Bi-level Graph Learning Unveils Prognosis-Relevant Tumor Microenvironment Patterns from Breast Multiplexed Digital Pathology.

The tumor microenvironment is widely recognized for its central role in driving cancer progression and influencing prognostic outcomes. Despite extensive research efforts dedicated to characterizing this complex and heterogeneous environment, considerable challenges persist. In this study, we introduce a data-driven approach for identifying patterns of cell organizations in the tumor microenvironment that are associated with patient prognoses. Our methodology relies on the construction of a bi-level graph model: (i) a cellular graph, which models the intricate tumor microenvironment, and (ii) a population graph that captures inter-patient similarities, given their respective cellular graphs, by means of a soft Weisfeiler-Lehman subtree kernel. This systematic integration of information across different scales enables us to identify patient subgroups exhibiting unique prognoses while unveiling tumor microenvironment patterns that characterize them. We demonstrate our approach in a cohort of breast cancer patients, where the identified tumor microenvironment patterns result in a risk stratification system that provides complementary, new information with respect to alternative standards. Our results, which are validated in a completely independent cohort, allow for new insights into the prognostic implications of the breast tumor microenvironment, and this methodology could be applied to other cancer types more generally.

Effect of polyphenols from Ascophyllum nodosum seaweeds on the rheology and digestion of corn starch gels and gluten-free bread features.

The main objective of this work is to study the effect of polyphenols, from the brown seaweed Ascophyllum nodosum, on the structure and digestion behaviour of gels at two corn starch concentrations (1.95 and 5.00% w/w) as well as the structure, color and texture features of crumbs from gluten-free breads. Adsorption isotherms of polyphenols on native and gelled starches were carried out and modelled by means of Langmuir and Henry models, respectively. The formation and characteristics of tested gels were rheologically monitored by means of heating ramp, time sweep at high temperature, cooling ramp and frequency sweep at 25 °C. Elastic modulus values decreased with the presence of polyphenols. Additionally, the polyphenols significantly decreased the digestion rate, measured by both chemical and rheological procedures, and the final concentration of digested starch. Finally, the presence of polyphenols in breads increased the hardness and chewiness values and decreased the cohesiveness and resilience values as well as the crumb hardening during storage.

Online and offline dating violence: same same, but different?

BACKGROUND: Violent behaviors in romantic relationships among adolescents and young people are pressing social matter as they have an effect on both victims and aggressors. Moreover, in the last decades, new forms of harassment, control, and abuse through social networks and mobile phones have arisen. Therefore, now forms of online and offline dating violence coexist. OBJECTIVES: The aim was to analyze the prevalence rates by sex and age and the co-occurrence of online and offline dating violence. Moreover, the roles of online and offline dating violence aggressors and victims for their self-esteem, hostility, general psychological state, and emotional intelligence were investigated. METHOD: Three hundred forty-one university students from the Basque Country, Spain, participated in the study. They completed six validated instruments related to the mentioned variables. RESULTS: Results highlight the high prevalence of online and offline dating violence in the sample and the co-occurrence of both types. No gender nor sex differences were found for online and offline dating violence perpetration and victimization. The correlation between online and offline dating violence was confirmed, and the reciprocity of violence is greater for offline violence. In relation to the role, both types of victims (online and offline) showed higher levels of hostility and psychological symptomatology than non-victims, but differences in self-esteem and emotional regulation were found in these modalities. Online and offline perpetrators shared hostility and some psychological symptoms as characteristics compared to non-victims, but differed in other symptoms and emotional intelligence. CONCLUSION: There is a continuum between offline and online victimization perpetration albeit differences in the characteristics such as self-esteem, emotional intelligence, and general functioning exist.

Epithelial Expressed B7-H4 Drives Differential Immunotherapy Response in Murine and Human Breast Cancer.

Combinations of immune checkpoint inhibitors (ICI, including anti-PD-1/PD-L1) and chemotherapy have been FDA approved for metastatic and early-stage triple-negative breast cancer (TNBC), but most patients do not benefit. B7-H4 is a B7 family ligand with proposed immunosuppressive functions being explored as a cancer immunotherapy target and may be associated with anti-PD-L1 resistance. However, little is known about its regulation and effect on immune cell function in breast cancers. We assessed murine and human breast cancer cells to identify regulation mechanisms of B7-H4 in vitro. We used an immunocompetent anti-PD-L1-sensitive orthotopic mammary cancer model and induced ectopic expression of B7-H4. We assessed therapy response and transcriptional changes at baseline and under treatment with anti-PD-L1. We observed B7-H4 was highly associated with epithelial cell status and transcription factors and found to be regulated by PI3K activity. EMT6 tumors with cell-surface B7-H4 expression were more resistant to immunotherapy. In addition, tumor-infiltrating immune cells had reduced immune activation signaling based on transcriptomic analysis. Paradoxically, in human breast cancer, B7-H4 expression was associated with survival benefit for patients with metastatic TNBC treated with carboplatin plus anti-PD-L1 and was associated with no change in response or survival for patients with early breast cancer receiving chemotherapy plus anti-PD-1. While B7-H4 induces tumor resistance to anti-PD-L1 in murine models, there are alternative mechanisms of signaling and function in human cancers. In addition, the strong correlation of B7-H4 to epithelial cell markers suggests a potential regulatory mechanism of B7-H4 independent of PD-L1. SIGNIFICANCE: This translational study confirms the association of B7-H4 expression with a cold immune microenvironment in breast cancer and offers preclinical studies demonstrating a potential role for B7-H4 in suppressing response to checkpoint therapy. However, analysis of two clinical trials with checkpoint inhibitors in the early and metastatic settings argue against B7-H4 as being a mechanism of clinical resistance to checkpoints, with clear implications for its candidacy as a therapeutic target.

Hierarchical organization of human physical activity.

Human physical activity (HPA), a fundamental physiological signal characteristic of bodily motion is of rapidly growing interest in multidisciplinary research. Here we report the existence of hitherto unidentified hierarchical levels in the temporal organization of HPA on the ultradian scale: on the minute's scale, passive periods are followed by activity bursts of similar intensity ('quanta') that are organized into superstructures on the hours- and on the daily scale. The time course of HPA can be considered a stochastic, quasi-binary process, where quanta, assigned to task-oriented actions are organized into work packages on higher levels of hierarchy. In order to grasp the essence of this complex dynamic behaviour, we established a stochastic mathematical model which could reproduce the main statistical features of real activity time series. The results are expected to provide important data for developing novel behavioural models and advancing the diagnostics of neurological or psychiatric diseases.

Diagnosis and approach of pseudohypoparathyroidism type 1A and related disorders during long term follow-up: a case report.

OBJECTIVES: Pseudohypoparathyroidism type 1A (PHP1A) encompasses the association of resistance to multiple hormones, features of Albright hereditary osteodystrophy and decreased Gsα activity. Little is known about the early signs of PHP1A, with a delay in diagnosis. We report two PHP1A cases and their clinical and biochemical findings during a 20-year follow-up. CASE PRESENTATION: Clinical suspicion was based on obesity, TSH resistance and ectopic ossifications which appeared several months before PTH resistance, at almost 3 years of age. Treatment with levothyroxine, calcitriol and calcium was required in both patients. DNA sequencing of GNAS gene detected a heterozygous pathogenic variant within exon 7 (c.569_570delAT) in patient one and a deletion from XLAS to GNAS-exon 5 on the maternal allele in patient 2. In patient 1, ectopic ossifications that required surgical excision were found. Noticeably, patient 2 displayed adult short stature, intracranial calcifications and psychomotor delay. In terms of weight, despite early diagnosis of obesity, dietary measures were established successfully in both cases. CONCLUSIONS: GNAS mutations should be considered in patients with obesity, ectopic ossifications and TSH resistance presented in early infancy. These cases emphasize the highly heterogeneous clinical picture PHP1A patients may present, especially in terms of final height and cognitive impairment.

17-Oxime ethers of oxidized ecdysteroid derivatives modulate oxidative stress in human brain endothelial cells and dose-dependently might protect or damage the blood-brain barrier.

20-Hydroxyecdysone and several of its oxidized derivatives exert cytoprotective effect in mammals including humans. Inspired by this bioactivity of ecdysteroids, in the current study it was our aim to prepare a set of sidechain-modified derivatives and to evaluate their potential to protect the blood-brain barrier (BBB) from oxidative stress. Six novel ecdysteroids, including an oxime and five oxime ethers, were obtained through regioselective synthesis from a sidechain-cleaved calonysterone derivative 2 and fully characterized by comprehensive NMR techniques revealing their complete 1H and 13C signal assignments. Surprisingly, several compounds sensitized hCMEC/D3 brain microvascular endothelial cells to tert-butyl hydroperoxide (tBHP)-induced oxidative damage as recorded by impedance measurements. Compound 8, containing a benzyloxime ether moiety in its sidechain, was the only one that exerted a protective effect at a higher, 10 µM concentration, while at lower (10 nM- 1 µM) concentrations it promoted tBHP-induced cellular damage. Brain endothelial cells were protected from tBHP-induced barrier integrity decrease by treatment with 10 µM of compound 8, which also mitigated the intracellular reactive oxygen species production elevated by tBHP. Based on our results, 17-oxime ethers of oxidized ecdysteroids modulate oxidative stress of the BBB in a way that may point towards unexpected toxicity. Further studies are needed to evaluate any possible risk connected to dietary ecdysteroid consumption and CNS pathologies in which BBB damage plays an important role.

Dendritic Cells as a Therapeutic Strategy in Acute Myeloid Leukemia: Vaccines.

Dendritic cells (DCs) serve as professional antigen-presenting cells (APC) bridging innate and adaptive immunity, playing an essential role in triggering specific cellular and humoral responses against tumor and infectious antigens. Consequently, various DC-based antitumor therapeutic strategies have been developed, particularly vaccines, and have been intensively investigated specifically in the context of acute myeloid leukemia (AML). This hematological malignancy mainly affects the elderly population (those aged over 65), which usually presents a high rate of therapeutic failure and an unfavorable prognosis. In this review, we examine the current state of development and progress of vaccines in AML. The findings evidence the possible administration of DC-based vaccines as an adjuvant treatment in AML following initial therapy. Furthermore, the therapy demonstrates promising outcomes in preventing or delaying tumor relapse and exhibits synergistic effects when combined with other treatments during relapses or disease progression. On the other hand, the remarkable success observed with RNA vaccines for COVID-19, delivered in lipid nanoparticles, has revealed the efficacy and effectiveness of these types of vectors, prompting further exploration and their potential application in AML, as well as other neoplasms, loading them with tumor RNA.

Tissue-specific early and late activated lymphocytes immunophenotype in chronic rhinosinusitis with nasal polyps.

KEY POINTS: T-cell activation in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) is enriched by late cytotoxic T cells. The proportion of early and intermediate activated cytotoxic T cells decreases in nasal polyps of patients with CRSwNP. Our results identify late activated cytotoxic T cells as potential biomarkers or therapeutic targets for patients with CRSwNP.

Atezolizumab in Combination With Carboplatin and Survival Outcomes in Patients With Metastatic Triple-Negative Breast Cancer: The TBCRC 043 Phase 2 Randomized Clinical Trial.

Importance: Agents targeting programmed death ligand 1 (PD-L1) have demonstrated efficacy in triple-negative breast cancer (TNBC) when combined with chemotherapy and are now the standard of care in patients with PD-L1-positive metastatic disease. In contrast to microtubule-targeting agents, the effect of combining platinum compounds with programmed cell death 1 (PD-1)/PD-L1 immunotherapy has not been extensively determined. Objective: To evaluate the efficacy of atezolizumab with carboplatin in patients with metastatic TNBC. Design, Setting, and Participants: This phase 2 randomized clinical trial was conducted in 6 centers from August 2017 to June 2021. Interventions: Patients with metastatic TNBC were randomized to receive carboplatin area under the curve (AUC) 6 alone or with atezolizumab, 1200 mg, every 3 weeks until disease progression or unacceptable toxic effects with a 3-year duration of follow-up. Main Outcome and Measures: The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall response rate (ORR), clinical benefit rate (CBR), and overall survival (OS). Other objectives included correlation of response with tumor PD-L1 levels, tumor-infiltrating lymphocytes (TILs), tumor DNA- and RNA-sequenced biomarkers, TNBC subtyping, and multiplex analyses of immune markers. Results: All 106 patients with metastatic TNBC who were enrolled were female with a mean (range) age of 55 (27-79) years, of which 12 (19%) identified as African American/Black, 1 (1%) as Asian, 73 (69%) as White, and 11 (10%) as unknown. Patients were randomized and received either carboplatin (n = 50) or carboplatin and atezolizumab (n = 56). The combination improved PFS (hazard ratio [HR], 0.66; 95% CI, 0.44-1.01; P = .05) from a median of 2.2 to 4.1 months, increased ORR from 8.0% (95% CI, 3.2%-18.8%) to 30.4% (95% CI, 19.9%-43.3%), increased CBR at 6 months from 18.0% (95% CI, 9.8%-30.1%) to 37.5% (95% CI, 26.0%-50.6%), and improved OS (HR, 0.60; 95% CI, 0.37-0.96; P = .03) from a median of 8.6 to 12.6 months. Subgroup analysis showed PD-L1-positive tumors did not benefit more from adding atezolizumab (HR, 0.62; 95% CI, 0.23-1.65; P = .35). Patients with high TILs (HR, 0.12; 95% CI, 0.30-0.50), high mutation burden (HR, 0.50; 95% CI, 0.23-1.06), and prior chemotherapy (HR, 0.59; 95% CI, 0.36-0.95) received greater benefit on the combination. Patients with obesity and patients with more than 125 mg/dL on-treatment blood glucose levels were associated with better PFS (HR, 0.35; 95% CI, 0.10-1.80) on the combination. TNBC subtypes benefited from adding atezolizumab, except the luminal androgen receptor subtype. Conclusions and Relevance: In this randomized clinical trial, the addition of atezolizumab to carboplatin significantly improved survival of patients with metastatic TNBC regardless of PD-L1 status. Further, lower risk of disease progression was associated with increased TILs, higher mutation burden, obesity, and uncontrolled blood glucose levels. Trial Registration: ClinicalTrials.gov Identifier: NCT03206203.

NKG2A Is a Therapeutic Vulnerability in Immunotherapy Resistant MHC-I Heterogeneous Triple-Negative Breast Cancer.

Despite the success of immune checkpoint inhibition (ICI) in treating cancer, patients with triple-negative breast cancer (TNBC) often develop resistance to therapy, and the underlying mechanisms are unclear. MHC-I expression is essential for antigen presentation and T-cell-directed immunotherapy responses. This study demonstrates that TNBC patients display intratumor heterogeneity in regional MHC-I expression. In murine models, loss of MHC-I negates antitumor immunity and ICI response, whereas intratumor MHC-I heterogeneity leads to increased infiltration of natural killer (NK) cells in an IFNγ-dependent manner. Using spatial technologies, MHC-I heterogeneity is associated with clinical resistance to anti-programmed death (PD) L1 therapy and increased NK:T-cell ratios in human breast tumors. MHC-I heterogeneous tumors require NKG2A to suppress NK-cell function. Combining anti-NKG2A and anti-PD-L1 therapies restores complete response in heterogeneous MHC-I murine models, dependent on the presence of activated, tumor-infiltrating NK and CD8+ T cells. These results suggest that similar strategies may enhance patient benefit in clinical trials. SIGNIFICANCE: Clinical resistance to immunotherapy is common in breast cancer, and many patients will likely require combination therapy to maximize immunotherapeutic benefit. This study demonstrates that heterogeneous MHC-I expression drives resistance to anti-PD-L1 therapy and exposes NKG2A on NK cells as a target to overcome resistance. This article is featured in Selected Articles from This Issue, p. 201.

Mechanisms linking cerebrovascular dysfunction and tauopathy: Adding a layer of epiregulatory complexity.

Intracellular accumulation of hyperphosphorylated misfolded tau proteins are found in many neurodegenerative tauopathies, including Alzheimer's disease (AD). Tau pathology can impact cerebrovascular physiology and function through multiple mechanisms. In vitro and in vivo studies have shown that alterations in the blood-brain barrier (BBB) integrity and function can result in synaptic abnormalities and neuronal damage. In the present review, we will summarize how tau proteostasis dysregulation contributes to vascular dysfunction and, conversely, we will examine the factors and pathways leading to tau pathological alterations triggered by cerebrovascular dysfunction. Finally, we will highlight the role epigenetic and epitranscriptomic factors play in regulating the integrity of the cerebrovascular system and the progression of tauopathy including a few observartions on potential therapeutic interventions. LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc.

Divulgación higiénica-sanitaria y prevención de la obesidad en España: la obra de Jesús Noguer Moré (1903-1983) / Hygiene and health diffusion and the prevention of obesity in Spain: the work of Jesús Noguer Moré (1903-1983)

Introducción: entre los retos epidemiológicos de la sociedad española de la primera mitad del siglo XX, destacaba el problema de la malnutrición. Aunque eran el hambre y la desnutrición las formas más prevalentes, el sobrepeso y la obesidad empezaban a emerger entre las clases acomodadas. En todos los casos y, sobre todo, en el escenario de la sobrealimentación, la cuestión no era tanto económica como de falta de conocimientos. Por esta razón, para los higienistas eran fundamentales la divulgación y la educación en alimentación y nutrición. En este ámbito, destaca la aportación del endocrinólogo catalán Jesús Noguer Moré (1903-1983). El objetivo es analizar los trabajos que dedicó a la obesidad. Material y método: análisis bibliográfico de las obras de Jesús Noguer Moré. Resultados y conclusión: consideraba la obesidad una patología de etiología multifactorial con graves consecuencias para la morbimortalidad. Intervendrían desde la genética hasta patologías previas, pasando por hábitos alimentarios y de vida inadecuados. Su abordaje terapéutico debía basarse en restricciones calóricas y actividad física. Subrayaba el papel de determinados tipos de actividades familiares o profesionales en el fomento del sobrepeso y la obesidad. En materia preventiva, resaltaba la importancia de las prácticas culinarias y gastronómicas, al mismo tiempo que hacía recaer la responsabilidad de las mismas en las amas de casa, un discurso de género que llevó a Noguer a situar a las mujeres como colectivo diana de su acción divulgadora y donde estuvo muy presente el ideal de belleza femenina vigente en el periodo de entreguerras. (AU)

Introduction: among the epidemiological challenges facing Spanish society in the first half of the 20th century, the problem of malnutrition stood out. Although hunger and malnutrition were the most prevalent forms, overweight and obesity were beginning to emerge, particularly among the wealthier classes. In all cases, and especially in the overnutrition situation, the issue was not so much economic as one of lack of knowledge. For this reason, for the hygienists, dissemination and education in food and nutrition was fundamental. In this field, the contribution of the Catalan endocrinologist Jesús Noguer Moré (1903-1983) stands out. The aim is to analyze the work he devoted to obesity. Material and methods: bibliographic analysis of the works of Jesús Noguer Moré. Results and conclusion: he considered obesity as a pathology of multifactorial etiology with serious consequences for morbidity and mortality. It would involve everything from genetics to previous pathologies, as well as inadequate dietary and lifestyle habits. Its therapeutic approach should be based on calorie restriction and physical activity. He underlined the role of certain types of family or professional activities in promoting overweight and obesity. In terms of prevention, he emphasized the importance of culinary and gastronomic practices, while at the same time placing the responsibility for these practices on housewives. A gender discourse that led Noguer to place women as the target group for his dissemination activities and where the ideal of feminine beauty in force in the inter-war period was very much present. (AU)

Tridimensional Structural Analysis of Tau Isoforms Generated by Intronic Retention.

Background: Tauopathies are a subset of neurodegenerative diseases characterized by abnormal tau inclusions. Recently, we have discovered a new, human specific, tau isoform termed W-tau that originates by intron 12 retention. Our preliminary data suggests this newly discovered W-tau isoform might prevent aberrant aggregation of other tau isoforms but is significantly downregulated in tauopathies such as Alzheimer's disease. Objective: To accurately predict, examine, and understand tau protein structure and the conformational basis for the neuroprotective role of W-tau. Methods: A tridimensional deep learning-based approach and in vitro polymerization assay was included to accurately predict, analyze, and understand tau protein structure and the conformational basis for the neuroprotective role of W-tau. Results: Our findings demonstrate: a) the predicted protein tridimensionality structure of the tau isoforms raised by intron retention and their comparison with the other tau isoforms; b) the interaction of W-tau peptide (from W-tau isoform) with other tau isoforms; c) the effect of W-tau peptide in the polymerization of those tau isoforms. Conclusions: This study supports the importance of the structure-function relationship on the neuroprotective behavior of W-tau inhibiting tau fibrillization in vitro.

A questionnaire-based survey in Spain provides relevant information to improve the control of ovine coccidiosis.

Ovine coccidiosis is a widespread intestinal parasitic disease caused by Eimeria spp. Lambs are infected by the ingestion of sporulated oocysts, experiencing diarrhea and low growth rates. Control should be based on measures to reduce infection pressure and stress on the animals as well as on appropriate diagnosis and strategic treatment. To obtain information on how control measures are implemented in the ovine sector in Spain, a questionnaire-based survey was completed in 2022 by 154 veterinarians and 173 farmers working in this sector. Coccidiosis was highlighted as a relevant disease by 34% of the respondents. The period of greatest risk seemed to differ between production systems, being mainly early after weaning (7-15 days after weaning) in meat flocks and feedlots and later (1-2 months after weaning) in dairy flocks. The absence of cleaning and disinfection measures was identified as a risk factor by 51% of the veterinarians, with 22% mentioning overcrowding of animals and 22% indicating that coccidiosis has more incidence in flocks with large number of animals. The use of laboratory diagnosis methods (fecal oocyst count) was unusual in 70 and 84% of the veterinarians and farmers, respectively. Regarding control, dairy flocks usually housed a larger number of animals under intensive conditions, and they implemented more frequently control measures for coccidiosis than meat flocks. Anticoccidial drugs were used in 79% of the flocks, and in 74-82% of them, they were applied based on clinical criteria. Comparing protocols for anticoccidial treatment among different production systems, in meat flocks, anticoccidial drugs were applied more frequently when clinical signs were observed, and coccidiostats were used for less than 28 days compared to dairy flocks. These results highlight the need for improvement in the use of anticoccidial treatments adjusted to the new regulatory framework in the EU, which in turn will rationalize the use of antimicrobial compounds and may help to mitigate the impact of coccidiosis in flocks.

Normative Values for the Spanish Version of the Voice Symptom Scale (VoiSS)

Objective: The aim of this study was to establish normative values for the Voice Symptom Scale (VoiSS) in the Spanish community population (without voice problems), using a sample from a large area of southeastern Spain. Method: The sample consisted of 115 adults from ages 16 to 87, 60 of whom were women and 55 were men. Participants included the family members of patients who attended the Otorhinolaryngology (ENT) and Speech Therapy Clinic at a referral hospital in the region of Murcia, Spain, and some of the clinic's staff. All the participants reported never having suffered from any voice disorder before. Results: The normative values obtained in this study for the VoiSS were 14.61 (SD=8.18) for the total score, 7.57 (SD = 5.42) for the Impairment subscale, 1.04 (SD = 1.65) for the Emotional subscale, and 5.99 (SD = 3.61) for the Physical subscale. The percentile values were also obtained for the VoiSS scale and for its three subscales. Conclusions: This study presents normative values for the VoiSS scale that have not previously been obtained in Spain. These values can be used as a reference to detect possible voice disorders.

Objetivo: El objetivo de este estudio fue establecer valores normativos para la escala Voice Symptom Scale (VoiSS) en población comunitaria española (sin problemas de voz), utilizando una muestra de un área extensa del sureste de España. Metodología: La muestra estuvo compuesta por 115 personas (60 mujeres y 55 hombres) con edades comprendidas entre los 16 y 87 años. Los participantes eran familiares que acompañaron a los pacientes a las sesiones clínicas de ORL y de Logopedia de un hospital de referencia de la Región de Murcia, así como personal del hospital. Todos declararon no padecer ningún trastorno de la voz. Resultados: Los valores normativos obtenidos en este estudio para el VoiSS fueron 14.61 (SD=8.18) para la puntuación total, 7.57 (SD = 5.42) para la subescala Limitación, 1.04 (SD = 1.65) para la subescala Emocional y 5.99 (SD = 3.61) para la subescala Física. Los valores percentílicos se obtuvieron también para la escala VoiSS y para sus tres subescalas. Conclusiones: Este estudio presenta valores normativos para la escala VoiSS que no han sido todavía obtenidos en España. Estos valores pueden utilizarse como referencia para detectar posibles trastornos de voz.

Nogo-A is secreted in extracellular vesicles, occurs in blood and can influence vascular permeability.

Nogo-A is a transmembrane protein with multiple functions in the central nervous system (CNS), including restriction of neurite growth and synaptic plasticity. Thus far, Nogo-A has been predominantly considered a cell contact-dependent ligand signaling via cell surface receptors. Here, we show that Nogo-A can be secreted by cultured cells of neuronal and glial origin in association with extracellular vesicles (EVs). Neuron- and oligodendrocyte-derived Nogo-A containing EVs inhibited fibroblast spreading, and this effect was partially reversed by Nogo-A receptor S1PR2 blockage. EVs purified from HEK cells only inhibited fibroblast spreading upon Nogo-A over-expression. Nogo-A-containing EVs were found in vivo in the blood of healthy mice and rats, as well as in human plasma. Blood Nogo-A concentrations were elevated after acute stroke lesions in mice and rats. Nogo-A active peptides decreased barrier integrity in an in vitro blood-brain barrier model. Stroked mice showed increased dye permeability in peripheral organs when tested 2 weeks after injury. In the Miles assay, an in vivo test to assess leakage of the skin vasculature, a Nogo-A active peptide increased dye permeability. These findings suggest that blood borne, possibly EV-associated Nogo-A could exert long-range regulatory actions on vascular permeability.

[Hygiene and health diffusion and the prevention of obesity in Spain: the work of Jesús Noguer Moré (1903-1983)]. / Divulgación higiénica-sanitaria y prevención de la obesidad en España: la obra de Jesús Noguer Moré (1903-1983).

Introduction: Introduction: among the epidemiological challenges facing Spanish society in the first half of the 20th century, the problem of malnutrition stood out. Although hunger and malnutrition were the most prevalent forms, overweight and obesity were beginning to emerge, particularly among the wealthier classes. In all cases, and especially in the overnutrition situation, the issue was not so much economic as one of lack of knowledge. For this reason, for the hygienists, dissemination and education in food and nutrition was fundamental. In this field, the contribution of the Catalan endocrinologist Jesús Noguer Moré (1903-1983) stands out. The aim is to analyze the work he devoted to obesity. Material and methods: bibliographic analysis of the works of Jesús Noguer Moré. Results and conclusion: he considered obesity as a pathology of multifactorial etiology with serious consequences for morbidity and mortality. It would involve everything from genetics to previous pathologies, as well as inadequate dietary and lifestyle habits. Its therapeutic approach should be based on calorie restriction and physical activity. He underlined the role of certain types of family or professional activities in promoting overweight and obesity. In terms of prevention, he emphasized the importance of culinary and gastronomic practices, while at the same time placing the responsibility for these practices on housewives. A gender discourse that led Noguer to place women as the target group for his dissemination activities and where the ideal of feminine beauty in force in the inter-war period was very much present.

Introducción: Introducción: entre los retos epidemiológicos de la sociedad española de la primera mitad del siglo XX, destacaba el problema de la malnutrición. Aunque eran el hambre y la desnutrición las formas más prevalentes, el sobrepeso y la obesidad empezaban a emerger entre las clases acomodadas. En todos los casos y, sobre todo, en el escenario de la sobrealimentación, la cuestión no era tanto económica como de falta de conocimientos. Por esta razón, para los higienistas eran fundamentales la divulgación y la educación en alimentación y nutrición. En este ámbito, destaca la aportación del endocrinólogo catalán Jesús Noguer Moré (1903-1983). El objetivo es analizar los trabajos que dedicó a la obesidad. Material y método: análisis bibliográfico de las obras de Jesús Noguer Moré. Resultados y conclusión: consideraba la obesidad una patología de etiología multifactorial con graves consecuencias para la morbimortalidad. Intervendrían desde la genética hasta patologías previas, pasando por hábitos alimentarios y de vida inadecuados. Su abordaje terapéutico debía basarse en restricciones calóricas y actividad física. Subrayaba el papel de determinados tipos de actividades familiares o profesionales en el fomento del sobrepeso y la obesidad. En materia preventiva, resaltaba la importancia de las prácticas culinarias y gastronómicas, al mismo tiempo que hacía recaer la responsabilidad de las mismas en las amas de casa, un discurso de género que llevó a Noguer a situar a las mujeres como colectivo diana de su acción divulgadora y donde estuvo muy presente el ideal de belleza femenina vigente en el periodo de entreguerras.

The PD-1- and LAG-3-targeting bispecific molecule tebotelimab in solid tumors and hematologic cancers: a phase 1 trial.

Tebotelimab, a bispecific PD-1×LAG-3 DART molecule that blocks both PD-1 and LAG-3, was investigated for clinical safety and activity in a phase 1 dose-escalation and cohort-expansion clinical trial in patients with solid tumors or hematologic malignancies and disease progression on previous treatment. Primary endpoints were safety and maximum tolerated dose of tebotelimab when administered as a single agent (n = 269) or in combination with the anti-HER2 antibody margetuximab (n = 84). Secondary endpoints included anti-tumor activity. In patients with advanced cancer treated with tebotelimab monotherapy, 68% (184/269) experienced treatment-related adverse events (TRAEs; 22% were grade ≥3). No maximum tolerated dose was defined; the recommended phase 2 dose (RP2D) was 600 mg once every 2 weeks. There were tumor decreases in 34% (59/172) of response-evaluable patients in the dose-escalation cohorts, with objective responses in multiple solid tumor types, including PD-1-refractory disease, and in LAG-3+ non-Hodgkin lymphomas, including CAR-T refractory disease. To enhance potential anti-tumor responses, we tested margetuximab plus tebotelimab. In patients with HER2+ tumors treated with tebotelimab plus margetuximab, 74% (62/84) had TRAEs (17% were grade ≥3). The RP2D was 600 mg once every 3 weeks. The confirmed objective response rate in these patients was 19% (14/72), including responses in patients typically not responsive to anti-HER2/anti-PD-1 combination therapy. ClinicalTrials.gov identifier: NCT03219268 .