Triple-negative breast cancer (TNBC) lacks prognostic and predictive markers. Here, we use high-throughput phosphoproteomics to build a functional TNBC taxonomy. A cluster of 159 phosphosites is ...upregulated in relapsed cases of a training set (n = 34 patients), with 11 hyperactive kinases accounting for this phosphoprofile. A mass-spectrometry-to-immunohistochemistry translation step, assessing 2 independent validation sets, reveals 6 kinases with preserved independent prognostic value. The kinases split the validation set into two patterns: one without hyperactive kinases being associated with a >90% relapse-free rate, and the other one showing ≥1 hyperactive kinase and being associated with an up to 9.5-fold higher relapse risk. Each kinase pattern encompasses different mutational patterns, simplifying mutation-based taxonomy. Drug regimens designed based on these 6 kinases show promising antitumour activity in TNBC cell lines and patient-derived xenografts. In summary, the present study elucidates phosphosites and kinases implicated in TNBC and suggests a target-based clinical classification system for TNBC.
Background and Aim
The role of capsule endoscopy (CE) in established celiac disease (CD) remains unclear. Our objective was to analyze the usefulness of CE in the suspicion of complicated CD.
Methods
...This was a retrospective multicenter study. One hundred and eighty‐nine celiac patients (mean age: 46.6 ± 16.6, 30.2% males) who underwent CE for alarm symptoms (n = 86, 45.5%) or non‐responsive CD (n = 103, 54.5%) were included. Diagnostic yield (DY), therapeutic impact and safety were analyzed.
Results
Capsule endoscopy was completed in 95.2% of patients (small bowel transit time: 270.5 ± 100.2 min). Global DY was 67.2%, detecting atrophic mucosa (n = 92, 48.7%), ulcerative jejunoileitis (n = 21, 11.1%), intestinal lymphoma (n = 7, 3.7%) and other enteropathies (n = 7, 3.7%, six Crohn's disease cases and one neuroendocrine tumor).
The DY of CE was significantly higher in patients presenting with non‐responsive disease compared to patients with alarm symptoms (73.8% vs 59.3%, P = 0.035). The new findings of the CE modified management in 59.3% of the cases. There were no major complications.
Conclusion
Capsule endoscopy may be a moderately helpful and safe diagnostic tool in the suspicion of complicated CD, modifying the clinical course of these patients.
Safety is an important consideration in decisions on treatment for patients with moderate-to-severe psoriasis and the study of drug safety is the main purpose of the BIOBADADERM registry. The ...combination of a biologic agent and a conventional systemic drug generally methotrexate (MTX) is a common treatment in clinical practice. However, there is a paucity of evidence from real-world practice on the safety of such combination regimens in the treatment of psoriasis.
The primary objective of this study was to ascertain whether the use of regimens combining biologic drugs with MTX in the management of moderate-to-severe psoriasis increases the risk of adverse events (AEs) or serious AEs (SAEs). We compared monotherapy using tumour necrosis factor (TNF), interleukin (IL)-17 and IL-23 inhibitors with the use of the same drugs in combination with MTX.
Using data from the BIOBADADERM registry, we compared biologic monotherapies with therapies that were combined with MTX. We estimated adjusted incidence rate ratios (aIRR) using a random effects Poisson regression with 95% confidence intervals for all AEs, SAEs, infections and serious infections and other AEs by system organ class.
We analysed data from 2829 patients and 5441 treatment cycles, a total of 12 853 patient-years. The combination of a biologic with MTX was not associated with statistically significant increases in overall risk of AEs or SAEs in any treatment group. No increase in the total number of infections or serious infections in patients receiving combined therapy was observed for any group. However, treatment with a TNF inhibitor combined with MTX was associated with an increase in the incidence of gastrointestinal AEs (aIRR 2.50, 95% CI 1.57-3.98; P < 0.002).
The risk of AEs and SAEs was not significantly increased in patients with moderate-to-severe psoriasis receiving different classes of biologic drugs combined with MTX compared with those on biologic monotherapy.
► Little is known about the interaction between media and message for new products. ► Findings demonstrate that using quality claims is advisable only in the e-context. ► ICT products are perceived ...less complex when quality claims are advertised online. ► ICT products are perceived more trustworthy when quality claims are used online. ► Complexity and risk are higher offline than online when advertising quality.
Firms frequently make quality claims when launching new products in the market. However, little is known about the interaction effects that occur between the media (online/offline channels of distribution) and the message (making/not making quality claims) when new products are launched. By sampling 568 online and offline customers of ICT products, we demonstrate that using quality claims is advisable only in the online context. Specifically, ICT products are perceived less complex and more trustworthy when quality claims are advertised online. In addition, perceived complexity and perceived risk are higher in the offline context than in the online context when product quality claims are used. Therefore, firms should be aware of which quality claims they introduce on their websites so as not to interfere with the product launch. This study adds to the body of research on Internet advertising and innovative products. This study is also useful for marketers who wish to improve the advertising efficiency (in terms of content and media) of innovative and complex products to consumers.
Purpose - The purpose of this paper is to develop a research model that examines the effect of information overload and information disorganisation upon customers' perceived risk and purchase ...intention online in a single integrative model. In addition the paper investigates whether internet experience moderates these relationships. Design/methodology/approach - To achieve the paper's objectives an experiment that involved visiting the ten most visited e-commerce web sites in Spain was conducted. Hypotheses were tested by using structural equation modelling on a data set of 1,396 online shopping customers. Findings - The results suggest a positive relationship between information overload and customer purchase intention and that internet experience reinforces this positive effect. Moreover the results confirm that the relationship between information disorganisation and customer purchase intention is not significant and that internet experience does not moderate the relationship. The findings also indicate that perceived risk mediates the relationship between information overload and information disorganisation on customer purchase intention. Originality/value - This work contributes to the literature by exploring the phenomenon of information overload and information disorganisation upon customers' perceived risk and purchase intention in the e-commerce environment as well as the moderating effect of internet experience on these relationships in a single integrative model. The main conclusions of this investigation can be valuable to organisations that implement or intend to implement e-commerce.
Gallstone ileus is a rare complication of cholecystoduodenal fistula. Gastric ischemia due to intestinal obstruction is an extremely rare event that, if not diagnosed in time, can have a fatal ...outcome. We present the case of a patient with intestinal occlusion due to a gallstone obstructing the middle jejunum in which gastric ischemia was diagnosed intraoperatively due to the distension caused by the intestinal obstruction.
The introduction of point-of-care (POC) assays into clinical practice in patients with inflammatory disease enables on-demand therapeutic decision making. The aim of this study was to compare the POC ...test Quantum blue (Bühlmann Laboratories) for infliximab (IFX), adalimumab (ADL), and its anti-drug antibodies with the traditional ELISA assay (Promonitor). A total of 200 serum samples were analyzed. Samples were classified into the following three different groups; sub-therapeutic range (IFX < 3 μg/mL and ADL < 5 μg/mL); therapeutic range (IFX: 3–7 μg/mL and ADL: 5–12 μg/mL) and supra-therapeutic range (IFX levels > 7 μg/mL and ADL levels > 12 μg/mL). Significant higher values were measured using the POC test (p < 0.001) for IFX results but no differences in ADL trough levels were observed (p = 0.3101). Spearman’s correlation indicated a good correlation between the two assays (rs = 0.88 for ADL and rs = 0.93 for IFX), and McNemar’s test revealed significant differences (p = 0.016) when classifying IFX samples between therapeutic and supra-therapeutic ranges but no significant differences were found among the other ranges for either IFX or ADL. These results show that we should be cautious when using these rapid measurement methods, and new targets should probably be defined for IFX when using this new analytical method.
Ghrelin is a peptidic hormone, which stimulates cell proliferation and inhibits apoptosis in several tissues, including pancreas. In preclinical stage of type 1 diabetes, proinflammatory cytokines ...generate a destructive environment for β-cells known as insulitis, which results in loss of β-cell mass and impaired insulin secretion, leading to diabetes. Our aim was to demonstrate that ghrelin could preserve β-cell viability, turnover rate, and insulin secretion acting as a counter balance of cytokines. In the present work we reproduced proinflammatory milieu found in insulitis stage by treating murine cell line INS-1E and rat islets with a cytokine cocktail including IL-1β, IFNγ, and TNFα and/or ghrelin. Several proteins involved in survival pathways (ERK 1/2 and Akt/PKB) and apoptosis (caspases and Bcl-2 protein family and endoplasmic reticulum stress markers) as well as insulin secretion were analyzed. Our results show that ghrelin alone has no remarkable effects on β-cells in basal conditions, but interestingly it activates cell survival pathways, downregulates apoptotic mediators and endoplasmic reticulum stress, and restores insulin secretion in response to glucose when beta-cells are cytokine-exposed. These data suggest a potential role of ghrelin in preventing or slowing down the transition from a preclinical to clinically established diabetes by ameliorating the effects of insulitis on β-cells.
Type 2 diabetes (T2D) mellitus and Alzheimer's disease (AD) are two prevalent diseases with comparable pathophysiological features and genetic predisposition. Patients with AD are more susceptible to ...develop T2D. However, the molecular mechanism linking AD and T2D remains elusive. In this study, we have generated a new mouse model to test the hypothesis that AD would prompt the onset of T2D in mice. To test our hypothesis, we crossed Alzheimer APPswe/PS1dE9 (APP/PS1) transgenic mice with mice partially deficient in leptin signaling (db/+). Body weight, plasma glucose, and insulin levels were monitored. Phenotypic characterization of glucose metabolism was performed using glucose and insulin tolerance tests. β-Cell mass, islet volume, and islet number were analyzed by histomorphometry. APP/PS1 coexpression in mice with intact leptin receptor signaling did not show any metabolic perturbations in glucose metabolism or insulin sensitivity. In contrast, APP/PS1 coexpression in db/+ mice resulted in nonfasting hyperglycemia, hyperinsulinemia, and hypercholesterolemia without changes in body weight. Conversely, fasting blood glucose and cholesterol levels remained unchanged. Coinciding with altered glucose metabolism, APP/PS1 coexpression in db/+ mice resulted in glucose intolerance, insulin resistance, and impaired insulin signaling. In addition, histomorphometric analysis of pancreata revealed augmented β-cell mass. Taken together, these findings provide experimental evidence to support the notion that aberrant Aβ production might be a mechanistic link underlying the pathology of insulin resistance and T2D in AD.
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