NB compounds are potent and efficacious FOXM1 inhibitors in high-grade serous ovarian cancer cells.

BACKGROUND: Genetic studies implicate the oncogenic transcription factor Forkhead Box M1 (FOXM1) as a potential therapeutic target in high-grade serous ovarian cancer (HGSOC). We evaluated the activity of different FOXM1 inhibitors in HGSOC cell models. RESULTS: We treated HGSOC and fallopian tube epithelial (FTE) cells with a panel of previously reported FOXM1 inhibitors. Based on drug potency, efficacy, and selectivity, determined through cell viability assays, we focused on two compounds, NB-73 and NB-115 (NB compounds), for further investigation. NB compounds potently and selectively inhibited FOXM1 with lesser effects on other FOX family members. NB compounds decreased FOXM1 expression via targeting the FOXM1 protein by promoting its proteasome-mediated degradation, and effectively suppressed FOXM1 gene targets at both the protein and mRNA level. At the cellular level, NB compounds promoted apoptotic cell death. Importantly, while inhibition of apoptosis using a pan-caspase inhibitor rescued HGSOC cells from NB compound-induced cell death, it did not rescue FOXM1 protein degradation, supporting that FOXM1 protein loss from NB compound treatment is specific and not a general consequence of cytotoxicity. Drug washout studies indicated that FOXM1 reduction was retained for at least 72 h post-treatment, suggesting that NB compounds exhibit long-lasting effects in HGSOC cells. NB compounds effectively suppressed both two-dimensional and three-dimensional HGSOC cell colony formation at sub-micromolar concentrations. Finally, NB compounds exhibited synergistic activity with carboplatin in HGSOC cells. CONCLUSIONS: NB compounds are potent, selective, and efficacious inhibitors of FOXM1 in HGSOC cells and are worthy of further investigation as HGSOC therapeutics.

The Impact of COVID-19 Pandemic on Inequity in Routine Childhood Vaccination Coverage: A Systematic Review.

BACKGROUND: Routine childhood vaccination coverage rates fell in many countries during the COVID-19 pandemic, but the impact of inequity on coverage is unknown. METHODS: We synthesised evidence on inequities in routine childhood vaccination coverage (PROSPERO, CRD 42021257431). Studies reporting empirical data on routine vaccination coverage in children 0-18 years old during the COVID-19 pandemic by equity stratifiers were systematically reviewed. Nine electronic databases were searched between 1 January 2020 and 18 January 2022. The risk of bias was assessed using the Newcastle-Ottawa Quality Assessment Tool for Cohort Studies. Overall, 91 of 1453 studies were selected for full paper review, and thirteen met the inclusion criteria. RESULTS: The narrative synthesis found moderate evidence for inequity in reducing the vaccination coverage of children during COVID-19 lockdowns and moderately strong evidence for an increase in inequity compared with pre-pandemic months (before March 2020). Two studies reported higher rates of inequity among children aged less than one year, and one showed higher inequity rates in middle- compared with high-income countries. CONCLUSIONS: Evidence from a limited number of studies shows the effect of the pandemic on vaccine coverage inequity. Research from more countries is required to assess the global effect on inequity in coverage.

Spirocyclic dimer SpiD7 activates the unfolded protein response to selectively inhibit growth and induce apoptosis of cancer cells.

The unfolded protein response (UPR) is an adaptation mechanism activated to resolve transient accumulation of unfolded/misfolded proteins in the endoplasmic reticulum. Failure to resolve the transient accumulation of such proteins results in UPR-mediated programmed cell death. Loss of tumor suppressor gene or oncogene addiction in cancer cells can result in sustained higher basal UPR levels; however, it is not clear if these higher basal UPR levels in cancer cells can be exploited as a therapeutic strategy. We hypothesized that covalent modification of surface-exposed cysteine (SEC) residues could simulate unfolded/misfolded proteins to activate the UPR, and that higher basal UPR levels in cancer cells would provide the necessary therapeutic window. To test this hypothesis, here we synthesized analogs that can covalently modify multiple SEC residues and evaluated them as UPR activators. We identified a spirocyclic dimer, SpiD7, and evaluated its effects on UPR activation signals, that is, XBP1 splicing, phosphorylation of eIF2α, and a decrease in ATF 6 levels, in normal and cancer cells, which were further confirmed by RNA-Seq analyses. We found that SpiD7 selectively induced caspase-mediated apoptosis in cancer cells, whereas normal cells exhibited robust XBP1 splicing, indicating adaptation to stress. Furthermore, SpiD7 inhibited the growth of high-grade serous carcinoma cell lines ~3-15-fold more potently than immortalized fallopian tube epithelial (paired normal control) cells and reduced clonogenic growth of high-grade serous carcinoma cell lines. Our results suggest that induction of the UPR by covalent modification of SEC residues represents a cancer cell vulnerability and can be exploited to discover novel therapeutics.

Greenhouse gas emissions from cattle dung depositions in two Urochloa forage fields with contrasting biological nitrification inhibition (BNI) capacity.

Grazing-based production systems are a source of soil greenhouse gas (GHG) emissions triggered by excreta depositions. The adoption of Urochloa forages (formerly known as Brachiaria) with biological nitrification inhibition (BNI) capacity is a promising alternative to reduce nitrous oxide (N2O) emissions from excreta patches. However, how this forage affects methane (CH4) or carbon dioxide (CO2) emissions from excreta patches remains unclear. This study investigated the potential effect of soils under two Urochloa forages with contrasting BNI capacity on GHG emissions from cattle dung deposits. Additionally, the N2O and CH4 emission factors (EF) for cattle dung under tropical conditions were determined. Dung from cattle grazing star grass (without BNI) was deposited on both forage plots: Urochloa hybrid cv. Mulato and Urochloa humidicola cv. Tully, with a respectively low and high BNI capacity. Two trials were conducted for GHG monitoring using the static chamber technique. Soil and dung properties and GHG emissions were monitored in trial 1. In trial 2, water was added to simulate rainfall and evaluate GHG emissions under wetter conditions. Our results showed that beneath dung patches, the forage genotype influenced daily CO2 and cumulative CH4 emissions during the driest conditions. However, no significant effect of the forage genotype was found on mitigating N2O emissions from dung. We attribute the absence of a significant BNI effect on N2O emissions to the limited incorporation of dung-N into the soil and rhizosphere where the BNI effect occurs. The average N2O EFs was 0.14%, close to the IPCC 2019 uncertainty range (0.01-0.13% at 95% confidence level). Moreover, CH4 EFs per unit of volatile solid (VS) averaged 0.31 g CH4 kgVS-1, slightly lower than the 0.6 g CH4 kgVS-1 developed by the IPCC. This implies the need to invest in studies to develop more region-specific Tier 2 EFs, including farm-level studies with animals consuming Urochloa forages to consider the complete implications of forage selection on animal excreta based GHG emissions.

COVID-19 in children and the influence on the employment activity of their female caregivers: A cross sectional gender perspective study.

Introduction: During the COVID-19 pandemic, women disproportionately assume more unpaid activities, affecting their employment. Objective: Describe the influence of COVID-19 on the employment of caregivers of children and adolescents from a gender perspective. Methods: Cross-sectional study in three high-complexity hospitals in Bogotá, Colombia from April 2020 to June 2021. A subsample of the FARA cohort was taken, including those patients with a positive test for SARS-COV2. We took as our analysis category children older than 8 years and younger than 18 years who had a positive SARS-COV2 test, as well as, caregivers of all children with a positive SARS-COV2 test. This subsample was drawn from the FARA cohort. A survey was applied to them. We carried out a descriptive and stratified analysis by age group, educational, and socioeconomic level. Results: We included 60 surveys of caregivers and 10 surveys of children. The main caregiver in 94.8% of the cases was a female. At the beginning of the pandemic, 63.3% of the caregivers were employed, and 78.9% of those lost their employment. The vast majority of these caregiver were women (96.6%, n = 29). A predominance of loss of work activity was documented in caregivers of children in early childhood 66.6% (n = 20), with lower education 66.6% (n = 20), and from lower strata 56.6% (n = 17). Conclusion: Caregivers of children with COVID-19 with low educational levels and lower socioeconomic conditions, as well as those with children under 5 years showed greater likelihood of employment loss between the interviewed subsample.

Predicting and Characterizing Neurodegenerative Subtypes with Multimodal Neurocognitive Signatures of Social and Cognitive Processes.

BACKGROUND: Social cognition is critically compromised across neurodegenerative diseases, including the behavioral variant frontotemporal dementia (bvFTD), Alzheimer's disease (AD), and Parkinson's disease (PD). However, no previous study has used social cognition and other cognitive tasks to predict diagnoses of these conditions, let alone reporting the brain correlates of prediction outcomes. OBJECTIVE: We performed a diagnostic classification analysis using social cognition, cognitive screening (CS), and executive function (EF) measures, and explored which anatomical and functional networks were associated with main predictors. METHODS: Multiple group discriminant function analyses (MDAs) and ROC analyses of social cognition (facial emotional recognition, theory of mind), CS, and EF were implemented in 223 participants (bvFTD, AD, PD, controls). Gray matter volume and functional connectivity correlates of top discriminant scores were investigated. RESULTS: Although all patient groups revealed deficits in social cognition, CS, and EF, our classification approach provided robust discriminatory characterizations. Regarding controls, probabilistic social cognition outcomes provided the best characterization for bvFTD (together with CS) and PD, but not AD (for which CS alone was the best predictor). Within patient groups, the best MDA probabilities scores yielded high classification rates for bvFTD versus PD (98.3%, social cognition), AD versus PD (98.6%, social cognition + CS), and bvFTD versus AD (71.7%, social cognition + CS). Top MDA scores were associated with specific patterns of atrophy and functional networks across neurodegenerative conditions. CONCLUSION: Standardized validated measures of social cognition, in combination with CS, can provide a dimensional classification with specific pathophysiological markers of neurodegeneration diagnoses.

Co-regulation and function of FOXM1/RHNO1 bidirectional genes in cancer.

The FOXM1 transcription factor is an oncoprotein and a top biomarker of poor prognosis in human cancer. Overexpression and activation of FOXM1 is frequent in high-grade serous carcinoma (HGSC), the most common and lethal form of human ovarian cancer, and is linked to copy number gains at chromosome 12p13.33. We show that FOXM1 is co-amplified and co-expressed with RHNO1, a gene involved in the ATR-Chk1 signaling pathway that functions in the DNA replication stress response. We demonstrate that FOXM1 and RHNO1 are head-to-head (i.e., bidirectional) genes (BDG) regulated by a bidirectional promoter (BDP) (named F/R-BDP). FOXM1 and RHNO1 each promote oncogenic phenotypes in HGSC cells, including clonogenic growth, DNA homologous recombination repair, and poly-ADP ribosylase inhibitor resistance. FOXM1 and RHNO1 are one of the first examples of oncogenic BDG, and therapeutic targeting of FOXM1/RHNO1 BDG is a potential therapeutic approach for ovarian and other cancers.

Classifying Parkinson's Disease Patients With Syntactic and Socio-emotional Verbal Measures.

Frontostriatal disorders, such as Parkinson's disease (PD), are characterized by progressive disruption of cortico-subcortical dopaminergic loops involved in diverse higher-order domains, including language. Indeed, syntactic and emotional language tasks have emerged as potential biomarkers of frontostriatal disturbances. However, relevant studies and models have typically considered these linguistic dimensions in isolation, overlooking the potential advantages of targeting multidimensional markers. Here, we examined whether patient classification can be improved through the joint assessment of both dimensions using sentential stimuli. We evaluated 31 early PD patients and 24 healthy controls via two syntactic measures (functional-role assignment, parsing of long-distance dependencies) and a verbal task tapping social emotions (envy, Schadenfreude) and compared their classification accuracy when analyzed in isolation and in combination. Complementarily, we replicated our approach to discriminate between patients on and off medication. Results showed that specific measures of each dimension were selectively impaired in PD. In particular, joint analysis of outcomes in functional-role assignment and Schadenfreude improved the classification accuracy of patients and controls, irrespective of their overall cognitive and affective state. These results suggest that multidimensional linguistic assessments may better capture the complexity and multi-functional impact of frontostriatal disruptions, highlighting their potential contributions in the ongoing quest for sensitive markers of PD.

Assessment of Conjunctive Binding in Aging: A Promising Approach for Alzheimer's Disease Detection.

The visual experience of objects lies in the ability to perceive and integrate their constitutive features. Conjunctive binding (CB) is the cognitive function that integrates the features of objects as wholes. This review covers the main findings (over the last 10 years) concerning the role of CB in visual working memory (VWM) and cognitive theory, its neural correlates, as well as perspectives for future work. First, we discuss the theoretical cognitive models of CB and how these relate to other cognitive functions. We then integrate neuroimaging evidence with cognitive theory to identify the neural functional network of CB for encoding and maintenance. Also, we describe the field's transition from experimental to clinical research, which paves the way for work in the area of VWM binding and aging. Finally, we expose the challenges faced by this field of research and analyze its role in the study of dementia and the construction of neuro-cognitive models of conjunctive binding.

Adequate vegetative cover decreases nitrous oxide emissions from cattle urine deposited in grazed pastures under rainy season conditions.

A decline in pasture productivity is often associated with a reduction in vegetative cover. We hypothesize that nitrogen (N) in urine deposited by grazing cattle on degraded pastures, with low vegetative cover, is highly susceptible to losses. Here, we quantified the magnitude of urine-based nitrous oxide (N2O) lost from soil under paired degraded (low vegetative cover) and non-degraded (adequate vegetative cover) pastures across five countries of the Latin America and the Caribbean (LAC) region and estimated urine-N emission factors. Soil N2O emissions from simulated cattle urine patches were quantified with closed static chambers and gas chromatography. At the regional level, rainy season cumulative N2O emissions (3.31 versus 1.91 kg N2O-N ha-1) and emission factors (0.42 versus 0.18%) were higher for low vegetative cover compared to adequate vegetative cover pastures. Findings indicate that under rainy season conditions, adequate vegetative cover through proper pasture management could help reduce urine-induced N2O emissions from grazed pastures.

Imagen corporal (IC) y estrategias de afrontamiento (EA): Análisis de las características médico quirúrgicas en mujeres con diagnóstico de cáncer de mama / Body image (BI) and coping strategies (CS): Analysis of medical and surgical characteristics in women diagnosed with breast cancer

Resumen A partir de un diseño No-experimental transversal, se buscó identificar la posible relación entre la IC y las EA, y sus diferencias según variables médico quirúrgicas (intervención quirúrgica, tiempo de diagnóstico y estadio del cáncer). Participaron treinta y siete mujeres diagnosticadas con cáncer de mama de todos los estadios. Se usó el Cuestionario de Afrontamiento al Estrés para Pacientes Oncológicos (CAEPO), la Escala de Imagen Corporal (BIS) y un cuestionario Ad-hoc. No se encontró relación entre la IC y las EA, y éstas no varían según la intervención quirúrgica (mastectomía radical y cirugía conservadora), el tiempo de diagnóstico en años (menos de 1, entre 1 y 3, entre 3 y 5, y más de 5), o el estadio (0 o in situ, I, II, III y IV); sin embargo, las pacientes que no recibieron intervención quirúrgica evidenciaron mayor deterioro de su IC que aquellas que sí lo hicieron.

Abstract From a non-experimental transverse design, we sought to identify the possible relationship between BI and CS, and their differences according to surgical-medical variables (surgical intervention, time of diagnosis and stage of cancer). Thirty-seven women diagnosed with breast cancer from all stages participated. The Stress Coping Questionnaire for Oncological Patients (CAEPO), the Body Image Scale (BIS) and an Ad-hoc questionnaire were used. No relationship was found between BI and CS, and these did not vary according to the surgical procedure (radical mastectomy and conservative surgery), the time of diagnosis in years (less than 1, between 1 and 3, between 3 and 5, and more of 5), or the stage (0 or in situ, I, II, III and IV); however, the patients who did not receive surgical intervention showed greater deterioration of their BI than those who did.