Multicenter Evaluation of the Idylla GeneFusion in Non-Small-Cell Lung Cancer.

Targeted therapy in lung cancer requires the assessment of multiple oncogenic driver alterations, including fusion genes. This retrospective study evaluated the Idylla GeneFusion prototype, an automated and ease-of-use (<2 minutes) test, with a short turnaround time (3 hours) to detect fusions involving ALK, ROS1, RET, and NTRK1/2/3 genes and MET exon 14 skipping. This multicenter study (18 centers) included 313 tissue samples from lung cancer patients with 97 ALK, 44 ROS1, 20 RET, and 5 NTRKs fusions, 32 MET exon 14 skipping, and 115 wild-type samples, previously identified with reference methods (RNA-based next-generation sequencing/fluorescence in situ hybridization/quantitative PCR).

Age-related changes in the BACH2 and PRDM1 genes in lymphocytes from healthy donors and chronic lymphocytic leukemia patients.

Background: Age-related genetic changes in lymphocyte subsets are not currently well documented. BACH2 is a transcription factor that plays an important role in immune-mediated homeostasis by tightly regulating PRDM1 expression in both B-cells and T-cells. BACH2 gene expression is highly sensitive to DNA damage in aged mice.

Paracrine nitric oxide induces expression of cardiac sarcomeric proteins in adult progenitor cells through soluble guanylyl cyclase/cyclic-guanosine monophosphate and Wnt/β-catenin inhibition.

Aim: Cardiac progenitor cells (CPC) from adult hearts can differentiate to several cell types composing the myocardium but the underlying molecular pathways are poorly characterized. We examined the role of paracrine nitric oxide (NO) in the specification of CPC to the cardiac lineage, particularly through its inhibition of the canonical Wnt/β-catenin pathway, a critical step preceding cardiac differentiation.

Methods And Results: Sca1 + CPC from adult mouse hearts were isolated by magnetic-activated cell sorting and clonally expanded.

p53 Reactivation by PRIMA-1(Met) (APR-246) sensitises (V600E/K)BRAF melanoma to vemurafenib.

Intrinsic and acquired resistance of metastatic melanoma to (V600E/K)BRAF and/or MEK inhibitors, which is often caused by activation of the PI3K/AKT survival pathway, represents a major clinical challenge. Given that p53 is capable of antagonising PI3K/AKT activation we hypothesised that pharmacological restoration of p53 activity may increase the sensitivity of BRAF-mutant melanoma to MAPK-targeted therapy and eventually delay and/or prevent acquisition of drug resistance. To test this possibility we exposed a panel of vemurafenib-sensitive and resistant (innate and acquired) (V600E/K)BRAF melanomas to a (V600E/K)BRAF inhibitor (vemurafenib) alone or in combination with a direct p53 activator (PRIMA-1(Met)/APR-246).

Consanguinity Protecting Effect Against Breast Cancer among Tunisian Women: Analysis of BRCA1 Haplotypes.

The purpose of this study is to assess the effect of consanguinity on breast cancer incidence in Tunisia. We conducted a case-control study to evaluate the involvement of heterozygote and homozygote haplotypes of BRCA1 gene SNPs according to consanguinity among 40 cases of familial breast cancer, 46 cases with sporadic breast cancer and 34 healthy controls. We showed significant difference in consanguinity rate between breast cancer patients versus healthy controls P = 0.

Myofibroblastoma of the breast with smooth muscle differentiation showing deletion of 13q14 region: report of a case.

Breast myofibroblastomas are rare benign mesenchymal tumors belonging to the group of stromal breast tumors composed of spindle-shaped cells and characterized by a broad morphologic spectrum. Among the different morphologic variants described, breast MFBs can show smooth muscle cell differentiation in very rare cases. In terms of the genetic abnormalities found in this type of tumor, a deletion of chromosome 13q14 was recently confirmed by FISH in some cases of mammary MFB.

CD4⁺ follicular helper T cell infiltration predicts breast cancer survival.

CD4⁺ T cells are critical regulators of immune responses, but their functional role in human breast cancer is relatively unknown. The goal of this study was to produce an image of CD4⁺ T cells infiltrating breast tumors using limited ex vivo manipulation to better understand the in vivo differences associated with patient prognosis. We performed comprehensive molecular profiling of infiltrating CD4⁺ T cells isolated from untreated invasive primary tumors and found that the infiltrating T cell subpopulations included follicular helper T (Tfh) cells, which have not previously been found in solid tumors, as well as Th1, Th2, and Th17 effector memory cells and Tregs.

Molecular profiling of CD3-CD4+ T cells from patients with the lymphocytic variant of hypereosinophilic syndrome reveals targeting of growth control pathways.

The clonal CD3(-)CD4(+) T-cell population characterizing lymphocytic variant hypereosinophilic syndrome (L-HES) persists for years, with a subgroup of patients ultimately progressing to T lymphoma. The molecular changes associated with the premalignant clone and the emergence of malignant subclones are unknown, precluding the development of targeted therapy for this HES variant. In this study, we used whole genome arrays to examine gene expression in the CD3(-)CD4(+) T cells and found that 850 genes were differentially regulated during chronic disease compared with CD3(+)CD4(+) T cells from healthy donors.

Current limitations to the histopathological diagnosis of some frequently encountered bone tumours.

The final diagnosis of a bone tumour comes in many cases like the last piece of a puzzle which requires integration of clinical, imaging and pathological data. However there are situations in which a discrepancy exists between histology and imaging studies and where histology alone cannot be decisive. This paper reviews such situations.

Partial proximal 10q trisomy: a new case associated with biliary atresia.

Herein we describe a unique case of partial proximal 10q trisomy presenting biliary atresia, anal anteposition and cardiac malformation. The 10q duplication was confirmed by G banding on prophase chromosomes. A review of the literature confirmed that the patient displayed characteristic dysmorphic features of the recently defined partial proximal trisomy 10q syndrome and emphasized the interindividual variability of visceral malformations.

Human skin fibroblasts: From mesodermal to hepatocyte-like differentiation.

The phenotypic homology of fibroblasts and mesenchymal stem cells (MSCs) has been recently described. Our study investigated the in vitro potential of human skin fibroblasts to differentiate into mesodermal (osteocyte and adipocyte) and endodermal (hepatocyte) cell lineages by comparison with human bone marrow (hBM) MSCs. The endodermal potential of fibroblasts was then explored in vivo in a mouse model of liver injury.

Retinoblastoma and deletion of the long arm of chromosome 13: an underestimated diagnosis?

We report an infant with normal neurological development and phenotype who developed bilateral retinoblastoma (RB). This patient, despite lack of dysmorphic features, demonstrated constitutional abnormality of the long arm of chromosome 13 on standard karyotype. We recommend systematic cytogenetic examinations complemented by fluorescent in situ hybridization as second-line screening in all patients suspected for hereditary RB despite negative RB1 molecular screening and normal phenotype.

Sustained engraftment and tissue enzyme activity after liver cell transplantation for argininosuccinate lyase deficiency.

Background & Aims: Donor cell engraftment with expression of enzyme activity is the goal of liver cell transplantation for inborn errors of liver metabolism with a view to achieving sustained metabolic control.

Methods: Sequential hepatic cell transplantations using male and female cells were performed in a 3.5-year-old girl with argininosuccinate lyase deficiency over a period of 5 months.

Unilateral retinoblastoma, lack of familial history and older age does not exclude germline RB1 gene mutation.

Conclusive identification of RB1 mutations in retinoblastoma is predicted to improve the clinical management of affected children and relatives. However, despite clear clinical benefits, RB1 screening remains difficult, most of the alterations being unique and randomly distributed throughout the entire coding sequence. In this report, we present the results of a constitutional RB1 analysis undertaken in our institution over the last four years.

Defective CD3gamma gene transcription is associated with NFATc2 overexpression in the lymphocytic variant of hypereosinophilic syndrome.

Objective: Determine the molecular defects underlying the CD3(-)CD4(+) T-cell phenotype and persistence of this clonal population in patients with hypereosinophilic syndrome.

Patients And Methods: Patients in this study suffer from the lymphocytic variant of hypereosinophilic syndrome distinguished by a CD3(-)CD4(+) T-cell clone that overexpresses Th2 cytokines upon activation and thereby provokes the eosinophilia. Interleukin-2-dependent CD3(-)CD4(+) T-cell lines were derived from patient blood at various disease stages and used to investigate the molecular modifications correlated with their abnormal phenotype.

6q- is an early and persistent chromosomal aberration in CD3-CD4+ T-cell clones associated with the lymphocytic variant of hypereosinophilic syndrome.

Background And Objectives: The lymphocytic variant of hypereosinophilic syndrome (LV-HES) is an underrated disease defined by the monoclonal proliferation of interleukin-5 secreting T-cells. This disease is distinguished by a period of chronic lymphoproliferation without clinical transformation, which is frequently a precursor to T-cell lymphoma. In this study, LV-HES was used as a model of pre-malignancy to identify specific marker(s) predictive of the potential for malignant transformation.

CD4(+), CD56(+) DC2 acute leukemia is characterized by recurrent clonal chromosomal changes affecting 6 major targets: a study of 21 cases by the Groupe Français de Cytogénétique Hématologique.

CD4(+), CD56(+) DC2 malignancies constitute a novel disease entity, which has recently been shown to arise from a transformed lymphoid-related plasmacytoid dendritic cell (DC2). Diagnosis is primarily based on a particular immunophenotype with tumor cells expressing CD4 and CD56 antigens in the absence of common lymphoid or myeloid lineage markers. Little is currently known about the cytogenetic features of this disease entity.