Metabolomic Signatures of Treatment Response in Bladder Cancer.

Bladder cancer (BC) stands as one of the most prevalent urological malignancies, with over 500 thousand newly diagnosed cases annually. Treatment decisions in BC depend on factors like the risk of recurrence, the type of tumor, and the stage of the disease. While standard therapeutic approaches encompass transurethral resection of the bladder tumor, radical cystectomy, and chemo- or immunotherapy, these methods exhibit limited efficacy in mitigating the aggressive and recurrent nature of bladder tumors. To overcome this challenge, it is crucial to develop innovative methods for monitoring and predicting treatment responses among patients with BC. Metabolomics is gaining recognition as a promising approach for discovering biomarkers. It has the potential to reveal metabolic disruptions that precisely reflect how BC patients respond to particular treatments, providing a revolutionary method to improve accuracy in monitoring and predicting outcomes. In this article, we present a comprehensive review of studies employing metabolomics approaches to investigate the metabolic responses associated with different treatment modalities for BC. The review encompasses an exploration of various models, samples, and analytical techniques applied in this context. Special emphasis is placed on the reported changes in metabolite levels derived from these studies, highlighting their potential as biomarkers for personalized medicine in BC.

Generative Deep Learning for Targeted Compound Design.

In the past few years, de novo molecular design has increasingly been using generative models from the emergent field of Deep Learning, proposing novel compounds that are likely to possess desired properties or activities. De novo molecular design finds applications in different fields ranging from drug discovery and materials sciences to biotechnology. A panoply of deep generative models, including architectures as Recurrent Neural Networks, Autoencoders, and Generative Adversarial Networks, can be trained on existing data sets and provide for the generation of novel compounds. Typically, the new compounds follow the same underlying statistical distributions of properties exhibited on the training data set Additionally, different optimization strategies, including transfer learning, Bayesian optimization, reinforcement learning, and conditional generation, can direct the generation process toward desired aims, regarding their biological activities, synthesis processes or chemical features. Given the recent emergence of these technologies and their relevance, this work presents a systematic and critical review on deep generative models and related optimization methods for targeted compound design, and their applications.

Brazilian Society of Surgical Oncology guidelines for surgical treatment of endometrial cancer in regions with limited resources.

BACKGROUND: Approximately 70% of cancer-related deaths occur in low- and middle-income countries. In addition to social and racial inequalities, treatment options in these countries are usually limited because of the lack of trained staff and equipment, limited patient access to health services, and a small number of clinical guidelines. OBJECTIVES: The Brazilian Society of Surgical Oncology developed this guideline to address these barriers and guide physicians treating patients with endometrial cancer (EC) in regions with limited resources and few specialized centers. METHODS: The guideline was prepared from 10 January to 25 October 20192019 by a multidisciplinary team of 56 experts to discuss the main obstacles faced by EC patients in Brazil. Thirteen questions considered critical to the surgical treatment of these patients were defined. The questions were assigned to groups that reviewed the literature and drafted preliminary recommendations. Following a review by the coordinators and a second review by all participants, the groups made final adjustments for presentations in meetings, classified the level of evidence, and voted on the recommendations. RESULTS: For all questions including staging, fertility spearing treatment, genetic testing, sentinel lymph node use, surgical treatment, and other clinical relevant questions, major agreement was achieved by the participants, always using accessible alternatives. CONCLUSIONS: It is possible to provide adequate treatment for most EC patients in resource-limited areas, but the first option should be referral to specialized centers with more resources.

Butterfly neural equalizer applied to optical communication systems with two-dimensional digital modulation.

This article aims to present, analyze and evaluate a new equalizer architecture, inspired by the butterfly equalizer used in optical communication, based on Artificial Neural Networks (ANN) of the Multi-Layer Perceptron (MLP) type for nonlinear systems with two-dimensional modulation named the Butterfly Neural Equalizer (NE-Butterfly). The NE-Butterfly is intended to equalize any channel that has real or complex taps, whether linear or nonlinear. Simulation results are presented for different types of nonlinear fiber optic channels with complex and real taps, also containing inter symbolic interference and additive noise. The results are compared with other neural equalizers in the literature with the objective of validating the performance of the NE-Butterfly, which stands out as having the overall best performance against the ones it was compared to.

Numerical tool for estimating the dielectric constant, the thickness, and the coverage of immobilized inhomogeneous protein films on gold in aqueous solution.

A numerical simulation tool is reported for nanometer thin and inhomogeneous immobilized protein films on gold in aqueous solution. It allows for the first time, to the best of our knowledge, the simultaneous assessment of refractive index, film thickness, and surface coverage. The model relies on and combines the convective diffusion equation, the Langmuir adsorption isotherm, and the Helmholtz equation, with appropriate boundary conditions. These three differential equations were jointly solved using a multiphysics software. The physical film parameters were extracted employing an optimization procedure for immobilized bovine serum albumin, hemoglobin, and neutravidin films. The relatively good agreement between the extracted values for the refractive index, film thickness, and surface coverage and the corresponding values reported in the open literature show the correctness of the proposed methodology.

Adaptive Beamforming Applied to OFDM Systems.

This work proposes an adaptive beamforming scheme applied to time domain, pre-FFT (Fast Fourier Transformation), Orthogonal Frequency-Division Multiplexing (OFDM) systems. This scheme improves the performance and the capacity of OFDM systems, using a supervised adaptive algorithm, with frequency domain multiplexed pilots of the OFDM system as a reference. The simplicity of the proposed structure, as well as the method used to obtain reference signals for the adaptive beamforming, are essential aspects that distinguish this paper from other publications. Details on the operation of the proposed scheme, as well as the performance curves, are presented in this manuscript. The proposal investigated here allows a significant reduction in the guard interval of the OFDM system, thereby increasing its robustness or transmission capacity.

Reliability and validity of the Portuguese version of the Generalized Anxiety Disorder (GAD-7) scale.

BACKGROUND: Generalized anxiety disorder has a strong impact on health-related quality of life. For this reason, it seems relevant to develop strategies allowing early diagnoses in order to promote appropriate treatments. The objective of this study was to culturally adapt and validate the GAD-7 for the Portuguese patients with generalized anxiety disorder. METHODS: For the cultural adaptation of the Portuguese version of the GAD-7 scale we started with a previous translation made by Mapi Institute and decided to perform a clinical review followed by a cognitive debriefing with patients. Once piloted, this version was then tested in a larger sample for feasibility and reliability (1-week test-retest). Construct validity was assessed by the relationship between GAD-7 and socio-demographic and clinical variables. Its unidimensionality was tested by principal component factor analysis. Criterion validity was assessed by comparing GAD-7 scores with those obtained by HADS, and EQ-5D. STAI was mainly used as a screening indicator for patient inclusion. RESULTS: GAD-7 was considered feasible with a mean completion time of 2.3 minutes and no major floor or ceiling effects. We found an excellent Cronbach's alpha internal consistency score (0.880) and the test-retest and interclass correlation coefficients were also very good. Regarding the construct validity, younger patients, those with higher education, employed and without anxiety symptoms revealed lower GAD-7 scores, meaning better health. The unidimensionality of GAD-7 index was also confirmed by principal component factor analysis. At last, GAD-7 was significantly correlated with other health outcome indices and the classification levels created by it and by HADS showed to be dependent. CONCLUSION: The excellent metric properties confirmed the cultural adaptation and validity of GAD-7 into Portuguese population, allowing the clinicians an early detection and treatment of these patients.

Vortex-assisted liquid-liquid micro-extraction and high-performance liquid chromatography for a higher sensitivity methyl methacrylate determination in biological matrices.

A vortex-assisted liquid-liquid micro-extraction coupled with high-performance liquid chromatography, with UV-vis, is proposed to pre-concentrate methyl methacrylate and to improve separation in biological matrices. The use of 1-octanol as extracting phase, its volume, the need for a dispersant agent, the agitation conditions and the cooling time before phase separation were evaluated. In optimum conditions, enrichment factors of 20 (±0.5) and enrichment recovery of 99% were obtained. The straightforward association of this extraction process with the HPLC method, previously regulated by the International Organization for Standardization, afforded a detection limit of 122 ng/mL and a quantification limit of 370 ng/mL. The within-batch precision, relative standard deviation, was 3% for a sample with 1.49 µg/mL and 4% for a sample with 13.4 µg/mL. The results showed a between batch-precision of 21% for experiments performed on five different days, for a sample with a concentration of 1.10 µg/mL in methyl methacrylate.

Females Present Reduced Minimum Toe Clearance During Walking As Compared to Males in Active Older Adults.

BACKGROUND: Physical decline due to aging has been associated with the risk of falls. Minimum toe clearance (MTC) is a gait parameter that might play a role in the mechanism of tripping and falling. However, it is unclear if there are any sex-related effects regarding MTC as people age. The present study investigated if there are sex-related differences in MTC in older active adults. METHODS: Twenty-three females and 23 males (F: 65.5 ±â€…4.8 years; M: 61.9 ±â€…5.2 years) walked on a treadmill at a preferred walking speed, while kinematic data were obtained at a sampling frequency of 100 Hz and up-sampled to 120 and 240 Hz. MTC was calculated from the kinematics data and evaluated concerning its magnitude (ie, MTC and MTC/leg length), the time between left/right MTC (ie, T-MTC), amount of variability (ie, coefficient of variation [CV] and coefficient of variation modified [CVm]), and temporal structure of variability, that is, the complexity of the time series (ie, MTC α, T-MTC α). RESULTS: No sex effects were found for MTC/leg length, for the amount of variability (ie, CV and CVm), and for the complexity of the time series (MTC α, T-MTC α). However, females exhibited significantly lower MTC and T-MTC after adjusting for walking speed, mass, and age as covariates. CONCLUSIONS: The reduced MTC in females suggests a potential sex-related disparity in the risk of tripping and falling among active older adults.

Identification of SNP Markers and Candidate Genes Associated with Major Agronomic Traits in Coffea arabica.

Genome-wide association studies (GWASs) allow for inferences about the relationships between genomic variants and phenotypic traits in natural or breeding populations. However, few have used this methodology in Coffea arabica. We aimed to identify chromosomal regions with significant associations between SNP markers and agronomic traits in C. arabica. We used a coffee panel consisting of 195 plants derived from 13 families in F2 generations and backcrosses of crosses between leaf rust-susceptible and -resistant genotypes. The plants were phenotyped for 18 agronomic markers and genotyped for 21,211 SNP markers. A GWAS enabled the identification of 110 SNPs with significant associations (p < 0.05) for several agronomic traits in C. arabica: plant height, plagiotropic branch length, number of vegetative nodes, canopy diameter, fruit size, cercosporiosis incidence, and rust incidence. The effects of each SNP marker associated with the traits were analyzed, such that they can be used for molecular marker-assisted selection. For the first time, a GWAS was used for these important agronomic traits in C. arabica, enabling applications in accelerated coffee breeding through marker-assisted selection and ensuring greater efficiency and time reduction. Furthermore, our findings provide preliminary knowledge to further confirm the genomic loci and potential candidate genes contributing to various structural and disease-related traits of C. arabica.

Current Advances in Mitochondrial Targeted Interventions in Alzheimer's Disease.

Alzheimer's disease is the most prevalent neurodegenerative disorder and affects the lives not only of those who are diagnosed but also of their caregivers. Despite the enormous social, economic and political burden, AD remains a disease without an effective treatment and with several failed attempts to modify the disease course. The fact that AD clinical diagnosis is most often performed at a stage at which the underlying pathological events are in an advanced and conceivably irremediable state strongly hampers treatment attempts. This raises the awareness of the need to identify and characterize the early brain changes in AD, in order to identify possible novel therapeutic targets to circumvent AD's cascade of events. One of the most auspicious targets is mitochondria, powerful organelles found in nearly all cells of the body. A vast body of literature has shown that mitochondria from AD patients and model organisms of the disease differ from their non-AD counterparts. In view of this evidence, preserving and/or restoring mitochondria's health and function can represent the primary means to achieve advances to tackle AD. In this review, we will briefly assess and summarize the previous and latest evidence of mitochondria dysfunction in AD. A particular focus will be given to the recent updates and advances in the strategy options aimed to target faulty mitochondria in AD.

Dual-energy Computed Tomographic Pulmonary Angiography Accurately Estimates Lobar Perfusion Before Lung Volume Reduction for Severe Emphysema.

PURPOSE: To assess if dual-energy computed tomographic pulmonary angiography (DECTPA) derived lobar iodine quantification can provide an accurate estimate of lobar perfusion in patients with severe emphysema, and offer an adjunct to single-photon emission CT perfusion scintigraphy (SPECT-PS) in assessing suitability for lung volume reduction (LVR). MATERIALS AND METHODS: Patients with severe emphysema (forced expiratory volume in 1 s <49% predicted) undergoing evaluation for LVR between May 2018 and April 2020 imaged with both SPECT-PS and DECTPA were included in this retrospective study. DECTPA perfused blood volume maps were automatically segmented and lobar iodine mass was estimated and compared with lobar technetium (Tc99m) distribution acquired with SPECT-PS. Pearson correlation and Bland-Altman analysis were used for intermodality comparison between DECTPA and SPECT-PS. Univariate and adjusted multivariate linear regression were modelled to ascertain the effect sizes of possible confounders of disease severity, sex, age, and body mass index on the relationship between lobar iodine and Tc99m values. Effective radiation dose and adverse reactions were recorded. RESULTS: In all, 123 patients (64.5±8.8 y, 71 men; mean predicted forced expiratory volume in 1 s 32.1 ±12.7%,) were eligible for inclusion. There was a linear relationship between lobar perfusion values acquired using DECTPA and SPECT-PS with statistical significance ( P <0.001). Lobar relative perfusion values acquired using DECTPA and SPECT-PS had a consistent relationship both by linear regression and Bland-Altman analysis (mean bias, -0.01, mean r2 0.64; P <0.0001). Individual lobar comparisons demonstrated moderate correlation ( r =0.79, 0.78, 0.84, 0.78, 0.8 for the right upper, middle, lower, left upper, and lower lobes, respectively, P <0.0001). The relationship between lobar iodine and Tc99m values was not significantly altered after controlling for confounders including symptom and disease severity, age, sex, and body mass index. CONCLUSIONS: DECTPA provides an accurate estimation of lobar perfusion, showing good agreement with SPECT-PS and could potentially streamline preoperative assessment for LVR.

Influence of Tactical and Situational Variables on Offensive Sequences During Elite European Handball Matches.

The main objective of this study was to analyze the influence of tactical and situational variables on offensive sequences during elite European handball matches. A sample of 55 games and 5.857 offensive sequences from the European Handball Federation Champions League, the selected teams were classified as the top eight teams in the league, were analyzed using X 2 and logistic regression analyses. Results indicated that positional attacks [odds ratio (OR) = 0.34; 95% CI: 0.28-0.42; p < 0.001] and fast attacks (OR = 0.46; 95% CI: 0.36-0.57; p < 0.001) decreased the probability of success for an offensive sequence by 66% and 54% when compared with counterattacks. Offensive sequences that start in the attacking zone seem to be less effective (~78%) than those that start from a situation of "ball in center." Additionally, offensive sequences that finished in the defensive zone of the observed team were 3.19 times more effective than those that ended before the 9 m zone. We concluded that compared with offensive sequences where the shot is performed from the 9 m zone, the chances of an offensive sequence ending successfully are 3.65, 3.60, and 2.21 times higher, for offensive sequences where the shot is performed from 9 m, 6 m, and the defensive zone, respectively. On the other hand, many variables seem to impact the performance of handball teams. Nevertheless, a significant challenge remains, and more research needs to be conducted to analyze the obstacles that teams need to overcome while attacking in the most effective way possible.

Pioneering evaluation of GaN transistors in geostationary satellites.

In this paper, we present the results of a 6-year experiment in space that studied the effects of radiation in Gallium Nitride (GaN) electronics in geostationary orbit. Four GaN transistors in a Colpitts oscillator configuration were flown in the Component Technology Test-Bed aboard the Alphasat telecommunication satellite. A heuristic analysis was performed by observing the variation in the power output of the oscillators with the total ionizing dose gathered during the mission. The total ionizing dose was measured with a Radiation Sensing Field Effect Transistors (RadFET) placed close to the GaN devices. The experiment showed that GaN is a robust technology that can be used in the space radiation environment of a geostationary orbit. The work presented here starts with a brief introduction of the subject, the motivation, and the main goal. This is followed by the description of the experimental setup, including the details of the oscillator design and simulations, as well as the implementation of the test-bed and the Components Technology Test-Bed. Finally, the results obtained during the 6 years of experience in space are discussed.

Designing the best breeding strategy for Coffea canephora: Genetic evaluation of pure and hybrid individuals aiming to select for productivity and disease resistance traits.

Breeding programs of the species Coffea canephora rely heavily on the significant genetic variability between and within its two varietal groups (conilon and robusta). The use of hybrid families and individuals has been less common. The objectives of this study were to evaluate parents and families from the populations of conilon, robusta, and its hybrids and to define the best breeding and selection strategies for productivity and disease resistance traits. As such, 71 conilon clones, 56 robusta clones, and 20 hybrid families were evaluated over several years for the following traits: vegetative vigor, incidence of rust and cercosporiosis, fruit ripening time, fruit size, plant height, canopy diameter, and yield per plant. Components of variance and genetic parameters were estimated via residual maximum likelihood (REML) and genotypic values were predicted via best linear unbiased prediction (BLUP). Genetic variability among parents (clones) and hybrid families was detected for most of the evaluated traits. The Mulamba-Rank index suggests potential gains up to 17% for the genotypic aggregate of traits in the hybrid population. An intrapopulation recurrent selection within the hybrid population would be the best breeding strategy because the genetic variability, narrow and broad senses heritabilities and selective accuracies for important traits were maximized in the crossed population. Besides, such strategy is simple, low cost and quicker than the concurrent reciprocal recurrent selection in the two parental populations, and this maximizes the genetic gain for unit of time.

Gingival crevicular fluid levels of MMP-8, MMP-9, TIMP-2, and MPO decrease after periodontal therapy.

BACKGROUND: This study aimed at comparing the levels of matrix metalloproteinase (MMP)-8, tissue Inhibitor of MMPs (TIMP)-1 and TIMP-2, Myeloperoxidase (MPO), and MMP-9 in the gingival crevicular fluid (GCF) of chronic periodontitis (CP) patients and controls at baseline and 3 months after non-surgical therapy. MATERIALS AND METHODS: GCF was collected from one site of 15 control subjects and 27 CP patients. MMP-8, MMP-9, TIMP-1, and TIMP-2 were determined by Enzyme-linked immunoabsorbent assay; different forms of MMP-9, by gelatin zymography; and MPO, colorimetrically. RESULTS: At baseline, higher levels of MMP-8, TIMP-2, MPO, and the 87 kDa-MMP-9 were found in patients compared with controls (p<0.001), and these molecules decreased after therapy (p<0.03). There were no differences between the groups with respect to the higher molecular forms of MMP-9 (180, 130, 92 kDa) or total MMP-9 at baseline. No differences were observed in TIMP-1 levels. In controls, decreased levels of TIMP-2 and the higher molecular forms of MMP-9 (180, 130, 92 kDa) were found 3 months after therapy compared with baseline (p<0.01). CONCLUSIONS: Higher levels of MMP-8, TIMP-2, MPO, and 87 kDa MMP-9 were found in the GCF of patients compared with controls, and these markers decreased 3 months after periodontal therapy.

Comparative Analysis of the Offensive Effectiveness in Winner and Losing Handball Teams.

The purpose of this study was to determine differences related to the offensive process between winning and losing teams among teams participating in the European Handball Federation Champions League (EHFCL) in 55 matches across five seasons. The key indicators used in this study are the offensive actions, team possession type and the zones of the field, goals, and shooting effectiveness. A total of 34 indicators were analyzed and compared using Mann-Whitney U tests. Sixteen key indicators are identified to confirm differences both from the aspect of the collective game in terms of assists (9.10 ± 2.75 vs. 7.29 ± 2.65), goals of positional attack (21.38 ± 4.60 vs. 18.20 ± 3.62) and from the aspect of individual goals from 6 m (16.67 ± 3.98 vs. 13.64 ± 3.70), and the effectiveness of shots (68.19 ± 6.83 vs. 59.41 ± 6.33). Winning teams performed better regarding the variables that defined the effectiveness of offensive shots, especially successful positioned attacks and fast attacks. They also had a greater number of assists. The profiles of the most successful teams can help coaches and practitioners to achieve better performances adjusting the training process according the performance indicators that seem to lead more often to success.

Seaweed-Based Products and Mushroom ß-Glucan as Tomato Plant Immunological Inducers.

The effects of the abiotic inducers ß-glucan, extracted from Shiitake (Lentinula edodes), BFIICaB® (Kappaphycus alvarezii) and BKPSGII® (K. alvarezii X Sargassum sp.) on tomato plants infected with Fusarium oxysporum f. sp. lycopersici (FOL) were evaluated through the activity of enzymes related to the induction of resistance at 5 and 10 days after inoculation (DAI). Tomato plants (21 days old, after germination) were inoculated with the pathogen conidia suspension and sprayed with 0.3% aqueous solutions of the inducers. The activities of the enzymes ß-1,3-glucanase, peroxidase and phenylalanine ammonia lyase (PAL) were evaluated in fresh tomato leaves collected at 5 and 10 DAI. In all treatments, peroxidase showed the highest enzymatic activity, followed by ß-1,3-glucanase and PAL. Between the seaweeds, the inducers extracted from the red alga Kappaphycus alvarezii (BFIICaB®) promoted the highest enzymatic activity. The exception was BKPSGII® (K. alvarezii X Sargassum sp.) where the influence of Sargassum sp. resulted in higher peroxidase activity (4.48 Δab600 mg P-1 min-1) in the leaves, 10 DAI. Both the red seaweed K. alvarezii and the brown alga Sargassum sp. promoted activities of ß-1,3-glucanase, peroxidase and PAL.

The gastrointestinal microbiota as a site for the biotransformation of drugs.

There are 100 trillion microbes in the human gastrointestinal tract with numbers increasing distally. These microbiota secrete a diverse array of enzymes (primarily for carbohydrate and protein fermentation) giving them substantial metabolic potential which can have major implications for drug stability. At least thirty drugs which are, or have been, available commercially, were subsequently shown to be substrates for these bacterial enzymes, and with increasing numbers of new and existing drugs having the potential for contact with the distal gut (through modified release systems or poor solubility/permeability), many more are expected to be discovered. The major concern with bacterial drug degradation is the behaviour of the metabolite; is it more or less active than the parent compound, or has toxicity resulted? For example, there were eighteen deaths in 1993 due to a drug interaction in which a toxic drug metabolite was produced by bacterial fermentation. Thus, the objective of this review is the provision of a comprehensive overview of this area; the gastrointestinal microbiota, their drug substrates and metabolic mechanisms, and approaches to studying this further are discussed.

Early Selection Enabled by the Implementation of Genomic Selection in Coffea arabica Breeding.

Genomic Selection (GS) has allowed the maximization of genetic gains per unit time in several annual and perennial plant species. However, no GS studies have addressed Coffea arabica, the most economically important species of the genus Coffea. Therefore, this study aimed (i) to evaluate the applicability and accuracy of GS in the prediction of the genomic estimated breeding value (GEBV); (ii) to estimate the genetic parameters; and (iii) to evaluate the time reduction of the selection cycle by GS in Arabica coffee breeding. A total of 195 Arabica coffee individuals, belonging to 13 families in generation of F2, susceptible backcross and resistant backcross, were phenotyped for 18 agronomic traits, and genotyped with 21,211 SNP molecular markers. Phenotypic data, measured in 2014, 2015, and 2016, were analyzed by mixed models. GS analyses were performed by the G-BLUP method, using the RKHS (Reproducing Kernel Hilbert Spaces) procedure, with a Bayesian algorithm. Heritabilities and selective accuracies were estimated, revealing moderate to high magnitude for most of the traits evaluated. Results of GS analyses showed the possibility of reducing the cycle time by 50%, maximizing selection gains per unit time. The effect of marker density on GS analyses was evaluated. Genomic selection proved to be promising for C. arabica breeding. The agronomic traits presented high complexity for they are controlled by several QTL and showed low genomic heritabilities, evidencing the need to incorporate genomic selection methodologies to the breeding programs of this species.