HR-positive/HER2-negative breast cancer arising in patients with or without BRCA2 mutation: different biological phenotype and similar prognosis.

Background: BRCA2 plays a key role in homologous recombination. However, information regarding its mutations in Chinese patients with breast cancer remains limited. Objectives: This study aimed to assess the clinicopathological characteristics of BRCA2 mutation breast cancer and explore the mutation's effect on hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer survival in China. Design: This hospital-based cohort study prospectively included 629 women with breast cancer diagnosed from 2008 to 2023 at Zhejiang Cancer Hospital in China. Methods: We compared the clinicopathological characteristics and metastatic patterns and analysed the invasive disease-free survival (iDFS), distant relapse-free survival (DRFS) and first-line progression-free survival (PFS1) of patients with HR-positive/HER2-negative breast cancer according to BRCA2 mutations. Results: Among the 629 patients, 78 had BRCA2 mutations (12.4%) and 551 did not (87.6%). The mean age at diagnosis was lower in the BRCA2 mutation breast cancer group than in the non-mutation breast cancer group (38.91 versus 41.94 years, p = 0.016). BRCA2 mutation breast cancers were more likely to be lymph node-positive than non-mutation breast cancers (73.0% versus 56.6%, p = 0.037). The pathological grade was higher in 47.1% of BRCA2 mutation breast cancers than in 29.6% of non-mutation breast cancers (p = 0.014). The proportions of patients with BRCA2 mutations who developed contralateral breast cancer (19.2% versus 8.8%, p = 0.004), breast cancer in the family (53.8% versus 38.3%, p = 0.009) and ovarian cancer in the family (7.6% versus 2.4%, p = 0.022) were higher than those of patients without the mutation. The median follow-up time was 92.78 months. Multivariate analysis showed that BRCA2 mutation was not associated with poorer iDFS [hazard ratio = 0.9, 95% confidence interval (CI) = 0.64-1.27, p = 0.56] and poorer distant relapse-free survival (DRFS) (hazard ratio = 1.09, 95% CI = 0.61-1.93, p = 0.76). There was no significant difference between the two groups with regard to metastatic patterns in the advanced disease setting. In the first-line metastatic breast cancer setting, PFS1 expression was broadly similar between the two groups irrespective of chemotherapy or endocrine therapy. Conclusion: HR-positive/HER2-negative breast cancer with BRCA2 mutations differs from those without mutations in clinical behaviour and reflects more aggressive tumour behaviour. Our results indicate that BRCA2 mutations have no significant effect on the survival of Chinese women with HR-positive/HER2-negative breast cancer.

Fluorofenidone attenuates renal fibrosis by inhibiting lysosomal cathepsin­mediated NLRP3 inflammasome activation.

Currently, no antifibrotic drug in clinical use can effectively treat renal fibrosis. Fluorofenidone (AKFPD), a novel pyridone agent, significantly reduces renal fibrosis by inhibiting the activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome; however, the underlying mechanism of this inhibition is not fully understood. The present study aimed to reveal the molecular mechanism underlying the suppression of NLRP3 inflammasome activation by AKFPD. It investigated the effect of AKFPD on NLRP3 activation and lysosomal cathepsins in a unilateral ureteral obstruction (UUO) rat model, and hypoxia/reoxygenation (H/R)-treated HK-2 cells and murine peritoneal-derived macrophages (PDMs) stimulated with lipopolysaccharide (LPS) and ATP. The results confirmed that AKFPD suppressed renal interstitial fibrosis and inflammation by inhibiting NLRP3 inflammasome activation in UUO rat kidney tissues. In addition, AKFPD reduced the production of activated caspase-1 and maturation of IL-1ß by suppressing NLRP3 inflammasome activation in H/R-treated HK-2 cells and murine PDMs stimulated with LPS and ATP. AKFPD also decreased the activities of cathepsins B, L and S both in vivo and in vitro. Notably, AKFPD downregulated cathepsin B expression and NLRP3 colocalization in the cytoplasm after lysosomal disruptions. Overall, the results suggested that AKFPD attenuates renal fibrosis by inhibiting lysosomal cathepsin-mediated activation of the NLRP3 inflammasome.

Sand Erosion Resistance and Failure Mechanism of Polyurethane Film on Helicopter Rotor Blades.

Polyurethane is widely used on the surface of composite materials for rotor blades as sand erosion protection materials. The failure mechanism investigation of polyurethane film under service conditions is useful for developing the optimal polyurethane film for rotor blades. In this article, the sand erosion test parameters were ascertained according to the service environment of the polyurethane film. The sand erosion resistance and failure mechanism of polyurethane film at different impact angles were analyzed by an infrared thermometer, a Fourier transform infrared spectrometer (FTIR), a differential scanning calorimeter (DSC), a field emission scanning electron microscope (FESEM), and a laser confocal microscope (CLSM). The results show that the direct measurement method of volume loss can better characterize the sand erosion resistance of the polyurethane film compared to traditional mass loss methods, which avoids the influence of sand particles embedded in the polyurethane film. The sand erosion resistance of polyurethane film at low-angle impact is much lower than that at high-angle impact. At an impact rate of 220 m/s, the volume loss after sand erosion for 15 min at the impact angle of 30° is 57.8 mm3, while that at the impact angle of 90° is only 2.6 mm3. The volume loss prediction equation was established according to the experimental data. During low-angle erosion, the polyurethane film damage is mainly caused by sand cutting, which leads to wrinkling and accumulation of surface materials, a rapid increase in roughness, and the generation of long cracks. The linking of developing cracks would lead to large-scale shedding of polyurethane film. During high-angle erosion, the polyurethane film damage is mainly caused by impact. The connection of small cracks caused by impact leads to the shedding of small pieces of polyurethane, while the change in the roughness of the film is not as significant as that during low-angle erosion. The disordered arrangement of the soft and hard blocks becomes locally ordered under the action of impact and cutting loads. Then, the disordered state is restored after the erosion test finishes. The erosion of sand particles leads to an increase in the temperature of the erosion zone of the polyurethane film, and the maximum temperature rise is 6 °C, which does not result in a significant change in the molecular structure of the polyurethane film. The erosion failure mechanism is cracking caused by sand cutting and impact.

A tumor microenvironment-responsive core-shell tecto dendrimer nanoplatform for magnetic resonance imaging-guided and cuproptosis-promoted chemo-chemodynamic therapy.

Theranostic nanoplatforms for combination tumor therapy have gained lots of attention recently due to the optimized therapeutic efficiency and simultaneous diagnosis performance. Herein, a novel tumor microenvironment (TME)-responsive core-shell tecto dendrimer (CSTD) was assembled by phenylboronic acid- and mannose-modified poly(amidoamine) dendrimers via the phenylboronic ester bonds that are responsive to low pH and reactive oxygen species (ROS), and efficiently loaded with copper ions and chemotherapeutic drug disulfiram (DSF) for tumor-targeted magnetic resonance (MR) imaging and cuproptosis-promoted chemo-chemodynamic therapy. The formed CSTD-Cu(II)@DSF could be specifically taken up by MCF-7 breast cancer cells, accumulated to the tumor model after circulation, and released drugs in response to the weakly acidic TME with overexpressed ROS. The enriched intracellular Cu(II) ions could induce the oligomerization of lipoylated proteins and proteotoxic stress for cuproptosis, and lipid peroxidation for chemodynamic therapy as well. Moreover, the CSTD-Cu(II)@DSF could cause the dysfunction of mitochondria and arrest the cell cycle at the G2/M phase, leading to enhanced DSF-mediated cell apoptosis. As a result, CSTD-Cu(II)@DSF could effectively inhibit the growth of MCF-7 tumors by a combination therapy strategy integrating chemotherapy with cuproptosis and chemodynamic therapy. Lastly, the CSTD-Cu(II)@DSF also displays Cu(II)-associated r1 relaxivity, allowing for T1-weighted real-time MR imaging of tumors in vivo. The developed tumor-targeted and TME-responsive CSTD-based nanomedicine formulation may be developed for accurate diagnosis and synergistic treatment of other cancer types. STATEMENT OF SIGNIFICANCE: Constructing an effective nanoplatform for the combination of therapeutic effects and real-time tumor imaging remains a challenge. In this study, we reported for the first time an all-in-one tumor-targeted and tumor microenvironment (TME) responsive nanoplatform based on core-shell tecto dendrimer (CSTD) for the cuproptosis-promoted chemo-chemodynamic therapy and enhanced MR imaging. The efficient loading, selective tumor-targeting, and TME-responsive release of Cu(II) and disulfiram could enhance the intracellular accumulation of drugs, induce cuproptosis of cancer cells, and amplify the synergistic chemo-chemodynamic therapeutic effect, resulting in enhanced MR imaging and accelerated tumor eradication. This study sheds new light on the development of theranostic nanoplatforms for early accurate diagnosis and effective treatment of cancers.

The lncRNA NEAT1 Inhibits miRNA-216b and Promotes Colorectal Cancer Progression by Indirectly Activating YY1.

Background: Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) is commonly considered an oncogene in various cancers. The long noncoding RNA NEAT1 has been reported to be overexpressed in colorectal cancer (CRC). However, the exact role of NEAT1 in CRC remains unknown. Our research aimed to explore the function of NEAT1 in the tumorigenesis and the development of CRC. Methods: Real-time quantitative PCR (qRT-PCR) was used to detect the NEAT1, miR-216b, and YIN-YANG-1 (YY1) mRNA levels in CRC tissues and cells, then immunohistochemistry (IHC) was used to detect the expression of YY1 in CRC tissues. Luciferase reporter, qPCR, western blot, and DNA pulldown assays were conducted to study the relationships between NEAT1, miR-216b, and YY1. Flow cytometry analysis was performed for cell cycle and apoptosis analyses, and a colony formation assay was performed to test cell proliferation. Transwell assays were performed to detect cell invasion and migration. Results: The NEAT1 expression was significantly upregulated in CRC tissues compared with its expression in normal tissues, and downregulation of NEAT1 suppressed the proliferation, migration, and invasion of CRC cells. Moreover, we found NEAT1 decreased the miR-216b level directly, and the suppression of miR-216b could inhibit the function of downstream YY1. However, overexpression of YY1 accelerated CRC cell proliferation, migration, and invasion. Conclusion: Our results indicated that NEAT1 acted as an oncogene in CRC and promoted the progression of CRC by directly sponging miR-216 b expression to activate the expression of YY1. The NEAT1/miR-216b/YY1 axis may be a novel therapeutic target for CRC.

Discovery of MAO-B Inhibitor with Machine Learning, Topomer CoMFA, Molecular Docking and Multi-Spectroscopy Approaches.

Alzheimer's disease (AD) is the most common type of dementia and is a serious disruption to normal life. Monoamine oxidase-B (MAO-B) is an important target for the treatment of AD. In this study, machine learning approaches were applied to investigate the identification model of MAO-B inhibitors. The results showed that the identification model for MAO-B inhibitors with　K-nearest neighbor(KNN) algorithm had a prediction accuracy of 94.1% and 88.0% for the 10-fold cross-validation test and the independent test set, respectively. Secondly, a quantitative activity prediction model for MAO-B was investigated with the Topomer CoMFA model. Two separate cutting mode approaches were used to predict the activity of MAO-B inhibitors. The results showed that the cut model with q2 = 0.612 (cross-validated correlation coefficient) and r2 = 0.824 (non-cross-validated correlation coefficient) were determined for the training and test sets, respectively. In addition, molecular docking was employed to analyze the interaction between MAO-B and inhibitors. Finally, based on our proposed prediction model, 1-(4-hydroxyphenyl)-3-(2,4,6-trimethoxyphenyl)propan-1-one (LB) was predicted as a potential MAO-B inhibitor and was validated by a multi-spectroscopic approach including fluorescence spectra and ultraviolet spectrophotometry.

Anti-phospholipase A2 receptor antibody levels at diagnosis predicts outcome of TAC-based treatment for idiopathic membranous nephropathy patients.

BACKGROUND: Idiopathic membranous nephropathy (iMN) is recognized as an organ-specific autoimmune disease, mainly caused by anti-PLA2R antibody. This study aimed to study between anti-PLA2R antibody level at diagnosis and the response to tacrolimus (TAC)-based treatment in iMN patients. METHODS: This was a retrospective cohort study including 94 kidney biopsy-proven MN patients with positive anti-PLA2R antibody at diagnosis from May 2017 to September 2021 in our center. All iMN patients received the TAC regimen as the initial immunosuppressive therapy. All patients were divided into two groups according to anti-PLA2R antibody titer at diagnosis: high-level group (> 150 RU/ml; n = 42) and low-level group (≤ 150 RU/ml; n = 52). The association between anti-PLA2R antibody levels and clinical outcomes was assessed using the Kaplan-Meier method. RESULTS: The low density lipoprotein in the high-level group was significantly higher than low-level group at diagnosis, otherwise, serum albumin was significantly lower than low-level group; however, there was no significant difference in creatinine levels between two groups. The remission rates were significantly higher in the low-level group than high-level group after treatment with TAC for 12, 18, or 24 months (all P < 0.05). After 12 months of treatment with TAC, 82.7% of the patients in the low-level group achieved complete remission (CR) or partial remission (PR) (mean, 6.52 ± 0.53 months). However, 38.1% of the patients in high-level group achieved CR or PR (mean, 9.86 ± 0.51 months). Moreover, CR rate at 12 months in the high-level group was only 4.7% (mean, 11.88 ± 0.63 months). The infection frequency in the high-level group (35.6%) was higher than the low-level group (20%) during the TAC treatment, although there was no significant difference (P = 0.065). There were 19% patients who had end-stage kidney disease (ESKD), and 7.1% of patients died of ESKD in the high-level group during the follow-up period. CONCLUSION: Anti-PLA2R antibody level above 150 RU/ml at diagnosis can predict a poor treatment response and outcome of TAC treatment in iMN patients, who may not benefit from TAC or other calcineurin inhibitor regimens as the initial treatment.

In Situ Construction of Protective Films on Zn Metal Anodes via Natural Protein Additives Enabling High-Performance Zinc Ion Batteries.

The strong activity of water molecules causes a series of parasitic side reactions on Zn anodes in the aqueous electrolytes. Herein, we introduce silk fibroin (SF) as a multifunctional electrolyte additive for aqueous zinc-ion (Zn-ion) batteries. The secondary structure transformation of SF molecules from α-helices to random coils in the aqueous electrolytes allows them to break the hydrogen bond network among free water molecules and participate in Zn2+ ion solvation structure. The SF molecules released from the [Zn(H2O)4(SF)]2+ solvation sheath appear to be gradually adsorbed on the surface of Zn anodes and in situ form a hydrostable and self-healable protective film. This SF-based protective film not only shows strong Zn2+ ion affinity to promote homogeneous Zn deposition but also has good insulating behavior to suppress parasitic reactions. Benefiting from these multifunctional advantages, the cycle life of the Zn||Zn symmetric cells reaches over 1600 h in SF-containing ZnSO4 electrolytes. In addition, by adopting a potassium vanadate cathode, the full cell shows excellent cycling stability for 1000 cycles at 3 A g-1. The in situ construction of a protective film on the Zn anode from natural protein molecules provides an effective strategy to achieve high-performance Zn metal anodes for Zn-ion batteries.

Microbial diversity response to geochemical gradient characteristics on AMD from abandoned Dashu pyrite mine in Southwest China.

The formation and release of acid mine drainage (AMD) have caused extremely serious pollution in the environment around many mining areas. The biological oxidation of metal sulfide minerals causes the production and release of AMD. To understand the interaction mechanism between microbial and AMD, the study uses Southwest Dashu pyrite as an example to investigate the geochemical gradient characteristics and microbial diversity response on AMD from abandoned mine. Through collecting and testing the water samples, the geochemical parameters such as physical and chemical indexes, main ion composition and microbial community composition of seven mine drainage points were obtained. The results showed that the geochemical and microbial community structure the decrease of AMD pollution in the study area with the decrease of altitude has obvious gradient characteristics. Although AMD has the distribution of acid-resistant iron and sulfur bacteria oxidizing bacteria, the microbial community diversity has obvious gradient characteristics. The categories with a relative abundance of > 5% include Proteobacteria, Actinobacteriota, Firmicutes, WPS-2, Chloroflexi, Bacteroidota, and Acidobacteriota. Actinobacteriota, which was common in the AMD, was distributed throughout the samples. The correlation analysis between water quality parameters and microbial community showed that the microbial community structure was affected by environmental factors. With the increase of acidity and metal ion content, the diversity of microbial community decreased, and the content of acid-resistant iron and sulfur oxidizing bacteria increased. The results showed that pH, dissolved oxygen (Do), the total iron (Fe) content (TFe), SO42-, and Al3+ were the five parameters that most affected microbiological diversity and interaction. Hydrogeochemistry and major ions analysis revealed that AMD in the study area mainly comes from the biological oxidation of metal sulfides and the dissolution and cation exchange of other minerals around the deposit. The degree of AMD pollution is related to the hydrogeochemical conditions in the mine. The higher the mine's water level, the lower the pollutants, and the less AMD is produced and released. The findings confirmed that geochemical gradients significantly changed the biota of the mine water and enriched the related microbial diversity adapted to different environmental factors. Therefore, the findings provide strong support for mine containment to inhibit oxidation and lay the foundation for prevention and control strategies of AMD pollution sources.

Changes in the spectrum of kidney diseases: a survey of 2803 patients from 2010 to 2018 at a single center in southeastern China.

Primary glomerular disease was the leading cause of chronic kidney disease (CKD) in China; however, changes in the economy and environment introduce variations in the spectrum of kidney diseases. This study aimed to analyze renal biopsy data to inform disease prevention and public health interventions. In this retrospective cohort study, data from 2,803 consecutive renal biopsies conducted at our center between January 2010 and December 2018 were analyzed. The sample was disaggregated by age and the date of biopsy to facilitate analysis. Primary glomerulonephritis (PGN) is the most frequent (81.84%) finding, followed by secondary glomerulonephritis (SGN; 15.38%), tubulointerstitial nephritis (15.38%), and others (1.57%). IgA nephropathy (IgAN), idiopathic membranous nephropathy (iMN), and minimal change disease were the primary causes of PGN. Among PGN cases, the incidence of iMN arose, especially among those aged ≥ 60 years old, during the observation period. Contrary to the case of iMN, the proportion of IgAN in PGN trended downward, continuously, and at length. Moreover, IgAN mainly affected those aged 25-44 years old and less so those aged ≥ 60 years old. Lupus nephritis, Henoch-Schönlein purpura nephritis, and diabetic nephropathy (DN) were key causes of SGN. A ratio reversal between infectious disease and chronic disease dramatically changed SGN patterns. In the past year, the incidence of hepatitis B-related nephritis has constantly declined; however, the proportion of DN among SGN had steadily increased. The incidence of iMN significantly increased during these years. Among SGN cases, the proportion of DN has increased.

Glasgow prognostic score and combined positive score for locally advanced rectal cancer.

Purpose: This study was performed to investigate the association of Glasgow prognostic score (GPS), combined positive score (CPS), and clinicopathological characteristics of locally advanced rectal cancer. Methods: Between February 2012 and February 2018, 103 patients with locally advanced rectal cancer treated by neoadjuvant chemoradiotherapy and total mesorectal excision (TME) were retrospectively evaluated. Results: According to the classification of the GPS, 85 (82.5%), 13 (12.6%), and 5 patients (4.9%) were classified as a score of 0, 1, and 2, respectively. Patients were classified into the GPS-low group (GPS of 0, n = 85) and GPS-high group (GPS of 1 or 2, n = 18) with an area under the curve of 0.582 for overall survival (OS). The mean programmed death-ligand 1 (PD-L1) CPS of the whole group was 2.24 (range, 0-70). The PD-L1 CPS of the GPS-high group was higher than the GPS-low group (P < 0.001). Multivariate analysis by Cox proportional hazards model indicated that GPS was associated with OS and disease-free survival (DFS). Furthermore, PD-L1 CPS was associated with DFS (hazard ratio, 1.050; 95% confidence interval, 1.017-1.083; P = 0.003). Conclusion: Elevated GPS was related to the PD-L1 CPS. GPS and PD-L1 CPS were associated with the prognosis of locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy followed by TME.

Programmed death-ligand 1 and mammalian target of rapamycin signaling pathway in locally advanced rectal cancer.

PURPOSE: To evaluate the role of programmed death-ligand 1 (PD-L1) and mammalian target of rapamycin (mTOR) signaling pathway in locally advanced rectal cancer (LARC). METHODS: Between February 2012 and February 2018, 103 patients with LARC treated by neoadjuvant chemoradiotherapy (neoCRT) and total mesorectal excision (TME) were included. PD-L1, mTOR and p-mTOR of pair-matched pre-neoCRT biopsies and post-neoCRT surgical tissue were evaluated by immunohistochemistry. RESULTS: The mean combined positive score (CPS), tumor proportion score (TPS) and immune cell score (IC) of pre-neoCRT were 2.24 (0-70), 1.87 (0-70) and 0.67 (0-10), respectively. The mean CPS, TPS and IC of post-neoCRT were 2.19 (0-80), 1.38 (0-80) and 1.60 (0-20), respectively. Significant difference was observed in terms of IC between pre-neoCRT and post-neoCRT (p = 0.010). The 5-year disease-free survival (DFS) rate of the whole group was 62.4%. Multivariate analysis by Cox model indicated that pre-neoCRT TPS [hazard ratio (HR) 1.052, 95% confidence interval (CI) 1.020-1.086, p = 0.001] and post-neoCRT CPS (HR 0.733, 95% CI 0.555-0.967, p = 0.028) were associated with DFS. In the 89 patients without pathological complete response, p-mTOR and IC were upregulated after neoCRT. CONCLUSIONS: For patients with LARC treated by neoCRT and TME, p-mTOR and IC were upregulated after neoCRT. Pre-neoCRT TPS and post-neoCRT CPS were independent prognostic predictors of DFS.

Transfer Learning of the ResNet-18 and DenseNet-121 Model Used to Diagnose Intracranial Hemorrhage in CT Scanning.

OBJECTIVE: The aim of the study was to verify the ability of the deep learning model to identify five subtypes and normal images in non-contrast enhancement CT of intracranial hemorrhage. METHODS: A total of 351 patients (39 patients in the normal group, 312 patients in the intracranial hemorrhage group) who underwent intracranial hemorrhage noncontrast enhanced CT were selected, obtaining 2768 images in total (514 images for the normal group, 398 images for the epidural hemorrhage group, 501 images for the subdural hemorrhage group, 497 images for the intraventricular hemorrhage group, 415 images for the cerebral parenchymal hemorrhage group, and 443 images for the subarachnoid hemorrhage group). Based on the diagnostic reports of two radiologists with more than 10 years of experience, the ResNet-18 and DenseNet-121 deep learning models were selected. Transfer learning was used. 80% of the data was used for training models, 10% was used for validating model performance against overfitting, and the last 10% was used for the final evaluation of the model. Assessment indicators included accuracy, sensitivity, specificity, and AUC values. RESULTS: The overall accuracy of ResNet-18 and DenseNet-121 models was obtained as 89.64% and 82.5%, respectively. The sensitivity and specificity of identifying five subtypes and normal images were above 0.80. The sensitivity of the DenseNet-121 model to recognize intraventricular hemorrhage and cerebral parenchymal hemorrhage was lower than 0.80, 0.73, and 0.76, respectively. The AUC values of the two deep learning models were found to be above 0.9. CONCLUSION: The deep learning model can accurately identify the five subtypes of intracranial hemorrhage and normal images, and it can be used as a new tool for clinical diagnosis in the future.

Combined expression of the BRAFV600E mutation and PD-L1 in early papillary thyroid carcinoma and its relationship with clinicopathological features and recurrence-a retrospective cohort study.

Background: Identifying the high recurrence group of patients with early-stage papillary thyroid cancer (PTC) is the greatest challenge in the management of this disease. It has been noted that B-type Rafkinase (BRAF) V600E mutation and programmed death ligand 1 (PD-L1) are associated in PTC and highly expressed in PTC, correlating in PTC as potential prognostic biomarkers. However, whether they can be used to predict the aggressiveness and recurrence of early PTC remains unclear. Methods: Clinicopathological data of 137 patients with early PTC [tumor-node-metastasis (TNM) stage I-II] who underwent surgery in Zhejiang Cancer Hospital between 2008 and 2010 were retrospectively analyzed. BRAFV600E mutation and PD-L1 was detected by immunohistochemistry. The median follow-up time was 136 months (interquartile range 5.8). The presence of tumor confirmed by imaging or pathology or lymph node metastasis was considered as tumor recurrence. The association of both alone and in combination with clinicopathological features and recurrence was statistically analyzed respectively. The risk of recurrence was assessed using Cox regression models. Results: Most of the 137 early PTC were female (78.1%). The mean age was 43.2±12.1 years. The median tumor size was 1.4 cm; 14 patients developed recurrence during follow-up period; 56 patients (40.9%) were detected positive for BRAFV600E mutation; 76 patients (55.5%) were detected positive for PD-L1. Patients with both BRAFV600E mutation and PD-L1 expression had larger tumors (P=0.038), were more likely to have extrathyroidal invasion (P=0.045), and had a lower rate of cervical lymph node metastasis (P=0.046). The recurrence rate was 17.5% (7/40) in patients with BRAFV600E mutation and PD-L1 double expression compared to 8.9% (4/45) in patients with BRAFV600E mutation and PD-L1 double negative [hazard ratio (HR) =1.267; 95% CI: 0.841-1.909; P=0.257]. Survival curves showed flatter recurrence-free survival (RFS) curves in positive BRAFV600E mutation only and PD-L1 expression only, whereas decreased sharply in positive expression of both BRAFV600E mutation and PD-L1; however, the differences were not significant (P>0.05). Conclusions: The combination of BRAFV600E mutation and PD-L1 to identify group at higher risk of recurrence in early PTC has insufficient clinical evidence and should be used with caution in the clinical management of PTC.

Can texture analysis based on single unenhanced CT accurately predict the WHO/ISUP grading of localized clear cell renal cell carcinoma?

OBJECTIVE: The purpose was to investigate the value of texture analysis in predicting the World Health Organization (WHO)/International Society of Urological Pathology (ISUP) grading of localized clear cell renal cell carcinoma (ccRCC) based on unenhanced CT (UECT). MATERIALS AND METHODS: Pathologically confirmed subjects (n = 104) with localized ccRCC who received UECT scanning were collected retrospectively for this study. All cases were classified into low grade (n = 53) and high grade (n = 51) according to the WHO/ISUP grading and were randomly divided into training set and test set as a ratio of 7:3. Using 3D-ROI segmentation on UECT images and extracted ninety-three texture features (first-order, gray-level co-occurrence matrix [GLCM], gray-level run length matrix [GLRLM], gray-level size zone matrix [GLSZM], neighboring gray tone difference matrix [NGTDM] and gray-level dependence matrix [GLDM] features). Univariate analysis and the least absolute shrinkage selection operator (LASSO) regression were used for feature dimension reduction, and logistic regression classifier was used to develop the prediction model. Using receiver operating characteristic (ROC) curve, bar chart and calibration curve to evaluate the performance of the prediction model. RESULTS: Dimension reduction screened out eight optimal texture features (maximum, median, dependence variance [DV], long run emphasis [LRE], run entropy [RE], gray-level non-uniformity [GLN], gray-level variance [GLV] and large area low gray-level emphasis [LALGLE]), and then the prediction model was developed according to the linear combination of these features. The accuracy, sensitivity, specificity, and AUC of the model in training set were 86.1%, 91.4%, 81.1%, and 0.937, respectively. The accuracy, sensitivity, specificity, and AUC of the model in test set were 81.2%, 81.2%, 81.2%, and 0.844, respectively. The calibration curves showed good calibration both in training set and test set (P > 0.05). CONCLUSION: This study has demonstrated that the radiomics model based on UECT texture analysis could accurately evaluate the WHO/ISUP grading of localized ccRCC.

The association of CMTM6 expression with prognosis and PD-L1 expression in triple-negative breast cancer.

BACKGROUND: Immune checkpoint inhibitors play a vital role in triple-negative breast cancer (TNBC) immunotherapy. A recent study showed that chemokine-like factor (CKLF)-like MARVEL transmembrane domain containing 6 (CMTM6) has a crucial role in programmed death-ligand 1 (PD-L1) stability. The aim of this study was to investigate the relationship between CMTM6 and PD-L1 in TNBC and the association with clinical characteristics. METHODS: A total of 143 patients, including 75 with human epidermal growth factor receptor 2 (HER2)-driven breast cancer and 68 with TNBC, were included in this study. In 83 paired primary breast cancers (PBCs) and metastatic breast cancers (MBC) comprising 45 HER2-driven breast cancers and 38 TNBC, CMTM6 and PD-L1 were detected based on immunohistochemistry (IHC) with FFPE tissues. Another 60 PBCs comprising 30 HER2-driven breast cancers and 30 TNBC in order to detect CMTM6 and PD-L1 mRNA expressions based on real-time polymerase chain reaction (RT-PCR) using frozen tissues. Furthermore, 153 patients comprising 30 TNBC and 123 HER2-driven breast cancer based on The Cancer Genome Atlas (TCGA) database were used to confirm the difference mRNA expression. RESULTS: The expression of CMTM6 in patients with TNBC was significantly higher than in those with HER2-driven PBC (IHC, P=0.036, mRNA, P=0.036, TCGA dataset, P=0.039). CMTM6 was correlated with PD-L1 based on IHC in triple-negative MBC (P=0.004); the same result was found based on mRNA data in triple- negative PBC (P=0.021). Moreover, a high expression of CMTM6 in TNBC was associated with poor progression-free survival (PFS) (P=0.030, 95% CI: 1.08-4.57, HR =2.22). After multiple Cox regression analysis, CMTM6 in TNBC emerged as an independent risk factor for PFS (P=0.027, 95% CI: 1.11-5.20, HR =2.40). The expression of PD-L1 was negatively correlated with lymph node metastasis (P=0.026) and was not associated with PFS. CONCLUSIONS: The expression of CMTM6 was higher in TNBC than in HER2-driven breast cancer. In TNBC, CMTM6 was correlated with PD-L1 expression, and potentially could be used as an independent risk factor for predicting PFS.

Three new steroidal components from the roots of reineckia carnea.

A new coprostanol glycoside, 26-trihydroxy-16, 22-dioxo-3ß-[(α-L-rhamnopyranosyl)oxy]-5ß-cholestan-1ß-yl O-α-L-rhamnopyranosyl-(1→2)-ß-D-fucopyranoside (1) (25S)-5ß-spirostan-1ß,2ß,3ß, 4ß,5ß, 6ß-hexol (2), a new C-22 steroidal lactone saponin, (20 R)-16ß-trihydroxy-3ß-[(α-L-rhamnopyranosyl)oxy]-1ß-[(O-α-L-rhamnopyranosyl-(1→2)-ß-D-xylopyranosyl)oxy]-5ß-pregnane-20-oic acid γ-lactone (3) along with two known pregnane glycosides (4 and 5) were obtained from the roots of Reineckia carnea. Their structures were determined by 1 D, 2 D NMR, IR and MS data analysis. In addition, the cytotoxic activities in HT-29, HCT116, H1299 and A549 tumor cells of the isolated compounds (1 - 5) were determined by the MTT method. The results showed that only compound 1 exhibited weak effect against these cells with IC50 values ranging from 63.36 µM to 105.01 µM.

Epidemic analysis of COVID-19 in Italy based on spatiotemporal geographic information and Google Trends.

Since the first two novel coronavirus cases appeared in January of 2020, the outbreak of the COVID-19 epidemic seriously threatens the public health of Italy. In this article, the distribution characteristics and spreading of COVID-19 in various regions of Italy were analysed by heat maps. Meanwhile, spatial autocorrelation, spatiotemporal clustering analysis and kernel density method were also applied to analyse the spatial clustering of COVID-19. The results showed that the Italian epidemic has a temporal trend and spatial aggregation. The epidemic was concentrated in northern Italy and gradually spread to other regions. Finally, the Google Trends index of the COVID-19 epidemic was further employed to build a prediction model combined with machine learning algorithms. By using Adaboost algorithm for single-factor modelling,the results show that the AUC of these six features (mask, pneumonia, thermometer, ISS, disinfection and disposable gloves) are all >0.9, indicating that these features have a large contribution to the prediction model. It is also implied that the public's attention to the epidemic is increasing as well as the awareness of the need for protective measures. This increased awareness of the epidemic will prompt the public to pay more attention to protective measures, thereby reducing the risk of coronavirus infection.

WNT/ß-catenin pathway activation via Wnt1 overexpression and Axin1 downregulation correlates with cadherin-catenin complex disruption and increased lymph node involvement in micropapillary-predominant lung adenocarcinoma.

BACKGROUND: Micropapillary-predominant adenocarcinoma (MPA) of the lung is associated with extensive lymph node involvement and rapid terminal metastasis. However, this subtype has been recognized for only a few years, and there have been few studies of the molecular mechanisms associated with its highly invasive behaviors. METHODS: The present study utilized immunohistochemical staining of surgically resected tissue blocks of MPA and lepidic-predominant lung adenocarcinoma to quantify the expression of specific biological markers in the WNT/ß-catenin pathway and evaluate their influence on the lymph nodes invasion of these two types of lung adenocarcinomas. RESULTS: Our findings revealed that disruption of the cell membrane cadherin-catenin complex, which weakens the tumor cell adherence of MPA, was caused by the dissociation of ß-catenin from the cadherin-catenin complex and the subsequent accumulation of ß-catenin in the cytoplasm. This caused abnormal activation of the WNT/ß-catenin pathway. We also found that Wnt-1-specific overexpression and Axin1 inhibition in MPA could explain the redistribution and cytoplasmic retention of ß-catenin. Collectively, these findings suggest that an abnormality in the WNT/ß-catenin pathway could enhance the invasiveness of MPA through the overexpression of Wnt-1 and downregulation of Axin1 molecules. CONCLUSIONS: Our data support the need for further research regarding the WNT/ß-catenin pathway and the need to develop novel targeted therapies for restoration of tumor cell adherence and improvement of the prognosis of MPA.