Bone remodeling is essential for adult bone homeostasis. It comprises two phases: bone formation and resorption. The balance between the two phases is crucial for sustaining bone mass and systemic mineral homeostasis. This review highlights recent work on physiological bone remodeling and discusses our knowledge of how systemic and growth factors regulate this process.

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FAS expression was generally low in 30 of 31 cutaneous T-cell lymphoma (CTCL) cases (mycosis fungoides/Sezary syndrome, SS) as well as in 5 of 6 large plaque parapsoriasis cases (a CTCL precursor). To investigate this phenomenon, we explored FAS transcript levels, cell-surface FAS protein expression and susceptibility to FAS-mediated apoptosis in four CTCL lines (MyLa, HH, SZ4, and SeAx), freshly isolated leukemic cells from a patient with SS, an acute lymphoblastic leukemia T-cell line (Jurkat), and JFL (a FAS-low variant of Jurkat). Results confirmed low FAS expression by the leukemic SS cells, HH, SZ4, SeAx, and JFL relative to normal peripheral blood mononuclear leukocytes and the other cell lines. There was a direct correlation among FAS transcript level, FAS protein level, and FAS-mediated apoptotic sensitivity in the CTCL samples. When the FAS-deficient cell lines were transfected with a wild-type FAS construct, FAS expression and sensitivity to FAS-mediated apoptosis were restored. In aggregate, these findings provide evidence that like normal T cells, CTCL cells exhibit a mechanistic connection between transcriptional regulation of FAS and sensitivity to FAS-mediated apoptosis, point to the development of FAS deficiency as one molecular mechanism responsible for acquired resistance to apoptosis in CTCL, and indicate that upregulation of FAS expression can restore sensitivity to apoptosis.

Background: Despite aggressive multimodal therapy, locally advanced and/or metastatic penile squamous cell carcinoma (SqCC) is associated with significant morbidity and mortality, indicating a need for new therapeutic options. Given the emerging clinical utility of immunotherapeutics, we sought to assess the incidence and potential clinical significance of PD-L1 expression in penile SqCC.Patients and methods: Using an anti-PD-L1 primary antibody (clone 5H1), immunohistochemistry was carried out on whole tumor sections from 37 patients with penile SqCC treated at our institution between 2005 and 2013. PD-L1positive tumors were defined as those with membranous staining in ≥5% of tumor cells. Association between PD-L1 expression and clinicopathologic parameters was examined using Fisher's exact test. Correlation between PD-L1 expression in primary tumors and matched metastases was assessed using the Spearman rank correlation coefficient (ρ). The difference in cancer-specific mortality between PD-L1-positive and -negative groups was examined using the log-rank test.Results: Twenty-three (62.2%) of 37 primary tumors were positive for PD-L1 expression, and there was strong positive correlation of PD-L1 expression in primary and metastatic samples (ρ = 0.72; 0.032 < P < 0.036). Primary tumor PD-L1 expression was significantly associated with usual type histology (P = 0.040) and regional lymph node metastasis (P = 0.024), as well as decreased cancer-specific survival (P = 0.011). Conclusions:The majority of primary penile SqCC tumors express PD-L1, which is associated with high-risk clinicopathologic features and poor clinical outcome. These data provide a rational basis for further investigation of anti-PD-1 and anti-PD-L1 immunotherapeutics in patients with advanced penile SqCC.

Chromogranin A knockout (Chga-KO) mice exhibit enhanced insulin sensitivity despite obesity. Here, we probed the role of the chromogranin A-derived peptide pancreastatin (PST: CHGA ) by investigating the effect of diet-induced obesity (DIO) on insulin sensitivity of these mice. We found that on a high-fat diet (HFD), Chga-KO mice (KO-DIO) remain more insulin sensitive than wild-type DIO (WT-DIO) mice. Concomitant with this phenotype is enhanced Akt and AMPK signaling in muscle and white adipose tissue (WAT) as well as increased FoxO1 phosphorylation and expression of mature Srebp-1c in liver and downregulation of the hepatic gluconeogenic genes, Pepck and G6pase. KO-DIO mice also exhibited downregulation of cytokines and proinflammatory genes and upregulation of anti-inflammatory genes in WAT, and peritoneal macrophages from KO mice displayed similarly reduced proinflammatory gene expression. The insulin-sensitive, anti-inflammatory phenotype of KO-DIO mice is masked by supplementing PST. Conversely, a PST variant peptide PSTv1 (PST-ND3: CHGA 276-301 ), lacking PST activity, simulated the KO phenotype by sensitizing WT-DIO mice to insulin. In summary, the reduced inflammation due to PST deficiency prevented the development of insulin resistance in KO-DIO mice. Thus, obesity manifests insulin resistance only in the presence of PST, and in its absence obesity is dissociated from insulin resistance.The chromogranin A (human CHGA/mouse Chga) proprotein (1-4) undergoes proteolysis and gives rise to bioactive peptides including the antihypertensive catestatin (CHGA 352-372 ) (5-8) and the diabetogenic pancreastatin (PST: CHGA 250-301 ) (9-12). We have shown that Chgadeficient mice (Chga-KO) are obese, hyperadrenergic, and hypertensive. They display elevated levels of circulating leptin and catecholamines but lower levels of interleukin (IL)-6 and Mcp-1 (11,13-16). Despite these abnormalities, Chga-KO mice exhibit enhanced insulin sensitivity (11), a phenotype masked by supplementing PST. PST regulates hepatic insulin signaling through conventional (c) PKC and Srebp-1c (11). Increased plasma PST levels in diabetic populations correlate with insulin resistance (10). Similarly, increased circulating levels of PST in diet-induced obesity (DIO) and db/ db mice are associated with insulin resistance. Despite high levels of plasma leptin and catecholamines, Chga-KO mice are obese owing to peripheral leptin and catecholamine resistance (17).Since normal chow diet (NCD)-fed Chga-KO mice displayed increased insulin sensitivity (11), we hypothesized that Chga-KO mice may be able to maintain insulin sensitivity when exposed to the dysglycemic stress of a highfat diet (HFD). The hallmarks of insulin resistance in DIO mice are obesity, hyperinsulinemia, and increased inflammation (18)(19)(20)(21)(22). Suppression of inflammation in DIO mice can improve insulin sensitivity (23-25). For example, rosiglitazone can improve inflammation and insulin sensitivity in DIO mice without reducing obesity significantly (23-25). Chga-KO mice are...