Differential expression and analysis of extrachromosomal circular DNAs as serum biomarkers in lung adenocarcinoma.

BACKGROUND: Extrachromosomal circular DNAs (eccDNAs) increase the number of proto-oncogenes by enhancing oncogene expression to promote tumorigenesis. However, there are limited reports on differential eccDNA expression and analysis in lung cancer, especially in lung adenocarcinoma (LAD). METHODS: Three LAD and three corresponding NT tissues samples were used for eccDNA next-generation sequencing analysis, and an additional 20 were used for quantitative PCR (qPCR) evaluations. We further performed qPCR amplification using serum samples from LAD patients and healthy medical examiners. RESULTS: eccDNAs from LAD samples were mainly 200-1000 bp in length. Gene annotation analysis revealed that most eccDNAs were derived from chromosomes 1 and 2. The top-ten increased and top-ten decreased eccDNAs in LAD tissues were CircD-ARPC1B, CircD-ARPC1A, CircD-FAM49B, CircD-SDK1, CircD-KCNG1, CircD-POLR2F, CircD-SS18L1, CircD-SLC16A3, CircD-CSNK1D, CircD-KCTD1, and CircD-TMIGD2, CircD-PDIA5, CircD-VAV2, CircD-GATAD2A, CircD-CAB39L, CircD-KHDC1, CircD-FOXN3, CircD-SULT2B1, CircD-DPP9, and CircD-CSNK1D. qPCR demonstrated that the expression of CircD-DZRN3 was higher in LAD tissues than in normal lung tissues, whereas CircD-LGR6 and CircD-UMODL1 expression levels were lower in LAD than in normal lung tissues. Furthermore, the serum CircD-PDZRN3 level increased, while CircD-LGR6 decreased in LAD. Receiver operating characteristic (ROC) analysis showed that area under curve (AUC) of serum CircD-PDZRN3 (0.991), CircD-LGR6 (0.916) was higher than that of serum carcinoembryonic antigen (CEA) (0.825), CY211 (cytokeratin 19 fragment) (0.842), SCCA(squamous cell carcinoma antigen) (0.857) for the diagnosis of LAD. CONCLUSIONS: Our study first showed that several eccDNAs were aberrantly expressed in LAD, among which CircD-PDZRN3 and CircD-LGR6 clearly distinguished LAD patients from healthy controls, indicating their potential as biomarkers.

Concordance of BRCA mutation detection in tumor versus blood, and frequency of bi-allelic loss of BRCA in tumors from patients in the phase III SOLO2 trial.

OBJECTIVE: Maintenance olaparib provided a progression-free survival benefit in the phase III SOLO2 trial (NCT01874353) in patients with platinum-sensitive relapsed ovarian cancer and a BRCA mutation (BRCAm). However, questions remain regarding tumor versus germline BRCA testing and the impact of heterozygous versus bi-allelic loss of BRCA1 or BRCA2 in the tumor. METHODS: Blood and tumor samples were analyzed. A concordance analysis of germline BRCAm status (BRACAnalysis® CLIA test) and tumor BRCAm status (myChoice® CDx test) was conducted (Myriad Genetic Laboratories, Inc.). Bi-allelic loss of BRCA1 and BRCA2 and a genomic instability score (GIS) (myChoice® CDx test) were also determined. RESULTS: 289 of 295 enrolled patients had a germline BRCAm confirmed centrally and tumor BRCAm status was evaluable in 241 patients. There was 98% and 100% concordance between tumor and germline testing for BRCA1m and BRCA2m, respectively, with discordance found in four cases. Of 210 tumor samples evaluable for BRCA zygosity, 100% of germline BRCA1-mutated tumors (n = 144) and 98% of germline BRCA2-mutated tumors (n = 66) had bi-allelic loss of BRCA. One patient with a heterozygous BRCA2m had a GIS of 53, was progression free for 911 days and remained on olaparib at data cut-off. CONCLUSIONS: Very high concordance was demonstrated between tumor and germline BRCA testing, supporting wider implementation of tumor BRCA testing in ovarian cancer. Near 100% rates of bi-allelic loss of BRCA in platinum-sensitive relapsed ovarian tumors suggest routine testing for BRCA zygosity is not required in this population and reflects BRCA loss being a driver of tumorigenesis.

Immune biomarkers link air pollution exposure to blood pressure in adolescents.

BACKGROUND: Childhood exposure to air pollution contributes to cardiovascular disease in adulthood. Immune and oxidative stress disturbances might mediate the effects of air pollution on the cardiovascular system, but the underlying mechanisms are poorly understood in adolescents. Therefore, we aimed to identify immune biomarkers linking air pollution exposure and blood pressure levels in adolescents. METHODS: We randomly recruited 100 adolescents (mean age, 16 years) from Fresno, California. Using central-site data, spatial-temporal modeling, and distance weighting exposures to the participant's home, we estimated average pollutant levels [particulate matter (PM), polyaromatic hydrocarbons (PAH), ozone (O3), carbon monoxide (CO) and nitrogen oxides (NOx)]. We collected blood samples and vital signs on health visits. Using proteomic platforms, we quantitated markers of inflammation, oxidative stress, coagulation, and endothelial function. Immune cellular characterization was performed via mass cytometry (CyTOF). We investigated associations between pollutant levels, cytokines, immune cell types, and blood pressure (BP) using partial least squares (PLS) and linear regression, while adjusting for important confounders. RESULTS: Using PLS, biomarkers explaining most of the variance in air pollution exposure included markers of oxidative stress (GDF-15 and myeloperoxidase), acute inflammation (C-reactive protein), hemostasis (ADAMTS, D-dimer) and immune cell types such as monocytes. Most of these biomarkers were independently associated with the air pollution levels in fully adjusted regression models. In CyTOF analyses, monocytes were enriched in participants with the highest versus the lowest PM2.5 exposure. In both PLS and linear regression, diastolic BP was independently associated with PM2.5, NO, NO2, CO and PAH456 pollution levels (P ≤ 0.009). Moreover, monocyte levels were independently related to both air pollution and diastolic BP levels (P ≤ 0.010). In in vitro cell assays, plasma of participants with high PM2.5 exposure induced endothelial dysfunction as evaluated by eNOS and ICAM-1 expression and tube formation. CONCLUSIONS: For the first time in adolescents, we found that ambient air pollution levels were associated with oxidative stress, acute inflammation, altered hemostasis, endothelial dysfunction, monocyte enrichment and diastolic blood pressure. Our findings provide new insights on pollution-related immunological and cardiovascular disturbances and advocate preventative measures of air pollution exposure.

Role of a novel circulatory RNA-based biomarker panel expression in ovarian cancer.

Ovarian cancer (OC) is considered the sixth commonest cancer affecting women globally. We choose novel integrated specific ovarian cancer RNA biomarker panel; pellino E3 ubiquitin protein ligase family member 3 (PELI3) gene expressions along with its selected epigenetic regulators (microRNA (miR-361-3p) and long noncoding RNA (lncRNA RP5-837J1.2) by bioinformatic methods. Then, differential expressions of the selected panel in the sera of 50 OC patients, 42 cases with benign ovarian lesions, and among 45 controls were determined using real-time polymerase chain reaction quantitative (qRT-PCR). Furthermore, their expression was measured also in malignant ovarian tissues and adjacent nontumor tissues in 23 of 50 OC patients by quantitative qRT-PCR. The current study reported, for the first time, upregulation of serum lncRNA RP5-837J1.2 with concomitant downregulation of miR-361-3p and PELI3 mRNA in malignant group compared with benign and controls groups. There were associations of serum lncRNA RP5-837J1.2 with the affected ovary and worse International Federation of Gynecology and Obstetrics staging; associations of miR-361-3p with tumor size, grade, stage, and presence of metastasis; as well as associations among PELI3 mRNA expression and tumor size, grade, stage, and presence of metastasis among the OC group. In tumor tissues, miR-361-3p and PELI3 mRNA levels were at a higher level than that of nontumor tissues; however, tumor tissue showed lower level of lncRNA RP5-837J1.2 compared to normal tissue. There were positive correlations between serum and tissue level of RNA RP5-837J1.2, miR-361-3p, and PELI3 mRNA, but they did not reach statistical significance. Receiver operating characteristics curve analyses showed that lncRNA RP5-837J1.2, miR-361-3p, and PELI3 mRNA expression levels can discriminate among OC patient, cases with benign mass, and controls with an accuracy of 96, 76, and 83%, respectively; which increased if they are combined. This novel diagnostic RNA-based panel biomarker could be helpful for OC diagnosis.

Deltex1 suppresses T cell function and is a biomarker for diagnosis and disease activity of systemic lupus erythematosus.

OBJECTIVE: Deletion of Deltex1 (DTX1) in mice caused hyperactivation of T cells and lupus-like autoimmune syndromes, however, the association of DTX1 with human autoimmune diseases is totally unknown. This study investigated the role of DTX1 in human T cell functions and its correlation with disease activity in patients with SLE. METHODS: The influence of DTX1 on T cell function was evaluated using human primary cells. DTX1 expression in peripheral blood mononuclear cells (PBMCs) from healthy controls and SLE patients was measured by quantitative real-time PCR and the SLEDAI was used to assess disease activity. RESULTS: After stimulation with anti-CD3 and anti-CD28, silencing of DTX1 expression enhanced IFN-γ secretion by human T cells. The expression of DTX1 in PBMCs was significantly lower in 100 SLE patients than in 50 age- and sex-matched healthy controls (DTX1/glyceraldehyde 3-phosphate dehydrogenase, 0.452 vs 1.269, P < 0.001). The area under the receiver operator characteristics curve of the model was 0.737 (95% CI 0.658, 0.815). Intriguingly, a low DTX1 level in T cells led to high IFN-γ production in SLE patients and had a correlation with severe disease activity. In addition, low DTX1 expression in SLE patients was associated with active LN, lung involvement or hypocomplementaemia. CONCLUSION: Knockdown DTX1 expression in human T cells reduced IFN-γ secretion. DTX1 expression in the PBMCs was significantly lower in SLE patients and had an inverse correlation with disease activity, indicating that the DTX1 level may be a good disease marker of SLE.

Changes E3 ubiquitin protein ligase 1 gene mRNA expression correlated with IgA1 glycosylation in patients with IgA nephropathy.

BACKGROUND: Recent genomewide association study suggested that the top single-nucleotide polymorphism, rs978056, in HECW1 gene (which encodes HECT, C2 and WW domain containing E3 ubiquitin protein ligase 1) associated with the levels of galactose-deficient IgA1 (Gd-IgA1) in IgA nephropathy (IgAN). However, HECW1 expression in IgAN has not yet been examined. METHODS: In the following study, we have enrolled 40 patients with IgAN and 40 healthy controls. The expression level of HECW1, as well as plasma levels of Gd-IgA1 and IgA1, were determined detected. RESULTS: IgAN patients presented with significantly elevated Gd-IgA1 and IgA1 levels compared with those of the healthy controls (p < .001 and p = .03, respectively). We further divided the patients into two groups according to the median level of HECW1 (0.58). We found the levels of Gd-IgA1 and IgA1 were significantly higher in low HECW1 level group compared with those in high HECW1 level group (p = .02 and p = .04, respectively). And HECW1 mRNA expression had a significant inverse correlation with Gd-IgA1 levels in IgAN patients (r= -0.34, p = .03). It seemed that the risk genotype (rs978056 GG) was associated with reduced HECW1 expression in 80 Han Chinese from Beijing, although the difference was not significant (p = .09). No significant association with clinical and pathological manifestations was observed between patients with high and low levels of HECW1. CONCLUSION: We reported for the first time that HECW1 mRNA levels were negatively correlated with Gd-IgA1 levels. Our study points to a new regulatory mechanism of IgAN that can explain the aberrant glycosylation of IgA1.

Sequences and combinations of multifaceted therapy in advanced prostate cancer.

PURPOSE OF REVIEW: Multiple agents with very distinct mechanisms of actions and unique toxicities and efficacies have become available for use in advanced prostate cancer. The next wave of investigations is focused on the development of combinations and optimal sequences of the currently available agents. The focus of this article is to provide an update on clinical developments in advanced prostate cancer occurring within the past year and to highlight the ongoing investigations of promising novel targets and compounds. RECENT FINDINGS: The clinical use of enzalutamide prior to chemotherapy demonstrated improvement in progression-free survival and overall survival as compared with placebo in metastatic castrate resistant prostate cancer. This report of the Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (PREVAIL) trial led to the Food and Drug Administration approval of this agent. Novel agents such as cabozantinib and custirsen that had shown promising results in phase II trials revealed disappointing results in the phase III setting. The breakthrough report, of the ability of the androgen receptor splice variant mutation, detected in circulating tumor cells, to predict lack of response to abiraterone or enzalutamide, and the remarkable responses of poly(ADP-ribose) polymerase inhibitors in prostate cancer with breast cancer genes 1 and 2 (BRCA1/2) mutations, have elevated hopes of a bright future in the biomarker-driven therapeutic arena. SUMMARY: As the clinical application of the recently approved multifaceted therapies widens, trials addressing optimal sequences and combinations are gaining importance. In addition, exploring the utility of therapies in the hormone naive or nonmetastatic settings is an area of active investigation. Early use of available agents, optimal sequencing and aid of biomarkers to guide therapeutic choices will make the achievement of lifetime remissions in advanced prostate cancer a reachable goal.

Circulating E3 ligases are novel and sensitive biomarkers for diagnosis of acute myocardial infarction.

Ubiquitin ligase (E3) is a decisive element of the ubiquitin-proteasome system (UPS), which is the main pathway for intracellular protein turnover. Recently, circulating E3 ligases have been increasingly considered as cancer biomarkers. In the present study, we aimed to determine if cardiac-specific E3 ligases in circulation can serve as novel predictors for early diagnosis of acute myocardial infarction (AMI). By screening and verifying their tissue expression patterns with microarray and real-time PCR analysis, six of 261 E3 ligases, including cardiac-specific Rnf207 and cardiac- and muscle-enriched Fbxo32/atrogin-1, Trim54/MuRF3, Trim63/MuRF1, Kbtbd10/KLHL41, Asb11 and Asb2 in mouse heart, were selected for the present study. In the AMI rats, the levels of five E3 ligases including Rnf207, Fbxo32, Trim54, Trim63 and Kbtbd10 in the plasma were significantly increased compared with control animals. Especially, the plasma levels of Rnf207 was markedly increased at 1 h, peaked at 3 h and decreased at 6-24 h after ligation. Further evaluation of E3 ligases in AMI patients confirmed that plasma Rnf207 level increased significantly compared with that in healthy people and patients without AMI, and showed a similar time course to that in AMI rats. Simultaneously, plasma level of cardiac troponin I (cTnI) was measured by ELISA assays. Finally, receiver operating characteristic (ROC) curve analysis indicated that Rnf207 showed a similar sensitivity and specificity to the classic biomarker troponin I for diagnosis of AMI. Increased cardiac-specific E3 ligase Rnf207 in plasma may be a novel and sensitive biomarkers for AMI in humans.

Association between hepatic steatosis and hepatic expression of genes involved in innate immunity in patients with chronic hepatitis C.

BACKGROUNDS/AIMS: We investigated the association between hepatic steatosis and hepatic expression of genes involved in innate immunity, both of which are reportedly associated with resistance to peginterferon (PEG-IFN) and ribavirin combination therapy for hepatitis C virus (HCV) infection. METHODS: A total of 122 patients infected with HCV genotype 1b who underwent and completed PEG-IFN and ribavirin combination therapy were studied. Hepatic steatosis was evaluated on the basis of the liver specimen biopsied prior to antiviral therapy. The levels of mRNA of innate immunity genes (RIG-I, MDA5, LGP2, Cardif, RNF125, ISG15, and USP18) were measured by real-time polymerase chain reaction in RNA extracted from biopsied liver tissue and compared between patients with and without hepatic steatosis. RESULTS: The proportion of patients with hepatic steatosis, the hepatic expression levels of RIG-I gene, and RIG-I/Cardif and RIG-I/RNF125 ratios were significantly higher in patients in whom serum HCV RNA did not disappear throughout the treatment period. Hepatic expression of RIG-I and the ratios of RIG-I/Cardif and RIG-I/RNF125 were significantly higher in patients with steatosis than those without. CONCLUSIONS: Changes in hepatic expression of some genes involved in innate immunity were observed along with hepatic steatosis, possibly playing a mechanistic role in resistance to IFN-based therapy in patients with hepatic steatosis.

Radiotherapy for carcinoma of the vagina. Immunocytochemical and cytofluorometric analysis of prognostic factors.

BACKGROUND AND PURPOSE: The aim of this study was to assess the potential prognostic factors in patients with primary invasive vaginal carcinoma (PIVC) treated with radical irradiation. PATIENTS AND METHODS: The analysis was performed on 77 patients with PIVC treated between 1985 and 2005 in the Maria Sklodowska-Curie Memorial Institute of Oncology, Cancer Center in Krakow. A total of 36 patients (46.8 %) survived 5 years with no evidence of disease (NED). The following groups of factors were assessed for potential prognostic value: population-based (age), clinical (Karnofsky Performance Score [KPS], hemoglobin level, primary location of the vaginal lesion, macroscopic type, length of the involved vaginal wall, FIGO stage), microscopic (microscopic type, grade, mitotic index, presence of atypical mitoses, lymphatic vessels invasion, lymphocytes/plasmocytes infiltration, focal necrosis, VAIN-3), immunohistochemical (protein p53 expression, MIB-1 index), cytofluorometric (ploidity, index DI, S-phase fraction, proliferation index SG2M) factors. RESULTS: Significantly better 5-year NED was observed in patients: < 60 years, KPS ≥ 80, FIGO stage I and II, grade G1-2, MIB-1 index < 70, S-phase fraction < 10, and proliferation index < 25. Independent factors for better prognosis in the multivariate Cox analysis were age < 60 years, FIGO stage I or II, and MIB-1 index < 70. CONCLUSION: Independent prognostic factors in the radically irradiated PIVC patients were as follows: age, FIGO stage, MIB-1 index.

Effects of age on serum hormone concentrations and intramuscular proteolytic signaling before and after a single bout of resistance training.

This study examined mRNA expression patterns for atrogin-1 and muscle ring finger-1 (MuRF-1) before and 24 hours after a resistance training bout. Furthermore, basal, 5-minute and 24-hour postexercise serum concentrations of cortisol and insulin like growth factor-1 (IGF-1) and the relationships between these hormones and the genetic expression patterns of atrogin-1 and MuRF-1 were examined. Younger and older men completed a resistance exercise bout consisting of 3 × 10 repetitions at 80% of their predetermined 1 repetition maximum for Smith squat, leg press and leg extension. Muscle biopsies from the vastus lateralis were obtained before and 24 hours after exercise. Basal and postexercise gene expression differences between age groups were analyzed using the Mann-Whitney U test, whereas separate 2 × 3 repeated measures analyses of variance were performed to analyze changes in hormone concentrations. Spearman's correlations were performed to examine relationships between gene expression patterns and hormone concentrations. Serum cortisol was significantly greater in younger men before and 24 hours after exercise (p < 0.05), whereas serum IGF-1 was significantly greater in younger men at all time points (p < 0.001). Exercise significantly increased cortisol 5 minutes after exercise in both groups (p < 0.05), whereas older men experienced significant elevations in IGF-1 24 hours postexercise (p < 0.05). At baseline, MuRF-1 gene expression was significantly greater in older men (p = 0.03), whereas no age-related differences were found for atrogin-1 (p = 0.24). Fold change in atrogin-1 and MuRF-1 24 hours postexercise revealed no significant differences between younger and older men. Differential baseline expression of MuRF-1 may suggest a regulatory attempt by the aging transcriptome to accommodate changes necessary for homeostatic maintenance. An enhanced understanding of molecular and genetic level adaptations can aid researchers in developing optimal therapeutic and exercise interventions to mitigate decrements in force, power, and loss of muscle mass seen in aging and many clinical populations.

Serum Mitochondrial Quality Control Related Biomarker Levels are Associated with Organ Dysfunction in Septic Patients.

BACKGROUND: To investigate the feasibility and the value of using mitochondrial quality control (MQC)-related proteins as biomarkers in septic patients. METHODS: The enrolled subjects were divided into four groups: healthy control group (n = 30), intensive care unit (ICU) control group (n = 62), septic nonshock group (n = 40), and septic shock group (n = 94). Serum levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), fission protein 1 (Fis1), mitofusin2 (Mfn2), and Parkin were measured by enzyme-linked immunosorbent assay at the time of enrollment for all groups. Clinical parameters and laboratory test results were also collected. RESULTS: The levels of MQC-related biomarkers between any two of the four groups were significantly different (P < 0.001 for all). The serum levels of PGC-1α, Mfn2, and Parkin were lowest in healthy individuals; the levels were dramatically higher in the ICU control group compared with the others, and they decreased progressively from the septic nonshock group to the septic shock group. However, the pattern for Fis1 was inverse; the more severe the condition was, the higher the level of Fis1. Moreover, there was moderate correlation between MQC-related biomarkers and the SOFA score (PGC-1α, r = -0.662; Fis1, r = 0.609; Mfn2, r = -0.677; Parkin, r = 0.-0.674, P < 0.001 for all). CONCLUSIONS: The serum levels of PGC-1α, Fis1, Mfn2, and Parkin were significantly correlated with organ dysfunction and reflected the disease progression and severity. The dynamic surveillance of these four biomarkers could be beneficial to predict outcome and guide treatment.

BARD1 Autoantibody Blood Test for Early Detection of Ovarian Cancer.

BACKGROUND: Ovarian cancer (OC) is the most lethal gynaecological cancer. It is often diagnosed at an advanced stage with poor chances for successful treatment. An accurate blood test for the early detection of OC could reduce the mortality of this disease. METHODS: Autoantibody reactivity to 20 epitopes of BARD1 and concentration of cancer antigen 125 (CA125) were assessed in 480 serum samples of OC patients and healthy controls. Autoantibody reactivity and CA125 were also tested for 261 plasma samples of OC with or without mutations in BRCA1/2, BARD1, or other predisposing genes, and healthy controls. Lasso statistic regression was applied to measurements to develop an algorithm for discrimination between OC and controls. Findings and interpretation: Measurement of autoantibody binding to a number of BARD1 epitopes combined with CA125 could distinguish OC from healthy controls with high accuracy. This BARD1-CA125 test was more accurate than measurements of BARD1 autoantibody or CA125 alone for all OC stages and menopausal status. A BARD1-CA125-based test is expected to work equally well for average-risk women and high-risk women with hereditary breast and ovarian cancer syndrome (HBOC). Although these results are promising, further data on well-characterised clinical samples shall be used to confirm the potential of the BARD1-CA125 test for ovarian cancer screening.

Serum level of NPTX1 is independent of serum MKRN3 in central precocious puberty.

OBJECTIVES: Makorin ring finger protein 3 (MKRN3) is associated with the initiation of puberty, and loss of function mutation of MKRN3 is the most common genetic cause of central precocious puberty (CPP). A recent study reported that MKRN3 interacts with and suppresses neural pentraxin-1 precursor (NPTX1) activity via polyubiquitination during early puberty in the mouse hypothalamus. This study investigated the correlation between serum NPTX1 and MKRN3 in CPP girls and predicted the potential role of NPTX1 in pubertal progression. METHODS: In this case-control study, we examined 34 girls diagnosed with CPP and 34 healthy prepubertal girls. Anthropometric and hormonal parameters were measured and serum levels of NPTX1 and MKRN3 were evaluated with commercial enzyme-linked immunosorbent assay kits. RESULTS: Serum MKRN3 level decreased significantly in CPP patients compared to controls (344.48 ± 333.77 and 1295.21 ± 780.80 pg/mL, respectively, p<0.001). Serum MKRN3 tended to decrease as Tanner breast stage increased. However, no significant difference was observed in serum NPTX1 levels between patients and controls (20.14 ± 31.75 ng/mL and 12.93 ± 8.28 ng/mL, respectively, p=0.248). The serum level of NPTX1 did not change significantly with the Tanner breast stage. Serum NPTX1 was correlated with the height standard deviation score (r=0.255; p<0.05), but was not correlated with serum MKRN3 level or the others. Conclusion: Although serum NPTX1 level was independent of serum MKRN3 level, the possibility they might be involved in the progression of puberty or CPP remains. Further research is needed to determine their role in the hypothalamus.

Potential of PINK1 and PARKIN Proteins as Biomarkers for Active Multiple Sclerosis: A Japanese Cohort Study.

Background: Mitochondrial dysfunction has been suggested to play an important role in all stages of multiple sclerosis (MS). Objective: To determine the expression of two mitophagy-related proteins, PTEN-induced kinase 1 (PINK1) and PARKIN, in a cohort of Japanese patients with different neuroinflammatory disorders. Methods: Protein concentrations were measured using commercial ELISA in paired cerebrospinal fluid (CSF) and serum samples from patients with multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein antibody disorders (MOGAD), and from age- and sex-matched controls. Results: CSF and serum concentrations of PINK1 were higher in patients with MS than in patients with NMOSD (p = 0.004 and p < 0.001, respectively), MOGAD (p = 0.008 and p = 0.011, respectively), and controls (p = 0.021 and p = 0.002, respectively). CSF and concentrations of PARKIN were elevated in patients with MS in comparison with those in controls (p = 0.016 and p = 0.05, respectively). Conclusions: Our study highlighted the importance of mitophagy in MS and suggested the potential application of PINK1 and PARKIN as biomarkers to predict disease activity.

BARD1, a possible biomarker for breast and ovarian cancer.

Breast cancer is the leading cause of cancer death in women. Ovarian cancer, although less frequent, is detected very late, and survival is correlated to early detection. Therefore, better methods for early detection would help to increase the number of survivors. The incidence of young women diagnosed with breast cancer is increasing. These women and women who are at risk because of a family history of breast cancer would benefit from more accurate and less invasive screening methods than those in place today. A blood test based on BARD1, a protein that interacts with the breast cancer gene product BRCA1, is a promising candidate for fulfilling these conditions. The science behind BARD1 and its role in breast and ovarian cancer is explained in this article.

Evaluation of the Diagnostic and Predictive Value of Serum Levels of ANT1, ATG5, and Parkin in Multiple Sclerosis.

OBJECTIVE: Multiple Sclerosis (MS) is a disease of the central nervous system, which ultimately may lead to various disabilities in patients. No definitive cure has yet been developed for the disease. MRI is the method of choice for imaging MS plaques, which would be useful in disease diagnosis as it becomes progressive. Therefore, this study aimed to investigate the serum levels of ANT1 (adenine nucleotide translocase 1), ATG5 (autophagy-related protein 5), and Parkin in patients with MS, all of which play essential roles in MS pathophysiology, as novel serum biomarkers for early diagnosis of the disease. DESIGN AND METHODS: Forty patients in the early stages of the disease, and 40 healthy individuals were selected as the case and control groups. Upon sampling, the serum levels of the biomarkers were measured. RESULTS: The results indicated that autophagy, mitophagy, and mitochondrial apoptosis were different in the case and control groups. The oxidative stress level evaluation revealed low concertation of total antioxidant status (TAS) in the MS patients, while a partial increase accompanied the malondialdehyde (MDA). No significant correlation was observed between oxidative stress and autophagy or mitophagy factors. CONCLUSION: According to the results obtained from this study, the evaluation of serum levels of ANT1, ATG5, and Parkin could be applied in the diagnosis and follow-up of MS patients.

Evaluation of serum makorin ring finger protein 3 (MKRN3) levels in girls with idiopathic central precocious puberty and premature thelarche.

This study aims to investigate serum makorin ring finger protein 3 (MKRN3) levels in girls with idiopathic central precocious puberty (ICPP) and premature thelarche (PT), in order to determine whether circulating MKRN3 level is associated with ICPP and PT. A total of 90 girls were enrolled in the stud. 30 age-matched girls were allocated for each group (ICPP, PT and healthy controls [HC], respectively). The base LH (B-LH) and E2 levels were higher in ICPP girls than those in HC and PT girls. The peak LH (P-LH) levels and P-LH/P-FSH values were obviously higher in ICPP girls than those in PT girls, while higher peak FSH (P-FSH) levels were detected in PT girls when compared to those in ICPP girls. Kisspeptin levels were lower in HC girls than those in ICPP and PT girls. MKRN3 levels were the highest in HC girls among the three groups. There were relatively strong negative correlations among MKRN3, kisspeptin and P-LH/P-FSH. Circulating MKRN3 can have an important role in the onset of ICPP and PT. However, this should not be used as an independent diagnostic criterion for diagnosing ICPP or differentiating ICPP from PT, but should be used only as an adjunctive diagnostic biomarker.

The relationship between ANT1 and NFL with autophagy and mitophagy markers in patients with multiple sclerosis.

Multiple sclerosis (MS) is the most common inflammatory neurodegenerative disease. Neurofilament light chain (NFL) is a novel adverting biomarker of axonal damage that suggested as a useful assistant in the monitoring of MS patients. It has been shown that the auto/mitophagy associated with MS pathogenesis. In this study, we aimed to study correlation between ATG5 and Parkin, as markers of autophagy and mitophagy respectively, with NFL and ANT1 in serum and cerebrospinal fluid (CSF) in MS subjects. ATG5, Parkin, NFL, and ANT1 levels were measured in a cross-sectional study of 40 MS patients compared with gender, age and BMI matching healthy volunteers. Based on our results, levels of ATG5, Parkin, and NFL significantly were elevated in both serum and CSF of MS patients comparing control individuals (p < 0.0001) but ANT1 levels significantly was decreased in both serum and CSF of MS patients comparing control individuals (p < 0.0001). The correlation indices between NFL, ANTI1, ATG5 and Parkin in both case and control groups showed a direct and moderate the correlation between ANTI1 and ATG5 in the CSF level of the control group (r = 0.554, P = 0.011). Our data support the feasibility of quantifying of NFL as a sensitive and clinically meaningful serum/CSF biomarker to follow-up nerve tissue injury in MS condition.