Vaccination-based immunotherapy to target profibrotic cells in liver and lung.

Fibrosis is the final path of nearly every form of chronic disease, regardless of the pathogenesis. Upon chronic injury, activated, fibrogenic fibroblasts deposit excess extracellular matrix, and severe tissue fibrosis can occur in virtually any organ. However, antifibrotic therapies that target fibrogenic cells, while sparing homeostatic fibroblasts in healthy tissues, are limited. We tested whether specific immunization against endogenous proteins, strongly expressed in fibrogenic cells but highly restricted in quiescent fibroblasts, can elicit an antigen-specific cytotoxic T cell response to ameliorate organ fibrosis. In silico epitope prediction revealed that activation of the genes Adam12 and Gli1 in profibrotic cells and the resulting "self-peptides" can be exploited for T cell vaccines to ablate fibrogenic cells. We demonstrate the efficacy of a vaccination approach to mount CD8+ T cell responses that reduce fibroblasts and fibrosis in the liver and lungs in mice. These results provide proof of principle for vaccination-based immunotherapies to treat fibrosis.

Skin marker-based subject-specific spinal alignment modeling: A feasibility study.

Musculoskeletal models have the potential to improve diagnosis and optimize clinical treatment by predicting accurate outcomes on an individual basis. However, the subject-specific modeling of spinal alignment is often strongly simplified or is based on radiographic assessments, exposing subjects to unnecessary radiation. We therefore developed and introduced a novel skin marker-based approach for modeling subject-specific spinal alignment and evaluated its feasibility by comparing the predicted L1/L2 spinal loads during various functional activities with the loads predicted by the generically scaled models as well as with in vivo measured data obtained from the OrthoLoad database. Spinal loading simulations resulted in considerably higher compressive forces for both scaling approaches over all simulated activities, and AP shear forces that were closer or similar to the in vivo data for the subject-specific approach during upright standing activities and for the generic approach during activities that involved large flexions. These results underline the feasibility of the proposed method and associated workflow for inter- and intra-subject investigations using musculoskeletal simulations. When implemented into standard model scaling workflows, it is expected to improve the accuracy of muscle activity and joint loading simulations, which is crucial for investigations of treatment effects or pathology-dependent deviations.

Fear-avoidance beliefs are associated with reduced lumbar spine flexion during object lifting in pain-free adults.

ABSTRACT: There is a long-held belief that physical activities such as lifting with a flexed spine is generally harmful for the back and can cause low back pain (LBP), potentially reinforcing fear-avoidance beliefs underlying pain-related fear. In patients with chronic LBP, pain-related fear has been shown to be associated with reduced lumbar range of motion during lifting, suggesting a protective response to pain. However, despite short-term beneficial effects for tissue health, recent evidence suggests that maintaining a protective trunk movement strategy may also pose a risk for (persistent) LBP due to possible pronociceptive consequences of altered spinal motion, potentially leading to increased loading on lumbar tissues. Yet, it is unknown if similar protective movement strategies already exist in pain-free individuals, which would yield potential insights into the role of fear-avoidance beliefs in motor behavior in the absence of pain. Therefore, the aim of this study is to test whether fear-avoidance beliefs influence spinal motion during lifting in a healthy cohort of pain-free adults without a history of chronic pain. The study subjects (N = 57) filled out several pain-related fear questionnaires and were asked to perform a lifting task (5kg-box). High-resolution spinal kinematics were assessed using an optical motion capturing system. Time-sensitive analyses were performed based on statistical parametric mapping. The results demonstrated time-specific and negative relationships between self-report measures of pain-related fear and lumbar spine flexion angles during lifting, indicating potential unfavorable interactions between psychological factors and spinal motion during lifting in pain-free subjects.

Exploring the Role of Osteosarcoma-Derived Extracellular Vesicles in Pre-Metastatic Niche Formation and Metastasis in the 143-B Xenograft Mouse Osteosarcoma Model.

The pre-metastatic niche (PMN) is a tumor-driven microenvironment in distant organs that can foster and support the survival and growth of disseminated tumor cells. This facilitates the establishment of secondary lesions that eventually form overt metastasis, the main cause of cancer-related death. In recent years, tumor-derived extracellular-vesicles (EVs) have emerged as potentially key drivers of the PMN. The role of the PMN in osteosarcoma metastasis is poorly understood and the potential contribution of osteosarcoma cell-derived EVs to PMN formation has not been investigated so far. Here, we characterize pulmonary PMN development using the spontaneously metastasizing 143-B xenograft osteosarcoma mouse model. We demonstrate the accumulation of CD11b+ myeloid cells in the pre-metastatic lungs of tumor-bearing mice. We also establish that highly metastatic 143-B and poorly metastatic SAOS-2 osteosarcoma cell-derived EV education in naïve mice can recapitulate the recruitment of myeloid cells to the lungs. Surprisingly, despite EV-induced myeloid cell infiltration in the pre-metastatic lungs, 143-B and SAOS-2 EVs do not contribute towards the 143-B metastatic burden in the context of both spontaneous as well as experimental metastasis in severe-combined immunodeficient (SCID) mice. Taken together, OS-derived EVs alone may not be able to form a functional PMN, and may perhaps require a combination of tumor-secreted factors along with EVs to do so. Additionally, our study gives a valuable insight into the PMN complexity by providing the transcriptomic signature of the premetastatic lungs in an osteosarcoma xenograft model for the first time. In conclusion, identification of regulators of cellular and molecular changes in the pre-metastatic lungs might lead to the development of a combination therapies in the future that interrupt PMN formation and combat osteosarcoma metastasis.

Spinal sagittal alignment goals based on statistical modelling and musculoskeletal simulations.

The definition of target alignment for spinal fusion surgery follows anatomical criteria and strongly relies on surgical experience. However, the optimal patient-specific alignment often remains unknown. Statistical models could provide information about physiological alignments, and musculoskeletal models are powerful tools to investigate biomechanics. We aimed to statistically predict alignments and hypothesized they would be biomechanically favorable. A statistical model was trained with 60 annotated radiographs to predict physiological sagittal alignment based on position of femoral heads and sacrum. Predicted alignments for 11 back pain patients were clinically evaluated in terms of balance and compared to Original alignments. The normative ranges for spinal balance parameters were obtained from Surgimap™. Musculoskeletal loads were furthermore simulated in upright standing and 30° forward flexion, using alignment-specific musculoskeletal models. For the majority of Predicted alignments (n = 9) at least two of three investigated balance parameters were within the normative range, as opposed to the minority of the Original alignments (n = 4). Predicted alignments resulted in significantly lowered overall muscle activity and compressive loads (all levels, both postures). Shear force magnitudes in upright standing decreased significantly at levels L1L2 (-68 N) and L2L3 (-69 N) and clearly yet not significantly at L3L4 (-39 N) and L4L5 (-152 N). Shear loads at level L5S1 remained the same. In flexed postures identical trends were observed. The statistical model was able to predict spinal alignments that led to both improved balance and reduced musculoskeletal loads. Further studies are needed to investigate clinical validity of such models.