Modeling iPSC-derived human neurofibroma-like tumors in mice uncovers the heterogeneity of Schwann cells within plexiform neurofibromas

Fibroblast; Neural crest; SpheroidsFibroblasto; Cresta neural; EsferoidesFibroblast; Cresta neural; EsferoidesPlexiform neurofibromas (pNFs) are developmental tumors that appear in neurofibromatosis type 1 individuals, constituting a major source of morbidity and potentially transforming into a highly metastatic sarcoma (MPNST). pNFs arise after NF1 inactivation in a cell of the neural crest (NC)-Schwann cell (SC) lineage. Here, we develop an iPSC-based NC-SC in vitro differentiation system and construct a lineage expression roadmap for the analysis of different 2D and 3D NF models. The best model consists of generating heterotypic spheroids (neurofibromaspheres) composed of iPSC-derived differentiating NF1(−/−) SCs and NF1(+/−) pNF-derived fibroblasts (Fbs). Neurofibromaspheres form by maintaining highly proliferative NF1(−/−) cells committed to the NC-SC axis due to SC-SC and SC-Fb interactions, resulting in SC linage cells at different maturation points. Upon engraftment on the mouse sciatic nerve, neurofibromaspheres consistently generate human NF-like tumors. Analysis of expression roadmap genes in human pNF single-cell RNA-seq data uncovers the presence of SC subpopulations at distinct differentiation states.This work has mainly been supported by an agreement from the Johns Hopkins University School of Medicine and the Neurofibromatosis Therapeutic Acceleration Program (NTAP). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Johns Hopkins University School of Medicine. The work has also been partially supported by the Spanish Ministry of Science and Innovation, Carlos III Health Institute (ISCIII) (PI17/00524; PI20/00228) Plan Estatal de I + D + I 2013–2016, co-financed by the FEDER program – a way to build Europe, the Fundación PROYECTO NEUROFIBROMATOSIS, and by the Government of Catalonia (2017-SGR-496) and CERCA Program/Generalitat de Catalunya. M.M.-L. is supported by Fundación PROYECTO NEUROFIBROMATOSIS

Clinical malaria in African pregnant women

<p>Abstract</p> <p>Background</p> <p>There is a widespread notion, based on limited information, that in areas of stable malaria transmission most pregnant women with <it>Plasmodium falciparum </it>infection are asymptomatic. This study aim to characterize the clinical presentation of malaria in African pregnant women and to evaluate the adequacy of case management based on clinical complaints.</p> <p>Methods</p> <p>A hospital-based descriptive study between August 2003 and November 2005 was conducted at the maternity clinic of a rural hospital in Mozambique. All women attending the maternity clinic were invited to participate. A total of 2,330 women made 3,437 eligible visits, 3129 were analysed, the remainder were excluded because diagnostic results were unavailable or they were repeat visits. Women gave a standardized clinical history and had a medical exam. Malaria parasitaemia and haematocrit in capillary blood was determined for all women with signs or symptoms compatible with malaria including: presence and history of fever, arthromyalgias, headache, history of convulsions and pallor. Outcome measure was association of malaria symptoms or signs with positive blood slide for malaria parasitaemia.</p> <p>Results</p> <p>In 77.4% of visits pregnant women had symptoms suggestive of malaria; 23% (708/3129) were in the first trimester. Malaria parasitaemia was confirmed in 26.9% (842/3129) of visits. Headache, arthromyalgias and history of fever were the most common symptoms (86.5%, 74.8% and 65.4%) presented, but their positive predictive values for malaria parasitaemia were low [28% (27–30), 29% (28–31), and 33% (31–35), respectively].</p> <p>Conclusion</p> <p>Symptoms suggestive of malaria were very frequent among pregnant women attending a rural maternity clinic in an area of stable malaria transmission. However, less than a third of them were parasitaemic. In the absence of microscopy or rapid diagnostic tests, a large proportion of women, including those in the first trimester of gestation, would be unnecessarily receiving antimalarial drugs, often those with unknown safety profiles for pregnancy. Accessibility to malaria diagnostic tools needs to be improved for pregnant women and drugs with a safety profile in all gestational ages are urgently needed.</p

A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin

Signatura genètica; Biomarcadors predictius; TrabectedinaFirma genética; Biomarcadores predictivos; TrabectedinaGene signature; Predictive biomarkers; TrabectedinPredictive biomarkers of trabectedin represent an unmet need in advanced soft-tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively. The majority of these studies only focused on specific factors (ERCC1, ERCC5, and BRCA1) and did not evaluate several other DDR-related genes that could have a relevant role for trabectedin efficacy. In this retrospective translational study, 118 genes involved in DDR were evaluated to determine, by transcriptomics, a predictive gene signature of trabectedin efficacy. A six-gene predictive signature of trabectedin efficacy was built in a series of 139 tumor samples from patients with advanced STS. Patients in the high-risk gene signature group showed a significantly worse progression-free survival compared with patients in the low-risk group (2.1 vs 6.0 months, respectively). Differential gene expression analysis defined new potential predictive biomarkers of trabectedin sensitivity (PARP3 and CCNH) or resistance (DNAJB11 and PARP1). Our study identified a new gene signature that significantly predicts patients with higher probability to respond to treatment with trabectedin. Targeting some genes of this signature emerges as a potential strategy to enhance trabectedin efficacy.This study was funded by the Spanish Group for Research on Sarcoma (GEIS) and partially by PharmaMar. The authors would like to thank the GEIS data center for data management. The authors also thank the donors and the Hospital Universitario Virgen del Rocío—Instituto de Biomedicina de Sevilla Biobank (Andalusian Public Health System Biobank and ISCIII-Red de Biobancos PT17/0015/0041) for part of the human specimens used in this study. David S. Moura is recipient of a Sara Borrell postdoctoral fellowship funded by the National Institute of Health Carlos III (ISCIII) (CD20/00155)

An Autopsy Study of Maternal Mortality in Mozambique: The Contribution of Infectious Diseases

Clara Menendez and colleagues analyze 139 complete autopsies following maternal deaths in Maputo, Mozambique and find a predominance of infectious and preventable causes

miR-125b Acts as a Tumor Suppressor in Breast Tumorigenesis via Its Novel Direct Targets ENPEP, CK2-α, CCNJ, and MEGF9

MicroRNAs (miRNAs) play important roles in diverse biological processes and are emerging as key regulators of tumorigenesis and tumor progression. To explore the dysregulation of miRNAs in breast cancer, a genome-wide expression profiling of 939 miRNAs was performed in 50 breast cancer patients. A total of 35 miRNAs were aberrantly expressed between breast cancer tissue and adjacent normal breast tissue and several novel miRNAs were identified as potential oncogenes or tumor suppressor miRNAs in breast tumorigenesis. miR-125b exhibited the largest decrease in expression. Enforced miR-125b expression in mammary cells decreased cell proliferation by inducing G2/M cell cycle arrest and reduced anchorage-independent cell growth of cells of mammary origin. miR-125b was found to perform its tumor suppressor function via the direct targeting of the 3'-UTRs of ENPEP, CK2-alpha, CCNJ, and MEGF9 mRNAs. Silencing these miR-125b targets mimicked the biological effects of miR-125b overexpression, confirming that they are modulated by miR-125b. Analysis of ENPEP, CK2-alpha, CCNJ, and MEGF9 protein expression in breast cancer patients revealed that they were overexpressed in 56%, 40-56%, 20%, and 32% of the tumors, respectively. The expression of ENPEP and CK2-alpha was inversely correlated with miR-125b expression in breast tumors, indicating the relevance of these potential oncogenic proteins in breast cancer patients. Our results support a prognostic role for CK2-alpha, whose expression may help clinicians predict breast tumor aggressiveness. In particular, our results show that restoration of miR-125b expression or knockdown of ENPEP, CK2-alpha, CCNJ, or MEGF9 may provide novel approaches for the treatment of breast cancer

An autopsy study of maternal mortality in Mozambique: the contribution of infectious diseases

Background Maternal mortality is a major health problem concentrated in resource-poor regions. Accurate data on its causes using rigorous methods is lacking, but is essential to guide policy-makers and health professionals to reduce this intolerable burden. The aim of this study was to accurately describe the causes of maternal death in order to contribute to its reduction, in one of the regions of the world with the highest maternal mortality ratios. Methods and Findings We conducted a prospective study between October 2002 and December 2004 on the causes of maternal death in a tertiary-level referral hospital in Maputo, Mozambique, using complete autopsies with histological examination. HIV detection was done by virologic and serologic tests, and malaria was diagnosed by histological and parasitological examination. During 26 mo there were 179 maternal deaths, of which 139 (77.6%) had a complete autopsy and formed the basis of this analysis. Of those with test results, 65 women (52.8%) were HIV-positive. Obstetric complications accounted for 38.2% of deaths; haemorrhage was the most frequent cause (16.6%). Nonobstetric conditions accounted for 56.1% of deaths; HIV/AIDS, pyogenic bronchopneumonia, severe malaria, and pyogenic meningitis were the most common causes (12.9%, 12.2%, 10.1% and 7.2% respectively). Mycobacterial infection was found in 12 (8.6%) maternal deaths. Conclusions In this tertiary hospital in Mozambique, infectious diseases accounted for at least half of all maternal deaths, even though effective treatment is available for the four leading causes, HIV/AIDS, pyogenic bronchopneumonia, severe malaria, and pyogenic meningitis. These observations highlight the need to implement effective and available prevention tools, such as intermittent preventive treatment and insecticide-treated bed-nets for malaria, antiretroviral drugs for HIV/AIDS, or vaccines and effective antibiotics for pneumococcal and meningococcal diseases. Deaths due to obstetric causes represent a failure of health-care systems and require urgent improvement

A Randomized Placebo-Controlled Trial of Intermittent Preventive Treatment in Pregnant Women in the Context of Insecticide Treated Nets Delivered through the Antenatal Clinic

Background:Current recommendations to prevent malaria in African pregnant women rely on insecticide treated nets(ITNs) and intermittent preventive treatment (IPTp). However, there is no information on the safety and efficacy of theircombined use.Methods:1030 pregnant Mozambican women of all gravidities received a long-lasting ITN during antenatal clinic (ANC)visits and, irrespective of HIV status, were enrolled in a randomised, double blind, placebo-controlled trial, to assess thesafety and efficacy of 2-dose sulphadoxine-pyrimethamine (SP). The main outcome was the reduction in low birth weight.Findings:Two-dose SP was safe and well tolerated, but was not associated with reductions in anaemia prevalence atdelivery (RR, 0.92 [95% CI, 0.79-1.08]), low birth weight (RR, 0.99 [95% CI, 0.70-1.39]), or overall placental infection(p = 0.964). However, the SP group showed a 40% reduction (95% CI, 7.40-61.20]; p = 0.020) in the incidence of clinicalmalaria during pregnancy, and reductions in the prevalence of peripheral parasitaemia (7.10% vs 15.15%) (p,0.001), and ofactively infected placentas (7.04% vs 13.60%) (p = 0.002). There was a reduction in severe anaemia at delivery of borderlinestatistical significance (p = 0.055). These effects were not modified by gravidity or HIV status. Reported ITN's use was morethan 90% in both groups.Conclusions:Two-dose SP was associated with a reduction in some indicators, but these were not translated to significantimprovement in other maternal or birth outcomes. The use of ITNs during pregnancy may reduce the need to administerIPTp. ITNs should be part of the ANC package in sub-Saharan Afric

Determinacions del perfil genètic del càncer pediàtric

Oncologia; Perfil genètic; Càncer pediàtric; PrecisióOncología; Perfil genético; Cáncer pediátrico; PrecisiónOncology; Genetic profile; Pediatric cancer; AccuracyL'àmbit d'aquest grup de treball és la implementació de panels NGS per a diagnòstic / pronòstic / tractament de càncer en pacients menors de 18 anys (oncologia i hematologia). Els casos de predisposició genètica en pacients pediàtrics es tractaran en el grup de predisposició genètica. El càncer infantil comprèn més de 40 entitats entre leucèmies, limfomes, tumors cerebrals i sòlids extracranials; per la qual cosa no és possible tècnicament o operativament fer panels específics per a cada un d'aquests càncers. Serà necessari utilitzar panels comercials o acadèmics dissenyats específicament per a càncer infantil

Determinacions del perfil genètic del càncer pediàtric

Oncologia; Perfil genètic; Càncer pediàtric; PrecisióOncología; Perfil genético; Cáncer pediátrico; PrecisiónOncology; Genetic profile; Pediatric cancer; AccuracyL'àmbit d'aquest grup de treball és la implementació de panels NGS per a diagnòstic / pronòstic / tractament de càncer en pacients menors de 18 anys (oncologia i hematologia). Els casos de predisposició genètica en pacients pediàtrics es tractaran en el grup de predisposició genètica. El càncer infantil comprèn més de 40 entitats entre leucèmies, limfomes, tumors cerebrals i sòlids extracranials; per la qual cosa no és possible tècnicament o operativament fer panels específics per a cada un d'aquests càncers. Serà necessari utilitzar panels comercials o acadèmics dissenyats específicament per a càncer infantil