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BACKGROUND: Limited data are available on the outcomes of patients with non-muscle invasive bladder cancer (NMIBC) unresponsive to intravesical bacillus Calmette-Guérin (BCG), as defined by the United States Food and Drug Administration. OBJECTIVE: To define the outcomes of patients with BCG-unresponsive NMIBC. METHODS: This was a retrospective, single-institution observational cohort study. Records of patients managed at our institution for BCG-unresponsive NMIBC between 2005 and 2020 were reviewed and clinical outcomes evaluated. RESULTS: The study included 149 patients. Management was with initial radical cystectomy in 60 patients (40%) and initial bladder-sparing therapy (BST) in 89 patients (60%). Overall survival was greater among patients undergoing RC than BST (HR 1.83, 95% CI 1.04–3.22, p = 0.036), potentially due to patient selection, as no significant difference was noted for metastasis-free or cancer-specific survival. Patients opting for initial BST had high rates of treatment failure, with estimated 5-year cystectomy-free survival of only 42%. Patients who received additional lines of BST after a subsequent failure were at increased risk of having ≥pT3 or pN+ disease at cystectomy (42% for ≥2 lines BST, versus 18% for 1 line BST and 15% for initial cystectomy, p = 0.038). CONCLUSION: Among patients who underwent initial BST for BCG-unresponsive NMIBC, rates of treatment failure were very high. Patients who underwent delayed cystectomy after ≥2 lines of BST had elevated rates of extravesical disease. Our observations emphasize the importance of recent and ongoing clinical trials in this clinical space.

Social media has become a platform for passenger train operating companies to share information and engage with their customers. Twitter, in particular, is used by operators to provide live service updates and engage with their customers. A gap in the literature exists regarding the concept of the social license to operate, where organisations engage with stakeholders to gain legitimacy of their operations, within the transportation industry. Further, there is a lack of literature on the use of social media by private train operating companies. This article fills a gap in the literature regarding the use of Twitter by private passenger train operating companies and use of this social media platform for obtaining a social license to operate from customers. Therefore, the aim of this research is to understand how the functions of Twitter use by private train operating companies in the United Kingdom can serve as a means to obtain a social license to operate through an analysis of their Twitter accounts, tweets, and policies. The findings indicate 1) that Twitter is primarily a tool for communication and engagement with their customers; 2) as Twitter functions evolved, providing customer service has become a key function; and 3) the key elements of the social license to operate: legitimacy, credibility, and trust; can be obtained through customer engagement using Twitter.

Recipients of left ventricular assist system (LVAS) require long-term anticoagulation with warfarin to prevent thromboembolic complications. We discuss a successful case of the use of four factor prothrombin complex concentrate (4F-PCC) for temporary warfarin reversal in a patient with a HeartMate 3 LVAS requiring robotic assisted laparoscopic prostatectomy.

The transcription factor TCF7L1 is an embryonic stem cell signature gene that is upregulated in multiple aggressive cancer types, but its role in skin tumorigenesis has not yet been defined. Here we document TCF7L1 upregulation in skin squamous cell carcinoma (SCC) and demonstrate that TCF7L1 overexpression increases tumor incidence, tumor multiplicity, and malignant progression in the chemically induced mouse model of skin SCC. Additionally, we show that downregulation of TCF7L1 and its paralogue TCF7L2 reduces tumor growth in a xenograft model of human skin SCC. Using separation-of-function mutants, we show that TCF7L1 promotes tumor growth, enhances cell migration, and overrides oncogenic RAS-induced senescence independently of its interaction with β-catenin. Through transcriptome profiling and combined gain- and loss-of-function studies, we identified LCN2 as a major downstream effector of TCF7L1 that drives tumor growth. Our findings establish a tumor-promoting role for TCF7L1 in skin and elucidate the mechanisms underlying its tumorigenic capacity. DOI: http://dx.doi.org/10.7554/eLife.23242.001

The Lef/Tcf-family transcription factor Tcf3 has important roles in development, stem cell function and malignancy. Previous gain- and loss-of-function studies have suggested that Tcf3 is a mediator of self-renewal and an undifferentiated state in stem and progenitor cells in skin, but little is known of its role in other postnatal tissues. Here, we explore the distribution and behavior of Tcf3-expressing cells in several adult tissues using a novel Tcf3-CreER knock-in mouse model. By lineage tracing in dorsal skin, we verify that Tcf3-expressing cells in the hair follicle bulge are self-renewing stem cells with multilineage potential. We then demonstrate, for the first time, the presence of Tcf3-expressing cells in the basal layer of several other stratified epithelia, including the paw skin, tongue and esophagus. By lineage tracing, we demonstrate that the Tcf3-expressing population in these tissues includes persistent stem cells, transient progenitors and cells undergoing active differentiation. Our observations here suggest that the role of Tcf3 in cell-fate decision is more complex than previously appreciated and is highly dependent on cellular context.

Cell migration is an integral part of re-epithelialization during skin wound healing, a complex process involving molecular controls that are still largely unknown. Here we identify a novel role for Tcf3, an essential transcription factor regulating embryonic and adult skin stem cell functions, as a key effector of epidermal wound repair. We show that Tcf3 is upregulated in skin wounds and that Tcf3 overexpression accelerates keratinocyte migration and skin wound healing. We also identify Stat3 as an upstream regulator of Tcf3. We show that the pro-migration effects of Tcf3 are non-cell autonomous and occur independently of its ability to interact with β-catenin. Finally, we identify lipocalin-2 as the key secreted factor downstream of Tcf3 that promotes cell migration in vitro and wound healing in vivo. Our findings provide new insights into the molecular controls of wound-associated cell migration and identify potential therapeutic targets for the treatment of defective wound repair.

Hair follicles cyclically degenerate and regenerate throughout adult life and require regular stem cell activation to drive the cycle. In the resting phase of the hair cycle, hair follicle stem cells are maintained in a quiescent state until they receive signals to proliferate. We found that the forkhead transcription factor Foxp1 is crucial for maintaining the quiescence of hair follicle stem cells. Loss of Foxp1 in skin epithelial cells leads to precocious stem cell activation, resulting in drastic shortening of the quiescent phase of the hair cycle. Conversely, overexpression of Foxp1 in keratinocytes prevents cell proliferation by promoting cell cycle arrest. Finally, through both gain- and loss-of-function studies, we identify fibroblast growth factor 18 (Fgf18) as the key downstream target of Foxp1. We show that exogenously supplied FGF18 can prevent the hair follicle stem cells of Foxp1 null mice from being prematurely activated. As Fgf18 controls the length of the quiescent phase and is a key downstream target of Foxp1, our data strongly suggest that Foxp1 regulates the quiescent stem cell state in the hair follicle stem cell niche by controlling Fgf18 expression.

Adoptive immunotherapy is an appealing approach to cancer treatment, with the potential for more precise targeting and reduced toxicity. While early clinical trial data using adoptive T cells against post-transplant virus-associated hematologic malignancies, lymphoma and melanoma have been promising, treating other solid tumors has proven to be more challenging. Adoptive lymphocytes have been genetically modified in many ways to improve activity and circumvent tumor evasion, including transfer of transgenic T-cell receptors and chimeric antigen receptors to redirect T cell and natural killer cell antigen specificity. Gene transfer may also allow expression of homeostatic cytokines or their receptors to overcome the lack of stimulatory signals or expression of dominant-negative receptors for inhibitory cytokines to compensate for an immunosuppressive tumor milieu. In addition, suicide genes can install a 'safety switch' on adoptively transferred cells to allow ablation if necessary. Although further refinement and validation are necessary, these genetic modification strategies offer hope for significant improvements in cancer immunotherapy.