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BACKGROUND: Postnatal depression affects women from all cultures and countries. The postnatal period is thought to be a vulnerable time for all mothers. Immigrant women may be at particular risk as they attempt to adhere to childbirth rituals in western societies which might exacerbate stress, while navigating through the multiple stressors they face from migration in the transition to motherhood. METHODS: This study utilized a meta-synthesis approach to synthesize qualitative studies exploring postnatal depression in immigrant mothers living in western countries. Searching six databases identified 16 studies that met criteria. RESULTS: The synthesis revealed two overarching themes of migration and cultural influences on immigrant mothers that interact and give rise to psychosocial understandings of postnatal depression, remedies and healthcare barriers. Mothers used self-help coping strategies in line with this. CONCLUSIONS: Immigrant mothers living in western countries are subject to multifactorial stressors following childbirth, increasing their susceptibility to postnatal depression. These stressors relate to being an immigrant in a western society and cultural influences, which may be harder to comply with, when removed from their sociocultural context. Social support appears to play a mediating role for these immigrant mothers. There were several similarities between immigrant and non-immigrant mothers including their views of healthcare and medication, their health-seeking behaviours and their fears of having their baby removed. All these findings have implications for healthcare settings in terms of assessments and service delivery. Copyright © 2016 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: In this meta-synthesis, we explored the experience of postnatal depression in immigrant women living in western countries, including the UK, the USA and Canada. Sixteen qualitative studies were reviewed, and their methodological quality was examined. The findings are based a total sample of 337 women. Two overarching themes were identified that are termed 'cultural influences' and 'migration factors', which influenced how these mothers coped with their postnatal depression. Social support played a mediating role for these immigrant mothers.
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Depressão Pós-Parto/psicologia , Emigrantes e Imigrantes/psicologia , Etnicidade/psicologia , Mães/psicologia , Adolescente , Adulto , Ásia/etnologia , Austrália , Canadá , Região do Caribe/etnologia , Cultura , Depressão Pós-Parto/etnologia , Feminino , Humanos , Pessoa de Meia-Idade , Pesquisa Qualitativa , Apoio Social , Reino Unido , Estados Unidos , Adulto JovemRESUMO
PURPOSE: Minimal residual disease (MRD) detection can identify the recurrence in patients with colorectal cancer (CRC) following definitive treatment. We evaluated a plasma-only MRD assay to predict recurrence and survival in patients with metastatic CRC who underwent curative intent procedures (surgery and/or radiotherapy), with or without (neo)adjuvant chemotherapy. The primary objective of this study was to assess the correlation of postprocedure tumor cell-free DNA detection status with radiographic disease recurrence. EXPERIMENTAL DESIGN: Preprocedure and postprocedure longitudinal samples were collected from 53 patients and analyzed with a multiomic MRD assay detecting circulating tumor DNA (ctDNA) from genomic and epigenomic signals. Preprocedure and postprocedure ctDNA detection correlated with recurrence-free and overall survival (OS). RESULTS: From 52 patients, 230/233 samples were successfully analyzed. At the time of data cutoff, 36 (69.2%) patients recurred with median follow-up of 31 months. Detectable ctDNA was observed in 19/42 patients (45.2%) with ctDNA analyzed 3 weeks postprocedure. ctDNA detection 3 weeks postprocedure was associated with shorter median recurrence-free survival (RFS; HR, 5.27; 95% CI, 2.31-12.0; P < 0.0001) and OS (HR, 12.83; 95% CI, 3.6-45.9; P < 0.0001). Preprocedure ctDNA detection status was not associated with RFS but was associated with improved OS (HR, 4.65; 95% CI, 1.4-15.2; P = 0.0111). Undetectable ctDNA preprocedure had notable long-term OS, >90% 3 years postprocedure. CONCLUSIONS: In this cohort of oligometastatic CRC, detection of ctDNA preprocedure or postprocedure was associated with inferior outcomes even after accounting for known prognostic clinicopathologic variables. This suggests ctDNA may enhance current risk stratification methods helping the evaluation of novel treatments and surveillance strategies toward improving patient outcomes.
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Biomarcadores Tumorais , DNA Tumoral Circulante , Neoplasias Colorretais , Recidiva Local de Neoplasia , Neoplasia Residual , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/sangue , Neoplasias Colorretais/terapia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/diagnóstico , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Neoplasia Residual/genética , Feminino , Masculino , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/sangue , Pessoa de Meia-Idade , Idoso , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Prognóstico , Adulto , Metástase Neoplásica , Idoso de 80 Anos ou maisRESUMO
Angiogenesis, the sprouting of new blood vessels from existing vessels, is one of six known mechanisms employed by solid tumors to recruit blood vessels necessary for their initiation, growth, and metastatic spread. The vascular network within the tumor facilitates the transport of nutrients, oxygen, and immune cells and is regulated by pro- and anti-angiogenic factors. Nearly four decades ago, VEGF was identified as a critical factor promoting vascular permeability and angiogenesis, followed by identification of VEGF family ligands and their receptors (VEGFR). Since then, over a dozen drugs targeting the VEGF/VEGFR pathway have been approved for approximately 20 solid tumor types, usually in combination with other therapies. Initially designed to starve tumors, these agents transiently "normalize" tumor vessels in preclinical and clinical studies, and in the clinic, increased tumor blood perfusion or oxygenation in response to these agents is associated with improved outcomes. Nevertheless, the survival benefit has been modest in most tumor types, and there are currently no biomarkers in routine clinical use for identifying which patients are most likely to benefit from treatment. However, the ability of these agents to reprogram the immunosuppressive tumor microenvironment into an immunostimulatory milieu has rekindled interest and has led to the FDA approval of seven different combinations of VEGF/VEGFR pathway inhibitors with immune checkpoint blockers for many solid tumors in the past 3 years. In this review, we discuss our understanding of the mechanisms of response and resistance to blocking VEGF/VEGFR, and potential strategies to develop more effective therapeutic approaches.
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Neoplasias , Fator A de Crescimento do Endotélio Vascular , Humanos , Fator A de Crescimento do Endotélio Vascular/farmacologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Inibidores da Angiogênese/uso terapêutico , Neoplasias/tratamento farmacológico , Transdução de Sinais , Microambiente TumoralRESUMO
PURPOSE: Patients with advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutations are initially responsive to tyrosine kinase inhibitors (TKI). However, therapeutic resistance eventually emerges, often via secondary EGFR mutations or EGFR-independent mechanisms such as epithelial-to-mesenchymal transition. Treatment options after EGFR-TKI resistance are limited as anti-PD-1/PD-L1 inhibitors typically display minimal benefit. Given that IL6 is associated with worse outcomes in patients with NSCLC, we investigate whether IL6 in part contributes to this immunosuppressed phenotype. EXPERIMENTAL DESIGN: We utilized a syngeneic genetically engineered mouse model (GEMM) of EGFR-mutant NSCLC to investigate the effects of IL6 on the tumor microenvironment and the combined efficacy of IL6 inhibition and anti-PD-1 therapy. Corresponding in vitro studies used EGFR-mutant human cell lines and clinical specimens. RESULTS: We identified that EGFR-mutant tumors which have oncogene-independent acquired resistance to EGFR-TKIs were more mesenchymal and had markedly enhanced IL6 secretion. In EGFR-mutant GEMMs, IL6 depletion enhanced activation of infiltrating natural killer (NK)- and T-cell subpopulations and decreased immunosuppressive regulatory T and Th17 cell populations. Inhibition of IL6 increased NK- and T cell-mediated killing of human osimertinib-resistant EGFR-mutant NSCLC tumor cells in cell culture. IL6 blockade sensitized EGFR-mutant GEMM tumors to PD-1 inhibitors through an increase in tumor-infiltrating IFNγ+ CD8+ T cells. CONCLUSIONS: These data indicate that IL6 is upregulated in EGFR-mutant NSCLC tumors with acquired EGFR-TKI resistance and suppressed T- and NK-cell function. IL6 blockade enhanced antitumor immunity and efficacy of anti-PD-1 therapy warranting future clinical combinatorial investigations.
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Carcinoma Pulmonar de Células não Pequenas , Interleucina-6 , Neoplasias Pulmonares , Animais , Humanos , Camundongos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB , Interleucina-6/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais , Microambiente TumoralRESUMO
Effective therapeutic strategies are needed for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations that acquire resistance to EGFR tyrosine kinase inhibitors (TKIs) mediated by epithelial-to-mesenchymal transition (EMT). We investigate cell surface proteins that could be targeted by antibody-based or adoptive cell therapy approaches and identify CD70 as being highly upregulated in EMT-associated resistance. Moreover, CD70 upregulation is an early event in the evolution of resistance and occurs in drug-tolerant persister cells (DTPCs). CD70 promotes cell survival and invasiveness, and stimulation of CD70 triggers signal transduction pathways known to be re-activated with acquired TKI resistance. Anti-CD70 antibody drug conjugates (ADCs) and CD70-targeting chimeric antigen receptor (CAR) T cell and CAR NK cells show potent activity against EGFR TKI-resistant cells and DTPCs. These results identify CD70 as a therapeutic target for EGFR mutant tumors with acquired EGFR TKI resistance that merits clinical investigation.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Ligante CD27/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Receptores ErbB/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , /uso terapêuticoRESUMO
PURPOSE: Ataxia-telangiectasia mutated (ATM) is the most frequently mutated DNA damage repair gene in non-small cell lung cancer (NSCLC). However, the molecular correlates of ATM mutations and their clinical implications have not been fully elucidated. EXPERIMENTAL DESIGN: Clinicopathologic and genomic data from 26,587 patients with NSCLC from MD Anderson, public databases, and a de-identified nationwide (US-based) NSCLC clinicogenomic database (CGDB) were used to assess the co-mutation landscape, protein expression, and mutational processes in ATM-mutant tumors. We used the CGDB to evaluate ATM-associated outcomes in patients treated with immune checkpoint inhibitors (ICI) with or without chemotherapy, and assessed the effect of ATM loss on STING signaling and chemotherapy sensitivity in preclinical models. RESULTS: Nonsynonymous mutations in ATM were observed in 11.2% of samples (2,980/26,587) and were significantly associated with mutations in KRAS, but mutually exclusive with EGFR (q < 0.1). KRAS mutational status constrained the ATM co-mutation landscape, with strong mutual exclusivity with TP53 and KEAP1 within KRAS-mutated samples. Those ATM mutations that co-occurred with TP53 were more likely to be missense mutations and associate with high mutational burden, suggestive of non-functional passenger mutations. In the CGDB cohort, dysfunctional ATM mutations associated with improved OS only in patients treated with ICI-chemotherapy, and not ICI alone. In vitro analyses demonstrated enhanced upregulation of STING signaling in ATM knockout cells with the addition of chemotherapy. CONCLUSIONS: ATM mutations define a distinct subset of NSCLC associated with KRAS mutations, increased TMB, decreased TP53 and EGFR co-occurrence, and potential increased sensitivity to ICIs in the context of DNA-damaging chemotherapy.
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Ataxia Telangiectasia , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Fator 2 Relacionado a NF-E2/genética , Mutação , Receptores ErbB/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismoRESUMO
Protein lysine acetylation is a post-translational modification that regulates protein structure and function. It is targeted to proteins by lysine acetyltransferases (KATs) or removed by lysine deacetylases. This work identifies a role for the KAT enzyme general control of amino acid synthesis protein 5 (GCN5; KAT2A) in regulating muscle integrity by inhibiting DNA binding of the transcription factor/repressor Yin Yang 1 (YY1). Here we report that a muscle-specific mouse knockout of GCN5 (Gcn5skm-/-) reduces the expression of key structural muscle proteins, including dystrophin, resulting in myopathy. GCN5 was found to acetylate YY1 at two residues (K392 and K393), disrupting the interaction between the YY1 zinc finger region and DNA. These findings were supported by human data, including an observed negative correlation between YY1 gene expression and muscle fiber diameter. Collectively, GCN5 positively regulates muscle integrity through maintenance of structural protein expression via acetylation-dependent inhibition of YY1. This work implicates the role of protein acetylation in the regulation of muscle health and for consideration in the design of novel therapeutic strategies to support healthy muscle during myopathy or aging.
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Distrofina/genética , Músculos/metabolismo , Fator de Transcrição YY1/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo , Acetilação , Envelhecimento/metabolismo , Animais , DNA/metabolismo , Distrofina/metabolismo , Regulação da Expressão Gênica , Humanos , Lisina/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Contração Muscular/genética , Fibras Musculares Esqueléticas/metabolismo , Músculos/patologia , Músculos/ultraestrutura , Atrofia Muscular/patologia , Distrofias Musculares/patologia , Transcriptoma/genética , Fatores de Transcrição de p300-CBP/deficiênciaRESUMO
BACKGROUND: The benefit of chemotherapy combined with immunotherapy in EGFR-mutant lung adenocarcinoma (LUAD) patients whose tumor developed resistance to EGFR tyrosine kinase inhibitors (TKIs) is not thoroughly investigated. The goal of this retrospective cohort study is to assess the clinical efficiency of immunotherapy alone or in combination with chemotherapy in a real-world setting. METHODS: This retrospective cohort study enrolled LUAD patients with EGFR sensitive mutations whose tumor had acquired resistance to EGFR TKIs and received systemic treatment with chemotherapy (chemo; n = 84), chemotherapy combined with immunotherapy (chemoIO; n = 30), chemotherapy plus bevacizumab with or without IO (withBev; n = 42), and IO monotherapy (IO-mono; n = 22). Clinical progression-free survival (PFS) and overall survival (OS) were evaluated. Associations of clinical characteristics with outcomes were assessed using univariable and multi-covariate Cox Proportional Hazards regression models. RESULTS: A total of 178 patients (median age = 63.3; 57.9% females) with a median follow-up time of 42.0 (Interquartile range: 22.9-67.8) months were enrolled. There was no significant difference in PFS between chemoIO vs. chemo groups (5.3 vs. 4.8 months, p = 0.8). Compared to the chemo group, patients who received withBev therapy trended towards better PFS (6.1 months vs. 4.8; p = 0.3; HR 0.79; 95% CI: 0.52-1.20), while patients treated with IO-mono had inferior PFS (2.2 months; p = 0.001; HR 2.22; 95% CI: 1.37-3.59). Furthermore, PD-L1 level was not associated with PFS benefit in the chemoIO group. Patients with EGFR-mutant LUAD with high PD-L1 (≥50%) had shorter PFS (5.8 months) than non-EGFR/ALK LUAD patients who received chemoIO (12.8 months, p = 0.002; HR 0.22; 95% CI: 0.08-0.56) as first-line treatment. Chemotherapy-based therapy rendered similar benefit to patients with either EGFR exon19 deletion vs. L858R in the LUAD. CONCLUSIONS: This retrospective analysis revealed that immunotherapy provided limited additional benefit to chemotherapy in TKI-refractory EGFR-mutant LUAD. Chemotherapy alone or combined with bevacizumab remain good choices for patients with actionable EGFR mutations.
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The important roles of mitochondrial function and dysfunction in the process of neurodegeneration are widely acknowledged. Retinal ganglion cells (RGCs) appear to be a highly vulnerable neuronal cell type in the central nervous system with respect to mitochondrial dysfunction but the actual reasons for this are still incompletely understood. These cells have a unique circumstance where unmyelinated axons must bend nearly 90° to exit the eye and then cross a translaminar pressure gradient before becoming myelinated in the optic nerve. This region, the optic nerve head, contains some of the highest density of mitochondria present in these cells. Glaucoma represents a perfect storm of events occurring at this location, with a combination of changes in the translaminar pressure gradient and reassignment of the metabolic support functions of supporting glia, which appears to apply increased metabolic stress to the RGC axons leading to a failure of axonal transport mechanisms. However, RGCs themselves are also extremely sensitive to genetic mutations, particularly in genes affecting mitochondrial dynamics and mitochondrial clearance. These mutations, which systemically affect the mitochondria in every cell, often lead to an optic neuropathy as the sole pathologic defect in affected patients. This review summarizes knowledge of mitochondrial structure and function, the known energy demands of neurons in general, and places these in the context of normal and pathological characteristics of mitochondria attributed to RGCs.
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Dinâmica Mitocondrial , Doenças do Nervo Óptico/patologia , Células Ganglionares da Retina/patologia , Animais , Metabolismo Energético , Humanos , Mitocôndrias/patologia , Terapia de Alvo MolecularRESUMO
Genetic engineering of nanoparticle biosynthesis in bacteria could help facilitate the production of nanoparticles with enhanced or desired properties. However, this process remains limited due to the lack of mechanistic knowledge regarding specific enzymes and other key biological factors. Herein, we report on the ability of small noncoding RNAs (sRNAs) to affect silver nanoparticle (AgNP) biosynthesis using the supernatant from the bacterium Deinococcus radiodurans. Deletion strains of 12 sRNAs potentially involved in the oxidative stress response were constructed, and the supernatants from these strains were screened for their effect on AgNP biosynthesis. We identified several sRNA deletions that drastically decreased AgNP yield compared to the wild-type (WT) strain, suggesting the importance of these sRNAs in AgNP biosynthesis. Furthermore, AgNPs biosynthesized using the supernatants from three of these sRNA deletion strains demonstrated significantly enhanced antimicrobial and catalytic activities against environmentally relevant dyes and bacteria relative to AgNPs biosynthesized using the WT strain. Characterization of these AgNPs using electron microscopy (EM), energy-dispersive X-ray spectroscopy (EDX), X-ray photoelectron spectroscopy (XPS), and X-ray diffraction (XRD) revealed that the deletion of these small RNAs led to changes within the supernatant composition that altered AgNP properties such as the surface chemistry, surface potential, and overall composition. Taken together, our results demonstrate that modulating specific sRNA levels can affect the composition of supernatants used to biosynthesize AgNPs, resulting in AgNPs with unique material properties and improved functionality; as such, we introduce sRNAs as a new platform for genetically engineering the biosynthesis of metal nanoparticles using bacteria. Many of the sRNAs examined in this work have potential regulatory roles in oxidative stress responses; further studies into their targets could help provide insight into the specific molecular mechanisms underlying bacterial biosynthesis and metal reduction, enabling the production of nanoparticles with enhanced properties.
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Antibacterianos/farmacologia , Nanopartículas Metálicas/química , Pequeno RNA não Traduzido/metabolismo , Prata/farmacologia , Antibacterianos/biossíntese , Antibacterianos/química , Catálise , Corantes/química , Deinococcus/metabolismo , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Oxirredução , Pseudomonas aeruginosa/efeitos dos fármacos , Prata/química , Prata/metabolismo , Staphylococcus epidermidis/efeitos dos fármacosRESUMO
INTRODUCTION: Subgroup analyses from clinical studies have suggested that among patients with metastatic NSCLC receiving chemotherapy, females may derive less benefit from the addition of the vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (BV) than males. This has raised the question of whether estrogen may affect the response to antiangiogenic therapy. METHODS: To address this, we investigated the effects of estrogen on tumor growth, angiogenesis, and the response to BV in human xenograft models of NSCLC. RESULTS: We observed that estrogen induced marked resistance to BV, which was accompanied by a 2.3-fold increase in tumor vascular pericyte coverage (p = 0.01) and an up-regulation of proangiogenic factors, VEGF and platelet-derived growth factor-BB. We also investigated the role of infiltrating myeloid cells, a population that has been associated with resistance to anti-VEGF therapies. We observed that estrogen induced a greater than twofold increase (p = 0.001) in the recruitment of tumor-infiltrating myeloid cells and concomitant increases in the myeloid recruitment factors, G-CSF and CXCL1. Blockade of the estrogen receptor pathway using fulvestrant resensitized tumors to VEGF targeting as evidenced by reduced tumor vasculature and an increase in overall survival in our NSCLC xenograft models. CONCLUSIONS: Collectively, these data provide evidence that estrogen may promote resistance to VEGF-targeted therapies, potentially by enhancing pericyte coverage and myeloid recruitment, and suggest that estrogen receptor blockade merits further investigation as an approach to enhance the effects of antiangiogenic therapy.
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Inibidores da Angiogênese , Bevacizumab , Resistencia a Medicamentos Antineoplásicos , Estrogênios/farmacologia , Neoplasias Pulmonares , Inibidores da Angiogênese/farmacologia , Animais , Bevacizumab/farmacologia , Modelos Animais de Doenças , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Camundongos , Neovascularização Patológica/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
INTRODUCTION: The treatment of patients with EGFR-mutant NSCLC with vascular endothelial growth factor (VEGF) inhibitors in combination with EGFR inhibitors provides a greater benefit than EGFR inhibition alone, suggesting that EGFR mutation status may define a patient subgroup with greater benefit from VEGF blockade. The mechanisms driving this potentially enhanced VEGF dependence are unknown. METHODS: We analyzed the effect of EGFR inhibition on VEGF and HIF-1α in NSCLC models in vitro and in vivo. We determined the efficacy of VEGF inhibition in xenografts and analyzed the impact of acquired EGFR inhibitor resistance on VEGF and HIF-1α. RESULTS: NSCLC cells with EGFR-activating mutations exhibited altered regulation of VEGF compared with EGFR wild-type cells. In EGFR-mutant cells, EGFR, not hypoxia, was the dominant regulator of HIF-1α and VEGF. NSCLC tumor models bearing classical or exon 20 EGFR mutations were more sensitive to VEGF inhibition than EGFR wild-type tumors, and a combination of VEGF and EGFR inhibition delayed tumor progression. In models of acquired EGFR inhibitor resistance, whereas VEGF remained overexpressed, the hypoxia-independent expression of HIF-1α was delinked from EGFR signaling, and EGFR inhibition no longer diminished HIF-1α or VEGF expression. CONCLUSIONS: In EGFR-mutant NSCLC, EGFR signaling is the dominant regulator of HIF-1α and VEGF in a hypoxia-independent manner, hijacking an important cellular response regulating tumor aggressiveness. Cells with acquired EGFR inhibitor resistance retained elevated expression of HIF-1α and VEGF, and the pathways were no longer EGFR-regulated. This supports VEGF targeting in EGFR-mutant tumors in the EGFR inhibitor-naive and refractory settings.
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Neoplasias Pulmonares , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Fenótipo , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
INTRODUCTION: Lung adenocarcinomas harboring EGFR mutations do not respond to immune checkpoint blockade therapy and their EGFR wildtype counterpart. The mechanisms underlying this lack of clinical response have been investigated but remain incompletely understood. METHODS: We analyzed three cohorts of resected lung adenocarcinomas (Profiling of Resistance Patterns of Oncogenic Signaling Pathways in Evaluation of Cancer of Thorax, Immune Genomic Profiling of NSCLC, and The Cancer Genome Atlas) and compared tumor immune microenvironment of EGFR-mutant tumors to EGFR wildtype tumors, to identify actionable regulators to target and potentially enhance the treatment response. RESULTS: EGFR-mutant NSCLC exhibited low programmed death-ligand 1, low tumor mutational burden, decreased number of cytotoxic T cells, and low T cell receptor clonality, consistent with an immune-inert phenotype, though T cell expansion ex vivo was preserved. In an analysis of 75 immune checkpoint genes, the top up-regulated genes in the EGFR-mutant tumors (NT5E and ADORA1) belonged to the CD73/adenosine pathway. Single-cell analysis revealed that the tumor cell population expressed CD73, both in the treatment-naive and resistant tumors. Using coculture systems with EGFR-mutant NSCLC cells, T regulatory cell proportion was decreased with CD73 knockdown. In an immune-competent mouse model of EGFR-mutant lung cancer, the CD73/adenosine pathway was markedly up-regulated and CD73 blockade significantly inhibited tumor growth. CONCLUSIONS: Our work revealed that EGFR-mutant NSCLC has an immune-inert phenotype. We identified the CD73/adenosine pathway as a potential therapeutic target for EGFR-mutant NSCLC.
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Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adenosina , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Camundongos , Mutação , Microambiente TumoralRESUMO
The omentum is the most common site of ovarian cancer metastasis. Immune cell clusters called milky spots are found throughout the omentum. It is however unknown if these immune cells contribute to ovarian cancer metastasis. Here we report that omental macrophages promote the migration and colonization of ovarian cancer cells to the omentum through the secretion of chemokine ligands that interact with chemokine receptor 1 (CCR1). We found that depletion of macrophages reduces ovarian cancer colonization of the omentum. RNA-sequencing of macrophages isolated from mouse omentum and mesenteric adipose tissue revealed a specific enrichment of chemokine ligand CCL6 in omental macrophages. CCL6 and the human homolog CCL23 were both necessary and sufficient to promote ovarian cancer migration by activating ERK1/2 and PI3K pathways. Importantly, inhibition of CCR1 reduced ovarian cancer colonization. These findings demonstrate a critical mechanism of omental macrophage induced colonization by ovarian cancer cells via CCR1 signaling.
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Quimiocinas/metabolismo , Macrófagos/metabolismo , Omento/patologia , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/secundário , Receptores CCR1/metabolismo , Animais , Proteína 9 Associada à CRISPR , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Quimiocinas CC/metabolismo , Feminino , Citometria de Fluxo , Edição de Genes , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , TranscriptomaRESUMO
The advent of direct-acting antiviral (DAA) therapies has dramatically transformed HCV treatment, with most recent trials demonstrating high efficacy rates (>90%) across all genotypes and special populations, including patients with HIV/HCV coinfection. The efficacy rates of HCV treatment are nearly identical between patients with HCV monofection and patients with HIV/HCV coinfection; however, there are limited studies to compare real-world efficacy with efficacy observed in clinical trials. Using a database from HIV clinics across the United States (US), we identified 432 patients with HIV/HCV coinfection who completed DAA therapy from January 1, 2014 to March 31, 2017 and were assessed for efficacy. Efficacy was evaluated as sustained virologic response (SVR) 12 weeks after DAA completion; furthermore, factors associated with achieving SVR12 were identified. In this analysis, we found DAA therapies to be effective, with 94% of the patients achieving SVR12 and 6% experiencing virologic failure. Baseline variables, including older age, HCV viral load <800K IU/ML, FIB-4 score <1.45, absence of depression, diabetes, substance abuse, and use of DAA regimens without ribavirin were significant predictors of achieving SVR12. Patients with fewer comorbidities, better liver health, and lower HCV viral loads at baseline were more likely to achieve treatment success. Our results were consistent with other real-world studies, supporting the use of HCV therapy in HIV/HCV coinfected patients.
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Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Adulto , Idoso , Benzimidazóis/uso terapêutico , Carbamatos/uso terapêutico , Coinfecção/virologia , Quimioterapia Combinada , Feminino , Fluorenos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Hepacivirus/metabolismo , Hepatite C Crônica/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ribavirina/uso terapêutico , Simeprevir/uso terapêutico , Sofosbuvir , Resposta Viral Sustentada , Resultado do Tratamento , Estados Unidos , Uridina Monofosfato/análogos & derivados , Uridina Monofosfato/uso terapêutico , Carga ViralRESUMO
The United States Federal Centers for Disease Control and Prevention (CDC) has been working with state investigators on reported cases of lung illnesses linked to e-cigarette or vaping products. Symptoms of difficulty breathing, shortness of breath, chest pains, gastrointestinal sickness leading to serious lung damage and death has been linked to the risk behavior of using vaping products bought on the streets in healthy young people. CDC has detected vitamin E acetate as a chemical of concern among people with the lung injury. Vitamin E acetate is a condensing agent in vaping products, and all injured lung fluid samples appear to harbor this agent. The mysterious outbreak is identified in individuals vaping within the 90 days, ranging over a few days to developing over several weeks. There is growing evidence that vaping is hazardous to your health including immediate health dangers such as death from respiratory causes, long term health effects, cardiovascular events, depression which increases the risk of suicidal thoughts and suicide. This review article summarizes the growing knowledge of acute respiratory complications associated with vaping.
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Milk protein concentrates (MPCs) are complete dairy proteins (containing both caseins and whey proteins) that are available in protein concentrations ranging from 42% to 85%. As the protein content of MPCs increases, the lactose levels decrease. MPCs are produced by ultrafiltration or by blending different dairy ingredients. Although ultrafiltration is the preferred method for producing MPCs, they also can be produced by precipitating the proteins out of milk or by dry-blending the milk proteins with other milk components. MPCs are used for their nutritional and functional properties. For example, MPC is high in protein content and averages approximately 365 kcal/100 g. Higher-protein MPCs provide protein enhancement and a clean dairy flavor without adding significant amounts of lactose to food and beverage formulations. MPCs also contribute valuable minerals, such as calcium, magnesium, and phosphorus, to formulations, which may reduce the need for additional sources of these minerals. MPCs are multifunctional ingredients and provide benefits, such as water binding, gelling, foaming, emulsification, and heat stability. This article will review the development of MPCs and milk protein isolates including their composition, production, development, functional benefits, and ongoing research. The nutritional and functional attributes of MPCs are discussed in some detail in relation to their application as ingredients in major food categories.
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Laticínios/análise , Proteínas do Leite/química , Leite/química , Animais , Bovinos , Tecnologia de Alimentos , PaladarRESUMO
BACKGROUND: Early afterdepolarizations (EADs) are triggers of cardiac arrhythmia driven by L-type Ca(2+) current (ICaL) reactivation or sarcoplasmic reticulum Ca(2+) release and Na(+)/Ca(2+) exchange. In large mammals the positive action potential plateau promotes ICaL reactivation, and the current paradigm holds that cardiac EAD dynamics are dominated by interaction between ICaL and the repolarizing K(+) currents. However, EADs are also frequent in the rapidly repolarizing mouse action potential, which should not readily permit ICaL reactivation. This suggests that murine EADs exhibit unique dynamics, which are key for interpreting arrhythmia mechanisms in this ubiquitous model organism. We investigated these dynamics in myocytes from arrhythmia-susceptible calcium calmodulin-dependent protein kinase II delta C (CaMKIIδC)-overexpressing mice (Tg), and via computational simulations. METHODS AND RESULTS: In Tg myocytes, ß-adrenergic challenge slowed late repolarization, potentiated sarcoplasmic reticulum Ca(2+) release, and initiated EADs below the ICaL activation range (-47 ± 0.7 mV). These EADs were abolished by caffeine and tetrodotoxin (but not ranolazine), suggesting that sarcoplasmic reticulum Ca(2+) release and Na(+) current (INa), but not late INa, are required for EAD initiation. Simulations suggest that potentiated sarcoplasmic reticulum Ca(2+) release and Na(+)/Ca(2+) exchange shape late action potential repolarization to favor nonequilibrium reactivation of INa and thereby drive the EAD upstroke. Action potential clamp experiments suggest that lidocaine eliminates virtually all inward current elicited by EADs, and that this effect occurs at concentrations (40-60 µmol/L) for which lidocaine remains specific for inactivated Na(+) channels. This strongly suggests that previously inactive channels are recruited during the EAD upstroke, and that nonequilibrium INa dynamics underlie murine EADs. CONCLUSIONS: Nonequilibrium reactivation of INa drives murine EADs.
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Ventrículos do Coração/metabolismo , Miócitos Cardíacos/metabolismo , Sódio/metabolismo , Função Ventricular , Potenciais de Ação , Antagonistas Adrenérgicos beta/farmacologia , Animais , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Simulação por Computador , Feminino , Ventrículos do Coração/efeitos dos fármacos , Masculino , Camundongos Transgênicos , Modelos Cardiovasculares , Miócitos Cardíacos/efeitos dos fármacos , Retículo Sarcoplasmático/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Bloqueadores dos Canais de Sódio/farmacologia , Trocador de Sódio e Cálcio/metabolismo , Fatores de TempoRESUMO
OBJECTIVE: to explore illness beliefs in women with postnatal depression and suggest an appropriate health belief model. About 10% of recently delivered mothers suffer from depression. Postnatal depression may differ from depression occurring at other times in an individual's life not only symptomatically but also experiences, perceptions and beliefs about the illness differ because of the individual's specific role as a carer for a newborn baby. Whilst illness beliefs have been extensively examined using models from physical health, recent studies have pointed out that physical health models may not provide an appropriate framework to explore mental health difficulties and require adapting. DESIGN: qualitative study using face-to-face interviews for data collection. SETTING: Greater Manchester, England. METHODS: as illness beliefs have not yet been formally assessed using established questionnaires, the present study employed qualitative methodology to explore illness beliefs in mothers with postnatal depression (PND). Semi-structured interviews were conducted with 11 participants who were depressed following the birth of their child. Interview transcripts were analysed using grounded theory methodology. The point of theoretical sufficiency was reached with this sample size. FINDINGS: the rich data allowed for a theory of illness beliefs in PND to be developed encompassing six core categories: 'unmet expectations', 'identifying stressors in their life context', 'conflict over label', 'antidepressants: the lesser of two evils', 'loss of time' and 'uncertain futures.' KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: participants made multiple appraisals of their PND in light of their initial difficulties, their improvements and consequences, the future and subsequent service involvement. Participants' narratives were conflicting and uncertain with internal struggles evident as mothers were torn between their desire to be good mothers and their perceptions that PND meant that they were not good enough mothers. Thus, the themes identified in this study did not match onto the key dimensions postulated by Leventhal's self-regulation model of illness beliefs.