CD276 Promotes an Inhibitory Tumor Microenvironment in Hepatocellular Carcinoma and is Associated with Poor Prognosis.

Background: CD276 is an emerging immune checkpoint molecule that has been implicated in various cancers. However, its specific role in hepatocellular carcinoma (HCC) remains unclear. This study examined the impact of CD276 on patient prognosis and the tumor microenvironment (TME). Methods: The Cancer Genome Atlas (TCGA) database was utilized to evaluate CD276 expression in HCC and the association between CD276 and immune indicators was also analyzed. The signaling pathways correlated with CD276 expression were identified by gene set enrichment analysis (GSEA). Different algorithms were used to assess immune cell infiltration. The effect of CD276 knockdown on HCC cell phenotypes and its relationship with macrophage polarization was examined using the cell counting kit 8 (CCK-8) assay and co-culture system. Results: CD276 was upregulated in HCC and associated with unfavorable clinical outcomes. Hgh CD276 expression was associated with enrichment of the G2/M checkpoint, E2F targets, and mitotic spindles. CD276 expression was correlated with the infiltration of immune cells, including high level of tumor-associated macrophages and low levels of CD8+ T cells. Knockdown of CD276 decreased HCC cell proliferation and increased apoptosis. CD276 silencing in HCC cells and co-culture with THP-1-derived macrophages had a regulatory effect on macrophage polarization and macrophage-mediated cell proliferation and migration. Conclusion: CD276 expression in HCC is associated with unfavorable clinical outcomes and may contribute to the development of an immunosuppressive microenvironment. Specifically, CD276 was associated with alterations in immune cell infiltration, immune marker expression, and macrophage polarization during HCC progression, suggesting its potential as a prognostic indicator and promising target for immunotherapeutic intervention in HCC.

Super-enhancer-driven IRF2BP2 enhances ALK activity and promotes neuroblastoma cell proliferation.

BACKGROUND: Super-enhancers (SEs) typically govern the expression of critical oncogenes and play a fundamental role in the initiation and progression of cancer. Focusing on genes that are abnormally regulated by SE in cancer may be a new strategy for understanding pathogenesis. In the context of this investigation, we have identified a previously unreported SE-driven gene IRF2BP2 in neuroblastoma (NB). METHODS: The expression and prognostic value of IRF2BP2 were detected in public databases and clinical samples. The effect of IRF2BP2 on NB cell growth and apoptosis was evaluated through in vivo and in vitro functional loss experiments. The molecular mechanism of IRF2BP2 was investigated by the study of chromatin regulatory regions and transcriptome sequencing. RESULTS: The sustained high expression of IRF2BP2 results from the activation of a novel SE established by NB master transcription factors MYCN, MEIS2 and HAND2, and they form a new complex that regulates the gene network associated with the proliferation of NB cell populations. We also observed a significant enrichment of the AP-1 family at the binding sites of IRF2BP2. Remarkably, within NB cells, AP-1 plays a pivotal role in shaping the chromatin accessibility landscape, thereby exposing the binding site for IRF2BP2. This orchestrated action enables AP-1 and IRF2BP2 to collaboratively stimulate the expression of the NB susceptibility gene ALK, thereby upholding the highly proliferative phenotype characteristic of NB. CONCLUSION: Our findings indicate that SE-driven IRF2BP2 can bind to AP-1 to maintain the survival of tumor cells via regulating chromatin accessibility of NB susceptibility gene ALK.

Ag Modified SnS2 Monolayer as a Potential Sensing Material for C4F7N Decompositions: A Density Functional Theory Study.

As the field of 2D materials rapidly evolves, substances such as graphene, metal dichalcogenides, MXenes, and MBenes have garnered extensive attention from scholars in the gas sensing domain due to their unique and superior properties. Based on first-principles calculations, this work explored the adsorption characteristics of both intrinsic and silver (Ag) doped tin disulfide (SnS2) toward the decomposition components of the insulating medium C4F7N (namely, CF4, C3F6, and COF2), encompassing the adsorption energy, charge transfer, density of state (DOS), band structure, and adsorption stability. The results indicated that Ag-doped SnS2 exhibited an effective and stable adsorption for C3F6 and COF2, whereas its adsorption for CF4 was comparatively weaker. Additionally, the potential for Ag-SnS2 in detecting C3F6 was highlighted, inferred from the contributions of the band gap variations. This research provides theoretical guidance for the application of Ag-SnS2 as a sensing material in assessing the operational status of gas-insulated equipment.

Enhancing surgical decision-making in NEC with ResNet18: a deep learning approach to predict the need for surgery through x-ray image analysis.

Background: Necrotizing enterocolitis (NEC) is a severe neonatal intestinal disease, often occurring in preterm infants following the administration of hyperosmolar formula. It is one of the leading causes of neonatal mortality in the NICU, and currently, there are no clear standards for surgical intervention, which typically depends on the joint discretion of surgeons and neonatologists. In recent years, deep learning has been extensively applied in areas such as image segmentation, fracture and pneumonia classification, drug development, and pathological diagnosis. Objective: Investigating deep learning applications using bedside x-rays to help optimizing surgical decision-making in neonatal NEC. Methods: Through a retrospective analysis of anteroposterior bedside chest and abdominal x-rays from 263 infants diagnosed with NEC between January 2015 and April 2023, including a surgery group (94 cases) and a non-surgery group (169 cases), the infants were divided into a training set and a validation set in a 7:3 ratio. Models were built based on Resnet18, Densenet121, and SimpleViT to predict whether NEC patients required surgical intervention. Finally, the model's performance was tested using an additional 40 cases, including both surgical and non-surgical NEC cases, as a test group. To enhance the interpretability of the models, the study employed 2D-Grad-CAM technology to describe the models' focus on significant areas within the x-ray images. Results: Resnet18 demonstrated outstanding performance in binary diagnostic capability, achieving an accuracy of 0.919 with its precise lesion imaging and interpretability particularly highlighted. Its precision, specificity, sensitivity, and F1 score were significantly high, proving its advantages in optimizing surgical decision-making for neonatal NEC. Conclusion: The Resnet18 deep learning model, constructed using bedside chest and abdominal imaging, effectively assists clinical physicians in determining whether infants with NEC require surgical intervention.

Fangyukangsuan granules ameliorate hyperuricemia and modulate gut microbiota in rats.

Hyperuricaemia (HUA) is a metabolic disorder characterised by high blood uric acid (UA) levels; moreover, HUA severity is closely related to the gut microbiota. HUA is also a risk factor for renal damage, diabetes, hypertension, and dyslipidaemia; however, current treatments are associated with detrimental side effects. Alternatively, Fangyukangsuan granules are a natural product with UA-reducing properties. To examine their efficacy in HUA, the binding of small molecules in Fangyukangsuan granules to xanthine oxidase (XOD), a key factor in UA metabolism, was investigated via molecular simulation, and the effects of oral Fangyukangsuan granule administration on serum biochemical indices and intestinal microorganisms in HUA-model rats were examined. Overall, 24 small molecules in Fangyukangsuan granules could bind to XOD. Serum UA, creatinine, blood urea nitrogen, and XOD levels were decreased in rats treated with Fangyukangsuan granules compared to those in untreated HUA-model rats. Moreover, Fangyukangsuan granules restored the intestinal microbial structure in HUA-model rats. Functional analysis of the gut microbiota revealed decreased amino acid biosynthesis and increased fermentation of pyruvate into short-chain fatty acids in Fangyukangsuan granule-treated rats. Together, these findings demonstrate that Fangyukangsuan granules have anti-hyperuricaemic and regulatory effects on the gut microbiota and may be a therapeutic candidate for HUA.

The effect of first-wave COVID-19 restrictions on HCV testing in Alberta, Canada: A trend analysis from 2019 to 2022.

Background: Prior to the COVID-19 pandemic, Alberta was on track to meet national HCV elimination targets by 2030. However, it is unclear how the pandemic has affected progress. Here, we aim to assess the impact of first-wave COVID-19 restrictions on Alberta HCV testing trends. Methods: HCV testing information was extracted from the provincial public health laboratory from 2019 to 2022. HCV antibody and RNA testing were categorized into (1) number ordered, (2) number positive, and (3) percent positivity, and stratified by HCV history status. Testing trends were evaluated across locations engaging high-risk individuals and priority demographics. An interrupted time-series analysis was used to identify average monthly testing rates before, during, and after first-wave COVID-19 restrictions. Results: Overall, HCV testing trends were significantly affected by COVID-19 restrictions in April 2020. Average monthly rates decreased by 98.39 antibody tests ordered per 100,000 among individuals without an HCV history and by 1.78 RNA tests ordered per 100,000 among those with an HCV history. While antibody and RNA testing trends started to rebound in the follow-up period relative to pre-restriction period, testing levels in the follow-up period remained below pre-restriction levels for all groups, except for addiction/recovery centres and emergency room/acute care facilities, which increased. Conclusions: If rates are to return to pre-restriction levels and elimination goals are to be met, more work is needed to engage individuals in HCV testing. As antibody testing rates are rebounding, reengaging those with a history of HCV for viral load monitoring and treatment should be prioritized.

AMPK signaling pathway regulated the expression of the ApoA1 gene via the transcription factor Egr1 during G. parasuis stimulation.

Glaesserella parasuis (G. parasuis) is the causative agent of porcine Glässer's disease, resulting in high mortality rates in pigs due to excessive inflammation-induced tissue damage. Previous studies investigating the protective effects of G. parasuis vaccination indicated a possible role of ApoA1 in reflecting disease progression following G. parasuis infection. However, the mechanisms of ApoA1 expression and its role in these infections are not well understood. In this investigation, newborn porcine tracheal (NPTr) epithelial cells infected with G. parasuis were used to elucidate the molecular mechanism and role of ApoA1. The study revealed that the AMPK pathway activation inhibited ApoA1 expression in NPTr cells infected with G. parasuis for the first time. Furthermore, Egr1 was identified as a core transcription factor regulating ApoA1 expression using a CRISPR/Cas9-based system. Importantly, it was discovered that APOA1 protein significantly reduced apoptosis, pyroptosis, necroptosis, and inflammatory factors induced by G. parasuis in vivo. These findings not only enhance our understanding of ApoA1 in response to bacterial infections but also highlight its potential in mitigating tissue damage caused by G. parasuis infection.

Reduced graphene oxide-encaged submicron-silicon anode interfacially stabilized by Al2O3 nanoparticles for efficient lithium-ion batteries.

Silicon-carbon composites have been recognized as some of the most promising anode candidates for advancing new-generation lithium-ion batteries (LIBs). The development of high-efficiency silicon/graphene anodes through a simple and cost-effective preparation route is significant. Herein, by using micron silicon as raw material, we designed a mesoporous composite of silicon/alumina/reduced graphene oxide (Si/Al2O3/RGO) via a two-step ball milling combined annealing process. Commercial Al2O3 nanoparticles are introduced as an interlayer due to the toughening effect, while RGO nanosheets serve as a conductive and elastic coating to protect active submicron silicon particles during lithium alloying/dealloying reactions. Owing to the rational porous structure and dual protection strategy, the core/shell structured Si/Al2O3/RGO composite is efficient for Li+ storage and demonstrates improved electrical conductivity, accelerated charge transfer and electrolyte diffusion, and especially high structural stability upon charge/discharge cycling. As a consequence, Si/Al2O3/RGO yields a high discharge capacity of 852 mA h g-1 under a current density of 500 mA g-1 even after 200 cycles, exhibiting a high capacity retention of ∼85%. Besides, Si/Al2O3/RGO achieves excellent cycling reversibility and superb high-rate capability with a stable specific capacity of 405 mA h g-1 at 3000 mA g-1. Results demonstrate that the Al2O3 interlayer is synergistic with the indispensable RGO nanosheet shells, affording more buffer space for silicon cores to alleviate the mechanical expansion and thus stabilizing active silicon species during charge/discharge cycles. This work provides an alternative low-cost approach to achieving high-capacity silicon/carbon composites for high-performance LIBs.

Transparent medical image AI via an image-text foundation model grounded in medical literature.

Building trustworthy and transparent image-based medical artificial intelligence (AI) systems requires the ability to interrogate data and models at all stages of the development pipeline, from training models to post-deployment monitoring. Ideally, the data and associated AI systems could be described using terms already familiar to physicians, but this requires medical datasets densely annotated with semantically meaningful concepts. In the present study, we present a foundation model approach, named MONET (medical concept retriever), which learns how to connect medical images with text and densely scores images on concept presence to enable important tasks in medical AI development and deployment such as data auditing, model auditing and model interpretation. Dermatology provides a demanding use case for the versatility of MONET, due to the heterogeneity in diseases, skin tones and imaging modalities. We trained MONET based on 105,550 dermatological images paired with natural language descriptions from a large collection of medical literature. MONET can accurately annotate concepts across dermatology images as verified by board-certified dermatologists, competitively with supervised models built on previously concept-annotated dermatology datasets of clinical images. We demonstrate how MONET enables AI transparency across the entire AI system development pipeline, from building inherently interpretable models to dataset and model auditing, including a case study dissecting the results of an AI clinical trial.

Telehealth Utilization and Associations in the United States During the Third Year of the COVID-19 Pandemic: Population-Based Survey Study in 2022.

BACKGROUND: The COVID-19 pandemic rapidly changed the landscape of clinical practice in the United States; telehealth became an essential mode of health care delivery, yet many components of telehealth use remain unknown years after the disease's emergence. OBJECTIVE: We aim to comprehensively assess telehealth use and its associated factors in the United States. METHODS: This cross-sectional study used a nationally representative survey (Health Information National Trends Survey) administered to US adults (≥18 years) from March 2022 through November 2022. To assess telehealth adoption, perceptions of telehealth, satisfaction with telehealth, and the telehealth care purpose, we conducted weighted descriptive analyses. To identify the subpopulations with low adoption of telehealth, we developed a weighted multivariable logistic regression model. RESULTS: Among a total of 6252 survey participants, 39.3% (2517/6252) reported telehealth use in the past 12 months (video: 1110/6252, 17.8%; audio: 876/6252, 11.6%). The most prominent reason for not using telehealth was due to telehealth providers failing to offer this option (2200/3529, 63%). The most common reason for respondents not using offered telehealth services was a preference for in-person care (527/578, 84.4%). Primary motivations to use telehealth were providers' recommendations (1716/2517, 72.7%) and convenience (1516/2517, 65.6%), mainly for acute minor illness (600/2397, 29.7%) and chronic condition management (583/2397, 21.4%), yet care purposes differed by age, race/ethnicity, and income. The satisfaction rate was predominately high, with no technical problems (1829/2517, 80.5%), comparable care quality to that of in-person care (1779/2517, 75%), and no privacy concerns (1958/2517, 83.7%). Younger individuals (odd ratios [ORs] 1.48-2.23; 18-64 years vs ≥75 years), women (OR 1.33, 95% CI 1.09-1.61), Hispanic individuals (OR 1.37, 95% CI 1.05-1.80; vs non-Hispanic White), those with more education (OR 1.72, 95% CI 1.03-2.87; at least a college graduate vs less than high school), unemployed individuals (OR 1.25, 95% CI 1.02-1.54), insured individuals (OR 1.83, 95% CI 1.25-2.69), or those with poor general health status (OR 1.66, 95% CI 1.30-2.13) had higher odds of using telehealth. CONCLUSIONS: To our best knowledge, this is among the first studies to examine patient factors around telehealth use, including motivations to use, perceptions of, satisfaction with, and care purpose of telehealth, as well as sociodemographic factors associated with telehealth adoption using a nationally representative survey. The wide array of descriptive findings and identified associations will help providers and health systems understand the factors that drive patients toward or away from telehealth visits as the technology becomes more routinely available across the United States, providing future directions for telehealth use and telehealth research.

CDK5RAP3 is a novel super-enhancer-driven gene activated by master TFs and regulates ER-Phagy in neuroblastoma.

Super enhancers (SEs) are genomic regions comprising multiple closely spaced enhancers, typically occupied by a high density of cell-type-specific master transcription factors (TFs) and frequently enriched in key oncogenes in various tumors, including neuroblastoma (NB), one of the most prevalent malignant solid tumors in children originating from the neural crest. Cyclin-dependent kinase 5 regulatory subunit-associated protein 3 (CDK5RAP3) is a newly identified super-enhancer-driven gene regulated by master TFs in NB; however, its function in NB remains unclear. Through an integrated study of publicly available datasets and microarrays, we observed a significantly elevated CDK5RAP3 expression level in NB, associated with poor patient prognosis. Further research demonstrated that CDK5RAP3 promotes the growth of NB cells, both in vitro and in vivo. Mechanistically, defective CDK5RAP3 interfered with the UFMylation system, thereby triggering endoplasmic reticulum (ER) phagy. Additionally, we provide evidence that CDK5RAP3 maintains the stability of MEIS2, a master TF in NB, and in turn, contributes to the high expression of CDK5RAP3. Overall, our findings shed light on the molecular mechanisms by which CDK5RAP3 promotes tumor progression and suggest that its inhibition may represent a novel therapeutic strategy for NB.

Human-AI interaction in skin cancer diagnosis: a systematic review and meta-analysis.

The development of diagnostic tools for skin cancer based on artificial intelligence (AI) is increasing rapidly and will likely soon be widely implemented in clinical use. Even though the performance of these algorithms is promising in theory, there is limited evidence on the impact of AI assistance on human diagnostic decisions. Therefore, the aim of this systematic review and meta-analysis was to study the effect of AI assistance on the accuracy of skin cancer diagnosis. We searched PubMed, Embase, IEE Xplore, Scopus and conference proceedings for articles from 1/1/2017 to 11/8/2022. We included studies comparing the performance of clinicians diagnosing at least one skin cancer with and without deep learning-based AI assistance. Summary estimates of sensitivity and specificity of diagnostic accuracy with versus without AI assistance were computed using a bivariate random effects model. We identified 2983 studies, of which ten were eligible for meta-analysis. For clinicians without AI assistance, pooled sensitivity was 74.8% (95% CI 68.6-80.1) and specificity was 81.5% (95% CI 73.9-87.3). For AI-assisted clinicians, the overall sensitivity was 81.1% (95% CI 74.4-86.5) and specificity was 86.1% (95% CI 79.2-90.9). AI benefitted medical professionals of all experience levels in subgroup analyses, with the largest improvement among non-dermatologists. No publication bias was detected, and sensitivity analysis revealed that the findings were robust. AI in the hands of clinicians has the potential to improve diagnostic accuracy in skin cancer diagnosis. Given that most studies were conducted in experimental settings, we encourage future studies to further investigate these potential benefits in real-life settings.

Endogenous stimuli-responsive separating microneedles to inhibit hypertrophic scar through remodeling the pathological microenvironment.

Hypertrophic scar (HS) considerably affects the appearance and causes tissue dysfunction in patients. The low bioavailability of 5-fluorouracil poses a challenge for HS treatment. Here we show a separating microneedle (MN) consisting of photo-crosslinked GelMA and 5-FuA-Pep-MA prodrug in response to high reactive oxygen species (ROS) levels and overexpression of matrix metalloproteinases (MMPs) in the HS pathological microenvironment. In vivo experiments in female mice demonstrate that the retention of MN tips in the tissue provides a slowly sustained drug release manner. Importantly, drug-loaded MNs could remodel the pathological microenvironment of female rabbit ear HS tissues by ROS scavenging and MMPs consumption. Bulk and single cell RNA sequencing analyses confirm that drug-loaded MNs could reverse skin fibrosis through down-regulation of BCL-2-associated death promoter (BAD), insulin-like growth factor 1 receptor (IGF1R) pathways, simultaneously regulate inflammatory response and keratinocyte differentiation via up-regulation of toll-like receptors (TOLL), interleukin-1 receptor (IL1R) and keratinocyte pathways, and promote the interactions between fibroblasts and keratinocytes via ligand-receptor pair of proteoglycans 2 (HSPG2)-dystroglycan 1(DAG1). This study reveals the potential therapeutic mechanism of drug-loaded MNs in HS treatment and presents a broad prospect for clinical application.

Research progress in parameterizing irrigation and fertilization in land surface model.

Under the context of global climate change and growing population, irrigation and fertilization have become important ways to ensure food production, with consequences on water cycling, energy flow, and materials cycling in terrestrial ecosystems. In the land surface model (LSM), coupling irrigation and fertilization schemes are of great importance for clearly understanding the land-atmosphere interactions to ensure food security. We reviewed the expression methods of three key parameters, namely, the applied method, usage, and time in the parameterization process of irrigation and fertilization (nitrogen fertilizer) in LSM. We found that the ways to irrigate and ferti-lize in LSM are different from the ways used in actual practice due to the limitation of the high resolution of spatio-temporal data, which makes it difficult to understand the actual influences of irrigation and fertilization on grain yield, environment, and local climate. Finally, we proposed future works: 1) taking the differences of crop water demand into account and making the different irrigation thresholds for different crops to properly evaluate the total and intensity of water consumption of different crops; 2) using the field records and the regional grid data of fertilization and irrigation developed in recent years to develop parameterized schemes that are more in line with actual agricultural operations, which can accurately reveal their economic, ecological, and climatic effects; 3) developing fertilization diagnosis scheme considering crop type, phenological stage, and soil basic fertility as the supplementary scheme in LSM, to improve the applicability and simulation accuracy of LSM in the areas without nitrogen fertilizer data.

Sex-Specific Alterations in Placental Proteomics Induced by Intrauterine Hyperglycemia.

Gestational diabetes mellitus (GDM) with intrauterine hyperglycemia induces a series of changes in the placenta, which have adverse effects on both the mother and the fetus. The aim of this study was to investigate the changes in the placenta in GDM and its gender differences. In this study, we established an intrauterine hyperglycemia model using ICR mice. We collected placental specimens from mice before birth for histological observation, along with tandem mass tag (TMT)-labeled proteomic analysis, which was stratified by sex. When the analysis was not segregated by sex, the GDM group showed 208 upregulated and 225 downregulated proteins in the placenta, primarily within the extracellular matrix and mitochondria. Altered biological processes included cholesterol metabolism and oxidative stress responses. After stratification by sex, the male subgroup showed a heightened tendency for immune-related pathway alterations, whereas the female subgroup manifested changes in branched-chain amino acid metabolism. Our study suggests that the observed sex differences in placental protein expression may explain the differential impact of GDM on offspring.

HIF1A transcriptional regulation of COX4I2 impacts angiogenesis in pheochromocytoma.

BACKGROUND: Pheochromocytoma (PCC) is a rare neuroendocrine tumor. Angiogenesis is primary contributing factor for tumorigenesis. Cytochrome c oxidase 4I2 (COX4I2) has been confirmed to take part in the progression of cancer. Hypoxia-inducible factor 1A (HIF1A) is the main regulatory factor for the steady-state response of hypoxia, involved in metabolism and angiogenesis. In this study, we intended to explore the functions of COX4I2 in PCC and the effect mechanism between HIF1A and COX4I2. MATERIALS AND METHODS: The RNA-sequencing and immunohistochemistry tested COX4I2 expression in highly vascular PCC. Small interfering RNA (siRNA) was used to reduce the mRNA expression of COX4I2, and a small molecule inhibitor was utilized to reduce the protein expression of HIF1A. Culturing cells in 1% O2environment was performed to activate HIF1A. Western blot was applied to quantify the expression of target genes at the protein levels. The supernatant from PCC cells and fibroblasts acted as the conditioned medium. We conducted the tube formation and transwell assays in human vascular endothelial cells (HUVECs) to determine angiogenesis, the binding of COX4I2 promoter and HIF1A was evaluated by the dual luciferase reporter assay. RESULTS: COX4I2 had been rigorously shown to be overexpressed in highly vascular PCC. Knockdown of COX4I2 in PCC cells (MPC) did not significantly impact angiogenesis, while knockdown of COX4I2 in fibroblast (3T3) notably inhibited angiogenesis. RNA sequencing suggested that the expression of 11 vascular markers, such as CD34 and angiogenesis associated pathways in 3T3, decreased with knockdown of COX4I2. HIF1A had been shown to enhance the mRNA expression of COX4I2 through transcriptional regulation. Activation and inhibition of HIF1A resulted in upregulation and downregulation of COX4I2, respectively. The HIF1A inhibitor demonstrated a reduction in angiogenesis. CONCLUSION: COX4I2 is overexpressed in highly vascular PCC and contributes to angiogenesis in fibroblasts. Mechanistically, HIF1A transcriptional regulation enhances COX4I2 and its effects on angiogenesis in PCC. COX4I2 might serve as a vascular marker and represent a potential target for vascular therapy.

Acidity-activated aggregation and accumulation of self-complementary zwitterionic peptide-decorated gold nanoparticles for photothermal biofilm eradication.

Drug-resistant biofilm infection is an extremely serious clinical problem, that easily leads to failure of antibiotic treatment. Although gold nanoparticles (AuNPs) as photothermal agents have been widely used in biofilm eradication, there are still challenges to be addressed, such as insignificantly redshifted absorption and slow assembly process of aggregated AuNPs. Herein, we developed an acidity-activated dispersion-to-aggregation transition to enhance the accumulation of self-complementary zwitterionic peptide-decorated AuNPs for photothermal eradication of drug-resistant biofilm infections. AuNPs were decorated with self-complementary zwitterionic peptides (ZP1 and ZP2) coupled with pH-sensitive anhydride (DMA) and pH-insensitive anhydride (SA), respectively. ZP2-decorated AuNPs with DMA modification (AuNP@ZP2(DMA)) exhibited prolonged blood circulation and enhanced accumulation in acidic biofilm microenvironment. Moreover, the electrostatic attraction between self-complementary ligands drove AuNPs to form closely packed aggregates with strong near-infrared absorption, leading to in vivo photoacoustic imaging ability and photothermal effect against drug-resistant bacteria and fungus, as well as microbial biofilms. AuNP@ZP2(DMA) with longer charge domains and a polyethylene glycol oligomer spacer showed greater photothermal antimicrobial and biofilm resistance in vitro and in vivo. This study develops an innovative acidity-activated AuNP photothermal agent, which provides an effective approach for treatment of biofilm infections.

The BET inhibitor GNE-987 effectively induces anti-cancer effects in T-cell acute lymphoblastic leukemia by targeting enhancer regulated genes.

T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy originating from T progenitor cells. It accounts for 15% of childhood and 25% of adult ALL cases. GNE-987 is a novel chimeric molecule developed using proteolysis-targeting chimeras (PROTAC) technology for targeted therapy. It consists of a potent inhibitor of the bromodomain and extraterminal (BET) protein, as well as the E3 ubiquitin ligase Von Hippel-Lindau (VHL), which enables the effective induction of proteasomal degradation of BRD4. Although GNE-987 has shown persistent inhibition of cell proliferation and apoptosis, its specific antitumor activity in T-ALL remains unclear. In this study, we aimed to investigate the molecular mechanisms underlying the antitumor effect of GNE-987 in T-ALL. To achieve this, we employed technologies including RNA sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq) and CUT&Tag. The degradation of BET proteins, specifically BRD4, by GNE-987 has a profound impact on T-ALL cell. In in vivo experiments, sh-BRD4 lentivirus reduced T-ALL cell proliferation and invasion, extending the survival time of mice. The RNA-seq and CUT&Tag analyses provided further insights into the mechanism of action of GNE-987 in T-ALL. These analyses revealed that GNE-987 possesses the ability to suppress the expression of various genes associated with super-enhancers (SEs), including lymphoblastic leukemia 1 (LCK). By targeting these SE-associated genes, GNE-987 effectively inhibits the progression of T-ALL. Importantly, SE-related oncogenes like LCK were identified as critical targets of GNE-987. Based on these findings, GNE-987 holds promise as a potential novel candidate drug for the treatment of T-ALL.