Objective To test the hypothesis that high-fat (HF) diet-induced obesity increases pro-inflammatory cytokine expression, macrophage infiltration and M1 polarization in the infrapatellar fat pad (IFP) prior to knee cartilage degeneration. Methods We characterized the effect of HF feeding on knee OA pathology, body adiposity, and glucose intolerance in male C57BL/6J mice and identified a diet duration that induces metabolic dysfunction prior to cartilage degeneration. Magnetic resonance imaging and histomorphology were used to quantify changes in epididymal, subcutaneous, and infrapatellar fat pads and adipocyte sizes. Finally, we utilized targeted gene expression and protein arrays, immunohistochemsitry, and flow cytometry to quantify differences in fat pad inflammatory markers and immune cell populations. Results 20 weeks of HF diet treatment induced marked obesity, glucose intolerance, and early osteoarthritis (OA), including osteophytes and cartilage tidemark duplication. This duration of HF feeding increased IFP volume. However, it did not increase IFP inflammation, macrophage infiltration, or M1 macrophage polarization as observed in epididymal fat. Furthermore, leptin protein was reduced. This protection from obesity-induced inflammation corresponded with increased IFP fibrosis and the absence of adipocyte hypertrophy. Conclusion The IFP does not recapitulate classical abdominal adipose tissue inflammation during the early stages of knee OA in a high-fat diet-induced model of obesity. Consequently, these findings do not support the hypothesis that IFP inflammation is an initiating factor of obesity-induced knee OA. Furthermore, the pro-fibrotic and anti-hypertrophic responses of IFP adipocytes to high-fat feeding suggest that intra-articular adipocytes are subject to distinct spatial-temporal structural and metabolic regulation among fat pads.

Immunotherapy fails to cure most cancer patients. Preclinical studies indicate that radiotherapy synergizes with immunotherapy, promoting radiation-induced antitumor immunity. Most preclinical immunotherapy studies utilize transplant tumor models, which overestimate patient responses. Here, we show that transplant sarcomas are cured by PD-1 blockade and radiotherapy, but identical treatment fails in autochthonous sarcomas, which demonstrate immunoediting, decreased neoantigen expression, and tumor-specific immune tolerance. We characterize tumor-infiltrating immune cells from transplant and primary tumors, revealing striking differences in their immune landscapes. Although radiotherapy remodels myeloid cells in both models, only transplant tumors are enriched for activated CD8+ T cells. The immune microenvironment of primary murine sarcomas resembles most human sarcomas, while transplant sarcomas resemble the most inflamed human sarcomas. These results identify distinct microenvironments in murine sarcomas that coevolve with the immune system and suggest that patients with a sarcoma immune phenotype similar to transplant tumors may benefit most from PD-1 blockade and radiotherapy.

Posttraumatic arthritis commonly develops following articular fracture. The objective of this study was to develop a closed joint model of transarticular impact with and without creation of an articular fracture that maintains the physiologic environment during loading. Fresh intact porcine knees were preloaded and impacted at 294 J via a drop track. Osteochondral cores were obtained from the medial and lateral aspects of the femoral condyles and tibial plateau. Chondrocyte viability was assessed at days 0, 3 and 5 post-impact in sham, impacted nonfractured, and impacted fractured joints. Total matrix metalloproteinase (MMP) activity, aggrecanase (ADAMTS-4) activity, and sulfated glycosaminoglycan (S-GAG) release was measured in culture media from days 3 and 5 post-trauma. No differences were observed in chondrocyte viability of impacted nonfractured joints (95.9±6.9%) when compared to sham joints (93.8±7.7%). In impacted fractured joints, viability of the fractured edge was 40.5±27.6% and significantly lower than all other sites, including cartilage adjacent to the fractured edge (p<0.001). MMP and aggrecanase activity and S-GAG release were significantly increased in specimens from the fractured edge. This study showed that joint impact resulting in articular fracture significantly decreased chondrocyte viability, increased production of MMPs and aggrecanases, and enhanced S-GAG release, whereas the same level of impact without fracture did not cause such changes.

Metastatic breast cancer has traditionally been considered incurable, with treatments focused on systemic therapies and palliative local treatment. However, evidence is emerging that in some patients with limited metastatic disease, or "oligometastatic disease," often defined as five or fewer metastases diagnosed on imaging, aggressive metastasis-directed therapy (MDT) with surgery and/or hypofractionated imageguided radiation therapy (HIGRT) improves outcomes and may even be curative. This practice is becoming more common as evidence has grown to support the approach and as technology has made it more feasible.Treatment of certain oligometastatic breast cancers in particular (i.e., hormone receptor positive and boneonly metastases) may be especially useful given the long natural history of the disease in some of these patients. Recently, high quality data supporting ablative MDT in patients with oligometastatic disease has emerged from randomized trials for specific sites such as non-small cell lung cancer and prostate cancer, as well as from histology agnostic studies (i.e., SABR-COMET). However, randomized data in breast cancer specifically is currently lacking. Retrospective series and subgroup analysis from prospective trials have demonstrated improved outcomes with MDT for oligometastatic breast cancer. The ongoing phase II/III NRG BR002 trial seeks to provide the first randomized data to determine whether MDT in oligometastatic breast cancer improves outcomes. This may be especially important as improved systemic therapies such as targeted agents and immunotherapy prolong the disease course. Alternatively, if improved systemic therapies render patients disease free, MDT may not be necessary and only adds toxicity. However, MDT may also provide non-curative benefits for patients such as palliation of symptoms and extended time off systemic therapy. For now, aggressive MDT for certain favorable subgroups of oligometastatic breast cancer such as those with few metastases, hormone positive disease, and/or bone-only metastases is reasonable and may improve outcomes. We eagerly anticipate the results of NRG BR002 to further clarify the role of ablative therapy to all sites of disease in these patients.

The objective of this study was to investigate the expression of the chemokine CXCL10 and its role in joint tissues following articular fracture. We hypothesized that CXCL10 is upregulated following articular fracture and contributes to cartilage degradation associated with posttraumatic arthritis (PTA). To evaluate CXCL10 expression following articular fracture, gene expression was quantified in synovial tissue from knee joints of C57BL/6 mice that develop PTA following articular fracture, and MRL/MpJ mice that are protected from PTA. CXCL10 protein expression was assessed in human cartilage in normal, osteoarthritic (OA), and post-traumatic tissue using immunohistochemistry. The effects of exogenous CXCL10, alone and in combination with IL-1, on porcine cartilage explants were assessed by quantifying the release of catabolic mediators. Synovial tissue gene expression of CXCL10 was upregulated by joint trauma, peaking one day in C57BL/6 mice (25-fold) vs. three days post-fracture in MRL/MpJ mice (15-fold). CXCL10 protein in articular cartilage was most highly expressed following trauma compared with normal and OA tissue. In a dose dependent manner, exogenous CXCL10 significantly reduced total matrix metalloproteinase (MMP) and aggrecanase activity of culture media from cartilage explants. CXCL10 also trended toward a reduction in IL-1α-stimulated total MMP activity (p=0.09) and S-GAG (p=0.09), but not NO release. In conclusion, CXCL10 was upregulated in synovium and chondrocytes following trauma. However, exogenous CXCL10 did not induce a catabolic response in cartilage. CXCL10 may play a role in modulating the chondrocyte response to inflammatory stimuli associated with joint injury and the progression of PTA. This article is protected by copyright. All rights reserved