In vitro and in vivo evaluation of novel chromeno[2,3-d]pyrimidinones as therapeutic agents for triple negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and the limited therapeutic options show poor efficacy in patients, associated to severe side effects and development of resistance. Considering that chromene-based scaffolds proved to be attractive candidates for cancer therapy, herein we prepared new chromeno[2,3-d]pyrimidinone derivatives by a simple two step procedure, starting from the reaction of cyanoacetamide and a salicylaldehyde. A cell viability screening in several breast cancer cell lines allowed to identify two promising compounds with IC50 values in the low micromolar range for TNBC cells. These chromenes inhibited cell proliferation, induced cell cycle arrest and triggered cell death through apoptosis. In vivo studies revealed a safe profile in invertebrate and vertebrate animal models and confirmed their capacity to inhibit tumor growth in the CAM model, inducing significant tumor regression after 4 days of treatment. The two compounds identified in this study are promising drug candidates for TNBC treatment and valuable hits for future optimization, using the versatile synthetic platform that was developed.

Farmers' Perceptions on Implementing Automatic Milking Systems in Large USA Dairies: Decision-Making Process, Management Practices, Labor, and Herd Performance.

Automatic Milking System (AMS) installations are increasing in the USA despite the higher investment cost than conventional systems. Surveys on AMSs conducted outside the USA focused on small-medium herds, specific regions, or aspects of AMS milking. This study described farmers' perceptions about the decision-making process of adopting an AMS in the USA's large dairies (≥7 AMS boxes) regarding changes in technology, housing, management practices, labor, herd performance, and health. After being contacted, 27 of 55 farmers from large AMS herds completed the survey. The main reasons for adopting an AMS were labor costs, cows' welfare, and herd performance. Most farms constructed new barns, used a free-flow traffic system, and changed their feed management. Increases in water and energy use were perceived by 42% and 62% of farmers, respectively. Farmers estimated decreases in labor costs of over 21%, and AMS employees worked 40-60 h/week. Milk production increases were reported by 58%, with 32% observing higher milk fat and protein content. Easier sick cow detection, better mastitis management, and improvements in pregnancy rates were reported. Thus, farmers transitioning to AMSs perceived altered resource utilization, labor cost savings, and improvements in employee quality of life, animal welfare, and farm management. While 54% of respondents would recommend an AMS to other farms, 38% suggested considering additional aspects prior to adoption.

Advancement in Paper-Based Electrochemical Biosensing and Emerging Diagnostic Methods.

The utilization of electrochemical detection techniques in paper-based analytical devices (PADs) has revolutionized point-of-care (POC) testing, enabling the precise and discerning measurement of a diverse array of (bio)chemical analytes. The application of electrochemical sensing and paper as a suitable substrate for point-of-care testing platforms has led to the emergence of electrochemical paper-based analytical devices (ePADs). The inherent advantages of these modified paper-based analytical devices have gained significant recognition in the POC field. In response, electrochemical biosensors assembled from paper-based materials have shown great promise for enhancing sensitivity and improving their range of use. In addition, paper-based platforms have numerous advantageous characteristics, including the self-sufficient conveyance of liquids, reduced resistance, minimal fabrication cost, and environmental friendliness. This study seeks to provide a concise summary of the present state and uses of ePADs with insightful commentary on their practicality in the field. Future developments in ePADs biosensors include developing novel paper-based systems, improving system performance with a novel biocatalyst, and combining the biosensor system with other cutting-edge tools such as machine learning and 3D printing.

Regioselective Synthesis of 2-Aryl-5-cyano-1-(2-hydroxyaryl)-1H-imidazole-4-carboxamides Self-Assisted by a 2-Hydroxyaryl Group.

The reactivity of the diaminomaleonitrile-based imines containing hydroxyphenyl substituents with diverse aromatic aldehydes has been explored for the synthesis of novel highly substituted nitrogen heterocycles, which are considered privileged scaffolds in drug discovery. We report here a simple and efficient method for the regiocontrolled synthesis of a variety of 2-aryl-5-cyano-1-(2-hydroxyaryl)-1H-imidazole-4-carboxamides from 2-hydroxybenzylidene imines and aromatic aldehydes. Computational studies on the reaction path revealed that the regioselectivity of the reaction toward the formation of imidazole derivatives instead of 1,2-dihydropyrazines, most likely via a diaza-Cope rearrangement, is driven by the 2-hydroxyaryl group in the scaffold. The latter group promotes the intramolecular abstraction and protonation process in the cycloadduct intermediate, triggering the evolution of the reaction toward the formation of imidazole derivatives.

Effect of Resistance Training With Total and Partial Blood Flow Restriction on Biomarkers of Oxidative Stress and Apoptosis in Untrained Men.

Introduction: The characterization of immune and oxidative stress responses to acute and chronic exercise training is important because it may aid in the safety and dose-response prescription of resistance training (RT) in many populations. Purpose: The present study compared changes in acute oxidative stress and markers of apoptosis in immune cells before and after 8 weeks of low-load RT with total or partial blood flow restriction (BFR) versus high-load traditional RT. Methods: Twenty-seven untrained men were randomly divided into three groups: traditional RT [75% one-repetition maximum (1-RM)], RT with partial (20% 1-RM), and total BFR (20% 1-RM). Over an 8-week period, participants performed six sets of arm curls until failure with 90 seconds of recovery for 3 days/week. Blood samples were obtained before and after the first and last training sessions. Results: Data indicated that all training groups showed similar increases in muscular strength (p < 0.001), reduction in mitochondrial membrane potential (MMP) after exercise in neutrophils (p < 0.001), and increase in caspase-3 activity after exercise (p < 0.001). Traditional RT and total BFR showed increased plasma lipid peroxidation (p < 0.001) and protein carbonyls (p < 0.001) and lower levels of reduced glutathione (GSH) (p < 0.001) after exercise. No change was observed in oxidative stress biomarkers in response to partial BFR (p > 0.05). Conclusion: Data show that RT with partial BFR can increase muscular strength but still does not augment biomarkers of oxidative stress in untrained men. In addition, RT with total BFR promoted similar responses of oxidative stress and markers of immune cell apoptosis versus traditional RT.

Recent advances and future directions for uterine diseases diagnosis, pathogenesis, and management in dairy cows.

Researchers, veterinarians, and farmers' pursuit of a consistent diagnosis, treatment, and prevention of uterine diseases remains challenging. The diagnosis and treatment of metritis is inconsistent, a concerning situation when considered the global threat of antimicrobial resistance dissemination. Endometritis is an insidious disease absent on routine health programs in many dairy farms and from pharmaceutical therapeutics arsenal in places like the US market. Conversely, a multitude of studies advanced the understanding of how uterine diseases compromise oocyte, follicle, and embryo development, and the uterine environment having long-lasting effects on fertility. The field of uterine disease microbiome also experienced tremendous progress and created opportunities for the development of novel preventives to improve the management of uterine diseases. Activity monitors, biomarkers, genomic selection, and machine learning predictive models are other innovative developments that have been explored in recent years to help mitigate the negative impacts of uterine diseases. Albeit novel tools such as vaccines for metritis, immune modulators, probiotics, genomic selection, and selective antimicrobial therapy are promising, further research is warranted to implement these technologies in a systematic and cost-effective manner.

Ectoparasitism and infections in the exoskeletons of large fossil cingulates.

Studies on paleopathological alterations in fossil vertebrates, including damages caused by infections and ectoparasites, are important because they are potential sources of paleoecological information. Analyzing exoskeleton material (isolated osteoderms, carapace and caudal tube fragments) from fossil cingulates of the Brazilian Quaternary Megafauna, we identified damages that were attributed to attacks by fleas and dermic infections. The former were compatible with alterations produced by one species of flea of the genus Tunga, which generates well-delimited circular perforations with a patterned distribution along the carapace; the latter were attributable to pathogenic microorganisms, likely bacteria or fungi that removed the ornamentation of osteoderms and, in certain cases, generated craters or pittings. Certain bone alterations observed in this study represent the first record of flea attack and pitting in two species of large glyptodonts (Panochthus and Glyptotherium) and in a non-glyptodontid large cingulate (Pachyarmatherium) from the Quaternary of the Brazilian Intertropical Region. These new occurrences widen the geographic distribution of those diseases during the Cenozoic and provide more evidence for the co-evolutionary interaction between cingulates and parasites registered to date only for a small number of other extinct and extant species.

Rating of Perceived Exertion During Circuit Weight Training: A Concurrent Validation Study.

The aim of this study was to determine whether rating of perceived exertion (RPE) is a valid method to control the effort during the circuit weight training (CWT) in trained men. Ten men (21.3 ± 3.3 years) with previous experience in resistance training (13.1 ± 6.3 months) performed 3 sessions: 1 orientation session and 2 experimental sessions. The subjects were randomly counterbalanced to 2 experimental sessions: CWT or multiple-set resistance training (control). In both sessions, 8 exercises (bench press, leg press 45°, seated row, leg curl, triceps pulley, leg extension, biceps curl, and adductor chair) were performed with the same work: 60% of 1 repetition maximum, 24 stations (3 circuits) or 24 sets (3 sets/exercise), 10 repetitions, 1 second in the concentric and eccentric phases, and rest intervals between sets and exercise of 60 seconds. Active muscle RPEs were measured after each 3 station/sets using the OMNI-Resistance Exercise Scale (OMNI-RES). In this same time, blood lactate was collected. Compared with baseline, both levels of blood lactate and RPE increased during whole workout in both sessions, the RPE at third, 23rd, and 27th minute and the blood lactate at third, seventh, 11th, 15th, 27th, and 31st minute were higher in multiple set compared with CWT. Positive correlation between blood lactate and RPE was observed in both experimental sessions. The results indicated that the RPE is a valid method to control the effort during the CWT in trained men and can be used to manipulate the intensity without the need to perform invasive assessments.

Electrodeposition of reduced graphene oxide on a Pt electrode and its use as amperometric sensor in microchip electrophoresis.

This report describes the development and application of a novel graphene-modified electrode to be used as amperometric sensor in microchip electrophoresis (ME) devices. The modified electrode was achieved based on electroreduction of graphene oxide on an integrated Pt working electrode of a commercial ME device. The surface modification was characterized by SEM and cyclic voltammetry techniques. The results indicated that graphene sheets were successfully deposited exhibiting higher surface conductivity and greater electrode sensitivity. The performance of the modified electrode for the amperometric detection on ME devices has been demonstrated by the separation and detection of an anionic mixture containing iodide and ascorbate. The graphene-modified electrode provided significantly higher sensitivity (896.7 vs. 210.9 pA/µM for iodide and 217.8 vs. 127.8 pA/µM for ascorbate), better separation efficiencies (3400 vs. 700 plates/m for iodide and 10 000 vs. 2400 plates/m for ascorbate), enhanced peak resolutions (1.6 vs. 1.0), and LODs (1.5 vs. 5.3 µM for iodide and 3.1 vs. 7.3 µM for ascorbate) in comparison with the unmodified Pt electrode. The proposed amperometric sensor was successfully applied for the analysis of ascorbic acid (through its anionic form) in a commercial medicine sample, and the results achieved were in agreement with the value provided by the supplier. Based on the data here presented, the modified graphene electrode shows great promise for ME applications.

Oxidized/reduced graphene nanoribbons facilitate charge transfer to the Fe(CN)6³â»/Fe(CN)64⁻ redox couple and towards oxygen reduction.

This study investigated the synthesis of graphene oxide nanoribbons (GONRs) and graphene nanoribbons (GNRs) from multiwalled carbon nanotubes (MWCNTs), and the behavior of thin films of MWCNTs, GONRs, and GNRs on a glassy carbon surface in the presence of two redox probes (Fe(CN)6(3-)/Fe(CN)6(4-) and O2) employing cyclic voltammetry, electrochemical impedance spectroscopy, and hydrodynamic voltammetry (HV) as a simple procedure for characterizing these films. The feasibility of using these electrochemical techniques for this purpose opens up the possibility of applying them to biosensors and electrocatalysts using surface-supported MWCNT, GONR, and GNR materials. GNR1 resembles an internodal segment of bamboo cut lengthwise, with a shallow troughing at its center, while GNR2 resembles stacked ribbons, each ∼16 nm wide, with points of structural damage and points of four-ribbon connection measuring 60 nm or wider, sufficiently catalytic for the oxygen reduction reaction to occur, unlike the other modified electrodes investigated in acidic, 0.1 M KH2PO4 (pH 7.0), and 0.1 M KOH solutions (HV results). Transmission electron microscopy and thermogravimetric analysis were employed to characterize the MWCNTs, GONRs, and GNRs.

Determination of thiodicarb using a biosensor based on alfalfa sprout peroxidase immobilized in self-assembled monolayers.

A biosensor based on alfalfa sprout (Medicago sativa) homogenate as a source of peroxidase is proposed for the determination of thiodicarb by square-wave voltammetry. This enzyme was immobilized in self-assembled monolayers of l-cysteine on a gold electrode. Several parameters were investigated to evaluate the optimum conditions for operation of the biosensor. The analytical curve was linear for thiodicarb concentrations of 2.27 x 10(-6) to 4.40 x 10(-5) mol L(-1) with a detection limit of 5.75 x 10(-7) mol L(-1). The lifetime of the Au-alfalfa sprout-SAMs was 20 days (at least 220 determinations). The average recovery of thiodicarb from samples of vegetable extracts ranged from 99.02 to 101.04%. The results obtained for thiodicarb in vegetable extracts using the proposed method are in close agreement with those using a high performance liquid chromatography procedure at the 95% confidence level.

Protocolo combinado de 99mTc-Ciprofloxacina y 99mTc-MDP en el diagnóstico de osteomielitis y prótesis articular infectada / 99mTc-ciprofloxacin/99mTc-MDP combined protocol in the diagnosis of osteomyelitis and infected joint prosthesis

Introducción. El centellograma óseo con 99mTc-MDP es una técnica útil en el diagnóstico de osteomielitis, sin embargo, presenta especificidad limitada en presencia de patología ósea previa (osteomielitis complicada). La 99mTc-ciprofloxacina es uno de los radiofármacos más difundidos para la detección de infecciones óseas, aunque persisten controversias sobre su rendimiento diagnóstico. Objetivo. Determinar el valor clínico del protocolo combinado de centellograma con 99mTc-ciprofloxacina y 99mTc-MDP en el diagnóstico de osteomielitis complicada y prótesis articular infectada. Materiales y métodos 37 pacientes con sospecha clínica de osteomielitis complicada o prótesis infectada fueron estudiados mediante centellograma con 99mTc-ciprofloxacina y 99mTc-MDP. 26/37 pacientes presentaban fractura previa, 7 prótesis de rodilla y 4 prótesis de cadera. En todos ellos se realizó seguimiento clínico y bacteriológico. Resultados. El método presentó sensibilidad de 94 por ciento, especificidad de 79 por ciento, valor predictivo positivo de 81 por ciento y valor predictivo negativo de 94 por ciento, con una exactitud de 86 por ciento. Conclusiones. El protocolo combinado de 99mTc-ciprofloxacina y 99mTc-MDP presenta elevado rendimiento para el diagnóstico de osteomielitis complicada y prótesis articular infectada.

Introduction. Bone scintigraphy with 99mTc-MDP is a useful technique in the diagnosis of osteomyelitis, however, has limited specificity in the presence of previous bone pathology (complicated osteomyelitis). 99mTc-ciprofloxacin is one of the most widely used radiotracers for the detection of bone infection, although controversies persist on its diagnostic performance. Objective To determine the clinical value of 99mTc-ciprofloxacin/99mTc-MDP combined protocol in the diagnosis of complicated osteomyelitis and infected joint prosthesis. Materials and methods 37 patients with clinically suspected complicated osteomyelitis or infected prosthesis were studied with 99mTc-ciprofloxacin and 99mTc-MDP scintigraphy. 26/37 patients had previous fractures, 7 had knee replacements and 4 had hip replacements. All of the patients underwent clinical and bacteriological follow-up. Results. The method presented sensitivity of 94 percent, 79 percent specificity, 81 percent positive predictive value and 94 percent negative predictive value, with an accuracy of 86 percent. Conclusions. The combined protocol using 99mTc-ciprofloxacin/99mTc-MDP showed high diagnostic performance in complicated osteomyelitis and infected joint prosthesis.

[99mTc-OCTREOTIDE in patients with neuroendocrine tumors from the GI tract]. / 99mTc-OCTREOTIDE en pacientes con tumores neuroendócrinos gastroenteropancreáticos.

INTRODUCTION: It has been demonstrated that scintigraphy with somatostatin analogues is useful for the diagnosis, staging and follow up of patients with neuroendocrine tumors from the gastrointestinal tract (NET-GIT). Some studies suggest that the use of 99mTc-Hydrazinonicotinyl-Tyr3-octreotide (99mTc-HYNIC-TOC) yields similar diagnostic results than the use of 111In-DTPA-octreotide. OBJECTIVE: To determine the clinical value of scintigraphy using 99mTc-HYNIC-TOC for the detection of primary and secondary lesions in patients with NET-GIT. METHODS: From September 2004 to May 2009, 32 patients (17 women, age range 18 to 82 years old) with histologically proven or clinically suspected NET-GIT underwent scintigraphy using 99mTc-HYNIC-TOC Patients underwent a whole body scan, with additional static images of abdomen and pelvis, followed by SPECT at 4-hrs post injection of 925 MBq of the tracer. Patients underwent clinical, imaging and histopathology follow-up during 3 to 18 months. RESULTS: Histopathology demonstrated carcinoid tumor in 20 patients, insulinoma in 2, gastrinoma in 2 and non-specific NET-GIT in 6. Total sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 87%, 100%, 100%, 89% and 94%, respectively. To detect the primary lesion, the values were 94%, 100% 100%, 94% and 97%, respectively and to detect secondary lesions, 79%, 100%, 100%, 86% and 91%, respectively. CONCLUSIONS: 99mTc-HYNIC-TOC is a specific somatostatin analog, with high affinity to receptor subtype SST-2, widely available and affordable by Latin American countries. It has a good performance to be used for diagnosis, staging and follow-up of patients with NET-GIT.

Angiofibroma nasofaríngeo juvenil: Hospital Universitario Dr. Luis Gómez López enero 1990-agosto 1998-Barquisimeto, 1998 / Juvenile nasopharyngeal angiofibroma: Hospital Universitario \"Dr. Luis Gómez López\" january 1990-august 1998-Barquisimeto, 1998

Se realizó un estudio retrospectivo de casos de Angiofibroma Nasofaríngeo juvenil desde Enero a Agosto de 1998, con el objetivo de determinar las características de presentación, las vías de abordaje y su relación con tumor residual. Ingresaron al estudio 7 casos, todos con TAC preoperatoria y postoperatoria, que nos permitió estudiar los tumores y evaluar la enfermedad residual. Todos los pacientes resultaron varones, el promedio de edad fue 16 años. Epistaxis 7 (100 por ciento) y obstrucción nasal 4 (57 por ciento), fueron los síntomas más frecuentes. Un caso era estadio I, 6 (86 por ciento) estaban en estadio II. En 3 (43 por ciento) pacientes se presentó tumor residual, 2 (29 por ciento) en estadio II y uno en estadio I. Las técnicas utilizadas fueron el degloving, la rinotomía lateral y el abordaje transnasal con similares tasas de recurrencia de la enfermedad. El angiofibroma Nasofaríngeo Juvenil se presenta exclusivamente en varones, jóvenes, el diagnóstico temprano permite instaurar tratamiento precoz por lo que son poco frecuentes los estadios más avanzados, no parece haber relación entre la técnica de abordaje y la recurrencia del tumor. El abordaje transnasal para tumores hasta estadio II es una alternativa óptima por los resultados estéticos faciales y tasa de recurrencia similar a las vías convencionales