Factor Profile Research Articles

Tissue distribution of epirubicin after severe extravasation in humans

PurposeAs critical parameter after extravasation of cytotoxic vesicants, anthracyclines were determined in removed tissue from patients requiring surgical intervention due to tissue necrosis. We monitored their distribution within the affected lesion to establish a possible dose–toxicity relation.MethodsFrom six patients scheduled for surgery, removed tissue flaps were systematically analysed by HPLC (epirubicin: 5 subjects; doxorubicin: 1 subject).ResultsAfter extravasation, tissue concentrations were highly variable with an individual anthracycline distribution pattern ranging from a few nanograms up to 17 µg per 100 mg tissue, which indicated a substantial difference in tissue sensitivity among patients. The resection borders coincided with the extension of the erythema and guided the surgical intervention after demarcation of the lesion, which occurred usually 2 or 3 weeks after extravasation. At that time, drug was hardly detected at the resection borders. Wound drains were negative for the extravasated drugs while showing a time profile of vascular growth factors and inflammatory cytokines, which was highly similar to routine surgery. In all six patients, surgical debridement with immediate wound closure led to healing within approximately 2 weeks, when therapy was resumed in all patients with reasonable time delay.ConclusionSurgical intervention after demarcation of the extravasation lesion allows for almost uninterrupted continuation of treatment independent of the amount of extravasated anthracycline. As even minor amounts of the vesicants may trigger tissue necrosis, preventive measures merit the highest priority.

Associations Between Developmental Risk Profiles, Mental Disorders, and Student Absences Among Primary and Secondary Students in Australia

This study assessed if the association between mental disorders and higher student absences varies across different profiles of risk factors, and estimated the proportion of student absences associated with mental disorders. Data included responses from a nationally representative Australian survey of child and adolescent mental health (Young Minds Matter, N = 5,081). A latent class analysis identified four classes of multiple risk exposure for students and their families, including On Track (55%), Low Resources (22%), Child Concerns (15%), and Overwhelmed (7%). Negative binomial regression models with adjustment for misclassification probabilities showed that absence rate ratios were higher among students classified as Low Resources (1.8 times), Child Concerns (1.7 times), or Overwhelmed (3.0 times) than On Track students. Overall, students with an anxiety or depressive disorder had 1.2 times as many absences as students without a disorder, after adjusting for latent class membership. There was no support for the hypothesis that the association between anxiety/depressive disorder and absences would be greater for students experiencing multiple risk exposures. Behavioral disorders were not associated with higher absences. Mental disorders accounted for approximately 8.6% of absences among secondary students (Years 7–12) and 2.4% of absences among primary students (Years 1–6). The estimated contribution of mental disorders to school absences is not trivial; however, the contribution is about half that estimated by previous research. The educational impacts of mental disorders must be considered in conjunction with the broader social contexts related to both mental disorders and student absences.

Longitudinal association between an overall diet quality index and latent profiles of cardiovascular risk factors: results from a population based 13-year follow up cohort study

BackgroundCardiovascular diseases (CVDs) are associated with an unhealthy lifestyle, including poor diet. Indices reflecting the overall quality of diets are more effective than single food or nutrient-based approaches in clarifying the diet disease relationship. The present study aims to use latent variable modeling to examine the longitudinal joint relationships between the latent profiles of CVDs risk factors and the diet quality index (DQI).MethodsA total of 4390 Iranian adults aged 35 and older within the framework of the Isfahan Cohort Study were included in the current secondary analysis. DQI focused on food groups, including fast foods, sweets, vegetables, fruits, fats, and proteins, based on a validated food frequency questionnaire. The score of DQI has a range between 0 (indicating healthy and high diet quality) and 2 (indicating unhealthy and low diet quality). Blood pressure (BP), anthropometric measurements, blood glucose, serum lipids, and high-sensitivity C-Reactive Protein (hs-CRP) were measured according to standard protocols in 2001, 2007, and 2013 to evaluate the profiles of CVDs risk factors. A Bayesian Multidimensional Graded Responses Linear Mixed Model was used for data analysis.ResultsAt baseline, the participants’ mean ± standard deviation age was 50.09 ± 11.21, and 49.5% of them were male. Three latent profiles of CVDs risk factors were derived: (1) Fit Pre-Metabolic Syndrome (FPMS) profile characterized by normal anthropometric indices and some impaired metabolic risk factors; (2) DysLipoproteinemia Central Obese (DLCO) profile with abdominal obesity and impaired low-density lipoprotein cholesterol as well as other normal risk factors; (3) Impaired Laboratory Inflammatory State (ILIS) profile with impaired high-density lipoprotein cholesterol and hs-CRP and other normal risk factors. In general, higher scores of the extracted latent profiles indicated more impaired function in the related risk factors. After controlling for various potential fixed and time-varying confounding variables, a significant positive longitudinal association was found between FPMS, DLCO, and ILIS profiles and DQI (β (95% CrI): 0.26 (0.03,0.51), 0.14 (0.01,0.27), and 0.24 (0.11,0.38), respectively), demonstrating that lower overall diet quality was associated with more impaired function of the related risk factors.ConclusionsMore adherence to a healthy quality diet is associated with lower levels of all emerging latent profiles of CVDs risk factors. Increasing the knowledge of the community about the importance of the quality of consumed foods may help to prevent CVDs. It is recommended that further investigations, particularly interventional studies, be conducted to confirm our results.

Abstract P245: Sex Differences in the Association Between Cardiovascular Risk Profiles and Hospitalizations/ED Visits Among Patients With a History of Stroke/TIA

Background: Secondary prevention addressing cardiovascular risk factors is a key care component for reducing the risk of vascular events among those who had a stroke/TIA. We assessed cardiovascular risk factor (CVD-RF) profiles and their impact on hospitalizations and Emergency Department (ED) visits and whether the association differs for men and women with prior stroke/TIA. Methods: We used data from the nationally representative Medical Expenditure Panel Survey (2012-2015) for persons aged ≥ 18 years with a prior stroke/TIA. CVD-RF score included 6 self-reported factors (hypertension, diabetes, high cholesterol, lack of exercise, smoking, obesity), categorized as low (0-1 factors), intermediate (2-3), or high (4-6). Outcomes included ≥ 1 hospitalization discharges or ED visits during the participant’s survey year. Multivariable logistic regression models assessed the association between CVD-RF scores and outcomes, stratified by sex. We tested for interaction by sex in a combined model with men and women. Results: The weighted sample represents 9.9 million individuals (mean age 65.1 years; 54.3% women). Overall, 16.7%, 59.3%, and 24.1% of men had low, intermediate, and high CVD-RF scores compared to 21.6%, 59.5%, and 18.9% of women. Among men, there was no significant association between CVD-RF score and the two outcomes ( Table ). Among women, even after adjustment for covariates, those with high scores had 1.89 and 2.06-fold increases in the odds of hospitalizations and ED visits, compared to those with low CVD-RF scores ( P <0.05). Furthermore, women with intermediate CVD-RF scores had a 1.68-fold increase in the odds of ED visits compared to those with low scores ( P <0.05). The combined model showed a significant interaction by sex. Conclusion: Women with increased CVD-RF scores had increased odds of ED visits and hospitalizations, which could be due to less effective secondary prevention. Further research is needed to explore reasons for this sex disparity.

Abstract P461: Contemporary National Estimates of Characteristics and Outcomes Associated With Supra and Infratentorial Intracerebral Hemorrhage

Introduction: Location specific Intracerebral Hemorrhage (ICH) characteristics and outcomes are important for risk stratification and clinical trial design. However, they have not been described at the population level. Methods: We analyzed the National Inpatient Sample (90% of US hospitalizations) from 09/2015 to 12/2017 and utilized ICD-10 codes to identify ICH patients with a primary diagnosis of either supra-tentorial (ST) or infra-tentorial (IT) hemorrhage; excluding intraventricular or unspecified location. Utilizing sampling weights, nationally representative proportions of ST and IT ICH patients across demographic, comorbidity, healthcare utilization, disease acuity and outcomes are provided. We fit survey design logistic regression models for in-hospital mortality (IHM) and home discharge (HD). Odds Ratios (OR) and 95% confidence Intervals (CI) are reported. Results: Across the analysis time period, a total of 161,395 ICH patients were identified, of whom 51,025 (31.6%) and 20,135(12.5%) had ST and IT ICH respectively. IT ICH patients (vs. ST ICH) were younger (66.9 vs. 67.9 years), with higher proportions of Black (19.1% vs. 17.6%) and un-insured (5.9% vs. 4.7%). A significantly greater proportion of IT ICH patients had prior myocardial infarction, congestive heart failure, atrial fibrillation, renal disease and hypertension. Whereas the prior cerebrovascular disease, dementia, depression and alcohol abuse was associated with ST ICH. Smaller proportion of IT ICH patients (vs. ST ICH) were treated in urban teaching hospitals (81.4% vs. 83.2%). A greater proportion of IT ICH underwent invasive mechanical ventilation (58.1% vs. 46.7%), ventriculostomy (18.2% vs. 10.2%), and tracheostomy (6.4% vs. 4.6%). The total charges and charges per day were significantly higher for IT ICH patients. The overall IHM was 22.6%. A greater proportion of IT ICH patients (vs. ST ICH) experienced IHM (28.2% vs. 17.3%) and smaller proportion had HD (16.7% vs. 20.7%). In the fully adjusted models, IT ICH was associated with a significantly higher IHM (OR, CI: 1.47, 1.26 - 1.71) and lower likelihood of HD (OR, CI: 0.56, 0.46 - 0.68). Conclusion: ST and IT ICH patients have distinctive risk factor and demographic profiles. IT ICH is associated with poor outcomes.

Застосування мобільних додатків у превентивній кардіології та кардіореабілітації: огляд літератури

Мета. За даними літературних джерел розглянути сучасні підходи до можливостізастосування мобільних додатків у превентивній кардіології та кардіореабілітації. Методи.Аналіз та узагальнення даних наукової та науково-методичної літератури. Результати. Існуютьзагальновідомі прогалини у реабілітації та вторинній профілактиці ішемічної хвороби серця.Використання технологій на базі смартфона може забезпечити інноваційну платформудля заповнення цих прогалин. Висновки. Використання мобільних додатків потенційноможе сприяти вдосконаленню програм кардіореабілітації та вторинної профілактикишляхом збільшення їх доступності для пацієнтів, підвищення прихильності хворих до участів кардіореабілітаційних програмах, забезпечення телемоніторингу та зворотного зв’язкув режимі реального часу, покращення профілю факторів ризику. Не зважаючи на високийвідсоток користувачів мобільних додатків серед населення України, потенціал даних технологійвсе ще не використовується у програмах кардіореабілітації та вторинної профілактики, щопотребує проведення наукових досліджень у даному напрямку.

Serum Cytokine Profiles of Melanoma Patients and Their Association with Tumor Progression and Metastasis.

Purpose Previous studies have shown that melanoma cells produce excessive levels of cytokines, which have various biological roles during melanoma development. The aim of this study was to expand the profile of serum cytokines, chemokines, growth factors, and angiogenic factors that are associated with melanoma, to find more cytokines with abnormal concentrations in melanoma patients, to identify whether the level of cytokines correlated with prognostic variants, such as Breslow thickness and BRAF mutation, and, finally, to find out the cytokines that play important roles during melanoma development. Materials and Methods Multiplex immunobead assay technology and 45-plex immunoassays ProcartaPlex™ kits were used to simultaneously compare the levels of cytokines, growth factors, angiogenic factors, and chemokines between the serum of healthy patients (n = 30) and those with melanoma (n = 72). Data were analyzed according to the clinical characteristics of the designated patient subgroups. Results Compared to the control group, melanoma patients had higher levels of VEGF-A, PDGF-BB, IL-1RA, PIGF-1, IFN-γ, TNF-α, MIP-1α, and SCF, but lower levels of BDNF, SDF-1α, MCP-1, Eotaxin, EGF, and IL-7. Furthermore, the levels of TNF-α (P=0.320, r = 0.019), IFN-γ (P=0.311, r = 0.023), VEGF-A (P=0.014, r = 0.337), and BDNF (0.004, r = −0.391) showed a significant correlation with Breslow thickness. IL-7 was of lower levels in patients harboring BRAF mutants. Melanoma patients with high levels of MIP-1α and MCP-1 showed the poorest overall survival. Conclusions We found that the levels of VEGF-A and PDGF-BB in the serum of both primary and metastatic melanoma patients are elevated. TNF-α, IFN-γ, and VEGF-A presented a positive correlation with Breslow thickness, whereas BDNF showed a negative association. MIP-1α and MCP-1 correlated negatively with survival. In addition, lower levels of IL-7 were found in patients harboring BRAF mutants. These findings indicate that these cytokines may play critical roles in the progression of melanoma.

Gender difference of geographic distribution of the stroke incidence affected by socioeconomic, clinical and urban-rural factors: an ecological study based on data from the Brest stroke registry in France

BackgroundMapping the spatial distribution of disease occurrence is a strategy to identify contextual factors that could be useful for public health policies. The purpose of this ecological study was to examine to which extent the socioeconomic deprivation and the urbanization level can explain gender difference of geographic distribution in stroke incidence in Pays de Brest, France between 2008 and 2013.MethodsStroke cases aged 60 years or more were extracted from the Brest stroke registry and combined at the census block level. Contextual socioeconomic, demographic, and geographic variables at the census block level come from the 2013 national census. We used spatial and non-spatial regression models to study the geographic correlation between socioeconomic deprivation, degree or urbanization and stroke incidence. We generated maps using spatial geographically weighted models, after longitude and latitude smoothing and adjustment for covariates.ResultsStroke incidence was comparable in women and men (6.26 ± 3.5 vs 6.91 ± 3.3 per 1000 inhabitants-year, respectively). Results showed different patterns of the distribution of stroke risk and its association with deprivation or urbanisation across gender. For women, stroke incidence was spatially homogeneous over the entire study area, but was associated with deprivation level in urban census blocks: age adjusted risk ratio of high versus low deprivation = 1.24, [95%CI 1.04–1.46]. For men, three geographic clusters were identified. One located in the northern rural and deprived census blocks with a 9–14% increase in the risk of stroke. Two others clusters located in the south-eastern (mostly urban part) and south-western (suburban and rural part) with low deprivation level and associated with higher risk of stroke incidence between (3 and 8%) and (8.5 and 19%) respectively. There were no differences in profile of cardiovascular risk factors, stroke type and stroke severity between clusters, or when comparing clusters cases to the rest of the study population.ConclusionsUnderstanding whether and how neighborhood and patient’s characteristics influence stroke risk may be useful for both epidemiological research and healthcare service planning.

Phase-dependent expression profiling and quantification of several growth factors in liver regeneration after partial hepatectomy

Growth factors are the potential operational members which control different phases of liverregeneration. Different growth factors have expression regulation in the whole process relating todifferent phases of liver regeneration. Objective: To assess the expression regulation of differentgrowth factors and cytokines involved in liver regeneration in a phase-dependent manner. Methods:Blood and liver samples were collected and analyzed on 1st, 3rd, 5th, 7th and 14th postoperative days after50% Partia hepatectomy (PHx). Results: Steady increase of liver regeneration rate was recorded from90.8% (1st day) to 97.9% (7th day). Liver function tests further confirmed the steady liver recovery in PHxmice. Several growth factors such as HGF and VEGF exhibited an up-regulation till 5th day and latergradual decrease till 14th day compared to control mice. Albumin, CK18 and CK19 showed sequentialexpression increase from 1st to 14th day compared to AFP and HNF-4α upregulated until 5th and 1st day,respectively. Quantification of these growth factors further confirm our results. Conclusions:Conclusively, these results highlight a phase-dependent regulation and role of growth factors in liverregeneration and recovery .

Assessment of Plasma Biochemistry Profile of Corvus and Environmental Factor that Bridges the Gap between Corvus albus and Man in Nsukka

Assessment of Plasma Biochemistry Profile of Corvus and Environmental Factor that Bridges the Gap between Corvus albus and Man in Nsukka

Measuring IGF-1 and IGFBP-3 profiles in women seeking assisted reproduction; relevance to clinical outcomes from in vitro fertilization (Study 5).

In this fifth study examining the relevance of the insulin-like growth factor (IGF) profiles, namely serum IGF-1 levels, its main binding protein, serum IGFBP-3 levels and the IGF ratio (IGFBP-3/IGF-1), we have examined clinical outcomes with respect to the quartile ranges of each parameter measured in 1633 IVF-naïve women. The outcomes were derived from 1035 of these women who initiated 1747 IVF cycles. Of the three parameters, only IGF-1 levels proved relevant to the clinical outcomes. In particular, this study confirmed our earlier report that IGF-1 levels decline across the quartiles with the woman’s advancing age and the proportion of women with IGF-1 levels in the highest quartile comprised the younger, whilst those women ≥40 years were mostly in the lowest quartile (p<0.0001). IVF cycle cancellations were not different across the quartiles but at oocyte pick-up (OPU) there were significantly more oocytes from the highest IGF-1 quartile (10.4 oocytes) compared to the lowest (8.9 oocytes; p<0.01). Furthermore, the proportion of oocytes shown to be at the mature MII stage were also significantly higher (p=0.01). Consequently, the oocyte utilization rate was significantly greater from those women with the highest IGF-1 levels generating 5.3 embryos vs 4.3 embryos for the lowest quartile. However, the utilization rate of those embryos generated were similar across the IGF-1 quartiles and there were similar rates of “freeze-all embryos”, albeit more women had increased monitoring for ovarian hyperstimulation risk, related to the higher egg numbers in the highest IGF-1 quartile. The most striking clinical outcomes were that of the pregnancy productivity rate (including fresh and frozen embryo transfers from a single OPU) which was greatest in the highest IGF-1 quartile (61.5% vs 48.2% per OPU across all ages p<0.0002). Miscarriage rates were not different but live birth productivity rates were significantly greatest for the highest IGF-1 quartile (49% vs 33% per OPU across all ages; p<0.0002). We conclude that a preliminary measurement of the IGF-1 level can help to define the poor-prognosis female prior to IVF treatment and on whom adjuvant studies can be focused.

The expression/methylation profile of adipogenic and inflammatory transcription factors in adipose tissue are linked to obesity related-colorectal cancer

The expression/methylation profile of adipogenic and inflammatory transcription factors in adipose tissue are linked to obesity related-colorectal cancer

Measuring IGF-1 and IGFBP-3 profiles in women seeking assisted reproduction; relationship to ovarian reserve parameters, namely AFC and AMH (study 2).

This is the second of five studies undertaken on women preparing for assisted reproduction, to sequentially examine the relevance of the insulin-like growth factor (IGF) profile (IGF-1, IGFBP-3 and the IGFBP-3/ IGF-1 ratio) which, in children, provides the essential criteria to identify the GH-deficient individual. Whilst our first, published study, focussed on clinical parameters, this study examines its relevance to the two parameters which define the ovarian reserve. The first, that of the antral follicle count (AFC), shows highly significant, sequential changes across 4 age groups ranging from high counts in the younger women <35 years and low counts in the older women, namely those aged 35-39 years, those aged 40-44 years and those aged ≥45 years (p<0.0001). Similarly, the serum levels of anti-Mullerian hormone (AMH), a later introduced marker of ovarian reserve, also showed highly significant sequential changes across the 4 age groups with high levels recorded in the young women and low counts in the older women (p<0.0001). At the higher AFC range, concordance between AFC groups and AMH groups was high at r=0.79 for precise matching and r=0.95 when neighbouring groups were included. The correlation was also clear with inter-quartile AMH levels ranging 27 pmol/L to 50 pmol/L across the higher AFC groups and 8 pmol/L to 10 pmol/L in the lowest groupings. However, IGF profiles showed no significant variations across the entire range, neither for the AFC nor for the AMH groups. Our next study will report on the relevance of the IGF profile to clinical outcomes.

Abstract 15488: Epidemiological Profile of Cardiovascular Risk Factors and Outcomes in Patients With Solid Organ and Haematological Malignancies

Introduction: Chemotherapy remains the cornerstone in the management of solid organ malignancies (SOM) and hematological malignancies (HM). Although life-prolonging, it is not without cost, with heart failure and arrhythmia becoming increasingly recognised complications of treatment. Although there is significant overlap in the chemotherapeutic management of SOM and HM, epidemiological information on the differential prevalence of baseline cardiovascular risk factors and outcomes in these populations is scarce. Hypothesis: A differential cardiovascular risk profile and clinical course will be appreciated in patients with SOM and HM undergoing chemotherapy. Methods: Retrospective observational study design. Patients admitted to our institution undergoing chemotherapy for SOM (2014-2018) or HM (2012-2015) were reviewed. Baseline demographic and clinical data was collated and patients were followed for up to five years following chemotherapy for occurrence of major adverse cardiac events (MACE) defined as the development of new-onset heart failure or arrhythmia. Results: 545 hematology and 435 oncology patients with malignancy were assessed. Compared to those with HM, those treated for SOM had a poorer cardiovascular risk profile (table 1). At mean follow-up period of 22.8±17.8 months, no significant difference in the incidence of the composite endpoint (9.4% vs 9.0%, p=0.45) or its components was observed. Higher rates of anthracycline therapy was observed in patients with HM (100% vs 17%, p < 0.01), however its use did not have a differential effect on MACE (12% vs 9%, p=0.25). Conclusions: Compared to patients treated for HM, patients with SOM had a greater burden of cardiovascular risk factors and lower use of anthracycline chemotherapy. Despite this, MACE occurred at similar rates in both groups. The use of anthracyclines was not associated with the development of MACE, suggesting alternative pathways contributing to its development.

Clinico-epidemiological, risk factor and angiographic profile of acute coronary syndrome within six hours of symptoms

Clinico-epidemiological, risk factor and angiographic profile of acute coronary syndrome within six hours of symptoms

Coronary artery calcification and cardiovascular outcomes after chest radiation therapy in breast cancer patients

Abstract Introduction Coronary artery calcification (CAC) is associated with and identifies patients at higher risk of major adverse cardiovascular events (MACE). However, the prevalence, characteristics, and outcomes of cancer patients with CAC on CT before or after chest radiation therapy (RT) are not well addressed. Methods Retrospective cohort study of all breast cancer patients who underwent chest RT at Mayo Clinic Rochester in 2010. All pre-RT CTs were reviewed and the extent of CAC was recorded in addition to history of pre-RT atherosclerotic risk factors (hypertension (HTN), diabetes mellitus (DM), dyslipidemia, and smoking), history of pre-RT cardiovascular disease (CVD), and RT dosage. MACE (sudden cardiac death (SCD), acute coronary syndrome (ACS), and stroke), and CAC progression in follow-up were recorded. CAC extent was quantified before and on 5-year follow-up CT scan in all patients, and a positive change was considered progression. Patients were divided into 2 groups based on the presence of CAC before RT: present (group 1) or absent (group 2). Results Our cohort was comprised of 244 breast cancer patients who received chest RT. A total of 39 patients (16.9%) had evidence of CAC on CT prior to RT. Compared with patients without CAC before RT (n=205), those with CAC before RT were found to be older (71.8±7.7 vs 58.9±11.3, p<0.01), had higher pre-RT history of HTN (84.6% vs 47.8%); p<0.01), DM (20.5% vs 4.4%; p<0.01), dyslipidemia (74.2% vs 40%; p<0.01), CAD (23.1% vs 3.9%; p<0.01), and stroke (7.69% vs 1.45%; p=0.04). Following RT, patients in group 1 were more likely to exhibit ACS (33.3% vs 2.9%; p<0.01), and stroke (22.6% vs 5.2%; p<0.01). Multinomial logistic regression identified pre-RT CAD pre-RT CAC (β=1.01 (0.33–1.69), OR=7.60 (1.93–29.93); p=0.02) pre-RT CAD (β=0.78 (0.06–1.49), OR=4.74 (1.14–19.74); p=0.03) as independent predictors for the development of MACE after RT. Progression in CAC after RT was found in 61.9% of all patients (13/21) who developed MACE. Conclusion MACE in breast cancer patients undergoing RT can be predicted before RT based on the CV risk factor and disease profile. The strongest predictor for MACE, however, is evidence of CAC before RT. These data provide a unique window for the identification and follow-up of breast cancer RT patients who have a risk of MACE. Funding Acknowledgement Type of funding source: None

Systemic profile of immune factors in an elderly Italian population affected by chronic strongyloidiasis

BackgroundStrongyloidiasis caused by Strongyloides stercoralis is a soil-transmitted helminthiasis affecting an estimated 370 million people and considered one of the most neglected tropical diseases. Although mostly distributed in tropical and subtropical areas, autochthonous infections have also been documented in north-eastern Italy, even though the transmission presumably stopped decades ago. Because of its peculiar auto-infective cycle, strongyloidiasis can persist lifelong, but the pathophysiological mechanisms associated with the maintenance of such a chronic infection are yet to be fully deciphered.MethodsSerum levels of 23 immune factors were retrospectively assessed in a subgroup of participants in a randomised clinical trial for the treatment of strongyloidiasis (Strong Treat). Here we included Italian subjects born between 1931 and 1964 and diagnosed with strongyloidiasis between 2013 and 2017 (Ss+, n = 32). Serum samples obtained before (BT) and 6 months (6M AT) after ivermectin treatment, as well as from age- and gender-matched uninfected controls (CTRL, n = 34) were analysed.ResultsThe assessed immune factors showed a general reduced concertation in Ss+ patients and a lack of association with eosinophilia. In our cohort, we did not observe the classical shift towards a type 2 immune response, since Th1 and Th2 cytokines were mostly unaltered. Instead, we observed chemokines as particularly affected by the presence of the parasite, since IL-8, CCL3, CCL4 and CCL5 were significantly reduced in concentration in Ss+ subjects compared to CTRL, suggesting that immune cell recruitment to the infection site might be dampened in these patients. This observation was further sustained by a significant increase of CCL4, CCL5 and CCL11 concentrations 6M AT. A significant raised systemic concentration of three growth factors, bFGF, PDGF-BB and IL-7 (haematopoietic growth factor) was also observed post-treatment, indicating a potential involvement in restoring tissue integrity and homeostasis following parasite elimination.ConclusionsThese preliminary data suggest that, in order to survive for such a long period, S. stercoralis might suppress host responses that could otherwise result in its ejection. Our results offer novel insights in the potential mechanisms of disease tolerance that might take place during this chronic infection, including a potential T-cell hypo-responsiveness and a role for chemokines.

BANΔIT: B'-Factor Analysis for Drug Design and Structural Biology.

The analysis of B‐factor profiles from X‐ray protein structures can be utilized for structure‐based drug design since protein mobility changes have been associated with the quality of protein‐ligand interactions. With the BANΔIT (B’‐factor analysis and ΔB’ interpretation toolkit), we have developed a JavaScript‐based browser application that provides a graphical user interface for the normalization and analysis of B’‐factor profiles. To emphasize the usability for rational drug design applications, we have analyzed a selection of crystallographic protein‐ligand complexes and have given exemplary conclusions for further drug optimization including the development of a B’‐factor‐supported pharmacophore model for SARS CoV‐2 main protease inhibitors. BANΔIT is available online at https://bandit.uni‐mainz.de. The source code can be downloaded from https://github.com/FBarthels/BANDIT.

Abstract 6565: Impact of TIM-3 modulation on the sensitivity of anti-PD-1

Abstract Concurrent inhibition of TIM-3 and PD-1 may have enhanced anti-tumor effects. In this study, computational models were established to identify factors involved in the interactions between these two immunotherapeutic targets. Abstracts published on TIM-3, PD-1, PD-L1, anti-PD-1/PD-L1 were downloaded from PubMed, and analyzed by natural language processing and text mining. Interactions among genes, compound/therapies, cell/animal models, pathway/disease, and clinical studies were retrieved from the text. Networks were constructed to simulate effects of TIM-3 inhibition on anti-PD-1. The TIM-3/anti-PD-1 network consists of 57 nodes, 175 interactions with 11,626 possible regulatory paths from TIM-3 to anti-PD-1. Overall, 6142 paths are associated with the agonistic interactions between TIM-3 inhibition and anti-PD-1, while 5484 are antagonistic. Factors associated with the enhancement of anti-PD-1 by TIM-3 inhibition include up-regulation of IL-2, IFN-gamma, Th1 cells/cytokines, CD8+ T cells or NK cells, and down-regulation of IL-10, NFkB-p65, COX2 or EMT. Treatments with either EGFR inhibitors (e.g. gefitinib), anti-CTLA-4, IL-2 agonist or radiation therapy may enhance the combination efficacy of TIM-3 and PD-1 inhibitors. On the other hand, CTLA-4, galectin-9, Wnt/beta-catenin or Tregs combined with TIM-3 over-expression may confer resistance to anti-PD-1. PD-L1 is a validated biomarker for anti-PD-1 response and its expression can be correlated with TIM-3. Similar text-mining approach was adopted to construct the TIM-3/PD-L1 network which consists of 65 nodes, 165 interactions and 1372 paths from TIM-3 to PD-L1. Up-regulation of either galectin-9, WNT/beta-catenin or Tregs by TIM-3 results in the induction of PD-L1. As the network analyses revealed, interactions between TIM-3 and PD-L1 are context dependent, and assessment of the effect of TIM-3 inhibition on anti-PD-1 requires profiling of multiple factors along the regulatory and signaling pathways. The TIM-3/PD-L1 and TIM-3/anti-PD-1 networks prove to be useful tools to facilitate the therapeutic development of TIM-3 and PD-1 inhibitors, especially for selecting patients with potential agonistic effects of this promising drug combination. Citation Format: Jian Zhu, Rebecca L. Zhu. Impact of TIM-3 modulation on the sensitivity of anti-PD-1 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6565.

Abstract 2071: Identification of FOXO1 as a tumor suppressor modulated by androgen receptor/estrogen receptor-βsignals: Implications for bladder cancer promotion and chemoresistance

Abstract Introduction and Objective: The androgen receptor (AR) and estrogen receptor-β (ERβ) pathways have been implicated in urothelial tumor outgrowth, as well as chemoresistance, for which underlying mechanisms are poorly understood. Therefore, the present study aims to identify downstream effectors of AR and ERβ signals and further investigate their role in bladder cancer promotion and chemosensitivity. Methods: We first performed a transcription factor (TF) profiling assay in an AR/ERβ-positive and ERα-negative bladder cancer line, UMUC3. We then performed in vitro and in vivo assays, using cell line and mouse models, as well as immunohistochemical staining in two sets of bladder cancer tissue microarray. Results: The TF array data in UMUC3 cells treated with mock versus synthetic androgen R1881 displayed that 14 out of 96 were down-regulated. Specifically, the expression levels of FOXC1, STAT4, and FOXO1 were reduced by >60%. Subsequent RT-PCR showed that dihydrotestosterone and estradiol treatment significantly down-regulated the expression of FOXO1 (58% and 28% decreases), but not that of STAT4 (22% and 2% decreases) or FOXC1 (10% and 2% decreases), respectively. Of note, our online search identified 6 and 3 putative binding sites of AR and ERβ, respectively, in the FOXO1 promoter region. In chemical carcinogen-induced models, FOXO1 knockdown via shRNA virus infection or inhibitor treatment resulted in considerable induction of the neoplastic transformation of urothelial cells or bladder cancer development in mice. Similarly, FOXO1 inhibition significantly induced the viability/migration/invasion of bladder cancer cells and reduced the cytotoxic effects of cisplatin. Finally, immunohistochemistry in surgical specimens showed down-regulation and up-regulation of the expression of FOXO1 and its phosphorylated inactive form (p-FOXO1), respectively, in bladder cancer tissues, which was further associated with patient outcomes. In a separate tissue microarray consisting of muscle-invasive bladder cancer specimens from patients who received cisplatin-based neoadjuvant chemotherapy, p-FOXO1 expression tended to correlate with chemoresistance (i.e. 41% of responders vs. 69% of non-responders; P=0.068). Conclusions: FOXO1 is found to be a potential tumor suppressor modulated by both AR and ERβ signals. FOXO1 signaling may thus represent a novel chemopreventive and/or therapeutic target for bladder cancer. Its inactivation may also be useful for overcoming chemoresistance. Citation Format: Hiroki Ide, Satoshi Inoue, Taichi Mizushima, Guiyang Jiang, Takuro Goto, Yujiro Nagata, Yuki Teramoto, George J. Netto, Mototsugu Oya, Hiroshi Miyamoto. Identification of FOXO1 as a tumor suppressor modulated by androgen receptor/estrogen receptor-βsignals: Implications for bladder cancer promotion and chemoresistance [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2071.