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Distress screening has become mandatory and essential in comprehensive cancer care. We evaluated an electronic psycho-oncological adaptive screening (EPAS) which assesses objective indicators of care needs and subjectively perceived care needs and subsequently provides patient feedback with individualized recommendations about psychosocial care services.Patients were assessed within clusters, i.e., different oncological facilities of the competence network of the University Cancer Center Hamburg (UCCH). Patients in the intervention arm underwent the screening, controls received standard care. Patients were assessed at baseline (t0), 3-month (t1), and 6-month (t2) follow-up. Outcomes included information level and use of/access to nine psychosocial services at UCCH, well-being (GAD-7, PHQ-9, SF-8), and treatment satisfaction (SCCC). Conditional linear and logistic regressions were used to identify screening effects at t1 and t2.Of 1320 eligible patients across 11 clusters, 660 were included (50%). The average age was 60 years; 46% were female. The intervention was associated with increased information level for all psychosocial services at t1 and t2 (all p .001), increased use in some of these services at t1 and t2, respectively (p ≤ .02), and better evaluation of access (e.g., more recommendations for services provided by physicians, p .01). At t2, the intervention was associated with a lower level of satisfaction with disease-related information (p = .02).EPAS may improve information about psychosocial services as well as utilization of and access to these services. The effect on information level seems not to be generalizable to other aspects of oncological care. Future studies should incorporate novel technologies and condense the procedure to its core factors.The screening may help to enhance self-management competencies among cancer survivors.The trial was retrospectively registered (2/2021) at ClinicalTrials.gov (number: NCT04749056).

Oncogenic Ras proteins are implicated in the most common life‐threatening cancers. Despite intense research over the past two decades, the progress towards small‐molecule inhibitors has been limited. One reason for this failure is that Ras proteins interact with their effectors only via protein‐protein interactions, which are notoriously difficult to address with small organic molecules. Herein we describe an alternative strategy, which prevents farnesylation and subsequent membrane insertion, a prerequisite for the activation of Ras proteins. Our approach is based on sequence‐selective supramolecular receptors which bind to the C‐terminal farnesyl transferase recognition unit of Ras and Rheb proteins and covalently modify the essential cysteine in the so‐called CaaX‐box., Thinking inside the (CaaX) box: Despite intense research, the progress towards small‐molecule inhibitors, targeting specific protein‐protein interaction sites of oncogenic Ras proteins, has been limited. A different concept is based on sequence‐selective supramolecular receptors which covalently modify the C‐terminal CaaX‐box and prevent activation of Ras proteins.

Summary Kinase inhibitors represent the backbone of targeted cancer therapy, yet only a limited number of oncogenic drivers are directly druggable. By interrogating the activity of 1,505 kinase inhibitors, we found that BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells are specifically killed by CDK9 inhibition (CDK9i) and depend on CDK9 and Cyclin-T1 expression. We show that CDK9i leads to robust induction of apoptosis and of markers of DNA damage response in NMC cells. While both CDK9i and bromodomain inhibition over time result in reduced Myc protein expression, only bromodomain inhibition induces cell differentiation and a p21-induced cell-cycle arrest in these cells. Finally, RNA-seq and ChIP-based analyses reveal a BRD4-NUT-specific CDK9i-induced perturbation of transcriptional elongation. Thus, our data provide a mechanistic basis for the genotype-dependent vulnerability of NMC cells to CDK9i that may be of relevance for the development of targeted therapies for NMC patients., Graphical Abstract, Highlights • Screening 1,505 compounds against 78 cancer cell lines reveals distinct vulnerabilities • NUT midline carcinoma cells are specifically sensitive to CDK9 inhibition (CDK9i) • CDK9i perturbs MYC signaling, represses MCL1, and induces apoptosis in NMC cells • CDK9 may represent a promising therapeutic target in NUT midline carcinoma, By screening 1,505 compounds against 78 cancer cell lines, Brägelmann et al. identify a specific sensitivity of BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells to CDK9 inhibition. CDK9 inhibition affects transcriptional elongation, de-regulates MYC signaling, and induces apoptosis by suppressing anti-apoptotic MCL1. CDK9 may thus be a promising target in NMC.

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see [insert ACS Articles on Request author-directed link to Published Work, see https://doi.org/10.1021/acs.jmedchem.9b01006. In this work, we demonstrate that the indole-oxazole-pyrrole framework of the breitfussin family of natural products is a promising scaffold for kinase inhibition. Six new halogenated natural products, breitfussin C–H (3 – 8) were isolated and characterized from the Arctic, marine hydrozoan Thuiaria breitfussi. The structures of two of the new natural products were also confirmed by total synthesis. Two of the breitfussins (3 and 4) were found to selectively inhibit the survival of several cancer cell lines, with the lowest IC50 value of 340 nM measured against the drug-resistant triple negative breast cancer cell line MDA-MB-468, while leaving the majority of the tested cell lines not or significantly less affected. When tested against panels of protein kinases, 3 gave IC50 and Kd values as low as 200 and 390 nM against the PIM1 and DRAK1 kinases, respectively. The activity was confirmed to be mediated through ATP competitive binding in the ATP binding pocket of the kinases. Furthermore, evaluation of potential off-target and toxicological effects, as well as relevant in vitro ADME parameters for 3 revealed that the breitfussin scaffold holds promise for the development of selective kinase inhibitors.

Background: Previous experimental research on testosterone (T) and psychological traits is inconclusive. Thus, we performed the first large-scale observational study of the association between T and dispositional optimism / pessimism. Methods: We used prospective data from 6,493 primary-care patients (3,840 women) of the DETECT study (Diabetes Cardiovascular Risk-Evaluation: Targets and Essential Data for Commitment of Treatment), including repeated immunoassay-based measurement of serum T and optimism / pessimism assessed by the revised Life-Orientation Test (LOT-R). Cross-sectional and longitudinal associations of baseline T and one-year change in T with optimism and pessimism were investigated using age- and multivariable-adjusted regression models. Results: Cross-sectional analyses showed no association of T with optimism or pessimism in both sexes. Longitudinal analyses also showed no association of baseline T with optimism or pessimism at four-year follow-up. Multivariable analyses of total LOT-R score yielded similarly non-significant results (β-coefficient per unit change in T for men: -0.01 (95% CI: -0.24–0.22), women: 0.08 (-0.03–0.20)). Furthermore, change in T was not related to optimism or pessimism at four-year follow-up. Conclusions: The present observational study of a large-scale prospective sample showed no association of T with optimism or pessimism. Integrating further experimental and interventional evidence from alternative methodological approaches would strengthen this conclusion and establish stronger evidence about the potential hormonal basis of psychological traits.

Covalent modifications of nonactive site lysine residues by small molecule probes has recently evolved into an important strategy for interrogating biological systems. Here, we report the discovery of a class of bioreactive compounds that covalently modify lysine residues in DegS, the rate limiting protease of the essential bacterial outer membrane stress response pathway. These modifications lead to an allosteric activation and allow the identification of novel residues involved in the allosteric activation circuit. These findings were validated by structural analyses via X-ray crystallography and cell-based reporter systems. We anticipate that our findings are not only relevant for a deeper understanding of the structural basis of allosteric activation in DegS and other HtrA serine proteases but also pinpoint an alternative use of covalent small molecules for probing essential biochemical mechanisms.

Background Anxiety and depression can be a long-term strain in cancer survivors. Little is known about the emotional situation of cancer survivors who have to deal with work- and family-related issues. The purpose of this study was to investigate anxiety and depression in working-age cancer survivors and associated factors. Methods A register-based sample of 3370 cancer survivors (25 to 55 years at time of diagnosis) diagnosed up to six years prior to the survey was recruited from two German cancer registries. Demographic and medical characteristics as well as self-reported measures were used. Results Overall, approximately 40% of the survivors reported moderate to high anxiety scores and approximately 20% reported moderate to high depression scores. Compared to the general population, working-age cancer survivors were more anxious but less depressed (p

Background This paper focuses on the lifetime prevalence of mental disorders in individuals with Turkish migration backgrounds in Germany, as there is a lack of reliable epidemiological data on this subject. Methods In total, 662 adults with Turkish migration backgrounds were interviewed in Hamburg and Berlin by trained, bilingual interviewers using the computerized Composite International Diagnostic Interview (CIDI DIA-X Version 2.8) to assess diagnoses according to the DSM-IVTR. Results The analyses showed a weighted lifetime prevalence of 78.8% for any mental disorder, 21.6% for more than one and 7.3% for five or more disorders. Any mood disorder (41.9%), any anxiety disorder (35.7%) and any somatoform disorder/syndrome (33.7%) had the highest prevalences. Despite the sociodemographic differences between the first and second generations, there were no significant differences in the lifetime prevalence between generations, with the exception of any bipolar disorder. Female gender, older age and no current partnership were significantly associated with the occurrence of any mood disorder. Conclusions Overall, the results indicate a high lifetime prevalence in individuals with Turkish migration backgrounds in Germany. These initial data are highly relevant to the German clinical and psychosocial healthcare system; however, the methodological limitations and potential biases should be considered when interpreting the results.

The increasing volume of biomedical data in chemistry and life sciences requires the development of new methods and approaches for their handling. Here, we briefly discuss some challenges and opportunities of this fast growing area of research with a focus on those to be addressed within the BIGCHEM project. The article starts with a brief description of some available resources for “Big Data” in chemistry and a discussion of the importance of data quality. We then discuss challenges with visualization of millions of compounds by combining chemical and biological data, the expectations from mining the “Big Data” using advanced machine-learning methods, and their applications in polypharmacology prediction and target de-convolution in phenotypic screening. We show that the efficient exploration of billions of molecules requires the development of smart strategies. We also address the issue of secure information sharing without disclosing chemical structures, which is critical to enable bi-party or multi-party data sharing. Data sharing is important in the context of the recent trend of “open innovation” in pharmaceutical industry, which has led to not only more information sharing among academics and pharma industries but also the so-called “precompetitive” collaboration between pharma companies. At the end we highlight the importance of education in “Big Data” for further progress of this area.

We investigated the comparative effectiveness of cognitive-behavioural (CBT) and psychodynamic therapy (PDT) under clinically representative conditions as a subtrial of a prior study (Watzke et al., 2010, BJP). A consecutive sample of 147 patients with common mental disorders was randomised to either CBT or PDT in routine mental health care. In a primary per-protocol analysis patients randomised to CBT had a significantly better longer term outcome in the primary outcome symptom severity (General Severity Index of the SCL-14; p=.001; partial η(2)=0.073) as well as in health related quality of life (Mental Component Summary of the SF-8; p=.013; partial η(2)=.041) and concerning interpersonal issues (Inventory of Interpersonal Problems, IIP-C; p=.001; partial η(2)=.070) 6 months after treatment than patients randomised to PDT. These results could be confirmed in intention-to-treat analyses (n=180) suggesting that there was no substantial attrition bias due to drop outs at the follow-up assessment. Thus, the so called equivalence outcome paradox was not replicated in this study.

Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts. Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain. Structure-activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate. The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection.

It is still an open question whether psychotherapists adhere to their therapeutic conceptions in routine practice (clinician's treatment adherence) and thus to what extent the two most common approaches, cognitive-behavioural (CBT) and psychodynamic therapy (PDT), differ from each other as theoretically expected (treatment differentiation). This holds true especially in case of group therapy.The study compares essential process components of CBT and PDT group treatments under clinically representative conditions using non-participating observer ratings. Results demonstrate that CBT group therapists use more cognitive, behavioural and psychoeducational strategies, foster self-efficacy to a larger extent and are more supporting and empathetic. PDT group therapists use more interpretative and confrontative interventions and focus on interactional and dynamic aspects. The results strongly support that not only in individual psychotherapy-as shown in prior research-but also in the group setting do CBT and PDT reveal very distinct profiles and that therapists primarily abide by their theoretical training also in clinical practice. They allow one to identify differential process components of the group setting and to trace back parameters of outcome to the process of CBT and PDT for clinical routines.

Usability criteria sum up cognitions and percep- tions of professional methods and problem solutions such as quality assurance in health care. They are important for the dissemination and implementation of innovations and the effectivity and efficiency of systems. In order to extract such criteria in an explorative structured review, publications from five fields were examined: (a) quality assurance in health care, (b) health promotion and education, (c) psychological methodology, (d) evaluation studies, and (e) comparative policy assessment. One hundred thirty-eight English and German basic and applied research contributions were selected. Usability criteria and comments on their interfer- ence were extracted. The review provided a two-dimensional taxonomy of the concept of usability. The first dimension is defined by five functional aspects of quality assurance instruments: (1) easy and efficient handling, (2) scope of practical functions and options for usage, (3) completeness of information, (4) users' compliance and motivation, and (5) scientific quality of results and data. Between these usability areas some characteristic antagonisms are per- ceived. The second dimension is defined by four levels of increasing precision of professional cognitions: The usability area constitutes level 1. Each consists of several main criteria (level 2). Twenty-one main criteria of usability were found that were each specified by alternative sub-criteria (level 3) and their empirical indicators (level 4). This taxonomy offers an approach to the empirical exploration of users' expec- tations concerning quality assurance. It may contribute to the transparency of stakeholders' perspectives, to the prepara- tion of consensus procedures in QA and to systematical comparison of quality assurance systems.

A strategy to obtain a fully orthogonal estrogen-receptor-based gene switch responsive to molecules with acceptable pharmacological properties is presented. From a series of tetrahydrofluorenones active on the wild-type estrogen receptor (ER) an inactive analogue is chosen as a new lead compound. Coevolution of receptor mutants and ligands leads to an ER-based gene switch suitable for studies in animal models.

The hepatitis C virus (HCV) serine protease is necessary for viral replication and represents a valid target for developing new therapies for HCV infection. Potent and selective inhibitors of this enzyme have been identified and shown to inhibit HCV replication in tissue culture. The optimization of these inhibitors for clinical development would greatly benefit from in vitro systems for the identification and the study of resistant variants. We report the use HCV subgenomic replicons to isolate and characterize mutants resistant to a protease inhibitor. Taking advantage of the replicons' ability to transduce resistance to neomycin, we selected replicons with decreased sensitivity to the inhibitor by culturing the host cells in the presence of the inhibitor and neomycin. The selected replicons replicated to the same extent as those in parental cells. Sequence analysis followed by transfection of replicons containing isolated mutations revealed that resistance was mediated by amino acid substitutions in the protease. These results were confirmed by in vitro experiments with mutant enzymes and by modeling the inhibitor in the three-dimensional structure of the protease.

Background The EU currently lacks reliable data on the prevalence and incidence of mental disorders in older people. Despite the availability of several national and international epidemiological studies, the size and burden of mental disorders in the elderly remain unclear due to various reasons. Therefore, the aims of the MentDis_ICF65+ study are (1) to adapt existing assessment instruments, and (2) to collect data on the prevalence, the incidence, and the natural course and prognosis of mental disorders in the elderly. Method/design Using a cross-sectional and prospective longitudinal design, this multi-centre study from six European countries and associated states (Germany, Great Britain, Israel, Italy, Spain, and Switzerland) is based on age-stratified, random samples of elderly people living in the community. The study program consists of three phases: (1) a methodological phase devoted primarily to the adaptation of age- and gender-specific assessment tools for older people (e.g., the Composite International Diagnostic Interview, CIDI) as well as psychometric evaluations including translation, back translation; (2) a baseline community study in all participating countries to assess the lifetime, 12 month and 1 month prevalence and comorbidity of mental disorders, including prior course, quality of life, health care utilization and helpseeking, impairments and participation and, (3) a 12 month follow-up of all baseline participants to monitor course and outcome as well as examine predictors. Discussion The study is an essential step forward towards the further development and improvement of harmonised instruments for the assessment of mental disorders as well as the evaluation of activity impairment and participation in older adults. This study will also facilitate the comparison of cross-cultural results. These results will have bearing on mental health care in the EU and will offer a starting point for necessary structural changes to be initiated for mental health care policy at the level of mental health care politics.

Altered expression of mitochondrial DNA (mtDNA) occurs in ageing and a range of human pathologies (for example, inborn errors of metabolism, neurodegeneration and cancer). Here we describe first-in-class specific inhibitors of mitochondrial transcription (IMTs) that target the human mitochondrial RNA polymerase (POLRMT), which is essential for biogenesis of the oxidative phosphorylation (OXPHOS) system1–6. The IMTs efficiently impair mtDNA transcription in a reconstituted recombinant system and cause a dose-dependent inhibition of mtDNA expression and OXPHOS in cell lines. To verify the cellular target, we performed exome sequencing of mutagenized cells and identified a cluster of amino acid substitutions in POLRMT that cause resistance to IMTs. We obtained a cryo-electron microscopy (cryo-EM) structure of POLRMT bound to an IMT, which further defined the allosteric binding site near the active centre cleft of POLRMT. The growth of cancer cells and the persistence of therapy-resistant cancer stem cells has previously been reported to depend on OXPHOS7–17, and we therefore investigated whether IMTs have anti-tumour effects. Four weeks of oral treatment with an IMT is well-tolerated in mice and does not cause OXPHOS dysfunction or toxicity in normal tissues, despite inducing a strong anti-tumour response in xenografts of human cancer cells. In summary, IMTs provide a potent and specific chemical biology tool to study the role of mtDNA expression in physiology and disease. Inhibitors of mitochondrial transcription that target human mitochondrial RNA polymerase provide a chemical biology tool for studying the role of mitochondrial DNA expression in a wide range of pathologies.

Background Empirical studies investigating the prevalence of mental disorders and psychological distress in cancer patients have gained increasing importance during recent years, particularly with the objective to develop and implement psychosocial interventions within the cancer care system. Primary purpose of this epidemiological cross-sectional multi-center study is to detect the 4-week-, 12-month-, and lifetime prevalence rates of comorbid mental disorders and to further assess psychological distress and psychosocial support needs in cancer patients across all major tumor entities within the in- and outpatient oncological health care and rehabilitation settings in Germany. Methods/Design In this multicenter, epidemiological cross-sectional study, cancer patients across all major tumor entities will be enrolled from acute care hospitals, outpatient cancer care facilities, and rehabilitation centers in five major study centers in Germany: Freiburg, Hamburg, Heidelberg, Leipzig and Würzburg. A proportional stratified random sample based on the nationwide incidence of all cancer diagnoses in Germany is used. Patients are consecutively recruited in all centers. On the basis of a depression screener (PHQ-9) 50% of the participants that score below the cutoff point of 9 and all patients scoring above are assessed using the Composite International Diagnostic Interview for Oncology (CIDI-O). In addition, all patients complete validated questionnaires measuring emotional distress, information and psychosocial support needs as well as quality of life. Discussion Epidemiological data on the prevalence of mental disorders and distress provide detailed and valid information for the estimation of the demands for the type and extent of psychosocial support interventions. The data will provide information about specific demographic, functional, cancer- and treatment-related risk factors for mental comorbidity and psychosocial distress, specific supportive care needs and use of psychosocial support offers.

G-Protein Coupled Receptors (GPCR) are involved in all the major signaling pathways. As a result, they often serve as potential target for therapeutic drugs. In this study we analyze publicly available assays involving different classes of GPCR to identify false positives. Using the latest developments in Machine Learning, we then build models that can predict such compounds with high confidence. Given the ubiquity of GPCR assays, we believe such models will be very helpful in flagging potential false positives for further testing.