Zika virus (ZIKV) infection has been associated with fetal abnormalities by compromising placental integrity, but the mechanisms by which this occurs are unknown. Flavivirus can deregulate the host proteome, especially extracellular matrix (ECM) proteins. We hypothesize that a deregulation of specific ECM proteins by ZIKV, affects placental integrity. Using twelve different placental samples collected during the 2016 ZIKV Puerto Rico epidemic, we compared the proteome of five ZIKV infected samples with four uninfected controls followed by validation of most significant proteins by immunohistochemistry. Quantitative proteomics was performed using tandem mass tag TMT10plex™ Isobaric Label Reagent Set followed by Q Exactive™ Hybrid Quadrupole Orbitrap Mass Spectrometry. Identification of proteins was performed using Proteome Discoverer 2.1. Proteins were compared based on the fold change and p value using Limma software. Significant proteins pathways were analyzed using Ingenuity Pathway (IPA). TMT analysis showed that ZIKV infected placentas had 94 reviewed differentially abundant proteins, 32 more abundant, and 62 less abundant. IPA analysis results indicate that 45 of the deregulated proteins are cellular components of the ECM and 16 play a role in its structure and organization. Among the most significant proteins in ZIKV positive placenta were fibronectin, bone marrow proteoglycan, and fibrinogen. Of these, fibrinogen was further validated by immunohistochemistry in 12 additional placenta samples and found significantly increased in ZIKV infected placentas. The upregulation of this protein in the placental tissue suggests that ZIKV infection is promoting the coagulation of placental tissue and restructuration of ECM potentially affecting the integrity of the tissue and facilitating dissemination of the virus from mother to the fetus.
Leptomeningeal carcinomatosis (LMC) is a fatal but uncommon complication occurring in 5–15% of patients with stage IV cancer. Current treatment options are ineffective at managing leptomeningeal spread, with a median overall survival (mOS) of 2–6 months. We aimed to conduct a systematic review of the literature to identify past and future therapies for LMC from solid tumors. Forty-three clinical trials (CTs) published between 1982–2022 were identified. Of these, 35 (81.4%) were non-randomized CTs and 8 (18.6%) were randomized CTs. The majority consisted of phase I (16.3%) and phase II CTs (65.1%). Trials enrolled patients with LMC from various primary histology (n = 23, 57.5%), with one CT evaluating LCM from melanoma (2.4%). A total of 21 trials evaluated a single modality treatment. Among CTs, 23.7% closed due to low accrual. Intraventricular (ITV)/intrathecal (IT) drug delivery was the most common route of administration (n = 22, 51.2%) vs. systemic drug delivery (n = 13, 30.3%). Two clinical trials evaluated the use of craniospinal irradiation for LMC with favorable results. LMC continues to carry a dismal prognosis, and over the years, increments in survival have remained stagnant. A paradigm shift towards targeted systemic therapy with continued standardization of efficacy endpoints will help to shed light on promising treatments.
Zika virus (ZIKV) compromises placental integrity, infecting the fetus. However, the mechanisms associated with ZIKV penetration into the placenta leading to fetal infection are unknown. Cystatin B (CSTB), the receptor for advanced glycation end products (RAGE), and tyrosine-protein kinase receptor UFO (AXL) have been implicated in ZIKV infection and inflammation. This work investigates CSTB, RAGE, and AXL receptor expression and activation pathways in ZIKV-infected placental tissues at term. The hypothesis is that there is overexpression of CSTB and increased inflammation affecting RAGE and AXL receptor expression in ZIKV-infected placentas. Pathological analyses of 22 placentas were performed to determine changes caused by ZIKV infection. Quantitative proteomics, immunofluorescence, and western blot were performed to analyze proteins and pathways affected by ZIKV infection in frozen placentas. The pathological analysis confirmed decreased size of capillaries, hyperplasia of Hofbauer cells, disruption in the trophoblast layer, cell agglutination, and ZIKV localization to the trophoblast layer. In addition, there was a significant decrease in CSTB, RAGE, and AXL expression and upregulation of caspase 1, tubulin beta, and heat shock protein 27. Modulation of these proteins and activation of inflammasome and pyroptosis pathways suggest targets for modulation of ZIKV infection in the placenta.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.