Substrate recognition by the 4-hydroxytryptamine kinase PsiK in psilocybin biosynthesis.

Psilocybin, the natural hallucinogen from Psilocybe (magic) mushrooms, is a highly promising drug candidate for the treatment of depression and several other mental health conditions. Biosynthesis of psilocybin from the amino acid l-tryptophan involves four strictly sequential modifications. The third of these, ATP-dependent phosphorylation of the intermediate 4-hydroxytryptamine, is catalysed by PsiK. Here we present a crystallographic analysis and a structure-based mutagenesis study of this kinase, providing insight into its mode of substrate recognition. The results of our work will support future bioengineering efforts aimed at generating variants of psilocybin with enhanced therapeutic properties.

The Second Methylation in Psilocybin Biosynthesis Is Enabled by a Hydrogen Bonding Network Extending into the Secondary Sphere Surrounding the Methyltransferase Active Site.

The Psilocybe cubensis SAM-dependent methyltransferase, PsiM, catalyzes the last step in the biosynthesis of psilocybin. Likely evolved from monomethylating RNA methyltransferases, PsiM acquired a key amino acid exchange in the secondary sphere of the active site, M247N, which is responsible for its capacity to dimethylate. Two variants, PsiMN247M and PsiMN247A, were generated to further examine the role of Asn247 for mono- and dimethylation in PsiM. Herein, we present the kinetic profiles of both variants and crystal structures at resolutions between 0.9 and 1.0 Å. Each variant was crystallized as a ternary complex with the non-methylated acceptor substrate, norbaeocystin and S-adenosyl-l-homocysteine, and in a second complex with the cofactor analog, sinefungin, and the monomethylated substrate, baeocystin. Consistent with the inability of the variants to catalyze a second methyl transfer, these structures reveal catalytically non-productive conformations and a high level of disorder of the methylamine group of baeocystin. Additionally, both variants exhibit destabilization in the ß5-ß7 sheets and a conserved ß-turn of the core Rossmann fold, causing 20-fold reduced substrate binding and 2-fold lower catalytic efficiency even with norbaeocystin.

Progression of Heart Failure in People with Type 2 Diabetes in Germany: An Analysis Using German Health Insurance Claims Data.

Background: Individuals with type 2 diabetes (T2D) show high risk of heart failure (HF). Left ventricular ejection fraction is a major factor for disease progression. In Germany, no recent longitudinal data are available. Objectives: To (1) measure the proportion of individuals with T2D who acquire HF over 2 years and (2) categorize ejection fraction using routine data and an algorithm, and (3) understand progression of HF in 5-year follow-up. Methods: This descriptive, retrospective study used longitudinal data from German statutory health insurance claims. A model using coded data classified the patients with HF into ejection fraction (EF) categories. Individuals were selected during 2013, with an inclusion period from 2014 to 2015 and a follow-up from 2016 to 2020. Baseline characteristics included demographic data, disease stage, comorbidities, and risk factors. Follow-up criteria included major adverse cardiac events (MACEs), EF category, and mortality. Disease progression was visualized by Sankey plots. Results: Among the 173 195 individuals with T2D identified in 2013, 6725 (median age, 74 years) developed HF in 2014 or 2015. 34.4% of individuals had MACEs, and 42.9% died over 5 years. Myocardial infarction (42%) was the most common event, followed by stroke (32%) and hospitalization (28%). A total of 5282 (78.54%) patients were classified into preserved EF and 1443 (21.46%) into reduced EF. Survival after 5 years was 71% in HF for preserved EF patients, and 29% in the HF for those with reduced EF. Conclusion: Heart failure is relevant in individuals with diabetes. A high number of patients may likely not survive a 5-year period. Validation of the model with German data is highly desirable. New ways of close monitoring could help improve outcomes.

Recruitment of CTCF to the SIRT1 promoter after Oxidative Stress mediates Cardioprotective Transcription.

Because most DNA-binding transcription factors (dbTFs), including the architectural regulator CTCF, bind RNA and exhibit di-/multimerization, a central conundrum is whether these distinct properties are regulated post-transcriptionally to modulate transcriptional programs. Here, investigating stress-dependent activation of SIRT1, encoding an evolutionarily-conserved protein deacetylase, we show that induced phosphorylation of CTCF acts as a rheostat to permit CTCF occupancy of low-affinity promoter DNA sites to precisely the levels necessary. This CTCF recruitment to the SIRT1 promoter is eliciting a cardioprotective cardiomyocyte transcriptional activation program and provides resilience against the stress of the beating heart in vivo . Mice harboring a mutation in the conserved low-affinity CTCF promoter binding site exhibit an altered, cardiomyocyte-specific transcriptional program and a systolic heart failure phenotype. This transcriptional role for CTCF reveals that a covalent dbTF modification regulating signal-dependent transcription serves as a previously unsuspected component of the oxidative stress response.

Enhancer-promoter specificity in gene transcription: molecular mechanisms and disease associations.

Although often located at a distance from their target gene promoters, enhancers are the primary genomic determinants of temporal and spatial transcriptional specificity in metazoans. Since the discovery of the first enhancer element in simian virus 40, there has been substantial interest in unraveling the mechanism(s) by which enhancers communicate with their partner promoters to ensure proper gene expression. These research efforts have benefited considerably from the application of increasingly sophisticated sequencing- and imaging-based approaches in conjunction with innovative (epi)genome-editing technologies; however, despite various proposed models, the principles of enhancer-promoter interaction have still not been fully elucidated. In this review, we provide an overview of recent progress in the eukaryotic gene transcription field pertaining to enhancer-promoter specificity. A better understanding of the mechanistic basis of lineage- and context-dependent enhancer-promoter engagement, along with the continued identification of functional enhancers, will provide key insights into the spatiotemporal control of gene expression that can reveal therapeutic opportunities for a range of enhancer-related diseases.

Mn-promoted MoS2 catalysts for CO2 hydrogenation: enhanced methanol selectivity due to MoS2/MnOx interfaces.

Considering the alarming scenario of climate change, CO2 hydrogenation to methanol is considered a key process for phasing out fossil fuels by means of CO2 utilization. In this context, MoS2 catalysts have recently shown to be promising catalysts for this reaction, especially in the presence of abundant basal-plane sulfur vacancies and due to synergistic mechanisms with other phases. In this work, Mn-promoted MoS2 prepared by a hydrothermal method presents considerable selectivity for CO2 hydrogenation to methanol in comparison with pure MoS2 and other promoters such as K and Co. Interestingly, if CO is used as a carbon source for the reaction, methanol production is remarkably lower, which suggests the absence of a CO intermediate during CO2 hydrogenation to methanol. After optimization of synthesis parameters, a methanol selectivity of 64% is achieved at a CO2 conversion of 2.8% under 180 °C. According to material characterization by X-ray Diffraction and X-ray Absorption, the Mn promoter is present mainly in the form of MnO and MnCO3 phases, with the latter undergoing convertion to MnO upon H2 pretreatment. However, following exposure to reaction conditions, X-ray photoelectron spectroscopy suggests that higher oxidation states of Mn may be present at the surface, suggesting that the improved catalytic activity for CO2 hydrogenation to methanol arises from a synergy between MoS2 and MnOx at the catalyst surface.

S1 basic leucine zipper transcription factors shape plant architecture by controlling C/N partitioning to apical and lateral organs.

Plants tightly control growth of their lateral organs, which led to the concept of apical dominance. However, outgrowth of the dormant lateral primordia is sensitive to the plant's nutritional status, resulting in an immense plasticity in plant architecture. While the impact of hormonal regulation on apical dominance is well characterized, the prime importance of sugar signaling to unleash lateral organ formation has just recently emerged. Here, we aimed to identify transcriptional regulators, which control the trade-off between growth of apical versus lateral organs. Making use of locally inducible gain-of-function as well as single and higher-order loss-of-function approaches of the sugar-responsive S1-basic-leucine-zipper (S1-bZIP) transcription factors, we disclosed their largely redundant function in establishing apical growth dominance. Consistently, comprehensive phenotypical and analytical studies of S1-bZIP mutants show a clear shift of sugar and organic nitrogen (N) allocation from apical to lateral organs, coinciding with strong lateral organ outgrowth. Tissue-specific transcriptomics reveal specific clade III SWEET sugar transporters, crucial for long-distance sugar transport to apical sinks and the glutaminase GLUTAMINE AMIDO-TRANSFERASE 1_2.1, involved in N homeostasis, as direct S1-bZIP targets, linking the architectural and metabolic mutant phenotypes to downstream gene regulation. Based on these results, we propose that S1-bZIPs control carbohydrate (C) partitioning from source leaves to apical organs and tune systemic N supply to restrict lateral organ formation by C/N depletion. Knowledge of the underlying mechanisms controlling plant C/N partitioning is of pivotal importance for breeding strategies to generate plants with desired architectural and nutritional characteristics.

Coupling of Ferromagnetic and Antiferromagnetic Spin Dynamics in Mn_{2}Au/NiFe Thin Film Bilayers.

We investigate magnetization dynamics of Mn_{2}Au/Py (Ni_{80}Fe_{20}) thin film bilayers using broadband ferromagnetic resonance (FMR) and Brillouin light scattering spectroscopy. Our bilayers exhibit two resonant modes with zero-field frequencies up to almost 40 GHz, far above the single-layer Py FMR. Our model calculations attribute these modes to the coupling of the Py FMR and the two antiferromagnetic resonance (AFMR) modes of Mn_{2}Au. The coupling strength is in the order of 1.6 T nm at room temperature for nm-thick Py. Our model reveals the dependence of the hybrid modes on the AFMR frequencies and interfacial coupling as well as the evanescent character of the spin waves that extend across the Mn_{2}Au/Py interface.

Does experience change the role of systematic biopsy during MRI-fusion biopsy of the prostate?

PURPOSE: To determine the role of biopsy experience regarding a potential benefit of additional systematic biopsies and fusion failures during MRI-targeted biopsy of the prostate. SUBJECTS/PATIENTS AND METHODS: We retrospectively evaluated 576 men undergoing transrectal (MRI)-targeted biopsy of the prostate by seven residents in urology between November 2019 and March 2022. Benefit of systematic biopsies (detection of ISUP ≥ 2 PCa (clinically significant PCa (csPCa)) solely in systematic biopsies) and fusion failure (detection of csPCa during systematic biopsies in the area of a reported MRI-lesion and no detection of csPCa in targeted biopsy) were compared by growing biopsy experience levels. Multivariable regression analyses were calculated to investigate the association with benefit of systematic biopsies and fusion failure. RESULTS: The overall PCa detection rate was 72% (413/576). A benefit of systematic biopsies was observed in 11% (63/576); of those, fusion failure was seen in 76% (48/63). Benefit of systematic biopsies and fusion failure were more common among residents with very low experience compared to highly experienced residents (18% versus 4%, p = 0.026; 13% versus 3%, p = 0.015, respectively). Increasing biopsy experience was associated with less benefit from systematic biopsies (OR: 0.98, 95% CI 0.97-0.99) and less fusion failure (OR: 0.98, 95% CI 0.97-0.99). CONCLUSIONS: The benefit of systematic biopsies following targeted biopsy decreases with growing biopsy experience. The higher risk of fusion failure among inexperienced residents necessitates systematic biopsies to ensure the detection of csPCa. Further prospective trials are warranted before a targeted only approach can be recommended in routine clinical practice.

Uncertainty estimation for deep learning-based pectoral muscle segmentation via Monte Carlo dropout.

Objective. Deep Learning models are often susceptible to failures after deployment. Knowing when your model is producing inadequate predictions is crucial. In this work, we investigate the utility of Monte Carlo (MC) dropout and the efficacy of the proposed uncertainty metric (UM) for flagging of unacceptable pectoral muscle segmentations in mammograms.Approach. Segmentation of pectoral muscle was performed with modified ResNet18 convolutional neural network. MC dropout layers were kept unlocked at inference time. For each mammogram, 50 pectoral muscle segmentations were generated. The mean was used to produce the final segmentation and the standard deviation was applied for the estimation of uncertainty. From each pectoral muscle uncertainty map, the overall UM was calculated. To validate the UM, a correlation between the dice similarity coefficient (DSC) and UM was used. The UM was first validated in a training set (200 mammograms) and finally tested in an independent dataset (300 mammograms). ROC-AUC analysis was performed to test the discriminatory power of the proposed UM for flagging unacceptable segmentations.Main results. The introduction of dropout layers in the model improved segmentation performance (DSC = 0.95 ± 0.07 versus DSC = 0.93 ± 0.10). Strong anti-correlation (r= -0.76,p< 0.001) between the proposed UM and DSC was observed. A high AUC of 0.98 (97% specificity at 100% sensitivity) was obtained for the discrimination of unacceptable segmentations. Qualitative inspection by the radiologist revealed that images with high UM are difficult to segment.Significance. The use of MC dropout at inference time in combination with the proposed UM enables flagging of unacceptable pectoral muscle segmentations from mammograms with excellent discriminatory power.

[Costs of potentially outpatient endoscopic procedures in cases with a 1-day hospital stay versus a longer stay]. / Kosten potenziell ambulant erbringbarer endoskopischer Leistungen in Fällen mit 1-Tages-Verweildauer gegenüber einer längeren Verweildauer.

INTRODUCTION: The transfer of patient care and medical interventions that was previously provided on an inpatient basis to outpatient settings is a stated goal of health politics. It is unclear to what extent costs of an endoscopic procedure and the disease severity depend on the duration of inpatient treatment. We therefore examined whether endoscopic services for cases with a one-day length of stay (VWD) are comparably expensive to cases with a longer VWD. METHODS: Outpatient services were selected from the DGVS service catalog. Day cases with exactly one such gastroenterological endoscopic (GAEN) service were compared with cases with VWD>1 day regarding their patient clinical complexity levels (PCCL) and mean costs. Data from the DGVS-DRG project with §21-KHEntgG cost data from a total of 57 hospitals from 2018 and 2019 served as the basis. Endoscopic costs were taken from cost center group 8 of the InEK cost matrix and plausibility checked. RESULTS: A total of 122,514 cases with exactly one GAEN service were identified. Statistically equal costs were shown in 30 of 47 service groups. In 10 groups, the cost difference was not relevant (<10%). Cost differences >10% existed only for EGD with variceal therapy, insertion of a self-expanding prosthesis, dilatation/bougienage/exchange with PTC/PTCD in place, non-extensive ERCP, endoscopic ultrasound in the upper gastrointestinal tract, and colonoscopy with submucosal or full thickness resection, or foreign object removal. PCCL differed in all but one group. CONCLUSION: Gastroenterology endoscopy services provided as part of inpatient care but potentially performable on an outpatient basis are predominantly equally expensive for day cases as for patients with a length of stay greater than one day. The disease severity is lower. Calculated §21-KHEntgG cost data thus form a reliable basis for the calculation of appropriate reimbursement for hospital services to be provided as outpatient services under the AOP in the future.

SARS-CoV-2 Saliva Mass Screening in Primary Schools: A 10-Week Sentinel Surveillance Study in Munich, Germany.

Representative, actively collected surveillance data on asymptomatic SARS-CoV-2 infections in primary schoolchildren remain scarce. We evaluated the feasibility of a saliva mass screening concept and assessed infectious activity in primary schools. During a 10-week period from 3 March to 21 May 2021, schoolchildren and staff from 17 primary schools in Munich participated in the sentinel surveillance, cohort study. Participants were tested using the Salivette® system, testing was supervised by trained school staff, and samples were processed via reverse transcription quantitative polymerase chain reaction (RT-qPCR). We included 4433 participants: 3752 children (median age, 8 [range, 6-13] years; 1926 girls [51%]) and 681 staff members (median age, 41 [range, 14-71] years; 592 women [87%]). In total, 23,905 samples were processed (4640 from staff), with participants representing 8.3% of all primary schoolchildren in Munich. Only eight cases were detected: Five out of 3752 participating children (0.13%) and three out of 681 staff members (0.44%). There were no secondary cases. In conclusion, supervised Salivette® self-sampling was feasible, reliable, and safe and thus constituted an ideal method for SARS-CoV-2 mass screenings in primary schoolchildren. Our findings suggest that infectious activity among asymptomatic primary schoolchildren and staff was low. Primary schools appear to continue to play a minor role in the spread of SARS-CoV-2 despite high community incidence rates.

Impact of diastolic pulmonary gradient and pulmonary artery pulse index on outcomes in heart transplant patients-Results from the Eurotransplant database.

Background: Predicting complications associated with pulmonary hypertension (PH) after cardiac transplantation is an important factor when considering cardiac transplantation. The transpulmonary gradient (TPG) is recommended to quantify PH in transplant candidates. Nonetheless, PH remains a common driver of mortality. The diastolic pressure gradient (DPG) and pulmonary vascular resistance (PVR) can differentiate post- from combined pre- and post-capillary PH and may improve estimation of PH-associated risks. We used a large European cohort of transplant candidates to assess whether the pulmonary pulsatility index (PAPi), improves prediction of graft failure and mortality compared to DPG and PVR. Methods: Out of all patients undergoing heart transplantation between 2009 and 2019 in Eurotransplant member states (n = 10,465), we analyzed the impact of PH (mPAP > 25 mmHg) and right heart catheter hemodynamic data on graft failure and mortality within 1-5 years. Results: In 1,407 heart transplant patients with PH (79% male, median age 54 years, IQR 39-69 years), the median PVR was 2.5 WU (IQR 1.6 WU) with a median mPAP (pulmonary arterial pressure) of 32 mmHg (IQR 9 mmHg). Patients with low (< 3 mmHg) DPG had a better 5 year survival than those with higher DPG (log rank p = 0.023). TPG, mPAP, PAPi, and PVR did not improve prediction of survival. Low PAPi (OR = 2.24, p < 0.001) and high PVR (OR = 2.12, p = 0.005) were associated with graft failure. Conclusion: PAPI and PVR are associated with graft failure in patients with PH undergoing cardiac transplantation. DPG is associated with survival in this cohort.

Feasibility of assessing utilities with a single-item standard gamble questionnaire in patients with melanoma.

OBJECTIVES: To determine the feasibility of eliciting utilities with a standard gamble self-completion questionnaire that uses a single-item approach in melanoma patients. METHODS: 150 patients with low-risk melanoma completed a paper standard gamble questionnaire. Six scenarios described the adjuvant treatment of high-risk melanoma with interferon alfa-2b with varied side effects. Patients were asked to directly state the maximum death risk they would accept to prevent these health states. Methods were the same as in a study by Kilbridge et al. (J Clin Oncol 19(3):812-823, 2021. https://doi.org/10.1200/JCO.2001.19.3.812 ), except that they used computerised interviews and an iterative risk variation (Ping-Pong method) to elicit utilities. RESULTS: The rate of missing values in the standard gamble was 1.0%. The percentage of patients who misordered scenarios was very similar to the reference study (11.3% vs. 11.2%). Mean utilities were also similar with a maximum difference of 0.02 points, but median utilities were not (between 0.21 points below and 0.05 points above the reference study). CONCLUSIONS: One-item utility elicitation with questionnaires might be a feasible alternative to computerised face-to-face interviews to conduct a standard gamble in melanoma patients.

Mechanistic insights into p53-regulated cytotoxicity of combined entinostat and irinotecan against colorectal cancer cells.

Late-stage colorectal cancer (CRC) is still a clinically challenging problem. The activity of the tumor suppressor p53 is regulated via post-translational modifications (PTMs). While the relevance of p53 C-terminal acetylation for transcriptional regulation is well defined, it is unknown whether this PTM controls mitochondrially mediated apoptosis directly. We used wild-type p53 or p53-negative human CRC cells, cells with acetylation-defective p53, transformation assays, CRC organoids, and xenograft mouse models to assess how p53 acetylation determines cellular stress responses. The topoisomerase-1 inhibitor irinotecan induces acetylation of several lysine residues within p53. Inhibition of histone deacetylases (HDACs) with the class I HDAC inhibitor entinostat synergistically triggers mitochondrial damage and apoptosis in irinotecan-treated p53-positive CRC cells. This specifically relies on the C-terminal acetylation of p53 by CREB-binding protein/p300 and the presence of C-terminally acetylated p53 in complex with the proapoptotic BCL2 antagonist/killer protein. This control of C-terminal acetylation by HDACs can mechanistically explain why combinations of irinotecan and entinostat represent clinically tractable agents for the therapy of p53-proficient CRC.

Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors.

The chromatin reader protein Spindlin1 plays an important role in epigenetic regulation, through which it has been linked to several types of malignant tumors. In the current work, we report on the development of novel analogs of the previously published lead inhibitor A366. In an effort to improve the activity and explore the structure-activity relationship (SAR), a series of 21 derivatives was synthesized, tested in vitro, and investigated by means of molecular modeling tools. Docking studies and molecular dynamics (MD) simulations were performed to analyze and rationalize the structural differences responsible for the Spindlin1 activity. The analysis of MD simulations shed light on the important interactions. Our study highlighted the main structural features that are required for Spindlin1 inhibitory activity, which include a positively charged pyrrolidine moiety embedded into the aromatic cage connected via a propyloxy linker to the 2-aminoindole core. Of the latter, the amidine group anchor the compounds into the pocket through salt bridge interactions with Asp184. Different protocols were tested to identify a fast in silico method that could help to discriminate between active and inactive compounds within the A366 series. Rescoring the docking poses with MM-GBSA calculations was successful in this regard. Because A366 is known to be a G9a inhibitor, the most active developed Spindlin1 inhibitors were also tested over G9a and GLP to verify the selectivity profile of the A366 analogs. This resulted in the discovery of diverse selective compounds, among which 1s and 1t showed Spindlin1 activity in the nanomolar range and selectivity over G9a and GLP. Finally, future design hypotheses were suggested based on our findings.

qSOFA Score Is Useful to Assess Disease Severity in Patients With Heart Failure in the Setting of a Heart Failure Unit (HFU).

Aims: There is no gold standard to predict outcome in acute decompensated heart failure (ADHF). Several scores for mortality prediction of patients with ADHF have been developed and mostly consist of complex regression models. None of these models has been widely adopted by clinicians. The quick SOFA score (qSOFA) is a simple score including three parameters (systolic blood pressure ≤ 100 mmHg, respiratory rate ≥22 breathes/min, and GCS <15) and is validated for discrimination of mortality risk in septic patients. Here, we adapted qSOFA score to patients admitted to a Heart Failure Unit (HFU) and assessed the prognostic accuracy. Methods and Results: qSOFA, SOFA score, and SIRS criteria were assessed at admission. Clinical, laboratory, and echocardiographic parameters were recorded. A follow-up was performed 30 days after discharge. Primary outcome was all-cause mortality or readmission to hospital due do worsening of heart failure symptoms. Of 240 patients (73% male, 16-93 years), 25 patients (10%) had a qSOFA ≥2 points and 126 patients (53%) fulfilled none of qSOFA criteria. Within 30 days, the primary endpoint occurred in 46 patients (19%). Seventeen patients (7%) died and 34 patients (14%) were readmitted to hospital due to worsening heart failure. Patients with qSOFA ≥2 reached this endpoint more frequently (48 vs. 19%, p = 0.002), had more often dyspnea NYHA III-IV (OR 2.4, p = 0.005) and a higher risk for multi organ failure during hospital stay (28 vs. 9%, P = 0.005). Conclusions: qSOFA is useful to identify patients with heart failure at high risk for worse outcome and to operationalize severity of decompensation.

Right heart failure before LVAD implantation predicts right heart failure after LVAD implantation - is it that easy?

BACKGROUND: Right heart failure (RHF) after left ventricular assist device (LVAD) implantation is common and associated with worse outcome. Prediction of RHF remains challenging. Our study aims to assess predictors of RHF focusing on clinical manifestations. METHODS: We retrospectively analyzed clinical, echocardiographic and hemodynamic parameters of 112 patients undergoing LVAD implantation. Pre-operative, early (ERHF, day 7 and 14) and late postoperative RHF (LRHF, after 1, 3, 6 and 12 months) were assessed. RESULTS: In the total study population (87.5% men, mean age 55 years), early RHF was frequent (47% on day 7 and 30% on day 14). Prevalence of late RHF and death from RHF was high after 3, 6 and 12 months (23, 24 and 17%). Pre-existing RHF was only associated with early RHF and persistent, but not for new onset late RHF. Early RHF was associated with lower INTERMACS level (p < 0.001), higher pulmonary vascular resistance (p = 0.046) and CVP/PAWP quotient (p = 0.011), higher bilirubin (p = 0.038) and creatinine (p = 0.013). LRHF was associated with creatinine (p = 0.006), urea (p = 0.012) and load adaption index (p = 0.007). Binary logistic regression models identified no single risk factors. Comparing the predictive value of regression models with a model of three clinical findings (INTERMACS level, age and pre-operative RHF) did not reveal differences in RHF. CONCLUSIONS: RHF before LVAD implantation enhances the risk of early RHF and persistent late RHF, but not for new onset late RHF, supporting the hypothesis of differences in the etiology. Echocardiographic or hemodynamic parameters did not show a predictive value for new onset late RHF. Similar predictive value of clinical findings and statistic models of risk factors suggest that a clinical evaluation is equally matched to predict RHF.

Application of the SCAI classification in a cohort of patients with cardiogenic shock.

BACKGROUND: The Society of Cardiovascular Angiography and Interventions (SCAI) have recently proposed a new classification of cardiogenic shock (CS) dividing patients into five subgroups. OBJECTIVE: Aim of this study was to apply the SCAI classification to a cohort of patients presenting with CS and to evaluate its ability to predict 30-day survival. METHODS: SCAI CS subgroups were interpreted based on the recent consensus statement and then applied to N = 1,007 consecutive patients presenting with CS or large myocardial infarction (MI) between October 2009 and October 2017. The association between SCAI classification and 30-day all-cause mortality was assessed by logistic regression analysis. RESULTS: Mean age in the study cohort was 67 (±15) years, 72% were male. Mean lactate at baseline was 6.05 (±5.13) mmol/l and 51% of the patients had prior cardiac arrest. Overall survival probability was 50.6% (95% confidence interval [CI] 47.5-54.0%). In view of the SCAI classification, the survival probability was 96.4% (95% CI 93.7-99.0%) in class A, 66.1% (95% CI 50.2-87.1%) in class B, 46.1% (95% CI 40.6-52.4%) in class C, 33.1% (95% CI 26.6-41.1%) in class D, and 22.6% (95% CI 17.1-30.0%) in class E. Higher SCAI classification was significantly associated with lower 30-day survival (p < .01). CONCLUSION: In this large clinical cohort, the SCAI classification was significantly associated with 30-day survival. This finding supports the rationale of the SCAI CS classification and calls for a validation in a prospective trial.

Salinomycin: Anti-tumor activity in a pre-clinical colorectal cancer model.

OBJECTIVES: Salinomycin is a polyether antibiotic with selective activity against human cancer stem cells. The impact of salinomycin on patient-derived primary human colorectal cancer cells has not been investigated so far. Thus, here we aimed to investigate the activity of salinomycin against tumor initiating cells isolated from patients with colorectal cancer. METHODS: Primary tumor-initiating cells (TIC) isolated from human patients with colorectal liver metastases or from human primary colon carcinoma were exposed to salinomycin and compared to treatment with 5-FU and oxaliplatin. TICs were injected subcutaneously into NOD/SCID mice to induce a patient-derived mouse xenograft model of colorectal cancer. Animals were treated either with salinomycin, FOLFOX regimen, or salinomycin and FOLFOX. Human colorectal cancer cells were used to delineate an underlying molecular mechanism of salinomycin in this tumor entity. RESULTS: Applying TICs isolated from human patients with colorectal liver metastases or from human primary colon carcinoma, we demonstrated that salinomycin exerts increased antiproliferative activity compared to 5-fluorouracil and oxaliplatin treatment. Consistently, salinomycin alone or in combination with FOLFOX exerts superior antitumor activity compared to FOLFOX therapy in a patient-derived mouse xenograft model of colorectal cancer. Salinomycin induces apoptosis of human colorectal cancer cells, accompanied by accumulation of dysfunctional mitochondria and reactive oxygen species. These effects are associated with expressional down-regulation of superoxide dismutase-1 (SOD1) in response to salinomycin treatment. CONCLUSION: Collectively, the results of this pre-clinical study indicate that salinomycin alone or in combination with 5-fluorouracil and oxaliplatin exerts increased antitumoral activity compared to common chemotherapy.