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Abstract Background Genes responsible for biosynthesis of fungal secondary metabolites are usually tightly clustered in the genome and co-regulated with metabolite production. Epipolythiodioxopiperazines (ETPs) are a class of secondary metabolite toxins produced by disparate ascomycete fungi and implicated in several animal and plant diseases. Gene clusters responsible for their production have previously been defined in only two fungi. Fungal genome sequence data have been surveyed for the presence of putative ETP clusters and cluster data have been generated from several fungal taxa where genome sequences are not available. Phylogenetic analysis of cluster genes has been used to investigate the assembly and heredity of these gene clusters. Results Putative ETP gene clusters are present in 14 ascomycete taxa, but absent in numerous other ascomycetes examined. These clusters are discontinuously distributed in ascomycete lineages. Gene content is not absolutely fixed, however, common genes are identified and phylogenies of six of these are separately inferred. In each phylogeny almost all cluster genes form monophyletic clades with non-cluster fungal paralogues being the nearest outgroups. This relatedness of cluster genes suggests that a progenitor ETP gene cluster assembled within an ancestral taxon. Within each of the cluster clades, the cluster genes group together in consistent subclades, however, these relationships do not always reflect the phylogeny of ascomycetes. Micro-synteny of several of the genes within the clusters provides further support for these subclades. Conclusion ETP gene clusters appear to have a single origin and have been inherited relatively intact rather than assembling independently in the different ascomycete lineages. This progenitor cluster has given rise to a small number of distinct phylogenetic classes of clusters that are represented in a discontinuous pattern throughout ascomycetes. The disjunct heredity of these clusters is discussed with consideration to multiple instances of independent cluster loss and lateral transfer of gene clusters between lineages.

The maximum aortic diameter is the main risk predictor for type A acute aortic syndromes and understanding the growth rate of ascending thoracic aortic aneurysms (aTAAs) is pivotal for risk assessment and stratification for pre-emptive aortic surgery. Prevailing guidelines recommend serial imaging of aTAA patients until the thresholds for prophylactic surgery are met. Based on early landmark studies, it was thought that the growth rate of aTAAs is substantially higher than that of the normal-sized aorta. However, more recent studies have reported that aTAA growth is generally slow, questioning the need for frequent imaging during follow-up. The current systematic review provides an overview of studies reporting annual diameter growth rates of non-syndromic aTAAs and explains differences in findings between early and recent studies. [ABSTRACT FROM AUTHOR]

Summary: Background: Data on cost‐effectiveness of first‐line infliximab in paediatric patients with Crohn's disease are limited. Since biologics are increasingly prescribed and accompanied by high costs, this knowledge gap needs to be addressed. Aim: To investigate the cost‐effectiveness of first‐line infliximab compared to conventional treatment in children with moderate‐to‐severe Crohn's disease. Methods: We included patients from the Top‐down Infliximab Study in Kids with Crohn's disease randomised controlled trial. Children with newly diagnosed moderate‐to‐severe Crohn's disease were treated with azathioprine maintenance and either five induction infliximab (biosimilar) infusions or conventional induction treatment (exclusive enteral nutrition or corticosteroids). Direct healthcare consumption and costs were obtained per patient until week 104. This included data on outpatient hospital visits, hospital admissions, drug costs, endoscopies and surgeries. The primary health outcome was the odds ratio of being in clinical remission (weighted paediatric Crohn's disease activity index<12.5) during 104 weeks. Results: We included 89 patients (44 in the first‐line infliximab group and 45 in the conventional treatment group). Mean direct healthcare costs per patient were €36,784 for first‐line infliximab treatment and €36,874 for conventional treatment over 2 years (p = 0.981). The odds ratio of first‐line infliximab versus conventional treatment to be in clinical remission over 104 weeks was 1.56 (95%CI 1.03–2.35, p = 0.036). Conclusions: First‐line infliximab treatment resulted in higher odds of being in clinical remission without being more expensive, making it the dominant strategy over conventional treatment in the first 2 years after diagnosis in children with moderate‐to‐severe Crohn's disease. Trial registration number: NCT02517684. [ABSTRACT FROM AUTHOR]

Abstract Background In multicellular organisms, alternative splicing is central to tissue differentiation and identity. Unicellular protists lack multicellular tissue but differentiate into variable cell types during their life cycles. The role of alternative splicing in transitions between cell types and establishing cellular identity is currently unknown in any unicellular organism. Results To test whether alternative splicing in unicellular protists plays a role in cellular differentiation, we conduct RNA-seq to compare splicing in female and male sexual stages to asexual intraerythrocytic stages in the rodent malaria parasite Plasmodium berghei. We find extensive changes in alternative splicing between stages and a role for alternative splicing in sexual differentiation. Previously, general gametocyte differentiation was shown to be modulated by specific transcription factors. Here, we show that alternative splicing establishes a subsequent layer of regulation, controlling genes relating to consequent sex-specific differentiation of gametocytes. Conclusions We demonstrate that alternative splicing is reprogrammed during cellular differentiation of a unicellular protist. Disruption of an alternative splicing factor, PbSR-MG, perturbs sex-specific alternative splicing and decreases the ability of the parasites to differentiate into male gametes and oocysts, thereby reducing transmission between vertebrate and insect hosts. Our results reveal alternative splicing as an integral, stage-specific phenomenon in these protists and as a regulator of cellular differentiation that arose early in eukaryotic evolution.

Summary: Fibroblast growth factor receptor 1 (FGFR1) is frequently amplified in human small-cell lung cancer (SCLC), but its contribution to SCLC and other lung tumors has remained elusive. Here, we assess the tumorigenic capacity of constitutive-active FGFR1 (FGFR1K656E) with concomitant RB and P53 depletion in mouse lung. Our results reveal a context-dependent effect of FGFR1K656E: it impairs SCLC development from CGRPPOS neuroendocrine (NE) cells, which are considered the major cell of origin of SCLC, whereas it promotes SCLC and low-grade NE bronchial lesions from tracheobronchial-basal cells. Moreover, FGFR1K656E induces lung adenocarcinoma (LADC) from most lung cell compartments. However, its expression is not sustained in LADC originating from CGRPPOS cells. Therefore, cell context and tumor stage should be taken into account when considering FGFR1 inhibition as a therapeutic option. : Ferone et al. show that inducing FGFR signaling in lung neuroendocrine (NE) cells of Rb;p53 mice results in impairment of SCLC and enhancement of peripheral NE lesions. The location and tumor characteristics depend on the targeted cell type. Rb;p53;Fgfr1 mice also develop adenocarcinomas with the incidence depending on the targeted cell type.

Abstract Background Thoracic aortic aneurysms and dissections (TAAD) may have a heritable cause in up to 20% of cases. We aimed to investigate the pathogenic effect of a TGFBR1 mutation in relation to TAAD. Methods Co‐segregation analysis was performed followed by functional investigations, including myogenic transdifferentiation. Results The c.1043G>A TGFBR1 mutation was found in the index patient, in a deceased brother, and in five presymptomatic family members. Evidence for pathogenicity was found by the predicted damaging effect of this mutation and the co‐segregation in the family. Functional analysis with myogenic transdifferentiation of dermal fibroblasts to smooth muscle‐like cells, revealed increased myogenic differentiation in patient cells with the TGFBR1 mutation, shown by a higher expression of myogenic markers ACTA2, MYH11 and CNN1 compared to cells from healthy controls. Conclusion Our findings confirm the pathogenic effect of the TGFBR1 mutation in causing TAAD in Loeys–Dietz syndrome and show increased myogenic differentiation of patient fibroblasts.

Summary: Small-cell lung cancer is the most aggressive type of lung cancer, characterized by a remarkable response to chemotherapy followed by development of resistance. Here, we describe SCLC subtypes in Mycl- and Nfib-driven GEMM that include CDH1-high peripheral primary tumor lesions and CDH1-negative, aggressive intrapulmonary metastases. Cisplatin treatment preferentially eliminates the latter, thus revealing a striking differential response. Using a combined transcriptomic and proteomic approach, we find a marked reduction in proliferation and metabolic rewiring following cisplatin treatment and present evidence for a distinctive metabolic and structural profile defining intrinsically resistant populations. This offers perspectives for effective combination therapies that might also hold promise for treating human SCLC, given the very similar response of both mouse and human SCLC to cisplatin. : Böttger et al. show the presence of histologically and molecularly distinct sub-populations of small-cell lung cancer (SCLC) in advanced mouse models. They demonstrate that the heterogeneity of SCLC is responsible for the differential sensitivity to cisplatin and identify metabolic circuitries that likely contribute to cisplatin resistance. Keywords: SCLC, mouse models, tumor heterogeneity, cisplatin, chemotherapy, RNA-seq, transcriptomics, mass spectrometry, proteomics

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor, and no effective treatment is available to date. Mouse models of SCLC based on the inactivation of Rb1 and Trp53 show frequent amplifications of the Nfib and Mycl genes. Here, we report that, although overexpression of either transcription factor accelerates tumor growth, NFIB specifically promotes metastatic spread. High NFIB levels are associated with expansive growth of a poorly differentiated and almost exclusively E-cadherin (CDH1)-negative invasive tumor cell population. Consistent with the mouse data, we find that NFIB is overexpressed in almost all tested human metastatic high-grade neuroendocrine lung tumors, warranting further assessment of NFIB as a tumor progression marker in a clinical setting.

Summary: Liver tissue-resident memory T (Trm) cells migrate throughout the sinusoids and are capable of protecting against malaria sporozoite challenge. To gain an understanding of liver Trm cell development, we examined various conditions for their formation. Although liver Trm cells were found in naive mice, their presence was dictated by antigen specificity and required IL-15. Liver Trm cells also formed after adoptive transfer of in vitro-activated but not naive CD8+ T cells, indicating that activation was essential but that antigen presentation within the liver was not obligatory. These Trm cells patrolled the liver sinusoids with a half-life of 36 days and occupied a large niche that could be added to sequentially without effect on subsequent Trm cell cohorts. Together, our findings indicate that liver Trm cells form as a normal consequence of CD8+ T cell activation during essentially any infection but that inflammatory and antigenic signals preferentially tailor their development. : Holz et al. demonstrate that tissue-resident memory T (Trm) cells routinely develop in the liver after T cell activation. Within the liver, IL-15, antigen, and inflammation aid Trm cell formation, but only IL-15 is essential. Newly formed Trm cells do not displace existing populations, demonstrating a flexible liver niche. Keywords: tissue-resident memory, liver, T cell memory, liver immunology, malaria, niche

Background Despite its efficacy, rational guidance for starting/stopping first-line biologic treatment in individual paediatric Crohn's disease [CD] patients is needed. We assessed how serum immune profiles before and after first-line infliximab [FL-IFX] or conventional [CONV] induction therapy associate with disease remission at week 52. Methods Pre- [ n  = 86], and 10–14-week post-treatment [ n  = 84] sera were collected from patients with moderate-to-severe paediatric CD in the TISKids trial, randomized to FL-IFX [ n  = 48; five 5-mg/kg infusions over 22 weeks] or CONV [ n  = 43; exclusive enteral nutrition or oral prednisolone]; both groups received azathioprine maintenance. The relative concentrations of 92 inflammatory proteins were determined with Olink Proteomics; fold changes [FC] with |log2FC| > 0.5 after false discovery rate adjustment were considered significant. Results FL-IFX modulated a larger number of inflammatory proteins and induced stronger suppression than CONV; 18/30 proteins modulated by FL-IFX were not regulated by CONV. Hierarchical clustering based on IFX-modulated proteins at baseline revealed two clusters of patients: CD-hi patients had significantly higher concentrations of 23/30 IFX-modulated proteins [including oncostatin-M, TNFSF14, HGF and TGF-α], and higher clinical disease activity, C-reactive protein and blood neutrophils at baseline than CD-lo patients. Only 24% of CD-hi FL-IFX-treated patients maintained remission without escalation at week 52 vs 58% of CD-lo FL-IFX-treated patients. Similarly, 6% of CD-hi CONV-treated patients achieved remission vs 20% of CONV-treated CD-lo patients. Clustering based on immune profiles post-induction therapy did not relate to remission at week 52. Conclusion FL-IFX leads to stronger reductions and modulates more immune proteins than CONV. Stratification on pre-treatment profiles of IFX-modulated proteins directly relates to maintenance of remission without treatment escalation. Trial registration number NCT02517684. [ABSTRACT FROM AUTHOR]

Abstract Human cancers modeled in Genetically Engineered Mouse Models (GEMMs) can provide important mechanistic insights into the molecular basis of tumor development and enable testing of new intervention strategies. The inherent complexity of these models, with often multiple modified tumor suppressor genes and oncogenes, has hampered their use as preclinical models for validating cancer genes and drug targets. In our newly developed approach for the fast generation of tumor cohorts we have overcome this obstacle, as exemplified for three GEMMs; two lung cancer models and one mesothelioma model. Three elements are central for this system; (i) The efficient derivation of authentic Embryonic Stem Cells (ESCs) from established GEMMs, (ii) the routine introduction of transgenes of choice in these GEMM‐ESCs by Flp recombinase‐mediated integration and (iii) the direct use of the chimeric animals in tumor cohorts. By applying stringent quality controls, the GEMM‐ESC approach proofs to be a reliable and effective method to speed up cancer gene assessment and target validation. As proof‐of‐principle, we demonstrate that MycL1 is a key driver gene in Small Cell Lung Cancer.

To authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1111/j.1559-1816.2009.00495.x Byline: Kene Henkens (1), Hanna van Solinge (*), Rabina Cozijnsen ([dagger]) Abstract: This study's central research question is: 'How do managers evaluate the desirability of early retirement of their employees, and under what circumstances and for what types of workers are they in favor of delay?' We sought to compare managers' and business students' decision making regarding older workers. We examined the extent to which student samples are appropriate to study organizational behavior. An identical factorial survey was carried out among 26 managers and 25 business school students. The results revealed that business students concentrate on performance-related individual characteristics when making selection decisions, whereas managers also recognize contextual factors (need for downsizing, tight labor market) and older workers' attitudes toward retirement. Author Affiliation: (*)Netherlands Interdisciplinary Demographic InstituteThe Hague, The Netherlands ([dagger])Department of SociologyVU University AmsterdamAmsterdam, The Netherlands Article note: (1) Kene Henkens, Netherlands Interdisciplinary Demographic Institute, P. O. Box 11650 2502 AR The Hague, The Netherlands. E-mail: henkens@nidi.nl

The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. It is currently believed that four to six crypt stem cells reside at the +4 position immediately above [...]

Author(s): Johan H. van Es [1, 5]; Marielle E. van Gijn [1, 5]; Orbicia Riccio [2, 5]; Maaike van den Born [1]; Marc Vooijs [1]; Harry Begthel [1]; Miranda Cozijnsen [...]