A low-dose metronomic TMZ regimen, but not a standard TMZ regimen, reduced the number of circulating Tregs. These results can have clinical applications for immunotherapeutic approaches in GBM.

Fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling plays essential roles in bone development and diseases. Missense mutations in FGFs and FGFRs in humans can cause various congenital bone diseases, including chondrodysplasia syndromes, craniosynostosis syndromes and syndromes with dysregulated phosphate metabolism. FGF/FGFR signaling is also an important pathway involved in the maintenance of adult bone homeostasis. Multiple kinds of mouse models, mimicking human skeleton diseases caused by missense mutations in FGFs and FGFRs, have been established by knock-in/out and transgenic technologies. These genetically modified mice provide good models for studying the role of FGF/FGFR signaling in skeleton development and homeostasis. In this review, we summarize the mouse models of FGF signaling-related skeleton diseases and recent progresses regarding the molecular mechanisms, underlying the role of FGFs/FGFRs in the regulation of bone development and homeostasis. This review also provides a perspective view on future works to explore the roles of FGF signaling in skeletal development and homeostasis.

Acquired drug resistance is a major obstacle to chemotherapy of cancers. In this study, we aim to investigate the role of exosomes in drug-resistance transfer between breast cancer cells and detect the probable mechanism. A docetaxel-resistant variant of MCF-7 cell line (MCF-7/DOC) was established and then compared with the drug-sensitive variant (MCF-7/S). Exosomes were expelled from the cell supernatant using ultracentrifugation. Drug resistance was assessed by apoptosis assay and MTT examination. Expressions of P-glycoprotein (P-gp) were analyzed by flow cytometry. Stained exosomes were absorbed by receipt cells. MCF-7/S in the presence of exosomes extracted from the supernatant of MCF-7/DOC (DOC/exo) acquired drug resistance, while MCF-7/S exposed to their own exosomes (S/exo) did not. P-gp expression patterns of exosomes were similar as the originated cells. P-gp expression of MCF-7/S increased after incubation with DOC/exo and was affected by the amount of exosomes. Exosomes are effective in transferring drug resistance as well as P-gp from drug-resistant breast cancer cells to sensitive ones. The delivery of P-gp via exosomes may be a mechanism of exosome-mediated drug resistance transfer.

Immunotherapy strategies have been emerging as powerful weapons against cancer. Early clinical trials reveal that overall response to immunotherapy is low in breast cancer patients, suggesting that effective strategies to overcome resistance to immunotherapy are urgently needed. In this study, we investigated whether epigenetic reprograming by modulating histone methylation could enhance effector T lymphocyte trafficking and improve therapeutic efficacy of immune checkpoint blockade in breast cancer with focus on triple-negative breast cancer (TNBC) subtype. In silico analysis of The Cancer Genome Atlas (TCGA) data shows that expression of histone lysine-specific demethylase 1 (LSD1) is inversely associated with the levels of cytotoxic T cell-attracting chemokines (C-C motif chemokine ligand 5 (CCL5), C-X-C motif chemokine ligand 9 and 10 (CXCL9, CXCL10)) and programmed death-ligand 1 (PD-L1) in clinical TNBC specimens. Tiling chromatin immunoprecipitation study showed that re-expression of chemokines by LSD1 inhibition is associated with increased H3K4me2 levels at proximal promoter regions. Rescue experiments using concurrent treatment with small interfering RNA or inhibitor of chemokine receptors blocked LSD1 inhibitor-enhanced CD8+ T cell migration, indicating a critical role of key T cell chemokines in LSD1-mediated CD8+ lymphocyte trafficking to the tumor microenvironment. In mice bearing TNBC xenograft tumors, anti-PD-1 antibody alone failed to elicit obvious therapeutic effect. However, combining LSD1 inhibitors with PD-1 antibody significantly suppressed tumor growth and pulmonary metastasis, which was associated with reduced Ki-67 level and augmented CD8+ T cell infiltration in xenograft tumors. Overall, these results suggest that LSD1 inhibition may be an effective adjuvant treatment with immunotherapy as a novel management strategy for poorly immunogenic breast tumors.

Exosomes participate in many physiological and pathological processes by regulating cell-cell communication, which are involved in numerous diseases, including osteoarthritis (OA). Exosomes are detectable in the human articular cavity and were observed to change with OA progression. Several joint cells, including chondrocytes, synovial fibroblasts, osteoblasts, and tenocytes, can produce and secrete exosomes that influence the biological effects of targeted cells. In addition, exosomes from stem cells can protect the OA joint from damage by promoting cartilage repair, inhibiting synovitis, and mediating subchondral bone remodeling. This review summarizes the roles and therapeutic potential of exosomes in OA and discusses the perspectives and challenges related to exosome-based treatment for OA patients in the future.

The direct interaction of hyaluronic acid (HA) and proteins of the inter-␣-inhibitor family plays a critical role in organization and stabilization of the expanding cumulus extracellular matrix (cECM) following an ovulatory stimulus. Despite similarities in the morphology of cumulus oocyte complexes (COCs) expanding in vivo and in vitro, we find that the cECM of COCs which expand within intact follicles are more elastic and resistant to shear stress than the cECM of those stabilized in vitro. Western blot analysis shows that only the heavy chains of inter-␣-inhibitor are incorporated into the cECM and appears to be covalently linked to HA after stabilization in vivo while intact inter-␣-inhibitor is bound to the HA-enriched cECM by a non-covalent mechanism in in vitro stabilized COCs. However, purified pre-␣-inhibitor and HA can form covalent linkage in the presence of granulosa cells or with granulosa cellconditioned medium. In addition, COCs resistance to shear stress is also enhanced by coincubation with granulosa cells. Upon formation of the apparent covalent linkage between heavy chains and HA in culture medium, the light chain (bikunin) is concomitantly released into the medium as a complex with chondroitin sulfate moieties of inter-␣-inhibitor supporting the possibility that HA may replace the chondroitin sulfate linkage to the heavy chains. We speculate that a factor(s) secreted by granulosa cells within the follicle may catalyze a transesterification reaction resulting in an exchange of chondroitin sulfate with HA at the heavy chain/chondroitin sulfate junction followed by release of chondroitin sulfate-bikunin into the follicular fluid. It is also possible that the consequent further stabilization of the cECM through the covalent interaction of HA and heavy chains of inter-␣-inhibitor may play an important role in the process of ovulation.In most mammalian species (including mouse, rat, and human), cumulus-oocyte complexes (COCs) 1 of pre-ovulatory follicles undergo a dramatic change following an ovulatory stimulus. The tightly packed cumulus cells first disaggregate and then synthesize and secrete large amounts of hyaluronic acid (HA) into their extracellular matrices (ECMs). The ECM, cumulus cells, and oocyte are thus integrally bound within an expanded mucoid complex which is about 20 to 40 times larger (volume) dependent upon the species (1). This process of cumulus expansion is required for ovulation and may also facilitate the process of fertilization (2-4).We have previously identified a serum factor (proteins of the inter-␣-inhibitor family), critical in organizing and stabilizing the expanding cumulus matrix (5). This protein factor appears to be excluded from follicular fluid until the ovulatory gonadotropin surge and then quickly diffuses into the follicular fluid where it becomes integrated within the cumulus ECM (5, 6). Two major forms of this factor, pre-␣-inhibitor (P␣I) and inter-␣-inhibitor (I␣I), exist in mammalian species including mouse, bovine, and human (7,8). They each include a ...

Achondroplasia (ACH) is a short-limbed dwarfism resulting from gain-of-function mutations in fibroblast growth factor receptor 3 (FGFR3). Previous studies have shown that ACH patients have impaired chondrogenesis, but the effects of FGFR3 on bone formation and bone remodeling at adult stages of ACH have not been fully investigated. Using micro-computed tomography and histomorphometric analyses, we found that 2-month-old Fgfr3 G369C/1 mice (mouse model mimicking human ACH) showed decreased bone mass due to reduced trabecular bone volume and bone mineral density, defect in bone mineralization and increased osteoclast numbers and activity. Compared with primary cultures of bone marrow stromal cells (BMSCs) from wild-type mice, Fgfr3 G369C/1 cultures showed decreased cell proliferation, increased osteogenic differentiation including up-regulation of alkaline phosphatase activity and expressions of osteoblast marker genes, and reduced bone matrix mineralization. Furthermore, our studies also suggest that decreased cell proliferation and enhanced osteogenic differentiation observed in Fgfr3 G369C/1 BMSCs are caused by upregulation of p38 phosphorylation and that enhanced Erk1/2 activity is responsible for the impaired bone matrix mineralization. In addition, in vitro osteoclast formation and bone resorption assays demonstrated that osteoclast numbers and bone resorption area were increased in cultured bone marrow cells derived from Fgfr3 G369C/1 mice. These findings demonstrate that gain-of-function mutation in FGFR3 leads to decreased bone mass by regulating both osteoblast and osteoclast activities. Our studies provide new insight into the mechanism underlying the development of ACH.

We investigated the associations of baseline epidermal nerve fiber (ENF) densities and morphology (percent ENF swellings) and quantitative sensory testing (QST) with clinically defined human immunodeficiency virus (HIV)-associated distal polyneuropathy (DSP) and whether these measures are predictive of development of symptomatic DSP over time. Fifty-seven HIV-infected subjects with and without DSP and 19 controls participated. Mean ENF densities were lower at the distal leg and proximal thigh in asymptomatic or symptomatic DSP than in controls. Mean ENF densities did not differ significantly among the HIV groups. Percent ENF swellings was higher in patients with symptomatic DSP than controls at the distal leg, and was also greater at the proximal thigh in patients with asymptomatic or symptomatic DSP than in controls. The percent ENF swellings at the distal leg correlated with the thresholds for both minimal (HP 0.5) and intermediate (HP 5.0) heat pain (HP) intensity. A higher percent ENF swellings in the distal leg [hazard ratio (HR) 1.16, 95% CI 1.02-1.31] and HP 0.5 thresholds (HR 1.03, 95% CI 1.01-1.05) were the only two measures associated with a shorter time to development of symptomatic DSP. Quantitation of ENF swellings and heat pain thresholds deserve further study as predictors of symptomatic neuropathy.