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PURPOSE: Large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine malignancy that, like small cell lung cancer (SCLC), is associated with an absence of druggable oncogenic drivers and dismal prognosis. In contrast to SCLC, however, there is little evidence to guide optimal treatment strategies which are often adapted from SCLC and non-small cell lung cancer (NSCLC) approaches. EXPERIMENTAL DESIGN: To better define the biology of LCNEC, we analyzed cell line and patient genomic data and performed immunohistochemistry and single-cell (sc)RNAseq of core needle biopsies from LCNEC patients and preclinical models. RESULTS: Here, we demonstrate that the presence or absence of YAP1 distinguishes two subsets of LCNEC. The YAP1-high subset is mesenchymal and inflamed and characterized, alongside TP53 mutations, by co-occurring alterations in CDKN2A/B and SMARCA4. Therapeutically, the YAP1-high subset demonstrates vulnerability to MEK and AXL targeting strategies, including a novel preclinical AXL CAR-T cell. Meanwhile, the YAP1-low subset is epithelial and immune-cold and more commonly features TP53 and RB1 co-mutations, similar to those observed in pure SCLC. Notably, the YAP1-low subset is also characterized by expression of SCLC subtype-defining transcription factors - especially ASCL1 and NEUROD1 - and, as expected given its transcriptional similarities to SCLC, exhibits putative vulnerabilities reminiscent of SCLC, including Delta-like ligand 3 (DLL3) and CD56 targeting, as with novel preclinical DLL3 and CD56 CAR T-cells, and DNA damage repair (DDR) inhibition. CONCLUSION: YAP1 defines distinct subsets of LCNEC with unique biology. These findings highlight the potential for YAP1 to guide personalized treatment strategies for LCNEC.
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PURPOSE: To determine whether there are differences in care experience of adolescent cancer patients and their main caregiver, treated in Adolescent Cancer Units (ACUs), compared to those treated in Non-Adolescent Cancer Units (NACUs), including the COVID-19 pandemic period. METHOD: Measurement of Reported Experience in adolescent oncology patients (12-19 years old) and caregivers through ad hoc surveys. The responses of the study group of patients and caregivers treated in Adolescent Units were compared with the group not treated in them. RESULTS: It is noted that many respondents consider that they have not been affected by the COVID-19 pandemic. Significant differences were seen in communication, with better perception by the group of patients treated in ACU (87.1%) and caregivers of ACU (97.3%) compared to patients and caregivers of NACU (53.3% and 68.2% respectively). Regarding information received about the side effects, a better perception was observed among patients treated in the ACU than in the NACU (p=0.247). In the transmission of information and the possibility of fertility preservation, a significant difference was observed in favour of ACU in patients and direct caregivers (p=0.010 and p=0.018). CONCLUSIONS: ACU represents an improvement in the quality perceived by patients and main caregiver on key points in the comprehensive care of the adolescent with cancer such as information, participation in the process and decision making, approach to side effects, psychological care and help in returning to normal life. However, fertility and strategies for talking about the cancer experience, were identified as areas for future improvement.
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OBJECTIVES: The aims of this study were to investigate the prevalence of dose reduction in patients with SLE treated with belimumab (BEL) in Spain, analyze treatment modalities, and determine impact on control of disease activity. METHODS: Retrospective longitudinal and multicentre study of SLE patients treated with BEL. Data on disease activity, treatments and outcomes were recorded before and after reduction (6-12 months), and they were compared. RESULTS: A total of 324 patients were included. The dose was reduced in 29 patients (8.9%). The dosing interval was increased in 9 patients receiving subcutaneous BEL and in 6 patients receiving intravenous BEL. The dose per administration was reduced in 16 patients.Pre-reduction status was remission (2021 DORIS) in 15/26 patients (57.7%) and LLDAS in 23/26 patients (88.5%). After reduction, 2/24 patients (8.3%) and 3/22 patients (13.6%) lost remission at 6 months and 12 months, respectively (not statistically significant [NS]). As for LLDAS, 2/23 patients (8.7%) and 2/21 patients (9.5%) lost their status at 6 and 12 months, respectively (NS). Significantly fewer patients were taking glucocorticoids (GCs) at their 12-month visit, although the median dose of GCs was higher at the 12-month visit (5 [0.62-8.75] vs 2.5 [0-5] at baseline). CONCLUSION: Doses of BEL can be reduced with no relevant changes in disease activity-at least in the short term-in a significant percentage of patients, and most maintain the reduced dose. However, increased clinical or serologic activity may be observed in some patients. Consequently, tighter post-reduction follow-up is advisable.
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Cancer therapy relies on new antitumoral drugs called immune checkpoint inhibitors (ICI), which produce long-lasting anti-tumor responses and lengthen survival, but cause autoimmune-type toxicity. The clinical characteristics induced by ICI are not well characterized to date and careful collection of clinical data is required to accurately define its safety profile. We conducted a literature search in the main clinical search engines to identify pharmacological ocular iatrogenic events of ICIs related to ocular motility. Four systematic reviews were found that included this type of ocular iatrogenesis as well as numerous isolated case reports. Reported adverse effects include: oculomotor paresis, optic neuropathy, optic atrophy, myastheniform syndromes, thyroid pseudo-orbitopathy, orbital apex syndrome, and hypophysitis. Most were managed without interruption or with partial interruption of cancer treatment. Aggressive systemic treatments were required for adequate management of ocular iatrogenic events. It is essential that the ophthalmologist become familiar with the new ICI oncological treatments, capable of causing severe and disabling motilidad ocular iatrogenesis for the patient. The communication of adverse effects and the report of the treatments used can help the most appropriate management of these patients. Research should be oriented towards complex differential diagnosis and to optimize decisions on cancer treatments.
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Oftalmopatia de Graves , Atrofia Óptica , Doenças do Nervo Óptico , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Movimentos Oculares , OlhoRESUMO
OBJECTIVE: To estimate the epidemiology of Leber's optic neuropathy (NOHL) in the Region of Madrid. MATERIAL AND METHODS: The neuro-ophthalmologists who work at public hospitals of the CAM were interviewed by telephone. They were asked about the number of patients with NOHL that they had diagnosed during the time that they had been responsible for the neuro-ophthalmology department of that public hospital. The time worked and the population attended by the hospital were used to calculate the number of inhabitant-years in follow-up by each center during the corresponding period. The basic information of each case (date of birth, mutation, date of visual loss) was registered to avoid duplications. RESULTS: Our work estimates a global incidence of 2.34 cases for 10,000,000 inhabitants-year and a prevalence estimated from incidence of one case for each 106.682 inhabitants. This prevalence was very similar in all the studied areas and considerably lower than that reported by other studies. CONCLUSION: This work constitutes the first approach to the epidemiology of this disease in Spain. The prevalence of LHON in the region of Madrid, is probably lower than that reported in the literature in other regions. The prevalence and the incidence were homogeneously low in the 26 studied areas.
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Oftalmologistas , Atrofia Óptica Hereditária de Leber , Humanos , Atrofia Óptica Hereditária de Leber/diagnóstico , Atrofia Óptica Hereditária de Leber/genética , Mutação , Cegueira , Espanha/epidemiologiaRESUMO
Non-small cell lung cancers that harbor concurrent KRAS and TP53 (KP) mutations are immunologically warm tumors with partial responsiveness to anti-PD-(L)1 blockade; however, most patients observe little or no durable clinical benefit. To identify novel tumor-driven resistance mechanisms, we developed a panel of KP murine lung cancer models with intrinsic resistance to anti-PD-1 and queried differential gene expression between these tumors and anti-PD-1-sensitive tumors. We found that the enzyme autotaxin (ATX), and the metabolite it produces, lysophosphatidic acid (LPA), were significantly upregulated in resistant tumors and that ATX directly modulated antitumor immunity, with its expression negatively correlating with total and effector tumor-infiltrating CD8+ T cells. Pharmacological inhibition of ATX, or the downstream receptor LPAR5, in combination with anti-PD-1 was sufficient to restore the antitumor immune response and efficaciously control lung tumor growth in multiple KP tumor models. Additionally, ATX was significantly correlated with inflammatory gene signatures, including a CD8+ cytolytic score in multiple lung adenocarcinoma patient data sets, suggesting that an activated tumor-immune microenvironment upregulates ATX and thus provides an opportunity for cotargeting to prevent acquired resistance to anti-PD-1 treatment. These data reveal the ATX/LPA axis as an immunosuppressive pathway that diminishes the immune checkpoint blockade response in lung cancer.
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Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Animais , Camundongos , Linfócitos T Citotóxicos , Morte Celular , Microambiente Tumoral , Receptores de Ácidos LisofosfatídicosRESUMO
BACKGROUND: The effect of cymenol mouthwashes on levels of dental plaque has not been evaluated thus far. OBJECTIVE: To analyse the short-term, in situ, anti-plaque effect of a 0.1% cymenol mouthwash using the DenTiUS Deep Plaque software. METHODS: Fifty orally healthy participants were distributed randomly into two groups: 24 received a cymenol mouthwash for eight days (test group A) and 26 a placebo mouthwash for four days and a cymenol mouthwash for a further four days thereafter (test group B). They were instructed not to perform other oral hygiene measures. On days 0, 4, and 8 of the experiment, a rinsing protocol for staining the dental plaque with sodium fluorescein was performed. Three intraoral photographs were taken per subject under ultraviolet light. The 504 images were analysed using the DenTiUS Deep Plaque software, and visible and total plaque indices were calculated (ClinicalTrials ID NCT05521230). RESULTS: On day 4, the percentage area of visible plaque was significantly lower in test group A than in test group B (absolute = 35.31 ± 14.93% vs. 46.57 ± 18.92%, p = 0.023; relative = 29.80 ± 13.97% vs. 40.53 ± 18.48%, p = 0.024). In comparison with the placebo, the cymenol mouthwash was found to have reduced the growth rate of the area of visible plaque in the first four days by 26% (absolute) to 28% (relative). On day 8, the percentage areas of both the visible and total plaque were significantly lower in test group A than in test group B (visible absolute = 44.79 ± 15.77% vs. 65.12 ± 16.37%, p < 0.001; visible relative = 39.27 ± 14.33% vs. 59.24 ± 16.90%, p < 0.001; total = 65.17 ± 9.73% vs. 74.52 ± 13.55%, p = 0.007). Accounting for the growth rate with the placebo mouthwash on day 4, the above results imply that the cymenol mouthwash in the last four days of the trial reduced the growth rate of the area of visible plaque (absolute and relative) by 53% (test group A) and 29% (test group B), and of the area of total plaque by 48% (test group A) and 41% (test group B). CONCLUSIONS: The 0.1% cymenol mouthwash has a short-term anti-plaque effect in situ, strongly conditioning the rate of plaque growth, even in clinical situations with high levels of dental plaque accumulation.
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Placa Dentária , Gengivite , Humanos , Antissépticos Bucais/uso terapêutico , Placa Dentária/tratamento farmacológico , Placa Dentária/prevenção & controle , Método Duplo-Cego , Higiene Bucal , Índice de Placa Dentária , Gengivite/tratamento farmacológico , Clorexidina/uso terapêuticoRESUMO
Introduction: Despite significant clinical advancement with the use of immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) there are still a major subset of patients that develop adaptive/acquired resistance. Understanding resistance mechanisms to ICB is critical to developing new therapeutic strategies and improving patient survival. The dynamic nature of the tumor microenvironment and the mutational load driving tumor immunogenicity limit the efficacy to ICB. Recent studies indicate that myeloid cells are drivers of ICB resistance. In this study we sought to understand which immune cells were contributing to resistance and if we could modify them in a way to improve response to ICB therapy. Results: Our results show that combination anti-PD-1/CTLA-4 produces an initial antitumor effect with evidence of an activated immune response. Upon extended treatment with anti-PD-1/CTLA-4 acquired resistance developed with an increase of the immunosuppressive populations, including T-regulatory cells, neutrophils and monocytes. Addition of anti-Ly6C blocking antibody to anti-PD-1/CTLA-4 was capable of completely reversing treatment resistance and restoring CD8 T cell activity in multiple KP lung cancer models and in the autochthonous lung cancer KrasLSL-G12D/p53fl/fl model. We found that there were higher classical Ly6C+ monocytes in anti-PD-1/CTLA-4 combination resistant tumors. B7 blockade illustrated the importance of dendritic cells for treatment efficacy of anti-Ly6C/PD-1/CTLA-4. We further determined that classical Ly6C+ monocytes in anti-PD-1/CTLA-4 resistant tumors are trafficked into the tumor via IFN-γ and the CCL2-CCR2 axis. Mechanistically we found that classical monocytes from ICB resistant tumors were unable to differentiate into antigen presenting cells and instead differentiated into immunosuppressive M2 macrophages or myeloid-derived suppressor cells (MDSC). Classical Ly6C+ monocytes from ICB resistant tumors had a decrease in both Flt3 and PU.1 expression that prevented differentiation into dendritic cells/macrophages. Conclusions: Therapeutically we found that addition of anti-Ly6C to the combination of anti-PD-1/CTLA-4 was capable of complete tumor eradication. Classical Ly6C+ monocytes differentiate into immunosuppressive cells, while blockade of classical monocytes drives dendritic cell differentiation/maturation to reinvigorate the anti-tumor T cell response. These findings support that immunotherapy resistance is associated with infiltrating monocytes and that controlling the differentiation process of monocytes can enhance the therapeutic potential of ICB.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Monócitos , Antígeno CTLA-4 , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Imunoterapia/métodos , Microambiente TumoralRESUMO
BACKGROUND: Persistent periapical lesions (PPL) are the result of pulpar necrosis induced by bacterial infection resulting in bone degradation and culminating with the loss of dental piece. Pathological changes in the peripapice are associated with the presence of free radicals. The transcription factor Nrf2 is the main regulator of the endogenous antioxidant response against oxidative stress and has been implicated in the regulation of osteoclastogenesis.The aim is to determine the oxidative condition in samples from patients with Persistent Periapical Injuries as a detonating factor of tissue damage. MATERIAL AND METHODS: An observational, descriptive, cross-sectional study was carried out in samples with PPL (cases) and samples by removal of third molars (controls) obtained in the clinic of the specialty in endodontics, University of Guadalajara. Samples were submitted to histological staining with Hematoxylin-Eosin, lipoperoxide analysis, Superoxide Dismutase (SOD), Glutathione-Peroxidase (GPx) and Catalase (CAT) activities were determined by immunoenzymatic assays and NrF2 by Western Blot analysis. RESULTS: Samples from PPL patients histologically showed an increased presence of lymphocytes, plasma cells, and eosinophils, as well as a decrease in extracellular matrix proteins and fibroblast cells. There was a rise in lipid peroxidation, GPx and SOD activities, but an important decline (36%) in Catalase activity was observed (p<0.005); finally, NrF2-protein was diminished at 10.41%. All comparisons were between cases vs controls. CONCLUSIONS: The alterations in antioxidants endogenous NrF2-controlled are related to osseous destruction in patients with PPL.
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Antioxidantes , Fator 2 Relacionado a NF-E2 , Catalase/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estudos Transversais , Antioxidantes/metabolismo , Superóxido Dismutase/metabolismo , Glutationa Peroxidase/metabolismoRESUMO
Chronic endemic regional hydroarsenicism (CERHA) is a global issue that affects over 200 million people exposed to arsenic (As) in drinking water. This includes 1.75 million individuals residing in La Comarca Lagunera, a region in north-central Mexico. Arsenic levels in this region typically exceeds the WHO guideline of 10 µg L-1. Biochemical alterations related to the human As metabolism may increase the risk of overweight and obesity (O&O), type 2 diabetes (T2D), and hypertension (AHT). In our study, we investigated the role of As in drinking water as a risk factor for these metabolic diseases. We focused on populations with historically moderate (San Pedro) and low (Lerdo) drinking water As levels and people with no historical evidence of As water contamination. The exposure assessment to As was based on measurements of the drinking water (medians 67.2, 21.0, 4.3 µg L-1) and urinary As concentrations in women (9.4, 5.3, 0.8 µg L-1) and men (18.1, 4.8, 1.0 µg L-1). A significant correlation between As in drinking water and urine evidenced the As exposure in the population (R2 = 0.72). Adjusted odds ratios with 95% confidence intervals evidenced higher chances of being diagnosed with T2D (1.7, 1.2-2.0) and AHT (1.8, 1.7-1.9) in individuals living in San Pedro than those in Lerdo. Still, there was no significant association with obesity. Individuals living in CERHA towns were found to have a higher risk of obesity (1.3-1.9), T2D (1.5 to 3.3), and AHT (1.4 to 2.4) compared to those residing in non-CERHA towns. Finally, obesity is more probable in women [inverse of OR and 95%CI 0.4 (0.2-0.7)] compared to men, while men is more likely to be diagnosed with T2D [OR = 2.0 (1.4-2.3)] and AHT [OR = 2.0 (1.5-2.3)] than women, independently of the municipality.
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Arsênio , Diabetes Mellitus Tipo 2 , Água Potável , Hipertensão , Poluentes Químicos da Água , Masculino , Humanos , Feminino , Arsênio/toxicidade , Arsênio/análise , Água Potável/efeitos adversos , Água Potável/análise , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , México/epidemiologia , Poluentes Químicos da Água/toxicidade , Hipertensão/epidemiologia , Hipertensão/etiologia , Obesidade/epidemiologia , Exposição Ambiental/efeitos adversosRESUMO
Epithelial-to-mesenchymal transition results in loss of specialized epithelial cell contacts and acquisition of mesenchymal invasive capacity. The transcription repressor zinc finger E-box-binding homeobox 1 (ZEB1) binds to E-boxes of gene promoter regions to suppress the expression of epithelial genes. ZEB1 has inconsistent molecular weights, which have been attributed to posttranslational modifications (PTM). We performed mass spectrometry and identified K811 acetylation as a novel PTM in ZEB1. To define the role of ZEB1 acetylation in regulating function, we generated ZEB1 acetyl-mimetic (K811Q) and acetyl-deficient (K811R) mutant-expressing non-small cell lung cancer cell lines (NSCLC). We demonstrate that the K811R ZEB1 (125 kDa) has a shorter protein half-life than wild-type (WT) ZEB1 and K811Q ZEB1 (â¼225 kDa), suggesting that lack of ZEB1 acetylation in the lower molecular weight form affects protein stability. Further, the acetylated form of ZEB1 recruits the nucleosome remodeling and deacetylase (NuRD) complex to bind the promoter of its target genes mir200c-141 and SEMA3F. RNA-sequencing revealed that WT ZEB1 and K811Q ZEB1 downregulate the expression of epithelial genes to promote lung adenocarcinoma invasion and metastasis, whereas the K811R ZEB1 does not. Our findings establish that the K811 acetylation promotes ZEB1 protein stability, interaction with other protein complexes, and subsequent invasion/metastasis of lung adenocarcinoma via epithelial-to-mesenchymal transition. IMPLICATIONS: The molecular mechanisms by which ZEB1 is regulated by K811 acetylation to promote protein stability, NuRD complex and promoter interactions, and function are relevant to the development of treatment strategies to prevent and treat metastasis in patients with NSCLC.
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Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , Acetilação , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Processamento de Proteína Pós-Traducional , Adenocarcinoma de Pulmão/genética , Transição Epitelial-Mesenquimal/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genéticaRESUMO
Epithelial-to-mesenchymal transition results in loss of specialized epithelial cell contacts and acquisition of mesenchymal invasive capacity. The transcription repressor zinc finger E-box-binding homeobox 1 (ZEB1) binds to E-boxes of gene promoter regions to suppress the expression of epithelial genes. ZEB1 has inconsistent molecular weights, which have been attributed to post-translational modifications (PTMs). We performed mass spectrometry and identified K811 acetylation as a novel PTM in ZEB1. To define the role of ZEB1 acetylation in regulating function, we generated ZEB1 acetyl-mimetic (K811Q) and acetyl-deficient (K811R) mutant-expressing non-small cell lung cancer cell lines (NSCLC). We demonstrate that the K811R ZEB1 (125 kDa) has a shorter protein half-life than wild-type (WT) ZEB1 and K811Q ZEB1 (&tilde225 kDa), suggesting that lack of ZEB1 acetylation in the lower molecular weight form affects protein stability. Further, the acetylated form of ZEB1 recruits the nucleosome remodeling and deacetylase (NuRD) complex to bind the promoter of its target genes mir200c-141 and SEMA3F. RNA-sequencing revealed that WT ZEB1 and K811Q ZEB1 downregulate the expression of epithelial genes to promote lung adenocarcinoma invasion and metastasis, while the K811R ZEB1 does not. Our findings establish that the K811 acetylation promotes ZEB1 protein stability, interaction with other protein complexes, and subsequent invasion/metastasis of lung adenocarcinoma via epithelial-to-mesenchymal transition. Implications: The molecular mechanisms by which ZEB1 is regulated by K811 acetylation to promote protein stability, NuRD complex and promoter interactions, and function are relevant to the development of treatment strategies to prevent and treat metastasis in NSCLC patients.
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BACKGROUND AND PURPOSE: Simulation in surgical learning responds to ethical and pragmatic needs. Our purpose is to describe the effects on surgical skills of conducting a surgical training workshop on strabismus surgery with phantoms. Concern for patient safety makes it necessary to consider the use of simulators (virtual and three-dimensional physical) and animal models that allow the applicant to safely practice the procedures before facing a real case. MATERIAL AND METHODS: Realization of a workshop with previous theoretical content and real practice with phantoms designed to simulate strabismus surgery (eyeball, 6 muscles, conjunctiva, eyelid and tenon capsule inserted in the skull) of real anatomical dimensions. Satisfaction survey and subjective evaluation of learning by the student and the expert tutor according to the Kirkpatrick evaluation model. RESULTS: Total, 100% of the 26 students attending two courses (15 students in one course and 11 students in another course) and 100% of the 3 tutors who participated in both courses completed the survey. 20 were resident doctors and 20 specialists in ophthalmology. The overall satisfaction of the students was 8.2 (±0.68). CONCLUSIONS: According to the results of the Kirkpatrick training actions evaluation survey, the perception of students and tutors is that training with phantoms in strabismus surgery can help improve the skills necessary for safe and independent practice. The ultimate goal being to improve patient safety.
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Oftalmologia , Estrabismo , Estudantes de Medicina , Humanos , Oftalmologia/educação , Competência Clínica , Estrabismo/cirurgiaRESUMO
Objetivo: Determinar los factores asociados al inicio de las actividades sexuales en adolescentes de los centros educativos de Cushcanday-Agallpampa y San Isidro-Otuzco. Material y métodos: Entre septiembre de 2021 y marzo de 2022, se realizó un estudio observacional, analítico transversal en 265 escolares del nivel secundario de los centros educativos de Cushcanday-Agallpampa y San Isidro-Otuzco que cumplieron los criterios de inclusión aplicando como instrumento la encuesta sobre sexualidad. Resultados: 129 hombres y 126 mujeres. Con una edad media de 15.41 años. Con un 11% que ha iniciado su vida sexual. El factor de riesgo asociado de mayor peso para el inicio de la vida sexual es la nomofobia con un OR de 22.55 (IC = 5.24 - 96.97), seguido del analfabetismo, con un OR de 6.41 (IC = 1.22 - 6.74). La visita de páginas web sin contenido erótico es un factor protector para la coitarquia. Conclusiones: 1 de cada 10 adolescentes de la zona rural Cushcanday-Agallpampa y San Isidro-Otuzco-La Libertad ha iniciado su vida sexual. La nomofobia moderada en la adolescencia incrementa 22 veces el riesgo de tener relaciones sexuales. Los hijos de padres analfabeto tienen 6.41 veces mayor probabilidad de iniciar las relaciones sexuales en la adolescencia.
Objective: To determine the factors associated with the beginning of sexual activities in adolescents from the educational centers of Cushcanday-Agallpampa and San Isidro-Otuzco. Material and methods: Between September 2021 and March 2022, an observational, cross-sectional analytical study was carried out in 265 secondary school students from the educational centers of CushcandayAgallpampa and San Isidro-Otuzco who met the inclusion criteria applying as an instrument the sexuality survey. Results: 129 men and 126 women with an average age of 15.41 years. With 11% who have started their sexual life. The risk factor associated with the greatest weight for the beginning of sexual life is nomophobia with an OR of 22.55 (CI = 5.24 - 96.97), followed by illiteracy, with an OR of 6.41 (CI = 1.22 - 6.74). Visiting web pages without erotic content is a protective factor for coitarche. Conclusions: 1 out of every 10 adolescents in the rural area Cushcanday-Agallpampa and San Isidro-Otuzco-La Libertad has started their sexual life. Moderate level nomophobia in adolescence increases the risk of having sexual intercourse by 22 times. Children of illiterate parents are 6.41 times more likely to start sexual relations in adolescence.
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A healthy state of the vaginal microbiome can prevent vaginal disease and promote successful fertilization and healthy pregnancies. Little is known about the stability of the vaginal microbiome and the influence of factors such as diet and probiotics. While less explored, yeast probiotics have an interesting potential because of their immunomodulatory and pathogen inhibition capacities. In this study, we investigated the impact of the oral yeast probiotic Saccharomyces cerevisiae CNCM I-3856 on the vaginal microbiomes of 52 healthy women using 16S and internal transcribed spacer (ITS) amplicon sequencing and quantitative PCR (qPCR). The vaginal fungal loads remained low, even after oral yeast supplementation, complicating the analysis of the vaginal mycobiome. Lactobacillus crispatus and Lactobacillus iners were the most dominant species in our study population and were found to codominate in 23% of the baseline samples. Bifidobacterium, Streptococcus, and Prevotella were also frequently found. The microbiome profiles were dynamic: 69% of women showed a shift in the dominant community members at least once during the 42-day sampling period. In addition, lower Lactobacillus abundances were observed at the time points after menstruation. Higher relative abundances of Lactobacillus with more L. iners-dominated samples and a trend toward lower relative abundances of Prevotella were observed in the probiotic group, but analyses of the effects of the yeast probiotic were complicated by differences already present at the onset of the study. Thus, our findings especially highlighted that the impact of menstruation and the stratification of women based on the dominant vaginal taxa before randomization and inclusion is important for future research: while the impact of the yeast probiotic on vaginal microbiome in healthy women was limited. IMPORTANCE How to define and promote a healthy state of the vaginal microbiome is not well understood. Knowledge of which underlying factors shape the microbial community composition of the vagina and how to modulate them will contribute to vaginal disease prevention and improve fertility. Here, we found that taking the menstrual cycle into account when designing a microbiome study is highly recommended: menstruation also showed to be poses an interesting time point for intervention because of the drop in the abundance of L. crispatus. Furthermore, the early stratification of groups (e.g., placebo versus treatment) according to the dominant taxa can be of high added value since menstruation impacts vaginal taxa differently, i.e., L. iners remains stable, in contrast to L. crispatus.
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Microbiota , Probióticos , Doenças Vaginais , Gravidez , Humanos , Feminino , Saccharomyces cerevisiae , Menstruação , Vagina/microbiologiaRESUMO
Hemispatial neglect is one of the most frequent attention disorders after stroke. The presence of neglect is associated with longer hospital stays, extended rehabilitation periods, and poorer functional recovery. Transcranial direct current stimulation (tDCS) is a new technique with promising results in neglect rehabilitation; therefore, the objective of this systematic review, performed following the PRISMA guidelines, is to evaluate the effectiveness of tDCS on neglect recovery after stroke. The search was done in MEDLINE (PubMed), Web of Science, Scopus, Cochrane Library, and BioMed Central databases. A total of 311 articles were found; only 11 met the inclusion criteria, including 152 post-stroke patients in total. Methodological quality and risk of bias were assessed for all the studies, and methodological characteristics of the studies, sample sizes, methods, main results, and other relevant data were extracted. tDCS intervention ranged from one to twenty sessions distributed in 1 day to 4 weeks, with intensity ranged from 1 to 2 mA. We found moderate evidence for the efficacy of tDCS in the rehabilitation of hemispatial neglect after a stroke, being more effective in combination with other interventions. Nonetheless, the limited number of studies and some studies' design characteristics makes it risky to draw categorical conclusions. Since scientific evidence is still scarce, further research is needed to determine the advantage of this treatment in acute, sub-acute and chronic stroke patients. Future studies should include larger samples, longer follow-ups, and broader neurophysiological assessments, with the final aim of establishing the appropriate use of tDCS as an adjuvant intervention in neurorehabilitation settings.
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Transtornos da Percepção , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral , Estimulação Transcraniana por Corrente Contínua , Humanos , Estimulação Transcraniana por Corrente Contínua/métodos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/terapia , Transtornos da Percepção/complicações , Recuperação de Função FisiológicaRESUMO
Lung cancer is a highly aggressive and metastatic disease responsible for approximately 25% of all cancer-related deaths in the United States. Using high-throughput in vitro and in vivo screens, we have previously established Impad1 as a driver of lung cancer invasion and metastasis. Here we elucidate that Impad1 is a direct target of the epithelial microRNAs (miRNAs) miR-200 and miRâ¼96 and is de-repressed during epithelial-to-mesenchymal transition (EMT); thus, we establish a mode of regulation of the protein. Impad1 modulates Golgi apparatus morphology and vesicular trafficking through its interaction with a trafficking protein, Syt11. These changes in Golgi apparatus dynamics alter the extracellular matrix and the tumor microenvironment (TME) to promote invasion and metastasis. Inhibiting Impad1 or Syt11 disrupts the cancer cell secretome, regulates the TME, and reverses the invasive or metastatic phenotype. This work identifies Impad1 as a regulator of EMT and secretome-mediated changes during lung cancer progression.