Predicting Alzheimer's progression in MCI: a DTI-based white matter network model.

OBJECTIVE: This study aimed to identify features of white matter network attributes based on diffusion tensor imaging (DTI) that might lead to progression from mild cognitive impairment (MCI) and construct a comprehensive model based on these features for predicting the population at high risk of progression to Alzheimer's disease (AD) in MCI patients. METHODS: This study enrolled 121 MCI patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Among them, 36 progressed to AD after four years of follow-up. A brain network was constructed for each patient based on white matter fiber tracts, and network attribute features were extracted. White matter network features were downscaled, and white matter markers were constructed using an integrated downscaling approach, followed by forming an integrated model with clinical features and performance evaluation. RESULTS: APOE4 and ADAS scores were used as independent predictors and combined with white matter network markers to construct a comprehensive model. The diagnostic efficacy of the comprehensive model was 0.924 and 0.919, sensitivity was 0.864 and 0.900, and specificity was 0.871 and 0.815 in the training and test groups, respectively. The Delong test showed significant differences (P < 0.05) in the diagnostic efficacy of the combined model and APOE4 and ADAS scores, while there was no significant difference (P > 0.05) between the combined model and white matter network biomarkers. CONCLUSIONS: A comprehensive model constructed based on white matter network markers can identify MCI patients at high risk of progression to AD and provide an adjunct biomarker helpful in early AD detection.

Short-term Outcomes of Transcatheter Aortic Valve Replacement in Low-risk Patients with Pure Severe Aortic Regurgitation.

Transcatheter aortic valve replacement (TAVR) has emerged as an alternative treatment for patients with pure severe aortic regurgitation (PSAR) who are contraindicated for surgery or have a high surgical risk. However, the therapeutic efficacy and safety of TAVR in low Society of Thoracic Surgeons score (STS) risk patients remain to be clarified. This study aimed to explore the feasibility of TAVR treatment in different STS risk patients and to compare the adverse events between the groups. In this study, patients with PSAR who underwent TAVR at Zhongshan Hospital, Fudan University, China, during the inclusion period were included and categorized into three groups based on STS scores. The baseline data, imaging results, and follow-up data of the patients were documented. As a result, out of 75 TAVR patients, 38 (50.7%) patients were categorized as low risk (STS<4) and 37 (49.3%) patients were categorized as intermediate- and high-risk (STS≥4). Compared with patients at intermediate- and high-risk, those in the low-risk group were younger, had a lower body mass index, had a lower prevalence of hypertension, chronic obstructive pulmonary disease, and prior PCI and had better cardiac function (p all < 0.05). In the hospital and at the 1-month follow-up, the degree of AR and cardiac function were significantly improved. No significant difference was found between the two groups in the hospital or during the 30-day follow-up. In conclusion: TAVR for PSAR in low STS risk patients is safe and efficient during 30 days of follow-up compared with intermediate and high STS risk groups. TAVR for PSAR should not be limited to inoperable or STS-defined high-risk patients. Long-term follow-up is needed for further investigation.

Prognostic impact of sodium fluorescein-guided microsurgery on cognitive function, neuropeptide dynamics, and short-term outcomes in brain glioma patients.

This study conducted a retrospective analysis on 107 brain glioma patients treated from January 2018 to February 2020 to assess the impact of sodium fluorescein-guided microsurgery on postoperative cognitive function and short-term outcomes. Patients were divided into two groups: a control group (n=50 patients) undergoing routine surgery and a research group (n=57 patients) receiving sodium fluorescein-guided microsurgery. The study compared postoperative total resection rates, changes in cognitive scores, and neuropeptide levels in cerebrospinal fluid between the groups. The findings revealed that the research group experienced shorter surgical time and hospitalization duration, reduced blood loss, and higher total resection rates compared to the control group. Furthermore, the research group demonstrated improvements in cognitive scores and an increase in neuropeptide levels after surgery. There was no significant difference in the comparison of the incidence of postoperative complications between the two groups. The WHO classification and preoperative performance scores were independent prognostic factors for the evaluation of 3-year survival, highlighting the clinical significance of sodium fluorescein-guided microsurgery in improving quality of life and cognitive functions of patients without compromising their long-term survival outcomes.

Development of a mobile, high-throughput, and low-cost image-based plant growth phenotyping system.

Nondestructive plant phenotyping forms a key technique for unraveling molecular processes underlying plant development and response to the environment. While the emergence of high-throughput phenotyping facilities can further our understanding of plant development and stress responses, their high costs greatly hinder scientific progress. To democratize high-throughput plant phenotyping, we developed sets of low-cost image- and weight-based devices to monitor plant shoot growth and evapotranspiration. We paired these devices to a suite of computational pipelines for integrated and straightforward data analysis. The developed tools were validated for their suitability for large genetic screens by evaluating a cowpea (Vigna unguiculata) diversity panel for responses to drought stress. The observed natural variation was used as an input for a genome-wide association study, from which we identified nine genetic loci that might contribute to cowpea drought resilience during early vegetative development. The homologs of the candidate genes were identified in Arabidopsis (Arabidopsis thaliana) and subsequently evaluated for their involvement in drought stress by using available T-DNA insertion mutant lines. These results demonstrate the varied applicability of this low-cost phenotyping system. In the future, we foresee these setups facilitating the identification of genetic components of growth, plant architecture, and stress tolerance across a wide variety of plant species.

Risk of cardiovascular death in patients with hepatocellular carcinoma based on the Fine-Gray model.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common types of cancers worldwide, ranking fifth among men and seventh among women, resulting in more than 7 million deaths annually. With the development of medical technology, the 5-year survival rate of HCC patients can be increased to 70%. However, HCC patients are often at increased risk of cardiovascular disease (CVD) death due to exposure to potentially cardiotoxic treatments compared with non-HCC patients. Moreover, CVD and cancer have become major disease burdens worldwide. Thus, further research is needed to lessen the risk of CVD death in HCC patient survivors. AIM: To determine the independent risk factors for CVD death in HCC patients and predict cardiovascular mortality (CVM) in HCC patients. METHODS: This study was conducted on the basis of the Surveillance, Epidemiology, and End Results database and included HCC patients with a diagnosis period from 2010 to 2015. The independent risk factors were identified using the Fine-Gray model. A nomograph was constructed to predict the CVM in HCC patients. The nomograph performance was measured using Harrell's concordance index (C-index), calibration curve, receiver operating characteristic (ROC) curve, and area under the ROC curve (AUC) value. Moreover, the net benefit was estimated via decision curve analysis (DCA). RESULTS: The study included 21545 HCC patients, of whom 619 died of CVD. Age (< 60) [1.981 (1.573-2.496), P < 0.001], marital status (married) [unmarried: 1.370 (1.076-1.745), P = 0.011], alpha fetoprotein (normal) [0.778 (0.640-0.946), P = 0.012], tumor size (≤ 2 cm) [(2, 5] cm: 1.420 (1.060-1.903), P = 0.019; > 5 cm: 2.090 (1.543-2.830), P < 0.001], surgery (no) [0.376 (0.297-0.476), P < 0.001], and chemotherapy(none/unknown) [0.578 (0.472-0.709), P < 0.001] were independent risk factors for CVD death in HCC patients. The discrimination and calibration of the nomograph were better. The C-index values for the training and validation sets were 0.736 and 0.665, respectively. The AUC values of the ROC curves at 2, 4, and 6 years were 0.702, 0.725, 0.740 in the training set and 0.697, 0.710, 0.744 in the validation set, respectively. The calibration curves showed that the predicted probabilities of the CVM prediction model in the training set vs the validation set were largely consistent with the actual probabilities. DCA demonstrated that the prediction model has a high net benefit. CONCLUSION: Risk factors for CVD death in HCC patients were investigated for the first time. The nomograph served as an important reference tool for relevant clinical management decisions.

Fatigue Affects Body Acceleration During Vertical Jumping and Agility Tasks in Elite Young Badminton Players.

BACKGROUND: Badminton is a sport demanding both high aerobic and anaerobic fitness levels, and fatigue can significantly impact game performance. However, relevant studies are limited, and none have employed a wearable inertial measurement unit (IMU) to investigate the effects of fatigue on athletic performance in the field. HYPOTHESIS: Overall performance and body acceleration in both time and frequency domains during the fundamental badminton skills of vertical jumping and changes of direction will be affected by fatigue. STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: Level 3. METHODS: A total of 38 young badminton players competing at the Division I level participated. Body accelerations while performing vertical jump and agility-T tests before and immediately after undergoing a fatigue protocol were measured by an IMU, positioned at the L4 to L5 level. RESULTS: Jumping height decreased significantly by 4 cm (P < 0.01) after fatigue with greater downward acceleration (1.03 m/s2, P < 0.05) during the squatting subphase. Finishing time increased significantly by 50 ms only during the 10-m side-shuffling of the agility-T test (P = 0.02) after fatigue with greater peak and mean accelerations (3.83 m/s2, P = 0.04; 0.43 m/s2, P < 0.01), and higher median and mean frequency (0.38 Hz, P = 0.04, 0.11 Hz, P = 0.01). CONCLUSION: This study using a wearable IMU demonstrates the effects of fatigue on body acceleration in badminton players. The frequency-domain analysis further indicated that fatigue might lead to loss of voluntary control of active muscles and increased impacts on the passive elastic elements. CLINICAL RELEVANCE: The findings imply that fatigue can lead to diminished athletic performance and highlight the potential for an increased risk of sports injuries. Consequently, maintaining precision in monitoring fatigue is crucial for elite young badminton players.

A comprehensive exploration of twist1 to identify a biomarker for tumor immunity and prognosis in pan-cancer.

Twist1 has been identified as a critical gene in tumor, but current study of this gene remains limitative. This study aims to investigate its roles and potential mechanisms across pan-cancer. The study used various databases and computational techniques to analyze twist's RNA expression, clinical data, gene mutations, tumor stemness, tumor microenvironment, immune regulation. Furthermore, the experimental method of fluorescence staining was carried out to identify twist1 expression in various tumor masses. After analyzing the protein-protein interaction of TWIST, enrichment analysis and predictive potential drugs were performed, and molecular docking was conducted to validate. We found that twist1 expression was significantly higher in various types of cancer and associated with tumor stage, grade, and poor prognosis in multiple cancers. Differential expression of twist1 was linked to gene mutation, RNA modifications, and tumor stemness. Additionally, twist1 expression was positively associated with tumor immunoregulation and immune checkpoint. Salinomycin, klugline, isocephaelince, manassantin B, and pimonidazole are predictive potential drugs targeting TWIST1. This study revealed that twist1 plays an important role in tumor, and might be a curial marker in tumor diagnose and prognosis. The study also highlighted twist1 as a promising therapeutic target for cancer treatment and provided a foundation for future research.

Effects of Aging Treatment on the Microstructures and Mechanical Properties of a TC18 Alloy.

In the present work, the effects of aging treatment on the microstructures of a TC18 alloy are studied. The influence of aging treatment on the tensile properties and failure mechanisms is systematically analyzed. It is found that the size and morphology of the primary α (αp) phases are insensitive to aging temperature and time. Furthermore, the aging temperature and time dramatically influence the precipitation of the secondary α (αs) phases. Massive αs phases precipitate and gradually coarsen, and finally weave together by increasing the aging temperature or extending the aging time. The variations in αp and αs phases induced by aging parameters also affect the mechanical properties. Both yield strength (YS) and ultimate tensile strength (UTS) first increase and then decrease by increasing the aging temperature and time, while ductility first decreases and then increases. There is an excellent balance between the strengths and ductility. When the aging temperature is changed from 450 to 550 °C, YS varies from 1238.6 to 1381.6 MPa, UTS varies from 1363.2 to 1516.8 MPa, and the moderate elongation ranges from 9.0% to 10.3%. These results reveal that the thickness of αs phases is responsible for material strengths, while the content of α phases can enhance material ductility. The ductile characteristics of the alloy with coarser αs phases are more obvious than those with thinner αs phases. Therefore, the aging treatment is helpful for the precipitation and homogeneous distribution of αs phases, which are essential for balancing the strengths and ductility of the studied Ti alloy.

MulStack: An ensemble learning prediction model of multilabel mRNA subcellular localization.

Subcellular localization of mRNA is related to protein synthesis, cell polarity, cell movement and other biological regulation mechanisms. The distribution of mRNAs in subcellulars is similar to that of proteins, and most mRNAs are distributed in multiple subcellulars. Recently, some computational methods have been designed to predict the subcellular localization of mRNA. However, these methods only employed a sin-gle level of mRNA features and did not employ the position encoding of nucleotides in mRNA. In this paper, an ensemble learning prediction model is proposed, named MulStack, which is based on random forest and deep learning for multilabel mRNA subcellular localization. The proposed method employs two levels of mRNA features, including sequence-level and residue-level features, and position encoding is employed for the first time in the field of subcellular localization of mRNA. Random forest is employed to learn mRNA sequence-level feature, deep learning is employed to learn mRNA sequence-level feature and mRNA residue-level combined with position encoding. And the outputs of random forest and deep learning model will be weighted sum as the prediction probability. Compared with existing methods, the results show that MulStack is the best in the localization of the nucleus, cytosol and exosome. In addition, position weight matrices (PWMs) are extracted by convolutional neural networks (CNNs) that can be matched with known RNA binding protein motifs. Gene ontology (GO) enrichment analysis shows biological processes, molecular functions and cellular components of mRNA genes. The prediction web server of MulStack is freely accessible at http://bliulab.net/MulStack.

Ursolic acid molecules dock MAPK1 to modulate gut microbiota diversity to reduce neuropathic pain.

To investigate the efficacy of Ursolic acid in alleviating neuropathic pain in rats with spinal nerve ligation (SNL), the SNL rat model was surgically induced. Different concentrations of Ursolic acid and manipulated target mitogen-activated protein kinase 1 (MAPK1) were administered to the SNL rats. Fecal samples were collected from each group of rats for 16S rDNA analysis to examine the impact of gut microbiota. Molecular docking experiments were conducted to assess the binding energy between Ursolic acid and MAPK1. In vivo studies were carried out to evaluate the expression of inflammatory factors and signaling pathways in spinal cord and colon tissues. Ursolic acid was found to have a beneficial effect on pain reduction in rats by increasing plantar withdrawal latency (PWL) and paw withdrawal threshold (PWT). Comparing the Ursolic acid group with the control group revealed notable differences in the distribution of Staphylococcus, Allobaculum, Clostridium, Blautia, Bifidobacterium, and Prevotella species. Network pharmacology analysis identified MAPK1 and intercellular adhesion molecule-1 (ICAM1) as common targets for Ursolic acid, SNL, and neuropathic pain. Binding sites between Ursolic acid and these targets were identified. Additionally, immunofluorescent staining showed a decrease in GFAP and IBA1 intensity in the spinal cord along with an increase in NeuN following Ursolic acid treatment. Overexpression of MAPK1 in SNL rats led to an increase in inflammatory factors and a decrease in PWL and PWT. Furthermore, MAPK1 counteracted the pain-relieving effects of Ursolic acid in SNL rats. Ursolic acid was found to alleviate neuropathic pain in SNL rats by targeting MAPK1 and influencing gut microbiota homeostasis.

Co-doped NiFe carbonate hydroxide hydrate nanosheets with edge effect constructed from spent lithium-ion battery ternary cathodes for oxygen evolution reaction.

The recycling of spent lithium-ion batteries (LIBs) has received increasing attention for environment and resource reclamation. Converting LIBs wastes into high-efficiency catalysts is a win-win strategy for realizing resource reclamation and addressing sustainable energy challenges. Herein, we developed a simple method to upcycle spent-LIBs cathode powder into Co-doped NiFe carbonate hydroxide hydrate (Co/NFCH-FF) as a low-cost and efficient oxygen evolution reaction (OER) electrocatalyst. The optimized Co/NFCH-FF electrode appears very competitive OER performances with low overpotentials of 201 and 249 mV at 10 and 100 mA cm-2, respectively, a small Tafel slope of 48.4 mV dec-1, and a high long-term stability. Moreover, we reveal that the existence of Co atoms leads to the formation of a crystalline/amorphous (c/a) interface at the Co/NFCH nanosheet edge, inducing the nanosheets possess a unique edge effect to enhance electric fields and accumulate hydroxide ions (OH-) at the edge during the OER process. Benefiting from edge effect, Co/NFCH-FF shows outstanding intrinsic activity. Furthermore, Co atoms as dopants stabilize the electronic structure of Co/NFCH-FF, enabling Co/NFCH-FF to exhibit excellent catalytic stability. This work provides an effective strategy for converting the end-life LIBs to high-performance multicomponent OER electrocatalysts and proposes new insights into the mechanism of enhanced catalytic activity of Co/NFCH.

Efficiency and mechanism of enhanced norfloxacin removal using amorphous TiO2-modified biochar.

Inadequate treatment of antibiotic-contaminated wastewater, including compounds such as norfloxacin (NOR), poses a substantial treat to both ecological safety and human well-being. An innovative approach was devised to address NOR pollution using amorphous TiO2 modified biochar (A-TiO2/BC) prepared via sol-gel impregnation. The resultant had a commendably specific surface area of 131.8 m2/g-1, which was 1.91 times more than the original surface area of unmodified BC. A-TiO2/BC also exhibited abundant hydroxyl and oxygen-containing functional groups, thereby provided adequately active sites for NOR adsorption. R2 values obtained from NOR isotherm adsorption models descended in order of Freundlich < Temkin < Sips < Langmuir, which indicated that the NOR removal by A-TiO2/BC mainly complied with monolayer adsorption accompanied by heterogeneous surface adsorption. Under weakly acidic conditions, NOR adsorption benefits from the synergistic physicochemical interactions of A-TiO2 and BC. Notably, A-TiO2/BC demonstrated an impressive NOR adsorption capacity of up to 78.14 mg g-1, with a dosage of 20 mg L-1 at 25 °C under pH 6. Such A-TiO2 modified biochar thus presents a promising alternative for NOR removal.

Activation of the Photosensitive Potential of 2D GaSe by Interfacial Engineering.

Two-dimensional (2D) gallium selenide (GaSe) holds great promise for pioneering advancements in photodetection due to its exceptional electronic and optoelectronic properties. However, in conventional photodetectors, 2D GaSe only functions as a photosensitive layer, failing to fully exploit its inherent photosensitive potential. Herein, we propose an ultrasensitive photodetector based on out-of-plane 2D GaSe/MoSe2 heterostructure. Through interfacial engineering, 2D GaSe serves not only as the photosensitive layer but also as the photoconductive gain and passivation layer, introducing a photogating effect and extending the lifetime of photocarriers. Capitalizing on these features, the device exhibits exceptional photodetection performance, including a responsivity of 28 800 A/W, specific detectivity of 7.1 × 1014 Jones, light on/off ratio of 1.2 × 106, and rise/fall time of 112.4/426.8 µs. Moreover, high-resolution imaging under various wavelengths is successfully demonstrated using this device. Additionally, we showcase the generality of this device design by activating the photosensitive potential of 2D GaSe with other transition metal dichalcogenides (TMDCs) such as WSe2, WS2, and MoS2. This work provides inspiration for future development in high-performance photodetectors, shining a spotlight on the potential of 2D GaSe and its heterostructure.

Relationship between bleeding sites and clinical data: experience of 646 epistaxis cases in 8 years.

PURPOSE: This study aims to investigate the bleeding sites and their relationship with clinical characteristics in hospitalized epistaxis patients. METHODS: We retrospectively reviewed the data of 646 hospitalized epistaxis patients. RESULTS: The bleeding sites were identified in 395 (61.1%) patients and unidentified in 251 (38.9%). We found that age > 50 years (P = 0.030) and the history of cardiovascular diseases (P = 0.027) were more frequent in patients with unidentified bleeding sites. Among patients with identified sites, inferior meatus (n = 130, 32.9%) was the most common site, followed by the septal surface of the olfactory region (n = 102, 25.8%), nasal septum (n = 80, 20.3%), middle meatus (n = 60, 15.2%), and others (n = 23, 5.8%). After dividing patients into five groups by the area of the bleeding sites, we found significant differences in age (P = 0.026), history of hypertension (P = 0.001), cardiovascular diseases (P = 0.032), and nasal packing (P = 0.011). The logistic regression also revealed that these four factors were predictors for different bleeding sites. CONCLUSION: The bleeding sites can be identified in most epistaxis patients. Age > 50 years and the history of cardiovascular diseases are more frequent in patients with unidentified bleeding sites. In our patients, the most common bleeding site is inferior meatus, followed by the septal surface of the olfactory region, nasal septum, and middle meatus. Age, histories of hypertension, cardiovascular diseases, and nasal packing are factors associated with the bleeding risks of different bleeding sites. According to the different clinical characteristics of patients, the order of the nasal endoscopic examination should be adjusted to develop their treatment plans.

Expression of immune related genes and possible regulatory mechanisms in different stages of non-alcoholic fatty liver disease.

Background: Non-alcoholic fatty liver disease (NAFLD), which includes simple steatosis (SS) and non-alcoholic steatohepatitis (NASH), is a significant contributor to liver disease on a global scale. The change of immunity-related genes (IRGs) expression level leads to different immune infiltrations. However, the expression of IRGs and possible regulatory mechanisms involved in NAFLD remain unclear. The objective of our research is to investigate crucial genes linked to the development of NAFLD and the transition from SS to NASH. Methods: Dataset GSE89632, which includes healthy controls, SS patients, and NASH patients, was obtained using the GEO database. To examine the correlation between sets of genes and clinical characteristics, we employed weighted gene co-expression network analysis (WGCNA) and differential expression analysis. Hub genes were extracted using a network of protein-protein interactions (PPI) and three different machine learning algorithms. To validate the findings, another dataset that is publicly accessible and mice that were subjected to a high-fat diet (HFD) or MCD diet were utilized. Furthermore, the ESTIMATE algorithm and ssGSEA were employed to investigate the immune landscape in the normal versus SS group and SS versus NASH group, additionally, the relationship between immune infiltration and the expression of hub genes was also examined. Results: A total of 28 immune related key genes were selected. Most of these genes expressed reverse patterns in the initial and progressive stages of NAFLD. GO and KEGG analyses showed that they were focused on the cytokine related pathways and immune cell activation and chemotaxis. After screening by various algorithms, we obtained two hub genes, including JUN and CCL20. Validation of these findings was confirmed by analyzing gene expression patterns in both the validation dataset and the mouse model. Ultimately, two hub genes were discovered to have a significant correlation with the infiltration of immune cells. Conclusion: We proposed that there were dynamic changes in the expression levels of IRGs in different stages of NAFLD disease, which led to different immune landscapes in SS and NASH. The findings of our research could serve as a guide for the accurate management of various phases of NAFLD.

The Molecular Profile of Soil Microbial Communities Inhabiting a Cambrian Host Rock.

The process of soil genesis unfolds as pioneering microbial communities colonize mineral substrates, enriching them with biomolecules released from bedrock. The resultant intricate surface units emerge from a complex interplay among microbiota and plant communities. Under these conditions, host rocks undergo initial weathering through microbial activity, rendering them far from pristine and challenging the quest for biomarkers in ancient sedimentary rocks. In addressing this challenge, a comprehensive analysis utilizing Gas Chromatography Mass Spectrometry (GC-MS) and Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) was conducted on a 520-Ma-old Cambrian rock. This investigation revealed a diverse molecular assemblage with comprising alkanols, sterols, fatty acids, glycerolipids, wax esters, and nitrogen-bearing compounds. Notably, elevated levels of bacterial C16, C18 and C14 fatty acids, iso and anteiso methyl-branched fatty acids, as well as fungal sterols, long-chained fatty acids, and alcohols, consistently align with a consortium of bacteria and fungi accessing complex organic matter within a soil-type ecosystem. The prominence of bacterial and fungal lipids alongside maturity indicators denotes derivation from heterotrophic activity rather than ancient preservation or marine sources. Moreover, the identification of long-chain (>C22) n-alkanols, even-carbon-numbered long chain (>C20) fatty acids, and campesterol, as well as stigmastanol, provides confirmation of plant residue inputs. Furthermore, findings highlight the ability of contemporary soil microbiota to inhabit rocky substrates actively, requiring strict contamination controls when evaluating ancient molecular biosignatures or extraterrestrial materials collected.

A nanomedicine composed of polymer-ss-DOX and polymer-Ce6 prodrugs with monoclonal antibody targeting effect for anti-tumor chemo-photodynamic synergetic therapy.

Anticancer drugs used for systemic chemotherapy often exhibit off-target toxicity and uncontrolled drug release due to their lack of targeting. To improve the bioavailability of drugs and reduce side effects, we have developed a mixed micelle of nanomedicine composed of two prodrugs with surface modified monoclonal antibody for cancer therapy. In this system, Nimotuzumab was used as targeting ligands of the mixed micelles (named as DCMMs) that is composed of polymer-doxorubicin prodrug (abbreviated as PEG-b-P(GMA-ss-DOX)) and maleimide polyethylene glycol-chlorin e6 (abbreviated as Mal-PEG-Ce6). The mixed micelles modified with Nimotuzumab (named as NTZ-DCMMs) bind to overexpressed EGFR receptors on Hepatoma-22 (H22) cells. Disulfide bonds in PEG-b-P(GMA-ss-DOX) are disrupted in tumor microenvironment, inducing the reduction-responsive release of DOX and leading to tumor cell apoptosis. Simultaneously, Chlorin e6 (Ce6) produced plenty of singlet oxygen (1O2) under laser irradiation to kill tumor cells. In vivo biological distribution and antineoplastic effect experiments demonstrate that NTZ-DCMMs enhanced drug enrichment at tumor sites through targeting function of antibody, dramatically suppressing tumor growth and mitigating cardiotoxicity of drugs. All results prove that NTZ-DCMMs have the ability to actively target H22 cells and quickly respond to tumor microenvironment, which is expected to become an intelligent and multifunctional drug delivery carrier for efficient chemotherapy and photodynamic therapy of hepatoma. STATEMENT OF SIGNIFICANCE: Anticancer drugs used for systemic chemotherapy often exhibit off-target toxicity due to their lack of targeting. Therefore, it's necessary to develop effective, targeted, and collaborative treatment strategies. We construct a mixed micelle of nanomedicine based on two polymer prodrugs and modified with monoclonal antibody on surface for cancer therapy. Under the tumor cell microenvironment, the disulfide bonds of polymer-ss-DOX were broken, effectively triggering DOX release. The photosensitizer Ce6 could generate a large amount of ROS under light, which synergistically promotes tumor cell apoptosis. By coupling antibodies to the hydrophilic segments of polymer micelles, drugs can be specifically delivered. Compared with monotherapy, the combination of chemotherapy and photodynamic therapy can significantly enhance the therapeutic effect of liver cancer.

Telocinobufagin, a PLK1 suppressor that inhibits tumor growth and metastasis by modulating CDC25c and CTCF in HNSCC cells.

BACKGROUND: The high metastasis and mortality rates of head and neck squamous cell carcinoma (HNSCC) urgently require new treatment targets and drugs. A steroidal component of ChanSu, telocinobufagin (TBG), was verified to have anti-cancer effects in various tumors, but its activity and mechanism in anti-HNSCC were still unknown. PURPOSE: This study tried to demonstrate the anti-tumor effect of TBG on HNSCC and verify its potential mechanism. METHODS: The effect of TBG on cell proliferation and metastasis were performed and the TBG changed genes were detected by RNA-seq analysis in HNSCC cells. The GSEA and PPI analysis were used to identify the pathways targeted for TBG-regulated genes. Meanwhile, the mechanism of TBG on anti-proliferative and anti-metastasis were investigated in vitro and in vivo. RESULTS: The in vitro and in vivo experiments confirmed that TBG has favorable anti-tumor effects by induced G2/M phase arrest and suppressed metastasis in HNSCC cells. Further RNA-seq analysis demonstrated the genes regulated by TBG were enriched at the G2/M checkpoint and PLK1 signaling pathway. Then, the bioinformatic analysis of clinical data found that high expressed PLK1 were closely associated with poor overall survival in HNSCC patients. Furthermore, PLK1 directly and indirectly modulated G2/M phase and metastasis (by regulated CTCF) in HNSCC cells, simultaneously. TBG significantly inhibited the protein levels of PLK1 in both phosphorylated and non-phosphorylated forms and then, in one way, inactivated PLK1 failed to activate G2/M phase-related proteins (including CDK1, CDC25c, and cyclin B1). In another way, be inhibited PLK1 unable promote the nuclear translocation of CTCF and thus suppressed HNSC cell metastasis. In contrast, the anti-proliferative and anti-metastasis effects of TBG on HNSCC cell were vanished when cells high-expressed PLK1. CONCLUSION: The present study verified that PLK1 mediated TBG induced anti-tumor effect by modulated G2/M phase and metastasis in HNSCC cells.

A theoretical model for predicting the startup performance of pumps as turbines.

Using the unsteady Bernoulli equation for the piping system and the angular momentum equation for the rotor, derives here a theoretical model to predict the startup performance of a pump as turbine (PAT). This model is effective for predicting the instantaneous evolution characteristics of the main performance parameters of PAT during startup, and these changings are initially faster and then slowly as a whole. The effect of the rotor moment of inertia and the final stabilized rotational speed of PAT on evolution characteristics of parameters is opposite. The rotational speed, head, hydraulic power, and conversion efficiency show a upward rising trend with the startup time, whereas the flow rate and hydraulic head loss display a downward trend.

Anti-ENO1 antibody combined with metformin against tumor resistance: a novel antibody-based platform.

Background: Antibody-based platforms (i.e., ADC) have emerged as one of the most encouraging tools for the cancer resistance caused by cancer stem cells (CSCs) enrichment. Our study might provide a promising therapeutic direction against drug resistance and serve as a potential precursor platform for screening ADC. Methods: The cell migration, invasion, drug resistance, and self-renewal were assessed by the cell invasion and migration assay, wound healing assay, CCK-8 assay, colony formation assay, and sphere formation assay, respectively. The expression profiles of CSCs (ALDH+ and CD44+) subpopulations were screened by flow cytometry. The western blot and cell immunofluorescence assay were used to evaluate pathway-related protein expression in both anti-ENO1 antibody, MET combined with DPP/CTX-treated CSCs. Results: In the present study, western blot and flow cytometry verified that anti-ENO1 antibody target the CD44+ subpopulation by inhibiting the PI3K/AKT pathway, while metformin might target the ALDH+ subpopulation through activation of the AMPK pathway and thus reverse drug resistance to varying degrees. Subsequently, in vitro investigation indicated that anti-ENO1 antibody, metformin combined with cisplatin/cetuximab could simultaneously target ALDH+ and CD44+ subpopulations. The combination also inhibited the CSCs proliferation, migration, invasion, and sphere formation; which may result in overcoming the drug resistance. Then, molecular mechanism exploration verified that the anti-ENO1 antibody, metformin combined with cisplatin/cetuximab inhibited the Wnt/ß-catenin signaling. Conclusions: The study preliminarily revealed anti-ENO1 antibody combined with metformin could overcome drug resistance against CSCs by inhibiting the Wnt//ß-catenin pathway and might serve as a potential precursor platform for screening ADC. More importantly, it is reasonably believed that antibody-based drug combination therapy might function as an encouraging tool for oncotherapy.