Combined Panel Research Articles

A novel combined miRNA and methylation marker panel (miMe) for prediction of prostate cancer outcome after radical prostatectomy.

Improved prognostic biomarkers are needed to guide personalized prostate cancer (PC) treatment decisions. Due to the prominent molecular heterogeneity of PC, multimarker panels may be more robust. Here, 25 selected top-candidate miRNA and methylation markers for PC were profiled by qPCR in malignant radical prostatectomy (RP) tissue specimens from 198 PC patients (Cohort 1, training). Using GLMnet, we trained a novel multimarker model (miMe) comprising nine miRNAs and three methylation markers that predicted postoperative biochemical recurrence (BCR) independently of the established clinicopathological CAPRA-S nomogram in Cox multivariate regression analysis in Cohort 1 (HR [95% CI]: 1.53 [1.26-1.84], p < 0.001). This result was successfully validated in two independent RP cohorts (Cohort 2, n = 159: HR [95% CI]: 1.35 [1.06-1.73], p = 0.015. TCGA, n = 350: HR [95% CI]: 1.34 [1.01-1.77], p = 0.04). Notably, in CAPRA-S low-risk patients, a high miMe score was associated with >6 times higher risk of BCR, suggesting that miMe may help identify PC patients at high risk of progression despite favorable clinicopathological factors postsurgery. Finally, miMe was a significant predictor of cancer-specific survival (p = 0.019, log-rank test) in a merged analysis of 357 RP patients. In conclusion, we trained, tested and validated a novel 12-marker panel (miMe) that showed significant independent prognostic value in three RP cohorts. In the future, combining miMe score with existing clinical nomograms may improve PC risk stratification and thus help guide treatment decisions.

Genome-wide association mapping in a diverse spring barley collection reveals the presence of QTL hotspots and candidate genes for root and shoot architecture traits at seedling stage

BackgroundAdaptation to drought-prone environments requires robust root architecture. Genotypes with a more vigorous root system have the potential to better adapt to soils with limited moisture content. However, root architecture is complex at both, phenotypic and genetic level. Customized mapping panels in combination with efficient screenings methods can resolve the underlying genetic factors of root traits.ResultsA mapping panel of 233 spring barley genotypes was evaluated for root and shoot architecture traits under non-stress and osmotic stress. A genome-wide association study elucidated 65 involved genomic regions. Among them were 34 root-specific loci, eleven hotspots with associations to up to eight traits and twelve stress-specific loci. A list of candidate genes was established based on educated guess. Selected genes were tested for associated polymorphisms. By this, 14 genes were identified as promising candidates, ten remained suggestive and 15 were rejected. The data support the important role of flowering time genes, including HvPpd-H1, HvCry2, HvCO4 and HvPRR73. Moreover, seven root-related genes, HERK2, HvARF04, HvEXPB1, PIN5, PIN7, PME5 and WOX5 are confirmed as promising candidates. For the QTL with the highest allelic effect for root thickness and plant biomass a homologue of the Arabidopsis Trx-m3 was revealed as the most promising candidate.ConclusionsThis study provides a catalogue of hotspots for seedling growth, root and stress-specific genomic regions along with candidate genes for future potential incorporation in breeding attempts for enhanced yield potential, particularly in drought-prone environments. Root architecture is under polygenic control. The co-localization of well-known major genes for barley development and flowering time with QTL hotspots highlights their importance for seedling growth. Association analysis revealed the involvement of HvPpd-H1 in the development of the root system. The co-localization of root QTL with HERK2, HvARF04, HvEXPB1, PIN5, PIN7, PME5 and WOX5 represents a starting point to explore the roles of these genes in barley. Accordingly, the genes HvHOX2, HsfA2b, HvHAK2, and Dhn9, known to be involved in abiotic stress response, were located within stress-specific QTL regions and await future validation.

Storage System for Solar Plants

Power supply to consumers, especially in remote areas, is often subject to emergency power outages. This leads to numerous problems such as the breakdown of household appliances and electronics, the inability to provide vital functions in homes and special institutions, and production failure. Also, grid companies sometimes cannot efficiently provide energy to private consumers due to insufficient capacity of the power grid. This journal discusses the use of power plants on alternative energy sources and systems of accumulation of electric energy connected to renewable energy sources. Such systems can be used in parallel with the existing electric power grid, as well as directly by autonomous consumers. This journal also describes the possibility of providing electric power to individual consumers using solar panels in combination with a system of accumulator batteries. The process of charge–discharge of capacitive batteries in the photovoltaic module–battery system is studied in order to increase the efficiency of low-power autonomous power plants. Studies show an increase in the efficiency of the system designed for the individual consumer by 30%, as well as the possibility of uninterrupted operation. The proposed model of the combined photovoltaic and storage system avoids the problems associated with emergency power outages. More importantly, for various Russian Federation regions that are neither close to the generating facilities nor have reliable uninterrupted electricity supply, the presented system can significantly extend both the time of efficient use of energy resources and the service life of the equipment.

Factors driving global carbon emissions: A complex network perspective

Carbon emission is one of the most important topics in the environmental and economic issues. Although previous studies have largely revealed the drivers of carbon emissions, there is still a big challenge to uncover the impacts of the positions of countries in the global supply chains. This paper combined multi-regional input-output analysis, complex network and panel regression analysis to quantify the influence of the roles of countries in the global carbon emissions embodied in trade (EET) transfer networks on their direct carbon emissions. The results showed the network structures had significant evolutionary characteristics. Countries played different roles in the embodied carbon emission transfers, and their roles changed over time. Furthermore, we found the direct carbon emissions of countries were significantly determined by some roles in the networks, including import universality, import strength, media capability and the importance of transfer partners. Our work demonstrated the import of embodied carbon emissions significantly decreased countries’ direct carbon emissions. For the global emission reduction, these important importing countries should reduce their domestic consumptions, and take the responsibility to help their import sources reduce the environmental pressure. It also indicated developing the trade relations with some important countries would help reduce the unnecessary carbon emissions in the domestic productions. Moreover, our work indicated reducing carbon emissions should consider both direct and indirect influence from the entire supply chains. One country’s carbon emission reduction would need the improvement of the trade structures of all the direct and indirect importer and exporters in the same supply chain.

Five serum microRNAs for detection and predicting of ovarian cancer

ObjectiveOvarian cancer (OC) was one of the deadliest gynecological malignancy among women in global. Serum microRNAs (miRNAs) could serve as promising diagnostic biomarkers for patients with OC.Study designUsing quantitative reverse transcription polymerase chain reaction (qRT-PCR) based Exiqon panel, we identified 27 differentially expressed miRNAs from one normal control (NC) pool and two OC pool samples in the initial screening stage. We further verified the miRNAs in the training (30 OC VS. 36 NCs) and validation stages (80 OC VS. 80 NCs) based on qRT-PCR. Later, the expression levels of the identified miRNAs were also evaluated in exosomes and tissues.ResultsWe found a serum microRNA signature including five overexpressed miRNAs (miR-200c-3p, miR-346, miR-127-3p, miR-143-3p and miR-205-5p) in OC in comparison with NCs. The areas under the receiver operating characteristic (ROC) curve (AUC) of the five-miRNA panel were 0.783 for the training stage and 0.745 for the validation stage. The diagnostic sensitivity and specificity of the combined five-miRNA panel was 0.818 and 0.609 when the cut-off value was 0.636. The levels of miR-200c-3p, miR-346 and miR-127-3p in serum were related to tumor grade and distant metastasis of OC. The expression levels of the five miRNAs were also significantly up-regulated in serum exosomes (32 OC VS. 32 NCs). Furthermore, miR-200c-3p was significantly elevated in OC tissues (22 OC VS. 22 NCs). But the levels of the miR-346 and miR-143-3p were significantly lower in OC tissues.ConclusionOur findings showed a five-miRNA panel in serum for the detection of OC. Moreover, serum expression levels of miR-200c-3p, miR-346 and miR-127-3p were concerned with tumor grade and distant metastasis of OC.

Promoter methylation of ADAMTS1 and BNC1 as potential biomarkers for early detection of pancreatic cancer in blood

BackgroundDespite improvements in cancer management, most pancreatic cancers are still diagnosed at an advanced stage. We have recently identified promoter DNA methylation of the genes ADAMTS1 and BNC1 as potential blood biomarkers of pancreas cancer. In this study, we validate this biomarker panel in peripheral cell-free tumor DNA of patients with pancreatic cancer.ResultsSensitivity and specificity for each gene are as follows: ADAMTS1 87.2% and 95.8% (AUC = 0.91; 95% CI 0.71–0.86) and BNC1 64.1% and 93.7% (AUC = 0.79; 95% CI 0.63–0.78). When using methylation of either gene as a combination panel, sensitivity increases to 97.3% and specificity to 91.6% (AUC = 0.95; 95% CI 0.77–0.90). Adding pre-operative CA 19-9 values to the combined two-gene methylation panel did not improve sensitivity. Methylation of ADAMTS1 was found to be positive in 87.5% (7/8) of stage I, 77.8% (7/9) of stage IIA, and 90% (18/20) of stage IIB disease. Similarly, BNC1 was positive in 62.5% (5/8) of stage I patients, 55.6% (5/9) of stage IIA, and 65% (13/20) of patients with stage IIB disease. The two-gene panel (ADAMTS1 and/or BNC1) was positive in 100% (8/8) of stage I, 88.9% (8/9) of stage IIA, and 100% (20/20) of stage IIB disease. The sensitivity and specificity of the two-gene panel for localized pancreatic cancer (stages I and II), where the cancer is eligible for surgical resection with curative potential, was 94.8% and 91.6% respectively. Additionally, the two-gene panel exhibited an AUC of 0.95 (95% CI 0.90–0.98) compared to 57.1% for CA 19-9 alone.ConclusionThe methylation status of ADAMTS1 and BNC1 in cfDNA shows promise for detecting pancreatic cancer during the early stages when curative resection of the tumor is still possible. This minimally invasive blood-based biomarker panel could be used as a promising tool for diagnosis and screening in a select subset of high-risk populations.

Consumers Behind Solar Energy: A Case Study of Households’ Demand for Four OECD Countries

We investigate households’ demand for solar energy in France, Germany, Italy and US, using a loglinear demand for each, and a combined panel data, with fixed effects, for 2000-2012. The dependent variable is household’s installed solar panels; whereas the independent variables are income, price of solar panels, interest rate, representing the cost of financing of a project, and price of “traditional energy.” With R2 being 0.9, all coefficients having expected theoretical signs and statistical significance in all specifications, our model can be generalized for other countries’ households’ solar demand. This is a major contribution to the theoretical and empirical literature.

Detection of culture-negative sepsis in clinical blood samples using a microfluidic assay for combined CD64 and CD69 cell capture

Sepsis is a life-threatening disease that affects millions of people every year. Rapid detection of sepsis assists clinicians to initiate timely antibiotic therapy and to reduce mortality. At the same time, accurate point-of-care detection is needed to reduce unnecessary use of antibiotics. One of the principal challenges in sepsis diagnosis is that many sepsis cases do not result in positive blood cultures. These so-called culture-negative cases present a significant health threat. In this work, we present a microfluidic cells separation system for the detection of sepsis in both culture-positive and culture-negative cases. Leukocytes were captured in several affinity separation zones of a microchip based on CD64, CD69, and CD25 expression. To validate this assay 40 septic patients and 10 healthy volunteers were enrolled in this study. Septic patients were divided into culture-positive (n = 12) and culture-negative cases (n = 21). CD64 + cell capture demonstrated excellent accuracy for sepsis detection with an area under the receiver operating characteristic curves (AUC) of 0.962. A combined panel of CD64 + and CD69 + cell counts was constructed, and the new panel outperformed each of these two biomarkers alone with the AUC of 0.978. Our affinity microfluidic devices were validated by conventional flow cytometry analysis. Results showed that the cell capture number of specific affinity region increased along with the increase of its corresponding antigen expression. This clinical validation confirms that CD64 and CD69 cell separations are a powerful sepsis assay with the potential for point-of-care analysis in culture-positive and culture-negative cases.

Combining Circulating MicroRNA andNT-proBNP to Detect and CategorizeHeart Failure Subtypes.

Clinicians need improved tools to better identify nonacute heart failure with preserved ejection fraction (HFpEF). The purpose of this study was to derive and validate circulating microRNA signatures for nonacute heart failure (HF). Discovery and validation cohorts (N=1,710), comprised 903 HF and 807 non-HF patients from Singapore and New Zealand (NZ). MicroRNA biomarker panel discovery in a Singapore cohort (n=546) was independently validated in a second Singapore cohort (Validation 1; n=448) and a NZ cohort (Validation 2; n=716). In discovery, an 8-microRNA panel identified HF with an area under the curve (AUC) 0.96, specificity 0.88, and accuracy 0.89. Corresponding metrics were 0.88, 0.66, and 0.77 in Validation 1, and 0.87, 0.58, and 0.74 in Validation 2. Combining microRNA panels with N-terminal pro-B-type natriuretic peptide (NT-proBNP) clearly improved specificity and accuracy from AUC 0.96, specificity 0.91, and accuracy 0.90 for NT-proBNP alone to corresponding metrics of 0.99, 0.99, and 0.93 in the discovery and 0.97, 0.96, and 0.93 in Validation 1. The 8-microRNA discovery panel distinguished HFpEF from HF with reduced ejection fraction with AUC 0.81, specificity 0.66, and accuracy 0.72. Corresponding metrics were 0.65, 0.41, and 0.56 in Validation 1 and 0.65, 0.41, and 0.62 in Validation 2. For phenotype categorization, combined markers achieved AUC 0.87, specificity 0.75, and accuracy 0.77 in the discovery with corresponding metrics of 0.74, 0.59, and 0.67 in Validation 1 and 0.72, 0.52, and 0.68 in Validation 2, as compared with NT-proBNP alone of AUC 0.71, specificity 0.46, and accuracy 0.62 in the discovery; with corresponding metrics of 0.72, 0.44, and 0.57 in Validation 1 and 0.69, 0.48, and 0.66 in Validation 2. Accordingly, false negative (FN) (81% Singapore and all NZ FN cases were HFpEF) as classified by a guideline-endorsed NT-proBNP ruleout threshold, were correctly reclassified by the 8-microRNA panel in the majority (72% and 88% of FN in Singapore and NZ, respectively) of cases. Multi-microRNA panels in combination with NT-proBNP are highly discriminatory and improved specificity and accuracy in identifying nonacute HF. These findings suggest potential utility in the identification of nonacute HF, where clinical assessment, imaging, and NT-proBNP may not be definitive, especially in HFpEF.

Market value of PV battery systems for autonomous rural energy supply

Abstract Solar photovoltaics (PV) panels in combination with batteries are often proposed as a solution to provide stable power supply in rural areas. PV generation is mostly dominated by the solar diurnal cycle and has, in some countries, already started to have influence on the daily price distribution on the electricity market. In this work, we study the performance and optimisation of rural PV-battery hybrid systems in a future renewable Polish power system. We use data on generation potentials to study PV and battery deployment. Together with a power system optimisation and dispatch model for the Polish power system, we study market values when selling at the national market for different CO2 price scenarios. We show that optimal orientations with respect to tilt/azimuth are subject to change as the PV share grows and that the benefit from batteries grows for higher shares of renewables.

The clinical feature of myocilin Y437H mutation in a Chinese family with primary open-angle glaucoma

PurposeTo characterise the genotype(s), phenotype(s) and age-related penetrance of glaucoma in a Chinese family with primary open-angle glaucoma (POAG).MethodsRecruited from a Chinese family spanning four generations, 7 individuals with POAG,...

Comparison of genotype imputation strategies using a combined reference panel for chicken population

Using whole-genome sequence (WGS) data are supposed to be optimal for genome-wide association studies and genomic predictions. However, sequencing thousands of individuals of interest is expensive. Imputation from single nucleotide polymorphisms panels to WGS data is an attractive approach to obtain highly reliable WGS data at low cost. Here, we conducted a genotype imputation study with a combined reference panel in yellow-feather dwarf broiler population. The combined reference panel was assembled by sequencing 24 key individuals of a yellow-feather dwarf broiler population (internal reference panel) and WGS data from 311 chickens in public databases (external reference panel). Three scenarios were investigated to determine how different factors affect the accuracy of imputation from 600 K array data to WGS data, including: genotype imputation with internal, external and combined reference panels; the number of internal reference individuals in the combined reference panel; and different reference sizes and selection strategies of an external reference panel. Results showed that imputation accuracy from 600 K to WGS data were 0.834±0.012, 0.920±0.007 and 0.982±0.003 for the internal, external and combined reference panels, respectively. Increasing the reference size from 50 to 250 improved the accuracy of genotype imputation from 0.848 to 0.974 for the combined reference panel and from 0.647 to 0.917 for the external reference panel. The selection strategies for the external reference panel had no impact on the accuracy of imputation using the combined reference panel. However, if only an external reference panel with reference size >50 was used, the selection strategy of minimizing the average distance to the closest leaf had the greatest imputation accuracy compared with other methods. Generally, using a combined reference panel provided greater imputation accuracy, especially for low-frequency variants. In conclusion, the optimal imputation strategy with a combined reference panel should comprehensively consider genetic diversity of the study population, availability and properties of external reference panels, sequencing and computing costs, and frequency of imputed variants. This work sheds light on how to design and execute genotype imputation with a combined external reference panel in a livestock population.

Combined Plasma MicroRNA and Fecal Occult Blood Tests in Early Detection of Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common malignancies and a major cause of cancer-related death worldwide. Fecal occult blood tests (FOBT) are non-invasive colorectal cancer screening tests. In recent years plasma microRNAs (miRNAs) have shown great potential in early non-invasive cancer detection. FOBT (immunochemical) and a panel of 12 plasma miRNAs were tested in two independent groups: 57 CRC patients and 125 neoplasm free controls, in addition to 58 advanced adenoma patients and 67 neoplasm free controls. miRNA levels were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). Plasma levels of 7 miRNAs (miR-18a, miR-20a, miR-21, miR-92a, miR-133a, miR-143, miR-145) differed significantly between CRC patients and neoplasm free controls. miRNA plasma levels did not differ between advanced adenoma patients and controls. For 7 dysregulated miRNAs in CRC patients, AUCs ranged from 0.585 to 0.632 for CRC detection, in comparison to an AUC of 0.857 for iFOBT. The combination of miR-133a and iFOBT achieved a higher AUC (0.894) than iFOBT alone. At 97.8% specificity, miRNAs showed much lower sensitivities than iFOBT, but the miRNA panel and iFOBT in combination detected CRC with a higher sensitivity than iFOBT alone. The diagnostic performance of miRNAs was poorer than iFOBT. Nevertheless, plasma miRNA profiles offer an innovative non-invasive approach for early CRC detection. The potential advantage of combining plasma miRNA profiles with iFOBT needs to be further studied in a larger cohort of patients.

Parametric assessment of a building active façade by means of a combined metallic sandwich panel with an unglazed solar collector

The building sector has a poor performance in terms of energy efficiency and is looking for alternatives to reduce the use of fossil fuels on building use stage. Renewables are unlimited and solar thermal energy is a technology with a demonstrated potential. The façade is a key element able to harness renewable energy coming from the sun becoming in an Active Solar Thermal Façade (ASTF). The main purpose of this study is the development of a parametric study using a numerical model to analyze the behavior of an unglazed solar collector. Thus, evaluating different design and meteorological parameters to show their influence on the heat transfer and the efficiency. The study shows that solar irradiation and mass flow are the most influential on thermal difference. However, for the efficiency ambient temperature and inlet temperature both are the most influencing ones. In brief, a set of parameters have a significant influence on the behavior of the ASTF that are fully governed by environmental conditions. Nevertheless, there are some other parameters that can be controlled during the operation. The challenge is to make a continuous configuration of this adaptable values depending on the external situation to achieve a higher performance for the ASTF.

Chondroitin sulfate degradation and eicosanoid metabolism pathways are impaired in focal segmental glomerulosclerosis: Experimental confirmation of an in silico prediction.

Introduction: Focal segmental glomerulosclerosis (FSGS), the most common primary glomerular disease, is a diverse clinical entity that occurs after podocyte injury. Although numerous studies have suggested molecular pathways responsible for the development of FSGS, many still remain unknown about its pathogenic mechanisms. Two important pathways were predicted as candidates for the pathogenesis of FSGS in our previous in silico analysis, whom we aim to confirm experimentally in the present study. Methods: The expression levels of 4 enzyme genes that are representative of "chondroitin sulfate degradation" and "eicosanoid metabolism" pathways were investigated in the urinary sediments of biopsy-proven FSGS patients and healthy subjects using real-time polymerase chain reaction (RT-PCR). These target genes were arylsulfatase, hexosaminidase, cyclooxygenase-2 (COX-2), and prostaglandin I2 synthase. The patients were sub-divided into 2 groups based on the range of proteinuria and glomerular filtration rate and were compared for variation in the expression of target genes. Correlation of target genes with clinical and pathological characteristics of the disease was calculated and receiver operating characteristic (ROC) analysis was performed. Results: A combined panel of arylsulfatase, hexosaminidase, and COX-2 improved the diagnosis of FSGS by 76%. Hexosaminidase was correlated with the level of proteinuria, while COX-2 was correlated with interstitial inflammation and serum creatinine level in the disease group. Conclusion: Our data supported the implication of these target genes and pathways in the pathogenesis of FSGS. In addition, these genes can be considered as non-invasive biomarkers for FSGS.

Ultrasound/Elastography techniques, lipidomic and blood markers compared to Magnetic Resonance Imaging in non-alcoholic fatty liver disease adults.

Introduction: Non-alcoholic fatty liver disease (NAFLD) may progress to steatohepatitis, cirrhosis and complicated hepatocellular carcinoma with defined differential symptoms and manifestations.Objective: To evaluate the fatty liver status by several validated approaches and to compare imaging techniques, lipidomic and routine blood markers with magnetic resonance imaging in adults subjects with non-alcoholic fatty liver disease.Materials and methods: A total of 127 overweight/obese with NAFLD, were parallelly assessed by Magnetic Resonance Imaging (MRI), ultrasonography, transient elastography and a validated metabolomic designed test to diagnose NAFLD in this cross-sectional study. Body composition (DXA), hepatic related biochemical measurements as well as the Fatty Liver Index (FLI) were evaluated. This study was registered as FLiO: Fatty Liver in Obesity study; NCT03183193.Results: The subjects with more severe liver disease were found to have worse metabolic parameters. Positive associations between MRI with inflammatory and insulin biomarkers were found. A linear regression model including ALT, RBP4 and HOMA-IR was able to explain 40.9% of the variability in fat content by MRI. In ROC analyses a combination panel formed of ALT, HOMA-IR and RBP4 followed by ultrasonography, ALT and metabolomic test showed the major predictive ability (77.3%, 74.6%, 74.3% and 71.1%, respectively) for liver fat content.Conclusions: A panel combination including routine blood markers linked to insulin resistance showed highest associations with MRI considered as a gold standard for determining liver fat content. This combination of tests can facilitate the diagnosis of early stages of non-alcoholic liver disease thereby avoiding other invasive and expensive methods.

Genetic Diversity and Population Structure in Elite U.S. and Race Stock Accessions of Upland Cotton (Gossypium hirsutum)

Assessing genetic diversity and population structure is prerequisite to the systematic utilization and conservation of germplasm resources of crop plants. The genetic diversity and population structure in a combined panel of 557 Gossypium hirsutum L. accessions including 375 cultivars and 182 race stocks using 114 pairs of simple sequence repeat primers were evaluated in the current study. Six G. barbadense L. accessions were included as an out-group. Genotyping the diversity panel of 563 accessions with the markers identified a total of 819 alleles and 662 alleles within G. hirsutum. Population structure analysis identified one G. barbadense group and five G. hirsutum groups corresponding to southwestern cultivars, Mexican collections, western cultivars, southeastern and mid-south cultivars, and Guatemalan collections. Average genetic distance of 0.253 indicated a moderate level of genetic diversity in this panel. Analysis of molecular variance revealed a low level of differentiation among cultivated cotton groups compared to landrace accessions. Genetic diversity and population structure analyses suggest landraces of Guatemala could be a potential source of novel genetic variability for U.S. cotton. Further, multiple core sets with different levels of allele richness were identified. The diversity panel and the core sets identified could be a good resource for broadening the genetic base of U.S. cotton and for genetic analysis of agronomic traits.

4: Have genomic screening advances gone far enough?

Advances in genomics have expanded the screening modalities available in pregnancy. Expanded carrier screening (ECS) is used to identify couples with reproductive risks for autosomal recessive (AR) and X-linked (XLR) disorders, and cell-free fetal DNA prenatal multigene screening (cffMGS) is available to detect de novo single base pair mutations noninvasively. We sought to determine the ability of ECS and cffMGS individually and in combination to detect genetic syndromes identified in a cohort of fetuses with congenital anomalies. Since 2015 we have offered whole exome sequencing (WES) to all parents with a fetus possessing any structural anomaly. Fetuses with a proven single gene variant causing the anomaly formed the basis of the present study. We evaluated whether the genomic finding would have been identified by one of 7 commercially available ECS panels and/or 1 commercially available cffMGS panel. ECS panels used targeted sequencing for detection of carriers and included between 141 and 992 genes. The cffMGS panel included 30 genes. 364 fetuses with ultrasound-identified anomalies, a normal karyotype and a nonpathogenic microarray had WES via trio analysis. Among these, there were 14 (3.8%) AR, 3 (0.8%) inherited XLR, and 27 (7.4%) de novo diagnoses. Parental sequencing confirmed the mothers of the XLR cases were carriers, as were both parents of the AR disorders (Table 1). Trio analysis confirmed de novo findings in all de novo dominant cases (Table 2). Detection by ECS panel of the causative AR and XLR genes ranged from 0 to 11, with larger panels identifying a greater number of causative genes. Two ECS panels would miss all 17 at-risk couples. The largest ECS panel included 73% of the pathogenic genes identified in our cohort. Among the 27 de novo variants, cffMGS could potentially have detected 8/27 (29.6%). The combined use of the largest ECS panel and cffMGS could have detected up to 43.2% of causative genes in the present study cohort. Commonly used ECS panels (<400 genes) in combination with cffMGS could have detected 22.3% of causative mutations in the present study cohort. Increasing the number of genes included on ECS and cffMGS screening panels has the potential to enhance early detection of fetal anomalies caused by Mendelian disease.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Thrombospondin-2 is a Highly Specific Diagnostic Marker and is Associated with Prognosis in Pancreatic Cancer.

Thrombospondin-2 (TSP-2) has been reported as an early diagnostic marker for pancreatic ductal adenocarcinoma (PDAC) in Caucasian populations. This study was designed to validateTSP-2 as a diagnostic marker in a large Taiwan cohort and to investigate the association of TSP-2 with the clinical outcomes of PDAC patients. The serum TSP-2 levels in 263 PDAC patients and 230 high-risk individuals (HRIs) were measured via an enzyme-linked immunosorbent assay. The sensitivity, specificity, and accuracy of TSP-2 as a diagnostic marker to discriminating PDAC patients from HRIs and correlations between TSP-2 levels and prognosis of PDAC patients were analyzed. Serum TSP-2 levels were significantly higher in patients with PDAC (44.90 ± 40.70ng/ml) than in the HRIs (17.52 ± 6.23ng/ml). At a level of ≥ 29.8ng/ml, TSP-2 exhibited 100% specificity, 55.9% sensitivity, 100% positive predictive value (PPV), and 66.5% negative predictive value (NPV) for discriminating PDAC patients from HRIs. The Cox regression analysis showed that higher serum TSP-2 levels were significantly associated with poor outcomes in PDAC patients (hazard ratio = 1.54, 95% confidence interval = 1.143-2.086, P = 0.005). Combining the carbohydrate antigen 19-9 (CA19-9) (cutoff value of 62.0 U/ml) and TSP-2 (cutoff value of 29.8ng/ml) levels yielded 98.7% specificity, 90.5% sensitivity, 98.8% PPV, and 90.1% NPV for discriminating patients with PDAC from HRIs. TSP-2 is a highly specific diagnostic marker and an independent prognostic marker in patients with PDAC. A combined biomarker panel, including TSP-2 and CA19-9, may facilitate future PDAC screening.

A combined score of clinical factors and serum proteins can predict time to recurrence in high grade serous ovarian cancer

ObjectiveTo investigate the utility of a combined panel of protein biomarkers and clinical factors to predict recurrence in serous ovarian cancer patients. MethodsWomen at Augusta University diagnosed with ovarian cancer were enrolled between 2005 and 2015 (n = 71). Blood was drawn at enrollment and follow-up visits. Patient serum collected at remission was analyzed using the SOMAscan array (n = 35) to measure levels of 1129 proteins. The best 26 proteins were confirmed using Luminex assays in the same 35 patients and in an additional 36 patients (ntotal = 71) as orthogonal validation. The data from these 26 proteins was combined with clinical factors using an elastic net multivariate model to find an optimized combination predictive of progression-free survival (PFS). ResultsOf the 26 proteins, Brain Derived Neurotrophic Factor and Platelet Derived Growth Factor molecules were significant for predicting PFS on both univariate and multivariate analyses. All 26 proteins were combined with clinical factors using the elastic net algorithm. Ten components were determined to predict PFS (HR of 6.55, p-value 1.12 × 10−6, CI 2.57–16.71). This model was named the serous high grade ovarian cancer (SHOC) score. ConclusionThe SHOC score can predict patient prognosis in remission. This tool will hopefully lead to early intervention and consolidation therapy strategies in remission patients destined to recur.