Liquid biopsy testing in metastatic or advanced breast cancer patients during the COVID-19 pandemic

Objective: During the COVID-19 pandemic, cancer patients had restricted access to standard of care tissue biopsy. Liquid biopsy assays using next generation sequencing technology provides a less invasive method for determining circulating tumour mutations (ctDNA) associated with targeted treatments or prognosis. As part of deploying technology to help cancer patients obtain molecular testing, a clinical program was initiated to offer liquid biopsy testing for Canadian patients with advanced or metastatic breast cancer. Method(s): Blood was drawn in two 10 mL StreckTM DNA BCTs and sent to the CAP/CLIA/DAP accredited Imagia Canexia Health laboratory for testing using the clinically validated Follow ItTM liquid biopsy assay. Plasma was isolated using a double spin protocol and plasma cell-free DNA (cfDNA) extracted using an optimized Promega Maxwell RSC method. Extracted cfDNA was amplified using the multiplex amplicon-based hotspot 30 or 38 gene panel and sequenced. An inhouse developed bioinformatics pipeline and reporting platform were used to identify pathogenic single nucleotide variants (SNVs), indels (insertions and deletions), and gene amplification. Included in the panel are genes associated with metastatic breast cancer: AKT1, BRAF, ERBB2, ESR1, KRAS, PIK3CA, TP53. Result(s): To identify biomarkers, 1214 metastatic or advanced breast cancer patient cfDNA samples were tested. There were 15 cases sent for repeat testing. We reported 48% of samples harboring pathogenic ctDNA mutations in TP53 (22%), PIK3CA (19%), ESR1 (18%), AKT1 (2%), ERBB2 (1.5%). Co-occurring variants were identified in samples with ESR1/PIK3CA as well as TP53/PIK3CA (both p-values <0.001). Interestingly, 29% of samples with mutated ESR1 harbored >= 2 ESR1 ctDNA mutations. In 56% of cases, previous molecular testing indicated the cancer subtype as hormone receptor (ER, PR) positive with/without HER2 negative status. In this specific subgroup, 49% harbored ctDNA mutations with 63% of those being PIK3CA and/or ESR1 mutations. Conclusion(s): A population of Canadian women with metastatic breast cancer were tested using a liquid biopsy gene panel during the COVID-19 pandemic for identification of biomarkers for targeted therapeutic options. Over 50% of the samples were identified as hormone positive, with greater than 60% harboring PIK3CA and ESR1 ctDNA mutations. Studies have shown that metastatic PIK3CA mutated ER-positive/HER2-negative tumors are predictive to respond to alpelisib therapy and have FDA and Health Canada approval. Additionally, ESR1 mutations are associated with acquired resistance to antiestrogen therapies, and interestingly we identified 29% of ESR1 mutated samples with multiple mutations possibly indicating resistance subclones. In future studies, longitudinal monitoring for presence of multiple targetable and resistance mutations could be utilized to predict or improve clinical management.

Ups and Downs of Business Activity in the Waves of Crises, the Coronavirus Pandemic and Unprecedented Western Sanctions

Subject of article - the dynamics of the integrated Business Activity Index of the Institute of Economics of the Russian Academy of Sciences in 10 main areas of the national economy and the Index of output of goods and services by basic types of economic activity of Rosstat (Rosstat Index) from 2018 to July 2022 inclusive. Growth factors and a list of key macro indicators that determine the level of business activity in the relevant sectors of the economy, as well as the results of calculating the weights of these sectors, are considered. The aim of the article is to substantiate the advantages of the methodology for constructing the IE RAS Index, which includes development indicators of 10 areas of the national economy, in comparison with the Rosstat Index. Theoretical studies are based on practical calculations performed on the basis of official statistical reporting, and a comparative analysis of the results with the dynamics of the Rosstat Index. Research period: post-crisis 2018-2019, pandemic and post-pandemic 2020-2021 and initial stage of the mobilization period for the economy- January-July 2022. To calculate the IE RAS Index, the method of construction of integral estimates of macroeconomic dynamics, correlation analysis, as well as a matrix of coefficients of pair correlation for determination of index weights are used, which is a convincing justification of scientific novelty of the proposed methodology of construction and practical use of the IE RAS Index. Based on a comparative analysis of the dynamics of the indices, it was found that the maximum drop in the IE RAS Index and the Rosstat Index was observed in 2020, and the maximum growth was observed in the post-pandemic 2021. Moreover, according to the IE RAS methodology, larger parameters and earlier dates for the start of decline and growth of business activity in comparison with the Rosstat Index were recorded. As a result, new convincing evidence of the advantages of the IE RAS Index was obtained, the main of which is a more reliable and accurate determination of the critical moments of a change in the business activity trend and, accordingly, the timing of the onset and overcoming of crisis processes in socio-economic development. The authors conclude that, in the new geopolitical reality, it is necessary to include the IE RAS Index as a target indicator for the country's ability to secure state sovereignty. © Frenkel A. A., Tikhomirov B. I., Surkov A. A., 2023 .

Insights Into the Role of Angiotensin-Converting Enzyme 2 in the Onset of Severe Acute Respiratory Syndrome Coronavirus 2 Pathogenesis

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the outbreak of pneumonia which originated in Wuhan, China, at the end of 2019 has turned into a global pandemic—now termed coronavirus diseases 2019 (COVID-19). Like previously reported SARS-CoV strains, the newly discovered SARS-CoV-2 was also found to initiate the pathogenesis by binding with the angiotensin-converting enzyme 2 (ACE2), a receptor produced by various organs in the human body. Hence, COVID-19 is a viral multisystem disease which particularly infects the vascular system expressing ACE2 and reduced the ACE2 function;this further complexed by organ-specific pathogenesis related to the damage of cells expressing ACE2, such as alveolus, glomerulus, endothelium, and cardiac microvasculature. Under these conditions, it was advocated that the upregulation of ACE2 expression in predisposing individuals with aberrant renin–angiotensin system (RAS) level to advanced viral load on infection and relatively a greater number of cell death. Recently, a significant role of decreased ACE2 production and inequality between the RAS and ACE2/angiotensin-(1–7)/ MAS (mitochondrial Ang system) after the onset of SARS-CoV-2 infection was established as a key factor for multiple organ injury in SARS-CoV-2-infected individuals. Furthermore, restoration of this imbalance has been suggested as a therapeutic approach to attenuate organ injuries in SARS-CoV-2 infection. Based on available data, this chapter presents the updated mechanism of the multi-organ diseases causes by COVID-19 via ACE2 which can be further helpful in the development of specific therapeutics. © The Author(s), under exclusive licence to Springer Nature Singapore Pte Ltd. 2021.

Computational and Enzymatic Studies of Sartans in SARS-CoV-2 Spike RBD-ACE2 Binding: The Role of Tetrazole and Perspectives as Antihypertensive and COVID-19 Therapeutics.

This study is an extension of current research into a novel class of synthetic antihypertensive drugs referred to as "bisartans", which are bis-alkylated imidazole derivatives bearing two symmetric anionic biphenyltetrazoles. Research to date indicates that bisartans are superior to commercially available hypertension drugs, since the former undergo stronger docking to angiotensin-converting enzyme 2 (ACE2). ACE2 is the key receptor involved in SARS-CoV-2 entry, thus initiating COVID-19 infection and in regulating levels of vasoactive peptides such as angiotensin II and beneficial heptapeptides A(1-7) and Alamandine in the renin-angiotensin system (RAS). In previous studies using in vivo rabbit-iliac arterial models, we showed that Na+ or K+ salts of selected Bisartans initiate a potent dose-response inhibition of vasoconstriction. Furthermore, computational studies revealed that bisartans undergo stable binding to the vital interfacial region between ACE2 and the SARS-CoV-2 "receptor binding domain" (i.e., the viral RBD). Thus, bisartan homologs are expected to interfere with SARS-CoV-2 infection and/or suppress disease expression in humans. The primary goal of this study was to investigate the role of tetrazole in binding and the network of amino acids of SARS-CoV-2 Spike RBD-ACE2 complex involved in interactions with sartans. This study would, furthermore, allow the expansion of the synthetic space to create a diverse suite of new bisartans in conjunction with detailed computational and in vitro antiviral studies. A critical role for tetrazole was uncovered in this study, shedding light on the vital importance of this group in the binding of sartans and bisartans to the ACE2/Spike complex. The in silico data predicting an interaction of tetrazole-containing sartans with ACE2 were experimentally validated by the results of surface plasmon resonance (SPR) analyses performed with a recombinant human ACE2 protein.

Angiotensin and COVID-19

Coronavirus disease 2019 (COVID-19) is a highly contagious illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has spread rapidly worldwide since 2019, causing a high rate of deaths and disabilities. This virus exerts its pathogenicity through angiotensin-converting enzyme 2 (ACE2) receptor, expressed on a wide array of human cells. The infectious process starts with the engagement of ACE2 by protein S of the virus, which leads to the entry of viral genetic material within the host cell. COVID-19 induces imbalances of the renin–angiotensin system (RAS) manifesting with ACE upregulation and ACE2 downregulation. ACE converts angiotensin I into the peptide angiotensin (Ang) II, which binds to and activates Ang II type 1 (AT1) and Ang II type 2 (AT2) receptors. The upregulation of the ACE/Ang II/AT1 signaling induces a series of deleterious effects in tissue and organs along with direct viral damage and proinflammatory cytokines. In general, Ang II mediates proliferation, inflammation, endothelial dysfunction, oxidative stress, and apoptosis. However, the negative effect of ACE signaling tends to be specific for all the organs (lungs, endothelium, kidneys, brain, and bowel) mainly affected by the virus. Given the key role of angiotensin in COVID-19, numerous experimental treatments have been tested to dampen the severe consequences of this unbalanced activation of RAS. © 2023 Elsevier Inc. All rights reserved.

The contribution of angiotensin peptides to cardiovascular neuroregulation in health and disease

The brain renin–angiotensin system (RAS) is critically involved in the cardiovascular regulation and energy homeostasis. The overwhelming evidence indicates that the central RAS closely cooperates with the systemic RAS by means of interactions with the autonomic nervous system and hormonal and humoral factors linking RAS with regulation of blood pressure, water–electrolyte equilibrium, and energy balance. Particularly significant roles in these interactions are played by aldosterone and vasopressin;however, other factors such as proinflammatory cytokines, growth factors, nitric oxide, prostaglandins, and ROS appear to be also essential players, especially during challenges (stress, hypoxia), and under pathological conditions (hypertension, heart failure, metabolic syndrome, atherosclerosis, COVID-19). Current pharmacotherapies of cardiovascular diseases are focused on the angiotensin-converting enzyme inhibitors and angiotensin type 1 receptor blockers and their effects on systemic RAS. A better understanding of neuroanatomical and neurochemical connections between central RAS and other regulatory systems should advance pharmacological interventions aimed at central RAS. © 2023 Elsevier Inc. All rights reserved.

Twitterchats as a means to educate patients with CRC and caregivers and stimulate collaborations

Background: During the COVID-19 pandemic, Twitter has been instrumental in accelerating knowledge dissemination and forging collaborations within the medical community and amongst patient advocates. Tweetchats within Twitter are scheduled conversations on a specific topic. In oncology, Tweetchats have been used by cancer advocates to spread awareness and for patient and caregiver education. A colorectal cancer (CRC) specific tweetchat did not previously exist. This describes the creation, and experiences with a CRC specific tweetchat. Method(s): The #CRCTrialsChat tweetchat was created by a patient advocate for colorectal cancer patients, caregivers and clinicians to meet and exchange clinical trial-related information. Two gastrointestinal (GI) medical oncologists and two radiation oncologists were enlisted as moderators. The topic for each session is chosen by the patient advocate, who creates an outline and divides the content, which is designed to last a one hour session. The idea is to create engaging, technical, but easy to understand content. Each moderator then works on the answers to their assigned section, which is edited to fit tweet character limit. Sessions may also have guest moderators with expertise on a specific topic. Through tweeting, moderators answer specific questions that come up during the session and later. Result(s): To date, we have had four sessions covering the following topics: Clinical trial basics, CRC Updates from ASCO22, ClinicalTrialFinders and BRAF-mutated tumors. The content created has been simple and engaging, the format has functioned smoothly, and the reach of #CRCTrialsChat has been steadily increasing. After the most recent session on BRAF in September 2022, the @CRCTrialsChat has 281 followers, 17K impressions and 14.6K profile visits, a reflection of its excellent content. From a clinician perspective, this is a great format to interact with colleagues, discuss enrolling trials and also become familiar with using Twitter. Conclusion(s): A CRC clinical trial focused tweetchat is an engaging way to deliver trial-related content to an audience of clinicians, patients and caregivers. The current format appears to be an effective way to create and disseminate information. Future sessions will focus on ctDNA, molecular markers such as KRAS and HER2, and rectal cancer trials. Our hope is that #CRCTrialsChat will stimulate continued patient and clinician engagement, increase awareness of clinical trials, enhance trial participation and initiate patient-centric research and collaborations.

Outcomes in Patients with Diabetes Mellitus Affected by COVID-19

Background: An important prognostic factor in any form of infection seems to be glucose control in patients with diabetes mellitus. Therefore, we examined the effects of optimal glycemic control in patients with diabetes mellitus and affected by COVID-19. Interplay between severities of COVID-19 in earliest data on the pandemic. Relative risks of death 1.7 to 2.2 based on studies from China and Italy. People with diabetes appear to be at greater risk of severe disease. 31% mortality in Wuhan vs 14% hospitalized non DM. Most endemic related to T2DM rather than T1DM. Obesity and insulin resistance may be particular risk factors. Similar finding with previous SARS coronavirus outbreaks. (Ref, Wu, Jama 2020 Graselli Jama 2020 Zhon). Further study from France Coranado study including 1317 people with diabetes mellitus and COVID-19 in 53 hospitals, 88% with T2DM, 3% new diagnosis, mean BMI 28 kg/m2, HBA1c 65 mmol/mol. Primary endpoint death or ventilation at day 7. 410 required Intensive care unit admissions, 267 ventilated, 140 deaths and 237 patient discharged by day 7. Comprehensive dataset from UK comparing primary care and national diabetes audited data reported 33% of in hospital death related to COVID-19 occurred in people with diabetes (31.3% T2DM, 1.5% for type 1 diabetes). 5.1% of total individual population had diabetes. Adjusted relative risk of death of death 2.9% for type 1 diabetes, 1.8% for type 2 diabetes. It was also noted there is clear association between renal function and outcome with increased mortality with e GFR<60 ml/min/1.73 m2. Further data from the United States the authors further compared the outcome for those with hyperglycemia with those with normoglycemia at admission. 41% had poor outcome in those with hyperglycemia without known diabetes vs under 15% in context of COVID-19 for those with previous diabetes. Marked hyperglycemia at admission had strong impact on prognosis and the development of diabetes mellitus in context of COVID-19 is particular serious events. (Bode et al, J Diab Sci Tech, 2020). These worked was also identified a significant increase in total death in diabetes during 2020. Objective(s): To evaluate the effect of optimal glycemic control on the outcome for patients with type 2 diabetes affected by COVID- 19 infection. Method(s): This is a retrospective analysis of 100 patients with type 2 diabetes, who were affected by moderate disease of COVID-19 infection and admitted to Fujairah hospital (UAE), compared with 100 non diabetic patient admitted to the same hospital, with the same severity of COVID-19 disease. Result(s): Out of 200 patients studied, 100 patients were non-diabetic and 100 patients were having diabetes mellitus. In the diabetic group, all patients were diagnosed to have diabetes already before admission, and these 100 (100%) were treated with insulin infusion or basal -bolus regime. At baseline, D-dimer levels were not significantly higher in the diabetic group (mean D-dimer = 1.327) than in the normoglycemic group (mean of D-dimer = 1.544) (P < 0.001). Even though all patients were on standard treatment for COVID-19 infection, IL-6 and D-dimer levels persisted higher in patients with diabetes mellitus during hospitalization. Patients with diabetes had a higher risk of severe disease and prolonged length of stay and death 7% deceased (n=7), than those without diabetes and with normoglycemia.5% (n=5) deceased with length of stay of 13.7 days for diabetic group and 12.6 days for non-diabetic group. It was shown in our study, that there are contributory factors like hypertension which was found in 42% of our diabetic patients, and obesity that affect 34% of the same group, ischemic heart disease in three patients, could potentially contributed to the poor outcome and death. We looked to the effect of ethnicity in our patients outcome, the Emirati nationals contributed 14.29% (26) of the cohort, while 13.19% (n=24) were other Arab nationalities and 72.53% (n=132) were South-Asian (chart 5), it clearly showed those people of South-Asian background with high ctopic lipid and increased insulin resistance had worse outcome. Conclusion(s): Insulin infusion and basal/bolus regime was an effective method for achieving glycemic targets and improving outcomes in patients with COVID-19 and it was showed effect in reducing the rate of admission to an ICU, the use of mechanical ventilation and prevent death. Immediate evidence from our study, that COVID-19 was associated with particular challenges in diabetes management. High rate of ketosis and acidosis in people with type 2 diabetes (not normally, ketosis prone), extreme level of hyperglycemia and associated hyperosmolar. Associated with significant acute kidney injury in some cases. Extreme insulin resistance with very high insulin requirement. Many cases of new onset diabetes mellitus mostly required insulin. Some unusual biochemical features, marked fall in serum albumin, variable CRP, Ferritin response, raised D-dimer and high rate of thromboembolic complications. It was shown in our study, that there are contributory factors like hypertension, obesity, ischemic heart disease and presence of acute kidney injury, were potentially contributed to the poor outcome and death.

SARS-CoV-2 infection and smoking: What is the association? A brief review.

Susceptibility to severe illness from COVID-19 is anticipated to be associated with cigarette smoking as it aggravates the risk of cardiovascular and respiratory illness, including infections. This is particularly important with the advent of a new strain of coronaviruses, the severe acute respiratory syndrome coronavirus (SARS-CoV-2) that has led to the present pandemic, coronavirus disease 2019 (COVID-19). Although, the effects of smoking on COVID-19 are less described and controversial, we presume a link between smoking and COVID-19. Smoking has been shown to enhance the expression of the angiotensin-converting enzyme-2 (ACE-2) and transmembrane serine protease 2 (TMPRSS2) key entry genes utilized by SARS-CoV-2 to infect cells and induce a 'cytokine storm', which further increases the severity of COVID-19 clinical course. Nevertheless, the impact of smoking on ACE-2 and TMPRSS2 receptors expression remains paradoxical. Thus, further research is necessary to unravel the association between smoking and COVID-19 and to pursue the development of potential novel therapies that are able to constrain the morbidity and mortality provoked by this infectious disease. Herein we present a brief overview of the current knowledge on the correlation between smoking and the expression of SARS-CoV-2 key entry genes, clinical manifestations, and disease progression.

ACE2 enhance viral infection or viral infection aggravate the underlying diseases.

ACE2 plays a critical role in SARS-CoV-2 infection to cause COVID-19 and SARS-CoV-2 spike protein binds to ACE2 and probably functionally inhibits ACE2 to aggravate the underlying diseases of COVID-19. The important factors that affect the severity and fatality of COVID-19 include patients' underlying diseases and ages. Therefore, particular care to the patients with underlying diseases is needed during the treatment of COVID-19 patients.

Headache medication and the COVID-19 pandemic.

The world is currently dominated by the Corona Virus Disease 2019 (COVID-19) pandemic. Besides the obvious concerns about limitation of virus spread and providing the best possible care to infected patients, a concomitant concern has now arisen in view of a putative link between the use of certain drugs, such as Renin-Angiotensin System (RAS) inhibitors and ibuprofen, and an increased risk for COVID-19 infection. We here discuss this concern in relation to headache treatment and conclude that, based on current evidence, there is no reason to abandon treatment of headache patients with RAS inhibitors or ibuprofen.

IMMUNE STATUS AND CYTOKINE SPECTRUM AS PREDICTORS OF THE RISK OF SEVERE DISEASE AND PERFORMANCE INDICATORS OF INTENSIVE THERAPY IN PATIENTS WITH CORONAVIRUS INFECTION COVID-19

The pandemic caused by a new strain of the SARS-CoV-2 coronavirus has swept the whole world but effective methods for treating this severe pathology have not yet been created. It has now been established that a risk of a severe course of COVID-19 is not so much a patient's age itself, but so-called age-related diseases;the renin-angiotensin system (RAS) is directly or indirectly involved into their development. The SARS-CoV-19 virus interacts with one of the main regulatory elements of this system, ACE2, and disrupts the balance between the two RAS branches. This ultimately manifests itself in an increase in levels of angiotensin II, which, through binding to the angiotensin type 1 receptor (AT1R), causes a number of pathological conditions, including hypertension, atherosclerosis, and cardiovascular diseases, enhances cell proliferation, apoptosis, death of vascular endothelial cells, etc. This process has been described in many reviews by Russian and foreign authors. However, cells of innate and adaptive immunity are another less well-described but no less important target of angiotensin II. The consequences of this interaction are analyzed in detail in this review. With COVID-19, dendritic cells are activated, macrophage proliferation and neutrophil infiltration increase with further involvement of CD4-lymphocytes and other cellular elements of the adaptive immunity in this process. Hyperactivation of the immune system is accompanied with the release of a large amount of pro-inflammatory cytokines, which can lead to the occurrence of a cytokine storm. The picture is aggravated by the inhibitory effect produced by the virus itself on the synthesis of signaling interferons at initial stages in its internalization into the cell. A separate section in the review addresses the problem how to predict a risk of a developing serious condition and search for its predictors by analyzing the state of the RAS and ratios of key cellular elements in the immune system. This is extremely important for making decisions concerning the amount of necessary medical care and strategies for subsequent treatment. © Sadykov V.F., Poltavtseva R.A., Chaplygina A.V., Bobkova N.V., 2022

Evolution of pancreatic ductal adenocarcinoma diagnosis during the last decade

Background: Pancreatic Ductal Adenocarcinoma (PDAC) has historically been an important diagnostic and therapeutic challenge. The multidisciplinary approach and new diagnostic techniques' implementation have modified this process. Method(s): We conducted a retrospective analysis based on clinical data of patients with PDAC between the years 2010 to 2021, analyzing the diagnosis and initial treatment evolution. Result(s): 673 patients between 2010-2021 with a suspected diagnosis of pancreatic adenocarcinoma were reviewed. Most of them were metastatic (n=362;53.8%), followed by locally advanced unresectable (n=166;24.7%) and resectable or borderline resectable (n=145;21.5%). Regarding the pathological diagnosis, it was not possible in 62 patients (9.2%), varying over time from 21.2%in 2010-2012 to 1% in 2019-2021 (p<0,0001). Moreover, the number of biopsies has decreased with a mean number of biopsies to obtain a pathological diagnosis of 1.55 (2010-2012) vs 1.31 (2019-2021). During this last period, most of the diagnoses were made by cytological analysis (61.4%;n=121). Specifically in the 2019-2021 patients subgroup, we found that 18 NGS (9,1%) were performed in this period (solid tumor), with 4 patients having actionable mutations (22.2%;3 KRAS G12C). Germline (g) mutational panels were carried out in 89 patients, finding only 9 positive cases (10.1%), being 3 of them gBRCA1/2 mutated (3,4%). In our study, a decrease in palliative management was evidenced over time. In 2010-2012, 28,8% of patients received exclusively palliative care against 9,6% in 2019-21 (p, 0.0001). An increase in PDAC diagnosis was observed since 2010, 44 patients/year in 2010-12 vs. 66 patients/year in 2019-21 (including COVID-19 pandemic period). All previous results are summarized. Conclusion(s): The diagnosis of PDAC has changed throughout the last decade, increasing the percentage of patients with a pathological diagnosis without increasing the number of invasive procedures. The number of patients suitable for anti-cancer therapy has also increased among time. In our cohort, the implementation of molecular testing would change the therapeutic approach in more than 20% of patients.

The Significance of Angiotensin-Converting Enzyme-2 (ACE2) in SARS-Cov-2 Infection and COVID-19

The new coronavirus was first reported in 2019 (China) and officially announced by the World Health Organization as a pandemic in March 2020. Severe acute respiratory syndrome coro-navirus 2 (SARS-CoV-2) is the causative agent of the pneumonia-associated illnesses and shares structural homology with the related Severe acute respiratory syndrome coronavirus-1 (SARS-CoV--1). One of the mechanisms for SARS-Cov-1 and-2 infection is mediated by the angiotensin-con-verting enzyme-2 (ACE2) cell receptor, enabling the virus to enter the host cells. ACE2 is an iso-form of the angiotensin-converting enzyme 1 (ACE). The actions of ACE2 counterbalance the clas-sic renin-angiotensin system (RAS) axis through the production of Ang 1-7, which promotes car-diovascular, renal, and lung-protective effects. The ACE2 is not the only route for SARS-CoV-2 to enter the host cells. However, due to its roles in the RAS and its participation in the SARS-CoV-2 virulence, ACE2 has gained attention regarding viral mechanisms of pathogenesis, effects of drugs that interfere with the RAS, and as a potential target for therapeutic strategies for the damages caused by SARS-CoV-2 infection. Among other tissues, ACE2 gene expression seems to be in-creased in the lungs upon SARS-CoV-2 infection;however, amid other variables, expression and/or activity of ACE2 is shown as a disease, sex, and age-dependent. The present review covers critical aspects for a comprehensive understanding of ACE2 and its current involvement in SARS-CoV-2 infection and the development of COVID-19.Copyright © 2021 Bentham Science Publishers.

Identification of the regulatory mechanism of ACE2 in COVID-19-induced kidney damage with systems genetics approach.

Studies showed that SARS-CoV-2 can directly target the kidney and induce renal damage. As the cell surface receptor for SARS-CoV-2 infection, the angiotensin-converting enzyme 2 (ACE2) plays a pivotal role for renal physiology and function. Thus, it is important to understand ACE2 through which pathway influences the pathogenesis of renal damage induced by COVID-19. In this study, we first performed an eQTL mapping for Ace2 in kidney tissues in 53 BXD mice strains. Results demonstrated that Ace2 is highly expressed and strongly controlled by a genetic locus on chromosome 16 in the kidney, with six genes (Dnase1, Vasn, Usp7, Abat, Mgrn1, and Rbfox1) dominated as the upstream modulator, as they are highly correlated with Ace2 expression. Gene co-expression analysis showed that Ace2 co-variates are significantly involved in the renin-angiotensin system (RAS) pathway which acts as a reno-protector. Importantly, we also found that Ace2 is positively correlated with Pdgf family members, particularly Pdgfc, which showed the most association among the 76 investigated growth factors. Mammalian Phenotype Ontology enrichment indicated that the cognate transcripts for both Ace2 and Pdgfc were mainly involved in regulating renal physiology and morphology. Among which, Cd44, Egfr, Met, Smad3, and Stat3 were identified as hub genes through protein-protein interaction analysis. Finally, in aligning with our systems genetics findings, we found ACE2, pdgf family members, and RAS genes decreased significantly in the CAKI-1 kidney cancer cells treated with S protein and receptor binding domain structural protein. Collectively, our data suggested that ACE2 work with RAS, PDGFC, as well as their cognate hub genes to regulate renal function, which could guide for future clinical prevention and targeted treatment for COVID-19-induced renal damage outcomes. KEY MESSAGES: • Ace2 is highly expressed and strongly controlled by a genetic locus on chromosome 16 in the kidney. • Ace2 co-variates are enriched in the RAS pathway. • Ace2 is strongly correlated with the growth factor Pdgfc. • Ace2 and Pdgfc co-expressed genes involved in the regulation of renal physiology and morphology. • SARS-CoV-2 spike glycoprotein induces down-regulation of Ace2, RAS, and Pdgfc.

COVID-19 pandemic and hypertension: an updated report from the Japanese Society of Hypertension project team on COVID-19.

The number of reported cases with coronavirus disease 2019 (COVID-19) has exceeded 620 million worldwide, still having a profound impact on people's health and daily lives since its occurrence and outbreak in December 2019. From the early phase of the COVID-19 pandemic, there has been a concern that the rapid spread of this communicable disease can negatively influence non-communicable diseases. Accumulating data indicate that the restriction on the access to medical care, psychological distress, and life-style changes triggered by the pandemic have indeed affected blood pressure control in hypertensive patients. Since our previous report in 2020 that summarized the findings of the literature related to COVID-19 and hypertension, there has been a considerable progress in our understanding of the association between these two disorders; nonetheless, there are remaining challenges and emerging questions in the field. In this article, we aim to summarize the latest information on the impact of the pandemic on blood pressure control, the use of the renin-angiotensin system inhibitors in patients with COVID-19, and the blood pressure changes as one of the possible post-acute sequelae of COVID-19 (also known as long COVID). We also summarize the evidence of telemedicine and COVID-19 vaccination in hypertensive subjects, based on data available as of June 2022.

Effects of PM2.5 Exposure on the ACE/ACE2 Pathway: Possible Implication in COVID-19 Pandemic.

Particulate matter (PM) is a harmful component of urban air pollution and PM2.5, in particular, can settle in the deep airways. The RAS system plays a crucial role in the pathogenesis of pollution-induced inflammatory diseases: the ACE/AngII/AT1 axis activates a pro-inflammatory pathway counteracted by the ACE2/Ang(1-7)/MAS axis, which in turn triggers an anti-inflammatory and protective pathway. However, ACE2 acts also as a receptor through which SARS-CoV-2 penetrates host cells to replicate. COX-2, HO-1, and iNOS are other crucial proteins involved in ultrafine particles (UFP)-induced inflammation and oxidative stress, but closely related to the course of the COVID-19 disease. BALB/c male mice were subjected to PM2.5 sub-acute exposure to study its effects on ACE2 and ACE, COX-2, HO-1 and iNOS proteins levels, in the main organs concerned with the pathogenesis of COVID-19. The results obtained show that sub-acute exposure to PM2.5 induces organ-specific modifications which might predispose to greater susceptibility to severe symptomatology in the case of SARS-CoV-2 infection. The novelty of this work consists in using a molecular study, carried out in the lung but also in the main organs involved in the disease, to analyze the close relationship between exposure to pollution and the pathogenesis of COVID-19.

ACE2 receptor Polymorphism and its correlation with anti-SARS-CoV-2 IgM Antibodies - a case-control study.

BACKGROUND: It has been reported that the SARS-CoV-2 pandemic originated in Wuhan, China in December 2019 and spread rapidly worldwide. The virus gets entry into target cells via angiotensin-converting enzyme 2 (ACE2) receptors and its gene is highly polymorphic. INTRODUCTION: the variations in SARS-CoV-2 susceptibility and severity can be explained on a genetic level by studying the polymorphism in ACE2 receptor polymorphism. OBJECTIVE: A prospective case-control study was designed to compare the ACE2 levels in SARS-CoV-2 patients with the healthy controls in the local population, for which a total of 100 EDTA-containing blood samples were included (50 SARS-CoV-2 IgM positive case and 50 healthy controls). METHODS: PCR-RFLP was performed to investigate the polymorphism of ACE2 in genomic DNA and the ACE2 plasma levels were determined through ELISA. RESULTS: No significant difference in allelic and genotype frequencies (GG, GA, AA) were observed while the ACE2 plasma levels were found to be decreased in positive samples. CONCLUSION: No significant association of the ACE2 gene polymorphism (G8790A) was found with the SARS-CoV-2 susceptibility in the Pakistani population which intimates the search for other genetic factors within the local population.

Current approaches for the diagnosis and management of immune thrombocytopenia.

Immune thrombocytopenia (ITP), is an acquired autoimmune disorder characterized by the destruction of platelets and megakaryocytes, resulting in thrombocytopenia (platelet count <100 × 109/L). This review focuses on the diagnosis and current management of ITP. The diagnosis of ITP is based principally on the exclusion of other causes of isolated thrombocytopenia using patient history, physical examination, blood count, and evaluation of the peripheral blood film. The clinical treatment goals should be to resolve bleeding events and to prevent severe bleeding episodes. The platelet count should be improved to attain a minimum of > 20-30 × 109/L. Therapy should be given as an inpatient in newly diagnosed ITP with a platelet count of > 20 × 109/L or if there is active bleeding. Corticosteroids are considered the standard initial treatment for newly diagnosed patients. Subsequent medical therapies with robust evidence include thrombopoietin receptor agonists (TPO-RAs), rituximab and fostamatinib. Surgical therapy with splenectomy may be considered for patients failing medical therapy. The choice between therapy options is highly dependent upon patient values and preferences.

Angiotensin converting enzyme 2 level and its significance in COVID-19 and other diseases patients.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) expressions and its modulation are of great interest as being a key receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) and the protective arm of the rennin-angiotensin axis, maintaining cardiovascular homeostasis. However, ACE2 expressions and their modulation in the healthy and disease background are yet to be explored. METHOD: We performed a meta-analysis, extracting the data for ACE2 expression in human subjects with various diseases, including SARS-CoV2 infection without or with co-morbidity. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Out of 203 studies, 39 met the inclusion criteria with SARS-CoV2 patients without co-morbidity, SARS-CoV2 patients with co-morbidity, cardiovascular (CVD) patients, diabetes patients, kidney disorders patients, pulmonary disease patients, and other viral infections patients. RESULTS: Angiotensin-converting enzyme 2 expression was significantly increased in all diseases. There was an elevated level of ACE2, especially membrane-bound ACE2, in COVID-19 patients compared to healthy controls. A statistically significant increase in ACE2 expression was observed in CVD patients and patients with other viral diseases compared to healthy subjects. Moreover, subgroup analysis of ACE2 expression as soluble and membrane-bound ACE2 revealed a remarkable increase in membrane-bound ACE2 in CVD patients, patients with viral infection compared to soluble ACE2 and pooled standard mean difference (SMD) with the random-effects model was 0.37 and 2.23 respectively. CONCLUSION: It was observed that utilizing the ACE2 by SARS-CoV2 for its entry and its consequence leads to several complications. So there is a need to investigate the underlying mechanism along with novel therapeutic strategies.