Natural history and surgical outcomes of Rathke's cleft cysts: a Spanish multicenter study.

Rathke's cleft cysts (RCC) are a common type of lesion found in the sellar or suprasellar area. They are usually monitored clinically, but in some cases, surgery may be required. However, their natural progression is not yet well understood, and the outcomes of surgery are uncertain. The objective of this study is to evaluate the natural history of Rathke's cleft cysts in patients who are clinically monitored without treatment, and to determine the outcomes of surgery and the incidence of recurrences over time. Design and patients: National multicentric study of patients diagnosed of Rathke's cleft cyst (RCC- Spain) from 2000 onwards and followed in 15 tertiary centers of Spain. A total of 177 patients diagnosed of RCC followed for 67.3 months (6-215) and 88 patients who underwent surgery, (81 patients underwent immediate surgery after diagnosis and 7 later for subsequent growth) followed for 68.8 months (3-235). Results: The cyst size remained stable or decreased in 73.5% (133) of the patients. Only 44 patients (24.3%) experienced a cyst increase and 9 of them (5.1%) experienced an increase greater than 3 mm. In most of the patients who underwent surgery headaches and visual alterations improved, recurrence was observed in 8 (9.1%) after a median time of 96 months, and no predictors of recurrence were discovered. Conclusions: Rathke's cleft cysts without initial compressive symptoms have a low probability of growth, so conservative management is recommended. Patients who undergo transsphenoidal surgery experience rapid clinical improvement, and recurrences are infrequent. However, they can occur after a long period of time, although no predictors of recurrence have been identified.

Valoración de la densidad mineral ósea en personas transgénero posicionamiento de la Sociedad Argentina de Osteoporosis / Evaluation of bone health in transgender people. Position of the Argentine Osteoporosis Society

Resumen La Sociedad Argentina de Osteoporosis convocó a especialistas reconocidos en la atención de personas transgénero para la elaboración del primer posiciona miento local sobre la evaluación de la salud ósea en esta población. La ley 26.743 de "Identidad de género" reco noce todas las identidades y garantiza su atención de manera gratuita en el sistema de salud. El impacto de los diferentes tratamientos de afirmación de género sobre la masa ósea ha sido tópico de debate internacional. Hasta la fecha la evidencia sigue siendo limitada y diferentes sociedades han emitido sugerencias y recomendaciones. Por tal motivo, creemos relevante mencionar nuestra experiencia plasmando mediante este documento una serie de sugerencias para ser utilizadas en la atención médica.

Abstract The Argentine Osteoporosis Society convened renowned specialists in the care of transgender people to prepare the first local position on the evaluation of bone health in this population. Law 26.743 on "Gender Identity" recognize all identities and guarantees free care throughout the health system. The impact of different gender affirmation treatments on bone mass has been topic of international debate. To date the evidence remains limited and different societies have issued suggestions and recommendations. For this reason, we believe it is relevant to mention our experience, capturing through this document a series of suggestions to be used in medical care.

Development and characterization of a poloxamer hydrogel composed of human mesenchymal stromal cells (hMSCs) for reepithelization of skin injuries.

Wound healing is a natural physiological reaction to tissue injury. Hydrogels show attractive advantages in wound healing not only due to their biodegradability, biocompatibility and permeability but also because provide an excellent environment for cell migration and proliferation. The main objective of the present study was the design and characterization of a hydrogel loaded with human mesenchymal stromal cells (hMSCs) for use in would healing of superficial skin injures. Poloxamer 407® was used as biocompatible biomaterial to embed hMSCs. The developed hydrogel containing 20 % (w/w) of polymer resulted in the best formulation with respect to physical, mechanical, morphological and biological properties. Its high swelling capacity confirmed the hydrogel's capacity to absorb wounds' exudate. LIVE/DEAD® assay confirm that hMSCs remained viable for at least 48 h when loaded into the hydrogels. Adding increasing concentrations of hMSCs-loaded hydrogel to the epithelium did not affect keratinocytes' viability and healing capacity and all wound area was closed in less than one day. Our study opens opportunities to exploit poloxamer hydrogels as cell carriers for the treatment of skin superficial wound.

The human discs large protein 1 interacts with and maintains connexin 43 at the plasma membrane in keratinocytes.

Gap junction channels, composed of connexins, allow direct cell-to-cell communication. Connexin 43 (Cx43; also known as GJA1) is widely expressed in tissues, including the epidermis. In a previous study of human papillomavirus-positive cervical epithelial tumour cells, we identified Cx43 as a binding partner of the human homologue of Drosophila Discs large (Dlg1; also known as SAP97). Dlg1 is a member of the membrane associated-guanylate kinase (MAGUK) scaffolding protein family, which is known to control cell shape and polarity. Here, we show that Cx43 also interacts with Dlg1 in uninfected keratinocytes in vitro and in keratinocytes, dermal cells and adipocytes in normal human epidermis in vivo. Depletion of Dlg1 in keratinocytes did not alter Cx43 transcription but was associated with a reduction in Cx43 protein levels. Reduced Dlg1 levels in keratinocytes resulted in a reduction in Cx43 at the plasma membrane with a concomitant reduction in gap junctional intercellular communication and relocation of Cx43 to the Golgi compartment. Our data suggest a key role for Dlg1 in maintaining Cx43 at the plasma membrane in keratinocytes.

Preservation of critical quality attributes of mesenchymal stromal cells in 3D bioprinted structures by using natural hydrogel scaffolds.

Three dimensional (3D) bioprinting is an emerging technology that enables complex spatial modeling of cell-based tissue engineering products, whose therapeutic potential in regenerative medicine is enormous. However, its success largely depends on the definition of a bioprintable zone, which is specific for each combination of cell-loaded hydrogels (or bioinks) and scaffolds, matching the mechanical and biological characteristics of the target tissue to be repaired. Therefore proper adjustment of the bioink formulation requires a compromise between: (i) the maintenance of cellular critical quality attributes (CQA) within a defined range of specifications to cell component, and (ii) the mechanical characteristics of the printed tissue to biofabricate. Herein, we investigated the advantages of using natural hydrogel-based bioinks to preserve the most relevant CQA in bone tissue regeneration applications, particularly focusing on cell viability and osteogenic potential of multipotent mesenchymal stromal cells (MSCs) displaying tripotency in vitro, and a phenotypic profile of 99.9% CD105+ /CD45,- 10.3% HLA-DR,+ 100.0% CD90,+ and 99.2% CD73+ /CD31- expression. Remarkably, hyaluronic acid, fibrin, and gelatin allowed for optimal recovery of viable cells, while preserving MSC's proliferation capacity and osteogenic potency in vitro. This was achieved by providing a 3D structure with a compression module below 8.8 ± 0.5 kPa, given that higher values resulted in cell loss by mechanical stress. Beyond the biocompatibility of naturally occurring polymers, our results highlight the enhanced protection on CQA exerted by bioinks of natural origin (preferably HA, gelatin, and fibrin) on MSC, bone marrow during the 3D bioprinting process, reducing shear stress and offering structural support for proliferation and osteogenic differentiation.

Cable and Mirror Sutures and the Nasal Septum Sublaminar Dissection.

Managing the nasal septum (NS) position is crucial in septorhinoplasty. The analysis and the preparation of the anterior nasal spine and the quadrangular cartilage as well as the strategy defined to efficiently stabilize the septum will dictate considerably the success of the result. Moreover, what we see in the surgical table can suffer modifications during the healing process because of poor fixation or the cheese-wire effect of the cartilage. We will present a logical sequence and tools to achieve a proper and stable position of the NS and the nasal pyramid. The sublaminar (supraperichondral) dissection of the quadrangular cartilage as an option to the subperichondral one and the use of cable and mirror sutures to three-dimensionally positioning and stabilizing the NS will be described.

Biofabrication approaches and regulatory framework of metastatic tumor-on-a-chip models for precision oncology.

The complexity of the tumor microenvironment (TME) together with the development of the metastatic process are the main reasons for the failure of conventional anticancer treatment. In recent years, there is an increasing need to advance toward advanced in vitro models of cancer mimicking TME and simulating metastasis to understand the associated mechanisms that are still unknown, and to be able to develop personalized therapy. In this review, the commonly used alternatives and latest advances in biofabrication of tumor-on-chips, which allow the generation of the most sophisticated and optimized models for recapitulating the tumor process, are presented. In addition, the advances that have allowed these new models in the area of metastasis, cancer stem cells, and angiogenesis are summarized, as well as the recent integration of multiorgan-on-a-chip systems to recapitulate natural metastasis and pharmacological screening against it. We also analyze, for the first time in the literature, the normative and regulatory framework in which these models could potentially be found, as well as the requirements and processes that must be fulfilled to be commercially implemented as in vitro study model. Moreover, we are focused on the possible regulatory pathways for their clinical application in precision medicine and decision making through the generation of personalized models with patient samples. In conclusion, this review highlights the synergistic combination of three-dimensional bioprinting systems with the novel tumor/metastasis/multiorgan-on-a-chip systems to generate models for both basic research and clinical applications to have devices useful for personalized oncology.

Transmembrane stem cell factor protein therapeutics enhance revascularization in ischemia without mast cell activation.

Stem cell factor (SCF) is a cytokine that regulates hematopoiesis and other biological processes. While clinical treatments using SCF would be highly beneficial, these have been limited by toxicity related to mast cell activation. Transmembrane SCF (tmSCF) has differential activity from soluble SCF and has not been explored as a therapeutic agent. We created novel therapeutics using tmSCF embedded in proteoliposomes or lipid nanodiscs. Mouse models of anaphylaxis and ischemia revealed the tmSCF-based therapies did not activate mast cells and improved the revascularization in the ischemic hind limb. Proteoliposomal tmSCF preferentially acted on endothelial cells to induce angiogenesis while tmSCF nanodiscs had greater activity in inducing stem cell mobilization and recruitment to the site of injury. The type of lipid nanocarrier used altered the relative cellular uptake pathways and signaling in a cell type dependent manner. Overall, we found that tmSCF-based therapies can provide therapeutic benefits without off target effects.

Combining familial hypercholesterolemia and statin genetic studies as a strategy for the implementation of pharmacogenomics. A multidisciplinary approach.

The diagnostic process of familial hypercholesterolemia frequently involves the use of genetic studies. Patients are treated with lipid-lowering drugs, frequently statins. Although pharmacogenomic clinical practice guidelines focusing on genotype-based statin prescription have been published, their use in routine clinical practice remains very modest.We have implemented a new NGS strategy that combines a panel of genes related to familial hypercholesterolemia with genomic regions related to the pharmacogenomics of lipid-lowering drugs described in clinical practice guidelines and in EMA and FDA drug labels. A multidisciplinary team of doctors, biologists, and pharmacists creates a clinical report that provides diagnostic and therapeutic findings using a knowledge management and clinical decision support system, as well as an algorithm for treatment selection.For 12 months, a total of 483 genetic diagnostic studies for familial hypercholesterolemia were carried out, of which 221 (45.8%) requested a complementary pharmacogenomic test. Of these 221 patients, 66.5% were carriers of actionable variants in any of the studied pharmacogenomic pathways: 46.6% of patients in one pathway, 19.0% in two pathways, and 0.9% in three pathways. 45.7% of patients could have a response to atorvastatin different from that of the reference population, 45.7% for simvastatin and lovastatin, 29.0% for fluvastatin, and 6.7% patients for pitavastatin.This implementation approach facilitates the incorporation of pharmacogenomic studies in clinical care practice, it does not add complexity nor additional steps to laboratory processes, and improves the pharmacotherapeutic process of patients.

Necrotic debris and STING exert therapeutically relevant effects on tumor cholesterol homeostasis.

Malignant tumors commonly display necrosis, which invariably triggers an inflammatory response that supports tumor growth. However, the effect on tumor cells of necrotic debris, or damage-associated molecular patterns (DAMPs) released by dying cells is unknown. Here, we addressed the effect of DAMPs on primary Ewing sarcoma (EwS) cells and cell lines grown in 3D (spheroids) and 2D culture. We show that DAMPs promote the growth of EwS spheroids but not 2D cultures and that the underlying mechanism implicates an increase in cholesterol load in spheroids. In contrast, stimulation of the nucleic acid sensor signaling platform STING by its ligand cyclic GMP-AMP decreases the tumor cell cholesterol load and reduces their tumor initiating ability. Overexpression of STING or stimulation with cyclic GMP-AMP opposes the growth stimulatory effect of DAMPs and synergizes with the cholesterol synthesis inhibitor simvastatin to inhibit tumor growth. Our observations show that modulation of cholesterol homeostasis is a major effect of necrotic cell debris and STING and suggest that combining STING agonists with statins may help control tumor growth.

Neurological complications induced by immune checkpoint inhibitors: a comprehensive descriptive case-series unravelling high risk of long-term sequelae.

Neurological immune-related adverse events are complications of programmed-cell death 1 or programmed-cell death 1 ligand immunotherapies that can be life threatening and often lead to anticancer immunotherapy withdrawal. Scant clinical data are available that integrate the clinical presentation, therapeutic management and long-term outcome. All consecutive adult patients treated by programmed-cell death 1 or programmed-cell death 1 ligand immunotherapies, given alone or in combination with other treatment, who experienced a neurological immune-related adverse event with a severity grade ≥2 in Paris Saclay-University hospitals were investigated from June 2014 to February 2019. The frequency of neurological immune-related adverse events was calculated from the prospective Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie cohort. Forty patients presenting with 51 distinct neurological immune-related adverse events were included. The prevalence of grade ≥2 neurological immune-related adverse events was estimated to be 1.22% in the Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie cohort. Among 40 patients with neurological immune-related adverse events, 65% received programmed-cell death 1 or programmed-cell death 1 ligand monotherapy and 35% received a combination of programmed-cell death 1 plus anti-CTLA4 (Common Terminology Criteria for Adverse Events). Clinical neurological presentations were peripheral (48%), central (35%), or mixed (18%). The severity of neurological immune-related adverse events was grade 2 for 14 (35%) and ≥grade 3 for 26 patients (65%). The mortality rate related to neurological immune-related adverse events was 8%. Corticosteroid treatment led to neurological recovery in 74%. Long-term follow-up highlighted that 53% of patients experienced long-term neurological sequelae. Five patients were rechallenged by programmed-cell death 1 monotherapy without recurrence of their neurological immune-related adverse event(s). Neurological immune-related adverse events induced by programmed-cell death 1 or programmed-cell death 1 ligand are rare but are severe with a mortality rate of 8% and long-term sequelae for 53% of patients. Corticosteroids should be started when neurological immunological complications are identified to avoid long-term sequelae.

The determinants of very severe immune-related adverse events associated with immune checkpoint inhibitors: A prospective study of the French REISAMIC registry.

BACKGROUND: Immune-related adverse events (irAEs) remain generally unpredictable, and severe irAEs remain challenging to detect early and manage. Very severe (grade IV-V) irAEs have not been extensively characterised in prospective studies, and their predictive factors remain unknown. OBJECTIVE: The objective of the study was to describe and identify predictive factors of very severe (grade IV-V) irAEs. DESIGN: The French Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC) registry has prospectively collected all clinically significant irAEs occurring in patients treated with immune checkpoint inhibitors at Gustave Roussy Institute since 2014. SETTING: This was a single-centre prospective cohort study at the Gustave Roussy Institute cancer centre (Villejuif, France). PARTICIPANTS: The participants were all adult patients with a solid or haematological cancer treated with an anti-programmed cell death 1 (PD-1) or an anti-programmed cell death-ligand 1 (PD-L1) and who presented a clinically significant irAE. MAIN OUTCOMES AND MEASURES: The main outcomes included the clinical and laboratory characteristics of patients with very severe irAEs, including tumour type, affected organs, time to irAE occurrence, blood cell count and serum biochemistry parameters. RESULTS: Of the 1187 patients prospectively followed in REISAMIC between December 2014 and January 2020, 380 (32.0%) had at least one irAE, and 34 (2.86%) presented with very severe irAEs (grades IV-V). Among the 380 patients with an irAE, the distribution of very severe irAEs (grades IV-V) was 8.95% and death (grade V) was 3.95%. Among the 34 patients with very severe irAEs, 33 were treated with monotherapy of PD-1 or PD-L1 inhibitors, and one patient was treated with a combination of PD-1 and cytotoxic T-lymphocyte-associated protein 4 inhibitors. The median time to occurrence was shorter for very severe irAEs (median [interquartile range]: 41 days [0-634] for grades IV-V; versus 91 days [0-1123] for grades I-III; p = 0.01680). On initiation of immunotherapy, the predictive factors for very severe irAEs were performance status ≥2, elevated neutrophil/lymphocyte ratio and treatment for lung cancer. CONCLUSIONS: Very severe (grade IV-V) immunological toxicities occurred earlier than mild severe toxicities. On initiation of immunotherapy, patients with poor performance status, elevated neutrophil/lymphocyte ratio and lung cancer are identified at risk of developing these very severe toxicities. These results could help to develop risk scores to identify patients at risk of developing severe toxicities.

Duchenne muscular dystrophy cell culture models created by CRISPR/Cas9 gene editing and their application in drug screening.

Gene editing methods are an attractive therapeutic option for Duchenne muscular dystrophy, and they have an immediate application in the generation of research models. To generate myoblast cultures that could be useful in in vitro drug screening, we have optimised a CRISPR/Cas9 gene edition protocol. We have successfully used it in wild type immortalised myoblasts to delete exon 52 of the dystrophin gene, modelling a common Duchenne muscular dystrophy mutation; and in patient's immortalised cultures we have deleted an inhibitory microRNA target region of the utrophin UTR, leading to utrophin upregulation. We have characterised these cultures by demonstrating, respectively, inhibition of dystrophin expression and overexpression of utrophin, and evaluating the expression of myogenic factors (Myf5 and MyH3) and components of the dystrophin associated glycoprotein complex (α-sarcoglycan and ß-dystroglycan). To demonstrate their use in the assessment of DMD treatments, we have performed exon skipping on the DMDΔ52-Model and have used the unedited DMD cultures/ DMD-UTRN-Model combo to assess utrophin overexpression after drug treatment. While the practical use of DMDΔ52-Model is limited to the validation to our gene editing protocol, DMD-UTRN-Model presents a possible therapeutic gene edition target as well as a useful positive control in the screening of utrophin overexpression drugs.

Outcomes of patients with cancer and sarcoid-like granulomatosis associated with immune checkpoint inhibitors: A case-control study.

PURPOSE: Sarcoid-like granulomatosis (SLG) reaction caused by immunotherapy remains poorly understood. This study aims to investigate the outcome of patients with cancer and SLG associated with immunotherapy. PATIENTS AND METHODS: Between April 2016 and June 2020, 434 patients with immunological adverse events were screened from the ImmunoTOX assessment board of Gustave Roussy, an academic cancer centre in France. Among them, 28 patients had SLG associated with immunotherapy (SLG cohort) and 406 patients had other immunological adverse events (control cohort). Clinical characteristics and outcome of patients were compared from SLG and control cohort. RESULTS: The SLG cohort consisted of 28 patients, 14 women and 14 men, with the median (range) age of 56.5 (28.7-75.3) years. Patients in the SLG cohort with sarcoidosis were asymptomatic (only radiographical finding) in 13 (46.4%) cases; otherwise, the most frequent symptoms were dyspnoea in 8 (28.6%) patients and cough in 5 (17.8%) patients. The computerised tomography scan found sarcoidosis localisations in mediastinal or peri-hilar thoracic lymph nodes in 26 (92.9%) patients, and lung parenchymal involvement was found in 14 (50.0%) patients. The radiographic Scadding stages for sarcoidosis classification were distributed in stages 0, I, II, III and IV in 2 patients (7.1%), 13 patients (46.4%), 11 patients (39.3%), 1 patient (3.6%) and 1 patient (3.6%), respectively. Compared with patients with other immunological toxicities (cohort control), patients with sarcoidosis presented most frequently with melanoma (75.0% versus 21.9% of patients; p < 0.001) and more often received combined therapies of anti-programmed cell death 1 plus anti-cytotoxic T-lymphocyte antigen 4 protein (46.4% versus 12.6% of patients; p = 0.002). Patients with sarcoidosis had an improved overall survival (OS); the median OS was not reached in the SLG cohort and 40.4 months in the control cohort, hazard ratio = 0.232 (95% confidence interval: 0.086-0.630) (p = 0.002). CONCLUSION: Sarcoidosis-like reactions in patients receiving immunotherapy were reported as non-severe immunological reactions in most cases and were correlated with improved OS. SLG should not be misdiagnosed as tumour progression in patients receiving immunotherapy treatment for cancer.

Afectación respiratoria en paciente con acrodisostosis: una asociación infrecuente de una enfermedad rara / Respiratory impairment in a patient with acrodysostosis: A rare association of an uncommon pathology

La acrodisostosis es una displasia esquelética rara, de herencia autosómica dominante, que se caracteriza por la presencia de disostosis facial y periférica, talla baja y diferentes grados de obesidad. La acrodisostosis de tipo 1, secundaria a la mutación heterocigota en el gen PRKAR1A (17q24.2), se caracteriza por la asociación de resistencia hormonal múltiple con anomalías esqueléticas. Su incidencia está infradiagnosticada debido a que comparte rasgos clínicos y de laboratorio con otras entidades como el seudohipoparatiroidismo. Presentamos el caso de una niña de 8 años, con acrodisostosis tipo 1, confirmada mediante estudio genético. Además del fenotipo característico descrito, la talla baja y la resistencia hormonal, la paciente presentó una afectación progresiva de la función pulmonar: un patrón pulmonar obstructivo no reversible. En la literatura revisada, no se han encontrado otros casos que describan esta asociación entre acrodisostosis y afectación respiratoria.

Acrodysostosis is a rare skeletal displasia, of autosomal dominant inheritance, characterized by the presence of facial and peripheral dysostosis, short stature and obesity. Type 1 acrodysostosis is secondary to a mutation in the PRKAR1A (17q24.2) gene, which results in multi hormonal resistance and skeletal anomalities. This syndrome is under-diagnosed as it shares analytical and clinical characteristics with other entities, such as pseudohypoparathyroidism. We report the case of an eight-year-old girl with genetically confirmed type 1 acrodysostosis. In addition to the characteristic phenotype described, the short stature and the hormonal resistance, the patient suffered a progressive lung function deterioration: an irreversible pulmonary obstructive pattern. We have not found in previous literature cases reporting an association between acrodysostosis and lung function impairement.

Classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OHD) in adult males: Clinical presentation, hormone function and the detection of adrenal and testicular adrenal rest tumors (TARTs).

INTRODUCTION: 21-hydroxylase deficiency (21-OHD) is the most common form of congenital adrenal hyperplasia (CAH). In adulthood, most studies are reported in females. By contrast, data on adult males are scarce. OBJECTIVE: To describe a series of adult males with classic 21-OHD and to assess the presence of adrenal masses and testicular adrenal rest tumors (TARTs). MATERIAL AND METHODS: Eight males (21-42 years) were included. We evaluated clinical presentation, 17-Hydroxyprogesterone (17-OHP), Testosterone (T), Δ4Androstenedione (Δ4A) ACTH, LH, FSH and plasma renin activitiy (PRA) levels at consultation. Molecular studies of the CYP21A2 gene, testicular ultrasound (US), semen analysis and adrenal computed tomography (CT) scan were performed. Treatment and compliance were assessed. RESULTS: Basal 17-OHP levels were >20ng/ml in all patients. At consultation, median 17OH-P was 11.5 (2.3-81) ng/ml, FSH: 3 (0.3-4) mUI/ml, LH: 1.1 (0.1-6) mUI/ml, T: 4.3 (1.7-8) ng/ml, Δ4A: 5.7 (1.4-16) ng/ml, ACTH: 86.4 (76-334) pg/ml, PRA: 9.5 (1.3-23.6) ng/ml/h. Semen analysis was performed in 5/8 patients, showing azoospermia in two. Molecular genetic analysis was performed in 4/8 patients. TARTs were found in 5/6, being bilateral in four. Adrenal masses were found in 4/6. In the 7 patients diagnosed in childhood, their follow-up was referred to as irregular, both in their attendance at consultations and in compliance with the indicated treatment. CONCLUSIONS: To our knowledge, this is the first series on adult males with classic 21-OHD which concomitantly assesses clinical presentation, molecular biology, adrenal and testicular imaging studies, semen analysis and compliance to treatment. A high prevalence of adrenal masses and TARTs was observed, possibly associated with poor treatment compliance leading to elevated ACTH and increased proliferation. Our findings on TARTs agree with reports in international publications of CAH in males, with adrenal imaging being added in our group. Although we are aware that further studies with a larger sample size and more data are needed, we consider that our findings contribute to the clinical management of classical 21-OHD in the male population.

A live single-cell reporter assay links intratumor heterogeneity to metastatic proclivity in Ewing sarcoma.

Targeting of the most aggressive tumor cell subpopulations is key for effective management of most solid malignancies. However, the metastable nature of tumor heterogeneity, which allows cells to transition between strong and weak tumorigenic phenotypes, and the lack of reliable markers of tumor-promoting properties hamper identification of the most relevant cells. To overcome these obstacles, we designed a functional microRNA (miR)-based live-cell reporter assay to identify highly tumorigenic cells in xenotransplants of primary Ewing sarcoma (EwS) 3D cultures. Leveraging the inverse relationship between cell pluripotency and miR-145 expression, we successfully separated highly tumorigenic, metastasis-prone (miR-145low) cells from poorly tumorigenic, nonmetastatic (miR-145high) counterparts. Gene expression and functional studies of the two cell populations identified the EPHB2 receptor as a prognostic biomarker in patients with EwS and a major promoter of metastasis. Our study provides a simple and powerful means to identify and isolate tumor cells that display aggressive behavior.

[Respiratory impairment in a patient with acrodysostosis: A rare association of an uncommon pathology]. / Afectación respiratoria en paciente con acrodisostosis: una asociación infrecuente de una enfermedad rara.

Acrodysostosis is a rare skeletal displasia, of autosomal dominant inheritance, characterized by the presence of facial and peripheral dysostosis, short stature and obesity. Type 1 acrodysostosis is secondary to a mutation in the PRKAR1A (17q24.2) gene, which results in multi hormonal resistance and skeletal anomalities. This syndrome is under-diagnosed as it shares analytical and clinical characteristics with other entities, such as pseudohypoparathyroidism. We report the case of an eight-year-old girl with genetically confirmed type 1 acrodysostosis. In addition to the characteristic phenotype described, the short stature and the hormonal resistance, the Afectación respiratoria en paciente con acrodisostosis: una asociación infrecuente de una enfermedad rara Respiratory impairment in a patient with acrodysostosis: A rare association of an uncommon pathology patient suffered a progressive lung function deterioration: an irreversible pulmonary obstructive pattern. We have not found in previous literature cases reporting an association between acrodysostosis and lung function impairement.

La acrodisostosis es una displasia esquelética rara, de herencia autosómica dominante, que se caracteriza por la presencia de disostosis facial y periférica, talla baja y diferentes grados de obesidad. La acrodisostosis de tipo 1, secundaria a la mutación heterocigota en el gen PRKAR1A (17q24.2), se caracteriza por la asociación de resistencia hormonal múltiple con anomalías esqueléticas. Su incidencia está infradiagnosticada debido a que comparte rasgos clínicos y de laboratorio con otras entidades como el seudohipoparatiroidismo. Presentamos el caso de una niña de 8 años, con acrodisostosis tipo 1, confirmada mediante estudio genético. Además del fenotipo característico descrito, la talla baja y la resistencia hormonal, la paciente presentó una afectación progresiva de la función pulmonar: un patrón pulmonar obstructivo no reversible. En la literatura revisada, no se han encontrado otros casos que describan esta asociación entre acrodisostosis y afectación respiratoria.

Dysregulation of Connexin Expression Plays a Pivotal Role in Psoriasis.

BACKGROUND: Psoriasis, a chronic inflammatory disease affecting 2-3% of the population, is characterised by epidermal hyperplasia, a sustained pro-inflammatory immune response and is primarily a T-cell driven disease. Previous work determined that Connexin26 is upregulated in psoriatic tissue. This study extends these findings. METHODS: Biopsies spanning psoriatic plaque (PP) and non-involved tissue (PN) were compared to normal controls (NN). RNA was isolated and subject to real-time PCR to determine gene expression profiles, including GJB2/CX26, GJB6/CX30 and GJA1/CX43. Protein expression was assessed by immunohistochemistry. Keratinocytes and fibroblasts were isolated and used in 3D organotypic models. The pro-inflammatory status of fibroblasts and 3D cultures was assessed via ELISA and RnD cytokine arrays in the presence or absence of the connexin channel blocker Gap27. RESULTS: Connexin26 expression is dramatically enhanced at both transcriptional and translational level in PP and PN tissue compared to NN (>100x). In contrast, CX43 gene expression is not affected, but the protein is post-translationally modified and accumulates in psoriatic tissue. Fibroblasts isolated from psoriatic patients had a higher inflammatory index than normal fibroblasts and drove normal keratinocytes to adopt a "psoriatic phenotype" in a 3D-organotypic model. Exposure of normal fibroblasts to the pro-inflammatory mediator peptidoglycan, isolated from Staphylococcus aureus enhanced cytokine release, an event protected by Gap27. CONCLUSION: dysregulation of the connexin26:43 expression profile in psoriatic tissue contributes to an imbalance of cellular events. Inhibition of connexin signalling reduces pro-inflammatory events and may hold therapeutic benefit.