Anti-TNF Non-Response in Ulcerative Colitis: Correcting for Mucosal Drug Exposure Reveals Distinct Cytokine Profiles.

Introduction: It remains unclear why up to 30% of ulcerative colitis patients (UC) do not respond to tumor necrosis factor inhibitors (TNFi). Validated biomarkers for (non-)response ((N)R) are lacking. Most studies investigating underlying mechanisms do not differentiate between pharmacokinetic and inflammatory mechanisms.

Evaluation of a Novel Smart Capsule Bacterial Detection System Device for Diagnosis of Small Intestinal Bacterial Overgrowth.

Background: There is a large unmet need for alternative, non-invasive, and accurate diagnosis of small intestinal bacterial overgrowth (SIBO). The smart capsule bacterial detection system (SCBDS) device contains a targeted sampling technology and an onboard SCBDS assay to detect metabolically active bacteria in the small intestine. Here, we evaluated the agreement of SCBDS assay with duodenal aspiration/culture ex vivo in a multicenter clinical study.

Current Trends in IBD-Development of Mucosal-Based Biomarkers and a Novel Minimally Invasive Recoverable Sampling System.

Despite recent developments in therapy for inflammatory bowel diseases (IBDs), there have been limited advances in diagnostic tools available to aid in disease management. A growing body of evidence suggests that there are important host-microbe interactions at the mucosal interface that modulate the inflammatory response in patients with IBD. Additionally, the importance of mucosal integrity and its disruption appears to be important in the pathophysiology and perpetuation of the disease.

Development of a Novel Drug Delivery System to Deliver Drugs Directly to the Colonic Mucosa, Resulting in Improved Efficacy and Reduced Systemic Exposure for the Treatment of Ulcerative Colitis.

Despite recent drug approvals for the treatment of inflammatory bowel diseases (IBDs), there remains a high unmet need for new technologies that can increase drug efficacy by improving site-specific drug delivery while reducing systemic exposure. These technologies must address challenges with formulation; in particular, drugs that are liquid, peptides, or proteins are difficult to formulate using existing delayed and extended oral release technologies. They also have the potential to improve efficacy and reduce systemic exposure for certain drugs by delivering higher doses directly to the site of inflammation.

A novel class of polymeric fluorescent dyes assembled using a DNA synthesizer.

In the pursuit of a novel class of fluorescent dyes we have developed a programmable polymer system that enables the rational design and control of macromolecular constructs through simple control of polymer primary sequence. These polymers are assembled using standard phosphoramidite chemistry on a DNA synthesizer which allows for extremely rapid prototyping and enables many permutations due to the large selection of phosphoramidite monomers presently available on the market. This programmability to some extent allows us to control the interactions/spacing of payload molecules distributed along the designed polymeric backbone.

Tumor necrosis factor-mediated disposition of infliximab in ulcerative colitis patients.

Ulcerative Colitis (UC) is an inflammatory bowel disease typically affecting the colon. Patients with active UC have elevated tumor necrosis factor (TNF) concentrations in serum and colonic tissue. Infliximab is a monoclonal antibody directed against TNF and binds with high affinity.

Evolution of cytokines and inflammatory biomarkers during infliximab induction therapy and the impact of inflammatory burden on primary response in patients with Crohn's disease.

Objective: Primary non-response to infliximab in Crohn's disease is still incompletely understood. Our aim was to further characterize the role of inflammatory burden during infliximab induction therapy.

Materials And Methods: We studied a well-characterized cohort of 201 anti-TNF naive Crohn's disease patients treated with infliximab 5mg/kg at week 0, 2, 6 and 14 who had serum samples drawn just before every infusion.

A clinically feasible multiplex proteomic immunoassay as a novel functional diagnostic for pancreatic ductal adenocarcinoma.

To date, targeted therapy for pancreatic ductal adenocarcinoma (PDAC) remains largely unsuccessful in the clinic. Current genomics-based technologies are unable to reflect the quantitative, dynamic signaling changes in the tumor, and require larger tumor samples that are difficult to obtain in PDAC patients. Therefore, a highly sensitive functional tool that can reliably and comprehensively inform intra-tumoral signaling events is direly needed to guide treatment decision.

HER2-Overexpressing Breast Cancers Amplify FGFR Signaling upon Acquisition of Resistance to Dual Therapeutic Blockade of HER2.

Dual blockade of HER2 with trastuzumab and lapatinib or pertuzumab has been shown to be superior to single-agent trastuzumab. However, a significant fraction of HER2-overexpressing (HER2) breast cancers escape from these drug combinations. In this study, we sought to discover the mechanisms of acquired resistance to the combination of lapatinib + trastuzumab.

Feedback activation of HER3 attenuates response to EGFR inhibitors in colon cancer cells.

The EGFR inhibitor cetuximab is approved for the treatment of colorectal cancer. However, both innate and acquired resistance mechanisms, including compensatory feedback loops, limit its efficacy. Nevertheless, the emergence of these feedback loops has remained largely unexplored to date.

Commensal-Specific CD4(+) Cells From Patients With Crohn's Disease Have a T-Helper 17 Inflammatory Profile.

Background & Aims: Crohn's disease (CD) has been associated with an altered immune response to commensal microbiota, mostly based on increased seroreactivity to microbial proteins. Although T cells are believed to contribute to the development of CD, little is known about the antigens involved. We investigated the antigen-specificity of T cells isolated from patients with CD.

Stratified Medicine: Maximizing Clinical Benefit by Biomarker-Driven Health Care.

Stratified medicine involves the use of biomarkers to differentiate patient populations into subsets that provide more detailed information about the specific causes of conditions, and predict how patients will respond to a given drug or combination of drugs. Biomarker-driven patient stratification can empower clinicians by providing accurate assessments of patient status (diagnostic and prognostic utility) in order to strategize treatment planning and delivery (predictive and monitoring utility) based on information extracted from biomarker profiles. This approach may also help presymptomatic individuals by delaying the onset of disease, minimize the severity of the disease, or possibly prevent disease occurrence.

Higher Adalimumab Levels Are Associated with Histologic and Endoscopic Remission in Patients with Crohn's Disease and Ulcerative Colitis.

Background: Optimal levels of adalimumab (ADA) have not been defined according to the ultimate goal of inflammatory bowel disease treatment--histologic and/or endoscopic healing. The aim of this study was to assess the relationship between random serum ADA levels and histologic and endoscopic healing in patients with inflammatory bowel disease.

Methods: This was a cross-sectional study including 66 patients receiving maintenance therapy with ADA for Crohn's disease or ulcerative colitis.

Pharmacokinetic Features and Presence of Antidrug Antibodies Associate With Response to Infliximab Induction Therapy in Patients With Moderate to Severe Ulcerative Colitis.

Background & Aims: The pharmacokinetics of infliximab during induction treatment for ulcerative colitis (UC) have not been studied. We investigated serum concentrations of infliximab and the early appearance of antibodies to infliximab (ATI) during induction treatment in patients with moderate-to-severe UC.

Methods: We performed a prospective analysis of 19 consecutive patients with moderate-severe UC (endoscopic Mayo ≥ 2) receiving induction therapy with infliximab (5 mg/kg at weeks 0, 2, and 6) at 2 centers in Amsterdam, The Netherlands, from July 2012 through March 2014.

Low EGFR/MET ratio is associated with resistance to EGFR inhibitors in non-small cell lung cancer.

Purpose: Although activating mutations in the epidermal growth factor receptor (EGFR) gene are predictive markers for response to EGFR inhibitors, 30-40% of EGFR-mutant non-small cell lung cancer (NSCLC) patients are de novo non-responders. Hence, we sought to explore additional biomarkers of response.

Methods: We conducted a prospective pilot study to characterize the expression and/or activation of key receptor tyrosine kinases (RTKs) in stage IIIB-IV NSCLC tumors.

A Matrix-based Model Predicts Primary Response to Infliximab in Crohn's Disease.

Background: Prediction of primary non-response [PNR] to anti-tumour necrosis factors [TNFs] in inflammatory bowel disease [IBD] is direly needed to select the optimal therapeutic class for a given patient. We developed a matrix-based prediction tool to predict response to infliximab [IFX] in Crohn's disease [CD] patients.

Methods: This retrospective single-centre study included 201 anti-TNF naïve CD patients who started with IFX induction therapy.

Antibodies to adalimumab are associated with future inflammation in Crohn's patients receiving maintenance adalimumab therapy: a post hoc analysis of the Karmiris trial.

Introduction: Data on immunogenicity to adalimumab (ADL) therapy in patients with IBD is limited. We performed additional analyses on the Karmiris cohort using the homogeneous mobility shift assay (HMSA) focusing on the inter-relationship of serum ADL concentration, antibodies-to-adalimumab (ATA), inflammatory markers and sustained response.

Methods: 536 prospectively collected serum samples were available for analysis of ADL concentration and ATA using HMSA.

The association of tissue anti-TNF drug levels with serological and endoscopic disease activity in inflammatory bowel disease: the ATLAS study.

Objective: The aim of this study was to assess the correlation between serum and intestinal anti-tumour necrosis factor (TNF) levels, and their relationship to endoscopic disease activity and levels of TNF.

Design: Cross-sectional study of 30 patients receiving treatment with infliximab or adalimumab for Crohn's disease or UC. For each patient, a sample of serum was matched to tissue biopsies.

Antibodies to infliximab are associated with lower infliximab levels and increased likelihood of surgery in pediatric IBD.

Background: Adult studies suggest antibodies to infliximab (ATI) correlate with loss of response in inflammatory bowel disease but pediatric data are limited.

Methods: We conducted a cross-sectional study of trough infliximab levels and ATI in 134 pediatric and young adult patients receiving infliximab. At the time serum was obtained demographics, disease phenotype, duration of infliximab therapy, use of combination therapy (methotrexate or 6-mercaptopurine with infliximab), and surgery were recorded.

Concentrations of 6-thioguanine nucleotide correlate with trough levels of infliximab in patients with inflammatory bowel disease on combination therapy.

Background & Aims: In patients with inflammatory bowel diseases, the combination of infliximab and thiopurines (such as 6-thioguanine) is more effective treatment than monotherapy. We assessed the correlation between serum levels of 6-thioguanine (6-TGN) and infliximab levels or antibodies to infliximab (ATI).

Methods: We performed a cross-sectional study of 72 patients receiving maintenance therapy with infliximab and a thiopurine for inflammatory bowel disease at the Crohn's and Colitis Center of the University of Miami, FL.

Long-term outcome of patients with Crohn's disease who discontinued infliximab therapy upon clinical remission.

Background & Aims: There are limited data on the effects of discontinuing infliximab therapy for Crohn's disease (CD). We investigated the long-term outcome of patients with CD who discontinued infliximab while in clinical remission, and searched for prognostic markers of continued remission after infliximab cessation.

Methods: We performed a retrospective, single-center study of 100 patients with CD who discontinued infliximab upon achieving clinical remission; 84 patients continued immunomodulator therapy.

The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn's disease.

Objective: Although low infliximab trough concentrations and antibodies to infliximab (ATI) are associated with poor outcomes in patients with Crohn's disease (CD), the clinical relevance of ATI in patients with adequate infliximab concentrations is uncertain. We evaluated this question using an assay sensitive for identification of ATI in the presence of infliximab.

Design: In an observational study, 1487 trough serum samples from 483 patients with CD who participated in four clinical studies of maintenance infliximab therapy were analysed using a fluid phase mobility shift assay.

The tyrosine phosphatase PTPRO sensitizes colon cancer cells to anti-EGFR therapy through activation of SRC-mediated EGFR signaling.

Inappropriate activation of epidermal growth factor receptor (EGFR) plays a causal role in many cancers including colon cancer. The activation of EGFR by phosphorylation is balanced by receptor kinase and protein tyrosine phosphatase activities. However, the mechanisms of negative EGFR regulation by tyrosine phosphatases remain largely unexplored.