ResearchPad - editor's-choice https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin–angiotensin–aldosterone inhibitors]]> https://www.researchpad.co/article/elastic_article_12417 The current pandemic coronavirus SARS-CoV-2 infects a wide age group but predominantly elderly individuals, especially men and those with cardiovascular disease. Recent reports suggest an association with use of renin–angiotensin–aldosterone system (RAAS) inhibitors. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for coronaviruses. Higher ACE2 concentrations might lead to increased vulnerability to SARS-CoV-2 in patients on RAAS inhibitors.Methods and resultsWe measured ACE2 concentrations in 1485 men and 537 women with heart failure (index cohort). Results were validated in 1123 men and 575 women (validation cohort).The median age was 69 years for men and 75 years for women. The strongest predictor of elevated concentrations of ACE2 in both cohorts was male sex (estimate = 0.26, P < 0.001; and 0.19, P < 0.001, respectively). In the index cohort, use of ACE inhibitors, angiotensin receptor blockers (ARBs), or mineralocorticoid receptor antagonists (MRAs) was not an independent predictor of plasma ACE2. In the validation cohort, ACE inhibitor (estimate = –0.17, P = 0.002) and ARB use (estimate = –0.15, P = 0.03) were independent predictors of lower plasma ACE2, while use of an MRA (estimate = 0.11, P = 0.04) was an independent predictor of higher plasma ACE2 concentrations.ConclusionIn two independent cohorts of patients with heart failure, plasma concentrations of ACE2 were higher in men than in women, but use of neither an ACE inhibitor nor an ARB was associated with higher plasma ACE2 concentrations. These data might explain the higher incidence and fatality rate of COVID-19 in men, but do not support previous reports suggesting that ACE inhibitors or ARBs increase the vulnerability for COVID-19 through increased plasma ACE2 concentrations. ]]> <![CDATA[Deducing the N- and O-glycosylation profile of the spike protein of novel coronavirus SARS-CoV-2]]> https://www.researchpad.co/article/elastic_article_12396 The current emergence of the novel coronavirus pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) demands the development of new therapeutic strategies to prevent rapid progress of mortalities. The coronavirus spike (S) protein, which facilitates viral attachment, entry and membrane fusion is heavily glycosylated and plays a critical role in the elicitation of the host immune response. The spike protein is comprised of two protein subunits (S1 and S2), which together possess 22 potential N-glycosylation sites. Herein, we report the glycosylation mapping on spike protein subunits S1 and S2 expressed on human cells through high-resolution mass spectrometry. We have characterized the quantitative N-glycosylation profile on spike protein and interestingly, observed unexpected O-glycosylation modifications on the receptor-binding domain of spike protein subunit S1. Even though O-glycosylation has been predicted on the spike protein of SARS-CoV-2, this is the first report of experimental data for both the site of O-glycosylation and identity of the O-glycans attached on the subunit S1. Our data on the N- and O-glycosylation are strengthened by extensive manual interpretation of each glycopeptide spectra in addition to using bioinformatics tools to confirm the complexity of glycosylation in the spike protein. The elucidation of the glycan repertoire on the spike protein provides insights into the viral binding studies and more importantly, propels research toward the development of a suitable vaccine candidate.

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<![CDATA[Neuro-oncology management during the COVID-19 pandemic with a focus on WHO grades III and IV gliomas]]> https://www.researchpad.co/article/elastic_article_12351 Because of the increased risk in cancer patients of developing complications caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), physicians have to balance the competing risks of the negative impact of the pandemic and the primary tumor disease. In this consensus statement, an international group of experts present mitigation strategies and treatment guidance for patients suffering from high grade gliomas (HGGs) during the coronavirus disease 2019 (COVID-19) pandemic.Methods Sixteeninternational experts in the treatment of HGG contributed to this consensus-based practice recommendation, including neuro-oncologists, neurosurgeons, radiation oncologists, and a medical physicist. Generally, treatment of neuro-oncological patients cannot be significantly delayed and initiating therapy should not be outweighed by COVID-19. We present detailed interdisciplinary treatment strategies for molecular subgroups in 2 pandemic scenarios, a scale-up phase and a crisis phase.ConclusionThis practice recommendation presents a pragmatic framework and consensus-based mitigation strategies for the treatment of HGG patients during the SARS-CoV-2 pandemic. ]]> <![CDATA[Adherence to Treatment Guideline Improves Patient Outcomes in a Prospective Cohort of Adults Hospitalized for Community-Acquired Pneumonia]]> https://www.researchpad.co/article/elastic_article_10126 In this prospective study involving adults hospitalized with community-acquired pneumonia, adherence to treatment guidelines was independently associated with shorter hospitalization and improved survival. Our findings provided evidence for atypical pathogen coverage with doxycycline, which was less evaluated in other cohorts.

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<![CDATA[TASUKE+: a web-based platform for exploring GWAS results and large-scale resequencing data]]> https://www.researchpad.co/article/elastic_article_8842 Recent revolutionary advancements in sequencing technologies have made it possible to obtain mass quantities of genome-scale sequence data in a cost-effective manner and have drastically altered molecular biological studies. To utilize these sequence data, genome-wide association studies (GWASs) have become increasingly important. Hence, there is an urgent need to develop a visualization tool that enables efficient data retrieval, integration of GWAS results with diverse information and rapid public release of such large-scale genotypic and phenotypic data. We developed a web-based genome browser TASUKE+ (https://tasuke.dna.affrc.go.jp/), which is equipped with the following functions: (i) interactive GWAS results visualization with genome resequencing data and annotation information, (ii) PCR primer design, (iii) phylogenetic tree reconstruction and (iv) data sharing via the web. GWAS results can be displayed in parallel with polymorphism data, read depths and annotation information in an interactive and scalable manner. Users can design PCR primers for polymorphic sites of interest. In addition, a molecular phylogenetic tree of any region can be reconstructed so that the overall relationship among the examined genomes can be understood intuitively at a glance. All functions are implemented through user-friendly web-based interfaces so that researchers can easily share data with collaborators in remote places without extensive bioinformatics knowledge.

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<![CDATA[Prospective Longitudinal Analysis of Immune Responses in Pediatric Subjects After Pharyngeal Acquisition of Group A Streptococci]]> https://www.researchpad.co/article/elastic_article_8822 Despite the significant burden of disease associated with infection by group A streptococcus (GAS), little is known about the human immune response to GAS antigens after natural infection.Methods.We evaluated 195 serum samples obtained prospectively over a consecutive 24-month period from 41 pediatric subjects who experienced a new pharyngeal GAS acquisition. An enzyme-linked immunoassay was used to determine the kinetics and antigen specificity of antibodies against 13 shared GAS antigens and 18 type-specific M peptides. The majority of the antigens tested are currently being considered as vaccine candidates.Results.Twelve M types of GAS were recovered from 41 subjects who experienced 51 new GAS acquisitions that elicited antibody responses against at least 1 of the 31 antigens tested (immunologically significant new GAS acquisitions). The immune responses to the 13 shared antigens were highly variable. Increases in antibody levels were detected against a mean of 3.5 shared antigens (range, 1–8). Antibody responses to the homologous M peptide were observed in 32 (63%) of the 51 episodes. Seven subjects acquired more than 1 M type of GAS. There were no new immunologically significant acquisitions of an M type against which the subject had preexisting antibodies to the homologous M peptide. Of the subjects with new GAS acquisition, 65% were asymptomatic, yet immune responses were detected against 1 or more GAS antigens. Immune responses to streptolysin O and/or deoxyribonuclease B were observed after 67% of the new GAS acquisitions. Persistently positive (>12 weeks) throat culture results were returned for 20% of the 41 subjects despite immune responses to homologous M peptides and/or shared antigens.Conclusions.The availability of throat culture results, GAS isolates, and serial serum samples collected prospectively over a 2-year period of observation provided a unique opportunity for us to assess the serologic status of pediatric subjects before and after new pharyngeal acquisitions of GAS. With the exception of antibody responses to the homologous M peptides, no clear pattern of immune responses against the remaining GAS antigens was seen. There were no new immunologically significant acquisitions ofemm types of GAS against which the subjects had preexisting elevated levels of antibodies against the homologous M peptide. The observation that 65% of new GAS acquisitions caused no symptoms yet were immunologically significant suggests that the majority of infections are not detected, which would result in missed opportunities for primary prevention of rheumatic fever and rheumatic heart disease with appropriate antimicrobial therapy. ]]> <![CDATA[Structure of the <i>Cannabis sativa</i> olivetol‐producing enzyme reveals cyclization plasticity in type III polyketide synthases]]> https://www.researchpad.co/article/elastic_article_8276 Tetraketide synthase from Cannabis sativa is a type III polyketide synthase involved in cannabinoid production. Unlike chalcone and stilbene synthases, it cannot catalyse classical cyclization reactions to generate chalcone or stilbene acid products. Instead, it releases a linear tetraketide product that undergoes a non‐enzymatic C2→C7 decarboxylative aldol condensation to form a stilbene. In this study by Nigel Scrutton and co‐authors, structure determination and mutagenesis studies are performed to investigate mechanistic details of this Cannabis sativa tetraketide synthase.

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<![CDATA[Therapeutic Vaccine for Genital Herpes Simplex Virus-2 Infection: Findings From a Randomized Trial]]> https://www.researchpad.co/article/elastic_article_7218 Genital herpes simplex virus type 2 (HSV-2) infection causes recurrent lesions and frequent viral shedding. GEN-003 is a candidate therapeutic vaccine containing HSV-2 gD2∆TMR and ICP4.2, and Matrix-M2 adjuvant.Methods.Persons with genital herpes were randomized into 3 dose cohorts to receive 3 intramuscular doses 21 days apart of 10 µg, 30 µg, or 100 µg of GEN-003, antigens without adjuvant, or placebo. Participants obtained genital swab specimens twice daily for HSV-2 detection and monitored genital lesions for 28-day periods at baseline and at intervals after the last dose.Results.One hundred and thirty-four persons received all 3 doses. Reactogenicity was associated with adjuvant but not with antigen dose or dose number. No serious adverse events were attributed to GEN-003. Compared with baseline, genital HSV-2 shedding rates immediately after dosing were reduced with GEN-003 (from 13.4% to 6.4% for 30 μg [P < .001] and from 15.0% to 10.3% for 100 µg [P < .001]). Lesion rates were also significantly (P < .01) reduced immediately following immunization with 30 µg or 100 µg of GEN-003. GEN-003 elicited increases in antigen binding, virus neutralizing antibody, and T-cell responses.Conclusions.GEN-003 had an acceptable safety profile and stimulated humoral and cellular immune responses. GEN-003 at doses of 30 µg and 100 µg reduced genital HSV shedding and lesion rates.Clinical Trials Registration.NCT01667341 (funded by Genocea). ]]> <![CDATA[The effect of sleep restriction, with or without high‐intensity interval exercise, on myofibrillar protein synthesis in healthy young men]]> https://www.researchpad.co/article/elastic_article_6996 Sleep restriction has previously been associated with the loss of muscle mass in both human and animal models.The rate of myofibrillar protein synthesis (MyoPS) is a key variable in regulating skeletal muscle mass and can be increased by performing high‐intensity interval exercise (HIIE), although the effect of sleep restriction on MyoPS is unknown.In the present study, we demonstrate that participants undergoing a sleep restriction protocol (five nights, with 4 h in bed each night) had lower rates of skeletal muscle MyoPS; however, rates of MyoPS were maintained at control levels by performing HIIE during this period.Our data suggest that the lower rates of MyoPS in the sleep restriction group may contribute to the detrimental effects of sleep loss on muscle mass and that HIIE may be used as an intervention to counteract these effects.

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<![CDATA[Safety and Immunogenicity of the Respiratory Syncytial Virus Vaccine RSV/ΔNS2/Δ1313/I1314L in RSV-Seronegative Children]]> https://www.researchpad.co/article/N995bb3e9-b66b-4e90-a450-bd56d19e3756 A live attenuated respiratory syncytial virus (RSV) vaccine containing a deletion of the interferon antagonist NS2 gene and mutations in the polymerase gene was well tolerated and infectious, inducing primary neutralizing antibody responses and potent memory antibody responses in RSV-seronegative children.

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<![CDATA[COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options]]> https://www.researchpad.co/article/N70c389f1-f94c-463b-8546-7e6fca98c865 The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical challenge in decades. We provide a comprehensive review of the clinical course of COVID-19, its comorbidities, and mechanistic considerations for future therapies. While COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the cardiovascular system. Risk of severe infection and mortality increase with advancing age and male sex. Mortality is increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer. The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury [elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels], fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (DIC). Mechanistically, SARS-CoV-2, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane angiotensin-converting enzyme 2 (ACE2) —a homologue of ACE—to enter type 2 pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes. This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction (MI). While ACE2 is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis. Hence, patients should not discontinue their use. Moreover, renin–angiotensin–aldosterone system (RAAS) inhibitors might be beneficial in COVID-19. Initial immune and inflammatory responses induce a severe cytokine storm [interleukin (IL)-6, IL-7, IL-22, IL-17, etc.] during the rapid progression phase of COVID-19. Early evaluation and continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (D-dimer) after hospitalization may identify patients with cardiac injury and predict COVID-19 complications. Preventive measures (social distancing and social isolation) also increase cardiovascular risk. Cardiovascular considerations of therapies currently used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritonavir, as well as experimental therapies, such as human recombinant ACE2 (rhACE2), are discussed.

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<![CDATA[A quantitative framework for modeling COVID-19 risk during adjuvant therapy using published randomized trials of glioblastoma in the elderly]]> https://www.researchpad.co/article/Ne1f37f36-f8be-4537-bbec-2f067e4a42db During the ongoing COVID-19 pandemic, contact with the health care system for cancer treatment can increase risk of infection and associated mortality. Treatment recommendations must consider this risk for elderly and vulnerable cancer patients. We reanalyzed trials in elderly glioblastoma (GBM) patients, incorporating COVID-19 risk, in order to provide a quantitative framework for comparing different radiation (RT) fractionation schedules on patient outcomes.MethodsWe extracted individual patient-level data for 1321 patients from Kaplan–Meier curves from 5 randomized trials on treatment of elderly GBM patients including available subanalyses based on O6-methylguanine-DNA methyltransferase (MGMT) methylation status. We simulated trial data with incorporation of COVID-19–associated mortality risk in several scenarios (low, medium, and high infection and mortality risks). Median overall survival and hazard ratios were calculated for each simulation replicate.ResultsOur simulations reveal how COVID-19–associated risks affect survival under different treatment regimens. Hypofractionated RT with concurrent and adjuvant temozolomide (TMZ) demonstrated the best outcomes in low and medium risk scenarios. In frail elderly patients, shorter courses of RT are preferable. In patients with methylated MGMT receiving single modality treatment, TMZ-alone treatment approaches may be an option in settings with high COVID-19–associated risk.ConclusionsIncorporation of COVID-19–associated risk models into analysis of randomized trials can help guide clinical decisions during this pandemic. In elderly GBM patients, our results support prioritization of hypofractionated RT and highlight the utility of MGMT methylation status in decision making in pandemic scenarios. Our quantitative framework can serve as a model for assessing COVID-19 risk associated with treatment across neuro-oncology.Key Points• Re-analysis of randomized controlled trials in COVID-19 era gives insight on optimal treatment of GBM.• Hypofractionated RT or temozolomide alone may be reasonable options in high risk pandemic settings.• A quantitative framework incorporating COVID-19 risks can be applied across neuro-oncology. ]]> <![CDATA[Impact of the digital divide in the age of COVID-19]]> https://www.researchpad.co/article/N921e4ef4-a7ae-4f9f-8c6d-e23eb23a0d7f <![CDATA[Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum]]> https://www.researchpad.co/article/N3a9d367b-bcb5-4151-a6e0-f0abeb91d196

Bevan-Jones, Cope et al. report that neuroinflammation co-localizes with protein aggregation in all major types of frontotemporal dementia, both in vivo with positron emission tomography, and at post mortem. In vivo neuroinflammation patterns are disease-specific and can accurately classify patients into groups.

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<![CDATA[Long-term post-mortem studies following neurturin gene therapy in patients with advanced Parkinson’s disease]]> https://www.researchpad.co/article/N0afcdc7f-fa66-42c2-996e-1e1d0801fa5f

Chu et al. present findings from post-mortem assessment of two individuals with advanced Parkinson’s disease who received gene therapy with the trophic factor neurturin, 8 and 10 years prior to death. The cases represent the longest survival times reported to date for recipients of gene therapy for Parkinson’s disease.

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<![CDATA[Secondary prevention medications after coronary artery bypass grafting and long-term survival: a population-based longitudinal study from the SWEDEHEART registry]]> https://www.researchpad.co/article/N434e1c72-97a4-4973-85c2-103eb3153afe

Abstract

Aims

To evaluate the long-term use of secondary prevention medications [statins, β-blockers, renin–angiotensin–aldosterone system (RAAS) inhibitors, and platelet inhibitors] after coronary artery bypass grafting (CABG) and the association between medication use and mortality.

Methods and results

All patients who underwent isolated CABG in Sweden from 2006 to 2015 and survived at least 6 months after discharge were included (n = 28 812). Individual patient data from SWEDEHEART and other mandatory nationwide registries were merged. Multivariable Cox regression models using time-updated data on dispensed prescriptions were used to assess associations between medication use and long-term mortality. Statins were dispensed to 93.9% of the patients 6 months after discharge and to 77.3% 8 years later. Corresponding figures for β-blockers were 91.0% and 76.4%, for RAAS inhibitors 72.9% and 65.9%, and for platelet inhibitors 93.0% and 79.8%. All medications were dispensed less often to patients ≥75 years. Treatment with statins [hazard ratio (HR) 0.56, 95% confidence interval (95% CI) 0.52–0.60], RAAS inhibitors (HR 0.78, 95% CI 0.73–0.84), and platelet inhibitors (HR 0.74, 95% CI 0.69–0.81) were individually associated with lower mortality risk after adjustment for age, gender, comorbidities, and use of other secondary preventive drugs (all P < 0.001). There was no association between β-blockers and mortality risk (HR 0.97, 95% CI 0.90–1.06; P = 0.54).

Conclusion

The use of secondary prevention medications after CABG was high early after surgery but decreased significantly over time. The results of this observational study, with inherent risk of selection bias, suggest that treatment with statins, RAAS inhibitors, and platelet inhibitors is essential after CABG whereas the routine use of β-blockers may be questioned.

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<![CDATA[Low Sensitivity of Procalcitonin for Bacteremia at an Academic Medical Center: A Cautionary Tale for Antimicrobial Stewardship]]> https://www.researchpad.co/article/Nbe912c12-f2ec-425d-8aa3-7170de88cc6a

Abstract

Background

Procalcitonin testing has been adopted by antimicrobial stewardship programs as a means of reducing inappropriate antibiotic use, including within intensive care units (ICUs). However, concerns regarding procalcitonin’s sensitivity exist. The purpose of this study is to calculate the sensitivity of procalcitonin for bacteremia among hospitalized patients.

Methods

This was a retrospective cohort study of adult patients admitted to an academic medical center between July 1, 2018, and June 30, 2019, with ≥1 positive blood culture within 24 hours of admission and procalcitonin testing within 48 hours. Low procalcitonin was defined as <0.5 µg/L.

Results

A total of 332 patients were included. The sensitivity of procalcitonin for bacteremia was 62% at the sepsis threshold of 0.5 µg/L, 76% at a threshold of 0.25 µg/L, and 92% at a threshold of 0.1 µg/L. Of the 125 patients with low procalcitonin, 14% were initially admitted to the ICU and 9% required the use of vasopressors. In that same group, the top 3 organisms isolated were Staphylococcus aureus (39%), Escherichia coli (17%), and Klebsiella spp. (7%). Compared with those patients with elevated procalcitonin, patients with low procalcitonin were significantly more likely to have >24-hour delayed receipt of antibiotic therapy (3% vs 8%; P = .04), including among patients admitted to the ICU (1% vs 18%; P = .02).

Conclusions

The sensitivity of procalcitonin for bacteremia is unacceptably low for a rule-out test. Antimicrobial stewardship programs should use caution before promoting the withholding of antibiotic therapy for patients with low initial procalcitonin values.

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<![CDATA[2019_nCoV/SARS‐CoV‐2: rapid classification of betacoronaviruses and identification of Traditional Chinese Medicine as potential origin of zoonotic coronaviruses]]> https://www.researchpad.co/article/Nb31becdc-18ff-42c9-ab3a-16bced26325d

Abstract

The current outbreak of a novel severe acute respiratory syndrome‐like coronavirus, 2019_nCoV (now named SARS‐CoV‐2), illustrated difficulties in identifying a novel coronavirus and its natural host, as the coding sequences of various Betacoronavirus species can be highly diverse. By means of whole‐genome sequence comparisons, we demonstrate that the noncoding flanks of the viral genome can be used to correctly separate the recognized four betacoronavirus subspecies. The conservation would be sufficient to define target sequences that could, in theory, classify novel virus species into their subspecies. Only 253 upstream noncoding sequences of Sarbecovirus are sufficient to identify genetic similarities between species of this subgenus. Furthermore, it was investigated which bat species have commercial value in China, and would thus likely be handled for trading purposes. A number of coronavirus genomes have been published that were obtained from such bat species. These bats are used in Traditional Chinese Medicine, and their handling poses a potential risk to cause zoonotic coronavirus epidemics.

Significance and Impact of the Study

The noncoding upstream and downstream flanks of coronavirus genomes allow for rapid classification of novel Betacoronavirus species and correct identification of genetic relationships. Although bats are the likely natural host of 2019_nCoV, the exact bat species that serves as the natural host of the virus remains as yet unknown. Chinese bat species with commercial value were identified as natural reservoirs of coronaviruses and are used in Traditional Chinese Medicine. Since their trading provides a potential risk for spreading zoonoses, a change in these practices is highly recommended.

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<![CDATA[Coronavirus Disease 2019 Treatment: A Review of Early and Emerging Options]]> https://www.researchpad.co/article/N5cfa7dae-0ece-496a-b6a6-640a71707191

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has spread across the globe resulting in a pandemic. At the time of this review, COVID-19 has been diagnosed in more than 200 000 patients and associated with over 8000 deaths (Centers for Disease Control and Prevention, World Health Organization).

On behalf of the Society of Infectious Diseases Pharmacists, we herein summarize the current evidence as of March 18, 2020 to provide guidance on potential COVID-19 treatment options. It is important to caution readers that new data emerges daily regarding clinical characteristics, treatment options, and outcomes for COVID-19. Optimized supportive care remains the mainstay of therapy, and the clinical efficacy for the subsequent agents is still under investigation.

Antimicrobial stewardship programs, including infectious diseases pharmacists and physicians, are at the forefront of COVID-19 emergency preparedness.

We encourage all readers to continue to assess clinical data as it emerges and share their experience within our community in a well-controlled, adequately powered fashion.

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<![CDATA[HLA-B-associated transcript 3 (Bat3) stabilizes and activates p53 in a HAUSP-dependent manner]]> https://www.researchpad.co/article/N13c4ee2a-2984-4d72-9cd6-b9ee1c843c5e

Abstract

The p53 pathway is a highly complex signaling network including several key regulators. HAUSP is a critical component of the p53 pathway acting as a deubiquitinase for both p53 and its key repressor Mdm2. Here, we identified a novel HAUSP-interacting protein, HLA-B-associated transcript 3 (Bat3) and found it to be capable of inducing p53 stabilization and activation via a HAUSP-dependent mechanism, resulting in cell growth inhibition. Surprisingly, the deubiquitylating enzymatic activity of HAUSP was not required for this phenomenon. Co-immunoprecipitation showed that p53 coexisted in a complex with Bat3 and HAUSP in vivo, and HAUSP may serve as a binding mediator to enhance the interaction between p53 and Bat3. Further studies revealed that formation of this three-protein complex interfered with the binding of p53 to its proteasome receptor S5a and promoted the accumulation of p53 in nucleus. Notably, Mdm2 protein abundance is also regulated by Bat3 in the presence of HAUSP. Overexpression of Bat3 and HAUSP increases Mdm2 protein levels without influencing the p53–Mdm2 interaction and Mdm2-mediated p53 ubiquitination, indicating that Bat3–HAUSP-mediated protein stabilization is not specific to p53 and different mechanisms may be involved in Bat3-mediated regulation of p53–Mdm2 pathway. Together, our study unravels a novel mechanism by which p53 is stabilized and activated by HAUSP-mediated interaction with Bat3 and implies that Bat3 might function as a tumor suppressor through the stabilization of p53.

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