Search

Background & aimsBesides their physiological role in bile formation and fat digestion, bile acids (BAs) synthesised from cholesterol in hepatocytes act as signalling molecules that modulate hepatocellular carcinoma (HCC). Trafficking of cholesterol to mitochondria through steroidogenic acute regulatory protein 1 (STARD1) is the rate-limiting step in the alternative pathway of BA generation, the physiological relevance of which is not well understood. Moreover, the specific contribution of the STARD1-dependent BA synthesis pathway to HCC has not been previously explored.MethodsSTARD1 expression was analyzed in a cohort of human non-alcoholic steatohepatitis (NASH)-derived HCC specimens. Experimental NASH-driven HCC models included MUP-uPA mice fed a high-fat high-cholesterol (HFHC) diet and diethylnitrosamine (DEN) treatment in wild-type (WT) mice fed a HFHC diet. Molecular species of BAs and oxysterols were analyzed by mass spectrometry. Effects of NASH-derived BA profiles were investigated in tumour-initiated stem-like cells (TICs) and primary mouse hepatocytes (PMHs).ResultsPatients with NASH-associated HCC exhibited increased hepatic expression of STARD1 and an enhanced BA pool. Using NASH-driven HCC models, STARD1 overexpression in WT mice increased liver tumour multiplicity, whereas hepatocyte-specific STARD1 deletion (Stard1ΔHep) in WT or MUP-uPA mice reduced tumour burden. These findings mirrored the levels of unconjugated primary BAs, β-muricholic acid and cholic acid, and their tauroconjugates in STARD1-overexpressing and Stard1ΔHep mice. Incubation of TICs or PMHs with a mix of BAs mimicking this profile stimulated expression of genes involved in pluripotency, stemness and inflammation.ConclusionsThe study reveals a previously unrecognised role of STARD1 in HCC pathogenesis, wherein it promotes the synthesis of primary BAs through the mitochondrial pathway, the products of which act in TICs to stimulate self-renewal, stemness and inflammation.Lay summaryEffective therapy for hepatocellular carcinoma (HCC) is limited because of our incomplete understanding of its pathogenesis. The contribution of the alternative pathway of bile acid (BA) synthesis to HCC development is unknown. We uncover a key role for steroidogenic acute regulatory protein 1 (STARD1) in non-alcoholic steatohepatitis-driven HCC, wherein it stimulates the generation of BAs in the mitochondrial acidic pathway, the products of which stimulate hepatocyte pluripotency and self-renewal, as well as inflammation.

Lessons learnedAndrogen receptor as assessed by immunohistochemistry is expressed in a high proportion of patients with hepatocellular carcinoma (HCC). Enzalutamide at 160 mg orally daily is safe and tolerable in patients with advanced HCC but has no single-agent antitumor activity. Enzalutamide, a CYP3A4 inducer, at a standard dose of 160 mg reduces the exposure of sorafenib, a CYP3A4 substrate. Enzalutamide and sorafenib is safe and tolerable in patients with advanced HCC, but the addition of enzalutamide to sorafenib did not enhance the antitumor activity of sorafenib.BackgroundAndrogen receptor (AR) interference is deleterious to hepatocellular carcinoma (HCC) in preclinical models.MethodsThis is a multicenter, phase Ib study of enzalutamide ± sorafenib in patients with advanced HCC. In part 1, a 3 + 3 dose de-escalation design with expansion established the recommended phase II dose (RP2D) of enzalutamide in patients in whom sorafenib treatment had failed. In part 2, a 3 + 3 dose escalation with expansion established the safety of enzalutamide with sorafenib in treatment-naive patients with HCC. Secondary objectives included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), pharmacokinetics (PK), and determination of AR expression by immunohistochemistry. A 7-day run-in with sorafenib alone in part 2 allowed assessment of the impact of enzalutamide on sorafenib pharmacokinetics.ResultsIn part 1, 16 patients received enzalutamide 160 mg daily. No dose-limiting toxicity (DLT) occurred; 1 patient required dose reduction. Responses were not observed; median PFS and OS were 1.8 (95% confidence interval [CI]: 1.6-3.6) and 7 (95% CI: 3.6 to not reached [NR]) months, respectively. In part 2, patients received sorafenib 400 mg daily (4) or twice a day (8) both with enzalutamide at the recommended phase II dose-no DLTs were observed. ORR was 10% (95% CI: 0.3-44.5), and median PFS and OS were 2.9 (95% CI: 1.6 to NR) and 6.7 (95% CI: 4.6 to NR) months, respectively. Enzalutamide reduced sorafenib exposure by 60%. Tumor AR expression did not associate with outcome.ConclusionEnzalutamide is ineffective in HCC; further development is not supported by this study.

Infrared (IR) spectroscopy is a vibrational spectroscopic technique useful in chemical, pharmaceutical, and forensic sciences. It is essential to identify chemicals for reasons spanning from scientific research and academic practices to quality control in companies. However, in some university degrees, graduate students do not get the proficiency to optimize the experimental parameters to obtain the best IR spectra; to correlate the IR spectral bands with the molecular vibrations (chemical elucidation); to have some criteria for any substance identification (especially relevant in quality control to recognize counterfeit); and to apply chemometrics for comparing, visualizing, and classifying the IR spectra. This work presents an experimental laboratory practice for an introductory teaching of the IR instrumental conditions in the identification of substances based on visual spectra comparison and statistical analysis and matching. Then, the selected IR conditions are applied to different commercial drugs, in the solid state or in solution, mostly composed of acetaminophen. Finally, the students apply chemometrics analysis to the IR data. This practice was designed for the training in a chemistry subject for undergraduate students of the chemistry, pharmacy, or forensics degrees, among others related to science, medical, food, or technological sciences.

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.

Young players report that they dropout of organized football due to excessive emphasis on technical execution, low success, and the lack of autonomy and motivation experienced by players during training sessions. Purpose: To determine whether a TGfU intervention during a youth football program led players to improve in variables related to dropout. That means tactical-technical competence (decision-making, skill execution), success (successful game performance), autonomy (number of decisions made, player autonomy, number of game involvements, player participation), and motivation (enjoyment, intention to be physically active). Method: Twenty under-11-players and two coaches were recruited from 17 clubs. A pretest-posttest design with a multi-method approach was used. Coaches were trained and mentored in TGfU. Data were collected using Game Performance Assessment Instrument, enjoyment and intention to be physically active scales, and two focus groups with the players and the coaches. Results: Players improved in decision-making, skill execution, successful game performance, number of decisions made, number of game involvements, and intention to be physically active (p < 0.05). Participants attributed the results to the TGfU pedagogical features emphasized during the coaches' training and mentoring. Conclusion: Considering the reasons for dropout in football, in terms of excessive emphasis on technical execution, low success, and the lack of autonomy and motivation experienced by players, TGfU could be a useful pedagogical approach for teaching-learning organized youth football. The TGfU pedagogical features emphasized during coaches' training and mentoring could be crucial to obtain these results due to the fact that they were the sub-themes highlighted during the focus groups.

The COVID‐19 pandemic triggered an unprecedented health crisis that impacted healthcare systems worldwide. This study explores how Spanish healthcare workers learned, internalised and integrated values and work behaviours during the COVID‐19 pandemic and their impact on the personal sphere. This documentary research, using images, narratives and audiovisual content, was framed within the interpretative hermeneutic paradigm. Categories and subcategories emerged after a final theoretical sampling that focused on the analysis. Data triangulation between researchers favoured theoretical saturation. A total of 117 images and 27 texts were selected. The analysis identified three stages: bewilderment, seeking functionality in the chaos and integrating chaos into care. The data reflects how the need for security and knowledge, and the exhaustion and frustration caused by the initial working conditions, prompted adaptive responses. These responses involved focusing on problem‐solving and strengthening group sentiments and solidarity. Subsequently, the data indicates the acceptance of new structural, organisational and communication aspects. The findings of the analysis will contribute towards finding a framework that can help understand community health crisis events. [ABSTRACT FROM AUTHOR]

Objectives: The presence of a mechanical aortic valve has been a contraindication to the use of an arch branch aortic endograft due to the risk of damaging the valve, resulting in acute aortic regurgitation, or a trapped endograft. Methods: We present a 67-year-old woman, with a background of Marfan's syndrome and a previous Bentall's procedure, who presented with a symptomatic enlarging aortic arch and descending thoracic aortic aneurysm, with a type 1A endoleak. Results: Using an inner branch arch endograft (Cook Medical, Bloomington, Indiana), the nose cone of the delivery system was passed laterally through the semi-circular aperture of the mechanical aortic valve to facilitate deployment just distal to the coronary buttons. Conclusions: With advancement of endovascular technology, techniques and experience, endovascular aortic arch repair in the presence of a mechanical aortic valve is feasible. [ABSTRACT FROM AUTHOR]

Thrombotic microangiopathy (TMA), characterized by microangiopathic hemolytic anemia, thrombocytopenia, and multisystem organ dysfunction, is a life‐threatening disease. Patients with TMA who do not exhibit a severe ADAMTS‐13 deficiency (defined as a disintegrin‐like and metalloprotease with thrombospondin type 1 motif no. 13 activity ≥10%: TMA‐13n) continue to experience elevated mortality rates. This study explores the prognostic indicators for augmented mortality risk or necessitating chronic renal replacement therapy (composite outcome: CO) in TMA‐13n patients. We included 42 TMA‐13n patients from January 2008 to May 2018. Median age of 41 years and 60% were female. At presentation, 62% required dialysis, and 57% warranted intensive care unit admission. CO was observed in 45% of patients, including a 9‐patient mortality subset. Multivariate logistic regression revealed three independent prognostic factors for CO: early administration of eculizumab (median time from hospitalization to eculizumab initiation: 5 days, range 0–19 days; odds ratio [OR], 0.14; 95% confidence interval [CI], 0.02–0.94), presence of neuroradiological lesions (OR, 6.67; 95% CI, 1.12–39.80), and a PLASMIC score ≤4 (OR, 7.39; 95% CI, 1.18–46.11). In conclusion, TMA‐13n patients exhibit a heightened risk of CO in the presence of low PLASMIC scores and neuroradiological lesions, while early eculizumab therapy was the only protective factor. [ABSTRACT FROM AUTHOR]

Background/Objectives: Reverdin–Isham osteotomy is effective in correcting moderate hallux valgus deformity but has certain limitations when correcting a deformity in the sagittal plane. This study aimed to evaluate the impact on pain, functionality, and radiological measures of angular corrections, and the safety of the Reverdin–Isham lateral translation technique through minimally invasive surgery in the treatment of a moderate hallux valgus compared to Reverdin–Isham standard osteotomy. Methods: A pilot 6-month prospective cohort study was conducted on adults over 18 years old with a hallux valgus in at least one foot. The study exposure was the use of the Reverdin–Isham lateral translation technique. The outcome variables were pain and functionality through VAS and AOFAS scales, respectively, and radiological measurements of the first toe metatarsophalangeal angle (MPA), first space intermetatarsal angle (IMA), proximal articular set angle (PASA), distal articular set angle (DASA), metatarsal formula, and position of sesamoids in the AP projection. Results: The study involved 60 participants. Results indicate significant reductions in pain and radiological measures in both cohorts: MPA improved by 23.13 degrees, IMA by 5.93 degrees, and sesamoid position by 4.23 degrees in patients who underwent the lateral translation technique versus 13.20, 3.30, and 1.57 degrees, respectively, in patients who experienced the standard Reverdin–Isham technique. The lateral translation method showed greater reductions in these metrics compared to the standard Reverdin–Isham technique (p < 0.05). Conclusions: Percutaneous Reverdin–Isham techniques, both standard and with lateral translations, effectively corrected moderate hallux valguses. However, the lateral translation method provided greater reductions in MPA, IMA, and sesamoid positions, making it more suitable for deformities with IMAs over 15 degrees. [ABSTRACT FROM AUTHOR]

The assessment of tactics is a subject of great interest in physical education and sport pedagogy. However, the lack of knowledge of the topic and the variety of assessment instruments make the assessment of tactics difficult. This study aimed to describe assessment in relation to tactical learning outcomes through an analysis of assessment instruments, based on variables that must be considered when using an instrument: (a) criteria definitions; (b) tactical levels; (c) indexes; (d) units of observation; (e) player/learner roles; and (f) institutional contexts. Hence, the following instruments were found: Game Performance Assessment Instrument, spatial location instruments, game performance evaluation tool, team sport assessment procedure, and system of tactical assessment in Soccer. Building on the review's purpose, the following issues were found. First, some studies reviewed used non-validated criteria. Second, not all studies considered the three tactical levels (match level, partial forefront level and primary level). Third, the majority of the studies used indexes that masked the results. Fourth, the individual unit of observation was widely used to assess global tactical learning outcomes. Fifth, many instruments were used in contexts for which they were not validated. According to these limitations, general recommendations are proposed. First, researchers should use validated instruments as long as the characteristics of the instruments are aligned with the nature of the study. Second, it is recommended when validating an instrument to consider the following general guidelines: (a) only use validated criteria descriptions; (b) include all three tactical levels; (c) do not use indexes; (d) use the team as the unit of observation; (e) assess both defender and attacker roles; (f) develop the instrument in the same institutional context as the study context; (g) include context variables if applicable.