Establishment of patient-derived organoids for guiding personalized therapies in breast cancer patients.

Breast cancer has become the most commonly diagnosed cancer. The intra- and interpatient heterogeneity induced a considerable variation in treatment efficacy. There is an urgent requirement for preclinical models to anticipate the effectiveness of individualized drug responses. Patient-derived organoids (PDOs) can accurately recapitulate the architecture and biological characteristics of the origin tumor, making them a promising model that can overtake many limitations of cell lines and PDXs. However, it is still unclear whether PDOs-based drug testing can benefit breast cancer patients, particularly those with tumor recurrence or treatment resistance. Fresh tumor samples were surgically resected for organoid culture. Primary tumor samples and PDOs were subsequently subjected to H&E staining, immunohistochemical (IHC) analysis, and whole-exome sequencing (WES) to make comparisons. Drug sensitivity tests were performed to evaluate the feasibility of this model for predicting patient drug response in clinical practice. We established 75 patient-derived breast cancer organoid models. The results of H&E staining, IHC, and WES revealed that PDOs inherited the histologic and genetic characteristics of their parental tumor tissues. The PDOs successfully predicted the patient's drug response, and most cases exhibited consistency between PDOs' drug susceptibility test results and the clinical response of the matched patient. We conclude that the breast cancer organoids platform can be a potential preclinical tool used for the selection of effective drugs and guided personalized therapies for patients with advanced breast cancer.

Paxlovid reduces the 28-day mortality of patients with COVID-19: a retrospective cohort study.

PURPOSE: In this study, we aim to explore the efficacy of paxlovid on reducing mortality of COVID-19 patients in clinical setting, especially whether paxlovid modifies the risk of death in these severe and critical patients. METHODS: Our retrospective cohort study was conducted on the medical records of patients, consecutively admitted for COVID-19 to five hospitals in Chongqing, China from Dec 8, 2022 to Jan 20, 2023. Based on whether patients received paxlovid during their hospitalization, patients were grouped as paxlovid group and non-paxlovid group. We used 1:1 ratio propensity score matching (PSM) in our study to adjust for confounding factors and differences between groups. Statistical analysis were performed by SPSS 23.0. The differences in 28-day mortality between these two groups and its influencing factors were the main results we focused on. RESULTS: There were 1018 patients included in our study cohort. With 1:1 ratio PSM, each of the paxlovid group and non-paxlovid group included 237 patients. The results showed that patients using paxlovid have a lower 28-day mortality in overall population either before PSM (OR 0.594, 95% CI 0.385-0.917, p = 0.019) or after PSM (OR 0.458, 95% CI 0.272-0.774, p = 0.003) with multivariable adjusted logistic regression models. Meanwhile, in severe subgroup, it showed similar findings.With paxlovid treatment, it showed a significantly lower 28-day mortality in severe subgroup both before PSM (28% vs.41%, p = 0.008) and after PSM (19% vs.32%, p = 0.007). CONCLUSION: Paxlovid can significantly reduce the risk of 28-day mortality in overall population and severe subgroup patients.This study distinguished the severe subgroup patients with COVID-19 who benefit more from paxlovid treatment.

Sublethal effect and detoxifying metabolism of metaflumizone and indoxacarb on the fall armyworm, Spodoptera frugiperda.

The fall armyworm (FAW), Spodoptera frugiperda (J.E. Smith) (Lepidoptera, Noctuidae), is a highly polyphagous invasive pest that damages various crops. Pesticide control is the most common and effective strategy to control FAW. In this study, we evaluated the toxicity of metaflumizone and indoxacarb against third-instar FAW larvae using the insecticide-incorporated artificial diet method under laboratory conditions. Both metaflumizone and indoxacarb exhibited substantial toxicity against FAW, with LC50 values of 2.43 and 14.66 mg/L at 72 h, respectively. The sublethal effects of metaflumizone and indoxacarb on parental and F1 generation FAW were investigated by exposing third-instar larvae to LC10 and LC30 concentrations of these insecticides. Sublethal exposure to these two insecticides significantly shortened adult longevity, extended pupal developmental times and led to reduced pupal weight, pupation rates, and adult fecundity in the treated parental generation and F1 generation at LC10 or LC30 concentrations, in comparison to the control group. The larval developmental times were shortened in the parental generation but prolonged in the F1 generation, after being treated with sublethal concentrations of metaflumizone. Furthermore, larvae exposed to LC10 or LC30 concentrations of indoxacarb exhibited elevated activity levels of cytochrome P450 monooxygenase and glutathione S-transferase, which coincides with the observed synergistic effect of piperonyl butoxide and diethyl maleate. In conclusion, the high toxicity and negative impact of metaflumizone and indoxacarb on FAW provided significant implications for the rational utilization of insecticides against this pest.

Novel models by machine learning to predict prognosis of breast cancer brain metastases.

BACKGROUND: Breast cancer brain metastases (BCBM) are the most fatal, with limited survival in all breast cancer distant metastases. These patients are deemed to be incurable. Thus, survival time is their foremost concern. However, there is a lack of accurate prediction models in the clinic. What's more, primary surgery for BCBM patients is still controversial. METHODS: The data used for analysis in this study was obtained from the SEER database (2010-2019). We made a COX regression analysis to identify prognostic factors of BCBM patients. Through cross-validation, we constructed XGBoost models to predict survival in patients with BCBM. Meanwhile, a BCBM cohort from our hospital was used to validate our models. We also investigated the prognosis of patients treated with surgery or not, using propensity score matching and K-M survival analysis. Our results were further validated by subgroup COX analysis in patients with different molecular subtypes. RESULTS: The XGBoost models we created had high precision and correctness, and they were the most accurate models to predict the survival of BCBM patients (6-month AUC = 0.824, 1-year AUC = 0.813, 2-year AUC = 0.800 and 3-year survival AUC = 0.803). Moreover, the models still exhibited good performance in an externally independent dataset (6-month: AUC = 0.820; 1-year: AUC = 0.732; 2-year: AUC = 0.795; 3-year: AUC = 0.936). Then we used Shiny-Web tool to make our models be easily used from website. Interestingly, we found that the BCBM patients with an annual income of over USD$70,000 had better BCSS (HR = 0.523, 95%CI 0.273-0.999, P < 0.05) than those with less than USD$40,000. The results showed that in all distant metastasis sites, only lung metastasis was an independent poor prognostic factor for patients with BCBM (OS: HR = 1.606, 95%CI 1.157-2.230, P < 0.01; BCSS: HR = 1.698, 95%CI 1.219-2.365, P < 0.01), while bone, liver, distant lymph nodes and other metastases were not. We also found that surgical treatment significantly improved both OS and BCSS in BCBM patients with the HER2 + molecular subtypes and was beneficial to OS of the HR-/HER2- subtype. In contrast, surgery could not help BCBM patients with HR + /HER2- subtype improve their prognosis (OS: HR = 0.887, 95%CI 0.608-1.293, P = 0.510; BCSS: HR = 0.909, 95%CI 0.604-1.368, P = 0.630). CONCLUSION: We analyzed the clinical features of BCBM patients and constructed 4 machine-learning prognostic models to predict their survival. Our validation results indicate that these models should be highly reproducible in patients with BCBM. We also identified potential prognostic factors for BCBM patients and suggested that primary surgery might improve the survival of BCBM patients with HER2 + and triple-negative subtypes.

Knockdown of the glutamate-gated chloride channel gene decreases emamectin benzoate susceptibility in the fall armyworm, Spodoptera frugiperda.

Emamectin benzoate (EB), a derivative of avermectin, is the primary insecticide used to control the fall armyworm (FAW) in China. However, the specific molecular targets of EB against FAW remain unclear. In this study, we cloned the glutamate-gated chloride channel (GluCl) gene, which is known to be a primary molecular target for avermectin. We first investigated the transcript levels of SfGluCl in FAW and found that the expression level of SfGluCl in the head and nerve cord was significantly higher than that in other tissues. Furthermore, we found that the expression level of SfGluCl was significantly higher in eggs than that in other developmental stages, including larvae, pupae, and adults. Additionally, we identified three variable splice forms of SfGluCl in exons 3 and 9 and found that their splice frequencies remained unaffected by treatment with the LC50 of EB. RNAi mediated knockdown of SfGluCl showed a significant reduction of 42% and 65% after 48 and 72 h of dsRNA feeding, respectively. Importantly, knockdown of SfGluCl sifgnificantly reduced LC50 and LC90 EB treatment induced mortality of FAW larvae by 15% and 44%, respectively, compared to the control group feeding by dsEGFP. In contrast, there were no significant changes in the mortality of FAW larvae treated with the control insecticides chlorantraniliprole and spinetoram. Finally, molecular docking simulations revealed that EB bound to the large amino-terminal extracellular domain of SfGluCl by forming five hydrogen bonds, two alkyl hydrophobic interactions and one salt bridge. These findings strongly suggest that GluCl may serve as one of the molecular targets of EB in FAW, shedding light on the mode of action of this important insecticide.

Genome of the parasitoid wasp Cotesia chilonis sheds light on amino acid resource exploitation.

BACKGROUND: A fundamental feature of parasitism is the nutritional exploitation of host organisms by their parasites. Parasitoid wasps lay eggs on arthropod hosts, exploiting them for nutrition to support larval development by using diverse effectors aimed at regulating host metabolism. However, the genetic components and molecular mechanisms at the basis of such exploitation, especially the utilization of host amino acid resources, remain largely unknown. To address this question, here, we present a chromosome-level genome assembly of the parasitoid wasp Cotesia chilonis and reconstruct its amino acid biosynthetic pathway. RESULTS: Analyses of the amino acid synthetic pathway indicate that C. chilonis lost the ability to synthesize ten amino acids, which was confirmed by feeding experiments with amino acid-depleted media. Of the ten pathways, nine are known to have been lost in the common ancestor of animals. We find that the ability to synthesize arginine was also lost in C. chilonis because of the absence of two key genes in the arginine synthesis pathway. Further analyses of the genomes of 72 arthropods species show that the loss of arginine synthesis is common in arthropods. Metabolomic analyses by UPLC-MS/MS reveal that the temporal concentrations of arginine, serine, tyrosine, and alanine are significantly higher in host (Chilo suppressalis) hemolymph at 3 days after parasitism, whereas the temporal levels of 5-hydroxylysine, glutamic acid, methionine, and lysine are significantly lower. We sequence the transcriptomes of a parasitized host and non-parasitized control. Differential gene expression analyses using these transcriptomes indicate that parasitoid wasps inhibit amino acid utilization and activate protein degradation in the host, likely resulting in the increase of amino acid content in host hemolymph. CONCLUSIONS: We sequenced the genome of a parasitoid wasp, C. chilonis, and revealed the features of trait loss in amino acid biosynthesis. Our work provides new insights into amino acid exploitation by parasitoid wasps, and this knowledge can specifically be used to design parasitoid artificial diets that potentially benefit mass rearing of parasitoids for pest control.

FOXD1 promotes dedifferentiation and targeted therapy resistance in melanoma by regulating the expression of connective tissue growth factor.

Metastatic melanoma is an aggressive skin cancer and associated with a poor prognosis. In clinical terms, targeted therapy is one of the most important treatments for patients with BRAFV600E -mutated advanced melanoma. However, the development of resistance to this treatment compromises its therapeutic success. We previously demonstrated that forkhead box D1 (FOXD1) regulates melanoma migration and invasion. Here, we found that FOXD1 was highly expressed in melanoma cells and was associated with a poor survival of patients with metastatic melanoma. Upregulation of FOXD1 expression enhanced melanoma cells' resistance to vemurafenib (BRAF inhibitor [BRAFi]) or vemurafenib and cobimetinib (MEK inhibitor) combination treatment whereas loss of FOXD1 increased the sensitivity to treatment. By comparing gene expression levels between FOXD1 knockdown (KD) and overexpressing (OE) cells, we identified the connective tissue growth factor (CTGF) as a downstream factor of FOXD1. Chromatin immunoprecipitation and luciferase assay demonstrated the direct binding of FOXD1 to the CTGF promoter. Similar to FOXD1, knockdown of CTGF increased the sensitivity of BRAFi-resistant cells to vemurafenib. FOXD1 KD cells treated with recombinant CTGF protein were less sensitive towards vemurafenib compared to untreated FOXD1 KD cells. Based on these findings, we conclude that FOXD1 might be a promising new diagnostic marker and a therapeutic target for the treatment of targeted therapy resistant melanoma.

An Ovarian Protein Involved in Passive Avoidance of an Endoparasitoid To Evade Its Host Immune Response.

Through a combination of transcriptomic and proteomic analyses, we identified 817 secreted ovarian proteins from an endoparasitoid wasp, Cotesia chilonis, of which five proteins are probably involved in passive evasion. The results of an encapsulation assay revealed that one of these passive evasion-associated proteins (Crp32B), a homologue of a 32-kDa protein (Crp32) from C. rubecula, could protect resin beads from being encapsulated by host hemocytes in a dose-dependent manner. Crp32B is transcribed in ovarian cells, nurse cells, follicular cells, and oocytes, and the protein is located throughout the ovary and on the egg surface. Moreover, Crp32B has antigenic similarity to several host components. These results indicate that C. chilonis may use molecular mimicry as a mechanism to avoid host cellular immune response.

Loss of neural crest-associated gene FOXD1 impairs melanoma invasion and migration via RAC1B downregulation.

Recent studies suggest that malignant melanoma heterogeneity includes subpopulations of cells with features of multipotent neural crest (NC) cells. Zebrafish and mouse models have shown that reactivation of neural crest-specific pathways during transformation determines the invasiveness of melanoma cells. In our study, we show that the neural crest-associated transcription factor FOXD1 plays a key role in the invasion and the migration capacities of metastatic melanomas both in vivo and in vitro. Gene expression profiling analysis identified both an upregulation of FOXD1 in NC and melanoma cells, as well as a downregulation of several genes related to cell invasion in FOXD1 knockdown cells, including MMP9 and RAC1B. Furthermore, we demonstrate that knockdown of RAC1B a tumor-specific isoform of RAC1, significantly impaired melanoma cell migration and invasion and could abrogate enhanced invasiveness induced by FOXD1 overexpression. We conclude that FOXD1 may influence invasion and migration via indirect regulation of MMP9 and RAC1B alternative splicing in melanoma cells.

Host adaptability of Microplitis manilae (Hymenoptera: Braconidae) in Noctuidae.

Biological control is an effective and sustainable method of integrated pest management. Microplitis manilae (Hymenoptera: Braconidae) is a common internal parasitoid wasp of the order Lepidoptera. To determine a suitable host species for the reproduction of parasitoids, it is essential to assess host suitability and parasitic potential of the parasitized pests. Herein, we investigated host selection and exploitation of M. manilae. We evaluated the parasitic efficacy of M. manilae in 4 pest species in the Spodoptera and Mythimna genera of the Noctuidae family. The results indicated that the parasitism rate of M. manilae on 3 species in the Spodoptera genus is higher than on Mythimna separata in the Mythimna genus, with M. manilae exhibiting a higher parasitism rate and shorter development duration on Spodoptera litura compared to other species. The parasitism rate for 1st instars hosts was 86.67 ±â€…0.04%, while the development duration was 14.1 ±â€…0.03 days. However, when parasitizing the 3rd instar of Spodoptera frugiperda, parasitoids showed a higher sex ratio, of 0.71 ±â€…0.05. Additionally, M. manilae had parasitic effect on M. separata, providing a new choice for its parasitism. The results identify the optimal host, which could enhance and reproduction rate and survival rate of M. manilae, thus facilitating their large-scale propagation. Understanding the parasitic effects of M. manilae on pests can further its field application, also plays a major role in promoting the development of biological control technologies and sustainable agricultural production.

The chromosome-level genome assembly of Aphidoletes aphidimyza Rondani (Diptera: Cecidomyiidae).

Aphidoletes aphidimyza is widely recognized as an effective predator of aphids in agricultural systems. However, there is limited understanding of its predation mechanisms. In this study, we generated a high-quality chromosome level of the A. aphidimyza genome by combining PacBio, Illumina, and Hi-C data. The genome has a size of 192.08 Mb, with a scaffold N50 size of 46.85 Mb, and 99.08% (190.35 Mb) of the assembly is located on four chromosomes. The BUSCO analysis of our assembly indicates a completeness of 97.8% (n = 1,367), including 1,307 (95.6%) single-copy BUSCOs and 30 (2.2%) duplicated BUSCOs. Additionally, we annotated a total of 13,073 protein-coding genes, 18.43% (35.40 Mb) repetitive elements, and 376 non-coding RNAs. Our study is the first time to report the chromosome-scale genome for the species of A. aphidimyza. It provides a valuable genomic resource for the molecular study of A. aphidimyza.

Intraguild species presence alters Aphidoletes aphidimyza (Diptera: Cecidomyiidae) and Aphidius gifuensis (Hymenoptera: Braconidae) foraging responses.

The predatory gall midge, Aphidoletes aphidimyza (Rondani), and tobacco aphid cocoon wasp, Aphidius gifuensis Ashmead, are important natural enemies of Myzus persicae (Sulzer) (Hemiptera: Aphididae). Predation by A. aphidimyza and A. gifuensis can regulate M. persicae; however, how interspecific interference competition affects their foraging efficiency is unknown. Here, we investigated the consumption and parasitization abilities of A. aphidimyza 3rd instar larva and A. gifuensis adults under various conditions. Consumption of parasitized aphids by A. aphidimyza 3rd instar larvae was significantly lower than that of nonparasitized controls, with a substantial increase in handling time. The presence of A. gifuensis adults did not significantly affect the predation capacity of A. aphidimyza larvae. Relative to controls, A. aphidimyza larvae predation trace (PT) and imago activity significantly decreased A. gifuensis parasitism rates at different aphid densities. Further, A. aphidimyza larvae PT increased the A. gifuensis handling time of M. persicae, whereas the presence of A. aphidimyza adults had the opposite effect. Coexistence with heterospecific natural enemies reduced the parasitic capacity of A. gifuensis, whereas A. aphidimyza larvae predation capability was influenced to a lesser extent. Our results demonstrate that intraguild interactions strongly influence the predatory and parasitic efficacy of A. aphidimyza and A. gifuensis, although the effect on A. gifuensis was more pronounced. For effective biological control of M. persicae using A. aphidimyza and A. gifuensis, we recommend releasing A. aphidimyza first to mitigate intraguild predation and enhance the overall success of the pest control program.

Corticosteroids for hospitalized patients with severe/critical COVID-19: a retrospective study in Chongqing, China.

Corticosteroids have always been recommended for severe cases of COVID-19. However, the efficacy of treatment with corticosteroids for COVID-19 during the SARS-CoV-2 omicron outbreak in China has not been reported. Clinical data from 406 patients hospitalized for severe/critical COVID-19 from December 2022 to January 2023 at six hospitals in Chongqing were retrospectively analyzed. The primary outcome was all-cause mortality at 28 days in the groups with and without corticosteroids treatment after propensity score matching (PSM). Secondary outcomes were to compare in-hospital mortality and length of survival time with corticosteroids and those without corticosteroids. This study included 406 patients with severe or critical COVID-19, divided into the corticosteroids group (231, 56.9%) and non-corticosteroids group (175, 43.1%). After PSM, the use of corticosteroids did not reduce all-cause mortality at 28 days (42.5% vs. 39.1%). Univariate analysis showed that corticosteroids were not associated with improved all-cause mortality at 28 days [hazard ratio (HR), 1.019; 95% confidence interval (CI), 0.639-1.623; p = 0.938]. Multivariate analysis showed similar results (HR, 1.047; 95% CI, 0.633-1.732; p = 0.858). Among non-survivors, the survival time was significantly larger in those who received corticosteroids compared with the non-corticosteroid users [median 13 (IQR 6.5-15.5) vs. 6 (4-11.25), p = 0.007]. The use of systemic corticosteroids in severe/critical COVID-19 may provide certain potential survival benefits but does not improve prognosis.

Personalized circulating tumor DNA monitoring improves recurrence surveillance and management after curative resection of colorectal liver metastases: a prospective cohort study.

BACKGROUND: Approximately 60% of patients with colorectal liver metastases (CRLM) experience relapse within 2 years after radical resection, previous studies have proven that repeat local treatment (LT) could prolong survival, however, it is difficult to seize the window for LT due to the lack of a high-sensitive surveillance method. In this study, the authors aim to examine the value of longitudinal circulating tumor DNA (ctDNA) in guiding adjuvant chemotherapy, optimizing clinical surveillance strategy, and thereby improving CRLM outcomes. MATERIALS AND METHODS: The authors conducted a prospective clinical trial using a personalized, tumor-informed ctDNA assay to monitor 60 CRLM patients undergoing resection with curative intent. Formalin-fixed paraffin-embedded tumor samples were collected after surgery. Blood samples were collected before surgery, 30 days after surgery (post-OP), and every third month until relapse or up to 2 years. RESULTS: A total of 394 plasma samples from 60 eligible patients were analyzed, with a median follow-up time of 31.3 months. Landmark analyses revealed that detectable ctDNA at post-OP (HR, 4.8), postadjuvant chemotherapy (HR, 6.0), and end-of-treatment (HR, 5.6) were associated with higher recurrence risk ( P <0.001). Post-OP ctDNA positivity served as the only independent prognostic marker in the multivariant analysis (HR, 5.1; P <0.001). Longitudinal ctDNA analysis identified relapsed patients at both sensitivity and specificity of 100%. Most (75%) patients were found with radiological relapse within 6 months after the first detectable ctDNA with a median lead time of 3.5 months. In relapsed patients, 73.2% had oligometastatic disease and 61% were liver-restricted, of which 72.0% received repeat LTs, and 60.0% achieved a secondary no evidence of disease status. CONCLUSIONS: Longitudinal ctDNA monitoring assists in early prediction of relapse, and thereby improves survival of CRLM patients by increased secondary resection rate and secondary no evidence of disease rate.

FUT3 promotes gastric cancer cell migration by synthesizing Lea on ITGA6 and GLG1, affecting adhesion and vesicle distribution.

AIMS: Lewis antigen plays an important role in the progression of gastric cancer (GC), FUT3 is a key enzyme in the synthesis of Lewis antigen, but the molecular mechanism of its promotion of GC progression remains unclear. MAIN METHODS: We used Lea-antibody capturing coupled with mass spectrometry to identify the target proteins of FUT3, immunofluorescence (IF), molecular biology and cell function experiments were conducted to clarify the molecular mechanism of FUT3 promoting the migration and invasion of GC cells by regulating Lea glycosylation on ITGA6 and GLG1. KEY FINDINGS: FUT3 promote migration and invasion of GC cells. FUT3 silencing in GC cells led to the aggregation of integrin α6ß4 on the plasma membrane, associated with focal adhesion and hemidesmosome, and decreased GLG1 distribution in cellular vesicles. IGP analysis revealed Lea structure in 10 N-glycans of 2 glycosites for ITGA6 and 31 N-glycans of 4 glycosites for GLG1. Silencing ITGA6 promoted migration and invasion, while silencing GLG1 inhibited these processes in GC cells, regulated by FUT3-mediated Lea synthesis. SIGNIFICANCE: In conclusion, FUT3's promotion of GC cell migration and invasion is attributed to Lea synthesis on ITGA6, impacting cell adhesion, and on GLG1, influencing distribution in intracellular vesicles. These findings may contribute to developing novel therapeutic targets for inhibiting or controlling the metastatic behavior of GC cells and enhancing our understanding of Lea's role in regulating protein functions.

Genome-wide DNA methylation analysis identifies potent CpG signature for temzolomide response in non-G-CIMP glioblastomas with unmethylated MGMT promoter: MGMT-dependent roles of GPR81.

PURPOSES: To identify potent DNA methylation candidates that could predict response to temozolomide (TMZ) in glioblastomas (GBMs) that do not have glioma-CpGs island methylator phenotype (G-CIMP) but have an unmethylated promoter of O-6-methylguanine-DNA methyltransferase (unMGMT). METHODS: The discovery-validation approach was planned incorporating a series of G-CIMP-/unMGMT GBM cohorts with DNA methylation microarray data and clinical information, to construct multi-CpG prediction models. Different bioinformatic and experimental analyses were performed for biological exploration. RESULTS: By analyzing discovery sets with radiotherapy (RT) plus TMZ versus RT alone, we identified a panel of 64 TMZ efficacy-related CpGs, from which a 10-CpG risk signature was further constructed. Both the 64-CpG panel and the 10-CpG risk signature were validated showing significant correlations with overall survival of G-CIMP-/unMGMT GBMs when treated with RT/TMZ, rather than RT alone. The 10-CpG risk signature was further observed for aiding TMZ choice by distinguishing differential outcomes to RT/TMZ versus RT within each risk subgroup. Functional studies on GPR81, the gene harboring one of the 10 CpGs, indicated its distinct impacts on TMZ resistance in GBM cells, which may be dependent on the status of MGMT expression. CONCLUSIONS: The 64 TMZ efficacy-related CpGs and in particular the 10-CpG risk signature may serve as promising predictive biomarker candidates for guiding optimal usage of TMZ in G-CIMP-/unMGMT GBMs.

Assessment of a pharmacokinetic and pharmacodynamic interaction between simvastatin and Ginkgo biloba extracts in healthy subjects.

1. Ginkgo biloba extract (GBE) is one of the most commonly used herbal remedies worldwide. It is usually concomitantly administrated with statins to treat diseases in geriatric patients. We aim to determine the influence of GBE on the pharmacokinetics (PK) and pharmacodynamics of simvastatin, which is currently unknown. 2. An open-label, randomized, two-period, two-treatment, balanced, crossover study was performed in 14 healthy volunteers. Subjects received simvastatin 40 mg once daily, co-treated with placebo or GBE 120 mg twice daily. Each treatment was administered for 14 d, separated by a wash-out period of 1 month. Simvastatin, simvastatin acid and lipoprotein concentrations were assessed. 3. GBE administration reduced mean simvastatin area under the curve (AUC)0-24, AUC0-∞ and Cmax by 39% (p = 0.000), 36%(p = 0.001) and 32% (p = 0.002), respectively, but did not cause significant differences in simvastatin acid PK or its cholesterol-lowering efficacy. 4. GBE consumption decreased simvastatin system exposure, but did not affect simvastatin acid PK. However, we cannot rule out the possibility for a pharmacodynamic interaction between GBE and simvastatin in vivo.

Chromosome-Scale Genome Assembly of the Solitary Parasitoid Wasp Microplitis manilae Ashmead, 1904 (Braconidae: Microgastrinae).

Parasitoid wasps are invaluable natural enemies extensively used to control coleopteran, dipteran, and lepidopteran pests in agriculture and forestry owing to their killing and reproductive actions on hosts. The important larval endoparasitoid wasp Microplitis manilae, which belongs to the Microgastrinae subfamily, parasitizes the larval stages of Spodoptera spp., such as Spodoptera litura and Spodoptera frugiperda. The absence of a genomic resource for M. manilae has impeded studies on chemosensory- and detoxification-related genes. This study presents a chromosome-level genome assembly of M. manilae with a genome size of 293.18 Mb, which includes 222 contigs (N50 size, 7.58 Mb) and 134 scaffolds (N50 size, 27.33 Mb). A major proportion of the genome (284.76 Mb; 97.13%) was anchored to 11 pseudochromosomes with a single-copy BUSCO score of 98.4%. Furthermore, 14,316 protein-coding genes, 165.14 Mb (57.99%) repetitive elements, and 871 noncoding RNAs were annotated and identified. Additionally, a manual annotation of 399 genes associated with chemosensation and 168 genes involved in detoxification was conducted. This study provides a valuable and high-quality genomic resource to facilitate further functional genomics research on parasitoid wasps.

Comprehensive analysis of NT5DC family prognostic and immune significance in breast cancer.

Among the most common malignancies, breast cancer has a high incidence and mortality rate. NT5DC family is a highly well-conserved 5'-nucleotidase. Previous studies showed that the progression of tumors was associated with some NT5DC family members. However, there are no studies about the comprehensive analysis such as expression, prognosis, and immune properties of NT5DC family in breast cancer. Based on the data from The Cancer Genome Atlas database, we used UALCAN, Tumor Immune Estimation Resource, Breast cancer gene-expression miner (Bc-GenExMiner), Kaplan-Meier Plotter, TISIDB, cBioPortal, GeneMANIA, Search Tool for the Retrieval of Interacting Genes, Metascape, Tumor Immune Single-cell Hub, The Database for Annotation, Visualization and Integrated Discovery, and Gene Set Cancer Analysis databases to explore expression, prognostic and diagnostic value, genetic alterations, biological function, immune value and drug sensitivity of NT5DC family in breast cancer patients. There was a downregulation of NT5C2, NT5DC1, and NT5DC3 in breast cancer compared to normal tissues, and NT5DC2 instead. All NT5DC family members were associated with the clinicopathological parameters of breast cancer patients. Survival and ROC analysis revealed that NT5DC family genes were related to the prognosis and diagnosis of breast cancer. NT5DC family were mainly involved in nucleotide metabolism. Moreover, NT5DC family were significantly associated with tumor immune microenvironment, diverse immune cells, and immune checkpoints in breast cancer. This research showed that NT5DC family might be novel prognostic biomarkers and immunotherapeutic targets of breast cancer.

Causal associations of Sjögren's syndrome with cancers: a two-sample Mendelian randomization study.

BACKGROUND: Several observational studies have explored the associations between Sjögren's syndrome (SS) and certain cancers. Nevertheless, the causal relationships remain unclear. Mendelian randomization (MR) method was used to investigate the causality between SS and different types of cancers. METHODS: We conducted the two-sample Mendelian randomization with the public genome-wide association studies (GWASs) summary statistics in European population to evaluate the causality between SS and nine types of cancers. The sample size varies from 1080 to 372,373. The inverse variance weighted (IVW) method was used to estimate the causal effects. A Bonferroni-corrected threshold of P < 0.0031 was considered significant, and P value between 0.0031 and 0.05 was considered to be suggestive of an association. Sensitivity analysis was performed to validate the causality. Moreover, additional analysis was used to assess the associations between SS and well-accepted risk factors of cancers. RESULTS: After correcting the heterogeneity and horizontal pleiotropy, the results indicated that patients with SS were significantly associated with an increased risk of lymphomas (odds ratio [OR] = 1.0010, 95% confidence interval [CI]: 1.0005-1.0015, P = 0.0002) and reduced risks of prostate cancer (OR = 0.9972, 95% CI: 0.9960-0.9985, P = 2.45 × 10-5) and endometrial cancer (OR = 0.9414, 95% CI: 0.9158-0.9676, P = 1.65 × 10-5). Suggestive associations were found in liver and bile duct cancer (OR = 0.9999, 95% CI: 0.9997-1.0000, P = 0.0291) and cancer of urinary tract (OR = 0.9996, 95% CI: 0.9992-1.0000, P = 0.0281). No causal effect of SS on other cancer types was detected. Additional MR analysis indicated that causal effects between SS and cancers were not mediated by the well-accepted risk factors of cancers. No evidence of the causal relationship was observed for cancers on SS. CONCLUSIONS: SS had significant causal relationships with lymphomas, prostate cancer, and endometrial cancer, and suggestive evidence of association was found in liver and bile duct cancer and cancer of urinary tract, indicating that SS may play a vital role in the incidence of these malignancies.