Identification of anti-fibrotic and pro-apoptotic bioactive compounds from Ganoderma formosanum and their possible mechanisms in modulating TGF-ß1-induced lung fibrosis.

ETHNOPHARMACOLOGICAL RELEVANCE: The Compendium of Materia Medica and the Classic of Materia Medica, the two most prominent records of traditional Chinese medicine, documented the therapeutic benefits of Ganoderma sinense particularly in addressing pulmonary-related ailments. Ganoderma formosanum, an indigenous subspecies of G. sinense from Taiwan, has demonstrated the same therapeutic properties. AIM OF THE STUDY: The aim of this study is to identify bioactive compounds and evaluate the potential of G. formosanum extracts as a novel treatment to alleviate pulmonary fibrosis (PF). Using an in-house drug screening platform, two-stage screening was performed to determine their anti-fibrotic efficacy. METHODS AND MATERIALS: G. formosanum was fractionated into four partitions by solvents of different polarities. To determine their antifibrotic and pro-apoptotic properties, the fractions were analyzed using two TGF-ß1-induced pulmonary fibrosis cell models (NIH-3T3) and human pulmonary fibroblast cell lines, immunoblot, qRT-PCR, and annexin V assays. Subsequently, transcriptomic analysis was conducted to validate the findings and explore possible molecular pathways. The identification of potential bioactive compounds was achieved through UHPLC-MS/MS analysis, while molecular interaction study was investigated by multiple ligands docking and molecular dynamic simulations. RESULTS: The ethyl acetate fraction (EAF) extracted from G. formosanum demonstrated substantial anti-fibrotic and pro-apoptotic effects on TGF-ß1-induced fibrotic models. Moreover, the EAF exhibited no discernible cytotoxicity. Untargeted UHPLC-MS/MS analysis identified potential bioactive compounds in EAF, including stearic acid, palmitic acid, and pentadecanoic acid. Multiple ligands docking and molecular dynamic simulations further confirmed that those bioactive compounds possess the ability to inhibit TGF-ß receptor 1. CONCLUSION: Potential bioactive compounds in G. formosanum were successfully extracted and identified in the EAF, whose anti-fibrotic and pro-apoptotic properties could potentially modulate pulmonary fibrosis. This finding not only highlights the EAF's potential as a promising therapeutic candidate to treat pulmonary fibrosis, but it also elucidates how Ganoderma confers pulmonary health benefits as described in the ancient texts.

Evaluation of the amelioration effect of Ganoderma formosanum extract on delaying PM2.5 damage to lung macrophages.

SCOPE: Particulate matter (PM) contains toxic organic matter and heavy metals that enter the entire body through blood flow and may cause mortality. Ganoderma formosanum mycelium, a valuable traditional Chinese medicine that has been used since ancient times, contains various active ingredients that can effectively impede inflammatory responses on murine alveolar macrophages induced by PM particles. METHODS AND RESULTS: An experimental study assessing the effect of G. formosanum mycelium extract's water fraction (WA) on PM-exposed murine alveolar macrophages using ROS measurement shows that WA reduces intracellular ROS by 12% and increases cell viability by 16% when induced by PM particles. According to RNA-Sequencing, western blotting, and real-time qPCR are conducted to analyze the metabolic pathway. The WA reduces the protein ratio in p-NF-κB/NF-κB by 18% and decreases the expression of inflammatory genes, including IL-1ß by 38%, IL-6 by 29%, and TNF-α by 19%. Finally, the identification of seven types of anti-inflammatory compounds in the WA fraction is achieved through UHPLC-ESI-Orbitrap-Elite-MS/MS analysis. These compounds include anti-inflammatory compounds, namely thiamine, adenosine 5'-monophosphate, pipecolic acid, L-pyroglutamic acid, acetyl-L-carnitine, D-mannitol, and L-malic acid. CONCLUSIONS: The study suggests that the WA has the potential to alleviate the PM -induced damage in alveolar macrophages, demonstrating its anti-inflammatory properties.

Discovery of HDAC6, HDAC8, and 6/8 Inhibitors and Development of Cell-Based Drug Screening Models for the Treatment of TGF-ß-Induced Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis is incurable, and its progression is difficult to control and thus can lead to pulmonary deterioration. Pan-histone deacetylase inhibitors such as SAHA have shown potential for modulating pulmonary fibrosis yet with off-target effects. Therefore, selective HDAC inhibitors would be beneficial for reducing side effects. Toward this goal, we designed and synthesized 24 novel HDAC6, HDAC8, or dual HDAC6/8 inhibitors and established a two-stage screening platform to rapidly screen for HDAC inhibitors that effectively mitigate TGF-ß-induced pulmonary fibrosis. The first stage consisted of a mouse NIH-3T3 fibroblast prescreen and yielded five hits. In the second stage, human pulmonary fibroblasts (HPFs) were used, and four out of the five hits were tested for caco-2 permeability and liver microsome stability to give two potential leads: J27644 (15) and 20. This novel two-stage screen platform will accelerate the discovery and reduce the cost of developing HDAC inhibitors to mitigate TGF-ß-induced pulmonary fibrosis.

Effects of selective cyclooxygenase-2 inhibitor robenacoxib on primary cells derived from feline injection-site sarcoma.

Feline injection-site sarcomas (FISSs) are highly invasive malignant mesenchymal neoplasms that arise from injection sites in cats. Although the tumorigenesis of FISSs is still uncertain, there is a consensus that FISS is associated with chronic inflammation caused by irritation of injection-related trauma and foreign chemical substances. Chronic inflammation can provide a proper microenvironment for tumour development, which has been known as one of the risk factors of tumorigenesis in many tumours. To investigate the tumorigenesis of FISS and screen for its potential therapeutic targets, cyclooxygenase-2 (COX-2), an inflammation-enhancing enzyme, was selected as a target for this study. In vitro experiments using FISS- and normal tissue-derived primary cells and robenacoxib, a highly selective COX-2 inhibitor, were performed. The results demonstrated that expression of COX-2 could be detected in formalin-fixed and paraffin-embedded FISS tissues and FISS-derived primary cells. Cell viability, migration and colony formation of FISS-derived primary cells were inhibited, and cell apoptosis was enhanced by robenacoxib in a dose-dependent manner. However, susceptibility to robenacoxib varied in different lines of FISS primary cells and was not completely correlated with COX-2 expression. Our results suggest that COX-2 inhibitors could be potential adjuvant therapeutics against FISSs.

Neoantigen vaccination augments antitumor effects of anti-PD-1 on mouse hepatocellular carcinoma.

Immune checkpoint inhibitors are groundbreaking resources for cancer therapy. However, only a few patients with hepatocellular carcinoma (HCC) have shown positive responses to anti-PD-1 therapy. Neoantigens are sequence-altered proteins resulting from somatic mutations in cancer. This study identified the neoantigens of Hep-55.1C and Dt81 Hepa1-6 HCCs by comparing their whole exome sequences with those of a normal C57BL/6 mouse liver. Immunogenic long peptides were pooled as peptide vaccines. The vaccination elicited tumor-reactive immune responses in C57BL/6 mice, as demonstrated by IFN-γ ELISPOT and an in vitro killing assay of splenocytes. In the treatment of three mouse HCC models, combined neoantigen vaccination and anti-PD-1 resulted in more significant tumor regression than monotherapies. Flow cytometry of the tumor-infiltrating lymphocytes showed decreased Treg cells and monocytic myeloid-derived suppressor cells, increased CD8+ T cells, enhanced granzyme B expression, and reduced exhaustion-related markers PD-1 and Lag-3 on CD8+ T cells in the combination group. These findings provide a strong rationale for conducting clinical studies of using neoantigen vaccination in combination with anti-PD-1 to treat patients with HCC.

Production and analysis of metabolites from solid-state fermentation of Chenopodium formosanum (Djulis) sprouts in a bioreactor.

The study utilized fresh fourth-day Chenopodium formosanum sprouts as the substrate for Rhizopus oligosporus fermentation. The resultant products showed higher antioxidant capacity than those from C. formosanum grains. Compared to traditional plate fermentation (PF), fermentation in a bioreactor (BF) (35 °C, 0.4 vvm aeration at 5 rpm) led to higher free peptide content (99.56 ± 7.77 mg casein tryptone/g) and enzyme activity (amylase, glucosidase, and proteinase are 2.21 ± 0.01, 54.57 ± 10.88, and 40.81 ± 6.52 U/g, respectively) than traditional plate fermentation (PF). Using mass spectrometry analysis, two peptides TDEYGGSIENRFMN and DNSMLTFEGAPVQGAAAITEK were predicted to possess high bioactive properties as DPP IV and ACE inhibitors. Additionally, over twenty new metabolites (aromatics, amines, fatty acids, and carboxylic acids) were discovered in the BF system compared to its PF counterpart. Results suggest that using a BF system to ferment C. formosanum sprouts is an appropriate method to scale-up fermentation and enhance nutritional values as well as bioactivities.

Glycine-rich peptides from fermented Chenopodium formosanum sprout as an antioxidant to modulate the oxidative stress.

Rhizopus oligosporus was utilized in the solid-state fermentation of Chenopodiumformosanumsprouts (FCS) in a bioreactor. Subsequently, the antioxidant activity of food proteins derived from FCS was investigated. Results showed that glycine-rich peptide (GGGGGKP, G-rich peptide), identified from the <2 kDa FCS proteins, had antioxidant values. According to SwissADME, AllerTOP, ToxinPred, and BIOPEP-UWM analyses, G-rich peptide was identified as safe, non-toxic, and non-allergenic. Afterward, the peptide was examined using in silico and in vitro studies to evaluate its potential alleviating oxidative stress caused by particulate matter. This study proposed plausible mechanisms that involve the binding of G-rich peptide which inhibited phosphorylation of the v-rel avian reticuloendotheliosis viral oncogene homologA(RELA) subunit onNF-κB pathway. The inhibition then resulted in down regulation of NF-κB transcription and genetic expression of inflammatory responses. These findings suggested that G-rich peptide from FCS proteins can potentially alleviate oxidative stress.

ECMO in neonates: The association between cerebral hemodynamics with neurological function.

Extracorporeal membrane oxygenation (ECMO) is a superior life support technology, commonly employed in critical patients with severe respiratory or hemodynamic failure to provide effective respiratory and circulatory support, which is especially recommended for the treatment of critical neonates. However, the vascular management of neonates with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is still under controversy. Reconstruction or ligation for the right common carotid artery (RCCA) after ECMO is inconclusive. This review summarized the existed studies on hemodynamics and neurological function after vascular ligation or reconstruction hoping to provide better strategies for vessel management in newborns after ECMO. After reconstruction, the right cerebral blood flow can increase immediately, and the normal blood supply can be restored rapidly. But the reconstructed vessel may be occluded and stenotic in long-term follow-ups. Ligation may cause lateralization damage, but there could be no significant effect owing to the establishment of collateral circulation. The completion of the circle of Willis, the congenital anomalies of cerebral or cervical vasculature, the duration of ECMO, and the vascular condition at the site of arterial catheterization should be assessed carefully before making the decision. It is also necessary to follow up on the reconstructed vessel sustainability, and the association between cerebral hemodynamics and neurological function requires further large-scale multi-center studies.

The Role of Cytokines and Chemokines in Severe Acute Respiratory Syndrome Coronavirus 2 Infections.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in countless infections and caused millions of deaths since its emergence in 2019. Coronavirus disease 2019 (COVID-19)-associated mortality is caused by uncontrolled inflammation, aberrant immune response, cytokine storm, and an imbalanced hyperactive immune system. The cytokine storm further results in multiple organ failure and lung immunopathology. Therefore, any potential treatments should focus on the direct elimination of viral particles, prevention strategies, and mitigation of the imbalanced (hyperactive) immune system. This review focuses on cytokine secretions of innate and adaptive immune responses against COVID-19, including interleukins, interferons, tumor necrosis factor-alpha, and other chemokines. In addition to the review focus, we discuss potential immunotherapeutic approaches based on relevant pathophysiological features, the systemic immune response against SARS-CoV-2, and data from recent clinical trials and experiments on the COVID-19-associated cytokine storm. Prompt use of these cytokines as diagnostic markers and aggressive prevention and management of the cytokine storm can help determine COVID-19-associated morbidity and mortality. The prophylaxis and rapid management of the cytokine storm appear to significantly improve disease outcomes. For these reasons, this study aims to provide advanced information to facilitate innovative strategies to survive in the COVID-19 pandemic.

Thoracic para-aortic lymph node recurrence in patients with esophageal squamous cell carcinoma: A propensity score-matching analysis.

BACKGROUND: Thoracic para-aortic lymph node (TPLN) recurrence in esophageal squamous cell carcinoma (ESCC) is rare and its impact on survival is unknown. We studied survival in patients with ESCC who developed TPLN recurrence. AIM: To study the survival in patients with ESCC who developed TPLNs recurrence. METHODS: Data were collected retrospectively for 219 patients who had undergone curative surgery for ESCC during January 2012 to November 2017 and who developed recurrences (36.29% of 604 patients who had undergone curative surgeries for ESCC). The patients were classified into positive (+) and negative (-) TPLN metastasis subgroups. We also investigated TPLN recurrence in 223 patients with ESCC following definitive chemoradiotherapy during 2012-2013. Following propensity score matching (PSM) and survival estimation, factors predictive of overall survival (OS) were explored using a Cox proportional hazards model. RESULTS: Among the patients with confirmed recurrence, 18 were TPLN (+) and 13 developed synchronous distant metastases. Before PSM, TPLN (+) was associated with worse recurrence-free (P = 0.00049) and OS [vs TPLN (-); P = 0.0027], whereas only the intergroup difference in recurrence-free survival remained significant after PSM (P = 0.013). The Cox analysis yielded similar results. Among the patients who had received definitive chemoradiotherapy, 3 (1.35%) had preoperative TPLN enlargement and none had developed recurrences. CONCLUSION: TPLN metastasis is rare but may be associated with poor survival.

More than causing (epi)genomic instability: emerging physiological implications of transposable element modulation.

Transposable elements (TEs) initially attracted attention because they comprise a major portion of the genomic sequences in plants and animals. TEs may jump around the genome and disrupt both coding genes as well as regulatory sequences to cause disease. Host cells have therefore evolved various epigenetic and functional RNA-mediated mechanisms to mitigate the disruption of genomic integrity by TEs. TE associated sequences therefore acquire the tendencies of attracting various epigenetic modifiers to induce epigenetic alterations that may spread to the neighboring genes. In addition to posting threats for (epi)genome integrity, emerging evidence suggested the physiological importance of endogenous TEs either as cis-acting control elements for controlling gene regulation or as TE-containing functional transcripts that modulate the transcriptome of the host cells. Recent advances in long-reads sequence analysis technologies, bioinformatics and genetic editing tools have enabled the profiling, precise annotation and functional characterization of TEs despite their challenging repetitive nature. The importance of specific TEs in preimplantation embryonic development, germ cell differentiation and meiosis, cell fate determination and in driving species specific differences in mammals will be discussed.

Role of the Immune Microenvironment in SARS-CoV-2 Infection.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) first emerged in December 2019 in Wuhan, China, and has since spread rapidly worldwide. As researchers seek to learn more about COVID-19, the disease it causes, this novel virus continues to infect and kill. Despite the socioeconomic impacts of SARS-CoV-2 infections and likelihood of future outbreaks of other pathogenic coronaviruses, options to prevent or treat coronavirus infections remain limited. In current clinical trials, potential coronavirus treatments focusing on killing the virus or on preventing infection using vaccines largely ignore the host immune response. The relatively small body of current research on the virus indicates pathological responses by the immune system as the leading cause for much of the morbidity and mortality caused by COVID-19. In this review, we investigated the host innate and adaptive immune responses against COVID-19, collated information on recent COVID-19 experimental data, and summarized the systemic immune responses to and histopathology of SARS-CoV-2 infection. Finally, we summarized the immune-related biomarkers to define patients with high-risk and worst-case outcomes, and identified the possible usefulness of inflammatory markers as potential immunotherapeutic targets. This review provides an overview of current knowledge on COVID-19 and the symptomatological differences between healthy, convalescent, and severe cohorts, while offering research directions for alternative immunoregulation therapeutic targets.

Enhanced antioxidant activity of Chenopodium formosanum Koidz. by lactic acid bacteria: Optimization of fermentation conditions.

In this study, different probiotics commonly used to produce fermented dairy products were inoculated independently for Chenopodium formosanum Koidz. fermentation. The strain with the highest level of antioxidant activity was selected and the fermentation process was further optimized via response surface methodology (RSM). Lactobacillus plantarum BCRC 11697 was chosen because, compared to other lactic acid bacteria, it exhibits increased free radical scavenging ability and can produce more phenolic compounds, DPPH (from 72.6% to 93.2%), and ABTS (from 64.2% to 76.9%). Using RSM, we further optimize the fermentation protocol of BCRC 11697 by adjusting the initial fermentation pH, agitation speed, and temperature to reach the highest level of antioxidant activity (73.5% of DPPH and 93.8% of ABTS). The optimal protocol (pH 5.55, 104 rpm, and 24.4°C) resulted in a significant increase in the amount of phenolic compounds as well as the DPPH and ABTS free radical scavenging ability of BCRC 11697 products. The IC50 of the DPPH and ABTS free radical scavenging ability were 0.33 and 2.35 mg/mL, respectively, and both protease and tannase activity increased after RSM. An increase in lower molecular weight (<24 kDa) protein hydrolysates was also observed. Results indicated that djulis fermented by L. plantarum can be a powerful source of natural antioxidants for preventing free radical-initiated diseases.

Attentional Resource Associated With Visual Feedback on a Postural Dual Task in Parkinson's Disease.

BACKGROUND: Restricted attentional resource and central processing in patients with Parkinson's disease (PD) may reduce the benefit of visual feedback in a dual task. OBJECTIVES: Using brain event-related potentials (ERPs), this study aims to investigate the neural mechanisms of posture visual feedback and supraposture visual feedback during performing of a posture-motor dual task. METHODS: Eighteen patients with PD and 18 healthy controls stood on a mobile platform (postural task) and executed a manual force-matching task (suprapostural task) concurrently with provided visual feedback of platform movement (posture-feedback condition) or force output (force-feedback condition). The platform movement, force-matching performance, and ERPs (P1, N1, and P2 waves) were recorded. RESULTS: Both PD and control groups had superior force accuracy in the force-feedback condition. Decreased postural sway by posture-feedback was observed in healthy controls but not in PD. Force-feedback led to a greater frontal area N1 peak in PD group but smaller N1 peaks in control group. In addition, force-feedback led to smaller P2 peaks of the frontal and sensorimotor areas among PD patients but greater P2 peaks of the sensorimotor and parietal-occipital areas among healthy controls. However, P1 modulations was present only in healthy controls. CONCLUSIONS: Force-feedback had positive effect on force accuracy in both PD and healthy individuals; however, the beneficial effect of posture-feedback on posture balance is not observed in PD. These findings are the first to suggest that PD could recruit more attentional resources in dual-task preparation to enhance suprapostural accuracy and avoid degrading postural stability by supraposture visual feedback.

Nanoparticle interactions with immune cells dominate tumor retention and induce T cell-mediated tumor suppression in models of breast cancer.

The factors that influence nanoparticle fate in vivo following systemic delivery remain an area of intense interest. Of particular interest is whether labeling with a cancer-specific antibody ligand ("active targeting") is superior to its unlabeled counterpart ("passive targeting"). Using models of breast cancer in three immune variants of mice, we demonstrate that intratumor retention of antibody-labeled nanoparticles was determined by tumor-associated dendritic cells, neutrophils, monocytes, and macrophages and not by antibody-antigen interactions. Systemic exposure to either nanoparticle type induced an immune response leading to CD8+ T cell infiltration and tumor growth delay that was independent of antibody therapeutic activity. These results suggest that antitumor immune responses can be induced by systemic exposure to nanoparticles without requiring a therapeutic payload. We conclude that immune status of the host and microenvironment of solid tumors are critical variables for studies in cancer nanomedicine and that nanoparticle technology may harbor potential for cancer immunotherapy.

The paradox of aging and health-related quality of life in Asian Chinese: results from the Healthy Aging Longitudinal Study in Taiwan.

BACKGROUND: Declines in health, physical, cognitive, and mental function with age suggest a lower level of health-related quality of life (HRQoL) in late life; however, previous studies found that the associations were weak and varied, depending on the study designs and cohort characteristics. METHODS: The present study examined the paradox of aging in an East Asian context by regressing the age patterns of objective health indicators (physical, cognitive, and mental function), and subjective HRQoL (12-item Short Form, SF-12), on the independent and interactive effects of age and physical function in a cohort study of 5022 community-dwelling adults aged 55 and older in Taiwan. RESULTS: Age patterns differed across measures. The SF-12 mental health score (MCS) showed a slight positive association with age and this effect remained stable after controlling for various age-related covariates. The SF-12 physical health score (PCS), in turn, was negatively associated with age. Age differences in PCS were fully explained by age decrements in objective physical health. However, consistent with the so-called paradox of aging, the association between objective and subjective physical health weakened with age. CONCLUSION: These findings add to prior evidence indicating that - in spite of objective health decrements - subjective HRQoL is maintained in later life among Asian Chinese. Also, these paradoxical patterns appear to vary for mental and physical components of HRQoL, and future research is needed to explore the underlying mechanism. TRIAL REGISTRATION: Healthy Aging Longitudinal Study in Taiwan (HALST) is retrospectively registered at ClinicalTrials.gov on January 24, 2016 with trial registration number NCT02677831.

Front-line Therapy in Advanced Non-Small Cell Lung Cancer With Sensitive Epidermal Growth Factor Receptor Mutations: A Network Meta-analysis.

PURPOSE: Several epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were firmly established as front-line treatment for non-small cell lung cancer (NSCLC) that harbored an activating EGFR mutation. Gefitinib or erlotinib was considered the standard of care. TKI-based combination therapy has been investigated and has shown encouraging results. METHODS: The PubMed and EMBASE databases, the Cochrane Central Register of Controlled Trials, and meeting abstracts were screened for relevant studies between January 2000 and February 2019. Prospective randomized controlled trials were included that investigated EGFR TKIs (alone or in combination) in untreated patients with NSCLC whose tumors had sensitive EGFR mutations. A frequentist random effects network meta-analysis model was conducted to assess objective response rate, progression-free survival, and overall survival. P-score was used to rank treatment effects. FINDINGS: Seventeen trials involving 9 treatments and 4373 patients were included. Heterogeneity existed in the network analysis. For progression-free survival, the top 3 treatments were osimertinib, standard of care plus chemotherapy, and standard of care plus bevacizumab; corresponding p-scores were 0.88, 0.79, and 0.75, respectively. For overall survival, the top 3 treatments were standard of care plus chemotherapy, osimertinib, and dacomitinib; corresponding p-scores were 0.89, 0.85, and 0.64. TKI-based combination therapy caused more toxicity than a TKI alone. IMPLICATIONS: Osimertinib seemed to be a better option as upfront therapy for EGFR-mutant NSCLC in terms of efficacy and tolerability.

First-line checkpoint inhibitors for wild-type advanced non-small-cell cancer: a pair-wise and network meta-analysis.

AIM: To estimate efficacy of checkpoint inhibitors and rank treatment effects in non-small-cell lung cancer. MATERIALS & METHODS: Prospective randomized trials were included. p-score was used to rank treatment effects. RESULTS: A total of nine trials were identified, involving 5504 patients and three checkpoint inhibitors. Pembrolizumab plus chemotherapy had the highest p-score of 0.95 among all the treatments, and was superior to pembrolizumab alone (hazard ratio: 0.87; 95% CI: 0.79-0.95). Combination therapy had more grade 3-5 adverse events; but toxicity-related discontinuation and treatment-related death did not increase. CONCLUSION: Pembrolizumab plus chemotherapy was likely to be the most effective treatment for patients with wild-type advanced NSCLC.

Neuronal Responses to a Postural Dual-Task With Differential Attentional Prioritizations: Compensatory Resource Allocation With Healthy Aging.

OBJECTIVES: Restricted central processing in older adults prevents optimization of a dual task with a flexible prioritization strategy. This study investigated the neural mechanisms of task-priority in young and older adults when performing a posture-motor dual-task. METHOD: Sixteen healthy young and 16 older adults performed a force-matching task on a mobile-platform under posture-focus (PF) and supraposture-focus (SF) conditions. The platform movement, force-matching performance, and event-related potentials in the preparatory period were recorded. RESULTS: For the elders, the postural stability and force-matching accuracy using the PF strategy were inferior to those using the SF strategy; whereas, the dual-task performances of the young adults were less affected by the prioritization. Only the elders exhibited the P1 wave, with the PF strategy associated with a smaller P1 and larger P1 than the SF strategy in the sensorimotor-parietal and right frontotemporal areas, respectively. The PF strategy also led to a larger P2 wave in the right frontotemporal area of elders, but a greater P2 wave in the sensorimotor-parietal area of young adults. DISCUSSION: For both prioritization strategies, older adults entailed a longer preparatory process than younger adults. Dual-task performance of older adults was more vulnerable to PF strategy, underlying compensatory resource allocation in the preparatory period for resolution of dual-task interference due to degenerated frontal function.

A role for paracrine interleukin-6 signaling in the tumor microenvironment in prostate tumor growth.

BACKGROUND: Interleukin-6 (IL-6) is a mediator of inflammation that can facilitate prostate cancer progression. We previously demonstrated that IL-6 is present in the prostate tumor microenvironment and is restricted almost exclusively to the stromal compartment. The present study examined the influence of paracrine IL-6 signaling on prostate tumor growth using allograft models of mouse prostate cancer (TRAMP-C2), colon cancer (MC38), and melanoma (B16) cell lines in wildtype (WT) and IL-6 knockout (IL-6-/- ) mice. METHODS: Cells were implanted into WT or IL-6-/- mice and tumor sizes were measured at a 3 to 4 day interval. Serum, tumors, and other organs were collected for IL-6 analysis by ELISA and RNA in situ hybridization (RISH). RESULTS: There was a significant reduction in TRAMP-C2 and B16 tumor size grown in IL-6-/- mice versus WT mice (P = 0.0006 and P = 0.02, respectively). This trend was not observed for the MC38 cell line. RISH analysis of TRAMP-C2 tumors grown in WT mice showed that cells present in the tumor microenvironment were the primary source of IL-6 mRNA, not the TRAMP-C2 cells. Serum IL-6 ELISA analyses showed an increase in the circulating levels of IL-6 in WT mice bearing TRAMP-C2 tumors. Similar phospho-STAT3 expression and tumor vascularization were observed in TRAMP-C2 tumors grown in WT and IL-6-/- mice. CONCLUSIONS: Our results are consistent with previous studies in prostate cancer patients demonstrating that paracrine IL-6 production in the tumor microenvironment may influence tumor growth. Additionally, these data provide evidence that elevated systemic IL-6 levels may be involved in tumor growth regulation in prostate cancer, and are not simply caused by or indicative of tumor burden.