Genetic aberrations of homologous recombination repair pathways in prostate cancer: The prognostic and therapeutic implications.

Prostate cancer (PC) is the second most common cancer in men worldwide. Homologous recombination repair (HRR) gene defects have been identified in a significant proportion of metastatic castration-resistant PC (mCRPC) and are associated with an increased risk of PC and more aggressive PC. Importantly, it has been well-documented that poly ADP-ribose polymerase (PARP) inhibition in cells with HR deficiency (HRD) can cause cell death. This has been exploited for the targeted treatment of PC patients with HRD by PARP inhibitors. Moreover, it has been shown that platinum-based chemotherapy is more effective in mCRPC patients with HRR gene alterations. This review highlights the prognosis and therapeutic implications of HRR gene alterations in PC.

Effect of Europium Substitution on the Structural, Magnetic and Relaxivity Properties of Mn-Zn Ferrite Nanoparticles: A Dual-Mode MRI Contrast-Agent Candidate.

Magnetic nanoparticles (MNPs) have been widely applied as magnetic resonance imaging (MRI) contrast agents. MNPs offer significant contrast improvements in MRI through their tunable relaxivities, but to apply them as clinical contrast agents effectively, they should exhibit a high saturation magnetization, good colloidal stability and sufficient biocompatibility. In this work, we present a detailed description of the synthesis and the characterizations of europium-substituted Mn-Zn ferrite (Mn0.6Zn0.4EuxFe2-xO4, x = 0.00, 0.02, 0.04, 0.06, 0.08, 0.10, and 0.15, herein named MZF for x = 0.00 and EuMZF for others). MNPs were synthesized by the coprecipitation method and subsequent hydrothermal treatment, coated with citric acid (CA) or pluronic F127 (PF-127) and finally characterized by X-ray Diffraction (XRD), Inductively Coupled Plasma (ICP), Vibrating Sample Magnetometry (VSM), Fourier-Transform Infrared (FTIR), Dynamic Light Scattering (DLS) and MRI Relaxometry at 3T methods. The XRD studies revealed that all main diffraction peaks are matched with the spinel structure very well, so they are nearly single phase. Furthermore, XRD study showed that, although there are no significant changes in lattice constants, crystallite sizes are affected by europium substitution significantly. Room-temperature magnetometry showed that, in addition to coercivity, both saturation and remnant magnetizations decrease with increasing europium substitution and coating with pluronic F127. FTIR study confirmed the presence of citric acid and poloxamer (pluronic F127) coatings on the surface of the nanoparticles. Relaxometry measurements illustrated that, although the europium-free sample is an excellent negative contrast agent with a high r2 relaxivity, it does not show a positive contrast enhancement as the concentration of nanoparticles increases. By increasing the europium to x = 0.15, r1 relaxivity increased significantly. On the contrary, europium substitution decreased r2 relaxivity due to a reduction in saturation magnetization. The ratio of r2/r1 decreased from 152 for the europium-free sample to 11.2 for x = 0.15, which indicates that Mn0.6Zn0.4Eu0.15Fe1.85O4 is a suitable candidate for dual-mode MRI contrast agent potentially. The samples with citric acid coating had higher r1 and lower r2 relaxivities than those of pluronic F127-coated samples.

Homologous recombination repair gene mutations in Malaysian prostate cancer patients.

Genetic alterations in the homologous recombination repair (HRR) genes are associated with an increased risk of prostate cancer development, and patients harboring these mutations can benefit from targeted therapy. The main aim of this study is to identify genetic alterations in HRR genes as a potential target for targeted treatment. In this study, targeted next generation sequencing (NGS) is used to analyze mutations in the protein-coding regions of the 27 genes involved in HRR and mutations in hotspots of 5 cancer-associated genes in four FFPE samples and three blood samples from prostate cancer patients. We identified two mutations in TP53 and KRAS. We also identified four conflicting interpretations of pathogenicity variants in BRCA2, STK11 genes and one variant of uncertain significance in the RAD51B gene. In addition, we detected one drug response variant in TP53, and two novel variants in CDK12 and ATM. Our results revealed some actionable pathogenic and potential pathogenic variants that may be associated with response to the Poly (ADP-ribose) polymerase (PARP) inhibitor treatment. More studies in a larger cohort are needed to evaluate and determine the association of HRR mutations with prostate cancer.

T-Cell Exhaustion in Chronic Infections: Reversing the State of Exhaustion and Reinvigorating Optimal Protective Immune Responses.

T-cell exhaustion is a phenomenon of dysfunction or physical elimination of antigen-specific T cells reported in human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infections as well as cancer. Exhaustion appears to be often restricted to CD8+ T cells responses in the literature, although CD4+ T cells have also been reported to be functionally exhausted in certain chronic infections. Although our understanding of the molecular mechanisms associated with the transcriptional regulation of T-cell exhaustion is advancing, it is imperative to also explore the central mechanisms that control the altered expression patterns. Targeting metabolic dysfunctions with mitochondrion-targeted antioxidants are also expected to improve the antiviral functions of exhausted virus-specific CD8+ T cells. In addition, it is crucial to consider the contributions of mitochondrial biogenesis on T-cell exhaustion and how mitochondrial metabolism of T cells could be targeted whilst treating chronic viral infections. Here, we review the current understanding of cardinal features of T-cell exhaustion in chronic infections, and have attempted to focus on recent discoveries, potential strategies to reverse exhaustion and reinvigorate optimal protective immune responses in the host.