Efficacy of vedolizumab and ustekinumab in pediatric-onset inflammatory bowel disease: A real-world multicenter study.

Objectives: Vedolizumab and ustekinumab are effective in inducing and maintaining corticosteroid-free clinical remission (CFR) in adult patients with inflammatory bowel disease (IBD). This study describes the efficacy and safety of vedolizumab and ustekinumab in pediatric IBD.

Methods: All patients ≤18 years of age with Crohn's disease (CD) or ulcerative colitis (UC) treated with vedolizumab or ustekinumab in three centers in Northern France were followed retrospectively.

Disruption of the pro-oncogenic c-RAF-PDE8A complex represents a differentiated approach to treating KRAS-c-RAF dependent PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is considered the third leading cause of cancer mortality in the western world, offering advanced stage patients with few viable treatment options. Consequently, there remains an urgent unmet need to develop novel therapeutic strategies that can effectively inhibit pro-oncogenic molecular targets underpinning PDACs pathogenesis and progression. One such target is c-RAF, a downstream effector of RAS that is considered essential for the oncogenic growth and survival of mutant RAS-driven cancers (including KRAS PDAC).

JAK/STAT3 represents a therapeutic target for colorectal cancer patients with stromal-rich tumors.

Colorectal cancer (CRC) is a heterogenous malignancy underpinned by dysregulation of cellular signaling pathways. Previous literature has implicated aberrant JAK/STAT3 signal transduction in the development and progression of solid tumors. In this study we investigate the effectiveness of inhibiting JAK/STAT3 in diverse CRC models, establish in which contexts high pathway expression is prognostic and perform in depth analysis underlying phenotypes.

CXCL8 expression is associated with advanced stage, right sidedness, and distinct histological features of colorectal cancer.

CXCL8 is an inflammatory chemokine elevated in the colorectal cancer (CRC) tumour microenvironment. CXCR2, the major receptor for CXCL8, is predominantly expressed by neutrophils. In the cancer setting, CXCL8 plays important roles in neutrophil chemotaxis, facilitating angiogenesis, invasion, and metastasis.

Spatial expression of IKK-alpha is associated with a differential mutational landscape and survival in primary colorectal cancer.

Background: To understand the relationship between key non-canonical NF-κB kinase IKK-alpha(α), tumour mutational profile and survival in primary colorectal cancer.

Methods: Immunohistochemical expression of IKKα was assessed in a cohort of 1030 patients who had undergone surgery for colorectal cancer using immunohistochemistry. Mutational tumour profile was examined using a customised gene panel.

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer.

Background & Aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress, and novel therapeutic response in PC to develop a biomarker-driven therapeutic strategy targeting DDR and replication stress in PC.

Methods: We interrogated the transcriptome, genome, proteome, and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress.

Gene expression profiling of the preclinical scrapie-infected hippocampus.

The molecular events that underlie prion disease neuropathology remain poorly defined. Within the hippocampus of the ME7/CV mouse scrapie model, profound CA1 neuronal loss occurs between 160 and 180 days post-infection (dpi). To elucidate the molecular events that may contribute to this neuronal loss, we have applied Affymetrix high-density oligonucleotide probe arrays to the study of ME7-infected hippocampal gene expression at 170 dpi.

Identification of up-regulated genes by array analysis in scrapie-infected mouse brains.

The major neuropathological features of the transmissible spongiform encephalopathies (TSEs) are well documented, however, the underlying molecular events are poorly defined. We have applied cDNA expression arrays and quantitative RT-PCR to the study of gene expression in the brain, and more specifically in the hippocampus, of the well-characterized ME7/CV mouse model of scrapie. The number of genes showing consistent, scrapie-associated changes in expression was limited, and was primarily restricted to glial-associated genes.

Inducible cytokine gene expression in the brain in the ME7/CV mouse model of scrapie is highly restricted, is at a strikingly low level relative to the degree of gliosis and occurs only late in disease.

The temporal course of cerebral cytokine gene expression was investigated in the ME7/CV murine scrapie model to determine any association with neuropathological events. Analysis by RNase protection assay (RPA) demonstrated no transcripts for ILs 2, 3, 4, 5, 6, 7, 10, 12p40 and 13, granulocyte macrophage colony-stimulating factor, IFN-gamma or lymphotoxin-alpha at any time during the course of this disease. Transcripts for transforming growth factor-beta 1 were constitutively expressed in both control and scrapie-infected brain and were elevated at terminal disease.

The molecular epidemiology of human immunodeficiency virus type 1 in six cities in Britain and Ireland.

We have sequenced the p17 coding regions of the gag gene from 211 patients infected either through injecting drug use (IDU) or by sexual intercourse between men from six cities in Scotland, N. England, N. Ireland, and the Republic of Ireland.

Hepatitis B serology and DNA detection in multitransfused haemophiliacs and factor VIII and IX concentrates.

To assess the effect of HIV infection and the introduction of virus-inactivated concentrates, we conducted a retrospective 20-year longitudinal study of hepatitis B virus (HBV) serology and look for HBV DNA in recent serum samples of 63 multiply transfused haemophiliacs. Of 63 haemophiliacs, 51 had evidence of previous HBV infection and 12 vaccinees had anti-HBs only. Of 40 HIV-negative, two had persistent HBsAg but all were HBV DNA negative.

Human immunodeficiency virus and the brain: investigation of virus load and neuropathologic changes in pre-AIDS subjects.

Brain tissue was examined for evidence of human immunodeficiency virus (HIV) infection in 23 intravenous drug users who died suddenly some years after seroconversion but while still in presymptomatic stages of infection. None showed giant cell encephalitis, but 14 showed T cell lymphocytic leptomeningitis and 3 showed other significant neuropathologic features. Quantitative polymerase chain reaction for HIV was applied to 13 of the 23 with negative results in 6 and very low positive results in the other 7, a finding consistent with contamination by residual infected blood in the brain tissue.

Use of several second generation serological assays to determine the true prevalence of hepatitis C virus infection in haemophiliacs treated with non-virus inactivated factor VIII and IX concentrates.

To investigate the prevalence of hepatitis C virus infection in two risk groups, stored serum samples from treated haemophiliacs and intravenous drug users were tested for anti-HCV by both anti-C-100 based and second generation ELISAs (Abbott and Ortho) followed by testing in two confirmatory immunoblot assays that incorporate core as well as other non-structural antigens (Innogenetics LIA and Chiron RIBA-HCV test). Clear evidence of HCV infection was found in all but one of 78 haemophiliacs treated with non-virus inactivated clotting factor concentrates, but in none exposed only to super dry heat-treated concentrates. Only four samples gave rise to conflicting serological results between the four tests, two of these occurred in patients with advanced HIV related disease and almost certainly reflected loss of humoral immunity associated with disease progression, and the others occurred in the only two patients tested who were chronic carriers of hepatitis B infection and may reflect an interaction between the two viruses.

Hepatitis C quantification and sequencing in blood products, haemophiliacs, and drug users.

The polymerase chain reaction (PCR) detected specific hepatitis C viral (HCV) RNA sequences in plasma from 15 of 21 haemophiliacs (12 HCV-antibody positive) and 7 of 27 intravenous drug users (13 HCV-antibody positive). Quantification of RNA-positive samples showed high levels of HCV (10(5) to 10(6) copies of RNA/ml) in infected patients. HCV was more frequently found in haemophiliacs infected with human immunodeficiency virus (11/11 HIV-positive and 4/10 HIV-negative patients).

Five year prospective study of HIV infection in the Edinburgh haemophiliac cohort.

Objective: To identify measures of immune state that reflect the course of HIV related disease in order to predict deterioration of symptoms and assess response to treatment.

Design: Five year longitudinal clinical and laboratory study.

Setting: Regional haemophilia centre, university virology laboratory, and Medical Research Council laboratory.

Vertical transmission of HIV: a prospective study.

Forty nine infants of HIV seropositive women were followed up for a median of 24 months, together with 24 controls. The infection status of 11 index children under 18 months of age was indeterminate; 34 were presumed uninfected while four showed clinical and laboratory evidence of HIV disease. Based on current definitions of HIV infection and excluding children under 18 months old as well as those who had not been studied from birth, two out of 28 children were infected.

Human immunodeficiency virus detection: correlation with clinical progression in the Edinburgh haemophiliac cohort.

HIV p24 antigenaemia and virus detection in cultures of peripheral blood lymphocytes were examined in 16 of 18 haemophiliacs infected with HIV by a single batch of Scottish National Blood Transfusion Service factor VIII concentrate. Six (38%) had p24 antigenaemia and 11 (69%) had positive lymphocyte cultures. All seven patients with serious HIV disease (CDC group IV) had positive lymphocyte cultures whereas four (57%) had p24 antigenaemia.