Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma.

In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes1-3. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5' splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5' cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.

Gold-catalyzed endo-selective cyclization of alkynylcyclobutanecarboxamides: synthesis of cyclobutane-fused dihydropyridones.

Cyclobutane-fused dihydropyridones can be efficiently synthesized by a completely endo-selective gold-catalyzed cyclization of alkynylcyclobutanes bearing an appended amide, which proceeds under mild conditions. The observed selectivity, which is reversed from that previously observed for the cyclization of related alcohols and acids, is supported by DFT calculations.

[Superficial siderosis of the central nervous system. Report of one case]. / Siderosis idiopática del sistema nervioso central y asociación con atrofia óptica e infarto cerebral. Caso clínico.

Superficial siderosis of the central nervous system is produced by the deposit of hemosiderin within the subpial layers of the central nervous system and central parts of the cranial nerves, leading to progressive degeneration. We report a 55-year-old male who consulted for hearing loss and long-standing progressive decrease in visual acuity, associated with sudden onset of left hemiparesis. A brain CAT scan showed subacute ischemic lesions in the territory of the right posterior cerebral artery (thalamus and right subcortical temporal regions), old ischemic lesions in the right subcortical occipital regions and cerebellar atrophy. A magnetic resonance confirmed the lesions and the presence of superficial diffuse siderosis. A cerebrospinal fluid analysis showed slight xanthochromia, 26 leukocytes/mm3, glucose 51 mg/dL and proteins 1.23 g/L. He was managed with aspirin in low doses and statins. His motor function improved and was discharged two weeks after admission.

Management experience of pediatric meningioma in a Mexican reference center.

OBJECTIVE: Determine the histopathological and clinical characteristics of patients diagnosed with meningiomas and to establish the frequency of these tumors in the pediatric population Mexican. Determine the NF1/2 frequency in meningioma pediatric. METHODS: Samples from the histopathology file were reviewed, and from the complete clinical file the following patient data was reviewed: age, gender, diagnosis, diagnosis year, surgical resection, location, tumor size, symptoms, and family background. The frequency of NF1/2 in pediatric meningioma was reviewed in literature. RESULTS: Forty-four de novo cases were collected from pediatric patients; 19 were female patients and 25 males. The most frequent histological subtype was transitional meningioma. Of all the cases, 75% had a supratentorial localization and 20% had an extramedullary intrarachidian localization. Some clinical manifestations included seizures, paresis, headache, and visual disturbances. CONCLUSION: There is a low incidence of meningiomas in the pediatric population, more than 70% are Grade I, and they have supratentorial localization.

Predictors of anthracycline-induced cardiotoxicity in a retro-prolective cohort of children surviving cancer.

INTRODUCTION: Cardiotoxicity is an adverse reaction associated with the use of anthracyclines. OBJECTIVE: To estimate the factors associated with the development of anthracycline cardiotoxicity in pediatric patients surviving cancer. METHOD: Retro-prolective cohort of children diagnosed with cancer and treated with anthracyclines. Baseline echocardiographic determination of ejection fraction (LVEF0) was carried out before the start of treatment and again at 12 months (LVEF1). Demographic characteristics and treatment were obtained from the medical record. A multiple logistic regression (MLR) model was constructed; LVEF1 < 50 % was the dependent variable, which was adjusted for the main confounding variables. RESULTS: Sixty-five patients were included, out of which 36.9 % were females and 56.8 % had a solid tumor. LVEF0 was 74.79 ± 7.3 % and LVEF1, 67.96 ± 6.7 % (p = 0.001); 60 % developed cardiotoxicity. In the MLR, only a cumulative dose > 430 mg was associated with cardiotoxicity (p = 0.001). CONCLUSIONS: In Mexican children, an anthracycline cumulative dose > 430 mg should be avoided in order to prevent cardiotoxicity.

INTRODUCCIÓN: La cardiotoxicidad es una reacción adversa asociada al uso de antraciclinas. OBJETIVO: Estimar los factores asociados al desarrollo de cardiotoxicidad por antraciclinas en pacientes pediátricos supervivientes de cáncer. MÉTODO: Cohorte retroprolectiva de niños con diagnóstico de cáncer tratados con antraciclinas. Se realizó determinación ecocardiográfica basal de la fracción de expulsión (FEVi0) antes del inicio del tratamiento y a los 12 meses (FEVi1). Del expediente se obtuvieron las características demográficas y el tratamiento. Se realizó un modelo de regresión logística múltiple (RLM); la FEVi1 < 50 % fue la variable dependiente, que se ajustó por las principales variables confusoras. RESULTADOS: Se incluyeron 65 pacientes, 36.9 % fue del sexo femenino y 56.8 % presentó un tumor sólido. La FEVi0 fue de 74.79 ± 7.3 % y la FEVi1, de 67.96 ± 6.7 % (p = 0.001); 60 % desarrolló cardiotoxicidad. En la RLM solo la dosis acumulada > 430 mg se asoció a cardiotoxicidad (p = 0.001). CONCLUSIONES: En los niños mexicanos se debe evitar una dosis acumulada > 430 mg de antraciclinas para evitar la cardiotoxicidad.

Kisspeptins and reproduction: physiological roles and regulatory mechanisms.

Procreation is essential for survival of species. Not surprisingly, complex neuronal networks have evolved to mediate the diverse internal and external environmental inputs that regulate reproduction in vertebrates. Ultimately, these regulatory factors impinge, directly or indirectly, on a final common pathway, the neurons producing the gonadotropin-releasing hormone (GnRH), which stimulates pituitary gonadotropin secretion and thereby gonadal function. Compelling evidence, accumulated in the last few years, has revealed that kisspeptins, a family of neuropeptides encoded by the Kiss1 gene and produced mainly by neuronal clusters at discrete hypothalamic nuclei, are pivotal upstream regulators of GnRH neurons. As such, kisspeptins have emerged as important gatekeepers of key aspects of reproductive maturation and function, from sexual differentiation of the brain and puberty onset to adult regulation of gonadotropin secretion and the metabolic control of fertility. This review aims to provide a comprehensive account of the state-of-the-art in the field of kisspeptin physiology by covering in-depth the consensus knowledge on the major molecular features, biological effects, and mechanisms of action of kisspeptins in mammals and, to a lesser extent, in nonmammalian vertebrates. This review will also address unsolved and contentious issues to set the scene for future research challenges in the area. By doing so, we aim to endow the reader with a critical and updated view of the physiological roles and potential translational relevance of kisspeptins in the integral control of reproductive function.

Diagnostics and treatment of diffuse intrinsic pontine glioma: where do we stand?

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a rare clinically, neuro-radiologically, and molecularly defined malignancy of the brainstem with a median overall survival of approximately 11 months. Our aim is to evaluate the current tendency for its treatment in Europe in order to develop (inter)national consensus guidelines. METHODS: Healthcare professionals specialized in DIPG were asked to fill in an online survey with questions regarding usual treatment strategies at diagnosis and at disease progression in their countries and/or their centers, respectively. RESULTS: Seventy-four healthcare professionals responded to the survey, of which 87.8% were pediatric oncologists. Only 13.5% of the respondents biopsy all of their patients, 41.9% biopsy their patients infrequently. More than half of the respondents (54.1%) treated their patients with radiotherapy only at diagnosis, whereas 44.6% preferred radiotherapy combined with chemotherapy. When the disease progresses, treatment strategies became even more diverse, and the tendency for no treatment increased from 1.4% at diagnosis to 77.0% after second progression. 36.5% of the healthcare professionals treat children younger than 3 years differently than older children at diagnosis. This percentage decreased, when the disease progresses. Most of the participants (51.4%) included less than 25% of their patients in clinical trials. CONCLUSION: This survey demonstrates a large heterogeneity of treatment regimens, especially at disease progression. We emphasize the need for international consensus guidelines for the treatment of DIPG, possible by more collaborative clinical trials.

Regiodivergent Electrophilic Cyclizations of Alkynylcyclobutanes for the Synthesis of Cyclobutane-Fused O-Heterocycles.

Cyclobutane-fused dihydropyrans and methylenetetrahydrofurans are highly interesting cores found in numerous natural products. Both these cores are selectively prepared from a common alkynylcyclobutane precursor bearing an appended hydroxyl group herein. Thus, cyclobutane-fused dihydropyrans can be obtained by a selective 6-endo-dig iodocyclization, whereas gold-catalyzed 5-exo-dig cycloisomerization provides a bicyclic core containing a methylenetetrahydrofuran moiety as major product. Several cyclobutane-fused O-heterocycles with diverse substituents are synthesized following the reported methodology.

Intracerebroventricular administration of growth hormone induces morphological changes in pyramidal neurons of the hippocampus and prefrontal cortex in adult rats.

A growing body of evidence suggests that growth hormone (GH) affects synaptic plasticity at both the molecular and electrophysiological levels. However, unclear is whether plasticity that is stimulated by GH is associated with changes in neuron structure. This study investigated the effect of intracerebroventricular (ICV) administration of GH on the morphology of pyramidal neurons of the CA1 region of the dorsal hippocampus and layer III of the prefrontal cortex. Male Wistar rats received daily ICV injections of GH (120 ng) for 7 days, and they were euthanized 21 days later. Changes in neuronal morphology were evaluated using Golgi-Cox staining and subsequent Sholl analysis. GH administration increased total dendritic length in the CA1 region of the dorsal hippocampus and prefrontal cortex. The Sholl analysis revealed an increase in dendritic length of the third to eighth branch orders in the hippocampus and from the third to sixth branch orders in the prefrontal cortex. Interestingly, GH treatment increased the density of dendritic spines in both brain regions, favoring the presence of mushroom-like spines only in the CA1 hippocampal region. Our results indicated that GH induces changes in the length of dendritic trees and the density of dendritic spines in two high-plasticity brain regions, suggesting that GH-induced synaptic plasticity at the molecular and electrophysiological levels may be associated with these structural changes in neurons.

1,3-Dien-5-ynes: Versatile Building Blocks for the Synthesis of Carbo- and Heterocycles.

1,3-Dien-5-ynes have been extensively used as starting materials for the synthesis of a wide number of different carbo- and heterocycles. The aim of this review is to give an overview of their utility in organic synthesis, highlighting the variety of compounds that can be directly accessed from single reactions over these systems. Thus, cycloaromatization processes are initially commented, followed by reactions directed toward the syntheses of five-membered rings, other carbocycles and, finally, heterocycles. The diverse methodologies that have been developed for the synthesis of each of these types of compounds from 1,3-dien-5-ynes are presented, emphasizing the influence of the reaction conditions and the use of additional reagents in the outcome of the transformations.

Adipokines, insulin resistance, and adiposity as a predictors of metabolic syndrome in child survivors of lymphoma and acute lymphoblastic leukemia of a developing country.

BACKGROUND: There is a growing body of evidence indicating that pediatric survivors of cancer are at a greater risk of developing metabolic syndrome. This study evaluated some probable predictors of metabolic syndrome (MS), such as leptin and adiponectin concentrations, the leptin/adiponectin ratio, insulin resistance, and adiposity, in a sample of child survivors of lymphoma and leukemia in Mexico City. METHODS: Fifty two children (leukemia n = 26, lymphoma n = 26), who were within the first 5 years after cessation of therapy, were considered as eligible to participate in the study. Testing included fasting insulin, glucose, adipokines and lipids; body fat mass was measured by DXA. The MS components were analyzed according to tertiles of adipokines, insulin resistance, and adiposity. Comparisons between continuous variables were performed according to the data distribution. The MS components were analyzed according to tertiles of adipokines, insulin resistance, and adiposity. With the purpose of assessing the risk of a present MS diagnosis, odds ratios (OR) with a 95% confidence interval (95% IC) were obtained using logistic regression analysis according to the various metabolic markers. RESULTS: The median children age was 12.1 years, and the interval time from the completion of therapy to study enrollment was 4 years. Among the MS components, the prevalence of HDL-C low was most common (42%), followed by central obesity (29%). The HOMA-IR (OR 9.0, 95% CI 2.0; 41.1), body fat (OR 5.5, 95% CI 1.6; 19.3), leptin level (OR 5.7, 95% CI 1.6; 20.2) and leptin/adiponectin ratio (OR 9.4, 95% CI 2.0; 49.8) in the highest tertile, were predictive factors of developing MS; whereas the lowest tertile of adiponectin was associated with a protective effect but not significant. CONCLUSIONS: Biomarkers such as HOMA-IR, leptin and leptin/adiponectin are associated with each of the components of the MS and with a heightened risk of suffering MS among children survivors of cancer. Given the close relationship between MS with risk of developing type 2 diabetes and cardiovascular disease, it is imperative to implement prevention measures in this population and especially in developing countries where these pathologies have become the leading cause of death.

Dramatic Reduction in 30-Day Readmissions Through High-Risk Screening and Two-Phase Interdisciplinary Care.

OBJECTIVES: Thirty-day readmissions are common, serious, and costly. Most important, often they are preventable. The purpose of this quality improvement study was to evaluate an interdisciplinary, two-phase intervention to reduce 30-day readmissions among high-risk medical patients. One or two high-risk patients were selected each weekday by a hospitalist using literature-based, locally tested criteria that included common medical illnesses, active psychiatric illness, and recent or recurrent hospital admissions. METHODS: Patients admitted to 1 of 5 medical hospitalist teams were selected to receive the intervention; patients admitted to the 4 remaining teams were used for comparison. The two-phase care coordination intervention consisted of a daily interdisciplinary team meeting for the selected high-risk patients and postdischarge interventions that included outpatient care coordination until the patients' first follow-up appointment. The care plan addressed medical/geriatric assessment, social stability, medication reconciliation, nutritional needs, care coordination including future appointments/testing, and community services. Eighty-five patients in the intervention group were compared with 84 patients from the comparison group using propensity score matching. Patient characteristics were similar at baseline. RESULTS: The intervention group demonstrated a reduction in 30-day readmissions by 52% (11 vs 23, P = 0.019). Length of stay was reduced: 5.5 days compared with 7.2 days (P = 0.258). CONCLUSIONS: This intervention produced a significant reduction in 30-day readmissions for high-risk patients and a trend for shorter lengths of stay compared with similarly matched patients. Future research trials are needed to verify these results.

Unsuspected Lung Pathology in Autopsies of Children with Cancer.

BACKGROUND: Although pulmonary involvement is common in patients with cancer, its frequency and nature is seldom reported in the medical literature. OBJECTIVE: To determine the frequency and type of lung pathological conditions revealed by autopsy in children with cancer. METHODS: All reports from autopsies performed in children with cancer from 1989 to 2012 in a pediatric hospital were reviewed. RESULTS: In the analyzed period, 118 autopsies (10.2% of all autopsies) corresponded to children who died with cancer; 76 had complete information and were included in the analysis. Children were seen in the Hematology (41 cases) or the Oncology (35 cases) services. Their median age at decease was 7 years (range, 15 days to 16.1 years) and 46.1% were females. Main diagnoses were acute lymphoblastic (31 patients) or myeloblastic (10 patients) leukemias and tumors of the central nervous system (12 patients). A pathological respiratory condition was diagnosed antemortem in 31 (40.8%) patients, and at autopsy in 62 (81.6%) cases. Omitted diagnoses occurred in 58 (76.3%) children, being pneumonia (24 cases) and pulmonary hemorrhage (23 cases) the most frequent omissions. Nine patients had clinically unsuspected tumor infiltration or metastases. CONCLUSIONS: In these children with cancer, more than 80% of autopsies revealed some lung pathology, mainly of infectious or hemorrhagic nature. Thus, pulmonary involvement should be investigated in all children with cancer in a timely and intentional manner.

Risk Factors for Febrile Neutropenia in Children With Solid Tumors Treated With Cisplatin-based Chemotherapy.

Febrile neutropenia (FN) is a common and potentially fatal adverse drug reaction of cisplatin-based chemotherapy (CDDPBC) in pediatric patients. Hence, the aim of this study was to determine the incidence and independent risk factors for FN in pediatric patients with solid tumors treated with CDPPBC. Cohort integration was performed in the first cycle of chemotherapy with CDDPBC and patients were followed up to 6 months after the last cycle. FN was defined according to the Common Terminology Criteria for Adverse Events. Relative risks were calculated with confidence intervals at 95% (95% CI) to determine FN risk factors. Multiple logistic regression was performed to identify independent risk factors. One hundred and thirty-nine pediatric patients (median age 7.4 y, range 0.08 to 17 y) were included in the study. FN incidence was 62.5%. Independent risk factors for FN were chemotherapy regimens including anthracyclines (odds ratio [OR]=19.44 [95% CI, 5.40-70.02), hypomagnesaemia (OR=8.20 [95% CI, 1.81-37.14]), and radiotherapy (OR=6.67 [95% CI, 1.24-35.94]). It is therefore concluded that anthracyclines-containing regimens, hypomagnesaemia, and radiotherapy are independent risk factors for FN in patients receiving CDDPBC.

Onychomycosis in immunosuppressed children receiving chemotherapy.

Onychomycosis in children has a low incidence worldwide; certain conditions such as immunosuppression have been described as risk factors for it. We studied 72 children receiving chemotherapy for different neoplasms to determine the frequency of onychomycosis. Only one patient had white superficial onychomycosis from Trichophyton rubrum, a frequency of 1.3%, not different from that reported in healthy patients.

Editorial for the Special Issue "Hydrogels for 3D Printing".

Hydrogels, which are three-dimensional networks of hydrophilic polymers capable of absorbing and retaining large amounts of water, have emerged as versatile materials with vast potential in various fields [...].

Differential modulation of cell morphology, migration, and Neuropilin-1 expression in cancer and non-cancer cell lines by substrate stiffness.

Physical changes in the tumor microenvironment, such as increased stiffness, regulate cancer hallmarks and play an essential role in gene expression, cell morphology, migration, and malignancy. However, the response of cancer cells to stiffness is not homogeneous and varies depending on the cell type and its mechanosensitivity. In this study, we investigated the differential responses of cervical (HeLa) and prostate (PC-3) cancer cell lines, as well as non-tumoral cell lines (HEK293 and HPrEC), to stiffness using polyacrylamide hydrogels mimicking normal and tumoral tissues. We analyzed cell morphology, migration, and the expression of neuropilin 1 (NRP1), a receptor involved in angiogenesis, cell migration, and extracellular matrix remodeling, known to be associated with cancer progression and poor prognosis. Our findings reveal that NRP1 expression increases on substrates mimicking the high stiffness characteristic of tumoral tissue in the non-tumoral cell lines HPrEC and HEK293. Conversely, in tumoral PC-3 cells, stiffness resembling normal prostate tissue induces an earlier and more sustained expression of NRP1. Furthermore, we observed that stiffness influences cell spreading, pseudopodia formation, and the mode of cell protrusion during migration. Soft substrates predominantly trigger bleb cell protrusion, while pseudopodia protrusions increase on substrates mimicking normal and tumor-like stiffnesses in HPrEC cells compared to PC-3 cells. Stiffer substrates also enhance the percentage of migratory cells, as well as their velocity and total displacement, in both non-tumoral and tumoral prostate cells. However, they only improve the persistence of migration in tumoral PC-3 cells. Moreover, we found that NRP1 co-localizes with actin, and its suppression impairs tumoral PC-3 spreading while decreasing pseudopodia protrusion mode. Our results suggest that the modulation of NRP1 expression by the stiffness can be a feedback loop to promote malignancy in non-tumoral and cancer cells, contingent upon the mechanosensitivity of the cells.

Sonchus oleraceus L.: ethnomedical, phytochemical and pharmacological aspects.

Sonchus oleraceus L. (Asteraceae) is a cosmopolitan species native to Europe commonly known as lettuce, sowthistle, chicory, or fake dandelion, considered a weed. However, for many years in various cultures around the world, it has been used as food and medicinal plant. The aim of this integrative review is to document the ethnomedical, phytochemical, and pharmacological information of this species. Forty-one papers document the use of S. oleraceus to heal of a wide variety of diseases. However, gastrointestinal problems, diabetes, inflammation, infections, hepatitis, wounds, and to consume it as food are the most common uses. On the other hand, only 11 items highlight that the main groups of secondary metabolites in this species are flavonoids and terpene lactones. Finally, 45 items reveal that antioxidant, antimicrobial, antiproliferative and cytotoxic were the most studied pharmacological activities. In vitro and in vivo studies of extracts and components isolated from different parts of S. oleraceus have provided a concrete overview of the pharmacological properties of this species that supports its ethnomedical uses in cultures from different parts of the world. The reports of this species have focused solely on the study of the complete plant, leaves, and aerial parts, so it is necessary to study other parts of this species to search for bioactive compounds. No clinical studies were found, which creates an opportunity to expand scientific knowledge of this species.

Characterization of the reproductive effects of the Vgf-derived peptide TLQP-21 in female rats: in vivo and in vitro studies.

BACKGROUND: VGF (non-acronymic), a protein expressed in the hypothalamus and pituitary, is involved in the control of metabolism and body weight homeostasis. Different active peptide fragments are generated from VGF, including TLQP-21. Previous studies of our group reported that this molecule participates also in the regulation of reproductive function in male rats, with predominant stimulatory effects. METHODS: We report herein a series of studies on the reproductive effects of TLQP-21 in female rats, as evaluated by a combination of in vivo and in vitro analyses. RESULTS: TLQP-21 modestly increased serum LH levels after systemic administration and directly stimulated pituitary LH and FSH secretion in prepubertal female rats, while acute central injection of TLQP-21 was unable to modify LH secretion at this age. Repeated central administration of TLQP-21 during the pubertal transition (between PND-28 and -35) to female rats fed ad libitum advanced the timing of vaginal opening and increased the percentage of animals with signs of ovulation. Moreover, an analogous treatment slightly enhanced ovarian maturation in pubertal female rats subjected to chronic undernutrition, but was unable to rescue the delay of vaginal opening induced by food deprivation. In addition, TLQP-21 oppositely modified LH secretion in adult female rats depending on the stage of the ovarian cycle: it stimulated LH secretion when injected in the morning of diestrus and decreased the magnitude of the preovulatory LH (but not FSH) surge when injected in the afternoon of proestrus. CONCLUSIONS: Our data are the first to document the potential involvement of TLQP-21 in the control of reproductive function in female rats.