Next-generation chemotherapy treatments based on black hole algorithms: From cancer remission to chronic disease management.

PROBLEM: Therapeutic planning strategies have been developed to enhance the effectiveness of cancer drugs. Nevertheless, their performance is highly limited by the inefficient biological representativeness of predictive tumor growth models, which hinders their translation to clinical practice. OBJECTIVE: This study proposes a disruptive approach to oncology based on nature-inspired control using realistic Black Hole physical laws, in which tumor masses are trapped to experience attraction dynamics on their path to complete remission or to become a chronic disease. This control method is designed to operate independently of individual patient idiosyncrasies, including high tumor heterogeneities and highly uncertain tumor dynamics, making it a promising avenue for advancing beyond the limitations of the traditional survival probabilistic paradigm. DESIGN: Here, we provide a multifaceted study of chemotherapy therapeutic planning that includes: (1) the design of a pioneering controller algorithm based on physical laws found in the Black Holes; (2) investigation of the ability of this controller algorithm to ensure stable equilibrium treatments; and (3) simulation tests concerning tumor volume dynamics using drugs with significantly different pharmacokinetics (Cyclophosphamide and Atezolizumab), tumor volumes (200 mm3 and 12 732 mm3) and modeling characterizations (Gompertzian and Logistic tumor growth models). RESULTS: Our results highlight the ability of this new astrophysical-inspired control algorithm to perform effective chemotherapy treatments for multiple tumor-treatment scenarios, including tumor resistance to chemotherapy, clinical scenarios modelled by time-dependent parameters, and highly uncertain tumor dynamics. CONCLUSIONS: Our findings provide strong evidence that cancer therapy inspired by phenomena found in black holes can emerge as a disruptive paradigm. This opens new high-impacting research directions, exploring synergies between astrophysical-inspired control algorithms and Artificial Intelligence applied to advanced personalized cancer therapeutics.

Universe-inspired algorithms for control engineering: A review.

Control algorithms have been proposed based on knowledge related to nature-inspired mechanisms, including those based on the behavior of living beings. This paper presents a review focused on major breakthroughs carried out in the scope of applied control inspired by the gravitational attraction between bodies. A control approach focused on Artificial Potential Fields was identified, as well as four optimization metaheuristics: Gravitational Search Algorithm, Black-Hole algorithm, Multi-Verse Optimizer, and Galactic Swarm Optimization. A thorough analysis of ninety-one relevant papers was carried out to highlight their performance and to identify the gravitational and attraction foundations, as well as the universe laws supporting them. Included are their standard formulations, as well as their improved, modified, hybrid, cascade, fuzzy, chaotic and adaptive versions. Moreover, this review also deeply delves into the impact of universe-inspired algorithms on control problems of dynamic systems, providing an extensive list of control-related applications, and their inherent advantages and limitations. Strong evidence suggests that gravitation-inspired and black-hole dynamic-driven algorithms can outperform other well-known algorithms in control engineering, even though they have not been designed according to realistic astrophysical phenomena and formulated according to astrophysics laws. Even so, they support future research directions towards the development of high-sophisticated control laws inspired by Newtonian/Einsteinian physics, such that effective control-astrophysics bridges can be established and applied in a wide range of applications.

Relationship between knee extensor and flexor muscle strength and age in professional volleyball players.

We aimed to analyse the relationship of peak torque (PT) of the knee extensors (Ext) and flexors (Fle) with age, and the relationship between conventional ratio and age progression in volleyball players. A total of 41 elite male volleyball players (age: 25.0 ± 6.1 years, body mass: 93.0 ± 9.8 kg, height: 198.0 ± 6.8 cm) were evaluated in a isokinetic dynamometer at speeds of 60, 180 and 300 deg/s, and at dominant (D) and non-dominant (ND) legs. In general, the knee flexor and extensor muscles varied greatly among the athletes (from 81 to 156 N.m for flexors; from 116 to 250 N.m for extensors at 300 deg/s and at dominant side). The mass-specific PT of knee extensors showed strong and negative correlation with ageing at 60 and 180 deg/s (r = -0.52-0.62, p < 0.01). The conventional ratio showed regular and positive relationship at all evaluated velocities (60°.s-1, r = 0.453, p < 0.01; 180°.s-1, r = 0.498, p < 0.01; 300°.s-1, r = 0.316, p = 0.04). The results demonstrated that volleyball players are susceptible to age-related effects on muscular performance during their career; this finding illustrates the importance of adopting training strategies to improve the production of strength in the lower limbs, which is essential for vertical jumps.

Bioelectronic multifunctional bone implants: recent trends.

The concept of Instrumented Smart Implant emerged as a leading research topic that aims to revolutionize the field of orthopaedic implantology. These implants have been designed incorporating biophysical therapeutic actuation, bone-implant interface sensing, implant-clinician communication and self-powering ability. The ultimate goal is to implement revist interface, controlled by clinicians/surgeons without troubling the quotidian activities of patients. Developing such high-performance technologies is of utmost importance, as bone replacements are among the most performed surgeries worldwide and implant failure rates can still exceed 10%. In this review paper, an overview to the major breakthroughs carried out in the scope of multifunctional smart bone implants is provided. One can conclude that many challenges must be overcome to successfully develop them as revision-free implants, but their many strengths highlight a huge potential to effectively establish a new generation of high-sophisticated biodevices.

Modelling 5-km Running Performance on Level and Hilly Terrains in Recreational Runners.

Incline and level running on treadmills have been extensively studied due to their different cardiorespiratory and biomechanical acute responses. However, there are no studies examining the performance determinants of outdoor running on hilly terrains. We aimed to investigate the influence of anthropometrics, muscle strength, and cardiorespiratory and gait spatiotemporal parameters during level (0%) and inclined (+7%) running on performance in level and hilly 5-km races. Twenty male recreational runners completed two 5-km outdoor running tests (0% vs. +7% and −7%), and two submaximal (10 km·h−1) and incremental treadmill tests at 0 and 7% slopes, after complete laboratory evaluations. The velocity at maximal oxygen consumption (VO2max) evaluated at 7% incline and level treadmill running were the best performance predictors under both hilly (R2 = 0.72; p < 0.05) and level (R2 = 0.85; p < 0.01) conditions, respectively. Inclusion of ventilatory and submaximal heart rate data improved the predictive models up to 100%. Conversely, none of the parameters evaluated in one condition contributed to the other condition. The spatiotemporal parameters and the runners' strength levels were not associated to outdoor performances. These results indicate that the vVO2max evaluated at similar slopes in the lab can be used to predict 5-km running performances on both level and hilly terrains.

Towards an effective sensing technology to monitor micro-scale interface loosening of bioelectronic implants.

Instrumented implants are being developed with a radically innovative design to significantly reduce revision surgeries. Although bone replacements are among the most prevalent surgeries performed worldwide, implant failure rate usually surpasses 10%. High sophisticated multifunctional bioelectronic implants are being researched to incorporate cosurface capacitive architectures with ability to deliver personalized electric stimuli to peri-implant target tissues. However, the ability of these architectures to detect bone-implant interface states has never been explored. Moreover, although more than forty technologies were already proposed to detect implant loosening, none is able to ensure effective monitoring of the bone-implant debonding, mainly during the early stages of loosening. This work shows, for the first time, that cosurface capacitive sensors are a promising technology to provide an effective monitoring of bone-implant interfaces during the daily living of patients. Indeed, in vitro experimental tests and simulation with computational models highlight that both striped and circular capacitive architectures are able to detect micro-scale and macro-scale interface bonding, debonding or loosening, mainly when bonding is weakening or loosening is occurring. The proposed cosurface technologies hold potential to implement highly effective and personalized sensing systems such that the performance of multifunctional bioelectronic implants can be strongly improved. Findings were reported open a new research line on sensing technologies for bioelectronic implants, which may conduct to great impacts in the coming years.

NEOTROPICAL CARNIVORES: a data set on carnivore distribution in the Neotropics.

Mammalian carnivores are considered a key group in maintaining ecological health and can indicate potential ecological integrity in landscapes where they occur. Carnivores also hold high conservation value and their habitat requirements can guide management and conservation plans. The order Carnivora has 84 species from 8 families in the Neotropical region: Canidae; Felidae; Mephitidae; Mustelidae; Otariidae; Phocidae; Procyonidae; and Ursidae. Herein, we include published and unpublished data on native terrestrial Neotropical carnivores (Canidae; Felidae; Mephitidae; Mustelidae; Procyonidae; and Ursidae). NEOTROPICAL CARNIVORES is a publicly available data set that includes 99,605 data entries from 35,511 unique georeferenced coordinates. Detection/non-detection and quantitative data were obtained from 1818 to 2018 by researchers, governmental agencies, non-governmental organizations, and private consultants. Data were collected using several methods including camera trapping, museum collections, roadkill, line transect, and opportunistic records. Literature (peer-reviewed and grey literature) from Portuguese, Spanish and English were incorporated in this compilation. Most of the data set consists of detection data entries (n = 79,343; 79.7%) but also includes non-detection data (n = 20,262; 20.3%). Of those, 43.3% also include count data (n = 43,151). The information available in NEOTROPICAL CARNIVORES will contribute to macroecological, ecological, and conservation questions in multiple spatio-temporal perspectives. As carnivores play key roles in trophic interactions, a better understanding of their distribution and habitat requirements are essential to establish conservation management plans and safeguard the future ecological health of Neotropical ecosystems. Our data paper, combined with other large-scale data sets, has great potential to clarify species distribution and related ecological processes within the Neotropics. There are no copyright restrictions and no restriction for using data from this data paper, as long as the data paper is cited as the source of the information used. We also request that users inform us of how they intend to use the data.

Altering the Course of Technologies to Monitor Loosening States of Endoprosthetic Implants.

Musculoskeletal disorders are becoming an ever-growing societal burden and, as a result, millions of bone replacements surgeries are performed per year worldwide. Despite total joint replacements being recognized among the most successful surgeries of the last century, implant failure rates exceeding 10% are still reported. These numbers highlight the necessity of technologies to provide an accurate monitoring of the bone-implant interface state. This study provides a detailed review of the most relevant methodologies and technologies already proposed to monitor the loosening states of endoprosthetic implants, as well as their performance and experimental validation. A total of forty-two papers describing both intracorporeal and extracorporeal technologies for cemented or cementless fixation were thoroughly analyzed. Thirty-eight technologies were identified, which are categorized into five methodologies: vibrometric, acoustic, bioelectric impedance, magnetic induction, and strain. Research efforts were mainly focused on vibrometric and acoustic technologies. Differently, approaches based on bioelectric impedance, magnetic induction and strain have been less explored. Although most technologies are noninvasive and are able to monitor different loosening stages of endoprosthetic implants, they are not able to provide effective monitoring during daily living of patients.

Novel magnetic stimulation methodology for low-current implantable medical devices.

Recent studies highlight the ability of inductive architectures to deliver therapeutic magnetic stimuli to target tissues and to be embedded into small-scale intracorporeal medical devices. However, to date, current micro-scale biomagnetic devices require very high electric current excitations (usually exceeding 1 A) to ensure the delivery of efficient magnetic flux densities. This is a critical problem as advanced implantable devices demand self-powering, stand-alone and long-term operation. This work provides, for the first time, a novel small-scale magnetic stimulation system that requires up to 50-fold lower electric current excitations than required by relevant biomagnetic technology recently proposed. Computational models were developed to analyse the magnetic stimuli distributions and densities delivered to cellular tissues during in vitro experiments, such that the feasibility of this novel stimulator can be firstly evaluated on cell culture tests. The results demonstrate that this new stimulative technology is able to deliver osteogenic stimuli (0.1-7 mT range) by current excitations in the 0.06-4.3 mA range. Moreover, it allows coil designs with heights lower than 1 mm without significant loss of magnetic stimuli capability. Finally, suitable core diameters and stimulator-stimulator distances allow to define heterogeneity or quasi-homogeneity stimuli distributions. These results support the design of high-sophisticated biomagnetic devices for a wide range of therapeutic applications.

Capacitive technologies for highly controlled and personalized electrical stimulation by implantable biomedical systems.

Cosurface electrode architectures are able to deliver personalized electric stimuli to target tissues. As such, this technology holds potential for a variety of innovative biomedical devices. However, to date, no detailed analyses have been conducted to evaluate the impact of stimulator architecture and geometry on stimuli features. This work characterizes, for the first time, the electric stimuli delivered to bone cellular tissues during in vitro experiments, when using three capacitive architectures: stripped, interdigitated and circular patterns. Computational models are presented that predict the influence of cell confluence, cosurface architecture, electrodes geometry, gap size between electrodes and power excitation on the stimuli delivered to cellular layers. The results demonstrate that these stimulators are able to deliver osteoconductive stimuli. Significant differences in stimuli distributions were observed for different stimulator designs and different external excitations. The thickness specification was found to be of utmost importance. In vitro experiments using an osteoblastic cell line highlight that cosurface stimulation at a low frequency can enhance osteoconductive responses, with some electrode-specific differences being found. A major feature of this type of work is that it enables future detailed analyses of stimuli distribution throughout more complex biological structures, such as tissues and organs, towards sophisticated biodevice personalization.

Tempo de provas curtas e volume de treinamento como preditores do desempenho de maratona / Short-time race time and training volume as predictors of Marathon performance / Tiempo de pruebas cortas y volumen de entrenamiento como predictores del rendimiento de Maratón

Resumo Além das determinantes fisiológicas, o desempenho em maratonas é influenciado por características antropométricas, de treinamento e de experiência dos atletas. O objetivo do estudo foi investigar a associação desses fatores com o desempenho de maratonistas brasileiros. Um questionário foi aplicado nos dois dias anteriores à Maratona Internacional de Porto Alegre. Dentre os achados, os atletas de menor índice de massa corporal foram mais rápidos e o desempenho em provas de 5 e 21 km apresentou correlações altas com o desempenho (r = 0,76 e r = 0,81, p < 0,01). Isso sugere que corredores mais rápidos na maratona são mais rápidos em provas de distâncias menores. Além disso, índices como experiência anterior e distância dos treinos longos não foram bons preditores do desempenho para maratona.

Abstract Not only physiological variables, but anthropometric, training and experience characteristics influence marathon performance. The aim of this study was to investigate the correlation of those factors on Brazilian marathoners performance. A questionnaire was applied in the two days prior to the International Porto Alegre Marathon. Mainly, athletes with lower body mass index were faster on the race, and performance at 5 km and 21 km have high correlations with marathon performance (r=0.76 and r=0.81, p<0.01), suggesting that the fastest runners in the marathon are faster over shorter distances. In addition, indices like previous experience and long session distances were not good performance predictors for marathoners.

Resumen Además de los determinantes fisiológicos, el rendimiento en maratones está influenciado por las características antropométricas, el entrenamiento y la experiencia de los atletas. El objetivo del estudio fue investigar la asociación de estos factores con el rendimiento de los corredores de maratón brasileños. Se aplicó un cuestionario en los dos días antes de la Maratón Internacional de Porto Alegre. Entre los hallazgos, los atletas con menor índice de masa corporal fueron más rápidos, y el rendimiento en las pruebas de 5 y 21 km están altamente correlacionados con el rendimiento (r = 0,76 yr = 0,81, p <0,01), lo que sugiere que los corredores más rápidos en la maratón son más rápidos en pruebas de distancias más cortas. Además, los índices tales como la experiencia previa y la distancia de entrenamientos largos no fueron buenos indicadores de rendimiento para la maratón.

Ulnar Lengthening/Reconstruction of Interosseous Membrane in Treatment of Osteochondroma.

BACKGROUND: We aim to measure the quality of life and clinical and functional outcomes of a patient who had undergone ligament reconstruction of the forearm interosseous membrane, using brachioradialis tendon more ulna distraction osteogenesis in treatment with multiple cartilaginous exostosis. CASE DESCRIPTION: We present a 11-year-old boy with congenital deformity in his right, dominant forearm,Type IIb by Masada classification. Distraction of the ulna, resection of exostosis, and reconstruction of the distal part of the interosseous membrane was performed. One year later, the patient experienced good evaluation. Wrist flexion was 70 degrees, extension was 60 degrees, radial deviation was 20 degrees, and ulnar deviation was 30 degrees. Forearm pronation was 60 degrees and supination was 90 degrees. Elbow flexion was 120 degrees, extension was -5 degrees, and digit motion was full. DASH score of 5, VAS of 0, and grip strength of 92% compared to the unaffected side were obtained. Forearm radiographic aspects showed healing of the distraction, articular congruency, the distal radioulnar joint (DRUJ), and radiocapitellum joint. The distraction distance was 28 mm, the distraction period was 67 days, the consolidation period was 96 days, and the period of fixator treatment was 92 days. The distraction speed was 0.5 mm/day. Good stability and joint congruency of the DRUJ and elbow were obtained. Good radiographic, clinical, and functional results were obtained improving the life quality of that patient. LITERATURE REVIEW: The treatment of forearm deformities is difficult and complicated. There is no consensus to the overall management. As there is still a lack of long-term results, the indications for surgery, various surgical options, and the timing of the intervention have been a matter of controversy in the literature. Would DRUJ be stable when ulnar lengthening is combined with excision of exostosis? Is it possible to reduce the radial head with this technique? CLINICAL RELEVANCE: We would like to suggest an interosseous membrane (distal oblique band) reconstruction to improve this treatment. We believe this suggestion could maintain DRUJ and elbow more stable and functional. We agree that the best time to perform the corrections is early and gradually. We prefer to correct the ulna, radius, DRUJ and elbow in many steps than in only one procedure.

The biochemical characterization of two phosphate transport systems in Phytomonas serpens.

Inorganic phosphate (Pi) is an essential nutrient for all organisms because it is required for a variety of biochemical processes, such as signal transduction and the synthesis of phosphate-containing biomolecules. Assays of 32Pi uptake performed in the absence or in the presence of Na+ indicated the existence of a Na+-dependent and a Na+-independent Pi transporter in Phytomonas serpens. Phylogenetic analysis of two hypothetical protein sequences of Phytomonas (EM1) showed similarities to the high-affinity Pi transporters of Saccharomyces cerevisiae: Pho84, a Na+-independent Pi transporter, and Pho89, a Na+-dependent Pi transporter. Plasma membrane depolarization by FCCP, an H+ ionophore, strongly decreased Pi uptake via both Na+-independent and Na+-dependent carriers, indicating that a membrane potential is essential for Pi influx. In addition, the furosemide-sensitive Na+-pump activity in the cells grown in low Pi conditions was found to be higher than the activity detected in the plasma membrane of cells cultivated at high Pi concentration, suggesting that the up-regulation of the Na+-ATPase pump could be related to the increase of Pi uptake by the Pho89p Na+:Pi symporter. Here we characterize for the first time two inorganic phosphate transporters powered by Na+ and H+ gradients and activated by low Pi availability in the phytopathogen P. serpens.

Leishmania amazonensis: inhibition of 3'-nucleotidase activity by Cu2+ ions.

Free Cu(2+) is toxic due to the capacity of free copper ions to catalyze the production of reactive oxygen species (ROS) that can modify the structure and/or function of biomolecules. In addition, non-specific binding to enzymes, which modifies their catalytic activities, can occur. In this work, the mechanisms underlying the ability of copper to inhibit 3'-nucleotidase from Leishmania amazonensis (La3'-nucleotidase) were investigated. To that end, La3'-nucleotidase activity was assayed with CuCl(2) in the presence of ascorbate or hydrogen peroxide to discriminate non-specific binding effects from pro-oxidant effects of copper. Copper inhibitory effects were greater at more acidic pH than at alkaline pH. The addition of enzyme substrate, adenosine 3'-monophosphate (3'AMP), prevented the inhibition of enzyme activity by copper. Thiol-containing compounds were able to protect the enzyme activity against inhibition due to copper. The specific copper chelating agent bathocuproine sulphonate (BCS) restored enzyme activity after pre-treatment of the enzyme with copper. La3'-nucleotidase activity was found to be resistant to ROS generated during oxidation reactions of ascorbate and hydrogen peroxide catalyzed by copper. Our results suggest that Cu(2+) ions exert their inhibitory effects by binding to specific motifs of the 3'-nucleotidase protein and that the enzyme appears to be extremely resistant to ROS.

Leishmania amazonensis: characterization of an ecto-3'-nucleotidase activity and its possible role in virulence.

Ecto-3'-nucleotidase/nuclease (3'NT/NU) is a membrane-bound enzyme that plays a key role in the nutrition of Leishmania sp. protozoan parasites. This enzyme generates nucleosides via hydrolyzes of 3'mononucleotides and nucleic acids, which enter the cell by specific transporters. In this work, we identify and characterize Leishmania amazonensis ecto-3'-nucleotidase activity (La3'-nucleotidase), report ammonium tetrathiomolybdate (TTM) as a novel La3'-nucleotidase inhibitor and approach the possible involvement of ecto-3'-nucleotidase in cellular adhesion. La3'-nucleotidase presented characteristics similar to those reported for the class I single-strand nuclease family; a molecular weight of approximately 40 kDa and optimum activity in an alkaline pH range were observed. Although it is conserved among the genus, La3'-nucleotidase displays different kinetic properties; it can be inhibited by vanadate, molybdate and Cu(2+) ions. Interestingly, ecto-3'-nucleotidase activity is 60-fold higher than that of ecto-5'-nucleotidase in L. amazonensis. Additionally, ecto-3'-nucleotidase activity is two-fold higher in virulent L. amazonensis cells than in avirulent ones. Notably, macrophage-parasite attachment/invasion was increased by 400% in the presence of adenosine 3'-monophosphate (3'AMP); however, this effect was reverted by TTM treatment. We believe that La3'-nucleotidase may play a significant role in the generation of adenosine, which may contribute to mammalian host immune response impairment and establishment of infection.