Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors.

Irisin is secreted by muscle, increases with exercise, and mediates certain favorable effects of physical activity. In particular, irisin has been shown to have beneficial effects in adipose tissues, brain, and bone. However, the skeletal response to exercise is less clear, and the receptor for irisin has not been identified. Here we show that irisin binds to proteins of the αV class of integrins, and biophysical studies identify interacting surfaces between irisin and αV/ß5 integrin. Chemical inhibition of the αV integrins blocks signaling and function by irisin in osteocytes and fat cells. Irisin increases both osteocytic survival and production of sclerostin, a local modulator of bone remodeling. Genetic ablation of FNDC5 (or irisin) completely blocks osteocytic osteolysis induced by ovariectomy, preventing bone loss and supporting an important role of irisin in skeletal remodeling. Identification of the irisin receptor should greatly facilitate our understanding of irisin's function in exercise and human health.

The impact of atezolizumab and bevacizumab in hepatocellular carcinoma with activated ß-catenin signaling.

BACKGROUND: To date, no biomarkers exist to predict response or resistance to immunotherapy in hepatocellular carcinoma (HCC). Recent approaches to classify HCC into different immunological states revealed a negative correlation between Wnt/ß-catenin activation and immunogenicity and T-cell infiltration. If these "cold" tumors with primary resistance to checkpoint inhibition (CPI) may benefit from dual treatment of CPI and anti-angiogenic therapy has not been proved. CASE: Here, we describe the case of a male patient with metastatic HCC. After failure of standard of care treatment with lenvatinib, sorafenib and ramucirumab fourth-line systemic therapy with atezolizumab and bevacizumab were applied leading to a phenomenal response. Immunohistochemical evaluations were compatible with Wnt/ß-catenin pathway activation and accompanying low T-cell infiltration as well as low PD-L1 score. CONCLUSION: Patients with Wnt/ß-catenin activation may benefit from combination therapy with atezolizumab and bevacizumab regardless of potential predictive markers for immune checkpoint inhibition.

Effects of obesity on NK cells in a mouse model of postmenopausal breast cancer.

Obesity is a widely spread disease and a crucial risk factor for malign disorders, including breast cancer of women in the postmenopause. Studies demonstrated that in case of obesity crucial natural killer (NK) cell functions like combating tumor cells are affected. This study aims to analyze NK cells and NK cell receptor expression of obese mice in a model for postmenopausal breast cancer. Therefore, female BALB/c mice were fed either a high fat or a standard diet. Thereafter, ovaries were ectomized and a syngeneic and orthotopical injection of 4T1-luc2 mouse mammary tumor cells into the mammary adipose tissue pad was performed. Obese mice showed increased body weights and visceral fat mass as well as increased levels of leptin and IL-6 in plasma. Moreover, compared to the lean littermates, tumor growth was increased and the NKp46-expression on circulating NK cells was decreased. Furthermore, the activating NK cell receptor NKG2D ligand (MULT1) expression was enhanced in adipose tissue of obese tumor bearing mice. The present study gives novel insights into gene expression of NK cell receptors in obesity and aims to promote possible links of the obesity-impaired NK cell physiology and the elevated breast cancer risk in obese women.

Perioperative support reduces mortality of obese BALB/c mice after ovariectomy.

The incidence of obesity is on the rise in most western countries and represents major risks to health. Obesity causes complex metabolic dysfunctions and can be associated with a large number of secondary diseases. To investigate causal mechanisms of obesity and develop better options for treatment, researchers study the condition in animal models. In addition to genetically engineered animal models, diet-induced obesity is often used because it occurs similarly in animals as it does in humans. For several types of investigations that use obesity models, investigators must carry out surgical interventions and they frequently encounter severe perioperative complications induced by anesthesia. In an example of this problem, we observed 100% mortality in obese BALB/c mice after ovariectomy, despite no obvious surgical complications. We supposed that a failure to recover from surgery was the primary cause of this increased mortality. Therefore, to support their recovery from surgery we administered atropine to obese mice in order to facilitate blood circulation, and we also increased the oxygen content of the ambient air. With this specific support before and after surgery, we increased the survival rate of obese ovariectomized mice up to 83%. These results confirm the assumption that obesity is a risk factor for the recovery of obese animal models after ovariectomy, and they highlight the need to provide additional interventions for such experimental animals.