More than 80% of individuals in low and middle-income countries (LMICs) are unvaccinated against coronavirus disease 2019 (COVID-19). In contrast, the greatest burden of cardiovascular disease is seen in LMIC populations. Hypertension (HTN), diabetes mellitus (DM), ischaemic heart disease (IHD) and myocardial injury have been variably associated with adverse COVID-19 outcomes. A systematic comparison of their impact on specific COVID-19 outcomes is lacking. We quantified the impact of DM, HTN, IHD and myocardial injury on six adverse COVID-19 outcomes: death, acute respiratory distress syndrome (ARDS), invasive mechanical ventilation (IMV), admission to intensive care (ITUadm), acute kidney injury (AKI) and severe COVID-19 disease (SCov), in an unvaccinated population.st December 2019 and 16th July 2020 with extractable data on patients ≥18 years of age with suspected or confirmed SARS-CoV-2 infection. Odds ratios (OR) for the association between DM, HTN, IHD and myocardial injury with each of six COVID-19 outcomes were measured.We included studies published between 1We included 110 studies comprising 48,809 COVID-19 patients. Myocardial injury had the strongest association for all six adverse COVID-19 outcomes . HTN and DM were also significantly associated with death, ARDS, ITUadm, AKI and SCov. There was substantial heterogeneity in the results, partly explained by differences in age, gender, geographical region and recruitment period.COVID-19 patients with myocardial injury are at substantially greater risk of death, severe disease and other adverse outcomes. Weaker, yet significant associations are present in patients with HTN, DM and IHD. Quantifying these associations is important for risk stratification, resource allocation and urgency in vaccinating these populations.https://www.crd.york.ac.uk/prospero/, registration no: CRD42020201435 and CRD42020201443. The global coronavirus disease 2019 (COVID-19) pandemic has impacted healthcare systems and economies worldwide. It has laid bare health inequalities and magnified unequal effects of public health measures implemented across the world, with associated ramifications on global health. This is well-exemplified by the global COVID-19 vaccine inequality, where only 14.4% of individuals in low-income countries have received one dose of COVID-19 vaccine, as of March 2022 (Low and middle-income countries (LMICs) are plagued by the difficult decision between strict non-pharmaceutical interventions such as national lockdowns and their socioeconomic impact, particularly on the urban poor. Moreover, these countries suffer from increased COVID-19 associated mortality owing to insufficient healthcare resources and poorly funded emergency response programmes , 3.While high-income countries (HICs) have made significant progress in vaccination rollout programmes, LMICs continue to lag behind. Importantly, studies from HIC populations have suggested the COVID-19 incidence and hospitalization rates among unvaccinated individuals are approximately 2 and 5-times that of vaccinated (but without a booster) individuals respectively .Multiple observational studies have shown associations between cardiovascular (CV) risk factors such as hypertension (HTN), diabetes mellitus (DM), previous ischaemic heart disease (IHD), myocardial injury and outcomes such as mortality or severe disease due to COVID-19 (SCov). Other studies have challenged these findings, showing heterogeneous associations between these risk factors and COVID-19 related death , 6. In aTherefore, quantifying the risk of COVID-19-related adverse outcomes attributable to CV risk factors, IHD and myocardial injury in unvaccinated persons is essential, not only for patient-specific care but also for risk stratification and planning of healthcare delivery in already stretched LMICs. This is especially relevant where the greatest burden of cardiovascular disease is amongst LMICs. In this meta-analysis, we quantify the association between CV risk factors, IHD and myocardial injury, and specific adverse clinical outcomes in unvaccinated adults with COVID-19 infection.The protocol for this meta-analysis with pre-specified aims and objectives was prospectively registered on PROSPERO (CRD42020201435 and CRD42020201443). The aim of the meta-analysis was to study the impact of pre-specified cardiovascular risk factors  on adverse COVID-19 outcomes . We included studies published (in print or pre-print version) during the early phase of the COVID-19 pandemic, prior to widespread use of COVID-19 vaccinations.We included studies that reported prevalence of pre-existing cardiovascular risk factors in adult patients (≥18 years of age) with suspected or confirmed COVID-19 disease and any one of the COVID-19 related adverse outcomes.We searched databases of published  and pre-print (medRxiv) articles without language restrictions, between 1st December 2019 and 16th July 2020. We also searched data from the COVID-19 specific World Health Organization (WHO) global research database. Duplicate studies were identified and removed initially through a Mendeley folder (AT) followed by manual de-duplication by two authors working independently (JP and SMN). The final study list was agreed by consensus. Three authors  screened references of full-text studies, review articles and existing meta-analyses for additional studies. Studies were included if they had extractable data on (i) patients ≥ 18 years of age with suspected or confirmed SARS-CoV-2 infection (COVID-19); (ii) pre-existing CV risk factors, specifically HTN and DM, IHD, or evidence of myocardial injury (defined as serum troponin level above the 99th percentile upper reference limit); and (iii) COVID-19 related outcomes, in particular all-cause mortality, ARDS, IMV, admission to intensive care (ITUadm), AKI, and study-defined severe COVID-19 disease (SCoV). Data from Chinese studies were translated and extracted by JP. Studies reporting only on special populations  were excluded . Case reThree authors  independently screened all titles and abstracts, reviewed full text articles, extracted data onto pre-specified forms and performed risk of bias assessments. Disagreements were resolved by consensus. Risk of bias assessment for individual studies was performed using the Newcastle-Ottawa Scale (NOS) . The quaI2 statistic (Associations between disease status and COVID-19 outcomes were quantified using odds ratios (OR) which were combined using fixed-effects meta-analysis . Random-tatistic  and wherWe identified 110 studies comprising 49,017 patients with COVID-19. The full list of included and excluded studies are detailed in Presence of DM , HTN  or IHD  was strongly associated with death from COVID-19 . These cardiovascular risk factors were also associated with severe COVID-19 disease .p = 0.30], though only 2 studies involving 310 patients (15 with IHD) were included in this meta-analysis. Only one study (393 patients) explored the association between HTN and IMV, finding no significant association [OR 1.25 (0.82–1.90)].Fewer studies explored the association between DM, HTN and IHD with ARDS, IMV, ITUadm and AKI. Nevertheless, we observed significant associations between these CV risk factors, IHD and ITUadm as well as AKI. While DM and HTN were significant risk factors for developing ARDS, a similar association was not observed in patients with pre-existing IHD [OR 1.42 (0.49–4.10), There was some discrepancy between the fixed-effects and random-effect analysis of the association between IHD and ITUadm. However, the odds ratio and confidence intervals from the fixed-effects model are entirely within the confidence intervals from the random-effect analysis. This would be expected when a random-effect analysis is simply a less efficient estimate of the same parameter or a numerically similar one estimated by the fixed-effects analysis.Forty-nine studies reported on the risks of death and other adverse outcomes associated with the presence of myocardial injury at baseline in patients with COVID-19. Presence of myocardial injury was associated with all six adverse COVID-19 outcomes . There wI2 < 10%), all with small numbers of included studies.The mean NOS score for all studies combined was 6.95, indicating that they were of satisfactory quality . ModeratWe performed a meta-regression to assess the effect modification by age, gender, publication date and geographic region, on the association of cardiovascular risk factors and myocardial injury on death and severe COVID-19 disease. Overall, advanced age, studies conducted in Asia and male gender showed stronger association between cardiovascular risk factors, ischaemic heart disease and myocardial injury with the COVID-19 outcomes of interest. Gender did not appear to affect the association between myocardial injury and death whereas age did not modify the association between myocardial injury and COVID-19 disease severity. All four modifiers also partly accounted for the observed heterogeneity between studies. Importantly, the GRADE assessment shows low to moderate levels of certainty for associations studied . We did The co-existence of HTN, DM, IHD and/or myocardial injury among patients with COVID-19 has been considered to be a harbinger of adverse clinical outcomes. By undertaking this meta-analysis, we confirmed a significant association between four risk factors  and six important adverse COVID-19 outcomes: death, ARDS, IMV, ITUadm, AKI and SCoV. Furthermore, we demonstrated the differential impact of these risk factors on individual COVID-19 outcomes, with myocardial injury emerging as the most adverse indicator of all. These findings may be considered when risk-stratifying unvaccinated patients and unexposed individuals for potential of severe unfavorable outcomes of COVID-19, as well as prioritization of vaccination rollout programmes.It is worth reviewing the pathogenesis of COVID-19 disease to better understand the detrimental effects of cardiovascular risk factors and myocardial injury on COVID-19 related outcomes. Entry of SARS-CoV-2 into host cells relies on the surface glycoprotein, spike (S) protein, which has a receptor-binding domain (RBD) mediating direct contact with angiotensin-converting enzyme 2 (ACE2). In addition, the betacoronavirus also contains an S1/S2 polybasic cleavage site that is cleaved by cellular transmembrane protease serine 2 (TMPRSS2) and cathepsin L, which further facilitate viral entry. Whilst the predominant tissue tropism of SARS-CoV-2 is that of the alveolar epithelial cells, ACE2 is widely expressed in other organs such as the gastrointestinal tract, myocardium, kidneys and vascular endothelial cells . The latPre-existing DM, HTN and IHD were associated with a higher risk of death and severe COVID-19 disease in our meta-analysis, each comprising data from more than 30 studies. These findings concur with pre-existing studies showing worse COVID-19 outcomes in patients with DM and HTN. We further quantified risks of developing specific COVID-19 adverse outcomes, namely death, ARDS, IMV, ITUadm, SCov and AKI in patients with these co-morbidities.Whilst patients with DM were at an increased risk of developing all six adverse outcomes, the strongest association was seen between DM and the development of ARDS. The pathogenic mechanism underlying severe respiratory complications in patients with DM and COVID-19 is speculated to be due to alveolar-capillary microangiopathy and interstitial fibrosis, resulting from overactive pro-inflammatory pathways and vascular inflammation. A proposed key player to the ongoing inflammation and endothelial damage in DM is interleukin-6 (IL-6), a pro-inflammatory cytokine suggested as a severity predictor of lung disease in DM , 14. TheThe development of a cytokine storm in patients with severe COVID-19 is well-described . PreviouSimilarly, patients with pre-existing HTN are at increased odds of COVID-19 related death, SCov and AKI. This may reflect the interlink between SARS-CoV-2 cell entry via angiotensin converting enzyme 2 (ACE2) binding, the renin-angiotensin-aldosterone system (RAAS) and the ubiquity of ACE2 in multiple organs including the lungs, myocardium, kidneys and gastrointestinal tract. Chronic mechanical stress on the vascular wall as a result of increased intraluminal pressure in hypertension leads to endothelial dysfunction, release of reactive oxygen species and a pro-coagulant state. In conjunction with RAAS dysfunction following SARS-CoV-2 infection, this facilitates a pro-inflammatory state, cytokine release syndrome and progression to multi-organ involvement in COVID-19 resulting in more severe disease and adverse outcomes .Whilst also at increased odds of respiratory complications such as ARDS and requirement for IMV, patients with HTN and COVID-19 appear to be at a lower risk of these complications when compared to DM patients. Here, it may be worth raising whether there is a protective role of regular antihypertensives such as ACE-inhibitors and angiotensin receptor blockers (ARB). The reduction in angiotensin-2 levels and suppression of angiotensin-2 binding to angiotensin-I receptors (AT1R) by ACE-inhibitors and ARBs, respectively, may in fact prevent the downstream pro-inflammatory and vasoconstrictive effects of angiotensin-2, lowering the risk of respiratory complications such as ARDS. Indeed, large cohort-based population studies have suggested a protective effect of ACE-inhibitors and ARBs  against SCoV, death and IMV in patients with hypertension  of the deceased patients had evidence of myocardial injury, which was associated with a near 9-fold increased odds of COVID-19 related death. Further, our study explores the association between myocardial injury and AKI, demonstrating patients with COVID-19 and myocardial injury are at 10-fold increased odds of developing AKI. 28% of patients with myocardial injury developed AKI as compared to 2.4% of patients without myocardial injury.The exact mechanism linking myocardial injury with ARDS and AKI in COVID-19 infection is poorly understood. Several hypotheses include a bystander process with cytokine storm and hyperinflammation in severe COVID-19 disease as the driver of multi-organ involvement, endothelial damage and thrombo-inflammation secondary to ACE2-mediated entry of SARS-CoV-2 into endothelial cells of multiple vascular beds and right ventricular dysfunction secondary to increased afterload from raised pulmonary artery pressures in ARDS, thereby causing dysregulated renal blood flow , 33.Our meta-analysis pools data from studies across the world and focuses on COVID-19 outcomes in the early phase of the pandemic, before effective evidence-based treatments and vaccines were commonplace. The geographical diversity of included studies overcomes concerns regarding generalisability of earlier meta-analyses, while avoiding biases introduced by novel therapies and vaccines in later stages of the pandemic. Our meta-analysis comprehensively explores the multiple associations between CV risk factors, IHD and myocardial injury with specific COVID-19 outcomes and complications such as AKI and ARDS alongside more commonly reported outcomes such as mortality and IMV.The generalisability of findings from our meta-analysis was enhanced by not setting language restrictions in our search strategy and by including studies from conventional as well as novel databases . Moreover, risk of bias was minimized by excluding studies involving specific population cohorts or pre-selected COVID-19 outcomes. By undertaking meta-regression analyses, we were able to explore sources of heterogeneity including age, gender, study recruitment date and geographic region.Our study has several limitations. Firstly, it is limited in its scope, focusing on outcomes of COVID-19 in a relatively unexposed population in the immediate months following its initial outbreak. Its applicability to populations with high vaccination or herd immunity rates may be limited. Indeed, the emergence of variants with significant mutations affecting virulence features such as transmissibility and pathogenesis may alter aspects of the natural history of COVID-19. At the same time, variants could affect effectiveness of current vaccines . In ordeIn addition, the majority of included studies explored adverse outcomes in hospitalized COVID-19 patients. This introduces an inherent selection bias as patients presenting with mild symptoms were likely excluded. Unvaccinated, non-hospitalized individuals with mild COVID-19 symptoms remain an important cohort to study, particularly with the changing trends of disease severity with different SARS-CoV-2 variants.As our meta-analysis focused specifically on the pre-vaccination phase of the pandemic, we are unable to comment on the association between DM, HTN, IHD and myocardial injury with biomarkers of disease severity including coagulation indicators such as fibrinogen degradation products, prothrombin time, D-dimer and platelets, as these were infrequently reported in earlier studies included. Indeed, the pro-coagulation state in COVID-19 disease is now well-recognized and biomarkers such as D-dimer are used to guide routine use of anticoagulants in COVID-19 patients . Whilst The inclusion of studies conducted at different centers across geographical regions also results in considerable between-study heterogeneity. This could be due to multiple reasons including different sociodemographic factors, varying definitions of outcomes  and variations in clinical practice between the countries . For outcomes with fewer studies , the level of certainty of evidence is low owing to the small study size and wide confidence intervals, limiting the veracity of these findings.Notwithstanding the above limitations, our meta-analysis quantifies the excess risk of adverse COVID-19 outcomes in unvaccinated patients with pre-existing CV risk factors, IHD and myocardial injury. In addition, we demonstrate the differential impact of these factors on six important adverse COVID-19 outcomes. Our findings will help inform clinicians, policymakers and patients in terms of risk prediction, stratification and resource allocation. Our meta-analysis contributes to the expanding body of evidence reporting on risk factors for poor COVID-19 outcomes, which could inform public health advice regarding social isolation guidelines and vaccine prioritization strategies, especially relevant for LMICs.Future studies evaluating the altered impact of cardiovascular risk factors such as HTN, DM and IHD on COVID-19 outcomes in a post-vaccination population are required. In addition, the immunogenicity of different COVID-19 vaccines in these patient groups remain poorly elucidated and should be better characterized to guide design of vaccination programmes and choice of vaccine.In summary, our meta-analysis demonstrates a significant association between myocardial injury and adverse clinical outcomes in COVID-19 patients. To a lesser extent, we also found that DM, HTN and IHD predict poorer outcomes, especially for death and severe disease. These findings provide comprehensive quantitative data that can be used in risk prediction and risk stratification by clinicians as well as policymakers. It also provides the underpinning evidence for the vaccination policies targeting vulnerable patients.The original contributions presented in the study are included in the article/SN, SK, VK, and AG designed the study. SN, JP, and KM identified studies and extracted data. KR performed the statistical analysis. SN, JP, KM, SK, VK, KR, and AG wrote the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the British Heart Foundation (BHF) Accelerator Award ‘Cardiac Inflammation' (PI) AA/18/5/34222. Dr. Ajay K Gupta is part-funded by the Barts Charity grant to the Cardiovascular Clinical Trials Unit (CVCTU), William Harvey Research Institute.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Cryptococcus neoformans (C neoformans) infection typically occurs in immunocompromised patients infected with human immunodeficiency virus (HIV), or those taking immunosuppressive drugs, corticosteroids, or chemotherapy. Recently, there have been an increasing number of reports of cryptococcosis as opportunistic infections in COVID-19 patients, all of which have been related to immunocompromising conditions, underlying medical diseases, immune suppression drugs, or corticosteroids. Here, we report the first case of pulmonary cryptococcosis in an immunocompetent patient with a history of COVID-19 who had no history of underlying diseases or immune modulation drugs.A previously healthy 46-year-old man presented with tiny lung nodules. He had quit smoking 6 years prior. He had no significant medical history except for COVID-19 3 months prior, and had not received corticosteroids or cytokine blockers when he had COVID-19. He had been coughing since he recovered from COVID-19.C neoformans. A CT-guided percutaneous needle biopsy of the lung lesion was performed. Histopathology of the biopsy specimen showed granulomas with encapsulated yeast. There was no growth of C neoformans in the CSF or blood. He was diagnosed with pulmonary cryptococcosis.Bronchoalveolar lavage cultures showed the growth of Antifungal drug (fluconazole) was administered for 6 months in the outside clinic.The lung lesions disappeared after 6 months medication.Cryptococcus. Third, these changes in the immune system due to COVID-19 may last for several weeks. Thus, we suggest careful consideration of lung lesions in patients with a history of COVID-19.This case may illustrate the risk of pulmonary cryptococcosis after SARS-CoV-2 infection in an immunocompetent patient. Opportunistic infections can occur even after recovery from COVID-19 for several reasons. First, SARS-CoV-2 infection causes immune dysregulation including lymphocytopenia. Second, T lymphocytes play a principal role against  Cryptococcus neoformans (C neoformans) is an encapsulated pathogenic yeast found in the environment that is not normally a component of the human microbial flora. C neoformans infections (cryptococcosis) are rare in healthy individuals, even though they inhale C neoformans. Cryptococcosis generally occurs in immunocompromised patients, such as those with HIV/AIDS, organ transplant, liver cirrhosis, chronic kidney disease, malignancies, diabetes, autoimmune diseases, or immunological deficiencies such as CD4 + T-cell lymphocytopenia or anti-GMCSF antibodies, or those who have been treated with immunosuppressants, corticosteroids, cytokine blockers, or chemotherapy.–5–9 pneumonia,,11 or cryptococcemia.–15 However, all reported cases of cryptococcosis in COVID-19 patients occurred currently with an immunocompromised status, corticosteroid use, cytokine blocker use, immunosuppressants use, HIV, malignancies, or medical comorbidities.–17 Thus far, there have been no reports of cryptococcosis in immunocompetent COVID-19 patients who had no underlying disease and no history of corticosteroid therapy.Recently, cases of cryptococcosis have been reported in patients with SARS-CoV-2 infection, presenting as meningoencephalitis,In this case report, we describe pulmonary cryptococcosis developed in an immunocompetent patient after the acute convalescence period from COVID-19. To our best knowledge, this is the first case report of cryptococcosis related to COVID-19 who had not received any immunosuppressants or corticosteroids and had no underlying disease. We also provide a review of the related literatures.A 46-year-old man was referred to our hospital from a health checkup center in July 2021 for tiny scattered nodules on a chest low-dose computed tomography (CT) scan  for lung lesions. The patient had no adverse events of therapeutic drug. After 6 months of treatment, the consolidative cryptococcosis masses disappeared , C-reactive protein was <0.5 mg/dL, and rheumatoid factor was normal. Screening for antibodies against HIV was negative. Chest CT Fig. A–C scan  CT Fig. D to eval CT Fig. D were peion Fig. A–C. We p–5 Recently, C neoformans infections have been increasingly reported in COVID-19 patients.–11 However, all prior cases have been linked to immunocompromised conditions caused by either an underlying disease, immunodeficiency, or immunosuppressive drugs such as corticosteroids, cytokine blockers, or chemotherapy.–15 Although there are cases of cryptococcosis that have reported in immunocompetent patients related to COVID-19, they were also patients who had hypertension,,16,17 diabetes,,17 chronic kidney disease, cirrhosis, or treated with corticosteroid for COVID-19. In case of pulmonary cryptococcosis developed 2 months after recovering from COVID-19, also the patient had hypertension, diabetes, and treatment with corticosteroids for COVID-19. The patient in the present case had not received any immunosuppressive drugs or corticosteroids for COVID-19 and had no medical comorbidities or immunodeficiency diseases. Thus, this is the first report of cryptococcosis diagnosed in an immunocompetent patient who had COVID-19 3 months previously.Immunocompromised conditions are major risk factors for cryptococcosis.Cryptococcus were detected from the PCNB and culture. It was assumed that the BAL might worsen the cryptococcal seeding in the patient.The initial tiny nodules on the chest CT scan conducted at the health checkup center progressed to a consolidative mass 14 days after BAL. No microorganisms other than Generally, SARS-CoV-2 causes hyperinflammation and cytokine storm syndrome. Immunosuppressive drugs such as corticosteroids or cytokine blockers have been administered to alleviate these unexpected inflammatory responses in patients with COVID-19. Unfortunately, these immunosuppressive therapies for COVID-19 increase opportunistic infections.The current patient developed pulmonary cryptococcosis after recovering from COVID-19. This suggests that changes in immune regulation following SARS-CoV-2 infection persist even after recovery from COVID-19. Even in people who have fully recovered from COVID-19, changes in the immune system caused by SARS-CoV-2 infection raise concerns about opportunistic infections. This is mainly, because the immune system does not fully recover even though the symptoms fully disappear after COVID-19.–20 SARS-CoV-2 infection promotes pulmonary microbial proliferation and alters the human microbiota, which may affect the immune system and contribute to fungal infections. SARS-CoV-2 infection is associated with immune dysregulation and global T-cell depletion. COVID-19 patients show increased circulating proinflammatory cytokines and significantly decreased absolute numbers of T lymphocytes, CD4 + T cells, and CD8 + T cells.–23 These immune system alterations after SARS-CoV-2 infection may increase susceptibility to fungal infections. Lymphocytes are an important component of the host defense against Cryptococcus. IL-2-activated T cells and NK cells form conjugates with C neoformans and directly inhibit the growth of Cryptococcus. T cells (CD4 + and CD8+) and NK cells (CD16/56+) have the capacity to bind and directly inhibit the growth of C neoformans. These immune modulations from SARS-CoV-2 infection might affect the protective immune response against fungal infections. The resolution of lymphopenia correlates with recovery from COVID- 19, but this may take several weeks. This case highlights that the changes in the immune system occurring due to SARS-CoV-2 infection in immunocompetent patients may persist even after convalescence from the initial illness.Although the exact mechanism by which COVID-19 induces or promotes fungal infection has not been identified, many reports have suggested that SARS-CoV-2 infection is the predisposing factor of fungal infection.This study has several limitations. First, we did not measure the absolute numbers of T lymphocytes and NK cells in the patient. Thus, we could not clearly identify the pathogenesis of cryptococcosis. Second, although the patient did not have any underlying disease at the time of diagnosis, the possibility of an incubation period for immunodeficiency disease cannot be completely ruled out. However, there are currently no test methods to identify this.Cryptococcus. We hypothesized that the changes in the immune profile from SARS-CoV-2 infection might be sustained for several weeks even though it was eradicated, which can cause fungal infection.SARS-CoV-2 infection has been conclusively shown to activate the innate and adaptive immune responses, which decreases the number of T-cell lymphocytes and NK T cells, which play a critical role in host defense against All authors participated in the management of the patient described in this case report. HSC collected all the references and was a major contributor in the writing of the article. All authors have read and approved the article.Conceptualization: Hye Sook ChoiData curation: Hye Sook ChoiFormal analysis: Hye Sook ChoiInvestigation: Hye Sook ChoiMethodology: Hye Sook ChoiResources: Hye Sook ChoiSupervision: Hye Sook ChoiValidation: Hye Sook ChoiWriting—original draft: Hye Sook ChoiWriting—review and editing: Hye Sook Choi


As SARS-CoV-2 testing declines worldwide, surveillance of international travelers for SARS-CoV-2 enables detection of emerging variants and fills gaps in global genomic surveillance  was collected from each plane during normal maintenance using a device that attaches to the lavatory service panel port and the lavatory service truck hose.After concentration with affinity-capture magnetic nanoparticles . In combination with traveler-based surveillance (


Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, many cases of arrhythmias have been reported in patients with COVID-19 infection. We present the case of a 66-year-old female with no known cardiovascular history who presented with worsening shortness of breath and productive cough and tested positive for COVID-19 infection in the ED. The patient had a recent hospitalization for COVID-19 infection during which she was treated with dexamethasone and remdesivir therapy and her course remained uncomplicated at that time. Following this, she developed worsening shortness of breath at home for which she presented to the ED. During this hospitalization, she was treated with dexamethasone, remdesivir, and supplemental oxygen. On day six of hospitalization, the patient became tachycardic and had palpitations. Cardiac monitor and EKG showed evidence of new-onset atrial fibrillation (NOAF). Initially patient received metoprolol and diltiazem, both of which failed to achieve adequate rate control. Following this, the patient was started on carvedilol 30 mg every six hours, which attained good rate control. Her CHA2DS2-VASc , diabetes, stroke (doubled), vascular disease, age 65 to 74, and sex category) score was 4 for which she was started on apixaban 5mg twice daily. The patient was discharged on the same medications. Despite increasing reported incidences of NOAF in COVID-19 infection, only little is known about the optimal management strategies and possible etiopathology. The aim of our review is to highlight the possible mechanisms triggering atrial fibrillation in COVID-19 infection and go over the management strategies while reviewing the available literature. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) potentiates the highly contagious viral infection that leads to the development of coronavirus disease 2019 (COVID-19) . The atrWe present a 66-year-old female with a past medical history of asthma, non-insulin-dependent type 2 diabetes mellitus, and hypertension presented to the emergency department with worsening shortness of breath and productive cough with white sputum one day after a recent discharge during which she was treated for acute hypoxic respiratory failure secondary to COVID-19 infection. The patient was treated with five days of dexamethasone and remdesivir after which she was discharged without supplemental oxygen. During the above-mentioned admission, the patient required 3L of oxygen via nasal cannula and required no supplemental oxygen upon discharge. On this presentation, the patient was saturating at 81% on room air, tachycardic to 106/min, and had bilateral expiratory wheezing. Chest x-ray showed bilateral mid to lower lung hazy opacities consistent with COVID-19 pneumonia , diabetes/hypertension (with good control), metformin (850 mg/d) (for seven years), and ACE inhibitory therapies . The phyTable The worldwide reporting of arrhythmias (and related cardiovascular complications) during the COVID-19 pandemic warrant the development of evidence-based treatment pathways to reduce the incidence of cardiac deaths. This case report concisely emphasizes the possible mechanisms triggering atrial fibrillation including acid-base imbalances/electrolyte abnormalities, endothelial damage, cytokine storm, decreased ACE-2 availability, sympathetic drive stimulation, systemic inflammation, microthrombi formation, myocardial injury, and increased adrenergic drive in patients with COVID-19 infection. It also highlights the medical management strategies including beta-blockers and calcium channel blockers use, and their impact on recovery and prognosis. Research should further investigate the pathophysiology concerning atrial fibrillation and its correlation with COVID-19 infection. The follow-up measures are conducive to unraveling the treatment responses and long-term outcomes in patients with COVID-19 and atrial fibrillation.


Cancer cells and immune cells all undergo remarkably metabolic reprogramming during the oncogenesis and tumor immunogenic killing processes. The increased dependency on glycolysis is the most typical trait, profoundly involved in the tumor immune microenvironment and cancer immunity regulation. However, how to best utilize glycolytic targets to boost anti-tumor immunity and improve immunotherapies are not fully illustrated. In this review, we describe the glycolytic remodeling of various immune cells within the tumor microenvironment (TME) and the deleterious effects of limited nutrients and acidification derived from enhanced tumor glycolysis on immunological anti-tumor capacity. Moreover, we elucidate the underlying regulatory mechanisms of glycolytic reprogramming, including the crosstalk between metabolic pathways and immune checkpoint signaling. Importantly, we summarize the potential glycolysis-related targets that are expected to improve immunotherapy benefits. Our understanding of metabolic effects on anti-tumor immunity will be instrumental for future therapeutic regimen development. In the latest decade, immunotherapy has achieved great advances in cancer treatment in several malignancies . Immune Unlike normal cells, tumor cells prefer aerobic glycolysis to generate energy and meet other biological requirements of malignant phenotype . ResearcNormal cells utilize mitochondrial respiration, termed oxidative phosphorylation (OXPHOS), to sustain bioenergy synthesis and viability. Conversely, in response to hypoxia and oncogenic signals, like MYC and PI3K, cancer cells predominantly utilize glycolysis to support rapid growth and genome replication, even under abundant oxygen . This me+ for continuous glycolysis and NAD+/NADH redox balance (The glycolytic process is composed of glucose transporter 1 (GLUT1)-mediated glucose uptake and the conversion from glucose into pyruvate through ten consecutive enzymatic reactions in an oxygen-independent manner. Newly generated pyruvate is either catalyzed in acetyl-CoA to fuel the tricarboxylic acid (TCA) cycle or is reduced toward lactate by lactate dehydrogenase (LDH) to achieve the regeneration of NAD balance . Redunda balance .Glycolytic preference is a shared mechanism to satisfy biosynthesis and energy requirements in rapidly proliferating cells. In the TME, cancer cells, effector T cells, and M1-like macrophages are prone to upregulate glycolysis and glutaminolysis fluxes. In contrast, memory T cells, regulatory T cells (Tregs), and M2-like macrophages mainly rely on fatty acid oxidation (FAO)  Andreje.2+-ATPase (SERCA)-mediated ER calcium uptake to retain cytosol Ca2+ and nuclear factor of activated T-cells (NFAT) signaling, which is indispensable for TCR signaling transduction  coupled with CD28 activates PI3K-AKT-mTORC1 and MYC signaling pathway to trigger metabolic reprogramming . To enhasduction . Phosphounctions .+T cells prefer glycolysis to OXPHOS, and this metabolic adaptation to TME further dampens their cancer-inhibiting function  have high glucose activity. The pyruvate dehydrogenase (PDH) inhibitor, pyruvate dehydrogenase kinase isozyme 1 (PDHK1), is exclusively expressed in Th17 cells, whose ablation changes the immune cell composition, including selective reduction of Th17 cells (ex vivo culture condition even dampens their stability (The functions of CD4nd LAG-3 . Inflamm17 cells . Instead17 cells . The Tre17 cells . Moreovetability . These dM1-like macrophages mainly rely on glycolysis to sustain inflammatory phenotype . Instead+T cell inhibition and cancer progression (The intrinsic heterogeneity of tumor-associated neutrophils (TANs) and cancer contexts determine these myeloid cells’ pro- or anti-tumor effects. In pancreatic ductal adenocarcinoma (PDAC), the multi-omics approach exhibits that TANs undergoing glycolytic switch mediated by LDHA upregulation showed tumor-promoting phenotype . Triple-gression . Moreovegression .Of note, TME is characterized by loss of essential nutrients, inadequate vascularization, lactate accumulation, and hypoxia, and all these detrimental conditions contribute to cancer-killing T cell disability to a large extent. Here we focus on the direct results of the increased glycolytic flux, including limited glucose and acidic TME.+T cells  and TCR expression, along with STAT5 and extracellular signal-regulated kinase (ERK) inactivation -AMPK pathway regulates cell metabolism according to different energy statuses . Upon st+T cell primary response and Th1 and Th17 differentiation (Loss of LKB1 increases glycolytic transcription and flux in T cells by mechanisms including upregulated expression of GLUT1 and hexokinase2 (HK2)  MacIver. Intriguntiation . Antagonntiation , AMPK isntiation . Moreoventiation .The PI3K-AKT-mTOR axis is extensively involved in cell proliferation, survival, cell cycle, and glucose metabolism . As a ma+T cells. Blocking mTOR activity by rapamycin can promote memory cell precursors   . ACT hasex vivo expansion, IL-2, IL-7, and IL-15 are commonly added cytokines , cooperate with TCR signaling to initiate activation, persistence, and exhaustion of TILs. Functional alternations during the exhaustion process are concurrent with metabolic adaptations, which further support the immunosuppressive functions of checkpoints. Therefore, targeting critical glycolytic regulators or metabolites that contribute to immune checkpoints-mediated T cell inhibition is a promising therapeutic strategy in combination with ICBs.+T cells and destabilize Tregs in glycolysis-defective tumors, indicating that the combination of CTLA-4 blockers and glycolysis inhibitors is a promising strategy in cancer (Programmed cell death protein 1 (PD-1) and CTLA-4 are two well-known immune checkpoints. CTLA-4 only expresses on T cells, plays an immunosuppressive role in the initial phase when naïve T cells are activated by antigen-presenting cells (APCs) in lymphoid tissues, and impedes primary T cell activation-induced glycolysis . PD-1 exn cancer . Addition cancer . PD-1 aln cancer . Tkachevn cancer . Of noten cancer .+T cell proliferation, and its agonist significantly activates the glycolysis, mitochondrial functions, and fatty acid metabolism of T cells by increasing GLUT1 expression and activating the AMPK-acetyl-CoA carboxylase (ACC) pathway  catalyzes glucose-6-phosphate (G6P) toward fructose-6-phosphate (F6P), and its overexpression is documented in various cancer types, such as lung adenocarcinoma  and gastGlyceraldehyde-3-phosphate dehydrogenase (GAPDH) reduces glyceraldehyde-3-phosphate toward 1,3-bisphosphoglycerate within the glycolytic pathway. GAPDH inhibitor, Dimethyl fumarate (DMF), is reported to facilitate the oxidative pentose phosphate pathway (PPP) while inhibiting glycolysis and OXPHOS in tumor cells. The reduced glucose competition between cancer cells and T cells mediated by DMF improves the efficacy of ICB and IL-2 therapy in BRCA and COAD patients . Intrigu+T cell effects by leading to metabolic expression and upregulating PD-1 and LAG-3 expression in the context of Type 1 Diabetes, suggesting the considerable role of PFK15 plays in T cell immunogenetic regulation  catalyzes the synthesis and degradation of fructose 2-6 biphosphate , the positive allosteric effector of glycolytic rate-limiting enzyme PFK. gulation . Combinegulation .in vitro and mice xenograft models, such as Shikonin and Isovitexin (Pyruvate kinase isoform M2 (PKM2) is the critical enzyme for the final rate-limiting step of glycolysis, converting phosphoenolpyruvate toward pyruvate. Palsson-McDermott found that PKM2 accelerates tumor progression by promoting PD-L1 expression in macrophages, DCs, and tumor cells . In PDACovitexin , need moThe reversibility of adverse effects on anti-tumor immunity mediated by TME acidification is the prerequisite for targeting lactate to improve anti-tumor immunity and optimize immunotherapy. A study validates that the attenuated functions of CTLs would be restored when cultured in the lactic acid-free medium . The tre+, which will be consumed at the glyceraldehyde-3-phosphate dehydrogenase step of glycolysis. Thus, LDH is indispensable for glycolytic persistence. The research found that NAD precursors like nicotinamide riboside (NR) can reduce the mitochondrial disability in CD8+T cells and elicit more potent inhibition of cancers when combined with ICBs  is upregulated in tumor-infiltrating monocytes and macrophages upon the glycolytic switch induced by HIF-1α. CA12 promoted macrophage survival and HCC metastasis, and CA12 inhibitors synthetically repress cancer growth and metastasis by combining with ICBs in Hepa1-6 mouse models .Glucose shunted to other metabolic pathways is also helpful for glycolysis constraint. The Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of PPP, whose high expression will partition glucose flux from glycolysis. Lu et al. found that G6PD activator AG1 could increase H3K9 acetylation at the Gzmb locus through upregulating acetyl-CoA to enhance Gzmb expression and TILs cancer-lytic ability .+T cells synchronously increase acetate metabolism to fuel TCA-coupled OXPHOS and achieve more prolonged survival upon glutamine inhibition (Glutamine metabolism is closely associated with glycolysis by supplying substrates for TCA cycle . Glutamihibition . This diBesides the metabolic crosstalk between glycolysis and glutamine, subsets of TILs that can not uptake glucose efficiently have high ROS levels in hyperpolarized mitochondria, and in this case, pyruvate supplementation can ignore glycolysis defects and eliminate ROS to partially reinvigorate T cells . CollectGlycolytic activation is a key link process of metabolism reprogramming in cancer and immune cells, tightly associated with the efficiency of anti-tumor immunity, and affects the performance of immunotherapies. We explain at length the glycolytic barriers within checkpoint inhibition and adoptive cell therapies, and emphatically summarize the critical glycolytic targets helpful for enhancing immunotherapy. However, only the tip of the iceberg has been unraveled regarding the mechanisms related to cellular metabolism in optimizing cancer immunotherapy, and large-scale studies are warranted for a deeper understanding of the crosstalk between metabolic pathways with cancer immunity.Given the complication and systematicness of cellular metabolism regulation, it is reasonable to consider the holistic influence induced by genetic or pharmacological interference of metabolic-related molecules in future studies. Especially, due to the metabolic plasticity of cancer cells and immune cells, more attention is warranted to focus on the secondary effects of metabolic therapy, including compensatory activation of metabolic pathways and the TME reshaping. In addition, the metabolic interaction between cells in the TME may play a crucial role in cancer behavior and immunity. For example, the enhanced methionine uptake promoted by SLC43A2 upregulation in cancer cells significantly causes T cell dysfunction , the nutIn conclusion, we give a full-scale review of glycolysis in cancer immunity. We hope our work can offer novel insights into cancer metabolism and contribute to the development of novel therapeutic strategies in the era of immunotherapy.


Nervous system cancers are the 10th leading cause of death worldwide, many of which are difficult to diagnose and exhibit varying degrees of treatment resistance. The limitations of existing cancer models, such as patient-derived xenograft (PDX) models and genetically engineered mouse (GEM) models, call for the development of novel preclinical cancer models to more faithfully mimic the patient’s cancer and offer additional insights. Recent advances in human stem cell biology, organoid, and genome-editing techniques allow us to model nervous system tumors in three types of next-generation tumor models: cell-of-origin models, tumor organoids, and 3D multicellular coculture models. In this review, we introduced and compared different human stem cell/organoid-derived models, and comprehensively summarized and discussed the recently developed models for various primary tumors in the central and peripheral nervous systems, including glioblastoma (GBM), H3K27M-mutant Diffuse Midline Glioma (DMG) and H3G34R-mutant High-grade Glioma (HGG), Low-grade Glioma (LGG), Neurofibromatosis Type 1 (NF1), Neurofibromatosis Type 2 (NF2), Medulloblastoma (MB), Atypical Teratoid/rhabdoid Tumor (AT/RT), and meningioma. We further compared these models with PDX and GEM models, and discussed the opportunities and challenges of precision nervous cancer modeling with human stem cells and organoids. Primary nervous system tumors, whether noncancerous (benign) or cancerous , arise from the nervous tissues in the brain, spinal cord, and peripheral nerves  models and genetically engineered mouse (GEM) models -of-origin for cancer Visvader . For cerUnlike cell-of-origin models that start from genetically modified normal cells, tumor organoids are directly generated from human tumor tissues. Under three-dimensional (3D) culture conditions, neoplastic cells from patient samples can self-assemble into organoids that mimic key histopathological, genetic, and phenotypic characteristics, including the treatment response of the parental tumors  . These human stem cell-derived GBM models are generally useful for mechanism studies and drug screening. When combined with single-cell transcriptomics, these models revealed the malignant transformation trajectory from mutant NSCs to GBM  or induced pluripotent stem cells (IPSCs)  transcriptionally and cellularly resembled primitive neuroectodermal tumors of the central nervous system (CNS-PNETs), while the remaining three  resembled GBM. Similarly, Ogawa et al. used HRasG12V knockin into the TP53 locus to generate highly invasive GBM-like tumor cells in the brain organoids . To investigate the underlying mechanism, Bressan et al. and Funato et al. independently compared the oncogenic effects of H3K27M and H3G34R on both forebrain and hindbrain fetal human NSCs using similar cell-of-origin models (Bressan et al. IDH1/TP53/ATRX into human NSCs (Modrek et al. LGG is classified as a WHO grade II tumor, which includes low-grade astrocytoma, oligodendroglioma, and mixed glioma (Louis et al. NF1 gene (Gutmann et al. NF1-/- Schwann cell lineage cells differentiated from patient IPSCs can develop into neurofibromas in immunocompromised mice (Mazuelas et al. NF1 is a familiar cancer-predisposing syndrome caused by germline mutations in the NF2 gene (Coy et al. Similar to NF1, NF2 is a genetic condition caused by mutations in the CTNNB1 and likely originates from neural progenitor cells of the lower rhombic lip (Gibson et al. PTCH1 and SUFU, negative regulators of the SHH pathway (Taylor et al. th ventricle (Schuller et al. MYC amplification and may arise from CGNPs or Prominin1-positive, lineage-negative NSCs (Kawauchi et al. MYCN and CDK6, yet there is no faithful preclinical models for this subgroup.MB is the most common brain tumor in children that usually originate in the cerebellum (Louis et al. MYC overexpression and TP53 loss (Xue et al. MYCN overexpression in human neuroepithelial stem cells (Čančer et al. PTCH1 mutations (Huang et al. Cell-of-origin models for MB built upon the finding in GEM models to introduce MB drivers into human NSCs to initiate MB development. In 2016, Hanaford et al. develop the first human NSC-derived model for Group 3 MB. They transduced human NSCs from the cerebellar anlage with overexpression of c-MYC, dominant-negative p53, constitutively active AKT and hTERT (Hanaford et al. Currently, there are only a few studies using organoids to model MB. Ballabio et al. established the first human cerebellar organoid-derived cell-of-origin models for MB (Ballabio et al. SMARCB1 mutations and exhibits rhabdoid cell histology. Studies in GEM models demonstrated that AT/RT may develop from Smarcb1-mutant embryonic neural stem/progenitor cells (Han et al. TP53 and SMARCB1 in ESCs, and uncovered the ESC transcriptional signature as a key driver for AT/RT (Terada et al. AT/RT is a lethal childhood malignant CNS tumor (Louis et al. NF2-inactivated (Riemenschneider et al. TRAF7, KLF4, AKT1, and SMO (Clark et al. FOXM1, a meningioma-relevant gene, in the maintenance of these tumor organoids. There are currently no cell-of-origin models for meningioma, possibly due to the technical difficulties in culturing the meninges as cell lines or organoids.Meningioma is the most common primary CNS tumor that arises from arachnoid cap cells in the meninges (Louis et al. Human stem cell/organoid-derived models have provided new tools for precision nervous system tumor modeling. Compared to GEM models, they are more human-relevant since they directly model the behavior of human cells, and do not require time-consuming multi-generation crossing. Compared to 2D cancer cell lines and PDX models, cell-of-origin models offer unique insights into the de novo tumorigenesis from genetically defined tumor-initiating human cells, tumor organoid models better preserve the genetic/transcriptional diversity of parental tumors and generally have a higher success rate to establish, while 3D multicellular coculture models reconstitute the complex human tumor microenvironment in a 3D setting. These models are especially valuable for the study of tumor types wherein few GEM and PDX models are available.While human stem cell/organoid-derived models bring new opportunities for understanding the tumorigenesis and progression of nervous system tumors, there are several challenges that need to be addressed in the next phase development of these models.For human stem cell-based models, one potential problem is that similar to PDX models, they require xenograft into immunocompromised mice, and essentially developing tumors in a mouse brain microenvironment. To make these models more human-relevant, we could use humanized mice through engraftment of human cell types such as microglia and other immune cells.For human brain organoid-based models, a key issue is that they miss key cell types in the tumor microenvironment. Unlike epithelial organoids that can be derived from both adult stem cells and pluripotent stem cells, currently brain organoids can only be generated from pluripotent stem cells Clevers . ConsequWhile human stem cell/organoid-derived models are in theory very promising for drug screening, it is yet to be demonstrated that these screening schemes are more suitable or more predictive of patient responses than less expensive cell-based multi-well-plate screenings in a head-to-head comparison. As a step in this direction, Jabs et al. showed that drug effects in organoids were more diverse than in cell lines (Jabs et al. Human stem cell/organoid-derived models start a new era of precision nervous system tumor modeling, and the field is rapidly evolving. Looking forward, we would expect that more models will be developed for different types of nervous system tumors using different genetic combinations and initiating cell types. The current organoid models could be further optimized by integrating more diverse cell types as tumor-initiating cells or tumor microenvironmental cells to study the complex process of tumorigenesis. Together, these technological advancements will hopefully help establish more faithful models for the development of life-saving therapies.


Malignant pleural mesothelioma (MPM) is a malevolent tumor originated from pleura and often leads to poor prognosis. Chemotherapy of pemetrexed and cisplatin combined with antiangiogenic therapy of bevacizumab is recommended as the first-line regimen by guidelines. However, there are few sustainable second-line anti-tumor theraies that bring distinct survival benefit after the occurrence of drug resistance as the reported mPFS  scarcely exceeds 6 months. Immune checkpoint inhibitors are extensively investigated in pan-cancer, and dual immunotherapy has been listed in the first-line recommendation of MPM in several guidelines, while MPM patients benefit modestly from immune checkpoint inhibitors combination or monotherapy in second-line practice.We report a 59-year-old male patient who was diagnosed with unresectable MPM in April 2021.He received firstly pemetrexed combined with platinum and bevacizumab, which barely curbed disease progression; When the first line treatment failed, he was switched to tislelizumab combined with anlotinib.Tislelizumab combined with anlotinib significantly relieved his clinical symptoms, and imaging examination further validated the improvement. Until present, the second-line treatment PFS is more than 10 months.The case firstly demonstrated the efficacy of tislelizumab combined with anlotinib in the second-line management of MPM. Thus, immunotherapy combined with small-molecule multi-target anti-angiogenic medication may be alternative for the second-line schemes of MPM. Malignant pleural mesothelioma (MPM) is a malevolent tumor originated from pleura and often leads to poor prognosis with 5-year overall survival (OS) rate of 5% to 10% for all stages. The first-line treatment relies on chemotherapy including pemetrexed and cisplatin, and combination of bevacizumab can prolong patient survival; however, few second-line anti-tumor strategies distinctly bring distinct survival benefit to resistant cases with progression-free survival (mPFS) less than 6 months. Immune checkpoint inhibitors (CKIs) are extensively investigated in pan-cancer, and dual immunotherapy has been listed for the first-line use of MPM in some international guidelines, while MPM patients benefit modestly from CKIs combination or monotherapy in second-line use. Basic researches and clinical practices of other tumor types have revealed that anti-angiogenic therapy such as anti-VEGF and multi-targeted small molecule anti- angiogenesis drugs can synergistically enhance the efficacy of immunotherapy by modulating tumor microenvironment, while little is reported on their combined use in MPM. Here we report a 59-year-old male patient who was diagnosed with unresectable malignant pleural mesothelioma in April 2021. The disease continued to progress under the first-line treatments of pemetrexed and platinum in combination with bevacizumab. Fortunately, the case responded favorably to second-line therapy, namely the combination of tislelizumab (PD-1 inhibitor) and anlotinib . This report provides a new management paradigm for second-line treatment of MPM.The patient was a 59-year-old male employee of a professional construction company. On April 30, 2021, he complained of “cough, expectoration of sputum for 1 month, and shortness of breath for 2 days” and underwent enhanced chest CT. As shown in Figure Meanwhile, the lesions progressed slowly but significantly accelerated at 6 months of treatment as manifested by chest CT Fig. , B1–3. W,2 Most MPM patients have progressed to late stage at diagnosis, consequently confronted with treatment obstacles and unfavorable curative effect, leading to median OS of about 1 year, 5-year survival rate around 10% and even smaller rate of cured cases.MPM is a rare but highly fatal disease that closely related to asbestos exposure but often attacks after 20 to 40 years of the exposure.,4 despite of its limited efficacy. The recommended first-line chemotherapy regimen is pemetrexed plus cisplatin, with a median OS of about 12 months and mPFS of 5.7 months, but only 35% to 41% of patients respond to first-line therapy. Results of IFCT-GFPC-0701 MAPS demonstrated that the combination of bevacizumab can prolong median OS by 2.7 months and thus pemetrexed, cisplatin plus bevacizumab regimen is incorporated in first-line recommendations. However, in this patient, lesions continued to progress slowly and the clinical symptoms deteriorated despite the combined regimen. The progression significantly exacerbated at 6 months of administration.Among the main interventions for MPM that include surgery and radiation therapy, systemic therapy is the only treatment able to improve overall survival as reported by randomized clinical trials CKIs have manifested its anti-tumor effects in a variety of malignant tumors. In unresectable MPM, dual immunotherapy has achieved remarkable efficacy in the first-line application. Piling researches on second-line immunotherapy, despite small-scale and single-arm designs, investigated the benefit of keytruda, nivolumab, ipilimumab and so on, which only attain unsatisfactory mPFS less than 6 months.–10Upon the resistance of MPM to first-line treatments, there is currently few standard second-line recommendations in most guidelines, including the NCCN guidelines. The second-line regimens commonly used in clinical practice are single-agent chemotherapy, such as vinorelbine, gemcitabine, etc, but only obtain mPFS of about 3 months. Along MPM carcinogenesis, chronic inflammatory reaction to asbestos fibers causes immunosuppressed tumor microenvironment. Previous studies have confirmed that anti-angiogenesis therapy can directly or indirectly alleviate the immunosuppressive state by changing the tumor microenvironment,,14 while immunotherapy can also facilitate the normalization of tumor vasculature, highlighting the synergistic effect of immunotherapy and anti-angiogenesis agents in anti-tumor strategies, which has been validated in in a variety of tumors including non-small cell lung cancer, renal cell carcinoma and so forth.,17 In particular, combination of arotinib and CKIs has proved its safety and significant advancement of efficacy in case reports and clinical researches.,19 However, few researches focus on its application in MPM. In clinical practice, our case continued to progress after chemotherapy combined with bevacizumab. Given that he was negative for PD-L1 expression, we ruled out single drug immunotherapy when modifying treatment scheme. With the consent of the patient and his family, we chose immunotherapy combined with anti-angiogenesis drugs. As bevacizumab failed in this patient, we selected arotinib in the second line, which is a small molecule multi target anti-angiogenesis drug that inhibits VEGFR 1/2/3  and other major tyrosine kinase receptors  to potently block tumor angiogenesis and suppress proliferation. Second-line treatment with arotinib and tirelizumab significantly relieved his clinical symptoms and imaging examination also verify the improvement. At present, his PFS of second-line treatment has sustained 10 months, presenting satisfactory responsiveness that markedly exceeds the existing second-line scheme in contemporary researches.Both basic and clinical studies found that abnormal tumor microenvironment has a negative impact on the efficacy of PD-1/PD-L1 inhibitors.Here we report a case that firstly demonstrated the efficacy of tislelizumab combined with anlotinib in the second-line treatment of MPM. Thus, immunotherapy combined with small-molecule multi-target anti-angiogenic therapy may be alternative for the second-line treatment of MPM.Conceptualization: Dandan Zhang, Weihong Guo.Data curation: Weihong Guo, Jianping Liang.Formal analysis: Dandan Zhang.Investigation: Jianping Liang.Methodology: Yanhua Lv, Jianping Liang.Software: Xikun Huang.Writing – original draft: Dandan Zhang, Weihong Guo.Writing – review & editing: Dandan Zhang, Weihong Guo.


We describe the clinical presentation, radiological findings, treatment and outcomes of three patients with delayed leukoencephalopathy occurring after endovascular treatment (EVT) for cerebral aneurysms—a rare, albeit recurring, complication. The symptoms occurred 6 to 12 months following the EVT of the cerebral aneurysm. Characteristic imaging findings included high-signal changes on T2 images in the white matter without diffusion restriction predominantly at the distribution of the vascular territory of the catheterized arteries, coupled with patchy gadolinium enhancement or low susceptibility weighted imaging (SWI) signals within the white-matter lesions. Steroid pulse therapy is the treatment of choice and promptly improves clinical and imaging findings. Tapering or cessation of steroids may result in clinical and imaging relapses; close- and long-term follow-up for patients presenting this complication is warranted. Endovascular treatment (EVT), performed with coils, stents, and flow diverters, is considered an evolving therapy for cerebral aneurysms . The mosIn view of these considerations, we describe three consecutive cases presenting at our tertiary care stroke center with delayed non ischemic cerebral enhancing (NICE) lesions after EVT of cerebral aneurysms during the last three years . We alsoA 64-year-old woman presented to the emergency department with subacute-onset headache, auditory hallucinations, paresthesias and weakness of the left upper limb with an initial National Institutes of Health Stroke Scale (NIHSS) score of 3 points. Her past medical history included non-traumatic subarachnoid hemorrhage (SAH) one year ago, due to aneurysm rupture of the right posterior communicating artery (PCom), which was uneventfully treated with endovascular coil embolization . Computed tomography (CT) of the brain revealed right temporoparietal hypodense lesions. Magnetic resonance imaging (MRI) of the brain confirmed right temporoparietal subcortical lesions, surrounded by vasogenic edema without diffusion restriction. Additionally, susceptibility-weighted imaging (SWI) showed low-signal spots within the lesions, suggesting deposition of paramagnetic material and slight gadolinium enhancement in the post-gadolinium T1-weighted sequences A,B. ExteTwo years after a slow attempt in tapering steroid treatment, the patient presented with a clinical relapse with headache, dysarthria and left upper arm weakness (NIHSS score 2). Brain MRI also revealed a radiological relapse with enhancing lesions and low-signal spots on SWI along with extensive vasogenic edema, and a second steroid pulse treatment was initiated resulting in clinical and radiological recession D.A 62-year-old woman presented in our outpatient clinic with gradual left-sided hemiparesis, auditory hallucinations and seizures over the last six months (NIHSS score 3). Her medical history included non-traumatic SAH three years ago due to aneurysm rupture of the right posterior communicating artery (PCom), successfully treated with EVT and a surgical aneurysmal clipping of unruptured aneurysm in the anterior communicating artery (Acom). Six months after the EVT, the patient developed left homonymous hemianopsia and brain CT revealed right occipital hypodense lesion. Unfortunately, the patient declined further evaluation at that time. Brain MRI at the time of admission in our department revealed right occipitoparietal and occipitotemporal white matter lesions with radiological characteristics of vasogenic edema. SWI showed low-signal spots within the lesions, while post-gadolinium T1-weighted sequences demonstrated slight gadolinium-enhancement of the lesions A,B. BlooA 49-year-old woman was referred to our neurologic department due to gait disorders, right-sided hemiparesis, partial seizures of the right upper limb and mild cognitive and concentration difficulties, gradually deteriorating over the last 6 months (NIHSS score 4). A remarkable piece of information from her medical history was the application of a flow diverter stent (P 64-MW-HPC-450-15 FD) in a non-ruptured aneurysm of the supraclinoid segment of left internal cerebral artery (ICA) one year ago. The microcatheter that was used, had a hydrophilic coat (Rebar 18 105-5081-153). The patient was admitted to another hospital 5 months ago and brain MRI revealed multiple white-mater lesions in the left frontoparietal region with parenchymal enhancement as well as leptomeningeal enhancement after intravenous contrast administration A,B. A thOver the last few years, delayed non ischemic cerebral enhancing lesions suggesting immune-mediated leukoencephalopathy have been recognized as an increasing complication after aneurysm EVT, including coils, stents, and flow diverters with an estimated incidence between 0.05% and 2.3% mostly observed in women aged 41–65 years with median time of weeks up to 12 months after the procedure ,8. ConsiBrain MRIs of all similar cases reported so far in the literature have distinctive features: T2-fluid-attenuated inversion recovery hyperintensities predominantly in the subcortical white matter and at the grey–white matter border, predominantly at the distribution of the vascular territory of the catheterized arteries as well as perilesional edema, which varies in extent. Gadolinium enhancement is either solid or rim-shaped. Partially, low signals in SWI in the fluid-attenuated inversion recovery (FLAIR) hyperintensities are reported, probably due to deposition of microembolic paramagnetic coil-related materials ,15,16,17Brain biopsy was performed in few cases demonstrating granulomas, angiitis, periadventitial foreign-body giant cell response, and microabscesses encasing foreign material, neutrophilic granulocytes, and multinucleated macrophages ,9,11. BrIn terms of treatment, steroid pulse therapy followed by oral prednisone is considered the first treatment option, leading to significant resolution of neurological symptoms along with improvement of MR findings ,14,15,16In conclusion, delayed leucencephalopathy is a rare complication after EVT treatment of cerebral aneurysms. Approximately a hundred cases have been published so far over the last 14 years . The maiNevertheless, it is remarkable that in the three largest cohort studies ,6,7 16,


Foods primarily obtained from plant materials, such as fruits, vegetable, grains, legumes and other plant foods, provide not only nutrients but also non-nutrients. In addition to nutrients, non-nutrients in plant foods are bioactive compounds such as phytochemicals  and dietary fiber. A bioactive compound is generally defined as a substance with the biological potential to influence health in a beneficial way.Accumulating studies support that dietary bioactive compounds and/or whole plant extracts have been linked to health promotion and disease prevention. These natural bioactive compounds have been known to have various biological functions including antioxidant, anti-inflammatory, anti-obesity, and anti-cancer activities. Thus, dietary bioactive compounds show preventive and/or therapeutic effects for various diseases such as obesity, diabetes, cancer, and skin diseases. Even though pure isolated bioactive compounds have potent biological actions, it is also important to investigate the benefits of plant extracts for human health. As a result of the combined action of multiple compounds within them, plant extracts exhibit additive, antagonistic or synergistic activity.This Special Issue aims to provide scientific evidence focusing on all aspects of bioactive compounds with health benefits. This Special Issue includes several studies about the various biological effects of natural products and their derived compounds on multiple diseases related to metabolic syndrome, cachexia, melanogenesis, tumors, and bone loss. The Special Issues also covers two review papers including nutrients against glucocorticoid-induced muscle atrophy  and the (1)Obesity and related metabolic abnormalities are closely related to multiple metabolic diseases and cancers. Marzo et al. examined the beneficial effects of apple extract on neoplastic lesions and cachexia using Crl:CD-1 mice treated with azoxymethane (AOM) and a high-fat diet to induce colon polyps related to obesity. After the treatment with AOM, Crl:CD-1 mice were fed either a high-fat diet or a high-fat diet supplemented with apple extract at 1% or 1.5%. The treatment with apple extract did not affect body weight, energy expenditure, or respiratory quotient but ameliorated signs of cachexia. The apple-extract-treated group exhibited lower sucrase, dipeptidyl-peptidase IV, and aminopeptidase N activities, and fewer intestinal lesions .(2)Hwang et al. tested the cholesterol-lowering effect of the ethanol extract of capsella bursa-pastoris (CBE) using diet-induced obese mice and HepG2 cells . The ora(3)Sargassum serratifolium using B16F10 cells treated with alpha-melanocyte-stimulating hormone (α-MSH). The treatment of SHQA significantly reduced cellular tyrosinase activity and melanin content partly by downregulating the expression of tyrosinase and tyrosinase-related protein 1. Further experiments revealed that SHQA inhibited the main transcription factors for melanogenesis, including microphthalmia-associated transcription factor and cAMP-responsive element-binding protein, indicating that SHQA may be applied to a pharmaceutical or cosmetic agent against hyperpigmentation [Azam et al. tested the anti-melanogenic activity of sargahydroquinoic acid (SHQA) abundant in the brown alga entation .(4)Rubus coreanus Miquel (R. coreanus), have been reported, the effects on the PD-1/PD-L1 immune checkpoint have not been tested. Kim et al. proved that the water extract of R. coreanus suppressed the binding of PD-1 to PDL1 using competitive enzyme-linked immunosorbent assay (ELISA) and cell-based bioassay [R. coreanus extract [Although various biological activities, including the antioxidant and anti-tumor effects of the extract of bioassay . When it extract .(5)Agastache rugosa, an aromatic herb widely used as a food ingredient, on bone health. They focused on the beneficial effects of A. rugosa on osteoclast differentiation and bone loss in ovariectomized mice that can be used as a model for postmenopausal osteoporosis [A. rugosa may be used as a therapeutic agent against postmenopausal osteoporosis [Jang et al. examined the effects of the water extract of oporosis . The oraoporosis . Furtheroporosis .


Galectins constitute a protein family of soluble and non-glycosylated animal lectins that show a β-galactoside-binding activity via a conserved sequence of approximately 130–140 amino acids located in the carbohydrate recognition domain (CRD). To date, fifteen members, named in the order of their identification, have been identified in mammals. The galectin family members are classified into three types on the basis of their structures. Galectins are stored in the cytoplasm of many types of immune and stromal cells that occur at the entry sites of pathogenic micro-organisms, including fibroblasts, keratinocytes, endothelial cells, and mucosal membrane epithelial cells. Despite the highly conserved nature of galectin CRDs, subtle yet significant differences occur in the binding affinity between different members of the galectin protein family. Galectins are also released from injured cells and express a variety of activities under pathological conditions. This Special Issue aims to present studies that describe novel aspects of galectins.Kuśnierz-Cabala et al. described “Diagnostic Significance of Serum Galectin-3 in Hospitalized Patients with COVID-19” . Gal-3 iPlasma levels of Gal-9 are elevated in various disaster-related infectious diseases such as dengue, malaria, and AIDS/TB . Gal-9 iFinally, it should be mentioned that both Gal-3 and Gal-9 are potential immune checkpoint molecules, because Gal-3 interacts with LAG3 and the interaction of Gal-9 Tim-3 induces either apoptosis or suppression of T cell effector functions via engagement with its receptor TIM-3. In agreement, Gal-9 knockout mice mount a more robust and vigorous virus-specific immune response, resulting in rapid viral clearance .Wałek et al. wrote “SerumGalectin-3 Concentration Reflects Left Atrial Remodeling and Function in Patients with Persistent Atrial Fibrillation” . Atrial Dr. Meggy described the influence of Gal-9 treatment on the phenotype and function of NK-92MI cells. The cytotoxic activity of the natural killer (NK) cells can be triggered without prior sensitization or immunization in a major histocompatibility complex (MHC)-unrestricted manner and regulated by various activating and inhibitory receptors, depending on the presence of their ligands on the target cells and the activation state of the NK cells . For tumKlebsiella pneumoniae (Kpn) and non-typeable Haemophilus influenzae (NTHi) cells, and confocal microscopy attested binding to bacterial cells in suspension. They illustrated galectins’ versatility for recognizing different bacterial structures, and point out the occurrence of so far overlooked galectin ligands on bacterial surfaces. Galectins’ plasticity in targeting diverse ligands in multifarious pathogens, including Gram-negative and -positive bacteria, virus, fungi, and parasites, points to a key role of these lectins in immune protection.Campanero-Rhodes et al. examined the binding of four human galectins to the Gram-negative bacteria . Galecti+CD25+ Foxp3+ Treg cells within the tumor, draining lymph nodes, spleen, and lung metastases [Huang et al. described the immunosuppressive roles of Gal-1 in the tumor microenvironment . Gal-1 itastases . The mecTo conclude, this Special Issue described the novel activities of galectins. Galectins have been present in various organisms since ancient times and maybe the root of their complexity. Further research is desired.


Cisplatin (CDDP) is a well-known platinum-based drug used in the treatment of various malignancies. However, the widespread side effects that this drug leaves on normal tissues make its use limited. Since cisplatin is mainly eliminated from the kidneys, CDDP-induced nephrotoxicity is the most significant dose-limiting complication attributed to cisplatin, which often leads to dose withdrawal. Considering the high efficiency of cisplatin in chemotherapy, finding renoprotective drug delivery systems for this drug is a necessity. In this regard, we can take advantages of different nanoparticle-based approaches to deliver cisplatin into tumors either using passive targeting or using specific receptors. In an effort to find more effective cisplatin-based nano-drugs with less nephrotoxic effect, the current 2011–2022 review study was conducted to investigate some of the nanotechnology-based methods that have successfully been able to mitigate CDDP-induced nephrotoxicity. Accordingly, although cisplatin can cause renal failures through inducing mitochondria dysfunction, oxidative stress, lipid peroxidation and endoplasmic reticulum stress, some CDDP-based nano-carriers have been able to reverse a wide range of these advert effects. Based on the obtained results, it was found that the use of different metallic and polymeric nanoparticles can help renal cells to strengthen their antioxidant systems and stay alive through reducing CDDP-induced ROS generation, inhibiting apoptosis-related pathways and maintaining the integrity of the mitochondrial membrane. For example, nanocurcumin could inhibit oxidative stress and acting as a ROS scavenger. CONPs could reduce lipid peroxidation and pro-inflammatory cytokines. CDDP-loaded silver nanoparticles (AgNPs) could inhibit mitochondria-mediated apoptosis. In addition, tea polyphenol-functionalized SeNPs (Se@TE) NPs could mitigate the increased level of dephosphorylated AKT, phosphorylated p38 MAPK and phosphorylated c-Jun N-terminal kinase (JNK) induced by cisplatin. Moreover, exosomes mitigated cisplatin-induced renal damage through inhibiting Bcl2 and increasing Bim, Bid, Bax, cleaved caspase-9, and cleaved caspase-3. Hence, nanoparticle-based techniques are promising drug delivery systems for cisplatin so that some of them, such as lipoplatins and nanocurcumins, have even reached phases 1–3 trials. CisplatOH2)2]2+ . These cOH2)2]2+ , 6.The main anticancer mechanism proposed for CDDP is the induction of DNA damage through forming cross-linking complexes with purine residues , 5, 6. ISince CDDP is excreted predominately in the urine, it accumulates more in kidneys than other organs. Therefore, nephrotoxicity is the most important side effect attributed to CDDP . CisplatThe use of cisplatin derivatives, i.e., carboplatin [di-aminePt (II)] and oxaliplatin [-diaminocyclohexane)oxalate-Pt(II)], is one of the most effective methods to mitigate cisplatin-induced nephrotoxicity. Instead of the chlorides in the chemical formula of cisplatin, these drugs have cyclobutane-1, 1-dicarboxylato and oxalate, which can chelate Pt more strongly . Thus, tNanotechnology is a cutting-edge approach that may be effective in developing some drug delivery systems for CDDP. As shown in Fig. To design new CDDP-based nano-carrier with less nephrotoxic effect, this study aimed to review some of the nanotechnology-based methods that have been able to alleviate the CDDP-induced nephrotoxicity. For this purpose, some of the main nephrotoxic mechanisms of cisplatin are firstly introduced and then the applications of both metallic and polymeric nanoparticles in reduction of the CDDP-associated nephrotoxicity were reviewed between 2011 and 2022.Histologically, cisplatin can cause some dose–response changes in the collecting ducts, distal tubules, and most importantly, in the S3 segment of the proximal tubules of renal tissue , OCT2 is probably involved in the renal absorption of cisplatin , 27. MorOn the other hand, by forming DNA adducts in both mitochondrial and nuclear DNA, cisplatin can induce either apoptosis at low doses (8 μM) or necrosis at higher doses (800 μM) . The celThe CDDP-induced apoptosis is mediated by different signaling pathways in kidneys  from the cell. The conversion of Ce4+ to Ce3+ can oxidize hydrogen peroxide to O2 , NFR2 protein, p53 protein and its inducible genes  were significantly less in the mice treated with P2Ns-GA-UA compared to the cisplatin group. On the other hand, P2Ns-GA UA did not affect the hypoxic state of the renal. In general, P2Ns-GA UA treated group had less oxidative phosphorylation deficiencies and kidney apoptosis [poptosis .-Cisplatin-polyacrylic acid (PAA) nano capsule (CDDP-PAA-NC): conjugating CDDP to PAA helps to enhance drug loading and reduce drug leakage through replacing anionic chlorides in the drug with carboxylic residues in PAA. We can also inhibit the drug leakage via encapsulating this complex in PVA/superparamagnetic iron oxide (SPIO) shell. A prolonged blood circulation enhances the opportunity for nano-drugs to accumulate in tumor by leaky sites in vessels. Thus, these nanoparticles could successfully decrease the cisplatin-induced nephrotoxicity, while they increased CDDP tumor accumulation, and prolonged drug release [ release .-Hyaluronan–cisplatin conjugate nanoparticles (HCNPs) entrapped in Eudragit S100-coated pectinate/alginate microbeads (PAMs) (HCNP-PAMs): enzyme- or pH-dependent systems can be used to deliver drugs to colon. Pectin is a natural polysaccharide which can inhibit metastasis through attaching to the galectin-3 receptor. The use of pectin alone as a microencapsulation matrix needs high concentrations of pectin in electrospray method, owing to its low carboxyl groups; therefore, alginate is mixed with pectin to solve this problem. However, this matrix quickly releases drugs under gastric condition, which can be solved by coating Eudragit on the surface of these microbeads. Moreover, hyaluronan not only can form stable complexes with CDDP, but also can actively target CD44 receptors on cells, and ameliorate the cisplatin-induced nephrotoxicity .-Cysteine Pt(IV) prodrug NPs: as mentioned earlier, intracellular thiol-containing molecules can induce cisplatin resistance in tumors. However, these nanoparticles are made of poly(disulfide amide) polymers that can reverse the drug resistance by a GSH-scavenging process, which rapidly induced the release of Pt ions in a thiol-rich medium. Thus, they are suitable for increasing CDDP efficiency, as they can deliver the active Pt to cisplatin-resistant cells and deplete GSH concentration in the cells. In addition, these nanoparticles activate apoptotic pathways by increasing p53 and caspase-3, and decreasing Bcl2. Interestingly, they had less systemic toxicity, including nephrotoxicity [toxicity .-Hyaluronic acid-cisplatin/polystyrene-polymetformin (HA-CDDP/PMET): it is used for co-delivery of metformin (MET) and CDDP to lung cancer. In a study, this nanoparticle could enhance the survival rate of animals without inducing nephrotoxicity. This was due to the fact that this nanoparticle could accumulate in the kidneys less than cisplatin. On the other hand, apoptosis was upregulated in tumor cell by the synergistic effect of CDDP and MET in HA-CDDP/PMET NPs, resulting in the regulation of cleaved PARP protein [ protein .-Aptamers (Apt): Apts have some significant features, including great tissue penetration, low toxicity, lack of immunogenicity, thermal stability, high surface modification and being non-reactive to negatively charged proteins of blood circulation. Indeed, Apts interact only with their receptors on surface of tumor cells, resulting in less cisplatin accumulation in kidney and less nephrotoxicity in comparison with free CDDP at the same doses [me doses .-Glycyrrhetinic acid (GA) Aliginate acid (ALG) Pt nanoparticles: alginate is a biodegradable and non-toxic polysaccharide which operating as the shell and skeleton of nanoparticles. The presence of several carboxy groups in the structure of this polymer give it a negative surface charge. Therefore, GA-ALG@Pt NPs cannot interact with blood elements and show low systemic toxicity and long blood circulation [culation .Silk fibroin peptide/baicalein nanofibers (SFP/BA NFs): this nano-formulation could enhance the CDDP uptake and localization to mitochondria in renal cells, which led to an inhibition of the cisplatin-induced ROS formation and mitochondrial membrane potential disruption. As a result, they successfully protected against cisplatin-induced AKI via improving antioxidant responses, e.g., SOD and GSH, and suppressing DNA damage and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation in kidney [-n kidney .-Folate grafted albumin nanoparticles: folic acid receptors are over-expressed on the surface of various cancer cells, so this vitamin can be used for targeted therapy. Based on one study, the administration of cisplatin loaded folic acid decorated bovine serum albumin nanoparticles (Cp-FA-BSA-Nps) limits the cisplatin adverse effects on kidneys [ kidneys .As shown in Table This study was conducted with the aim of finding effective drug delivery systems to reduce the nephrotoxic effect of cisplatin. In this regard, nanomedicines based on metallic and polymeric nanoparticles were investigated between 2011 and 2022. The current review demonstrated that after treating with cisplatin, these nanoparticles can strengthen the renal antioxidant system and reduce ROS generation either by their innate antioxidant properties, such as cerium oxide, or by carrying antioxidants. In addition, cisplatin can activate various apoptotic and inflammatory pathways in kidneys, whereas both metallic and polymeric nanoparticles have been able to preserve the kidney tissue by regulating these pathways and maintaining the survival of renal cells. In fact, the present review shows that some cisplatin-based nanosystems with their renoprotective mechanisms are probably helpful in finding renoprotective formulations of cisplatin. Nanocurcumin could inhibit oxidative stress and acting as a ROS scavenger. CONPs could reduce lipid peroxidation and pro-inflammatory cytokines, such as IL-6 and TNF-α, and increase antioxidants, such as CAT and GSH, in cisplatin-treated mice. CDDP-loaded AgNPs could inhibit mitochondria-mediated apoptosis and the release of AIF and cytochrome c from mitochondria. In addition, Se@TE NPs could mitigate the increased level of dephosphorylated AKT, phosphorylated p38 MAPK and phosphorylated c-Jun N-terminal kinase (JNK) induced by cisplatin. Furthermore, PLGA-encapsulated nano-Boldin reduced the cisplatin-induced nephrotoxicity by increasing SOD activity and decreasing LPO level. Also, the co-treatment of PLGA nanoparticle encapsulating THY with cisplatin decreased cisplatin-induced nephrotoxicity in ESC mice model without losing antitumor properties of cisplatin as well as kidney damage markers were reduced in the treated mice in comparison with the cisplatin group. Moreover, exosomes as new nanoparticles could mitigate cisplatin-induced renal damage through inhibiting Bcl2 and increasing Bim, Bid, Bax, cleaved caspase-9, and cleaved caspase-3.The reviewed renoprotective nanoparticles have been classified and summarized in Fig.


Recently, the Coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread globally. Although the specific role of NK cells in COVID-19 pathophysiology still need to be explored, mounting evidence indicates that NK cell tissue distribution and effector functions could be affected by SARS-CoV-2 infection and that a prompt NK cell response could determine a good clinical outcome in COVID-19 patients. In this review, we give a comprehensive overview of how SARS-CoV-2 infection interferes with NK cell antiviral effectiveness and their crosstalk with other innate immune cells. We also provide a detailed characterization of the specific NK cell subsets in relation to COVID-19 patient severity generated from publicly available single cell RNA sequencing datasets. Finally, we summarize the possible NK cell-based therapeutic approaches against SARS-CoV-2 infection and the ongoing clinical trials updated at the time of submission of this review. We will also discuss how a deep understanding of NK cell responses could open new possibilities for the treatment and prevention of SARS-CoV-2 infection.Natural Killer (NK) cells are lymphocytes of the innate immunity that play a crucial role in the control of viral infections in the absence of a prior antigen sensitization. Indeed, they display rapid effector functions against target cells with the capability of direct cell killing and antibody-dependent cell-mediated cytotoxicity. Furthermore, NK cells are endowed with immune-modulatory functions innate and adaptive immune responses  They display rapid effector functions with the capability of direct target cell killing and antibody-dependent cell-mediated cytotoxicity (ADCC) , 2. Furts (APCs) .bright/CD16neg (CD56bright) and CD56dim/CD16pos (CD56dim) -γ and tumor necrosis factor (TNF)-α, and establishment of cellular interplays]. Conversely, CD56dim NK cells (up to 90% of the whole blood NK cell population) were primarily reported to act as cytotoxic effectors. Different subsets of human NK cells have been also described in peripheral tissues. The tissue-specific human NK cell populations often carry phenotypic hallmarks that distinguish them from their circulating counterparts and are present under homeostatic conditions in both secondary lymphoid organs  , 5. The d organs  and non-d organs , 9.In addition to canonical NK cells, increasing evidence demonstrated the existence of tissue-resident and circulating NK cells endowed with adaptive-like features. These adaptive/memory-like NK cells have been firstly described in response to Cytomegalovirus (CMV) infection and re-activation and are characterized by more vigorous functional responses, longer life span and more resistance to immune suppression than the other NK cell subsets , 11.NK cell activation and functions are regulated by the interplay between a large number of inhibitory and activating receptors in combination with the presence of certain cytokines , 12. Togvia the absence of inhibitory MHC-I engagement is known as the “missing-self” hypothesis  molecules, which interact with inhibitory receptors present on the NK cell surface. This inhibitory receptor-mediated signaling is essential to counteract activating signaling in order to protect against NK cell over-activity. This mechanism of target cell recognition pothesis . Human Npothesis , 17. KIRpothesis .In humans, NK cells are important mediators of the responses against viruses, including members of the herpesvirus, retroviruses, poxvirus and papilloma virus families. In fact, patients with identified NK cell deficiencies are predisposed to particularly severe, recurrent viral infections .NK cells have multiple mechanisms to kill virus-infected cells.The most important one is represented by the ability of some viruses to downregulate surface expression of MHC class I on the host cell surface to interfere with the presentation of viral antigens to T cells . AccordiAccumulating evidence has revealed the importance of NK cell-activating receptors in antiviral defense . For insKIR3DS1 combined with HLA-Bw4-I80 allele in patients with human immunodeficiency (HIV) infection has a protective effect and is associated with lower viral load and delayed progression to Acquired Immunodeficiency Syndrome (AIDS)  .via CD16-mediated ADCC. In fact, NK cell-mediated ADCC prevents HIV infection via the engagement of Fcγ receptors after the administration of the anti-HIV neutralizing Ab (NAbs)  .Although NK cells are essential in the early response against viral infections, through the killing of virus-infected cells, several viruses have evolved multiple mechanisms to evade NK cell-mediated viral clearance that affect NK cell phenotype and effector functions.Coronaviruses are a group of enveloped single-stranded RNA viruses having an extensive range of natural hosts, including a variety of economically important vertebrates and humans. Indeed, seven coronaviruses have been known to infect human hosts causing respiratory diseases. Among them, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are zoonotic and highly pathogenic coronaviruses that have resulted in regional and global outbreaks in the last decades. In 2019, a third zoonotic coronavirus, named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), causing the Coronavirus disease 2019 (COVID-19) has spread globally .The specific role of NK cells in Coronavirus disease pathophysiology still needs to be explored, however, several studies in both SARS-CoV-1 and SARS-CoV-2 suggest that NK cells could be affected by these infections , 30.Seminal studies in SARS-CoV-1 infected subjects demonstrated that the number of circulating NK cells and the expression of the inhibitory KIR CD158b is reduced with respect to those in healthy individuals and patients affected by Mycoplasma pneumoniae infection. This correlated with disease severity and the presence of anti-SARS coronavirus-specific antibodies . MoreoveIn this review, we provide a comprehensive overview of how SARS-CoV-2 infection interferes with the antiviral effector functions of NK cells and with the interactions between NK cells and other innate immune cells. Moreover, we will summarize the current ongoing clinical trials aiming at “fine tuning” NK cell activity in the context of COVID-19.pos Th1, Tregs, and CD8pos T cells) counts with respect to non-infected subjects and to mild cases. Similarly, several independent reports indicated that the number of NK cells in the bloodstream is also affected by SARS-CoV-2 infection, without differences in NK cell subset distribution , expand in severely infected individuals (The data obtained showed that proliferating NK cells (cluster 7) is increased in severe patients. Moreover, in agreement with previous findings, our data demonstrated that inflamed CD56ividuals , 69.PRF1 (Perforin) and GZMB (Granzyme B) at transcriptional level  inhibitory checkpoint molecule, thus suggesting that the disease status and circulating cytokines could directly influence NK cell phenotype , and CCL4 are upregulated in COVID-19 patients compared to controls , as well as from moderate patients   .dim NK cells after their activation by target cells or after cross-linking of CD16 with antibodies, and results in an increased IFN-γ production , Lymphocyte-Activation Gene 3 (LAG-3), and TIGIT expression is higher in COVID-19 patients compared to healthy controls, while DNAM-1 and NKG2D-expressing NK cells are decreased in frequency , 66, 70.Furthermore, it has been proposed that the increased circulating levels of IL-6 could contribute to lowering NKG2D expression .In this regard, the local and systemic inflammation could also determine an impairment in circulating NK cell effector functions , 78.in vitro experimental findings showed a marked dysfunction of blood NK cells from COVID-19 patients, in particular those from severe ones, in terms of IFN-γ and TNF production, degranulation and killing ability against K562 target cells, as well as in the ability to control virus replication  have been used for the treatment of disorders characterized by impaired NK cell function - mobilized peripheral blood mononuclear cells (G-PBMCs) or stem cells , 118, byNK cells .posCD57pos NK cells, may be generated also in response to SARS-CoV-2 infection  and by Fondazione Cariplo-Fondazione Umberto Veronesi . ST is a recipient of competitive fellowship awarded from the Data Science in Medicine and Nutrition (DASMEN) Ph.D program from Humanitas University. We also thank the financial support from Fondazione Romeo ed Enrica Invernizzi.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.