Frontline treatment and resultant cure rates in patients with advanced ovarian cancer have changed little over the past several decades. Here, we outline a multidisciplinary approach aimed at gaining ...novel therapeutic insights by focusing on the poorly understood minimal residual disease phase of ovarian cancer that leads to eventual incurable recurrences.
Abstract Objectives To assess the association between clinical and socio-demographic features and anti-Parkinson drug (APD) treatment modifications in patients with PD and to describe neurologist and ...patient opinions regarding the need for changes in APD therapy. Methods Subjects with PD with stable APD treatment over ≥3 months prior to baseline were enrolled and evaluated for socio-demographic data, disability, disease severity and neurologist and patient views on the need to modify APD treatment. Results 775 Patients were included, 51% with Hoehn and Yahr (HY) stage 1–2 (early PD) and 49% with HY stage 2.5–4 (advanced PD). Neurologists modified APD treatment in 255 patients, 97 (25%) early PD and 158 (41%; p < 0.0001) advanced PD. APD modification was strongly associated with a low educational level and UPDRS part IV score. The most common reasons behind the APD therapy changes among neurologists were presence/worsening of motor or non-motor symptoms (88% and 37% of subjects respectively). Out of 216 patients, 92% and 51% were willing to undergo APD changes to therapy because of the presence/worsening of motor or non-motor symptoms. Conclusions Neurologist decision to change APD therapy and patients reasons for dissatisfaction with it can be prevalently attributed to the presence/worsening of motor symptoms and motor fluctuations in the advanced stages. Non-motor symptoms were considered more often by patients. The patient educational level played a key role in treatment decision.
Impairment of endosomal/lysosomal functions are reported as some of the earliest changes in several age-related neurological disorders such as Alzheimer’s disease. Dysregulation of the lysosomal ...system is also accompanied by the accumulation of age-associated pigments and several recent reports have indicated that this age-related lipofuscin accumulation can sensitize cells to oxidative stress and apoptotic cell death. In this study, we have established and evaluated an
in vitro age-related pathology paradigm that models lipofuscin accumulation. Our model consists of the treatment of cultured primary mouse neurons with lysosomotropic detergents. We have observed that one of the earliest biochemical changes associated with lysosomotropic detergent-induced membrane instability is a loss of the endosomal/lysosomal proton gradient integrity, followed by an activation of sphingomyelin hydrolysis and ceramide accumulation within enlarged endosomal/lysosomal vesicles. In addition, we demonstrate that ceramide accumulation correlates with the activation of proximal procaspases-8 and -9 as well as distal caspase-3, prior to the appearance of cell death. Taken together, we propose that disturbances of the endosomal/lysosomal system, in addition to the activation of the sphingomyelinase hydrolysis cycle, play essential roles in the course of post-mitotic neuronal aging. The abnormal accumulation of undigested lipids and proteins within dysfunctional endosomal/lysosomal vesicle populations during the process of pathological aging may serve as triggers of the cell death programs that are associated with downstream neurodegeneration.
Dans les couches aurignaciennes de la Grotte de Fumane (Préalpes de la Vénétie), les fouilles ont mis au jour cinq fragments rocheux détachés des parois. En partie couverts de concrétions au moment ...de la découverte, ils portent des traces de peinture à l’ocre rouge (un être humain schématique à la tête surmontée de deux cornes, un animal à quatre pattes, trois motifs à l’interprétation difficile). À la base des couches aurignaciennes, deux taches de sédiment intensément rougi par la présence d’ocre sont datées autour de 35 500 B.P. (nouvelles datations
14C réalisées au Laboratoire d’Oxford par le prétraitement ABOx). Dans le cadre de l’art aurignacien, ces datations peuvent expliquer le caractère « primitif » de ces réalisations, au même titre que la fonction d’habitat de la grotte.
In the Aurignacian layers of the Fumane Cave (Venetian Pre-Alps), the excavations have shown five rocky fragments detached from the walls, at the time of the discovery, they were partially covered by concretions, that consist of the traces of paintings made with the red ochre (a schematic human with the head surmounted by two horns, a four-legged animal, three motifs of difficult interpretation). At the basis of the Aurignacian layers, two spots of sediment intensely blushed for the presence of ochre are dated around 35,500 B.P. (new datings
14C achieved at the Laboratory of Oxford by the ABOx pre-treatment method). In the setting of the aurignacian art, these datings can explain the “primitive” character of these realizations, for the same reason as the function of the inhabited cave.
Presenilins are polytopic, integral proteins that control intramembranous proteolysis at the "gamma-" and "epsilon-" cleavage sites of the Alzheimer amyloid-beta precursor protein (APP) to yield ...amyloid-beta peptide (Abeta) and the APP intracellular domain (AICD). We have overexpressed a constitutively active, pathogenic form of PS1 (known as PS1 Delta exon 9) together with its substrate, APP-C99, in Spodoptera frugiperda (Sf9) cells. Sf9 cells have been reported to lack endogenous gamma-secretase, an unexpected finding since there exists an insect homologue of PS1. In our hands, neither intact insect cells coexpressing PS1 Delta exon 9/APP-C99 nor the aqueous homogenates of these cells displayed obvious products of the gamma- or epsilon-secretase reactions, as reported. Surprisingly, when APP-C99-expressing cells were homogenized in 3(3-cholamidopropyl) dimethylammonio-2-hydroxypropanesulfonic acid (CHAPSO), a detergent known to support gamma-secretase activity, subsequent incubation led to the accumulation of an AICD-like peptide (AICD-L). Aspartyl proteinase inhibitors were effective in preventing the appearance of AICD-L, but inhibitors of other classes of proteinases were ineffective. Immunoprecipitation-mass spectrometry of AICD-L revealed its identity as the minor of the two known AICDs.
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