Abbreviations: BMMs, bone marrow monocytes; M-CSF, macrophage colony stimulating factor; RANKL, receptor activator of nuclear factor-kB ligand; Pten, phosphatase and tensin homolog; OC-TG214, osteoclast specific miR-214 transgenic mice; NFATc1, nuclear factor of activated T-cells cytoplasmic; TRAP, tartrate-resistant acid phosphatase; Dnm3os, Dnm3 opposite strand; WT, wild-type; micro CT, Micro computed tomography; BMD, bone mineral density; BV/TV, ratio of bone volume to tissue volume; Tb.Sp, trabecular spacing; qRT-PCR, quantitative real-time PCR microRNA is necessary for osteoclast differentiation, function and survival. It has been reported that miR-199/214 cluster plays important roles in vertebrate skeletal development and miR-214 inhibits osteoblast function by targeting ATF4. Here, we show that miR-214 is up-regulated during osteoclastogenesis from bone marrow monocytes (BMMs) with macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor-kB ligand (RANKL) induction, which indicates that miR-214 plays a critical role in osteoclast differentiation. Overexpression of miR-214 in BMMs promotes osteoclastogenesis, whereas inhibition of miR-214 attenuates it. We further find that miR-214 functions through PI3K/Akt pathway by targeting phosphatase and tensin homolog (Pten). In vivo, osteoclast specific miR-214 transgenic mice (OC-TG214) exhibit down-regulated Pten levels, increased osteoclast activity, and reduced bone mineral density. These results reveal a crucial role of miR-214 in the differentiation of osteoclasts, which will provide a potential therapeutic target for osteoporosis.

Rationale : PD1/PD-L1 immune checkpoint inhibitors have shown promising results for several malignancies. However, PD1/PD-L1 signaling and its therapeutic significance remains largely unknown in intrahepatic cholangiocarcinoma (ICC) cases with complex etiology. Methods : We investigated the expression and clinical significance of CD3 and PD1/PD-L1 in 320 ICC patients with different risk factors. In addition, we retrospectively analyzed 7 advanced ICC patients who were treated with PD1 inhibitor. Results : The cohort comprised 233 patients with HBV infection, 18 patients with hepatolithiasis, and 76 patients with undetermined risk factors. PD-L1 was mainly expressed in tumor cells, while CD3 and PD1 were expressed in infiltrating lymphocytes of tumor tissues. PD1/PD-L1 signals were activated in tumor tissues, and expression was positively correlated with HBV infection and lymph node invasion. More PD1 + T cells and higher PD-L1 expression were observed in tumor tissues of ICC patients with HBV infection compared to patients with hepatolithiasis or undetermined risk factors. More PD1 + T cells and/or high PD-L1 expression negatively impacted the prognosis of patients with HBV infection but not those with hepatolithiasis. Multivariate analysis showed PD1/PD-L1 expression was an independent indicator of ICC patient prognosis. Advanced ICC patients with HBV infection and less PD1 + T cells tended to have good response to anti-PD1 therapy. Conclusion : Hyperactivated PD1/PD-L1 signals in tumor tissues are a negative prognostic marker for ICCs after resection. HBV infection- and hepatolithiasis-related ICCs have distinct PD1/PD-L1 profiles. Further, PD1 + T cells could be used as a biomarker to predict prognosis and assay the efficiency of anti-PD1 immunotherapy in ICC patients with HBV infection.

Background & Aims: In patients with unresectable hepatocellular carcinoma (HCC), the combination of atezolizumab and bevacizumab improved progression-free survival (PFS) and overall survival compared with sorafenib in the IMbrave150 trial. However, whether the price of the combination could be affordable is unknown. The current study assessed the cost-effectiveness of the combination of atezolizumab and bevacizumab as first-line systemic therapy for patients with unresectable HCC from the Chinese and American payers' perspective.Methods: A Markov model was built based on a global, multicentre, open-label, phase III randomized trial (IMbrave150, NCT03434379) that included three states of the patient's health: stable disease (SD), progressive disease (PD) and death. Data for all medical costs were acquired from the Red Book, published literature and West China Hospital. Quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) were the primary outcomes. Sensitivity analyses were performed to evaluate the model uncertainty.