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1.
Cell Host Microbe ; 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32585135

RESUMO

There are as yet no licensed therapeutics for the COVID-19 pandemic. The causal coronavirus (SARS-CoV-2) binds host cells via a trimeric spike whose receptor binding domain (RBD) recognizes angiotensin-converting enzyme 2, initiating conformational changes that drive membrane fusion. We find that the monoclonal antibody CR3022 binds the RBD tightly, neutralizing SARS-CoV-2, and report the crystal structure at 2.4 Å of the Fab/RBD complex. Some crystals are suitable for screening for entry-blocking inhibitors. The highly conserved, structure-stabilizing CR3022 epitope is inaccessible in the prefusion spike, suggesting that CR3022 binding facilitates conversion to the fusion-incompetent post-fusion state. Cryogenic electron microscopy (cryo-EM) analysis confirms that incubation of spike with CR3022 Fab leads to destruction of the prefusion trimer. Presentation of this cryptic epitope in an RBD-based vaccine might advantageously focus immune responses. Binders at this epitope could be useful therapeutically, possibly in synergy with an antibody that blocks receptor attachment.

2.
Oxid Med Cell Longev ; 2020: 7156579, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32509151

RESUMO

Testicular dysfunction due to hyperglycemia is the main cause of infertility in diabetic men. Over the years, in order to solve this growing problem, a lot of research has been done and a variety of treatments have been created, but so far, there is no safe, effective, and practical method to prevent male infertility caused by diabetes. In this review, we emphasize the male infertility mechanism caused by diabetes from the effects of oxidative stress and autophagy on the function of testes via the PI3K/Akt/mTOR signaling pathway, and we highlight that oxidative stress-induced autophagy breaks the feedforward loop linking Nrf2 and p62 and promotes oxidative damage in diabetic testes.

3.
Neuroimage ; 215: 116812, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32276075

RESUMO

Behavioral studies investigating fundamental cognitive abilities provide evidence that processing speed accounts for large proportions of performance variability between individuals. Processing speed decline is a hallmark feature of the cognitive disruption observed in healthy aging and in demyelinating diseases such as multiple sclerosis (MS), neuromyelitis optica, and Wilson's disease. Despite the wealth of evidence suggesting a central role for processing speed in cognitive decline, the neural mechanisms of this fundamental ability remain unknown. Intact neurovascular coupling, acute localized blood flow increases following neural activity, is essential for optimal neural function. We hypothesized that efficient coupling forms the neural basis of processing speed. Because MS features neural-glial-vascular system disruption, we used it as a model to test this hypothesis. To assess the integrity of the coupling system, we measured blood-oxygen-level-dependent (BOLD) signal in healthy controls (HCs) and MS patients using a 3T MRI scanner while they viewed radial checkerboards that flickered periodically at 8 â€‹Hz. To assess processing speed and cognitive function, we administered a battery of neuropsychological tests. While MS patients exhibited reduced ΔBOLD with reductions in processing speed, no such relationships were observed in HCs. To further investigate the mechanisms that underlie ΔBOLD-processing speed relationships, we assessed the physiologic components that constitute ΔBOLD signal (i.e., cerebral blood flow, ΔCBF; cerebral metabolic rate of oxygen, ΔCMRO2; neurovascular coupling ratio) in speed-preserved and -impaired MS patients. While ΔCBF and ΔCMRO2 showed no group-differences, the neurovascular coupling ratio was significantly reduced in speed-impaired MS patients compared to speed-preserved MS patients. Together, these results suggest that neurovascular uncoupling might underlie cognitive slowing in MS and might be the central pathogenic mechanism governing processing speed decline.

4.
Medicine (Baltimore) ; 99(10): e19440, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32150096

RESUMO

RATIONALE: Although the early detection and treatment of non-metastatic esophageal cancer has improved, these patients' prognoses are still poor. Most patients with radical treatment for esophageal cancer will relapse in 3 years, and the best treatment strategy after recurrence has not been uniformly accepted. Multiform treatments may be beneficial to recurrent patients. PATIENT CONCERNS: A 60-year-old male patient, due to routinely health examination, ulcerated lesions 30 cm away from the incisors were found by gastroscopy, pathology showed esophageal squamous cell carcinoma (ESCC). DIAGNOSIS: Due to the patient's pathology, he was diagnosed with ESCC. INTERVENTIONS: The patient underwent radical surgery for ESCC on June 28, 2015. The left cervical lymph node metastasis occurred after 20 months, and lymph node metastasis carcinoma resection was performed. After that, concurrent chemoradiotherapy was implemented, 40 days after the end of the 4 courses of chemotherapy, the left cervical metastatic lymph nodes relapsed, radioactive particle implantation was carried out, and progressed again after 1 month. The patient took apatinib for 1 week but could not tolerate due to hand-foot syndrome. Immune checkpoint inhibitor (ICI) was administered since October 27, 2017. OUTCOMES: The therapeutic effect of immune checkpoint inhibitor was evaluated as partial response (PR) after 6 courses of treatment and complete response (CR) after 15 courses of treatment. To our knowledge, this is the first case report of successful immunotherapy for refractory esophageal squamous cell carcinoma. LESSONS: The emergence of ICIs promotes the treatment of esophageal cancer to a new era. Our observations suggest that patients for whom schedule to receive anti-programmed cell death protein-1 (anti-PD-1)/programmed cell death-ligand 1 (PD-L1) immunotherapy may require genomic testing to predict whether tumors respond to ICIs. In this case, we also present the predictors for the efficacy of targeted immunotherapy. At present, no matter which predictor of PD-L1 expression, tumor mutational burden (TMB), microsatellite instability (MSI), and tumor-infiltrating lymphocyte (TIL), a single predictor may be unconvincing and cannot accurately estimate the efficacy of immunotherapy. Multiplex detecting methods and combined biomarkers may provide new strategies. Consensus need to be reached in order to be widely applied in future studies.


Assuntos
Vértebras Cervicais , Neoplasias Esofágicas/diagnóstico , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Quimiorradioterapia , Diagnóstico Diferencial , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago/secundário , Carcinoma de Células Escamosas do Esôfago/terapia , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade
5.
J Med Chem ; 63(6): 3252-3260, 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32049522

RESUMO

Misregulation of Wnt signaling is common in human cancer. The development of small molecule inhibitors against the Wnt receptor, frizzled (FZD), may have potential in cancer therapy. During small molecule screens, we observed binding of carbamazepine to the cysteine-rich domain (CRD) of the Wnt receptor FZD8 using surface plasmon resonance (SPR). Cellular functional assays demonstrated that carbamazepine can suppress FZD8-mediated Wnt/ß-catenin signaling. We determined the crystal structure of the complex at 1.7 Å resolution, which reveals that carbamazepine binds at a novel pocket on the FZD8 CRD. The unique residue Tyr52 discriminates FZD8 from the closely related FZD5 and other FZDs for carbamazepine binding. The first small molecule-bound FZD structure provides a basis for anti-FZD drug development. Furthermore, the observed carbamazepine-mediated Wnt signaling inhibition may help to explain the phenomenon of bone loss and increased adipogenesis in some patients during long-term carbamazepine treatment.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31957251

RESUMO

PURPOSE: Nonsmall cell lung cancer (NSCLC) patients with brain metastases (BM) have a poor prognosis. Despite the traditional methods including radiotherapy and chemotherapy, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) might benefit patients on survival and quality of life. We investigated the cost-effectiveness of icotinib compared with whole-brain irradiation (WBI) with or without chemotherapy for NSCLC patients with BM. MATERIALS AND METHODS: A Markov model was conducted based on the data of BRAIN trial. We compared the economic benefit between icotinib and the combination of WBI and WBI plus chemotherapy group. We considered disease progression as intracranial progression and overall progression separately. Sensitivity analyses were performed to observe the stability of the model. The willingness-to-pay (WTP) was set as 3× per capita gross domestic product ($25929/quality-adjusted life year [QALY]) from the Chinese healthcare perspective. RESULTS: When considering progression as intracranial progression and overall progression, respectively, the incremental cost-effectiveness ratio was $14 882.64/QALY and $13 484.21/QALY between icotinib and WBI/WBI-chemotherapy. Besides, both of the average cost-effective ratio (ACER) and net benefit showed advantage of icotinib (ACER: $34 521.42/QALY for intracranial progression and $36 562.63/QALY for overall progression; net benefit: -$8407.36 for intracranial progression and -$9836.41 for overall progression). One-way sensitivity analyses demonstrated that no thresholds were encountered. The probabilistic sensitivity analyses showed even at a WTP under $18 000/QALY, icotinib could be cost-effective. CONCLUSION: Icotinib was cost-effective compared with WBI with or without chemotherapy.

7.
Nat Commun ; 11(1): 38, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911601

RESUMO

Coxsackievirus A10 (CV-A10) is responsible for an escalating number of severe infections in children, but no prophylactics or therapeutics are currently available. KREMEN1 (KRM1) is the entry receptor for the largest receptor-group of hand-foot-and-mouth disease causing viruses, which includes CV-A10. We report here structures of CV-A10 mature virus alone and in complex with KRM1 as well as of the CV-A10 A-particle. The receptor spans the viral canyon with a large footprint on the virus surface. The footprint has some overlap with that seen for the neonatal Fc receptor complexed with enterovirus E6 but is larger and distinct from that of another enterovirus receptor SCARB2. Reduced occupancy of a particle-stabilising pocket factor in the complexed virus and the presence of both unbound and expanded virus particles suggests receptor binding initiates a cascade of conformational changes that produces expanded particles primed for viral uncoating.


Assuntos
Enterovirus Humano A/fisiologia , Infecções por Enterovirus/metabolismo , Vírus da Febre Aftosa/fisiologia , Doença de Mão, Pé e Boca/metabolismo , Proteínas de Membrana/metabolismo , Receptores Virais/metabolismo , Enterovirus Humano A/química , Enterovirus Humano A/genética , Enterovirus Humano A/ultraestrutura , Infecções por Enterovirus/genética , Infecções por Enterovirus/virologia , Vírus da Febre Aftosa/genética , Doença de Mão, Pé e Boca/genética , Doença de Mão, Pé e Boca/virologia , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/genética , Receptores Virais/química , Receptores Virais/genética , Desenvelopamento do Vírus
8.
Neuroimage ; 206: 116232, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31593794

RESUMO

Facial recognition ability declines in adult aging, but the neural basis for this decline remains unknown. Cortical areas involved in face recognition exhibit lower dopamine (DA) receptor availability and lower blood-oxygen-level-dependent (BOLD) signal during task performance with advancing adult age. We hypothesized that changes in the relationship between these two neural systems are related to age differences in face-recognition ability. To test this hypothesis, we leveraged positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to measure D1 receptor binding potential (BPND) and BOLD signal during face-recognition performance. Twenty younger and 20 older participants performed a face-recognition task during fMRI scanning. Face recognition accuracy was lower in older than in younger adults, as were D1 BPND and BOLD signal across the brain. Using linear regression, significant relationships between DA and BOLD were found in both age-groups in face-processing regions. Interestingly, although the relationship was positive in younger adults, it was negative in older adults (i.e., as D1 BPND decreased, BOLD signal increased). Ratios of BOLD:D1 BPND were calculated and relationships to face-recognition performance were tested. Multiple linear regression revealed a significant Group × BOLD:D1 BPND Ratio interaction. These results suggest that, in the healthy system, synchrony between neurotransmitter (DA) and hemodynamic (BOLD) systems optimizes the level of BOLD activation evoked for a given DA input (i.e., the gain parameter of the DA input-neural activation function), facilitating task performance. In the aged system, however, desynchronization between these brain systems would reduce the gain parameter of this function, adversely impacting task performance and contributing to reduced face recognition in older adults.

9.
Bioorg Med Chem Lett ; 30(3): 126751, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31862412

RESUMO

The carboxylesterase Notum is a key negative regulator of the Wnt signaling pathway by mediating the depalmitoleoylation of Wnt proteins. Our objective was to discover potent small molecule inhibitors of Notum suitable for exploring the regulation of Wnt signaling in the central nervous system. Scaffold-hopping from thienopyrimidine acids 1 and 2, supported by X-ray structure determination, identified 3-methylimidazolin-4-one amides 20-24 as potent inhibitors of Notum with activity across three orthogonal assay formats (biochemical, extra-cellular, occupancy). A preferred example 24 demonstrated good stability in mouse microsomes and plasma, and cell permeability in the MDCK-MDR1 assay albeit with modest P-gp mediated efflux. Pharmacokinetic studies with 24 were performed in vivo in mouse with single oral administration of 24 showing good plasma exposure and reasonable CNS penetration. We propose that 24 is a new chemical tool suitable for cellular studies to explore the fundamental biology of Notum.

10.
J Pineal Res ; 68(2): e12630, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31876313

RESUMO

The hormone melatonin, secreted from the pineal gland, mediates multiple physiological effects including modulation of Wnt/ß-catenin signalling. The Wnt palmitoleate lipid modification is essential for its signalling activity, while the carboxylesterase Notum can remove the lipid from Wnt and inactivate it. Notum enzyme inhibition can therefore upregulate Wnt signalling. While searching for Notum inhibitors by crystallographic fragment screening, a hit compound N-[2-(5-fluoro-1H-indol-3-yl)ethyl]acetamide that is structurally similar to melatonin came to our attention. We then soaked melatonin and its precursor N-acetylserotonin into Notum crystals and obtained high-resolution structures (≤1.5 Å) of their complexes. In each of the structures, two compound molecules bind with Notum: one at the enzyme's catalytic pocket, overlapping the space occupied by the acyl tail of the Wnt palmitoleate lipid, and the other at the edge of the pocket opposite the substrate entrance. Although the inhibitory activity of melatonin shown by in vitro enzyme assays is low (IC50 75 µmol/L), the structural information reported here provides a basis for the design of potent and brain accessible drugs for neurodegenerative diseases such as Alzheimer's disease, in which upregulation of Wnt signalling may be beneficial.

11.
Onco Targets Ther ; 12: 8601-8609, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31802896

RESUMO

Resveratrol, as a natural product compound, has been recently attracted much attention for its potent effects on cancer. Cancer is a serious disease threatening human survival and social development. Autophagy is a cellular pathway to realize the metabolic needs of the cell itself and the renewal of some organelles and plays opposing, context-dependent role in tumorigenesis. So the regulation of autophagy is of great significance in the treatment of cancer. p62, as an autophagy adaptor protein, is a preferred target for autophagy and is constantly controlled by constitutive autophagy. As a tumor-suppression mechanism, autophagy deficiency is common in tumors, which results in aberrant accumulation of p62 and activates p62-regulated pathways, such as activation of mTOR in nutrient sensing, and the activation of the Keap1-Nrf2 pathway for antioxidant stress, which are associated with cancer development. In this review, we emphasize that resveratrol can induce autophagy in the treatment of cancer and accelerates the degradation of p62, and then, the mTOR activation is blocked and Nrf2 activation is suppressed. As a result, the multidrug resistance of cancer cells can be reversed by resveratrol.

13.
Sci Rep ; 9(1): 15380, 2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31653901

RESUMO

Small artery occlusion (SAO) is the one of the primary subtype of ischemic stroke in China. However, its outcomes among elderly patients are unclear. Consecutive patients with SAO were recruited at Jiamusi University First Hospital, China between January 2008 and December 2016. Stroke subtype, severity, and risk factors were collected; outcomes at 3, 12, and 36 months after stroke onset were assessed. A total of 1464 SAO patients were included in this study. Participants aged ≥75 years had higher dependency rates than Participants aged <75 years with SAO in all three follow-up periods, in addition to a higher recurrence rate at 12 months and a higher mortality rate 36 months after stroke. After adjusting for confounders, elevated triglyceride level was found to be a protective factor against mortality 36 months after stroke. Stroke severity, diabetes mellitus, artery stenosis, gender, obesity, and high-density lipoprotein cholesterol level were independently associated with the risk of dependency; elevated triglyceride level was an independent risk factor for recurrence at 3 months point after stroke onset. These findings suggest that it is vital to manage risk factors that may affect prognosis of stroke among elderly patients with SAO to improve patient prognosis and reduce the burden of stroke in China.

14.
Exp Ther Med ; 18(4): 2893-2900, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31572533

RESUMO

Short-term efficacy and safety of prednisone in herpes zoster and the effect on IL-6 and IL-10 were investigated. A total of 125 patients (aged 40-70 years) with acute infective herpes zoster who were admitted to Daqing Oilfield General Hospital were selected and divided into 3 groups according to different treatment methods: low-dose (n=44), middle-dose (n=42) and high-dose (n=39) groups. The therapeutic effect, visual analogue scale (VAS) pain score, pain relieving and disappearing time, herpes stopping and disappearing time, incrustation and decrustation time, and incidence of adverse reactions in the three groups were recorded. The changes of IL-6 and IL-10 levels in the peripheral blood of patients before and after treatment were detected by enzyme-linked immunosorbent assay (ELISA) in order to analyze their relationship with pain degree and the time of symptom remission and subsidence. There were no significant differences in cure rate, significant effective rate, effective rate, ineffective rate and total effective rate among the three groups (P>0.05). The pain relieving and disappearing time in the middle-dose group were shorter than those in the low- and high-dose groups (P<0.05). The levels of IL-6 and IL-10 showed no statistical differences in the 3 groups before treatment (P>0.05). Pearson correlation analysis showed that IL-6 was positively correlated with VAS pain score, pain relieving and disappearing time, herpes stopping and disappearing time, incrustation and decrustation time (P<0.05), while IL-10 was negatively correlated with the above indicators (P<0.05). In conclusion, middle-dose prednisone has similar short-term efficacy to high-dose prednisone in the treatment of herpes zoster, but with lower complication and higher safety. IL-6 and IL-10 are closely related to the pain degree and the time of symptom remission and subsidence, which may provide a reference for clinical evaluation of the therapeutic effect of patients with herpes zoster.

15.
Neurosci Biobehav Rev ; 107: 927-944, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31499083

RESUMO

Theories of neurocognitive aging rely heavily on functional magnetic resonance imaging (fMRI) to test hypotheses regarding the brain basis of age-differences in cognition. This technique is based on the blood-oxygen level dependent signal (BOLD) that arises from the coordinated neural-vascular coupling that leads to increased blood flow following an increase in neural activity. Here we review the literature and current controversies regarding the mechanisms by which blood flow and neural activity are coupled, and how they change in the aging process. This literature suggests that neural-vascular coupling is a complex of processes, involving dynamic signaling between neurons, glia, and blood vessels. Nearly every component of this process is affected in aging leading to changes in BOLD and pervasive age-related cognitive changes.

16.
Medchemcomm ; 10(8): 1361-1369, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31534655

RESUMO

NOTUM is a carboxylesterase that has been shown to act by mediating the O-depalmitoleoylation of Wnt proteins resulting in suppression of Wnt signaling. Here, we describe the development of NOTUM inhibitors that restore Wnt signaling for use in in vitro disease models where NOTUM over activity is an underlying cause. A crystallographic fragment screen with NOTUM identified 2-phenoxyacetamide 3 as binding in the palmitoleate pocket with modest inhibition activity (IC50 33 µM). Optimization of hit 3 by SAR studies guided by SBDD identified indazole 38 (IC50 0.032 µM) and isoquinoline 45 (IC50 0.085 µM) as potent inhibitors of NOTUM. The binding of 45 to NOTUM was rationalized through an X-ray co-crystal structure determination which showed a flipped binding orientation compared to 3. However, it was not possible to combine NOTUM inhibition activity with metabolic stability as the majority of the compounds tested were rapidly metabolized in an NADPH-independent manner.

17.
Mult Scler ; : 1352458519866605, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31373536

RESUMO

BACKGROUND: Cognitive slowing occurs in ~70% of multiple sclerosis (MS) patients. The pathophysiology of this slowing is unknown. Neurovascular coupling, acute localized blood flow increases following neural activity, is essential for efficient cognition. Loss of vascular compliance along the cerebrovascular tree would result in suboptimal vasodilation, neurovascular uncoupling, and cognitive slowing. OBJECTIVE: To assess vascular compliance along the cerebrovascular tree and its relationship to MS-related cognition. METHODS: We tested vascular compliance along the cerebrovascular tree by dividing cerebral cortex into nested layers. MS patients and healthy controls were scanned using a dual-echo functional magnetic resonance imaging (fMRI) sequence while they periodically inhaled room air and hypercapnic gas mixture. Cerebrovascular reactivity was calculated from both cerebral blood flow (arterial) and blood-oxygen-level-dependent signal (venous) increases per unit increase in end-tidal CO2. RESULTS: Arterial cerebrovascular reactivity changes along the cerebrovascular tree were reduced in cognitively slow MS compared to cognitively normal MS and healthy controls. These changes were fit to exponential functions, the decay constant (arterial compliance index; ACI) of which was associated with individual subjects' reaction time and predicted reaction time after controlling for disease processes. CONCLUSION: Such associations suggest prospects for utility of ACI in predicting future cognitive disturbances, monitoring cognitive deficiencies and therapeutic responses, and implicates neurovascular uncoupling as a mechanism of cognitive slowing in MS.

18.
Materials (Basel) ; 12(9)2019 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-31035412

RESUMO

Most methods used for strengthening metallic materials, such as thermal-mechanical treatment, will sacrifice the ductility. A novel technology, electric pulsing treatment (EPT), is applied to break this trade-off, which produces an Al-Mg-Si alloy with superior ductility and higher strength within only 560 ms. Systematic electron microscopy characterization and finite element simulation reveal that EPT promotes the formation of clusters Mg2(Si,Cu)3 and sub-grain boundaries. The results of quantitative calculation indicate that the dislocation entanglement is delayed due to the existence of clusters and longer dislocation glide distance, so that ultimate strength is fully improved. Moreover, the superior ductility is mainly governed by sub-grains which lead to higher mobile dislocation density, appearance of new crystal orientations, and prevention of crack propagation. Thereupon, this interesting finding paves the way in developing the Al-Mg-Si alloy with higher mechanical properties efficiently.

19.
Crit Rev Oncol Hematol ; 135: 39-46, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30819445

RESUMO

BACKGROUND: We conducted a meta-analysis to examine the associations of age, human papillomavirus (HPV) infection, and performance status with the overall survival (OS) benefits of patients with head and neck squamous cell carcinoma (HNSCC) after treatment with versus without epidermal growth factor receptor (EGFR) inhibitors. METHODS: We systematically searched literature for randomized controlled trials comparing chemotherapy or radiotherapy with versus without EGFR inhibitors in locoregionally advanced, recurrent, or metastatic HNSCCs. Hazard ratios (HRs) for OS were calculated using random-effects models for patient groups according to age (younger vs. older), HPV infection status (p16-positive vs. p16-negative), and performance status score (better vs. poorer). RESULTS: Five phase III trials with 2653 patients were included. EGFR inhibition was associated with a greater OS benefit in younger patients than in older counterparts (HR 0.70 vs. 1.05, P < 0.001). There were no apparent differences in OS based on HPV status (P = 0.860) or performance status score (P = 0.235). Largely consistent results were obtained following stratification by treatment strategy (i.e., chemotherapy and radiotherapy). CONCLUSIONS: Patient age appears to impact OS independent of HPV infection and performance status after adding EGFR inhibitor agents during HNSCC treatment. This finding may help design relevant clinical trials.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Adulto , Fatores Etários , Idoso , Cetuximab/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Feminino , Gefitinibe/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Panitumumabe/uso terapêutico , Infecções por Papillomavirus/epidemiologia , Inibidores de Proteínas Quinases/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia
20.
J Mol Cell Cardiol ; 129: 193-196, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30831134

RESUMO

Although there is an increasing understanding of the signaling pathways that promote cardiac hypertrophy, negative regulatory factors of this process have received less attention. Increasing evidence indicates that Krüppel-like factor 15 (KLF15) plays an important role in maintaining cardiac function by controlling the transcriptional pathways that regulating cardiac metabolism. Recent studies have also revealed a vital role for KLF15 as an inhibitor of pathological cardiac hypertrophy and fibrosis via its effects on factors such as myocyte enhancer factor 2 (MEF2), GATA-binding protein 4 (GATA4), transforming growth factor-ß (TGF-ß), and myocardin. KLF15 may therefore be an effective therapeutic target for the treatment of heart failure and other cardiovascular diseases. In this review, we focus on the physiological and pathophysiological roles of KLF15 in the heart and the potential mechanisms through which KLF15 is regulated in various cardiac diseases.

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