Ligand-dependent Hedgehog pathway activation in Rhabdomyosarcoma: the oncogenic role of the ligands.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children. The Hedgehog (HH) pathway is known to develop an oncogenic role in RMS. However, the molecular mechanism that drives activation of the pathway in RMS is not well understood. METHODS: The expression of HH ligands was studied by qPCR, western blot and immunohistochemistry. Functional and animal model studies were carried out with cells transduced with shRNAs against HH ligands or treated with HH-specific inhibitors (Vismodegib and MEDI-5304). Finally, the molecular characterisation of an off-target effect of Vismodegib was also made. RESULTS: The results showed a prominent expression of HH ligands supporting an autocrine ligand-dependent activation of the pathway. A comparison of pharmacologic Smoothened inhibition (Vismodegib) and HH ligand blocking (MEDI-5304) is also provided. Interestingly, a first description of pernicious off-target effect of Vismodegib is also reported. CONCLUSIONS: The clarification of the HH pathway activation mechanism in RMS opens a door for targeted therapies against HH ligands as a possible alternative in the future development of better treatment protocols. Moreover, the description of a pernicious off-target effect of Vismodegib, via unfolded protein response activation, may mechanistically explain its previously reported inefficiency in several ligand-dependent cancers.

A skincare combined with combination of adapalene and benzoyl peroxide provides a significant adjunctive efficacy and local tolerance benefit in adult women with mild acne.

INTRODUCTION: Acne in adult women is an increasing reason for dermatological consultations. OBJECTIVE: The aim of this study was to assess in adult women with mild acne the efficacy and tolerance of a daily adjunctive application of a skincare (Normaderm® , Laboratoires Vichy, France) to a fixed combination of adapalene/benzoyl peroxide daily or every other evening and a standard emollient. METHODS: Subjects were randomized to receive the fixed combination applied either every evening or every other evening and a daily application of the standard emollient and the test care or a once daily application of the fixed combination and the standard emollient alone. Clinical evaluations at Day 0, Day 45 and Day 90 included the count of acne lesions, assessment of clinical improvement and local tolerance. The quantitative lipid profile of the stratum corneum of the forehead was also determined. RESULTS: After 90 days of application, acne had improved in all 299 subjects with a statistically significant difference in favour of the test care regimens (P < 0.05). Moreover, skin quality, subject satisfaction, skin discomfort and sebum composition were in favour of these regimens. CONCLUSION: In conclusion, the tested skincare combined with a fixed adapalene and benzoyl peroxide combination provides a significant adjunctive efficacy and local tolerance benefit in adult women with mild acne.

Patient-derived xenografts for childhood solid tumors: a valuable tool to test new drugs and personalize treatments

The use of preclinical models is essential in translational cancer research and especially important in pediatric cancer given the low incidence of each particular type of cancer. Cell line cultures have led to significant advances in cancer biology. However, cell lines have adapted to growth in artificial culture conditions, thereby undergoing genetic and phenotypic changes which may hinder the translational application. Tumor grafts developed in mice from patient tumor tissues, generally known as patient-derived xenografts (PDXs), are interesting alternative approaches to reproducing the biology of the original tumor. This review is focused on highlighting the interest of PDX models in pediatric cancer research and supporting strategies of personalized medicine. This review provides: (1) a description of the background of PDX in cancer, (2) the particular case of PDX in pediatric cancer, (3) how PDX can improve personalized medicine strategies, (4) new methods to increase engraftment, and, finally, (5) concluding remarks (AU)

No disponible

Patient-derived xenografts for childhood solid tumors: a valuable tool to test new drugs and personalize treatments.

The use of preclinical models is essential in translational cancer research and especially important in pediatric cancer given the low incidence of each particular type of cancer. Cell line cultures have led to significant advances in cancer biology. However, cell lines have adapted to growth in artificial culture conditions, thereby undergoing genetic and phenotypic changes which may hinder the translational application. Tumor grafts developed in mice from patient tumor tissues, generally known as patient-derived xenografts (PDXs), are interesting alternative approaches to reproducing the biology of the original tumor. This review is focused on highlighting the interest of PDX models in pediatric cancer research and supporting strategies of personalized medicine. This review provides: (1) a description of the background of PDX in cancer, (2) the particular case of PDX in pediatric cancer, (3) how PDX can improve personalized medicine strategies, (4) new methods to increase engraftment, and, finally, (5) concluding remarks.

Evolución clínica de la cirugía descompresiva en el tratamiento del canal lumbar estrecho degenerativo / Clinical results of decompressive surgery in degenerative lumbar spinal stenosis

Resumen: Antecedentes: Diversos autores y publicaciones se han enfocado en comparar la evolución clínica de la cirugía descompresiva de las raíces, ya sea con o sin fusión, para el tratamiento del canal lumbar estrecho degenerativo. Sin embargo, no existen muchos reportes que analicen la evolución clínica tras la cirugía descompresiva de una sola raíz nerviosa (la más sintomática) contra la descompresión de todas las raíces de un segmento. El presente estudio pretende comparar la evolución clínica de la liberación radicular lumbar de la raíz más sintomática con respecto a la liberación de múltiples raíces lumbares para el alivio del dolor neuropático en el canal lumbar estrecho degenerativo. Material y métodos: Se realizó un estudio prospectivo observacional, descriptivo, longitudinal con 38 pacientes divididos en dos grupos de 19 casos a quienes se les practicó recalibraje de una sola raíz o de múltiples raíces de un segmento; se obtuvieron porcentajes, t de Student y coeficiente de correlación de Pearson. Resultados: En el grupo A, se evidenció una disminución de 46.63 puntos en la escala de Oswestry, lo que traduce una mejoría del dolor de 66.73%. En el grupo B, en cambio, se observó una disminución promedio de 34.54 puntos en la escala de Oswestry, equivalente al 47.23%, con una t de Student donde p = 0.11 y el coeficiente de correlación de Pearson, 0.08. Conclusiones: No se encontraron diferencias estadísticamente significativas entre ambos grupos de estudio.

Abstract: Background: Several authors and publications have focused on comparing the clinical course of nerve root decompressive surgery, with or without fusion, to treat degenerative lumbar stenosis. However, there are not many reports analyzing the clinical course after decompressive surgery of a single nerve root (the most symptomatic one) comparing it with decompression of all the roots in a segment. This study intends to compare the clinical course after decompressing the most symptomatic lumbar nerve root with the release of multiple lumbar nerve roots to relieve neuropathic pain resulting from degenerative lumbar stenosis. Material and methods: A prospective, observational, descriptive longitudinal study was performed. A total of 38 patients were divided into two groups that included each 19 cases. Patients underwent recalibration of either a single nerve root or multiple nerve roots of a segment. Percentages were calculated as well as the Student t test and the Pearson correlation. Results: In group A, a decrease of 46.63 points was seen in the Oswestry scale, representing a 66.73% improvement in pain. In group B, in turn, a mean decrease of 34.54 points was seen in the Oswestry scale, equivalent to a 47.23% improvement in pain, with a Student t in which p = 0.11 and a Pearson correlation coefficient of 0.08. Conclusions: No statistically significant differences were found between both study groups.

BRG1/SMARCA4 is essential for neuroblastoma cell viability through modulation of cell death and survival pathways.

Neuroblastoma (NB) is a neoplasm of the sympathetic nervous system, and is the most common solid tumor of infancy. NBs are very heterogeneous, with a clinical course ranging from spontaneous regression to resistance to all current forms of treatment. High-risk patients need intense chemotherapy, and only 30-40% will be cured. Relapsed or metastatic tumors acquire multi-drug resistance, raising the need for alternative treatments. Owing to the diverse mechanisms that are responsible of NB chemoresistance, we aimed to target epigenetic factors that control multiple pathways to bypass therapy resistance. We found that the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4/BRG1) was consistently upregulated in advanced stages of NB, with high BRG1 levels being indicative of poor outcome. Loss-of-function experiments in vitro and in vivo showed that BRG1 is essential for the proliferation of NB cells. Furthermore, whole-genome transcriptome analysis revealed that BRG1 controls the expression of key elements of oncogenic pathways such as PI3K/AKT and BCL2, which offers a promising new combination therapy for high-risk NB.

[Clinical course of decompressive surgery for the treatment of lumbar stenosis]. / Evolución clínica de la cirugía descompresiva en el tratamiento del canal lumbar estrecho degenerativo.

BACKGROUND: Several authors and publications have focused on comparing the clinical course of nerve root decompressive surgery, with or without fusion, to treat degenerative lumbar stenosis. However, there are not many reports analyzing the clinical course after decompressive surgery of a single nerve root (the most symptomatic one) comparing it with decompression of all the roots in a segment. This study intends to compare the clinical course after decompressing the most symptomatic lumbar nerve root with the release of multiple lumbar nerve roots to relieve neuropathic pain resulting from degenerative lumbar stenosis. MATERIAL AND METHODS: A prospective, observational, descriptive longitudinal study was performed. A total of 38 patients were divided into two groups that included each 19 cases. Patients underwent recalibration of either a single nerve root or multiple nerve roots of a segment. Percentages were calculated as well as the Student t test and the Pearson correlation. RESULTS: In group A, a decrease of 46.63 points was seen in the Oswestry scale, representing a 66.73% improvement in pain. In group B, in turn, a mean decrease of 34.54 points was seen in the Oswestry scale, equivalent to a 47.23% improvement in pain, with a Student t in which p = 0.11 and a Pearson correlation coefficient of 0.08. CONCLUSIONS: No statistically significant differences were found between both study groups.

Diversos autores y publicaciones se han enfocado en comparar la evolución clínica de la cirugía descompresiva de las raíces, ya sea con o sin fusión, para el tratamiento del canal lumbar estrecho degenerativo. Sin embargo, no existen muchos reportes que analicen la evolución clínica tras la cirugía descompresiva de una sola raíz nerviosa (la más sintomática) contra la descompresión de todas las raíces de un segmento. El presente estudio pretende comparar la evolución clínica de la liberación radicular lumbar de la raíz más sintomática con respecto a la liberación de múltiples raíces lumbares para el alivio del dolor neuropático en el canal lumbar estrecho degenerativo.

Biliary Lithiasis with Choledocolithiasis in Children.

Although biliary lithiasis has been considered a less common pathology in the pediatric population than in adults, in recent years, it has increasingly been diagnosed in children, with a prevalence of between 0.13 to 0.22. The elective treatment of symptomatic biliary lithiasis is cholecystectomy, the laparoscopic approach being considered the œgold standard. We present 3 cases referred to our clinic with biliary lithiasis, in which we performed laparoscopic cholecystectomy. We performed intraoperative cholangiography with a 4 Fr transcystic catheter. In the first case, the cholangiography showed a dilated CBD, without obstruction. Considering the patient'™s history, with recurrent episodes of choledocal lithiasis, we decided to perform a transcystic drainage. In the second case, cholangiography showed a normal CBD and no obstruction. In the third case cholangiography could not be performed due to technical issues. In all cases we performed retrograde laparoscopic cholecystectomy. The postoperative evolution in all cases was favorable. Studies conducted in the last years showed that laparoscopic cholecystectomy is a safe and efficient approach in the management of symptomatic biliary lithiasis in the paediatric age group. The management of choledocolithiasis is still not well defined: perioperative ERCP with ES, intraoperative cholangiography or intraoperative ultrasound were proposed as options in exploring the biliary tree.

Left congenital diaphragmatic hernia -- case report.

Congenital diaphragmatic hernia (CDH) occurs when the abdominal contents protrude into the thoracic cavity through an anatomical defect in the diaphragm. The incidence of CDH is 1 in 2500 births, with left congenital diaphragmatic hernias(LCDH) being more common than right-side hernias (85% to 12%). While many cases are discovered prenatally or during the immediate postnatal period, 5 to 25% of CDH can be late presenting events which are detected by routine examinations,during medical check-ups, because of respiratory or gastrointestinal problems or complications such as gastric volvulus,occlusion, perforation, peritonitis or necrosis. Trans-abdominal or trans-thoracic approach is mandatory in those cases where complications have been identified. The prognosis for late presenting patients with LCDH is usually favorable. We report he case of a 7-year-old girl with recent history of trauma,who was admitted to a local hospital with respiratory distress. In our clinic, LCDH was diagnosed and closure of the defect was performed through an open trans-abdominal approach with favorable outcome.

Difficulties in the diagnostics and treatment of near-total congenital megacolon.

Near total colonic aganglionosis is one of the rarest forms of Hirschsprung's disease and until recent years it has been considered deadly. Establishing a correct diagnosis has proven to be challenging, because while the clinical and radiological features can be useful, they are not pathognomonic. Chronic intestinal obstruction and long-term parenteral nutrition dependency are associated with a high mortality risk for these patients. While there is no current consensus with regards to a superior operative method, the patients benefit from surgical techniques aimed at lengthening the intestine, as well as from intestine transplant. We report the case of a newborn baby girl who was admitted to our clinic for abdominal distension,biliary and fecaloid vomiting. With an initial suspicion of digestive tract malformation, the diagnosis of near total congenital megacolon was established with great difficulty and the infant underwent serial surgeries, ending up with an extended myotomy-myectomy (Ziegler's procedure) as a curative approach, with favorable immediate postoperative evolution.However, the patient developed sepsis and although the infection was treated accordingly, the baby's general condition kept deteriorating and exitus was recorded 77 days after admission.

Associated type IIIB and type IV multiple intestinal atresia in a pediatric patient.

Multiple intestinal atresia (MIA) is a complex congenital defect which represents a challenge for the pediatric surgeon,especially in the rare event of encountering type IIIb or apple peel atresia, which has a high mortality rate. The surgeon's aim is to preserve as much bowel length as possible, to avoid postoperative sepsis and to prevent long-term complications such as short bowel syndrome. Access to a good neonatal intensive care unit and to parenteral nutritional support is crucial in the survival of these children. We report a rare case of multiple intestinal atresia associated with an apple peel atresia, which was managed by multiple intestinal resections and anastomosis without the placement of transanastomotic tubes or stomas.

Anomalies associated with anorectal malformations.

BACKGROUND: The purpose of the paper is to review the incidence of associated congenital anomalies that are encountered in patients presenting anorectal malformations and compare these results with those previously published. MATERIAL AND METHODS: A number of 50 cases with ARM from our institution were reviewed (from 2005 to 2012) and information was collected on patient demographics, type of ARM and associated congenital anomalies, the latter being then categorized according to organ systems. RESULTS: Out of 50 newborns, 28 were males and 22 females (1.27:1). 34 (68%) had at least one associated abnormality. The majority of patients (40%) had imperforated anus without fistula. The most frequent seen anomalies were gastrointestinal (36%), urogenital (24%) and cardiovascular (16%). CONCLUSIONS: More than half of the children included in our series have other associated abnormalities. We found gastrointestinal anomalies to be the most common associated congenital defects in our patients. A higher incidence of this type of anomalies was encountered in newborns with persistent cloacal anomaly. The rectovestibular fistula group was most likely to present cardiac abnormalities. The incidence of genitourinary anomalies in the perineal fistula group is higher than the one described in other studies.

Notch-mediated induction of N-cadherin and α9-integrin confers higher invasive phenotype on rhabdomyosarcoma cells.

BACKGROUND: Rhabdomyosarcoma (RMS) is the commonest type of soft-tissue sarcoma in children. Patients with metastatic RMS continue to have very poor prognosis. Recently, several works have demonstrated a connection between Notch pathway activation and the regulation of cell motility and invasiveness. However, the molecular mechanisms of this possible relationship remain unclear. METHODS: The Notch pathway was manipulated pharmacologically and genetically. The mRNA changes were analysed by quantitative PCR and protein variations by western blot and immunofluorescence. Finally, the capabilities of RMS cells to adhere, heal a wound and invade were assessed in the presence of neuronal cadherin (N-cadherin)- and α9-integrin-blocking antibodies. RESULTS: Cells treated with γ-secretase inhibitor showed lower adhesion capability and downregulation of N-cadherin and α9-integrin. Genetic manipulation of the Notch pathway led to concomitant variations in N-cadherin and α9-integrin. Treatment with anti-N-cadherin-blocking antibody rendered marked inhibition of cell adhesion and motility, while anti-α9-integrin-blocking antibody exerted a remarkable effect on cell adhesion and invasiveness. CONCLUSION: Neuronal cadherin and α9-integrin are postulated as leading actors in the association between the Notch pathway and promotion of cell adhesion, motility and invasion, pointing to these proteins and the Notch pathway itself as interesting putative targets for new molecular therapies against metastases in RMS.

Mechanisms of non-pharmacologic adjunct therapies used during exercise in COPD.

Individuals with chronic obstructive pulmonary disease (COPD) are often limited in their ability to perform exercise due to a heightened sense of dyspnea and/or the occurrence of leg fatigue associated with a reduced ventilatory capacity and peripheral skeletal muscle dysfunction, respectively. Pulmonary rehabilitation programs have been shown to improve exercise tolerance and health related quality of life. Additional therapeutic approaches such as non-invasive ventilatory support (NIVS), heliox (He-O(2)) and supplemental oxygen have been used as non-pharmacologic adjuncts to exercise to enhance the ability of patients with COPD to exercise at a higher exercise-intensity and thus improve the physiological benefits of exercise. The purpose of the current review is to examine the pathophysiology of exercise limitation in COPD and to explore the physiological mechanisms underlying the effect of the adjunct therapies on exercise in patients with COPD. This review indicates that strategies that aim to unload the respiratory muscles and enhance oxygen saturation during exercise alleviate exercise limiting factors and improve exercise performance in patients with COPD. However, available data shows significant variability in the effectiveness across patients. Further research is needed to identify the most appropriate candidates for these forms of therapies.

Translocaciones cromosómicas en los sarcomas de partes blandas: de la biología molecular a la aplicación clínica / Chromosomal translocations in soft tissue sarcomas: from molecular biology to clinical application

Los avances recientes en el campo de la biología molecular de los sarcomas pediátricos, en especial el descubrimiento y caracterización de translocaciones cromosómicas específicas, han sentado las bases para la implantación de nuevas herramientas diagnósticas. En esta revisión se repasan las principales translocaciones asociadas a tumores pediátricos y se resumen sus características moleculares en relación a su capacidad oncogénica, su posible utilidad como herramientas de diagnóstico diferencial así como su posible relación con parámetros clínicos(AU)

Recent advances in the knowledge of the molecular biology of paediatric sarcomas, especially the characterisation of chromosomal translocations associated specifically with particular types of cancer, have established bases for the introduction of new diagnostic tools. This article reviews the main chromosomal translocations associated with paediatric tumours, and summarises their molecular characteristics regarding their oncogenic capabilities, possible usefulness as a differential diagnostic tools and possible correlation with clinical parameters(AU)

[Chromosomal translocations in soft tissue sarcomas: from molecular biology to clinical application]. / Translocaciones cromosómicas en los sarcomas de partes blandas: de la biología molecular a la aplicación clínica.

Recent advances in the knowledge of the molecular biology of paediatric sarcomas, especially the characterisation of chromosomal translocations associated specifically with particular types of cancer, have established bases for the introduction of new diagnostic tools. This article reviews the main chromosomal translocations associated with paediatric tumours, and summarises their molecular characteristics regarding their oncogenic capabilities, possible usefulness as a differential diagnostic tools and possible correlation with clinical parameters.

[Effects of different toxic compounds (Pb, Cu, formol, NH4) on the carp: histologic changes in excretory and hematopoietic organs]. / Effet de différents toxiques (Pb, Cu, formol, NH4) chez la carpe: altérations histologiques des organes excréteurs et hématopoïétiques

Here is a comparative study of the impairments observed on the histological structure of the excretory and hematopoietic organs of carps after acute intoxication (by formol and ammonia) and chronic intoxication (by copper sulfate and lead nitrate). Although all these toxic substances induce the same type of impairments, their degree of seriousness vary. The most affected organs are the gills which present with congestive reactions and partial destruction of respiratory lamellae, and the spleen whose red pulp is usually destroyed. On the other hand, the proliferation of a parasitic fungus was observed on all intoxicated carps. This was understood as a weakening of their body's natural defenses.