BCL-2-family protein tBID can act as a BAX-like effector of apoptosis.

During apoptosis, the BCL-2-family protein tBID promotes mitochondrial permeabilization by activating BAX and BAK and by blocking anti-apoptotic BCL-2 members. Here, we report that tBID can also mediate mitochondrial permeabilization by itself, resulting in release of cytochrome c and mitochondrial DNA, caspase activation and apoptosis even in absence of BAX and BAK. This previously unrecognized activity of tBID depends on helix 6, homologous to the pore-forming regions of BAX and BAK, and can be blocked by pro-survival BCL-2 proteins. Importantly, tBID-mediated mitochondrial permeabilization independent of BAX and BAK is physiologically relevant for SMAC release in the immune response against Shigella infection. Furthermore, it can be exploited to kill leukaemia cells with acquired venetoclax resistance due to lack of active BAX and BAK. Our findings define tBID as an effector of mitochondrial permeabilization in apoptosis and provide a new paradigm for BCL-2 proteins, with implications for anti-bacterial immunity and cancer therapy.

Multicenter development of a PET-based risk assessment tool for product-specific outcome prediction in large B-cell lymphoma patients undergoing CAR T-cell therapy.

PURPOSE: The emergence of chimeric antigen receptor (CAR) T-cell therapy fundamentally changed the management of individuals with relapsed and refractory large B-cell lymphoma (LBCL). However, real-world data have shown divergent outcomes for the approved products. The present study therefore set out to evaluate potential risk factors in a larger cohort. METHODS: Our analysis set included 88 patients, treated in four German university hospitals and one Italian center, who had undergone 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (PET) before CAR T-cell therapy with tisagenlecleucel or axicabtagene ciloleucel. We first determined the predictive value of conventional risk factors, treatment lines, and response to bridging therapy for progression-free survival (PFS) through forward selection based on Cox regression. In a second step, the additive potential of two common PET parameters was assessed. Their optimal dichotomizing thresholds were calculated individually for each CAR T-cell product. RESULTS: Extra-nodal involvement emerged as the most relevant of the conventional tumor and patient characteristics. Moreover, we found that inclusion of metabolic tumor volume (MTV) further improves outcome prediction. The hazard ratio for a PFS event was 1.68 per unit increase of our proposed risk score (95% confidence interval [1.20, 2.35], P = 0.003), which comprised both extra-nodal disease and lymphoma burden. While the most suitable MTV cut-off among patients receiving tisagenlecleucel was 11 mL, a markedly higher threshold of 259 mL showed optimal predictive performance in those undergoing axicabtagene ciloleucel treatment. CONCLUSION: Our analysis demonstrates that the presence of more than one extra-nodal lesion and higher MTV in LBCL are associated with inferior outcome after CAR T-cell treatment. Based on an assessment tool including these two factors, patients can be assigned to one of three risk groups. Importantly, as shown by our study, metabolic tumor burden might facilitate CAR T-cell product selection and reflect the individual need for bridging therapy.

MARCKS affects cell motility and response to BTK inhibitors in CLL.

Bruton tyrosine kinase (BTK) inhibitors are highly active drugs for the treatment of chronic lymphocytic leukemia (CLL). To understand the response to BTK inhibitors on a molecular level, we performed (phospho)proteomic analyses under ibrutinib treatment. We identified 3466 proteins and 9184 phosphopeptides (representing 2854 proteins) in CLL cells exhibiting a physiological ratio of phosphorylated serines (pS), threonines (pT), and tyrosines (pY) (pS:pT:pY). Expression of 83 proteins differed between unmutated immunoglobulin heavy-chain variable region (IGHV) CLL (UM-CLL) and mutated IGHV CLL (M-CLL). Strikingly, UM-CLL cells showed higher basal phosphorylation levels than M-CLL samples. Effects of ibrutinib on protein phosphorylation levels were stronger in UM-CLL, especially on phosphorylated tyrosines. The differentially regulated phosphopeptides and proteins clustered in pathways regulating cell migration, motility, cytoskeleton composition, and survival. One protein, myristoylated alanine-rich C-kinase substrate (MARCKS), showed striking differences in expression and phosphorylation level in UM-CLL vs M-CLL. MARCKS sequesters phosphatidylinositol-4,5-bisphosphate, thereby affecting central signaling pathways and clustering of the B-cell receptor (BCR). Genetically induced loss of MARCKS significantly increased AKT signaling and migratory capacity. CD40L stimulation increased expression of MARCKS. BCR stimulation induced phosphorylation of MARCKS, which was reduced by BTK inhibitors. In line with our in vitro findings, low MARCKS expression is associated with significantly higher treatment-induced leukocytosis and more pronounced decrease of nodal disease in patients with CLL treated with acalabrutinib.

Telmisartan induces a specific gut microbiota signature which may mediate its antiobesity effect.

Telmisartan prevents diet-induced obesity (DIO) in rodents. Given that the precise underlying mechanism is not known, we examined whether a gut-related mechanism might be involved. Sprague-Dawley rats received cafeteria diet (CD) for 3 months to develop DIO and were administered either telmisartan (8 mg/kgbw) or vehicle. In addition, pair-fed (PF) rats received CD adjusted to TEL and control rats (CON) only received chow. Stool samples were analysed by 16 S rRNA gene amplicon sequencing. CD-fed rats became obese while TEL, PF and CON rats remained lean. Alpha diversity analyses indicated that bacterial diversity was similar before the study but changed over time. Beta diversity revealed a time-, CD- and telmisartan-dependent effect. The Firmicutes/Bacteroidetes ratio and the abundance of Blautia, Allobaculum and Parasutterella were higher in DIO and PF than in CON, but not in TEL. Enterotype (ET)-like clustering analyses, Kleinberg's hub network scoring and random forest analyses also indicated that telmisartan induced a specific signature of gut microbiota. In response to stool transfer from telmisartan-pre-treated donor to high-fat fed acceptor mice, body weight gain was slightly attenuated. We attribute the anti-obesity action of telmisartan treatment to diet-independent alterations in gut microbiota as the microbiota from telmisartan-treated, CD-fed rats clearly differed from those of DIO and PF rats. ET-like clustering network, random forest classification and the higher stability in bacterial co-occurrence network analyses indicate that there is more than one indicator species for telmisartan's specific signature, which is further strengthened by the fact that we cannot identify a single indicator species.

Importation and deprivation factors influencing teacher-targeted aggression among secondary school students in Germany: A multilevel analysis.

Relying on an importation and deprivation framework, the study assessed a variety of risk factors associated with self-reported teacher-targeted aggression among ninth grade students (n = 5,673). Using a cross-sectional school survey conducted in one German federal state, two forms of teacher-targeted aggression were assessed: verbal (insulting, threatening, and mocking) and physical (beating and pushing) aggression. Every ninth student reported verbal aggression, while 0.5% of students reported physical aggression against teachers. Multilevel probability models showed that individual importation factors (low self-control, male gender, and exposure to severe parental violence), together with individual deprivation factors (repeated victimization by teachers and low school achievement) play a role in explaining teacher-targeted aggression. The school-level deprivation factor of negative teacher-student relationships was also relevant, whereas low teacher control and attending lower-level schools were unrelated to the perpetration of teacher-targeted aggression. The present study stresses the need to acknowledge the multilevel etiology of teacher-targeted aggression.

Outcome Prediction in Patients With Large B-cell Lymphoma Undergoing Chimeric Antigen Receptor T-cell Therapy.

The introduction of chimeric antigen receptor (CAR) T-cell therapy has led to a fundamental shift in the management of relapsed and refractory large B-cell lymphoma. However, our understanding of risk factors associated with non-response is still insufficient and the search for predictive biomarkers continues. Some parameters measurable on 18F-fluorodeoxyglucose positron emission tomography (PET) may be of additional value in this context. A total of 47 individuals from three German university centers who underwent re-staging with PET prior to CAR T-cell therapy were enrolled into the present study. After multivariable analysis considering tumor characteristics and patient factors that might affect progression-free survival (PFS), we investigated whether metabolic tumor volume (MTV) or maximum standardized uptake value (SUVmax) further improve risk stratification. Their most suitable cut-offs were determined by Cox and logistic regression. Forward selection identified extra-nodal disease as the most predictive factor of those routinely available, and we found it to be associated with significantly inferior overall survival after CAR T-cell treatment (P = 0.012). Furthermore, patients with MTV and SUVmax higher than the optimal threshold of 11 mL and 16.7, respectively, experienced shorter PFS (P = 0.016 and 0.002, respectively). Hence, these risk factors might be useful for selection of individuals likely to benefit from CAR T-cell therapy and their management.

Plasma exchange with COVID-19 convalescent plasma in a patient with severe ANCA-associated vasculitis and COVID-19 pneumonia after rituximab therapy.

The combination of coronavirus disease 2019 (COVID-19) pneumonia and pulmonary-renal syndrome due to ANCA-associated vasculitis (AAV) poses diagnostic uncertainty and a therapeutic dilemma. According to current limited knowledge of COVID-19, the application of commonly used drugs in AAV, cyclophosphamide (CYC) and rituximab (RTX), must be weighed carefully in active COVID-19 infection. We report a case of a 52-year-old male patient with concurrent severe COVID-19 pneumonia and acute relapse of pulmonary-renal syndrome due to AAV after recent RTX maintenance dose. The patient presented with severe hypoxaemia, complete B-cell depletion and severe acute respiratory syndrome coronavirus 2 viraemia. He was successfully treated with therapeutic plasma exchange employing COVID-19 convalescent plasma.

Additive and Interactive Effects of Victimization on Adolescent Aggression Across Social Settings.

Considering that children and adolescents can face multiple exposures to violence due to their involvement in different socialization domains, this study aimed to analyze additive and interactive effects of physical and verbal victimization by parents, peers, and schoolteachers on adolescent aggression across social settings. With regard to parent-child and teacher-adolescent relationships, physical and verbal forms of aggression were differentiated, whereas aggression by and toward peers was assessed by a composite measure of overt and indirect aggression. Data were drawn from three large secondary school surveys of ninth-grade students within one federal German state conducted in the years 2013, 2015, and 2017. Based on a sample of 8,458 adolescents (mean age = 14.9 years), results provided evidence for additive as well as interactive effects of victimization across settings. Controlling for a range of risk factors associated with victimization and aggression, victimization by parents, peers, and teachers was uniquely related to adolescent aggression across social settings. In addition, three significant interaction effects were identified between different combinations of victimization: Students exposed to earlier parent-to-child physical aggression perpetrated more physical aggression toward parents within the last 12 months if they were also recently victimized by peers. Furthermore, parent-to-child physical aggression exacerbated the positive relationship between teacher-to-adolescent physical aggression and adolescent-to-teacher physical aggression. In contrast, exposure to teacher-to-adolescent verbal aggression reduced the positive link between peer-to-adolescent aggression and aggression toward peers. Findings suggest that intervention should be particularly sensitive toward multiple exposure to violence across socialization contexts, as well as toward the interdependence of cross-setting victimization.

Associations Between Classroom Normative Climate and the Perpetration of Teen Dating Violence Among Secondary School Students.

The aim of this study was to investigate how classroom normative climate regarding the perpetration of teen dating violence (TDV) was related to adolescents' self-reported perpetration of (verbal/emotional, threatening, relational, physical, and sexual) violence within romantic relationships in the previous 12 months. Based on Theory of Normative Conduct, we hypothesized that higher classroom levels of TDV perpetration were associated with a higher likelihood of individual TDV perpetration. Data were drawn from a large survey of ninth-grade students conducted in the state of Lower Saxony, Germany (n = 10,638). From this sample, an analysis sample of n = 4,351 students at risk was drawn (mean age: 15.0, SD: 0.76; 46.6% male). More than half (54.8%) of the at-risk sample reported engagement in any form of TDV within the previous 12 months, whereby rates varied considerably by the dimension of TDV. Controlling for a range of risk factors on the classroom level (proportion of students dependent on social welfare, proportion of students with migration background) and individual level (exposure to family violence, sociodemographic characteristics, TDV victimization, and peer- and school-related factors), regression analyses showed that higher rates of classroom-level TDV perpetration were positively related to individual verbal/emotional TDV perpetration. This pattern of results was observable across all dimensions of TDV. Furthermore, gender-specific patterns of TDV perpetration were observable: Girls were more affected by classroom levels of verbal/emotional and physical TDV than boys, while boys were more affected by classroom levels of relational and sexual TDV. Results highlight the role of the wider peer context in shaping adolescent dating experiences and specifically point to the relevance of the classroom ecology for the socialization of dating violence in adolescents.

Risk and Protective Factors of Child-to-Parent Violence: A Comparison Between Physical and Verbal Aggression.

Child-to-parent violence (CPV) is a social problem that remains vastly understudied compared with other forms of family violence. The aim of this study is to identify family and child risk and protective factors of CPV, and to investigate whether they differentially predict physical and verbal parent-directed violence among boys and girls. Predictors include parenting behavior during childhood (physical and verbal violence, warmth, monitoring) and respondents' individual characteristics (suicidal ideation, self-control, problematic substance use). Data were examined from a large representative sample of ninth graders (N = 6,444) in Lower Saxony, Germany. Bivariate analyses showed that female adolescents were more likely to aggress verbally, while no gender differences were found for physical CPV. Multilevel logistic regression models revealed that direct experiences of parental physical and verbal violence during childhood were among the strongest predictors of physical and verbal CPV, both among males and females. While parental monitoring was not significantly associated with CPV, parental warmth protected girls from physical parent-directed aggression. Furthermore, high self-control was protective against verbal CPV as well as boys' physical CPV, while problematic substance use predicted physical violence toward parents in both sexes but only boys' verbal CPV. Suicidal ideation was a risk factor of aggression in males only. Except for parental warmth, the importance of risk and protective factors did not substantially vary across child gender. These findings broaden our understanding of different family and child-related factors that either promote or prevent CPV. Specifically, they point to the importance of the parenting context and especially harsh discipline practices for the occurrence of both physical and verbal CPV.