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1.
IEEE Trans Cybern ; 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31484153

RESUMO

This article addresses two key issues in RGB-D salient object detection based on the convolutional neural network (CNN). 1) How to bridge the gap between the ``data-hungry'' nature of CNNs and the insufficient labeled training data in the depth modality? 2) How to take full advantages of the complementary information among two modalities. To solve the first problem, we model the depth-induced saliency detection as a CNN-based cross-modal transfer learning problem. Instead of directly adopting the RGB CNN as initialization, we additionally train a modality classification network (MCNet) to encourage discriminative modality-specific representations in minimizing the modality classification loss. To solve the second problem, we propose a densely cross-level feedback topology, in which the cross-modal complements are combined in each level and then densely fed back to all shallower layers for sufficient cross-level interactions. Compared to traditional two-stream frameworks, the proposed one can better explore, select, and fuse cross-modal cross-level complements. Experiments show the significant and consistent improvements of the proposed CNN framework over other state-of-the-art methods.

2.
Ann Intern Med ; 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31450238

RESUMO

Background: Smaller (<3-mm) infarctions are associated with stroke and stroke mortality, but relationships with cognitive decline are unknown. Objective: To characterize the relationships of smaller, larger, and both smaller and larger infarctions in middle age with 20-year cognitive decline. Design: Longitudinal cohort study. Setting: Two ARIC (Atherosclerosis Risk in Communities) study sites with magnetic resonance imaging data (1993 to 1995) and up to 5 cognitive assessments over 20 years. Participants: Stroke-free participants aged 50 years or older. Measurements: Infarctions were categorized as none, smaller only, larger only (3 to 20 mm), or both smaller and larger. Global cognitive Z scores were derived from 3 cognitive tests administered up to 5 times. Mixed-effects models estimated adjusted associations between infarctions and cognitive decline. Results are the average difference in standardized cognitive decline associated with infarctions versus no infarctions. Results: Among 1884 participants (mean age, 62 years; 60% women; 50% black), 1611 (86%) had no infarctions, 50 (3%) had smaller infarctions only, 185 (10%) had larger infarctions only, and 35 (2%) had both. Participants with both smaller and larger infarctions had steeper cognitive decline by more than half an SD (difference, -0.57 SD [95% CI, -0.89 to -0.26 SD]) compared with those who had no infarctions. Amounts of cognitive decline associated with only smaller infarctions and only larger infarctions were similar and were not statistically different from that associated with no infarctions. Limitation: Few participants had only smaller infarctions or both smaller and larger infarctions, and the data lacked counts of smaller infarctions and volumes of white matter hyperintensities. Conclusion: The substantial cognitive decline from middle age associated with having both smaller and larger infarctions, but not larger infarctions alone, suggests that the combination of smaller and larger infarctions may escalate risk for cognitive decline later in life in stroke-free persons. Primary Funding Source: National Institutes of Health.

3.
Gene ; : 144057, 2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31430519

RESUMO

OBJECTIVE: Fork head domain-containing transcription factor family (FOX), is comprised of >20 members. Members of FOX family have been implicated in a wide range of physiological and/or diseased conditions. Many of FOX members have been shown to be involved in tumorigenesis and progression. The potential roles in carcinogenesis of FOXN4, a member as one of the vast FOX family, remains relatively unknown. METHOD: Here, we explored the potential involvement of FOXN4 in breast cancer. RESULTS: First, observed that a higher FOXN4 was identified in the normal adjacent breast tissue as compared to that in the breast cancer samples; an increased FOXN4 level was associated with a better prognosis in patients with breast cancer. In addition, ectopically expression of FOXN4 led to the decreased cell proliferation, reduced colony formation and metastatic abilities (EMT, migration and invasion) in breast cancer cell lines. Furthermore, we showed the direct interaction between FOXN4 and TP53 and FOXN4 binding led to the increased activity of TP53. Silencing FOXN4 led to reduced TP53 and increased expression of Dll4, Notch and survivin, providing a link between FOXN4 and Notch signaling. Finally, we used patient-derived xenograft mouse model to demonstrate the tumor inhibitory effects of Notch-inhibitor, PF-3084014. We found that PF-3084014 treatment led to a significantly smaller tumor burden and higher survival ratio in patient-derived xenograft mice as compared to the vehicle. This tumor suppressive effect was accompanied by the increased expression of TP53, FOXN4 and decreased Dll4 and Notch. CONCLUSION: Collectively, our data strongly suggested the tumor suppressive roles of FOXN4 in breast tumorigenesis via the activation of TP53 while suppressing Notch signaling. Future studies are warranted to explore the clinical application of PF-3084104 (Notch inhibitor) for the treatment of breast cancer patients.

4.
J Med Chem ; 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31381333

RESUMO

Aberrant activation of Bruton's tyrosine kinase (BTK) plays an important role in pathogenesis of B-cell lymphomas, suggesting that inhibition of BTK is useful in the treatment of hematological malignancies. The discovery of a more selective on-target covalent BTK inhibitor is of high value. Herein, we disclose the discovery and preclinical characterization of a potent, selective, and irreversible BTK inhibitor as our clinical candidate by using in vitro potency, selectivity, pharmacokinetics (PK), and in vivo pharmacodynamic for prioritizing compounds. Compound BGB-3111 (31a, Zanubrutinib) demonstrates (i) potent activity against BTK and excellent selectivity over other TEC, EGFR and Src family kinases, (ii) desirable ADME, excellent in vivo pharmacodynamic in mice and efficacy in OCI-LY10 xenograft models.

5.
Nat Commun ; 10(1): 2978, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278276

RESUMO

There has been a dramatic increase in the detection of lung nodules, many of which are preneoplasia atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) or invasive adenocarcinoma (ADC). The molecular landscape and the evolutionary trajectory of lung preneoplasia have not been well defined. Here, we perform multi-region exome sequencing of 116 resected lung nodules including AAH (n = 22), AIS (n = 27), MIA (n = 54) and synchronous ADC (n = 13). Comparing AAH to AIS, MIA and ADC, we observe progressive genomic evolution at the single nucleotide level and demarcated evolution at the chromosomal level supporting the early lung carcinogenesis model from AAH to AIS, MIA and ADC. Subclonal analyses reveal a higher proportion of clonal mutations in AIS/MIA/ADC than AAH suggesting neoplastic transformation of lung preneoplasia is predominantly associated with a selective sweep of unfit subclones. Analysis of multifocal pulmonary nodules from the same patients reveal evidence of convergent evolution.

6.
Chemistry ; 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31313383

RESUMO

Three chiral bicyclic pillar[5]arene derivatives termed as molecular universal joints (MUJs), were synthesized and separated enantiomerically. These MUJs showed temperature-driven chirality switching in certain solvents. Herein, it is demonstrated that temperature-driven chirality switching could also be realized by mixing two miscible organic solvents, in each of which chirality inversion is not accomplishable. Additionally, solvent mixing drastically varied the inversion temperature of the MUJs, for example, from far below zero to room temperature. Moreover, the temperature-driven Sp /Rp to Rp /Sp chirality switching direction could be reversed by the solvent mixing and it was critically controlled by the mixing ratios of the two solvents. These observations allowed precise manipulation of the chirality switching behavior of the MUJs. Such a chirality switching was ascribed to the influences of solvent and temperature on the in-out equilibrium of the side rings, which is delicately controlled by several processes, including the solvation/desolvation and the inclusion/exclusion of the side rings and solvent molecules. Crucially, the solvent mixing introduced new supramolecular processes, in particular the desolvation of solvent molecules from the mixed solvent system and the solvation of the side ring by the mixed solvent, which significantly disturbed the original in-out equilibrium of MUJs and drastically switched the entropy and enthalpy changes of conformational interconversion.

7.
EMBO J ; 38(16): e102003, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31313851

RESUMO

Many eukaryotic proteins are regulated by modification with the ubiquitin-like protein small ubiquitin-like modifier (SUMO). This linkage is reversed by SUMO proteases, of which there are two in Saccharomyces cerevisiae, Ulp1 and Ulp2. SUMO-protein conjugation regulates transcription, but the roles of SUMO proteases in transcription remain unclear. We report that Ulp2 is recruited to transcriptionally active genes to control local polysumoylation. Mutant ulp2 cells show impaired association of RNA polymerase II (RNAPII) with, and diminished expression of, constitutively active genes and the inducible CUP1 gene. Ulp2 loss sensitizes cells to 6-azauracil, a hallmark of transcriptional elongation defects. We also describe a novel chromatin regulatory mechanism whereby histone-H2B ubiquitylation stimulates histone sumoylation, which in turn appears to inhibit nucleosome association of the Ctk1 kinase. Ctk1 phosphorylates serine-2 (S2) in the RNAPII C-terminal domain (CTD) and promotes transcript elongation. Removal of both ubiquitin and SUMO from histones is needed to overcome the impediment to S2 phosphorylation. These results suggest sequential ubiquitin-histone and SUMO-histone modifications recruit Ulp2, which removes polySUMO chains and promotes RNAPII transcription elongation.

8.
Hell J Nucl Med ; 22(2): 96-102, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31273350

RESUMO

OBJECTIVE: This study was to explore the correlation between the standardized uptake value (SUV) of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging and the apparent diffusion coefficient (ADC) value of magnetic resonance imaging (MRI) to the pathological features of cervical cancer (CC). SUBJECTS AND METHODS: The maximum and mean SUV of 18F-FDG PET/CT (SUVmax and SUVmean) and the minimum ADC (ADCmin) were collected from 72 patients with CC. The correlation between SUVmax and ADCmin was also assessed. Furthermore, the relationship between SUVmax, SUVmin, ADCmin and the clinical pathological characteristics of CC was analyzed. RESULTS: A significant increase in the SUVmax was observed in the group of CC cases with lymph node metastases and in the group with distant metastases compared to those without metastases (F=6.782, P=0.002; F=4.483, P=0.015). Furthermore, in the low differentiation groups compared to high/middle differentiation groups (F=3.342,P=0.024), in the squamocellular carcinoma groups compared to the adenocarcinoma and adenosquamous carcinoma groups (F=3.295, P=0.026) and finally in the International Federation of Gynecology and Obstetrics (FIGO) stage III-IV groups compared with stage III-IV groups (F=3.123, P=0.020).The SUVmean values of the lymph node metastases and distant metastases groups were significantly higher than those without lymph node metastases (F=5.802, P=0.005; F=3.486, P=0.036). We saw no correlation between the ADCmin and lymph node metastases. The SUVmax value had weak correlation with the ADCmin (r=-0.306, P=0.036). The SUVmax is most closely related to the clinical pathological characteristics of CC. CONCLUSION: An increased SUVmax suggests lymph node metastases or distant metastases, low differentiation and FIGO stage III-IV. A low negative correlation was observed between the SUVmax and ADCmin, while we observed no correlation between the ADCmin and the clinical pathological characteristics of cervical cancer.

10.
Arch Biochem Biophys ; 672: 108058, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31356775

RESUMO

Propionate 3-nitronate (P3N) is a natural toxin that irreversibly inhibits mitochondrial succinate dehydrogenase. P3N poisoning leads to a variety of neurological disorders and even death. Nitronate monooxygenase (NMO) from Pseudomonas aeruginosa PAO1 was the first NMO characterized in bacteria and serves as a paradigm for Class I NMO. Here, we hypothesized that the carboxylate group of P3N might form a hydrogen bond with one or more of the four tyrosine or a lysine residues that are conserved in the active site of the enzyme. In the wild-type enzyme, the kcat value was pH independent between pH 6.0 and 11.0, while the kcat/KP3N value decreased at high pH, suggesting that a protonated group with a pKa value of 9.5 is required for binding the anionic substrate. A pH titration of the UV-visible absorption spectrum of the enzyme showed an increased absorbance at 297 nm with increasing pH, defining a pKa value of 9.5 and a Δε297 nm of 2.4 M-1cm-1, consistent with a tyrosine being important for substrate binding. The N3 atom of the oxidized flavin, instead, did not ionize likely because its pKa was perturbed by the ionization of a tyrosine in the active site of the enzyme. The Y109F, Y254F, Y299F, Y303F, and K307 M, substitutions had small effects (i.e., <3.5-fold) on the steady-state kinetic parameters of the enzyme. With all mutated enzymes, the kcat/KP3N value was less than 2.5-fold different from the wild-type enzyme, suggesting that none of the residues is solely essential for substrate binding.

11.
Ann Surg Oncol ; 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31359285

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) patients who achieve a pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) have better prognoses. OBJECTIVE: This study aimed to develop an intuitive nomogram based on simple laboratory indexes to predict the pCR of standard NAC in TNBC patients. METHODS: A total of 80 TNBC patients who received eight cycles of thrice-weekly standard NAC (anthracycline and cyclophosphamide followed by taxane) and subsequently underwent surgery in Zhejiang Cancer Hospital were retrospectively enrolled, and data on their pretreatment clinical features and multiple simple laboratory indexes were collected. The optimal cut-off values of the laboratory indexes were determined by the Youden index using receiver operating characteristic (ROC) curve analyses. Forward stepwise logistic regression (likelihood ratio) analysis was applied to identify predictive factors for a pCR of NAC. A nomogram was then developed according to the logistic model, and internally validated using the bootstrap resampling method. RESULTS: pCR was achieved in 39 (48.8%) patients after NAC. Multivariate analysis identified four independent indicators: clinical tumor stage, lymphocyte to monocyte ratio, fibrinogen level, and D-dimer level. The nomogram established based on these factors showed its discriminatory ability, with an area under the curve (AUC) of 0.803 (95% confidence interval 0.706-0.899) and a bias-corrected AUC of 0.771. The calibration curve and Hosmer-Lemeshow test showed that the predictive ability of the nomogram was a good fit to actual observation. CONCLUSIONS: The nomogram proposed in the present study exhibited a sufficient discriminatory ability for predicting pCR of NAC in TNBC patients.

12.
J Econ Entomol ; 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31218343

RESUMO

Most plant viruses maintain complex interactions with their vector or nonvector insects and can indirectly (via host plants) or directly affect the fitness of insects. However, little is known about the genes involved in the interactions between insects and transmitted or nontransmitted viruses, particularly nontransmitted viruses. Sitobion avenae (Fabricius) is a vector of barley yellow dwarf virus GAV strains (BYDV-GAV), but not a vector of wheat dwarf virus (WDV), which is transmitted by the leafhopper [Psammotettix alienus (Dahlbom)]. In this study, S. avenae was utilized to determine the transcriptomic responses after feeding on wheat infected by each of the two viruses, respectively, using an Illumina Hiseq sequencing platform. The transcriptomic data presented 61,508 genes, of which 854 differentially expressed. Moreover, in addition to sharing 208 genes, the number of differentially expressed genes (DEGs) in S. avenae exposed to BYDV was higher (800) than that when exposed to WDV (262). The DEGs related to the immune system and fitness of S. avenae in response to BYDV-/WDV-infected plants were identified and analyzed using Gene Ontologies (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG), and the number of related DEGs was lower as nonvector than as vector. This study provides the baseline information to further examine molecular mechanisms of how wheat viruses affect S. avenae fitness and immune response either as a vector for BYDV-GAV or as a nonvector for WDV.

13.
J Adv Nurs ; 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31225645

RESUMO

AIM: To present a study protocol for evaluating the feasibility and effectiveness of an individual face-to-face intervention based on protective factors to improve resilience among breast cancer patients. BACKGROUND: Research involving the effectiveness of universal interventions to improve resilience for breast cancer patients has seldom been reported and there is an urgent need to find a more acceptable, cost-effective method of providing emotional support. Through health education and psychological interventions, increasing protective factors could promote recovery to the original condition and improve resilience. DESIGN: A randomized controlled trial of an individual face-to-face intervention. METHODS: A total of 160 adults diagnosed with confirmed breast cancer will be recruited. The patients will be randomly assigned to the control group (N = 80) or the intervention group (N = 80). An intervention focusing on protective factors will be implemented in the intervention group. A survey of the patients from the two groups will be conducted at baseline, 1, 3, 6, and 12 months. The primary outcome is resilience, measured by the 14-item Resilience Scale. Secondary outcomes include self-efficacy, optimism, perceived social support, and mastery. The Chinese versions of the General Self-Efficacy Scale, revised Life Orientation Test, Multidimensional Scale of Perceived Social Support, and Self-Mastery Scale will be used to measure the four protective factors. IMPACT: One-to-one and face-to-face interventions have many potential advantages for inpatients, including convenience, accessibility and individuality. Once its effectiveness is confirmed, the intervention will be implemented broadly and make support available for a large number of patients.

14.
JAMA Otolaryngol Head Neck Surg ; 145(7): 626-633, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31169892

RESUMO

Importance: Audiometric evidence of hearing loss does not always relate to self-reported hearing loss. Objective: To determine the prevalence of self-reported good hearing in a population with audiometrically defined hearing loss and identify associated factors. Design, Setting, and Participants: We analyzed audiometric data from adults aged 20 to 69 years from the 1999 to 2002 cycles of the US National Health and Nutrition Examination Survey, a cross-sectional, nationally representative interview and examination survey of the civilian, noninstitutionalized population. Logistic regression was used to examine unadjusted and multivariable-adjusted relationships between demographic, hearing health, and general health factors related to self-perceived hearing status. Analysis was conducted between September 4, 2018, and November 30, 2018. Interventions: Audiometry and questionnaires. Main Outcomes and Measure: The prevalence of persons reporting good hearing among those with audiometrically defined hearing loss and the variables associated with this population. Results: The mean (SD) age was 47.0 (0.4) years for hearing loss defined by any frequency >25 dB HL and 52.5 (1.1) years for hearing loss defined by PTA >25 dB HL. For the sample with hearing loss defined by any frequency >25 dB HL, 744 (56.1%) were men and 629 (43.9%) were women. For the sample with hearing loss defined by PTA >25 dB HL 251 (68.5%) were men and 114 (31.5%) were women. Of the 1373 participants who were found to have hearing loss (at least 1 individual frequency >25 dB HL in either ear) 993 (68.5%) reported good hearing. Younger age, nonwhite race, and women were all more likely to report good hearing. When the definition of hearing loss was made more stringent (pure-tone average >25 dB HL), 365 participants had audiometric hearing loss, but 174 (43%) continued to report good hearing. We observed that better self-perceived general health status (OR, 1.90; 95% CI, 1.25-2.90) and higher dietary quality (OR, 1.01; 95% CI, 1.00-1.02) were significantly associated with increased self-report of good hearing, whereas tinnitus (OR, 0.25; 95% CI, 0.14-0.44), noise exposure (OR, 0.39; 95% CI, 0.26-0.58), and several comorbid conditions were associated with decreased self-report of good hearing. Conclusions and Relevance: A significant proportion of the study population reported good hearing despite having audiometric evidence of hearing loss; the prevalence was related to how hearing loss was defined. The report of good hearing was significantly associated with demographics and general health status. The high prevalence of mild hearing loss and self-reported good hearing was associated with the low reported use of hearing aids.

15.
BMC Cancer ; 19(1): 459, 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31096933

RESUMO

BACKGROUND: Gastric cancer ranks the fifth most common cancer, and the third leading cause of cancer-related deaths worldwide. Gastric cancer with liver metastasis (GCLM) has devastating prognosis, however, optimal treatment of GCLM, especially in elderly patients, has yet to be clarified. CASE PRESENTATION: A 75-year-old man was diagnosed with advanced gastric cancer (GC), presenting with acute gastrointestinal bleeding and synchronous metastatic lesion in liver. Based on multidisciplinary team (MDT)'s decision, this patient underwent distal palliative gastrectomy with R1 margin. Histopathological diagnosis was stage IV gastric adenocarcinoma (pT3N2M1), HER2 negative. The patient was treated with chemotherapy and argon-helium cryoablation of liver and lung metastases.HER-2 gene amplification was identified in peripheral blood at later stage of therapy. The patient had been followed-up for 39 months, in sharp contrast to a median survival time of 13.8 months for majority of advanced GC. CONCLUSIONS: Palliative distal gastrectomy in combination with chemotherapy and cryoablation significantly prolongs overall survival of an elderly patient with GCLM.

16.
J Zhejiang Univ Sci B ; 20(5): 399-413, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31090266

RESUMO

Necroptosis is a tightly regulated form of necrosis that requires the activation of receptor-interacting protein (RIP) kinases RIPK1 and RIPK3, as well as the RIPK3 substrate mixed lineage kinase domain-like protein (MLKL). Because of membrane rupture, necroptotic cells release damage-associated molecular patterns (DAMPs) that evoke immune responses. Necroptosis is emerging as an important cellular response in the modulation of cancer initiation, progression, and metastasis. Necroptosis of cancer cells is considered to be an immunogenic cell death capable of activating anti-tumor immunity. Necroptosis also participates in the promotion of myeloid cell-induced adaptive immune suppression and thus contributes to oncogenesis. In addition, necroptosis of endothelial cells and tumor cells is conducive to tumor metastasis. In this review, we summarize the current knowledge of the complex role of necroptosis in cancer and discuss the potential of targeting necroptosis components for cancer therapies.

17.
Nat Microbiol ; 4(8): 1378-1388, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31110366

RESUMO

Mycobacterium tuberculosis (Mtb)-derived components are usually recognized by pattern recognition receptors to initiate a cascade of innate immune responses. One striking characteristic of Mtb is their utilization of different type VII secretion systems to secrete numerous proteins across their hydrophobic and highly impermeable cell walls, but whether and how these Mtb-secreted proteins are sensed by host immune system remains largely unknown. Here, we report that MPT53 (Rv2878c), a secreted disulfide-bond-forming-like protein of Mtb, directly interacts with TGF-ß-activated kinase 1 (TAK1) and activates TAK1 in a TLR2- or MyD88-independent manner. MPT53 induces disulfide bond formation at C210 on TAK1 to facilitate its interaction with TRAFs and TAB1, thus activating TAK1 to induce the expression of pro-inflammatory cytokines. Furthermore, MPT53 and its disulfide oxidoreductase activity is required for Mtb to induce the host inflammatory responses via TAK1. Our findings provide an alternative pathway for host signalling proteins to sense Mtb infection and may favour the improvement of current vaccination strategies.

18.
J Adv Nurs ; 75(8): 1805-1814, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31037755

RESUMO

AIM: To describe a protocol that examines the feasibility and effectiveness of a face-to-face guided self-disclosure intervention for facilitating benefit finding and other related psychological outcomes for breast cancer patients. BACKGROUND: Benefit finding can promote a positive attitude among patients facing disease. However, limited studies have focused on improving benefit finding among breast cancer patients. Previous research has been based on group interventions, which may not suit all patients. Self-disclosure was recognized as a strong predictor of benefit finding. This protocol is based on a brief face-to-face disclosure intervention to improve benefit finding for breast cancer patients. DESIGN: A non-blinded randomized controlled trial. METHODS: A total of 154 patients with breast cancer who have undergone radical mastectomy will be randomly assigned to either the experimental group, which will participate in a six-session face-to-face individual intervention, or the control group at a ratio of 1:1. Baseline assessments will take place after the breast cancer diagnosis, with follow-up assessments at 3, 6 and 9 months after baseline. The primary outcome is benefit finding; other outcomes are self-disclosure, cognitive reappraisal, social support, optimism and medical coping modes. DISCUSSION: This study is to design a protocol for guided self-disclosure interventions to promote benefit finding in Chinese breast cancer patients. If this intervention is feasible and effective, it could be implemented in clinical practice. IMPACT: This study will provide useful advice for health professionals to guide breast cancer patients in benefit finding during stressful events. If it is effective, it will be implemented broadly in clinical practice.

19.
PLoS Biol ; 17(4): e3000229, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31039149

RESUMO

Hepatitis A virus (HAV), an enigmatic and ancient pathogen, is a major causative agent of acute viral hepatitis worldwide. Although there are effective vaccines, antivirals against HAV infection are still required, especially during fulminant hepatitis outbreaks. A more in-depth understanding of the antigenic characteristics of HAV and the mechanisms of neutralization could aid in the development of rationally designed antiviral drugs targeting HAV. In this paper, 4 new antibodies-F4, F6, F7, and F9-are reported that potently neutralize HAV at 50% neutralizing concentration values (neut50) ranging from 0.1 nM to 0.85 nM. High-resolution cryo-electron microscopy (cryo-EM) structures of HAV bound to F4, F6, F7, and F9, together with results of our previous studies on R10 fragment of antigen binding (Fab)-HAV complex, shed light on the locations and nature of the epitopes recognized by the 5 neutralizing monoclonal antibodies (NAbs). All the epitopes locate within the same patch and are highly conserved. The key structure-activity correlates based on the antigenic sites have been established. Based on the structural data of the single conserved antigenic site and key structure-activity correlates, one promising drug candidate named golvatinib was identified by in silico docking studies. Cell-based antiviral assays confirmed that golvatinib is capable of blocking HAV infection effectively with a 50% inhibitory concentration (IC50) of approximately 1 µM. These results suggest that the single conserved antigenic site from complete HAV capsid is a good antiviral target and that golvatinib could function as a lead compound for anti-HAV drug development.

20.
Nat Commun ; 10(1): 1670, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975989

RESUMO

Esophageal squamous cell carcinoma (ESCC) ranks fourth among cancer-related deaths in China due to the lack of actionable molecules. We performed whole-exome and T-cell receptor (TCR) repertoire sequencing on multi-regional tumors, normal tissues and blood samples from 39 ESCC patients. The data revealed 12.8% of ERBB4 mutations at patient level and functional study supported its oncogenic role. 18% of patients with early BRCA1/2 variants were associated with high-level contribution of signature 3, which was validated in an independent large cohort (n = 508). Furthermore, knockdown of BRCA1/2 dramatically increased sensitivity to cisplatin in ESCC cells. 5% of patients harbored focal high-level amplification of CD274 that led to massive expression of PD-L1, and might be more sensitive to immune checkpoint blockade. Finally, we found a tight correlation between genomic and TCR repertoire intra-tumor heterogeneity (ITH). Collectively, we reveal high-level ITH in ESCC, identify several potential actionable targets and may provide novel insight into ESCC treatment.


Assuntos
Antineoplásicos/farmacologia , Carcinogênese/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Regulação Neoplásica da Expressão Gênica , Adulto , Idoso , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , China , Estudos de Coortes , Variações do Número de Cópias de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago/sangue , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/terapia , Esôfago/patologia , Esôfago/cirurgia , Feminino , Amplificação de Genes , Perfilação da Expressão Gênica , Genômica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Medicina de Precisão/métodos , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/genética , Transcriptoma/genética , Sequenciamento Completo do Exoma/métodos
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