Publications by authors named "Renyuan Bai"

11 Publications

  • Page 1 of 1

Alpha-1 adrenergic receptor antagonists to prevent hyperinflammation and death from lower respiratory tract infection.

Elife 2021 Jun 11;10. Epub 2021 Jun 11.

Stanford Graduate School of Business, Stanford University, Stanford, United States.

In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by hyperinflammation, which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously demonstrated that alpha-1 adrenergic receptor (⍺-AR) antagonists can prevent hyperinflammation and death in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n = 18,547) and three cohorts with pneumonia (n = 400,907). Federated across two ARD cohorts, we find that patients exposed to ⍺-AR antagonists, as compared to unexposed patients, had a 34% relative risk reduction for mechanical ventilation and death (OR = 0.70, p = 0.021). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of ⍺-AR antagonists ameliorates lower respiratory tract infection-associated hyperinflammation and death, as observed in COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.61700DOI Listing
June 2021

Deuterium oxide as a contrast medium for real-time MRI-guided endovascular neurointervention.

Theranostics 2021 15;11(13):6240-6250. Epub 2021 Apr 15.

Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Endovascular intervention plays an important role in the treatment of various diseases, in which MRI-guidance can potentially improve precision. However, the clinical applications of currently available contrast media, including Gadolinium-based contrast agents and superparamagnetic iron oxide particles (SPIO), are hindered by safety concerns. In the present study, we sought to develop DO as a novel contrast agent for guiding endovascular neurointervention. Animal studies were approved by institutional ACUC and conducted using an 11.7 T Bruker Biospec system and a 3T Siemens Trio clinical scanner for rodent and canine imaging, respectively. The locally selective blood brain barrier opening (BBBO) in rat brains was obtained by intraarterial (IA) injection of mannitol. The dynamic T* EPI MRI sequence was used to study the trans-catheter perfusion territory by IA administered SPIO before mannitol administration, whereas a dynamic T FLASH sequence was used to acquire Gd contrast-enhanced MRI for assessing BBBO after injection of mannitol. The contrast generated by DO assessed by either EPI or FLASH methods was compared with the corresponding results assessed by SPIO or Gd. The utility of DO MRI was also demonstrated to guide drug delivery to glioma in a mouse model. Finally, the clinical utility of DO-MRI was demonstrated in a canine model. Our study has shown that the contrast generated by DO can be used to precisely delineate trans-catheter perfusion territory in both small and large animals. The perfusion territories determined by DO-MRI show moderate correlation with those by SPIO-MRI (Spearman coefficient r = 0.5234, P < 0.001). Moreover, our results show that the perfusion territory determined by DO-MRI can successfully predict the areas with BBBO after mannitol treatment similar to that assessed by Gd-MRI (Spearman coefficient r = 0.6923, P < 0.001). Using DO-MRI as imaging guidance, the optimal infusion rate in the mouse brain was determined to be 150 µL/min to maximize the delivery efficacy to the tumor without serious off-target delivery to the brain parenchyma. The enhanced drug delivery of antibodies to the brain tumor was confirmed by fluorescence imaging. Our study demonstrated that DO can be used as a negative MRI contrast medium to guide endovascular neurointervention. The established DO -MRI method is safe and quantitative, without the concern of contrast accumulation. These qualities make it an attempting approach for a variety of endovascular procedures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.55953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120199PMC
April 2021

Tumor Microenvironment Composition and Severe Cytokine Release Syndrome (CRS) Influence Toxicity in Patients with Large B-Cell Lymphoma Treated with Axicabtagene Ciloleucel.

Clin Cancer Res 2020 09 15;26(18):4823-4831. Epub 2020 Jul 15.

Department of Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Purpose: One of the challenges of adoptive T-cell therapy is the development of immune-mediated toxicities including cytokine release syndrome (CRS) and neurotoxicity (NT). We aimed to identify factors that place patients at high risk of severe toxicity or treatment-related death in a cohort of 75 patients with large B-cell lymphoma treated with a standard of care CD19 targeted CAR T-cell product (axicabtagene ciloleucel).

Experimental Design: Serum cytokine and catecholamine levels were measured prior to lymphodepleting chemotherapy, on the day of CAR T infusion and daily thereafter while patients remained hospitalized. Tumor biopsies were taken within 1 month prior to CAR T infusion for evaluation of gene expression.

Results: We identified an association between pretreatment levels of IL6 and life-threatening CRS and NT. Because the risk of toxicity was related to pretreatment factors, we hypothesized that the tumor microenvironment (TME) may influence CAR T-cell toxicity. In pretreatment patient tumor biopsies, gene expression of myeloid markers was associated with higher toxicity.

Conclusions: These results suggest that a proinflammatory state and an unfavorable TME preemptively put patients at risk for toxicity after CAR T-cell therapy. Tailoring toxicity management strategies to patient risk may reduce morbidity and mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-1434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501265PMC
September 2020

MRI detection of bacterial brain abscesses and monitoring of antibiotic treatment using bacCEST.

Magn Reson Med 2018 08 25;80(2):662-671. Epub 2018 Mar 25.

Russell H. Morgan Department of Radiology and Radiological Sciences, Division of MR Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Purpose: To develop a new MRI method to detect and characterize brain abscesses using the CEST contrast inherently carried by bacterial cells, namely bacCEST.

Methods: Bacteria S. aureus (ATCC #49775) and F98 and 9L glioma cells were injected stereotactically in the brains of F344 rats to form abscesses and tumors. The CEST signals of brain abscesses (n = 4) and tumors (n = 7) were acquired using 2 B values (i.e., 1 and 3 µT) and compared. The bacCEST signal of the brain abscesses in the rats (n = 3) receiving ampicillin (intraperitoneal injection 40 mg/kg twice daily) was acquired before, 4 and 10 days after the treatment.

Results: The bacCEST signal of S. aureus was characterized in vitro as a strong and broad signal in the range of 1 to 4 ppm, with the maximum contrast occurring at 2.6 ppm. The CEST signal in S. aureus-induced brain abscesses was significantly higher than that of contralateral parenchyma (p = .003). Moreover, thanks to their different B independence, brain abscesses and tumors could be effectively differentiated (p = .005) using ΔCEST(2.6 ppm, 3 µT-1 µT), defined by the difference between the CEST signal (offset = 2.6 ppm) acquired using B  = 3 µT and that of 1 µT. In treated rats, bacCEST MRI could detect the response of bacteria as early as 4 days after the antibiotic treatment (p = .035).

Conclusion: BacCEST MRI provides a new imaging method to detect, discriminate, and monitor bacterial infection in deep-seated organs. Because no contrast agent is needed, such an approach has a great translational potential for detecting and monitoring bacterial infection in deep-seated organs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mrm.27180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910221PMC
August 2018

Characterization of tumor vascular permeability using natural dextrans and CEST MRI.

Magn Reson Med 2018 02 28;79(2):1001-1009. Epub 2017 Nov 28.

F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland, USA.

Purpose: To investigate the use of natural dextrans as nano-sized chemical exchange saturation transfer (CEST) MRI probes for characterizing size-dependent tumor vascular permeability.

Methods: Dextrans of different molecular weight (10, 70, 150, and 2000 kD) were characterized for their CEST contrast. Mice (N = 5) bearing CT26 subcutaneous colon tumors were injected intravenously with 10 kD (D10, 6 nm) and 70 kD (D70, 12 nm) dextran at a dose of 375 mg/kg. The CEST-MRI signal in the tumors was assessed before and approximately 40 min after each injection using a dynamic CEST imaging scheme.

Results: All dextrans of different molecular weights have a strong CEST signal with an apparent maximum of approximately 0.9 ppm. The detectability and effects of pH and saturation conditions (B and T ) were investigated. When applied to CT26 tumors, the injection of D10 could produce a significant "dexCEST" enhancement in the majority of the tumor area, whereas the injection of D70 only resulted in an increase in the tumor periphery. Quantitative analysis revealed the differential permeability of CT26 tumors to different size particles, which was validated by fluorescence imaging and immunohistochemistry.

Conclusions: As a first application, we used 10- and 70-kD dextrans to visualize the spatially variable, size-dependent permeability in the tumor, indicating that nano-sized dextrans can be used for characterizing tumor vascular permeability with dexCEST MRI and, potentially, for developing dextran-based theranostic drug delivery systems. Magn Reson Med 79:1001-1009, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mrm.27014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772994PMC
February 2018

One-Component Supramolecular Filament Hydrogels as Theranostic Label-Free Magnetic Resonance Imaging Agents.

ACS Nano 2017 01 11;11(1):797-805. Epub 2017 Jan 11.

Department of Oncology, The First Affiliated Hospital of Zhengzhou University , 1 Jianshe Eastern Road, Zhengzhou 450052, Henan, China.

Gadolinium (Gd)-based compounds and materials are the most commonly used magnetic resonance imaging (MRI) contrast agents in the clinic; however, safety concerns associated with their toxicities in the free ionic form have promoted the development of new generations of metal-free contrast agents. Here we report a supramolecular strategy to convert an FDA-approved anticancer drug, Pemetrexed (Pem), to a molecular hydrogelator with inherent chemical exchange saturation transfer (CEST) MRI signals. The rationally designed drug-peptide conjugate can spontaneously associate into filamentous assemblies under physiological conditions and consequently form theranostic supramolecular hydrogels for injectable delivery. We demonstrated that the local delivery and distribution of Pem-peptide nanofiber hydrogels can be directly assessed using CEST MRI in a mouse glioma model. Our work lays out the foundation for the development of drug-constructed theranostic supramolecular materials with an inherent CEST MRI signal that enables noninvasive monitoring of their in vivo distribution and drug release.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsnano.6b07196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773287PMC
January 2017

Noninvasive imaging of infection after treatment with tumor-homing bacteria using Chemical Exchange Saturation Transfer (CEST) MRI.

Magn Reson Med 2013 Dec 7;70(6):1690-8. Epub 2013 Oct 7.

F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland, USA; Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Purpose: To develop a noninvasive MRI method for determining the germination and infection of tumor-homing bacteria in bacteriolytic cancer therapy using endogenous CEST contrast.

Methods: The CEST parameters of the anaerobic gram-positive bacterium Clostridium novyi-NT (C. novyi-NT) were first characterized in vitro, then used to detect C. novyi-NT germination and infection in subcutaneous CT26 colorectal tumor-bearing mice (n = 6) after injection of 300 million bacterial spores. Lipopolysacharide (LPS) injected mice were used to exclude that the changes of CEST MRI were due to inflammation.

Results: CEST contrast was observed over a broad frequency range for bacterial suspensions in vitro, with the maximum contrast around 2.6 ppm from the water resonance. No signal could be detected for bacterial spores, demonstrating the specificity for germination. In vivo, a significant elevation of CEST contrast was identified in C. novyi-NT infected tumors as compared to those before bacterial germination and infection (P < 0.05; n = 6). No significant change was observed in tumors with LPS-induced sterile inflammation (P > 0.05; n = 4).

Conclusion: Endogenous bacterial CEST contrast (bacCEST) can be used to monitor the germination and proliferation of the therapeutic bacterium C. novyi-NT without a need for exogenous cell labeling probes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mrm.24955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3857583PMC
December 2013

A robust approach to enhance tumor-selective accumulation of nanoparticles.

Oncotarget 2011 Jan-Feb;2(1-2):59-68

The Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and Sidney Kimmel Cancer Center at the Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.

While nanoparticles have shown great promise as drug carriers in cancer therapy, their effectiveness is critically dependent on the structural characteristics of the tumor vasculature. Here we demonstrate that several agents capable of inducing vascular responses akin to those observed in inflammatory processes enhance the accumulation of nanoparticles in tumors. The vascular-active agents tested in this study included a bacterium, a pro-inflammatory cytokine, and microtubule-destabilizing drugs. Using radiolabeled nanoparticles, we show that such agents can increase the tumor to blood ratio of radioactivity by more than 20-fold compared to nanoparticles alone. Moreover, vascular-active agents dramatically improved the therapeutic effect of nanoparticles containing radioactive isotopes or chemotherapeutic agents. This resulted in cures of animals with subcutaneous tumors and significantly prolonged the survival of animals with orthotopic brain tumors. In principle, a variety of vascular-active agents and macromolecular anticancer formulations can be combined, which makes this approach broadly applicable and particularly suited for the treatment of patients who have failed standard therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069713PMC
http://dx.doi.org/10.18632/oncotarget.227DOI Listing
July 2011

Evaluation of retinoic acid therapy for OTX2-positive medulloblastomas.

Neuro Oncol 2010 Jul 5;12(7):655-63. Epub 2010 Feb 5.

Department of Neurosurgery, Johns Hopkins University, CRB II Rm. 257, 1550 Orleans Street, Baltimore, MD 21231, USA.

The homeobox transcription factor OTX2 plays an essential role during embryonic brain development. It is normally silenced in the adult brain, but is overexpressed by genomic amplification or other mechanisms in the majority of medulloblastomas (MBs). Retinoic acids (RAs) can suppress OTX2 expression and inhibit MB growth. In this study, 9-cis RA most potently inhibited MB cell growth. 9-cis RA functions through the downregulation of OTX2 expression, which subsequently induces neuronal differentiation of OTX2-expressing cells. Treatment with 9-cis RA reduced the growth of D425 flank xenograft tumors in mice. In an intracranial model, however, MB tumors showed resistance to 9-cis RA treatment, and we implicated fibroblast growth factor (FGF) as a potential mediator of resistance to RA therapy. These findings suggest a mechanism for RA-mediated anti-tumor effect on OTX2-positive MB cells and indicate that therapeutic targeting of OTX2 might be effective if FGF pathway-mediated resistance can be overcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/nop062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940451PMC
July 2010

The origins of 168, W23, and other Bacillus subtilis legacy strains.

J Bacteriol 2008 Nov 22;190(21):6983-95. Epub 2008 Aug 22.

Bacillus Genetic Stock Center, The Ohio State University, 484 W. 12th Ave., Columbus, OH 43210, USA.

Bacillus subtilis is both a model organism for basic research and an industrial workhorse, yet there are major gaps in our understanding of the genomic heritage and provenance of many widely used strains. We analyzed 17 legacy strains dating to the early years of B. subtilis genetics. For three--NCIB 3610T, PY79, and SMY--we performed comparative genome sequencing. For the remainder, we used conventional sequencing to sample genomic regions expected to show sequence heterogeneity. Sequence comparisons showed that 168, its siblings (122, 160, and 166), and the type strains NCIB 3610 and ATCC 6051 are highly similar and are likely descendants of the original Marburg strain, although the 168 lineage shows genetic evidence of early domestication. Strains 23, W23, and W23SR are identical in sequence to each other but only 94.6% identical to the Marburg group in the sequenced regions. Strain 23, the probable W23 parent, likely arose from a contaminant in the mutagenesis experiments that produced 168. The remaining strains are all genomic hybrids, showing one or more "W23 islands" in a 168 genomic backbone. Each traces its origin to transformations of 168 derivatives with DNA from 23 or W23. The common prototrophic lab strain PY79 possesses substantial W23 islands at its trp and sac loci, along with large deletions that have reduced its genome 4.3%. SMY, reputed to be the parent of 168, is actually a 168-W23 hybrid that likely shares a recent ancestor with PY79. These data provide greater insight into the genomic history of these B. subtilis legacy strains.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JB.00722-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2580678PMC
November 2008

Coexpression of neuronatin splice forms promotes medulloblastoma growth.

Neuro Oncol 2008 Oct 13;10(5):716-24. Epub 2008 Aug 13.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231 USA.

Medulloblastoma (MB) is the most common pediatric brain cancer. Several important developmental pathways have been implicated in MB formation, but fewer therapeutic targets have been identified. To locate frequently overexpressed genes, we performed a comprehensive gene expression survey of MB. Our comparison of 20 primary tumors to normal cerebellum identified neuronatin (NNAT) as the most frequently overexpressed gene in our analysis. NNAT is a neural-specific developmental gene with alpha and beta splice forms. Functional evaluation revealed that RNA interference knockdown of NNAT causes a significant decrease in proliferation. Conversely, coexpression of both splice forms in NNAT-negative MB cell lines increased proliferation, caused a significant shift from G(1) to G(2)/M, and increased soft agar colony formation and size. When expressed individually, each NNAT splice form had much less effect on these in vitro oncogenic predictors. In an in vivo model, the coexpression of both splice forms conferred the ability of xenograft formation to human MB cells that do not normally form xenografts, whereas a control gene had no effect. Our findings suggest that the frequently observed overexpression of both NNAT splice forms in MB enhances growth in this cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1215/15228517-2008-038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2666248PMC
October 2008