Peripheral inflammation in behavioural variant frontotemporal dementia: associations with central degeneration and clinical measures.

BACKGROUND: Neuroinflammation plays a significant role in the progression of frontotemporal dementia (FTD). However, the association between peripheral inflammatory factors and brain neurodegeneration is poorly understood. We aimed to examine changes in peripheral inflammatory markers in patients with behavioural variant FTD (bvFTD) and explore the potential association between peripheral inflammation and brain structure, metabolism, and clinical parameters. METHODS: Thirty-nine bvFTD patients and 40 healthy controls were enrolled and underwent assessment of plasma inflammatory factors, positron emission tomography/magnetic resonance imaging, and neuropsychological assessments. Group differences were tested using Student's t test, Mann‒Whitney U test, or ANOVA. Partial correlation analysis and multivariable regression analysis were implemented using age and sex as covariates to explore the association between peripheral inflammatory markers, neuroimaging, and clinical measures. The false discovery rate was used to correct for the multiple correlation test. RESULTS: Plasma levels of six factors, including interleukin (IL)-2, IL-12p70, IL-17A, tumour necrosis superfamily member 13B (TNFSF/BAFF), TNFSF12 (TWEAK), and TNFRSF8 (sCD30), were increased in the bvFTD group. Five factors were significantly associated with central degeneration, including IL-2, IL-12p70, IL-17A, sCD30/TNFRSF8, and tumour necrosis factor (TNF)-α; the association between inflammation and brain atrophy was mainly distributed in frontal-limbic-striatal brain regions, whereas the association with brain metabolism was mainly in the frontal-temporal-limbic-striatal regions. BAFF/TNFSF13B, IL-4, IL-6, IL-17A and TNF-α were found to correlate with clinical measures. CONCLUSION: Peripheral inflammation disturbance in patients with bvFTD participates in disease-specific pathophysiological mechanisms, which could be a promising target for diagnosis, treatment, and monitoring therapeutic efficacy.

High-quality and robust protein quantification in large clinical/pharmaceutical cohorts with IonStar proteomics investigation.

Robust, reliable quantification of large sample cohorts is often essential for meaningful clinical or pharmaceutical proteomics investigations, but it is technically challenging. When analyzing very large numbers of samples, isotope labeling approaches may suffer from substantial batch effects, and even with label-free methods, it becomes evident that low-abundance proteins are not reliably measured owing to unsufficient reproducibility for quantification. The MS1-based quantitative proteomics pipeline IonStar was designed to address these challenges. IonStar is a label-free approach that takes advantage of the high sensitivity/selectivity attainable by ultrahigh-resolution (UHR)-MS1 acquisition (e.g., 120-240k full width at half maximum at m/z = 200) which is now widely available on ultrahigh-field Orbitrap instruments. By selectively and accurately procuring quantitative features of peptides within precisely defined, very narrow m/z windows corresponding to the UHR-MS1 resolution, the method minimizes co-eluted interferences and substantially enhances signal-to-noise ratio of low-abundance species by decreasing noise level. This feature results in high sensitivity, selectivity, accuracy and precision for quantification of low-abundance proteins, as well as fewer missing data and fewer false positives. This protocol also emphasizes the importance of well-controlled, robust experimental procedures to achieve high-quality quantification across a large cohort. It includes a surfactant cocktail-aided sample preparation procedure that achieves high/reproducible protein/peptide recoveries among many samples, and a trapping nano-liquid chromatography-mass spectrometry strategy for sensitive and reproducible acquisition of UHR-MS1 peptide signal robustly across a large cohort. Data processing and quality evaluation are illustrated using an example dataset ( http://proteomecentral.proteomexchange.org ), and example results from pharmaceutical project and one clinical project (patients with acute respiratory distress syndrome) are shown. The complete IonStar pipeline takes ~1-2 weeks for a sample cohort containing ~50-100 samples.

A cross-sectional study on the mental health of patients with COVID-19 1 year after discharge in Huanggang, China.

OBJECTIVE: This study is aimed to investigate the mental health status of COVID-19 survivors 1 year after discharge from hospital and reveal the related risk factors. METHODS: From April 11 to May 11, 2021, 566 COVID-19 survivors in Huanggang city were recruited through their primary doctors. A total of 535 participants (94.5%) admitted to participate in the survey and completed the questionnaires. Five scales were applied including 7-Items Generalized Anxiety Disorder Scale, Patient Health Questionnaire-9, Impact of Event Scale-Revised, Pittsburgh Sleep Quality Index, and Fatigue Scale-14. The chi-square and the Fisher's exact test were used to evaluate the classification data, multivariate logistic regression was used to explore the related factors of sleep quality, fatigue, anxiety, depression, and post-traumatic stress disorder (PTSD). RESULTS: One year after being discharged, of the 535 COVID-19 survivors, 252 (47.1%) had poor sleep quality; 157 (29.3%) had the symptoms of fatigue; 84 (15.7%),112 (20.9%), and 130 (24.3%) suffered from symptoms of anxiety, depression, and PTSD, respectively. The logistic regression analysis showed that history of chronic disease was risk factor for poor sleep quality (OR 2.501; 95% CI, 1.618-3.866), fatigue (OR 3.284; 95% CI 2.143-5.033), PTSD (OR 2.323; 95% CI 1.431-3.773) and depression (OR 1.950; 95% CI 1.106-3.436) in COVID-19 survivors. Smoking contributed to the poor sleep quality (OR 2.005; 95% CI 1.044-3.850), anxiety (OR 4.491; 95% CI 2.276-8.861) and depression (OR 5.459; 95% CI 2.651-11.239) in survivors. Drinking influenced fatigue (OR 2.783; 95% CI 1.331-5.819) and PTSD (OR 4.419; 95% CI 1.990-9.814) in survivors. Compared with college-educated survivors, survivors with high school education were at higher risk for poor sleep quality (OR 1.828; 95% CI 1.050-3.181) and PTSD (OR 2.521; 95% CI 1.316-4.830), and survivors with junior high school education were at higher risk for PTSD (OR 2.078; 95% CI 1.039-4.155). Compared with overweight survivors (BMI ≥ 23.0), survivors with normal BMI (18.5-22.9) (OR 0.600; 95% CI 0.405-0.889) were at lower risk for fatigue. While being housewife (OR 0.390; 95% CI 0.189-0.803) was protective factor for fatigue and having more family members was protective factor for PTSD (OR 0.404 95% CI 0.250-0.653) in survivors. CONCLUSIONS: One year after infection, poor sleep quality, fatigue, anxiety, depression, and PTSD, still existed in a relatively high proportion of COVID-19 survivors. Chronic disease history was an independent risk factor for poor sleep quality, fatigue, depression, and PTSD. Participants with low education levels were more likely to have mental problems than the others. We should focus on the long-term psychological impact of COVID-19 on survivors, and the government should apply appropriate mental health services to offer psychiatric support.

Knowledge mapping of copper-induced cell death: A bibliometric study from 2012 to 2022.

BACKGROUND: The recent article Copper induces cell death by targeting lipoylated TCA cycle proteins has attracted much attention. Although copper-induced cell death has only recently been formally proposed, it has been studied much earlier. This study aims to undertake a bibliometric analysis of the literature on copper-induced cell death to understand the development of copper-induced cell death better and identify potential new research directions. METHODS: With the help of Cite Space software, visual analysis is carried out on the annual number of published papers, countries/regions and institutions, journals co-citation, literature co-citation and reference burst, keywords co-occurrence, clustering, and burst. RESULTS: A search of 770 articles published in English over the last ten years showed a fluctuating trend of increasing numbers of articles. China had the highest number of articles (190% or 24.68%), followed by the USA and India. Inflammation, biological evaluation, nanoparticle, and cu(ii) have been popular research themes in the last 4 years. The keyword clusters are summarized in 8 categories, including exposure, complexe, er stress, cleavage, paraptosis, cancer, glutamate, reactive oxygen species (ROS), expression. The hot topics are mainly focused on the exploration of mechanisms and related diseases, including induced apoptosis, aggregation, autophagy, endoplasmic reticulum stress, induced oxidative stress, and inflammation. Parkinson's disease and cancer are 2 diseases that are closely related to copper-induced cell death. CONCLUSION: This study provides a visual analysis of copper-induced cell death trends and provides some hidden potentially useful information for future research directions.

Parallel, High-Quality Proteomic and Targeted Metabolomic Quantification Using Laser Capture Microdissected Tissues.

Quantitative proteomics/metabolomics investigation of laser-capture-microdissection (LCM) cell populations from clinical cohorts affords precise insights into disease/therapeutic mechanisms, nonetheless high-quality quantification remains a prominent challenge. Here, we devised an LC/MS-based approach allowing parallel, robust global-proteomics and targeted-metabolomics quantification from the same LCM samples, using biopsies from prostate cancer (PCa) patients as the model system. The strategy features: (i) an optimized molecular weight cutoff (MWCO) filter-based separation of proteins and small-molecule fractions with high and consistent recoveries; (ii) microscale derivatization and charge-based enrichment for ultrasensitive quantification of key androgens (LOQ = 5 fg/1k cells) with excellent accuracy/precision; (iii) reproducible/precise proteomics quantification with low-missing-data using a detergent-cocktail-based sample preparation and an IonStar pipeline for reproducible and precise protein quantification with excellent data quality. Key parameters enabling robust/reproducible quantification have been meticulously evaluated and optimized, and the results underscored the importance of surveying quantitative performances against key parameters to facilitate fit-for-purpose method development. As a proof-of-concept, high-quality quantification of the proteome and androgens in LCM samples of PCa patient-matched cancerous and benign epithelial/stromal cells was achieved (N = 16), which suggested distinct androgen distribution patterns across cell types and regions, as well as the dysregulated pathways involved in tumor-stroma crosstalk in PCa pathology. This strategy markedly leverages the scope of quantitative-omics investigations using LCM samples, and combining with IonStar, can be readily adapted to larger-cohort clinical analysis. Moreover, the capacity of parallel proteomics/metabolomics quantification permits precise corroboration of regulatory processes on both protein and small-molecule levels, with decreased batch effect and enhanced utilization of samples.

Efficacy and safety of Morinda officinalis oligosaccharide capsules for depressive disorder: a systematic review and meta-analysis

Objective: To evaluate the efficacy and safety of Morinda officinalis oligosaccharide (MOO) capsules for depressive disorder. Methods: Eight electronic databases were searched for relevant studies from inception to April 19, 2020. Randomized controlled trials comparing MOO capsules with antidepressants were included. Data analysis was conducted using Review Manager 5.3 software. The risk of bias was assessed using the Cochrane Risk of Bias Tool, and the quality of the studies was evaluated by two researchers using the Grading of Recommendation, Assessment, Development and Evaluations (GRADE) software. Results: Seven studies involving 1,384 participants were included in this study. The effect of MOO capsules for moderate depressive disorder was not different from that of antidepressants (risk ratio [RR] = 0.99, 95%CI 0.92-1.06). Regarding adverse events, no significant difference was found between MOO capsules and antidepressants (RR = 0.84, 95%CI 0.65-1.07). In addition, the quality of evidence related to these adverse events was rated as low. Conclusion: This systematic review suggests that the efficacy of MOO capsules in the treatment of mild to moderate depression is not inferior to that of conventional antidepressants, which may provide a new direction for clinical alternative selection of antidepressants. However, more high-quality research and detailed assessments are needed.

Homeostasis Research Model Based on Yin-Yang Theory: Five Examples.

In recent years, the ancient Yin-Yang theory has been gradually adopted by modern researchers, especially European and American scholars, and it has also been applied to modern scientific research on sleep, viruses, metabolism, cancer, genes, autoimmune diseases, and so on. It is very promising and fruitful results have been reported. However, the understanding of the connotations of Yin-Yang theory is not sufficient and thorough enough in these studies. If we understand and apply Yin-Yang theory more comprehensively, it may provide us with additional potential mechanisms and research directions worthy of study. On the basis of promoting a comprehensive understanding of all three connotations of Yin-Yang theory, this review attempts to illustrate this theory, summarize its applications in modern scientific research, and reveal the potential research direction of modern medicine.

Corticosterone induces neurotoxicity in PC12 cells via disrupting autophagy flux mediated by AMPK/mTOR signaling.

AIMS: Our previous study indicated that chronic stress caused autophagy impairment and subsequent neuron apoptosis in hippocampus. However, the mechanism underlying the stress-induced damage to neurons is unclear. In present work, we investigated whether stress-level glucocorticoids (GCs) GCs promoted PC12 cell damage via AMPK/mTOR signaling-mediated autophagy. METHODS: Chronic stress-induced PC12 cell injury model was built by treatment with high level corticosterone (CORT). Cell injury was evaluated by flow cytometry assay and transmission electron microscopy observation. RESULTS: Autophagy flux was measured based on the changes in LC3-II and P62 protein expressions, and the color alteration of mCherry-GFP-LC3-II transfection. Our results showed that CORT not only increased cell injury and apoptosis, but also dysregulated AMPK/mTOR signaling-mediated autophagy flux, as indicated by the upregulated expression of LC3-II and P62 proteins, and the lowered ration of autolysosomes to autophagosomes. Mechanistically, our results demonstrated that autophagy activation by AMPK activator metformin or mTOR inhibitor rapamycin obviously promotes cell survival and autophagy flux, improved mitochondrial ultrastructure, and reduced expression of Cyt-C and caspase-3 in CORT-induced PC12 cells. CONCLUSION: These results indicate that high CORT triggers PC12 cell damage through disrupting AMPK/mTOR-mediated autophagy flux. Targeting this signaling may be a promising approach to protect against high CORT and chronic stress-induced neuronal impairment.

Surfactant Cocktail-Aided Extraction/Precipitation/On-Pellet Digestion Strategy Enables Efficient and Reproducible Sample Preparation for Large-Scale Quantitative Proteomics.

For quantitative proteomics, efficient, robust, and reproducible sample preparation with high throughput is critical yet challenging, especially when large cohorts are involved, as is often required by clinical/pharmaceutical studies. We describe a rapid and straightforward surfactant cocktail-aided extraction/precipitation/on-pellet digestion (SEPOD) strategy to address this need. Prior to organic solvent precipitation and on-pellet digestion, SEPOD treats samples with a surfactant cocktail (SC) containing multiple nonionic/anionic surfactants, which achieves (i) exhaustive/reproducible protein extraction, including membrane-bound proteins; (ii) effective removal of detrimental nonprotein matrix components (e.g., >94% of phospholipids); (iii) rapid/efficient proteolytic digestion owing to dual (surfactants + precipitation) denaturation. The optimal SC composition and concentrations were determined by Orthogonal-Array-Design investigation of their collective/individuals effects on protein extraction/denaturation. Key parameters for cleanup and digestion were experimentally identified as well. The optimized SEPOD procedures allowed a rapid 6 h digestion providing a clean digest with high peptide yields and excellent quantitative reproducibility (especially low-abundance proteins). Compared with filter-assisted sample preparation (FASP) and in-solution digestion, SEPOD showed superior performance by recovering substantially more peptide/proteins (including integral membrane proteins), yielding significantly higher peptide intensities and improving quantification for peptides with extreme physicochemical properties. SEPOD was further applied in a large-cohort temporal investigation of 44 IAV-infected mouse lungs, providing efficient and reproducible peptide yields (77.9 ± 4.6%) across all samples. With the IonStar pipeline, >6 400 unique protein groups were quantified (≥2 peptide/protein, peptide-FDR < 0.05%), ∼99% without missing data in any sample with <7% technical median-intragroup CV. Altered proteome patterns revealed interesting novel insights into pathophysiological changes by IAV infection. In summary, SEPOD offers a feasible solution for rapid, efficient, and reproducible preparation of biological samples, facilitating high-quality proteomic quantification of large sample cohorts.

Blockage of cytosolic phospholipase A2 alpha sensitizes aggressive breast cancer to doxorubicin through suppressing ERK and mTOR kinases.

Advanced breast cancer is resistant to chemotherapy and its underlying mechanisms are not fully explored. In this work, we identified cytosolic phospholipase A2 alpha (cPLA2α) as a novel target to overcome chemoresistance in breast cancer. We demonstrated the increased transcriptional and translational expression of cPLA2α in breast cancer cells to acute and chronic exposure to doxorubicin. cPLA2α upregulation is also observed in breast cancer patients in response to chemotherapy. Inhibition of cPLA2α using two pharmacological inhibitors significantly enhances doxorubicin's effects to almost complete suppression in breast cancer cell growth, survival and migration. Similarly, depletion of cPLA2α significantly sensitizes breast cancer cells to doxorubicin treatment. We further found that cPLA2α inhibition led to decreased phosphorylation of ERK, mTOR, S6 and 4EBP1, suggesting the suppression of ERK and mTOR signaling pathways. These findings indicate the positive roles of cPLA2α in breast cancer cell growth, survival, migration and response to chemotherapy. Our work also highlights the therapeutic value of blocking cPLA2α to overcome chemoresistance in breast cancer.

Expansion of CD26 positive fibroblast population promotes keloid progression.

BACKGROUND: Keloid is a skin fibrosis disease that characterised by invasive growth of fibroblasts and aberrant deposition of extracellular matrix. Studies indicated that keloid fibroblasts (KFs) is a class of 'activated' fibroblasts, which show accelerated proliferation and excessive extracellular matrix formation as compared with normal fibroblasts (NFs). However, the mechanism underlying keloid fibroblasts dysfunction is still unknown. OBJECTIVE: To verify CD26 expression difference between KFs and NFs, and investigate the function of CD26 positive fibroblasts in keloid progression. METHODS: KFs and NFs were isolated from Keloid tissues and normal skin tissues respectively. Flow cytometry was performed to isolate CD26+/CD26- fibroblasts from KFs and NFs. Proliferation of different fibroblasts were analyzed by CCK8 assay and Ki 67 straining. Profibrotic phenotype difference was detected by qRT-PCR, western blot, ELISA and immunofluorescence. Scratching experiment and transwell assay were used to assess invasion ability of CD26+/CD26- fibroblasts. Diprotin A was used as a CD26 inhibitor to further investigated the function of CD26 fibroblasts in keloid disease. RESULT: CD26 expression was increased in KFs, and the proportion of CD26+ fibroblasts was significantly increased in KFs. Cell viability analysis showed that CD26+ fibroblasts was more active in proliferation. Furthermore, the expression of profibrotic genes were increased in CD26+ fibroblasts, including TGF-ß1, IGF-1, IL6, collagen 1, collagen 3 and fibronectin. And meanwhile, CD26+ fibroblasts showed stronger invasion ability as compared to CD26- fibroblasts. Moreover, Diprotin A significantly suppressed proliferation and extracellular matrix secretion of CD26+ fibroblasts isolated from keloid tissues. CONCLUSION: Our findings suggest that CD26+ fibroblasts possess proliferation advantage in compare to CD26- fibroblasts, and the advantage caused expansion of CD26 positive fibroblast population promotes keloid progression.

Quantitative proteomic profiling of paired cancerous and normal colon epithelial cells isolated freshly from colorectal cancer patients.

PURPOSE: The heterogeneous structure in tumor tissues from colorectal cancer (CRC) patients excludes an informative comparison between tumors and adjacent normal tissues. Here, we develop and apply a strategy to compare paired cancerous (CEC) versus normal (NEC) epithelial cells enriched from patients and discover potential biomarkers and therapeutic targets for CRC. EXPERIMENTAL DESIGN: CEC and NEC cells are respectively isolated from five different tumor and normal locations in the resected colon tissue from each patient (N = 12 patients) using an optimized epithelial cell adhesion molecule (EpCAM)-based enrichment approach. An ion current-based quantitative method is employed to perform comparative proteomic analysis for each patient. RESULTS: A total of 458 altered proteins that are common among >75% of patients are observed and selected for further investigation. Besides known findings such as deregulation of mitochondrial function, tricarboxylic acid cycle, and RNA post-transcriptional modification, functional analysis further revealed RAN signaling pathway, small nucleolar ribonucleoproteins (snoRNPs), and infection by RNA viruses are altered in CEC cells. A selection of the altered proteins of interest is validated by immunohistochemistry analyses. CONCLUSION AND CLINICAL RELEVANCE: The informative comparison between matched CEC and NEC enhances our understanding of molecular mechanisms of CRC development and provides biomarker candidates and new pathways for therapeutic intervention.

Inhibiting the MNK-eIF4E-ß-catenin axis increases the responsiveness of aggressive breast cancer cells to chemotherapy.

Advanced breast cancer (eg. stage IV) is resistant to chemotherapy. In this work, we identified potentially druggable targets that are critically involved in chemoresistance. We showed that eIF4E is highly phosphorylated at serine 209 in breast cancer patients in response to chemotherapy, which significantly correlated with poorer clinical responses and outcomes. Depletion of eIF4E enhanced the anti-proliferative and pro-apoptotic effects of chemotherapeutic drugs in breast cancer cells. Chemotherapy activated the Wnt/ß-catenin signaling in an eIF4E-dependent manner. However, MNK inhibitors prevented chemotherapeutic drug-induced eIF4E phosphorylation and ß-catenin activation, which enhanced the breast cancer cell response to chemotherapy in vitro and in vivo. These findings indicate MNK-eIF4E-ß-catenin is an activator of the breast cancer cell response to chemotherapy and highlights the therapeutic value of inhibiting MNK to overcome chemoresistance in breast cancer.

Viability of human composite tissue model for experimental study of burns.

Experimental studies of burns are primarily performed with animal models that have important anatomical and physiological differences relative to human systems. The aim of this study was to develop a human experimental burn model using composite tissue obtained from bariatric surgery. We established a new protocol to maintain viable sections of human cutaneous and subcutaneous (sub/cutaneous) tissue in vitro. Under the conditions selected, multiparametric flow cytometry and histological analysis confirmed the viability and integrity of the human sub/cutaneous tissue for at least 5 days. Furthermore, we utilized a precision McKenna burner to inflict burns on the human tissue model under well-defined thermal conditions in vitro. Our data showed a localized, temporally restricted polarization of the resident macrophages in the subcutaneous human tissue in response to specific thermal forces. Therefore, our model provides a useful alternative to animal studies for further detailed investigations of human responses to injuries and treatments.

Ion Current-Based Proteomic Profiling for Understanding the Inhibitory Effect of Tumor Necrosis Factor Alpha on Myogenic Differentiation.

Despite a demonstrated role for TNF-α in promoting muscle wasting and cachexia, the associated molecular mechanisms and signaling pathways of myoblast differentiation dysregulated by TNF-α remain poorly understood. This study presents well-controlled proteomic profiling as a means to investigate the mechanisms of TNF-α-regulated myogenic differentiation. Primary human muscle precursor cells (MPCs) cultured in growth medium (GM), differentiation medium (DM) to induce myogenic differentiation, and DM with 20 ng/mL of TNF-α (n = 5/group) were comparatively analyzed by an ion current-based quantitative platform consisting of reproducible sample preparation/on-pellet digestion, a long-column nano-LC separation, and ion current-based differential analysis. The inhibition of myogenic differentiation by TNF-α was confirmed by reduced formation of multinucleated myotubes and the recovered expression of altered myogenic proteins such as MYOD and myogenin during myogenic differentiation. Functional analysis and validation by immunoassay analysis suggested that the cooperation of NF-κB and STAT proteins is responsible for dysregulated differentiation in MPCs by TNF-α treatment. Increased MHC class I components such as HLA-A, HLA-B, HLA-C, and beta-2-microglobulin were also observed in cultures in DM treated with TNF-α. Interestingly, inhibition of the cholesterol biosynthesis pathway during myogenic differentiation induced by serum starvation was not recovered by TNF-α treatment, which combined with previous reports, implies that this process may be an early event of myogenesis. This finding could lay the foundation for the potential use of statins in modulating myogenesis through cholesterol, for example, in stem cell-based myocardial infarction treatment, where differentiation of myoblasts and stem cells into force-generating mature muscle cells is a key step to the therapeutic capacity. In conclusion, the landscapes of altered transcription regulators, metabolic processes, and signaling pathways in MPCs are revealed in the regulation of myogenic differentiation by TNF-α, which is valuable for myogenic cellular therapeutics.

Sorafenib exerts an anti-keloid activity by antagonizing TGF-ß/Smad and MAPK/ERK signaling pathways.

Keloid disease is characterized by hyperproliferation of responsive fibroblasts with vigorously continuous synthesis of extracellular matrix (ECM) components. Although the process by which keloids develop is poorly understood, most theories of the etiology are referred to fibroblast dysfunction. A central event in dermal repair is the release of growth factors in response to skin injury, which leads to the dysregulation of several crucial pathways that initiate the activation of keloid fibroblasts (KFs) and promote ECM accumulation. Hence, strategies aimed at reducing the production of these cytokines and/or disrupting their intracellular signal transduction have potential clinical significance for curing keloid. As the first oral multikinase inhibitor, sorafenib blocks a number of intracellular signaling pathways which are also pivotal for keloid pathogenesis. Therefore, evaluation of the effects of sorafenib on keloid disease seems timely and pertinent. In this study, we reported the identification of sorafenib that antagonized TGF-ß/Smad and MAPK/ERK signaling pathways in primary KFs. Impressively, treatment with sorafenib inhibited KF cell proliferation, migration, and invasion, and simultaneously reduced collagen production in KFs. Furthermore, we present ex vivo evidence that sorafenib induced the arrest of KF migration, the inhibition of angiogenesis, and the reduction of collagen accumulation. These preclinical observations suggest that sorafenib deserves systematic exploration as a candidate agent for the future treatment of keloids. KEY MESSAGE: The intracellular TGF-ß/Smad and MAPK/ERK signaling pathways is blocked by sorafenib. Sorafenib inhibits the proliferation, migration, invasion, and ECM deposition in keloid fibroblasts. Sorafenib reduces KF migration and concomitantly angiogenesis in keloid explants. Sorafenib is a promising agent for the treatment of keloids and hypertrophic scars.

Precise positioning of an intraoral distractor using augmented reality in patients with hemifacial microsomia.

BACKGROUND: Through three-dimensional real time imaging, augmented reality (AR) can provide an overlay of the anatomical structure, or visual cues for specific landmarks. In this study, an AR Toolkit was used for distraction osteogenesis with hemifacial microsomia to define the mandibular osteotomy line and assist with intraoral distractor placement. METHODS: 20 patients with hemifacial microsomia were studied and were randomly assigned to experimental and control groups. Pre-operative computed tomography was used in both groups, whereas AR was used in the experimental group. Afterwards, pre- and post-operative computed tomographic scans of both groups were superimposed, and several measurements were made and analysed. RESULTS: Both the conventional method and AR technique achieved proper positioning of the osteotomy planes, although the AR was more accurate. The difference in average vertical distance from the coronoid and condyle process to the pre- and post-operative cutting planes was significant (p < 0.01) between the two groups, whereas no significant difference (p > 0.05) was observed in the average angle between the two planes. The difference in deviations between the intersection points of the overlaid mandible across two cutting planes was also significant (p < 0.01). CONCLUSION: This study reports on an efficient approach for guiding intraoperative distraction osteogenesis. Augmented reality tools such as the AR Toolkit may be helpful for precise positioning of intraoral distractors in patients with hemifacial microsomia in craniofacial surgery.

[Application of three-dimensional printing technique in artificial bone fabrication for bone defect after mandibular angle ostectomy].

OBJECTIVE: To investigate the application of three-dimensional (3-D) printing technique combining with 3-D CT and computer aided-design technique in customized artificial bone fabrication, correcting mandibular asymmetry deformity after mandibular angle ostectomy. METHODS: Between April 2011 and June 2013, 23 female patients with mandibular asymmetry deformity after mandibular angle ostectomy were treated. The mean age was 27 years (range, 22-34 years). The disease duration of mandibular asymmetry deformity was 6-16 months (mean, 12 months). According to the CT data and individualized mandibular angle was simulated based on mirror theory, 3-D printed implants were fabricated as the standard reference for manufacturers to fabricated artificial bone graft, and then mandible repair operation was performed utilizing the customized artificial bone to improve mandibular asymmetry. RESULTS: The operation time varied from 40 to 60 minutes (mean, 50 minutes). Primary healing of incisions was obtained in all patients; no infection, hematoma, and difficulty in opening mouth occurred. All 23 patients were followed up 3-10 months (mean, 6.7 months). After operation, all patients obtained satisfactory facial and mandibular symmetry. 3-D CT reconstructive examination results after 3 months of operation showed good integration of the artificial bone. CONCLUSION: 3-D printing technique combined with 3-D CT and computer aided design technique can be a viable alternative to the approach of maxillofacial defects repair after mandibular angle ostectomy, which provides a accurate and easy way.

Pathological niche environment transforms dermal stem cells to keloid stem cells: a hypothesis of keloid formation and development.

Keloid is a disease that is difficult to cure because of its high recurrence rate after chemotherapy or radiotherapy, therefore it is considered as a benign skin tumor. Tumor stem cells are proposed as the source for tumor development and post-therapy recurrence. Interestingly, keloid stem cells have also been discovered, which share some characters with those of skin progenitor cells. Keloid patients possess specific diathesis including genetic predisposition and gene mutation, abnormal levels of hormones, growth factors and cytokines, and strong inflammatory response. This article reviews related literatures and hypothesizes that keloid stem cells might be transformed from normal dermal progenitor cells in the pathological niche of keloid tissues. These keloid stem cells are highly self-renewal and drug resistant, and can sustain themselves by asymmetric division, and continually generate new keloid cells to replenish the cells killed by drugs or radiation, thus leading to over growth of keloid and high post-therapy recurrence rate.