Spatially preserved multi-region transcriptomic subtyping and biomarkers of chemoimmunotherapy outcome in extensive-stage small cell lung cancer.

BACKGROUND: Transcriptomic subtyping holds promise for personalized therapy in extensive-stage small-cell lung cancer (ES-SCLC). In this study, we aimed to assess intratumoral transcriptomic subtype diversity and to identify biomarkers of long-term chemoimmunotherapy benefit in human ES-SCLC. PATIENTS AND METHODS: We analyzed tumor samples from 58 ES-SCLC patients enrolled in two multicenter single-arm phase IIIb studies evaluating front-line chemoimmunotherapy in Spain: n=32 from the IMfirst trial, and n=26 from the CANTABRICO trial. We utilized the GeoMxTM DSP system to perform multi-region transcriptomic analysis. For subtype classification, we performed hierarchical clustering using the relative expression of ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1 (SCLC-Y). RESULTS: Subtype distribution was similar between both cohorts, except for SCLC-P, not identified in the CANTABRICO_DSP cohort. A total of 44% of the patients in both cohorts had tumors with multiple co-existing transcriptional subtypes. Transcriptional subtypes or subtype heterogeneity were not associated with outcomes. Most potential targets did not show subtype-specific expression. Consistently in both cohorts, tumors from patients with long-term benefit (time to progression ³12 months) contained an IFNg-dominated mRNA profile, including enhanced capacity for antigen presentation. Hypoxia and glycolytic pathways were associated with resistance to chemoimmunotherapy. CONCLUSIONS: This work suggests that intratumoral heterogeneity, inconsistent association with outcome, and unclear subtype-specific target expression might be significant challenges for subtype-based precision oncology in SCLC. Pre-existing IFNg-driven immunity and mitochondrial metabolism seem correlates of long-term efficacy in this study, although the absence of a chemotherapy control arm precludes concluding that these are predictive features specific for immunotherapy.

The Role of Cardiolipin in Mitochondrial Function and Neurodegenerative Diseases.

Cardiolipin (CL) is a mitochondria-exclusive phospholipid synthesized in the inner mitochondrial membrane. CL plays a key role in mitochondrial membranes, impacting a plethora of functions this organelle performs. Consequently, it is conceivable that abnormalities in the CL content, composition, and level of oxidation may negatively impact mitochondrial function and dynamics, with important implications in a variety of diseases. This review concentrates on papers published in recent years, combined with basic and underexplored research in CL. We capture new findings on its biological functions in the mitochondria, as well as its association with neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease. Lastly, we explore the potential applications of CL as a biomarker and pharmacological target to mitigate mitochondrial dysfunction.

Immunological aspects of central neurodegeneration.

The etiology of various neurodegenerative disorders that mainly affect the central nervous system including (but not limited to) Alzheimer's disease, Parkinson's disease and Huntington's disease has classically been attributed to neuronal defects that culminate with the loss of specific neuronal populations. However, accumulating evidence suggests that numerous immune effector cells and the products thereof (including cytokines and other soluble mediators) have a major impact on the pathogenesis and/or severity of these and other neurodegenerative syndromes. These observations not only add to our understanding of neurodegenerative conditions but also imply that (at least in some cases) therapeutic strategies targeting immune cells or their products may mediate clinically relevant neuroprotective effects. Here, we critically discuss immunological mechanisms of central neurodegeneration and propose potential strategies to correct neurodegeneration-associated immunological dysfunction with therapeutic purposes.

Heat shock and thermotolerance in Caenorhabditis elegans: An overview of laboratory techniques.

The soil nematode worm Caenorhabditis elegans is a simple and well-established model for the study of many biological processes. Heat shock and thermotolerance assays have been developed for this nematode, and have been used to decipher the molecular relationships between thermal stress and aging, among others. Nevertheless, a systematic and methodological comparison of the different approaches and tools utilized is lacking in the literature. Here, we aim to provide a comprehensive summary of the most commonly used strategies for carrying out heat shock and thermotolerance assays that have been reported, highlighting specific readouts and scientific questions that can be addressed. Furthermore, we offer examples of thermotolerance assays performed with wild type nematodes, that can serve as a gauge of the animal survival under diverse conditions of stress.

Ecological and Syntaxonomic Analysis of the Communities of Glebionis coronaria and G. discolor (Malvion neglectae) in the European Mediterranean Area.

Nitrophilous communities dominated by Glebionis coronaria and Glebionis discolor in the European Mediterranean area were studied. The nomenclature was corrected according to the current taxonomy, following the International Code of Phytosociological Nomenclature (ICPN). The statistical analysis revealed six new associations and one subassociation, with four in Spain, one in Greece, and one in Italy. Additionally, a subassociation of high relevance due to its endemic character was identified. These grasslands exhibit requirements for organic matter and other edaphic nutrients that are closer to those of Malva neglecta communities than to those of Hordeum murinum subsp. leporinum. We confirmed the published syntaxon with the rank of Resedo albae-Glebionenion coronariae suballiance and its subordination to the Malvion neglectae alliance, and we established the type association for this suballiance. Sisimbrietalia officinalis J. Tüxen in Lohmeyer et al. 1962 em. Rivas-Martínez, Báscones, T. E. Díaz, Fernández-González & Loidi 1991. Stellarietea mediae Tüxen, Lohmeyer & Preising ex von Rochow 1951.

Vitamin D Receptor Polymorphisms in a Spanish Cohort of Parkinson's Disease Patients.

Background: Vitamin D receptor (VDR) is a nuclear hormone receptor widely expressed in the substantia nigra. Its association with an increased risk of Parkinson's disease (PD) is based on vitamin D deficiency and/or different polymorphisms in its gene receptor. This fact has been demonstrated by several case-control studies. Materials and Methods: Consequently, we investigated the association between VDR ApaI, BsmI, FokI, and TaqI gene polymorphisms and PD in a Spanish cohort that included 54 cases and 17 healthy controls. The detection of single nucleotide polymorphisms (SNPs) was performed using a polymerase chain reaction-restriction fragment length polymorphism. Results: Our data indicate that the SNPs were not associated with the age of onset of PD, nor with the occurrence of motor symptoms. However, only BsmI polymorphism was significantly associated with PD in this Spanish cohort. In fact, BsmI genotype was five times higher among PD patients than among controls, and the A allele was considered as a genetic risk for PD. Additionally, the combination of FokI and BsmI polymorphisms was significantly associated with PD and could represent a risk factor. Conclusion: We conclude that ApaI, TaqI, and FokI polymorphisms were not associated with PD, but BsmI could be a risk factor for PD in this randomized population.

Ligand Hydrogenation during Hydroformylation Catalysis Detected by In Situ High-Pressure Infra-Red Spectroscopic Analysis of a Rhodium/Phospholene-Phosphite Catalyst.

Phospholane-phosphites are known to show highly unusual selectivity towards branched aldehydes in the hydroformylation of terminal alkenes. This paper describes the synthesis of hitherto unknown unsaturated phospholene borane precursors and their conversion to the corresponding phospholene-phosphites. The relative stereochemistry of one of these ligands and its Pd complex was assigned with the aid of X-ray crystal structure determinations. These ligands were able to approach the level of selectivity observed for phospholane-phosphites in the rhodium-catalysed hydroformylation of propene. High-pressure infra-red (HPIR) spectroscopic monitoring of the catalyst formation revealed that whilst the catalysts showed good thermal stability with respect to fragmentation, the C=C bond in the phospholene moiety was slowly hydrogenated in the presence of rhodium and syngas. The ability of this spectroscopic tool to detect even subtle changes in structure, remotely from the carbonyl ligands, underlines the usefulness of HPIR spectroscopy in hydroformylation catalyst development.

Lysosomal Dysfunction: Connecting the Dots in the Landscape of Human Diseases.

Lysosomes are the main organelles responsible for the degradation of macromolecules in eukaryotic cells. Beyond their fundamental role in degradation, lysosomes are involved in different physiological processes such as autophagy, nutrient sensing, and intracellular signaling. In some circumstances, lysosomal abnormalities underlie several human pathologies with different etiologies known as known as lysosomal storage disorders (LSDs). These disorders can result from deficiencies in primary lysosomal enzymes, dysfunction of lysosomal enzyme activators, alterations in modifiers that impact lysosomal function, or changes in membrane-associated proteins, among other factors. The clinical phenotype observed in affected patients hinges on the type and location of the accumulating substrate, influenced by genetic mutations and residual enzyme activity. In this context, the scientific community is dedicated to exploring potential therapeutic approaches, striving not only to extend lifespan but also to enhance the overall quality of life for individuals afflicted with LSDs. This review provides insights into lysosomal dysfunction from a molecular perspective, particularly in the context of human diseases, and highlights recent advancements and breakthroughs in this field.

Modulation of D3R Splicing, Signaling, and Expression by D1R through PKA→PTB Phosphorylation.

The D1R and D3R receptors functionally and synergistically interact in striatonigral neurons. Dopaminergic denervation turns this interaction antagonistic, which is correlated with a decrement in D3nf isoform and an increment in D3R membranal expression. The mechanisms of such changes in D3R are attributed to the dysregulation of the expression of their isoforms. The cause and mechanism of this phenomenon remain unknown. Dopaminergic denervation produces a decrement in D1R and PKA activity; we propose that the lack of phosphorylation of PTB (regulator of alternative splicing) by PKA produces the dysregulation of D3R splicing and changes D3R functionality. By using in silico analysis, we found that D3R mRNA has motifs for PTB binding and, by RIP, co-precipitates with PTB. Moreover, D1R activation via PKA promotes PTB phosphorylation. Acute and 5-day D1R blockade decreases the expression of D3nf mRNA. The 5-day treatment reduces D3R, D3nf, and PTB protein in the cytoplasm and increases D3R in the membrane and PTB in the nucleus. Finally, the blockade of D1R mimics the effect of dopaminergic denervation in D1R and D3R signaling. Thus, our data indicate that through PKA→PTB, D1R modulates D3R splicing, expression, and signaling, which are altered during D1R blockade or the lack of stimulation in dopaminergic denervation.

CRISPR/sgRNA-directed synergistic activation mediator (SAM) as a therapeutic tool for Parkinson´s disease.

Parkinson`s disease (PD) is the second most prevalent neurodegenerative disease, and different gene therapy strategies have been used as experimental treatments. As a proof-of-concept for the treatment of PD, we used SAM, a CRISPR gene activation system, to activate the endogenous tyrosine hydroxylase gene (th) of astrocytes to produce dopamine (DA) in the striatum of 6-OHDA-lesioned rats. Potential sgRNAs within the rat th promoter region were tested, and the expression of the Th protein was determined in the C6 glial cell line. Employing pseudo-lentivirus, the SAM complex and the selected sgRNA were transferred into cultures of rat astrocytes, and gene expression and Th protein synthesis were ascertained; furthermore, DA release into the culture medium was determined by HPLC. The DA-producing astrocytes were implanted into the striatum of 6-OHDA hemiparkinsonian rats. We observed motor behavior improvement in the lesioned rats that received DA-astrocytes compared to lesioned rats receiving astrocytes that did not produce DA. Our data indicate that the SAM-induced expression of the astrocyte´s endogenous th gene can generate DA-producing astrocytes that effectively reduce the motor asymmetry induced by the lesion.

Dopamine D3 receptor modulates D2 receptor effects on cAMP and GABA release at striatopallidal terminals-Modulation by the Ca2+-Calmodulin-CaMKII system.

Dopamine D2 receptor (D2R) is expressed in striatopallidal neurons and decreases forskolin-stimulated cyclic adenine monophosphate (cAMP) accumulation and gamma-aminobutyric acid (GABA) release. Dopamine D3 receptor (D3R) mRNA is expressed in a population of striatal D2R-expressing neurons. Also, D3R protein and binding have been reported in the neuropil of globus pallidus. We explore whether D2R and D3R colocalize in striatopallidal terminals and whether D3R modulates the D2R effect on forskolin-stimulated [3H]cAMP accumulation in pallidal synaptosomes and high K+ stimulated-[3H]GABA release in pallidal slices. Previous reports in heterologous systems indicate that calmodulin (CaM) and CaMKII modulate D2R and D3R functions; thus, we study whether this system regulates its functional interaction. D2R immunoprecipitates with CaM, and pretreatment with ophiobolin A or depolarization of synaptosomes with 15 mM of K+ decreases it. Both treatments increase the D2R inhibition of forskolin-stimulated [3H]cAMP accumulation when activated with quinpirole, indicating a negative modulation of CaM on D2R function. Quinpirole also activates D3R, potentiating D2R inhibition of cAMP accumulation in the ophiobolin A-treated synaptosomes. D2R and D3R immunoprecipitate in pallidal synaptosomes and decrease after the kainic acid striatal lesion, indicating the striatal origin of the presynaptic receptors. CaM-kinase II alfa (CaMKIIα) immunoprecipitates with D3R and increases after high K+ depolarization. In the presence of KN62, a CaMKIIα blocker, D3R potentiates D2R effects on cAMP accumulation in depolarized synaptosomes and GABA release in pallidal slices, indicating D3R function regulation by CaMKIIα. Our data indicate that D3R potentiates the D2R effect on cAMP accumulation and GABA release at pallidal terminals, an interaction regulated by the CaM-CaMKIIα system.

UDC- COVID 19: herramienta digital para predecir el retiro de la ventilación mecánica invasiva de pacientes con COVID-19

En diciembre de 2019 las Autoridades de la República Popular China, comunicaron a la OMS varios casos de neumonía de etiología desconocida en Wuhan, una ciudad situada en la provincia china de Hubei. Una semana más tarde confirmaron que se trataba de un nuevo coronavirus que fue denominado SARS-CoV-2, este virus causa diversas manifestaciones clínicas englobadas bajo el término COVID-19. El presente trabajo presenta un prototipo de aplicación con el nombre UDC-COVID19 que propone una herramienta digital sobre la base de una revisión actualizada de la evaluación ultrasonográfica del diafragma como elemento predictivo para retirar la ventilación mecánica invasiva en pacientes con COVID-19, proporcionando una excelente herramienta digital para la evaluación de la estructura y función dinámica diafragmática, es precisa, reproducible, sin radiación ionizante, fácil de realizar a la cabecera del paciente y costo efectiva en pacientes críticamente enfermos.

In December 2019, the Authorities of the People's Republic of China reported to the WHO several cases of pneumonia of unknown etiology in Wuhan, a city located in the Chinese province of Hubei. A week later, they confirmed that it was a new coronavirus called SARS-CoV-2, which causes various clinical manifestations encompassed under the term COVID-19. The present work presents an application prototype with the name UDC-COVID19 that proposes a digital tool based on an updated review of the ultrasonographic evaluation of the diaphragm as a predictive element to withdraw invasive mechanical ventilation in patients with COVID-19, providing an excellent digital tool for the evaluation of the diaphragmatic structure and dynamic function since it is precise, reproducible, without ionizing radiation, easy to perform at the patient's bedside and cost effective in critically ill patients; mechanical ventilation.

Comparative Genetic Analysis of the Promoters of the ATG16L1 and ATG5 Genes Associated with Sporadic Parkinson's Disease.

Sporadic Parkinson's disease, characterised by a decline in dopamine, usually manifests in people over 65 years of age. Although 10% of cases have a genetic (familial) basis, most PD is sporadic. Genome sequencing studies have associated several genetic variants with sporadic PD. Our aim was to analyse the promoter region of the ATG16L1 and ATG5 genes in sporadic PD patients and ethnically matched controls. Genotypes were obtained by using the Sanger method with primers designed by us. The number of haplotypes was estimated with DnaSP software, phylogeny was reconstructed in Network, and genetic divergence was explored with Fst. Seven and two haplotypes were obtained for ATG16L1 and ATG5, respectively. However, only ATG16L1 showed a significant contribution to PD and a significant excess of accumulated mutations that could influence sporadic PD disease. Of a total of seven haplotypes found, only four were unique to patients sharing the T allele (rs77820970). Recent studies using MAPT genes support the notion that the architecture of haplotypes is worthy of being considered genetically risky, as shown in our study, confirming that large-scale assessment in different populations could be relevant to understanding the role of population-specific heterogeneity. Finally, our data suggest that the architecture of certain haplotypes and ethnicity determine the risk of PD, linking haplotype variation and neurodegenerative processes.

Covered Rutile-TiO2 Nanoparticles Enhance Tomato Yield and Growth by Modulating Gas Exchange and Nutrient Status.

Nanotechnology has developed materials that can increase food production while reducing the use of conventional fertilizers. In this study, the effect of two forms of application (foliar and drench) as well as covering or non-covering of the surface of titanium dioxide nanoparticles (nTiO2) with maltodextrin (MDX) at 1500 ppm was investigated on tomato plants. The results show that treatment of tomato with nTiO2 increased yield (+21%), while covering the surface of the NPs resulted in a further yield increase (+27%). Similar trends were observed in the dry weight of vegetative plant parts. Fruit firmness (+33%) and total soluble solids (+36%) were enhanced by MDX-covered nTiO2. Application of nTiO2 resulted in enhanced SPAD index, photosynthesis rate, NO3-, K, and Ca concentration in the petiole sap, whereas in the fruits there was an increase in P and K in MDX-covered nTiO2. Considering the dilution effect due to the higher fruit yield, N, P, Mg, Cu, and B increased in plants treated with nTiO2. Covering the surface with MDX resulted in an enhanced response to nTiO2, as fruit yield and quality increased compared to plants treated with non-covered nTiO2.

Methylation-related genes involved in renal carcinoma progression.

Renal carcinomas are a group of malignant tumors often originating in the cells lining the small tubes in the kidney responsible for filtering waste from the blood and urine production. Kidney tumors arise from the uncontrolled growth of cells in the kidneys and are responsible for a large share of global cancer-related morbidity and mortality. Understanding the molecular mechanisms driving renal carcinoma progression results crucial for the development of targeted therapies leading to an improvement of patient outcomes. Epigenetic mechanisms such as DNA methylation are known factors underlying the development of several cancer types. There is solid experimental evidence of relevant biological functions modulated by methylation-related genes, associated with the progression of different carcinomas. Those mechanisms can often be associated to different epigenetic marks, such as DNA methylation sites or chromatin conformation patterns. Currently, there is no definitive method to establish clear relations between genetic and epigenetic factors that influence the progression of cancer. Here, we developed a data-driven method to find methylation-related genes, so we could find relevant bonds between gene co-expression and methylation-wide-genome regulation patterns able to drive biological processes during the progression of clear cell renal carcinoma (ccRC). With this approach, we found out genes such as ITK oncogene that appear hypomethylated during all four stages of ccRC progression and are strongly involved in immune response functions. Also, we found out relevant tumor suppressor genes such as RAB25 hypermethylated, thus potentially avoiding repressed functions in the AKT signaling pathway during the evolution of ccRC. Our results have relevant implications to further understand some epigenetic-genetic-affected roles underlying the progression of renal cancer.

Necesidad de aprendizaje del médico general sobre Imagenología durante la COVID-19 para su formación laboral / The General Practitioner's Need for Learning Imaginology during COVID-19

Para afrontar la reciente emergencia global por COVID-19, la comunidad científica y los profesionales de la salud en Cuba trabajan constantemente en el desarrollo de nuevos tratamientos y tecnologías que posibiliten el diagnóstico precoz de esta enfermedad, todo ello para facilitar el manejo general de esta pandemia.1) De ahí que se requiere el perfeccionamiento continuo de este proceso en correspondencia con los principios de la medicina, con una formación humanista, científica y con una visión integral de los problemas de salud como elemento esencial que caracteriza la formación de profesionales de la salud en territorio cubano donde la especialidad de Medicina General Integral constituye la principal disciplina integradora de contenidos, para ofrecer una atención preventiva, sistemática y continua al paciente a lo largo del tiempo, donde el médico en formación sea expresión de sus cualidades humanas. Coherente con esto, en 1984 se inició en Cuba la formación de especialistas en Medicina General Integral (MGI). Esta especialidad no tenía antecedentes en el país, por lo cual su propuesta constituye el perfeccionamiento del enfoque social de la medicina, que desde su implantación es la premisa básica del sistema de salud cubano. La formación de estos profesionales ocurre en la propia comunidad, con una alta calidad en los servicios que se brindan a la población.2 Para cumplir con esta función...(AU)

Mitochondrial Dysfunction in Repeat Expansion Diseases.

Repeat expansion diseases are a group of neuromuscular and neurodegenerative disorders characterized by expansions of several successive repeated DNA sequences. Currently, more than 50 repeat expansion diseases have been described. These disorders involve diverse pathogenic mechanisms, including loss-of-function mechanisms, toxicity associated with repeat RNA, or repeat-associated non-ATG (RAN) products, resulting in impairments of cellular processes and damaged organelles. Mitochondria, double membrane organelles, play a crucial role in cell energy production, metabolic processes, calcium regulation, redox balance, and apoptosis regulation. Its dysfunction has been implicated in the pathogenesis of repeat expansion diseases. In this review, we provide an overview of the signaling pathways or proteins involved in mitochondrial functioning described in these disorders. The focus of this review will be on the analysis of published data related to three representative repeat expansion diseases: Huntington's disease, C9orf72-frontotemporal dementia/amyotrophic lateral sclerosis, and myotonic dystrophy type 1. We will discuss the common effects observed in all three repeat expansion disorders and their differences. Additionally, we will address the current gaps in knowledge and propose possible new lines of research. Importantly, this group of disorders exhibit alterations in mitochondrial dynamics and biogenesis, with specific proteins involved in these processes having been identified. Understanding the underlying mechanisms of mitochondrial alterations in these disorders can potentially lead to the development of neuroprotective strategies.

Urethral Slings for Irradiated Patients With Male Stress Urinary Incontinence: A Meta-analysis.

OBJECTIVE: To systematically compare success, cure and complication rates of urethral sling surgeries in stress urinary incontinence patients with and without a history of pelvic radiotherapy (RT). MATERIALS AND METHODS: We searched PUBMED, EMBASE, and Web of Science to identify relevant articles. The primary outcomes were the success and cure rates. The secondary outcomes included the rates of infection, urethral erosion, total complications, explantation, and satisfaction. Outcomes were analyzed using a random-effects model to calculate the unadjusted odds ratio (OR) in patients with a history of RT compared with those without prior RT. RESULTS: On pooled analysis, we found significantly lower odds of success (OR 0.68; 95% confidence interval [CI] 0.53-0.87, P < .001) and cure (OR 0.67; 95% CI 0.55-0.82, P < .001) in radiated patients than in nonirradiated patients. Subgroup analysis by type of sling showed significantly lower odds of success in Advance subgroup (OR 0.66; 95% CI 0.45-0.95, P < .001) and significantly lower odds of cure in Advance (OR 0.59; 95% CI 0.36-0.95, P < .001) and Atoms subgroups (OR 0.70; 95% CI 0.54-0.93, P < .001). We also found significantly greater odds of sling explantation (OR 2.93; 95% CI 1.62-5.29, P < .001) and infection (OR 3.06, 95% CI 1.03-9.07, P < .001) in radiated patients than in nonradiated patients. CONCLUSION: Patients with a history of pelvic RT have lower odds of success and cure and higher odds of infection and sling explantation than those without a history of pelvic RT.

Effect of Glutamic Acid and 6-benzylaminopurine on Flower Bud Biostimulation, Fruit Quality and Antioxidant Activity in Blueberry.

Blueberry is a highly demanded and consumed fruit due to its beneficial effects on human health, because of its bioactive compounds with a high antioxidant capacity. The interest in increasing the yield and quality of blueberries has led to the application of some innovative techniques such as biostimulation. The objective of this research was to assess the effect of the exogenous application of glutamic acid (GLU) and 6-benzylaminopurine (6-BAP) as biostimulants on flower bud sprouting, fruit quality, and antioxidant compounds in blueberry cv. Biloxi. The application of GLU and 6-BAP positively affected bud sprouting, fruit quality, and antioxidant content. The application of 500 and 10 mg L-1 GLU and 6-BAP, respectively, increased the number of flower buds, while 500 and 20 mg L-1 generated fruits with higher content of flavonoids, vitamin C, and anthocyanins and higher enzymatic activity of catalase and ascorbate peroxidase enzymes. Hence, the application of these biostimulants is an effective way to enhance the yield and fruit quality of blueberries.