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https://www.readbyqxmd.com/read/29227302/the-target-invites-a-foe-antibody-drug-conjugates-in-gynecologic-oncology
#1
Maira P Campos, Gottfried E Konecny
PURPOSE OF REVIEW: Antibody-drug conjugates (ADCs) represent a promising new class of cancer therapeutics. Currently more than 60 ADCs are in clinical development, however, only very few trials focus on gynecologic malignancies. In this review, we summarize the most recent advances in ADC drug development with an emphasis on how this progress relates to patients diagnosed with gynecologic malignancies and breast cancer. RECENT FINDINGS: The cytotoxic payloads of the majority of the ADCs that are currently in clinical trials for gynecologic malignancies or breast cancer are auristatins (MMAE, MMAF), maytansinoids (DM1, DM4), calicheamicin, pyrrolobenzodiazepines and SN-38...
December 8, 2017: Current Opinion in Obstetrics & Gynecology
https://www.readbyqxmd.com/read/29209172/the-role-of-netrin-1-in-improving-functional-recovery-through-autophagy-stimulation-following-spinal-cord-injury-in-rats
#2
Liangjie Bai, Xifan Mei, Yanfeng Wang, Yajiang Yuan, Yunlong Bi, Gang Li, Hongyu Wang, Peng Yan, Gang Lv
Our previous findings indicated that treatment with Netrin-1 could improve functional recovery through the stimulation of autophagy, by activating the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) signaling pathway in rats following spinal cord injury (SCI). However, the underlying mechanisms were not elucidated. The purpose of this study was to investigate the underlying mechanisms by which Netrin-1 promotes autophagy and improves functional recovery after SCI. Following controlled SCI in Sprague-Dawley rats, we observed that the autophagic flux in neurons was impaired, as reflected by the accumulation of light chain 3-II (LC3-II)-positive and LC3-positive autophagosomes (APs), accompanied by the accumulation of the autophagic substrate, Sequestosome 1 (SQSTM1; also known as p62)...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29170033/6-hydroxydopamine-induces-autophagic-flux-dysfunction-by-impairing-transcription-factor-eb-activation-and-lysosomal-function-in-dopaminergic-neurons-and-sh-sy5y-cells
#3
Xin He, Wei Yuan, Zijian Li, Yang Hou, Liu Fei, Juan Feng
Autophagy deregulation has been implicated in Parkinson's disease (PD), yet the role of autophagy in neuronal survival remains controversial. In this study, we comprehensively investigated the time-course of autophagy-related markers in 6-OHDA-induced Parkinsonian rat models and assessed its effect on the state of autophagic flux both in vivo and in vitro. We observed an early activation of autophagy followed by autophagic flux impairment, which was confirmed with autophagy inhibitor chloroquine in vivo and Ad-GFP-mCherry-LC3-infected SH-SY5Y cells in vitro...
November 20, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/29158485/cytoplasmic-cleavage-of-dppa3-is-required-for-intracellular-trafficking-and-cleavage-stage-development-in-mice
#4
Seung-Wook Shin, Edgar John Vogt, Maria Jimenez-Movilla, Boris Baibakov, Jurrien Dean
Degradation of maternal proteins by the ubiquitin-proteasome system (UPS) accompanies the maternal-to-zygotic transition. DPPA3/Stella/PGC7, encoded by a maternal effect gene, is present in the nucleus and cytoplasm of zygotes and has been associated with protecting the female pronucleus from TET3-mediated demethylation. We now report that cytoplasmic DPPA3 is partially cleaved by the ubiquitin-proteasome system and an N-terminus fragment remains in the cytoplasm where it associates with early and re-cycling endosomes...
November 21, 2017: Nature Communications
https://www.readbyqxmd.com/read/29152606/ethanol-induced-steatosis-involves-impairment-of-lipophagy-associated-with-reduced-dynamin2-activity
#5
Karuna Rasineni, Terrence M Donohue, Paul G Thomes, Li Yang, Dean J Tuma, Mark A McNiven, Carol A Casey
Background: Lipid droplets (LDs), the organelles central to alcoholic steatosis, are broken down by lipophagy, a specialized form of autophagy. Here, we hypothesize that ethanol administration retards lipophagy by down-regulating Dynamin 2 (Dyn2), a protein that facilitates lysosome re-formation, contributing to hepatocellular steatosis. Methods: Primary hepatocytes were isolated from male Wistar rats fed Lieber-DeCarli control or EtOH liquid diets for 6-8 wk. Hepatocytes were incubated in complete medium (fed) or nutrient-free medium (fasting) with or without the Dyn2 inhibitor Dynasore or the Src inhibitor SU6656...
August 2017: Hepatology Communications
https://www.readbyqxmd.com/read/29145829/effect-of-a-rare-genetic-variant-of-tm7sf4-gene-on-osteoclasts-of-patients-with-paget-s-disease-of-bone
#6
Emilie Laurier, Nathalie Amiable, Edith Gagnon, Jacques P Brown, Laëtitia Michou
BACKGROUND: Dendritic Cell-Specific Transmembrane Protein (DC-STAMP) is involved in osteoclastogenesis with a key role in mononucleated osteoclasts fusion. We reported in patients with Paget's disease of bone (PDB) a rare variant (rs62620995) in the TM7SF4 gene, encoding for DC-STAMP, which changes a highly conserved amino acid, possibly damaging according to in silico predictions. This study aimed at determining the functional effects of this variant on osteoclast phenotype in PDB. METHODS: Fifty ml of peripheral blood were collected in pagetic patients carrier of this variant (n = 4) or not (n = 4) and healthy controls (n = 4)...
November 16, 2017: BMC Medical Genetics
https://www.readbyqxmd.com/read/29142303/fus-toxicity-is-rescued-by-the-modulation-of-lncrna-hsr%C3%AF-expression-in-drosophila-melanogaster
#7
Luca Lo Piccolo, Salinee Jantrapirom, Yoshitaka Nagai, Masamitsu Yamaguchi
FUS is an aggregation-prone hnRNP involved in transcriptional and post-transcriptional regulation that aberrantly forms immunoreactive inclusion bodies in a range of neurological diseases classified as FUS-proteinopathies. Although FUS has been extensively examined, the underlying molecular mechanisms of these diseases have not yet been elucidated in detail. We previously reported that RNAi of the lncRNA hsrω altered the expression and sub-cellular localization of Drosophila FUS in the central nervous system of the fly...
November 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29135969/hla-b27-correlates-with-the-intracellular-elimination-replication-and-trafficking-of-salmonella-enteritidis-collected-from-reactive-arthritis-patients
#8
Yi Zhao, Honghu Tang, Chunyu Tan, Hua Zhao, Yi Liu
BACKGROUND The aim of this study was to explore the correlation between HLA-B27 and the intracellular elimination, replication, and trafficking of Salmonella enteritidis (S. enteritidis) collected from patients with reactive arthritis. MATERIAL AND METHODS Confocal microscopy, flow cytometry, and sandwich enzyme-linked immunosorbent assay (ELISA) were employed in this study to evaluate the localization of proteins of interest, to assess the intracellular trafficking of S. enteritidis, and to measure the production of cytokines of interest...
November 14, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/29125872/impaired-placental-autophagy-in-placental-malaria
#9
Kris Genelyn Dimasuay, Lan Gong, Fredrick Rosario, Emma McBryde, Tim Spelman, Jocelyn Glazier, Stephen J Rogerson, James G Beeson, Thomas Jansson, Rodney J Devenish, Philippe Boeuf
BACKGROUND: Placental malaria is a major cause of low birthweight, principally due to impaired fetal growth. Intervillositis, a local inflammatory response to placental malaria, is central to the pathogenesis of poor fetal growth as it impairs transplacental amino acid transport. Given the link between inflammation and autophagy, we investigated whether placental malaria-associated intervillositis increased placental autophagy as a potential mechanism in impaired fetal growth. METHODS: We examined placental biopsies collected after delivery from uninfected women (n = 17) and from women with Plasmodium falciparum infection with (n = 14) and without (n = 7) intervillositis...
2017: PloS One
https://www.readbyqxmd.com/read/29092745/strategies-for-imaging-mitophagy-in-high-resolution-and-high-throughput
#10
Deepa Indira, Shankara Narayanan Varadarajan, Santhik Subhasingh Lupitha, Asha Lekshmi, Krupa Ann Mathew, Aneesh Chandrasekharan, Prakash Rajappan Pillai, Ishaque Pulikkal Kadamberi, Indu Ramachandran, Hari Sekar, Anurup Kochucherukkan Gopalakrishnan, Santhoshkumar Tr
The selective autophagic removal of mitochondria called mitophagy is an essential physiological signaling for clearing damaged mitochondria and thus maintains the functional integrity of mitochondria and cells. Defective mitophagy is implicated in several diseases, placing mitophagy as a target for drug development. The identification of key regulators of mitophagy as well as chemical modulators of mitophagy requires sensitive and reliable quantitative approaches. Since mitophagy is a rapidly progressing event and sub-microscopic in nature, live cell image-based detection tools with high spatial and temporal resolution is preferred over end-stage assays...
October 27, 2017: European Journal of Cell Biology
https://www.readbyqxmd.com/read/29055015/small-molecule%C3%A2-inhibition-of-pd-1-transcription-is-an-effective-alternative-to-antibody-blockade-in-cancer-therapy
#11
Alison Taylor, David Rothstein, Christopher E Rudd
The impact of PD-1 immune checkpoint therapy prompts exploration of other strategies to downregulate PD-1 for cancer therapy. We previously showed that the serine/threonine kinase, glycogen synthase kinase GSK-3α/β, is a central regulator of PD-1 transcription in CD8+ T cells. Here, we show that the use of small molecule inhibitors of GSK-3α/β (GSK-3i) to reduce pcdc1 (PD-1) transcription and expression was as effective as anti-PD-1 and PDL-1 blocking antibodies in the control of B16 melanoma, or EL4 lymphoma, in primary tumor and metastatic settings...
October 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/29030552/bad-lamp-controls-tlr9-trafficking-and-signalling-in-human-plasmacytoid-dendritic-cells
#12
Alexis Combes, Voahirana Camosseto, Prudence N'Guessan, Rafael J Argüello, Julie Mussard, Christophe Caux, Nathalie Bendriss-Vermare, Philippe Pierre, Evelina Gatti
Toll-like receptors (TLR) are essential components of the innate immune system. Several accessory proteins, such as UNC93B1, are required for transport and activation of nucleic acid sensing Toll-like receptors in endosomes. Here, we show that BAD-LAMP (LAMP5) controls TLR9 trafficking to LAMP1(+) late endosomes in human plasmacytoid dendritic cells (pDC), leading to NF-κB activation and TNF production upon DNA detection. An inducible VAMP3(+/)LAMP2(+/)LAMP1(-) endolysosome compartment exists in pDCs from which TLR9 activation triggers type I interferon expression...
October 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/29028815/striatal-astrocytes-engulf-dopaminergic-debris-in-parkinson-s-disease-a-study-in-an-animal-model
#13
Ingrid Morales, Alberto Sanchez, Clara Rodriguez-Sabate, Manuel Rodriguez
The role of astrocytes in Parkinson's disease is still not well understood. This work studied the astrocytic response to the dopaminergic denervation. Rats were injected in the lateral ventricles with 6-hydroxydopamine (25μg), inducing a dopaminergic denervation of the striatum not accompanied by non-selective tissue damage. The dopaminergic debris were found within spheroids (free-spheroids) which retained some proteins of dopaminergic neurons (e.g., tyrosine hydroxylase, the dopamine transporter protein, and APP) but not others (e...
2017: PloS One
https://www.readbyqxmd.com/read/29022892/the-lncrna-hulc-functions-as-an-oncogene-by-targeting-atg7-and-itgb1-in-epithelial-ovarian-carcinoma
#14
Shuo Chen, Dan-Dan Wu, Xiu-Bo Sang, Li-Li Wang, Zhi-Hong Zong, Kai-Xuan Sun, Bo-Liang Liu, Yang Zhao
Highly upregulated in liver cancer (HULC) is a long noncoding RNA (lncRNA), which has recently been identified as a key regulator in the progression of hepatocellular carcinoma, gliomas and gastric cancer. However, its role in epithelial ovarian carcinoma (EOC) remains unknown. In this study, HULC expression was examined in EOC, borderline and benign ovarian tumors, and normal ovarian tissues by RT-PCR. Ovarian cancer cell phenotypes, as well as autophagy-associated proteins were examined after HULC overexpression or downregulation by plasmid or small interfering RNA (siRNA) transfection, respectively...
October 12, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28986830/studies-of-lassa-virus-cell-entry
#15
Antonella Pasquato, Antonio Herrador Fernandez, Stefan Kunz
Host cell entry is the first and most fundamental step of every virus infection and represents a major barrier for zoonotic transmission and viral emergence. Targeting viral entry appears further as a promising strategy for therapeutic intervention. Several cellular receptors have been identified for Lassa virus, including dystroglycan, TAM receptor tyrosine kinases, and C-type lectins. Upon receptor binding, LASV enters the host cell via a largely unknown clathrin- and dynamin-independent endocytotic pathway that delivers the virus to late endosomes, where fusion occurs after engagement of a second, intracellular receptor, the late endosomal/lysosomal resident protein LAMP1...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28984607/co-localization-of-glia-maturation-factor-with-nlrp3-inflammasome-and-autophagosome-markers-in-human-alzheimer-s-disease-brain
#16
Mohammad Ejaz Ahmed, Shankar Iyer, Ramasamy Thangavel, Duraisamy Kempuraj, Govindhasamy Pushpavathi Selvakumar, Sudhanshu P Raikwar, Smita Zaheer, Asgar Zaheer
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the presence of intracellular neurofibrillary tangles (NFTs) containing hyperphosphorylated tau, and the extracellular deposition of amyloid plaques (APs) with misfolded amyloid-β (Aβ) peptide. Glia maturation factor (GMF), a highly conserved pro-inflammatory protein, isolated and cloned in our laboratory, has been shown to activate glial cells leading to neuroinflammation and neurodegeneration in AD. We hypothesized that inflammatory reactions promoted by NLRP3-Caspase-1inflammasome pathway trigger dysfunction in autophagy and accumulation of Aβ which is amplified and regulated by GMF in AD...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28983474/helicobacter-pylori-caga-protein-negatively-regulates-autophagy-and-promotes-inflammatory-response-via-c-met-pi3k-akt-mtor-signaling-pathway
#17
Na Li, Bin Tang, Yin-Ping Jia, Pan Zhu, Yuan Zhuang, Yao Fang, Qian Li, Kun Wang, Wei-Jun Zhang, Gang Guo, Tong-Jian Wang, You-Jun Feng, Bin Qiao, Xu-Hu Mao, Quan-Ming Zou
Cytotoxin-associated-gene A (CagA) of Helicobacter pylori (H. pylori) is a virulence factor that plays critical roles in H. pylori-induced gastric inflammation. In the present study, gastric biopsies were used for genotyping cagA and vacA genes, determining the autophagic activity, and the severity of gastric inflammation response. It was revealed that autophagy in gastric mucosal tissues infected with cagA(+)H. pylori strains was lower than the levels produced by cagA(-)H. pylori strains, accompanied with accumulation of SQSTM1 and decreased LAMP1 expression...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/28973369/alterations-in-corneal-sensory-nerves-during-homeostasis-aging-and-after-injury-in-mice-lacking-the-heparan-sulfate-proteoglycan-syndecan-1
#18
Sonali Pal-Ghosh, Gauri Tadvalkar, Mary Ann Stepp
Purpose: To determine the impact of the loss of syndecan 1 (SDC1) on intraepithelial corneal nerves (ICNs) during homeostasis, aging, and in response to 1.5-mm trephine and debridement injury. Methods: Whole-mount corneas are used to quantify ICN density and thickness over time after birth and in response to injury in SDC1-null and wild-type (WT) mice. High-resolution three-dimensional imaging is used to visualize intraepithelial nerve terminals (INTs), axon fragments, and lysosomes in corneal epithelial cells using antibodies against growth associated protein 43 (GAP43), βIII tubulin, and LAMP1...
October 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28968876/iga-protease-variants-facilitate-intracellular-survival-in-epithelial-cells-by-nontypeable-haemophilus-influenzae-that-persist-in-the-human-respiratory-tract-in-copd
#19
Timothy F Murphy, Charmaine Kirkham, Mary C Gallo, Yang Yang, Gregory E Wilding, Melinda M Pettigrew
Background: Nontypeable Haemophilus influenzae (NTHi) persists in the airways in chronic obstructive pulmonary disease (COPD). NTHi expresses four IgA protease variants (A1, A2, B1, B2) with distinct cleavage specificities for human IgA1. Little is known about the different roles of IgA protease variants in NTHi infection. Methods: Twenty-six NTHi isolates from a 20-year longitudinal study of COPD were analyzed for IgA protease expression, survival in human respiratory epithelial cells and cleavage of lysosomal-associated membrane protein 1 (LAMP1)...
September 15, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28939436/structure-based-functional-analysis-of-effector-protein-sifa-in-living-cells-reveals-motifs-important-for-salmonella-intracellular-proliferation
#20
Mahsa Namakchian, Kristin Kassler, Heinrich Sticht, Michael Hensel, Jörg Deiwick
The facultative intracellular pathogen Salmonella enterica survives and replicates inside the Salmonella-containing vacuole (SCV) of mammalian host cells. SifA is a key effector protein translocated by a type III secretion system and involved in formation of Salmonella-induced filaments (SIF), extensive tubular endosomal compartments. Recruitment of LAMP1 (lysosomal-associated membrane protein 1)-positive membranes to SIF ensures integrity and dynamics of the membrane network. The binding of SifA to the host protein SKIP (SifA and kinesin interacting protein) was proposed as crucial for this function...
September 8, 2017: International Journal of Medical Microbiology: IJMM
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