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Success in extreme environments comes with a cost of subtle performance decrements that if not mitigated properly can lead to lifethreatening consequences. Identification and prediction of performance decline could alleviate deleterious consequences and enhance success in challenging and high-risk operations. The Rim-to-Rim Wearables at the Canyon for Health (R2R WATCH) project was designed to examine the cognitive, physiological, and biological markers of performance decline in the extreme environment of the Grand Canyon Rim-to-Rim (R2R) hike. The study utilized commercial off-the-shelf cognitive and physiological monitoring techniques, along with subjective self-assessments and hematologic measurements to determine subject performance and changes across the hike. The multiyear effort collected these multiple data streams in parallel on a large sample of participants hiking the R2R, leading to a rich and complex data set. This article describes the methodology and its evolution as devices and measurements were assessed after each data collection event. It also highlights a subset of the patterns of results found across the data streams. Subsequent work will draw on this data set to focus on building more sophisticated, predictive statistical models and dive deeper into specific analyses (such as the physiological and biological profiles of hikers who were left behind by their hiking partners).

ObjectiveThe aim of this study was to catalog and evaluate response biomarkers correlated with autism spectrum disorder (ASD) symptoms to improve clinical trials.MethodsA systematic review of MEDLINE, Embase, and Scopus was conducted in April 2020. Seven criteria were applied to focus on original research that includes quantifiable response biomarkers measured alongside ASD symptoms. Interventional studies or human studies that assessed the correlation between biomarkers and ASD-related behavioral measures were included.ResultsA total of 5,799 independent records yielded 280 articles for review that reported on 940 biomarkers, 755 of which were unique to a single publication. Molecular biomarkers were the most frequently assayed, including cytokines, growth factors, measures of oxidative stress, neurotransmitters, and hormones, followed by neurophysiology (e.g., EEG and eye tracking), neuroimaging (e.g., functional MRI), and other physiological measures. Studies were highly heterogeneous, including in phenotypes, demographic characteristics, tissues assayed, and methods for biomarker detection. With a median total sample size of 64, almost all of the reviewed studies were only powered to identify biomarkers with large effect sizes. Reporting of individual-level values and summary statistics was inconsistent, hampering mega- and meta-analysis. Biomarkers assayed in multiple studies yielded mostly inconsistent results, revealing a "replication crisis."ConclusionsThere is currently no response biomarker with sufficient evidence to inform ASD clinical trials. This review highlights methodological imperatives for ASD biomarker research necessary to make definitive progress: consistent experimental design, correction for multiple comparisons, formal replication, sharing of sample-level data, and preregistration of study designs. Systematic "big data" analyses of multiple potential biomarkers could accelerate discovery.

The approach-avoidance conflict (AAC), i.e. the competing tendencies to undertake goal-directed actions or to withdraw from everyday life challenges, stands at the basis of humans' existence defining behavioural and personality domains. Gray's Reinforcement Sensitivity Theory posits that a stable bias toward approach or avoidance represents a psychopathological trait associated with excessive sensitivity to reward or punishment. Optogenetic studies in rodents and imaging studies in humans associated with cross-species AAC paradigms granted new emphasis to the hippocampus as a hub of behavioural inhibition. For instance, recent functional neuroimaging studies show that functional brain activity in the human hippocampus correlates with threat perception and seems to underlie passive avoidance. Therefore, our commentary aims to (i) discuss the inhibitory role of the hippocampus in approach-related behaviours and (ii) promote the integration of functional neuroimaging with cross-species AAC paradigms as a means of diagnostic, therapeutic, follow up and prognosis refinement in psychiatric populations.

The Environmental Health Research Institute for Nurse and Clinician Scientists (EHRI-NCS) is designed to build the nursing discipline-wide capacity and rigor for translational and clinical research methods in environmental health. The goal of this program is to enhance the discipline-wide capacity of nurse scientists and their interdisciplinary clinician scientist collaborators for advanced research methods in environmental health through a flipped classroom, train-the-trainer and mentorship program. The flipped classroom model will be utilized as the best-practice pedagogy to achieve higher order learning objectives with pre-recorded, online didactic lectures provided for participant preparation, followed by a synchronous 5-day training and post-course mentorship follow-up. The objectives are for the participant to 1) Design clinical research studies and research education with advanced environmental health methodologies, 2) Mentor other peer, student, and early career nurse scientists in environmental health methodologies, 3) Examine broader theoretical, philosophical, ethical, and legal contexts related to environmental health exposure science with implications for clinical policy, practice, education, and research, 4) Analyze strategies used for clinical environmental health interventions, 5) Describe trends in environmental health molecular approaches of symptom science, 6) Acquire new analytic skills applied to environmental health data, and 7) Compare and contrast the strengths, weaknesses, and applications of environmental exposure science measurements and methods in clinical research. We will recruit participants who have already achieved their terminal doctoral degree and those currently enrolled in a graduate nursing program who educate, train, and mentor registered nurses in research trajectories. We will include specialized recruitment and support structured for participants from under-represented minority groups. Course topics will include 1) Theoretical conceptualization, 2) Intervention Study Designs, 3) Participatory Action Designs, 4) Physiologic Measurement with Spirometry, 5) Biomarker Measurement, 6) Personal and Area Exposure Measurement, 7) Informatics and Analytics, and 8) Health Disparities and At-Risk Populations. Aligned with the NIH/NIEHS 2018-2023 strategic goal to “Enhance environmental health science through stewardship and support,” the impact of this successful program will include developing a discipline-wide, highly qualified research workforce dedicated to solving environmental health problems relevant to nursing practice. This registration provides the evaluation plan for the first five years of the workshop program, with an anticipated enrollment of 144 total participants across five annual cohorts of 16-32 participants each.

Background Autoimmune atrophic gastritis (AAG) is a chronic disease that can progress to gastric cancer (GC). To better understand AAG pathology, this proteomics study investigated gastric proteins whose expression levels are altered in this disease and also in GC. Methods Using two-dimensional difference gel electrophoresis (2D-DIGE), we compared protein maps of gastric corpus biopsies from AAG patients and controls. Differentially abundant spots (|fold change|≥ 1.5, P Helicobacter pylori infection) and from GC patients and unaffected first-degree relatives of GC patients. Results 2D-DIGE identified 67 differentially abundant spots, with 28 more and 39 less abundant in AAG-corpus than controls. LC–MS/MS identified these as 53 distinct proteins. The most significant (adjusted P H. pylori infection status. The differential abundance was also observed in GC biopsies for 14 of 28 more abundant and 35 of 39 less abundant spots, and in normal gastric biopsies of relatives of GC patients for 6 and 25 spots, respectively. Immunoblotting confirmed the different expression levels of two more abundant proteins (PDIA3, GSTP gene products) and four less abundant proteins (ATP5F1A, PGA3, SDHB, PGC). Conclusion This study identified a proteomics signature of AAG. Many differential proteins were shared by GC and may be involved in the progression of AAG to GC.

Background Forkhead box M1 (FOXM1) is closely related to the formation and development of cancer. Because of differences in cellular origin, lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SCC) usually exhibit different signatures. Therefore, it is essential to investigate the abnormalities of FOXM1 in the two subtypes separately. Methods Through the Oncomine and TCGA databases, we investigated the expression of FOXM1 mRNA, its prognostic value and possible mechanisms leading to its dysregulation. Furthermore, networks involving FOXM1 and its significantly altered neighboring genes were identified using the cBioPortal database. GO and KEGG enrichment analyses were performed using DAVID. Results Expression of FOXM1 mRNA was higher in lung tumor tissues than in normal tissues, and higher in SCC tissues than in ADC tissues. FOXM1 mRNA expression was correlated with N stage, TNM stage, age, sex and smoking history in ADC, but only correlated with N stage, age and sex in SCC. Survival analysis indicated that high expression of FOXM1 mRNA resulted to poor overall survival (OS) for ADC patients, but not for SCC patients. Cox regression analysis confirmed that FOXM1 mRNA expression was an independent prognostic indicator for ADC patients, and regression analysis identified a moderately positive correlation between FOXM1 mRNA levels and copy number alterations (CNAs), but a weakly negative association with DNA methylation. FOXM1 was mainly involved in cell cycle regulation, G2/M transition, G1/S transition and p53, PI3K-Akt and TGF-beta signaling pathway. Conclusions High expression of FOXM1 mRNA might be an independent biomarker of poor OS in ADC patients.

Clinical practice guidelines recommend several routine laboratory tests in patients diagnosed with hypertension. However, the rates of clinically relevant laboratory abnormalities are unknown. Therefore, we conducted a retrospective cohort study using administrative and laboratory data of patients diagnosed with hypertension between April 2010 and March 2015 in Alberta, Canada. Laboratory investigations for renal function, serum electrolytes (sodium and potassium), low‐density lipoprotein (LDL) cholesterol, and diabetes (fasting blood glucose and hemoglobin A1c), measured within 1 year of diagnosis, were examined, and the frequency of abnormalities determined. A total of 225 296 cases of incident hypertension were identified. Of these, 74.3% received at least one of the four guideline‐recommended laboratory tests, but only 42.3% received all four tests. Patients who received any testing, compared to subjects who did not, were on average older (median age 55.9 vs 51.2 years, P

Background: The prevalence of varicose veins of small pelvic veins in women of reproductive age varies widely – from 5.4 to 80 %, due to the low specificity and low sensitivity of clinical diagnostic techniques, and the absence of biomarkers that can be used to identify the formation and progression of varicose veins of small pelvic veins in women.Aims: To identify changes in the levels of parameters of the system “lipid peroxidation – antioxidant protection” with the development of varicose veins of the pelvis in women, as well as the possibility of their diagnostic use.Materials and methods: We examined 200 women with clinical signs of varicose veins of small pelvis. Control group included 30 women without any pathology of venous system. Treatment group included 137 women with varicose veins of small pelvis: with mild degree of severity – 39 women, with moderate degree of severity – 65 women, with severe degree of severity – 33 women. We performed comparative analysis of lipid peroxidation – antioxidant defense system in women with and without varicose veins of small pelvis taking into account the severity degrees of pathological process.Results: We obtained the most informative indices for lipid peroxidation – antioxidant defense processes in blood of women with varicose veins of small pelvis: concentration of diene conjugate (DC) for the mild degree of severity of pathological process, lipid hydroperoxide (LHP), DC and malonic dialdehyde (MDA) – for the moderate and severe degree of severity, and also changes in the activity of antioxidant enzymes with increase of the severity of the disease. Assessment of the level of catalase (Cat) and glutathione peroxidase (GP) showed their highest informative value at the mild degree of severity. Concentrations of glutathione reductase (GR), glutathione S-transferase (GST) and reduced glutathione (GSH) are more statistically significant markers for severe forms of pathological process.Conclusions: Our research showed the relevance and advisability of the studying the levels of lipid peroxidation – antioxidant defense indices in women with varicose veins of small pelvis. We registered the highest diagnostic value of DC, Cat and GP in the beginning of the disease and of LHP, DC, MDA, GR, GST and GSH – at severe forms of the pathological process. We obtained reference values for DC, MDA, Cat, SOD and GP concentration that can be considered as the predictors of the development of varicose veins of small pelvis.

Biomarkers, also called biological markers, are indicators to identify a biological case or situation as well as detecting any presence of biological activities and processes. Proteins are considered as a type of biomarkers based on their characteristics. Therefore, proteomics approach is one of the most promising approaches in this field. The purpose of this review is to summarize the use of proteomics approach and techniques to identify proteins as biomarkers for different diseases. This review was obtained by searching in a computerized database. So, different researches and studies that used proteomics approach to identify different biomarkers for different diseases were reviewed. Also, techniques of proteomics that are used to identify proteins as biomarkers were collected. Techniques and methods of proteomics approach are used for the identification of proteins' activities and presence as biomarkers for different types of diseases from different types of samples. There are three essential steps of this approach including: extraction and separation of proteins, identification of proteins, and verification of proteins. Finally, clinical trials for new discovered biomarker or undefined biomarker would be on. Keywords: Proteomics, Diseases biomarkers, Biological markers, Protein informatics, Bioinformatics

Temporal bone squamous cell carcinoma (TBSCC) is an uncommon malignancy with a poor prognosis in advanced cases. The dismal outcome of advanced TBSSC cases is largely due to the cancer’s local aggressiveness and the complex anatomy of this region, as well as to persistent pitfalls in diagnosis and treatment. Molecular changes occur in malignancies before any morphological changes become visible, and are responsible for the disease’s clinical behavior. The main purpose of this critical systematic review is to assess the level of knowledge on the molecular markers involved in the biology, behavior, and prognosis of TBSCC. A search (updated to March 2022) was run in PubMed, Scopus, and Web of Science electronic databases without publication date limits for studies investigating molecular markers in cohorts of patients with primary TBSCC. The search terms used were: “temporal bone” OR “external auditory canal” OR “ear”, AND “cancer” OR “carcinoma” OR “malignancy”. We preliminarily decided not to consider series with less than five cases. Twenty-four case series of TBSCC were found in which different analytical techniques had been used to study the role of several biomarkers. In conclusion, only very limited information on the prognostic role of molecular markers in TBSCC are currently available; prospective, multi-institutional, international prognostic studies should be planned to identify the molecular markers involved in the clinical behavior and prognosis of TBSCC. A further, more ambitious goal would be to find targets for therapeutic agents able to improve disease-specific survival in patients with advanced TBSCC.

In the present study, the effect of long-term exercise training was investigated on myocardial morphological and functional remodeling and on proarrhythmic sensitivity in a rabbit athlete’s heart model. New-Zealand white rabbits were trained during a 12-week long treadmill running protocol and compared with their sedentary controls. At the end of the training protocol, echocardiography, in vivo and in vitro ECG recordings, proarrhythmic sensitivity with dofetilide (nM) were performed in isolated hearts, and action potential duration (APD) measurements at different potassium concentrations (4.5 and 2 mM) were made in the isolated papillary muscles. Expression levels of the slow component of delayed rectifier potassium current and fibrosis synthesis and degradation biomarkers were quantified. Echocardiography showed a significantly dilated left ventricle in the running rabbits. ECG PQ and RR intervals were significantly longer in the exercised group (79 ± 2 vs. 69 ± 2 ms and 325 ± 11 vs. 265 ± 6 ms, p < 0.05, respectively). The in vivo heart rate variability (HRV) (SD of root mean square: 5.2 ± 1.4 ms vs. 1.4 ± 0.2 ms, p < 0.05) and Tpeak-Tend variability were higher in the running rabbits. Bradycardia disappeared in the exercised group in vitro. Dofetilide tended to increase the QTc interval in a greater extent, and significantly increased the number of arrhythmic beats in the trained animals in vitro. APD was longer in the exercised group at a low potassium level. Real-time quantitative PCR (RT-qPCR) showed significantly greater messenger RNA expression of fibrotic biomarkers in the exercised group. Increased repolarization variability and higher arrhythmia incidences, lengthened APD at a low potassium level, increased fibrotic biomarker gene expressions may indicate higher sensitivity of the rabbit “athlete’s heart” to life-threatening arrhythmias.

Background Despite papillary renal cell carcinoma (pRCC) being the second most common type of kidney cancer, the underlying molecular mechanism remains unclear. Targeted therapies in the past have not been successful because of the lack of a clear understanding of the molecular mechanism. Hence, exploring the underlying mechanisms and seeking novel biomarkers for pursuing a precise prognostic biomarker and appropriate therapies are critical. Material and methods In our research, the differentially expressed genes (DEGs) were screened from the TCGA and GEO databases, and a total of 149 upregulated and 285 downregulated genes were sorted. This was followed by construction of functional enrichment and protein–protein interaction (PPI) network, and then the top 15 DEGs were selected for further analysis. The P4HB gene was chosen as our target gene by repetitively validating multiple datasets, and higher levels of P4HB expression predicted lower overall survival (OS) in patients with pRCC. Results We found that P4HB not only connects with immune cell infiltration and co-expression with PD-1, PD-L2, and CTLA-4, but also has a strong connection with the newly discovered hot gene, TOX. Conclusion We speculate that P4HB is a novel gene involved in the progression of pRCC through immunomodulation.

Background Fecal calprotectin is largely applied as a non-invasive intestinal inflammation biomarker in human medicine. Previous studies in pigs investigated the levels of fecal calprotectin in healthy animals only. Thus, there is a knowledge gap regarding its application during infectious diarrhea. This study investigated the usefulness of fecal calprotectin as a biomarker of intestinal inflammation in Brachyspira hyodysenteriae and Salmonella Typhimurium infected pigs. Results Fecal samples from pigs with colitis (n = 18) were collected from animals experimentally inoculated with B. hyodysenteriae (n = 8) or from sham-inoculated controls (n = 3). Fecal samples from pigs with enteritis (n = 14) were collected from animals inoculated with Salmonella enterica serovar Typhimurium (n = 8) or from sham-inoculated controls (n = 4). For both groups, fecal samples were scored as: 0 = normal; 1 = soft, wet cement; 2 = watery feces; 3 = mucoid diarrhea; and 4 = bloody diarrhea. Fecal calprotectin levels were assayed using a sandwich ELISA, a turbidimetric immunoassay and a point-of-care dipstick test. Fecal calprotectin levels were greater in colitis samples scoring 4 versus ≤ 4 using ELISA, and in feces scoring 3 and 4 versus ≤ 1 using immunoturbidimetry (P Conclusions Fecal calprotectin levels are increased following the development of colitis, but do not significantly change due to enteritis. While practical, the use of commercially available human kits present sensitivity limitations. Further studies are needed to validate the field application of calprotectin as a marker of intestinal inflammation.

Orientador: Domingo Marcolino Braile Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas Resumo: Objetivo: avaliar se há ou não associação na ocorrência de fibrilação atrial (FA) e os níveis séricos de troponina I cardíaca no pós-operatório imediato da revascularização do miocárdio (RM). Casuística e Método: estudo retrospectivo incluindo 95 pacientes submetidos à revascularização cirúrgica do miocárdio, entre dezembro de 1996 a março de 1998. Os pacientes foram divididos em 2 grupos: Grupo I constituído de 25 pacientes (26,31%) com fibrilação atrial (FA); Grupo II constituído de 70 pacientes (73,69%) sem FA. As variáveis avaliadas foram: tempos de circulação extracorpórea (CEC), pinçamento aórtico e isquemia, fração de ejeção e o diâmetro do átrio esquerdo. O ritmo cardíaco foi avaliado por monitorização contínua por exames eletrocardiográficos durante o período de internação. Todos os pacientes foram submetidos à dosagens dos níveis séricos de troponina-I cardíaca no pré e pós-operatório imediato da RM pelo método de quimioluminiscência, admitindo-se como normais valores abaixo de 0,1 ng/ml. Resultados: Os grupos I e II não apresentaram diferenças significantes quanto à fração de ejeção, diâmetro do átrio esquerdo, tempos de pinçamento da aorta e de isquemia. O tempo de CEC mostrou diferença significante entre os grupos. A análise pareada dos valores séricos da troponina I cardíaca dos pacientes dos grupos I e II no pré-operatório não mostrou diferença significante, com valor de P=0,9689. No pós-operatório, houve diferença significante entre os grupos, sendo que o grupo I mostrou maior aumento em relação ao II com P=0,0018. O valor de corte de troponina I cardíaca que melhor se associou com ocorrência de FA foi = 0,936 µg/ L. Conclusão: A ocorrência da FA está associada com os níveis séricos de troponina I cardíaca no pós-operatório imediato da RM quando considerado o valor de corte = 0,936 µg/L, sugerindo que a troponina I cardíaca é um marcador para FA e alertando para a necessidade de medidas diagnósticas ou terapêuticas preventivas Abstract: Objective: To evaluate if there is any association among atrial fibrillation (AF) events and serum cardiac Troponin I levels in the immediate postoperative period of myocardium revascularization (MR). Patients and method: A retrospective study was made of 95 patients who underwent myocardial revascularization surgery between December 1996 and March 1998. The patients were divided into 2 groups: Group I comprised 25 patients (26.31%) who presented with atrial fibrillation (AF) and Group II 70 patients (73.69%) without AF. The variables evaluated were: time of extracorporeal circulation (ECC), aortic clamping and ischemia, ejection fraction and the diameter of the left atrium. The heart rhythm was evaluated by continuous monitoring by electrocardiography during hospitalization. The serum cardiac Troponin I levels were measured for all patients in the pre- and immediate postoperative periods of MR by chemoluminescence; normal values were consider to be below 0.1 ng/mL. Results: There were no significant differences between groups in respect to the ejection fraction, diameter of the left atrium and duration of aortic clamping and ischemia. The ECC time gave a significant difference between the groups. A comparison of the serum cardiac Troponin I levels of the patients in both groups in the preoperative period did not prove to be statistically significant (P-value = 0.9689). In the postoperative period however, there was a significant difference; Group I presented with a greater increase when compared to Group II (P-value = 0.0018). Levels of cardiac Troponin I =0.936 µg/L were associated with a risk of AF. Conclusion: AF events are associated with serum cardiac Troponin I levels =0.936 µg/L in the immediate postoperative period of MR. This suggests that cardiac Troponin I is a marker for AF, highlighting the necessity of diagnostic investigations and preventive therapeutic procedures Doutorado Cirurgia Doutor em Cirurgia

Prior studies have described distinct patterns of brain gray matter and white matter alterations in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), as well as differences in their cerebrospinal fluid (CSF) biomarkers profiles. We aim to investigate the relationship between early‐onset AD (EOAD) and FTLD structural alterations and CSF biomarker levels. We included 138 subjects (64 EOAD, 26 FTLD, and 48 controls), all of them with a 3T MRI brain scan and CSF biomarkers available (the 42 amino acid‐long form of the amyloid‐beta protein [Aβ42], total‐tau protein [T‐tau], neurofilament light chain [NfL], neurogranin [Ng], and 14‐3‐3 levels). We used FreeSurfer and FSL to obtain cortical thickness (CTh) and fraction anisotropy (FA) maps. We studied group differences in CTh and FA and described the “AD signature” and “FTLD signature.” We tested multiple regression models to find which CSF‐biomarkers better explained each disease neuroimaging signature. CTh and FA maps corresponding to the AD and FTLD signatures were in accordance with previous literature. Multiple regression analyses showed that the biomarkers that better explained CTh values within the AD signature were Aβ and 14‐3‐3; whereas NfL and 14‐3‐3 levels explained CTh values within the FTLD signature. Similarly, NfL levels explained FA values in the FTLD signature. Ng levels were not predictive in any of the models. Biochemical markers contribute differently to structural (CTh and FA) changes typical of AD and FTLD.

BACKGROUND The objective of the present study was to identify prognostication biomarkers in patients with cervical cancer. MATERIAL AND METHODS Survival related genes were identified in The Cancer Genome Atlas (TCGA) cervical cancer study, and they were included into an elastic net regularized Cox proportional hazards regression model (CoxPH). The genes that their coefficients that were not zero were combined to build a prognostication combination. The prognostication performance of the multigene combination was evaluated and validated using Kaplan-Meier curve and univariate and multivariable CoxPH model. Meanwhile, a nomogram was built to translate the multigene combination into clinical application. RESULTS There were 37 survival related genes identified, 9 of which were integrated to build a multigene combination. The area under the curve (AUC) of receiver operating characteristic (ROC) curve at 1-year, 3-year, 5-year, and 7-year in the training set were 0.757, 0.744, 0.799, and 0.854, respectively, and the multigene combination could stratify patients into significantly different prognostic groups (hazard ratio [HR]=0.2223, log-rank P

BACKGROUND The aim of this study was to investigate the differentially expressed genes (DEGs) relevant to prognosis of ovarian cancer by use of integrated bioinformatics analysis. MATERIAL AND METHODS The DEGs between normal ovariy tissue and ovarian cancer tissue were screened in GSE54388, GSE14407, and GSE18520 datasets and the overlapping DEGs were then indentified. GO and KEEG enrichment were performed to analyze the biological functions and pathways of the DEGs. A protein-protein interaction (PPI) network of the identified DEGs was constructed using the STRING database. Differences in prognosis between low and high expression of the hub DEGs were also evaluated using the Kaplan-Meier Plotter database. Protein expression of 2 hub genes - BUB1B and KIF201A - was assessed by immunohistochemistry assay and evaluated with the patient's clinical pathology characteristics. RESULTS We identified 361 DEGs, mainly involving oncogene-induced cell senescence, cyclin B1-CDK1 complex, protein kinase A catalytic subunit binding, cell cycle, and p53 signaling pathway. Ten hub genes were identified from among the 361 DEGs. The overall survival (OS) and progression-free survival (PFS) of these 10 hub genes were evaluated in the Kaplan-Meier-plotter database. Three (BUB1B, KIF11, and KIF20A) of the 10 hub genes were found to be correlated with ovarian cancer OS and PFS. BUB1B expression level was correlated with ovarian FIGO stage (p

BACKGROUND The serine peptidase inhibitor Kazal type 13 (SPINK13) gene has tumor suppressor activity, but its role in renal cell carcinoma (RCC) remains unknown. This study aimed to investigate mRNA expression of SPINK13 in clear cell renal cell carcinoma (CCRCC) in human tissue and to use bioinformatics data to investigate the role of SPINK13 expression as a clinicopathological and prognostic biomarker for patients with CCRCC. MATERIAL AND METHODS Patients with CCRCC (N=533) with available RNA sequence data from The Cancer Genome Atlas (TCGA)-CCRCC database were analyzed with patients who had a tissue diagnosis of CCRCC (N=305) at the Fudan University Shanghai Cancer Center (FUSCC). Differential transcriptional and proteome expression profiles were obtained from the ONCOMINE cancer microarray database, TCGA, and the Human Protein Atlas (HPA) database. Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) measured SPINK13 mRNA expression in 305 samples of CCRCC tissue from the FUSCC. The effects of clinicopathological parameters on progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier and log-rank test. RESULTS Transcriptional and proteome expression of SPINK13 were significantly increased CCRCC tissue samples. Increased SPINK13 mRNA expression was significantly associated with reduced PFS and OS in 838 patients with CCRCC patients from the two independent cohorts, the FUSCC and the TCGA-CCRCC cohorts (p

BACKGROUND Oral squamous cell carcinoma (OSCC), one of the most common cavity-associated cancers, has a high incidence and worldwide mortality. However, the cause and underlying molecular mechanisms of OSCC remain unclear. MATERIAL AND METHODS Three microarray datasets (GSE23558, GSE34105, and GSE74530) from the Gene Expression Omnibus (GEO) database were downloaded and then integrated to gain differentially expressed genes (DEGs). We performed Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments of DEGs in order to elucidate DEGs' biological roles. Protein-protein interaction (PPI) networks were established in order to identify hub genes. To validate the gene markers for OSCC, the data of TCGA OSCC were also assessed. RESULTS Together, 651 DEGs containing 288 upregulated genes and 363 downregulated genes were screened out, which could completely distinguish between OSCC and normal control tissues by principal component analysis (PCA). The GO analysis indicated the DEGs were enriched in chemokine activity in the biological process group. The molecular functions of DEGs included growth factor activity. The molecular functions included oxidoreductase activity. The main DEG-associated cellular components included extracellular exosome. The KEGG pathway analysis indicated the DEGs were mainly participated in the cytokine-cytokine receptor interaction, metabolism of xenobiotics by cytochrome P450 and glutathione metabolism signal pathway. The co-expression network identified core genes from the PPI network. Additionally, Kaplan-Meier survival analysis showed that CSF2 and EGF genes were significantly correlated with OSCC patients' overall survival. CONCLUSIONS Our study using an integrated bioinformatics analysis might provide valuable information for exploring potential new molecular biomarkers and therapeutic targets for OSCC.

ObjectiveSensory overresponsivity (SOR), an atypical negative reaction to sensory stimuli, is highly prevalent in autism spectrum disorder (ASD). Previous work has related SOR to increased brain response in sensory-limbic regions. This study investigated where these atypical responses fall in three fundamental stages of sensory processing: arousal (i.e., initial response), habituation (i.e., change in response over time), and generalization of response to novel stimuli. Different areas of atypical response would require distinct intervention approaches.MethodsFunctional MRI was used to examine these patterns of neural habituation to two sets of similar mildly aversive auditory and tactile stimuli in 42 high-functioning children and adolescents with ASD (21 with high levels of SOR and 21 with low levels of SOR) and 27 age-matched typically developing youths (ages 8-17). The relationship between SOR and change in amygdala-prefrontal functional connectivity across the sensory stimulation was also examined.ResultsAcross repeated sensory stimulation, high-SOR participants with ASD showed reduced ability to maintain habituation in the amygdala and relevant sensory cortices and to maintain inhibition of irrelevant sensory cortices. These results indicate that sensory habituation is a dynamic, time-varying process dependent on sustained regulation across time, which is a particular deficit in high-SOR participants with ASD. However, low-SOR participants with ASD also showed distinct, nontypical neural response patterns, including reduced responsiveness to novel but similar stimuli and increases in prefrontal-amygdala regulation across the sensory exposure.ConclusionsThe results suggest that all children with autism have atypical brain responses to sensory stimuli, but whether they express atypical behavioral responses depends on top-down regulatory mechanisms. Results are discussed in terms of targeted intervention approaches.

BACKGROUND Breast cancer has a high mortality rate and is the most common cancer of women worldwide. Our gene co-expression network analysis identified the genes closely related to the pathological stage of breast cancer. MATERIAL AND METHODS We performed weighted gene co-expression network analysis (WGCNA) from the Gene Expression Omnibus (GEO) database, and performed pathway enrichment analysis on genes from significant modules. RESULTS A non-metastatic sample (374) of breast cancer from GSE102484 was used to construct the gene co-expression network. All 49 hub genes have been shown to be upregulated, and 19 of the 49 hub genes are significantly upregulated in breast cancer tissue. The roles of the genes CASC5, CKAP2L, FAM83D, KIF18B, KIF23, SKA1, GINS1, CDCA5, and MCM6 in breast cancer are unclear, so in order to better reveal the staging of breast cancer markers, it is necessary to study those hub genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes indicated that 49 hub genes were enriched to sister chromatid cohesion, spindle midzone, microtubule motor activity, cell cycle, and something else. Additionally, there is an independent data set - GSE20685 - for module preservation analysis, survival analysis, and gene validation. CONCLUSIONS This study identified 49 hub genes that were associated with pathologic stage of breast cancer, 19 of which were significantly upregulated in breast cancer. Risk stratification, therapeutic decision making, and prognosis predication might be improved by our study results. This study provides new insights into biomarkers of breast cancer, which might influence the future direction of breast cancer research.

Background Screening and diagnosis of iron deficiency anemia (IDA) is cumbersome as it may require testing for hemoglobin, ferritin, and an inflammatory biomarker. Objective The aim of this study was to compare the diagnostic capacity of hematologic biomarkers to detect IDA among pregnant women in Tanzania. Methods We pooled data from an iron supplementation trial of 1500 iron replete pregnant woman and a prospective cohort of 600 iron deficient pregnant women. Receiver operating characteristic curves (ROC) for hematologic biomarkers were used to assess the sensitivity, specificity, and area under the curve (AUC) for iron deficiency (ID) and iron deficiency anemia (IDA), crude, or corrected for inflammation. Regression models assessed the relationship of baseline biomarker categories (gestational age 110g/L with IDA at delivery (RR = 0.73; 95% CI: 0.47, 1.13) was attenuated. Baseline hepcidin>1.6μg/L was associated with reduced risk of anemia at delivery by 49% (95% CI: 27%, 45%). Conclusion Ascertaining hemoglobin and hepcidin levels may improve the targeting of iron supplementation programs in resource-limited countries, though hepcidin’s high costs may limit its use.

REDISSEC-CARESS/CCR group., [Introduction] Few studies have been conducted to establish the relationship between colorectal cancer screening programmes and survival adjusting by stage and, to determine whether there are differences, at a biological level, between the tumours of asymptomatic and symptomatic patients. Accordingly, the aim of this study is to evaluate clinical, biological and survival differences between symptomatic colorectal tumours and those detected by screening., [Study method] A prospective cohort study was performed of patients subjected to surgical intervention during the period 2010–2012, at different hospitals in Spain. In every case, clinical, pathological, biological and survival-related variables were obtained., [Results] A total of 2634 patients from the CARESS-CCR cohort were analysed; of these, 220 were diagnosed through screening. The asymptomatic patients were younger, had a higher Body Mass Index (BMI), a lower degree of perineural invasion and a less advanced T stage and nodular stage, and the tumour was frequently located on the right side of the colon. All of these differences were statistically significant. The serum tumour marker carbohydrate antigen 19.9 (CA 19.9) was found more frequently in the symptomatic patients (p, [Conclusions] The detection method employed influenced the survival of patients with colorectal cancer and there were no significant biological differences between the study groups., This research was partially supported by grants from REDISSEC (RD12/0001/0010 and RD16/0001/0006), Instituto de Salud Carlos III (PI 09/00910, PI 13/00013, PI 18/01181) and the European Regional Development Fund.

strongBACKGROUND/strongIschemic stroke in cancer patients is associated with poor prognosis. However, the specific biomarkers of cancer-associated ischemic stroke (CaIS) have not been well defined.strongMATERIAL AND METHODS/strongA retrospective study was conducted on PCaIS patients. Clinical data and laboratory and imaging findings were collected. Multivariable logistic regression analysis was used to analyze the independent risk factors for PCaIS. A multiple model combining the independent risk factors of PCaIS was developed using the receiver operating characteristic (ROC) and area under the ROC curve (AUC).strongRESULTS/strongA total of 83 PCaIS patients and 83 prostate cancer (PCa) patients were included. PCaIS patients had higher levels of D-dimer, neutrophil-to-lymphocyte ratio (NLR), and total prostate-specific antigen (T-PSA). In the multivariate analysis, D-dimer [OR=1.001, 95% CI: 1.00,1.00,iP/i=0.002], NLR [OR=1.12, 95% CI: 1.04,1.22,iP/i=0.005], and T-PSA [OR=6.275, 95% CI: 2.57,15.31,iP/i0.001] were independent risk factors of PCaIS. Additionally, the AUC of the multiple model of PCaIS was 0.815 (95% CI, 0.750-0.869), with sensitivity of 81.71% and specificity of 70.21%.strongCONCLUSIONS/strongElevated levels of D-dimer and T-PSA and increased NLR are independent risk factors of PCaIS. The multiple model of PCaIS can be a specific biomarker and is a reliable predictor of development of PCaIS.

Acute kidney injury (AKI) is a frequent and serious complication of orthotopic liver transplantation (OLT), with a significant impact on mortality, graft survival, and chronic kidney disease. Currently, the diagnosis of AKI is based on changes in serum creatinine, which is a late marker, usually rising when there is already significant damage to the renal parenchyma. During the last 2 decades, various biomarkers have been studied in many clinical situations, mostly after cardiac surgery, in drug-induced AKI, or in sepsis. The present article summarizes the data on those biomarkers that have been evaluated for the prediction of AKI in patients undergoing OLT.

BACKGROUND The aim of this study was to identify gene signals for lower-grade glioma (LGG) and to assess their potential as recurrence biomarkers. MATERIAL AND METHODS An LGG-related mRNA sequencing dataset was downloaded from The Cancer Genome Atlas (TCGA) Informix. Multiple bioinformatics analysis methods were used to identify key genes and potential molecular mechanisms in recurrence of LGG. RESULTS A total of 326 differentially-expressed genes (DEGs), were identified from 511 primary LGG tumor and 18 recurrent samples. Gene ontology (GO) analysis revealed that the DEGs were implicated in cell differentiation, neuron differentiation, negative regulation of neuron differentiation, and cell proliferation in the forebrain. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database suggests that DEGs are associated with proteoglycans in cancer, the Wnt signaling pathway, ECM-receptor interaction, the PI3K-Akt signaling pathway, transcriptional deregulation in cancer, and the Hippo signaling pathway. The hub DEGs in the protein-protein interaction network are apolipoprotein A2 (APOA2), collagen type III alpha 1 chain (COL3A1), collagen type I alpha 1 chain (COL1A1), tyrosinase (TYR), collagen type I alpha 2 chain (COL1A2), neurotensin (NTS), collagen type V alpha 1 chain (COL5A1), poly(A) polymerase beta (PAPOLB), insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), and anomalous homeobox (ANHX). GSEA revealed that the following biological processes may associated with LGG recurrence: cell cycle, DNA replication and repair, regulation of apoptosis, neuronal differentiation, and Wnt signaling pathway. CONCLUSIONS Our study demonstrated that hub DEGs may assist in the molecular understanding of LGG recurrence. These findings still need further molecular studies to identify the assignment of DEGs in LGG.

d_abstr_R Worldwide, bladder cancer represents the ninth most common malignancy and is the 13th cause of cancer-associated death. Although surgery combined with chemotherapy and radiotherapy has improved patient outcomes, the prognosis remains poor for most patients with muscle-invasive bladder cancer. The exact mechanisms and critical regulators of bladder cancer remain unknown. Circular RNAs (circRNAs) are a distinct type of endogenous non-coding RNA. Recent studies have shown that circRNAs participate in many processes, including proliferation, invasion, migration, and apoptosis in multiple types of malignancy, including bladder cancer. Some circRNAs are dysregulated in bladder cancer and play essential roles in cancer progression. Importantly, some circRNAs may serve as diagnostic and prognostic biomarkers for bladder cancer. This review aims to summarize the findings from recent studies that have focused on the roles of human circRNAs in bladder cancer and discusses the clinical roles for circRNAs, including their potential roles as diagnostic or prognostic biomarkers.

BACKGROUND Thyroid cancer is a type of endocrine cancers with rapidly increased incidence. Recent studies have indicated long non-coding RNAs (lncRNAs) played crucial roles in thyroid cancer tumorigenesis and progression. However, the roles of most lncRNAs in thyroid cancer were still unclear. MATERIAL AND METHODS We used TCGA (The Cancer Genome Atlas), GSE50901, GSE29265, and GSE33630 datasets to analyze the expression pattern of ZFAS1 (ZNFX1 antisense RNA 1). The correlation between ZFAS1 and clinicopathological features in thyroid cancer was analyzed. Cell proliferation and cell cycle assays were used to validate the roles of ZFAS1 in thyroid cancer cell lines. DAVID (the database for annotation, visualization and integrated discover) system was used to perform GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis. The starBase datasets and Cytoscape was used to perform ceRNA (competitive endogenous RNA) network. RESULTS We demonstrated ZFAS1 was highly expressed in thyroid cancer compared to normal samples. Moreover, upregulation of ZFAS1 was positively correlated with clinicopathological features and poor prognosis in thyroid cancer. Functional validation showed knockdown of ZFAS1 suppressed cell proliferation and cell cycle in thyroid cancer cells. Bioinformatics analysis showed ZFAS1 was associated with translation, rRNA processing, intra-Golgi vesicle-mediated transport, ribosome, and ubiquitin-mediated proteolysis. CONCLUSIONS Our study suggested ZFAS1 could serve as a biomarker for thyroid cancer.

We study desensitization to crime in a lab experiment by showing footage of criminal acts to a group of subjects, some of whom have been previously victimized. We measure biological markers of stress and behavioral indices of cognitive control before and after treated participants watch a series of real, crime-related videos (while the control group watches non-crime-related videos). Not previously victimized participants exposed to the treatment video show significant changes in cortisol level, heart rate, and measures of cognitive control. Instead, previously victimized individuals who are exposed to the treatment video show biological markers and cognitive performance comparable to those measured in individuals exposed to the control video. These results suggest a phenomenon of desensitization or habituation of victims to crime exposure. Fil: Di Tella, Rafael. Harvard Business School; Fil: Freira, Lucía. Universidad Torcuato di Tella; Argentina Fil: Gálvez, Ramiro Heraclio. Universidad Torcuato di Tella; Argentina Fil: Schargrodsky, Ernesto Santiago. Universidad Torcuato di Tella; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; Argentina Fil: Shalom, Diego. Universidad Torcuato di Tella; Argentina Fil: Sigman, Mariano. Universidad Torcuato di Tella; Argentina

ObjectiveAnxiety disorders are common, can result in lifelong suffering, and frequently begin before adolescence. Evidence from adults suggests that altered prefrontal-limbic connectivity is a pathophysiological feature of anxiety disorders. More specifically, in adults with anxiety disorders, decreased fractional anisotropy (FA), a measure of white matter integrity, has been observed in the uncinate fasciculus, the major tract that connects limbic and prefrontal regions. Because of the early onset of anxiety disorders and the increased incidence in anxiety disorders in females during their reproductive years, it is important to understand whether the reduction in uncinate fasciculus FA exists in children with anxiety disorders and the extent to which this alteration is sex related. To address these issues, the authors assessed FA in the uncinate fasciculus in unmedicated boys and girls with anxiety disorders.MethodsFA measures were derived from diffusion tensor images that were acquired from 98 unmedicated children (ages 8-12); 52 met criteria for generalized anxiety disorder, separation anxiety disorder, social anxiety disorder, or anxiety disorder not otherwise specified, and 46 were matched control subjects.ResultsTract-based results demonstrated that children with anxiety disorders have significant reductions in uncinate fasciculus FA. A significant sex-by-group interaction and post hoc testing revealed that this effect was evident only in boys. No other main effects or sex-by-group interactions were found for other white matter tracts.ConclusionsThese findings provide evidence of uncinate fasciculus white matter alterations in boys with anxiety disorders. The data demonstrate that anxiety disorder-related alterations in prefrontal-limbic structural connectivity are present early in life, are not related to psychotropic medication exposure, and are sex specific. Building on these findings, future research has the potential to provide insights into the genesis and sexual dimorphism of the pathophysiology that leads to anxiety disorders, as well as to identify sex-specific early-life treatment targets.

BACKGROUND Circular RNAs (circRNAs) are novel non-coding RNAs that have important roles in tumor progression. This study aimed to measure the levels of hsa_circ_0000885 in serum samples and tumor tissue from patients with osteosarcoma compared with controls and to evaluate the findings with disease-free survival and overall survival. MATERIAL AND METHODS Fifty pairs of osteosarcoma tissues and matched adjacent normal tissue were obtained from patients who underwent the same chemotherapy regimen before surgery. Blood samples were obtained from 30 patients with osteosarcoma before and after chemotherapy, 25 patients with osteosarcoma before and after surgery, 27 patients with benign bone tumors, and 25 age-matched and sex-matched healthy controls. Circular RNA sequencing and quantitative real-time polymerase chain reaction (qRT-PCR) were used to analyze hsa_circ_0000885 expression. RESULTS Hsa_circ_0000885 expression was significantly increased in tissue and serum samples from patients with osteosarcoma, compared with controls, with significantly increased expression levels in patients with Enneking stage IIB and III osteosarcoma, compared with early-stage osteosarcoma. Patients with high serum and tumor levels of hsa_circ_0000885 had lower rates of disease-free survival and overall survival. The serum expression levels of hsa_circ_0000885 were significantly higher in patients with osteosarcoma compared with patients with benign bone tumors or healthy controls. CONCLUSIONS Hsa_circ_0000885 was upregulated in osteosarcoma, and it could serve as a good prognostic biomarker indicating poor clinical outcomes of osteosarcoma. Hsa_circ_0000885 was upregulated in serum of osteosarcoma patients and could serve as a good diagnostic biomarker for osteosarcoma.

Orientador: Adriana Franco Paes Leme Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia Resumo: A espectrometria de massas aplicada à análise proteômica permite a caracterização e quantificação em larga-escala de proteínas expressas em uma determinada condição ou sistema biológico. Na presente tese, mostramos por meio de diferentes abordagens a utilidade da espectrometria de massas (1) no estudo de proteínas secretadas ou clivadas da superfície (secretoma) por células tumorigênicas como fonte de biomarcadores em câncer (2) na validação de candidatos biomarcadores em saliva humana de pacientes com câncer oral e (3) no estudo de alvos de uma metaloprotease envolvida na progressão de câncer, a ADAM17 (A disintegrin and metalloproteinase 17). Os resultados gerados pela espectrometria de massas juntamente com ferramentas estatísticas e de bioinformática para visualização de dados em agrupamento, heatmaps, rede de interação proteína-proteína, enriquecimento de vias e processos biológicos indicaram proteínas específicas direcionadas à hipótese que puderam ser validadas por métodos complementares quantitativos e funcionais. No contexto de biomarcadores em câncer, um painel de marcadores foi indicado a partir da análise do secretoma de células de carcinoma, melanoma e não cancerosas. Dentre os candidatos em carcinoma, proteínas envolvidas no sistema complemento foram validadas com expressão aumentada tanto em tecidos (proteínas C3 e CFB) quanto em saliva de pacientes com carcinoma oral de células escamosas (proteínas C3, CFB, C4B e SERPINA1). Agrina e perlecan, também observados com expressão alterada no secretoma de células de carcinoma e validados com expressão aumentada em tecidos de paciente com câncer oral, foram estudados quanto à função em processos tumorigênicos: migração, adesão, proliferação e sensibilidade à cisplatina. No estudo do degradoma da ADAM17, mimecan, perlecan e glypican-1 foram revelados como novos alvos dessa protease, e os sítios de clivagem determinados por espectrometria de massas. Além disso, funções e processos biológicos associados à clivagem de glypican-1 também foram estudados por meio da análise de seus parceiros de interação no meio extracelular seguido de ensaios funcionais. Em resumo, a espectrometria de massas esteve presente em todos os passos do método científico, desde a geração de hipóteses por meio da proteômica baseada em descoberta, até o teste e confirmação de hipóteses por meio da proteômica baseada em alvos Abstract: Mass spectrometry applied to proteomic analysis allows large-scale characterization and quantification of proteins in specific conditions or biological systems. In this thesis, we showed different mass spectrometry-based approaches for (1) the study of cell secreted or released from the cell-surface proteins (secretome) as a source of candidate biomarkers in cancer (2) validation of candidate biomarkers in human saliva of patients with oral cancer and (3) the study of the target substrates of an important metalloprotease involved in cancer progression, the ADAM17 (A disintegrin and metalloproteinase 17). Together with statistical and bioinformatics tools, such as clustering, heatmaps, network analysis and enrichment analysis, we found specific hyphothesis-driven proteins that were further validated using complementary quantitative and functional methods. In the context of cancer biomarker, a panel of candidate biomarkers was revealed from the secretome analysis of carcinoma, melanoma and non-tumorigenic cell lines. Among the carcinoma candidates, proteins involved in complement system were validated with higher expression in tissues (C3 and CFB) and saliva (C3, CFB, C4B and SERPINA1) from patients with oral squamous cell carcinoma. The function of agrin and perlecan, which were also found with increased expression in squamous cell carcinoma tissue, were studied in tumorigenic processes: migration, adhesion, proliferation and sensibility to cisplatin. In the context of ADAM17 degradome, mimecan, perlecan and glypican-1 (GPC1) were revealed as novel substrates and their cleavage sites were determined using mass spectrometry. Besides, the function and biological processes associated with GPC1 shedding were studied by identifying the binding partners of GPC1 in the extracellular media and by performing functional assays. In summary, mass spectrometry was present in all part of the scientific method, from hyphothesis generation using discovery proteomics to hyphothesis testing using targeted proteomics Doutorado Bioquímica Doutora em Biologia Funcional e Molecular FAPESP

Orientador: Enilson Antonio Sallum Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba Resumo: O objetivo deste estudo foi avaliar prospectivamente o resultado clínico do tratamento de retrações gengivais localizadas com a técnica de retalho posicionado coronariamente (RPC), associada ou não a enxerto de matriz de colágeno xenógeno (MC) e o efeito nos níveis de biomarcadores angiogênicos no fluido crevicular gengival (FCG). Para tanto, 40 pacientes apresentando retração gengival Classe I ou II de Miller ? 2 mm em caninos ou pré-molares superiores foram selecionados. Os 40 defeitos foram aleatoriamente designados para o grupo RPC ou para o grupo RPC+MC. Os parâmetros clínicos avaliados foram profundidade de sondagem (PS), nível de inserção clínico (NIC), altura da retração gengival (RG), espessura de tecido queratinizado (ETQ) e altura de tecido queratinizado (ATQ). Medidas clínicas foram tomadas no início do estudo (baseline), 6 meses, 1 e 2 anos após a cirurgia. A variável primária do estudo foi redução da retração gengival. FCG foi coletado no baseline, 45 dias, 2, 3 e 6 meses após a cirurgia. Os níveis de fator de crescimento de fibroblastos (FGF-2), fator de crescimento derivado de plaquetas (PDGF-BB), fator de crescimento vascular endotelial (VEGF) e fator estimulador de colônias de macrófagos e granulócitos (GM-CSF) no FCG foram avaliadas por imunoensaio multianalito (Luminex/Magpix, Millipore Corporation, Billerica, MA, EUA). Clinicamente, os dois grupos estudados resultaram em significativa redução da retração gengival, entretanto, o grupo RPC apresentou maior RG residual (1.13±0.49 mm) ao final de 2 anos de acompanhamento, comparado ao grupo RPC+MC (0.85±0.90 mm) (p>0,05). A porcentagem de cobertura radicular reduziu de 77,2±21,20% para 75,70±25,28% no grupo RPC+MC e de 72,11±14,45% para 63,43±14,75% no grupo RPC, sem diferença estatisticamente significante entre os tratamentos (p>0,05). Cobertura radicular completa foi alcançada em 28% (n=5) dos sítios no grupo RPC+MC e 22% (n=4) dos sítios no grupo RPC. No final do estudo, não foi observado ganho estatisticamente significante na ETQ (p>0,05). Adicionalmente, houve um aumento na ATQ em ambos os tratamentos, comparado aos valores de baseline, embora sem diferença estatisticamente significante (p>0,05). Com relação ao perfil imunológico, nenhuma diferença estatisticamente significante foi encontrada na análise intragrupo, para ambos os tratamentos. Os níveis de PDGF-BB e VEGF foram significativamente maiores no grupo RPC+MC quando comparado ao grupo RPC após 2 meses da cirurgia (p0,05). Dentro dos limites deste estudo, pode-se concluir que RPC, associado ou não a MC, resultou em significativa redução da retração gengival. Entretanto, quando a matriz foi utilizada, maior estabilidade da margem gengival foi observada após 2 anos de acompanhamento e maiores níveis de biomarcadores angiogênicos FCG foram detectados, sugerindo um papel da matriz de colágeno na modulação da resposta tecidual Abstract: The aim of this study was to prospectively evaluate the clinical outcome of localized gingival recessions treatment with coronally positioned flap technique (CAF), with or without xenogeneic collagen matrix graft (MC) and the effect on the levels of angiogenic biomarkers in the gingival crevicular fluid (GCF). For this purpose, 40 patients with Miller Class I or II gingival recession ? 2 mm in maxillary canines or premolars were selected. The 40 defects were randomly assigned to either the CAF group or CAF+CM group. The clinical parameters evaluated were probing depth (PD), clinical attachment level (CAL), gingival recession depth (GR), keratinized tissue thickness (KTT) and keratinized tissue width (KTW). Clinical measurements were performed at baseline, 6 months, 1 and 2 years after surgery. The primary endpoint of the study was gingival recession reduction. Gingival crevicular fluid (GCF) was collected at baseline, 45 days 2, 3 and 6 months after surgery. The levels of fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were assessed by multiplex immunoassay. Clinically, the two groups resulted in significant recession reduction. However, CAF group presented greater residual gingival recession (1.13±0.49 mm) at the end of 2 years follow-up, compared to CAF+CM group (0.85±0.90 mm) (p>0.05). The percentage of root coverage reduced from 77.2±21.20% to 75.70±25.28% in CAF+CM group, and from 72.11±14.45% to 63.43±14.75% in CAF group, with no statistically significant difference between treatments (p> 0.05). Complete root coverage was achieved in 28% (n = 5) of sites in CAF+CM group and 22% (n = 4) of sites in the CAF group. At the end of the study, no statistically significant difference for KTT was observed for intra- and inter-group analysis (p>0.05). Additionally, gain in KTW was observed in both treatment groups compared to baseline values, although no statistically significant difference have been detected. Regarding immunological profile analysis, no significant difference was found in intra-group analysis for both treatments (p>0.05). The levels of PDGF-BB and VEGF were significantly higher in CAF+CM group compared with CAF alone 2 months after surgery (p0.05). Within the limits of this study, it can be concluded that CAF, with or without CM, resulted in significant gingival recession reduction. However, when the matrix was used, higher stability of the gingival margin was observed after 2 years follow-up and higher levels of angiogenic biomarkers were detected, suggesting a role in modulating tissue response Doutorado Periodontia Doutora em Clínica Odontológica

Orientadores: Maria Beatriz Duarte Gavião, Paula Midori Castelo Ferrua Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba Resumo: Este estudo teve como objetivo avaliar o estresse percebido, quantificar biomarcadores salivares, sanguíneos e fatores biológicos em Policiais Militares. A amostra foi constituída de 44 Policiais Militares do 20 Batalhao da Policia Militar do Estado de Santa Catarina (20 BPM/SC), do sexo masculino, de 22 a 52 anos de idade, baseados na cidade de Chapecó/SC. A amostra foi categorizada de acordo com o posto hierárquico em soldados (n= 28) e graduados (n= 16). Foi aplicada a Escala de Estresse Percebido (PSS-10). Os biomarcadores salivares quantificados foram o cortisol, alfa amilase, proteína C reativa (PCR) e glicose. Para a quantificação do cortisol, coletou-se em domicílio a saliva ao despertar e 30 minutos após. A glicose e a PCR salivar foram quantificadas na mesma amostra coletada ao despertar. Para a alfa amilase foi coletada uma terceira amostra de saliva nas dependências do 20 BPM. Logo após esta, foi aferida a pressão arterial (PA) e a frequência cardíaca (FC). Na ficha de identificação o participante informou a idade, o tempo na PM e escolaridade. O peso e altura foram informados e com estes determinado o Índice de Massa Corporal (IMC). Foi então coletado sangue venoso em jejum, e neste foram analisados o hemograma, a glicemia, o colesterol total, Lipoproteína de Alta Densidade Colesterol (HDL-C) e a PCR. Os dados foram analisados pela estatística descritiva, correlação de Pearson, Spearman e Qui-quadrado. Para comparação das variáveis contínuas entre os dois postos hierárquicos foram aplicados o teste t independente ou Mann-Whitney, de acordo com a distribuição dos dados, considerando-se o nível de significância de 0,05. O número de soldados foi proporcionalmente igual a categoria de graduados (X2, P>0,05), sendo que esses apresentaram tempo na função significativamente menor (P 0,05), which presented time in the significantly lower function (P

Orientador: Marco Aurélio Zezzi Arruda Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química Resumo: O transtorno afetivo bipolar (TAB) é uma doença psiquiátrica caracterizada por alterações de humor que afeta milhares de pessoas no mundo. A escassez de conhecimentos científicos acerca de sua patogênese faz do TAB uma doença de complexa e de difícil diagnóstico. Alguns pacientes portadores do TAB são, por exemplo, diagnosticados equivocadamente como depressivos unipolares e, como consequência, são tratados ineficazmente. Diante desse fato, uma análise exploratória utilizando estratégias ômicas (proteômica e ionômica) comparativas no soro sanguíneo de pacientes com TAB, controles saudáveis, incluindo não familiares (CSNF) e familiares (CSF), pacientes com esquizofrenia (ESQ) e pacientes com outros transtornos mentais (OTM) foi realizado, a fim de determinar potenciais marcadores biológicos do TAB. Para o estudo proteômico, três métodos foram avaliados para simplificar o proteoma do soro sanguíneo: depleção de proteínas abundantes usando agentes químicos (acetonitrila, ACN; e ditiotreitol, DTT) em sequência; depleção de proteínas abundantes, usando nanopartículas magnéticas (MNPs) e a equalização de proteínas usando kit comercial ProteoMiner® (PM). Para o estudo ionômico, dois métodos foram testados para a decomposição da amostra: decomposição assistida por microondas (método convencional) e decomposição rápida assistida por ultrassom de alta potência (método proposto). Como resultado do estudo proteômico, o método PM apresentou-se como a melhor estratégia para remover as proteínas de alta abundância. Por meio da comparação de imagens de géis 2-D DIGE, 37 spots de proteínas foram encontrados como diferencialmente abundantes (p

Postpartum depression (PPD) is a serious health issue that can affect about 15% of the female population within after giving birth. It often conveys significant negative consequences to the offsprings. The symptoms and risk factors are somewhat similar to those found in non-postpartum depression. The main difference resides in the fact that PPD is triggered by postpartum specific factors, including especially biological changes in the hormone levels. Patients are usually diagnosed using a questionnaire onsite or in a clinic. Treatment of PPD often involves psychotherapy and antidepressant medications. In recent years, there have been more researches on the identification of biological markers for PPD. In this review, we will focus on the current research status of PPD, with an emphasis on the recent progress made on the identification of PPD biomarkers.

The change in levels of volatile organic compounds (VOC) present in exhaled breath can be indicative of bodily disorders. Detection of such low levels of VOCs can allow early detection and diagnosis of diseases. A polymer- modified Quartz Tuning Fork (QTF) is a promising, cost-effective sensor that can detect a change in ppm levels of VOCs exhaled from the breath at room temperature. Acetone and acetaldehyde are biomarkers that are readily exhaled by human beings. Increased levels of these analytes can serve as indicators for toxicity or a wide array of diseases. The present work uses an array of QTFs modified separately using nanomaterials embedded in polystyrene to detect low VOC concentrations present in simulated human breath successfully. The sensor response shows a clear distinction between healthy human breath and breath spiked with varying VOC concentrations (5–400 ppm). The sensor response proves it can potentially serve as an economical and non-invasive tool for disease diagnostics.

BACKGROUND Lung adenocarcinoma (LUAD) is a type of non-small cell carcinoma. Its pathogenesis is being explored and there is no cure for the disease. MATERIAL AND METHODS The Gene Expression Omnibus (GEO) was searched to obtain data on expression of messenger RNA. GEO2R, an interactive web tool, was used to calculate the differentially expressed genes (DEGs) in LUAD. All the DEGs from different datasets were imported into VENNY 2.1 (https://bioinfogp.cnb.csic.es/tools/venny/index.html) to identify the intersection of the DEGs. An online analysis tool, the Database for Annotation, Visualization, and Integrated Discovery (DAVID), was used to help understand the biological meaning of DEG enrichment in LUAD. Cytoscape 3.7.2 was used to perform centrality analysis and visualize hub genes and related networks. Furthermore, the prognostic value of the hub genes was evaluated with the Kaplan-Meier plotter survival analysis tool. RESULTS The GEO database was used to obtain RNA sequencing information for LUAD and normal tissue from the GSE118370, GSE136043, and GSE140797 datasets. A total of 376 DEGs were identified from GSE118370, 248 were identified from GSE136403, and 718 DEGs were identified from GSE140797. The 10 genes with the highest degrees of expression - the hub genes - were CAV1, TEK, SLIT2, RHOJ, DGSX, HLF, MEIS1, PTPRD, FOXF1, and ADRB2. In addition, Kaplan-Meier survival evaluation showed that CAV1, TEK, SLIT2, HLF, MEIS1, PTPRD, FOXF1, and ADRB2 were associated with favorable outcomes for LUAD. CONCLUSIONS CAV1, TEK, SLIT2, HLF, MEIS1, PTPRD, FOXF1, and ADRB2 are hub genes in the DEG interaction network for LUAD and are involved in the development of and prognosis for the disease. The mechanisms underlying these genes should be the subject of further studies.

Orientador: Sarah Arana Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia Resumo: Atrazina é um herbicida muito usado em agricultura intensiva e encontrado com alta freqüência em recursos hídricos na região do Pantanal Mato-grossense. Assim, devido aos riscos que a atrazina pode trazer à ictiofauna da região, foi proposta deste trabalho determinar a CL50 da atrazina em alevinos de pacu (Piaractus mesopotamicus). A determinação da CL50 em 96 h em sistema estático, realizada em duplicata, foi conduzida em aquários de vidro com 8 peixes cada, de peso médio de 5,06±0,31g, avaliando-se as seguintes concentrações nominais de atrazina: 0; 13,2; 17,6; 22,0; 26,4; 30,8; 35,2; 39,6 mg L-1, realizando-se também análise comportamental e análise anatomopatológica. Experimento de intoxicação aguda foi realizado em duplicata, nas mesmas condições do anterior, com a concentração da CL50 obtida (28,58 mg L-1), sendo empregados 6 exemplares de peso médio 6,68±0,36g. Amostras hepáticas e mesonéfricas foram colhidas e processadas para análise de microscopia de luz (ML), realizando-se nestas amostras análise semi-quantitativa das alterações encontradas, e para análise de microscopia eletrônica de transmissão (MET). Quanto à avaliação comportamental, foram observados nos grupos tratados: o escurecimento da pigmentação da pele, várias alterações na intensidade do movimento, perda de equilíbrio e presença da ação de boquejamento. Na avaliação anatomopatológica, foram observadas nos grupos tratados: dilatação da região ventral, exoftalmia, protrusão labial, hiperemia no opérculo e em todas as nadadeiras, presença de ar e/ou água no estômago e ascite sanguinolenta. Quanto à análise histopatológica, o grupo controle apresentou a típica morfologia hepática e renal para a espécie. No grupo tratado, severas alterações histopatológicas foram observadas em ML, a mais significativa em fígado foi a presença de inclusões hialinas no citoplasma dos hepatócitos e em rim a degeneração do túbulo proximal. À MET demonstrou que a atrazina causou severas alterações de organelas membranosas, sugestivas de estresse oxidativo e peroxidação lipídica, sendo as alterações mais freqüentes no fígado: inclusão lipídica nuclear e citoplasmática, tumefação do retículo endoplasmático rugoso e de mitocôndrias, degeneração do canalículo biliar com redução na quantidade de microvilos, e em rim, no túbulo proximal (TP): vacúolos citoplasmáticos e aumento do espaço intercelular na porção basolateral, figuras de mielina, tumefação mitocondrial, e, raramente, degeneração do TP. Estas alterações são compatíveis com intoxicação química, demonstrando que estes órgãos são bons biomarcadores de contaminação aquática em peixes. E por fim, o valor da CL50 sugere que a atrazina é levemente tóxica para o pacu, porém pelos demais resultados observados se inferem que só analisar a mortalidade não é o suficiente para determinar o dano causado por agrotóxicos em peixes, assim, recomenda-se o emprego de vários biomarcadores, tais como: análises comportamentais, histopatológicas, bioquímicas, etc. Abstract: Atrazine is a widely used herbicide in intensive agriculture and a frequent contaminant of waterways in the Pantanal region of Brazil. In view of the potential risks of atrazine to the ichthyofauna of this region, in this work we examined the LC50 of atrazine in pacu (Piaractus mesopotamicus) fingerlings. For this study, fish (5.06 ± 0.31g; mean±SD) were housed eight per glass aquarium and exposed to various concentrations of atrazine (0, 13.2, 17.6, 22.0, 26.4, 30.8, 35.2 and 39.6 mg L-1) for 96 h in static system and this experiment was performed in duplicate, after which the LC50 was determined. Changes in fish behavior and anatomopathological analysis were monitored throughout the experiment. The histopathological alterations caused by atrazine were examined in six fish (6.68 ± 0.36g; mean±SD) using the LC50 (28.58 mg L-1) calculated from the concentration-response curve obtained above. This experiment was done in 96h in static system and performed in duplicate. Liver and mesonephric samples were processed for light microscopy (LM), performing in these samples the semi-quantitative analysis of the changes found, and for transmission electron microscopy (TEM) analysis. Exposure to atrazine caused darkening of the skin, alterations in the intensity of movements, loss of balance and an increase in the frequency of gasping. Anatomopathological assessment revealed dilation of the ventral region, exophthalmia, lip protrusion, skin hyperemia in the opercular region and in all fins, the presence of air and/or water in the stomach, and bloody ascites after the herbicide exposition. The histopathological analysis revealed the typical hepatic and renal morphology for the specie, in control group. Several histopathological changes were observed in exposed fish, but the changes most significant were: in liver, the presence of hyaline inclusions in the cytoplasm of hepatocytes, and proximal tubule (PT) degeneration in the kidney. The ultrastructure showed that the atrazine caused several membrane alterations suggestive of oxidative stress and lipid peroxidation. The most frequent in liver, TEM findings, were: nuclear and cytoplasmic lipid inclusions, swollen rough endoplasmic reticulum and mitochondria, degeneration in the bile canaliculi with a loss in the number of microvilli, and for kidney: an increase in the intercellular space of the basolateral region, myelin figures, swollen mitochondria, and, rarely, degeneration of PT. These lesions are consistent with chemical intoxication and indicate that the liver and kidney are good biomarkers of aquatic contamination in pacu. And, finally, the LC50 value suggests that atrazine is not highly toxic to pacu, however, use of mortality index in acute toxicity as the sole marker in ecotoxicological assays is inadequate and should be completed with other biomarkers such as behavioral, histopathology, biochemistry analyses, etc. Mestrado Histologia Mestre em Biologia Celular e Estrutural

Orientadores: Fabio Rogerio, Roger Frigerio Castilho Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas Resumo: Glioblastoma multiforme (GBM) é o tumor cerebral primário mais frequente. Cerca de 90% dos GBMs são classificados como primários. Tais lesões acometem principalmente idosos, têm rápida evolução e não apresentam evidências de lesão precursora. Por outro lado, GBMs secundários acometem indivíduos mais jovens e progridem lentamente a partir de astrocitoma difuso de menor grau. As alterações moleculares apresentadas pelos tumores astrocitários são várias e seu conhecimento é importante para o melhor entendimento da fisiopatogênese e possível aferição prognóstica. Neste trabalho, investigamos a prevalência de casos de GBM tratados no Hospital de Clínicas da Faculdade de Ciências Médicas da Universidade Estadual de Campinas, entre janeiro de 2008 e dezembro de 2012, com informações clínico-radiológicas completas disponíveis (n=36), e descrevemos as características clínicas e histológicas. Ainda, classificamos a distribuição tecidual dos seguintes marcadores biológicos através de imunoistoquímica: forma selvagem do receptor do fator de crescimento epidérmico (EGFR), formas mutantes da proteína p53 e isocitrato desidrogenase 1 (IDH-1) e a proteína murina 2 (MDM2). Correlacionamos achados morfológicos e imunoistoquímicos com dados da evolução clínica e resposta ao tratamento com cirurgia, quimioterapia com Temozolamida e radioterapia. Observamos que a localização predominante do tumor foi o lobo frontal, sendo cerca de 97% dos casos primários. Em média, o tempo livre de doença clinica ou sintomática foi de 7,56 meses e, o tempo livre de doença radiológica (TLDR), de 7,14 meses. A média do número de figuras de mitose / 10 campos de grande aumento foi 3,9. A correlação entre a sobrevida total e as classes de imunomarcação para p53, IDH-1, EGFR e MDM2 não foi significativa para nenhum dos marcadores. Observou-se relação estatisticamente significativa entre p53 e MDM-2 (p-valor=0,00) e entre EGFR e MDM2 (p-valor=0,04). Por outro lado, não foi detectada relação estatisticamente significativa entre p53 e EGFR (p-valor=0,09). Quanto a correlação entre classes de imunomarcação para p53, MDM2 e EGFR com a sobrevida clínica e com a radiológica, a única relação estatisticamente significativa foi entre p53 e sobrevida clínica (p-valor=0,02), sendo observado que quanto maior a classe de p53, menor a sobrevida clínica. Não houve relação significativa entre imunomarcação para IDH-1, EGFR, MDM2 e a sobrevida total clínica e radiológica. A correlação entre a expressão de MDM2 e do EGFR selvagem também foi positiva (p-valor=0,04). As correlações entre as sobrevidas clínica, radiológica e total foram significativas (p-valor < 0,0001) e positivas, ou seja, o aumento de uma sobrevida implica aumento de outra. As correlações do gênero com as sobrevidas clínica, radiológica e total não foram significativas, assim como a relação da marcação da p53, MDM2 e EGFR com número de mitose e extensão de ressecção tumoral. Quanto à correlação das sobrevidas clínica, radiológica e total com a localização do tumor e a idade, não foram encontradas diferenças estatisticamente significativas em nenhuma das sobrevidas. Nossos resultados clínicos e morfológicos refletem parcialmente alguns dados da literatura. Especificamente, o fato de termos detectado correlação significativa apenas entre a marcação para p53 e sobrevida clínica pode ser decorrente da limitada amostragem disponível para avaliação Abstract: Glioblastoma (GBM) is the most common primary brain tumor. About 90 % of GBMs are classified as primary. Such lesions occur mostly in the elderly, evolve rapidly and show no evidence of precursor lesions. However, secondary GBMs affect younger individuals and progress slowly from lower grade diffuse astrocytomas. Molecular alterations in astrocytic tumors are diverse and their knowledge is important to understand the pathophysiology and prognosis of patients with GBM. Here we investigated the prevalence of GBM treated at the Hospital of the Faculty of Medical Sciences, State University of Campinas, from January 2008 to December 2012, with complete radiological and outcome information available (n = 36), and described the clinical and histopathological findings. Furthermore, we immunohistochemically classified the tissue distribution of four biomarkers: wild form of the epidermal growth factor receptor (EGFR), mutated forms of p53 protein and isocitrate dehydrogenase 1 (IDH-1) and murine protein 2 (MDM2). Morphological and immunohistochemical findings were correlated with data from the clinical course and response to treatment with surgery, chemotherapy and radiotherapy. We observed that the most common location of the tumor was the frontal lobe and about 97 % of cases were primary. On average, time free from clinical or symptomatic disease was 7.56 months and the free time of radiological disease (TLDR) was 7.14 months. The average number of mitotic figures/10 high power fields was 3.9. The correlation between overall survival and classes of p53, IDH- 1, MDM2 and EGFR immunostaining was not significant for any of the markers. There was a statistically significant relationship between p53 and MDM2 (p-value = 0.01) and between EGFR and MDM2 (p-value = 0.04). On the other hand, no significant relationship was detected between p53 and EGFR (p=0.09). Concerning the correlations between classes of immunostaining for p53, MDM2 and EGFR with clinical and radiological survival, the only significant relation was between p53 and clinical survival (p-value = 0.02), with the higher class of p53, the poorer the clinical survival. There was no significant relationship between immunostaining for IDH-1, EGFR, MDM2 and the total clinical and radiological survival. The correlation between the expression of MDM2 and wild type EGFR was also positive (p-value = 0.04). The correlations between clinical, radiological and overall survival were significant (p-value

Orientadores: Luiz Carlos Zeferino, Silvia Helena Rabelo dos Santos Texto em português e inglês Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas Resumo: O papel da proteína SOD2 na carcinogênese e progressão tumoral, particularmente no carcinoma de células escamosas do colo uterino, continua a ser o objeto de incerteza e controvérsia. Assim, este estudo teve como objetivo avaliar a variabilidade na expressão da proteína SOD2 em cortes histológicos de epitélio cervical. Este estudo transversal incluiu 277 mulheres com indicação de procedimento conização ou excisão da zona de transformação devido a suspeita de NIC 2 ou lesão mais grave. A expressão SOD2 foi avaliada por ensaios de imunoistoquímicos realizados com base na porcentagem de células coradas em áreas representativas do diagnóstico histopatológico. A expressão positiva, independentemente da intensidade foi positivamente associada com o diagnóstico de NIC2/ NIC3 (OR = 2,64; 1,57-4,60) e carcinoma (OR = 14,32; 4,08-50,26). Tomando expressão SOD2 como referência para casos de NIC2/ NIC3, observou-se que a expressão positiva, independentemente da intensidade foi positivamente associada com um diagnóstico de carcinoma (OR = 5,33; 1,56-18,25). Observou-se que a expressão intensa SOD2 foi positivamente associada com o diagnóstico de NIC2/ NIC3 (OR = 7,31; 1,68-31,86) e carcinoma (OR = 36,63; 7,76-172,85). Quando a expressão de SOD2 foi tomada como referência para casos NIC2/ NIC3, observou-se que a expressão intensa foi positivamente associada com um diagnóstico de carcinoma (OR = 5,01; 2,24-11,20). Expressão SOD2 é observada com maior frequência e mais intensa em NIC2/ NIC3 e carcinoma espinocelular do que em tecido normal / NIC 1 . Além disso, a expressão SOD2 também é mais frequente e intensa em carcinomas do que em NIC2/ NIC3. Embora NIC2/ NIC3 e carcinomas invasivos iniciais são lesões contíguas na carcinogênese cervical, a expressão SOD2 pode diferenciá-los Abstract: The role of SOD2 protein in carcinogenesis and tumor progression, particularly in squamous cell carcinoma of the uterine cervix, remains the object of uncertainty and controversy. Therefore this study aimed to evaluate the variability in SOD2 protein expression in histological specimens from cervical epithelium. This study cross-sectional study included 277 women with indication of conization procedure or transformation zone excision due to suspicion of CIN 2 or more severe lesion. The SOD2 expression was assessed by performed immunohistochemical assays based on the percentage of stained cells in representative areas of the histopathological diagnosis. Positive expression regardless of intensity was positively associated with a diagnosis of CIN2/CIN3 (OR=2.64; 1.57- 4.60) and carcinoma (OR=14.32; 4.08-50.26). Taking SOD2 expression as a reference for cases of CIN2/CIN3, it was observed that a positive expression, regardless of intensity was positively associated with a diagnosis of carcinoma (OR=5.33; 1.56-18.25). It was observed that intense SOD2 expression was positively associated with a diagnosis of CIN2/CIN3 (OR=7.31; 1.68-31.86) and carcinoma (OR=36.63; 7.76-172.85). When SOD2 expression was taken as a reference for CIN2/CIN3 cases, it was observed that intense expression was positively associated with a diagnosis of carcinoma (OR=5.01; 2.24-11.20). SOD2 expression is most frequently observed and more intense in CIN2/CIN3 and squamous carcinoma than in normal tissue/CIN 1. In addition, SOD2 expression is also more frequently observed and intense in carcinoma than in CIN2/CIN3. Although CIN 2/CIN 3 and early invasive carcinomas are contiguous lesions in cervical carcinogenesis, SOD2 expression can differentiate them Mestrado Oncologia Ginecológica e Mamária Mestra em Ciências da Saúde

Orientadores: Laura Sterian Ward, Márcio José da Silva Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas Resumo: Nódulos de tireoide, benignos e malignos, tem se tornado cada vez mais frequentes, obrigando a busca de marcadores de diagnóstico e prognóstico. Três fatores de transcrição tireoide-específicos estão envolvidos na manutenção do estado diferenciado da glândula e em sua carcinogênese: TTF-1, FOXE1 e PAX8. Os níveis de expressão destes genes estão relacionados com o grau de diferenciação tecidual em tumores tireoidianos. O repressor transcricional DREAM também está envolvido na expressão gênica tireoide-específica através da interação com o gene da tireoglobulina e com os fatores de transcrição TTF-1, FOXE1 e PAX8. O aumento da expressão de DREAM na tireoide está relacionado com o aumento da glândula e desenvolvimento nodular. O objetivo do presente estudo foi analisar a expressão dos genes TTF-1, FOXE1, PAX8 e DREAM em tecidos tumorais benignos e malignos da tireoide, além de identificar possíveis mutações no gene DREAM em pacientes com nódulos tireoidianos. Para tanto foram coletadas 200 amostras de tecido nodular, sendo 50 adenomas foliculares (AF), 49 bócios nodulares, 63 carcinomas papilíferos clássicos (CPTC), 36 carcinomas papilíferos de variante folicular (CPTVF). Todos os pacientes foram submetidos a um mesmo protocolo padrão e acompanhados por 12-87 meses (38 ± 17 meses). Foram extraídos DNA e RNA de todas as amostras. A análise de expressão foi realizada por qPCR e a detecção de mutações no gene DREAM foi feita por sequenciamento automático. Os dados obtidos foram relacionados com dados clínicos e de evolução dos pacientes. Demonstramos que, embora a expressão de TTF-1 tenha sido similar entre os diferentes nódulos analisados (p=0.7056), FOXE1 (pA está localizada na região promotora e foi encontrada em apenas um paciente. As alterações IVS2-131C>T e IVS3+17T>C foram encontradas em regiões intrônicas (intron 1 e 3 respectivamente) em um paciente cada. As alterações IVS1+41C>G, IVS3+10G>C e IVS8-118C>T foram encontradas em vários pacientes por se tratarem de polimorfismos já descritos (rs2248415, rs117109173 e rs58372613 respectivamente). As frequências alélicas e genotípicas das alterações não se associaram as características clínicas, de agressividade ou evolução. Concluímos que a expressão dos genes FOXE1, PAX8 e DREAM pode auxiliar o diagnóstico de malignidade e a diferenciação de lesões tireoidianas, mas não possui utilidade como marcador de prognóstico. Além disso, mutações e polimorfismos do gene DREAM em pacientes com nódulos tireoidianos não possuem clínica como biomarcadores de diagnóstico ou prognóstico do CT Abstract: Thyroid nodules, benign and malignant, have become increasingly frequent, impelling the search for markers for their diagnosis and prognosis. Three thyroid-specific transcription factors are involved in maintaining the differentiation of the gland and its carcinogenesis: TTF-1, FOXE1 and PAX8. The expression levels of these genes are related to the degree of tissue differentiation in thyroid tumors. The transcriptional repressor DREAM is also involved in thyroid-specific gene expression through interaction with the thyroglobulin gene and the transcription factors TTF-1, FOXE1 and PAX8. An increased expression of DREAM was related to the thyroid enlargement and nodular development. The purpose of this study was to analyze the expression of TTF-1, FOXE1, PAX8 and DREAM genes in benign and malignant thyroid tumor tissues and identify possible mutations in the DREAM gene in patients with thyroid nodules. For that purpose, we collected 200 thyroid nodules samples: 50 follicular adenomas (FA), 49 nodular goiters, 63 classic papillary carcinomas (CPTC), 36 follicular variant of papillary thyroid carcinomas (FVPTC). All patients were submitted to the same standard treatment protocol and followed by 12-87 months (38 ± 17 months). Gene expression analysis was performed by real time PCR and we performed automatic sequencing in order to detect mutations of DREAM gene. The data obtained were correlated to clinical and pathological features and to patients¿ outcomes. We demonstrated that FOXE1 (p A is located in the promoter region of the gene and was found in one patient. The alterations IVS2-131C>T and IVS3+17T> C were found in intronic regions (introns 1 and 3 respectively), each in one patient. The alterations IVS1+41C>G, IVS3+10G>C and IVS8-118C>T, corresponding to already described polymorphisms (rs2248415, rs58372613 and rs117109173 respectively), were found in several patients. Allelic and genotypic frequencies of the alterations were not associated with any clinical or pathological feature of aggressiveness or with outcome. We conclude that the expression of FOXE1, PAX8 and DREAM may help diagnose thyroid nodules, identifying malignancy and characterizing follicular-patterned thyroid lesions, but is not useful as a prognostic marker. In addition, mutations and polymorphisms in non-coding regions of the DREAM gene in patients with thyroid nodules are not associated with clinical features, not having utility as diagnostic or prognosis biomarkers for TC Mestrado Clínica Médica Mestre em Ciências FAPESP

BACKGROUND Gastric cancer is the most common gastrointestinal tumor, and the rates of recurrence and metastasis are high. Research results on molecular biomarkers used for prognosis of gastric cancer remain inconclusive. This study aimed to explore the gene expression module of gastric cancer and to determine potential prognostic biomarkers. MATERIAL AND METHODS Three microarray datasets (GSE13911, GSE79973, and GSE29272) from Gene Expression Omnibus (GEO), including 206 pairs of gastric tumors and adjacent normal samples, were used for analysis of differentially expressed genes (DEGs). The 3 microarray datasets yielded 144 genes associated with the progression and prognosis of gastric cancer. After this, a risk score model was developed for result validation using an independent dataset from The Cancer Genome Atlas. RESULTS The validation of the independent dataset showed significantly increased NID2, SPARC, and MFAP2 expression in gastric tumor tissues, which were associated with poor outcomes in gastric cancer patients. Moreover, the high risk score obtained was associated with poor overall survival (HR: 1.787; 1.069-2.986; P=0.027). Subgroup analyses revealed that these significant prognostic values were detected in patients aged

BACKGROUND Adrenocortical carcinoma (ACC) is an aggressive cancer with heterogeneous outcomes. In this study, we aimed to investigate genomic and prognostic features of ACC. MATERIAL AND METHODS Clinical, pathologic, and transcriptomic data from 2 independent datasets derived from ACC samples (TCGA-ACC dataset, GEO-GSE76021 dataset) were collected. Weighted gene co-expression network analysis (WGCNA) and survival analyses were performed to identify prognostic genes. Pathway analysis was performed for mechanistic analysis. xCell deconvolution was performed for tumor microenvironment analysis. RESULTS In the TCGA-ACC cohort, WGCNA identified a prognostic module of 5408 genes. Differential expression analysis identified 1969 genes that differed in expression level between long-term and short-term survivors. Univariate Cox regression model analysis identified 8393 genes with prognostic value. The intersection of these gene sets included 820 prognostic genes. Similar protocols were performed for the GSE76021 dataset, and 5 candidate genes were identified. Further intersection of these genes finally identified NDRG4 and CKS2 as key prognostic genes. Multivariate Cox regression model analysis validated the prognostic value of NDRG4 (HR=0.61, 95% CI 0.46-0.80) and CKS2 (HR=2.52, 95% CI 1.38-4.60). Moreover, NDRG4 and CKS2 expression predicted survival in patients treated with mitotane (P

Although clinical studies have been carried out on the effects of weight reduction in sleep apnea patients, no direct link has been shown between weight reduction and changes in cardio-metabolic risk factors. We aimed to analyze changes in the apnea–hypopnea index and selected cardio-metabolic parameters (total cholesterol, triglycerides, glucose, insulin, blood pressure) in relation to the reduction in body mass index in obstructive sleep apnea patients. Medline, Web of Science and Cochrane databases were searched to combine results from individual studies in a single meta-analysis. We identified 333 relevant articles, from which 30 papers were assigned for full-text review, and finally 10 (seven randomized controlled trials and three nonrandomized studies) were included for data analysis. One unit of body mass index reduction was found to significantly influence changes in the apnea–hypopnea index (−2.83/h; 95% CI: −4.24, −1.41), total cholesterol (−0.12 mmol/L; 95% CI: −0.22, −0.01), triglycerides (−0.24 mmol/L; 95% CI: −0.46, −0.02), fasting insulin (−7.3 pmol/L; 95% CI: −11.5, −3.1), systolic (−1.86 mmHg; 95% CI: −3.57, −0.15) and diastolic blood pressure (−2.07 mmHg; 95% CI: −3.79, −0.35). Practical application of lifestyle modification resulting in the reduction of one unit of body mass index gives meaningful changes in selected cardio-metabolic risk factors in obstructive sleep apnea patients.

Background Concurrent chemoradiotherapy followed by brachytherapy is the standard of care in locally advanced carcinoma cervix. There is no prognostic factor at present to predict the outcome of disease in locally advanced carcinoma cervix. Aim Differential expression of microRNAs can be used as biomarkers to predict clinical response in locally advanced carcinoma cervix patients. Methods Thirty‐two patients of locally advanced carcinoma cervix with International Federation of Gynecology and Obstetrics Stage IB‐IVA were enrolled from 2017 to 2018. Expression of microRNA‐9 5p, ‐31 3p, ‐100 5p, ‐125a 5p, ‐125b‐5p, and –200a 5p in formalin‐fixed paraffin embedded (FFPE) biopsied tissue were analyzed by real time quantitative reverse transcriptase polymerase chain reaction (RT qPCR). Pretreatment evaluation was done with clinical examination and MRI pelvis. All patients received concurrent chemoradiotherapy followed by brachytherapy. Patients were evaluated for the clinical response after 3 months of treatment, with clinical examination and MRI pelvis scan using RECIST 1.1 criteria. Patients with no residual disease were classified as Complete responders (CR) and with residual or progressive disease were classified as Nonresponders (NR). Results were statistically analyzed using Mann Whiney U test to examine significant difference between the expression of microRNA between complete responders (CR) and nonresponders (NR). Results microRNA‐100 5p was upregulated in complete responders (CR) which showed a trend towards statistical significance (p value = 0.05). Conclusion microRNA‐100 5p can serve as a potential molecular biomarker in predicting clinical response to chemoradiation in locally advanced Carcinoma cervix. Its role should be further investigated in a larger study population.

BACKGROUND Several risk factors contribute to the inflammation promoting hepatocellular carcinoma (HCC) development, but the underlying mechanisms are unknown. Human endogenous retrovirus H long terminal repeat-associating 2 (HHLA2), a B7 family member, is highly expressed in various malignant tumor tissues and is related to tumor progression and metastasis. MATERIAL AND METHODS Bioinformatics analysis was used to analyze the gene expression chip GSE33006 of HCC tissue in the GEO database, draw a heat map of differentially expressed genes, and analyze the GO pathway of gene function annotation. Then, we compared HCC tissues with para-carcinoma liver tissues from 55 patients for expression patterns and associations with HHLA2. Effects of HHLA2 knockdown were examined in the human HCC cell line HepG2 to explore effects of HHLA2 on HepG2 cells. RESULTS A significantly higher expression of HHLA2 at the mRNA and protein levels was detected in HCC tissues than in para-carcinoma liver tissues, which was similar to HHLA2 expression in the GSE33006 data. A higher expression of HHLA2 protein was associated with advanced cancer stage, tumor differentiation, and invasion of adjacent structures. In vitro knockdown of HHLA2 expression significantly increased HepG2 cell adhesion, promoted cell apoptosis, induced cell cycle arrest in the G1/S phase, and inhibited cell proliferation, migration, and invasion. CONCLUSIONS Our data indicated there was a higher expression of HHLA2 in HCC tissues than in para-carcinoma liver tissues, and HHLA2 plays a major role in the development and progression of HCC. Owing to its higher expression, HHLA2 is a potential prognostic biomarker for HCC.

Long non-coding RNAs (lncRNAs) are a group of transcripts that have been considered essential participants in cancer pathogenesis and progression over the past few decades. Small nucleolar RNA host gene 8 (SNHG8) is a newly discovered lncRNA that belongs to the SNHG family, a group of transcripts that can be processed into small nucleolar RNAs and exert important biological functions. As an oncogenic factor, SNHG8 is upregulated in multiple cancer types. Herein, we summarize the biological role of SNHG8 in different cancer types and the underlying mechanisms related to the interaction between SNHG8 and microRNAs, mRNAs, and proteins. In addition, this study emphasizes the clinical value of SNHG8 in cancer, hoping to provide new insights into cancer diagnosis, prognosis, and treatment.

BACKGROUND This study was designed to explore the incompletely investigated role of the complement component 3a receptor 1 (C3AR1) in the prognosis of stomach adenocarcinomas (STAD). MATERIAL AND METHODS Using bioinformatic methods, we systematically determined the expression and prognosis value of C3AR1 in various cancers by using the TIMER (Tumor Immune Estimation Resource) database, UALCAN platform, GEPIA (Gene Expression Profiling Interactive Analysis) server, and the OncoLnc tool. The biological processes influenced by C3AR1 were determined using the GSEA (Gene Set Enrichment Analysis) software (Copyright 2004-2020 Broad Institute, Inc., Massachusetts Institute of Technology, and Regents of the University of California). The correlation between C3AR1 expression and the immune-infiltrating cells as well as the correlation analysis between C3AR1 expression and the corresponding immune-marker sets were conducted using the TIMER and GEPIA databases. RESULTS The expression of C3AR1 was significantly (P

BACKGROUND Natural killer (NK) cells are important for the prognosis of multiple cancers, but their prognostic value remains to be evaluated in patients with gastric cancer. Thus, this retrospective study was conducted at a single center to investigate the association between percentage of NK cells in the peripheral blood and prognosis in patients with gastric cancer. MATERIAL AND METHODS The data of 180 gastric cancer patients were collected. Univariate and multivariate Cox regression models were applied to screen candidate prognostic factors. A time-dependent receiver operating characteristic curve was employed to evaluate the ability of NK cells as a prognostic marker. Furthermore, we determined the correlation between the NK cells percentage and other parameters and their clinical significance. RESULTS Patients with a higher percentage of NK cells survived longer than those with a lower percentage of NK cells. Cox analysis revealed that NK cells could be used as an independent indicator for patients with gastric cancer. The percentage of NK cells was positively correlated with lymphocyte count and albumin, but was negatively correlated with CA125 and neutrophil-lymphocyte ratio. The area under the curve for NK cells in predicting the 5-year survival rate for gastric cancer was 0.792. This increased to 0.830 upon combining NK cells with neutrophil-lymphocyte ratio. Patients at early T, N, and clinical stages possessed a significantly higher percentage of NK cells compared to those at advanced T, N, and clinical stages of gastric cancer. CONCLUSIONS Our results suggest that a higher percentage of NK cells predicts is associated with longer survival of gastric cancer patients and could serve as an independent prognostic biomarker.