Publications by authors named "Francisco Martínez"

279 Publications

Safe harbor-targeted CRISPR-Cas9 homology-independent targeted integration for multimodality reporter gene-based cell tracking.

Sci Adv 2021 Jan 20;7(4). Epub 2021 Jan 20.

Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.

Imaging reporter genes provides longitudinal information on the biodistribution, growth, and survival of engineered cells in vivo. A translational bottleneck to using reporter genes is the necessity to engineer cells with randomly integrating vectors. Here, we built homology-independent targeted integration (HITI) CRISPR-Cas9 minicircle donors for precise safe harbor-targeted knock-in of fluorescence, bioluminescence, and MRI () reporter genes. Our results showed greater knock-in efficiency using HITI vectors compared to homology-directed repair vectors. HITI clones demonstrated functional fluorescence and bioluminescence reporter activity as well as significant Oatp1a1-mediated uptake of the clinically approved MRI agent gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid. Contrast-enhanced MRI improved the conspicuity of both subcutaneous and metastatic Oatp1a1-expressing tumors before they became palpable or even readily visible on precontrast images. Our work demonstrates the first CRISPR-Cas9 HITI system for knock-in of large DNA donor constructs at a safe harbor locus, enabling multimodal longitudinal in vivo imaging of cells.
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http://dx.doi.org/10.1126/sciadv.abc3791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817109PMC
January 2021

Parents ethanol use impairs ethanol-naive offspring development and reproduction.

Reproduction 2021 Feb;161(2):195-204

Department of Structural and Functional Biology, Institute of Biosciences of Botucatu (IBB), UNESP - Univ Estadual Paulista, São Paulo, Brazil.

Parental ethanol consumption can influence the offspring phenotype. In this way, we analyzed the impairments of maternal and paternal high ethanol consumption during postpuberty on the physical development, feeding pattern, puberty onset and reproductive function of ethanol-naive offspring to birth to adulthood. Female and male UChB rats (voluntary 10%, v/v ethanol consumer) were divided into a control group (C) and an ethanol exposed group (E) from 65 to 80 days of age. The C and E were mated at 100 days. The maternal parameters and offspring development and reproduction parameters were monitored. We observed reduced feeding intake and body weight in the dams of E group throughout gestation and lactation period. Delay in physical development, lower body weight and altered feeding pattern were observed in female and male offspring of E group. In addition, the puberty onset was delayed in both sexes, with lower testosterone levels in the juvenile and pubertal males. There was a prolongation on the estrous and proestrus phases in females from E but the estrous cycle duration did not change between groups. Ovary and uterus weight were reduced in pubertal and adult females from E group. Reduced epididymis and seminal vesicle weight, increased sperm abnormalities, decrease in the daily sperm production and accelerated epididymal transit time were observed in E males. The high maternal and paternal ethanol use on postpuberty impairs the parameters of ethanol-naive offspring inducing alteration on development and reproduction.
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http://dx.doi.org/10.1530/REP-20-0316DOI Listing
February 2021

Strength training protects against prostate injury in alcoholic rats.

J Cell Physiol 2021 May 11;236(5):3675-3687. Epub 2020 Dec 11.

Department of Anatomy, Institute of Biosciences, São Paulo State University, UNESP, Botucatu, São Paulo, Brazil.

Alcoholic injury can alter the hormonal signaling pathway and lead to glucose and lipid metabolism disorders. In this study, we investigated whether the strength training could exert protective effects against the alterations caused by ethanol consumption on prostatic metabolism. A UChB, ethanol-preferring rats were used in this study. Strength training was conducted for 3 days per week for 13 weeks, rats performed jumps in water carrying a weight load strapped to their chests as part of a strength training protocol. The reduced alcohol consumption by strength training was accompanied by increased glucose, serum lipid profile, total protein levels, and reduced hormonal levels. The results of protein expression of prostatic tissues in the ethanol- and strength training-treated groups indicated that "steroidal hormone receptors," "fatty acid translocation," and "cell regulation" were significantly different between ethanol- and strength training-treated groups. Taken together, these findings show that strength training effectively ameliorated prostatic injuries in alcoholic rats at least partially by acting on lipids receptors and steroidal hormone receptors pathway, suggesting the strength training as a potential novel therapeutic strategy for treating prostate injuries caused by ethanol.
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http://dx.doi.org/10.1002/jcp.30108DOI Listing
May 2021

Standards in medication review: An international perspective.

Can Pharm J (Ott) 2020 Jul-Aug;153(4):215-223. Epub 2020 Jul 14.

impac2t research (Rose), Muenster, Germany.

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http://dx.doi.org/10.1177/1715163520929665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605065PMC
July 2020

Mortality and other adverse outcomes in patients with type 2 diabetes mellitus admitted for COVID-19 in association with glucose-lowering drugs: a nationwide cohort study.

BMC Med 2020 11 16;18(1):359. Epub 2020 Nov 16.

Internal Medicine Department, Regional University Hospital of Málaga, Biomedical Research Institute of Málaga (IBIMA), University of Málaga (UMA), Avenida de Carlos Haya, s/n, 29010, Málaga, Spain.

Background: Limited evidence exists on the role of glucose-lowering drugs in patients with COVID-19. Our main objective was to examine the association between in-hospital death and each routine at-home glucose-lowering drug both individually and in combination with metformin in patients with type 2 diabetes mellitus admitted for COVID-19. We also evaluated their association with the composite outcome of the need for ICU admission, invasive and non-invasive mechanical ventilation, or in-hospital death as well as on the development of in-hospital complications and a long-time hospital stay.

Methods: We selected all patients with type 2 diabetes mellitus in the Spanish Society of Internal Medicine's registry of COVID-19 patients (SEMI-COVID-19 Registry). It is an ongoing, observational, multicenter, nationwide cohort of patients admitted for COVID-19 in Spain from March 1, 2020. Each glucose-lowering drug user was matched with a user of other glucose-lowering drugs in a 1:1 manner by propensity scores. In order to assess the adequacy of propensity score matching, we used the standardized mean difference found in patient characteristics after matching. There was considered to be a significant imbalance in the group if a standardized mean difference > 10% was found. To evaluate the association between treatment and study outcomes, both conditional logit and mixed effect logistic regressions were used when the sample size was ≥ 100.

Results: A total of 2666 patients were found in the SEMI-COVID-19 Registry, 1297 on glucose-lowering drugs in monotherapy and 465 in combination with metformin. After propensity matching, 249 patients on metformin, 105 on dipeptidyl peptidase-4 inhibitors, 129 on insulin, 127 on metformin/dipeptidyl peptidase-4 inhibitors, 34 on metformin/sodium-glucose cotransporter 2 inhibitor, and 67 on metformin/insulin were selected. No at-home glucose-lowering drugs showed a significant association with in-hospital death; the composite outcome of the need of intensive care unit admission, mechanical ventilation, or in-hospital death; in-hospital complications; or long-time hospital stays.

Conclusions: In patients with type 2 diabetes mellitus admitted for COVID-19, at-home glucose-lowering drugs showed no significant association with mortality and adverse outcomes. Given the close relationship between diabetes and COVID-19 and the limited evidence on the role of glucose-lowering drugs, prospective studies are needed.
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http://dx.doi.org/10.1186/s12916-020-01832-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666969PMC
November 2020

Hidden etiology of cerebral palsy: genetic and clinical heterogeneity and efficient diagnosis by next-generation sequencing.

Pediatr Res 2020 Nov 11. Epub 2020 Nov 11.

Neuropediatric Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain.

Cerebral palsy (CP) is a heterogeneous neurodevelopmental disorder that causes movement and postural disabilities. Recent research studies focused on genetic diagnosis in patients with CP of unknown etiology. The present study was carried out in 20 families with one family member affected with idiopathic CP. Chromosomal microarray and exome sequencing techniques were performed in all patients. Chromosomal microarray analysis did not show any pathological or probable pathological structural variant. However, the next-generation sequencing study showed a high diagnostic yield. We report 11/20 patients (55%) with different pathogenic or potentially pathogenic variants detected by exome sequencing analysis: five patients with mutations in genes related to hereditary spastic paraplegia, two with mutations in genes related to Aicardi-Goutières syndrome, three with mutations in genes related to developmental/epileptic encephalopathies, and one with a mutation in the PGK1 gene. The accurate and precise patients' selection, the use of a high-throughput genetic platform, the selection of adequate target genes, and the application of rigorous criteria for the clinical interpretation are the most important elements for a good diagnostic performance. Based on our findings, next-generation sequencing should be considered in patients with cryptogenic CP as the first line of genetic workup. IMPACT: Sequencing techniques in CP of uncertain etiology provides a diagnostic yield of 55%. The appropriate selection of cases optimizes the diagnostic yield. NGS facilitate better understanding of new phenotypes of certain genetic diseases.
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http://dx.doi.org/10.1038/s41390-020-01250-3DOI Listing
November 2020

Advances in multimodal data fusion in neuroimaging: Overview, challenges, and novel orientation.

Inf Fusion 2020 Dec 17;64:149-187. Epub 2020 Jul 17.

Department of Signal Theory, Networking and Communications, University of Granada, Granada, Spain.

Multimodal fusion in neuroimaging combines data from multiple imaging modalities to overcome the fundamental limitations of individual modalities. Neuroimaging fusion can achieve higher temporal and spatial resolution, enhance contrast, correct imaging distortions, and bridge physiological and cognitive information. In this study, we analyzed over 450 references from PubMed, Google Scholar, IEEE, ScienceDirect, Web of Science, and various sources published from 1978 to 2020. We provide a review that encompasses (1) an overview of current challenges in multimodal fusion (2) the current medical applications of fusion for specific neurological diseases, (3) strengths and limitations of available imaging modalities, (4) fundamental fusion rules, (5) fusion quality assessment methods, and (6) the applications of fusion for atlas-based segmentation and quantification. Overall, multimodal fusion shows significant benefits in clinical diagnosis and neuroscience research. Widespread education and further research amongst engineers, researchers and clinicians will benefit the field of multimodal neuroimaging.
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http://dx.doi.org/10.1016/j.inffus.2020.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366126PMC
December 2020

Delineation of phenotypes and genotypes related to cohesin structural protein RAD21.

Hum Genet 2020 May 19;139(5):575-592. Epub 2020 Mar 19.

Department of Pediatrics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands.

RAD21 encodes a key component of the cohesin complex, and variants in RAD21 have been associated with Cornelia de Lange Syndrome (CdLS). Limited information on phenotypes attributable to RAD21 variants and genotype-phenotype relationships is currently published. We gathered a series of 49 individuals from 33 families with RAD21 alterations [24 different intragenic sequence variants (2 recurrent), 7 unique microdeletions], including 24 hitherto unpublished cases. We evaluated consequences of 12 intragenic variants by protein modelling and molecular dynamic studies. Full clinical information was available for 29 individuals. Their phenotype is an attenuated CdLS phenotype compared to that caused by variants in NIPBL or SMC1A for facial morphology, limb anomalies, and especially for cognition and behavior. In the 20 individuals with limited clinical information, additional phenotypes include Mungan syndrome (in patients with biallelic variants) and holoprosencephaly, with or without CdLS characteristics. We describe several additional cases with phenotypes including sclerocornea, in which involvement of the RAD21 variant is uncertain. Variants were frequently familial, and genotype-phenotype analyses demonstrated striking interfamilial and intrafamilial variability. Careful phenotyping is essential in interpreting consequences of RAD21 variants, and protein modeling and dynamics can be helpful in determining pathogenicity. The current study should be helpful when counseling families with a RAD21 variation.
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http://dx.doi.org/10.1007/s00439-020-02138-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170815PMC
May 2020

Role of mitochondrial DNA variants in the development of fragile X-associated tremor/ataxia syndrome.

Mitochondrion 2020 05 12;52:157-162. Epub 2020 Mar 12.

Biochemistry and Molecular Genetics Department, Hospital Clinic of Barcelona and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; CIBER of Rare Diseases, Instiuto de Salud Carlos III, Spain. Electronic address:

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that appears in at least one-third of adult carriers of FMR1 premutation. Several studies have shown that mitochondrial dysfunction may play a role in neurodegenerative disorders. In order to assess whether mitochondrial DNA variants are involved in the risk of developing FXTAS we evaluated the frequency of mitochondrial haplogroups in 132 unrelated Spanish FMR1 premutation carriers. In addition, the entire mitogenome of 26 FMR1 premutation carriers was sequenced using massively parallel sequencing technologies to analyze mitochondrial DNA variants. Statistical analyses reveal a significant difference in the frequency of T haplogroup. Data analysis of mitochondrial DNA sequences evidence an association between FXTAS and the burden of heteroplasmic variants as well as their distribution. Our results suggest that haplogroup T might be a potential protective factor for FXTAS and that FXTAS individuals accumulate higher rates of heteroplasmic variants in compromised regions of the mitochondrial genome. These results may explain, in part, the role of mitochondrial DNA in the development of FXTAS.
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http://dx.doi.org/10.1016/j.mito.2020.03.004DOI Listing
May 2020

Advances in smart roads for future smart cities.

Proc Math Phys Eng Sci 2020 Jan 22;476(2233):20190439. Epub 2020 Jan 22.

Computer Science and System Engineering Department, University of Zaragoza, Teruel, Spain.

Various countries throughout the world have started their efforts in designing and implementing smart cities. China alone has over 300 smart city projects, with strong participation by industries and government offices. India too have allocated trillions in budget to build over 100 smart cities. An essential part of a smart city is transport. In this paper, we will discuss the current state, developments, and some of the emerging advances in transportation technologies and how these advances in smart roads will prepare the society towards the realization of future smart cities.
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http://dx.doi.org/10.1098/rspa.2019.0439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016555PMC
January 2020

Molecular characterization of Spanish patients with MECP2 duplication syndrome.

Clin Genet 2020 04 23;97(4):610-620. Epub 2020 Feb 23.

Servicio de Medicina Genètica i Molecular, Hospital Universitario San Juan de Dios, Barcelona, Spain.

MECP2 duplication syndrome (MDS) is an X-linked neurodevelopmental disorder characterized by a severe to profound intellectual disability, early onset hypotonia and diverse psycho-motor and behavioural features. To date, fewer than 200 cases have been published. We report the clinical and molecular characterization of a Spanish MDS cohort that included 19 boys and 2 girls. Clinical suspicions were confirmed by array comparative genomic hybridization and multiplex ligation-dependent probe amplification (MLPA). Using, a custom in-house MLPA assay, we performed a thorough study of the minimal duplicated region, from which we concluded a complete duplication of both MECP2 and IRAK1 was necessary for a correct MDS diagnosis, as patients with partial MECP2 duplications lacked some typical clinical traits present in other MDS patients. In addition, the duplication location may be related to phenotypic severity. This observation may provide a new approach for genotype-phenotype correlations, and thus more personalized genetic counselling.
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http://dx.doi.org/10.1111/cge.13718DOI Listing
April 2020

Biliary tract cancers: systemic therapy for advanced disease.

Chin Clin Oncol 2020 Feb 19;9(1). Epub 2019 Dec 19.

Division of Hematology/Oncology, University of Arizona Cancer Center, Tucson, AZ, USA.

Biliary tract carcinomas (BTC) present with minimal symptoms and thus they are often diagnosed in advanced stages that require systemic therapy. Unfortunately, if not resected, BTC's prognosis is generally poor, in part due to limited therapeutic options. Herein we will highlight the various systemic therapies that have proven efficacy in these diseases in both 1st and 2nd line. As it stands now, the combination of Gemcitabine and Cisplatin is the gold standard. Gemcitabine plus Cisplatin (Gem-Cis)-nab-paclitaxel showed improved survival in a phase II trial compared with historical controls. SWOG 1815 is a phase III trial currently underway comparing Gem-Cis-nab-paclitaxel to Gem-Cis and if positive, this has the potential to establish a new standard of care. New data from the ABC-06 study has shown a survival benefit using FOLFOX in the 2nd line setting. Molecularly targeted agents in BTC have demonstrated potential beyond Gem-Cis and while currently limited to second- and later-line therapies, ongoing trials are testing their efficacy even in newly diagnosed patients. With both incremental improvements in existing therapies and the development of entirely novel agents, the future of systemic therapy for BTC is promising.
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http://dx.doi.org/10.21037/cco.2019.12.07DOI Listing
February 2020

Physical resistance training-induced changes in lipids metabolism pathways and apoptosis in prostate.

Lipids Health Dis 2020 Jan 29;19(1):14. Epub 2020 Jan 29.

Department of Anatomy, São Paulo State University, UNESP - Institute of Biosciences, Botucatu, SP, Brazil.

Background: Altered lipid metabolism is an important characteristic of neoplastic cells, with androgens and growth factors being major regulatory agents of the lipid metabolism process. We investigated the effect of physical resistance training on lipid metabolism and apoptosis in the adult Wistar rat prostate.

Methods: Two experimental groups represented sedentary and physical resistance training. Three days per week for 13 weeks, rats performed jumps in water carrying a weight load strapped to their chests as part of a physical resistance exercise protocol. Two days after the last training session, rats were anesthetized and sacrificed for blood and prostate analysis.

Results: Physical exercise improved feeding efficiency, decreased weight gain, regulated the serum-lipid profile, and modulated insulin-like growth factor-1 (IGF-1) and free testosterone concentration. Furthermore, upregulation of cluster of differentiation 36 (CD36), sterol regulatory element binding protein-1 (SREBP-1), sterol regulatory element-binding protein cleavage-activating protein (SCAP), and reduced lysosome membrane protein (LIMPII) expression were also observed in the blood and prostates of trained rats. Consistent with these results, caspase-3 expression was upregulating and the BCL-2/Bax index ratio was decreased in trained rats relative to sedentary animals.

Conclusions: In this work, physical resistance training can alter lipid metabolism and increase markers of apoptosis in the prostate, suggesting physical resistance training as a potential novel therapeutic strategy for treating prostate cancer.
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http://dx.doi.org/10.1186/s12944-020-1195-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990525PMC
January 2020

Mixed Phenotype of Langer-Giedion's and Cornelia de Lange's Syndromes in an 8q23.3-q24.1 Microdeletion without Deletion.

J Pediatr Genet 2020 Mar 3;9(1):53-57. Epub 2019 Sep 3.

Dysmorphology and Reproductive Genetics Unit, Neonatal Research Group, Health Research Institute Hospital La Fe, University and Polytechnic Hospital La Fe, Valencia, Spain.

Langer-Giedion's syndrome (LGS) or trichorhinophalangeal syndrome type II (TRPS II; MIM:150230) is a contiguous gene deletion syndrome caused by the haploinsufficiency of the and genes. Cornelia de Lange's syndrome (CdLS) is a genetically heterogeneous dysmorphic syndrome where heterozygous mutations of gene have been associated with a mild clinical presentation (CDLS type 4; MIM: 614701). We report a female patient with a 2.3-Mb interstitial deletion at 8q23.3-q24.1 encompassing and genes but not . Clinical findings in this patient are correlated with a mixed phenotype of LGS and CdLS type 4.
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http://dx.doi.org/10.1055/s-0039-1694779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976337PMC
March 2020

P-MAPA and IL-12 Differentially Regulate Proteins Associated with Ovarian Cancer Progression: A Proteomic Study.

ACS Omega 2019 Dec 11;4(26):21761-21777. Epub 2019 Dec 11.

Department of Anatomy, Institute of Biosciences and Center for the Study of Venoms and Venomous Animals (CEVAP), UNESP-Universidade Estadual Paulista, Botucatu, São Paulo 18618-689, Brazil.

To investigate the potential role of immunotherapies in the cellular and molecular mechanisms associated with ovarian cancer (OC), we applied a comparative proteomic toll using protein identification combined with mass spectrometry. Herein, the effects of the protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride, known as P-MAPA, and the human recombinant interleukin-12 (hrIL-12) were tested alone or in combination in human SKOV-3 cells. The doses and period were defined based on a previous study, which showed that 25 μg/mL P-MAPA and 1 ng/mL IL-12 are sufficient to reduce cell metabolism after 48 h. Indeed, among 2,881 proteins modulated by the treatments, 532 of them were strictly concordant and common. P-MAPA therapy upregulated proteins involved in tight junction, focal adhesion, ribosome constitution, GTP hydrolysis, semaphorin interactions, and expression of SLIT and ROBO, whereas it downregulated ERBB4 signaling, toll-like receptor signaling, regulation of NOTCH 4, and the ubiquitin proteasome pathway. In addition, IL-12 therapy led to upregulation of leukocyte migration, tight junction, and cell signaling, while cell communication, cell metabolism, and Wnt signaling were significantly downregulated in OC cells. A clear majority of proteins that were overexpressed by the combination of P-MAPA with IL-12 are involved in tight junction, focal adhesion, DNA methylation, metabolism of RNA, and ribosomal function; only a small number of downregulated proteins were involved in cell signaling, energy and mitochondrial processes, cell oxidation and senescence, and Wnt signaling. These findings suggest that P-MAPA and IL-12 efficiently regulated important proteins associated with OC progression; these altered proteins may represent potential targets for OC treatment in addition to its immunoadjuvant effects.
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http://dx.doi.org/10.1021/acsomega.9b02512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933580PMC
December 2019

P-MAPA and Interleukin-12 Reduce Cell Migration/Invasion and Attenuate the Toll-Like Receptor-Mediated Inflammatory Response in Ovarian Cancer SKOV-3 Cells: A Preliminary Study.

Molecules 2019 Dec 18;25(1). Epub 2019 Dec 18.

Department of Anatomy, UNESP-São Paulo State University, Institute of Biosciences, Botucatu, 18618-689 São Paulo, Brazil.

Immunotherapies have emerged as promising complementary treatments for ovarian cancer (OC), but its effective and direct role on OC cells is unclear. This study examined the combinatory effects of the protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride, known as P-MAPA, and the human recombinant interleukin-12 (hrIL-12) on cell migration/invasion, apoptosis, toll-like receptor (TLR)-mediated inflammation, and cytokine/chemokine profile in human OC cell line SKOV-3. P-MAPA and IL-12 showed cancer cell toxicity under low doses after 48 h. Although apoptosis/necrosis and the cell cycle were unchanged by the treatments, P-MAPA enhanced the sensitivity to paclitaxel (PTX) and P-MAPA associated with IL-12 significantly reduced the migratory potential and invasion capacity of SKOV-3 cells. P-MAPA therapy reduced TLR2 immunostaining and the myeloid differentiation factor 88 (MyD88), but not the TLR4 levels. Moreover, the combination of P-MAPA with IL-12 attenuated the levels of MyD88, interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-kB p65). The IL-12 levels were increased and P-MAPA stimulated the secretion of cytokines IL-3, IL-9, IL-10, and chemokines MDC/CCL22 and, regulated on activation, normal T cells expressed and secreted (RANTES)/CCL5. Conversely, combination therapy reduced the levels of IL-3, IL-9, IL-10, MDC/CCL22, and RANTES/CCL5. Collectively, P-MAPA and IL-12 reduce cell dynamics and effectively target the TLR-related downstream molecules, eliciting a protective effect against chemoresistance. P-MAPA also stimulates the secretion of anti-inflammatory molecules, possibly having an immune response in the OC microenvironment.
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http://dx.doi.org/10.3390/molecules25010005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982916PMC
December 2019

A woman's grace: gender, imperialism and religion in Emily Keene's philanthropic activities in Morocco, 1873-1941.

Med Confl Surviv 2020 Mar 18;36(1):61-81. Epub 2019 Dec 18.

CIDEHUS, University of Évora, Evora, Portugal.

Emily Keene (London 1849 - Tangier 1941) became a relevant figure in pre-colonial Moroccan history due to her involvement in British policy and to her philanthropic-medical initiatives during the late 19th and early 20th centuries. Such prominence was closely linked with her marriage to the sheriff of Wazzan, a powerful spiritual and political figure. 'Grace', in a triple romantic, political and religious sense, was a defining feature of Keene's marriage and widowhood and explained that, despite her continuing adscription to Christian religion, British imperialism and Western science, she deployed a weakly hegemonic stand towards her country of adoption. This attitude distanced her from the 'civilizing mission' policy that set off in the mid-1880s and from the active proselytising and scientific supremacism of the British missionaries during the same period. After her husband's death in 1892, she showed a strong commitment towards (Western-style) Moroccan social and political emancipation, which she tried to promote in close association with a small circle of women friends and Quakers based in Tangiers. Emily Keene's is thus an excellent case study for exploring the interplay between gender, imperialism and religion in pre-colonial Morocco and also the connection between private life and public activity in 19th century women humanitarians.
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http://dx.doi.org/10.1080/13623699.2019.1703528DOI Listing
March 2020

Molecular and Clinical Characterization of a Novel Nonsense Variant in Exon 1 of the Gene Found in a Large Spanish Basque Family (MRX82).

Front Genet 2019 31;10:1074. Epub 2019 Oct 31.

Spanish Consortium for Research on Rare Diseases (CIBERER), Valencia, Spain.

X-linked intellectual disability (XLID) is known to explain up to 10% of the intellectual disability in males. A large number of families in which intellectual disability is the only clinically consistent manifestation have been described. While linkage analysis and candidate gene testing were the initial approaches to find genes and variants, next generation sequencing (NGS) has accelerated the discovery of more and more XLID genes. Using NGS, we resolved the genetic cause of MRX82 (OMIM number 300518), a large Spanish Basque family with five affected males with intellectual disability and a wide phenotypic variability among them despite having the same pathogenic variant. Although the previous linkage study had mapped the locus to an interval of 7.6Mb in Xq24-Xq25 of the X chromosome, this region contained too many candidate genes to be analysed using conventional approaches. NGS revealed a novel nonsense variant: c.118C > T; p.Gln40* in , a gene previously implicated in XLID that encodes a protein involved in nonsense-mediated mRNA decay (NMD). Further molecular studies showed that the mRNA transcript was not completely degraded by NMD. However, UPF3B protein was not detected by conventional Western Blot analysis at least downstream of the 40 residue demonstrating that the phenotype could be due to the loss of functional protein. This is the first report of a premature termination codon before the three functional domains of the UPF3B protein and these results directly implicate the absence of these domains with XLID, autism and some dysmorphic features.
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http://dx.doi.org/10.3389/fgene.2019.01074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836624PMC
October 2019

Randomized Controlled Trial of Oropharyngeal Colostrum Administration in Very-low-birth-weight Preterm Infants.

J Pediatr Gastroenterol Nutr 2019 07;69(1):126-130

Division of Neonatology, Department of Pediatrics.

Objective: The purpose of this study was to evaluate the effects of oropharyngeal colostrum administration in the incidence of late-onset clinical and proven sepsis and in concentrations of immunoglobulin A (IgA) in very-low-birth-weight (VLBW) infants.

Methods: We conducted a double-blinded, randomized, placebo-controlled trial and assigned 113 VLBW infants to receive 0.2 mL of maternal colostrum or sterile water (placebo) via oropharyngeal route every 2 hours for 48 hours, beginning in the first 48 to 72 hours of life. Neonates of both groups were fed breast milk from the first 3 days of life until a volume of at least 100 mL · kg · day. IgA was measured in serum and urine before and after treatment. Clinical data during hospitalization were collected.

Results: We found no statistically significant differences between colostrum and placebo groups in the incidence of late-onset clinical sepsis (odds ratio 0.7602; CI 95% 0.3-1.6) and proven sepsis (odds ratio 0.7028; CI 95% 0.3-1.6). The measurement of IgA was similar in serum before (P value 0.87) and after treatment (P value 0.26 day 4 and 0.77 day 18). No differences were also observed in IgA in urine before (P value 0.8) and after treatment (P value 0.73 day 4 and 0.52).

Conclusions: This study could not confirm the hypothesis that oropharyngeal administration of maternal colostrum to VLBW could reduce the incidence of late-onset sepsis and increase the levels of IgA. We believe that this finding can be justified by the practice of feeding VLBW infants exclusively with breast milk in the first days of life and reinforces the prior knowledge of the importance of early nutrition, especially, with human milk. It also suggests that oropharyngeal administration of colostrum should be reserved for neonates who cannot be fed in first few days of life.
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http://dx.doi.org/10.1097/MPG.0000000000002356DOI Listing
July 2019

Role of age and comorbidities in mortality of patients with infective endocarditis.

Authors:
Carlos Armiñanzas Concepción Fariñas-Alvarez Jesús Zarauza Patricia Muñoz Víctor González Ramallo Manuel Martínez Sellés José Mª Miró Meda Juan Manuel Pericás Miguel Ángel Goenaga Guillermo Ojeda Burgos Regino Rodríguez Álvarez Laura Castelo Corral Juan Gálvez-Acebal Francisco Javier Martínez Marcos Maria Carmen Fariñas Fernando Fernández Sánchez Mariam Noureddine Gabriel Rosas Javier de la Torre Lima José Aramendi Elena Bereciartua María José Blanco Roberto Blanco María Victoria Boado Marta Campaña Lázaro Alejandro Crespo Josune Goikoetxea José Ramón Iruretagoyena Josu Irurzun Zuazabal Leire López-Soria Miguel Montejo Javier Nieto David Rodrigo David Rodríguez Regino Rodríguez Yolanda Vitoria Roberto Voces Mª Victoria García López Radka Ivanova Georgieva Guillermo Ojeda Isabel Rodríguez Bailón Josefa Ruiz Morales Ana María Cuende Tomás Echeverría Ana Fuerte Eduardo Gaminde Miguel Ángel Goenaga Pedro Idígoras José Antonio Iribarren Alberto Izaguirre Yarza Xabier Kortajarena Urkola Carlos Reviejo Rafael Carrasco Vicente Climent Patricio Llamas Esperanza Merino Joaquín Plazas Sergio Reus Nemesio Álvarez José María Bravo-Ferrer Laura Castelo José Cuenca Pedro Llinares Enrique Miguez Rey María Rodríguez Mayo Efrén Sánchez Dolores Sousa Regueiro Francisco Javier Martínez Mª Del Mar Alonso Beatriz Castro Dácil García Rosado Mª Del Carmen Durán Mª Antonia Miguel Gómez Juan Lacalzada Ibrahim Nassar Antonio Plata Ciezar José Mª Reguera Iglesias Víctor Asensi Álvarez Carlos Costas Jesús de la Hera Jonnathan Fernández Suárez Lisardo Iglesias Fraile Víctor León Arguero José López Menéndez Pilar Mencia Bajo Carlos Morales Alfonso Moreno Torrico Carmen Palomo Begoña Paya Martínez Ángeles Rodríguez Esteban Raquel Rodríguez García Mauricio Telenti Asensio Manuel Almela Juan Ambrosioni Manuel Azqueta Mercè Brunet Marta Bodro Ramón Cartañá Carlos Falces Guillermina Fita David Fuster Cristina García de la Mària Marta Hernández-Meneses Jaume Llopis Pérez Francesc Marco José M Miró Asunción Moreno David Nicolás Salvador Ninot Eduardo Quintana Carlos Paré Daniel Pereda Juan M Pericás José L Pomar José Ramírez Irene Rovira Elena Sandoval Marta Sitges Dolors Soy Adrián Téllez José M Tolosana Bárbara Vidal Jordi Vila Iván Adán Javier Bermejo Emilio Bouza Daniel Celemín Gregorio Cuerpo Caballero Antonia Delgado Montero Ana Fernández Cruz Ana García Mansilla Mª Eugenia García Leoni Víctor González Ramallo Martha Kestler Hernández Amaia Mari Hualde Mercedes Marín Manuel Martínez-Sellés Mª Cruz Menárguez Patricia Muñoz Cristina Rincón Hugo Rodríguez-Abella Marta Rodríguez-Créixems Blanca Pinilla Ángel Pinto Maricela Valerio Pilar Vázquez Eduardo Verde Moreno Isabel Antorrena Belén Loeches Alejandro Martín Quirós Mar Moreno Ulises Ramírez Verónica Rial Bastón María Romero Araceli Saldaña Jesús Agüero Balbín Cristina Amado Carlos Armiñanzas Castillo Ana Arnaiz García Manuel Cobo Belaustegui María Carmen Fariñas Concepción Fariñas-Álvarez Rubén Gómez Izquierdo Iván García Claudia González-Rico Manuel Gutiérrez-Cuadra José Gutiérrez Díez Marcos Pajarón José Antonio Parra Aurelio Sarralde Ramón Teira Jesús Zarauza Fernando Domínguez Pablo García Pavía Jesús González Beatriz Orden Antonio Ramos Tomasa Centella José Manuel Hermida José Luis Moya Pilar Martín-Dávila Enrique Navas Enrique Oliva Alejandro Del Río Soledad Ruiz Carmen Hidalgo Tenorio Manuel Almendro Delia Omar Araji José Miguel Barquero Román Calvo Jambrina Marina de Cueto Juan Gálvez Acebal Irene Méndez Isabel Morales Luis Eduardo López-Cortés Arístides de Alarcón Emilio García Juan Luis Haro José Antonio Lepe Francisco López Rafael Luque Luis Javier Alonso Pedro Azcárate José Manuel Azcona Gutiérrez José Ramón Blanco Lara García-Álvarez José Antonio Oteo Mercedes Sanz Natividad de Benito Mercé Gurguí Cristina Pacho Roser Pericas Guillem Pons M Álvarez A L Fernández Amparo Martínez A Prieto Benito Regueiro E Tijeira Marino Vega Andrés Canut Blasco José Cordo Mollar Juan Carlos Gainzarain Arana Oscar García Uriarte Alejandro Martín López Zuriñe Ortiz de Zárate José Antonio Urturi Matos Gloria García Domínguez Antonio Sánchez-Porto José Mª Arribas Leal Elisa García Vázquez Alicia Hernández Torres Ana Blázquez Gonzalo de la Morena Valenzuela Ángel Alonso Javier Aramburu Felicitas Elena Calvo Anai Moreno Rodríguez Paola Tarabini-Castellani Eva Heredero Gálvez Carolina Maicas Bellido José Largo Pau Mª Antonia Sepúlveda Pilar Toledano Sierra Sadaf Zafar Iqbal-Mirza Eva Cascales Alcolea Pilar Egea Serrano José Joaquín Hernández Roca Ivan Keituqwa Yañez Ana Peláez Ballesta Víctor Soriano Eduardo Moreno Escobar Alejandro Peña Monje Valme Sánchez Cabrera David Vinuesa García María Arrizabalaga Asenjo Carmen Cifuentes Luna Juana Núñez Morcillo Mª Cruz Pérez Seco Aroa Villoslada Gelabert Carmen Aured Guallar Nuria Fernández Abad Pilar García Mangas Marta Matamala Adell Mª Pilar Palacián Ruiz Juan Carlos Porres Begoña Alcaraz Vidal Nazaret Cobos Trigueros María Jesús Del Amor Espín José Antonio Giner Caro Roberto Jiménez Sánchez Amaya Jimeno Almazán Alejandro Ortín Freire Monserrat Viqueira González Pere Pericás Ramis Mª Ángels Ribas Blanco Enrique Ruiz de Gopegui Bordes Laura Vidal Bonet Mª Carmen Bellón Munera Elena Escribano Garaizabal Antonia Tercero Martínez Juan Carlos Segura Luque

Eur J Intern Med 2019 Jun 21;64:63-71. Epub 2019 Mar 21.

Complejo Hospitalario Universitario de Albacete Albacete, Spain.

Purpose: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality.

Methods: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups:<65 years,65 to 80 years,and ≥ 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk.

Results: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 ≥ 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients ≥80 years who underwent surgery were significantly lower compared with other age groups (14.3%,65 years; 20.5%,65-79 years; 31.3%,≥80 years). In-hospital mortality was lower in the <65-year group (20.3%,<65 years;30.1%,65-79 years;34.7%,≥80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%,≥80 years; p = 0.003).Independent predictors of mortality were age ≥ 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32-3.34), CCI ≥ 3 (HR:1.62; 95% CI:1.39-1.88),and non-performed surgery (HR:1.64;95% CI:11.16-1.58).When the three age groups were compared,the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality.

Conclusion: There were no differences in the clinical presentation of IE between the groups. Age ≥ 80 years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group.
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http://dx.doi.org/10.1016/j.ejim.2019.03.006DOI Listing
June 2019

Aerobic Glycolysis Is Required for Spatial Memory Acquisition But Not Memory Retrieval in Mice.

eNeuro 2019 Jan-Feb;6(1). Epub 2019 Feb 22.

Department of Biology, University of Western Ontario, London, Ontario N6A 5B7, Canada.

The consolidation of newly formed memories and their retrieval are energetically demanding processes. Aerobic glycolysis (AG), also known as the Warburg effect, consists of the production of lactate from glucose in the presence of oxygen. The astrocyte neuron lactate shuttle hypothesis posits that astrocytes process glucose by AG to generate lactate, which is used as a fuel source within neurons to maintain synaptic activity. Studies in mice have demonstrated that lactate transport between astrocytes and neurons is required for long-term memory formation, yet the role of lactate production in memory acquisition and retrieval has not previously been explored. Here, we examined the effect of dichloroacetate (DCA), a chemical inhibitor of lactate production, on spatial learning and memory in mice using the Morris water maze (MWM). hyperpolarized C-pyruvate magnetic resonance spectroscopy revealed decreased conversion of pyruvate to lactate in the mouse brain following DCA administration, concomitant with a reduction in the phosphorylation of pyruvate dehydrogenase. DCA exposure before each training session in the MWM impaired learning, which subsequently resulted in impaired memory during the probe trial. In contrast, mice that underwent training without DCA exposure, but received a single DCA injection before the probe trial exhibited normal memory. Our findings indicate that AG plays a key role during memory acquisition but is less important for the retrieval of established memories. Thus, the activation of AG may be important for learning-dependent synaptic plasticity rather than the activation of signaling cascades required for memory retrieval.
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http://dx.doi.org/10.1523/ENEURO.0389-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390195PMC
April 2019

Development of a human milk concentrate with human milk lyophilizate for feeding very low birth weight preterm infants: A preclinical experimental study.

PLoS One 2019 20;14(2):e0210999. Epub 2019 Feb 20.

Department of Pediatrics, Neonatology, Children´s Hospital, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.

Breast milk is considered the gold standard nutritional resource for very low birth weight (VLBW) infants in terms of nutrients and protective factors. If mother's milk is not available, the second choice is donated and fortified human milk (HM) from the Human Milk Bank (HMB). This study hypothesized that HM could be lyophilized and used as an additive to increase the levels of macronutrients and micronutrients available to VLBW infants. This study aimed to constitute a lyophilized HM concentrate and determine the osmolality and the concentration of macronutrients and micronutrients in HM samples at "baseline" and in "HM concentrates", analyzed immediately (HMCI), and after 3 (HMC3m) and 6 (HMC6m) months of freezing. Osmolality was verified using the freezing point osmometric method. Macronutrient quantification was performed using the MIRIS Human Milk Analyzer. Micronutrients were determined by Flame Atomic Absorption Spectrophotometry and by the automated colorimetric method. Bayesian linear mixed effect models were adjusted using OpenBUGS to estimate mean differences and 95% credibility intervals (CrI) of osmolality and of macro- and micronutrients between the types of HM samples. A comparison of dosage values showed a significant increase between HM baseline and HMCI, HMC3m, and HMC6m. Comparing HM baseline and HMCI highlighted the increase in energy content and the concentration of carbohydrates and total lipids. The Ca and P contents increased and the levels of energy, total lipids, and Cu were reduced in HMC3m compared to HMCI. Ca, Mg, K, Zn, and P increased and the levels of energy, total lipids, and Cu were reduced in HMC6m, compared to HMCI. The present study confirms the possibility of formulation and utilization of the immediate concentrate. Partial stability of HM concentrates generated from freeze-drying of donated milk do not recommend storage.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210999PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382113PMC
October 2019

A Machine Learning Approach to Reveal the NeuroPhenotypes of Autisms.

Int J Neural Syst 2019 Sep 13;29(7):1850058. Epub 2018 Dec 13.

5Department of Psychiatry, University of Cambridge, Cambridge, CB2 0SZ, UK.

Although much research has been undertaken, the spatial patterns, developmental course, and sexual dimorphism of brain structure associated with autism remains enigmatic. One of the difficulties in investigating differences between the sexes in autism is the small sample sizes of available imaging datasets with mixed sex. Thus, the majority of the investigations have involved male samples, with females somewhat overlooked. This paper deploys machine learning on partial least squares feature extraction to reveal differences in regional brain structure between individuals with autism and typically developing participants. A four-class classification problem (sex and condition) is specified, with theoretical restrictions based on the evaluation of a novel upper bound in the resubstitution estimate. These conditions were imposed on the classifier complexity and feature space dimension to assure generalizable results from the training set to test samples. Accuracies above on gray and white matter tissues estimated from voxel-based morphometry (VBM) features are obtained in a sample of equal-sized high-functioning male and female adults with and without autism (, /group). The proposed learning machine revealed how autism is modulated by biological sex using a low-dimensional feature space extracted from VBM. In addition, a spatial overlap analysis on reference maps partially corroborated predictions of the "extreme male brain" theory of autism, in sexual dimorphic areas.
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http://dx.doi.org/10.1142/S0129065718500582DOI Listing
September 2019

Correction: The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome.

Authors:
Pleuntje J van der Sluijs Sandra Jansen Samantha A Vergano Miho Adachi-Fukuda Yasemin Alanay Adila AlKindy Anwar Baban Allan Bayat Stefanie Beck-Wödl Katherine Berry Emilia K Bijlsma Levinus A Bok Alwin F J Brouwer Ineke van der Burgt Philippe M Campeau Natalie Canham Krystyna Chrzanowska Yoyo W Y Chu Brain H Y Chung Karin Dahan Marjan De Rademaeker Anne Destree Tracy Dudding-Byth Rachel Earl Nursel Elcioglu Ellen R Elias Christina Fagerberg Alice Gardham Blanca Gener Erica H Gerkes Ute Grasshoff Arie van Haeringen Karin R Heitink Johanna C Herkert Nicolette S den Hollander Denise Horn David Hunt Sarina G Kant Mitsuhiro Kato Hülya Kayserili Rogier Kersseboom Esra Kilic Malgorzata Krajewska-Walasek Kylin Lammers Lone W Laulund Damien Lederer Melissa Lees Vanesa López-González Saskia Maas Grazia M S Mancini Carlo Marcelis Francisco Martinez Isabelle Maystadt Marianne McGuire Shane McKee Sarju Mehta Kay Metcalfe Jeff Milunsky Seiji Mizuno John B Moeschler Christian Netzer Charlotte W Ockeloen Barbara Oehl-Jaschkowitz Nobuhiko Okamoto Sharon N M Olminkhof Carmen Orellana Laurent Pasquier Caroline Pottinger Vera Riehmer Stephen P Robertson Maian Roifman Caroline Rooryck Fabienne G Ropers Monica Rosello Claudia A L Ruivenkamp Mahmut S Sagiroglu Suzanne C E H Sallevelt Amparo Sanchis Calvo Pelin O Simsek-Kiper Gabriela Soares Lucia Solaeche Fatma Mujgan Sonmez Miranda Splitt Duco Steenbeek Alexander P A Stegmann Constance T R M Stumpel Saori Tanabe Eyyup Uctepe G Eda Utine Hermine E Veenstra-Knol Sunita Venkateswaran Catheline Vilain Catherine Vincent-Delorme Anneke T Vulto-van Silfhout Patricia Wheeler Golder N Wilson Louise C Wilson Bernd Wollnik Tomoki Kosho Dagmar Wieczorek Evan Eichler Rolph Pfundt Bert B A de Vries Jill Clayton-Smith Gijs W E Santen

Genet Med 2019 Sep;21(9):2160-2161

Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41436-018-0368-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752317PMC
September 2019

ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks.

Nat Commun 2019 01 8;10(1):87. Epub 2019 Jan 8.

The Wellcome Trust and Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.

Mutations in the ATM tumor suppressor gene confer hypersensitivity to DNA-damaging chemotherapeutic agents. To explore genetic resistance mechanisms, we performed genome-wide CRISPR-Cas9 screens in cells treated with the DNA topoisomerase I inhibitor topotecan. Thus, we here establish that inactivating terminal components of the non-homologous end-joining (NHEJ) machinery or of the BRCA1-A complex specifically confer topotecan resistance to ATM-deficient cells. We show that hypersensitivity of ATM-mutant cells to topotecan or the poly-(ADP-ribose) polymerase (PARP) inhibitor olaparib reflects delayed engagement of homologous recombination at DNA-replication-fork associated single-ended double-strand breaks (DSBs), allowing some to be subject to toxic NHEJ. Preventing DSB ligation by NHEJ, or enhancing homologous recombination by BRCA1-A complex disruption, suppresses this toxicity, highlighting a crucial role for ATM in preventing toxic LIG4-mediated chromosome fusions. Notably, suppressor mutations in ATM-mutant backgrounds are different to those in BRCA1-mutant scenarios, suggesting new opportunities for patient stratification and additional therapeutic vulnerabilities for clinical exploitation.
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http://dx.doi.org/10.1038/s41467-018-07729-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325118PMC
January 2019

Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay.

Am J Hum Genet 2019 01 20;104(1):164-178. Epub 2018 Dec 20.

Department of Pediatrics, CHU Sainte-Justine Research Center and University of Montreal, Montreal, QC H3T 1C5, Canada. Electronic address:

SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.
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http://dx.doi.org/10.1016/j.ajhg.2018.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323608PMC
January 2019

Gellan gum-based gels with tunable relaxation properties for MRI phantoms.

Magn Reson Imaging 2019 04 28;57:40-49. Epub 2018 Oct 28.

School of Biomedical Engineering, The University of Western Ontario, London, Canada; Department of Chemical and Biochemical Engineering, The University of Western Ontario, London, Canada. Electronic address:

Object: The research follows the analysis of gellan gum-based gels as novel MRI phantom material with the implementation of a design of experiments model to obtain tunable relaxation properties.

Materials And Methods: Gellan gum gels doped with newly synthesized superparamagnetic iron oxide nanoparticles (SPIONs) and either MnCl or GdCl were prepared and scanned from 230 μT to 3 T. Nineteen gel samples were formulated with varying concentrations of contrast agents to determine the linear, quadratic, and interactive effects of the contrast agents by a central composite design of experiment. To inhibit microbial growth in the gels and to enable long-term use, methyl 4‑hydroxybenzoate (methylparaben) was utilized.

Results: The model containing SPIONs and metal salts relaxivity was analyzed with ANOVA, and the resulting significant coefficients were tabulated. The mathematical model was able to accurately predict the intended relaxation property from the concentration of the contrast agent with adjusted R values > 0.97 for longitudinal (R) relaxation rates and 0.87 for transverse (R) relaxation rates.

Conclusion: The gel material maintained physical, chemical, and biological stability for at least four months and contained controllable relaxation properties while maintaining optical clarity.
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http://dx.doi.org/10.1016/j.mri.2018.10.017DOI Listing
April 2019

NEUROBEHAVIOR OF PRETERM, SMALL AND APPROPRIATE FOR GESTATIONAL AGE NEWBORN INFANTS.

Rev Paul Pediatr 2018 Oct-Dec;36(4):407-414. Epub 2018 Oct 29.

Universidade de São Paulo - campus Ribeirão Preto, Ribeirão Preto, SP, Brasil.

Objective: To compare the neurobehavioral development of preterm infants with postconceptional age between 32 and 36 weeks and 6 days, according to the adequacy of the weight for the gestational age at birth.

Methods: A cross-sectional study was performed comparing two independent groups. The 55 preterm infants who were included in the sample were hospitalized in a neonatal intermediate care unit and were evaluated using the Neurobehavioral Assessment of the Preterm Infant (NAPI) at the postconceptional age between 32 and 36 weeks and 6 days and compared according to the adequacy of the weight for the gestational age. In addition to the comparison between the groups, infants who were born small for gestational age (SGA) and those ones adequate for gestational age (AGA) were also compared, considering the type of intrauterine growth. The following instruments were used: NAPI, anamnesis script, Brazilian Economic Classification Criteria, and medical records.

Results: Infants were born with mean gestational age of 32.0 weeks, with the postconceptional age and postnatal age of 34.8 weeks and 19.5 days, respectively. The sample consisted of 55% of female infants. The results did not show any differences in NAPI domains between SGA and AGA groups, neither in the subgroups of SGA babies with symmetric or asymmetric growth.

Conclusions: There was no difference between SGA and AGA babies in relation to neurobehavioral development evaluated before reaching term.
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http://dx.doi.org/10.1590/1984-0462/;2018;36;4;00006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322798PMC
June 2019

The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome.

Authors:
Pleuntje J van der Sluijs Sandra Jansen Samantha A Vergano Miho Adachi-Fukuda Yasemin Alanay Adila AlKindy Anwar Baban Allan Bayat Stefanie Beck-Wödl Katherine Berry Emilia K Bijlsma Levinus A Bok Alwin F J Brouwer Ineke van der Burgt Philippe M Campeau Natalie Canham Krystyna Chrzanowska Yoyo W Y Chu Brain H Y Chung Karin Dahan Marjan De Rademaeker Anne Destree Tracy Dudding-Byth Rachel Earl Nursel Elcioglu Ellen R Elias Christina Fagerberg Alice Gardham Blanca Gener Erica H Gerkes Ute Grasshoff Arie van Haeringen Karin R Heitink Johanna C Herkert Nicolette S den Hollander Denise Horn David Hunt Sarina G Kant Mitsuhiro Kato Hülya Kayserili Rogier Kersseboom Esra Kilic Malgorzata Krajewska-Walasek Kylin Lammers Lone W Laulund Damien Lederer Melissa Lees Vanesa López-González Saskia Maas Grazia M S Mancini Carlo Marcelis Francisco Martinez Isabelle Maystadt Marianne McGuire Shane McKee Sarju Mehta Kay Metcalfe Jeff Milunsky Seiji Mizuno John B Moeschler Christian Netzer Charlotte W Ockeloen Barbara Oehl-Jaschkowitz Nobuhiko Okamoto Sharon N M Olminkhof Carmen Orellana Laurent Pasquier Caroline Pottinger Vera Riehmer Stephen P Robertson Maian Roifman Caroline Rooryck Fabienne G Ropers Monica Rosello Claudia A L Ruivenkamp Mahmut S Sagiroglu Suzanne C E H Sallevelt Amparo Sanchis Calvo Pelin O Simsek-Kiper Gabriela Soares Lucia Solaeche Fatma Mujgan Sonmez Miranda Splitt Duco Steenbeek Alexander P A Stegmann Constance T R M Stumpel Saori Tanabe Eyyup Uctepe G Eda Utine Hermine E Veenstra-Knol Sunita Venkateswaran Catheline Vilain Catherine Vincent-Delorme Anneke T Vulto-van Silfhout Patricia Wheeler Golder N Wilson Louise C Wilson Bernd Wollnik Tomoki Kosho Dagmar Wieczorek Evan Eichler Rolph Pfundt Bert B A de Vries Jill Clayton-Smith Gijs W E Santen

Genet Med 2019 06 8;21(6):1295-1307. Epub 2018 Nov 8.

Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting.

Methods: Clinicians entered clinical data in an extensive web-based survey.

Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified.

Conclusion: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.
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http://dx.doi.org/10.1038/s41436-018-0330-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752273PMC
June 2019