Search

INTRODUCCIÓN El diagnóstico de Tumores Malignos Primarios Múltiples (MPM) comprende solo el 1-6% de todas las neoplasias ginecológicas. Los tumores sincrónicos (o duales) son aquellos que surgen simultáneamente o dentro de 6 meses del diagnóstico del primer tumor; siendo más usuales entre ovario y endometrio (histología endometrioide) y también con cánceres de colon-recto y mama. MATERIALES Y MÉTODOS Se reporta un caso que describe dos tumores sincrónicos primarios que afectan el endometrio y pulmón. Se realizó una búsqueda electrónica sistemática de la relación ya descrita de tumores duales en PubMed, ScienceDirect, EBSCOhost, Ovid y documentos de estadística del Instituto Nacional de Cancerología. DESCRIPCIÓN DEL CASO Paciente de 59 años, hipertensa controlada, g8p8v8, con diagnóstico de adenocarcinoma de endometrio tipo endometrioide, FIGO 2, grado nuclear 2. IMC:28,4. Examen físico sin alteraciones, por probable estadio I se programó cirugía. En estudios prequirúrgicos, TAC abdomino-pélvico informa lesión nodular endometrial de 22mm hasta el OCI, sin compromiso del contorno uterino ni parametrios, TAC de tórax muestra nódulo basal derecho bilobulado sospechoso de 16x11mm. A quien se realiza cirugía oncológica (sept/2017) por grupo de cirugía de tórax: toracoscopia con biopsia en cuña + toracostomía, seguido por ginecología: Histerectomía total + salpingooforectomía bilateral + protocolo de ganglio centinela bilateral por laparoscopia. Con diagnóstico patológico definitivo: Adenocarcinoma Endometrioide FIGO 2, grado nuclear 2, invasión miometrial 60%, sin ILV, compromiso de istmo y estroma cervical, sincrónico con adenocarcinoma invasor primario pulmonar de patrón lepídico y focos de diseminación intraalveolar. Se consideró tumor dual endometrio Estadio II/Pulmonar Estadio IA1. Cirugía de tórax decide toracotomía 2 meses después con lobectomía basal derecha reportando bordes tumorales libres, actualmente en seguimiento. Desde el punto de vista ginecológico tratamiento adyuvante radioterapia pélvica. DISCUSIÓN Y CONCLUSIONES El caso descrito representa tumores sincrónicos entre cáncer endometrial y pulmonar. La incidencia en Colombia para el cáncer endometrial es 3.6/100.000 y del cáncer pulmonar en mujeres de 6.6/100.000 con una mortalidad para cada uno de 0.8/100.000 y 6.8/100.000 mujeres. En la literatura revisada, se encontró solo un caso similar al nuestro. En contraste a esto los estudios con cohortes de seguimiento en pacientes tratadas con primario endometrial reportan la aparición de un segundo primario pulmonar en 0.4% casos (metacrónicos). Para diagnosticar tumores sincrónicos, cada tumor debe representar una imagen definida de la malignidad, tener perfil inmunohistoquímico distinto y descartarse origen tumoral secundario, lo cual define una estrategia terapéutica diferente para cada tumor primario con un pronóstico favorable. Resaltando este caso de tumores duales por su rara aparición descrita en la literatura endometrio-pulmón, al excluirse compromiso secundario y la importancia del manejo multidisciplinario con resultados óptimos oncológicos en tumores sincrónicos. [ABSTRACT FROM AUTHOR]

Access to justice is limited for many worldwide. Although prior research generally recognizes the legal needs and barriers faced by women, less is known about mothers. This study examined the legal needs of mothers in different family configurations and the actions they took in response to these needs through the lens of help-seeking theories. We used unique data from the 2016 Colombian Quality of Life Survey (QLS) to produce descriptive statistics on the legal needs of mothers in two-parent families and custodial mothers. We then conducted multivariate analyses to examine the factors associated with having a family issue and seeking institutional help. Custodial mothers were more likely than mothers in two-parent families to have reported any legal need, and to report a family legal issue. The most frequent legal issues related to the family were issues with child support, custody, and/or visitation. The most frequent action taken to resolve issues was through an institutional actor. Among custodial mothers, single, younger mothers and mothers with more children were more likely to experience family legal issues, but they were not the ones seeking institutional help-those mothers were often more socioeconomically advantaged. That more socioeconomically disadvantaged mothers are more likely to experience a family legal issue but less likely to seek institutional help, the most frequent route to action, calls for research that examines the barriers faced by these mothers and policies to improve their access to justice., (© 2023 Family Process Institute.)

GRIN-related disorders are rare developmental encephalopathies with variable manifestations and limited therapeutic options. Here, we present the first non-randomized, open-label, single-arm trial (NCT04646447) designed to evaluate the tolerability and efficacy of L-serine in children with GRIN genetic variants leading to loss-of-function. In this phase 2A trial, patients aged 2-18 years with GRIN loss-of-function pathogenic variants received L-serine for 52 weeks. Primary end points included safety and efficacy by measuring changes in the Vineland Adaptive Behavior Scales, Bayley Scales, age-appropriate Wechsler Scales, Gross Motor Function-88, Sleep Disturbance Scale for Children, Pediatric Quality of Life Inventory, Child Behavior Checklist and the Caregiver-Teacher Report Form following 12 months of treatment. Secondary outcomes included seizure frequency and intensity reduction and EEG improvement. Assessments were performed 3 months and 1 day before starting treatment and 1, 3, 6 and 12 months after beginning the supplement. Twenty-four participants were enrolled (13 males/11 females, mean age 9.8 years, SD 4.8), 23 of whom completed the study. Patients had GRIN2B, GRIN1 and GRIN2A variants (12, 6 and 5 cases, respectively). Their clinical phenotypes showed 91% had intellectual disability (61% severe), 83% had behavioural problems, 78% had movement disorders and 58% had epilepsy. Based on the Vineland Adaptive Behavior Composite standard scores, nine children were classified as mildly impaired (cut-off score > 55), whereas 14 were assigned to the clinically severe group. An improvement was detected in the Daily Living Skills domain (P = 0035) from the Vineland Scales within the mild group. Expressive (P = 0.005), Personal (P = 0.003), Community (P = 0.009), Interpersonal (P = 0.005) and Fine Motor (P = 0.031) subdomains improved for the whole cohort, although improvement was mostly found in the mild group. The Growth Scale Values in the Cognitive subdomain of the Bayley-III Scale showed a significant improvement in the severe group (P = 0.016), with a mean increase of 21.6 points. L-serine treatment was associated with significant improvement in the median Gross Motor Function-88 total score (P = 0.002) and the mean Pediatric Quality of Life total score (P = 0.00068), regardless of severity. L-serine normalized the EEG pattern in five children and the frequency of seizures in one clinically affected child. One patient discontinued treatment due to irritability and insomnia. The trial provides evidence that L-serine is a safe treatment for children with GRIN loss-of-function variants, having the potential to improve adaptive behaviour, motor function and quality of life, with a better response to the treatment in mild phenotypes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Juvenile xanthogranuloma is the most frequent form of non-Langerhans cell histiocytosis in children. Clinically, it presents as well defined, yellowish papules that are typically located on the head, neck, upper trunk, and proximal region of the extremities. Although solitary lesions are the most common presentation, few cases of multiple juvenile xanthogranuloma have been described, more frequently associated with extracutaneous involvement. We report a 2-month-old girl with 22 cutaneous papules, clinically and histologically compatible with juvenile xanthogranulomas. Screening of visceral involvement was performed with no evidence of systemic disease. Identifying high-risk factors of systemic disease in patients with multiple juvenile xanthogranuloma is essential to perform an appropriate management of this entity.

Pathogenic variants in KANSL1 and 17q21.31 microdeletions are causative of Koolen-de Vries syndrome (KdVS), a neurodevelopmental syndrome with characteristic facial dysmorphia. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes have identifiable patterns of DNA methylation (DNAm) change: DNAm signatures or episignatures. Given the role of KANSL1 in histone acetylation, we tested whether variants underlying KdVS are associated with a DNAm signature. We profiled whole-blood DNAm for 13 individuals with KANSL1 variants, four individuals with 17q21.31 microdeletions, and 21 typically developing individuals, using Illumina's Infinium EPIC array. In this study, we identified a robust DNAm signature of 456 significant CpG sites in 8 individuals with KdVS, a pattern independently validated in an additional 7 individuals with KdVS. We also demonstrate the diagnostic utility of the signature and classify two KANSL1 VUS as well as four variants in individuals with atypical clinical presentation. Lastly, we investigated tissue-specific DNAm changes in fibroblast cells from individuals with KdVS. Collectively, our findings contribute to the understanding of the epigenetic landscape related to KdVS and aid in the diagnosis and classification of variants in this structurally complex genomic region., (© 2024. The Author(s).)

Introduction: RA patients are at higher risk of cardiovascular disease, influenced by therapies. Studying their cardiovascular and cardiometabolic proteome can unveil biomarkers and insights into related biological pathways., Methods: This study included two cohorts of RA patients: newly diagnosed individuals (n=25) and those with established RA (disease duration >25 years, n=25). Both cohorts were age and sex-matched with a control group (n=25). Additionally, a longitudinal investigation was conducted on a cohort of 25 RA patients treated with methotrexate and another cohort of 25 RA patients treated with tofacitinib for 6 months. Clinical and analytical variables were recorded, and serum profiling of 184 proteins was performed using the Olink technology platform., Results: RA patients exhibited elevated levels of 75 proteins that might be associated with cardiovascular disease. In addition, 24 proteins were increased in RA patients with established disease. Twenty proteins were commonly altered in both cohorts of RA patients. Among these, elevated levels of CTSL1, SORT1, SAA4, TNFRSF10A, ST6GAL1 and CCL18 discriminated RA patients and HDs with high specificity and sensitivity. Methotrexate treatment significantly reduced the levels of 13 proteins, while tofacitinib therapy modulated the expression of 10 proteins. These reductions were associated with a decrease in DAS28. Baseline levels of SAA4 and high levels of BNP were associated to the non-response to methotrexate. Changes in IL6 levels were specifically linked to the response to methotrexate. Regarding tofacitinib, differences in baseline levels of LOX1 and CNDP1 were noted between non-responder and responder RA patients. In addition, response to tofacitinib correlated with changes in SAA4 and TIMD4 levels., Conclusion: In summary, this study pinpoints molecular changes linked to cardiovascular disease in RA and proposes candidate protein biomarkers for distinguishing RA patients from healthy individuals. It also highlights how methotrexate and tofacitinib impact these proteins, with distinct alterations corresponding to each drug's response, identifying potential candidates, as SAA4, for the response to these therapies., Competing Interests: CP-S, NB, YH, and J-MM-M were co-founders of Cobiomic Biosciences S.L. 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 © 2024 Cuesta-López, Escudero-Contreras, Hanaee, Pérez-Sánchez, Ruiz-Ponce, Martínez-Moreno, Pérez-Pampin, González, Plasencia-Rodriguez, Martínez-Feito, Balsa, López-Medina, Ladehesa-Pineda, Rojas-Giménez, Ortega-Castro, Calvo-Gutiérrez, López-Pedrera, Collantes-Estévez, Arias-de la Rosa and Barbarroja.)

Hepatoid gastric adenocarcinoma (HGA) is a rare subtype of gastric cancer. It usually presents with non-specific digestive tract symptoms and is usually diagnosed in advanced stages. It has radiological and histological similarities to hepatocarcinoma (HCC), and serum elevation of alpha-fetoprotein (AFP) is characteristic, as is positive staining for this marker on immunohistochemistry. Given the low incidence and poor prognosis of this type of tumour, it is essential to make a correct differential diagnosis and to initiate early surgical treatment in localised stages and systemic treatment in those where the disease is disseminated. In this context, we present the case of a GHA diagnosed this year in our centre.

Background: The aim of this study was to explore the impact of arthritis on liver function using different approaches in vivo and in vitro., Methods: A cross-sectional study was performed on 330 non-obese/non-T2DM subjects: 180 RA patients, 50 NAFLD non-RA patients, and 100 healthy donors (HDs). A longitudinal study was conducted on 50 RA patients treated with methotrexate for six months. Clinical and laboratory parameters and markers of liver disease were collected. Mechanistic studies were carried out in both the CIA mouse model and hepatocytes treated with anti-citrullinated protein antibodies (ACPAs)., Results: RA patients have an increased risk of suffering from liver disease independent of obesity or T2DM. This risk was associated with factors such as insulin resistance, autoantibodies, inflammation, and component C3. Methotrexate treatment for six months was associated with liver abnormalities in those newly-diagnosed patients having CV risk factors. ACPAs induced a defective hepatocyte function, promoting IR and inflammation. The induction of arthritis in mice caused the infiltration of immune cells in the liver and increased inflammatory, apoptotic, and fibrotic processes., Conclusion: RA patients may experience mild to moderate liver inflammation due to the infiltration of T, B cells, and macrophages, and the action of ACPAs. This is independent of obesity or diabetes and linked to systemic inflammation, and disease activity levels. The negative effects of methotrexate on liver function could be restricted to the concomitant presence of cardiovascular risk factors., Competing Interests: Declaration of Competing Interest None of the authors has any conflicts of interest, financial or otherwise to disclosure., (Copyright © 2023. Published by Elsevier B.V.)

Background: The occurrence of liver abnormalities in Psoriatic Arthritis (PsA) has gained significant recognition. Identifying key factors at the clinical and molecular level can help to detect high-risk patients for non-alcoholic fatty liver disease in PsA., Objectives: to investigate the influence of PsA and cumulative doses of methotrexate on liver function through comprehensive in vivo and in vitro investigations., Methods: A cross-sectional study involving 387 subjects was conducted, 200 patients with PsA, 87 NAFLD-non-PsA patients, and 100 healthy donors (HDs), age and sex-matched. Additionally, a retrospective longitudinal study was carried out, including 83 PsA patients since initiation with methotrexate. Detailed clinical, and laboratory parameters along with liver disease risk were analyzed. In vitro, experiments with hepatocyte cell line (HEPG2) were conducted., Results: PsA patients present increased liver disease risk associated with the presence of cardiometabolic comorbidities, inflammatory markers, onychopathy, and psoriasis. The treatment with PsA serum on hepatocytes encompassed inflammatory, fibrotic, cell stress, and apoptotic processes. At the molecular level, methotrexate impacts liver biology, although the cumulative doses did not affect those alterations, causing any potential damage to liver function at the clinical level. Finally, anti-PDE-4 or anti-JAK decreased the inflammatory profile induced by PsA serum on hepatocytes., Conclusion: 1)This study identifies the complex link between liver disease risk, comorbidities, and disease-specific features in PsA patients. 2)Methotrexate dose in PsA patients had no significant effect on liver parameters, confirmed by hepatocyte in vitro studies. 3)Anti-PDE-4 and anti-JAK therapies show promise in reducing PsA serum-induced hepatocyte activation, potentially aiding liver complication management., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest. C.P-S and N.B are co-founders of Cobiomic Bioscience S.L., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Germ line predisposition in acute myeloid leukemia (AML) has gained attention in recent years because of a nonnegligible frequency and an impact on management of patients and their relatives. Risk alleles for AML development may be present in patients without a clinical suspicion of hereditary hematologic malignancy syndrome. In this study we investigated the presence of germ line variants (GVs) in 288 genes related to cancer predisposition in 47 patients with available paired, tumor-normal material, namely bone marrow stroma cells (n = 29), postremission bone marrow (n = 17), and saliva (n = 1). These patients correspond to 2 broad AML categories with heterogeneous genetic background (AML myelodysplasia related and AML defined by differentiation) and none of them had phenotypic abnormalities, previous history of cytopenia, or strong cancer aggregation. We found 11 pathogenic or likely pathogenic variants, 6 affecting genes related to autosomal dominant cancer predisposition syndromes (ATM, DDX41, and CHEK2) and 5 related to autosomal recessive bone marrow failure syndromes (FANCA, FANCM, SBDS, DNAJC21, and CSF3R). We did not find differences in clinical characteristics nor outcome between carriers of GVs vs noncarriers. Further studies in unselected AML cohorts are needed to determine GV incidence and penetrance and, in particular, to clarify the role of ATM nonsense mutations in AML predisposition., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

This paper aims to analyze the link between environmental degradation and institutional quality and the price of oil moderated by economic complexity and the underground economy. We use quantile regressions with annual panel data for 15 countries in the Middle East and North Africa during 1995-2021. The findings indicate that institutional quality, economic complexity, and output positively and heterogeneously impact environmental degradation. However, the square of production has a negative impact, confirming an inverted U relationship between production and environmental degradation. Likewise, we find that the price of oil and the underground economy have a negative and heterogeneous impact on environmental degradation. Based on our results, a potential recommendation for policymakers is that the institutional framework of Middle Eastern and North African countries should be accompanied by a more significant concern for the environment instead of prioritizing extractive growth that is detrimental to the environment's environmental sustainability. Likewise, economic diversification will mitigate environmental degradation and improve formal employment. Our findings are relevant to policymakers and researchers interested in promoting ecological sustainability., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We examined the role of couples' division of labor in the risk of union dissolution among parents of young children in Chile. We looked at whether specialization in the labor market and domestic work predicts union dissolution, and whether these associations differ by parents' marital status and mother's education. Using panel data from the Chilean Encuesta Longitudinal de Primera Infancia (ELPI) 2010 and 2012 waves, we found that specialization in the division of labor is associated with a lower probability of union dissolution among parents of young children in Chile. Unlike prior evidence for the US and the Netherlands, specialization is stabilizing for both married and cohabiting couples. However, there are differences by mother's education. Among mothers with high school education or less, specialization in the division of labor is associated with a lower probability of divorce and separation. On the other hand, among mothers with at least some college education, specialization has no advantage over equality in generating more union stability. Our findings shed light on how the interaction of couple's division of labor and socioeconomic disadvantage may create unequal economic prospects for women and their children following union dissolution., Competing Interests: Conflicts of interest/Competing interests: Not applicable.

Manufacturing is one of the primary sources of environmental pollution due to the emission of polluting gases and waste generation. This research aims to examine the manufacturing industry's effect on an environmental pollution index in nineteen Latin American countries using non-linear methods. The youth population, globalization, property rights, civil liberties, the unemployment gap, and government stability moderate the relationship between the two variables. The research has a temporal coverage between 1990 and 2017 and uses threshold regressions to verify the hypotheses. In order to obtain more specific inferences, we group countries according to the trade block and geographic region to which they belong. Our findings indicate that manufacturing has limited explanatory power for environmental pollution. This finding is supported by the fact that the manufacturing industry in the region is scarce. In addition, we find a threshold effect on the youth population, globalization, property rights, civil liberties, and government stability. Consequently, our results highlight the importance of institutional factors in designing and applying environmental mitigation mechanisms in developing regions., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Development of precision medicine requires the identification of easily detectable and druggable biomarkers. Despite recent targeted drug approvals, prognosis of acute myeloid leukemia (AML) patients needs to be greatly improved, as relapse and refractory disease are still difficult to manage. Thus, new therapeutic approaches are needed. Based on in silico-generated preliminary data and the literature, the role of the prolactin (PRL)-mediated signaling was interrogated in AML., Methods: Protein expression and cell viability were determined by flow cytometry. Repopulation capacity was studied in murine xenotransplantation assays. Gene expression was measured by qPCR and luciferase-reporters. SA-β-Gal staining was used as a senescence marker., Results: The prolactin receptor (PRLR) was upregulated in AML cells, as compared to their healthy counterpart. The genetic and molecular inhibition of this receptor reduced the colony-forming potential. Disruption of the PRLR signaling, either using a mutant PRL or a dominant-negative isoform of PRLR, reduced the leukemia burden in vivo, in xenotransplantation assays. The expression levels of PRLR directly correlated with resistance to cytarabine. Indeed, acquired cytarabine resistance was accompanied with the induction of PRLR surface expression. The signaling associated to PRLR in AML was mainly mediated by Stat5, in contrast to the residual function of Stat3. In concordance, Stat5 mRNA was significantly overexpressed at mRNA levels in relapse AML samples. A senescence-like phenotype, measured by SA-β-gal staining, was induced upon enforced expression of PRLR in AML cells, partially dependent on ATR. Similar to the previously described chemoresistance-induced senescence in AML, no cell cycle arrest was observed. Additionally, the therapeutic potential of PRLR in AML was genetically validated., Conclusions: These results support the role of PRLR as a therapeutic target for AML and the further development of drug discovery programs searching for specific PRLR inhibitors., (© 2023. The Author(s).)

Background: Chronic stress can produce a severe negative impact on health not only in the exposed individuals but also in their offspring. Indeed, chronic stress may be contributing to the current worldwide scenario of increasing infertility and decreasing gamete quality in human populations. Here, we evaluate the effect of chronic stress on behavior and male reproductive parameters in zebrafish. Our goal is to provide information on the impact that chronic stress has at molecular, histological, and physiological level in a vertebrate model species., Results: We evaluated the effects of a 21-day chronic stress protocol covering around three full waves of spermatogenesis in Danio rerio adult males. The induction of chronic stress produced anxiety-like behavior in stressed males as assessed by a novel tank test. At a molecular level, the induction of chronic stress consistently resulted in the overexpression of two genes related to endoplasmic reticulum (ER) stress in the brain. Gene set enrichment analysis (GSEA) of testes suggested a dysregulation of the nonsense-mediated decay (NMD) pathway, which was also confirmed on qPCR analysis. Histological analysis of the testicle did not show significant differences in terms of the relative proportions of each germ-cell type; however, the quality of sperm from stressed males was compromised in terms of motility. RNA-seq analysis in stress-derived larval progenies revealed molecular alterations, including those predicted to affect translation initiation, DNA repair, cell cycle control, and response to stress., Conclusions: Induction of chronic stress during a few cycles of spermatogenesis in the vertebrate zebrafish model affects behavior, gonadal gene expression, final gamete quality, and progeny. The NMD surveillance pathway (a key cellular mechanism that regulates the stability of both normal and mutant transcripts) is severely affected in the testes by chronic stress and therefore the control and regulation of RNAs during spermatogenesis may be affected altering the molecular status in the progeny., (© 2023. The Author(s).)

Objectives: 1) To characterize the inflammatory proteome of synovial fluid (SF) from patients with Psoriatic Arthritis (PsA) using a high-quality throughput proteomic platform, and 2) to evaluate its potential to stratify patients according to clinical features., Methods: Inflammatory proteome profile of SF from thirteen PsA patients with active knee arthritis were analyzed using proximity extension assay (PEA) technology (Olink Target 96 Inflammation panel). Four patients with OA were included as control group., Results: Seventy-nine inflammation-related proteins were detected in SF from PsA patients (SF-PsA). Unsupervised analyzes of the molecular proteome profile in SF-PsA identified two specific phenotypes characterized by higher or lower levels of inflammation-related proteins. Clinically, SF-PsA with higher levels of inflammatory proteins also showed increased systemic inflammation and altered glucose and lipid metabolisms. Besides, SF from PsA patients showed 39 out of 79 proteins significantly altered compared to SF-OA specifically related to cell migration and inflammatory response. Among these, molecules such as TNFα, IL-17A, IL-6, IL-10, IL-8, ENRAGE, CCL20, TNFSF-14, OSM, IFNγ, MCP-3, CXCL-11, MCP4, CASP-8, CXCL-6, CD-6, ADA, CXCL-10, TNFβ and IL-7 showed the most significantly change., Conclusion: This is the first study that characterizes the inflammatory landscape of synovial fluid of PsA patients by analyzing a panel of 92 inflammatory proteins using PEA technology. Novel SF proteins have been described as potential pathogenic molecules involved in the pathogenesis of PsA. Despite the flare, inflammatory proteome could distinguish two different phenotypes related to systemic inflammation and lipid and glucose alterations., Competing Interests: Authors NB, CP-S and CL-M were co-founders of the company Cobiomic Bioscience S.L. 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 © 2023 Barbarroja, López-Montilla, Cuesta-López, Pérez-Sánchez, Ruiz-Ponce, López-Medina, Ladehesa-Pineda, López-Pedrera, Escudero-Contreras, Collantes-Estévez and Arias-de la Rosa.)

Acute myeloid leukemia (AML) is a heterogeneous hematological cancer characterized by poor prognosis and frequent relapses. Aside from specific mutation-related changes, in AML, the overall function of lysosomes and mitochondria is drastically altered to fulfill the elevated biomass and bioenergetic demands. On the basis of previous results, in silico drug discovery screening was used to identify a new family of lysosome-/mitochondria-targeting compounds. These novel tetracyclic hits, with a cationic amphiphilic structure, specifically eradicate leukemic cells by inducing both mitochondrial damage and apoptosis, and simultaneous lysosomal membrane leakiness. Lysosomal leakiness does not only elicit canonical lysosome-dependent cell death, but also activates the terminal differentiation of AML cells through the Ca 2+ -TFEB-MYC signaling axis. In addition to being an effective monotherapy, its combination with the chemotherapeutic arsenic trioxide (ATO) used in other types of leukemia is highly synergistic in AML cells, widening the therapeutic window of the treatment. Moreover, the compounds are effective in a wide panel of cancer cell lines and possess adequate pharmacological properties rendering them promising drug candidates for the treatment of AML and other neoplasias., Competing Interests: Josep Carreras Leukaemia Research Institute has filed a patent application related to this work (PCT/EP2021/082705) in which R.M.R., J.M.C., and J.M.C.M. are listed as inventors. R.M.R. is a shareholder of Leukos Biotech.

Liver disease is one of the most important causes of morbidity and mortality worldwide whose prevalence is dramatically increasing. The first sign of hepatic damage is inflammation which could be accompanied by the accumulation of fat called non-alcoholic fatty liver disease (NAFLD), causing damage in the hepatocytes. This stage can progress to fibrosis where the accumulation of fibrotic tissue replaces healthy tissue reducing liver function. The next stage is cirrhosis, a late phase of fibrosis where a high percentage of liver tissue has been replaced by fibrotic tissue and liver functionality is substantially impaired. There is a close interplay of cardiovascular disease (CVD) and hepatic alterations, where different mechanisms mediating this relation between the liver and systemic vasculature have been described. In chronic inflammatory diseases such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), in which the CVD risk is high, hepatic alterations seem to be more prevalent compared to the general population and other rheumatic disorders. The pathogenic mechanisms involved in the development of this comorbidity are still unraveled, although chronic inflammation, autoimmunity, treatments, and metabolic deregulation seem to have an important role. In this review, we will discuss the involvement of liver disease in the cardiovascular risk associated with inflammatory arthritis, the pathogenic mechanisms, and the recognized factors involved. Likewise, monitoring of the liver disease risk in routine clinical practice through both, classical and novel techniques and indexes will be exposed. Finally, we will examine the latest controversies that have been raised about the effects of the current therapies used to control the inflammation in RA and PsA, in the liver damage of those patients, such as methotrexate, leflunomide or biologics., Competing Interests: The 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 Barbarroja, Ruiz-Ponce, Cuesta-López, Pérez-Sánchez, López-Pedrera, Arias-de la Rosa and Collantes-Estévez.)

Latin America experiences an increasing urban primacy index and a rapid expansion of the financial system, putting direct pressure on the demand for resources to satisfy the consumption of large cities. We investigate the convergence of per capita biocapacity in 16 Latin America countries and evaluate the factors that influence its evolution over time. Specifically, we analyze the impact of the urban primacy index, economic progress, and the financial globalization index on the convergence of per capita biocapacity. We use the methodological framework developed by Phillips and Sul Econometrica 75:1771-1855, (2007) to analyze the convergence and the formation of convergence clubs of biocapacity during 1970-2017. The findings indicate that the countries of the region do not share a common trend of biocapacity, although they are grouped into five converging clubs. Biocapacity transition analysis reveals that countries have heterogeneous transition pathways between them. Using marginal effects, we find that the urban primacy index and economic progress reduce the biocapacity. The effect of the financial globalization index on biocapacity is not conclusive. The quantile regressions reveal that quantiles' impact of the urban primacy index and financial globalization on per capita biocapacity is heterogeneous. However, the effect of economic progress on biocapacity that predominates among quantiles is positive. The adoption of common policies among the countries that form the converging clubs could improve the effectiveness of pro-environmental policies and promote the achievement of the Sustainable Development Goals related to environmental quality., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We aimed to evaluate the association between adipose tissue (AT) dysfunction, autoimmunity, and disease activity in rheumatoid arthritis (RA). A cross-sectional study including 150 RA patients and 50 healthy donors and longitudinal study with 122 RA patients treated with anti-tumor necrosis factor (TNF)-α, anti-interleukin 6 receptor (IL6R) or anti-CD20 therapies for 6 months were carried out. In vitro experiments with human AT and adipocyte and macrophage cell lines were performed. A collagen-induced arthritis mouse model was developed. The insulin resistance and the altered adipocytokine profile were associated with disease activity, the presence of anti-citrullinated proteins anti-bodies (ACPAs), and worse response to therapy in RA. AT in the context of arthritis is characterized by an inflammatory state alongside the infiltration of macrophages and B/plasmatic cells, where ACPAs can have a direct impact, inducing inflammation and insulin resistance in macrophages and promoting a defective adipocyte differentiation, partially restored by biologicals., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Despite the outstanding advances in understanding the biology underlying the pathophysiology of acute myeloid leukemia (AML) and the promising preclinical data published lastly, AML treatment still relies on a classic chemotherapy regimen largely unchanged for the past five decades. Recently, new drugs have been approved for AML, but the real clinical benefit is still under evaluation. Nevertheless, primary refractory and relapse AML continue to represent the main clinical challenge, as the majority of AML patients will succumb to the disease despite achieving a complete remission during the induction phase. As such, treatments for chemoresistant AML represent an unmet need in this disease. Although great efforts have been made to decipher the biological basis for leukemogenesis, the mechanism by which AML cells become resistant to chemotherapy is largely unknown. The identification of the signaling pathways involved in resistance may lead to new combinatory therapies or new therapeutic approaches suitable for this subset of patients. Several mechanisms of chemoresistance have been identified, including drug transporters, key secondary messengers, and metabolic regulators. However, no therapeutic approach targeting chemoresistance has succeeded in clinical trials, especially due to broad secondary effects in healthy cells. Recent research has highlighted the importance of lysosomes in this phenomenon. Lysosomes' key role in resistance to chemotherapy includes the potential to sequester drugs, central metabolic signaling role, and gene expression regulation. These results provide further evidence to support the development of new therapeutic approaches that target lysosomes in AML., (© The Author(s) 2022.)

Background: GRIN-related disorders (GRD), the so-called grinpathies, is a group of rare encephalopathies caused by mutations affecting GRIN genes (mostly GRIN1 , GRIN2A and GRIN2B genes), which encode for the GluN subunit of the N -methyl D-aspartate (NMDA) type ionotropic glutamate receptors. A growing number of functional studies indicate that GRIN-encoded GluN1 subunit disturbances can be dichotomically classified into gain- and loss-of-function, although intermediate complex scenarios are often present., Methods: In this study, we aimed to delineate the structural and functional alterations of GRIN1 disease-associated variants, and their correlations with clinical symptoms in a Spanish cohort of 15 paediatric encephalopathy patients harbouring these variants., Results: Patients harbouring GRIN1 disease-associated variants have been clinically deeply-phenotyped. Further, using computational and in vitro approaches, we identified different critical checkpoints affecting GluN1 biogenesis (protein stability, subunit assembly and surface trafficking) and/or NMDAR biophysical properties, and their association with GRD clinical symptoms., Conclusions: Our findings show a strong correlation between GRIN1 variants-associated structural and functional outcomes. This structural-functional stratification provides relevant insights of genotype-phenotype association, contributing to future precision medicine of GRIN1-related encephalopathies.

Despite the success of immunotherapy in several haematological neoplasms, the effectiveness in acute myeloid leukaemia (AML) is still controversial, partially due to the lack of knowledge regarding immune-related processes in this disease and similar neoplasias. In this study, we analysed the role and expression of histamine receptor 1 (HRH1) in haematological malignancies. Although the histamine receptor type 1 was widely expressed in healthy and malignant haematopoiesis, especially along the myeloid lineage, HRH1 lacked a relevant role in survival/proliferation and chemoresistance of AML cells, as analysed by HRH1 knockdown (KD) and pharmacological modulation. However, HRH1-mediated signalling was critical for the activation of the differentiation process induced by several agents including all-trans retinoic acid, establishing a role for HRH1 in myeloid differentiation. Pharmacological activation of Erk was able to partially restore differentiation capacity in HRH1 KD AML cells, suggesting that HRH1 signalling acts upstream MAPK-Erk pathway. As an indirect consequence of our results, treatment-related histamine release is not expected to confer a proliferative advantage in leukaemic cells., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Objective: We examined associations between resident and nonresident fathers' nonstandard work schedules, work hours, and their level of involvement with their young children in the United States., Background: Nonstandard work schedules may negatively impact father involvement either directly by reducing fathers' availability or indirectly by taking a toll on their wellbeing. Prior research on nonstandard schedules and father involvement has focused on two-parent households, yet nonstandard schedules may pose similar or greater challenges to nonresident fathers., Method: Using data on 1598 resident and 759 nonresident fathers from the Fragile Families and Child Wellbeing Study, we estimated regression models to test associations between fathers' nonstandard work schedules, work hours, and fathers' involvement-accessibility, engagement, and responsibility-controlling for confounding factors and using residualized change models. For nonresident fathers only, we estimated associations between nonstandard schedules, work hours, and child support., Results: Among nonresident fathers, working evenings was associated with lower engagement relative to working standard hours only and other nonstandard schedules, and in some models, working a variable schedule was associated with greater responsibility relative to other nonstandard schedules. Among resident fathers, working any nonstandard schedule versus standard hours only was associated with greater responsibility, and total work hours were negatively associated with each measure of involvement., Conclusion: Findings suggest that fathers' work schedules may be an important factor in understanding resident and nonresident fathers' involvement with their young children.

The aim of this prospective study in a phototherapy unit was to describe adverse events (AEs) associated with discontinuation of phototherapy in a clinical setting. A total of 872 included patients received 1,256 courses of phototherapy treatment: 76.9% narrow-band UVB (NBUVB); 9.6% systemic psoralen plus UVA (PUVA); 11.4% topical PUVA; and 2.1% UVA. Approximately a fifth of the treatments (n = 240, 19.1%) were associated with AEs, the most frequent of which was erythema (8.8%). Systemic PUVA had the highest rate of AEs (32.5%). Mycosis fungoides was the dermatosis with the highest rate of AE (36.9%). A total of 216 (17.2%) patients stopped treatment: 23.6% because of AEs (4.1% of all treatments). Treatment suspension due to AEs was associated with PUVA, both topical and systemic (p < 0.001), and diagnoses of mycosis fungoides (p <0.001), palmoplantar psoriasis (p = 0.002), hand eczema (p = 0.002) and pityriasis lichenoides (p = 0.01). In conclusion, one in every 5 patients receiving phototherapy had an AE, but few stopped treatment for this reason.

Background: High body mass index (BMI) is associated with neurocognitive impairments that contribute to overeating and interfere with weight loss efforts. Overweight and obesity at midlife can accelerate neurodegenerative changes and increase the risk of late-life dementia. Noninvasive neuromodulation represents a novel, affordable and scalable approach to improve neurocognitive function in this context. The purpose of this proof-of-concept study was to examine whether transcranial direct current stimulation (tDCS) aimed at enhancing prefrontal cortex activity could enhance weight loss, in combination with a hypocaloric diet, and study underlying mechanisms., Methods: Overall, 38 women with BMI 25-35 kg/m 2 underwent a 4 week randomized, double-blinded, sham-controlled, and parallel-design intervention, during which they received eight sessions of tDCS (n = 18 sham, n = 20 active) in combination with a diet (caloric goal of 20 kcal/kg/day). We evaluated longitudinal changes in body weight, appetite and food craving. In addition, we examined the contribution of cognitive-executive processes via food-modified computerized tasks., Results: We found that the active group had more reduction in body weight than the sham group throughout the study (p = 0.020) and significant weekly weight loss. At 4 weeks, the active group lost 2.32% of initial body weight (sham: 1.29%). Components of subjective appetite and food craving showed a trend toward more reduction in the active group. These changes were paralleled by significant improvements in task performance in the active group, particularly in a dual task that required inhibitory control and working memory (p = 0.007-0.031). Improvement in inhibitory control performance predicted reduction in lack of control overeating, explaining 43.5% of its variance at the end of the study (p = 0.003). No significant adverse effects were observed., Conclusions: Our results provide proof-of-concept validation of prefrontal-targeted tDCS, combined with a diet, in midlife women with excess body weight, paving the way for larger studies evaluating clinical efficacy and long-term effects of this intervention.

Background: Despite great efforts to identify druggable molecular targets for AML, there remains an unmet need for more effective therapies., Methods: An in silico screening was performed using Connectivity Maps to identify FDA-approved drugs that may revert an early leukaemic transformation gene signature. Hit compounds were validated in AML cell lines. Cytotoxic effects were assessed both in primary AML patient samples and healthy donor blood cells. Xenotransplantation assays were undertaken to determine the effect on engraftment of hit compounds. The mechanism of action responsible for the antileukaemic effect was studied focussing on lysosomes and mitochondria., Findings: We identified a group of antihistamines (termed ANHAs) with distinct physicochemical properties associated with their cationic-amphiphilic nature, that selectively killed leukaemic cells. ANHAs behaved as antileukaemic agents against primary AML samples ex vivo, sparing healthy cells. Moreover, ANHAs severely impaired the in vivo leukaemia regeneration capacity. ANHAs' cytotoxicity relied on simultaneous mitochondrial and lysosomal disruption and induction of autophagy and apoptosis. The pharmacological effect was exerted based on their physicochemical properties that permitted the passive targeting of both organelles, without the involvement of active molecular recognition., Interpretation: Dual targeting of lysosomes and mitochondria constitutes a new promising therapeutic approach for leukaemia treatment, supporting the further clinical development. FUND: This work was funded by the Fundación Mutua Madrileña (RMR), CaixaImpulse (RMR), the Spanish Ministry of Economy (RMR), the Josep Carreras International Leukaemia Foundation (RMR), l'Obra Social "La Caixa" (RMR), and Generalitat de Catalunya (IJC)., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)