Safety, Efficacy, and Immunogenicity of Therapeutic Vaccines for Patients with High-Grade Cervical Intraepithelial Neoplasia (CIN 2/3) Associated with Human Papillomavirus: A Systematic Review.

Despite the knowledge that HPV is responsible for high-grade CIN and cervical cancer, little is known about the use of therapeutic vaccines as a treatment. We aimed to synthesize and critically evaluate the evidence from clinical trials on the safety, efficacy, and immunogenicity of therapeutic vaccines in the treatment of patients with high-grade CIN associated with HPV. A systematic review of clinical trials adhering to the PRISMA 2020 statement in MEDLINE/PubMed, Embase, CENTRAL Cochrane, Web of Science, Scopus, and LILACS was undertaken, with no data or language restrictions. Primary endpoints related to the safety, efficacy, and immunogenicity of these vaccines were assessed by reviewing the adverse/toxic effects associated with the therapeutic vaccine administration via histopathological regression of the lesion and/or regression of the lesion size and via viral clearance and through the immunological response of individuals who received treatment compared to those who did not or before and after receiving the vaccine, respectively. A total of 1184 studies were identified, and 16 met all the criteria. Overall, the therapeutic vaccines were heterogeneous regarding their formulation, dose, intervention protocol, and routes of administration, making a meta-analysis unfeasible. In most studies (n = 15), the vaccines were safe and well tolerated, with clinical efficacy regarding the lesions and histopathological regression or viral clearance. In addition, eleven studies showed favorable immunological responses against HPV, and seven studies showed a positive correlation between immunogenicity and the clinical response, indicating promising results that should be further investigated. In summary, therapeutic vaccines, although urgently needed to avoid progression of CIN 2/3 patients, still present sparse data, requiring greater investments in a well-designed phase III RCT.

The Maze Pathway of Coevolution: A Critical Review over the Leishmania and Its Endosymbiotic History.

The description of the genus Leishmania as the causative agent of leishmaniasis occurred in the modern age. However, evolutionary studies suggest that the origin of Leishmania can be traced back to the Mesozoic era. Subsequently, during its evolutionary process, it achieved worldwide dispersion predating the breakup of the Gondwana supercontinent. It is assumed that this parasite evolved from monoxenic Trypanosomatidae. Phylogenetic studies locate dixenous Leishmania in a well-supported clade, in the recently named subfamily Leishmaniinae, which also includes monoxenous trypanosomatids. Virus-like particles have been reported in many species of this family. To date, several Leishmania species have been reported to be infected by Leishmania RNA virus (LRV) and Leishbunyavirus (LBV). Since the first descriptions of LRVs decades ago, differences in their genomic structures have been highlighted, leading to the designation of LRV1 in L. (Viannia) species and LRV2 in L. (Leishmania) species. There are strong indications that viruses that infect Leishmania spp. have the ability to enhance parasitic survival in humans as well as in experimental infections, through highly complex and specialized mechanisms. Phylogenetic analyses of these viruses have shown that their genomic differences correlate with the parasite species infected, suggesting a coevolutionary process. Herein, we will explore what has been described in the literature regarding the relationship between Leishmania and endosymbiotic Leishmania viruses and what is known about this association that could contribute to discussions about the worldwide dispersion of Leishmania.

Effectiveness of hospital clowns for symptom management in paediatrics: systematic review of randomised and non-randomised controlled trials.

OBJECTIVE: To evaluate evidence from randomised controlled trials and non-randomised controlled trials on the effectiveness of hospital clowns for a range of symptom clusters in children and adolescents admitted to hospital with acute and chronic conditions. DESIGN: Systematic review of randomised and non-randomised controlled trials. DATA SOURCES: Medline, ISI of Knowledge, Cochrane Central Register of Controlled Trials, Science Direct, Scopus, American Psychological Association PsycINFO, Cumulative Index to Nursing and Allied Health Literature, and Latin American and Caribbean Health Sciences Literature. STUDY SELECTION: Randomised and non-randomised controlled trials were peer reviewed using the following eligibility criteria: children and adolescents who were admitted to hospital for acute conditions or chronic disorders, studies comparing use of hospital clowns with standard care, and studies evaluating the effect of hospital clowns on symptom management of inpatient children and adolescents as a primary outcome. DATA EXTRACTION AND SYNTHESIS: Two investigators independently screened studies, extracted data, and appraised the risk of bias. Methodological appraisal was assessed by two investigators independently using the Jadad scale, the revised Cochrane risk-of-bias tool for randomised controlled trials (RoB 2), and the risk of bias in non-randomised studies (ROBINS-I) tool for non-randomised controlled trials. RESULTS: 24 studies (n=1612) met the inclusion criteria for data extraction and analysis. Most studies were randomised controlled trials (n=13). Anxiety was the most frequently analysed symptom (n=13), followed by pain (n=9), psychological and emotional responses and perceived wellbeing (n=4), stress (n=4), cancer related fatigue (n=3), and crying (n=2). Five studies used biomarkers, mainly cortisol, to assess stress or fatigue outcome following hospital clowns. Most of the randomised controlled trials (n=11; 85%) were rated as showing some concerns, and two trials were rated with a high risk of bias. Most non-randomised controlled trials (n=6; 55%) were rated with a moderate risk of bias according to ROBINS-I tool. Studies showed that children and adolescents who were in the presence of hospital clowns, either with or without a parent present, reported significantly less anxiety during a range of medical procedures, as well as improved psychological adjustment (P<0.05). Three studies that evaluated chronic conditions showed favourable results for the intervention of hospital clowns with significant reduction in stress, fatigue, pain, and distress (P<0.05). CONCLUSIONS: These findings suggest that the presence of hospital clowns during medical procedures, induction of anaesthesia in the preoperative room, and as part of routine care for chronic conditions might be a beneficial strategy to manage some symptom clusters. Furthermore, hospital clowns might help improve psychological wellbeing in admitted children and adolescents with acute and chronic disorders, compared with those who received only standard care. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018107099.

Lactobacillus bulgaricus inhibits colitis-associated cancer via a negative regulation of intestinal inflammation in azoxymethane/dextran sodium sulfate model.

BACKGROUND: Colitis-associated cancer (CAC) accounts for 2%-3% of colorectal cancer (CRC) cases preceded by inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis. Intestinal microbiota has been reported to play a central role in the pathogenesis of IBD and CAC. Recently, numerous prebiotics and probiotics have being investigated as antitumor agents due to their capacity to modulate inflammatory responses. Previous studies have indicated that lactic acid bacteria could be successfully used in managing sporadic CRC, however little is known about their role in CAC. AIM: To investigate the effect of the probiotic Lactobacillus bulgaricus (L. bulgaricus) during the development of an experimental model of colitis associated colon cancer (CAC). METHODS: C57BL/6 mice received an intraperitoneal injection of azoxymethane (10 mg/kg), followed by three cycles of sodium dextran sulphate diluted in water (5% w/v). Probiotic group received daily L. bulgaricus. Intestinal inflammation was determined by scoring clinical signs. Cytokines levels were determined from colon and/or tumor samples by ELISA BD OptEIATM kits. The level of significance was set at P < 0.05. Graphs were generated and statistical analysis performed using the software GraphPad Prism 6.0. RESULTS: L. bulgaricus treatment inhibited of total tumor volume and mean size of tumors. In addition, the probiotic also attenuated the clinical signs of intestinal inflammation inducing a decrease in intestinal and tumor levels of IL-6, TNF-α, IL-17, IL-23 and IL-1ß. CONCLUSION: Our results suggest a potential chemopreventive effect of probiotic on CAC. L. bulgaricus regulates the inflammatory response and preventing CAC.

The lectin ArtinM activates RBL-2H3 mast cells without inducing degranulation.

Mast cells are connective tissue resident cells with morphological and functional characteristics that contribute to their role in allergic and inflammatory processes, host defense and maintenance of tissue homeostasis. Mast cell activation results in the release of pro-inflammatory mediators which are largely responsible for the physiological functions of mast cells. The lectin ArtinM, extracted from Artocarpus heterophyllus (jackfruit), binds to D-manose, thus inducing degranulation of mast cells. ArtinM has several immunomodulatory properties including acceleration of wound healing, and induction of cytokine release. The aim of the present study was to investigate the role of ArtinM in the activation and proliferation of mast cells. The rat mast cell line RBL-2H3 was used throughout this study. At a low concentration (0.25µg/mL), ArtinM induced mast cell activation and the release of IL-6 without stimulating the release of pre-formed or newly formed mediators. Additionally, when the cells were activated by ArtinM protein tyrosine phosphorylation was stimulated. The low concentration of ArtinM also activated the transcription factor NFkB, but not NFAT. ArtinM also affected the cell cycle and stimulated cell proliferation. Therefore, ArtinM may have therapeutic applications by modulating immune responses due to its ability to activate mast cells and promote the release of newly synthesized mediators. Additionally, ArtinM could have beneficial effects at low concentrations without degranulating mast cells and inducing allergic reactions.

Moderate Exercise Modulates Tumor Metabolism of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) stands out for its aggressiveness and accelerated rate of proliferation. Evidence shows that exercise may exert antitumorigenic effects, but the biochemical mechanisms underlying them remain unclear. Our objective was to evaluate the ability of exercise to modulate tumor growth and energy metabolism in an experimental TNBC model. Female BALB/c mice were sedentary or trained for 12 weeks and inoculated with 1 × 104 4T1 cells in the eighth week. Analyzes of macronutrient oxidation, mitochondrial respiration, and expression of genes related to cell metabolism were performed. The results showed that the trained group had a smaller tumor mass and the mitochondria in the tumors presented lower respiratory rates in the state of maximum electron transport capacity. Additionally, the tumors of the exercised group showed a higher expression of genes related to tumor suppressors, while the genes linked with cellular growth were similar between groups. Furthermore, the training modulated the corporal macronutrient oxidation to almost exclusive carbohydrate oxidation, while the sedentary condition metabolized both carbohydrate and lipids. Therefore, the exercise reduced tumor growth, with an impact on mitochondrial and macronutrient metabolism. Our results shed light on the understanding of the antitumorigenic effects of physical exercise, particularly regarding the metabolic transformations in TNBC.

Clown Intervention on Psychological Stress and Fatigue in Pediatric Patients With Cancer Undergoing Chemotherapy.

BACKGROUND: Clown intervention has been shown to enhance emotional and behavioral processes, but few studies have comprehensively examined the effectiveness of this practice using biomarkers. OBJECTIVE: The aim of this study was to evaluate the effect of a clown intervention on the levels of psychological stress and cancer-related fatigue in pediatric patients with cancer undergoing chemotherapy. METHODS: Sixteen patients who met all criteria from a pediatric oncology inpatient unit in a Brazilian comprehensive cancer care hospital participated in this quasi-experimental study. Eight saliva samples were collected, comprising 4 at baseline and 4 after clown intervention (+1, +4, +9, and +13 hours after awakening). Salivary cortisol and α-amylase levels were determined using high-sensitivity enzyme-linked immunosorbent assay kits. Stress and fatigue were measured by the Child Stress Scale-ESI and the PedsQL Multidimensional Fatigue Scale, respectively. Relationships among stress, fatigue, and biomarker levels were investigated using nonparametric statistics. RESULTS: In comparison with baseline measurements, the total psychological stress and fatigue levels improved after the clown intervention at the collection time point +4 hours (P = .003 and P = .04, respectively). Salivary cortisol showed a significant decrease after clown intervention at the collection time points +1, +9, and +13 hours (P < .05); however, α-amylase levels remained unchanged. CONCLUSION: These findings provide preliminary evidence that clown intervention merits further study as a way to reduce stress and fatigue in pediatric cancer inpatients, and that self-report and biomarker measures are feasible to collect in this patient group. IMPLICATIONS FOR PRACTICE: Clown intervention as a nonpharmacological intervention may improve stress and fatigue levels in pediatric inpatients with cancer undergoing chemotherapy.

Expression of MicroRNAs miR-145, miR-181c, miR-199a and miR-1183 in the Blood and Hippocampus of Patients with Mesial Temporal Lobe Epilepsy.

The aim of this study was to analyze the expression profiles of the microRNAs (miRNAs) miR-145, miR-181c, miR-199a and miR-1183 in the hippocampus and blood of patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) and to investigate whether these can be used as diagnosis and prognosis biomarkers for epilepsy. Hippocampus and blood samples were collected from 20 patients with MTLE-HS, ten of whom had a favorable surgical outcome (Engel I) and ten with an unfavorable surgical outcome (Engel III-IV). Hippocampus samples from autopsied individuals with no neurological or psychiatric medical history (necropsy samples) and blood samples from healthy individuals were used as controls. Real-time quantitative PCR (RQ-PCR) was used to analyze miRNA expression. The results showed that the expressions of these miRNAs differed quantitatively in the hippocampus and blood of patients with MTLE-HS in comparison to the respective control. This difference was most pronounced for miR-145, which was hypo-expressed in the hippocampus and hyper-expressed in the blood of MTLE-HS patients. MiRNAs miR-145, miR-181c, miR-199a and miR-1183 were hyper-expressed in the blood of patients with MTLE-HS. No statistical differences in the levels of these miRNAs in the blood or hippocampus were found between Engel I patients and Engel III-IV patients. These results suggest that the analyzed microRNAs are potential circulating biomarkers for epilepsy diagnosis.

Safety, efficacy and immunogenicity of therapeutic vaccines in the treatment of patients with high-grade cervical intraepithelial neoplasia associated with human papillomavirus: a systematic review protocol.

INTRODUCTION: Eighty per cent of the sexually active population will get human papillomavirus (HPV) infection, which is the most prevalent sexually transmitted disease worldwide. Persistence of high-grade HPV infection may evolve to a cervical intraepithelial neoplasia (CIN), and these lesions may be precursors of cervical cancer. However, this progression can be prevented by the administration of therapeutic vaccines which use the main oncoproteins responsible for cancer development in an attempt to trigger a more specific and effective immunological response against this disorder. We aim to evaluate the safety, efficacy and immunogenicity of therapeutic vaccines in the treatment of patients with high-grade CIN 2/3 associated with HPV. METHODS AND ANALYSIS: A systematic review of clinical trials will be undertaken. Medline, Excerpta Medica Database, Cochrane Central Register of Controlled Trials, Web of Science, Latin American and Caribbean Health Sciences Literature, Scientific Electronic Library Online and Scopus will be searched, with no restriction regarding publication date. Primary outcomes will include measures related to safety, efficacy and the immunogenicity of the therapeutic vaccines used in these patients. Study selection will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Methodological appraisal of the studies will be assessed by the Cochrane Risk-of-Bias Tool for randomised controlled trials, and the quality evidence of the risk of bias in single studies will be evaluated by Grading of Recommendations Assessment, Development and Evaluation. A narrative synthesis will be done for all included studies. Outcomes will be analysed according to the subgroups of HPV type, CIN grade, route of vaccine administration and vaccine type. Also, if sufficient data are available, a meta-analysis will be conducted. The effect sizes will be generated using Hedges' g score for both fixed and random effect models. I 2 statistics will be used to assess heterogeneity and identify their potential sources. ETHICS AND DISSEMINATION: Ethical approval is not required as primary data will not be collected. Findings will be disseminated widely via peer-reviewed publication and in different media, for example, conferences, congresses or symposia. PROSPERO REGISTRATION NUMBER: CRD42017077428.

microRNA-181d associated with the methylation status of the MGMT gene in Glioblastoma multiforme cancer stem cells submitted to treatments with ionizing radiation and temozolomide.

Despite the increased understanding of the oncological mechanisms underlying Glioblastoma multiforme (GBM) pathophysiology, and recent advances in therapeutic strategies such as maximal surgical resection and post-operative radiotherapy with concomitant and adjuvant temozolomide chemotherapy, the prognosis for patients with brain tumors remains limited. Evidences indicate that the assessment of DNA methylation status in cancer stem cells would allow identifying molecules expressed in these cells, to lead to targeted elimination of this critical population from brain tumors, making the glioblastoma treatment more effective. This study aimed to analyze the role of microRNA-181d associated with the methylation status of the O6-methylguanine methyl transferase (MGMT) gene in Glioblastoma multiforme cancer stem cells subjected to treatment with temozolomide and ionizing radiation. Such responses were analyzed in terms of cell survival, evaluation of the MGMT gene methylation status by MS-HRM (Methylation-Sensitive High Resolution Melting), and analysis of miRNA-181d and MGMT gene expression by relative quantification of mRNA levels in cancer stem cells subjected to treatment with temozolomide and ionizing radiation, isolated or combined. We showed that ionizing radiation and temozolomide reduced the viability of cancer stem cells from GBM patients, as well as modified MGMT gene and miRNA-181d expression in cancer stem cells, suggesting that miRNA-181d interferes in the glioblastoma cancer stem cell response to treatment with temozolomide and ionizing radiation.

Complementary Therapies as a Strategy to Reduce Stress and Stimulate the Immunity of Women With Breast Cancer.

The stress associated with cancer development leads to disturbances in the hypothalamic-pituitary-adrenal axis and suppresses important facets of the immune response. The use of complementary therapies in the treatment of women with breast cancer has demonstrated therapeutic benefits that entail improvements in the patients' quality of life. The objective of this article is to present evidence on the use of complementary therapies as a stress reduction strategy and on its stimulating effects on the immune system of women with breast cancer. This is a reflexive updating article that will support the health professionals' understanding on the use of complementary therapies in breast cancer care. The use of complementary therapies in the treatment of women with breast cancer has significantly improved these subjects' stress, depression, fatigue, anxiety, and consequently, their quality of life, as well as their immune response, which is mainly illustrated by the increased number and cytotoxic activity of natural killer cells. Clinicians, health professionals and patients need to be cautious about using complementary therapies and fully understand the real benefits and risks associated with each therapy. Little or no supporting evidence is available to clarify the effects on the immune system of women with breast cancer, and the consequent therapeutic benefits obtained through the use of these practices.

Complementary Therapies as a Strategy to Reduce Stress and Stimulate Immunity of Women With Breast Cancer.

The stress associated with cancer development leads to disturbances in the hypothalamic-pituitary-adrenal axis and suppresses important facets of the immune response. The use of complementary therapies in the treatment of women with breast cancer has demonstrated therapeutic benefits that entail improvements in the patients' quality of life. The objective of this article is to present evidence on the use of complementary therapies as a stress reduction strategy and on its stimulating effects on the immune system of women with breast cancer. This is a reflexive updating article that will support the health professionals' understanding on the use of complementary therapies in breast cancer care. The use of complementary therapies in the treatment of women with breast cancer has significantly improved these subjects' stress, depression, fatigue, anxiety, and, consequently, their quality of life, as well as their immune response, which is mainly illustrated by the increased number and cytotoxic activity of natural killer cells. Clinicians, health professionals, and patients need to be cautious about using complementary therapies and fully understand the real benefits and risks associated with each therapy. Little or no supporting evidence is available to clarify the effects on the immune system of women with breast cancer, and the consequent therapeutic benefits obtained through the use of these practices.

Tumor resection ameliorates tumor-induced suppression of neuroinflammatory and behavioral responses to an immune challenge in a cancer survivor model.

Breast cancer survivors display altered inflammatory responses to immune challenges relative to cancer-naive controls likely due to previous cancer treatments, stress associated with cancer, and/or tumor physiology. Proper inflammatory responses are necessary for adaptive sickness behaviors (e.g., fatigue, anorexia, and fever) and neuroinflammatory pathways are also implicated in mental health disturbances (e.g., cognitive impairment, depression) suffered by cancer patients and survivors. Rodent cancer models indicate that tumors are sufficient to exacerbate neuroinflammatory responses after an immune challenge, however primary tumors are not usually present in cancer survivors, and the behavioral consequences of these brain changes remain understudied. Therefore, we tested the extent to which mammary tumor resection attenuates tumor-induced neuroinflammation and sickness behavior following an immune challenge (i.p. lipopolysaccharide [LPS] injection) in mice. Tnf-α, Il-1ß, and Il-6 mRNA decreased in multiple brain regions of LPS-treated tumor-bearing mice relative to LPS-treated controls; tumor resection attenuated these effects in some cases (but not Tnf-α). Tumors also attenuated sickness behaviors (hypothermia and lethargy) compared to LPS-treated controls. Tumor resection reversed these behavioral consequences, although basal body temperature remained elevated, comparable to tumor-bearing mice. Thus, tumors significantly modulate neuroinflammatory pathways with functional consequences and tumor resection mitigates most, but not all, of these changes.

Systematic review protocol examining the effectiveness of hospital clowns for symptom cluster management in paediatrics.

INTRODUCTION: Clown intervention may playing an important complementary role in paediatric care and recovery. However, data on its utility for symptom cluster management of hospitalised children and adolescents in acute and chronic disorders are yet to be critically evaluated. As clinicians strive to minimise the psychological burden during hospitalisation, it is important that they are aware of the scientific evidences available regarding clown intervention for symptom management. We aim to provide quality evidence for the effectiveness of clown intervention on symptom cluster management in paediatric inpatients, both in acute and chronic conditions. METHODS AND ANALYSIS: A systematic review of randomised controlled trials (RCTs) and non-randomised controlled trials (NRCTs) will be conducted. MEDLINE, Web of Science, Cochrane Library, Science Direct, PsycINFO, CINAHL, LILACS and SciELO databases will be searched from January 2000 to December 2018. Primary outcomes will include measures related with the effect of clown intervention on symptom cluster of paediatric inpatients (anxiety, depression, pain, fatigue, stress and psychological, emotional responses and perceived well-being). Study selection will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, and the methodological appraisal of the studies will be assessed by the Jadad Scale as well as Cochrane Risk-of-Bias Tool for RCTs, and Risk-of-Bias In Non-Randomized Studies Tool for NRCTs. A narrative synthesis will be conducted for all included studies. Also, if sufficient data are available, a meta-analysis will be conducted. The effect sizes will be generated using Hedges' g score for both fixed and random effect models. I 2 statistics will be used to assess heterogeneity and identify their potential sources. ETHICS AND DISSEMINATION: As it will be a systematic review, without human beings involvement, there will be no requirement for ethical approval. Findings will be disseminated widely through peer-reviewed publication and in various media, for example, conferences, congresses or symposia. TRIAL REGISTRATION NUMBER: CRD42018107099.

Cytokine modulation, oxidative stress and thymic dysfunctions: Role of age-related changes in the experimental Trypanosoma cruzi infection: Age-related thymic dysfunctions and Trypanosoma cruzi infection.

Aging is linked with a thymic oxidative damage and some infectious diseases such as Chagas' disease may aggravate this process. The aim of this study was to evaluate the production of distinct cytokines as well as the antioxidant/oxidant status of the thymus and thymocytes populations during Trypanosoma cruzi (T. cruzi) infection. Young (5 weeks old) and aged (18 weeks old) male Wistar rats were inoculated with blood trypomastigotes forms of the Y strain of T. cruzi. On the 16th day after T. cruzi infection, increased concentrations of transforming growth factor ß (TGF-ß), interleukin (IL)-12, IL-17 were detected in aged infected subjects as compared to young infected ones. Interestingly, a reduction in the production of tumor necrose factor (TNF)-α was observed in aged infected rats when compared to young infected subjects. Aged-infected rats presented increased O2- levels, compared to young counterparts. Significant raise in the generation of O2- in aged infected animals, as compared to uninfected counterparts was observed. Up-regulated expression of Nox2 in the thymus of young and aged infected animals was observed. An increased SOD2 expression was detected in the thymus of young animals infected with T. cruzi, when compared to uninfected young rats. Aged animals showed reduced thymus weight and the number of thymocytes. Decreased percentages of SPCD4+ and SPCD8+T cells were detected in aged and control groups when compared to young counterparts. In summary, this is the first data to directly examine the influence of aging on age-related dysfunctions during the acute phase of experimental Chagas disease. Concerning to oxidative stress, it is clear from our analysis that aged infected rats suffer a more intense oxidative damage when compared to young and infected ones. Age and infection triggered a dynamic interplay of cytokines, oxidative stress and thymic dysfunctions which led to impaired response from aged and infected rats. Such findings may have significant functional relevance in therapeutic strategies in order to reestablish the thymic immunological function which occurs in aged and T. cruzi infected subjects.

The Effect of Clown Intervention on Self-Report and Biomarker Measures of Stress and Fatigue in Pediatric Osteosarcoma Inpatients: A Pilot Study.

BACKGROUND: Pediatric cancer patients experience different psychological processes during hospitalization that may regulate the immune response and affect recovery and response to cancer treatment. In this study, we aimed to examine the feasibility of longitudinal testing of psychophysiological parameters of stress and fatigue in pediatric osteosarcoma patients hospitalized for chemotherapy submitted to clown intervention; and to investigate whether changes in the levels of biomarkers are associated with psychological stress and fatigue levels in these patients after the clown intervention. METHODS: A pretest-posttest quasi-experimental pilot study was conducted at the pediatric oncology inpatient unit in a comprehensive cancer care center in Brazil including children and adolescents with osteosarcoma hospitalized for chemotherapy. Eight saliva samples were collected, comprising 4 at baseline (pre-intervention) and 4 after the clown intervention (+1, +4, +9, and +13 hours post-awakening). Salivary cortisol, α-amylase (sAA), cytokines, and matrix metalloproteinase-9 (MMP-9) levels were determined using high-sensitivity enzyme-linked immunosorbent assay (ELISA) kits. Stress and fatigue were measured by Child Stress Scale-ESI and PedsQL Multidimensional Fatigue Scale respectively. Bivariate association analysis between stress and fatigue scores and biomarker levels were investigated using nonparametric statistics. Effect sizes were calculated for each outcome variable. RESULTS: Six pediatric osteosarcoma patients were enrolled with no missing data. No significant effects sizes were observed for psychophysiological outcomes. Effect sizes ranged from 0.54 (cortisol) to 0 (interleukin-1ß [IL-1ß]). Decreasing overall trends were observed for cortisol levels for all 6 pediatric osteosarcoma patients over time. In addition, a similar pattern of tumor necrosis factor-α (TNF-α) levels over time was found for all 6 patients. Patients with metastatic osteosarcoma showed a linear trend for a decrease in MMP-9 levels between 1 and 9 hours after the clown intervention and restoration to basal levels after 13 hours. CONCLUSIONS: The results of this pilot study suggest that it is feasible longitudinally measure psychophysiological outcomes in the pediatric osteosarcoma inpatients for chemotherapy. Clown intervention merits further study as a way to reduce stress as well as fatigue, since that the stress and cytokines measurements are feasible based on our work.

Elevated serum levels of proinflammatory cytokines potentially correlate with depression and anxiety in colorectal cancer patients in different stages of the antitumor therapy.

Depression and anxiety, the most important psychological disorders in cancer patients, have now been considered as psychoneuroimmunological disorders, in which peripheral immune activation, through the release of proinflammatory cytokines, is implicated in the variety of behavioral, neuroendocrine and neurochemical alterations associated with these disorders. Along with the tumor itself, cancer treatment can also contribute to exacerbate the production of proinflammatory cytokines. This study aimed to investigate whether proinflammatory cytokine levels are related to depression and anxiety in CRC patients in different stages of the antitumor therapy We evaluated 60 patients in three stages of antitumor therapy (Pre-chemotherapy, Under-chemotherapy and Post-chemotherapy, n=20 in each group) and 20 healthy volunteers by the Hospital Anxiety and Depression Scale (HADS). Serum levels of cytokines were measured by CBA. Depression and/or anxiety were found at clinically relevant levels in CRC patients during all antitumor therapy. Patients in pre-chemotherapy group exhibited the highest concentrations of pro-inflammatory cytokines and the lowest levels of IL-10. In latter stages of treatment, cytokines reached levels similar to the control group. Correlation analysis between HADS score and cytokine serum levels revealed positive associations of anxiety and/or depression with IL-1ß, IL-6, IL-8, and TNF-α, and a negative correlation with IL-10, suggesting that cytokines are involved in the pathophysiology of these psychological disorders in CRC patients. A better understanding of the molecular mechanisms involved in these psychological disorders will allow the design of new therapeutic strategies to assist in alleviating such symptoms in cancer patients.

Fractalkine (C-X3-C motif chemokine ligand 1) as a potential biomarker for depression and anxiety in colorectal cancer patients.

Fractalkine, a unique chemokine of the CX3C subfamily, is involved in the pathogenesis of different types of cancer and also in non-immune mechanisms associated with psychiatric disorders. The aim of the present study was to investigate whether there is a correlation between anxiety, depression and fractalkine serum levels in colorectal cancer (CRC) patients in different stages of antitumor therapy. Four groups of patients undergoing treatment (n=20 per group) were evaluated: Patients with CRC who did not undergo surgical resection of the tumor; patients who underwent resection and who did not start adjuvant therapy; patients undergoing chemotherapy for ~3 months; and patients who had completed adjuvant chemotherapy regimen for ~6 months. The control group was composed of 20 healthy volunteers free of any psychiatric or immune system disease. Depression and anxiety were evaluated using the Hospital Anxiety and Depression Scale (HADS) and serum levels of fractalkine were measured by cytometric bead array. Clinically relevant levels of anxiety and/or depression were observed in all of the CRC patients at the different stages of antitumor therapy. Elevated serum levels of fractalkine were identified in the CRC patients in the pre-surgery (P<0.001) and pre-chemotherapy (P<0.001) groups, but reduced upon chemotherapy (P<0.05). Furthermore, a positive correlation was observed between fractalkine levels and the HADS scores in the CRC patients at different stages of antitumor therapy. These results demonstrate a link between fractalkine, depression and anxiety in CRC patients indicating that this chemokine is involved in the pathophysiology of these comorbidities. An improved understanding of the molecular mechanisms involved in these psychological disorders will allow the design of novel therapeutic strategies to assist in alleviating such symptoms in cancer patients. Therefore, fractalkine may present as a relevant biomarker for depression and anxiety in CRC patients.

Jacalin Has Chemopreventive Effects on Colon Cancer Development.

Colorectal cancer, which is one of the most common causes of cancer-related deaths worldwide, has a slow natural history that provides a great opportunity for prevention strategies. Plant-derived natural products have received considerable attention because of their inherent colorectal cancer chemopreventive effects. The plant lectin jacalin specifically recognizes the tumor-associated Thomsen-Friedenreich antigen and has antiproliferative effects on human colon cancer cells, highlighting its potential antitumor activity. To evaluate jacalin's potential application in colorectal cancer chemoprevention, we studied its effects on the early stages of carcinogenesis. Balb/c mice were given 4 intrarectal deposits of 0.1 ml solution of Methyl-N'-Nitro-N-Nitroso-Guanidine (5 mg/ml) twice a week (with a 3-day interval) for 2 weeks. Starting 2 weeks before carcinogen administration, animals were treated orally with jacalin (0.5 and 25 µg) three times a week (on alternate weekdays) for 10 weeks. We show that jacalin treatment reduced the number of preneoplastic lesions in carcinogen-exposed mice. This anticarcinogenic activity was associated with decreased colonic epithelial cell proliferation and stromal COX-2 expression and with increased intestinal production of TNF-α. Our results demonstrate that jacalin is able to modulate the early stages of colon carcinogenesis and emphasize its promising chemopreventive activity in colorectal cancer.

Ageing is not associated with an altered immune response during Trypanosoma cruzi infection: Ageing and Trypanosoma cruzi infection.

The aims of this work were to evaluate the influence of ageing on the magnitude of the immune response in male Wistar rats infected with the Y strain of Trypanosoma cruzi (T. cruzi). Infected young animals displayed enhanced CD4+ T cells as compared to uninfected counterparts. Ageing also triggered a significant reduction in CD8+ T cells compared to young and uninfected groups. The percentage of spleen NKT cells was reduced for all groups, regardless of the infection status. Significant decreased B-cells was noted in aged controls and infected animals as compared to young counterparts. A significant decrease in MHC class II (RT1B) expression in all aged animals was observed, whether infected or not. The highest and significant levels of Thiobarbituric Acid Reactive Substances (TBARS) were noted in the aged and infected animals as compared to young-infected ones (16day). Consequently superoxide dismutase (SOD) activity was reduced for both control and infected aged animals. Significant elevation of 8-isoprostane levels was found in aged control and infected animals. Plasma glutathione (GSH) concentration was reduced in aged control animals, as well as, in the young infected animals. NO production was increased in both infected and uninfected aged animals compared to young infected and uninfected animals. Corticosterone levels were elevated in aged animals, whether infected or not. Thus, our results are inedited since the immune response is not worsened by the simple fact of animals being older. Ageing by itself triggered a damaged immune response as well as enhanced reactive oxygen species, when compared to young counterparts, but it did not contribute to impair the immune response of T. cruzi infected and aged rats.