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The FKM guideline nonlinear published in 2019 does not yet contain a definition for a cyclic utilization rate in the load direction. One of the reasons is the nonlinear material behavior, which makes it difficult to calculate a utilization rate in the load direction. In order to enable the definition of a cyclic utilization rate, the cyclic utilization rate according to the FKM guideline "Analytical Strength Assessment" (FKM linear) is examined in more detail and a proposal is made for an efficient iteration procedure for the calculation of the utilization rate based on the consequent Miner rule. This iteration procedure has an accuracy comparable to that of Newton's method. Unlike FKM linear, the FKM guideline nonlinear takes nonlinear elastic‐plastic material behavior into account when calculating component fatigue lives. This results in a nonlinearity in the calculation, which makes it difficult to define an objective function for the Newton method. Currently, the user can only use interval nesting, which requires considerable computational effort. The newly introduced efficient iteration method does not require the definition of an objective function and its derivative in order to calculate the next iteration value. The introduction of the efficient iteration procedure thus allows for the first time the fast calculation of a cyclic utilization rate based on FKM guideline nonlinear. The utilization rate is therefore defined for the first time within in this paper, including a termination criterion. [ABSTRACT FROM AUTHOR]

Pancreatic adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer deaths by 2030 and this is mostly due to therapy failure. Limited treatment options and resistance to standard-of-care (SoC) therapies makes PDAC one of the cancer types with poorest prognosis and survival rates [1,2]. Pancreatic tumors are renowned for their poor response to therapeutic interventions including targeted therapies, chemotherapy and radiotherapy. Herein, we review hallmarks of therapy resistance in PDAC and current strategies aiming to tackle escape mechanisms and to re-sensitize cancer cells to therapy. We will further provide insights on recent advances in the field of drug discovery, nanomedicine, and disease models that are setting the ground for future research., 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 © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: This study aimed to explore the disparities in PD-1 and PD-L1 expression among oral squamous cell carcinomas (OSCCs) in individuals categorized as never-smokers/never-drinkers versus smokers/drinkers., Methods: Immunohistochemical staining for PD-1 and PD-L1, along with PDCD1LG2/cen9 dual color probe analysis, was conducted on 130 OSCC specimens from both smoker/drinker and never-smoker/never-drinker cohorts. Associations between smoking/drinking status, clinicopathologic data, immunohistochemical antibody expression, fluorescence in situ hybridization, and survival outcomes were assessed., Results: OSCC in never-smokers/never-drinkers exhibited significantly elevated PD-1 expression (p = 0.003), increased PD-L1-TPS expression (p = 0.044), and elevated PD-L1-CPS expression (p < 0.001). High PD-L1-ICS expression was more prevalent in never-smokers (p = 0.042). Moreover, never-smokers and never-drinkers demonstrated augmented PD-L1 gene copy numbers (p = 0.081 and p = 0.054, respectively). Increased PD-L1 gene copy number, particularly amplification, correlated with PD-L1-TPS (p = 0.039 and p < 0.001). Conversely, PD-L1 gene copy loss was associated with negative PD-L1-CPS (p = 0.023). Notably, positive PD-L1-CPS was significantly linked with improved overall survival (p = 0.023)., Conclusions: OSCC arising in never-smokers/never-drinkers exhibit heightened PD-1/PD-L1 signaling, suggesting potential efficacy of immune checkpoint therapy in this subgroup of tumors., (© 2024 The Author(s). Head & Neck published by Wiley Periodicals LLC.)

Objectives: To determine the safety and oncological advantages of en bloc resection of bladder tumour (ERBT) vs conventional transurethral resection of bladder tumour (cTURBT) in terms of resection quality, staging quality, and safety., Patients and Methods: We conducted a single-blinded randomised controlled trial at seven European hospitals with the following inclusion criteria: first diagnosis of non-muscle-invasive bladder cancer, no singular carcinoma in situ, and tumour size >4.3 mm. Patients were randomised intraoperatively in a 1:1 ratio to either the ERBT or cTURBT group. Outcome analysis was performed using the chi-square test, t-test, and multivariate regression analysis., Results: A total of 97 patients were randomised into the study (cTURBT = 40, ERBT = 57). A switch to cTURBT was necessary in two patients (3.5%) and 11.5% of the screened patients were preoperatively excluded for ERBT. There was no difference in the specimen presence of detrusor muscle with 73.7% in cTURBT and 67.3% in ERBT specimens (P = 0.69). There were no significant differences in mean operative time (ERBT 27.6 vs cTURBT 25.4 min, P = 0.450) or mean resection time (ERBT 16.3 vs cTURBT 15.5 min, P = 0.732). Overall the complication rate did not differ significantly (ERBT 18.2% vs cTURBT 7.5%, P = 0.142). Bladder perforations occurred significantly more often in the ERBT group (ERBT seven vs cTURBT none, P = 0.020). R0 status was reported more often after ERBT, whilst a second resection was significantly less frequent after ERBT (P = 0.018). Recurrence rates were comparable for both techniques after 6 months of follow-up., Conclusion: The feasibility of ERBT is higher than previously reported. Whereas other perioperative and safety parameters are comparable to cTURBT, bladder perforations occurred significantly more often in the ERBT group and raised safety concerns. This is why this trial was terminated., (© 2024 The Author(s). BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Literature suggests that intravenous prophylaxis exceeding 48 h offers no additional benefit in preventing surgical site infections (SSI) in patients with microvascular head and neck reconstruction. However, protocols for antibiotic therapy duration post-reconstruction are not standardized. This study identifies factors predicting prolonged intravenous antibiotic use and antibiotic escalation in patients receiving free flap head neck reconstruction. A retrospective analysis of 446 patients receiving free flap reconstruction was conducted, examining predictors for antibiotic therapy > 10 days and postoperative escalation. 111 patients (24.8%) experienced escalation, while 159 patients (35.6%) received prolonged therapy. Multivariate regression analysis revealed predictors for escalation: microvascular bone reconstruction (p = 0.008, OR = 2.0), clinically suspected SSI (p < 0.001, OR = 5.4), culture-positive SSI (p = 0.03, OR = 2.9), extended ICU stay (p = 0.01, OR = 1.1) and hospital-acquired pneumonia (p = 0.01, OR = 5.9). Prolonged therapy was associated with bone reconstruction (p = 0.06, OR = 2.0), preoperative irradiation (p = 0.001, OR = 1.9) and culture-positive SSI (p < 0.001, OR = 3.5). The study concludes that SSIs are a primary factor driving the escalation of perioperative antibiotic use. Clinical suspicion of infection often necessitates escalation, even in the absence of confirmed microbiological evidence. Microvascular bone reconstruction was a significant predictor for both the escalation and extension of antibiotic therapy beyond 10 days. Furthermore, preoperative radiation therapy, hospital-acquired pneumonia, and prolonged ICU stay were associated with an increased likelihood of escalation, resulting in significantly extended antibiotic administration during hospitalization. Antibiotic stewardship programmes must be implemented to reduce postoperative antibiotic administration time.Trial registration The study was registered approved by the local Ethics Committee (Nr: 18-1131-104)., (© 2024. The Author(s).)

Various viral proteins are post-translationally modified by SUMO-conjugation during the human adenovirus (HAdV) replication cycle. This modification leads to diverse consequences for target proteins as it influences their intracellular localization or cell transformation capabilities. SUMOylated HAdV proteins include the multifunctional oncoprotein E1B-55K. Our previous research, along with that of others, has demonstrated a substantial influence of yet another adenoviral oncoprotein, E4orf6, on E1B-55K SUMOylation levels. Protein SUMOylation can be reversed by cellular sentrin/SUMO-specific proteases (SENPs). In this study, we investigated the interaction of E1B-55K with cellular SENPs to understand deSUMOylation activities and their consequences for cell transformation mediated by this adenoviral oncoprotein. We show that E1B-55K interacts with and is deSUMOylated by SENP 1, independently of E4orf6. Consistent with these results, we found that SENP 1 prevents E1A/E1B-dependent focus formation in rodent cells. We anticipate these findings to be the groundwork for future studies on adenovirus-host interactions, the mechanisms that underlie E1B-55K SUMOylation, as well as the role of this major adenoviral oncoprotein in HAdV-mediated cell transformation., 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 Ip, Fiedler, Gornott, Morische, Bertzbach and Dobner.)

Background/Objectives : The aim of this study was to investigate the feasibility and practicability of repeated three-day sequences of a hypocaloric oat-based nutrition intervention (OI) in insulin-treated outpatients with type 2 diabetes and severe insulin resistance. Methods : A randomized, two-armed pilot study was conducted with three months of intervention and three months follow-up with 17 participants with insulin resistance (≥1 IU/kg body weight). Group A ( n = 10) performed one sequence of OI; Group B ( n = 7) performed two sequences monthly. A sequence was 3 consecutive days of oat consumption with approximately 800 kcal/d. The main objective was to assess feasibility (≥70% completers) and practicability regarding performance aspects. Biomedical parameters such as HbA1 c were observed. To evaluate the state of health, a standardized questionnaire was used (EQ-5 D). Results : OI was feasible (13/17 completer participants (76.5%): 70.0% Group A, 85.7% Group B). Individually perceived practicability was reported as good by 10/16 participants (62.5%). Total insulin dosage decreased from 138 ± 35 IU at baseline to 126 ± 42 IU after OI ( p = 0.04) and 127 ± 42 IU after follow-up ( p = 0.05). HbA1 c was lower after OI (-0.3 ± 0.1%; p = 0.01) in all participants. Participants in Group B tended to have greater reductions in insulin (Δ-19 IU vs. Δ-4 IU; p = 0.42) and weight loss (Δ-2.8 kg vs. Δ-0.2 kg; p = 0.65) after follow-up. Severe hypoglycemia was not observed. EQ-5 D increase not significantly after follow-up (57.2 ± 24.0% vs. 64.7 ± 21.5%; p = 0.21). Conclusions : The feasibility and practicability of OI in outpatients were demonstrated. OI frequency appears to correlate with insulin reduction and weight loss. Proper insulin dose adaptation during OI is necessary. Presumably, repeated OIs are required for substantial beneficial metabolic effects.

Background: The aim of this study was to evaluate the difference between pre- and post-operative radiotherapy on the progress of ossification after free fibula flap reconstruction of the mandible using three-dimensional (3D) analysis. Methods: A total of 38 free fibula reconstructions of the mandible were evaluated retrospectively for ossification between bone segments by measuring Hounsfield Units (HU) in at least two postoperative computer tomography scans (average of 2.4 scans per patient; around the 5th, 12th, 16th, and 19th month postoperative). Three subgroups were created according to the time of irradiation: preoperative radiotherapy (preORT) ( n = 11), postoperative radiotherapy (postORT) ( n = 16), and patients without any radiation therapy ( n = 11) as the control group (noRT). HU in eight regions of interest (ROI) and overlapping surfaces between segments per contact point, as well as influencing factors, were analyzed. Results: The fastest progress in gain of HU ossification with a difference of 0.30 HU/day was observed in noRT compared to preORT ( p = 0.002). postORT was -0.24 HU/day slower than preORT ( p = 0.005). Original and grafted bone showed a significantly slower HU uptake than between two graft segments with -84.18 HU/day ( p < 0.001). Moreover, a larger initial overlapping surface between the segments in cm 2 resulted in a higher rise of HU/day ( p < 0.001). Conclusions: 3D analysis of post-reconstructive CT scans shows prolonged ossification of mandible reconstructions by free fibula after head and neck radiation. The effect is distinct in cases with post-operative adjuvant radiotherapy. The effects of radiotherapy on ossification may be minimized by a larger initial contact surface and improved operational techniques. Moreover, HU longitudinal measurements and 3D analysis offer new perspectives for clinical evaluation of successful bony healing.

Background: The increasing prevalence of atrial fibrillation (AF) and chronic kidney diseases highlights the need for a deeper comprehension of the molecular mechanisms linking them. Mutations in PKD1, the gene encoding Polycystin-1 (PKD1 or PC1), account for 85% of autosomal dominant polycystic kidney disease (ADPKD) cases. This disease often includes cardiac complications such as AF. In cardiomyocytes, PC1 deletion reduces hypertrophic response to pressure overload but promotes baseline ventricular dysfunction, while deletion in fibroblasts ameliorates post-myocardial infarction fibrosis. Despite its known cardiac impact, the role of PC1 in atrial cardiomyocytes and arrhythmias is less understood. Here, we sought to investigate the role of PC1 in AF., Methods: We used intracardiac programmed stimulation and optical mapping to evaluate AF inducibility in two mouse models, Pkd1 R3277C, which recapitulates human ADPKD progression, and cardiomyocyte-specific Pkd1 deletion, and their respective controls. Isolated adult mouse atrial cardiomyocytes, human iPSC-derived atrial cardiomyocytes (hiPSC-aCM), and HL-1 cells served as in vitro cellular models. Molecular mechanisms were evaluated using optical mapping and molecular and biochemical approaches., Results: Loss-of-function PC1 mutations significantly increased AF susceptibility in vivo and facilitated local reentry in ex vivo left atrial appendages. Comprehensive in vitro experiments supported a direct effect of PC1 in atrial cardiomyocytes. PC1-deficient monolayers exhibited increased arrhythmic events, escalating into reentrant spiral waves post-tachypacing. Transcriptomics analysis revealed PC1-dependent regulation of DNA repair, with PC1 deficiency leading to increased DNA damage under stress. PARP1 inhibitors or nicotinamide riboside, which counteract DNA damage-related metabolic consequences, reduced in vitro arrhythmias PC1-deficient monolayers. Overexpression of the C-terminus of PC1 had the opposite effects in DNA repair genes, suggesting its regulatory effects in atrial cardiomyocytes through retinoblastoma/E2F. Analyses of human atrial tissue from non-ADPKD patients showed reduced levels of mature PC1, suggesting a broader relevance of impaired PC1 in AF., Conclusions: Impaired PC1 increases in vivo AF inducibility under programmed electrical stimulation and promotes in vitro arrhythmias in hiPSC-aCM and HL-1 cells. Our findings indicate that PC1 protects against DNA damage to reduce AF susceptibility.