The mechanism of action of intravesical Mycobacterium bovis BCG immunotherapy treatment for bladder cancer is not completely known, leading to misinterpretation of BCG-unresponsive patients, who have scarce further therapeutic options. BCG is grown under diverse culture conditions worldwide, which can impact the antitumor effect of BCG strains and could be a key parameter of treatment success. Here, BCG and the nonpathogenic Mycobacterium brumae were grown in four culture media currently used by research laboratories and BCG manufacturers: Sauton-A60, -G15 and -G60 and Middlebrook 7H10, and used as therapies in the orthotopic murine BC model. Our data reveal that each mycobacterium requires specific culture conditions to induce an effective antitumor response. since higher survival rates of tumor-bearing mice were achieved using M. brumae-A60 and BCG-G15 than the rest of the treatments. M. brumae-A60 was the most efficacious among all tested treatments in terms of mouse survival, cytotoxic activity of splenocytes against tumor cells, higher systemic production of IL-17 and IFN-ɣ, and bladder infiltration of selected immune cells such as ILCs and CD4TEM. BCG-G15 triggered an antitumor activity based on a massive infiltration of immune cells, mainly CD3+ (CD4+ and CD8+) T cells, together with high systemic IFN-ɣ release. Finally, a reduced variety of lipids was strikingly observed in the outermost layer of M. brumae-A60 and BCG-G15 compared to the rest of the cultures, suggesting an influence on the antitumor immune response triggered. These findings contribute to understand how mycobacteria create an adequate niche to help the host subvert immunosuppressive tumor actions.
Objectives: Deliberative processes in Health Technologies Assessment (HTA) result in recommendations that determine the reimbursement of medicines, diagnostics or devices. These processes are governed by explicit criteria, but are also influenced by implicit factors. The objective of this work was to identify the implicit factors influencing HTA deliberative processes in five European countries (France, Germany, Italy, Spain and the UK). Methods: A systematic review of literature published between 2009 and 2019 was conducted. The search was performed in Pubmed, The Cochrane Database of Systematic Reviews, Google Scholar and Center for Reviews and Dissemination. The ISPOR database was searched manually. Results: Out of 100 eligible publications, eight articles were selected for data extraction and analysis. The implicit factors in the HTA deliberative process most frequently mentioned in the identified literature are value judgments, biases, preferences and subjectivity. Five out of the eight articles highlight the need to further improve the transparency of the process, and three provide recommendations on how to address the influence of implicit factors on the HTA deliberative process through a framework. Conclusion: Even in countries with a long HTA history, evidence on implicit factors is scarce. Some methods have been recommended for addressing these factors. Further research is required to characterize the implicit factors in the HTA deliberative process at a country level and explore potential ways to mitigate the influence of these factors on the HTA deliberative process.
The Large Hadron Collider beauty (LHCb) experiment at CERN is undergoing an upgrade in preparation for the Run 3 data collection period at the Large Hadron Collider (LHC). As part of this upgrade, the trigger is moving to a full software implementation operating at the LHC bunch crossing rate. We present an evaluation of a CPU-based and a GPU-based implementation of the first stage of the high-level trigger. After a detailed comparison, both options are found to be viable. This document summarizes the performance and implementation details of these options, the outcome of which has led to the choice of the GPU-based implementation as the baseline.
Background Lysosomal Storage Diseases (LSDs) are a group of Rare Diseases (RDs) caused by lysosomal enzyme deficiencies. Patients with LSDs suffer from a wide range of symptoms with a strong impact in their daily routines. In this study we aimed to explore the impact of the disease on the lives of patients with four LSDs, as well as how they experience Patient Journey from diagnosis to follow up. Unmet Needs (UNs) perceived by patients and clinicians were assessed to have a better understanding of which initiatives could improve LSDs management and especially those that could result in an improvement of patients’ quality of life. Methods Qualitative research was the research methodology selected for the study. It provides plentiful and holistic insights into people’s views and actions. The study was conducted through in-depth face-to-face semi-structured interviews. Results In total, 20 patients and 25 Health Care Professionals (HCPs) from different Spanish regions were interviewed. Patients perceived that the highest impact of the LSDs was on their daily routines, specifically on their emotional side, their work/school environment, their family and their social life. Regarding the Patient Journey experience, the worst perceived stage was the pre-diagnosis, where patients only reported negative perceptions, being the delay in diagnosis and misdiagnosis the most commented issues. On the contrary, the follow-up stage was the one with less negative perceptions. Overall, patients and HCPs agreed on the priority UNs, such as accelerating diagnosis, reducing bureaucracy for the treatment access and a more coordinated attention for the patients, not only among different physicians but also with other professionals such as genetic counselors or social workers. Conclusions Our data shows that there are still UNs to be addressed from the perspective of patients and HCPs. The main UN is accelerating diagnosis, which could be achieved by medical awareness and education, according to clinicians. A more comprehensive disease management was another main point to be worked on to improve LSD-patient experience and quality of life.
Background Clinical endpoints for upcoming therapeutic trials in frontotemporal dementia (FTD) are increasingly urgent. Cognitive composite scores are often used as endpoints but are lacking in genetic FTD. We aimed to create cognitive composite scores for genetic frontotemporal dementia (FTD) as well as recommendations for recruitment and duration in clinical trial design. Methods A standardized neuropsychological test battery covering six cognitive domains was completed by 69 C9orf72 , 41 GRN , and 28 MAPT mutation carriers with CDR® plus NACC-FTLD ≥ 0.5 and 275 controls. Logistic regression was used to identify the combination of tests that distinguished best between each mutation carrier group and controls. The composite scores were calculated from the weighted averages of test scores in the models based on the regression coefficients. Sample size estimates were calculated for individual cognitive tests and composites in a theoretical trial aimed at preventing progression from a prodromal stage (CDR® plus NACC-FTLD 0.5) to a fully symptomatic stage (CDR® plus NACC-FTLD ≥ 1). Time-to-event analysis was performed to determine how quickly mutation carriers progressed from CDR® plus NACC-FTLD = 0.5 to ≥ 1 (and therefore how long a trial would need to be). Results The results from the logistic regression analyses resulted in different composite scores for each mutation carrier group (i.e. C9orf72 , GRN , and MAPT ). The estimated sample size to detect a treatment effect was lower for composite scores than for most individual tests. A Kaplan-Meier curve showed that after 3 years, ~ 50% of individuals had converted from CDR® plus NACC-FTLD 0.5 to ≥ 1, which means that the estimated effect size needs to be halved in sample size calculations as only half of the mutation carriers would be expected to progress from CDR® plus NACC FTLD 0.5 to ≥ 1 without treatment over that time period. Discussion We created gene-specific cognitive composite scores for C9orf72 , GRN , and MAPT mutation carriers, which resulted in substantially lower estimated sample sizes to detect a treatment effect than the individual cognitive tests. The GENFI-Cog composites have potential as cognitive endpoints for upcoming clinical trials. The results from this study provide recommendations for estimating sample size and trial duration.
The fabrication of integrated circuits (ICs) employing two-dimensional (2D) materials is a major goal of semiconductor industry for the next decade, as it may allow the extension of the Moore’s law, aids in in-memory computing and enables the fabrication of advanced devices beyond conventional complementary metal-oxide-semiconductor (CMOS) technology. However, most circuital demonstrations so far utilizing 2D materials employ methods such as mechanical exfoliation that are not up-scalable for wafer-level fabrication, and their application could achieve only simple functionalities such as logic gates. Here, we present the fabrication of a crossbar array of memristors using multilayer hexagonal boron nitride (h-BN) as dielectric, that exhibit analog bipolar resistive switching in >96% of devices, which is ideal for the implementation of multi-state memory element in most of the neural networks, edge computing and machine learning applications. Instead of only using this memristive crossbar array to solve a simple logical problem, here we go a step beyond and present the combination of this h-BN crossbar array with CMOS circuitry to implement extreme learning machine (ELM) algorithm. The CMOS circuit is used to design the encoder unit, and a h-BN crossbar array of 2D hexagonal boron nitride (h-BN) based memristors is used to implement the decoder functionality. The proposed hybrid architecture is demonstrated for complex audio, image, and other non-linear classification tasks on real-time datasets.
Background When genes responsible for normal embryonic development are abnormally expressed in adults, it can lead to tumor development. This can suggest that the same mechanism that controls embryonic differentiation can also control tumor differentiation. We hypothesize that the malignant phenotype of lung cancer cells could acquire benign characteristics when in contact with an embryonic lung microenvironment. We cultured two lung cancer cell lines in embryonic lung mesenchyme-conditioned medium and evaluated morphological, functional and molecular changes. Methods The human embryonic mesenchymal lung-conditioned medium (hEML-CM) was obtained by culturing lung cells from embryos in the pseudoglandular stage of development. The NSCLC cell lines A549 and H1299 we cultured in the hEML-CM and in a tumor-conditioned medium. Morphological changes were analyzed with optical and transmission electron microscopy. To evaluate the functional effect of conditioned medium in tumor cells, we analyzed cell proliferation, migration, colony formation capacity in 2D and 3D and in vivo tumor growth capacity. The expression of the pluripotency genes OSKM, the adenocarcinoma marker NKX2-1, the lung surfactant proteins SFTP, the myofibroblast marker MYH and DNMT3A/3B was analyzed with qRT-PCR and the presence of the myofibroblast markers vimentin and α-SMA with immunofluorescence. Transcriptomic analysis was performed using Affymetrix arrays. Results The A549 and H1299 cells cultured in hEML-CM lost their epithelial morphology, acquired mesodermal characteristics, and decreased proliferation, migration, and colony formation capacity in 2D and 3D, as well as reduced its capacity to growth in vivo. The expression of OSKM, NKX2-1 and SFTP decreased, while that of DNMT3A/3B, vimentin, α-SMA and MYH increased. Distant matrix analysis based on transcriptomic profile showed that conditioned cells were closer to myoblast and human lung fibroblast than to normal epithelial immortalized lung cells. A total of 1631 for A549 and 866 for H1299 differentially expressed genes between control and conditioned cells were identified. Conclusions To the best of our knowledge, this is the first study to report that stimuli from the embryonic lung can modulate the malignant phenotype of lung cancer cells, control their growth capacity and activate their differentiation into myofibroblasts. These findings could lead to new strategies for lung cancer management.
The Mediterranean region has been declared a climate change hotspot due, among other reasons, to an expected increase in the torrential rains that frequently affect this densely populated area. However, the extent to which these torrential rains are connected to other regions outside the Mediterranean remains uncertain. Here we simulate 160 extreme precipitation events with an atmospheric model enabled for state-of-the-art moisture tracking and demonstrate that large scale moisture transport is a more important factor than evaporation over local sources. We find that the average precipitation fraction with source in the Mediterranean is only 35%, while 10% is from evapotranspiration over nearby land in continental Europe and 25% originates in the North Atlantic. The remaining 30% comes from several more distant source regions, sometimes as remote as the tropical Pacific or the Southern Hemisphere, indicating direct connections with multiple locations on the planet and a global scale energy redistribution. Our results point to the importance of approaching these extreme episodes from a more global rather than purely regional perspective, especially when attempting to attribute them to climate change.
Background Neurodevelopmental disorders (NDDs) are a group of heterogeneous conditions, which include mainly intellectual disability, developmental delay (DD) and autism spectrum disorder (ASD), among others. These diseases are highly heterogeneous and both genetic and environmental factors play an important role in many of them. The introduction of next generation sequencing (NGS) has lead to the detection of genetic variants in several genetic diseases. The main aim of this report is to discuss the impact and advantages of the implementation of NGS in the diagnosis of NDDs. Herein, we report diagnostic yields of applying whole exome sequencing in 87 families affected by NDDs and additional data of whole genome sequencing (WGS) from 12 of these families. Results The use of NGS technologies allowed identifying the causative gene alteration in approximately 36% (31/87) of the families. Among them, de novo mutation represented the most common cause of genetic alteration found in 48% (15/31) of the patients with diagnostic mutations. The majority of variants were located in known neurodevelopmental disorders genes. Nevertheless, some of the diagnoses were made after the use of GeneMatcher tools which allow the identification of additional patients carrying mutations in THOC2 , SETD1B and CHD9 genes. Finally the use of WGS only allowed the identification of disease causing variants in 8% (1/12) of the patients in which previous WES failed to identify a genetic aetiology. Conclusion NGS is more powerful in identifying causative pathogenic variant than conventional algorithms based on chromosomal microarray as first-tier test. Our results reinforce the implementation of NGS as a first-test in genetic diagnosis of NDDs.
Background Anthropometric measures have been classically used to understand the impact of environmental factors on the living conditions of individuals and populations. Most reference studies on development and growth in which anthropometric measures were used were carried out in populations that are located at sea level, but there are few studies carried out in high altitude populations. Objective The objective of this study was to evaluate the anthropometric and body composition in autochthonous Kiwcha permanently living at low and high altitudes. Methodology A cross-sectional study of anthropometric and body composition between genetically matched lowland Kiwcha from Limoncocha ( n = 117), 230 m in the Amazonian basin, and high-altitude Kiwcha from Oyacachi ( n = 95), 3800 m in Andean highlands. Student’s t -test was used to analyze the differences between continuous variables, and the chi-square test was performed to check the association or independence of categorical variables. Fisher’s exact test or Spearman’s test was used when the variable had evident asymmetries with histograms prior to the selection of the test. Results This study shows that high altitude men are shorter than their counterparts who live at low altitude, with p = 0.019. About body muscle percentage, women at high altitudes have less body muscle percentage (− 24.8%). In comparison, men at high altitudes have significantly more muscle body mass percentage (+ 13.5%) than their lowland counterparts. Body fat percentage was lower among low altitude women (− 15.5%), and no differences were found among men. Conclusions This is the first study to be performed in two genotyped controlled matching populations located at different altitudes to our best knowledge. The anthropometric differences vary according to sex, demonstrating that high altitude populations are, in general, lighter and shorter than their low altitude controls. Men at high altitude have more muscled bodies compared to their lowland counterparts, but their body age was older than their actual age.
First-episode psychosis (FEP) patients show structural brain abnormalities at the first episode. Whether the cortical changes that follow a FEP are progressive and whether age at onset modulates these changes remains unclear. This is a multicenter MRI study in a deeply phenotyped sample of 74 FEP patients with a wide age range at onset (15–35 years) and 64 neurotypical healthy controls (HC). All participants underwent two MRI scans with a 2-year follow-up interval. We computed the longitudinal percentage of change (PC) for cortical thickness (CT), surface area (CSA) and volume (CV) for frontal, temporal, parietal and occipital lobes. We used general linear models to assess group differences in PC as a function of age at FEP. We conducted post-hoc analyses for metrics where PC differed as a function of age at onset. We found a significant age-by-diagnosis interaction effect for PC of temporal lobe CT ( d = 0.54; p = 002). In a post-hoc-analysis, adolescent-onset (≤19 y) FEP showed more severe longitudinal cortical thinning in the temporal lobe than adolescent HC. We did not find this difference in adult-onset FEP compared to adult HC. Our study suggests that, in individuals with psychosis, CT changes that follow the FEP are dependent on the age at first episode, with those with an earlier onset showing more pronounced cortical thinning in the temporal lobe.
Neuroinflammation, in which activated microglia are involved, appears to contribute to the development of Parkinson’s disease (PD). However, the role of microglial activation and the mechanisms governing this process remain uncertain. We focused on one inhibitory mechanism involved in the control of microglial activation, the microglia inhibitory receptor CD200R1, and its ligand CD200, mainly expressed by neurons. The human CD200R1 gene encodes two membrane-associated and two soluble protein isoforms and the human CD200 gene encodes full-length proteins (CD200full) but also truncated (CD200tr) proteins which act as CD200R1 antagonists. Little is known about their expression in the human brain under pathological conditions. We used human peripheral blood monocytes and monocyte-derived microglia-like cells from control subjects to characterize the expression of the CD200R1 mRNA variants, which showed stimulus-specific responses. We provide evidence of increased CD200R1 (mRNA variants and protein isoforms) and CD200 expression (CD200tr mRNA) in brain tissue of PD patients, mainly in the hippocampus, as well as increased CD200 expression (CD200full and CD200tr mRNAs) in iPSCs-derived dopaminergic neurons generated from skin fibroblasts of PD patients. Our results suggest that CD200-CD200R1 signalling is altered in PD, which may affect the microglial function and constitute a potential target in therapeutic strategies for PD.
Objective To interpret the current evidence on the prevalence of neurodevelopmental disorders (NDDs) through a systematic review based on both DSM-5 (2013) and PRISMA criteria. Method Empirical studies complying with the PRISMA guidelines were identified from four databases (PubMed, Scopus, Science Direct, and ProQuest) and systematically reviewed. In total, 17 articles were selected for the study. Results In the scientific literature, there have been only a few studies measuring the prevalence of NDDs according to the DSM-5 (2013) criteria in people under 18 years old. The reported prevalence rates were as follows: intellectual disability (ID), 0.63%; attention-deficit/hyperactivity disorder (ADHD), 5–11%; autism spectrum disorder (ASD), 0.70–3%; specific learning disorder (SLD), 3–10%; communication disorders (CDs), 1–3.42%; and motor disorders (MDs), 0.76–17%. Although there is extensive literature on specific disorders, NDDs have rarely been assessed as a whole. All of the reviewed studies support the idea that such disorders can be considered chronic, heterogeneous, underdiagnosed conditions and that comorbidity of multiple NDDs is the norm. Likewise, it is estimated that the prevalence of the most studied disorders, such as ADHD, ASD and SLD, remains stable over time and is consistent in different cultures, ages, ethnicities and sexes. Conclusion The studies reviewed lead us to conclude that the prevalence rate of NDDs fluctuates globally between 4.70 and 88.50%; these variations depend on methodological aspects such as estimation procedures, as well as on sociocontextual phenomena. It is also important to consider that the prevalence found is probably highly influenced by the activity of the countries in the diagnosis and training of professionals who care for children and adolescents. Hence, there is a need for a secondary intervention in the fields of public health and education to minimize socioemotional consequences, prevent academic failure, and reduce the economic cost to society.
Background The potential role of the gut microbiome as a predictor of immune-mediated HIV-1 control in the absence of antiretroviral therapy (ART) is still unknown. In the BCN02 clinical trial, which combined the MVA.HIVconsv immunogen with the latency-reversing agent romidepsin in early-ART treated HIV-1 infected individuals, 23% (3/13) of participants showed sustained low-levels of plasma viremia during 32 weeks of a monitored ART pause (MAP). Here, we present a multi-omics analysis to identify compositional and functional gut microbiome patterns associated with HIV-1 control in the BCN02 trial. Results Viremic controllers during the MAP (controllers) exhibited higher Bacteroidales/Clostridiales ratio and lower microbial gene richness before vaccination and throughout the study intervention when compared to non-controllers. Longitudinal assessment indicated that the gut microbiome of controllers was enriched in pro-inflammatory bacteria and depleted in butyrate-producing bacteria and methanogenic archaea. Functional profiling also showed that metabolic pathways related to fatty acid and lipid biosynthesis were significantly increased in controllers. Fecal metaproteome analyses confirmed that baseline functional differences were mainly driven by Clostridial es . Participants with high baseline Bacteroidales/Clostridiales ratio had increased pre-existing immune activation-related transcripts. The Bacteroidales/Clostridiales ratio as well as host immune-activation signatures inversely correlated with HIV-1 reservoir size. Conclusions The present proof-of-concept study suggests the Bacteroidales/Clostridiales ratio as a novel gut microbiome signature associated with HIV-1 reservoir size and immune-mediated viral control after ART interruption.
Background Peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α) downregulation in skeletal muscle contributes to insulin resistance and type 2 diabetes mellitus. Here, we examined the effects of endoplasmic reticulum (ER) stress on PGC-1α levels in muscle and the potential mechanisms involved. Methods The human skeletal muscle cell line LHCN-M2 and mice exposed to different inducers of ER stress were used. Results Palmitate- or tunicamycin-induced ER stress resulted in PGC-1α downregulation and enhanced expression of activating transcription factor 4 (ATF4) in human myotubes and mouse skeletal muscle. Overexpression of ATF4 decreased basal PCG-1α expression, whereas ATF4 knockdown abrogated the reduction of PCG-1α caused by tunicamycin in myotubes. ER stress induction also activated mammalian target of rapamycin (mTOR) in myotubes and reduced the nuclear levels of cAMP response element-binding protein (CREB)-regulated transcription co-activator 2 (CRTC2), a positive modulator of PGC-1α transcription. The mTOR inhibitor torin 1 restored PCG-1α and CRTC2 protein levels. Moreover, siRNA against S6 kinase, an mTORC1 downstream target, prevented the reduction in the expression of CRTC2 and PGC-1α caused by the ER stressor tunicamycin. Conclusions Collectively, these findings demonstrate that ATF4 and the mTOR-CRTC2 axis regulates PGC-1α transcription under ER stress conditions in skeletal muscle, suggesting that its inhibition might be a therapeutic target for insulin resistant states.
Background and aim The appearance of alterations in normal metabolic activity has been increasingly considered a risk factor for the development of sporadic and late-onset neurodegenerative diseases. In this report, we induced chronic metabolic stress by feeding of a high-fat diet (HFD) in order to study its consequences in cognition. We also studied the effects of a loss of function of isoforms 1 and 3 of the c-Jun N-terminal Kinases (JNK), stress and cell death response elements. Methods Animals were fed either with conventional chow or with HFD, from their weaning until their sacrifice at 9 months. Before sacrifice, body weight, intraperitoneal glucose and insulin tolerance test (IP-GTT and IP‑ITT) were performed to evaluate peripheral biometrics. Additionally, cognitive behavioral tests and analysis of spine density were performed to assess cognitive function. Molecular studies were carried out to confirm the effects of metabolic stressors in the hippocampus relative to cognitive loss. Results Our studies demonstrated that HFD in Jnk3 −/− lead to synergetic responses. Loss of function of JNK3 led to increased body weight, especially when exposed to an HFD and they had significantly decreased response to insulin. These mice also showed increased stress in the endoplasmic reticulum and diminished cognitive capacity. However, loss of function of JNK1 promoted normal or heightened energetic metabolism and preserved cognitive function even when chronically metabolically stressed. Conclusions Downregulation of JNK3 does not seem to be a suitable target for the modulation of energetic-cognitive dysregulations while loss of function of JNK1 seems to promote a good metabolic-cognitive profile, just like resistance to the negative effects of chronic feeding with HFD.
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