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14 recordsLinked to original sources
PubMed2026

Clinical predictors of response to atezolizumab/bevacizumab in Child-Pugh B patients with hepatocellular carcinoma.

BACKGROUND & AIMS: We aimed to identify, among patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh B cirrhosis, typically excluded from clinical trials, a subgroup that may benefit from first-line atezolizumab/bevacizumab (A/B). METHODS: We conducted a retrospective international multicenter study including patients with unresectable HCC treated with first-line A/B between 2020 and 2024 across 12 centers. A cohort of Child-Pugh B patients treated with sorafenib served as a control. Baseline clinical, biological, and tumor features were correlated with radiological response, progression-free survival (PFS), and overall survival (OS). RESULTS: Among 1,499 patients, 246 (16.4%) had Child-Pugh B cirrhosis. Within Child-Pugh B, 72% were B7, 21.5% B8, and 6.5% B9; 73% had albumin-bilirubin (ALBI) grade 2 and 27% grade 3. Median OS and PFS were significantly shorter in Child-Pugh B (8.1 and 5.2 months, respectively) vs. Child-Pugh A (16.8 and 8.6 months, respectively; both p <0.001). Two-year OS was 20% for Child-Pugh B vs. 38% for Child-Pugh A. Child-Pugh B patients treated with A/B had longer OS than those treated with sorafenib (p = 0.002). A score combining ALBI grade 1/2 and metastatic status identified prognostic subgroups (10.3 vs. 7.9 vs. 4.2 months; p <0.0001). Improvement to Child-Pugh A occurred in 31% and was associated with recent treatment of underlying liver disease. Radiological response (hazard ratio = 0.58, p = 0.021) and liver function improvement (hazard ratio = 0.59, p = 0.006) correlated with reduced mortality. CONCLUSIONS: Although Child-Pugh B patients have poorer survival, a subgroup, those with ALBI grade 1/2 and no extrahepatic metastasis, can derive meaningful benefit from A/B therapy. Improving underlying liver disease may contribute to better outcomes. IMPACT AND IMPLICATIONS: Child-Pugh B patients with advanced HCC are systematically underrepresented in clinical trials, creating a critical evidence gap for a population frequently encountered in real-world practice. This large multicenter study shows that a subset of these patients, those with ALBI grade 1/2 and without extrahepatic metastases, can have clinically significant benefit from first-line A/B, providing a practical prognostic tool to guide patient selection. Moreover, the association between treatment of the underlying liver disease and Child-Pugh class improvement suggests that optimizing hepatic function alongside systemic therapy may represent an actionable strategy to improve outcomes, warranting prospective validation.

Humans↗
PubMed1975

[Enzyme system and coenzymes involved in the energy metabolism of leukocytes. Function and metabolism of polymorphonuclear neutrophils].

Mitochondria may be isolated from various types of leukocyte (neutrophil polymorphs and lymphocytes from human blood, neutrophil polymorphs and macrophages from peritoneal exudates of the guinea pig) after destruction by heparin of the cell membrane. This procedure is very simple and less traumatic for these subcellular structures than the usual mechanical procedures. The enzyme activities of the respiratory chain and oxygen consumption may be measured in these mitochondrial preparations. The oxygen consumption is determined using oxyhemoglobin which serves both as oxygen donor, as in the respiratory system in vivo, and as indicator of the reaction at 435.8 nm. The integrity of the mitochondria may be demonstrated by determination of the "acceptor control index", the existence of ADP phosphorylation coupled with oxygen consumption (phosphorylating oxidation) was proved in all the cells studied even if the ADP/O ratio can only be calculated for certain of them (lymphocytes, macrophages). In these cases, the ratios obtained are close to theoretical values whatever the oxidation substrate used. The mitochondria of leukemic cells have a higher oxidation activity than the corresponding reference cells. Determination of leukocyte coenzymes by enzyme cycling (NAD, NADH, NADP, NADPH) showed the following facts: -- Generally, the NAD concentrations remain constant, those of NADH increase whilst those of NADP and NADPH fall during incubation of neutrophil polymorphs in Dulbecco's medium. -- The metabolic changes observed during S. albi heat-induced endocytosis are in favour of simultaneous stimulation of NADH oxidase and NADPH oxidase in human polymorphs, and of NADPH oxidase in the corresponding cells of peritoneal exudates in guinea pigs.

Adenosine Triphosphate↗
PubMed1979

Magnesium ion dependent adenosine triphosphatase activity of heavy meromyosin as a function of temperature between +20 and -15 degrees C.

The hydrolysis of Mg2+-adenosine 5'-triphosphate (ATP) by heavy meromyosin has been studied between +20 and -15 degrees C, especially in the low-temperature range, in a medium containing 30% (v/v) ethylene glycol by fluorometric, spectrophotometric, and potentiometric measurements. The time course of the fluorescence changes of the enzyme during the reaction depends markedly on the temperature in consequence of large differences between the activation energies of the various steps. The observed kinetics have been analyzed according to the simplified scheme of Bagshaw & Trentham [Bagshaw, C. R., & Trentham, D. R. (1974) Biochem. J. 141, 331-349]. The following results have been obtained. (1) The rate-limiting step of the reaction changes in this temperature range; at 20 degrees C M**.ADP.Pi is the predominant steady-state complex, and M*.ADP predominates at -15 degrees C, with a half-life of approximately 10 min. (2) As expected, on the basis that it is the dissociation of the M*.ADP complex which becomes rate limiting at low temperature, one observes, in the pre-steady-state below 0 degrees C, both a proton burst and a lag phase in ADP release. (3) At low temperature, the equilibrium M*.ATP in equilibrium M**.ADP.Pi is displaced to the left All the kinetic data obtained in this study are compatible with a simple pathway for the Mg2+-ATP hydrolysis by myosin and with sequential release of the reaction products.

Adenosine Triphosphatases↗
PubMed1979

Myosin isoenzyme redistribution in chronic heart overload.

Since the first observation by Spann et al., it has become clear that in cardiac hypertrophy induced by a mechanical overloading, the velocity of shortening of the cardiac muscle (Vmax) is reduced (see ref. 2 for review). Most authors agree that this mechanical alteration is accompanied by a decrease in the Ca2+-dependent ATPase activity of myosin (see ref. 3 for review). The molecular basis of such changes was unknown because the structural modifications of the myosin molecule were ill-defined. Nevertheless, it has recently been shown that, like skeletal muscle myosin, cardiac myosin is composed of several polymorphic forms, comparable to isoenzymes. In the skeletal muscle, new functional requirements can induce changes in both contractile activity and type of myosin isoenzyme synthesised. We now report that an increase in cardiac work produced by mechanical overloading in rats induces the preferential synthesis of a cardiac myosin isoenzyme characterised by specific immunological and electrophoretic properties and exhibiting a lower ATPase activity. This adaptive change could account for the reduced shortening speed of this hypertrophied cardiac muscle.

Adaptation, Physiological↗
PubMed2024

The role of co-occurring conditions and genetics in the associations of eating disorders with attention-deficit/hyperactivity disorder and autism spectrum disorder.

Eating disorders (EDs) commonly co-occur with other psychiatric and neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD); however, the pattern of family history and genetic overlap among them requires clarification. This study investigated the diagnostic, familial, and genetic associations of EDs with ADHD and ASD. The nationwide population-based cohort study included all individuals born in Denmark, 1981-2008, linked to their siblings and cousins. Cox regression was used to estimate associations between EDs and ADHD or ASD, and mediation analysis was used to assess the effects of intermediate mood or anxiety disorders. Polygenic scores (PGSs) were used to investigate the genetic association between anorexia nervosa (AN) and ADHD or ASD. Significantly increased risk for any ED was observed following an ADHD or ASD diagnosis. Mediation analysis suggested that intermediate mood or anxiety disorders could account for 44%-100% of the association between ADHD or ASD and ED. Individuals with a full sibling or maternal half sibling with ASD had increased risk of AN compared to those with siblings without ASD. A positive association was found between ASD-PGS and AN risk whereas a negative association was found between AN-PGS and ADHD. In this study, positive phenotypic associations between EDs and ADHD or ASD, mediation by mood or anxiety disorder, and genetic associations between ASD-PGS and AN and between AN-PGS and ADHD were observed. These findings could guide future research in the development of new treatments that can mitigate the development of EDs among individuals with ADHD or ASD.

Humans↗
PubMed2026

Factors influencing the enhancement&#xa0;of the new iron triangle&#xa0;in healthcare organisations.

PURPOSE: A new paradigm, "healthcare's new iron triangle," has been developed to emphasise the technological perspective of healthcare delivery, focusing on automation, value and empathy. The study aims to build a conceptual model and to identify factors for the enhancement of the new iron triangle in healthcare organisations. DESIGN/METHODOLOGY/APPROACH: The healthcare organisation is the primary focus point of the current study. To determine the factors, a survey of the literature and healthcare experts' opinions was conducted. The&#xa0;healthcare professionals validated the identified factors. Data for this study were gathered using a closed-ended questionnaire and scheduled interviews. The study employed "Total Interpretive Structural Modeling methodology and Matriced' Impacts Croise&#xb4;s Multiplication Appliqu&#xe9;&#xb4; a UN Classement/Cross-Impact Matrix Multiplication Applied to a Classification (MICMAC) analysis" to address the "why" and "how" the factors interact and prioritise the identified factors. FINDINGS: The study found that organisational structure (F8), artificial intelligence (F1), innovation (F2) and human resources (F5) are the driving or key factors of the study. RESEARCH LIMITATIONS/IMPLICATIONS: The study primarily focused on identifying factors for the enhancement of a new iron triangle in healthcare organisations. The scope could eventually be expanded to explore more areas. PRACTICAL IMPLICATIONS: Academics and other stakeholders will have a better understanding of the key drivers for the enhancement of the new iron triangle in healthcare organisations. ORIGINALITY/VALUE: In this study, total interpretive structural modeling and cross-impact MICMAC analysis are proposed as an innovative approach to address the new iron triangle in healthcare organisations.

Humans↗
PubMed1978

Optical spectroscopic study of the ADP-myosin interaction.

The binding of ADP to heavy meromyosin, and the separated subfragment 1 components S-1(A1) and S-1 (A2), has been observed by ultraviolet spectrophotometry. The results are compatible with the presence of spectroscopically equivalent and independent sites, one per head, at both 10 degrees C and 25 degrees C. We do not observe the heterogeneity of binding and of the spectroscopic response that has been reported. The binding has also been followed by other methods sensitive to the effect of ligand on the aromatic residues of the protein, viz. intrinsic fluorescence of heavy meromyosin and changes in the near-ultraviolet Cotton effects of myosin, and its active fragments. Within the limits of our experimental precision, the binding profiles, based on concentration of myosin heads, are the same for myosin as for subfragment 1. A perturbation in the circular dichroism is also generated by pyrophosphate, which competes with ADP. The spectra suggest that subsites for the purine ring and the diphosphate can be recognized. The sensitivity of binding profiles obtained by methods of the kind used here to cooperative or antagonistic interactions between the binding sites has been analysed. It is clear that sizeable effects of this nature could be concealed by the binding curves, even for high experimental precision.

Adenosine Diphosphate↗
PubMed1979

An electrophoretic study of native myosin isozymes and of their subunit content.

Myosin polymorphism in muscles has been studied by a variety of electrophoretic techniques, in non-dissociating and in dissociating conditions. The analysis of myosin isozymes in the native state was achieved in pyrophosphate buffer and required only minute amounts of protein; identical results were obtained with purified or crudely extracted myosin. The determination of the subunit content of each isozyme was done in the presence of sodium dodecyl sulphate or urea for light chain, and in a phenol, acetic acid and urea system for heavy chain screening. Electrophoresis in non-dissociating conditions has led to the separation of up to a dozen of myosin isozymes, differing in mobilities by as much as 30%. Muscle specificity of myosin was clearly established. Apart from a few exceptions, all the muscles tested were shown to contain more than one myosin species; fast-twitch muscles for instance all contained the same three isozymes, but in variable ratios. Class specificity of myosin appeared related to the relative proportions of isozymes in a given muscle. A second electrophoresis in dissociating solvents of the myosin bands first resolved in pyrophosphate buffer has then allowed a further characterization of the various isozymes. The differences in mobilities observed in the native state were shown to come either from the light chains, or from the heavy chains, or from both. The first case was illustrated by the three species present in fast muscles, which were shown to correspond to three alkali light-chain isozymes, the heterodimer representing in some instances up to 40% of the total. Next to light-chain muscle type specificity, electrophoresis in the phenol, acetic acid, urea system has led to the detection of differences in the heavy chains of fast, slow and cardiac myosins. The application of these various electrophoretic techniques to the analysis of the modification of myosin isozymes during development or in pathology studies can be considered.

Adenosine Triphosphatases↗