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Abstract Overconsumption of dietary sugar can lead to many negative health effects including the development of Type 2 diabetes, metabolic syndrome, cardiovascular disease, and neurodegenerative disorders. Recently, the human intestinal microbiota, strongly associated with our overall health, has also been known to be affected by diet. However, mechanistic insight into the importance of the human intestinal microbiota and the effects of chronic sugar ingestion has not been possible largely due to the complexity of the human microbiome which contains hundreds of types of organisms. Here, we use an interspecies C. elegans/E. coli system, where E. coli are subjected to high sugar, then consumed by the bacterivore host C. elegans to become the microbiota. This glucose-fed microbiota results in a significant lifespan reduction accompanied by reduced healthspan (locomotion), reduced stress resistance, and changes in behavior and feeding. Lifespan reduction is also accompanied by two potential major contributors: increased intestinal bacterial density and increased concentration of reactive oxygen species. The glucose-fed microbiota accelerated the age-related development of intestinal cell permeability, intestinal distention, and dysregulation of immune effectors. Ultimately, the changes in the intestinal epithelium due to aging with the glucose-fed microbiota results in increased susceptibility to multiple bacterial pathogens. Taken together, our data reveal that chronic ingestion of sugar, such as a Western diet, has profound health effects on the host due to changes in the microbiota and may contribute to the current increased incidence of ailments including inflammatory bowel diseases as well as multiple age-related diseases.

In recent years, transcription factors of the Microphthalmia-TFE (MiT) family, including TFEB and TFE3 in mammals and HLH-30 in Caenorhabditis elegans, have emerged as important regulators of innate immunity and inflammation in invertebrates and vertebrates. Despite great strides in knowledge, the mechanisms that mediate downstream actions of MiT transcription factors in the context of innate host defense remain poorly understood. Here, we report that HLH-30, which promotes lipid droplet mobilization and host defense, induces the expression of orphan nuclear receptor NHR-42 during infection with Staphylococcus aureus. Remarkably, NHR-42 loss of function promoted host infection resistance, genetically defining NHR-42 as an HLH-30-controlled negative regulator of innate immunity. During infection, NHR-42 was required for lipid droplet loss, suggesting that it is an important effector of HLH-30 in lipid immunometabolism. Moreover, transcriptional profiling of nhr-42 mutants revealed wholesale activation of an antimicrobial signature, of which abf-2, cnc-2, and lec-11 were important for the enhanced survival of infection of nhr-42 mutants. These results advance our knowledge of the mechanisms by which MiT transcription factors promote host defense, and by analogy suggest that TFEB and TFE3 may similarly promote host defense via NHR-42-homologous nuclear receptors in mammals.

The ionosphere provides a channel that is able to propagate electromagnetic waves for long-haul communications, allowing Non-Line-Of-Sight (NLOS) radio communications in the high-frequency band (HF). Nonetheless, its performance as a communications channel mainly depends on solar activity, as Earth’s diurnal and seasonal cycles modify the ionospheric ionization by the sun and consequently the channel performance. La Salle and the Observatori de l’Ebre have conducted oblique soundings of a 12,760 km ionospheric channel from Livingston Island (South Shetland Archipelago—Antarctica −62.7∘S, 299.6∘E) to Cambrils (Spain −41.0∘N, 1.0∘E) to evaluate this evidence and analyze the characteristics of this particular channel. The final goal of the project is to establish a stable communications link to be used as a backup for low throughput data transmission from the various geomagnetic and meteorological sensors located in the Spanish Antarctic Station. The aim of this paper is to confirm the relationship between the channel availability of narrowband and wideband communications and the resulting channel parameters with the solar and ionospheric activity for four consecutive sounding campaigns.

Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-neoadjuvant chemotherapy. We found that intratumor genetic diversity was tumor-subtype specific, and it did not change during treatment in tumors with partial or no response. However, lower pretreatment genetic diversity was significantly associated with pathologic complete response. In contrast, phenotypic diversity was different between pre- and posttreatment samples. We also observed significant changes in the spatial distribution of cells with distinct genetic and phenotypic features. We used these experimental data to develop a stochastic computational model to infer tumor growth patterns and evolutionary dynamics. Our results highlight the importance of integrated analysis of genotypes and phenotypes of single cells in intact tissues to predict tumor evolution.

Abstract With the incorporation of cyclin-dependent kinase inhibitors in early breast cancer (BC), a better identification of biomarkers is needed. The PROMETEO II trial aimed to evaluate the antitumor activity of palbociclib plus letrozole and to identify response biomarkers in patients with operable HR+/HER2- BC and residual disease after neoadjuvant chemotherapy (NAC). The primary endpoint was the rate of complete cell cycle arrest (CCCA), centrally determined by Ki67 ≤ 2.7% at surgery. A comprehensive translational analysis was conducted. At surgery, the CCCA rate was 59.1%, with a 44.2% decrease in Ki67 from the end of NAC. Changes in intrinsic subtypes occurred in 48% of patients, with proliferation genes suppressed, and immune genes more upregulated in tumors with CCCA. Overall, 14% of tumors were classified as PD-L1+ after palbociclib. Nine patients experienced grade 3 adverse events (AEs). Palbociclib showed an anti-proliferative effect, with increased immune infiltration in residual tumors with CCCA. Trial registration: Palbociclib Plus Letrozole in Hormone Receptor Positive Residual Disease After Neoadjuvant Chemotherapy (PROMETEO II) ClinicalTrial.gov number NCT04130152. Study registration; October 17, 2019.

Abstract In this study, we performed genomic analyses of cell cycle and tumor microenvironment changes during and after ribociclib and letrozole or chemotherapy in the CORALLEEN trial. 106 women with untreated PAM50-defined Luminal B early breast cancers were randomly assigned to receive neoadjuvant ribociclib and letrozole or standard-of-care chemotherapy. Ki67 immunohistochemistry, tumor-infiltrating lymphocytes quantification, and RNA sequencing were obtained from tissue biopsies pre-treatment, on day 14 of treatment, and tumor specimens from surgical resection. Results showed that at surgery, Ki67 and the PAM50 proliferation scores were lower after ribociclib compared to chemotherapy. However, consistent reactivation of tumor cell proliferation from day 14 to surgery was only observed in the ribociclib arm. In tumors with complete cell cycle arrest (CCCA) at surgery, PAM50 proliferation scores were lower in the ribociclib arm compared to chemotherapy (p

Abstract Video games, specifically action video games, have been demonstrated to be a useful tool in improving certain visual aspects in the general population. Visual attention span, the ability to simultaneously process multiple distinct visual elements during a single fixation, has been shown to improve among action video game players. The goal of this study was to verify that visual attention span is better not only in action video games, but also in other video game genres such as sports simulators or role-playing games. A total of 41 participants, aged 18 to 40 years old, were asked about the type of video games they were playing, name and genre, and the frequency of play. Visual attention span was assessed in all participants. Participants were divided into 4 groups according to the genre of video game they played. The total percentage of letter identification in the visual attention span was not significantly different between groups. A significant difference was found in the sixth position letter, and the right hemifield performance between groups, especially in sports simulators and action video game participants who showed a better performance. The action video game group showed a significant correlation between visual attention span performance and weekly hours played. Playing regularly different genres other than action video games can contribute to raise visual attention resources.

Introducción: Este artículo, es un producto parcial del proyecto de investigación “Educación e Igualdad” del grupo de Investigaciones PROCARIBE, en el marco de la línea de investigación denominada Economía de la Educación, y aborda el problema de la desigualdad educativa en Colombia. Este es uno de los principales retos para el Plan de Desarrollo Nacional 2018-2022, centrado en la paz, la equidad y la educación. Objetivo: Identificar los desafíos en términos de desigualdad educativa que enfrenta Colombia, especialmente entre la población joven y considerando factores como la transmisión intergeneracional de las desigualdades educativas. Metodología: el artículo obedece a una investigación realizada bajo el paradigma empírico analítico, un diseño cuantitativo y un tipo de investigación explicativa. Los datos fueron obtenidos a partir de información secundaria y recolectados por el Departamento Nacional de Estadística, procesados a partir de la depuración de la base de datos y analizados mediante el uso del Índice de Pendiente de Desigualdad. Resultados: La brecha de desigualdad educativa entre jóvenes de diferentes estratos sociales ha aumentado entre 2011 y 2016, y hay una correlación positiva entre los años de escolaridad de los padres y sus hijos, lo cual valida la hipótesis de la transmisión intergeneracional de las desigualdades educativas. Además, se pudo establecer que los jóvenes que estudian en instituciones privadas tienen una mayor probabilidad de completar diez años de escolaridad, que aquellos en escuelas oficiales. Conclusión: En síntesis, poco se ha avanzado en materia de desfragmentación social y una mejor educación puede tener un impacto positivo en las generaciones futuras.

Abstract Background Benign paroxysmal positional vertigo (BPPV) is the most common type of vertigo. While BPPV is best treated with canalicular repositioning manoeuvres, they are not routinely performed in primary care (PC). Methods To evaluate the effectiveness of blended training (online and face-to-face) on the diagnosis and management of vertigo to improve adherence of family doctors to clinical practice guidelines, we designed a community multicentre cluster-randomised open-label trial with an intervention (IG) and a control (GC) group of 10 primary care teams (PCT) each. Outcome variables will be ICD-10 diagnostic codes (proportion of nonspecific diagnoses such as dizziness and vertigo versus specific diagnoses such as BPPV, vestibular neuritis, and Menière’s disease); number of referrals to ENT or neurology specialists; prescription of antivertigo agents; and duration of sick leave due to vertigo. The baseline comparability of the two study groups will be analysed to ensure homogeneity. A description of all baseline variables will be performed. Student’s t-test will be used to evaluate the differences between the groups. Logistic regression multivariate analysis will be performed to study the relationship between baseline variables of professionals and centres with outcome variables. Discussion With the improvement of the diagnosis and management of vertigo by family doctors after this training, we expect an increase in the proportion of specific diagnoses, a decrease in the prescription of antivertigo agents, a decrease in referrals to ENT or neurology specialists and a reduction in the duration of sick leave due to temporary disability. The blended training will be easily expanded within primary care services, since it is mainly delivered online, with a single face-to-face session to ensure that the manoeuvres have been adequately learned. Trial registration ClinicalTrials.gov NCT04929444 . Registered June 18, 2021. This protocol has been approved by the Ethics Committee of the Institut Universitari d’Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol) with the code 20/004-P. All patient data will be anonymised in agreement with the 2016/679 European Regulation.

Many advanced cases of cancer show central nervous system, pleural, or peritoneal involvement. In this study, we prospectively analyzed if cerebrospinal fluid (CSF), pleural effusion (PE), and/or ascites (ASC) can be used to detect driver mutations and guide treatment decisions. We collected 42 CSF, PE, and ASC samples from advanced non‐small‐cell lung cancer and melanoma patients. Cell‐free DNA (cfDNA) was purified and driver mutations analyzed and quantified by PNA‐Q‐PCR or next‐generation sequencing. All 42 fluid samples were evaluable; clinically relevant mutations were detected in 41 (97.6%). Twenty‐three fluids had paired blood samples, 22 were mutation positive in fluid but only 14 in blood, and the abundance of the mutant alleles was significantly higher in fluids. Of the 34 fluids obtained at progression to different therapies, EGFR resistance mutations were detected in nine and ALK acquired mutations in two. The results of testing of CSF, PE, and ASC were used to guide treatment decisions, such as initiation of osimertinib treatment or selection of specific ALK tyrosine–kinase inhibitors. In conclusion, fluids close to metastatic sites are superior to blood for the detection of relevant mutations and can offer valuable clinical information, particularly in patients progressing to targeted therapies.

Abstract Background The biological effect of oral metronomic vinorelbine (mVNB) alone or in combination with endocrine therapy in patients with hormone receptor-positive (HR+)/HER2-negative breast cancer has been scarcely addressed. Methods Postmenopausal women with untreated stage I–III HR+/HER2-negative breast cancer were randomized (1:1:1) to receive 3 weeks of letrozole (LTZ) 2.5 mg/day, oral mVNB 50 mg 3 days/week, or the combination. The primary objective was to evaluate, within PAM50 Luminal A/B disease, if the anti-proliferative effect of LTZ+mVNB was superior to monotherapy. An anti-proliferative effect was defined as the mean relative decrease of the PAM50 11-gene proliferation score in combination arm vs. both monotherapy arms. Secondary objectives included the evaluation of a comprehensive panel of breast cancer-related genes and safety. An unplanned analysis of stromal tumor-infiltrating lymphocytes (sTILs) was also performed. PAM50 analyses were performed using the nCounter®-based Breast Cancer 360™ gene panel, which includes 752 genes and 32 signatures. Results Sixty-one patients were randomized, and 54 paired samples (89%) were analyzed. The main patient characteristics were mean age of 67, mean tumor size of 1.7 cm, mean Ki67 of 14.3%, stage I (55.7%), and grades 1–2 (90%). Most baseline samples were PAM50 Luminal A (74.1%) or B (22.2%). The anti-proliferative effect of 3 weeks of LTZ+mVNB (− 73.2%) was superior to both monotherapy arms combined (− 49.9%; p = 0.001) and mVNB (− 19.1%; p

Abstract Background The Opti-HER HEART trial aimed to optimize activity while minimizing cardiac risk by combining trastuzumab, pertuzumab, and paclitaxel with non-pegylated liposomal doxorubicin in the treatment of HER2-positive early breast cancer. Methods Patients with stage II–IIIB HER2-positive breast cancer received neoadjuvant trastuzumab, pertuzumab, paclitaxel, and a non-pegylated liposomal doxorubicin every three weeks for six cycles. The primary endpoint was cardiac safety during neoadjuvant therapy. Type A (symptomatic congestive heart failure) and B (asymptomatic reduction of left ventricular ejection fraction) cardiac events were evaluated. Secondary endpoints included the evaluation of the pathological complete response (pCR) rate and overall response rate, among others. As an ad-hoc exploratory analysis, the expression of 55 breast cancer-related genes, including the PAM50 genes, was measured in 58 baseline tumor samples and 60 surgical specimens. Results Eighty-three patients were recruited. The incidence of cardiac events during neoadjuvant treatment was 2.4%. No type A cardiac event was observed. The overall pCR rate was 56.6% (95% confidence interval (CI) 45.3–67.5%). The HER2-enriched subtype, which represented 52.0% of all baseline samples, was associated with a higher pCR rate compared to non-HER2-enriched tumors (83.3% vs. 46.3%; odds ratio 5.76, 95% CI 1.71–19.42). The association of subtype with pCR was independent of known clinicopathological variables, including hormone receptor status. Compared to baseline samples, surgical specimens showed a significant downregulation of proliferation-related genes (MKI67 and CCNB1) and ERBB2 levels, and a significant upregulation of luminal-related (ESR1 and PGR) and immune (CD8A) genes. Conclusions The combination of dual HER2 blockade with trastuzumab and pertuzumab with paclitaxel and non-pegylated liposomal doxorubicin is associated with a low rate of cardiac events. The HER2-enriched subtype is associated with a high rate of pCR. Trial registration clinicaltrials.gov, NCT01669239, Registered 20 August 2012.

Antecedentes: La neuromonitorización intraoperatoria intermitente del nervio laríngeo recurrente es el complemento ideal en las cirugías tiroideas, ya que disminuye las lesiones. Objetivo: Analizar la prevalencia de lesiones del nervio laríngeo recurrente con y sin el uso de neuromonitorización en cirugía de tiroides. Método: Estudio observacional, descriptivo y retrospectivo, en el que se incluyeron 571 pacientes entre los años 2012 y 2018. De ellos, en 180 se utilizó neuromonitorización y en 391 no. Resultados: De los 180 pacientes que se sometieron a tiroidectomía total con neuromonitorización hubo 8 (4.4%) parálisis transitorias y 2 (1.1%) parálisis definitivas. Sin el uso de neuromonitorización hubo 12 (3%) parálisis transitorias y 7 (1.85%) definitivas. Conclusiones: Creemos que la neuromonitorización debe usarse sistemáticamente con la técnica habitual. Obtenemos resultados significativos con respecto a la reducción de las lesiones del nervio laríngeo recurrente con el uso de neuromonitorización intraoperatoria.

Drug–drug interactions are of significant concern in clinical practice in oncology, particularly in patients receiving Cyclin-dependent kinase (CDK) 4/6 inhibitors, which are typically exposed to long-term regimens. This article presents the highlights from the ‘First Workshop on Pharmacology and Management of CDK4/6 Inhibitors: Consensus about Concomitant Medications’. The article is structured into two modules. The educational module includes background information regarding drug metabolism, corrected QT (QTc) interval abnormalities, management of psychotropic drugs and a comprehensive review of selected adverse effects of palbociclib and ribociclib. The collaborative module presents the conclusions of the five working groups, each of which comprised five experts from different fields. From these conclusions positive lists of drugs for treating common comorbid conditions that can be safely administered concomitantly with palbociclib and/or ribociclib were developed.

Entrevista realizada com o crítico e professor na Columbia University, Estados Unidos, Jonathan Crary, tendo como ponto central o livro mais recente dele publicado no Brasil: Terra arrasada: além da era digital, rumo a um mundo pós-capitalista (2023). O livro traz uma noção de gerenciamento do Olhar a partir do uso das mídias digitais e da plataformização da cultura. O texto de Crary questiona como o capitalismo tardio se apodera das possibilidades de existência subjetiva e objetiva, mediante o que ele chama de “complexo internético”, conjunto de dispositivos, lógicas e equipamentos ligados à internet que tem como sintoma mais gritante as redes sociais. O autor busca entender como a atenção é requerida, dispensada e moldada com o uso das mídias digitais e como ela é fornecida de maneira permanente no contexto contemporâneo. Para ele, este universo da informação a que estamos sujeitos estabelece as transformações do Olhar que afetam de maneira profunda e definitiva o nosso comportamento. Por tratar de temas contemporâneos urgentes e agregar ao debate acadêmico insights estimulantes, a revisão de suas ideias tornou premente a necessidade de conversar mais a fundo com Crary e explorar seus conceitos e percepções.

BackgroundTrastuzumab improves survival outcomes in patients with HER2+ metastatic breast cancer. The Long-Her study was designed to identify clinical and molecular markers that could differentiate long-term survivors from patients having early progression after trastuzumab treatment.MethodsData were collected from women with HER2-positive metastatic breast cancer treated with trastuzumab that experienced a response or stable disease during at least 3 years. Patients having a progression in the first year of therapy with trastuzumab were used as a control. Genes related with trastuzumab resistance were identified and investigated for network and gene functional interrelation. Models predicting poor response to trastuzumab were constructed and evaluated. Finally, a mutational status analysis of selected genes was performed in HER2 positive breast cancer samples.Results103 patients were registered in the Long-HER study, of whom 71 had obtained a durable complete response. Median age was 58 years. Metastatic disease was diagnosed after a median of 24.7 months since primary diagnosis. Metastases were present in the liver (25%), lungs (25%), bones (23%) and soft tissues (23%), with 20% of patients having multiple locations of metastases. Median duration of response was 55 months. The molecular analysis included 35 patients from the group with complete response and 18 patients in a control poor-response group. Absence of trastuzumab as part of adjuvant therapy was the only clinical factor associated with long-term survival. Gene ontology analysis demonstrated that PI3K pathway was associated with poor response to trastuzumab-based therapy: tumours in the control group usually had four or five alterations in this pathway, whereas tumours in the Long-HER group had two alterations at most.ConclusionsTrastuzumab may provide a substantial long-term survival benefit in a selected group of patients. Whole genome expression analysis comparing long-term survivors vs. a control group predicted early progression after trastuzumab-based therapy. Multiple alterations in genes related to the PI3K-mTOR pathway seem to be required to confer resistance to this therapy.

Space Weather (SW) hazards are discussed in terms of the operation of national SW services and global SW centers for the International Civil Aviation Organization (ICAO). The definition of threshold values of monitored parameters which are used to identify moderate and severe SW events is one of the critical problems. Due to the lack of both physical data on severe events and user feedback, we tried to approach the problem statistically. In particular, we pursued the answer to the question about what intensity of ionospheric storms and flare effects should be reported by national and global SW entities to their users. We also discussed the possible role of an active region on the Sun, and the cosmic rays’ issues that may be helpful regarding SW operational work. The presented considerations are based on examples of the ionosphere state assessment for the low-latitude American sector with a focus on the Mexican region. This work attempts to argue the possible approaches to resolve the tasks that the SW national services and global centers face.

Possible ionospheric effects of the Morelian meteoroid that passed and exploded over Mexico on 19 February 2020 (18 February 2020 local time) were estimated. The meteoroid trajectory, velocity and time of occurrence were calculated based on outdoor camera records. Modeling was used to estimate the meteoroid initial diameter, density, mass, velocity, energy and their change during its flight in the atmosphere. The ensemble of ionospheric scintillation indices calculated from the high-rate GNSS data and the filtered slant Total Electron Content data were used to reveal the presence of ionospheric disturbances generated by shock waves excited by the meteoroid flight and explosion. The first ionospheric responses to phenomena accompanying the meteoroid were detected (2.5–3.5) min after the explosion. The disturbances were attenuated quickly with distance from their source and were rarely recorded by GNSS receivers located more than 600 km from the meteoroid explosion site. The ionospheric disturbances of intermediate-scale, small-scale, shock-acoustic-wave-scale and sometimes medium-scale were revealed. The detected disturbances corresponded to the range of acoustic-gravity waves. An asymmetry of the disturbance manifestation in different directions was observed. The obtained results are in accordance with results of the observation of other meteoroids. Although the object was smaller and of less energy than other known meteoroids, it is an interesting case because, to the best of our knowledge, it isthe first known to us low-latitude meteoroid with the detected ionospheric effects.