Zusammenfassung
Wir berichten über den Zufallsbefund eines Kaposi-Sarkoms des Kolons bei schwerer therapierefraktärer Colitis ulcerosa. Die Patientin war zuvor lange immunsuppressiv mit Infliximab, ...Vedolizumab und Prednisolon behandelt worden. Serologische Untersuchungen schlossen eine HIV(„human immunodeficiency virus“)-Infektion aus.
The toxicity of methylmercury (MeHg) in humans is well established and the main source of exposure is via the consumption of large marine fish and mammals. Of particular concern are the potential ...neurodevelopmental effects of early life exposure to low-levels of MeHg. Therefore, it is important that pregnant women, children and women of childbearing age are, as far as possible, protected from MeHg exposure.
Within the European project DEMOCOPHES, we have analyzed mercury (Hg) in hair in 1799 mother–child pairs from 17 European countries using a strictly harmonized protocol for mercury analysis. Parallel, harmonized questionnaires on dietary habits provided information on consumption patterns of fish and marine products. After hierarchical cluster analysis of consumption habits of the mother–child pairs, the DEMOCOPHES cohort can be classified into two branches of approximately similar size: one with high fish consumption (H) and another with low consumption (L). All countries have representatives in both branches, but Belgium, Denmark, Spain, Portugal and Sweden have twice as many or more mother–child pairs in H than in L. For Switzerland, Czech Republic, Hungary, Poland, Romania, Slovenia and Slovakia the situation is the opposite, with more representatives in L than H.
There is a strong correlation (r=0.72) in hair mercury concentration between the mother and child in the same family, which indicates that they have a similar exposure situation. The clustering of mother–child pairs on basis of their fish consumption revealed some interesting patterns. One is that for the same sea fish consumption, other food items of marine origin, like seafood products or shellfish, contribute significantly to the mercury levels in hair. We conclude that additional studies are needed to assess and quantify exposure to mercury from seafood products, in particular. The cluster analysis also showed that 95% of mothers who consume once per week fish only, and no other marine products, have mercury levels 0.55μg/g. Thus, the 95th percentile of the distribution in this group is only around half the US-EPA recommended threshold of 1μg/g mercury in hair. Consumption of freshwater fish played a minor role in contributing to mercury exposure in the studied cohort.
The DEMOCOPHES data shows that there are significant differences in MeHg exposure across the EU and that exposure is highly correlated with consumption of fish and marine products. Fish and marine products are key components of a healthy human diet and are important both traditionally and culturally in many parts of Europe. Therefore, the communication of the potential risks of mercury exposure needs to be carefully balanced to take into account traditional and cultural values as well as the potential health benefits from fish consumption. European harmonized human biomonitoring programs provide an additional dimension to national HMB programs and can assist national authorities to tailor mitigation and adaptation strategies (dietary advice, risk communication, etc.) to their country’s specific requirements.
•Hair mercury levels reported in 1799 mother–child pairs from 17 European countries.•The major source of mercury exposure is products from the marine environment.•Strong correlation in mercury levels between mother and child from the same family.•A minority European fish consumers reach mercury levels considered hazardous by WHO.•Seafood products could be an additional, ”hidden” source of mercury exposure.
•MAP2K1 mutations are rare genomic events in NSCLC.•They occur in both adenocarcinoma and squamous-cell carcinoma histology.•They are rarely exclusive, co-occurring with potentially targetable ...coaberrations.•Comprehensive multiplex sequencing at baseline is needed for detection.•Further analyses will investigate the use of MEK-inhibitors in these patients.
MAP2K1 mutations are rare in non-small cell lung cancer (NSCLC) and considered to be mutually exclusive from known driver mutations. Activation of the MEK1-cascade is considered pivotal in resistance to targeted therapy approaches, and MAP2K1 K57 N mutation could be linked to resistance in preclinical models. We set out this study to detect MAP2K1 mutations and potentially targetable co-mutations using a molecular multiplex approach.
Between 2012 and 2018, we routinely analyzed 14.512 NSCLC patients with two next-generation sequencing (NGS) panels. In a subset of patients, fluorescence in-situ hybridization was performed to detect rearrangements or amplifications. We assessed clinical parameters and co-occurring mutations and compared treatment outcomes of different forms of systemic therapy.
We identified 66 (0.5%) patients with MAP2K1 mutations. Both adenocarcinoma (n = 62) and squamous cell carcinoma (n = 4) histology. The presence of the mutations was linked to smoking, and transversions were more common than transitions. K57 N was the most frequent MAP2K1 mutation (n = 25). Additional mutations were found in 57 patients (86.4%). Mutations of TP53 were detected in 33 patients, followed by KEAP1 mutations in 28.1%. 24 patients (36.4%) had either MAP2K1-only or a co-occurring aberration considered targetable, including EGFR mutations, a BRAF V600E mutation and ROS1 rearrangements. Outcome analyses revealed a trend toward benefit from pemetrexed treatment.
Our analysis shows that MAP2K1-mutated NSCLC patients might frequently present with potentially targetable aberrations. Their role in providing resistance in these subtypes and the possible therapeutic opportunities justify further analyses of this rare NSCLC subgroup.
Abstract
The emergence of acquired resistance against targeted drugs remains a major clinical challenge in lung adenocarcinoma patients. In a subgroup of these patients we identified an association ...between selection of
EGFR
T790M
-negative but
EGFR
G724S
-positive subclones and osimertinib resistance. We demonstrate that
EGFR
G724S
limits the activity of third-generation EGFR inhibitors both in vitro and in vivo. Structural analyses and computational modeling indicate that
EGFR
G724S
mutations may induce a conformation of the glycine-rich loop, which is incompatible with the binding of third-generation TKIs. Systematic inhibitor screening and in-depth kinetic profiling validate these findings and show that second-generation EGFR inhibitors retain kinase affinity and overcome
EGFR
G724S
-mediated resistance. In the case of afatinib this profile translates into a robust reduction of colony formation and tumor growth of
EGFR
G724S
-driven cells. Our data provide a mechanistic basis for the osimertinib-induced selection of
EGFR
G724S
-mutant clones and a rationale to treat these patients with clinically approved second-generation EGFR inhibitors.
A set of seven Sm proteins assemble on the Sm-binding site of spliceosomal U snRNAs to form the ring-shaped Sm core. The U7 snRNP involved in histone RNA 3' processing contains a structurally similar ...but biochemically unique Sm core in which two of these proteins, Sm D1 and D2, are replaced by Lsm10 and by another as yet unknown component. Here we characterize this factor, termed Lsm11, as a novel Sm-like protein with apparently two distinct functions. In vitro studies suggest that its long N-terminal part mediates an important step in histone mRNA 3'-end cleavage, most likely by recruiting a zinc finger protein previously identified as a processing factor. In contrast, the C-terminal part, which comprises two Sm motifs interrupted by an unusually long spacer, is sufficient to assemble with U7, but not U1, snRNA. Assembly of this U7-specific Sm core depends on the noncanonical Sm-binding site of U7 snRNA. Moreover, it is facilitated by a specialized SMN complex that contains Lsm10 and Lsm11 but lacks Sm D1/D2. Thus, the U7-specific Lsm11 protein not only specifies the assembly of the U7 Sm core but also fulfills an important role in U7 snRNP-mediated histone mRNA processing.
The pilot study addresses the challenge of predicting postoperative outcomes, particularly body mass index (BMI) trajectories, following bariatric surgery. The complexity of this task makes ...preoperative personalized obesity treatment challenging.
To develop and validate sophisticated machine learning (ML) algorithms capable of accurately forecasting BMI reductions up to 5 years following bariatric surgery aiming to enhance planning and postoperative care. The secondary goal involves the creation of an accessible web-based calculator for healthcare professionals. This is the first article that compares these methods in BMI prediction.
The study was carried out from January 2012 to December 2021 at GZOAdipositas Surgery Center, Switzerland. Preoperatively, data for 1004 patients were available. Six months postoperatively, data for 1098 patients were available. For the time points 12 months, 18 months, 2 years, 3 years, 4 years, and 5 years the following number of follow-ups were available: 971, 898, 829, 693, 589, and 453.
We conducted a comprehensive retrospective review of adult patients who underwent bariatric surgery (Roux-en-Y gastric bypass or sleeve gastrectomy), focusing on individuals with preoperative and postoperative data. Patients with certain preoperative conditions and those lacking complete data sets were excluded. Additional exclusion criteria were patients with incomplete data or follow-up, pregnancy during the follow-up period, or preoperative BMI ≤30 kg/m2.
This study analyzed 1104 patients, with 883 used for model training and 221 for final evaluation, the study achieved reliable predictive capabilities, as measured by root mean square error (RMSE). The RMSE values for three tasks were 2.17 (predicting next BMI value), 1.71 (predicting BMI at any future time point), and 3.49 (predicting the 5-year postoperative BMI curve). These results were showcased through a web application, enhancing clinical accessibility and decision-making.
This study highlights the potential of ML to significantly improve bariatric surgical outcomes and overall healthcare efficiency through precise BMI predictions and personalized intervention strategies.
•Use of machine learning (ML) models can preoperatively predict body mass index (BMI) trajectory.•Personalized surgical intervention can be optimized using a prediction model.•Web-based tools can aid clinicians in pre- and postoperatively decision-making.•Study enhances personalized obesity treatment, suited to different scenarios.
Mineralocorticoid receptor antagonists have beneficial effects on left ventricular remodeling, cardiac fibrosis, and arrhythmia in heart failure, but efficacy and safety in dialysis patients is less ...clear. We evaluated the effect of spironolactone on left ventricular mass (LVM), an independent predictor of all-cause and cardiovascular mortality, in hemodialysis patients. In this placebo-controlled, parallel-group trial, 97 hemodialysis patients (23% female; mean age 60.3 years) were randomized to spironolactone 50 mg once daily (n=50) or placebo (n=47). The primary efficacy endpoint was change in LVM index (LVMi) from baseline to 40 weeks as determined by cardiac magnetic resonance imaging. Safety endpoints were development of hyperkalemia and change in residual renal function. There was no significant change in LVMi in participants randomized to spironolactone compared to placebo (-2.86±11.87 vs. 0.41±10.84 g/m2). There was also no difference in the secondary outcomes of mean 24-hour systolic or diastolic ambulatory blood pressure, left ventricular ejection fraction, 6-minute walk test distance, or New York Heart Association functional class. Moderate hyperkalemia (pre-dialysis potassium levels of 6.0-6.5 mmol/L) was more frequent with spironolactone treatment (155 vs. 80 events), but severe hyperkalemia (≥6.5 mmol/L) was not (14 vs. 24 events). Changes in residual urine volume and measured glomerular filtration rate did not differ between groups. There were no deaths in the spironolactone group and 4 deaths in the placebo group. Thus, treatment with 50 mg spironolactone did not change left ventricular mass index, cardiac function, or blood pressure in hemodialysis patients. Spironolactone increased the frequency of moderate hyperkalemia, but did not increase severe hyperkalemia.
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The metal cadmium (Cd) is a widespread environmental pollutant with documented adverse effects on the kidneys and bones from long-term environmental exposure, but with insufficiently elucidated ...public health consequences such as risk of cardiovascular disease, hormone-related cancer in adults and developmental effects in children. This study is the first pan-European human biomonitoring project that succeeded in performing harmonized measurements of Cd in urine in a comparable way in mother–child couples from 16 European countries. The aim of the study was to evaluate the overall Cd exposure and significant determinants of Cd exposure.
A study population of 1632 women (24–52 years of age), and 1689 children (5–12 years of age), from 32 rural and urban areas, was examined within a core period of 6 months in 2011–2012. Women were stratified as smokers and non-smokers. As expected, smoking mothers had higher geometric mean (gm) urinary cadmium (UCd; 0.24µg/g crea; n=360) than non-smoking mothers (gm 0.18µg/g crea; n=1272; p<0.0001), and children had lower UCd (gm 0.065µg/g crea; n=1689) than their mothers at the country level. Non-smoking women exposed to environmental tobacco smoke (ETS) at home had 14% (95% CI 1–28%) higher UCd than those who were not exposed to ETS at home (p=0.04). No influence of ETS at home or other places on UCd levels was detected in children. Smoking women with primary education as the highest educational level of the household had 48% (95% CI 18–86%) higher UCd than those with tertiary education (p=0.0008). The same observation was seen in non-smoking women and in children; however they were not statistically significant. In children, living in a rural area was associated with 7% (95% CI 1–13%) higher UCd (p=0.03) compared to living in an urban area. Children, 9–12 years had 7% (95% CI 1–13%) higher UCd (p=0.04) than children 5–8 years.
About 1% of the mothers, and 0.06% of the children, exceeded the tolerable weekly intake (TWI) appointed by EFSA, corresponding to 1.0µgCd/g crea in urine. Poland had the highest UCd in comparison between the 16 countries, while Denmark had the lowest. Whether the differences between countries are related to differences in the degree of environmental Cd contamination or to differences in lifestyle, socioeconomic status or dietary patterns is not clear.
•Comparable measures of urinary Cd for mother–child couples in 16 countries were achieved.•Main urinary Cd predictors were age, smoking, educational level and rural residence.•Mean urinary Cd in children differed by a factor of 7 between countries.•Among non-smoking and smoking women the difference was 3-fold between countries.•The margin between current exposure levels and suspected health effect levels is narrow.
In eukaryotic cells the phospholipid phosphatidylserine (PS) is restricted to the inner plasma-membrane leaflet. This lipid asymmetry, which is maintained by the concerted action of phospholipid ...transport proteins, is mainly lost during apoptosis. Here, we demonstrate that primary human CD8+ cytotoxic T lymphocytes (CTLs) expose PS on T-cell receptor (TCR)–mediated antigen (Ag) recognition. In contrast to PS externalization on apoptotic cells, activation-induced PS exposure is less pronounced and reversible. Fluorescence microscopic analysis revealed that PS is distributed nonhomogenously over the plasma membrane and concentrated in membrane lipid raft domains at the immunologic synapse. By studying the activity of PS transport proteins using a fluorescence-labeled PS analogue, we found that activation of CTLs inhibited the flippase-mediated inward-directed PS transport without affecting the outward transport. Shielding of exposed PS by annexin V protein during Ag recognition diminished cytokine secretion, activation, and cell-to-cell clustering of Ag-specific CTLs. In summary, our data demonstrate for the first time that externalized PS on Ag-stimulated CTLs is linked to T-cell activation and probably involved in cell-to-cell contact formation at the immunologic synapse.
Introduction
Extremely heterogeneous revision rates in total ankle arthroplasty (TAA) of the upper ankle joint are reported and result to heterogeneous collectives and to short follow-up times. The ...aim is to investigate revision rates and the underlying reasons, as well as treatment outcome and quality of life after TAA in post-traumatic cases with sufficient follow-up.
Methods
In 2008–2013, 74 patients with post-traumatic arthrosis were treated using TAA with a Tornier Salto prosthesis, and 60 (35 males and 25 females; mean age 56) were followed-up (mean: 59 months; range 24–91 months).
Results
The revision rate after TAA was 42% (
n
= 25), and it was 8% after 12 months and 18% after 24 months. Twenty percent of the patients had significant symptomatic periprosthetic bone cysts, 5% had impingement, 3% had soft tissue infections, and, in 14%, revision was caused by other factors. The most commonly performed procedures were cyst debridement and autologous spongy bone grafting (20%). Fifteen percent (
n
= 9) of the prosthetics were explanted or switched to a tibiotalar arthrodesis (TTA). The mean AOFAS (American Orthopaedic Foot and Ankle Society) score was 55.15 (range 12–100) and the mean FAO (Foot and Ankle Outcome) score was 49.6 (range 18–100). The revision subgroup had impaired outcomes (AOFAS 38.84; FAO 35.5) while the non-revision subgroup had improved outcomes (AOFAS 66.8; FAO 60.48). TAA patients undergoing conversion to TTA had worse outcomes (AOFAS 39; FAO 35.29).
Conclusion
Total ankle replacement in post-traumatic end-stage arthrosis patients is associated with high revision rates. High rates of symptomatic periprosthetic bone cysts caused high rates of revision surgery and worse outcomes, which were not improved by secondary TTA.
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