Association between MAPK and PI3K/Akt signaling pathway-related gene polymorphisms and migraine.

BACKGROUND: The causes of migraine remain unclear. Evidence suggests that the MAPK and PI3K/Akt signaling pathways play a role in migraine pathogenesis. However, studies on genetic polymorphisms in the two pathways associated with migraine are still limited. METHODS: This study included 226 migraineurs and 452 age- and sex-matched nonmigraine control individuals. Genotyping of 31 Single Nucleotide Polymorphisms (SNPs) in 21 genes was performed. The relationship between migraine and gene polymorphisms was analyzed by using logistic regression. SNP-SNP interactions were examined by a generalized multifactor dimension reduction (GMDR) approach. The possible role of SNPs was evaluated with gene expression data from the GTEx database. RESULTS: The RASGRP2-rs2230414 GT genotype was associated with decreased migraine risk compared with the wild-type GG genotype [ORadj (95% CI): 0.674(0.458-0.989)]. PIK3R1-rs3730089 was associated with migraine in the recessive model [ORadj (95% CI): 1.446(1.004-2.083)]. The CACNA1H-rs61734410 CT genotype was associated with migraine risk [ORadj (95% CI): 1.561(1.068-2.281)]. One significant two-way SNP-SNP interaction was found (PRKCA rs2228945-BDNF rs6265) (p = 0.0107). Significant eQTL and sQTL signals were observed for the SNP rs2230414. CONCLUSIONS: This is the first study to systematically reveal significant associations between MAPK and PI3K/Akt signaling pathway-related gene polymorphisms and migraine risk.

Prognostic scoring system based on eosinophil- and basophil-related markers for predicting the prognosis of patients with stage II and stage III colorectal cancer: a retrospective cohort study.

Background: Systemic inflammation is associated with the prognosis of colorectal cancer (CRC). The current study aimed to construct a comprehensively inflammatory prognostic scoring system named risk score (RS) based on eosinophil- and basophil-related markers and assess its prognostic value in patients with stage II and stage III CRC. Patients and methods: A total of 3,986 patients were enrolled from January 2007 to December 2013. The last follow-up time was January 2019. They were randomly assigned to the training set and testing set in a 3:2 split ratio. Least absolute shrinkage and selection operator (LASSO)-Cox regression analysis was performed to select the optimal prognostic factors in the construction of RS. The Kaplan-Meier curve, time-dependent receiver operating characteristic (ROC), and Cox analysis were used to evaluate the association between RS and overall survival (OS). Results: In the training set, all inflammatory markers showed certain prognostic values. Based on LASSO-Cox analysis, nine markers were integrated to construct RS. The Kaplan-Meier curve showed that a higher RS (RS > 0) had a significantly worse prognosis (log-rank p< 0.0001). RS (>0) remained an independent prognostic factor for OS (hazard ratio (HR): 1.70, 95% confidence interval (CI), 1.43-2.03, p< 0.001). The prognostic value of RS was validated in the entire cohort. Time-dependent ROC analysis showed that RS had a stable prognostic effect throughout the follow-up times and could enhance the prognostic ability of the stage by combination. Nomogram was established based on RS and clinicopathological factors for predicting OS in the training set and validated in the testing set. The area under the curve (AUC) values of the 3-year OS in the training and testing sets were 0.748 and 0.720, respectively. The nomogram had a satisfactory predictive accuracy and had better clinical application value than the tumor stage alone. Conclusions: RS might be an independent prognostic factor for OS in patients with stage II and III CRC, which is helpful for risk stratification of patients. Additionally, the nomogram might be used for personalized prediction and might contribute to formulating a better clinical treatment plan.

Paraoxonase 2 (PON2) plays a limited role in murine lung tumorigenesis.

Paraoxonase 2 (PON2) is a multifunctional intracellular enzyme that has received growing attention for its ability to modulate various aspects of normal and malignant cellular physiology. Recent research has revealed that PON2 is upregulated in tissues from patients with various types of solid tumors and hematologic cancers, likely due to its ability to suppress oxidative stress and evade apoptosis. However, the effects of PON2 on pulmonary oncogenesis are unknown. Here, we conducted studies to investigate how PON2 influences lung cancer cell proliferation in vitro and lung tumorigenesis in vivo using a variety of cellular and animal models. It was found that PON2 expression deficiency hampered the proliferation of cultured lung cancer cells with concomitant cell cycle arrest at the G1 phase. In addition, the loss of endogenous PON2 expression impaired key aspects of oxidative metabolism in lung adenocarcinoma cells. Moreover, we investigated how the interplay between PON2 expression in lung tumors and host mice influences lung tumor initiation and progression. PON2 status in both transplanted tumor cells and mice failed to influence the development of subcutaneously grafted Lewis lung carcinoma (LLC) tumors, orthotopically implanted LLC tumors, and oncogenic Kras-driven primary lung adenocarcinoma tumors. Importantly, the frequencies of tumor-infiltrating myeloid subsets that include myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages were not impacted by PON2 expression in LLC tumor-bearing mice. Overall, our studies indicate that PON2 plays a limited role in murine lung tumorigenesis.

Association between TRP channels and glutamatergic synapse gene polymorphisms and migraine and the comorbidities anxiety and depression in a Chinese population.

Background: Genetic and environmental factors contribute to migraine and the comorbidities of anxiety and depression. However, the association between genetic polymorphisms in the transient receptor potential (TRP) channels and glutamatergic synapse genes with the risk of migraine and the comorbidities of anxiety and depression remain unclear. Methods: 251 migraine patients containing 49 comorbidities with anxiety and 112 with depression and 600 controls were recruited. A customized 48-plex SNPscan kit was used for genotyping 13 SNPs of nine target genes. Logistic regression was conducted to analyze these SNPs' association with the susceptibility of migraine and comorbidities. The generalized multifactor dimension reduction (GMDR) was applied to analyze the SNP-SNP and gene-environment interactions. The GTEx database was used to examine the effects of the significant SNPs on gene expressions. Results: The TRPV1 rs8065080 and TRPV3 rs7217270 were associated with an increased risk of migraine in the dominant model [ORadj (95% CI): 1.75 (1.09-2.90), p = 0.025; 1.63 (1.02-2.58), p = 0.039, respectively]. GRIK2 rs2227283 was associated with migraine in the edge of significance [ORadj (95% CI) = 1.36 (0.99-1.89), p = 0.062]. In migraine patients, TRPV1 rs222741 was associated with both anxiety risk and depression risk in the recessive model [ORadj (95% CI): 2.64 (1.24-5.73), p = 0.012; 1.97 (1.02-3.85), p = 0.046, respectively]. TRPM8 rs7577262 was associated with anxiety (ORadj = 0.27, 95% CI = 0.10-0.76, p = 0.011). TRPV4 rs3742037, TRPM8 rs17862920 and SLC17A8 rs11110359 were associated with depression in dominant model [ORadj (95% CI): 2.03 (1.06-3.96), p = 0.035; 0.48 (0.23-0.96), p = 0.042; 0.42 (0.20-0.84), p = 0.016, respectively]. Significant eQTL and sQTL signals were observed for SNP rs8065080. Individuals with GRS (Genetic risk scores) of Q4 (14-17) had a higher risk of migraine and a lower risk of comorbidity anxiety than those with Genetic risk scores scores of Q1 (0-9) groups [ORadj (95% CI): 2.31 (1.39-3.86), p = 0.001; 0.28 (0.08-0.88), p = 0.034, respectively]. Conclusion: This study suggests that TRPV1 rs8065080, TRPV3 rs7217270, and GRIK2 rs2227283 polymorphism may associate with migraine risk. TRPV1 rs222741 and TRPM8 rs7577262 may associate with migraine comorbidity anxiety risk. rs222741, rs3742037, rs17862920, and rs11110359 may associate with migraine comorbidity depression risk. Higher GRS scores may increase migraine risk and decrease comorbidity anxiety risk.

Exosome-based cancer vaccine for prevention of lung cancer.

Background: Our earlier work has shown that a unique stem cell-based vaccine that comprises of murine embryonic stem cells (ESCs) and murine fibroblasts expressing the immunostimulant granulocyte-macrophage colony stimulating factor (GM-CSF) successfully protects mice from the outgrowth of an implantable form of murine lung cancer. The use of live ESCs raises the potential risks of inducing teratomas and autoimmunity. We have attempted to improve the safety and utility of this prophylactic vaccine by employing exosomes derived from murine ESCs engineered to produce GM-CSF (ES-exo/GM-CSF vaccine). Methods: We have previously reported that ES-exo/GM-CSF immunization does protect mice from the outgrowth of an implantable form of murine lung cancer. Here, we have investigated the cancer prevention efficacy of ES-exo/GM-CSF vaccine in an experimental metastasis model of murine lung cancer, in which Lewis lung carcinoma (LLC) cells were administered into female C57BL/6 mice (8 weeks of age) through tail vein injection and subsequently LLC tumors were established in lungs. Results: Our objective is to test the anti-cancer efficacy of ES-exo/GM-CSF vaccine in a mouse model of metastatic lung cancer. Our studies indicate that vaccination of mice with ES-exo/GM-CSF vaccine inhibited the growth of metastatic lung tumors. ES-exo/GM-CSF vactionation reduced lung tumor burden from 1.86% in non-vaccinated, LLC-challenged mice to 0.036% in corresponding vacinnated mice. Importantly, control exosomes without GM-CSF failed to provide protection against metastasized pulmonary tumors. The efficacy of ES-exo/GM-CSF vaccination was associated with a decrease in the frequencies of tumor-infiltrating immunosuppressive immune cells, including T regulatory cells, myeloid derived suppressor cells (MDSCs) and tumor-associated macrophages, as well as an increase in effector cytokine production from intra-tumoral CD8+ T cells. Conclusions: Overall, our research provides a novel strategy for developing a cell-free prophylactic vaccine against lung tumors.

A novel bioactive postbiotics: from microbiota-derived extracellular nanoparticles to health promoting.

In recent years, the emerging concern regarding safety issues associated with live bacterial cells is enhancing the interest in using cell components and metabolites derived from microbiota. Therefore, the term "postbiotics" is increasingly found in food microbiology, food scientific and commercial products. Postbiotics is defined as non-viable microorganisms or their components that provide benefits to the host. Many in vivo and in vitro experiments have shown that beneficial microbiota-generated extracellular nanoparticles (NPs) confer unique health promoting functions to the intestinal local and systemic effects, which can be considered as a novel postbiotics. Meanwhile, the postbiotics-NPs is a protective complex, delivering bioactive components to reach distant tissues and organs at high concentrations. These properties demonstrate that postbiotics-NPs may contribute to the improvement of host health by regulating specific gut microbiota and physiological functions, while the exact mechanisms are not fully elucidated. This review highlights the current understanding of postbiotics-NPs functional properties and mechanisms of health benefits, especially focusing on the interactions in gut microbiota and host, functions in human health and potential applications in future functional food and biomedical fields.

Astrocyte derived TSP2 contributes to synaptic alteration and visual dysfunction in retinal ischemia/reperfusion injury.

BACKGROUND: Despite current intervention measures/therapies are able to ameliorate neuronal death following retinal injuries/diseases, the recovery of visual function remains unsatisfactory. Previous studies revealed that the retinal synapse and neurite changed during the early stage after retinopathy, which was considered to be detrimental to visual signal transmission. However, the specific profiles and the mechanisms underlying retinal neurite and synaptic alteration after retinal pathologies remain poorly understood. METHODS: Here, we revealed the spatiotemporal pattern of neurite and synaptic alteration following retinal pathologies using a rat model of acute RI/R induced by high intraocular pressure (HIOP) with Western blotting, Immunofluorescence, and electron microscopy. We further explored the potential role of activated astrocytes and their derived thrombospondin 2 (TSP2) in RI/R induced retinal neurite and synaptic alteration and visual dysfunction through viral transduction and drug injection. RESULTS: We found a defasciculation of RGC axons, a compensatory increase of presynaptic proteins (synaptophysin and synapsin 1) and synaptic vesicles between bipolar cells and ganglion cells in the inner plexiform layer (IPL), and the degenerated visual function preceded the neuronal death in rat retinae. These events were accompanied by the activation of astrocytes. Furthermore, we showed that suppressing the activation of astrocytes (intravitreal injection of fluorocitric acid, FC), TSP2 knockdown (TSP2 shRNA-AAV transduction), and competitively inhibiting the binding of TSP2 and α2δ1 (intraperitoneal injection of gabapentin, GBP) effectively alleviated the retinal synaptic and neurite alteration and the visual dysfunction following RI/R injury. CONCLUSIONS: (1) At the early stage following RI/R injury, the rat retinae develop a degeneration of ganglion cell axons and the resulting compensatory synaptic remodeling between bipolar cells and ganglion cells in IPL. These changes occur earlier than the massive loss of neurons in the ganglion cell layer (GCL). (2) Activated astrocytes may secret TSP2, which bind to α2δ1, to mediate the degeneration of rat retinal ganglion cell axons, compensatory synaptic remodeling in IPL, and visual dysfunction following RI/R injury.

PON2 mediates mitochondrial dysfunction in tracheal epithelial cells in response to a quorum sensing molecule N-(-3-oxododecanoyl)-l-homoserine lactone.

The opportunistic bacterium Pseudomonas aeruginosa secretes the quorum-sensing molecule N-(3-oxododecanoyl)-l-homoserine lactone (C12) to co-ordinate gene expression profiles favorable for infection. Recent studies have demonstrated that high concentrations of C12 impair many aspects of host cell physiology, including mitochondrial function and cell viability. The cytotoxic effects of C12 are mediated by the lactonase enzyme, Paraoxonase 2 (PON2), which hydrolyzes C12 to a reactive metabolite. However, the influence of C12 on host cell physiology at concentrations observed in patients infected with P. aeruginosa is largely unknown. Since the primary site of P. aeruginosa infections is the mammalian airway, we sought to investigate how PON2 modulates the effects of C12 at subtoxic concentrations using immortalized murine tracheal epithelial cells (TECs) isolated from wild-type (WT) or PON2-knockout (PON2-KO) mice. Our data reveal that C12 at subtoxic concentrations disrupts mitochondrial bioenergetics to hinder cellular proliferation in TECs expressing PON2. Subtoxic concentrations of C12 disrupt normal mitochondrial network morphology in a PON2-dependent manner without affecting mitochondrial membrane potential. In contrast, higher concentrations of C12 depolarize mitochondrial membrane potential and subsequently trigger caspase signaling and apoptotic cell death. These findings demonstrate that different concentrations of C12 impact distinct aspects of host airway epithelial cell physiology through PON2 activity in mitochondria.

DNA Methylation of Imprinted Genes KCNQ1, KCNQ1OT1, and PHLDA2 in Peripheral Blood Is Associated with the Risk of Breast Cancer.

Methylation alterations of imprinted genes lead to loss of imprinting (LOI). Although studies have explored the mechanism of LOI in breast cancer (BC) development, the association between imprinted gene methylation in peripheral blood and BC risk is largely unknown. We utilized HumanMethylation450 data from TCGA and GEO (n = 1461) to identify the CpG sites of imprinted genes associated with BC risk. Furthermore, we conducted an independent case-control study (n = 1048) to validate DNA methylation of these CpG sites in peripheral blood and BC susceptibility. cg26709929, cg08446215, cg25306939, and cg16057921, which are located at KCNQ1, KCNQ1OT1, and PHLDA2, were discovered to be associated with BC risk. Subsequently, the association between cg26709929, cg26057921, and cg25306939 methylation and BC risk was validated in our inhouse dataset. All 22 CpG sites in the KCNQ1OT1 region were associated with BC risk. Individuals with a hypermethylated KCNQ1OT1 region (>0.474) had a lower BC risk (OR: 0.553, 95% CI: 0.397−0.769). Additionally, the methylation of the KCNQ1OT1 region was not significantly different among B cells, monocytes, and T cells, which was also observed at CpG sites in PHLDA2. In summary, the methylation of KCNQ1, KCNQ1OT1, and PHLDA2 was associated with BC risk, and KCNQ1OT1 methylation could be a potential biomarker for BC risk assessment.

Age of Rats Affects the Degree of Retinal Neuroinflammatory Response Induced by High Acute Intraocular Pressure.

PURPOSE: To investigate whether retinal neuroinflammatory response was affected by aging in a rat model of acute glaucoma. METHODS: Young adult and aged rats were randomly assigned into normal control, 45 mmHg, 60 mmHg, and 90 mmHg groups. Intraocular pressure (IOP) of rats was acutely elevated to 45 mmHg, 60 mmHg, and 90 mmHg, respectively. Three days after high IOP treatment, loss of retinal ganglion cells (RGCs), formation of proinflammatory microglia/macrophages and neurotoxic astrocytes, and deposition of complement C3 in the retina were detected by immunofluorescence. ELISA was used to assess the protein levels of proinflammatory cytokines TNF and IL-1ß in the retina. RESULTS: Compared with young adult retinae, (1) loss of RGCs was more severe in aged retinae under the same IOP treatment, (2) microglia/macrophages were more prone to adopt proinflammatory phenotype in aged retinae in response to elevated IOP, (3) high IOP treatment induced astrogliosis, formation of neurotoxic astrocytes, and deposition of complement C3 more easily in aged retinae, and (4) aged retinae induced higher levels of proinflammatory cytokines TNF and IL-1ß under the same IOP treatment. CONCLUSION: Our data indicated that aging affects the degree of retinal neuroinflammatory response initiated by ocular hypertension, which may contribute to the age-related susceptibility of RGCs to elevated IOP.

Transneuronal Degeneration in the Visual Pathway of Rats following Acute Retinal Ischemia/Reperfusion.

The maintenance of visual function not only requires the normal structure and function of neurons but also depends on the effective signal propagation of synapses in visual pathways. Synapses emerge alterations of plasticity in the early stages of neuronal damage and affect signal transmission, which leads to transneuronal degeneration. In the present study, rat model of acute retinal ischemia/reperfusion (RI/R) was established to observe the morphological changes of neuronal soma and synapses in the inner plexiform layer (IPL), outer plexiform layer (OPL), and dorsal lateral geniculate nucleus (dLGN) after retinal injury. We found transneuronal degeneration in the visual pathways following RI/R concretely presented as edema and mitochondrial hyperplasia of neuronal soma in retina, demyelination, and heterotypic protein clusters of axons in LGN. Meanwhile, small immature synapses formed, and there are asynchronous changes between pre- and postsynaptic components in synapses. This evidence demonstrated that transneuronal degeneration exists in RI/R injury, which may be one of the key reasons for the progressive deterioration of visual function after the injury is removed.

Isolation of Exosome-Enriched Extracellular Vesicles Carrying Granulocyte-Macrophage Colony-Stimulating Factor from Embryonic Stem Cells.

Embryonic stem cells (ESCs) are pluripotent stem cells capable of self-renewal and differentiation into all types of embryonic cells. Like many other cell types, ESCs release small membrane vesicles, such as exosomes, to the extracellular environment. Exosomes serve as essential mediators of intercellular communication and play a basic role in many (patho)physiological processes. Granulocyte-macrophage colony-stimulating factor (GM-CSF) functions as a cytokine to modulate the immune response. The presence of GM-CSF in exosomes has the potential to boost their immune-regulatory function. Here, GM-CSF was stably overexpressed in the murine ESC cell line ES-D3. A protocol was developed to isolate high-quality exosome-enriched extracellular vesicles (EVs) from ES-D3 cells overexpressing GM-CSF. Isolated exosome-enriched EVs were characterized by a variety of experimental approaches. Importantly, significant amounts of GM-CSF were found to be present in exosome-enriched EVs. Overall, GM-CSF-bearing exosome-enriched EVs from ESCs might function as cell-free vesicles to exert their immune-regulatory activities.

Polarization-Independent Optoelectronic Modulator Based on Graphene Ridge Structure.

In this paper, we propose a polarization-independent optoelectronic modulator based on the electrical absorption effect of graphene. Firstly, we use the simulation software COMSOL Multiphysics to design the structure, and find via changing the applied voltage on both ends of the graphene that the equivalent refractive index of graphene can be changed, thus changing the light absorption capacity of the modulator. The waveguides in the transverse magnetic (TM) and transverse electric (TE) modes have almost the same extinction coefficient by making a double-layer graphene ridge structure in the center of the silicon-based waveguide, which can achieve approaching modulation depth in the TM and TE modes. At 1550 nm wavelength, the two-dimensional cross-section of the structure is analyzed by the FEM method using COMSOL Multiphysics to obtain the effective refractive index of the structure. The simulation results show that when the distance between the double-layer graphene isolation layer is d = 20 nm, the TE and TM modes can achieve extinction ratios up to 110 dB over the wide communication band by selecting appropriate "ON" and "OFF" switching points. The bandwidth is 173.78 GHz and the insertion loss is only 0.0338 dB.

How to control cruise ship disease risk? Inspiration from the research literature.

The COVID-19 pandemic once brought the global cruise industry to a standstill. This has led to the realization that the development of viable disease risk management policies and measures will guarantee the sustainability of cruise tourism. The purpose of this study is to identify and develop a framework for risk management of cruise ship disease based on the research literature of cruise diseases in the Web of Science from 1996 to 2019. The study analyzed the characteristics of the literature researchers, the relationships between their research institutions organizations, the main cruise ship disease cases and measures. Based on the discussion of COVID-19 on cruise ships，risk management factors of cruise ship diseases were proposed，which include the port country's epidemic prevention capacity, the mode of disease transmission, the relevant regulations on international public health disposal, the design and construction of cruise ships, the medical and health conditions on cruise ships, and the characteristics of cruise tourism activities. A timeline and system framework for cruise ship disease risk management is proposed. A special "maritime mobile community prevention and control system" should be established, and a cooperation mechanism consisting of the government, non-governmental organizations, trade groups and industry experts should be established. The port should be capable of border isolation, detection and establishment of temporary shelter hospitals. At the same time, big data technologies such as disease tracking, investigation and health data are also important components of the risk management system.

Association Between Dietary Iron Intake and Serum Ferritin and Severe Headache or Migraine.

Background: Dietary iron intake and serum ferritin in relation to severe headache or migraine remain largely unknown. Therefore, we investigated the associations between dietary iron intake and serum ferritin with severe headache or migraine among American adults. Methods: This cross-sectional study included 7,880 adults (≥20 years) from the National Health and Nutrition Examination Surveys (NHANES) of America from 1999 to 2004. We performed multivariable logistic regression and restricted cubic spline (RCS) regression to assess the association of dietary iron and serum ferritin with severe headache or migraine. Results: Most women aged 20-50 years consumed less dietary iron than their recommended dietary allowances. Dietary iron intake was inversely associated with severe headache or migraine in women aged 20-50 years. For women over 50 years, serum ferritin was negatively associated with severe headache or migraine. For men, there was no significant relationship between dietary iron and serum ferritin, and severe headache or migraine. Conclusions: Dietary iron intake has different effects on migraine in women of different ages, and this different effect may be due to age-related menstrual changes. Women aged 20-50 years should have a higher awareness of RDA and increase their dietary iron intake if needed, which may play an important role in preventing severe headache or migraine. Higher serum ferritin levels in women aged 50 and above may have a protective effect against migraine.

Dietary Intake of Calcium and Magnesium in Relation to Severe Headache or Migraine.

Background: Migraine is a common neurological disorder and is affected by nutrients. Calcium and magnesium are essential minerals that play an important role in nerve function. So we investigated the association between dietary calcium and magnesium and migraine. Methods: We extracted 10,798 adults from the National Health and Nutrition Examination Surveys (NHANES) of America in 1999 to 2004. We classified patients who reported having severe headache or migraine as having possible migraine. Multivariable logistic regression and restricted cubic spline regression were conducted to determine the association between dietary calcium and magnesium and migraine. Results: We found that the adjusted ORs of the association between dietary calcium and magnesium and migraine for comparing the highest quintile intake with the lowest quintile intake were 0.77 (95% CI: 0.63-0.93, P = 0.008) and 0.69 (95% CI: 0.55-0.86, P = 0.001), respectively. For women, the adjusted ORs of dietary calcium and magnesium were 0.72 (95% CI: 0.56-0.93, P = 0.009) and 0.62 (95% CI: 0.47-0.83, P = 0.001), respectively. For men, the adjusted OR was 0.71 (95% CI: 0.52-0.97, P = 0.028) comparing the highest and the lowest quintile of calcium intake, but there was no statistically significant association between dietary magnesium intake and migraine. Joint analyses showed that the OR in the high-calcium and high-magnesium group was 0.74 (95% CI: 0.60-0.92, P = 0.006) compared with the low-calcium and low-magnesium group in women. Conclusions: High dietary intake of calcium and magnesium, independently or in combination, were inversely associated with migraine in women. For men, high dietary calcium was negatively related to migraine, but magnesium was not associated with migraine.

Prognostic Inflammatory Index Based on Preoperative Peripheral Blood for Predicting the Prognosis of Colorectal Cancer Patients.

Host inflammation is a critical component of tumor progression and its status can be indicated by peripheral blood cell counts. We aimed to construct a comprehensively prognostic inflammatory index (PII) based on preoperative peripheral blood cell counts and further evaluate its prognostic value for patients with colorectal cancer (CRC). A total of 9315 patients with stage II and III CRC from training and external validation cohorts were included. The PII was constructed by integrating all the peripheral blood cell counts associated with prognosis in the training cohort. Cox analyses were performed to evaluate the association between PII and overall survival (OS) and disease-free survival (DFS). In the training cohort, multivariate Cox analyses indicated that high OS-PII (>4.27) was significantly associated with worse OS (HR: 1.330, 95% CI: 1.189-1.489, p < 0.001); and high DFS-PII (>4.47) was significantly associated with worse DFS (HR: 1.366, 95% CI: 1.206-1.548, p < 0.001). The prognostic values of both OS-PII and DFS-PII were validated in the external validation cohort. The nomograms achieved good accuracy in predicting both OS and DFS. Time-dependent ROC analyses showed that both OS-PII and DFS-PII have a stable prognostic performance at various follow-up times. The prognostic value of tumor-node-metastasis staging could be enhanced by combining it with either OS-PII or DFS-PII. We demonstrated that PIIs are independent prognostic predictors for CRC patients, and the nomograms based on PIIs can be recommended for personalized survival prediction of patients with CRC.

Nonpharmacologic Interventions for Reducing Blood Pressure in Adults With Prehypertension to Established Hypertension.

Background Nonpharmacologic interventions that modify lifestyle can lower blood pressure (BP) and have been assessed in numerous randomized controlled trials and pairwise meta-analyses. It is still unclear which intervention would be most efficacious. Methods and Results Bayesian network meta-analyses were performed to estimate the comparative effectiveness of different interventions for lowering BP. From 60 166 potentially relevant articles, 120 eligible articles (14 923 participants) with a median follow-up of 12 weeks, assessing 22 nonpharmacologic interventions, were included. According to the surface under the cumulative ranking probabilities and Grading of Recommendations Assessment, Development and Evaluation (GRADE) quality of evidence, for adults with prehypertension to established hypertension, high-quality evidence indicated that the Dietary Approach to Stop Hypertension (DASH) was superior to usual care and all other nonpharmacologic interventions in lowering systolic BP (weighted mean difference, 6.97 mm Hg; 95% credible interval, 4.50-9.47) and diastolic BP (weighted mean difference, 3.54 mm Hg; 95% credible interval, 1.80-5.28). Compared with usual care, moderate- to high-quality evidence indicated that aerobic exercise, isometric training, low-sodium and high-potassium salt, comprehensive lifestyle modification, breathing-control, and meditation could lower systolic BP and diastolic BP. For patients with hypertension, moderate- to high-quality evidence suggested that the interventions listed (except comprehensive lifestyle modification) were associated with greater systolic BP and diastolic BP reduction than usual care; salt restriction was also effective in lowering both systolic BP and diastolic BP. Among overweight and obese participants, low-calorie diet and low-calorie diet plus exercise could lower more BP than exercise. Conclusions DASH might be the most effective intervention in lowering BP for adults with prehypertension to established hypertension. Aerobic exercise, isometric training, low-sodium and high-potassium salt, comprehensive lifestyle modification, salt restriction, breathing-control, meditation and low-calorie diet also have obvious effects on BP reduction.

Exosomes from GM-CSF expressing embryonic stem cells are an effective prophylactic vaccine for cancer prevention.

The antigenic similarity between embryos and tumors has raised the idea of using embryonic material as a preventative vaccine against neoplastic disease. Indeed, we have previously reported that a vaccine comprises allogeneic murine embryonic stem cells (ESCs) and murine fibroblasts expressing GM-CSF (to amplify immune responses) successfully blocks the outgrowth of an implantable cancer (Lewis lung carcinoma; LLC) and lung tumors generated in mice using a combination of a mutagen followed by chronic pulmonary inflammation. However, such a vaccine is obviously impractical for application to humans. The use of fibroblasts to generate GM-CSF is needlessly complicated, and intact whole ESCs carry the hazard of generating embryomas/teratomas. Here, we report the successful application of an alternative prophylactic vaccine comprises exosomes derived from murine ESCs engineered to produce GM-CSF. Vaccination of mice with these exosomes significantly slowed or blocked the outgrowth of implanted LLC while control exosomes lacking GM-CSF were ineffective. Examination of tumor-infiltrating immune cells from mice vaccinated with the GM-CSF-expressing exosomes showed robust tumor-reactive CD8+ T effector responses, Th1 cytokine responses, and higher CD8+ T effector/CD4+CD25+Foxp3+ T regulatory cell ratio in the tumors. We conclude that a similar vaccine derived from GM-CSF- expressing human ESCs can be employed as a preventative vaccine for humans with an increased risk of developing cancer.

N-(3-Oxo-acyl)-homoserine lactone induces apoptosis primarily through a mitochondrial pathway in fibroblasts.

N-(3-Oxododecanoyl)-l-homoserine lactone (C12) is produced by Pseudomonas aeruginosa to function as a quorum-sensing molecule for bacteria-bacteria communication. C12 is also known to influence many aspects of human host cell physiology, including induction of cell death. However, the signalling pathway(s) leading to C12-triggered cell death is (are) still not completely known. To clarify cell death signalling induced by C12, we examined mouse embryonic fibroblasts deficient in "initiator" caspases or "effector" caspases. Our data indicate that C12 selectively induces the mitochondria-dependent intrinsic apoptotic pathway by quickly triggering mitochondrial outer membrane permeabilisation. Importantly, the activities of C12 to permeabilise mitochondria are independent of activation of both "initiator" and "effector" caspases. Furthermore, C12 directly induces mitochondrial outer membrane permeabilisation in vitro. Overall, our study suggests a mitochondrial apoptotic signalling pathway triggered by C12, in which C12 or its metabolite(s) acts on mitochondria to permeabilise mitochondria, leading to activation of apoptosis.