(1) Background: molecular tumor boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited ...evidence is available regarding the regional impact and the outreach component of MTBs; (2) Methods: we analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in Würzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities; (3) Results: the highest MTB patient numbers were found close to the four cancer centers. However, peaks in absolute patient numbers were also detected in more distant and rural areas. Moreover, weighting absolute numbers with local population density allowed for identifying so-called white spots—regions within our catchment that were relatively underrepresented in WERA MTBs; (4) Conclusions: investigating patient data from four neighboring cancer centers, we comprehensively assessed the regional impact of our MTBs. The results confirmed the success of existing collaborative structures with our regional partners. Additionally, our results help identifying potential white spots in providing precision oncology and help establishing a joint WERA-wide outreach strategy.
Head and neck squamous cell carcinoma (HNSCC) is known to overexpress a variety of receptor tyrosine kinases, such as the HGF receptor Met. Like other malignancies, HNSCC involves a mutual ...interaction between the tumor cells and surrounding tissues and cells. We hypothesized that activation of HGF/Met signaling in HNSCC influences glucose metabolism and therefore substantially changes the tumor microenvironment. To determine the effect of HGF, we submitted three established HNSCC cell lines to mRNA sequencing. Dynamic changes in glucose metabolism were measured in real time by an extracellular flux analyzer. As expected, the cell lines exhibited different levels of Met and responded differently to HGF stimulation. As confirmed by mRNA sequencing, the level of Met expression was associated with the number of upregulated HGF-dependent genes. Overall, Met stimulation by HGF leads to increased glycolysis, presumably mediated by higher expression of three key enzymes of glycolysis. These effects appear to be stronger in Met
-expressing HNSCC cells. Collectively, our data support the hypothesized role of HGF/Met signaling in metabolic reprogramming of HNSCC.
Altered lipid metabolism has been shown to be of major importance in a range of metabolic diseases, with particular importance in cardiovascular disease (CVD). As a key metabolic product, altered ...lipoprotein(a) (Lp(a)) levels may be associated with adverse clinical outcomes in high-risk cardiovascular patients undergoing cardiac surgery. We aimed to investigate the impact of the important metabolite Lp(a) on complications and clinical outcomes in high-risk patients. A prospective observational cohort study was performed. Data were derived from the Bern Perioperative Biobank (ClinicalTrials.gov NCT04767685), and included 192 adult patients undergoing elective cardiac surgery. Blood samples were collected at 24 h preoperatively, before induction of general anaesthesia, upon weaning from cardiopulmonary bypass (CPB), and the first morning after surgery. Clinical endpoints included stroke, myocardial infarction, and mortality within 30 days after surgery or within 1 year. Patients were grouped according to their preoperative Lp(a) levels: <30 mg/dL (
= 121; 63%) or >30 mg/dL (
71, 37%). The groups with increased vs. normal Lp(a) levels were comparable with regard to preoperative demographics and comorbidities. Median age was 67 years (interquartile range (IQR) 60.0, 73.0), with median body mass index (BMI) of 23.1 kg/m
(23.7, 30.4), and the majority of patients being males (75.5%). Over the observational interval, Lp(a) levels decreased in all types of cardiac surgery after CPB (mean decline of approximately -5 mg/dL). While Lp(a) levels decreased in all patients following CPB, this observation was considerably pronounced in patients undergoing deep hypothermic circulatory arrest (DHCA) (decrease to preoperative Lp(a) levels by -35% (95% CI -68, -1.7),
= 0.039). Increased Lp(a) levels were neither associated with increased rates of perioperative stroke or major adverse events in patients undergoing cardiac surgery, nor with overall mortality in the perioperative period, or at one year after surgery. Other than for cohorts in neurology and cardiology, elevated Lp(a) might not be a risk factor for perioperative events in cardiac surgery.
Salivary gland cancer represents a heterogeneous group of malignant tumors. Due to their low incidence and the existence of multiple morphologically defined subtypes, these tumors are still poorly ...understood with regard to their molecular pathogenesis and therapeutically relevant genetic alterations.Performing a systematic and comprehensive study covering 13 subtypes of salivary gland cancer, next generation sequencing was done on 84 tissue samples of parotid gland cancer using multiplex PCR for enrichment of cancer related gene loci covering hotspots of 46 cancer genes.Mutations were identified in 22 different genes. The most frequent alterations affected TP53, followed by RAS genes, PIK3CA, SMAD4 and members of the ERB family. HRAS mutations accounted for more than 90% of RAS mutations, occurring especially in epithelial-myoepithelial carcinomas and salivary duct carcinomas. Additional mutations in PIK3CA also affected particularly epithelial-myoepithelial carcinomas and salivary duct carcinomas, occurring simultaneously with HRAS mutations in almost all cases, pointing to an unknown and therapeutically relevant molecular constellation. Interestingly, 14% of tumors revealed mutations in surface growth factor receptor genes including ALK, HER2, ERBB4, FGFR, cMET and RET, which might prove to be targetable by new therapeutic agents. 6% of tumors revealed mutations in SMAD4.In summary, our data provide novel insight into the fundamental molecular heterogeneity of salivary gland cancer, relevant in terms of tumor classification and the establishment of targeted therapeutic concepts.
The antibody-drug conjugate enfortumab vedotin (EV) releases a cytotoxic agent into tumor cells via binding to the membrane receptor NECTIN-4. EV was recently approved for patients with metastatic ...urothelial carcinoma (mUC) without prior assessment of the tumor receptor status as ubiquitous NECTIN-4 expression is assumed. Our objective was to determine the prevalence of membranous NECTIN-4 protein expression in primary tumors (PRIM) and patient-matched distant metastases (MET).
Membranous NECTIN-4 protein expression was measured (H-score) by IHC in PRIM and corresponding MET (N = 137) and in a multicenter EV-treated cohort (N = 47). Progression-free survival (PFS) after initiation of EV treatment was assessed for the NECTIN-4-negative/weak (H-score 0-99) versus moderate/strong (H-score 100-300) subgroup. The specificity of the NECTIN-4 IHC staining protocol was validated by establishing CRISPR-Cas9-induced polyclonal NECTIN-4 knockouts.
In our cohort, membranous NECTIN-4 expression significantly decreased during metastatic spread (Wilcoxon matched pairs P < 0.001; median H-score = 40; interquartile range, 0-140), with 39.4% of MET lacking membranous NECTIN-4 expression. In our multicenter EV cohort, absence or weak membranous NECTIN-4 expression (34.0% of the cohort) was associated with a significantly shortened PFS on EV (log-rank P < 0.001).
Membranous NECTIN-4 expression is frequently decreased or absent in mUC tissue. Of note, the clinical benefit of EV strongly depends on membranous NECTIN-4 expression. Thus, our results are of highest clinical relevance and argue for a critical reconsideration of the current practice and suggest that the NECTIN-4 receptor status should be determined (ideally in a metastatic/progressive lesion) before initiation of EV. See related commentary by Aggen et al., p. 1377.
Purpose
The aim of this study is to investigate the distribution of spherical equivalent and axial length in the general population and to analyze the influence of education on spherical equivalent ...with a focus on ocular biometric parameters.
Methods
The Gutenberg Health Study is a population-based cohort study in Mainz, Germany. Participants underwent comprehensive ophthalmologic examinations as part of the 5-year follow-up examination in 2012–2017 including genotyping. The spherical equivalent and axial length distributions were modeled with gaussian mixture models. Regression analysis (on person-individual level) was performed to analyze associations between biometric parameters and educational factors. Mendelian randomization analysis explored the causal effect between spherical equivalent, axial length, and education. Additionally, effect mediation analysis examined the link between spherical equivalent and education.
Results
A total of 8532 study participants were included (median age: 57 years, 49% female). The distribution of spherical equivalent and axial length follows a bi-Gaussian function, partially explained by the length of education (i.e., < 11 years education vs. 11–20 years). Mendelian randomization indicated an effect of education on refractive error using a genetic risk score of education as an instrument variable (− 0.35 diopters per SD increase in the instrument, 95% CI, − 0.64–0.05,
p
= 0.02) and an effect of education on axial length (0.63 mm per SD increase in the instrument, 95% CI, 0.22–1.04,
p
= 0.003). Spherical equivalent, axial length and anterior chamber depth were associated with length of education in regression analyses. Mediation analysis revealed that the association between spherical equivalent and education is mainly driven (70%) by alteration in axial length.
Conclusions
The distribution of axial length and spherical equivalent is represented by subgroups of the population (bi-Gaussian). This distribution can be partially explained by length of education. The impact of education on spherical equivalent is mainly driven by alteration in axial length.
Defects in nucleic acid metabolizing enzymes can lead to spontaneous but selective activation of either cGAS/STING or RIG-like receptor (RLR) signaling, causing type I interferon-driven inflammatory ...diseases. In these pathophysiological conditions, activation of the DNA sensor cGAS and IFN production are linked to spontaneous DNA damage. Physiological, or tonic, IFN signaling on the other hand is essential to functionally prime nucleic acid sensing pathways. Here, we show that low-level chronic DNA damage in mice lacking the Aicardi-Goutières syndrome gene SAMHD1 reduced tumor-free survival when crossed to a p53-deficient, but not to a DNA mismatch repair-deficient background. Increased DNA damage did not result in higher levels of type I interferon. Instead, we found that the chronic interferon response in SAMHD1-deficient mice was driven by the MDA5/MAVS pathway but required functional priming through the cGAS/STING pathway. Our work positions cGAS/STING upstream of tonic IFN signaling in Samhd1-deficient mice and highlights an important role of the pathway in physiological and pathophysiological innate immune priming.
Virulence of the nosocomial pathogen Staphylococcus epidermidis is crucially linked to formation of adherent biofilms on artificial surfaces. Biofilm assembly is significantly fostered by production ...of a bacteria derived extracellular matrix. However, the matrix composition, spatial organization, and relevance of specific molecular interactions for integration of bacterial cells into the multilayered biofilm community are not fully understood. Here we report on the function of novel 18 kDa Small basic protein (Sbp) that was isolated from S. epidermidis biofilm matrix preparations by an affinity chromatographic approach. Sbp accumulates within the biofilm matrix, being preferentially deposited at the biofilm-substratum interface. Analysis of Sbp-negative S. epidermidis mutants demonstrated the importance of Sbp for sustained colonization of abiotic surfaces, but also epithelial cells. In addition, Sbp promotes assembly of S. epidermidis cell aggregates and establishment of multilayered biofilms by influencing polysaccharide intercellular-adhesin (PIA) and accumulation associated protein (Aap) mediated intercellular aggregation. While inactivation of Sbp indirectly resulted in reduced PIA-synthesis and biofilm formation, Sbp serves as an essential ligand during Aap domain-B mediated biofilm accumulation. Our data support the conclusion that Sbp serves as an S. epidermidis biofilm scaffold protein that significantly contributes to key steps of surface colonization. Sbp-negative S. epidermidis mutants showed no attenuated virulence in a mouse catheter infection model. Nevertheless, the high prevalence of sbp in commensal and invasive S. epidermidis populations suggests that Sbp plays a significant role as a co-factor during both multi-factorial commensal colonization and infection of artificial surfaces.
Karst aquifers are important sources of fresh water on a global scale. The hydrological modelling of karst spring discharge, however, still poses a challenge. In this study we apply a transfer ...function noise (TFN) model in combination with a bucket-type recharge model to simulate karst spring discharge. The application of the noise model for the residual series has the advantage that it is more consistent with assumptions for optimization such as homoscedasticity and independence. In an earlier hydrological modeling study, named Karst Modeling Challenge (KMC; Jeannin et al., J Hydrol 600:126–508, 2021), several modelling approaches were compared for the Milandre Karst System in Switzerland. This serves as a benchmark and we apply the TFN model to KMC data, subsequently comparing the results to other models. Using different data-model-combinations, the most promising data-model-combination is identified in a three-step least-squares calibration. To quantify uncertainty, the Bayesian approach of Markov-chain Monte Carlo (MCMC) sampling is subsequently used with uniform priors for the previously identified best data-model combination. The MCMC maximum likelihood solution is used to simulate spring discharge for a previously unseen testing period, indicating a superior performance compared to all other models in the KMC. It is found that the model gives a physically feasible representation of the system, which is supported by field measurements. While the TFN model simulated rising limbs and flood recession especially well, medium and baseflow conditions were not represented as accurately. The TFN approach poses a well-performing data-driven alternative to other approaches that should be considered in future studies.
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