A Reinvestigation of the Role of the Sorbic Acid Tail on the Antibacterial and Anti-Tuberculosis Properties of Moiramide B.

Due to worldwide increasing resistances, there is a considerable need for antibacterial compounds with modes of action not yet realized in commercial antibiotics. One such promising structure is the acetyl-CoA carboxylase (ACC) inhibitor moiramide B which shows strong antibacterial activity against gram-positive bacteria such as Bacillus subtilis and weaker activities against gram-negative bacteria. However, the narrow structure-activity relationship of the pseudopeptide unit of moiramide B represents a formidable challenge for any optimization strategy. In contrast, the lipophilic fatty acid tail is considered an unspecific vehicle responsible only for the transport of moiramide into the bacterial cell. Here we show that the sorbic acid unit, in fact, is highly relevant for ACC inhibition. A hitherto undescribed sub-pocket at the end of the sorbic acid channel binds strongly aromatic rings and allows the development of moiramide derivatives with altered antibacterial profiles including anti-tubercular activity.

Synthesis, Biological Evaluation, and Binding Mode of a New Class of Oncogenic K-Ras4b Inhibitors.

Ras proteins are implicated in some of the most common life-threatening cancers. Despite intense research during the past three decades, progress towards small-molecule inhibitors of mutant Ras proteins still has been limited. Only recently has significant progress been made, in particular with ligands for binding sites located in the switch II and between the switch I and switch II region of K-Ras4B. However, the structural diversity of inhibitors identified for those sites to date is narrow. Herein, we show that hydrazones and oxime ethers of specific bis(het)aryl ketones represent structurally variable chemotypes for new GDP/GTP-exchange inhibitors with significant cellular activity.

Prevalence of mental disorders in patients with cancer compared to matched controls - secondary analysis of two nationally representative surveys.

AIM: To compare prevalence rates of mental disorders in patients with cancer and general population controls. METHOD: In two stratified nationally representative surveys, the 12-month prevalence of mental disorders was assessed in 2141 patients with cancer and 4883 general population controls by the standardized Composite International Diagnostic Interview (CIDI). We determined odds ratios (ORs) to compare the odds for mental disorders (combined and subtypes) in cancer patients with age- and gender-matched controls. RESULTS: The 12-month prevalences rate for any mental disorder was significantly higher in patients with cancer compared to controls (OR 1.28, 95% CI 1.14-1.45). Prevalence rates were at least two times higher for unipolar mood disorders (major depression: OR 2.07, 95% CI 1.71-2.51; dysthymia: OR 2.93, 95% CI 2.13-4.02) and mental disorders due to a general medical condition (OR 3.31, 95% CI 2.32-4.71). There was no significant elevation for anxiety disorders overall (OR 0.95, 95% CI 0.81-1.11). Mildly elevated prevalence rates emerged for post-traumatic stress disorder (OR 1.57, 95% CI 1.11-2.23) and social phobia (OR 1.57, 95% CI 1.07-2.31), while specific phobia (OR 0.82, 95% CI 0.67-1.00) and agoraphobia (OR 0.49, 95% CI 0.33-0.73) were significantly less frequent in cancer. CONCLUSIONS: While elevated depression rates reinforce the need for its systematic diagnosis and treatment, lower prevalences were unexpected given previous evidence. Whether realistic illness-related fears and worries contribute to lower occurrence of anxiety disorders with excessive fears in cancer may be of interest to future research.

Evaluation of an electronic psycho-oncological adaptive screening program (EPAS) with immediate patient feedback: findings from a German cluster intervention study.

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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. IMPLICATIONS FOR CANCER SURVIVORS: The screening may help to enhance self-management competencies among cancer survivors. TRIAL REGISTRATION: The trial was retrospectively registered (2/2021) at ClinicalTrials.gov (number: NCT04749056).

Highly Accurate Filters to Flag Frequent Hitters in AlphaScreen Assays by Suggesting their Mechanism.

AlphaScreen is one of the most widely used assay technologies in drug discovery due to its versatility, dynamic range and sensitivity. However, a presence of false positives and frequent hitters contributes to difficulties with an interpretation of measured HTS data. Although filters do exist to identify frequent hitters for AlphaScreen, they are frequently based on privileged scaffolds. The development of such filters is time consuming and requires deep domain knowledge. Recently, machine learning and artificial intelligence methods are emerging as important tools to advance drug discovery and chemoinformatics, including their application to identification of frequent hitters in screening assays. However, the relative performance and complementarity of the Machine Learning and scaffold-based techniques has not yet been comprehensively compared. In this study, we analysed filters based on the privileged scaffolds with filters built using machine learning. Our results demonstrate that machine-learning methods provide more accurate filters for identification of frequent hitters in AlphaScreen assays than scaffold-based methods and can be easily redeveloped once new data are measured. We present highly accurate models to identify frequent hitters in AlphaScreen assays.

Estimates of Prevalence Rates of Cancer Patients With Children and Well-Being in Affected Children: A Systematic Review on Population-Based Findings.

This review assessed population-based estimate rates of cancer patients with minor and young adult children (≤ 25 years), children and young adults having a parent with cancer as well as the psychosocial situation and well-being of children and young adults affected by parental cancer. Eighteen publications on population-based studies were included. Studies varied in the age ranges of both cancer patients and children. The prevalence rates of cancer patients having children ranged from 14 to 24.7% depending on the sample structure (e.g., age, gender). Studies reported that between 1.6 and 8.4% of children resp. young adult children have a parent with a history of cancer. Seven publications reported on the psychosocial situation or well-being in children and young adults affected by parental cancer. Estimate rates of psychosocial problems, psychiatric diagnoses or distress ranged between 2.5 and 34% of children depending on the method of measurement and outcome. The differences in the sample structure between the studies impeded the comparison of prevalence rates. However, the findings help to determine the need for specific support services and health care planning. The results emphazise the importance to routinely include issues on the parental role of patients and questions on the well-being and coping of children into psychooncological care. If necessary, support should be provided to families living with a cancer diagnosis.

Cancer-Related Distress: How Often Does It Co-occur With a Mental Disorder? - Results of a Secondary Analysis.

OBJECTIVES: The Distress Thermometer (DT) is a validated and widely used screening tool to identify clinically relevant distress in cancer patients. It is unclear, to which extend subjectively perceived distress measured by the DT is related to objective burden (mental disorder). We therefore examine the co-occurrence of a mental disorder for different DT thresholds and explore the diagnostic properties of the DT in detecting a mental disorder. METHODS: In this multicenter cross-sectional study, we included 4,020 patients with mixed cancer diagnoses. After selection of relevant cases, weighting procedure and imputation of missing data we evaluated the data of N = 3,212 patients. We used the DT to assess perceived distress and the standardized Composite International Diagnostic Interview for Oncology (CIDI-O) to assess the 4-week prevalence of mental disorders. The association between distress and any mental disorder (MD) is calculated using Pearson correlations. Relative risks for MD in patients with/without distress and the co-occurrence of distress and MD were calculated with Poisson regression. To assess the operating characteristics between distress and MD, we present the area under the curve (AUC). RESULTS: 22.9% of the participants had a cut-off DT level of ≥5 and were affected by MD. Each level of distress co-occurs with MD. The proportion of patients diagnosed with MD was not greater than the proportion of patients without MD until distress levels of DT = 6 were reached. The correlation between DT and MD was r = 0.27. The ROC-analysis shows the area under curve (AUC) = 0.67, which is classified as unsatisfactory. With increasing distress severity, patients are not more likely to have a mental disorder. CONCLUSION: Our results suggests viewing and treating cancer-related distress as a relatively distinct psychological entity. Cancer-related distress may be associated with an increased risk for a mental disorder and vice versa, but the overlap of both concepts is very moderate.

Development and preliminary psychometric investigation of the German Satisfaction with Comprehensive Cancer Care (SCCC) Questionnaire.

PURPOSE: The assessment of patient satisfaction during treatment is essential to provide patient-centered high-quality cancer care. Nevertheless, no German instrument assesses patient satisfaction with comprehensive cancer care, which not only includes oncological treatment, but also interpersonal quality of care as well as psychosocial support services. Based on the French REPERES-60, we developed the German Patient Satisfaction with Comprehensive Cancer Care (SCCC) questionnaire. METHODS: The REPERES-60 was translated and the items were adapted to make it applicable to the German healthcare system and across different tumor entities. Scales of the resulting instrument were extracted via principal axis factoring (PAF). Subsequently, we investigated the reliability (Cronbach's Alpha, CA), discriminatory power (corrected item-scale correlations) and convergent validity (pre-specified correlations of the SCCC with different outcomes). RESULTS: The SCCC consisted of 32 items which were subsequently tested among a sample of 333 patients across different tumor entities (response rate: 47%). Average age was 59 years (standard deviation: 14), 63% were male. PAF revealed four multi-item scales named Competence, Information, Access and Support accounting for 71% of the variance. Two single-items scales assess global satisfaction with medical and psychosocial care, respectively. CA across the multi-item scales ranged from .84 to .96. Discriminatory power was sufficiently high, with all r ≥ .5. Convergent validity was largely verified by negative associations of the four multi-item scales with depressive/anxious symptomatology (r ≥ - .18, p < .01) and fatigue/overall symptom burden (r ≥ - .14, p < .01). CONCLUSION: We developed a tool to assess patient satisfaction with comprehensive cancer care in Germany. The SCCC showed satisfactory psychometric properties. Further studies are needed to verify these preliminary findings.

Existential distress in patients with advanced cancer and their caregivers: study protocol of a longitudinal cohort study.

INTRODUCTION: At the end of life, patients with advanced cancer and their informal caregivers may confront multiple existential concerns. Despite the strong potential to alleviate existential distress through psychosocial interventions, existential distress and its impact on healthcare outcomes have not yet been studied systematically. We aim to investigate the frequency, longitudinal trajectory and predictive impact of existential distress on end-of-life outcomes. We further aim to determine patients' and caregivers' specific need for and utilisation of psychosocial support for existential distress. METHODS: This longitudinal cohort study will consecutively recruit 500 patients with advanced cancer and 500 caregivers from oncological outpatient and inpatient clinics. Participants will complete self-report questionnaires (sociodemographic and disease-related characteristics, existential distress, end-of-life outcomes, resources and support needs) at five points of assessment (at baseline and after 3, 6, 9 and 12 months). At baseline and 6-month follow-up, we will conduct structured diagnostic interviews to assess mental disorders. Statistical analyses will include descriptive statistics to determine the prevalence of existential distress, mental disorders and end-of-life outcomes; multiple linear and logistic regression analyses to calculate the predictive impact of existential distress on end-of-life outcomes; and growth mixture models to analyse longitudinal trajectories of existential distress. DISCUSSION: This study will provide comprehensive knowledge about patients' and caregivers' existential concerns. The longitudinal empirical data will allow for conclusions concerning the frequency and course of existential distress throughout 1 year. This important extension of existing cross-sectional research will contribute to further develop targeted psychosocial interventions. Profiles of existential distress may be applied by clinicians from multiple professions and help to address existential concerns effectively. ETHICS AND DISSEMINATION: The study was approved by the institutional research ethics committee (reference number LPEK-0177). Results will be presented at scientific conferences and published in peer-reviewed journals. Other forms of dissemination will include sharing results on the psychometric properties of the structured demoralisation interview with international research groups and communication with healthcare professionals providing psychosocial treatment for patients and caregivers. Following scientific standards, our progress will be regularly updated on ClinicalTrials.gov. TRIAL REGISTRATION NUMBER: NCT04600206.

Thoughts of death and suicidality among patients with cancer: Examining subtypes and their association with mental disorders.

OBJECTIVE: Cancer is associated with an increased risk for completed suicide. We explored subtypes of thoughts of death, death wishes, suicidal ideation and behavior and their association with mental disorders and demographic and disease-related characteristics. METHODS: We studied 2,141 cancer patients with the standardized Composite International Diagnostic Interview-Oncology (CIDI-O). Assessment included 4-weeks-prevalences of thoughts of death, wish to die, suicidal ideation, suicide plans, and lifetime suicide attempts. We further assessed 4-weeks-prevalences of mood, anxiety, adjustment, somatoform, substance use, and disorders due to general medical condition. We conducted latent class analyses (LCA). RESULTS: The LCA identified three classes with distinct patterns of suicidality. Class 1 (89.0% of the sample) showed no suicidality. Class 2 (6.9%) was characterized by thoughts of death without suicidal ideation. Class 3 (4.1%) was characterized by thoughts of death, suicidal ideation, and suicide plans. Death wishes occurred in both classes 2 and 3. Classes 2 and 3 were associated with a significantly higher risk for any mental disorder (OR from 4.22, adjustment disorder, to 10.20, mood disorders, p < 0.001) compared to class 1. Patients with mental disorders were equally likely in classes 2 and 3. Patients with incurable cancer were significantly more likely in class 2, and less likely in class 3. CONCLUSIONS: Cancer patients with suicidal ideation are not distinctly characterized by mental disorders. Further study of concepts that consider problematic adjustment to the cancer stressor such as death anxiety and demoralization may contribute to understand psychological distress underlying subtypes of thoughts of death and suicidality in cancer.

Sequence-Selective Covalent CaaX-Box Receptors Prevent Farnesylation of Oncogenic Ras Proteins and Impact MAPK/PI3†K Signaling.

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.

Prevalence and Severity of Pain in Cancer Patients in Germany.

Pain is a common symptom in cancer patients, restricts daily life activities and reduces survival time. Identification of sociodemographic, medical and psychological correlates of pain among cancer patients in Germany could help identify subgroups most in need of pain management. In this multicenter, epidemiologic cross-sectional study, we assessed pain prevalence and severity, quality of life (QoL) and psychological distress in a sample of 3,745 cancer patients across all tumor entities. In total, 37.9% patients suffered from cancer-related pain and 56.1% suffered from non-specific pain. Younger, female, less educated and unemployed patients reported pain more frequently and more severe pain (p < 0.001). Pain was associated with distress, depression, anxiety, QoL, tumor stage (p < 0.001), and time since diagnosis (p = 0.012). Pain assessment and pain management should be a routine part of cancer treatment and cancer survivorship care plans.

Small-molecule inhibitors of human mitochondrial DNA transcription.

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.

Risk and associated factors of depression and anxiety in men with prostate cancer: Results from a German multicenter study.

OBJECTIVE: In order to optimize psycho-oncological care, studies that quantify the extent of distress and identify certain risk groups are needed. Among patients with prostate cancer (PCa), findings on depression and anxiety are limited. METHODS: We analyzed data of PCa patients selected from a German multi-center study. Depression and anxiety were assessed with the PHQ-9 and the GAD-7 (cut-off ≥7). We provided physical symptom burden, calculated absolute and relative risk (AR and RR) of depression and anxiety across patient subsets and between patients and the general population (GP) and tested age as a moderator within the relationship of disease-specific symptoms with depression and anxiety. RESULTS: Among 636 participants, the majority reported disease-specific problems (sexuality: 60%; urination: 52%). AR for depression and anxiety was 23% and 22%, respectively. Significant RR were small, with higher risks of distress in patients who are younger (eg, RRdepression = 1.15; 95%-CI: 1.06-1.26), treated with chemotherapy (RRdepression = 1.46; 95%-CI: 1.09-1.96) or having metastases (RRdepression = 1.30; 95%-CI: 1.02-1.65). Risk of distress was slightly elevated compared to GP (eg, RRdepression = 1.13; 95%-CI: 1.07-1.19). Age moderated the relationship between symptoms and anxiety (Burination = -0.10, P = .02; Bsexuality = -0.11, P = .01). CONCLUSIONS: Younger patients, those with metastases or treatment with chemotherapy seem to be at elevated risk for distress and should be closely monitored. Many patients suffer from disease-specific symptom burden, by which younger patients seem to be particularly distressed. Support of coping mechanisms associated with disease-specific symptom burden seems warranted.

Cancer patients' preferred and perceived level of involvement in treatment decision-making: an epidemiological study.

Background: We aimed to analyze preferred and perceived levels of patients' involvement in treatment decision-making in a representative sample of cancer patients.Material and Methods: We conducted a multicenter, epidemiological cross-sectional study with a stratified random sample based on the incidence of cancer diagnoses in Germany. Data were collected between January 2008 and December 2010. Analyses were undertaken between 2017 and 2019. We included 5889 adult cancer patients across all cancer entities and disease stages from 30 acute care hospitals, outpatient facilities, and cancer rehabilitation clinics in five regions in Germany. We used the Control Preferences Scale to assess the preferred level of involvement and the nine-item Shared Decision-Making Questionnaire to assess the perceived level of involvement.Results: About 4020 patients (mean age of 58 years, 51% female) completed the survey. Response rate was 68.3%. About a third each preferred patient-led, shared, or physician-led decision-making. About 50.7% perceived high levels, about a quarter each reported moderate (26.0%) or low (24.3%) levels of shared decision-making. Sex, age, relationship status, education, health care setting, and tumor entity were linked to preferred and/or perceived decision-making. Of those patients who preferred active involvement, about 50% perceived high levels of shared decision-making.Conclusion: The majority of patients with cancer wanted to be involved in medical decisions. Many patients perceived a high level of shared decision-making. However, many patients' level of involvement did not fit their preference. This study provides a solid basis for efforts to improve shared decision-making in German cancer care.

Development of a PDEδ-Targeting PROTACs that Impair Lipid Metabolism.

The prenyl-protein chaperone PDEδ modulates the localization of lipidated proteins in the cell, but current knowledge about its biological function is limited. Small-molecule inhibitors that target the PDEδ prenyl-binding site have proven invaluable in the analysis of biological processes mediated by PDEδ, like KRas cellular trafficking. However, allosteric inhibitor release from PDEδ by the Arl2/3 GTPases limits their application. We describe the development of new proteolysis-targeting chimeras (PROTACs) that efficiently and selectively reduce PDEδ levels in cells through induced proteasomal degradation. Application of the PDEδ PROTACs increased sterol regulatory element binding protein (SREBP)-mediated gene expression of enzymes involved in lipid metabolism, which was accompanied by elevated levels of cholesterol precursors. This finding for the first time demonstrates that PDEδ function plays a role in the regulation of enzymes of the mevalonate pathway.