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2.
Anim Reprod ; 21(1): e20230121, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38384725

RESUMO

Germ cell transplantation in fish is a promising technique for surrogate broodstock parents with broader application in aquaculture and conserving endangered and valuable genetic resources. Herein, we describe the establishment of an intrapapillary xenogeneic transplant of germ cells from sexually mature goldfish (C. auratus) males into common carp (C. carpio) males cytoablated with a thermochemical treatment (two doses of busulfan at 40 mg/kg at 35°C). To analyze the presence and development of donor germ cells in recipient testes, donor germ cells were labeled with PKH26, a fluorescent cell membrane dye, before transplantation. Our results demonstrated that thermochemical treatment caused effective spermatogenesis suppression and pronounced germ cell loss. Moreover, transplanted spermatogonial cells were able to colonize the recipients' testes, resume spermatogenesis, and generate spermatozoa within eight weeks after germ cell transplantation. These findings suggested that recipient testes provided suitable conditions for the survival, colonization, proliferation, and differentiation of donor spermatogonia from a related species. This study indicated that recipients' testes exhibited a high degree of plasticity to accept and support xenogeneic donor germ cells, which were able to form sperm in a short time frame. This approach has significant implications for assisted animal reproduction, biotechnology, conservation, and the production of valuable genetic resources and endangered fish species.

3.
Nat Med ; 30(1): 207-217, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37978284

RESUMO

BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system-penetrant, type II RAF inhibitor tovorafenib (420 mg m-2 once weekly; 600 mg maximum) in patients with BRAF-altered, relapsed/refractory pLGG. Arm 2 (n = 60) is an extension cohort, which provided treatment access for patients with RAF-altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485 .


Assuntos
Vaga-Lumes , Glioma , Humanos , Criança , Animais , Proteínas Proto-Oncogênicas B-raf/genética , Glioma/tratamento farmacológico , Glioma/genética
4.
Gene ; 897: 148082, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38101710

RESUMO

Transforming growth factor-ß (TGF-ß) and bone morphogenetic protein (BMP) signaling has fundamental roles in the regulation of the stem cell niche for both embryonic and adult stem cells. In zebrafish, male germ stem cell niche is regulated by follicle-stimulating hormone (Fsh) through different members of the TGF-ß superfamily. On the other hand, the specific roles of TGF-ß and BMP signaling pathways are unknown in the zebrafish male germ stem cell niche. Considering this lack of information, the present study aimed to investigate the pharmacological inhibition of TGF-ß (A83-01) and BMP (DMH1) signaling pathways in the presence of recombinant zebrafish Fsh using testicular explants. We also reanalyzed single cell-RNA sequencing (sc-RNA-seq) dataset from adult zebrafish testes to identify the testicular cellular sites of smad expression, and to understand the physiological significance of the changes in smad transcript levels after inhibition of TGF-ß or BMP pathways. Our results showed that A83-01 potentiated the pro-stimulatory effects of Fsh on spermatogonial differentiation leading to an increase in the proportion area occupied by differentiated spermatogonia with concomitant reduction of type A undifferentiated (Aund) spermatogonia. In agreement, expression analysis showed lower mRNA levels for the pluripotency gene pou5f3, and increased expression of dazl (marker of type B spermatogonia and spermatocyte) and igf3 (pro-stimulatory growth factor) following the co-treatment with TGF-ß inhibitor and Fsh. Contrariwise, the inhibition of BMP signaling nullified the pro-stimulatory effects of Fsh, resulting in a reduction of differentiated spermatogonia and increased proportion area occupied by type Aund spermatogonia. Supporting this evidence, BMP signaling inhibition increased the mRNA levels of pluripotency genes nanog and pou5f3, and decreased dazl levels when compared to control. The sc-RNA-seq data unveiled a distinctive pattern of smad expression among testicular cells, primarily observed in spermatogonia (smad 2, 3a, 3b, 8), spermatocytes (smad 2, 3a, 8), Sertoli cells (smad 1, 3a, 3b), and Leydig cells (smad 1, 2). This finding supports the notion that inhibition of TGF-ß and BMP signaling pathways may predominantly impact cellular components within the spermatogonial niche, namely spermatogonia, Sertoli, and Leydig cells. In conclusion, our study demonstrated that TGF-ß and BMP signaling pathways exert antagonistic roles in the zebrafish germ stem cell niche. The members of the TGF-ß subfamily are mainly involved in maintaining the undifferentiated state of spermatogonia, while the BMP subfamily promotes spermatogonial differentiation. Therefore, in the complex regulation of the germ stem cell niche by Fsh, members of the BMP subfamily (pro-differentiation) should be more predominant in the niche than those belonging to the TGF-ß (anti-differentiation). Overall, these findings are not only relevant for understanding the regulation of germ stem cell niche but may also be useful for expanding in vitro the number of undifferentiated spermatogonia more efficiently than using recombinant hormones or growth factors.


Assuntos
Pirazóis , Espermatogônias , Tiossemicarbazonas , Peixe-Zebra , Animais , Masculino , Espermatogônias/metabolismo , Peixe-Zebra/genética , Hormônio Foliculoestimulante/farmacologia , Hormônio Foliculoestimulante/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Testículo/metabolismo , Diferenciação Celular/genética , RNA Mensageiro/genética , Espermatogênese/genética
5.
JMIR Aging ; 6: e41549, 2023 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-38147371

RESUMO

BACKGROUND: The Apple Watch is not a medical device per se; it is a smart wearable device that is increasingly being used for health monitoring. Evidence exists that the Apple Watch Series 6 can reliably measure blood oxygen saturation (SpO2) in patients with chronic obstructive pulmonary disease under controlled circumstances. OBJECTIVE: This study aimed to better understand older adults' acceptance of the Watch as a part of telemonitoring, even with these advancements. METHODS: This study conducted content analysis on data collected from 10 older adults with chronic obstructive pulmonary disease who consented to wear the Watch. RESULTS: Using the Extended Unified Theory of Acceptance and Use of Technology model, results showed that participants experienced potential health benefits; however, the inability of the Watch to reliably measure SpO2 when in respiratory distress was concerning. Participants' level of tech savviness varied, which caused some fear and frustration at the start, yet all felt supported by family and would have explored more features if they owned the Watch. All agreed that the Watch is mainly a medical tool and not a gadget. CONCLUSIONS: To conclude, although the Watch may enhance their physical health and well-being, results indicated that participants are more likely to accept the Watch if it ultimately proves to be useful when experiencing respiratory distress.

6.
JMIR Aging ; 6: e41539, 2023 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-37917147

RESUMO

BACKGROUND: Amid the rise in mobile health, the Apple Watch now has the capability to measure peripheral blood oxygen saturation (SpO2). Although the company indicated that the Watch is not a medical device, evidence suggests that SpO2 measurements among patients with chronic obstructive pulmonary disease (COPD) are accurate in controlled settings. Yet, to our knowledge, the SpO2 function has not been validated for patients with COPD in naturalistic settings. OBJECTIVE: This qualitative study explored the experiences of patients with COPD using the Apple Watch Series 6 versus a traditional finger pulse oximeter for home SpO2 self-monitoring. METHODS: We conducted individual semistructured interviews with 8 female and 2 male participants with moderate to severe COPD, and transcripts were qualitatively analyzed. All received a watch to monitor their SpO2 for 5 months. RESULTS: Due to respiratory distress, the watch was unable to collect reliable SpO2 measurements, as it requires the patient to remain in a stable position. However, despite the physical limitations and lack of reliable SpO2 values, participants expressed a preference toward the watch. Moreover, participants' health needs and their unique accessibility experiences influenced which device was more appropriate for self-monitoring purposes. Overall, all shared the perceived importance of prioritizing their physical COPD symptoms over device selection to manage their disease. CONCLUSIONS: Differing results between participant preferences and smartwatch limitations warrant further investigation into the reliability and accuracy of the SpO2 function of the watch and the balance among self-management, medical judgment, and dependence on self-monitoring technology.

7.
Cell Rep ; 42(2): 112074, 2023 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-36787741

RESUMO

Immune development is profoundly influenced by vertically transferred cues. However, little is known about how maternal innate-like lymphocytes regulate offspring immunity. Here, we show that mice born from γδ T cell-deficient (TCRδ-/-) dams display an increase in first-breath-induced inflammation, with a pulmonary milieu selectively enriched in type 2 cytokines and type 2-polarized immune cells, when compared with the progeny of γδ T cell-sufficient dams. Upon helminth infection, mice born from TCRδ-/- dams sustain an increased type 2 inflammatory response. This is independent of the genotype of the pups. Instead, the offspring of TCRδ-/- dams harbors a distinct intestinal microbiota, acquired during birth and fostering, and decreased levels of intestinal short-chain fatty acids (SCFAs), such as pentanoate and hexanoate. Importantly, exogenous SCFA supplementation inhibits type 2 innate lymphoid cell function and suppresses first-breath- and infection-induced inflammation. Taken together, our findings unravel a maternal γδ T cell-microbiota-SCFA axis regulating neonatal lung immunity.


Assuntos
Microbioma Gastrointestinal , Imunidade Inata , Animais , Camundongos , Linfócitos , Inflamação , Pulmão , Camundongos Endogâmicos C57BL
8.
Immunity ; 56(3): 592-605.e8, 2023 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-36804959

RESUMO

Plasmodium replicates within the liver prior to reaching the bloodstream and infecting red blood cells. Because clinical manifestations of malaria only arise during the blood stage of infection, a perception exists that liver infection does not impact disease pathology. By developing a murine model where the liver and blood stages of infection are uncoupled, we showed that the integration of signals from both stages dictated mortality outcomes. This dichotomy relied on liver stage-dependent activation of Vγ4+ γδ T cells. Subsequent blood stage parasite loads dictated their cytokine profiles, where low parasite loads preferentially expanded IL-17-producing γδ T cells. IL-17 drove extra-medullary erythropoiesis and concomitant reticulocytosis, which protected mice from lethal experimental cerebral malaria (ECM). Adoptive transfer of erythroid precursors could rescue mice from ECM. Modeling of γδ T cell dynamics suggests that this protective mechanism may be key for the establishment of naturally acquired malaria immunity among frequently exposed individuals.


Assuntos
Eritropoese , Malária Cerebral , Animais , Camundongos , Eritrócitos , Interleucina-17 , Fígado/parasitologia , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T gama-delta , Malária
9.
JBI Evid Synth ; 21(7): 1469-1476, 2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-36728743

RESUMO

OBJECTIVE: The objective of this review is to collate and analyze literature reporting on digital health education and training courses, or other pedagogical interventions, for nursing students at the undergraduate and graduate level to identify gaps and inform the development of future educational interventions. INTRODUCTION: In this era of technology-driven health care, upskilling and/or reskilling the nursing workforce is urgently needed for nurses to lead the digital health future and improve patient care. While informatics competency frameworks serve to inform nursing education and practice, they do not address the entire digital health spectrum. INCLUSION CRITERIA: This review will include research studies, theoretical/discussion papers, and reports, as well as gray literature from relevant sources published in the last 10 years. Opinion pieces, editorials, conference proceedings, and papers published in languages other than English will be excluded. METHODS: The JBI methodology for scoping reviews will be followed. Searches will be conducted in Embase, CINAHL, ERIC, MEDLINE, Scopus, and Education Research Complete to retrieve potentially relevant studies. Hand searches of reference lists of included studies will be conducted. Two reviewers will independently screen records against predefined eligibility criteria and consult a third reviewer if conflicts arise. Decisions will be documented using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram. Quantitative data will be analyzed using descriptive statistics. Content analysis will be applied to qualitative data to identify categories and themes. Findings will be synthesized and reported in tables and narrative format. REVIEW REGISTRATION NUMBER: Open Science Framework osf.io/42eug.


Assuntos
Estudantes de Enfermagem , Humanos , Escolaridade , Educação em Saúde , Instalações de Saúde , Literatura de Revisão como Assunto
10.
Sci Rep ; 12(1): 17650, 2022 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-36271101

RESUMO

Cannabidiol (CBD) is a substance derived from Cannabis sativa, widely studied in medicine for controlling neural diseases in humans. Besides the positive effects on humans, it also presents anxiolytic proprieties and decreases aggressiveness and stress in mammals. Therefore, CBD has the potential to increase welfare in reared animals, as it seems to reduce negative states commonly experienced in artificial environments. Here, we tested the effect of different CBD doses (0, 1, 10 and 20 mg/kg) on aggressiveness, stress and reproductive development of the Nile tilapia (Oreochromis niloticus) a fish reared worldwide for farming and research purposes. CBD mixed with fish food was offered to isolated fish for 5 weeks. The 10 mg/kg dose decreased fish's aggressiveness over time, whereas 20 mg/kg attenuated non-social stress. Both doses decreased the baseline cortisol level of fish and increased the gonadosomatic index. However, CBD 1 and 10 mg/kg doses decreased the spermatozoa number. No CBD dose affected feeding ingestion and growth variables, showing that it is not harmful to meat production amount. Despite the effect on spermatozoa, CBD supplementation exhibits high potential to benefit animals' lives in artificial environments. Therefore, we showed for the first time that CBD could be used as a tool to increase non-mammal welfare, presenting a great potential to be explored in other husbandry and captivity species.


Assuntos
Ansiolíticos , Canabidiol , Cannabis , Ciclídeos , Humanos , Masculino , Animais , Canabidiol/farmacologia , Hidrocortisona , Mamíferos
11.
Cent Nerv Syst Agents Med Chem ; 22(2): 139-150, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36104859

RESUMO

BACKGROUND: Alzheimer's disease is a progressive neurodegenerative process with multifactorial characteristics. This disease follows the natural aging process, affecting mainly people over 65 years. Pharmacotherapeutic treatment currently combats symptoms related to cognitive function. Several targets have begun to attract the interest of the scientific community to develop new drug candidates which have better pharmacokinetic and lower toxicity parameters. OBJECTIVE: The present study aims to design new candidates for acetylcholinesterase/ß-secretase (AChE/BACE1) multitarget inhibitor drugs. METHODS: 17 natural products were selected from the literature with anticholinesterase activity and 1 synthetic molecule with inhibitory activity for BACE1. Subsequently, the molecular docking study was performed, followed by the derivation of the pharmacophoric pattern and prediction of pharmacokinetic and toxicological properties. Finally, the hybrid prototype was designed. RESULTS: All selected molecules showed interactions with their respective target enzymes. Derivation of the pharmacophoric pattern from molecules that interacted with the AChE enzyme resulted in 3 pharmacophoric regions: an aromatic ring, an electron-acceptor region and a hydrophobic region. The molecules showed good pharmacokinetic and toxicological results, showing no warnings of mutagenicity and/or carcinogenicity. After the hybridization process, three hybrid molecules were obtained, which showed inhibitory activity for both targets. CONCLUSION: It is concluded that research in the field of medicinal chemistry is advancing towards the discovery of new drug candidates that bring a better quality of life to patients with AD.


Assuntos
Acetilcolinesterase , Secretases da Proteína Precursora do Amiloide , Secretases da Proteína Precursora do Amiloide/química , Ácido Aspártico Endopeptidases/química , Humanos , Simulação de Acoplamento Molecular , Qualidade de Vida
12.
Rev Bras Ortop (Sao Paulo) ; 56(5): 675-679, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34733442

RESUMO

Although lipomatous tumors are common, intra-articular occurrence is exceedingly rare and sparsely described in the literature. Regarding these rare entities, most are benign, progressively growing tumors and often occur in the knee, yet it is crucial to distinguish the less infrequent lipoma arborescens (LA) from the rarer synovial lipoma, as they differ in presentation and pathogenesis. Magnetic resonance imaging is the exam of choice in their assessment and in differential diagnosis, playing a central role nowadays. Excision and synovectomy, either arthroscopic or by arthrotomy, provide good outcomes with low recurrence rates. By reporting two surgically treated distinct cases of intra-articular lipomatous tumors of the knee, the authors intend to review the literature and discuss their etiology, clinical and imaging aspects as well as treatment approach.

13.
Clin Transl Sci ; 14(2): 664-670, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33340277

RESUMO

Small cell lung cancer (SCLC) is a leading cause of cancer death worldwide, with few treatment options. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate that targets delta-like 3 on SCLC cells to deliver a cytotoxic payload directly to tumor cells. In this study, the cardiac safety profile of Rova-T was assessed by evaluating changes in QT interval, electrocardiogram (ECG) waveform, heart rate, and proarrhythmic adverse events (AEs) after treatment with Rova-T in patients with previously treated extensive-stage SCLC. Patients underwent ECG monitoring for 2 weeks after each of 2 i.v. infusions of 0.3 mg/kg Rova-T over 30 minutes, administered 6 weeks apart. Forty-six patients received at least one dose of Rova-T. At the geometric mean Rova-T maximum serum concentration of 7,940 ng/mL, ECG monitoring showed no significant changes in the Fridericia-corrected QT (QTcF) interval; the upper limit of the 2-sided 90% confidence interval did not exceed 10 msec for any time point. There were no clinically significant changes in QRS or PR intervals, ECG waveforms, or heart rate after Rova-T administration. All patients experienced a treatment-emergent AE (TEAE); 78% had a grade ≥ 3 TEAE, 59% had a serious TEAE, and 41% had a cardiac-related TEAE. The TEAEs that might signal proarrhythmia tendencies were uncommon. Confirmed partial responses were observed in 24% of patients. Based on the evaluation of ECG data collected in this study from patients treated with Rova-T at 0.3 mg/kg i.v. administered every 6 weeks, a QTcF effect of clinical concern can be excluded.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Benzodiazepinonas/efeitos adversos , Imunoconjugados/efeitos adversos , Síndrome do QT Longo/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Benzodiazepinonas/administração & dosagem , Cardiotoxicidade/diagnóstico , Cardiotoxicidade/etiologia , Eletrocardiografia/efeitos dos fármacos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Imunoconjugados/administração & dosagem , Síndrome do QT Longo/induzido quimicamente , Masculino , Pessoa de Meia-Idade
14.
Sensors (Basel) ; 21(1)2020 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-33379236

RESUMO

In cognitive radio systems, identifying spectrum opportunities is fundamental to efficiently use the spectrum. Spectrum occupancy prediction is a convenient way of revealing opportunities based on previous occupancies. Studies have demonstrated that usage of the spectrum has a high correlation over multidimensions, which includes time, frequency, and space. Accordingly, recent literature uses tensor-based methods to exploit the multidimensional spectrum correlation. However, these methods share two main drawbacks. First, they are computationally complex. Second, they need to re-train the overall model when no information is received from any base station for any reason. Different than the existing works, this paper proposes a method for dividing the multidimensional correlation exploitation problem into a set of smaller sub-problems. This division is achieved through composite two-dimensional (2D)-long short-term memory (LSTM) models. Extensive experimental results reveal a high detection performance with more robustness and less complexity attained by the proposed method. The real-world measurements provided by one of the leading mobile network operators in Turkey validate these results.

15.
Toxicol In Vitro ; 69: 104992, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32889036

RESUMO

Euchromatic histone-lysine N-methyltransferase 1 (EHMT1) and EHMT2 are upregulated in various human cancers, and their deregulation is associated with tumor development and progression. In this paper, we investigated the expression level of EHMT1/EHMT2 in acute lymphoblastic leukemia (ALL) and whether the modulation of these enzymes could have any cellular or molecular impact on ALL cells. For this, we used UNC0646 as a priming strategy to target EHMT1/EHMT2 and investigated its effect on proliferation and cell viability of Jurkat cells by MTT assay. Then, considering the IC50 and IC75, cellular death was determined by Annexin V/PI staining using flow cytometry. Finally, we investigated by RT-PCR the molecular bases that could be involved in the observed effects. Interestingly, accessing the International Microarray Innovations in Leukemia (MILE) study group, we detected that both EHMT1 and EHMT2 are overexpressed in ALL. More important, we determined that inhibition of EHMT1/EHMT2 significantly decreased Jurkat cell viability in a dose-dependent manner. Accordingly, we observed that inhibition of EHMT1/EHMT2 promoted Jurkat cell death, which was accompanied by increased expression of P53, TP73, BAX, and MDM4. These results clearly indicate that inhibition of EHMT1/EHMT2 induces pro-apoptotic gene expression in ALL and promotes cell death. More importantly, the modulation of these histone methyltransferases may be a promising epigenetic target for ALL treatment.


Assuntos
Regulação Leucêmica da Expressão Gênica , Antígenos de Histocompatibilidade/genética , Histona-Lisina N-Metiltransferase/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteína Tumoral p73/genética , Proteína Supressora de Tumor p53/genética , Morte Celular , Proliferação de Células , Sobrevivência Celular , Simulação por Computador , Epigênese Genética , Humanos , Células Jurkat
16.
Int J Pharm Pract ; 28(4): 301-311, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31638309

RESUMO

OBJECTIVES: To identify consultation tools cited in the published literature and undertake a narrative review which establishes their scope to support the delivery of person-centred medicine-focused consultations between community pharmacists and patients in the United Kingdom (UK). KEY FINDINGS: Nine consultation tools used in a pharmacy context were identified. Four tools (Calgary-Cambridge guide, MRCF, MUR and NMS advanced services and PaCT) were selected for further appraisal. None of the tools identified provided a suitable format or sufficient guidance to address all components required for the delivery of a person-centred patient consultation in practice. SUMMARY: Tools available to UK pharmacists are inadequate for fully supporting delivery of a person-centred consultation in practice. Revision of existing tools or creation of more pharmacy-specific tools will support UK pharmacists' delivery of person-centred consultations in practice.


Assuntos
Serviços Comunitários de Farmácia , Assistência Centrada no Paciente , Farmacêuticos , Encaminhamento e Consulta , Comunicação , Humanos , Reino Unido
18.
Cell ; 179(5): 1207-1221.e22, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31730858

RESUMO

Accurate measurement of clonal genotypes, mutational processes, and replication states from individual tumor-cell genomes will facilitate improved understanding of tumor evolution. We have developed DLP+, a scalable single-cell whole-genome sequencing platform implemented using commodity instruments, image-based object recognition, and open source computational methods. Using DLP+, we have generated a resource of 51,926 single-cell genomes and matched cell images from diverse cell types including cell lines, xenografts, and diagnostic samples with limited material. From this resource we have defined variation in mitotic mis-segregation rates across tissue types and genotypes. Analysis of matched genomic and image measurements revealed correlations between cellular morphology and genome ploidy states. Aggregation of cells sharing copy number profiles allowed for calculation of single-nucleotide resolution clonal genotypes and inference of clonal phylogenies and avoided the limitations of bulk deconvolution. Finally, joint analysis over the above features defined clone-specific chromosomal aneuploidy in polyclonal populations.


Assuntos
Replicação do DNA/genética , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Análise de Célula Única , Aneuploidia , Animais , Ciclo Celular/genética , Linhagem Celular Tumoral , Forma Celular , Sobrevivência Celular , Cromossomos Humanos/genética , Células Clonais , Elementos de DNA Transponíveis/genética , Diploide , Feminino , Genótipo , Humanos , Masculino , Camundongos , Mutação/genética , Filogenia , Polimorfismo de Nucleotídeo Único/genética
19.
Cancer Chemother Pharmacol ; 84(1): 93-103, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31062077

RESUMO

PURPOSE: Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic p53 activator with oral administration. To determine the need to conduct dedicated trial(s) for organ impairment on pharmacokinetic (PK) exposure and/or drug-drug interactions, a single dose of [14C]- and [13C]-labeled idasanutlin was evaluated. METHODS: This study was an open-label, non-randomized, single-center trial of idasanutlin to investigate the excretion balance, pharmacokinetics, metabolism, and absolute bioavailability of a single oral dose of [14C]-labeled idasanutlin and an IV tracer dose of [13C]-labeled idasanutlin in a single cohort of patients with solid tumors. After completing cycle 1 assessments, patients could have participated in an optional treatment extension of idasanutlin. Clinical endpoints were PK, and safety/tolerability. RESULTS: Co-administration of an oral dose of idasanutlin with an IV tracer dose revealed low systemic CL, a moderate Vd, and a moderate (40.1%) absolute bioavailability of idasanutlin. Idasanutlin and its major inactive metabolite, M4, were the major circulating moieties in plasma, and excretion of idasanutlin-associated radioactivity was primarily via the fecal route (91.5% of the dose), with negligible amounts recovered in urine, following oral administration. CONCLUSION: The clinical implications of this study support the conclusion that renal impairment is unlikely to significantly impact exposure to idasanutlin and M4 metabolite, whereas a significant hepatic impairment may potentially alter exposure to the parent drug and/or metabolite(s). The potential for drug-drug interactions is low.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Pirrolidinas/administração & dosagem , para-Aminobenzoatos/administração & dosagem , Administração Oral , Adulto , Idoso , Disponibilidade Biológica , Estudos de Coortes , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirrolidinas/farmacocinética , para-Aminobenzoatos/farmacocinética
20.
MethodsX ; 5: 1166-1177, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30364661

RESUMO

Digital image correlation (DIC) is an optical technique commonly used for measuring displacement fields by tracking artificially applied random speckle patterns, which can sometimes be a problem for tracking small-scale displacements. DIC is particularly useful for tracking the crack mouth opening displacement (CMOD) of a notched metallic specimen subjected to three-point bending for fracture toughness determination because the edges of the notch provide the required textural features for DIC without the need for speckle patterns. This simplifies the set-up process as the specimen and stage geometries do not need to account for the placement of a strain gauge. To enhance the accuracy of DIC, this study then successfully downscaled a photogrammetry technique commonly used to track crack propagation in large scale concrete tests so that the pixel coordinates of the captured images can be automatically related to their real-world coordinates, allowing for small scale displacements to be accurately tracked.

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