Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): patient-reported outcomes from a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: In DESTINY-Breast02, patients with HER2-positive unresectable or metastatic breast cancer who received trastuzumab deruxtecan demonstrated superior progression-free and overall survival compared with those receiving treatment of physician's choice. We present the patient-reported outcomes (PROs) and hospitalisation data. METHODS: In this randomised, open-label, phase 3 trial conducted at 227 clinical sites globally, enrolled patients had to be aged 18 years or older with HER2-positive unresectable or metastatic breast cancer that had progressed on trastuzumab emtansine and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (2:1) using block randomisation (block size of 3) to receive trastuzumab deruxtecan (5·4 mg/kg intravenously once every 21 days) or treatment of physician's choice by an independent biostatistician using an interactive web-based system. Patients and investigators remained unmasked to treatment. Treatment of physician's choice was either capecitabine (1250 mg/m2 orally twice per day on days 1-14) plus trastuzumab (8 mg/kg intravenously on day 1 then 6 mg/kg once per day) or capecitabine (1000 mg/m2) plus lapatinib (1250 mg orally once per day on days 1-21), with a 21-day schedule. The primary endpoint, which was progression-free survival based on blinded independent central review, has previously been reported. PROs were assessed in the full analysis set (all patients randomly assigned to the study) using the oncology-specific European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), breast cancer-specific EORTC Quality of Life Questionnaire Breast 45 (QLQ-BR45), and the generic HRQoL EQ-5D-5L questionnaire. Analyses included change from baseline and time to definitive deterioration for PRO variables of interest and hospitalisation-related endpoints. This study is registered with ClinicalTrials.gov, NCT03523585, and is closed to recruitment. FINDINGS: Between Sept 6, 2018, and Dec 31, 2020, 608 patients were randomly assigned to receive either trastuzumab deruxtecan (n=406; two did not receive treatment) or treatment of physician's choice (n=202; seven did not receive treatment). Overall, 603 patients (99%) were female and five (<1%) were male. The median follow-up was 21·5 months (IQR 15·2-28·4) in the trastuzumab deruxtecan group and 18·6 months (IQR 8·8-26·0) in the treatment of physician's choice group. Median treatment duration was 11·3 months (IQR 6·2-20·5) in the trastuzumab deruxtecan group and approximately 4·5 months in the treatment of physician's choice group (4·4 months [IQR 2·5-8·7] with trastuzumab; 4·6 months [2·1-8·9] with capecitabine; and 4·5 months [2·1-10·6] with lapatinib). Baseline EORTC QLQ-C30 global health status (GHS) scores were similar with trastuzumab deruxtecan (n=393) and treatment of physician's choice (n=187), and remained stable with no clinically meaningful change (defined as ≥10-point change from baseline) over time. Median time to definitive deterioration was delayed with trastuzumab deruxtecan compared with treatment of physician's choice for the primary PRO variable EORTC QLQ-C30 GHS (14·1 months [95% CI 10·4-18·7] vs 5·9 months [4·3-7·9]; HR 0·5573 [0·4376-0·7099], p<0·0001) and all other prespecified PROs (EORTC QLQ-C30 subscales, EORTC QLQ-BR45 arm and breast symptoms, and EQ-5D-5L visual analogue scale). Patient hospitalisation rates were similar in the trastuzumab deruxtecan (92 [23%] of 406) and treatment of physician's choice (41 [20%] of 202) groups; however, median time to hospitalisation was 133 days (IQR 56-237) with trastuzumab deruxtecan versus 83 days (30-152) with treatment of physician's choice. INTERPRETATION: Overall, GHS and quality of life were maintained for both treatment groups, with prespecified PRO variables favouring trastuzumab deruxtecan over treatment of physician's choice, suggesting that despite a longer treatment duration, there was no detrimental impact on patient health-related quality of life with trastuzumab deruxtecan. When considered with efficacy and safety data from DESTINY-Breast02, these results support the overall benefit of trastuzumab deruxtecan for patients with HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab emtansine. FUNDING: Daiichi Sankyo and AstraZeneca.

Nanoparticles for inducing Gaucher disease-like damage in cancer cells.

Nutrient avidity is one of the most distinctive features of tumours. However, nutrient deprivation has yielded limited clinical benefits. In Gaucher disease, an inherited metabolic disorder, cells produce cholesteryl-glucoside which accumulates in lysosomes and causes cell damage. Here we develop a nanoparticle (AbCholB) to emulate natural-lipoprotein-carried cholesterol and initiate Gaucher disease-like damage in cancer cells. AbCholB is composed of a phenylboronic-acid-modified cholesterol (CholB) and albumin. Cancer cells uptake the nanoparticles into lysosomes, where CholB reacts with glucose and generates a cholesteryl-glucoside-like structure that resists degradation and aggregates into microscale crystals, causing Gaucher disease-like damage in a glucose-dependent manner. In addition, the nutrient-sensing function of mTOR is suppressed. It is observed that normal cells escape severe damage due to their inferior ability to compete for nutrients compared with cancer cells. This work provides a bioinspired strategy to selectively impede the metabolic action of cancer cells by taking advantage of their nutrient avidity.

Bridging biological and food monitoring: A colorimetric and fluorescent dual-mode sensor based on N-doped carbon dots for detection of pH and histamine.

Rapid and sensitive monitoring of pH and histamine is crucial for bridging biological and food systems and identifying corresponding abnormal situations. Herein, N-doped carbon dots (CDs) are fabricated by a hydrothermal method employing dipicolinic acid and o-phenylenediamine as precursors. The CDs exhibit colorimetric and fluorescent dual-mode responses to track pH and histamine variations in living cells and food freshness, respectively. The aggregation-induced emission enhancement and intramolecular charge transfer result in a decrease in absorbance and an increase in fluorescence, which become readily apparent as the pH changes from acidic to neutral. This property enables precise differentiation between normal and cancerous cells. Furthermore, given the intrinsic basicity of histamine, pH-responsive CDs are advantageous for additional colorimetric and fluorescent monitoring of histamine in food freshness, achieving linearities of 25-1000 µM and 30-1000 µM, respectively, which are broader than those of alternative nanoprobes. Interestingly, the smartphone-integrated sensing platform can portably and visually evaluate pH and histamine changes due to sensitive color changes. Therefore, the sensor not only establishes a dynamic connection between pH and histamine for the purposes of biological and food monitoring, but also presents a novel approach for developing a multifunctional biosensor that can accomplish environmental monitoring and biosensing simultaneously.

Effect of Manganese on the Strength-Toughness Relationship of Low-Carbon Copper and Nickel-Containing Hull Steel.

The influence of varying the manganese (Mn) contents of high-strength copper-containing hull steel on its microstructural evolution and mechanical properties was investigated. With increasing Mn content from 2 to 5%, the tensile strength of the steel increased by ~100 MPa, while the elongation of steel remained at ~23.5%, indicating good plasticity. However, the 2Mn sample had 128 J higher low-temperature (-84 °C) impact work than the 5Mn sample. The microstructures of different Mn steels were composed of fresh martensite (FM), ferrite/tempered martensite (F/TM), and reversed austenite (RA). The increase in Mn content markedly increased the presence of RA and intensified the work hardening caused by the transformation-induced plasticity (TRIP) effect during the tensile process. However, as the phase transformation in different Mn steels occurred in the early stage of strain and did not extend throughout the entire plastic deformation process, increasing plasticity via phase transformation was difficult. In addition, although the volume fraction of RA increased significantly in 4Mn and 5Mn steels, the stability of RA significantly decreased. The presence of numerous metastable blocks and coarse lath-like RA contributed little to low-temperature impact work and was even detrimental to toughness. The substantial fresh martensite resulting from phase transformation facilitated microcrack generation, owing to rapid volume expansion and mutual impacts, thus reducing the work required for crack formation. Additionally, the abundance of deformation twins significantly reduced the work needed for crack propagation. These combined actions significantly reduced the low-temperature toughness of 4Mn and 5Mn steels.

Novel salty peptides derived from bovine bone: Identification, taste characteristic, and salt-enhancing mechanism.

Excessive sodium intake is a major contributor to the incidence of cardiovascular diseases. The objective of this study was to prepare, isolate, and characterize peptides from bovine bone protein and investigate the salty/salt-enhancing mechanism of peptides. 1032 peptides were identified in the enzymatic hydrolysates of bovine bone protein and were further screened by the composition of amino acid residues and molecular docking analysis. 5 peptides were finally selected for solid-phase synthesis, and KER showed a better salty taste by sensory verification. Moreover, the synergistic effect of KER in NaCl and MSG solution could enhance the salty intensity by 65.26 %. The binding of KER to the salty receptor (TMC4) was driven by hydrogen bonding and electrostatic interactions with a binding energy of -88.0734 kcal/mol. This work may provide a new approach to efficiently screen salty peptides from natural food materials, which were expected as a taste enhancer used in salt-reducing foods.

Vitamin D status alters genes involved in ovarian steroidogenesis in muskrat granulosa cells.

This study aims to explore the relationship between altered vitamin D (VitD3) status and ovarian steroidogenesis in muskrats during the breeding and non-breeding seasons. During the breeding season, the ovaries of muskrats were observably enlarged and increased in weight, accompanied by elevated serum and ovarian VitD3 status. Vitamin D receptor (VDR), VitD3 metabolic molecules (CYP2R1, CYP27B1, and CYP24A1), and steroidogenic enzymes were immunolocalized in the ovarian cells of muskrats. The mRNA levels of VDR, CYP2R1, CYP27B1, and steroidogenic enzymes were considerably higher during the breeding season compared to the non-breeding season. RNA-seq analysis revealed a prominent enrichment of vitamin-related and ovarian steroidogenesis pathways. Furthermore, the addition of 1,25(OH)2D3 to the muskrat granulosa cells in vitro increased VDR and steroidogenic enzymes mRNA levels and enhanced the 17ß-estradiol level. Overall, these findings supported that VitD3 promotes the secretion of steroid hormones, thereby affecting seasonal changes in ovarian function in the muskrats.

Pharmacodynamic material basis and pharmacological mechanisms of Cortex Mori against diabetes mellitus.

ETHNOPHARMACOLOGICAL RELEVANCE: The application of Cortex Mori (CM) in the treatment of diabetes mellitus (DM) has been extensively documented in traditional medicine. In recent years, the chemical composition of CM has been gradually unraveled, and its therapeutic mechanism in treating DM, diabetic nephropathy, diabetic cardiomyopathy, and other related conditions has been highlighted in successive reports. However, there is no systematic study on the treatment of DM based on the chemical composition of CM. AIM OF THE STUDY: This study was conducted to systematically explore the hypoglycemic activity mechanism of CM based on its chemical composition. METHODS: The material basis of Cortex Mori extract (CME) was investigated through qualitative analyses based on liquid chromatography-mass spectrometry (LC-MS). The possible acting mechanism was simulated using network pharmacology and validated in streptozotocin (STZ) + high fat diet (HFD)-induced diabetic rats and glucosamine-induced IR-HepG2 model with the assistance of molecular docking techniques. RESULTS: A total of 39 compounds were identified in CME by the LC-MS-based qualitative analysis. In diabetic rats, it was demonstrated that CME significantly ameliorated insulin resistance, blood lipid levels, and liver injury. The network pharmacology analysis predicted five major targets, including AKT1, PI3K, FoxO1, Gsk-3ß, and PPARγ. Additionally, three key compounds (resveratrol, protocatechuic acid, and kaempferol) were selected based on their predicted contributions. The experimental results revealed that CME, resveratrol, protocatechuic acid, and kaempferol could promote the expression of AKT1, PI3K, and PPARγ, while inhibiting the expression of FoxO1 and Gsk-3ß. The molecular docking results indicated a strong binding affinity between resveratrol/kaempferol and their respective targets. CONCLUSIONS: CME contains a substantial amount of prenylated flavonoids, which may be the focal point of research on the efficacy of CM in the treatment of DM. Besides, CME is effective in controlling blood glucose and insulin resistance, improving lipid levels, and mitigating liver injury in patients with DM. Relevant mechanisms may be associated with the activation of the PI3K/Akt pathway, the inhibition of the expression of FoxO1 and Gsk-3ß, and the enhancement of PPARγ activity. This study represents the first report on the role of CME in the treatment of DM through regulating PPARγ, FoxO1, and Gsk-3ß.

Circ-SATB2 (hsa_circ_0008928) and miR-150-5p are regulators of TRIM66 in the regulation of NSCLC cell growth and metastasis of NSCLC cells via the ceRNA pathway.

Circular RNA (circRNA) was an important modulator and potential molecular target of nonsmall cell lung cancer (NSCLC). CircSATB2 was reported to be upregulated in NSCLC. However, the role and mechanism of circSATB2 in NSCLC progression remain to be illustrated. The RNA and protein expression was detected by quantitative real-time polymerase chain reaction, western blot, and immunohistochemistry assay. Cell counting kit-8, cell colony formation, and 5-ethynyl-2'-deoxyuridine assays were applied to assess cell growth. The migrated and invaded cells were examined by transwell assay. Flow cytometry was performed to measure apoptotic cells. The interaction among circSATB2, microRNA-150-5p (miR-150-5p), and tripartite motif-containing protein 66 (TRIM66) was identified by dual-luciferase reporter assay and RNA immunoprecipitation assay. An in vivo experiment was conducted to investigate the effect of circSATB2 on tumor growth. CircSATB2 expression was highly expressed in NSCLC tissues and cell lines. CircSATB2 and TRIM66 silencing both suppressed NSCLC cell growth, migration, and invasion whereas promoted NSCLC cell apoptosis. CircSATB2 acted as a molecular sponge for miR-150-5p, and miR-150-5p interacted with the 3' untranslated region (3'UTR) of TRIM66. Moreover, circSATB2 knockdown-induced effects were partly reversed by TRIM66 overexpression in NSCLC cells. Besides, cirSATB2 expression was negatively correlated with miR-150-5p level and positively correlated with TRIM66 level in NSCLC tumor tissues. CircSATB2 knockdown blocked xenograft tumor growth in vivo. In summary, this study verified that circSATB2 stimulated NSCLC cell malignant behaviors by miR-150-5p/TRIM66 pathway, providing a possible circRNA-targeted therapy for NSCLC.

Influence of different baking temperatures of red kojic rice on the physicochemical properties, antioxidant capacity, and functional components of red starter wine.

BACKGROUND: To improve the quality of red starter wine, this study explored the effects of baking red kojic rice at varying temperatures on the physicochemical characteristics of red starter wine. Baking was predicated on understanding crucial enzyme activities and starch granule structure of red kojic rice at 75, 95, and 105 °C, leading to the production of three red starter wine variants (BHQW1, BHQW2, and BHQW3). RESULTS: The results revealed an increased alcohol (increase 0.50%), total sugar (increase 0.14 g L-1 ), and total acid (increase 0.54 g L-1 ) content in red starter wine fermented using baked red kojic rice compared with the control group (wine fermented with unbaked rice, HQW). Furthermore, both the 105 °C baked red kojic rice and its resulting BHQW3 demonstrated significantly higher red color values than HQW (increase 2.03 U g-1 and 0.15 U mL-1 respectively). The highest lovastatin content was presented in red kojic rice baked at 105 °C and its corresponding fermented wine (1420.63 ± 507.9 µg g-1 and 3368.87 ± 228.16 µg L-1 respectively). Additionally, BHQW groups displayed higher total flavonoids and phenols content than HQW. Regarding antioxidant capacity, all BHQW groups showed stronger overall antioxidant capacity than HQW. The determination of volatile components revealed the highest content of volatile compounds in BHQW2 (2621.19 ± 548.24 µg L-1 ) and significantly higher volatile esters in BHQW1 (254.46 ± 16.63 µg L-1 ). Moreover, 16 volatile compounds were identified only in BHQW groups, including isoamyl caprylate, 2-ethylhexyl alcohol, and benzaldehyde. CONCLUSION: Our findings suggested that the baking technique of red kojic rice could enhance the quality of red starter wine through enhancing antioxidant properties, increasing functional components, and enriching volatile flavor compounds, thus providing a foundation for new techniques in red starter wine production. © 2023 Society of Chemical Industry.

In Vivo Base Editing of Scn5a Rescues Type 3 Long QT Syndrome in Mice.

BACKGROUND: Pathogenic variants in SCN5A can result in long QT syndrome type 3, a life-threatening genetic disease. Adenine base editors can convert targeted A T base pairs to G C base pairs, offering a promising tool to correct pathogenic variants. METHODS: We generated a long QT syndrome type 3 mouse model by introducing the T1307M pathogenic variant into the Scn5a gene. The adenine base editor was split into 2 smaller parts and delivered into the heart by adeno-associated virus serotype 9 (AAV9-ABEmax) to correct the T1307M pathogenic variant. RESULTS: Both homozygous and heterozygous T1307M mice showed significant QT prolongation. Carbachol administration induced Torsades de Pointes or ventricular tachycardia for homozygous T1307M mice (20%) but not for heterozygous or wild-type mice. A single intraperitoneal injection of AAV9-ABEmax at postnatal day 14 resulted in up to 99.20% Scn5a transcripts corrected in T1307M mice. Scn5a mRNA correction rate >60% eliminated QT prolongation; Scn5a mRNA correction rate <60% alleviated QT prolongation. Partial Scn5a correction resulted in cardiomyocytes heterogeneity, which did not induce severe arrhythmias. We did not detect off-target DNA or RNA editing events in ABEmax-treated mouse hearts. CONCLUSIONS: These findings show that in vivo AAV9-ABEmax editing can correct the variant Scn5a allele, effectively ameliorating arrhythmia phenotypes. Our results offer a proof of concept for the treatment of hereditary arrhythmias.

CO2 uptake in ethanol-driven chain elongation system: Microbial metabolic mechanisms.

CO2 as a byproduct of organic waste/wastewater fermentation has an important impact on the carboxylate chain elongation. In this study, a semi-continuous flow reactor was used to investigate the effects of CO2 loading rates (Low = 0.5 LCO2·L-1·d-1, Medium = 1.0 LCO2·L-1·d-1, High = 2.0 LCO2·L-1·d-1) on chain elongation system Ethanol and acetate were utilized as the electron donor and electron acceptor, respectively. The results demonstrate that low loading rate of CO2 has a positive effect on chain elongation. The maximum production of caproate and CH4 were observed at a low CO2 loading rate. Caproate production reached 1.88 g COD·L-1·d-1 with a selectivity of 62.55 %, while CH4 production reached 129.7 ml/d, representing 47.4 % of the total. Metagenomic analysis showed that low loading rate of CO2 favored the enrichment of Clostridium kluyveri, with its abundance being 3.8 times higher than at of high CO2 loading rate. Metatranscriptomic analysis revealed that high CO2 loading rate induced oxidative stress in microorganisms, as evidenced by increased expression of heat shock proteins and superoxide dismutase genes. Further investigation suggested that genes associated with the reverse ß-oxidation pathway, CO2 uptake pathway and hydrogenotrophic methanogenesis pathway were reduced at high CO2 loading rate. These findings provide insight into the underlying mechanisms of how CO2 affects chain elongation, and it could be a crucial reason for the poor performance of chain elongation systems with high endogenous CO2 production.

Seasonal changes in endoplasmic reticulum stress and steroidogenesis in the ovary of the wild ground squirrels (Citellus dauricus Brandt).

The development of the follicle is accompanied by steroidogenesis and secretion, the endoplasmic reticulum (ER) requires significant synthesis of relevant proteins to support changes in the follicular microenvironment. The aim of this study was to investigate whether seasonal changes in gonadotropins and ovarian steroid hormones in the wild ground squirrels induce endoplasmic reticulum stress (ERS) and changes in ERS-mediated unfolded protein response (UPR) signaling. There were significant seasonal differences in ovarian mass, with values higher in the breeding season and relatively low in the non-breeding season. Histological observations revealed that ovaries in the breeding season had germ cells including primordial follicles, primary follicles, secondary follicles, tertiary follicles, and the corpus luteal, whereas ovaries consisted mainly of primary and secondary follicles in the non-breeding season. Analysis of ovarian transcriptome data showed that 1298 genes were up-regulated in expression and 1432 genes were down-regulated in expression during both periods. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that these genes were mainly enriched in estrogen signaling pathways, ovarian steroidogenesis and endoplasmic reticulum protein processing pathways. The expression levels of steroidogenic enzymes (P450scc, P450c17, 3ß-HSD, and P450arom) and gonadotropin receptor (FSHR and LHR) were significantly increased during the breeding season compared to the non-breeding season. GRP78 and UPR signaling factors (ATF4, ATF6, XBP1s) associated with ERS were expressed in both seasons. The mRNA expressions of Atf6 and Xbp1s were higher in the breeding season than those of the non-breeding season. Conversely, Atf4 and its downstream homologous protein (Chop) exhibited higher expression during the non-breeding season. In addition, follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol-17ß, and progesterone of serum were significantly higher in the breeding season than those of the non-breeding season. These results suggested that UPR signaling, associated with seasonal changes in ovarian steroidogenesis, was activated during the breeding season and that ERS might be involved in regulating seasonal changes in ovarian steroidogenesis in the wild ground squirrels.

Rational Design of Orange-Red Emissive Carbon Dots for Tracing Lysosomal Viscosity Dynamics in Living Cells and Zebrafish.

Lysosomal viscosity is an essential microenvironment parameter in lysosomes, which is closely associated to the occurrence and development of various diseases, including cancer. Thus, accurately quantifying lysosomal viscosity changes is highly desirable for a better understanding of the dynamics and biological functions of lysosomes. In this study, lysosome self-targetable orange-red emissive carbon dots (OR-CDs) were rationally designed and developed for monitoring lysosomal viscosity fluctuations. The enhanced fluorescence of OR-CDs could be obviously observed as the viscosity increased from 1.07 to 950 cP. Moreover, the as-prepared OR-CDs could quickly enter cells for lysosome-targeting imaging and visualize viscosity variations in living cells and zebrafish. More importantly, by utilizing OR-CDs, we successfully achieved tracing the variations in lysosomal viscosity during the autophagy process. Additionally, as cancer cells possess high viscosity than normal cells, the OR-CDs have been effectively utilized for cancer imaging from cell, tissue, and organ to in vivo levels. It is expected that the developed OR-CDs not only provide a meaningful tool for visualizing investigations of lysosome viscosity-related diseases but also shed light on the development based on the nanomaterial for the clinical diagnosis of cancer.

Seasonal changes of vitamin D3 and ovarian steroidogenesis in the wild ground squirrels (Citellus dauricus Brandt).

There is mounting evidence that vitamin D3 regulates female reproductive function critically, while little is known about the function of seasonally variable vitamin D3 in regulating ovarian steroidogenesis. This study examined the seasonal expressions of vitamin D receptor (VDR), vitamin D metabolic molecules (CYP2R1, CYP27B1, and CYP24A1), and steroidogenic enzymes (P450scc, 3ß-HSD, P450c17, and P450arom) in the ovaries of the wild ground squirrels (Citellus dauricus Brandt) during the different breeding seasons. VDR, CYP2R1, CYP27B1, and CYP24A1 were shown to be localized in different types of ovarian cells in the wild ground squirrels during the breeding and non-breeding seasons. Meanwhile, the mRNA levels of VDR, CYP2R1, CYP27B1, CYP11A1, HSD3B1, CYP17A1, and CYP19A1 in the ovaries were remarkably higher in the breeding season. Furthermore, RNA-seq data of ovaries revealed that 6036 genes were differentially expressed genes (DEGs); further analysis revealed that several DEGs known to be involved in ovarian steroidogenesis pathway and cellular response to vitamin D pathway were identified. In addition, during the breeding season, the concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone, and 17ß-estradiol were greater in the serum of the wild female ground squirrels. This observation was positively correlated with seasonal changes in the concentration of 25(OH)D3, supporting the fact that the 25(OH)D3 content in the ovaries was significantly higher in the breeding season. These findings suggested that seasonal changes in vitamin D3 might regulate the ovarian steroidogenesis of the wild female ground squirrels.

Participation of FaTRAB1 Transcription Factor in the Regulation of FaMADS1 Involved in ABA-Dependent Ripening of Strawberry Fruit.

Abscisic acid (ABA) plays a crucial role in regulating the ripening of non-climacteric strawberry fruit. In the present study, ABA was confirmed to promote strawberry ripening and induce the down-regulation of FaMADS1. The transient silence of FaMADS1 in strawberries promoted fruit ripening and induced the content of anthocyanin and soluble pectin but reduced firmness and protopectin through a tobacco rattle virus-induced gene silencing technique. In parallel with the accelerated ripening, the genes were significantly induced in the transiently modified fruit, including anthocyanin-related PAL6, C4H, 4CL, DFR, and UFGT, softening-related PL and XTH, and aroma-related QR and AAT2. In addition, the interaction between FaMADS1 and ABA-related transcription factors was researched. Yeast one-hybrid analysis indicated that the FaMADS1 promoter could interact with FaABI5-5, FaTRAB1, and FaABI5. Furthermore, dual-luciferase assay suggested that FaTRAB1 could actively bind with the FaMADS1 promoter, resulting in the decreased expression of FaMADS1. In brief, these results suggest that the ABA-dependent ripening of strawberry fruit was probably inhibited through inhibiting FaMADS1 expression by the active binding of transcript FaTRAB1 with the FaMADS1 promoter.

Oncogenic role and drug sensitivity of ETV4 in human tumors: a pan-cancer analysis.

Background: Increasing evidence supports a relationship between E twenty-six variant transcription factor 4 (ETV4) and several cancers, but no pan-cancer analysis has been reported. Methods: The present study surveyed the effects of ETV4 on cancer using RNA sequencing data obtained from The Cancer Genome Atlas and GTEx, and further explored its role in drug sensitivity using data from Cellminer. Differential expression analyses were conducted for multiple cancers using R software. Cox regression and survival analysis were employed to calculate correlations between ETV4 levels and survival outcomes in multiple cancers using the online tool Sangerbox. ETV4 expression was also compared with immunity, heterogeneity, stemness, mismatch repair genes, and DNA methylation among different cancers. Results: ETV4 was found to be significantly upregulated in 28 tumors. Upregulation of ETV4 was associated with poor overall survival, progression free interval, disease-free-interval, and disease specific survival in several cancer types. Expression of ETV4 was also remarkably correlated with immune cell infiltration, tumor heterogeneity, mismatch repair gene expression, DNA methylation, and tumor stemness. Furthermore, ETV4 expression seemed to affect sensitivity to a number of anticancer drugs. Conclusions: These results suggest that ETV4 may be useful as a prognostic factor and therapeutic target.

Exploration of NPC2 as a Potential Biomarker for Immunotherapy Using RNA-seq and Protein Data - A New Hypothesis.

INTRODUCTION: NPC2 is well known as a player for cholesterol transport. However, the biological role of NPC2 in cancer development and therapy is far from clear. METHODS: Here, we explore the potential role of NPC2 in prognosis and immunotherapy across multiple cancer types by integrating RNA-seq data from TCGA and GTEx, protein data from CPTAC, and multiple web analysis databases. RESULTS: Expression depiction between tumour and normal tissues indicated that NPC2 is overexpressed in the majority of the most common cancer types, including glioblastoma and pancreatic cancer, two cancers mostly difficult to diagnose and treat. CONCLUSION: Cancer stemness in glioblastoma is negatively associated with NPC2 level. NPC2 expression is positively correlated with immune cell infiltration and the expression of several immune checkpoints. IDH1 mutation in GBM is negatively correlated with NPC2 level, while a positive correlation has been found between TP53 mutation and NPC2 expression in pancreatic cancer. NPC2 is also correlated with levels of serum biomarkers used for diagnosis of pancreatic cancer.

Multifunctional Fluorescent Probe for Simultaneous Detection of ONOO-, Viscosity, and Polarity and Its Application in Ferroptosis and Cancer Models.

Intracellular peroxynitrite anions (ONOO-) and microenvironments (such as viscosity and polarity) play an important role in maintaining redox homeostasis, regulating diffusion, transportation, and signal transduction in living cells. The abnormality of these factors is often closely related to various physiological/pathological processes. However, owing to the lack of suitable probes, the simultaneous visualization of ONOO-, viscosity, and polarity in ferroptosis and cancer models has not been achieved. To meet urgent needs, we presented a multifunctional near-infrared (NIR) fluorescent probe, named MQA-P, for simultaneously detecting ONOO-, viscosity, and polarity within mitochondria. The probe exhibited a remarkable turn-on response to ONOO- with the far-red emission of about 645 nm and was highly sensitive to viscosity/polarity in the NIR channel with λem > 704 nm. Facilitated by MQA-P, for the first time, we revealed that erastin-induced ferroptosis was accompanied by a significant upregulation of ONOO- and an increase of viscosity (or decrease of polarity) at the same time. Moreover, the concurrent use of ONOO-, viscosity, and polarity for the diagnosis of cancer has been successfully achieved not only at cell/tissue levels but also in tumor mice models. Compared with detecting only one factor, this simultaneous detection of multimarkers provides a more sensitive and reliable method/tool for tracking ferroptosis-related pathological processes and cancer diagnosis, holding great potential in preclinical research, medical diagnosis, and imaging-guided surgery.

Occupational health risks of VOCs emitted from the working face of municipal solid waste landfill: Temporal variation and influencing factors.

Volatile organic compounds (VOCs) emission on the working face of a large sanitary landfill in northern China was characterized in a one-year long sampling campaign. A total of 67 VOCs with average annual concentration of 2903.01 µg/m3 were detected. Ethanol was the dominant species of detected VOCs, accounting for 76.4-82.3% of the total volatile organic compounds (TVOCs) concentration. VOCs emission showed seasonal variation as the highest concentration was detected in summer and lowest appeared in winter. Furthermore, 50 VOCs identified were non-carcinogenic chemicals and 21 of them were carcinogenic chemicals. Risk assessment showed that the average total non-carcinogenic risk value (HIT) was 4.95, which far exceeded the threshold value of 1; and the average total carcinogenic risk value (RiskT) was 8.45 × 10-5, close to the limit of 1 × 10-4. That means both the non-carcinogenic and carcinogenic risks of long-term exposure to these VOCs could not be ignored. Some of the oxygenated compounds (Acrolein, Ethyl acetate, etc.), halocarbons (1,1,2-Trichloroethane, 1,2-Dichloropropane, etc.) and aromatic compounds (Naphthalene, m + p-Xylene, etc.) consisted the main contributors to non-carcinogenic risks. Meanwhile, carcinogenic risks were mainly caused by halocarbons (cis-1,2-Dichloroethylene, FREON11, etc.) and aromatic compounds (Benzene, Ethylbenzene, etc.). In addition, statistical analysis revealed that the HIT values were related to the concentrations of risk aromatic compounds, halocarbons and hydrocarbons; RiskT values were only related to the concentrations of risk aromatic compounds and halocarbons. The research results provide an important theoretical basis for occupational risk management and VOCs emission prevention in landfills.

GP73 is a promising indicator in HIV diagnosis and treatment: a one-year follow-up study.

Golgi protein 73 (GP73) has been recognized as a biomarker for evaluating liver diseases, although the serum profile of patients with HIV remains unclear. This study was designed to investigate the diagnostic values of serum GP73 in patients with HIV. A total of 92 patients with HIV and 60 healthy participants were selected, and serum samples were collected; 51 of 92 patients were followed up and all indicators were re-tested after 1 year. Patients with HIV had significantly lower GP73 concentration, lower viral load, and higher CD4+ T cell counts after antiretroviral treatment. A significant correlation between the changes of GP73 level and CD4+ T cell count was observed. The CD4+ T cell count was significantly correlated with the glycosylated GP73 level. The area under the ROC curve (AUC) of GP73 to predict negative viral load-negative conversion alone was 0.705. When the cut-off value was set at 146.7 ng/mL, the sensitivity and specificity were 73% and 70% respectively. These results indicate that serum GP73 may have predictive ability for negative viral load-negative conversion.