HNF4α, SP1 and c-myc are master regulators of CNS autoimmunity.

Hepatocyte nuclear factor 4 α (HNF4α), a transcription factor (TF) essential for embryonic development, has been recently shown to regulate the expression of inflammatory genes. To characterize HNF4a function in immunity, we measured the effect of HNF4α antagonists on immune cell responses in vitro and in vivo. HNF4α blockade reduced immune activation in vitro and disease severity in the experimental model of multiple sclerosis (MS).

Second-line therapy in pancreatic ductal adenocarcinoma (PDAC) patients with germline BRCA1-2 pathogenic variants (gBRCA1-2pv).

Background: Pancreatic ductal adenocarcinoma (PDAC) harbouring germline BRCA1-2 pathogenic variants (gBRCA1-2pv) is a distinct nosological entity. Information on second-line therapy (2LT) outcome in this setting is lacking.

Methods: Data of gBRCA1-2pv metastatic PDAC patients treated with chemotherapy were collected.

Epidemiology and geographic distribution of BRCA1-2 and DNA Damage response genes pathogenic variants in pancreatic ductal adenocarcinoma patients.

Incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing over the last years, while patients prognosis remains grim. Recently germline BRCA1 and 2 pathogenic variants (gBRCA1-2) have emerged as risk factors for PDAC development, as well as new predictors of response to specific therapeutic interventions. However, data on gBRCA1-2 incidence in PDAC are currently sparse and limited to selected categories of patients, as for positive cancer history cases, for patients affected only by early or late stages of disease and mainly from the North-American population, thus generating incomplete information about the gBRCA1/2 epidemiology.

Treatment opportunities and future perspectives for pancreatic cancer patients with germline BRCA1-2 pathogenic variants.

Personalized treatments and predictive biomarkers of pancreatic cancer (PDAC) are still lacking. Recently germline mutations in BRCA 1 and 2 genes, leading to homologous repair deficiency, have emerged as new targets for more specific and effective therapies, exploiting the increased susceptibility to platinum salts and PARP inhibitors. In addition to BRCA, pathogenic variants in PALB2 and in other genes involved in the DNA damage response pathway (DDR) represent potential targets, as well as their respective somatic alterations.

Exploring chemotherapy holiday and drugs re-challenge in advanced pancreatic cancer patients.

Purpose: We aimed to explore the role of drugs re-challenge at the disease progression after a chemotherapy-free interval for pancreatic adenocarcinoma (PDAC) patients.

Methods: We retrospectively analyzed the outcome of re-treatments at the progression in two cohorts of advanced PDAC patients who had disease control (DC) and a treatment holiday ≥ 3 months after upfront chemotherapy.

Results: Between 2015 and 2019, 66 advanced PDAC patients (cohort A) had DC with nab-paclitaxel-based chemotherapy (i.

Multidrug regimens for treatment of older patients with metastatic pancreatic cancer.

Background And Aims: Older patients with metastatic pancreatic adenocarcinoma (MPDAC) are under-represented in clinical trials.

Methods: Our single-center, retrospective study enrolled MPDAC patients ≥ 70 treated with chemotherapy RESULTS: 105 patients were divided in groups based on the received treatments: 44 gemcitabine or capecitabine monotherapy (A), 34 nabpaclitaxel-gemcitabine (B) 27 4-drugs combinations (gemcitabine, cisplatin, capecitabine plus either nab-paclitaxel or epirubicin or docetaxel) (C). Group A: median age was 78 (70-87) and Karnofsky performance status (KPS) ≥80 was found in 84% of patients; Group B: median age 77 (71-84) and KPS ≥ 80 in 88% of patients; Group C: median age 73 (70-78) and KPS ≥ 80 in 93% of patients.

MECP2 mutations affect ciliogenesis: a novel perspective for Rett syndrome and related disorders.

Mutations in MECP2 cause several neurological disorders of which Rett syndrome (RTT) represents the best-defined condition. Although mainly working as a transcriptional repressor, MeCP2 is a multifunctional protein revealing several activities, the involvement of which in RTT remains obscure. Besides being mainly localized in the nucleus, MeCP2 associates with the centrosome, an organelle from which primary cilia originate.

Role of human forkhead box P3 in early thymic maturation and peripheral T-cell homeostasis.

Background: Forkhead box P3 (FOXP3) is a key transcription factor in regulatory T (Treg) cell function. FOXP3 gene mutations cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, a fatal autoimmune syndrome. FOXP3 has also been proposed to act in effector T (Teff) cells, but to date, this role has not been confirmed.

The MMP-1/PAR-1 Axis Enhances Proliferation and Neuronal Differentiation of Adult Hippocampal Neural Progenitor Cells.

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that play a role in varied forms of developmental and postnatal neuroplasticity. MMP substrates include protease-activated receptor-1 (PAR-1), a G-protein coupled receptor expressed in hippocampus. We examined proliferation and differentiation of adult neural progenitor cells (aNPCs) from hippocampi of mice that overexpress the potent PAR-1 agonist MMP-1.

Upregulation of mGlu2 receptors via NF-κB p65 acetylation is involved in the Proneurogenic and antidepressant effects of acetyl-L-carnitine.

Acetyl-L-carnitine (ALC) is a naturally occurring molecule with an important role in cellular bioenergetics and as donor of acetyl groups to proteins, including NF-κB p65. In humans, exogenously administered ALC has been shown to be effective in mood disturbances, with a good tolerability profile. No current information is available on the antidepressant effect of ALC in animal models of depression and on the putative mechanism involved in such effect.

α2δ ligands act as positive modulators of adult hippocampal neurogenesis and prevent depression-like behavior induced by chronic restraint stress.

Although the role of adult hippocampal neurogenesis remains to be fully elucidated, several studies suggested that the process is involved in cognitive and emotional functions and is deregulated in various neuropsychiatric disorders, including major depression. Several psychoactive drugs, including antidepressants, can modulate adult neurogenesis. Here we show for the first time that the α2δ ligands gabapentin [1-(aminomethyl)cyclohexaneacetic acid] and pregabalin (PGB) [(S)-(+)-3-isobutyl-GABA or (S)-3-(aminomethyl)-5-methylhexanoic acid] can produce concentration-dependent increases in the numbers of newborn mature and immature neurons generated in vitro from adult hippocampal neural progenitor cells and, in parallel, a decrease in the number of undifferentiated precursor cells.