized, autologous cancer cell-based immunotherapy conceived to deliver a tumor-derived antigenic payload in the context of immunostimulatory signals to patients with glioblastoma (GBM). IGV-001 consists of patient-derived GBM cells treated with an antisense oligodeoxynucleotide against insulin-like growth factor 1 receptor (IGF1R) and placed in proprietary biodiffusion chambers (BDCs). The BDCs are then exposed to 5-6 Gy radiation and implanted at abdominal sites for ~48 hours. IGV-001 has previously been shown to be generally safe with promising clinical activity in newly diagnosed GBM patients. METHODS: Mouse (m) or human (h) variants of IGV-001 were prepared using GL261 mouse GBM cells or human GBM cells, respectively. BDCs containing vehicle or mIGV-001 were implanted in the flanks of C57BL/6 albino female mice in preventative and therapeutic experiments, optionally in combination with a programmed cell death 1 (PD-1) blocker. Bioactivity of the general approach was also measured against hepatocellular carcinoma Hepa 1-6 cells. Mice were followed for the growth of subsequently implanted or pre-existing tumors and survival. Draining lymph nodes from mice receiving mIGV-001 were immunophenotyped. mIGV-001 and hIGV-001 were analyzed for extracellular ATP and high mobility group box 1 (HMGB1) as indicators of immunogenic cell death (ICD), along with flow cytometric analysis of viability, surface calreticulin, and reactive oxygen species. Stress and cell death-related pathways were analyzed by immunoblotting. RESULTS: IGV-001 causes oxidative and endoplasmic reticulum stress in GL261 cells, resulting in a cytotoxic response that enables the release of antigenic material and immunostimulatory, ICD-associated molecules including ATP and HMGB1 from BDCs. Immunophenotyping confirmed that IGV-001 increases the percentage of dendritic cells, as well as effector, and effector memory T cells in BDC-draining lymph nodes. Consistent with these observations, preventative IGV-001 limited tumor progression and extended overall survival in mice intracranially challenged with GL261 cells, a benefit that was associated with an increase in tumor-specific T cells with effector features. Similar findings were obtained in the Hepa 1-6 model. Moreover, therapeutically administered IGV-001 combined with PD-1 delayed progression in GBM-bearing mice. CONCLUSIONS: These results support treatment with IGV-001 to induce clinically relevant ICD-driven anticancer immune responses in patients with GBM.

Assessment of the importance of glenohumeral peripheral mechanics by practicing physiotherapists.

BACKGROUND AND PURPOSE: Physiotherapists develop clinical reasoning theories and applied manual therapy skills through a variety of educational exposures. No studies have assessed the importance of selected theories such as the convex-concave rule, capsular pattern and scapulohumeral rhythm during clinical decision-making by physiotherapists. The present study investigated which variables physiotherapists considered were associated with the importance of these theories during practice and investigated physiotherapists' perception of translational motion biomechanics of the glenohumeral (GH) joint. METHOD: Six hundred and sixty physiotherapists in the USA volunteered to participate in this study. Using ologit regression analyses, the identifier themes and clinical background characteristics were associated with importance of peripheral biomechanics in manual therapy application and reliability/validity of the scapulohumeral rhythm theory in predicting pathological sequences of the shoulder complex. An intraclass correlation coefficient (ICC) was used to determine agreement regarding necessary translation of the GH joint for normal movement. RESULTS: The majority of physiotherapists indicated that all theories were important or very important during treatment decision-making and reported frequent utilization. Regression models identified that the importance placed on peripheral biomechanics was negatively influenced by academic qualification (bachelors and masters degrees) and gender (men were less likely to report that scapulohumeral rhythm was a reliable/valid predictor of shoulder pathology). ICC values identified excellent agreement among clinicians regarding translational motion. CONCLUSIONS: The importance of biomechanics of the periphery for use, validation and frequency was based heavily on adoption of selected theories of glenohumeral movements despite evidence that suggests the theories lack validity.

Non-invasive detection of acute allograft rejection in children by tissue Doppler imaging: myocardial velocities and myocardial acceleration during isovolumic contraction.

BACKGROUND: In adults, an acute decrease of regional myocardial velocities is a sensitive marker of rejection. In children, velocities are more variable. A new marker, myocardial acceleration during isovolumic contraction (IVA), appears to be less age-dependent than myocardial velocities. This study therefore compared tissue Doppler (TDI)-derived velocities and IVA as potential rejection markers for children. METHODS: TDI was performed in 15 pediatric heart transplant recipients (age 8.0 +/- 3.6 years) during acute rejection and at baseline without rejection, 50 additional transplant children without rejection (7.8 +/- 5.9 years) and 30 age-matched healthy children (7.5 +/- 5.2 years). Color Doppler cine-loops of 3 cardiac cycles were stored as echocardiographic raw data. Using off-line post-processing, systolic (S) and diastolic (E) myocardial velocities and IVA were measured in 5 basal left ventricular segments. IVA is the peak isovolumic contraction wave velocity divided by acceleration time. RESULTS: Without rejection, transplant children had significantly lower diastolic velocities (basal lateral E 10.4 +/- 2.9 vs 11.9 +/- 2.6 cm/s; p < 0.001) and systolic velocities (S 5.6 +/- 1.4 vs 7.1 +/- 2.0 cm/s; p < 0.001) than normal age-matched controls, but IVA was similar (1.2 +/- 1.4 vs 1.3 +/- 0.5 m/s2). During rejection, all markers decreased significantly compared with age-matched normal control, the non-rejecting transplant group and individual baseline values. CONCLUSIONS: Regional myocardial velocities change significantly during acute allograft rejection in children. However, many children already have wall motion abnormalities at baseline, so results are often difficult to interpret. In contrast, isovolumic acceleration was normal without rejection and selectively decreased during the event. IVA is a promising non-invasive rejection marker for pediatric patients.