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Osteoporosis is a chronic metabolic disease that increases bone fragility and, leads to severe osteoporotic fractures. In recent years, the use of high-throughput omics to explore physiological and pathological biomarkers related to bone metabolism has gained popularity. In this review, we first briefly review the technical approaches of proteomics. Additionally, we summarize the relevant literature in the last decade to provide a comprehensive overview of advances in human proteomics related to osteoporosis. We describe the specific roles of various proteins related to human bone metabolism, highlighting their potential as biomarkers for risk assessment, early diagnosis and disease course monitoring in osteoporosis. Finally, we outline the main challenges currently faced by human proteomics in the field of osteoporosis and offer suggestions to address these challenges, to inspire the search for novel osteoporosis biomarkers and a foundation for their clinical translation. In conclusion, proteomics is a powerful tool for discovering osteoporosis-related biomarkers, which can not only provide risk assessment, early diagnosis and disease course monitoring, but also reveal the underlying mechanisms of disease and provide key information for personalized treatment. The translational potential of this article: This review provides an insightful summary of recent human-based studies on osteoporosis-associated proteomics, which can aid the search for novel osteoporosis biomarkers based on human proteomics and the clinical translation of research results.

Abstract Swin Transformer is an important work among all the attempts to reduce the computational complexity of Transformers while maintaining its excellent performance in computer vision. Window-based patch self-attention can use the local connectivity of the image features, and the shifted window-based patch self-attention enables the communication of information between different patches in the entire image scope. Through in-depth research on the effects of different sizes of shifted windows on the patch information communication efficiency, this article proposes a Dual-Scale Transformer with double-sized shifted window attention method. The proposed method surpasses CNN-based methods such as U-Net, AttenU-Net, ResU-Net, CE-Net by a considerable margin (Approximately 3% $$\sim$$ ∼ 6% increase), and outperforms the Transformer based models single-scale Swin Transformer(SwinT)(Approximately 1% increase), on the datasets of the Kvasir-SEG, ISIC2017, MICCAI EndoVisSub-Instrument and CadVesSet. The experimental results verify that the proposed dual scale shifted window attention benefits the communication of patch information and can enhance the segmentation results to state of the art. We also implement an ablation study on the effect of the shifted window size on the information flow efficiency and verify that the dual-scale shifted window attention is the optimized network design. Our study highlights the significant impact of network structure design on visual performance, providing valuable insights for the design of networks based on Transformer architectures.

Background: Idiosyncratic drug-induced liver injury (IDILI) is a serious side effect of drugs, Epimedii Folium (EF) is unequivocally implicated in idiosyncratic liver injury onset, potentially due to its ability to perturb the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. Fructus Ligustri Lucidi (FLL), a frequently used medicinal combination with EF, has not yet been investigated for its ability to ameliorate EF-associated hepatotoxicity. Aims and Objectives: Study on the mechanism of compatibility of FLL to alleviate liver injury caused by EF. Materials and Methods: Western blot was used to determine the expression of related proteins, ELISA was used to detect the secretion of related inflammatory factors IL-1β, IL-18, IL-6 and TNF-α, liver injury indexes were detected and liver pathological tissue staining was used to evaluate the liver injury. Results: Our results demonstrated that EF exerted a particular augmenting effect on the stimulation of the NLRP3 inflammasome mediated by nigericin or ATP, whereas FLL suppressed the NLRP3 inflammasome stimulation. Furthermore, an equal EF to FLL ratio significantly reduced the stimulatory effects of EF. Moreover, EF has the potential to induce hepatic injury and augment pro-inflammatory cytokine synthesis in rats subjected to LPS. However, when combined with FLL, the detrimental effects of EF were mitigated. Conclusions: FLL possesses the capacity to attenuate EF-associated hepatotoxicity by suppressing EF-triggered NLRP3 inflammasome activation. Thus, FLL holds promise for improving the clinical safety profile of EF, shedding light on the potential of compatibility and detoxification theories in traditional Chinese medicine.

Abstract Background Nonalcoholic fatty liver disease (NAFLD) is associated with disordered lipid and iron metabolism. Our previous study has substantiated the pivotal role of Caveolin-1 (Cav-1) in protecting hepatocytes and mediating iron metabolism in the liver. This study aimed to explore the specific mechanisms underlying the regulation of iron metabolism by Cav-1 in NAFLD. Methods Hepatocyte-specific Cav-1 overexpression mice and knockout mice were used in this study. Cav-1-knockdown of RAW264.7 cells and mouse primary hepatocytes were performed to verify the changes in vitro. Moreover, a high-fat diet and palmitic acid plus oleic acid treatment were utilized to construct a NAFLD model in vivo and in vitro, respectively, while a high-iron diet was used to construct an in vivo iron overload model. Besides, iron concentration, the expression of Cav-1 and iron metabolism-related proteins in liver tissue or serum were detected using iron assay kit, Prussian blue staining, Western blotting, immunofluorescence staining, immunohistochemical staining and ELISA. The related indicators of lipid metabolism and oxidative stress were evaluated by the corresponding reagent kit and staining. Results Significant disorder of lipid and iron metabolism occurred in NAFLD. The expression of Cav-1 was decreased in NAFLD hepatocytes (P

Background: With our growing insight into the molecular heterogeneity and biological characteristics of breast cancer, individualized treatment is the future of cancer treatment. In this prospective Fudan University Shanghai Cancer Center Breast Cancer Precision Platform Series study – neoadjuvant therapy (FASCINATE-N) trial, we classify breast cancer patients using multiomic characteristics into different subtypes to evaluate the efficacy of precision-based targeted therapies compared to standard neoadjuvant chemotherapy. Methods and design: The FASCINATE-N trial is a prospective, randomized, precision-based umbrella trial that plans to enroll 716 women with early breast cancer. After enrollment, patients will first be divided into three groups: hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)−, HER2+, and HR−/HER2−. The HR+/HER2− patients are further stratified using fusion and clustering of similarity network fusion (SNF) algorithm into four subtypes; HER2+ patients are divided into HR+/HER2+ and HR−/HER2+ subtypes; and HR−/HER2− patients are stratified using the Fudan University Shanghai Cancer Center classification. For the assignment of drugs to patients, Bayesian methods of adaptive randomization will be used. The primary endpoint is pathological complete response rate; secondary endpoints include 3-year invasive disease-free survival, overall response rate, and toxicities according to common terminology criteria for adverse events (CTCAE) scale version 4.0 and the ratio of patients with complete cell cycle arrest (Ki67 < 2.7%) in HR+/HER2+ breast cancer. Discussion: The goal of our trial is to test the efficacy of our subtyping-based treatment in a neoadjuvant setting and to conduct a pilot study into the efficacy of targeted therapies within each precision-based subtype. The precision-based treatment arm can be updated with the refinement of our subtyping method, the discovery of new targets, and the development of novel targeted drugs. Our trial offers a unique opportunity to provide patients with individualized neoadjuvant therapy and test promising novel treatments that may further benefit patients. Trial registration: ClinicalTrials.gov identifier: NCT05582499 ( https://classic.clinicaltrials.gov/ct2/show/NCT05582499 ).

Background: Intestinal mucositis (IM) is characterized by damage to the intestinal mucosa resulting from inhibition of epithelial cell division and loss of renewal capacity following anticancer chemotherapy and radiotherapy. Cytarabine (Ara-C), the main chemotherapy drug for the treatment of leukemia and lymphoma, is a frequent cause of IM. Guiqi Baizhu prescription (GQBZP) is a traditional Chinese medicine with anti-cancer and anti-inflammatory effects. Purpose: To determine if GQBZP can ameliorate Ara-C induced IM and identify and characterize the pharmacologic and pharmacodynamic mechanisms. Study design and methods: IM was induced in mice with Ara-C and concurrently treated with orally administered GQBZP. Body weight and food intake was monitored, with HE staining to calculate ileal histomorphometric scoring and villus length/crypt depth. Immunoblotting was used to detect intestinal tissue inflammatory factors. M1 macrophages (M1) were labeled with CD86 by flow cytometry and iNOS + F4/80 by immunofluorescence. Virtual screening was used to find potentially active compounds in GQBZP that targeted JAK2. In vitro, RAW264.7 cells were skewed to M1 macrophage polarization by lipopolysaccharide (LPS) and interferon-γ (INF-γ) and treated orally with GQBZP or potential active compounds. M1 was labeled with CD86 by flow cytometry and iNOS by immunofluorescence. ELISA was used to detect inflammatory factor expression. Active compounds against JAK2, p-JAK2, STAT1 and p-STAT1 were identified by western blotting and HCS fluorescence. Molecular dynamics simulations and pharmacokinetic predictions were carried out on representative active compounds. Results: Experimental results with mice in vivo suggest that GQBZP significantly attenuated Ara-C-induced ileal damage and release of pro-inflammatory factors by inhibiting macrophage polarization to M1. Molecular docking was used to identify potentially active compounds in GQBZP that targeted JAK2, a key factor in macrophage polarization to M1. By examining the main components of each herb and applying Lipinski’s rules, ten potentially active compounds were identified. In vitro experimental results suggested that all 10 compounds of GQBZP targeted JAK2 and could inhibit M1 polarization in RAW264.7 cells treated with LPS and INF-γ. Among them, acridine and senkyunolide A down-regulated the expression of JAK2 and STAT1. MD simulations revealed that acridine and senkyunolide A were stable in the active site of JAK2 and exhibited good interactions with the surrounding amino acids. Conclusions: GQBZP can ameliorate Ara-C-induced IM by reducing macrophage polarization to M1, and acridine and senkyunolide A are representative active compounds in GQBZP that target JAK2 to inhibit M1 polarization. Targeting JAK2 to regulate M1 polarization may be a valuable therapeutic strategy for IM.

Abstract Background Complex lower limb reconstruction due to severe trauma remains a challenge for reconstructive surgeons. Here, we introduce a modified donor blood flow-preserved cross-leg anterolateral thigh flap procedure and evaluate its clinical efficacy. Methods Between January 2013 and December 2019, 22 patients (range 10 to 64 years old) with unilateral lower limb injury underwent modified donor blood flow-preserved cross-leg anterolateral thigh flap procedures. Among them, 16 cases were traffic accidents, 5 cases were persistent ulcers, and 1 case was a degloving injury. The arterial pedicle of the flap was prepared in a Y-shaped fashion and microanastomosed to the posterior tibial artery of intact leg in a flow-through style. A split-thickness skin graft was applied to wrap the vascular pedicle after anastomosis. The flap was designed in a single or bilobed fashion according to the shape of the tissue defect. The operation time, the intraoperative blood loss and the length of hospital stays were recorded. The vascular pedicle was divided 4 weeks after anastomosis. Doppler ultrasound was performed to evaluate the blood flow of the donor posterior tibial artery during postoperative follow-up. Results All 22 flaps survived. The tissue defects ranged from 12 × 6 to 21 × 18 cm2. The flap sizes ranged from 14 × 7.5 to 24 × 21 cm2. The average operation time, intraoperative blood loss and length of hospital stays were 6.73 ± 1.49 h, 280.95 ± 59.25 ml and 30.55 ± 2.52 days, respectively. Eighteen flaps were designed in a single fashion, while four were in bilobed fashion. Twenty patients underwent fasciocutaneous flap transplantations, while two underwent musculocutaneous flap transplantations. Two cases developed local lysis of the flap which healed after further debridement. Direct suture of the incision after flap harvest was performed in 16 cases, while additional full-thickness skin grafting was performed in the remaining 6 cases. Further bone transport procedures were performed in 15 patients who had severe tibia bone defects. The blood flow of donor posterior tibial artery was confirmed in all patients during follow-ups. All patients recovered flap sensation at the final follow-up. The postoperative follow-ups ranged from 18 to 84 months, and no long-term complications were observed. Conclusions The modified donor blood flow-preserved cross-leg anterolateral thigh flap procedure is an ideal method to repair severe lower limb trauma with tibial artery occlusion which avoids sacrificing the major artery of the uninjured lower limb.

Objective: This study aims to investigate the status of fertility preservation (FP) in young breast cancer patients. Materials and methods: A clinical database of six women with breast cancer who wished to undergo FP before starting chemotherapy were analyzed between January 2018 and December 2019 in our hospital. Among the six women, three were unmarried and three were married. Results: Three patients chose oocyte preservation and obtained 23, 7, and 17 MII oocytes, respectively. One patient chose embryo freezing, and three embryos were frozen. Fertility preservation failed for two patients, one of whom had premature ovulation, while the other patient abandoned egg retrieval on the human chorionic gonadotropin (HCG) day. Conclusion: The present results indicate that oocyte and embryo cryopreservation are effective optional methods for young breast cancer patients. However, a lack of knowledge, the urgency of cancer treatment, and financial constraints are causes for a low access rate regarding this process.

BackgroundPulmonary artery stenosis is often associated with congenital heart disease. The aim of the study was to evaluate the efficacy and safety of stenting for branch pulmonary artery stenosis using a biodegradable nitride iron stent (IBS® Angel™) and right ventricular systolic and diastolic function.MethodsFrom July 2021 to February 2022, a total of 11 cases (ages ranged from 36 to 86 months old) were included in this pre and post-intervention, prospective, cohort and preclinical study. All cases underwent transthoracic echocardiographic (TTE), chest radiography, along with computed tomography (256-slice scanner, multiple-detector) and right heart catheterization. Different types of biodegradable nitride iron stents were implanted. TTE was performed serially 1 day, 1 month and 3 months after the procedure to evaluate the rate of restenosis and right ventricular function.ResultsStenting was successful in 11 patients. There were no major adverse cardiovascular events related to the device or to the procedure. Blood perfusion in the branch pulmonary artery was improved immediately. At follow-up, there was no significant restenosis that required re-intervention. None of the patients suffered from in-stent thrombosis, vascular embolism, stent displacement or heart failure. Compared with normal values, there were statistical with regards to FAC, E/A and E′/A′. Furthermore, we found that TAPSE correlated significantly with pulsed Doppler S wave (p = 0.008) and left ventricular ejection fraction (p < 0.01). The early trans-tricuspid inflow velocities E/E′ (tissue doppler at the lateral tricuspid annulus) correlated significantly with E′/A′ (p = 0.009). FAC and E′/A′ were statistically different from those prior to stenting (p = 0.041 and p = 0.035) when tested one month postoperatively. At three months postoperatively, only E/A showed a statistical difference (p = 0.015).ConclusionOur analysis suggests that biodegradable nitride iron stents are feasible, safe, and effective in children. Some small improvements were observed in right ventricular systolic and diastolic function after successful transcatheter intervention, although change was not statistically significant due to the small sample number. (A clinical Trial to Evaluate the Safety and Efficacy of IBS Angel in Patients With Pulmonary Artery Stenosis (IRIS); NCT04973540).

Abstract Background The present study aims to use two different kinds of filling materials, oxidized regenerated cellulose and gelatin sponge, to repair defects of breast-conserving surgery due to breast cancer, and compare the clinical efficacy, cosmetic effect and complication rate among groups. Methods A total of 125 patients, who had breast -conserving surgery due to breast cancer, were enrolled into the present study. Postoperative efficacy was assessed by a doctor and patient, according to the Harvard/NSABP/RTOG Breast Cosmetic Grading Scale. Results Among these patients, 41 patients received conventional breast-conserving surgery, and 84 patients received breast-conserving surgery plus filling implantation (41 patients in the oxidized regenerated cellulose group and 43 patients in the gelatin sponge group). All patients had small to medium sized breasts (cup size A and B). The average weight of tumor tissues was 56.61 ± 11.57 g in the conventional breast-conserving surgery group, 58.41 ± 8.53 g in the oxidized regenerated cellulose group, and 58.77 ± 9.90 g in the gelatin sponge group. The difference in pathological factors, average operation time, length of stay and local infection rate was not statistically significant among the three groups. 18 patients in the oxidized regenerated cellulose group and 15 patients in the gelatin sponge group were evaluated to have a good cosmetic effect by the surgeon and patient, while 12 patients in the conventional breast-conserving surgery group were evaluated to be have good cosmetic effect by the surgeon and patient. The cosmetic effects in the oxidized regenerated cellulose group and gelatin sponge group were comparable, and these were superior to those in the conventional breast-conserving surgery group. Conclusion The use of oxidized regenerated cellulose and gelatin sponge is a feasible approach for defect repair after breast-conserving surgery.

Clear cell renal cell carcinoma (ccRCC) is the most common histological and devastating subtype of renal cell carcinoma. Necroptosis is a form of programmed cell death that causes prominent inflammatory responses. miRNAs play a significant role in cancer progression through necroptosis. However, the prognostic value of necroptosis-related miRNAs remains ambiguous. In this study, 39 necroptosis-related miRNAs (NRMs) were extracted and 17 differentially expressed NRMs between normal and tumor samples were identified using data form The Cancer Genome Atlas (TCGA). After applying univariate Cox proportional hazard regression analysis and LASSO Cox regression model, six necroptosis-related miRNA signatures were identified in the training cohort and their expression levels were verified by qRT-PCR. Using the expression levels of these miRNAs, all patients were divided into the high- and low-risk groups. Patients in the high-risk group showed poor overall survival (P

Gastric cancer (GC) is a globally important disease. Targeted therapies licensed to treat gastric cancer include trastuzumab, which targets HER2, and nivolumab or pembrolizumab, which block PD-1/PD-L1. The main challenge of tumor molecule-targeted drugs is resistance. Based on the multicomponent and multitarget characteristics of Traditional Chinese Medicine (TCM) and our previous research on Guiqi Baizhu Prescription (GQBZP) in targeting HER2/PD-L1, we used different cell models to verify the effect of quercetin targeting of HER2 and formononetin targeting of PD-L1. The results show that quercetin can inhibit MKN-45 cell proliferation by targeting HER2 to inhibit the PI3K-AKT pathway, and formononetin can regulate T-cell function by inhibiting the PD-1/PD-L1 pathway. We also used GC MKN-45 cells in a T lymphocyte co-culture model to show that quercetin and formononetin co-treatment can regulate T cell function and inhibit MKN-45 cell proliferation. More importantly, quercetin with formononetin treatment had a greater effect than treatment with either quercetin or formononetin alone. We believe that quercetin and formononetin may be useful to target HER2 and inhibit PD-1/PD-L1 in GC.

BackgroundLoco-regional recurrences (LRR) following breast-conserving surgery (BCS) remain a heterogeneous class of disease that has significant variation in its biological behavior and prognosis.MethodsTo delineate the spatiotemporal patterns of LRR after BCS, we analyzed the data of 4325 patients treated with BCS from 2006 to 2016. Clinico-pathological and treatment specific factors were analyzed using the Cox proportional hazards model to identify factors predictive for LRR events. Recurrence patterns were scrutinized based on recurrence type and recurrence-free interval (RFI). Annual recurrence rates (ARR) were compared according to recurrence type and molecular subtype.ResultsWith a median follow-up of 66 months, 120 (2.8%) LRRs were recorded as the first site of failure. Age, pathologic stage, and molecular subtype were identified as predictors of LRR. The major recurrence type was ipsilateral breast tumor recurrence, which mainly (83.6%) occurred ≤5y post surgery. In the overall population, ARR curves showed that relapse peaked in the first 2.5 years. Patients with regional nodal recurrence, shorter RFI, and synchronous distant metastasis were associated with a poorer prognosis. HER2-positive disease had a higher rate of LRR events, more likely to have in-breast recurrence, and had an earlier relapse peak in the first 2 years after surgery.ConclusionsLRR risk following BCS is generally low in Chinese ethnicity. Different recurrence patterns after BCS were related to distinct clinical outcomes. Management of LRR should be largely individualized and tailored to the extent of disease, the molecular profile of the recurrence, and to baseline clinical variables.

Abstract Background Endocrine therapy is the preferred treatment for patients with hormone receptor ‐positive metastatic breast cancer (MBC). While visceral metastasis is a negative prognostic factor, few studies have distinguished between the prognoses of patients with metastases at different visceral sites. Patients and methods In total, 398 patients receiving fulvestrant 500 mg at a single center over a 6‐year period were analyzed. Logistic regression models were used to identify the prognostic factors associated with progression‐free survival (PFS). Kaplan‐Meier analysis was used to compare the PFS of patients with lung and liver metastases. Results Baseline visceral metastases were present in 233 patients, including 138 with lungw/o liver metastases (lung metastases without liver involvement), 51 with liverw/o lung metastases (liver metastases without lung involvement) and 41 with lung and liver metastases. The median PFS was 6.8 months (5.6 and 9.2 months for visceral and nonvisceral metastases, respectively, P = .028). PFS was longer in patients with lungw/o liver metastases than in those with liverw/o lung metastases or lung and liver metastases (9.6, 3.7 and 3.2 months, respectively, P

Structural health monitoring is important to ensuring the health and safety of dams. An inverse analysis method based on a novel hybrid fireworks algorithm (FWA) and the radial basis function (RBF) model is proposed to diagnose the health condition of concrete dams. The damage of concrete dams is diagnosed by identifying the elastic modulus of materials using the displacement changes at different reservoir water levels. FWA is a global optimization intelligent algorithm. The proposed hybrid algorithm combines the FWA with the pattern search algorithm, which has a high capability for local optimization. Examples of benchmark functions and pseudo-experiment examples of concrete dams illustrate that the hybrid FWA improves the convergence speed and robustness of the original algorithm. To address the time consumption problem, an RBF-based surrogate model was established to replace part of the finite element method in inverse analysis. Numerical examples of concrete dams illustrate that the use of an RBF-based surrogate model significantly reduces the computation time of inverse analysis with little influence on identification accuracy. The presented hybrid FWA combined with the RBF network can quickly and accurately determine the elastic modulus of materials, and then determine the health status of the concrete dam. Keywords: Fireworks algorithm(FWA), Radial basis function (RBF) network, Surrogate model, Inverse analysis, Structural health monitoring

Abstract. Background:. Pulmonary artery hypertension associated with congenital heart disease (PAH-CHD) occurs predominantly among patients with uncorrected CHD. Treatment of severe pediatric PAH-CHD remains a major intractability. This study evaluated the predictors and prognoses of children with PAH-CHD who underwent surgical correction. Methods:. The data for 59 children with severe PAH-CHD who underwent surgical correction, with or without postoperative medication, between May 2011 and June 2015 at the Guangdong Provincial People's Hospital were analyzed retrospectively. A regression analysis, receiver-operating characteristic (ROC) curves, and Kaplan-Meier curves were used for survival analysis. Results:. Fifty-nine children with severe PAH-CHD underwent heart catheterization and correction, with or without specific anti-PAH drugs postoperatively, were included in this study. The pulmonary pressure, heart function, and ending events were observed and median observation period was 49 ± 20 months. Twenty-eight patients (50%) received at least one additional anti-PAH drug after correction. The survival rate after 2 years was 91.5% (54/59); two patients were in a critical condition, and three were lost to follow-up. Twelve patients (29%) still received over one additional PAH-specific therapy at follow-up, whereas 42 (75%) had successfully stopped drug treatment. Two patients (3.5%) died and one underwent a second thoracotomy to remove the ventricular septal defect patch. Acute vasoreactivity test (AVT) criteria had limited efficacy in predicting pediatric PAH-CHD, whereas pulmonary vascular resistance (PVR) ≤ 6.65 Wood units (WU)/m2 or PVR/systemic vascular resistance (SVR) ≤ 0.39 during AVT indicated a good prognosis after surgical correction with an AUC of 98.3% (95% confidence interval [CI]: 96.0–100%), 98.4% (95% CI: 96.0–100%) sensitivity of 100%, 100% and specificity of 82.1%, 92.9%, respectively. Conclusions:. Although the criteria for positive AVT currently used are unsuitable for pediatric patients with PAH-CHD, PVR and PVR/SVR during AVT are excellent predictors of outcome in pediatric PAH-CHD. Surgery aided by anti-PAH drugs is an effective strategy and should be recommended for severe pediatric PAH-CHD with PVR ≤ 6.65 WU/m2 and PVR/SVR ≤ 0.39 after iloprost aerosol inhalation.

Objective: To observe the dermoscopic features of psoriasis vulgaris in order to provide evidence basis for differential diagnosis of psoriasis. Methods: From January 2016 to February 2018, 86 cases of psoriasis, 11 of which confirmed by histopathology, were enrolled in this study. Common lesions included papule, erythema, plaque, scalp rash, palmoplantar rash, nail psoriasis and post-treatment lesions. The background color, scale color, scale distribution, vascular morphology, vascular arrangement and vascular orientation were observed using a dermoscope. Results: Typical dermoscopic features of psoriasis included bright red background, silver scales, scattered distribution of dotted vessels and small glomerular vessels arranged in a uniform pattern. These features varied with the types of lesions. Conclusions: Psoriasis displays typical dermoscopic features. Specific dermoscopic features of each type of lesion can facilitate clinical diagnosis of psoriasis.

Abstract Background Chemoresistance to temozolomide (TMZ) is a major challenge in the treatment of glioblastoma (GBM). We previously found that miR-519a functions as a tumor suppressor in glioma by targeting the signal transducer and activator of transcription 3 (STAT3)-mediated autophagy oncogenic pathway. Here, we investigated the effects of miR-519a on TMZ chemosensitivity and autophagy in GBM cells. Furthermore, the underlying molecular mechanisms and signaling pathways were explored. Methods In the present study, two stable TMZ-resistant GBM cell lines were successfully generated by exposure of parental cells to a gradually increasing TMZ concentration. After transfecting U87-MG/TMZ and U87-MG cells with miR-519a mimic or inhibitor, a series of biochemical assays such as MTT, apoptosis, and colony formation were performed to determine the chemosensitive response to TMZ. The autophagy levels in GBM cells were detected by transmission electron microscopy, LC3B protein immunofluorescence, and Western blotting analysis. Stable knockdown and overexpression of miR-519a in GBM cells were established using lentivirus. A xenograft nude mouse model and in situ brain model were used to examine the in vivo effects of miR-519a. Tumor tissue samples were collected from 48 patients with GBM and were used to assess the relationship between miR-519a and STAT3 expression. Results TMZ treatment significantly upregulated miR-519a in U87-MG cells but not in U87-MG/TMZ cells. Moreover, the expression of miR-519a and baseline autophagy levels was lower in U87-MG/TMZ cells as compared to U87-MG cells. miR-519a dramatically enhanced TMZ-induced autophagy and apoptotic cell death in U87-MG/TMZ cells, while inhibition of miR-519a promoted TMZ resistance and reduced TMZ-induced autophagy in U87-MG cells. Furthermore, miR-519a induced autophagy through modification of STAT3 expression. The in vivo results showed that miR-519a can enhance apoptosis and sensitized GBM to TMZ treatment by promoting autophagy and targeting the STAT3/Bcl-2/Beclin-1 pathway. In human GBM tissues, we found an inverse correlation between miR-519a and STAT3 expression. Conclusions Our results suggested that miR-519a increased the sensitivity of GBM cells to TMZ therapy. The positive effects of miR-519a may be mediated through autophagy. In addition, miR-519a overexpression can induce autophagy by inhibiting STAT3/Bcl-2 pathway. Therefore, a combination of miR-519a and TMZ may represent an effective therapeutic strategy in GBM.

AIM: To figure out the contributed factors of the hospitalization expenses of senile cataract patients (HECP) and build up an area-specified senile cataract diagnosis related group (DRG) of Shanghai thereby formulating the reference range of HECP and providing scientific basis for the fair use and supervision of the health care insurance fund. METHODS: The data was collected from the first page of the medical records of 22 097 hospitalized patients from tertiary hospitals in Shanghai from 2010 to 2012 whose major diagnosis were senile cataract. Firstly, we analyzed the influence factors of HECP using univariate and multivariate analysis. DRG grouping was conducted according to the exhaustive Chi-squared automatic interaction detector (E-CHAID) model, using HECP as target variable. Finally we evaluated the grouping results using non-parametric test such as Kruskal-Wallis H test, RIV, CV, etc. RESULTS: The 6 DRGs were established as well as criterion of HECP, using age, sex, type of surgery and whether complications/comorbidities occurred as the key variables of classification node of senile cataract cases. CONCLUSION: The grouping of senile cataract cases based on E-CHAID algorithm is reasonable. And the criterion of HECP based on DRG can provide a feasible way of management in the fair use and supervision of medical insurance fund.

Mangrove actinomycetia are considered one of the promising sources for discovering novel biologically active compounds. Traditional bioactivity- and/or taxonomy-based methods are inefficient and usually result in the re-discovery of known metabolites. Thus, improving selection efficiency among strain candidates is of interest especially in the early stage of the antibiotic discovery program. In this study, an integrated strategy of combining phylogenetic data and bioactivity tests with a metabolomics-based dereplication approach was applied to fast track the selection process. A total of 521 actinomycetial strains affiliated to 40 genera in 23 families were isolated from 13 different mangrove soil samples by the culture-dependent method. A total of 179 strains affiliated to 40 different genera with a unique colony morphology were selected to evaluate antibacterial activity against 12 indicator bacteria. Of the 179 tested isolates, 47 showed activities against at least one of the tested pathogens. Analysis of 23 out of 47 active isolates using UPLC-HRMS-PCA revealed six outliers. Further analysis using the OPLS-DA model identified five compounds from two outliers contributing to the bioactivity against drug-sensitive A. baumannii. Molecular networking was used to determine the relationship of significant metabolites in six outliers and to find their potentially new congeners. Finally, two Streptomyces strains (M22, H37) producing potentially new compounds were rapidly prioritized on the basis of their distinct chemistry profiles, dereplication results, and antibacterial activities, as well as taxonomical information. Two new trioxacarcins with keto-reduced trioxacarcinose B, gutingimycin B (16) and trioxacarcin G (20), together with known gutingimycin (12), were isolated from the scale-up fermentation broth of Streptomyces sp. M22. Our study demonstrated that metabolomics tools could greatly assist classic antibiotic discovery methods in strain prioritization to improve efficiency in discovering novel antibiotics from those highly productive and rich diversity ecosystems.

Background: Percutaneous balloon pulmonary valvuloplasty (PBPV) is the preferred therapy for pulmonary valve stenosis (PVS). This study retrospectively reviewed recent PBPV outcomes in infants with PVS. The aim of this study was to evaluate factors associated with immediate therapeutic outcomes and restenosis during medium-term follow-up. Methods: The study included 158 infants with PVS who underwent PBPV from January 2009 to July 2015. Demographic characteristics and patient records were reviewed, including detailed hospitalization parameters, hemodynamic data before and immediately after balloon dilation, cineangiograms, and echocardiograms before PBPV and at each follow-up. All procedures were performed by more than two experienced operators. Results: Immediately after balloon dilation, the pressure gradient across the pulmonary valve decreased from 73.09 ± 21.89 mmHg (range: 43–151 mmHg) to 24.49 ± 17.00 mmHg (range: 3–92 mmHg; P < 0.001) and the right ventricular systolic pressure decreased from 95.34 ± 23.44 mmHg (range: 60–174 mmHg) to 52.07 ± 18.89 mmHg (range: 22–134 mmHg; P < 0.001). Residual transvalvular pressure gradients of 67.31 ± 15.19 mmHg (range: 50–92 mmHg) were found in 8.2% of patients, indicating poor therapeutic effects; 6.4% of patients had variable-staged restenosis at follow-up and 3.8% underwent reintervention by balloon dilation or surgical repairs. Further analysis demonstrated that the balloon/annulus ratio showed statistically significant differences (P < 0.05) among groups with different therapeutic effects and between the restenosis and no-stenosis groups. Binary logistic regression analysis further revealed that higher balloon/annulus ratio (odds ratio: 0.005, 95% confidence interval: 0–0.39) was an independent protective factor for restenosis. The rate of severe complications was 1.9%. Conclusions: PBPV is a definitive therapy for infants with PVS based on its effectiveness, feasibility, and safety. Restenosis upon medium-term follow-up is relatively rare.

Based on the influence of the non-linear change in the consolidation process of permeability coefficient and compressibility of soft soils and the theory of elliptic cylinders, derived the control equation of the nonlinear consolidation of the vertical foundation of the strip plastic drainage board. Further, according to the complete orthogonal space theory, the equivalent polynomial analytical expression of the nonlinear term is given. Then, the analytic solutions of the nonlinear consolidation are given, and through numerical calculation and verification analysis, it is considered that the Indrarantna (2005) approximation has a relatively small error at Cc/Ck (close to 1) and Nu (4), the error is large.

AIM:To investigate the correlation between dry eye and different degrees of diabetic retinopathy(DR)in type 2 diabetic patients. METHODS: In the cross-sectional study, 340 patients(340 eyes)with type 2 diabetes were enrolled. Tear film function tests including tear meniscus height, tear film breakup time(BUT), fluorescein staining, Schirmer Ⅰ test were performed followed by surveying questionnaires about dry eye. Retinal status was evaluated by retinal color photography and indirect ophthalmoscopy exam with dilated pupils to evaluate DR and whether companied by macular edema. RESULTS: The prevalence of dry eye was 49.41%. The mean duration of diabetes in patients with dry eye was 11.15±7.07a, while 6.92±5.45a without dry eye(PCONCLUSION: Dry eye was more prevalent in people with type 2 diabetes. The incidence of dry eye increased gradually with the occurrence and development of diabetic retinopathy.

Disturbances of the microcirculation and abnormal hemorheological properties are important factors that play an important role in disseminated intravascular coagulation (DIC) and result in organ dysfunction or failure. In the present study, we established an animal model of DIC using intravenous Dextran 500 in rats, and used exogenous normal lymph corresponding to 1/15 of whole blood volume for injection through the left jugular vein. We found that normal lymph could improve the blood pressure and survival time of rats with DIC. The results regarding the mesenteric microcirculation showed that the abnormality of the diameter of mesenteric microvessels and micro-blood flow speed in the DIC+lymph group was significantly less than in the DIC+saline group. Whole blood viscosity, relative viscosity, plasma viscosity, hematocrit (Hct), erythrocyte sedimentation rate (ESR), and electrophoresis time of erythrocytes were significantly increased in the DIC+saline group compared to the control group. The electrophoretic length and migration of erythrocytes from the DIC+saline and DIC+lymph groups were significantly slower than the control group. Blood relative viscosity, Hct, ESR, and electrophoretic time of erythrocytes were significantly increased in the DIC+lymph group compared to the control group. Whole blood viscosity, relative viscosity and reduced viscosity were significantly lower in the DIC+lymph group than in the DIC+saline group, and erythrocyte deformability index was also significantly higher than in the DIC+saline and control groups. These results suggest that exogenous normal lymph could markedly improve the acute microcirculation disturbance and the abnormal hemorheological properties in rats with DIC induced by Dextran 500.

Disturbances of the microcirculation and abnormal hemorheological properties are important factors that play an important role in disseminated intravascular coagulation (DIC) and result in organ dysfunction or failure. In the present study, we established an animal model of DIC using intravenous Dextran 500 in rats, and used exogenous normal lymph corresponding to 1/15 of whole blood volume for injection through the left jugular vein. We found that normal lymph could improve the blood pressure and survival time of rats with DIC. The results regarding the mesenteric microcirculation showed that the abnormality of the diameter of mesenteric microvessels and micro-blood flow speed in the DIC+lymph group was significantly less than in the DIC+saline group. Whole blood viscosity, relative viscosity, plasma viscosity, hematocrit (Hct), erythrocyte sedimentation rate (ESR), and electrophoresis time of erythrocytes were significantly increased in the DIC+saline group compared to the control group. The electrophoretic length and migration of erythrocytes from the DIC+saline and DIC+lymph groups were significantly slower than the control group. Blood relative viscosity, Hct, ESR, and electrophoretic time of erythrocytes were significantly increased in the DIC+lymph group compared to the control group. Whole blood viscosity, relative viscosity and reduced viscosity were significantly lower in the DIC+lymph group than in the DIC+saline group, and erythrocyte deformability index was also significantly higher than in the DIC+saline and control groups. These results suggest that exogenous normal lymph could markedly improve the acute microcirculation disturbance and the abnormal hemorheological properties in rats with DIC induced by Dextran 500.

AIM: To observe the efficacy and side reaction of superselective ophthalmic artery chemotherapy for retinoblastoma(RB).METHODS: Eleven cases(11 eyes)of RB, ranging from stage A to D according to the latest International Intraocular Retinoblastoma classification, were treated with melphalan infusion by the ophthalmic artery.RESULTS: Such intra-arterial chemotherapy was administered for 23 times and the patients were followed up for 3-12 months. During the follow-up, 8 cases were effective with significant tumor shrinking and calcification; 2 patients progressed and received enucleation of eyeballs; 1 case was lost to follow-up. Postoperative transient nausea, vomiting and fever appeared in some cases, but serious complications were not found, such as death, stroke, myelosuppression,etc.CONCLUSION: Among 9 cases from group A, B and C, 7 cases were effective, 1 case continued to progress and 1 case was lost to follow-up, and the effective rate was 88%. In the 2 cases of group D, 1 case was effective and the other continueed to progress, so the effective rate was 50%.

The significant changes enabled by the fog computing had demonstrated that Internet of Things (IoT) urgently needs more evolutional reforms. Limited by the inflexible design philosophy; the traditional structure of a network is hard to meet the latest demands. However, Information-Centric Networking (ICN) is a promising option to bridge and cover these enormous gaps. In this paper, a Smart Collaborative Caching (SCC) scheme is established by leveraging high-level ICN principles for IoT within fog computing paradigm. The proposed solution is supposed to be utilized in resource pooling, content storing, node locating and other related situations. By investigating the available characteristics of ICN, some challenges of such combination are reviewed in depth. The details of building SCC, including basic model and advanced algorithms, are presented based on theoretical analysis and simplified examples. The validation focuses on two typical scenarios: simple status inquiry and complex content sharing. The number of clusters, packet loss probability and other parameters are also considered. The analytical results demonstrate that the performance of our scheme, regarding total packet number and average transmission latency, can outperform that of the original ones. We expect that the SCC will contribute an efficient solution to the related studies.

INTRODUCTION: Investigate the patterns of mammographically detected calcifications before and after neoadjuvant chemotherapy (NACT) to determine their value for efficacy evaluation and surgical decision making. METHODS: 187 patients with malignant mammographic calcifications were followed to record the appearances and changes in the calcifications and to analyze their responses to NACT. RESULTS: Patients with calcifications had higher rates of hormonal receptor (HR) positive tumors (74.3% versus 64.6%) and HER2 positive tumors (51.3% versus 33.4%, p = 0.004) and a similar pathologic complete response (pCR) rate compared to patients without calcifications (35.4% versus 29.8%). After NACT, the range of calcification decreased in 40% of patients, increased in 7.5% and remained stable in 52.5%; the calcification density decreased in 15% of patients, increased in 7.5% and remained stable in 77.5%; none of these change patterns were related to tumor response rate. No significant correlation was observed between the calcification appearance (morphology, distribution, range, diameter or density) and tumor subtypes or pCR rates. Among patients with malignant calcifications, 54 showed calcifications alone, 40 occurred with an architectural distortion (AD) and 93 with a mass. Calcifications were observed inside the tumor in 44% of patients and outside in 56%, with similar pCR rates and patterns of change. CONCLUSIONS: Calcification appearance did not clearly change after NACT, and calcification patterns were not related to pCR rate, suggesting that mammogram may not accurate to evaluate tumor response changes. Microcalcifications visible after NACT is essential for determining the extent of excision, patients with calcifications that occurred outside of the mass still had the opportunity for breast conservation.

BACKGROUND: Altered chloride homeostasis has been thought to be a risk factor for several brain disorders, while less attention has been paid to its role in liver disease. We aimed to analyze the involvement and possible mechanisms of altered chloride homeostasis of GABAergic neurons within the substantia nigra pars reticulata (SNr) in the motor deficit observed in a model of encephalopathy caused by acute liver failure, by using glutamic acid decarboxylase 67 - green fluorescent protein knock-in transgenic mice. METHODS: Alterations in intracellular chloride concentration in GABAergic neurons within the SNr and changes in the expression of two dominant chloride homeostasis-regulating genes, KCC2 and NKCC1, were evaluated in mice with hypolocomotion due to hepatic encephalopathy (HE). The effects of pharmacological blockade and/or activation of KCC2 and NKCC1 functions with their specific inhibitors and/or activators on the motor activity were assessed. RESULTS: In our mouse model of acute liver injury, chloride imaging indicated an increase in local intracellular chloride concentration in SNr GABAergic neurons. In addition, the mRNA and protein levels of KCC2 were reduced, particularly on neuronal cell membranes; in contrast, NKCC1 expression remained unaffected. Furthermore, blockage of KCC2 reduced motor activity in the normal mice and led to a further deteriorated hypolocomotion in HE mice. Blockade of NKCC1 was not able to normalize motor activity in mice with liver failure. CONCLUSION: Our data suggest that altered chloride homeostasis is likely involved in the pathophysiology of hypolocomotion following HE. Drugs aimed at restoring normal chloride homeostasis would be a potential treatment for hepatic failure.

Intercalated disk (ID), which electromechanically couples cardiomyocytes into a functional syncitium, is closely related to normal morphology and function of engineered heart tissues (EHTs), but the development mode of ID in the three-dimensional (3D) EHTs is still unclear. In this study, we focused on the spatiotemporal development of the ID in the EHTs constructed by mixing neonatal rat cardiomyocytes with collagen/Matrigel, and investigated the effect of 3D microenvironment provided by collagen/Matrigel matrix on the formation of ID. By histological and immmunofluorescent staining, the spatiotemporal distribution of ID-related junctions was detected. Furthermore, the ultra-structures of the ID in different developmental stages were observed under transmission electron microscope. In addition, the expression of the related proteins was quantitatively analyzed. The results indicate that accompanying the re-organization of cardiomyocytes in collagen/Matrigel matrix, the proteins of adherens junctions, desmosomes and gap junctions redistributed from diffused distribution to intercellular regions to form an integrated ID. The adherens junction and desmosome which are related with mechanical connection appeared earlier than gap junction which is essential for electrochemical coupling. These findings suggest that the 3D microenvironment based on collagen/Matrigel matrix could support the ordered assembly of the ID in EHTs and have implications for comprehending the ordered and coordinated development of ID during the functional organization of EHTs.

BACKGROUND: Dendritic cells (DCs) release bioactive exosomes that play an important role in immune regulation. Because they express low levels of class I major histocompatibility complex (MHC) and co-stimulatory molecules, exosomes derived from donor immature DCs (imDex) prolong allograft survival by inhibiting T-cell activation. However, this effect is limited and does not induce immunological tolerance when imDex are administered alone. Thus, we tested the effect of combined treatment with donor imDex and low-dose rapamycin on inducing tolerance in a mouse cardiac transplantation model. METHODS: ImDex were obtained from the culture supernatant of immature DCs derived from donor mouse (C57BL/6) bone marrow and were injected with suboptimal doses of rapamycin into recipient mouse (BALB/c) before and after transplantation. The capacity of this treatment to induce immune tolerance was analyzed in vitro and in vivo using the mouse cardiac transplantation model. RESULTS: Donor imDex expressed moderate levels of MHC class II and low levels of MHC class I and co-stimulatory molecules, but neither imDex nor subtherapeutic rapamycin dose alone induced cardiac allograft tolerance. Combined treatment with imDex and rapamycin, however, led to donor specific cardiac allograft tolerance. This effect was accompanied by decreased anti-donor antigen cellular response and an increased percentage of spleen CD4(+)CD25(+) T cells in recipients. Furthermore, this donor specific tolerance could be further transferred to naïve allograft recipients through injection of splenocytes, but not serum, from tolerant recipients. CONCLUSION: Combined with immunosuppressive treatment, donor imDex can prolong cardiac allograft survival and induce donor specific allograft tolerance.

PURPOSE: To investigate the relationship between age and axillary lymph node (LN) involvement in Chinese breast cancer patients, and to replicate a recently identified piecewise relationship between age and LN involvement. METHODS: A dataset, consisting of 3,715 patients (with complete information on study variables) with operable breast cancer consecutively surgically treated between 1996 and 2006, was derived from the database of Shanghai Cancer Hospital. Univariate and multivariate logistic regression were employed to analyze the relationship between age and LN. We subsequently performed a similar analysis on another dataset including 1,832 consecutive patients treated between 2007 and 2008 to replicate our findings in the first dataset. RESULTS: A U-shaped relationship (previously observed in two European populations) between age and LN status failed to be replicated in our dataset of Chinese patients. Instead, we observed a linear rather than piecewise relationship. After multivariate adjustment, the linear relationship was still present. Moreover, the interaction between age and LN involvement was not modified by tumor size. The odds of LN involvement decreased by 1.5% for each year increase in age (OR 0.985, 95% CI 0.979-0.991, P

ZMT04 muscovite serves as a quality control reference material for K--Ar dating, with a recommended age of 1804 ± 21 Ma (2σ). Here, we check the homogeneity for ZMT04 muscovite and compare its age against the reference material Fish Canyon sanidine (FCs). Five sub-samples of ZMT04 muscovite were irradiated in three different reactors with different irradiation doses, analysed at varying sample masses over different time periods, and subjected to different mass spectrometric measurement procedures in two independent laboratories, which yielded consistent plateau ages with a mean of 1772.2 ± 2.7 Ma (2σ, MSWD = 1.30, and P = 0.18) and RFCs=28.294±0.072Ma ZMT04 = 105.53 ± 0.25 (2sd, MSWD = 0.88, and P = 0.57). The single-grain results are consistent with the multi-grain stepwise heating results, indicating good reproducibility and homogeneity of 40Ar* and K at the single-grain level. A single grain is sufficient to yield a high precision result when the J-value >0.01. We recommend 1 mg as the minimum sample mass to yield enough neutron-induced 39Ar signals for high-precision analysis (J-value <0.001). Accordingly, ZMT04 muscovite can represent a reliable 40Ar/ 39Ar dating and K--Ar dating reference material for Paleoproterozoic geological samples. [ABSTRACT FROM AUTHOR]