Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment

Germline activating mutations of the protein tyrosine phosphatase SHP2 (encoded by PTPN11), a positive regulator of the RAS signalling pathway, are found in 50% of patients with Noonan syndrome. These patients have an increased risk of developing leukaemia, especially juvenile myelomonocytic leukaemia (JMML), a childhood myeloproliferative neoplasm (MPN). Previous studies have demonstrated that mutations in Ptpn11 induce a JMML-like MPN through cell-autonomous mechanisms that are dependent on Shp2 catalytic activity. However, the effect of these mutations in the bone marrow microenvironment remains unclear. Here we report that Ptpn11 activating mutations in the mouse bone marrow microenvironment promote the development and progression of MPN through profound detrimental effects on haematopoietic stem cells (HSCs). Ptpn11 mutations in mesenchymal stem/progenitor cells and osteoprogenitors, but not in differentiated osteoblasts or endothelial cells, cause excessive production of the CC chemokine CCL3 (also known as MIP-1α), which recruits monocytes to the area in which HSCs also reside. Consequently, HSCs are hyperactivated by interleukin-1β and possibly other proinflammatory cytokines produced by monocytes, leading to exacerbated MPN and to donor-cell-derived MPN following stem cell transplantation. Remarkably, administration of CCL3 receptor antagonists effectively reverses MPN development induced by the Ptpn11-mutated bone marrow microenvironment. This study reveals the critical contribution of Ptpn11 mutations in the bone marrow microenvironment to leukaemogenesis and identifies CCL3 as a potential therapeutic target for controlling leukaemic progression in Noonan syndrome and for improving stem cell transplantation therapy in Noonan-syndrome-associated leukaemias

Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5(p)15.33 TERT-CLPTM1Ll Region

Introduction: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. Methods: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. Results: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 x 10(-16)), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 x 10(-16)), and rs4975616 OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 x 10(-14)). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. Conclusions: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Personality traits and psychological complaints under patients suffering from headaches

Background and purpose – Although headaches are often comorbid with psychological symptoms, the underlying psychological processes, e.g. the role of personality dimensions as headache determinants remains unclear. Studies found associations between headaches and various personality traits; according to the Big Five model of personality, persons suffering from headaches exhibit a higher rate in neuroticism, while a lower rate in extraversion, openness to experiences and positive emotions. This is the first study to clarify the associations among duration, intensity, and frequency of headaches and personality dimensions. Through this study we could get into the personality dimensions in the background of pain experience and that which personality dimensions bear a part in the behaviour of the persons, who suffered from headache, but do not seek treatment through this complaint. Methods – Treated (Group1) and untreated (Group2) headache patients and healthy controls (Group3) were investigated (total of 360 participants). The main headache components of intensity, duration, and frequency were used as dependent variables with personality dimensions in the Big Five concept investigated by the NEO-PI-R Personality Inventory. Results – Employing multiple regression analysis, facets of personality described 14.7% of headache intensity, 10.9 % of duration, and 18.7 % of frequency variance. Group1 and Group2 reached significantly higher values on the dimension of anxiety, depression, and vulnerability to stress than Group3. Group1 showed a significantly higher value on trust personality dimension than Group3 and Group2. Group3 exhibited a significantly higher value in the trust dimension than Group2. Concerning vulnerability to stress, the highest value was yielded by the “treated and suffering from headaches” group and there was a significant difference also with the “untreated and suffering from headaches” group and with the control group. In this dimension, the “untreated and suffering from headaches” group’s point value was significantly higher than the control group’s (p<0.01, U=-4.501). Conclusion – Our study demonstrates that the three headache components are not independent from personality traits, and personality traits may interact with treatment seeking behavior even in the presence of significant headache complaints. The role of the personality traits are significant in the intensity, duration and frequency of headaches

Personality traits and psychological complaints under patients suffering from headaches

Background and purpose – Although headaches are often comorbid with psychological symptoms, the underlying psychological processes, e.g. the role of personality dimensions as headache determinants remains unclear. Studies found associations between headaches and various personality traits; according to the Big Five model of personality, persons suffering from headaches exhibit a higher rate in neuroticism, while a lower rate in extraversion, openness to experiences and positive emotions. This is the first study to clarify the associations among duration, intensity, and frequency of headaches and personality dimensions. Through this study we could get into the personality dimensions in the background of pain experience and that which personality dimensions bear a part in the behaviour of the persons, who suffered from headache, but do not seek treatment through this complaint. Methods – Treated (Group1) and untreated (Group2) headache patients and healthy controls (Group3) were investigated (total of 360 participants). The main headache components of intensity, duration, and frequency were used as dependent variables with personality dimensions in the Big Five concept investigated by the NEO-PI-R Personality Inventory. Results – Employing multiple regression analysis, facets of personality described 14.7% of headache intensity, 10.9 % of duration, and 18.7 % of frequency variance. Group1 and Group2 reached significantly higher values on the dimension of anxiety, depression, and vulnerability to stress than Group3. Group1 showed a significantly higher value on trust personality dimension than Group3 and Group2. Group3 exhibited a significantly higher value in the trust dimension than Group2. Concerning vulnerability to stress, the highest value was yielded by the “treated and suffering from headaches” group and there was a significant difference also with the “untreated and suffering from headaches” group and with the control group. In this dimension, the “untreated and suffering from headaches” group’s point value was significantly higher than the control group’s (p<0.01, U=-4.501). Conclusion – Our study demonstrates that the three headache components are not independent from personality traits, and personality traits may interact with treatment seeking behavior even in the presence of significant headache complaints. The role of the personality traits are significant in the intensity, duration and frequency of headaches

Competency-Based Training and Assessment of Listening Skills: A Waitlist-Controlled Study in European Telephone Emergency Services

[Background] Telephone emergency services (TES) provide an essential part of suicide prevention and emotional support services across different health care settings. TES are usually provided by paraprofessional counselors, who need specific training in listening skills to meet the demands of callers. [Method] This project developed a competency-based training for listening skills which was then evaluated in a randomized controlled waitlist study across four EU countries (Germany, Hungary, Italy, and the Netherlands). Each country provided one training group and one waitlist group. Across countries, a total of 71 (trained: n = 36, waiting: n = 35) counselor trainees were assessed in a standardized, simulated emergency call with an actor client either before or after training participation. Calls were audiotaped and competencies in listening skills were evaluated by external raters using a standardized rating form. [Results] Trained counselors showed significantly better listening skills than participants from the waitlist condition. [Conclusion] Results provide support for the efficacy of a competency-based training for listening skills in the field of TES across Europe. Furthermore, results demonstrated that a standardized competency-based assessment with an actor client is suitable to assess listening skills

Multilevel animal societies can emerge from cultural transmission

Multilevel societies, containing hierarchically nested social levels, are remarkable social structures whose origins are unclear. The social relationships of sperm whales are organized in a multilevel society with an upper level composed of clans of individuals communicating using similar patterns of clicks (codas). Using agent-based models informed by an 18-year empirical study, we show that clans are unlikely products of stochastic processes (genetic or cultural drift) but likely originate from cultural transmission via biased social learning of codas. Distinct clusters of individuals with similar acoustic repertoires, mirroring the empirical clans, emerge when whales learn preferentially the most common codas (conformism) from behaviourally similar individuals (homophily). Cultural transmission seems key in the partitioning of sperm whales into sympatric clans. These findings suggest that processes similar to those that generate complex human cultures could not only be at play in non-human societies but also create multilevel social structures in the wild.publishe