Dual-Specificity Phosphatase 4 Promotes Malignant Features in Colorectal Cancer Through Cyclic-AMP Response Element Binding Protein/Protein Kinase CAMP-Activated Catalytic Subunit Beta Activation.

INTRODUCTION: Previous studies have demonstrated that Dual-specificity phosphatase 4 (DUSP4) plays an important role in the progression of different tumor types. However, the role and mechanism of DUSP4 in colorectal cancer (CRC) remain unclear. AIMS: We investigate the role and mechanisms of DUSP4 in CRC. METHODS: Immunohistochemistry was used to investigate DUSP4 expression in CRC tissues. Cell proliferation, apoptosis and migration assays were used to validate DUSP4 function in vitro and in vivo. RNA-sequence assay was used to identify the target genes of DUSP4. Human phosphokinase array and inhibitor assays were used to explore the downstream signaling of DUSP4. RESULTS: DUSP4 expression was upregulated in CRC tissues relative to normal colorectal tissues, and DUSP4 expression showed a significant positive correlation with CRC stage. Consistently, we found that DUSP4 was highly expressed in colorectal cancer cells compared to normal cells. DUSP4 knockdown inhibits CRC cell proliferation, migration and promotes apoptosis. Furthermore, the ectopic expression of DUSP4 enhanced CRC cell proliferation, migration and diminished apoptosis in vitro and in vivo. Human phosphokinase array data showed that ectopic expression of DUSP4 promotes CREB activation. RNA-sequencing data showed that PRKACB acts as a downstream target gene of DUSP4/CREB and enhances CREB activation through PKA/cAMP signaling. In addition, xenograft model results demonstrated that DUSP4 promotes colorectal tumor progression via PRKACB/CREB activation in vivo. CONCLUSION: These findings suggest that DUSP4 promotes CRC progression. Therefore, it may be a promising therapeutic target for CRC.

Temporal-spatial deciphering mental subtraction in the human brain.

Mental subtraction, involving numerical processing and operation, requires a complex interplay among several brain regions. Diverse studies have utilized scalp electroencephalograph, electrocorticogram, or functional magnetic resonance imaging to resolve the structure pattern and functional activity during subtraction operation. However, a high resolution of the spatial-temporal understanding of the neural mechanisms involved in mental subtraction is unavailable. Thus, this study obtained intracranial stereoelectroencephalography recordings from 20 patients with pharmacologically resistant epilepsy. Specifically, two sample-delayed mismatch paradigms of numeric comparison and subtracting results comparison were used to help reveal the time frame of mental subtraction. The brain sub-regions were chronologically screened using the stereoelectroencephalography recording for mental subtraction. The results indicated that the anterior cortex, containing the frontal, insular, and parahippocampous, worked for preparing for mental subtraction; moreover, the posterior cortex, such as parietal, occipital, limbic, and temporal regions, cooperated during subtraction. Especially, the gamma band activities in core regions within the parietal-cingulate-temporal cortices mediated the critical mental subtraction. Overall, this research is the first to describe the spatiotemporal activities underlying mental subtraction in the human brain. It provides a comprehensive insight into the cognitive control activity underlying mental arithmetic. Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-023-09937-z.

Radioactive hybrid semiconducting polymer nanoparticles for imaging-guided tri-modal therapy of breast cancer.

Due to the rapid progression and aggressive metastasis of breast cancer, its diagnosis and treatment remain a great challenge. The simultaneous inhibition of tumor growth and metastasis is necessary for breast cancer to obtain ideal therapeutic outcomes. We herein report the development of radioactive hybrid semiconducting polymer nanoparticles (SPNH) for imaging-guided tri-modal therapy of breast cancer. Two semiconducting polymers are used to form SPNH with a diameter of around 60 nm via nano-coprecipitation and they are also labeled with iodine-131 (131I) to enhance the imaging functions. The formed SPNH show good radiolabeling stability and excellent photodynamic and photothermal effects under 808 nm laser irradiation to produce singlet oxygen (1O2) and heat. Moreover, SPNH can generate 1O2 with ultrasound irradiation via their sonodynamic properties. After intravenous tail vein injection, SPNH can effectively accumulate in the subcutaneous 4T1 tumors of living mice as verified via fluorescence and single photon emission computed tomography (SPECT) imaging. With the irradiation of tumors using an 808 nm laser and US, SPNH mediate photodynamic therapy (PDT), photothermal therapy (PTT) and sonodynamic therapy (SDT) to kill tumor cells. Such a tri-modal therapy leads to an improved efficacy in inhibiting tumor growth and suppressing tumor metastasis compared to the sole SDT and combinational PDT-PTT. This study thus demonstrates the applications of SPNH to diagnose tumors and combine different therapies for effective breast cancer treatment.

Spatial and Temporal Patterns of Disease Burden attributable to High Body Mass Index in Belt and Road Initiative Countries, 1990-2019.

OBJECTIVE: This study aimed to analyze the spatial and temporal patterns of disease burden attributed to high body mass index (DB-hBMI) from 1990 to 2019 in Belt and Road Initiative (BRI) countries, in light of increasing hBMI prevalence worldwide. DESIGN: The study was a secondary analysis of global burden of disease 2019 (GBD 2019) that analyzed (using Joinpoint regression analysis) numbers and the age-standardized rate of mortality and disability-adjusted life years (DALYs) of hBMI-induced diseases and their trends from 1990 to 2019 and in the final decade. SETTING: GBD 2019 study data for BRI countries were categorized by country, age, gender, and disease. PARTICIPANTS: GBD 2019 data were used to analyze DB-hBMI in BRI countries. RESULTS: In 2019, China, India, and Russia reported the highest mortality and DALYs among BRI countries. From 1990 to 2019, the age-standardized DALYs increased in Southeast Asia and South Asia, whereas many European countries saw declines. Notably, Bangladesh, Nepal, and Vietnam showed the steepest increases, with AAPC values of 4.42%, 4.19%, and 4.28%, respectively (all P<0.05). In contrast, Israel, Slovenia, and Poland experienced significant reductions, with APCC values of -1.70%, -1.63%, and -1.58%, respectively (all P<0.05). The most rapid increases among males were seen in Vietnam, Nepal, and Bangladesh, while Jordan, Poland, and Slovenia recorded the fastest declines among females. Across most BRI countries, the burden of diabetes and kidney diseases related to hBMI showed a significant uptrend. CONCLUSION: DB-hBMI varies significantly by region, age, gender, and disease type across BRI countries. It can pose a substantial threat to public health.

A portable transistor immunosensor for fast identification of porcine epidemic diarrhea virus.

Widespread distribution of porcine epidemic diarrhea virus (PEDV) has led to catastrophic losses to the global pig farming industry. As a result, there is an urgent need for rapid, sensitive and accurate tests for PEDV to enable timely and effective interventions. In the present study, we develop and validate a floating gate carbon nanotubes field-effect transistor (FG CNT-FET)-based portable immunosensor for rapid identification of PEDV in a sensitive and accurate manner. To improve the affinity, a unique PEDV spike protein-specific monoclonal antibody is prepared by purification, and subsequently modified on FG CNT-FET sensor to recognize PEDV. The developed FET biosensor enables highly sensitive detection (LoD: 8.1 fg/mL and 100.14 TCID50/mL for recombinant spike proteins and PEDV, respectively), as well as satisfactory specificity. Notably, an integrated portable platform consisting of a pluggable FG CNT-FET chip and a portable device can discriminate PEDV positive from negative samples and even identify PEDV and porcine deltacoronavirus within 1 min with 100% accuracy. The portable sensing platform offers the capability to quickly, sensitively and accurately identify PEDV, which further points to a possibility of point of care (POC) applications of large-scale surveillance in pig breeding facilities.

Longitudinal ultrasound-based AI model predicts axillary lymph node response to neoadjuvant chemotherapy in breast cancer: a multicenter study.

OBJECTIVES: Developing a deep learning radiomics model from longitudinal breast ultrasound and sonographer's axillary ultrasound diagnosis for predicting axillary lymph node (ALN) response to neoadjuvant chemotherapy (NAC) in breast cancer. METHODS: Breast cancer patients undergoing NAC followed by surgery were recruited from three centers between November 2016 and December 2022. We collected ultrasound images for extracting tumor-derived radiomics and deep learning features, selecting quantitative features through various methods. Two machine learning models based on random forest were developed using pre-NAC and post-NAC features. A support vector machine integrated these data into a fusion model, evaluated via the area under the curve (AUC), decision curve analysis, and calibration curves. We compared the fusion model's performance against sonographer's diagnosis from pre-NAC and post-NAC axillary ultrasonography, referencing histological outcomes from sentinel lymph node biopsy or axillary lymph node dissection. RESULTS: In the validation cohort, the fusion model outperformed both pre-NAC (AUC: 0.899 vs. 0.786, p < 0.001) and post-NAC models (AUC: 0.899 vs. 0.853, p = 0.014), as well as the sonographer's diagnosis of ALN status on pre-NAC and post-NAC axillary ultrasonography (AUC: 0.899 vs. 0.719, p < 0.001). Decision curve analysis revealed patient benefits from the fusion model across threshold probabilities from 0.02 to 0.98. The model also enhanced sonographer's diagnostic ability, increasing accuracy from 71.9% to 79.2%. CONCLUSION: The deep learning radiomics model accurately predicted the ALN response to NAC in breast cancer. Furthermore, the model will assist sonographers to improve their diagnostic ability on ALN status before surgery. CLINICAL RELEVANCE STATEMENT: Our AI model based on pre- and post-neoadjuvant chemotherapy ultrasound can accurately predict axillary lymph node metastasis and assist sonographer's axillary diagnosis. KEY POINTS: Axillary lymph node metastasis status affects the choice of surgical treatment, and currently relies on subjective ultrasound. Our AI model outperformed sonographer's visual diagnosis on axillary ultrasound. Our deep learning radiomics model can improve sonographers' diagnosis and might assist in surgical decision-making.

Discovery of new tricyclic spiroindole derivatives as potent P-glycoprotein inhibitors for reversing multidrug resistance enabled by a synthetic methodology-based library.

The discovery of novel and highly effective P-gp inhibitors is considered to be an effective strategy for overcoming tumor drug resistance. In this paper, a phenotypic screening via a self-constructed synthetic methodology-based library identified a new class of tricyclic spiroindole derivatives with excellent tumor multidrug resistance reversal activity. A stereospecific compound OY-103-B with the best reversal activity was obtained based on a detailed structure-activity relationship study, metabolic stability optimization and chiral resolution. For the VCR-resistant Eca109 cell line (Eca109/VCR), co-administration of 5.0 µM OY-103-B resulted in a reversal fold of up to 727.2, superior to the typical third-generation P-gp inhibitor tariquidar. Moreover, the compound inhibited the proliferation of Eca109/VCR cells in a concentration-dependent manner in plate cloning and flow cytometry. Furthermore, fluorescence substrate accumulation assay and chemotherapeutic drug reversal activity tests demonstrated that OY-103-B reversed tumor drug resistance via P-gp inhibition. In conclusion, this study provides a novel skeleton that inspires the design of new P-gp inhibitors, laying the foundation for the treatment of drug-resistant tumors.

Oncogenic functions and therapeutic potentials of targeted inhibition of SMARCAL1 in small cell lung cancer.

Small cell lung cancer (SCLC) is a recalcitrant cancer characterized by high frequency loss-of-function mutations in tumor suppressors with a lack of targeted therapy due to absence of high frequency gain-of-function abnormalities in oncogenes. SMARCAL1 is a member of the ATP-dependent chromatin remodeling protein SNF2 family that plays critical roles in DNA damage repair and genome stability maintenance. Here, we showed that SMARCAL1 was overexpressed in SCLC patient samples and was inversely associated with overall survival of the patients. SMARCAL1 was required for SCLC cell proliferation and genome integrity. Mass spectrometry revealed that PAR6B was a downstream SMARCAL1 signal molecule which rescued inhibitory effects caused by silencing of SMARCAL1. By screening of 36 FDA-approved clinically available agents related to DNA damage repair, we found that an aza-anthracenedione, pixantrone, was a potent SMARCAL1 inhibitor which suppressed the expression of SMARCAL1 and PAR6B at protein level. Pixantrone caused DNA damage and exhibited inhibitory effects on SCLC cells in vitro and in a patient-derived xenograft mouse model. These results indicated that SMARCAL1 functions as an oncogene in SCLC, and pixantrone as a SMARCAL1 inhibitor bears therapeutic potentials in this deadly disease.

RETFound-enhanced community-based fundus disease screening: real-world evidence and decision curve analysis.

Visual impairments and blindness are major public health concerns globally. Effective eye disease screening aided by artificial intelligence (AI) is a promising countermeasure, although it is challenged by practical constraints such as poor image quality in community screening. The recently developed ophthalmic foundation model RETFound has shown higher accuracy in retinal image recognition tasks. This study developed an RETFound-enhanced deep learning (DL) model for multiple-eye disease screening using real-world images from community screenings. Our results revealed that our DL model improved the sensitivity and specificity by over 15% compared with commercial models. Our model also shows better generalisation ability than AI models developed using traditional processes. Additionally, decision curve analysis underscores the higher net benefit of employing our model in both urban and rural settings in China. These findings indicate that the RETFound-enhanced DL model can achieve a higher net benefit in community-based screening, advocating its adoption in low- and middle-income countries to address global eye health challenges.

Achieving a Deeply Desodiated Stabilized Cathode Material by the High Entropy Strategy for Sodium-ion Batteries.

Manganese-based layered oxides are currently of significant interest as cathode materials for sodium-ion batteries due to their low toxicity and high specific capacity. However, the practical applications are impeded by sluggish intrinsic Na+ migration and poor structure stability as a result of Jahn-Teller distortion and complicated phase transition. In this study, a high-entropy strategy is proposed to enhance the high-voltage capacity and cycling stability. The designed P2-Na0.67Mn0.6Cu0.08Ni0.09Fe0.18Ti0.05O2 achieves a deeply desodiation and delivers charging capacity of 158.1 mA h g-1 corresponding to 0.61 Na with a high initial Coulombic efficiency of 98.2%. The charge compensation is attributed to the cationic and anionic redox reactions conjunctively. Moreover, the crystal structure is effectively stabilized, leading to a slight variation of lattice parameters. This research carries implications for the expedited development of low-cost, high-energy-density cathode materials for sodium-ion batteries.

Paroxysmal sympathetic hyperexcitability after brain injury: A clinical analysis of case series.

BACKGROUND: Paroxysmal sympathetic hyperexcitability (PSH) is a group of complex syndromes with various etiologies. Previous studies were limited to the description of traumatic brain injury (TBI), and the description of PSH after other types of brain injury was rare. We explored the clinical features, treatment, and prognosis of PSH after various types of brain injuries. METHODS: Patients admitted to the neurosurgery intensive care unit with PSH after brain injury from July 2019 to December 2022 were included. Demographic data, clinical manifestations, drug therapy, and disease prognosis were retrospectively collected and analyzed. RESULTS: Fifteen male and 9 female patients with PSH after brain injury were selected. TBI was most likely to cause PSH (66.7%), followed by spontaneous intracerebral hemorrhage (25%). Glasgow coma scale scores of 19 patients (79.2%) were lower than 8 and 14 patients (58.3%) underwent tracheotomy. Electroencephalogram monitoring was performed in 12 individuals, none of which showed epileptic waves. Clinical symptom scale showed mild symptoms in 17 cases (70.8%). Almost all patients were administered a combination of drugs. After follow-up, most patients had a poor prognosis and 2 (8.3%) died after discharge. CONCLUSION: The etiology of PSH is complex. TBI may be the most common cause of PSH. Non-TBI may also be an important cause of PSH. Therefore, early identification, prevention and diagnosis are helpful for determining the prognosis and outcome of the disease.

CCT6A facilitates lung adenocarcinoma progression and glycolysis via STAT1/HK2 axis.

BACKGROUND: Chaperonin Containing TCP1 Subunit 6 A (CCT6A) is a prominent protein involved in the folding and stabilization of newly synthesized proteins. However, its roles and underlying mechanisms in lung adenocarcinoma (LUAD), one of the most aggressive cancers, remain elusive. METHODS: Our study utilized in vitro cell phenotype experiments to assess CCT6A's impact on the proliferation and invasion capabilities of LUAD cell lines. To delve into CCT6A's intrinsic mechanisms affecting glycolysis and proliferation in lung adenocarcinoma, we employed transcriptomic sequencing and liquid chromatography-mass spectrometry analysis. Co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation (CHIP) assays were also conducted to substantiate the mechanism. RESULTS: CCT6A was found to be significantly overexpressed in LUAD and associated with a poorer prognosis. The silencing of CCT6A inhibited the proliferation and migration of LUAD cells and elevated apoptosis rates. Mechanistically, CCT6A interacted with STAT1 protein, forming a complex that enhances the stability of STAT1 by protecting it from ubiquitin-mediated degradation. This, in turn, facilitated the transcription of hexokinase 2 (HK2), a critical enzyme in aerobic glycolysis, thereby stimulating LUAD's aerobic glycolysis and progression. CONCLUSION: Our findings reveal that the CCT6A/STAT1/HK2 axis orchestrated a reprogramming of glucose metabolism and thus promoted LUAD progression. These insights position CCT6A as a promising candidate for therapeutic intervention in LUAD treatment.

Narrative Review and Consensus Recommendations for the Use of Transnasal Humidified Rapid-Insufflation Ventilatory Exchange in Modified Electroconvulsive Therapy.

Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) is a safe, effective, and novel technique that is currently being used in electroconvulsive therapy (ECT). This study aimed to summarize the clinical practices of THRIVE use in ECT to aid physicians and institutions in implementing the best practice guidelines for ECT. Thus, we reviewed the current literature and presented our consensus on the application of THRIVE in ECT in daily clinical practice. This consensus provides information regarding THRIVE use in ECT, including its safety, effectiveness, procedures, precautions, special case management, and application in special populations. Moreover, it guides the standardized use of THRIVE in ECT.

Rapid Detection of Bacterial Resistance to ß-Lactam Antibiotics with a Relay-Response Chemiluminescence Assay.

Bacterial resistance caused by ß-lactamases has been a major threat to public health around the world, seriously weakening the efficacy of ß-lactam antibiotics, the most widely used therapeutic agents against infectious diseases. To detect the bacterial resistance to ß-lactam antibiotics, particularly specific type of ß-lactam antibiotics, in a rapid manner, we report herein a relay-response chemiluminescence assay. This assay mainly consists of two reagents: a ß-lactam-caged thiophenol and a thiophenol-sensitive chemiluminescence reporter, both of which are synthetically feasible. The selective hydrolysis of ß-lactam by ß-lactamase leads to the releasing of free thiophenol, which then triggers the emission of a chemiluminescence signal in a relay manner. Three thiophenol-caged ß-lactams, structural analogues of cephalothin, cefotaxime, and meropenem, respectively, have been synthesized. And the application of this assay with these analogues of ß-lactam antibiotics allows fast detection of ß-lactamase-expressing resistant bacteria and, more impressively, provides detailed information on the resistant scope of bacteria.

Magicking an oxyhalide interface for 4.8 V-tolerant high-nickel cathodes in all-solid-state lithium-ion batteries.

All-solid-state lithium batteries (ASSBs) have received increasing attentions as one promising candidate for the next-generation energy storage devices. Among various solid electrolytes, sulfide-based ASSBs combined with layered oxide cathodes have emerged due to the high energy density and safety performance, even at high-voltage conditions. However, the interface compatibility issues remain to be solved at the interface between the oxide cathode and sulfide electrolyte. To circumvent this issue, we propose a simple but effective approach to magic the adverse surface alkali into a uniform oxyhalide coating on LiNi0.8Co0.1Mn0.1O2 (NCM811) via a controllable gas-solid reaction. Due to the enhancement of the close contact at interface, the ASSBs exhibit improved kinetic performance across a broad temperature range, especially at the freezing point. Besides, owing to the high-voltage tolerance of the protective layer, ASSBs demonstrate excellent cyclic stability under high cutoff voltages (500 cycles ~ 94.0% at 4.5 V, 200 cycles ~ 80.4% at 4.8 V). This work provides insights into using a high voltage stable oxyhalide coating strategy to enhance the development of high energy density ASSBs.

Cortistatin protects against septic cardiomyopathy by inhibiting cardiomyocyte pyroptosis through the SSTR2-AMPK-NLRP3 pathway.

BACKGROUND: Although the pathophysiological mechanism of septic cardiomyopathy has been continuously discovered, it is still a lack of effective treatment method. Cortistatin (CST), a neuroendocrine polypeptide of the somatostatin family, has emerged as a novel cardiovascular-protective peptide, but the specific mechanism has not been elucidated. PURPOSE: The aim of our study is to explore the role of CST in cardiomyocytes pyroptosis and myocardial injury in sepsis and whether CST inhibits cardiomyocytes pyroptosis through specific binding with somastatin receptor 2 (SSTR2) and activating AMPK/Drp1 signaling pathway. METHODS AND RESULTS: In this study, plasma CST levels were significantly high and were negatively correlated with N-terminal pro-B type natriuretic peptide (NT-proBNP), a biomarker for cardiac dysfunction, in patients with sepsis. Exogenous administration of CST significantly improved survival rate and cardiac function in mouse models of sepsis by inhibiting the activation of the NLRP3 inflammasome and pyroptosis of cardiomyocytes (decreased cleavage of caspase-1, IL-1ß and gasdermin D). Pharmacological inhibition and genetic ablation revealed that CST exerted anti-pyroptosis effects by specifically binding to somatostatin receptor subtype 2 (SSTR2), thus activating AMPK and inactivating Drp1 to inhibit mitochondrial fission in cardiomyocytes. CONCLUSIONS: This study is the first to report that CST attenuates septic cardiomyopathy by inhibiting cardiomyocyte pyroptosis through the SSTR2-AMPK-Drp1-NLRP3 pathway. Importantly, CST specifically binds to SSTR2, which promotes AMPK phosphorylation, inhibits Drp1-mediated mitochondrial fission, and reduces ROS levels, thereby inhibiting NLRP3 inflammasome activation-mediated pyroptosis and alleviating sepsis-induced myocardial injury.