Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T-cell lymphoma

Leukemic cutaneous T-cell lymphomas (L-CTCL) are lymphoproliferative disorders of skin-homing mature T-cells causing severe symptoms and high mortality through chronic inflammation, tissue destruction, and serious infections. Despite numerous genomic sequencing efforts, recurrent driver mutations have not been identified, but chromosomal losses and gains are frequent and dominant. We integrated genomic landscape analyses with innovative pharmacologic interference studies to identify key vulnerable nodes in L-CTCL. We detected copy number gains of loci containing the STAT3/5 oncogenes in 74% (n = 17/23) of L-CTCL, which correlated with the increased clonal T-cell count in the blood. Dual inhibition of STAT3/5 using small-molecule degraders and multi-kinase blockers abolished L-CTCL cell growth in vitro and ex vivo, whereby PAK kinase inhibition was specifically selective for L-CTCL patient cells carrying STAT3/5 gains. Importantly, the PAK inhibitor FRAx597 demonstrated encouraging anti-leukemic activity in vivo by inhibiting tumor growth and disease dissemination in intradermally xenografted mice. We conclude that STAT3/5 and PAK kinase interaction represents a new therapeutic node to be further explored in L-CTCL

Personality Influences the Relationship Between Primary Emotions and Religious/Spiritual Well-Being

The study of human emotions and personality provides valuable insights into the parameters of mental health and well-being. Affective neuroscience proposes that several levels of emotions – ranging from primary ones such as LUST or FEAR up to higher emotions such as spirituality – interact on a neural level. The present study aimed to further explore this theory. Furthermore, we hypothesized that personality – formed by bottom-up primary emotions and cortical top-down regulation – might act as a link between primary emotions and religious/spiritual well-being. A total sample of 167 (78% female) student participants completed the Affective Neuroscience Personality Scale (primary emotions), the Big Five Personality Inventory and the Multidimensional Inventory of Religious/Spiritual Well-Being (higher emotions). Correlation analyses confirmed the link between primary and higher emotions as well as their relation to personality. Further regression analyses indicated that personality dimensions mediate the relationship between primary and higher emotions. A substantial interaction between primary emotions, personality dimensions, and religious/spiritual well-being could be confirmed. From a developmental perspective, cortical top-down regulation might influence religious/spiritual well-being by forming relevant personality dimensions. Hence, CARE as well as Agreeableness seem of special importance. Future studies might focus on implications for clinical groups.© 2018 Hiebler-Ragger, Fuchshuber, Dröscher, Vajda, Fink and Unterraine

Acute liver failure after ingestion of fried rice balls: A case series of bacillus cereus food poisonings

Bacillus cereus foodborne intoxications and toxicoinfections are on a rise. Usually, symptoms are self-limiting but occasionally hospitalization is necessary. Severe intoxications with the emetic Bacillus cereus toxin cereulide, which is notably resistant heat and acid during cooking, can cause acute liver failure and encephalopathy. We here present a case series of food poisonings in five immunocompetent adults after ingestion of fried rice balls, which were massively contaminated with Bacillus cereus. The patients developed a broad clinical spectrum, ranging from emesis and diarrhoea to life-threatening acute liver failure and acute tubular necrosis of the kidney in the index patient. In the left-over rice ball, we detected 8 × 106Bacillus cereus colony-forming units/g foodstuff, and cereulide in a concentration of 37 μg/g foodstuff, which is one of the highest cereulide toxin contaminations reported so far from foodborne outbreaks. This report emphasizes the potential biological hazard of contaminated rice meals that are not freshly prepared. It exemplifies the necessity of a multidisciplinary approach in cases of Bacillus cereus associated food poisonings to rapidly establish the diagnosis, to closely monitor critically ill patients, and to provide supportive measures for acute liver failure and-whenever necessary-urgent liver transplantation

Increased attachment security is related to early therapy drop-out in substance use disorders

Objectives: Previous research work suggests a positive association between secure attachment and increased therapy adherence (TA) in different patient groups. However, there is still a strong need for research focusing on the influence of attachment on TA in substance use disorder (SUD) treatment. Hence, this study attempts to investigate the predictive value of different attachment patterns concerning TA in SUD inpatients. Results: 122 (34 female) SUD inpatients completed the Attachment Style Questionnaire (ASQ) during the entry phase of therapeutic community treatment. After 6 weeks, subjects who remained in therapy (n = 47) completed the ASQ for a second time. In line with the literature, agglomerative Cluster Analysis suggested a two-cluster solution (Cluster I: increased secure attachment pattern; Cluster II: increased insecure attachment pattern). Notably, inpatients in Cluster I were more likely to drop out of treatment within the first 6 weeks (p < .001). Furthermore, subjects showed less “Confidence in Self and Others” (p < .05) after 6 weeks of treatment. Our findings indicate a negative predictive value of increased attachment security for TA in SUD inpatients. This finding probably mirrors a more realistic kind of self-assessment. More generally, the importance of considering attachment styles in SUD treatment is underlined.© The Author(s) 201

Vaccine Based on Recombinant Fusion Protein Combining Hepatitis B Virus PreS with SARS-CoV-2 Wild-Type- and Omicron-Derived Receptor Binding Domain Strongly Induces Omicron-Neutralizing Antibodies in a Murine Model

COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a recurrent endemic disease affecting the whole world. Since November 2021, Omicron and its subvariants have dominated in the spread of the disease. In order to prevent severe courses of disease, vaccines are needed to boost and maintain antibody levels capable of neutralizing Omicron. Recently, we produced and characterized a SARS-CoV-2 vaccine based on a recombinant fusion protein consisting of hepatitis B virus (HBV)-derived PreS and two SARS-CoV-2 wild-type RBDs.To develop a PreS-RBD vaccine which induces high levels of Omicron-specific neutralizing antibodies.We designed, produced, characterized and compared strain-specific (wild-type: W-PreS-W; Omicron: O-PreS-O), bivalent (mix of W-PreS-W and O-PreS-O) and chimeric (i.e., W-PreS-O) SARS-CoV-2 protein subunit vaccines. Immunogens were characterized in vitro using protein chemical methods, mass spectrometry, and circular dichroism in combination with thermal denaturation and immunological methods. In addition, BALB/c mice were immunized with aluminum-hydroxide-adsorbed proteins and aluminum hydroxide alone (i.e., placebo) to study the specific antibody and cytokine responses, safety and Omicron neutralization.Defined and pure immunogens could be produced in significant quantities as secreted and folded proteins in mammalian cells. The antibodies induced after vaccination with different doses of strain-specific, bivalent and chimeric PreS-RBD fusion proteins reacted with wild-type and Omicron RBD in a dose-dependent manner and resulted in a mixed Th1/Th2 immune response. Interestingly, the RBD-specific IgG levels induced with the different vaccines were comparable, but the W-PreS-O-induced virus neutralization titers against Omicron (median VNT50: 5000) were seven- and twofold higher than the W-PreS-W- and O-PreS-O-specific ones, respectively, and they were six-fold higher than those of the bivalent vaccine.Among the tested immunogens, the chimeric PreS-RBD subunit vaccine, W-PreS-O, induced the highest neutralizing antibody titers against Omicron. Thus, W-PreS-O seems to be a highly promising COVID-19 vaccine candidate for further preclinical and clinical evaluation

The relationship between existential well-being and mood-related psychiatric burden in Indian young adults with attachment deficits: a cross-cultural validation study

Background: Attachment and spirituality are thought to have deep evolutionary roots but are always interpreted within the framework of culture, religion and personal beliefs. While insecure attachment has been observed to be positively related with psychopathology, a positive mental health effect has often been described for spirituality. To examine the cross-cultural validation of previous research focused on Austrian young adults with Western socialization, we attempt to replicate our study examining the influence spirituality has on the connection between insecure attachment and mood-related psychiatric burden with Indian young adults. Methods: We investigated Avoidant (AV) and Anxious (AX) Attachment (ECR-RD), Religious (RWB) and Existential (EWB) Well-Being (MI-RSWB), and mood-related psychiatric burden (Anxiety, Depression, Somatization; BSI-18) in 443 (31% female) Indian young adults (age range: 18–30 years) with a Hindu upbringing. Results: Compared to young adults with a Roman Catholic upbringing in a Western socialization, Indian participants did not differ in AX and EWB but scored higher in mood-related psychiatric burden (eta2 = .04), AV (eta2 = .14), as well as RWB (eta2 = .28; all p < .01). As in previous research only AX (β = .40) positively predicted mood-related psychiatric burden (ΔR2 = .15, all p < .01), while EWB was an additional negative predictor (β = −.11, p < .05). Conclusions: Our findings emphasize the universal importance of attachment and spirituality for mental health as well as the potential influence of socialization on their development. Furthermore, they underline that Existential Well-Being – including hope for a better future, forgiveness, and the experience of sense and meaning – appears to have a compensating effect on the relation between insecure attachment and impaired mental health.© The Author(s) 202

Psychobiology of Attachment and Trauma—Some General Remarks From a Clinical Perspective

Attachment refers to a psychobiological principle that is deeply rooted in evolutionary development; it is thought to contribute a major advantage in the survival of the social group. Within individual development it indicates a primary motivational system that guides the initial transactions between mother and baby and furthermore mediates affective attunement and regulation. Psychosocial learning, in close interaction with genetics and epigenetics, also develops a decisive foundation for further brain development of the infant. Finally, the attachment pattern established forms an enduring, relational context for later affective, cognitive, and social development of the child. As an unconsciously active matrix for future personal relationships it has a particular impact on the comprehensive psychological functions of empathy and mentalization. Early adverse and traumatic experiences or major emotional neglect may lead to different levels of security versus insecurity or disorientation-disorganization of the attachment pattern that corresponds to characteristic features of neurobiological regulation.© 2019 Lahousen, Unterrainer and Kapfhamme

Loss of SQSTM1/p62 Induces Obesity and Exacerbates Alcohol-induced Liver Injury in Aged Mice

Alcohol-associated liver disease (ALD) is a worldwide health problem, of which the effective treatment is still lacking. Both detrimental and protective roles of adipose tissue have been implicated in ALD. Although alcohol increases adipose tissue lipolysis to promote alcohol-induced liver injury, alcohol also activates brown adipose tissue (BAT) thermogenesis as an adaptive response in protecting against alcohol-induced liver injury. Moreover, aging and obesity are also risk factors for ALD. In the present study, we investigated the effects of autophagy receptor protein SQSTM1/p62 on adipose tissue and obesity in alcohol-induced liver injury in both young and aged mice.Young and aged whole-body SQSTM1/p62 knockout (KO) and their age-matched wild-type (WT) mice were subjected to chronic plus binge (Gao-binge) alcohol feeding. Blood, adipose and liver tissues were collected for biochemical and histologic analysis.Aged but not young SQSTM1/p62 KO mice had significantly increased body weight and fat mass compared with the matched WT mice. Gao-binge alcohol feeding induced white adipose atrophy and decreased levels of SQSTM1/p62 levels in adipose tissue in aged WT mice. SQSTM1/p62 KO aged mice were resistant to Gao-binge alcohol-induced white adipose atrophy. Alcohol feeding increased the expression of thermogenic genes in WT mouse BAT, which was significantly blunted in SQSTM1/p62 KO aged mice. Alcohol-fed aged SQSTM1/p62 KO mice showed significantly higher levels of serum alanine aminotransferase, hepatic triglyceride, and inflammation compared with young and aged WT mice fed with alcohol. Alcohol-fed SQSTM1/p62 KO mice also increased secretion of proinflammatory and angiogenic adipokines that may promote alcohol-induced liver injury.Loss of SQSTM1/p62 in aged mice leads to obesity and impairs alcohol-induced BAT adaptation, resulting in exacerbated alcohol-induced liver injury in mice

PDGFRβ promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma

Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin T cell lymphoma commonly driven by NPM-ALK. AP-1 transcription factors, cJUN and JUNb, act as downstream effectors of NPM-ALK and transcriptionally regulate PDGFRβ. Blocking PDGFRβ kinase activity with imatinib effectively reduces tumor burden and prolongs survival, although the downstream molecular mechanisms remain elusive.In a transgenic mouse model that mimics PDGFRβ-driven human ALCL in vivo, we identify PDGFRβ as a driver of aggressive tumor growth. Mechanistically, PDGFRβ induces the pro-survival factor Bcl-xL and the growth-enhancing cytokine IL-10 via STAT5 activation. CRISPR/Cas9 deletion of both STAT5 gene products, STAT5A and STAT5B, results in the significant impairment of cell viability compared to deletion of STAT5A, STAT5B or STAT3 alone. Moreover, combined blockade of STAT3/5 activity with a selective SH2 domain inhibitor, AC-4-130, effectively obstructs tumor development in vivo.We therefore propose PDGFRβ as a novel biomarker and introduce PDGFRβ-STAT3/5 signaling as an important axis in aggressive ALCL. Furthermore, we suggest that inhibition of PDGFRβ or STAT3/5 improve existing therapies for both previously untreated and relapsed/refractory ALK+ ALCL patients

Unto the third generation: evidence for strong familial aggregation of physicians, psychologists, and psychotherapists among first-year medical and psychology students in a nationwide Austrian cohort census

Background: Medical students present higher numbers of physician relatives than expectable from the total population prevalence of physicians. Evidence for such a familial aggregation effect of physicians has emerged in investigations from the Anglo-American, Scandinavian, and German-speaking areas. In particular, past data from Austria suggest a familial aggregation of the medical, as well as of the psychological and psychotherapeutic, professions among medical and psychology undergraduates alike. Here, we extend prior related studies by examining (1) the extent to which familial aggregation effects apply to the whole nation-wide student census of all relevant (eight) public universities in Austria; (2) whether effects are comparable for medical and psychology students; (3) and whether these effects generalize to relatives of three interrelated health professions (medicine, psychology, and psychotherapy). Methods: We investigated the familial aggregation of physicians, psychologists, and psychotherapists, based on an entire cohort census of first-year medical and psychology students (n = 881 and 920) in Austria with generalized linear mixed models. Results: For both disciplines, we found strong familial aggregation of physicians, psychologists, and psychotherapists. As compared with previous results, directionally opposite time trends within disciplines emerged: familial aggregation of physicians among medical students has decreased, whilst familial aggregation of psychologists among psychology students has increased. Further, there were sex-of-relative effects (i.e., more male than female physician relatives), but no substantial sex-of-student effects (i.e., male and female students overall reported similar numbers of relatives for all three professions of interest). In addition, there were age-benefit effects, i.e., students with a relative in the medical or the psychotherapeutic profession were younger than students without, thus suggesting earlier career decisions. Conclusions: The familial aggregation of physicians, psychologists, and psychotherapists is high among medical and psychology undergraduates in Austria. Discussed are implications of these findings (e.g., gender equity, feminization of the medical field, ideas for curricular implementation and student counselling), study limitations, and avenues for future research.© The Author(s). 201