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Background: Interactions between tumor and microenvironment determine individual response to immunotherapy. Triple negative breast cancer (TNBC) and hepatocellular carcinoma (HCC) have exhibited suboptimal responses to immune checkpoint inhibitors (ICIs). Aspartate β-hydroxylase (ASPH), an oncofetal protein and tumor associated antigen (TAA), is a potential target for immunotherapy., Methods: Subcutaneous HCC and orthotopic TNBC murine models were established in immunocompetent BALB/c mice with injection of BNL-T3 and 4 T1 cells, respectively. Immunohistochemistry, immunofluorescence, H&E, flow cytometry, ELISA and in vitro cytotoxicity assays were performed., Results: The ASPH-MYC signaling cascade upregulates PD-L1 expression on breast and liver tumor cells. A bio-nanoparticle based λ phage vaccine targeting ASPH was administrated to mice harboring syngeneic HCC or TNBC tumors, either alone or in combination with PD-1 blockade. In control, autocrine chemokine ligand 13 (CXCL13)-C-X-C chemokine receptor type 5 (CXCR5) axis promoted tumor development and progression in HCC and TNBC. Interactions between PD-L1 + cancer cells and PD-1 + T cells resulted in T cell exhaustion and apoptosis, causing immune evasion of cancer cells. In contrast, combination therapy (Vaccine+PD-1 inhibitor) significantly suppressed primary hepatic or mammary tumor growth (with distant pulmonary metastases in TNBC). Adaptive immune responses were attributed to expansion of activated CD4 + T helper type 1 (Th1)/CD8 + cytotoxic T cells (CTLs) that displayed enhanced effector functions, and maturation of plasma cells that secreted high titers of ASPH-specific antibody. Combination therapy significantly reduced tumor infiltration of immunosuppressive CD4 + /CD25 + /FOXP3 + Tregs. When the PD-1/PD-L1 signal was inhibited, CXCL13 produced by ASPH + cancer cells recruited CXCR5 + /CD8 + T lymphocytes to tertiary lymphoid structures (TLSs), comprising effector and memory CTLs, T follicular helper cells, B cell germinal center, and follicular dendritic cells. TLSs facilitate activation and maturation of DCs and actively recruit immune subsets to tumor microenvironment. These CTLs secreted CXCL13 to recruit more CXCR5 + immune cells and to lyse CXCR5 + cancer cells. Upon combination treatment, formation of TLSs predicts sensitivity to ICI blockade. Combination therapy substantially prolonged overall survival of mice with HCC or TNBC., Conclusions: Synergistic antitumor efficacy attributable to a λ phage vaccine specifically targeting ASPH, an ideal TAA, combined with ICIs, inhibits tumor growth and progression of TNBC and HCC., (© 2022. The Author(s).)

Objectives: Using a rabbit in vivo joint injury model, the primary objective of the study was to determine if a relationship exists between earlier time to initiation of ketotifen fumarate (KF) treatment and posttraumatic joint contracture (PTJC) reduction. The secondary objective was to determine if a coagulation response could be detected with serial thrombelastography (TEG) analysis following acute trauma in this model., Methods: PTJC of the knee were created in 25 skeletally mature, New Zealand White rabbits. Five groups of 5 animals were studied: a control group that received twice daily subcutaneous injections of normal saline and 4 treatment groups that received twice daily subcutaneous injections of KF (0.5 mg/kg) starting immediately, 1-, 2-, and 4-weeks post-injury. After 8 weeks of immobilization, flexion contractures were measured biomechanically. Serial TEG analysis was performed on the control group animals pre-injury and weekly post-injury., Results: The average joint contracture in the Control Group (43.1° ± 16.2°) was higher than all KF treatment groups; however, the differences were not statistically significant. The average joint contracture was lowest in the 2-week post-injury treatment group (29.4° ± 12.1°), although not statistically significant compared to the other treatment groups. Serial TEG analysis demonstrated significantly higher mean maximal amplitude (maximal amplitude = 68.9 ± 1.7 mm; P  < .001), alpha-angle (81.9° ± 0.9°; P  < .001), and coagulation index (4.5 ± 0.3; P  < .001) 1-week post-injury, which normalized to pre-injury values by 5-weeks post-injury., Conclusions: The use of the mast cell stabilizer KF within 2 weeks of injury demonstrated a nonsignificant trend towards reducing joint contracture in a rabbit in vivo model of PTJC. TEG and the in vivo rabbit joint injury model may be valuable in future preclinical studies of venous thromboembolism prevention and furthering our understanding of the pathophysiology of posttraumatic hypercoagulability., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Orthopaedic Trauma Association.)

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Cognitive impairments are prevalent in Parkinson's disease (PD), but the underlying mechanisms of their development are unknown. In this study, we aimed to predict global cognition (GC) in PD with machine learning (ML) using structural neuroimaging, genetics and clinical and demographic characteristics. As a post-hoc analysis, we aimed to explore the connection between novel selected features and GC more precisely and to investigate whether this relationship is specific to GC or is driven by specific cognitive domains. 101 idiopathic PD patients had a cognitive assessment, structural MRI and blood draw. ML was performed on 102 input features including demographics, cortical thickness and subcortical measures, and several genetic variants (APOE, MAPT, SNCA, etc.). Using the combination of RRELIEFF and Support Vector Regression, 11 features were found to be predictive of GC including sex, rs894280, Edinburgh Handedness Inventory, UPDRS-III, education, five cortical thickness measures (R-parahippocampal, L-entorhinal, R-rostral anterior cingulate, L-middle temporal, and R-transverse temporal), and R-caudate volume. The rs894280 of SNCA gene was selected as the most novel finding of ML. Post-hoc analysis revealed a robust association between rs894280 and GC, attention, and visuospatial abilities. This variant indicates a potential role for the SNCA gene in cognitive impairments of idiopathic PD.

Background: Some women with genetic risk of breast and/or ovarian cancer (e.g., BRCA1/2) opt to undergo prophylactic salpingo-oophorectomy (PSO, or surgical removal of the ovaries & fallopian tubes) in order to reduce their risk of cancer. As a consequence, these women experience "surgical menopause" - accompanied by more severe climacteric symptoms that occur in a much shorter time frame. While the risk of coronary artery disease (CAD) rises with menopause, little is known about how the sudden loss of ovarian function from PSO alters the whole-body physiology, and whether it predisposes women to premature CAD., Methods/design: To manage CAD risk there is a prerequisite for reliable biomarkers that can help guide risk assessment and therapeutic interventions. To address these needs, this prospective, observational cohort study will evaluate surrogate markers reflective of CAD health in women experiencing surgical menopause after PSO. Twenty women representing each of the following groups will be enrolled over 3 years (total participants = 240): (i) pre-menopausal PSO, (ii) post-menopausal PSO, (iii) pre-menopausal women undergoing other pelvic surgery, and (iv) pre-menopausal controls (no surgery). All participants will provide blood plasma samples pre- and 1, 3, 6, & 12 months post-operatively, with serial samples collectively assessed for measurements of the study's primary endpoints of interest. These include a hormone profile (estradiol, follicle stimulating hormone (FSH), luteinizing hormone (LH), and progesterone) and both conventional (lipid profile) and novel biomarkers (Heat Shock Protein 27 (HSP27), HSP27-antibodies (HSP27 Ab), proprotein convertase subtilisin/kexin 9 (PCSK9), inflammatory cytokines) of CAD. Another aspect of this study is the measurement and analysis of retinal vessel diameters - an emerging physiological parameter reflective of CAD risk. Finally, a patient engagement exercise will result in the drafting of patient-generated questionnaires that address the well-being and health concerns of these women as they transition through premature menopause and work with our research team to identify and discuss their health priorities., Discussion: The protocol of our planned study investigating the effects of PSO on CAD is described herein. Characterization of novel CAD markers in women experiencing surgical menopause will yield new insights into the role of the functional ovary in modulating lipid parameters and other CAD risk factors such as HSP27 and HSP27 Ab., Competing Interests: This research has obtained ethics approval at the University of Calgary (REB14–2335) and consent from participating PSO women and controls.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: The role, interplay, and relative importance of the multifactorial hemodynamic and myocardial mechanisms causing dysfunction of the Fontan circulation remain incompletely understood., Methods and Results: Using an MRI catheterization technique, we performed a differential analysis of pulmonary vascular resistance and aortopulmonary collateral blood flow in conjunction with global ventricular pump function, myocontractility (end-systolic pressure-volume relation), and diastolic compliance (end-diastolic pressure-volume relation) in 10 patients with a Fontan circulation at rest and during dobutamine stress. Pulmonary and ventricular pressures were measured invasively and synchronized with velocity-encoded MRI-derived pulmonary and aortic blood flows and cine MRI-derived ventricular volumes. Pulmonary vascular resistance and end-systolic and end-diastolic pressure-volume relations were then determined. Aortopulmonary collateral flow was calculated as the difference between aortic and pulmonary flow. Compared to rest, dobutamine caused a small increase in mean pulmonary pressures (P<0.05). Collateral flow was significantly augmented (P<0.001) and contributed importantly to an increase in pulmonary flow (P<0.01). Pulmonary vascular resistance decreased significantly (P<0.01). Dobutamine did not increase stroke volumes significantly despite slightly enhanced contractility (end-systolic pressure-volume relation). Active early relaxation (τ) was inconspicuous, but the end-diastolic pressure-volume relation shifted upward, indicating reduced compliance., Conclusions: In patients with a Fontan circulation, aortopulmonary collateral flow contributes substantially to enhanced pulmonary flow during stress. Our data indicate that pulmonary vascular response to augmented cardiac output was adequate, but decreased diastolic compliance was identified as an important component of ventricular dysfunction.

Objectives: This study sought to develop and validate a method for the integrated analysis of systolic and diastolic ventricular function., Background: An integrated approach to assess ventricular pump function, myocontractility (end-systolic pressure-volume relationship [ESPVR]), and diastolic compliance (end-diastolic pressure-volume relation [EDPVR]) is of high clinical value. Cardiac magnetic resonance (CMR) is well established for measuring global pump function, and catheterization-combined CMR was previously shown to accurately measure ESPVR, but not yet the EDPVR., Methods: In 8 pigs, the CMR technique was compared with conductance catheter methods (gold standard) for measuring the EDPVR in the left and right ventricle. Measurements were performed at rest and during dobutamine administration. For CMR, the ESPVR was estimated with a single-beat approach by synchronizing invasive ventricular pressures with cine CMR-derived ventricular volumes. The EDPVR was determined during pre-load reduction from additional volume data that were obtained from real-time velocity-encoded CMR pulmonary/aortic blood flow measurements. Pre-load reduction was achieved by transient balloon occlusion of the inferior vena cava. The stiffness coefficient beta was calculated by an exponential fit from the EDPVR. After validation in the animal experiments, the EDPVR was assessed in a pilot study of 3 patients with a single ventricle using identical CMR and conductance catheter techniques., Results: Bland-Altman tests showed good agreement between conductance catheter-derived and CMR-derived EDPVR. In both ventricles of the pigs, dobutamine enhanced myocontractility (p < 0.01), increased stroke volume (p < 0.01), and improved diastolic function. The latter was evidenced by shorter early relaxation (p < 0.05), a downward shift of the EDPVR, and a decreased stiffness coefficient beta (p < 0.05). In contrast, in the patients, early relaxation was inconspicuous but the EDPVR shifted left-upward and the stiffness constant remained unchanged. The observed changes in diastolic function were not significantly different when measured with conductance catheter and CMR., Conclusions: This novel CMR method provides differential information about diastolic function in conjunction with parameters of systolic contractility and global pump function.