Hidden secrets of the cancer genome: unlocking the impact of non-coding mutations in gene regulatory elements.

Discoveries in the field of genomics have revealed that non-coding genomic regions are not merely "junk DNA", but rather comprise critical elements involved in gene expression. These gene regulatory elements (GREs) include enhancers, insulators, silencers, and gene promoters. Notably, new evidence shows how mutations within these regions substantially influence gene expression programs, especially in the context of cancer. Advances in high-throughput sequencing technologies have accelerated the identification of somatic and germline single nucleotide mutations in non-coding genomic regions. This review provides an overview of somatic and germline non-coding single nucleotide alterations affecting transcription factor binding sites in GREs, specifically involved in cancer biology. It also summarizes the technologies available for exploring GREs and the challenges associated with studying and characterizing non-coding single nucleotide mutations. Understanding the role of GRE alterations in cancer is essential for improving diagnostic and prognostic capabilities in the precision medicine era, leading to enhanced patient-centered clinical outcomes.

Association of BDNF risk variant and dorsolateral cortical thickness with long-term treatment response to valproate in type I bipolar disorder: An exploratory study.

Valproate is among the most prescribed drugs for bipolar disorder; however, 87% of patients do not report full long-term treatment response (LTTR) to this medication. One of valproate's suggested mechanisms of action involves the brain-derived neurotrophic factor (BDNF), expressed in the brain areas regulating emotions, such as the prefrontal cortex. Nonetheless, data about the role of BDNF in LTTR and its implications in the structure of the dorsolateral prefrontal cortex (dlPFC) is scarce. We explore the association of BDNF variants and dorsolateral cortical thickness (CT) with LTTR to valproate in bipolar disorder type I (BDI). Twenty-eight BDI patients were genotyped for BDNF polymorphisms rs1519480, rs6265, and rs7124442, and T1-weighted 3D brain scans were acquired. LTTR to valproate was evaluated with Alda's scale. A logistic regression analysis was conducted to evaluate LTTR according to BDNF genotypes and CT. We evaluated CT differences by genotypes with analysis of covariance. LTTR was associated with BDNF rs1519480 and right dlPFC thickness. Insufficient responders with the CC genotype had thicker right dlPFC than TC and TT genotypes. Full responders reported thicker right dlPFC in TC and TT genotypes. In conclusion, different patterns of CT related to BDNF genotypes were identified, suggesting a potential biomarker of LTTR to valproate in our population.

Chromatin insulation orchestrates matrix metalloproteinase gene cluster expression reprogramming in aggressive breast cancer tumors.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype that exhibits a high incidence of distant metastases and lacks targeted therapeutic options. Here we explored how the epigenome contributes to matrix metalloprotease (MMP) dysregulation impacting tumor invasion, which is the first step of the metastatic process. METHODS: We combined RNA expression and chromatin interaction data to identify insulator elements potentially associated with MMP gene expression and invasion. We employed CRISPR/Cas9 to disrupt the CCCTC-Binding Factor (CTCF) binding site on an insulator element downstream of the MMP8 gene (IE8) in two TNBC cellular models. We characterized these models by combining Hi-C, ATAC-seq, and RNA-seq with functional experiments to determine invasive ability. The potential of our findings to predict the progression of ductal carcinoma in situ (DCIS), was tested in data from clinical specimens. RESULTS: We explored the clinical relevance of an insulator element located within the Chr11q22.2 locus, downstream of the MMP8 gene (IE8). This regulatory element resulted in a topologically associating domain (TAD) boundary that isolated nine MMP genes into two anti-correlated expression clusters. This expression pattern was associated with worse relapse-free (HR = 1.57 [1.06 - 2.33]; p = 0.023) and overall (HR = 2.65 [1.31 - 5.37], p = 0.005) survival of TNBC patients. After CRISPR/Cas9-mediated disruption of IE8, cancer cells showed a switch in the MMP expression signature, specifically downregulating the pro-invasive MMP1 gene and upregulating the antitumorigenic MMP8 gene, resulting in reduced invasive ability and collagen degradation. We observed that the MMP expression pattern predicts DCIS that eventually progresses into invasive ductal carcinomas (AUC = 0.77, p < 0.01). CONCLUSION: Our study demonstrates how the activation of an IE near the MMP8 gene determines the regional transcriptional regulation of MMP genes with opposing functional activity, ultimately influencing the invasive properties of aggressive forms of breast cancer.

Association study of Catechol-O-Methyltransferase (COMT) rs4680 Val158Met gene polymorphism and suicide attempt in Mexican adolescents with major depressive disorder.

AIM: We analyzed the association between SLC6A4, DRD2, COMT and MAOA genes and suicide attempt (SA) in Mexican adolescent patients with major depressive disorder (MDD). METHODS: The sample included 197 adolescents (127 females and 70 males) with principal diagnosis of MDD. Among them, 63 patients had SA at least once and 134 had not SA. The mean age of patients with and without SA was 15 ± 1.4 and 14 ± 1.5 years, respectively. We analyzed the genotype and allele distribution between patients with and without SA of SLC6A4 (5HTTLPR/rs25531), DRD2 (rs6275), COMT (rs4680), and MAOA (uVNTR). RESULTS: We did not find genotype or allele association between SA and SLC6A4 (χ2=0.67, p = 0.71; χ2=0.07, p = 0.77, respectively), DRD2 (χ2=0.05, p = 0.97; χ2=0.003, p = 0.95), and MAOA (females: χ2=0.86, p = 0.64; χ2=0, p = 1/males: χ2=0.008, p = 0.92) genes. However, there were differences in genotype frequencies of COMT/rs4680 between patients with SA and without SA (χ2=11.17, p = 0.003). Also, we observed a high frequency of Met158 allele showing an increased risk of having presented at least one SA (χ2=10.6, p = 0.001; OR = 1.43; 95% CI, 1.17-1.74). CONCLUSIONS: Our findings showed an association between low activity genotype and allele of Val158Met polymorphism of COMT gene and SA in Mexican adolescents with MDD.

Oscillatory and structural signatures of language plasticity in brain tumor patients: A longitudinal study.

Recent evidence suggests that damage to the language network triggers its functional reorganization. Yet, the spectro-temporal fingerprints of this plastic rearrangement and its relation to anatomical changes is less well understood. Here, we combined magnetoencephalographic recordings with a proxy measure of white matter to investigate oscillatory activity supporting language plasticity and its relation to structural reshaping. First, cortical dynamics were acquired in a group of healthy controls during object and action naming. Results showed segregated beta (13-28 Hz) power decreases in left ventral and dorsal pathways, in a time-window associated to lexico-semantic processing (~250-500 ms). Six patients with left tumors invading either ventral or dorsal regions performed the same naming task before and 3 months after surgery for tumor resection. When longitudinally comparing patients' responses we found beta compensation mimicking the category-based segregation showed by controls, with ventral and dorsal damage leading to selective compensation for object and action naming, respectively. At the structural level, all patients showed preoperative changes in white matter tracts possibly linked to plasticity triggered by tumor growth. Furthermore, in some patients, structural changes were also evident after surgery and showed associations with longitudinal changes in beta power lateralization toward the contralesional hemisphere. Overall, our findings support the existence of anatomo-functional dependencies in language reorganization and highlight the potential role of oscillatory markers in tracking longitudinal plasticity in brain tumor patients. By doing so, they provide valuable information for mapping preoperative and postoperative neural reshaping and plan surgical strategies to preserve language function and patient's quality of life.

[Effect of angiotensin converting enzyme 2 rs1978124 gene polymorphism on the hemodynamic response to exercise]. / Influencia del polimorfismo de la enzima convertidora de angiotensina 2 (rs1978124) en la respuesta hemodinámica posterior a la prueba aeróbica submáxima en jóvenes estudiantes chilenos sedentarios.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) has a protective role in the regulation of blood pressure. AIM: To evaluate the influence of ACE2 rs1978124 gene polymorphism on the hemodynamic response after a six-minute walk submaximal aerobic test. MATERIAL AND METHODS: A six-minute walk submaximal aerobic test was carried out in 47 men and 55 women, aged 22 ± 2 years. Blood pressure was recorded before and after the test. Pulse rate was recorded continuously. ACE2 polymorphism was determined in DNA extracted from a blood sample. RESULTS: For women, the genotype distribution did not deviate from Hardy-Weinberg equilibrium (x2 = 0.804, d.f. = 1, P = 0.4) and no significant differences in heart rate, systolic and diastolic blood pressure were observed between CC, CT and TT genotypes before and after the test. Among men no differences in these parameters were observed either between the three phenotypes. CONCLUSIONS: ACE2 rs1978124 gene polymorphism did not influence the hemodynamic response to submaximal exercise in these participants.

MULTIMAP: Multilingual picture naming test for mapping eloquent areas during awake surgeries.

Picture naming tasks are currently the gold standard for identifying and preserving language-related areas during awake brain surgery. With multilingual populations increasing worldwide, patients frequently need to be tested in more than one language. There is still no reliable testing instrument, as the available batteries have been developed for specific languages. Heterogeneity in the selection criteria for stimuli leads to differences, for example, in the size, color, image quality, and even names associated with pictures, making direct cross-linguistic comparisons difficult. Here we present MULTIMAP, a new multilingual picture naming test for mapping eloquent areas during awake brain surgery. Recognizing that the distinction between nouns and verbs is necessary for detailed and precise language mapping, MULTIMAP consists of a database of 218 standardized color pictures representing both objects and actions. These images have been tested for name agreement with speakers of Spanish, Basque, Catalan, Italian, French, English, German, Mandarin Chinese, and Arabic, and have been controlled for relevant linguistic features in cross-language combinations. The MULTIMAP test for objects and verbs represents an alternative to the Oral Denomination 80 (DO 80) monolingual pictorial set currently used in language mapping, providing an open-source, standardized set of up-to-date pictures, where relevant linguistic variables across several languages have been taken into account in picture creation and selection.

Association between 5-HTTLPR polymorphism, suicide attempt and comorbidity in Mexican adolescents with major depressive disorder.

INTRODUCTION: The World Health Organization reports that suicide is among the leading causes of death for young people. Depression is the most frequently related disorder with suicidal behaviors. There is increasing evidence that suicidal behavior has a strong genetic contribution. Several studies report an association between the genotype "SS" and the "S" allele of the 5-HTTLPR polymorphism of the serotonin transporter gene and suicidal behavior. The aim of the study was to determine the association of variants of the serotonin transporter gene with suicidal attempt and comorbidity in depressed adolescents. METHODS: The frequencies of ss genotypes and s allele were compared between a sample of 200 adolescents with a diagnosis of depression and the antecedent of a suicide attempt who were evaluated with K-SADS-PL and a group of 235 healthy controls. Genotyping of the 5-HTTLPR polymorphism was performed by PCR. RESULTS: Analysis of the frequencies of genotypes and alleles showed a statistically significant difference between the groups (Genotypes: x2=11.1, df=2, p=0.004, Alleles: x2=11.9, df=1, p=0.0009). There were no associations with comorbid disorders. CONCLUSIONS: The results support the hypothesis that the serotonin transporter gene, specifically the s allele and the ss genotype of the 5-HTTLPR polymorphism, are related to the history of depression and suicide attempt in adolescents.

Effect of a clinical pharmacist on 30-day revisits following discharge from an emergency department: a randomized controlled clinical trial. / Efecto del farmacéutico clínico en las reconsultas a los 30 días posalta del servicio de urgencias: ensayo clínico controlado.

OBJECTIVES: To evaluate a clinical pharmacist's inclusion in emergency department (ED) care in terms of the effect on on 30-day revisits after discharge from the ED and patient satisfaction. MATERIAL AND METHODS: Randomized, controlled parallel-group pragmatic trial in a university hospital ED. Recruited patients were randomly assigned to a control group for standard care only or an intervention group to receive standard care plus the attention of a clinical pharmacist integrated into the care team to optimize the selection and evaluation of medications and provide pharmacotherapeutic education on the patient's discharge. The primary outcome was unplanned revisits within 30 days after discharge because of the same complaint that led to the initial ED visit. Between-group differences were analyzed with Kaplan-Meier survival curves and log-rank tests. The association between the intervention and time to the outcome event was explored with multivariate Cox proportional hazard regression analysis. RESULTS: A total of 1001 patients were enrolled (intervention, 500; control, 501). Patients in both groups were similar. A majority were women (61.5%), and the median age (interquartile range) was 51 years (33-65 years). The pharmacist's intervention significantly reduced the number of 30-day revisits to any ED: 25 (6.3%) revisited vs 66 (16.7%) in the control group. The adjusted hazard ratio (aHR) was 0.29 (95% CI, 0.17-0.50). Fifteen patients (3.0%) from the intervention group revisited the same ED vs 32 (6.5%) from the control group (aHR, 0.46 [95% CI, 0.24-0.87]). More patients expressed satisfaction in the intervention group (87.2%) than in the control group ( 83.2%) (P .05). CONCLUSION: Including a clinical pharmacist in ED care substantially reduces the number of 30-day revisits and increases patient satisfaction.

OBJETIVO: Determinar el efecto de la inclusión del farmacéutico clínico en el servicio de urgencias (SU) en las reconsultas durante 30 días posalta y la satisfacción de los pacientes. METODO: Ensayo clínico controlado, aleatorizado, paralelo y pragmático, realizado en el SU de un hospital universitario. Los pacientes reclutados fueron asignados aleatoriamente al grupo control (GC) que recibió la atención habitual o al grupo intervenido (GI) que recibió además la atención de un farmacéutico clínico, el cual se integró al equipo clínico para optimizar la selección, evaluación y educación farmacoterapéutica en el SU y al alta. El desenlace primario fue reconsultas no programadas 30 días posaltarelacionadas con la atención inicial al SU. Las diferencias entre grupos se analizaron por curvas de supervivencia de Kaplan-Meier y prueba de log-rank. La asociación entre intervención y tiempo al evento fue analizada mediante regresión multivariada de riesgos proporcionales de Cox y se expresó como hazard ratio ajustada (HRa). RESULTADOS: Un total de 1.001 pacientes ingresaron al estudio (GI = 500 y GC = 501). Ambos grupos eran similares, predominaron las mujeres (61,5%), edad 51 años (RIC: 33-65). La intervención redujo significativamente las reconsultas a cualquier centro durante 30 días posalta comparado con GC [25 (6,3%) vs 66 (16,7%); HRa: 0,29 (IC 95%: 0,17-0,50)] y para el mismo centro [15 (3,0%) vs 32 (6,5%); HRa: 0,46 (IC 95%: 0,24-0,87)]. La satisfacción del usuario fue mayor en el GI que GC (87,2% vs 83,2%; p 0,05). CONCLUSIONES: La inclusión del farmacéutico clínico en un SU reduce sustancialmente las reconsultas durante 30 días posalta y mejora la satisfacción de los usuarios.

Recommendations for the management of hypokalemia in patients with cancer.

Hypokalemia is a common electrolyte disorder in cancer patients that may be associated with the primary disease or a complication of treatment. In this article, we provide a brief description of hypokalemia and its appropriate management in cancer patients.

La hipokalemia es un trastorno hidroelectrolítico común en pacientes con cáncer que puede estar asociado a la enfermedad primaria o a una complicación del tratamiento. En este artículo nos enfocamos en entregar una breve descripción de la hipokalemia y su adecuado manejo en pacientes con cáncer.

Grey matter reshaping of language-related regions depends on tumor lateralization.

A brain tumor in the left hemisphere can decrease language laterality as assessed with fMRI. However, it remains unclear whether or not this decreased language laterality is associated with a structural reshaping of the grey matter, particularly within the language network. Here, we examine if the disruption of language hubs exclusively affects macrostructural properties of contralateral homologues (as suggested by previous research), or whether it affects both hemispheres. This study uses voxel-based morphometry applied to high-resolution MR T1-weighted MPRAGE images from 31 adult patients left-dominant for language. Eighteen patients had brain tumors in the left hemisphere, and 13 had tumors in the right hemisphere. A cohort of 71 healthy individuals matched on age and sex was used as a baseline. We defined 10 ROIs per hemisphere known to subserve language function. Two separate repeated-measures ANOVAs were conducted with the volume per region as the dependent variables. For the patients, tumor lateralization (right versus left) served as a between-subject factor. The current study demonstrated that the presence of a brain tumor generates a global volumetric change affecting left language regions and their contralateral homologues. These changes are mediated by the lateralization of the lesion. Our findings suggest that compensatory functional mechanisms are supported by the rearrangement of the grey matter, although future longitudinal research should determine the temporal course of such changes.

Epigenetic Profiles of Triple-Negative Breast Cancers of African American and White Females.

Importance: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and appears to have disproportionately higher incidence and worse outcomes among younger African American females. Objective: To investigate whether epigenetic differences exist in TNBCs of younger African American females that may explain clinical disparities seen in this patient group. Design, Setting, and Participants: This cross-sectional study used clinical, demographic, DNA methylation (HumanMethylation450; Illumina), and gene expression (RNA sequencing) data for US patient populations from publicly available data repositories (The Cancer Genome Atlas [TCGA], 2006-2012, and Gene Expression Omnibus [GEO], 2004-2013) accessed on April 13, 2021. White and African American females with TNBC identified in TCGA (69 patients) and a validation cohort of 210 African American patients from GEO (GSE142102) were included. Patients without available race or age data were excluded. Data were analyzed from September 2022 through April 2023. Main Outcomes and Measures: DNA methylation and gene expression profiles of TNBC tumors by race (self-reported) and age were assessed. Age was considered a dichotomous variable using age 50 years as the cutoff (younger [<50 years] vs older [≥50 years]). Results: A total of 69 female patients (34 African American [49.3%] and 35 White [50.7%]; mean [SD; range] age, 55.7 [11.6; 29-82] years) with TNBC were included in the DNA methylation analysis; these patients and 210 patients in the validation cohort were included in the gene expression analysis (279 patients). There were 1115 differentially methylated sites among younger African American females. The DNA methylation landscape on TNBC tumors in this population had increased odds of enrichment of hormone (odds ratio [OR], 1.82; 95% CI, 1.21 to 2.67; P = .003), muscle (OR, 1.85; 95% CI, 1.44 to 2.36; P < .001), and proliferation (OR, 3.14; 95% CI, 2.71 to 3.64; P < .001) pathways vs other groups (older African American females and all White females). Alterations in regulators of these molecular features in TNBCs of younger African American females were identified involving hormone modulation (downregulation of androgen receptor: fold change [FC] = -2.93; 95% CI, -4.76 to -2.11; P < .001) and upregulation of estrogen-related receptor α (FC = 0.86; 95% CI, 0.34 to 1.38; P = .002), muscle metabolism (upregulation of FOXC1: FC = 1.33; 95% CI, 0.62 to 2.03; P < .001), and proliferation mediators (upregulation of NOTCH1: FC = 0.71; 95% CI, 0.23 to 1.19; P = .004 and MYC (FC = 0.81; 95% CI, 0.18 to 1.45; P = .01). Conclusions and Relevance: These findings suggest that TNBC of younger African American females may represent a distinct epigenetic entity and offer novel insight into molecular alterations associated with TNBCs of this population. Understanding these epigenetic differences may lead to the development of more effective therapies for younger African American females, who have the highest incidence and worst outcomes from TNBC of any patient group.

Grey Matter Reshaping of Language-Related Regions Depends on Tumor Lateralization.

A brain tumor in the left hemisphere can decrease language laterality as assessed through fMRI. However, it remains unclear whether or not this decreased language laterality is associated with a structural reshaping of the grey matter, particularly within the language network. Here, we examine if the disruption of the language hubs exclusively affects the macrostructural properties of the contralateral homologues or whether it affects both hemispheres. This study uses voxel-based morphometry applied to high-resolution MR T1-weighted MPRAGE images from 31 adult patients' left hemisphere, which is dominant for language. Eighteen patients had brain tumors in the left hemisphere, and thirteen had tumors in the right hemisphere. A cohort of 71 healthy individuals matched with respect to age and sex was used as a baseline. We defined 10 ROIs per hemisphere involved in language function. Two separate repeated-measure ANOVAs were conducted with the volume per region as the dependent variable. For the patients, tumor lateralization (right versus left) served as a between-subject factor. The current study demonstrated that the presence of a brain tumor generates global volumetric changes affecting the left language regions and their contralateral homologues. These changes are mediated by the lateralization of the lesion. Our findings suggest that functional mechanisms are supported by the rearrangement of the grey matter.

Construction and validation of a gene expression classifier to predict immunotherapy response in primary triple-negative breast cancer.

BACKGROUND: Immune checkpoint inhibitors (ICI) improve clinical outcomes in triple-negative breast cancer (TNBC) patients. However, a subset of patients does not respond to treatment. Biomarkers that show ICI predictive potential in other solid tumors, such as levels of PD-L1 and the tumor mutational burden, among others, show a modest predictive performance in patients with TNBC. METHODS: We built machine learning models based on pre-ICI treatment gene expression profiles to construct gene expression classifiers to identify primary TNBC ICI-responder patients. This study involved 188 ICI-naïve and 721 specimens treated with ICI plus chemotherapy, including TNBC tumors, HR+/HER2- breast tumors, and other solid non-breast tumors. RESULTS: The 37-gene TNBC ICI predictive (TNBC-ICI) classifier performs well in predicting pathological complete response (pCR) to ICI plus chemotherapy on an independent TNBC validation cohort (AUC = 0.86). The TNBC-ICI classifier shows better performance than other molecular signatures, including PD-1 (PDCD1) and PD-L1 (CD274) gene expression (AUC = 0.67). Integrating TNBC-ICI with molecular signatures does not improve the efficiency of the classifier (AUC = 0.75). TNBC-ICI displays a modest accuracy in predicting ICI response in two different cohorts of patients with HR + /HER2- breast cancer (AUC = 0.72 to pembrolizumab and AUC = 0.75 to durvalumab). Evaluation of six cohorts of patients with non-breast solid tumors treated with ICI plus chemotherapy shows overall poor performance (median AUC = 0.67). CONCLUSION: TNBC-ICI predicts pCR to ICI plus chemotherapy in patients with primary TNBC. The study provides a guide to implementing the TNBC-ICI classifier in clinical studies. Further validations will consolidate a novel predictive panel to improve the treatment decision-making for patients with TNBC.

Triple-Negative Breast Cancer (TNBC) is an aggressive type of breast cancer, responsible for a substantial burden of breast cancer-related deaths. In recent years, immunotherapy, a therapy that triggers the patient's immune system to attack the tumor, has arisen as a promising treatment in various cancers, including TNBC. However, a subset of patients with TNBC does not respond to this treatment. Here, we employed advanced computational techniques to predict response to immunotherapy plus chemotherapy in patients with primary TNBC. Our method is more accurate than using other existing markers, such as PD-L1, but is not very accurate in patients with non-TNBC breast cancers or non-breast cancers. This method could potentially be used to better select patients for immunotherapy, upfront, avoiding the side effects and costs of treating patients in which immunotherapy might not work.

Can psychopathy be prevented? Clinical, neuroimaging, and genetic data: an exploratory study.

The aim of the study was to explore the relationship among brain functional activations elicited by an emotional paradigm, clinical scores (PTSD, anxiety, and depression), psychopathic traits, and genetic characteristics (5-HTTLPR) in a group of severely maltreated children compared to a healthy control group before and after the implementation of a Trauma Focused-Cognitive Behavioral Therapy. The final sample consisted of an experimental group of 14 maltreated children (mean age = 8.77 years old, S.D. = 1.83) recruited from a non-governmental shelter in Mexico City for children who had experienced child abuse and a control group of 10 children from the general population (mean age = 9.57 years old, S.D. = 1.91). Both groups were matched according to age and gender and were assessed before and after the implementation of the aforementioned therapy by means of clinical scales and an emotional paradigm that elicited brain activations which were recorded through functional magnetic resonance imaging. Genotyping of the 5-HTTLPR polymorphism was made at first assessment. A region of interest analysis showed amygdala hyperactivation during exposure to fear and anger stimuli in the maltreated children before treatment. Following therapy, a decrease in brain activity as well as a decrease in clinical symptoms were also observed. 5-HTTLPR polymorphism did not show any effect on the severity of clinical symptoms in maltreated children. Trauma-Focused Behavioral Therapy may help reorganize the brain's processing of emotional stimuli. These observations reveal the importance of an early intervention when the mechanisms of neuroplasticity may be still recruited.

3-D chromatin conformation, accessibility, and gene expression profiling of triple-negative breast cancer.

OBJECTIVES: Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype with limited treatment options. Unlike other breast cancer subtypes, the scarcity of specific therapies and greater frequencies of distant metastases contribute to its aggressiveness. We aimed to find epigenetic changes that aid in the understanding of the dissemination process of these cancers. DATA DESCRIPTION: Using CRISPR/Cas9, our experimental approach led us to identify and disrupt an insulator element, IE8, whose activity seemed relevant for cell invasion. The experiments were performed in two well-established TNBC cellular models, the MDA-MB-231 and the MDA-MB-436. To gain insights into the underlying molecular mechanisms of TNBC invasion ability, we generated and characterized high-resolution chromatin interaction (Hi-C) and chromatin accessibility (ATAC-seq) maps in both cell models and complemented these datasets with gene expression profiling (RNA-seq) in MDA-MB-231, the cell line that showed more significant changes in chromatin accessibility. Altogether, our data provide a comprehensive resource for understanding the spatial organization of the genome in TNBC cells, which may contribute to accelerating the discovery of TNBC-specific alterations triggering advances for this devastating disease.

CANoE: a context-aware notification model to support the care of older adults in a nursing home.

Taking care of elders in a nursing home is not an easy task. Caregivers face two major problems: a lack of awareness of the situations surrounding the elderly care and the lack of information regarding the availability and the activities of other caregivers to support their coordination process. Various efforts have proposed solutions to cope with these problems, but they do it without considering all the requirements imposed by the criticality of this type of environment. In this paper we propose CANoE, a model for the design of context-aware notifications in critical environments, such as a nursing home. The main feature of this model is that it considers three sources of context (the environment, and the issuer and the receiver of the notification) for adapting the content, the terms of delivery and the presentation of the notification message. Based on the CANoE model we developed the CANoE-Aw and CU-IDA systems, which were evaluated through two case studies in a nursing home. The results of these evaluations provide evidence that caregivers achieved an increased awareness of the situations of care of the elderly and perceived the systems as adequate tools to support their coordination while attending a situation of care.

Glioblastoma Embryonic-like Stem Cells Exhibit Immune-Evasive Phenotype.

BACKGROUND: Glioma stem cells (GSCs) have self-renewal and tumor-initiating capacities involved in drug resistance and immune evasion mechanisms in glioblastoma (GBM). METHODS: Core-GSCs (c-GSCs) were identified by selecting cells co-expressing high levels of embryonic stem cell (ESC) markers from a single-cell RNA-seq patient-derived GBM dataset (n = 28). Induced c-GSCs (ic-GSCs) were generated by reprogramming GBM-derived cells (GBM-DCs) using induced pluripotent stem cell (iPSC) technology. The characterization of ic-GSCs and GBM-DCs was conducted by immunostaining, transcriptomic, and DNA methylation (DNAm) analysis. RESULTS: We identified a GSC population (4.22% ± 0.59) exhibiting concurrent high expression of ESC markers and downregulation of immune-associated pathways, named c-GSCs. In vitro ic-GSCs presented high expression of ESC markers and downregulation of antigen presentation HLA proteins. Transcriptomic analysis revealed a strong agreement of enriched biological pathways between tumor c-GSCs and in vitro ic-GSCs (κ = 0.71). Integration of our epigenomic profiling with 833 functional ENCODE epigenetic maps identifies increased DNA methylation on HLA genes' regulatory regions associated with polycomb repressive marks in a stem-like phenotype. CONCLUSIONS: This study unravels glioblastoma immune-evasive mechanisms involving a c-GSC population. In addition, it provides a cellular model with paired gene expression, and DNA methylation maps to explore potential therapeutic complements for GBM immunotherapy.

Genetic analysis of the ZNF804A gene in Mexican patients with schizophrenia, schizoaffective disorder and bipolar disorder.

BACKGROUND: Evidence suggests that schizophrenia (SCZ), schizoaffective disorder (SAD) and bipolar disorder (BPD) share genetic risk variants. ZNF804A gene has been associated with these disorders in different populations. GWAS and candidate gene studies have reported association between the rs1344706 A allele with SCZ, SAD and BPD in European and Asian populations. In Mexican patients, no studies have specifically analyzed ZNF804A gene variants with these disorders. The aim of the study was to analyze the rs1344706 and identify common and rare variants in a targeted region of the ZNF804A gene in Mexican patients with SCZ, BPD and SAD compared with a control group. METHODS: We genotyped the rs1344706 in 228 Mexican patients diagnosed with SCZ, SAD and BPD, and 295 controls. Also, an additional sample of 167 patients with these disorders and 170 controls was analyzed to identify rare and common variants using the Sanger-sequence analysis of a targeted region of ZNF804A gene. RESULTS: Association analysis of rs1344706 observed a higher frequency of A allele in the patients compared with the control group; however, did not show statistical differences after Bonferronís correction (χ2 = 5.3, p = 0.0208). In the sequence analysis, we did not identify rare variants; however, we identified three common variants: rs3046266, rs1366842 and rs12477430. A comparison of the three identified variants between patients and controls did not show statistical differences (p > 0.0125). Finally, haplotype analysis did not show statistical differences between SCZ, SAD and BPD and controls. CONCLUSIONS: Our findings did not support the evidence suggesting that ZNF804A gene participates in the etiology of SCZ, SAD and BPD. Future studies are needed in a larger sample size to identify the effect of this gene in psychiatric disorders.

iGlioSub: an integrative transcriptomic and epigenomic classifier for glioblastoma molecular subtypes.

BACKGROUND: Glioblastoma (GBM) is the most aggressive and prevalent primary brain tumor, with a median survival of 15 months. Advancements in multi-omics profiling combined with computational algorithms have unraveled the existence of three GBM molecular subtypes (Classical, Mesenchymal, and Proneural) with clinical relevance. However, due to the costs of high-throughput profiling techniques, GBM molecular subtyping is not currently employed in clinical settings. METHODS: Using Random Forest and Nearest Shrunken Centroid algorithms, we constructed transcriptomic, epigenomic, and integrative GBM subtype-specific classifiers. We included gene expression and DNA methylation (DNAm) profiles from 304 GBM patients profiled in the Cancer Genome Atlas (TCGA), the Human Glioblastoma Cell Culture resource (HGCC), and other publicly available databases. RESULTS: The integrative Glioblastoma Subtype (iGlioSub) classifier shows better performance (mean AUC = 95.9%) stratifying patients than gene expression (mean AUC = 91.9%) and DNAm-based classifiers (AUC = 93.6%). Also, to expand the understanding of the molecular differences between the GBM subtypes, this study shows that each subtype presents unique DNAm patterns and gene pathway activation. CONCLUSIONS: The iGlioSub classifier provides the basis to design cost-effective strategies to stratify GBM patients in routine pathology laboratories for clinical trials, which will significantly accelerate the discovery of more efficient GBM subtype-specific treatment approaches.