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In order to study the influence mechanism of structural type and size on the hydrodynamic performance of vertical curved V-type otter board, this paper based on the computational fluid dynamics method, a three-dimensional numerical model of vertical curved V-type otter board is established to calculate and analyze its hydrodynamic performance, and the validity of the numerical simulation results is verified by designing and constructing a scaled model for dynamic flume experiments. On this basis, the effects of different structural parameters, such as the deflector angle, camber, and spacing, on the hydrodynamic performance of the vertical curved V-Type otter board are investigated and the optimal structural design scheme is determined. The results demonstrate that single or synchronous changes of the angle, camber, and spacing of the two deflectors have varying degrees of impact on the hydrodynamic performance of the vertical curved V-Type otter board. To improve the expansion effect of the otter board, setting the angle of the deflector A to 40° and that of the deflector B to 30°, or setting the camber of deflectors A and B to 18%, or setting the spacing between deflectors A and B to 380 mm and that between the deflector and the main panel to 670 mm can increase the lift coefficient of the vertical curved V-Type otter board to its maximum value. Considering the overall performance of the otter board, when the angle of the deflector A is set to 25° and that of the deflector B is set to 30°, or the camber of the deflector A is set to 6% and that of the deflector B is set to 9%, or the spacing between deflectors A and B is set to 340 mm and that between the deflector and the main panel is set to 610 mm, the lift-to-drag ratio of the otter board can be increased to its maximum value.

Abstract Background To explore challenges of liquid-based cytology (LBC) specimens for next-generation sequencing (NGS) in lung adenocarcinoma and evaluate the efficacy of targeted therapy. Methods A retrospective analysis was conducted on the NGS test of 357 cases of advanced lung adenocarcinoma LBC specimens and compared with results of histological specimens to assess the consistency. The impact of tumor cellularity on NGS test results was evaluated. The utility of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) was collected. Clinical efficacy evaluation was performed and survival curve analysis was conducted using the Kaplan-Meier method. Results There were 275 TKI-naive and 82 TKI-treated specimens, the mutation rates of cancer-related genes detected in both groups were similar (86.2% vs. 86.6%). The EGFR mutation rate in the TKI treated group was higher than that in the TKI-naive group (69.5% > 54.9%, P = 0.019). There was no significant difference in the EGFR mutation frequency among different tumor cellularity in the TKI-naive group. However, in the TKI treated group, the frequency of EGFR sensitizing mutation and T790M resistance mutation in specimens with

Background: Our study aims to perform functional exploration and drug prediction of programmed cell death (PCD)-related biomarkers in lung adenocarcinoma (LUAD). Methods: UCSC-Xena obtained LUAD-related genes. DESeq2 screened PCD-specific differentially expressed genes (DEGs), and these DEGs were intersected with genes identified by weighted gene co-expression network analysis (WGCNA) to pinpoint the key genes. KOBAS-i was used for enrichment analysis. String and GeneMania were used to construct protein interaction networks and gene-gene interaction networks, respectively. Using two machine learning algorithms to screen for key genes, and taking the intersection as biomarkers, validating via receiver operating characteristic (ROC) and in vitro experiments. Building a diagnostic model with a nomogram. Construct transcription factor (TF) regulatory network. CIBERSORT was used for immune infiltration analysis. Enrichr predicts targeted drugs and AutodockTools simulates molecular docking. Results: 120 hub genes related to PCD were identified, and an intersection of these genes with DEGs yielded 10 key genes, which were enriched in apoptosis-related pathways. Further machine learning screening of these genes led to the selection of 7 genes, among which 6 genes (FGR, LAPTM5, SIRPA, TLR4, ZEB2, and NLRC4) exhibited significant differences upon ROC validation, ultimately serving as biomarkers, in vitro experiments also confirmed. A nomogram demonstrated their excellent diagnostic performance. These six biomarkers are correlated with the infiltration status of most immune cells, suggesting that they affect LUAD through the immune system. TF regulation analysis identified the upstream miRNAs. Finally, drug prediction yielded three potential drugs: Lenvatinib, methadone, and trimethoprim. Conclusion: PCD-related biomarkers in LUAD were explored, which may contribute to further understanding on PCD in LUAD.

BackgroundCD38 and CD47 are expressed in many hematologic malignancies, including multiple myeloma (MM), B-cell non-Hodgkin lymphoma (NHL), B-cell acute lymphoblastic leukemia (ALL), and B-cell chronic lymphocytic leukemia (CLL). Here, we evaluated the antitumor activities of CD38/CD47 bispecific antibodies (BsAbs).MethodsFive suitable anti-CD38 antibodies for co-targeting CD47 and CD38 BsAb were developed using a 2 + 2 “mAb-trap” platform. The activity characteristics of the CD38/CD47 BsAbs were evaluated using in vitro and in vivo systems.ResultsUsing hybridoma screening technology, we obtained nine suitable anti-CD38 antibodies. All anti-CD38 antibodies bind to CD38+ tumor cells and kill tumor cells via antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Five anti-CD38 antibodies (4A8, 12C10, 26B4, 35G5, and 65A7) were selected for designing CD38/CD47 BsAbs (IMM5605) using a “mAb-trap” platform. BsAbs had higher affinity and binding activity to the CD38 target than those to the CD47 target, decreasing the potential on-target potential and off-tumor effects. The CD38/CD47 BsAbs did not bind to RBCs and did not induce RBC agglutination; thus, BsAbs had much lower blood toxicity. The CD38/CD47 BsAbs had a greater ability to block the CD47/SIRPα signal in CD38+/CD47+ tumor cells than IMM01 (SIRPα Fc fusion protein). Through Fc domain engineering, CD38/CD47 BsAbs were shown to kill tumors more effectively by inducing ADCC and ADCP. IMM5605–26B4 had the strongest inhibitory effect on cellular CD38 enzymatic activity. IMM5605–12C10 had the strongest ability to directly induce the apoptosis of tumor cells. The anti-CD38 antibody 26B4 combined with the SIRPα-Fc fusion proteins showed strong antitumor effects, which were better than any of the mono-therapeutic agents used alone in the NCI-H929 cell xenograft model. The CD38/CD47 BsAbs exhibited strong antitumor effects; specifically, IMM5605–12C10 efficiently eradicated all established tumors in all mice.ConclusionA panel of BsAbs targeting CD38 and CD47 developed based on the “mAb-tarp” platform showed potent tumor-killing ability in vitro and in vivo. As BsAbs had lower affinity for binding to CD47, higher affinity for binding to CD38, no affinity for binding to RBCs, and did not induce RBC agglutination, we concluded that CD38/CD47 BsAbs are safe and have a satisfactory tolerability profile.

BackgroundA significant level of CD70 can be detected in various types of tumor tissues and CD27 is expressed on Treg cells, but CD70 expression is low in normal tissues. The interaction between CD70 and CD27 can stimulate the proliferation and survival of cancer cells and increase the level of soluble CD27, which is associated with poor prognosis in patients with lymphoma and certain solid tumors. Thus, it is a promising therapeutic target for the treatment of many major CD70+ cancer indications, including CD70+ lymphoma, RCC, NSCLC, HNSCC and OC.MethodsIMM40H was obtained through hybridoma screening and antibody humanization techniques. IMM40H was evaluated for its binding, blocking, Fc-dependent effector functions and antitumor activity characteristics in various in vitro and in vivo systems. The safety and tolerability profile of IMM40H were evaluated through single and repeated administration in cynomolgus monkeys.ResultsIn vitro cell-based assays demonstrated that IMM40H had considerably stronger CD70-binding affinity than competitor anti-CD70 antibodies, including cusatuzumab, which enabled it to block the interaction of between CD70 and CD27 more effectively. IMM40H also exhibited potent Fc-dependent effector functions (ADCC/CDC/ADCP), and could make a strong immune attack on tumor cells and enhance therapeutic efficacy. Preclinical findings showed that IMM40H had potent antitumor activity in multiple myeloma U266B1 xenograft model, and could eradicate subcutaneously established tumors at a low dose of 0.3 mg/kg. IMM40H (0.3 mg/kg) showed therapeutic effects faster than cusatuzumab (1 mg/kg). A strong synergistic effect between IMM01 (SIRPα-Fc fusion protein) and IMM40H was recorded in Burkitt’s lymphoma Raji and renal carcinoma cell A498 tumor models. In cynomolgus monkeys, the highest non-severely toxic dose (HNSTD) for repeat-dose toxicity was up to 30 mg/kg, while the maximum tolerated dose (MTD) for single-dose toxicity was up to 100 mg/kg, confirming that IMM40H had a good safety and tolerability profile.ConclusionIMM40H is a high-affinity humanized IgG1 specifically targeting the CD70 monoclonal antibody with enhanced Fc-dependent activities. IMM40H has a dual mechanism of action: inducing cytotoxicity against CD70+ tumor cells via various effector functions (ADCC, ADCP and CDC) and obstructs the proliferation and activation of Tregs by inhibiting CD70/CD27 signaling.

Objective: To explore the feasibility of sampling Chinese patients by suction curettage for cytological and histological screening of endometrial cancer related to Lynch syndrome. Methods: This retrospective study enrolled patients who underwent endometrial biopsy at our hospital between May 2018 and January 2019. Endometrial sampling (cytological and micro-histological specimens) was conducted by suction curettage. The gold standard for diagnosis was traditional sharp dilation and curettage (D&C). The sensitivity, specificity, and diagnostic accuracy of cytology, micro-histology, and the combination of cytology and micro-histology were calculated. Additionally, receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic efficiency of three screening methods. Mismatch repair proteins were further detected using immunohistochemistry (IHC) in endometrial cancer. Results: This retrospective finally enrolled 100 patients, which satisfactory samples were obtained from 96 patients for liquid-based cytology and 93 patients for microtissue histology. The concordance rates with D&C, sensitivity, and specificity were 94.8%, 76.9%, and 97.5% for liquid-based cytology, 96.8%, 84.6%, and 98.8% for microtissue histology, and 99.0%, 92.3%, and 100.0% for liquid-based cytology and microtissue histology combined, respectively. The AUC of ROC curves in liquid-based cytology, microtissue histology, and the combined methods for diagnostic ability were 0.873, 0.917, and 0.962, respectively. Absence rates of MLHl, MSH2, MSH6, and PMS2 proteins were 15.3% (2/13), 0% (0/13), 7.7% (1/13), and 15.3% (2/13) in the 13 endometrial cancer samples. Conclusion: Liquid-based cytology and microtissue histology samples from suction curettage combined IHC are useful for endometrial cancer screening.

Abstract A novel recombinant SIRPα-Fc fusion protein, IMM01, was constructed and produced using an in-house developed CHO-K1 cell expression system, and the anti-tumor mechanism of IMM01 targeting the CD47-SIRPα pathway was explored. The phagocytosis and in vitro anti-tumor activity of IMM01 were evaluated by antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC) assays. In vivo mouse tumor model studies were used to explore therapeutic efficacy as well as the mechanism of action. An in vitro binding assay revealed that IMM01 has a strong binding affinity to CD47 with an EC50 of 0.4967 nM. IMM01 can induce strong ADCP and moderate ADCC, but not CDC. IMM01-induced strong phagocytosis against tumor cells was attributed to dual activities of blocking the "don’t eat me" signal and activating the "eat me" signal, and IMM01 exhibits strong and robust in vivo anti-tumor activities either as monotherapy on hematological malignancies, or in combination therapy with PD-L1 monoclonal antibody (mAb), PD-1 mAb, and HER-2 mAb on solid tumors. Finally, IMM01 demonstrated a favorable safety profile with no human RBC binding activity or hemagglutination induction. IMM01 inhibits the growth of tumor cells by the following three possible mechanisms: (1) directly activating macrophages to phagocytize tumor cells; (2) activated macrophages degrade phagocytized tumor cells and present tumor antigens to T cells through MHC molecules to activate T cells; (3) activated macrophages can convert "cold tumors" into "hot tumors" and increase the infiltration of immune cells through chemotaxis by secreting some cytokines and chemokines.

Molecular testing of indeterminate thyroid nodules informs about the presence of point mutations, insertions/deletions, copy number variants, RNA fusions, transcript alterations and miRNA expression. American Thyroid Association (ATA) guidelines suggest molecular testing of indeterminate thyroid nodules may be considered to supplement risk of malignancy (ROM). Although these recommendations have been incorporated in clinical practices in the United States, molecular testing of indeterminate thyroid nodules is not common practice in Asia. Here, we performed molecular testing of 140 indeterminate nodules from Chinese patients using a novel molecular platform composed of RNA and DNA‐RNA classifiers, which is similar to Afirma GEC and ThyroSeq v3. Compared with reports from North America, the new RNA and DNA‐RNA classifiers had a higher positive predictive value (p1 = 0.000 and p2 = 0.020) but a lower negative predictive value (p1 = 0.004 and p2 = 0.098), with no significant differences in sensitivity (p1 = 0.625 and p2 = 0.179) or specificity (p1 = 0.391 and p2 = 0.264). Out of 58 resected nodules, 10 were borderline and 33 malignant, indicating a 74.1% ROM, which was higher than reports in North America (10–40% ROM). Our findings emphasize molecular testing with the newly reported RNA and DNA‐RNA classifiers can be used as a ‘rule‐in’ test when ROM is high.

Abstract Background Histone lysine-specific demethylase 1 (LSD1) expression has been shown to be significantly elevated in gastric cancer (GC) and may be associated with the proliferation and metastasis of GC. It has been reported that LSD1 repressed tumor immunity through programmed cell death 1 ligand 1 (PD-L1) in melanoma and breast cancer. The role of LSD1 in the immune microenvironment of GC is unknown. Methods Expression LSD1 and PD-L1 in GC patients was analyzed by immunohistochemical (IHC) and Western blotting. Exosomes were isolated from the culture medium of GC cells using an ultracentrifugation method and characterized by transmission electronic microscopy (TEM), nanoparticle tracking analysis (NTA), sucrose gradient centrifugation, and Western blotting. The role of exosomal PD-L1 in T-cell dysfunction was assessed by flow cytometry, T-cell killing and enzyme-linked immunosorbent assay (ELISA). Results Through in vivo exploration, mouse forestomach carcinoma (MFC) cells with LSD1 knockout (KO) showed significantly slow growth in 615 mice than T-cell-deficient BALB/c nude mice. Meanwhile, in GC specimens, expression of LSD1 was negatively correlated with that of CD8 and positively correlated with that of PD-L1. Further study showed that LSD1 inhibited the response of T cells in the microenvironment of GC by inducing the accumulation of PD-L1 in exosomes, while the membrane PD-L1 stayed constant in GC cells. Using exosomes as vehicles, LSD1 also obstructed T-cell response of other cancer cells while LSD1 deletion rescued T-cell function. It was found that while relying on the existence of LSD1 in donor cells, exosomes can regulate MFC cells proliferation with distinct roles depending on exosomal PD-L1-mediated T-cell immunity in vivo. Conclusion LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in GC; this finding indicates a new mechanism with which LSD1 may regulate cancer immunity in GC and provides a new target for immunotherapy against GC.

In this paper, sulfonic groups functionalized annealed bio-based carbon microspheres loaded polytetrafluoroethylene (A-BCMSs-SO3H@PTFE) fibers with high activity, high stability, and easy regeneration were successfully fabricated by a simple method using low-cost raw materials. The characterization results showed that the annealed biomass carbon microspheres derived from waste Camellia oleifera shells were evenly distributed on the polytetrafluoroethylene fibers and the sulfonic groups can be successfully loaded on the surface of annealed biomass carbon microspheres by room temperature sulfonation. Subsequently, the as-prepared A-BCMSs-SO3H@PTFE fibers were applied to the acid-catalyzed synthesis of liquid biofuel 5-ethoxymethylfurfural. The catalytic experiment results indicated that the annealing temperature and time during catalyst preparation have a significant effect on the activity and selectivity of A-BCMSs-SO3H@PTFE fibers. The results of catalytic reaction kinetics showed that the yield of 5-ethoxymethylfurfural can reach more than 60% after 72 h of acid-catalyzed reaction. The stability test showed that the as-prepared A-BCMSs-SO3H@PTFE fibers still maintained a stable acid catalytic activity after four recycles.

Abstract RNA modification plays a crucial role in many biological functions, and its abnormal regulation is associated with the progression of cancer. Among them, N6-methyladenine (m6A) is the most abundant RNA modification. Methyltransferase-like 14 (METTL14) is the central component of the m6A methylated transferase complex, which is involved in the dynamic reversible process of m6A modification. METTL14 acts as both an oncogene and tumor suppressor gene to regulate the occurrence and development of various cancers. The abnormal m6A level induced by METTL14 is related to tumorigenesis, proliferation, metastasis, and invasion. To date, the molecular mechanism of METTL14 in various malignant tumors has not been fully studied. In this paper, we systematically summarize the latest research progress on METTL14 as a new biomarker for cancer diagnosis and its biological function in human tumors and discuss its potential clinical application. This study aims to provide new ideas for targeted therapy and improved prognoses in cancer.

The recurrence and metastasis of children with mediastinal neuroblastoma (NB) are also occurred after surgery, chemotherapy, or radiotherapy. Strategies targeting the tumor microenvironment have been reported to improve survival; however, thorough investigations of monocytes and tumor-associated macrophages (Mϕs) with specialized functions in NB are still lacking. Our data first demonstrated polypyrimidine tract binding protein 2 (PTBP2) as a possible identifier in patients with mediastinal NB screened by proteomic profiling and that PTBP2 predicted good outcomes. Functional studies revealed that PTBP2 in NB cells induced the chemotactic activity and repolarization of tumor-associated monocytes and Mϕs, which, in turn, inhibited NB growth and dissemination. Mechanistically, PTBP2 prevents interferon regulatory factor 9 alternative splicing and upregulates signal transducers and activators of transcription 1 to stimulate C-C motif chemokine ligand 5 (CCL5) and interferon-stimulated gene factor-dependent type I interferon secretion, to induce monocyte/Mϕs chemotaxis, and to sustain monocytes in a proinflammatory phenotype. Our study defined a critical event of PTBP2-induced monocytes/Mϕs in NB progression and revealed that RNA splicing occurred by PTBP2 benefits immune compartmentalization between NB cells and monocytes. This work revealed the pathological and biological role of PTBP2 in NB development and indicates that PTBP2-induced RNA splicing benefits immune compartmentalization and predicted a favorable prognosis in mediastinal NB.

Diabetes is the most common metabolic disorder, with an extremely serious effect on health systems worldwide. It has become a severe, chronic, non-communicable disease after cardio-cerebrovascular diseases. Currently, 90% of diabetic patients suffer from type 2 diabetes. Hyperglycemia is the main hallmark of diabetes. The function of pancreatic cells gradually declines before the onset of clinical hyperglycemia. Understanding the molecular processes involved in the development of diabetes can provide clinical care with much-needed updates. This review provides the current global state of diabetes, the mechanisms involved in glucose homeostasis and diabetic insulin resistance, and the long-chain non-coding RNA (lncRNA) associated with diabetes.

The incidence of lung cancer is high and about 75% of the patients with lung cancer are found in the middle and advanced stage, which has a limited treatment strategy. Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers. In this article, we delineate the treatment process of a middle-aged male patient with advanced-stage lung cancer to explain the significance of individualized chemotherapy combined with immunotherapy and surgery. This patient has extensive bone metastasis with PS scores of 2. After nine cycles of preoperative neoadjuvant chemotherapy, surgery, and two cycles of postoperative adjuvant chemotherapy, the patient achieved complete response (CR) and his PS score was 0. Although there is a standard chemotherapy regimen for lung adenocarcinoma, the treatment effect varies because of individual differences. Comprehensive analysis of the characteristics of patients through a variety of means to develop a precise individualized chemotherapy plan will be a major direction of lung cancer treatment in the future. Additionally, surgical treatment for advanced lung cancer patients after chemotherapy can effectively reduce the primary lesion and prolong the survival time of patients.

Background and objective Pembrolizumab, an immunotherapy for advanced non-small cell lung cancer (NSCLC), needs to predict treatment response based on test results including immunohistochemistry (IHC), which detects the expression of programmed death ligand 1 (PD-L1). The aim of this study was to evaluate the feasibility of immunocytochemistry (ICC) in NSCLC cytology to detect PD-L1 and to investigate the correlation between PD-L1 expression and clinical pathology and molecular features. Methods Sixty cases of lung adenocarcinoma pleural cytology were collected and PD-L1 sp263 reagent was used for immunocytochemical staining according to the manufacturer's instructions. Next-generation sequencing (NGS) was performed on pleural cytology specimens to explore its correlation. Results Of the 60 cases of lung adenocarcinoma pleural effusion cell block, 35 cases were positive for PD-L1 expression, and the positive expression rate was 58.3%. The positive rate of PD-L1 expression in the specimens of our hospital was 33.3%, and there was no significant difference between the cytological specimens and the histological specimens (P>0.05). Of the 60 cytological specimens, 26 were tested for NGS, and 15 (57.7%) were found to have epidermal growth factor receptor (EGFR) mutations. No correlation was found between PD-L1 expression and EGFR mutation. The positive expression rate of PD-L1 were not correlated with the age and gender in the study population (P>0.05). Conclusion When no surgical specimens are available, pleural cytology cell block specimens can be used for immunocytochemical detection of PD-L1, and the results are feasible.

Abstract Background Overgrazing is a primary contributor to severe reduction in forage quality and production in Inner Mongolia, leading to extensive ecosystem degradation, sheep health impairment and growth performance reduction. Further studies to identify serum biomarkers that reflect changes in sheep health and nutritional status following overgrazing would be beneficial. We hereby hypothesize that reduced sheep growth performance under overgrazing conditions would be associated with metabolic and immune response alterations. This study used an untargeted metabolomics analysis by conducting ultra-high-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) of sheep serum under overgrazing and light grazing conditions to identify metabolic disruptions in response to overgrazing. Results The sheep body weight gains as well as serum biochemical variables associated with immune responses and nutritional metabolism (immunoglobulin G, albumin, glucose, and nonesterified fatty acids) were significantly decreased with overgrazing compared with light grazing condition. In contrast, other serum parameters such as alanine and aspartate aminotransferase, alkaline phosphatase, total bilirubin, blood urea nitrogen, and interleukin-8 were markedly higher in the overgrazing group. Principal component analysis discriminated the metabolomes of the light grazing from the overgrazing group. Multivariate and univariate analyses revealed changes in the serum concentrations of 15 metabolites (9 metabolites exhibited a marked increase, whereas 6 metabolites showed a significant decrease) in the overgrazing group. Major changes of fatty acid oxidation, bile acid biosynthesis, and purine and protein metabolism were observed. Conclusions These findings offer metabolic evidence for putative biomarkers for overgrazing-induced changes in serum metabolism. Target-identification of these particular metabolites may potentially increase our knowledge of the molecular mechanisms of altered immune responses, nutritional metabolism, and reduced sheep growth performance under overgrazing conditions.

Colorectal cancer (CRC) is the most common gastrointestinal cancer. Hippophae rhamnoides are reported to possess a variety of active substances. MiRNAs are new therapeutic targets. Here, it found that Hippophae rhamnoides L. polyphenols (named as HPs60) exhibited significant anti-colon cancer activity in vitro and in vivo. And the main components were identified by LC-MS as kaempferol and its derivatives. Subsequently, by RNA-sequencing and searching GEO and TCGA database, three reliable miRNAs including hsa-miR-195-5p, hsa-miR-497-5p and hsa-miR-1247-3p were eventually screened. As expected, hsa-miR-195-5p and hsa-miR-497-5p were upregulated upon HPs60 treatment, while hsa-miR-1247-3p was downregulated. Furthermore, HPs60 remarkably suppressed the expression of cyclinD1, cyclinD2, cyclinD3, cyclinE1 and Bcl-2, which are the targets of miR-195-5p and miR-497-5p. Correspondingly, HPs60 promoted expression of caspase-2, a target gene of miR-1247-3p. All of these results suggest that HPs60 may explore as natural bioactive ingredients and reveal the potential therapeutic targets responsible for HPs60 against CRC.

Polyphenol-rich foods are gaining popularity due to their potential beneficial effects in the prevention and treatment of cancer. Foxtail millet is one of the important functional foods, riches in a variety of biologically active substance. Our previous study showed that ferulic acid (FA) and p-coumaric acid (p-CA) are the main anticancer components of foxtail millet bran, and the two have a significant synergistic effect. In the present study, the clinical application potential of FA and p-CA (FA + p-CA) were evaluated in vivo and in vitro. The FA and p-CA target gene enrichment analysis discovered that FA + p-CA were associated with aerobic glycolysis. It was further shown that FA + p-CA remodel aerobic glycolysis by inhibiting the glycolysis-associated lncRNA 495810 and the glycolytic rate-limiting enzyme M2 type pyruvate kinase (PKM2). Moreover, PKM2 expression was positively correlated with lncRNA 495810. More interestingly, the exogenous expression of lncRNA 495810 eliminated the inhibitory effects of FA + p-CA on aerobic glycolysis. Collectively, FA + p-CA obstruct the aerobic glycolysis of colorectal cancer cells via the lncRNA 495810/PKM2 axis, which provides a nutrition intervention and treatment candidate for colorectal cancer.

Gliomas are the most prevalent brain tumors among children and adolescents. The occurrence and development of various malignant tumors is closely related with LIN28A gene, but its relationship with glioma susceptibility has not been widely discovered. In this case-control study, we conducted four single nucleotide polymorphisms (SNPs) (rs3811464 G>A, rs3811463 T>C, rs34787247 G>A, and rs11247957 G>A) of LIN28A gene to investigate whether they increase the risk of glioma. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate their relationship. There was no significant correlation between four SNPs and glioma risk in single polymorphism and conjoint analysis. However, in stratification analysis, we found that rs3811463 TC/CC may add to the risk of glioma with clinical stage III (adjusted OR = 3.16, 95% CI = 1.15-8.70, P = .026) or stage III+IV patients (adjusted OR = 2.05, 95% CI = 1.02-4.13, P = .044). Our research suggested that four SNPs of LIN28A gene have a weak relationship with the risk of glioma in Chinese children. LIN28A rs3811463 TC/CC may increase the possibility of glioma in clinical stage III or stage III+IV patients which need larger samples and further confirmation.

Hepatoblastoma is the most common malignant liver cancer in childhood. The etiology of hepatoblastoma remains obscure. Hepatoblastoma is closely related to genetic syndromes, hinting that hepatoblastoma is a genetic predisposition disease. However, no precise exposures or genetic events are reported to hepatoblastoma occurrence. During the past decade, significant advances have been made in the understanding of etiology leading to hepatoblastoma, and several important genetic events that appear to be important for the development and progression of this tumor have been identified. Advances in our understanding of the genetic changes that underlie hepatoblastoma may translate into better patient outcomes. Single nucleotide polymorphisms (SNPs) have been generally applied in the research of etiology’s exploration, disease treatment, and prognosis assessment. Here, we reviewed and discussed the molecular epidemiology, especially SNPs progresses in hepatoblastoma, to provide references for future studies and promote the study of hepatoblastoma’s etiology.

Abstract Background Cadmium (Cd) is a ubiquitous environmental toxicant for aquatic animals. The freshwater crab, Sinopotamon henanense (S. henanense), is a useful model for monitoring Cd exposure since it is widely distributed in sediments whereby it tends to accumulate several toxicants, including Cd. In the recent years, the toxic effects of Cd in the hepatopancreas of S. henanense have been demonstrated by a series of biochemical analysis and ultrastructural observations as well as the deep sequencing approaches and gene expression profile analysis. However, the post-transcriptional regulatory network underlying Cd toxicity in S.henanense is still largely unknown. Results The miRNA transcriptional profile of the hepatopancreas of S. henanense was used to investigate the expression levels of miRNAs in response to Cd toxicity. In total, 464 known miRNAs and 191 novel miRNAs were identified. Among these 656 miRNAs, 126 known miRNAs could be matched with the miRNAs of Portunus trituberculatus, Eriocheir sinensis and Scylla paramamosain. Furthermore, a total of 24 conserved miRNAs were detected in these four crab species. Fifty-one differentially expressed miRNAs were identified in the Cd-exposed group, with 31 up-regulated and 20 down-regulated. Eight of the differentially expressed miRNAs were randomly selected and verified by the quantitative real-time PCR (qRT-PCR), and there was a general consistency (87.25%) between the qRT-PCR and miRNA transcriptome data. A total of 5258 target genes were screened by bioinformatics prediction. GO term analysis showed that, 17 GO terms were significantly enriched, which were mainly related to the regulation of oxidoreductase activity. KEGG pathway analysis showed that 18 pathways were significantly enriched, which were mainly associated with the biosynthesis, modification and degradation of proteins. Conclusion In response to Cd toxicity, in the hepatopancreas of S. henanense, the expressions of significant amount of miRNAs were altered, which may be an adaptation to resist the oxidative stress induced by Cd. These results provide a basis for further studies of miRNA-mediated functional adaptation of the animal to combat Cd toxicity.

Abstract Background Overgrazing is a major factor that causes steppe degradation in Inner Mongolian, resulting in extensive ecosystem damage. Scarcity of grass means sheep are smaller and therefore mutton and cashmere production is greatly reduced, which has resulted in massive annual economic losses. Liver is the primary metabolic organ in mammals. It is also the key source of energy supply and detoxification of metabolites in animals, has a close relationship with animal growth. However, investigations on the responses of sheep induced by consequence of overgrazing, particularly those relating to liver-related molecular mechanisms and related metabolic pathways, remain elusive. Results The body weight daily gain of sheep, immune organ indices (liver and spleen), and serum parameters related to immune response, protein synthesis and energy supply (IgG, albumin, glucose and non-esterified fatty acid) were significantly lower in the overgrazing group. Other serum parameters including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, blood urea nitrogen and interleukin-6 were significantly higher in the overgrazing group. For the RNA-Seq results, we identified approximately 50 differentially expressed genes, of which half of were up-regulated and the other half were down-regulated (overgrazing group versus light grazing group). Bioinformatics analysis identified two enriched KEGG pathways including peroxisome proliferator-activated receptor (PPAR) signaling pathway (related to lipolysis) and ECM-receptor interaction (related to liver injury and apoptosis). Additionally, several of the down-regulated genes were related to detoxification and immune response. Conclusions Overall, based on the high-throughput RNA sequencing profile integrated with the results of serum biochemical analyses, consequences of lower forage availability and quality under overgrazing condition induced altered expression levels of genes participating in energy metabolism (particularly lipid metabolism) and detoxification and immune responses, causing lipolysis and impaired health status, which might be key reasons for the reduced growth performance of sheep. This investigation provides a novel foundation for the development of sheep hepatic gene interactive networks that are a response to the degraded forage availability under overgrazing condition.

Background: Targeting the CD47/SIRPα signaling pathway represents a novel approach to enhance anti-tumor immunity. However, the crystal structure of the CD47/SIRPα has not been fully studied. This study aims to analyze the structure interface of the complex of CD47 and IMM01, a novel recombinant SIRPα-Fc fusion protein. Methods: IMM01-Fab/CD47 complex was crystalized, and diffraction images were collected. The complex structure was determined by molecular replacement using the program PHASER with the CD47-SIRPαv2 structure (PDB code 2JJT) as a search model. The model was manually built using the COOT program and refined using TLS parameters in REFMAC from the CCP4 program suite. Results: Crystallization and structure determination analysis of the interface of IMM01/CD47 structure demonstrated CD47 surface buried by IMM01. Comparison with the literature structure (PDB ID 2JJT) showed that the interactions of IMM01/CD47 structure are the same. All the hydrogen bonds that appear in the literature structure are also present in the IMM01/CD47 structure. These common hydrogen bonds are stable under different crystal packing styles, suggesting that these hydrogen bonds are important for protein binding. In the structure of human CD47 in complex with human SIRPα, except SER66, the amino acids that form hydrogen bonds are all conserved. Furthermore, comparing with the structure of PDB ID 2JJT, the salt bridge interaction from IMM01/CD47 structure are very similar, except the salt bridge bond between LYS53 in IMM01 and GLU106 in CD47, which only occurs between the B and D chains. However, as the side chain conformation of LYS53 in chain A is slightly different, the salt bridge bond is absent between the A and C chains. At this site between chain A and chain C, there are a salt bridge bond between LYS53 (A) and GLU104 (C) and a salt bridge bond between HIS56 (A) and GLU106 (C) instead. According to the sequence alignment results of SIRPα, SIRPβ and SIRPγ in the literature of PDB ID 2JJT, except ASP100, the amino acids that form common salt bridge bonds are all conserved. Conclusion: Our data demonstrated crystal structure of the IMM01/CD47 complex and provides a structural basis for the structural binding interface and future clinical applications.

This paper establishes a fully automatic real-time image segmentation and recognition system for breast ultrasound intervention robots. It adopts the basic architecture of a U-shaped convolutional network (U-Net), analyses the actual application scenarios of semantic segmentation of breast ultrasound images, and adds dropout layers to the U-Net architecture to reduce the redundancy in texture details and prevent overfitting. The main innovation of this paper is proposing an expanded training approach to obtain an expanded of U-Net. The output map of the expanded U-Net can retain texture details and edge features of breast tumours. Using the grey-level probability labels to train the U-Net is faster than using ordinary labels. The average Dice coefficient (standard deviation) and the average IOU coefficient (standard deviation) are 90.5% (±0.02) and 82.7% (±0.02), respectively, when using the expanded training approach. The Dice coefficient of the expanded U-Net is 7.6 larger than that of a general U-Net, and the IOU coefficient of the expanded U-Net is 11 larger than that of the general U-Net. The context of breast ultrasound images can be extracted, and texture details and edge features of tumours can be retained by the expanded U-Net. Using an expanded U-Net can quickly and automatically achieve precise segmentation and multi-class recognition of breast ultrasound images.

Resistance to 5-Fluorouracil (5-Fu) chemotherapy is the main cause of treatment failure in the cure of colon cancer. Therefore, there is an urgent need to explore a safe and effective multidrug resistance reversal agent for colorectal cancer, which would be of great significance for improving clinical efficacy. The dietary flavonoid kaempferol plays a key role in the progression of colorectal cancer and 5-Fu resistance. However, the molecular mechanism of kaempferol in reversing 5-Fu resistance in human colorectal cancer cells is still unclear. We found that kaempferol could reverse the drug resistance of HCT8-R cells to 5-Fu, suggesting that kaempferol alone or in combination with 5-Fu has the potential to treat colorectal cancer. It is well known that aerobic glycolysis is related to tumor growth and chemotherapy resistance. Indeed, kaempferol treatment significantly reduced glucose uptake and lactic acid production in drug-resistant colorectal cancer cells. In terms of mechanism, kaempferol promotes the expression of microRNA-326 (miR-326) in colon cancer cells, and miR-326 could inhibit the process of glycolysis by directly targeting pyruvate kinase M2 isoform (PKM2) 3′-UTR (untranslated region) to inhibit the expression of PKM2 or indirectly block the alternative splicing factors of PKM mRNA, and then reverse the resistance of colorectal cancer cells to 5-Fu. Taken together, our data suggest that kaempferol may play an important role in overcoming resistance to 5-Fu therapy by regulating the miR-326-hnRNPA1/A2/PTBP1-PKM2 axis.

Grazing, one of the primary utilization modes of grassland, is the main cause of grassland degradation. Historical overgrazing results in dwarf phenotype and decreased photosynthesis of perennial plants. However, it remains unknown what the mechanism underlying of this legacy effect is, and the role of stomata in the resulting decreased photosynthesis also remains unclear. To address these questions, differences in stomatal density, length and width on both adaxial and abaxial epidermis were compared between overgrazing and ungrazed Leymus chinensis offspring by using rhizome buds cultivated in a greenhouse, and the correlation between photosynthetic capacity and stomatal behavior was also investigated. Our results showed that historical grazing significantly impacted phenotype, photosynthesis and stomatal traits of L. chinensis. The offspring plants taken from overgrazed parents were dwarfed compared to those taken from ungrazed parents, and the photosynthesis and stomatal conductance of plants with a grazing history decreased by 28.6% and 21.3%, respectively. In addition, stomatal density and length on adaxial and abaxial leaf surfaces were significantly increased; however, stomatal width on abaxial leaf surfaces of overgrazed L. chinensis was significantly decreased compared with ungrazed individuals. Moreover, the expression patterns of eight genes related to stomatal regulation were tested: seven were down-regulated (2–18 times) and one was up-regulated (three times). Genes, involved in ABC transporter and receptor-like serine/threonine protein kinase were down-regulated. These results suggest that legacy effects of historical grazing affect the stomatal conductance by decreasing the stomatal width in progeny plants, which thus results in lower photosynthesis. Furthermore, changes of stomatal traits and function were regulated by the inhibition of ABC transporter and serine/threonine protein kinase. These findings are helpful for future exploration of the possible mechanisms underlying the response of grassland plants to long-term overgrazing.

Malignant cells support tumor proliferation and progression by adopting to metabolic changes. Tumor cells altered metabolism by increasing glucose uptake and fermentation of glucose to lactate, even in the aerobic state and the presence of functioning mitochondria. Glucose metabolism in tumor plasticity has attracted great interests by clinicians and scientists in the past decades. This review discusses the previous and emerging researches on the tumor plasticity altered by changing glucose metabolism in different cancer cells, including cancer stem cells (CSCs). In addition, we summarize the rising applications of glucose metabolism in tumor diagnosis and treatment. Our objective is to direct future investigation on this altered metabolic phenotype and its application in patient care.

A series of biobased heterogeneous solid Brønsted acid catalysts with perfect spherical microstructures are successfully fabricated directly from waste Camellia oleifera shells by a simple hydrothermal carbonization-annealing-sulfonation process. 350 °C low temperature annealing process helps to increase the activity of the catalyst due to the simultaneous maintenance of the spherical microstructure and aromatic carbon framework. As a renewable catalyst with low cost, the as-prepared materials are successfully applied on the synthesis of green renewable liquid biofuel 5-ethoxymethylfurfural (EMF) directly from fructose. In the catalytic test, the influences of reaction time and temperature, fructose concentration, and adding amount of the catalyst on the yield of EMF are investigated systematically. As a result, the optimal reaction temperature is 100 °C, the EMF yield monotonically increases with prolonging the reaction time from 3 to 24 h, the optimal fructose concentration is 0.5 mmol, and the EMF yield gradually increases with increasing the adding amount of the catalyst from 50 to 150 mg. In addition, the as-prepared catalysts exhibit considerably high stability in the current EMF synthesis system, and they can maintain a similar level of reactivity after four catalytic cycles. Keywords: Hydrothermal carbonization, Annealing, Sulfonation, 5-Ethoxymethylfurfural, Fructose

Abstract Background This study was designed to reveal potential molecular mechanisms of long-term overgrazing-induced dwarfism in sheepgrass (Leymus chinensis). Methods An electrospray ionisation mass spectrometry system was used to generate proteomic data of dwarf sheepgrass from a long-term overgrazed rangeland and normal sheepgrass from a long-term enclosed rangeland. Differentially expressed proteins (DEPs) between dwarf and normal sheepgrass were identified, after which their potential functions and interactions with each other were predicted. The expression of key DEPs was confirmed by high-performance liquid chromatography mass spectrometry (HPLC–MS) using a multiple reaction monitoring method. Results Compared with normal sheepgrass, a total of 51 upregulated and 53 downregulated proteins were identified in dwarf sheepgrass. The amino acids biosynthesis pathway was differentially enriched between the two conditions presenting DEPs, such as SAT5_ARATH and DAPA_MAIZE. The protein–protein interaction (PPI) network revealed a possible interaction between RPOB2_LEPTE, A0A023H9M8_9STRA, ATPB_DIOEL, RBL_AMOTI and DNAK_GRATL. Four modules were also extracted from the PPI network. The HPLC–MS analysis confirmed the upregulation and downregulation of ATPB_DIOEL and DNAK_GRATL, respectively in dwarf samples compared with in the controls. Conclusions The upregulated ATPB_DIOEL and downregulated DNAK_GRATL as well as proteins that interact with them, such as RPOB2_LEPTE, A0A023H9M8_9STRA and RBL_AMOTI, may be associated with the long-term overgrazing-induced dwarfism in sheepgrass.

Mud pumping occurring in the subgrade bed can gradually deteriorate the performance of the slab track-subgrade, negatively affecting the comfort and safety of high-speed railway. In this paper, a full-scale model of the slab track-subgrade was established to analyze the vibration behavior of the model in normal condition and before and after mud pumping reinforced, as well as the reinforcement effect of mud pumping using low-viscosity epoxy resin. The research results show that the vibration acceleration and displacement and the settlement of the model in normal condition stabilize gradually with the increasing number of loading cycles. Under the upper layer of the subgrade bed saturated by water, mud pumping occurs in the subgrade bed as soon as the second loading stage reaches to 3.0 × 104 cycles, and the deterioration of mud pumping increases gradually with the increasing number of loading cycles. Moreover, a large volume of slurry composed of water and fine particles is squeezed out of the subgrade bed after the model is subjected to the second cyclic loading stage of 2.0 × 106 cycles, causing contact loss between the concrete base and the subgrade bed, which makes the acceleration and displacement of the concrete base increase abnormally compared with the model in normal condition, as well as the cumulative settlement of the subgrade bed. The model with significant mud pumping in the upper layer of the subgrade bed was reinforced by using low-viscosity epoxy resin. This effectively controlled the abnormal acceleration and displacement of the concrete base and restored the support capability of the subgrade bed for the concrete base of the slab track structure.

Background and objective Epidermal growth factor receptor (EGFR) and KRAS must be detected mutation status before patients of lung cancer use targeted drugs. The aim of this study is to elucidate the significance of EGFR and KRAS mutation in fine needle aspiration (FNA) cytology suspension specimens of non-small cell lung carcinoma. Methods EGFR gene exons 18-21 and KRAS codons 12, 13 of exons 2 were performed by Real-time PCR methods in fine needle aspiration cytology suspension specimens of lymph nodes. Results 85 metastasis lymph nodes were detected in fine needle aspiration cytology samples of lung cancer. EGFR mutation rate was 37.3%. KRAS mutation rate was 7.2%. 19 formalin fixed paraffin-embedded tissue specimens were available and match cytology specimens. Analysis of EGFR mutation status in those samples revealed agreement with the results obtained in cytological samples (kappa=1.0). Clinical follow-up was available for 13 who presented with stage IV disease. Based on the identification of such mutations, these patients received subsequent therapy with a TKI in clinic. We observed two cases complete remission (16.7%) and 8 cases partial remission (66.7%) and three had ongoing stable disease. Conclusion Fine-needle aspiration cytology samples were detected EGFR and KRAS mutation. The method which collects samples was easier, simple and convenient. This method has higher application value in clinical treatment.