Search

Tafirenyika Gwenzi,1,2 Anna Zhu,2,3 Petra Schrotz-King,1 Ben Schöttker,3 Michael Hoffmeister,3 Dominic Edelmann,4 Hermann Brenner1,3,5,6 1Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, 69120, Germany; 2Medical Faculty Heidelberg, Heidelberg University, Heidelberg, 69120, Germany; 3Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany; 4Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany; 5Network Aging Research, Heidelberg University, Heidelberg, 69115, Germany; 6German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, 69120, GermanyCorrespondence: Hermann Brenner, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, Heidelberg, 69120, Germany, Tel +49 6221 42 1300, Fax +49-6221 42 1302, Email h.brenner@Dkfz-Heidelberg.deAbstract: Post-operative inflammation in cancer patients can be modulated by drugs and diets, but evidence on its prognostic role, which would be crucial for personalized treatment and surveillance schemes, remains rather limited. We aimed to systematically review and meta-analyse studies on the prognostic value of post-operative C-reactive protein (CRP)-based inflammatory biomarkers among patients with colorectal cancer (CRC) (PROSPERO#: CRD42022293832). PubMed, Web of Science and Cochrane databases were searched until February 2023. Studies reporting associations between post-operative CRP, Glasgow Prognostic Score (GPS) or modified Glasgow Prognostic Score (mGPS) with overall survival (OS), CRC-specific survival (CSS) and recurrence-free survival (RFS) were included. Hazard ratios (HRs) with 95% confidence intervals (CIs) for the predictor-outcome associations were pooled using R-software, version 4.2. Sixteen studies (n = 6079) were included in the meta-analyses. Elevated post-operative CRP was a predictor of poor OS, CSS and RFS compared with low CRP levels [HR (95% CI): 1.72 (1.32– 2.25); 1.63 (1.30– 2.05); 2.23 (1.44– 3.47), respectively]. A unit increase in post-operative GPS predicted poor OS [HR (95% Cl): 1.31 (1.14– 1.51)]. Moreover, a unit increase in post-operative mGPS was associated with poor OS and CSS [HR (95% Cl): 1.93 (1.37– 2.72); 3.16 (1.48– 6.76), respectively]. Post-operative CRP-based inflammatory biomarkers have a significant prognostic role for patients with CRC. Prognostic value of these easy-to-obtain routine measurements thereby seems to outperform most of the much more complex blood- or tissue-based predictors in the current focus of multi-omics-based research. Future studies should validate our findings, establish optimal time for biomarker assessment and determine clinically useful cut-off values of these biomarkers for post-operative risk-stratification and treatment-response monitoring.Keywords: C-reactive protein, survival, assess, risk-stratification, treatment-response

The antiemetic response and side effects resulting from treatment with methylprednisolone (MPA) given on two different dose schedules were evaluated in 20 women with breast cancer who were undergoing chemotherapy consisting of cyclophosphamide, methotrexate and 5-fluorouracil (CMF). This randomized, crossover, double-blind study compared the antiemetic efficacy of a single dose of 125 mg MPN with that of two such doses. The study demonstrated the superiority of the latter protocol in preventing CMF-induced nausea and vomiting. The rate of antiemetic response to single vs double doses was as to follows: complete protection, 17% vs 30%; partial and minimal protection, 39% vs 55%; and no protection, 44% vs 15% of the courses, respectively (P = 0.0087). No difference in the antiemetic response rate was found between the first and the second course. Treatment with MPN was well tolerated, and no difference in the incidence of side effects was found between the single-dose and the double-dose schedule. We recommend the use of two doses of 125 mg MPN as prophylactic antiemetic treatment in breast-cancer patients receiving CMF chemotherapy. [ABSTRACT FROM AUTHOR]

Bacterial dormancy is a valuable strategy to survive stressful conditions. Toxins from chromosomal toxin-antitoxin systems have the potential to halt cell growth, induce dormancy, and eventually promote a stress-tolerant persister state. Due to their potential toxicity when overexpressed, sophisticated expression systems are needed when studying toxin genes. Here, we present a moderate expression system for toxin genes based on an artificial 5' untranslated region. We applied the system to induce expression of the toxin gene tisB from the chromosomal type I toxin-antitoxin system tisB/istR-1 in Escherichia coli . TisB is a small hydrophobic protein that targets the inner membrane, resulting in depolarization and ATP depletion. We analyzed TisB-producing cells by RNA-sequencing and revealed several genes with a role in recovery from TisB-induced dormancy, including the chaperone genes ibpAB and spy . The importance of chaperone genes suggested that TisB-producing cells are prone to protein aggregation, which was validated by an in vivo fluorescent reporter system. We moved on to show that TisB is an essential factor for protein aggregation upon DNA damage mediated by the fluoroquinolone antibiotic ciprofloxacin in E. coli wild-type cells. The occurrence of protein aggregates correlates with an extended dormancy duration, which underscores their importance for the life cycle of TisB-dependent persister cells., Importance: Protein aggregates occur in all living cells due to misfolding of proteins. In bacteria, protein aggregation is associated with cellular inactivity, which is related to dormancy and tolerance to stressful conditions, including exposure to antibiotics. In Escherichia coli , the membrane toxin TisB is an important factor for dormancy and antibiotic tolerance upon DNA damage mediated by the fluoroquinolone antibiotic ciprofloxacin. Here, we show that TisB provokes protein aggregation, which, in turn, promotes an extended state of cellular dormancy. Our study suggests that protein aggregation is a consequence of membrane toxins with the potential to affect the duration of dormancy and the outcome of antibiotic therapy.

While genome-wide association studies are valuable in identifying CRC survival predictors, the benefit of adding blood DNA methylation (blood-DNAm) to clinical features, including the TNM system, remains unclear. In a multi-site population-based patient cohort study of 2116 CRC patients with baseline blood-DNAm, we analyzed survival predictions using eXtreme Gradient Boosting with a 5-fold nested leave-sites-out cross-validation across four groups: traditional and comprehensive clinical features, blood-DNAm, and their combination. Model performance was assessed using time-dependent ROC curves and calibrations. During a median follow-up of 10.3 years, 1166 patients died. Although blood-DNAm-based predictive signatures achieved moderate performances, predictive signatures based on clinical features outperformed blood-DNAm signatures. The inclusion of blood-DNAm did not improve survival prediction over clinical features. M1 stage, age at blood collection, and N2 stage were the top contributors. Despite some prognostic value, incorporating blood DNA methylation did not enhance survival prediction of CRC patients beyond clinical features., (© 2024. The Author(s).)

Background: The transition from school to university is often accompanied by a change in students' lifestyles. So far little is known whether convenience behavior is an essential factor affecting students' health and social interaction. In a heterogeneous population regard to sociodemographic and anthropometric characteristics the Convenience Behavior Questionnaire (CBQ) showed a better relationship between convenience-related behavior with overweight and obesity than established questionnaires. Here we assessed convenience behavior in a large well characterized cohort of university students and its association with health-related (mainly sedentary behavior and physical activity), study-related and sociodemographic factors with the Convenience Behavior Questionnaire (CBQ)., Methods: A total of 4,351 students participated in an online survey, of which 3,983 (23.6 ± 5.3 years old, 71.3% females) answered the questions concerning convenience behavior. A low value in the CBQ indicates more convenience behavior [Convenience Behavior Index (CBI) range: 3-15]. Differences with regard to sociodemographic (age, gender, body mass index), study-related (semester, degree, field of study) and health-related (physical activity, sedentary behavior) variables were examined with Mann-Whitney-U test or Kruskal-Wallis test and post-hoc tests (Bonferroni)., Results: The CBI of men and women differed significantly ( z  = -6.847, p  < 0.001, r  = 0.11). First-year students and students beyond their first year showed significant differences ( z  = -2.355, p  ≤ 0.05, r  = 0.04). Differences were also found in the field of study (Chi2 (6) = 147.830, p  < 0.001) and the targeted degree (Chi2 (7) = 79.985, p  < 0.001). Furthermore, differences were found in the body mass index (Chi2 (5) = 70.678, p  < 0.001), physical activity (Chi2 (2) = 279.040, p  < 0.001) and sedentary behavior ( z  = -4.660, p  < 0.001, r  = 0.07)., Conclusion: The results showed risk groups of convenience behavior among students [men, first-year, students enrolled in "Science, Technology, Engineering and Mathematics (STEM)," bachelor]. Our results confirm for the first time in a very homogeneous population a gender difference and an association between CBI and health-related factors. Further studies are needed to analyze the health behavior of students in more detail, especially their convenience behavior., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Schwab, Reichel, Werner, Schäfer, Heller, Edelmann, Beutel, Letzel, Dietz, Simon and Kalo.)

Background: DNA methylation biomarkers in colorectal cancer (CRC) tissue hold potential as prognostic indicators. However, individual studies have yielded heterogeneous results, and external validation is largely absent. We conducted a comprehensive external validation and meta-analysis of previously suggested gene methylation biomarkers for CRC prognosis., Methods: We performed a systematic search to identify relevant studies investigating gene methylation biomarkers for CRC prognosis until March 2024. Our external validation cohort with long-term follow-up included 2303 patients with CRC from 22 hospitals in southwest Germany. We used Cox regression analyses to assess associations between previously suggested gene methylation biomarkers and prognosis, adjusting for clinical variables. We calculated pooled hazard ratios (HRs) and their 95% confidence intervals (CIs) using random-effects models., Findings: Of 151 single gene and 29 multiple gene methylation biomarkers identified from 121 studies, 37 single gene and seven multiple gene biomarkers were significantly associated with CRC prognosis after adjustment for clinical variables. Moreover, the directions of these associations with prognosis remained consistent between the original studies and our validation analyses. Seven single biomarkers and two multi-biomarker signatures were significantly associated with CRC prognosis in the meta-analysis, with a relatively strong level of evidence for CDKN2A, WNT5A, MLH1, and EVL., Interpretation: In a comprehensive evaluation of the so far identified gene methylation biomarkers for CRC prognosis, we identified candidates with potential clinical relevance for further investigation., Funding: The German Research Council, the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, the German Federal Ministry of Education and Research., Competing Interests: Declaration of interests JNK declares consulting services for Owkin, France; DoMore Diagnostics, Norway, Panakeia, UK, Scailyte, Switzerland, and Histofy, UK; furthermore he holds shares in StratifAI GmbH, Germany, and has received honoraria for lectures by AstraZeneca, Bayer, Eisai, MSD, BMS, Roche, Pfizer and Fresenius., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Beyond established anti-programmed cell death protein 1/programmed cell death ligand 1 immunotherapy, T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) and its ligand CD155 are promising novel inhibitory immune checkpoint targets in human malignancies. Yet, in cutaneous squamous cell carcinoma, evidence on the collective expression patterns of these inhibitory immune checkpoints is scarce. Complete tumour sections of 36 cutaneous squamous cell carcinoma, 5 cutaneous metastases and 9 keratoacanthomas, a highly-differentiated, squamoproliferative tumour, with disparately benign biologic behaviour, were evaluated by immunohistochemistry for expression of programmed cell death ligand 1 (Tumor Proportion Score, Immune Cell Score), TIGIT, CD155 and CD8+ immune infiltrates. Unlike keratoacanthomas, cutaneous squamous cell carcinoma displayed a strong positive correlation of programmed cell death ligand 1 Tumor Proportion Score and CD115 expression (p < 0.001) with significantly higher programmed cell death ligand 1 Tumor Proportion Score (p < 0.001) and CD155 expression (p < 0.01) in poorly differentiated G3-cutaneous squamous cell carcinoma compared with keratoacanthomas. TIGIT+ infiltrates were significantly increased in programmed cell death ligand 1 Immune Cell Score positive primary tumours (p = 0.05). Yet, a strong positive correlation of TIGIT expression with CD8+ infiltrates was only detected in cutaneous squamous cell carcinoma (p < 0.01), but not keratoacanthomas. Providing a comprehensive overview on the collective landscape of inhibitory immune checkpoint expression, this study reveals associations of novel inhibitory immune checkpoint with CD8+ immune infiltrates and tumour differentiation and highlights the TIGIT/CD155 axis as a potential new target for cutaneous squamous cell carcinoma immunotherapy.

The research aimed to identify previously published CpG-methylation-based prognostic biomarkers and prediction models for colorectal cancer (CRC) prognosis and validate them in a large external cohort. A systematic search was conducted, analyzing 298 unique CpGs and 12 CpG-based prognostic models from 28 studies. After adjustment for clinical variables, 48 CpGs and five prognostic models were confirmed to be associated with survival. However, the discrimination ability of the models was insufficient, with area under the receiver operating characteristic curves ranging from 0.53 to 0.62. Calibration accuracy was mostly poor, and no significant added prognostic value beyond traditional clinical variables was observed. All prognostic models were rated at high risk of bias. While a fraction of CpGs showed potential clinical utility and generalizability, the CpG-based prognostic models performed poorly and lacked clinical relevance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

We conducted the first large genome-wide association study to identify novel genetic variants that predict better (or poorer) prognosis in colorectal cancer patients receiving standard first-line oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin. We used data from two phase III trials, NCCTG N0147 and NCCTG N9741 and a population-based patient cohort, DACHS. Multivariable Cox proportional hazards models were employed, including an interaction term between each SNP and type of treatment for overall survival (OS) and progression-free survival. The analysis was performed for studies individually, and the results were combined using fixed-effect meta-analyses separately for resected stage III colon cancer (3098 patients from NCCTG N0147 and 549 patients from DACHS) and mCRC (505 patients from NCCTG N9741 and 437 patients from DACHS). We further performed gene-based analysis as well as in silico bioinformatics analysis for CRC-relevant functional genomic annotation of identified loci. In stage III colon cancer patients, a locus on chr22 (rs11912167) was associated with significantly poorer OS after oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin (P interaction  < 5 × 10 -8 ). For mCRC patients, three loci on chr1 (rs1234556), chr12 (rs11052270) and chr15 (rs11858406) were found to be associated with differential OS (P < 5 × 10 -7 ). The locus on chr1 located in the intronic region of RCSD1 was replicated in an independent cohort of 586 mCRC patients from ALGB/SWOG 80405 (P interaction  = .04). The GWA gene-based analysis yielded for RCSD1 the most significant association with differential OS in mCRC (P = 6.6 × 10 -6 ). With further investigation into its biological mechanisms, this finding could potentially be used to individualize first-line treatment and improve clinical outcomes., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: DNA methylation biomarkers have great potential in improving prognostic classification systems for patients with cancer. Machine learning (ML)-based analytic techniques might help overcome the challenges of analyzing high-dimensional data in relatively small sample sizes. This systematic review summarizes the current use of ML-based methods in epigenome-wide studies for the identification of DNA methylation signatures associated with cancer prognosis., Methods: We searched three electronic databases including PubMed, EMBASE, and Web of Science for articles published until 2 January 2023. ML-based methods and workflows used to identify DNA methylation signatures associated with cancer prognosis were extracted and summarized. Two authors independently assessed the methodological quality of included studies by a seven-item checklist adapted from 'A Tool to Assess Risk of Bias and Applicability of Prediction Model Studies (PROBAST)' and from the 'Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK). Different ML methods and workflows used in included studies were summarized and visualized by a sunburst chart, a bubble chart, and Sankey diagrams, respectively., Results: Eighty-three studies were included in this review. Three major types of ML-based workflows were identified. 1) unsupervised clustering, 2) supervised feature selection, and 3) deep learning-based feature transformation. For the three workflows, the most frequently used ML techniques were consensus clustering, least absolute shrinkage and selection operator (LASSO), and autoencoder, respectively. The systematic review revealed that the performance of these approaches has not been adequately evaluated yet and that methodological and reporting flaws were common in the identified studies using ML techniques., Conclusions: There is great heterogeneity in ML-based methodological strategies used by epigenome-wide studies to identify DNA methylation markers associated with cancer prognosis. In theory, most existing workflows could not handle the high multi-collinearity and potentially non-linearity interactions in epigenome-wide DNA methylation data. Benchmarking studies are needed to compare the relative performance of various approaches for specific cancer types. Adherence to relevant methodological and reporting guidelines are urgently needed., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: About half of AML patients achieving complete remission (CR) display measurable residual disease (MRD) and eventually relapse. FLYSYN is an Fc-optimized antibody for eradication of MRD directed to FLT3/CD135, which is abundantly expressed on AML cells., Methods: This first-in-human, open-label, single-arm, multicenter trial included AML patients in CR with persisting or increasing MRD and evaluated safety/tolerability, pharmacokinetics and preliminary efficacy of FLYSYN at different dose levels administered intravenously (cohort 1-5: single dose of 0.5 mg/m 2 , 1.5 mg/m 2 , 5 mg/m 2 , 15 mg/m 2 , 45 mg/m 2 ; cohort 6: 15 mg/m 2 on day 1, 15 and 29). Three patients were treated per cohort except for cohorts 4 and 6, which were expanded to nine and ten patients, respectively. Primary objective was safety, and secondary efficacy objective was ≥ 1 log MRD reduction or negativity in bone marrow., Results: Overall, 31 patients were treated, of whom seven patients (22.6%) experienced a transient decrease in neutrophil count (two grade 3, others ≤ grade 2). No infusion-related reaction or dose-limiting toxicity was observed. Adverse events (AEs) were mostly mild to moderate, with the most frequent AEs being hematologic events and laboratory abnormalities. Response per predefined criteria was documented in 35% of patients, and two patients maintained MRD negativity until end of study. Application of 45 mg/m 2 FLYSYN as single or cumulative dose achieved objective responses in 46% of patients, whereas 28% responded at lower doses., Conclusions: FLYSYN monotherapy is safe and well-tolerated in AML patients with MRD. Early efficacy data are promising and warrant further evaluation in an up-coming phase II trial. Trial registration This clinical is registered on clinicaltrials.gov (NCT02789254)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The gold standard for investigating the efficacy of a new therapy is a (pragmatic) randomized controlled trial (RCT). This approach is costly, time-consuming, and not always practicable. At the same time, huge quantities of available patient-level control condition data in analyzable format of (former) RCTs or real-world data (RWD) are neglected. Therefore, alternative study designs are desirable. The design presented here consists of setting up a prediction model for determining treatment effects under the control condition for future patients. When a new treatment is intended to be tested against a control treatment, a single-arm trial for the new therapy is conducted. The treatment effect is then evaluated by comparing the outcomes of the single-arm trial against the predicted outcomes under the control condition. While there are obvious advantages of this design compared to classical RCTs (increased efficiency, lower cost, alleviating participants' fear of being on control treatment), there are several sources of bias. Our aim is to investigate whether and how such a design-the prediction design-may be used to provide information on treatment effects by leveraging external data sources. For this purpose, we investigated under what assumptions linear prediction models could be used to predict the counterfactual of patients precisely enough to construct a test and an appropriate sample size formula for evaluating the average treatment effect in the population of a new study. A user-friendly R Shiny application (available at: https://web.imbi.uni-heidelberg.de/PredictionDesignR/) facilitates the application of the proposed methods, while a real-world application example illustrates them., (© 2023 The Authors. Biometrical Journal published by Wiley-VCH GmbH.)

Dose-finding designs for phase-I trials aim to determine the recommended phase-II dose (RP2D) for further phase-II drug development. If the trial includes patients for whom several lines of standard therapy failed or if the toxicity of the investigated agent does not necessarily increase with dose, optimal dose-finding designs should limit the frequency of treatment with suboptimal doses. We propose a two-stage design strategy with a run-in intra-patient dose escalation part followed by a more traditional dose-finding design. We conduct simulation studies to compare the 3 + 3 design, the Bayesian Optimal Interval Design (BOIN) and the Continual Reassessment Method (CRM) with and without intra-patient dose escalation. The endpoints are accuracy, sample size, safety, and therapeutic efficiency. For scenarios where the correct RP2D is the highest dose, inclusion of an intra-patient dose escalation stage generally increases accuracy and therapeutic efficiency. However, for scenarios where the correct RP2D is below the highest dose, intra-patient dose escalation designs lead to increased risk of overdosing and an overestimation of RP2D. The magnitude of the change in operating characteristics after including an intra-patient stage is largest for the 3 + 3 design, decreases for the BOIN and is smallest for the CRM., (© 2022 The Authors. Pharmaceutical Statistics published by John Wiley & Sons Ltd.)

Background & Aims: Polygenic risk scores (PRSs) could help to define personalized colorectal cancer (CRC) screening strategies. The aim of this study was to evaluate whether a PRS, along with adenoma characteristics, could help to define more personalized and risk-adapted surveillance intervals., Methods: In a population-based, case-control study from Germany, detailed information on previous colonoscopies and a PRS based on 140 CRC-related, single-nucleotide polymorphisms was obtained from 4696 CRC cases and 3709 controls. Participants were classified as having low, medium, or high genetic risk according to tertiles of PRSs among controls. We calculated the absolute risk of CRC based on the PRS and colonoscopy history and findings., Results: We observed major variations of CRC risk according to the PRS, including among individuals with detection and removal of adenomas at colonoscopy. For instance, the estimated 10-year absolute risk of CRC for 50-year-old men and women with no polyps, for whom repeat screening colonoscopy is recommended after 10 years only, was 0.2%. Equivalent absolute risks were estimated for people with low-risk adenomas and low PRS. However, the same levels of absolute risk were reached within 3 to 5 years by those with low-risk adenomas and high PRS and with high-risk adenomas irrespective of the PRS., Conclusions: Consideration of genetic predisposition to CRC risk, as determined by a PRS, could help to define personalized, risk-adapted surveillance intervals after detection and removal of adenomas at screening colonoscopy. However, whether the risk variation is strong enough to direct clinical risk stratification needs to be explored further., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Associations between candidate germline genetic variants and treatment outcome of oxaliplatin, a drug commonly used for patients with colorectal cancer, have been reported but not robustly established. This study aimed to construct polygenic hazard scores (PHSs) as predictive markers for oxaliplatin treatment outcome by using a supervised principal component approach (PCA)., Methods: Genome-wide association analysis for overall survival, including interaction terms (SNP*treatment type) was carried out using two phase III trials, 3,098 resected stage III colon cancer (rCC) patients of NCCTG N0147 and 506 metastatic colorectal cancer (mCRC) patients of NCCTG N9741, separately. SNPs showing interaction with genome-wide significance (P &lt; 5 × 10-8) were selected for PCA to derive a PHS. PHS interaction with treatment was included in Cox regression models to predict outcome. Replication of prediction models was performed in an independent cohort, DACHS., Results: The two PHSs based on the first two principal components of selected SNPs (15SNPs for rCC and 13SNPs for mCRC) were used to construct interaction terms with treatment type and included in models adjusted for clinical covariables. However, in the DACHS study, the addition of the two PHS terms to clinical models did not improve the prediction error in either patients with rCC or mCRC. PHS interaction was also not replicated., Conclusions: The PHSs derived using principal components efficiently combined multiple predictive SNPs for estimating likelihood of benefit from oxaliplatin versus other treatment but could not be replicated., Impact: These results highlight the potential but also challenges in generating evidence for a predictive polygenic score for oxaliplatin efficacy., (©2022 The Authors; Published by the American Association for Cancer Research.)

Distance covariance is a powerful new dependence measure that was recently introduced by Székely et al. and Székely and Rizzo. In this work, the concept of distance covariance is extended to measuring dependence between a covariate vector and a right-censored survival endpoint by establishing an estimator based on an inverse-probability-of-censoring weighted U-statistic. The consistency of the novel estimator is derived. In a large simulation study, it is shown that induced distance covariance permutation tests show a good performance in detecting various complex associations. Applying the distance covariance permutation tests on a gene expression dataset from breast cancer patients outlines its potential for biostatistical practice., (© 2021 The Authors. Biometrics published by Wiley Periodicals LLC on behalf of International Biometric Society.)

Background: Physical inactivity and sedentary behavior are modifiable risk factors for an unhealthy lifestyle in university students. The aim of this study was to identify subgroups among German university students with an increased risk for unhealthy behavior. For this purpose, differences in physical activity and sedentary behavior with respect to sociodemographic and study related factors were examined., Methods: A total of 4,351 students participated in an online survey. The amount of physical activity (metabolic equivalent of task-min/week) and the sitting time (h/day) were assessed using the German short form of the International Physical Activity Questionnaire. Differences in gender and age as well as field of study, targeted degree and study semester were analyzed using a single factorial ANOVA with Tukey correction or a Welch-ANOVA with Games-Howell correction., Results: For physical activity, significant differences were found for gender ( F (2, 80.46) = 17.79, p < 0.001, ηp2 = 0.009), for field of study ( F (5, 1738.09) = 7.41, p < 0.001, ηp2 = 0.01), and for study semester ( F (1, 948.12) = 5.53, p < 0.05, ηp2 =0.001), but not for age and targeted degree ( p > 0.05). For sedentary behavior, significant differences were found for field of study ( F (5, 3816) = 5.69, p < 0.001, ηp2 = 0.01) and targeted degree ( F (3, 3868) = 3.94, p < 0.01, ηp2 = 0.003), but not for gender, age and study semester ( p > 0.05)., Conclusion: Female students, students enrolled in "natural sciences, mathematics and informatics" and first year students appear to have an increased risk of an unhealthy lifestyle. Future research should identify barriers to and incentives of physical activity as well as reasons for high amounts of SB in sub-populations of university students. Suitable prevention and intervention programs are necessary., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Edelmann, Pfirrmann, Heller, Dietz, Reichel, Werner, Schäfer, Tibubos, Deci, Letzel, Simon and Kalo.)

Bacterial persistence is a phenomenon that is founded by the existence of a subpopulation of multidrug-tolerant cells. These so-called persister cells endure otherwise lethal stress situations and enable restoration of bacterial populations upon return to favorable conditions. Persisters are especially notorious for their ability to survive antibiotic treatments without conventional resistance genes and to cause infection relapse. The persister state is typically correlated with reduction or inhibition of cellular activity. Early on, chromosomal toxin-antitoxin (TA) systems were suspected to induce the persister state in response to environmental stress. However, this idea has been challenged during the last years. Especially the involvement of toxins from type II TA systems in persister formation is put into question. For toxins from type I TA systems the debate has just started. Here, we would like to summarize recent knowledge gained for the type I TA system tisB/istR-1 from Escherichia coli . TisB is a small, membrane-targeting toxin, which disrupts the proton motive force (PMF), leading to membrane depolarization. Based on experimental data, we hypothesize that TisB primarily stabilizes the persister state through depolarization and further, secondary effects. We will present a simple model that will provide a framework for future directions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Edelmann and Berghoff.)

Background: Associations between candidate genetic variants and treatment outcomes of oxaliplatin, a drug commonly used for colorectal cancer patients, have been reported but not robustly established. This study aimed to validate previously reported prognostic and predictive genetic markers for oxaliplatin treatment outcomes and evaluate additional putative functional variants., Methods: Fifty-three SNPs were selected based on previous reports (40 SNPs) or putative function in candidate genes (13 SNPs). We used data from 1,502 patients with stage II-IV colorectal cancer who received primary adjuvant chemotherapy, 37% of whom received oxaliplatin treatment. Multivariable Cox proportional hazards models for overall survival and progression-free survival were applied separately in stage II-III and stage IV patients. For predictive SNPs, differential outcomes according to the type of chemotherapy (oxaliplatin-based vs. others) were evaluated using an interaction term. For prognostic SNPs, the association was assessed solely in patients with oxaliplatin-based treatment., Results: Twelve SNPs were predictive and/or prognostic at P < 0.05 with differential survival based on the type of treatment, in patients with stage II-III ( GSTM5 -rs11807, ERCC2 -rs13181, ERCC2 -rs1799793, ERCC5 -rs2016073, XPC -rs2228000, P2RX7 -rs208294, HMGB1- rs1360485) and in patients with stage IV ( GSTM5 -rs11807, MNAT1 -rs3783819, MNAT1 -rs4151330, CXCR1 -rs2234671, VEGFA -rs833061, P2RX7- rs2234671). In addition, five novel putative functional SNPs were identified to be predictive ( ATP8B3 -rs7250872, P2RX7 -rs2230911, RPA1 -rs5030755, MGMT -rs12917, P2RX7 -rs2227963)., Conclusions: Some SNPs yielded prognostic and/or predictive associations significant at P < 0.05, however, none of the associations remained significant after correction for multiple testing., Impact: We did not robustly confirm previously reported SNPs despite some suggestive findings but identified further potential predictive SNPs, which warrant further investigation in well-powered studies., (©2021 The Authors; Published by the American Association for Cancer Research.)

The COVID-19 pandemic led to a shutdown of universities in Germany. In a longitudinal design, we compared mental health (depression, anxiety, somatic complaints) of university students in Germany before (June to August 2019) and in the course of the COVID-19 pandemic (June 2020) and determined the impact of pandemic-related stress and loneliness on students' mental health in self-report online surveys. We investigated 443 participants (mean age 22.8 years), among them 77% female, and 10.4% medical students. A small increase of depression mean scores was observed (F(1,420) = 5.21; p = .023), anxiety and somatic complaints have not significantly changed. There was a medium increase in loneliness from pre-pandemic scores to the pandemic situation (F(1,423) = 30.56; p < .001). Analyzed with regression analyses, current loneliness and pre-pandemic distress represented the strongest associations with mental health during the pandemic. Additionally, health-related concerns during the pandemic were associated with symptoms of depression [b = 0.21; 95%CI(0.08; 0.34); t = 3.12; p = .002], anxiety [b = 0.07; 95%CI(0.01; 0.12); t = 2.50; p = .013], somatic complaints [b = 0.33; 95%CI(0.18; 0.47); t = 4.49; p < .001], and loneliness [b = 0.10; 95%CI(0.03; 0.17); t = 2.74; p = .006]. Social stress due to the pandemic situation was associated with loneliness [b = 0.38; 95%CI(0.32; 0.45); t = 11.75; p < .001]. The results imply that university students represent a risk group for psychosocial long-term ramifications of the pandemic., (© 2021. The Author(s).)

DnaA is the initiator protein of chromosome replication, but the regulation of its homoeostasis in enterobacteria is not well understood. The DnaA level remains stable at different growth rates, suggesting a link between metabolism and dnaA expression. In a bioinformatic prediction, which we made to unravel targets of the sRNA rnTrpL in Enterobacteriaceae , the dnaA mRNA was the most conserved target candidate. The sRNA rnTrpL is derived from the transcription attenuator of the tryptophan biosynthesis operon. In Escherichia coli , its level is higher in minimal than in rich medium due to derepressed transcription without external tryptophan supply. Overexpression and deletion of the rnTrpL gene decreased and increased, respectively, the levels of dnaA mRNA. The decrease of the dnaA mRNA level upon rnTrpL overproduction was dependent on hfq and rne . Base pairing between rnTrpL and dnaA mRNA in vivo was validated. In minimal medium, the oriC level was increased in the ΔtrpL mutant, in line with the expected DnaA overproduction and increased initiation of chromosome replication. In line with this, chromosomal rnTrpL mutation abolishing the interaction with dnaA increased both the dnaA mRNA and the oriC level. Moreover, upon addition of tryptophan to minimal medium cultures, the oriC level in the wild type was increased. Thus, rnTrpL is a base-pairing sRNA that posttranscriptionally regulates dnaA in E. coli . Furthermore, our data suggest that rnTrpL contributes to the DnaA homoeostasis in dependence on the nutrient availability, which is represented by the tryptophan level in the cell.