Impact of therapeutic inhibition of oncogenic cell signaling tyrosine kinase on cell metabolism: in vivo-detectable metabolic biomarkers of inhibition.

BACKGROUND: Inhibition of kinases is the ever-expanding therapeutic approach to various types of cancer. Typically, assessment of the treatment response is accomplished by standard, volumetric imaging procedures, performed weeks to months after the onset of treatment, given the predominantly cytostatic nature of the kinase inhibitors, at least when used as single agents. Therefore, there is a great clinical need to develop new monitoring approaches to detect the response to kinase inhibition much more promptly. Noninvasive 1H magnetic resonance spectroscopy (MRS) can measure in vitro and in vivo concentration of key metabolites which may potentially serve as biomarkers of response to kinase inhibition. METHODS: We employed mantle cell lymphoma (MCL) cell lines demonstrating markedly diverse sensitivity of inhibition of Bruton's tyrosine kinase (BTK) regarding their growth and studied in-depth effects of the inhibition on various aspects of cell metabolism including metabolite synthesis using metabolomics, glucose and oxidative metabolism by Seahorse XF technology, and concentration of index metabolites lactate, alanine, total choline and taurine by 1H MRS. RESULTS: Effective BTK inhibition profoundly suppressed key cell metabolic pathways, foremost pyrimidine and purine synthesis, the citrate (TCA) cycle, glycolysis, and pyruvate and glutamine/alanine metabolism. It also inhibited glycolysis and amino acid-related oxidative metabolism. Finally, it profoundly and quickly decreased concentration of lactate (a product of mainly glycolysis) and alanine (an indicator of amino acid metabolism) and, less universally total choline both in vitro and in vivo, in the MCL xenotransplant model. The decrease correlated directly with the degree of inhibition of lymphoma cell expansion and tumor growth. CONCLUSIONS: Our results indicate that BTK inhibition exerts a broad and profound suppressive effect on cell metabolism and that the affected index metabolites such as lactate, alanine may serve as early, sensitive, and reliable biomarkers of inhibition in lymphoma patients detectable by noninvasive MRS-based imaging method. This kind of imaging-based detection may also be applicable to other kinase inhibitors, as well as diverse lymphoid and non-lymphoid malignancies.

Occupational exposure to silica and risk of gastrointestinal cancers: a systematic review and meta-analysis of cohort studies.

BACKGROUND: Although silica is a proven lung carcinogen, there is no convincing evidence linking crystalline silica to gastrointestinal malignancies. METHODS: We detailedly searched studies on the link between gastrointestinal malignancies and occupational silica exposure. Studies published between 1987 and 2023 were found by searching PubMed, Scopus, Cochrane Library, and Web of Science databases. Further studies were included from reference searching. We conducted a meta-analysis of the incidence and mortality of gastrointestinal malignancies and occupational silica exposure. We computed pooled-risk estimates using random effects models. Egger's regression asymmetry test and a funnel plot were used to identify publication bias. Moreover, sensitivity analysis and subgroup analysis were out. RESULTS: We identified 40 research with individuals from 13 different countries. The results indicate that occupational silica exposure raises the risk of gastric and esophageal cancer incidence, with pooled standardized incidence ratio of 1.35 (95% CI 1.21-1.51, p < 0.001), 1.31 (95% CI 1.04-1.65, p = 0.023), respectively, but there was a lack of statistically significant relationship between standardized mortality ratio. In addition, we found that silica exposure did not increase the risk of colorectal and pancreatic cancers. Occupational silica exposure was found to increase the risk of liver cancer, with pooled SIR and SMR of 1.19 (95% CI 1.04-1.35, p = 0.009), 1.24 (95% CI 1.03-1.49, p = 0.026), respectively. CONCLUSIONS: We discovered a link between occupational silica exposure and gastrointestinal malignancies, with cancers of the liver, stomach, and esophagus being the most prevalent. Colorectal and pancreatic cancer were not linked to occupational silica exposure.

Unraveling the Structure and Reactivity Patterns of the Indole Radical Cation in Regioselective Electrochemical Oxidative Annulations.

Oxidation-induced strategy for inert chemical bond activation through highly active radical cation intermediate has exhibited unique reactivity. Understanding the structure and reactivity patterns of radical cation intermediates is crucial in the mechanistic study and will be beneficial for developing new reactions. In this work, the structure and properties of indole radical cations have been revealed using time-resolved transient absorption spectroscopy, in situ electrochemical UV-vis, and in situ electrochemical electron paramagnetic resonance (EPR) technique. Density functional theory (DFT) calculations were used to explain and predict the regioselectivity of several electrochemical oxidative indole annulations. Based on the understanding of the inherent properties of several indole radical cations, two different regioselective annulations of indoles have been successfully developed under electrochemical oxidation conditions. Varieties of furo[2,3-b]indolines and furo[3,2-b]indolines were synthesized in good yields with high regioselectivities. Our mechanistic insights into indole radical cations will promote the further development of oxidation-induced indole functionalizations.

A transfer-RNA-derived small RNA regulates ribosome biogenesis.

Transfer-RNA-derived small RNAs (tsRNAs; also called tRNA-derived fragments) are an abundant class of small non-coding RNAs whose biological roles are not well understood. Here we show that inhibition of a specific tsRNA, LeuCAG3'tsRNA, induces apoptosis in rapidly dividing cells in vitro and in a patient-derived orthotopic hepatocellular carcinoma model in mice. This tsRNA binds at least two ribosomal protein mRNAs (RPS28 and RPS15) to enhance their translation. A decrease in translation of RPS28 mRNA blocks pre-18S ribosomal RNA processing, resulting in a reduction in the number of 40S ribosomal subunits. These data establish a post-transcriptional mechanism that can fine-tune gene expression during different physiological states and provide a potential new target for treating cancer.

Text Summarization Method Based on Gated Attention Graph Neural Network.

Text summarization is an information compression technology to extract important information from long text, which has become a challenging research direction in the field of natural language processing. At present, the text summary model based on deep learning has shown good results, but how to more effectively model the relationship between words, more accurately extract feature information and eliminate redundant information is still a problem of concern. This paper proposes a graph neural network model GA-GNN based on gated attention, which effectively improves the accuracy and readability of text summarization. First, the words are encoded using a concatenated sentence encoder to generate a deeper vector containing local and global semantic information. Secondly, the ability to extract key information features is improved by using gated attention units to eliminate local irrelevant information. Finally, the loss function is optimized from the three aspects of contrastive learning, confidence calculation of important sentences, and graph feature extraction to improve the robustness of the model. Experimental validation was conducted on a CNN/Daily Mail dataset and MR dataset, and the results showed that the model in this paper outperformed existing methods.

MLAM: Multi-Layer Attention Module for Radar Extrapolation Based on Spatiotemporal Sequence Neural Network.

Precipitation nowcasting is mainly achieved by the radar echo extrapolation method. Due to the timing characteristics of radar echo extrapolation, convolutional recurrent neural networks (ConvRNNs) have been used to solve the task. Most ConvRNNs have been proven to perform far better than traditional optical flow methods, but they still have fatal problems. These models lack differentiation in the prediction of echoes of different intensities, which leads to the omission of responses from regions with high intensities. Moreover, because it is difficult for these models to capture long-term feature dependencies among multiple echo maps, the extrapolation effect declines sharply over time. This paper proposes an embedded multi-layer attention module (MLAM) to address the shortcomings of ConvRNNs. Specifically, an MLAM mainly enhances attention to critical regions in echo images and the processing of long-term spatiotemporal features through the interaction between input and memory features in the current moment. Comprehensive experiments were conducted on the radar dataset HKO-7 provided by the Hong Kong Observatory and the radar dataset HMB provided by the Hunan Meteorological Bureau. Experiments show that ConvRNNs embedded with MLAMs achieve more advanced results than standard ConvRNNs.

A Laser Plane Attitude Evaluation Method for Rail Profile Measurement Sensors.

The non-coplanar lasers on both sides of the rail during full-section rail profile measurement based on line-structured light vision will cause the measured profile to be distorted, resulting in measurement errors. Currently, in the field of rail profile measurement, there are no effective methods for evaluating laser plane attitude, and it is impossible to determine the degree of laser coplanarity quantitatively and accurately. This study proposes an evaluation method based on fitting planes in response to this problem. Real-time fitting of laser planes with three planar targets of different heights provides information about the laser plane attitude on both sides of the rails. On this basis, laser coplanarity evaluation criteria were developed to determine whether the laser planes on both sides of the rails are coplanar. Using the method in this study, the laser plane attitude can be quantified and accurately assessed on both sides, effectively resolving the problem with traditional methods that can only assess the laser plane attitude qualitatively and roughly, thereby providing a solid foundation for calibration and error correction of the measurement system.

Electroreduction Enables Regioselective 1,2-Diarylation of Alkenes with Two Electrophiles.

Precisely introducing two similar functional groups into bulk chemical alkenes represents a formidable route to complex molecules. Especially, the selective activation of two electrophiles is in crucial demand, yet challenging for cross-electrophile-coupling. Herein, we demonstrate a redox-mediated electrolysis, in which aryl nitriles are both aryl radical precursors and redox-mediators, enables an intermolecular alkene 1,2-diarylation with a remarkable regioselectivity, thereby avoiding the involvement of transition-metal catalysts. This transformation utilizes cyanoarene radical anions for activating various aryl halides (including iodides, bromides, and even chlorides) and affords 1,2-diarylation adducts in up to 83 % yield and >20 : 1 regioselectivity with more than 80 examples, providing a feasible approach to complex bibenzyl derivatives.

Electrophotochemical Ce-Catalyzed Ring-Opening Functionalization of Cycloalkanols under Redox-Neutral Conditions: Scope and Mechanism.

Selective cleavage and functionalization of C-C bonds in alcohols is gaining increasing interest in organic synthesis and biomass conversion. In particular, the development of redox-neutral catalytic methods with cheap catalysts and clean energy is of utmost interest. In this work, we report a versatile redox-neutral method for the ring-opening functionalization of cycloalkanols by electrophotochemical (EPC) cerium (Ce) catalysis. The EPC-Ce-enabled catalysis allows for cycloalkanols with different ring sizes to be cleaved while tolerating a broad range of functional groups. Notably, in the presence of chloride as a counteranion and electrolyte, this protocol selectively leads to the formation of C-CN, C-C, C-S, or C-oxime bonds instead of a C-halide bond after ß-scission. A preliminary mechanistic investigation indicates that the redox-active Ce catalyst can be tuned by electro-oxidation and photo-reduction, thus avoiding the use of an external oxidant. Spectroscopic characterizations (cyclic voltammetry, UV-vis, electron paramagnetic resonance, and X-ray absorption fine structure) suggest a Ce(III)/Ce(IV) catalytic pathway for this transformation, in which a Ce(IV)-alkoxide is involved.

Time-Resolved EPR Revealed the Formation, Structure, and Reactivity of N-Centered Radicals in an Electrochemical C(sp3)-H Arylation Reaction.

Electrochemical synthesis has been rapidly developed over the past few years, while a vast majority of the reactions proceed through a radical pathway. Understanding the properties of radical intermediates is crucial in the mechanistic study of electrochemical transformations and will be beneficial for developing new reactions. Nevertheless, it is rather difficult to determine the "live" radical intermediates due to their high reactivity. In this work, the formation and structure of sulfonamide N-centered radicals have been researched directly by using the time-resolved electron paramagnetic resonance (EPR) technique under electrochemical conditions. Supported by the EPR results, the reactivity of N-centered radicals as a mediator in the hydrogen atom transfer (HAT) approach has been discussed. Subsequently, these mechanistic study results have been successfully utilized in the discovery of an unactivated C(sp3)-H arylation reaction. The kinetic experiments have revealed the rate-determined step is the anodic oxidation of sulfonamides.

Pneumoconiosis computer aided diagnosis system based on X-rays and deep learning.

PURPOSE: The objective of this study is to construct a computer aided diagnosis system for normal people and pneumoconiosis using X-raysand deep learning algorithms. MATERIALS AND METHODS: 1760 anonymous digital X-ray images of real patients between January 2017 and June 2020 were collected for this experiment. In order to concentrate the feature extraction ability of the model more on the lung region and restrain the influence of external background factors, a two-stage pipeline from coarse to fine was established. First, the U-Net model was used to extract the lung regions on each sides of the collection images. Second, the ResNet-34 model with transfer learning strategy was implemented to learn the image features extracted in the lung region to achieve accurate classification of pneumoconiosis patients and normal people. RESULTS: Among the 1760 cases collected, the accuracy and the area under curve of the classification model were 92.46% and 89% respectively. CONCLUSION: The successful application of deep learning in the diagnosis of pneumoconiosis further demonstrates the potential of medical artificial intelligence and proves the effectiveness of our proposed algorithm. However, when we further classified pneumoconiosis patients and normal subjects into four categories, we found that the overall accuracy decreased to 70.1%. We will use the CT modality in future studies to provide more details of lung regions.

A Rail Fastener Tightness Detection Approach Using Multi-source Visual Sensor.

At present, the method of two-dimensional image recognition is mainly used to detect the abnormal fastener in the rail-track inspection system. However, the too-tight-or-too-loose fastener condition may cause the clip of the fastener to break or loose due to the high frequency vibration shock, which is difficult to detect from the two-dimensional image. In this practical application background, 3D visual detection technology provides a feasible solution. In this paper, we propose a fundamental multi-source visual data detection method, as well as an accurate and robust fastener location and nut or bolt segmentation algorithm. By combining two-dimensional intensity information and three-dimensional depth information generated by the projection of line structural light, the locating of nut or bolt position and accurate perception of height information can be realized in the dynamic running environment of railway. The experimental results show that the static measurement accuracy in the vertical direction using the structural light vision sensor is 0.1 mm under the laboratory condition, and the dynamic measurement accuracy is 0.5 mm under the dynamic train running environment. We use dynamic template matching algorithm to locate fasteners from 2D intensity map, which achieves 99.4% accuracy, then use the watershed algorithm to segment the nut and bolt from the corresponding depth image of located fastener. Finally, the 3D shape of the nut and bolt is analyzed to determine whether the nut or bolt height meets the local statistical threshold requirements, so as to detect the hidden danger of railway transportation caused by too loose or too tight fasteners.

Amine-Responsive Disassembly of AuI -CuI Double Salts for Oxidative Carbonylation.

A sensitive amine-responsive disassembly of self-assembled AuI -CuI double salts was observed and its utilization for the synergistic catalysis was enlightened. Investigation of the disassembly of [Au(NHC)2 ][CuI2 ] revealed the contribution of Cu-assisted ligand exchange of N-heterocyclic carbene (NHC) by amine in [Au(NHC)2 ]+ and the capacity of [CuI2 ]- on the oxidative step. By integrating the implicative information coded in the responsive behavior and inherent catalytic functions of d10 metal complexes, a catalyst for the oxidative carbonylation of amines was developed. The advantages of this method were clearly reflected on mild reaction conditions and the significantly expanded scope (51 examples); both primary and steric secondary amines can be employed as substrates. The cooperative reactivity from Au and Cu centers, as an indispensable prerequisite for the excellent catalytic performance, was validated in the synthesis of (un)symmetric ureas and carbamates.

miR-26a promotes hepatocellular carcinoma invasion and metastasis by inhibiting PTEN and inhibits cell growth by repressing EZH2.

A previous study revealed that therapeutic miR-26a delivery suppresses tumorigenesis in a murine liver cancer model, whereas we found that forced miR-26a expression increased hepatocellular carcinoma (HCC) cell migration and invasion, which prompted us to characterize the causes and mechanisms underlying enhanced invasion due to ectopic miR-26a expression. Gain-of-function and loss-of-function experiments demonstrated that miR-26a promoted migration and invasion of BEL-7402 and HepG2 cells in vitro and positively modulated matrix metalloproteinase (MMP)-1, MMP-2, MMP-9, and MMP-10 expression. In addition, exogenous miR-26a expression significantly enhanced the metastatic ability of HepG2 cells in vivo. miR-26a negatively regulated in vitro proliferation of HCC cells, and miR-26a overexpression suppressed HepG2 cell tumor growth in nude mice. Further studies revealed that miR-26a inhibited cell growth by repressing the methyltransferase EZH2 and promoted cell migration and invasion by inhibiting the phosphatase PTEN. Furthermore, PTEN expression negatively correlated with miR-26a expression in HCC specimens from patients with and without metastasis. Thus, our findings suggest for the first time that miR-26a promotes invasion/metastasis by inhibiting PTEN and inhibits cell proliferation by repressing EZH2 in HCC. More importantly, our data also suggest caution if miR-26a is used as a target for cancer therapy in the future.

MiR-155 Enhances Insulin Sensitivity by Coordinated Regulation of Multiple Genes in Mice.

miR-155 plays critical roles in numerous physiological and pathological processes, however, its function in the regulation of blood glucose homeostasis and insulin sensitivity and underlying mechanisms remain unknown. Here, we reveal that miR-155 levels are downregulated in serum from type 2 diabetes (T2D) patients, suggesting that miR-155 might be involved in blood glucose control and diabetes. Gain-of-function and loss-of-function studies in mice demonstrate that miR-155 has no effects on the pancreatic ß-cell proliferation and function. Global transgenic overexpression of miR-155 in mice leads to hypoglycaemia, improved glucose tolerance and insulin sensitivity. Conversely, miR-155 deficiency in mice causes hyperglycemia, impaired glucose tolerance and insulin resistance. In addition, consistent with a positive regulatory role of miR-155 in glucose metabolism, miR-155 positively modulates glucose uptake in all cell types examined, while mice overexpressing miR-155 transgene show enhanced glycolysis, and insulin-stimulated AKT and IRS-1 phosphorylation in liver, adipose tissue or skeletal muscle. Furthermore, we reveal these aforementioned phenomena occur, at least partially, through miR-155-mediated repression of important negative regulators (i.e. C/EBPß, HDAC4 and SOCS1) of insulin signaling. Taken together, these findings demonstrate, for the first time, that miR-155 is a positive regulator of insulin sensitivity with potential applications for diabetes treatment.

Electrochemical Arylation of Electron-Deficient Arenes through Reductive Activation.

An electrochemical method has been developed to achieve arylation of electron-deficient arenes through reductive activation. Various electron-deficient arenes and aryldiazonium tetrafluoroborates are amenable to this transformation within the conditions of an undivided cell, providing the desired products in up to 92 % yield. Instead of preparing diazonium reagents, these reactions can begin from anilines, and they can be carried out in one pot. Electron paramagnetic resonance studies indicate that cathodic reduction of quinoxaline occurs using the transformation. Moreover, cyclic voltammetry indicates that both quinoxaline and aryl diazonium salt have relatively low reduction potentials, which suggests they can be activated through reduction during the reaction.

MicroRNA-19 triggers epithelial-mesenchymal transition of lung cancer cells accompanied by growth inhibition.

The miR-19 family (miR-19a and miR-19b-1) are key oncogenic components of the miR-17-92 cluster. Overexpression of miR-19 is strongly associated with cancer invasion and metastasis, and poor prognosis of cancer patients. However, the underlying mechanisms remain largely unknown. In the present study, we found that enforced expression of miR-19 including miR-19a and miR-19b-1 triggered epithelial-mesenchymal transition (EMT) of lung cancer cells A549 and HCC827 as shown by mesenchymal-like morphological conversion, downregulation of epithelial proteins (e.g., E-cadherin, ZO-1 (zona occludens 1), and α-catenin), upregulation of mesenchymal proteins (e.g., vimentin, fibronectin 1, N-cadherin, and snail1), formation of stress fibers, and reduced cell adhesion. In addition, enhanced migration and invasion were observed in the cancer cells A549 and HCC827 undergoing EMT. In contrast, silencing of endogenous miR-19 reversed EMT and reduced the migration and invasion abilities of A549 and HCC827 cells. DNA microarray results revealed significant changes of the expression of genes related to EMT, migration, and metastasis of miR-19-expressing A549 cells. Moreover, siRNA-mediated knockdown of PTEN, a target of miR-19, also resulted in EMT, migration, and invasion of A549 and HCC827 cells, suggesting that PTEN is involved in miR-19-induced EMT, migration and invasion of lung cancer cells. Furthermore, lung cancer cells undergoing EMT induced by miR-19 demonstrated reduced proliferation in vitro and in vivo, and enhanced resistance to apoptosis caused by TNF-α. Taken together, these findings suggest that miR-19 triggers EMT, which has an important role in the invasion and migration of lung cancer cells, accompanied by the reduced proliferation of cells.

Synthesis and antiproliferative activity of pterostilbene and 3'-methoxy pterostilbene Mannich base derivatives against Hela cells.

Fourteen novel pterostilbene (1) and [Formula: see text]-methoxy pterostilbene (2) Mannich base derivatives (3-16) were synthesized via the microwave-assisted Mannich reaction of 1 or 2 with various secondary amines and formaldehyde. The regioselectivity of the reaction occurred preferentially at [Formula: see text] position of the B-ring of stilbene. The biological testing results showed that all the target compounds exhibit antiproliferative activity against Hela cells from [Formula: see text]-[Formula: see text]. Compounds 1-3, 7, 11-13, and 16 displayed higher (lower [Formula: see text] values) activity than the positive control cisplatin [Formula: see text].

Hemiarthroplasty vs. internal fixation for nondisplaced femoral neck fracture in mainland China: a cost-effectiveness analysis.

Objective: Nondisplaced femoral neck fractures constitute a substantial portion of these injuries. The optimal treatment strategy between internal fixation (IF) and hemiarthroplasty (HA) remains debated, particularly concerning cost-effectiveness. Methods: We conducted a cost-effectiveness analysis using a Markov decision model to compare HA and IF in treating nondisplaced femoral neck fractures in elderly patients in China. The analysis was performed from a payer perspective with a 5-year time horizon. Costs were measured in 2020 USD, and effectiveness was measured in quality-adjusted life-years (QALYs). Sensitivity analyses, including one-way and probabilistic analyses, were conducted to assess the robustness of the results. The willingness-to-pay threshold for incremental cost-effectiveness ratio (ICER) was set at $11,083/QALY following the Chinese gross domestic product in 2020. Results: HA demonstrated higher cumulative QALYs (2.94) compared to IF (2.75) but at a higher total cost ($13,324 vs. $12,167), resulting in an ICER of $6,128.52/QALY. The one-way sensitivity analysis identified the costs of HA and IF as the most influential factors. Probabilistic sensitivity analysis indicated that HA was more effective in 69.3% of simulations, with an ICER below the willingness-to-pay threshold of $11,083 in 58.8% of simulations. Conclusions: HA is a cost-effective alternative to IF for treating nondisplaced femoral neck fractures in elderly patients in mainland China.

Para-selective nitrobenzene amination lead by C(sp2)-H/N-H oxidative cross-coupling through aminyl radical.

Arylamines, serving as crucial building blocks in natural products and finding applications in multifunctional materials, are synthesized on a large scale via an electrophilic nitration/reduction sequence. However, the current methods for aromatic C-H amination have not yet attained the same level of versatility as electrophilic nitration. Here we show an extensively investigated transition metal-free and regioselective strategy for the amination of nitrobenzenes, enabling the synthesis of 4-nitro-N-arylamines through C(sp2)-H/N-H cross-coupling between electron-deficient nitroarenes and amines. Mechanistic studies have elucidated that the crucial aspects of these reactions encompass the generation of nitrogen radicals and recombination of nitrobenzene complex radicals. The C(sp2)-N bond formation is demonstrated to be highly effective for primary and secondary arylamines as well as aliphatic amines under mild conditions, exhibiting exceptional tolerance towards diverse functional groups in both nitroarenes and amines (>100 examples with yields up to 96%). Notably, this C(sp2)-H/N-H cross-coupling exhibits exclusive para-selectivity.