Genomic and immune landscape in hepatocellular carcinoma: Implications for personalized therapeutics.

Hepatocellular carcinoma (HCC) is a globally prevalent malignancy, marked by genetic heterogeneity and intricate tumor microenvironment interactions. In this study, we undertook a detailed single-cell analysis of six active HCC patients, highlighting strong correlations between gene expression levels and cellular characteristics. UMAP clustering revealed seven distinct cell categories with associated gene expressions. A divergence was observed in tumor cells into high and low cuproptosis groups, each associated with distinct pathways: oxidative stress for the high cuproptosis group and inflammatory and angiogenesis pathways for the low group. CellChat analysis on the TCGA-LIHC cohort displayed unique intercellular interactions among hepatocytes, T cells, and other cells, with pathways like COLLAGEN and VEGF being pivotal. Functional enrichment analyses exposed pathways enriched between cuproptosis groups, with KEGG emphasizing diseases like Parkinson's. COX survival analysis identified key prognostic genes, revealing distinct survival rates between risk groups in TCGA and GSE14520 cohorts. Mutation data highlighted missense mutations, with TTN, TP53, and CTNNB1 being the most mutated in HCC. Immune infiltration analysis via CIBERSORTx indicated differences between risk groups in NK cells, neutrophils, and other cells. Our drug sensitivity investigation showed significant correlations between model genes and drug responsiveness, emphasizing the importance of patient risk stratification for therapeutic approaches. Further, ATP6V1G1 was recognized in its role in apoptosis and migration in HCC cells. In conclusion, our findings illuminate the complexities of HCC progression, potential predictive genetic markers for drug response, and the pivotal role of ATP6V1G1, suggesting avenues for targeted therapeutic strategies in HCC.

Astragaloside IV ameliorates peritoneal fibrosis by promoting PGC-1α to reduce apoptosis in vitro and in vivo.

Prolonged exposure of the peritoneum to high glucose dialysate leads to the development of peritoneal fibrosis (PF), and apoptosis of peritoneal mesothelial cells (PMCs) is a major cause of PF. The aim of this study is to investigate whether Astragaloside IV could protect PMCs from apoptosis and alleviate PF. PMCs and rats PF models were induced by high glucose peritoneal fluid. We examined the pathology of rat peritoneal tissue by HE staining, the thickness of rat peritoneal tissue by Masson's staining, the number of mitochondria and oxidative stress levels in peritoneal tissue by JC-1 and DHE fluorescence staining, and mitochondria-related proteins and apoptosis-related proteins such as PGC-1α, NRF1, TFAM, Caspase3, Bcl2 smad2 were measured. We used hoechst staining and flow cytometry to assess the apoptotic rate of PMCs in the PF model, and further validated the observed changes in the expressions of PGC-1α, NRF1, TFAM, Caspase3, Bcl2 smad2 in PMCs. We further incubated PMCs with MG-132 (proteasome inhibitor) and Cyclohexylamine (protein synthesis inhibitor). The results demonstrated that Astragaloside IV increased the expression of PGC-1α by reducing the ubiquitination of PGC-1α. It was further found that the protective effects of Astragaloside IV on PMCs were blocked when PGC-1α was inhibited. In conclusion, Astragaloside IV effectively alleviated PF both in vitro and in vivo, possibly by promoting PGC-1α to enhance mitochondrial synthesis to reduce apoptotic effects.

Integrating a phenotypic screening with a structural simplification strategy to identify 4-phenoxy-quinoline derivatives to potently disrupt the mitotic localization of Aurora kinase B.

We combined a mechanism-informed phenotypic screening (MIPS) assay with a structural simplification strategy to guide the discovery of compounds that disrupt the localization of the mitotic regulator, Aurora kinase B (AURKB), rather than inhibiting its catalytic activity. An initial hit 4-(4-methylthiophen-2-yl)-N-(4-(quinolin-4-yloxy)phenyl)phthalazin-1-amine was identified after screening an in-house library of small molecules and phenocopied the loss of function mutations in AURKB without inhibiting its catalytic activity. We isolated this hit compound activity to its 4-phenoxy-quinoline moiety. The fragment was further optimized into a class of new chemical entities that potently disrupt the mitotic localization of AURKB at low nanomolar concentrations and consequently elicit severe growth inhibition in diverse human cancer cell lines. A lead compound, N-(3-methoxy-5-(6-methoxyquinolin-4-yl)oxy)phenyl)acetamide possessed desirable pharmacokinetic properties such as AUC0-∞: 227.15 [ng∙h/mL/(mg/kg)]; Cmax: 3378.52 ng/mL T1/2: 3.52 h; and F%: 42 % and produced the AURKB-inhibitory phenotypes in a mouse xenograft model. A lead compound is a powerful tool for interrogating the regulation of AURKB and has the potential to be further developed as a first-in-class oncology therapeutic.

Treating High COD Dyeing Wastewater via a Regenerative Sorption-Oxidation Process Using a Nano-Pored Activated Carbon.

Nowadays, the structural complexity of dyes used in the textile industry and the widely adopted water-saving strategy in the dyeing processes often fail plants' biological wastewater treatment units due to chemical oxygen demand (COD) overload. To alleviate this problems, this study investigated a regenerable adsorption-oxidation process to treat dyeing wastewater with COD around 10,000 mg/dm3 using a highly nano-pored activated carbon (AC) as a COD adsorbent, followed by its regeneration using hydrogen peroxide as an oxidizing reagent. In addition to studying AC's COD adsorption and oxidation performance, its operational treatment conditions in terms of temperature and pH were assessed. The results firstly demonstrated that about 50-60% of the COD was consistently adsorbed during the repeated adsorption operation before reaching AC's maximum adsorption capacity (qmax) of 0.165 g-COD/g-AC. The optimal pH and temperature during adsorption were 4.7 and 25 °C, respectively. Secondly, AC regeneration was accomplished by using an initial peroxide concentration of 2.5% (by wt %) and EDTA-Fe of 2.12 mmole/dm3. The reuse of the regenerated ACs was doable. Surprisingly, after the first AC regeneration, the COD adsorption capacity of the regenerated AC even increased by ~7% with respect to the virgin AC. Thirdly, the results of a five-consecutive adsorption-regeneration operation showed that a total of 0.3625 g COD was removed by the 5 g AC used, which was equivalent to an adsorption capacity (q) of 0.0725 (= 0.3625/5) g-COD/g-AC during each adsorption stage. Based on the obtained results, a regenerable COD adsorption-oxidation process using a nano-pored AC to treat the high-textile-COD wastewater looks promising. Thus, a conceptual treatment unit was proposed, and its potential benefits and limitations were addressed.

The Effect of Circumscribed Exposure to the Pan-Aurora Kinase Inhibitor VX-680 on Proliferating Euploid Cells.

Small molecule inhibitors of aurora kinases are currently being investigated in oncology clinical trials. The long-term effects of these inhibitors on proliferating euploid cells have not been adequately studied. We examined the effect of the reversible pan-aurora kinase inhibitor VX-680 on p53-competent human euploid cells. Circumscribed treatment with VX-680 blocked cytokinesis and arrested cells in G1 or a G1-like status. Approximately 70% of proliferatively arrested cells had 4N DNA content and abnormal nuclei. The remaining 30% of cells possessed 2N DNA content and normal nuclei. The proliferative arrest was not due to the activation of the tumor suppressor Rb and was instead associated with rapid induction of the p53-p21 pathway and p16. The induction was particularly evident in cells with nuclear abnormalities but was independent of activation of the DNA damage response. All of these effects were correlated with the potent inhibition of aurora kinase B. After release from VX-680, the cells with normal nuclei robustly resumed proliferation whereas the cells with abnormal nuclei underwent senescence. Irrespective of their nuclear morphology or DNA content, cells pre-treated with VX-680 failed to grow in soft agar or form tumors in mice. Our findings indicate that an intermittent treatment strategy might minimize the on-target side effects of Aurora Kinase B (AURKB) inhibitory therapies. The strategy allows a significant fraction of dividing normal cells to resume proliferation.

The Phytochemical Scoulerine Inhibits Aurora Kinase Activity to Induce Mitotic and Cytokinetic Defects.

To identify novel bioactive compounds, an image-based, cell culture screening of natural product extracts was conducted. Specifically, our screen was designed to identify phytochemicals that might phenocopy inhibition of the chromosomal passenger protein complex in eliciting mitotic and cytokinetic defects. A known alkaloid, scoulerine, was identified from the rhizomes of the plant Corydalis decumbens as being able to elicit a transient mitotic arrest followed by either apoptosis induction or polyploidy. In examining the mitotic abnormality further, we observed that scoulerine could elicit supernumerary centrosomes during mitosis, but not earlier in the cell cycle. The localization of NUMA1 at spindle poles was also inhibited, suggesting diminished potential for microtubule recruitment and spindle-pole focusing. Polyploid cells emerged subsequent to cytokinetic failure. The concentration required for scoulerine to elicit all its cell division phenotypes was similar, and an examination of related compounds highlighted the requirement for proper positioning of a hydroxyl and a methoxy group about an aromatic ring for activity. Mechanistically, scoulerine inhibited AURKB activity at concentrations that elicited supernumerary centrosomes and polyploidy. AURKA was only inhibited at higher concentrations, so AURKB inhibition is the likely mechanism by which scoulerine elicited division defects. AURKB inhibition was never complete, so scoulerine may be a suboptimal AURK inhibitor or work upstream of the chromosomal passenger protein complex to reduce AURKB activity. Scoulerine inhibited the viability of a variety of human cancer cell lines. Collectively, these findings uncover a previously unknown activity of scoulerine that could facilitate targeting human cancers. Scoulerine, or a next-generation analogue, may be useful as a nontoxic component of combination therapies where inhibiting the chromosomal passenger protein complex is desired.

The anti-apoptotic proteins Bcl-2 and Bcl-xL suppress Beclin 1/Atg6-mediated lethal autophagy in polyploid cells.

Inhibition of Aurora-B kinase is a synthetic lethal therapy for tumors that overexpress the MYC oncoprotein. It is currently unclear whether co-occurring oncogenic alterations might influence this synthetic lethality by conferring more or less potency in the killing of tumor cells. To identify such modifiers, isogenic cell lines were utilized to test a variety of cancer genes that have been previously demonstrated to promote survival under conditions of cellular stress, contribute to chemoresistance and/or suppress MYC-primed apoptosis. It was found that Bcl-2 and Bcl-xL, two antiapoptotic members of the Bcl-2 family, can partially suppress the synthetic lethality, but not multinucleation, elicited by a pan-aurora kinase inhibitor, VX-680. Suppression was show to stem from the inhibition of autophagy, specifically in multinucleated cells, rather than a general inhibition of apoptosis. The anti-autophagic activity of Bcl-2 also impacted polyploid cell recovery in colony-forming assays, suggesting a route of escape from MYC-VX-680 synthetic lethality that may have clinical consequences. These findings expand on previous conclusions that autophagic death of VX-680-induced polyploid cells is mediated by Atg6. Bcl-2 and Bcl-xL negatively modulate MYC-VX-680 synthetic lethality and it is the anti-autophagic activity of these two Bcl-2 family proteins, specifically in multinucleate cells, that contributes to resistance to Aurora kinase-targeting drugs.

The 10-Year Prognosis and Prevalence of Brugada-Type Electrocardiograms in Elderly Women: A Longitudinal Nationwide Community-Based Prospective Study.

BACKGROUND: Brugada syndrome is a disorder associated with sudden cardiac death and characterized by an abnormal electrocardiogram (ECG). Previous studies were predominantly conducted in men, and the data on long-term prognosis are limited. Information about women, especially elderly women, is lacking. OBJECTIVE: The aim of this study was to investigate the long-term prognosis of the Brugada ECG pattern in elderly women. METHOD: We investigated the 10-year prognosis of the Brugada ECG pattern in elderly women in a nationwide community-based population in Taiwan. Community-dwelling women older than 55 years were prospectively recruited from December 2008 to March 2013 by a stratified random sampling method. All enrolled individuals were followed up annually until April 2019, and the cause of death was documented by citizen death records. RESULTS: Among 2597 women, 60 (2.31%) had a Brugada-type ECG, and this prevalence was higher than the mean global prevalence of 0.23%. One woman had a type 1 ECG (0.04%), whereas 15 (0.58%) and 44 (1.70%) women had type 2 and type 3 ECG patterns, respectively. Cox survival analysis revealed that all-cause mortality and cardiac mortality were similar in the individuals with and without a Brugada-type ECG during a mean follow-up of 96.1 ± 20.5 months. CONCLUSIONS: Our findings suggest that Brugada ECG patterns are not infrequent in elderly women but are not associated with increased risk of mortality in long-term follow-up; these findings may help reduce unnecessary anxiety for physicians, nurses, allied health caregivers, and patients.

Cyclodextrin has conflicting actions on autophagy flux in vivo in brains of normal and Alzheimer model mice.

2-hydroxypropyl-ß-cyclodextrin (CYCLO), a modifier of cholesterol efflux from cellular membrane and endo-lysosomal compartments, reduces lysosomal lipid accumulations and has therapeutic effects in animal models of Niemann-Pick disease type C and several other neurodegenerative states. Here, we investigated CYCLO effects on autophagy in wild-type mice and TgCRND8 mice-an Alzheimer's Disease (AD) model exhibiting ß-amyloidosis, neuronal autophagy deficits leading to protein and lipid accumulation within greatly enlarged autolysosomes. A 14-day intracerebroventricular administration of CYCLO to 8-month-old TgCRND8 mice that exhibit moderately advanced neuropathology markedly diminished the sizes of enlarged autolysosomes and lowered their content of GM2 ganglioside and Aß-immunoreactivity without detectably altering amyloid precursor protein processing or extracellular Aß/ß-amyloid burden. We identified two major actions of CYCLO on autophagy underlying amelioration of lysosomal pathology. First, CYCLO stimulated lysosomal proteolytic activity by increasing cathepsin D activity, levels of cathepsins B and D and two proteins known to interact with cathepsin D, NPC1 and ABCA1. Second, CYCLO impeded autophagosome-lysosome fusion as evidenced by the accumulation of LC3, SQSTM1/p62, and ubiquitinated substrates in an expanded population of autophagosomes in the absence of greater autophagy induction. By slowing substrate delivery to lysosomes, autophagosome maturational delay, as further confirmed by our in vitro studies, may relieve lysosomal stress due to accumulated substrates. These findings provide in vivo evidence for lysosomal enhancing properties of CYCLO, but caution that prolonged interference with cellular membrane fusion/autophagosome maturation could have unfavorable consequences, which might require careful optimization of dosage and dosing schedules.

Flexible and Semitransparent Organolead Triiodide Perovskite Network Photodetector Arrays with High Stability.

Organolead triiodide perovskite (CH3NH3PbI3) as a light-sensitive material has attracted extensive attention in optoelectronics. The reported perovskite photodetectors (PDs) mainly focus on the individual, which limits their spatial imaging applications. Uniform perovskite networks combining transparency and device performance were synthesized on poly(ethylene terephthalate) (PET) by controlling perovskite crystallization. Photodetector arrays based on above network were fabricated to demonstrate the potential for image mapping. The trade-off between the PD performance and transparency was systematically investigated and the optimal device was obtained from 30 wt % precursor concentration. The switching ratio, normalized detectivity, and equivalent dark current derived shot noise as the critical parameters of PD arrays reached 300, 1.02 × 10(12) Jones, and 4.73 × 10(-15)A Hz(-1/2), respectively. Furthermore, the PD arrays could clearly detect spatial light intensity distribution, thus demonstrating its preliminary imaging function. The perovskite network PD arrays fabricated on PET substrates could also conduct superior flexibility under wide angle and large number of bending. For the common problem of perovskite optoelectronics in stability, the perovskite networks sheathed with hydrophobic polymers greatly enhanced the device stability due to the improved interface contacts, surface passivation, and moisture isolation. Taking into consideration transparency, flexibility, imaging and stability, the present PD arrays were expected to be widely applied in visualized portable optoelectronic system.

Defective macroautophagic turnover of brain lipids in the TgCRND8 Alzheimer mouse model: prevention by correcting lysosomal proteolytic deficits.

Autophagy, the major lysosomal pathway for the turnover of intracellular organelles is markedly impaired in neurons in Alzheimer's disease and Alzheimer mouse models. We have previously reported that severe lysosomal and amyloid neuropathology and associated cognitive deficits in the TgCRND8 Alzheimer mouse model can be ameliorated by restoring lysosomal proteolytic capacity and autophagy flux via genetic deletion of the lysosomal protease inhibitor, cystatin B. Here we present evidence that macroautophagy is a significant pathway for lipid turnover, which is defective in TgCRND8 brain where lipids accumulate as membranous structures and lipid droplets within giant neuronal autolysosomes. Levels of multiple lipid species including several sphingolipids (ceramide, ganglioside GM3, GM2, GM1, GD3 and GD1a), cardiolipin, cholesterol and cholesteryl esters are elevated in autophagic vacuole fractions and lysosomes isolated from TgCRND8 brain. Lipids are localized in autophagosomes and autolysosomes by double immunofluorescence analyses in wild-type mice and colocalization is increased in TgCRND8 mice where abnormally abundant GM2 ganglioside-positive granules are detected in neuronal lysosomes. Cystatin B deletion in TgCRND8 significantly reduces the number of GM2-positive granules and lowers the levels of GM2 and GM3 in lysosomes, decreases lipofuscin-related autofluorescence, and eliminates giant lipid-containing autolysosomes while increasing numbers of normal-sized autolysosomes/lysosomes with reduced content of undigested components. These findings have identified macroautophagy as a previously unappreciated route for delivering membrane lipids to lysosomes for turnover, a function that has so far been considered to be mediated exclusively through the endocytic pathway, and revealed that autophagic-lysosomal dysfunction in TgCRND8 brain impedes lysosomal turnover of lipids as well as proteins. The amelioration of lipid accumulation in TgCRND8 by removing cystatin B inhibition on lysosomal proteases suggests that enhancing lysosomal proteolysis improves the overall environment of the lysosome and its clearance functions, which may be possibly relevant to a broader range of lysosomal disorders beyond Alzheimer's disease.

Single-walled carbon nanotubes alleviate autophagic/lysosomal defects in primary glia from a mouse model of Alzheimer's disease.

Defective autophagy in Alzheimer's disease (AD) promotes disease progression in diverse ways. Here, we demonstrate impaired autophagy flux in primary glial cells derived from CRND8 mice that overexpress mutant amyloid precursor protein (APP). Functionalized single-walled carbon nanotubes (SWNT) restored normal autophagy by reversing abnormal activation of mTOR signaling and deficits in lysosomal proteolysis, thereby facilitating elimination of autophagic substrates. These findings suggest SWNT as a novel neuroprotective approach to AD therapy.

Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC.

Tumor cells have a dysregulated cell cycle that may render their proliferation especially sensitive to the inhibition of cyclin-dependent kinases (CDKs), important regulators of cell cycle progression. We examined the effects of CDK1 inhibition in the context of different oncogenic signals. Cells transformed with MYC, but not cells transformed by a panel of other activated oncogenes, rapidly underwent apoptosis when treated with small-molecule CDK1 inhibitors. The inhibitor of apoptosis protein BIRC5 (survivin), a known CDK1 target, is required for the survival of cells overexpressing MYC. Inhibition of CDK1 rapidly downregulates survivin expression and induces MYC-dependent apoptosis. CDK1 inhibitor treatment of MYC-dependent mouse lymphoma and hepatoblastoma tumors decreased tumor growth and prolonged their survival. As there are no effective small-molecule inhibitors that selectively target the MYC pathway, we propose that CDK1 inhibition might therefore be useful in the treatment of human malignancies that overexpress MYC.

Innate Orientating Behavior of a Multi-Legged Robot Driven by the Neural Circuits of C. elegans.

The objective of this research is to achieve biologically autonomous control by utilizing a whole-brain network model, drawing inspiration from biological neural networks to enhance the development of bionic intelligence. Here, we constructed a whole-brain neural network model of Caenorhabditis elegans (C. elegans), which characterizes the electrochemical processes at the level of the cellular synapses. The neural network simulation integrates computational programming and the visualization of the neurons and synapse connections of C. elegans, containing the specific controllable circuits and their dynamic characteristics. To illustrate the biological neural network (BNN)'s particular intelligent control capability, we introduced an innovative methodology for applying the BNN model to a 12-legged robot's movement control. Two methods were designed, one involving orientation control and the other involving locomotion generation, to demonstrate the intelligent control performance of the BNN. Both the simulation and experimental results indicate that the robot exhibits more autonomy and a more intelligent movement performance under BNN control. The systematic approach of employing the whole-brain BNN for robot control provides biomimetic research with a framework that has been substantiated by innovative methodologies and validated through the observed positive outcomes. This method is established as follows: (1) two integrated dynamic models of the C. elegans' whole-brain network and the robot moving dynamics are built, and all of the controllable circuits are discovered and verified; (2) real-time communication is achieved between the BNN model and the robot's dynamical model, both in the simulation and the experiments, including applicable encoding and decoding algorithms, facilitating their collaborative operation; (3) the designed mechanisms using the BNN model to control the robot are shown to be effective through numerical and experimental tests, focusing on 'foraging' behavior control and locomotion control.

mTOR inhibition in Q175 Huntington's disease model mice facilitates neuronal autophagy and mutant huntingtin clearance.

Huntington's disease (HD) is caused by expansion of the polyglutamine stretch in huntingtin protein (HTT) resulting in hallmark aggresomes/inclusion bodies (IBs) composed of mutant huntingtin protein (mHTT) and its fragments. Stimulating autophagy to enhance mHTT clearance is considered a potential therapeutic strategy for HD. Our recent evaluation of the autophagic-lysosomal pathway (ALP) in human HD brain reveals upregulated lysosomal biogenesis and relatively normal autophagy flux in early Vonsattel grade brains, but impaired autolysosome clearance in late grade brains, suggesting that autophagy stimulation could have therapeutic benefits as an earlier clinical intervention. Here, we tested this hypothesis by crossing the Q175 HD knock-in model with our autophagy reporter mouse TRGL ( T hy-1- R FP- G FP- L C3) to investigate in vivo neuronal ALP dynamics. In the Q175 and/or TRGL/Q175 mice, mHTT was detected in autophagic vacuoles and also exhibited high level colocalization with autophagy receptors p62/SQSTM1 and ubiquitin in the IBs. Compared to the robust lysosomal pathology in late-stage human HD striatum, ALP alterations in Q175 models are also late-onset but milder that included a lowered phospho-p70S6K level, lysosome depletion and autolysosome elevation including more poorly acidified autolysosomes and larger-sized lipofuscin granules, reflecting impaired autophagic flux. Administration of a mTOR inhibitor to 6-mo-old TRGL/Q175 normalized lysosome number, ameliorated aggresome pathology while reducing mHTT-, p62- and ubiquitin-immunoreactivities, suggesting beneficial potential of autophagy modulation at early stages of disease progression.

Pathobiology of the autophagy-lysosomal pathway in the Huntington's disease brain.

Accumulated levels of mutant huntingtin protein (mHTT) and its fragments are considered contributors to the pathogenesis of Huntington's disease (HD). Although lowering mHTT by stimulating autophagy has been considered a possible therapeutic strategy, the role and competence of autophagy-lysosomal pathway (ALP) during HD progression in the human disease remains largely unknown. Here, we used multiplex confocal and ultrastructural immunocytochemical analyses of ALP functional markers in relation to mHTT aggresome pathology in striatum and the less affected cortex of HD brains staged from HD2 to HD4 by Vonsattel neuropathological criteria compared to controls. Immunolabeling revealed the localization of HTT/mHTT in ALP vesicular compartments labeled by autophagy-related adaptor proteins p62/SQSTM1 and ubiquitin, and cathepsin D (CTSD) as well as HTT-positive inclusions. Although comparatively normal at HD2, neurons at later HD stages exhibited progressive enlargement and clustering of CTSD-immunoreactive autolysosomes/lysosomes and, ultrastructurally, autophagic vacuole/lipofuscin granules accumulated progressively, more prominently in striatum than cortex. These changes were accompanied by rises in levels of HTT/mHTT and p62/SQSTM1, particularly their fragments, in striatum but not in the cortex, and by increases of LAMP1 and LAMP2 RNA and LAMP1 protein. Importantly, no blockage in autophagosome formation and autophagosome-lysosome fusion was detected, thus pinpointing autophagy substrate clearance deficits as a basis for autophagic flux declines. The findings collectively suggest that upregulated lysosomal biogenesis and preserved proteolysis maintain autophagic clearance in early-stage HD, but failure at advanced stages contributes to progressive HTT build-up and potential neurotoxicity. These findings support the prospect that ALP stimulation applied at early disease stages, when clearance machinery is fully competent, may have therapeutic benefits in HD patients.

ILC2s: Unraveling the innate immune orchestrators in allergic inflammation.

The prevalence rate of allergic diseases including asthma, atopic rhinitis (AR) and atopic dermatitis (AD) has been significantly increasing in recent decades due to environmental changes and social developments. With the study of innate lymphoid cells, the crucial role played by type 2 innate lymphoid cells (ILC2s) have been progressively unveiled in allergic diseases. ILC2s, which are a subset of innate lymphocytes initiate allergic responses. They respond swiftly during the onset of allergic reactions and produce type 2 cytokines, working in conjunction with T helper type 2 (Th2) cells to induce and sustain type 2 immune responses. The role of ILC2s represents an intriguing frontier in immunology; however, the intricate immune mechanisms of ILC2s in allergic responses remain relatively poorly understood. To gain a comphrehensive understanding of the research progress of ILC2, we summarize recent advances in ILC2s biology in pathologic allergic inflammation to inspire novel approaches for managing allergic diseases.

Clinical Validation of a Deep Learning-Based Software for Lumbar Bone Mineral Density and T-Score Prediction from Chest X-ray Images.

Screening for osteoporosis is crucial for early detection and prevention, yet it faces challenges due to the low accuracy of calcaneal quantitative ultrasound (QUS) and limited access to dual-energy X-ray absorptiometry (DXA) scans. Recent advances in AI offer a promising solution through opportunistic screening using existing medical images. This study aims to utilize deep learning techniques to develop a model that analyzes chest X-ray (CXR) images for osteoporosis screening. This study included the AI model development stage and the clinical validation stage. In the AI model development stage, the combined dataset of 5122 paired CXR images and DXA reports from the patients aged 20 to 98 years at a medical center was collected. The images were enhanced and filtered for hardware retention such as pedicle screws, bone cement, artificial intervertebral discs or severe deformity in target level of T12 and L1. The dataset was then separated into training, validating, and testing datasets for model training and performance validation. In the clinical validation stage, we collected 440 paired CXR images and DXA reports from both the TCVGH and Joy Clinic, including 304 pared data from TCVGH and 136 paired data from Joy Clinic. The pre-clinical test yielded an area under the curve (AUC) of 0.940, while the clinical validation showed an AUC of 0.946. Pearson's correlation coefficient was 0.88. The model demonstrated an overall accuracy, sensitivity, and specificity of 89.0%, 88.7%, and 89.4%, respectively. This study proposes an AI model for opportunistic osteoporosis screening through CXR, demonstrating good performance and suggesting its potential for broad adoption in preliminary screening among high-risk populations.

Therapeutic potential of a synthetic lethal interaction between the MYC proto-oncogene and inhibition of aurora-B kinase.

The Myc protein and proteins that participate in mitosis represent attractive targets for cancer therapy. However, their potential is presently compromised by the threat of side effects and by a lack of pharmacological inhibitors of Myc. Here we report that a circumscribed exposure to the aurora kinase inhibitor, VX-680, selectively kills cells that overexpress Myc. This synthetic lethal interaction is attributable to inhibition of aurora-B kinase, with consequent disabling of the chromosomal passenger protein complex (CPPC) and ensuing DNA replication in the absence of cell division; executed by sequential apoptosis and autophagy; not reliant on the tumor suppressor protein p53; and effective against mouse models for B-cell and T-cell lymphomas initiated by transgenes of MYC. Our findings cast light on how inhibitors of aurora-B kinase may kill tumor cells, implicate Myc in the induction of a lethal form of autophagy, indicate that expression of Myc be a useful biomarker for sensitivity of tumor cells to inhibition of the CPPC, dramatize the virtue of bimodal killing by a single therapeutic agent, and suggest a therapeutic strategy for killing tumor cells that overexpress Myc while sparing normal cells.

In-vitro metabolism of LXY18, an orally available, potent blocker of AURKB relocation in mitosis.

This study investigated the metabolism of LXY18, a quinolone-based compound that suppresses tumorigenesis by blocking AURKB localization. Metabolite profiling of LXY18 in liver microsomes from six species and human S9 fractions revealed that LXY18 undergoes various conserved metabolic reactions, such as N-hydroxylation, N-oxygenation, O-dealkylation, and hydrolysis, resulting in ten metabolites. These metabolites were produced through a combination of CYP450 enzymes, and non-CYP450 enzymes including CES1, and AO. Two metabolites, M1 and M2 were authenticated by chemically synthesized standards. M1 was the hydrolyzed product catalyzed by CES1 whereas M2 was a mono-N-oxidative derivative catalyzed by a CYP450 enzyme. AO was identified as the enzyme responsible for the formation of M3 with the help of AO-specific inhibitors and LXY18 analogs, 5b and 5c. M1 was the intermediate of LXY18 to produce M7, M8, M9, and M10. LXY18 potently inhibited 2C19 with an IC50 of 290 nM but had a negligible impact on the other CYP450s, indicating a low risk of drug-drug interaction. Altogether, the study provides valuable insights into the metabolic process of LXY18 and its suitability as a drug candidate. The data generated serves as a significant reference point for conducting further safety assessments and optimizing drug development.