Endothelial cells have emerged as key players in SARS-CoV-2 infection and COVID-19 inflammatory pathologies. Dysfunctional endothelial cells can promote chronic inflammation and disease processes like thrombosis, atherosclerosis, and lung injury. In endothelial cells, mitochondria regulate these inflammatory pathways via redox signaling, which is primarily achieved through mitochondrial reactive oxygen species (mtROS). Excess mtROS causes oxidative stress that can initiate and exacerbate senescence, a state that promotes inflammation and chronic endothelial dysfunction. Oxidative stress can also activate feedback loops that perpetuate mitochondrial dysfunction, mtROS overproduction, and inflammation. In this review, we provide an overview of phenotypes mediated by mtROS in endothelial cells – such as mitochondrial dysfunction, inflammation, and senescence – as well as how these chronic states may be initiated by SARS-CoV-2 infection of endothelial cells. We also propose that SARS-CoV-2 activates mtROS-mediated feedback loops that cause long-term changes in host redox status and endothelial function, promoting cardiovascular disease and lung injury after recovery from COVID-19. Finally, we discuss the implications of these proposed pathways on long-term vascular health and potential treatments to address these chronic conditions. R0, defined as the average number of infections caused by one infected individual) is still being evaluated, most estimates place SARS-CoV-2’s R0 at around 2.5 or higher (Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global public health crisis. With over 65.4 million cases and 1.51 million deaths worldwide, SARS-CoV-2 has been far more devastating than other coronaviruses like SARS-CoV and MERS-CoV . While Sr higher . This hir higher . Severe r higher . Notablyr higher . Notablyr higher . The prer higher . While tr higher .Endothelial cells (ECs), which mediate tissue inflammatory response and control solute and macromolecule transfer between the blood and tissue, are heavily involved in COVID-19 pathologies . Immunoh2–), a ROS that is involved in reactions that damage the electron transport chain (ETC)  . The incin (ETC) . This rein (ETC) .Under homeostatic conditions, ECs maintain vascular integrity and barrier function, while also controlling coagulation by producing an anti-coagulant glycocalyx layer and expressing anti-coagulant factors . ECs med1R), since there are fewer ACE2 binding sites on the cell to degrade Ang II into the anti-inflammatory Ang 1-7 , which is highly expressed on the surface of ECs and serves as the primary entry mechanism for SARS-CoV-2 . The hom Ang 1-7 . Support 1-7  by superoxide dismutases (SODs) (ATP), which allows influx of K+ into the organelle and subsequently increases the pH of the mitochondrial matrix  . Anotherl matrix . This inof mtROS . It has onfirmed .2– to H2O2, which is then reduced to H2O by antioxidants such as catalase and glutathione  activation . Past stated ROS . Ang II kinase C . Proteinkinase C . Importakinase C . Rac1 tht manner . Researct manner . Further2– created by the NADPH oxidase then react with NO to form ONOO–, which is known to damage and inactivate the mitochondria’s respiratory complexes through tyrosine nitration and cysteine oxidation , which has been viewed as a significant contributor to pulmonary pathologies in severe COVID-19 cases . While TNotably, TGF-β is one of the primary promoters of endothelial to mesenchymal cell transition (EndMT), a process by which ECs lose their endothelial characteristics and acquire mesenchymal, fibroblast-like phenotypes . Smad prThe proposed feedback loops induced by SARS-CoV-2 infection may result in persistent oxidative stress and inflammation in ECs. This phenomenon may be largely implicated in various pathologies and complications that are commonly associated with hospitalized COVID-19 patients . The folMany critically ill COVID-19 patients experience thrombotic complications as a result of inflammatory responses and EC damage in COVID-19-associated coagulopathy (CAC) . An earlCOVID-19-associated coagulopathy, like many other forms of coagulopathy, can be attributed to pathogenic interactions with the immune system. Proinflammatory pathways induced by SARS-CoV-2 infection can exacerbate the production of various pleiotropic cytokines that are known to maintain prothrombotic phenotypes in damaged ECs . Hence, Procoagulant activity induced by SARS-CoV-2 infection may partially be explained by oxidative stress resulting from excess mtROS production. Generally, ROS-mediated oxidative stress in ECs accelerates thrombotic processes through inflammatory stress . More spAtherosclerosis (AS) is a chronic inflammatory disease process characterized by the buildup of plasma lipoproteins in sub-endothelial spaces. Damage to ECs and irregular blood flow patterns contribute to low-density lipoprotein (LDL) deposition and oxidation, which in turn promotes constant inflammation and EC injury in arterial walls . ExistinAtherosclerotic development is mediated by oxidative stress, as various forms of ROS modify LDL to form oxidized low-density lipoproteins (oxLDL) . SARS-Co2– through JNK activation, which downregulates Mn-SOD  is one of the primary clinical manifestations of COVID-19-induced respiratory failure. Several studies have acknowledged the rapid progression of ARDS as a comorbidity associated with high mortality rates amongst severely ill COVID-19 patients . Non-surThe pulmonary endothelium regulates key homeostatic activities of the lungs through a wide variety of mechanisms, ranging from barrier integrity via inter-endothelial junctions to interactions with leukocytes and vasoactive mediators . Under oAcute respiratory distress syndrome pathology may also be characterized by mitochondrial dysfunction as a response to inflammatory events in ECs. Simmons et al., investigated the role of mtDNA DAMPs as a response to inflammatory stimuli and found that serum concentrations of mtDNA DAMPs were significantly higher in in patients who developed ARDS . AlthougOngoing clinical investigation is focused on finding novel therapeutics for treating COVID-19, as very few drugs have proven to be efficacious in improving outcomes for critically ill patients. Although the antiviral drug Remdesivir has displayed improved recovery times in some studies, it does not conclusively improve mortality rates amongst COVID-19 patients and has been shown to provide minimal clinical benefits in other studies . Based oThe cytokine storm in COVID-19 plays a significant role in initiating potent and widespread inflammatory EC damage. Thus, much of the current work concerning acute treatment of the cytokine storm via anti-inflammatory drugs can help to mitigate the initial damage that may lead to long-term dysfunctional phenotypes in multisystem ECs. Two of the most discussed drugs in recent literature and popular media are chloroquine and hydroxychloroquine, which are meant to treat SARS-CoV-2 infection by preventing the induction of inflammatory cytokines like TNF and IL-6 . AlthougThe selective targeting of senescence may be another means by which the potential acute and long-term effects of SARS-CoV-2 infection can be mitigated, as stimulated senescent cells produce SASP proteins that can facilitate systemic inflammation. Based on recent evidences, some of the most promising anti-senescent therapeutics include treatments that decrease SASP biomarker levels . Most stAntioxidant therapies are another class of potential therapeutics for COVID-19 and its associated pathologies. Theoretically, antioxidants would attenuate the extensive presence of mtROS within ECs and could prevent the chronic oxidative damage proposed by this review . This liSeveral collaborative efforts enabled the development of variety of vaccine candidates to prevent the spread and to provide the public with protection and immunity against the virus . NotablyAs the pandemic continues to rage worldwide, management of COVID-19 is a top public health priority for the global community. Some of the most significant COVID-19 complications, such as thrombosis, CVDs, and ARDS, are direct results of inflammation and mitochondrial oxidative stress in ECs. Through Ang II-mediated NADPH oxidase activation, viral/mitochondrial protein interactions, and dysregulation of mitochondrial metabolism, SARS-CoV-2 infection may induce mitochondrial dysfunction that leads to excess production of mtROS. The virus may further induce mitochondrial dysfunction through direct hijacking of the mitochondria by viral proteins and dysregulation of mitochondrial metabolism. By activating pathways such as NF-kB and the NRLP3 inflammasome, the elevated levels of mtROS can induce chronic inflammation and senescence in ECs, thus contributing to the pathologies observed in severe COVID-19 cases. Critically, oxidative stress and EC inflammation are involved in feedback loops that would pose a highly increased risk for dysfunctional endothelial pathologies even after the patient has recovered from the virus. Therefore, we suggest SARS-CoV-2 should not be viewed just as an acute inflammatory syndrome, but also as an instigator of long-term oxidative stress, inflammation leading to endothelial and vascular dysfunction. Although the recent clinical trials of COVID-19 vaccines bodes well for preventing future infections, the number of recovering and infected patients continues to rise worldwide, necessitating investigation of the virus’s long-term deleterious effects. While significant research is being done to develop vaccinations and acute treatment options, it is just as important to investigate the potential long-term damage done to the endothelium by the virus. To prevent a future outbreak of pulmonary and cardiovascular mortalities among recovered COVID-19 patients, it is essential to investigate SARS-CoV-2’s potential role in chronic oxidative stress and inflammation in ECs. Future research should also evaluate changes in EC redox status after COVID-19 recovery, potentially through analysis of oxidative stress biomarkers and redox-sensitive proteins like p90RSK and NLRP3. Researchers should also conduct clinical trials to verify the efficacy of antioxidant, anti-inflammatory, and senolytic therapeutics that may attenuate the proposed long-term effects on ECs. AS and CVD are important consequences of several systemic inflammatory syndromes . InteresRC and AM prepared the manuscript and figures and collected sources. AD designed and ideated the article, collected sources, prepared and revised the manuscript and figures. N-TL provided guidance, critical feedback and supervised the entire project. All authors contributed to the article and approved the submitted version.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.


Acute (ex vivo) and chronic (in vivo) methamphetamine exposure induces neuroplastic changes in the dorsal striatum, a critical region implicated in instrumental learning. For example, methamphetamine exposure alters high-frequency stimulation (HFS)-induced long-term depression in the dorsal striatum; however, the effect of methamphetamine on HFS-induced long-term potentiation (LTP) in the dorsal striatum is unknown. In the current study, dorsal striatal infusion of SCH23390, a D1R antagonist, prior to extended-access methamphetamine self-administration reduced methamphetamine addiction-like behavior. Reduced behavior was associated with reduced expression of PSD-95 in the dorsal striatum. Electrophysiological findings demonstrate that superfusion of methamphetamine reduced basal synaptic transmission and HFS-induced LTP in dorsal striatal slices, and SCH23390 prevented this effect. These results suggest that alterations in synaptic transmission and synaptic plasticity induced by acute methamphetamine via D1Rs could assist with methamphetamine-induced modification of corticostriatal circuits underlying the learning of goal-directed instrumental actions and formation of habits, mediating escalation of methamphetamine self-administration and methamphetamine addiction-like behavior.Extended-access methamphetamine self-administration results in unregulated intake of the drug; however, the role of dorsal striatal dopamine D Methamphetamine is abused worldwide for its stimulant-like effects, and methamphetamine use disorder (MUD) is a public health issue in the United States ,2. The aDopamine affects many physiological functions, such as the control of coordinated movements, as well as motivated and emotional behaviors by altering the neuroplasticity in the striatum ,14. Ther1-like receptor (D1R) knock-out in mice demonstrate that these mice do not self-administer cocaine compared with wild-type controls . T. T65]. TFor induction of synaptic plasticity or LTP in dorsal striatal synapses, the following HFS stimulation paradigm was used: four 1 s, 100 Hz trains delivered 10 s apart . For comp < 0.05. SPSS version 19  or GraphPad Prism version 7  were used for statistical analysis.The methamphetamine and saline self-administration data are expressed as the average total number of lever responses per session. Methamphetamine or saline self-administration during the 6 h FR sessions was examined using a two-way repeated-measures analysis of variance (ANOVA) followed by the uncorrected Fisher’s least significant difference (LSD) post hoc test. Active, inactive, and timeout lever presses were analyzed separately. A one-way ANOVA was conducted to determine differences between saline, methamphetamine only, and methamphetamine + SCH23390 groups for Western blots of all proteins followed by Tukey’s post hoc tests for each protein. Western blot analysis was conducted on percentage change values from saline controls. Data are expressed as mean ± standard error of the mean (SEM) in all graphs. Effects of methamphetamine and methamphetamine + SCH23390 on fEPSP slope were analyzed using a two-way ANOVA. Effects on paired-pulse ratio were analyzed using one-way ANOVA. Post hoc analyses were conducted when a significant interaction was detected. Significance was set at


Recently, an outbreak of viral pneumonitis in Wuhan, Hubei, China successively spread as a global pandemia, led to the identification of a novel betacoronavirus species, the 2019 novel coronavirus, successively designated 2019-nCoV then SARS-CoV-2). The SARS-CoV-2 causes a clinical syndrome designated coronavirus disease 2019 (COVID19) with a spectrum of manifestations ranging from mild upper respiratory tract infection to severe pneumonitis, acute respiratory distress syndrome (ARDS) and death. Few cases have been observed in children and adolescents who seem to have a more favorable clinical course than other age groups, and even fewer in newborn babies. This review provides an overview of the knowledge on SARS-CoV-2 epidemiology, transmission, the associated clinical presentation and outcomes in newborns and infants up to 6 months of life. If necessary respiratory support should be delivered via High-flow nasal cannula (HFNC), non-invasive ventilation or mechanical ventilation. Antibiotics should be prescribed only to patients with probable or confirmed bacterial infection; empirical use should be avoided. Surfactant replacement therapy, inhaled nitric oxide (iNO), and high-frequency oscillatory ventilation (HFOV) might be effective for newborns with severe acute respiratory distress syndrome but no evidence-based data exist. The question of antenatal corticosteroids for induction of foetal lung maturation in COVID-19 -positive or -suspected mothers with preterm labor or predicted preterm delivery is controversial, since there is strong evidence that their use prevents death and improve long-term outcomes across the range of prematurity ; conversThere are no data on effective antiviral drugs (ie remdesivir or lopinavir/ritonavir) and anti-cytokine storm (ie tocilizumab) for children with COVID-19 to date.Intravenous immunoglobulin can be used in severe cases when indicated , but its efficacy needs further evaluation .Newborns could be discharged after resolution of respiratory symptoms, lack of fever for at least 3–5 days, and after two nasal swabs negative for SARS-CoV-2 taken at least 48 h apart .As maternal separation may cause anxiety and maternal depression, psychological comfort should be offered to the parents .To our best knowledge, this review is the largest to date describing clinical features of SARS-CoV-2 infection in neonates and infants up to 6 months of age. Although we still do not know how massively SARS-CoV-2 will spread around the world and affect the population worldwide, the initial data reported in children so far are reassuring. However, due to the limited number of cases and clinical evidence, pediatricians should continually update their knowledge and be aware of the risks in particular in the high-risk population of newborn and preterm infants.


Metastasis, a leading contributor to the morbidity of cancer patients, occurs through a multi-step process: invasion, intravasation, extravasation, colonization, and metastatic tumor formation. Each process is not only promoted by cancer cells themselves but is also affected by their microenvironment. Given this complexity, drug discovery for anti-metastatic drugs must consider the interaction between cancer cells and their microenvironments. The zebrafish is a suitable vertebrate animal model for in vivo high-throughput screening studies with physiological relevance to humans. This review covers the zebrafish model used to identify anti-metastatic drugs. Overt metastases, the end result of malignant alteration in cancer cells, are responsible for approximately 90% of cancer-associated mortality. Metastasis consists of a multi-step process: invasion in which neoplastic epithelial cells invade into the adjacent tissue after they lose cell-cell adhesion; intravasation in which tumor cells penetrate through the endothelium of blood or lymphatic vessels to enter the systemic circulation; survival in the circulatory system in which certain circulating tumor cells appear able to survive in the bloodstream; extravasation in which cancer cells extravasate through the capillary endothelium at distal sites; colonization in which cancer cells proliferate in a new environment, and metastatic tumor formation in which cancer cells form a new tumor in secondary organs  1,2,3].,2,3.1,2,From the therapeutic point of view, the metastatic process can be divided into two phases: the early phase including tumor cell invasion and extravasation, and the late phase consisting of colonization and metastatic tumor formation. During the former phase, anti-metastatic treatments focus on inhibiting the spread of cancer cells to distant organs. Likewise, the goal of treatment during the latter phase is to inhibit the proliferation of disseminated cancer cells in distant organs .Cancer research using zebrafish as a model has attracted attention because this model offers many unique advantages that are not readily provided by other animal models ,8,9. ForHowever, there are several limitations associated with zebrafish. One limitation of zebrafish is that they are not mammals. Therefore, the effects of the drugs observed in zebrafish models must be validated in advanced preclinical models. Another limitation of using zebrafish for in vivo drug screening is that it is difficult to test drugs that are insoluble in water. A previous study that screened 23 drugs known to cause cardiotoxicity in humans yielded four out of five false-negative results in zebrafish due to poor absorption. The efficacy of drugs that yielded false negatives was confirmed by microinjection studies . The othSeveral anti-metastatic drugs have been identified through studies using zebrafish models . The traAnother approach that is frequently used to assess anti-metastatic drugs is phenotype-based screening. Phenotype-based screening has been increasingly employed in biomedical and pharmaceutical research since the contributions of phenotypic screening to the discovery of first-in-class small-molecule drugs exceeded that of target-based approaches . DiverseThis review focuses on zebrafish models that have been used as screening platforms for the identification of anti-metastatic drugs. Metastatic dissemination is the initial step of metastasis. During this step, cancer cells in the primary tumor site invade the neighboring tissue, enter the blood vessels, survive in the circulation, and exit the vessels to penetrate foreign tissues. Different genes and molecular mechanisms are responsible for each of these steps ,41.Tg(fli1: EGFP), which expresses EGFP in all blood vessels [Integrins are cell-surface adhesion receptors consisting of α and β transmembrane protein subunits, which directly interact with extracellular matrix (ECM) components. Integrins also contribute to tumor development and metastasis progression . The αv  vessels . In this vessels . Tg(kdrl:EGFP), which selectively expresses EGFP in endothelial cells. However, MDA-MB-231-B cells that are inoculated into −/−/cxcl12b−/−cxcl12a background Tg(kdrl:EGFP) zebrafish fail to induce invasion and the formation of micro-metastases in the tail fin. Moreover, pharmacological inhibition using IT1t, a potent CXCR4 antagonist, suppresses early metastatic events of the cells in vivo. Genetic inhibition of CXCR4 shows the same effect as treatment with IT1t [C-X-C chemokine receptor type 4 (CXCR4) and its cognate ligand C-X-C motif chemokine 12 (CXC12), which is also known as stromal cell-derived factor 1, play a pivotal role in regulating physiological processes such as hematopoiesis, leukocyte trafficking and cell migration . The binith IT1t .Tg(cldnb: EGFP) to mark the migrating posterior lateral line primordium as a readout for inhibition of collective cell migration identified the Src kinase inhibitor SU6656 has as an anti-metastatic agent. A murine model of metastatic cancer using 4T1 murine mammary carcinoma cells confirms that SU6656-treated mice show significantly fewer surface metastases in the lung compared with vehicle-treated mice [Members of the proto-oncogenic Src family of non-receptor protein tyrosine kinases also play critical roles in several metastatic cellular signal transduction pathways. The activation of Src family kinases in human cancers may occur through a variety of mechanisms, and the activity of Src family kinases is often critical for tumor progression. Several studies demonstrate that Src-mediated signaling plays a critical role in promoting metastasis ,48. A phted mice .Tg(kdrl: HsHRAS- mCherry)s896 zebrafish embryos [Tg(fli1: EGFP) [Besides the three aforementioned drugs, several other pharmacological agents suppress the metastatic dissemination of human cancer cells in zebrafish xenograft models. The transforming growth factor-β (TGF-β receptor inhibitors SB431542 or SB525334 suppress the metastatic dissemination of breast cancer cells or undifferentiated pleomorphic sarcoma (UPS) cells in zebrafish xenograft models, respectively ,20. The  embryos . The sir1: EGFP) . Other cHER-2 and PyMT transgenic mice [Experimental studies demonstrate that cancer cells can disseminate systemically from the earliest epithelial alterations in nic mice . Clinicanic mice . These fEMT plays a central role in early embryonic morphogenesis, its program enables various types of epithelial cells to convert into mesenchymal cells . ExperimT2Twist1a-ER transgenic zebrafish line T2)Tg transgenic zebrafish [in vivo screening using this model. Adrenosterone, an inhibitor of hydroxysteroid (11-beta) dehydrogenase 1 (HSD11β1), suppresses cellular dissemination in this model (Tg(kdrl:EGFP) transgenic zebrafish. Genetic inhibition of HSD11β1 also suppresses the metastatic dissemination of these cell lines in a zebrafish xenotransplantation model. This suppression results from the re-expression of E-cadherin and other epithelial markers and lost partial expression of mesenchymal markers through the down-regulation of Snail and Slug [A tamoxifen-controllable ebrafish , which dis model . This suand Slug .Tg(snailb: GFP), which provides a whole-animal EMT reporter system in zebrafish, is established for rapid drug screening. This model allows for the labeling of epithelial cells undergoing EMT to produce sox10-positive neural crest (NC) cells. Treating embryos of this model with candidate small-molecule EMT-inhibiting compounds previously demonstrated that TP-0903, an inhibitor of AXL receptor tyrosine kinase, blocked the delamination of cranial NC cells in both the lateral and medial populations. TP-0903 stimulates retinoic acid (RA) biosynthesis and RA-dependent transcription. These studies identified TP-0903 as an activator of RA in vivo and raised the possibility that its prior success in eliminating disseminated cancer cells depends upon the RA-dependent inhibition of EMT [n of EMT .The activation of EMT endows epithelial carcinoma cells with mesenchymal traits, stem-like characteristics, increased drug resistance, invasiveness, and metastatic ability . FurtherAngiogenesis is the formation and remodeling of new blood vessels and capillaries from pre-existing blood vessels. The growth potential of avascular tumors is severely restricted due to the lack of blood supply. The formation of new blood vessels provides avascular tumors with nutrients, oxygen, and more efficient removal of waste products . AlthougA pioneering study demonstrates that the treatment of zebrafish embryos with the VEGF receptor inhibitor PTK787/ZK222584 completely blocks the formation of all major blood vessels. Furthermore, the overexpression of the downstream effector AKT/PKB allows blood vessels to form in the presence of the drug . FollowiVEGFR2 promoter Tg(VEGFR2: GRCFP) offers a high-throughput platform for the discovery of anti-angiogenic drugs. Previous in vivo drug screening studies using this model identified indirubin-3′-monoxime (IRO) as an inhibitor of angiogenesis that did not affect vasculogenic vessel development or preexisting vasculature. An in vitro assay using human umbilical vein endothelial cells (HUVECs) confirmed that IRO inhibits two major components of the angiogenic process—endothelial tube formation and cell proliferation. However, IRO does not significantly affect endothelial cell migration [Tg(fli: EGFP) also identified the PhK subunit G1 (PhKG1) inhibitor F11 as an anti-angiogenic drug in vivo and in vitro using cultured human endothelial cells [A transgenic zebrafish that expresses green reef coral fluorescent protein (GRCFP) under the control of the igration . Anotheral cells . Tg(fli1: EGFP) zebrafish at 2 dpf. The interactions between the DsRed-labeled cells and the GFP-labeled vessels during angiogenesis are visualized through three-dimensional reconstructions of the interaction. The images reveal that RhoC amplification in the DsRed cells induces the formation of dynamic membrane protrusions and blebs and that VEGF secreted by the DsRed cells increases vascular permeability. These molecules work cooperatively to facilitate the invasion and intravasation by regulating the cytoskeletal and vascular remodeling. Pharmacological inhibition of VEGFR using SU5416 restored the integrity of the vessel wall and decreased the size of the DsRed tumor from 25.5 to 16 μm [A previous study using high-resolution confocal microscopy allows one to visualize the neovascularization and behavior of highly metastatic cells. In the study, the DsRed-labeled MDA-MB-435 human melanoma cell line was inoculated into the peritoneal cavity of to 16 μm .Tg(fli1: EGFP) zebrafish at 48 hpf and the zebrafish is subsequently transferred to a hypoxia chamber. Under hypoxia, the cells disseminate from their primary sites, invade the neighboring tissue, and metastasize to distal parts of the body through the upregulation of VEGF, which is a hypoxia-regulated angiogenic factor. In contrast, significant dissemination of cells does not occur under normoxia. Sunitinib, a VEGF inhibitor, inhibits hypoxia-induced invasion, dissemination, and metastasis of T241 tumors in this model [Another zebrafish model of metastasis may be used to visualize cancer cell dissemination, invasion, and metastasis at the single-cell level. Using this model, DiI-labeled T241 murine fibrosarcoma cells are injected into the perivitelline space of is model . The othThe U.S. Food and Drug Administration (FDA) has approved several anti-angiogenic drugs to treat cancer. Most of the inhibitors target VEGF, its receptor, or other specific molecules involved in angiogenesis . Among tin vivo high-throughput screening studies using Tg(lyve1: EGFP), which expresses EGFP in the lymphatic vessels [in vivo lymphangiogenesis Matrigel plug assay confirmed that kaempferol has anti-lymphatic activity. A mouse xenograft model where luciferase-expressing MDA-MB-231 cells (MDA-MB-231-luc-D3H2LN) were inoculated into the mammary fat pad of nude mice demonstrated that kaempferol reduced lymph node metastases compared with vehicle treatment. However, bioluminescence imaging and hematoxylin and eosin (H&E) staining showed that 80% of kaempferol-treated mice had metastatic tumors in the pancreas and diaphragm in both the prevention and intervention regimens, compared with 10% of control mice. These results indicate that kaempferol is only effective at reducing lymph node metastases [The growth of new lymphatic vessels (lymphangiogenesis) in tumors is an integral part of metastasis. Cancer cells in the primary tumor site initially spread via lymphatic vessels to their regional lymph nodes . Previou vessels , identiftastases .Kaempferol is widely distributed in the plant kingdom and is a common constituent of fruits and vegetables. Kaempferol and its derivatives have cardioprotective, neuroprotective, anti-inflammatory, antidiabetic, antioxidant, antimicrobial properties . Past stCancer cells are surrounded by many different types of cells: vascular endothelial cells, immune cells, fibroblasts, adipocytes, and the extracellular matrix (ECM). Experimental studies demonstrate that crosstalk between cancer cells and the surrounding microenvironment promotes metastasis. Therefore, targeting the tumor microenvironment may be an effective therapeutic strategy for suppressing metastasis .V600E; p53−/−)Tg of the fish showed widespread spontaneous metastases in the anterior region just behind the gill structure. Other metastases were observed on the posterior tail musculature and eye two weeks after the inoculation [The highly metastatic zebrafish melanoma cell line, ZMEL1 is established from melanomas of nths old . After sculation . Studiesculation . Also, eculation . in vitro screens using two-dimensional cell culture systems. Therefore, drug discovery needs to also consider the phenotypic plasticity of cancer cells. Zebrafish models can be used for in vivo drug screening to evaluate the effect of chemicals on cancer cells while accounting for the tumor microenvironment. Lipofermata, which targets the tumor microenvironment, is one example of an anti-metastatic drug that has been identified by using a zebrafish model [Due to the phenotypic plasticity of cancer cells that emerge from interactions between cancer cells and their microenvironment, cancer cells have developed resistance to anti-cancer drugs, which have been identified from sh model . A recensh model . This ev


Chemo-resistant breast cancer is a major barrier to curative treatment for a significant number of women with breast cancer. Neoadjuvant chemotherapy (NACT) is standard first- line treatment for most women diagnosed with high-risk TNBC, HER2+, and locally advanced ER+ breast cancer. Current clinical prognostic tools evaluate four clinicopathological factors: Tumor size, LN status, pathological stage, and tumor molecular subtype. However, many similarly treated patients with identical residual cancer burden (RCB) following NACT experience distinctly different tumor relapse rates, clinical outcomes and survival. This problem is particularly apparent for incomplete responders with a high-risk RCB classification following NACT. Therefore, there is a pressing need to identify new prognostic and predictive biomarkers, and develop novel curative therapies to augment current standard of care (SOC) treatment regimens to save more lives. Here, we will discuss these unmet needs and clinical challenges that stand in the way of precision medicine and personalized cancer therapy. Breast cancer is the second leading cause of cancer-relat-ed deaths in American women. Locally advanced and metastatic breast cancer is a highly heterogeneous, rapidly evolve-ing and therapy-refractory disease that challenges our ability to find curative therapies. An estimated 276,480 new cases of female breast cancer will be diagnosed and 42,170 women are expected to succumb to their malignant diseases in 2020 alone . These aDespite these clinical advancements, the prognosis for patients with high-grade, locally advanced, and metastatic breast cancers remains poor with an average survival of less than two or three years ,12–14. Tde novo and ac-quired tumor heterogeneity leads to diverse tumor responses to neoadjuvant and/or adjuvant systemic therapies, which in turn leads to varied clinical outcomes and disparities in patient survival [The clinical reality is that despite having similar clinical presentations at the time of initial diagnoses, breast cancer patients often display diverse and disparate tumor responses to standard therapies. The intrinsic diversity and evolving heterogeneity of mammary tumors can become more pronounced in locally advanced, relapsed or chemo-resistant malignant tumors post SOC therapies. This survival ,16,17.Clinicopathological parameters such as patient age, TNM  staging, tumor grade and histology, and molecular subtype of breast tumors have become commonplace in justifying medical decision making and prescribing treatment modalities. Standard radiographic assessment of newly diagnosed breast cancer involves high-resolution imaging tools including 3D digital mammography, ultrasound, MRI, and sometimes CT or PET/ CT. Traditional histopathological analysis of tumor staging in-cludes evaluating tumor size, lymph node status, and molecular sub typing using tissue markers such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor (HER2) . The cli+/PR+, HER2-, Ki67-), luminal B , HER2-over-expression , basal , and normal-like . The prevalence of luminal A, luminal B, HER2-overexpression, bas-al, and normal-like is 23.7%, 52.8%, 11.2%, 12.3% and 7.8%, respectively [The National Comprehensive Cancer Network (NCCN) clinical practice guidelines have been widely used by clinicians to treat breast cancer ,20. The ectively ,25. Breaectively –29.The state-of-the-art high-resolution imaging modalities provide detailed information regarding the tumor size and morphology, precise spreading patterns, and clinical outcomes. Patients with breast cancer detected by mammograms have an improved disease-specific survival compared to patients whose breast cancer was detected by another imaging method, regardless of a stage shift bias . Tumor sBreast cancer exhibits high inter- and intra-tumor hetero-geneity, which is especially pronounced in chemo-refracto-ry and high-grade lesions –36. TumoCurrently, there are multiple different types of genomic-and transcriptomic-based techniques that are being developed to predict tumor recurrence in ductal carcinoma in situ (DCIS) and in early-stage breast cancer following SOC treatment regimens . The Ame+ luminal type breast cancer treated with tamoxifen [The Oncotype DX 21-gene Recurrence Score (RS) was developed in order to determine the likelihood of distant recurrence of early-stage breast cancer patients who initially were diagnosed with node-negative, ERamoxifen ,45. The amoxifen .+, HER2-, and axillary node-negative breast cancer patients who had a low RS ≤ 10 and were treated with endocrine therapy alone had low rates of recurrence after 5-years [Multiple prospective studies have affirmed the ability of the RS to guide clinical treatment; the TAILORx trial determined that hormone receptor (HR) 5-years –49. The For patients with a midrange RS score between 11 to 25, the RS may guide treatment for early-stage luminal type breast cancer. The TAILORx trial studied the outcomes of patients with low to midrange RS scores (11 ≤ RS < 25), who were treated with endocrine therapy only or with chemo-endocrine therapy in combination. The study found that there was no inferiority of endocrine therapy when compared to chemo-endocrine therapy. The endocrine therapy group and chemo-endocrine therapy group had statistically similar 9-year invasive disease-free survival , freedom from disease recurrence at a distant site , and overall survival . As a result, the study concluded that the addition of chemotherapy does not improve the clinical outcome and overall survival for patients with early-stage luminal type breast cancer with a midrange RS. However, there was some benefit of the addition of chemotherapy for women under 50-years of age with an RS between 16 and 25 .The RS may also be used to guide treatment options for breast cancer patients stratified to have an intermediate-to high-risk score. Reanalysis of the TAILORx trial showed that patients with a RS > 25 who received chemotherapy and tamoxifen had a 10-year distant recurrence-free rate at 88%, compared to an estimated 10-year distant recurrence-free rate at 62% with tamoxifen alone. Therefore, the RS may be used to identify intermediate- to high-risk patients that may benefit from the addition of chemotherapy to tamoxifen .The MammaPrint assay was developed after comparing the gene expression profiles of primary breast cancer patients under 55-years old with negative lymph nodes who either did or did not have distant metastasis within 5-years ,54. FromThe MINDACT trial was the first prospective study to test the clinical utility of MammaPrint. The women enrolled all had primary invasive breast cancer with involvement of three or fewer axillary lymph nodes . The stu+/PR+, HER2- and node-negative breast cancers, as they may benefit from the withholding of adjuvant chemotherapy. For patients who have high clinical risk and are ER+/PR+, HER2-, node positive (one to three positive nodes), MammaPrint may in-form decision making on withholding adjuvant chemotherapy as well. However, it is important to reiterate the possible benefit in 5-year survival without distant metastasis with the addition of chemotherapy in this group, even though the benefit may be small. The use of MammaPrint is not recommended for high-risk patients diagnosed with HER2+ breast cancer or TNBC [From the MINDACT trial, ASCO made recommendations for the clinical use of MammaPrint to guide decision making regarding early-stage patients in the low-risk group, including ER or TNBC ,56.+, HER2- and node-negative breast cancer, and only half of all breast cancer patients qualify for RS analysis [Other recurrence prognosis tests like EndoPredict, Breast Cancer Index, and PAM50 are similar to the Oncotype DX RS and MammaPrint. Each of the tests measures and quantifies the expression of genes of interest to determine the risk of distant recurrence. Overall, these genomic and transcriptomic analyses provide a powerful tool to stratify the risk of recurrence in early-stage breast cancer patients. However, there are several limitations to these techniques in the spec-ificity and sensitivity of gene expression profiles, dynamic range, tumor purity, and tumor/TME composition. A major limitation is that these gene expression-based prognostic and predictive tools are not effective for risk stratification in locally advanced, high-grade, relapsed, and metastatic settings, where a timely intervention and the formulation of the correct sequence of aggressive therapies are urgently needed. For instance, an RS is limited to patients with ERanalysis . Patientanalysis . For MamPIK3CA mutation. The SOLAR-1 trial studied the effects of alpelisib therapy on progression-free survival of patients with HR+, HER2−, PIK3CA mutated, advanced breast cancer who had received endocrine therapy in the past. It found that patients who received alpelisib and fulvestrant had a progression-free survival of 11 months compared to 5.7 months for the patients who received a placebo and fulvestrant [in vitro next-generation sequencing di-agnostic tool that provides information about genomic mutations in 324 genes, gene rearrangements, microsatellite insta-bility, and tumor mutational burden (2018). Therefore, treatment-refractory HR+, HER2-, advanced breast cancer patients may undergo F1CDx analysis to determine if they possess a PIK3CA mutation and therefore may benefit from alpelisib treatment. With the increased clinical utility of WGS and WES data, new tumor vulnerabilities and actionable targets will be identified. New clinical trials and novel drug combination therapies will need to be deployed to treat the deadly, che-mo-resistant, and malignant tumors that kill 42,000 American women per year in the United States alone. Ultimately, to address this pressing unmet clinical need, we propose to develop a new and potent targeted therapy to control and conquer genetically diverse, heterogeneous, multidrug-resis-tant, relapsed, and metastatic breast cancer [For some patients with advanced breast cancer, there are new treatment options being developed to treat the drug-re-sistant tumor clones. For example, alpelisib is an α-specific PI3K inhibitor that has shown great promise in the treatment of advanced breast cancer containing a vestrant . As a ret cancer ,59.+, and locally advanced ER+ breast cancer of mixed molecular subtypes. Following neoadjuvant therapy and surgical resec-tion of the cancerous lesion, pathological analysis of the residual tumor may provide critical insight into the risk of tumor progression and early relapse. After completion of NACT and surgery, patients fall into two groups: Those with a pathologic complete response (pCR) or pathologic incomplete response (pIR). pCR is a reliable clinical prognostic biomarker that is associated with improved outcomes and prolonged survival. Conversely, those pIR patients with chemo-resistant and locally advanced residual diseases predict a higher risk of early tumor relapse. As such, many high-risk pIR patients are now commonly considered for additional adjuvant therapies.Aside from genomic and transcriptomic analysis, clinical and pathological assessment following neoadjuvant therapy may be the most reliable prognostic predictors of clinical outcomes. Neoadjuvant chemotherapy (NACT) has become a standard treatment for women with high-risk TNBC, HER2BRCA1/2 mutation status in the ERNEST-B trial comprised of breast cancer patients treated mainly with neoadjuvant anthracycline therapy [pCR at the primary tumor and axillary lymph nodes is associated with improved long-term survival . Moreover, it has the highest prognostic value in patients with aggressive breast cancers like TNBC . pCR was therapy .in situ disease, dimensions of the residual cancer in the tumor bed, the number of lymph nodes positive for residual tumor cells, and the longest diameter of the largest residual nodal metastasis. These RCB risk factors are convert-ed into a score between 0 and 3 where 0 represents a pCR tumor that has achieved a complete tumor eradication, and 3 represents the highest-risk pIR tumor that is likely to develop early tumor relapse and distant metastasis post-NACT. Some limitations to this method include the subjectivity in-volved with assessing the cellularity and the dimensions of the residual tumors [+/HER2- and HER2+ phenotypes independent of other prognostic factors [+ patients with an RCB of 3 had the highest risk of recurrence with a 3-year recurrence free survival of only 29% [+ patients with a yAJCC score of III especially had a particularly high risk of recurrence with a 3-year recurrence-free survival of only 27% [Unfortunately, most high-risk and high-grade patients have residual disease after receiving NACT. Incomplete responders can be further risk stratified by pathological staging systems like calculating the Residual Cancer Burden (RCB) or the American Joint Committee on Cancer Staging post-neoadjuvant therapy (yAJCC). The RCB assesses the proportion of the residual tumor bed that contains invasive carcinoma excluding l tumors . However factors ,63. Whilonly 29% . The yAJonly 27% .The Federal Drug Administration (FDA) has recognized the prognostic value of pCR as a biomarker in the assessment of high-risk breast cancer patients. As a result, the FDA has approved the use of pCR as a distinct endpoint post neoadjuvant breast cancer therapy. The FDA defined pCR as either the complete absence of residual invasive cancer on resected tissue biospecimen and LN-negative in all resected lymph nodes (ypT0/Tis ypN0 in AJCC staging system) or the complete absence of residual invasive cancer and DCIS in resected mammary biospecimen and all lymph nodes (ypT0 ypN0 in AJCC staging system). Although RCB has also been shown to be prognostic of tumor recurrence, the FDA has chosen to use the yAJCC as the clinical standard for defining pCR .The implementation of pathological response as an endpoint to NACT has aided in developing treatment strategies for high-risk and locally advanced breast cancer patients. New trials using novel therapeutic agents have been added to standard NACT with the assessment of pCR as its primary endpoint. Several post-neoadjuvant clinical trials have added a promising new drug to augment standard adjuvant therapy in hopes of reducing recurrence of metastasis, and improving the prognosis and survival of pIR patients post-NACT.+ breast cancer patients who achieved pIR after neoadjuvant taxane with or without anthracycline and trastuzumab. Patients who received adjuvant T-DM1 compared to adjuvant trastuzumab alone had a 50% reduced risk of recurrence of invasive breast cancer or death [- breast cancer patients were assessed. The study found that the addition of capecitabine to adjuvant chemotherapy improved patients’ 3-year and 5-year disease-free survival and overall survival. The survival benefit was especially prominent in the TNBC cohort [The KATHERINE trial studied the benefits of adjuvant ado-trastuzumab emtansine (T-DM1) over adjuvant trastuzumab only in HER2or death . In the C cohort .+/ERBB2-negative, and TNBC . Additionally, patients who achieved a pCR appeared to have a substantial long-term survival benefit as patients treated with pembrolizumab and standard therapy had an event-free survival of 93% at 3-years [The I-SPY2 trial studied the benefits of adding pembrolizumab to standard NACT for high-risk women with stage II or III, ERBB2-negative breast cancer ,67. The  3-years ,67.Studies like the KATHERINE, CREATE-X, and I-SPY 2 trial have created an interactive experimental platform address-ing multiple unmet needs facing high-risk partial responders. By using pIR as an endpoint, these studies were able to identify correct treatment sequence and stratify breast cancer patients faced with early tumor relapse, therapy-resistance, poor prognoses, and reduced survival ,69. AddiON/OFF expression can serve as an ON/OFF binary code and an excellent biomarker for cellular proliferation in residual tumor cells post-NACT. Furthermore, SIAH is a new, logical, and well-positioned therapeutic target to treat multidrug-resistant and incurable breast cancer [Seven in absentia homologue (SIAH) is a promising therapy-responsive and prognostic biomarker that may be used in conjunction with pathological response to NACT to identify high-risk breast cancer patients ,72. SIAHt cancer .SIAH has been found to be a tumor-specific, therapy-re-sponsive, and prognostic biomarker in breast cancer . In a reOFF) post-NACT are likely to remain in remission, have improved outcomes and increased disease-free survival. In contrast, partial responders with comparable RCB tumors with persistent high levels of SIAH expression (SIAHON) post-NACT are likely to develop early tumor relapse, suffer poor outcomes and reduced survival  of breast cancer patients found to have locally advanced or metastatic breast cancer have far worst outcomes. Current technology cannot conclusively distinguish whether a patient with residual disease after NACT will develop tumor recurrence or stay in remission. As such, a high priority is to accurately assess with molecular clarity and high precision which patients are at greatest risk for relapse. With the development of new genomic and transcriptomic analysis and FDA approval of pCR as an endpoint, high-risk breast cancer patients can be better identified and new therapies are being developed. The binary biomarker SIAH


MPO also mediates oxidative stress by promoting the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), modulating the polarization and inflammation-related signaling pathways in microglia and neutrophils. MPO can be a therapeutic target for attenuating oxidative damage and neuroinflammation in ischemic stroke. Targeting MPO with inhibitors or gene deficiency significantly reduced brain infarction and improved neurological outcomes. This article discusses the important roles of MPO in mediating oxidative stress and neuroinflammation during cerebral ischemia-reperfusion injury and reviews the current understanding of the underlying mechanisms. Furthermore, we summarize the active compounds from medicinal herbs with potential as MPO inhibitors for anti-oxidative stress and anti-inflammation to attenuate cerebral ischemia-reperfusion injury, and as adjunct therapeutic agents for extending the window of thrombolytic treatment. We highlight that targeting MPO could be a promising strategy for alleviating ischemic brain injury, which merits further translational study.Oxidative stress and inflammation are two critical pathological processes of cerebral ischemia-reperfusion injury. Myeloperoxidase (MPO) is a critical inflammatory enzyme and therapeutic target triggering both oxidative stress and neuroinflammation in the pathological process of cerebral ischemia-reperfusion injury. MPO is presented in infiltrated neutrophils, activated microglial cells, neurons, and astrocytes in the ischemic brain. Activation of MPO can catalyze the reaction of chloride and H Stroke is a major human disease burden leading to death and life-long disability. Tissue plasminogen activator (t-PA) is the only therapeutic drug for ischemic stroke approved by the US Food and Drug Administration (FDA). However, t-PA has a restricted time window of 4.5 h, and delayed t-PA infusion increases the risk of hemorrhagic transformation and carries high mortality . Delayed–), hydrogen peroxide (H2O2), hypochlorous acid (HOCl), nitric oxide (NO), and peroxynitrite (ONOO–). Antioxidant therapies such as edaravone, NXY-059, and allopurinol improved outcomes of acute ischemic stroke patients (NG-nitro-L-arginine methyl ester (L-NAME), a non-selective NOS inhibitor, attenuated the BBB disruption through inhibiting MMP-9 activity in an experimental ischemic stroke animal model  attenuated oxidative and nitrative damage in the cortex of ischemic core . Hypochle stress . HOCl hae stress . Activate stress . Of notee stress . Genetice stress . The MPOe stress . Of notee stress . The robe stress . These sFurthermore, the MPO-mediated inflammation affects post-stroke neurogenesis. Treatment of 4-ABAH promoted neurogenesis, and induced proliferation of astrocytes in the subventricular zone (SVZ), striatum and cortex . MPO knovia reducing the neutrophil infiltration  significantly decreased the neurological deficit in a rat ischemic stroke model with t-PA treatment, indicating the potential of targeting leukocytes to extend the therapeutic window of t-PA . The t-PIn summary, recent progress indicates that the study on the MPO-mediated oxidative injury and inflammation not only brings novel insight into understanding the molecular pathology of ischemic brain injury but also represents a promising strategy for drug discovery to target MPO for improving stroke outcome.Traditional herbal medicine is an important source for drug discovery due to its long history in clinical practice. Recent studies identified many active compounds with the bioactivities of inhibiting MPO activity, which can be potentially used to attenuate cerebral ischemia-reperfusion injury. Herein, we summarize representative active compounds in the following session. The chemical structures of the compounds refer to Bioflavonoids are well-known antioxidants with neuroprotective properties. Quercetin is a representative flavonoid compound widely existed in medicinal herbs, including Ginkgo biloba leaves and others . QuercetEriodictyol is widely distributed in fruits and vegetables, and isolated from the Chinese herb Dracocephalum rupestre. Oral administration of eriodictyol  exhibited inhibitory effects on MPO expression and inflammation in a permanent ischemic stroke rat model. Eriodictyol treatment down-regulated the expression of TNF-α and iNOS in the ischemic cortex, decreased infarct size, improved motor function, and attenuated the memory deficit in permanent ischemic stroke rats . EriodicHippophae rhamnoides  condition  (via the serotonergic 5-hydroxytryptamine 1A receptor-dependent mechanism (Cannabidiol (CBD) isolated from abaceae)  was repoechanism . CBD treechanism . A systeechanism . The neuechanism .Angelica sinen-sis (Oliv.) Diels (AS) and Ligusticum chuanxiong Hort. (LC) are medicinal herbs used for stroke treatment for centuries in China. Ferulic acid (FA) is a bioactive ingredient of AS and LC. FA has revealed to scavenge superoxide radicals and restore vasodilation in spontaneously hypertensive rats , a plant alkaloid from fenugreek seeds, inhibited MPO expression, improved the neurological outcomes and alleviated infarct size in ischemic stroke animal models . Dauriciltration .Paeonia lactiflora Pall and has anti-inflammatory properties. Intravenous injection of paeoniflorin  at 10 min before or 30 min after MCAO effectively reduced infarct size and ameliorated the neurological deficit via inhibiting PMN infiltration and down-regulating inflammatory factors including TNF-α, IL-1β, and ICAM-1  at the onset of ischemia or at 12 h after the reperfusion significantly alleviated infarct volume and neurological deficit. The underlying mechanisms could be related to inhibiting MPO, TNF-α, IL-1β, NF-κB expression and neutrophil adhesion  inhibited MPO activity and inflammation-associated cytokines such as IL-1, IL-6, TNF-α, and attenuated cerebral ischemia-reperfusion injury .Salvia miltiorrhiza, a commonly used medicinal herb for cardiovascular and cerebral vascular diseases. Tanshinone IIA had neuroprotective effects against focal cerebral I/R injury, and its underlying mechanisms were considered to inhibit the expression of NF-κB, MMP-9 and HMGB1 -α-bisabolol has anti-inflammatory, antioxidant and anti-apoptotic activities -α-bisabolol, sulforaphane, and allicin, also have anti-inflammation effects on inhibiting inflammatory cytokines, including TNF-α, IL-1β, and IL-6. Those compounds are considered as potential candidates for adjuvant therapy against cerebral ischemia-reperfusion injury. For example, (-)-α-bisabolol is an unsaturated sesquiterpene alcohol existed in a variety of plants, such as tivities . (-)-α-btivities . Sulforativities . Intrapetivities . Allicintivities . Allicintivities .Targeting MPO and cellular signaling cascades could be a therapeutic strategy to decrease infarct size and improve the neurological outcomes in ischemic stroke treatment . As an iBoth oxidative stress and inflammation are crucial pathological mechanisms in the BBB damage and hemorrhagic transformation in ischemic stroke with delayed t-PA treatment. The increased MPO in the plasma was found in ischemic stroke patients after receiving t-PA treatment . Treatmein vivo. It remains unknown whether those compounds have direct and specific actions of binding MPO or lead molecular modifications to MPO. Since most of the compounds exert antioxidant effects  of this study and refined the study. SC and HC wrote the first draft of the manuscript and contributed to the overall design. QD drew the structures of compounds. All authors read, critically reviewed, and approved the final manuscript.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.


Intensive care unit-acquired weakness syndrome (ICUAWS) can be a consequence of long-term mechanical ventilation. Despite recommendations of early patient mobilisation, little is known about the feasibility, safety and benefit of interval training in early rehabilitation facilities (ERF) after long-term invasive ventilation.n = 46). Patients conducted moderate continuous  or high-intensity interval training . The intensity of training was monitored with the BORG CR10 scale (intense phases ≥ 7/10 and moderate phases ≤ 4/10 points). The primary outcome was improvement  of six-minute-walk-test (6 MWT), while the secondary outcomes were improvement of vital capacity (VCmax), forced expiratory volume in 1 s (FEV1), maximal inspiratory pressure (PImax) and functional capabilities  after 3 weeks of training. No adverse events were observed. There was a trend towards a greater improvement of 6 MWT in HIIT than MCT , despite more days of invasive ventilation . VCmax , FEV1  PImax  and functional status  improved in HIIT and MCT.We retrospectively analysed two established training protocols of bicycle ergometry in ERF patients after long-term (> 7 days) invasive ventilation (We demonstrate the feasibility and safety of HIIT in the early rehabilitation of ICUAWS patients. Larger trials are necessary to find adequate dosage of HIIT in ICUAWS patients.The online version contains supplementary material available at 10.1186/s40798-021-00299-6. High-intensity interval training (HIIT) is feasible in critically ill patients with intensive care-acquired weakness syndrome (ICUAWS) after long-term invasive ventilation.HIIT is safe in ICUAWS patients after long-term invasive ventilation.Six minute-walk-test (6 MWT) improves in both high-intensity and moderate continuous training groups.A major problem after long-term intensive care treatment is the intensive care unit-acquired weakness syndrome (ICUAWS), which can be triggered by sepsis, multiorgan failure, glucocorticoids, neuromuscular blocking agents, hyperglycemia and immobility itself . Reporte2peak) as well as cardiac remodelling in heart failure patients with reduced ejection fraction (HFrEF) treated with HIIT ; however, objective criteria to measure intensity can only be applied by baseline exercise testing, which was not feasible directly after ICU discharge. Second, our population was heterogeneous in terms of baseline diseases  and, as a retrospective study, was not stratified for diagnoses and medical treatments . Third, our training protocol was arbitrary and illustrates a necessary compromise between training science to ensure maximal improvement in CRF and patient safety. Fourth, the significant increase of HR studies , 17. Alsmax) of less than 1-min duration to minimise muscular lactate accumulation. A run-in phase should be obligatory to ensure patients’ safety. Longer in- and out-of-hospital follow-ups will be necessary to investigate mortality in MCT and HIIT in ICUAWS patients.We have demonstrated the feasibility and safety of HIIT in ERF patients with ICUAWS. HIIT patients displayed more days of invasive mechanical ventilation but still there was a trend towards greater 6 MWT improvements than in the MCT group after a training period of 3 weeks. Patients in both HIIT and MCT groups improved lung function, maximal inspiratory pressure and functional status after three weeks of structured ERF training. Intensity should be increased in the HIIT group to really implement high-intensity training. Prospective, randomised, multi-centre studies with sufficient power will be necessary to properly investigate whether HIIT is superior to MCT in ICUAWS patients: HIIT should be done following incremental (spiroergometric) exercise testing and determination of thresholds. Exercise prescription should be based on the formula by Tschakert and Hofmann to ensure workload consistency , aiming Additional file 1.


Myeloid cells include various cellular subtypes that are distinguished into mononuclear and polymorphonuclear cells, derived from either common myeloid progenitor cells (CMPs) or myeloid stem cells. They play pivotal roles in innate immunity since, following invasion by pathogens, myeloid cells are recruited and initiate phagocytosis and secretion of inflammatory cytokines into local tissues. Moreover, mounting evidence suggests that myeloid cells may also regulate cancer development by infiltrating the tumor to directly interact with cancer cells or by affecting the tumor microenvironment. Importantly, mononuclear phagocytes, including macrophages and dendritic cells (DCs), can have either a positive or negative impact on the efficacy of chemotherapy, radiotherapy as well as targeted anti-cancer therapies. Tumor-associated macrophages (TAMs), profusely found in the tumor stroma, can promote resistance to chemotherapeutic drugs, such as Taxol and Paclitaxel, whereas the suppression of TAMs can lead to an improved radiotherapy outcome. On the contrary, the presence of TAMs may be beneficial for targeted therapies as they can facilitate the accumulation of large quantities of nanoparticles carrying therapeutic compounds. Tumor infiltrating DCs, however, are generally thought to enhance cytotoxic therapies, including those using anthracyclines. This review focuses on the role of tumor-infiltrating and stroma myeloid cells in modulating tumor responses to various treatments. We herein report the impact of myeloid cells in a number of therapeutic approaches across a wide range of malignancies, as well as the efforts toward the elimination of myeloid cells or the exploitation of their presence for the enhancement of therapeutic efficacy against cancer. Immunity is the result of an intricate interaction between the innate and adaptive immune system. Innate immunity is the initial immunological response against an invading pathogen and has no immunological memory. On the other hand, adaptive immunity involves the development of immunological memory and enables the host to respond more efficiently to future exposure to the antigen. Following antigen processing, the degraded peptides associate with major histocompatibility complex (MHC) molecules within the interior of an antigen-presenting cell (APC) and are exposed on its surface. Myeloid cells, including DC and macrophages, are considered “professional” APCs. They present foreign antigens to helper T-cells on class II MHC molecules and can prime naïve T-cells. Other myeloid lineage types of cells, such as neutrophils, have no or very low expression of MHC-II and are inefficient at priming naïve T-cell responses . Nearly Immune cells of various types and origins are integral components of the tumor microenvironment (TME) along with fibroblasts, endothelial cells, and extracellular components, such as collagen and hyaluronan. Cellular constituents from the lymphoid and myeloid lineage can elicit both immune suppressive and immune stimulatory functions and have an important role in regulating cancer progression and survival, as well as drug resistance –4. TumorHematopoietic stem cells (HSC) differentiate in the bone marrow into common myeloid progenitors (CMPs) which can give rise to DCs and to tumor-associated myeloid cells (TAMCs). TAMCs include at least four different myeloid cell populations: (a) Tumor-associated macrophages (TAMs) that exert crucial roles in regulating cancer-related inflammation, (b) monocytes that express the angiopoietin receptor Tie2  and have a pivotal function in tumor angiogenesis, (c) myeloid-derived suppressor cells (MDSCs) that can be further characterized as monocytic and granulocytic  depending on their morphology, phenotype and immune suppression functions and (d) tumor-associated neutrophils (TANs) that express pro-angiogenic factors and participate in tumor promotion .Ideally, a competent immune system recognizes tumor-specific and embryonic antigens; however, cancer cells manage to escape immune surveillance by secreting immune escape variants, recruiting myeloid-derived cells and either maintaining them in an immunosuppressive phenotype or polarizing them into tumor-promoting cell types , 7. The Cell populations of myeloid origin are critically important components of the TME as they play a central role in the regulation of anti-tumor immune responses. At the same time, inflammatory immune cells such as tumor-infiltrating lymphocytes (TILs), natural killer (NK) cells, NK T-cells, and B cells are also engaged within the TME, which further interact to affect the growth and function of cancer cells. While myeloid cells are required for enabling anti-tumor immunity, they can also have an immunosuppressive role in established tumors by promoting immune evasion, and facilitating primary tumor growth, progression and metastasis .via their receptor CSF-1R (Colony-stimulating factor-1 (CSF-1) and colony-stimulating factor-2 (CSF-2), also known as macrophage colony-stimulating factor (M-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF), respectively, are secreted cytokines that regulate mature myeloid cell populations by affecting their activation, survival, mobilization and differentiation. They have also been implicated in the development of many diseases, including in tumor progression and metastasis . Cancer r CSF-1R . The eler CSF-1R . M-CSF ir CSF-1R , 15. Sinr CSF-1R , the tarr CSF-1R –20.A combination of cytokines, particularly granulocyte colony-stimulating factor (G-CSF) or GM-CSF, interleukin (IL)-6, and the transcriptional regulator CCAAT/enhancer-binding protein (C/EBP) are required for the differentiation of bone marrow progenitors into MDSCs , 22. WhiDCs are essential for the cross-priming of cytotoxic T lymphocytes against tumor-specific antigens; however tumor-residing DCs can cause cell anergy and tolerance by expressing low levels of costimulatory molecules and pro-inflammatory cytokines . TAMs th+ T-cells. Cancer cells can be detected by NK cells through the expression of ligands for the receptor NKG2D (+ and CD8+ T-cells. T-cells can then produce interferon gamma (IFN-γ) to induce cytolysis in cancer cells  and granulocytic MDSCs (g-MDSCs) that are morphologically similar to monocytes and granulocytes, respectively. In humans, m-MDSC have the same density fraction as monocytes. However, monocytes express the MHC class II cell surface receptor HLA-DR in high levels while m-MDSCs are characterized by low or no HLA-DR expression. Furthermore, m-MDSCs have a CD11bhenotype . The exphenotype . Human g14−CD15+ .In addition to their morphological and phenotypic differences, m-MDSCs and g-MDSCs also have different mechanisms by which they suppress immune function. TAMs and m-MDSCs have a shared mechanism for the expression of inducible nitric oxide synthase (iNOS) and arginase. Indoleamine 2,3-dioxygenase (IDO), inducible nitric oxide synthase (iNOS), arginase I and effector cytokine production have been proposed to be involved in suppression of T-cell proliferation and cytotoxicity . iNOS geUnderstanding the interactions between the tumor and infiltrating cells will allow the prediction of tumor progression as well as the design of novel anticancer therapies which will target the tumor microenvironment. Working on the basis that cancer and myeloid cells use common pathways for immune system regulation, along with the fact that myeloid cells have the ability to network with different immune cell populations toward inducing an anti-tumor immune response, myeloid-based therapies have increasingly gained attention as possible adjuncts to improve efficacy of current therapies, including immune checkpoint inhibitors (ICIs), oncolytic viruses, dendritic cell vaccines, and traditional chemoradiation. Characterizing the myeloid compartment also allows for patient stratification on prognosis and response to immunotherapy based on the presence of myeloid-specific biomarkers in combination with tumor mutational burden, checkpoint expression, and T-cell receptor diversity .The presence of TAMs in the TME provides cancer cells with cytokines, growth factors and proteases that mediate survival, chemoresistance and promote invasion. One example is cysteine cathepsin proteases that are produced by macrophages and have been shown to enhance pancreatic tumor growth and invasion . PaclitaBRAF gene is commonly mutated in melanoma resulting in a constitutive function of the B-Raf protein  are also involved in the tumor-promoting functions of TAMs. The blockade of CSF-1 decreased macrophage infiltration and improved response of mammary and pancreatic carcinomas to chemotherapy . B-Raf i protein . In a mo protein . Anotherng MMP-9 . The cheng MMP-9 .+ T-cells by decreasing MDSCs and reversing the immunosuppressive microenvironment in an E.G7/OT-1 murine model (In two human hepatocellular carcinoma xenograft mouse models (HCCLM3-R and SMMC7721) tumor growth, lung metastasis, and tumor angiogenesis were observed following treatment with Sorafenib, a multi-kinases inhibitor. Sorafenib caused a significant increase in macrophage peripheral recruitment and intratumoral infiltration accompanied with elevation of CSF-1R, CXCL12/SDF-1 alpha, and VEGF. SDF-1/CXCL12 has been correlated with cancer cell invasion by recruiting macrophages to the area surrounding the tumor . Targetine model .via an increase in the number of M2 macrophages and that concurrent therapy with COX inhibitors and/or anti-IL-6R antibodies might facilitate platinum-based chemotherapy in resistant tumors , drive differentiation of monocytes to the M2 tumor-promoting phenotype. Treatment with Cisplatin or Carboplatin increased the potency of cervical and ovarian cell lines to induce M2 macrophages that produce IL-10. Tumor-produced IL-6 and PGE2 led to increased levels of activated Signal Transducer and Activator of Transcription 3 (STAT3) and decreased levels of activated STAT1 and STAT6, respectively. Blockade of canonical Nuclear Factor Kappa-light-chain-enhancer of activated B cells (NF-κB) reduced the production of PGE2 and/or IL-6 by the tumor cells and abrogated the effect of the chemotherapy. Blocking COX using the specific inhibitor indomethacin as well as inhibition of interleukin-6 receptor (IL-6R) with the clinical monoclonal antibody Tocilizumab, prevented M2 differentiation. These results propose that chemoresistance may be caused t tumors .+ CTL response, CD4+ T-effector lymphocytes enhance breast cancer metastasis to the lung by enhancing the activity of TAMCs  for patients with breast cancer  treatment in mice with pancreatic ductal adenocarcinoma (PDAC) tumors . GEM is survival . Inflammsurvival . Lapatinsurvival . Followiorubicin .In vitro co-culture of macrophages with cancer cells significantly reduced of Caspase-3 activation and apoptosis during GEM treatment. In in vivo PDAC models of mice, macrophages recruitment to the tumor using CSF1R-antagonist GW2580, enhanced the effect of GEM; the presence of TAMs in the tumor seems to convey resistance to GEM by inducing upregulation of the enzyme cytidine deaminase (CDA). CDA metabolizes GEM following its transfer into the cell. In PDAC cells, decreasing the expression of CDA inhibited the protective effect of TAMs against GEM . MITF plays a key role in melanocyte differentiation by transcriptional control of genes expressing enzymes involved in melanin synthesis; in addition, MITF has protumoral targets including B-cell lymphoma 2 (Bcl-2) and Hypoxia-Inducible Factor 1 (HIF-1) that convey survival signals . TNF binid cells .+ T-cell–dependent manner in murine breast cancer models, suggesting that combination of anti-angiogenic therapy with other types of drugs may facilitate anti-tumor effects by altering the phenotype of TAMs  protein. HMGB1 is an important chromatin protein that bends DNA, facilitates protein binding and helps regulate transcription . Activatvia angiogenesis and immunosuppression  increased macrophage motility and delivery of the NPs toward the cancer cells promoting apoptosis and inhibiting proliferation. Importantly, the NPs loaded with PTX induced macrophage differentiation toward the anti-cancer M1 phenotype . TNPs are generally applied as a vehicle to deliver drugs specifically to the tumor site and increase their accumulation. TNPs comprised by a fluorescent platinum (IV) pro-drug and a polymer platform (PLGA-b-PEG) were shown to accumulate in TAMs. TAMs acted as a local drug depot and allowed for the slow release of the DNA-damaging drug to neighboring tumor cells. The depletion of TAMs led to a decrease of intratumoral TNP accumulation and treatment efficacy in a lung cancer animal model. The presence of TAMs can therefore affect the design and use of TNPs for tumor targeting .Histidine-rich glycoprotein (HRG), is a host-produced immunomodulatory and antiangiogenic factor that regulates tumor vessel formation and inflammation. HRG is produced in the tumor stroma from plasma or platelets and has been reported to inhibit tumor growth and metastasis and to enhance chemotherapy in brain tumor models , 94. ThiThe therapeutic efficacy of anthracyclines, a group of conventional chemotherapeutic drugs that act by inhibiting topoisomerase II causing DNA damage, may depend on the presence of intratumoral dendritic cells. Specifically, mice bearing fibrosarcomas were treated with the anthracycline mitoxantrone (MTX). This caused cancer cell death which led to the release of Adenosine triphosphate (ATP), recruitment of myeloid cells and their differentiation locally into inflammatory DC-like cells. The presence of the DC-subset was responsible for the immune system-depended anti-tumor effect of anthracycline, by engulfing tumor antigens and presenting them to T-lymphocytes. Importantly, preventing tumor infiltration by myeloid cells, abolished the anti-tumor immune response following chemotherapy . The act+ T-cells compared to TAMs. The effect of Oxaliplatin combined with Cyclophosphamide (Oxa-Cyt) treatment on tumors relied on TLR4 signaling; Oxa-Cyt treatment led to an increase of TLR4 selectively in DC cells within the tumor stroma and ultimately led to CD8+ T-cell anti-tumor immunity in lung adenocarcinoma mouse models (+CD11b+) induced by CTX was associated with proliferation of DCs in the bone marrow (BM) prior to their increase in the circulation in a melanoma mouse model  alternated with longer drug-free periods, metronomic chemotherapy protocols suggest a more frequent administration of doses as low as 1/10th of the MTD . Besidesvia tumor cell DNA damage, recent evidence suggests that irradiation activates tumor-specific immunity (+) macrophages and led to prolonged survival in xenotransplant mouse tumor models   . The effth (ICD) . Even thth (ICD) .The main challenge of tumor immunologists is to control the vicious cycle of inflammation-immunosuppression taking place within the TME. The main approaches followed include among others, targeting immune checkpoint molecules on myeloid cells, the inhibition of recruitment and survival of myeloid cells, while novel approaches of nanomedicine regulating MDSCs are also under investigation.Immune checkpoints are among the regulators of the immune system that defend self-tolerance. Various tumor cells utilize these regulators to evade immune responses . Inhibitvia CD80/CD86–CD28 interaction. A subject of debate, however, is whether the anti-CTLA-4 antibodies act in favor of anti-tumor immune responses or not, in terms of targeting the CTLA-4 molecules expressed on regulatory T-cells (Tregs). CTLA-4 expression by Tregs comprise one their main cell contact-dependent mechanisms affecting antigen-presentation to T-cells. However, it seems that anti-CTLA-4 therapy favors the blockade of the inhibitory activity of CTLA-4 on both effector T-cells and Tregs , leads to a more pronounced reduction in circulating MDSCs compared to the anti-CTLA4 monotherapy   , 144. Tuals.gov) . Thus, i+ T-cells  revealed by apoptotic cells further contributing to their presentation to CD8 T-cells . DCs exp T-cells . HMGB1 a T-cells . Tumor ceraction . This ineraction , since geraction .Nowadays, numerous phase II and III clinical trials are testing the potential of antibodies against CTLA-4 , or the PD-1/PDL-1 axis , and also the combinatorial use of anti-PD-1/anti-CTLA-4 antibodies (nivolumab plus ipilimumab) in a series of human malignancies. Moreover, novel antibodies, not yet FDA approved, targeting TIM-3 immune checkpoint  are now being tested in phase I and II trials .clinicaltrials.gov) supports that the withdrawal of anti-CCL2 treatment may lead to a rebound of CCL2 levels; in the participants of this study there was an upregulation of the CCL2 serum levels that exceeded those before treatment , which recruits MDSCs (expressing the CCR2) in the site of tumor inflammation . Blockinreatment . Also, creatment . Thus, tRecent evidence supports that the interaction between CD200-CD200 receptor (CD200R) is essential for the control of immune responses in TME by regulating TAMCs. In humans, certain tumor cell types including melanoma cells , ovarianclinicaltrials.gov). Both studies were terminated, but the second one published results showing that administration of the drug was associated with reduced expression of CD200 on B-cells and CD4+ effector T-cells of B-CLL individuals, however inefficient in the three myeloma patients evaluated  mice with established tumors –164 havevaluated . What isunctions . A recenunctions .Novel approaches for the enhancement of anti-cancer therapeutics also lie in the field of nanomedicine: Based on the enhanced permeability and retention (EPR) effect therapeutic strategies that use carrier materials of < 100 nm can enhance the uptake of chemotherapeutics specifically by tumor cells, thus lowering non-specific cytotoxicity , 170. Inin vivo studies on mice with tumors or hematological malignancies have shown that intradermal administration of nanoparticles carrying the chemotherapeutic agents 6-thioguanine or a gemcitabine derivative were accumulated in macrophages and myeloid cells of the spleen and the tumors and finally led to the depletion of the MDSC compartments in these sites, promoting adoptive T-cell therapy  or micro RNAs (miRNAs) that are loaded on nanoparticles was applied to mice with melanoma, colon carcinoma, non-small cell lung cancer and other tumors, leading to encouraging results –180. Recoma mice . Lastly,oma mice  managed It is unambiguously accepted that immune cells in the tumor stroma exert fundamental effects not only on cancer development and disease progression but also for treatment efficacy. In particular, myeloid cells residing in the tumor microenvironment, including MDSCs, TAMs, DCs and tumor-associated neutrophils (TANs), can either enhance tumor rejection or facilitate cancer progression based on their functional interplay with cancer cells. Moreover, while the variety of tumor treatment options gradually increase, including targeted therapies, nanotherapies and immunotherapies, reaching optimal levels of efficacy often appears to be hindered by the infiltration and complex interactions with myeloid cells. It is therefore critically important for future studies to further subcategorize immune cells of myeloid origin based on their pro- or anti-tumor properties. Moreover, it may be appropriate to tailor conventional treatment approaches, such as chemotherapy, nanotherapy and radiotherapy, in terms of dosing, fractionation and scheduling in order to achieve optimal conditions for activation of anti-tumor immune responses. Finally, identification and validation of exclusive cell surface marker panels for each subpopulation as well as better understanding the common pro-tumor traits of these cells will allow for better stratification of cancer patient prognosis and the development of more effective therapeutic interventions.CN wrote the paper and helped with illustrations. T-CK wrote part of the paper, prepared illustrations. CP wrote part of the paper. M-IC wrote part of the paper and helped with illustrations. PC wrote part of the paper. PP conceived the theme, wrote the paper, and prepared illustrations. All authors critically read and approved the manuscript.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.


COVID-19 pandemic caused by SARS-CoV-2 started in China in late 2019. Clinical features include fever, cough, dyspnea, body aches, and gastrointestinal symptoms. Some COVID-19-positive patients presented with unusual manifestations such as olfactory dysfunction, parotitis, or cervical lymphadenopathy.Since many patients are diagnosed with SARS-CoV-2, the need for an up to date review of the atypical ENT presentations of COVID-19 is mandatory. Articles from PubMed and Google searches were reviewed and the atypical presentations in otolaryngology were presented.It is crucial for ENT physicians to have high index of suspicion to identify those COVID 19 patients with atypical presentations. This facilitates early case isolation to eliminate viral spread across the community. COVID-19 pandemic caused by SARS-CoV-2 started in China in late 2019 [COVID-19 has wide spectrum of clinical features starting from mild disease to severe illness. Incubation period ranges from 2 to 14 days. Common clinical features include fever, cough, rhinorrhea, dyspnea, and body ache. Other less common manifestations include nausea, vomiting, or diarrhea , 4.Source information was sought via PubMed and Google searches for “(coronavirus or COVID) and atypical presentations.” Online content was specifically sought because of the very recent nature of many source documents.All sources presenting objective evidence related to the topic were reviewed and filtered.The study was approved by The Hospital Ethics Committee and informed consent was not mandatory.The spectrum of the atypical presentations of COVID-19 in otolaryngology is summarized in Table Fidan  reportedThe first case of COVID-19-induced sensorineural hearing loss (SNHL) was reported in Thailand in an elderly female. The patient recovered from COVID-19 infection; however, the hearing loss did not improve .The effect of COVID-19 is an interesting issue in audiology. Several viral infections can directly damage inner ear structures causing hearing loss. Typically, virus-induced hearing loss is sensorineural (SNHL). The proposed mechanisms involved in virus-induced SNHL include direct damage to inner ear or indirect damage through induction of autoimmune response , 8. PrevA recent study of the effect of COVID-19 on the inner ear structures was done. The author compared between asymptomatic COVID-19 PCR-positive cases and control subjects. The persons enrolled in the study were 20–50 years to rule out any age-related hearing loss. Exclusion criteria were symptomatic COVID-19 patients and past history of hearing loss. The high-frequency pure tone thresholds and TEOAE amplitudes were significantly worse in COVID-19 patients [Cure et al.  suggesteMany physicians reported anosmia, with or without dysgeusia in patients with severe COVID-19 infection. The AAO-HNS and the British Association of Otorhinolaryngology are now recommending these symptoms to be added to the list of primary screening symptoms for COVID-19.A multi-center European study done by Lechien et al.  reportedThe concept of anosmia after viral infection is known as post-infectious/post-viral olfactory loss. Different kinds of viruses can induce olfactory loss, including COVID-19 . The exaPresence of cervical lymphadenopathy or strawberry tongue in children can be part of Kawasaki-like disease. There is growing number of children reported with COVID-19-induced Kawasaki-like disease. Kawasaki disease is an acute self-limiting vasculitis of the medium size blood vessels and almost exclusively affects children. Kawasaki disease was first reported by Tomisaku Kawasaki in Japan . The exaThe American Heart Association diagnostic criteria include  . Early rMany viruses including COVID-19 can present with exanthematous lesions as oral ulcers or blisters. The pathogenesis is similar to aphthous fever, hand, foot, and mouth disease, and herpetic gingivostomatitis . PainfulMany viruses as rubella, influenza, and HIV have predilection for salivary glands including the parotid . ParotitThe pathogenesis of subacute thyroiditis in the setting of viral infections like COVID-19 is unclear. The disease may be directly related the viral infection or indirectly as a result of post- viral inflammatory response in genetically susceptible persons .Authors reported a case of subacute thyroiditis in an 18-year-old female with COVID-19. Clinical manifestations included pain, tenderness, and enlargement in the thyroid gland. No history of upper respiratory tract infection was present. Laboratory work up showed elevated T3 and T4. Other markers of inflammation as ESR, CRP, and leucocytic count were also elevated. Thyroid US revealed multiple diffuse hypoechoic areas. Complete recovery of inflammation and improvement of thyroid function occurred within 2 weeks of prednisone treatment .It is crucial for ENT physicians to have high index of suspicion to identify those COVID-19 patients with atypical presentations. This facilitates early case isolation to eliminate viral spread across the community.


Innate immune interferons (IFNs), including type I and III IFNs, constitute critical antiviral mechanisms. Recent studies reveal that IFN dysregulation is key to determine COVID-19 pathogenesis. Effective IFN stimulation or prophylactic administration of IFNs at the early stage prior to severe COVID-19 may elicit an autonomous antiviral state, restrict the virus infection, and prevent COVID-19 progression. Inborn genetic flaws and autoreactive antibodies that block IFN response have been significantly associated with about 14% of patients with life-threatening COVID-19 pneumonia. In most severe COVID-19 patients without genetic errors in IFN-relevant gene loci, IFN dysregulation is progressively worsened and associated with the situation of pro-inflammation and immunopathy, which is prone to autoimmunity. In addition, the high correlation of severe COVID-19 with seniority, males, and individuals with pre-existing comorbidities will be plausibly explained by the coincidence of IFN aberrance in these situations. Collectively, current studies call for a better understanding of the IFN response regarding the spatiotemporal determination and subtype-specificity against SARS-CoV-2 infections, which are warranted to devise IFN-related prophylactics and therapies.  The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the current pandemic of new coronavirus disease 2019 (COVID-19), shows an evolutionary success to adapt its infectivity and contagiousness to efficiently spread in human societies ,4,5,6. TStudies using transcriptomic analysis in SARS-CoV2-infected human bronchial cells or IFN assays in clinical plasma samples demonstrated a distinct immune-reaction phenotype in symptomatic COVID-19 patients, being a highly impaired interferon (IFN) response . The impInterferon signaling, for either IFN induction or action, is not a linear cascade but an interacting network, dynamically adapting to alternative and crosstalk with other cytokine signaling pathways ,18,25,27The suppression of IFN response, especially IFN production at the early stage of COVID-19 progression, diminishes the host capacity to restrict (thus benefits) the virus spreading ,40. NotaBy genetic screening of 659 patients with life-threatening COVID-19 pneumonia, relative to 534 subjects with asymptomatic or benign infections, Zhang et al. (2020) detected an enrichment in a functional deficiency of 13 human gene loci that are known to govern TLR3- and IRF7-mediated antiviral IFN induction signaling in the severe COVID-19 patients . These iEffective IFN response or IFN dysregulation constitutes a key determinant of COVID-19 prognosis, which also highlights the potential of IFNs for therapeutic intervention . Prophyl


A substantial proportion of patients with coronavirus disease 19 (COVID-19) develop severe respiratory failure. Although the exact pathophysiology of severe COVID-19 pneumonia remains unknown and the characteristics of these patients are heterogeneous, the acute respiratory failure often fulfills criteria for acute respiratory distress syndrome (ARDS) and the clinical characteristics are also consistent with what is previously known about ARDS. Cohort studies also report distinctively high association between perioperative COVID-19 and postoperative mortality. In this special article, we review several publications on the pathophysiology of COVID-19, and discuss intraoperative ventilatory management for patients with COVID-19 based on the respiratory characteristics of COVID-19 pneumonia in light of the ongoing controversy of clinical phenotypes. The current COVID-19 pandemic has caused unprecedented economic burden and stress on both global healthcare systems and in-hospital management of patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date we have experienced tremendous advances in our understanding of COVID-19. However, there remains much to be learned about how SARS-CoV-2 affects the lungs to cause lasting lung injury and about how we should approach treatment of these patients. There is currently no treatment specifically approved for COVID-19. Refractory hypoxia due to COVID-19 pneumonia is the primary cause of death among COVID-19 associated patients , higher thrombotic complications , and higher 30-day mortality  compared to matched non-COVID-19 patients [It is clear that being perioperative COVID-19 positive significantly affects one’s postoperative outcomes and if a situation permits, postponing or withholding surgery is recommended , 4. HoweSevere COVID-19 pneumonia that deteriorated to ARDS-like lung pathology is known to be associated with elevated level of inflammatory cytokines, although the magnitude is smaller than previously reported in ARDS , 6. Mult. proposed clinical phenotypes of patients with COVID-19 pneumonia: Type L and Type H [Early description of a cohort of 16 COVID-19 patients in Italy by Gattinoni et ald Type H , 13. The. proposed that Type L of COVID-19 pneumonia consists of four Low respiratory characteristics: low elastance, low ventilation-to-perfusion, low lung weight, and low lung recruitability [More precisely, Gattinoni et altability . Elastantability . Accorditability , 15. COVtability . These h. proposed that the transition from Type L to Type H can occur. Type H consists of four high respiratory characteristics: high elastance, high right-to-left shunt, high lung weight, and high lung recruitability [When Type L patients do not improve, Gattinoni et altability . CT scan. hypothesized how Type L COVID-19 pneumonia transitions to Type H COVID-19 pneumonia. Type L patients increase minute ventilation to respond to hypoxia due to vasoplegia, which causes a more negative intrathoracic inspiratory pressure in spontaneous breathing. Also, inflammation due to COVID-19 pneumonia increases lung permeability as observed for any type of pneumonia. The combination of these factors is known as patient self-inflicted lung injury (P-SILI) [Gattinoni et al(P-SILI) , 17, whi(P-SILI) . "Box 1"The proposal of clinical phenotypes of COVID-19 pneumonia has evoked strong discussion. Gattinoni hypothesized that vasoplegia may be a primary reason for Type L COVID-19 pneumonia, although Jain and Doyle argued that these different respiratory characteristics of COVID-19 pneumonia were not due to phenotypes, rather staging of pneumonia secondary to apoptosis of alveolar epithelial and endothelial cells . Further. reported that very few patients of the cohort had near-normal compliance, which was different from the description of Type L by Gattinoni et al. Respiratory characteristics of the cohort described by Ziehr et al. were very similar to those observed in large cohorts of mechanically ventilated ARDS patients. Importantly, all patients were managed by contemporary evidence-based ARDS therapy and the mortality at 30-day follow-up was only 16.7%, although the median and interquartile range of the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (P/F ratio) was 182 (135–245).Subsequently, cohort studies of COVID-19 pneumonia by Bos et al. and Ziehr et al. demonstrated different perspectives about the phenotypes of COVID-19 pneumonia . Bos et . summarized their viewpoint on COVID-19 related ARDS [. and the number of patients in the cohort described by Gattinoni et al. was the smallest among all studies. Fan et al. argued that existing evidence was not enough to preclude the phenotypes of Type L with low elastance  in patients diagnosed as having COVID-19 pneumonia; however, there has been limited evidence to initiate a different approach to patients with COVID-19 pneumonia.Recently, Fan et alted ARDS . Their l. suggest, when a surgical patient presents COVID-19 related ARDS, we should focus on currently available evidence of ARDS management to treat patients with COVID-19 pneumonia given that most patients (on average) with COVID-19 related ARDS have similar respiratory characteristics of ARDS [During this uncertain pandemic, the real problem clinicians face is to “balance the trade-off between learning (evidence of mechanism) and doing (evidence of response to treatment)” . At this of ARDS . There iThe current review covers the ongoing discussion of respiratory characteristics in patients with COVID-19 and presents the limited findings from the literature that investigated intraoperative ventilatory support. We continue to explore respiratory characteristics of COVID-19 while ensuring provision of high-quality patient care. Given that preoperative PCR testing has up to 70% sensitivity and that perioperatively confirmed COVID-19 patients have a higher mortality rate, we should continue to discuss and accumulate evidence to improve perioperative patients’ outcomes. Until further evidence emerges, application of current evidence-based ARDS managements to intraoperative patients with COVID-19 related ARDS is recommended.Box 1. Summary of Patient Self-Inflicted Lung Injury (P-SILI). in 2017 to describe lung injury due to patients’ own spontaneous efforts [The concept of P-SILI was introduced by Brochard et al efforts . Assisti efforts . The foc