Olaparib Combined with Abiraterone versus Olaparib Monotherapy for Patients with Metastatic Castration-resistant Prostate Cancer Progressing after Abiraterone and Harboring DNA Damage Repair Deficiency: A Multicenter Real-world Study.

BACKGROUND AND OBJECTIVE: Olaparib + abiraterone has a combined antitumor effect in metastatic castration-resistant prostate cancer (mCRPC), but the efficacy of this combination in patients with DNA damage repair (DDR)-deficient mCRPC progressing after abiraterone is unknown. Our aim was to compare the efficacy of olaparib + abiraterone versus olaparib monotherapy for patients with DDR-deficient mCRPC progressing after abiraterone. METHODS: The study included 86 consecutive patients with DDR-deficient mCRPC progressing after abiraterone: 34 received olaparib + abiraterone, and 52 received olaparib monotherapy. DDR-deficient status was defined as the presence of a DDR gene with a pathogenic or likely pathogenic variant (DDR-PV), or with a variant of unknown significance (DDR-VUS). We assessed progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier method. Potential factors influencing PFS and OS were compared between the treatment arms using Cox proportional-hazards models. The prostate-specific antigen (PSA) response, the treatment effect across subgroups, and adverse events (AEs) were also evaluated. KEY FINDINGS AND LIMITATIONS: Median follow-up was 9 mo. In the overall cohort, median PFS and OS were significantly longer in the combination arm than in the monotherapy arm (PFS: 6.0 vs 3.0 mo; hazard ratio [HR] 0.41, 95% confidence interval [CI] 0.25-0.67; p < 0.01; OS: 25.0 vs 12.0 mo; HR 0.30, 95% CI 0.14-0.67; p < 0.01). PSA responses were significantly higher following combination therapy versus monotherapy. Combination therapy had significantly better efficacy in the DDR-PV and DDR-VUS subgroups, and was an independent predictor of better PFS and OS. AE rates were acceptable. The retrospective nature, small sample size, and short follow-up are limitations. CONCLUSIONS: Olaparib + abiraterone resulted in better PFS and OS than olaparib alone for patients with DDR-deficient mCRPC progressing after abiraterone. These results need to be confirmed by a large-scale prospective randomized controlled trial. PATIENT SUMMARY: Our study shows that the drug combination of olaparib plus abiraterone improved survival over abiraterone alone for patients who have mutations in genes affecting DNA repair and metastatic prostate cancer resistant to hormone therapy. The results provide evidence of a synergistic effect of the two drugs in these patients.

Concordance and Clinical Significance of Genomic Alterations in Progressive Tumor Tissue and Matched Circulating Tumor DNA in Aggressive-variant Prostate Cancer.

Sequencing of circulating tumor DNA (ctDNA) is a minimally invasive approach to reveal the genomic alterations of cancer; however, its comparison with sequencing of tumor tissue has not been well documented in real-world patients with aggressive-variant prostate cancer (AVPC). Concordance of genomic alterations was assessed between progressive tumor tissue and matched ctDNA by next-generation sequencing for 63 patients with AVPC. Associations of genomic alterations with progression-free survival (PFS) and overall survival (OS) were investigated using Kaplan-Meier and Cox regression analyses. A total of 161 somatic mutations (SMs) and 84 copy-number variants (CNVs) were detected in tumors, of which 97 were also found in ctDNA, giving concordance of 39.6% (97/245) across all SMs and CNVs, 49.7% for SMs only and 20.2% for CNVs only. Across all patients with AVPC, chemotherapy was associated with significantly longer median PFS (6 vs. 0.75 months, P = 0.001) and OS (11 vs. 8 months, P < 0.001) than next-generation hormonal therapy (NHT). Among types of chemotherapy, additional platinum-based chemotherapy was associated with significantly longer median PFS and OS than docetaxel only in patients with TP53, RB1, or PTEN alterations, and in those with ctDNA% ≥ 13.5%. The concordance analysis first provides evidence for combining the sequencing of ctDNA and tumor tissue in real-world patients with AVPC. Chemotherapy is associated with significantly better survival than NHT, and the benefit of additional platinum-based chemotherapy may depend on the presence of alterations in TP53, RB1, or PTEN and on a sufficiently high proportion of ctDNA in patients with AVPC. SIGNIFICANCE: AVPC is a highly malignant and heterogeneous disease. Sequencing of ctDNA is a minimally invasive approach to reveal genomic alterations. On the basis of the current real-world study, we found ctDNA does not fully recapitulate the landscape of genomic alterations from progressive tumor tissue in AVPC. We also revealed AVPC can benefit from chemotherapy, especially platinum-based regimens. TP53/RB1/PTEN alterations in ctDNA or tumor tissue could be biomarkers for platinum-based chemotherapy in this setting.

Newcastle disease virus nucleocapsid protein mediates the degradation of 14-3-3ε to antagonize the interferon response and promote viral replication.

Newcastle disease virus (NDV) is responsible for outbreaks that pose a threat to the global poultry industry. NDV triggers an interferon (IFN) response in the host upon infection. However, it also employs mechanisms that counteract this response. One important component in IFN-related signaling pathways is 14-3-3ε, which is known to interact with retinoic acid-inducible gene I (RIG-I) and mitochondrial antiviral signaling protein (MAVS). The relationship between 14 and 3-3ε and NDV infection has not been previously explored; therefore, this study aimed to investigate this relationship in vivo and in vitro using overexpressed and knockdown 14-3-3ε experiments, along with co-immunoprecipitation analysis. We found that NDV infection led to the degradation of 14-3-3ε. Furthermore, 14-3-3ε inhibited the replication of NDV, suggesting that NDV may enhance its own replication by promoting the degradation of 14-3-3ε during infection. The study revealed that 14-3-3ε is degraded by lysosomes and the viral protein nucleocapsid protein (NP) of NDV induces this degradation. It was also observed that 14-3-3ε is involved in activating the IFN pathway during NDV infection and mediates the binding of MDA5 to MAVS. Our study reveals that NDV NP mediates the entry of 14-3-3ε into lysosomes and facilitates its degradation. These findings contribute to the existing knowledge on the molecular mechanisms employed by NDV to counteract the IFN response and enhance its own replication.

NDV-induced autophagy enhances inflammation through NLRP3/Caspase-1 inflammasomes and the p38/MAPK pathway.

Newcastle disease (ND), caused by the Newcastle disease virus (NDV), is a highly virulent infectious disease of poultry. Virulent NDV can cause severe autophagy and inflammation in host cells. While studies have shown a mutual regulatory relationship between autophagy and inflammation, this relationship in NDV infection remains unclear. This study confirmed that NDV infection could trigger autophagy in DF-1 cells to promote cytopathic and viral replication. NDV-induced autophagy was positively correlated with the mRNA levels of inflammatory cytokines such as IL-1ß, IL-8, IL-18, CCL-5, and TNF-α, suggesting that NDV-induced autophagy promotes the expression of inflammatory cytokines. Further investigation demonstrated that NLRP3 protein expression, Caspase-1 activity, and p38 phosphorylation level positively correlated with autophagy, suggesting that NDV-induced autophagy could promote the expression of inflammatory cytokines through NLRP3/Caspase-1 inflammasomes and p38/MAPK pathway. In addition, NDV infection also triggered mitochondrial damage and mitophagy in DF-1 cells, but did not result in a large leakage of reactive oxygen species (ROS) and mitochondrial DNA (mtDNA), indicating that mitochondrial damage and mitophagy do not contribute to the inflammation response during NDV infection.

Public attention, oil and gold markets during the COVID-19: Evidence from time-frequency analysis.

This paper uses time-frequency analysis, including wavelet analysis and time-frequency domain causality, to evaluate the relationship between public attention to the COVID-19 pandemic, crude oil, and gold markets in the G7 countries over time and frequency. Empirical findings show that WTI oil lead gold returns during the COVID-19 outbreak, and vice versa when Omicron spread. The relationship between public attention to the COVID-19 and WTI oil/gold markets appears to be heterogeneous for G7 countries. European public attention caused by the COVID-19 outbreak has a strong impact on gold returns at the 32-64 day frequency, while public attention generated by Omicron has a significant effect on WTI oil returns at 4-128 day frequency. The public in the US and Canada is more concerned about the global stock and WTI oil markets slump than the COVID-19 pandemic. The Italian public seems to be the most sensitive to the EU's economic support plan. The heterogeneity of the public attention-oil/gold nexus in the G7 implies that portfolio diversification across markets and investment horizons may be extremely beneficial.

Deletion at an 1q24 locus reveals a critical role of long noncoding RNA DNM3OS in skeletal development.

BACKGROUND: Skeletal development and maintenance are complex processes known to be coordinated by multiple genetic and epigenetic signaling pathways. However, the role of long non-coding RNAs (lncRNAs), a class of crucial epigenetic regulatory molecules, has been under explored in skeletal biology. RESULTS: Here we report a young patient with short stature, hypothalamic dysfunction and mild macrocephaly, who carries a maternally inherited 690 kb deletion at Chr.1q24.2 encompassing a noncoding RNA gene, DNM3OS, embedded on the opposite strand in an intron of the DYNAMIN 3 (DNM3) gene. We show that lncRNA DNM3OS sustains the proliferation of chondrocytes independent of two co-cistronic microRNAs miR-199a and miR-214. We further show that nerve growth factor (NGF), a known factor of chondrocyte growth, is a key target of DNM3OS-mediated control of chondrocyte proliferation. CONCLUSIONS: This work demonstrates that DNM3OS is essential for preventing premature differentiation of chondrocytes required for bone growth through endochondral ossification.

MicroRNA-145 suppresses osteogenic differentiation of human jaw bone marrow mesenchymal stem cells partially via targeting semaphorin 3A.

Purpose: Human jaw bone marrow mesenchymal stem cells (h-JBMMSCs) are multipotent progenitor cells with osteogenic differentiation potential. MicroRNAs (miRNAs) have emerged as crucial modulators of osteoblast differentiation. In this study, we focus on the role of miR-145 and its target protein in osteoblast differentiation of h-JBMMSCs. Materials and Methods: h-JBMMSCs were isolated and cultured in osteogenic medium. miR-145 mimics and inhibitors were used to elevate and inhibit miR-145 expression, respectively. Osteogenic differentiation was determined by Alkaline phosphatase (ALP) and Alizarin red S (ARS) staining, and osteogenic marker detection using quantitative real-time reverse transcription PCR (qRT-PCR) assay. Bioinformatic analysis and luciferase reporter assay were used to identify the target gene of miR-145. Results: MiR-145 was down-regulated during osteogenesis of h-JBMMSCs. Inhibition of miR-145 promoted osteogenic differentiation of h-JBMMSCs, revealed by enhanced activity of alkaline phosphatase (ALP), greater mineralisation, and increased expression levels of the osteogenic markers, such as Runt-related transcription factor 2 (RUNX2), Osterix (OSX), ALP and COL1A1. MiR-145 could negatively regulate semaphorin3A (SEMA3A), which acts as a positive regulator of osteogenesis. MiR-145 inhibitor induced osteogenesis could be partially attenuated by SEMA3A siRNA treatment in h-JBMMSCs. Conclusions: Our data show that miR-145 directly targets SEMA3A, and also suggest miR-145 as a suppressor, plays an important role in the osteogenic differentiation of h-JBMMSCs.