Identification of aberrant luminal progenitors and mTORC1 as a potential breast cancer prevention target in BRCA2 mutation carriers.

Inheritance of a BRCA2 pathogenic variant conveys a substantial life-time risk of breast cancer. Identification of the cell(s)-of-origin of BRCA2-mutant breast cancer and targetable perturbations that contribute to transformation remains an unmet need for these individuals who frequently undergo prophylactic mastectomy. Using preneoplastic specimens from age-matched, premenopausal females, here we show broad dysregulation across the luminal compartment in BRCA2mut/+ tissue, including expansion of aberrant ERBB3lo luminal progenitor and mature cells, and the presence of atypical oestrogen receptor (ER)-positive lesions. Transcriptional profiling and functional assays revealed perturbed proteostasis and translation in ERBB3lo progenitors in BRCA2mut/+ breast tissue, independent of ageing. Similar molecular perturbations marked tumours bearing BRCA2-truncating mutations. ERBB3lo progenitors could generate both ER+ and ER- cells, potentially serving as cells-of-origin for ER-positive or triple-negative cancers. Short-term treatment with an mTORC1 inhibitor substantially curtailed tumorigenesis in a preclinical model of BRCA2-deficient breast cancer, thus uncovering a potential prevention strategy for BRCA2 mutation carriers.

Clinical usefulness of cerebrospinal fluid biomarkers in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a complex disease that shares clinical features with other dementias. It is important to establish a specific and reliable diagnosis. Nowadays, AD diagnosis is based on cerebrospinal fluid (CSF) biomarkers. However, the corresponding cut-offs differ amongst studies. This study aims to evaluate the CSF biomarkers in the AD differential diagnosis. METHODS: Clinical relevant biomarkers (amyloid ß42 (Aß42), t-Tau, p-Tau, amyloid ß40 (Aß40), neurofilament light chain (NfL)) were determined in CSF samples from participants classified as AD (n = 124) and non-AD (n = 148) patients from the Neurology Unit. They were included and evaluated consecutively (August 2018-October 2020). The clinical utility of these biomarkers was evaluated by AUC-ROC curves and the corresponding cut-off points were defined. RESULTS: The results showed satisfactory accuracy (AUC-ROC 0.91 for Aß42, 0.890 for t-Tau and 0.933 for p-Tau); whilst Aß40 and NfL did not show good discriminatory capacity (AUC-ROC 0.557 and 0.738, respectively). The ratios Aß42/Aß40 and t-Tau/Aß42 improved the diagnosis indices of each individual biomarker, with AUC-ROC of 0.980 and 0.971, respectively. Also, elevated levels of NfL were found in the frontotemporal dementia group compared with the other participant groups. CONCLUSIONS: The ratio Aß42/Aß40 showed the highest discriminating capacity between AD and non-AD patients and might be useful in clinical practice. Regarding NfL, it is not a specific biomarker for AD; however, it might be helpful for the differential diagnosis of frontotemporal dementia. Nevertheless, further analysis in an external cohort is required in order to validate these results.

mRNA spindle localization and mitotic translational regulation by CPEB1 and CPEB4.

Transition through cell cycle phases requires temporal and spatial regulation of gene expression to ensure accurate chromosome duplication and segregation. This regulation involves dynamic reprogramming of gene expression at multiple transcriptional and posttranscriptional levels. In transcriptionally silent oocytes, the CPEB-family of RNAbinding proteins coordinates temporal and spatial translation regulation of stored maternal mRNAs to drive meiotic progression. CPEB1 mediates mRNA localization to the meiotic spindle, which is required to ensure proper chromosome segregation. Temporal translational regulation also takes place in mitosis, where a large repertoire of transcripts are activated or repressed in specific cell cycle phases. However, whether control of localized translation at the spindle is required for mitosis is unclear, as mitotic and acentriolar-meiotic spindles are functionally and structurally different. Furthermore, the large differences in scale-ratio between cell volume and spindle size in oocytes compared to somatic mitotic cells may generate distinct requirements for gene expression compartmentalization in meiosis and mitosis. Here we show that mitotic spindles contain CPE-localized mRNAs and translating ribosomes. Moreover, CPEB1 and CPEB4 localize in the spindles and they may function sequentially in promoting mitotic stage transitions and correct chromosome segregation. Thus, CPEB1 and CPEB4 bind to specific spindle-associated transcripts controlling the expression and/or localization of their encoded factors that, respectively, drive metaphase and anaphase/cytokinesis.

The RNA binding protein CPEB2 regulates hormone sensing in mammary gland development and luminal breast cancer.

Organogenesis is directed by coordinated cell proliferation and differentiation programs. The hierarchical networks of transcription factors driving mammary gland development and function have been widely studied. However, the contribution of posttranscriptional gene expression reprogramming remains largely unexplored. The 3' untranslated regions of messenger RNAs (mRNAs) contain combinatorial ensembles of cis-regulatory elements that define transcript-specific regulation of protein synthesis through their cognate RNA binding proteins. We analyze the contribution of the RNA binding cytoplasmic polyadenylation element-binding (CPEB) protein family, which collectively regulate mRNA translation for about 30% of the genome. We find that CPEB2 is required for the integration of hormonal signaling by controlling the protein expression from a subset of ER/PR- regulated transcripts. Furthermore, CPEB2 is critical for the development of ER-positive breast tumors. This work uncovers a previously unknown gene expression regulation level in breast morphogenesis and tumorigenesis, coordinating sequential transcriptional and posttranscriptional layers of gene expression regulation.

[Hemophagocytic syndrome at a pediatric specialty hospital. Underdiagnosis and overdiagnosis]. / Síndrome hemofagocítico en un hospital de especialidades pediátrica. Subdiagnóstico y sobrediagnóstico.

BACKGROUND: The hemophagocytic syndrome is a serious complication of several systemic illnesses. OBJECTIVE: To define the characteristics of the hemophagocytic syndrome at a pediatric specialty hospital in Tuxtla Gutiérrez, Chiapas, Mexico; incidences, underdiagnosis and overdiagnosis, associated conditions, treatment, and prognosis were included. METHODS: 214 cases of probable hemophagocytic syndrome that were seen between January 2011 and May 2019 were analyzed. 26 patients diagnosed with hemophagocytic syndrome and 188 cases with suspicion of this entity and/or ferritin > 500 ug/L were included. The cases that met four or more criteria of the HFS (Histiocyte Society, 2004) were included in this study. RESULTS: Thirty-five cases were validated (fourteen were previously diagnosed, nine had suspicion, and twelve had ferritin > 500 µg/L). Neither twelve out of 26 of the cases that were previously diagnosed (46.2 % overdiagnosed). Of the 35 validated cases, 21 hadn't been diagnosed (60 % underdiagnosed) met the diagnostic criteria of the HFS. The annual occurrence was of 2.0/1000 egresses. The Epstein-Barr virus was involved in 42 % of the cases. The overall mortality was of 80 %. CONCLUSIONS: Hemophagocytic syndrome had been significantly underdiagnosed and overdiagnosed at the analyzed hospital. The clinical features allow early suspicion, diagnosis, and treatment. Specific and non-specific illnesses that were associated to hemophagocytic syndrome were identified.

Antecedentes: El síndrome hemofagocítico es una complicación grave que se observa en diversos padecimientos sistémicos. Objetivo: Conocer las características del síndrome hemofagocítico en el Hospital de Especialidades Pediátricas de Tuxtla Gutiérrez, Chiapas, México; se incluyó incidencia, subdiagnóstico y sobrediagnóstico, padecimientos asociados, tratamiento y pronóstico. Métodos: Se analizaron 214 casos probables de síndrome hemofagocítico atendidos entre enero de 2011 y mayo de 2019. Se incluyeron 26 pacientes con diagnóstico de síndrome hemofagocítico y 188 en los que se sospechaba esta entidad o con ferritina > 500 µg/L. Los casos en los que se cumplieron cuatro o más criterios de la Sociedad del Histiocito fueron incluidos en el estudio. Resultados: Se validaron 35 casos (14 con diagnóstico previo, nueve con sospecha y 12 con ferritina > 500 µg/L). No cumplieron con los criterios de la Sociedad del Histiocito, 12 casos diagnosticados previamente (sobrediagnóstico de 46.2 %). De los 35 validados, 21 no habían sido diagnosticados (subdiagnóstico de 60 %). La incidencia anual fue de 2.0/1000 egresos. El virus Epstein-Barr estuvo involucrado en 42 % de los casos. La mortalidad representó 80 %. Conclusiones: El síndrome hemofagocítico fue subdiagnosticado y sobrediagnosticado en el hospital estudiado. Las características clínicas permiten sospecharlo, diagnosticarlo y tratarlo oportunamente. Se identificaron padecimientos específicos y no específicos asociados a síndrome hemofagocítico.

IgG subclasses quantitation: Analytical performance of The Binding Site SPAPLUS® human assay and comparison with Siemens BNII® assay.

OBJECTIVES: Accurate evaluation of analyzers is highly recommended before these devices are broadly introduced for routine testing. Concerning quantification of IgG subclasses (IgGSc), standardization has not yet been reached and thus different assays might lead to different results. Here we report the analytical performances of The Binding Site (TBS) SPAPLUS® human IgGSc assay and the concordance with the Siemens BNII® human IgGSc assay. DESIGN AND METHODS: We evaluated precision, LoB, LoD and linearity of TBS SPAPLUS® human IgGSc immunoassay. Quantitation of IgGSc in 53 patients' serum samples was performed in parallel on both analyzers. Results from both assays were compared. RESULTS: Analytical performances of the TBS SPAPLUS® human IgGSc assay are acceptable for routine clinical use. According to the method comparison study, TBS assay measures lower values than Siemens assay for IgG1 and IgG4, whereas for IgG2 and IgG3 TBS provides greater values. All assays present a proportional bias, greater in the case of IgG3 and IgG4 assays. Individual subclass agreement, based on the classification of samples within three categories (low, normal and high) according to assay-specific reference intervals, range from 75% (IgG1) to 92% (IgG2). However, total classification agreement over all four subclasses only account for 55% of samples. CONCLUSION: Results obtained from both assays are not interchangeable. Standardization of IgGSc assay and review of the reference ranges must be accomplished in order to achieve a higher degree of agreement between different methods.

Eslicarbazepine acetate and carotid intima-media thickness in epileptic patients.

OBJECTIVE: Evaluate if eslicarbazepine acetate (ESL) in combination with other non-inducer antiepileptic drugs (AEDs) in the treatment of epilepsy may represent a positive impact in the cardiovascular risk profile. METHODS: multicentre, retrospective, observational, non-interventional, real-life study comparing patients treated with cytochrome P450 (CYP) inducer vs. ESL plus non-inducer AEDs. Primary endpoint: Carotid intima-media thickness (CIMT) measured following the Manheim Consensus criteria. RESULTS: Patients included: 163. The main demographic, clinical and vascular risk parameters were comparable between the two groups except for duration of the disease, prevalence of dyslipidemia and use of lipid-lowering drugs (significantly higher in the inducers group) and number of previous antiepileptic drugs (significantly higher in the non-inducers group). Bivariate analysis of the main endpoint showed almost significant differences (p=0.05) in CIMT measures favourable to non-inducers (average 0.617mm+SD=0.148) vs. inducers (average 0.663mm+SD=0.147). Other variables reaching statistical significance were: age >50 years (p<0.001), high blood pressure (p<0.01) and dyslipidemia (p<0.05). A multivariate analysis including these variables and biochemical vascular risk factors showed a predictor model including two variables: inducers group (p=0.031; Coefficient ß=0.234) and age >50 years (p=0.001; Coefficient ß=0.387). Regarding gender, the mean CIMT in males was significantly higher in the inducers (0.693mm; SD=0.139) than in the non- inducers groups (0.628mm; SD=0.151; p<0.05). In females the differences were not significant. SIGNIFICANCE: The use of CYP inducer AEDs is associated with a significant increase in CIMT as compared with ESL and other non-inducer AEDs. The study shows a decrease in the vascular risk measured by ultrasound criteria in male patients treated with ESL compared with patients treated with inducer AEDs.

AMPK and PFKFB3 mediate glycolysis and survival in response to mitophagy during mitotic arrest.

Blocking mitotic progression has been proposed as an attractive therapeutic strategy to impair proliferation of tumour cells. However, how cells survive during prolonged mitotic arrest is not well understood. We show here that survival during mitotic arrest is affected by the special energetic requirements of mitotic cells. Prolonged mitotic arrest results in mitophagy-dependent loss of mitochondria, accompanied by reduced ATP levels and the activation of AMPK. Oxidative respiration is replaced by glycolysis owing to AMPK-dependent phosphorylation of PFKFB3 and increased production of this protein as a consequence of mitotic-specific translational activation of its mRNA. Induction of autophagy or inhibition of AMPK or PFKFB3 results in enhanced cell death in mitosis and improves the anti-tumoral efficiency of microtubule poisons in breast cancer cells. Thus, survival of mitotic-arrested cells is limited by their metabolic requirements, a feature with potential implications in cancer therapies aimed to impair mitosis or metabolism in tumour cells.

Incidencia de hongos ambientales durante un año en la ciudad de Córdoba / Incidence of environmental fungi during one year in Cordoba city

Se procura establecer la incidencia de hongos anemófilos en la ciudad de Córdoba durante un año; se evalúa la influencia de los factores climáticos (temperatura, viento, humedad y presión atmosférica), los cambios atribuibles a la naturaleza del suelo, la vegetación y al progreso edilicio de la ciudad. Verano: presentan su pico de mayor frecuencia dentro de los Deuteromycotina: Fusarium, Oospora, Micelia Sterilia y Gliocladium; en Zygomicotina: Rhizopus y en Ascomycotina las Levaduras. Otoño: se aislan con mayor frecuencia los géneros Helminthosporium, Pullularia, Monotospora, Monilia y Trichoderma. Invierno: los géneros predominantes son Penicillium, Hormodendrum y Cephalosporium. Primavera: presentan su pico de mayor frecuencia Alternaria, Cladosporium, Nigrospora, Aspergillus y Acremonium. Estos registros fueron comparados mediante tablas estadísticas con un trabajo similar efectuado hace dos décadas y se obtuvieron diferencias ampliamente significativas atribuibles al aumento en las clases Zygomicotina y Deuteromycotina, no ocurrió lo mismo para la clase de los Ascomycotina

Incidencia de hongos ambientales durante un año en la ciudad de Córdoba / Incidence of environmental fungi during one year in Cordoba city

Se procura establecer la incidencia de hongos anemófilos en la ciudad de Córdoba durante un año; se evalúa la influencia de los factores climáticos (temperatura, viento, humedad y presión atmosférica), los cambios atribuibles a la naturaleza del suelo, la vegetación y al progreso edilicio de la ciudad. Verano: presentan su pico de mayor frecuencia dentro de los Deuteromycotina: Fusarium, Oospora, Micelia Sterilia y Gliocladium; en Zygomicotina: Rhizopus y en Ascomycotina las Levaduras. Otoño: se aislan con mayor frecuencia los géneros Helminthosporium, Pullularia, Monotospora, Monilia y Trichoderma. Invierno: los géneros predominantes son Penicillium, Hormodendrum y Cephalosporium. Primavera: presentan su pico de mayor frecuencia Alternaria, Cladosporium, Nigrospora, Aspergillus y Acremonium. Estos registros fueron comparados mediante tablas estadísticas con un trabajo similar efectuado hace dos décadas y se obtuvieron diferencias ampliamente significativas atribuibles al aumento en las clases Zygomicotina y Deuteromycotina, no ocurrió lo mismo para la clase de los Ascomycotina (AU)

Determinación de receptores hormonales de tumores mamarios en humanos / Identification of Hormonal Receptors in Human Breast Cancer

Se presentan las experiencias en el montaje de una técnica para la determinación de la hormon-dependencia del cáncer mamario humano. Se analizan y discuten los resultados encontrados con la utilización de esta técnica en 50 pacientes con tumor mamario maligno tratadas en el IOR (AU)