Outcome of Chinese patients with hepatitis B at 96 weeks after functional cure with IFN versus combination regimens.

BACKGROUND & AIMS: Nucleotides with add-on interferon treatment (NUC-IFN) provide significantly higher rates of hepatitis B surface antigen (HBsAg) loss in patients with chronic hepatitis B (CHB). This study aimed to investigate the sustainability of HBsAg loss and the prevention of clinical relapse. METHODS: Patients with CHB who achieved HBsAg loss and HBV DNA levels <20 IU/ml after IFN or NUC-IFN therapy were enrolled and followed up for 96 weeks. The primary outcome was HBsAg negativity without viremia at week 96. Secondary outcomes included virological or clinical relapse and predictors of relapse. RESULTS: 420 patients were included in intention-to-treat analysis with 290 and 130 in the IFN and NUC-IFN groups respectively. At week 96, the intention-to-treat analysis revealed similar outcomes between groups, including HBsAg seroreversion (24.83% vs. 23.08%, P = .70), viremia (16.90% vs 13.08%, P = .32) and clinical relapse (11.38% vs 10.00%, P = .68); the per-protocol analyses also showed HBsAg seroreversion, viremia and clinical relapse in IFN group (15.50%, 6.59% and 0.39%) did not differ from those in NUC-IFN group (15.25%, 4.24% and 0.85%, P > .05). These outcomes were similar between patients who received entecavir and those who received telbivudine/lamivudine/adefovir before the combination therapy. In NUC-IFN-treated patients, fibrosis regression was observed at week 96. Baseline HBsAb negativity was independent predictors of HBsAg sero-reversion and recurrence of viremia in IFN treated group. CONCLUSION: NUC-IFN and IFN therapies are equally effective in achieving sustained functional cure and fibrosis regression. (ClinicalTrials.gov, Number NCT02336399).

MiR-106a-5p modulates apoptosis and metabonomics changes by TGF-ß/Smad signaling pathway in cleft palate.

BACKGROUND: The molecular mechanisms of abnormal palatogenesis were investigated in this study. A key regulator, miR-106a-5p, and its target pathway were analyzed. OBJECTIVES: This research is trying to clarify the underlying mechanism of the modulation of miRNA transcription during the formation of cleft palate by 7T and 9.4T NMR metabolomic platforms. METHOD: Differentially expressed miRNAs and mRNAs were analyzed by microarray analysis and verified by qRT-PCR. The protein expression in TGFß signaling pathways were analyzed by Western Blotting. The relationship between miR-106a-5p and TGFß were analyzed by luciferase reporter assay. Cell apoptosis were analyzed by flow cytometer. And finally, the metabonomics were analyzed by NMR and multivariate data analysis models (MVDA). RESULTS: The expression of miR-106a-5p increased in cleft palatal tissue and negatively correlated with the protein level of Tgfbr2. The luciferase assay further proved that the tgfbr2 was a direct target of miR-106a-5p. In another aspect, miR-106a-5p increased apoptosis level in palatal mesenchymal cells, possibly because its inhibition of TGFß signaling pathway. Moreover, low cholesterol and choline levels with high citric acid and lipid levels were observed by 7T and 9.4T NMR metabonomic analysis, which inferred the disorder of cell membrane synthesis in cleft palate formation. Furthermore, transformation from choline to phosphatidylcholine regulated by miR-106a-5p was also disrupted, resulting in phosphatidic choline synthesis disorder and reduced cell membrane synthesis. CONCLUSIONS: The regulatory mechanism of cleft palate was studied at transcriptional and metabolomics levels, which may provide important information in understanding the primary cause of this abnormality.

Chondromyxoid fibroma-like osteosarcoma: a case series and literature review.

BACKGROUND: Chondromyxoid fibroma-like osteosarcoma (CMF-OS) is an exceedingly rare subtype of low-grade central osteosarcoma (LGCO), accounting for up to 10% of cases and making it difficult to diagnose. CMF-OS is frequently misdiagnosed on a radiological examination and biopsy, even after the initial operation. Its treatment is a controversial issue due to its low-grade classification and actual high-grade behavior. CASE PRESENTATION: We retrospectively reviewed the medical charts of more than 2000 osteosarcoma patients between 2008 and 2019; 11 patients with CMF-OS were identified, of which six patients were treated by our institution with complete clinical characteristics, including treatment and prognosis, radiological and pathological features were reviewed. Three males and three females with a median age of 46 (range 22-56) years were pathologically proven to have CMF-OS. The radiological presentation of CMF-OS is variable, thus radiological misdiagnoses are common. However, one must not ignore a malignant radiologic appearance. The most distinctive pathological feature conferring the diagnosis of CMF-OS is the presence of osteoid production directly by the tumor cells under a chondromyxoid fibroma (CMF)-like background. Differential diagnoses based on comprehensive data from CMF, LGCO, chondrosarcoma (CHS), conventional osteosarcoma (COS), etc., are needed. All patients were treated with an operation and chemotherapy, and one patient received additional radiotherapy. Nevertheless, recurrence and metastasis are common in CMF-OS patients. Relatively invasive biological behavior of CMF-OS is against the low-grade classification of this disease. CONCLUSIONS: It is important to recognize CMF-OS and distinguish it from CMF, CHS, COS and other LGCOs. CMF-OS has a relatively poor prognosis despite its low-grade classification.

Comparative biomechanical analysis of four different tooth- and bone-borne frog appliances for molar distalization : A three-dimensional finite element study.

PURPOSE: The purpose of this study was to analyze the biomechanical effects of four different designs of frog appliances for molar distalization using finite element analysis. METHODS: A three-dimensional finite element model including complete dentition, periodontal ligament, palatine, and alveolar bone was established. Four types of frog appliances were designed to simulate maxillary molar distalization: tooth-button-borne (Type A), bone-borne (Type B), bone-button-borne (Type C), and tooth-bone-borne (Type D) frog appliances. A force of 10 N was applied simulating a screw in the anteroposterior direction. To assess the von Mises stress distribution and the resultant displacements in the teeth and periodontal tissues, geometric nonlinear theory was utilized. RESULTS: Compared to the conventional tooth-borne frog appliance (Type A), the bone-borne frog appliances showed increased first molar distalization with enhanced mesiolingual rotation and distal tipping, but the labial inclination and intrusion of the incisors were insignificant. When replacing the palatal acrylic button with miniscrews (Types B and D), more anchorage forces were transmitted from the first premolar to palatine bone, which was further dispersed by the assistance of a palatal acrylic button (Type C). CONCLUSIONS: Compared to tooth-borne frog appliances, the bone-borne variants demonstrated a clear advantage for en masse molar distalization. The combined anchorage system utilizing palatal acrylic buttons and miniscrews (Type C) offers the most efficient stress distribution, minimizing force concentration on the palatine bone.

Pathological collagen targeting and penetrating liposomes for idiopathic pulmonary fibrosis therapy.

Idiopathic pulmonary fibrosis (IPF) is a fibrotic interstitial lung disease in which collagen progressively deposits in the supporting framework of the lungs. The pathological collagen creates a recalcitrant barrier in mesenchyme for drug penetration, thus greatly restricting the therapeutical efficacy. On the other hand, this overloaded collagen is gradually exposed to the bloodstream at fibrotic sites because of the vascular hyperpermeability, thus serving as a potential target. Herein, pathological collagen targeting and penetrating liposomes (DP-CC) were constructed to deliver anti-fibrotic dual drugs including pirfenidone (PFD) and dexamethasone (DEX) deep into injured alveoli. The liposomes were co-decorated with collagen binding peptide (CBP) and collagenase (COL). CBP could help vehicle recognize the pathological collagen and target the fibrotic lungs efficiently because of its high affinity to collagen, and COL assisted in breaking through the collagen barrier and delivering vehicle to the center of injured sites. Then, the released dual drugs developed a synergistic anti-fibrotic effect to repair the damaged epithelium and remodel the extracellular matrix (ECM), thus rebuilding the lung architecture. This study provides a promising strategy to deliver drugs deep into pathological collagen accumulated sites for the enhanced treatment of IPF.

Investigation of a Novel LRP6 Variant Causing Autosomal-Dominant Tooth Agenesis.

BACKGROUND: The low-density lipoprotein receptor-related protein 6 (LRP6) gene is a recently defined gene that is associated with the autosomal-dominant inherited tooth agenesis (TA). In the present study, a family of four generations having TA was recruited and subjected to a series of clinical, genetic, in silico, and in vitro investigations. METHODS: After routine clinical evaluation, the proband was subjected to whole-exome sequencing (WES) to detect the diagnostic variant. Next, in silico structural and molecular dynamics (MD) analysis was conducted on the identified novel missense variant for predicting its intramolecular impact. Subsequently, an in vitro study was performed to further explore the effect of this variant on protein maturation and phosphorylation. RESULTS: WES identified a novel variant, designated as LRP6: c.2570G > A (p.R857H), harbored by six members of the concerned family, four of whom exhibited varied TA symptoms. The in silico analysis suggested that this novel variant could probably damage the Wnt bonding function of the LRP6 protein. The experimental study demonstrated that although this novel variant did not affect the LRP6 gene transcription, it caused a impairment in the maturation and phosphorylation of LRP6 protein, suggesting the possibility of the disruption of the Wnt signaling. CONCLUSION: The present study expanded the mutation spectrum of human TA in the LRP6 gene. The findings of the present study are insightful and conducive to understanding the functional significance of specific LRP6 variants.

Downregulation of ROR2 promotes dental pulp stem cell senescence by inhibiting STK4-FOXO1/SMS1 axis in sphingomyelin biosynthesis.

Dental pulp stem cells (DPSCs) play a vital role in tooth restoration, regeneration, and homeostasis. The link between DPSC senescence and tooth aging has been well-recognized. ROR2 plays an important role in aging-related gene expression. However, the expression and function of ROR2 in DPSC aging remain largely unknown. In this study, we found that ROR2 expression was significantly decreased in aged pulp tissues and DPSCs. The depletion of ROR2 in young DPSCs inhibits their self-renewal capacity, while its overexpression in aged DPSCs restores their self-renewal capacity. Interestingly, we found that sphingomyelin (SM) is involved in the senescence of DPSCs regulated by ROR2. Mechanistically, we confirmed that ROR2 inhibited the phosphorylation of STK4, which promoted the translocation of Forkhead Box O1 (FOXO1) to the nucleus. STK4 inhibition or knockdown of FOXO1 markedly increased the proliferation of DPSCs and upregulated the expression of SMS1, which catalyzed SM biogenesis. Moreover, FOXO1 directly bound to the SMS1 promoter, repressing its transcription. Our findings demonstrated the critical role of the ROR2/STK4-FOXO1/SMS1 axis in the regulation of SM biogenesis and DPSC senescence, providing a novel target for antagonizing tooth aging.

[Practice and exploration of orbital anatomy and orbital imaging courses in dental students].

PURPOSE: To improve the teaching effect of orbital anatomy course for students majoring in stomatology. METHODS: Based on a retrospective analysis of average score of orbital anatomy course for previous dental and medical students, and the problems existing in teaching effect, orbital anatomy and orbital imaging course were designed and carried out in dental students. The course combined imaging with orbital anatomy, and included clinical examples. Medical students were set as control. Examination was carried out after the end of the whole course, and the professional knowledge of orbital anatomy of two groups was compared. A self-designed questionnaire was designed to evaluate the teaching effect of orbital anatomy and orbital imaging courses for dental students and residents over 1 year after graduation. SPSS 22 software package was used for Statistical analysis. RESULTS: The previous average score of dental students was 7.50, and the average score of medical students was 8.67. There was significant difference between the two groups (P=0.004). The average score of dental students after offering the course of orbital anatomy and orbital imaging was 9.67, and the average score of medical students was 9.00. No significant difference was noticed between the two groups(P=0.184). Questionnaire survey showed that the after-class review time of dental students was 20 min, and that of medical students was 30 min. 74.7% of the dental students and 80% of the dental residents did not study orbital anatomy and imaging courses before. 87.4% of the dental students and 100% of dental residents considered that the orbital imaging course was helpful to master the anatomical characteristics of the orbit. 89.7% of the dental students and 100% of dental residents believed that orbital imaging course was helpful to their clinical work. CONCLUSIONS: Orbital anatomy and orbital imaging course were designed for dental students as supplementary teaching programme. It successfully inspired students' interest in learning, cultivated the students' overall and comprehensive thinking, narrowed students to master the knowledge of orbital anatomy, closed the gap of teaching effect between dental and clinical medicine, and laid the foundation to develop dental professional work in the future.

Nano-Strategies for Improving the Bioavailability of Inhaled Pharmaceutical Formulations.

Pulmonary pharmaceutical formulations are targeted for the treatment of respiratory diseases. However, their application is limited due to the physiological characteristics of the lungs, such as branching structure, mucociliary and macrophages, as well as certain properties of the drugs like particle size and solubility. Nano-formulations can ameliorate particle sizes and improve drug solubility to enhance bioavailability in the lungs. The nano-formulations for lungs reviewed in this article can be classified into nanocarriers, no-carrier-added nanosuspensions and polymer-drug conjugates. Compared with conventional inhalation preparations, these novel pulmonary pharmaceutical formulations have their own advantages, such as increasing drug solubility for better absorption and less inflammatory reaction caused by the aggregation of insoluble drugs; prolonging pulmonary retention time and reducing drug clearance; improving the patient compliance by avoiding multiple repeated administrations. This review will provide the reader with some background information for pulmonary drug delivery and give an overview of the existing literature about nano-formulations for pulmonary application to explore nano-strategies for improving the bioavailability of pulmonary pharmaceutical formulations.

Odontoid calcification and crowned dens syndrome: data from a Chinese center.

OBJECTIVES: To assess the prevalence of calcification surrounding the odontoid process (odontoid calcification) with crowned dens syndrome (CDS) and without CDS (non-CDS) and investigate factors that may related to the onset of CDS. METHODS: Retrospective review of consecutive patients visited Sir Run Run Shaw Hospital between 1 January 2018 and 5 November 2019 who were identified to have odontoid calcification on cervical computed tomography (CT) images. Those who presented with an acute or subacute episode of cervico-occipital pain were defined as CDS, others were non-CDS. RESULTS: We diagnosed 69 cases of odontoid calcification among 2902 cervical CTs of 2556 patients (69/2556, 2.70%), 19 (19/2556, 0.74%) cases of which were CDS, 50 (50/2556, 1.96%) cases were non-CDS. Mean age was 71 (54-86) years old in odontoid calcification patients. The male-to-female ratio of patients with odontoid calcification was 27:42 (0.64). The prevalence of odontoid calcification was 69/1497 (6.14%) in individuals over 50 years old, The prevalence was 0.59% (4/679), 5.05% (26/515), 11.49% (27/235) and 20% (12/60) in patients aged 50-59, 60-69, 70-79 and 80-89 years old, respectively. Age and female gender were predictive factors of odontoid calcification. Lower hemoglobin (Hgb), red blood cell count (RBC), higher C-reactive protein (CRP), pain scale score were found in CDS patients comparing with non-CDS group. No difference of age, gender, hypertension, diabetes mellitus, smoking, alcohol history, creatinine, white blood cell count, mean corpuscular volume, uric acid, calcium was found between the two groups. CONCLUSIONS: Odontoid calcification is a common radiological entity in patients older than 50 years. Lower Hgb, RBC, higher CRP, pain scale score were found in CDS patients comparing with non-CDS.

A Cleverly Designed Novel Lipid Nanosystem: Targeted Retention, Controlled Visual Drug Release, and Cascade Amplification Therapy for Mammary Carcinoma in vitro.

OBJECTIVE: To construct an ideal theranostic nanoplatform (LIP3); to clarify its physicochemical properties; to confirm its characteristics of dual-modality imaging, active-targeting, and cascade amplification therapy for mammary carcinoma; and to perform a preliminary exploration of the cytotoxicity mechanism. DESIGN: A self-prepared liposome nanosystem, LIP3, can actively target 4T1 cells because the surface is linked with C-RGD. Haematoporphyrin monomethyl ether (HMME), an excellent sonosensitizer entrapped in the lipid bilayer, can function in photoacoustic imaging. Low-intensity focused ultrasound (LIFU) of ultrasound-targeted microbubble destruction (UTMD) promotes localized drug delivery into tumours because PFH, a phase-change substance, is loaded in the LIP3 core, achieving visualization of targeted drug release, and sonodynamic therapy (SDT) can kill tumour cells. SDT provides a favourable environment for AQ4N, resulting in amplification of LIP3 treatment. Therefore, LIP3 shows targeted aggregation and targeted release, integrating dual-mode imaging and precise treatment. RESULTS: The self-prepared lipid nanosystem, LIP3, meets the above expectations and has ideal physicochemical properties, with a regular sphere with uniform distribution. Contrast-enhanced ultrasound (CEUS), photoacoustic imaging, and bimodal imaging were effective in vitro. In 4T1 cell experiments, the cell capacity was as high as 42.9%, and the cytotoxicity to 4T1 was more than 5 times that of LIP1 (containing AQ4N only) and more than 2 times that of LIP2 (containing only HMME), achieving comparable results as cascade therapy for mammary cancer. CONCLUSION: LIP3, a theranostic nanoplatform, was successfully constructed and conformed to the physicochemical characterization of ideal nanoparticles, with active-targeting, dual-modality imaging, visualized drug release, and precise treatment under the action of LIFU. SDT provides a favourable environment for AQ4N, resulting in amplification of LIP3 treatment. Therefore, LIP3 shows targeted aggregation and targeted release, integrating dual-mode imaging, and precise cascade treatment. This unique theranostic NPS with multiple capabilities is expected to be a favourable anti-cancer method in the future.

Light-Responsive Core-Shell Nanoplatform for Bimodal Imaging-Guided Photothermal Therapy-Primed Cancer Immunotherapy.

Photothermal therapy (PTT) as a noninvasive and effective thermal therapeutic approach has attracted tremendously increasing interest because it can effectively eliminate the primary tumor and generate tumor-associated antigens, which could elicit antitumor immune responses. Herein, we report on the rational design and fabrication of copper sulfide (CuS)-based nanoplatform for cancer photothermal immunotherapy. The as-prepared core-shell CuS@mSiO2-PFP-PEG (CPPs) nanocomposites possess high biocompatibility, photoacoustic (PA)/ultrasound (US) imaging, and strong PTT effect upon 808 nm laser irradiation, indicating that the nanocomposites have a promising application in diagnosis and treatment of breast cancer with molecular classification. Importantly, we also elucidated that the CPP-triggered PTT in combination with anti-PD-1 checkpoint blockade therapy can not only obliterate primary tumor but also inhibit metastatic tumor in tumor-bearing mice. We believe that the CPPs have a good probability to serve as a useful nanoplatform for PTT, and this approach may provide a promising strategy for tumor-therapeutic modality with immunotherapy.

A clinical and multi­omics study of Van der Woude syndrome in three generations of a Chinese family.

Previous studies have suggested that pathogenic variants in interferon regulatoryse factor 6 (IRF6) can account for almost 70% of familial Van der Woude Syndrome (VWS) cases. However, gene modifiers that account for the phenotypic variability of IRF6 in the context of VWS remain poorly characterized. The aim of this study was to report a family with VWS with variable expressivity and to identify the genetic cause. A 4­month­old boy initially presented with cleft palate and bilateral lower lip pits. Examination of his family history identified similar, albeit milder, clinical features in another four family members, including bilateral lower lip pits and/or hypodontia. Peripheral blood samples of eight members in this three­generation family were subsequently collected, and whole­exome sequencing was performed to detect pathogenic variants. A heterozygous missense IRF6 variant with a c.1198C>T change in exon 9 (resulting in an R400W change at the amino acid level) was detected in five affected subjects, but not in the other three unaffected subjects. Moreover, subsequent structural analysis was indicative of damaged stability to the structure in the mutant IRF protein. Whole­transcriptome sequencing, expression analysis and Gene Ontology enrichment analysis were conducted on two groups of patients with phenotypic diversity from the same family. These analyses identified significant differentially expressed genes and enriched pathways in these two groups. Altogether, these findings provide insight into the mechanism underlying the variable expressivity of VWS.

A light-controllable specific drug delivery nanoplatform for targeted bimodal imaging-guided photothermal/chemo synergistic cancer therapy.

Breast cancer is a severe threat to the health and lives of women due to its difficult early diagnosis and the unsatisfactory therapeutic efficacy of breast cancer treatments. The development of theranostic strategies to combat breast cancer with high accuracy and effectiveness is therefore urgently needed. In this study, we describe a near-infrared (NIR) light-controllable, targeted and biocompatible drug delivery nanoplatform (PFH-PTX@PLGA/SPIO-Her) for photoacoustic (PA)/ultrasound (US) bimodal imaging-guided photothermal (PTT)/chemo synergistic cancer therapy of breast cancer. Carboxyl-modified PEGylated poly (lactic-co-glycolic acid) (PLGA-PEG-COOH) constituted the skeleton of the nanoplatform. Especially, the antibody Herceptin was modified onto the surface of nanoplatform for active HER2-targing to facilitate the tumor accumulation of the nanoplatform. The encapsulated superparamagnetic iron oxide (SPIO) nanoparticles could be employed as an excellent PA imaging agent to guide tumor therapy. When exposed to NIR light, the SPIO also could transform NIR light into thermal energy for photothermal ablation of tumor. The NIR-induced thermal effect subsequently triggered the optical droplet vaporization (ODV) of perfluorohexane (PFH) to generate PFH gas bubbles, which not only achieved the US imaging enhancement, but also contributed to the release of loaded paclitaxel (PTX) from the nanoplatform for significantly improving PTT therapeutic efficacy. Our results demonstrated that the targeted tumor accumulation, accurate real-time bimodal imaging, and the abundant drug release at the tumor site were all closely associated with the PTT therapeutic efficacy. Therefore, the theranostic nanoplatform is a very promising strategy for targeted imaging-guided photothermal/chemo synergistic tumor therapy with high therapeutic efficacy and minimized side effects. STATEMENT OF SIGNIFICANCE: Breast cancer is the most frequent cancer in women. Herein, we successfully developed a light-controllable and HER2 targeted theranostic nanoparticels (PFH-PTX@PLGA/SPIO-Her) as a specific drug delivery nanoplatform to overcome the low accuracy of tumor detection and the low specificity of traditional chemo-therapeutic protocols. The study demonstrated that PFH-PTX@PLGA/SPIO-Her could actively target to breast cancer cells with positive HER2 expression. The biocompatible PFH-PTX@PLGA/SPIO-Her nanoparticles as both photoacoustic/ultrasound bimodal imaging agents, photothermal-conversion nanomaterials (photothermal hyperthermia) and controllable drug delivery nanoagents (optical droplet vaporization) have completely eradicated the tumor without severe side effects. The theranostic strategy not only integrates strengthens of traditional imaging or therapeutic modalities, but also paves a new way for the efficient cancer treatment by taking the advantage of quickly-developing nanomedicine.

[En block frontal-temple silicone for humping the forehead and temple].

OBJECTIVE: To explore the reliability of humping the forehead and temple by en block frontal temporal silicone . METHODS: Make wax mold by piling up wax slices layer by layer according to the rang of depressing of the forehead and temple, the section being humped and the hight need to be projected. Order the silicone block according to the dimension of the wax mold. Make the implant from the silicon block. Under local anaesthesia dissection under the superficial temporal fascia and galea through forehead and two temporal incisions. Implant the silicon through the middle incision. RESULTS: Total 18 cases in this group were followed up for 3-12 months. Wound healed primarily without infection. I case with early blood effusion cured after aspiration. l case with later clear effusion cured after aspiration ad injection of prednisone in to the capsular. The frontal temporal contours were satisfactory . No outline of the implant was seen. CONCLUSION: It is safety and satisfied to hump the forehead and temple by en block frontal temporal silicone.