The MondoA-dependent TXNIP/GDF15 axis predicts oxaliplatin response in colorectal adenocarcinomas.

Chemotherapy, the standard of care treatment for cancer patients with advanced disease, has been increasingly recognized to activate host immune responses to produce durable outcomes. Here, in colorectal adenocarcinoma (CRC) we identify oxaliplatin-induced Thioredoxin-Interacting Protein (TXNIP), a MondoA-dependent tumor suppressor gene, as a negative regulator of Growth/Differentiation Factor 15 (GDF15). GDF15 is a negative prognostic factor in CRC and promotes the differentiation of regulatory T cells (Tregs), which inhibit CD8 T-cell activation.

Modulation of prion protein expression through cryptic splice site manipulation.

Lowering expression of prion protein (PrP) is a well-validated therapeutic strategy in prion disease, but additional modalities are urgently needed. In other diseases, small molecules have proven capable of modulating pre-mRNA splicing, sometimes by forcing inclusion of cryptic exons that reduce gene expression. Here, we characterize a cryptic exon located in human PRNP's sole intron and evaluate its potential to reduce PrP expression through incorporation into the 5' untranslated region.

Refining clinically relevant parameters for mis-splicing risk in shortened introns with donor-to-branchpoint space constraint.

Intronic deletions that critically shorten donor-to-branchpoint (D-BP) distance of a precursor mRNA impose biophysical space constraint on assembly of the U1/U2 spliceosomal complex, leading to canonical splicing failure. Here we use a series of β-globin (HBB) gene constructs with intron 1 deletions to define D-BP lengths that present low/no risk of mis-splicing and lengths which are critically short and likely elicit clinically relevant mis-splicing. We extend our previous observation in EMD intron 5 of 46 nt as the minimal productive D-BP length, demonstrating spliceosome assembly constraint persists at D-BP lengths of 47-56 nt.

Modulation of prion protein expression through cryptic splice site manipulation.

Lowering expression of prion protein (PrP) is a well-validated therapeutic strategy in prion disease, but additional modalities are urgently needed. In other diseases, small molecules have proven capable of modulating pre-mRNA splicing, sometimes by forcing inclusion of cryptic exons that reduce gene expression. Here, we characterize a cryptic exon located in human 's sole intron and evaluate its potential to reduce PrP expression through incorporation into the 5' untranslated region (5'UTR).

Pan-european landscape of research into neurodevelopmental copy number variants: A survey by the MINDDS consortium.

Background: Several rare copy number variants have been identified to confer risk for neurodevelopmental disorders (NDD-CNVs), and increasingly NDD-CNVs are being identified in patients. There is a clinical need to understand the phenotypes of NDD-CNVs. However due to rarity of NDD-CNVs in the population, within individual countries there is a limited number of NDD-CNV carriers who can participate in research.

Association of Consensus Molecular Subtypes and Molecular Markers With Clinical Outcomes in Patients With Metastatic Colorectal Cancer: Biomarker Analyses From LUME-Colon 1.

Introduction: LUME-Colon 1 (NCT02149108) was a global, placebo-controlled phase III study of nintedanib in advanced colorectal cancer (CRC). Pre-specified biomarker analyses investigated the association of CRC consensus molecular subtypes (CMS) and tumor genomic and circulating biomarkers with clinical outcomes.

Materials And Methods: Archival tumor tissue, cell-free DNA (cfDNA), and plasma samples were collected for genomic, transcriptomic, and proteomic analyses to investigate potential associations between CRC CMS and other biomarkers with nintedanib response and clinical outcomes.

A Belgian consensus strategy to identify familial hypercholesterolaemia in the coronary care unit and its subsequent cascade screening and treatment: BEL-FaHST (The BELgium Familial Hypercholesterolaemia STrategy).

Background And Aims: Familial hypercholesterolaemia (FH) is an autosomal dominant lipoprotein disorder characterized by significant elevation of low-density lipoprotein cholesterol (LDL-C) and markedly increased risk of premature cardiovascular disease (CVD). Because of the very high coronary artery disease risk associated with this condition, the prevalence of FH among patients admitted for CVD outmatches many times the prevalence in the general population. Awareness of this disease is crucial for recognizing FH in the aftermath of a hospitalization of a patient with CVD, and also represents a unique opportunity to identify relatives of the index patient, who are unaware they have FH.

Sacrococcygeal teratoma in a female newborn with clinical features of trisomy 13: a case report from Central Africa.

Introduction: The objective of this report is to describe the first patient presenting clinical features of trisomy 13 in association with a sacrococcygeal teratoma.

Case Presentation: We present the case of a Congolese female infant born with bilateral cleft lip and palate, hypotelorism, microcephaly, and capillary hemangioma on her face. She presented with a large sacrococcygeal mass (15.

Loss of AP-5 results in accumulation of aberrant endolysosomes: defining a new type of lysosomal storage disease.

Adaptor proteins (AP 1-5) are heterotetrameric complexes that facilitate specialized cargo sorting in vesicular-mediated trafficking. Mutations in AP5Z1, encoding a subunit of the AP-5 complex, have been reported to cause hereditary spastic paraplegia (HSP), although their impact at the cellular level has not been assessed. Here we characterize three independent fibroblast lines derived from skin biopsies of patients harbouring nonsense mutations in AP5Z1 and presenting with spastic paraplegia accompanied by neuropathy, parkinsonism and/or cognitive impairment.

Genotypic and phenotypic variation in six patients with solitary median maxillary central incisor syndrome.

Solitary Median Maxillary Central Incisor occurs in 1 of 50,000 live births. It is the mildest manifestation of the holoprosencephaly spectrum and is genetically heterogeneous. Here we report six patients with solitary median maxillary central incisor, and a range of other phenotypic anomalies with different degrees of severity, varying from mild signs of holoprosencephaly to associated intellectual disability, and with different genetic background.

22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion disorder, estimated to result mainly from de novo non-homologous meiotic recombination events occurring in approximately 1 in every 1,000 fetuses.

beta(2)-Adrenergic receptor and adenylate cyclase gene polymorphisms affect sickle red cell adhesion.

Sickle red cell (SS RBC) adhesion is thought to contribute to sickle cell disease (SCD) pathophysiology. SS RBC adhesion to laminin increases in response to adrenaline stimulation of beta(2)-adrenergic receptors (beta(2)ARs) and adenylate cyclase (ADCY6), and previous evidence suggests such activation occurs in vivo. We explored whether polymorphisms of the beta(2)AR and ADCY6 genes (ADRB2 and ADCY6, respectively) affect RBC adhesion to laminin.

Intellectual abilities in a large sample of children with Velo-Cardio-Facial Syndrome: an update.

Background: Learning disabilities are one of the most consistently reported features in Velo-Cardio-Facial Syndrome (VCFS). Earlier reports on IQ in children with VCFS were, however, limited by small sample sizes and ascertainment biases. The aim of the present study was therefore to replicate these earlier findings and to investigate intellectual abilities in a large sample of children with VCFS.

Real-time reverse transcription-PCR and fluorescence in-situ hybridization are complementary to understand the mechanisms involved in HER-2/neu overexpression in human breast carcinomas.

Aims: To evaluate the HER-2/neu status at the mRNA and DNA level of breast carcinomas and to compare it with HER-2/neu receptor overexpression by immunohistochemistry (IHC).

Methods And Results: In 32 invasive breast carcinomas, frozen tissue was available for real-time detection of HER-2/neu mRNA levels by reverse transcription-polymerase chain reaction (RT-PCR). Corresponding paraffin sections were examined by IHC and fluorescence in-situ hybridization (FISH).

Characterization of a double homeodomain protein (DUX1) encoded by a cDNA homologous to 3.3 kb dispersed repeated elements.

Target genes for the helicase-like transcription factor (HLTF), a member of the SNF/SWI family, were immunoprecipitated from HeLa chromatin fragments with an anti-HLTF antibody. A 182 bp fragment ( HEFT1 ) presented 87% sequence identity with 3.3 kb dispersed repeats from the 4q35 D4Z4 locus linked to facioscapulohumeral muscular dystrophy (FSHD).

The meiotic competence of in-vitro matured human oocytes is influenced by donor age: evidence that folliculogenesis is compromised in the reproductively aged ovary.

The human oocyte appears to be particularly prone to meiotic errors, and the incidence of these errors is strongly influenced by maternal age. We have initiated studies of human oocytes from unstimulated ovaries and have observed age-related effects on the meiotic process in oocytes from unselected antral follicles. Specifically, in oocytes obtained from donors over the age of 35 years, the majority of oocytes that extruded a first polar body in culture and arrested at second meiotic metaphase had aberrations in spindle formation and chromosome alignment.

Dibutyryl cAMP inhibits expression of transformation-related properties in Kirsten murine sarcoma virus transformed Balb/c-3T3 cells despite continued presence of p21v-Ki-ras.

We studied the effects of simultaneous treatment with 0.1 mM N6, O2'-dibutyryl cAMP (dbcAMP) and 1 mM theophylline on several transformation-specific properties and on levels of the Kirsten murine sarcoma virus (Ki-MSV) transforming gene product p21v-Ki-ras, in a Ki-MSV-transformed mouse cell line (Balb/c-3T3, clone A31; KA31). The rate of logarithmic growth, cell motility, and final saturation density were reduced in dbcAMP-treated KA31 cultures.