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1.
Cell ; 153(6): 1228-38, 2013 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-23683578

RESUMO

Reprogramming somatic cells into pluripotent embryonic stem cells (ESCs) by somatic cell nuclear transfer (SCNT) has been envisioned as an approach for generating patient-matched nuclear transfer (NT)-ESCs for studies of disease mechanisms and for developing specific therapies. Past attempts to produce human NT-ESCs have failed secondary to early embryonic arrest of SCNT embryos. Here, we identified premature exit from meiosis in human oocytes and suboptimal activation as key factors that are responsible for these outcomes. Optimized SCNT approaches designed to circumvent these limitations allowed derivation of human NT-ESCs. When applied to premium quality human oocytes, NT-ESC lines were derived from as few as two oocytes. NT-ESCs displayed normal diploid karyotypes and inherited their nuclear genome exclusively from parental somatic cells. Gene expression and differentiation profiles in human NT-ESCs were similar to embryo-derived ESCs, suggesting efficient reprogramming of somatic cells to a pluripotent state.


Assuntos
Linhagem Celular , Células-Tronco Embrionárias/citologia , Fibroblastos/citologia , Técnicas de Transferência Nuclear , Adulto , Animais , Blastocisto/citologia , Fusão Celular , Núcleo Celular/genética , Separação Celular , Feminino , Feto/citologia , Humanos , Macaca mulatta , Mitocôndrias/genética , Oócitos/citologia , Oócitos/metabolismo , Pele/citologia
3.
Anal Chem ; 95(5): 2645-2652, 2023 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-36693249

RESUMO

Aptamers incorporating chemically modified bases can achieve superior affinity and specificity compared to natural aptamers, but their characterization remains a labor-intensive, low-throughput task. Here, we describe the "non-natural aptamer array" (N2A2) system, in which a minimally modified Illumina MiSeq instrument is used for the high-throughput generation and characterization of large libraries of base-modified DNA aptamer candidates based on both target binding and specificity. We first demonstrate the capability to screen multiple different base modifications to identify the optimal chemistry for high-affinity target binding. We next use N2A2 to generate aptamers that can maintain excellent specificity even in complex samples, with equally strong target affinity in both buffer and diluted human serum. For both aptamers, affinity was formally calculated with gold-standard binding assays. Given that N2A2 requires only minor mechanical modifications to the MiSeq, we believe that N2A2 offers a broadly accessible tool for generating high-quality affinity reagents for diverse applications.


Assuntos
Aptâmeros de Nucleotídeos , Humanos , Aptâmeros de Nucleotídeos/química , Bioensaio , Técnica de Seleção de Aptâmeros
4.
Mol Syst Biol ; 18(11): e10886, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36366891

RESUMO

During development, cell state transitions are coordinated through changes in the identity of molecular regulators in a cell type- and dose-specific manner. The ability to rationally engineer such transitions in human pluripotent stem cells (hPSC) will enable numerous applications in regenerative medicine. Herein, we report the generation of synthetic gene circuits that can detect a desired cell state using AND-like logic integration of endogenous miRNAs (classifiers) and, upon detection, produce fine-tuned levels of output proteins using an miRNA-mediated output fine-tuning technology (miSFITs). Specifically, we created an "hPSC ON" circuit using a model-guided miRNA selection and circuit optimization approach. The circuit demonstrates robust PSC-specific detection and graded output protein production. Next, we used an empirical approach to create an "hPSC-Off" circuit. This circuit was applied to regulate the secretion of endogenous BMP4 in a state-specific and fine-tuned manner to control the composition of differentiating hPSCs. Our work provides a platform for customized cell state-specific control of desired physiological factors in hPSC, laying the foundation for programming cell compositions in hPSC-derived tissues and beyond.


Assuntos
MicroRNAs , Células-Tronco Pluripotentes , Humanos , Genes Sintéticos , Diferenciação Celular/genética , Células-Tronco Pluripotentes/metabolismo , Redes Reguladoras de Genes , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas/metabolismo
5.
Acc Chem Res ; 55(5): 685-695, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35130439

RESUMO

Although antibodies are a powerful tool for molecular biology and clinical diagnostics, there are many emerging applications for which nucleic acid-based aptamers can be advantageous. However, generating high-quality aptamers with sufficient affinity and specificity for biomedical applications is a challenging feat for most research laboratories. In this Account, we describe four techniques developed in our laboratory to accelerate the discovery of high-quality aptamer reagents that can achieve robust binding even for challenging molecular targets. The first method is particle display, in which we convert solution-phase aptamers into aptamer particles that can be screened via fluorescence-activated cell sorting (FACS) to quantitatively isolate individual aptamer particles based on their affinity. This enables the efficient isolation of high-affinity aptamers in fewer selection rounds than conventional methods, thereby minimizing selection biases and reducing the emergence of artifacts in the final aptamer pool. We subsequently developed the multiparametric particle display (MPPD) method, which employs two-color FACS to isolate aptamer particles based on both affinity and specificity, yielding aptamers that exhibit excellent target binding even in complex matrixes such as serum. The third method is an alkyne-azide chemistry ("click chemistry")-based particle display (click-PD) that enables the generation and screening of "non-natural" aptamers with a wide range of base modifications. We have shown that these base-modified aptamers can achieve robust affinity and specificity for targets that have proven challenging or inaccessible with natural nucleotide-based aptamer libraries. Finally, we describe the non-natural aptamer array (N2A2) platform in which a modified benchtop sequencing instrument is used to characterize base-modified aptamers in high throughput, enabling the efficient identification of molecules with excellent affinity and specificity for their targets. This system first generates aptamer clusters on the flow-cell surface that incorporate alkyne-modified nucleobases and then performs a click reaction to couple those nucleobases to an azide-modified chemical moiety. This yields a sequence-defined array of tens of millions of base-modified sequences, which can then be characterized for affinity and specificity in a high-throughput fashion. Collectively, we believe that these advancements are helping to make aptamer technology more accessible, efficient, and robust, thereby enabling the use of these affinity reagents for a wider range of molecular recognition and detection-based applications.


Assuntos
Aptâmeros de Nucleotídeos , Aptâmeros de Nucleotídeos/química , Química Click , Citometria de Fluxo , Técnica de Seleção de Aptâmeros/métodos
6.
Pediatr Blood Cancer ; : e30517, 2023 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-37338275

RESUMO

Calcineurin inhibitors (CNI), cyclosporine and tacrolimus, are commonly used for pharmacologic prophylaxis of graft-versus-host disease after allogeneic hematopoietic cell transplantation (HCT). Unfortunately, their use is associated with significant toxicities. While intolerance to CNI is well defined, there is very little information on how they impact outcomes after HCT in children. Our retrospective study in a cohort of 82 children shows a high intolerance rate of 39% in this population associated with lower event-free survival and a higher transplant-related mortality.

7.
Nature ; 548(7668): 413-419, 2017 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-28783728

RESUMO

Genome editing has potential for the targeted correction of germline mutations. Here we describe the correction of the heterozygous MYBPC3 mutation in human preimplantation embryos with precise CRISPR-Cas9-based targeting accuracy and high homology-directed repair efficiency by activating an endogenous, germline-specific DNA repair response. Induced double-strand breaks (DSBs) at the mutant paternal allele were predominantly repaired using the homologous wild-type maternal gene instead of a synthetic DNA template. By modulating the cell cycle stage at which the DSB was induced, we were able to avoid mosaicism in cleaving embryos and achieve a high yield of homozygous embryos carrying the wild-type MYBPC3 gene without evidence of off-target mutations. The efficiency, accuracy and safety of the approach presented suggest that it has potential to be used for the correction of heritable mutations in human embryos by complementing preimplantation genetic diagnosis. However, much remains to be considered before clinical applications, including the reproducibility of the technique with other heterozygous mutations.


Assuntos
Proteínas de Transporte/genética , Embrião de Mamíferos/metabolismo , Edição de Genes/métodos , Mutação/genética , Adulto , Alelos , Blastocisto/metabolismo , Blastocisto/patologia , Divisão Celular , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Quebras de DNA de Cadeia Dupla , Embrião de Mamíferos/patologia , Marcação de Genes , Teste de Complementação Genética , Heterozigoto , Homozigoto , Humanos , Masculino , Mosaicismo , Reparo de DNA por Recombinação/genética , Fase S , Moldes Genéticos , Zigoto/metabolismo , Zigoto/patologia
8.
Pediatr Blood Cancer ; 69(9): e29693, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35373875

RESUMO

BACKGROUND: Ketamine is an NMDA-receptor antagonist with analgesic and opioid-sparing properties. Although well studied in adults, more robust evidence supporting ketamine's use for pediatric pain management is needed. This retrospective study evaluates ketamine's opioid-sparing effectiveness in pediatric and young adult oncology and hematology patients. PROCEDURE: Continuous ketamine infusions administered for pain management between 2010-2020 were reviewed. Data including demographic characteristics, oncology/hematology and pain diagnoses, concurrent pain medications, and ketamine infusions' dose and duration were collected. Opioid consumption data based on delivery via patient-controlled analgesia were collected 1 day before (D1), all days during (cumulatively named D2), and 1 day after (D3) ketamine infusions and calculated as morphine-equivalent doses (mg/kg/day). Data were reported for the entire study group as well as for distinct oncology and end-of-life categories, and short-term acute pain circumstances which included vaso-occlusive crises in hematology patients. Side effects were reviewed. RESULTS: Significantly lower daily opioid consumption was noted in the oncology group, while decreases were not significant in the end-of-life group and in the overall study population. The acute pain group did not show an opioid reduction associated with the ketamine infusions. A largely tolerable side-effect profile was observed, with no differences among each group's incidence. CONCLUSIONS: Ketamine infusions were associated with significantly reduced opioid consumption for oncology patients. The opioid-sparing effects of ketamine may vary according to clinical diagnoses and circumstances of use. Overall, low-dose ketamine infusions present an acceptable safety profile in pediatric and young adult patients; nevertheless, individual risks and benefits should be considered.


Assuntos
Dor Aguda , Ketamina , Neoplasias , Transtornos Relacionados ao Uso de Opioides , Dor Aguda/tratamento farmacológico , Analgésicos/uso terapêutico , Analgésicos Opioides/uso terapêutico , Criança , Morte , Humanos , Infusões Intravenosas , Ketamina/uso terapêutico , Morfina/uso terapêutico , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Dor Pós-Operatória/induzido quimicamente , Dor Pós-Operatória/tratamento farmacológico , Estudos Retrospectivos , Adulto Jovem
9.
Pediatr Blood Cancer ; 69(6): e29613, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35322524

RESUMO

OBJECTIVE: To compare outcomes of obese and nonobese pediatric patients with acute promyelocytic leukemia (APL) from the Cancer and Leukemia Group B trial (CALGB) 9710 and the Children's Oncology Group trial AAML0631. METHODS: Data including demographics, adverse events, overall and event-free survival (EFS) were analyzed. RESULTS: The prevalence of obesity was 34% on C9710 and 35% on AAML0631. There was significantly lower overall and EFS in the obese population on multivariable analysis on AAML0631 but not on CALGB 9710. Eleven patients died during therapy or in follow-up. CONCLUSION: The prevalence of obesity is higher in pediatric patients with APL compared to the general population. The decreased EFS and OS in obese patients on AAML0631 suggest that the presence of obesity can influence outcomes using the most current treatment. These findings support the need for further research on the potential role of obesity in pediatric APL leukemogenesis.


Assuntos
Leucemia Promielocítica Aguda , Obesidade Infantil , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Intervalo Livre de Doença , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Prevalência , Prognóstico , Resultado do Tratamento
10.
Nature ; 540(7632): 270-275, 2016 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-27919073

RESUMO

Maternally inherited mitochondrial (mt)DNA mutations can cause fatal or severely debilitating syndromes in children, with disease severity dependent on the specific gene mutation and the ratio of mutant to wild-type mtDNA (heteroplasmy) in each cell and tissue. Pathogenic mtDNA mutations are relatively common, with an estimated 778 affected children born each year in the United States. Mitochondrial replacement therapies or techniques (MRT) circumventing mother-to-child mtDNA disease transmission involve replacement of oocyte maternal mtDNA. Here we report MRT outcomes in several families with common mtDNA syndromes. The mother's oocytes were of normal quality and mutation levels correlated with those in existing children. Efficient replacement of oocyte mutant mtDNA was performed by spindle transfer, resulting in embryos containing >99% donor mtDNA. Donor mtDNA was stably maintained in embryonic stem cells (ES cells) derived from most embryos. However, some ES cell lines demonstrated gradual loss of donor mtDNA and reversal to the maternal haplotype. In evaluating donor-to-maternal mtDNA interactions, it seems that compatibility relates to mtDNA replication efficiency rather than to mismatch or oxidative phosphorylation dysfunction. We identify a polymorphism within the conserved sequence box II region of the D-loop as a plausible cause of preferential replication of specific mtDNA haplotypes. In addition, some haplotypes confer proliferative and growth advantages to cells. Hence, we propose a matching paradigm for selecting compatible donor mtDNA for MRT.


Assuntos
DNA Mitocondrial/genética , DNA Mitocondrial/uso terapêutico , Herança Materna/genética , Doenças Mitocondriais/genética , Doenças Mitocondriais/patologia , Terapia de Substituição Mitocondrial/métodos , Mutação , Oócitos/metabolismo , Blastocisto/citologia , Blastocisto/metabolismo , Linhagem Celular , Sequência Conservada/genética , DNA Mitocondrial/biossíntese , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Feminino , Haplótipos/genética , Humanos , Masculino , Meiose , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/prevenção & controle , Doação de Oócitos , Oócitos/citologia , Oócitos/patologia , Fosforilação Oxidativa , Linhagem , Polimorfismo Genético
11.
Int J Mol Sci ; 23(24)2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36555616

RESUMO

Breast cancer is among the most common cancers in women, second to skin cancer. Mammary gland development can influence breast cancer development in later life. Processes such as proliferation, invasion, and migration during mammary gland development can often mirror processes found in breast cancer. MicroRNAs (miRNAs), small, non-coding RNAs, can repress post-transcriptional RNA expression and can regulate up to 80% of all genes. Expression of miRNAs play a key role in mammary gland development, and aberrant expression can initiate or promote breast cancer. Here, we review the role of miRNAs in mammary development and breast cancer, and potential parallel roles. A total of 32 miRNAs were found to be expressed in both mammary gland development and breast cancer. These miRNAs are involved in proliferation, metastasis, invasion, and apoptosis in both processes. Some miRNAs were found to have contradictory roles, possibly due to their ability to target many genes at once. Investigation of miRNAs and their role in mammary gland development may inform about their role in breast cancer. In particular, by studying miRNA in development, mechanisms and potential targets for breast cancer treatment may be elucidated.


Assuntos
Neoplasias da Mama , Glândulas Mamárias Humanas , MicroRNAs , Feminino , Humanos , Apoptose , Neoplasias da Mama/metabolismo , Perfilação da Expressão Gênica , Glândulas Mamárias Humanas/metabolismo , MicroRNAs/metabolismo
12.
Pediatr Blood Cancer ; 68(11): e29215, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34264551

RESUMO

BACKGROUND: Despite a more robust experience with lidocaine infusions for pain management in adults and general pediatric population, there is limited evidence of efficacy of lidocaine infusions for pain management in patients with pediatric hematology and oncology diagnoses. METHODS: Data pertaining to continuous intravenous lidocaine infusions prescribed between January 2009 and June 2019 were reviewed, including patients' demographic characteristics, hematology/oncology and pain diagnoses, concurrent pain medications, and lidocaine infusion dose regimens and duration. Pain scores and opioid consumption calculations based on morphine equivalent doses (mg/kg/day) of patient-controlled analgesia were collected 1 day before infusion (D1), during infusion (D2), and 1 day after infusion (D3). RESULTS: The mean opioid consumption on D3 was significantly lower than that on D2 (p = .01). The pain scores on D3 were significantly lower than those on D1 when measured as average pain scores per 24 hours (p < .001) or as single pain scores immediately before and after infusions (p < .001). No significant associations were found between cumulative doses of lidocaine (loading dose plus total infusion dose) and either a decrease in the opioid consumption or a decrease in pain scores. CONCLUSIONS: In this retrospective series of pediatric hematology and oncology cases, we report positive outcomes in reducing opioid consumption and pain scores after lidocaine infusions. Prospective investigations designed in a collaborative, multi-institutional fashion, including a variety of pediatric populations are needed to further investigate the efficacy of lidocaine infusions.


Assuntos
Analgésicos Opioides , Lidocaína , Neoplasias , Dor Intratável , Analgésicos Opioides/uso terapêutico , Anestésicos Locais , Criança , Hematologia , Humanos , Infusões Intravenosas , Lidocaína/uso terapêutico , Oncologia , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Dor Intratável/tratamento farmacológico , Pediatria , Estudos Retrospectivos
13.
Postgrad Med J ; 97(1151): 605-607, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33790034

RESUMO

INTRODUCTION: Metronidazole is commonly prescribed for intra-abdominal infections. Oral metronidazole has high bioavailability (>95%) and intravenous metronidazole should be reserved for patients not suitable for oral preparations. METHODS AND MATERIALS: This full cycle audit evaluated the type of metronidazole preparation prescribed in adult emergency surgical patients requiring first-line empirical antimicrobial therapy for intra-abdominal infections. The criterion for audit was the proportion of patients who were prescribed intravenous metronidazole when the oral route was available. The first cycle included all consecutive eligible patients between 20 April and 14 May 2020. After an intervention phase educating prescribers about the similar pharmacokinetic properties of oral and intravenous metronidazole, clinical practice was reaudited between 22 June and 16 July 2020. Data were collected by case note and drug chart review. RESULTS: A total of 54 patients were included in the first audit cycle. Of these, 11 (20.4%) were prescribed oral metronidazole and 43 (79.6%) were prescribed intravenous metronidazole. In the majority of cases (35/43, 81.4%), intravenous metronidazole was prescribed in the absence of clear contraindications to the oral preparation. Of the 61 patients included in the reaudit cycle, 23 (37.7%) were prescribed oral metronidazole and 38 (62.3%) were prescribed intravenous metronidazole. The proportion of patients prescribed intravenous metronidazole despite being suitable for oral preparation decreased from 81.4% in the first cycle to 34.2% (13/38) in the reaudit cycle (risk ratio 0.42, 95% CI: 0.26 to 0.67, p<0.0001). Prescribing oral metronidazole when suitable saved up to £10.53/day per patient. CONCLUSION: This full cycle audit led to a significant improvement in the use of oral metronidazole in suitable patients, as well as a considerable reduction in healthcare costs.


Assuntos
Antibacterianos/uso terapêutico , Uso de Medicamentos/estatística & dados numéricos , Metronidazol/uso terapêutico , Prescrições/estatística & dados numéricos , Abscesso Abdominal/tratamento farmacológico , Administração Oral , Idoso , Antibacterianos/administração & dosagem , Feminino , Custos de Cuidados de Saúde , Humanos , Prescrição Inadequada/prevenção & controle , Infecções Intra-Abdominais/tratamento farmacológico , Masculino , Metronidazol/administração & dosagem , Pessoa de Meia-Idade , Peritonite/tratamento farmacológico , Estudos Prospectivos
14.
Curr Opin Organ Transplant ; 26(4): 347-352, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34074941

RESUMO

PURPOSE OF REVIEW: Renal transplantation offers the chance for patients with end-stage renal disease (ESRD) to have a significantly longer, healthier and better quality life compared with remaining on dialysis. Inequities have been demonstrated at multiple points in the transplantation pathway. In this review, the factors contributing to inequity in access to renal transplantation will be explored from a European perspective. RECENT FINDINGS: Despite improvements in patient assessment and revision of organ-offering schemes, there remain persistent inequities in access to the waiting list, allocation of a deceased donor transplant, receiving a living donor transplant and achieving preemptive transplantation. Older age, lower socioeconomic status and health literacy are key factors that continue to impact equity of access to transplantation. SUMMARY: A number of modifiable factors have been identified affecting access to transplantation, Increased patient education together with a better access to and promotion of living donation may help address some of these inequities.


Assuntos
Falência Renal Crônica , Transplante de Rim , Idoso , Acessibilidade aos Serviços de Saúde , Humanos , Falência Renal Crônica/cirurgia , Diálise Renal , Listas de Espera
15.
Nature ; 493(7434): 627-31, 2013 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-23103867

RESUMO

Mutations in mitochondrial DNA (mtDNA) are associated with severe human diseases and are maternally inherited through the egg's cytoplasm. Here we investigated the feasibility of mtDNA replacement in human oocytes by spindle transfer (ST; also called spindle-chromosomal complex transfer). Of 106 human oocytes donated for research, 65 were subjected to reciprocal ST and 33 served as controls. Fertilization rate in ST oocytes (73%) was similar to controls (75%); however, a significant portion of ST zygotes (52%) showed abnormal fertilization as determined by an irregular number of pronuclei. Among normally fertilized ST zygotes, blastocyst development (62%) and embryonic stem cell isolation (38%) rates were comparable to controls. All embryonic stem cell lines derived from ST zygotes had normal euploid karyotypes and contained exclusively donor mtDNA. The mtDNA can be efficiently replaced in human oocytes. Although some ST oocytes displayed abnormal fertilization, remaining embryos were capable of developing to blastocysts and producing embryonic stem cells similar to controls.


Assuntos
Terapia Genética , Doenças Mitocondriais/genética , Doenças Mitocondriais/terapia , Técnicas de Transferência Nuclear/normas , Adulto , Animais , Núcleo Celular/genética , Criopreservação , Citoplasma/genética , DNA Mitocondrial/análise , DNA Mitocondrial/genética , Embrião de Mamíferos/embriologia , Células-Tronco Embrionárias/citologia , Feminino , Fertilização , Humanos , Macaca mulatta/genética , Macaca mulatta/crescimento & desenvolvimento , Repetições de Microssatélites/genética , Oócitos/citologia , Gravidez , Adulto Jovem , Zigoto/citologia , Zigoto/patologia
17.
Kidney Int ; 91(6): 1287-1299, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28320531

RESUMO

Worldwide, the number of patients able to benefit from kidney transplantation is greatly restricted by the severe shortage of deceased donor organs. Allocation of this scarce resource is increasingly challenging and complex. Striking an acceptable balance between efficient use of (utility) and fair access to (equity) the limited supply of donated kidneys raises controversial but important debates at ethical, medical, and social levels. There is no international consensus on the recipient and donor factors that should be considered in the kidney allocation process. There is a general trend toward a reduction in the influence of human leukocyte antigen mismatch and an increase in the importance of other factors shown to affect posttransplant outcomes, such as cold ischemia, duration of dialysis, donor and recipient age, and comorbidity. Increased consideration of equity has led to improved access to transplantation for disadvantaged patient groups. There has been an overall improvement in the transparency and accountability of allocation policies. Novel and contentious approaches in kidney allocation include the use of survival prediction scores as a criterion for accessing the waiting list and at the point of organ offering with matching of predicted graft and recipient survival. This review compares the diverse international approaches to deceased donor kidney allocation and their evolution over the last decade.


Assuntos
Seleção do Doador/tendências , Saúde Global/tendências , Acessibilidade aos Serviços de Saúde/tendências , Transplante de Rim/tendências , Doadores de Tecidos/provisão & distribuição , Obtenção de Tecidos e Órgãos/tendências , Difusão de Inovações , Seleção do Doador/legislação & jurisprudência , Saúde Global/legislação & jurisprudência , Equidade em Saúde/tendências , Política de Saúde/tendências , Acessibilidade aos Serviços de Saúde/legislação & jurisprudência , Disparidades em Assistência à Saúde/tendências , Humanos , Transplante de Rim/efeitos adversos , Transplante de Rim/legislação & jurisprudência , Formulação de Políticas , Fatores de Tempo , Doadores de Tecidos/legislação & jurisprudência , Obtenção de Tecidos e Órgãos/legislação & jurisprudência
18.
Nephrol Dial Transplant ; 32(5): 890-900, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28379431

RESUMO

BACKGROUND: Living donor kidney transplantation (LDKT) provides more timely access to transplantation and better clinical outcomes than deceased donor kidney transplantation (DDKT). This study investigated disparities in the utilization of LDKT in the UK. METHODS: A total of 2055 adults undergoing kidney transplantation between November 2011 and March 2013 were prospectively recruited from all 23 UK transplant centres as part of the Access to Transplantation and Transplant Outcome Measures (ATTOM) study. Recipient variables independently associated with receipt of LDKT versus DDKT were identified. RESULTS: Of the 2055 patients, 807 (39.3%) received LDKT and 1248 (60.7%) received DDKT. Multivariable modelling demonstrated a significant reduction in the likelihood of LDKT for older age {odds ratio [OR] 0.11 [95% confidence interval (CI) 0.08-0.17], P < 0.0001 for 65-75 years versus 18-34 years}; Asian ethnicity [OR 0.55 (95% CI 0.39-0.77), P = 0.0006 versus White]; Black ethnicity [OR 0.64 (95% CI 0.42-0.99), P = 0.047 versus White]; divorced, separated or widowed [OR 0.63 (95% CI 0.46-0.88), P = 0.030 versus married]; no qualifications [OR 0.55 (95% CI 0.42-0.74), P < 0.0001 versus higher education qualifications]; no car ownership [OR 0.51 (95% CI 0.37-0.72), P = 0.0001] and no home ownership [OR 0.65 (95% CI 0.85-0.79), P = 0.002]. The odds of LDKT varied significantly between countries in the UK. CONCLUSIONS: Among patients undergoing kidney transplantation in the UK, there are significant age, ethnic, socio-economic and geographic disparities in the utilization of LDKT. Further work is needed to explore the potential for targeted interventions to improve equity in living donor transplantation.


Assuntos
Seleção do Doador , Conhecimentos, Atitudes e Prática em Saúde , Transplante de Rim , Doadores Vivos , Obtenção de Tecidos e Órgãos , Adolescente , Adulto , Negro ou Afro-Americano , Idoso , Barreiras de Comunicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reino Unido , População Branca , Adulto Jovem
19.
Xenobiotica ; 44(11): 1014-25, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24831541

RESUMO

1. The metabolism, pharmacokinetics, excretion and tissue distribution of a hepatitis C NS3/NS4 protease inhibitor, faldaprevir, were studied in rats following a single 2 mg/kg intravenous or 10 mg/kg oral administration of [(14)C]-faldaprevir. 2. Following intravenous dosing, the terminal elimination t1/2 of plasma radioactivity was 1.75 h (males) and 1.74 h (females). Corresponding AUC0-∞, CL and Vss were 1920 and 1900 ngEq · h/mL, 18.3 and 17.7 mL/min/kg and 2.32 and 2.12 mL/kg for males and females, respectively. 3. After oral dosing, t1/2 and AUC0-∞ for plasma radioactivity were 1.67 and 1.77 h and 11 300 and 17 900 ngEq · h/mL for males and females, respectively. 4. In intact rats, ≥90.17% dose was recovered in feces and only ≤1.08% dose was recovered in urine for both iv and oral doses. In bile cannulated rats, 54.95, 34.32 and 0.27% dose was recovered in feces, bile and urine, respectively. 5. Glucuronidation plays a major role in the metabolism of faldaprevir with minimal Phase I metabolism. 6. Radioactivity was rapidly distributed into tissues after the oral dose with peak concentrations of radioactivity in most tissues at 6 h post-dose. The highest levels of radioactivity were observed in liver, lung, kidney, small intestine and adrenal gland.


Assuntos
Oligopeptídeos/farmacocinética , Inibidores de Proteases/farmacocinética , Tiazóis/farmacocinética , Administração Oral , Ácidos Aminoisobutíricos , Animais , Bile , Biotransformação , Radioisótopos de Carbono/análise , Fezes , Feminino , Injeções Intravenosas , Leucina/análogos & derivados , Masculino , Prolina/análogos & derivados , Quinolinas , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Urina
20.
Microbiol Spectr ; 12(1): e0229023, 2024 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-38059614

RESUMO

IMPORTANCE: Breast cancer is a leading cause of cancer mortality worldwide. There is a growing interest in using dietary approaches, including flaxseed (FS) and its oil and lignan components, to mitigate breast cancer risk. Importantly, there is recognition that pubertal processes and lifestyle, including diet, are important for breast health throughout life. Mechanisms remain incompletely understood. Our research uncovers a link between mammary gland miRNA expression and the gut microbiota in young female mice. We found that this relationship is modifiable via a dietary intervention. Using data from The Cancer Genome Atlas, we also show that the expression of miRNAs involved in these relationships is altered in breast cancer in humans. These findings highlight a role for the gut microbiome as a modulator, and thus a target, of interventions aiming at reducing breast cancer risk. They also provide foundational knowledge to explore the effects of early life interventions and mechanisms programming breast health.


Assuntos
Linho , Microbioma Gastrointestinal , MicroRNAs , Neoplasias , Humanos , Feminino , Camundongos , Animais , MicroRNAs/genética , Linho/genética , Dieta
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