Anti-prion Drugs Targeting the Protein Folding Activity of the Ribosome Reduce PABPN1 Aggregation

Prion diseases are caused by the propagation of PrP^Sc, the pathological conformation of the PrP^C prion protein. The molecular mechanisms underlying PrP^Sc propagation are still unsolved and no therapeutic solution is currently available. We thus sought to identify new anti-prion molecules and found that flunarizine inhibited PrP^Sc propagation in cell culture and significantly prolonged survival of prion-infected mice. Using an in silico therapeutic repositioning approach based on similarities with flunarizine chemical structure, we tested azelastine, duloxetine, ebastine, loperamide and metixene and showed that they all have an anti-prion activity. Like flunarizine, these marketed drugs reduced PrP^Sc propagation in cell culture and in mouse cerebellum organotypic slice culture, and inhibited the protein folding activity of the ribosome (PFAR). Strikingly, some of these drugs were also able to alleviate phenotypes due to PABPN1 nuclear aggregation in cell and Drosophila models of oculopharyngeal muscular dystrophy (OPMD). These data emphasize the therapeutic potential of anti-PFAR drugs for neurodegenerative and neuromuscular proteinopathies.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-020-00992-6.Key Words: Prions, PrP^Sc, drug repositioning, PFAR, OPMD, PABPN1     

Peripheral blood natural killer cell count is associated with clinical outcome in patients with aaIPI 2-3 diffuse large B-cell lymphoma.

BACKGROUND: Lymphocytopenia is a prognostic factor in Hodgkin's disease. In diffuse large B-cell lymphoma (DLBCL), data are much less established, in spite of numerous reports on immune system-lymphoma interactions. This study addresses the prognostic value of blood lymphocyte subsets at diagnosis in DLBCL. PATIENTS AND METHODS: Absolute values of blood lymphocyte subsets and monocytes were prospectively determined by flow cytometry in 140 patients with 2 or 3 adverse age-adjusted International Prognostic Index (aaIPI) factors included in a Groupe d'Etude des Lymphomes de l'Adulte protocol (LNH98B3). Absolute cell counts at diagnosis and aaIPI were evaluated with regard to clinical outcome. RESULTS: Low median cell counts of 337, 211, and 104/mul were evidenced for the CD4+, CD8+ T, and natural killer (NK) cells, respectively. In univariate analysis, only NK cell count [odds ratio (OR) = 1.81 (1.27, 2.57), P = 0.001] and aaIPI [OR = 2.29 (0.95, 5.45), P = 0.06] were associated with induction treatment response. Low NK cell count [Hazard ratio (HR) = 1.27 (1.06, 1.52), P = 0.01] and aaIPI 3 [HR = 1.95 (1.20, 3.16), P = 0.01] were also associated with a shorter event free survival (EFS). In multivariate analysis, NK cell count was associated with response [OR = 1.77 (1.24, 2.54), P = 0.002] and EFS [HR = 1.25 (1.04, 1.50) P = 0.02] independently of aaIPI. CONCLUSIONS: This study shows an association between circulating NK cell number and clinical outcome in DLBCL, possibly important in the context of the broadening use of rituximab, a likely NK-dependent therapy.     

Enamel reduction procedures in orthodontic treatment

Various combinations of enamel reduction procedures can be used to create space between teeth, to correct discrepancies between mandibular and maxillary teeth and to correct morphologic anomalies during orthodontic treatment. In particular, acid-enhanced interproximal enamel reduction significantly reduces surface roughness. This article presents a review of the literature on enamel reduction procedures.     

Adenoviral-mediated gene transfer of vascular endothelial growth factor in critical limb ischemia: safety results from a phase I trial

Critical limb ischemia (CLI) is typified by rest pain and/or tissue necrosis secondary to advanced peripheral arterial disease (PAD) and is characterized by diminution in limb perfusion at rest. We tested the safety of an angiogenic strategy with CI-1023 (Ad(GV)VEGF121.10), a replication-deficient adenovirus encoding human vascular endothelial growth factor isoform 121 in patients with CLI as part of a phase I trial. Fifteen subjects >35 years of age with CLI and angiographic disease involving the infra-inguinal vessels underwent intramuscular injection of CI-1023 (4 x 10(8) to 4 x 10(10) particle units, n = 13) or placebo (n = 2). All of the patients tolerated the injection well and there were no serious complications related to the procedure. Transient edema was noted in one patient. A total of 79 adverse events were reported over the course of one year. One death (day 136) and one malignancy (day 332) occurred in the CI-1023 group. CI-1023 appears to be well tolerated and safe for single-dose administration in patients with critical limb ischemia due to PAD. Further studies are needed to determine the efficacy of this form of therapeutic angiogenesis.     

Evidence and mechanisms of retrogenesis in Alzheimer's and other dementias: management and treatment import

Retrogenesis is the process by which degenerative mechanisms reverse the order of acquisition in normal development. Alzheimer's disease (AD) and related conditions in the senium have long been noted to resemble "a return to childhood" Previously, we noted that the functional stages of AD precisely and remarkably recapitulated the acquisition of the same functional landmarks in normal human development. Subsequent work indicated that this developmental recapitulation also applied to the cognitive and related symptoms in AD. Remarkably, further investigations revealed that the same neurologic "infantile" reflexes, which mark the emergence from infancy in normal development, are equally robust indicators of corresponding stages in AD. Neuropathologic and biomolecular mechanisms for these retrogenic processes are now evident. For example, the pattern of myelin loss in AD appears to mirror the pattern of myelin acquisition in normal development. Also, recent findings indicate that mitogenic factors become reactivated in AD, and, consequently, the most actively "growing" brain regions are the most vulnerable. Because of this robust retrogenic process, the stages of AD can be translated into corresponding developmental ages (DAs). These DAs can account for the overall management and care needs of AD patients. A science of AD management can be formulated on the basis of the DA of the Alzheimer's patient, taking into consideration differences of AD from normal development as well as homologies.     

A novel ultrasound method for evaluation of collateral development in limb ischemia

Although clinical studies are underway to evaluate the effectiveness of angiogenesis, there are no validated, non-invasive methods to assess peripheral collateral development. This study was performed to validate a novel ultrasound-based method of assessing collateral formation in a pig model of hindlimb ischemia. Ultrasonography of predefined ultrasound planes was performed on 12 pigs immediately after ligation of the right common femoral artery, and 7, 14, 28 and 42 days thereafter. A custom software program was used to evaluate both color Doppler (CD) and power Doppler (PD) images to generate flow indices. Collateral development was observed with ultrasound as early as 7 days post-arteriectomy and increased dramatically by 28 days. Areas of persistent ischemia resulting from inadequate collateral formation were easily quantified in all images. Collaterals detected on ultrasound were confirmed by angiography and histology, and tissue perfusion by a fluorescent microsphere method. As demonstrated with color and power Doppler measurements, collateral formation is initiated early after ischemic injury in this large juvenile animal model of angiogenesis. This non-invasive method is useful to quantify blood flow, visualize angiogenesis and determine areas of persistent lower limb ischemia, and may have an important role in evaluating new approaches to modulate angiogenesis.