High-Sensitivity Differential Helmholtz Photoacoustic System Combined with the Herriott Multipass Cell and Its Application in Seed Respiration.

A highly sensitive photoacoustic detection system using a differential Helmholtz resonator (DHR) combined with a Herriott multipass cell is presented, and its implementation to sub-ppm level carbon dioxide (CO2) detection is demonstrated. Through the utilization of erbium-doped optical fiber amplifier (EDFA), the laser power was amplified to 150 mW. Within the multipass cell, a total of 22 reflections occurred, contributing to an impressive 33.6 times improvement in the system sensitivity. The normalized noise equivalent absorption coefficient (NNEA) was 8.64 × 10-11 cm-1·W·Hz-1/2 [signal-to-noise ratio, (SNR) = 1] and according to the Allan variance analysis, a minimum detection limit of 500 ppb could be achieved for CO2 at 1204 s, which demonstrates the long-term stability of the system. The system was applied to detect the respiration of rice and upland rice seeds. It is demonstrated that the system can monitor and distinguish the respiration intensity and respiration rate of different seeds in real time.

NEDD4L mediates ITGB4 ubiquitination and degradation to suppress esophageal carcinoma progression.

The ubiquitination-mediated protein degradation exerts a vital role in the progression of multiple tumors. NEDD4L, which belongs to the E3 ubiquitin ligase NEDD4 family, is related to tumor genesis, metastasis and drug resistance. However, the anti-tumor role of NEDD4L in esophageal carcinoma, and the potential specific recognition substrate remain unclear. Based on public esophageal carcinoma database and clinical sample data, it was discovered in this study that the expression of NEDD4L in esophageal carcinoma was apparently lower than that in atypical hyperplastic esophageal tissue and esophageal squamous epithelium. Besides, patients with high expression of NEDD4L in esophageal carcinoma tissue had longer progression-free survival than those with low expression. Experiments in vivo and in vitro also verified that NEDD4L suppressed the growth and metastasis of esophageal carcinoma. Based on co-immunoprecipitation and proteome analysis, the NEDD4L ubiquitination-degraded protein ITGB4 was obtained. In terms of the mechanism, the HECT domain of NEDD4L specifically bound to the Galx-ß domain of ITGB4, which modified the K915 site of ITGB4 in an ubiquitination manner, and promoted the ubiquitination degradation of ITGB4, thus suppressing the malignant phenotype of esophageal carcinoma.

The potential health effects associated with electronic-cigarette.

A good old gateway theory that electronic-cigarettes (e-cigarettes) are widely recognized as safer tobacco substitutes. In actuality, demographics also show that vaping cannibalizes smoking, the best explanation of the data is the "common liability". However, the utilization of e-cigarette products remains a controversial topic at present. Currently, there has been a widespread and substantial growth in e-cigarette use worldwide owing to their endless new flavors and customizable characteristics. Furthermore, e-cigarette has grown widespread among smokers as well as non-smokers, including adolescents and young adults. And some studies have shown that e-cigarette users are at greater risk to start using combustible cigarettes while e-cigarettes use was also observed the potential benefits to people who want to quit smoking or not. Although it is true that e-cigarettes generally contain fewer toxic substances than combustible cigarettes, this does not mean that the chemical composition in e-cigarettes aerosols poses absolutely no risks. While concerns about toxic substances in e-cigarettes and their widespread use in the population are reasonable, it is also crucial to consider that e-cigarettes have been associated with the potential for promoting smoking cessation and the clinically relevant improvements in users with smoking-related pathologies. Meanwhile, there is still short of understanding of the health impacts associated with e-cigarette use. Therefore, in this review, we discussed the health impacts of e-cigarette exposure on oral, nasal, pulmonary, cardiovascular systems and brain. We aspire for this review to change people's previous perceptions of e-cigarettes and provide them with a more balanced perspective. Additionally, we suggest appropriate adjustments on regulation and policy for e-cigarette to gain greater public health benefits.

Integration of apaQTL and eQTL analysis reveals novel SNPs associated with occupational pulmonary fibrosis risk.

To explore the association between apaQTL/eQTL-SNPs and the susceptibility to silicosis. A silicosis-related GWAS was initially conducted to screen for single nucleotide polymorphisms (SNPs) associated with the risk of silicosis. Candidate SNPs with apaQTL and eQTL functions were then obtained from the 3'aQTL-atlas and GTEx databases. Subsequently, additional case-control studies were performed to validate the relationship between the candidate apaQTL/eQTL-SNPs and the risk of silicosis. Finally, experiments were conducted to illustrate APA events occurring at different alleles of the identified apaQTL/eQTL-SNPs. The combined results of the GWAS and iMLDR validations indicate that the variant T allele of the rs2974341 located on SMIM19 (additive model: OR = 0.66, the 95% CI = 0.53-0.84, P = 0.001) and the variant T allele of the rs2390488 located on TMTC4 (additive model: OR = 0.72, 95% CI = 0.57-0.90, P = 0.005) were significantly associated with decreased risk of developing silicosis susceptibility. Furthermore, 3'RACE experiments verified the presence of two poly (A) sites (proximal and distal) in SMIM19, rs2974341 may remotely regulate the binding between miRNA-3646 and SMIM19 with its high LD locus rs2974353 to affect the expression level of SMIM19. The rs2974341 variant T allele may contribute to the generation of the shorter 3'UTR transcript of SMIM19 and affect the binding of miRNA-3646 to the target gene SMIM19. The apaQTL/eQTL-SNPs may provide new perspectives for evaluating the regulatory function of SNPs in the development of silicosis.

JP1, a polypeptide specifically targeting integrin αVß3, ameliorates choroidal neovascularization and diabetic retinopathy in mice.

Anti-vascular endothelial growth factor (VEGF) drugs have revolutionized the treatment of neovascular eye diseases, but responses are incomplete in some patients. Recent evidence shows that integrins are involved in the pathogenesis of neovascular age-related macular degeneration and diabetic retinopathy. JP1, derived from an optimized seven-amino-acid fragment of JWA protein, is a polypeptide specifically targeting integrin αVß3. In this study we evaluated the efficacy of JP1 on laser-induced choroidal neovascularization (CNV) and retinal vascular leakage. CNV mice received a single intravitreal (IVT) injection of JP1 (10, 20, 40 µg) or ranibizumab (RBZ, 10 µg). We showed that JP1 injection dose-dependently inhibited laser-induced CNV; the effect of RBZ was comparable to that of 20 µg JP1; a combined IVT injection of JP1 (20 µg) and RBZ (5 µg) exerted a synergistic effect on CNV. In the 3rd month after streptozotocin injection, diabetic mice receiving IVT injection of JP1 (40 µg) or RBZ (10 µg) once a week for 4 weeks showed significantly suppressed retinal vascular leakage. In both in vivo and in vitro experiments, JP1 counteracted oxidative stress and inflammation via inhibiting ROS/NF-κB signaling in microglial cells, and angiogenesis via modulating MEK1/2-SP1-integrin αVß3 and TRIM25-SP1-MMP2 axes in vascular endothelial cells. In addition, intraperitoneal injection of JP1 (1, 5 or 10 mg) once every other day for 3 times also dose-dependently inhibited CNV. After intraperitoneal injection of FITC-labeled JP1 (FITC-JP1) or FITC in laser-induced CNV mice, the fluorescence intensity in the CNV lesion was markedly increased in FITC-JP1 group, compared with that in FITC group, confirming that JP1 could penetrate the blood-retinal barrier to target CNV lesion. We conclude that JP1 can be used to design novel CNV-targeting therapeutic agents that may replace current invasive intraocular injections.

JAC4 Inhibits EGFR-Driven Lung Adenocarcinoma Growth and Metastasis through CTBP1-Mediated JWA/AMPK/NEDD4L/EGFR Axis.

Lung adenocarcinoma (LUAD) is the most common lung cancer, with high mortality. As a tumor-suppressor gene, JWA plays an important role in blocking pan-tumor progression. JAC4, a small molecular-compound agonist, transcriptionally activates JWA expression both in vivo and in vitro. However, the direct target and the anticancer mechanism of JAC4 in LUAD have not been elucidated. Public transcriptome and proteome data sets were used to analyze the relationship between JWA expression and patient survival in LUAD. The anticancer activities of JAC4 were determined through in vitro and in vivo assays. The molecular mechanism of JAC4 was assessed by Western blot, quantitative real-time PCR (qRT-PCR), immunofluorescence (IF), ubiquitination assay, co-immunoprecipitation, and mass spectrometry (MS). Cellular thermal shift and molecule-docking assays were used for confirmation of the interactions between JAC4/CTBP1 and AMPK/NEDD4L. JWA was downregulated in LUAD tissues. Higher expression of JWA was associated with a better prognosis of LUAD. JAC4 inhibited LUAD cell proliferation and migration in both in-vitro and in-vivo models. Mechanistically, JAC4 increased the stability of NEDD4L through AMPK-mediated phosphorylation at Thr367. The WW domain of NEDD4L, an E3 ubiquitin ligase, interacted with EGFR, thus promoting ubiquitination at K716 and the subsequent degradation of EGFR. Importantly, the combination of JAC4 and AZD9191 synergistically inhibited the growth and metastasis of EGFR-mutant lung cancer in both subcutaneous and orthotopic NSCLC xenografts. Furthermore, direct binding of JAC4 to CTBP1 blocked nuclear translocation of CTBP1 and then removed its transcriptional suppression on the JWA gene. The small-molecule JWA agonist JAC4 plays a therapeutic role in EGFR-driven LUAD growth and metastasis through the CTBP1-mediated JWA/AMPK/NEDD4L/EGFR axis.

Design, Synthesis and In Vivo Fluorescence Imaging Study of a Cytochrome P450 1B1 Targeted NIR Probe Containing a Chelator Moiety.

Cytochrome P450 (CYP) 1B1 has been found to be overexpressed specifically in tumor tissues at an early stage, which makes it a potential cancer biomarker for molecular imaging. Multimodal imaging combines different imaging modalities and offers more comprehensive information. Thus, imaging probes bearing more than one kind of signal fragment have been extensively explored and display great promise. Herein, we developed a near infrared (NIR) probe with a chelator moiety targeting CYP1B1 by conjugating α-naphthoflavone (ANF) derivatives with both an NIR dye and a chelator for potential application in bimodal imaging. Enzymatic inhibitory studies demonstrated inhibitory activity against CYP1B1 and selectivity among CYP1 were successfully retained after chemical modification. Cell-based saturation studies indicated nanomolar range binding affinity between the probe and CYP1B1 overexpressed cancer cells. In vitro competitive binding assays monitored by confocal microscopy revealed that the probe could specifically accumulate in tumor cells. In vivo and ex vivo imaging studies demonstrated that the probe could effectively light-up the tumor tissues as early as 2 hours post-injection. In addition, the fluorescence was significantly blocked by co-injection of CYP1B1 inhibitor, which indicated the probe accumulation in tumor sites was due to specific binding to CYP1B1.

Characterization of a Potent, Selective, and Safe Inhibitor, Ac15(Az8)2, in Reversing Multidrug Resistance Mediated by Breast Cancer Resistance Protein (BCRP/ABCG2).

Overexpression of breast cancer resistance transporter (BCRP/ABCG2) in cancers has been explained for the failure of chemotherapy in clinic. Inhibition of the transport activity of BCRP during chemotherapy should reverse multidrug resistance. In this study, a triazole-bridged flavonoid dimer Ac15(Az8)2 was identified as a potent, nontoxic, and selective BCRP inhibitor. Using BCRP-overexpressing cell lines, its EC50 for reversing BCRP-mediated topotecan resistance was 3 nM in MCF7/MX100 and 72 nM in S1M180 in vitro. Mechanistic studies revealed that Ac15(Az8)2 restored intracellular drug accumulation by inhibiting BCRP-ATPase activity and drug efflux. It did not down-regulate the cell surface BCRP level to enhance drug retention. It was not a transport substrate of BCRP and showed a non-competitive relationship with DOX in binding to BCRP. A pharmacokinetic study revealed that I.P. administration of 45 mg/kg of Ac15(Az8)2 resulted in plasma concentration above its EC50 (72 nM) for longer than 24 h. It increased the AUC of topotecan by 2-fold. In an in vivo model of BCRP-overexpressing S1M180 xenograft in Balb/c nude mice, it significantly reversed BCRP-mediated topotecan resistance and inhibited tumor growth by 40% with no serious body weight loss or death incidence. Moreover, it also increased the topotecan level in the S1M180 xenograft by 2-fold. Our results suggest that Ac15(Az8)2 is a promising candidate for further investigation into combination therapy for treating BCRP-overexpressing cancers.

A novel regQTL-SNP and the risk of lung cancer: a multi-dimensional study.

RegQTL, a novel concept, indicates that different genotypes of some SNPs have differential effects on the expression patterns of miRNAs and their target mRNAs. We aimed to identify the association between regQTL-SNPs and lung cancer risk and to explore the underlying mechanisms. The two-stage case-control study included the first stage in a Chinese population (626 lung cancer cases and 667 healthy controls) and the second stage in a European population (18,082 lung cancer cases and 13,780 healthy controls). Functional annotations were conducted based on the GTEx and the TCGA databases. Functional experiments were performed to explore the underlying biological mechanisms in vitro and vivo. After strict screening, five candidate regQTL-SNPs (rs7110737, rs273957, rs6593210, rs3768617, and rs6836432) were selected. Among them, the variant T allele of rs3768617 in LAMC1 was found to significantly increase the risk of lung cancer (first stage: P = 0.044; second stage: P = 0.007). The eQTL analysis showed that LAMC1 expression level was significantly higher in subjects with the variant T allele of rs3768617 (P = 1.10 × 10-14). In TCGA paired database, the regQTL annotation indicated the different expression patterns between LAMC1 and miRNA-548b-3p for the distinct genotypes of rs3768617. Additionally, LAMC1 knockdown significantly inhibited malignant phenotypes in lung cancer cell lines and suppressed tumor growth. A novel regQTL-SNP, rs3768617, might affect lung cancer risk by modulating the expression patterns of miRNA-548b-3p and LAMC1. RegQTL-SNPs could provide a new perspective for evaluating the regulatory function of SNPs in lung cancer development.

DMAKO-20 as a New Multitarget Anticancer Prodrug Activated by the Tumor Specific CYP1B1 Enzyme.

To reduce the pervasive toxicity of natural shikonin, alkannin, and their synthetic analogues and to enhance the selectivity of these chemotherapeutics toward cancer cells, a novel 5,8-dimethyl alkannin oxime derivative (DMAKO-20) was designed, synthesized, and evaluated for its strong antitumor activity both in vitro and in vivo. It showed potent growth inhibitory effects against HCT-15, HCT-116, and K562 cells (IC50 < 1 µM), moderate antiproliferative activity toward MDA-MB-231, HepG2, PANC, Bel7402, and MGC803 cancer cells (IC50 < 10 µM), and was nontoxic to the human normal VEC and HSF cells. In vivo efficacy studies demonstrated that DMAKO-20 (10 mg/kg, i.v. on every the other day, 8 times in 14 days) resulted in 59.3% reduction in HCT-15 xenograft volume. It was as effective as the toxic antimetabolite 5-FU but revealed neither toxicity nor death in mice. The mechanistic investigations indicated that DMAKO-20 underwent the tumor-specific CYP1B1-catalyzed bioactivation to afford nitric oxide and active naphthoquinone mono-oximes, which exhibited combined anticancer effects. It was defined as a representative of the "Multi-target Anticancer Prodrugs Activated by Specific Enzymes in cancer cells". The produced active metabolites exerted anticancer effects by the direct nucleophilic alkylation and the induction of the apoptosis of cancer cells through activation of the mitochondrial pathway. The discovery of DMAKO-20 and the illustration of its molecular mechanisms may provide a new strategy to overcome the nonselective toxicity of the current chemotherapeutics.

Single-polarization large-mode-area fiber laser mode-locked with a nonlinear amplifying loop mirror.

The generation of high-power ultrashort pulses from a passively mode-locked fiber laser is reported based on the combination of a single-polarization large-mode-area (LMA) photonic crystal fiber with a nonlinear amplifying loop mirror design. The introduction of a non-reciprocal phase shift in the loop mirror enables self-starting of the mode-locked laser, while the polarizing LMA fiber supports environmentally stable high-power operation. Mode locking in the soliton-like, stretched-pulse, and all-normal-dispersion regime is characterized. The laser generates stable pulses with up to 2 W average power at a 72 MHz repetition rate, corresponding to a single-pulse energy of 28 nJ. The output pulses are dechirped to a near transform-limited duration of 152 fs. The proposed fiber oscillator presents an alternative approach to high-power ultrafast laser sources, along with environmental stability.

Cytotoxicity of Synthesized 1,4-Naphthoquinone Oxime Derivatives on Selected Human Cancer Cell Lines.

In an effort to develop potent and selective antitumor agents, a series of 1,4-naphthoquinone oxime derivatives were designed and synthesized. The cytotoxicity of these compounds were evaluated against five human cancer cell lines (colorectal cancer cell: HCT-15, breast cancer cell: MDA-MB-231, liver cancer cell: BEL-7402, colorectal cancer cell: HCT-116 and ovarian cancer cell: A2780) in vitro. Among them, compound 14 was found to be the most potent cytotoxic compound against three cell lines (MDA-MB-231, BEL-7402 and A2780) with IC50 values of 0.66±0.05, 5.11±0.12 and 8.26±0.22 µM, respectively. Additionally, the length of the side chains and the position of the substituent may also affect the cytotoxic activity of the naphthoquinone oxime derivatives. In general, compound 14 effectively inhibited breast cancer cell proliferation and may become a promising anticancer agent.

Design and synthesis of new alfa-naphthoflavanones as potent and selective CYP1B1 inhibitors.

Natural Flavanones are abundant in human diet and a few of them exhibited chemopreventive effects against xenobiotic procarcinogens through the inhibition of tumour specific CYP1B1 enzyme. Herein, a series of new alfa-naphthoflavanones were synthesised and evaluated for their enzymatic inhibitory potency and selectivity of CYP1B1 over its isoenzyme CYP1A1. The most active compound 8c displayed highest inhibitory potency against CYP1B1 with the IC50 value of 0.1 nM. The structure activity relationship studies implied that the methoxy groups on the core scaffold of naphthalene ring significantly influenced CYP1B1 inhibition efficacy, while B-ring substitutions played important roles in activity. Molecular docking studies were conducted to provide a better understanding on the key structural features involved in CYP1B1 inhibitory activity. The results of the study implied that these naphthoflavanones could be considered as new leads and further investigation be conducted to explore the flavanone scaffold as skeleton for inhibiting CYP1B1.

Dual-signal amplified electrochemical aptasensor based on Au/MrGO and DNA nanospheres for ultra-sensitive detection of BPA without directly modified working electrode.

Rapid and sensitive analysis of bisphenol A (BPA) is essential for preventing health risks to humans and animals. Hence, a signal-amplified electrochemical aptasensor without repetitive polishing and modification of working electrode was developed for BPA using Au-decorated magnetic reduced graphene oxide (Au/MrGO)-based recognition probe (RP) and DNA nanospheres (DNS)-based signal probe (SP) cooperative signal amplification. The DNS served as a signal molecule carrier and signal amplifier, while Au/MrGO acted as a signal amplifier and excellent medium for magnetic adsorption and separation. Moreover, utilizing the excellent magnetic properties of Au/MrGO eliminates the need for repetitive polishing and multi-step direct modification of the working electrode while ensuring that all detection processes take place in solution and that used Au/MrGO can be easily recycled. The proposed aptasensor exhibited not only good stability and selectivity, but also excellent sensitivity with a limit of detection (LOD) of 8.13 fg/mL (S/N = 3). The aptasensor's practicality was proven by spiking recovery tests on actual water samples and comparing the results with those detected by HPLC. The excellent sensitivity and selectivity make this aptasensor an alternative and promising avenue for rapid detection of BPA in environmental monitoring.

Inhibitory Effects and Mechanisms of the Novel Shikonin Derivative DMAKO-20 on Melanoma Metastasis and Invasion.

BACKGROUND: Cutaneous melanoma is a malignant tumor with an increasing incidence, prone to recurrence and metastasis. This study aims to explore the effects and mechanisms of the novel shikonin derivative 5,8-dimethyl alkannin oxime derivative (DMAKO-20) on the metastasis and invasion of melanoma cells. METHODS: The inhibitory effects of DMAKO-20 on the melanoma cell line A375 were investigated through Cell Counting Kit-8 (CCK-8), Transwell and angiogenesis experiments. Network pharmacology and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were employed to explore potential sites and pathways involved in this process. Additionally, quantitative polymerase chain reaction (qPCR) and Western blot experiments were conducted before and after drug treatment to verify the expression trends of related pathways and proteins. RESULTS: DMAKO-20 demonstrated selective inhibition of proliferation, invasion and migration of melanoma cells at low concentrations. The WNT pathway appears to be implicated in this process, as DMAKO-20 effectively attenuates its activation, consequently reducing matrix metalloproteinase 9 (MMP9) and Cellular Communication Network Factor 1 (CCN1)/cysteine-rich angiogenic inducer 61 (CYR61) levels. Such modulation inhibits melanoma dissemination and invasion into other tissues. CONCLUSION: DMAKO-20 exhibits the capability to suppress metastasis and invasion of melanoma cells, suggesting its potential for clinical application as an adjuvant therapy against melanoma.

Universal adhesion using mussel foot protein inspired hydrogel with dynamic interpenetration for topological entanglement.

Achieving adhesion of hydrogels to universal materials with desirable strength remains a challenge despite emerging application of hydrogels. Herein we present a mussel foot protein (Mfp) inspired polyelectrolyte hydrogel of poly(ethylenimine)/poly(acrylic acid)-dopamine (PEI/PAADA) developed for universal tough adhesion. The highly-concentrated electrostatic and hydrogen-bonding interactions in PEI/PAADA hydrogel resulted in a tensile strength, strain at break, and toughness of 0.297 MPa, 2784 % and 5.440 MJ m-3, respectively. Moreover, the hydrogel can heal itself from physical damages, even can be recycled after totally dried via rehydration because of the high flexibility and reversibility of its dynamic bonds. Combining the strategies of topological stitching and direct bonding, Mfp-derived catechol and PEI/PAA backbone in PEI/PAADA corporately facilitated robust adhesion of universal materials with shear strength of up to 4.4 MPa and peeling strength of 870 J m-2, which is over 10 times greater than that of commercial fibrin gel. The adhesive also exhibited self-healing capability for at least 5 cycles, good stability in 1 M NaCl solution and characteristic debonding catalyzed by calcium. Moreover, in vitro cell behavior and in vivo wound healing assays suggested the potential of PEI/PAADA as wound dressing.

A cytotoxicity and mechanistic investigation of mono- and di-chloro naphthalenes.

Polychlorinated naphthalenes (PCNs) were characterized as persistent organic pollutants (POPs) that were widely distributed in the environment. Although the striking in vivo toxicity of these pollutants towards both animals and humans was well documented, their cytotoxicity and mechanism of action have not been extensively investigated. In this study, the in vitro antiproliferative activity of mono- and di-chloronaphthalenes as representative PCNs were evaluated and the results indicated strong growth inhibitory effects against mammalian cells, especially the human breast MCF-10A cell and human hepatic HL-7702 cells. 2-Chloronaphthalene with the most potent antiproliferative effects within the tested PCNs, which showed IC50 values ranging from 0.3 mM to 1.5 mM against selected human cell lines, was investigated for its working mechanisms. It promoted cellular apoptosis of MCF-10A cells upon the concentration of 200 µM. It also induced the autophagy of MCF-10A cells in a dose-dependent manner, resulting in cell death via the interaction of autophagy and apoptosis. Thus, these findings supported the theoretical foundation for interventional treatment of PCNs toxicity and also provided implications for the use of chemopreventive agents against the toxic chlorinated naphthalenes in the environments.

Identification of the consistently differential expressed hub mRNAs and proteins in lung adenocarcinoma and construction of the prognostic signature: a multidimensional analysis.

BACKGROUND: This study aimed to elucidate the consistency of differentially expressed hub mRNAs and proteins in lung adenocarcinoma (LUAD) across populations and to construct a comprehensive LUAD prognostic signature. METHODS: The transcriptomic and proteomics data from different populations were standardized and analyzed using the same criteria to identify the consistently differential expressed mRNAs and proteins across genders and races. We then integrated prognosis-related mRNAs with clinical, pathological, and EGFR (epidermal growth factor receptor) mutation data to construct a survival model, subsequently validating it across populations. Through plasma proteomics, plasma proteins that consistently differential expressed with LUAD tissues were screened and validated, with their associations discerned by measuring expressions in tumor tissues and tumor vascular normalization. RESULTS: The consistency rate of differentially expressed mRNAs and proteins was ~20-40%, with ethnic factors leading to about 40-60% consistency of differentially expressed mRNA or protein across populations. The survival model based on the identified eight hub mRNAs as well as stage, smoking status, and EGFR mutations, demonstrated good prognostic prediction capabilities in both Western and East Asian populations, with a higher number of unfavorable variables indicating poorer LUAD prognosis. Notably, GPI expression in tumor tissues was inversely correlated with vascular normalization and positively correlated with plasma GPI expression. CONCLUSION: Our study underscores the significance of integrating transcriptomics and proteomics data, emphasizing the need to account for genetic diversity among ethnic groups. The developed survival model may offer a holistic perspective on LUAD progression, enhancing prognosis and therapeutic strategies.

Plasma GPI and PGD are associated with vascular normalization and may serve as novel prognostic biomarkers for lung adenocarcinoma: Multi-omics and multi-dimensional analysis.

The aim of this study was to explore potential novel plasma protein biomarkers for lung adenocarcinoma (LUAD). A plasma proteomics analysis was carried out and candidate protein biomarkers were validated in 102 LUAD cases and 102 matched healthy controls. The same LUAD tumor tissues were detected to explore the correlation between the expression of candidate proteins in tissues and plasma and vascular normalization. A LUAD active metastasis mice model was constructed to explore the role of candidate proteins for lung metastasis. GPI and PGD were verified to be upregulated in plasma from LUAD patients, and the expression of GPI in tumor tissue was positively correlated with the expression of GPI in plasma and negatively correlated with the normalization of tumor blood vessels. Meanwhile, a negative correlation between the expression of GPI and PGD in plasma and tumor vascular normalization was discovered. In the LUAD active metastasis model, the lowest levels of vascular normalization and the highest expression of GPI and PGD were found in mice with lung metastases. This study found that GPI and PGD may be potential plasma biomarkers for LUAD, and monitoring those may infer the risk of metastasis and malignancy of the tumor. SIGNIFICANT: We identified GPI and PGD as potential novel diagnostic and prognostic biomarkers for LUAD. PGD and GPI can be used as diagnostic biomarkers in combination with other available strategies to assist in the screening and diagnosis of LUAD, and as prognostic biomarkers aid in predict the risk of tumor metastasis and malignancy in patients with LUAD.

A pH-responsive cetuximab-conjugated DMAKO-20 nano-delivery system for overcoming K-ras mutations and drug resistance in colorectal carcinoma.

Cetuximab (Cet) and oxaliplatin (OXA) are used as first-line drugs for patients with colorectal carcinoma (CRC). In fact, the heterogeneity of CRC, mainly caused by K-ras mutations and drug resistance, undermines the effectiveness of drugs. Recently, a hydrophobic prodrug, (1E,4E)-6-((S)-1-(isopentyloxy)-4-methylpent-3-en-1-yl)-5,8-dimethoxynaphthalene-1,4­dione dioxime (DMAKO-20), has been shown to undergo tumor-specific CYP1B1-catalyzed bioactivation. This process results in the production of nitric oxide and active naphthoquinone mono-oximes, which exhibit specific antitumor activity against drug-resistant CRC. In this study, a Cet-conjugated bioresponsive DMAKO-20/PCL-PEOz-targeted nanocodelivery system (DMAKO@PCL-PEOz-Cet) was constructed to address the issue of DMAKO-20 dissolution and achieve multitargeted delivery of the cargoes to different subtypes of CRC cells to overcome K-ras mutations and drug resistance in CRC. The experimental results demonstrated that DMAKO@PCL-PEOz-Cet efficiently delivered DMAKO-20 to both K-ras mutant and wild-type CRC cells by targeting the epidermal growth factor receptor (EGFR). It exhibited a higher anticancer effect than OXA in K-ras mutant cells and drug-resistant cells. Additionally, it was observed that DMAKO@PCL-PEOz-Cet reduced the expression of glutathione peroxidase 4 (GPX4) in CRC cells and significantly inhibited the growth of heterogeneous HCT-116 subcutaneous tumors and patient-derived tumor xenografts (PDX) model tumors. This work provides a new strategy for the development of safe and effective approaches for treating CRC. STATEMENT OF SIGNIFICANCE: (1) Significance: This work reports a new approach for the treatment of colorectal carcinoma (CRC) using the bioresponsible Cet-conjugated PCL-PEOz/DMAKO-20 nanodelivery system (DMAKO@PCL-PEOz-Cet) prepared with Cet and PCL-PEOz for the targeted transfer of DMAKO-20, which is an anticancer multitarget drug that can even prevent drug resistance, to wild-type and K-ras mutant CRC cells. DMAKO@PCL-PEOz-Cet, in the form of nanocrystal micelles, maintained stability in peripheral blood and efficiently transported DMAKO-20 to various subtypes of colorectal carcinoma cells, overcoming the challenges posed by K-ras mutations and drug resistance. The system's secure and effective delivery capabilities have also been confirmed in organoid and PDX models. (2) This is the first report demonstrating that this approach simultaneously overcomes the K-ras mutation and drug resistance of CRC.