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Abstract Background Candida albicans resides on epithelial surfaces as part of the physiological microflora. However, under certain conditions it may cause life-threatening infections like Candida sepsis. Human β-defensins (hBDs) are critical components of host defense at mucosal surfaces and we have recently shown that hBD-2 and hBD-3 are upregulated in Candida esophagitis. We therefore studied the role of Candidate signalling pathways in order to understand the mechanisms involved in regulation of hBD-expression by C. albicans. We used the esophageal cell line OE21 and analysed the role of paracrine signals from polymorphonuclear leukocytes (PMN) in an in vitro model of esophageal candidiasis. Results Supernatants of C. albicans or indirect coculture with C. albicans induces upregulation of hBD-2 and hBD-3 expression. PMNs strongly amplifies C. albicans-mediated induction of hBDs. By EMSA we demonstrate that C. albicans activates NF-κB and AP-1 in OE21 cells. Inhibition of these pathways revealed that hBD-2 expression is synergistically regulated by both NF-κB and AP-1. In contrast hBD-3 expression is independent of NF-κB and relies solely on an EGFR/MAPK/AP-1-dependent pathway. Conclusion Our analysis of signal transduction events demonstrate a functional interaction of epithelial cells with PMNs in response to Candida infection involving divergent signalling events that differentially govern hBD-2 and hBD-3 expression.

Germline and somatic TP53 variants play a crucial role during tumorigenesis. However, genetic variations that solely affect the alternatively spliced p53 isoforms, p53β and p53γ, are not fully considered in the molecular diagnosis of Li-Fraumeni syndrome and cancer. In our search for additional cancer predisposing variants, we identify a heterozygous stop-lost variant affecting the p53β isoforms (p.*342Serext*17) in four families suspected of an autosomal dominant cancer syndrome with colorectal, breast and papillary thyroid cancers. The stop-lost variant leads to the 17 amino-acid extension of the p53β isoforms, which increases oligomerization to canonical p53α and dysregulates the expression of p53's transcriptional targets. Our study reveals the capacity of p53β mutants to influence p53 signalling and contribute to the susceptibility of different cancer types. These findings underscore the significance of p53 isoforms and the necessity of comprehensive investigation into the entire TP53 gene in understanding cancer predisposition., (© 2024. The Author(s).)

Two independent exome sequencing initiatives aimed to identify new genes involved in the predisposition to nonpolyposis colorectal cancer led to the identification of heterozygous loss-of-function variants in NPAT, a gene that encodes a cyclin E/CDK2 effector required for S phase entry and a coactivator of histone transcription, in two families with multiple members affected with colorectal cancer. Enrichment of loss-of-function and predicted deleterious NPAT variants was identified in familial/early-onset colorectal cancer patients compared to non-cancer gnomAD individuals, further supporting the association with the disease. Previous studies in Drosophila models showed that NPAT abrogation results in chromosomal instability, increase of double strand breaks, and induction of tumour formation. In line with these results, colorectal cancers with NPAT somatic variants and no DNA repair defects have significantly higher aneuploidy levels than NPAT-wildtype colorectal cancers. In conclusion, our findings suggest that constitutional inactivating NPAT variants predispose to mismatch repair-proficient nonpolyposis colorectal cancer., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)

Background: In the twenty-first century, the success story of the Post-World-War-II World has been called into question by climate change and other challenges. De-growth or zero economic growth are discussed as possible solutions for mitigating climate change. The traditional economic growth model is increasingly challenged by the demand for sustained economic growth expressed in United Nations Sustainable Development Goal 8 "sustained economic growth" (UN-SDG 8) and supported by the European Green Deal. The aim of this paper is to contribute to the general understanding of characteristics, effects and challenges of new economic growth ideas as well as their interlinkages with the food-energy-water (FEW) nexus., Methods: To address these challenges, a stylized dynamic General Equilibrium Model (GEM) was developed, which consists of two countries: an emerging, developing European country A and a developed European country B. Country A is assumed to grow, while country B shrinks. The model is based on artificial data sets. This approach was chosen to prevent the blurring of counterfactual comparison by country-specific effects of economic turbulences such as the Lehman crash or the economic break-in during the Covid-19 pandemic., Results: The gross output of the emerging European country increases, whereas the output of the developed European country decreases according to the different growth strategies. The analysis reveals that a constantly widening gap between the emerging and the developed country is created. It can further be shown how this influences the relevant economic indicators (CO 2 emissions, household budget, trade balance, utility and social welfare)., Conclusions: The analysis of the two-country stylized GE model makes distortions visible: insignificant gaps in the values and development of analyzed economic indicators become prevalent. The welfare gap affects the core of the traditional socio-economic system, because the development of the utility of the households is central for the stability of political processes. A sufficiency and subsistence sector may be an option to even out the welfare losses from the de-growth strategy of the traditional economic system to avoid that the de-growth gaps are perceived by the community as welfare losses which can endanger the realization of UN-SDG 8., Competing Interests: Competing interestsWe do not have competing interests., (© The Author(s) 2022.)

Lynch syndrome is the most common cause of hereditary colorectal cancer (CRC), and it is characterized by DNA mismatch repair (MMR) deficiency. The term Lynch-like syndrome (LLS) is used for patients with MMR-deficient tumors and neither germline mutation in MLH1, MSH2, MSH6, PMS2, or EPCAM nor MLH1 somatic methylation. Biallelic somatic inactivation or cryptic germline MMR variants undetected during genetic testing have been proposed to be involved. Sixteen patients with early-onset LLS CRC were selected for germline and tumor whole-exome sequencing. Two potentially pathogenic germline MCM8 variants were detected in a male patient with LLS with fertility problems. A knockout cellular model for MCM8 was generated by CRISPR/Cas9 and detected genetic variants were produced by mutagenesis. DNA damage, microsatellite instability, and mutational signatures were monitored. DNA damage was evident for MCM8KO cells and the analyzed genetic variants. Microsatellite instability and mutational signatures in MCM8KO cells were compatible with the involvement of MCM8 in MMR. Replication in an independent familial cancer cohort detected additional carriers. Unexplained MMR-deficient CRC cases, even showing somatic biallelic MMR inactivation, may be caused by underlying germline defects in genes different than MMR genes. We suggest MCM8 as a gene involved in CRC germline predisposition with a recessive pattern of inheritance.

Pinpointing heritability factors is fundamental for the prevention and early detection of cancer. Up to one-quarter of colorectal cancers (CRCs) occur in the context of familial aggregation of this disease, suggesting a strong genetic component. Currently, only less than half of the heritability of CRC can be attributed to hereditary syndromes or common risk loci. Part of the missing heritability of this disease may be explained by the inheritance of elusive high-risk variants, polygenic inheritance, somatic mosaicism, as well as shared environmental factors, among others. A great deal of the missing heritability in CRC is expected to be addressed in the coming years with the increased application of cutting-edge next-generation sequencing technologies, routine multigene panel testing and tumour-focussed germline predisposition screening approaches. On the other hand, it will be important to define the contribution of environmental factors to familial aggregation of CRC incidence. This review provides an overview of the known genetic causes of familial CRC and aims at providing clues that explain the missing heritability of this disease., (© The Author(s) 2019. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society.)

We describe a family severely affected by colorectal cancer (CRC) where whole-exome sequencing identified the coinheritance of the germline variants encoding MSH6 p.Thr1100Met and MUTYH p.Tyr179Cys in, at least, three CRC patients diagnosed before 60 years of age. Digenic inheritance of monoallelic MSH6 variants of uncertain significance and MUTYH variants has been suggested to predispose to Lynch syndrome-associated cancers; however, cosegregation with disease in the familial setting has not yet been established. The identification of individuals carrying multiple potential cancer risk variants is expected to rise with the increased application of whole-genome sequencing and large multigene panel testing in clinical genetic counseling of familial cancer patients. Here we demonstrate the coinheritance of monoallelic variants in MSH6 and MUTYH consistent with cosegregation with CRC, further supporting a role for digenic inheritance in cancer predisposition., (© 2020 The Authors. Genes, Chromosomes & Cancer published by Wiley Periodicals LLC.)

Objectives: β-Blocker use is associated with fewer cardiac complications in patients undergoing noncardiac surgery and is a quality metric for coronary artery bypass grafting. We sought to determine the influence of preoperative β-blocker administration before aortic valve replacement (AVR)., Methods: All patients undergoing isolated AVR from 2002 to 2016 were extracted from a multi-institutional, statewide database composed of Society of Thoracic Surgeons data. Patients were propensity score matched by preoperative and operative variables, and the effects of preoperative β-blockers on outcomes were assessed., Results: Of 7380 eligible patients, 53% received a preoperative β-blocker. After propensity matching, a total of 4592 patients were well matched (1:1) with minimal baseline differences between groups. Within the matched cohort, the operative mortality rate (β-blocker: 2.8% vs no β-blocker: 2.4%; P = .454) and rate of major morbidity (14.4% vs 12.7%; P = .101) were similar between groups. The rates of cardiac arrest (2.1% vs 1.3%; P = .034), renal failure requiring dialysis (1.7% vs 0.9%; P = .007), and postoperative transfusion (38.2% vs 33.8%; P = .002) after AVR were significantly greater in the cohort receiving preoperative β-blockade. Postoperative atrial fibrillation was also more prevalent in patients receiving a preoperative β-blocker (26.9% vs 23.4%; P = .007). Finally, preoperative β-blocker use was associated with longer postoperative intensive care unit stays (45.2 vs 47.0 hours; P = .001), but clinically similar hospital length of stay., Conclusions: Preoperative β-blocker administration is not associated with improved outcomes after AVR but instead is associated with increased postoperative morbidity. Routinely initiating preoperative β-blockade is not supported in patients undergoing AVR., (Copyright © 2019. Published by Elsevier Inc.)

Objectives: Pulmonary hypertension portends worse outcomes in cardiac valve surgery; however, isolated pulmonary artery pressures may not reflect patients' global cardiac function accurately. To better account for the interventricular relationship, the authors hypothesized that patients with greater pulmonary-systemic ratios (mean pulmonary arterial pressure)/(mean systemic arterial pressure) would correlate with worse outcomes after valve surgery., Design: Retrospective cohort study., Setting: Single academic hospital., Participants: The study comprised 314 patients undergoing valve surgery with or without coronary artery bypass grafting (2004-2016) with Society of Thoracic Surgeons predicted risk scores and preoperative right heart catheterization., Interventions: None., Measurements and Main Results: The pulmonary-systemic ratio was calculated as follows: mean pulmonary arterial pressure/mean systemic arterial pressure. Patients were stratified by pulmonary-systemic ratio quartile. Logistic regression was used to assess the risk-adjusted association between pulmonary-systemic ratio or mean pulmonary arterial pressure. Median pulmonary-systemic ratio was 0.33 (Q1-Q3: 0.23-0.65); median pulmonary arterial pressure was 29 (21-30) mmHg. Patients with the highest pulmonary-systemic ratio had the highest rates of morbidity and mortality (p < 0.0001). A high pulmonary-systemic ratio was associated with longer duration in the intensive care unit (p < 0.0001) and hospital (p < 0.0001). After risk-adjustment, pulmonary-systemic ratio and pulmonary arterial pressure were independently associated with morbidity and mortality, but the pulmonary-systemic ratio (odds ratio 23.88, p = 0.008, Wald 7.1) was more strongly associated than the pulmonary arterial pressure (odds ratio 1.035, p = 0.011, Wald 6.5)., Conclusions: The pulmonary-systemic ratio is more strongly associated with risk-adjusted morbidity and mortality in valve surgery than pulmonary arterial pressure. By integrating ventricular interactions, this metric may better characterize the risk of valve surgery., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The Ruth L. Kirschstein Institutional National Research Service Award (T32) provides institutions with financial support to prepare trainees for careers in academic medicine. In 1990, the Cardiac Surgery Branch of the National Heart, Lung and Blood Institute (NHLBI) was replaced by T32 training grants, which became crucial sources of funding for cardiothoracic (CT) surgical research. We hypothesized that T32 grants would be valuable for CT surgery training and yield significant publications and subsequent funding., Methods: Data on all trainees (past and present) supported by CT T32 grants at two institutions were obtained (T32), along with information on trainees from two similarly sized programs without CT T32 funding (Non-T32). Data collected were publicly available and included publications, funding, degrees, fellowships, and academic rank. Non-surgery residents and residents who did not pursue CT surgery were excluded., Results: Out of 76 T32 trainees and 294 Non-T32 trainees, data on 62 current trainees or current CT surgeons (T32: 42 vs Control: 20) were included. Trainees who were supported by a CT T32 grant were more likely to pursue CT surgery after residency (T32: 40% [30/76] vs Non-T32: 7% [20/294], P < .0001), publish manuscripts during residency years (P < .0001), obtain subsequent NIH funding (T32: 33% [7/21] vs Non-T32: 5% [1/20], P = .02), and pursue advanced fellowships (T32: 41% [9/22] vs Non-T32: 10% [2/20], P = .02)., Conclusions: T32 training grants supporting CT surgery research are vital to develop academic surgeons. These results support continued funding by the NHLBI to effectively develop and train the next generation of academic CT surgeons., (Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: A substantial fraction of familial colorectal cancer (CRC) and polyposis heritability remains unexplained. This study aimed to identify predisposing loci in patients with these disorders., Methods: Homozygosity mapping was performed using 222 563 SNPs in 302 index patients with various colorectal neoplasms and 3367 controls. Linkage analysis, exome and whole-genome sequencing were performed in a family affected by microsatellite stable CRCs. Candidate variants were genotyped in 10 554 cases and 21 480 controls. Gene expression was assessed at the mRNA and protein level., Results: Homozygosity mapping revealed a disease-associated region at 1q32.3 which was part of the linkage region 1q32.2-42.2 identified in the CRC family. This includes a region previously associated with risk of CRC. Sequencing identified the p.Asp1432Glu variant in the MIA3 gene (known as TANGO1 or TANGO) and 472 additional rare, shared variants within the linkage region. In both cases and controls the population frequency was 0.02% for this MIA3 variant. The MIA3 mutant allele showed predominant mRNA expression in normal, cancer and precancerous tissues. Furthermore, immunohistochemistry revealed increased expression of MIA3 in adenomatous tissues., Conclusions: Taken together, our two independent strategies associate genetic variations in chromosome 1q loci and predisposition to familial CRC and polyps, which warrants further investigation.

Degenerative mitral valve disease causing mitral regurgitation is the most common organic valve pathology and is classified based on leaflet motion. The "French correction" mitral valve repair method restores normal valvular anatomy with extensive leaflet resection, chordal manipulation, and rigid annuloplasty. The American correction attempts to restore normal valve function through minimal leaflet resection, flexible annuloplasty, and use of artificial chordae. These differing methods of mitral valve repair reflect an evolution in principles, but both require understanding of the valve pathology and correction of leaflet prolapse and annular dilatation. Adhering to those unifying principles and ensuring that no patient leaves the operating room with significant persistent mitral regurgitation produces durable results and satisfactory patient outcomes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Perioperative anemia and blood product transfusion increases short-term and long-term morbidity and mortality during cardiac surgery. We hypothesized that streamlined cardiopulmonary bypass circuit and rotational thromboelastometry (ROTEM) would reduce blood product usage and improve outcomes., Methods: All patients with Society of Thoracic Surgeons risk scores at our institution from January 2013 to June 2015 were included. Individuals were chronologically stratified into 2 groups according to institutional changes to a streamlined bypass circuit and ROTEM-guided transfusion. Blood product transfusion, hematocrit, and observed to expected outcomes (O/E) were compared between the groups., Results: Patients were defined as either control group (533 patients, 12 months) or intervention group (804 patients, 18 months). The intervention group was further subdivided into streamlined circuit (290 patients, 6 months) and ROTEM (514 patients, 12 months). Use of streamlined bypass circuit correlated with significantly reduced intraoperative transfusion of packed red blood cells (pRBCs) (23.8% versus 17.9%; p = 0.05) and platelets (28.0% versus 19.3; p = 0.01) with improvement in lowest intraoperative hematocrit (26.0 versus 26.9; p = 0.02). ROTEM was associated with a further reduction in intraoperative pRBCs (17.9% versus 11.28%; p = 0.01) and postoperative transfusion pRBCs (38.3% versus 23.5%; p = 0.02). The combination was associated with reduced intraoperative (44.6% versus 34.1; p < 0.001) and postoperative transfusions (45.6% versus 40.1; p < 0.001) in the intervention group, while maintaining a higher hematocrit at discharge (28.1 versus 29.1; p < 0.001). Finally, the intervention was associated with a statistically significant reduction in the O/E for reoperation (p = 0.003)., Conclusions: Use of streamlined cardiopulmonary bypass circuit and ROTEM may reduce transfusion and reoperation rates and improve perioperative anemia in cardiac surgical patients. This study demonstrates reproducible intraoperative methods for reducing blood product usage and improving outcomes., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin. DMD is associated with specific learning and behavioural disabilities. In the brain, dystrophin is associated with GABAA receptors and aquaporin-4 in neurons and astrocytes, respectively, but little is known about its function., Objective and Methods: In this study we aimed to compare the biochemical composition between patients and healthy controls in brain regions that are naturally rich in dystrophin using magnetic resonance spectroscopy. Given previous conflicting results obtained at clinical field strengths, we obtained data using a 7 Tesla system with associated higher signal-to-noise ratio and spectral resolution., Results: Results indicated unchanged biochemical composition in all regions investigated, and increased variance in glutamate in the frontal cortex.

Objectives: The long-term evolution of coexistent mitral regurgitation (MR) after aortic valve replacement (AVR) for aortic stenosis remains poorly defined. Prior studies have demonstrated that acute improvement in MR after AVR is modest, and more aggressive approaches have been advocated. This study examines the evolution of MR after AVR and identifies prognostic indicators for MR improvement., Methods: We retrospectively evaluated demographic and echocardiographic data of 423 patients who underwent primary isolated AVR for aortic stenosis with coexistent mild (n = 314) or moderate (n = 109) MR at our institution, from 2004 to 2013. For each patient, preoperative and postoperative MR was extracted from 903 echocardiograms and graded on a 0 to 4+ scale. Hierarchic linear models were used to estimate postoperative residual MR over a 5-year follow-up period. Patients were then stratified by improvement in MR, and preoperative risk factors and survival were compared between groups. Cox proportional hazards regression was used to assess the association between survival and preoperative and postoperative MR., Results: The overall acute reduction in MR was -0.23 degrees per patient. Patients with moderate MR had a -0.53 degree reduction in MR, whereas patients with mild MR had only a -0.13 degree reduction in MR (P < .001). Residual MR, however, worsened over time and regressed back to baseline, particularly in patients with preoperative moderate MR. At last follow-up, 70 (17%) patients returned to 2+ or worse MR. Residual MR at last echocardiographic follow-up was not affected by left ventricular ejection fraction, severity of preoperative aortic valve gradient (AVG), magnitude of reduction of AVG, or other comorbidities. Degree of preoperative MR did not affect midterm survival. Patients whose MR improved after AVR demonstrated a trend toward improved survival (75% vs 65% 5-year survival; P = .06), compared with those without MR whose survival remained unchanged or worsened., Conclusions: Coexistent MR modestly improves after AVR, but eventually regresses back to baseline or worsens over time in many patients. Preoperative AVG, reduction of AVG, heart failure, or atrial fibrillation was not predictive of residual MR. Moderate preoperative MR did not adversely affect 5-year survival. Patients with improvement in MR, however, demonstrated a trend toward improved survival at 5 years. More aggressive approaches for coexistent moderate MR should be considered in patients who need AVR for aortic stenosis., (Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Bovine pericardial valves are often used for pulmonary valve replacement (PVR) in patients with previously repaired congenital heart disease. Attention has recently focused on the safety of the Mitroflow (Sorin Group USA, Arvada, CO) bovine pericardial valve after a national alert describing several cases of sudden valve failure in young patients. In response, we reviewed our experience using the Mitroflow bioprosthesis for PVR., Methods: Medical records were reviewed for all patients who underwent PVR using a Mitroflow valve at our center (2008-2013)., Results: The cohort included 84 patients with a median age of 18.3 years (range, 0.8-62.1 years) and weight of 48.4 kg (range, 5.7-167.8 kg). Indications for surgical intervention included native outflow tract insufficiency (59 patients), valved conduit failure (20 patients), and isolated prosthetic valve failure (5 patients). Median length of stay was 3 days (range, 2-13 days). There were no hospital deaths. Median follow-up was 2.4 years (range, 0.2-5.6 years). Pulmonary valve insufficiency and peak gradient increased with time. At latest follow-up, freedom from insufficiency greater than or equal to a moderate degree was 83%, and freedom from a peak gradient greater than or equal to 50 mm Hg was 92%. Reintervention was required in 4 patients. One patient experienced endocarditis and underwent surgical PVR (0.6 years after initial intervention). Three patients underwent transcatheter treatment for valve stenosis including PVR (at 4.2 and 4.4 years in 2 patients) and balloon valvuloplasty (at 5.2 years in the third patient). Kaplan-Meier freedom from reintervention at 5 years was 81%., Conclusions: Early outcomes using the Mitroflow bovine pericardial valve for PVR in children and adults with repaired congenital heart disease appear acceptable and similar to reported outcomes for other tissue valve options. Valve failure from premature structural deterioration was not observed., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

We report a case of severe hemolysis and pulmonary valve insufficiency (PI) following right ventricular support using a paracorporeal pneumatic pump (Abiomed, Danvers, MA, USA). We speculate that the high velocity jet of blood emanating from the outflow cannula caused turbulence above the pulmonary valve, leading to PI and hemolysis. Despite the growing number of implanted ventricular assist devices, we could find no report in the literature describing pulmonary valve insufficiency secondary to right ventricular assist device (RVAD) placement. Fortunately, in this case, right ventricular function recovered sufficiently after seven days of support, allowing explantation of the device and resolution of PI and hemolysis.