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1.
Nature ; 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38718835

RESUMO

The introduction of AlphaFold 21 has spurred a revolution in modelling the structure of proteins and their interactions, enabling a huge range of applications in protein modelling and design2-6. In this paper, we describe our AlphaFold 3 model with a substantially updated diffusion-based architecture, which is capable of joint structure prediction of complexes including proteins, nucleic acids, small molecules, ions, and modified residues. The new AlphaFold model demonstrates significantly improved accuracy over many previous specialised tools: far greater accuracy on protein-ligand interactions than state of the art docking tools, much higher accuracy on protein-nucleic acid interactions than nucleic-acid-specific predictors, and significantly higher antibody-antigen prediction accuracy than AlphaFold-Multimer v2.37,8. Together these results show that high accuracy modelling across biomolecular space is possible within a single unified deep learning framework.

2.
Acta Neuropathol Commun ; 11(1): 181, 2023 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-37964332

RESUMO

Tau seed amplification assays (SAAs) directly measure the seeding activity of tau and would therefore be ideal biomarkers for clinical trials targeting seeding-competent tau in Alzheimer's disease (AD). However, the precise relationship between tau seeding measured by SAA and the levels of pathological forms of tau in the AD brain remains unknown. We developed a new tau SAA based on full-length 0N3R tau with sensitivity in the low fg/ml range and used it to characterize 103 brain samples from three independent cohorts. Tau seeding clearly discriminated between AD and control brain samples. Interestingly, seeding was absent in Progressive Supranuclear Palsy (PSP) putamen, suggesting that our tau SAA did not amplify 4R tau aggregates from PSP brain. The specificity of our tau SAA for AD brain was further supported by analysis of matched hippocampus and cerebellum samples. While seeding was detected in hippocampus from Braak stages I-II, no seeding was present in AD cerebellum that is devoid of tau inclusions. Analysis of 40 middle frontal gyrus samples encompassing all Braak stages showed that tau SAA seeding activity gradually increased with Braak stage. This relationship between seeding activity and the presence of tau inclusions in AD brain was further supported by robust correlations between tau SAA results and the levels of phosphorylated tau212/214, phosphorylated tau181, aggregated tau, and sarkosyl-insoluble tau. Strikingly, we detected tau seeding in the middle frontal gyrus already at Braak stage II-III, suggesting that tau SAA can detect tau pathology earlier than conventional immunohistochemical staining. In conclusion, our data suggest a quantitative relationship between tau seeding activity and pathological forms of tau in the human brain and provides an important basis for further development of tau SAA for accessible human samples.


Assuntos
Doença de Alzheimer , Paralisia Supranuclear Progressiva , Humanos , Doença de Alzheimer/patologia , Proteínas tau/metabolismo , Encéfalo/patologia , Paralisia Supranuclear Progressiva/patologia , Cerebelo/patologia
3.
J Neuroinflammation ; 20(1): 272, 2023 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-37990275

RESUMO

BACKGROUND: Microglia are increasingly understood to play an important role in the pathogenesis of Alzheimer's disease. The rs75932628 (p.R47H) TREM2 variant is a well-established risk factor for Alzheimer's disease. TREM2 is a microglial cell surface receptor. In this multi-modal/multi-tracer PET/MRI study we investigated the effect of TREM2 p.R47H carrier status on microglial activation, tau and amyloid deposition, brain structure and cognitive profile. METHODS: We compared TREM2 p.R47H carriers (n = 8; median age = 62.3) and participants with mild cognitive impairment (n = 8; median age = 70.7). Participants underwent two [18F]DPA-714 PET/MRI scans to assess TSPO signal, indicative of microglial activation, before and after receiving the seasonal influenza vaccination, which was used as an immune stimulant. Participants also underwent [18F]florbetapir and [18F]AV1451 PET scans to assess amyloid and tau burden, respectively. Regional tau and TSPO signal were calculated for regions of interest linked to Braak stage. An additional comparison imaging healthy control group (n = 8; median age = 45.5) had a single [18F]DPA-714 PET/MRI. An expanded group of participants underwent neuropsychological testing, to determine if TREM2 status influenced clinical phenotype. RESULTS: Compared to participants with mild cognitive impairment, TREM2 carriers had lower TSPO signal in Braak II (P = 0.04) and Braak III (P = 0.046) regions, despite having a similar burden of tau and amyloid. There were trends to suggest reduced microglial activation following influenza vaccine in TREM2 carriers. Tau deposition in the Braak VI region was higher in TREM2 carriers (P = 0.04). Furthermore, compared to healthy controls TREM2 carriers had smaller caudate (P = 0.02), total brain (P = 0.049) and white matter volumes (P = 0.02); and neuropsychological assessment revealed worse ADAS-Cog13 (P = 0.03) and Delayed Matching to Sample (P = 0.007) scores. CONCLUSIONS: TREM2 p.R47H carriers had reduced levels of microglial activation in brain regions affected early in the Alzheimer's disease course and differences in brain structure and cognition. Changes in microglial response may underlie the increased Alzheimer's disease risk in TREM2 p.R47H carriers. Future therapeutic agents in Alzheimer's disease should aim to enhance protective microglial actions.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Vacinas contra Influenza , Humanos , Pessoa de Meia-Idade , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Microglia/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Imageamento por Ressonância Magnética/métodos , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Receptores de GABA/metabolismo
4.
J Vasc Access ; : 11297298221147571, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609176

RESUMO

BACKGROUND: The optimal vascular access in the elderly remains contentious in the context of increasingly limited resources and anticipated survival on hemodialysis. Research focus has shifted to include the impact of vascular access on quality of life. This study explored clinical outcomes in individuals aged ⩾75 years who had an arteriovenous fistula (AVF) created in a single center over a 10-year period. MATERIALS AND METHODS: Demographic and clinical data concerning AVFs created January 2009-December 2019 were identified from a prospective database for retrospective analysis. Outcome measures were AVF patency and failure to mature rates plus overall patient and vascular access survival. The Vascular Access Specific Quality of life measure (VASQoL) was completed in a contemporary cohort aged ⩾75 years established on HD in October 2021. RESULTS: AVF outcomes were available for 272 patients (93%). The failure to mature (FTM) rate was 36% with the significant predictors of AVF FTM being the creation of a radiocephalic AVF (OR 8.13, 95% CI 8.02-8.52, p < 0.01), female gender (OR 4.84, 95% CI 4.70-5.41, p < 0.01), and a history of peripheral vascular disease (OR 5.25, 95% CI 5.22-6.00, p value = 0.02). Functional patency was associated with a median 12-month survival benefit compared to those whose fistula FTM (p < 0.01). The median patency duration for a functionally patent AVF was 3 years. Elderly patients with a fistula reported a lower quality of life in VASQoL scoring than those with central venous catheters. CONCLUSIONS: In this cohort, AVF creation in individuals aged ⩾75 years AVFs was associated with comparable AVF patency rates to younger patients. AVF functional patency was associated with superior patient survival compared to those with AVF FTM. A multi-disciplinary surveillance program may help reduce AVF loss. Further work on how vascular access choice impacts quality of life in elderly patients is required.

5.
Ir J Med Sci ; 192(3): 1277-1280, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35849315

RESUMO

OBJECTIVE: Audit is a recognised tool for evaluating the performance and improving the quality of health services. In Ireland and the UK, clear resources are available outlining audit elements. This study was undertaken to evaluate paediatric audits published from 2007 to 2020 to determine the adherence level to the definition of audit and to assess the quality of audit standards. DESIGN: PUBMED, MEDLINE and CINAHL databases were searched to identify relevant articles published in the English language. Each was reviewed to assess whether the following criteria were met: (1) a paediatric healthcare topic was described, (2) practice was reviewed, (3) the standard was specified, (4) an intervention was made and data collection was repeated to assess improvement. The quality of the standard for each true audit was graded utilising the Oxford Centre for Evidence-Based Medicine Levels of Evidence. RESULTS: Of 1230 published paediatric healthcare articles reviewed, 144 (11.4%) fulfilled the full criteria of an audit. Sixty-three (43.8%) true audits used the highest quality of evidence (level 1a and 1b), predominantly international or national guidelines. Fifty-six (38.9%) audits used the lowest quality of evidence (level 5), predominantly expert opinion. CONCLUSIONS: There is a mismatch between the common usage of the term audit, and the definition, despite its incorporation into training curricula and institutional support. Many articles published as audits do not adhere to the definition of audit. There are variable levels of evidence supporting the standards utilised in published true audits.


Assuntos
Instalações de Saúde , Auditoria Médica , Criança , Humanos , Coleta de Dados , Irlanda
6.
Ir J Med Sci ; 192(3): 1021-1026, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35962252

RESUMO

Recruitment and retention of doctors is a priority for the Irish healthcare service, with many leaving to work in regions with more favourable conditions. Aligning flexible training options with other jurisdictions may be an effective means of improving working conditions. We sought to assess possible improvements to the existing system and to review barriers to flexible training. We carried out a survey using 'Survey Monkey' and disseminated it to 1557 basic specialist (BST) and higher specialist trainee (HST) doctors of the Institute of Medicine, 3500 members of the Irish Medical Organisation (IMO), and across social media. There were 854 respondents; 303 (35.5%) BST, 352 (41.2%) HST, 125 (14.6%) non-training doctors, unknown, n = 74. The response rate was approximately 15-23%. Non-consultant doctors identified a preference for access to flexible training (n = 849, 99.4%), with 82.2 of doctors reporting that they would consider applying (n = 702). Most (92.4%) considered the current provision of 16 whole-time equivalent positions as inadequate (n = 789). Of doctors who would not apply for flexible training, themes identified included a perceived negative impact on their career, not meeting eligibility criteria, prolonged training, and salary implications. Suggestions for improving the system included expanding the number of places available, removing eligibility criteria, job sharing options, and the provision of regional training schemes. Access to flexible training should be a priority for the healthcare service, which may enhance recruitment and retention. A majority of our sample of non-consultant doctors identified a preference for access to flexible training options.


Assuntos
Médicos , Humanos , Irlanda , Estudos Transversais , Educação de Pós-Graduação em Medicina , Inquéritos e Questionários , Atitude do Pessoal de Saúde
7.
J Sci Med Sport ; 25(4): 351-355, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34764011

RESUMO

OBJECTIVES: The planning and control of team sport training activities is an extremely important aspect of athletic development and team performance. This research introduces a novel system which leverages techniques from the fields of control system theory and artificial intelligence to construct optimal future training plans when unexpected disturbances and deviations from a training plan goal occur. DESIGN: Simulation-based experimental design. METHODS: The adaptation of training load prescriptions was formulated as an optimal control problem where we seek to minimize the difference between a desired training plan goal and an observed training outcome. To determine the most suitable approach to optimize future training loads the performance of an artificial intelligence-based feedback controller was compared to random and proportional controllers. Computational simulations (N = 1800) were conducted using a non-linear training plan spanning 60 days over a 12-week period, and the control strategies were assessed on their ability to adapt future training loads when disturbances and deviations from an optimal planning policy have occurred. Statistical analysis was conducted to determine if significant differences existed between the three control strategies. RESULTS: The results of a repeated measures analysis of variance demonstrated that an intelligent feedback controller significantly outperforms the random (p < .001, ES = 7.41, very large) and proportional control (p < .001, ES = 7.41, very large) strategies at reducing the deviations from a training plan goal. CONCLUSIONS: This system can be used to support the decision making of practitioners across several areas considered important for the effective planning and adaption of athletic training.


Assuntos
Inteligência Artificial , Atletas , Simulação por Computador , Retroalimentação , Humanos
8.
Ir J Med Sci ; 191(1): 271-278, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33576922

RESUMO

INTRODUCTION: Postgraduate medical training incorporates education, both formal and informal, combined with clinical service. This study explored the early training experience of pediatricians in Ireland and its potential impact on patient safety. AIM: We sought to identify factors that contribute to the patient safety experience of new entrant pediatric trainees. METHODS: Trainees, or senior house officers (SHOs), in their first year of postgraduate training, participated in an interview conducted using a critical interview technique (CIT). They described an adverse event where the medical care delivered to the patient was not ideal. Thematic analysis identified themes that influenced the described event. RESULTS: Thirteen trainees participated in the interviews. This study identified influences on the relationship between the SHO and patient safety, including the SHO themselves, teamwork and communication. Colleagues within the workplace, including consultants, registrars, and nurses, also affect this relationship. The registrar is described as a central figure holding an active role in clinical care in 11 of the 13 stories told. In the participants' experience, the registrar was the senior decision-maker, teacher, team builder, and communication intermediary within the teams' hierarchical structure. The registrars' previous clinical experience, communication style, along with their ability to supervise and provide feedback shaped the SHO experience. CONCLUSIONS: Through a process designed to focus on exploring patient safety, it emerged that the registrar plays a crucial role in the working experience of their junior colleagues. The influence of the registrar needs to be recognized within clinical teams and by postgraduate training bodies.


Assuntos
Pediatria , Médicos , Criança , Educação de Pós-Graduação em Medicina , Humanos , Corpo Clínico Hospitalar , Segurança do Paciente , Gestão da Segurança
9.
World J Pediatr ; 18(1): 43-49, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34797500

RESUMO

INTRODUCTION: The acquisition of non-contaminated urine samples in pre-continent infants remains a challenge. The Quick Wee method uses bladder stimulation to induce voiding. A previous randomized trial showed a higher rate of voiding within 5 minutes using this method. We evaluated this method in an Irish hospital providing secondary care. METHODS: A non-blinded, randomized, controlled trial was carried out. Eligible infants were between 1 and 12 months of age, who required urine sampling as part of clinical care. Participants were randomly allocated to receive the intervention (Quick Wee Method-supra-pubic stimulation with cold saline) or the control (usual care-clean catch with no bladder stimulation) for 5 min. Primary outcome was voiding of urine within 5 min. RESULTS: A total of 140 infants were included in this study (73 in intervention group; 67 in control group). Baseline characteristics were similar. 25% in the intervention group passed urine in the 5-min trial period compared with 18% in the control group [P = 0.4, absolute difference 7% (95% confidence interval: - 7% to + 20%)]. CONCLUSION: The Quick Wee method is a simple and inexpensive intervention that did not show a statistically significant increase in urine samples obtained in pre-continent infants.


Assuntos
Infecções Urinárias , Coleta de Urina , Hospitais , Humanos , Lactente , Atenção Secundária à Saúde
10.
Nat Rev Chem ; 6(7): 444-445, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37117307
11.
ACS Med Chem Lett ; 12(11): 1794-1801, 2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34795869

RESUMO

The PI3K/AKT/mTOR and PIM kinase pathways contribute to the development of several hallmarks of cancer. Cotargeting of these pathways has exhibited promising synergistic therapeutic effects in liquid and solid tumor types. To identify molecules with combined activities, we cross-screened our collection of PI3K/(±mTOR) macrocycles (MCXs) and identified the MCX thieno[3,2-d]pyrimidine derivative 2 as a moderate dual PI3K/PIM-1 inhibitor. We report the medicinal chemistry exploration and biological characterization of a series of thieno[3,2-d]pyrimidine MCXs, which led to the discovery of IBL-302 (31), a potent, selective, and orally bioavailable triple PI3K/mTOR/PIM inhibitor. IBL-302, currently in late preclinical development (AUM302), has recently demonstrated efficacy in neuroblastoma and breast cancer xenografts. Additionally, during the course of our experiments, we observed that macrocyclization was essential to obtain the desired multitarget profile. As a matter of example, the open precursors 35-37 were inactive against PIM whereas MCX 28 displayed low nanomolar activity.

12.
Cancers (Basel) ; 13(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946744

RESUMO

PIM kinases are constitutively active proto-oncogenic serine/threonine kinases that play a role in cell cycle progression, metabolism, inflammation and drug resistance. PIM kinases interact with and stabilize p53, c-Myc and parallel signaling pathway PI3K/Akt. This study evaluated PIM kinase expression in NSCLC and in response to PI3K/mTOR inhibition. It investigated a novel preclinical PI3K/mTOR/PIM inhibitor (IBL-301) in vitro and in patient-derived NSCLC tumor tissues. Western blot analysis confirmed PIM1, PIM2 and PIM3 are expressed in NSCLC cell lines and PIM1 is a marker of poor prognosis in patients with NSCLC. IBL-301 decreased PIM1, c-Myc, pBAD and p4EBP1 (Thr37/46) and peIF4B (S406) protein levels in-vitro and MAP kinase, PI3K-Akt and JAK/STAT pathways in tumor tissue explants. IBL-301 significantly decreased secreted pro-inflammatory cytokine MCP-1. Altered mRNA expression, including activated PIM kinase and c-Myc, was identified in Apitolisib resistant cells (H1975GR) by an IL-6/STAT3 pathway array and validated by Western blot. H1975GR cells were more sensitive to IBL-301 than parent cells. A miRNA array identified a dysregulated miRNA signature of PI3K/mTOR drug resistance consisting of regulators of PIM kinase and c-Myc (miR17-5p, miR19b-3p, miR20a-5p, miR15b-5p, miR203a, miR-206). Our data provides a rationale for co-targeting PIM kinase and PI3K-mTOR to improve therapeutic response in NSCLC.

13.
Blood Adv ; 4(20): 5093-5106, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33085757

RESUMO

The B-cell receptor signaling pathway and dysregulation of the Bcl-2 family of proteins play crucial roles in the pathogenesis of chronic lymphocytic leukemia (CLL). Despite significant advances in the treatment of the disease, relapse and drug resistance are not uncommon. In the current study, we investigated the dual PI3/PIM kinase inhibitor IBL-202 in combination with venetoclax as a treatment option for CLL using both primary CLL cells and TP53-deficient OSU-CLL cells generated using the CRISPR-Cas9 system. IBL-202 and venetoclax were highly synergistic against primary CLL cells cocultured with CD40L fibroblasts (combination index [CI], 0.4, at a fractional effect of 0.9) and TP53-knockout (KO) OSU-CLL cells (CI, 0.5, at a fractional effect of 0.9). Synergy between the drugs was consistent, with a significant (P < .05) reduction in the 50% inhibitory concentration for both drugs. IBL-202 and venetoclax in combination induced cell-cycle arrest and slowed the proliferation of both wild-type and TP53-KO cell lines. The drug combination inhibited AKT phosphorylation, reduced expression of Bcl-xL and NF-κB, and increased the Noxa/Mcl-1 ratio. Downregulation of CXCR4 was consistent with inhibition of the SDF-1α-induced migratory capacity of CLL cells. Synergy between IBL-202 and venetoclax against primary CLL cells cultured under conditions that mimic the tumor microenvironment suggests this drug combination may be effective against CLL cells within the lymph nodes and bone marrow. Furthermore, the efficacy of the combination against the TP53-KO OSU-CLL cell line suggests the combination may be a highly effective treatment strategy for high-risk CLL.


Assuntos
Leucemia Linfocítica Crônica de Células B , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Sulfonamidas/farmacologia , Microambiente Tumoral
14.
Brain ; 143(8): 2576-2593, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32705145

RESUMO

The glymphatic system, that is aquaporin 4 (AQP4) facilitated exchange of CSF with interstitial fluid (ISF), may provide a clearance pathway for protein species such as amyloid-ß and tau, which accumulate in the brain in Alzheimer's disease. Further, tau protein transference via the extracellular space, the compartment that is cleared by the glymphatic pathway, allows for its neuron-to-neuron propagation, and the regional progression of tauopathy in the disorder. The glymphatic system therefore represents an exciting new target for Alzheimer's disease. Here we aim to understand the involvement of glymphatic CSF-ISF exchange in tau pathology. First, we demonstrate impaired CSF-ISF exchange and AQP4 polarization in a mouse model of tauopathy, suggesting that this clearance pathway may have the potential to exacerbate or even induce pathogenic accumulation of tau. Subsequently, we establish the central role of AQP4 in the glymphatic clearance of tau from the brain; showing marked impaired glymphatic CSF-ISF exchange and tau protein clearance using the novel AQP4 inhibitor, TGN-020. As such, we show that this system presents as a novel druggable target for the treatment of Alzheimer's disease, and possibly other neurodegenerative diseases alike.


Assuntos
Doença de Alzheimer/metabolismo , Aquaporina 4/metabolismo , Encéfalo/metabolismo , Sistema Glinfático/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/patologia , Líquido Cefalorraquidiano/metabolismo , Modelos Animais de Doenças , Líquido Extracelular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
15.
Cell Rep ; 30(6): 2040-2054.e5, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32049030

RESUMO

Alzheimer's disease (AD) is associated with the intracellular aggregation of hyperphosphorylated tau and the accumulation of ß-amyloid in the neocortex. We use transgenic mice harboring human tau (rTg4510) and amyloid precursor protein (J20) mutations to investigate transcriptional changes associated with the progression of tau and amyloid pathology. rTg4510 mice are characterized by widespread transcriptional differences in the entorhinal cortex with changes paralleling neuropathological burden across multiple brain regions. Differentially expressed transcripts overlap with genes identified in genetic studies of familial and sporadic AD. Systems-level analyses identify discrete co-expression networks associated with the progressive accumulation of tau that are enriched for genes and pathways previously implicated in AD pathology and overlap with co-expression networks identified in human AD cortex. Our data provide further evidence for an immune-response component in the accumulation of tau and reveal molecular pathways associated with the progression of AD neuropathology.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/efeitos adversos , Proteínas tau/efeitos adversos , Animais , Modelos Animais de Doenças , Progressão da Doença , Humanos , Camundongos , Camundongos Transgênicos
16.
Oncogene ; 39(14): 3028-3040, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32042115

RESUMO

The proviral integration of Moloney virus (PIM) family of protein kinases are overexpressed in many haematological and solid tumours. PIM kinase expression is elevated in PI3K inhibitor-treated breast cancer samples, suggesting a major resistance pathway for PI3K inhibitors in breast cancer, potentially limiting their clinical utility. IBL-302 is a novel molecule that inhibits both PIM and PI3K/AKT/mTOR signalling. We thus evaluated the preclinical activity of IBL-302, in a range of breast cancer models. Our results demonstrate in vitro efficacy of IBL-302 in a range of breast cancer cell lines, including lines with acquired resistance to trastuzumab and lapatinib. IBL-302 demonstrated single-agent, anti-tumour efficacy in suppression of pAKT, pmTOR and pBAD in the SKBR-3, BT-474 and HCC-1954 HER2+/PIK3CA-mutated cell lines. We have also shown the in vivo single-agent efficacy of IBL-302 in the subcutaneous BT-474 and HCC-1954 xenograft model in BALB/c nude mice. The combination of trastuzumab and IBL-302 significantly increased the anti-proliferative effect in HER2+ breast cancer cell line, and matched trastuzumab-resistant line, relative to testing either drug alone. We thus believe that the novel PIM and PI3K/mTOR inhibitor, IBL-302, represents an exciting new potential treatment option for breast cancer, and that it should be considered for clinical investigation.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Piridinas/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Tiofenos/farmacologia , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Lapatinib/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Trastuzumab/farmacologia
18.
Insects ; 11(1)2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31861592

RESUMO

Potato psyllid (Bactericera cockerelli) is one of the most important pests in potatoes (Solanum tuberosum L.) due to its feeding behavior and the transmission of a bacterium (Candidatus Liberibacter solanacearum) that causes zebra chip disease, altering the quality of the potato tuber and the fried potato chip or french fry. This pest is thus a threat to the chip potato industry and often requires preventive measures including the use of costly insecticides. The objectives of this research were to monitor the variation in B. cockerelli adult abundance and to evaluate the risk of zebra chip disease in northwestern New Mexico, USA. Yellow sticky traps were used to collect the pest at the Agricultural Experiment Station at Farmington, NM and in nearby commercial fields at the Navajo Agricultural Products Industry (NAPI) and Navajo Mesa Farms during the 2017-2019 period. The collected adult pests were analyzed at Texas A & M University for the presence of Candidatus L. solanacearum (Lso). The results showed field infestation by B. cockerelli in early June and that the population peaked during the second half of July and decreased as the potato growing season progressed. However, a second less important peak of the pest was revealed around mid- to late-August, depending on the growing season and field. While the B. cockerelli population increased linearly with average air temperature, it showed strong third order polynomial relationships with the accumulated thermal units and the Julian days. The test of B. cockerelli for the Lso infection revealed a low incidence of the pathogen varying from 0.22% to 6.25% and the infected adult B. cockerelli were collected during the population peak period. The results of this study may be helpful to potato growers in pest management decision-making and control. However, more study is needed to evaluate zebra chip disease in terms of its prevention and economic impact, and to develop economic thresholds and pest management programs for northwestern New Mexico and neighboring regions.

19.
Sci Rep ; 9(1): 14837, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619689

RESUMO

Alzheimer's disease (AD)-associated synaptic dysfunction drives the progression of pathology from its earliest stages. Amyloid ß (Aß) species, both soluble and in plaque deposits, have been causally related to the progressive, structural and functional impairments observed in AD. It is, however, still unclear how Aß plaques develop over time and how they progressively affect local synapse density and turnover. Here we observed, in a mouse model of AD, that Aß plaques grow faster in the earlier stages of the disease and if their initial area is >500 µm2; this may be due to deposition occurring in the outer regions of the plaque, the plaque cloud. In addition, synaptic turnover is higher in the presence of amyloid pathology and this is paralleled by a reduction in pre- but not post-synaptic densities. Plaque proximity does not appear to have an impact on synaptic dynamics. These observations indicate an imbalance in the response of the pre- and post-synaptic terminals and that therapeutics, alongside targeting the underlying pathology, need to address changes in synapse dynamics.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Placa Amiloide/patologia , Densidade Pós-Sináptica/patologia , Terminações Pré-Sinápticas/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Camundongos , Camundongos Transgênicos , Mutação
20.
Insects ; 10(11)2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31653101

RESUMO

This study was conducted to monitor the population dynamics of six major insect pests at the NMSU Agricultural Science Center at Farmington (ASC-Farmington) and within an adjacent commercial farm (Navajo Agricultural Products Industry, NAPI) for more effective and efficient pest management during the 2013-2019 period. Specific pheromone traps, sticky and net traps were used to collects moths of beet armyworm (Spodoptera exigua), cabbage looper (Trichoplusia ni), corn earworm (Helicoverpa zea), fall armyworm (Spodoptera frugiperda), potato psyllid (Bactericera cockerelli), and western bean cutworm (Striacosta albicosta). These insects generally appear in early June and their population decreases toward the end of August/early September with different peak times and magnitudes during July and August. Bactericera cockerelli was not substantially present in the commercial farm due to intensive insecticide application. Overall, all six insect species were present at ASC-Farmington, with relative abundance, in percent of the total collected moths by all traps, varying from 6.5 to 19% for Trichoplusia ni, 16 to 29.2% for Spodoptera exigua, 1.5 to 20.6% for Striacosta albicosta, 10 to 25% for Helicoverpa zea, 18.5 to 25.6% for Spodoptera frugiperda and 8.5 to 26.9% for Bactericera cockerelli. In NAPI's commercial field, while the potato psyllid Bactericera cockerelli was not recorded, Trichoplusia ni and Spodoptera exigua showed decreasing rates that varied from 27.5 to 4.2% and from 49.3 to 7.8%, respectively. Striacosta albicosta, Helicoverpa zea and Spodoptera exigua showed increasing rates varying from 2.9 to 28%, from 7.8 to 25.3% and from 10.9 to 52%, respectively. The results of this study could serve as a guideline for sustainable management strategies for each of the six species for production profitability.

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