Corrigendum: Mucinous adenocarcinoma of the rectum: a whole genome sequencing study.

[This corrects the article DOI: 10.3389/fonc.2020.

Comparative analysis of deeply phenotyped GBM cohorts of 'short-term' and 'long-term' survivors.

Background: Glioblastoma (GBM) is an aggressive brain cancer that typically results in death in the first 15 months after diagnosis. There have been limited advances in finding new treatments for GBM. In this study, we investigated molecular differences between patients with extremely short (≤ 9 months, Short term survivors, STS) and long survival (≥ 36 months, Long term survivors, LTS).

An atlas of inter- and intra-tumor heterogeneity of apoptosis competency in colorectal cancer tissue at single-cell resolution.

Cancer cells' ability to inhibit apoptosis is key to malignant transformation and limits response to therapy. Here, we performed multiplexed immunofluorescence analysis on tissue microarrays with 373 cores from 168 patients, segmentation of 2.4 million individual cells, and quantification of 18 cell lineage and apoptosis proteins.

An Insight Into the Driver Mutations and Molecular Mechanisms Underlying Mucinous Adenocarcinoma of the Rectum.

Background: Mucinous adenocarcinoma of the rectum accounts for 10% of all rectal cancers and has an impaired response to neoadjuvant chemoradiotherapy and worse overall survival. To date, insufficient genomic research has been performed on this histological subtype.

Objective: This study aims to define the mismatch repair deficiency rate and the driver mutations underpinning mucinous adenocarcinoma of the rectum and to compare it with rectal adenocarcinoma not otherwise specified.

Development of a protein signature to enable clinical positioning of IAP inhibitors in colorectal cancer.

Resistance to chemotherapy-induced cell death is a major barrier to effective treatment of solid tumours such as colorectal cancer, CRC. Herein, we present a study aimed at developing a proteomics-based predictor of response to standard-of-care (SoC) chemotherapy in combination with antagonists of IAPs (inhibitors of apoptosis proteins), which have been implicated as mediators of drug resistance in CRC. We quantified the absolute expression of 19 key apoptotic proteins at baseline in a panel of 12 CRC cell lines representative of the genetic diversity seen in this disease to identify which proteins promote resistance or sensitivity to a model IAP antagonist [birinapant (Bir)] alone and in combination with SoC chemotherapy (5FU plus oxaliplatin).

Molecular subtype-specific responses of colon cancer cells to the SMAC mimetic Birinapant.

Colorectal cancer is a molecularly heterogeneous disease. Responses to genotoxic chemotherapy in the adjuvant or palliative setting vary greatly between patients, and colorectal cancer cells often resist chemotherapy by evading apoptosis. Antagonists of an inhibitor of apoptosis proteins (IAPs) can restore defective apoptosis signaling by degrading cIAP1 and cIAP2 proteins and by inhibition of XIAP.

Mucinous Adenocarcinoma of the Rectum: A Whole Genome Sequencing Study.

Introduction: Mucinous adenocarcinoma of the rectum is an infrequently encountered histological subtype that is associated with an impaired response to chemoradiotherapy and a worse overall prognosis. A genomic profile analysis of mucinous rectal tumors has not yet been performed. The aim of this study was to comprehensively describe the burden of somatic mutations and copy number variation as well as perform mutational signature and microbial analysis of an in-house collected cohort of mucinous adenocarcinoma of the rectum.

Mucinous adenocarcinoma is a pharmacogenomically distinct subtype of colorectal cancer.

Mucinous colorectal cancer is a unique histological subtype that is known to respond poorly to cytotoxic chemotherapy and radiotherapy. There are a number of genes known to be associated with resistance to 5-fluorouracil (5-FU), oxaliplatin, and irinotecan. The aim of this study was to compare the somatic mutation frequency and copy number variation (CNV) in these genes between mucinous and non-mucinous colorectal cancer.

Mucinous adenocarcinoma of the colon and rectum: A genomic analysis.

Background And Objectives: Mucinous adenocarcinoma is a distinct subtype of colorectal cancer (CRC) with a worse prognosis when compared with non-mucinous adenocarcinoma. The aim of this study was to compare somatic mutations and copy number alteration (CNA) between mucinous and non-mucinous CRC.

Methods: Data from The Cancer Genome Atlas-colon adenocarcinoma and rectum adenocarcinoma projects were utilized.

Mucin Pools Following Neoadjuvant Chemoradiotherapy for Rectal Cancer: A Marker of Response or Epiphenomenon?

Neoadjuvant chemoradiotherapy (CRT) is the standard of care for locally advanced rectal cancer. Morphologic changes such as fibrosis, inflammatory infiltrates, and the formation of extracellular mucin pools can be identified in the resection specimen after neoadjuvant CRT. The association of mucin pool formation with clinicopathologic variables and outcomes is unclear.

Heterogeneous responses to low level death receptor activation are explained by random molecular assembly of the Caspase-8 activation platform.

Ligand binding to death receptors activates apoptosis in cancer cells. Stimulation of death receptors results in the formation of intracellular multiprotein platforms that either activate the apoptotic initiator Caspase-8 to trigger cell death, or signal through kinases to initiate inflammatory and cell survival signalling. Two of these platforms, the Death-Inducing Signalling Complex (DISC) and the RIPoptosome, also initiate necroptosis by building filamentous scaffolds that lead to the activation of mixed lineage kinase domain-like pseudokinase.

Mucin glycoproteins block apoptosis; promote invasion, proliferation, and migration; and cause chemoresistance through diverse pathways in epithelial cancers.

Overexpression of mucin glycoproteins has been demonstrated in many epithelial-derived cancers. The significance of this overexpression remains uncertain. The aim of this paper was to define the association of mucin glycoproteins with apoptosis, cell growth, invasion, migration, adhesion, and clonogenicity in vitro as well as tumor growth, tumorigenicity, and metastasis in vivo in epithelial-derived cancers by performing a systematic review of all published data.

Increased A20-E3 ubiquitin ligase interactions in bid-deficient glia attenuate TLR3- and TLR4-induced inflammation.

Background: Chronic pro-inflammatory signaling propagates damage to neural tissue and affects the rate of disease progression. Increased activation of Toll-like receptors (TLRs), master regulators of the innate immune response, is implicated in the etiology of several neuropathologies including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. Previously, we identified that the Bcl-2 family protein BH3-interacting domain death agonist (Bid) potentiates the TLR4-NF-κB pro-inflammatory response in glia, and specifically characterized an interaction between Bid and TNF receptor associated factor 6 (TRAF6) in microglia in response to TLR4 activation.

The role of B cell antigen receptors in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is characterized by an aggressive clinical course and secondary resistance to currently available therapies in most cases. Therefore, despite recent advances in the treatment of this disease, it is still considered to be incurable in the majority of cases. MCL B cells retain their B cell antigen receptor (BCR) expression during and after neoplastic transformation.

Identification of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor.

The discovery of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor is described. The characterization and redressing of the issues associated with these compounds is detailed. An efficient three-step synthesis and a binding assay were relied upon as the primary means of rapidly improving potency and ADMET properties for this class of inverse agonist compounds.

Discovery and evaluation of spirocyclic derivatives as antagonists of the neuropeptide Y5 receptor.

A novel series of spirocyclic derivatives was synthesized and evaluated as NPY Y5R antagonists for the treatment of obesity. Cis and trans analogs 7a and 8a were equipotent in a Y5R binding assay (K(i)'s ≤ 1 nM) and displayed good stability in human and rat liver microsome preparations. Compound 7a failed to demonstrate weight loss activity in a diet-induced obese (DIO) rat model at unbound drug levels in the brain that exceeded the Y5R K(i) value by 25-fold over a 24-h time-period.

An asymmetric synthesis of (2S,5S)-5-substituted azepane-2-carboxylate derivatives.

To facilitate a drug discovery project, we needed to develop a robust asymmetric synthesis of (2S,5S)-5-substituted-azepane-2-carboxylate derivatives. Two key requirements for the synthesis were flexibility for elaboration at C5 and suitability for large scale preparation. To this end we have successfully developed a scalable asymmetric synthesis of these derivatives that starts with known hydroxy-ketone 8.

New bicyclic cannabinoid receptor-1 (CB1-R) antagonists.

A series of conformationally constrained bicyclic derivatives derived from SR141716 was prepared and evaluated as hCB(1)-R antagonists and inverse agonists. Optimization of the structure-activity relationships around the 2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one derivative 2a led to the identification of two compounds with oral activity in rodent feeding models (2h and 4a). Replacement of the PP group in 2h with other bicyclic groups resulted in a loss of binding affinity.