Research
Abstract
Convalescent plasma with severe acute respiratory disease coronavirus 2 (SARS-CoV-2) antibodies (CCP) may hold promise as treatment for Coronavirus Disease 2019 (COVID-19). We compared the mortality and clinical outcome of patients with COVID-19 who received 200mL of CCP with a Spike protein IgG titer ≥1:2,430 (median 1:47,385) within 72 hours of admission to propensity score-matched controls cared for at a medical center in the Bronx, between April 13 to May 4, 2020. Matching criteria for controls were age, sex, body mass index, race, ethnicity, comorbidities, week of admission, oxygen requirement, D-dimer, lymphocyte counts, corticosteroids, and anticoagulation use. There was no difference in mortality or oxygenation between CCP recipients and controls at day 28. When stratified by age, compared to matched controls, CCP recipients <65 years had 4-fold lower mortality and 4-fold lower deterioration in oxygenation or mortality at day 28. For CCP recipients, pre-transfusion Spike protein IgG, IgM and IgA titers were associated with mortality at day 28 in univariate analyses. No adverse effects of CCP were observed. Our results suggest CCP may be beneficial for hospitalized patients <65 years, but data from controlled trials is needed to validate this finding and establish the effect of ageing on CCP efficacy.
Authors
Hyun ah Yoon, Rachel Bartash, Inessa Gendlina, Johanna Rivera, Antonio Nakouzi, Robert H. Bortz III, Ariel S. Wirchnianski, Monika Paroder, Karen Fehn, Leana Serrano-Rahman, Rachelle Babb, Uzma N. Sarwar, Denise Haslwanter, Ethan Laudermilch, Catalina Florez, M. Eugenia Dieterle, Rohit K. Jangra, J. Maximilian Fels, Karen Tong, Margarette C. Mariano, Olivia Vergnolle, George I. Georgiev, Natalia G. Herrera, Ryan J. Malonis, Jose A. Quiroz, Nicholas C. Morano, Gregory J. Krause, Joseph M. Sweeney, Kelsie Cowman, Stephanie A. Allen, Jayabhargav Annam, Ariella Applebaum, Daniel Barboto, Ahmed Khokhar, Brianna J. Lally, Audrey Lee, Max Lee, Avinash Malaviya, Reise Sample, Xiuyi A. Yang, Yang Li, Rafael E. Ruiz, Raja Thota, Jason Barnhill, Doctor Y. Goldstein, Joan Uehlinger, Scott J. Garforth, Steven C. Almo, Jonathan R. Lai, Morayma Reyes Gil, Amy S. Fox, Kartik Chandran, Tao Wang, Johanna P. Daily, Liise-anne Pirofski
Abstract
The metabotropic glutamate receptor 7 (mGlu7) is a G protein-coupled receptor that has been recently linked to neurodevelopmental disorders. This association is supported by the identification of GRM7 variants in patients with autism spectrum disorder, attention deficit hyperactivity disorder, and severe developmental delay. One GRM7 mutation previously reported in two patients results in a single amino acid change, I154T, within the mGlu7 ligand-binding domain. Here, we report two new patients with this mutation who present with severe developmental delay and epilepsy. Functional studies of the mGlu7-I154T mutant reveal that this substitution results in significant loss of mGlu7 protein expression in HEK293A cells and in mice. We show that this occurs post-transcriptionally at the level of protein expression and trafficking. Similar to mGlu7 global knockout mice, mGlu7-I154T animals exhibit reduced motor coordination, deficits in contextual fear learning, and seizures. This provides the first functional evidence that a disease-associated mutation affecting the mGlu7 receptor is sufficient to cause neurological dysfunction in mice and further validates GRM7 as a disease-causing gene in the human population.
Authors
Nicole M. Fisher, Aqeela AlHashim, Aditi B. Buch, Hana Badivuku, Manar M. Samman, Kelly M. Weiss, Gabriela I. Cestero, Mark D. Does, Jerri M. Rook, Craig W. Lindsley, P. Jeffrey Conn, Rocco G. Gogliotti, Colleen M. Niswender
Effective virus-neutralizing activities in antisera from the first wave of severe COVID-19 survivors
Abstract
The pandemic of Coronavirus Disease 19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become one of the worst public health crises. However, knowledge about the dynamics of antibody responses in COVID-19 patients is still poorly understood. In this study, we performed serological study with serum specimens collected at the acute and the convalescent phases from 104 severe COVID-19 patients who were the first wave of COVID-19 cases in Wuhan, China. Our findings uncovered that neutralizing antibodies to SARS-CoV-2 are persistent at least for more than 6 months in severe COVID-19 patients, despite that immunoglobulin G (IgG) levels against receptor binding domain (RBD) and nucleocapsid protein (N) IgG declined from the acute to the convalescent phase. Moreover, we demonstrate that the level of RBD-IgG is capable of correlating with SARS-CoV-2-neutralizing activities in COVID-19 serum. In summary, our findings identify the magnitude, functionality and longevity of antibody responses in COVID-19 patients, which sheds light on better understanding of humoral immune response to COVID-19, and would be beneficial for developing vaccines.
Authors
Yang Han, Peipei Liu, Yang Qiu, Jie Zhou, Ying Liu, Xujuan Hu, Qingyu Yang, Rui Huang, Xinyue Wen, Hao Song, Pengcheng Yu, Mengjie Yang, Jing Zhang, William J. Liu, Ke Peng, Guizhen Wu, Dingyu Zhang, Xi Zhou, Ying Wu
Abstract
TAK-243 is a first-in-class inhibitor of ubiquitin-like modifier activating enzyme 1 (UBA1) that catalyzes ubiquitin activation, the first step in the ubiquitylation cascade. Based on its preclinical efficacy and tolerability, TAK-243 has been advanced to phase 1 clinical trials in advanced malignancies. Nonetheless, the determinants of TAK-243 sensitivity remain largely unknown. Here, we conducted a genome-wide CRISPR/Cas9 knockout screen in acute myeloid leukemia (AML) cells in the presence of TAK-243 to identify genes essential for TAK-243 action. We identified BEN domain-containing protein 3 (BEND3), a transcriptional repressor and a regulator of chromatin organization, as the top gene whose knockout confers resistance to TAK-243 in vitro and in vivo. Knockout of BEND3 dampened TAK-243 effects on ubiquitylation, proteotoxic stress, and DNA damage response. BEND3 knockout upregulated the ABC efflux transporter breast cancer resistance protein (BCRP; ABCG2), and reduced the intracellular levels of TAK-243. TAK-243 sensitivity correlated with BCRP expression in cancer cell lines of different origin. Moreover, chemical inhibition and genetic knockdown of BCRP sensitized intrinsically resistant high-BCRP cells to TAK-243. Thus, our data demonstrate that BEND3 regulates the expression of BCRP for which TAK-243 is a substrate. Moreover, BCRP expression could serve as a predictor of TAK-243 sensitivity.
Authors
Samir H. Barghout, Ahmed Aman, Kazem Nouri, Zachary Blatman, Karen Arevalo, Geethu E. Thomas, Neil MacLean, Rose Hurren, Troy Ketela, Mehakpreet Saini, Moustafa Abohawya, Taira Kiyota, Rima Al-Awar, Aaron D. Schimmer
Abstract
Hair cell loss is the leading cause of hearing and balance disorders in humans. It can be caused by many factors, including noise, aging, and therapeutic agents. Previous studies have shown the therapeutic potential of quinoxaline against drug-induced ototoxicity. Here, we screened a library of 68 quinoxaline derivatives for protection against aminoglycoside-induced damage of hair cells from the zebrafish lateral line. We identified Qx28 as the best quinoxaline derivative that provides robust protection against both aminoglycosides and cisplatin in zebrafish and mouse cochlear explants. FM1-43 and aminoglycoside uptake, as well as antibiotic efficacy studies, reveal that Qx28 is neither blocking the mechanotransduction channels nor interfering with aminoglycoside antibacterial activity, suggesting that it may be protecting the hair cells by directly counteracting the ototoxin’s mechanism of action. Only when animals were incubated with higher doses of Qx28 we observed a partial blockage of the mechanotransduction channels. Finally, we assessed the regulation of NF-κB pathway in vitro in mouse embryonic fibroblasts and in vivo in zebrafish larvae. Those studies showed that Qx28 protects hair cells by blocking NF-κB canonical pathway activation. Thus, Qx28 is a promising and versatile otoprotectant that can act across different species and toxins.
Authors
Marisa Zallocchi, Santanu Hati, Zhenhang Xu, William Hausman, Huizhan Liu, David Z. He, Jian Zuo
Abstract
Triple negative breast cancers (TNBC) lack effective targeted therapies and cytotoxic chemotherapies remain the standard of care for this subtype. Owing to their increased genomic instability, PARP inhibitors (PARPi) are being tested against TNBCs. In particular, clinical trials are now interrogating the efficacy of PARPi combined with chemotherapies. Intriguingly, while response rates are low, cohorts of patients do respond. Moreover, recent studies suggest that an increase in levels of reactive oxygen species (ROS) may sensitize cells to PARPi. This represents a therapeutic opportunity, as several chemotherapies, including doxorubicin, function in part by producing ROS. We previously demonstrated that the p66ShcA adaptor protein is variably expressed in TNBCs. We now show that in response to therapy-induced stress, p66ShcA stimulates ROS production, which, in turn, potentiates synergy between doxorubicin/PARPi combination therapy in TNBCs. This p66ShcA-induced sensitivity relies on the accumulation of oxidative damage in TNBCs, rather than genomic instability, to potentiate cell death. These findings suggest that increasing the expression of p66ShcA protein levels in TNBCs represents a rational approach to bolster the synergy between PARPi and doxorubicin.
Authors
Eduardo Cepeda Cañedo, Stephanie Totten, Ryuhjin Ahn, Paul Savage, Deanna MacNeil, Jesse Hudson, Chantal Autexier, Genevieve Deblois, Morag Park, Michael Witcher, Josie Ursini-Siegel
Abstract
Multiple myeloma (MM) is characterized by an accumulation of malignant plasma cells (PCs) within the bone marrow (BM). The BM microenvironment supports survival of the malignant cells and is comprised of cellular fractions that foster myeloma development and progression by suppression of the immune response. Despite major progress in understanding the biology and pathophysiology of MM, this disease is still incurable and requires aggressive treatment with significant side effects. CD84 is a self-binding immuno-receptor belonging to the signaling lymphocyte activating molecule (SLAM) family. Previously, we showed that CD84 bridges between chronic lymphocytic leukemia cells and their microenvironment, and regulates T cell function. In the current study, we investigated the role of CD84 in MM. Our results show that MM cells express low levels of CD84. However, these cells secrete the cytokine macrophage migration inhibitory factor (MIF), which induces CD84 expression on cells in their microenvironment. Its activation leads to an elevation of expression of genes regulating differentiation to M/G- myeloid derived suppressor cells (MDSCs) and upregulation of PD-L1 expression on MDSCs, which together suppress T cell function. Downregulation of CD84 or its blocking reduces MDSC accumulation, resulting in elevated T cell activity and reduced tumor load. Our data suggest that CD84 might serve as a novel therapeutic target in MM.
Authors
Hadas Lewinsky, Emine Gulsen Gunes, Keren David, Lihi Radomir, Matthias P. Kramer, Bianca Pellegrino, Michal Perpinial, Jing Chen, Ting-fang He, Anthony Mansour, Kun-Yu Teng, Supriyo Bhattacharya, Enrico Caserta, Estelle Troadec, Peter P. Lee, Mingye Feng, Jonathan J. Keats, Amrita Krishnan, Michael Rosenzweig, Jianhua Yu, Michael A. Caligiuri, Yosef Cohen, Olga Shvetz, Shirly Becker-Herman, Flavia Pichiorri, Steven Rosen, Idit Shachar
Abstract
Novel prime-boost immunization strategies are required to control the global Tuberculosis (TB) pandemic, which claims approximately 3 lives every minute. Here, we have generated an immunogenic complex against Mycobacterium tuberculosis (M.tb), consisting of promiscuous T cell epitopes (M.tb peptides) and TLR ligands assembled in liposomes. Interestingly, this complex (PTLs; peptide-TLR agonist-liposomes) induced significant activation of CD4+ T cells and IFNγ production in the PBMCs derived from PPD+ healthy individuals as compared to PPD- controls. Furthermore, intranasal delivery of PTLs significantly reduced the bacterial burden in the infected mice by inducing M.tb specific polyfunctional (IFNγ+IL17+TNFα+IL2+) immune responses and long-lasting central memory responses thereby reducing the risk of TB recurrence in DOTS treated infected animals. The transcriptome analysis of peptide-stimulated immune cells unveiled the molecular basis of enhanced protection. Furthermore, PTLs immunization significantly boosted the BCG-primed immune responses against TB. The greatly enhanced efficacy of BCG-PTLs vaccine model in controlling pulmonary TB projects PTLs as an adjunct vaccine against TB.
Authors
Santosh Kumar, Ashima Bhaskar, Gautam Patnaik, Chetan Sharma, Dhiraj K. Singh, Sandeep Kaushik, Shivam Chaturvedi, Gobardhan Das, Ved Prakash Dwivedi
Abstract
Somatostatin (SS) inhibits glucagon-like peptide-1 (GLP-1) secretion in a paracrine manner. We hypothesized that blocking somatostatin subtype receptor 2 (SSTR2) and 5 (SSTR5) would improve glycaemia by enhancing GLP-1 secretion. In the perfused mouse small intestine the selective SSTR5 antagonist (SSTR5a) stimulated glucose-induced GLP-1 secretion to a larger degree than the SSTR2 antagonist (SSTR2a). In parallel, mice lacking the SSTR5R showed increased glucose-induced GLP-1 secretion. Both antagonists improved glycaemia in vivo in a GLP-1 receptor (GLP-1R) dependent manner, as the glycaemic improvements were absent in mice with impaired GLP-1R signalling and in mice treated with a GLP-1R specific antagonist. SSTR5a had no direct effect on insulin secretion in the perfused pancreas whereas SSTR2a increased insulin secretion in a GLP-1R independent manner. Adding a dipeptidyl peptidase 4 inhibitor (DPP-4i) in vivo resulted in additive effects on glycaemia, however, when glucose was administered intraperitoneally the antagonists was incapable of lowering blood glucose. Oral administration of SSTR5a, but not SSTR2a lowered blood glucose in diet induced obese mice. In summary, we demonstrate that selective SSTR antagonists can improve glucose control primarily through the intestinal GLP-1 system in mice.
Authors
Sara L. Jepsen, Nicolai J. Wewer Albrechtsen, Johanne Agerlin Windeløv, Katrine D. Galsgaard, Jenna Elizabeth Hunt, Thomas B. Farb, Hannelouise Kissow, Jens Pedersen, Carolyn F. Deacon, Rainer E. Martin, Jens J. Holst
Abstract
Rewiring tumor cells to undergo drug-induced apoptosis could be a promising way to overcome chemoresistance, therefore identifying causative factors for chemoresistance is of high importance. Global proteome-profiling of sensitive, early and late cisplatin resistant OSCC lines identified CMTM6 as a top ranked up-regulated protein. Analyses of OSCC patient tumor samples demonstrated significantly higher CMTM6 expression in chemotherapy-non-responders as compared to responders. In addition, a significant association between higher CMTM6 expression and poorer relapse-free survival in ESCC, HNSCC was monitored from Kaplan-Meier-Plot analysis. Stable knockdown of CMTM6 restores cisplatin-mediated cell death in chemoresistant OSCC cell lines. Similarly, upon CMTM6 overexpression in CMTM6KD lines, the cisplatin resistant phenotype was efficiently rescued. The patient-derived cell xenograft model of chemoresistant OSCC displayed CMTM6 depletion restored the cisplatin-induced cell death and tumor burden significantly. The transcriptome analysis of CMTM6KD and control chemoresistant cells depicted enrichment of Wnt-signaling pathway. Mechanistically, we demonstrated that CMTM6 interaction with membrane bound Enolase-1 stabilized its expression, leading to AKT-GSK3β mediated activation of Wnt-signaling. CMTM6 has been identified as a stabilizer of PD-L1 thereby facilitates immune evasion by tumor cells. As CMTM6 facilitates tumor cells for immune evasion and mediates cisplatin resistance, it can be an important therapeutic target for therapy resistant OSCC.
Authors
Pallavi Mohapatra, Omprakash Shriwas, Sibasish Mohanty, Arup Ghosh, Shuchi Smita, Sandeep Rai Kaushik, Rakesh Arya, Rachna Rath, Saroj Das Majumdar, Dillip Kumar Muduly, Sunil Raghav, Ranjan K. Nanda, Rupesh Dash
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