Individual Variation In Sensitivity Research Articles

Odor, air quality, and well-being: understanding the urban smellscape using crowd-sourced science

Abstract Odors are a topic of emerging environmental health interest given their potential links to air quality, health, well-being, and quality of life. However, odors have traditionally been challenging to study given variability in individual sensitivity and perception, atmospheric physico-chemical processes, and emissions of mixtures of odorous contaminants. Here, we explore the potential utility of crowd-sourced odor report data in improving understanding of spatiotemporal patterns of odor experiences and their impacts. We conduct quantitative and qualitative analyses of a 12-month data set from a web application collecting crowd-sourced odor reports, including spatiotemporal information, odor and self-reported impacts description (OSAC: odors, symptoms, actions in response, and suspected causes), and demographics, in Vancouver, Canada. Users report diverse OSAC with strong seasonality and spatial variability. Reported symptoms, ranging from neurological to emotion- and mood-related, highlight the complexity of odor-related health and well-being impacts. Odors can trigger maladaptive actions, where individuals are exposed to other environmental stressors (e.g. heat stress) or curtail healthy behaviors (e.g. exercising outside) to cope with odor impacts. Clustering analysis of OSAC suggests that odor exposures may be linked to health, well-being, and quality of life impacts through complex mechanisms, related not only to the odor experienced but also perceived causes. Spatiotemporal patterns in reports highlight the potential influence of persistent sources (e.g. waste management) and transient events (e.g. accidents). Exploratory multiple linear regression models suggest that monitoring of air quality and meteorology may be insufficient to capture odor issues. Overall, these results suggest that crowd-sourced science incorporating self-reported health and well-being effects and behavioral responses can enrich understanding of the impacts of odorous emissions at large spatiotemporal scales and complement traditional air pollution monitoring.

Exploring the association between oral tactile sensitivity measures and phenotypic markers of oral responsiveness.

This study investigated the individual variability in oral tactile sensitivity considering touch, by means of Von Frey Hair monofilaments (VFH) and spatial resolution, using the grating orientation test (GOT). The relationships of the two measures with 6-n-propylthiouracil (PROP) responsiveness and fungiform papillae density and size were investigated. One hundred and forty-four subjects (48.6% women, aged 18-30) participated in the study. VFH and GOT thresholds were assessed by three-down/one-up staircase method. Responsiveness to 3.2 mM PROP was assessed on the general Labeled Magnitude Scale. Fungiform papillae density (FPD) and size were determined from automated counting. VFH thresholds appeared unsuitable to reveal individual variation in responsiveness to point-pressure on the tongue. The frequency of GOT thresholds approximated a normal distribution and covered the whole range of variation, thus indicating an ability to measure individual variation in oral tactile sensitivity. No significant linear correlations were found between any of the oral tactile sensitivity measures and PROP responsiveness, FPD total and size class. VFH and GOT thresholds were not significantly associated. Agglomerative hierarchical clustering was used to classify participants for their PROP responsiveness, total FPD and GOT threshold. Three clusters were identified, C1 (n=67), Cl2 (n=42), and Cl3 (n=35), differing for PROP responsiveness and FPD only. Results encourage future studies to explore association between GOT and both perception and preference for different food texture. Furthermore, deeper investigation of individual variability in sensitivity to different types of oral tactile stimuli would be helpful to capture differences in tactile sensitivity among the most sensitive individuals.

Empathy but not musicality is at the root of musical reward: A behavioral study with adults and children

Music is one of the most pleasurable human experiences. However, the determinants of the variation in individual sensitivity to musical reward are not yet fully unraveled. Empathy has been identified as a determinant of musical affect, including consciously experiencing pleasure from listening to sad music. Additionally, higher musical expertise may enhance pleasurable responses to music, whereas aging decreases individual sensitivity to musical pleasure. We conducted a study to investigate the contribution of empathy and musical abilities on musical pleasure, measured by Interpersonal Reactivity Index, Musical Ear Test, and Barcelona Musical Reward Questionnaire, respectively. To this purpose, we performed a developmental comparison between 48 children (9–11 years old) and 42 adults (18–32 years old). Our findings suggest that individual sensitivity to musical reward is positively correlated with empathy trait in both adults and children, but not with musical abilities. However, when inserted in a regression model including empathy, musical abilities are also predictive of musical reward, but only among adults. These results show that empathy plays a crucial role in determining the individual sensitivity to music reward, whereas musical abilities are less influential. More broadly, this study contributes to shed light on the determinants of the emotional responses to music affect.

What drives phenological synchrony? Warm springs advance and desynchronize flowering in oaks

Annually variable and synchronous seed production, or masting, is often correlated with environmental factors and in oaks involves differential pollination success that depends on phenological synchrony in flowering. The synchronization of phenology of flowering was thought to be driven by temperature during flowering (microclimatic hypothesis). We tested an alternative, whereby phenological synchronization is driven by the timing of the onset of flowering (photoperiod-sensitivity hypothesis). This hypothesis assumes that flowering synchrony is driven by interaction between daylength and temperature, and individual variation in sensitivity to daylength as a phenological cue. We used long-term (23–26 years) records of airborne pollen in Quercus robur, Q. petraea, Q. ilex, and Q. humilis. Late pollen seasons were short, as predicted by photoperiod-sensitivity hypothesis. The onset of pollen seasons was delayed as preseason temperatures cooled over the last three decades at our Mediterranean sites, which was paralleled by shortening in pollen seasons, providing additional support for the photoperiod-sensitivity hypothesis. Global warming under the microclimatic hypothesis is predicted to lead to less frequent reproductive failures and thus decreased variability and synchrony of mast seeding. In contrast, warming under the photoperiod-sensitivity hypothesis should advance the onset of and desynchronize flowering, a pattern supported by our data. This pattern suggests that global warming will lead to more frequent vetoes and more stochastic and variable patterns of oak reproduction.

Intolerance of uncertainty, depression and the error-related negativity

Prior work has yielded contradictory findings regarding the association between depression and the error-related negativity (ERN), an event-related potential thought to reflect individual variation in sensitivity to internal threat (i.e., errors), and the error positivity (Pe), which is thought to reflect more elaborative, conscious processing of errors. One possibility is that variation in transdiagnostic dimensional constructs related to threat processing might help explain inconsistencies in the relationship between depression and the ERN and Pe. Here, we used a large, unselected sample (N = 100) to determine whether variation in intolerance of uncertainty (IU), a transdiagnostic trait dimension that is implicated in both depression and anxiety, might moderate associations between depressive symptomatology and error processing. Results showed that greater levels of depressive symptomatology were associated with larger ΔERNs (error minus correct trials) when IU was low, but were unrelated to ΔERN when IU was high; main effects of depression and IU on ΔERN were not observed. The Pe was not associated with IU or depression. Additionally, IU, but not depression, was associated with faster response times on error and correct trials. Overall, results suggest that error processing may differ for individuals with elevated depression with versus without elevated IU. Moreover, prior failures to observe associations between depression and the ERN might stem from failure to account for related transdiagnostic constructs.

Higher scores on the Mini-K life history battery are associated with greater disgust sensitivity on the three domains of disgust scale

Disgust is a universal emotion that promotes protective behaviors in three distinct domains: sexual, moral, and pathogenic. There is considerable individual variation in sensitivity to disgust, and past research suggests individuals with slower life history strategies are more sensitive to stimuli that provoke pathogen and moral disgust. We hypothesized that such individuals would also be more sensitive to disgust in a sexual context. Two hundred seventyseven participants completed the Mini-K Life History Battery and the Three Domains of Disgust Scale. A slower life history strategy (as reflected by a higher Mini-K score) was associated with increased sensitivity to sexual, pathogen, and moral disgust. Removal of items with potential overlap did not affect the significance of the results. These findings suggest that the K-factor of life history is associated with increased disgust sensitivity across all three domains.

Revisiting baclofen in the treatment of alcoholism: just a question of enantiomer?

The benefit-risk balance of the GABA (α-aminobutyric acid)-B receptor agonist baclofen in the treatment of alcohol addiction is still controversial not only because the efficacy has not been clearly demonstrated but also because of the recent safety concern. Most of the preclinical and clinical studies used the racemic baclofen [RS(±)-baclofen], however, recent data showed that the effect of baclofen on alcohol intake may be enantiomer dependent. Here we used the gold standard animal model of alcohol dependence with the aim of analyzing the effects of the RS-baclofen and its enantiomers, R-baclofen and S-baclofen, on different alcohol-related behaviors. We showed that: – R-Bac was more effective than RS-Bac in suppressing alcohol intake, while S-Bac failed to affect alcohol consumption. – The effects of R-Bac and RS-Bac (1.5 and 2 mg/kg, respectively) on alcohol intake were not explained by any motor impairment. – Some animals (around 27%) were less sensitive to the effects of R-Bac (1.5 mg/kg). Also, there was a negative correlation between the efficacy of this dose and the motivation for alcohol. – R-Bac (1 mg/kg, IP) suppressed intake for both nondependent and dependent animals. However, the sensitivity to this dose was reduced in dependent rats. In conclusion, our results suggest that R-Bac could be a potentially more effective medication than RS-Bac in the treatment of alcohol dependence, and actually our studies are focused on the individual variability in sensitivity to blaclofen.

Molecularly diverse odors advance olfactory threshold testing

AbstractMultiple‐compound mixtures of odorants are likely to produce significantly more reliable and favorable results of olfactory sensitivity testing. Within the current study, we aimed to investigate this hypothesis and determine the optimal number of odor compounds within a testing stimulus. One‐hundred individuals volunteered to participate in the study procedure wherein their olfactory threshold was measured with stimuli varying in the number of compounds during two sessions. We found that molecularly varied stimuli made olfactory threshold assessments relatively independent from an individual variability in sensitivity to specific odorants. Nevertheless, this was only true in certain conditions—depending on the number of components and quality of the odorants. On this basis, we outline future directions for studies aimed to advance assessments of the olfactory threshold by discussing the relationships between the chemical and physical properties of odorants and results of the threshold assessment they produce.Practical applicationsThis study provides empirical evidence that olfactory threshold testing becomes more favorable and reliable when an odor stimulus contains ~10 types of molecules. This is assumed due to an efficient activation of olfactory receptors. These findings advance the current state of knowledge in the field of biology by presenting behavioral responses to the augmented potential for binding molecules through olfactory receptors. Results presented in this manuscript constitute a significant improvement in the methods of olfactory function assessments and should be of interest to both scientific and clinical audience in the fields of neuroscience, chemosensory research, chemistry, and biology. These results are likely to translate to a more accurate assessment of olfactory abilities in commercial settings, that is, perfumes, or wine experts.

Visual discomfort indoors

Visual discomfort refers to discomfort or pain in or around the eyes, often associated with headache and/or nausea, and sometimes accompanied by signs such as red, itchy or watering eyes. The lighting conditions likely to cause visual discomfort are insufficient light for the task at hand, dramatic differences in illuminance around the task, shadows, veiling reflections, glare and flicker. To date, research on visual discomfort has been largely reactive, i.e. in response to complaints, but there is now proactive work that explores why discomfort occurs. The hypothesis underlying this work is that the human visual system has evolved to extract information from the natural world efficiently so that when the visual environment departs from the temporal, spatial or chromatic characteristics of the natural world, discomfort is likely because of inefficient neural processing. An important implication is that visual discomfort therefore depends on both the lighting and the décor of a space. Until this approach becomes more established, visual discomfort can be minimised by following carefully developed standards and guidance, by using products that meet appropriate standards, by paying attention to both lighting and décor and by being aware of the wide variation in individual sensitivity.

Physiological determinants of individual variation in sensitivity to an organophosphate pesticide in Nile tilapia Oreochromis niloticus

Individual variation in sub-lethal sensitivity to the organophosphate pesticide trichlorfon was investigated in Nile tilapia, using critical swimming speed (Ucrit) as an indicator. Tilapia exposed for 96h to 500μgl−1 trichlorfon at 26°C (Tcfn group, n=27) showed a significant decline in mean Ucrit, compared to their own control (pre-exposure) performance in clean water (−14.5±2.3%, mean±SEM), but also compared to a Sham group (n=10) maintained for 96h in clean water. Individuals varied in their relative sensitivity to the pesticide, with the decline in Ucrit after exposure varying from 1 to 41%. The Ucrit of the Tcfn group did not recover completely after 96h in clean water, remaining 9.4±3.2% below their own control performance. The decline in performance was associated with a significant increase in net cost of aerobic swimming, of +28.4±6.5% at a sustained speed of 2bodylengthss−1, which translated into a significant decline in swimming efficiency (Eswim) of −17.6±4.0% at that speed. Within the Tcfn group, individual Eswim was a strong positive determinant of individual Ucrit across all trials, and a strong negative determinant of individual% decline in Ucrit after pesticide exposure (P<0.001, linear mixed effect models). Trichlorfon had no effects on standard metabolic rate or active metabolic rate (AMR) but, nonetheless, individual Ucrit in all trials, and% decline in Ucrit after exposure, were strongly associated with individual AMR (positively and negatively, respectively, P<0.001). Individual Ucrit under control conditions was also a strong positive determinant of Ucrit after trichlorfon exposure (P<0.001), but not of the% decline in Ucrit performance. In conclusion, the OP pesticide impaired Ucrit performance by reducing Eswim but individual tilapia varied widely in their relative sensitivity. Intrinsic individual physiology determined effects of the pesticide on performance and, in particular, good swimmers remained better swimmers after exposure.

Reproductive activity triggers accelerated male mortality and decreases lifespan: genetic and gene expression determinants in Drosophila.

Reproduction and aging evolved to be intimately associated. Experimental selection for early-life reproduction drives the evolution of decreased longevity in Drosophila whereas experimental selection for increased longevity leads to changes in reproduction. Although life history theory offers hypotheses to explain these relationships, the genetic architecture and molecular mechanisms underlying reproduction-longevity associations remain a matter of debate. Here we show that mating triggers accelerated mortality in males and identify hundreds of genes that are modulated upon mating in the fruit fly Drosophila melanogaster. Interrogation of genome-wide gene expression in virgin and recently mated males revealed coherent responses, with biological processes that are upregulated (testis-specific gene expression) or downregulated (metabolism and mitochondria-related functions) upon mating. Furthermore, using a panel of genotypes from the Drosophila Synthetic Population Resource (DSPR) as a source of naturally occurring genetic perturbation, we uncover abundant variation in longevity and reproduction-induced mortality among genotypes. Genotypes displayed more than fourfold variation in longevity and reproduction-induced mortality that can be traced to variation in specific segments of the genome. The data reveal individual variation in sensitivity to reproduction and physiological processes that are enhanced and suppressed upon mating. These results raise the prospect that variation in longevity and age-related traits could be traced to processes that coordinate germline and somatic function.

A Review of the Evidence Supporting the Taste of Non‐esterified Fatty Acids in Humans

AbstractDietary fats contribute to the flavor of foods by multiple mechanisms. A role for their taste has only recently gained credence. Current evidence indicates non‐esterified fatty acids (NEFA) are the effective stimuli for the taste component. CD36 and GPR120 are putative receptors, but may not fully account for the totality of the range of sensations elicited by fatty acids. The sensory quality of long‐chain NEFA is not adequately characterized by commonly accepted taste primary qualities and has been termed oleogustus. There is marked individual variability in sensitivity to the taste of NEFA prompting hypotheses of genetic and environmental determinants. Though an association with BMI has been proposed, the preponderance of evidence is not supportive. The importance of oleogustus has not been fully established, but likely contributes to flavor, which influences food choice as well as lipid metabolism and chronic disease risk. A better understanding of oleogustus may provide insights useful for product formulation.

EP 134. Effect of transcranial random noise stimulation depends on sensitivity to sham stimulation

Introduction Tranccranial random noise stimulation (tRNS) induces a consistent excitability increase lasting at least 60 min after 10 min of stimulation, as demonstrated by both physiological measures and behavioural Tasks ( Terney et al., 2008 ). The present study tests whether the tRNS-induced changes in corticospinal excitability varies as a function of individual differences in sensitivity to sham stimulation. Methods The study was approved by the Ethic Committee of the Faculty of Medicine Christian-Albrechts University Kiel. 24 participants, aged between 18 and 30 years, participated in the study. All subjects were right-handed according to the Edinburgh handedness inventory ( Oldfield, 1971 ). Stimulation techniques : tRNS (1 mA, 10 min) was applied through a pair of saline-soaked surface sponge electrodes (5 × 7 cm). The minimum period between sessions for a single subject was 7 days, and sessions were applied in randomized order. Monitoring of motor cortical excitability: To examine changes in corticospinal excitability, motor evoked potentials (MEPs) of the right first dorsal interosseous muscle (FDI) were recording following stimulation of its motor-cortical representation field by single-pulse TMS. For further analysis we divided three subgroups according to excitatory (‘Excitatory group’, n = 9), inhibitory (‘Inhibitory group’, n = 7) or no respond (‘Non responder group’, n = 8) to sham- stimulation (Wilcoxon signed-rank test for dependent sampling). For this, we compared the MEP-amplitude in mean of the three time points after stimulation with the MEP-amplitude in mean before. Results In all subjects the tRNS was well tolerated. The general finding of present study is that sensitivity to sham stimulation has impact on effect of tRNS; namely, ‘Excitatory group’ resulted in inhibition of tRNS, whereas inhibitory group shows excitation of tRNS. For ‘Non responder group’ the 1 mA tRNS resulted in a significant increase of MEP amplitudes compared to sham stimulation, which is consistent with the literature Conclusion Accounting for variation in individual sensitivity to sham stimulation, stimulation may influence the utility of tRNS as a tool for understanding brain-behavior interactions and as a method for clinical interventions.

Efficacy of Anodal Transcranial Direct Current Stimulation is Related to Sensitivity to Transcranial Magnetic Stimulation.

Transcranial direct current stimulation (tDCS) has become an important non-invasive brain stimulation tool for basic human brain physiology and cognitive neuroscience, with potential applications in cognitive and motor rehabilitation. To date, tDCS studies have employed a fixed stimulation level, without considering the impact of individual anatomy and physiology on the efficacy of the stimulation. This approach contrasts with the standard procedure for transcranial magnetic stimulation (TMS) where stimulation levels are usually tailored on an individual basis. The present study tests whether the efficacy of tDCS-induced changes in corticospinal excitability varies as a function of individual differences in sensitivity to TMS. We performed an archival review to examine the relationship between the TMS intensity required to induce 1 mV motor-evoked potentials (MEPs) and the efficacy of (fixed-intensity) tDCS over the primary motor cortex (M1). For the latter, we examined tDCS-induced changes in corticospinal excitability, operationalized by comparing MEPs before and after anodal or cathodal tDCS. For comparison, we performed a similar analysis on data sets in which MEPs had been obtained before and after paired associative stimulation (PAS), a non-invasive brain stimulation technique in which the stimulation intensity is adjusted on an individual basis. MEPs were enhanced following anodal tDCS. This effect was larger in participants more sensitive to TMS as compared to those less sensitive to TMS, with sensitivity defined as the TMS intensity required to produce MEPs amplitudes of the size of 1 mV. While MEPs were attenuated following cathodal tDCS, the magnitude of this attenuation was not related to TMS sensitivity nor was there a relationship between TMS sensitivity and responsiveness to PAS. Accounting for variation in individual sensitivity to non-invasive brain stimulation may enhance the utility of tDCS as a tool for understanding brain-behavior interactions and as a method for clinical interventions.

MOLECULAR AND CELLULAR ASPECTS OF DIOXIN TOXICITY

Background: Using methods of molecular toxicology to study dioxin intoxication consequences the contribution was accessed of pathologic alterations induced and manifested by specific biomarkers and ecogenetic effects among Vietnamese population living on contaminated territories. The causes of variability in individual sensitivity to toxic activity were also evaluated. Materials and methods: Individual biomedical indices were compared between those living in contaminated with dioxins (n =8142) and control (n =4421) regions. Dioxin concentrations were measured by high resolution chromato-mass spectrometry (84 samples). The characteristics of cytochrome P-450 system state (94 persons) and cytogenetic parameters (368 persons, 331 450 cells) reflected the molecular and genetic effects. Variable sensitivity to dioxins was demonstrated by associations of genetic polymorphism (CYP1A1, GSTM1, GSTT1, n =195) and congenital morphogenetic variants among children (n =1734). Results: Numerous consequences were demonstrated among the exposed individuals: noticeable absobtion of dioxins from environmental objects; direct effects of P-450 system’s induction; systemic alterations in nucleus and genetic stability; changes in cellular generation’s rate. The associations were revealed of genetic polymorphism in xenobiotic biotransformation / detoxification system and the peculiarities of development and morphogenesis among exposed children. Conclusion: Characteristics of population chronicle intoxication with dioxins permitted to describe its numerous preclinical and clinical manifestations, to show the key elements in pathogenesis of revealed alterations. Future investigations are to create the groundwork for developing a method for prevention of dioxin pathology induction and realization based on revealing preclinical signs and effects of intoxication.

The perceptual properties of the virgin olive oil phenolic oleocanthal are not associated with PROP taster status or dietary intake

Oleocanthal, has been identified as the sole oropharyngeal irritant in virgin olive oil with large individual variation in the perceived intensity of irritation. In this study participants were screened for sensitivity to the oropharyngeal irritation of oleocanthal and bitterness of 6-n-propylthiouracil (PROP), and categorized as hypersensitive (extremely sensitive) or hyposensitive (extremely insensitive). In addition, we determined if a relationship existed between sensitivity to oleocanthal and PROP and dietary intake. Participants (n=168) took part in the initial screening for irritation to oleocanthal (gLMS range 1.70–70.31). From this sample 87 participants also completed a 4-day diet diary and rated the intensity of oropharyngeal irritation of olive oil and the bitterness of PROP using a gLMS scale. There was large variability in the perceived intensity of irritation from olive oil (gLMS range 4.26–57.15) and the perceived bitterness of PROP (gLMS range 0.0–62.52) with no association between PROP sensitivity and oleocanthal irritation (r=−0.04, p=0.71). We report no relationship between oleocanthal sensitivity and total energy intake (r=0.13, p=0.29), carbohydrate intake (r=0.12, p=0.92), protein intake (r=−0.11, p=0.37), or fat intake (r=0.14, p=0.22). There was no association between PROP sensitivity and total energy intake (r=−0.08, p=0.46), carbohydrate intake (r=0.12, p=0.31), protein intake (r=0.12, p=0.32), or fat intake (r=−0.08, p=0.53). We did find a significant negative correlation between PROP sensitivity status and the intake of broccoli (r=−0.24, p<0.05). In the present study individual variation in sensitivity to the irritation of virgin olive oil or bitterness of PROP was not related to diet with the exception of PROP sensitivity and broccoli intake.

Addiction resistance: Definition, validation and association with mastery

BackgroundFor given levels of psychoactive substance use, symptoms of substance use disorder (SUD) can vary widely. The concept of addiction resistance (AR) seeks to capture this variation so we can understand its causes. MethodsIn a population-based twin sample, AR was defined as the deviation in the number of reported SUD criteria for a given substance from that predicted from the level of maximal consumption. Therefore, subjects with strong AR demonstrate few symptoms of SUD even at high levels of consumption. Twin modeling was performed by Mx. ResultsWe assessed AR for alcohol, nicotine and cannabis. Heritability was assessed at two occasions thereby correcting for measurement error and ranged from 35 to 52% with no evidence for shared environment. ARs for alcohol, nicotine and cannabis were relatively stable over time and were substantially predicted by parental history of SUD, early adversity, comorbidity with both internalizing and externalizing disorders, personality and especially by the trait of mastery. ConclusionsAR, which assesses individual variation in sensitivity to the development of SUD for a given level of drug exposure, may be a useful concept for addiction research. As applied to common psychoactive substances, AR is moderately heritable, relatively stable and predicted by family history, comorbidity and personality. The relationship with mastery is of particular interest in that it may reflect an ability to resist the progression of the addictive process into key life domains and to avoid loss of control of intake, even when consuming at high levels.

Radiogenomics helps to achieve personalized therapy by evaluating patient responses to radiation treatment

Radiogenomics is the whole genome application of radiogenetics, which focuses on uncovering the underlying genetic causes of individual variation in sensitivity to radiation. There is a growing consensus that radiosensitivity is a complex, inherited polygenic trait, dependent on the interaction of many genes involved in multiple cell processes. An understanding of the genes involved in processes such as DNA damage response and oxidative stress response, has evolved toward examination of how genetic variants, most often, single nucleotide polymorphisms (SNPs), may influence interindividual radioresponse. Many experimental approaches, such as candidate SNP association studies, genome-wide association studies and massively parallel sequencing are being proposed to address these questions. We present a review focusing on recent advances in association studies of SNPs to radiotherapy response and discuss challenges and opportunities for further studies. We also highlight the clinical perspective of radiogenomics in the future of personalized treatment in radiation oncology.

Association between autoimmune disease and cutaneous melanoma with regard to melanoma prognosis.

An association between autoimmune disease and malignant melanoma (MM) has often been reported in the literature as a positive prognostic factor for MM. Consequently, we evaluated the influence of different autoimmune diseases on the prognosis of MM. To evaluate the prognosis of patients with MM who also had an autoimmune disorder, whether tumour-associated, paraneoplastic or drug-induced. Autoimmune diseases were classified and analysed as tumour-associated, paraneoplastic or drug-induced. Patients were enrolled according to their clinicopathological features and matched with control groups. Kaplan-Meier analysis was used to estimate disease-free survival (DFS) and overall survival (OS), and log-rank test was used to evaluate differences between the survival curves. In total, 49 patients with MM and tumour-associated autoimmune disease were included in our analysis. No case of paraneoplastic autoimmune disease was detected. The survival analyses showed a range of results, from a worsening of DFS and OS to a lack of any difference. In a second analysis, we separately analysed patients who developed autoimmune disorders after starting adjuvant therapy with interferon-α; we did not find significant differences between these patients and the untreated patients. Autoimmune disease, whether tumour-associated or drug-induced, was not associated with better prognosis in patients with MM. The results suggest that the reported relationship between autoimmunity and MM may be a result of individual variation in sensitivity to the autoimmune disease, the tumour or the treatments.

Abstract 2020: Spheroid culture of primary colorectal cancer cells from liver metastases as an in vitro model of patient tumors

Abstract More than 65 % of patients with colorectal cancer require chemotherapeutic treatment during the course of their disease. However, colorectal tumors demonstrate pronounced heterogeneity, leading to significant individual variation in sensitivity to standard chemotherapeutic drugs. Tools for assessing chemosensitivity and tailoring therapeutic regimens to the individual patient are therefore urgently needed. A promising approach is to isolate viable cancer cells from patient tissue and to test the chemosensitivity of the individual tumor in vitro. The aim of the current study was to establish primary colorectal cancer cell cultures from patient liver metastases and investigate if the cultured cells retained important characteristics of the original tumor. Small cell clusters were isolated from metastatic tissue and allowed to form cell spheroids in suspension culture. The cell composition of patient spheroids was characterized by immunostaining with cell type specific antibodies. Cancer stem cells were identified by staining for the markers CD44, CD166 and Lgr5. Spheroid size was monitored over time and growth curves established for each patient. The distribution of proliferating and apoptotic cells in the spheroids was assessed by staining for specific markers. Overall, the 3-D culture system was verified as a tumor model by comparing the results obtained for the spheroids to paraffin-embedded sections of the original tumors. Successful spheroid culture was obtained from more than 80 % of tissue samples. Immunostaining confirmed that the primary cultures were composed of epithelial cells with minimal contamination by other cell types. Cell morphology and expression of intestinal markers confirmed their malignant nature and colorectal origin. The dominating cell populations of the original tumor could generally be identified in the derived spheroids as well. The spheroids demonstrated significant growth in vitro with no decrease in proliferation or increase in apoptosis during short-term culture. In summary, spheroid cultures of colorectal cancer cells can be established from liver metastases of individual patients with a high success rate and the spheroids retain important cellular characteristics of the original tumor. Spheroid culture therefore represents a promising technique for establishing primary cultures for chemotherapeutic screening of the individual patient. Citation Format: Maria Jeppesen, Grith Hagel, Ben Vainer, Henrik Harling, Ole Thastrup, Lars Nannestad Jorgensen, Jacob Thastrup. Spheroid culture of primary colorectal cancer cells from liver metastases as an in vitro model of patient tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2020. doi:10.1158/1538-7445.AM2014-2020