97 research outputs found
Isoprenylcysteine Carboxylmethyltransferase-Based Therapy for Hutchinson-Gilford Progeria Syndrome.
Hutchinson-Gilford progeria syndrome (HGPS, progeria) is a rare genetic disease characterized by premature aging and death in childhood for which there were no approved drugs for its treatment until last November, when lonafarnib obtained long-sought FDA approval. However, the benefits of lonafarnib in patients are limited, highlighting the need for new therapeutic strategies. Here, we validate the enzyme isoprenylcysteine carboxylmethyltransferase (ICMT) as a new therapeutic target for progeria with the development of a new series of potent inhibitors of this enzyme that exhibit an excellent antiprogeroid profile. Among them, compound UCM-13207 significantly improved the main hallmarks of progeria. Specifically, treatment of fibroblasts from progeroid mice with UCM-13207 delocalized progerin from the nuclear membrane, diminished its total protein levels, resulting in decreased DNA damage, and increased cellular viability. Importantly, these effects were also observed in patient-derived cells. Using the Lmna G609G/G609G progeroid mouse model, UCM-13207 showed an excellent in vivo efficacy by increasing body weight, enhancing grip strength, extending lifespan by 20%, and decreasing tissue senescence in multiple organs. Furthermore, UCM-13207 treatment led to an improvement of key cardiovascular hallmarks such as reduced progerin levels in aortic and endocardial tissue and increased number of vascular smooth muscle cells (VSMCs). The beneficial effects go well beyond the effects induced by other therapeutic strategies previously reported in the field, thus supporting the use of UCM-13207 as a new treatment for progeria.This work was supported by grants from The Progeria
Research Foundation (PRF 2016-65) and the Spanish
MINECO (PID2019-106279RB-I00, PID2019-108489RBI00). The authors thank Fundación La Caixa (A.G.), CEI
Moncloa (N.I.M.-R.), MINECO (F.J.O.-N. and M.B.) and
Ministerio de Ciencia, Innovación y Universidades (N.K.-F.)
for predoctoral fellowships. The authors thank C. López-Otín
for kindly donating LmnaG609G/G609G progeroid and their
corresponding wild-type fibroblasts and UCM’s CAIs
Cytometry and Fluorescence Microscopy, Genomics, NMR,
and Mass Spectrometry, for their assistance. The CNIC is
supported by the Ministerio de Ciencia e Innovación, the
Instituto de Salud Carlos III, and the pro-CNIC Foundation,
and is a Severo Ochoa Center of Excellence (grant SEV-2015-
0505). The generation of the antiprogerin antibody was funded
by the Wellcome Trust (098291/Z/12/Z to S.N.).S
A experiência vivida das mulheres numa zona rural de Asientos, Aguascalientes durante o período climatérico
Introduction: Nursing care seeks the integrity of the person in all spheres of development and thus improves quality of life. Objective: To know the experience of women who are in the climacteric stage and who live in a rural area of the municipality of Asientos, Aguascalientes. Methodology: Qualitative study with Heiddeger's hermeneutic phenomenological approach. Seven women participated. Seven phenomenological interviews were conducted for the collection of information to guarantee the quality of the study. Results: The interviews lasted approximately 40 minutes. Nine units of meaning were obtained, which were divided into two groups: ontic and ontological. The ontic meaning units included: ignorance of climacteric as a stage of life, distress in climacteric and medical care during climacteric. The other group includes the ontological meaning units: sexual desire in darkness, absence of a partner, the family world and the climacteric period, transcendence in the climacteric period, and suffering in the climacteric period. Conclusion: Climacteric women have an influence on the sociocultural environment, repetitive patterns and scarce knowledge of the subject.Introducción: El cuidado de enfermería busca la integridad de la persona en todas sus esferas de desarrollo y con ello mejora calidad de vida. Objetivo: Conocer la experiencia que tienen las mujeres que cursan la etapa del climaterio y que viven en zona rural del municipio de Asientos, Aguascalientes. Metodología: Estudio cualitativo con enfoque fenomenológico hermenéutico de Heiddeger. Participaron 7 mujeres. Para la recolección de la información se realizaron siete entrevistas fenomenológicas, para garantizar la calidad del estudio. Resultados: Las entrevistas tuvieron una duración aproximada de 40 minutos. Se obtuvo 9 unidades de significado, las cuales se dividieron en dos grupos: óntico y ontológico. En las unidades de significado óntico se incluyó: desconocimiento del climaterio como etapa de la vida, angustia en el climaterio y atención medica durante el climaterio. El otro grupo abarca las unidades de significado ontológico integrado por: el deseo sexual en tinieblas, ausencia de compañero, el mundo familiar y el climaterio, trascendencia en el climaterio, sufrimiento en el climaterio. Conclusión: Las mujeres climatéricas tienen una influencia sobre el entorno sociocultural, patrones repetitivos y conocimientos escasos del tema.Resumo: Introdução: Os cuidados de enfermagem procuram a integridade da pessoa em todas as esferas de desenvolvimento e assim melhorar a qualidade de vida. Objectivo: Descobrir a experiência das mulheres na fase climatérica da vida que vivem numa zona rural do município de Asientos, Aguascalientes. Metodologia: Estudo qualitativo com a abordagem fenomenológica hermenêutica de Heiddeger. Sete mulheres participaram. Foram realizadas sete entrevistas fenomenológicas para recolher a informação, a fim de garantir a qualidade do estudo. Resultados: As entrevistas duraram aproximadamente 40 minutos. Foram obtidas nove unidades de significado, que foram divididas em dois grupos: ontico e ontológico. As unidades de significado ôntico incluíam: ignorância do climatério como fase da vida, angústia no climatério e cuidados médicos durante o climatério. O outro grupo compreende as unidades de significado ontológico: desejo sexual na escuridão, ausência de parceiro, o mundo familiar e o climatério, transcendência no climatério, sofrimento no climatério. Conclusão: As mulheres climatéricas são influenciadas pelo ambiente sócio-cultural, padrões repetitivos e fraco conhecimento do assunto
Divulgación en tiempos de pandemia: el poder de las webs
Trabajo presentado en el simposio Micromundo Aprendizaje-Servicio para el descubrimiento de antibiótico
In Vitro Cytotoxic Activity of Methanol Extracts of Selected Medicinal Plants Traditionally Used in Mexico against Human Hepatocellular Carcinoma
Medicinal plants are traditionally used in Mexico to treat diseases such as cancer. The present study aimed to evaluate the cytotoxic, antioxidant, and anti-hemolytic activity of 15 plants of ethnopharmacological use in Mexico. For this, plant methanol extracts were prepared by the Soxhlet method, after which their cytotoxic activity was evaluated against human hepatocellular carcinoma (HEP-G2) and monkey kidney epithelial (Vero) cells by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction colorimetric assay. The selectivity index (SI) of each extract was then determined by the IC50 ratio of normal to tumor cells. We showed that Ruta chalepensis extract possessed an IC50 of 1.79 µg/mL and 522.08 µg/mL against HEP-G2 and Vero cells, respectively, resulting in an SI of 291.50. Furthermore, antioxidant activity was evaluated by the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging technique, where the best antioxidant potential was shown by the Heterotheca inuloides extract (IC50 = 19.24 µg/mL). Furthermore, the hemolytic potential was determined against human erythrocytes, which showed that the extracts with the highest anti-hemolytic activity were Smilax aspera (IC50 = 4.41 µg/mL) and Amphipterygium adstringens (IC50 = 5.35 µg/mL). In conclusion, we observed that R. chalepensis methanol extract possesses cytotoxic activity against HEP-G2 cells, without affecting non-tumorigenic Vero cells. Our results indicated the antitumor potential of medicinal plants used in Mexico
Unravelling the mechanisms that determine the uptake and metabolism of magnetic single and multicore nanoparticles in a Xenopus laevis model.
Multicore superparamagnetic nanoparticles have been proposed as ideal tools for some biomedical applications because of their high magnetic moment per particle, high specific surface area and long term colloidal stability. Through controlled aggregation and packing of magnetic cores it is possible to obtain not only single-core but also multicore and hollow spheres with internal voids. In this work, we compare toxicological properties of single and multicore nanoparticles. Both types of particles showed moderate in vitro toxicity (MTT assay) tested in Hep G2 (human hepatocellular carcinoma) and Caco-2 (human colorectal adenocarcinoma) cells. The influence of surface chemistry in their biological behavior was also studied after functionalization with O,O′-bis(2-aminoethyl) PEG (2000 Da). For the first time, these nanoparticles were evaluated in a Xenopus laevis model studying their whole organism toxicity and their impact upon iron metabolism. The degree of activation of the metabolic pathway depends on the size and surface charge of the nanoparticles which determine their uptake. The results also highlight the potential of Xenopus laevis model bridging the gap between in vitro cell-based assays and rodent models for toxicity assessment to develop effective nanoparticles for biomedical applications
Assessment of a New ROS1 Immunohistochemistry Clone (SP384) for the Identification of ROS1 Rearrangements in Patients with Non–Small Cell Lung Carcinoma: the ROSING Study
Introduction: The ROS1 gene rearrangement has become an important biomarker in NSCLC. The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology testing guidelines support the use of ROS1 immunohistochemistry (IHC) as a screening test, followed by confirmation with fluorescence in situ hybridization (FISH) or a molecular test in all positive results. We have evaluated a novel anti-ROS1 IHC antibody (SP384) in a large multicenter series to obtain real-world data.
Methods: A total of 43 ROS1 FISH-positive and 193 ROS1 FISH-negative NSCLC samples were studied. All specimens were screened by using two antibodies (clone D4D6 from Cell Signaling Technology and clone SP384 from Ventana Medical Systems), and the different interpretation criteria were compared with break-apart FISH (Vysis). FISH-positive samples were also analyzed with next-generation sequencing (Oncomine Dx Target Test Panel, Thermo Fisher Scientific).
Results: An H-score of 150 or higher or the presence of at least 70% of tumor cells with an intensity of staining of 2+ or higher by the SP384 clone was the optimal cutoff value (both with 93% sensitivity and 100% specificity). The D4D6 clone showed similar results, with an H-score of at least 100 (91% sensitivity and 100% specificity). ROS1 expression in normal lung was more frequent with use of the SP384 clone (p < 0.0001). The ezrin gene (EZR)-ROS1 variant was associated with membranous staining and an isolated green signal FISH pattern (p = 0.001 and p = 0.017, respectively).
Conclusions: The new SP384 ROS1 IHC clone showed excellent sensitivity without compromising specificity, so it is another excellent analytical option for the proposed testing algorithm
Association between Use of Enhanced Recovery after Surgery Protocol and Postoperative Complications in Total Hip and Knee Arthroplasty in the Postoperative Outcomes Within Enhanced Recovery after Surgery Protocol in Elective Total Hip and Knee Arthroplasty Study (POWER2)
Importance: The Enhanced Recovery After Surgery (ERAS) care protocol has been shown to improve outcomes compared with traditional care in certain types of surgery.
Objective: To assess the association of use of the ERAS protocols with complications in patients undergoing elective total hip arthroplasty (THA) and total knee arthroplasty (TKA).
Design, Setting, and Participants: This multicenter, prospective cohort study included patients recruited from 131 centers in Spain from October 22 through December 22, 2018. All consecutive adults scheduled for elective THA or TKA were eligible for inclusion. Patients were stratified between those treated in a self-designated ERAS center (ERAS group) and those treated in a non-ERAS center (non-ERAS group). Data were analyzed from June 15 through September 15, 2019.
Exposures: Total hip or knee arthroplasty and perioperative management. Sixteen individual ERAS items were assessed in all included patients, whether they were treated at a center that was part of an established ERAS protocol or not. Main Outcomes and Measures: The primary outcome was postoperative complications within 30 days after surgery. Secondary outcomes included length of stay and mortality. Results: During the 2-month recruitment period, 6146 patients were included (3580 women [58.2%]; median age, 71 [interquartile range (IQR), 63-76] years). Of these, 680 patients (11.1%) presented with postoperative complications. No differences were found in the number of patients with overall postoperative complications between ERAS and non-ERAS groups (163 [10.2%] vs 517 [11.4%]; odds ratio [OR], 0.89; 95% CI, 0.74-1.07; P =.22). Fewer patients in the ERAS group had moderate to severe complications (73 [4.6%] vs 279 [6.1%]; OR, 0.74; 95% CI, 0.56-0.96; P =.02). The median overall adherence rate with the ERAS protocol was 50.0% (IQR, 43.8%-62.5%), with the rate for ERAS facilities being 68.8% (IQR, 56.2%-81.2%) vs 50.0% (IQR, 37.5%-56.2%) at non-ERAS centers (P <.001). Among the patients with the highest and lowest quartiles of adherence to ERAS components, the patients with the highest adherence had fewer overall postoperative complications (144 [10.6%] vs 270 [13.0%]; OR, 0.80; 95% CI, 0.64-0.99; P <.001) and moderate to severe postoperative complications (59 [4.4%] vs 143 [6.9%]; OR, 0.62; 95% CI, 0.45-0.84; P <.001) and shorter median length of hospital stay (4 [IQR, 3-5] vs 5 [IQR, 4-6] days; OR, 0.97; 95% CI, 0.96-0.99; P <.001).
Conclusions and Relevance: An increase in adherence to the ERAS program was associated with a decrease in postoperative complications, although only a few ERAS items were individually associated with improved outcomes
Generating and repairing genetically programmed DNA breaks during immunoglobulin class switch recombination
Adaptive immune responses require the generation of a diverse repertoire of immunoglobulins (Igs) that can recognize and neutralize a seemingly infinite number of antigens. V(D)J recombination creates the primary Ig repertoire, which subsequently is modified by somatic hypermutation (SHM) and class switch recombination (CSR). SHM promotes Ig affinity maturation whereas CSR alters the effector function of the Ig. Both SHM and CSR require activation-induced cytidine deaminase (AID) to produce dU:dG mismatches in the Ig locus that are transformed into untemplated mutations in variable coding segments during SHM or DNA double-strand breaks (DSBs) in switch regions during CSR. Within the Ig locus, DNA repair pathways are diverted from their canonical role in maintaining genomic integrity to permit AID-directed mutation and deletion of gene coding segments. Recently identified proteins, genes, and regulatory networks have provided new insights into the temporally and spatially coordinated molecular interactions that control the formation and repair of DSBs within the Ig locus. Unravelling the genetic program that allows B cells to selectively alter the Ig coding regions while protecting non-Ig genes from DNA damage advances our understanding of the molecular processes that maintain genomic integrity as well as humoral immunity
Reconstructing Native American Population History
The peopling of the Americas has been the subject of extensive genetic, archaeological and linguistic research; however, central questions remain unresolved1–5. One contentious issue is whether the settlement occurred via a single6–8 or multiple streams of migration from Siberia9–15. The pattern of dispersals within the Americas is also poorly understood. To address these questions at higher resolution than was previously possible, we assembled data from 52 Native American and 17 Siberian groups genotyped at 364,470 single nucleotide polymorphisms. We show that Native Americans descend from at least three streams of Asian gene flow. Most descend entirely from a single ancestral population that we call “First American”. However, speakers of Eskimo-Aleut languages from the Arctic inherit almost half their ancestry from a second stream of Asian gene flow, and the Na-Dene-speaking Chipewyan from Canada inherit roughly one-tenth of their ancestry from a third stream. We show that the initial peopling followed a southward expansion facilitated by the coast, with sequential population splits and little gene flow after divergence, especially in South America. A major exception is in Chibchan-speakers on both sides of the Panama Isthmus, who have ancestry from both North and South America
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