Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson-Gilford Progeria Syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disorder characterized by premature aging features. Cells from HGPS patients express progerin, a truncated form of Lamin A, which perturbs cellular homeostasis leading to nuclear shape alterations, genome instability, heterochromatin loss, telomere dysfunction and premature entry into cellular senescence. Recently, we reported that telomere dysfunction induces the transcription of telomeric non-coding RNAs (tncRNAs) which control the DNA damage response (DDR) at dysfunctional telomeres.

CXCR3 Identifies Human Naive CD8 T Cells with Enhanced Effector Differentiation Potential.

In mice, the ability of naive T (T) cells to mount an effector response correlates with TCR sensitivity for self-derived Ags, which can be quantified indirectly by measuring surface expression levels of CD5. Equivalent findings have not been reported previously in humans. We identified two discrete subsets of human CD8 T cells, defined by the absence or presence of the chemokine receptor CXCR3.

Association of Genomic Domains in and with Prostate Cancer Risk and Aggressiveness.

Pathogenic sequence variants (PSV) in or () are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 and 171 male PSV carriers with prostate cancer, and 3,388 and 2,880 male PSV carriers without prostate cancer. PSVs in the 3' region of (c.

Correction: Dual role for miR-34a in the control of early progenitor proliferation and commitment in the mammary gland and in breast cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The :p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes , , , , and are associated with breast cancer risk. , which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes.

Correction to: A practical algorithmic approach to mature aggressive B cell lymphoma diagnosis in the double/triple hit era: selecting cases, matching clinical benefit.

The first and family names of the authors were interchanged and are now presented correctly. The original article has been corrected.

Tuning mTORC1 activity dictates the response of acute myeloid leukemia to LSD1 inhibition.

Lysine specific demethylase-1 (LSD1) has been shown to be critical in acute myeloid leukemia (AML) pathogenesis and this has led to the development of LSD1 inhibitors (LSD1i) which are currently tested in clinical trials. Nonetheless, preclinical studies reported that AML cells frequently exhibit intrinsic resistance to LSD1 inhibition, and the molecular basis for this phenomenon is largely unknown. We explored the potential involvement of mammalian target of rapamycin (mTOR) in mediating the resistance of leukemic cells to LSD1i.

Two truncating variants in FANCC and breast cancer risk.

Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies.

A practical algorithmic approach to mature aggressive B cell lymphoma diagnosis in the double/triple hit era: selecting cases, matching clinical benefit : A position paper from the Italian Group of Haematopathology (G.I.E.).

An accurate diagnosis of clinically distinct subgroups of aggressive mature B cell lymphomas is crucial for the choice of proper treatment. Presently, precise recognition of these disorders relies on the combination of morphological, immunophenotypical, and cytogenetic/molecular features. The diagnostic workup in such situations implies the application of costly and time-consuming analyses, which are not always required, since an intensified treatment option is reasonably reserved to fit patients.

The Role of Prep1 in the Regulation of Mesenchymal Stromal Cells.

Molecular mechanisms governing cell fate decision events in bone marrow mesenchymal stromal cells (MSC) are still poorly understood. Herein, we investigated the homeobox gene as a candidate regulatory molecule, by adopting hypomorphic mice as a model to investigate the effects of downregulation, using in vitro and in vivo assays, including the innovative single cell RNA sequencing technology. Taken together, our findings indicate that low levels of are associated to enhanced adipogenesis and a concomitant reduced osteogenesis in the bone marrow, suggesting Prep1 as a potential regulator of the adipo-osteogenic differentiation of mesenchymal stromal cells.

Endothelial cell clonal expansion in the development of cerebral cavernous malformations.

Cerebral cavernous malformation (CCM) is a neurovascular familial or sporadic disease that is characterised by capillary-venous cavernomas, and is due to loss-of-function mutations to any one of three CCM genes. Familial CCM follows a two-hit mechanism similar to that of tumour suppressor genes, while in sporadic cavernomas only a small fraction of endothelial cells shows mutated CCM genes. We reported that in mouse models and in human patients, endothelial cells lining the lesions have different features from the surrounding endothelium, as they express mesenchymal/stem-cell markers.

Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers.

Background: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown.

Methods: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants.

Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis.

Tumor cells may adapt to metabolic challenges by alternating between glycolysis and oxidative phosphorylation (OXPHOS). To target this metabolic plasticity, we combined intermittent fasting, a clinically feasible approach to reduce glucose availability, with the OXPHOS inhibitor metformin. In mice exposed to 24-h feeding/fasting cycles, metformin impaired tumor growth only when administered during fasting-induced hypoglycemia.

Correction to: DNA Damage In situ Ligation followed by Proximity Ligation Assay (DI-PLA).

Work in Fabrizio d'Adda di Fagagna's laboratory is supported by the Associazione Italiana per la Ricerca sul Cancro, AIRC (application 12971), Cariplo Foundation (grant 2010.0818 and 2014-0812), Fondazione Telethon (GGP12059 and GGP17111), Association for International Cancer Research (AICR-Worldwide Cancer Research Rif. N.

Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer.

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function.

FM19G11-Loaded Gold Nanoparticles Enhance the Proliferation and Self-Renewal of Ependymal Stem Progenitor Cells Derived from ALS Mice.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. In ALS mice, neurodegeneration is associated with the proliferative restorative attempts of ependymal stem progenitor cells (epSPCs) that normally lie in a quiescent in the spinal cord. Thus, modulation of the proliferation of epSPCs may represent a potential strategy to counteract neurodegeneration.

F-actin dynamics regulates mammalian organ growth and cell fate maintenance.

Background & Aims: In vitro, cell function can be potently regulated by the mechanical properties of cells and of their microenvironment. Cells measure these features by developing forces via their actomyosin cytoskeleton, and respond accordingly by regulating intracellular pathways, including the transcriptional coactivators YAP/TAZ. Whether mechanical cues are relevant for in vivo regulation of adult organ homeostasis, and whether this occurs through YAP/TAZ, remains largely unaddressed.

Identification and clinical validation of a multigene assay that interrogates the biology of cancer stem cells and predicts metastasis in breast cancer: A retrospective consecutive study.

Background: Breast cancers show variations in the number and biological aggressiveness of cancer stem cells that correlate with their clinico-prognostic and molecular heterogeneity. Thus, prognostic stratification of breast cancers based on cancer stem cells might help guide patient management.

Methods: We derived a 20-gene stem cell signature from the transcriptional profile of normal mammary stem cells, capable of identifying breast cancers with a homogeneous profile and poor prognosis in in silico analyses.

The genetics and the molecular functions of the PREP1 homeodomain transcription factor.

Prep1 (pKnox1) is a homeodomain transcription factor of the TALE superclass whose members can act as co-factors of Hox. Prep1 is essential for embryogenesis, but in the adult it also acts as a tumor suppressor. We describe and analyze here the available mutant mice, their phenotypes and a few discordant cases.

Fine-Tuning of Sox17 and Canonical Wnt Coordinates the Permeability Properties of the Blood-Brain Barrier.

Rationale: The microvasculature of the central nervous system includes the blood-brain barrier (BBB), which regulates the permeability to nutrients and restricts the passage of toxic agents and inflammatory cells. Canonical Wnt/β-catenin signaling is responsible for the early phases of brain vascularization and BBB differentiation. However, this signal declines after birth, and other signaling pathways able to maintain barrier integrity at postnatal stage are still unknown.

Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes.

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets.

Biochemical Characterization of AroH, a Putative Aromatic Amino Acid Aminotransferase.

The rise in the frequency of nosocomial infections is becoming a major problem for public health, in particular in immunocompromised patients. is an opportunistic fungus normally present in the environment directly responsible for lethal invasive infections. Recent results suggest that the metabolic pathways related to amino acid metabolism can regulate the fungus-host interaction and that an important role is played by enzymes involved in the catabolism of L-tryptophan.

DNA Damage In Situ Ligation Followed by Proximity Ligation Assay (DI-PLA).

Cells have evolved DNA repair mechanisms to maintain their genetic information unaltered and a DNA damage response pathway that coordinates DNA repair with several cellular events. Despite a clear role for DNA damage in the form of DNA double-strand breaks (DSBs) in several cellular processes, the most commonly used methods to detect DNA lesions are indirect, and rely on antibody-based recognition of DNA damage-associated factors, leaving several important questions unanswered. Differently, here we describe DNA damage In situ ligation followed by Proximity Ligation Assay (DI-PLA), that allows sensitive detection of physical DSBs in fixed cells, through direct labeling of the DSBs with biotinylated oligonucleotides, and subsequent signal amplification by PLA between biotin and a partner protein in the proximity of the DNA break.

Identification of nephropathy predictors in urine from children with a recent diagnosis of type 1 diabetes.

Despite research progresses, the chance to accurately predict the risk for diabetic nephropathy (DN) is still poor. So far, the first evidence of DN is micro-albuminuria, which is detected only 10-20 years after the onset of diabetes. Our goal is to develop new predictive tools of nephropathy starting from urine, which can be easily obtained using noninvasive procedures and it is directly related to kidney.