Guanylate cyclase C as a target for prevention, detection, and therapy in colorectal cancer.

INTRODUCTION: Colorectal cancer remains the second leading cause of cancer death in the United States, and new strategies to prevent, detect, and treat the disease are needed. The receptor, guanylate cyclase C (GUCY2C), a tumor suppressor expressed by the intestinal epithelium, has emerged as a promising target. Areas covered: This review outlines the role of GUCY2C in tumorigenesis, and steps to translate GUCY2C-targeting schemes to the clinic. Endogenous GUCY2C-activating ligands disappear early in tumorigenesis, silencing its signaling axis and enabling transformation. Pre-clinical models support GUCY2C ligand supplementation as a novel disease prevention paradigm. With the recent FDA approval of the GUCY2C ligand, linaclotide, and two more synthetic ligands in the pipeline, this strategy can be tested in human trials. In addition to primary tumor prevention, we also review immunotherapies targeting GUCY2C expressed by metastatic lesions, and platforms using GUCY2C as a biomarker for detection and patient staging. Expert commentary: Results of the first GUCY2C targeting schemes in patients will become available in the coming years. The identification of GUCY2C ligand loss as a requirement for colorectal tumorigenesis has the potential to change the treatment paradigm from an irreversible disease of genetic mutation, to a treatable disease of ligand insufficiency

GUCY2C maintains intestinal LGR5+ stem cells by opposing ER stress

Long-lived multipotent stem cells (ISCs) at the base of intestinal crypts adjust their phenotypes to accommodate normal maintenance and post-injury regeneration of the epithelium. Their long life, lineage plasticity, and proliferative potential underlie the necessity for tight homeostatic regulation of the ISC compartment. In that context, the guanylate cyclase C (GUCY2C) receptor and its paracrine ligands regulate intestinal epithelial homeostasis, including proliferation, lineage commitment, and DNA damage repair. However, a role for this axis in maintaining ISCs remains unknown. Transgenic mice enabling analysis of ISCs (Lgr5-GFP) in the context of GUCY2C elimination (Gucy2c-/-) were combined with immunodetection techniques and pharmacological treatments to define the role of the GUCY2C signaling axis in supporting ISCs. ISCs were reduced in Gucy2c-/- mice, associated with loss of active Lgr5+ cells but a reciprocal increase in reserve Bmi1+ cells. GUCY2C was expressed in crypt base Lgr5+ cells in which it mediates canonical cyclic (c) GMPdependent signaling. Endoplasmic reticulum (ER) stress, typically absent from ISCs, was elevated throughout the crypt base in Gucy2c-/- mice. The chemical chaperone tauroursodeoxycholic acid resolved this ER stress and restored the balance of ISCs, an effect mimicked by the GUCY2C effector 8Br-cGMP. Reduced ISCs in Gucy2c-/-mice was associated with greater epithelial injury and impaired regeneration following sub-lethal doses of irradiation. These observations suggest that GUCY2C provides homeostatic signals that modulate ER stress and cell vulnerability as part of the machinery contributing to the integrity of ISCs. © Kraft et al

APC-β-catenin-TCF signaling silences the intestinal guanylin-GUCY2C tumor suppressor axis.

Sporadic colorectal cancer initiates with mutations in APC or its degradation target β-catenin, producing TCF-dependent nuclear transcription driving tumorigenesis. The intestinal epithelial receptor, GUCY2C, with its canonical paracrine hormone guanylin, regulates homeostatic signaling along the crypt-surface axis opposing tumorigenesis. Here, we reveal that expression of the guanylin hormone, but not the GUCY2C receptor, is lost at the earliest stages of transformation in APC-dependent tumors in humans and mice. Hormone loss, which silences GUCY2C signaling, reflects transcriptional repression mediated by mutant APC-β-catenin-TCF programs in the nucleus. These studies support a pathophysiological model of intestinal tumorigenesis in which mutant APC-β-catenin-TCF transcriptional regulation eliminates guanylin expression at tumor initiation, silencing GUCY2C signaling which, in turn, dysregulates intestinal homeostatic mechanisms contributing to tumor progression. They expand the mechanistic paradigm for colorectal cancer from a disease of irreversible mutations in APC and β-catenin to one of guanylin hormone loss whose replacement, and reconstitution of GUCY2C signaling, could prevent tumorigenesis

Educational and behavioural interventions for anticoagulant therapy in patients with atrial fibrillation

BACKGROUND: Current guidelines recommend oral anticoagulation therapy for patients with atrial fibrillation (AF) with one or more risk factors for stroke; however, anticoagulation control (time in therapeutic range (TTR)) with vitamin K antagonists (VKAs) is dependent on many factors. Educational and behavioural interventions may impact patients' ability to maintain their international normalised ratio (INR) control. This is an updated version of the original review first published in 2013. OBJECTIVES: To evaluate the effects of educational and behavioural interventions for oral anticoagulation therapy (OAT) on TTR in patients with AF. SEARCH METHODS: We updated searches from the previous review by searching the Cochrane Central Register of Controlled Trials (CENTRAL) and the Database of Abstracts of Reviews of Effects (DARE) in The Cochrane Library (January 2016, Issue 1), MEDLINE Ovid (1949 to February week 1 2016), EMBASE Classic + EMBASE Ovid (1980 to Week 7 2016), PsycINFO Ovid (1806 to Week 1 February 2016) and CINAHL Plus with Full Text EBSCO (1937 to 16/02/2016). We applied no language restrictions. SELECTION CRITERIA: We included randomised controlled trials evaluating the effect of any educational and behavioural intervention compared with usual care, no intervention, or intervention in combination with other self-management techniques among adults with AF who were eligible for, or currently receiving, OAT. DATA COLLECTION AND ANALYSIS: Two of the review authors independently selected studies and extracted data. Risk of bias was assessed using the Cochrane 'Risk of bias' tool. We included outcome data on TTR, decision conflict (patient's uncertainty in making health-related decisions), percentage of INRs in the therapeutic range, major bleeding, stroke and thromboembolic events, patient knowledge, patient satisfaction, quality of life (QoL), beliefs about medication, illness perceptions, and anxiety and depression. We pooled data for three outcomes - TTR, anxiety and depression, and decision conflict - and reported mean differences (MD). Where insufficient data were present to conduct a meta-analysis, we reported effect sizes and confidence intervals (CI) from the included studies. We evaluated the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. MAIN RESULTS: Eleven trials with a total of 2246 AF patients (ranging from 14 to 712 by study) were included within the review. Studies included education, decision aids, and self-monitoring plus education interventions. The effect of self-monitoring plus education on TTR was uncertain compared with usual care (MD 6.31, 95% CI -5.63 to 18.25, I(2) = 0%, 2 trials, 69 participants, very low-quality evidence). We found small but positive effects of education on anxiety (MD -0.62, 95% CI -1.21 to -0.04, I(2) = 0%, 2 trials, 587 participants, low-quality evidence) and depression (MD -0.74, 95% CI -1.34 to -0.14, I(2) = 0%, 2 trials, 587 participants, low-quality evidence) compared with usual care. The effect of decision aids on decision conflict favoured usual care (MD -0.1, 95% CI -0.17 to -0.02, I(2) = 0%, 2 trials, 721 participants, low-quality evidence). AUTHORS' CONCLUSIONS: This review demonstrates that there is insufficient evidence to draw definitive conclusions regarding the impact of educational or behavioural interventions on TTR in AF patients receiving OAT. Thus, more trials are needed to examine the impact of interventions on anticoagulation control in AF patients and the mechanisms by which they are successful. It is also important to explore the psychological implications for patients suffering from this long-term chronic condition

Distinct domains of erythroid Kruppel-like factor modulate chromatin remodeling and transactivation at the endogenous beta-globin gene promoter

Characterization of the mechanism(s) of action of trans-acting factors in higher eukaryotes requires the establishment of cellular models that test their function at endogenous target gene regulatory elements. Erythroid Kruppel-like factor (EKLF) is essential for beta -globin gene transcription. To elucidate the in vivo determinants leading to transcription of the adult beta -globin gene, functional domains of EKLF were examined in the context of chromatin remodeling and transcriptional activation at the endogenous locus. Human EKLF (hEKLF) sequences, linked to an estrogen-responsive domain, were studied with an erythroblast cell line lacking endogenous EKLF expression (J2e Delta eklf). J2e Delta eklf cells transduced with hEKLF demonstrated a dose-dependent rescue of beta -globin transcription in the presence of inducing ligand. Further analysis using a series of amino-terminal truncation mutants of hEKLF identified a distinct internal domain, which is sufficient for transactivation. Interestingly, studies of the chromatin structure of the beta -promoter revealed that a smaller carboxy-terminal domain generated an open promoter configuration. In vitro and in vivo binding studies demonstrated that this region interacted with BRG1, a component of the SWI/SNF chromatin remodeling complex. However, further study revealed that BRG1 interacted with an even smaller domain of EKLF, suggesting that additional protein interactions are required for chromatin remodeling at the endogenous beta -promoter. Taken together, our findings support a stepwise process of chromatin remodeling and coactivator recruitment to the beta -globin promoter in vivo. The J2e Delta eklf inducible hEKLF system will be a valuable tool for further characterizing the temporal series of events required for endogenous beta -globin gene transcription

The impact of injecting networks on hepatitis C transmission and treatment in people who inject drugs

With the development of new highly efficacious direct acting antiviral treatments (DAAs) for hepatitis C (HCV), the concept of treatment as prevention is gaining credence. To date the majority of mathematical models assume perfect mixing with injectors having equal contact with all other injectors. This paper explores how using a networks based approach to treat people who inject drugs (PWID) with DAAs affects HCV prevalence. Method: Using observational data we parameterized an Exponential Random Graph Model containing 524 nodes. We simulated transmission of HCV through this network using a discrete time, stochastic transmission model. The effect of five treatment strategies on the prevalence of HCV was investigated; two of these strategies were 1) treat randomly selected nodes and 2) “treat your friends” where an individual is chosen at random for treatment and all their infected neighbours are treated. Results: As treatment coverage increases, HCV prevalence at 10 years reduces for both the high efficacy and low efficacy treatment. Within each set of parameters, the “treat your friends” strategy performed better than the random strategy being most marked for higher efficacy treatment. For example over 10 years of treating 25 per 1000 PWID, the prevalence drops from 50% to 40% for the random strategy, and to 33% for the “treat your friends” strategy (6.5% difference, 95% CI 5.1 – 8.1%). Discussion: “Treat your friends” is a feasible means of utilising network strategies to improve treatment efficiency. In an era of highly efficacious and highly tolerable treatment such an approach will benefit not just the individual but the community more broadly by reducing the prevalence of HCV amongst PWID

An immunotherapy survivor population: health-related quality of life and toxicity in patients with metastatic melanoma treated with immune checkpoint inhibitors

© The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Purpose The immune checkpoint inhibitors (ICIs) have resulted in subgroups of patients with metastatic melanoma achievinghigh-quality durable responses. Metastatic melanoma survivors are a new population in the era of cancer survivorship. The aimofthis study was to evaluate metastatic melanoma survivors in terms of health-related quality of life (HRQoL), immune-relatedadverse events (irAEs) and exposure to immunosuppressive agents in a large single centre in the UK.Methods We defined the survivor population as patients with a diagnosis of metastatic melanoma who achieved a durableresponse to an ICI and had been followed-up for a minimum of 12 months from initiation of ICI without disease progression.HRQoL was assessed using SF-36. Electronic health records were accessed to collect data on demographics, treatments, irAEsand survival. HRQoL data was compared with two norm-based datasets.Results Eighty-four metastatic melanoma survivors were eligible and 87% (N = 73) completed the SF-36. ICI-related toxicity ofany grade occurred in 92%of patients and 43%had experienced a grade 3 or 4 toxicity. Almost half (49%) of the patients requiredsteroids for the treatment of ICI-related toxicity, whilst 14% required treatment with an immunosuppressive agent beyondsteroids.Melanoma survivors had statistically significant lower HRQoL scores with regard to physical, social and physical rolefunctioning and general health compared with the normative population. There was a trend towards inferior scores in patientswith previous exposure to ipilimumab compared with those never exposed to ipilimumab.Conclusions Our results show that metastatic melanoma survivors have potentially experienced significant ICI-related toxicityand experience significant impairments in specific HRQoL domains. Future service planning is required to meet this population’sunique survivorship needs.Peer reviewe

Crystal structure and high-field magnetism of La2CuO4

Neutron diffraction was used to determine the crystal structure and magnetic ordering pattern of a La2CuO4 single crystal, with and without applied magnetic field. A previously unreported, subtle monoclinic distortion of the crystal structure away from the orthorhombic space group Bmab was detected. The distortion is also present in lightly Sr-doped crystals. A refinement of the crystal structure shows that the deviation from orthorhombic symmetry is predominantly determined by displacements of the apical oxygen atoms. An in-plane magnetic field is observed to drive a continuous reorientation of the copper spins from the orthorhombic b-axis to the c-axis, directly confirming predictions based on prior magnetoresistance and Raman scattering experiments. A spin-flop transition induced by a c-axis oriented field previously reported for non-stoichiometric La2CuO4 is also observed, but the transition field (11.5 T) is significantly larger than that in the previous work

Hepatitis C transmission and treatment as prevention - The role of the injecting network

Background: The hepatitis C virus (HCV) epidemic is a major health issue; in most developed countries it is driven by people who inject drugs (PWID). Injecting networks powerfully influence HCV transmission. In this paper we provide an overview of 10 years of research into injecting networks and HCV, culminating in a network-based approach to provision of direct-acting antiviral therapy. Methods: Between 2005 and 2010 we followed a cohort of 413 PWID, measuring HCV incidence, prevalence and injecting risk, including network-related factors. We developed an individual-based HCV transmission model, using it to simulate the spread of HCV through the empirical social network of PWID. In addition, we created an empirically grounded network model of injecting relationships using exponential random graph models (ERGMs), allowing simulation of realistic networks for investigating HCV treatment and intervention strategies. Our empirical work and modelling underpins the TAP Study, which is examining the feasibility of community-based treatment of PWID with DAAs. Results: We observed incidence rates of HCV primary infection and reinfection of 12.8 per 100 person-years (PY) (95%CI: 7.7-20.0) and 28.8 per 100 PY (95%CI: 15.0-55.4), respectively, and determined that HCV transmission clusters correlated with reported injecting relationships. Transmission modelling showed that the empirical network provided some protective effect, slowing HCV transmission compared to a fully connected, homogenous PWID population. Our ERGMs revealed that treating PWID and all their contacts was the most effective strategy and targeting treatment to infected PWID with the most contacts the least effective. Conclusion: Networks-based approaches greatly increase understanding of HCV transmission and will inform the implementation of treatment as prevention using DAAs