•No technical bias between fresh frozen and FFPE samples.•A high fraction of adenocarcinoma patients with activating KRAS mutations.•Mutations in TP53, STK11 and SMARCA4 linked to poor prognosis in ...adenocarcinoma.•Mutations in CSMD3 linked to better prognosis in squamous cell carcinoma.•Co-mutations in TP53 or STK11 confer poor prognosis in KRAS positive patients.
Non-small cell lung cancer (NSCLC) is a heterogeneous disease with unique combinations of somatic molecular alterations in individual patients, as well as significant differences in populations across the world with regard to mutation spectra and mutation frequencies. Here we aim to describe mutational patterns and linked clinical parameters in a population-based NSCLC cohort.
Using targeted resequencing the mutational status of 82 genes was evaluated in a consecutive Swedish surgical NSCLC cohort, consisting of 352 patient samples from either fresh frozen or formalin fixed paraffin embedded (FFPE) tissues. The panel covers all exons of the 82 genes and utilizes reduced target fragment length and two-strand capture making it compatible with degraded FFPE samples.
We obtained a uniform sequencing coverage and mutation load across the fresh frozen and FFPE samples by adaption of sequencing depth and bioinformatic pipeline, thereby avoiding a technical bias between these two sample types. At large, the mutation frequencies resembled the frequencies seen in other western populations, except for a high frequency of KRAS hotspot mutations (43%) in adenocarcinoma patients. Worse overall survival was observed for adenocarcinoma patients with a mutation in either TP53, STK11 or SMARCA4. In the adenocarcinoma KRAS-mutated group poor survival appeared to be linked to concomitant TP53 or STK11 mutations, and not to KRAS mutation as a single aberration. Similar results were seen in the analysis of publicly available data from the cBioPortal. In squamous cell carcinoma a worse prognosis could be observed for patients with MLL2 mutations, while CSMD3 mutations were linked to a better prognosis.
Here we have evaluated the mutational status of a NSCLC cohort. We could not confirm any survival impact of isolated driver mutations. Instead, concurrent mutations in TP53 and STK11 were shown to confer poor survival in the KRAS-positive adenocarcinoma subgroup.
Abstract
The aim of this study was to examine the validity of the Gender Dysphoria (GD) diagnoses in the Swedish National Patient Register (NPR), to discuss different register-based definitions of GD ...and to investigate incidence trends. We collected data on all individuals with registered GD diagnoses between 2001 and 2016 as well as data on the coverage in the NPR. We regarded gender confirming medical intervention (GCMI) as one proxy for a clinically valid diagnosis and calculated the positive predictive value (PPV) for receiving GCMI for increasing number of registered GD diagnoses. We assessed crude and coverage-adjusted time trends of GD during 2004–2015 with a Poisson regression, using assigned sex and age as interaction terms. The PPV for receiving GCMI was 68% for ≥ 1 and 79% for ≥ 4 GD-diagnoses. The incidence of GD was on average 35% higher with the definition of ≥ 1 compared to the definition of ≥ 4 diagnoses. The incidence of GD, defined as ≥ 4 diagnoses increased significantly during the study period and mostly in the age categories 10–17 and 18–30 years, even after adjusting for register coverage. We concluded that the validity of a single ICD code denoting clinical GD in the Swedish NPR can be questioned. For future research, we propose to carefully weight the advantages and disadvantages of different register-based definitions according to the individual study’s needs, the time periods involved and the age-groups under study.
High neuroticism is related to cardiovascular morbidity. Early detection of metabolic and cardiovascular risk is important in high-risk groups to enable preventive measures. The aim of this study was ...therefore to explore if neuroticism is associated with early biomarkers for cardiovascular and metabolic disease in young adults from a psychiatry cohort. Blood samples and self-ratings on neuroticism with the Swedish universities Scales of Personality (SSP) questionnaire were collected from 172 psychiatric outpatients and 46 healthy controls. The blood samples were analysed for plasma leptin, adiponectin, CRP, IL-6 and TNF-α. Associations between neuroticism and biomarkers were assessed using Spearman's correlation coefficients and generalized linear models adjusting for confounders. In the adjusted generalized linear models, neuroticism predicted the leptin/adiponectin ratio (p = 0.003), leptin (p = 0.004) and IL-6 (p = 0.001). These associations were not better explained by current major depressive disorder and/or anxiety disorder. Adiponectin, CRP and TNF-α were not associated with neuroticism. In conclusion, the findings suggest that high neuroticism is related to elevated levels of plasma leptin/adiponectin ratio, leptin and IL-6 in young adults. Young adults with high neuroticism may therefore benefit from preventive interventions to decrease the risk for future metabolic and cardiovascular morbidity, but more research is required to test this hypothesis.
One strategy to combat antimicrobial resistance is the discovery of new classes of antibiotics. Most antibiotics will at some point interact with the bacterial membrane to either interfere with its ...integrity or to cross it. Reliable and efficient tools for determining the dissociation constant for membrane binding (K
) and the partitioning coefficient between the aqueous- and membrane phases (K
) are therefore important tools for discovering and optimizing antimicrobial hits. Here we demonstrate that microscale thermophoresis (MST) can be used for label-free measurement of K
by utilising the intrinsic fluorescence of tryptophan and thereby removing the need for chromophore labelling. As proof of principle, we have used the method to measure the binding of a set of small cyclic AMPs to large unilamellar vesicles (LUVs) and two types of lipid nanodiscs assembled by styrene maleic acid (SMA) and quaternary ammonium SMA (SMA-QA). The measured K
values correlate well with the corresponding measurements using surface plasmon resonance (SPR), also broadly reflecting the tested AMPs' minimal inhibition concentration (MIC) towards S. aureus and E. coli. We conclude that MST is a promising method for fast and cost-efficient detection of peptide-lipid interactions or mapping of sample conditions in preparation for more advanced studies that rely on expensive sample preparation, labelling and/or instrument time.
There is a lack of agreement on whether children and adolescents with different cultural/ethnic backgrounds react to trauma in a similar fashion. This study adds to the existing literature by ...providing ethnicity and gender perspectives on the longitudinal associations between the degree of community violence exposure (CVE) and mental health problems in U.S. inner-city youth. The study was conducted on a representative sample of predominantly ethnic minority youth (N = 2,794; 54.1% female; age 11–16 years old (M SD = 12.77 1.29); 60.0% African-American, 26.1% Hispanic American, 13.9% White). Self-reported information was obtained on CVE in year 1 and on mental health problems (depressive symptoms, posttraumatic stress, alcohol use, and conduct problems) in year 1 and year 2. Multivariate analyses of covariance (MANCOVA) were used to compare mental health problems in youth from the three ethnic groups in relation to the different degrees of CVE experienced one year prior, while controlling for their baseline mental health problem levels, age, and socio-economic status. Mental health problems in year 2 increased in a similar fashion in relation to the degree of severity of CVE in year 1 in all three ethnic groups. The interaction effects suggested a gender-specific response to CVE, where girls in the three ethnic groups reported higher levels of depression and posttraumatic stress in relation to the same degree of CVE, as compared to boys. Adolescents from different ethnic backgrounds respond similarly to differing degrees of CVE with an increase in mental health problems over time. In response to a similar degree of exposure, girls tend to experience greater levels of internalizing problems than boys. Timely recognition of traumatic exposure and associated mental health problems is important for early prevention and intervention strategies.
Tumor‐associated macrophages (TAMs) are attractive targets for immunotherapy. Recently, studies in animal models showed that treatment with an anti‐TAM antibody directed against the scavenger ...receptor MARCO resulted in suppression of tumor growth and metastatic dissemination. Here we investigated the expression of MARCO in relation to other macrophage markers and immune pathways in a non‐small cell lung cancer (NSCLC) cohort (n = 352). MARCO, CD68, CD163, MSR1 and programmed death ligand‐1 (PD‐L1) were analyzed by immunohistochemistry and immunofluorescence, and associations to other immune cells and regulatory pathways were studied in a subset of cases (n = 199) with available RNA‐seq data. We observed a large variation in macrophage density between cases and a strong correlation between CD68 and CD163, suggesting that the majority of TAMs present in NSCLC exhibit a protumor phenotype. Correlation to clinical data only showed a weak trend toward worse survival for patients with high macrophage infiltration. Interestingly, MARCO was expressed on a distinct subpopulation of TAMs, which tended to aggregate in close proximity to tumor cell nests. On the transcriptomic level, we found a positive association between MARCO gene expression and general immune response pathways including strong links to immunosuppressive TAMs, T‐cell infiltration and immune checkpoint molecules. Indeed, a higher macrophage infiltration was seen in tumors expressing PD‐L1, and macrophages residing within tumor cell nests co‐expressed MARCO and PD‐L1. Thus, MARCO is a potential new immune target for anti‐TAM treatment in a subset of NSCLC patients, possibly in combination with available immune checkpoint inhibitors.
What's new?
Because of their dual anti‐ and proinflammatory role, tumor‐associated macrophages (TAMs) are attractive targets for immunotherapy. Treatment with antibodies targeting the scavenger receptor MARCO has previously been shown to result in a more proinflammatory macrophage phenotype and reduced tumor growth. Here, the authors show that MARCO defines a distinct subset of immune‐suppressive TAMs in a large lung cancer cohort. A higher macrophage infiltration was observed in tumors expressing PD‐L1, and transcriptomic data revealed a correlation between MARCO, checkpoint molecules and T‐cell infiltration. MARCO could thus be a potential new immune target for anti‐TAM treatment in a subset of NSCLC patients.
Few studies have addressed gender differences in autism in relation to functioning and across cultures. We aimed to explore functional gender differences in autism from a multidisciplinary, global ...perspective using the International Classification of Functioning, Disability, and Health. Perceptions among professionals in high-income countries and middle-income countries were examined based on qualitative survey data from N = 225 professionals. Of these, n = 131 professionals provided information on functional gender differences in autism. Thirty-two professionals reported perceiving no gender differences. Remaining respondents (n = 99)—representing 31 countries, all World Health Organization regions, and 10 different professions—were included in a content analysis on functional gender differences, which generated three main categories and 13 subcategories. The subcategories were subsequently linked to International Classification of Functioning, Disability, and Health categories. Autistic males were described as displaying more externalizing behaviors, and females as having more internalizing problems and being more socially motivated. Thirty-two International Classification of Functioning, Disability, and Health categories were identified, of which 31 were covered by the comprehensive Core Set for autism. Gender differences in core symptoms and co-existing problems were acknowledged by professionals from both high-income countries and middle-income countries, while differences in social behaviors, including camouflaging, were more frequently described by experts from high-income countries.
Lay abstract
In this study, we explored if professionals working with autistic people in different regions of the world perceive differences between females and males diagnosed with the condition. A total of 131 professionals responded to a survey that included an open question about gender differences in autism. Of these, 32 responded that they do not perceive gender differences in autism. The information provided by the other 99 experts was analyzed to identify common patterns. Three main differences were found, (1) Matching the clinical conceptualization of autism where professionals described differences in core symptoms of autism, and that autistic females were less similar to the conceptualization of autism. In (2) Co-existing problems, professionals described that autistic males display more apparent problems including hyperactivity, while autistic females were perceived as having more internalizing issues such as anxiety and eating disorders. In the last category, (3) Navigating the social environment, experts perceived autistic females as more socially motivated, and more inclined to camouflage social difficulties, making their challenges less evident. Professionals also perceived differences in the social environment, for example, that autistic girls receive more support from their peers while autistic boys are more often bullied. Our results suggest that professionals working in different parts of the world acknowledge gender differences in autism, but also that there might be some regional differences. Finally, we found that gender differences reported by the international professionals could largely be assessed with a shortened version of the International Classification of Functioning by the World Health Organization, specifically developed for autism.
The aim of this study was to investigate the clinical value of liquid biopsy as a primary source for variant analysis in lung cancer. In addition, we sought to characterize liquid biopsy variants and ...to correlate mutational load to clinical data.
Circulating cell-free DNA was extracted from plasma from patients with lung cancer (n = 60) and controls with benign lung disease (n = 16). Variant analysis was performed using the AVENIO ctDNA Surveillance kit and the results were correlated to clinical and variant analysis data from tumor tissue or cytology retrieved from clinical routine diagnostics.
There were significantly more variants detected in lung cancer cases compared to controls (p = 0.011), but no difference between the histological subgroups of lung cancer was found (p = 0.465). Furthermore, significantly more variants were detected in patients with stage IIIb-IV disease compared to patients with stage I-IIIa (median 7 vs 4, p = 0.017). Plasma cfDNA mutational load was significantly associated with overall survival (p = 0.010). The association persisted when adjusted for stage and ECOG performance status (HR: 3.64, 95% CI 1.37-9.67, p = 0.009). Agreement between tumor and plasma samples significantly differed with stage; patients with stage IIIb-IV disease showed agreement in 88.2% of the cases with clinically relevant variants, compared to zero cases in stage I-IIIa (p = 0.004). Furthermore, one variant in EGFR, two in KRAS, and one in BRAF were detected in plasma but not in tumor samples.
This study concludes that in the vast majority of advanced NSCLC patients a reliable variant analysis can be performed using liquid biopsy from plasma. Furthermore, we found that the number of variants in plasma is associated with prognosis, possibly indicating a strategy for closer follow up on this crucial patient group.
Purpose of review To evaluate and summarize recent research investigating psychological, social and environmental risk factors for development of psychopathology in childhood, while controlling for ...biological (genetic) influences by using a matched sibling, twin or adoptee design. Recent findings Nineteen studies were included, of which eleven were longitudinal and eight were cohort studies. Included studies used adequate designs and statistical methods, controlled for unmeasured confounders and, in many cases, for other measured risk factors. None of the studies used the framework for environmental factors presented in the International Classification of Functioning, Disability and Health (ICF). The outcome variable psychopathology was rarely assessed using a diagnostic standard. The findings were sorted in five themes based on included exposures: ‘ Social support, social rejection and perceived identity,’ ‘Early symptoms of psychopathology,’ ‘ Antibiotic exposure,’ ‘Factors in the family’ and ‘Nature versus nurture’. Summary Using twin/sibling/adoptee designs, a number of unique predictors of psychopathology were found, even when controlling for familial confounders and other specified risk factors. Future studies of psychopathology development should benefit from longitudinal, genetically sensitive designs and from use of diagnostic standards for psychopathology outcome, and should also incorporate ICF for classification of risk factors.
Theory of mind (ToM), or the ability to attribute mental states to oneself and others, is a core element of social cognition (SC). Even though its importance for social functioning in general, and ...neurodevelopmental disorders (NDDs), in particular, is well established, the links between ToM and other cognitive functions are not. Especially the familial underpinnings of such links remain unclear. Using a co-twin control design, we examined
N
= 311 twins (mean age
M
= 17.19 years, 47% females) diagnosed with autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), other NDDs, or typically developing individuals. We used the Reading the Mind in the Eyes Test to operationalize ToM, the Fragmented Pictures Test for central coherence (CC), the Tower Test for executive functioning (EF), and the general ability index in the Wechsler Intelligence Scales for IQ. In the linear regressions, weak CC and a lower IQ were associated with a reduced ToM ability across pairs. Female sex and higher age were robustly associated with increased ToM ability, whereas EF was not associated with ToM. In the within-pair analyses, where unmeasured familial confounders are implicitly adjusted, the associations between ToM and other cognitive functions, were attenuated and the association with CC was non-significant. The result suggests that familial factors shared by the twins, such as genetic and shared environment, influence the association between CC, IQ, and ToM. Future studies need to include a larger sample of monozygotic twins, who are genetically identical, in order to draw more firm conclusions regarding the influence of familial factors, and to differentiate between shared environmental and genetic effects on the associations between cognitive functions.
PDF
