Establishment of human corneal epithelial organoids for ex vivo modelling dry eye disease.

Dry eye disease (DED) is a growing public health concern affecting millions of people worldwide and causing ocular discomfort and visual disturbance. Developing its therapeutic drugs based on animal models suffer from interspecies differences and poor prediction of human trials. Here, we established long-term 3D human corneal epithelial organoids, which recapitulated the cell lineages and gene expression signature of the human corneal epithelium. Organoids can be regulated to differentiate ex vivo, but the addition of FGF10 inhibits this process. In the hyperosmolar-induced DED organoid model, the release of inflammatory factors increased, resulting in damage to the stemness of stem cells and a decrease in functional mucin 1 protein. Furthermore, we found that the organoids could mimic clinical drug treatment responses, suggesting that corneal epithelial organoids are promising candidates for establishing a drug testing platform ex vivo. In summary, we established a functional, long-term 3D human epithelial organoid that may serve as an ex vivo model for studying the functional regulation and disease modelling.

Development and validation of gestational diabetes mellitus health literacy scale.

OBJECTIVE: While there are various health literacy scales that exist, none of health literacy scale suitable for pregnant women with gestational diabetes mellitus (GDM). To address this gap, this study aimed to develop GDM health literacy scale and evaluate its psychometric properties. METHODS: Based on the Delphi expert consultation, we developed the initial GDM health literacy scale. Item analysis was taken using a sample (n = 299) recruited in China to form formal scale. Additional participants (n = 395) completed survey to assess the internal consistency reliability, test-retest reliability, content validity, construct validity and criterion correlation validity of scale. RESULTS: The scale performed well in terms of internal consistency reliability, content validity, construct validity and criterion correlation validity. Test-retest reliability indicated that the instrument was effective at measuring health literacy of GDM over time. CONCLUSION: The scale is a reliable and valid measure of six domains of health literacy for GDM. PRACTICE IMPLICATIONS: The scale can be used to effectively evaluate the level of health literacy of pregnant women with GDM. The information can provide targeted health support for pregnant women with GDM to improve their health literacy and self-management ability.

Cultivation of novel Atribacterota from oil well provides new insight into their diversity, ecology, and evolution in anoxic, carbon-rich environments.

BACKGROUND: The Atribacterota are widely distributed in the subsurface biosphere. Recently, the first Atribacterota isolate was described and the number of Atribacterota genome sequences retrieved from environmental samples has increased significantly; however, their diversity, physiology, ecology, and evolution remain poorly understood. RESULTS: We report the isolation of the second member of Atribacterota, Thermatribacter velox gen. nov., sp. nov., within a new family Thermatribacteraceae fam. nov., and the short-term laboratory cultivation of a member of the JS1 lineage, Phoenicimicrobium oleiphilum HX-OS.bin.34TS, both from a terrestrial oil reservoir. Physiological and metatranscriptomics analyses showed that Thermatribacter velox B11T and Phoenicimicrobium oleiphilum HX-OS.bin.34TS ferment sugars and n-alkanes, respectively, producing H2, CO2, and acetate as common products. Comparative genomics showed that all members of the Atribacterota lack a complete Wood-Ljungdahl Pathway (WLP), but that the Reductive Glycine Pathway (RGP) is widespread, indicating that the RGP, rather than WLP, is a central hub in Atribacterota metabolism. Ancestral character state reconstructions and phylogenetic analyses showed that key genes encoding the RGP (fdhA, fhs, folD, glyA, gcvT, gcvPAB, pdhD) and other central functions were gained independently in the two classes, Atribacteria (OP9) and Phoenicimicrobiia (JS1), after which they were inherited vertically; these genes included fumarate-adding enzymes (faeA; Phoenicimicrobiia only), the CODH/ACS complex (acsABCDE), and diverse hydrogenases (NiFe group 3b, 4b and FeFe group A3, C). Finally, we present genome-resolved community metabolic models showing the central roles of Atribacteria (OP9) and Phoenicimicrobiia (JS1) in acetate- and hydrocarbon-rich environments. CONCLUSION: Our findings expand the knowledge of the diversity, physiology, ecology, and evolution of the phylum Atribacterota. This study is a starting point for promoting more incisive studies of their syntrophic biology and may guide the rational design of strategies to cultivate them in the laboratory. Video Abstract.

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Precipitation in the plum rain period accounts for 40%-50% of annual precipitation in the monsoon region. To clarify the temporal variability of the isotopic composition of precipitation during the plum rain period from event to interannual time scale and identify the influencing factors, we analyzed the isotopic composition of precipitation and its influencing factors in Nanjing from 2015 to 2022. By using the Hybrid Single-particle Lagran-gian Integrated Trajectory (HYSPLIT) model with specific humidity analysis, we investigated the water vapor source and influencing factors. The results showed that 1) the isotopic abundance of atmospheric precipitation was depleted in the summer and enriched in winter. dx was lower in summer and higher in winter. The isotopic abundance of precipitation from the plum rain was depleted compared to mean value of the whole-year. 2) There was no significant correlation between δ2H and δ18O of the plum rain (precipitation) with local meteorological factors. However, dx was lower in light rain, reflecting the effect of sub-cloud evaporation. The average dx was higher during plum rain period in years with more total plum rain precipitation. 3) The low-latitude South China Sea and the western Pacific Ocean source area provided water vapor for the plum rain. The shift of moisture source region led to abrupt changes in precipitation isotopes. Our results could provide data support for studies on precipitation isotopes in the monsoon region, as well as a reference point for further understanding the precipitation mechanism of the plum rain and stu-dying the seasonal variability of atmospheric circulation in the East Asian monsoon region.

Gas6-Axl signal promotes indoor VOCs exposure-induced pulmonary fibrosis via pulmonary microvascular endothelial cells-fibroblasts cross-talk.

Volatile organic compounds (VOCs) as environmental pollutants were associated with respiratory diseases. Pulmonary fibrosis (PF) was characterized by an increase of extracellular matrix, leading to deterioration of lung function. The adverse effects on lung and the potential mechanism underlying VOCs induced PF had not been elucidated clearly. In this study, the indoor VOCs exposure mouse model along with an ex vivo biosensor assay was established. Based on scRNA-seq analysis, the adverse effects on lung and potential molecular mechanism were studied. Herein, the results showed that VOCs exposure from indoor decoration contributed to decreased lung function and facilitated pulmonary fibrosis in mice. Then, the whole lung cell atlas after VOCs exposure and the heterogeneity of fibroblasts were revealed. We explored the molecular interactions among various pulmonary cells, suggesting that endothelial cells contributed to fibroblasts activation in response to VOCs exposure. Mechanistically, pulmonary microvascular endothelial cells (MPVECs) secreted Gas6 after VOCs-induced PANoptosis phenotype, bound to the Axl in fibroblasts, and then activated fibroblasts. Moreover, Atf3 as the key gene negatively regulated PANoptosis phenotype to ameliorate fibrosis induced by VOCs exposure. These novel findings provided a new perspective about MPVECs could serve as the initiating factor of PF induced by VOCs exposure.

Endometrial stem cell-derived exosomes repair cisplatin-induced premature ovarian failure via Hippo signaling pathway.

Stem cells have been documented as a new therapeutic method for ovarian injuries such as premature ovarian failure (POF). However, effects of exosomes (Exos) derived from human endometrial stem cells (EnSCs) on diminished ovarian failure remain to be carefully elucidated. Our study aims to investigate the mechanisms of EnSC-Exos in the recovery of the cisplatin-induced granulosa cell injury model in vitro or POF mouses model in vivo and whether the Hippo signaling pathway is involved in the regulation. In this study, we established successful construction of the cisplatin-induced granulosa cell injury model and evaluated Hippo signaling pathway activation in cisplatin-damaged granulosa cells (GCs). Furthermore, laser scanning confocal microscope and immunofluorescence demonstrated that EnSC-Exos can be transferred to cisplatin-damaged GCs to decrease apoptosis. In addition, the enhanced expression of YAP at the protein level as well as YAP/TEAD target genes, such as CTGF, ANKRD1, and the increase of YAP into the nucleus in immunofluorescence staining after the addition of EnSC-Exos to cisplatin-damaged GCs confirmed the suppression of Hippo signaling pathway. While in vivo, EnSC-Exos successfully remedied POF in a mouse model. Collectively, our findings suggest that chemotherapy-induced POF was associated with the activating of Hippo signaling pathway. Human EnSC-Exos significantly elevated the proliferation of ovarian GCs and the ovarian function by regulating Hippo signaling pathway. These findings provide new insights for further understanding of EnSC-Exos in the recovery of ovary function.

Red nucleus mGluR1 and mGluR5 facilitate the development of neuropathic pain through stimulating the expressions of TNF-α and IL-1ß.

Our previous study has identified that glutamate in the red nucleus (RN) facilitates the development of neuropathic pain through metabotropic glutamate receptors (mGluR). Here, we further explored the actions and possible molecular mechanisms of red nucleus mGluR Ⅰ (mGluR1 and mGluR5) in the development of neuropathic pain induced by spared nerve injury (SNI). Our data indicated that both mGluR1 and mGluR5 were constitutively expressed in the RN of normal rats. Two weeks after SNI, the expressions of mGluR1 and mGluR5 were significantly boosted in the RN contralateral to the nerve injury. Administration of mGluR1 antagonist LY367385 or mGluR5 antagonist MTEP to the RN contralateral to the nerve injury at 2 weeks post-SNI significantly ameliorated SNI-induced neuropathic pain. However, unilateral administration of mGluRⅠ agonist DHPG to the RN of normal rats provoked a significant mechanical allodynia, this effect could be blocked by LY367385 or MTEP. Further studies indicated that the expressions of TNF-α and IL-1ß in the RN were also elevated at 2 weeks post-SNI. Administration of mGluR1 antagonist LY367385 or mGluR5 antagonist MTEP to the RN at 2 weeks post-SNI significantly inhibited the elevations of TNF-α and IL-1ß. However, administration of mGluR Ⅰ agonist DHPG to the RN of normal rats significantly enhanced the expressions of TNF-α and IL-1ß, these effects were blocked by LY367385 or MTEP. These results suggest that activation of red nucleus mGluR1 and mGluR5 facilitate the development of neuropathic pain by stimulating the expressions of TNF-α and IL-1ß. mGluR Ⅰ maybe potential targets for drug development and clinical treatment of neuropathic pain.

Integrating Patient-Based Real-Time Quality Control (PBRTQC) in a New Field: Inter-Comparison between Biochemical Instrumentations with LDL-C.

BACKGROUND: Patient-based real-time quality control (PBRTQC) can be a valuable tool in clinical laboratories due to its cost-effectiveness and constant monitoring. More focus is placed on discovering and improving algorithms that compliment conventional internal control techniques. The practical implementation of PBRTQC with a biochemical instrument comparison is lacking. We aim to evaluate PBRTQC's efficacy and practicality by comparing low-density lipoprotein cholesterol (LDL-C) test results to ensure consistent real-time monitoring across biochemical instrumentations in clinical laboratories. METHOD: From 1 September 2021 to 30 August 2022, the First Affiliated Hospital of Xi'an Jiaotong University collected data from 158,259 both healthy and diseased patients, including 84,187 male and 74,072 female patients, and examined their LDL-C results. This dataset encompassed a group comprising 50,556 individuals undergoing health examinations, a group comprising 42,472 inpatients (IP), and a group comprising 75,490 outpatients (OP) for the PBRTQC intelligent monitoring platform to conduct daily tests, parameter configuration, program development, real-time execution, and performance validation of the patients' data. Moreover 40 patients' LDL-C levels were assessed using two biochemical analyzers, designated as the reference and comparator instruments. A total of 160 LDL-C results were obtained from 40 both healthy and diseased patients, including 14 OP, 16 IP, and 10 health examination attendees, who were selected to represent LDL-C levels broadly. Two biochemical instruments measured LDL-C measurements from the same individuals to investigate consistency and reproducibility across patient statuses and settings. We employed exponentially weighted moving average (EWMA) and moving median (MM) methods to calculate inter-instrument bias and ensure analytical accuracy. Inter-instrument bias for LDL-C measurements was determined by analyzing fresh serum samples, different concentrations of quality control (QC), and commercialized calibrators, employing both EWMA and MM within two assay systems. The assessment of inter-instrumental bias with five different methods adhered to the external quality assessment standards of the Clinical Laboratory Center of the Health Planning Commission, which mandates a bias within ±15.0%. RESULT: We calculated inter-instrument comparison bias with each of the five methods based on patient big data. The comparison of fresh serum samples, different concentrations of QC, commercialized calibrators, and EWMA were all in the permissive range, except for MM. MM showed that the bias between two biochemical instruments in the concentration ranges of 1.5 mmoL/L-6.2 mmoL/L exceeded the permissible range. This was mainly due to the small number of specimens, affected by variations among individual patients, leading to increased false alarms and reduced effectiveness in monitoring the consistency of the inter-instrumental results. Moreover, the inter-comparison bias derived from EWMA was less than 3.01%, meeting the 15% range assessment criteria. The bias result for MM was lower than 24.66%, which was much higher than EWMA. Thus, EWMA is better than MM for monitoring inter-instrument comparability. PBRTQC can complement the use of inter-comparison bias between biochemical analyzers. EWMA has comparable inter-instrument comparability monitoring efficacy. CONCLUSIONS: The utilization of AI-based PBRTQC enables the automated real-time comparison of test results across different biochemical instruments, leading to a reduction in laboratory operating costs, enhanced work efficiency, and improved QC. This advanced technology facilitates seamless data integration and analysis, ultimately contributing to a more streamlined and efficient laboratory workflow in the biomedical field.

Associations between genomic aberrations, increased nuchal translucency, and pregnancy outcomes: a comprehensive analysis of 2,272 singleton pregnancies in women under 35.

Objectives: Regarding increased nuchal translucency (NT), the cutoff values used are heterogeneous in clinical practice, this study aims to assess the efficacy of prenatal detection for chromosomal abnormalities and pregnancy outcomes in fetuses with varying NT thicknesses, in order to provide data that supports informed prenatal diagnosis and genetic counseling for such cases. Methods: We included 2,272 pregnant women under 35 with singleton pregnancies who underwent invasive prenatal diagnosis between 2014 and 2022. The cohort comprised 2,010 fetuses with increased NT (≥2.5 mm) and 262 fetuses with normal NT but exhibiting a single soft marker. Prenatal diagnoses were supported by chromosomal microarray (CMA) and copy number variation sequencing (CNV-seq) analyses. Results: The detection rates of numerical chromosomal abnormalities were 15.4% (309/2,010) and 17.3% (297/1,717) in the NT ≥2.5 and ≥ 3.0 groups, respectively. Pathogenic/likely pathogenic CNV incidence increased with NT thickness (χ2 = 8.60, p < 0.05), peaking at 8.7% (22/254) in the NT 4.5-5.4 mm group. Structural defects were found in 18.4% of fetuses with NT values between 2.5 mm and 2.9 mm. Chromosomal abnormality rates in the isolated increased NT groups of 2.5-2.9 mm and 3.0-3.4 mm were 6.7% (16/239) and 10.0% (47/470), respectively, with no statistical significance (χ2 = 2.14, p > 0.05). Fetuses with NT thickness between 2.5 and 2.9 mm combined with the presence of soft markers or non-lethal structural abnormalities exhibited a significantly higher chromosomal abnormality risk (19.0%) compared to fetuses with isolated increased NT ranging from 3.5 to 4.4 mm (13.0%). Pregnancy termination rates increased with NT thickness (χ2 = 435.18, p < 0.0001), ranging from 12.0% (30/249) in the NT 2.5-2.9 mm group to 87.0% (141/162) in the NT ≥ 6.5 mm group. Conclusion: CMA or CNV-seq exhibited good performance in identifying genomic aberrations in pregnancies with increased NT thickness. NT ranging from 2.5 mm to 2.9 mm elevated the risk of fetal chromosomal abnormalities, particularly when combined with other soft markers.

Congenital Midline Upper Lip Sinus: Case Report and Review of the Literature.

Congenital midline sinus of the upper lip are rare congenital malformations. We recently identified a case featuring a congenital midline sinus of the upper lip. The punctate opening was positioned at the midline of the philtrum, immediately below the base of the columella. Surgical removal of the sinus tract was conducted through an intraoral approach. Up to now, fewer than 70 cases have been reported. Several postulates, including the fusion theory, merging theory, and invagination theory, have been proposed to explain the formation of the congenital midline sinus of the upper lip. Nevertheless, the etiology of this uncommon abnormality remains unclear. This report details a case of a congenital upper lip sinus presenting as a congenital midline sinus of the upper lip and reviews the current literature on this condition.

FGF2 promotes the proliferation of injured granulosa cells in premature ovarian failure via Hippo-YAP signaling pathway.

Young women undergoing anticancer treatment are at risk of premature ovarian failure (POF). Endometrial-derived stem cells (EnSCs) have demonstrated significant therapeutic potential for treating ovarian insufficiency, although the underlying mechanisms remain to be fully understood. This study aims to further investigate the therapeutic effects of EnSCs, particularly through the paracrine action of fibroblast growth factor 2 (FGF2), on POF. The findings show that exogenous FGF2 enhances the survival of ovarian granulosa cells damaged by cisplatin. FGF2 stimulates the proliferation of these damaged cells by suppressing the Hippo signaling pathway and activating YAP expression. In vivo experiments also revealed that FGF2 treatment significantly improves ovarian reserve and endocrine function in mice with POF. These results suggest that FGF2 can boost the proliferative capacity of damaged ovarian granulosa cells through the Hippo-YAP signaling pathway, providing a theoretical foundation for using EnSCs and FGF2 in clinical treatments for POF.

Synergistic effects of rhizosphere effect and combined organic and chemical fertilizers application on soil bacterial diversity and community structure in oilseed rape cultivation.

The combined application of chemical and organic fertilizers has been recognized to enhance soil fertility and foster the soil microbial ecosystem. However, the optimal ratio of chemical and organic fertilizers in oilseed rape cultivation is still uncertain, and the role of rhizosphere effect is still unclear. Thus, this study aimed to elucidate the impacts of varying ratios of chemical and organic fertilizers on the structure and potential functionalities of rhizosphere and non-rhizosphere soil microbial communities. The interplay of microbial communities with soil properties and oilseed rape root exudates was investigated in controlled pot cultivations receiving varying ratios of chemical and organic fertilizers. Results indicated clear segregation in the soil bacterial community, influenced by both fertilization treatments and rhizosphere effects. The bacterial community structure significantly correlated with nitrate nitrogen, organic acids, and dissolved organic carbon (DOC) content. Rhizosphere effects led to increased bacteria abundance, reduced diversity, and decreased network stability. Notably, F3 treatment receiving 25% chemical and 75% organic fertilizers showed a significantly higher abundance at 1.43 × 1011 copies g-1 dry soil, accompanied by increased species and genetic diversity, and ecological network complexity. This treatment also yielded the highest aboveground biomass of oilseed rape. However, the application of organic fertilizers also increased the risk of plant pathogenicity. This study reveals the impact of fertilizers and rhizosphere effects on soil microbial community structure and function, shedding light on the establishment of more effective fertilization schemes for oilseed rape agriculture.

A novel microbial community restructuring strategy for enhanced hydrogen production using multiple pretreatments and CSTR operation.

To achieve rapid enrichment of the targeted hydrogen-producing bacterial population and reconstruction of the microbial community in the biological hydrogen-producing reactor, the activated sludge underwent multiple pretreatments using micro-aeration, alkaline treatment, and heat treatment. The activated sludge obtained from the multiple pretreatments was inoculated into the continuous stirred tank reactor (CSTR) for continuous operations. The community structure alteration and hydrogen-producing capability of the activated sludge were analyzed throughout the operation of the reactor. We found that the primary phyla in the activated sludge population shifted to Proteobacteria, Firmicutes, and Bacteroidetes, which collectively accounted for 96.69% after undergoing several pretreatments. This suggests that the multiple pretreatments facilitated in achieving the selective enrichment of the fermentation hydrogen-producing microorganisms in the activated sludge. The CSTR start-up and continuous operation of the biological hydrogen production reactor resulted in the reactor entering a highly efficient hydrogen production stage at influent COD concentrations of 4000 mg/L and 5000 mg/L, with the highest hydrogen production rate reaching 8.19 L/d and 9.33 L/d, respectively. The main genus present during the efficient hydrogen production stage in the reactor was Ethanoligenens, accounting for up to 33% of the total population. Ethanoligenens exhibited autoaggregation capabilities and a superior capacity for hydrogen production, leading to its prevalence in the reactor and contribution to efficient hydrogen production. During high-efficiency hydrogen production, flora associated with hydrogen production exhibited up to 46.95% total relative abundance. In addition, redundancy analysis (RDA) indicated that effluent pH and COD influenced the distribution of the primary hydrogen-producing bacteria, including Ethanoligenens, Raoultella, and Pectinatus, as well as other low abundant hydrogen-producing bacteria in the activated sludge. The data indicates that the multiple pretreatments and reactor's operation has successfully enriched the hydrogen-producing genera and changed the community structure of microbial hydrogen production.

The interactions of subcellular organelles in pulmonary fibrosis induced by carbon black nanoparticles: a comprehensive review.

Owing to the widespread use and improper emissions of carbon black nanoparticles (CBNPs), the adverse effects of CBNPs on human health have attracted much attention. In toxicological research, carbon black is frequently utilized as a negative control because of its low toxicity and poor solubility. However, recent studies have indicated that inhalation exposure to CBNPs could be a risk factor for severe and prolonged pulmonary inflammation and fibrosis. At present, the pathogenesis of pulmonary fibrosis induced by CBNPs is still not fully elucidated, but it is known that with small particle size and large surface area, CBNPs are more easily ingested by cells, leading to organelle damage and abnormal interactions between organelles. Damaged organelle and abnormal organelles interactions lead to cell structure and function disorders, which is one of the important factors in the development and occurrence of various diseases, including pulmonary fibrosis. This review offers a comprehensive analysis of organelle structure, function, and interaction mechanisms, while also summarizing the research advancements in organelles and organelle interactions in CBNPs-induced pulmonary fibrosis.

Curcumol: a review of its pharmacology, pharmacokinetics, drug delivery systems, structure-activity relationships, and potential applications.

Curcumol (Cur), a guaiane-type sesquiterpenoid hemiketal, is an important and representative bioactive component extracted from the essential oil of the rhizomes of Curcumae rhizoma which is also known as "Ezhu" in traditional Chinese medicine. Recently, Cur has received considerable attention from the research community due to its favorable pharmacological activities, including anti-cancer, hepatoprotective, anti-inflammatory, anti-viral, anti-convulsant, and other activities, and has also exerted therapeutic effect on various cancers, liver diseases, inflammatory diseases, and infectious diseases. Pharmacokinetic studies have shown that Cur is rapidly distributed in almost all organs of rats after intragastric administration with high concentrations in the small intestine and colon. Several studies focusing on structure-activity relationship (SAR) of Cur have shown that some Cur derivatives, chemically modified at C-8 or C-14, exhibited more potent anti-cancer activity and lower toxicity than Cur itself. This review aims to comprehensively summarize the latest advances in the pharmacological and pharmacokinetic properties of Cur in the last decade with a focus on its anti-cancer and hepatoprotective potentials, as well as the research progress in drug delivery system and potential applications of Cur to date, to provide researchers with the latest information, to highlighted the limitations of relevant research at the current stage and the aspects that should be addressed in future research. Our results indicate that Cur and its derivatives could serve as potential novel agents for the treatment of a variety of diseases, particularly cancer and liver diseases.

Amino acid formula induces microbiota dysbiosis and depressive-like behavior in mice.

Amino acid formula (AAF) is increasingly consumed in infants with cow's milk protein allergy; however, the long-term influences on health are less described. In this study, we established a mouse model by subjecting neonatal mice to an amino acid diet (AAD) to mimic the feeding regimen of infants on AAF. Surprisingly, AAD-fed mice exhibited dysbiotic microbiota and increased neuronal activity in both the intestine and brain, as well as gastrointestinal peristalsis disorders and depressive-like behavior. Furthermore, fecal microbiota transplantation from AAD-fed mice or AAF-fed infants to recipient mice led to elevated neuronal activations and exacerbated depressive-like behaviors compared to that from normal chow-fed mice or cow's-milk-formula-fed infants, respectively. Our findings highlight the necessity to avoid the excessive use of AAF, which may influence the neuronal development and mental health of children.

Predictive value of CDC37 gene expression for targeted therapy in metastatic colorectal cancer.

BACKGROUND: CDC37 is a key determinant of client kinase recruitment to the HSP90 chaperoning system. We hypothesized that kinase-specific dependency on CDC37 alters the efficacy of targeted therapies for metastatic colorectal cancer (mCRC). MATERIAL AND METHODS: Two independent mCRC cohorts were analyzed to compare the survival outcomes between CDC37-high and CDC37-low patients (stratified by the median cutoff values): the CALGB/SWOG 80405 trial (226 and 207 patients receiving first-line bevacizumab- and cetuximab-containing chemotherapies, respectively) and Japanese retrospective (50 refractory patients receiving regorafenib) cohorts. A dataset of specimens submitted to a commercial CLIA-certified laboratory was utilized to characterize molecular profiles of CDC37-high (top quartile, N = 5055) and CDC37-low (bottom quartile, N = 5055) CRCs. RESULTS: In the bevacizumab-treated group, CDC37-high patients showed significantly better progression-free survival (PFS) (median 13.3 vs 9.6 months, hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.44-0.79, p < 0.01) than CDC37-low patients. In the cetuximab-treated group, CDC37-high and CDC37-low patients had similar outcomes. In the regorafenib-treated group, CDC37-high patients showed significantly better overall survival (median 11.3 vs 6.0 months, HR 0.24, 95% CI 0.11-0.54, p < 0.01) and PFS (median 3.5 vs 1.9 months, HR 0.51, 95% CI 0.28-0.94, p = 0.03). Comprehensive molecular profiling revealed that CDC37-high CRCs were associated with higher VEGFA, FLT1, and KDR expressions and activated hypoxia signature. CONCLUSIONS: CDC37-high mCRC patients derived more benefit from anti-VEGF therapies, including bevacizumab and regorafenib, but not from cetuximab. Molecular profiles suggested that such tumors were dependent on angiogenesis-relating pathways.

Dual-modality probe nanodrug delivery systems with ROS-sensitivity for atherosclerosis diagnosis and therapy.

Most acute cardiovascular and cerebrovascular diseases are caused by atherosclerotic plaque rupture leading to blocked arteries. Targeted nanodelivery systems deliver imaging agents or drugs to target sites for diagnostic imaging or the treatment of various diseases, providing new insights for the detection and treatment of atherosclerosis. Based on the pathological characteristics of atherosclerosis, a hydrogen peroxide-sensitive bimodal probe PPIS@FC with integrated diagnosis and treatment function was designed. Bimodal probes Fe3O4@SiO2-CDs (FC) were prepared by coupling superparamagnetic iron oxide and carbon quantum dots synthesized with citric acid, and self-assembled with hydrogen peroxide stimulus-responsive amphiphilic block polymer PGMA-PEG modified with simvastatin (Sim) and target molecule ISO-1 to obtain drug-loaded micelles PGMA-PEG-ISO-1-Sim@FC (PPIS@FC). PPIS@FC could release Sim and FC in an H2O2-triggered manner, achieving the goal of releasing drugs using the special microenvironment at the plaque. At the same time, in vivo magnetic resonance and fluorescence imaging results proved that PPIS@FC possessed targeting ability, magnetic resonance imaging and fluorescence imaging effects. The results of the FeCl3 and ApoE-/- model showed that PPIS@FC had an excellent therapeutic effect and in vivo safety. Therefore, dual-modality imaging drug delivery systems with ROS response will become a promising strategy for the diagnosis and treatment of atherosclerosis.

Theoretical Investigation of the BCN Monolayer and Their Derivatives for Metal-free CO2 Photocatalysis, Capture, and Utilization.

In recent years, carbon capture and utilization (CCU) has been explored as an attractive solution to global warming, which is mainly caused by increasing CO2 emission levels. Many functional materials have been developed for removing atmospheric CO2 and converting it to more useful forms of carbon. Traditional metallic photocatalytic species have drawbacks-photocorrosion, low visible-light absorbance, and environmental damage; therefore, metal-free materials have attracted considerable research attention. In particular, boron nitride (BN) possesses unique B-N bonds, characterized by a large difference in the electronegativity of atoms that facilitates CO2 reduction, and catalytic CO2 reduction by boron carbon nitride (BCN) has been demonstrated under visible light; hence, these two materials can be considered potential CO2 reduction photocatalysts. However, further modification of the materials and their applicability to other CCU applications have not been extensively explored. Therefore, we decided to investigate the modification of BCN monolayers, with the aim of ensuring that the properties of the materials are better suited, first, to the requirements of CO2 photocatalysis, and second, to those of carbon capture or other optoelectronic applications. In this study, we considered various novel BCN monolayers, based on modification via metal-free substitutional doping and nitrogen vacancy creation, and performed first-principles density functional theory calculations. The effects of the modifications on band gap tuning, charge transfer, and the CO2 adsorption ability were all studied. Specifically, ON-B13C8N11 and SiC-2 × 2-BC6N were shown to possess excellent properties for photocatalytic CO2 reduction, and OC-2 × 2-BC6N and Nv-4 × 4-BN can be considered for future CO2 capture materials. These results contribute to existing CCU approaches, suggesting that BCN monolayer modification merits further investigation, and offering insights relevant to other photocatalytic applications.

CCR5 and CCL5 gene expression in colorectal cancer: comprehensive profiling and clinical value.

BACKGROUND: The C-C motif chemokine receptor 5 (CCR5)/C-C motif chemokine ligand 5 (CCL5) axis plays a major role in colorectal cancer (CRC). We aimed to characterize the molecular features associated with CCR5/CCL5 expression in CRC and to determine whether CCR5/CCL5 levels could impact treatment outcomes. METHODS: 7604 CRCs tested with NextGen Sequencing on DNA and RNA were analyzed. Molecular features were evaluated according to CCR5 and CCL5 tumor gene expression quartiles. The impact on treatment outcomes was assessed in two cohorts, including 6341 real-world patients and 429 patients from the Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial. RESULTS: CCR5/CCL5 expression was higher in right-sided versus left-sided tumors, and positively associated with consensus molecular subtypes 1 and 4. Higher CCR5/CCL5 expression was associated with higher tumor mutational burden, deficiency in mismatch repair and programmed cell death ligand 1 (PD-L1) levels. Additionally, high CCR5/CCL5 were associated with higher immune cell infiltration in the tumor microenvironment (TME) of MMR proficient tumors. Ingenuity pathway analysis revealed upregulation of the programmed cell death protein 1 (PD-1)/PD-L1 cancer immunotherapy pathway, phosphatase and tensin homolog (PTEN) and peroxisome proliferator-activated receptors (PPAR) signaling, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) signaling in cytotoxic T lymphocytes, whereas several inflammation-related pathways were downregulated. Low CCR5/CCL5 expression was associated with increased benefit from cetuximab-FOLFOX treatment in the CALGB/SWOG 80405 trial, where significant treatment interaction was observed with biologic agents and chemotherapy backbone. CONCLUSIONS: Our data show a strong association between CCR5/CCL5 gene expression and distinct molecular features, gene expression profiles, TME cell infiltration, and treatment benefit in CRC. Targeting the CCR5/CCL5 axis may have clinical applications in selected CRC subgroups and may play a key role in developing and deploying strategies to modulate the immune TME for CRC treatment.