GCclassifier: An R package for the prediction of molecular subtypes of gastric cancer.

Gastric cancer (GC) is one of the most commonly diagnosed malignancies, threatening millions of lives worldwide each year. Importantly, GC is a heterogeneous disease, posing a significant challenge to the selection of patients for more optimized therapy. Over the last decades, extensive community effort has been spent on dissecting the heterogeneity of GC, leading to the identification of distinct molecular subtypes that are clinically relevant. However, so far, no tool is publicly available for GC subtype prediction, hindering the research into GC subtype-specific biological mechanisms, the design of novel targeted agents, and potential clinical applications. To address the unmet need, we developed an R package GCclassifier for predicting GC molecular subtypes based on gene expression profiles. To facilitate the use by non-bioinformaticians, we also provide an interactive, user-friendly web server implementing the major functionalities of GCclassifier. The predictive performance of GCclassifier was demonstrated using case studies on multiple independent datasets.

Ethylenediamine Salt Enhances the Solubility and Dissolution of Flurbiprofen.

Drugs that are poorly soluble in water are difficult to absorb orally, resulting in low bioavailability. Flurbiprofen (FLU) is an arylpropionic acid nonsteroidal anti-inflammatory drug belonging to BCS class II, with low water solubility. In this study, a novel flurbiprofen-ethylenediamine salt (FLU-EDA) was successfully prepared via solvent crystallization. Its crystal structure was determined via single-crystal X-ray diffraction (SXRD). Further, the physicochemical properties of FLU-EDA salt were characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FT-IR). The solubility and intrinsic dissolution rate (IDR) of FLU-EDA salt in water were investigated. The results showed that compared with FLU, the solubility and IDR of FLU-EDA salt increased by 57-fold and 32-fold, respectively. This indicates that FLU-EDA salt can significantly enhance the solubility and dissolution rate of flurbiprofen in water. This study provides basic data and theory for the development of new formulations of flurbiprofen.

Hydrophilic Cocrystals with Water Switched Luminescence.

Utilizing water molecules to regulate the luminescence properties of solid materials is highly challenging. Herein, we develop a strategy to produce water-triggered luminescence-switching cocrystals by coassembling hydrophilic donors with electron-deficient acceptors, where 1,2,4,5-Tetracyanobenzene (TCNB) was used as the electron acceptor and pyridyl benzimidazole derivatives were used as the electron donors enabling multiple hydrogen-bonds. Two cocrystals, namely 2PYTC and 4PYTC were obtained and showed heat-activated emission, and such emission could be quenched or weakened by adding water molecules. The cocrystal structure exhibited the donor molecule that can form multiple hydro bonds with water and acceptor molecules due to the many nitrogen atoms of them. The analyses of the photophysical data, powder X-ray diffraction, and other data confirmed the reversible fluorescence "on-off" effects were caused by eliminating and adding water molecules in the crystal lattice. The density functional theory calculations indicate that the vibration of the O-H bond of water molecules in the cocrystal can absorb the excitation energy and suppress fluorescence. Furthermore, the obtained cocrystals also showed temperature, humidity, and H+ /NH4 + responsive emission behavior, which allows their applications as thermal and humidity sensors, and multiple information encryptions. This research paves the way for preparing intelligent hydrophilic organic cocrystal luminescent materials.

Emerging role of radiogenomics in genetically triggered thoracic aortic aneurysm and dissection: a narrative review.

Background and Objective: Thoracic aortic aneurysm and dissection (TAAD) and its complications are life-threatening conditions. Hypertension and atherosclerosis had all along been recognized as the predominant risk factors for the development of TAAD. However, it was increasingly reported that genetic factors, such as single nucleotide polymorphisms (SNPs), are playing an important role in the disease development. The development of next-generation sequencing (NGS) and the rapid growth in radiomics provide a promising new platform to evaluate genetically triggered thoracic aortic aneurysm and dissection (GTAAD) from a new angle. This review is to present an overview of currently available knowledge regarding the use of radiomics and radiogenomics in GTAAD. Methods: We performed literature searches in PubMed, EMBASE and Cochrane database from 2012 to 2022 regarding the use of radiomics and radiogenomics in GTAAD. Key Content and Findings: There were only 13 studies on radiomics and 4 studies on radiogenomics integration retrieved from the search and it signifies there is still a significant knowledge gap in this field of translational medicine. An overview of the current knowledge of GTAAD, the workflow and role of radiomics, the radiogenomics integration for GTAAD including its potential role in the development of polygenic scores, as well as the implications, challenges, and limitations of radiogenomics research were discussed. Conclusions: In the contemporary era, radiogenomics has been emerging as a state-of-the art approach to establish statistical correlation with radiomics features with genomic information in diagnosis, risk modeling and prediction and treatment decision in TAAD.

Deep learning-derived spatial organization features on histology images predicts prognosis in colorectal liver metastasis patients after hepatectomy.

Histopathological images of colorectal liver metastases (CRLM) contain rich morphometric information that may predict patients' outcomes. However, to our knowledge, no study has reported any practical deep learning framework based on the histology images of CRLM, and their direct association with prognosis remains largely unknown. In this study, we developed a deep learning-based framework for fully automated tissue classification and quantification of clinically relevant spatial organization features (SOFs) in H&E-stained images of CRLM. The SOFs based risk-scoring system demonstrated a strong and robust prognostic value that is independent of the current clinical risk score (CRS) system in independent clinical cohorts. Our framework enables fully automated tissue classification of H&E images of CRLM, which could significantly reduce assessment subjectivity and the workload of pathologists. The risk-scoring system provides a time- and cost-efficient tool to assist clinical decision-making for patients with CRLM, which could potentially be implemented in clinical practice.

Optical Control of Protein Functions via Genetically Encoded Photocaged Aspartic Acids.

Site-specific protein decaging by light has become an effective approach for in situ manipulation of protein activities in a gain-of-function fashion. Although successful decaging of amino acid side chains of Lys, Tyr, Cys, and Glu has been demonstrated, this strategy has not been extended to aspartic acid (Asp), an essential amino acid residue with a range of protein functions and protein-protein interactions. We herein reported a genetically encoded photocaged Asp and applied it to the photocontrolled manipulation of a panel of proteins including firefly luciferase, kinases (e.g., BRAF), and GTPase (e.g., KRAS) as well as mimicking the in situ phosphorylation event on kinases. As a new member of the increasingly expanded amino acid-decaging toolbox, photocaged Asp may find broad applications for gain-of-function study of diverse proteins as well as biological processes in living cells.

Type II Transmembrane Serine Proteases as Modulators in Adipose Tissue Phenotype and Function.

Adipose tissue is a crucial organ in energy metabolism and thermoregulation. Adipose tissue phenotype is controlled by various signaling mechanisms under pathophysiological conditions. Type II transmembrane serine proteases (TTSPs) are a group of trypsin-like enzymes anchoring on the cell surface. These proteases act in diverse tissues to regulate physiological processes, such as food digestion, salt-water balance, iron metabolism, epithelial integrity, and auditory nerve development. More recently, several members of the TTSP family, namely, hepsin, matriptase-2, and corin, have been shown to play a role in regulating lipid metabolism, adipose tissue phenotype, and thermogenesis, via direct growth factor activation or indirect hormonal mechanisms. In mice, hepsin deficiency increases adipose browning and protects from high-fat diet-induced hyperglycemia, hyperlipidemia, and obesity. Similarly, matriptase-2 deficiency increases fat lipolysis and reduces obesity and hepatic steatosis in high-fat diet-fed mice. In contrast, corin deficiency increases white adipose weights and cell sizes, suppresses adipocyte browning and thermogenic responses, and causes cold intolerance in mice. These findings highlight an important role of TTSPs in modifying cellular phenotype and function in adipose tissue. In this review, we provide a brief description about TTSPs and discuss recent findings regarding the role of hepsin, matriptase-2, and corin in regulating adipose tissue phenotype, energy metabolism, and thermogenic responses.

Hydrogen-bond induced and hetero coupling dual effects in N-doped carbon coated CrN/Ni nanosheets for efficient alkaline freshwater/seawater hydrogen evolution.

Developing efficient and robust non-precious-metal-based hydrogen evolution reaction (HER) catalysts is highly desirable but remains quite challenging for alkaline freshwater/seawater electrolysis. In the present study, we report a theory-guided design and synthesis of a nickel foam (NF) supported N-doped carbon-coated (NC) nickel (Ni)/chromium nitride (CrN) nanosheets (NC@CrN/Ni) as a highly active and durable electrocatalyst. Our theoretical calculation firstly reveals that CrN/Ni heterostructure can greatly promote the H2O dissociation via hydrogen-bond induced effect, and the N site can be optimized by hetero coupling to achieve a facile hydrogen associative desorption, thereby significantly boosting alkaline HER. Guided by theoretical calculation, we prepared the nickel-based metal-organic framework as a precursor, and introduced the Cr by the subsequent hydrothermal treatment, finally obtained the target catalyst by ammonia pyrolysis. Such a simple process ensures the exposure of abundant accessible active sites. Consequently, the as-prepared NC@CrN/Ni catalyst exhibits outstanding performance in both alkaline freshwater and seawater, with the respective overpotential of only 24 and 28 mV at a current density of 10 mA cm-2, respectively. More impressively, the catalyst also possesses superior durability in the constant-current test of 50 h at the different current densities of 10, 100, and 1000 mA cm-2.

Renal Corin Is Essential for Normal Blood Pressure and Sodium Homeostasis.

Atrial natriuretic peptide (ANP)-mediated natriuresis is known as a cardiac endocrine function in sodium and body fluid homeostasis. Corin is a protease essential for ANP activation. Here, we studied the role of renal corin in regulating salt excretion and blood pressure. We created corin conditional knockout (cKO), in which the Corin gene was selectively disrupted in the kidney (kcKO) or heart (hcKO). We examined the blood pressure, urinary Na+ and Cl- excretion, and cardiac hypertrophy in wild-type, corin global KO, kcKO, and hcKO mice fed normal- and high-salt diets. We found that on a normal-salt diet (0.3% NaCl), corin kcKO and hcKO mice had increased blood pressure, indicating that both renal and cardiac corin is necessary for normal blood pressure in mice. On a high-salt diet (4% NaCl), reduced urinary Na+ and Cl- excretion, increased body weight, salt-exacerbated hypertension, and cardiac hypertrophy were observed in corin kcKO mice. In contrast, impaired urinary Na+ and Cl- excretion and salt-exacerbated hypertension were not observed in corin hcKO mice. These results indicated that renal corin function is important in enhancing natriuresis upon high salt intakes and that this function cannot be compensated by the cardiac corin function in mice.

Corin Deficiency Alters Adipose Tissue Phenotype and Impairs Thermogenesis in Mice.

Atrial natriuretic peptide (ANP) is a key regulator in body fluid balance and cardiovascular biology. In addition to its role in enhancing natriuresis and vasodilation, ANP increases lipolysis and thermogenesis in adipose tissue. Corin is a protease responsible for ANP activation. It remains unknown if corin has a role in regulating adipose tissue function. Here, we examined adipose tissue morphology and function in corin knockout (KO) mice. We observed increased weights and cell sizes in white adipose tissue (WAT), decreased levels of uncoupling protein 1 (Ucp1), a brown adipocyte marker in WAT and brown adipose tissue (BAT), and suppressed thermogenic gene expression in BAT from corin KO mice. At regular room temperature, corin KO and wild-type mice had similar metabolic rates. Upon cold exposure at 4 °C, corin KO mice exhibited impaired thermogenic responses and developed hypothermia. In BAT from corin KO mice, the signaling pathway of p38 mitogen-activated protein kinase, peroxisome proliferator-activated receptor c coactivator 1a, and Ucp1 was impaired. In cell culture, ANP treatment increased Ucp1 expression in BAT-derived adipocytes from corin KO mice. These data indicate that corin mediated-ANP activation is an important hormonal mechanism in regulating adipose tissue function and body temperature upon cold exposure in mice.

Corin: A Key Mediator in Sodium Homeostasis, Vascular Remodeling, and Heart Failure.

Atrial natriuretic peptide (ANP) is a crucial element of the cardiac endocrine function that promotes natriuresis, diuresis, and vasodilation, thereby protecting normal blood pressure and cardiac function. Corin is a type II transmembrane serine protease that is highly expressed in the heart, where it converts the ANP precursor to mature ANP. Corin deficiency prevents ANP activation and causes hypertension and heart disease. In addition to the heart, corin is expressed in other tissues, including those of the kidney, skin, and uterus, where corin-mediated ANP production and signaling act locally to promote sodium excretion and vascular remodeling. These results indicate that corin and ANP function in many tissues via endocrine and autocrine mechanisms. In heart failure patients, impaired natriuretic peptide processing is a common pathological mechanism that contributes to sodium and body fluid retention. In this review, we discuss most recent findings regarding the role of corin in non-cardiac tissues, including the kidney and skin, in regulating sodium homeostasis and body fluid excretion. Moreover, we describe the molecular mechanisms underlying corin and ANP function in supporting orderly cellular events in uterine spiral artery remodeling. Finally, we assess the potential of corin-based approaches to enhance natriuretic peptide production and activity as a treatment of heart failure.

CD320 expression and apical membrane targeting in renal and intestinal epithelial cells.

Vitamin B12 is an essential nutrient acquired via dietary intake. Receptor-mediated endocytosis is a key mechanism in vitamin B12 absorption, cellular uptake, and reabsorption. CD320 is a type I transmembrane protein responsible for cellular uptake of vitamin B12 in peripheral tissues. In this study, we examined segmental distribution and cellular expression of CD320 in mouse kidneys and intestines. We show that CD320 is expressed on the luminal surface in the small intestine and in proximal tubules in the kidney, suggesting that, in addition to its role in vitamin B12 uptake in peripheral tissues, CD320 may participate in vitamin B12 absorption in the small intestine and reabsorption in the kidney. Moreover, we show that an amino acid motif, DSSDE, in the second low-density lipoprotein receptor class A domain of CD320 is a key apical membrane targeting signal in both renal and intestinal epithelial cells. Mutations or deletion of this motif abolish the specific apical membrane expression of CD320 in polarized Madin-Darby canine kidney cells and human colon cancer-derived Caco-2 cells. In short-hairpin RNA-based gene knockdown experiments, we show that the apical membrane targeting of CD320 is mediated by a Rab11a-dependent mechanism. These results extend our knowledge regarding the cell biology of CD320 and its role in vitamin B12 metabolism.

Conditional Adversarial Domain Adaptation Neural Network for Motor Imagery EEG Decoding.

Decoding motor imagery (MI) electroencephalogram (EEG) signals for brain-computer interfaces (BCIs) is a challenging task because of the severe non-stationarity of perceptual decision processes. Recently, deep learning techniques have had great success in EEG decoding because of their prominent ability to learn features from raw EEG signals automatically. However, the challenge that the deep learning method faces is that the shortage of labeled EEG signals and EEGs sampled from other subjects cannot be used directly to train a convolutional neural network (ConvNet) for a target subject. To solve this problem, in this paper, we present a novel conditional domain adaptation neural network (CDAN) framework for MI EEG signal decoding. Specifically, in the CDAN, a densely connected ConvNet is firstly applied to obtain high-level discriminative features from raw EEG time series. Then, a novel conditional domain discriminator is introduced to work as an adversarial with the label classifier to learn commonly shared intra-subjects EEG features. As a result, the CDAN model trained with sufficient EEG signals from other subjects can be used to classify the signals from the target subject efficiently. Competitive experimental results on a public EEG dataset (High Gamma Dataset) against the state-of-the-art methods demonstrate the efficacy of the proposed framework in recognizing MI EEG signals, indicating its effectiveness in automatic perceptual decision decoding.

A Mitochondrion-Localized Two-Photon Photosensitizer Generating Carbon Radicals Against Hypoxic Tumors.

The efficacy of photodynamic therapy is typically reliant on the local concentration and diffusion of oxygen. Due to the hypoxic microenvironment found in solid tumors, oxygen-independent photosensitizers are in great demand for cancer therapy. We herein report an iridium(III) anthraquinone complex as a mitochondrion-localized carbon-radical initiator. Its emission is turned on under hypoxic conditions after reduction by reductase. Furthermore, its two-photon excitation properties (λex =730 nm) are highly desirable for imaging. Upon irradiation, the reduced form of the complex generates carbon radicals, leading to a loss of mitochondrial membrane potential and cell death (IC50light =2.1 µm, IC50dark =58.2 µm, PI=27.7). The efficacy of the complex as a PDT agent was also demonstrated under hypoxic conditions in vivo. To the best of our knowledge, it is the first metal-complex-based theranostic agent which can generate carbon radicals for oxygen-independent two-photon photodynamic therapy.

FerriIridium: A Lysosome-Targeting Iron(III)-Activated Iridium(III) Prodrug for Chemotherapy in Gastric Cancer Cells.

Reported is the FeIII -activated lysosome-targeting prodrug FerriIridium for gastric cancer theranostics. It contains a meta-imino catechol group that can selectively bond to, and be oxidized by, free FeIII inside the cell. Subsequent oxidative rearrangement releases FeII and hydrolyses the amine bond under acidic conditions, forming an aminobipyridyl Ir complex and 2-hydroxybenzoquinone. Thus, FeII catalyzes the Fenton reaction, transforming hydrogen peroxide into hydroxyl radicals, the benzoquinone compounds interfere with the respiratory chain, and conversion of the prodrug into the Ir complex leads to an increase in phosphorescence and toxicity. These properties, combined with the high FeIII content and acidity of cancer cells, make FerriIridium a selective and efficient theranostic agent (IC50 =9.22 µm for AGS cells vs. >200 µm for LO2 cells). FerriIridium is the first metal-based compound that has been developed for chemotherapy using FeIII to enhance both selectivity and potency.

A Channel-Projection Mixed-Scale Convolutional Neural Network for Motor Imagery EEG Decoding.

Motor imagery electroencephalography (EEG) decoding is an essential part of brain-computer interfaces (BCIs) which help motor-disabled patients to communicate with the outside world by external devices. Recently, deep learning algorithms using decomposed spectrums of EEG as inputs may omit important spatial dependencies and different temporal scale information, thus generated the poor decoding performance. In this paper, we propose an end-to-end EEG decoding framework, which employs raw multi-channel EEG as inputs, to boost decoding accuracy by the channel-projection mixed-scale convolutional neural network (CP-MixedNet) aided by amplitude-perturbation data augmentation. Specifically, the first block in CP-MixedNet is designed to learn primary spatial and temporal representations from EEG signals. The mixed-scale convolutional block is then used to capture mixed-scale temporal information, which effectively reduces the number of training parameters when expanding reception fields of the network. Finally, based on the features extracted in previous blocks, the classification block is constructed to classify EEG tasks. The experiments are implemented on two public EEG datasets (BCI competition IV 2a and High gamma dataset) to validate the effectiveness of the proposed approach compared to the state-of-the-art methods. The competitive results demonstrate that our proposed method is a promising solution to improve the decoding performance of motor imagery BCIs.

TEMPI Syndrome: Erythrocytosis in Plasma Cell Dyscrasia.

TEMPI (telangiectasias, erythrocytosis with elevated erythropoietin, monoclonal gammopathy, perinephric fluid collections, intrapulmonary shunting) syndrome is a newly described clinical entity that is generally considered a plasma cell dyscrasia with multiple system involvement. The etiology and pathophysiology of this condition remains elusive. Nevertheless, clonal plasma cells and monoclonal protein appear to be major contributors. The early diagnosis of TEMPI syndrome is essential because therapies targeting the underlying plasma cells can lead to a dramatic response. Bortezomib-based chemotherapy, daratumumab monotherapy, and autologous hematopoietic stem cell transplantation can result in reversal of most manifestations. Nevertheless, the diagnosis of TEMPI syndrome remains a substantial challenge owing to its rarity and the complexity of clinical presentations. TEMPI syndrome is often misdiagnosed as other causes of erythrocytosis, resulting in a delayed diagnosis and further clinical deterioration. The aim of the present review was to present the clinical and biologic features of TEMPI syndrome, highlighting the differential diagnosis and outlining the present understanding of its pathophysiology and treatment.

An Investigation Into Vortioxetine Salts: Crystal Structure, Thermal Stability, and Solubilization.

Three 1:1 salts containing vortioxetine (VOT), an orally antidepressant drug, and 3 aryl monoacids have been designed and successfully prepared by liquid-assisted grinding based on the ΔpKa rule. The C-O bond lengths (∼1.25 Å) in the COOH groups show that the proton transfer has occurred from aryl monoacid to piperazine N1 atom of vortioxetine in the crystal structures. Three salts feature cyclic [2 + 2] structural units through R(4)4 (12) N-H···O hydrogen bonding interactions which result in the remarkable thermal stabilities, and VOT-p-aminobenzoic acid shows 2-dimensional framework by linking cyclic [2 + 2] units through additional hydrogen bonding interactions. The equilibrium solubility of VOT in VOT-p-aminobenzoic acid salt can be largely improved up to 0.50 mg/mL (about 450% above the free base) at 25°C in water, which also accelerates the intrinsic dissolution rate.

[A meta-analysis on efficacy of intra-aortic balloon pump therapy in patients with acute myocardial infarction].

OBJECTIVE: To analyze the efficacy and safety of intra-aortic balloon pump (IABP) therapy in patients with acute myocardial infarction(AMI) based on the meta-analysis. METHODS: Eligible published randomized controlled clinical research (RCT) were retrieved in the Pubmed, EMBase, Cochrane, China biological medical literature, Wanfang, VIP and CNKI database from 1980 to April 2, 2012. The analysis was performed with the software of RevMan 5.1. RESULTS: Thirteen RCTs with 1958 patients (AMI with IABP therapy, n = 970,without IABP therapy, n = 988) were included. The 30-day mortality between the two groups was similar (RR = 0.77, 95%CI 0.58-1.03, P = 0.08), but the 30-day mortality in the cardiac shock subgroup was significantly lower in IABP group than in without IABP group (RR = 0.65, 95%CI 0.44-0.97, P = 0.04). The 6-month mortality was significantly lower in IABP group than in without IABP group (RR = 0.72, 95%CI 0.55-0.94, P = 0.02). The incidence of major bleeding was significantly higher in IABP group than in without IABP group (RR = 1.43, 95%CI 1.16-1.75, P < 0.01). CONCLUSION: IABP therapy is effective to reduce earlier mortality post AMI, particularly for patients with cardiac shock.