Reproducible Marker Research Articles

Comparison of prognostic factors in different age groups and prognostic significance of neutrophil-lymphocyte ratio in patients with gastric cancer.

BACKGROUNDGastric cancer (GC) is one of the most common malignant tumors in the world. Although in recent years tremendous progress has been made in its early detection, the postoperative overall survival (OS) of GC patients remains extremely low. A number of studies have shown that age, to varying degrees, affects the prognosis of patients with GC. Therefore, this study retrospectively analyzed the clinical and pathologic data of patients with GC to explore the differences in the clinical characteristics and prognostic factors in different age groups.AIMTo explore the difference in clinicopathological characteristics and prognostic factors in GC patients in different age groups.METHODSIn this retrospective study, we analyzed 1037 GC patients admitted to Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from May 2010 to January 2013. The patients were divided into two groups based on age: Younger group (less than 70 years old) and older group (no less than 70 years old). In the younger group, we subdivided the patients in two subgroups by a cut-off value of 45 years. The clinical features and prognostic factors were analyzed in both groups. Subsequently, we retrieved studies that evaluated the predictive role of neutrophil-lymphocyte ratio (NLR) by searching two medical databases, PubMed and EMBASE, to conduct a meta-analysis. Random-effects model was used to pool the data.RESULTSIn the retrospective study, the mean OS time of the younger group (64.7 mo) was significantly longer than that of the older group (48.1 mo) (P < 0.001). Among patients under 70 years of age, hospitalization time, tumor–node–metastasis (TNM) stage, vascular invasion, and preoperative low pre-albumin were independently associated with OS (P < 0.005). In patients aged 70 years and above, TNM stage, esophageal invasion, histological type, and preoperative NLR were independent factors for OS (P < 0.05). The OS of these older patients was also significantly shorter (P < 0.05). In the meta-analysis, 19 retrieved studies included a total of 8312 patients, among whom 3558 had elevated NLR values. The results showed that high NLR value was a risk factor for the prognosis of GC (P < 0.01).CONCLUSIONThe OS of elderly patients is significantly worse than that of younger patients. There are significant differences in clinicopathological characteristics and prognostic factors between younger and older patients. NLR is a convenient, inexpensive, and reproducible marker that can be used as an important predictor of the prognosis of GC.

71TiP P16 protein expression as a predictive biomarker for response to neoadjuvant chemotherapy in osteosarcoma

Osteosarcoma is the most common primary malignancy of bone in children and young adults. Necrotic response in the tumor specimen after preoperative chemotherapy is a reproducible and reliable prognostic marker for survival in patients with OS. Pathologic tumor necrosis 90% or greater in the surgical specimen has been correlated with a 5-year survival of 75% to 90%. Although several molecular markers, including P-glycoprotein, Ki-67, p53, ezrin and HER2 have been associated with OS, a clear consensus has not emerged regarding the prognostic and predictive significance. The downregulation of p16 INK4A proteins is found in around 60% of high-grade osteosarcomas and plays an important role in growth of osteosarcoma cells by deregulation of both the pRb and p53 cell growth control pathways. Based on previously published studies, p16 protein negative expression on IHC is a predictive biomarker to poor pathologic response to neoadjuvant chemotherapy and is associated with a worse prognosis. p16 expression is correlated to the tumor biology and is not influenced by chemotherapy treatment. Thus, given the paucity of Indian data and lack of prospective studies, we aimed to investigate the role of P16 protein expression as a predictive biomarker in osteosarcoma. Aim: To investigate the relationship of p16 expression in pretreatment osteosarcoma tumors to pathologic necrotic response after neoadjuvant chemotherapy in a prospective pilot study. Inclusion criteria: Histologically proven cases of newly diagnosed osteosarcoma planned for neoadjuvant chemotherapy. Exclusion criteria: 1. Metastatic and relapsed osteosarcoma; 2. Upfront operated cases of osteosarcoma; 3. Prior therapy. Study procedure: Immuno-histochemistry for p16 will be conducted in core biopsy samples upfront before starting neoadjuvant chemotherapy in newly diagnosed case of osteosarcoma tumor cell necrosis rate will be calculated after neoadjuvant chemotherapy on surgical specimen. The grade of tumour cell necrosis rate will be classified using the Huvos necrosis grading system P16 correlation with good response to chemotherapy in terms of tumour necrosis will be evaluated. The author.

VP27.08: Reliability of corpus callosum‐fastigium and tectal length measurements in the third trimester

To examine the reliability of corpus callosum-fastigium length (CCF) and tectal length (TL) measurements for the evaluation of fetal midbrain in the third trimester of gestation. A prospective cohort of 33 singleton low-risk pregnancies were enrolled for fetal neurosonography assessment. Neurosonography was performed between 31.6 and 32.2 weeks of gestation. Two blinded-observers measured off-line CCF and TL twice using preselected 2D images of mid-sagittal cranial plane. Intra- and interobserver agreements for CCF and TL were evaluated by using the intraclass correlation coefficient (ICC) and Bland-Altman plots. The mean values obtained were 44.44 ± 0.72mm for CCF and 10.21 ± 0.13mm for TL. The mean interobserver difference was -0.0292 ± 0.3984 for CCF (P = 0.676) and 0.0758 ± 0.2822 for TL (P = 0.133). The ICCs for interobserver and intraobserver analysis showed excellent agreement for both CCF and TL. CCF intraobserver: 0.987 (95% CI, 0.974–0.995), interobserver: 0.964 (95% CI, 0.927–0.982) and TL intraobserver: 0.967 (95% CI, 0.933–0.986) and interobserver: 0.963 ( 95% CI,0.895–0.984). Figure 1 shows mid-sagittal fetal midbrain measurements. Corpus callosum-fastigium and tectal length measurements showed an excellent intraobserver and interobserver agreement. Corpus callosum-fastigium and tectal length could be used as reproducible markers of fetal midbrain assessment. Supporting information can be found in the online version of this abstract Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Transcriptomic Profiling of Various Developmental Stages of Aphis Aurantii to Provide a Genetic Resource for Gene Expression and SSR Analysis.

The tea aphid, Aphis aurantii Boyer de Fonscolombe (Hemiptera: Aphididae), is found in regions where the tea plant grows, and has become one of the most important pests in tea gardens in the tropics and subtropics (Han et al., 2012; Deng et al., 2019). This species is also known as the black citrus aphid and destroys citrus orchards (Wang and Tsai, 2001). Ap. aurantii is a polyphagous aphid with over 190 genera hosts, including many other economically important plants in addition to tea and citrus, such as coffee, cacao, loquat, litchi, mango, and camellia (Carver, 1978; Deng et al., 2019). This aphid directly damages trees by sucking the phloem sap out of the shoot tip or from new fresh leaves and injecting its saliva, which causes phytotoxicity and stunting in the plant (Guidolin and Consoli, 2018). Moreover, this aphid secretes honeydew when sap-feeding, and sooty molds frequently grow on the honeydew, which hinders photosynthetic activity (Sevim et al., 2012). Aphids are wide-spread pests that feed on a wide range of fruits and vegetables, most of them are vectors of plant viruses (Huang and Qiao, 2014; Hulle et al., 2020). Except the tea aphid, there have been previous functional studies on genes associated with the development (Ding et al., 2017; Ye et al., 2019), reproduction (Shang et al., 2018; Ullah et al., 2019b), wing development (Shang et al., 2020b), response to the stress (Gao et al., 2018; Jing et al., 2018), and pest control (Mohammed et al., 2018; Ullah et al., 2019a) of other aphids pests (e.g., Ap. citricidus, Ap. gossypii, Acyrthosiphon pisum). Moreover, functional studies of the new insecticide targets in aphids were also conducted in these aphids (Ye et al., 2019; Shang et al., 2020a). However, most previously published papers have focused on the ecology (Alizadeh Kafeshani et al., 2018; Guidolin and Consoli, 2018; Li et al., 2019), control (Aslam et al., 2015; Gholamzadeh-Chitgar and Pourmoradi, 2017), and mitochondrial genome (Wang et al., 2019) in tea aphid Ap. aurantii. There have been few functional studies that focused on the development and reproduction of Ap. aurantii, because there are limited reference sequences. Quantitative and qualitative transcriptome analyses can reveal the integrated biochemical and physiological processes at a molecular level that are associated with specific aspects of the organism, such as identification of the critical genes during the different developmental stages in insects (Morandin et al., 2018; Liu et al., 2020). For instance, RNA-Seq was used to elucidate the underlying molecular mechanisms of metamorphic development of Henosepilachna vigintioctopunctata (Zhang et al., 2018). Using available insect genomes, comparative transcriptome analysis was conducted to analyze gene expression during all developmental stages of Zeugodacus cucurbitae (Wei et al., 2020), Bactrocera dorsalis (Liu et al., 2020). In addition, gene expression has been studied by RNA-Seq in multiple tissues to identify tissue-specific genes involved in female fertility in B. dorsalis [e.g., vitellogenin and vitelline membrane protein in female (Wei et al., 2018, 2019)]. In aphids, RNA-Seq was used to analyze the gene expression between dispersing and non-dispersing morphs (Shang et al., 2016, 2020b). Thus, RNA-Seq technology allows us to determine the gene expression to underlie certain biological functions of critical genes and identify potential targets of new environmentally friendly insecticides for pest control. Simple sequence repeats (SSRs), also known as microsatellites, are short, tandemly arranged, repeating motifs (1–6 bp), which are widely distributed throughout the genomes of eukaryotic organisms (Temnykh et al., 2001). SSRs are co-dominant, hypervariable, neutral, and reproducible molecular markers; therefore, they have become the most widely used molecular markers in population genetic and conservation studies to evaluate the level of genetic variation in a species (King, 2012). Transcriptomic sequencing is also a highly efficient approach to identify SSRs in insects with no accessible genome. This method was extensively used to identify and analyze the SSRs in Liposcelis entomophila (Wei et al., 2013) and H. vigintioctopunctata (Zhang et al., 2018). SSRs were also identified in specific tissues in B. dorsalis (Wei et al., 2015). In this study, RNA-Seq was conducted on samples from six stages of Ap. aurantii with four biological replicates. A comprehensive transcriptome was sequenced, the transcripts were de novo assembled, and the gene's functional annotation was performed. Gene expression during development and SSRs were analyzed. These results will be valuable for the future functional studies of genes involved in Ap. aurantii development, reproduction, and wing differentiation.

Radiation-induced modification of secondary metabolites contents in plants of Salvia officinalis L. and Silybum marianum L.

Aim. Long-term studies of the effect of sublethal doses of pre-sowing low-LET ionizing radiation on seeds have demonstrated the effectiveness of radiation biotechnology to stimulate the accumulation of pharmaceutically valuable secondary metabolites in medicinal raw materials of a number of common medicinal plants in Ukraine. The aim of this research was to evaluate the effectiveness of radiation technology in the case of seeds of Salvia officinalis L. and Silybum marianum L. Methods. X-ray irradiation of seeds at doses up to 50 Gy, spectrophotometric analysis of water-ethanol extracts, fluorescence microscopy of leaf epidermis were used. Results. Doses of pre-sowing X-ray irradiation were selected which maximally stimulate both the increase of biomass of medicinal raw materials and the accumulation of secondary metabolites. In particular for Salvia officinalis L. doses are 5 Gy and 20 Gy, for Silybum marianum L. are 10 Gy and 20 Gy. Conclusions. It is recommended to use two stimulating doses at the same time, as the result of exposure depends essentially on the physiological status of the seeds, growing conditions, varietal characteristics. Increasing the content of flavonoids and phenols in medicinal raw materials has been shown to be a reliable and reproducible marker of stimulating of rosemary acid accumulation in Salvia officinalis leaves.&#x0D; Keywords: radiation-induced stimulation, Salvia officinalis, Silybum marianum, rosemary acid, silibinin.

The Role of DNA Methylation and Histone Modification in Periodontal Disease: A Systematic Review.

Despite a number of reports in the literature on the role of epigenetic mechanisms in periodontal disease, a thorough assessment of the published studies is warranted to better comprehend the evidence on the relationship between epigenetic changes and periodontal disease and its treatment. Therefore, the aim of this systematic review is to identify and synthesize the evidence for an association between DNA methylation/histone modification and periodontal disease and its treatment in human adults. A systematic search was independently conducted to identify articles meeting the inclusion criteria. DNA methylation and histone modifications associated with periodontal diseases, gene expression, epigenetic changes after periodontal therapy, and the association between epigenetics and clinical parameters were evaluated. Sixteen studies were identified. All included studies examined DNA modifications in relation to periodontitis, and none of the studies examined histone modifications. Substantial variation regarding the reporting of sample sizes and patient characteristics, statistical analyses, and methodology, was found. There was some evidence, albeit inconsistent, for an association between DNA methylation and periodontal disease. IL6, IL6R, IFNG, PTGS2, SOCS1, and TNF were identified as candidate genes that have been assessed for DNA methylation in periodontitis. While several included studies found associations between methylation levels and periodontal disease risk, there is insufficient evidence to support or refute an association between DNA methylation and periodontal disease/therapy in human adults. Further research must be conducted to identify reproducible epigenetic markers and determine the extent to which DNA methylation can be applied as a clinical biomarker.

Genetic diversity in oil palm (Elaeis guineensis and Elaeis oleifera) germplasm as revealed by microsatellite (SSR) markers

Genetic variability and relationship of 29 germplasm accessions of two species, viz. Elaeis guineensis Jacq (25 accessions) and Elaeis oleifera (4 accessions) along with two Palode teneras were evaluated at ICAR-Indian Institute of Oil Palm Research, Regional Station, Palode, India during 2014-2016 with an objective to assess the germplasm diversity.Nine oil palms specific SSR primer pairs were used to assess the genetic diversity. All the nine primer pairs produced reproducible unambiguous markers. The total number of alleles per primer pair varied from six (sMo00129, sMo00128, mEgCIR3890, sMo00130, mEgCIR0268, mEgCIR0905, sMo00020, sMo00154,) to seventeen (mEgCIR3399). It produced a total of 107 alleles from the selected two oil palm species and all the makers were polymorphic. Cluster analysis, based on UPGMA was performed in order to realize the extent of similarity/ dissimilarity among the germplasm accessions. The dendrogram showed two major clusters at 0.09 similarity coefficient one with E. oleifera and other with E. guineensis. Among E. oleifera, Chithara (Oleifera palms identified in the commercial plantation owned by OPIL, Kerala) accessions were grouped separately indicating confirmation of distinctness. Among E. guineensis accessions, G1(Nigerian dwarf tenera) and G55 (Tanzanian dura) showed maximum diversity. Evaluation data obtained in this study on the ‘extent of genetic distance’ among accessions can be explored carefully for planning hybridization programme so as to accelerate palm oil yield by maximizing the hybrid vigour. The significant genetic diversity observed among the germplasm accessions indicated the scope of introgression into the current breeding programme.

OP0038 IMPROVING RISK-STRATIFICATION OF RHEUMATOID ARTHRITIS PATIENTS FOR INTERSTITIAL LUNG DISEASE

Background: Interstitial lung disease (ILD) is the most common pulmonary manifestation of rheumatoid arthritis (RA). It has emerged in recent series as a key prognostic factor including survival. The big challenge for rheumatologists is now the risk-stratification of RA patients for ILD. Chest high-resolution computed tomography (HRCT) is the gold standard for RA-ILD diagnosis, but costs and ionizing radiation may limit its use in clinical practice. Thus, circulating biomarkers could aid in this risk-stratification. Objectives: to evaluate the merit of 3 circulating markers for the diagnosis and the progression of RA-ILD. Methods: We included consecutive patients with RA, >18 years of age, from 3 tertiary rheumatology centers (Paris, France, Tokyo, Japan and Zurich, Switzerland) over a 36-month period. All patients had at least one chest HRCT during the inclusion period. In the subset of French patients with ILD, HRCT lung images were obtained both at baseline (time of blood sample collection) and at a follow-up visit. The ILD status of patients with RA was established by chest HRCT. The chest HRCT pattern was classified as usual interstitial pneumonia, UIP or non-specific interstitial pneumonia, NSIP, by the local radiologist. Serum levels of lung epithelial-derived surfactant protein D, SDP, CCL-18 et Krebs von den Lungen-6 glycoprotein, KL-6 were measured by ELISA. Results: 147 patients were included (age: 66+/-12 ans, 69% of women, disease duration 11+/-10 years). Among these patients, 40 (27%) had fibrosing ILD on HRCT: 21 had a UIP pattern, 17 a NSIP pattern, and 2 had NSIP associated with chronic obstructive pulmonary disease. SPD (21.91+/-2.17 vs. 15.76+/-1.34 ng/mL, p=0.017) CCL18 (102+/-13 vs. 78+/-5 ng/mL, p=0.026) and KL6 (961+/-128 vs. 376+/-26 U/mL, p 15% as compared to patients with milder disease. ROC curve analysis to assess the diagnostic abilities of the three markers for the diagnosis of RA-ILD showed a superiority of KL-6 (Area under the curve, AUC: 0.79 95% CI 0.72-0.86) compared to SPD (AUC: 0.66 95% CI 0.58-0.74) and CCL18 (AUC: 0.62, 95% CI 0.53-0.70) (Figure 1D). The sensitivity of KL-6 for the diagnosis of RA-ILD was 68% with a specificity of 83%. In the French subset with longitudinal data (n=15), extension of ILD was detected on 7 patients. Baseline KL6 serum levels were significantly increased in patients who experienced ILD progression (1987+/-1294 vs. 799+/-375 U/mL, p=0.027) (Figure 1E). The degree of ILD progression on HRCT was also proportional to baseline KL-6 concentrations (Figure 1F). Conclusion: KL-6 is relevant for the diagnosis and the prognosis of RA-ILD. It may be used as a circulating non-invasive first-line marker to stratify for indication of HRCT. Indeed, given the emerging lung issues in RA patients, this simple and highly reproducible marker, which is already available in routine care in some countries, could be a good prerequisite to chest HRCT in rheumatology clinics. Disclosure of Interests: Jerome Avouac Grant/research support from: Pfizer, Bristol Myers Squibb, Consultant of: Sanofi, Bristol Myers Squibb, Abbvie, Boerhinger, Nordic Pharma, Speakers bureau: Sanofi, Bristol Myers Squibb Abbvie, MSD, Pfizer, Nordic Pharma, Alexia Steelandt: None declared, Anne Cauvet: None declared, Yuichiro Shirai: None declared, Masataka Kuwana Grant/research support from: Acetelion, Consultant of: Acetelion, Bayer, Chugai, Corbus Pharmaceuticals, CSL Behring and Reata Pharmaceuticals. He was a member of the SENSCIS trial Steering Committee (Boehringer Ingelheim), Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche, Yannick Allanore Shareholder of: Sanofi, Roche, Consultant of: Actelion, Bayer, BMS, Boehringer Ingelheim, Inventiva, Sanofi

Prognostic Value of Histopathological Features and Loss of H3K27me3 Immunolabeling in Anaplastic Meningioma: A Multicenter Retrospective Study.

The diagnosis of anaplastic meningioma (AM) (WHO grade III) is based on the presence of a high mitotic index (MI) and/or overt anaplasia. Only few data exist about the reproducibility and prognostic value of overt anaplasia. Additionally, the prognostic value of H3K27me3 loss in AM has not yet been demonstrated. Our objectives were to evaluate the reproducibility and prognostic value of WHO criteria and H3K27me3 loss in a multicenter series of 66 AM. Interobserver reproducibility was good for the determination of WHO grade (Kappa = 0.671) and MI (intraclass correlation coefficient [ICC] = 0.649), and fair for assessment of overt anaplasia (Kappa = 0.366). Patients with meningiomas showing high MI had significantly shorter overall survival (OS) than patients with meningiomas showing overt anaplasia without high MI (p = 0.009). OS was significantly lower in case of overt anaplasia with low MI (<20/1.6 mm2) than in atypical meningiomas (p = 0.008). H3K27me3 loss was present in 10/47 (21%) of AM and independently associated with shorter OS (p = 0.036; Cox multivariate analysis), with a good reproducibility (Kappa = 0.643). In conclusion, the presence of overt anaplasia could give additional prognostic information in tumors lacking high MI. Finally, loss of H3K27me3 is an easy-to-use and reproducible marker of poorer prognosis.

Molecular Sex Identification in the Hardy Rubber Tree (Eucommia ulmoides Oliver) via ddRAD Markers.

Eucommia ulmoides, also known as the industrially and medicinally important hardy rubber tree, is the sole species of Eucommiaceae. Nevertheless, its dioecious property hinders sex recognition by traditional morphological observation at very early developmental stages, thus inhibiting breeding and economic cropping. In this study, double-digest restriction site-associated DNA sequencing (ddRAD-seq) was applied to screen sex-linked molecular markers for sex identification and investigation of the sex determination system in 20 male and female E. ulmoides individual plants, respectively. In consequence, five candidate male-specific loci but no female-specific loci were predicated among the 183,752 male and 147,122 female catalogue loci by bioinformatics analysis. Subsequent PCR (polymerase chain reaction) amplification and Sanger sequencing examinations were performed on another 24 individuals, 12 for each sex, from a separate population. One ideal sex-linked locus, MSL4, was identified among the five putative male-specific loci that were found using ddRAD data. MSL4 is 479 bp in length and highly conserved in all the male individuals, suggesting its feature of being stable and repeatable. Our results also indicated that the sex of E. ulmoides is likely determined genetically. In short, this study provides a consistent and reproducible ddRAD marker (MSL4) that is able to discriminate male from female seedlings in E. ulmoides, which will be valuable for rapid breeding practice and better commercial production of this economically important tree.

Immature Stroma and Prognostic Profiling in Colorectal Carcinoma: Development and Validation of Novel Classification Systems

Many pathological characteristics have utility for predicting prognosis in colorectal carcinoma (CRC). Some of the most important include tumor stage (TS), lymph node status (LNS) and tumor budding (TB). Tumor budding is a phenomenon originally described in 1949 as sprouting. TB assessment is not always reliable however, as it is subject to high inter-observer variation. This finding persists despite the current trends for sub-specialty training in surgical pathology. In light of this, new and reproducible histological prognostic markers could change the way we diagnose and manage patients with colorectal carcinoma. Studies have shown that desmoplastic reaction (DR) categorization can actually outperform other conventional prognostic factors, including tumor budding and tumor stage in predicting disease-free survival (DFS). Our study aimed to evaluate and assess the prognostic value of desmoplastic reaction in an American cohort with colorectal cancer using 3 different stromal classification scoring systems. In all three stromal grading systems, immature stroma was the most significant independent prognostic factor in CRC. Currently, none of the reporting protocols for the College of American Pathologists, the Royal College of Pathologists of the United Kingdom, and the Japanese Society for Cancer report on the presence of immature stroma. Importantly, regarding the ability to predict survival outcomes, our novel classification system has the potential to outperform other scoring methodologies.

Evaluation of serum ARGS neoepitope as an osteoarthritis biomarker using a standardized model for exercise-induced cartilage extra cellular matrix turnover

To propose a standardized model for exercise-induced cartilage turnover and investigate residual levels and dynamics of biomarker serum ARGS (sARGS) in primary osteoarthritis (OA) patients and a supportive group of young healthy subjects. The trial is a randomized, cross-over, exploratory study with interventions of exercise and inactivity. 20 subjects with knee OA, as well as 20 young healthy subjects (mean age 25.7 years (range; 19-30), 50% male), underwent cycling, running and resting interventions on separate days one week apart. Blood samples were taken at baseline, immediately, 1, 2, 3 and 24h after activity start. sARGS was measured by sandwich ELISA. Intraclass correlation between visits were 0.97 and 0.77 for the OA and healthy group, respectively. An acute drop in sARGS in response to high-intensity exercise was observed in both groups. Minute acute sARGS increase was observed in OA subjects in response to moderate intensity running and cycling, which normalized within 24h. In healthy subjects an acute drop in sARGS was seen immediately after running, but not cycling, and no other changes were observed. A negative correlation between baseline Kellgren-Lawrence (KL) grade and baseline sARGS (r=-0.69, p=0.002) in OA was found. A negative correlation between age and sARGS was found in healthy subjects (r=-0.67, p = <0.002). sARGS sensitivity to physical activity is considered low and sARGS is a reproducible and stable marker. Minute acute increases in sARGS were observed in the hours following moderate intensity exercise.

P67 Transcranial magnetic stimulation induced perturbations of resting-state-networks are reproducible markers of causal network-to-network dynamics

P67 Transcranial magnetic stimulation induced perturbations of resting-state-networks are reproducible markers of causal network-to-network dynamics

Monocyte-to-high-density lipoprotein cholesterol ratio is associated with the presence and size of thyroid nodule irrespective of the gender

BackgroundSystemic inflammation may be involved in the formation and progression of thyroid nodule (TN). The aim of this large-scale study was to investigate the association of several simple inflammatory markers with the presence and size of TN.MethodsA total of 133,698 adults were included for the current analysis. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and monocyte-to-high-density lipoprotein cholesterol ratio (MHR) were calculated. The logistic regression was used to explore the association of the four markers with the presence and size of TN.ResultsThe prevalence of TN was 55.1% among females and 44% among males; 13% of women and 8% of men had non-micronodule. In women, MHR and PLR were significantly associated with the presence of TN and non-micronodule; in men, MHR and NLR were significantly associated with the presence of TN and non-micronodule.ConclusionsAs a low-cost, simple, and reproducible inflammatory marker, MHR is strongly associated with the presence and size of TN irrespective of the gender.

Comparative Study between Fractional Excretion of Sodium and Fractional Excretion of Urea in Differentiating Prerenal From Renal Acute Kidney Injury in ICU Patients with Circulatory Shock

Abstract Background The incidence of acute renal injury (AKI) in ICU is 5%. The mortality rate increases up to 50% if AKI is a part of multiple organ dysfunction syndrome. Aim of the Work Comparison between FENa and FEurea in differentiating renal from prerenal acute kidney injury in circulatory shock, and the effect of diuretics on their handling. Patients and Methods This retrospective study was conducted on 45 Egyptian patients with AKI complicating circulatory shock admitted to the ICUs of AIN SHAMS University Hospital, from August 2018 to February 2019. Consents were taken from all of them according to the local ethics committee approval. Results The cutoff points of both FENa and FEurea as a predictor of mortality were not statistically justified. This is explained as all our patients had circulatory shock, and so patients with mild renal impairment may die from their severe shock state, and patients with severe renal affection may survive if their shock could be rapidly corrected. This cutoff point calculation is recommended only in patients with AKI without other organ affections or shock that may affect the mortality. Conclusion Although both fractional excretion of urea (FEurea) and fractional excretion of sodium (FENa) are feasible, reproducible, and inexpensive markers used in differentiating renal from prerenal azotemia, in our study FEurea showed higher sensitivity and specificity than FENa, not only in differentiating renal from prerenal azotemia in critically ill patients complicating circulatory shock, but also its values were not affected by the use of diuretics like FENa in the same group of patients.

Metabolic and Genetic Determinants of Glucose Shape After Oral Challenge in Obese Youths: A Longitudinal Study

The time-to-glucose-peak following the oral glucose tolerance test (OGTT) is a highly reproducible marker for diabetes risk. In obese youths, we lack evidence for the mechanisms underlying the effects of the TCF7L2 rs7903146 variant on glucose peak. We analyzed the metabolic phenotype and the genotype for the TCF7L2 rs7903146 in 630 obese youths with normal (NGT) and impaired (IGT) glucose tolerance. Participants underwent a 3-hour, 9-point OGTT to estimate, using the oral minimal model, the disposition index (DI), the static (φstatic) and dynamic (φdynamic) components β-cell responsiveness and insulin sensitivity (SI). In a subgroup (n = 241) longitudinally followed for 2 years, we estimated the effect of time-to-glucose-peak on glucose tolerance change. Participants were grouped into early (<30 minutes) and late (≥30 minutes) glucose peakers. A delayed glucose peak was featured by a decline in φstatic (P < .001) in the absence of a difference in φdynamic. The prevalence of T-risk allele for TCF7L2 rs7903146 variant significantly increased in the late peak group. A lower DI was correlated with higher glucose concentration at 1 and 2 hours, whereas SI was inversely associated with 1-hour glucose. Glucose peak <30 minutes was protective toward worsening of glucose tolerance overtime (odds ratio 0.35 [0.15-0.82]; P = .015), with no subjects progressing to NGT or persisting IGT, in contrast to the 40% of progressor in those with late glucose peak. The prevalence of T-risk allele for the TCF7L2 rs7903146 prevailed in the late time-to-glucose peak group, which in turn is associated with impaired β-cell responsiveness to glucose (φ), thereby predisposing to prediabetes and diabetes in obese youths.

NeuroMark: An automated and adaptive ICA based pipeline to identify reproducible fMRI markers of brain disorders

Many mental illnesses share overlapping or similar clinical symptoms, confounding the diagnosis. It is important to systematically characterize the degree to which unique and similar changing patterns are reflective of brain disorders. Increasing sharing initiatives on neuroimaging data have provided unprecedented opportunities to study brain disorders. However, it is still an open question on replicating and translating findings across studies. Standardized approaches for capturing reproducible and comparable imaging markers are greatly needed. Here, we propose a pipeline based on the priori-driven independent component analysis, NeuroMark, which is capable of estimating brain functional network measures from functional magnetic resonance imaging (fMRI) data that can be used to link brain network abnormalities among different datasets, studies, and disorders. NeuroMark automatically estimates features adaptable to each individual subject and comparable across datasets/studies/disorders by taking advantage of the reliable brain network templates extracted from 1828 healthy controls as guidance. Four studies including 2442 subjects were conducted spanning six brain disorders (schizophrenia, autism spectrum disorder, mild cognitive impairment, Alzheimer’s disease, bipolar disorder, and major depressive disorder) to evaluate validity of the proposed pipeline from different perspectives (replication of brain abnormalities, cross-study comparison, identification of subtle brain changes, and multi-disorder classification using identified biomarkers). Our results highlight that NeuroMark effectively identified replicated brain network abnormalities of schizophrenia across different datasets; revealed interesting neural clues on the overlap and specificity between autism and schizophrenia; demonstrated brain functional impairments present to varying degrees in mild cognitive impairments and Alzheimer's disease; and captured biomarkers that achieved good performance in classifying bipolar disorder and major depressive disorder.

A prospective, longitudinal monocentric study on laser Doppler imaging of microcirculation: comparison with macrovascular pathophysiology and effect of adalimumab treatment in early rheumatoid arthritis

Increased cardiovascular (CV) morbidity and mortality have been found in rheumatoid arthritis (RA). Tumour necrosis factor α (TNF-α) inhibitors may improve vascular function. In the first part of this study, we determined microcirculation during postoocclusive reactive hyperemia (PORH) representing endothelial function. In a nonselected population (n = 46) we measured flow-mediated vasodilation (FMD) of the brachial artery and laser Doppler flow (LDF) by ultrasound. Among LDF parameters, we determined TH1 (time to half before hyperemia), TH2 (time to half after hyperemia), Tmax (time to maximum) and total hyperemic area (AH). We measured von Willebrand antigen (vWF:Ag) by ELISA. In the second part of the study, we assessed the effects of adalimumab treatment on microcirculatory parameters in 8 early RA patients at 0, 2, 4, 8 and 12 weeks. We found significant positive correlations between FMD and LDF Tmax (R = 0.456, p = 0.002), FMD and TH2 (R = 0.435, p = 0.004), and negative correlation between vWF:Ag and Tmax (R = − 0.4, p = 0.009) and between vWF:Ag and TH2 (R = − 0.446, p = 0.003). Upon adalimumab therapy in early RA, TH2 times improved in comparison to baseline (TH2baseline = 26.9 s vs. TH24weeks = 34.7 s, p = 0,032), and this effect prolonged until the end of treatment (TH28weeks = 40.5, p = 0.026; TH212weeks = 32.1, p = 0.013). After 8 weeks of treatment, significant improvement was found in AHa (AHbaseline = 1599 Perfusion Units [PU] vs. AH8weeks = 2724 PU, p = 0.045). The PORH test carried out with LDF is a sensitive option to measure endothelial dysfunction. TH1 and TH2 may be acceptable and reproducible markers. In our pilot study, treatment with adalimumab exerted favorable effects on disease activity, endothelial dysfunction and microcirculation in early RA patients.

Predictive and Prognostic Properties of Human Equilibrative Nucleoside Transporter 1 Expression in Gemcitabine-Treated Pancreatobiliary Cancer: A Meta-Analysis.

Gemcitabine, the primary drug for the treatment of pancreatobiliary cancer (PBC), requires human equilibrative nucleoside transporter 1 (hENT1) to enter cells. High tumoral hENT1 expression has been linked with improved survival among patients with PBC treated with gemcitabine; however, this finding has been inconsistent, and studies used different expression assays. Databases were reviewed for studies that examined hENT1 and clinical outcome in PBC. Of 307 publications, 34 studies were found that used immunohistochemistry (IHC) with one of eight anti-hENT1 antibody assays. Five studies were excluded for redundancy, and 29 studies underwent detailed review. On average, 51% of tumor samples had high hENT1 expression (range, 7% to 92%). Among studies that examined hENT1 expression and overall survival (OS), 58% (15 of 26 studies) showed an association between high tumoral hENT1 and improved OS for gemcitabine-treated patients. Among 10D7G2 antibody studies, 88% (seven of eight studies) demonstrated this association. Studies with other antibodies-in particular, SP120 (two of nine studies)-were less consistent. The ability to detect an association between improved OS and high hENT1 was antibody dependent (χ2 P = .0237). An association between high tumoral hENT1 expression and improved disease-free/progression-free survival (DFS/PFS) was demonstrated in 71% of studies (15 of 21 studies). Pooled hazard ratio (HR) analyses of all antibody studies demonstrated a link between high hENT1 tumor expression and improved OS (HR, 0.674; 95% CI, 0.509 to 0.893; P = .006) and DFS/PFS (HR, 0.740; 95% CI, 0.517 to 0.1.059; P = .10). This signal was stronger among studies that used the 10D7G2 antibody in comparison to those in which another antibody was used, with HRs of 0.488 (95% CI, 0.396 to 0.602; P < .001) and 0.410 (95% CI, 0.280 to 0.599; P < .001), respectively. High tumoral hENT1 expression on IHC with 10D7G2 is a strong and reproducible prognostic marker for improved outcome among gemcitabine-treated patients with PBC.

Microsatellite and inter-microsatellite markers linked with resistance to vascular streak dieback in cocoa (Theobroma cacao L.)

ABSTRACTVascular streak dieback is a serious disease of cocoa throughout the world and breeding of resistant varieties is the most reliable management strategy. Molecular markers linked with resistance enable marker-assisted breeding by tracking the resistance genes in each generation. To identify the markers linked with resistance, four accessions each of highly resistant, highly susceptible and partially resistant categories were screened with ISSR and SSR primers. Of the 71 ISSR and 46 SSR primers used, five ISSR primers UBC811, UBC815, UBC826, UBC857 and UBC866 have yielded reproducible markers for resistance. Cloning and sequencing of UBC857 marker showed 94% identity with SSR clone mTcCIR42. Screening of genotypes with mTcCIR42 primers generated distinct markers for resistance. Identified ISSR markers represent at least three different genes. Results were further validated using the resistant and susceptible progenies and are being used in marker-assisted selection for VSD resistance in cocoa.