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Background To investigate retrospectively an association between the number of metastatic sentinel lymph nodes (SLNs) per total number of SLNs per patient (i.e., the SLN positive rate, or SLN-PR) and non-SLN metastasis in breast cancer. Methods A large population (n = 2250) underwent SLN dissection from January 1, 2014 to January 1, 2020; 627 (27.87%) had at least one positive SLN (SLN+). Among these, 283 underwent axillary lymph node (ALN) dissection, and formed the test group. Four external validation groups comprised 43 patients treated in 2019. SLN mappings were examined using methylene blue and indocyanine green. Lymph node ultrasound, SLN-PR, and pathological characteristics were compared between patients with and without non-SLN metastasis. An SLN-PR cutoff value was calculated using receiver operating characteristic (ROC) curves. Associations between clinicopathological variables and SLN-PR with non-SLN metastasis were analyzed by multivariate logistic regression model. Results The median age was 47 years (IQR: 42-56 y). The median number of resected SLNs was 4. Patients with positive non-SLNs (126/283, 44.52%) had a median of 2 positive node. SLN-PR > 0.333 was a risk factor for non-SLN positivity (area under the ROC curve, 0.726); and carried significantly higher risk of non-SLN metastasis (P Conclusions SLN-PR > 0.333 was associated with greater risk of non-SLN metastasis. This provides a reference to non-SLN metastasis in patients with SLN metastasis, an indication for ALN dissection and choice of adjuvant treatment.

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.

A facile one-step strategy involving the reaction of antimony chloride with thioacetamide at room temperature is successfully developed for the synthesis of strongly coupled amorphous Sb2S3 spheres and carbon nanotubes (CNTs). Benefiting from the unique amorphous structure and its strongly coupled effect with the conductive network of CNTs, this hybrid electrode (Sb2S3@CNTs) exhibits remarkable sodium and lithium storage properties with high capacity, good cyclability, and prominent rate capability. For sodium storage, a high capacity of 814 mAh·g−1 at 50 mA·g−1 is delivered by the electrode, and a capacity of 732 mAh·g−1 can still be obtained after 110 cycles. Even up to 2000 mA·g−1, a specific capacity of 584 mAh·g−1 can be achieved. For lithium storage, the electrode exhibits high capacities of 1136 and 704 mAh·g−1 at 100 and 2000 mA·g−1, respectively. Moreover, the cell holds a capacity of 1104 mAh·g−1 under 100 mA·g−1 over 110 cycles. Simple preparation and remarkable electrochemical properties make the Sb2S3@CNTs electrode a promising anode for both sodium-ion (SIBs) and lithium-ion batteries (LIBs).

Background Antegrade intramedullary nailing (AIMN) with Kirschner wire (K-wire) is a minimally invasive osteosynthesis technique. This procedure has been widely performed to treat the fifth metacarpal neck fracture (FMNF) in adults. This study was performed to determine whether using AIMN with a single K-wire to treat FMNF in adolescents would have good clinical and radiographic outcomes. Methods In this retrospective study, 21 children (aged 11–16 years) with FMNF were treated using AIMN with a single K-wire from May 2017 to January 2020 in our hospital. Indications for intervention were severe displacement with malrotation deformity, apex dorsal angulation of greater than 40°, or both. Collected data included apex dorsal angulation, range of motion (ROM) in the fifth metacarpophalangeal (MCP) joint, Visual Analog Scale (VAS) for pain, grip strength, and Disabilities of the Arm, Shoulder, and Hand (DASH) score. Results All patients were followed up for 12–24 months (average, 16.57 months), and all patients obtained anatomical reduction postoperatively. The healing time was 2.69 ± 0.83 months (range, 2–4 months). Average apex dorsal angulation was reduced significantly from 44.49°±2.64° to 15.74°±2.47° (P Conclusions Antegrade intramedullary fixation with single K-wire was an effective and reliable technique that successfully resulted in good functional and cosmetic outcomes for treating adolescents with FMNF. The impact on the growth plate was low in this population given that most patients were at or approaching skeletal maturity. Level of evidence Level IV.

We investigated the effects of the transverse components of a tendon core suture on tensile resistance and strength of 4-strand repairs. Forty-four pig flexor tendons were repaired with one of the following four methods: double Tsuge, U-shaped, 4-strand cross and 4-strand rectangular repairs. We recorded the number of the repaired tendons that formed a 2 mm gap between the tendon ends during cyclic loading for 20 cycles, stiffness of the tendon at the 1st and 20th cycle, gap distance at the repair site and ultimate strength of the repair at the 20th cycle. When transverse components were added to the core suture, a greater number of tendons formed a 2 mm gap during cyclic loading. The stiffness gradually decreased, and the repair site's gap distance after cyclic loading increased with the presence of transverse components of the sutures. We conclude that the core suture's transverse components negatively impact the tensile resistance of 4-strand tendon repairs.

Objective This study aimed at evaluating the quality and readability of online information about breast cancer written in Chinese. Methods An Internet search was conducted for “breast cancer” in Chinese using the Baidu search engine. Website quality was evaluated using the DISCERN instrument, and readability was evaluated using the Chinese Readability Index Explorer (CRIE). Higher DISCERN score indicated higher quality of websites, while higher CRIE score indicated lower readability of the content of the websites. We also investigated the effects of website producer category, and the associations of search engine ranking with DISCERN and CRIE scores. Results A total of 49 websites were included. The mean overall DISCERN score was 50.27 ± 4.14, and the mean CRIE score was 6.78 ± 0.16. Websites produced by non-profit organizations had the highest overall DISCERN scores, while those produced by private individuals had the lowest CRIE scores. Search engine ranking had no significant correlation with website quality or readability. Conclusions The quality and readability of breast cancer websites in Chinese were not satisfactory, and they varied among different website producer categories. Practice implications Website producers should seek to provide more accurate, comprehensive, and easy-to-understand information to better meet the needs of breast cancer patients. In addition, search engines should revise algorithms to promote websites with higher quality and accessibility.

BACKGROUND: Triple negative breast cancer (TNBC), accounting for 15% of all breast cancer cases, was usually considered as the most aggressive subtype. The present study evaluated the prognosis of T1a TNBC and the impact of tumor size on T1 TNBC survival in large-scale population. METHODS: This retrospective study enrolled T1a/T1b/T1c TNBC and HER2(+)/hormone receptor (HoR)(−) patients diagnosed between 2010 to 2012 from the Surveillance, Epidemiology, and End Results database. The following information was extracted for further analyses: demographic variables including age at diagnosis, race, marital status, laterality, histological grade, T/N stage, American Joint Committee on Cancer (AJCC) stage, radiation therapy, survival and cause of death. Kaplan-Meier method and Cox regression were engaged for breast cancer specific survival (BCSS) and overall survival (OS) analyses. RESULTS: In all, the present study enrolled 6,953 TNBC and 2,648 HER2(+)/HoR(−) patients. T1a TNBC which generally omitted adjuvant chemotherapy had worse prognosis than T1a HER2(+)/HoR(−) [BCSS: hazard ratio (HR) 3.23, 95% confidence interval (CI): 1.05–9.09, P=0.03; OS: HR 2.63, 95% CI: 1.25–5.56, P=0.01] and T1b HER2(+)/HoR(−) (BCSS: HR 5.26, 95% CI: 1.61–16.7, P=0.006; OS: HR 3.03, 95% CI: 1.27–7.14, P=0.013) tumors which both were recommended by the National Comprehensive Cancer Network (NCCN) guideline to have chemotherapy. T1a TNBC also showed a trend with poorer prognosis than T1b TNBC, but did not reach statistical significance. CONCLUSIONS: T1a TNBC had the worst prognosis among all small tumors (

Tall cell carcinoma of the breast with reverse polarity (TCCRP), described firstly and also known as tall cell variant of papillary breast carcinoma (TCVPBC), is a rare type of breast cancer that mimics papillary thyroid carcinoma (PTC) histopathologically. As the incidence of this type of tumor is very low, awareness of it is crucial to ensuring that unnecessary clinical investigations are avoided. The present study examined a 45-year-old woman in China who was diagnosed with TCCRP. This paper outlines her demographic and clinicopathologic data, and her follow-up and immunohistochemical examination results. Furthermore, this study used the next-generation sequencing (NGS) technique to identify concurrent isocitrate dehydrogenase 2 (IDH2) and phosphatidylinositol 3-kinase catalytic alpha (PIK3CA) hotspot mutations. Notably, the novel results of the study showed that the IDH2 R120 (rather than the IDH2 R172) mutation may also be present in this disease. Additionally, a comprehensive literature review was conducted to elucidate some of the significant clinical and pathological features of this type of disease. This information may provide important insights that can be used in diagnosis and treatment. It is essential both for physicians and pathologists to recognize the existence of TCCRP, with its own specific clinical and pathological characteristics. Further research using molecular biology techniques should be conducted in the future to characterize this unique entity.

Diabetic kidney disease (DKD) is a major complication of diabetes. Expression of members of the microRNA (miRNA) miR-379 cluster is increased in DKD. miR-379, the most upstream 5′-miRNA in the cluster, functions in endoplasmic reticulum (ER) stress by targeting EDEM3. However, the in vivo functions of miR-379 remain unclear. We created miR-379 knockout (KO) mice using CRISPR-Cas9 nickase and dual guide RNA technique and characterized their phenotype in diabetes. We screened for miR-379 targets in renal mesangial cells from WT vs. miR-379KO mice using AGO2-immunopreciptation and CLASH (cross-linking, ligation, sequencing hybrids) and identified the redox protein thioredoxin and mitochondrial fission-1 protein. miR-379KO mice were protected from features of DKD as well as body weight loss associated with mitochondrial dysfunction, ER- and oxidative stress. These results reveal a role for miR-379 in DKD and metabolic processes via reducing adaptive mitophagy. Strategies targeting miR-379 could offer therapeutic options for DKD., Kato, Abdollahi et al. identify a redox protein thioredoxin and mitochondrial fission-1 (FIS1) protein as miR-379 targets in mouse kidney. They find that miR-379 knockout mice are protected from diabetic kidney disease by enhancing mitophagy via FIS1, suggesting miR-379 as a potential therapeutic target for diabetic kidney disease.

OBJECTIVE: To explore the specific contrast-enhanced ultrasound (CEUS) features of hepatocellular adenomas (HCA) according to their pathological molecular classifications. METHODS & MATERIALS: In this retrospective study, fifty-three histopathologically proved HCA lesions (mean size, 39.7±24.9 mm) were included. Final histopathological diagnosis of HCA lesions were identified by surgical resection (n = 51) or biopsy (n = 2) specimens. CEUS imaging features were compared among four subgroups according to World Health Organization (WHO) 2019 pathological molecular classifications standards. Analysis of variance (ANOVA) were used for statistical analysis of continuous variables. Fisher’s exact test were used for categorical variables. The sensitivity (SE), specificity (SP), and accuracy of CEUS feature in diagnosis of each HCA subtype were calculated and compared. RESULTS: Final histopathological diagnosis included HNF-1α inactivated HCAs (H-HCA, n = 12), β-catenin activated HCAs (B-HCA, n = 8), inflammatory HCAs (I-HCA, n = 31), and unclassified HCAs (U-HCA, n = 2). During arterial phase of CEUS, all HCAs were hyper-enhanced, 66.6% (8/12) of H-HCAs and 50% (4/8) of B-HCAs displayed complete hyperenhancement, whereas 58.0% (18/31) of I-HCAs showed centripetal filling hyperenhancement pattern (P = 0.016). Hyper-enhanced subcapsular arteries could be detected in 64.5% (20/31) I-HCAs during early arterial phase. During portal venous and late phase, sustained hyper- or iso-enhancement were observed in 91.7% (11/12) of H-HCAs, while most of I-HCAs (61.3%, 19/31) and B-HCAs (7/8, 87.5%) were hypo-enhanced (P = 0.000). Central unenhanced areas were most commonly observed in I-HCAs (29.0%, 9/31) (P = 0.034). CONCLUSION: Depending on its unique imaging features including enhancement filling pattern, hyper-enhanced subcapsular artery and presence of washout, CEUS might provide helpful diagnostic information for preoperative prediction of various HCA molecular subtypes.

In this study, human skin fibroblasts human dermis fibroblasts were used as the object, the possible effects and mechanisms of rosemary extract on repeated exposure to Ultraviolet A (UVA) induced senescence of human skin fibroblasts were investigated. During the research, we mainly carried out through two parts. The first part mainly explores the effect of repeated UVA radiation on human skin fibroblasts; the second part mainly discusses the effect of rosemary extract on the induction of human skin formation by repeated UVA radiation. The results showed that repeated UVA irradiation of human skin fibroblasts can induce aging phenomena, such as slow proliferation and an increase in β-galactosidase staining positive rate; repeated exposure of rosemary extract to low-dose UVA can slow down human skin fibroblasts to age. Its mechanism may be related to reducing the total intracellular ROS, the mRNA expression of MMP-1 and MMP-3, and the expression of p53 protein. In short, this study provides a new approach and theoretical basis for the development and application of natural sunscreens.

Background. Testosterone replacement therapy (TRT) is commonly used for the treatment of hypogonadism in men, which is often associated with type 2 diabetes mellitus (T2DM) and metabolic syndrome (Mets). Recent compiling evidence shows that TRT has beneficial metabolic effects on these patients. Objective. A meta-analysis has been conducted to evaluate the effects of TRT on cardiovascular metabolic factors. Methods. We conducted a systemic search on PubMed, Embase, Cochrane Library, Wanfang, and CNKI and selected randomized controlled trials (RCTs) to include. The efficacy of TRT on glycemia, insulin sensitivity, lipid profile, and body weight was meta-analyzed by Review Manager. Results. A total of 18 RCTs, containing 1415 patients (767 in TRT and 648 in control), were enrolled for the meta-analysis. The results showed that TRT could reduce HbA1c (MD = −0.67, 95% CI −1.35, −0.19, and P = 0.006 ) and improve HOMA-IR (homeostatic model assessment of insulin resistance) (SMD = −1.94, 95% CI −2.65, −1.23, and P < 0.0001 ). TRT could also decrease low-density lipoprotein (SMD = −0.50, 95% CI −0.82, −0.90, and P = 0.002 ) and triglycerides (MD = −0.64, 95% CI −0.91, −0.36, and P < 0.0001 ). In addition, TRT could reduce body weight by 3.91 kg (MD = −3.91, 95% CI −4.14, −3.69, and P < 0.00001 ) and waist circumference by 2.8 cm (MD −2.80, 95% CI −4.38, −1.21 and P = 0.0005 ). Erectile dysfunction (measured by IIEF-5) did not improve, while aging-related symptoms (measured by AMS scores) significantly improved. Conclusions. TRT improves glycemic control, insulin sensitivity, and lipid parameters in hypogonadism patients with T2DM and MetS, partially through reducing central obesity.

To compare the circular pathological changes of chronic hepatitis B (CHB) patients according to the tongue diagnosis. Totally 41 CHB patients with typical white tongue coating (WTC) or yellow tongue coating (YTC) were enrolled and 14 healthy volunteers with normal tongue manifestation served as controls. The mRNA expression of peripheral leukocytes was detected by GeneChips, and 9 genes were randomly selected for expression validation. Circular metabolites were detected by gas chromatographymass spectrometry. Biological information was analyzed based on ingenuity pathways analysis or metabolomics database and the integrated networks were constructed by ClueGO. A total of 945 and 716 differentially expressed genes were found in patients with WTC and YTC relative to healthy volunteers respectively. The biological information analysis indicated that CHB patients had obviously increased functions in cell death, apoptosis and necrosis (Z-score ⩾2, P

Tendon stem/progenitor cells (TSPCs) are considered promising seed cells for tendon regeneration. Previous studies reported that a low seeding density favors TSPC growth, whereas a high seeding density favors tenocyte growth. We aimed to distinguish TSPCs from tenocytes by seeding tendon-derived cells at a density gradient. In this study, tendon-derived cells were isolated from flexor digitorum profundus tendons of mice and seeded at the initial densities of 50, 500, 5,000, and 50,000/cm

Background: Metabolic disorders such as obesity and diabetes mellitus can cause dysfunction of endothelial cells (ECs) and vascular rarefaction in adipose tissues. However, the modulatory role of ECs in adipose tissue function is not fully understood. Other than vascular endothelial growth factor–vascular endothelial growth factor receptor-mediated angiogenic signaling, little is known about the EC-derived signals in adipose tissue regulation. We previously identified Argonaute 1 (AGO1; a key component of microRNA-induced silencing complex) as a crucial regulator in hypoxia-induced angiogenesis. In this study, we intend to determine the AGO1-mediated EC transcriptome, the functional importance of AGO1-regulated endothelial function in vivo, and the relevance to adipose tissue function and obesity. Methods: We generated and subjected mice with EC-AGO1 deletion (EC-AGO1-knockout [KO]) and their wild-type littermates to a fast food–mimicking, high-fat high-sucrose diet and profiled the metabolic phenotypes. We used crosslinking immunoprecipitation- and RNA-sequencing to identify the AGO1-mediated mechanisms underlying the observed metabolic phenotype of EC-AGO1-KO. We further leveraged cell cultures and mouse models to validate the functional importance of the identified molecular pathway, for which the translational relevance was explored using human endothelium isolated from healthy donors and donors with obesity/type 2 diabetes mellitus. Results: We identified an antiobesity phenotype of EC-AGO1-KO, evident by lower body weight and body fat, improved insulin sensitivity, and enhanced energy expenditure. At the organ level, we observed the most significant phenotype in the subcutaneous and brown adipose tissues of KO mice, with greater vascularity and enhanced browning and thermogenesis. Mechanistically, EC-AGO1 suppression results in inhibition of thrombospondin-1 ( THBS1 /TSP1), an antiangiogenic and proinflammatory cytokine that promotes insulin resistance. In EC-AGO1-KO mice, overexpression of TSP1 substantially attenuated the beneficial phenotype. In human endothelium isolated from donors with obesity or type 2 diabetes mellitus, AGO1 and THBS1 are expressed at higher levels than the healthy controls, supporting a pathological role of this pathway. Conclusions: Our study suggests a novel mechanism by which ECs, through the AGO1-TSP1 pathway, control vascularization and function of adipose tissues, insulin sensitivity, and whole-body metabolic state.

The actin fiber-associated protein 1-antisense RNA1 (AFAP1-AS1) is upregulated in various cancers and associated with cancer proliferation and metastasis. Several cancer-related pathways have been linked to up-expression of this long non-coding (lnc)RNA, but the underlying mechanisms are yet unknown. In triple negative breast cancer (TNBC), AFAP1-AS1 expression is also significantly overexpressed compared to that in other subtypes of breast cancer from the TCGA dataset. In this study, we performed bioinformatic RNAhybrid analyses and identified that miR-145 is a potential target of AFAP1-AS1 and able to reduce MutT homolog-1 (MTH1) expression. Thus, this study investigated the oncogenic activity of AFAP1-AS1 in TNBC cells and the underlying mechanisms that are yet poorly understood. The results showed that miR-145 expression was low, whereas AFAP1-AS1 and MTH1 expression was high in TNBC cells and that miR-145 mimics reduced TNBC cell proliferation and invasion, whereas miR-145 knockdown exerted the opposite activity in TNBC cells. Moreover, knockdown of AFAP1-AS1 reduced tumor cell proliferation and invasion, but miR-145 co-transfection rescued tumor cell viability and colony formation ability. The dual luciferase reporter assay showed that AFAP1-AS1 could directly target miR-145, while miR-145 could directly target MTH1. After knockdown of ATF6, AFAP1-AS1 was reduced along with AFAP1-AS1 promoter activity. This study revealed that AFAP1-AS1 could promote TNBC cell proliferation and invasion via regulation of MTH1 expression through targeting of miR-145.

Purpose To investigate the effects of Mytilus edulis water extract (MWE) on an anterior cruciate ligament transection and a partial medial meniscectomy surgery to induced osteoarthritis (OA) with the high-fat diet (HFD)-induced obese rats. Methods The male Sprague-Dawley rats were fed with HFD for 4 weeks before surgery. The OA rats were orally administered with MWE (108.5, 217.0, and 542.5 mg/kg) for 6 weeks. Results The administration of MWE affected weight loss, triglycerides content, and total cholesterol level. MWE also enhanced the activity of superoxide dismutase and decreased lipid peroxidation degree. Moreover, MWE reduced proinflammatory cytokines level, alleviated inflammation and swelling of the osteoarthritic knee, and reduced loss of proteoglycan in articular cartilage tissue. Conclusion MWE suppressed proinflammatory mediators and attenuated the cartilage degradation and pain in osteoarthritis rats under obesity condition. Therefore, MWE has the potential to act as an alternative for osteoarthritis treatment.

Background The 21‐gene recurrence score (RS) assay has been recommended by major guidelines for treatment decision in hormone receptor (HR)‐positive early breast cancer (EBC). However, the genomic assay is not accessible and affordable worldwide. Alternatively, an increasing number of studies have shown that traditional immunohistochemistry (IHC) can partially or even completely replace the role of the 21‐gene genomic assay. Here, we developed and validated a predictive model (IHC3 model) combining the Ki‐67 index, progesterone receptor (PR) expression, histologic grade, and tumor size to predict the recurrence risk of HR‐positive EBC. Methods The data from 389 patients (development set) with HR‐positive, human epidermal growth factor receptor 2‐negative, lymph node non‐metastasized invasive breast cancer were used to construct the IHC3 model based on the Surexam® 21‐gene RS and the TAILORx clinical trial criteria. An additional 146 patients with the same characteristics constituted the validation set. The predictive accuracy of the IHC3 model was compared with that of Orucevic et al.’s nomogram. Invasive disease‐free survival (IDFS) was analyzed in the IHC3 predictive low‐recurrence risk (pLR) group and the predictive high‐recurrence risk (pHR) group. The Pearson chi‐square test, Fisher exact test, and log‐rank test were used for analysis. Results The pLR and pHR group could be easily stratified using the decision tree model without network dependence. The accuracies of the IHC3 model were 86.1% in the development set and 87.7% in the validation set. The predictive accuracy of the IHC3 model and Orucevic et al.’s nomogram for the whole cohort was 86.5% and 86.9%, respectively. After a 52‐month of median follow‐up, a significant difference was found in IDFS between of the IHC3 pLR and the pHR groups (P = 0.001) but not in the IDFS between the low‐ and high‐recurrence risk groups according to the Surexam® 21‐gene RS and the TAILORx clinical trial criteria (P = 0.556) or 21‐gene binary RS group (P = 0.511). Conclusions The proposed IHC3 model could reliably predict low and high recurrence risks in most HR‐positive EBC patients. This easy‐to‐use predictive model may be a reliable replacement for the 21‐gene genomic assay in patients with EBC who have no access to or cannot afford the 21‐gene genomic assay.

Severe anorexia limits the clinical application of cisplatin, and even leads to the discontinuation of treatment. However, the mechanisms underlying cisplatin-induced anorexia are unknown. Herein, we demonstrated that cisplatin could affect neuronal gamma oscillations and induce abnormal neuronal theta-gamma phase-amplitude coupling in the arcuate nucleus (Arc) of the hypothalamus, and these findings were associated with significantly decreased food intake and weight loss in mice. Chemogenetic activation of AgRP neurons in the Arc reversed the cisplatin-induced food intake reduction in mice. We further demonstrated that endothelial peroxynitrite (ONOO−) formation in the Arc induced nitrosative stress following cisplatin treatment via a previously uncharacterized pathway involving neuronal caspase-1 activation. Strikingly, treatment with the ONOO− scavenger uric acid (UA) reversed the reduced action potential (AP) frequency of AgRP neurons and increased the AP frequency of POMC neurons induced by SIN1, a donor of ONOO−, in the Arc, as determined by whole-cell patch-clamp electrophysiological recording. Consistent with these findings, UA treatment effectively alleviated cisplatin-induced dysfunction of neuronal oscillations and neuronal theta-gamma phase-amplitude coupling in the Arc of mice. Taken together, these results suggest, for the first time, that targeting the overproduction of endothelial ONOO− can regulate cisplatin-induced neurotoxicity through neuronal caspase-1, and thereby serve as a potential therapeutic approach to alleviate chemotherapy-induced anorexia and weight loss., Highlights • Endothelial ONOO– induced the abnormal neuronal oscillations following cisplatin treatment through caspase-1 in the Arc. • ONOO– scavenger UA could attenuate cisplatin-induced neurotoxicity and caspase-1 activation in the Arc. • Targeting endothelial ONOO– provided a promising approach to alleviate chemotherapy-induced anorexia and weight loss.

As a T cell-mediated autoimmune disease, type 1 diabetes mellitus (T1DM) is marked by insulin defect resulting from the destruction of pancreatic β-cells. The understanding of various aspects of T1DM, such as its epidemiology, pathobiology, pathogenesis, clinical manifestations, and complications, has been greatly promoted by valuable research performed during the past decades. However, these findings have not been translated into an effective treatment. The ideal treatment should safely repair the destroyed immune balance in a long-lasting manner, preventing or stopping the destruction of β-cells. As a type of immune hypo-responsiveness to the orally administrated antigen, oral tolerance may be induced by enhancement of regulatory T cells (Tregs) or by anergy/deletion of T cells, depending on the dosage of orally administrated antigen. Acting as an antigen-specific immunotherapy, oral tolerance therapy for T1DM has been mainly performed using animal models and some clinical trials have been completed or are still ongoing. Based on the review of the proposed mechanism of the development of T1DM and oral tolerance, we give a current overview of oral tolerance therapy for T1DM conducted in both animal models and clinical trials.

Fibrolamellar hepatocellular carcinoma (f-HCC) is a rare primary liver tumor. Imaging plays an important role in diagnosis. The aim of this retrospective study was to analyze contrast-enhanced ultrasound (CEUS) features of histologically proven f-HCC in comparison to benign focal nodular hyperplasia (FNH). 16 patients with histologically proven f-HCC lesions and 30 patients with FNH lesions were retrospectively reviewed regarding CEUS features to determine the malignant or benign nature of the focal liver lesions (FLL). Five radiologists assessed the CEUS enhancement pattern and came to a consensus using the EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology) guideline criteria. Fibrolamellar hepatocellular carcinoma manifested as a single and huge FLL. On CEUS, f-HCC showed heterogeneous hyperenhancement in the arterial phase and hypoenhancement (16/16, 100 %) in the portal venous and late phases (PVLP) as a sign of malignancy. In contrast to the hypoenhancement of f-HCC in the PVLP, all patients with FNH showed hyperenhancement as the most distinctive feature (P 0.01). 8 f-HCC lesions showed a central scar as an unenhanced area (8/16, 50.0 %), which could also be detected in 53.3 % (16/30) of FNH lesions (P 0.05). By analyzing the hypoenhancement in the PVLP, CEUS imaging reliably diagnosed f-HCC as a malignant FLL. CEUS also showed differentiation between f-HCC and FNH lesions, showing similar non-enhanced central scars, whereas f-HCC lesions showed peripheral hyperenhancement in the arterial phase and early washout in the PVLP.ZIEL: Das fibrolamelläre hepatozelluläre Karzinom (f-HCC) ist ein seltener primärer Lebertumor. Die Bildgebung spielt bei der Diagnose eine wichtige Rolle. Ziel dieser retrospektiven Studie war es, die Merkmale im kontrastverstärkten Ultraschall (CEUS) bei histologisch nachgewiesenem f-HCC im Vergleich zur benignen fokalen nodulären Hyperplasie (FNH) zu analysieren. 16 Patienten mit histologisch nachgewiesenen f-HCC-Läsionen und 30 Patienten mit FNH-Läsionen wurden retrospektiv auf CEUS-Merkmale untersucht, um die maligne oder benigne Natur der fokalen Leberläsionen (FLL) zu bestimmen. 5 Radiologen bewerteten das CEUS-Enhancement-Muster und kamen zu einem Konsens unter Verwendung der Kriterien der EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology) -Richtlinien. Das fibrolamelläre Leberzellkarzinom manifestierte sich als eine einzige und große FLL. Im CEUS zeigte das f-HCC ein heterogenes Hyperenhancement in der arteriellen Phase und ein Hypoenhancement (16/16, 100 %) in der portalvenösen und späten Phase (PVLP) als Marker für Malignität. Im Gegensatz zum Hypoenhancement des f-HCC in der PVLP zeigten alle Patienten mit FNH ein Hyperenhancement als auffälligstes Merkmal (p 0,01). 8 f-HCC-Läsionen zeigten eine zentrale Narbe als Bereich ohne Anreicherung (8/16; 50,0 %), welche auch bei 53,3 % (16/30) der FNH-Läsionen nachgewiesen werden konnte (p 0,05). Durch die Untersuchung des Hypoenhancements in der PVLP konnte die CEUS-Bildgebung f-HCC zuverlässig als maligne FLL diagnostizieren. Außerdem konnte CEUS zwischen f-HCC und FNH-Läsionen differenzieren und zeigte ähnliche zentrale Narben ohne Anreicherung, wobei f-HCC-Läsionen ein peripheres Hyperenhancement in der arteriellen Phase und ein frühes Wash-out in der PVLP zeigten.

Background: Non-alcoholic fatty liver disease (NAFLD) was a common disease and a frequent side effect of endocrine therapy for breast cancer patients. This was the first meta-analysis to investigate the impact of NAFLD on breast cancer survival. Material and Methods: We searched Pubmed, Embase and Cochrane Central Register of Controlled Trials database for relevant studies that investigated the correlation between NAFLD and breast cancer survival. Fixed- and random-effect meta-analyses were conducted according to the heterogeneity of enrolled studies. Subgroup analyses were based on whether NAFLD was induced by Selective-estrogen receptor modulator (SERM) administration. Results: Six cohorts from five studies including 935 NAFLD and 2102 non-NAFLD patients were enrolled. NAFLD was significantly associated with advanced age (p< 0.001), obesity (p< 0.001), lymph node metastasis (p = 0.003), hormone receptor positivity (p < 0.001) and human epidermal growth factor receptor 2 positivity (p = 0.008). NAFLD had no significant impact on disease free survival(DFS) [hazard ratio (HR) 0.95, 95% confidence interval (CI) = 0.48-1.87, p = 0.87] and overall survival (OS) (HR 1.28, 95% CI = 0.59-2.78, p = 0.53). In subgroup analyses, SERM-associated NAFLD showed no significant impact on DFS and OS. Nonetheless, non-SERM-associated NAFLD had a strong prognostic correlation with poor OS (HR 1.92, 95% CI = 1.09-2.06, p = 0.02). Conclusion: NAFLD had no significant impact on breast cancer survival. However, non-SERM-associated NAFLD implied increasing death risk. Future large-scale studies are warranted to further elucidate the correlation between NAFLD and breast cancer prognosis. Keywords: breast cancer; non-alcoholic fatty liver disease; selective estrogen receptor modulator; liver metastasis TABLES Table 1. Characteristics of studies enrolled in meta-analysisStudyCountryDesignNMedian follow-up (month)TNM StageNAFLD AssessmentLiver Metastasis AssessmentClinical EndpointsHormone ReceptorRelationship Between SERM-treatment and NAFLDDuran(2015)TurkeyRC107NAIVContrast-enhanced/ Non-Contrast CTNAOSNANon-SERM-associated NAFLDYan(2017)ChinaRC64664(7-91)I-IIIUSGUSGDFS, OSER+ and/or PR+SERM-associated NAFLDWu(2017)ChinaRC123030.7±24.9 32.4±26.3I-IIIUSGUSG/CT/MRILiver-MFSER/PR+799 ER/PR- 331NAZheng(2015)ChinaRC78576(14-122)I-IIIUSGNADFS, OSER/PR+SERM-associated NAFLDYang(2015) Cohort A*KoreaRC28NAII/IIIUSG/ Non-Contrast CT/ Contrast CTNADFS, OSNANon-SERM-associated NAFLDYang(2015) Cohort B*KoreaRC24NAII/IIIUSG/ Non-Contrast CT/ Contrast CTNADFS, OSNANon-SERM-associated NAFLDRC, retrospective cohort; NA, not available; CT, computed tomography; OS, overall survival; DFS, disease free survival; SERM, selective estrogen receptor modular; USG, ultrasonography; MRI, Magnetic resonance imaging; MFS, metastasis free survival.*Study by Yang et al. included two cohorts Table 2. Correlation Between NAFLD Presence and Clinicopathological FeaturesNAFLD(%)Non-NAFLD(%)P valueAge (years)50397(32.4%)829(67.6)BMI (kg/m2)25320(43.2%)421(56.8%)Tumor Size (mm)5080(30.3%)184(69.7%)LN MetastasisYes540(40.9%)780(59.1%)0.003*No281(36.6%)486(63.4%)MenopausePre153(33.5%)304(66.5%)0.766Post96(32.4%)200(85.9%)ER/PR StatusER/PR +630(34.9%)1173(65.1%) Citation Format: Yu Song, Changjun Wang, Wei Huang, Yidong Zhou, Ziyuan Chen, Hanjiang Zhu, Feng Mao, Yan Lin, Xiaohui Zhang, Songjie Shen, Ying Zhong, Xin Huang, Chang Chen, Qiang Sun. The impact of pre-existed and SERM-induced non-alcoholic fatty liver disease on breast cancer survival: A meta-analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-12-14.

Background: Non-alcoholic fatty liver disease (NAFLD) is a common disorder and a frequent side effect of endocrine therapy (ET) for breast cancer treatment. This was the first meta-analysis to investigate the impact of NAFLD on breast cancer survival. Material and Methods: We searched Pubmed, Embase and Cochrane Central Register of Controlled Trials database for relevant studies that investigated the correlation between NAFLD and breast cancer survival. Fixed- and random-effect meta-analyses were conducted according to the heterogeneity of enrolled studies. Subgroup analyses were performed based on whether NAFLD was induced by ET administration Results: Eight cohorts from six studies including 3684 breast cancer patients were enrolled. NAFLD was significantly associated with advanced age (p < 0.001), obesity (p < 0.001), lymph node metastases (p = 0.003) and hormone receptor positivity (p < 0.001). NAFLD had no significant impact on disease free survival (DFS) [hazard ratio (HR) 1.07, 95% confidence interval (CI) = 0.64-1.77, p = 0.81] and overall survival (OS) (HR 1.29, 95% CI = 0.68-2.44, p = 0.44). In subgroup analyses, ET-associated NAFLD showed no significant impact on DFS and OS. Nonetheless, non-ET-associated NAFLD had a strong prognostic correlation with poor OS (HR 1.92, 95% CI = 1.09-3.41, p = 0.02). Conclusion: NAFLD had no significant impact on breast cancer survival. However, non-ET-associated NAFLD implied increasing death risk. Future large-scale studies are warranted to further elucidate the correlation between NAFLD and breast cancer prognosis.

Background: The diagnostic performance of an automated breast volume scanner (ABVS) compared with that of a hand-held ultrasound (HHUS) for breast cancer remains unclear. We performed a meta-analysis to compare the diagnostic performances of the ABVS and HHUS for breast cancer. Methods: We searched PubMed, EMBASE, Cochrane, and SinoMed databases to identify eligible studies up until November 14, 2018. Studies comparing ABVS and HHUS for differentiating benign and malignant breast tumors were included. A meta-analysis was performed to generate pooled diagnostic accuracy parameters [sensitivity, specificity, diagnostic odds ratio (DOR), area under the curve (AUC), and the Q* index] and detection rates for ABVS and HHUS. Results: Nine studies involving 1,376 patients and 1,527 lesions were included in the meta-analysis for diagnostic accuracy. The pooled sensitivity was 0.93 [95% confidence interval (CI), 0.91–0.95] for ABVS and 0.90 (95% CI, 0.88–0.92) for HHUS, and the pooled specificity was 0.86 (95% CI, 0.83–0.88) for ABVS and 0.82 (95% CI, 0.79–0.84) for HHUS. The pooled DOR was 88.66 (95% CI, 51.44–152.78) for ABVS and 41.06 for HHUS (95% CI, 26.58–63.42). The AUC of the summary receiver operating characteristic (SROC) was 0.9496 for ABVS and 0.9143 for HHUS, and the Q* index was 0.8899 for ABVS and 0.8469 for HHUS. Meta-regression showed no significant difference between the diagnostic accuracy of ABVS and HHUS (P=0.0771). No publication bias was found. Thirteen published studies involving 1,047 pathologically confirmed malignant lesions were included to generate a pooled detection rate. The pooled detection rate was 1.00 (95% CI, 1.00–1.00) for both ABVS and HHUS, for which a publication bias was found. Conclusions: ABVS can be used as an appropriate screening tool for breast cancer as well as HHUS in diagnostic accuracy and detection rate. Considering other advantages of ABVS including non-radioactivity, sensitivity to dense breast, three-dimensional reconstruction, time-saving and repeatability, it might be a promising screening tool for young or dense-breast women in the future.

Three mol.% yttria-stabilized tetragonal zirconia polycrystalline ceramics (3Y-TZP) billets were dipped in dyeing solution and then sintered for external dyeing. The effect of Pr and Er single elements on 3Y-TZP coloring and the rule of multivariate influence on the overall coloring effect after mixing were investigated and clarified. The structure, morphology, color and physical properties of 3Y-TZP were characterized by x-ray diffraction, scanning electron microscopy and spectrophotometry. The results show that Pr and Er show yellow and red, respectively, in the process of coloring, and the effect of Pr coloring is confirmed. When the two elements are used for dyeing at the same time, the value of a*, b* of the mixed color shows the additivity of the value of a*, b*, and the value of L* increases. This mixed dyeing is of great significance to the development of dental ceramics.

BACKGROUND In previous studies, higher expression of PREX1 (PtdIns (3,4,5)P3-dependent Rac exchanger 1) has been detected in some subsets of breast cancer, and activation of PREX1 has been associated with tumor progression in vivo. However, an association between PREX1 and breast cancer prognosis has not been examined. MATERIAL AND METHODS In this study, we investigated the expression and correlation of PREX1 with important clinical factors and prognosis of patients with breast cancer. Immunohistochemical staining was performed for 121 tumor tissue specimens obtained from primary breast cancer lesions. RESULTS We found that 55 tissues exhibited positive staining for PREX1. Moreover, tumors positive for PREX1 were found to have significant association with recurrence rate (P=0.000) and metastasis rate (P=0.001). Univariate and multivariate regression analyses also identified PREX1 expression as an independent variable of disease-free survival. Our analyses indicate that high levels of PREX1 expression were related to longer disease-free survival in patients with breast cancer (P=0.013). CONCLUSIONS PREX1 is a favorable variable of prognosis for breast cancer patients, these study results need to be confirmed in larger research studies.

Purpose Human epidermal growth factor receptor 2 (HER2) status is both an independent prognostic factor and a predictive factor for the efficacy of targeted therapy for breast cancer, so it is critical to accurately detect HER2 protein expression and/or gene amplification. According to the recommendations of the 2013 American Society of Clinical Oncology and College of American Pathologists (ASCO/CAP) guidelines for HER2 breast cancer testing, an additional test should be pursued on a different block from the same tumor as one of the options for patients with immunohistochemistry (IHC) 2+ and a HER2/CEP17 ratio of

Background: Metastatic triple negative breast cancer (mTNBC) is a heterogeneous disease with poor prognosis. Molecular evolution of TNBC through chemotherapy selection pressure is well recognized but poorly understood. PI3K/AKT/mTOR is one of the most commonly identified oncogenic-driver pathways in breast cancer. The current study is designed to understand the genomic and transcriptomic changes, focusing on the PI3K/AKT/mTOR pathway alterations in paired primary and metastatic TNBCs. Results: Genomic analysis of 7 paired specimens identified 67 known mutations including those from the following signaling pathways: cell cycle, p53, PI3K/AKT/mTOR, RAS/MAPK, and RTK/GF. Principle coordinate analysis (PCoA) identified 4 distinctive molecular groups based on the gene expression patterns of PI3K/AKT/mTOR pathway. Key differentially-expressed genes included AKT3, GSK3B, GNA11, PI3KR1, and GNAQ. Importantly, AKT-targeted therapy showed efficacy in a patient-derived xenograft (PDX) model of TNBC in vivo. Conclusion: Genomic discordance of paired primary and metastatic TNBCs was identified, with significant increase in tumor proliferation pathways seen in metastases. Among the differentially expressed genes, AKT3 can potentially serve as a target for novel combination therapy for treatment of metastatic TNBC. Methods: Paired specimens from 10 patients with TNBCs were identified through an IRB-approved protocol (2002–2015). FoundationOneTM sequencing was performed for genomic profiling, and Affymetrix Human Genechip 2.0st was used for mRNA expression profiling. The similarity among samples was calculated based on Pearson correlation coefficients, which were used to construct hierarchical clustering and heat maps.

Background: Chemotherapy impairs ovarian function in premenopausal breast cancer patients. Many breast cancer patients experience menopause earlier and therefore lose their reproductive abilities. The protective effect of gonadotropin-releasing hormone agonist (GnRha) upon the ovary is clearly apparent for hormone receptor (HR) negative patients, although the available data is not consistent for the patient body as a whole when considered regardless of HR status. It is also unknown whether levels of Anti-Mullerian Hormone (AMH) can reflect the influence of chemotherapy upon the ovary. Methods: We randomly assigned 98 premenopausal breast cancer patients regardless HR-positive or -negative to receive either standard chemotherapy with GnRHa (GnRHa group) or standard chemotherapy without GnRHa (control group). Our primary end point was ovarian failure rate (OVF) at 1 year. In addition, we observed the change of AMH level during chemotherapy and the association between AMH and OVF. Results: OVF was significantly lower (44.7%) in the GnRHa group than in the control group (80.6%; P=0.002). Median AMH levels were significantly higher before chemotherapy when compared to after 1/2cycles of chemotherapy, both in the GnRHa group (1.86ng/ml vs 0.12ng/ml; P=0.000) and in the control group (1.57ng/ml vs 0.10ng/ml; P=0.000). OVF was 91.3% in the AMH baseline level 1.1ng/ml group (P=0.013). Conclusion: Data showed that GnRHa may have a protective effect on young breast cancer patients regardless of HR during chemotherapy. AMH could reflect changes of OVF during chemotherapy and predict OVF after chemotherapy.

Background The incidence of bilateral breast cancer (BBC) is increasing nowadays comprising 2%‐11% of all breast cancer (BC). According to the interval time between the first and second cancer, BBC could be divided into synchronous (SBBC) and metachronous (MBBC). However, this interval time is quite different across studies. It remains controversial whether the survival of BBC, SBBC, and MBBC is similar or worse compared to that of unilateral breast cancer (UBC), and whether the survival of SBBC is similar or worse compared to MBBC. To better understand the survival of UBC, BBC, SBBC, and MBBC and how the interval time would influence the prognosis of SBBC and MBBC, we performed this meta‐analysis on studies from recent 10 years (2008‐2018). Methods Databases of PubMed, Embase, and Web of Science were searched for relevant studies within recent 10 years. Hazard ratio (HR) was adopted to evaluate the difference of overall survival (OS) of UBC, BBC, SBBC, and MBBC. HR of OS comparisons were performed between BBC vs UBC, SBBC vs UBC, MBBC vs UBC, and SBBC vs MBBC with 3, 6, 12 months as the interval time, respectively. Results There were 15 studies of 72 302 UBC and 2912 BBC included in the meta‐analysis. The summary HR of OS comparison between BBC vs UBC was 1.68 (95% CI: 1.28‐2.20), SBBC vs UBC was 2.01 (95% CI: 1.14‐3.55), MBBC vs UBC was 3.22 (95% CI: 0.75‐13.78). When 3, 6, 12 months were used as the interval time, the summary HR of the OS comparison between of SBBC vs MBBC were 0.64 (95% CI: 0.44‐0.94), 1.17 (95% CI: 0.84‐1.63) and 1.45 (95% CI: 1.10‐1.92), respectively. Conclusion BBC and SBBC showed worse prognosis in terms of OS compared to UBC while MBBC manifested similar or non‐superior survival as UBC. The OS comparison between SBBC and MBBC changed with different interval time used. The longer the interval time used, the worse the survival of SBBC. SBBC with interval of 3‐12 months between the two cancers had the worst prognosis. When 6 months was used to differentiate SBBC from MBBC, these two clinical entities showed similar OS.

Tissues and cells in organism are continuously exposed to complex mechanical cues from the environment. Mechanical stimulations affect cell proliferation, differentiation, and migration, as well as determining tissue homeostasis and repair. By using a specially designed skin-stretching device, we discover that hair stem cells proliferate in response to stretch and hair regeneration occurs only when applying proper strain for an appropriate duration. A counterbalance between WNT and BMP-2 and the subsequent two-step mechanism are identified through molecular and genetic analyses. Macrophages are first recruited by chemokines produced by stretch and polarized to M2 phenotype. Growth factors such as HGF and IGF-1, released by M2 macrophages, then activate stem cells and facilitate hair regeneration. A hierarchical control system is revealed, from mechanical and chemical signals to cell behaviors and tissue responses, elucidating avenues of regenerative medicine and disease control by demonstrating the potential to manipulate cellular processes through simple mechanical stimulation., Mechanical stimulation is known to affect cell proliferation, differentiation, and regeneration. Here, the authors demonstrate that stretching mouse skin recruits macrophages and polarizes them into M2 cells that facilitate hair regeneration through the release of growth factors, including HGF and IGF-1

BackgroundThe presence of anti-HER2 agents, such as trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1), significantly improved the prognosis of metastatic HER2-positive (HER2+) breast cancers (BC). However, drug resistance and disease progression are still common. In order to further improve the treatment efficacy, new clinical trials about anti-HER2 agents in combination with chemotherapy are growing rapidly. We conducted the network meta-analysis to synthesize evidences of clinical trials to identify the best therapy for metastatic HER2+ BC.MethodsA systematic search of randomized controlled trials regarding anti-HER2 agents in combination with chemotherapy for advanced or metastatic breast cancers up to May 2020 was conducted in Embase, PubMed, and the Cochrane Library. The primary outcome was progression-free survival (PFS). The secondary outcomes were overall survival (OS), objective response rate (ORR), and safety. Bayesian network meta-analysis was conducted to synthesize the results and rank the therapies.ResultsTwenty-six studies, including 16 studies for first-line treatments and 10 studies for second- or later-line treatments were included in the network meta-analysis. For first-line studies, the THP (taxanes + trastuzumab + pertuzumab) regimen exhibited the highest probability to be the optimal treatment in all efficacy outcomes and moderate safety. For second- or later-line studies, the T-DM1 and XHTuC (capecitabine + trastuzumab + tucatinib) regimens ranked top two in all efficacy outcomes according to the surface under the cumulative ranking (SUCRA) results. T-DM1 ranked first in PFS and OS whereas XHTuC ranked first in ORR. The safety outcomes of T-DM1 and XHTuC were acceptable.ConclusionsTHP was still the optimal first-line treatment for metastatic HER2+ BC. T-DM1 and XHTuC were recommended for second-line treatments.Systematic Review RegistrationINPLASY.com, identifier (INPLASY202090086).

The honeybee species A. mellifera and A. cerana have evolved substantial differences in olfactory-driven behaviors and in peripheral olfactory systems. Knowledge of the central nervous system regulating these olfaction differences is limited, however. We compared the phosphoproteome of the antennal lobes (ALs, the primary olfactory neuropil) of A. mellifera and A. cerana, and identified a total of 2812 phosphopeptides carrying 2971 phosphosites from 1265 phosphoproteins. Of these, 76% of the phosphoproteins were shared by both species, which were mainly presynapse and cytoskeleton components, and were involved in signal transduction and neurotransmitter secretion. This finding indicates the fundamental role of protein phosphorylation in regulating signal transduction in the ALs. The mTOR signaling pathway, the phagosome pathway, and the autophagy pathway, which are important in protein metabolism, were enriched, suggesting glomeruli plasticity and olfactory processing are intensively modulated by phosphorylation via these pathways. Compared with A. mellifera, 107 phosphoproteins associated with protein metabolism and transport were uniquely expressed in A. cerana, indicating the protein synthesis-dependent synaptic plasticity is enhanced in A. cerana to facilitate the processing of more complex floral odor clues in mountain foraging areas. This finding is further supported by the significantly upregulated key phosphoproteins of the mTOR signaling pathway in A. cerana ALs. These results provide insights into the phosphoproteomic basis of neuroplasticity that is coupled with the divergent evolution of bees in different environments. Significance To adapt to their own ecological niche, the two major honeybee species, A. mellifera and A. cerana, have developed significant difference in olfactory-driven behaviors, but our understanding of the underlying regulation of the central nervous system is still limitate. Here we performed the first comprehensive phosphoproteomic comparison of antennal lobes (Als) between A. mellifera and A. cerena. A large proportion of the identified phosphosites and phosphoproteins were shared between the two species to serve as a core network in the regulation of signal transduction and glomeruli plasticity of ALs. However, compared with A. mellifera, 107 phosphoproteins associated with protein metabolism and transport were uniquely identified in A. cerana ALs, and also several key phosphoproteins in mTOR signaling pathway were found upregulated in A. cerana. These findings indicate protein phosphorylation enhanced the protein synthesis-dependent synaptic plasticity in A. cerana to facilitate the processing of more complex floral odor clues in mountain foraging areas. Our data provide a valuable insight into phosphoproteome-driven cerebral regulation of honeybee olfactory behaviors, which is potentially useful for further neurobiological investigation in both honeybees and other insects.

Background: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising approach for the management of peritoneal carcinomatosis, but is associated with significant morbidity and prolonged hospital stay. Herein, we review the impact of Enhanced recovery after surgery (ERAS) protocol on length of stay (LOS) and early complications in patients undergoing CRS and HIPEC for peritoneal carcinomatosis.Methods: PubMed and Embase were searched for studies comparing ERAS protocol with control for CRS + HIPEC. Mean difference (MD) and risk ratios (RR) were calculated for LOS and complications respectively.Results: Six retrospective studies were included. Meta-analysis indicated statistically significant reduction in LOS with ERAS (MD: −2.82 95% CI: −3.79, −1.85 I2 = 29% p < 0.00001). Our results demonstrated significantly reduced risk of Calvien Dindo grade III/IV complications with the use of ERAS protocol as compared to the control group (RR: 0.60 95% CI: 0.41, 0.87 I2 = 0% p = 0.007). Pooled analysis of limited studies demonstrated no statistically significant difference in the risk of reoperation (RR: 1.04 95% CI: 0.54, 2.03 I2 = 50% p = 0.90) readmission (RR: 0.55 95% CI: 0.21, 1.49 I2 = 0% p = 0.24), acute kidney injury (RR: 0.55 95% CI: 0.28, 1.10 I2 = 0% p = 0.09) or mortality (RR: 0.62 95% CI: 0.17, 2.26 I2 = 0% p = 0.46) between the study groups.Conclusion: For CRS + HIPEC, ERAS is associated with significantly reduced LOS along with lower incidence of complications. Limited data suggest that use of ERAS protocol is not associated with increased readmission, reoperation, and mortality rates in these patients. There is a need for randomized controlled trials to corroborate the current evidence.

Long noncoding ribonucleic acids (LncRNAs) have been found to be involved in the proliferation, apoptosis, invasion, migration, and other pathological processes of triple-negative breast cancer (TNBC). Expression of the lncRNA actin filament-associated protein 1 antisense RNA1 (AFAP1-AS1) has been found to be significantly higher in TNBC than in other subtypes or in normal tissue samples, but the specific mechanism by which AFAP1-AS1 affects the occurrence and development of TNBC is yet to be revealed. In this study, we used Cell Counting Kit-8 (CCK-8), colony formation, wound healing migration, Transwell invasion, and nude mouse xenograft assays to confirm the role of AFAP1-AS1 in the proliferation, migration of TNBC cells in vitro and in vivo. In addition, we performed bioinformatics analyses, reverse transcriptase quantitative polymerase chain reaction (RT-qPCR), western blot (WB), and dual-luciferase reporter assays (dual-LRA) to confirm interaction among AFAP1-AS1, micro-RNA 2110 (miR-2110), and Sp1 transcription factor (Sp1). We found that silencing AFAP1-AS1 and Sp1 or upregulating miR-2110 suppressed the proliferation, migration, and invasion of MDA–MB-231 and MDA–MB-468 cells in vitro as well as tumor growth in vivo. Mechanistically, the dual-LRA highlighted that miR-2110 was an inhibitory target of AFAP1-AS1, and that AFAP1-AS1 functioned as a miR-2110 sponge to increase Sp1 expression. AFAP1-AS1 silencing led to a reduction in Sp1 mRNA and protein levels, which could be reversed by joint transfection with miR-2110 inhibitor. Our findings demonstrated that AFAP1-AS1 could modulate the progression of breast cancer cells and affect tumorigenesis in mice by acting as a miR-2110 sponge, resulting in regulation of Sp1 expression. Therefore, AFAP1-AS1 could play a pivotal role in the treatment of TNBC.

Background: The objective was to explore the discordance in the expression of the estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 between primary and recurrent/metastatic lesions in patients with early stage breast cancer as well as the prognostic impact.Method: Patients with early-stage primary breast cancer and confirmed recurrence/metastasis at Peking Union Medical College Hospital between January 2005 and August 2018 were screened. The details of discordance in each parameter between primary and recurrent/metastatic lesions and progression were recorded. Regression and survival analysis were applied to determine the association and clinical impact of the discordance.Results: We evaluated 75 patients. The discordance rate of ER, PR, HER2, and Ki-67 expression was 9.3, 14.7, 14.7, and 21.5%, respectively. Additionally, 66.7, 11.8, 14.3, and 0% of patients with Luminal A, Luminal B, HER2, and triple-negative primary tumors presented with a different subtype for the recurrent/metastatic tumors, respectively. No statistical difference in progression-free survival was observed according to the subtype of the recurrent or metastatic breast cancer (p > 0.05). Among 69 patients for whom treatment was adjusted after recurrence or metastasis, 66 patients remained recurrence-free during the follow-up period.Conclusion: For patients with early-stage breast cancer, the ER, PR, HER2, and Ki-67 expression profile for recurrent/metastatic tumors does not always match that of the primary tumor. After adjusting treatment according to the receptor expression in recurrent/metastatic lesions, most patients remained progression-free during the follow-up period.

As lifestyle changes, the prevalence of diabetes increases every year. Diabetes-induced male reproductive dysfunction is predominantly due to increased oxidative stress and then results in sperm damage and infertility. Echinacea purpurea is a traditional medicinal herb and is well-known for its immune-modulatory, antioxidative, anti-inflammatory, anticancer, and antiviral activities. The Toll-like receptor 4 (TLR4) plays a critical role in innate immune responses leading to nuclear factor (NF)-κB phosphorylation and release of proinflammatory cytokines including nitric oxide (NO), interleukin (IL)-1β, and tumor necrosis factor (TNF)-α. However, the relation between Echinacea purpurea extract and TLR4 remains unclear. This study aimed to investigate the protective effects on male reproduction of Echinacea purpurea ethanol extract (EPE) against diabetic rats and whether the anti-inflammatory effects were through the TLR4 pathway. Diabetic male Sprague–Dawley (SD) rats were induced by streptozotocin (65 mg/kg) and nicotinamide (230 mg/kg). EPE was tested in three doses (93, 279, and 465 mg/kg p.o. daily) for 4 weeks. Besides, metformin administration (100 mg/kg/day) was treated as a positive control. Results indicated that EPE administration for about 4 weeks improved hyperglycemia and insulin resistance. Additionally, EPE increased sperm motility, protected sperm morphology and mitochondrial membrane potential, as well as protein for testosterone synthesis enzyme. In sperm superoxide dismutase, catalase, and glutathione antioxidants were increased, whereas proinflammatory cytokines, such as NO, IL-1β, and TNF-α were decreased. The testis protein content of TLR4 and downstream phospho-NF-κB p65 also were reduced. The EPE might reduce the production of proinflammatory cytokines via TLR4 pathways and improve diabetes-induced male infertility.

Objective: To investigate the value of high-frame rate vector flow imaging technique (V flow) in evaluating the hemodynamic changes of carotid stenosis caused by atherosclerotic plaques.Methods and Materials: In this prospective study, patients with stenosis rate (diameter) ≥30% caused by carotid atherosclerotic plaques were included. Degrees of carotid stenosis were graded according to North American Symptomatic Carotid Endarterectomy Trial criteria: moderate (30–69%) or severe (70–99%). Mindray Resona 7s ultrasound machine with a linear array transducer (3–11 MHz) was used for ultrasound examinations. The mean WSS value of carotid arteries was measured at the proximal, narrowest region and distal of carotid stenosis. The mean WSS values were correlated with peak systolic velocity (PSV) measured by color Doppler flow imaging and stenosis degree detected by digital subtraction angiography (DSA). The vector arrows and flow streamline detected by V flow dynamic imaging were analyzed. Imaging findings of DSA in carotid arteries were used as the gold standard.Results: Finally, 51 patients were included. V flow measurements were performed successfully in 17 patients (100%) with moderate-grade stenosis and in 30 patients (88.2%) with severe-grade stenosis. Dynamic V flow imaging showed yellow or red vectors at the stenotic segment, indicating fast speed blood flow (up to 260.92 cm/s). Changes of streamlines were detected in the stenotic segment. The mean WSS value measured at the narrowest region of the carotid artery had a moderately positive correlation with stenosis degree (r = 0.58, P < 0.05) and PSV value (r = 0.54, P < 0.05), respectively. Significant difference was detected in mean WSS value at the narrowest region of the carotid artery between severe carotid stenosis (1.47 ± 0.97 Pa) and moderate carotid stenosis (0.96 ± 0.44 Pa) (P < 0.05).Conclusion: The hemodynamic changes detected by V flow of the carotid stenosis might be a potential non-invasive imaging tool for assessing the degree of carotid stenosis.

Behavioral specialization is key to the success of social insects and leads to division of labor among colony members. Response thresholds to task-specific stimuli are thought to proximally regulate behavioral specialization, but their neurobiological regulation is complex and not well understood. Here, we show that response thresholds to task-relevant stimuli correspond to the specialization of three behavioral phenotypes of honeybee workers in the well-studied and importantApis melliferaandApis cerana. Quantitative neuropeptidome comparisons suggest two tachykinin-related peptides (TRP2 and TRP3) as candidates for the modification of these response thresholds. Based on our characterization of their receptor binding and downstream signaling, we confirm a functional role of tachykinin signaling in regulating specific responsiveness of honeybee workers: TRP2 injection and RNAi-mediated downregulation cause consistent, opposite effects on responsiveness to task-specific stimuli of each behaviorally specialized phenotype but not to stimuli that are unrelated to their tasks. Thus, our study demonstrates that TRP signaling regulates the degree of task-specific responsiveness of specialized honeybee workers and may control the context specificity of behavior in animals more generally.

Background and AimPoor response to immune checkpoint inhibitors (ICIs) has been observed in most triple-negative breast cancer (TNBC) cases (around 80%). Our aim was to investigate the status of mismatch repair (MMR), microsatellite instability (MSI), programmed death-ligand 1 (PD-L1), and lymphocyte-activation gene 3 (LAG-3) in TNBC.MethodsA total of 74 TNBC samples were retrospectively analyzed. MMR and MSI were evaluated by immunohistochemistry (IHC) and polymerase chain reaction (PCR) using Promega 1.2 and NCI panels, respectively. PD-L1, LAG-3, and CD8 expression was assessed by IHC.ResultsNone of the cases demonstrated deficient MMR (dMMR) or MSI. In total, 43/74 cases (58.1%) were PD-L1+, including 1 tumor PD-L1+, 25 tumor-infiltrating lymphocytes (TILs) PD-L1+, and 17 cases involving concurrence of tumor and TIL PD-L1+. The rate of TIL PD-L1+ was remarkably higher than that of tumor PD-L1+ (PConclusiondMMR/MSI characteristics may not be a practical predictive marker for ICIs in TNBC. PD-L1+ is more common in TILs than in tumors. In the PD-L1+ population, approximately half of the cases showed LAG-3 co-expression. For patients with a poor response to PD-1(L1) mono ICI, dual blockade of PD-1(L1) and LAG-3 may be a viable option for the management of TNBC.