BACKGROUND. The angiotensin-converting enzyme (ACE) D allele is more prevalent among African Americans (AA) compared to other races/ethnicities and has previously been associated with severe COVID-19 pathogenesis through excessive ACE1 activity. Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACE-I/ARB) may counteract this mechanism, but their association with COVID-19 outcomes has not been specifically tested in the AA population. METHODS. We identified 6,218 patients who were admitted into Mount Sinai hospitals with COVID-19 between February 24 and May 31, 2020 in the New York City. We evaluated whether the outpatient and in-hospital use of ACE-I/ARB is associated with COVID-19 in-hospital mortality in AA compared with non-AA population. RESULTS. Of the 6,218 COVID-19 patients, 1,138 (18.3%) were ACE-I/ARB users. In a multivariate logistic regression model, ACE-I/ARB use was independently associated with reduced risk of in-hospital mortality in the entire population (OR, 0.655; 95% CI, 0.505-0.850; P=0.001), AA population (OR, 0.44; 95% CI, 0.249-0.779; P=0.005), and non-AA population (OR, 0.748, 95% CI, 0.553-1.012, P=0.06). In the AA population, in-hospital use of ACE-I/ARB was associated with improved mortality (OR, 0.378; 95% CI, 0.188-0.766; P=0.006) while outpatient use was not (OR, 0.889; 95% CI, 0.375-2.158; P=0.812). When analyzing each medication class separately, ARB in-hospital use was significantly associated with reduced in-hospital mortality in the AA population (OR, 0.196; 95% CI, 0.074-0.516; P=0.001), while ACE-I use was not associated with impact on mortality in any population. CONCLUSION. In-hospital use of ARB was associated with a significant reduction in in-hospital mortality among COVID-19-positive AA patients. FUNDING. None.
Shilong Li, Rangaprasad Sarangarajan, Tomi Jun, Yu-Han Kao, Zichen Wang, Ke Hao, Emilio Schadt, Michael A. Kiebish, Elder Granger, Niven R. Narain, Rong Chen, Eric E. Schadt, Li Li
BACKGROUND. Chimeric antigen receptor (CAR)-modified T cells have emerged as a novel approach to treat malignant tumors. This strategy has also been proposed for the treatment of HIV-1 infection. We have developed a broadly neutralizing antibody (bNAb)-derived CAR-T cell therapy which can exerted specific cytotoxic activity against HIV-1-infected cells. METHODS. We conducted an open-label trial of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of bNAb-derived CAR-T cell therapy in HIV-1-infected individuals who were undergoing analytical interruption of antiretroviral therapy (ART). RESULTS. A total of 14 participants completed only a single administration of bNAb-derived CAR-T cells. CAR-T administration was safe and well tolerated. Six participants discontinued ART, and viremia rebound occurred in all of them, with a 5.3-week median time. Notably, the cell-associated viral RNA and intact proviruses decreased significantly after CAR-T treatment. Analyses of HIV-1 variants before or after CAR-T administration suggested that CAR-T cells exerted pressure on rebound viruses, resulting in a selection of viruses with less diversity and mutations against CAR-T-mediated cytotoxicity. CONCLUSIONS. No safety concerns were identified with adoptive transfer of bNAb-derived CAR-T cells. They reduced viral reservoir. All the rebounds were due to preexisting or emergence of viral escape mutations. TRIAL REGISTRATION. ClinicalTrials.gov number, NCT03240328. FUNDING. Ministry of Science and Technology of China, National Natural Science Foundation of China, and Department of Science and Technology of Guangdong Province.
Bingfeng Liu, Wanying Zhang, Baijin Xia, Shuliang Jing, Yingying Du, Fan Zou, Rong Li, Lijuan Lu, Shaozhen Chen, Yonghong Li, Qifei Hu, Yingtong Lin, Yiwen Zhang, Zhangping He, Xu Zhang, Xiejie Chen, Tao Peng, Xiaoping Tang, Weiping Cai, Ting Pan, Linghua Li, Hui Zhang
BACKGROUND. Germline mutations in telomerase and other telomere maintenance genes manifest in the premature aging short telomere syndromes. Myelodysplastic syndromes and acute myeloid leukemia (MDS/AML) account for 75% of associated malignancies, but how these cancers overcome the inherited telomere defect is unknown. METHODS. We used ultra-deep targeted sequencing to detect somatic reversion mutations in 17 candidate telomere lengthening genes among controls and short telomere syndrome patients with and without MDS/AML and we tested the functional significance of these mutations. RESULTS. While no controls carried somatic mutations in telomere maintenance genes, 29% (16 of 56) of adults with germline telomere maintenance defects carried at least one (P<0.001) and 13% (7 of 56) had 2 or more. In addition to TERT promoter mutations which were present in 19%, we identified POT1 and TERF2IP mutations in 13%. POT1 mutations impaired telomere binding in vitro and some mutations were identical to ones seen in familial melanoma associated with longer telomere length. Exclusively in patients with germline defects in telomerase RNA (TR), we identified somatic mutations in nuclear RNA exosome genes, RBM7, SKIV2L2, and DIS3, where loss-of-function upregulates mature TR levels. Somatic reversion events in six telomere-related genes were more prevalent in patients who were MDS/AML-free (P = 0.02, RR 4.4, 95% CI 1.2-16.7), and no MDS/AML patient had more than one reversion mutation. CONCLUSIONS. Our data identify diverse adaptive somatic mechanisms in the short telomere syndrome; they raise the possibility that their presence alleviates the telomere crisis that promotes transformation to MDS/AML.
Kristen E. Schratz, Valeriya Gaysinskaya, Zoe L. Cosner, Emily A. DeBoy, Zhimin Xiang, Laura Kasch-Semenza, Liliana Florea, Pali D. Shah, Mary Armanios
BACKGROUND Necrotizing soft-tissue infections (NSTIs) are rapidly progressing infections frequently complicated by septic shock and associated with high mortality. Early diagnosis is critical for patient outcome, but challenging due to vague initial symptoms. Here, we identified predictive biomarkers for NSTI clinical phenotypes and outcomes using a prospective multicenter NSTI patient cohort.METHODS Luminex multiplex assays were used to assess 36 soluble factors in plasma from NSTI patients with positive microbiological cultures (n = 251 and n = 60 in the discovery and validation cohorts, respectively). Control groups for comparative analyses included surgical controls (n = 20), non-NSTI controls (i.e., suspected NSTI with no necrosis detected upon exploratory surgery, n = 20), and sepsis patients (n = 24).RESULTS Thrombomodulin was identified as a unique biomarker for detection of NSTI (AUC, 0.95). A distinct profile discriminating mono- (type II) versus polymicrobial (type I) NSTI types was identified based on differential expression of IL-2, IL-10, IL-22, CXCL10, Fas-ligand, and MMP9 (AUC >0.7). While each NSTI type displayed a distinct array of biomarkers predicting septic shock, granulocyte CSF (G-CSF), S100A8, and IL-6 were shared by both types (AUC >0.78). Finally, differential connectivity analysis revealed distinctive networks associated with specific clinical phenotypes.CONCLUSIONS This study identifies predictive biomarkers for NSTI clinical phenotypes of potential value for diagnostic, prognostic, and therapeutic approaches in NSTIs.TRIAL REGISTRATION ClinicalTrials.gov NCT01790698.FUNDING Center for Innovative Medicine (CIMED); Region Stockholm; Swedish Research Council; European Union; Vinnova; Innovation Fund Denmark; Research Council of Norway; Netherlands Organisation for Health Research and Development; DLR Federal Ministry of Education and Research; and Swedish Children’s Cancer Foundation.
Laura M. Palma Medina, Eivind Rath, Sanjeevan Jahagirdar, Trond Bruun, Martin B. Madsen, Kristoffer Strålin, Christian Unge, Marco Bo Hansen, Per Arnell, Michael Nekludov, Ole Hyldegaard, Magda Lourda, Vitor A.P. Martins dos Santos, Edoardo Saccenti, Steinar Skrede, Mattias Svensson, Anna Norrby-Teglund
BACKGROUND. Certain components of rest-activity rhythms such as greater eveningness (delayed phase), physical inactivity (blunted amplitude) and shift work (irregularity) are associated with increased risk for drug use. Dopaminergic (DA) signaling has been hypothesized to mediate the associations, though clinical evidence is lacking. METHODS. We examined associations between rhythm components and striatal D1 (D1R) and D2/3 receptor (D2/3R) availability in 32 healthy adults (12 female, age: 42.40±12.22) and its relationship to drug reward. Rest-activity rhythms were assessed by one-week actigraphy combined with self-reports. [11C]NNC112 and [11C]raclopride Positron Emission Tomography (PET) scans were conducted to measure D1R and D2/3R availability, respectively. Additionally, self-reported drug-rewarding effects of 60 mg oral methylphenidate were assessed. RESULTS. We found that delayed rhythm was associated with higher D1R availability in caudate, which was not attributable to sleep loss or ‘social jet lag’, whereas physical inactivity was associated with higher D2/3R availability in nucleus accumbens (NAc). Delayed rest-activity rhythm, higher caudate D1R and NAc D2/3R availability were associated with greater sensitivity to the rewarding effects of methylphenidate. CONCLUSION. These findings reveal specific components of rest-activity rhythms associated with striatal D1R, D2/3R availability and drug-rewarding effects. Personalized interventions that target rest-activity rhythms may help prevent and treat substance use disorders. TRIAL REGISTRATION. ClinicalTrials.gov: NCT03190954 FUNDING. This work was accomplished with support from the National Institute on Alcohol Abuse and Alcoholism (ZIAAA000550).
Rui Zhang, Peter Manza, Dardo Tomasi, Sung Won Kim, Ehsan Shokri-Kojori, Sukru B. Demiral, Danielle S. Kroll, Dana E. Feldman, Katherine L. McPherson, Catherine L. Biesecker, Gene-Jack Wang, Nora D. Volkow
BACKGROUND. Molecular characterization in pediatric papillary thyroid cancer (PTC), distinct from adult PTC, is important for developing molecular targeted therapies for progressive 131I-refractory PTC. METHODS. PTC samples from 106 pediatric patients (age: 4.3–19.8 years; 21 boys) who attended Seoul National University Hospital (January 1983–March 2020) were available for genomic profiling. Previous transcriptome data from 125 adult PTCs were used for comparison. RESULTS. Genetic drivers were found in 80 tumors; 31 with fusion oncogenes (RET in 21, ALK in 6, and NTRK1/3 in 4), 47 with point mutations (BRAFV600E in 41, TERTC228T in 2, and DICER1 variants in 5), and 2 with amplifications. Fusion-oncogene PTCs, predominantly detected in younger patients, presented with a more advanced stage and showed more recurrent or persistent disease than BRAFV600E PTCs, which were detected mostly in adolescents. Pediatric fusion PTCs (in those aged < 10 years) showed lower expression of thyroid differentiation genes, including SLC5A5, than adult fusion PTCs. Two girls with progressive 131I-refractory lung metastases harboring a TPR-NTRK1 or CCDC6-RET fusion received fusion-targeted therapy; larotrectinib and selpercatinib decreased the tumor extent and restored radioiodine uptake. The girl with the CCDC6-RET fusion received 131I therapy combined with selpercatinib, leading to a tumor response. In vitro 125I uptake and 131I clonogenic assays showed that larotrectinib inhibited growth and restored radioiodine avidity. CONCLUSIONS. In pediatric fusion-oncogene PTC cases with 131I-refractory advanced disease, selective fusion-directed therapy may restore radioiodine avidity and lead to a dramatic tumor response, underscoring the importance of molecular testing in pediatric PTC patients. FUNDING. The Ministry of Science, ICT & Future Planning (grant number NRF-2016R1A2B4012417 91 and 2019R1A2C2084332), the Ministry of Health & Welfare, Republic of Korea (grant number 92 H14C1277), the Ministry of Education (grant number 2020R1A6A1A03047972), and the Seoul 93 National University Hospital Research Fund (grant number 04-2015-0830).
Young Ah Lee, Hyunjung Lee, Sun-Wha Im, Young Shin Song, Do-Youn Oh, Hyoung Jin Kang, Jae-Kyung Won, Kyeong Cheon Jung, Dohee Kwon, Eun-Jae Chung, J. Hun Hah, Jin Chul Paeng, Ji-hoon Kim, Jaeyong Choi, Ok-Hee Kim, Ji Min Oh, Byeong-Cheol Ahn, Lori J. Wirth, Choong Ho Shin, Jong-Il Kim, Young Joo Park
BACKGROUND Although convalescent plasma has been widely used to treat severe coronavirus disease 2019 (COVID-19), data from randomized controlled trials that support its efficacy are limited.METHODS We conducted a randomized, double-blind, controlled trial among adults hospitalized with severe and critical COVID-19 at 5 sites in New York City (USA) and Rio de Janeiro (Brazil). Patients were randomized 2:1 to receive a single transfusion of either convalescent plasma or normal control plasma. The primary outcome was clinical status at 28 days following randomization, measured using an ordinal scale and analyzed using a proportional odds model in the intention-to-treat population.RESULTS Of 223 participants enrolled, 150 were randomized to receive convalescent plasma and 73 to receive normal control plasma. At 28 days, no significant improvement in the clinical scale was observed in participants randomized to convalescent plasma (OR 1.50, 95% confidence interval [CI] 0.83–2.68, P = 0.180). However, 28-day mortality was significantly lower in participants randomized to convalescent plasma versus control plasma (19/150 [12.6%] versus 18/73 [24.6%], OR 0.44, 95% CI 0.22–0.91, P = 0.034). The median titer of anti–SARS-CoV-2 neutralizing antibody in infused convalescent plasma units was 1:160 (IQR 1:80–1:320). In a subset of nasopharyngeal swab samples from Brazil that underwent genomic sequencing, no evidence of neutralization-escape mutants was detected.CONCLUSION In adults hospitalized with severe COVID-19, use of convalescent plasma was not associated with significant improvement in day 28 clinical status. However, convalescent plasma was associated with significantly improved survival. A possible explanation is that survivors remained hospitalized at their baseline clinical status.TRIAL REGISTRATION ClinicalTrials.gov, NCT04359810.FUNDING Amazon Foundation, Skoll Foundation.
Max R. O’Donnell, Beatriz Grinsztejn, Matthew J. Cummings, Jessica E. Justman, Matthew R. Lamb, Christina M. Eckhardt, Neena M. Philip, Ying Kuen Cheung, Vinay Gupta, Esau João, Jose Henrique Pilotto, Maria Pia Diniz, Sandra Wagner Cardoso, Darryl Abrams, Kartik N. Rajagopalan, Sarah E. Borden, Allison Wolf, Leon Claude Sidi, Alexandre Vizzoni, Valdilea G. Veloso, Zachary C. Bitan, Dawn E. Scotto, Benjamin J. Meyer, Samuel D. Jacobson, Alex Kantor, Nischay Mishra, Lokendra V. Chauhan, Elizabeth F. Stone, Flavia Dei Zotti, Francesca La Carpia, Krystalyn E. Hudson, Stephen A. Ferrara, Joseph Schwartz, Brie A. Stotler, Wen-Hsuan W. Lin, Sandeep N. Wontakal, Beth Shaz, Thomas Briese, Eldad A. Hod, Steven L. Spitalnik, Andrew Eisenberger, Walter I. Lipkin
BACKGROUND SARS-CoV-2 plasma viremia has been associated with severe disease and death in COVID-19 in small-scale cohort studies. The mechanisms behind this association remain elusive.METHODS We evaluated the relationship between SARS-CoV-2 viremia, disease outcome, and inflammatory and proteomic profiles in a cohort of COVID-19 emergency department participants. SARS-CoV-2 viral load was measured using a quantitative reverse transcription PCR–based platform. Proteomic data were generated with Proximity Extension Assay using the Olink platform.RESULTS This study included 300 participants with nucleic acid test–confirmed COVID-19. Plasma SARS-CoV-2 viremia levels at the time of presentation predicted adverse disease outcomes, with an adjusted OR of 10.6 (95% CI 4.4–25.5, P < 0.001) for severe disease (mechanical ventilation and/or 28-day mortality) and 3.9 (95% CI 1.5–10.1, P = 0.006) for 28-day mortality. Proteomic analyses revealed prominent proteomic pathways associated with SARS-CoV-2 viremia, including upregulation of SARS-CoV-2 entry factors (ACE2, CTSL, FURIN), heightened markers of tissue damage to the lungs, gastrointestinal tract, and endothelium/vasculature, and alterations in coagulation pathways.CONCLUSION These results highlight the cascade of vascular and tissue damage associated with SARS-CoV-2 plasma viremia that underlies its ability to predict COVID-19 disease outcomes.FUNDING Mark and Lisa Schwartz; the National Institutes of Health (U19AI082630); the American Lung Association; the Executive Committee on Research at Massachusetts General Hospital; the Chan Zuckerberg Initiative; Arthur, Sandra, and Sarah Irving for the David P. Ryan, MD, Endowed Chair in Cancer Research; an EMBO Long-Term Fellowship (ALTF 486-2018); a Cancer Research Institute/Bristol Myers Squibb Fellowship (CRI2993); the Harvard Catalyst/Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, NIH awards UL1TR001102 and UL1TR002541-01); and by the Harvard University Center for AIDS Research (National Institute of Allergy and Infectious Diseases, 5P30AI060354).
Yijia Li, Alexis M. Schneider, Arnav Mehta, Moshe Sade-Feldman, Kyle R. Kays, Matteo Gentili, Nicole C. Charland, Anna L.K. Gonye, Irena Gushterova, Hargun K. Khanna, Thomas J. LaSalle, Kendall M. Lavin-Parsons, Brendan M. Lilley, Carl L. Lodenstein, Kasidet Manakongtreecheep, Justin D. Margolin, Brenna N. McKaig, Blair A. Parry, Maricarmen Rojas-Lopez, Brian C. Russo, Nihaarika Sharma, Jessica Tantivit, Molly F. Thomas, James Regan, James P. Flynn, Alexandra-Chloé Villani, Nir Hacohen, Marcia B. Goldberg, Michael R. Filbin, Jonathan Z. Li
BACKGROUND. VRC01, a potent, broadly-neutralizing monoclonal antibody, inhibits simian-HIV infection in animal models. HVTN 104 assessed VRC01 safety and pharmacokinetics in humans. We extend the clinical evaluation to determine intravenous-infused VRC01 distribution and protective function at mucosal sites of HIV-1 entry. METHODS. Healthy, HIV-1-uninfected men (n=7) and women (n=5) receiving VRC01 every two months provided mucosal and serum samples once, 4-13 days post-infusion. Eleven male and 8 female HIV-seronegative volunteers provided untreated control samples. VRC01 levels were measured in serum, secretions and tissue, and HIV-1 inhibition was determined in tissue explants. RESULTS. Median VRC01 levels were quantifiable in serum (96.2 µg/ml or 1.3 pg/ng protein), rectal tissue (0.11 pg/ng protein), rectal secretions (0.13 pg/ng protein), vaginal tissue (0.1 pg/ng protein) and cervical secretions (0.44 pg/ng protein) from all recipients. VRC01/IgG ratios in male serum correlated with those in paired rectal tissue (r=0.893, P=0.012) and rectal secretions (r=0.9643, P=0.003). Ex vivo HIV-1Bal26 challenge infected 4/21 rectal explants from VRC01-infused versus 20/22 from controls (P=0.005); HIV-1 Du422.1 infected 20/21 rectal explants of VRC01 recipients and 12/12 from controls (P=0.639). HIV-1Bal26 infected 0/14 vaginal explants of VRC01 recipients compared to 23/28 control explants (P=0.003). CONCLUSION. Intravenous VRC01 distributes into the female genital and male rectal mucosa and retains anti-HIV-1 functionality, inhibiting a highly neutralization-sensitive but not a highly-resistant HIV-1 strain in mucosal tissue. These findings lend insight into VRC01 mucosal infiltration and provide perspective to in vivo protective efficacy. FUNDING. National Institute of Allergy and Infectious Diseases and Bill & Melinda Gates Foundation.
Rena D. Astronomo, Maria P. Lemos, Sandeep R. Narpala, Julie Czartoski, Lamar Ballweber Fleming, Kelly E. Seaton, Madhu Prabhakaran, Yunda Huang, Yiwen Lu, Katharine Westerberg, Lily Zhang, Mary K. Gross, John Hural, Hong-Van Tieu, Lindsey R. Baden, Scott Hammer, Ian Frank, Christina Ochsenbauer, Nicole Grunenberg, Julie E. Ledgerwood, Kenneth Mayer, Georgia Tomaras, Adrian B. McDermott, M. Juliana McElrath
Pyridoxine-dependent epilepsy (PDE-ALDH7A1), also known as antiquitin deficiency, is an inborn error of lysine metabolism that presents with refractory epilepsy in newborns. Bi-allelic ALDH7A1 variants lead to deficiency of α-aminoadipic semialdehyde dehydrogenase, resulting in accumulation of piperideine-6-carboxylate (P6C), and secondary deficiency of the important co-factor pyridoxal-5’-phosphate (PLP, active vitamin B6) through its complexation with P6C. Vitamin B6 supplementation resolves epilepsy in patients, but despite this treatment, intellectual disability may occur. Early diagnosis and treatment, preferably based on newborn screening, potentially optimize long-term clinical outcome. However, the currently known diagnostic PDE-ALDH7A1 biomarkers are incompatible with newborn screening procedures. Combining of the innovative analytical methods untargeted metabolomics and infrared ion spectroscopy, we were able to discover a novel biomarker for PDE-ALDH7A1,2S,6S- and 2S,6R-oxopropylpiperidine-2-carboxylic acid (2-OPP), and confirmed 6-oxopiperidine-2-carboxylic acid (6-oxoPIP)as biomarker. We demonstrated the applicability of 2-OPP as a PDE-ALDH7A1 biomarker in newborn screening. Additionally, we showed that 2-OPP accumulates in brain tissue of patients and aldh7a1 knock-out mice, and induced epilepsy-like behavior in a zebrafish model system. We speculate that 2-OPP may contribute to ongoing neurotoxicity, also in treated PDE-ALDH7A1 patients. As 2-OPP formation appears to increase upon ketosis, we emphasize the importance of avoiding catabolism in PDE-ALDH7A1 patients.
Udo F.G. Engelke, Rianne E. van Outersterp, Jona Merx, Fred A.M.G. van Geenen, Arno van Rooij, Giel Berden, Marleen C.D.G. Huigen, Leo A.J. Kluijtmans, Tessa M.A. Peters, Hilal H. Al-Shekaili, Blair R. Leavitt, Erik de Vrieze, Sanne Broekman, Erwin van Wijk, Laura A. Tseng, Purva Kulkarni, Floris P.J.T. Rutjes, Jasmin Mecinovic, Eduard A. Struys, Laura A. Jansen, Sidney M. Gospe, Jr., Saadet Mercimek-Andrews, Keith Hyland, Michel A.A.P. Willemsen, Levinus A. Bok, Clara D.M. Van Karnebeek, Ron A. Wevers, Thomas J. Boltje, Jos Oomens, Jonathan Martens, Karlien L.M. Coene
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