Müllerian adenosarcoma with sarcomatous overgrowth and heterologous elements: A case report and literature review.

Uterine mullerian adenosarcoma (MA) is a rare biphasic tumour that accounts for less than 0.5% of uterine neoplasms. The age range of presentation is wide, with the median age in the 5th decade of life. It usually has a good prognosis; however, it worsens when it presents with sarcomatous overgrowth, heterologous elements or infiltrates the myometrium. We report the case of a 63-year-old woman presenting with abnormal vaginal bleeding and a sensation of solid material coming out of the cervical canal who was diagnosed with mullerian adenosarcoma with sarcomatous overgrowth (MASO) and presence of heterologous elements after performing a mass biopsy and subsequent hysterectomy. We reviewed the literature, focusing especially on the differential diagnoses to be evaluated, as well as the differences in prognosis and treatment according to whether or not they present histologic features of poor prognosis.

Centenarian hippocampus displays high levels of astrocytic metallothioneins.

The hippocampus is a brain area linked to cognition. The mechanisms that maintain cognitive activity in humans are poorly understood. Centenarians display extreme longevity which is generally accompanied by better quality of life, lower cognitive impairment, and reduced incidence of pathologies including neurodegenerative diseases. We performed transcriptomic studies in hippocampus samples from individuals of different ages (centenarians [≥97 years], old, and young) and identified a differential gene expression pattern in centenarians compared to the other two groups. In particular, several isoforms of metallothioneins (MTs) were highly expressed in centenarians. Moreover, we identified that MTs were mainly expressed in astrocytes. Functional studies in human primary astrocytes revealed that MT1 and MT3 are necessary for their homeostasis maintenance. Overall, these results indicate that the expression of MTs specifically in astrocytes is a mechanism for protection during aging.

Identification of a novel gene signature related to prognosis and metastasis in gastric cancer.

BACKGROUND: Gastric Cancer (GC) presents poor outcome, which is consequence of the high incidence of recurrence and metastasis at early stages. GC patients presenting recurrent or metastatic disease display a median life expectancy of only 8 months. The mechanisms underlying GC progression remain poorly understood. METHODS: We took advantage of public available GC datasets from TCGA using GEPIA, and identified the matched genes among the 100 genes most significantly associated with overall survival (OS) and disease free survival (DFS). Results were confirmed in ACRG cohort and in over 2000 GC cases obtained from several cohorts integrated using our own analysis pipeline. The Kaplan-Meier method and multivariate Cox regression analyses were used for prognostic significance and linear modelling and correlation analyses for association with clinic-pathological parameters and biological hallmarks. In vitro and in vivo functional studies were performed in GC cells with candidate genes and the related molecular pathways were studied by RNA sequencing. RESULTS: High expression of ANKRD6, ITIH3, SORCS3, NPY1R and CCDC178 individually and as a signature was associated with poor prognosis and recurrent disease in GC. Moreover, the expression of ANKRD6 and ITIH3 was significantly higher in metastasis and their levels associated to Epithelial to Mesenchymal Transition (EMT) and stemness markers. In line with this, RNAseq analysis revealed genes involved in EMT differentially expressed in ANKRD6 silencing cells. Finally, ANKRD6 silencing in GC metastatic cells showed impairment in GC tumorigenic and metastatic traits in vitro and in vivo. CONCLUSIONS: Our study identified a novel signature involved in GC malignancy and prognosis, and revealed a novel pro-metastatic role of ANKRD6 in GC.

KRT5+/p63+ Stem Cells Undergo Senescence in the Human Lung with Pathological Aging.

Adult lungs present high cellular plasticity against stress and injury, mobilizing stem/progenitor populations from conducting airways to maintain tissue homeostasis and gas exchange in alveolar spaces. With aging, pulmonary functional and structural deterioration occurs, mainly in pathological conditions, which is associated with impaired stem cell activity and increased senescence in mice. However, the impact of these processes underlying lung physiopathology in relation to aging has not been explored in humans. In this work, we analyzed stem cell (SOX2, p63, KRT5), senescence (p16INK4A, p21CIP, Lamin B1) and proliferative (Ki67) markers in lung samples from young and aged individuals, with and without pulmonary pathology. We identified a reduction in SOX2+ cells but not p63+ and KRT5+ basal cells in small airways with aging. In alveoli, we revealed the presence of triple SOX2+, p63+ and KRT5+ cells specifically in aged individuals diagnosed with pulmonary pathologies. Notably, p63+ and KRT5+ basal stem cells displayed colocalization with p16INK4A and p21CIP, as well as with low Lamin B1 staining in alveoli. Further studies revealed that senescence and proliferation markers were mutually exclusive in stem cells with a higher percentage colocalizing with senescence markers. These results provide new evidence of the activity of p63+/KRT5+ stem cells on human lung regeneration and point out that regeneration machinery in human lung is activated under stress due to aging, but fails to repair in pathological cases, as stem cells would likely become senescent.

Norovirus Intestinal Infection and Lewy Body Disease in an Older Patient with Acute Cognitive Impairment.

We present a case report on an older woman with unspecific symptoms and predominant long-term gastrointestinal disturbances, acute overall health deterioration with loss of autonomy for daily activities, and cognitive impairment. Autopsy revealed the presence of alpha-synuclein deposits spread into intestinal mucosa lesions, enteric plexuses, pelvic and retroperitoneal nerves and ganglia, and other organs as well as Lewy pathology in the central nervous system (CNS). Moreover, we isolated norovirus from the patient, indicating active infection in the colon and detected colocalization of norovirus and alpha-synuclein in different regions of the patient's brain. In view of this, we report a concomitant norovirus infection with synthesis of alpha-synuclein in the gastrointestinal mucosa and Lewy pathology in the CNS, which might support Braak's hypothesis about the pathogenic mechanisms underlying synucleinopathies.

High SOX9 Maintains Glioma Stem Cell Activity through a Regulatory Loop Involving STAT3 and PML.

Glioma stem cells (GSCs) are critical targets for glioma therapy. SOX9 is a transcription factor with critical roles during neurodevelopment, particularly within neural stem cells. Previous studies showed that high levels of SOX9 are associated with poor glioma patient survival. SOX9 knockdown impairs GSCs proliferation, confirming its potential as a target for glioma therapy. In this study, we characterized the function of SOX9 directly in patient-derived glioma stem cells. Notably, transcriptome analysis of GSCs with SOX9 knockdown revealed STAT3 and PML as downstream targets. Functional studies demonstrated that SOX9, STAT3, and PML form a regulatory loop that is key for GSC activity and self-renewal. Analysis of glioma clinical biopsies confirmed a positive correlation between SOX9/STAT3/PML and poor patient survival among the cases with the highest SOX9 expression levels. Importantly, direct STAT3 or PML inhibitors reduced the expression of SOX9, STAT3, and PML proteins, which significantly reduced GSCs tumorigenicity. In summary, our study reveals a novel role for SOX9 upstream of STAT3, as a GSC pathway regulator, and presents pharmacological inhibitors of the signaling cascade.

Reply to Twycross et al. Comment on "Ramos-Rincon et al. Palliative Sedation in COVID-19 End-of-Life Care. Retrospective Cohort Study. Medicina 2021, 57, 873".

First of all, we want to thank Twycross, Wong, and Vivat [...].

Alteraciones oftalmológicas en pacientes de 3 a 6 años de edad, productos de embarazos múltiples / Ophthalmological alterations in patients from 3 to 6 years of age, products of multiple pregnancies

Resumen Objetivo: Determinar alteraciones oftalmológicas en pacientes de 3-6 años de edad, productos de embarazo múltiple, técnicas de reproducción asistida (PPEM TRA) y espontáneos (PPEM E). Métodos: Estudio retrospectivo, observacional, descriptivo y transversal de enero de 1996 a julio del 2019. Muestra compuesta por 202 PPEM con exploración oftalmológica completa: 78 PPEM TRA y 124 PPEM E. Se distribuyeron por TRA, semanas de gestación, retinoscopia, edad y frecuencia de alteraciones anatómicas. Resultados: Las ametropías más frecuentes fueron astigmatismo mixto (A.Mx), astigmatismo hipermetrópico compuesto (AHC), astigmatismo hipermetrópico simple (AHS) y astigmatismo miópico simple (AMS). Conclusiones: Los defectos refractivos diagnosticados son similares a lo obtenido por diversos autores del ámbito nacional e internacional. La frecuencia de alteraciones oftalmológicas es más frecuente en PPEM TRA, pero más diversas en pacientes PPEM E.

Abstract Objective: To determine ophthalmological alterations in patients of 3-6 years of age, products of Multiple Pregnancy Assisted Reproduction Techniques (MPPP ART) and Spontaneous (MPPP S). Methods: Retrospective, observational, descriptive, and cross-sectional study from January 1996 to July 2019. Sample composed of 202 Multiple Pregnancy Product Patients with complete ophthalmological examination 78 MPPP ART and 124 MPPP S. They were distributed by ART, weeks of gestation, retinoscopy, age, and frequency of anatomical alterations. Results: The most frequent ametropias were mixed astigmatism (A.Mx), compound hyperopic astigmatism (CHA), simple hyperopic astigmatism (SHA) and simple myopic astigmatism (SMA). Conclusions: The refractive defects diagnosed are similar to those obtained by various national and international authors. The frequency of ophthalmological alterations is more frequent in MPPP ART, but more diverse in MPPP S patients.

The Pseudokinase TRIB3 Negatively Regulates the HER2 Receptor Pathway and Is a Biomarker of Good Prognosis in Luminal Breast Cancer.

BACKGROUND: Tribbles pseudokinase 3 (TRIB3) has been proposed to both promote and restrict cancer generation and progression. However, the precise mechanisms that determine this dual role of TRIB3 in cancer remain to be understood. In this study we aimed to investigate the role of TRIB3 in luminal breast cancer, the most frequent subtype of this malignancy. METHODS: We genetically manipulated TRIB3 expression in a panel of luminal breast cancer cell lines and analyzed its impact on cell proliferation, and the phosphorylation, levels, or subcellular localization of TRIB3 and other protein regulators of key signaling pathways in luminal breast cancer. We also analyzed TRIB3 protein expression in samples from luminal breast cancer patients and performed bioinformatic analyses in public datasets. RESULTS: TRIB3 enhanced the proliferation and AKT phosphorylation in luminal A (HER2-) but decreased them in luminal B (HER2+) breast cancer cell lines. TRIB3 negatively regulated the stability of HER2 in luminal B breast cancer cell lines. TRIB3 expression was associated with increased disease-free survival and a better response to therapy in luminal breast cancer patients. CONCLUSIONS: Our findings support the exploration of TRIB3 as a potential biomarker and therapeutic target in luminal breast cancer.

Palliative Sedation in COVID-19 End-of-Life Care. Retrospective Cohort Study.

Background and Objectives: Descriptions of end-of-life in COVID-19 are limited to small cross-sectional studies. We aimed to assess end-of-life care in inpatients with COVID-19 at Alicante General University Hospital (ALC) and compare differences according to palliative and non-palliative sedation. Material and Methods: This was a retrospective cohort study in inpatients included in the ALC COVID-19 Registry (PCR-RT or antigen-confirmed cases) who died during conventional admission from 1 March to 15 December 2020. We evaluated differences among deceased cases according to administration of palliative sedation. Results: Of 747 patients evaluated, 101 died (13.5%). Sixty-eight (67.3%) died in acute medical wards, and 30 (44.1%) received palliative sedation. The median age of patients with palliative sedation was 85 years; 44% were women, and 30% of cases were nosocomial. Patients with nosocomial acquisition received more palliative sedation than those infected in the community (81.8% [9/11] vs 36.8% [21/57], p = 0.006), and patients admitted with an altered mental state received it less (20% [6/23] vs. 53.3% [24/45], p = 0.032). The median time from admission to starting palliative sedation was 8.5 days (interquartile range [IQR] 3.0-14.5). The main symptoms leading to palliative sedation were dyspnea at rest (90%), pain (60%), and delirium/agitation (36.7%). The median time from palliative sedation to death was 21.8 h (IQR 10.4-41.1). Morphine was used in all palliative sedation perfusions: the main regimen was morphine + hyoscine butyl bromide + midazolam (43.3%). Conclusions: End-of-life palliative sedation in patients with COVID-19 was initiated quite late. Clinicians should anticipate the need for palliative sedation in these patients and recognize the breathlessness, pain, and agitation/delirium that foreshadow death.

Frailty is associated with mortality in brain tumor patients.

Frailty represents a state of vulnerability that increases the risk of adverse health outcomes. In the last years, frailty has emerged as a good indicator of patient's functional reserve and it seems to be a predictor of negative outcomes in oncological patients. In this work, we analyzed the clinical utility of frailty as preoperative risk assessment tool in a brain tumor cohort from Donostia University Hospital (Spain). For that, we used several frailty tools consisting of questionnaires based on frailty phenotype (FRAIL scale), evaluating functional performance (Gait Speed) and a self-report questionnaire that includes variables related to the physical, cognitive and psychosocial domains of frailty (Tilburg Frailty Indicator). We identified a higher percentage of patients in vulnerable situation prior to surgery when using frailty tools compared to routine scales such as Karnosfky score and Barthel Index. Remarkably, patients diagnosed with malignant tumors were frailer and presented significant less six-month survival than patients with benign tumors by all the frailty scales abovementioned. In line with this, the vast majority of patients that became pre-frail or frail after neurosurgery (by FRAIL scale) harbored a malignant tumor. Moreover, frailty status significantly correlated with patient's mortality and autonomy, but not with the presence of postoperative outcomes in our cohort. Taken together, our results show that frailty measurement, mainly by FRAIL scale, is a useful tool to evaluate preoperative risk in brain tumor patients as well as patient's prognosis after neurosurgery.

Ki-67 immunoexpression and radiological assessment of necrosis improves accuracy of conventional and modified core biopsy systems in predicting the final grade assigned to adult-soft tissue sarcomas. An international collaborative study.

Based on the French Federation Nationale des Centers de Lutte Contre le Cancer (FNCLCC) grading system, this study assesses the accuracy of conventional and modified core biopsy (CB) systems in predicting the final grade (low vs high) assigned to the resected specimen. Substituting Ki-67 immunoexpression for mitotic count, and radiological for histological assessment of necrosis, we used two modified FNCLCC CB grading systems: (1) Ki-67 immunoexpression alone, and (2) Ki-67 plus radiological assessment of necrosis. We graded 199 soft tissue sarcomas (STS) from nine centers, and compared the results for the conventional (obtained from local histopathology reports) and modified CB systems with the final FNCLCC grading of the corresponding resected specimens. Due to insufficient sample quality or lack of available radiologic data, five cases were not evaluated for Ki67 or radiological assessment of necrosis. The conventional FNCLCC CB grading system accurately identified 109 of the 130 high-grade cases (83.8%). The CB grading matched the final FNCLCC grading (low vs high) in 175 (87.9%) of the 199 resected tumors; overestimating the final grade in three cases and underestimating in 21 cases. Modified system 1 (Ki-67) accurately identified 117 of the 130 high-grade cases (90.0%). The CB grading matched the final FNCLCC grading (low vs high) in 175 (89.7%) of the 195 evaluated cases; overestimating seven and underestimating 13 cases. Modified system 2 (Ki-67 plus radiological necrosis) accurately identified 120 of the 130 high-grade cases (92.3%). This last matched the final FNCLCC grading (low vs high) in 177 (91.2%) of the 194 evaluated cases; overestimating seven and underestimating 10 cases. Modified system 2 obtained highest area under ROC curves, although not statistically significant. Underestimated CB grades did not correlate with histological subtypes, although many of the discrepant cases were myxoid tumors (myxofibrosarcomas or myxoid liposarcomas), leiomyosarcomas or undifferentiated pleomorphic/spindle cell sarcomas. Using modified FNCLCC CB grading systems to replace conventional mitotic count and histologic assessment of necrosis may improve the distinction between low and high-grade STS on CB. Our study confirms that classifying grade 1 as low grade and grades 2 and 3 as high grade improves correlation between CB and final grade by up to 21%, irrespective of CB system used. A higher than expected Ki-67 score in a low-grade sarcoma diagnosed on CB should raise concern that a higher-grade component may not have been sampled. Furthermore, correlation of all clinicopathological and radiological findings at multidisciplinary meetings is essential to assess the histological grade on CB as accurately as possible.

CD8+ T cells are present at low levels in the white matter with physiological and pathological aging.

The presence and functional role of T cell infiltration in human brain parenchyma with normal aging and neurodegeneration is still under intense debate. Recently, CD8+ cells have been shown to infiltrate the subventricular zone in humans and mice with a deleterious effect on neural stem cells. However, to which extent T cell infiltration in humans also occurs in other regions such as cortical areas and, especially, white matter (WM) has not yet been addressed. In this work, we report a low-grade infiltration of T cells (CD3+, CD4+ and CD8+) in the WM of aged individuals that is also observed at similar levels in patients with neurodegenerative disorders (Alzheimer´s disease). In particular, CD3+ and CD8+ cells were increased in perivascular and parenchymal WM and cortical regions (enthorinal cortex). These results reveal that T cell infiltration in brain parenchyma occurs with physiological and pathological aging in several regions, but it seems to be lower than in the subventricular zone neurogenic niche.

CD8+ T cells are increased in the subventricular zone with physiological and pathological aging.

Age-related cognitive decline and neurodegenerative diseases are associated with less functional neurogenic niches. It has been recently shown that aged subventricular zone (SVZ) suffers an infiltration of T cells, which affects neural stem cell activity in mice. Whether this occurs in human neurogenic niches or to which extent T-cell infiltration is also taking place in neurodegenerative diseases remains unknown. In this work, we studied the presence of T cells in both human neurogenic niches in young and old individuals. There was a significant increase in the number of CD3+ and CD8+ T cells in the SVZ of elderly individuals, which was not detected in the dentate gyrus. Moreover, we also found CD3+ and CD8+ T cells in the SVZ of individuals with neurodegenerative diseases. However, T-cell count was similar when compared non-neuropathological elderly with disease diagnosed patients. Our study reveals the infiltration of T cells in old human brains, particularly in the SVZ under non-pathological conditions and also in neurodegenerative contexts.

Retinopathy of prematurity, frequency and risk factors in very low birth weight infants.

Background: Retinopathy of prematurity (ROP) is the principal cause of blindness during childhood. The objective of this study was to analyze the frequency of ROP and risk factors associated with ROP in a cohort of very low birth weight infants. Methods: A cases (ROP) and controls (no ROP) study of infants less than 1500 g was conducted. Perinatal and neonatal variables were analyzed. For the statistical analysis, χ2 test, Student's t-test and Mann-Whitney's U-test were used. Results: For the study, 282 neonates were included: 152 (53.9%) with ROP and 130 (46.1%) without ROP. The most frequent stages observed were stage 1 and 2, with 139 (91.4%) patients, and stages 3 to 5, with only 13 patients (8.5%). In those neonates with ROP compared with neonates without ROP, the birth weight was less (902.7 vs. 1037.9 g) and the difference was significant (p < 0.0001). Also, the difference with gestational age (28.2 vs. 29.6; p < 0.0001), total ventilation days (32.8 vs. 16.1; p < 0.00001) and total oxygen days (87.7 vs. 62.6; p < 0.0001) was significant in neonates with ROP and neonates without the disease. Bronchopulmonary dysplasia, intraventricular hemorrhage and late onset sepsis were significant with patients with ROP. Conclusions: The frequency of ROP reported here is higher than the reported in Mexican population, with less cases of severe ROP. The neonatal surveillance in babies with less birth weight and gestational age is important to decrease the incidence of ROP.

Introducción: La retinopatía del prematuro (ROP) es una de las principales causas de ceguera infantil. La inmadurez y la exposición a oxígeno son algunos factores de riesgo. El objetivo de este artículo fue analizar la frecuencia y los factores de riesgo de ROP en una cohorte de recién nacidos menores de 1,500 g. Métodos: Se llevó a cabo un estudio de casos (con ROP) y controles (sin ROP) de recién nacidos menores de 1,500 g. Se analizaron variables prenatales y neonatales, y para su comparación se utilizaron las pruebas estadísticas t de Student, χ2 y U de Mann-Whitney. Resultados: Se analizaron 282 recién nacidos: 152 (53.9%) con ROP y 130 (46.1%) sin ROP. La mayor frecuencia se encontró en los estadios 1 y 2, con 139 pacientes (91.4%), seguidos de los estadios 3 a 5, con 13 pacientes (8.5%). En los pacientes con ROP, el peso al nacer fue menor (902.7 vs. 1037.9 g; p < 0.0001), así como la edad gestacional (28.2 vs. 29.6 semanas de gestación; p < 0.0001). Los días de ventilación (32.8 vs. 16.1; p < 0.00001) y los días de oxígeno requerido durante la estancia hospitalaria (87.7 vs. 62.6; p < 0.0001) fueron mayores en los pacientes con ROP. La displasia broncopulmonar, la hemorragia intraventricular y la sepsis tardía fueron comorbilidades significativas para el desarrollo de ROP. Conclusiones: En este estudio, la frecuencia de ROP fue mayor que la reportada en la población mexicana, con una baja proporción de formas graves. La vigilancia estrecha del manejo de los neonatos con menor peso y menos edad gestacional es fundamental para lograr disminuir esta enfermedad.

Análisis de la frecuencia y factores de riesgo asociados a la retinopatía del prematuro en neonatos de muy bajo peso al nacer / Retinopathy of prematurity, frequency and risk factors in very low birth weight infants

Resumen Introducción: La retinopatía del prematuro (ROP) es una de las principales causas de ceguera infantil. La inmadurez y la exposición a oxígeno son algunos factores de riesgo. El objetivo de este artículo fue analizar la frecuencia y los factores de riesgo de ROP en una cohorte de recién nacidos menores de 1,500 g. Métodos: Se llevó a cabo un estudio de casos (con ROP) y controles (sin ROP) de recién nacidos menores de 1,500 g. Se analizaron variables prenatales y neonatales, y para su comparación se utilizaron las pruebas estadísticas t de Student, χ2 y U de Mann-Whitney. Resultados: Se analizaron 282 recién nacidos: 152 (53.9%) con ROP y 130 (46.1%) sin ROP. La mayor frecuencia se encontró en los estadios 1 y 2, con 139 pacientes (91.4%), seguidos de los estadios 3 a 5, con 13 pacientes (8.5%). En los pacientes con ROP, el peso al nacer fue menor (902.7 vs. 1037.9 g; p < 0.0001), así como la edad gestacional (28.2 vs. 29.6 semanas de gestación; p < 0.0001). Los días de ventilación (32.8 vs. 16.1; p < 0.00001) y los días de oxígeno requerido durante la estancia hospitalaria (87.7 vs. 62.6; p < 0.0001) fueron mayores en los pacientes con ROP. La displasia broncopulmonar, la hemorragia intraventricular y la sepsis tardía fueron comorbilidades significativas para el desarrollo de ROP. Conclusiones: En este estudio, la frecuencia de ROP fue mayor que la reportada en la población mexicana, con una baja proporción de formas graves. La vigilancia estrecha del manejo de los neonatos con menor peso y menos edad gestacional es fundamental para lograr disminuir esta enfermedad.

Abstract Background: Retinopathy of prematurity (ROP) is the principal cause of blindness during childhood. The objective of this study was to analyze the frequency of ROP and risk factors associated with ROP in a cohort of very low birth weight infants. Methods: A cases (ROP) and controls (no ROP) study of infants less than 1500 g was conducted. Perinatal and neonatal variables were analyzed. For the statistical analysis, χ2 test, Student’s t-test and Mann-Whitney’s U-test were used. Results: For the study, 282 neonates were included: 152 (53.9%) with ROP and 130 (46.1%) without ROP. The most frequent stages observed were stage 1 and 2, with 139 (91.4%) patients, and stages 3 to 5, with only 13 patients (8.5%). In those neonates with ROP compared with neonates without ROP, the birth weight was less (902.7 vs. 1037.9 g) and the difference was significant (p < 0.0001). Also, the difference with gestational age (28.2 vs. 29.6; p < 0.0001), total ventilation days (32.8 vs. 16.1; p < 0.00001) and total oxygen days (87.7 vs. 62.6; p < 0.0001) was significant in neonates with ROP and neonates without the disease. Bronchopulmonary dysplasia, intraventricular hemorrhage and late onset sepsis were significant with patients with ROP. Conclusions: The frequency of ROP reported here is higher than the reported in Mexican population, with less cases of severe ROP. The neonatal surveillance in babies with less birth weight and gestational age is important to decrease the incidence of ROP.

SOX9 promotes tumor progression through the axis BMI1-p21CIP.

The developmental regulator SOX9 is linked to cancer progression mainly as a result of its role in the regulation of cancer stem cells (CSCs). However, its activity in the differentiated cells that constitute the heterogeneous tumor bulk has not been extensively studied. In this work, we addressed this aspect in gastric cancer, glioblastoma and pancreatic adenocarcinoma. SOX9 silencing studies revealed that SOX9 is required for cancer cell survival, proliferation and evasion of senescence in vitro and tumor growth in vivo. Gain of-SOX9 function showed that high levels of SOX9 promote tumor cell proliferation in vitro and in vivo. Mechanistically, the modulation of SOX9 changed the expression of the transcriptional repressor BMI1 in the same direction in the three types of cancer, and the expression of the tumor suppressor p21CIP in the opposite direction. In agreement with this, SOX9 expression positively correlated with BMI1 levels and inversely with p21CIP in clinical samples of the different cancers. Moreover, BMI1 re-establishment in SOX9-silenced tumor cells restored cell viability and proliferation as well as decreased p21CIP in vitro and tumor growth in vivo. These results indicate that BMI1 is a critical effector of the pro-tumoral activity of SOX9 in tumor bulk cells through the repression of p21CIP. Our results highlight the relevance of the SOX9-BMI1-p21CIP axis in tumor progression, shedding novel opportunities for therapeutic development.

Neuronal p38α mediates age-associated neural stem cell exhaustion and cognitive decline.

Neuronal activity regulates cognition and neural stem cell (NSC) function. The molecular pathways limiting neuronal activity during aging remain largely unknown. In this work, we show that p38MAPK activity increases in neurons with age. By using mice expressing p38α-lox and CamkII-Cre alleles (p38α∆-N), we demonstrate that genetic deletion of p38α in neurons suffices to reduce age-associated elevation of p38MAPK activity, neuronal loss and cognitive decline. Moreover, aged p38α∆-N mice present elevated numbers of NSCs in the hippocampus and the subventricular zone. These results reveal novel roles for neuronal p38MAPK in age-associated NSC exhaustion and cognitive decline.