The mechanism of enhanced electrocatalytic water splitting on S-doped NiFe2O4/Ni-Fe alloy@copper foams.

The development of bifunctional catalysts with subtle structures, high efficiencies, and good durabilities for the oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) is crucial for overall water splitting. In this work, a multicomponent S-doped NiFe2O4/Ni-Fe micro nano flower electrocatalyst was synthesized rapidly on foam copper using a simple one-step constant current electrodeposition method. The introduction of S leads to the transformation of the microsphere structure of the Ni-Fe alloy into a cauliflower-like morphology and induces changes in the surface electronic structure, significantly enhancing the catalytic performance for the HER and OER. The S-NiFe2O4/Ni-Fe alloy/CF showed low overpotentials of 220 and 66 mV at 10 mA cm-2in 1.0 M KOH for the OER and HER, respectively. High durability OER and HER performances were demonstrated through 60 h of chronopotentiometry and 6000 CV cycles test. Excellent overall water splitting electrocatalytic activity was observed in the S-NiFe2O4/Ni-Fe alloy/CF‖S-NiFe2O4/Ni-Fe alloy/CF two-electrode system. In particular, active-phase NiOOH, a highly active substance for OER, can be controllably formed in the reaction process owing to the nanoflower structure of multi-layer sulfur which slows down the dissolution of NiFe2O4/Ni-Fe alloy. These results suggest that this composite structure is a promising bifunctional electrocatalyst.

The effect of the root dilaceration on the treatment duration and prognosis of unilateral impacted immature maxillary central incisors.

INTRODUCTION: This study aimed to investigate the effect of root dilaceration on the closed-eruption technique treatment and prognosis on impacted immature maxillary central incisors. METHODS: In this retrospective study, we compared the age at the beginning of the treatment, the treatment duration, root development, and alveolar bone mass after the closed-eruption technique between the impacted immature maxillary central incisors with dilacerated roots (group 1) and those with straight roots (group 2). RESULTS: The mean age at the time of the surgery of group 1 was 0.9 years younger than that of group 2 (P = 0.008). The mean traction time was greater in group 1 (8.0 ± 1.8 months), with a difference of 1.4 months than in group 2 (6.6 ± 2.1 months) (P = 0.042). The measurements of lingual bone thickness at the alveolar crest (C) showed significant differences between the 2 groups (P = 0.025). No significant differences were found in other treatment duration or measurements of root development and alveolar bone mass between the 2 groups. CONCLUSIONS: Patients with impacted immature incisors with dilacerated roots were younger at the beginning of the closed-eruption treatment and had a longer traction time than those with impacted immature incisors having straight roots. The root dilaceration had little or no effect on root development and alveolar bone mass after the closed-eruption treatment. The closed-eruption treatment of impacted immature incisors with root dilaceration is suggested to commence as early as possible.

A novel ENAM mutation causes hypoplastic amelogenesis imperfecta.

OBJECTIVES: To identify the genetic cause of one Chinese family with hypoplastic amelogenesis imperfecta (AI) and explore the relationship between genotype and its phenotype. MATERIAL AND METHODS: One Chinese family with generalized hypoplastic AI was recruited. One deciduous tooth from the proband was subjected to scanning electron microscopy. Whole-exome sequencing was performed and identified mutation was confirmed by Sanger sequencing. Bioinformatics studies were further conducted to analyze potential deleterious effects of the mutation. RESULTS: The proband presented a typical hypoplastic AI phenotype whose teeth in deciduous and permanent dentitions showed thin, yellow, and hard enamel surface. The affected enamel in deciduous tooth showed irregular, broken, and collapsing enamel rods with borders of the enamel prisms undulated and structural shapes of prisms irregular. A novel homozygous nonsense mutation in the last exon of the enamelin (ENAM) gene (NM_031889.3; c.2078C>G) was identified in the proband, which was predicted to produce a highly truncated protein (NP_114095.2; p.(Ser693*)). This mutation was also identified in the proband's parents in heterozygous form. Surprisingly, the clinical phenotype of the heterozygous parents varied from a lack of penetrance to mild enamel defects. Additional bioinformatics studies demonstrated that the detected mutation could change the 3D structure of the ENAM protein and severely damaged the function of ENAM. CONCLUSION: The novel homozygous ENAM mutation resulted in hypoplastic AI in the present study. Our results provide new genetic evidence that mutations involved in ENAM contribute to hypoplastic AI.

Self-assembled peptide hydrogel scaffolds with VEGF and BMP-2 enhanced in vitro angiogenesis and osteogenesis.

OBJECTIVES: The reconstruction of bone defects remains a major clinical issue. Our study aims to investigate the ability of RATEA16 (RA, [CH3CONH] RADARADARADARADA-[CONH2]) for the sustained delivering VEGF and BMP-2 to promote angiogenesis and osteogenesis in bone reconstruction. MATERIALS AND METHODS: We prepared and investigated the characterization of RATEA16. The survival of human umbilical vein endothelial cells (HUVECs) and human stem cells of the apical papilla (SCAPs) encapsulated in RATEA16 hydrogel was detected. Then, we established RA-VEGF/BMP-2 drug delivery systems and measured their drug release pattern. The effects of RA-VEGF scaffolds on HUVECs angiogenesis were investigated in vitro. Then, osteoblastic differentiation capacity of SCAPs with RA-BMP-2 scaffolds was analyzed by ALP activity and expression of osteoblast-related genes. RESULTS: A porous nanofiber microstructure endowed this scaffold with the ability to maintain the survival of HUVECs and SCAPs. The RA-VEGF/BMP-2 drug delivery systems exhibited several advantagesin vitro: injectability, biodegradability, good biocompatibility, and noncytotoxicity. Released rhVEGF165 /BMP-2 were proved to promote angiogenesis of HUVECs as well as osteogenesis of SCAPs abilities. CONCLUSION: RATEA16 loading with VEGF and BMP-2 might be a potential clinical strategy for tissue engineering, especially in bone reconstruction, due to its ability of delivering growth factors effectively and efficiently.

Dental Caries Clusters among Adolescents in England, Wales, and Northern Ireland in 2013: Implications for Proportionate Universalism.

Management of dental caries in adolescents presents a population health challenge; thus, it is important to use national epidemiological data to inform policy and action to improve oral health and address inequalities. The aims of this research were to examine dental caries clusters among 15-year-olds, taking account of caries thresholds, and explore associated factors to inform public health action. Secondary analysis of the oral health data on 2,160 15-year-olds from the 2013 Children's Dental Health Survey in England, Wales, and Northern Ireland was performed. Hierarchical cluster analysis of dental caries experience was conducted across all surfaces and at 4 decay diagnostic thresholds (clinical: International Caries Detection and Assessment System [ICDAS] 1-6, cavitated: ICDAS 3-6, obvious: ICDAS 4-6, and extensive obvious: ICDAS 5-6 decay). Ordered logistic regression was used to estimate the association of behavioural and psychosocial factors with the clusters generated in relation to both clinical and obvious decay experience which are of clinical and epidemiological relevance. A 4-cluster decay pattern representing "low" to "extremely high" decay experience was observed under each of the dental caries diagnostic criteria. For clinical decay, which includes visual enamel caries, 28.70% had low, 39.77% medium, 26.71% high, and 4.81% extremely high caries status. In the adjusted model, significant risk factors for clinical decay included non-modifiable (sex, region, school type, and area deprivation) and modifiable (higher sugar intake at 4 or more times per day and suboptimal dental attendance) factors. This study suggests 4 distinct dental caries patterns among adolescent children nationally. Dental caries clusters demonstrate the importance of embracing proportionate universalism in addressing dental caries in the population oral health strategy.

Dental caries thresholds among adolescents in England, Wales, and Northern Ireland, 2013 at 12, and 15 years: implications for epidemiology and clinical care.

BACKGROUND: Dental caries is the most prevalent condition globally. Despite improvements over the past few decades, there remains a significant disease burden in childhood. Epidemiological surveys provide insight to disease patterns and trends, and have traditionally focused on obvious decay which are inconsistent with contemporary clinical criteria. This study examined the distribution of dental caries in 12- and 15-year-olds in England, Wales and Northern Ireland, by severity threshold, at surface, tooth and child level and explored its association with socioeconomic, psychological and behavioural factors. METHODS: Data from 12- and 15-year-olds in the 2013 Children's Dental Health Survey (CDHS 2013) were analysed at three levels, taking account of dental caries thresholds which involved recording both clinical decay [visual enamel caries (AV) and above] and obvious decay [non-cavitated dentine lesions (2V) and above]. Negative binomial regression was used to identify factors associated with dental caries experience at both thresholds. RESULTS: The prevalence and severity of dental caries experience was higher among 15-year-olds at all levels. Visual change in enamel (AV) was by far the most common stage of caries recorded in both ages. The average number of surfaces with obvious decay experience, which has been the traditional epidemiological threshold, in 12- and 15-year-olds was 2.3 and 3.9 respectively. The corresponding values under the clinical decay threshold were higher, at 3.9 and 5.9 respectively. Visualisation of the distribution of dental caries at surface/tooth-level exhibited horizontal symmetry and to a lesser extent vertical symetry. In the adjusted models for both ages, country/region, school type, area deprivation, high frequency sugar consumption and irregular dental attendance were associated with greater caries experience in both groups. Dental anxiety was inversely associated with caries experience among 15-year-olds. CONCLUSION: This research highlights the importance of recognising dental caries patterns by surface, tooth and child-level amongst adolescents and the value of reporting dental caries distribution by threshold in epidemiological surveys, including its relevance for clinical care. Inclusion of enamel caries reveals the extent of caries management required at a point when non-invasive care is possible, emphasising the importance of prevention through contemporary primary care, which includes supporting self-care.

Diagnostic sensitivity and specificity of host-derived salivary biomarkers in periodontal disease amongst adults: Systematic review.

OBJECTIVE: To systematically assess the diagnostic value of host-derived salivary biomarkers based on their reported sensitivity and specificity in relation to clinical parameters of periodontal disease diagnosis in adults. MATERIALS AND METHODS: Comprehensive search of PubMed, Nature, Cochrane and OVID (Embase, MEDLINE [R] and PsycINFO) was conducted up to 1 August 2018, using key terms relevant to the research questions and Cochrane methodology, supplemented by a grey literature search. The revised Quality Assessment of Diagnostic Accuracy Studies (QUADAS- 2) tool was used to assess the methodological quality of all included studies. RESULTS: Seven studies were included in the review. Macrophage inflammatory protein-1αlpha (MIP-1α), interleukin-1beta (IL-1ß), interleukin-6 (IL-6) and matrix metalloproteinase-8 (MMP-8) were identified as diagnostically acceptable biomarkers for periodontal disease. Overall, the combination of IL-6 and MMP-8 showed best diagnostic performance. Also, a combination of the four key biomarkers (IL-1ß, IL-6, MMP-8 and MIP-1α) showed promising results for distinction between gingivitis and periodontitis, as well as for periodontitis compared with gingival health. Results are interpreted with caution due to limitations in the number of studies included and their quality. CONCLUSION: Certain salivary biomarkers can potentially be useful in combination and singularly for the diagnosis of periodontal disease. However, further methodically robust research is required to validate these biomarkers.

RUNX2 mutation reduces osteogenic differentiation of dental follicle cells in cleidocranial dysplasia.

Disturbed permanent tooth eruption is common in cleidocranial dysplasia (CCD), a skeletal disorder caused by heterozygous mutation of RUNX2, but the mechanism underlying is still unclear. As it is well known that dental follicle cells (DFCs) play a critical role in tooth eruption, the changed biological characteristics of DFCs might give rise to disturbance of permanent tooth eruption in CCD patients. Thus, primary DFCs from one CCD patient and normal controls were collected to investigate the effect of RUNX2 mutation on the bone remodeling activity of DFCs and explore the mechanism of impaired permanent tooth eruption in this disease. Conservation and secondary structure analysis revealed that the RUNX2 mutation (c.514delT, p.172fs) found in the present CCD patient was located in the highly conserved RUNT domain and converted the structure of RUNX2. After osteogenic induction, we found that the mineralised capacity of DFCs and the expression of osteoblast-related genes, including RUNX2, ALP, OSX, OCN and Col Iα1, in DFCs was severely interfered by the RUNX2 mutation found in CCD patients. To investigate whether the osteogenic deficiency of DFCs from the CCD patient can be rescued by RUNX2 restoration, we performed 'rescue' experiments. Surprisingly, the osteogenic deficiency and the abnormal expression of osteoblast-associated genes in DFCs from the CCD patient were almost rescued by overexpression of wild-type RUNX2 using lentivirus. All these findings indicate that RUNX2 mutation can reduce the osteogenic capacity of DFCs through inhibiting osteoblast-associated genes, thereby disturbing alveolar bone formation, which serves as a motive force for tooth eruption. This effect may provide valuable explanations and implications for the mechanism of delayed permanent tooth eruption in CCD patients.

A novel FAM83H mutation in one Chinese family with autosomal-dominant hypocalcification amelogenesis imperfecta.

Autosomal-dominant hypocalcification amelogenesis imperfecta (ADHCAI) is characterized by soft enamel that easily disintegrates and exposed dark dentin. ADHCAI is caused by mutations in a gene called family with sequence similarity 83 member H (FAM83H). To investigate the molecular genetics of ADHCAI, a Chinese family in which three generations exhibited ADHCAI was recruited. The enamel ultrastructure was analysed by environmental scanning electron microscopy (ESEM), which showed altered enamel rod (prism) structures in ADHCAI patients compared to the structures in healthy controls. Mutational analysis of the FAM83H gene identified a novel nonsense mutation (c.1222A>T) in the affected family members that encodes a stop codon at amino acid position 408, causing premature protein truncation (p. K408X). Green fluorescent protein (GFP) and FAM83H fusion protein analyses in vitro showed that normal cytoplasmic accumulation of the FAM83H protein was prevented by the K408X mutation in both rat dental epithelial SF2 cells and human embryonic kidney 293T cells. The mutant fusion protein localized primarily to the nucleus, in contrast to the cytoplasmic subcellular localization of the wild-type FAM83H protein. Our results provide new genetic evidence that mutations in FAM83H contribute to ADHCAI.

DNA damage activates a spatially distinct late cytoplasmic cell-cycle checkpoint network controlled by MK2-mediated RNA stabilization.

Following genotoxic stress, cells activate a complex kinase-based signaling network to arrest the cell cycle and initiate DNA repair. p53-defective tumor cells rewire their checkpoint response and become dependent on the p38/MK2 pathway for survival after DNA damage, despite a functional ATR-Chk1 pathway. We used functional genetics to dissect the contributions of Chk1 and MK2 to checkpoint control. We show that nuclear Chk1 activity is essential to establish a G(2)/M checkpoint, while cytoplasmic MK2 activity is critical for prolonged checkpoint maintenance through a process of posttranscriptional mRNA stabilization. Following DNA damage, the p38/MK2 complex relocalizes from nucleus to cytoplasm where MK2 phosphorylates hnRNPA0, to stabilize Gadd45α mRNA, while p38 phosphorylates and releases the translational inhibitor TIAR. In addition, MK2 phosphorylates PARN, blocking Gadd45α mRNA degradation. Gadd45α functions within a positive feedback loop, sustaining the MK2-dependent cytoplasmic sequestration of Cdc25B/C to block mitotic entry in the presence of unrepaired DNA damage. Our findings demonstrate a critical role for the MK2 pathway in the posttranscriptional regulation of gene expression as part of the DNA damage response in cancer cells.

Abnormal bone remodelling activity of dental follicle cells from a cleidocranial dysplasia patient.

OBJECTIVES: To explore the role of dental follicle cells (DFCs) with a novel cleidocranial dysplasia (CCD) causative gene RUNX2 mutation (DFCsRUNX2+/m ) in delayed permanent tooth eruption. MATERIALS AND METHODS: A CCD patient with typical clinical features was involved in this study. DFCsRUNX2+/m were cultured and DNA was extracted for RUNX2 mutation screening. Measurements of cell proliferation, alkaline phosphatase (ALP) activity, alizarin red staining and osteoblast-specific genes expression were performed to assess osteogenesis of DFCsRUNX2+/m . Co-culture of DFCs and peripheral blood mononuclear cells (PBMCs), followed tartrate-resistant acid phosphatase (TRAP) staining, real-time PCR and western blot were performed to evaluate osteoclast-inductive capacity of DFCsRUNX2+/m . RESULTS: A missense RUNX2 mutation (c. 557G>C) was found in DFCsRUNX2+/m from the CCD patient. Compared with normal controls, this mutation did not affect the proliferation of DFCsRUNX2+/m , but down-regulated the expression of osteogenesis-related genes, leading to a decrease in ALP activity and mineralisation. Co-culture results showed that DFCsRUNX2+/m reduced the formation of TRAP+ multinucleated cells and the expression of osteoclastogenesis-associated genes. Furthermore, the mutation reduced the ratio of RANKL/OPG in DFCsRUNX2+/m . CONCLUSIONS: DFCsRUNX2+/m disturbs bone remodelling activity during tooth eruption through RANK/RANKL/OPG signalling pathway and may thus be responsible for impaired permanent tooth eruption in CCD patients.

Salivary peptidome profiling for diagnosis of severe early childhood caries.

BACKGROUND: Severe early childhood caries (s-ECC), which has quite high prevalence among children, is a widespread problem with significant impacts among both developing and developed countries. At present, it is widely known that no early detective techniques and diagnostic tests could have high sensitivity and specificity when using for clinical screening of s-ECC. In this study, we had applied magnetic bead (MB)-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) to screen distinctive candidate biomarkers of this disease, so as to establish protein profiles and diagnostic models of s-ECC. METHODS: Firstly, we used the technique mentioned above to detect specifically expressed peptides in saliva samples from ten children with s-ECC, separately at the time point of before, 1 and 4 weeks after dental treatment. Then a diagnostic model for s-ECC was established with the K nearest-neighbour method, which was validated in another six children in the next stage of study. After that, linear ion trap-orbitrap-mass spectrometry (LTQ-Orbitrap-MS) was performed to identify which of the proteins in saliva might be the origination of these peptides. RESULTS: We found that seven peptide peaks were significantly different when comparing the three time points, among them two were higher, while other five were lower in the pre-treatment s-ECC group compared with post-treatment. The sensitivity and specificity of the diagnostic model we built were both 83.3 %. Two of these peptides were identified to be segments of histatin-1, which was one important secretory protein in saliva. CONCLUSIONS: Hereby we confirmed that MB-based MALDI-TOF MS is an effective method for screening distinctive peptides from the saliva of junior patients with s-ECC, and histatin-1 may probably be one important candidate biomarker of this common dental disease. These findings might have bright prospect in future in establishing new diagnostic methods for s-ECC.

RUNX2 mutation impairs bone remodelling of dental follicle cells and periodontal ligament cells in patients with cleidocranial dysplasia.

RUNX2 is an important osteo-specific factor with crucial functions in bone formation and remodelling as well as resorption of teeth. Heterozygous mutation of RUNX2 can cause cleidocranial dysplasia (CCD), a systemic disease with extensive skeletal dysplasia and abnormality of tooth growth. In our study, dental follicle cells (DFCs) and periodontal ligament cells (PDLCs) were isolated, cultured and identified from one patient with CCD and compared with normal controls. This CCD patient was confirmed to have a heterozygous frameshift mutation of RUNX2 (c.514delT, p.Ser172fs) in the previous study. The results showed that the proliferation abilities of DFCs and PDLCs were both disturbed by the RUNX2 mutation in the CCD patient compared with the normal control. A co-culture system of these cells with human peripheral blood mononuclear cells was then used to investigate the effect of RUNX2 mutation on osteoclastogenesis. We found that the RUNX2 mutation in CCD reduced the expression of osteoclast-related genes, such as RUNX2, CTR, CTSK, RANKL and OPG The ability of osteoclastogenesis in DFCs and PDLCs detected by tartrate-resistant acid phosphatase staining in the co-culture system was also reduced by the RUNX2 mutation compared with the normal control. These outcomes indicate that the RUNX2 mutation disturbs the modulatory effects of DFCs and PDLCs on the differentiation of osteoclasts and osteoblasts, thereby interfering with bone remodelling. These effects may contribute in part to the pathological manifestations of retention of primary teeth and delayed eruption of permanent teeth in patients with CCD.

A hybrid solution for extracting structured medical information from unstructured data in medical records via a double-reading/entry system.

BACKGROUND: Healthcare providers generate a huge amount of biomedical data stored in either legacy system (paper-based) format or electronic medical records (EMR) around the world, which are collectively referred to as big biomedical data (BBD). To realize the promise of BBD for clinical use and research, it is an essential step to extract key data elements from unstructured medical records into patient-centered electronic health records with computable data elements. Our objective is to introduce a novel solution, known as a double-reading/entry system (DRESS), for extracting clinical data from unstructured medical records (MR) and creating a semi-structured electronic health record database, as well as to demonstrate its reproducibility empirically. METHODS: Utilizing the modern cloud-based technologies, we have developed a comprehensive system that includes multiple subsystems, from capturing MRs in clinics, to securely transferring MRs, storing and managing cloud-based MRs, to facilitating both machine learning and manual reading, and to performing iterative quality control before committing the semi-structured data into the desired database. To evaluate the reproducibility of extracted medical data elements by DRESS, we conduct a blinded reproducibility study, with 100 MRs from patients who have undergone surgical treatment of lung cancer in China. The study uses Kappa statistic to measure concordance of discrete variables, and uses correlation coefficient to measure reproducibility of continuous variables. RESULTS: Using the DRESS, we have demonstrated the feasibility of extracting clinical data from unstructured MRs to create semi-structured and patient-centered electronic health record database. The reproducibility study with 100 patient's MRs has shown an overall high reproducibility of 98 %, and varies across six modules (pathology, Radio/chemo therapy, clinical examination, surgery information, medical image and general patient information). CONCLUSIONS: DRESS uses a double-reading, double-entry, and an independent adjudication, to manually curate structured data elements from unstructured clinical data. Further, through distributed computing strategies, DRESS protects data privacy by dividing MR data into de-identified modules. Finally, through internet-based computing cloud, DRESS enables many data specialists to work in a virtual environment to achieve the necessary scale of processing thousands MRs within days. This hybrid system represents probably a workable solution to solve the big medical data challenge.

The carboxyl terminus of FANCE recruits FANCD2 to the Fanconi Anemia (FA) E3 ligase complex to promote the FA DNA repair pathway.

Fanconi anemia (FA) is a genome instability syndrome characterized by bone marrow failure and cellular hypersensitivity to DNA cross-linking agents. In response to DNA damage, the FA pathway is activated through the cooperation of 16 FA proteins. A central player in the pathway is a multisubunit E3 ubiquitin ligase complex or the FA core complex, which monoubiquitinates its substrates FANCD2 and FANCI. FANCE, a subunit of the FA core complex, plays an essential role by promoting the integrity of the complex and by directly recognizing FANCD2. To delineate its role in substrate ubiquitination from the core complex assembly, we analyzed a series of mutations within FANCE. We report that a phenylalanine located at the highly conserved extreme C terminus, referred to as Phe-522, is a critical residue for mediating the monoubiquitination of the FANCD2-FANCI complex. Using the FANCE mutant that specifically disrupts the FANCE-FANCD2 interaction as a tool, we found that the interaction-deficient mutant conferred cellular sensitivity in reconstituted FANCE-deficient cells to a similar degree as FANCE null cells, suggesting the significance of the FANCE-FANCD2 interaction in promoting cisplatin resistance. Intriguingly, ectopic expression of the FANCE C terminus fragment alone in FA normal cells disrupts DNA repair, consolidating the importance of the FANCE-FANCD2 interaction in the DNA cross-link repair.

Evaluation of root and alveolar bone development of unilateral osseous impacted immature maxillary central incisors after the closed-eruption technique.

INTRODUCTION: In this study, we evaluated root and alveolar bone development in unilateral osseous impacted immature maxillary central incisors by cone-beam computed tomography before and after closed-eruption treatment, in comparison with naturally erupted contralateral immature maxillary central incisors. METHODS AND RESULTS: The study included 30 patients, 20 boys and 10 girls, with a mean age of 8.44 ± 1.20 years (range, 6.5-11.2 years). After treatment, the root lengths of both the impacted maxillary central incisors (10.66 ± 2.10 mm) and the contralateral maxillary central incisors (11.04 ± 1.76 mm) were significantly greater than their pretreatment values (6.67 ± 1.94 and 9.02 ± 2.13 mm, respectively). The root canal widths of the incisors decreased significantly after treatment. From the posttreatment cone-beam computed tomography images, the ratio of exposed root length to total root length and the thickness of the alveolar bone at 1 mm under the alveolar crest and at the apex were calculated to evaluate alveolar bone development. Impacted immature maxillary central incisors differed significantly from contralateral immature maxillary central incisors in labial exposed root length, labial ratio to total root length, and lingual alveolar crest. Clinical crown height was higher (statistically but not clinically) for the impacted incisors (9.87 mm) than for the contralateral incisors (9.37 mm). CONCLUSIONS: Impacted immature incisors grew to the same stage as did erupted contralateral incisors after closed-eruption treatment. Both incisor types had some alveolar bone loss, and thin alveolar bone surrounded the roots.

Model-Informed Selection of the Recommended Phase III Dose of the Inhibitor of Apoptosis Protein Inhibitor, Xevinapant, in Combination with Cisplatin and Concurrent Radiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck.

Xevinapant, an oral inhibitor of apoptosis protein (IAP) inhibitor, demonstrated efficacy in combination with chemoradiotherapy in a randomized phase II study (NCT02022098) in patients with locally advanced squamous cell carcinoma of the head and neck at 200 mg/day on days 1-14 of a 3-week cycle. To confirm 200 mg/day as the recommended phase III dose (RP3D), we integrated preclinical, clinical, pharmacokinetic/pharmacodynamic (PK/PD), and exposure-response modeling results. Population PK/PD modeling of IAP inhibition in peripheral blood mononuclear cells in 21 patients suggested the pharmacologically active dose range was 100-200 mg/day, with a trend for more robust inhibition at the end of the dosing interval at 200 mg/day based on an indirect response model. Additionally, the unbound average plasma concentration at 200 mg/day was similar to that associated with efficacy in preclinical xenograft models. Logistic regression exposure-response analyses of data from 62 patients in the phase II study showed exposure-related increases in probabilities of locoregional control at 18 months (primary end point), overall response, complete response, and the radiosensitization mechanism-related composite safety end point "mucositis and/or dysphagia" (P < 0.05). Exposure-response relationships were not discernible for 12 of 13 evaluated safety end points, incidence of dose reductions, and time to first dose reduction. Quantitative integration of all available data, including model-derived target inhibition profiles, positive exposure-efficacy relationships, and lack of discernible exposure-safety relationships for most safety end points, supports selection of xevinapant 200 mg/day on days 1-14 of a 3-week cycle as the RP3D, allowing for successive dose reductions to 150 and 100 mg/day to manage adverse events.

Avelumab Versus Platinum-Based Doublet Chemotherapy as First-Line Treatment for Patients With High-Expression Programmed Death-Ligand 1-Positive Metastatic NSCLC: Primary Analysis From the Phase 3 JAVELIN Lung 100 Trial.

INTRODUCTION: We report the primary analysis from JAVELIN Lung 100, a phase 3 trial comparing avelumab (anti⁠-programmed death-ligand 1 [PD-L1]) versus platinum-based doublet chemotherapy as first-line treatment for PD-L1-positive (+) advanced NSCLC. METHODS: Adults with PD-L1+ (≥1% of tumor cells; PD-L1 immunohistochemistry 73-10 pharmDx), EGFR and ALK wild-type, previously untreated, stage IV NSCLC were randomized to avelumab 10 mg/kg every 2 weeks (Q2W), avelumab 10 mg/kg once weekly (QW) for 12 weeks and Q2W thereafter, or platinum-based doublet chemotherapy every 3 weeks. Primary end points were overall survival (OS) and progression-free survival (PFS) per independent review committee. The primary analysis population was patients with high-expression PD-L1+ tumors (≥80% of tumor cells). RESULTS: A total of 1214 patients were randomized to avelumab Q2W (n = 366), avelumab QW (n = 322), or chemotherapy (n = 526). In the primary analysis population, hazard ratios (HRs) for OS and PFS with avelumab Q2W (n = 151) versus chemotherapy (n = 216) were 0.85 (95% confidence interval [CI]: 0.67-1.09; one-sided p = 0.1032; median OS, 20.1 versus 14.9 mo) and 0.71 (95% CI: 0.54-0.93; one-sided p = 0.0070; median PFS, 8.4 versus 5.6 mo), respectively. With avelumab QW (n = 130) versus chemotherapy (n = 129), HRs were 0.79 (95% CI: 0.59-1.07; one-sided p = 0.0630; median OS, 19.3 versus 15.3 mo) and 0.72 (95% CI: 0.52-0.98; one-sided p = 0.0196; median PFS, 7.5 versus 5.6 mo), respectively. No new safety signals were observed. CONCLUSIONS: Longer median OS and PFS were observed with avelumab versus platinum-based doublet chemotherapy in advanced NSCLC, but differences in OS and PFS were not statistically significant, and the trial did not meet its primary objective. CLINICALTRIALS: gov Identifier: NCT02576574.

Multi-Enzyme-Based Superabsorbent Hydrogel for Self-Enhanced NIR-II Photothermal-Catalytic Antibacterial Therapy.

The synergistic strategy of nanozyme-based catalytic therapy and photothermal therapy holds great potential for combating bacterial infection. However, challenges such as single and limited enzyme catalytic property, unfavorable catalytic environment, ineffective interaction between nanozymes and bacteria, unsafe laser irradiation ranges, and failed trauma fluid management impede their antibacterial capability and wound healing speed. Herein, for the first time, a PNMn hydrogel is fabricated with multi-enzyme activities and excellent near-infrared (NIR)-II photothermal performance for self-enhanced NIR-II photothermal-catalytic capabilities to efficiently eradicate bacteria. This hydrogel triggers parallel and cascade reactions to generate •OH, •O2 - , and 1 O2 radicals from H2 O2 and O2 without external energy input. Notably, it provides a suitable catalytic environment while capturing bacteria (≈30.1% of Escherichia coli and ≈29.3% of Staphylococcus aureus) to reinforce antibacterial activity. Furthermore, the PNMn hydrogel expedites skin wound healing by managing excess fluid (swelling rate up to ≈7299%). The PNMn hydrogel possesses remarkable stretching, elasticity, toughness, and adhesive characteristics under any shape of the wound, thus making it suitable for wound dressing. Therefore, the PNMn hydrogel has great potential to be employed as a next-generation wound dressing in the clinical context, providing a non-antibiotic strategy to improve the antibacterial performance and promote wound healing.

Spin Glass Behavior in Amorphous Cr2 Ge2 Te6 Phase-Change Alloy.

The layered crystal structure of Cr2 Ge2 Te6 shows ferromagnetic ordering at the two-dimensional limit, which holds promise for spintronic applications. However, external voltage pulses can trigger amorphization of the material in nanoscale electronic devices, and it is unclear whether the loss of structural ordering leads to a change in magnetic properties. Here, it is demonstrated that Cr2 Ge2 Te6 preserves the spin-polarized nature in the amorphous phase, but undergoes a magnetic transition to a spin glass state below 20 K. Quantum-mechanical computations reveal the microscopic origin of this transition in spin configuration: it is due to strong distortions of the CrTeCr bonds, connecting chromium-centered octahedra, and to the overall increase in disorder upon amorphization. The tunable magnetic properties of Cr2 Ge2 Te6 can be exploited for multifunctional, magnetic phase-change devices that switch between crystalline and amorphous states.