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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.

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.

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.

Understanding the spatial distribution characteristics and formation mechanism of urban facilities (city functional components) constitutes the basis of urban layout optimization. Currently, research on the overall distribution of the various types of city functional components is lacking. In this study, by applying the gradient analysis method common in ecology, we considered 13 types of city functional components (80,214 individuals in total) in large, medium and small Chinese cities (9 cities in total) to carry out quantitative analysis of the distribution of components along urban–rural gradients through density distribution curves. The results indicated that: (1) a higher density of city functional components near the city centre revealed an obvious aggregated distribution; (2) the spatial distribution dynamics of city functional components were related to the city size, providing a reference for the rational distribution of components in cities of different sizes; (3) the distribution of city functional components was affected by their ecosystem services. This study offers a new perspective for the application of ecological methods in the examination of the distribution of city functional components.

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).