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There is increasing awareness of radiotherapy's potential side effects, such as lymphopenia. Therefore, this study aimed to establish the association between WBRT and the development of lymphopenia in patients with brain metastases undergoing brain radiotherapy (RT), along with evaluating the corresponding clinical outcomes. Including 116 patients with brain metastases undergoing brain radiotherapy, the study collected the absolute lymphocyte counts (ALC) within 2 weeks before brain radiotherapy (pre-radiotherapy, pre-RT), as well as ones at 1 and 2 months after completing RT (post-RT). Univariate and multivariate analyses were performed to identify associations between radiation modality and post-RT ALC. The relationships between post-RT ALC and overall survival were evaluated with Kaplan-Meier analysis and a multivariate Cox regression model. The median ALC definitely decreased at 1 month post-RT, but at 2 months post-RT, gradually rose but not to the pre-RT ALC. The multivariate analysis identified WBRT and lower pre-RT ALC as independent risk factors associated with the decrease in post-RT ALC at 1 month. It also revealed more than 4 brain metastases, G3-4 lymphopenia at 1 month and lower post-RT ALC at 2 months exhibited significantly worse prognosis regardless of the radiation modality. However, there was indeed an independent correlation between radiation modality and the outcome of intracranial progression-free survival (PFS). To approach the feasibility and reasonableness of treatment, clinicians should carefully consider various factors to achieve long-term survival of patients.

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Cells living in geometrically confined microenvironments are ubiquitous in various physiological processes, e.g., wound closure. However, it remains unclear whether and how spatially geometric constraints on host cells regulate bacteria-host interactions. Here, we reveal that interactions between bacteria and spatially constrained cell monolayers exhibit strong spatial heterogeneity, and that bacteria tend to adhere to these cells near the outer edges of confined monolayers. The bacterial adhesion force near the edges of the micropatterned monolayers is up to 75 nN, which is ~3 times higher than that at the centers, depending on the underlying substrate rigidities. Single-cell RNA sequencing experiments indicate that spatially heterogeneous expression of collagen IV with significant edge effects is responsible for the location-dependent bacterial adhesion. Finally, we show that collagen IV inhibitors can potentially be utilized as adjuvants to reduce bacterial adhesion and thus markedly enhance the efficacy of antibiotics, as demonstrated in animal experiments.

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Oral potentially malignant disorders (OPMDs) are precursor lesions with an increased risk of malignant transformation. Topical photodynamic therapy (PDT) mediated by 5-aminolevulinic acid (ALA) (ALA-PDT) is a promising therapeutic method in the treatment of OPMDs. However, the clinical application of topical ALA-PDT is restricted by several limitations, including low delivery efficiency, poor comfort, and easy influence by saliva. Here, we designed a highly adhesion-strength dry polyacrylic acid (PAA)-chitosan (CHI)-ALA interpenetrating network hydrogel (PACA) patch after investigating the spatiotemporal dynamics of ALA drug delivery via diffusion-based finite-element models. The PACA patch could adhere to the moist oral mucosa fast and stably and deliver ALA. PACA hydrogel-mediated PDT (PACA-PDT) effectively improved OPMDs in vitro and in a hamster oral carcinogenesis model. In particular, we conducted a trial to recruit 60 OPMD volunteers to demonstrate the feasibility and comfort of the PACA hydrogel patch. This study provides evidence that PACA hydrogel-mediated PDT could be a patient-friendly treatment modality for OPMDs.

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It is challenging for injectable hydrogels to achieve high underwater adhesiveness. Based on this concern, we report a fully physically crosslinked injectable hydrogel composed of gelatin, tea polyphenols and urea, capable of realising smart adhesion to various materials, like glass and porcine skin, in diverse aqueous environments. The urea molecules are designed as crosslinking disruptors for interfering with the formation of hydrogen bonds in the hydrogel, therefore modulating its crosslinking density and mechanical properties such as tensile strength, toughness and adhesive strength. Triggered by physical diffusion of the urea molecules towards the surrounding liquid environment, the hydrogel can achieve efficient (∼10 s), self-strengthening and long-lasting (>2 weeks) underwater adhesion. Remarkably, for fresh porcine skin, the instantaneous underwater adhesive strength is 10.4 kPa whereas the peak strength is as high as 152.9 kPa with the aid of the self-strengthening effect. More interestingly, it can simultaneously form controllable underwater non-adhesive surfaces, regulated by changes in the diffusion-triggered local concentration of urea. Further, it is also biocompatible, antibacterial, biodegradable and 3D printable in water, which offers great convenience for various applications concerning smart interfacial adhesion, like biomedicine and flexible electronics. Likewise, the physical diffusion-mediated mechanism represents an innovative strategy for developing next-generation smart hydrogels.

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Diabetes is an important public health problem and finding quick testing methods with high accuracy, reliability, and convenience are important to control the blood glucose of diabetic patients. In this study, a sensor based on a weak measurement scheme was developed for the specific detection of glucose for the first time. The detection of glucose using the proposed method was completed by the high sensitivity and resolution of the weak measurement based on optical rotation detection, as well as the change in the optical rotation before and after the specific oxidation of glucose. The resolution of the as-obtained glucose sensor was around 2.71×10-3 g/L (1.50×10-2 mmol/L), and the detection range was 0-11 g/L (0-61 mmol/L).

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Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening disease, which is characterized by severe systemic inflammation with cytokine storm as well as histologic evidence of hemophagocytosis. Besides, coagulopathy and hemorrhages are two common severe complications in HLH patients. Recent literatures indicate that Epstein-Barr virus (EBV) infection is one of the important triggers for the disease. In the study, we present three cases of EBV related HLH (EBV-HLH) with coagulopathy in patients with distinct backgrounds. Case 1 is a 45-year-old female diagnosed with EBV associated NK/T cell lymphoproliferative disorder (EBV-T/NK-LPD) and EBV-HLH. Case 2 is a 17-year-old male with a diagnosis of EBV-T-LPD and EBV-HLH. Case 3 is a 51-year-old male and also diagnosed with EBV-T-LPD and EBV-HLH. All cases were given with treatment with HLH-94 protocol, and the symptoms of the three patients improved. Furthermore, during the treatment, protamine, which has not been reported in the literature previously, was given to the three cases with EBV-HLH, and our results showed that after treatment with protamine, the coagulopathy and bleedings in these patients were improved rapidly. Unfortunately, the three patients relapsed soon and died despite intensive treatment. However, these cases suggest that protamine may serve as a potential treatment option for coagulation associated with EBV-HLH. Besides, the study helps us improve the understanding of the EBV-HLH related coagulation disorders, and provide a potential strategy for future treatment of the disease.

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Hyperthermia, particularly in combination with chemoradiotherapy, is widely used to treat various cancers. However, hyperthermia treatment is often insufficient due to thermo-tolerance. To date, the detailed mechanism underlying thermo-tolerance has not been clarified. The nuclear factor erythroid 2-related factor 2 (Nrf2)/ antioxidant response element (ARE) pathway is an important cellular cytoprotective defense system that is activated by various stresses. In this study, using immunocytochemistry and western blot analysis, we demonstrated that heat stress induced Nrf2/ARE activation through the nuclear translocation of Nrf2 in non-small cell lung cancer cells. Luciferase activity was also increased. Additionally, antioxidant enzymes were increased through Nrf2 activation after heat stress. Transfection of lung cancer cells with siRNA directed against Nrf2 increased heat cytotoxicity and cell apoptosis. Heat stress could induce reactive oxygen species (ROS) accumulation, while the antioxidant NAC obviously reduced cell apoptosis ratio, indicating that heat stress induced cell apoptosis in a ROS-dependent manner. Knockdown of Nrf2 led to an abnormal elevation of ROS, and the antioxidant NAC could increase Nrf2 activation, indicating that ROS and Nrf2 act within a negative feedback loop. Taken together, these results demonstrated that Nrf2 pathway is important for maintaining resistance to heat stress, and we postulated that Nrf2 may represent a potential therapeutic target for hyperthermia in lung cancer.

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Amine-functionalized silicon nanoparticles (A-SiNPs) with intense green fluorescence and photostability are synthesized via a one-step, low-cost hydrothermal method under mild conditions using 3-aminopropyl triethoxysilane (APTES) as a silicon source and L-ascorbic acid (AA) as a reducing reagent. The amine-rich surface not only improves water dispersability and stability of the A-SiNPs but also offers a specific copper(II) ion (Cu2+) coordination capability. The as-prepared A-SiNPs can be directly employed for Cu2+ detection in "turn-off" mode, resulting from Cu2+ coordination-induced fluorescence quenching effect. Under optimal conditions, Cu2+ detection was accomplished with a linear range from 1 to 500 µM and a limit of detection (LOD) at 0.1 µM, which was much lower than the maximum level (~ 20 µM) of Cu2+ in drinking water permitted by the US Environmental Protection Agency (EPA). In addition, the A-SiNPs were successfully used to detect Cu2+ in spiked river water, demonstrating its good selectivity and potential application for analysis of surface water samples. Graphical abstract.

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Microfluidic microbial fuel cells (MMFCs) are promising green power sources for future ultra-small electronic devices. The MMFCs with co-laminar microfluidic structure are superior to other MMFCs according to their low internal resistance and relative high power density. However, the area for interfacial electron transfer between the bacteria and the anode is quite limited in the typical Y-shaped device, which apparently restricts the current generation performance. In this study, we developed a membraneless MMFC with serpentine microchannel to enhance the interfacial electron transfer and promote the power generation of the device. Owing to the merit of laminar flow, the proposed MMFC was working well without any proton exchange membrane (PEM). At the same time, the serpentine microchannel greatly increased the power density. The S-MMFC catalyzed by Shewanella putrefaciens CN32 achieves a peak power density of 360 mW/m2 with the optimal channel configuration and the flow rate of 5 ml/h. Meanwhile, this device possesses much shorter start-up time and much longer duration time at high current plateau than the previous reported MMFCs. The presented MMFC appears promising for biochip technology and extends the scope of microfluidic energy.

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BACKGROUND AND OBJECTIVE: Insulin-like growth factor 1 (IGF1) gene three prime untranslated region (3'-UTR) polymorphisms have been reported to be associated with cancer risk. However, the conclusions of the relevant studies are not consistent. The present meta-analysis evaluates the relationship between IGF1 gene 3'-UTR polymorphisms (rs5742714, rs6214, and rs6220) and cancer risk. METHODS: Articles regarding the relationship between IGF1 rs5742714, rs6214, and rs6220 polymorphisms and cancer risk were selected by searching the PubMed, Embase, and Web of Science databases before April 30, 2018. Altogether, we obtained 34 case-controlled studies from 20 articles, including 21,568 cases and 31,199 controls. The strength of associations was quantified using odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). RESULTS: In the present meta-analysis, no significant associations were detected between rs5742714, rs6214, and rs6220 and overall cancer risk. Thus, in stratified analyses, we found that rs6214 was associated with a significantly reduced risk of breast cancer under the allele, heterozygote, and dominant models (A vs G: OR, 0.94, 95% CI,0.88-1.00, P = .044; GA vs GG: OR, 0.88, 95% CI, 0.80-0.97, P = .012; AA + GA vs GG: OR, 0.89, 95% CI, 0.81-0.97, P = .011), as well as pancreatic cancer under the recessive model (AA vs GA + GG: OR, 0.68, 95% CI,0.53-0.87, P = .003). Also, rs6220 was associated with a significantly increased risk of breast cancer under the homozygote model (GG vs AA: OR, 1.23, 95% CI, 1.02-1.48, P = .031). In addition, rs6220 was found to increase overall cancer risk among Caucasians under the allele model (G vs A: OR, 1.06, 95% CI, 1.00-1.13, P = .043). CONCLUSIONS: In this meta-analysis, we investigated and reviewed the relationship between IGF1 gene 3'-UTR polymorphisms (rs5742714, rs6214, and rs6220) and cancer risk based on present epidemiological studies. Further studies are needed to draw more precise conclusions in the future.

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In this paper, we propose a post-Gaussian filtering theory for weak measurement in the frequency domain, and propose a highly deformed digital filtering technique that can be used to optimize sensors based on weak-frequency measurement techniques. We completed the experimental verification based on the weak measurement total internal reflection sensor. The experimental results show that digital filtering technology can optimize the system in the working range, sensitivity, and resolution of the frequency domain weak measurement system, so that it can reach 0.210 rad, 3210.9 nm/RIU, and 7.12×10-7 RIU, respectively.

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BACKGROUND: The rs1520220 polymorphism in the insulin-like growth factor 1 (IGF1) gene has been reported to affect cancer susceptibly in several studies. However, the results of the relevant studies are inconsistent. We conduct a current meta-analysis to investigate the association between rs1520220 and cancer susceptibly. METHODS: Three databases (PubMed, Embase, and Web of Science) were searched for studies regarding the relationship between rs1520220 and cancer susceptibly. Odds ratios (ORs) and the related 95% confidence intervals (CIs) were employed to assess the strength of the associations. A stratified analysis was performed according to cancer type, ethnicity, and quality score, and when results were obtained from no fewer than two studies, these results were pooled. RESULTS: There was no positive association between rs1520220 and overall cancer risk. However, the analysis stratified by ethnicity revealed that rs1520220 significantly increased cancer susceptibility in Asian populations (allele model OR = 1.10, 95%Cl = 1.00-1.21, p = 0.040; homozygote model OR = 1.22, 95%Cl = 1.01-1.47, p = 0.040; dominant model OR = 1.19, 95%Cl = 1.01-1.39, p = 0.033). No significantly association was detected in Caucasian populations. The analysis stratified by cancer type suggested that rs1520220 was not associated with susceptibility to breast cancer. CONCLUSIONS: The results of our meta-analysis demonstrate that the role of IGF1 rs1520220 in cancer susceptibility varies by ethnicity and cancer type and that rs1520220 increases cancer susceptibility in Asian populations.

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Phase-sensitive weak measurement systems have been receiving an increasing amount of attention. In this paper, we introduce a series of weak measurement working areas. By adjusting the pre-selection and post-selection states and the total phase difference between vertically polarized light and horizontally polarized light, the measurement of the weak value is amplified by several times in one system. Its applicability is verified in a label-free total internal reflection system. The original sensitivity and resolution are improved at different working areas, reaching 1.85 um/refractive index unit (RIU) and 6.808 × 10-7 RIU, respectively.

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A high-resolution colorimetric immunoassay platform has been developed based on enzyme-catalyzed multicolor generation and smartphone-assisted signal readout. The multi-color generation is accomplished in this system through the urease-catalyzed urea hydrolysis-induced color change of the pH indicator phenol red, from yellow to orange to red over pH 6.6 to 8.0. The color change is easily tailored by controlling the urease activity via the inhibitor silver ion (Ag+), the amount of which is in turn adjusted by alkaline phosphatase (ALP)-catalyzed ascorbic acid (AA) production. An ALP-linked colorimetric immunoassay is readily realized based on the above urease catalyzed multicolor generation system. Under optimal conditions, a limit of detection (LOD) of 1.73 ng mL-1 and a dynamic range from 0 to 18 ng mL-1 are achieved with rabbit IgG as a model analyte. A colored picture for each test is directly taken using a smartphone and then quantitatively analyzed with the free software ImageJ, eliminating the use of expensive and desktop equipment. The dose-dependent multicolor display is easier to distinguish with the naked eye for qualitative or semiquantitative detection over the traditional one-color system. The developed immunoassay scheme provides a promising platform for on-site testing or applications in resource-poor areas.

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Many studies have reported that BRCA1 polymorphisms are associated with cancer risk, but the results remain controversial. The purpose of this meta-analysis is to evaluate the relationship between BRCA1 polymorphisms (rs799917, rs1799950, rs1799966, or rs16941) and cancer risk. Relevant studies were identified via a systematic search of the PubMed, Embase, and Web of Science databases up to July 31, 2017. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to examine the strength of the associations. Thirty-five studies published in 19 publications involving 28,094 cases and 50,657 controls were included in this meta-analysis. There was no obvious association between rs799917, rs1799966, or rs16941 polymorphisms and overall cancer risk in any genetic models. However, subgroup analyses revealed that the rs799917 polymorphism could decrease the risk of cervical cancer, esophageal squamous cell carcinoma (ESCC), gastric cancer, and non-Hodgkin lymphoma (NHL) among Asian populations in one or more genetic models and that rs16941 could increase overall cancer risk among Caucasian populations in the homozygote and recessive models. Our meta-analysis also indicated that rs1799950 could decrease the breast cancer (BC) risk among Caucasian populations in the homozygote and recessive models. In summary, our results suggest that BRCA1 polymorphisms may play an important role in the etiology of cancer. However, due to the limited number of studies, these findings should be confirmed by new studies with larger sample sizes that address various types of cancer.

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The rapid growth of demand for high-throughput multiplexed biochips from modern biotechnology has led to growing interest in suspension array based on multi-channel encoded microbeads. We prepare dual-spectra encoded PEGDA microbeads (DSEPM) by reversed-phase microemulsion UV curing method and layer-by-layer electrostatic self-assembly method. Excitation of the synthesized DSEPM results in two spectra, including fluorescence spectra from quantum dots and laser induced breakdown spectra from nanoparticles with specific elements. With further surface modification and bio-probes grafting, we use DSEPM to carry a series of detection experiments of biomolecules. The adsorption experiment to two types of anti-IgG in mixture sample has demonstrated the availability of DSEPM in multiplexing. Then, the contrast experiment has verified the specificity of DSEPM in detection. Finally, we carry out the concentration gradient experiment and obtain the response curve to show the performance of DSEPM in quantitative analysis. The results indicate our method provide an effective way to improve multiplexed biochips with more coding capacity, accuracy and stability.

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Bombesin receptor-activated protein (BRAP) is highly expressed in human bronchial epithelial cells. Recent studies have shown that BRAP reduces oxidative stress, inhibits airway inflammation and suppresses nuclear factor kappaB (NF-κB) activity. Mucus overproduction is an important feature in patients with chronic inflammatory airway diseases. Neutrophil elastase (NE) is a potent inducer of mucin5AC (MUC5AC), which is considered the predominant mucin secreted by human airway epithelial cells. Here, we hypothesize that BRAP may regulate NE-induced MUC5AC hypersecretion in a bronchial epithelial cell line (HBE16). We also investigated the underlying mechanism involved in the process. In this study, we found that BRAP was present in HBE16 human bronchial epithelial cells and was significantly increased by NE. Next, we found that the up-regulation of BRAP by pEGFP-N1-BRAP caused a significant decrease in the increased levels of MUC5AC expression, NF-κB activity, and the phosphorylation of extracellular signal-regulated kinases (ERK) and epidermal growth factor receptor (EGFR) induced by NE. Meanwhile, there was a significant decrease in ROS, interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) levels when BRAP was up-regulated by pEGFP-N1-BRAP. Moreover, when cells were transfected with pEGFP-N1-BRAP and pretreated with NF-κB, ERK or EGFR inhibitors before the NE stimulation, there were further decreased in MUC5AC expression, NF-κB activity, and the phosphorylation of ERK and EGFR. These results suggest that BRAP plays an important role in airway inflammation and its overexpression may regulate NE-induced MUC5AC hypersecretion in HBE16 cells via the EGFR/ERK/NF-κB signaling pathway.

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The occurrence and mechanisms of autophagy induced by heat stress are not well known in lung cancer cells. Here, we have demonstrated that heat stress induces autophagy in A549 and NCI-H460 cells through morphological and biochemical analyses. The inhibition of autophagy by chloroquine, 3-methyladenine and Beclin 1 siRNA enhanced heat-induced apoptosis. Moreover, the combination of chloroquine and heat stress inhibited tumor growth and enhanced apoptosis in vivo experiments. In addition, heat-induced autophagy involved the ER stress pathway (PERK- or IRE1-dependent). Further, heat treatment led to the increased phosphorylation of AMPK and the decreased phosphorylation of mTOR in vitro and in vivo. Knockdown of GRP78 inhibited the AMPK-mTOR pathway, and the AMPK inhibitor compound C decreased heat-induced autophagy, suggesting that activation of ER stress was involved in autophagy induction and promotion of the AMPK-mTOR pathway. In conclusion, our data suggested that the heat treatment of lung cancer cells triggered protective autophagy, as mediated by ER stress. Thus, inhibition of autophagy can be a promising strategy to enhance hyperthermia in the treatment of lung cancer patients.

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Mucus overproduction is an important feature in patients with chronic inflammatory airway diseases and cold air stimulation has been shown to be associated with the severity of these diseases. However, the regulatory mechanisms that mediate excessive mucin production under cold stress remain elusive. Recently, the cold-inducible RNA-binding protein (CIRP) has been shown to be markedly induced after exposure to cold air. In this study, we sought to explore the expression of CIRP within bronchial biopsy specimens, the effect on mucin5AC (MUC5AC) production in chronic inflammatory airway diseases and the potential signaling pathways involved in cold air stimulation process. We found that CIRP protein expression was significantly increased in patients with COPD and in mice treated with cold air. Moreover, cold air stimulation induced MUC5AC expression in wild-type mice but not in CIRP(-/-) mice. In vitro, cold air stress significantly elevated the transcriptional and protein expression levels of MUC5AC in human bronchial epithelial cells. CIRP, toll-like receptor 4 (TLR4) and phosphorylated NF-κB p65 (p-p65) increased significantly in response to cold stress and CIRP siRNA, TLR4 - neutralizing Ab and a specific inhibitor of NF-κB could attenuated cold stress inducible MUC5AC expression. In addition, CIRP siRNA could hindered the expression levels of TLR4 and p-p65 both induced by cold stress. Taken together, these results suggest that airway epithelial cells constitutively express CIRP in vitro and in vivo. CIRP is responsible for cold-inducible MUC5AC expression by activating TLR4/NF-κB signaling pathway.

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Mucus overproduction is an important manifestation of chronic airway inflammatory diseases, however, the mechanisms underlying the association between cold air and mucus overproduction remain unknown. We found that the expression of the cold-inducible RNA binding protein (CIRP) was increased in patients with chronic obstructive pulmonary disease (COPD). In the present study, we tested whether CIRP was involved in inflammatory factors and mucin5AC (MUC5AC) expression after cold stimulation and investigated the potential signaling pathways involved in this process. We found that CIRP was highly expressed in the bronchi of COPD patients. The expression of CIRP, interleukin-1ß (IL-1ß) and tumor necrosis factor α (TNF-α) were increased, and the CIRP was localized in cytoplasm after cold stimulation. MUC5AC mRNA and protein expression levels were elevated in a temperature- and time-dependent manner after cold stimulation and were associated with the phosphorylation of ERK and NF-κB, which reflected their activation. These responses were suppressed by knockdown of CIRP with a specific siRNA or the ERK and NF-κB inhibitors. These results demonstrated that CIRP was expressed in the bronchi of human COPD patients and was involved in inflammatory factors and MUC5AC expression after cold stimulation through the ERK and NF-κB pathways.

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