Properties and Functional Analysis of Two Chorismate Mutases from Maritime Pine.

Through the shikimate pathway, a massive metabolic flux connects the central carbon metabolism with the synthesis of chorismate, the common precursor of the aromatic amino acids phenylalanine, tyrosine, and tryptophan, as well as other compounds, including salicylate or folate. The alternative metabolic channeling of chorismate involves a key branch-point, finely regulated by aromatic amino acid levels. Chorismate mutase catalyzes the conversion of chorismate to prephenate, a precursor of phenylalanine and tyrosine and thus a vast repertoire of fundamental derived compounds, such as flavonoids or lignin. The regulation of this enzyme has been addressed in several plant species, but no study has included conifers or other gymnosperms, despite the importance of the phenolic metabolism for these plants in processes such as lignification and wood formation. Here, we show that maritime pine (Pinus pinaster Aiton) has two genes that encode for chorismate mutase, PpCM1 and PpCM2. Our investigations reveal that these genes encode plastidial isoenzymes displaying activities enhanced by tryptophan and repressed by phenylalanine and tyrosine. Using phylogenetic studies, we have provided new insights into the possible evolutionary origin of the cytosolic chorismate mutases in angiosperms involved in the synthesis of phenylalanine outside the plastid. Studies based on different platforms of gene expression and co-expression analysis have allowed us to propose that PpCM2 plays a central role in the phenylalanine synthesis pathway associated with lignification.

Under Stress: Searching for Genes Involved in the Response of Abies pinsapo Boiss to Climate Change.

Currently, Mediterranean forests are experiencing the deleterious effects of global warming, which mainly include increased temperatures and decreased precipitation in the region. Relict Abies pinsapo fir forests, endemic in the southern Iberian Peninsula, are especially sensitive to these recent environmental disturbances, and identifying the genes involved in the response of this endangered tree species to climate-driven stresses is of paramount importance for mitigating their effects. Genomic resources for A. pinsapo allow for the analysis of candidate genes reacting to warming and aridity in their natural habitats. Several members of the complex gene families encoding late embryogenesis abundant proteins (LEAs) and heat shock proteins (HSPs) have been found to exhibit differential expression patterns between wet and dry seasons when samples from distinct geographical locations and dissimilar exposures to the effects of climate change were analyzed. The observed changes were more perceptible in the roots of trees, particularly in declining forests distributed at lower altitudes in the more vulnerable mountains. These findings align with previous studies and lay the groundwork for further research on the molecular level. Molecular and genomic approaches offer valuable insights for mitigating climate stress and safeguarding this endangered conifer.

ZEB1 hypermethylation is associated with better prognosis in patients with colon cancer.

BACKGROUND: Colon cancer (CC) is a heterogeneous disease that is categorized into four Consensus Molecular Subtypes (CMS) according to gene expression. Patients with loco-regional CC (stages II/III) lack prognostic factors, making it essential to analyze new molecular markers that can delineate more aggressive tumors. Aberrant methylation of genes that are essential in crucial mechanisms such as epithelial mesenchymal transition (EMT) contributes to tumor progression in CC. We evaluate the presence of hyper- and hypomethylation in subrogate IHC markers used for CMS classification (CDX2, FRMD6, HTR2B, ZEB1) of 144 stage II/III patients and CC cell lines by pyrosequencing. ZEB1 expression was also studied in control and shRNA-silenced CC cell lines and in paired normal tissue/tumors by quantitative PCR. The pattern of ZEB1 staining was also analyzed in methylated/unmethylated tumors by immunohistochemistry. RESULTS: We describe for the first time the hypermethylation of ZEB1 gene and the hypomethylation of the FRMD6 gene in 32.6% and 50.9% of tumors, respectively. Additionally, we confirm the ZEB1 re-expression by epigenetic drugs in methylated cell lines. ZEB1 hypermethylation was more frequent in CMS1 patients and, more importantly, was a good prognostic factor related to disease-free survival (p = 0.015) and overall survival (p = 0.006) in our patient series, independently of other significant clinical parameters such as patient age, stage, lymph node involvement, and blood vessel and perineural invasion. CONCLUSIONS: Aberrant methylation is present in the subrogate genes used for CMS classification. Our results are the first evidence that ZEB1 is hypermethylated in CC and that this alteration is an independent factor of good prognosis.

Relaciones de la deontología en ciencias de la salud: cuatro principios más alcance / Relationships of ethics in health sciences: four more principles reach

Los profesionales de distintas áreas de salud han fortalecido hábitos relacionados con faltas de consideración y trato cordial con pacientes y colegas, sugiriendo que la práctica de la ética profesional no se aplica como cualidad relevante en la atención sanitaria. Por otra parte, en Ecuador se han registrado innumerables demandas por causa de mala praxis médica y falta de valores éticos y morales en el ejercicio de la salud. Se realizó un estudio descriptivo y transversal en 47 estudiantes y 10 docentes de la Facultad de Ciencias Médicas de una universidad de Ecuador, a quienes se les aplicó un instrumento con la finalidad de conocer la práctica de los 4 principios básicos de bioética (autonomía, beneficencia, no ­ maleficencia y justicia) y analizar la importancia que tiene la deontología en la formación universitaria. Se observó que una alta proporción de docentes de odontología aplican la bioética en su labor profesional, con menos énfasis en el principio de no-maleficencia, refieren no recordar los derechos del paciente ante una demanda de mala práctica y desconocer la responsabilidad civil y penal. Mientras que, los estudiantes mostraron un nivel aceptable en los principios de autonomía y beneficencia pero pocos aplican los principios de no-maleficencia y justicia, asimismo, en su mayoría carecen de conocimientos sobre la deontología, códigos de ética médica en Ecuador y leyes que rigen el ejercicio profesional de la odontología, siendo necesario fortalecer la formación docente universitaria en bioética y optimizar programas y estrategias de aprendizaje en bioética y deontología odontológica(AU)

Professionals from different health areas have strengthened habits related to lack of consideration and cordial treatment with patients and colleagues, suggesting that the practice of professional ethics is not applied as a relevant quality in health care. On the other hand, in Ecuador there have been countless lawsuits due to medical malpractice and lack of ethical and moral values in the exercise of health. A descriptive and cross-sectional study was carried out in 47 students and 10 teachers from the Faculty of Medical Sciences of a university in Ecuador, to whom an instrument was applied in order to know the practice of the 4 basic principles of bioethics (autonomy, beneficence, no ­ maleficence and justice) and analyze the importance of ethics in university education. It was observed that a high proportion of dentistry teachers apply bioethics in their professional work, with less emphasis on the principle of non-maleficence, they refer not to remember the rights of the patient in the event of a malpractice claim and to ignore civil and criminal liability. While the students showed an acceptable level in the principles of autonomy and beneficence but few apply the principles of non-maleficence and justice, likewise, most of them lack knowledge about deontology, codes of medical ethics in Ecuador and laws that govern the professional practice of dentistry, being necessary to strengthen university teaching training in bioethics and optimize programs and learning strategies in bioethics and dental ethics(AU)

[Intraepidermal Merkel cell carcinoma with INSM1 expression. A case report]. / Carcinoma de Merkel intraepidérmico. Presentación de un caso con expresión de INSM1.

We report the case of a 90-year-old male who presented with an erythematous desquamative plaque on his left cheek. Histopathology demonstrated an epidermal lesion with multifocal epithelial growth. The cells were small, with scant cytoplasm and hyperchromatic nuclei with molding and a high mitotic and apopototic rate. Immunohistochemistry showed positivity for CK20, CK7, synaptophysin and INMS1. These findings are consistent with a Merkel cell carcinoma in situ. This tumor corresponds to a primary neuroendocrine neoplasm of the skin, which usually affects elderly people with sun-exposed skin. Usually, it presents as a dermal tumor but intraepidermal involvement alone is extremely rare. In this scenario, a broad differential diagnosis should be considered, excluding all neoplasms that may present intraepidermal forms. The evolution of this entity is unknown.

Carcinoma adenoide quístico de mama, 22 años de experiencia / Adenoid cystic carcinoma of the breast, 22 years of experience

INTRODUCCIÓN: El carcinoma adenoide quístico (CAQ) es una neoplasia infrecuente en la mama (menos del 0,1%). Típicamente es triple negativo con un pronóstico favorable. Su baja frecuencia y su curso indolente provocan dificultades en el convenio de la evaluación y el consenso terapéutico, así como en el uso de la técnica del ganglio centinela en estos carcinomas. OBJETIVO: Aportar una serie nueva de casos procedentes del Complejo Hospitalario de Navarra, mediante la revisión retrospectiva en un periodo de 22 años. MATERIAL Y MÉTODOS: Se revisan todos los casos de CAQ mamario diagnosticados entre 1998 y 2020. Analizamos los datos clínicos y anatomopatológicos y los comparamos con la literatura. RESULTADOS: Identificamos 12 CAQ, de un total de 18.241 pacientes con diagnóstico de carcinoma de mama, con un tamaño tumoral medio de 23,8mm y una edad media de 63,5 años. Todos ellos se encontraban en un estadio I-II al diagnóstico. Un caso presentó una micrometástasis ganglionar. Un caso presentó recidiva local y un caso presentó metástasis a distancia a los 5 meses del diagnóstico (93,5 meses de seguimiento medio). Según el grado histológico de Nottingham, 8 casos tuvieron un grado 1, 2 casos un grado 2 y 2 pacientes un grado 3. Según la clasificación de Ro et al., 3 casos fueron grado 1, 4 casos grado 2 y 5 casos grado 3. Un caso fue RE positivo (10%). Ningún caso presentó positividad para BRAF V600E con inmunohistoquímica. CONCLUSIÓN: El manejo y pronóstico del CAQ mamario, dentro de la benignidad, sigue siendo incierto, siendo necesarios más datos para comprender la evolución clínica y realizar un adecuado manejo terapéutico

INTRODUCTION: Adenoid cystic carcinoma (ACC) is an uncommon neoplasm in the breast (less than 0.1%). ACC is typically triple negative with a favourable prognosis. Its low frequency and indolent course cause difficulties in the agreement of the evaluation and therapeutic consensus, as well as the use of the sentinel node excision in these carcinomas. OBJECTIVE: Our goal is to provide a new series of cases from the Complejo Hospitalario de Navarra, through retrospective review over a period of 22 years. MATERIAL AND METHODS: Every case of breast ACC diagnosed between 1998-2020 is reviewed. We analyze the clinical and pathological characteristics, and compare them with the literature. RESULTS: We identified twelve cases of ACC, from a total of 18,241 patients diagnosed with breast carcinoma, with an average tumor size of 23.8mm and mean of 63.5 years. All of them were in a stage I-II at diagnosis. One case presented a lymph node micrometastases. One of them presented local recurrences and one case presented metastases 5 months after diagnosis (93.5 months of mean follow-up). According to Nottingham Histological Score, eight cases had a grade 1, two grade 2 and two grade 3. According to the classification of Ro et al., three were grade 1, four grade 2 and five grade 3. One case was ER positive (10%). No case presents positivity for BRAF-V600E in immunohistochemistry. CONCLUSION: The management and prognosis ACC of breast, within benignity, remains uncertain, with more studies being needed to understand the clinical evolution and perform adequate therapeutic management

[Adenoid cystic carcinoma of the breast, 22 years of experience]. / Carcinoma adenoide quístico de mama, 22 años de experiencia.

INTRODUCTION: Adenoid cystic carcinoma (ACC) is an uncommon neoplasm in the breast (less than 0.1%). ACC is typically triple negative with a favourable prognosis. Its low frequency and indolent course cause difficulties in the agreement of the evaluation and therapeutic consensus, as well as the use of the sentinel node excision in these carcinomas. OBJECTIVE: Our goal is to provide a new series of cases from the Complejo Hospitalario de Navarra, through retrospective review over a period of 22 years. MATERIAL AND METHODS: Every case of breast ACC diagnosed between 1998-2020 is reviewed. We analyze the clinical and pathological characteristics, and compare them with the literature. RESULTS: We identified twelve cases of ACC, from a total of 18,241 patients diagnosed with breast carcinoma, with an average tumor size of 23.8mm and mean of 63.5 years. All of them were in a stage I-II at diagnosis. One case presented a lymph node micrometastases. One of them presented local recurrences and one case presented metastases 5 months after diagnosis (93.5 months of mean follow-up). According to Nottingham Histological Score, eight cases had a grade 1, two grade 2 and two grade 3. According to the classification of Ro et al., three were grade 1, four grade 2 and five grade 3. One case was ER positive (10%). No case presents positivity for BRAF-V600E in immunohistochemistry. CONCLUSION: The management and prognosis ACC of breast, within benignity, remains uncertain, with more studies being needed to understand the clinical evolution and perform adequate therapeutic management.

Country-specific costs of implementing the WHO FCTC tobacco control policies and potential financing sources.

BACKGROUND: One of the major obstacles to the full implementation of the World Health Organization (WHO) Framework Convention of Tobacco Control (FCTC) tobacco control measures is the lack of sustainable financing resources. GOAL: To update and simulate country-specific indicators that are highly relevant to the costs and financial resources of the treaty policy implementation. We also developed an Excel tool for simulation and assessed the aggregated-level indicators by the 2016 World Bank income groups. APPROACHES: Using mostly 2016 data or 2014-15 data if 2016 one are not available, we updated five indicators relevant to the treaty implementation, which are the gap between current and desirable policy implementation, cigarette affordability, the costs of implementing best- buy tobacco control policies, the number of smoking-attributable deaths, and the simulated tax revenue resulting from a $1 tax increase. We also aggregated indicators and simulation results by the World Bank income groups, encompassing the five indicators and the reduction in smoking and in attributable deaths due to a hypothetical 1I$ tax increase. Finally, the policy implementation cost was compared with tax revenue and revenue increases. FINDINGS: As of 2016, smoking remains one of the leading causes of premature deaths worldwide while the implementation of best-buy tobacco control policies was below the recommended levels. Meanwhile, there was room to further increase cigarette taxes and prices, as cigarettes remained affordable in many countries. The total costs of implementing best-buy policies in the next 15 years merely account for 8.3% of the 2016 excise tax revenue, indicating that a small proportion of annual tax revenue could fund the implementation of tobacco control policies recommended by the WHO FCTC. CONCLUSIONS: Increasing taxes could have a multiplier impact on curbing tobacco use through aiding the implementation of the WHO FCTC.

N-Methyl-D-Aspartate Receptor Link to the MAP Kinase Pathway in Cortical and Hippocampal Neurons and Microglia Is Dependent on Calcium Sensors and Is Blocked by α-Synuclein, Tau, and Phospho-Tau in Non-transgenic and Transgenic APPSw,Ind Mice.

N-methyl-D-aspartate receptors (NMDARs) respond to glutamate to allow the influx of calcium ions and the signaling to the mitogen-activated protein kinase (MAPK) cascade. Both MAPK- and Ca2+-mediated events are important for both neurotransmission and neural cell function and fate. Using a heterologous expression system, we demonstrate that NMDAR may interact with the EF-hand calcium-binding proteins calmodulin, calneuron-1, and NCS1 but not with caldendrin. NMDARs were present in primary cultures of both neurons and microglia from cortex and hippocampus. Calmodulin in microglia, and calmodulin and NCS1 in neurons, are necessary for NMDA-induced MAP kinase pathway activation. Remarkably, signaling to the MAP kinase pathway was blunted in primary cultures of cortical and hippocampal neurons and microglia from wild-type animals by proteins involved in neurodegenerative diseases: α-synuclein, Tau, and p-Tau. A similar blockade by pathogenic proteins was found using samples from the APPSw,Ind transgenic Alzheimer's disease model. Interestingly, a very marked increase in NMDAR-NCS1 complexes was identified in neurons and a marked increase of both NMDAR-NCS1 and NMDAR-CaM complexes was identified in microglia from the transgenic mice. The results show that α-synuclein, Tau, and p-Tau disrupt the signaling of NMDAR to the MAPK pathway and that calcium sensors are important for NMDAR function both in neurons and microglia. Finally, it should be noted that the expression of receptor-calcium sensor complexes, specially those involving NCS1, is altered in neural cells from APPSw,Ind mouse embryos/pups.