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Background: An essential component of residential hospice care is the provision of high quality palliative care. The perspectives of quality of care from palliative care patients and bereaved caregivers have increasingly been studied to guide quality improvements. Aim: The study aimed to explore the experiences and perceptions of bereaved caregivers of patients who died in residential hospice during the coronavirus disease-19 (COVID-19) pandemic to determine perceptions of quality of care, caregiver grief and bereavement, and the impact of the COVID-19 pandemic. Design: Qualitative exploratory study using secure, web-based semistructured interviews. Data were analyzed using thematic analysis. Setting/Participants: A total of 15 bereaved caregiver participants were recruited from two residential hospice sites in Ottawa, Ontario. Results: Participants identified several factors that impacted the quality of care in residential hospice, including the impact of the COVID-19 pandemic itself. The findings are presented in three main themes: (1) quality of residential hospice end-of-life care; (2) caregiver perceptions of their grief and bereavement; and (3) impact of the COVID-19 pandemic on hospice quality of care and caregiver bereavement. Conclusions: The COVID-19 pandemic had a significant impact on the patient and caregivers experience of hospice, including perception of quality of care and caregiver experience of grief and bereavement.
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BACKGROUND: Returning home from the hospital for palliative-focused care is a common transition, but the process can be emotionally distressing and logistically challenging for patients and caregivers. While interventions exist to aid in the transition, none have been developed in partnership with patients and caregivers. OBJECTIVE: To undergo the initial stages of codesign to create an intervention (Advancing the Care Experience for patients receiving Palliative care as they Transition from hospital to Home [ACEPATH]) to improve the experience of hospital-to-home transitions for adult patients receiving palliative care and their caregiver(s). METHODS: The codesign process consisted of (1) the development of codesign workshop (CDW) materials to communicate key findings from prior research to CDW participants; (2) CDWs with patients, caregivers and healthcare providers (HCPs); and (3) low-fidelity prototype testing to review CDW outputs and develop low-fidelity prototypes of interventions. HCPs provided feedback on the viability of low-fidelity prototypes. RESULTS: Three patients, seven caregivers and five HCPs participated in eight CDWs from July 2022 to March 2023. CDWs resulted in four intervention prototypes: a checklist, quick reference sheets, a patient/caregiver workbook and a transition navigator role. Outputs from CDWs included descriptions of interventions and measures of success. In April 2023, the four prototypes were presented in four low-fidelity prototype sessions to 20 HCPs. Participants in the low-fidelity prototype sessions provided feedback on what the interventions could look like, what problems the interventions were trying to solve and concerns about the interventions. CONCLUSION: Insights gained from this codesign work will inform high-fidelity prototype testing and the eventual implementation and evaluation of an ACEPATH intervention that aims to improve hospital-to-home transitions for patients receiving a palliative approach to care. PATIENT OR PUBLIC CONTRIBUTION: Patients and caregivers with lived experience attended CDWs aimed at designing an intervention to improve the transition from hospital to home. Their direct involvement aligns the intervention with patients' and caregivers' needs when transitioning from hospital to home. Furthermore, four patient/caregiver advisors were engaged throughout the project (from grant writing through to manuscript writing) to ensure all stages were patient- and caregiver-centred.
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Cuidadores , Cuidados Paliativos , Adulto , Humanos , Cuidadores/psicología , Personal de Salud , Transición del Hospital al Hogar , Cuidados Paliativos/métodosRESUMEN
Genotype-phenotype correlations add value to the management of families with hereditary hearing loss (HL), where age-related typical audiograms (ARTAs) are generated from cross-sectional regression equations and used to predict the audiogram phenotype across the lifespan. A seven-generation kindred with autosomal dominant sensorineural HL (ADSNHL) was recruited and a novel pathogenic variant in POU4F3 (c.37del) was identified by combining linkage analysis with whole exome sequencing (WES). POU4F3 is noted for large intrafamilial variation including the age of onset of HL, audiogram configuration and presence of vestibular impairment. Sequential audiograms and longitudinal analyses reveal highly variable audiogram features among POU4F3 (c.37del) carriers, limiting the utility of ARTAs for clinical prognosis and management of HL. Furthermore, a comparison of ARTAs against three previously published families (1 Israeli Jewish, 2 Dutch) reveals significant interfamilial differences, with earlier onset and slower deterioration. This is the first published report of a North American family with ADSNHL due to POU4F3, the first report of the pathogenic c.37del variant, and the first study to conduct longitudinal analysis, extending the phenotypic spectrum of DFNA15.
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Sordera , Pérdida Auditiva Sensorineural , Pérdida Auditiva , Humanos , Estudios Transversales , Proteínas de Homeodominio/genética , Pérdida Auditiva/genética , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/patología , Linaje , Factor de Transcripción Brn-3C/genéticaRESUMEN
OBJECTIVE: The aim of the study is to report adverse effects from clinical studies on ultrasound-guided percutaneous cryoneurolysis for spasticity. DESIGN: Patients were prospectively enrolled in three studies at a single institution. Cryoneurolysis was performed to primarily motor nerve branches (medial and lateral pectoral, musculocutaneous, radial, median, ulnar, tibial, obturator) and mixed motor sensory nerve trunks (median, ulnar, suprascapular, radial, and tibial). RESULTS: Cryoneurolysis was performed for 277 nerves (99 mixed motor sensory), on 113 patients (59 F, 54 M, average age 54.4 yrs). One patient had a local skin infection and two patients had bruising or swelling; all resolved within 1 mo. Nine reported nerve pain or dysesthesia (two motor, seven mixed motor sensory nerves). Four received no treatment, four oral or topical medications, two perineural injections, one botulinum toxin. Three patients' symptoms remained until 3 mos and one had numbness at six. One patient had botulinum toxin injections for cramping. All had at minimum 3-mo follow-up; seven withdrew (xÌ = 5.4 mos), four passed away. None of these 11 reported adverse effects. CONCLUSIONS: A total of 96.75% of nerve treatments had no pain or dysesthesias beyond treatment. Few had pain or numbness beyond 3 mos. Cryoneurolysis has potential to be a safe spasticity treatment with manageable adverse effects.
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BACKGROUND: Due to the COVID-19 pandemic, many community palliative healthcare providers shifted from providing care in a patient's home to providing almost exclusively virtual palliative care, or a combination of in-person and virtual care. Research on virtual palliative care is thus needed to provide evidence-based recommendations aiming to enhance the delivery of palliative care during and beyond the pandemic. AIM: To explore the experiences and perceptions of community palliative care providers, patients and caregivers who delivered or received virtual palliative care as a component of home-based palliative care during the COVID-19 pandemic. DESIGN: Qualitative study using phone and video-based semi-structured interviews. Data were analyzed using thematic analysis. SETTING/PARTICIPANTS: A total of 37 participants, including community palliative care patients/caregivers (n = 19) and healthcare providers (n = 18) recruited from sites in Ottawa and Toronto, Ontario, Canada. RESULTS: Overall, participants preferred in-person palliative care compared to virtual care, but suggested virtual care could be a useful supplement to in-person care. The findings are presented in three main themes: (1) Impact of COVID-19 pandemic on community palliative care services; (2) Factors influencing transition from exclusively virtual model of care back to a blended model of care; and (3) Recommended uses and implementation of virtual palliative care. CONCLUSIONS: Incorporating virtual palliative care into healthcare provider practice models (blended care models) may be the ideal model of care and standard practice moving forward beyond the COVID-19 pandemic, which has important implications toward organization and delivery of community palliative care services and funding of healthcare providers.
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COVID-19 , Cuidados Paliativos , Humanos , Cuidadores , Pandemias , Personal de Salud , Investigación Cualitativa , OntarioRESUMEN
BACKGROUND: We have previously developed and validated a biomarker-based metric of overall health status using Mahalanobis distance (DM) to measure how far from the norm of a reference population (RP) an individual's biomarker profile is. DM is not particularly sensitive to the choice of biomarkers; however, this makes comparison across studies difficult. Here we aimed to identify and validate a standard, optimized version of DM that would be highly stable across populations, while using fewer and more commonly measured biomarkers. METHODS: Using three datasets (the Baltimore Longitudinal Study of Aging, Invecchiare in Chianti and the National Health and Nutrition Examination Survey), we selected the most stable sets of biomarkers in all three populations, notably when interchanging RPs across populations. We performed regression models, using a fourth dataset (the Women's Health and Aging Study), to compare the new DM sets to other well-known metrics [allostatic load (AL) and self-assessed health (SAH)] in their association with diverse health outcomes: mortality, frailty, cardiovascular disease (CVD), diabetes, and comorbidity number. RESULTS: A nine- (DM9) and a seventeen-biomarker set (DM17) were identified as highly stable regardless of the chosen RP (e.g.: mean correlation among versions generated by interchanging RPs across dataset of r = 0.94 for both DM9 and DM17). In general, DM17 and DM9 were both competitive compared with AL and SAH in predicting aging correlates, with some exceptions for DM9. For example, DM9, DM17, AL, and SAH all predicted mortality to a similar extent (ranges of hazard ratios of 1.15-1.30, 1.21-1.36, 1.17-1.38, and 1.17-1.49, respectively). On the other hand, DM9 predicted CVD less well than DM17 (ranges of odds ratios of 0.97-1.08, 1.07-1.85, respectively). CONCLUSIONS: The metrics we propose here are easy to measure with data that are already available in a wide array of panel, cohort, and clinical studies. The standardized versions here lose a small amount of predictive power compared to more complete versions, but are nonetheless competitive with existing metrics of overall health. DM17 performs slightly better than DM9 and should be preferred in most cases, but DM9 may still be used when a more limited number of biomarkers is available.
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Envejecimiento , Fragilidad , Biomarcadores , Femenino , Humanos , Estudios Longitudinales , Encuestas NutricionalesRESUMEN
Sequencing exomes/genomes have been successful for identifying recessive genes; however, discovery of dominant genes including deafness genes (DFNA) remains challenging. We report a new DFNA gene, ATP11A, in a Newfoundland family with a variable form of bilateral sensorineural hearing loss (SNHL). Genome-wide SNP genotyping linked SNHL to DFNA33 (LOD = 4.77), a locus on 13q34 previously mapped in a German family with variable SNHL. Whole-genome sequencing identified 51 unremarkable positional variants on 13q34. Continuous clinical ascertainment identified several key recombination events and reduced the disease interval to 769 kb, excluding all but one variant. ATP11A (NC_000013.11: chr13:113534963G>A) is a novel variant predicted to be a cryptic donor splice site. RNA studies verified in silico predictions, revealing the retention of 153 bp of intron in the 3' UTR of several ATP11A isoforms. Two unresolved families from Israel were subsequently identified with a similar, variable form of SNHL and a novel duplication (NM_032189.3:c.3322_3327+2dupGTCCAGGT) in exon 28 of ATP11A extended exon 28 by 8 bp, leading to a frameshift and premature stop codon (p.Asn1110Valfs43Ter). ATP11A is a type of P4-ATPase that transports (flip) phospholipids from the outer to inner leaflet of cell membranes to maintain asymmetry. Haploinsufficiency of ATP11A, the phospholipid flippase that specially transports phosphatidylserine (PS) and phosphatidylethanolamine (PE), could leave cells with PS/PE at the extracellular side vulnerable to phagocytic degradation. Given that surface PS can be pharmaceutically targeted, hearing loss due to ATP11A could potentially be treated. It is also likely that ATP11A is the gene underlying DFNA33.
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Transportadoras de Casetes de Unión a ATP , Sordera , Pérdida Auditiva Sensorineural , Pérdida Auditiva , Humanos , Regiones no Traducidas 3' , Transportadoras de Casetes de Unión a ATP/genética , Sordera/genética , Pérdida Auditiva/genética , Pérdida Auditiva Sensorineural/genética , Mutación , Linaje , Fosfolípidos/metabolismo , Sitios de Empalme de ARNRESUMEN
BACKGROUND: Epidemiological studies consistently indicate that alcohol consumption is an independent risk factor for female breast cancer (BC). Although the aldehyde dehydrogenase 2 (ALDH2) polymorphism (rs671: Glu>Lys) has a strong effect on acetaldehyde metabolism, the association of rs671 with BC risk and its interaction with alcohol intake have not been fully elucidated. We conducted a pooled analysis of 14 case-control studies, with individual data on Asian ancestry women participating in the Breast Cancer Association Consortium. METHODS: We included 12,595 invasive BC cases and 12,884 controls for the analysis of rs671 and BC risk, and 2,849 invasive BC cases and 3,680 controls for the analysis of the gene-environment interaction between rs671 and alcohol intake for BC risk. The pooled odds ratios (OR) with 95% confidence intervals (CI) associated with rs671 and its interaction with alcohol intake for BC risk were estimated using logistic regression models. RESULTS: The Lys/Lys genotype of rs671 was associated with increased BC risk (OR = 1.16, 95% CI 1.03-1.30, p = 0.014). According to tumor characteristics, the Lys/Lys genotype was associated with estrogen receptor (ER)-positive BC (OR = 1.19, 95% CI 1.05-1.36, p = 0.008), progesterone receptor (PR)-positive BC (OR = 1.19, 95% CI 1.03-1.36, p = 0.015), and human epidermal growth factor receptor 2 (HER2)-negative BC (OR = 1.25, 95% CI 1.05-1.48, p = 0.012). No evidence of a gene-environment interaction was observed between rs671 and alcohol intake (p = 0.537). CONCLUSION: This study suggests that the Lys/Lys genotype confers susceptibility to BC risk among women of Asian ancestry, particularly for ER-positive, PR-positive, and HER2-negative tumor types.
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Aldehído Deshidrogenasa Mitocondrial/genética , Neoplasias de la Mama/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Consumo de Bebidas Alcohólicas/epidemiología , Pueblo Asiatico/genética , Neoplasias de la Mama/epidemiología , Femenino , Interacción Gen-Ambiente , Humanos , Persona de Mediana EdadRESUMEN
OBJECTIVE: To explore health care providers' perceptions of the provision of palliative care in the Qikiqtaaluk (formerly known as Baffin) region of Nunavut. DESIGN: An exploratory, qualitative, cross-sectional design using in-depth, semistructured interviews. SETTING: Qikiqtaaluk region of Nunavut. PARTICIPANTS: Seven physicians and 6 registered nurses who worked in Iqaluit or other northern Inuit communities in the Qikiqtaaluk region of Nunavut. METHODS: Thirteen health care providers participated in in-person or telephone semistructured interviews, which were audiorecorded and transcribed verbatim. MAIN FINDINGS: Interviews with the participating health care providers in the Qikiqtaaluk region of Nunavut revealed 5 complex and interwoven themes that influence the provision of comprehensive, culturally competent palliative care services to Indigenous patients: respecting Inuit culture, end-of-life care planning, and the role of family; recognizing the importance of the northern community (sense of home); being aware of the limited health care resources; recognizing the critical role of medical interpreters; and improving the quality of palliative care programs and resources, as well as health care provider training in palliative care and Inuit end-of-life care. CONCLUSION: Health care providers in the Qikiqtaaluk region of Nunavut have identified several important themes that influence the provision of culturally sensitive and comprehensive palliative care, most notably the need to develop palliative care resources and programs. It is hoped that the results of this study can be used to help guide palliative care strategies including program development and educational initiatives for health care providers. These initiatives can help build community capacity within a currently underserviced population and improve end-of-life care services available to Nunavut patients and their families. Further studies are required to determine the perspectives of medical interpreters, as well as palliative care patients and their families.
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Actitud del Personal de Salud , Asistencia Sanitaria Culturalmente Competente/normas , Inuk/psicología , Cuidados Paliativos/organización & administración , Planificación Anticipada de Atención/organización & administración , Estudios Transversales , Humanos , Nunavut , Relaciones Profesional-Familia , Investigación CualitativaRESUMEN
OBJECTIVE: To provide a proof-of-concept study demonstrating that the decades old procedure of cryoneurotomy, used traditionally for analgesia, is a safe adjunctive and effective treatment for limb spasticity. DESIGN: Case series. SETTING: Publicly funded outpatient hospital spasticity clinic and community interventional anesthesia clinic. PARTICIPANTS: Patients (N=3) who had plateaued with standard of care spasticity treatments including botulinum toxin. Two hemiplegic stroke patients with elbow spasticity and 1 pregnant patient with multiple sclerosis and a spastic equinovarus foot for whom botulinum toxin was now contraindicated. INTERVENTIONS: Selective anesthetic diagnostic motor nerve blocks with ultrasound and e-stimulation with 1cc of 1% lidocaine to the motor nerve to the targeted spastic muscle were performed to either the musculocutaneous nerve to brachialis, radial nerve to the brachioradialis or the tibial nerve. If the benefits included improved active and passive range motion and or decreased clonus, a percutaneous cryoneurotomy was performed. MAIN OUTCOME MEASURES: Active and passive range of motion were measured using the Modified Tardieu Scale. The change in resistance to passive stretch was measured using the Modified Ashworth Scale (MAS). Videos of the before and after treatment were collected. RESULTS: Both elbows' treatments resulted in MAS improving from a 3 to a 1+. Greatly improved active range of motion was noted at 94 and 64 degrees, respectively, as well as improvements in passive range on the Modified Tardieu Scale. The tibial nerve cryoneurotomy resulted in improvements in all parameters with a much improved gait. Results were maintained up to 17 months of follow-up. CONCLUSION: Cryoneurotomy as a treatment for spasticity is a novel safe adjuvant treatment. Our initial results suggest patients can achieve significantly increased active and passive range of motion in the upper extremity and decreased clonus, and improved gait after tibial nerve cryoneurotomy.
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BACKGROUND: Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers, and cancer-related traits. METHODS: The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers, and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background. RESULTS: The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis. CONCLUSIONS: Results from these analyses will enable researchers to identify new susceptibility loci, perform fine-mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental, and lifestyle-related exposures. IMPACT: Ongoing analyses will shed light on etiology and risk assessment for many types of cancer. Cancer Epidemiol Biomarkers Prev; 26(1); 126-35. ©2016 AACR.
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Predisposición Genética a la Enfermedad/epidemiología , Variación Genética/genética , Estudio de Asociación del Genoma Completo/métodos , Neoplasias/genética , Polimorfismo de Nucleótido Simple/genética , Femenino , Genotipo , Humanos , Masculino , Neoplasias/epidemiología , Neoplasias/fisiopatología , Prevalencia , Pronóstico , Medición de Riesgo , Selección GenéticaRESUMEN
BACKGROUND: As the world population grows towards 9 billion by 2050, it is projected that food production will need to increase by 60%. A critical part of this growth includes the safe and effective use of insecticides to reduce the estimated 20-49% loss of global crop yields owing to pests. The development of new insecticides will help to sustain this protection and overcome insecticide resistance. RESULTS: A novel class of mesoionic compounds has been discovered, with exceptional insecticidal activity on a range of Hemiptera and Lepidoptera. These compounds bind to the orthosteric site of the nicotinic acetylcholine receptor and result in a highly potent inhibitory action at the receptor with minimal agonism. The synthesis, biological activity, optimization and mode of action will be discussed. CONCLUSION: Triflumezopyrim insect control will provide a powerful tool for control of hopper species in rice throughout Asia. Dicloromezotiaz can provide a useful control tool for lepidopteran pests, with an underexploited mode of action among these pests. © 2016 Society of Chemical Industry.
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Hemípteros/efectos de los fármacos , Insecticidas/farmacología , Mariposas Nocturnas/efectos de los fármacos , Periplaneta/efectos de los fármacos , Animales , Áfidos/efectos de los fármacos , Áfidos/crecimiento & desarrollo , Hemípteros/crecimiento & desarrollo , Proteínas de Insectos/metabolismo , Insecticidas/síntesis química , Mariposas Nocturnas/crecimiento & desarrollo , Antagonistas Nicotínicos/metabolismo , Periplaneta/crecimiento & desarrolloRESUMEN
A novel class of mesoionic pyrido[1,2-a]pyrimidinones has been discovered with exceptional insecticidal activity controlling a number of insect species, particularly hemiptera and lepidoptera. Mode-of-action studies showed that they act on nicotinic acetylcholine receptors (nAChRs) primarily as inhibitors. Here we report the discovery, evolution, and preparation of this class of chemistry. Our efforts in structure-activity relationship elucidation and biological activity evaluation are also presented.
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Insecticidas/química , Insecticidas/toxicidad , Antagonistas Nicotínicos/química , Antagonistas Nicotínicos/toxicidad , Pirimidinonas/química , Pirimidinonas/toxicidad , Animales , Hemípteros/efectos de los fármacos , Hemípteros/fisiología , Proteínas de Insectos/metabolismo , Lepidópteros/efectos de los fármacos , Lepidópteros/fisiología , Receptores Nicotínicos/metabolismo , Relación Estructura-ActividadRESUMEN
Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele OR ER+ = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10-30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER-) breast cancer (lead SNP rs6864776: per-a allele OR ER- = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10-12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10-05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in â¼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.
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Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Cromosomas Humanos Par 5/genética , Factor 10 de Crecimiento de Fibroblastos/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Receptores de Estrógenos/metabolismo , Alelos , Estudios de Casos y Controles , Línea Celular Tumoral , Elementos de Facilitación Genéticos/genética , Factor 10 de Crecimiento de Fibroblastos/metabolismo , Haplotipos/genética , Humanos , Regiones Promotoras Genéticas/genética , Sitios de Carácter Cuantitativo/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismoRESUMEN
Triflumezopyrim, a newly commercialized molecule from DuPont Crop Protection, belongs to the novel class of mesoionic insecticides. This study characterizes the biochemical and physiological action of this novel insecticide. Using membranes from the aphid, Myzus persicae, triflumezopyrim was found to displace (3)H-imidacloprid with a Ki value of 43 nM with competitive binding results indicating that triflumezopyrim binds to the orthosteric site of the nicotinic acetylcholine receptor (nAChR). In voltage clamp studies using dissociated Periplaneta americana neurons, triflumezopyrim inhibits nAChR currents with an IC50 of 0.6 nM. Activation of nAChR currents was minimal and required concentrations ≥100 µM. Xenopus oocytes expressing chimeric nAChRs (Drosophila α2/chick ß2) showed similar inhibitory effects from triflumezopyrim. In P. americana neurons, co-application experiments with acetylcholine reveal the inhibitory action of triflumezopyrim to be rapid and prolonged in nature. Such physiological action is distinct from other insecticides in IRAC Group 4 in which the toxicological mode of action is attributed to nAChR agonism. Mesoionic insecticides act via inhibition of the orthosteric binding site of the nAChR despite previous beliefs that such action would translate to poor insect control. Triflumezopyrim is the first commercialized insecticide from this class and provides outstanding control of hoppers, including the brown planthopper, Nilaparvata lugens, which is already displaying strong resistance to neonicotinoids such as imidacloprid.
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Áfidos/efectos de los fármacos , Insecticidas/farmacología , Antagonistas Nicotínicos/metabolismo , Periplaneta/efectos de los fármacos , Piridinas/farmacología , Pirimidinonas/farmacología , Xenopus laevis/metabolismo , Animales , Áfidos/fisiología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Periplaneta/fisiologíaRESUMEN
BACKGROUND: Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer. It is often associated with invasive ductal carcinoma (IDC), and is considered to be a non-obligate precursor of IDC. It is not clear to what extent these two forms of cancer share low-risk susceptibility loci, or whether there are differences in the strength of association for shared loci. METHODS: To identify genetic polymorphisms that predispose to DCIS, we pooled data from 38 studies comprising 5,067 cases of DCIS, 24,584 cases of IDC and 37,467 controls, all genotyped using the iCOGS chip. RESULTS: Most (67 %) of the 76 known breast cancer predisposition loci showed an association with DCIS in the same direction as previously reported for invasive breast cancer. Case-only analysis showed no evidence for differences between associations for IDC and DCIS after considering multiple testing. Analysis by estrogen receptor (ER) status confirmed that loci associated with ER positive IDC were also associated with ER positive DCIS. Analysis of DCIS by grade suggested that two independent SNPs at 11q13.3 near CCND1 were specific to low/intermediate grade DCIS (rs75915166, rs554219). These associations with grade remained after adjusting for ER status and were also found in IDC. We found no novel DCIS-specific loci at a genome wide significance level of P < 5.0x10(-8). CONCLUSION: In conclusion, this study provides the strongest evidence to date of a shared genetic susceptibility for IDC and DCIS. Studies with larger numbers of DCIS are needed to determine if IDC or DCIS specific loci exist.
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Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/genética , Carcinoma Intraductal no Infiltrante/genética , Ciclina D1/genética , Estudios de Asociación Genética , Adulto , Anciano , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Carcinoma Intraductal no Infiltrante/patología , Femenino , Genotipo , Humanos , Antígeno Ki-67/genética , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Polimorfismo de Nucleótido Simple , Receptor ErbB-2/genética , Receptores de Estrógenos/genética , Receptores de Progesterona/genéticaRESUMEN
Investigating 5-methylcytosine (5mC) has led to many hypotheses regarding molecular mechanism underlying human diseases and disorders. Many of these studies, however, utilize bisulfite conversion alone, which cannot distinguish 5mC from its recently discovered oxidative product, 5-hydroxymethylcytosine (5hmC). Furthermore, previous array-based technologies do not have the necessary probes to adequately investigate both modifications simultaneously. In this manuscript, we used technical replicates of DNA from human brain, human blood, and human saliva, in combination with oxidative bisulfite conversion and Illumina's Infinium MethylationEPIC array, to analyze 5mC and 5hmC at more than 650 000 and 450 000 relevant loci, respectively, in the human genome. We show the presence of loci with detectable 5mC and 5hmC to be equally distributed across chromosomes and genomic features, while also being present in genomic regions with transcriptional regulatory properties. We also describe 2528 5hmC sites common across tissue types that show a strong association with immune-related functions. Lastly, in human brain, we show that 5hmC accounts for one-third of the total signal from bisulfite-converted data. As such, not only do our results confirm the efficacy and sensitivity of pairing oxidative bisulfite conversion and the EPIC array to detect 5mC and 5hmC in all three tissue types, but they also highlight the importance of dissociating 5hmC from 5mC in future studies related to cytosine modifications.