Search

Abstract Background Orthodontic pain affects the physical and mental health of patients. The spinal trigeminal subnucleus caudalis (SPVC) contributes to the transmission of pain information and serves as a relay station for integrating orofacial damage information. Recently, glial cells have been found to be crucial for both acute and maintenance phases of pain. It has also been demonstrated that rho kinase (ROCK) inhibitors can manage different pain models by inhibiting glial cell activation. Here, we hypothesized that orthodontic pain is related to glial cells in the SPVC, and Fasudil, a representative rho/rock kinase inhibitor, can relieve orthodontic pain by regulating the function of glial cells and the related inflammatory factors. In this study, we constructed a rat model of tooth movement pain and used immunofluorescence staining to evaluate the activation of microglia and astrocytes. Quantitative real-time PCR was used to detect the release of related cytokines and the expression of pain-related genes in the SPVC. Simultaneously, we investigated the effect of Fasudil on the aforementioned indicators. Results In the SPVC, the expression of c-Fos peaked on day 1 along with the expression of OX42 (related to microglial activation), CD16 (a pro-inflammatory factor), and CD206 (an anti-inflammatory factor) on day 3 after tooth movement, followed by a gradual decrease. GFAP-staining showed that the number of activated astrocytes was the highest on day 5 and that cell morphology became complex. After Fasudil treatment, the expression of these proteins showed a downward trend. The mRNA levels of pro-inflammatory factors (IL-1β and TNF-α) peaked on day 3, and the mRNA expression of the anti-inflammatory factor TGF-β was the lowest 3 days after tooth movement. Fasudil inhibited the mRNA expression of pain-related genes encoding CSF-1, t-PA, CTSS, and BDNF. Conclusion This study shows that tooth movement can cause the activation of glial cells in SPVC, and ROCK inhibitor Fasudil can inhibit the activation of glial cells and reduce the expression of the related inflammatory factors. This study presents for the first time the potential application of Fasudil in othodontic pain.

Background: Retinal sublayer thickness is associated with both ophthalmic and neurodegenerative diseases, serving as a valuable biomarker. Despite the established role of diet in chronic disease prevention, the relationship between healthy dietary patterns and retinal sublayer thickness remains underexplored. Objective: This study aims to investigate the associations between four commonly used diet assessment scores and retinal sublayer thickness in a large-scale population. Methods: This study utilized data from the UK Biobank, including 13,993 participants with complete optical coherence tomography (OCT) measurements and dietary assessments. The dietary patterns analyzed were the Alternate Mediterranean Diet (AMED), Anti-Empirical Dietary Inflammatory Index (AEDII), Alternate Healthy Eating Index-2010 (AHEI-2010), and Healthful Plant-Based Diet Index (HPDI). Retinal sublayers measured included macular retinal nerve fiber layer (mRNFL), macular ganglion cell-inner plexiform layer (mGCIPL), macular ganglion cell complex (mGCC), retinal pigment epithelium (mRPE), the outer nuclear layer of the central subfield (ONL), photoreceptor inner segment of the central subfield (IS) and total macular thickness. Multivariable linear regression models adjusted for demographics, ophthalmic measurements, and lifestyle factors were employed to examine associations. Mediation analysis was applied to explore the potential mediation effect of several blood biochemical indicators in simple mediation models. Results: Higher HPDI scores were significantly associated with increased central retinal macular thickness (β = 0.106, p = 0.001), mGCIPL thickness (β = 0.017, p = 0.033), mRPE (β = −0.012, p = 0.161), ONL (β = 0.044, p = 0.003), IS (β = 0.003, p = 0.005) and mGCC thickness (β = 0.027, p = 0.025). In contrast, the AMED, AEDII, and AHEI-2010 scores did not show consistent associations with retinal sublayer thickness except ONL and IS. The mediation analysis revealed that cholesterol acted as a suppressor variable, partially mediating the relationship between HPDI and retinal sublayer thickness. Sensitivity analyses indicated that the associations between HPDI and retinal sublayer thickness were more pronounced in younger individuals and females. Additionally, the variability in associations across different age and sex subgroups highlighted the potential influence of demographic factors on dietary impacts. Conclusion: The study findings suggest that adherence to a healthful plant-based diet may confer neuroprotective benefits, particularly for retinal ganglion cell health. This large-scale population-based study underscores the potential role of diet in mitigating early neurodegenerative changes detectable through non-invasive retinal imaging. Further longitudinal research is needed to establish causal relationships and elucidate the underlying mechanisms between diet and retinal health.

IntroductionCognitive impairment is a frequent clinical symptom of non-communicating hydrocephalus (NCH) involving multiple domains, including executive function, working memory, visual-spatial function, language, and attention. Functional magnetic resonance imaging (fMRI) can be used to obtain information on functional activity in local brain areas and functional connectivity (FC) across multiple brain regions. However, studies on the associated cognitive impairment are limited; further, the pathophysiological mechanisms of NCH with cognitive impairment remain unclear. Here, we aimed to explore alterations in regional neural activity and FC, as well as the mechanisms of cognitive impairment, in patients with NCH.MethodsOverall, 16 patients with NCH and 25 demographically matched healthy controls (HCs) were assessed using the Mini-Mental State Examination (MMSE) and fMRI. Changes in regional homogeneity (ReHo), degree centrality (DC), and region of interest-based FC were analyzed in both groups. The relationship between fMRI metrics (ReHo, DC, and FC) and MMSE scores in patients with NCH was also investigated.Results and discussionCompared with the HC group, the NCH group exhibited significantly lower ReHo values in the left precentral and postcentral gyri, and significantly higher ReHo values in the left medial prefrontal cortex (MPFC). The NCH group also showed significantly higher DC values in the bilateral MPFC compared with the HC group. Regarding seed-based FC, the MPFC showed reduced FC values in the right superior parietal and postcentral gyrus in the NCH group compared with those in the HC group. Moreover, within the NCH group, MMSE scores were significantly negatively correlated with the ReHo value in the left MPFC and the DC value in the bilateral MPFC, whereas MMSE scores were significantly positively correlated with FC values. To conclude, regional neural activity and FC are altered in patients with NCH and are correlated with cognitive impairment. These results advance our understanding of the pathophysiological mechanisms underlying the association between NCH and cognitive impairment.

Summary: Background: The survival rates of patients with nasopharyngeal carcinoma (NPC) have improved significantly, but there is no consensus on whether they can be considered cured. We aimed to determine whether a statistical cure could be achieved for patients with NPC in the contemporary therapeutic landscape. Methods: This retrospective multicenter study enrolled 6315 patients with nonmetastatic NPC from nonendemic and endemic regions of China from 2007 to 2020. We applied mixture and nonmixture cure models to estimate the cure probabilities and cure times by incorporating background mortality for the general population, matching by gender, age, and diagnosed year. Findings: With death as the uncured event, the probability of patients with NPC achieving a life expectancy at par with the general population was 78.1%. Considering progression as the uncured event, the likelihood of patients attaining a life expectancy without progression equivalent to that of the general population was 72.4%. For individuals, the probabilities of achieving cure were conditional and time-dependent, requiring approximately 7.1 and 4.7 years with 95% certainty, respectively. The corresponding cure times for uncured patients were 8.9 and 6.8 years, respectively. The cure probability was correlated with age, Eastern Cooperative Oncology Group score, TNM staging, Epstein–Barr virus DNA copies, and lactate dehydrogenase. The correlation was excellent between 5-year overall survival/progression-free survival and cure fractions. Interpretation: Statistical cure is potentially achievable among patients with NPC undergoing contemporary treatment modalities. The results hold significant potential implications for both clinical practice and patient perspectives. Funding: National High Level Hospital Clinical Research Funding; Beijing Xisike Clinical Oncology Research Foundation; Beijing hope run fund.

BackgroundSarcopenia is linked to an unfavorable prognosis in individuals with rheumatoid arthritis (RA). Early identification and treatment of sarcopenia are clinically significant. This study aimed to create and validate a nomogram for predicting sarcopenia risk in RA patients, providing clinicians with a reliable tool for the early identification of high-risk patients.MethodsPatients with RA diagnosed between August 2022 and January 2024 were included and randomized into training and validation sets in a 7:3 ratio. Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis and multifactorial logistic regression analysis were used to screen the risk variables for RA-associated muscle loss and to create an RA sarcopenia risk score. The predictive performance and clinical utility of the risk model were evaluated by plotting the receiver operating characteristic curve and calculating the area under the curve (AUC), along with the calibration curve and clinical decision curve (DCA).ResultsA total of 480 patients with RA were included in the study (90% female, with the largest number in the 45–59 age group, about 50%). In this study, four variables (body mass index, disease duration, hemoglobin, and grip strength) were included to construct a nomogram for predicting RA sarcopenia. The training and validation set AUCs were 0.915 (95% CI: 0.8795–0.9498) and 0.907 (95% CI: 0.8552–0.9597), respectively, proving that the predictive model was well discriminated. The calibration curve showed that the predicted values of the model were basically in line with the actual values, demonstrating good calibration. The DCA indicated that almost the entire range of patients with RA can benefit from this novel prediction model, suggesting good clinical utility.ConclusionThis study developed and validated a nomogram prediction model to predict the risk of sarcopenia in RA patients. The model can assist clinicians in enhancing their ability to screen for RA sarcopenia, assess patient prognosis, make early decisions, and improve the quality of life for RA patients.

Objective: Accurate prognostic predictions and personalized decision-making on induction chemotherapy (IC) for individuals with locally advanced nasopharyngeal carcinoma (LA-NPC) remain challenging. This research examined the predictive function of tumor burden-incorporated machine-learning algorithms for overall survival (OS) and their value in guiding treatment in patients with LA-NPC. Methods: Individuals with LA-NPC were reviewed retrospectively. Tumor burden signature-based OS prediction models were established using a nomogram and two machine-learning methods, the interpretable eXtreme Gradient Boosting (XGBoost) risk prediction model, and DeepHit time-to-event neural network. The models' prediction performances were compared using the concordance index (C-index) and the area under the curve (AUC). The patients were divided into two cohorts based on the risk predictions of the most successful model. The efficacy of IC combined with concurrent chemoradiotherapy was compared to that of chemoradiotherapy alone. Results: The 1 221 eligible individuals, assigned to the training (n = 813) or validation (n = 408) set, showed significant respective differences in the C-indices of the XGBoost, DeepHit, and nomogram models (0.849 and 0.768, 0.811 and 0.767, 0.730 and 0.705). The training and validation sets had larger AUCs in the XGBoost and DeepHit models than the nomogram model in predicting OS (0.881 and 0.760, 0.845 and 0.776, and 0.764 and 0.729, P < 0.001). IC presented survival benefits in the XGBoost-derived high-risk but not low-risk group. Conclusion: This research used machine-learning algorithms to create and verify a comprehensive model integrating tumor burden with clinical variables to predict OS and determine which patients will most likely gain from IC. This model could be valuable for delivering patient counseling and conducting clinical evaluations.

Abstract Peri-implantitis is one of the most important biological complications in the field of oral implantology. Identifying the causative factors of peri-implant inflammation and osteolysis is crucial for the disease’s prevention and treatment. The underlying risk factors and detailed pathogenesis of peri-implantitis remain to be elucidated. Titanium-based implants as the most widely used implant inevitably release titanium particles into the surrounding tissue. Notably, the concentration of titanium particles increases significantly at peri-implantitis sites, suggesting titanium particles as a potential risk factor for the condition. Previous studies have indicated that titanium particles can induce peripheral osteolysis and foster the development of aseptic osteoarthritis in orthopedic joint replacement. However, it remains unconfirmed whether this phenomenon also triggers inflammation and bone resorption in peri-implant tissues. This review summarizes the distribution of titanium particles around the implant, the potential roles in peri-implantitis and the prevalent prevention strategies, which expects to provide new directions for the study of the pathogenesis and treatment of peri-implantitis.

Abstract Background Panax notoginseng (Burk) F. H. Chen is a valuable traditional Chinese medicinal plant, but its commercial production is seriously affected by root rot caused by some pathogenic fungi, including Fusarium solani. Nevertheless, the genetic breeding for disease resistance of P. notoginseng remains limited. The WRKY transcription factors have been revealed to play important roles in plant defense responses, which might provide an inspiration for resistance improvement in P. notoginseng. Results In this study, the regulatory mechanism of transcription factor PnWRKY15 on P. notoginseng resistance to F. solani infection was revealed. The suppressed expression of PnWRKY15 via RNA interference increased the sensitivity of P. notoginseng to F. solani and decreased the expression levels of some defense-related genes, including PnOLP1, which encodes an osmotin-like protein that confers resistance to F. solani. Ectopic expression of PnWRKY15 in the model plant tobacco significantly enhanced the resistance to F. solani. Moreover, the transcriptome sequencing analysis discovered that some pathogenesis-related genes were expressed at higher levels in the PnWRKY15-overexpressing tobacco than that in the wild-type tobacco. In addition, the jasmonic acid (JA) and salicylic acid (SA) signaling pathways were evidently induced by PnWRKY15-overexpression, that was evidenced by that the JA and SA contents were significantly higher in the PnWRKY15-overexpressing tobacco than that in the wild-type. Furthermore, PnWRKY15, which was localized in the nucleus, can trans-activate and up-regulate PnOLP1 expression according to the EMSA, yeast one-hybrid and co-expression assays. Conclusions PnWRKY15 contributes to P. notoginseng resistance to F. solani by up-regulating the expression of resistance-related gene PnOLP1 and activating JA/SA signaling pathways. These findings will help to further elucidate the transcriptional regulatory mechanism associated with the P. notoginseng defense response to F. solani.

Rheumatoid arthritis is a chronic systemic autoimmune disease that involves mainly synovitis and joint injury and is one of the main causes of disability. The pathogenesis of rheumatoid arthritis is complicated, and the treatment cycle is long. The traditional methods of inhibiting inflammation and immunosuppression are no longer sufficient for treatment of the disease, so there is an urgent need to seek new treatments. The exocrine microenvironment is a kind of microvesicle with a lipid bilayer membrane structure that can be secreted by most cells in the body. This structure contains cell-specific proteins, lipids and nucleic acids that can transmit this information from one cell to another. To achieve cell-to-cell communication. Exocrine microRNAs can be contained in exocrine cells and can be selectively transferred to target receptor cells via exocrine signaling, thus regulating the physiological function of target cells. This article focuses on the pathological changes that occur during the development of rheumatoid arthritis and the biological regulation of exocrine and exocrine microRNAs in rheumatoid joints. Research on the roles of exocrine and exocrine microRNAs in regulating the inflammatory response, cell proliferation/apoptosis, autophagy, effects on fibroblast-like synoviocytes and immune regulation in rheumatoid arthritis was reviewed. In addition, the challenges faced by this new treatment are discussed.

Diabetic retinopathy (DR) is one of the most common complications of diabetes and induces severe visual impairment worldwide. Endothelial cell dysfunction plays an important role in the pathogenesis of DR. Here, we keep a watchful eye on α/β-hydrolase domain–containing 1 (ABHD1), a potential regulator in lipid metabolism and neovascularization. Results revealed that ABHD1 expression increased both in retina tissues of DR patients and in high-glucose–treated human retina endothelial cells. Inhibition of ABHD1 remitted endothelial cell proliferation and migration. And GSEA uncovered that ABHD1 knockdown remits endothelial cell chemotaxis and intermediate filament (IF) might be mediated in the progress by regulating keratin 1 (KRT1) and keratin 2 (KRT2). Therefore, we assume that ABHD1 is concerned with endothelial cell proliferation and migration in DR, consequently leading to pathological neovascularization. The findings may provide a potential therapeutic target for DR.

To rapidly evaluate the quality of complex herbal preparations, a new strategy was proposed based on multi-color scale and efficacy-oriented high-performance thin-layer chromatography (HPTLC) characteristic fingerprint combined with chemometric method. Firstly, effective components were screened through high-performance liquid chromatography with ultraviolet detection and evaporative light-scattering (HPLC-UV-ELSD), using multi-wavelength fusion combined with network pharmacology and molecular docking techniques. Subsequently, guided by the effective components, the targeted HPTLC characteristic fingerprint was established by multi-color scale scanning. Finally, combined with the chemometric method, the consistency of the preparation quality was evaluated, the marker components leading to quality differences were screened, and the quality control limit was established. Sanwujiao Pills (SWJPs) is a herbal preparation composed of six herbs for treating rheumatoid arthritis (RA). Through this strategy, four HPTLC characteristic fingerprints were established, they were derived from five herbs and guided by eight effective components in SWJPs. Through similarity, clustering heatmap, principal component analysis (PCA), and orthogonal partial least squares discriminant analysis (OPLS-DA), the quality distinctions among the 12 batches of SWJPs were determined. These batches were categorized into two groups based on their production time, and eight components affecting the quality of the preparation were identified. Meanwhile, the quality control threshold for SWJPs was determined based on Hotelling's T2 and DModX methods. This strategy aims to rapidly evaluate the quality of complex herbal preparations by HPTLC and extends the application of HPTLC fingerprint chromatography for identifying herbal medicine species and activity-related quality detection. The proposed strategy is also helpful for the quality control of other complex herbal preparations.

Notoginsenoside R1 is known as the main bioactive compound of the traditional Chinese medicine and functional food, Panax notoginseng. Network pharmacology prediction indicated that notoginsenoside R1 might be effective in the treatment of pulmonary fibrosis. This study investigated the effectiveness and pharmacological mechanism of notoginsenoside R1 on attenuating pulmonary fibrosis in mice. The results showed that notoginsenoside R1 alleviated the inflammatory response in the lung by down-regulating the polarization of M1 macrophages via the SOCS3/STAT3 pathway. Meanwhile, notoginsenoside R1 promoted the transcription of SH2 domain containing inositol 5′-phosphatase (SHIP) by down-regulating methyl-CpG binding domain 2 (MBD2) expression, thus attenuated PI3K/AKT-mediated polarization of M2 macrophages, and finally regulated the TGF-β1/Smad3 signaling pathway in order to attenuate pulmonary fibrosis. This study presented some possible mechanism of notoginsenoside R1 in the treatment of pulmonary fibrosis, suggesting that P. notoginseng may be served as potential medicined diet in preventing and treating such diseases.

Abstract Receptor‐type protein tyrosine phosphatases (RPTPs), Class I protein tyrosine phosphatases, are involved in human tumor cell proliferation, apoptosis, migration, and invasion through reversible phosphorylation of tyrosine residues. This review summarizes the expression and role of RPTPs in cancer and illustrates the signaling pathway mechanisms of effecting oncogenesis, tumor progression, prognosis, and angiogenesis, so as to provide more effective targets for gene therapy of related cancers.

Abstract Purpose To evaluate prognosis for reducing postoperative radiotherapy (PORT) dose to lymph node levels of supraglottic cancer (SC) on real-world data. Method and materials Patients were derived from two cancer centers. In center 1, the involved nodal levels (high-risk levels, HRL) and the next level received a dose of 60.06 Gy/1.82 Gy per fraction, while the other uninvolved levels (low-risk levels, LRL) received 50.96 Gy/1.82 Gy per fraction. In center 2, all received 50 Gy/2 Gy per fraction. The rates of high-risk levels control (HRC), regional control (RC), overall survival (OS), progression-free survival (PFS) and distant metastasis-free survival (DMFS) were calculated by Kaplan–Meier method. Result Totally, 124 patients were included (62 in center 1, 62 in center 2). Most patients (106, 85.5%) had a stage T3/N + tumor. The median follow-up was 45 months (range 1–163 months). There were no significant differences in terms of OS (p = 0.126), RC (p = 0.514), PFS (p = 0.195) and DMFS (p = 0.834). Most regional recurrences (4, 80%) occurred within three years of treatment, and all occurred within the target volumes. No regional failure occurred in HRL in center 1, while three (3/4) failures occurred in center 2. Dose reduction prescription to HRL led to a lower HRC rate (100% vs. 90.6%, p = 0.009). While the rates of LRL control (98.4%) were equal between the two centers. Conclusion Compared with a standard dose, the reduced dose to involved nodal levels showed inferior regional control for PORT, while uninvolved nodal levels showed equal outcomes. A dose of 50 Gy for HRL may be an unfavorable treatment option for SC.

ObjectivesThis study aims to explore the crashworthiness of a nuclear power platform's double-skin side structure.MethodsFinite element models of the full platform and partial double-skin side structure are established respectively, and the collision is carried out using LS-DYNA software. Based on the simulation analysis, a scale quasi-static squeeze test model is designed, and the quasi-static squeeze test of the double-skin side structure is carried out and compared with the numerical simulation. ResultsThe results show that for low-speed ship collisions, the structural response calculated using the local double-skin side structure model is basically consistent with that calculated using the whole ship model; thus, the quasi-static scaled test results are in good agreement with the numerical simulation results and can reflect the characteristics and structural deformation mode, thereby verifying the numerical simulation method. Meanwhile, the test results show that the double-skin side structure of the nuclear power platform remains intact when colliding with a 5 000 ton class ship at a speed of 2 m/s, which means that it has good crashworthiness. ConclusionsThis study shows that using a local double-skin side structure model to calculate collision response has high accuracy and greatly reduces the modelling and calculation workloads. The results of this study can provide valuable references for structural crashworthiness design in marine engineering.

Abstract Purpose Concurrent chemoradiotherapy (CCRT) is a standard treatment choice for locally advanced hypopharyngeal carcinoma. The aim of this study was to investigate whether induction chemotherapy (IC) followed by CCRT is superior to CCRT alone to treat locally advanced hypopharyngeal carcinoma. Methods and materials Patients (n = 142) were randomized to receive two cycles of paclitaxel/cisplatin/5-fluorouracil (TPF) IC followed by CCRT or CCRT alone. The primary end point was overall survival (OS). The secondary end points included the larynx-preservation rate, progression-free survival (PFS), distant metastasis-free survival (DMFS), and toxicities. Results Ultimately, 113 of the 142 patients were analyzed. With a median follow-up of 45.6 months (interquartile range 26.8–57.8 months), the 3-year OS was 53.1% in the IC + CCRT group compared with 54.8% in the CCRT group (hazard ratio, 1.004; 95% confidence interval, 0.573–1.761; P = 0.988). There were no statistically significant differences in PFS, DMFS, and the larynx-preservation rate between the two groups. The incidence of grade 3–4 hematological toxicity was much higher in the IC+ CCRT group than in the CCRT group (54.7% vs. 10%, P

Abstract Deep learning has been used extensively in histopathological image classification, but people in this field are still exploring new neural network architectures for more effective and efficient cancer diagnosis. Here, we propose multi-scale, multi-view progressive feature encoding network (MSMV-PFENet) for effective classification. With respect to the density of cell nuclei, we selected the regions potentially related to carcinogenesis at multiple scales from each view. The progressive feature encoding network then extracted the global and local features from these regions. A bidirectional long short-term memory analyzed the encoding vectors to get a category score, and finally the majority voting method integrated different views to classify the histopathological images. We tested our method on the breast cancer histology dataset from the ICIAR 2018 grand challenge. The proposed MSMV-PFENet achieved 93.0 $$\%$$ % and 94.8 $$\%$$ % accuracies at the patch and image levels, respectively. This method can potentially benefit the clinical cancer diagnosis.

Transient receptor potential cation channel subfamily V member 1 (TRPV1) is a Ca2+permeable, non-selective cation channel that is found primarily in sensory nerve fibres. Previous studies focused on pain transmission. However, recent studies have found that the TRPV1 channel, in addition to being associated with pain, also plays a role in immune regulation and their dysregulation frequently affects the development of rheumatoid arthritis (RA). A thorough understanding of the mechanism will facilitate the design of new TRPV1-targeted drugs and improve the clinical efficacy of RA. Here, we provide an updated and comprehensive overview of how the TRPV1 channel intrinsically regulates neuronal and immune cells, and how alterations in the TRPV1 channel in synoviocytes or chondrocytes extrinsically affect angiogenesis and bone destruction. Rapid progress has been made in research targeting TRPV1 for the treatment of inflammatory arthritis, but there is still much-uncharted territory regarding the therapeutic role of RA. We present a strategy for targeting the TRPV1 channel in RA therapy, summarising the difficulties and promising advances in current research, with the aim of better understanding the role of the TRPV1 channel in RA pathology, which could accelerate the development of TRPV1-targeted modulators for the design and development of more effective RA therapies.

Introducing bone regeneration–promoting factors into scaffold materials to improve the bone induction property is crucial in the fields of bone tissue engineering and regenerative medicine. This study aimed to develop a Sr-HA/PTH1-34-loaded composite hydrogel system with high biocompatibility. Teriparatide (PTH1-34) capable of promoting bone regeneration was selected as the bioactive factor. Strontium-substituted hydroxyapatite (Sr-HA) was introduced into the system to absorb PTH1-34 to promote the bioactivity and delay the release cycle. PTH1-34-loaded Sr-HA was then mixed with the precursor solution of the hydrogel to prepare the composite hydrogel as bone-repairing material with good biocompatibility and high mechanical strength. The experiments showed that Sr-HA absorbed PTH1-34 and achieved the slow and effective release of PTH1-34. In vitro biological experiments showed that the Sr-HA/PTH1-34-loaded hydrogel system had high biocompatibility, allowing the good growth of cells on the surface. The measurement of alkaline phosphatase activity and osteogenesis gene expression demonstrated that this composite system could promote the differentiation of MC3T3-E1 cells into osteoblasts. In addition, the in vivo cranial bone defect repair experiment confirmed that this composite hydrogel could promote the regeneration of new bones. In summary, Sr-HA/PTH1-34 composite hydrogel is a highly promising bone repair material.

Morphology and structure play a crucial role in influencing the performance of gas sensors. Hollow structures, in particular, not only increase the specific surface area of the material but also enhance the collision frequency of gases within the shell, and have been studied in depth in the field of gas sensing. Taking SnO2 as an illustrative example, a dual-shell structure SnO2 (D-SnO2) was prepared. D-SnO2@Polyaniline (PANI) (DSPx, x represents D-SnO2 molar content) composites were synthesized via the in situ oxidative polymerization method, and simultaneously deposited onto a polyethylene terephthalate (PET) substrate to fabricate an electrode-free, flexible sensor. The impact of the SnO2 content on the sensing performance of the DSPx-based sensor for NH3 detection at room temperature was discussed. The results showed that the response of a 20 mol% D-SnO2@PANI (DSP20) sensor to 100 ppm NH3 at room temperature is 37.92, which is 5.1 times higher than that of a pristine PANI sensor. Moreover, the DSP20 sensor demonstrated a rapid response and recovery rate at the concentration of 10 ppm NH3, with response and recovery times of 182 s and 86 s.

Digital optical phase conjugation (DOPC) is considered as a promising solution to achieve optical focusing against scattering. The implementation of DOPC based on the digital micromirror device (DMD) has been proven to have great potential, supporting a large number of modulation modes and a high modulation rate. However, the accuracy of optical alignment seriously affects the focusing contrast, limiting the applications of DMD-based DOPC systems. Here we demonstrate a simple alignment protocol including a marker-assisted tuning and an embedded compensation. Our approach can realize an exact pixelwise optical conjugation between the DMD and detector, as well as a rapid compensation for aberrations and minor misalignment. Experimental results show that the proposed alignment protocol improves the focusing contrast to 66% of the highest value predicted in the theory.

Wavefront shaping using digital micromirror devices (DMDs) allows inertia-free focus manipulation with numerous modulation modes and high refresh rates. However, the aberration caused by the curvature of DMDs affects the focusing performance. Here, we propose an aberration self-calibration method based on separable natural evolution strategies. This method searches optimal Zernike coefficients of aberration globally and completes compensation using super-pixel encoding. Compared to the genetic algorithm method, we improve the speed by 62% and achieve better-focused spots. The method enables simultaneous scanning of 25 independent focal spots. This advancement supports wavefront-shaping applications in optical imaging, industrial inspection, and laser processing.

Abstract Background Osteoarthritis, a common degenerative disease of articular cartilage, is characterized by degeneration of articular cartilage, changes in subchondral bone structure, and formation of osteophytes, with main clinical manifestations including increasingly serious swelling, pain, stiffness, deformity, and mobility deficits of the knee joints. With the advent of the big data era, the processing of mass data has evolved into a hot topic and gained a solid foundation from the steadily developed and improved machine learning algorithms. Aiming to provide a reference for the diagnosis and treatment of osteoarthritis, this paper using machine learning identifies the key feature genes of osteoarthritis and explores its relationship with immune infiltration, thereby revealing its pathogenesis at the molecular level. Methods From the GEO database, GSE55235 and GSE55457 data were derived as training sets and GSE98918 data as a validation set. Differential gene expressions of the training sets were analyzed, and the LASSO regression model and support vector machine model were established by applying machine learning algorithms. Moreover, their intersection genes were regarded as feature genes, the receiver operator characteristic (ROC) curve was drawn, and the results were verified using the validation set. In addition, the expression spectrum of osteoarthritis was analyzed by immunocyte infiltration and the co-expression correlation between feature genes and immunocytes was construed. Conclusion EPYC and KLF9 can be viewed as feature genes for osteoarthritis. The silencing of EPYC and the overexpression of KLF9 are associated with the occurrence of osteoarthritis and immunocyte infiltration.

Abstract Background Osteoarthritis (OA) is the most common joint disease, and is most frequently seen in the knees. However, there is no effective therapy to relieve the progression of knee OA. Metformin is a safe, well-tolerated oral medication that is extensively used as first-line therapy for type 2 diabetes. Previous observational studies and basic researches suggested that metformin may have protective effects on knee OA, which needs to be verified by clinical trials. This study, therefore, aims to examine the effects of metformin versus placebo on knee cartilage volume loss and knee symptoms in overweight knee OA patients by a randomized controlled trial over 24 months. Methods This protocol describes a multicenter, randomized, double-blind, and placebo-controlled clinical trial aiming to recruit 262 overweight knee OA patients. Participants will be randomly allocated to the two arms of the study, receiving metformin hydrochloride sustained-release tablets or identical inert placebo for 24 months (start from 0.5 g/day for the first 2 weeks, and increase to 1 g/day for the second 2 weeks, and further increase to 2 g/day for the remaining period if tolerated). Primary outcomes will be changes in tibiofemoral cartilage volume and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score over 24 months. Secondary outcomes will be changes in visual analogue scale (VAS) knee pain, tibiofemoral cartilage defects, effusion-synovitis volume, and tibiofemoral bone marrow lesions maximum size over 24 months. The primary analyses will be intention-to-treat analyses of primary and secondary outcomes. Per-protocol analyses will be performed as the secondary analyses. Discussion If metformin is proved to slow knee cartilage volume loss and to relieve knee symptoms among overweight knee OA patients, it will have the potential to become a disease modifying drug for knee OA. Metformin is a convenient intervention with low cost, and its potential effects on slowing down the structural progression and relieving the symptoms of knee OA would effectively reduce the disease burden worldwide. Trial registration ClinicalTrials. gov NCT05034029 . Registered on 30 Sept 2021.

Abstract Background Labor represents a period of significant physical activity. Inefficient energy supply may delay labor process and even lead to cesarean delivery. Herein we investigated whether ingestion of a carbohydrate-rich beverage could reduce cesarean delivery in laboring women with epidural analgesia. Methods This multicenter randomized trial was conducted in obstetrician-led maternity units of nine tertiary hospitals in China. Primigravidae with single term cephalic pregnancy who were preparing for vaginal birth under epidural analgesia were randomized to intake a carbohydrate-rich beverage or commercially available low-carbohydrate beverages during labor. The primary outcome was the rate of cesarean delivery. Secondary outcomes included maternal feeling of hunger, assessed with an 11-point scale where 0 indicated no hunger and 10 the most severe hunger, and maternal and neonatal blood glucose after childbirth. Results Between 17 January 2018 and 20 July 2018, 2008 women were enrolled and randomized, 1953 were included in the intention-to-treat analysis. The rate of cesarean delivery did not differ between the two groups (11.3% [111/982] with carbohydrate-rich beverage vs. 10.9% [106/971] with low-carbohydrate beverages; relative risk 1.04, 95% CI 0.81 to 1.33; p = 0.79). Women in the carbohydrate-rich beverage group had lower subjective hunger score (median 3 [interquartile range 2 to 5] vs. 4 [2 to 6]; median difference − 1; 95% CI − 1 to 0; p

Objective: This study aimed to evaluate the prognostic value of the pretreatment systemic immune-inflammation index (SII) in non-metastatic nasopharyngeal carcinoma (NPC). Methods: We retrospectively analyzed the data of 839 patients with non-metastatic NPC recruited from two independent institutions. The training-set cohort and the external validation-set cohort was comprised of 459 and 380 patients from each institution, respectively. The optimal cut-off value of SII was determined, and a prognostic risk stratification model was developed based on the training cohort and further assessed in the validation cohort. The propensity score matching (PSM) method was applied to minimize the confounding effects of unbalanced covariables. Results: The optimal cut-off value of the SII in the training cohort was 686, which was confirmed using the validation cohort. Multivariate analysis showed that both before and after PSM, SII values > 686 were independently associated with worse progression-free survival (PFS) ratio in both cohorts (before PSM, P = 0.008 and P = 0.008; after PSM, P = 0.008 and P = 0.007, respectively). Based on the analysis of independent prognostic factors of SII and N stage, we developed a categorical risk stratification model, which achieved significant discrimination among risk indexes associated with PFS and distant metastasis-free survival (DMFS) in the training cohort. There was no significant difference in PFS between RT alone and combined therapies within the low- and intermediate-risk groups (5-year PFS, 77.5% vs. 75.3%, P = 0.275). Patients in the high-risk group who received concurrent chemoradiotherapy experienced superior PFS compared with those who received other therapies (5-year PFS, 64.9% vs. 40.3%, P = 0.003). Conclusion: Pretreatment SII predicts PFS of patients with non-metastatic NPC. Prognostic risk stratification incorporating SII is instructive for selecting individualized treatment.

Abstract Background To investigate the clinical characteristics of metachronous second primary malignancies (Met‐SPMs) and its impact on prognosis in hypopharyngeal carcinoma (HPC). Methods We reviewed 593 newly diagnosed HPC patients without invasive synchronous SPMs (Syn‐SPMs) who were treated in our cancer center between 2009 and 2019. According to the status during follow‐up, patients were classified into three groups: (a) without SPMs (No‐SPMs, n = 440), (b) with tumors in situ in the esophagus or stomach (Tis, n = 80), or (c) with Met‐SPMs (n = 73). Results The median follow‐up time for entire cohort (n = 593) was 66.7 months. Met‐SPMs were present in 12.3% of the cohort (73/593). The predominant site of SPMs was esophagus, followed by lung, oral cavity, thyroid, stomach, and oropharynx. In Met‐SPMs group, both index tumor and SPMs were the main causes of death. Tis group exhibited comparable 5‐year overall survival (OS) and disease‐specific survival (DSS) with that of No‐SPMs group. The Met‐SPMs group had similar 5‐year OS rate and better 5‐year DSS rate of 47.3% versus 43.6% (odds ratio [OR], 0.931; 95% confidence interval [CI], 0.681–1.274, p = 0.657) and 66.3% vs. 46.2% (OR, 0.600; 95% CI, 0.402–0.896, p = 0.012), respectively, compared with the No‐SPMs group. Conclusion The overall incidence of Met‐SPMs in HPC was 12.3%. The occurrence of Met‐SPMs does not jeopardize the survival outcome of HPC. Routine surveillance of Met‐SPMs was requisite for patients with HPC.

Abstract Purpose To define the clinical characteristics of irradiation-induced nasopharyngeal necrosis (INN) after intensity-modulated radiotherapy (IMRT) and identify the influence of treatment strategies on INN in primary nasopharyngeal carcinoma (NPC) patients. Patients and methods From 2008 to 2019, NPC patients pathologically diagnosed with INN after primary IMRT were reviewed. Those patients were matched with propensity scores for patients without INN in our center. The impact of treatment strategies on INN occurrence was assessed using univariate and multivariate logistic regression analysis. Results The incidence rate of INN was 1.9% among the primary NPC population, and 53 patients with INN were enrolled. Headache and foul odor were the main symptoms, and 71.7% of cases had pseudomembrane during or at the end of radiotherapy. All patients were in early or middle stage INN, and no one presented with skull-based osteoradionecrosis. Then 212 non-INN patients were included based on propensity scores match. Overall survival (p = 0.248) and progression-free survival (p = 0.266) curves were similar between the INN and non-INN groups. Treatment strategies including combining chemotherapy or molecular targeted therapy with radiotherapy were not associated with INN occurrence, while boost dose (OR 7.360; 95% CI 2.301–23.547; p = 0.001) was a predictor factor for it. However, the optimal threshold for an accumulated dose to predict INN's occurrence was failed to determine. Conclusion In the IMRT era, the severity of INN in primary NPC patients is lessened. This study showed that treatment strategies contributed little to develop INN, while the accumulated dose of radiation may relate to its occurrence.

BackgroundEpithelioid hemangioendothelioma (EHE) is an extremely uncommon malignant neoplasm that originates from vascular endothelial or pre-endothelial cells. In this report, we present the case of patient who was diagnosed with a primary giant EHE of the spine and underwent treatment with total en-bloc spondylectomy (TES).Case presentationA 43-year-old male patient with a history of he presented to our hospital with chronic and progressive back pain. Physical examination revealed weakened sensation of acupuncture and touch on the left costal arch, while relatively normal neurological functions were preserved. Radiological examinations identified a giant destructive soft tissue lesion occupying the T8 vertebral region, with moderate destruction of the pedicle and lamina, as well as the 7th left rib. A preoperative biopsy of the 8th vertebra resulted in a diagnosis of epithelioid hemangioendothelioma(EHE). Postoperative immunohistochemical and pathological reports confirmed the presence of EHE in the left ribs and T8 ribs. The patient underwent resection of the 7th left rib and posterior pedicle screw fixation with 8 pairs of screws and a titanium mesh cage. Subsequently, thoracic en bloc spondylectomy was performed on the T8 vertebra. The patient did not receive radiation or chemotherapy following surgery. Over a period of 3 years, the patient remained free of disease and relapse.ConclusionThe use of transarterial embolization with spherical embolic agents (TES) has been demonstrated to be a safe, effective, and reliable treatment option for hepatic epithelioid hemangioendothelioma (EHE). Nevertheless, it is crucial to conduct long-term follow-up of this patient in order to assess their clinical outcome.

Osteosarcoma is a highly aggressive cancer common in children and adolescents. There is still a lack of effective treatments for metastatic or recurrent osteosarcoma. The role of long non-coding RNAs (lncRNAs) in osteosarcoma has gradually attracted attention. Here, we identified lncRNAs that were abnormally expressed in metastatic osteosarcoma through analyzing the sequencing data of osteosarcoma tissues and selected upregulated lncRNA MELTF-AS1 for detailed study. The qRT-PCR analysis showed that the expression of MELTF-AS1 was increased in osteosarcoma tissues and cells, and the high expression of MELTF-AS1 indicated a poor prognosis of osteosarcoma patients. The high expression of MELTF-AS1 in osteosarcoma was partly due to the transcriptional activation of RREB1. The results of transwell assays, scratch wound healing assays, and the tail vein injection lung metastasis model demonstrated that knocking down MELTF-AS1 inhibited metastasis ability of osteosarcoma cells. Furthermore, the results of RNA pull-down assays, luciferase reporter assays, and RNA immunoprecipitation (RIP) assays revealed that MELTF-AS1 could regulate MMP14 expression through interaction with miR-485-5p. Our study suggested that MELTF-AS1 functioned as a pro-metastasis gene in osteosarcoma by upregulating MMP14 and that it could be a potential therapeutic and diagnostic target for osteosarcoma.

BackgroundKetamine is approved for antidepressant therapy, but evidence regarding its use in women with perinatal depression is lacking. Herein, we investigated the effects of low-dose ketamine in women with prenatal depressive symptoms and tested the feasibility of a future large randomized trial.MethodsThis was a randomized, double-blind, placebo-controlled pilot trial. Sixty-six women with prenatal depressive symptoms who were scheduled for elective cesarean delivery were randomized to receive either low-dose ketamine (0.5 mg/kg) or placebo (normal saline). The study drugs were intravenously infused over a 40-minute period after clamping the umbilical cord. The primary outcome was depression score assessed with the Edinburgh Postnatal Depression Scale at 48 h postpartum. Among other and safety outcomes, occurrence of nausea or vomiting was observed, pain intensity was assessed with the numeric rating scale. The feasibility of implementing the protocol was also evaluated.ResultsA total of 64 parturients were included in the intention-to-treat analysis. The depression score at 48 h did not differ between groups: median 9 (interquartile range 6 to 13) with ketamine vs. 8 (6 to 10) with placebo; median difference 1, 95% CI −1 to 3; P = 0.608. The pain intensity at 4 h postpartum was less severe in the ketamine group (median difference −1, 95% CI −1 to 0, P = 0.002). Among safety outcomes, intraoperative nausea or vomiting was less common in patients given ketamine (0.0% [0/33] with ketamine vs. 21.2% [7/33] with placebo, P = 0.011). Recruitment was satisfactory and the protocol was acceptable to participants and clinicians.ConclusionsA single low-dose ketamine infusion did not decrease the depression score at 2 days, but reduced intraoperative nausea and vomiting and lowered pain intensity at 4 h after cesarean delivery among women with prenatal depressive symptoms. The study protocol is feasible for a large randomized trial.Clinical Trial RegistrationThe study was registered with ClinicalTrials.gov (identifier: NCT03336541; 08/11/2017).

PurposeThis study aims to investigate the prognostic value of composition and spatial architecture of tumor-infiltrating lymphocytes (TILs) as well as PDL1 expression on TILs subpopulations in nasopharyngeal carcinoma (NPC).MethodsA total of 121 patients with NPC were included and divided into two groups: favorable (n = 68) and unfavorable (n = 53). The archived tumor tissues of the included patients were retrieved, and a tissue microarray was constructed. The density and spatial distribution of TILs infiltration were analyzed using the multiplex fluorescent immunohistochemistry staining for CD3, CD4, CD8, Foxp3, cytokeratin (CK), PDL1, and 4′,6-diamidino-2-phenylindole (DAPI). The infiltration density of TILs subpopulations and PDL1 expression were compared between the two groups. The Gcross function was calculated to quantify the relative proximity of any two types of cells. The Cox proportional hazards regression model was used to identify factors associated with overall survival (OS) and disease-free survival (DFS).ResultsThe densities of regulatory T-cells (Tregs), effector T-cells (Teffs), PDL1+ Tregs, and PDL1+ Teffs were significantly higher in patients with unfavorable outcomes. PDL1 expression on tumor cells (TCs) or overall TILs was not associated with survival. Multivariate analysis revealed that higher PDL1+ Tregs infiltration density was independently associated with inferior OS and DFS, whereas Tregs infiltration density was only a prognostic marker for DFS. Spatial analysis revealed that unfavorable group had significantly stronger Tregs and PDL1+ Tregs engagement in the proximity of TCs and cytotoxic T lymphocyte (CTLs). Gcross analysis further revealed that Tregs and PDL1+ Tregs were more likely to colocalize with CTLs. Moreover, increased GTC : Treg (Tregs engagement surrounding TCs) and GCTL : PDL1+ Treg were identified as independent factors correlated with poor outcomes.ConclusionTILs have a diverse infiltrating pattern and spatial distribution in NPC. Increased infiltration of Tregs, particularly PDL1+ Tregs, as well as their proximity to TCs and CTLs, correlates with unfavorable outcomes, implying the significance of intercellular immune regulation in mediating disease progression.

Abstract Speed and enhancement are the two most important metrics for anti-scattering light focusing by wavefront shaping (WS), which requires a spatial light modulator with a large number of modulation modes and a fast speed of response. Among the commercial modulators, the digital-micromirror device (DMD) is the sole solution providing millions of modulation modes and a pattern rate higher than 20 kHz. Thus, it has the potential to accelerate the process of anti-scattering light focusing with a high enhancement. Nevertheless, modulating light in a binary mode by the DMD restricts both the speed and enhancement seriously. Here, we propose a multi-pixel encoded DMD-based WS method by combining multiple micromirrors into a single modulation unit to overcome the drawbacks of binary modulation. In addition, to efficiently optimize the wavefront, we adopted separable natural evolution strategies (SNES), which could carry out a global search against a noisy environment. Compared with the state-of-the-art DMD-based WS method, the proposed method increased the speed of optimization and enhancement of focus by a factor of 179 and 16, respectively. In our demonstration, we achieved 10 foci with homogeneous brightness at a high speed and formed W- and S-shape patterns against the scattering medium. The experimental results suggest that the proposed method will pave a new avenue for WS in the applications of biomedical imaging, photon therapy, optogenetics, dynamic holographic display, etc.

Bipolar disorder (BD) is associated with a high risk of suicide. We used proton magnetic resonance spectroscopy (1H-MRS) to detect biochemical metabolite ratios in the bilateral prefrontal white matter (PWM) and hippocampus in 32 BD patients with suicidal ideation (SI) and 18 BD patients without SI, identified potential brain biochemical differences and used abnormal metabolite ratios to predict the severity of suicide risk based on the support vector machine (SVM) algorithm. Furthermore, we analyzed the correlations between biochemical metabolites and clinical variables in BD patients with SI. There were three main findings: (1) the highest classification accuracy of 88% and an area under the curve of 0.9 were achieved in distinguishing BD patients with and without SI, with N-acetyl aspartate (NAA)/creatine (Cr), myo-inositol (mI)/Cr values in the bilateral PWM, NAA/Cr and choline (Cho)/Cr values in the left hippocampus, and Cho/Cr values in the right hippocampus being the features contributing the most; (2) the above seven features could be used to predict Self-rating Idea of Suicide Scale scores (r = 0.4261, p = 0.0302); and (3) the level of neuronal function in the left hippocampus may be related to the duration of illness, the level of membrane phospholipid catabolism in the left hippocampus may be related to the severity of depression, and the level of inositol metabolism in the left PWM may be related to the age of onset in BD patients with SI. Our results showed that the combination of multiple brain biochemical metabolites could better predict the risk and severity of suicide in patients with BD and that there was a significant correlation between biochemical metabolic values and clinical variables in BD patients with SI.

Abstract Purpose Conditional survival (CS) and failure hazard estimations can provide important dynamic prognostic information for clinical decision‐making and surveillance counseling. The current study aimed to investigate the CS and dynamic failure hazard in non‐metastatic nasopharyngeal carcinoma (NPC) treated with intensity‐modulated radiotherapy (IMRT). Methods Conditional overall survival (COS) and progression‐free survival (CPFS) estimates adjusted for age and gender against each AJCC 8th stage were calculated. Multivariable Cox regression (MCR) models were fitted in the entire population at baseline and subsequently separate MCR models were fitted in patients who have maintained event‐free time of 1 to 10 years to generate respective hazard ratio (HR). Annual hazard rates of death and progression over 10 years for each stage were also estimated. Results A total of 1993 patients were eligible for analysis. The estimated 5‐year OS and PFS for entire cohort were 79.0% and 70.7% at initial diagnosis. After 5 years of event‐free follow‐up, additional 5‐year COS and CPFS increased to 85.9% and 85.5%, respectively. Stage I/II maintained dramatically favorable CS and low hazard (< 5%) of death and progression over time. Relative to stage I/II, stage III manifested non‐significantly higher failure hazard for the first 3 years of survivorship and approached to similar level of stage I/II afterwards. Stage IVA presented most impressive improvement in terms of both COS (∆=9.8%) and CPFS (∆ = 16.8%) whereas still drastically inferior to that of stage I‐III across all conditional time points. After 4 years of follow‐up, progression hazard of stage IVA became relatively steady of approximate 6%. Conclusions Survival prospect of non‐metastatic NPC improves over years with distinct dynamic patterns across stages, providing important implications for personalized decision‐making in terms of both clinical management and surveillance counseling. Stage‐dependent and hazard‐adapted clinical management and surveillance are warranted.

Abstract Oxysterol-binding protein-like 2 (OSBPL2), also known as oxysterol-binding protein-related protein (ORP) 2, is a member of lipid transfer protein well-known for its role in regulating cholesterol homeostasis. A recent study reported that OSBPL2/ORP2 localizes to lipid droplets (LDs) and is associated with energy metabolism and obesity. However, the function of OSBPL2/ORP2 in adipocyte differentiation is poorly understood. Here, we report that OSBPL2/ORP2 contributes to the developmental progression of preadipocytes. We found that OSBPL2/ORP2 binds to β-catenin, a key effector in the Wnt signaling pathway that inhibits adipogenesis. This complex plays a role in regulating the protein level of β-catenin only in preadipocytes, not in mature adipocytes. Our data further indicated that OSBPL2/ORP2 mediates the transport of β-catenin into the nucleus and thus regulates target genes related to adipocyte differentiation. Deletion of OSBPL2/ORP2 markedly reduces β-catenin both in the cytoplasm and in the nucleus, promotes preadipocytes maturation, and ultimately leads to obesity-related characteristics. Altogether, we provide novel insight into the function of OSBPL2/ORP2 in the developmental progression of preadipocytes and suggest OSBPL2/ORP2 may be a potential therapeutic target for the treatment of obesity-related diseases.

Background: Panax stipuleanatus represents a folk medicine for treatment of inflammation. However, lack of experimental data does not confirm its function. This article aims to investigate the analgesic and anti-inflammatory activities of triterpenoid saponins isolated from P. stipuleanatus. Methods: The chemical characterization of P. stipuleanatus allowed the identification and quantitation of two major compounds. Analgesic effects of triterpenoid saponins were evaluated in two models of thermal- and chemical-stimulated acute pain. Anti-inflammatory effects of triterpenoid saponins were also evaluated using four models of acetic acid–induced vascular permeability, xylene-induced ear edema, carrageenan-induced paw edema, and cotton pellet–induced granuloma in mice. Results: Two triterpenoid saponins of stipuleanosides R1 (SP-R1) and R2 (SP-R2) were isolated and identified from P. stipuleanatus. The results showed that SP-R1 and SP-R2 significantly increased the latency time to thermal pain in the hot plate test and reduced the writhing response in the acetic acid–induced writhing test. SP-R1 and SP-R2 caused a significant decrease in vascular permeability, ear edema, paw edema, and granuloma formation in inflammatory models. Further studies showed that the levels of inflammatory mediators, nitric oxide, malondialdehyde, tumor necrosis factor-α, and interleukin 6 in paw tissues were downregulated by SP-R1 and SP-R2. In addition, the rational harvest of three- to five-year-old P. stipuleanatus was preferable to obtain a higher level of triterpenoid saponins. SP-R2 showed the highest content in P. stipuleanatus, which had potential as a chemical marker for quality control of P. stipuleanatus. Conclusion: This study provides important basic information about utilization of P. stipuleanatus resources for production of active triterpenoid saponins.

Phenolic glycosides are the important bioactive molecules, and their bioavailability can be influenced by enzyme hydrolysis, such as β-glucosidases (EC3.2.1.21) and other glycosyl hydrolases (GHs). Wood rotting fungi possess a superfamily of GHs, but little attention has been paid to the GHs and their potential applications in biotransformation of phenolic glycosides. In this study, two GH3 gene family members of Trametes trogii S0301, mainly expressed in the carbon sources conversion stage were cloned, and TtBgl3 coded by T_trogii_12914 showed β-glucosidase activity toward 4-nitrophenyl β-D-glucopyranoside (pNPG). The recombinant TtBgl3 preferred an intermediately neutral optimum pH with >80% of the maximum activity at pH 5.0–7.0 and was stable at a wide range of pH (5.0–10.0). Phenolic glycosides transformation experiments showed that TtBgl3 was a dual-activity enzyme with both activities of aryl-β-D-glucosidase and β-glucuronidase, and could hydrolyze the β-glucoside/glucuronide bond of phenolic glycosides. Under optimized conditions, the recombinant TtBgl3 had much higher transformation efficiency toward the β-glucoside bond of gastrodin, esculin and daidzin than β-glucuronide bond of baicalin, with the transformation rate of 100 and 50%, respectively. Our homology modeling, molecular docking, and mutational analysis demonstrated that His85 and Lys467 in the acceptor-binding pocket of TtBgl3 were the potential active sites. The point mutation of His85 and Lys467 leads to the significantly impaired catalytic activity toward pNPG and also the weak transformation efficiency toward gastrodin. These findings provide insights for the identification of novel GH3 β-glucosidases from T. trogii and other wood-rotting fungi. Furthermore, TtBgl3 might be applied as green and efficient biological catalysts in the deglycosylation of diverse phenolics to produce bioactive glycosides for drug discovery in the future.

ObjectivesTo analyze the incidence and spread of lymph node metastasis (LNM) and the effectiveness of prophylactic neck irradiation in patients with SNSCC.MethodsA total of 255 patients with SNSCC were retrospectively reviewed. The LNM spread pattern was revealed. The clinical parameters related to LNM, and the prognostic value of elective neck irradiation (ENI) were assessed. A 1:1 matching with propensity scores was performed between ENI group and observation (OBS) group.ResultsThe initial LNM rate was 20.8%, and the regional recurrence (RR) rate was 7.5%. Lymphatic spreading in SNSCC followed the common trajectories: a. level Ib ➔ level II ➔ level Va/level III/IV lymph nodes (LNs); b. retropharyngeal lymph nodes (RPLNs) ➔ level II LNs. The most frequently involved site was level II LNs (16.1%), followed by level Ib LNs (10.2%), RPLNs (4.7%), level III LNs (3.2%), level Va LNs (1.6%), level IVa LNs (1.4%) and level VIII LNs (0.8%). The median follow-up time was 105 months. The 5-year overall survival (OS) was 55.7% for N0 patients and 38.5% for patients with initial N+ or N- relapse (p = 0.009). After PSM, the 5-year regional recurrence-free survival was 71.6% and 94.7% (p = 0.046) in OBS and ENI group, respectively. The multivariate analysis showed that ENI (p = 0.013) and absence of nasopharynx involvement (p = 0.026) were associated with a significantly lower RR rate.ConclusionsPatients with LNM had poorer survival than those who never experienced LNM. Lymphatic spread in SNSCC followed predictable patterns. ENI effectively reduced the RR rate in patients at high risk.

Abstract Background Bone turnover and metabolic indicators are related to age and gender. Age and gender should be matched in subjects in disease control research of bone turnover and metabolism, but strict matching of gender and age increases the difficulty and cost of the research. Therefore, the aim of this study was to solve it is necessary to strictly match age and gender in clinical research in bone metabolism. Methods A cross-sectional study was conducted from the data were extracted from the HIS of ZhuJiang Hospital. Data relating to seven bone turnover and metabolic indicators from 1036 patients between January 2018 and October 2019 were analyzed. Results P1NP, β-CTx and 25(OH)D were significant different in individuals younger than 20 years of age. ALP was significantly higher in those under 20 years of age and lower at age 20–39 compared with other age groups. The concentrations of Ca and P were different among the groups aged 0–19, 20–39, and 40–59 years of age groups but exhibited no difference above 60 years of age. PTH expression was not dependent on age. P1NP, β-CTx and PTH concentrations were not significantly different between the genders within the same age group. ALP was significantly different between genders within the age range 20–59 years. Ca and 25(OH)D were significantly different between the genders for those older than 60. Serum P was significantly different in the two genders for those aged 40–79. Patients received both alfacalcidol and calcium treatment differently from the others in P1NP, β-CTx, Serum Ca, P and ALP. Conclusion P1NP and β-CTx were highly correlated with age. If these two indictors require analysis in a case control study, the patients and controls should be strictly matched by age under 20 years. The demarcation point for ALP was 40 years of age. Ca and P were strongly recommended strict matching according to age in disease research. The difference in P1NP, β-CTx, 25(OH)D and ALP between genders depends on age differences. Medication history should be considered in bone turnover and metabolic clinical research.

Abstract Background The aim of this study is to evaluate the efficacy of different treatment strategies and the potential prognostic factors of esthesioneuroblastoma (ENB). Materials and methods Between April 1984 and December 2018, 138 patients with non-metastatic ENB were retrospectively analyzed. The treatment modalities mainly included surgery alone (n = 7), radiotherapy alone (n = 33), concurrent chemoradiotherapy (n = 17), surgery combined with current chemoradiotherapy (n = 32), and surgery plus radiotherapy (n = 49). Results The median follow-up time for the entire cohort was 61 months (range, 4–231 months). The 5-year overall survival (OS), locoregional failure-free survival (LRFFS), and distant metastasis-free survival (DMFS) rate were 69.6, 78.0 and 73.9%, respectively. Surgery combined with radiotherapy elicited superior survival results, and the combination of surgery and current chemoradiotherapy achieved the best prognoses for all patients, patients with advanced Kadish disease, patients receiving intensity modulated radiation therapy and those with positive surgical margin. Univariate analysis identified orbital invasion and treatment modalities were predictors for OS, LRFFS and DMFS. Lymph node metastasis was associated with OS and DMFS, but not LRFFS. Intracranial invasion, advanced Kadish stage and not receiving concurrent chemotherapy were also predictive of lower OS. Multivariate analyses indicated that lymph node metastasis was an independent prognostic factor affecting DMFS, whereas treatment modalities was independent prognostic factors for OS and LRFFS. Conclusion Orbital invasion, intracranial invasion, lymph node metastasis and advanced Kadish disease at initial diagnosis were significantly associated with inferior prognosis. Regarding the treatment modality, the optimal strategy remined surgery with radiotherapy-based multimodality treatment. The concurrent chemoradiotherapy may play a more beneficial role.

Abstract Background We developed a computational model integrating clinical data and imaging features extracted from contrast-enhanced computed tomography (CECT) images, to predict lymph node (LN) metastasis in patients with pancreatic ductal adenocarcinoma (PDAC). Methods This retrospective study included 159 patients with PDAC (118 in the primary cohort and 41 in the validation cohort) who underwent preoperative contrast-enhanced computed tomography examination between 2012 and 2015. All patients underwent surgery and lymph node status was determined. A total of 2041 radiomics features were extracted from venous phase images in the primary cohort, and optimal features were extracted to construct a radiomics signature. A combined prediction model was built by incorporating the radiomics signature and clinical characteristics selected by using multivariable logistic regression. Clinical prediction models were generated and used to evaluate both cohorts. Results Fifteen features were selected for constructing the radiomics signature based on the primary cohort. The combined prediction model for identifying preoperative lymph node metastasis reached a better discrimination power than the clinical prediction model, with an area under the curve of 0.944 vs. 0.666 in the primary cohort, and 0.912 vs. 0.713 in the validation cohort. Conclusions This pilot study demonstrated that a noninvasive radiomics signature extracted from contrast-enhanced computed tomography imaging can be conveniently used for preoperative prediction of lymph node metastasis in patients with PDAC.

Psoriatic arthritis (PsA) is a unique immune-mediated disease with cutaneous and osteoarticular involvement. However, only a few studies have explored the susceptibility of osteoarticular involvement in psoriasis (Ps) at the genetic level. This study investigated the biomarkers associated with osteoarticular participation and potential shared molecular mechanisms for PsA and ankylosing spondylitis (AS).MethodsThe RNA-seq data of Ps, PsA, and AS in the Gene Expression Omnibus (GEO) database were obtained. First, we used the limma package and the weighted gene co-expression network analysis (WGCNA) to identify the potential genes related to PsA and AS. Then, the shared genes in PsA and AS were performed using the GO, KEGG, and GSEA analyses. We also used machine learning to screen hub genes. The results were validated using external datasets and native cohorts. Finally, we used the CIBERSORT algorithm to estimate the correlation between hub genes and the abundance of immune cells in tissues.ResultsAn overlap was observed between the PsA and AS-related modules as 9 genes. For differentially expressed genes in AS and PsA, only one overlapping gene was found (COX7B). Gene enrichment analysis showed that the above 9 genes might be related to the mRNA surveillance pathway. The GSEA analyses showed that COX7B was involved in adaptive immune response, cell activation, etc. The PUM1 and ZFP91, identified from the support vector machine, had preferable values as diagnostic markers for osteoarticular involvement in Ps and AS (AUC > 0.7). Finally, CIBERSORT results showed PUM1 and ZFP91 involvement in changes of the immune microenvironment.ConclusionFor the first time, this study showed that the osteoarticular involvement in psoriasis and AS could be mediated by the mRNA surveillance pathway-mediated abnormal immunologic process. The biological processes may represent the cross talk between PsA and AS. Therefore, PUM1 and ZFP91 could be used as potential biomarkers or therapeutic targets for AS and Ps patients.

Achieving high conductivity in n-type AlGaN of deep ultraviolet light-emitting diodes is still a challenge nowadays. In the Lei–Ting equilibrium equation method framework, a four-layer quantum well with n-Al0.7Ga0.3N barriers and an Al0.55Ga0.45N/AlxGa1−xN bi-component well could obtain a much higher electron mobility μT than that in a single-component quantum well over a relatively broad Al content range 0.56 < x < 0.68. While the built-in electric field induces strong confinement, pushing the electron to the interface, the optical phonon mode at this interface could be component-modulated to disappear due to the ternary mixed crystal effect. A significant enhancement of electron mobility can be achieved by avoiding the scattering from optical phonons at the interface where the electron gathers. The optical phonon limited μT could reach 7966 cm2/V s at x = 0.58, which is almost five times of 1518 cm2/V s in the case of x = 0.55 and ten times of 822 cm2/V s for x = 0.70. Such a step-shaped quantum well with high electron mobility could be an alternate or insert layer to the high Al content n-layer to alleviate the current crowding.

Panax notoginseng (Burk.) F. H. Chen is a Chinese medicinal plant of the Araliaceae family used for the treatment of cardiovascular and cerebrovascular diseases in Asia. P. notoginseng is vulnerable to root rot disease, which reduces the yield of P. notoginseng. In this study, we analyzed the rhizosphere soil and root endophyte microbial communities of P. notoginseng from different geographical locations using high-throughput sequencing. Our results revealed that the P. notoginseng rhizosphere soil microbial community was more diverse than the root endophyte community. Rhodopseudomonas, Actinoplanes, Burkholderia, and Variovorax paradoxus can help P. notoginseng resist the invasion of root rot disease. Ilyonectria mors-panacis, Pseudomonas fluorescens, and Pseudopyrenochaeta lycopersici are pathogenic bacteria of P. notoginseng. The upregulation of amino acid transport and metabolism in the soil would help to resist pathogens and improve the resistance of P. notoginseng. The ABC transporter and gene modulating resistance genes can improve the disease resistance of P. notoginseng, and the increase in the number of GTs (glycosyltransferases) and GHs (glycoside hydrolases) families may be a molecular manifestation of P. notoginseng root rot. In addition, the complete genomes of two Flavobacteriaceae species and one Bacteroides species were obtained. This study demonstrated the microbial and functional diversity in the rhizosphere and root microbial community of P. notoginseng and provided useful information for a better understanding of the microbial community in P. notoginseng root rot. Our results provide insights into the molecular mechanism underlying P. notoginseng root rot and other plant rhizosphere microbial communities.

Abstract Purpose The purpose of this study was to determine the associations between pathological complete remission (pCR) and clinical outcomes in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) who received preoperative radiotherapy or chemoradiotherapy in a phase 3 clinical study. Methods A total of 222 newly diagnostic stage III/IVM0 HNSCC patients were randomly assigned to a preoperative concurrent chemoradiotherapy group (n = 104) or preoperative radiotherapy alone group (n = 118). Over a mean follow-up of 59 months, 72 patients were defined as non-responders to preoperative therapy and subsequently underwent resection of the primary lesion with or without neck dissection. The relationship between the pathological tumor response of the primary lesion and treatment prognosis was analyzed. Kaplan–Meier and Cox regression multivariate analyses were performed to evaluate the impact of pCR on local control (LC), overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS). Results Among the 72 non-responders, 25 patients, 10 in the chemotherapy group and 15 in the radiotherapy group, achieved pCR. The 5-year LC, OS, PFS, and DMFS of pCR patients and non-pCR patients were 93.2% vs. 67.7% (p = 0.007), 83.3% vs. 39.7% (p = 0.0006), 76.1% vs. 44.0% (p = 0.009), and 90.4% vs. 56.3% (p = 0.005), respectively. In multivariate analysis, pCR is also an independent prognostic factor in prognosis, with statistically significant differences. Conclusion pCR after preoperative radiotherapy or concurrent chemoradiotherapy is a good prognostic factor in locally advanced HNSCC. Trial registration Number:ChiCTR-TRC-114004322 Date:05 Mar, 2014

Abstract Backgrounds To assess the changes in individual retinal layer thickness and visual function associated with gains in visual acuity after an intravitreal conbercept injection in the diabetic macular edema (DME) on spectral domain optical coherence tomography (SD-OCT) and microperimetry during 1-year follow-up. Methods Retrospective observational study. Twenty patients with clinically significant DME in the study eye were imaged by SD-OCT every 3 months and MP1 microperimeter in the third month while receiving anti-vascular endothelial growth factor (VEGF) (conbercept) treatment. In each patient, seven retinal layers were segmented in 98 scans covering a 6 mm × 6 mm area of the macula at baseline and during 1 year of treatment. An automatic, full-threshold microperimetry of the central field (10° × 10°, 40 stimulated points) with the MP1 microperimeter. Thickness and microperimetry changes were quantitatively measured and evaluated for their correlation with increases in visual acuity. Results Although thicknesses of the inner nuclear layer (INL) and the outer nuclear layer (ONL) were reduced the most after treatment (p

An accurate recognition of a dimensional variation pattern is very important for producing high-quality body-in-white (BIW). The wide application of optical coordination measurement machines (OCMM) in vehicle factory provided massive online dimensional data for the variation pattern recognition. However, the massive serially correlated or autocorrelated and 100% measurement data generated from the OCMM challenge the traditional statistical process control (SPC) technology and the common variation recognition approaches. This paper presents a novel deep-learning method, long short-term memory neural network (LSTM NN), to recognize the variation pattern of the BIW OCMM online measurement data. A comparative study between the backpropagation neural network (BP NN) and the LSTM NN was implemented, and the practicability of the proposed intelligent method was demonstrated by a case study. With the efficient use of time series information, the LSTM NN has a good performance in variation patterns' recognition and high practicability in improving the quality of the BIW.

Progranulin is closely related to neuronal survival in a neuroinflammatory mouse model and attenuates inflammatory reactions. Atsttrin is an engineered protein composed of three progranulin fragments and has been shown to have an effect similar to that of progranulin. Atsttrin has anti-inflammatory actions in multiple arthritis mouse models, and it protects against further arthritis development. However, whether Atsttrin has a role in neuroinflammation remains to be elucidated. In this study, we produced a neuroinflammatory mouse model by intracerebroventricular injection of 1 μL lipopolysaccharide (10 μg/μL). Atsttrin (2.5 mg/kg) was administered via intraperitoneal injection every 3 days over a period of 7 days before intracerebroventricular injection of 1 μL lipopolysaccharide (10 μg/μL). In addition, astrocyte cultures were treated with 0, 100 or 300 ng/mL lipopolysaccharide, with 200 ng/mL Atsttrin simultaneously. Immunohistochemistry, enzyme-linked immunosorbent assay and real-time reverse transcription-polymerase chain reaction were performed to examine the protein and mRNA levels of inflammatory mediators and to assess activation of the nuclear factor kappa B signaling pathway. Progranulin expression in the brain of wild-type mice and in astrocyte cultures was increased after lipopolysaccharide administration. The protein and mRNA expression levels of tumor necrosis factor-α, interleukin-1β and inducible nitric oxide synthase were increased in the brain of progranulin knockout mice after lipopolysaccharide administration. Atsttrin treatment reduced the lipopolysaccharide-induced increase in the protein and mRNA levels of tumor necrosis factor-α, interleukin-1β, matrix metalloproteinase-3 and inducible nitric oxide synthase in the brain of progranulin knockout mice. Atsttrin also reduced the expression of cyclooxygenase-2, inducible nitric oxide synthase and matrix metalloproteinase 3 mRNA in lipopolysaccharide-treated astrocytes in vitro, and decreased the concentration of tumor necrosis factor a and interleukin-1β in the supernatant. Furthermore, Atsttrin significantly reduced the levels of phospho-nuclear factor kappa B inhibitor a in the brain of lipopolysaccharide-treated progranulin knockout mice and astrocytes, and it decreased the expression of nuclear factor kappa B2 in astrocytes. Collectively, our findings show that the anti-neuroinflammatory effect of Atsttrin involves inhibiton of the nuclear factor kappa B signaling pathway, and they suggest that Atsttrin may have clinical potential in neuroinflammatory therapy. The study was approved by the Animal Ethics Committee of Qilu Hospital of Shandong University, China (approval No. KYLL-2015(KS)-088) on February 10, 2015.