Predictive Potential of RNA Polymerase B (II) Subunit 1 (RPB1) Cytoplasmic Aggregation for Neoadjuvant Chemotherapy Failure

We aimed to investigate the contribution of co-translational protein aggregation to the chemotherapy resistance of tumor cells. Increased co-translational protein aggregation reflects altered translation regulation that may have the potential to buffer transcription under genotoxic stress. As an indicator for such an event, we followed the cytoplasmic aggregation of RPB1, the aggregation-prone largest subunit of RNA polymerase II, in biopsy samples taken from patients with invasive carcinoma of no special type. RPB1 frequently aggregates co-translationally in the absence of proper HSP90 chaperone function or in ribosome mutant cells as revealed formerly in yeast. We found that cytoplasmic foci of RPB1 occur in larger sizes in tumors that showed no regression after therapy. Based on these results, we propose that monitoring the cytoplasmic aggregation of RPB1 may be suitable for determining—from biopsy samples taken before treatment—the effectiveness of neoadjuvant chemotherapy

Cerebrovascular Pathology in Hypertriglyceridemic APOB-100 Transgenic Mice

Hypertriglyceridemia is not only a serious risk factor in the development of cardiovascular diseases, but it is linked to neurodegeneration, too. Previously, we generated transgenic mice overexpressing the human APOB-100 protein, a mouse model of human atherosclerosis. In this model we observed high plasma levels of triglycerides, oxidative stress, tau hyperphosphorylation, synaptic dysfunction, cognitive impairment, increased neural apoptosis and neurodegeneration. Neurovascular dysfunction is recognized as a key factor in the development of neurodegenerative diseases, but the cellular and molecular events linking cerebrovascular pathology and neurodegeneration are not fully understood. Our aim was to study cerebrovascular changes in APOB-100 transgenic mice. We described the kinetics of the development of chronic hypertriglyceridemia in the transgenic animals. Increased blood-brain barrier permeability was found in the hippocampus of APOB-100 transgenic mice which was accompanied by structural changes. Using transmission electron microscopy, we detected changes in the brain capillary endothelial tight junction structure and edematous swelling of astrocyte endfeet. In brain microvessels isolated from APOB-100 transgenic animals increased Lox-1, Aqp4, and decreased Meox-2, Mfsd2a, Abcb1a, Lrp2, Glut-1, Nos2, Nos3, Vim, and in transgenic brains reduced Cdh2 and Gfap-σ gene expressions were measured using quantitative real-time PCR. We confirmed the decreased P-glycoprotein (ABCB1) and vimentin expression related to the neurovascular unit by immunostaining in transgenic brain sections using confocal microscopy. We conclude that in chronic hypertriglyceridemic APOB-100 transgenic mice both functional and morphological cerebrovascular pathology can be observed, and this animal model could be a useful tool to study the link between cerebrovascular pathology and neurodegeneration

BC-Monitor: Towards a Routinely Accessible Circulating Tumor DNA-Based Tool for Real-Time Monitoring Breast Cancer Progression and Treatment Effectiveness

, László Tordai 4 , Rozália Tóth 4 , Zsuzsanna Kahán 4 and Lajos Haracska 5,

Abstracts from the 20th International Symposium on Signal Transduction at the Blood-Brain Barriers

https://deepblue.lib.umich.edu/bitstream/2027.42/138963/1/12987_2017_Article_71.pd

RGB-02 (biosimilar pegfilgrastim) in the treatment of chemotherapy-induced neutropenia

Pegfilgrastim is widely used for the prevention of chemotherapy-induced neutropenia. The development and use of biosimilar agents help to rationalize healthcare expenditure and improve access to modern therapies to all who need them. This review focuses on pegfilgrastims with important role in oncology supportive care. RGB-02 (Gedeon Richter) is a proposed biosimilar to pegylated granulocyte-colony stimulating factor (Neulasta((R)), Amgen) with sustained release properties. The clinical analyses in three randomized clinical studies provided comparative data between RGB-02 and Neulasta, in a Phase III study patients receiving docetaxel-doxorubicin chemotherapy treatment equivalence was found. No difference was detected in any safety measure including immunogenicity; treatment switch, from the reference product to RGB-02 proved safe. Long-acting pegylated filgrastim RGB-02 has successfully accomplished various steps of biosimilar development

Capsaicin-induced rapid neutrophil leukocyte activation in the rat urinary bladder microcirculatory bed

AIMS: This study was initiated to investigate the involvement of neutrophil leukocyte activation in neurogenic inflammation, a process also involved in human urinary pathologies, elicited in the rat urinary bladder by the local administration of capsaicin, the archetypal TRPV1 agonist. The contribution of afferent nerves and sensory neuropeptides to leukocyte activation in the urinary bladder microcirculatory bed was examined. METHODS: Following a 15-min topical application of capsaicin (50 muM), leukocyte-endothelial interactions were examined for an observation period of 45 min with intravital microscopy. Expression of adhesion molecules E-selectin and ICAM-1 implicated in these interactions was assessed by immunohistochemistry. Selective sensory denervation was performed by neonatal treatment with capsaicin. The role of the TRPV1 receptor and two sensory neuropeptides (CGRP and substance P [SP]) were studied using the selective antagonists capsazepine, CGRP8-37 and RP67580, respectively. RESULTS: Capsaicin induced rapid increases in leukocyte rolling and adhesion and increased the expression of E-selectin and ICAM-1 in the postcapillary venules. Sensory chemodenervation via capsaicin and also TRPV1 receptor antagonism effectively prevented these changes. A similar reduction was observed in leukocyte adhesion after topical application of CGRP8-34 or RP67580, but only CGRP8-34 reduced the capsaicin-evoked leukocyte rolling. CONCLUSIONS: Topical application of capsaicin induces early neurogenically mediated cellular microcirculatory inflammatory reactions via the activation of the TRPV1 receptor and the release of CGRP and SP from sensory nerves in the bladder. Co-administration of SP and CGRP receptor antagonists may ameliorate microcirculatory inflammatory changes elicited by capsaicin in the urinary bladder

Capecitabine in Combination with Docetaxel in First Line in HER2-Negative Metastatic Breast Cancer: an Observational Study

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