First-in-human study of alpibectir (BVL-GSK098), a novel potent anti-TB drug.

BACKGROUND: The clinical candidate alpibectir augments the activity of, and overcomes resistance to, the anti-TB drug ethionamide in vitro and in vivo. OBJECTIVES: A Phase 1, double-blind, randomized, placebo-controlled study to investigate the safety, tolerability, pharmacokinetics (PK) and food effect of alpibectir administered as single and multiple oral doses in healthy volunteers (NCT04654143). METHODS: Eighty participants were randomized. In single ascending dose (SAD), a total of six dose levels of alpibectir (0.5 to 40 mg) were tested under fasted and fed (10 mg) conditions as single daily doses in sequential cohorts. In multiple ascending dose (MAD), repeat doses (5 to 30 mg) were administered once daily for 7 days in three sequential cohorts. RESULTS: No serious adverse event was reported. Thirteen participants across groups experienced a total of 13 mild or moderate treatment-emergent adverse events. Alpibectir showed rapid absorption after single dose (mean Tmax range of 0.88 to 1.53 h). Food affected the PK of alpibectir, characterized by a slower absorption (mean Tmax 3.87 h), a lower Cmax (-17.7%) and increased AUC0-t (+19.6%) compared with the fasted condition. Following repeat dosing, dose proportionality was shown for both Cmax and AUC0-tau. Accumulation of alpibectir was observed across all doses, with a more profound effect on AUC during a dosing interval (AUC0-tau) compared with Cmax (1.8- and 1.3-fold on average), respectively. Steady state was considered to have been achieved by Day 7 of dosing. CONCLUSIONS: Alpibectir was generally well tolerated, and no clinically relevant safety findings were identified in the participants treated during SAD or MAD. The PK is dose-proportional and affected by food.

Analysis of Dietary Intake and Body Composition of Collegiate Runners / Análisis de la Ingesta Dietética y Composición Corporal de Corredores Universitarios

SUMMARY: The aim of this cross-sectional study was to compare dietary intake to published recommendations and to analyze the potential relationship between body composition and dietary intake in collegiate athletes. Eighteen healthy male middle- and long- distance runners (age 20.11 ± 2.72 y; height, 174.7 ± 6.1 cm; body mass, 64.0 ± 7.7 kg), were recruited from a Mexican university track and field team at the beginning of the general preparation phase for national competitions. Participants completed three 24-hour dietary recalls, which were used to estimate dietary intake. Body composition was measured by Dual-energy X-ray absorptiometry (DXA). Athletes displayed high body fat values. Protein intake was significantly higher than published recommendations. Iron, zinc, sodium, and vitamin C intake were significantly higher than recommended values, while potassium and calcium intake were below established recommendations. No significant correlations between body composition variables (i.e body fat, lean body mass, bone mineral content) and dietary intake (i.e energy, macronutrients and selected vitamins and minerals) could be found. These findings suggest that coaches and practitioners should pay close attention to dietary intake and body composition of endurance athletes starting general preparation for competition. Future studies on changes of dietary intake and body composition during off-season and competitive phase, which also track physical activity, are warranted.

El objetivo de este estudio transversal fue comparar la ingesta dietética con las recomendaciones publicadas y analizar la relación potencial entre la composición corporal y la ingesta dietética en corredores universitarios. Dieciocho atletas masculinos sanos de media y larga distancia (edad 20,11 ± 2,72 años; altura, 174,7 ± 6,1 cm; masa corporal, 64,0 ± 7,7 kg), fueron reclutados de un equipo de atletismo de una universidad mexicana al comienzo de la fase de preparación general de competiciones nacionales. Los participantes completaron tres recordatorios dietéticos de 24 horas, que se utilizaron para estimar la ingesta dietética. La composición corporal se midió mediante absorciometría de rayos X de energía dual (DXA). Los atletas mostraron altos valores de grasa corporal. La ingesta de proteínas fue significativamente mayor que las recomendaciones publicadas. La ingesta de hierro, zinc, sodio y vitamina C fue significativamente superior a los valores recomendados, mientras que la ingesta de potasio y calcio estuvo por debajo de las recomendaciones establecidas. No se encontraron correlaciones significativas entre las variables de composición corporal (es decir, grasa corporal, masa corporal magra, contenido mineral óseo) y la ingesta dietética (es decir, energía, macronutrientes y vitaminas y minerales seleccionados). Estos hallazgos sugieren que los entrenadores y los practicantes deberían prestar mucha atención a la ingesta dietética y la composición corporal de los atletas de resistencia que comienzan la preparación general para la competencia. Se justifican estudios futuros sobre los cambios en la ingesta dietética y la composición corporal durante la fase fuera de temporada y competitiva, como también un seguimiento de la actividad física.

Análisis cienciométrico de la producción científica sobre la hipoxantina y xantina en el ejercicio, publicada en la base de datos Scopus (2016-2021) / Scientometric Analysis of the Scientific Production on Hypoxanthine and Xanthine in Exercise, Published in Scopus Database (2016-2021)

La hipoxantina y la xantina son biomarcadores metabólicos que resultan de la degradación de las proteínas purinas. Los análisis cienciométricos constituyen una herramienta para estudiar las publicaciones científicas en torno a un determinado tema con la finalidad de determinar tendencias en la literatura. Se realizó un análisis cienciométrico de la producción científica reciente sobre la hipoxantina y xantina en el ejercicio, publicada en la base de datos Scopus durante el período 2016 - 2021. Para la búsqueda en Scopus se utilizaron las palabras clave en idioma inglés: exercise, hypoxanthine y xanthine. Se realizó un análisis cuantitativo, tomando en cuenta los artículos encontrados, así como la información proporcionada por el software VOSviewer. Se identificaron 64 artículos, de estos, 56 fueron de investigación aplicada y ocho de revisión. La categoría de efecto del ejercicio tuvo una mayor cantidad de estudios con 23; dentro de esta se encuentra la subcategoría de metabolismo que presentó 21 artículos. Tanto Estados Unidos como Polonia son los países con mayor número de publicaciones. Existen distintos enfoques y protocolos de ejercicio utilizados para cuantificar la respuesta de la hipoxantina y xantina, así como los perfiles de los sujetos de estudio utilizados como muestra para las investigaciones. La cuantificación de hipoxantina y xantina en el cuerpo es importante para la investigación en el campo de las ciencias del ejercicio(AU)

Hypoxanthine and xanthine are metabolic biomarkers that result from the degradation of purine proteins. Scientometric analyzes constitute a tool to study scientific publications around a certain topic in order to determine trends in the literature. A scientometric analysis was carried out of the recent scientific production on hypoxanthine and xanthine in exercise, published in Scopus database during the period 2016-2021. For the search in Scopus, we used the English keywords exercise, hypoxanthine and xanthine. A quantitative analysis was carried out, taking into account the articles found, as well as the information provided by VOSviewer software. Sixty-four articles were identified, 56 of them were applied research and eight were review. The exercise effect category had a larger number of studies (23). Here there is a subcategory of metabolism that had 21 articles. The United States and Poland are both the countries with the highest number of publications. There are different approaches and exercise protocols used to quantify the response of hypoxanthine and xanthine, as well as the profiles of the study subjects used as a sample for the investigations. The quantification of hypoxanthine and xanthine in the body is important for research in the field of exercise science(AU)

Brain metabolic pattern analysis using a magnetic resonance spectra classification software in experimental stroke.

BACKGROUND: Magnetic resonance spectroscopy (MRS) provides non-invasive information about the metabolic pattern of the brain parenchyma in vivo. The SpectraClassifier software performs MRS pattern-recognition by determining the spectral features (metabolites) which can be used objectively to classify spectra. Our aim was to develop an Infarct Evolution Classifier and a Brain Regions Classifier in a rat model of focal ischemic stroke using SpectraClassifier. RESULTS: A total of 164 single-voxel proton spectra obtained with a 7 Tesla magnet at an echo time of 12 ms from non-infarcted parenchyma, subventricular zones and infarcted parenchyma were analyzed with SpectraClassifier ( http://gabrmn.uab.es/?q=sc ). The spectra corresponded to Sprague-Dawley rats (healthy rats, n = 7) and stroke rats at day 1 post-stroke (acute phase, n = 6 rats) and at days 7 ± 1 post-stroke (subacute phase, n = 14). In the Infarct Evolution Classifier, spectral features contributed by lactate + mobile lipids (1.33 ppm), total creatine (3.05 ppm) and mobile lipids (0.85 ppm) distinguished among non-infarcted parenchyma (100% sensitivity and 100% specificity), acute phase of infarct (100% sensitivity and 95% specificity) and subacute phase of infarct (78% sensitivity and 100% specificity). In the Brain Regions Classifier, spectral features contributed by myoinositol (3.62 ppm) and total creatine (3.04/3.05 ppm) distinguished among infarcted parenchyma (100% sensitivity and 98% specificity), non-infarcted parenchyma (84% sensitivity and 84% specificity) and subventricular zones (76% sensitivity and 93% specificity). CONCLUSION: SpectraClassifier identified candidate biomarkers for infarct evolution (mobile lipids accumulation) and different brain regions (myoinositol content).

Improving Ribosomal RNA Integrity in Surgically Resected Human Brain Tumor Biopsies.

BACKGROUND: Biopsies extracted from brain cancer patients often display degraded ribosomal RNA, which makes them unusable in transcriptomic experiments. This has not been properly documented in previous works aimed at refining the molecular classification of brain cancer. OBJECTIVE: To determine RNA integrity in a large cohort of human brain cancer biopsies and to evaluate different factors that may influence RNA integrity in both a murine model of glioblastoma and in additional subsets of patient biopsies. METHODS: Total RNA was isolated from 255 biopsies of various human brain tumors (HBTs) and processed on a Bioanalyzer. Correct RNA integrity was considered for samples showing either the ribosomal 28S/18S peak ratio ≥ 1.2 or RNA integrity number ≥ 6. The time-dependent effect of ex vivo ischemia was evaluated in a murine model, whose results were tested in a new collection of 27 human biopsies. Multiple biopsy sampling was considered in a further set comprising 32 biopsies. RESULTS: The 255 human biopsies revealed a substantial percentage of samples displaying degraded RNA (27.5%). The murine model confirmed the known relevance of ex vivo ischemia time in increased RNA degradation. Human biopsies extracted immediately after cauterization showed a trend toward less RNA degradation. Combining snap freezing and multiple sampling of biopsies, the percentage of patients with degraded RNA was reduced by twofold (15.6%). CONCLUSIONS: We provide a first concise study of factors influencing RNA degradation in HBT biopsies. Immediate biopsy removal after cauterization of the tumor area, snap freezing, and multiple sampling improve RNA quality.

In vivo and ex vivo magnetic resonance spectroscopy of the infarct and the subventricular zone in experimental stroke.

Ex vivo high-resolution magic-angle spinning (HRMAS) provides metabolic information with higher sensitivity and spectral resolution than in vivo magnetic resonance spectroscopy (MRS). Therefore, we used both techniques to better characterize the metabolic pattern of the infarct and the neural progenitor cells (NPCs) in the ipsilateral subventricular zone (SVZi). Ischemic stroke rats were divided into three groups: G0 (non-stroke controls, n = 6), G1 (day 1 after stroke, n = 6), and G7 (days 6 to 8 after stroke, n = 12). All the rats underwent MRS. Three rats per group were analyzed by HRMAS. The remaining rats were used for immunohistochemical studies. In the infarct, both techniques detected significant metabolic changes. The most relevant change was in mobile lipids (2.80 ppm) in the G7 group (a 5.53- and a 3.95-fold increase by MRS and HRMAS, respectively). In the SVZi, MRS did not detect any significant metabolic change. However, HRMAS detected a 2.70-fold increase in lactate and a 0.68-fold decrease in N-acetylaspartate in the G1 group. None of the metabolites correlated with the 1.37-fold increase in NPCs detected by immunohistochemistry in the G7 group. In conclusion, HRMAS improves the metabolic characterization of the brain in experimental ischemic stroke. However, none of the metabolites qualifies as a surrogate biomarker of NPCs.

Minimization of spectral pattern changes during HRMAS experiments at 37 degrees celsius by prior focused microwave irradiation.

OBJECT: High-resolution magic angle spinning (HRMAS) magnetic resonance spectroscopy provides detailed metabolomic information from intact tissue. However, long acquisition times and high rotation speed may lead to timedependent spectral pattern changes, which may affect proper interpretation of results. We report a strategy to minimize those changes, even at physiological recording temperature. MATERIALS AND METHODS: Glioblastoma(Gbm) tumours were induced in 12 mice by stereotactic injection of GL261 cells. Animals were sacrificed and tumours were removed and stored in liquid N2. Half of the samples were exposed to focused microwave (FMW) irradiation prior to HRMAS while the other half was not. Time-course experiments (374 min at 37°C, 9.4T, 3,000 Hz spinning rate) were carried out to monitor spectral pattern changes. Differences were assessed with Unianova test while post-HRMAS histopathology analysis was performed to assess tissue integrity. RESULTS: Significant changes (up to 1.7 fold) were observed in samples without FMW irradiation in several spectral regions e.g. mobile lipids/lactate (0.90-1.30 ppm), acetate (1.90 ppm), N-acetyl aspartate (2.00 ppm), and Choline-containing compounds (3.19-3.25 ppm). No significant changes in the spectral pattern of FMW-irradiated samples were recorded. CONCLUSION: We describe here a successful strategy to minimize spectral pattern changes in mouse Gbm samples using a FMW irradiation system.

Short-term temperature effect on the HRMAS spectra of human brain tumor biopsies and their pattern recognition analysis.

OBJECT: To investigate the effect of temperature (0 versus 37 degrees C) in the high-resolution magic angle spinning spectroscopy (HRMAS) pattern of human brain tumor biopsies and its influence in recognition-based tumor type prediction. This proof-of-principle study addressed the bilateral discrimination between meningioma (MM) and glioblastoma multiforme (GBM) cases. MATERIALS AND METHODS: Forty-three tumor biopsy samples were collected (20 MM and 23 GBM), kept frozen and later analyzed at 0 degrees C and 37 degrees C by HRMAS. Post-HRMAS histopathology was used to validate the tumor type. Time-course experiments (100 min) at both temperatures were carried out to monitor HRMAS pattern changes. Principal component analysis and linear discriminant analysis were used for classifier development with a training set of 20 biopsies. RESULTS: Temperature-dependent, spectral pattern changes mostly affected mobile lipids and choline-containing compounds resonances and were essentially reversible. Incubation of 3 MM and 3 GBM at 37 degrees C during 100 minutes produced irreversible pattern changes below 13% in a few resonances. Classification performance of an independent test set of 7 biopsies was 100% for the pulse-and-acquire, CPMG at echo times (TE) of 30 ms and 144 ms and Hahn Echo at TE 30 ms at 0 degrees C and 37 degrees C. The performance for Hahn Echo spectra at 136 ms was 83.3% at 0 degrees C and 100% at 37 degrees C. CONCLUSION: The spectral pattern of mobile lipids changes reversibly with temperature. HRMAS demonstrated potential for automated brain tumor biopsy classification. No advantage was obtained when acquiring spectra at 37 degrees C with respect to 0 degrees C in most of the conditions used for the discrimination addressed.