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Background: Research on circulating tumor cells (CTCs) offers the opportunity to better understand the initial steps of blood‐borne metastasis as main cause of cancer‐related deaths. Here, we have used the colon cancer CTC‐MCC‐41 and breast cancer CTC‐ITB‐01 lines, which were both established from human CTCs as permanent cell lines as models to further study CTC biology with special emphasis on anchorage‐independent survival and growth. Methods and Results: Both cell lines showed a marked intrinsic plasticity to switch between suspension and adherent in vitro growth, in 2D adherent culture conditions, and established an equilibrium of both growth patterns with predominant adherent cells in the CTC‐MCC‐41 line (77%) and suspension cells in the CTC‐ITB‐01 line (85%). Western blot analysis revealed a higher expression of pERK1/2 in CTC‐ITB‐01 adherent cells compared to the suspension counterpart that suggested the involvement of kinases in this process. Subsequent functional kinome profiling identified several serine/threonine as well as tyrosine kinases that were differentially regulated in adherent and suspension CTCs. In the adherent cells of the breast cancer line CTC‐ITB‐01 the activity of MSK1, Src family kinases and the PKG family was increased compared to the suspension counterpart. In adherent cells of the colorectal CTC‐MCC‐41 line, an increased activity of TYRO3 and JAK2 was detected, whereas p38 MAPK was strongly impaired in the suspension CTC‐MCC‐41 cells. Some of the regulated kinases, which include the Src family, TYRO3, MSK1, JAK2 and p38 MAPK, have been associated with crucial cellular processes including proliferation, migration and dormancy in the past. Conclusions: The investigated CTC lines exhibit a high plasticity, similar to the concept of 'adherent‐to‐suspension transition (AST)' that was recently suggested as a new hallmark of tumor biology by Huh et al. Moreover, we identified differentially regulated kinome profiles that may represent potential targets for future studies on therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background: Adjuvant treatment of stage II–IV melanoma with PD‐1‐based immune checkpoint inhibitors (ICI) has improved relapse‐free survival (RFS) and has therefore become a standard‐of‐care treatment option. Approximately 25%–30% of patients still recur within 1 year. Predictive biomarkers reflecting real‐world data are desired. The predictive relevance of tumour tissue PD‐L1 expression in the adjuvant setting remains inconclusive. Objectives: This retrospective, observational study was conducted to evaluate the value of PD‐L1 expression scores in different tumour tissue locations in predicting response towards adjuvant immunotherapeutic treatment. Methods: Tumour tissue taken prior to anti‐PD‐1 adjuvant ICI in 243 stage II–IV melanoma patients was collected at University Skin Cancer Center Hamburg. PD‐L1 expression was evaluated on immune cells (ICS), tumour cells (TPS) and combined (CPS). Scores were determined by independent pathological physician quantification and correlated with therapy outcome at different cut‐off (CO) levels (relapse‐free survival, RFS) for different tumour tissue locations (primary tumour, metastases). Results: A total of 104 patients were eligible for analysis. Positivity of ICS, TPS and CPS showed no predictive RFS outcome association at different CO levels when analysed irrespective of tissue origin. In primary tumours, ICS at CO 1% showed a significantly improved RFS upon positivity (HR 0.22). In contrast, positivity to TPS (CO 1%) correlated significantly and independently with improved RFS when evaluated in metastatic tumour tissue specimens (HR 0.37). Conclusions: PD‐L1 tumour tissue expression may serve as a predictive biomarker for adjuvant ICI treatment response stratification in melanoma, but caution should be spent on the origin of tumour tissue analysed. The cell‐type relevant for the predictive value of PD‐L1 expression is tissue‐specific with immune cells being important in primary tumours while tumour cells are key in metastases. The present results should be validated in a multicentre cohort. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is frequently detected in late stages, which leads to limited therapeutic options and a dismal overall survival rate. To date, no robust method for the detection of early-stage PDAC that can be used for targeted screening approaches is available. Liquid biopsy allows the minimally invasive collection of body fluids (typically peripheral blood) and the subsequent analysis of circulating tumor cells or tumor-associated molecules such as nucleic acids, proteins, or metabolites that may be useful for the early diagnosis of PDAC. Single biomarkers may lack sensitivity and/or specificity to reliably detect PDAC, while combinations of these circulating biomarkers in multimarker panels may improve the sensitivity and specificity of blood test-based diagnosis. In this narrative review, we present an overview of different liquid biopsy biomarkers for the early diagnosis of PDAC and discuss the validity of multimarker panels. [ABSTRACT FROM AUTHOR]

The femoral head is one of the most commonly used bones for allografts and biomechanical studies. However, there are few reports on the trabecular bone microarchitectural parameters of freshly harvested trabecular bones. To our knowledge, this is the first study to characterize the microstructure of femoral heads tested immediately after surgery and compare it with the microstructure obtained with conventional freezing. This study aims to investigate whether freezing at −80 °C for 6 weeks affects the trabecular microstructure of freshly harvested bone tissue. This study was divided into two groups: one with freshly harvested human femoral heads and the other with the same human femoral heads frozen at −80 °C for 6 weeks. Each femoral head was scanned using an X-ray microcomputed tomography scanner (µCT) to obtain the microarchitectural parameters, including the bone volume fraction (BV/TV), the mean trabecular thickness (Tb.th), the trabecular separation (Tb.sp), the degree of anisotropy (DA), and the connectivity density (Conn.D). There was no statistically significant difference between the fresh and the frozen groups for any of the parameters measured. This study shows that freezing at −80 °C for 6 weeks does not alter bone microstructure compared with freshly harvested femoral heads tested immediately after surgery. [ABSTRACT FROM AUTHOR]

Background: Cefiderocol is a siderophore-conjugated cephalosporin increasingly used in the management of Achromobacter infections. Testing for cefiderocol susceptibility is challenging with distinct recommendations depending on the pathogens. Objectives: We evaluated the performance of commercial tests for testing cefiderocol susceptibility in the Achromobacter genus and reviewed the literature. Methods: Diffusion (disks, MIC gradient test strips [MTS], Liofilchem) and broth microdilution (BMD) methods (ComASP™, Liofilchem; UMIC®, Bruker) were compared with the BMD reference method according to the EUCAST guidelines on 143 Achromobacter strains from 14 species with MIC50/90 of ≤ 0.015/0.5 mg/L. A literature search was conducted regardless of method or species. Results: None of the methods tested fulfilled an acceptable essential agreement (EA). MTS displayed the lowest EA (30.8%) after UMIC® (49%) and ComASP™ (76.9%). All methods achieved an acceptable bias, with MICs either underestimated using MTS (-1.3%) and ComASP™ (-14.2%) or overestimated with UMIC® (+ 9.1%). Inhibition zone diameters ranged from 6 to 38 mm (IZD50/90=33/30 mm). UMIC® and ComASP™ failed to categorize one or the two cefiderocol-resistant strains of this study as resistant unlike the diffusion-based methods. The literature review highlighted distinct performance of the available methods according to pathogens and testing conditions. Conclusions: The use of MTS is discouraged for Achromobacter spp. Disk diffusion can be used to screen for susceptible strains by setting a threshold diameter of 30 mm. UMIC® and ComASP™ should not be used as the sole method but have to be systematically associated with disk diffusion to detect the yet rarely described cefiderocol-resistant Achromobacter sp. strains. Highlights: Performance of commercial methods are highly diverse and species-dependent. The use of MTS is discouraged due to low essential agreement. UMIC® and ComASP™ failed to detect one or the two cefiderocol-resistant strains. UMIC® or ComASP™ should not be used as the sole method for Achromobacter cefiderocol susceptibility testing. A threshold diameter of 30 mm is proposed for susceptible strain screening. [ABSTRACT FROM AUTHOR]

Background: The treatment of melanoma has been revolutionized by the use of immune checkpoint inhibition (ICI), but many patients do not benefit. Furthermore, immune‐related adverse events may occur during therapy. A predictive biomarker is needed to reliably identify patients benefitting. In lung, renal cell and bladder cancer early C‐reactive protein (CRP) kinetics were shown to be a predictive biomarker for ICI. Objective: Here, we investigate early CRP kinetics as predictive biomarker for ICI in melanoma patients. Methods: Two independent prospectively collected cohorts were analysed: Cohort 1 (n = 87) with advanced and Cohort 2 (n = 99) with completely resected melanoma. Patients were stratified by in the dynamics of CRP after ICI initiation: A doubling of baseline CRP within 30 days followed by at least a 30% drop within 3 months was classified as a CRP flare. If no doubling of CRP was reported, but a 30% drop within 3 months, patients were classified as CRP responders and all others as CRP non‐responders. Analysed factors included clinical characteristics like S100B and LDH. Median follow‐up was 1.5 and 1.7 years for Cohorts 1 and 2. Results: In Cohort 1 CRP flare (n = 12), CRP responders (n = 43) and CRP non‐responders (n = 32) with a progression‐free survival (PFS) of 0.7, 0.6 and 0.2 years (p = 0.017) and an overall survival (OS) of 2.2, 1.5 and 1.0 years (p = 0.014), respectively. Multivariable Cox analysis showed an independent risk reduction of progression for CRP responders by 62% compared to CRP non‐responders (p = 0.001). In Cohort 2 CRP flare (n = 13), CRP responders (n = 70) and CRP non‐responders (n = 16) the log‐rank analysis showed a significant difference between OS and recurrence‐free survival (RFS) curves (p = 0.046 and p = 0.049). Conclusion: Early CRP kinetics could indicate a response to ICI with improved OS and RFS/PFS. CRP flare and CRP response indicating significantly improved outcomes compared to CRP non‐responders. [ABSTRACT FROM AUTHOR]

The concept of liquid biopsy analysis has been established more than a decade ago. Since the establishment of the term, tremendous advances have been achieved and plenty of methods as well as analytes have been investigated in basic research as well in clinical trials. Liquid biopsy refers to a body fluid-based biopsy that is minimal-invasive, and most importantly, allows dense monitoring of tumor responses by sequential blood sampling. Blood is the most important analyte for liquid biopsy analyses, providing an easily accessible source for a plethora of cells, cell-derived products, free nucleic acids, proteins as well as vesicles. More than 12,000 publications are listed in PubMed as of today including the term liquid biopsy. In this manuscript, we critically review the current implications of liquid biopsy, with special focus on circulating tumor cells, and describe the hurdles that need to be addressed before liquid biopsy can be implemented in clinical standard of care guidelines. [ABSTRACT FROM AUTHOR]

Background: Multimodal lifestyle interventions can benefit overall health, including cognition, in populations at-risk for dementia. However, little is known about the effect of lifestyle interventions in patients with prodromal Alzheimer's disease (AD). Even less is known about dietary intake and adherence to dietary recommendations within this population making it difficult to design tailored interventions for them. Method: A 6-month MIND-ADmini pilot randomized controlled trial (RCT) was conducted among 93 participants with prodromal AD in Sweden, Finland, Germany, and France. Three arms were included in the RCT: 1) multimodal lifestyle intervention (nutritional guidance, exercise, cognitive training, vascular/metabolic risk management, and social stimulation); 2) multimodal lifestyle intervention + medical food product; and 3) regular health advice (control group). Adherence to dietary advice was assessed with a brief food intake questionnaire by using the Healthy Diet Index (HDI) and Mediterranean Diet Adherence Screener (MEDAS). The intake of macro- and micronutrients were analyzed on a subsample using 3-day food records. Results: The dietary quality in the intervention groups, pooled together, improved compared to that of the control group at the end of the study, as measured with by HDI (p = 0.026) and MEDAS (p = 0.008). The lifestyle-only group improved significantly more in MEDAS (p = 0.046) and almost significantly in HDI (p = 0.052) compared to the control group, while the lifestyle + medical food group improved in both HDI (p = 0.042) and MEDAS (p = 0.007) during the study. There were no changes in macro- or micronutrient intake for the intervention groups at follow-up; however, the intakes in the control group declined in several vitamins and minerals when adjusted for energy intake. Conclusion: These results suggest that dietary intervention as part of multimodal lifestyle interventions is feasible and results in improved dietary quality in a population with prodromal AD. Nutrient intakes remained unchanged in the intervention groups while the control group showed a decreasing nutrient density. Trial registration: ClinicalTrials.gov NCT03249688, 2017–07-08. [ABSTRACT FROM AUTHOR]

Purpose: In recent years, the number of elderly cochlear implant (CI) candidates is continuously rising. In addition to the audiological improvement, other positive effects of CI treatment can also be observed in clinical routine. The "quality of life" as a parameter of success directly experienced by the patient is increasingly becoming the focus of clinical research. Although there are already clear indications of a rapid and significant improvement in quality of life, there is still a lack of systematic, prospectively collected longitudinal long-term data in patients over the age of 65. Methods: This prospective longitudinal observational study included 31 patients between the age of 71 and 92 years who had first been treated unilaterally with a CI 6 years ago. In addition to free-field monosyllable recognition, quality of life was assessed using the World Health Organization Quality-of-Life Scale-old (WHOQL-OLD). The results were compared with the data from our previous study, in which we focused on the short- and medium-term effects on quality of life. In both studies, the same patient population was examined. In addition, these study data were compared with an age-matched average population. Results: In speech recognition, there was no significant change from the control 6 months postoperatively compared with the results 6 years postoperatively. No significant changes occurred in the total quality of life score or any of the other six facets of quality of life when comparing the results 6 months postoperatively with the results 6 years postoperatively. In "Social participation", the CI patients even exceed the values of the age-matched average population 6 years after treatment. Conclusion: Improvement in the quality of life and especially in social participation appears stable over many years in elderly patients after hearing rehabilitation with a CI. [ABSTRACT FROM AUTHOR]

While the elucidation of regulatory mechanisms of folded proteins is facilitated due to their amenability to high-resolution structural characterization, investigation of these mechanisms in disordered proteins is more challenging due to their structural heterogeneity, which can be captured by a variety of biophysical approaches. Here, we used the transcriptional master corepressor CtBP, which binds the putative metastasis suppressor RAI2 through repetitive SLiMs, as a model system. Using cryo-electron microscopy embedded in an integrative structural biology approach, we show that RAI2 unexpectedly induces CtBP polymerization through filaments of stacked tetrameric CtBP layers. These filaments lead to RAI2-mediated CtBP nuclear foci and relieve its corepressor function in RAI2-expressing cancer cells. The impact of RAI2-mediated CtBP loss-of-function is illustrated by the analysis of a diverse cohort of prostate cancer patients, which reveals a substantial decrease in RAI2 in advanced treatment-resistant cancer subtypes. As RAI2-like SLiM motifs are found in a wide range of organisms, including pathogenic viruses, our findings serve as a paradigm for diverse functional effects through multivalent interaction-mediated polymerization by disordered proteins in healthy and diseased conditions. CtBP is a transcriptional master co-repressor with oncogenic activity. Here, the authors use structural and biophysical methods to show that CtBP interacts with RAI2 through SLiMs that induce CtBP polymerization and inactivation. [ABSTRACT FROM AUTHOR]

Background: Achromobacter spp. are opportunistic pathogens, mostly infecting immunocompromised patients and patients with cystic fibrosis (CF) and considered as difficult-to-treat pathogens due to both intrinsic resistance and the possibility of acquired antimicrobial resistance. Species identification remains challenging leading to imprecise descriptions of resistance in each taxon. Cefiderocol is a broad-spectrum siderophore cephalosporin increasingly used in the management of Achromobacter infections for which susceptibility data remain scarce. We aimed to describe the susceptibility to cefiderocol of a collection of Achromobacter strains encompassing different species and isolation sources from CF or non-CF (NCF) patients. Methods: We studied 230 Achromobacter strains (67 from CF, 163 from NCF patients) identified by nrdA gene-based analysis, with available susceptibility data for piperacillin–tazobactam, meropenem and trimethoprim–sulfamethoxazole. Minimal inhibitory concentrations (MICs) of cefiderocol were determined using the broth microdilution reference method according to EUCAST guidelines. Results: Strains belonged to 15 species. A. xylosoxidans represented the main species (71.3%). MICs ranged from ≤ 0.015 to 16 mg/L with MIC50/90 of ≤ 0.015/0.5 mg/L overall and 0.125/2 mg/L against 27 (11.7%) meropenem-non-susceptible strains. Cefiderocol MICs were not related to CF/NCF origin or species although A. xylosoxidans MICs were statistically lower than those of other species considered as a whole. Considering the EUCAST non-species related breakpoint (2 mg/L), 228 strains (99.1%) were susceptible to cefiderocol. The two cefiderocol-resistant strains (A. xylosoxidans from CF patients) represented 3.7% of meropenem-non-susceptible strains and 12.5% of MDR strains. Conclusions: Cefiderocol exhibited excellent in vitro activity against a large collection of accurately identified Achromobacter strains, irrespective of species and origin. [ABSTRACT FROM AUTHOR]

Evolutionary and ecological dynamics can occur on similar timescales and thus influence each other. While it has been shown that the relative contribution of ecological and evolutionary change to population dynamics can vary, it still remains unknown what influences these differences. Here, we test whether prey populations with increased variation in their defence and competitiveness traits will have a stronger impact on evolution for predator growth rates. We controlled trait variation by pairing distinct clonal lineages of the green alga Chlamydomonas reinhardtii with known traits as prey with the rotifer Brachionus calyciforus as predator and compared those results with a mechanistic model matching the empirical system. We measured the impact of evolution (shift in prey clonal frequency) and ecology (shift in prey population density) for predator growth rate and its dependency on trait variation using an approach based on a 2-way ANOVA. Our experimental results indicated that higher trait variation, i.e. a greater distance in trait space, increased the relative contribution of prey evolution to predator growth rate over 3–4 predator generations, which was also observed in model simulations spanning longer time periods. In our model, we also observed clone-specific results, where a more competitive undefended prey resulted in a higher evolutionary contribution, independent of the trait distance. Our results suggest that trait combinations and total prey trait variation combine to influence the contribution of evolution to predator population dynamics, and that trait variation can be used to identify and better predict the role of eco-evolutionary dynamics in predator–prey systems. [ABSTRACT FROM AUTHOR]

Background: The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) showed cognitive benefits from a multidomain lifestyle intervention in at-risk older people. The LipiDiDiet trial highlighted benefits of medical food in prodromal Alzheimer's disease (AD). However, the feasibility and impact of multimodal interventions combining lifestyle with medical food in prodromal AD is unclear. Methods: MIND-ADmini was a 6-month multinational (Sweden, Finland, Germany, France) proof-of-concept randomized controlled trial (RCT). Participants were 60–85 years old, had prodromal AD (International Working Group-1 criteria), and vascular/lifestyle risk factors. The parallel-group RCT had three arms: multimodal lifestyle intervention (nutritional guidance, exercise, cognitive training, vascular/metabolic risk management and social stimulation); multimodal lifestyle intervention + medical food (Fortasyn Connect); and regular health advice/care (control). Participants were randomized 1:1:1 (computer-generated allocation at each site). Outcome evaluators were blinded to randomization. Primary outcome was feasibility of the multimodal intervention, evaluated by recruitment rate during a 6-month recruitment phase, overall adherence in each intervention arm, and 6-month retention rate. Successful adherence was pre-specified as attending ≥ 40% of sessions/domain in ≥ 2/4 domains (lifestyle intervention), and consuming ≥ 60% of the medical food (lifestyle intervention + medical food). The secondary outcomes included adherence/participation to each intervention component and overall adherence to healthy lifestyle changes, measured using a composite score for healthy lifestyle. Cognitive assessments were included as exploratory outcomes, e.g. Clinical Dementia Rating scale. Results: During September 2017-May 2019, 93 individuals were randomized (32 lifestyle intervention, 31 lifestyle + medical food, and 30 control group). Overall recruitment rate was 76.2% (64.8% during the first 6 months). Overall 6-month retention rate was 91.4% (lifestyle intervention 87.5%; lifestyle + medical food 90.3%; control 96.7%). Domain-specific adherence in the lifestyle intervention group was 71.9% to cognitive training, 78.1% exercise, 68.8% nutritional guidance, and 81.3% vascular risk management; and in the lifestyle + medical food group, 90.3% to cognitive training, 87.1% exercise, 80.7% nutritional guidance, 87.1% vascular risk management, and 87.1% medical food. Compared with control, both intervention arms showed healthy diet improvements (βLifestyle×Time = 1.11, P = 0.038; βLifestyle+medical food×Time = 1.43, P = 0.007); the lifestyle + medical food group also showed vascular risk reduction (P = 0.043) and less cognitive-functional decline (P < 0.05, exploratory analysis). There were 5 serious adverse events (control group: 1; lifestyle intervention: 3; lifestyle + medical food: 1) unrelated to interventions. Conclusions: The multidomain lifestyle intervention, alone or combined with medical food, had good feasibility and adherence in prodromal AD. Longer-term cognitive and other health benefits should be further investigated in a larger-scale trial. Trial registration: ClinicalTrials.gov NCT03249688. [ABSTRACT FROM AUTHOR]

The prognosis for metastatic gastric adenocarcinoma (mGAC) remains poor. Gene alterations in receptor tyrosine kinases (RTKs) such as epidermal growth factor receptor (EGFR) and their downstream effectors including catalytic subunit alpha of the phosphatidylinositol 3-kinase (PIK3CA) are common in mGAC. Targeted RTK and phosphatidylinositol-3-kinase (PI3K) treatments have demonstrated clinical benefits in other solid tumours and are key potential targets for clinical development against mGAC given the presence of recurrent alterations in these pathways. Furthermore, combination RTK/PI3K treatments may overcome compensatory mechanisms that arise using monotherapies, leading to improved patient outcomes. Herein, we investigated RTK/PI3K single and combination drug responses against our unique human mGAC-derived PIK3CA gain-of-function mutant, human epidermal growth factor receptor 2 (HER2)-negative, EGFR-expressing circulating tumour cell line, UWG02CTC, under two- and three-dimensional culture conditions to model different stages of metastasis. UWG02CTCs were highly responsive to the PI3K p110α-subunit targeted drugs PIK-75 (IC50 = 37.0 ± 11.1 nM) or alpelisib (7.05 ± 3.7 µM). Drug sensitivities were significantly increased in 3D conditions. Compensatory MAPK/ERK pathway upregulation by PI3K/Akt suppression was overcome by combination treatment with the EGFR inhibitor gefitinib, which was strongly synergistic. PIK-75 plus gefitinib significantly impaired UWG02CTC invasion in an organotypic assay. In conclusion, UWG02CTCs are a powerful ex vivo mGAC drug responsiveness model revealing EGFR/PI3K-targeted drugs as a promising combination treatment option for HER2-negative, RAS wild-type mGAC patients. [ABSTRACT FROM AUTHOR]

The development of offshore wind farms requires robust bonding solutions that can withstand harsh marine conditions for the easy integration of secondary structures. This paper investigates the durability performance of two adhesives: Sikadur 30 epoxy resin and Loctite UK 1351 B25 urethane-based adhesive for use in offshore wind environments. Tensile tests on adhesive samples and accelerated aging tests were carried out under a variety of temperatures and environmental conditions, including both dry and wet conditions. The long-term effects of aging on adhesive integrity are investigated by simulating the operational life of offshore installations. The evolution of mechanical properties, studied under accelerated aging conditions, provides an important indication of the longevity of structures under normal conditions. The results show significant differences in performance between the two adhesives, highlighting their suitability for specific operating parameters. It should also be noted that for both adhesives, their exposure to different environments (seawater, distilled water, humid climate) over a prolonged period showed that (i) Loctite adhesive has a slightly faster initial uptake than Sikadur adhesive, but the latter reaches an asymptotic plateau with a lower maximum absorption rate than Loctite adhesive; and (ii) a progressive deterioration in the tensile properties occurred following an exponential function. Therefore, aging behavior results showed a clear correlation with the Arrhenius law, providing a predictive tool for the aging process and the aging process of the two adhesives followed Arrhenius kinetics. Ultimately, the knowledge gained from this study is intended to inform best practice in the use of adhesives, thereby improving the reliability and sustainability of the offshore renewable energy infrastructure. [ABSTRACT FROM AUTHOR]

Simple Summary: In this prospective cohort study of metastatic melanoma patients receiving immune checkpoint inhibitors, we identified a serum chemokine CCL20 increase at baseline with a significantly impaired progression-free and overall survival and as an independent negative prognostic factor for PFS and OS in univariate as well as in multivariate analysis. CCL20 may represent a novel blood biomarker for the prediction of prognosis in advanced melanoma under immunotherapy with a special emphasis on progression. Background: Immune checkpoint inhibition has revolutionized melanoma therapy, but many patients show primary or secondary resistance. Biomarkers are, therefore, urgently required to predict response prior to the initiation of therapy and to monitor disease progression. Methods: In this prospective study, we analyzed the serum C-C motif chemokine ligand 20 (CCL20) concentration using an enzyme-linked immunosorbent assay. Blood was obtained at baseline before the initiation of immunotherapy with anti-PD-1 monotherapy or Nivolumab and Ipilimumab in advanced melanoma patients (stages III and IV) enrolled at the University Medical Center Hamburg-Eppendorf. The CCL20 levels were correlated with clinico-pathological parameters and disease-related outcomes. Results: An increased C-C motif chemokine ligand 20 (CCL20) concentration (≥0.34 pg/mL) at baseline was associated with a significantly impaired progression-free survival (PFS) in the high-CCL20 group (3 months (95% CI: 2–6 months) vs. 11 months (95% CI: 6–26 months)) (p = 0.0033) and could be identified as an independent negative prognostic factor for PFS in univariate (Hazard Ratio (HR): 1.98, 95% CI 1.25–3.12, p = 0.004) and multivariate (HR: 1.99, 95% CI 1.21–3.29, p = 0.007) Cox regression analysis, which was associated with a higher risk than S100 (HR: 1.74). Moreover, high CCL20 levels were associated with impaired overall survival (median OS not reached for low-CCL20 group, p = 0.042) with an HR of 1.85 (95% CI 1.02–3.37, p = 0.043) in univariate analysis similar to the established prognostic marker S100 (HR: 1.99, 95% CI: 1.02–3.88, p = 0.043). Conclusions: CCL20 may represent a novel blood-based biomarker for the prediction of resistance to immunotherapy that can be used in combination with established strong clinical predictors (e.g., ECOG performance score) and laboratory markers (e.g., S100) in advanced melanoma patients. Future prospective randomized trials are needed to establish CCL20 as a liquid biopsy-based biomarker in advanced melanoma. [ABSTRACT FROM AUTHOR]

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Background: Spondylodiscitis is an infectious disease affecting an intervertebral disc and the adjacent vertebral bodies and is often the complication of a distant focus of infection. This study aims to ascertain the regional and hospital-specific disparities in bacterial patterns and resistance profiles in spontaneous and iatrogenic spondylodiscitis and their implications for patient treatment. Methods: We enrolled patients from two German hospitals, specifically comparing a university hospital (UVH) with a peripheral non-university hospital (NUH). We documented patient demographics, laboratory results, and surgical interventions. Microbiological assessments, antibiotic regimens, treatment durations, and resistance profiles were recorded. Results: This study included 135 patients. Upon admission, 92.4% reported pain, with 16.2% also presenting neurological deficits. The primary microbial species identified in both the UVH and NUH cohorts were S. aureus (37.3% vs. 31.3%) and cog. neg. staphylococci (28.8% vs. 34.4%), respectively. Notably, a higher prevalence of resistant bacteria was noted in the UVH group (p < 0.001). Additionally, concomitant malignancies were significantly more prevalent in the UVH cohort. Conclusion: Significant regional variations exist in bacterial prevalence and resistance profiles. Consequently, treatment protocols need to consider these nuances and undergo regular critical evaluation. Moreover, patients with concurrent malignancies face an elevated risk of spondylodiscitis. [ABSTRACT FROM AUTHOR]

To help operators perform their diagnosis tasks more efficiently, the authors put forward a novel methodology introducing a new type of model, dedicated to operations, co‐created in parallel with the design models, in the preliminary stages of system development, using the language semantics of behavior trees. In this paper, the authors present the need for this new model type as expressed by the industry and justify their choice for adopting behavior trees, while illustrating in detail the proposed methodology. [ABSTRACT FROM AUTHOR]

Background: Metastasis is the leading cause of cancer-related death in non-small cell lung cancer (NSCLC) patients. We previously showed that low HERC5 expression predicts early tumor dissemination and a dismal prognosis in NSCLC patients. Here, we performed functional studies to unravel the mechanism underlying the "metastasis-suppressor" effect of HERC5, with a focus on mitochondrial metabolism pathways. Methods: We assessed cell proliferation, colony formation potential, anchorage-independent growth, migration, and wound healing in NSCLC cell line models with HERC5 overexpression (OE) or knockout (KO). To study early tumor cell dissemination, we used these cell line models in zebrafish experiments and performed intracardial injections in nude mice. Mass spectrometry (MS) was used to analyze protein changes in whole-cell extracts. Furthermore, electron microscopy (EM) imaging, cellular respiration, glycolytic activity, and lactate production were used to investigate the relationships with mitochondrial energy metabolism pathways. Results: Using different in vitro NSCLC cell line models, we showed that NSCLC cells with low HERC5 expression had increased malignant and invasive properties. Furthermore, two different in vivo models in zebrafish and a xenograft mouse model showed increased dissemination and metastasis formation (in particular in the brain). Functional enrichment clustering of MS data revealed an increase in mitochondrial proteins in vitro when HERC5 levels were high. Loss of HERC5 leads to an increased Warburg effect, leading to improved adaptation and survival under prolonged inhibition of oxidative phosphorylation. Conclusions: Taken together, these results indicate that low HERC5 expression increases the metastatic potential of NSCLC in vitro and in vivo. Furthermore, HERC5-induced proteomic changes influence mitochondrial pathways, ultimately leading to alterations in energy metabolism and demonstrating its role as a new potential metastasis suppressor gene. [ABSTRACT FROM AUTHOR]

Population medical genetics aims at translating clinically relevant findings from recent studies of large cohorts into healthcare for individuals. Genetic counseling concerning reproductive risks and options is still mainly based on family history, and consanguinity is viewed to increase the risk for recessive diseases regardless of the demographics. However, in an increasingly multi‐ethnic society with diverse approaches to partner selection, healthcare professionals should also sharpen their intuition for the influence of different mating schemes in non‐equilibrium dynamics. We, therefore, revisited the so‐called out‐of‐Africa model and studied in forward simulations with discrete and not overlapping generations the effect of inbreeding on the average number of recessive lethals in the genome. We were able to reproduce in both frameworks the drop in the incidence of recessive disorders, which is a transient phenomenon during and after the growth phase of a population, and therefore showed their equivalence. With the simulation frameworks, we also provide the means to study and visualize the effect of different kin sizes and mating schemes on these parameters for educational purposes. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction is a hallmark of cellular senescence and many age-related neurodegenerative diseases. We therefore investigated the relationship between mitochondrial function in peripheral blood cells and cerebral energy metabolites in young and older sex-matched, physically and mentally healthy volunteers. Cross-sectional observational study involving 65 young (26.0 ± 0.49 years) and 65 older (71.7 ± 0.71 years) women and men recruited. Cognitive health was evaluated using established psychometric methods (MMSE, CERAD). Blood samples were collected and analyzed, and fresh peripheral blood mononuclear cells (PBMCs) were isolated. Mitochondrial respiratory complex activity was measured using a Clarke electrode. Adenosine triphosphate (ATP) and citrate synthase activity (CS) were determined by bioluminescence and photometrically. N-aspartyl-aspartate (tNAA), ATP, creatine (Cr), and phosphocreatine (PCr) were quantified in brains using 1H- and 31P-magnetic resonance spectroscopic imaging (MRSI). Levels of insulin-like growth factor 1 (IGF-1) were determined using a radio-immune assay (RIA). Complex IV activity (CIV) (− 15%) and ATP levels (− 11%) were reduced in PBMCs isolated from older participants. Serum levels of IGF-1 were significantly reduced (− 34%) in older participants. Genes involved in mitochondrial activity, antioxidant mechanisms, and autophagy were unaffected by age. tNAA levels were reduced (− 5%), Cr (+ 11%), and PCr (+ 14%) levels were increased, and ATP levels were unchanged in the brains of older participants. Markers of energy metabolism in blood cells did not significantly correlate with energy metabolites in the brain. Age-related bioenergetic changes were detected in peripheral blood cells and the brains of healthy older people. However, mitochondrial function in peripheral blood cells does not reflect energy related metabolites in the brain. While ATP levels in PBMCs may be be a valid marker for age-related mitochondrial dysfunction in humans, cerebral ATP remained constant. [ABSTRACT FROM AUTHOR]

Traffic noise is a pervasive pollutant that affects wildlife at individual and group levels through mechanisms such as disrupting communication, affecting antipredator strategy, and/or changing how they use space within a habitat. Urbanization is expanding rapidly—few places remain untouched by anthropogenic noise disturbance—so understanding the implications of noise on wildlife behavior is paramount to conservation efforts. We asked whether traffic noise could change space use and social network metrics in flocks of captive birds. Specifically, we quantified the effects of playbacks of traffic noise on individual sociality (weighted degree, number of social partners weighted by the frequency of interactions with those social partners) and flock clustering (global clustering coefficient, connectivity of neighbors). In this study, we recorded social interactions and space use of flocks of captive zebra finches (Taeniopygia guttata) before, during, and after an experimental traffic noise introduction in two treatments: high- and lower-amplitude noise. Our results demonstrated that individual sociality and flock clustering increased in response to the noise introduction in both high-amplitude and low-amplitude treatments. Additionally, birds in the high-amplitude treatment spent more time in the room with active playback during noise playback whereas birds in the lower-amplitude treatment decreased time spent in the room closest to the high-amplitude treatment. Increased social behavior in response to traffic noise could influence disease transmission, social learning, and mating dynamics. We suggest future studies explore the mechanisms driving increased social behavior in traffic noise, such as perceived predation risk, vigilance, and cross-sensory interference. [ABSTRACT FROM AUTHOR]

Background: Steroid-resistant nephrotic syndrome (SRNS) is the second most common cause of kidney failure in children and adults under the age of 20 years. Previously, we were able to detect by exome sequencing (ES) a known monogenic cause of SRNS in 25–30% of affected families. However, ES falls short of detecting copy number variants (CNV). Therefore, we hypothesized that causal CNVs could be detected in a large SRNS cohort. Methods: We performed genome-wide single nucleotide polymorphism (SNP)-based CNV analysis on a cohort of 138 SRNS families, in whom we previously did not identify a genetic cause through ES. We evaluated ES and CNV data for variants in 60 known SRNS genes and in 13 genes in which variants are known to cause a phenocopy of SRNS. We applied previously published, predefined criteria for CNV evaluation. Results: We detected a novel CNV in two genes in 2 out of 138 families (1.5%). The 9,673 bp homozygous deletion in PLCE1 and the 6,790 bp homozygous deletion in NPHS2 were confirmed across the breakpoints by PCR and Sanger sequencing. Conclusions: We confirmed that CNV analysis can identify the genetic cause in SRNS families that remained unsolved after ES. Though the rate of detected CNVs is minor, CNV analysis can be used when there are no other genetic causes identified. Causative CNVs are less common in SRNS than in other monogenic kidney diseases, such as congenital anomalies of the kidneys and urinary tract, where the detection rate was 5.3%. [ABSTRACT FROM AUTHOR]

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Copyright of Der Schmerz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: The proliferation marker Ki-67 is a major pathological feature for the description of the state of disease in breast cancer. It helps to define the molecular subtype and to stratify between therapy regimens in early breast cancer and helps to assess the therapy response. Circulating tumor cells (CTCs) are a negative prognostic biomarker for progression free (PFS) and overall survival (OS) in patients with metastatic breast cancer. Therefore, the CTC count is often described as surrogate for the tumor burden. Both, decrease of Ki-67 and CTC count are considered as evidence for therapy response. The presented work analyzed the correlation between the Ki-67 indices of metastatic tissue biopsies and CTC counts in biopsy time-adjacent peripheral blood samples. Patients and methods: Blood samples from 70 metastatic breast cancer patients were obtained before the start of a new line of systemic therapy. CTCs were enumerated using CellSearch® (Menarini Silicon Biosystems, Bologna, Italy) whereas intact CTCs (iCTCs) and non-intact or apoptotic CTCs (aCTCs) were distinguished using morphologic criteria. The proportion of cells expressing Ki-67 was evaluated using immunohistochemistry on biopsies of metastases obtained concurrently with CTC sampling before the start of a new line of systemic therapy. Results: 65.7% of patients had a Ki-67 index of > 25%. 28.6% of patients had ≥ 5, 47.1% ≥ 1 iCTCs. 37.1% had ≥ 5, 51.4% ≥ 1 aCTCs. No correlation was shown between Ki-67 index and iCTC and aCTC count (r = 0.05 resp. r = 0.05, Spearman's correlation index). High CTC-counts did not coincide with high Ki-67 index. High Ki-67, ≥ 5 iCTCs and aCTCs are associated with poor progression free (PFS) and overall survival (OS). Conclusion: CTCs and Ki-67 are independent prognostic markers in metastatic breast cancer. High Ki-67 in metastatic tumor tissue is not correlated to high iCTC or aCTC counts in peripheral blood. [ABSTRACT FROM AUTHOR]

Simple Summary: Modern rectal cancer treatment in the form of total neoadjuvant therapy (TNT) offers additional opportunities for organ preservation and consideration for a watch-and-wait (WW) surveillance only approach. Preoperative predictors of pCR after TNT can guide the ideal selection criteria for WW in the current era. An exhaustive literature review found predictors for pCR to include the following: (1) biochemical factors; (2) clinical factors; (3) patient demographics; and (4) treatment sequence for TNT. Additional data from long-term trials using TNT is critical to better inform those considering watch-and-wait approaches following a clinical complete response. The modern rectal cancer treatment paradigm offers additional opportunities for organ preservation, most notably via total neoadjuvant therapy (TNT) and consideration for a watch-and-wait (WW) surveillance-only approach. A major barrier to widespread implementation of a WW approach to rectal cancer is the potential discordance between a clinical complete response (cCR) and a pathologic complete response (pCR). In the pre-TNT era, the identification of predictors of pCR after neoadjuvant therapy had been previously studied. However, the last meta-analysis to assess the summative evidence on this important treatment decision point predates the acceptance and dissemination of TNT strategies. The purpose of this systematic review was to assess preoperative predictors of pCR after TNT to guide the ideal selection criteria for WW in the current era. An exhaustive literature review was performed and the electronic databases Embase, Ovid, MEDLINE, PubMed, and Cochrane were comprehensively searched up to 27 June 2023. Search terms and their combinations included "rectal neoplasms", "total neoadjuvant therapy", and "pathologic complete response". Only studies in English were included. Randomized clinical trials or prospective/retrospective cohort studies of patients with clinical stage 2 or 3 rectal adenocarcinoma who underwent at least 8 weeks of neoadjuvant chemotherapy in addition to chemoradiotherapy with pCR as a measured study outcome were included. In this systematic review, nine studies were reviewed for characteristics positively or negatively associated with pCR or tumor response after TNT. The results were qualitatively grouped into four categories: (1) biochemical factors; (2) clinical factors; (3) patient demographics; and (4) treatment sequence for TNT. The heterogeneity of studies precluded meta-analysis. The level of evidence was low to very low. There is minimal data to support any clinicopathologic factors that either have a negative or positive relationship to pCR and tumor response after TNT. Additional data from long-term trials using TNT is critical to better inform those considering WW approaches following a cCR. [ABSTRACT FROM AUTHOR]

Purpose: To demonstrate the feasibility of continuous infusion of meropenem–vaborbactam to optimize the treatment of carbapenem-resistant Enterobacterales. Methods: Report of a case of a Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae bloodstream infection comfirmed by whole genome sequencing and therapeutic drug monitoring (TDM) of meropenem. Results: A patient with augmented renal clearance (ARC) went into septic shock caused by an ST11 KPC-3-producing K. pneumoniae bloodstream infection that was successfully treated with a continuous infusion of meropenem–vaborbactam at a dosage of 1 g/1 g q4h as a 4-h infusion. TDM confirmed sustained concentrations of meropenem ranging from 8 to 16 mg/L throughout the dosing interval. Conclusion: Continuous infusion of meropenem–vaborbactam was feasible. It could be appropriate for optimizing the management of critically ill patients with ARC, as it resulted in antibiotic concentrations above the minimum inhibitory concentration for susceptible carbapenem-resistant Enterobacterales (up to 8 mg/L) throughout the dosing interval. [ABSTRACT FROM AUTHOR]

Daptomycin (DAP) represents an interesting alternative to treat methicillin-resistant Staphylococcus aureus (MRSA) infections. Different mechanisms of DAP resistance have been described; however, in vivo-acquired resistance is uncharacterized. This study described the phenotypic and genotypic evolution of MRSA strains that became resistant to DAP in two unrelated patients with bacteremia under DAP treatment, in two hospitals in the South of France. DAP MICs were determined using broth microdilution method on the pairs of isogenic (DAP-S/DAP-R) S. aureus isolated from bloodstream cultures. Whole genome sequencing was carried out using Illumina MiSeq Sequencing system. The two cases revealed DAP-R acquisition by MRSA strains within three weeks in patients treated by DAP. The isolates belonged to the widespread ST5 (patient A) and ST8 (patient B) lineages and were of spa-type t777 and t622, respectively. SNP analysis comparing each DAP-S/DAP-R pair confirmed that the isolates were isogenic. The causative mutations were identified in MprF (Multiple peptide resistance Factor) protein: L826F (Patient A) and S295L (Patient B), and in Cls protein: R228H (Patient B). These proteins encoded both proteins of the lipid biosynthetic enzymes. The resistance to DAP is particularly poorly described whereas DAP is highly prescribed to treat MRSA. Our study highlights the non-systematic cross-resistance between DAP and glycopeptides and the importance of monitoring DAP MIC in persistent MRSA bacteremia. [ABSTRACT FROM AUTHOR]

Expression of CYP3A5 protein is a basal and acquired resistance mechanism of pancreatic ductal adenocarcinoma cells conferring protection against the CYP3A and CYP2C8 substrate paclitaxel through metabolic degradation. Inhibition of CYP3A isozymes restores the cells sensitivity to paclitaxel. The combination of gemcitabine and nab‐paclitaxel is an established regimen for the treatment of metastasized or locally advanced inoperable pancreatic cancer. Cobicistat is a CYP3A inhibitor developed for the pharmacoenhancement of protease inhibitors. The addition of cobicistat to gemcitabine and nab‐paclitaxel may increase the antitumor effect. We will conduct a phase I dose escalation trial with a classical 3 + 3 design to investigate the safety, tolerability, and pharmacokinetics (PKs) of gemcitabine, nab‐paclitaxel, and cobicistat. Although the doses of gemcitabine (1000 mg/m2) and cobicistat (150 mg) are fixed, three dose levels of nab‐paclitaxel (75, 100, and 125 mg/m2) will be explored to account for a potential PK drug interaction. After the dose escalation phase, we will set the recommended dose for expansion (RDE) and treat up to nine patients in an expansion part of the trial. The trial is registered under the following identifiers EudraCT‐Nr. 2019‐001439‐29, drks.de: DRKS00029409, and ct.gov: NCT05494866. Overcoming resistance to paclitaxel by CYP3A5 inhibition may lead to an increased efficacy of the gemcitabine and nab‐paclitaxel regimen. Safety, efficacy, PK, and RDE data need to be acquired before investigating this combination in a large‐scale clinical study. [ABSTRACT FROM AUTHOR]

This letter discusses the different types of positron emission tomography (PET) scanners based on their axial field-of-view (FOV). Conventional PET scanners have a short-axial FOV (SAFOV) and cover a limited range of the body. To capture more signal, scanners with a long-axial FOV (LAFOV) have been developed. These LAFOV scanners can image from the vertex to the thighs in a single-bed position. There is also a classification for total-body (TB) PET scanners, which can scan from the vertex to the toes in a single bed position. The authors propose a precise clinical definition for these different scanner types based on their FOV to improve clarity in research and clinical practice. [Extracted from the article]

Adhesive bonding is an excellent candidate for realising connections for secondary structures in structural applications such as offshore wind turbines and installations, avoiding the risk and associated welding problems. The strength of the adhesive layer is an important parameter to consider in the design process it being lower than the strength capacity of the bonding material. The presence of defects in the adhesive materials undoubtedly influences the mechanical behaviour of bonded composite structures. More specifically, the reduction in strength is more pronounced as the presence of defects (voids) increases. For this reason, a correct evaluation of the presence of defects, which can be translated into damage parameters, has become essential in predicting the actual behaviour of the bonded joints under different external loading conditions. In this paper, an extensive experimental programme has been carried out on adhesively bonded connections subjected to Mode I and Mode II loading conditions in order to characterise the mechanical properties of a commercial epoxy resin and to define the damage parameters. The initial damage parameters of the adhesive layer have been identified according to the Kachanov–Sevostianov material definition, which is able to take into account the presence of diffuse initial cracking. [ABSTRACT FROM AUTHOR]

Although exercise guidelines now recommend exercise for patients with MCI, the long-term effects of exercise in patients with MCI has not been reviewed systematically. The aim was to assess (1) the effectiveness of exercise and physical activity (EXPA) interventions in improving long-term patient-relevant cognitive and non-cognitive outcomes in people with mild cognitive impairment, (2) how well the included trials reported details of the intervention, and (3) the extent to which reported endpoints were in line with patient preferences that were assessed in patient workshops. Following PRISMA guidelines, we performed a systematic review and meta-analysis including randomized controlled trials. A total of ten studies were included after searching in six electronic sources from 1995 onwards. There is a trend that 6 + -month EXPA interventions improve global cognition 12 months after initiation. Evidence on long-term effects of EXPA interventions on non-cognitive health outcomes could not be meaningfully pooled and the individual studies reported mixed results. Workshop participants considered freedom from pain and stress, mood, motivation and self-efficacy to be important, but these outcomes were rarely addressed. Too little information is available on intervention details for EXPA programs to be replicated and confidently recommended for patients with MCI. PROSPERO registration in December, 2021 (CRD42021287166). [ABSTRACT FROM AUTHOR]

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Copyright of Psychotherapie im Alter is the property of Psychosozial-Verlag and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)