Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Tumor Targeting Using Anti–Epidermal Growth Factor Receptor (ior egf/r3) Immunoconjugate with a Tetraaza Macrocyclic Agent (DO3A-EA)

Epidermal growth factor receptor (EGFR) signaling inhibition represents a highly promising arena for the application of molecularly targeted cancer therapies. EGFR conjugated metal chelates have been proposed as potential imaging agents for cancers that overexpress EGFR receptors. Through improved understanding of EGFR biology in human cancers, there is anticipation that more tumor-selective therapy approaches with diminished collateral normal tissue toxicity can be advanced. We report here on the results with a thermodynamically stable chelate, 1,4,7-tris(carboxymethyl)-10-(2-aminoethyl)-1,4,7,10-tetraazacyclododecane (DO3A-EA) and anti-EGFr (ior egf/r3) conjugate to develop immunospecifc imaging agent. Conjugation and labelling with anti-EGFr was performed using standard procedure and subjected to purification on size exclusion chromatography. The conjugated antibodies were labeled with a specific activity 20-30 mCi/mg of protein. Labeling efficiencies were measured by ascending paper chromatography on ITLC-SG strips. Radiolabeling of the immunoconjugate was found to be 98.5 ± 0.30%. 99m Tc-DO3A-EA-EGFr conjugate was studied in athymic mice bearing U-87MG, MDA-MB-468 tumors following intravenous injection. Pharmacokinetic and biodistribution studies confirmed long circulation times (t 1/2 (fast)= 45 min and t 1/2 (slow)=4 hours 40 min) and efficient accumulation in tumors. Biodistribution studies in athymic mice grafted with U-87MG human glioblastoma multiforme and Hela human cervical carcinoma tumors revealed significant localization of 99m Tc-labeled antibodies conjugate in tumors and reduced accumulation in normal organs. This new chelating agent is promising for immunoscintigraphy since good tumour-to-normal organ contrast could be demonstrated. These properties can be exploited for immunospecifc contrast agents in nuclear medicine and SPECT imaging

A deconvolution algorithm for multi-echo functional MRI: Multi-echo Sparse Paradigm Free Mapping

Available online 13 August 2019.This work introduces a novel algorithm for deconvolution of the BOLD signal in multi-echo fMRI data: Multi-echo Sparse Paradigm Free Mapping (ME-SPFM). Assuming a linear dependence of the BOLD percent signal change on the echo time (TE) and using sparsity-promoting regularized least squares estimation, ME-SPFM yields voxelwise time-varying estimates of the changes in the apparent transverse relaxation (⁎) without prior knowledge of the timings of individual BOLD events. Our results in multi-echo fMRI data collected during a multi-task event-related paradigm at 3 Tesla demonstrate that the maps of ⁎ changes obtained with ME-SPFM at the times of the stimulus trials show high spatial and temporal concordance with the activation maps and BOLD signals obtained with standard model-based analysis. This method yields estimates of ⁎ having physiologically plausible values. Owing to its ability to blindly detect events, ME-SPFM also enables us to map ⁎ associated with spontaneous, transient BOLD responses occurring between trials. This framework is a step towards deciphering the dynamic nature of brain activity in naturalistic paradigms, resting-state or experimental paradigms with unknown timing of the BOLD events.We thank Prof. Penny A. Gowland for helpful discussion regarding the contents of this manuscript, as well as the anonymous reviewers for their valuable comments and feedback. This research was possible thanks to the support of the Spanish Ministry of Economy and Competitiveness through the Juan de la Cierva Fellowship (IJCI-2014-20821) and Ramon y Cajal Fellowship (RYC-2017-21845), the Spanish State Research Agency through the BCBL ”Severo Ochoa” excellence accreditation (SEV-2015-490), the Basque Government through the BERC 2018- 2021 program, the National Institute of Mental Health Intramural Research Program (NIH clinical protocol number NCT00001360, protocol ID 93-M-0170, Annual report ZIAMH002783-16), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 713673, and a fellowship from La Caixa Foundation (ID 100010434) (fellowship code LCF/BQ/IN17/11620063). Portions of this study used the highperformance computational capabilities of the NIH High Performance Cluster (Biowulf) at the National Institutes Health, Bethesda, MD (http://hpc.nih.gov)

Novel positron emission tomography radiotracers in brain tumor imaging

Although [18F] 2-fluoro-2-deoxy-D-glucose (FDG) is the most widely used radiopharmaceutical the world over, it is not the ideal tracer for brain imaging, owing to its high physiological cortical uptake and lack of specificity. This has paved the way for the introduction of several novel radiotracers, each with their own inherent strengths and limitations. We present the insights gained from the use of these radiotracers at our institution

Radiolabeling and Preclinical Evaluation of a New S‑Alkylated Cysteine Derivative Conjugated to C‑Substituted Macrocycle for Positron Emission Tomography

A new S-alkylated cysteine-derivatized tumor targeting agent, 2,2′-(12-(2-((2-acetamido-2-carboxyethyl)­thio)­acetamido)-11,13-dioxo-1,4,7,10-tetraazacyclotridecane-4,7-diyl)­diacetic acid was developed for positron emission tomography (PET) imaging. <i>N</i>-Acetyl cysteine (NAC) was conjugated to ATRIDAT as a specific targeting agent toward L-type and ASC amino acid transporter systems in the oncogenic cells. NAC was attached via S-alkylation to prevent its incorporation at undesired recognition sites affecting the signal-to-noise ratio. NAC-ATRIDAT was subjected to gallium-68 complexation with >75% radiolabeling yield. The radiocomplex was purified through the tc18 cartridge to obtain 99.89% radiochemical yield. IC-50 of the NAC-ATRIDAT conjugate was 0.8 mM in A549 cells as evaluated through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide assay. Binding affinity experiments on A549 cells showed noteworthy binding with <i>K</i>_D in the nanomolar range. A time course study showed a <i>K</i>_m value of 0.19 μM and <i>V</i>_max value of 0.49 pmol/μg protein/min showing reasonable tumor kinetics. Efflux studies showed that the synthesized radioligand is transported majorly by LAT followed by the ASC system. Clearance was found to be renal with 7.67 ± 1.48% ID/g uptake at 30 min which substantially declined to 0.52 ± 0.% ID/g at 4 h. A significant uptake of 10.06 ± 1.056% ID/g was observed at the tumor site in mice at 1 h. μPET images revealed a high contrast with a tumor-to-kidney ratio of 4.8 and a tumor-to-liver ratio of 35.85 at 1 h after injection. These preclinical in vitro and in vivo evaluation supports its potential on the way of becoming a successful ⁶⁸Ga-radiolabeled amino acid-based PET imaging agent

DMA, a Small Molecule, Increases Median Survival and Reduces Radiation-Induced Xerostomia via the Activation of the ERK1/2 Pathway in Oral Squamous Cell Carcinoma

Survival, recurrence, and xerostomia are considerable problems in the treatment of oral squamous carcinoma patients. In this study, we investigated the role of DMA (5-(4-methylpiperazin-1-yl)-2-[2&prime;-(3,4-dimethoxyphenyl)5&Prime;benzimidazoyl]benzimidazole) as a salivary gland cytoprotectant in a patient-derived xenograft mouse model. A significant increase in saliva secretion was observed in the DMA-treated xenograft compared to radiation alone. Repeated doses of DMA with a high dose of radiation showed a synergistic effect on mice survival and reduced tumor growth. The mean survival rate of tumor-bearing mice was significantly enhanced. The increased number of Ki-67-stained cells in the spleen, intestine, and lungs compared to the tumor suggests DMA ablates the tumor but protects other organs. The expression of aquaporin-5 was restored in tumor-bearing mice injected with DMA before irradiation. The reduced expression of &alpha;v&beta;3 integrin and CD44 in DMA alone and DMA with radiation-treated mice suggests a reduced migration of cells and stemness of cancer cells. DMA along with radiation treatment results in the activation of the Ras/Raf/MEK/ERK pathway in the tumor, leading to apoptosis through caspase upregulation. In conclusion, DMA has strong potential for use as an adjuvant in radiotherapy in OSCC patients