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Objective To explore the association between early neutrophil-to-lymphocyte ratio (ENLR) and prognosis of anterior circulation large-vessel occlusion stroke (LVOS) after patients undergo endovascular treatment (EVT) with successful revascularization. Methods Patients who experienced acute anterior circulation LVOS and underwent EVT at Changzhou Second People's Hospital Affiliated to Nanjing Medical University between May 2017 and May 2020 were included in this retrospective study. We collected information about patients' baseline characteristics, medical history, laboratory test results, imaging data, and endovascular treatment outcomes, as well as data from follow-up at 3 months. Univariate and multivariate logistic regression models were used to evaluate the association between ENLR and functional disease prognosis. A piecewise linear regression model was also applied to compute the threshold effect of ENLR on poor prognosis (defined as modified Rankin Scale score 3–6) at 3 months using a smoothing plot. Results Of 224 patients who received EVT during the study period, 160 patients were included in the analysis. After adjustments were made for potential confounders, multivariate analysis demonstrated a significant association between ENLR and poor prognosis at 3 months (odds radio 1.19; 95% confidence interval 1.07–1.32; P = 0.0016). An ENLR ≥9.75 was found to be significantly associated with poor prognosis at 3 months (odds ratio 1.54; 95% confidence interval 1.19–2.00; P = 0.0119). Conclusions Increased ENLR after successful revascularization is independently associated with poor prognosis. These findings suggest that ENLR could be used to inform treatment strategies for patients who experience anterior circulation LVOS.

Introduction Plants containing aristolochic acid and its derivatives are nephrotoxic, mutagenic, and carcinogenic to humans; chronic diet poisoning caused by the aristolochic acid is the cause of endemic (Balkan) nephropathy and related cancers. Objective To develop a colloidal gold immunochromatographic test strip (ICS) based on the competitive format for the rapid detection of aristolochic acid A (AA-A) in herbal medicinal materials. Materials and methods For the ICS based on gold nanoparticles (AuNPs), the antigen [AA-A-bovine serum albumin (BSA)], and goat anti-mouse IgG were drawn on the nitrocellulose membrane as the test line (T line) and the control line (C line), respectively. Monoclonal antibody (MAb)-AuNP conjugates were sprayed onto the conjugate pad. The sensitivity of the ICS was 6 ng/mL, and the test was completed in 10 min. The analysis of AA-A in traditional Chinese medicine samples showed that the ICS results were in good agreement with those obtained by high-performance liquid chromatography methods. Conclusion These results demonstrated that the ICS test could be used as a reliable, rapid, cost-effective, and convenient qualitative tool for on-site screening techniques to detect AA-A in herbal medicinal materials without any special instrumentation.

Although the antimicrobial, nutritional, and health-promoting properties of royal jelly (RJ) have been widely confirmed, the effects of storage temperature and time on RJ quality remain to be further explored. Herein, the antimicrobial and proteomic dynamics of RJ stored under different conditions were comprehensively investigated to identify consistent and sensitive markers of RJ degradation. We confirmed the negative correlation between antimicrobial properties and increased the storage temperature and duration in RJ. Using surface plasmon resonance, we showed the protein degradation-induced conformation changes in RJ, which reflected the overall variation in RJ proteins caused by the storage conditions. Further proteomic and western blotting analyses demonstrated the sensitivity and reliability of major RJ protein 4 (MRJP4) as a measure of temperature- and time-dependent RJ changes. Based on these results, we developed a colloidal gold immunoassay strip for MRJP4 detection, providing a reliable, simple, and rapid method for the evaluation of RJ freshness.

BACKGROUND: Citrin deficiency (CD) is an autosomal recessive disease resulting from biallelic mutations of the SLC25A13 gene. This study aimed to investigate the molecular epidemiological features of CD in the Guangdong and Shaanxi provinces of China. METHODS: A total of 3,409 peripheral blood samples from Guangdong and 2,746 such samples from Shaanxi province were collected. Four prevalent SLC25A13 mutations NG_012247.2 (NM_014251.3): c.852_855del, c.1638_1660dup, c.615+5G>A, and c.1751-5_1751-4ins(2684) were screened by using the conventional polymerase chain reaction (PCR)/PCR-restriction fragment length polymorphism and newly-developed multiplex PCR methods, respectively. The mutated SLC25A13 allele frequencies, carrier frequencies, and CD morbidity rates were calculated and then compared with the Chi-square and Fisher’s exact tests. RESULTS: The mutations were detected in 68 out of 6,818 SLC25A13 alleles in Guangdong and 29 out of 5,492 alleles in the Shaanxi population. The carrier frequencies were subsequently calculated to be 1/51 and 1/95, while the CD morbidity rates were 1/10,053 and 1/35,865, in the 2 populations, respectively. When compared with the Shaanxi population, Guangdong exhibited a higher frequency of mutated SLC25A13 allele (68/6,818 vs. 29/5,492, χ(2)=8.570, P=0.003) in general, with higher c.852_855del (54/6,818 vs. 13/5,492, χ(2)=17.328, P=0.000) but lower c.1751-5_1751 -4ins(2684) (2/6,818 vs. 9/5,492, P=0.015) allele frequencies. The distribution of c.615+5G>A and c.1638_1660dup between the 2 provinces, as well as all 4 prevalent mutations among different geographic regions within the 2 provinces, did not differed significantly. CONCLUSIONS: Our findings depicted the CD molecular epidemiological features in Guangdong and Shaanxi populations, providing preliminary but significant laboratory evidences for the subsequent CD diagnosis and management in the 2 provinces of mainland China.

Background The purpose of this study was to compare the degree of accuracy of coronal alignment correction with use of the “alignment adjustment under valgus stress technique” between expert and novice surgeons during medial opening-wedge high tibial osteotomy (MOWHTO). Methods Forty-eight patients who underwent MOWHTO performed by an expert surgeon (expert group) and 29 by a novice surgeon (novice group) were enrolled in analysis. During surgery, lower-extremity alignment was corrected using the “alignment adjustment under valgus stress technique”. Normocorrection was defined as a weight-bearing line ratio between 55 and 70% and the correction accuracy was compared between expert and novice groups using the ratio of normocorrection to outliers. The clinical outcomes were also compared using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at 1 year after surgery. Results The undercorrection rate was 14.6% in the expert group and 13.8% in the novice group, while the overcorrection rate was 2.1% in the expert group and 3.4% in the novice group. In the ratio of normocorrection to outliers, no difference was found between the two groups at the one-year follow-up visit (83.3% in the expert group vs. 82.8% in the novice group; p > 0.05). Also, no significant differences were seen in WOMAC subscores immediately preoperatively and at 1 year after surgery (all p > 0.05). Conclusion Adhering to the “alignment adjustment under valgus stress technique” protocol enabled novice surgeons to achieve similar surgical accuracy as that of an expert surgeon in coronal alignment during MOWHTO. Level of evidence Level III.

PURPOSE Propagation of contours from high-quality magnetic resonance (MR) images to treatment planning ultrasound (US) images with severe needle artifacts is a challenging task, which can greatly aid the organ contouring in high dose rate (HDR) prostate brachytherapy. In this study, a deep learning approach was developed to automatize this registration procedure for HDR brachytherapy practice. METHODS Because of the lack of training labels and difficulty of accurate registration from inferior image quality, a new segmentation-based registration framework was proposed for this multi-modality image registration problem. The framework consisted of two segmentation networks and a deformable registration network, based on the weakly -supervised registration strategy. Specifically, two 3D V-Nets were trained for the prostate segmentation on the MR and US images separately, to generate the weak supervision labels for the registration network training. Besides the image pair, the corresponding prostate probability maps from the segmentation were further fed to the registration network to predict the deformation matrix, and an augmentation method was designed to randomly scale the input and label probability maps during the registration network training. The overlap between the deformed and fixed prostate contours was analyzed to evaluate the registration accuracy. Three datasets were collected from our institution for the MR and US image segmentation networks, and the registration network learning, which contained 121, 104, and 63 patient cases, respectively. RESULTS The mean Dice similarity coefficient (DSC) results of the two prostate segmentation networks are 0.86 ± 0.05 and 0.90 ± 0.03, for MR images and the US images after the needle insertion, respectively. The mean DSC, center-of-mass (COM) distance, Hausdorff distance (HD), and averaged symmetric surface distance (ASSD) results for the registration of manual prostate contours were 0.87 ± 0.05, 1.70 ± 0.89 mm, 7.21 ± 2.07 mm, 1.61 ± 0.64 mm, respectively. By providing the prostate probability map from the segmentation to the registration network, as well as applying the random map augmentation method, the evaluation results of the four metrics were all improved, such as an increase in DSC from 0.83 ± 0.08 to 0.86 ± 0.06 and from 0.86 ± 0.06 to 0.87 ± 0.05, respectively. CONCLUSIONS A novel segmentation-based registration framework was proposed to automatically register prostate MR images to the treatment planning US images with metal artifacts, which not only largely saved the labor work on the data preparation, but also improved the registration accuracy. The evaluation results showed the potential of this approach in HDR prostate brachytherapy practice.

Background and Purpose: Rates of emergency medical services (EMS) utilization for acute stroke remain low nationwide, despite the time-sensitive nature of the disease. Prior research suggests several demographic and social factors are associated with EMS use. We sought to evaluate which demographic or socioeconomic factors are associated with EMS utilization in our region, thereby informing future education efforts. Methods: We performed a retrospective analysis of patients for whom the stroke code system was activated at 2 hospitals in our region. Univariate and logistic regression analysis was performed to identify factors associated with use of EMS versus private vehicle. Results: EMS use was lower in patients who were younger, had higher income, were married, more educated and in those who identified as Hispanic. Those arriving by EMS had significantly faster arrival to code, arrival to imaging, and arrival to thrombolytic treatment times. Conclusion: Analysis of regional data can identify specific populations underutilizing EMS services for acute stroke symptoms. Factors effecting EMS utilization varies by region and this information may be useful for targeted education programs promoting EMS use for acute stroke symptoms. EMS use results in more rapid evaluation and treatment of stroke patients.

The effect of perioperative acupuncture on accelerating gastrointestinal function recovery has been reported in colorectal surgery and distal gastrectomy (Billroth-II). However, the evidence in pancreatectomy and other gastrectomy is still limited. A prospective, randomized controlled trial was conducted between May 2018 and August 2019. Consecutive patients undergoing pancreatectomy or gastrectomy in our hospital were randomly assigned to the electroacupuncture (EA) group and the control group. The patients in the EA group received transcutaneous EA on Bai-hui (GV20), Nei-guan (PC6), Tian-shu (ST25), and Zu-san-li (ST36) once a day in the afternoon, and the control group received sham EA. Primary outcomes were the time to first flatus and time to first defecation. In total, 461 patients were randomly assigned to the groups, and 385 were analyzed finally (EA group, n = 201; control group, n = 184). Time to first flatus (3.0 ± 0.7 vs 4.2 ± 1.0, P < 0.001 ) and first defecation (4.2 ± 0.9 vs 5.4 ± 1.2, P < 0.001 ) in the EA group were significantly shorter than those in the control group. Of patients undergoing pancreatectomy, those undergoing pancreaticoduodenectomy and intraoperative radiation therapy (IORT) surgery benefitted from EA in time to first flatus ( P < 0.001 ) and first defecation ( P < 0.001 ), while those undergoing distal pancreatectomy did not ( P flatus = 0.157 , P defecation = 0.007 ) completely. Of patients undergoing gastrectomy, those undergoing total gastrectomy and distal gastrectomy (Billroth-II) benefitted from EA ( P < 0.001 ), as did those undergoing proximal gastrectomy ( P = 0.015 ). Patients undergoing distal gastrectomy (Billroth-I) benefitted from EA in time to first defecation ( P = 0.012 ) but not flatus ( P = 0.051 ). The time of parenteral nutrition, hospital stay, and time to first independent walk in the EA group were shorter than those in the control group. No severe EA complications were reported. EA was safe and effective in accelerating postoperative gastrointestinal function recovery. Patients undergoing pancreaticoduodenectomy, IORT surgery, total gastrectomy, proximal gastrectomy, or distal gastrectomy (Billroth-II) could benefit from EA. This trial is registered with NCT03291574.

Background Neuroinflammation and immune responses occurring minutes to hours after stroke are associated with brain injury after acute ischemic stroke (AIS). PPARγ coactivator-1α (PGC-1α), as a master coregulator of gene expression in mitochondrial biogenesis, was found to be transiently upregulated in microglia after AIS. However, the role of microglial PGC-1α in poststroke immune modulation remains unknown. Methods PGC-1α expression in microglia from human and mouse brain samples following ischemic stroke was first determined. Subsequently, we employed transgenic mice with microglia-specific overexpression of PGC-1α for middle cerebral artery occlusion (MCAO). The morphology and gene expression profile of microglia with PGC-1α overexpression were evaluated. Downstream inflammatory cytokine production and NLRP3 activation were also determined. ChIP-Seq analysis was performed to detect PGC-1α-binding sites in microglia. Autophagic and mitophagic activity was further monitored by immunofluorescence staining. Unc-51-like autophagy activating kinase 1 (ULK1) expression was evaluated under the PGC-1α interaction with ERRα. Finally, pharmacological inhibition and genomic knockdown of ULK1 were performed to estimate the role of ULK1 in mediating mitophagic activity after ischemic stroke. Results PGC-1α expression was shortly increased after ischemic stroke, not only in human brain samples but also in mouse brain samples. Microglia-specific PGC-1α overexpressing mice exhibited significantly decreased neurologic deficits after ischemic injury, with reduced NLRP3 activation and proinflammatory cytokine production. ChIP-Seq analysis and KEGG pathway analysis revealed that mitophagy was significantly enhanced. PGC-1α significantly promoted autophagic flux and induced autolysosome formation. More specifically, the autophagic clearance of mitochondria was enhanced by PGC-1α regulation, indicating the important role of mitophagy. Pharmacological inhibition or knockdown of ULK1 expression impaired autophagic/mitophagic activity, thus abolishing the neuroprotective effects of PGC-1α. Conclusions Mechanistically, in AIS, PGC-1α promotes autophagy and mitophagy through ULK1 and reduces NLRP3 activation. Our findings indicate that microglial PGC-1α may be a promising therapeutic target for AIS.

BACKGROUND Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease, which is characterized by daily fever and arthritis, with an evanescent rash and neutrophilic leukocytosis. To date, there has been no definite laboratory or imaging test available for diagnosing AOSD; the diagnosis is one of exclusion, which can be very challenging. In particular, AOSD patients may experience different complications affecting their clinical picture, management, and prognosis. The treatment of AOSD remains largely empirical and involves therapeutic agents. CASE SUMMARY We report the case of a 36-year-old woman who presented with fever, red rash, arthralgia, and sore throat. Her serum ferritin level and white blood cell count were markedly elevated, and the first diagnosis 22 years prior was "juvenile rheumatoid arthritis of systemic type". The patient was treated with prednisone, sulfasalazine, methotrexate, and leflunomide. After remission of her symptoms, the patient stopped taking the medications, and the disease recurred. Ultimately, the patient was diagnosed with adult-onset Still's disease. Relapse occurred several times due to self-medication withdrawal, and an interleukin-6 antagonist (tocilizumab/Actemra) was administered to control the disease. Recently, she was hospitalized because an incision did not heal, and the patient suddenly developed high fever and diarrhea during hospitalization. The patient's disease progressed violently and quickly developed into macrophage activation syndrome, disseminated intravascular coagulation, shock, and multiple organ failure. The patient had sudden cardiac arrest, and she died despite emergency rescue efforts. CONCLUSION AOSD patients need regular follow-up in the long-term treatment process, and must press formulary standard medication, and do not voluntarily withdraw or reduce the dose. Otherwise it may cause disease back-and-forth or serious life-threatening complications. Meanwhile, strict management of trauma, infections, tumors, and other diseases may contribute to improved outcomes in patients with complications.

Background BRAFV600E mutation is the most common mutation in thyroid cancer. It strongly activates MAPK/ERK pathway and indicates an invasive subtype of thyroid cancer. PLX4032 is a selective oral inhibitor of the BRAFV600 kinase although with limited effect in treating this panel of thyroid cancer, due to the feedback activation of MAPK/ERK as well as PI3K/AKT pathways. It was investigated that Vitamin C plays a positive role in inhibiting these pathways in thyroid cancer. However, whether Vitamin C could enhance the antitumor effect of PLX4032 remains largely unclear. Methods The antitumor efficacy of combination therapy with PLX4032 and Vitamin C on BRAFMT thyroid cancer cell was assessed by the MTT assay, EdU assay and colony formation, Chou-Talalay way was employed to analyze the synergistic effect. Flow cytometry were employed to assess cells’ apoptosis and cell cycle arrest in response to combination therapy. Xenograft models were used to test its in vivo antitumor activity. Western blot and IHC were applied to investigate the mechanism underlying synergistic effect. Results PLX4032 or Vitamin C monotherapy was mildly effective in treating BRAFMT thyroid cancer cell and xenografts model. The combination therapy significantly inhibited cancer cell proliferation and tumor growth in nude mice, and induced cell apoptosis and cell cycle arrest compared to either monotherapy. PLX4032 monotherapy induced feedback activation of MAPK/ERK as well as PI3K/AKT pathway; while combination therapy significantly relieved this feedback. Conclusion Vitamin C promotes the antitumor effect of PLX4032 in BRAFMT thyroid cancer cell and xenografts model via relieving the feedback activation of MAPK/ERK as well as PI3K/AKT pathway. PLX4032/Vitamin C combination may be a potential therapeutic approach to treat BRAFMT thyroid cancer.

A custom-designed, wearable, lightweight, and passive exoskeleton was proposed to provide gravity support for industrial workers to reduce prevalence of musculoskeletal disorders, joint injures, and arthritis caused by repeatedly or persistently squatting task. The designed exoskeleton can act as a wearable chair to allow workers to squat for an extended period when performing prolonged tasks. The exoskeleton employs torsion springs to store energy harvested from the squatting motion, and the stored energy is released to help the workers stand up. Dimensions optimization designs based on the finite element analysis program were implemented for a lightweight of the device. Besides, the exoskeleton effectiveness was investigated by performing an ergonomic assessment on muscular activity, plantar pressure, endurance time, and comfort. The plantar pressure and electromyography of rectus femoris, biceps femoris, vastus medialis, and vastus laterals were measured in a simulated assembly task with the knee bend for three different angles (60°, 90°, 120°) under two conditions of with and without the exoskeleton. The endurance time was recorded in three different static squatting tasks. The comfort with the exoskeleton was recorded. Under the condition of wearing the exoskeleton, the average reduction of muscle activity was 44.8–71.5%, and the plantar pressure was 58.5–64.2%. The exoskeleton contributed to an increase in endurance time from 2.76 to 13.58 min. Moreover, 70% of the subjects exhibited a comprehensive exoskeleton comfort score of higher than 70. The experimental results demonstrated that this exoskeleton has good potential to reduce physical workload and increase endurance time during industrial assembly tasks.

OBJECTIVEFew studies have addressed that dynamic sagittal imbalance can develop distal to the spinal fusion and cause sagittal malalignment, unlike proximal junctional kyphosis (PJK) in the proximal portion. The purpose of this study was to investigate risk factors between the 2 different types of postoperative sagittal imbalance after long fusion to the sacrum for the treatment of degenerative sagittal imbalance (DSI).METHODSEighty patients who had undergone surgical correction for DSI were included. Radiographic measurements included spinopelvic parameters on whole-spine plain radiographs and degeneration of paravertebral muscles on MRI. Univariate and multivariate analyses for clinical and radiological factors were conducted for respective risk factors. In subgroup analyses, the 2 different types of postoperative sagittal imbalance were directly compared.RESULTSForty patients (50%) developed postoperative sagittal imbalance; of these patients, 22 (55.0%) developed static proximal kyphosis from PJK, and 18 patients (45.0%) developed dynamic sagittal imbalance without PJK. The independent risk factors in proximal kyphosis were greater postoperative pelvic tilt (HR 1.11) and less change in sacral slope (SS) (HR 1.09), whereas there were more fusion levels (HR 3.11), less change in SS (HR 1.28), and less change in thoracic kyphosis (HR 1.26) in dynamic sagittal imbalance. Directly compared with the proximal kyphosis group, dynamic sagittal imbalance was more commonly found in patients who had less correction of sagittal parameters as well as fatty atrophy of the paravertebral muscles. Clinical outcomes in the dynamic sagittal imbalance group were superior to those in the proximal kyphosis group.CONCLUSIONSOptimal correction of sagittal alignment should be considered in long instrumented fusion for DSI, because insufficient correction might cause one of 2 different types of postoperative sagittal imbalance at different sites of decompression. Dynamic sagittal imbalance compared with proximal kyphosis was significantly associated with less correction of sagittal alignment, in conjunction with more fusion levels and degeneration of the paravertebral muscles.

In the last decade, a relatively novel, ubiquitous and highly stable subclass of non-coding RNAs, called circular (circ)-RNAs, has increasingly been implicated in cancer development, and several of them have been shown to act as microRNA sponges. As yet, however, the role of circRNAs in lung adenocarcinoma (LUAD) development has largely remained unexplored.Bioinformatics, microarray-based and qRT-PCR expression assays were used to assess circRNA, miRNA and mRNA expression in LUAD patient samples and cell lines. siRNA-mediated silencing was used to assess the effect of circCSNK1G3 on various LUAD-associated characteristics such as proliferation, migration, invasion and tumorigenesis, both in vitro and in vivo. Western blotting, immunohistochemistry, fluorescence in situ hybridization (FISH) and luciferase reporter activity assays were used to characterize relationships between circCSNK1G3, miR-143-3p and HOXA10 in LUAD cells.By screening for differentially expressed circRNAs, we found that circCSNK1G3 was aberrantly expressed in primary LUAD tissues and cell lines. An oncogenic role of circCSNK1G3 was deduced from its aberrant expression and associated enhancement of LUAD A549 and H1299 cell proliferation, migration and invasion. We also found that circCSNK1G3 can directly interact with and suppress miR-143-3p expression by serving as a 'miR-143-3p sponge'. In addition, we found that circCSNK1G3 can modulate homeobox (HOX) A10 expression through miR-143-3p signaling and, thereby, affect LUAD tumorigenesis.Our data indicate that circCSNK1G3 can induce HOXA10 expression and, thereby, promote the growth and metastasis of LUAD cells through hsa-miR-143-3p sponging. As such, our data highlight the targetability of the circCSNK1G3/miR-143-3p/HOXA10 signaling axis in patients with LUAD. Graphical abstract.

Purpose Contouring intraprostatic lesions is a prerequisite for dose-escalating these lesions in radiotherapy to improve the local cancer control. In this study, a deep learning-based approach was developed for automatic intraprostatic lesion segmentation in multiparametric magnetic resonance imaging (mpMRI) images contributing to clinical practice. Methods Multiparametric magnetic resonance imaging images from 136 patient cases were collected from our institution, and all these cases contained suspicious lesions with Prostate Imaging Reporting and Data System (PI-RADS) score ≥ 4. The contours of the lesion and prostate were manually created on axial T2-weighted (T2W), apparent diffusion coefficient (ADC) and high b-value diffusion-weighted imaging (DWI) images to provide the ground truth data. Then a multiple branch UNet (MB-UNet) was proposed for the segmentation of an indistinct target in multi-modality MRI images. An encoder module was designed with three branches for the three MRI modalities separately, to fully extract the high-level features provided by different MRI modalities; an input module was added by using three sub-branches for three consecutive image slices, to consider the contour consistency among different image slices; deep supervision strategy was also integrated into the network to speed up the convergency of the network and improve the performance. The probability maps of the background, normal prostate and lesion were output by the network to generate the segmentation of the lesion, and the performance was evaluated using the dice similarity coefficient (DSC) as the main metric. Results A total of 162 lesions were contoured on 652 image slices, with 119 lesions in the peripheral zone, 38 in the transition zone, four in the central zone and one in the anterior fibromuscular stroma. All prostates were also contoured on 1,264 image slices. As for the segmentation of lesions in the testing set, MB-UNet achieved a per case DSC of 0.6333, specificity of 0.9993, sensitivity of 0.7056; and global DSC of 0.7205, specificity of 0.9993, sensitivity of 0.7409. All the three deep learning strategies adopted in this study contributed to the performance promotion of the MB-UNet. Missing the DWI modality would degrade the segmentation performance more markedly compared with the other two modalities. Conclusions A deep learning-based approach with proposed MB-UNet was developed to automatically segment suspicious lesions in mpMRI images. This study makes it feasible to adopt boosting intraprostatic lesions in clinical practice to achieve better outcomes.

MicroRNAs (miRNAs) play an essential role in the chondrogenesis and the progression of osteoarthritis (OA). This study aimed to determine miRNAs associated with chondrogenesis of human mesenchymal stem cells (hMSCs) and chondrocyte metabolism. MiRNAs were screened in hMSCs during chondrogenesis by RNA-seq and qRT-PCR. MiRNA expression was determined in primary human chondrocytes (PHCs), and degraded cartilage samples. MiRNA mimics and inhibitors were transfected to cells to determine the effect of miRNA. Bioinformatic analysis and luciferase reporter assays were applied to determine the target gene of miRNA. The results demonstrated that miR-520d-5p was increased in hMSCs chondrogenesis. The overexpression and knockdown of miR-520d-5p promoted and inhibited chondrogenesis, and regulated chondrocyte metabolism. Histone deacetylase 1 (HDAC1) was decreased in hMSCs chondrogenesis, and HDAC1 was a targeting gene of miR-520d-5p. CI994, HDAC1 inhibitor, elevated cartilage-specific gene expressions and promoted hMSCs chondrogenesis. In IL-1β-treated PHCs, CI994 promoted AGGRECAN expression and suppressed MMP-13 expression, abolishing the effect of IL-1β on PHCs. Taken together, these results suggest that miR-520d-5p promotes hMSCs chondrogenesis and regulates chondrocyte metabolism through targeting HDAC1. This study provides novel understanding of the molecular mechanism of OA progression.

Although intravesical bacillus Calmette-Guérin (BCG) immunotherapy has been the gold standard for nonsurgical management of non–muscle-invasive bladder cancer, a considerable number of patients exhibit resistance to the adjuvant treatment with unexplained mechanisms. This study aimed to investigate whether and how androgen receptor (AR) signals modulate BCG cytotoxicity in bladder cancer. AR knockdown or overexpression in bladder cancer lines resulted in induction or reduction, respectively, in intracellular BCG quantity and its cytotoxic activity. Microarray screening identified Rab27b, a small GTPase known to mediate bacterial exocytosis, which was upregulated in BCG-resistant cells and downregulated in AR-shRNA cells. Knockdown of Rab27b, or its effector SYTL3, or overexpression of Rab27b also induced or reduced, respectively, BCG quantity and cytotoxicity. In addition, treatment with GW4869, which was previously shown to inhibit Rab27b-dependent secretion, induced them and reduced Rab27b expression in bladder cancer cells. Meanwhile, AR expression was upregulated in BCG-resistant lines, compared with respective controls. In a mouse orthotopic xenograft model, Rab27b/SYTL3 knockdown or GW4869 treatment enhanced the amount of BCG within tumors and its suppressive effect on tumor growth. Moreover, in non–muscle-invasive bladder cancer specimens from patients subsequently undergoing BCG therapy, positivity of AR/Rab27b expression was associated with significantly higher risks of tumor recurrence. AR activation thus correlates with resistance to BCG treatment, presumably via upregulating Rab27b expression. Mechanistically, it is suggested that BCG elimination from urothelial cells is induced by Rab27b/SYTL3-mediated exocytosis. Accordingly, Rab27b inactivation, potentially via antiandrogenic drugs and/or exocytosis inhibition are anticipated to sensitize the efficacy of BCG therapy, especially in patients with BCG-refractory AR/Rab27b-positive bladder cancer.

Background This study investigated the prognostic impact of (neo‐)adjuvant radiation therapies in early stage esophageal cancer. Methods A retrospective analysis using the Surveillance, Epidemiology, and End Results (SEER) database was conducted from 2004 to 2016. Patients with pathologically staged T1‐4N0M0 esophageal cancer were divided into two treatment groups: (i) neoadjuvant radiotherapy followed by surgery; and (ii) upfront esophagectomy followed by adjuvant radiotherapy. Propensity scored match and Cox proportional hazards model were used to identify covariates associated with overall survival and cancer‐specific survival. Results There were 821 patients selected, of whom 588 (71.6%) received neoadjuvant radiotherapy and 233 (28.4%) received adjuvant radiotherapy. For the entire cohort, neoadjuvant radiotherapy was associated with a significantly benefit in five‐year survival outcomes compared with adjuvant radiotherapy (P, In this population‐based study, we indicated that the addition of neoadjuvant RT for pT3‐4N0 diseases followed by esophagectomy was associated with improved cancer‐specific survival in patients with tumor lengths 5 cm and squamous cell carcinoma. The identification of higher‐risk patients for neoadjuvant therapy would be expected to yield better results than taking a uniform approach to this population, to avoid unnecessary and possibly harmful treatment in node‐negative diseases.

Background The impact of neoadjuvant chemoradiotherapy (nCRT) on early stage esophageal cancer is unknown. Here, we compared the outcomes after esophagectomy alone or nCRT plus surgery for clinically staged node‐negative esophageal cancer. Methods We searched the Surveillance, Epidemiology, and End Results database for patients with clinically node‐negative (cN0) esophageal cancer from 2004 to 2016 who underwent surgery alone or nCRT plus surgery. Propensity score matching and Cox regression analysis were used to identify covariates associated with overall survival and cancer‐specific survival. Results A total of 1587 patients were retrospectively identified, of whom 49.8% (n = 791) received nCRT and 80.2% (n = 1273) were truly node‐negative diseases. For the entire cohort, surgery alone was associated with a statistically significant but modest absolute increase in survival outcomes (P, This study focuses on the use of neoadjuvant chemoradiotherapy to esophageal carcinoma patients with clinically staged node‐negative (cN0) status. Finally, compared with surgery alone, cN0 esophageal cancer with falsely node‐negative (pN+) or localized truly node‐negative (pT3‐4N0) gain a significant survival benefit from neoadjuvant chemoradiation. However, neoadjuvant chemoradiation plus surgery was associated with decreased survival for early‐staged true node‐negative (pT1‐2N0) patients. Despite the inherent limitations, this population‐based study allows for a robust analysis of patients with cN0 esophageal carcinoma and the benefits of neoadjuvant chemoradiation when stratified by nodal and tumor status, and this finding may have significant implications on the use of neoadjuvant chemoradiation in patients with cN0 disease.

PURPOSE High-Dose-Rate (HDR) brachytherapy is one of the most effective ways to treat the prostate cancer, which is the second most common cancer in men worldwide. This treatment delivers highly conformal dose through the transperineal needle implants and is guided by a real time ultrasound (US) imaging system. Currently, the brachytherapy needles in the US images are manually segmented by physicists during the treatment, which is time consuming and error prone. In this study, we propose a set of deep learning-based algorithms to accurately segment the brachytherapy needles and locate the needle tips from the US images. METHODS Two deep neural networks are developed to address this problem. First, a modified deep U-Net is used to segment the pixels belonging to the brachytherapy needles from the US images. Second, an additional VGG-16-based deep convolutional network is combined with the segmentation network to predict the locations of the needle tips. The networks are trained and evaluated on a clinical US images dataset with labeled needle trajectories collected in our hospital (Institutional Review Board approval (IRB 41755)). RESULTS The evaluation results show that our method can accurately extract the trajectories of the needles with a resolution of 0.668 mm and 0.319 mm in x and y direction, respectively. 95.4% of the x direction and 99.2% of the y direction have error ≤ 2 mm. Moreover, the position resolutions of the tips are 0.721, 0.369, and 1.877 mm in x, y, and z directions, respectively, while 94.2%, 98.3%, and 67.5% of the data have error ≤ 2 mm. CONCLUSIONS This paper proposed a neural network-based algorithm to segment the brachytherapy needles from the US images and locate the needle tip. It can be used in the HDR brachytherapy to help improve the efficiency and quality of the treatments.

Ovarian cancer is a serious threat to women's life and health, with a high mortality rate. Therefore, in addition to improving surgery for ovarian cancer, it is particularly important to develop novel drug treatments. In the present study, the anticancer effects of cucurbitacin I, a natural product, were investigated. Cucurbitacin I impaired the viability of SKVO3 cells in a concentration‑ and time‑dependent manner. Apoptosis was involved in the process of cucurbitacin I‑induced cell death, with an increase observed in cleaved‑caspase 3 and BAX, and a decrease in Bcl‑2. Cucurbitacin I caused a notable increase in intracellular reactive oxygen species, and regulated Kelch‑like ECH‑associated protein 1 and nuclear factor erythroid‑derived 2‑like 2 to decrease the expression of antioxidant‑related genes. In addition, Cucurbitacin I induced cell shrinkage by regulating the p190BRhoGAP (p190B)‑Rac1 signaling axis related to the cytoskeleton. In brief, these results suggested that cucurbitacin I induced cell death through oxidative stress and the p190B‑Rac1 signaling axis in SKVO3 cells. The results may provide novel evidence for the treatment of ovarian cancer.

Purpose The microRNA (miRNA) profile changes in the tumor-associated macrophages. However, the role of miR-106b-5p in the glioblastoma-associated macrophages is poorly understood. Materials and methods In our study, miR-106b-5p and M2 macrophage markers were detected by qRT-PCR and Western blotting in THP1 cells, with the conditioned medium from U251 cells or M2 macrophages in response to IL-4 stimulation and M1 macrophages stimulated by LPS and IFN-γ. IFN regulatory factor (IRF1) was identified as a target of miR-106b-5p in the glioma infiltrating macrophages by luciferase reporter assay. The molecular mechanisms involved in the miR-106b-5p-mediated regulation of M2 polarization were clarified by shRNA knockdown assay. Results Our results showed miR-106b-5p expression was upregulated in glioma-infiltrating macrophages. miR-106b-5p regulated M2 polarization of glioma infiltrating macrophages and enhanced the growth of glioma-infiltrating macrophages. IRF1 was identified as a target of miR-106b-5p. Furthermore, miR-106b-5p inhibited IRF1 expression by targeting IRF1/IFN-β pathway to promote M2 polarization of macrophages. Conclusion miR-106b-5p may inhibit IRF1/IFN-β signaling to promote M2 macrophage polarization of glioblastoma, and it may become a novel target for the treatment of glioblastoma.

As ideal cells that can be used for adoptive cell therapy, γδ T cells are a group of homogeneous cells with high proliferative and tumor killing ability. However, γδ T cells are apt to apoptosis and show decreased cytotoxicity under persistent stimulation in vitro and cannot aggregate at tumor sites efficiently in vivo, both of which are two main obstacles to tumor adoptive immunotherapy. In this study, we found that the immune checkpoint T-cell immunoglobulin domain and mucin domain 3 (TIM-3) were up-regulated significantly on γδ T cells during their ex vivo expansion and this up-regulation contributed to the dysfunction of γδ T cells. Although the killing ability of γδ T cells against breast cancer cells which exhibited a high level of epithelial cell adhesion molecule (EpCAM) was enhanced, the level of TIM-3 on γδ T cells was also further up-regulated under the application of the bispecific antibody MT110 (anti-CD3 × anti-EpCAM) which can redirect T cells to target cells. Besides, these γδ T cells with up-regulated TIM-3 exhibited an increased susceptibility to apoptosis. By reinvigorating dysfunctional γδ T cells and promoting them to accumulate at tumor sites, the combined use of TIM-3 inhibitor and MT110 could further enhance the anti-tumor effect of the adoptively transfused γδ T cells. These results may have clinical implications for the design of new translational anti-tumor regimens aimed at combining checkpoint blockade and immune cell redirection.