Systemic Response Research Articles

MXene-based nanozymes remodel tumor microenvironment for heterojunction-enhanced sonodynamic and chemodynamic therapy to boost robust cancer immunotherapy

Reactive oxygen species (ROS)-mediated sonodynamic therapy (SDT) holds increasing potential in treating deep-seated tumor owing to the high tissue-penetration depth, but hardly controls remote metastasis. To trigger robust cancer immunotherapy against malignant metastatic cancers, we report the rational construction of Z-scheme heterojunctions through decorating biocompatible Co3O4 nanoparticles with multiple enzyme-like catalytic activities onto Ti3C2Tx nanosheets to realize the augmented SDT and chemodynamic therapy (CDT). The deposition of Co3O4 nanoparticles not only sensitizes the sonodynamic activity of Ti3C2Tx nanosheets owing to the regulation of separation dynamics of electron-hole pairs, but also achieves the cascade amplification of ROS generation through Co2+-mediated Fenton-like reaction, Co3+-facilitated GSH depletion, and catalytic decomposition of endogenous H2O2 to relieve hypoxia. More importantly, the immunosuppressive TME could be reversed by the greatly enhanced ROS levels, ultimately inducing immunogenic cell death that promotes robust systemic immune responses. The heterojunction-enhanced SDT and CDT via Co3O4@Ti3C2Tx could trigger robust cancer immunotherapy, which achieves the eradication of primary tumors and suppression of distant tumors. This work highlights the potential of heterojunction engineering-enhanced SDT and CDT to trigger robust cancer immunotherapy.

Experimental and Numerical Integrated Strategy for the Optimization of Microfluidic Parameters for Eudragit L100 Nanoparticles and Microparticles.

Oral immunization offers a minimally invasive administration, inducing local and systemic immune responses and facilitating mass immunization without needle-related risks. However, the gastrointestinal environment poses challenges, compromising vaccine effectiveness through enzymatic degradation and poor absorption by Peyer's patches. Advances in nanoparticle and microparticle (NP/MP) technology protect vaccines from degradation and enhance targeted release. The aim of this study was to develop pH-controlled polymeric carriers for the oral delivery of protein vaccines in order to target the antigen-presenting cells and M cells in the region of Peyer's patches. Here, myoglobin was chosen as a model protein vaccine. This study focuses on Eudragit L100, a pH-responsive polymer stable in acidic conditions and dissolving at higher pH, to develop carriers for controlled myoglobin release in the intestinal tract. A microfluidic-based manufacturing process for Eudragit L100 NPs and MPs is optimized using a comprehensive experimental and computational approach to obtain NPs and MPs through the same setup. Integrating in silico and experimental methods highlights the potential of numerical simulations to streamline final product development. This approach improves the efficiency and cost-effectiveness of NP/MP production, demonstrating how the combination of design of experiment and numerical simulations can optimize production parameters and refine manufacturing processes for advanced drug delivery systems.

Preparing the Laboratory for Neoadjuvant Cancer Immunotherapy: Insights from a Pathology Learning Collaborative

Abstract Introduction/Objective Neoadjuvant immunotherapy (NIT) is an emerging strategy to treat multiple types of early- stage resectable cancers by inducing a systemic anti-tumor immune response and increasing the likelihood of complete pathological response (pCR). The evaluation of pathological response following NIT is challenging and requires specific expertise. Traditional response criteria may be difficult to apply since immunotherapy may lead to unique changes in the tumor bed. Moreover, many laboratories may not feel prepared to evaluate pathologic response following immunotherapy given their lack of experience and the time required to accurately assess specimens and report findings. Methods/Case Report To explore ways to help laboratories prepare for these challenges, the American Society for Clinical Pathology (ASCP) formed an immuno-oncology learning collaborative to engage pathologists from different institutions and subspecialties. The group met over six months to review and discuss the implications of relevant literature, guideline recommendations, and emerging trends such as tumor-specific recommendations (eg, IASLC Neoadjuvant Therapy Pathologic Response Initiative) to pan-tumor immune-related pathologic response criteria (irPRC). ASCP then developed a series of educational resources based on recommendations made by the group. Results (if a Case Study enter NA) Members of the ASCP learning collaborative identified and prioritized several topics to help laboratories prepare and equip their teams to perform pathologic assessment after neoadjuvant immunotherapy in routine clinical practice. These included: definition and classification of pathological response criteria, assessing unique changes in the tumor bed (ie, regression bed), interpreting data from clinical trials, reporting results in routine clinical practice, organizing educational resources, and staffing workload. The group also emphasized the importance of collaborating with oncologists and surgeons and promoting communication about these topics within each institution. Conclusion Based on promising results from neoadjuvant immunotherapy clinical trials, we can expect more FDA approvals for neoadjuvant indications and a growing number of patients receiving this treatment. Pathologists and laboratory professionals need to prepare their institutions for a future where the assessment of pathological response in routine clinical practice will impact treatment decisions following surgical resection.

Lymphocyte-derived and lipoprotein-derived inflammatory ratios as biomarkers in bipolar disorder type I: Characteristics, predictive values, and influence of current psychopharmacological treatments

Purpose of this researchThe purpose of this research was to investigate peripheral inflammation by analyzing lymphocyte and lipoprotein-derived inflammatory ratios in patients with bipolar disorder type I (BD-I) and healthy controls (HCs), considering mood stabilizer drug treatments, sex and clinical trajectories. MethodsThis was a cross-sectional case-control study of BD-I patients (n=252) and healthy controls (n=62). We investigated peripheral inflammation biomarkers through blood count values (CBCs), lipoproteins and a complex panel of inflammatory ratios, including the neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), neutrophil-to-HDL ratio (NHR), monocyte-to-HDL ratio (MHR), platelet-to-HDL ratio (PHR) and lymphocyte-to-HDL ratio (LHR). Furthermore, we examined the effects of sex, drug treatment and clinical outcome on the inflammatory profile. ResultsWe found that the monocyte-to-lymphocyte ratio (MLR) and lipoprotein-derived inflammatory ratio (NHR, MHR, PHR, and LHR) were significantly greater in BD-I patients than in control individuals. The monocyte-to-HDL ratio (MHR) showed acceptable accuracy as a disease predictor. Logistic regression analysis adjusted for sex, age and BMI indicated that the risk of having a BD-I diagnosis was greater for participants with MHR levels in quartiles 3 (OR= 5.2, p=0.001) and 4 (OR=13, p<0.001). There was a strong association between lithium treatment and increased inflammation represented by elevated lymphocyte-derived inflammatory ratios (NLR, MLR, PLR, SII, and SIRI) in lithium-treated BD-I patients compared to those in lithium-free or lithium treatment-naïve BD-I patients. The main limitations are the cross-sectional nature of the study and limited sample size of HCs. Major conclusionsSeveral CBCs, lipoproteins, and a complex panel of inflammatory ratios, including lymphocyte-derived inflammatory ratios (NLR, MLR, PLR, SII, and SIRI) and lipoprotein-derived inflammatory ratios (NHR, MHR, PHR, and LHR), are altered in individuals diagnosed with BD-I. The monocyte-to-HDL ratio (MHR) emerged as a disease predictor in our BD-I sample. A remarkable finding is the association of lithium and valproate treatment with the inflammatory state. Considering the study limitations, our results underscore the importance of pharmacological treatments when researching inflammation markers in mood disorders. Lymphocyte-derived and lipoprotein-derived inflammatory ratios are easy-to-implement and relevant biomarkers in BD-I patients.

Burns, Sepsis and Procalcitonin

The basis of the pathogenesis of burn disease is a systemic inflammatory response syndrome with episodes of bacteremia and the development of sepsis. An analysis of the literature showed that the existing clinical diagnostic scales for sepsis do not allow a confident diagnosis. The interest in changes in the concentration of procalcitonin in the blood serum is justified by the fact that this prohormone is one of the proinflammatory mediators, the concentration of which quickly increases during local and systemic bacterial and fungal infections. It seems important to consider the possibilities of various scales for determining the criteria for sepsis, analyze the values of procalcitonin and its monitoring for more effective diagnosis and procalcitonin-controlled antibiotic therapy in patients with burns.CONCLUSION. The problem of clinical diagnosis of sepsis in patients with burns has not yet been solved. Procalcitonin is an effective biomarker of bacterial infection, and its monitoring reflects the dynamics of the burn disease, predicts the outcome, indicates the effectiveness of antibiotic therapy and allows for its correction.

Reshaping Immunosuppressive Tumor Microenvironment Using Ferroptosis/Cuproptosis Nanosensitizers for Enhanced Radioimmunotherapy

AbstractRadiotherapy, a traditional cancer treatment, not only controls local tumor growth but also potentially induces immunogenic cell death, initiating systemic immune responses. However, radiotherapy resistance and immunosuppressive tumor microenvironments often limit the potency of radiation‐induced anti‐tumor immune responses, rendering them insufficient for clinical applications. Consequently, trimetallic nanoparticles are constructed with dual enzymatic activity, AuBiCu‐distearoyl phosphoethanolamine‐PEG nanoparticles (AuBiCu‐PEG NPs), to synergistically improve radiotherapy resistance through X‐ray deposition, hypoxia alleviation, and ferroptosis and cuproptosis induction. This approach promotes radiotherapy‐induced immunogenic cell death and boosts anti‐tumor immune responses. Furthermore, AuBiCu‐PEG NPs effectively reversed radiation‐induced upregulation of programmed cell death 1 ligand 1 (PD‐L1), inhibit tumor immune evasion, and reshaped the immune microenvironment. Non‐invasive and real‐time longitudinal monitoring of nanoparticle accumulation in tumors can be achieved using spectral computed tomography (CT) and photoacoustic (PA) imaging. In summary, the designed AuBiCu‐PEG NPs serve as promising nanoplatforms for immune microenvironment remodeling and can be used in multimodal molecular imaging‐guided ferroptosis‐cuproptosis‐enhanced radiotherapy.

Watt’s fair in Mumbai: intermediaries’ impact on energy justice in informal settlements

Abstract India’s ongoing energy transitions are a systemic response to addressing critical challenges associated with climate change. Importantly, it leverages decarbonization as a strategic pivot to simultaneously mitigate and adapt to climate risks. The decarbonization agenda is largely skewed towards mitigation, struggling with adaptation alignments. Energy justice is a core dimension of adaptation intervention and it is important to explore how energy justice is or can be conceptualized and delivered as the decarbonization agenda is underway. Existing research suggests that, in the cities of the Global South, active involvement of intermediaries becomes a pivotal anchor and pathway to access infrastructure services, especially in low-income and informal settlements. Importantly, advocacy efforts by intermediaries also tackle existing injustices that restrict these settlements from accessing essential infrastructure services. Intermediaries become especially important in cities like Mumbai, where 41% of the people live in informal settlements (slums). Using Mumbai as a case study, this paper explores two questions in the context of intermediaries, energy access, and energy justice. First, how do intermediaries engage with infrastructure and governance structures to enable access to electricity in informal settlements? Second, does this ‘intermediation’ deliver just outcomes? Empirical fieldwork reveals that intermediaries serve as a quasi-political counterbalance by engaging in ‘politics from the bottom’ to articulate justice concerns, mobilize stakeholders, and produce knowledge that feeds back into the intermediation process. We argue that this is important if we need to ensure that energy transitions do not create systemic inequities and that the benefits of the ongoing transition are widespread and just.

Monosodium glutamate induces hypothalamic–pituitary–adrenal axis hyperactivation, glucocorticoid receptors down-regulation, and systemic inflammatory response in young male rats: Impact on miR-155 and miR-218

Abstract Young children are attracted to flavored foods with enhancers, particularly monosodium glutamate (MSG). Experimental studies have proven that MSG can alter the hypothalamic–pituitary–adrenal (HPA) axis response in neonates. We, therefore, investigated the modulation of microRNAs (miRNAs) by dietary MSG and its association with the stimulation of the HPA axis and inflammatory response in young male rats. One-month-old male rats were fed chow enriched with MSG (3 g/kg) for 16 weeks. Feeding MSG to rats markedly up-regulated hypothalamic miR-218, Toll-like receptors-4, and nuclear factor-kB but down-regulated miR-155 and glucocorticoid receptors (GR). In addition, it triggered a remarkable elevation in adrenocortical lipid peroxidation and depletion of antioxidants. These changes were coupled with increased plasma levels of the HPA axis hormones, comprising corticotropin-releasing hormone, adrenocorticotropic hormone, corticosterone levels, and serum pro-inflammatory cytokines. Taken together, current findings indicated that MSG caused an activation of the HPA axis, a down-regulation of GRs, and a systemic inflammatory response. These disturbances were associated with modulating hypothalamic miRNAs, encompassing miR-218 and 155.

Effects of monoglyceride blend on systemic and intestinal immune responses, and gut health of weaned pigs experimentally infected with a pathogenic Escherichia coli

BackgroundMonoglycerides have emerged as a promising alternative to conventional practices due to their biological activities, including antimicrobial properties. However, few studies have assessed the efficacy of monoglyceride blend on weaned pigs and their impacts on performance, immune response, and gut health using a disease challenge model. Therefore, this study aimed to investigate the effects of dietary monoglycerides of short- and medium-chain fatty acids on the immunity and gut health of weaned pigs experimentally infected with an enterotoxigenic Escherichia coli F18.ResultsPigs supplemented with high-dose zinc oxide (ZNO) had greater (P < 0.05) growth performance than other treatments, but no difference was observed in average daily feed intake between ZNO and monoglycerides groups during the post-challenge period. Pigs in ZNO and antibiotic groups had lower (P < 0.05) severity of diarrhea than control, but the severity of diarrhea was not different between antibiotic and monoglycerides groups. Pigs fed with monoglycerides or ZNO had lower (P < 0.05) serum haptoglobin on d 2 or 5 post-inoculation than control. Pigs in ZNO had greater (P < 0.05) goblet cell numbers per villus, villus area and height, and villus height:crypt depth ratio (VH:CD) in duodenum on d 5 post-inoculation than pigs in other treatments. Pigs supplemented with monoglycerides, ZNO, or antibiotics had reduced (P < 0.05) ileal crypt depth compared with control on d 5 post-inoculation, contributing to the increase (P = 0.06) in VH:CD. Consistently, pigs in ZNO expressed the lowest (P < 0.05) TNFa, IL6, IL10, IL12, IL1A, IL1B, and PTGS2 in ileal mucosa on d 5 post-inoculation, and no difference was observed in the expression of those genes between ZNO and monoglycerides. Supplementation of ZNO and antibiotic had significant impacts on metabolic pathways in the serum compared with control, particularly on carbohydrate and amino acid metabolism, while limited impacts on serum metabolites were observed in monoglycerides group when compared with control.ConclusionsThe results suggest that supplementation of monoglyceride blend may enhance disease resistance of weaned pigs by alleviating the severity of diarrhea and mitigating intestinal and systemic inflammation, although the effectiveness may not be comparable to high-dose zinc oxide.

Immune Dysregulation in the Oral Cavity during Early SARS-CoV-2 Infection.

Tissue-specific immune responses are critical determinants of health-maintaining homeostasis and disease-related dysbiosis. In the context of COVID-19, oral immune responses reflect local host-pathogen dynamics near the site of infection and serve as important "windows to the body," reflecting systemic responses to the invading SARS-CoV-2 virus. This study leveraged multiplex technology to characterize the salivary SARS-CoV-2-specific immunological landscape (37 cytokines/chemokines and 11 antibodies) during early infection. Cytokine/immune profiling was performed on unstimulated cleared whole saliva collected from 227 adult SARS-CoV-2+ participants and 37 controls. Statistical analysis and modeling revealed significant differential abundance of 25 cytokines (16 downregulated, 9 upregulated). Pathway analysis demonstrated early SARS-CoV-2 infection is associated with local suppression of oral type I/III interferon and blunted natural killer-/T-cell responses, reflecting a potential novel immune-evasion strategy enabling infection. This virus-associated immune suppression occurred concomitantly with significant upregulation of proinflammatory pathways including marked increases in the acute phase proteins pentraxin-3 and chitinase-3-like-1. Irrespective of SARS-CoV-2 infection, prior vaccination was associated with increased total α-SARS-CoV-2-spike (trimer), -S1 protein, -RBD, and -nucleocapsid salivary antibodies, highlighting the importance of COVID-19 vaccination in eliciting mucosal responses. Altogether, our findings highlight saliva as a stable and accessible biofluid for monitoring host responses to SARS-CoV-2 over time and suggest that oral-mucosal immune dysregulation is a hallmark of early SARS-CoV-2 infection, with possible implications for viral evasion mechanisms.

Impact of Intraoperative Blood Transfusion on Cerebral Injury in Pediatric Patients Undergoing Congenital Septal Heart Defect Surgery

Background: The components of donor blood themselves have the potential to initiate a systemic inflammatory response and exacerbate neuroinflammation, resulting in subsequent cerebral injury. The aim of this study was to establish the role of transfusion in the development of cerebral injury during the correction of congenital heart defects in children. Material and Methods: A total of 78 patients aged from 1 to 78 months, with body weights ranging from 3.3 to 21.5 kg, were investigated. Biomarkers of cerebral injury and systemic inflammatory response were studied at three time points. First: prior to the surgical intervention. Second: after the completion of cardiopulmonary bypass. Third: 16 h after the conclusion of the surgery. Results: The strongest correlation was found for S-100-β protein with the volume of transfusion at the second (Rho = 0.48, p = 0.00065) and third time points (Rho = 0.36, p = 0.01330). Neuron-specific enolase demonstrated a similar trend: Rho = 0.41 and p = 0.00421 after the completion of cardiopulmonary bypass. Conclusions: The use of red blood cell suspension and its dosage per kilogram of body weight correlated with the biomarkers of cerebral injury and systemic inflammatory response with moderate to significant strength.

Methylprednisolone for acute type A aortic dissection patients undergoing total arch replacement: Design and rationale of the Medal trial

BackgroundThe mortality and morbidity of emergency total aortic arch replacement (TAAR) for acute type A aortic dissection (ATAAD) is high, which is partly due to the excessively activated systemic inflammatory response. Methylprednisolone, an anti-inflammatory agent, might suppress the systemic inflammatory response and lead to improved outcomes. However, the protective effects of methylprednisolone on TAAR for ATAAD were not clarified. The usage and dosage varied in different centers across the world. Methods and resultsThe Medal trial is a prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate whether 500 mg methylprednisolone IV before cardiopulmonary bypass could reduce the incidence of postoperative major organ injury, compared to placebo. Adult patients with the diagnosis with ATAAD, awaiting emergency total aortic arch replacement with hypothermic circulatory arrest and selective cerebral perfusion will be included in the trial. A total of 340 eligible subjects from nine large cardiovascular centers will be randomized in a 1:1 ratio to recieve 500mg methylprednislone or placebo before cardiopulmonary bypass. The primary outcome is postoperative major adverse outcome [defined as all-cause death or postoperative neurological deficit or KDIGO II -III acute kidney injury or respiratory syndrome (tracheal intubation> 72 hours, tracheostomy or re-intubation) until postoperative day 30 or patient discharge]. The study has received approval from the local Ethics Committees of the nine participating centers, and enrolled its first subject in June 24, 2022. As of September 5,2024, 323 subjects have been enrolled. Results of the Medal trial will be published once data collection and analysis have been completed. ConclusionsThe Medal trial will determine the effectiveness of 500 mg methylprednisolone on the outcomes of patients with ATAAD undergoing TAAR. RegistrationURL https://www.chictr.org.cn/searchprojEN.html (Chinese Clinical Trial Registry). Unique identifier: ChiCTR2200059286

Local Inflammatory and Systemic Antibody Responses Initiated by a First Intradermal Administration of Autogenous Salmonella-Killed Vaccines and Their Components in Pullets

Vaccination strategies are used to manage Salmonella in chickens. Salmonella-killed vaccines are considered safer since they are inactivated. However, little is known regarding the cellular immune activities at the site of vaccine administration of Salmonella-killed vaccines. The growing feather (GF) cutaneous test has been shown to be an effective bioassay to monitor local tissue/cellular responses. We assessed local and systemic antibody responses initiated by intradermal injection of Salmonella-killed vaccines into GF-pulps of 14–15-week-old pullets. Treatments consisted of two autogenous Salmonella-killed vaccines (SV1 and SV2), S. Enteritidis (SE) lipopolysaccharide (SE-LPS), and the water-oil-water (WOW) emulsion vehicle. GF-pulps were collected before (0 h) and at 6, 24, 48, and 72 h post-GF-pulp injection for leukocyte population analysis, while heparinized blood samples were collected before (0 d) and at 3, 5, 7, 10, 14, 21, and 28 d after GF-pulp injections to assess plasma levels (a.u.) of SE-specific IgM, avian IgY (IgG), and IgA antibodies using an ELISA. Injection of GF-pulps with SV1, SV2, or SE-LPS, all in a WOW vehicle, initiated inflammatory responses characterized by the recruitment of heterophils, monocytes/macrophages, and a few lymphocytes. The WOW vehicle emulsion alone recruited more lymphocytes than vaccines or SE-LPS. The SV1 and SV2 vaccines stimulated Salmonella-specific IgM and IgA early, while IgG levels were greatly elevated later during the primary response. Overall, SV1 and SV2 stimulated a heterophil and macrophage-dominated local inflammatory- and SE-specific humoral response with an isotype switch from IgM to IgG, characteristic of a T-dependent primary antibody response. This study provides comprehensive information on innate and adaptive immune responses to autogenous Salmonella-killed vaccines and their components that will find application in the management of Salmonella in poultry.

Development and Validation of a Machine Learning Model for Early Detection of Untreated Infection.

Early diagnostic uncertainty for infection causes delays in antibiotic administration in infected patients and unnecessary antibiotic administration in noninfected patients. To develop a machine learning model for the early detection of untreated infection (eDENTIFI), with the presence of infection determined by clinician chart review. Three thousand three hundred fifty-seven adult patients hospitalized between 2006 and 2018 at two health systems in Illinois, United States. We validated in 1632 patients in a third Illinois health system using area under the receiver operating characteristic curve (AUC). Using a longitudinal discrete-time format, we trained a gradient boosted machine model to predict untreated infection in the next 6 hours using routinely available patient demographics, vital signs, and laboratory results. eDENTIFI had an AUC of 0.80 (95% CI, 0.79-0.81) in the validation cohort and outperformed the systemic inflammatory response syndrome criteria with an AUC of 0.64 (95% CI, 0.64-0.65; p < 0.001). The most important features were body mass index, age, temperature, and heart rate. Using a threshold with a 47.6% sensitivity, eDENTIFI detected infection a median 2.0 hours (interquartile range, 0.9-5.2 hr) before antimicrobial administration, with a negative predictive value of 93.6%. Antibiotic administration guided by eDENTIFI could have decreased unnecessary IV antibiotic administration in noninfected patients by 10.8% absolute or 46.4% relative percentage points compared with clinicians. eDENTIFI could both decrease the time to antimicrobial administration in infected patients and unnecessary antibiotic administration in noninfected patients. Further prospective validation is needed.

A study on subcutaneous infection model of colibacillosis in broilers: Selected immunological and hematological aspects

Colibacillosis is still a major challenge to poultry industry. This study examined selected immune and hematological features of broilers experimentally infected with E. coli via subcutaneous (sc) route. Fifty-one 5-week-old chickens were randomly assigned to three groups: two controls (NC and SCC) and one experimental (SC) group. The SC group was inoculated by O2 E. coli suspension via sc route in the inguinal region. Three days after inoculation, blood sampling was performed. Bacterial count of liver was determined. Histopathological samples of liver, lung, spleen, thymus, and bursa were also collected. Serum total protein and globulin significantly increased in birds of SC group as compared to control birds (P < 0.05). Birds in SC group also showed decreased albumin/globulin ratio. Serum levels of IL-6, IL-10, and IFN-γ remained statistically the same among groups. Lymphocytosis, monocytosis, thrombocytosis and heterophilia were present in SC group. Heterophils/lymphocytes ratio increased in SC birds. Left shift was observed in SC group with cells showing vacuolated cytoplasm that contained toxic granules. Histologically, lung involvement was less severe than liver. Lymphoid depletion was present in all examined lymphoid organs. E. coli growth was observed in liver samples from SC group but not in control birds. In conclusion, using sc route for induction of colibacillosis was associated with a systemic inflammatory response in broilers and histopathological lesions of thymus, bursa, and spleen three days post-infection. It seems that detection of changes in serum cytokine levels (IL-6, IL-10, and IFN-γ) should be performed in earlier hours of the disease in this model.

Proteomic profiling of the local and systemic immune response to pediatric respiratory viral infections.

We describe the first proteomic profiling of the lower airway and blood in critically ill children with severe viral lower respiratory tract infection (vLRTI). From tracheal aspirate (TA), we defined a proteomic signature of vLRTI characterized by increased expression of interferon signaling proteins and decreased expression of proteins involved in immune modulation including FABP and MIP-5. Using machine learning, we developed a parsimonious diagnostic classifier that distinguished vLRTI from non-infectious respiratory failure with high accuracy. Comparative analysis of paired TA and plasma specimens demonstrated limited concordance, although the interferon-stimulated protein ISG15 was significantly upregulated with vLRTI in both compartments. We further identified TSG-6 and CRP as airway biomarkers of bacterial-viral coinfection, and viral load analyses demonstrated positive correlation with interferon-related protein expression and negative correlation with the expression of neutrophil activation proteins. Taken together, our study provides new insight into the lower airway and systemic proteome of severe pediatric vLRTI.

A New Frontier in Tumor Eradication: Harnessing In Vivo Cellular Reprogramming for Durable Cancer Immunotherapy.

Tumors evade immune detection by downregulating antigen presentation and hindering immune responses. Type 1 conventional dendritic cells (cDC1s) are vital in stimulating cytotoxic T cells against tumors. Ascic et al. are now demonstrating the in situ ability of PU.1, IRF8, and BATF3 (PIB) transcription factors to directly reprogram a plethora of tumors bypassing the suppressive effects of the tumor microenvironment, and leading to overall tumor regression while eliciting a systemic immune response that can protect from secondary tumor induction.

The Crucial Triad: Endothelial Glycocalyx, Oxidative Stress, and Inflammation in Cardiac Surgery-Exploring the Molecular Connections.

Since its introduction, the number of heart surgeries has risen continuously. It is a high-risk procedure, usually involving cardiopulmonary bypass, which is associated with an inflammatory reaction that can lead to perioperative and postoperative organ dysfunction. The extent of complications following cardiac surgery has been the focus of interest for several years because of their impact on patient outcomes. Recently, numerous scientific efforts have been made to uncover the complex mechanisms of interaction between inflammation, oxidative stress, and endothelial dysfunction that occur after cardiac surgery. Numerous factors, such as surgical and anesthetic techniques, hypervolemia and hypovolemia, hypothermia, and various drugs used during cardiac surgery trigger the development of systemic inflammatory response and the release of oxidative species. They affect the endothelium, especially endothelial glycocalyx (EG), a thin surface endothelial layer responsible for vascular hemostasis, its permeability and the interaction between leukocytes and endothelium. This review highlights the current knowledge of the molecular mechanisms involved in endothelial dysfunction, particularly in the degradation of EG. In addition, the major inflammatory events and oxidative stress responses that occur in cardiac surgery, their interaction with EG, and the clinical implications of these events have been summarized and discussed in detail. A better understanding of the complex molecular mechanisms underlying cardiac surgery, leading to endothelial dysfunction, is needed to improve patient management during and after surgery and to develop effective strategies to prevent adverse outcomes that complicate recovery.

Association Between Scalp Microbiota Imbalance, Disease Severity, and Systemic Inflammatory Markers in Alopecia Areata.

Alopecia areata (AA) is an autoimmune disease causing non-scarring hair loss, with both genetic and environmental factors implicated. Recent research highlights a possible role for scalp microbiota in influencing both local and systemic inflammatory responses, potentially impacting AA progression. This study examines the link among scalp microbiota imbalances, AA severity, and systemic inflammation. We conducted a cross-sectional study with 24 participants, including patients with AA of varying severities and healthy controls. Scalp microbial communities were analyzed using swab samples and ion torrent sequencing of the 16S rRNA gene across multiple hypervariable regions. We explored correlations among bacterial abundance, microbiome metabolic pathways, and circulating inflammatory markers. Our findings reveal significant dysbiosis in the scalp microbiota of patients with AA compared to healthy controls. Severe AA cases had an increased presence of pro-inflammatory microbial taxa like Proteobacteria, whereas milder cases had higher levels of anti-inflammatory Actinobacteria. Notable species differences included abundant gram-negative bacteria such as Alistipes inops and Bacteroides pleibeius in severe AA, contrasted with Blautia faecis and Pyramydobacter piscolens predominantly in controls. Significantly, microbial imbalance correlated with AA severity (SALT scores) and systemic inflammatory markers, with elevated pro-inflammatory cytokines linked to more severe disease. These results suggest that scalp microbiota may play a role in AA-related inflammation, although it is unclear whether the shifts are a cause or consequence of hair loss. Further research is needed to clarify the causal relationship and mechanisms involved.

Prognostic value of systemic inflammation response index in cancer patients treated with PD-1/PD-L1 immune checkpoint inhibitors: a meta-analysis.

The prognostic significance of the systemic inflammatory response index (SIRI) in patients with cancer receiving programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) has been widely investigated; however, the results have been conflicting. As such, the present meta-analysis aimed to analyze the precise significance of the SIRI in predicting prognosis in patients with cancer undergoing ICI therapy. A comprehensive literature search of the Web of Science, PubMed, Embase, and Cochrane Library databases for relevant studies, published from inception to April 25, 2024, was performed. The SIRI was analyzed for its prognostic utility in patients undergoing ICI therapy by calculating combined hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Six studies comprising 1133 patients were included in the analysis. Pooled data revealed that a higher SIRI was significantly associated with poor overall survival (OS) (HR 1.96 [95% CI 1.55-2.47]; p < 0.001) and progression-free survival (PFS) (HR 1.41 [95% CI 1.19-1.67]; p < 0.001) for patients who underwent PD-1/PD-L1 ICI treatment. Subgroup analysis revealed that SIRI was markedly associated with dismal OS and PFS, independent of sample size, cut-off value, and survival analysis (p < 0.05). The findings were verified to be robust against publication bias and sensitivity analyses. In summary, an elevated SIRI was significantly associated with OS and PFS in patients with cancer undergoing PD-1/PD-L1 ICI treatment. SIRI may a candidate indicator for predicting the prognosis of patients undergoing ICI therapy.