Design, synthesis and biological evaluation of a novel PAK1 degrader for the treatment of triple negative breast cancer.

Triple-negative breast cancer is one of the most malignant subtypes in clinical practice, and it is urgent to find new therapies. The p21-activated kinase I (PAK1) has been considered to be an attractive therapeutic target for TNBC. In this study, we designed and synthesized a series of novel PROTAC PAK1 degraders by conjugating VHL or CRBN ligase ligands to PAK1 inhibitors which are connected by alkyl chains or PEG chains. The most promising compound, 19s, can significantly degrade PAK1 protein at concentrations as low as 0.1 µM, and achieves potent anti-proliferative activity with an IC50 value of 1.27 µM in MDA-MB-231 cells. Additionally, 19s exhibits potent anti-migration activity in vitro and induces rapid tumor regression in vivo. Collectively, these findings document that 19s is a potent and novel PAK1 degrader with promising potential for TNBC treatment.

Prediction of clear cell renal cell carcinoma ≤ 4cm: visual assessment of ultrasound characteristics versus ultrasonographic radiomics analysis.

Objective: To investigate the diagnostic efficacy of the clinical ultrasound imaging model, ultrasonographic radiomics model, and comprehensive model based on ultrasonographic radiomics for the differentiation of small clear cell Renal Cell Carcinoma (ccRCC) and Renal Angiomyolipoma (RAML). Methods: The clinical, ultrasound, and contrast-enhanced CT(CECT) imaging data of 302 small renal tumors (maximum diameter ≤ 4cm) patients in Tianjin Medical University Cancer Institute and Hospital from June 2018 to June 2022 were retrospectively analyzed, with 182 patients of ccRCC and 120 patients of RAML. The ultrasound images of the largest diameter of renal tumors were manually segmented by ITK-SNAP software, and Pyradiomics (v3.0.1) module in Python 3.8.7 was applied to extract ultrasonographic radiomics features from ROI segmented images. The patients were randomly divided into training and internal validation cohorts in the ratio of 7:3. The Random Forest algorithm of the Sklearn module was applied to construct the clinical ultrasound imaging model, ultrasonographic radiomics model, and comprehensive model. The efficacy of the prediction models was verified in an independent external validation cohort consisting of 69 patients, from 230 small renal tumor patients in two different institutions. The Delong test compared the predictive ability of three models and CECT. Calibration Curve and clinical Decision Curve Analysis were applied to evaluate the model and determine the net benefit to patients. Results: 491 ultrasonographic radiomics features were extracted from 302 small renal tumor patients, and 9 ultrasonographic radiomics features were finally retained for modeling after regression and dimensionality reduction. In the internal validation cohort, the area under the curve (AUC), sensitivity, specificity, and accuracy of the clinical ultrasound imaging model, ultrasonographic radiomics model, comprehensive model, and CECT were 0.75, 76.7%, 60.0%, 70.0%; 0.80, 85.6%, 61.7%, 76.0%; 0.88, 90.6%, 76.7%, 85.0% and 0.90, 92.6%, 88.9%, 91.1%, respectively. In the external validation cohort, AUC, sensitivity, specificity, and accuracy of the three models and CECT were 0.73, 67.5%, 69.1%, 68.3%; 0.89, 86.7%, 80.0%, 83.5%; 0.90, 85.0%, 85.5%, 85.2% and 0.91, 94.6%, 88.3%, 91.3%, respectively. The DeLong test showed no significant difference between the clinical ultrasound imaging model and the ultrasonographic radiomics model (Z=-1.287, P=0.198). The comprehensive model showed superior diagnostic performance than the ultrasonographic radiomics model (Z=4. 394, P<0.001) and the clinical ultrasound imaging model (Z=4. 732, P<0.001). Moreover, there was no significant difference in AUC between the comprehensive model and CECT (Z=-0.252, P=0.801). Both in the internal and external validation cohort, the Calibration Curve and Decision Curve Analysis showed a better performance of the comprehensive model. Conclusion: It is feasible to construct an ultrasonographic radiomics model for distinguishing small ccRCC and RAML based on ultrasound images, and the diagnostic performance of the comprehensive model is superior to the clinical ultrasound imaging model and ultrasonographic radiomics model, similar to that of CECT.

Design, synthesis and biological evaluation of novel SIRT3 inhibitors targeting both NAD+ and substrate binding sites for the treatment of acute myeloid leukemia.

Acute myeloid leukemia (AML) represents a highly malignant subtype of leukemia with limited therapeutic options. In this study, we propose a novel therapeutic strategy for treating AML by inhibiting SIRT3 to regulate mitochondrial metabolism network involved in energy metabolism and epigenetic modifications essential for AML survival. A series of thieno [3,2-d]pyrimidine-6-carboxamide derivatives were designed and synthesized by structure-based strategy, 17f was documented to be a potent and acceptable selective SIRT3 inhibitor with IC50 value of 0.043 µM and exhibited profound anti-proliferative activity in MOLM13, MV4-11, and HL-60 cells. Through CETSA assay and the degree of deacetylation of intracellular SIRT3 substrates, we confirmed that 17f could effectively bind and inhibit SIRT3 activity in AML cells. Mechanistically, 17f suppressed mitochondrial function, triggered the accumulation of ROS, and significantly inhibited the production of ATP in AML cells. With the breakdown of mitochondrial function, 17f eventually induced apoptosis of AML cells. In addition, 17f also showed excellent anti-AML potential in nude mouse tumor models of HL-60-Luc. Collectively, these results demonstrate that 17f is a potent and acceptable selective SIRT3 inhibitor with promising potential to treat AML.

G-MBRMD: Lightweight liver segmentation model based on guided teaching with multi-head boundary reconstruction mapping distillation.

BACKGROUND AND OBJECTIVES: Liver segmentation is pivotal for the quantitative analysis of liver cancer. Although current deep learning methods have garnered remarkable achievements for medical image segmentation, they come with high computational costs, significantly limiting their practical application in the medical field. Therefore, the development of an efficient and lightweight liver segmentation model becomes particularly important. METHODS: In our paper, we propose a real-time, lightweight liver segmentation model named G-MBRMD. Specifically, we employ a Transformer-based complex model as the teacher and a convolution-based lightweight model as the student. By introducing proposed multi-head mapping and boundary reconstruction strategies during the knowledge distillation process, Our method effectively guides the student model to gradually comprehend and master the global boundary processing capabilities of the complex teacher model, significantly enhancing the student model's segmentation performance without adding any computational complexity. RESULTS: On the LITS dataset, we conducted rigorous comparative and ablation experiments, four key metrics were used for evaluation, including model size, inference speed, Dice coefficient, and HD95. Compared to other methods, our proposed model achieved an average Dice coefficient of 90.14±16.78%, with only 0.6 MB memory and 0.095 s inference speed for a single image on a standard CPU. Importantly, this approach improved the average Dice coefficient of the baseline student model by 1.64% without increasing computational complexity. CONCLUSION: The results demonstrate that our method successfully realizes the unification of segmentation precision and lightness, and greatly enhances its potential for widespread application in practical settings.

Evaluation of image-pro plus assisted superb microvascular imaging for differential diagnosis of renal masses.

OBJECTIVE: Previous research on diagnostic assessment by superb microvascular imaging (SMI) were based on qualitative or semi-quantitative assessments of vascularity, which may be subjective and unrepeatable by different sonographers. This study aimed to evaluate diagnostic performance of SMI Image-pro Plus (IPP) based vascular index (VI) for malignant renal masses. METHOD: We retrospectively reviewed 222 masses in 214 patients who underwent SMI between August 2019 and August 2022 in our study. We evaluated the diagnostic performance of blood flow via Alder grade, VI based on both IPP and SMI. RESULTS: The kappa consistency of the Adler grade and VI for renal masses was classified among different observers were 0.765 and 0.824. The intra-observers correlation ecoefficiency (ICC) were 0.727 and 0.874. Benign renal masses were mainly Adler grade 0, grade I, and grade II, VI was 4.30 ± 4.27 (Range 0.98-16.42); while malignant masses were mainly Adler grade III, VI was 14.95 ± 10.94 (Range 0.79-56.89). VI was higher in malignant than benign masses (t = 15.638, P < 0.01). Among the malignant masses, the mean VI in clear cell renal cell carcinoma was higher than that in papillary renal cell carcinoma and chromophobe renal cell carcinoma (F = 30.659, P < 0.01). The sensitivity, specificity and accuracy of SMI were 80.00%, 71.15%, and 78.64%, respectively. The sensitivity, specificity, and accuracy were 60.59%, 88.46%, and 80.18% by using a VI of 7.95 as the cutoff value to identify malignant lesions from benign masses yielded. VI had better diagnostic efficiency than ultrasonic characteristics and Adler grade in benign and malignant differential diagnosis (Z = 4.851, P < 0.01; Z = 2.732, P < 0.01). CONCLUSION: VI was higher in malignant than benign in renal masses. In malignant masses, VI in CCRCC was higher than that in papillary renal cell carcinoma and ChRCC. As a noninvasive examination, it had important clinical significance in the differential diagnosis of renal masses. VI from IPP may assist sonographer in distinguish renal malignances as a quantitative tool for vascularity.

Preoperative Differentiation of HER2-Zero and HER2-Low from HER2-Positive Invasive Ductal Breast Cancers Using BI-RADS MRI Features and Machine Learning Modeling.

BACKGROUND: Accurate determination of human epidermal growth factor receptor 2 (HER2) is important for choosing optimal HER2 targeting treatment strategies. HER2-low is currently considered HER2-negative, but patients may be eligible to receive new anti-HER2 drug conjugates. PURPOSE: To use breast MRI BI-RADS features for classifying three HER2 levels, first to distinguish HER2-zero from HER2-low/positive (Task-1), and then to distinguish HER2-low from HER2-positive (Task-2). STUDY TYPE: Retrospective. POPULATION: 621 invasive ductal cancer, 245 HER2-zero, 191 HER2-low, and 185 HER2-positive. For Task-1, 488 cases for training and 133 for testing. For Task-2, 294 cases for training and 82 for testing. FIELD STRENGTH/SEQUENCE: 3.0 T; 3D T1-weighted DCE, short time inversion recovery T2, and single-shot EPI DWI. ASSESSMENT: Pathological information and BI-RADS features were compared. Random Forest was used to select MRI features, and then four machine learning (ML) algorithms: decision tree (DT), support vector machine (SVM), k-nearest neighbors (k-NN), and artificial neural nets (ANN), were applied to build models. STATISTICAL TESTS: Chi-square test, one-way analysis of variance, and Kruskal-Wallis test were performed. The P values <0.05 were considered statistically significant. For ML models, the generated probability was used to construct the ROC curves. RESULTS: Peritumoral edema, the presence of multiple lesions and non-mass enhancement (NME) showed significant differences. For distinguishing HER2-zero from non-zero (low + positive), multiple lesions, edema, margin, and tumor size were selected, and the k-NN model achieved the highest AUC of 0.86 in the training set and 0.79 in the testing set. For differentiating HER2-low from HER2-positive, multiple lesions, edema, and margin were selected, and the DT model achieved the highest AUC of 0.79 in the training set and 0.69 in the testing set. DATA CONCLUSION: BI-RADS features read by radiologists from preoperative MRI can be analyzed using more sophisticated feature selection and ML algorithms to build models for the classification of HER2 status and identify HER2-low. TECHNICAL EFFICACY: Stage 2.

Identification of a novel PAK1/HDAC6 dual inhibitor ZMF-23 that triggers tubulin-stathmin regulated cell death in triple negative breast cancer.

Triple-negative breast cancer (TNBC) is the most poorly treated subtype of breast cancer, and targeting the heterogeneity of TNBC has emerged as a fascinating therapeutic strategy. In this study, we propose for the first time that dual-targeting PAK1 and HDAC6 is a promising novel strategy for TNBC treatment due to their essential roles in the regulation of energy metabolism and epigenetic modification. We discovered a novel dual-targeting PAK1/HDAC6 inhibitor, 6 - (2-(cyclopropylamino) - 6 - (2,4-dichlorophenyl) - 7 - oxopyrido [2,3-d] pyrimidin - 8 (7H) -yl) - N-hydroxyhexanamide (ZMF-23), which presented profound inhibitory activity against PAK1 and HDAC6 and robust antiproliferative potency in MDA-MB-231 cells. In addition, SPR and CETSA assay demonstrated the targeted binding of ZMF-23 with PAK1/HDAC6. Mechanically, ZMF-23 strongly inhibited the cellular PAK1 and HDAC6 activity, impeded PAK1 and HDAC6 regulated aerobic glycolysis and migration. By RNA-seq analysis, ZMF-23 was found to induce TNF-α-regulated necroptosis, which further enhanced apoptosis. Additionally, ZMF-23 triggered PAK1-tubulin/HDAC6-Stathmin regulated microtubule structure changes, which further induced the G2/M cycle arrest. Moreover, prominent anti-proliferative effect of ZMF-23 was confirmed in the TNBC xenograft zebrafish and mouse model via PAK1 and HDAC6 inhibition. Collectively, ZMF-23 is a novel dual PAK1/HDAC6 inhibitor with TNBC treatment potential.

High-stability spherical lanthanide nanoclusters for magnetic resonance imaging.

High-nuclear lanthanide clusters have shown great potential for the administration of high-dose mononuclear gadolinium chelates in magnetic resonance imaging (MRI). The development of high-nuclear lanthanide clusters with excellent solubility and high stability in water or solution has been challenging and is very important for expanding the performance of MRI. We used N-methylbenzimidazole-2-methanol (HL) and LnCl3·6H2O to synthesize two spherical lanthanide clusters, Ln32 (Ln = Ho, Ho32; and Ln = Gd, Gd32), which are highly stable in solution. The 24 ligands L- are all distributed on the periphery of Ln32 and tightly wrap the cluster core, ensuring that the cluster is stable. Notably, Ho32 can remain highly stable when bombarded with different ion source energies in HRESI-MS or immersed in an aqueous solution of different pH values for 24 h. The possible formation mechanism of Ho32 was proposed to be Ho(III), (L)- and H2O → Ho3(L)3/Ho3(L)4 → Ho4(L)4/Ho4(L)5 → Ho6(L)6/Ho6(L)7 → Ho16(L)19 → Ho28(L)15 → Ho32(L)24/Ho32(L)21/Ho32(L)23. To the best of our knowledge, this is the first study of the assembly mechanism of spherical high-nuclear lanthanide clusters. Spherical cluster Gd32, a form of highly aggregated Gd(III), exhibits a high longitudinal relaxation rate (1 T, r1 = 265.87 mM-1·s-1). More notably, compared with the clinically used commercial material Gd-DTPA, Gd32 has a clearer and higher-contrast T1-weighted MRI effect in mice bearing 4T1 tumors. This is the first time that high-nuclear lanthanide clusters with high water stability have been utilized for MRI. High-nuclear Gd clusters containing highly aggregated Gd(III) at the molecular level have higher imaging contrast than traditional Gd chelates; thus, using large doses of traditional gadolinium contrast agents can be avoided.

The effect of refined nursing education on improving the urination of patients after renal biopsy.

BACKGROUND: To investigate the clinical effect of better nursing education on patients' postoperative urination after renal biopsy. METHODS: In this study, patients who underwent renal biopsy in the Department of Nephrology at our hospital were selected as the observation group (July-December 2018, n = 120) and control group (January-June 2018, n = 110) and received refined nursing education and routine nursing education, respectively. Postoperatively, the causes of dysuria after puncture, the degree of postoperative pain, and the urination mode were compared between the two groups. RESULTS: Six patients in the observation group and 23 patients in the control group needed urethral catheterization, accounting for about 5% and 15.2%, respectively. Therefore, the postoperative catheterization rate in the observation group was significantly lower than the control group, with a statistically significant difference. CONCLUSION: The refined nursing education proposed in this study can effectively improve urinary dysfunction after renal biopsy and has a clinical promotional value.

Normative values of hand grip strength in a large unselected Chinese population: Evidence from the China National Health Survey.

BACKGROUND: Hand grip strength (HGS) is a powerful indicator of sarcopenia and other adverse health outcomes. Normative values for HGS for general Chinese people with a broad age spectrum are lacking. This study aims to establish normative values of HGS and explore the correlations between HGS and body composition among unselected people aged 8-80 in China. METHODS: From 2012 to 2017, 39 655 participants aged 8-80 years in the China National Health Survey were included. Absolute HGS was measured using a Jamar dynamometer. The relative HGS was normalized by body mass index. Body composition indexes included body mass index, body fat percentage, muscle mass, fat mass index (FMI) and muscle mass index (MMI). Sex-specific smoothed centile tables for the P1 , P5 , P25 , P50 , P75 , P95 and P99 centiles of HGS and body composition were generated using lambda-mu-sigma method. The correlations between muscle strength and body composition were estimated by partial Spearman correlation analysis. RESULTS: The median values (25th and 75th percentile) of HGS in boys and girls (8-19 years old) were 22 (14, 34) kg and 18 (12, 22) kg, respectively; in men and women aged 20-80 were 39 (33, 44) kg and 24 (20, 27) kg, respectively. Values of upper and lower HGS across ages had three periods: an increase to a peak in the 20 s in men (with the 5th and 95th values of 30 and 55 kg, respectively) and 30 s in women (with the 5th and 95th values of 18 and 34 kg, respectively), preservation through midlife (20s-40 s), and then a decline after their 50 s. The lowest HGS values in both sexes were in the 70- to 80-year-old group, with the 5th and 95th percentile values of 16 and 40 kg in men, and 10 and 25 kg in women. There were substantial sex differences in body composition in the life course (all P values <0.001). In ageing, the decrease of muscle strength was faster than that of muscle mass in both sexes. The correlations between muscle mass and HGS were most robust than other correlations, especially in women (0.68 vs. 0.50), children and adolescents. CONCLUSIONS: Our study established the age- and sex-specific percentile reference values for hand grip strength in an unselected Chinese population across a broad age-spectrum. The rich data can facilitate the practical appraisal of muscle strength and promote early prediction of sarcopenia and other impairments associated with neuromuscular disorders.

Real-world effectiveness of regorafenib in the treatment of patients with metastatic colorectal cancer: A retrospective, observational study.

AIM: To evaluate the real-world usage pattern and factors associated with the effectiveness of regorafenib in patients with metastatic colorectal cancer (mCRC). METHODS: This retrospective study analyzed data for 209 patients with mCRC treated with regorafenib as third or later line of therapy. TheKaplan-Meier method was used to draw the survival curves. Cox proportional hazard regression models were used to analyze the prognostic value for overall survival (OS). RESULTS: Of 209 patients, 156 (75%) were treated with regorafenib, and 53 (25%) were given regorafenib combined with programmed cell death-1 (PD-1) inhibitors. About 182 (87%) patients had a dose record of regorafenib. The initial daily doses of regorafenib were 160, 120, 80, and 40 mg, accounting for 29%, 17%, 48%, and 6% of patients, respectively. The median follow-up time was 11.3 months, and the median OS was 12.0 months (95% CI: 9.7-14.3). Patients treated with PD-1 inhibitors plus regorafenib had a longer OS than the non-PD-1 group (13.5 vs. 10.1 months, hazard ratio [HR] = .534, 95% CI: .325-.879; p = .014). A total of 49 patients with microsatellite stable or mismatch repair-proficient genotype treated with PD-1 inhibitors plus regorafenib had a longer OS than the non-PD-1 group (13.5 vs. 9.7 months; HR = .563, p = .027). The median OS of patients continuing treatment with regorafenib after progression (n = 19, with five patients receiving additional immunotherapy) was marginally longer than patients discontinuing regorafenib after progression (12.7 vs. 11.9 months, p = .425) observed in a smaller cohort. CONCLUSION: In real-world practice, patients with mCRC in whom standard regimens had failed have a good survival benefit with regorafenib. Combination with PD-1 inhibitor may further prolong survival of the patients.

Dual factor coactivatable fluorescent nanosensor with boosted cytoplasmic biomarker accessibility toward selective tumor imaging.

Fluorescent nanosensor-based tumor imaging holds great promise in cancer diagnosis and treatment assistance, yet the signal contrast is heavily hampered by the unspecific/unwanted activation at microscopic regions with a highly restricted local abundance of biomarkers. Herein, we developed an activation boosting strategy by the integration and manipulation of dual-factor coactivation of sensing and lysosome escape facilitated the rise of cytosolic biomarker accessibility. By employing hybrid DNA probes on gold nanoquenchers, ATP sensing initiated conformation switch of the corresponding aptamer units triggered the exposure of a hidden toehold in a loop structure. Sequentially, miRNA-21 sensing was triggered by toehold-mediated strand displacement and detachment of the binding complexes. The application of lysosomotropic agent chloroquine at optimized time interval facilitated the release of nanosensors into the cytosol and a ∼10.5-fold increment of intracellular fluorescence in vitro, while coactivation improved the cancer-to-normal cell signal ratio by ∼5.9 times. The synergy effects led to a high tumor-to-normal tissue ratio value of ∼7.9 in the in vivo imaging results. This strategy establishes a new paradigm of fluorescent nanosensors for selective and specific tumor imaging.

Ophthalmic Solution of Smart Supramolecular Peptides to Capture Semaphorin 4D against Diabetic Retinopathy.

Diabetic retinopathy (DR) is the leading cause of vision loss in working age population. Intravitreal injection of anti-VEGF antibody is widely used in clinical practice. However, about 27% of patients show poor response to anti-VEGF therapy and about 50% of these patients continue to have macular thickening. Frequent intravitreal injections of antibody may increase the chance of endophthalmitis and cause visual loss or even blindness once happened. Therefore, there is a greatly urgent need for novel noninvasive target to treat DR clinically. Here, the formulation of a smart supramolecular peptide (SSP) eye drop for DR treatment that is effective via specifically identifying and capturing soluble semaphorin 4D (sSema4D), a strongly pro-angiogenesis and exudates factor, is reported. The SSP nanostructures encapsulate sSema4D so that all biological effects mediated by three receptors of sSema4D are inhibited, thereby significantly alleviating pathological retinal angiogenesis and exudates in DR. Moreover, it is found that combination of SSPs eye drop and anti-VEGF injection shows better therapeutic effect over anti-VEGF treatment alone. Overall, SSP eye drop provide an alternative and effective method for noninvasive treatment for DR.

Efficacy and safety of regorafenib as second-line treatment for patients with hepatocellular carcinoma and macrovascular invasion and(or) extrahepatic metastasis.

Background: Macrovascular invasion and(or) extrahepatic metastasis are the main clinical characteristics of Chinese patients with hepatocellular carcinoma (HCC) after entering the second-line treatment. The aim of this study was to explore the efficacy and safety of regorafenib as a second-line treatment for these patients with HCC. Methods: We selected 253 patients with primary liver cancer who were treated in Henan Cancer Hospital from June 2017 to September 2020. According to the inclusion and exclusion criteria, 63 patients with HCC with macrovascular invasion and/or extrahepatic metastasis were finally included. The clinical data of patients were obtained by consulting the electronic medical record system and through telephone follow-up. The median overall survival (mOS), duration of drug use, and disease control rate (DCR) of patients were evaluated, and the Cox regression model was used to analyze the risk factors of prognosis. Results: The mOS of 63 patients with HCC administered regorafenib as second-line treatment was 9.6 months, the duration of drug use was 3.8 months, and the DCR was 59% (37/63). Cox multivariate analysis showed that overall survival (OS) was closely related to the level of alpha-fetoprotein (AFP) and treatment method but not to the type of first-line drug. The mOS of patients with AFP ≥400 ng/mL was 7.4 months, which was significantly lower than that of those with AFP <400 ng/mL (12.5 months) (P=0.0052). The mOS of patients treated with regorafenib alone was 6.8 months, which was significantly lower than that of those treated with regorafenib combined with immunotherapy (24.3 months) and intervention therapy (17.5 months) (P<0.0001). The mOS of patients using regorafenib as second-line treatment in the first-line sorafenib group and first-line nonsorafenib group were 9.5 and 9.6 months, respectively (P=0.9766). The grade ≥3 adverse events (AEs) with an incidence of more than 10% included hand-foot syndrome, increased bilirubin, decreased albumin, and elevated transaminase, with incidences of 22%, 14%, 11%, and 10%, respectively. Conclusions: As second-line treatment for patients with HCC with macrovascular invasion and(or) extrahepatic metastasis, regorafenib has definite efficacy and tolerable adverse reactions. It is the preferred drug for the second-line treatment of patients with advanced HCC.

Exploitation of Synchrotron Radiation Photoionization Mass Spectrometry in the Analysis of Complex Organics in Interstellar Model Ices.

Unravelling the generation of complex organic molecules (COMs) on interstellar nanoparticles (grains) is essential in establishing predictive astrochemical reaction networks and recognizing evolution stages of molecular clouds and star-forming regions. The formation of COMs has been associated with the irradiation of interstellar ices by ultraviolet photons and galactic cosmic rays. Herein, we pioneer the first incorporation of synchrotron vacuum ultraviolet photoionization reflectron time-of-flight mass spectrometry (SVUV-PI-ReTOF-MS) in laboratory astrophysics simulation experiments to afford an isomer-selective identification of key COMs (ketene (H2C═CO); acetaldehyde (CH3CHO); vinyl alcohol (H2C═CHOH)) based on photoionization efficiency (PIE) curves of molecules desorbing from exposed carbon monoxide-methane (CO-CH4) ices. Our results demonstrate that the SVUV-PI-ReTOF-MS approach represents a versatile, rapid methodology for a comprehensive identification and explicit understanding of the complex organics produced in space simulation experiments. This methodology is expected to significantly improve the predictive nature of astrochemical models of complex organic molecules formed abiotically in deep space, including biorelated species linked to the origins-of-life topic.

Characterization of E-cadherin expression in normal mucosa, dysplasia and adenocarcinoma of gastric cardia and its influence on prognosis.

BACKGROUND: Gastric cardia adenocarcinoma (GCA), which has been classified as type II adenocarcinoma of the esophagogastric junction in western countries, is of similar geographic distribution with esophageal squamous cell carcinoma in China, and even referred as "sister cancer" by Chinese oncologists. The molecular mechanism for GCA is largely unknown. Recent studies have shown that decreased expression of E-cadherin is associated with the invasion and metastasis of multiple cancers. However, the E-cadherin expression has not been well characterized in gastric cardia carcinogenesis and its effect on GCA prognosis. AIM: To characterize E-cadherin expression in normal gastric cardia mucosa, dysplasia and GCA tissues, and its influence on prognosis for GCA. METHODS: A total of 4561 patients with GCA were enrolled from our previously established GCA and esophageal cancer databases. The enrollment criteria included radical surgery for GCA, but without any radio- or chemo-therapy before operation. The GCA tissue from 4561 patients and matched adjacent normal epithelial tissue (n = 208) and dysplasia lesions (n = 156) were collected, and processed as tissue microarray for immunohistochemistry. The clinicopathological characteristics were retrieved from the medical records in hospital and follow-up was carried out through letter, telephone or home interview. E-cadherin protein expression was determined by two step immunohistochemistry. Kaplan-Meier and Cox regression analyses were used to correlate E-cadherin protein expression with survival of GCA patients. RESULTS: Of the 4561 GCA patients, there were 3607 males with a mean age of 61.6 ± 8.8 and 954 females with a mean age of 61.9 ± 8.6 years, respectively. With the lesions progressed from normal gastric cardia mucosa to dysplasia and GCA, the positive immunostaining rates for E-cadherin decreased significantly from 100% to 93.0% and 84.1%, respectively (R2 = 0.9948). Furthermore, E-cadherin positive immunostaining rate was significantly higher in patients at early stage (0 and I) than in those at late stage (II and III) (92.7% vs 83.7%, P = 0.001). E-cadherin positive expression rate was significantly associated with degree of differentiation (P = 0.001) and invasion depth (P < 0.001). Multivariate analysis showed that the GCA patients with positive E-cadherin immunostaining had better survival than those with negative (P = 0.026). It was noteworthy that E-cadherin positive expression rate was similar in patients with positive and negative lymph node metastasis. However, in patients with negative lymph node metastasis, those with positive expression of E-cadherin had better survival than those with negative expression (P = 0.036). Similarly, in patients with late stage GCA, those with positive expression of E-cadherin had better survival than those with negative expression (P = 0.011). CONCLUSION: E-cadherin expression may be involved in gastric cardia carcinogenesis and low expression of E-cadherin may be a promising early biomarker and overall survival predictor for GCA.

AHU-MultiNet: Adaptive loss balancing based on homoscedastic uncertainty in multi-task medical image segmentation network.

Medical image segmentation is an important field in medical image analysis and a vital part of computer-aided diagnosis. Due to the challenges in acquiring image annotations, semi-supervised learning has attracted high attention in medical image segmentation. Despite their impressive performance, most existing semi-supervised approaches lack attention to ambiguous regions (e.g., some edges or corners around the organs). To achieve better performance, we propose a novel semi-supervised method called Adaptive Loss Balancing based on Homoscedastic Uncertainty in Multi-task Medical Image Segmentation Network (AHU-MultiNet). This model contains the main task for segmentation, one auxiliary task for signed distance, and another auxiliary task for contour detection. Our multi-task approach can effectively and sufficiently extract the semantic information of medical images by auxiliary tasks. Simultaneously, we introduce an inter-task consistency to explore the underlying information of the images and regularize the predictions in the right direction. More importantly, we notice and analyze that searching an optimal weighting manually to balance each task is a difficult and time-consuming process. Therefore, we introduce an adaptive loss balancing strategy based on homoscedastic uncertainty. Experimental results show that the two auxiliary tasks explicitly enforce shape-priors on the segmentation output to further generate more accurate masks under the adaptive loss balancing strategy. On several standard benchmarks, the 2018 Atrial Segmentation Challenge and the 2017 Liver Tumor Segmentation Challenge, our proposed method achieves improvements and outperforms the new state-of-the-art in semi-supervised learning.

Relationship between glutathione S-transferase M1 gene polymorphism and gastric cancer.

This experiment was designed to investigate the relationship between glutathione S-transferase M1 (GSTM1) gene polymorphism and gastric cancer (GC). For this purpose, from January 2013 to December 2014, 116 patients with GC diagnosed in the Department of Gastroenterology of our hospital and 120 healthy people in the physical examination center were selected as the research objects. 116 patients with GC served as the observation group and 120 healthy people in the physical examination center served as the control group. Collect and isolate the peripheral blood nucleated cells of the subjects, obtain the GSTM1 gene polymorphism by sequencing, analyze the differences of GSTM1 genotype between the two groups, compare the differences of clinicopathological characteristics of patients with different genotypes in the observation group, look for the survival relative risk factors of patients with GC, and analyze the risk factors of death risk of GC by multivariate Cox risk proportional regression. Results showed that the proportion of GSTM1 (-) in the observation group (62.07%) was raised compared with the control group (48.33%) (p<0.05). There was a correlation between GSTM1 gene polymorphism and smoking, TNM stage differentiation and GSTM1 gene polymorphism in the observation group. The specific analysis found that the proportion of non-smoking, stage I-III and low differentiation in the GSTM1 (-) group was raised compared with that in the GSTM1 (+) group (p<0.05). TNM stage, differentiation degree and GSTM1 gene polymorphism were correlated with the median survival time of patients with GC (p<0.05). Further multivariate Cox risk proportional regression analysis showed that TNM stage IV, low differentiation and GSTM1 (-) the relative risk coefficients of death in patients with GC were stage Ⅰ - Ⅲ, high/medium differentiation and GSTM1, respectively (+) patients were 1.75, 1.46, and 2.14 times higher. In conclusion, GSTM1 gene polymorphism is associated with susceptibility to GC, and the GSTM1 deletion genotype is an unfavourable factor for poor prognosis in patients with GC.

Profile and early outcomes of surgical reconstruction of coronary artery atresia in children.

OBJECTIVES: Coronary artery atresia is a rare coronary artery anomaly in children and has a high rate of misdiagnosis. We aimed to summarize the profile and early outcomes after the surgical reconstruction of coronary artery atresia in children. METHODS: A retrospective analysis was performed in 12 consecutive patients with coronary artery atresia who were admitted to the Department of Paediatric Cardiac Surgery of Fuwai Hospital between October 2016 and September 2020. Ten patients underwent surgical reconstruction of the coronary artery with the pulmonary artery anterior wall, and 8 patients underwent concomitant mitral valvuloplasty. RESULTS: There were 6 females and 6 males, with an age of 1.75 years [interquartile range (IQR), 1.0-3.5] and weight of 10.0 kg (IQR, 8.9-14.75). There were 10 cases of left coronary artery atresia and 2 cases of right coronary artery atresia. All the patients were initially misdiagnosed in the outpatient clinic, but further nonselective coronary angiography confirmed the diagnosis of coronary artery atresia. In all 10 patients with mitral regurgitation, echocardiogram of the mitral valve chordae and papillary muscle revealed ischaemic changes. The clamp time was 89.0 min (IQR, 75.0-101.0), the pump time was 126.0 min (IQR, 119.0-132.0) and the intensive care unit stay time was 1.5 days (IQR, 1.0-3.0). No perioperative deaths were noted. After 9.5 months (IQR, 5.5-13.5) of follow-up, 2 patients with fractional shortening that significantly decreased to 14.1% and 14.8% died and 1 patient had moderate pericardial effusion that improved after treatment with oral diuretics. Coronary artery ultrasound and enhanced computed tomography showed a patent main coronary artery in all the patients. CONCLUSIONS: Coronary artery atresia in children is often associated with mitral regurgitation, and mitral valve chordae and papillary muscle exhibit ischaemic changes. Coronary artery reconstruction is safe and effective in children with coronary artery atresia.

ERK Modulates Macrophage Polarization and Alters Exosome miRNA Expression in Diabetic Nephropathy.

BACKGROUND: The aim is to probe into the differential expression of miRNA in macrophage exosomes in diabetic nephropathy (DN) by ERK regulating macrophage polarization through the NF-κB/JAK-STAT signaling pathway. METHODS: Our team cultivated the mouse macrophage line RAW264 cells. When the cell growth status was good, we added 30 mmol/L glucose, and then added ERK/JAK-STAT/NF-κB inhibitors separately. We adopted western blot for observing macrophage polarization and the impact of JAK-STAT inhibitor on caspase-9, eNOS, NF-κB p65 expression, extracted exosomes, and total exosome RNA of each group of cells. Their miRNA expression profiles were also analyzed by high-throughput sequencing. RESULTS: (1) In comparison with the control group, relative iNOS protein expression in ERK inhibitor group dramatically declined (p < 0.05), and the iNOS protein content in the NF-κB inhibitor group and the JAK-STAT inhibitor group conspicuously dwindled (p < 0.05); relative CD206 protein expression in each inhibitor group was clearly augmented (p > 0.05). Under the intervention of high glucose, ERK/JAK-STAT/NF-κB inhibitors brilliantly diminished the up-regulation of caspase-9 (p < 0.05), and ERK/JAK-STAT inhibitors notably minimized the up-regulation of NF-κB p65 (p < 0.05). ELISA results unveiled that in contrast to the control group, TNF-α, IL-1ß, and CXCL10 levels in the macrophage supernatant of the inhibitor group was tellingly augmented (p < 0.05), whereas TGF-ß level had strikingly declined (p < 0.05), proving that macrophages were activated to M1. (2) Flow cytometry uncloaked that the phagocytic ability of macrophages in inhibitor group was compellingly lower than that in the control group. (3) One hundred thirty-six known miRNAs with notably differential expression and 5,134 miRNA sequences were detected in the exosomes of the macrophage supernatant of each experimental group. Of those, some differentially expressed miRNAs include miR-193a-3p, miR-1260B, and miR-3175. miR-193a-3p, miR-1260B, and miR-3175 extensively participate in the development of cancer, arthritis, osteogenic differentiation, Alzheimer's disease, and other diseases, as well as in the regulation of MAPK/ERK, TLR4/NF-κB, and other signaling pathways. CONCLUSIONS: ERK modulates macrophage activation to M1 and alters exosome miRNA expression profile via NF-κB/JAK-STAT pathway.