Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1.

An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumors is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target, which when inhibited improved radiotherapy, even in tumors displaying immunosuppressive features and poor CD8+ T cell infiltration.

FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2.

Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2), could represent a new chemoprophylactic approach for COVID-19 that complements vaccination. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems.

Targeting Acid Ceramidase to Improve the Radiosensitivity of Rectal Cancer.

Previous work utilizing proteomic and immunohistochemical analyses has identified that high levels of acid ceramidase (AC) expression confers a poorer response to neoadjuvant treatment in locally advanced rectal cancer. We aimed to assess the radiosensitising effect of biological and pharmacological manipulation of AC and elucidate the underlying mechanism. AC manipulation in three colorectal cancer cell lines (HT29, HCT116 and LIM1215) was achieved using siRNA and plasmid overexpression.

miR-31-3p Expression and Benefit from Anti-EGFR Inhibitors in Metastatic Colorectal Cancer Patients Enrolled in the Prospective Phase II PROSPECT-C Trial.

Purpose: Anti-EGFR mAbs are effective in the treatment of metastatic colorectal cancer (mCRC) patients. status and tumor location (sidedness) are predictive markers of patients' response to anti-EGFR mAbs. Recently, low miR-31-3p expression levels have been correlated with clinical benefit from the anti-EGFR mAb cetuximab.

Longitudinal Liquid Biopsy and Mathematical Modeling of Clonal Evolution Forecast Time to Treatment Failure in the PROSPECT-C Phase II Colorectal Cancer Clinical Trial.

Sequential profiling of plasma cell-free DNA (cfDNA) holds immense promise for early detection of patient progression. However, how to exploit the predictive power of cfDNA as a liquid biopsy in the clinic remains unclear. RAS pathway aberrations can be tracked in cfDNA to monitor resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer.

Patient-derived organoids model treatment response of metastatic gastrointestinal cancers.

Patient-derived organoids (PDOs) have recently emerged as robust preclinical models; however, their potential to predict clinical outcomes in patients has remained unclear. We report on a living biobank of PDOs from metastatic, heavily pretreated colorectal and gastroesophageal cancer patients recruited in phase 1/2 clinical trials. Phenotypic and genotypic profiling of PDOs showed a high degree of similarity to the original patient tumors.

Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study.

Objective: Regorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need for better patient selection.

Design: Patients with mutant mCRC with biopsiable metastases were enrolled in this phase II trial.

Towards the development of an enzyme replacement therapy for the metabolic disorder propionic acidemia.

Propionic acidemia (PA) is a life-threatening disease caused by the deficiency of a mitochondrial biotin-dependent enzyme known as propionyl coenzyme-A carboxylase (PCC). This enzyme is responsible for degrading the metabolic intermediate, propionyl coenzyme-A (PP-CoA), derived from multiple metabolic pathways. Currently, except for drastic surgical and dietary intervention that can only provide partial symptomatic relief, no other form of therapeutic option is available for this genetic disorder.

Development of an UPLC-MS/MS method for assaying the enzymatic activity of propionyl coenzyme-A carboxylase.

Background: Propionyl coenzyme-A carboxylase (PCC) is a mitochondrial enzyme previously quantifiable only by radiometric assay. Herein, we report a UPLC-MS/MS method as a superior alternative method for assaying PCC's activity. METHODOLOGY & RESULTS: For the development of the UPLC-MS/MS method, the mass spectra of propionyl coenzyme-A and methyl malonyl coenzyme-A precursor ions, and their full scan product ions were determined.

A systematic review of efficacy and tolerability of mebeverine in irritable bowel syndrome.

We evaluated the efficacy and tolerability of mebeverine, a musculotropic antispasmodic agent, in irritable bowel syndrome (IBS) and compared its usual dosages by meta-analysis. Medical databases and all relevant literature were searched from 1965 to June 2009 for any placebo-controlled clinical trials of mebeverine, using search terms such as mebeverine, clinical trials, and IBS. Eight randomized trials met our criteria, including six trials that compared mebeverine with placebo and two that compared mebeverine tablets with capsules.