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Cancer neuroscience is an emerging field of cancer biology focused on defining the interactions and relationships between the nervous system, developing malignancies, and their environments. Our previous work demonstrates that small extracellular vesicles (sEVs) released by head and neck squamous cell carcinomas (HNSCCs) recruit loco-regional nerves to the tumor. sEVs contain a diverse collection of biological cargo, including microRNAs (miRNAs). Here, we asked whether two genes commonly amplified in HNSCC, CCND1, and PIK3CA, impact the sEV miRNA cargo and, subsequently, sEV-mediated tumor innervation. To test this, we individually overexpressed these genes in a syngeneic murine HNSCC cell line, purified their sEVs, and tested their neurite outgrowth activity on dorsal root ganglia (DRG) neurons in vitro. sEVs purified from Ccnd1-overexpressing cells significantly increased neurite outgrowth of DRG compared to sEVs from parental or Pik3ca over-expressing cells. When implanted into C57BL/6 mice, Ccnd1 over-expressing tumor cells promoted significantly more tumor innervation in vivo. qPCR analysis of sEVs shows that increased expression of Ccnd1 altered the packaging of miRNAs (miR-15-5p, miR-17-5p, and miR-21-5p), many of which target transcripts important in regulating axonogenesis. These data indicate that genetic amplifications harbored by malignancies impose changes in sEV miRNA cargo, which can influence tumorc innervation.
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Classe I de Fosfatidilinositol 3-Quinases , Vesículas Extracelulares , Neoplasias de Cabeça e Pescoço , Camundongos Endogâmicos C57BL , MicroRNAs , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , Camundongos , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Linhagem Celular Tumoral , Ciclina D1/genética , Ciclina D1/metabolismo , Gânglios Espinais/metabolismo , Humanos , Amplificação de Genes , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologiaRESUMO
Introduction: Physical capacity is an important determinant of physical activity in people with obstructive airway disease (OAD). This study aimed to extend the "can do, do do" concept in people with OAD, to identify if people categorised into quadrants based on physical capacity and activity differ by clinical and movement behaviour characteristics. Methods: A total of 281 participants (bronchiectasis n=60, severe asthma n=93, COPD n=70 and control n=58) completed assessments to characterise physical capacity as "can do" versus "can't do" (6-min walk distance < or ≥70% pred) and physical activity as "do do" versus "don't do" (accelerometer-derived moderate to vigorous intensity physical activity (MVPA) < or ≥150â min·week-1). Results: The control group had a greater proportion of people in the "can do, do do" quadrant compared with the OAD groups (76% versus 10-33%). People with OAD in the "can't do, don't do" quadrant had worse clinical characteristics (airflow limitation, comorbidities, quality of life and functional dyspnoea) and spent less time doing light-intensity physical activity (LPA) and more time being sedentary compared with the "can do, do do" quadrant. Discussion: This study highlights that many people with OAD may be inactive because they do not have the physical capacity to participate in MVPA, which is further impacted by greater disease severity. It is important to consider the potential benefits of addressing LPA and sedentary behaviour due to suboptimal levels of these movement behaviours across different quadrants. Future research is needed to investigate if tailoring intervention approaches based on quadrant allocation is effective in people with OAD.
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Macro-level events such as elections can improve or harm population health across existing axes of stratification through policy changes and signals of inclusion or threat. This study investigates whether rates of, and disparities in, adverse birth outcomes between racialized and nativity groups changed after Donald Trump's November 2016 election, a period characterized by increases in xenophobic and racist messages, policies, and actions in the United States. Using data from 15,568,710 U.S. births between November 2012 and November 2018, we find that adverse birth outcomes increased after Trump's election among U.S.- and foreign-born mothers racialized as Black, Hispanic, and Asian and Pacific Islander (API), compared with the period encompassing the two Obama presidencies. Results for Whites suggest no change or a slight decrease in adverse outcomes following Trump's election, yet this finding was not robust to checks for seasonality. Black-White, Hispanic-White, and API-White disparities in adverse birth outcomes widened among both U.S.- and foreign-born mothers after Trump's election. Our findings suggest that Trump's election was a racist and xenophobic macro-level political event that undermined the health of infants born to non-White mothers in the United States.
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Política , Humanos , Estados Unidos , Feminino , Recém-Nascido , Lactente , Saúde do Lactente/estatística & dados numéricos , Adulto , Emigrantes e Imigrantes/estatística & dados numéricos , Disparidades nos Níveis de Saúde , Mortalidade Infantil/tendências , Mortalidade Infantil/etnologia , Mães/estatística & dados numéricos , GravidezRESUMO
BACKGROUND: Breathlessness is a disabling symptom, with complexity that is often under-recognized and undertreated in asthma. OBJECTIVE: To highlight the burden of breathlessness in people with severe compared with mild-to-moderate asthma and identify psychophysiological correlates of breathlessness. METHODS: This was a cross-sectional study of people with mild-to-severe asthma, who attended 2 in-person visits to complete a multidimensional assessment. The proportion of people with mild-to-moderate versus severe asthma who reported physically limiting breathlessness (modified Medical Research Council [mMRC] dyspnea score ≥2) was compared. Psychophysiological factors associated with breathlessness in people with asthma were identified via a directed acyclic graph and explored with multivariate logistic regression to predict breathlessness. RESULTS: A total of 144 participants were included, of whom, 74 (51%) had mild-to-moderate asthma and 70 (49%) severe asthma. Participants were predominantly female (n = 103, 72%) with a median (quartile 1, quartile 3) age of 63.4 (50.5, 69.5) years and body mass index (BMI) of 31.3 (26.2, 36.0) kg/m2. The proportion of people reporting mMRC ≥2 was significantly higher in those with severe- (n = 37, 53%) than those with mild-to-moderate (n = 21, 31%) asthma (P = .013). Dyspnoea-12 Total (8.00 [4.75, 17.00] vs 5.00 [2.00, 11.00], P = .037) score was also significantly higher in the severe asthma group. Significant predictors of physically limiting breathlessness were BMI, asthma control, exercise capacity, and hyperventilation symptoms. Airflow limitation and type 2 inflammation were poor breathlessness predictors. CONCLUSIONS: Over half of people with severe asthma experience physically limiting breathlessness despite treatment. Targeting psychophysiological factors, or traits, associated with breathlessness may help relieve this distressing symptom, which is of high priority to people with asthma.
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SUMMARY: The field of cancer neuroscience has begun to define the contributions of nerves to cancer initiation and progression; here, we highlight the future directions of basic and translational cancer neuroscience for malignancies arising outside of the central nervous system.
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Neoplasias , Neurociências , Humanos , Sistema Nervoso Central , Previsões , ProteômicaRESUMO
ABSTRACT: Severe pain is often experienced by patients with head and neck cancer and is associated with a poor prognosis. Despite its frequency and severity, current treatments fail to adequately control cancer-associated pain because of our lack of mechanistic understanding. Although recent works have shed some light of the biology underlying pain in HPV-negative oral cancers, the mechanisms mediating pain in HPV+ cancers remain unknown. Cancer-derived small extracellular vesicles (cancer-sEVs) are well positioned to function as mediators of communication between cancer cells and neurons. Inhibition of cancer-sEV release attenuated pain in tumor-bearing mice. Injection of purified cancer-sEVs is sufficient to induce pain hypersensitivity in naive mice that is prevented by QX-314 treatment and in Trpv1-/- mice. Cancer-sEVs triggered calcium influx in nociceptors, and inhibition or ablation of nociceptors protects against cancer pain. Interrogation of published sequencing data of human sensory neurons exposed to human cancer-sEVs suggested a stimulation of protein translation in neurons. Induction of translation by cancer-sEVs was validated in our mouse model, and its inhibition alleviated cancer pain in mice. In summary, our work reveals that HPV+ head and neck squamous cell carcinoma-derived sEVs alter TRPV1+ neurons by promoting nascent translation to mediate cancer pain and identified several promising therapeutic targets to interfere with this pathway.
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Dor do Câncer , Vesículas Extracelulares , Neoplasias de Cabeça e Pescoço , Infecções por Papillomavirus , Humanos , Animais , Camundongos , Dor do Câncer/etiologia , Neoplasias de Cabeça e Pescoço/complicações , Dor , Neurônios , Canais de Cátion TRPV/genéticaRESUMO
Cancer patients often experience changes in mental health, prompting an exploration into whether nerves infiltrating tumors contribute to these alterations by impacting brain functions. Using a male mouse model for head and neck cancer, we utilized neuronal tracing techniques and show that tumor-infiltrating nerves indeed connect to distinct brain areas via the ipsilateral trigeminal ganglion. The activation of this neuronal circuitry led to behavioral alterations represented by decreased nest-building, increased latency to eat a cookie, and reduced wheel running. Tumor-infiltrating nociceptor neurons exhibited heightened activity, as indicated by increased calcium mobilization. Correspondingly, the specific brain regions receiving these neural projections showed elevated cFos and delta FosB expression in tumor-bearing mice, alongside markedly intensified calcium responses compared to non-tumor-bearing counterparts. The genetic elimination of nociceptor neurons in tumor-bearing mice led to decreased brain Fos expression and mitigated the behavioral alterations induced by the presence of the tumor. While analgesic treatment successfully restored behaviors involving oral movements to normalcy in tumor-bearing mice, it did not have a similar therapeutic effect on voluntary wheel running. This discrepancy points towards an intricate relationship, where pain is not the exclusive driver of such behavioral shifts. Unraveling the interaction between the tumor, infiltrating nerves, and the brain is pivotal to developing targeted interventions to alleviate the mental health burdens associated with cancer. Significance Statement: Head and neck cancers are infiltrated by sensory nerves which connect to a pre-existing circuit that includes areas in the brain. Neurons within this circuit are altered and mediate modifications in behavior.
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BACKGROUND: Ventilation heterogeneity (VH) is a feature of asthma and indicates small airway disease. Nuclear imaging methods assess VH, which can facilitate clinical diagnosis and further our understanding of disease aetiology. OBJECTIVE: We sought to assess VH in severe eosinophilic asthma (SEA) using ventilation/perfusion single-photon emission computed tomography (V/P SPECT), and to assess its use as an objective test of the effect of biologic treatment for ventilation defects in SEA. METHODS: Adults (≥18 y) with severe asthma were recruited to participate in a cross-sectional observational study. Participants underwent a clinical assessment and V/P SPECT CT using Technegas as the ventilation agent. Measures were repeated for a nested before-after treatment study in people with SEA commencing biologics. RESULTS: A total of 62 participants with severe asthma were recruited. From this, 38 participants with SEA were included in the before-after study. The VH was associated with clinical variables such as lung function impairment and significantly improved after monoclonal antibody treatment in the severe asthma group. The changes in VH correlated with change in post bronchodilator forced expiratory volume in 1 second (FEV1) %predicted (r = -0.503; P = .001) and post bronchodilator FEV1/FVC (forced vital capacity) (r = -0.415; P = .01). CONCLUSIONS: The VH is clinically significant, measurable, and treatable, which establishes VH as a treatable trait in severe asthma.
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Asma , Doença Pulmonar Obstrutiva Crônica , Adulto , Humanos , Broncodilatadores/uso terapêutico , Estudos Transversais , Pulmão , Asma/terapia , Asma/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Volume Expiratório ForçadoRESUMO
People with asthma tend to be less physically active and more sedentary than people without asthma. This narrative review aimed to present key considerations when addressing physical inactivity and sedentary behaviour in people with asthma by identifying barriers and facilitators, determinants and correlates, and intervention approaches. Using a search strategy, electronic databases were searched for relevant studies. Data extracted from studies were qualitatively synthesised. A total of 26 studies were included in the review. Six studies reported asthma symptoms as a barrier to physical activity, while four studies reported having a supportive network as a physical activity facilitator. Across studies, physical activity correlates/determinants were pulmonary function, exercise capacity, body mass index, dyspnoea, psychological health, and asthma control. Interventions that effectively improved physical activity in the short term were a step-based prescription programme, a weight loss programme incorporating aerobic and resistance training, and a weight loss lifestyle intervention, while a high-intensity interval training pulmonary rehabilitation program was effective in the long term. The collective findings suggest that a personalised physical activity programme incorporating different strategies is needed. There was minimal evidence to provide recommendations to optimise sedentary behaviour in asthma, and more research is needed on the topic.
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The molecular and functional contributions of intratumoral nerves to disease remain largely unknown. We localized synaptic markers within tumors suggesting that these nerves form functional connections. Consistent with this, electrophysiological analysis shows that malignancies harbor significantly higher electrical activity than benign disease or normal tissues. We also demonstrate pharmacologic silencing of tumoral electrical activity. Tumors implanted in transgenic animals lacking nociceptor neurons show reduced electrical activity. These data suggest that intratumoral nerves remain functional at the tumor bed. Immunohistochemical staining demonstrates the presence of the neuropeptide, Substance P (SP), within the tumor space. We show that tumor cells express the SP receptor, NK1R, and that ligand/receptor engagement promotes cellular proliferation and migration. Our findings identify a mechanism whereby intratumoral nerves promote cancer progression.
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Neoplasias da Mama , Neurônios , Neoplasias Ovarianas , Carcinoma de Células Escamosas de Cabeça e Pescoço , Animais , Camundongos , Modelos Animais de Doenças , Humanos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Substância P/metabolismo , Linhagem Celular Tumoral , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/secundário , Neurônios/patologia , Camundongos Endogâmicos C57BL , Organismos Livres de Patógenos Específicos , Ovário/inervação , Papillomavirus Humano , Análise de SobrevidaRESUMO
Persistent fatigue is a debilitating side effect that impacts a significant proportion of cancer survivors for which there is not yet an FDA-approved treatment. While certainly a multi-factorial problem, persistent fatigue could be due, in part, to associations learned during treatment. Therefore, we sought to investigate the role of associative learning in the persistence of fatigue using a preclinical model of cancer survivorship. For this purpose, we used a murine model of human papilloma virus-related head and neck cancer paired with a curative regimen of cisplatin-based chemoradiation in male C57BL/6J mice. Fatigue-like behavior was assessed by measuring variations in voluntary wheel running using a longitudinal design. Treatment robustly decreased voluntary wheel running, and this effect persisted for more than a month posttreatment. However, when wheels were removed during treatment, to minimize treatment-related fatigue, mice showed a more rapid return to baseline running levels. We confirmed that the delayed recovery observed in mice with continual wheel access was not due to increased treatment-related toxicity, in fact running attenuated cisplatin-induced kidney toxicity. Finally, we demonstrated that re-exposure to a treatment-related olfactory cue acutely re-instated fatigue. These data provide the first demonstration that associative processes can modulate the persistence of cancer-related fatigue-like behavior.
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Sobreviventes de Câncer , Neoplasias , Humanos , Masculino , Camundongos , Animais , Camundongos Endogâmicos C57BL , Atividade Motora , PesquisaRESUMO
CONTEXT: The Mediterranean diet (MD) is a dietary pattern with evidence of positive health impact, and some nutrients in this diet have already been researched for their effectiveness in fertility. However, there are still questions about whether high adherence to the MD could be a factor that contributes to positive fertility outcomes in infertile men and women. OBJECTIVE: A systematic review and meta-analysis were conducted to determine whether a greater adherence to the MD can improve fertility markers and outcomes in infertile men and women. DATA SOURCES: The MEDLINE, BVS, SciELO, CENTRAL, and Embase databases and gray literature were searched from their inception to May 2022. STUDY SELECTION: Data were included from cohort studies that addressed MD and outcomes. DATA EXTRACTION: Data searches, article selection, data extraction, and risk-of-bias assessments were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: A total of 11 studies met the inclusion criteria (n = 13â157 women and 1338 men). Greater adherence to the MD was associated with live births (I2 = 83.16%; odds ratio [OR], 0.652; 95%CI, 0.408-3.194), pregnancy rate (I2 = 93.83%; OR, 1.192; 95%CI, 0.349-4.325), sperm concentration >15 × 106/mL (I2 = 32.97%; OR 2.862; 95%CI, 1.583-5.174), and sperm count > 39 × 106/mL (I2 = 48.1%; OR, 2.543; 95%CI, 1.319-4.904); however, in an inconsistent scenario regarding the meta-analysis. CONCLUSION: Current evidence of high adherence to MD and fertility markers is insufficient to support their clinical application, even though it indicates sperm improvement and a possibility of better pregnancy outcomes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. 169396.
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Dieta Mediterrânea , Infertilidade , Gravidez , Masculino , Humanos , Feminino , Sêmen , Resultado da Gravidez , Estudos de CoortesRESUMO
Background: The aim of this study was to evaluate the effect of propolis or metformin versus placebo on glycemic control in pharmacological treatment-naïve patients with type 2 diabetes mellitus (T2DM). Methods: A double-blind, randomized, placebo-controlled in parallel groups clinical trial was performed in 36 pharmacological treatment-naïve patients with T2DM. They received propolis (300 mg), metformin (850 mg), or placebo twice daily before breakfast and dinner for 12 weeks. At the beginning and end of the study, fasting plasma glucose (FPG), 2-h postload glucose (2-h PG) during a 75-g oral glucose tolerance test, glycated hemoglobin A1c (A1C) and a metabolic profile were measured. Areas under the curve (AUC) of glucose and insulin, total insulin secretion (insulinogenic index), the first phase of insulin secretion (Stumvoll index), and insulin sensitivity (Matsuda index) were calculated. Statistical analyses: Kruskal-Wallis, Mann-Whitney U and Wilcoxon tests. Results: The propolis and metformin groups exhibited significant reductions in FPG (p=0.009 and p=0.001, respectively), 2-h PG (p=0.034 and p=0.001, respectively) levels, AUC of insulin, Stumvoll index, and an increment in the Matsuda index. The comparison of the changes from baseline to the end showed significant differences between placebo and propolis in FPG (p=0.004) and A1C (p=0.049) levels, while between placebo and metformin were in FPG (p=0.002), 2-h PG (p=0.004) and A1C (p=0.007) levels. Conclusions: The administration of propolis and metformin compared to placebo reduced FPG and A1C levels; in addition, metformin decreased 2-h PG, AUC of glucose and insulin, high-density lipoprotein cholesterol, and increased the insulin sensitivity.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Metformina , Própole , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Metformina/uso terapêutico , Metformina/farmacologia , Própole/uso terapêutico , Hemoglobinas Glicadas , Glicemia/metabolismo , Insulina/metabolismo , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/farmacologia , Método Duplo-CegoRESUMO
Beer is an alcoholic beverage, rich in carbohydrates, amino acids, vitamins and polyphenols, consumed worldwide as a social drink. There is a large number of beer styles which depends on the ingredients and brewing process. The consumption of beer as a fluid replacement after sport practice is a current discussion in literature. A non-alcoholic pale-ale microparticles-based beverage (PABM) have been previously designed, however, its phenolic profile and ergogenic effect remain unknown. Thus, this study aims to verify the ergogenic potential (increase of running performance) of PAMB in male Wistar rats. Beer microparticles were obtained by spray drying and beverages with different concentrations were prepared in water. Wistar rats were subjected to a training protocol on a treadmill (5 times/week, 60 min/day) and daily intake of PABM (20 mg.kg-1 or 200 mg.kg-1) or water by gavage. Chlorogenic acid was found to be the main component in the phenolic profile (12.28 mg·g-1) of PABM analyzed with high-performance liquid chromatography and mass spectrometry. An increase in the aerobic performance was observed after 4 weeks in the 20 mg.kg-1 group, but the same dose after 8 weeks and a higher dose (200 mg.kg-1) blunted this effect. A higher dose was also related to decrease in food intake. These data suggest that PABM can improve satiety and aerobic performance, but its effect depends on the dose and time of consumption.
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Solid tumours are innervated by nerve fibres that arise from the autonomic and sensory peripheral nervous systems1-5. Whether the neo-innervation of tumours by pain-initiating sensory neurons affects cancer immunosurveillance remains unclear. Here we show that melanoma cells interact with nociceptor neurons, leading to increases in their neurite outgrowth, responsiveness to noxious ligands and neuropeptide release. Calcitonin gene-related peptide (CGRP)-one such nociceptor-produced neuropeptide-directly increases the exhaustion of cytotoxic CD8+ T cells, which limits their capacity to eliminate melanoma. Genetic ablation of the TRPV1 lineage, local pharmacological silencing of nociceptors and antagonism of the CGRP receptor RAMP1 all reduced the exhaustion of tumour-infiltrating leukocytes and decreased the growth of tumours, nearly tripling the survival rate of mice that were inoculated with B16F10 melanoma cells. Conversely, CD8+ T cell exhaustion was rescued in sensory-neuron-depleted mice that were treated with local recombinant CGRP. As compared with wild-type CD8+ T cells, Ramp1-/- CD8+ T cells were protected against exhaustion when co-transplanted into tumour-bearing Rag1-deficient mice. Single-cell RNA sequencing of biopsies from patients with melanoma revealed that intratumoral RAMP1-expressing CD8+ T cells were more exhausted than their RAMP1-negative counterparts, whereas overexpression of RAMP1 correlated with a poorer clinical prognosis. Overall, our results suggest that reducing the release of CGRP from tumour-innervating nociceptors could be a strategy to improve anti-tumour immunity by eliminating the immunomodulatory effects of CGRP on cytotoxic CD8+ T cells.
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Linfócitos T CD8-Positivos , Melanoma , Nociceptores , Animais , Camundongos , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Melanoma/imunologia , Melanoma/patologia , Nociceptores/fisiologia , Células Receptoras Sensoriais/metabolismo , Neuritos/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Taxa de Sobrevida , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Genes RAG-1/genética , Humanos , Biópsia , PrognósticoRESUMO
INTRODUCTION: Physical inactivity is common in asthma and is recognised as an important modifiable risk for poor clinical outcomes such as impaired asthma control and health-related quality of life (HRQoL). Despite evidence supporting the role of physical activity in reducing the risk of these outcomes, little is known about optimal interventions for increasing physical activity in those with severe disease. This systematic review and meta-analysis evaluates the effectiveness of interventions in increasing physical activity in severe asthma. METHODS: MEDLINE, the Cumulative Index to Nursing and Allied Health Literature, Embase, PubMed, Informit, SPORTDiscus and Cochrane databases were searched up to September 2021 for physical activity-based intervention studies that assessed physical activity outcomes (e.g. steps per day, time spent undertaking physical activity) in adults with severe asthma. Data on asthma-related (e.g. asthma control) and health-related outcomes (e.g. HRQoL) were assessed as secondary outcomes. The revised Cochrane Risk of Bias tool was used to assess risk of bias. Random-effects meta-analyses synthesised data where possible. RESULTS: Four randomised controlled trials (all 12â weeks in duration) including 176 adults with moderate-to-severe asthma were included. An increase in physical activity was reported with a moderate-vigorous intensity aerobic and resistance training intervention (steps per day and time spent undertaking physical activity), and an unsupervised pedometer-based intervention (steps per day). Meta-analyses showed that physical activity interventions had an overall positive effect on steps per day (mean difference (MD) 1588, 95% CI 399-2778; p=0.009, I2=23), asthma control (MD -0.65, 95% CI -0.95--0.35; p<0.0001, I2=0%) and HRQoL (MD 0.56, 95% CI 0.10-1.01; p=0.02, I2=16%) compared to control. CONCLUSION: While there is some evidence supporting the effectiveness of interventions in improving physical activity in adults with severe asthma, higher-quality, large-scale studies of longer duration are needed to determine the optimal intervention.
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Asma , Qualidade de Vida , Adulto , Humanos , Exercício Físico , Comportamento Sedentário , Asma/terapia , ActigrafiaRESUMO
BACKGROUND: Chemoradiotherapy is a standard treatment for HNSCC. Blockade of the PD-1/L1-2 interaction may represent a target to overcome immune escape during this treatment. METHODS: Utilizing a HNSCC mEERL C57BL/6 mouse model, we evaluated a PD-1 blockade alone or in combination with cisplatin-based chemoradiotherapy. Next, we evaluated peripheral blood mononuclear cells (PBMCs) with relative PD-1, TIM-3, and LAG-3 expression, and myeloid-derived suppressor-like (MDSC-like) populations from a clinical trial evaluating PD-1 blockade with chemoradiotherapy in HNSCC. Finally, we analyzed the effect of therapy on human T-cell clonality through T-cell Receptor (TCR) sequencing. RESULTS: Anti-PD-1 monotherapy induced no response in the mEERL model; however, combination with chemoradiotherapy improved tumor clearance and survival. PBMCs from patients treated with this combination therapy demonstrate a decline in circulating T-cell populations with knockdown of PD-1 expressing CD3+CD4+ and CD3+CD8+ T cells during treatment. However, TIM-3, LAG-3 expressing T-cell and MDSC-like populations concordantly rose. During treatment, the TCR repertoire demonstrates overall clonal expansion, with both unique and previously reported T-cell clones. CONCLUSIONS: Our murine HNSCC model demonstrates efficacy of PD-1 blockade during chemoradiotherapy. However, while PD-1-expressing T cells decreased with this therapy, human PBMC findings also identified an increase in populations contributing to immune exhaustion. These findings further characterize PD-1 blockade during chemoradiotherapy for HNSCC and highlight potential competing mechanisms of immune evasion.
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Phenolic compounds (PCs) present in foods are associated with a decreased risk of developing inflammatory diseases. The aim of this study was to extract and characterize PCs from craft beer powder and evaluate their potential benefits in an experimental model of inflammatory bowel disease (IBD). PCs were extracted and quantified from pure beer samples. BALB/c mice received either the beer phenolic extract (BPE) or beer powder fortified with phenolic extract (BPFPE) of PCs daily for 20 days by gavage. Colon samples were collected for histopathological and immunohistochemical analyses. Dextran sodium sulfate (DSS)-induced mice lost more weight, had reduced colon length, and developed more inflammatory changes compared with DSS-induced mice treated with either BPE or BPFPE. In addition, in DSS-induced mice, the densities of CD4- and CD11b-positive cells, apoptotic rates, and activation of NF-κB and p-ERK1/2 MAPK intracellular signaling pathways were higher in those treated with BPE and BPFPE than in those not treated. Pretreatment with the phenolic extract and BPFPE remarkably attenuated DSS-induced colitis. The protective effect of PCs supports further investigation and development of therapies for human IBD.
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Cerveja , Colite , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Colite/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pós , Dodecilsulfato de Sódio/toxicidadeRESUMO
The identification of nerves in the tumor microenvironment has ushered in a new area of research in cancer biology. Numerous studies demonstrate the presence of various types of peripheral nerves (sympathetic, parasympathetic, sensory) within the tumor microenvironment; moreover, an increased density of nerves in the tumor microenvironment correlates with worse prognosis. In this review, we address the current understanding of nerve-mediated alterations of the tumor microenvironment and how they impact disease through a variety of processes, including direct nerve-cancer cell communication, alteration of the infiltrative immune population, and alteration of stromal components.