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The aim of this study was to find new protein biomarkers that could be used to detect hepatocellular carcinoma (HCC) in the serum. We identified 11 proteins in the tissue that could be used to classify samples from HCC and control subjects. The 11 identified tissue biomarkers were combined with 10 commonly used serum HCC biomarkers for further verification in a large number of serum samples from HCC patients and healthy controls. 17 of the 21 prospective serum biomarkers were determined to be differentially expressed through collinearity and significance analysis. Through the method of supervised learning, a random forest model was constructed to reduce the dimensionality of the number of differentially expressed proteins, and finally, 4 differentially expressed proteins were identified: AFP, GDF15, CEACAM-1, and MMP-9, and suggested to have potential application in clinical diagnosis of HCC.

The study evaluated the effect of calcium-based desensitizing toothpastes on the dentinal tubule occlusion and its influence on the dentin bond strength of universal adhesive. Mid-coronal dentin samples were prepared for hypersensitivity model and treated by the following calcium-based desensitizing toothpastes: no treatment (Control), Clinpro (fTCP), Pro-Relief (Pro-Argin), and RepairProtect (Novamin). Single Bond Universal adhesive was applied in self-etch or etch-and-rinse mode. The dentinal tubule occlusion and adhesion interface were evaluated under scanning electron microscope (SEM). A double-fluorescence technique was used to examine interfacial permeability under confocal laser scanning microscopy (CLSM). The micro-tensile bond strength (μTBS) was employed, followed by the fracture interface observation. SEM showed the toothpastes occluded dentinal tubules, and the occlusion exhibited stability against acid and abrasion. Hindered resin infiltration was observed in the adhesion interface after desensitization. CLSM showed more water permeation within or under the adhesion interface in etch-and-rinse mode than self-etch mode. Desensitization decreased the μTBS in self-etch mode. When using etch-and-rinse mode, the desensitized samples presented similar μTBS to the control group. No difference in μTBS was found between the two bonding modes, except for the control group. Calcium-based desensitizing toothpastes can effectively occlude the exposed dentinal tubules with acid-resistant and abrasion-resistant stability. The desensitization reduced the dentin bond strength of the universal adhesive system in self-etch mode but did not affect the bond strength of etch-and-rinse mode.

Aberrant cell-cycle progression is characteristic of melanoma, and CDK4/6 inhibitors, such as palbociclib, are currently being tested for efficacy in this disease. Despite the promising nature of CDK4/6 inhibitors, their use as single agents in melanoma has shown limited clinical benefit. Herein, we discovered that treatment of tumor cells with palbociclib induces the phosphorylation of the mRNA translation initiation factor eIF4E. When phosphorylated, eIF4E specifically engenders the translation of mRNAs that code for proteins involved in cell survival. We hypothesized that cancer cells treated with palbociclib use upregulated phosphorylated eIF4E (phospho-eIF4E) to escape the antitumor benefits of this drug. Indeed, we found that pharmacologic or genetic disruption of MNK1/2 activity, the only known kinases for eIF4E, enhanced the ability of palbociclib to decrease clonogenic outgrowth. Moreover, a quantitative proteomics analysis of melanoma cells treated with combined MNK1/2 and CDK4/6 inhibitors showed downregulation of proteins with critical roles in cell-cycle progression and mitosis, including AURKB, TPX2, and survivin. We also observed that palbociclib-resistant breast cancer cells have higher basal levels of phospho-eIF4E, and that treatment with MNK1/2 inhibitors sensitized these palbociclib-resistant cells to CDK4/6 inhibition. In vivo we demonstrate that the combination of MNK1/2 and CDK4/6 inhibition significantly increases the overall survival of mice compared with either monotherapy. Overall, our data support MNK1/2 inhibitors as promising drugs to potentiate the antineoplastic effects of palbociclib and overcome therapy-resistant disease.

This study aims to find out the possible optimal therapy and assess the prognosis properly for patient with spontaneous rupture of hepatocellular carcinoma (HCC).Propensity score matching (PSM) analysis was used to study the data from 325 patients with ruptured HCC (RHCC) and 2,291 patients with non-RHCC.The incidence and hospital mortality of RHCC were 5.1% and 0.8% respectively, with a median overall survival (OS) time of 17 months. There was no difference between ruptured and non-RHCC patients undergoing conservation treatment in terms of OS. Trans-arterial embolization (TAE) was carried out in 69 (21.2%) cases with RHCC, with a median OS of 7 months, which was no difference from that of non-RHCC (pre- and post-PSM). One hundred and sixty-nine (52.0%) RHCC cases underwent one-stage hepatectomy, with a median OS and disease-free survival (DFS) of 30 and 6 months respectively, which were shorter than that of non-RHCC (post-PSM). TAE plus two-stage hepatectomy was performed in 30 RHCC cases, with a median OS and DFS of 28 and 10 months respectively; these outcomes were better than that from RHCC patients undergoing TAE alone or one-stage hepatectomy (post-PSM), which were no difference from that of non-RHCC patients undergoing hepatectomy. The risk of death for RHCC patient undergoing one-stage hepatectomy is 1.545 times higher than that of one undergoing TAE + two-stage hepatectomy.TAE plus two-stage hepatectomy might be the optimal treatment for RHCC patient. Under the premise of the same pathological properties, there is no difference in prognosis between ruptured and non-RHCC patients if the therapy is appropriate.

Phase-amplitude coupling (PAC) plays an important role in anesthetic-induced unconsciousness. The delta-alpha PAC signature during anesthetic-induced unconsciousness is gradually becoming known; however, the frequency dependence and spatial characteristics of PAC are still unclear. Multi-channel electroencephalography (EEG) was performed during the loss and recovery phases of consciousness in patients undergoing general anesthesia using sevoflurane. First, a spectral analysis was used to investigate the power change of the different frequency bands in the EEG signals. Second, PAC comodulogram analysis was performed to confirm the frequencies of the PAC phase drivers. Finally, to investigate the spatial characteristics of PAC, a novel PAC network was constructed using within- and cross-lead PAC, and a K-means clustering algorithm was used to identify PAC network patterns. Our results show that, in addition to the delta-alpha PAC, unconsciousness induced by sevoflurane was accompanied by spatial non-uniform alpha-gamma PAC in the cortical network, and dynamic PAC patterns between the anterior and posterior brain were observed during the unconscious phase. The dynamic transition of PAC network patterns indicates that brain states under sevoflurane-induced unconsciousness emerge from the regulation of functional integration and segregation instantiated by delta-alpha and alpha-gamma PAC.

Context Red clover (Trifolium pratense L.) is an important legume forage in temperate agricultural zones. Evaluation of self- and cross-pollination fertility is important for setting up an effective breeding-program scale. However, the outcrossing rate of red clover under open-pollination conditions is not certain. Development of a reliable and time-saving marker system is needed to quantify and characterise outcrossing rates. Aim We aimed to develop a duplex PCR-based protocol based on a genome-wide simple sequence repeat (SSR) screen, and to determine the outcrossing rate of red clover under open-pollination environments. Methods We screened 209 SSR markers with pooled DNA samples of 60 plants from 20 red clover accessions, and selected 185 SSR markers that produced clear scorable bands for testing with 24 individual DNA samples to determine polymorphism. We selected 70 primer pairs, and then assembled a core set of 24 loci into 12 sets of duplex markers, which were used for outcrossing behaviour analysis of 60 maternal parents and their respective 22 half-sib progenies. Key results Mean polymorphic information content (PIC) for the 70 markers was 0.490 (range 0.117–0.878). Minimum, mean and maximum PIC values for the 24 markers constituting the 12 duplexes were 0.226, 0.594 and 0.781, respectively. The outcrossing rate was identified as 99.4% for red clover in a natural environment. Conclusion We successfully developed a duplex SSR-based PCR protocol consisting of 24 markers. This SSR system was applied to determine the outcrossing rate of red clover in a natural environment.

This study proposed a semisupervised loss function named level-set loss (LSLoss) for cerebral white matter hyperintensities (WMHs) segmentation on fluid-attenuated inversion recovery images. The training procedure did not require manually labeled WMH masks. Our image preprocessing steps included biased field correction, skull stripping, and white matter segmentation. With the proposed LSLoss, we trained a V-Net using the MRI images from both local and public databases. Local databases were the small vessel disease cohort (HKU-SVD, n = 360) and the multiple sclerosis cohort (HKU-MS, n = 20) from our institutional imaging center. Public databases were the Medical Image Computing Computer-assisted Intervention (MICCAI) WMH challenge database (MICCAI-WMH, n = 60) and the normal control cohort of the Alzheimer's Disease Neuroimaging Initiative database (ADNI-CN, n = 15). We achieved an overall dice similarity coefficient (DSC) of 0.81 on the HKU-SVD testing set (n = 20), DSC = 0.77 on the HKU-MS testing set (n = 5), and DSC = 0.78 on MICCAI-WMH testing set (n = 30). The segmentation results obtained by our semisupervised V-Net were comparable with the supervised methods and outperformed the unsupervised methods in the literature.

Every country, including China, is deeply concerned and interested in the topic of agricultural machinery automation. The world’s population is growing at an astronomical rate, and as a result, the need of food is also growing at an astronomical rate. Farmers are forced to apply more toxic pesticides since traditional methods are not up to the task of meeting the rising demand. This has a major impact on agricultural practices, and in the long run, the land becomes barren and unproductive. Intelligent technologies such as Internet of Things, wireless communication, and machine learning can help with crop disease and pesticide storage management, as well as water management and irrigation. In this paper, we design and analyze an intelligent system that automatically predicts the agricultural land features for irrigation purpose. Initially, the dataset is collected and preprocessed using normalization. The features are extracted using principal component analysis (PCA). For automatic prediction by the equipment, we propose heterogeneous fuzzy-based artificial neural network (HF-ANN) with genetic quantum spider monkey optimization (GQ-SMO) algorithm. Analyses and comparisons are made between the proposed approach and current methodologies. The findings indicate the effectiveness of the proposed system.

The Sijiaying iron deposit is located in the Eastern Hebei area of the southern section of the northern margin of the North China Craton (NCC) and is the largest single iron deposit in China. The deposit contains many banded iron formations (BIFs) and was proven to have more than 3 million tons of high-grade iron ore resources. This study carried out geochemistry and zircon U–Pb analysis of normal-grade iron ore, high-grade iron ore, and wall rock (biotite–leptynite, chlorite–sericite schist) in the Sijiaying deposit and discussed the genesis and metallogenic age of high-grade iron ore. BIFs have low concentrations of Al2O3 and TiO2 and high field strength element (HFSE) depletion, indicating almost no contamination via terrestrial debris. The standardized post-Archean Australian shale (PAAS) rare earth element (REE) distribution pattern indicates that the iron formation exhibits positive Eu, Y, and heavy rare earth element (HREE) anomalies and lacks negative Ce anomalies, indicating that the Sijiaying BIF was enriched with iron sources via high-temperature hydrothermal fluids from the seabed and deposited in an anoxic ancient marine environment. In addition, geological field work identified two types of high-grade iron ore in the mining area: primitive sedimentary and hydrothermally altered high-grade iron ore. Further ore geochemical research showed that the primitive sedimentary-type iron ore is similar in geochemistry to the BIF. In addition to low Eu/Eu* values, the hydrothermally altered high-grade iron ore shows geochemical characteristics similar to those of the BIF, suggesting that they share the same iron source but did not form at the same time. The total large ion lithophile element (LILE) (Sr, Ba, Pb) contents in primitive sedimentary-type high-grade iron ore are higher than those in hydrothermally altered high-grade iron ore, indicating that LILEs are carried away via fluids during the hydrothermal alteration process in normal-grade iron ore. The geochemical characteristics of biotite–leptynite and chlorite–sericite schist include high contents of SiO2 and Al2O3, light rare earth elements (LREEs), LILE enrichment (Rb, Ba, Sr, Zr), and HFSE depletion (Nb, Ta, P, Ti), characteristics that are similar to island arc volcanic rocks. The reconstruction of the original rock indicates that the wall rock is a product of volcanic sedimentary cycles in an island arc setting. Zircon cathodoluminescence images and LA–ICP–MS zircon U–Pb dating can be divided into four age groups (3283 Ma, 2547 Ma, 2500 Ma, and 2407 Ma), which correspond to the earliest volcanic activity in eastern Hebei, the main mineralization age of the Sijiaying BIF (the mineralization age of primitive sedimentary high-grade iron ore), a regional tectonic–metamorphic event, and the occurrence of migmatization (the mineralization age of hydrothermally altered high-grade iron ore), respectively. Therefore, the Sijiaying BIF and primitive sedimentary high-grade iron ores were deposited and mineralized at 2547 Ma, and the iron orebody was later altered via the hydrothermal solution at 2407 Ma, forming large-scale high-grade iron ores.

The significance of HBV in cerebrospinal fluid (CSF) is unclear. In the present study,synchronous serum and CSF samples were collected from 13 patients. HBV-DNA, full-length genome, quasispecies, phylogenetic tree, compartmentalization and mutation of reverse transcriptase (RT) region analyses were performed based on PCR and sequencing methods. We found HBV-DNA was detected in the CSF of 3 antiviral-naïve patients and one patient after successful antiviral therapy. Complete full-length HBV genomes were isolated from the CSF of 5 patients, including 2 patients with undetectable serum HBV-DNA. Ten patients exhibited distinct CSF-serum quasispecies, 8 harbored independent CSF-serum genetic compartmentalization and phylogenetic trees, and 5 patients presented lamivudine/entecavir-associated resistance mutations in only the CSF. The frequencies of rtL180M and rtM204I/V mutations in both serum and CSF were higher in HIV/HBV-coinfected patients than in HBV-monoinfected patients (serum: rtL180M: 3.9% vs. 0, P = 0.004; rtM204I/V: 21.3% vs. 0, P < 0.001; CSF: rtL180M: 7.6% vs. 0, P = 0.026; rtM204I/V 7.6% vs. 1.6%, P = 0.097). Our data suggested CSF is a potential HBV reservoir, and HBV in CSF harbors distinct evolution and mutation models from that in serum. HIV infection increases the possibility of HBV rtL180M and rtM204I/V mutations in both serum and CSF.

Aberrant cell-cycle progression is characteristic of melanoma, and CDK4/6 inhibitors, such as palbociclib, are currently being tested for efficacy in this disease. Despite the promising nature of CDK4/6 inhibitors, their use as single agents in melanoma has shown limited clinical benefit. Herein, we discovered that treatment of tumor cells with palbociclib induces the phosphorylation of the mRNA translation initiation factor eIF4E. When phosphorylated, eIF4E specifically engenders the translation of mRNAs that code for proteins involved in cell survival. We hypothesized that cancer cells treated with palbociclib use upregulated phosphorylated eIF4E (phospho-eIF4E) to escape the antitumor benefits of this drug. Indeed, we found that pharmacologic or genetic disruption of MNK1/2 activity, the only known kinases for eIF4E, enhanced the ability of palbociclib to decrease clonogenic outgrowth. Moreover, a quantitative proteomics analysis of melanoma cells treated with combined MNK1/2 and CDK4/6 inhibitors showed downregulation of proteins with critical roles in cell-cycle progression and mitosis, including AURKB, TPX2, and survivin. We also observed that palbociclib-resistant breast cancer cells have higher basal levels of phospho-eIF4E, and that treatment with MNK1/2 inhibitors sensitized these palbociclib-resistant cells to CDK4/6 inhibition. In vivo we demonstrate that the combination of MNK1/2 and CDK4/6 inhibition significantly increases the overall survival of mice compared with either monotherapy. Overall, our data support MNK1/2 inhibitors as promising drugs to potentiate the antineoplastic effects of palbociclib and overcome therapy-resistant disease.

Supplementary Figure 2

Supplementary Figure 3

List of differentially expressed proteins annotated by cluster with pathway analysis in BLM cells

Supplementary Figure 1

Supplementary Data from Extracellular Vesicle–Packaged CDH11 and ITGA5 Induce the Premetastatic Niche for Bone Colonization of Breast Cancer Cells

The supplementary material file provides extended data to further support that the MNK1/NODAL pathway plays a critical role in the DCIS to IDC transition, as well as information about the antibodies and statistical analyses used in this study.

The mechanisms by which breast cancers progress from relatively indolent ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) are not well understood. However, this process is critical to the acquisition of metastatic potential. MAPK-interacting serine/threonine-protein kinase 1 (MNK1) signaling can promote cell invasion. NODAL, a morphogen essential for embryogenic patterning, is often reexpressed in breast cancer. Here we describe a MNK1/NODAL signaling axis that promotes DCIS progression to IDC. We generated MNK1 knockout (KO) or constitutively active MNK1 (caMNK1)-expressing human MCF-10A–derived DCIS cell lines, which were orthotopically injected into the mammary glands of mice. Loss of MNK1 repressed NODAL expression, inhibited DCIS to IDC conversion, and decreased tumor relapse and metastasis. Conversely, caMNK1 induced NODAL expression and promoted IDC. The MNK1/NODAL axis promoted cancer stem cell properties and invasion in vitro. The MNK1/2 inhibitor SEL201 blocked DCIS progression to invasive disease in vivo. In clinical samples, IDC and DCIS with microinvasion expressed higher levels of phospho-MNK1 and NODAL versus low-grade (invasion-free) DCIS. Cumulatively, our data support further development of MNK1 inhibitors as therapeutics for preventing invasive disease.Significance:These findings provide new mechanistic insight into progression of ductal carcinoma and support clinical application of MNK1 inhibitors to delay progression of indolent ductal carcinoma in situ to invasive ductal carcinoma.

Although most breast cancer metastases in bone cause osteolytic lesions, the osteogenic niche has commonly been described as an initiator of early-stage bone colonization of disseminated cancer cells. Tumor cell–derived extracellular vesicles (EV) have been shown to determine the organotropism of cancer cells by transferring their cargo, such as nucleic acids and proteins, to resident cells at future metastatic sites and preparing a favorable premetastatic niche. Runt-related transcription factor 2 (RUNX2) and its regulated genes have been shown to facilitate the acquisition of osteomimetic features and to enhance the bone metastatic potential of breast cancer cells. In this study, we present in vivo and in vitro evidence to clarify the role of EVs released by breast cancer cells with high RUNX2 expression in the education of osteoblasts to form an osteogenic premetastatic niche. Furthermore, different extracellular vesicular proteins were identified that mediate events subsequent to the specific recognition of tumor-derived EVs by osteoblasts via cadherin 11 (CDH11) and the induction of the osteogenic premetastatic niche by integrin α5 (ITGA5). CDH11high/ITGA5high EVs were demonstrated to be responsible for the formation of a premetastatic niche that facilitates RUNX2 high-expressing breast cancer cell colonization in bone, revealing a potential EV-based premetastatic niche blockage strategy.Significance:This study provides mechanistic insights into the generation of an osteogenic premetastatic niche by breast cancer–derived EVs and identifies potential EV-derived diagnostic biomarkers and targets for breast cancer bone metastasis.

Objective: To explore the applicability of three-dimensional transvaginal ultrasonography (3D-TVS) in the evaluation of diminished ovarian reserve (DOR) and premature ovarian failure (POF). Methods: One hundred and twenty female patients, who received 3D-TVS in our hospital from January 2020 to March 2022, were included in the study. Based on sex hormone examination, 25 cases were DOR (DOR-group), 32 cases were POF (POF-group) and 63 cases had normal ovarian function (Normal-group). The 3D-TVS quantitative examination results of the three groups of patients were analyzed and compared. Results: There was no significant difference between the DOR-group and POF-group regarding antral follicles count (AFC), ovarian volume (OV), vascularization index (VI), vascularization flow index (VFI) and flow index (FI) of left and right ovaries (p>0.05). Compared with the Normal-group, the 3D-TVS examination indexes of the DOR-group and POF-group were significantly lower, and the 3D-TVS examination results of the POF-group were significantly lower than those of the DOR-group (p

Temperature variation at the nanoscale is pivotal for the thermodynamics and kinetics of small entities. Surface-enhanced Raman spectroscopy (SERS) is a promising technique for monitoring temperature variations at the nanoscale. A key but ambiguous topic is methods to design a sensitive SERS thermometer. Here, we elucidate that the type of chemical bond of molecular probes and the surface chemical bonding effect are crucial for maximizing the sensitivity of the SERS thermometer, as illustrated by the variable-temperature SERS measurements and quantum chemistry calculations for the frequency-temperature functions of a series of molecules. The sensitivity of the frequency-temperature function follows the sequence of triple bonddouble bondsingle bond, which is available for both aliphatic and aromatic molecules. The surface chemical bonding effect between the SERS substrate and molecular probe substantially increases the sensitivity of the frequency-temperature function. These results provide universally available guidelines for the rational design of a sensitive SERS thermometer by examining the functional groups of molecular probes.