PURPOSE Camrelizumab is an antibody against programmed death protein 1. We assessed the activity and safety of camrelizumab plus apatinib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2, in patients with advanced cervical cancer. METHODS This multicenter, open-label, single-arm, phase II study enrolled patients with advanced cervical cancer who progressed after at least one line of systemic therapy. Patients received camrelizumab 200 mg every 2 weeks and apatinib 250 mg once per day. The primary end point was objective response rate (ORR) assessed by investigators per RECIST version 1.1. Key secondary end points were progression-free survival (PFS), overall survival (OS), duration of response, and safety. RESULTS Forty-five patients were enrolled and received treatment. Median age was 51.0 years (range, 33-67 years), and 57.8% of patients had previously received two or more lines of chemotherapy for recurrent or metastatic disease. Ten patients (22.2%) had received bevacizumab. Median follow-up was 11.3 months (range, 1.0-15.5 months). ORR was 55.6% (95% CI, 40.0% to 70.4%), with two complete and 23 partial responses. Median PFS was 8.8 months (95% CI, 5.6 months to not estimable). Median duration of response and median OS were not reached. Treatment-related grade 3 or 4 adverse events (AEs) occurred in 71.1% of patients, and the most common AEs were hypertension (24.4%), anemia (20.0%), and fatigue (15.6%). The most common potential immune-related AEs included grade 1-2 hypothyroidism (22.2%) and reactive cutaneous capillary endothelial proliferation (8.9%). CONCLUSION Camrelizumab plus apatinib had promising antitumor activity and manageable toxicities in patients with advanced cervical cancer. Larger randomized controlled trials are warranted to validate our findings.

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Bone remodeling is tightly controlled by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Fine tuning of the osteoclast–osteoblast balance results in strict synchronization of bone resorption and formation, which maintains structural integrity and bone tissue homeostasis; in contrast, dysregulated bone remodeling may cause pathological osteolysis, in which inflammation plays a vital role in promoting bone destruction. The alveolar bone presents high turnover rate, complex associations with the tooth and periodontium, and susceptibility to oral pathogenic insults and mechanical stress, which enhance its complexity in host defense and bone remodeling. Alveolar bone loss is also involved in systemic bone destruction and is affected by medication or systemic pathological factors. Therefore, it is essential to investigate the osteoimmunological mechanisms involved in the dysregulation of alveolar bone remodeling. The inflammasome is a supramolecular protein complex assembled in response to pattern recognition receptors and damage-associated molecular patterns, leading to the maturation and secretion of pro-inflammatory cytokines and activation of inflammatory responses. Pyroptosis downstream of inflammasome activation also facilitates the clearance of intracellular pathogens and irritants. However, inadequate or excessive activity of the inflammasome may allow for persistent infection and infection spreading or uncontrolled destruction of the alveolar bone, as commonly observed in periodontitis, periapical periodontitis, peri-implantitis, orthodontic tooth movement, medication-related osteonecrosis of the jaw, nonsterile or sterile osteomyelitis of the jaw, and osteoporosis. In this review, we present a framework for understanding the role and mechanism of canonical and noncanonical inflammasomes in the pathogenesis and development of etiologically diverse diseases associated with alveolar bone loss. Inappropriate inflammasome activation may drive alveolar osteolysis by regulating cellular players, including osteoclasts, osteoblasts, osteocytes, periodontal ligament cells, macrophages, monocytes, neutrophils, and adaptive immune cells, such as T helper 17 cells, causing increased osteoclast activity, decreased osteoblast activity, and enhanced periodontium inflammation by creating a pro-inflammatory milieu in a context- and cell type-dependent manner. We also discuss promising therapeutic strategies targeting inappropriate inflammasome activity in the treatment of alveolar bone loss. Novel strategies for inhibiting inflammasome signaling may facilitate the development of versatile drugs that carefully balance the beneficial contributions of inflammasomes to host defense.

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Dental Caries is a kind of chronic oral disease that greatly threaten human being’s health. Though dentists and researchers struggled for decades to combat this oral disease, the incidence and prevalence of dental caries remain quite high. Therefore, improving the disease management is a key issue for the whole population and life cycle management of dental caries. So clinical difficulty assessment system of caries prevention and management is established based on dental caries diagnosis and classification. Dentists should perform oral examination and establish dental records at each visit. When treatment plan is made on the base of caries risk assessment and carious lesion activity, we need to work out patient‑centered and personalized treatment planning to regain oral microecological balance, to control caries progression and to restore the structure and function of the carious teeth. And the follow-up visits are made based on personalized caries management. This expert consensus mainly discusses caries risk assessment, caries treatment difficulty assessment and dental caries treatment plan, which are the most important parts of caries management in the whole life cycle.

LIM homeobox 8 (Lhx8) is a highly conserved transcriptional factor with recently illustrated roles in cholinergic and GABAergic differentiation, and is expressed in neural crest derived craniofacial tissues during development. However, Lhx8 functions and signaling pathways are largely elusive. Here we showed that Lhx8 regulates dental mesenchyme differentiation and function via Wnt and TGFβ pathways. Lhx8 expression was restricted to dental mesenchyme from E11.5 to a peak at E14.5, and absent in dental epithelium. By reconstituting dental epithelium and mesenchyme in an E16.5 tooth organ, Lhx8 knockdown accelerated dental mesenchyme differentiation; conversely, Lhx8 overexpression attenuated dentin formation. Lhx8 overexpressed adult human dental pulp stem/progenitor cells in β-tricalcium phosphate cubes attenuated mineralized matrix production in vivo. Gene profiling revealed that postnatal dental pulp stem/progenitor cells upon Lhx8 overexpression modified several matrix related gene expression including Dspp, Cola1 and osteocalcin. Lhx8 transcriptionally activates Wnt and TGFβ pathways, and its attenuation upregulates multiple dentinogenesis genes. Together, Lhx8 regulates dentin development and regeneration by fine-turning Wnt and TGFβ signaling.

Dental follicle cells (DFCs) are reported to contain stem cells. The canonical Wnt signaling pathway plays an important role in stem cell self-renewal and tooth development through β-catenin expression. The objective of this study was to investigate whether Wnt/β-catenin signaling pathway participates in the cementoblast/osteoblast differentiation of rat DFCs. Immunohistochemistry was used to compare the expression of β-catenin in rat mandibular first molars from postnatal days 1-13. The effects of Wnt/β-catenin signaling on DFCs in vitro were examined by lithium chloride (LiCl) treatment by immunofluorescence, cell counting, dual-luciferase reporter assays, western blotting, and alkaline phosphatase activity analysis. β-Catenin expression was absent in the dental follicles on days 1 and 3 in vivo. It then progressively increased from days 5 to 13. In vitro studies of the DFCs showed that LiCl stimulation caused β-catenin, which was mainly located in the cell membrane and cytoplasm of DFCs, to be immediately transferred to the nucleus and led to the inhibition of proliferation at 12 and 24 hr. LiCl treatment also downregulated the levels of phosphorylated-β-catenin, while upregulating the levels of total β-catenin, nuclear β-catenin, osteocalcin, runt-related transcription factor 2, and collagen type I. In addition, LiCl enhanced the β-catenin/T-cell factor luciferase activity and alkaline phosphatase activity. These results suggest that Wnt/β-catenin signaling pathway positively regulates the cementoblast/osteoblast differentiation of the DFCs.

As transcription factors of the lines (LIN)-11/Islet (Isl)-1/mitosis entry checkpoint (MEC)-3 (LIM)-homeobox subfamily, LIM homeobox (Lhx)6 and -8 are remarkably conserved and involved in the morphogenesis of multiple organ systems. Lhx6 and -8 play overlapping and distinctive roles, but in general act as cell fate mediators and in turn are regulated by several transcriptional factors, such as sonic hedgehog, fibroblast growth factors, and wingless-int (Wnt)/b-catenin. In this review, we first summarize Lhx6 and -8 distributions in development and then explore how Lhx6 and -8 act as transcription factors and coregulators of cell lineage specification. Known Lhx6 and -8 functions and targets are outlined in neurogenesis, craniofacial development, and germ cell differentiation. The underlying mechanisms of Lhx6 and -8 in regulating cell fate remain elusive. Whether Lhx6 and -8 affect functions in tissues and organs other than neural, craniofacial, oocytes, and germ cells is largely unexplored. Taken together, Lhx6 and -8 are important regulators of cell lineage specification and may act as one of the pivotal mediators of stem cell fate. Undoubtedly, future investigations of Lhx6 and -8 biology will continue to yield fascinating insights into tissue development and homeostasis, in addition to their putative roles in tissue regeneration and ageing.-Zhou, C., Yang, G., Chen, M., He, L., Xiang, L., Ricupero, C., Mao, J. J., Ling, J. Lhx6 and Lhx8: cell fate regulators and beyond. FASEB J. 29, 4083-4091 (2015). www.fasebj.org