Study on the Effect of Microstructure and Inclusions on Corrosion Resistance of Low-N 25Cr-Type Duplex Stainless Steel via Additive Manufacturing.

Duplex stainless steels are widely used in many fields due to their excellent corrosion resistance and mechanical properties. However, it is a challenge to achieve duplex microstructure and excellent properties through additive manufacturing. In this work, a 0.09% N 25Cr-type duplex stainless steel was prepared by additive manufacturing (AM) and heat treatment, and its corrosion resistance was investigated. The results show that, compared with S32750 duplex stainless steel prepared by a conventional process, the combination value of film resistance and charge transfer resistance of AM duplex stainless steel was increased by 3.2-5.5 times and the pitting potential was increased by more than 100 mV. The disappearance of residual thermal stress and the reasonable distribution of Cr and N elements in the two phases are the reasons for the improvement of the corrosion resistance of AM duplex stainless steel after heat treatment. In addition, the extremely high purity of AM duplex stainless steel with no visible inclusions resulted in a higher corrosion resistance exhibited at lower pitting-resistance-equivalent number values.

Targeting estrogen mediated CYP4F2/CYP4F11-20-HETE metabolic disorder decelerates tumorigenesis in ER+ breast cancer.

Purpose: As the most common subset of breast cancer (BC), estrogen receptor positive (ER+) BC accounting for 80% of cases, has become a global public health concern. The female hormone estrogen (E2) unequivocally drives ER + breast malignancies. The reasons that estrogen affects BC development has long been considered, yet further study remains to be conducted of the molecular events in the E2-estrogen receptor α (ERα) signaling pathway in ER + BC progression, especially lipid metabolism, so providing more options for tailored and individualized therapy. Our aim is to find out new targets and clinical biomarkers for ER + breast cancer treatment from the perspective of lipid metabolism. Methods: Lipid metabolomics profiling was used to examine the membrane phospholipid stimulated by E2. Clinical BC samples were used to assess the association of CYP4F2, CYP4F11 expression with clinicopathological characteristics and patient outcomes. Some inhibitors of main enzymes in AA metabolism were used combined with E2 to assess roles of CYP4F2/CYP4F11 in the progression of ER + BC. CYP4F2, CYP4F11 overexpression and knockdown BC cell lines were employed to examine the effects of CYP4F2, CYP4F11 on cellular proliferation, apoptosis and tumor growth. Western blotting, qPCR, Immunohistochemical staining and flow cytometry were also conducted to determine the underlying mechanisms related to CYP4F2, CYP4F11 function. Results: The activation of the CYP450 signaling pathway in arachidonic acid metabolism contributed to ER + BC tumorigenesis. In ER + BC, CYP4F2 and CYP4F11 overexpression induced by E2 could promote cancer cell proliferation and resistance to apoptosis by producing the metabolite 20-HETE and activating the antiapoptotic protein Bcl-2. CYP4F2 and CYP4F11 elevation correlates with poorer overall survival and disease-free survival in ER + BC patients. Conclusion: CYP4F2, CYP4F11 and their metabolite 20-HETE could serve as effective prognostic markers and attractive therapeutic targets for novel anticancer drug development about ER + BC.

Stereotactic ablative brachytherapy versus percutaneous microwave ablation as salvage treatments for lung oligometastasis from colorectal cancer.

BACKGROUND: The treatment for lung oligometastasis from colorectal cancer (CRC) remains challenging. This retrospective study aimed to compare the local tumor control, survival and procedure-related complications in CRC patients undergoing low-dose rate stereotactic ablative brachytherapy (L-SABT) versus percutaneous microwave ablation (MWA) for lung oligometastasis. METHODS: Patients between November 2017 and December 2020 were retrospectively analyzed. Local tumor progression-free survival (LTPFS) and overall survival (OS) were analyzed in the entire cohort as well as by stratified analysis based on the minimal ablation margin (MAM) around the tumor. RESULTS: The final analysis included 122 patients: 74 and 48 in the brachytherapy and MWA groups, respectively, with a median follow-up of 30.5 and 35.3 months. The 1- and 3-year LTPFS rate was 54.1% and 40.5% in the brachytherapy group versus 58.3% and 41.7% in the MWA group (P = 0.524 and 0.889, respectively). The 1- and 3-year OS rate was 75.7% and 48.6% versus 75.0% and 50.0% (P = 0.775 and 0.918, respectively). Neither LTPFS nor OS differed significantly between the patients with MAM of 5-10 mm versus > 10 mm. Pulmonary complication rate did not differ in the overall analysis, but was significantly higher in the MWA group in the subgroup analysis that only included patients with lesion within 10 mm from the key structures (P = 0.005). The increased complications was primarily bronchopleural fistula. CONCLUSIONS: Considering the caveats associated with radioisotope use in L-SABT, MWA is generally preferable. In patients with lesion within 10 mm from the key pulmonary structures, however, L-SABT could be considered as an alternative due to lower risk of bronchopleural fistula.

Multi-scale consistent self-training network for semi-supervised orbital tumor segmentation.

PURPOSE: Segmentation of orbital tumors in CT images is of great significance for orbital tumor diagnosis, which is one of the most prevalent diseases of the eye. However, the large variety of tumor sizes and shapes makes the segmentation task very challenging, especially when the available annotation data is limited. METHODS: To this end, in this paper, we propose a multi-scale consistent self-training network (MSCINet) for semi-supervised orbital tumor segmentation. Specifically, we exploit the semantic-invariance features by enforcing the consistency between the predictions of different scales of the same image to make the model more robust to size variation. Moreover, we incorporate a new self-training strategy, which adopts iterative training with an uncertainty filtering mechanism to filter the pseudo-labels generated by the model, to eliminate the accumulation of pseudo-label error predictions and increase the generalization of the model. RESULTS: For evaluation, we have built two datasets, the orbital tumor binary segmentation dataset (Orbtum-B) and the orbital multi-organ segmentation dataset (Orbtum-M). Experimental results on these two datasets show that our proposed method can both achieve state-of-the-art performance. In our datasets, there are a total of 55 patients containing 602 2D images. CONCLUSION: In this paper, we develop a new semi-supervised segmentation method for orbital tumors, which is designed for the characteristics of orbital tumors and exhibits excellent performance compared to previous semi-supervised algorithms.

Hydrogen gas alleviates acute ethanol-induced hepatotoxicity in mice via modulating TLR4/9 innate immune signaling and pyroptosis.

Alcoholic liver disease (ALD), which is induced by chronic heavy alcohol consumption, accompanies complicated pathological mechanisms, including oxidative stress, inflammation, cell death, epigenetic changes and acetaldehyde-mediated toxicity. Hydrogen (H2) is the lightest gas with multiple biological effects such as high selective anti-oxidation, anti-inflammation and anti-apoptosis. However, the dose effects and innate immune mechanisms of intraperitoneal injection of H2 on ALD are limited. Here, we used acute ethanol-induced hepatotoxicity mice models to estimate the actions of intraperitoneal injection of H2 on ALD. The effects of H2 on acute ethanol-induced liver damage were examined by hepatic oil red O staining, quantitative PCR (qPCR) for lipid metabolic genes, hepatic triglyceride (TG) and serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Hepatic mitochondrial superoxide (MitoSOX), 3-nitrotyrosine (3-NT), malondialdehyde (MDA), and glutathione (GSH) levels were examined to evaluate oxidative stress. Immunoblot, and immunofluorescence staining were used to further confirm the innate immune molecular targets of H2. Our results showed that intraperitoneal injection of H2 improved acute ethanol-induced liver injury in mice in a dose dependent manner, as indicated by decreasing serum ALT and AST levels, hepatic TG levels, and increasing lipid export genes (Mttp and Apob) mRNA levels and reducing fatty acid uptake gene (CD36) mRNA levels. Mechanistically, H2 inhibited hepatic oxidative stress as indicated by reducing reactive oxygen species (ROS), 3-NT, and MDA levels in the liver, while increasing hepatic GSH levels; inhibited the overactived TLR4/9-NF-κB-TNF-α/IL-1ß/IL-18 innate immune signaling; suppressed the canonical Caspase-1-GSDMD pyroptosis signaling, and the non-canonical pyroptosis signaling, such as Caspase-11-GSDMD, Caspase-8-GSDMD and Caspase-3-GSDME signaling. Therefore, our study highlights that intraperitoneal injection of H2 may represent a novel therapeutic and safe strategy for ALD via modulating oxidative stress, innate immunity and pyroptosis.

Assessment of geriatric and clinical domains for development and validation of a novel nomogram to predict the prognosis of older patients with breast cancer: a real-world retrospective cohort study.

Background: Breast cancer is a relatively heterogeneous disease in the older population. Survival in older breast cancer patients is not only affected by tumor-related factors, but also by geriatric assessment domains. How tumor clinical factors and geriatric factors specifically affect the survival rate of older patients and how to combine these two factors to predict the risk of death in older patients with breast cancer remain clinical questions to be addressed. Method: We used the Peking Union Medical College Hospital database to identify older patients (≥65 years) who were newly diagnosed with breast cancer between January 2013 and December 2019. Of the 641 eligible patients, we retrospectively analyzed the clinical and geriatric data of 556 patients who formed our study population. The primary outcomes were overall survival (OS) and breast cancer-specific survival (BCSS). Univariate and multivariate Cox regression analyses were conducted to identify independent prognostic factors and construct a nomogram to predict the 1-, 3-, and 5-year survival rates. The performance of the constructed nomogram was evaluated using calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA). Results: Multivariate Cox regression analysis revealed seven independent prognostic factors associated with OS in older patients with breast cancer: age, tumor stage, lymph node stage, intrinsic molecular subtype, functional status, comorbidities, and psychological state. Nomogram based on these seven factors yielded excellent performance, with area under the ROC curve (AUROC) of 0.748. Similarly, the nomogram for BCSS had an AUROC of 0.760. Moreover, the calibration curve and DCA revealed good predictive accuracy between the actual and predicted probabilities. Conclusion: Independent prognostic factors for OS and BCSS in older patients with breast cancer in China were determined in our study. A novel nomogram for predicting the 1-, 3-, and 5-year OS and BCSS in this patient population was developed and validated. The nomogram exhibited good accuracy, indicating its potential for clinical decision making and improving outcomes.

Nomogram prediction of the 70-gene signature (MammaPrint) binary and quartile categorized risk using medical history, imaging features and clinicopathological data among Chinese breast cancer patients.

BACKGROUND: The 70-gene signature (70-GS, MammaPrint) test has been recommended by the main guidelines to evaluate prognosis and chemotherapy benefit of hormonal receptor positive human epidermal receptor 2 negative (HR + /Her2-) early breast cancer (BC). However, this expensive assay is not always accessible and affordable worldwide. Based on our previous study, we established nomogram models to predict the binary and quartile categorized risk of 70-GS. METHODS: We retrospectively analyzed a consecutive cohort of 150 female patients with HR + /Her2- BC and eligible 70-GS test. Comparison of 40 parameters including the patients' medical history risk factors, imaging features and clinicopathological characteristics was performed between patients with high risk (N = 62) and low risk (N = 88) of 70-GS test, whereas risk calculations from established models including Clinical Treatment Score Post-5 years (CTS5), Immunohistochemistry 3 (IHC3) and Nottingham Prognostic Index (NPI) were also compared between high vs low binary risk of 70-GS and among ultra-high (N = 12), high (N = 50), low (N = 65) and ultra-low (N = 23) quartile categorized risk of 70-GS. The data of 150 patients were randomly split by 4:1 ratio with training set of 120 patients and testing set 30 patients. Univariate analyses and multivariate logistic regression were performed to establish the two nomogram models to predict the the binary and quartile categorized risk of 70-GS. RESULTS: Compared to 70-GS low-risk patients, the high-risk patients had significantly less cardiovascular co-morbidity (p = 0.034), more grade 3 BC (p = 0.006), lower progesterone receptor (PR) positive percentage (p = 0.007), more Ki67 high BC (≥ 20%, p < 0.001) and no significant differences in all the imaging parameters of ultrasound and mammogram. The IHC3 risk and the NPI calculated score significantly correlated with both the binary and quartile categorized 70-GS risk classifications (both p < 0.001). The area under curve (AUC) of receiver-operating curve (ROC) of nomogram for binary risk prediction were 0.826 (C-index 0.903, 0.799-1.000) for training and 0.737 (C-index 0.785, 0.700-0.870) for validation dataset respectively. The AUC of ROC of nomogram for quartile risk prediction was 0.870 (C-index 0.854, 0.746-0.962) for training and 0.592 (C-index 0.769, 0.703-0.835) for testing set. The prediction accuracy of the nomogram for quartile categorized risk groups were 55.0% (likelihood ratio tests, p < 0.001) and 53.3% (p = 0.04) for training and validation, which more than double the baseline probability of 25%. CONCLUSIONS: To our knowledge, we are the first to establish easy-to-use nomograms to predict the individualized binary (high vs low) and the quartile categorized (ultra-high, high, low and ultra-low) risk classification of 70-GS test with fair performance, which might provide information for treatment choice for those who have no access to the 70-GS testing.

Maintaining Excellent Mechanical Properties via Additive Manufacturing of Low-N 25Cr-Type Duplex Stainless Steel.

Duplex stainless steel (DSS) exhibits good mechanical properties and corrosion resistance, and has attracted more and more attention within the fields of both science and technology. However, the increasing levels of N and of Cr, Mo, etc., as alloying elements in DSS increase production difficulty. In particular, the N element increases the risk of Cr2N precipitation, which can seriously deteriorate the thermal plasticity of DSS, while increasing its strength. For this reason, a low-N-content 25Cr-type DSS was designed in order to adapt additive manufacturing processes. With regard to the nano-inclusions of oxide precipitation and effective grain refinement, and considering the benefits of selective laser melting fabrication, a low-N 25Cr-type duplex stainless steel with a 0.09 wt.% N content achieved high mechanical properties, with a yield strength of 712 MPa and an elongation of 27.5%, while the V-notch impact toughness was 160 J/cm2. The microstructure evolution and the reasons behind the improvement in mechanical properties will be discussed in detail.

The Prognostic Value of the Age-Adjusted Charlson Comorbidity Index Among the Elderly with Breast Cancer.

Purpose: This study aimed to assess the effect of comorbidities on prognosis using the Age-adjusted Charlson Comorbidity Index (ACCI) among the elderly with breast cancer (BC). Methods: This study included 745 patients divided into two groups following the ACCI score (≤3 vs >3). Multivariate logistic regression analysis was conducted for all kinds of outcomes, including BC-specific death (BCSD) and non-breast cancer-specific death (NBCSD). The Kaplan-Meier curves were plotted, and survival analysis was conducted for disease-free survival (DFS), overall survival (OS), BC-specific survival (BCSS), and non-BCSS (NBCSS). Results: A significantly higher NBCSD was found in the high-score (ACCI > 3) group than in the low-score (ACCI < 3) group (p = 0.032). The multivariate logistic regression analysis revealed ACCI score as an independent affecting factor for all-cause death (hazard ratio [HR] = 0.42, 95% confidence interval [CI]: 0.22-0.83, p = 0.012) and NBCSD (HR = 0.41, 95% CI: 0.20-0.87, p = 0.020). The Kaplan-Meier curves revealed statistical differences only in NBCSS between the two groups (p = 0.039). Subgroup analysis revealed a worse prognosis in the high-score group for OS and NBCSS among hormone receptor-positive participants and those who without undergoing axillary dissection or receiving chemotherapy (all p < 0.05). Multivariate Cox regression analysis revealed ACCI as an independent prognostic predictor for OS (HR = 2.18, 95% CI: 1.22-3.92, p = 0.009) and NBCSS (HR = 2.04, 95% CI: 1.02-4.08, p = 0.044). Conclusion: ACCI was indeed an effective indicator of the effects of comorbidities on survival among elderly patients with BC. However, the co-effect from age and comorbidities was not significant enough on cancer-specific prognosis, although it exerted a significant effect on treatments received.

Characterization of Mu-Like Yersinia Phages Exhibiting Temperature Dependent Infection.

Yersinia pestis is the etiological agent of plague. Marmota himalayana of the Qinghai-Tibetan plateau is the primary host of flea-borne Y. pestis. This study is the report of isolation of Mu-like bacteriophages of Y. pestis from M. himalayana. The isolation and characterization of four Mu-like phages of Y. pestis were reported, which were named as vB_YpM_3, vB_YpM_5, vB_YpM_6, and vB_YpM_23 according to their morphology. Comparative genome analysis revealed that vB_YpM_3, vB_YpM_5, vB_YpM_6, and vB_YpM_23 are phylogenetically closest to Escherichia coli phages Mu, D108 and Shigella flexneri phage SfMu. The role of LPS core structure of Y. pestis in the phages' receptor was pinpointed. All the phages exhibit "temperature dependent infection," which is independent of the growth temperature of the host bacteria and dependent of the temperature of phage infection. The phages lyse the host bacteria at 37°C, but enter the lysogenic cycle and become prophages in the chromosome of the host bacteria at 26°C. IMPORTANCE Mu-like bacteriophages of Y. pestis were isolated from M. himalayana of the Qinghai-Tibetan plateau in China. These bacteriophages have a unique temperature dependent life cycle, follow a lytic cycle at the temperature of warm-blooded mammals (37°Ð¡), and enter the lysogenic cycle at the temperature of its flea-vector (26°Ð¡). A switch from the lysogenic to the lytic cycle occurred when lysogenic bacteria were incubated from lower temperature to higher temperature (initially incubating at 26°C and shifting to 37°C). It is speculated that the temperature dependent lifestyle of bacteriophages may affect the population dynamics and pathogenicity of Y. pestis.

MLP-Like Model With Convolution Complex Transformation for Auxiliary Diagnosis Through Medical Images.

Medical images such as facial and tongue images have been widely used for intelligence-assisted diagnosis, which can be regarded as the multi-label classification task for disease location (DL) and disease nature (DN) of biomedical images. Compared with complicated convolutional neural networks and Transformers for this task, recent MLP-like architectures are not only simple and less computationally expensive, but also have stronger generalization capabilities. However, MLP-like models require better input features from the image. Thus, this study proposes a novel convolution complex transformation MLP-like (CCT-MLP) model for the multi-label DL and DN recognition task for facial and tongue images. Notably, the convolutional Tokenizer and multiple convolutional layers are first used to extract the better shallow features from input biomedical images to make up for the loss of spatial information obtained by the simple MLP structure. Subsequently, the Channel-MLP architecture with complex transformations is used to extract deep-level contextual features. In this way, multi-channel features are extracted and mixed to perform the multi-label classification of the input biomedical images. Experimental results on our constructed multi-label facial and tongue image datasets demonstrate that our method outperforms existing methods in terms of both accuracy (Acc) and mean average precision (mAP).

Alcohol remodels the immunosuppressive tumor microenvironment by targeting myeloid-derived suppressor cells.

The tumor immunosuppressive microenvironment plays an important role in tumor progression. Alcohol is well-known as a regulator of the immune system and several studies have also reported that chronic alcohol intake can activate the immune system. However, it is unclear whether alcohol can affect liver cancer progression by regulating the immunosuppressive microenvironment. In this study, we investigated the effects of different alcohol concentrations on the growth of liver cancer and tumor immune microenvironment. We examined the growth of tumors in mice provided with water, or alcohol (for 2 weeks before tumor injection, and for 3 weeks after tumor injection). We found that alcohol consumption at 5% and 20% inhibited the growth of subcutaneous tumors in hepatocellular carcinoma-bearing mice, whereas 2% alcohol concentration did not significantly inhibit liver cancer growth. The ratio of myeloid-derived suppressor cells (MDSCs) in peripheral blood and spleen of mice treated with 5% or 20% alcohol for 2 weeks before tumor inoculation was downregulated. After tumor inoculation, the proportion of MDSCs in peripheral blood, spleen, and tumor of mice treated with 5% or 20% alcohol for another 3 weeks also decreased and the proportion of CD4+ T cells and CD8+ T cells increased. In addition, Alcohol consumption of 20% reduced levels of the inflammatory factor IL-6 by inhibiting JAK/STAT3 signaling. These results indicate that chronic alcohol consumption may inhibit the growth of liver cancer by regulating MDSCs.

All-trans-retinoic acid inhibits hepatocellular carcinoma progression by targeting myeloid-derived suppressor cells and inhibiting angiogenesis.

Hepatocellular carcinoma is characterized by a high infiltration of myeloid-derived suppressor cells (MDSC), which are key drivers of maintaining the immunosuppressive tumor microenvironment. Therefore, targeting MDSCs will improve immunotherapies for cancers. It has been shown that all-trans retinoic acid (ATRA) can differentiate MDSCs into mature myeloid cells. However, whether ATRA suppression of MDSCs function could inhibit the growth of liver cancer remains unknown. Here we found that ATRA significantly inhibited hepatocellular carcinoma promotion, tumor cell proliferation, and angiogenesis markers. Moreover, ATRA decreased the number of mononuclear myeloid-derived suppressor cells (M-MDSCs), granulocytic myeloid-derived suppressor cells (G-MDSCs) and tumor-associated macrophages (TAMs) in spleens. In addition, ATRA significantly reduced the intratumoral infiltrating G-MDSCs and the expression of protumor immunosuppressive molecules (arginase 1, iNOS, IDO and S100A8 + A9), which was accompanied by increased cytotoxic T cell infiltration. Our study demonstrates that ATRA not only has direct intrinsic inhibitory effect on tumor angiogenesis and fibrosis, but also reeducates the tumor microenvironment toward an antitumor phenotype by altering the relative proportion between protumor and antitumor immune cells. This information introduces ATRA as a potential druggable target for treatment of hepatocellular carcinoma.

G6PD activation in TNBC cells induces macrophage recruitment and M2 polarization to promote tumor progression.

Glucose-6-phosphate dehydrogenase (G6PD) is involved in triple-negative breast cancer (TNBC) progression. Metabolic crosstalk between cancer cells and tumor-associated macrophages mediates tumor progression in TNBC. Molecular biological methods were applied to clarify the mechanism of the crosstalk between TNBC cells and M2 macrophages. In the present study, we verified that G6PD overexpression drives M2 macrophage polarization by directly combining with phospho-STAT1 and upregulating CCL2 and TGF-ß1 secretion in TNBC cells. In turn, M2-like TAMs activated TNBC cells through IL-10 secretion, providing feedback to upregulate G6PD and promote TNBC cell migration and proliferation in vitro. Furthermore, we found that 6-AN (a specific inhibitor of G6PD) not only suppressed the cancer-driven polarization of macrophages toward the M2 phenotype but also inhibited the inherent M2 polarization of macrophages. Targeting the G6PD-regulated pentose phosphate pathway restrained TNBC progression and M2-type polarization of macrophages in vitro and in vivo.

Geriatric assessment for older patients with breast cancer: A single-institution study.

Introduction: Although geriatric assessment (GA) has been used for a long time in the field of geriatrics and internal medicine, there are few studies on its application in the field of breast surgery. Therefore, the utility of specific GA domains for the assessment of older patients with breast cancer remains unclear. The aim of the present study was to evaluate the association between specific GA domains and the survival rate of older patients with breast cancer. Methods: We used the database of Peking Union Medical College Hospital to identify older patients who were newly diagnosed with breast cancer between 2012 and 2018 and retrospectively analysed the data of 541 patients aged ≥65 years. Patients with metastatic cancer and those with missing vital status data were excluded. The primary outcomes were overall survival (OS) and breast cancer-specific survival. The GA domains used in this study included functional status, comorbidities, and psychological state. Multivariate regression analysis was used to estimate hazard ratios for these three domains. Results: After a median follow-up of 72 months, we observed a significant relationship between functional impairment and mortality (adjusted HR: 3.06, 95% confidence interval [CI]: 1.83-5.10, P<0.001). Similarly, patients with severe comorbidities (adjusted HR: 2.35; 95% CI: 1.16-4.75, P=0.017) and an impaired psychological state (adjusted HR: 2.82, 95% CI: 1.45-5.50, P=0.002) showed worse OS rates. Accordingly, addition of the three GA domains to the basic model, which included age, tumour stage, lymph node stage, and intrinsic molecular subtype as baseline variables, yielded higher C-statistics for mortality analysis (from 0.713 to 0.740). Conclusion: To our knowledge, this is the first study to include specific GA domains in a prognostic model for older patients with breast cancer in China. Three domains, namely functional status, comorbidities, and psychological state, should be considered for survival analyses in this particular population. The full model including these three GA domains may be more accurate in predicting the survival of older patients with breast cancer.

End-to-End Deep-Learning-Based Diagnosis of Benign and Malignant Orbital Tumors on Computed Tomography Images.

Determining the nature of orbital tumors is challenging for current imaging interpretation methods, which hinders timely treatment. This study aimed to propose an end-to-end deep learning system to automatically diagnose orbital tumors. A multi-center dataset of 602 non-contrast-enhanced computed tomography (CT) images were prepared. After image annotation and preprocessing, the CT images were used to train and test the deep learning (DL) model for the following two stages: orbital tumor segmentation and classification. The performance on the testing set was compared with the assessment of three ophthalmologists. For tumor segmentation, the model achieved a satisfactory performance, with an average dice similarity coefficient of 0.89. The classification model had an accuracy of 86.96%, a sensitivity of 80.00%, and a specificity of 94.12%. The area under the receiver operating characteristics curve (AUC) of the 10-fold cross-validation ranged from 0.8439 to 0.9546. There was no significant difference on diagnostic performance of the DL-based system and three ophthalmologists (p > 0.05). The proposed end-to-end deep learning system could deliver accurate segmentation and diagnosis of orbital tumors based on noninvasive CT images. Its effectiveness and independence from human interaction allow the potential for tumor screening in the orbit and other parts of the body.

A reversible SRC-relayed COX2 inflammatory program drives resistance to BRAF and EGFR inhibition in BRAFV600E colorectal tumors.

BRAFV600E mutation confers a poor prognosis in metastatic colorectal cancer (CRC) despite combinatorial targeted therapies based on the latest understanding of signaling circuitry. To identify parallel resistance mechanisms induced by BRAF-MEK-EGFR co-targeting, we used a high-throughput kinase activity mapping platform. Here we show that SRC kinases are systematically activated in BRAFV600E CRC following targeted inhibition of BRAF ± EGFR and that coordinated targeting of SRC with BRAF ± EGFR increases treatment efficacy in vitro and in vivo. SRC drives resistance to BRAF ± EGFR targeted therapy independently of ERK signaling by inducing transcriptional reprogramming through ß-catenin (CTNNB1). The EGFR-independent compensatory activation of SRC kinases is mediated by an autocrine prostaglandin E2 loop that can be blocked with cyclooxygenase-2 (COX2) inhibitors. Co-targeting of COX2 with BRAF + EGFR promotes durable suppression of tumor growth in patient-derived tumor xenograft models. COX2 inhibition represents a drug-repurposing strategy to overcome therapeutic resistance in BRAFV600E CRC.

Meta-Viromic Sequencing Reveals Virome Characteristics of Mosquitoes and Culicoides on Zhoushan Island, China.

Mosquitoes and biting Culicoides species are arbovirus vectors. Effective virome profile surveillance is essential for the prevention and control of insect-borne diseases. From June to September 2021, we collected eight species of female mosquito and Culicoides on Zhoushan Island, China, and used meta-viromic sequencing to analyze their virome compositions and characteristics. The classified virus reads were distributed in 191 genera in 66 families. The virus sequences in mosquitoes with the largest proportions were Iflaviridae (30.03%), Phasmaviridae (23.09%), Xinmoviridae (21.82%), Flaviviridae (13.44%), and Rhabdoviridae (8.40%). Single-strand RNA+ viruses formed the largest proportions of viruses in all samples. Blood meals indicated that blood-sucking mosquito hosts were mainly chicken, duck, pig, and human, broadly consistent with the habitats where the mosquitoes were collected. Novel viruses of the Orthobunyavirus, Narnavirus, and Iflavirus genera were found in Culicoides by de-novo assembly. The viruses with vertebrate hosts carried by mosquitoes and Culicoides also varied widely. The analysis of unclassified viruses and deep-learning analysis of the "dark matter" in the meta-viromic sequencing data revealed the presence of a large number of unknown viruses. IMPORTANCE The monitoring of the viromes of mosquitoes and Culicoides, widely distributed arbovirus transmission vectors, is crucial to evaluate the risk of infectious disease transmission. In this study, the compositions of the viromes of mosquitoes and Culicoides on Zhoushan Island varied widely and were related mainly to the host species, with different host species having different core viromes. and many unknown sequences in the Culicoides viromes remain to be annotated, suggesting the presence of a large number of unknown viruses.

Epirubicin may enhance the inhibition of hepatocellular carcinoma induced by iodine-125 seeds through downregulating WNT pathway.

AIM: To investigate the role of iodine-125 (125 I) combined with epirubicin (EPI) in inhibiting hepatocellular carcinoma (HCC) growth and promoting apoptosis. METHODS: Both in vivo and in vitro experiments were conducted. CCK-8 assay was performed to determine the cells viability after EPI treatment. HepG2 and SMMC7721 cells were treated with EPI or 125 I or in combination. Colony formation assays were performed to verify the antiproliferation effect. Annexin V-FITC/PI, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays, and western blotting were performed to analyze cellular apoptosis. Scratch wound healing assays and transwell assays were used to examine migration following different treatments. An isobaric tag for relative and absolute quantitation analysis was used to detect changes in protein expression after 125 I treatment, identifying the potential mediating protein cathelicidin (LL-37). LL-37 protein and WNT pathway-related proteins were detected by western blotting in SMMC7721 and HepG2 cells. Mice were treated with 125 I and EPI to evaluate whether EPI enhanced the antitumor effect of 125 I. RESULTS: EPI promoted 125 I-induced apoptosis and reduced the proliferation of HepG2 and SMMC7721 cells. EPI also prevented the migration of HepG2 and SMMC7721 cells. EPI combined with 125 I may interfere with the WNT signaling pathway by decreasing LL-37 to inhibit HCC development. The antitumor effects of EPI with 125 I were verified in mice. CONCLUSION: EPI combined with 125 I induced apoptosis and inhibited the proliferation of HCC cells by LL-37 downregulating the WNT pathway.

Targeting glucose-6-phosphate dehydrogenase by 6-AN induces ROS-mediated autophagic cell death in breast cancer.

Dysregulation of G6PD involved in the pentose phosphate pathway (PPP) is known to promote tumorigenesis. The PPP plays a pivotal role in meeting the anabolic demands of cancer cells. However, the detailed underlying molecular mechanisms of targeting the G6PD-regulated PPP in breast cancer remain unclear. In this study, we aimed to elucidate the molecular pathways mediating the effects of G6PD on cancer progression. Clinical sample analysis found that the expression of G6PD in breast cancer patients was higher than that in normal controls, and patients with higher G6PD expression had poor survival. Gene knockdown or inhibition of G6PD by 6-AN in MCF-7 and MDA-MB-231 cells significantly decreased cell viability, migration, and colony formation ability. G6PD enzyme activity was inhibited by 6-AN treatment, which caused a transient upregulation of ROS. The elevated ROS was independent of cell apoptosis and thus associated with abnormal activated autophagy. Accumulated ROS levels induced autophagic cell death in breast cancer. Inhibition of G6PD suppresses tumour growth in preclinical models of breast cancer. Our results indicate that targeting the G6PD-regulated PPP could restrain tumours in vitro and in vivo, inhibiting G6PD caused cell death by over-activating autophagy, therefore leading to inhibited proliferation and tumour formation.