When an inflammatory response occurs in the body, primary immune cells, such as macrophages, phagocytize and present antigens, and secondary immune cells, such as T cells, produce antibodies against ...the presented antigens to prevent infection in the body. Abnormalities in the immune system releases pro-inflammatory cytokines such as TNF-α and IL-6, leading to rheumatoid arthritis and sepsis. This study aimed to confirm the change in inflammatory activity across innate immunity and acquired immunity while investigating the effects of pulsed magnetic field (PMF) on the immune system to regulate excessive inflammation. Raw 264.7 and EL4 cells were co-cultured in a DMEM medium using permeable cell culture inserts and inflammation was induced using LPS. Our PMF stimulator has the maximum intensity of 4700 G at a transition time of 136 μs with pulse intervals of 1 Hz. In order to confirm anti-inflammatory effects of PMF, the level of IL-6, pH and mitochondrial respiration rate (MRR) were measured using ELISA, pH meter and MTT assay, respectively. It was observed in vitro that inflammation-induced macrophages induce activation of T cells, as evidenced by the faster acidification in pH, increased IL-6 expression, and enhanced MRR, compared to T cells. But after PMF stimulation, pH levels improved, the concentration of IL-6 reduced, and MRR decreased in both macrophages and T-cells, which indicates inflammation relief. Our results show that macrophages, the primary immune cells, are first involved in the inflammatory response and recovery and influence T cells, the secondary immune cells. Therefore PMF stimulus is thought to affect the immune system of the human body by balancing the activation and suppression of immune cells and improve anti-inflammation. For clinical use, non-invasive PMF can be developed as a medical devices modulating immune system with optimizing the PMF conditions such as pulse shape, duration, or repetition rate.
Maintenance of homoeostasis in human body is a very important indicator in all cell activities. When exposed to a disease, various immune cells are activated due to the inflammatory response, and ...particularly T cells play a role in inducing apoptosis of mutated cells such as tumor cells. When the activity of T cells is very low, infection by external invasion is easy, and on the contrary, excessive activation leads to chronic inflammation caused by autoimmune diseases. Many clinical studies related to pulsed magnetic field (PMF) demonstrated its efficacy in reducing pain, improving blood circulation, as well as blood’s acid-base balance. Therefore, our study has tried to investigate the influence of PMF on the regulation of acid-base homeostasis in EL4 T lymphoma cell. In addition, we have tried to explain the role of PMF on immune cell activity by measuring the level of pro-inflammatory cytokine, TNF-α in culture supernatants. EL4 cells were cultured in a DMEM medium supplemented with 10% FBS and 1% penicillin in an incubator at 37 °C and 5% CO2 condition. Our PMF stimulator has the maximum strength of 4700 G at a transition time of 222 μs with pulse intervals of 1 Hz. The homoeostasis in pH was improved as PMF strength increases. Cell viability decreased by 32% after PMF stimulation of 4700 G. It was observed that the concentration of TNF-α, a cytokine related to inflammation, also decreased as the strength of PMF increased. These results suggest that PMF stimulation improves the anti-inflammatory effect, therefore, it is thought to affect the immune system by balancing the activation and suppression of immune cells. For clinical use, our study might suggest non-invasive PMF can be developed as a medical devices modulating immune system, although it is necessary to optimize the PMF conditions such as pulse shape, duration, or repetition rate.
Predictive factors associated with postoperative mortality have not been extensively studied in plastic and reconstructive surgery. Neutrophil-lymphocyte ratio (NLR), a systemic inflammation index, ...has been shown to have a predictive value in surgery. We aimed to evaluate association between preoperative NLR and postoperative outcomes in patients undergoing plastic and reconstructive surgery. From January 2011 to July 2019, we identified 7089 consecutive adult patients undergoing plastic and reconstructive surgery. The patients were divided according to median value of preoperative NLR of 1.84. The low NLR group was composed of 3535 patients (49.9%), and 3554 patients (50.1%) were in the high NLR group. The primary outcome was mortality during the first year, and overall mortality and acute kidney injury were also compared. In further analysis, outcomes were compared according to quartile of NLR, and a receiver operating characteristic curve was constructed to estimate the threshold associated with 1-year mortality. This observational study showed that mortality during the first year after plastic and reconstructive surgery was significantly increased in the high NLR group (0.7% vs. 3.5%; hazard ratio, 4.23; 95% confidence interval, 2.69-6.63; p < 0.001), and a graded association was observed between preoperative NLR and 1-year mortality. The estimated threshold of preoperative NLR was 2.5, with an area under curve of 0.788. Preoperative NLR may be associated with 1-year mortality after plastic and reconstructive surgery. Further studies are needed to confirm our findings.
Fluorescent boronate-modified polyacrylonitrile (BPAN) nanoparticles of 50 nm diameter were fabricated for use as a selective H2O2 sensor. The fluorescence intensity changed and an emission peak ...shifted when BPAN nanoparticles selectively interacted with H2O2, relative to other reactive oxygen species (ROS). The BPAN nanoparticles undergo photoinduced electron transfer (PET) between a Schiff base moiety and boronate, which enhances the fluorescence and makes the nanoparticles suitable for selective ROS recognition. We demonstrate the use of these nanoparticles as a detector of endogenous H2O2 produced in living cells. The representative features of the fluorescent BPAN nanoparticles that make them particularly attractive for H2O2 and ROS detection are the following: they are easily synthesized as PET sensors; they exhibit a characteristic emission peak and peak shift that distinguishes reaction with H2O2 from other ROS; and compared to organic compounds, the sensing moiety on BPAN polymer nanoparticles is more thermally stable and has superior mechanical properties, enabling their use in various biomedical applications.
Purpose
To understand the tumor immune microenvironment precisely, it is important to secure the quantified data of tumor-infiltrating immune cells, since the immune cells are true working unit. We ...analyzed unit immune cell number per unit volume of core tumor tissue of high-grade gliomas (HGG) to correlate their immune microenvironment characteristics with clinical prognosis and radiomic signatures.
Methods
The number of tumor-infiltrating immune cells from 64 HGG core tissue were analyzed using flow cytometry and standardized. After sorting out patient groups according to diverse immune characteristics, the groups were tested if they have any clinical prognostic relevance and specific radiomic signature relationships. Sparse partial least square with discriminant analysis using multimodal magnetic resonance images was employed for all radiomic classifications.
Results
The median number of CD45 + cells per one gram of HGG core tissue counted 865,770 cells which was equivalent to 8.0% of total cells including tumor cells. There was heterogeneity in the distribution of immune cell subpopulations among patients. Overall survival was significantly better in T cell-deficient group than T cell-enriched group (
p
= 0.019), and T8 dominant group than T4 dominant group (
p
= 0.023). The number of tumor-associated macrophages (TAM) and M2-TAM was significantly decreased in isocitrate dehydrogenase mutated HGG. Radiomic signature classification showed good performance in predicting immune phenotypes especially with features extracted from apparent diffusion coefficient maps.
Conclusions
Absolute quantification of tumor-infiltrating immune cells confirmed the heterogeneity of immune microenvironment in HGG which harbors prognostic impact. This immune microenvironment could be predicted by radiomic signatures non-invasively.
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease linked to oxidative stress, which is associated with significant morbidity. The NADPH oxidase complex (NOX) produces reactive ...oxygen species (ROS) that are among the key markers for determining RA's pathophysiology. Therefore, understanding ROS-regulated molecular pathways and their interaction is necessary for developing novel therapeutic approaches for RA. Here, by combining mouse genetics and biochemistry with clinical tissue analysis, we reveal that in vivo Rubicon interacts with the p22phox subunit of NOX, which is necessary for increased ROS-mediated RA pathogenesis. Furthermore, we developed a series of new aryl propanamide derivatives consisting of tetrahydroindazole and thiadiazole as p22phox inhibitors and selected 2-(tetrahydroindazolyl)phenoxy-N-(thiadiazolyl)propanamide 2 (TIPTP, M.W. 437.44), which showed considerably improved potency, reaching an IC
value up to 100-fold lower than an inhibitor that we previously synthesized reported N8 peptide-mimetic small molecule (blocking p22phox-Rubicon interaction). Notably, TIPTP treatment showed significant therapeutic effects a mouse model for RA. Furthermore, TIPTP had anti-inflammatory effects ex vivo in monocytes from healthy individuals and synovial fluid cells from RA patients. These findings may have clinical applications for the development of TIPTP as a small molecule inhibitor of the p22phox-Rubicon axis for the treatment of ROS-driven diseases such as RA.
Myocardial injury after non-cardiac surgery (MINS) is a well-known and relevant indicator of early postoperative mortality, but factors related to increased mortality in MINS patients are as yet ...unknown. The Charlson Comorbidity Index (CCI) is widely used to classify various comorbid conditions and underlying diseases. Our study aimed to determine the prognostic value of CCI with regard to mortality of patients with MINS. This study comprises 5633 patients who had MINS as diagnosed by a rise of postoperative cardiac troponin I above the normal range (≥ 0.04 ng/mL) from January 2010 to June 2019. Patients were divided into two groups according to median weighted CCI score: low CCI (≤ 2) and high CCI (> 2) groups. The primary outcome was 30-day mortality after surgery, and secondary outcomes were 1-year and overall mortalities. Of the 5633 patients, 3428 (60.9%) were in the low CCI group (1.21 ± 0.84) and 2205 (39.1%) were in the high CCI group (4.17 ± 1.82). After propensity score matching, mortality during the first 30 days after surgery was significantly greater in the high CCI group than the low CCI group (9.4% vs. 6.0%, respectively; hazard ratio 1.56, 95% confidence interval 1.23-1.98, p < 0.001). A high CCI score was associated with increased 30-day mortality in patients with MINS, suggesting that the CCI may need to be considered when predicting outcomes of MINS patients.
The development of premalignant colorectal polyps is significantly influenced by various lifestyle and modifiable risk factors. In our study, we used a large cohort of 9025 patients, who underwent ...screening colonoscopies at a university hospital, to assess the risk factors associated with the development of three different colorectal cancer precursor lesions: non-advanced adenomas (NAs), advanced adenomatous lesions (ADLs), and sessile serrated lesions (SSLs). Among the participants, 3641 had NAs, 836 had ADLs, and 533 had SSLs. We identified obesity, current smoking, and appendicular skeletal muscle mass as modifiable lifestyle risk factors that increase the development of NAs and ADLs (all P < 0.05). Furthermore, we found a positive correlation between the degree of obesity and an increased risk of developing NAs and ADLs (all P for trend < 0.001), while non-smoking was associated with a decreased risk (P for trend < 0.001 and 0.003, respectively). Smoking was the only modifiable risk factor for developing SSLs (adjusted odds ratio aOR 1.58; 95% confidence interval CI 1.20–2.07), and the risk was even higher in patients with metabolic syndrome (aOR 1.71; 95% CI 1.05–2.77). Addressing modifiable lifestyle factors such as smoking and obesity could play an important role in reducing the risk of both non-advanced and advanced adenomatous lesions. Smoking cessation is especially important as it is a significant modifiable risk factor for sessile serrated lesions.
Atomically thin MoS2 is of great interest for electronic and optoelectronic applications because of its unique two-dimensional (2D) quantum confinement; however, the scaling of optoelectronic ...properties of MoS2 and its junctions with metals as a function of layer number as well the spatial variation of these properties remain unaddressed. In this work, we use photocurrent spectral atomic force microscopy (PCS-AFM) to image the current (in the dark) and photocurrent (under illumination) generated between a biased PtIr tip and MoS2 nanosheets with thickness ranging between n = 1 to 20 layers. Dark current measurements in both forward and reverse bias reveal characteristic diode behavior well-described by Fowler–Nordheim tunneling with a monolayer barrier energy of 0.61 eV and an effective barrier scaling linearly with layer number. Under illumination at 600 nm, the photocurrent response shows a marked decrease for layers up to n = 4 but increasing thereafter, which we describe using a model that accounts for the linear barrier increase at low n, but increased light absorption at larger n creating a minimum at n = 4. Comparative 2D Fourier analysis of physical height and photocurrent images shows high spatial frequency spatial variations in substrate/MoS2 contact that exceed the frequencies imposed by the underlying substrates. These results should aid in the design and understanding of optoelectronic devices based on quantum confined atomically thin MoS2.
The tumor immune microenvironment (TIME) in high-grade glioma (HGG) exhibits high spatial heterogeneity. Though the tumor core and peripheral regions have different biological features, the cause of ...this spatial heterogeneity has not been clearly elucidated. Here, we examined the spatial heterogeneity of HGG using core and peripheral regions obtained separately from the patients with HGG. We analyzed infiltrating immune cells by flow cytometry from 34 patients with HGG and the transcriptomes by RNA-seq analysis from 18 patients with HGG. Peripheral region-infiltrating immune cells were in vitro cultured in hypoxic conditions and their immunophenotypes analyzed. We analyzed whether the frequencies of exhausted CD8
+
T cells and immunosuppressive cells in the core or peripheral regions are associated with the survival of patients with HGG. We found that terminally exhausted CD8
+
T cells and immunosuppressive cells, including regulatory T (T
REG
) cells and M2 tumor-associated macrophages (TAMs), are more enriched in the core regions than the peripheral regions. Terminally exhausted and immunosuppressive profiles in the core region significantly correlated with the hypoxia signature, which was enriched in the core region. Importantly, in vitro culture of peripheral region-infiltrating immune cells in hypoxic conditions resulted in an increase in terminally exhausted CD8
+
T cells, CTLA-4
+
T
REG
cells, and M2 TAMs. Finally, we found that a high frequency of PD-1
+
CTLA-4
+
CD8
+
T cells in the core regions was significantly associated with decreased progression-free survival of patients with HGG. The hypoxic condition in the core region of HGG directly induces an immunosuppressive TIME, which is associated with patient survival.
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