Quantification of finger grasps during activities of daily life using convolutional neural networks: A pilot study.

Quantifying finger kinematics can improve the authors' understanding of finger function and facilitate the design of efficient prosthetic devices while also identifying movement disorders and assessing the impact of rehabilitation interventions. Here, the authors present a study that quantifies grasps depicted in taxonomies during selected Activities of Daily Living (ADL). A single participant held a series of standard objects using specific grasps which were used to train Convolutional Neural Networks (CNN) for each of the four fingers individually. The experiment also recorded hand manipulation of objects during ADL. Each set of ADL finger kinematic data was tested using the trained CNN, which identified and quantified the grasps required to accomplish each task. Certain grasps appeared more often depending on the finger studied, meaning that even though there are physiological interdependencies, fingers have a certain degree of autonomy in performing dexterity tasks. The identified and most frequent grasps agreed with the previously reported findings, but also highlighted that an individual might have specific dexterity needs which may vary with profession and age. The proposed method can be used to identify and quantify key grasps for finger/hand prostheses, to provide a more efficient solution that is practical in their day-to-day tasks.

Electrical impedance tomography image reconstruction for lung monitoring based on ensemble learning algorithms.

Electrical impedance tomography (EIT) is a promising non-invasive imaging technique that visualizes the electrical conductivity of an anatomic structure to form based on measured boundary voltages. However, the EIT inverse problem for the image reconstruction is nonlinear and highly ill-posed. Therefore, in this work, a simulated dataset that mimics the human thorax was generated with boundary voltages based on given conductivity distributions. To overcome the challenges of image reconstruction, an ensemble learning method was proposed. The ensemble method combines several convolutional neural network models, which are the simple Convolutional Neural Network (CNN) model, AlexNet, AlexNet with residual block, and the modified AlexNet model. The ensemble models' weights selection was based on average technique giving the best coefficient of determination (R2 score). The reconstruction quality is quantitatively evaluated by calculating the root mean square error (RMSE), the coefficient of determination (R2 score), and the image correlation coefficient (ICC). The proposed method's best performance is an RMSE of 0.09404, an R2 score of 0.926186, and an ICC of 0.95783 using an ensemble model. The proposed method is promising as it can construct valuable images for clinical EIT applications and measurements compared to previous studies.

S100A7 Orchestrates Neutrophil Chemotaxis and Drives Neutrophil Extracellular Traps (NETs) Formation to Facilitate Lymph Node Metastasis in Cervical Cancer Patients.

Neutrophil extracellular traps (NETs) have been shown to promote the metastatic potential of many kinds of tumors. Our study aimed to investigate the role and mechanisms of NETs in lymph node metastasis (LNM) of cervical cancer (CCa), and evaluated the therapeutic value of targeting NETs in CCa. Immunohistochemistry demonstrated that neutrophil infiltration and NETs formation were increased in CCa patients with LNM, as well as confirming a positive correlation between S100A7 expression and neutrophil infiltration in CCa. NETs enhanced the migratory capability of CCa by activating the P38-MAPK/ERK/NFκB pathway through interaction with TLR2. Digesting NETs with deoxyribonuclease 1 (DNase 1) or inhibiting TLR2 with chloroquine eliminated the NETs-induced metastatic potential of CCa. Additionally, NETs promoted lymphangiogenesis and increased the permeability of lymphatic vessels, thus facilitating translymphatic movement of CCa. CCa-derived S100A7 exhibited a chemotactic effect on neutrophils and promoted NETs generation by elevating ROS levels rather than activating autophagy in neutrophils. The mouse model with footpad implantation illustrated that DNase 1 effectively reduced LNM in LPS-induced mice and in mice seeded with S100A7-overexpressing CCa cells. In conclusion, our study reveals a new tumor-promoting mechanism of S100A7, clarifies the crucial role and mechanism of NETs in LNM of CCa, and indicates that the NETs-targeted therapy emerges as a promising anti-metastasis therapy in CCa.

AAV-mouse DNase I sustains long-term DNase I expression in vivo and suppresses breast cancer metastasis.

Neutrophil extracellular traps (NETs) have been implicated in the pathology of various inflammatory conditions. In cancer, NETs have been demonstrated to induce systemic inflammation, impair peripheral vessel and organ function and promote metastasis. Here we show that the plasma level of NETs is significantly higher in patients with metastatic breast cancer compared to those with local disease, or those that were considered cured at a 5-year follow-up, confirming NETs as interesting therapeutic targets in metastatic breast cancer. Administration of DNase I is one strategy to eliminate NETs but long-term treatment requires repeated injections and species-specific versions of the enzyme. To enhance administration and therapeutic efficacy, we have developed an adeno-associated virus (AAV) vector system for delivery of murine DNase I and addressed its potential to counteract cancer-associated pathology in the murine MMTV-PyMT model for metastatic mammary carcinoma. The AAV vector is comprised of capsid KP1 and an expression cassette encoding hyperactive murine DNase I (AAV-mDNase I) under the control of a liver-specific promotor. This AAV-mDNase I vector could support elevated expression and serum activity of murine DNase I over at least 8 months. Neutrophil Gelatinase-Associated Lipocalin (NGAL), a biomarker for kidney hypoperfusion that is upregulated in urine from MMTV-PyMT mice, was suppressed in mice receiving AAV-mDNase I compared to an AAV-null control group. Furthermore, the proportion of mice that developed lung metastasis was reduced in the AAV-mDNase I group. Altogether, our data indicate that AAV-mDNase I has the potential to reduce cancer-associated impairment of renal function and development of metastasis. We conclude that AAV-mDNase I could represent a promising therapeutic strategy in metastatic breast cancer.

Genetic determinants of antidepressant and antipsychotic drug response.

Today, more than 90% of inpatients hospitalized with Major Depression or Schizophrenia are treated with psychotropic drugs. Since none of the treatment options is causal, response rates are modest and the course of recovery is very heterogeneous. Genetic studies on the etiology and pathogenesis of major psychiatric disorders over the past decades have been largely unsuccessful. Likewise, genetic studies to predict response to psychopharmacological treatment have also not been particularly successful. In this project we have recruited 902 inpatients with ICD-10 diagnoses of schizophrenic ("F2 patients") or depressive disorders ("F3 patients"). The study assessed today's acute inpatient treatment regimens with up to 8 repeated measurements regarding the time course of recovery and adverse side effects. The genotyping included 100 candidate genes with genotypic patterns computed from 549 Single Nucleotide Polymorphisms (SNPs). To predict response to psychopharmacological treatment, we relied on a multidimensional approach to analyzing genetic diversity in combination with multilayer Neural Nets (NNs). Central to this new method were the "gene vectors" that (1) assessed the multidimensional genotypic patterns observed with genes; and (2) evaluated the correlations between genes. By means of these methods, we searched for combinations of multidimensional genotypic patterns that were characteristic of treatment responders while being rare among non-responders. The chosen method of approach provided a powerful technique to detail the complex structures of SNP data that are not detectable by conventional association methods. Molecular-genetic NNs enabled correct classification of 100% "non-responders", along with 94.7% correctly classified "responders" among the F2 patients, and 82.6% correctly classified "responders" among the F3 patients. The F2 and F3 classifiers were not disjoint but showed an overlap of 29.6% and 35.7% between the diagnostic groups, thus indicating that clinical diagnoses may not constitute etiologic entities. Our results suggested that patients may have an unspecific physical-genetic disposition that enables, facilitates, impedes or prevents recovery from major psychiatric disorders by setting various thresholds for exogenous triggers that initiate improvement ("recovery disposition"). Even though this disposition is not causally linked to recovery, it can nonetheless be clinically used in the sense of a "surrogate". Indeed, clinicians are also interested in reliable tools that can "do the job", despite the fact that etiology and pathogenesis of the treated disorders remain unknown.

Perineuronal Net Alterations Following Early-Life Stress: Are Microglia Pulling Some Strings?

The extracellular matrix plays a key role in synapse formation and in the modulation of synaptic function in the central nervous system. Recent investigations have revealed that microglia, the resident immune cells of the brain, are involved in extracellular matrix remodeling under both physiological and pathological conditions. Moreover, the dysregulation of both innate immune responses and the extracellular matrix has been documented in stress-related psychopathologies as well as in relation to early-life stress. However, the dynamics of microglial regulation of the ECM and how it can be impacted by early-life adversity have been understudied. This brief review provides an overview of the recent literature on this topic, drawing from both animal model and human post mortem studies. Direct and indirect mechanisms through which microglia may regulate the extracellular matrix-including perineuronal nets-are presented and discussed in light of the interactions with other cell types.

Association of corticosteroid therapy with reduced acute kidney injury and lower NET markers in severe COVID-19: an observational study.

BACKGROUND: Acute kidney injury (AKI) is common in critical cases of coronavirus disease 2019 (COVID-19) and associated with worse outcome. Dysregulated neutrophil extracellular trap (NET) formation is one of several suggested pathophysiological mechanisms involved in the development of COVID-19 associated AKI. The corticosteroid dexamethasone was implemented as a standard treatment for severe COVID-19 as of June 2020. A sub-analysis of a prospective observational single center study was performed to evaluate the effect of corticosteroid treatment on AKI development and NET markers in critical cases of COVID-19. RESULTS: Two hundred and ten adult patients admitted to intensive care at a tertiary level hospital due to respiratory failure or shock secondary to SARS-CoV-2-infection between March 13th 2020 and January 14th 2021 were included in the study. Ninety-seven of those did not receive corticosteroids. One hundred and thirteen patients were treated with corticosteroids [dexamethasone (n = 98) or equivalent treatment (n = 15)], but the incidence of AKI was assessed only in patients that received corticosteroids before any registered renal dysfunction (n = 63). Corticosteroids were associated with a lower incidence of AKI (19% vs 55.8%, p < 0.001). Fewer patients demonstrated detectable concentrations of extracellular histones in plasma when treated with corticosteroids (8.7% vs 43.1%; p < 0.001). Extracellular histones and in particular non-proteolyzed histones were observed more frequently with increasing AKI severity (p < 0.001). MPO-DNA was found in lower concentrations in patients that received corticosteroids before established renal dysfunction (p = 0.03) and was found in higher concentrations in patients with AKI stage 3 (p = 0.03). Corticosteroids did not ameliorate established AKI during the first week of treatment. CONCLUSION: Corticosteroid treatment in severe COVID-19 is associated with a lower incidence of AKI and reduced concentrations of NET markers in plasma.

Neutrophils: a key component in ECMO-related acute organ injury.

Extracorporeal membrane oxygenation (ECMO), as an extracorporeal life support technique, can save the lives of reversible critically ill patients when conventional treatments fail. However, ECMO-related acute organ injury is a common complication that increases the risk of death in critically ill patients, including acute kidney injury, acute brain injury, acute lung injury, and so on. In ECMO supported patients, an increasing number of studies have shown that activation of the inflammatory response plays an important role in the development of acute organ injury. Cross-cascade activation of the complement system, the contact system, and the coagulation system, as well as the mechanical forces of the circuitry are very important pathophysiological mechanisms, likely leading to neutrophil activation and the production of neutrophil extracellular traps (NETs). NETs may have the potential to cause organ damage, generating interest in their study as potential therapeutic targets for ECMO-related acute organ injury. Therefore, this article comprehensively summarized the mechanism of neutrophils activation and NETs formation following ECMO treatment and their actions on acute organ injury.

Neutrophil-fibroblast crosstalk drives immunofibrosis in Crohn's disease through IFNα pathway.

Introduction: Crohn's disease (CD) is characterized by chronic inflammation and intestinal fibrosis leading to lifelong complications. However, the disease pathogenesis remains elusive, and the therapeutic options are limited. Here, we investigated the interaction between neutrophils and intestinal fibroblasts in the development of CD immunofibrosis, a disease mechanism predisposing to inflammatory and fibrotic complications. Methods: Peripheral neutrophils, enriched neutrophil extracellular traps (eNETs), serum, primary intestinal fibroblasts (PIFs) and intestinal biopsies from CD, ulcerative colitis (UC) patients, and healthy individuals (HI), were studied. Transcriptome analysis of neutrophils, multi-cytokine profiling and cell-based functional assays at mRNA/protein level were performed. Results: Compared to UC, PIFs from CD patients, independently to the presence of strictures, displayed a distinct pro-fibrotic phenotype characterized by negative Krüppellike Factor-2 (KLF2) and increased cellular communication network factor-2 (CCN2) expression leading to collagen production. In both UC and CD, PIFs-derived IL-8 acted as a culprit chemoattractant for neutrophils in the intestine, where CD neutrophils were accumulated close to fibrotic lesions. Functionally, only CD neutrophils via eNETs induced a CD-like phenotype in HI PIFs, suggesting their fibrotic plasticity. High IFNa in serum and IFΝ-responsive signature in peripheral neutrophils were observed in CD, distinguishing it from UC. Moreover, CD serum stimulated the release of fibrogenic eNETs from neutrophils in an IFNa-dependent manner, suggesting the priming role of IFNa in circulating neutrophils. Inhibition of eNETs or JAK signaling in neutrophils or PIFs prevented the neutrophil-mediated fibrotic effect on PIFs. Furthermore, both serum IFNa levels and mRNA levels of key IFN signaling components in neutrophils were wellcorrelated with CD severity. Conclusions: This study reveals the important role of the IFNa/neutrophil/fibroblast axis in CD immunofibrosis, suggesting candidate biomarkers and putative therapeutic targets.

A Return to Biased Nets: New Specifications and Approximate Bayesian Inference.

The biased net paradigm was the first general and empirically tractable scheme for parameterizing complex patterns of dependence in networks, expressing deviations from uniform random graph structure in terms of latent "bias events," whose realizations enhance reciprocity, transitivity, or other structural features. Subsequent developments have introduced local specifications of biased nets, which reduce the need for approximations required in early specifications based on tracing processes. Here, we show that while one such specification leads to inconsistencies, a closely related Markovian specification both evades these difficulties and can be extended to incorporate new types of effects. We introduce the notion of inhibitory bias events, with satiation as an example, which are useful for avoiding degeneracies that can arise from closure bias terms. Although our approach does not lead to a computable likelihood, we provide a strategy for approximate Bayesian inference using random forest prevision. We demonstrate our approach on a network of friendship ties among college students, recapitulating a relationship between the sibling bias and tie strength posited in earlier work by Fararo.

Neutrophil extracellular traps and citrullinated fibrinogen contribute to injury in a porcine model of limb ischemia and reperfusion.

Background: Ischemia/reperfusion injury (IRI) is a complex pathological process, triggered by the restoration of blood flow following an interrupted blood supply. While restoring the blood flow is the only option to salvage the ischemic tissue, reperfusion after a prolonged period of ischemia initiates IRI, triggering a cascade of inflammatory responses ultimately leading to neutrophil recruitment to the inflamed tissue, where they release neutrophil extracellular traps (NETs). NETs are web-like structures of decondensed chromatin and neutrophilic proteins, including peptidyl-arginine deiminase 2 and 4 (PAD2, PAD4), that, once outside, can citrullinate plasma proteins, irreversibly changing their conformation and potentially their function. While the involvement of NETs in IRI is known mainly from rodent models, we aimed to determine the effect of NET formation and especially PADs-mediated extracellular protein citrullination in a porcine model of limb IRI. Methods: We conducted our study on amputated pig forelimbs exposed to 1 h or 9 h of ischemia and then reperfused in vivo for 12 h. Limb weight, edema formation, compartmental pressure were measured, and skeletal muscle was analyzed by immunofluorescence (TUNEL assay and dystrophin staining) to evaluate tissue damage. Fibrin tissue deposition, complement deposition and NETs were investigated by immunofluorescence. Citrullinated plasma proteins were immunoprecipitated and citrullinated fibrinogen was identified in the plasma by Western blot and in the tissue by immunofluorescence and Western blot. Results: Our data consolidate the involvement of NETs in a porcine model of limb IRI, correlating their contribution to damage extension with the duration of the ischemic time. We found a massive infiltration of NETs in the group subjected to 9 h ischemia compared to the 1 h and citrullinated fibrinogen levels, in plasma and tissue, were higher in 9 h ischemia group. We propose fibrinogen citrullination as one of the mechanisms contributing to the worsening of IRI. NETs and protein citrullination represent a potential therapeutic target, but approaches are still a matter of debate. Here we introduce the idea of therapeutic approaches against citrullination to specifically inhibit PADs extracellularly, avoiding the downstream effects of hypercitrullination and keeping PADs' and NETs' intracellular regulatory functions.

AOC3 accelerates lung metastasis of osteosarcoma by recruiting tumor-associated neutrophils, neutrophil extracellular trap formation and tumor vascularization.

Osteosarcoma (OS) has strong invasiveness, early metastasis, high drug resistance, and poor prognosis. At present, OS still lacks reliable biomarkers, which makes early diagnosis of OS more difficult. AOC3 is highly expressed in OS and highly correlated with lung metastasis. qRT-PCR could identify mRNA levels of genes. Immunohistochemistry and Western blot assays could detect protein levels. Immunofluorescence and ELISA assays were applied to evaluate the activation of neutrophils. Additionally, transwell and wound healing assays evaluated cell migration and invasion abilities. Tube formation and sphere-forming assays were applied to detect the angiogenesis. C57BL/6 mice were injected with OS cells to establish a xenograft tumor model to observe the lung metastasis of OS. Flow cytometry is used to evaluate the ability of tumor cells to recruit neutrophils. AOC3 was significantly overexpressed in OS, and down-regulation of AOC3 could inhibit OS migration, invasion, and angiogenesis. AOC3 could increase tumor development and lung metastasis of OS in vivo experiments. The promoting effect of AOC3 on tumor lung metastasis was achieved by recruiting tumor neutrophils. Activated NETs could up-regulate the metastatic ability of OS cells. Tumor neovascularization also played a role in metastasis, and AOC3 supported tumor neovascularization. AOC3 accelerates lung metastasis of OS by recruiting tumor-related neutrophils and utilizing NETs and tumor vascularization formation.

Microglia inversely regulate the level of perineuronal nets with the treatment of lipopolysaccharide and valproic acid.

Perineuronal nets (PNNs) are extracellular matrix which mostly surround the inhibitory neurons. They are changed in several brain diseases, such as autism spectrum disorder, but the mechanism of PNNs degradation is still unclear. In this study, we investigated the role of microglial cells in regulating PNNs levels. Specifically, 1 day or 3 days after a single dose of lipopolysaccharide (LPS, 0.25 mg/kg) increased the density of microglia and further reduced the density of PNNs in both hippocampus CA1 and visual cortex. Minocycline, an inhibitor of microglia activation, took effect time-dependently. Minocycline for 7 days before a single LPS injection (0.25 mg/kg) inhibited microglia increase and PNNs loss, but minocycline for 3 days did not work. Finally, in a valproic acid (VPA)-treated autism mouse model, microglia were reduced while PNNs+ cells were increased in both hippocampus CA1 and visual cortex. In summary, the microglia are involved in the balanced level of PNNs, while in the autism model, the altered level of PNNs might be due to the microglia hypofunction.

COVID-19 mRNA vaccines induce robust levels of IgG but limited amounts of IgA within the oronasopharynx of young children.

BACKGROUND: Understanding antibody responses to SARS-CoV-2 vaccination is crucial for refining COVID-19 immunization strategies. Generation of mucosal immune responses, including mucosal IgA, could be of potential benefit to vaccine efficacy, yet limited evidence exists regarding the production of mucosal antibodies following the administration of current mRNA vaccines to young children. METHODS: We measured the levels of antibodies against SARS-CoV-2 from a cohort of children under 5 years of age (N=24) undergoing SARS-CoV-2 mRNA vaccination (serially collected, matched serum and saliva samples) or in a convenience sample of children under 5 years of age presenting to pediatric emergency department (nasal swabs, N=103). Further, we assessed salivary and nasal samples for the ability to induce SARS-CoV-2 spike-mediated neutrophil extracellular traps (NET) formation. RESULTS: Longitudinal analysis of post-vaccine responses in saliva revealed the induction of SARS-CoV-2 specific IgG but not IgA. Similarly, SARS-CoV-2 specific IgA was only observed in nasal samples obtained from previously infected children with or without vaccination, but not in vaccinated children without a history of infection. In addition, oronasopharyngeal samples obtained from children with prior infection were able to trigger enhanced spike-mediated NET formation, and IgA played a key role in driving this process. CONCLUSIONS: Despite the induction of specific IgG in the oronasal mucosa, current intramuscular vaccines have limited ability to generate mucosal IgA in young children. These results confirm the independence of mucosal IgA responses from systemic humoral responses following mRNA vaccination and suggest potential future vaccination strategies for enhancing mucosal protection in this young age group.

Calpain-1 weakens the nuclear envelope and promotes the release of neutrophil extracellular traps.

The inducers of neutrophil extracellular trap (NET) formation are heterogeneous and consequently, there is no specific pathway or signature molecule indispensable for NET formation. But certain events such as histone modification, chromatin decondensation, nuclear envelope breakdown, and NET release are ubiquitous. During NET formation, neutrophils drastically rearrange their cytoplasmic, granular and nuclear content. Yet, the exact mechanism for decoding each step during NET formation still remains elusive. Here, we investigated the mechanism of nuclear envelope breakdown during NET formation. Immunofluorescence microscopic evaluation revealed a gradual disintegration of outer nuclear membrane protein nesprin-1 and alterations in nuclear morphology during NET formation. MALDI-TOF analysis of NETs that had been generated by various inducers detected the accumulation of nesprin-1 fragments. This suggests that nesprin-1 degradation occurs before NET release. In the presence of a calpain-1, inhibitor nesprin-1 degradation was decreased in calcium driven NET formation. Microscopic evaluation confirmed that the disintegration of the lamin B receptor (LBR) and the collapse of the actin cytoskeleton occurs in early and later phases of NET release, respectively. We conclude that the calpain-1 degrades nesprin-1, orchestrates the weakening of the nuclear membrane, contributes to LBR disintegration, and promoting DNA release and finally, NETs formation.

The therapeutic targets and signaling mechanisms of ondansetron in the treatment of critical illness in the ICU.

Background: There is accumulating evidence regarding the benefits of the 5-HT3 receptor antagonist ondansetron for the treatment of critical illness due to its potential anti-inflammatory effect. This study attempted to determine the potential targets and molecular mechanisms of ondansetron's action against critical illnesses. Methods: A bioinformatics analysis of network pharmacology was conducted to demonstrate screening targets and the signaling pathways of ondansetron action against the most common critical illnesses such as acute kidney injury (AKI), sepsis, and acute respiratory distress syndrome (ARDS). Experiments of LPS-stimulated rat neutrophils with ondansetron treatment were conducted to further validate the relevant hypothesis. Results: A total of 198, 111, and 26 primary causal targets were identified from the data for the action of ondansetron against AKI, sepsis, and ARDS respectively. We found that the pathway of neutrophil extracellular traps (NETs) formation is statistically significantly involved in the action of ondansetron against these three critical illnesses. In the pathway of NETs formation, the common drug-disease intersection targets in these three critical illnesses were toll-like receptor 8 (TLR8), mitogen-activated protein kinase-14 (MAPK14), nuclear factor kappa-B1 (NFKB1), neutrophil elastase (NE), and myeloperoxidase (MPO). Considering these bioinformatics findings, we concluded that ondansetron anti-critical illness effects are mechanistically and pharmacologically implicated with suppression of neutrophils-associated inflammatory processes. It was also showed that after treatment of LPS-stimulated rat neutrophils with ondansetron, the key proteins NE, MPO, and Peptide Arginine Deaminase 4 (PAD4) in the NETs formation were significantly reduced, and the inflammatory factors IL-6, IL-1ß, TNF-α, and chemokine receptor (CXCR4) were also significantly decreased. Conclusion: The excessive formation of NETs may have important research value in the development and progression of critical illness. Ondansetron may reduce excessive inflammatory injury in critical diseases by reducing the formation of NETs via influencing the five targets: TLR8, NFKB1, MAPK14, NE, and MPO. Ondansetron and these primary predictive biotargets may potentially be used to treat critical illness in future clinical practice.

Leishmania amazonensis-derived extracellular vesicles (EVs) induce neutrophil extracellular traps (NETs).

Neutrophils interact with Leishmania when the sandfly vector inoculates these parasites in the host with saliva and promastigotes-derived extracellular vesicles (EVs). It has been shown that this co-injection induces inflammation and exacerbates leishmaniasis lesions. EVs are a heterogeneous group of vesicles released by cells that play a crucial role in intercellular communication. Neutrophils are among the first cells to interact with the parasites and release neutrophil extracellular traps (NETs) that ensnare and kill the promastigotes. Here, we show that Leishmania amazonensis EVs induce NET formation and identify molecular mechanisms involved. We showed the requirement of neutrophils' Toll-like receptors (TLRs) for EVs-induced NET. EVs carrying the virulence factors lipophosphoglycan (LPG) and the zinc metalloproteases were endocytosed by some neutrophils and snared by NETs. EVs-induced NET formation required reactive oxygen species, myeloperoxidase, elastase, peptidyl arginine deiminase (PAD), and Ca++. The proteomic analysis of the EVs cargo revealed 1,189 proteins; the 100 most abundant identified comprised some known Leishmania virulent factors. Importantly, L. amazonensis EVs-induced NETs lead to the killing of promastigotes and could participate in the exacerbated inflammatory response induced by the EVs, which may play a role in the pathogenesis process.

Theranostics in Neuroendocrine Tumors: Updates and Emerging Technologies.

Advancements in somatostatin receptor (SSTR) targeted imaging and treatment of well-differentiated neuroendocrine tumors (NETs) have revolutionized the management of these tumors. This comprehensive review delves into the current practice, discussing the use of the various FDA-approved SSTR-agonist PET tracers and the predictive imaging biomarkers, and elaborating on Lu177-DOTATATE peptide receptor radionuclide therapy (PRRT) including the evolving areas of post-therapy imaging practices, PRRT retreatment, and the potential role of dosimetry in optimizing patient treatments. The future directions sections highlight ongoing research on investigational PET imaging radiotracers, future prospects in alpha particle therapy, and combination therapy strategies.

Mitochondrial Plasticity and Glucose Metabolic Alterations in Human Cancer under Oxidative Stress-From Viewpoints of Chronic Inflammation and Neutrophil Extracellular Traps (NETs).

Oxidative stress elicited by reactive oxygen species (ROS) and chronic inflammation are involved both in deterring and the generation/progression of human cancers. Exogenous ROS can injure mitochondria and induce them to generate more endogenous mitochondrial ROS to further perpetuate the deteriorating condition in the affected cells. Dysfunction of these cancer mitochondria may possibly be offset by the Warburg effect, which is characterized by amplified glycolysis and metabolic reprogramming. ROS from neutrophil extracellular traps (NETs) are an essential element for neutrophils to defend against invading pathogens or to kill cancer cells. A chronic inflammation typically includes consecutive NET activation and tissue damage, as well as tissue repair, and together with NETs, ROS would participate in both the destruction and progression of cancers. This review discusses human mitochondrial plasticity and the glucose metabolic reprogramming of cancer cells confronting oxidative stress by the means of chronic inflammation and neutrophil extracellular traps (NETs).

Association of neutrophil extracellular traps burden with clinical and angiographic characteristics in patients with ST-elevation myocardial infarction.

BACKGROUND: The precise triggers for atherosclerotic plaque rupture and the underlying pathophysiology of coronary thrombogenesis remain elusive. Polymorphonuclear neutrophils, particularly their formation of neutrophil extracellular traps (NETs), have garnered attention in the context of coronary atherothrombosis. This study sought to explore the association of NETs burden with clinical and angiographic characteristics in ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (pPCI) and thrombus aspiration (TA). METHODS: For this study, 336 consecutive STEMI patients undergoing pPCI were considered for TA. Aspirated thrombi underwent histological analysis and NETs quantification via immunohistochemistry. Potential associations of clinical variables and angiographic outcomes with NETs burden were assessed. RESULTS: Manual TA was selectively performed in 72 cases with increased thrombotic burden, and 60 thrombi were suitable for analysis and included in the current study. Most thrombi specimens displayed lytic features (63%), and almost three out of four were identified as white thrombi. Increased NETs burden was significantly associated with prolonged pain-to-balloon time (>300 min), OR = 10.29 (95% CI 2.11-42.22, p = 0.001), and stress-induced hyperglycemia OR = 6.58 (95% CI 1.23-52.63, p < 0.01) after multivariate regression analysis. Additionally, distal embolization, and left ventricular ejection fraction ≤40% were more frequent among patients with an elevated NETs burden OR = 16.9 (95% CI 4.23-44.52, p < 0.01) and OR = 3.2 (95% CI 1.05-12.1, p = 0.05), respectively. CONCLUSION: Elevated NETs burden in STEMI thrombi may be due to delayed reperfusion and stress-induced hyperglycemia, and it is associated with an increased risk of distal embolization and lower left ventricular ejection fraction. Further research is needed to elucidate the role of NETs as a potential therapeutic target in acute atherothrombosis.