Optimal fluid therapy in the perioperative and critical care settings depends on understanding the underlying cardiovascular physiology and individualizing assessment of the dynamic patient state.The Perioperative Quality Initiative (POQI-5) consensus conference brought together an international team of multidisciplinary experts to survey and evaluate the literature on the physiology of volume responsiveness and perioperative fluid management. The group used a modified Delphi method to develop consensus statements applicable to the physiologically based management of intravenous fluid therapy in the perioperative setting.We discussed the clinical and physiological evidence underlying fluid responsiveness and venous capacitance as relevant factors in fluid management and developed consensus statements with clinical implications for a broad group of clinicians involved in intravenous fluid therapy. Two key concepts emerged as follows: (1) The ultimate goal of fluid therapy and hemodynamic management is to support the conditions that enable normal cellular metabolic function in order to produce optimal patient outcomes, and (2) optimal fluid and hemodynamic management is dependent on an understanding of the relationship between pressure, volume, and flow in a dynamic system which is distensible with variable elastance and capacitance properties. The ultimate goal of fluid and hemodynamic management is to support normal cellular metabolic function.Achieving normal cellular metabolic function requires maintenance or restoration of effective coordinated function of the macrocirculation and the microcirculation, as well as intact cellular metabolism.Practically speaking, most clinical management is currently targeted at macrocirculatory variables and surrogates of cellular metabolism .The therapeutic rationale of intravenous fluid administration is to optimize macrocirculatory function in order to improve or optimize microcirculatory and cellular function.There is a minimal intravascular volume required to maintain cardiac output and stroke volume and normal tissue perfusion. Below this volume, cardiac output and blood pressure may be maintained at the expense of microcirculatory blood flow and cellular function.The majority of intravascular volume is in the venous circulation; therefore, the venous capacitance is a critical determinant of effective macrocirculatory function.There is no readily available method of measuring intravascular volume and it is uncertain if knowing this static value would have clinical utility.Optimal intravascular volume can only be characterized through dynamic evaluation.Administration of a fluid bolus as part of a fluid challenge is a means of increasing intravascular volume to evaluate the effect on stroke volume.Fluid responsiveness is defined as a state of recruitable stroke volume in response to intravascular fluid administration.The venous circulation is comprised of stressed and unstressed volumes.Stressed volume is the  volume of blood that exerts distending pressure against the venous wall. In contrast, unstressed volume is the volume of blood up to the point of filling the veins but without exerting any pressure on the vessel walls.Stressed volume determines the mean systemic filling pressure , related to the elastic recoil of the venous system. The difference between the MSFP and right atrial pressure is the major factor determining venous return to the heart. The MSFP provides driving pressure against right atrial pressure which creates a gradient promoting forward flow.Full characterization of fluid responsiveness requires consideration of the type, amount and timing of fluid as well as the expected change in stroke volume.The best method of measuring fluid responsiveness is a continuous or rapidly repeatable measure of stroke volume.A common approach to test fluid responsiveness is the administration of 250-500 mL bulos in < 15 min with a positive response defined by a 10-15% increase in stroke volume.The passive leg-raise maneuver replicates a transient fluid bolus and predicts fluid responsiveness without administration of intravenous (IV) fluids (positive response definted as > 10% increase in stroke volume), thereby mitigating the risks of excess IV fluid administration. This maneuver has limited utility in the intraoperative setting.Alternative methods for predicting fluid responsiveness include stroke volume variation (SVV), pulse pressure variation (PPV), systolic pressure variation (SPV), and  end-expiratory occlusion test and respiratory systolic variation test. All have limitations Table .Sonographic evaluation of IVC size, distensibility, or collapsibility has limited and unproven utility at the present time.The actions of vasoactive drugs are typically considered in relation to the arterial circulation but many have significant effects on the venous circulation.Venoconstrictors  increase venous tone and thereby reduce venous capacitance, thus increasing the stressed volume at the expense of the unstressed volume. In a hypovolemic patient, this reduction in unstressed volume may in turn reduce microcirculatory blood flow and thereby compromise cellular metabolism, due to reduced perfusion despite maintenance of normal blood pressure.Venodilators  reduce venous tone and thereby increase venous capacitance and decrease the stressed volume. This typically decreases venous return and left ventricular end-diastolic volume.Intra-abdominal hypertension  may reduce venous return or venous capacitance.More than 230 million major surgical procedures are undertaken worldwide each year , was invited to participate. In total, 21 experts from around North America and Europe met in Durham, NC, on June 16-17, 2018, to iteratively discuss the clinical and physiological evidence of fluid responsiveness and venous capacitance as relevant factors in fluid management, in order to develop consensus statements with practical recommendations for a broad group of clinicians involved in intravenous fluid therapy.Based on literature searches performed by POQI group members, a list of relevant questions was collectively formulated and circulated electronically prior to the meeting. In the first plenary session, these questions were presented to receive feedback and assistance in refining the questions. There were then at least two Delphi rounds to develop the statements before final agreement. This manuscript is based on these multiple rounds of feedback from all the experts present at the POQI meeting.Key physiologic and clinical terminology are shown in Tables I.The ultimate goal of fluid therapy and hemodynamic management is to provide the conditions that enable normal homeostasis and cellular metabolic function in order to produce optimal patient outcomes.II.Fluid and hemodynamic management is dependent on the relationship between pressure, volume, and flow in a dynamic system which is distensible with variable elastance and capacitance properties.2) and central venous oxygen saturation (ScvO2), heart rate (HR), and urine output. While these parameters may indicate the presence of, or the risk for, cellular metabolic dysfunction, they are insensitive in this regard and do not differentiate cellular dysfunction due to macrocirculatory versus microcirculatory abnormalities.The ultimate goal of fluid therapy and hemodynamic management is to provide the conditions that enable normal cellular metabolic function in order to produce optimal patient outcomes. The discrete goals of fluid therapy exist at several levels: at the level of the macrocirculation, the microcirculation, and at the cellular level Fig. . It is aAlthough restoration of the macrocirculation provides the basis for normal microcirculatory and cellular metabolic function, it does not guarantee them. Microcirculatory and cellular metabolic dysfunction may develop or persist despite establishing normal microcirculatory parameters, such as MAP and CO. However, because dysfunction of the macrocirculation  often produces dysfunction at the microcirculatory and cellular levels, the first step in therapeutic fluid resuscitation is restoration of the macrocirculation. It is worth noting that restoration of the macrocirculation is not achieved by reaching the same target in every patient. Macrocirculatory parameters such as MAP and CO should be personalized both for the individual and for the patients’ current condition.Recently, several investigators introduced the term “hemodynamic coherence” to describe the physiologic state in which improved macrocirculatory function results in improvements in the microcirculation Ince, . In cont, the first hemodynamic goal is to achieve a MAP > 65-70 mmHg to preserve organ perfusion  because they are measurable and they represent the most apparent clinical markers of organ or tissue perfusion, particularly in combination with other clinical and laboratory assessments. When the MAP falls below an organ’s autoregulatory range, there is an almost linear decrease in organ blood flow  that the fluid bolus increases the stressed blood volume causing an increase in MSFP, thereby increasing venous return, and (2) that both ventricles are functioning on the ascending limb of the Frank-Starling curve.Organ blood flow is driven by the difference in the pressure between the arterial and venous circulation. For example, the MAP minus the CVP is the driving force for organ blood flow while the difference between post-arteriolar and venular pressure determines microcirculatory flow. In circumstances of increased venous pressure, such as high right atrial pressure, the backwards transmission of pressure may impede microcirculatory flow in the tissues and organs.Fluid optimization must consider each of the fluid compartments in the body: total body water divided into the intracellular and extracellular spaces, and more discretely the plasma volume and blood volume, the interstitial fluid volume, and the tissue-bound water volume Fig. .Fig. 2FThe left ventricle can only pump into the arterial circulation; the volume of blood that it receives from venous return . Therefore, fluid non-responsiveness does not indicate hypervolemia.The term fluid overload is confusing and is not the appropriate term to indicate intravascular hypervolemia  produce an increase in SV Pinsky, . At the The only method of directly measuring fluid responsiveness is continuous or rapidly repeatable measures of SV in response to a fluid challenge, a passive leg raise (PLR) maneuver, or controlled changes in intra-thoracic pressure. Passive leg raising is a postural maneuver raising the lower extremities up to 45 degrees from the recumbent position, which results in a transient increase in the venous return from the lower extremities in order to measure the hemodynamic effect and thus determine if a patient is responsive to fluid therapy Fig. . BecauseInvestigations into fluid responsiveness vary in fluid type, volume, infusion time, and consequent change in SV.Patients at risk for adverse effects from fluid administration, such as CHF and ESRD, may receive lower volume fluid challenges , although the accuracy of the test to predict fluid responsiveness is reduced .The volume of fluid challenge depends on the type of fluid given: crystalloid, colloid, or blood.A common approach to test fluid responsiveness is the administration of a 500 mL fluid challenge over < 15 min with a positive response defined by a ≥ 15% increase in SV, or a 250 mL fluid challenge over < 15 min with a positive response defined by a ≥ 10% increase in SV. However:Recognizing that SV cannot be measured in all settings, MAP or HR may be used as crude surrogate indicators, recognizing they have limited predictive value. Although the existing literature has examined the effect of a fluid challenge on SV, a fluid challenge or PLR could be useful in detecting whether inadequate preload is contributing to hypotension. If the fluid challenge/PLR does not correct hypotension, additional monitoring may be appropriate and further management should focus on vascular tone and chronotropy/inotropy . The same assessments apply to the decision to stop giving intravenous fluids, which may be based upon the parameters judging fluid responsiveness and the clinical context of the patient for a global assessment or benefit and risk.A key clinical question to ask when assessing a patient’s fluid responsiveness is whether increasing the SV and CO is beneficial. For example, a patient might have an adequate or high SV index and cardiac index and still show evidence of fluid responsiveness. Giving fluid might not be indicated since achieving a still higher SV index and cardiac index might not yield important clinical benefits.All tests for fluid responsiveness have limitations Table . For exaDespite these limitations the assessment of fluid responsiveness probably leads to improved patient outcomes among patients who undergo high-risk and complex surgery  The ultimate goal of fluid therapy and hemodynamic management is to provide the conditions that enable normal cellular metabolic function in order to produce optimal patient outcomes, and (2) fluid and hemodynamic management is dependent on the relationship between pressure, volume, and flow in a dynamic system which is distensible and has variable elastance and capacitance.


Septic shock (SS) is a condition whereby the circulation cannot meet the tissue’s metabolic demand and/or when cellular metabolism is impaired. Microcirculatory anomalies correlate with organ failure severity and are predictive of in-ICU mortality , whereasIn this issue of the journal, Castro et al.  report aEarly correction of macro-hemodynamic parameters is a no-brainer in circulatory shock. However, early goal-directed therapy based on macrocirculatory parameters, such as higher MAP , CVP, Sva CRT- based fluid protocol is a tailored strategy allowing restoration of microcirculatory flow and tissue oxygenation,” a gross overreaching statement. Indeed, the so-called “sepsis-induced endotheliopathy,” primary substratum of microcirculatory failure, is a multi-faceted syndrome involving several distinct physiological processes [Recently, the ANDROMEDA-SHOCK trial and its post hoc analysis  suggesterocesses . For exaAnother point to consider is the lactate-guided resuscitation in the control group. It stands on the assumption that elevated blood lactate reflects organ hypoperfusion with inadequate oxygen delivery and subsequent anaerobic lactatogenesis. Nevertheless, the reasoning that hyperlactatemia must be treated by fluid resuscitation—in order to increase the cardiac output and oxygen delivery––and intensified until the blood lactate level has normalized is highly arguable. Indeed, much evidence has shown that stress hyperlactatemia is due to both an adaptive switch in cell metabolism toward increased aerobic lactate production and adrenergic stimulation . The kinWhat can we conclude from the study of Castro et al.? Probably that administrating fluids based on lactate levels can lead to excessive fluid administration, and such a strategy should be reconsidered. Then that a CRT-based strategy seems to be a useful and straightforward tool to refine fluid resuscitation efficacy assessment and ultimately improve global tissue perfusion. What is next? We should now better understand the best resuscitation strategies in septic shock, including timing and strategies for fluid administration and vasopressors but also the role of more specific treatment targeting the microcirculation, such as ilomedine. Such works are underway and results eagerly awaited .


In other words, both a “Darwinian” selection driven by somatic mutations and a “Lamarckian” induction driven by epigenetic changes and transcriptional plasticity can contribute to the establishment of drug resistanceBRAFV600E or BRAFV600K mutations (hereinafter referred to as BRAFV600E/K), which result in activation of the mitogen‐activated protein kinase (MAPK) pathway, sustaining cancer cell proliferation and survival. In 2011, a landmark phase III study demonstrated that vemurafenib, a drug specifically targeting cells with BRAFV600E mutations, significantly improved progression‐free survival over the conventional chemotherapy drug dacarbazine  still progress after 12 months , defined as the subpopulation(s) of cells within a tumour that confer resistance upon treatment and eventually drive relapse. In order to do this, they established patient‐derived xenograft (PDX) models of BRAFV600E/K‐mutant melanomas and exposed mice to BRAFi/MEKi treatment with the dabrafenib/trametinib combination. They observed three phases of treatment response: A rapid tumour shrinkage phase (phase 1), a phase where the tumour became impalpable (phase 2) and finally a phase where the tumour relapsed (phase 3). However, they realized that cells sampled from phase 2, where MRD remained, did not have significantly different genomic profiles from cells taken before tumours were exposed to BRAFi/MEKi. This result suggested, perhaps surprisingly, that MRD was established in this model through non‐mutational mechanisms.In their remarkable study, Rambow Next, the authors extensively characterized the MRD cell population by single‐cell RNA sequencing and pseudo‐time analysis. They found that drug exposure induced a transcriptional state characterized by intermediate MITF activity and a gene expression profile reminiscent of nutrient‐deprived cells, which they termed “starved‐like melanoma cells,” or SMCs. They observed that these cells could move along a differentiation trajectory to become either a “pigmented” subpopulation, characterized by elevated MITF activity and markers of differentiation and pigmentation, or adopt a de‐differentiated state that can then become either an “invasive” phenotype characterized by the expression of epithelial‐to‐mesenchymal transition markers, or a “neural crest stem cell (NCSC) like” population characterized by high expression of NCSC markers. All these subpopulations are drug‐tolerant, and the authors’ analyses suggest that these states can all co‐exist in MRD. They show regional heterogeneity of these drug‐tolerant cells within tumours as well as great interpatient variability.NRAS‐mutant and triple wild‐type melanoma cell cultures. The authors also elegantly identified the retinoid X receptor Y (RXRG) as a key driver of the NCSC state through a gene regulatory network analysis and showed that targeting it together with BRAFi/MEKi can significantly delay the development of resistance.The NCSC subpopulation was noteworthy—it increased dramatically even as the tumour was shrinking during drug exposure. Intriguingly, cells seemed to be able to reversibly transition into this state through phenotype switching, as some of the cell lines analysed by the authors did not initially display NCSC markers but did so upon drug exposure, and lost marker expression upon drug removal. This plasticity lent further support to the non‐mutational nature of this phenomenon. Moreover, the increase in the proportion of NCSCs seemed to be a BRAFi/MEKi‐specific effect, as it was not observed in cell lines exposed to other cell proliferation inhibitors. It also seemed to be independent of genetic background and mutational state, as it was seen both in et al, followed by the acquisition of somatic mutations that provide cells in this drug‐tolerant state with a growth advantage. In other words, both a “Darwinian” selection driven by somatic mutations and a “Lamarckian” induction driven by epigenetic changes and transcriptional plasticity can contribute to the establishment of drug resistance. The latter phenomenon suggests that a better, “adapted” cell state can be induced by environmental cues and inherited to daughter cells. This model combining mutational and non‐mutational resistance mechanisms would fit well with observations made by Rambow et al in their study, which revealed that the NCSC population emerged independently of genetic background and that some phase 3 tumours, after relapse, carried known resistance‐associated mutational events such as de novo mutations in MEK and NRAS as well as BRAF amplifications and splice variants . Obstacles still remain—BRAF/MEK/RXRi‐treated PDX tumours still relapsed , and the “invasive” cell population expanded and took over the tumour upon reduction in the NCSC population. Therefore, we might require concomitant targeting of the “invasive” and NCSC tumour subpopulations in addition to MAPK pathway inhibition, or we might need to block the ability of cells within a tumour to undergo phenotype switching in response to drug exposure. Given that this mechanism may represent a generalized path to the acquisition of tumour drug resistance, this significant work brings to light the importance of considering the duality of mutational and non‐mutational mechanisms when devising cancer treatment strategies.Although drug resistance remains a major problem in cancer treatment, we might be getting closer to understanding it. The study by Rambow


Cancer heterogeneity and progression are subject to complex interactions between neoplastic cells and their microenvironment, including the immune system. Although glioblastomas (GBMs) are classified as ‘cold tumours’ with very little lymphocyte infiltration, they can contain up to 30–40% of tumour-associated macrophages, reported to contribute to a supportive microenvironment that facilitates tumour proliferation, survival and migration. In GBM, tumour-associated macrophages comprise either resident parenchymal microglia, perivascular macrophages or peripheral monocyte-derived cells. They are recruited by GBMs and in turn release growth factors and cytokines that affect the tumour. Notably, tumour-associated microglia/macrophages (TAMs) acquire different expression programs, which shape the tumour microenvironment and contribute to GBM molecular subtyping. Further, emerging evidence highlights that TAM programs may adapt to specific tumour features and landscapes. Here, we review key evidence describing TAM transcriptional and functional heterogeneity in GBM. We propose that unravelling the intricate complexity and diversity of the myeloid compartment as well as understanding how different TAM subsets may affect tumour progression will possibly pave the way to new immune therapeutic avenues for GBM patients. Gliomas represent approximately 80% of all malignant tumours of the central nervous system (CNS) . Among tThe immune landscape of brain tumours is intensely investigated, unveiling new insight in the interactions between neoplastic cells and the immune system . GBM is Due to their large number in the tumour microenvironment, TAMs represent a key target for GBM immunotherapy and a range of immunomodulatory agents are currently being trialled in patients. For example, as TAMs critically depend on colony-stimulating factor-1 (CSF-1) for their survival, differentiation and proliferation, strategies to target TAMs in the clinic include CSF-1 receptor (CSF-1R) blockade ,8. HowevDespite extensive efforts in this direction, the precise role of TAMs in GBM onset and progression as well as how TAMs may affect current immunotherapeutic approaches, including vaccines, oncolytic viruses and immune-checkpoint inhibitors, remains unclear. Therefore, a deeper understanding of the complexity and diversity of TAM adaptive features is critical to develop novel personalized immune therapeutic strategies for GBM patients.In this review, we will describe different features underlying TAMs heterogeneity and adaptation in GBM. Further, we will pinpoint the aspects linked to their diversity that warrant further investigations and how this heterogeneity may ultimately be harnessed for the development of novel personalized immune therapeutic strategies.Macrophages are highly dynamic cells whose molecular profiles are substantially influenced by specific environmental cues. In vitro studies enabled classification of activated macrophages according to a binary system, with pro-inflammatory cytokines  skewing them towards a classical (M1-like) activation state, while anti-inflammatory cytokines  polarizing macrophages into an alternative (M2-like) phenotype . A similThe healthy brain harbours specific populations of tissue-resident macrophages effectively located in the parenchyma, perivascular spaces, meninges and choroid plexus where they maintain tissue homeostasis and ensure immune functions . Within In GBM, TAMs are recruited to the tumour site through various mediators, including CCL2, CX3CL1, CSF-1, GM-CSF and osteopontin released by neoplastic cells ,27,28,29+CD45low cells) from peripheral monocyte-derived macrophages (CD11b+CD45high cells) [Itga4 (CD49D), enabling the distinction between microglia and monocyte-derived macrophages in murine tumours [P2ry12, Tmem119, Slc2a5 and Fcrls, whereas Emilin2, Gda, Hp and Sell were mainly expressed by peripheral monocytes/macrophages [Experimentally, approaches to distinguish resident microglia from other inflammatory immune cells entering the CNS have traditionally relied on CD45 expression to discriminate resident microglia (CD11bh cells) . Howeverh cells) . Recentl tumours   signalling pathways in microglia reducing their phagocytic and inflammatory responses . In cancTo date, the combination of radio-chemotherapy with immunotherapeutic agents has not been effective in GBM and drugs driving anti-tumour immune responses are currently evaluated in clinical trials. In principle, radiation can increase in situ immunogenicity of malignant cells, thus improving tumour immune recognition and T-cell mediated anti-tumour responses . In thesCcl2 genetic ablation, prolonged the survival of tumour-bearing mice [+ population and contributed to 30% of tumour increase in the GBM syngeneic GL261 mouse model [Upon accumulation to the tumour site, TAMs are thought to drive immune-suppression and promote tumour progression. Due to their high numbers in GBM, their genomic stability and adaptability to the microenvironment, several strategies to deplete TAMs have been developed. For example, liposome-encapsulated clodronate, which has been commonly used to deplete macrophage populations by inducing their apoptosis once phagocytosed by the cells, reduced tumour invasion in GL261 cultured brain slices, which was restored after addition of TAMs . Howevering mice , but these model . A majorse model . Furtherse model .These results highlight that depleting TAMs indiscriminately is probably not the optimal approach, as TAMs might play different roles depending on GBM features, including immunogenicity.Immunotherapy is emerging as a promising approach holding great potential to foster tumour elimination by unleashing the immune system. The intense crosstalk between tumour cells, antigen presenting cells (APCs) and T cells is intricately controlled by multiple ligand-receptor interactions, known as checkpoints, which generally inhibit T-cell activation, ultimately affecting T cell cytotoxicity against tumour cells . For exaCcr2RFP) and microglia (Cx3cr1GFP), in which microglia were found to effectively phagocytose tumour cells in response to anti-CD47 blockade with a reduced inflammatory signature, making them a promising target for clinical applications [Due to TAMs abundance within GBM and their fast response to external stimuli, strategies to re-educate TAMs in mouse glioma models may be more efficient than their depletion or the use of immune checkpoint inhibitors. In this context, a promising target is signal-regulatory protein (SIRP) α, an inhibitory receptor expressed on myeloid cells that recognizes the CD47 ligand on tumour cells and contributes to immune evasion. The targeting of this axis with humanized anti-CD47 antibodies enhanced tumour phagocytosis and reduced tumour burden in patient-derived orthotopic xenografts of paediatric brain tumours . Interesications . Anotherications .+ regulatory T cells as well as accumulation of tumour-infiltrating effector T cells exhibiting anti-tumorigenic features [Combinatorial approaches targeting immune-suppressive populations concomitantly with promoting endogenous anti-tumour immune responses successfully impaired tumour progression in various subcutaneous tumour models. For example, dual targeting of suppressive myeloid populations by inhibiting CSF-1/CSF-1R signalling and activation of APCs with CD40 agonists conferred superior anti-tumour efficacy and increased survival compared with monotherapy. This effect was attributed to the decrease of immunosuppressive TAMs and Foxp3features . Furtherfeatures . Lastly,Taken together, strategies aiming at reprogramming immunosuppressive myeloid cell populations and/or fostering anti-tumour immune responses in the tumour microenvironment may be necessary to empower checkpoint-based immune therapeutics in GBM. However, TAMs heterogeneity may represent a barrier to non-selective immunotherapies, which seek to target TAMs indiscriminately.In the last 10 years, multiple attempts have used transcriptional profiling to sub-classify GBMs into clinically meaningful tumour subtypes ,60,61. ARecent scRNA-seq studies also highlighted tissue-specific myeloid cell heterogeneity associated with distinct brain region-dependent transcriptional identities in health and disease ,67,68. FIL1α and IL1β) were highly expressed at the tumour periphery, while a more anti-inflammatory phenotype  was observed in the tumour core  and alternatively activated (M2) genes in individual cells  Figure . Furtherour core . Lastly,ignature .The cellular composition of IDH-mutant gliomas was also unveiled by scRNA-seq, suggesting that astrocytomas (IDH-A) and oligodendrogliomas (IDH-O) share common lineages of glial differentiation with distinct tumour microenvironment signatures . SpecifiIn IDH-wildtype gliomas, it has been very recently shown that TAMs acquire a disease-associated signature related to aging microglia programs, including downregulation of the microglia homeostatic genes and upregulation of inflammatory, metabolic and interferon-associated genes. Various TAM clusters, including subsets enriched for positive regulation of vasculature development or antigen processing via MHC class I, have been identified  Figure . Taken tMicroglia and macrophages in GBM are educated by the tumour and display unique molecular programs, which largely drive tumour-supportive phenotypes. However, the available subpopulations and functions of these cells along GBM development and progression are only partially understood. TAMs have been classified based on their activation state, their function and their morphology. With the advent of single cell analyses, it has become increasingly clear that the classification is complex and does not fully capture the heterogeneity of these cells in the context of GBM. Immunotherapeutic approaches in GBM will need to take into account the role of TAMs and their functional, spatial and temporal heterogeneity.The local GBM microenvironment actively reprograms TAMs to establish new functional states with distinct gene expression profiles. If so, which TAM subsets arise during GBM development? Which subset of TAMs are more prone to be re-educated? Are their dynamic molecular states associated to TAM specific functions along GBM development and progression? Will their dissection help to improve TAM targeted therapies in combination with current treatment regimens? Taken together, it will be critical to address these questions to determine the most appropriate combinatorial approaches and to identify patient subgroups that may benefit most.As perspectives, it will be fundamental to combine single-cell approaches, such as scRNA-seq and imaging mass cytometry, with functional screening of inferred cellular diversity, which will be critical to identify TAM subsets across GBM subtypes, landscapes and tumour stages, thus enabling targeting of putative pro-tumorigenic TAM subpopulations and/or to empower the anti-tumorigenic ones. Further, shedding light on the functional crosstalk between neoplastic cells and the tumour microenvironment at single-cell resolution will enable to dissect complex cell–cell interactions and how these may affect patient outcomes. Using a combination of scRNA-seq and flow cytometry in syngeneic mouse models of solid tumours allowed to profile potential cell-cell interactions between neoplastic and non-neoplastic cells . Buildin


To evaluate renal responsiveness in oliguric critically ill patients after a fluid challenge.We conducted a prospective observational study in one university intensive care unit. Patients with urine output < 0.5mL/kg/h for 3 hours with a mean arterial pressure > 60mmHg received a fluid challenge. We examined renal fluid responsiveness (defined as urine output > 0.5mL/kg/h for 3 hours) after fluid challenge.Forty-two patients  were evaluated. Patient characteristics were similar between renal responders and renal nonresponders. Thirteen patients (31%) were renal responders. Hemodynamic or perfusion parameters were not different between those who did and those who did not increase urine output before the fluid challenge. The areas under the receiver operating characteristic curves were calculated for mean arterial pressure, heart rate, creatinine, urea, creatinine clearance, urea/creatinine ratio and lactate before the fluid challenge. None of these parameters were sensitive or specific enough to predict reversal of oliguria.After achieving hemodynamic stability, oliguric patients did not increase urine output after a fluid challenge. Systemic hemodynamic, perfusion or renal parameters were weak predictors of urine responsiveness. Our results suggest that volume replacement to correct oliguria in patients without obvious hypovolemia should be done with caution. Oliguria is often viewed as a sign of renal hypoperfusion and triggers interventions, such as a fluid challenge, with the aim of improving systemic hemodynamics to improve renal perfusion and consequently renal function. However, oliguria does not always indicate ongoing renal hypoperfusion in a critically ill patient. The pathophysiologic mechanisms implicated in acute oliguria are multifactorial: reversible renal hypoperfusion due to low cardiac output or due to vasoplegic hypotension; augmented liberation of antidiuretic hormone unrelated to kidney perfusion or damage and with maintained glomerular filtration rate, and renal damage. Both experimental and clinical studies showed that the glomerular filtration rate and renal blood flow can be dissociated.-6Hypovolemia is a major risk factor for the development of acute kidney injury (AKI) and is associated with low urinary output.,7-9 In these situations, injudicious use of fluids carries its own risks of contributing to the development or worsening of AKI by fluid overload.,11 Nevertheless, hypotension, hypernatremia or low urine sodium concentration have long been considered markers of a low intravascular volume state in an oliguric patient and often leads to a fluid challenge or aggressive fluid repositions.,13Thus, there are many uncertainties about when AKI is considered volume responsive, in particular in cases that hypovolemia is unlikely and AKI is not caused by renal hypoperfusion.,13As a result, at the bedside, renal responsiveness  is observed in only half of oliguric patients, even if there are reasons to consider that the patient's blood volume is depleted.Therefore, the objective of this study was to evaluate renal responsiveness in oliguric intensive care unit (ICU) patients after a fluid challenge.Complexo Hospitalar Santa Casa de Porto Alegre approved the present study and waived the requirement for obtaining consent.Because this study was observational and did not change daily practice, the Institutional Review Board of the Complexo Hospitalar Santa Casa de Porto Alegre, a 20-bed adult medical-surgical ICU. Patients were included if they met the following criteria: oliguria, defined by urine output < 0.5mL/kg/h for 3 consecutive hours; administration of a fluid challenge  as indicated by the physician in charge and mean arterial pressure (MAP) ≥ 60mmHg.This study was performed in the central ICU of the The indications for fluid challenge were obtained from the physicians in charge or from the patient's records. The exclusion criteria were patients under 18 years old, treated with diuretics on the study day, with stage 3 AKI, pregnancy, with chronic renal failure, with a decision to withhold or withdraw treatment, and likely to die in the next 48 hours. Patient characteristics, Acute Physiology Chronic Health Evaluation II (APACHE II) score at admission, and reasons for ICU admission were recorded. At inclusion  and at completion of the fluid challenge, we recorded MAP, heart rate (HR) and norepinephrine infusion rate. Capillary refill time both at inclusion and after the fluid challenge was recorded as normal (< 5 seconds) or abnormal (≥ 5 seconds). All available routine laboratory measurements of study interest during the previous 3 hours were recorded . The same parameters were recorded in the following 3 hours after the fluid challenge if available. Creatinine clearance was calculated using the Cockcroft-Gault equation.The main endpoint of the study was renal fluid responsiveness, defined as a post-fluid challenge urine output > 0.5mL/kg/h for more than 3 hours .Categorical variables were compared using a Chi-squared test. The area under the Receiver Operating Characteristic (AUROC) Curve to predict urine responsiveness was built for MAP, HR, serum creatinine, blood urea, urea/creatinine ratio, creatinine clearance and arterial lactate. We determined the optimal threshold value for each variable. All analyses were performed using IBM Statistical Package for Social Science (SPSS) Statistics software . All p values were two-tailed, and a p value < 0.05 was considered significant. Values are expressed as number and percentage, mean or median and interquartile range accordingly.Forty-two patients were evaluated between March 2017 and October 2017. The patient features are shown in 2) nor central venous to arterial carbon dioxide difference (Pcv-aCO2) improved after the volume load.2 decreased in RR when compared to that in non-RR. Norepinephrine infusion rates decreased in the non-RR and RR groups, but with marginal significance for the RR group (p = 0.052).Thirteen patients (31%) were renal responders . There wA 10% increase in MAP (n = 17) and a decrease in HR (n = 4) and in the norepinephrine rate (n = 9) was not associated with reversal of oliguria. Even when considering a change in at least one of these three parameters, there was not an association with oliguria reversal.AUROC were calculated for MAP, HR, creatinine, urea, creatinine clearance, urea/creatinine ratio  and lactate (n = 37) before the fluid challenge. In our study, most patients with transient oliguria did not increase their urine output after a fluid challenge. None of measured parameters were reliable predictors of urine responsiveness previous to fluid challenge. However, physiological reasons exist to consider oliguria a poor marker of hypovolemia or low intravascular volume. Shock, pain, and the perioperative period are associated with alterations in intrarenal hemodynamics and activation of the renin-angiotensin system, leading to antinatriuresis and antidiuresis.,17 Our study shows that oliguria in normotensive ICU patients may not reflect hypovolemia in a large proportion of patients. Hence, fluid challenge may not translate into an increase in urine output and use of oliguria alone as triggers for fluid therapy is often not fully supported by physiological reasoning.,12In routine practice, low urine output often leads to performing fluid challenge in ICU patients. This is based on the hypothesis of a systemic hemodynamic contribution to low renal blood flow and low urine output.2, MAP) improved (p = NS) among RR, similar changes in the same parameters were not associated with reversal of oliguria and the prediction value of these variables was poor. These observations are consistent with previous investigations that showed the lack of correlation between systemic hemodynamic changes and response in urine output.,5,18 In fact, even an increase in cardiac output after a fluid challenge is not consistently associated to a reversal of oliguria.,12,13 Legrand et al. reported that the fluid challenge reversed oliguria in only one-half of the patients and that neither urinary sodium nor fractional excretion of sodium or urea were good predictors of the renal response to a fluid challenge.The poor ability of systemic hemodynamic variables to predict an increase in urine output following fluid challenge was notable. First, RR and non-RR had similar baseline hemodynamic or perfusion markers. Second, although some parameters  ratio and 62% were mechanically ventilated. Thus, it is reasonable to argue that this group of patients was sicker and suffered physiological disarrangements accompanying their critical illness.It should be noted that the effects of fluid therapy are highly dependent on the phase of acute illness. Acutely, in a hypotensive and oliguric patient, the early effects of fluids in the resuscitation phase is not only likely beneficial but also potentially deleterious when established AKI later in the course of critical illness is almost the rule. Non-RR patients had a significantly lower arterial oxygen tension to inspired oxygen fraction , which may have limited the number of patients eligible for inclusion. Second, they had to be off drugs that induce diuresis, . Third, monitoring of cardiac output was not performed to monitor stroke volume during the fluid challenge, and among RR one could argue that our data suggest a possible increase in blood flow not so evident because of the small sample. Fourth, data on urine obstruction or the use of nephrotoxins  were not recorded. In relation to this last limitation, someone could criticize the failure to include causes of nephrotoxicity as exclusion criteria, which would make the cohort less homogeneous. On the other hand, our focus was to show that the practice of challenging blood volume in oliguric patients is often ineffective and this approach is used even in patients with complex causes that lead to oliguria.In our study, oliguric patients, after achieving hemodynamic stability, did not increase urine output after a fluid challenge. Systemic hemodynamic or perfusion parameters were weak predictors of urine responsiveness. Our results suggest that volume replacement to correct oliguria in patients without obvious hypovolemia should be done with caution.


The authors wish to make the following corrections to this paper : The infFunding: This research was funded by the National Science Centre of Poland grant number 2017/25/B/NZ7/00388 (to M.S.).The correct funding is as below:Funding: This research was funded by the National Science Centre of Poland grant numbers 2016/23/N/NZ5/01428 (to E.M.) and 2013/11/D/NZ7/00925 and by the National Leading Research Centre (KNOW-MMRC1) project (E.M.). J.M. was supported by Grant SAF2015-64501-R from the Spanish Ministry of Economy and Competitivity.This change does not affect the scientific results. The manuscript will be updated and the original version will remain online on the article webpage, with a reference to this erratum. The authors would like to apologize for any inconvenience caused to the readers by this change.


In current study natural convection flow of second grade fluid in an oscillating infinite vertical cylinder is investigated. The dimensionless governing equations for temperature and velocity are obtained by introducing the non-dimensional variables. Exact solutions for temperature and velocity field are computed by means of integral transformation. Solutions for cosine and sine oscillations of velocity field are introduced in the form of transient and post-transient arrangements. A special case for Newtonian fluid is obtained from general results and transients solutions are computed in terms of tables. In the end, the impact of dimensionless numbers (Grashof and Prandtl numbers) at different values of time is presented in graphical form and found that velocity for Newtonian fluid has greater values than the second grade fluid. Furthermore, there are some comparisons of calculated solutions with existing solutions in literature. Viscous fluids flow has attracted the attention of scientists and engineers because of its important applications notably in the flow of oil through porous rocks, the extraction of energy from geothermal regions, the filtration of solids from liquids and drug penetration through human skin. Second grade fluid is a subclass of non-Newtonian fluid in which velocity field has up to two derivatives in stress strain tensor relationship where as in Newtonian fluid it has derivatives up to first order. Flow of second grade fluid gains attention of the researchers in many boundary layer flows and have been successfully studied in various kinds of flows. Study of heat transfer in non-Newtonian fluids is much interesting for researchers now-a-days. The influences of temperature dependent viscosity on second grade fluid causes changes in the properties of the fluid. For the case of gases, the viscosity of the gas increases as heat given to gas while for liquid it becomes thin as temperature increases. As a result many scientist devoted to study the effects of variable viscosity models. Fetecau4 worked on the uniqueness of some helical flows of a second grade and Oldroyd-B fluids in cylindrical domains, they studied the fluid motion by applying time dependent stress on the boundary and studied the effects of physical parameters on the fluid motion. Further Jamil and Khan5 used the same technique for Burger’s fluid and obtain the result for velocity and shear stress. Keeping in view the importance of fluid flow in cylindrical domain researchers studied fluid motion in cylinders by considering different fluids and boundary conditions. Barnes et al.7 analyzed the polymer flow in circular cylinder by considering pulsatile APG, Davies et al.8 and Phan-Thien9 worked on the same problem for White-Metzner fluid. Jamil et al.10 obtained exact solutions for the motion of a fractionalized second grade fluid due to longitudinal and torsional oscillations of an infinite circular cylinder are determined by means of Laplace and finite Hankel transforms. Fetecau et al.11 obtained the solutions for the oscillating motion of a generalized Burgers fluid due to longitudinal oscillations of an infinite circular cylinder, as well as those corresponding to an oscillating pressure gradient, are established as Fourier–Bessel series in terms of some suitable eigenfunctions. The propagation of a heat wave in an incompressible second grade fluid within the context of a potential vortex was studied by Fetecau et al.12. Flow induced by non-coaxial rotation of a porous disk executing non-torsional oscillations of a second grade fluid was studied by Hayat et al.13. The fractional calculus approach in the constitutive relationship model of second grae fluid was introduced and the flow characteristics of the viscoelastic fluid in double cylinder rheometer were studied by Huang et al.14.Due to complicated relation between stress and strain in non-Newtonian fluids and their technological application, their study in fluid dynamics is more valuableet al.15. Gul et al.16 studied heat transfer in MHD mixed convection flow of a ferrofluid along a vertical channel and found that temperature and velocity of ferrofluids depend strongly on viscosity and thermal conductivity together with magnetic field. Gul et al.17 studied energy transfer in mixed convection MHD flow of nanofluid containing different shapes of nanoparticles in a channel filled with saturated porous medium. They concluded that viscosity and thermal conductivity are the most prominent parameters responsible for different results of velocity and temperature. Due to higher viscosity and thermal conductivity, C2H6O2 is regarded as better convectional base fluid compared to H2O. Chamkha18 studied non-similar solutions for mixed convective boundary layer flow a non-Newtonian fluid over a wedge embedded on a porous medium filled with a nanofluid. Sheikhzadeh et al.19 performed parametric study on MHD mixed convection of Cu-water nanofluid in a two-sided lid-driven porous cavity with a partial slip. Prasad et al.20 studied a convection flow over a permeable non-isothermal wedge and reveal many interesting behaviors and study of the flow and heat transfer characteristics over the permeable wedge. Hasnain et al.21 studied the effects of porosity and convection on MHD two phase fluid flow in an inclined channel. Straub et al.22 proposed a simple model that allow estimating the achievable drag reduction rates in duct flows as a function of the width of the duct and the spanwise extent of the controlled region and showed that this spanwise limitation of the oscillating region strongly diminishes the drag reduction potential of the control technique. Straub et al.23 studied the effect of selected thermal boundary conditions on a fully developed turbulent pipe flow. Younghae et al.24 studied Navier’s slip condition on time dependent Darcy-Forchheimer nanofluid using spectral relaxation method. A numerical investigation of laminar natural double diffusive convection in an open ended vertical cylindrical annulus with unheated entry and un-heated exit was performed by Sankar25. Natural convection flows in a vertical annulus filled with a fluid-saturated porous medium was investigated when the inner wall is subject to discrete heating by Sankar et al.26.In fluid motion free convection is induced by buoyancy forces. These forces may arise due to density gradients and body forces. In free convection the Grashof number plays the same role as in forced convection the Reynolds number. The Grashof number is actually the ratio of buoyancy forces to viscous forces. Heat transfer due to convection has several industrial and technological applications. Their examples may be found in wire and fiber coating, manufacturing plastic films, artificial fibers, polymer sheets, chemical processing equipment and in the design of various heat exchangers. Mixed convection heat transfer in a horizontal channel filled with nanofluids studied by Fan 27. Fetecau et al. observed effects of convection of fractional Oldroyd-B fluid flow with thermal diffusion28. Heat transfer in oscillating fractional Maxwell fluid is studied by Khan et al.29. Free convection flow of a unsteady second grade fluid is calculated by Ali et al.30. Hayat et al.31 studied slip flow and heat transfer of a second grade fluid past a stretching sheet through a porous space. Cortell32 studied the flow, chemical reaction and mass transfer of a steady laminar boundary layer flow of an electrically conducting fluid of second grade in a porous medium subject to a transverse uniform magnetic field past a semi-infinite impermeable stretching sheet. Ariel33 studied axisymmetric flow of a second grade fluid past a stretching sheet by using a perturbation method. Vajravelu et al.34 studied the flow and heat transfer characteristics in a second grade fluid over a stretching sheet with prescribed surface temperature including the effects of frictional heating, internal heat generation or absorption, and work due to deformation. Natural convection heat transfer for Newtonian fluid in an oscillating vertical cylinder is studied by Khan et al.35.Shah and Khan studied heat transformation in second grade fluid by using fractional Caputo-Fabrizio derivativesThe aim of current study is to study the second grade fluid flow and natural convection heat transfer. We are pleased to acknowledge here that there is no work on natural convection heat transfer in cylindrical domains, current work in oscillating cylinder is new one. Integral transform technique is used to find exact solutions for temperature distribution and cosine and sine oscillations of velocity field. Moreover, velocity field is introduced in the form of transient and post-transient arrangements. To check the impact of dimensionless numbers (Grashof and Prandtl numbers) at different values of time, graphical illustrations are used. The transient solutions are also computed in tables. Furthermore, a special case for Newtonian fluid is obtained and a comparison between Newtonian and second grade fluid is depicted by a graph. Moreover, there are comparisons with solutions for second grade fluids obtained in various works by other researchers.R. The z-axis is considered along the axis of cylinder in vertical upward direction and the radial coordinate r is taken normal to it, flow is consider to be unidirectional. Fluid flow is considered along z-direction and there is no fluid motion along θ and r. At time t ≤ 0 cylinder is at rest and both cylinder and fluid are at the same temperature T∞. After time t > 0 cylinder starts to oscillate with frequency ω along its axis. At the same time, the cylinder temperature raised to Tw which is thereafter maintained constant as shown in Fig. Consider a viscous second grade fluid in a vertical infinite cylinder having radius r and t only. Therefore, velocity and temperature is of the following form35,We assume that the velocity and temperature are the function of 35,v, v, α, ρ, g, β, T, k and cp is velocity, viscosity, material constant, density, gravitational acceleration, volumetric coefficient of thermal expansion, temperature, thermal conductivity and the heat capacity at constant pressure respectively.For such a flow, taking the usual Boussinesq approximation, following set of partial differential equations governed the flowvo and H(t) are characteristic velocity and unit step function respectively.The suitable initial and boundary conditions areGr and Pr are Grashof number and Prandtl number respectively.Next we use the non-dimensional variables and functions in order to determine solutions which are independent of the flow geometry,After dropping out the “•” notation Eqs. –5 reduce36 of Eqs.  an an36 of  of Eqs. ,11\docum36 of order zero on Eq.  an an10) an36Applying the finite Hankel transform to Eq. 3618\docu36, we obtainApplying inverse Laplace transform to above equation36 the expression for the velocity field is obtainedFinally, applying the inverse Hankel transformThe velocity field corresponding to cosine oscillation can be obtained form Eq.  by takinSimilarly, the velocity field corresponding to sine oscillation can be obtained form Eq.  by takinα → 0 in Eq. . With the decrease in Prandtl number the area of thermal boundary layer increases, therefore, the temperature gradient decreases with Pr.Figure Pr = 0.75, ω = 1.5. It must be accentuated that, for smaller values of Gr the fluid velocity has low values. This is due the effect of the temperature on the fluid velocity solution. Low values of the Gr lead to reduced contribution of the temperature in the fluid flow, therefore, the viscous forces increases and the velocity decreases and vice versa for larger values of Gr.Figure Pr. We take Gr = 0.7, ω = 1.7. For larger Pr, fluid velocity decreases. The buoyancy forces created by the density differences are high for the smaller values of the Prandtl number when the temperature is high. When the Prandtl number is large, the viscous damping action becomes bigger and fluid velocity decreases.Figure vct and vst can be observe from the Tables t = 31 solution for vct approaches to zero. From Table t = 6 solution for vst approaches to zero.The decrease in the transient solution et al.10 obtained exact solutions for the motion of a fractionalized second grade fluid, by applying limits on fractional parameter we reduce the result to second grade fluid and compare with our solution Table et al.11 obtained the solutions for the oscillating motion of a generalized Burgers fluid due to longitudinal oscillations of an infinite circular cylinder. By applying some limits we reduce the solutions for second grade fluid and compare with our calculated results Table Jamil In Fig. Pr.Temperature is an increasing function of Pr.The Nusselt number is increasing function of Gr and decreases for Pr.Fluid velocity increasing with respect to −14, after that point the fluid moves according with the post-transient solution.The transient solutions are noteworthy up to 10The velocity of the Newtonian fluid is greater in comparison to second grade fluid.This validate our results as Newtonian fluid offer low resistance to fluid flow as compared to second grade fluid.Unsteady natural convection flow of second grade over an oscillating infinite vertical cylinder is investigated. The exact solutions for temperature and velocity fields are computed by means of integral transformations. Following important points are observed from the studied problem


We propose a way to model topic-based implicit interactions among Twitter users. Our model relies on grouping Twitter hashtags, in a given context, into themes/topics and then using the multiplex network model to construct a thematic multiplex where each layer corresponds to a topic/theme, and users within a layer are connected if and only if they used the same hashtag. We show, by testing our model on a real-world Twitter dataset, that applying multiplex community detection on the thematic multiplex can reveal new types of communities that were not observed before using the traditional ways of modeling Twitter interactions. Within this context, Twitter can easily claim the award for the most researched social media platform. Thanks to the large user-base and a relatively generous API policy, this micro-blogging platform has quickly evolved into the The detection of cohesive subgroups in social networks, also called as community detection, has been perceived as one of the most valuable tools to better understand social networks  which captures the Twitter interactions among Danish politicians during the parliamentary elections of 2015. We discuss our results in section 4 and conclude our findings in section 5imagined audience in the literature  among all the users who used the same hashtag. We first show that detecting communities on the thematic multiplex reveals communities that are largely different from those detected using the traditional ways of modeling twitter interactions. Given the DkPol dataset, we constructed a twelve-layer thematic multiplex (layer per theme/topic). A topic/theme with As to the selection of the community detection method for our multiplex networks in this paper, we chose a modularity-maximization based community detection method, Generalized Louvain . The reason behind choosing “1 week” as a time-window based on which we split the data is that during the month leading to the elections, politicians had to debate on a public TV show once per week.C1 in As illustrated in By looking at This scenario seems to change during the second week as During the third week can observe a new polarization of the picture. This topical difference is largely maintained into the fourth week, the week of election, where we can see—A clear difference has been shown when analyzing the communities on the thematic multiplex versus those detected on a multiplex constituted of the following/follower, retweet, and reply layers. This strongly suggests that community detection on the thematic multiplex reveals different dynamics than those observed using traditional ways of modeling twitter interactions. This is not to say that the thematic multiplex can substitute the traditional ways of modeling Twitter activities, but just to shed a light on different dynamics that can be observed using this way of modeling.Applying longitudinal community detection on the thematic multiplex network obtained from Twitter data allowed us to observe several interesting dynamics. Given that the dataset captured the interactions among Danish politicians during the month leading the parliamentary elections of 2015, we were able to capture the interest of a political party  in specific issues, regardless of the fact that the issue produced an explicit interaction with other users through retweets or replies. During a political campaign, when much of the communication is aimed at promoting the party's agenda to the potential voters, which does not necessarily involve retweeting or replying actions , this type of implicit communication is of key importance. Nevertheless, the thematic multiplex network approach was also able to observe the topics that were more contentious between the parties as well as the topics highly polarized. Moreover, the combination between multiplex thematic analysis and longitudinal data allowed us to show how the political debate, and resulting political communities, are highly dynamic and driven by the ongoing events or campaign themes.While there might exist other ways to model topic driven implicit interactions on Twitter for clustering tasks, we still think that using multiplex network model offers clear advantages. First, the multiplex network model is a well-developed and widely used model for modeling complex systems  and #dajegvar12 (translate: when I was twelve). In both cases an emotional hashtag is used to discuss specific issues, the refugee crisis with the first and children policies with the latter. The connection between the topic and the hashtag is not explicit, and while both hashtags are clearly topical hashtags  was originally introduced by Twitter, many other platforms such as Facebook and Instagram have adopted this idea in various ways. Thus, we suggest that this model should not be limited to Twitter data as it could be easily applied to other hashtag-based communicative contexts  as well as to other conceptually similar digital contexts .On a separate note, we would like to mention the fact the resulted communities may largely depend on the chosen community detection method. Indeed, weather or not the thematic communities will be significantly different among different community detection methods can be a research question on its own and we think that answering this question is out of the scope of this paper.In this paper we propose an innovative model, the thematic multiplex, to model topic-driven interactions on Twitter. The thematic multiplex is a multi-layer network where each layer corresponds to a different topic, and users (nodes) within a layer will be connected via a clique if and only if they used the same hashtag. We explain the motivation behind the thematic multiplex which is the fact that it considers implicit interactions among users on Twitter that are usually neglected in other models. We construct the thematic multiplex of a real-world Twitter dataset describing the Twitter interactions among the danish politicians during the parliamentary elections of 2015. We show that applying multiplex community detection on the thematic multiplex allows us to observe different dynamics than those we would observe on other models.https://github.com/obaidaITU/dkpol].The datasets analyzed for this study can be found in the dkpol GitHub repository on the following link [OH and LR conceived of the presented idea and developed the theory, discussed the results, and contributed to the final manuscript. OH performed the experiments. LR supervised the findings of this work.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. The handling editor and reviewer (SG) declared their involvement as co-editors in the Research Topic, and confirm the absence of any other collaboration


Karwinskia genus consists of shrubs and small trees. Four toxic compounds have been isolated from Karwinskia plants, which were typified as dimeric anthracenones and named T496, T514, T516, and T544. Moreover, several related compounds have been isolated and characterized. Here we review the toxicity of the fruit of Karwinskia plants when ingested , as well as the toxicity of its isolated compounds. Additionally, we analyze the probable antineoplastic effect of T514. Toxins cause damage mainly to nervous system, liver, lung, and kidney. The pathophysiological mechanism has not been fully understood but includes metabolic and structural alterations that can lead cells to apoptosis or necrosis. T514 has shown selective toxicity in vitro against human cancer cells. T514 causes selective and irreversible damage to peroxisomes; for this reason, it was renamed peroxisomicine A1 (PA1). Since a significant number of malignant cell types contain fewer peroxisomes than normal cells, tumor cells would be more easily destroyed by PA1 than healthy cells. Inhibition of topoisomerase II has also been suggested to play a role in the effect of PA1 on malignant cells. More research is needed, but the evidence obtained so far indicates that PA1 could be an effective anticancer agent. Karwinskia (Rhamnaceae family) consists of small trees and shrubs native to southern United States and Mexico in North America; Guatemala, El Salvador, Honduras, Nicaragua, Costa Rica, and Panama in Central America; Colombia and Venezuela in South America; and Cuba, Haiti, and the Dominican Republic in the Caribbean )terature ,37,38,39terature  establisoldtiana .K. humboldtiana fruit is proportional to the amount of fruit ingested. High dose fruit ingestion (acute intoxication) causes death after 24–48 h by cardiopulmonary arrest without paralysis signs, with extensive damage in lungs, liver and kidneys [The severity of the disease that develops in humans and animals after accidental ingestion of  kidneys ,42,43. I kidneys ,39,44,45K. humboldtiana fruit may be very difficult if there is no prior evidence of ingestion of the fruit. Most patients present with nonspecific signs and symptoms, including diarrhea, vomiting, loss of strength in limbs, breathing difficulty, fever, coughing, and myalgias. The latency period between ingestion and onset of nervous symptoms also difficulties diagnosis. Moreover, intoxication can be interpreted as Guillain-Barré syndrome, poliomyelitis, or other similar pathologies [K. humboldtiana can be determined by thin-layer chromatography (TLC) [Clinical diagnosis of intoxication with hologies ,37,38,39hologies ,47,48,49hologies  detectedhy (TLC) ,51.K. humboldtiana toxins is not fully understood. Therefore, there is no specific antidote for these toxins. Treatment consists of supportive care and physical rehabilitation [K. humboldtiana. However, no improvement was observed on the clinical manifestations or in the histopathological lesions evaluated. It has been suggested that administration of thiamine may be helpful [At the present time, the mechanism of damage caused by litation ,49,51. Flitation . Furtherlitation  administ helpful .Karwinskia toxicity are focused on the PNS. Oral administration of crude homogenate of K. humboldtiana fruit, or toxins isolated from it, produces distal segmental demyelinization and degenerative changes of peripheral nerves in several animal species [Most of the published reports about  species ,57,58,59 species ,61 and a species ,63,64. F species ,65.Axonal degeneration is more extensive at the ends of long nerves ,56,57. RK. humboldtiana or toxins T514 or T544, swollen nerve fibers, disorganized and vacuolated myelin sheaths, and areas of segmental demyelinization, without inflammatory infiltrate. Similar findings have been encountered in intoxicated humans [Histopathologically, Bermudez et al.  found ind humans ,51.Karwinskia toxins. Charlton and Pierce [K. humboldtiana. Ultrastructurally, Schwann cells showed degeneration of mitochondria and glycogen depletion. Mitochondrial injury would result in impaired active transport and in the intracellular edema previously described [K. humboldtiana cause inhibition and uncoupling on respiration and oxidative phosphorylation of mitochondria [K. humboldtiana seed decrease the ATP synthesis [Karwinskia toxins. Additionally, Mitchell et al. [It has been proposed that Schwann cells are the primary target of d Pierce ,56,57 rechondria . In vivoynthesis  and prodynthesis . These fl et al.  injectedKarwinskia toxins on the neuronal elements. Aoki and Muñoz-Martinez [On the other hand, there is evidence of a direct action of Martinez  suggesteMartinez  using myHowever, Muñoz-Martínez et al.  found alK. humboldtiana. Lesions were more evident in the cerebellum , while some swelling occurred in axons of the white matter of the spinal cord. There was a positive relationship between the cerebellar lesions and clinical signs observed in affectated goats: increased alertness, tremor, increased responsiveness to external stimuli, and high-stepping movements.Charlton and Pierce  reportedK. humboldtiana. Hyperchromasia, cell death, and widening of the Virchow-Robin spaces were observed in cerebral motor cortex; hyperchromasia, cell shrinkage, and cell death were evident in the CA1 region of hippocampus; and neuronphagia and cell shrinkage occurred in caudate nucleus. These alterations may be related to the nonparalytic motor disturbances occurring early after K. humboldtiana intoxication.Ortiz et al.  studied K. humboldtiana, Becerra-Verdin et al. [K. humboldtiana. Finally, in the cerebral motor cortex, pyramidal internal and external neurons showed characteristics related to ischemia and hypoxia.In rats chronically poisoned with the fruit of n et al.  found chK. humboldtiana.Using the same experimental model mentioned in the last paragraph, Díaz-Pérez et al.  analyzedK. humboldtiana fruit causes death within first 48 h by cardiopulmonary arrest without paralysis signs, with extensive damage in several organs, mainly liver, lungs and kidneys [As mentioned earlier, copious ingestion of  kidneys ,42,43.K. humboldtiana produced gross alterations in liver and lung. In liver, alterations consisted of degeneration of hepatocytes, necrosis of central zone, acute diffuse necrosis, congestion, and hemorrhage. In lungs, vascular congestion and hemorrhage were the principal findings [Acute experimental intoxication of mice with either fruit or isolated toxins T514 or T544 of K. humboldtiana fruit was given to rats, guinea-pigs, hamsters, and dogs. Interestingly, there were no clinical or histopathological evidence of damage in dogs. There is currently no explanation for this finding. Curiously, the coyote (Canis latrans), a species close to the dog, can eat the fruit of K. humboldtiana without becoming intoxicated. In fact, one of the common names for the plant is coyotillo [A single oral preparation of oyotillo . All othoyotillo .Several studies have attempted to clarify the mechanisms behind the histopathological findings described above. Garza-Ocañas et al.  assessedProduction of reactive oxygen species (ROS) by T514 was analyzed in primary liver cell cultures and microsomes. The protective role of two antioxidant enzymes, catalase (CAT) and superoxide dismutase (SOD), against T514 cytotoxicity was also investigated. Cytotoxicity was determined by the MTT assay. The dichlorofluorescein diacetate (DCFDA) fluorescent probe and the reduction of ferricytochrome c were used as indicators of intracellular ROS. T514 induced the production of ROS in both hepatocytes and microsomes. CAT and SOD had a protective effect in both in vitro systems. It was concluded that T514 leads to the formation of ROS, and that oxidative stress may be a mechanism of cytotoxicity of T514 .T514 injected intraperitoneally induced apoptosis in hepatocytes from mouse. Apoptosis occurred through the intrinsic mitochondrial apoptotic pathway. An increased expression of the pro-apoptotic markers p53, Bax, and Bak was observed, whereas a down regulation of the proliferating cell nuclear antigen (PCNA) and the anti-apoptotic molecule Bcl-2 occurred .K. humboldtiana seeds administered to rats resulted in a decrease in blood pressure, along with a marked reduction in renal perfusion pressure. Also, decrements of the glomerular filtration rate (GFR), renal plasma flow (RPF), and filtration fraction (FF), and an increment in the fractional excretion of sodium (FENa) were observed. These data suggest that the effect of K. humboldtiana in kidney is both on hemodynamic and epithelial parameters, since GFR, RPF, and FF are dependent on circulatory conditions, whereas FENa is mainly dependent on tubular epithelial function [A single oral dose of ground function .K. humboldtiana on kidney energetic metabolism was analyzed. In treated rats, the concentration of total proteins in renal tissue and the ATP concentration in renal cortex decreased significantly. Also, concentration of ATP in total blood and hemoglobin decreased significantly. These metabolic alterations might explain, at least partially, the mortality observed in the treated rats [Using the same experimental model mentioned in the last paragraph, the effect of ted rats .K. humboldtiana, García-Garza et al. [K. humboldtiana there is a damage in liver that may be reversible. In experimental chronic intoxication, damage in lung and kidney has also been observed. In lung, García et al. [On the other hand, in the liver of rats chronically poisoned with the fruit of a et al.  found nea et al.  found vaa et al. .K. humboldtiana fruit. In heart, some of the animals showed fatty degeneration involving all cardiac fibers, while other exhibited only areas of granular degeneration. Some fibers showed more advanced changes, like a greater eosinophilia of the sarcoplasm, or fragmented sarcoplasm with pyknotic nuclei. In skeletal muscles, alterations were more variable in severity, including vacuolar degeneration, sarcoplasm fragmentation, and proliferation of sarcolemmal nuclei with infiltration of macrophages and lymphocytes.Dewan et al.  describeK. humboldtiana fruit on pancreatic tissue of rat. In the exocrine pancreas, damage included a reduction in the number of zymogen granules, presence of autophagy-like vesicles, apoptosis, necrosis, and inflammatory infiltrate, culminating with a complete loss of acinar and lobular architecture. Of note, morphology of the islets of Langerhans was preserved.Carcano-Diaz et al.  examinedMouse embryos were exposed in vitro to T544 for 24 h. Alterations observed included encephalic dilatation, swelling and hemorrhage of the mandible, and kinky tail. Furthermore, a significant decrease in protein content was observed .K. humboldtiana toxins on the developing mouse embryo was analyzed in vivo. At day 8 of gestation, dams were injected intraperitoneally with either T514 or T544. Animals treated with T544 showed a significantly higher incidence of reabsorptions and malformations compared with control groups. Also, fetal crown-rump (CR) length and weight were significantly lower than controls. Malformations observed included lower limb deformities, abdominal evisceration, and exencephaly. The animals treated with T514 did not show significant differences compared with the controls. Thus, T514 had no teratogenic effects, which is important in view of its probable use as antineoplastic agent [Later, the effect of ic agent .Karwinskia cause damage mainly to nervous system, liver, lung, kidney, cardiac and skeletal muscles, pancreas, and to embryo and fetus. The pathophysiological mechanism has not been fully understood but includes metabolic and structural alterations that can lead cells to apoptosis or necrosis.In summary, toxins of Piñeyro-López et al.  analyzedHansenula polymorpha and Candida boidinii as model organisms. At sublethal doses (2 µg/mL), T514 caused an irreversible and selective damage of peroxisomes: disruptions appeared in the organelle membrane causing leakage of matrix proteins. Damaged peroxisomes were eliminated by macropexophagy . As menboidinii .Taking into account the works described above, a hypothesis was raised about the mechanism of action of PA1 as an anticancer agent: since PA1 attacks peroxisomes, and a significant number of malignant cell types contain fewer peroxisomes than normal cells ,88,89, tSeveral works have been carried out in order to deepen in the mechanism of action of PA1 as a potential anticancer agent. Since CAT is a peroxisomal marker enzyme, Moreno-Sepúlveda et al.  evaluateLater, the effect of PA1 on liver CAT in tissue fragments (in situ) and in mice poisoned intraperitoneally with isolated PA1 (in vivo) was reported. Results demonstrated that PA1 is not able to inhibit CAT activity in both situations. However, morphometric analysis showed that PA1 produce a decrease in the number of hepatic peroxisomes .In rats treated intraperitoneally with isolated PA1, morphometric analysis also demonstrated a significant decrease in the number of liver peroxisomes .In the experiments with yeasts described above in which peroxisomes were damaged by PA1, PA2, and T544 ,86, inhiTaken together, results of these studies suggested that PA1 causes a direct damage to peroxisomes, and that CAT is not directly involved in the effect of PA1 on malignant cells.Distribution of PA1 showed to be homogeneous on peroxisomal, mitochondrial, microsomal, and nuclear subcellular fractions prepared from rat liver treated with an acute dose of PA1 . Therefo1 cells. Since these kinds of cells are considered apoptotic, activation of the apoptotic machinery by PA1was investigated. Flow cytometry and Western blot analyses revealed that PA1 induced apoptosis in these leukemic cells. Collectively, the results suggested that inhibition of topoisomerase II plays a role in the mechanism of action of PA1 [The interaction of PA1 with DNA, and its inhibition on topoisomerase I and II, were examined using complementary biophysical and biochemical methods. The results showed that PA1 has practically no interaction with DNA. It also was found that PA1 inhibit topoisomerase II but not topoisomerase I. In order to assess the cytotoxic potential of PA1 and its effect on the cell cycle, two human leukemia cell lines, HL-60 and HL-60/MX2, were used. HL-60/MX2 cells have reduced topoisomerase II activity. Cell growth inhibition assays revealed a marked cytotoxic effect of PA1 on the HL-60 line, whereas HL-60/MX2 cells showed a reduced sensibility. Likewise, changes in the cell cycle were more pronounced in HL-60 cells than in HL-60/MX2 cells. These changes included the apparition of cells with a DNA content that was less than that of Gn of PA1 .Velazco et al.  analyzedH. polymorpha affected in the utilization of methanol as sole source of carbon and energy after their treatment with PA1. One of those strains was functionally complemented by means of transformation with a genomic library coming from H. polymorpha. The authors attributed these findings to the interaction of PA1 with yeast DNA, which had a mutagenic effect. Considering this work and those described in the previous two paragraphs [Vargas-Zapata et al.  isolatedragraphs ,95, it i2/M phases of cell cycle. These results indicated that PA1 inhibits proliferation and induces apoptosis in malignant cells in vitro [Another controversy that exists concerns the mode of cell death by which PA1 would kill cancer cells. In a study, seven malignant cell lines  were induced to die by PA1. In contrast, PA1 did not induce any significant increase of death in the non-tumorigenic cell lines Rat2 and BALB/3T3. Fluorescence microscopy with Hoechst 33,342 staining revealed chromatin condensation and nuclear fragmentation, characteristics of apoptosis, in the cells affected by PA1. Flow cytometry revealed the presence of cells with less than 2C DNA, another hallmark of apoptosis. This technique also demonstrated a significant accumulation of cells in Gin vitro . Previouin vitro ).TC-1 tumor cells were implanted subcutaneously into the hind limb of mice. The treatment group received PA1 injected intraperitoneally at days 2, 4, 6, and 8 post-implantation. Tissue samples from the implantation site and from liver, lungs, and kidneys were collected at day 10 after TC-1 cells were implanted; at that time, a tumor cannot yet be detected. Samples were processed for light and electron microscopy, and by TUNEL assay to detect apoptosis. Analysis of the implantation site by light microscopy revealed characteristics of necrosis in TC-1 cells, such as the presence of pyknotic nuclei. Morphological characteristics of necrosis were also found by electron microscopy, since tumor cells showed pyknotic nuclei with rupture of the nuclear envelope, swollen mitochondria with loss of matrix, and rupture of the plasma membrane and leakage of cytoplasm. TUNEL reaction was negative. Control group, in which PA1 was not administered, showed integrity of TC-1 cells. Liver, lungs, and kidneys showed no alterations in both groups. These results indicate that, in vivo, PA1 causes the death of malignant cells by necrosis, and that this toxicity is selective, since liver, lungs, and kidneys showed no alterations. According to the authors of this work, the differences between this and in vitro studies, in which cancer cells die by apoptosis, could be due to the concentration of PA1 that reaches the cells, which could be higher in vitro than in vivo. Regarding selectivity, the difference with other studies in which several organs were damaged by PA1 was attributed to the use of lower doses of PA1 in this study, and also to the fact that doses were administered early after cell implantation . InteresOn the other hand, the metabolism of PA1 has also been analyzed. The metabolism of this compound was evaluated in vitro in rat and monkey liver microsomes, and in rat and human primary cultured hepatocytes. Microsomes and hepatocytes were incubated with PA1 and the samples were analyzed using HPLC and UV spectra. Two major metabolites  were found and isolated. Afterwards, Chang liver and Hep G2 cells were exposed to PA1 and metabolites M1 and M2. The metabolites were less toxic than PA1 and did not show the same selective cytotoxicity on tumor cells as PA1. These data indicate that M1 and M2 are not involved in the selective effect of PA1 .Since the pharmacology and pharmacokinetics of a drug depend on the degree to which it bounds to plasma proteins, the interaction of PA1 with human serum albumin (HSA) and bovine serum albumin (BSA) was investigated using spectrophotometric methods. Results indicated that PA1 binds to both HAS and BSA at physiological pH; binding is stronger with the former. From titration analysis of HAS or BSA with PA1, it was determined that both albumins have two types of binding sites for PA1. Titrations were performed at four different temperatures, and thermodynamic parameters suggested that binding occurs through hydrogen bonding and hydrophobic interactions .Finally, in a clinical phase I study, patients with recurrent cervical cancer treated with PA1 showed stable disease and increased survival time . PatentsIn summary, T514 (PA1) has shown selective toxicity in vitro against human cancer cells. More research is needed, but the evidence obtained so far indicates that PA1 could be an effective anticancer agent.Karwinskia plants have been previously isolated and well characterized, including toxins T496, T514, T516, and T544, and several related compounds, such as peroxisomicine A2, peroxisomicine A3, isoperoxisomicines A1 and A2, toxin T510, and tullidinol B1 and B2. However, there is relatively little information about the mechanisms of action by which these substances exert their detrimental effects. Additionally, literature related to the potential antineoplastic effect of T514 or PA1 is scarce and sometimes contradictory. The main bioactive agents of Karwinskia cause damage mainly to nervous system, liver, lung, kidney, cardiac and skeletal muscles, pancreas, and to embryo and fetus. In the future, research regarding damage provoked by Karwinskia toxins must be focused in obtaining easily accessible diagnostic methods and effective treatments. Studies devoted to finding the specific targets of the toxins, as well as those that analyze in depth the metabolism of the latter in the organism, can be very useful. Toxins of On the other hand, T514 has shown selective toxicity in vitro against human cancer cells. T514 causes an irreversible and selective damage of peroxisomes (for this reason it was renamed peroxisomicine A1 or PA1) and since a significant number of malignant cell types contain fewer peroxisomes than normal cells, tumor cells could be more easily destroyed than healthy cells. As a perspective, analyzes involving animal cancer models, and the performance of more clinical trials, are necessary to know the true therapeutic value of PA1. Despite these limitations, the evidence obtained so far indicates that PA1 could be an effective anticancer agent.


Adropin is a secretory protein encoded by the energy balance gene and is closely associated with regulation of energy metabolism and insulin resistance. The clinical findings demonstrated its decreased expression in various inflammatory diseases, its negative correlation with the expression levels of inflammatory cytokines, and its potential anti-inflammatory effects. We speculate that adropin plays a pivotal regulatory role in immune cells and inflammatory factors. In this study, we reviewed the advances in researches concentrated on immunological effects of adropin. Adropin is a peptide hormone encoded by the energy homeostasis-associated (ENHO) gene. The nomenclature of adropin is derived from the Latin roots “aduro” and “pinquis,” meaning “promoting fat burning,” with identical amino acid sequences in humans and mice . At presμg/L, in which its expression level in males is slightly higher than that in females [The expression level of adropin in normal human plasma is 1-10  females . Meanwhi females .A number of scholars studied functions of adropin, while they have mainly concentrated on metabolic disorders and cardiovascular diseases. Adropin enhances glucose oxidation and ameliorates metabolic inflexibility of utilizing glucose in obese and insulin-resistant mice. The underlying mechanisms appear to involve suppressions of carnitine palmitoyltransferase-1B (CPT-1B) and CD36, two key enzymes in fatty acid utilization. Adropin treatment activates pyruvate dehydrogenase (PDH), a rate-limiting enzyme in glucose oxidation, and downregulates PDH kinase-4 (PDK-4) that inhibits PDH . AdropinObesity intervention results from a persistent energy imbalance. Adipose tissue is increasingly considered as a key regulator of energy balance and is a “crossroad” of energy homeostasis, inflammation, and atherosclerosis . If the α (TNF-α), a multifunctional proinflammatory cytokine that plays a significant role in the inflammatory process [γ (PPAR-γ) in the adipose tissues and liver, and is a main regulator of lipogenesis as well. Besides, PPAR-γ was found to be significantly decreased in mice with overexpression of adropin [Numerous studies demonstrated that visceral adipose tissue is associated with macrophages in chronic inflammatory conditions around the adipocytes, and infiltration of visceral adipose tissues by proinflammatory macrophages is a key event driving adipose-tissue inflammation and insulin resistance . The mac process , 17. The process . Adropin adropin . Thus, aTreg cells are involved in controlling the inflammatory state of adipose tissues. Treg cells are the main cells responsible for the negative regulation of immune-mediated inflammation. It is involved in the negative regulation of autoimmune diseases, allergies, acute, and chronic infections, cancer, and metabolic inflammation. In obese mice, the number of Treg cells in adipose tissue is strikingly reduced, and the imbalance of immune cells leads to fat inflammation. Meanwhile, the decrease of Treg cells in adipose tissue also leads to the occurrence of insulin resistance, so it is believed that Treg cells play an important role in metabolic regulation , 21. Addγ is highly expressed in adipose tissues and plays an irreplaceable role in adipocyte differentiation, and is involved in fatty acid metabolism. In addition, activation of PPAR-γ has potential effects on the expressions and secretions of numerous factors, including reducing expressions and secretions of adipokines, such as adiponectin and resisting, and proinflammatory cytokines , TNF-α, and monocyte chemotactic protein-1 (MCP-1)); MCP-1 and TNF-α can induce macrophage infiltration and inflammation [γ may reduce macrophage infiltration and inflammation of adipose tissues. The study demonstrated that adropin regulates the anti-inflammatory or proinflammatory phenotypes of macrophages by up-regulating the expression of PPAR-γ [γ expression is often unclear, PPAR-γ may be an important target for adropin to exert anti-inflammatory effects  at the mRNA level in pancreatic tissues of diabetic rats [α) in women with PCOS [Adropin plays a significant role in other metabolic disorders, such as diabetic nephropathy, polycystic ovary syndrome (PCOS), etc. Studies indicated that adropin can significantly reduce the expressions of TNF-tic rats , 29. Furith PCOS . The aboα-induced adhesion of THP1 monocytes to endothelial cells in the process of atherosclerosis. With impeding monocyte-endothelial cell interactions, it can inhibit the inflammatory response of endothelial cells and monocytes/macrophages. With regulation of the phenotype of macrophages, it exerts proinflammatory or anti-inflammatory effects on atherosclerosis. In terms of energy metabolism, metabolic disorders caused by insulin resistance or inflammation leads to activations of inflammatory transcription factor nuclear factor kB (NF-κB) and inflammatory signaling system, as well as elevated levels of cytokines, thereby accelerating the damage to function of endothelial cells and formation of atherosclerotic plaques [Studies on the correlation between adropin and pathogenesis of cardiovascular diseases mainly concentrated on the protection and regulation of function of endothelial cells by adropin. Adropin can also upregulate the expression level of eNOS by upregulating PI3K/Akt and extracellular signal-regulated kinase (ERK) signal transduction pathways in vitro and in vivo, thereby increasing bioavailability of NO . On the  plaques . As a reα and IL-6 at the mRNA level by regulating the expression of iNOS, thereby exerting anti-inflammatory effects on the atherosclerosis. (3) CD36: CD36, which can be downregulated by adropin, is a multi-ligand and multifunctional inflammatory receptor that induces inflammatory responses through activation of various ligands and cellular responses; for example, the interaction with fibrillar β-amyloid (fAβ)/integrin can induce an inflammatory response by increasing expressions of proinflammatory cytokines and chemokines; CD36 receptor for oxidized low-density lipoprotein (oxLDL) can alter cytoskeletal dynamics, enhance macrophage spreading, and inhibit migration. This may result in macrophages being captured in the endarterium, as well as further promoting atherosclerosis [Additionally, in studies on cardiovascular diseases, such as coronary artery disease (CAD) and atherosclerosis, scholars found that adropin has a significant negative correlation with homocysteine (Hcy), hypersensitive C-reactive protein (hs-CRP), and levels of cytokines. (1) Hcy: Hcy is known to mediate cardiovascular problems by its adverse effects on cardiovascular endothelium and smooth muscle cells with resultant alterations in subclinical arterial structure and function. Serum Hcy level is negatively correlated with serum adropin level in CAD patients . Hyperhoclerosis , 35, 36.In addition to metabolic disorders and cardiovascular diseases, adropin has been shown as a potential anti-inflammatory factor in other inflammatory diseases. Gao et al.  demonstrα level, white blood cell (WBC) count, and neutrophil-lymphocyte ratio (NLR) [α, thereby applying its anti-inflammatory effects [It was previously revealed that adropin can inhibit hepatic cell inflammation in hyperlipidemia rats . In AdrKio (NLR) . The und effects .Adropin has the effect of antioxidative stress. Study has shown that adropin deficiency correlates with increased oxidative stress associated with endothelial dysfunction in the brain of rats . MeanwhiAt present, studies concentrated on adropin protein and its functions are still in the preliminary stage. However, there is increasing evidence that adropin is highly associated with various inflammatory diseases, and is also involved in the inflammatory process of different diseases. Moreover, it plays a substantial role in regulating the phenotype and biological behavior of immune cells, in addition to the secretion of inflammatory cytokines. The specific mechanisms have not been fully and systematically elucidated, and a larger sample size is also required to confirm the immunomodulatory effects of adropin. Nevertheless, as a potential anti-inflammatory protein, its immunological effects should be investigated in the future researches.