Epithelial aPKC deficiency leads to stem cell loss preceding metaplasia in colorectal cancer initiation.

The early mechanisms of spontaneous tumor initiation that precede malignancy are largely unknown. We show that reduced aPKC levels correlate with stem cell loss and the induction of revival and metaplastic programs in serrated- and conventional-initiated premalignant lesions, which is perpetuated in colorectal cancers (CRCs). Acute inactivation of PKCλ/ι in vivo and in mouse organoids is sufficient to stimulate JNK in non-transformed intestinal epithelial cells (IECs), which promotes cell death and the rapid loss of the intestinal stem cells (ISCs), including those that are LGR5.

Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis.

The metabolic and signaling pathways regulating aggressive mesenchymal colorectal cancer (CRC) initiation and progression through the serrated route are largely unknown. Although relatively well characterized as BRAF mutant cancers, their poor response to current targeted therapy, difficult preneoplastic detection, and challenging endoscopic resection make the identification of their metabolic requirements a priority. Here, we demonstrate that the phosphorylation of SCAP by the atypical PKC (aPKC), PKCλ/ι promotes its degradation and inhibits the processing and activation of SREBP2, the master regulator of cholesterol biosynthesis.

Global longitudinal strain assessment of cardiac function and extravascular lung water formation after diving using semi-closed circuit rebreather.

Purpose: The aim of the present investigation is to study the relationship of ventricular global longitudinal strain (GLS) and ultrasound lung comets (ULC) formation to establish a link between extravascular pulmonary water formation and cardiac contractile dysfunction.

Methods: This is a prospective observational study including 14 active military divers. The subjects performed two sea dives of 120 min each with a semi-closed SCUBA circuit at 10 m depth.

Global Methylome Scores Correlate with Histological Subtypes of Colorectal Carcinoma and Show Different Associations with Common Clinical and Molecular Features.

Background: The typical methylation patterns associated with cancer are hypermethylation at gene promoters and global genome hypomethylation. Aberrant CpG island hypermethylation at promoter regions and global genome hypomethylation have not been associated with histological colorectal carcinomas (CRC) subsets. Using Illumina's 450 k Infinium Human Methylation beadchip, the methylome of 82 CRCs were analyzed, comprising different histological subtypes: 40 serrated adenocarcinomas (SAC), 32 conventional carcinomas (CC) and 10 CRCs showing histological and molecular features of microsatellite instability (hmMSI-H), and, additionally, 35 normal adjacent mucosae.

Biology and Therapeutic Targets of Colorectal Serrated Adenocarcinoma; Clues for a Histologically Based Treatment against an Aggressive Tumor.

Serrated adenocarcinoma (SAC) is a tumor recognized by the WHO as a histological subtype accounting for around 9% of colorectal carcinomas. Compared to conventional carcinomas, SACs are characterized by a worse prognosis, weak development of the immune response, an active invasive front and a frequent resistance to targeted therapy due to a high occurrence of KRAS or BRAF mutation. Nonetheless, several high-throughput studies have recently been carried out unveiling the biology of this cancer and identifying potential molecular targets, favoring a future histologically based treatment.

ColPortal, an integrative multiomic platform for analysing epigenetic interactions in colorectal cancer.

Colorectal cancer (CRC) is the third leading cause of cancer mortality worldwide. Different pathological pathways and molecular drivers have been described and some of the associated markers are used to select effective anti-neoplastic therapy. More recent evidence points to a causal role of microbiota and altered microRNA expression in CRC carcinogenesis, but their relationship with pathological drivers or molecular phenotypes is not clearly established.

Two histologically colorectal carcinomas subsets from the serrated pathway show different methylome signatures and diagnostic biomarkers.

Background: Altered methylation patterns are driving forces in colorectal carcinogenesis. The serrated adenocarcinoma (SAC) and sporadic colorectal carcinoma showing histological and molecular features of microsatellite instability (hmMSI-H) are two endpoints of the so-called serrated pathological route sharing some characteristics but displaying a totally different immune response and clinical outcome. However, there are no studies comparing the methylome of these two subtypes of colorectal carcinomas.

A Polymorphism Predicts Anti-drug Antibodies in Chronic Inflammatory Bowel Disease Patients Treated With Anti-TNF.

Background: The production of anti-drug antibodies (ADAs) against IgG monoclonal antibodies (mAbs) targeting tumour necrosis factor (TNF) is an important cause of loss of response to anti-TNF mAbs in patients with inflammatory bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC). Since receptors for the Fc portion of IgG (FCGRs) are involved in the degradation of IgG complexes, we hypothesised that a polymorphism in (V158F; rs396991) gene could be involved in anti-TNF ADA generation and treatment resistance.

Material And Methods: A cohort of 103 IBD patients (80 CD, 23 UC) were genotyped and serum level of both anti-TNFs (infliximab or adalimumab) and ADA against them were measured.

BARHL1 Is Downregulated in Alzheimer's Disease and May Regulate Cognitive Functions through ESR1 and Multiple Pathways.

The Transcription factor BarH like homeobox 1 (BARHL1) is overexpressed in medulloblastoma and plays a role in neurogenesis. However, much about the BARHL1 regulatory networks and their functions in neurodegenerative and neoplastic disorders is not yet known. In this study, using a tissue microarray (TMA), we report for the first time that BARHL1 is downregulated in hormone-negative breast cancers and Alzheimer's disease (AD).

Reasons for Discontinuation and Adverse Effects of TNFα Inhibitors in a Cohort of Patients With Rheumatoid Arthritis and Ankylosing Spondylitis.

Background: The introduction of anti-tumor necrosis factor α (anti-TNFα) drugs has improved the clinical outcomes in rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, these drugs may cause adverse effects that motivate a change in or discontinuation of the treatment.

Objective: To evaluate the causes of discontinuation or changes in the dosage regimen in a cohort of patients with RA and AS treated with infliximab, adalimumab, etanercept, and golimumab under clinical practice conditions.

Biomarkers for the identification of precursor polyps of colorectal serrated adenocarcinomas.

Background: In contrast to conventional colorectal carcinomas (CCs), which develop through a so-called chromosome instability or suppressor phenotype pathway, the sequence of events leading from precursor polyps/adenomas to serrated adenocarcinomas (SACs), which are more aggressive and exhibit a poorer survival than CCs, is as yet not clearly defined. Here, we aimed at detecting protein and DNA biomarkers for SAC in a series of primary colorectal polyps.

Methods: In total 303 colorectal polyps were included: 121 serrated polyps (33 hyperplastic polyps, 37 sessile serrated adenomas (SSA), 51 traditional serrated adenomas (TSA)), 143 conventional polyps (72 tubular polyps, 34 tubulovillous polyps, 37 villious adenomas), and 39 bi-phenotypic serrated-conventional polyps.

Methylome profiling reveals functions and genes which are differentially methylated in serrated compared to conventional colorectal carcinoma.

Background: Serrated adenocarcinoma (SAC) is a recently recognized colorectal cancer (CRC) subtype accounting for 7.5-8.7 % of CRCs.

Immune responses against virus and tumor in cervical carcinogenesis: treatment strategies for avoiding the HPV-induced immune escape.

Despite the availability of prophylactic vaccines against human papillomavirus (HPV), cervical cancer (CC) is still a major problem globally. It is the cancer with the second highest incidence and the third highest mortality in women worldwide, but, in less developed countries, it is an even greater problem being the second most common cause of cancer death. Although HPV infection is one of the most common sexually transmitted diseases, and high-risk HPV16 is the most frequent genotype involved, only a small number of HPV-infected women develop high-grade squamous intraepithelial lesions whereas, in the remainder of the women, the virus disappears spontaneously.

Evaluation of the association of NKG2C copy number variations with susceptibility to human papillomavirus-induced cervical lesions.

Squamous intraepithelial lesions (SIL) and cervical cancer are primary due to suboptimal host-dependent immune response against human papillomavirus (HPV). Natural killer cells (NK) are innate-immune response components against virus and tumors. We studied whether the null allele of NKG2C NK cell receptor could be associated with low-grade (LSIL) to high-grade SIL (HSIL) transition or likelihood of HPV infection.

Influence of polymorphisms in ERCC5, XPA and MTR DNA repair and synthesis genes in B-cell lymphoma risk. A case-control study in Spanish population.

Purpose: Functions pertaining to DNA repair and synthesis are believed to play a critical role in cancer development and seem to be affected by genetic polymorphisms. Herein we performed a case-control study evaluating the influence of three single nucleotide polymorphisms (SNPs) in XPA, ERCC5 and MTR [rs1800975 (G-4A), rs17655 (Asp1104His) and rs1805087 (A2756G), respectively] in lymphoma risk.

Methods: Genotype distributions were studied in 213 lymphoma Caucasian patients (193 non-Hodgkin/NHL and 20 Hodgkin lymphoma/HL) and 214 controls, residents in a region of Southeast Spain.

Polymorphisms in xenobiotic metabolizing genes (EPHX1, NQO1 and PON1) in lymphoma susceptibility: a case control study.

Background: The interplay between genetic susceptibility and carcinogenic exposure is important in the development of haematopoietic malignancies. EPHX1, NQO1 and PON1 are three genes encoding proteins directly involved in the detoxification of potential carcinogens.

Methods: We have studied the prevalence of three functional polymorphisms affecting these genes rs1051740 EPHX1, rs1800566 NQO1 and rs662 PON1 in 215 patients with lymphoma and 214 healthy controls.

Colorectal serrated adenocarcinoma shows a different profile of oncogene mutations, MSI status and DNA repair protein expression compared to conventional and sporadic MSI-H carcinomas.

Molecular characterization has been extensively studied in serrated polyps but very little is known in serrated adenocarcinomas (SACs). We analyzed the incidence of KRAS, BRAF and PIK3CA mutations, microsatellite instability (MSI) status and loss of the DNA repair proteins MLH1, MSH2, MSH6 and MGMT in a series of 89 SAC, 81 matched conventional carcinomas (CC) and 13 sporadic colorectal cancer showing histological and molecular features of high-level MSI (sMSI-H). Our results demonstrate that KRAS are more prevalent than BRAF mutations in SAC (42.