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In recent years, deep learning has been widely used in breast cancer diagnosis, and many high-performance models have emerged. However, most of the existing deep learning models are mainly based on static breast ultrasound (US) images. In actual diagnostic process, contrast-enhanced ultrasound (CEUS) is a commonly used technique by radiologists. Compared with static breast US images, CEUS videos can provide more detailed blood supply information of tumors, and therefore can help radiologists make a more accurate diagnosis. In this paper, we propose a novel diagnosis model based on CEUS videos. The backbone of the model is a 3D convolutional neural network. More specifically, we notice that radiologists generally follow two specific patterns when browsing CEUS videos. One pattern is that they focus on specific time slots, and the other is that they pay attention to the differences between the CEUS frames and the corresponding US images. To incorporate these two patterns into our deep learning model, we design a domain-knowledge-guided temporal attention module and a channel attention module. We validate our model on our Breast-CEUS dataset composed of 221 cases. The result shows that our model can achieve a sensitivity of 97.2% and an accuracy of 86.3%. In particular, the incorporation of domain knowledge leads to a 3.5% improvement in sensitivity and a 6.0% improvement in specificity. Finally, we also prove the validity of two domain knowledge modules in the 3D convolutional neural network (C3D) and the 3D ResNet (R3D).

The effect of defect distribution and pitch length of carbon nanosprings fabricated by different construction methods on their tensile and compressive mechanical properties is comprehensively studied. Twelve examples of nanosprings with various defect distribution are constructed according to three widely used methods based on two parent toroidal carbon nanotubes (TCNTs). Their mechanical performances are studied by using molecular dynamic (MD) simulations through tensile and compressive tests. The results reveal that the spring constant, ductility, strength, gravimetric energy density and deformation process obviously depend on the defect distribution, indicating that the mechanical properties of nanosprings can be enhanced greatly by skillfully introducing defect distribution for specific purposes. Remarkably, the tensile stiffness (1.89–68.13 nN/nm) and ductility (84%–794.8%) can be adjusted by changing the defect positions and geometries of nanosprings. The force-strain curves of nanosprings under tensile loads show sawtooth-like patterns and the oscillations of force-strain curves can be controlled by the defect distribution to produce the high energy absorbing capacity. Furthermore, all nanosprings show excellent reversibility under compressive loads, and energy storage densities ranging from 53.31 to 859.67 J/g are achieved by adjusting the defect distribution and pitch length. The findings are meaningful for scientists to design carbon nanosprings with high performance.

Nasopharyngeal carcinoma (NPC) is characterised by distinct geographical distribution and is particularly prevalent in Asian countries. But the mechanisms related to the progression of nasopharyngeal carcinoma (NPC) are not completely understood. MiR-124-3p functions as a tumor suppressor in many kinds of human cancers. Here, we explored the effects and mechanism of miR-124-3p on the proliferation and colony formation in NPC. In our study, we reported that miR-124-3p was significantly downregulated in NPC tissues and cell lines. Overexpression miR-124-3p decreased NPC cell proliferation and colony formation abilities. Meanwhile, knockdown miR-124-3p increased proliferation and colony formation abilities. Additionally, dual-luciferase assay showed that miR-124-3p could positively regulated PCDH8 by targeting its 3'-UTR. Overexpression of PCDH8 could partially rescue the proliferation and colony formation role of miR-124-3p inhibitor. Our study indicated that miR-124-3p played a tumor suppressor by directly interacting with PCDH8 and inhibiting the activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway. Overall, we found that miR-124-3p inhibited the activation of the PI3K/AKT/mTOR signaling pathway in NPC by interacting with PCDH8. Thus, PCDH8 may be a potential molecular target that impeded NPC proliferation and colony formation.

TGF-β/Smad signaling pathway plays an important role in EMT during cancer progression. Long non-coding RNAs (lncRNAs) are involved in various behaviors of cancer cells, including EMT. Here, we report a novel lncRNA adjacent to Smad3, named Smad3-associated long non-coding RNA (SMASR). SMASR is downregulated by TGF-β via Smad2/3 in lung cancer cells. Knockdown of SMASR induces EMT and increases the migration and invasion of lung cancer cells. Moreover, knockdown of SMASR promotes the phosphorylation of Smad2/3. Mechanistically, SMASR interacts with Smad2/3 and inhibits the expression of TGFBR1, the TGF-β type I receptor responsible for phosphorylation of Smad2/3, thus leading to inactivation of TGF-β/Smad signaling pathway. Clinically, SMASR is downregulated in lung cancer tissues. Collectively, our findings prove a critical role of SMASR in EMT of lung cancer by forming a negative feedback loop with TGF-β/Smad signaling pathway.

Lymph node metastasis is one of the most malignant clinical features in patients with esophageal squamous cell carcinoma (ESCC). Understanding the mechanism of lymph node metastasis will provide treatment strategies for patients with ESCC. Long noncoding RNAs (lncRNA) play a critical role in the development and progression of human cancers. However, the role and mechanism of lncRNAs in lymph node metastasis remain largely unknown. Here we show that VEGFC mRNA stability–associated long noncoding RNA (VESTAR) is involved in lymph node metastasis of ESCC. VESTAR was overexpressed in ESCC tissues and was predictive of poor prognosis in patients with ESCC. In ESCC, NXF1 and SRSF3 facilitated nuclear export of VESTAR to the cytoplasm, which was associated with lymph node metastasis. Depletion of VESTAR inhibited ESCC-associated lymphangiogenesis and lymphatic metastasis. Mechanistically, VESTAR directly bound and stabilized VEGFC mRNA. VESTAR also interacted with HuR, a positive regulator of VEGFC mRNA stability, and increased HuR binding to VEGFC mRNA. Our study reveals a novel lncRNA-guided mechanism of lymph node metastasis in ESCC and may provide a potential target for treatment of ESCC lymphatic metastasis. Significance: These findings illustrate the lncRNA-guided regulation of VEGFC mRNA stability via direct RNA–RNA interactions, highlighting a therapeutic target for patients with ESCC with lymphatic metastasis.

Attraction to feces in wild mammalian species is extremely rare. Here we introduce the horse manure rolling (HMR) behavior of wild giant pandas (Ailuropoda melanoleuca). Pandas not only frequently sniffed and wallowed in fresh horse manure, but also actively rubbed the fecal matter all over their bodies. The frequency of HMR events was highly correlated with an ambient temperature lower than 15 °C. BCP/BCPO (beta-caryophyllene/caryophyllene oxide) in fresh horse manure was found to drive HMR behavior and attenuated the cold sensitivity of mice by directly targeting and inhibiting transient receptor potential melastatin 8 (TRPM8), an archetypical cold-activated ion channel of mammals. Therefore, horse manure containing BCP/BCPO likely bestows the wild giant pandas with cold tolerance at low ambient temperatures. Together, our study described an unusual behavior, identified BCP/BCPO as chemical inhibitors of TRPM8 ion channel, and provided a plausible chemistry-auxiliary mechanism, in which animals might actively seek and utilize potential chemical resources from their habitat for temperature acclimatization.

Cancer immune plays a critical role in cancer progression. Tumour immunology and immunotherapy are one of the exciting areas in bladder cancer research. In this study, we aimed to develop an immune‐related gene signature to improve the prognostic prediction of bladder cancer. Firstly, we identified 392 differentially expressed immune‐related genes (IRGs) based on TCGA and ImmPort databases. Functional enrichment analysis revealed that these genes were enriched in inflammatory and immune‐related pathways, including in ‘regulation of signaling receptor activity’, ‘cytokine‐cytokine receptor interaction’ and ‘GPCR ligand binding’. Then, we separated all samples in TCGA data set into the training cohort and the testing cohort in a ratio of 3:1 randomly. Data set GSE13507 was set as the validation cohort. We constructed a prognostic six‐IRG signature with LASSO Cox regression in the training cohort, including AHNAK, OAS1, APOBEC3H, SCG2, CTSE and KIR2DS4. Six IRGs reflected the microenvironment of bladder cancer, especially immune cell infiltration. The prognostic value of six‐IRG signature was further validated in the testing cohort and the validation cohort. The results of multivariable Cox regression and subgroup analysis revealed that six‐IRG signature was a clinically independent prognostic factor for bladder cancer patients. Further, we constructed a nomogram based on six‐IRG signature and other clinicopathological risk factors, and it performed well in predict patients' survival. Finally, we found six‐IRG signature showed significant difference in different molecular subtypes of bladder cancer. In conclusions, our research provided a novel immune‐related gene signature to estimate prognosis for patients' survival with bladder cancer.

Botrytis cinerea, the causal agent of the grey mould disease, developed resistance to multiple fungicides. However, the role of cell membrane in survival competition of B. cinerea upon quinone outside inhibitor (QoI) fungicide has not yet been elucidated. In this paper, the enhancement of cystamine, a transglutaminase inhibitor, on membrane integrity of B. cinerea was determined, and the effect of the enhancement on the sensitivity of B. cinerea to pyraclostrobin was investigated. The results showed that pyraclostrobin inhibited mycelial growth with EC₅₀ as 1.122 and 3.042 μg/ml at 24 and 48 hr, respectively. In the treatment of 5 and 50 μg/ml pyraclostrobin, membrane integrity of B. cinerea was broken, causing high permeability, lipid peroxidation, flocculent and malformed surface with vague septum and abundant agglomerates inside and outside the mycelia. Cystamine even at 50 and 200 μg/ml had little inhibitory effect on mycelial growth. However, in presence of 50 or 200 μg/ml cystamine, the mycelia from pyraclostrobin treatment possessed a significantly reduced leakage, lower MDA content, and a revived fibrous and transparent surface. Meanwhile, SEM images showed that membrane integrity of the mycelia was significantly improved and the agglomerates were dramatically disappeared. Synergy assays further revealed that B. cinerea regained less sensitivity to pyraclostrobin inhibition. In conclusion, membrane integrity controls mycelia sensitivity and is required for survival competition of B. cinerea upon pyraclostrobin.

Background Bladder cancer is having a gradually increasing incidence in China. Except for the traditional chemotherapy drugs, there are no emerging new drugs for almost 30 years in bladder cancer. New potential therapeutic targets and biomarkers are urgently needed. Methods BORA is the activator of kinase Aurora A and plays an important role in cell cycle progression. To investigate the function of BORA in BCa, we established BORA knockdown and overexpression cell models for in vitro studies, xenograft and pulmonary metastasis mouse models for in vivo studies. Results Our results indicated that BORA was upregulated in human bladder cancer (BCa) compared to the normal bladder and paracancerous tissues at transcriptional and translational levels. We found that BORA was positively related to BCa cell proliferation. Furthermore, BORA knockdown induced cell cycle arrest in G2/M phase while BORA overexpression decreased the proportion of cells in G2/M, associated with PLK1–CDC25C–CDK1 alteration. Interestingly, we observed that knockdown of BORA inhibited BCa cell migration and invasion, accompanied with alterations of epithelial–mesenchymal transition (EMT) pathway related proteins. In vivo studies confirmed the inhibition effect of BORA knockdown on BCa cell growth and migration. Conclusions Our study indicates that BORA regulates BCa cell cycle and growth, meanwhile influences cell motility by EMT, and could be a novel biomarker and potential therapeutic target in BCa.

The present work was mainly focused on the single and binary adsorption of methylene blue(MB) and methyl orange(MO) from alcohol aqueous solution over rice husk based activated carbon(RHAC). The study of single dye adsorption equilibrium experiments found that the Langmuir adsorption model was consistent with the adsorption behavior of RHAC on MB and MO, indicating that it was a single layer adsorption. The adsorption behavior conformed to the pseudo-second-order kinetic model. The binary dye adsorption experiments showed that the Langmuir-Freundlich model could be applied to describe the adsorption behavior of RHAC on MB and MO. Comparation with the single dye system, the adsorption capacity on the binary dye system was larger, and there was “competitive adsorption” and “synergistic adsorption” effects existed. Meanwhile, the pseudo-second-order kinetic model also fit for the binary dye adsorption behavior.

Introduction Accumulating evidence has demonstrated that circular RNAs (circRNAs) play a key role in the tumorigenesis of various types of cancers, including clear cell renal cell carcinoma (ccRCC). Materials and methods Reverse transcription-quantitative polymerase chain reaction was used to detect the expression of circRNA homeodomain interacting protein kinase 3 (circHIPK3) and microRNAs (miRNAs), including miR-508-3p. The clinical measurement of circHIPK3 was evaluated by Kaplan-Meier survival analysis and receiver operating characteristic analysis. Cell Counting Kit-8 and Transwell chamber assays were performed to determine the changes in the proliferative and metastatic ability of A498 and 786-O cells. C-X-C motif chemokine ligand 13 (CXCL13) protein expression was detected by Western blot analysis. The targeted binding effect between miR-508-3p and circHIPK3 or CXCL13 was confirmed by constructed luciferase and RNA immunoprecipitation (RIP) assays, respectively. Fluorescence in situ hybridization (FISH) assay was used to measure the subcellular localization of circHIPK3 and miR-508-3p. Results It was found that circHIPK3 was markedly upregulated in ccRCC tissue and cell lines, and circHIPK3-upregulation was closely correlated with poor clinicopathological features in patients with ccRCC. It was found that both miR-508-3p and circHIPK3 were localized in the cytoplasm of ccRCC cells. The up- and downregulation of circHIPK3 positively regulated ccRCC cell proliferation and metastasis, and this regulatory effect was reversed by miR-508-3p. Through luciferase and RIP assays, it was confirmed that circHIPK3 could interacted with miR-508-3p. Furthermore, it was revealed that CXCL13, which was negatively correlated with miR-508-3p, was upregulated in ccRCC. It was also shown that CXCL13 was a downstream target of miR-508-3p. miR-508-3p suppressed ccRCC cell proliferation and metastasis by targeting CXCL13. Lastly, it was demonstrated that circHIPK3 promoted CXCL13 to facilitate ccRCC cell proliferation and metastasis by decoying miR-508-3p. Conclusion In brief, the results of the present study showed that circHIPK3 promoted ccRCC cell proliferation and metastasis by altering miR-5083p/CXCL13 signaling. The present findings might provide a novel target for the molecular treatment of ccRCC.

Background: Recent advances in nanomedicine provided promising alternatives for tumor treatment to improve the survival and life quality of cancer patients. This study was designed to explore the insight mechanisms of the anti-tumor effects of the novel nanocomposites (NCs) MFP-FePt-GO with non-small cell lung cancer (NSCLC). Methods: A chemical co-reduction method was applied to the synthesis process of MFP-FePt-GO NCs. The chemical synthesis efficiency and morphology of the NCs were measured with spectroscope and transmission electron microscope. Colony formation assay and cell apoptosis were conducted to assess the radiosensitivity effect of NCs with radiation. Then, we detected cell mitochondrial membrane potential and reactive oxygen species (ROS) level by flow cytometry to further explore the cause of cell death. Immunofluorescence staining and Confocal were carried out to determine the DNA damage repair. A Lewis lung carcinoma animal model was used to measure safety and anti-tumor efficiency in vivo. Results: The novel NCs MFP-FePt-GO designed on a lamellar-structure magnetic graphene oxide and polyethylene glycol drug delivery system was synthesized and functionalized for co-delivery of metronidazole and 5-fluorouracil. While no severe allergies, liver and kidney damage, or drug-related deaths were observed, MFP-FePt-GO NCs promoted radiosensitivity of NSCLC cells both in vivo and in vitro. It improved the effects of radiation via activating intrinsic mitochondrial-mediated apoptosis and impairing DNA damage repair. This NCs also induced a ROS burst, which suppressed the antioxidant protein expression and induced cell apoptosis. Furthermore, MFP-FePt-GO NCs prevented NSCLC cell migration and invasion. Conclusion: MFP-FePt-GO NCs showed a synergistic anti-tumor effect with radiation to eliminate tumors. With good safety and efficacy, this novel NCs could be a potential radiosensitive agent for NSCLC patients.

Split air conditioner (SAC) plays a critical role for temperature control of buildings. In recent years, the manufacturing process of SAC tends to consider energy-saving and environmental protection factors to reduce air pollution and alleviate energy crisis. However, the design of environmental-friendly SAC will increase the manufacturing cost, thereby increasing the burden on air-conditioning companies. Therefore, the eco-cost analysis of SAC is of great significance for air conditioner manufacturers. To this end, a new SAC eco-cost assessment method based on activity based costing method is innovatively proposed in this paper. In this method, a K-nearest neighbor algorithm is used to deal with the missing data in SAC samples. An environmental and non-environmental cost assessment approach is developed based on the activity-based costing method to estimate the eco-cost of SAC over its whole life cycle. In addition, the impact of energy efficiency deviation on SAC eco-cost is numerically analyzed. Finally, the proposed eco-cost assessment method is programmed on a Gabi software, and validated using real SAC data from a Chinese air-conditioning company. Simulation results show that the proposed method can provide an estimate of the eco-cost of SAC, thus helping air-conditioning companies to improve their competitiveness in the future where energy-saving and emission reduction are increasingly important.

Background Primary bladder sarcoma (PBS) is a rare malignant tumor of the bladder with a poor prognosis, and its disease course is inadequately understood. Therefore, our study aimed to establish a prognostic model to determine individualized prognosis of patients with PBS. Patients and Methods Data of 866 patients with PBS, registered from 1973 to 2015, were extracted from the surveillance, epidemiology, and end result (SEER) database. The patients included were randomly split into a training (n = 608) and a validation set (n = 258). Univariate and multivariate Cox regression analyses were employed to identify the important independent prognostic factors. A nomogram was then established to predict overall survival (OS). Using calibration curves, receiver operating characteristic curves, concordance index (C-index), decision curve analysis (DCA), net reclassification improvement (NRI) and integrated discrimination improvement (IDI), the performance of the nomogram was internally validated. We compared the nomogram with the TNM staging system. The application of the risk stratification system was tested using Kaplan–Meier survival analysis. Results Age at diagnosis, T-stage, N-stage, M-stage, and tumor size were identified as independent predictors of OS. C-index of the training cohort were 0.675, 0.670, 0.671 for 1-, 3- and 5-year OS, respectively. And that in the validation cohort were 0.701, 0.684, 0.679, respectively. Calibration curves also showed great prediction accuracy. In comparison with TNM staging system, improved net benefits in DCA, evaluated NRI and IDI were obtained. The risk stratification system can significantly distinguish the patients with different survival risk. Conclusion A prognostic nomogram was developed and validated in the present study to predict the prognosis of the PBS patients. It may assist clinicians in evaluating the risk factors of patients and formulating an optimal individualized treatment strategy.

Background Regularly updated data on stroke and its pathological types, including data on their incidence, prevalence, mortality, disability, risk factors, and epidemiological trends, are important for evidence-based stroke care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) aims to provide a standardised and comprehensive measurement of these metrics at global, regional, and national levels. Methods We applied GBD 2019 analytical tools to calculate stroke incidence, prevalence, mortality, disability-adjusted life-years (DALYs), and the population attributable fraction (PAF) of DALYs (with corresponding 95% uncertainty intervals [UIs]) associated with 19 risk factors, for 204 countries and territories from 1990 to 2019. These estimates were provided for ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and all strokes combined, and stratified by sex, age group, and World Bank country income level. Findings In 2019, there were 12·2 million (95% UI 11·0–13·6) incident cases of stroke, 101 million (93·2–111) prevalent cases of stroke, 143 million (133–153) DALYs due to stroke, and 6·55 million (6·00–7·02) deaths from stroke. Globally, stroke remained the second-leading cause of death (11·6% [10·8–12·2] of total deaths) and the third-leading cause of death and disability combined (5·7% [5·1–6·2] of total DALYs) in 2019. From 1990 to 2019, the absolute number of incident strokes increased by 70·0% (67·0–73·0), prevalent strokes increased by 85·0% (83·0–88·0), deaths from stroke increased by 43·0% (31·0–55·0), and DALYs due to stroke increased by 32·0% (22·0–42·0). During the same period, age-standardised rates of stroke incidence decreased by 17·0% (15·0–18·0), mortality decreased by 36·0% (31·0–42·0), prevalence decreased by 6·0% (5·0–7·0), and DALYs decreased by 36·0% (31·0–42·0). However, among people younger than 70 years, prevalence rates increased by 22·0% (21·0–24·0) and incidence rates increased by 15·0% (12·0–18·0). In 2019, the age-standardised stroke-related mortality rate was 3·6 (3·5–3·8) times higher in the World Bank low-income group than in the World Bank high-income group, and the age-standardised stroke-related DALY rate was 3·7 (3·5–3·9) times higher in the low-income group than the high-income group. Ischaemic stroke constituted 62·4% of all incident strokes in 2019 (7·63 million [6·57–8·96]), while intracerebral haemorrhage constituted 27·9% (3·41 million [2·97–3·91]) and subarachnoid haemorrhage constituted 9·7% (1·18 million [1·01–1·39]). In 2019, the five leading risk factors for stroke were high systolic blood pressure (contributing to 79·6 million [67·7–90·8] DALYs or 55·5% [48·2–62·0] of total stroke DALYs), high body-mass index (34·9 million [22·3–48·6] DALYs or 24·3% [15·7–33·2]), high fasting plasma glucose (28·9 million [19·8–41·5] DALYs or 20·2% [13·8–29·1]), ambient particulate matter pollution (28·7 million [23·4–33·4] DALYs or 20·1% [16·6–23·0]), and smoking (25·3 million [22·6–28·2] DALYs or 17·6% [16·4–19·0]). Interpretation The annual number of strokes and deaths due to stroke increased substantially from 1990 to 2019, despite substantial reductions in age-standardised rates, particularly among people older than 70 years. The highest age-standardised stroke-related mortality and DALY rates were in the World Bank low-income group. The fastest-growing risk factor for stroke between 1990 and 2019 was high body-mass index. Without urgent implementation of effective primary prevention strategies, the stroke burden will probably continue to grow across the world, particularly in low-income countries. Funding Bill & Melinda Gates Foundation.

Because of the important diagnostic value, computed tomography (CT) has been widely used in clinic. However, there are still some limitations in CT examination of small intestinal lesions. At present, the diagnosis of these lesions mainly depends on doctors' experience in CT image so that there would be some problems such as high labor cost, low efficiency and misdiagnosis risk. Therefore, a segmentation and identification method for small intestinal lesions based on U-Net with batch normalization (BN) and virtual sample, named as U-NetBV, is proposed in this paper. BN can help to improve the performance of the network and virtual sample can increase the number of samples which is usually small in CT image. Through U-NetBV, these lesions can be identified and segmented automatically. The experimental results show that the proposed U-NetBV has a promising prospect in the field of segmentation and identification of small intestinal lesions.

The high-grade glioma is characterized by cell heterogeneity, gene mutations, and poor prognosis. The deletions and mutations of the tumor suppressor gene PTEN (5%-40%) in glioma patients are associated with worse survival and therapeutic resistance. Characterization of unique prognosis molecular signatures by PTEN status in glioma is still unclear. This study established a novel risk model, screened optimal prognostic signatures, and calculated the risk score for the individual glioma patients with different PTEN status. Screening results revealed fourteen independent prognostic gene signatures in PTEN-wt and three in the -50PTEN-mut subgroup. Moreover, we verified risk score as an independent prognostic factor significantly correlated with tumor malignancy. Due to the higher malignancy of the PTEN-mut gliomas, we explored the independent prognostic signatures (CLCF1, AEBP1, and OS9) for a potential therapeutic target in PTEN-mut glioma. We further separated IDH wild-type glioma patients into GBM and LGG to verify the therapeutic target along with PTEN status, notably, the above screened therapeutic targets are also significant prognostic genes in both IDH-wt/PTEN-mut GBM and LGG patients. We further identified the small molecule compound (+)-JQ1 binds to all three targets, indicating a potential therapy for PTEN-mut glioma. In sum, gene signatures and risk scores in the novel risk model facilitate glioma diagnosis, prognosis prediction, and treatment.

Digestive diseases have become an important source of morbidity and mortality. The considerable financial and health burdens caused by digestive diseases confirm the importance of extensive research to better understand and treat these diseases. The development of reliable preclinical models is essential for understanding the pathogenesis of digestive diseases and developing treatment and prevention methods. However, traditional established cell lines and animal models still have many limitations in the study of the digestive system. Conditional reprogramming (CR) cell culture is a newly developed primary technology that uses irradiated Swiss-3T3-J2 mouse fibroblast cells and the Rho-associated kinase (ROCK) inhibitor Y-27632 to rapidly and efficiently generate many cells from diseased and normal tissues. CR cells (CRCs) can be reprogrammed to maintain a highly proliferative state and recapitulate the histological and genomic features of the original tissue. Moreover, after removing these conditions, the phenotype was completely reversible. Therefore, CR technology may represent an ideal model to study digestive system diseases, to test drug sensitivity, to perform gene profile analysis, and to undertake xenograft research and regenerative medicine. Indeed, together with organoid cultures, CR technology has been recognized as one of the key new technologies by NIH precision oncology and also used for NCI human cancer model initiatives (HCMI) program with ATCC. In this article, we review studies that use CR technology to conduct research on diseases of the digestive system.

Accurate identification of the shape and texture properties of cervical cell nuclei and cytoplasm in the pap smear test is crucial for the diagnosis of cervical cancer. Fast and high-precision polarization modulation in the Polarization Indirect Microscopic Imaging (PIMI) is achieved by utilizing a liquid crystal polarization rotator. Imaging results of cervical cells show that the PIMI method can resolve detailed fine structural features of a cervical cell which are invisible in conventional microscopy. It also demonstrated the ability of embossed three-dimensional visualization as that in differential interference contrast microscopy (DIC), but with finer structural features.

“Retest Positive” for severe acute respiratory syndrome‐related coronavirus‐2 (SARS‐CoV‐2) from “recovered” coronavirus disease‐19 (COVID‐19) has been reported and raised several important questions for this novel coronavirus and COVID‐19 disease. In this commentary, we discussed several questions: (a) Can SARS‐CoV‐2 re‐infect the individuals who recovered from COVID‐19? This question is also associated with other questions: whether or not SARS‐CoV‐2 infection induces protective reaction or neutralized antibody? Will SARS‐CoV‐2 vaccines work? (b) Why could some recovered patients with COVID‐19 be re‐tested positive for SARS‐CoV‐2 RNA? (c) Are some recovered pwith atients COVID‐19 with re‐testing positive for SARS‐CoV‐2 RNA infectious? and (d) How should the COVID‐19 patients with retest positive for SARS‐CoV‐2 be managed?, Highlights Reinfection with SARS‐CoV‐2 of the recovered COVID‐19 patients is unlikely.Re‐test positive for SARS‐CoV‐2 of the recovered COVID‐19 patients may be due to "false‐negative", sampling sites and procedures, and delayed clearance, etc.Patients with re‐test positive for SARS‐CoV‐2 should be treated or quarantined according the guidance.

Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent cancers with poor prognosis. Metastasis is the leading cause of cancer-related deaths. The growth arrest and DNA damage-inducible 45 gamma (GADD45G) has been reported to correlate with survival, invasion, and metastasis of ESCC. This study was aimed to investigate the role and mechanism of GADD45G in ESCC cell migration and invasion. Both the effects of GADD45G and its need for E-cadherin to function on ESCC cell migration and invasion were determined through loss- and gain-of-function approaches via Transwell assays. The interaction between GADD45G and E-cadherin was detected by GST-pull down and IP assays. The expression of E-cadherin upon GADD45G overexpression was evaluated by RT-qPCR and western blot. The level of E-cadherin in cytoplasmic, nuclear, and membrane fractions was examined by western blot following subcellular fractionation. Knockdown of GADD45G increased the migration and invasion abilities of KYSE150 cells, while overexpression of GADD45G showed the opposite effects on YES2 and KYSE30 cells. GADD45G could interact with E-cadherin and enhanced its membrane level. Knockdown of E-cadherin abolished the inhibitory effects of GADD45G on ESCC cell migration and invasion. Intriguingly, dimer-dissociating mutant of GADD45G could not interact with E-cadherin and almost lost its ability to suppress the ESCC cell migration and invasion. This study reveals a novel role for GADD45G in inhibiting the ESCC cell migration and invasion, which will provide a new insight in understanding the ESCC metastatic mechanism.

Background Bladder cancer is common malignant tumor around the world. Ras-association domain family 1 (RASSF1A) gene is inactivated in most of cancers. The aim of the study is to analyze the relationship between RASSF1A and the progression of bladder and investigate the effects of RASSF1A overexpression on bladder cancer cell in vitro. Materials and methods Immunohistochemistry assay analyzed the RASSF1A expression in bladder tissue of bladder cancer patients. Besides, the data of 138 bladder cancer patients about RASSF1A expression was analyzed. Kaplan-Meier method analyzed the connection between disease free survival (DFS) and abnormal expression of RASSF1A and E-cadherin in bladder cancer patients. RASSF1A gene transfected the bladder cancer cells by lipofectamine. Cell proliferation was determined by methyl thiazolyl tetrazolium (MTT) assay. Cell apoptosis and cell cycle was detected using flow cytometry. Scratch assay evaluated cell migration, and transwell assay evaluated cell invasion. Western blot analyzed protein expression while qRT-PCR analyzed mRNA expression. Results Bladder cancer tissues had lower RASSF1A expression compared with normal tissues, and the Patients with abnormal expression of RASSF1A had lower DFS and had higher possibility of recurrence and muscular layer infiltration. Besides, RASSF1A had significant difference with E-cadherin. RASSF1A overexpression inhibited the bladder cancer cell proliferation, migration and invasion, besides, it promoted apoptosis and the expression of E-cadherin and β-catenin. Conclusion RASSF1A may be a biomarker to evaluate the progression and recurrence of bladder cancer.

Clear cell renal cell carcinoma (ccRCC) is a heterogeneous tumor that the underlying molecular mechanisms are largely unclear. This study aimed to elucidate the key candidate genes and pathways in ccRCC by integrated bioinformatics analysis. 1387 differentially expressed genes were identified based on three expression profile datasets, including 673 upregulated genes and 714 downregulated genes. Then we used weighted correlation network analysis to identify 6 modules associated with pathological stage and grade, blue module was the most relevant module. GO and KEGG pathway analyses showed that genes in blue module were enriched in cell cycle and metabolic related pathways. Further, 25 hub genes in blue module were identified as hub genes. Based on GEPIA database, 9 genes were associated with progression and prognosis of ccRCC patients, including PTTG1, RRM2, TOP2A, UHRF1, CEP55, BIRC5, UBE2C, FOXM1 and CDC20. Then multivariate Cox regression showed that the risk score base on 9 key genes signature was a clinically independent prognostic factor for ccRCC patients. Moreover, we screened out several new small molecule drugs that have the potential to treat ccRCC. Few of them were identified as biomarkers in ccRCC. In conclusion, our research identified 9 potential prognostic genes and several candidate small molecule drugs for ccRCC treatment.

In May 2018, a bacterial tumor disease was observed on Populus koreana in Shuangyang county, Changchun city, Jilin Province. Based on physiological characteristics, Biolog and genetic sequences analysis, the bacterium was identified as Pseudomonas aeruginosa. The pathogenicity was verified with Koch’s postulates. To our knowledge, this is the first report of tumor disease caused by P. aeruginosa on P. koreana.

Esophageal squamous cell carcinoma (ESCC) ranks fourth among cancer-related deaths in China due to the lack of actionable molecules. We performed whole-exome and T-cell receptor (TCR) repertoire sequencing on multi-regional tumors, normal tissues and blood samples from 39 ESCC patients. The data revealed 12.8% of ERBB4 mutations at patient level and functional study supported its oncogenic role. 18% of patients with early BRCA1/2 variants were associated with high-level contribution of signature 3, which was validated in an independent large cohort (n = 508). Furthermore, knockdown of BRCA1/2 dramatically increased sensitivity to cisplatin in ESCC cells. 5% of patients harbored focal high-level amplification of CD274 that led to massive expression of PD-L1, and might be more sensitive to immune checkpoint blockade. Finally, we found a tight correlation between genomic and TCR repertoire intra-tumor heterogeneity (ITH). Collectively, we reveal high-level ITH in ESCC, identify several potential actionable targets and may provide novel insight into ESCC treatment., Esophageal squamous cell carcinoma (ESCC) is highly prevalent in China. Here, the authors carry out multi-region sampling of Chinese ESCC samples, and find recurrent ERBB4 mutations, BRCA1/2 variants, and amplification of CD274; together with high levels of genomic and T-cell receptor heterogeneity.

Background Non-small cell lung cancer (NSCLC) is the most common type of lung cancer with a poor prognosis. We previously found that protein disulfide isomerase family 6 (PDIA6) is upregulated in lung squamous cell carcinoma (LSCC). This study aimed to elucidate the clinical relevance, biological functions, and molecular mechanisms of PDIA6 in NSCLC. Methods The expression of PDIA6 in NSCLC was assessed using the TCGA database, western blotting, and immunohistochemistry. Correlations of PDIA6 expression with clinicopathological and survival features were evaluated. The functions of PDIA6 in regulating NSCLC cell growth, apoptosis, and autophagy were investigated using gain-and loss-of-function strategies in vitro or in vivo. The underlying molecular mechanisms of PDIA6 function were examined by human phospho-kinase array and co-immunoprecipitation. Findings PDIA6 expression was upregulated in NSCLC compared with adjacent normal tissues, and the higher PDIA6 expression was correlated with poor prognosis. PDIA6 knockdown decreased NSCLC cell proliferation and increased cisplatin-induced intrinsic apoptosis, while PDIA6 overexpression had the opposite effects. In addition, PDIA6 regulated cisplatin-induced autophagy, and this contributed to PDIA6-mediated apoptosis in NSCLC cells. Mechanistically, PDIA6 reduced the phosphorylation levels of JNK and c-Jun. Moreover, PDIA6 interacted with MAP4K1 and inhibited its phosphorylation, ultimately inhibiting the JNK/c-Jun signaling pathway. Interpretation PDIA6 is overexpressed in NSCLC and inhibits cisplatin-induced NSCLC cell apoptosis and autophagy via the MAP4K1/JNK/c-Jun signaling pathway, suggesting that PDIA6 may serve as a biomarker and therapeutic target for NSCLC patients. Fund National Natural Science Foundation of China and Institutions of higher learning of innovation team from Liaoning province.

Aim: We investigated a promising cooperative combination of radiotherapy (RT) and programmed death ligand 1 (PD-L1) monoclonal antibodies (mAb) in both local and abscopal tumors. Materials & methods: C57BL/6 mice were randomly grouped and received RT, α-PD-L1 mAb or combination therapy 13 days after implantation of Lewis lung carcinoma cells. Flow cytometry and immunohistochemistry analyses demonstrated CD8+T-cell infiltration and PD-L1 expression in tumor issue. Cytometric bead arrays were used to examine cytokine levels. Results: Our studies revealed that administration of 8 Gy × 3 F with α-PD-L1 mAb promoted both local and distant control. Only local hypofractionated RT enhanced CD8+T-cell infiltration with increased PD-L1 expression at distant foci, which might occur via serum IFN-γ modulation. Addition of α-PD-L1 mAb reduced PD-L1 expression and further increased CD8+T-cell infiltration. Conclusion: We identified a novel mechanism through which combination therapy enhanced the abscopal effect.

Objective Growing evidence indicates that FAT atypical cadherin 1 (FAT1) has aberrant genetic alterations and exhibits potential tumor suppressive function in esophageal squamous cell carcinoma (ESCC). However, the role of FAT1 in ESCC tumorigenesis remains not well elucidated. The aim of this study was to further investigate genetic alterations and biological functions of FAT1, as well as to explore its transcriptional regulation and downstream targets in ESCC. Methods The mutations of FAT1 in ESCC were achieved by analyzing a combined study from seven published genomic data, while the copy number variants of FAT1 were obtained from an analysis of our previous data as well as of The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) databases using the cBioPortal. The transcriptional regulation of FAT1 expression was investigated by chromatin immunoprecipitation (ChIP) and the luciferase reporter assays. In-cell western, Western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to assess the indicated gene expression. In addition, colony formation and Transwell migration/invasion assays were employed to test cell proliferation, migration and invasion. Finally, RNA sequencing was used to study the transcriptomes. Results FAT1 was frequently mutated in ESCC and was deleted in multiple cancers. Furthermore, the transcription factor E2F1 occupied the promoter region of FAT1, and depletion of E2F1 led to a decrease in transcription activity and mRNA levels of FAT1. Moreover, we found that knockdown of FAT1 promoted KYSE30 and KYSE150 cell proliferation, migration and invasion; while overexpression of FAT1 inhibited KYSE30 and KYSE410 cell proliferation, migration and invasion. In addition, knockdown of FAT1 led to enrichment of the mitogen-activated protein kinase (MAPK) signaling pathway and cell adhesion process. Conclusions Our data provided evidence for the tumor suppressive function of FAT1 in ESCC cells and elucidated the transcriptional regulation of FAT1 by E2F1, which may facilitate the understanding of molecular mechanisms of the progression of ESCC.

We aim to determine clinical recurrence and progression risk factors of T1G3 bladder cancer (BCa), and to establish recurrence and progression prediction models. 5-year follow-up records of 106 T1G3 BCa patients from January 2012 to December 2016 were analyzed for recurrence and progression. Two-sample T-test, Chi-square test, Mann-Whitney test, Kaplan-Meier curves, Cox univariate and multivariate analyses were performed to determine the independent risk factors. Effective prognostic nomograms were established to provide individualized prediction, and the calibration curves were founded to evaluate the agreements of the predicted probability with the actual observed probability. Receiver operating characteristic (ROC) curves were generated for the recurrence and progression prediction models. The stability of prediction models was validated with an external cohort included 61 T1G3 BCa patients. Of the 106 T1G3 BCa patients, 77 were males (72.6%) and 29 were females (27.4%), with median age 70 years. Within 5 years, recurrence was identified in 67 cases (63.2%), and progression was identified in 31 cases (29.2%). The results showed that large size of tumor, multifocal tumors, recrudescent tumor, non-BCG perfusion therapy were the independent risk factors for recurrence, and large size of tumor, multifocal tumors, recrudescent tumor, concomitant carcinoma in situ (CIS) were the independent risk factors for progression. However, no evidence shown that tumor location or operative method was independent risk factors for recurrence and progression. Based on the results of Cox regression analyses, the independent risk factors were used to establish the prediction nomograms to calculate the recurrence and progression probability of each T1G3 BCa patient. Calibration curves, ROC curves and external validation displayed that the nomograms had great value of prediction.

We collected clinical data from 308 prostate cancer (PCa) patients to investigate the clinical characteristics and independent risk factors of bone metastasis (BM) and to establish a prediction model for BM of PCa and determine the necessity of bone scans. Univariate and multivariate analyses were performed based on age, biopsy Gleason score (BGS), clinical tumor stage (cTx), total prostate specific antigen (tPSA), free prostate specific antigen (fPSA), fPSA/tPSA, prostate volume, alkaline phosphatase (ALP), serum calcium and serum phosphorus. Moreover, 80 of the 308 PCa patients had a PI-RADS v2 score and were analysed retrospectively. The univariate analysis showed that the BGS, cTx, tPSA, fPSA, prostate volume and ALP were significant. The multivariate logistic regression analysis showed significant differences among the BGS, cTx, tPSA and ALP. Four cases should be highly suspected with BM: (i) cTl-cT2, BGS ≤7, ALP >120 U/L and tPSA >90.64 ng/ml; (ii) cTl-cT2, BGS ≥8, and ALP >120 U/L; (iii) cT3-cT4, BGS ≤7, and ALP >120 U/L; and (iv) cT3-cT4 and BGS ≥8. After the PI-RADS v2 score was included in the model, the AUC of the prediction model rose from 0.884 (95% CI: 0.813-0.996) to 0.934 (95% CI: 0.883-0.986). This model may help determine the necessity of bone scans to diagnose BM for PCa patients.