RESUMO
The radiation-based sterile insect technique (SIT) has successfully suppressed field populations of several insect pest species, but its effect on mosquito vector control has been limited. The related incompatible insect technique (IIT)-which uses sterilization caused by the maternally inherited endosymbiotic bacteria Wolbachia-is a promising alternative, but can be undermined by accidental release of females infected with the same Wolbachia strain as the released males. Here we show that combining incompatible and sterile insect techniques (IIT-SIT) enables near elimination of field populations of the world's most invasive mosquito species, Aedes albopictus. Millions of factory-reared adult males with an artificial triple-Wolbachia infection were released, with prior pupal irradiation of the released mosquitoes to prevent unintentionally released triply infected females from successfully reproducing in the field. This successful field trial demonstrates the feasibility of area-wide application of combined IIT-SIT for mosquito vector control.
Assuntos
Aedes/microbiologia , Aedes/fisiologia , Controle de Mosquitos/métodos , Mosquitos Vetores/microbiologia , Mosquitos Vetores/fisiologia , Wolbachia/patogenicidade , Aedes/crescimento & desenvolvimento , Animais , China , Copulação , Estudos de Viabilidade , Feminino , Humanos , Mordeduras e Picadas de Insetos/prevenção & controle , Larva/crescimento & desenvolvimento , Larva/microbiologia , Larva/fisiologia , Masculino , Mosquitos Vetores/crescimento & desenvolvimento , Controle de Qualidade , ReproduçãoRESUMO
Mammalian hearing involves the mechanoelectrical transduction (MET) of sound-induced fluid waves in the cochlea. Essential to this process are the specialised sensory cochlear cells, the inner (IHCs) and outer hair cells (OHCs). While genetic hearing loss is highly heterogeneous, understanding the requirement of each gene will lead to a better understanding of the molecular basis of hearing and also to therapeutic opportunities for deafness. The Neuroplastin (Nptn) gene, which encodes two protein isoforms Np55 and Np65, is required for hearing, and homozygous loss-of-function mutations that affect both isoforms lead to profound deafness in mice. Here we have utilised several distinct mouse models to elaborate upon the spatial, temporal, and functional requirement of Nptn for hearing. While we demonstrate that both Np55 and Np65 are present in cochlear cells, characterisation of a Np65-specific mouse knockout shows normal hearing thresholds indicating that Np65 is functionally redundant for hearing. In contrast, we find that Nptn-knockout mice have significantly reduced maximal MET currents and MET channel open probabilities in mature OHCs, with both OHCs and IHCs also failing to develop fully mature basolateral currents. Furthermore, comparing the hearing thresholds and IHC synapse structure of Nptn-knockout mice with those of mice that lack Nptn only in IHCs and OHCs shows that the majority of the auditory deficit is explained by hair cell dysfunction, with abnormal afferent synapses contributing only a small proportion of the hearing loss. Finally, we show that continued expression of Neuroplastin in OHCs of adult mice is required for membrane localisation of Plasma Membrane Ca2+ ATPase 2 (PMCA2), which is essential for hearing function. Moreover, Nptn haploinsufficiency phenocopies Atp2b2 (encodes PMCA2) mutations, with heterozygous Nptn-knockout mice exhibiting hearing loss through genetic interaction with the Cdh23ahl allele. Together, our findings provide further insight to the functional requirement of Neuroplastin for mammalian hearing.
Assuntos
Caderinas/genética , Células Ciliadas Auditivas Internas/fisiologia , Audição/genética , Glicoproteínas de Membrana/genética , Isoformas de Proteínas/genética , Animais , Mutação com Perda de Função , Camundongos , Camundongos Knockout , ATPases Transportadoras de Cálcio da Membrana Plasmática/metabolismoRESUMO
The tumour stroma regulates nearly all stages of carcinogenesis. Stromal heterogeneity in human triple-negative breast cancers (TNBCs) remains poorly understood, limiting the development of stromal-targeted therapies. Single-cell RNA sequencing of five TNBCs revealed two cancer-associated fibroblast (CAF) and two perivascular-like (PVL) subpopulations. CAFs clustered into two states: the first with features of myofibroblasts and the second characterised by high expression of growth factors and immunomodulatory molecules. PVL cells clustered into two states consistent with a differentiated and immature phenotype. We showed that these stromal states have distinct morphologies, spatial relationships and functional properties in regulating the extracellular matrix. Using cell signalling predictions, we provide evidence that stromal-immune crosstalk acts via a diverse array of immunoregulatory molecules. Importantly, the investigation of gene signatures from inflammatory-CAFs and differentiated-PVL cells in independent TNBC patient cohorts revealed strong associations with cytotoxic T-cell dysfunction and exclusion, respectively. Such insights present promising candidates to further investigate for new therapeutic strategies in the treatment of TNBCs.
Assuntos
Neoplasias de Mama Triplo Negativas/imunologia , Evasão Tumoral , Matriz Extracelular/imunologia , Matriz Extracelular/patologia , Feminino , Humanos , RNA-Seq , Células Estromais/imunologia , Células Estromais/patologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Innovative therapeutic strategies have emerged over the past decade to improve outcomes for most lymphoma patients. Nevertheless, the aggressive presentation seen in high-risk mantle cell lymphoma (MCL) patients remains an unmet medical need. The highly proliferative cells that characterize these tumors depend on nucleotide synthesis to ensure high DNA replication and RNA synthesis. To take advantage of this vulnerability, STP-B, a clinically available small molecule selectively targeting CTP synthase 1 (CTPS1) has been recently developed. CTPS1 is a key enzyme of the pyrimidine synthesis pathway mediated through its unique ability to provide enough CTP in highly proliferating cells. Herein, we demonstrated that CTPS1 was expressed in all MCL cells, and that its high expression was associated with unfavorable outcomes for patients treated with chemotherapy. Using aggressive MCL models characterized by blastoid morphology, TP53 mutation or polyresistance to targeted therapies, we showed that STP-B was highly effective at nanomolar concentrations in vitro and in vivo, irrespective of these high-risk features. Inhibition of CTPS1 rapidly leads to cell cycle arrest in early S-phase accompanied by inhibition of translation, including of the anti-apoptotic protein MCL1. Consequently, CTPS1 inhibition induced synergistic cell death in combination with the selective BCL2 inhibitor venetoclax, both in vitro and in vivo. Overall, our study identified CTPS1 as a promising target for MCL patients and provided a mechanism-based combination with the BCL2 inhibitor venetoclax for the design of future chemotherapy-free treatment regimens to overcome resistance.
Assuntos
Sinergismo Farmacológico , Linfoma de Célula do Manto , Proteínas Proto-Oncogênicas c-bcl-2 , Animais , Humanos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes , Carbono-Nitrogênio Ligases , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/patologia , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/genética , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The sensory cells that are responsible for hearing include the cochlear inner hair cells (IHCs) and outer hair cells (OHCs), with the OHCs being necessary for sound sensitivity and tuning1. Both cell types are thought to arise from common progenitors; however, our understanding of the factors that control the fate of IHCs and OHCs remains limited. Here we identify Ikzf2 (which encodes Helios) as an essential transcription factor in mice that is required for OHC functional maturation and hearing. Helios is expressed in postnatal mouse OHCs, and in the cello mouse model a point mutation in Ikzf2 causes early-onset sensorineural hearing loss. Ikzf2cello/cello OHCs have greatly reduced prestin-dependent electromotile activity, a hallmark of OHC functional maturation, and show reduced levels of crucial OHC-expressed genes such as Slc26a5 (which encodes prestin) and Ocm. Moreover, we show that ectopic expression of Ikzf2 in IHCs: induces the expression of OHC-specific genes; reduces the expression of canonical IHC genes; and confers electromotility to IHCs, demonstrating that Ikzf2 can partially shift the IHC transcriptome towards an OHC-like identity.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Células Ciliadas Auditivas Externas/citologia , Células Ciliadas Auditivas Externas/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Gênica , Transcriptoma/genética , Animais , Sequência de Bases , Biomarcadores/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Despite the availability of effective vaccines against pneumococcal disease, pneumococcus is a common bacterial cause of pneumonia, causing approximately 100,000 hospitalizations among U.S. adults per year. In addition, approximately 30,000 invasive pneumococcal disease (IPD) cases and 3,000 IPD deaths occur among U.S. adults each year. Previous health care provider surveys identified gaps in provider knowledge about and understanding of the adult pneumococcal vaccine recommendations, and pneumococcal vaccine coverage remains suboptimal. To assess the feasibility and acceptability domains of the Advisory Committee on Immunization Practices (ACIP) Evidence to Recommendations (EtR) framework, a health care provider knowledge and attitudes survey was conducted during September 28-October 10, 2022, by the Healthcare and Public Perceptions of Immunizations Survey Collaborative before the October 2022 ACIP meeting. Among 751 provider respondents, two thirds agreed or strongly agreed with the policy option under consideration to expand the recommendations for the new 20-valent pneumococcal conjugate vaccine (PCV20) to adults who had only received the previously recommended 13-valent pneumococcal conjugate vaccine (PCV13). Gaps in providers' knowledge and perceived challenges to implementing recommendations were identified and were included in ACIP's EtR framework discussions in late October 2022 when ACIP updated the recommendations for PCV20 use in adults. Currently, use of PCV20 is recommended for certain adults who have previously received PCV13, in addition to those who have never received a pneumococcal conjugate vaccine. The survey findings indicate a need to increase provider awareness and implementation of pneumococcal vaccination recommendations and to provide tools to assist with patient-specific vaccination guidance. Resources available to address the challenges to implementing pneumococcal vaccination recommendations include the PneumoRecs VaxAdvisor mobile app and other CDC-developed tools, including summary documents and overviews of vaccination schedules and CDC's strategic framework to increase confidence in vaccines and reduce vaccine-preventable diseases, Vaccinate with Confidence.
Assuntos
Infecções Pneumocócicas , Vacinas Pneumocócicas , Estados Unidos/epidemiologia , Adulto , Humanos , Vacinas Conjugadas , Pessoal de Saúde , Infecções Pneumocócicas/prevenção & controle , AtitudeRESUMO
Having two forward-facing eyes with slightly different viewpoints enables animals, including humans, to discriminate fine differences in depth (disparities), which can facilitate interaction with the world. The binocular visual system starts in the primary visual cortex because that is where information from the eyes is integrated for the first time. Magnetic resonance imaging (MRI) is an ideal tool to non-invasively investigate this system since it can provide a range of detailed measures about structure, function, neurochemistry and connectivity of the human brain. Since binocular disparity is used for both action and object recognition, the binocular visual system is a valuable model system in neuroscience for understanding how basic sensory cues are transformed into behaviourally relevant signals. In this review, we consider how MRI has contributed to the understanding of binocular vision and depth perception in the human brain. Firstly, MRI provides the ability to image the entire brain simultaneously to compare the contribution of specific visual areas to depth perception. A large body of work using functional MRI has led to an understanding of the extensive networks of brain areas involved in depth perception, but also the fine-scale macro-organisation for binocular processing within individual visual areas. Secondly, MRI can uncover mechanistic information underlying binocular combination with the use of MR spectroscopy. This method can quantify neurotransmitters including GABA and glutamate within restricted regions of the brain, and evaluate the role of these inhibitory and excitatory neurochemicals in binocular vision. Thirdly, it is possible to measure the nature and microstructure of pathways underlying depth perception using diffusion MRI. Understanding these pathways provides insight into the importance of the connections between areas implicated in depth perception. Finally, MRI can help to understand changes in the visual system resulting from amblyopia, a neural condition where binocular vision does not develop correctly in childhood.
Assuntos
Percepção de Profundidade , Córtex Visual , Animais , Humanos , Visão Binocular , Percepção Visual , Disparidade Visual , Imageamento por Ressonância Magnética , Estimulação LuminosaRESUMO
Research has demonstrated that performing a sequence of saccadic horizontal eye movements prior to retrieval facilitates performance on tests of episodic memory. This has been observed in both laboratory tasks of retention and autobiographical memory. To date, the work has centred on performance in younger individuals. This paper extends previous investigations by examining the effects of saccadic eye movements in older persons. Autobiographical episodic and semantic memory fluency was assessed in younger (age range 18-35, mean = 22.50), and older (age range 55-87, mean = 70.35) participants following saccadic (vs. fixation control) manipulations. The main effects of eye movements and age were found for episodic autobiographical memory (greater fluency after eye movements and in younger participants). Semantic autobiographical memory showed a main effect of age (greater fluency in younger participants), whereas general semantic memory showed no effect of age or eye movement. These findings indicate that saccadic horizontal eye movements can enhance episodic personal memory in older individuals. This has implications as a technique to improve autobiographical recollection in the elderly and as an adjunct in reminiscence therapy.
Assuntos
Memória Episódica , Humanos , Idoso , Idoso de 80 Anos ou mais , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Movimentos Sacádicos , Semântica , Movimentos Oculares , Rememoração MentalRESUMO
BACKGROUND: Eosinophils are implicated as effector cells in asthma, but the functional implications of the precise location of eosinophils in the airway wall is poorly understood. We aimed to quantify eosinophils in the different compartments of the airway wall and associate these findings with clinical features of asthma and markers of airway inflammation. METHODS: In this cross-sectional study, we utilised design-based stereology to accurately partition the numerical density of eosinophils in both the epithelial compartment and the subepithelial space (airway wall area below the basal lamina including the submucosa) in individuals with and without asthma and related these findings to airway hyperresponsiveness (AHR) and features of airway inflammation. RESULTS: Intraepithelial eosinophils were linked to the presence of asthma and endogenous AHR, the type that is most specific for asthma. In contrast, both intraepithelial and subepithelial eosinophils were associated with type 2 (T2) inflammation, with the strongest association between IL5 expression and intraepithelial eosinophils. Eosinophil infiltration of the airway wall was linked to a specific mast cell phenotype that has been described in asthma. We found that interleukin (IL)-33 and IL-5 additively increased cysteinyl leukotriene (CysLT) production by eosinophils and that the CysLT LTC4 along with IL-33 increased IL13 expression in mast cells and altered their protease profile. CONCLUSIONS: We conclude that intraepithelial eosinophils are associated with endogenous AHR and T2 inflammation and may interact with intraepithelial mast cells via CysLTs to regulate airway inflammation.
Assuntos
Asma , Eosinófilos , Estudos Transversais , Eosinófilos/metabolismo , Humanos , Inflamação/metabolismo , Sistema RespiratórioRESUMO
Two experiments investigated differences in short-term storage and processing capacity on the magnitude of eye-closure effects on episodic memory. Experiment 1 compared individuals with high (vs. low) forward and backward spans in the free-recall of words retrieved under both eyes closed and open conditions. Main effects of both forward and backward span capacity (greater recall for the high span group) and eye-closure (higher recall with eyes closed) were found. Eye-closure was also associated with more "remember" responses. Experiment 2 compared individuals with high (vs. low) reading spans and found both main effects for reading span and eye-closure (greater recall for the high span group and with eyes closed). Remember responses were associated with both high reading span and eye-closure. The absence of interactions is discussed in terms of explanations of eye-closure effects that differentiate between modality-general and modality-specific processes.
Assuntos
Memória Episódica , Humanos , Memória de Curto Prazo/fisiologia , Rememoração Mental/fisiologia , LeituraRESUMO
Variability in cortical neural activity potentially limits sensory discriminations. Theoretical work shows that information required to discriminate two similar stimuli is limited by the correlation structure of cortical variability. We investigated these information-limiting correlations by recording simultaneously from visual cortical areas primary visual cortex (V1) and extrastriate area V4 in macaque monkeys performing a binocular, stereo depth discrimination task. Within both areas, noise correlations on a rapid temporal scale (20-30 ms) were stronger for neuron pairs with similar selectivity for binocular depth, meaning that these correlations potentially limit information for making the discrimination. Between-area correlations (V1 to V4) were different, being weaker for neuron pairs with similar tuning and having a slower temporal scale (100+ ms). Fluctuations in these information-limiting correlations just prior to the detection event were associated with changes in behavioral accuracy. Although these correlations limit the recovery of information about sensory targets, their impact may be curtailed by integrative processing of signals across multiple brain areas.NEW & NOTEWORTHY Correlated noise reduces the stimulus information in visual cortical neurons during experimental performance of binocular depth discriminations. The temporal scale of these correlations is important. Rapid (20-30 ms) correlations reduce information within and between areas V1 and V4, whereas slow (>100 ms) correlations between areas do not. Separate cortical areas appear to act together to maintain signal fidelity. Rapid correlations reduce the neuronal signal difference between stimuli and adversely affect perceptual discrimination.
Assuntos
Potenciais de Ação/fisiologia , Percepção de Profundidade/fisiologia , Aprendizagem por Discriminação/fisiologia , Neurônios/fisiologia , Visão Binocular/fisiologia , Córtex Visual/fisiologia , Animais , Macaca mulatta , Masculino , Estimulação Luminosa/métodos , Desempenho Psicomotor/fisiologiaRESUMO
OBJECTIVE: The objective of this study was to examine the potential impact of provider social networks and experiences with patients on deimplementation of breast cancer screening. RESEARCH DESIGN: We constructed the Breast Cancer-Social network Agent-based Model (BC-SAM), which depicts breast cancer screening decisions, incidence, and progression among 10,000 women ages 40 and over and the screening recommendations of their providers over a 30-year period. The model has patient and provider modules that each incorporate social network influences. Patients and providers were connected in a network, which represented patient-patient peer connections, provider-provider peer connections, connections between providers and patients they treat, and friend/family relationships between patients and providers. We calibrated provider decisions in the model using data from the CanSNET national survey of primary care physicians in the United States, which we fielded in 2016. RESULTS: First, assuming that providers' screening recommendations for women ages 50-74 remain unchanged but their recommendations for screening among younger (below 50 y old) and older (75+ y old) women decrease, we observed a decline in predicted screening rates for women ages 50-74 due to spillover effects. Second, screening rates for younger and older women were slow to respond to changes in provider recommendations; a 78% decline in provider recommendations to older women over 30 years resulted in an estimated 23% decline in patient screening in that group. Third, providers' experiences with unscreened patients, friends, and family members modestly increased screening recommendations over time (7 percentage points). Finally, we found that provider peer effects can have a substantial impact on population screening rates and can entrench existing practices. CONCLUSION: Modeling cancer screening as a complex social system demonstrates a range of potential effects and may help target future interventions designed to reduce overscreening.
Assuntos
Neoplasias da Mama/diagnóstico , Detecção Precoce de Câncer/estatística & dados numéricos , Guias como Assunto/normas , Padrões de Prática Médica/estatística & dados numéricos , Rede Social , Adulto , Idoso , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Médicos de Atenção Primária , Estados UnidosRESUMO
On May 10, 2021, the Food and Drug Administration (FDA) expanded its Emergency Use Authorization for the Pfizer-BioNTech COVID-19 vaccine to include adolescents aged 12-15 years; this authorization was followed by interim recommendations from the Advisory Committee on Immunization Practices (ACIP) for the vaccine among this age group (1). Using data from nonprobability-based Internet panel surveys administered by the Healthcare and Public Perceptions of Immunizations (HaPPI) Survey Collaborative, the acceptability of adolescent COVID-19 vaccination and self-reported factors increasing vaccination intent were assessed among independently recruited samples of 985 adolescents aged 13-17 years and 1,022 parents and guardians (parents) of adolescents aged 12-17 years during April 15-April 23, 2021, prior to vaccine authorization for this age group. Approximately one quarter (27.6%) of parents whose adolescents were already vaccine-eligible (i.e., aged 16-17 years) reported their adolescent had received ≥1 COVID-19 vaccine dose, similar to the proportion reported by vaccine-eligible adolescents aged 16-17 years (26.1%). However, vaccine receipt reported by parents of adolescents differed across demographic groups; parents identifying as female or Hispanic, or who had an education lower than a bachelor's degree reported the lowest adolescent COVID-19 vaccination receipt. Among parents of unvaccinated adolescents aged 12-17 years, 55.5% reported they would "definitely" or "probably" have their adolescent receive a COVID-19 vaccination. Among unvaccinated adolescents aged 13-17 years, 51.7% reported they would "definitely" or "probably" receive a COVID-19 vaccination. Obtaining more information about adolescent COVID-19 vaccine safety and efficacy, as well as school COVID-19 vaccination requirements, were the most commonly reported factors that would increase vaccination intentions among both parents and adolescents. Federal, state, and local health officials and primary care professionals were the most trusted sources of COVID-19 vaccine information among both groups. Efforts focusing on clearly communicating to the public the benefits and safety of COVID-19 vaccination for adolescents, particularly by health care professionals, could help increase confidence in adolescent COVID-19 vaccine and vaccination coverage.
Assuntos
Vacinas contra COVID-19/administração & dosagem , Pais/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Vacinação/psicologia , Adolescente , COVID-19/epidemiologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Criança , Informação de Saúde ao Consumidor , Feminino , Humanos , Intenção , Masculino , Estados Unidos/epidemiologiaRESUMO
Two experiments examined the effects of directed (intentional) forgetting on information processed for its survival value. Experiment 1 used the list-method directed forgetting procedure in which items processed for their relevance to survival, moving house or pleasantness were followed by the cue to remember or forget. Following the encoding of a second list, free-recall of both lists showed that survival encoding brought about greater remembering (after the remember cue) and forgetting (after the forget cue). Experiment 2 also used the list-method and manipulated mental context reinstatement prior to recall. Although this manipulation was effective in enhancing memory, more directed forgetting was again shown in the survival condition. In both experiments the effects of survival processing were shown also in free-recall "remember" (vs. "know") responses, indicative of the retrieval of associative or contextual details. The mechanisms that might underpin these were evaluated and considered in relation to future work.
Assuntos
Sinais (Psicologia) , Rememoração Mental , Humanos , Projetos de PesquisaRESUMO
PURPOSE: Decompressive craniectomy remains controversial because of uncertainty regarding its benefit to patients; this study aimed to explore current practice following the RESCUEicp Trial, an important study in the evolving literature on decompressive craniectomies. MATERIALS AND METHODS: Neurosurgeons in New Zealand, Australia, USA and Nepal were sent a survey consisting of two case scenarios and several multi-choice questions exploring their utilisation of decompressive craniectomy following the RESCUEicp Trial. RESULTS: One in ten neurosurgeons (n = 6, 10.3%) were no longer performing decompressive craniectomies for TBI following the RESCUEicp Trial and two fifths (n = 23, 39.7%) were less enthusiastic. Most neurosurgeons would not operate in the face of severe disability (n = 46, 79.3%) or vegetative state/death (n = 57, 98.3%). Neurosurgeons tended give more optimistic prognoses than the CRASH prognostic model. Those who suggested more pessimistic prognoses and those who use decision support tools were less likely to advise decompressive surgery. CONCLUSIONS: RESCUEicp has had a notable impact on neurosurgeons and their management of TBI. Although there remains no clear clinical consensus on the contraindications for decompressive craniectomy, most neurosurgeons would not operate if severe disability or vegetative state (the rates of which are increased by such surgery) seemed likely. Whilst unreliable, prognostic estimates still have an impact on clinical decision making and neurosurgical management. Wider use of decision support tools should be considered.
Assuntos
Lesões Encefálicas Traumáticas , Craniectomia Descompressiva , Lesões Encefálicas Traumáticas/diagnóstico , Lesões Encefálicas Traumáticas/cirurgia , Humanos , Neurocirurgiões , Prognóstico , Inquéritos e Questionários , Resultado do TratamentoRESUMO
We investigated the relationship between neurochemical and hemodynamic responses as a function of image contrast in the human primary visual cortex (V1). Simultaneously acquired BOLD-fMRI and single voxel proton MR spectroscopy signals were measured in V1 of 24 healthy human participants of either sex at 7 tesla field strength, in response to presentations (64 s blocks) of different levels of image contrast (3%, 12.5%, 50%, 100%). Our results suggest that complementary measures of neurotransmission and energy metabolism are in partial agreement: BOLD and glutamate signals were linear with image contrast; however, a significant increase in glutamate concentration was evident only at the highest intensity level. In contrast, GABA signals were steady across all intensity levels. These results suggest that neurochemical concentrations are maintained at lower ranges of contrast levels, which match the statistics of natural vision, and that high stimulus intensity may be critical to increase sensitivity to visually modulated glutamate signals in the early visual cortex using MR spectroscopy.SIGNIFICANCE STATEMENT Glutamate and GABA are the major excitatory and inhibitory neurotransmitters of the brain. To better understand the relationship between MRS-visible neurochemicals, the BOLD signal change, and stimulus intensity, we measured combined neurochemical and BOLD signals (combined fMRI-MRS) to different image contrasts in human V1 at 7 tesla. While a linear change to contrast was present for both signals, the increase in glutamate was significant only at the highest stimulus intensity. These results suggest that hemodynamic and neurochemical signals reflect common metabolic markers of neural activity, whereas the mismatch at lower contrast levels may indicate a sensitivity threshold for detecting neurochemical changes during visual processing. Our results highlight the challenge and importance of reconciling cellular and metabolic measures of neural activity in the human brain.
Assuntos
Oxigênio/sangue , Córtex Visual/química , Córtex Visual/fisiologia , Adulto , Mapeamento Encefálico , Feminino , Ácido Glutâmico/fisiologia , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Desempenho Psicomotor , Visão Ocular/fisiologia , Percepção Visual , Adulto JovemRESUMO
BACKGROUND: Resistance to endocrine therapy is a major clinical challenge in the management of oestrogen receptor (ER)-positive breast cancer. In this setting, p53 is frequently wildtype and its activity may be suppressed via upregulation of its key regulator MDM2. This underlies our rationale to evaluate MDM2 inhibition as a therapeutic strategy in treatment-resistant ER-positive breast cancer. METHODS: We used the MDM2 inhibitor NVP-CGM097 to treat in vitro and in vivo models alone and in combination with fulvestrant or palbociclib. We perform cell viability, cell cycle, apoptosis and senescence assays to evaluate anti-tumour effects in p53 wildtype and p53 mutant ER-positive cell lines (MCF-7, ZR75-1, T-47D) and MCF-7 lines resistant to endocrine therapy and to CDK4/6 inhibition. We further assess the drug effects in patient-derived xenograft (PDX) models of endocrine-sensitive and endocrine-resistant ER-positive breast cancer. RESULTS: We demonstrate that MDM2 inhibition results in cell cycle arrest and increased apoptosis in p53-wildtype in vitro and in vivo breast cancer models, leading to potent anti-tumour activity. We find that endocrine therapy or CDK4/6 inhibition synergises with MDM2 inhibition but does not further enhance apoptosis. Instead, combination treatments result in profound regulation of cell cycle-related transcriptional programmes, with synergy achieved through increased antagonism of cell cycle progression. Combination therapy pushes cell lines resistant to fulvestrant or palbociclib to become senescent and significantly reduces tumour growth in a fulvestrant-resistant patient-derived xenograft model. CONCLUSIONS: We conclude that MDM2 inhibitors in combination with ER degraders or CDK4/6 inhibitors represent a rational strategy for treating advanced, endocrine-resistant ER-positive breast cancer, operating through synergistic activation of cell cycle co-regulatory programmes.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Receptores de Estrogênio/metabolismo , Animais , Apoptose , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Fulvestranto/administração & dosagem , Humanos , Isoquinolinas/administração & dosagem , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Piperazinas/administração & dosagem , Piridinas/administração & dosagem , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Seasonal influenza vaccination is an important behavior with significant individual and public health consequences, yet fewer than half of individuals in the USA are vaccinated annually. To promote vaccination adherence, it is important to understand the factors that affect vaccination behavior. PURPOSE: In this research, we focused on one such factor, an individual's vaccination history. We gathered longitudinal data to track and understand the relationship between an individual's vaccination history and their current behaviors. METHODS: U.S. adults completed multiple surveys over an 8 year period, which asked about whether they had received the influenza vaccination during the previous flu season. We analyzed the data to determine the strength of the relationship between vaccination decisions across single-year and multiyear intervals. Additionally, we fitted two mathematical models to the data to determine whether individuals were better characterized as having a stable propensity to vaccinate or a stable propensity to repeat their previous decisions. RESULTS: Individuals exhibited highly consistent behavior across adjacent years, yet, across the complete extent of the longitudinal study, they were far more likely to repeat the earlier decision to vaccinate. Surprisingly, the results of the mathematical model suggest that individuals are better characterized as having a stable propensity to repeat their previous decisions rather than a stable propensity to vaccinate per se. Although most individuals had an extremely strong tendency to repeat the previous decision, some had a far weaker propensity to do so. CONCLUSIONS: This suggests that interventions intended to increase vaccination uptake might be most impactful for those individuals with only a weak tendency to vaccinate or not to vaccinate.
Assuntos
Tomada de Decisões , Comportamentos Relacionados com a Saúde , Conhecimentos, Atitudes e Prática em Saúde , Influenza Humana/prevenção & controle , Vacinação/psicologia , Adulto , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Estações do Ano , Estados Unidos/epidemiologia , Vacinação/estatística & dados numéricosRESUMO
Two experiments investigated the effect of eye-closure on visual and auditory memory under conditions based on the retrieval of item-specific information. Experiment 1 investigated visual recognition memory for studied, perceptually similar and unrelated items. It was found that intermittent eye-closure increased memory for studied items and decreased memory for related items. This finding was reflected by enhanced item-specific and reduced gist memory. Experiment 2 used the Deese-Roediger-McDermott (DRM) paradigm to assess auditory recognition memory for studied, related and unrelated words that had (vs. had not) been accompanied by pictures during encoding. Pictures but not eye-closure produced a picture superiority effect by enhancing memory for studied items. False memory was reduced by pictures but not eye-closure. Methodological and theoretical considerations are discussed in relation to existing explanations of eye-closure and retrieval strategies.