Publications by authors named "Arjun Patel"

14 Publications

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Increased peripheral blood neutrophil activation phenotypes and NETosis in critically ill COVID-19 patients: a case series and review of the literature.

Clin Infect Dis 2021 May 14. Epub 2021 May 14.

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA.

Background: Increased inflammation has been well defined in COVID-19, while definitive pathways driving severe forms of this disease remain uncertain. Neutrophils are known to contribute to immunopathology in infections, inflammatory diseases and acute respiratory distress syndrome (ARDS), a primary cause of morbidity and mortality in COVID-19. Changes in neutrophil function in COVID-19 may give insight into disease pathogenesis and identify therapeutic targets.

Methods: Blood was obtained serially from critically ill COVID-19 patients for eleven days. Neutrophil extracellular trap formation (NETosis), oxidative burst, phagocytosis and cytokine levels were assessed. Lung tissue was obtained immediately post-mortem for immunostaining. Pubmed searches for neutrophils, lung and COVID-19 yielded ten peer-reviewed research articles in English.

Results: Elevations in neutrophil-associated cytokines IL-8 and IL-6, and general inflammatory cytokines IP-10, GM-CSF, IL-1b, IL-10 and TNF, were identified both at first measurement and across hospitalization (p<0.0001). COVID neutrophils had exaggerated oxidative burst (p<0.0001), NETosis (p<0.0001) and phagocytosis (p<0.0001) relative to controls. Increased NETosis correlated with leukocytosis and neutrophilia, and neutrophils and NETs were identified within airways and alveoli in lung parenchyma of 40% of SARS-CoV-2 infected lungs available for examination (2 out of 5). While elevations in IL-8 and ANC correlated with disease severity, plasma IL-8 levels alone correlated with death.

Conclusions: Literature to date demonstrates compelling evidence of increased neutrophils in the circulation and lungs of COVID-19 patients. importantly, neutrophil quantity and activation correlates with severity of disease. Similarly, our data shows that circulating neutrophils in COVID-19 exhibit an activated phenotype with enhanced NETosis and oxidative burst.
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http://dx.doi.org/10.1093/cid/ciab437DOI Listing
May 2021

Restoration of fitness lost due to dysregulation of the pyruvate dehydrogenase complex is triggered by ribosomal binding site modifications.

Cell Rep 2021 Apr;35(1):108961

Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kemitorvet, Building 220, 2800 Kongens, Lyngby, Denmark. Electronic address:

Pyruvate dehydrogenase complex (PDC) functions as the main determinant of the respiro-fermentative balance because it converts pyruvate to acetyl-coenzyme A (CoA), which then enters the TCA (tricarboxylic acid cycle). PDC is repressed by the pyruvate dehydrogenase complex regulator (PdhR) in Escherichia coli. The deletion of the pdhR gene compromises fitness in aerobic environments. We evolve the E. coli pdhR deletion strain to examine its achievable growth rate and the underlying adaptive strategies. We find that (1) optimal proteome allocation to PDC is critical in achieving optimal growth rate; (2) expression of PDC in evolved strains is reduced through mutations in the Shine-Dalgarno sequence; (3) rewiring of the TCA flux and increased reactive oxygen species (ROS) defense occur in the evolved strains; and (4) the evolved strains adapt to an efficient biomass yield. Together, these results show how adaptation can find alternative regulatory mechanisms for a key cellular process if the primary regulatory mode fails.
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http://dx.doi.org/10.1016/j.celrep.2021.108961DOI Listing
April 2021

The Expanding Computational Toolbox for Engineering Microbial Phenotypes at the Genome Scale.

Microorganisms 2020 Dec 21;8(12). Epub 2020 Dec 21.

Department of Bioengineering, University of California, San Diego, San Diego, CA 92093, USA.

Microbial strains are being engineered for an increasingly diverse array of applications, from chemical production to human health. While traditional engineering disciplines are driven by predictive design tools, these tools have been difficult to build for biological design due to the complexity of biological systems and many unknowns of their quantitative behavior. However, due to many recent advances, the gap between design in biology and other engineering fields is closing. In this work, we discuss promising areas of development of computational tools for engineering microbial strains. We define five frontiers of active research: (1) Constraint-based modeling and metabolic network reconstruction, (2) Kinetics and thermodynamic modeling, (3) Protein structure analysis, (4) Genome sequence analysis, and (5) Regulatory network analysis. Experimental and machine learning drivers have enabled these methods to improve by leaps and bounds in both scope and accuracy. Modern strain design projects will require these tools to be comprehensively applied to the entire cell and efficiently integrated within a single workflow. We expect that these frontiers, enabled by the ongoing revolution of big data science, will drive forward more advanced and powerful strain engineering strategies.
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http://dx.doi.org/10.3390/microorganisms8122050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767376PMC
December 2020

An Improved Recombineering Toolset for Plants.

Plant Cell 2020 01 30;32(1):100-122. Epub 2019 Oct 30.

Department of Plant and Microbial Biology, Program in Genetics, North Carolina State University, Raleigh, North Carolina 27695

Gene functional studies often rely on the expression of a gene of interest as transcriptional and translational fusions with specialized tags. Ideally, this is done in the native chromosomal contexts to avoid potential misexpression artifacts. Although recent improvements in genome editing have made it possible to directly modify the target genes in their native chromosomal locations, classical transgenesis is still the preferred experimental approach chosen in most gene tagging studies because of its time efficiency and accessibility. We have developed a recombineering-based tagging system that brings together the convenience of the classical transgenic approaches and the high degree of confidence in the results obtained by direct chromosomal tagging using genome-editing strategies. These simple, scalable, customizable recombineering toolsets and protocols allow a variety of genetic modifications to be generated. In addition, we developed a highly efficient recombinase-mediated cassette exchange system to facilitate the transfer of the desired sequences from a bacterial artificial chromosome clone to a transformation-compatible binary vector, expanding the use of the recombineering approaches beyond Arabidopsis (). We demonstrated the utility of this system by generating more than 250 whole-gene translational fusions and 123 Arabidopsis transgenic lines corresponding to 62 auxin-related genes and characterizing the translational reporter expression patterns for 14 auxin biosynthesis genes.
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http://dx.doi.org/10.1105/tpc.19.00431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961616PMC
January 2020

Spontaneous splenic rupture: a rare first presentation of diffuse large B cell lymphoma.

BMJ Case Rep 2019 Aug 26;12(8). Epub 2019 Aug 26.

Department of Surgery, Wexham Park Hospital, Slough, UK.

Spontaneous splenic rupture (SSR) is a rare but potentially life-threatening entity. It can be due to neoplastic, infectious, haematological, inflammatory and metabolic causes. An iatrogenic or an idiopathic aetiology should also be considered. Depending on the degree of splenic injury and the haemodynamic status of the patient, it can be managed conservatively. A 61-year-old man presented to the emergency department with an acute abdomen, hypovolaemic shock and clotting abnormalities. However, his focused assessment with sonography for trauma showed no evidence of an aortic aneurysm, rupture or dissection. Further investigation with a CT angiogram aorta confirmed a subcapsular splenic haematoma with free fluid in the pelvis and a mass in the superior pole of the spleen. He was diagnosed with an SSR. He was initially managed non-operatively. However, his repeat CT showed an enlarging haematoma and he underwent embolisation of his splenic artery. Ultrasound-guided core biopsy of his splenic mass confirmed the diagnosis of diffuse large B-cell lymphoma. This paper will discuss the clinical presentation, differential diagnosis and management of SSR. Furthermore, it provides an important clinical lesson to maintain a high index of clinical suspicion for splenic injury in patients presenting with left upper quadrant abdominal pain radiating to the shoulder. This case also reinforces the importance of close observation and monitoring of those individuals treated conservatively for signs of clinical deterioration.
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http://dx.doi.org/10.1136/bcr-2019-231101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721361PMC
August 2019

Defining Pancreatitis as a Risk Factor for Pancreatic Cancer: The Role, Incidence, and Timeline of Development.

Pancreas 2019 09;48(8):1098-1101

From the Division of Gastroenterology, Allegheny Health Network, Pittsburgh, PA.

Objectives: Acute and/or chronic pancreatitis has been implicated as an important risk factor for pancreatic cancer; however, the incidence and temporal relationship of pancreatitis before pancreatic cancer diagnosis are unclear. We aim to understand the role and incidence of pancreatitis temporally with the development of pancreatic cancer.

Methods: A population-based study was used to investigate a temporal relationship between pancreatitis and pancreatic cancer diagnoses. Intervals of 3, 6, 12, 24, and 36 months were developed. Demographical data including age, sex, and race were also recorded and analyzed.

Results: A total of 50,080 patients were found to have a diagnosis of pancreatic cancer, of which 7420 (14.8%) had prior diagnoses of pancreatitis. Of those, 92% were between the ages of 40 and 89 years. African Americans had a higher rate of pancreatitis before cancer diagnosis when compared with whites (21.2% vs 14.8%, P < 0.0001). Further analysis revealed that pancreatitis occurred in 81.3% of patients 3 months before a diagnosis of pancreas cancer and 98.9% had established diagnoses of pancreatic cancer within 3 years.

Conclusions: Screening of patients older than 40 years who have pancreatitis and unclear etiology of pancreatitis may be warranted, especially in African Americans and male individuals.
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http://dx.doi.org/10.1097/MPA.0000000000001367DOI Listing
September 2019

Endovascular treatment of pulmonary embolism: Selective review of available techniques.

World J Radiol 2017 Dec;9(12):426-437

Division of Interventional Radiology, Department of Radiology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, United States.

Acute pulmonary embolism (PE) is the third most common cause of death in hospitalized patients. The development of sophisticated diagnostic and therapeutic modalities for PE, including endovascular therapy, affords a certain level of complexity to the treatment of patients with this important clinical entity. Furthermore, the lack of level I evidence for the safety and effectiveness of catheter directed therapy brings controversy to a promising treatment approach. In this review paper, we discuss the pathophysiology and clinical presentation of PE, review the medical and surgical treatment of the condition, and describe in detail the tools that are available for the endovascular therapy of PE, including mechanical thrombectomy, suction thrombectomy, and fibrinolytic therapy. We also review the literature available to date on these methods, and describe the function of the Pulmonary Embolism Response Team.
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http://dx.doi.org/10.4329/wjr.v9.i12.426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746646PMC
December 2017

Trypan Blue for the Assessment of Filtering Bleb Function During Cataract Surgery.

J Glaucoma 2018 03;27(3):246-250

Glaucoma Research Center, Wills Eye Hospital, Philadelphia, PA.

Purpose: Phacoemulsification has been cited as a possible cause of bleb failure in eyes with prior trabeculectomy. No method has been developed to directly evaluate the risk of bleb failure after phacoemulsification. We investigate the use of trypan blue during cataract surgery in the setting of a preexisting trabeculectomy to evaluate the functional status of the bleb and predict postoperative bleb function.

Materials And Methods: In total, 14 patients contributing 1 eye each with a history of prior trabeculectomy with mitomycin C undergoing phacoemulsification with intraocular lens implantation were enrolled in this prospective, nonrandomized clinical trial. At the time of phacoemulsification, trypan blue was instilled into the anterior chamber before capsulorhexis creation. Staining of the bleb was grouped as being mild or diffuse using intraoperative photographs. These eyes were followed for 1 year postoperatively and evaluated for intraocular pressure (IOP) control.

Results: The change in IOP was not significantly different between the 2 groups (P=0.14). A trend towards greater need for IOP-lowering medications was noted (P<0.10) in eyes with mild bleb staining. No statistically significant difference in rates of decreased bleb function was noted at 1-year follow-up after phacoemulsification.

Conclusion: The intensity of bleb staining with trypan blue during phacoemulsification is not associated with changes in IOP postoperatively. A trend towards decreased need for IOP-lowering medications was noted in eyes with diffuse bleb staining at 1 year after cataract surgery.
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http://dx.doi.org/10.1097/IJG.0000000000000865DOI Listing
March 2018

AMP-activated protein kinase fortifies epithelial tight junctions during energetic stress via its effector GIV/Girdin.

Elife 2016 11 4;5. Epub 2016 Nov 4.

Department of Medicine, University of California, San Diego, San Diego, United States.

Loss of epithelial polarity impacts organ development and function; it is also oncogenic. AMPK, a key sensor of metabolic stress stabilizes cell-cell junctions and maintains epithelial polarity; its activation by Metformin protects the epithelial barrier against stress and suppresses tumorigenesis. How AMPK protects the epithelium remains unknown. Here, we identify GIV/Girdin as a novel effector of AMPK, whose phosphorylation at a single site is both necessary and sufficient for strengthening mammalian epithelial tight junctions and preserving cell polarity and barrier function in the face of energetic stress. Expression of an oncogenic mutant of GIV (cataloged in TCGA) that cannot be phosphorylated by AMPK increased anchorage-independent growth of tumor cells and helped these cells to evade the tumor-suppressive action of Metformin. This work defines a fundamental homeostatic mechanism by which the AMPK-GIV axis reinforces cell junctions against stress-induced collapse and also provides mechanistic insight into the tumor-suppressive action of Metformin.
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http://dx.doi.org/10.7554/eLife.20795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119889PMC
November 2016

ATP13A3 and caveolin-1 as potential biomarkers for difluoromethylornithine-based therapies in pancreatic cancers.

Am J Cancer Res 2016 1;6(6):1231-52. Epub 2016 Jun 1.

Department of Medical Education, University of Central Florida College of Medicine 12722 Research Parkway, Orlando, Florida 32826, USA.

The purpose of this paper was to better understand the role of polyamine transport in pancreatic cancers.This paper identifies potential biomarkers for assessing the relative tumor commitment to polyamine biosynthesis or transport. Cell lines with low polyamine import activity and low ATP13A3 protein levels appear committed to polyamine biosynthesis and required high concentrations of the polyamine biosynthesis inhibitor, difluoromethylornithine (DFMO) to inhibit their growth (e.g., AsPC-1 and Capan 1). In contrast, cell lines with high polyamine import activity and high ATP13A3 protein expression (e.g., L3.6pl) demonstrated a commitment to polyamine transport and required lower DFMO concentrations to inhibit their growth. Pancreatic cancer cell lines which were most sensitive to DFMO also gave the highest EC50 values for the polyamine transport inhibitors (PTIs) tested indicating that more PTI was needed to inhibit the active polyamine transport systems of these cell lines. Most significant is that the combination therapy of DFMO+PTI was efficacious against both cell types with the PTI showing low efficacy in cell lines with low polyamine transport activity and high efficacy in cell lines with high polyamine transport activity. High ATP13A3 protein expression and moderate to low Cav-1 protein expression was shown to be predictive of tumors which effectively escape DFMO via polyamine import. In summary, this report demonstrates for the first time the role of ATP13A3 in polyamine transport and its use as a potential biomarker along with Cav-1 to select tumors most susceptible to DFMO. These findings may help stratify patients in the ongoing clinical trials with DFMO-based therapies and help predict tumor response.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937730PMC
July 2016

Pharmacokinetics of centhaquin citrate in a rat model.

J Pharm Pharmacol 2016 Jan 4;68(1):56-62. Epub 2016 Jan 4.

Department of Pharmacy Practice, Chicago College of Pharmacy, Midwestern University, Downers Grove, IL, USA.

Objective: Centhaquin citrate is a novel agent being developed for use in the treatment of haemorrhagic shock. It has decreased mortality in rat, rabbit and pig models of hypovolaemic shock compared to hypertonic saline and lactated Ringer's resuscitation. The pharmacokinetics of centhaquin citrate have not been described to date.

Methods: Sixteen male Sprague Dawley rats were given an intravenous bolus of 0.45 mg/kg centhaquin citrate. Rats were divided into two groups; plasma concentrations were measured at five time points for each group within 24 h after administration. Competing compartmental pharmacokinetic models were assessed. The nonparametric adaptive grid function within the Pmetrics package for R was used for parameter estimation. Predicted concentrations were calculated using population median and individual Bayesian posterior parameters.

Key Findings: A two-compartment model of centhaquin citrate best fit the data. Median (IQR) values for elimination coefficient (Ke), volume of distribution (V) and intercompartmental transfer rates (Kcp, Kpc) were 8.8 (5.2-12.8) h(-1), 6.4 (2.8-10.4) l, 11.9 (4.6-15.0) h(-1) and 3.7 (2.3-9.1) h(-1), respectively.

Conclusion: This is the first report of the pharmacokinetic parameters of centhaquin citrate in a rat model. Centhaquin citrate was found to have a short half-life with a large volume of distribution.
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http://dx.doi.org/10.1111/jphp.12498DOI Listing
January 2016

Thymosin β4 coated nanofiber scaffolds for the repair of damaged cardiac tissue.

J Nanobiotechnology 2014 Mar 24;12:10. Epub 2014 Mar 24.

Nanomedicine Research Laboratory, Department of Medical Laboratory Science, College of Health Sciences, University of Delaware, Newark, DE 19716, USA.

After a cardiac event, proper treatment and care of the damaged tissue is crucial in restoring optimal cardiac function and preventing future cardiac events. Recently, thymosin β4 has been found to play a vital role in cardiac cell health and development by regulating angiogenesis, inflammatory responses, and wound healing. We proposed that defined poly(ϵ-caprolactone) (PCL) nanoscaffolds coated with thymosin β4 could efficiently differentiate murine-derived cardiomyocytes into functioning cardiac tissue. PCL nanoscaffolds were developed through electrospinning technology, and subsequently coated with a thymosin β4 solution. Cardiomyocytes were seeded on coated and uncoated nanoscaffolds and observed for six days via fluorescent and electron microscopy. Our results demonstrated a robust growth and differentiation of cardiomyocytes on coated nanoscaffolds compared with uncoated, showing potential for nanoscaffold-mediated cardiac cell replacement in vivo after an MI or other cardiac event.
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http://dx.doi.org/10.1186/1477-3155-12-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3996948PMC
March 2014

An unusual case of abdominal distension: pneumoperitoneum secondary to pneumomediastinum in a patient with chronic obstructive pulmonary disease.

BMJ Case Rep 2012 Oct 10;2012. Epub 2012 Oct 10.

Department of Upper GI Surgery, St George's Hospital, London, UK.

A 68-year-old lady with end-stage chronic obstructive pulmonary disease presented with vomiting and abdominal pain. On examination her abdomen was grossly distended, diffusely tender and hyper-resonant. Imaging showed dilated loops of bowel and free air in the abdomen with no intestinal perforation. The free abdominal air had come down from the thorax by dissecting down around the oesophagus. A pneumomediastinum was present in her chest, secondary to her extensive emphysematous disease. She was treated conservatively and her pneumomediastinum resolved several weeks later, with subsequent resumption of intestinal motility and return to premorbid function. Surgical intervention would not have helped her condition.
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http://dx.doi.org/10.1136/bcr-2012-006969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560108PMC
October 2012

Clinical and biological significance of E-cadherin protein expression in invasive lobular carcinoma of the breast.

Am J Surg Pathol 2010 Oct;34(10):1472-9

Department of Histopathology, Nottingham University Hospitals NHS Trust, UK.

Background: Although virtually all cases of lobular carcinoma in situ lack E-cadherin expression, a proportion of morphologically typical invasive lobular carcinomas (ILCs) retain its expression. The frequency and significance of E-cadherin expression in ILC remain to be elucidated. In this study, we have assessed E-cadherin protein expression in a well-characterized series of histologically defined ILC (239 cases) with a long-term clinical follow-up to determine the frequency, clinical and biological significance of its expression. E-cadherin-positive ILCs (ILC+) were subsequently examined to assess the expression of component members of the E-cadherin membrane complex (E-cadherin, p120, α, β, and γ-catenins) to determine its integrity.

Results: Thirty-eight ILC cases (16%) showed positive E-cadherin expression (ILC+). Membranous expression of E-cadherin was mainly circumferential with frequent coexisting perimembranous cytoplasmic expression. No association between E-cadherin expression and any of the clinicopathologic variables, immunophenotype, or tumor behavior was identified, apart from an association with lobular histologic subtype and vascular invasion. Analysis of the E-cadherin-catenin complex showed abnormal expression of one or more of the catenin complex members in the majority of cases. The most frequent observation was the diffuse cytoplasmic expression of catenins, in particular p120, which showed similar expression to that reported in E-cadherin-negative ILCs.

Conclusions: These results provide evidence that E-cadherin is expressed in a proportion of ILC, however, unlike ductal carcinoma, its expression seems to be of limited significance and it is usually associated with evidence of impaired integrity of the E-cadherin-catenin membrane complex. Our data offer a possible explanation for the presence but lack functionality of E-cadherin in some cases of ILC and imply that immunohistochemical expression of E-cadherin per se in ILC histologic phenotypic tumors should not preclude its diagnosis.
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http://dx.doi.org/10.1097/PAS.0b013e3181f01916DOI Listing
October 2010