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BackgroundIntellectual disability (ID) affects approximately 1% of the worldwide population and individuals with ID have a higher comorbidity with mental illness, and specifically psychotic disorders. Unfortunately, among individuals with ID, limited research has been conducted since ID individuals are usually excluded from mental illness epidemiological studies and clinical trials. Here we perform a clinical trial to investigate the effectiveness of clozapine in the treatment of resistant psychosis in individuals with ID. The article highlights the complexity of diagnosing and treating psychopathological alterations associated with ID and advocates for more rigorous research in this field.MethodsA Phase IIB, open-label, randomized, multicenter clinical trial (NCT04529226) is currently ongoing to assess the efficacy of oral clozapine in individuals diagnosed with ID and suffering from treatment-resistant psychosis. We aim to recruit one-hundred and fourteen individuals (N=114) with ID and resistant psychosis, who will be randomized to TAU (treatment as usual) and treatment-with-clozapine conditions. As secondary outcomes, changes in other clinical scales (PANSS and SANS) and the improvement in functionality, assessed through changes in the Euro-QoL-5D-5L were assessed. The main outcome variables will be analyzed using generalized linear mixed models (GLMM), assessing the effects of status variable (TAU vs. Clozapine), time, and the interaction between them.DiscussionThe treatment of resistant psychosis among ID individuals must be directed by empirically supported research. CLOZAID clinical trial may provide relevant information about clinical guidelines to optimally treat adults with ID and treatment-resistant psychosis and the benefits and risks of an early use of clozapine in this underrepresented population in clinical trials.Trial registrationClinicaltrials.gov: NCT04529226. EudraCT: 2020-000091-37.

Malignant growth is defined by multiple aberrant cellular features, including metabolic rewiring, inactivation of tumor suppressors and the activation of oncogenes. Even though these features have been described as separate hallmarks, many studies have shown an extensive mutual regulatory relationship amongst them. On one hand, the change in expression or activity of tumor suppressors and oncogenes has extensive direct and indirect effects on cellular metabolism, activating metabolic pathways required for malignant growth. On the other hand, the tumor microenvironment and tumor intrinsic metabolic alterations result in changes in intracellular metabolite levels, which directly modulate the protein modification of oncogenes and tumor suppressors at both epigenetic and post-translational levels. In this mini-review, we summarize the crosstalk between tumor suppressors/oncogenes and metabolism-induced protein modifications at both levels and explore the impact of metabolic (micro)environments in shaping these.

Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases worldwide and it is associated with an increased risk of osteoporosis and fragility fractures. Our aim is to analyze the effect of T2DM on bone quality. This is a case-control study. The studied population consisted of 140 patients: 54 subjects with hip fracture (OP) without T2DM, 36 patients with hip fracture and T2DM (OP-T2DM), 28 patients with osteoarthritis (OA) without T2DM, and 22 patients with OA and T2DM (OA-T2DM). Bone markers, bone mineral density, FRAX score, microstructural, and bone material strength from femoral heads were assessed. The group with hip fracture presented lower BMD values than OA (p < 0.05). The OP, OP-T2DM, and OA-T2DM groups showed a decrease in bone volume fraction (BV/TV), in trabecular number (Tb.N), and in trabecular thickness (Tb.Th), while an increase was presented in the structural model index (SMI) and trabecular bone pattern factor (Tb.Pf), The groups OP, OP-T2DM, and OA-T2DM also presented lower values than those in group OA regarding the biomechanical parameters in the form of Young’s modulus or elastic modulus, toughness, ultimate stress, ultimate load, extrinsic stiffness, and work to failure (p < 0.05). Our results show the negative effect of type 2 diabetes mellitus on trabecular bone structure and mechanical properties.

Diet can influence tumor aggressiveness. Recently in Nature , a study by Pascual et al. provided evidence that dietary palmitic acid induces an epigenetic memory by modulating particular histone methylation marks in cancer cells. This allows cancer cells to activate extracellular matrix secretion from Schwann cells of the tumor microenvironment, which ultimately potentiates metastasis initiation. [ABSTRACT FROM AUTHOR]

Over the last two decades, major advances in the field of tumor dormancy have been made. Yet, it is not completely understood how dormant disseminated tumor cells survive and transition to a proliferative state to generate a metastatic lesion. On the other hand, metabolic rewiring has been shown to influence metastasis development through the modulation of both intracellular signaling and the crosstalk between metastatic cells and their microenvironment. Thus, studying the metabolic features of dormant disseminated tumor cells has gained importance in understanding the dormancy process. Here, we describe a method to perform metabolomics and 13 C tracer analysis in 3D cultures of dormant breast cancer cells., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Inhibition of the electron transport chain (ETC) prevents the regeneration of mitochondrial NAD + , resulting in cessation of the oxidative tricarboxylic acid (TCA) cycle and a consequent dependence upon reductive carboxylation for aspartate synthesis. NAD + regeneration alone in the cytosol can rescue the viability of ETC-deficient cells. Yet, how this occurs and whether transfer of oxidative equivalents to the mitochondrion is required remain unknown. Here, we show that inhibition of the ETC drives reversal of the mitochondrial aspartate transaminase (GOT2) as well as malate and succinate dehydrogenases (MDH2 and SDH) to transfer oxidative NAD + equivalents into the mitochondrion. This supports the NAD + -dependent activity of the mitochondrial glutamate dehydrogenase (GDH) and thereby enables anaplerosis-the entry of glutamine-derived carbon into the TCA cycle and connected biosynthetic pathways. Thus, under impaired ETC function, the cytosolic redox state is communicated into the mitochondrion and acts as a rheostat to support GDH activity and cell viability., Competing Interests: Declaration of interests S.-M.F. has received funding from Alesta Therapeutics, Bayer AG, Merck, and Black Belt Therapeutics; has consulted for Fund+; and serves on the advisory board of Alesta Therapeutics and Molecular Cell., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

T cells dynamically rewire their metabolism during an immune response. We applied single-cell RNA sequencing to CD8 + T cells activated and differentiated in vitro in physiological medium to resolve these metabolic dynamics. We identify a differential time-dependent reliance of activating T cells on the synthesis versus uptake of various non-essential amino acids, which we corroborate with functional assays. We also identify metabolic genes that potentially dictate the outcome of T cell differentiation, by ranking them based on their expression dynamics. Among them, we find asparagine synthetase (Asns), whose expression peaks for effector T cells and decays toward memory formation. Disrupting these expression dynamics by ASNS overexpression promotes an effector phenotype, enhancing the anti-tumor response of adoptively transferred CD8 + T cells in a mouse melanoma model. We thus provide a resource of dynamic expression changes during CD8 + T cell activation and differentiation, and identify ASNS expression dynamics as a modulator of CD8 + T cell differentiation., Competing Interests: Declaration of interests P.-C.H. is on the scientific advisory board for Elixiron Immunotherapeutics, Acepodia, and Novartis; has received funding from Elixiron Immunotherapeutics; and is the founder of Pilatus Biosciences. S.-M.F. has received funding from Bayer, Merck, Black Belt Therapeutics, and Alesta Therapeutics; has consulted for Fund+; and is on the scientific advisory board for Alesta Therapeutics and the editorial board of Cell Reports., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Malignant growth is defined by multiple aberrant cellular features, including metabolic rewiring, inactivation of tumor suppressors and the activation of oncogenes. Even though these features have been described as separate hallmarks, many studies have shown an extensive mutual regulatory relationship amongst them. On one hand, the change in expression or activity of tumor suppressors and oncogenes has extensive direct and indirect effects on cellular metabolism, activating metabolic pathways required for malignant growth. On the other hand, the tumor microenvironment and tumor intrinsic metabolic alterations result in changes in intracellular metabolite levels, which directly modulate the protein modification of oncogenes and tumor suppressors at both epigenetic and post-translational levels. In this mini-review, we summarize the crosstalk between tumor suppressors/oncogenes and metabolism-induced protein modifications at both levels and explore the impact of metabolic (micro)environments in shaping these., Competing Interests: S.-MF has received funding from Bayer AG, Merck, Black Belt Therapeutics and Alesta Therapeutics; has consulted for Fund+; and serves on the advisory board of Alesta Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Vandekeere, Xu, Fendt and Altea-Manzano.)

Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases worldwide and it is associated with an increased risk of osteoporosis and fragility fractures. Our aim is to analyze the effect of T2DM on bone quality. This is a case-control study. The studied population consisted of 140 patients: 54 subjects with hip fracture (OP) without T2DM, 36 patients with hip fracture and T2DM (OP-T2DM), 28 patients with osteoarthritis (OA) without T2DM, and 22 patients with OA and T2DM (OA-T2DM). Bone markers, bone mineral density, FRAX score, microstructural, and bone material strength from femoral heads were assessed. The group with hip fracture presented lower BMD values than OA ( p < 0.05). The OP, OP-T2DM, and OA-T2DM groups showed a decrease in bone volume fraction (BV/TV), in trabecular number (Tb.N), and in trabecular thickness (Tb.Th), while an increase was presented in the structural model index (SMI) and trabecular bone pattern factor (Tb.Pf), The groups OP, OP-T2DM, and OA-T2DM also presented lower values than those in group OA regarding the biomechanical parameters in the form of Young's modulus or elastic modulus, toughness, ultimate stress, ultimate load, extrinsic stiffness, and work to failure ( p < 0.05). Our results show the negative effect of type 2 diabetes mellitus on trabecular bone structure and mechanical properties.

In this manuscript, we report the development of a versatile, robust, and stable targeting nanocarrier for active delivery. This nanocarrier is based on bifunctionalized polymeric nanoparticles conjugated to a monoclonal antibody that allows for active targeting of either (i) a fluorophore for tracking or (ii) a drug for monitoring specific cell responses. This nanodevice can efficiently discriminate between cells in coculture based on the expression levels of cell surface receptors. As a proof of concept, we have demonstrated efficient delivery using a broadly established cell surface receptor as the target, the epidermal growth factor receptor (EGFR), which is overexpressed in several types of cancers. Additionally, a second validation of this nanodevice was successfully carried out using another cell surface receptor as the target, the cluster of differentiation 147 (CD147). Our results suggest that this versatile nanocarrier can be expanded to other cell receptors and bioactive cargoes, offering remarkable discrimination efficiency between cells with different expression levels of a specific marker. This work supports the ability of nanoplatforms to boost and improve the progress towards personalized medicine.

In tumors, nutrient availability and metabolism are known to be important modulators of growth signaling. However, it remains elusive whether cancer cells that are growing out in the metastatic niche rely on the same nutrients and metabolic pathways to activate growth signaling as cancer cells within the primary tumor. We discovered that breast-cancer-derived lung metastases, but not the corresponding primary breast tumors, use the serine biosynthesis pathway to support mTORC1 growth signaling. Mechanistically, pyruvate uptake through Mct2 supported mTORC1 signaling by fueling serine biosynthesis-derived α-ketoglutarate production in breast-cancer-derived lung metastases. Consequently, expression of the serine biosynthesis enzyme PHGDH was required for sensitivity to the mTORC1 inhibitor rapamycin in breast-cancer-derived lung tumors, but not in primary breast tumors. In summary, we provide in vivo evidence that the metabolic and nutrient requirements to activate growth signaling differ between the lung metastatic niche and the primary breast cancer site., Competing Interests: Declaration of Interests S.-M.F. has received funding from Bayer AG, Merck, and Black Belt Therapeutics; has consulted for Fund+; and serves on the advisory board of Molecular Cell. All other authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Nutrients are indispensable resources that provide the macromolecular building blocks and energy requirements for sustaining cell growth and survival. Cancer cells require several key nutrients to fulfill their changing metabolic needs as they progress through stages of development. Moreover, both cell-intrinsic and microenvironment-influenced factors determine nutrient dependencies throughout cancer progression-for which a comprehensive characterization remains incomplete. In addition to the widely studied role of genetic alterations driving cancer metabolism, nutrient use in cancer tissue may be affected by several factors including the following: (i) diet, the primary source of bodily nutrients which influences circulating metabolite levels; (ii) tissue of origin, which can influence the tumor's reliance on specific nutrients to support cell metabolism and growth; (iii) local microenvironment, which dictates the accessibility of nutrients to tumor cells; (iv) tumor heterogeneity, which promotes metabolic plasticity and adaptation to nutrient demands; and (v) functional demand, which intensifies metabolic reprogramming to fuel the phenotypic changes required for invasion, growth, or survival. Here, we discuss the influence of these factors on nutrient metabolism and dependence during various steps of tumor development and progression., (© 2020 The Authors.)

Metabolism is at the cornerstone of all cellular functions and mounting evidence of its deregulation in different diseases emphasizes the importance of a comprehensive understanding of metabolic regulation at the whole-organism level. Stable-isotope measurements are a powerful tool for probing cellular metabolism and, as a result, are increasingly used to study metabolism in in vivo settings. The additional complexity of in vivo metabolic measurements requires paying special attention to experimental design and data interpretation. Here, we review recent work where in vivo stable-isotope measurements have been used to address relevant biological questions within an in vivo context, summarize different experimental and data interpretation approaches and their limitations, and discuss future opportunities in the field., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Metastasis formation is the leading cause of death in cancer patients. It has recently emerged that cancer cells adapt their metabolism to successfully transition through the metastatic cascade. Consequently, measuring and analyzing the in vivo metabolism of metastases has the potential to reveal novel treatment strategies to prevent metastasis formation. Here, we describe two different metastasis mouse models and how their metabolism can be analyzed with metabolomics and 13 C tracer analysis.

Aim: To develop an efficient nanotechnology fluorescence-based method to track cell proliferation to avoid the limitations of current cell-labeling dyes., Material & Methods: Synthesis, PEGylation, bifunctionalization and labeling with a fluorophore (Cy5) of 200 nm polystyrene nanoparticles (NPs) were performed. These NPs were characterized and assessed for in vitro long-term monitoring of cell proliferation., Results: The optimization and validation of this method to track long-term cell proliferation assays have been achieved with high reproducibility, without cell cycle disruption. This method has been successfully applied in several adherent and suspension cells including hard-to-transfect cells and isolated human primary lymphocytes., Conclusion: A novel approach to track efficiently cellular proliferation by flow cytometry using fluorescence labeled NPs has been successfully developed. [Formula: see text].

Engineered nanoparticles (eNPs) for biological and biomedical applications are produced from functionalised nanoparticles (NPs) after undergoing multiple handling steps, giving rise to an inevitable loss of NPs. Herein we present a practical method to quantify nanoparticles (NPs) number per volume in an aqueous suspension using standard spectrophotometers and minute amounts of the suspensions (up to 1 μL). This method allows, for the first time, to analyse cellular uptake by reporting NPs number added per cell, as opposed to current methods which are related to solid content (w/V) of NPs. In analogy to the parameter used in viral infective assays (multiplicity of infection), we propose to name this novel parameter as multiplicity of nanofection.