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Currently, there are no U.S. Food and Drug Administration (FDA)-approved medical countermeasures (MCMs) for radiation combined injury (RCI), partially due to limited understanding of its mechanisms. Our previous research suggests that endothelial dysfunction may contribute to a poor prognosis of RCI. In this study, we demonstrated an increased risk of mortality, body weight loss, and delayed skin wound healing in RCI mice compared to mice with skin wounds alone or radiation injury (RI) 30 days post-insult. Furthermore, we evaluated biomarkers of endothelial dysfunction, inflammation, and impaired wound healing in mice at early time points after RCI. Mice were exposed to 9.0 Gy total-body irradiation (TBI) followed by skin wound. Samples were collected on days 3, 7, and 14 post-TBI. Endothelial dysfunction markers were measured by ELISA, and skin wound healing was assessed histologically. Our results show that endothelial damage and inflammation are more severe and persistent in the RCI compared to the wound-alone group. Additionally, RCI impairs granulation tissue formation, reduces myofibroblast presence, and delays collagen deposition, correlating with more severe endothelial damage. TGF signaling may play a key role in this impaired healing. These findings suggest that targeting the endothelial dysfunction and TGF-β pathways may provide potential therapeutic strategies for improving delayed wound healing in RCI, which could subsequently influence outcomes such as survival after RCI. [ABSTRACT FROM AUTHOR]

IL-18 has been shown to play important roles in response to total body irradiation. However, homogenous total body irradiation is not a realistic model to reflect the radiation exposure in a real nuclear event. To further study the roles of IL-18 in a real nuclear scenario, we developed a mouse partial body irradiation with 5% bone marrow sparing (PBI/BM5) model to mimic the inhomogeneous radiation exposure. We established the dose response curves of PBI/BM5 using different radiation doses ranging from 12 to 16 Gy. Using the PBI/BM5 model, we showed that IL-18 knockout mice were significantly more radiation resistant than the wild-type mice at 14.73 Gy. We further studied the hematopoietic changes using a complete blood count, bone marrow colony-forming assays, and serum cytokine assays on the mice exposed to PBI/BM5 with IL-18BP treatment and wild-type/IL-18 knockout mice. In conclusion, our data suggest that IL-18 plays important roles in mouse survival in a realistic nuclear exposure model, potentially through the IL-18/IFNγ pathway. [ABSTRACT FROM AUTHOR]

Radiation injury- and radiation combined with skin injury-induced inflammatory responses in the mouse brain were evaluated in this study. Female B6D2F1/J mice were subjected to a sham, a skin wound (SW), 9.5 Gy 60Co total-body gamma irradiation (RI), or 9.5 Gy RI combined with a skin puncture wound (RCI). Survival, body weight, and wound healing were tracked for 30 days, and mouse brain samples were collected on day 30 after SW, RI, RCI, and the sham control. Our results showed that RCI caused more severe animal death and body weight loss compared with RI, and skin wound healing was significantly delayed by RCI compared to SW. RCI and RI increased the chemokines Eotaxin, IP-10, MIG, 6Ckine/Exodus2, MCP-5, and TIMP-1 in the brain compared to SW and the sham control mice, and the Western blot results showed that IP-10 and p21 were significantly upregulated in brain cells post-RI or -RCI. RI and RCI activated both astrocytes and endothelial cells in the mouse brain, subsequently inducing blood–brain barrier (BBB) leakage, as shown by the increased ICAM1 and GFAP proteins in the brain and GFAP in the serum. The Doublecortin (DCX) protein, the "gold standard" for measuring neurogenesis, was significantly downregulated by RI and RCI compared with the sham group. Furthermore, RI and RCI decreased the expression of the neural stem cell marker E-cadherin, the intermediate progenitor marker MASH1, the immature neuron cell marker NeuroD1, and the mature neuron cell marker NeuN, indicating neural cell damage in all development stages after RI and RCI. Immunohistochemistry (IHC) staining further confirmed the significant loss of neural cells in RCI. Our data demonstrated that RI and RCI induced brain injury through inflammatory pathways, and RCI exacerbated neural cell damage more than RI. [ABSTRACT FROM AUTHOR]

Administration of recombinant human IL-18 binding protein (rhIL-18BP), a natural antagonist of IL-18, significantly increased mouse survival after lethal doses of irradiation. To further understand the roles of IL-18BP in radiation mitigation, we studied the pharmacokinetic (PK) parameters of rhIL-18BP, and the serum and intestinal cytokine changes in CD2F1 mice treated with vehicle or rhIL-18BP after 9.0 Gy total body irradiation (TBI). For the PK study, non-compartmental pharmacokinetic analysis was performed using PKsolver. Serum and intestine specimens were collected to measure 44-cytokine levels. Principal component analysis showed a clear separation of the non-irradiated samples from the irradiated samples; and partial separation with or without rhIL-18BP treatment. Cytokine clusters that were significantly correlated in the serum or intestine, respectively were identified. On the individual cytokine levels, serum and intestinal cytokines that were significantly changed by irradiation and rhIL-18BP treatment were identified. Finally, cytokines that were significantly correlated between their serum and intestinal levels were identified. The current study established the PK parameters of rhIL-18BP in mice, identified significantly changed cytokines in mouse serum and intestine after radiation exposure and rhIL-18BP treatment. Current data provide critical insights into IL-18BP's mechanism of action as a radiation mitigator. [ABSTRACT FROM AUTHOR]

Radiation-combined injury (RCI) augments the risk of morbidity and mortality when compared to radiation injury (RI) alone. No FDA-approved medical countermeasures (MCMs) are available for treating RCI. Previous studies implied that RI and RCI elicit differential mechanisms leading to their detrimental effects. We hypothesize that accelerating wound healing improves the survival of RCI mice. In the current study, we examined the effects of RCI at different doses on lethality, weight loss, wound closure delay, and proinflammatory status, and assessed the relative contribution of systemic and local elements to their delayed wound closure. Our data demonstrated that RCI increased the lethality and weight loss, delayed skin wound closure, and induced a systemic proinflammatory status in a radiation dose-dependent manner. We also demonstrated that delayed wound closure did not specifically depend on the extent of hematopoietic suppression, but was significantly influenced by the toxicity of the radiation-induced systemic inflammation and local elements, including the altered levels of proinflammatory chemokines and factors, and the dysregulated collagen homeostasis in the wounded area. In conclusion, the results from our study indicate a close association between delayed wound healing and the significantly altered pathways in RCI mice. This insightful information may contribute to the evaluation of the prognosis of RCI and development of MCMs for RCI. [ABSTRACT FROM AUTHOR]

In nuclear and radiological incidents, overexposure to ionizing radiation is life-threatening. It is evident that radiation depletes blood cells and increases circulating cytokine/chemokine concentrations as well as mortality. While microglia cells of female mice have been observed to be less damaged by radiation than in male mice, it is unclear whether sex affects physio-pathological responses in the bone marrow (BM) and gastrointestinal system (GI). We exposed B6D2F1 male and female mice to 0, 1.5, 3, or 6 Gy with mixed-field radiation containing 67% neutron and 33% gamma at a dose rate of 0.6 Gy/min. Blood and tissues were collected on days 1, 4, and 7 postirradiation. Radiation increased cytokines/chemokines in the femurs and ilea of female and male mice in a dose-dependent manner. Cytokines and chemokines reached a peak on day 4 and declined on day 7 with the exception of G-CSF which continued to increase on day 7 in female mice but not in male mice. MiR-34a (a Bcl-2 inhibitor), G-CSF (a miR-34a inhibitor), MAPK activation (pro-cell death), and citrulline (a biomarker of entroepithelial proliferation), active caspase-3 (a biomarker of apoptosis) and caspase-1 activated gasdermin D (a pyroptosis biomarker) were measured in the sternum, femur BM and ileum. Sternum histopathology analysis with H&E staining and femur BM cell counts as well as Flt-3L showed that BM cellularity was not as diminished in females, with males showing a 50% greater decline on day 7 postirradiation, mainly mediated by pyroptosis as indicated by increased gasdermin D in femur BM samples. Ileum injury, such as villus height and crypt depth, was also 43% and 30%, respectively, less damaged in females than in males. The severity of injury in both sexes was consistent with the citrulline and active caspase-3 measurements as well as active caspase-1 and gasdermin D measurements, suggesting apoptosis and pyroptosis occurred. On day 7, G-CSF in the ileum of female mice continued to be elevated by sevenfold, whereas G-CSF in the ileum of male mice returned to baseline. Furthermore, G-CSF is known to inhibit miR-34a expression, which in ileum on day 1 displayed a 3- to 4-fold increase in female mice after mixed-field (67% neutron + 33% gamma) irradiation, as compared to a 5- to 9-fold increase in male mice. Moreover, miR-34a blocked Bcl-2 expression. Mixed-field (60% neutron + 33% gamma) radiation induced more Bcl-2 in females than in males. On day 7, AKT activation was found in the ileums of females and males. However, MAPK activation including ERK, JNK, and p38 showed no changes in the ileum of females (by 0-fold; P > 0.05), whereas the MAPK activation was increased in the ileum of males (by 100-fold; P < 0.05). Taken together, the results suggest that organ injury from mixed-field (67% neutron + 33% gamma) radiation is less severe in females than in males, likely due to increased G-CSF, less MAPK activation, low miR-34a and increased Bcl-2/Bax ratio. [ABSTRACT FROM AUTHOR]

Simple Summary: Due to most traditional high-throughput experiments are tedious and laborious in identifying potential protein–protein interaction. To better improve accuracy prediction in protein–protein interactions. We proposed a novel computational method that can identify unknown protein–protein interaction efficiently and hope this method can provide a helpful idea and tool for proteomics research. Protein–protein interactions (PPIs) play an essential role in many biological cellular functions. However, it is still tedious and time-consuming to identify protein–protein interactions through traditional experimental methods. For this reason, it is imperative and necessary to develop a computational method for predicting PPIs efficiently. This paper explores a novel computational method for detecting PPIs from protein sequence, the approach which mainly adopts the feature extraction method: Locality Preserving Projections (LPP) and classifier: Rotation Forest (RF). Specifically, we first employ the Position Specific Scoring Matrix (PSSM), which can remain evolutionary information of biological for representing protein sequence efficiently. Then, the LPP descriptor is applied to extract feature vectors from PSSM. The feature vectors are fed into the RF to obtain the final results. The proposed method is applied to two datasets: Yeast and H. pylori, and obtained an average accuracy of 92.81% and 92.56%, respectively. We also compare it with K nearest neighbors (KNN) and support vector machine (SVM) to better evaluate the performance of the proposed method. In summary, all experimental results indicate that the proposed approach is stable and robust for predicting PPIs and promising to be a useful tool for proteomics research. [ABSTRACT FROM AUTHOR]

Objective: To develop and validate a clinical score to predict the risk of tympanosclerosis before surgery. Methods: A sample of 404 patients who underwent middle ear microsurgery for otitis media was enrolled. These patients were randomly divided into 2 cohorts: the training cohort (n = 243, 60%) and the validation cohort (n = 161, 40%). The preoperative predictors of tympanosclerosis were determined by multivariate logistic regression analysis and implemented using a clinical score tool. The predictive accuracy and discriminative ability of the clinical score were determined by the area under the curve (AUC) and the calibration curve. Results: The multivariate analysis in the training cohort (n = 243, 60%) identified independent factors for tympanosclerosis as the female sex (odds ratio [OR]: 3.83; 95% CI: 1.66-9.37), the frequency-specific air-bone gap at 250 Hz ≥ 45 dB HL (OR: 3.68; 95% CI: 1.68-8.57), aditus ad antrum blockage (OR: 3.29; 95% CI: 1.38-8.43), type I eardrum calcification (OR: 25.37; 95% CI: 8.41-88.91) or type II eardrum calcification (OR: 18.86; 95% CI: 6.89-58.77), and a history of otitis media ≥ 10 years (OR: 4.10; 95% CI: 1.58-11.83), which were all included in the clinical score tool. The AUC of the clinical score for predicting tympanosclerosis was 0.89 (95% CI: 0.85-0.93) in the training cohort and 0.89 (95% CI: 0.84-0.95) in the validation cohort. The calibration curve also showed good agreement between the predicted and observed probability. Conclusions: The clinical score achieved an optimal prediction of tympanosclerosis before surgery. The presence of calcification pearls on the promontorium tympani is a strong predictor of tympanosclerosis with stapes fixation. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) has raised extensive concern in healthcare and academia as one of the most prevalent health threats to the elderly. Due to the irreversible nature of AD, early and accurate diagnoses are significant for effective prevention and treatment. However, diverse clinical symptoms and limited neuroimaging accuracy make diagnoses challenging. In this article, we built a brain network for each subject, which assembles several commonly used neuroimaging data simply and reasonably, including structural magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), and amyloid positron emission tomography (PET). Based on some existing research results, we applied statistical methods to analyze (i) the distinct affinity of AD burden on each brain region, (ii) the topological lateralization between left and right hemispheric sub-networks, and (iii) the asymmetry of the AD attacks on the left and right hemispheres. In the light of advances in graph convolutional networks for graph classifications and summarized characteristics of brain networks and AD pathologies, we proposed a regional brain fusion-graph convolutional network (RBF-GCN), which is constructed with an RBF framework mainly, including three sub-modules, namely, hemispheric network generation module, multichannel GCN module, and feature fusion module. In the multichannel GCN module, the improved GCN by our proposed adaptive native node attribute (ANNA) unit embeds within each channel independently. We not only fully verified the effectiveness of the RBF framework and ANNA unit but also achieved competitive results in multiple sets of AD stages' classification tasks using hundreds of experiments over the ADNI clinical dataset. [ABSTRACT FROM AUTHOR]

Abstract Background As a key gene in the immunosurveillance of cell malignancy, Cytotoxic T-lymphocyte antigen 4 (CTLA-4 is an important negative regulator of T cell activation and proliferation. The CTLA-4 +49G > A polymorphism is one of the most commonly studied polymorphisms in this gene due to its association with cancer risks, but previous results have been conflicting. Methods We preformed a meta-analysis using 22 eligible case-control studies (including 32 datasets) with a total of 11,273 patients and 13,179 controls to summarize the existing data on the association between the CTLA-4 +49G > A polymorphism and cancer risk. Results Compared with the common CTLA-4 +49G > A GG genotype, the carriers of variant genotypes (CTLA-4 +49 GC/CC) had a 1.24-fold elevated risk of cancer (95% CI = 1.18-1.32, P < 0.05) under the dominant genetic model, as estimated using a fixed effect model. The effect of the CTLA-4 +49G > A polymorphism was further evaluated using stratification analysis. In four breast cancer studies, patients with the variant genotypes had a significantly increased risk of breast cancer (OR = 1.31, 95% CI = 1.17-1.48, P < 0.00001). A similar result was found in three skin cancer studies (OR = 1.30, 95% CI = 1.10-1.52, P = 0.001). In 26 solid tumor studies, subjects with the variant genotypes had a significantly higher risk of developing solid tumors (OR = 1.25, 95% CI = 1.18-1.33, P < 0.00001) compared with the 6 non-solid tumor studies (OR = 1.08, 95% CI = 0.79-1.48, P = 0.62). Patients with variant genotypes had significantly increased risk of non-epithelial tumors and epithelial tumors, with ORs of 1.23 (95% CI = 1.14-1.32, P < 0.00001) and 1.29 (95% CI = 1.17-1.41, P < 0.00001), respectively. It was also demonstrated that the increased risk of cancer associated with CTLA-4 +49G > A variant genotypes was more pronounced in Caucasians (OR = 1.29, 95% CI = 1.13-1.47, P = 0.0002), Asians (OR = 1.23, 95% CI = 1.16-1.32, P < 0.00001) and Chinese (OR = 1.23, 95% CI = 1.15-1.31, P < 0.00001). Conclusion Our meta-analysis suggests that the CTLA-4 +49G > A polymorphism genotypes (GA + AA) might be associated with an increased risk of cancer, especially in Caucasians and Chinese.

Abstract Background The tumor suppressor TP53 and its negative regulator MDM2 play crucial roles in carcinogenesis. Previous case-control studies also revealed TP53 72Arg>Pro and MDM2 309T>G polymorphisms contribute to the risk of common cancers. However, the relationship between these two functional polymorphisms and nasopharyngeal carcinoma (NPC) susceptibility has not been explored. Methods In this study, we performed a case-control study between 522 NPC patients and 722 healthy controls in a Chinese population by using PCR-RFLP. Results We found an increased NPC risk associated with the MDM2 GG (odds ratio [OR] = 2.83, 95% confidence interval [CI] = 2.08-3.96) and TG (OR = 1.49, 95% CI = 1.16-2.06) genotypes. An increased risk was also associated with the TP53 Pro/Pro genotype (OR = 2.22, 95% CI = 1.58-3.10) compared to the Arg/Arg genotype. The gene-gene interaction of MDM2 and TP53 polymorphisms increased adult NPC risk in a more than multiplicative manner (OR for the presence of both MDM2 GG and TP53 Pro/Pro genotypes = 7.75, 95% CI = 3.53-17.58). Conclusion The findings suggest that polymorphisms of MDM2 and TP53 genes may be genetic modifier for developing NPC.

Radiation combined injury (RCI, radiation exposure coupled with other forms of injury, such as burn, wound, hemorrhage, blast, trauma and/or sepsis) comprises approximately 65% of injuries from a nuclear explosion, and greatly increases the risk of morbidity and mortality when compared to that of radiation injury alone. To date, no U.S. Food and Drug Administration (FDA)-approved countermeasures are available for RCI. Currently, three leukocyte growth factors (Neupogen®, Neulasta® and Leukine®) have been approved by the FDA for mitigating the hematopoietic acute radiation syndrome. However these granulocyte-colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) products have failed to increase 30-day survival of mice after RCI, suggesting a more complicated biological mechanism is in play for RCI than for radiation injury. In the current study, the mitigative efficacy of combination therapy using pegylated (PEG)-G-CSF (Neulasta) and -citrulline was evaluated in an RCI mouse model. L-citrulline is a neutral alpha-amino acid shown to improve vascular endothelial function in cardiovascular diseases. Three doses of PEG-G-CSF at 1 mg/kg, subcutaneously administered on days 1, 8 and 15 postirradiation, were supplemented with oral -citrulline (1 g/kg), once daily from day 1 to day 21 postirradiation. The combination treatment significantly improved the 30-day survival of mice after RCI from 15% (vehicle-treated) to 42%, and extended the median survival time by 4 days, as compared to vehicle controls. In addition, the combination therapy significantly increased body weight and bone marrow stem and progenitor cell clonogenicity in RCI mice, and accelerated recovery from RCI-induced intestinal injury, compared to animals treated with vehicle. Treatment with -citrulline alone also accelerated skin wound healing after RCI. In conclusion, these data indicate that the PEG-G-CSF and -citrulline combination therapy is a potentially effective countermeasure for mitigating RCI, likely by enhancing survival of the hematopoietic stem/progenitor cells and accelerating recovery from the RCI-induced intestinal injury and skin wounds. [ABSTRACT FROM AUTHOR]

Inflammatory cytokines have been suggested to play important roles in radiation-induced lung injury (RILI). Identifying significantly changed circulating and tissue cytokines after thoracic irradiation will aid in deciphering the mechanism of RILI and identifying potential biomarkers to predict clinical outcome. Herein, the levels of 24 cytokines were measured in serial plasma samples and lung tissue samples collected from a pilot study where nonhuman primates (NHPs) received 11.5 Gy whole thoracic lung irradiation (WTLI) and were then treated with or without a medical countermeasure, AEOL 10150 [a superoxide dismutase (SOD) mimetic]. Seven plasma cytokines (i.e., IP-10, MCP-1, IL-12, IL-15, IL-16, IL-7 and IL-6) were found to be significantly changed at different time points due to WTLI. Plasma IP-10 and MDC were significantly changed between the vehicle group and the drug group. The levels of IP-10, MCP-1, MIP-1α, TARC, IL-17, TNF-β and IL-6 were significantly elevated in the lung tissue lysates of NHPs that received WTLI versus radiation-naïve NHPs. The terminal plasma concentrations of IP-10, MDC, TARC, IL-12, IL-15 and IL-6 were significantly correlated with their levels in the lung tissue. The levels of four cytokines (MCP-4, IL-17, TNF-β and IL-2) at early time points (≤8 weeks postirradiation) were significantly correlated with their terminal plasma levels, respectively. Statistical analysis indicated that circulating cytokines could be discriminatory predictors of AEOL 10150 treatment. Taken together, our data suggested that the cytokine profiles were significantly changed after WTLI as well as mitigator treatment, and that the plasma cytokine profiles could potentially be used to distinguish vehicle or mitigator treatment after WTLI in a NHP model. [ABSTRACT FROM AUTHOR]

Background: Peripheral blood inflammation factor neutrophil-lymphocyte ratio (NLR), platelet count (PLT) and nutritional factor serum albumin (ALB) have been proposed as prognostic markers of head and neck squamous carcinoma cancer (HNSCC) in recent years. In the current study, nomogram predict models based on pre-treatment hematological parameters and a modified risk-stratified score system have been built. Methods: A total of 197 patients with oropharyngeal, hypopharyngeal and laryngeal cancers receiving multimodality treatment between 2012 and 2014 were included. The pre-treatment ALB, neutrophil, lymphocyte and platelet count (PLT) were detected. Cancer-specific survival and locoregional recurrence (LRC) by 5 years' follow-up in the cases were obtained. To integrate clinical characteristics, we propose a modified risk-stratified score system. Kaplan–Meier method, proportional hazards COX model, logistic models were used to establish nomograms within external validation. Results: Five-year LRC was decreased (p=0.004) for 140 patients with pre-treatment NLR < 2.77. Five-year LRC and 5-year cancer-specific survival were decreased (p=0.031, p=0.021) with pre-treatment PLT ≥ 248× 109/L. Comparison of univariate parametric models demonstrated that pre-treatment NLR evaluation and PLT> 248× 109/L were better among tested models. On Bayesian information criteria (BIC) analysis, the optimal prognostic model was then used to develop nomograms predicting 3- and 5-year LRC. The external validation of this predictive model was confirmed in 57 patients from another hospital. Conclusion: Pre-treatment NLR elevation and PLT> 248× 109/L are promising predictors of prognosis in patients with operable HNSCC. Nomograms based on the pre-treatment hematological markers and modified risk-stratified score system provide distinct risk stratifications. There results provided the feasibility of anti-inflammatory and antiplatelet treatments for HNSCC patients. [ABSTRACT FROM AUTHOR]

Introduction: RSL3-induced ferroptosis is a cell death pathway dependent upon intracellular iron and is characterized by accumulation of lipid hydroperoxides. Glutaminolysis, a glutamine-fueled intracellular metabolic pathway, is an essential pathway of ferroptosis in cancer cells. Recent findings showed low-concentration paclitaxel (PTX) could inhibit cell death by upregulating p53 expression; downregulating glutaminolysis-related genes. Methods: The therapeutic effect of RSL3 plus low-concentration PTX combination therapy was investigated in HPSCC cells harboring mutant p53 (mtp53). Relative cell viability, ferroptosis-specific lipid peroxidation and relevant protein expression were evaluated. Results: We demonstrated that neither PTX nor RSL3 in low concentration caused significant cell death; however, the combination therapy is shown to induce ferroptosis and significant cell death in mtp53 HPSCC. We discovered that low-concentration PTX enhanced the RSL3-induced ferroptosis by upregulating mtp53 expression. Furthermore, mtp53-mediated transcriptional regulation of SLC7A11 could be the key determinant. Discussion: Although gain-of-function of p53 variants remains to be characterized, our findings provide new insight into the synergistical cell death by regulating ferroptosis and p53. [ABSTRACT FROM AUTHOR]

Image completion is an approach to repair a damaged region (a hole) in an image. In this study, a novel image completion algorithm is proposed using texture direction to guide the completion process. We first analyse and detect the dominant texture direction using a gray-level co-occurrence matrix (GLCM). Based on the detected direction, we then generate a direction map that serves as a soft constraint during the completion process. Further, we propose an objective function that can balance the global texture structure and local coherency in order to maintain the structure consistency. Experimental results show that the proposed method has potential performance in maintaining the structure continuity and texture smoothness. [ABSTRACT FROM AUTHOR]