Research progress of immunotherapy for advanced head and neck cancer.

Head and neck cancer accounts for about one-fifth of all malignant tumors, and the incidence is increasing year by year. The overall mortality rate was high and the 5-year survival rate was low. At present, the combination of surgery, radiotherapy, and chemotherapy is the main treatment in clinical practice, but the treatment of recurrent or metastatic advanced head and neck cancer is still a challenge. With the rise of immunotherapy, more and more studies on immune checkpoint inhibitors have been conducted. This review summarizes the mechanism, clinical application and safety of immunotherapy for advanced head and neck cancer.

Inhibition of PI3K/Akt/mTOR Signaling Pathway Suppresses 5-Fluorouracil Resistance in Gastric Cancer.

BACKGROUND: At present, 5-Fluorouracil (5-FU) is a crucial anti-cancer drug and is widely used for the treatment of various carcinomas, including gastric cancer (GC). The resistance of GC cells to 5-FU is still a matter of great concern. OBJECTIVE: To illustrate the role of PI3K/Akt/mTOR signaling in regulating the cell cycle progression and migration of 5-FU-resistant GC cells. MATERIAL AND METHODS: After the establishment of drug-resistant GC cell lines, the effects of 5-FU and/or BEZ235 (the dual inhibitor of PI3K and mTOR) on the activity of parental or drug-resistant GC cells were explored. The viability and localization of GC cells (MKN-45 and MKN-74) and their drug-resistant cells (MKN-45/R and MKN-74/R) were assessed using MTT assays and immunofluorescence staining. The impacts of 5-FU and/or BEZ235 on GC cell cycle progression and cell migration were assessed via flow cytometry analyses and wound healing assays, respectively. GC tissues were collected from patients with GC sensitive or refractory to 5-FU chemotherapy. RT-qPCR and western blot were conducted to measure PI3K, AKT, and mTOR levels in GC cells or tissues. RESULTS: After 5-FU treatment, GC cells displayed 5-FU resistance and the viability of drug-resistant cells (MKN-45/R and MKN-74/R) was higher than that of parental cells (MKN-45 and MKN-74). The IC50 values for MKN-45 and MKN-45/R were 8.93 ug/ml and 140 ug/ml, and the values for MKN-74 and MKN-74/R were 3.93 ug/ml and 114.29 ug/ml. Additionally, the PI3K/Akt/mTOR signaling pathway was activated in drug-resistant GC cells and tumor tissues of patients refractory to 5-FU chemotherapy, as evidenced by high PI3K, Akt, and mTOR levels in MKN-45/R, MKN-74/R, and GC tissues resistant to 5-FU. BEZ235 promoted cell cycle arrest and suppressed the migration of GC cells. Moreover, the combination of BEZ235 and 5-FU led to more effective suppressive influence on cell cycle progression and cell migration relative to the single 5-FU or BEZ235 treatment. CONCLUSIONS: Silencing of the PI3K/Akt/mTOR signaling pathway suppressed the 5-FU resistance of GC cells.

Submandibular suction lipectomy and single-hole inflator-free endoscopic thyroidectomy with a submental approach: a new surgical technique.

We have successfully carried out single-hole inflator-free endoscopic thyroidectomy through a submental approach, which has the advantages of less trauma, fewer complications, and hidden incisions. However, for patients with submandibular fat accumulation, submental incisions are not easy to hide, which directly affects the cosmetic effect. We developed a new surgical strategy "submandibular suction lipectomy and single-hole inflator-free endoscopic thyroidectomy with a submental approach" for these patients. We initially used submandibular suction lipectomy to reduce the accumulation of submandibular fat and obvious fat protrusion and, thus, restore the normal depression, placing the submental incision back where it is hidden in the submental shadow. Subsequentially, we began to use single-hole inflator-free endoscopic thyroidectomy with a submental approach. We aimed to explore the feasibility and cosmetic effect of this method for the treatment of thyroid disease patients with submandibular fat accumulation. The average operation time was 4.2 hours; and the average hospitalization time was 4.75 days. There were no postoperative complications, such as hoarseness, low calcium, hand and foot numbness, etc., and no special complications and no recurrence or metastasis seen in the 6-month follow-up examination. The aesthetic satisfaction survey results of patients half a year after surgery were satisfactory and above. For thyroid cancer patients with submandibular fat accumulation, this method not only hides the surgical incision in the neck but also meets the patient's requirement for "submental aesthetics"; thus it has good application prospects. It should be pointed out that the current findings are preliminary results, based on data from only four patients.

METTL14 suppresses cancer stem cell phenotype of colorectal cancer via regulating of ß-catenin/NANOG.

Cancer stem cell (CSC) characteristic contributes to tumor malignancy and progression. The role of N6-methyladenosine (m6A) modification in CSC characteristic is largely unknown. In this study, we found that m6A methyltransferase METTL14 was downregulated in colorectal cancer (CRC) and negatively correlated with the poor prognosis of CRC patients. Overexpression of METTL14 inhibited CSC characteristic, while knockdown of METTL14 promoted this characteristic. Through screening, NANOG was identified as the downstream of METTL14. Mechanically, we demonstrated that METTL14 inhibited cancer stem cell characteristic by regulating ß-catenin. Collectively, our findings suggested that METTL16/ß-catenin /NANOG axis might be promising therapeutic targets for CRC.

Engineering of global transcription factor FruR to redirect the carbon flow in Escherichia coli for enhancing L-phenylalanine biosynthesis.

BACKGROUND: The catabolite repressor/activator protein (FruR) is a global regulatory protein known to control the expression of several genes concerned with carbon utilization and energy metabolism. This study aimed to illustrate effects of the FruR mutant on the L-phenylalanine (L-PHE) producing strain PHE01. RESULTS: Random mutagenesis libraries of fruR generated in vitro were first integrated into the chromosome of PHE01 by CRISPR/Cas9 technique, and then the best mutant PHE07 (FruRE173K) was obtained. With this mutant, a final L-PHE concentration of 70.50 ± 1.02 g/L was achieved, which was 23.34% higher than that of PHE01. To better understand the mechanism, both transcriptomes and metabolomes of PHE07 were carried out and compared to that of PHE01. Specifically, the transcript levels of genes involved in gluconeogenesis pathway, pentose phosphate pathway, Krebs cycle, and glyoxylate shunt were up-regulated in the FruRE173K mutant, whereas genes aceEF, acnB, and icd were down-regulated. From the metabolite level, the FruRE173K mutation led to an accumulation of pentose phosphate pathway and Krebs cycle products, whereas the products of pyruvate metabolism pathway: acetyl-CoA and cis-aconic acid, were down-regulated. As a result of the altered metabolic flows, the utilization of carbon sources was improved and the supply of precursors (phosphoenolpyruvate and erythrose 4-phosphate) for L-PHE biosynthesis was increased, which together led to the enhanced production of L-PHE. CONCLUSION: A novel strategy for L-PHE overproduction by modification of the global transcription factor FruR in E. coli was reported. Especially, these findings expand the scope of pathways affected by the fruR regulon and illustrate its importance as a global regulator in L-PHE production.

Explorations on Growth of Blue-Green-Yellow-Red InGaN Quantum Dots by Plasma-Assisted Molecular Beam Epitaxy.

Self-assembled growth of blue-green-yellow-red InGaN quantum dots (QDs) on GaN templates using plasma-assisted molecular beam epitaxy were investigated. We concluded that growth conditions, including small N2 flow and high growth temperature are beneficial to the formation of InGaN QDs and improve the crystal quality. The lower In/Ga flux ratio and lower growth temperature are favorable for the formation of QDs of long emission wavelength. Moreover, the nitrogen modulation epitaxy method can extend the wavelength of QDs from green to red. As a result, visible light emissions from 460 nm to 622 nm have been achieved. Furthermore, a 505 nm green light-emitting diode (LED) based on InGaN/GaN MQDs was prepared. The LED has a low external quantum efficiency of 0.14% and shows an efficiency droop with increasing injection current. However, electroluminescence spectra exhibited a strong wavelength stability, with a negligible shift of less than 1.0 nm as injection current density increased from 8 A/cm2 to 160 A/cm2, owing to the screening of polarization-related electric field in QDs.

Case report: Surgical treatment of McCune-Albright syndrome with hyperthyroidism and retrosternal goiter: A case report and literature review.

Introduction: McCune-Albright syndrome (MAS) is a low-incidence syndrome consisting of the clinical triad of fibrous structural dysplasia of bone, endocrine disease, and skin pigmentation. Thyroid dysfunction is the second most common endocrine dysregulation in MAS. However, there are no treatment guidelines for MAS complicated with hyperthyroidism. Notably, no case of MAS complicated with retrosternal goiter and hyperthyroidism has been reported to our knowledge. Case presentation: We report a 27-year-old man with MAS who developed the typical triad of bone fibrous dysplasia, skin pigmentation and hyperthyroidism, complaining of recent fast-growing neck mass and difficulty in breathing. Hyperthyrodism was under control by Thiamazole, and computed tomography showed an enlarged thyroid extending retrosternally. We performed a total thyroidectomy on the patient. At the 1-year follow-up, the patient's dyspnea, hyperthyroidism, and bone pain were all significantly alleviated. Review: We searched the literature for previous case reports concerning MAS patients complicated with thyroid dysregulation. A total of 17 articles and 22 patients were identified to form our database. Among them, 9 studies clearly mentioned surgical intervention in 11 patients, and prognoses were also reported. Surgery was the most common intervention chosen and indicated a satisfactory prognosis. Conclusion: We report a rare case of MAS patient complicated with retrosternal goiter and hyperthyroidism. Our review provides an overview of MAS cases requiring interventions on thyroid function, and total thyroidectomy should be a proper treatment for these patients.

Quantitative amplitude-modulation scanning Kelvin probe microscopy via the second eigenmode excitation.

Amplitude modulation scanning Kelvin probe microscopy (AM-SKPM) is widely used to measure the contact potential difference (CPD) between probe and samples in ambient or dry inert atmosphere. However, AM-SKPM is generally considered quantitatively inaccurate due to crosstalk between the cantilever and the sample. Here we demonstrate that the accuracy of AM-SKPM-based CPD measurements is drastically improved by exciting the SKPM probe at its second eigenmode. In the second eigenmode of oscillation, there exists a stationary node at the cantilever towards its free end, across which the displacement bears opposite signs; therefore driving the SKPM probe at its second eigenmode helps to partially cancel the virtual work done by the cantilever and reduce the crosstalk effect. The improvement in accuracy is experimentally confirmed with interdigitating electrodes calibration samples as well as practical samples such as the cross-section of wafer-bonded GaAs/GaN heterojunction.

Comprehensive characterization and clinical relevance of the SWI/SNF copy number aberrations across human cancers.

BACKGROUND: Alterations in genes encoding chromatin regulatory proteins are prevalent in cancers and may confer oncogenic properties and molecular changes linked to therapy resistance. However, the impact of copy number alterations (CNAs) of the SWItch/Sucrose NonFermentable (SWI/SNF) complex on the oncogenic and immunologic properties has not been systematically explored across human cancer types. METHODS: We comprehensively analyzed the genomic, transcriptomic and clinical data of The Cancer Genome Atlas (TCGA) dataset across 33 solid cancers. RESULTS: CNAs of the SWI/SNF components were identified in more than 25% of all queried cancers, and tumors harboring SWI/SNF CNAs demonstrated a worse overall survival (OS) than others in several cancer types. Mechanistically, the SCNA events in the SWI/SNF complex are correlated with dysregulated genomic features and oncogenic pathways, including the cell cycle, DNA damage and repair. Notably, the SWI/SNF CNAs were associated with homologous recombination deficiency (HRD) and improved clinical outcomes of platinum-treated ovarian cancer. Furthermore, we observed distinct immune infiltrating patterns and immunophenotypes associated with SWI/SNF CNAs in different cancer types. CONCLUSION: The CNA events of the SWI/SNF components are a key process linked to oncogenesis, immune infiltration and therapeutic responsiveness across human cancers.

Improved photocatalytic activity and stability of InGaN quantum dots/C3N4heterojunction photoelectrode for CO2reduction and hydrogen production.

Photocatalytic conversion of CO2to produce fuel is considered a promising approach to reduce CO2emissions and tackle energy crisis. GaN-based materials have been studied for CO2reduction because of their excellent optical properties and band structure. However, low photocatalytic activity and severe photocorrosion of GaN-based photoelectrode greatly limit their applications. In this work, photocatalytic activity was improved by adopting InGaN quantum dots (QDs) combined with C3N4nano-sheets as photoanode, and thus the efficiency of CO2reduction and the selectivity of hydrogen production were increased significantly. In addition, the photoelectron-chemical corrosion of photoelectrodes has been apparently controlled. InGaN QDs/C3N4has the highest CO and H2productions rates of 14.69µmol mol-1h-1and 140µmol mol-1h-1which were 2.2 times and 14.5 times than that of InGaN film photoelectrode, respectively. The enhancement of photocatalytic activity is attributed to C3N4modification and a large electric dipole forming on the surface of InGaN QDs, which facilitate the separation and transfer of photo-generated carriers and thus promote CO2reduction reaction. This work provides a promising strategy for the development of GaN-based photoanodes with superior stability and efficiency.

Co-expression of CD24 and Hsp70 as a prognostic biomarker for lung cancer.

Lung cancer is one of the most common malignant neoplasms worldwide. CD24 is a marker of tumor stem cells that plays an important role in tumorigenesis. Hsp70 is an important molecular chaperone. However, the co-expression and interaction of CD24 and Hsp70, as well as the significance for the prognosis of lung cancer are still unclear. The expression levels of CD24 and Hsp70 were detected by immunohistochemistry and their correlation was analyzed. The expression levels of CD24 mRNA and protein were examined using qRT-PCR and western blotting in SPCA1, A549, H1975, and H1650 cell lines. A CD24-overexpressing cell model was established. The interaction between CD24 and Hsp70 was verified by co-immunoprecipitation and western blotting. CD24 and Hsp70 expression were significantly higher in lung cancer tissues than in adjacent tissues (CD24: p=0.008; Hsp70: p<0.001). CD24 protein expression showed a positive correlation with lymph node metastasis, TNM stage, and vascular cancer thrombus. Hsp70 protein expression showed a positive correlation with differentiation, lymph node metastasis, and TNM stage. CD24 and Hsp70 high expression were also correlated with poor survival. The positive co-expression rate of CD24 and Hsp70 in lung cancer tissues was 52.7% (49/93). CD24 and Hsp70 expression in lung cancer were positively correlated (r=0.368, p<0.001), and co-immunoprecipitation was verified that both endogenous and exogenous CD24 co-precipitated with Hsp70 directly or indirectly. When Hsp70 inhibitor VER15508 was added to A549 cells, Hsp70 and CD24 protein expression were significantly decreased. The present study demonstrated that CD24 and Hsp70 were highly expressed in lung cancer tissues, and associated with invasion, metastasis, and poor survival. Hsp70 may regulate CD24 expression. Co-expression of CD24 and Hsp70 may be a prognostic biomarker for lung cancer.

Bacille Calmette-Guérin attenuates vascular amyloid pathology and maximizes synaptic preservation in APP/PS1 mice following active amyloid-ß immunotherapy.

Despite effective clearance of parenchymal amyloid-ß (Aß) in patients with Alzheimer's disease, Aß immunotherapy exacerbates the vascular Aß (VAß)-associated pathology in the brain. We have previously shown that BCG immunization facilitates protective monocyte recruitment to the brain of APP/PS1 mice. Here, we confirmed that the 4Aß1-15 vaccine exacerbates VAß deposits in this model, which coincides with a decrease in the number of cerebrovascular endothelial cells and pericytes, infiltration of neutrophils into the brain, and induction of cerebral microhemorrhage. Moreover, combined 4Aß1-15/BCG treatment abrogates the development of the VAß-associated pathology. In addition, BCG treatment is required for the upregulation of interleukin-10 in the brain. Notably, BCG treatment selectively enhances Aß phagocytosis by recruited macrophages. Furthermore, combined 4Aß1-15/BCG treatment is more effective than 4Aß1-15 monotherapy in synaptic preservation and the enhancement of the learning efficiency. Overall, our study suggests that the combination of Aß-targeted therapy with an immunomodulatory strategy may improve the efficacy of Aß vaccine in Alzheimer's disease.

Influenza vaccine combined with moderate-dose PD1 blockade reduces amyloid-ß accumulation and improves cognition in APP/PS1 mice.

Immune dysfunction is implicated in Alzheimer's disease (AD), whereas systemic immune modulation may be neuroprotective. Our previous results have indicated immune challenge with Bacillus Calmette-Guerin attenuates AD pathology in animal models by boosting the systemic immune system. Similarly, independent studies have shown that boosting systemic immune system, by blocking PD-1 checkpoint pathway, modifies AD. Here we hypothesized that influenza vaccine would potentiate function of moderate dose anti-PD-1 and therefore combining them might allow reducing the dose of PD-1 antibody needed to modify the disease. We found that moderate-dose PD-1 in combination with influenza vaccine effectively attenuated cognitive deficit and prevented amyloid-ß pathology build-up in APP/PS1 mice in a mechanism dependent on recruitment of peripheral monocyte-derived macrophages into the brain. Eliminating peripheral macrophages abrogated the beneficial effect. Moreover, by comparing CD11b+ compartments in the mouse parenchyma, we observed an elevated subset of Ly6C+ microglia-like cells, which are reportedly derived from peripheral monocytes. In addition, myeloid-derived suppressor cells are strongly elevated in the transgenic model used and normalized by combination treatment, indicating restoration of brain immune homeostasis. Overall, our results suggest that revitalizing brain immunity by combining IV with moderate-dose PD-1 inhibition may represent a therapeutic immunotherapy for AD.

Dual-wavelength visible photodetector based on vertical (In,Ga)N nanowires grown by molecular beam epitaxy.

Due to the wide applications of blue and red photodetectors, dual-wavelength (blue/red) photodetectors are promising for future markets. In this work, a dual-wavelength photodetector based on vertical (In,Ga)N nanowires and graphene has been fabricated successfully. By using the transparent graphene, both blue and red responses can be clearly detected. The rise time of response can reach 3.5 ms. Furthermore, the underlying mechanism of double responses has also been analyzed. The main reason contributing to the dual-wavelength response could be the different diameters of nanowires, leading to different In components within (In,Ga)N sections.

Intraperitoneal injection of IFN-γ restores microglial autophagy, promotes amyloid-ß clearance and improves cognition in APP/PS1 mice.

Autophagy is a major self-degradative process that maintains cellular homeostasis and function in mammalian cells. Autophagic dysfunction occurs in the early pathogenesis of Alzheimer's disease (AD) and directly regulates amyloid-ß (Aß) metabolism. Although it has been proven that the cytokine IFN-γ enhances autophagy in macrophage cell lines, whether the signaling cascade is implicated in Aß degradation in AD mouse models remains to be elucidated. Here, we found that 9 days of the intraperitoneal administration of IFN-γ significantly increased the LC3II/I ratio and decreased the level of p62 in APP/PS1 mice, an AD mouse model. In vitro, IFN-γ protected BV2 cells from Aß toxicity by upregulating the expressions of Atg7 and Atg5 and the LC3II/I ratio, whereas these protective effects were ablated by interference with Atg5 expression. Moreover, IFN-γ enhanced autophagic flux, probably through suppressing the AKT/mTOR pathway both in vivo and in vitro. Importantly, using intravital two-photon microscopy and fluorescence staining, we found that microglia interacted with exogenous IFN-γ and Aß, and surrounded Aß in APP/PS1;CX3CR1-GFP+/- mice. In addition, IFN-γ treatment decreased the Aß plaque load in the cortex and hippocampus and rescued cognitive deficits in APP/PS1 mice. Our data suggest a possible mechanism by which the peripheral injection of IFN-γ restores microglial autophagy to induce the phagocytosis of cerebral Aß, which represents a potential therapeutic approach for the use of exogenous IFN-γ in AD.

The lncRNA LINC01194/miR-486-5p Axis Facilitates Malignancy in Non-Small Cell Lung Cancer via Regulating CDK4.

BACKGROUND: This experimental design was based on lncRNA LINC01194 to explore the pathogenesis of NSCLC. METHODS: RT-qPCR was used to detect the expression of lncRNA LINC01194 and miR-486-5p in NSCLC tissues and cell lines. CCK-8, colony formation, and transwell assays were used to examine the effects of lncRNA LINC01194 and miR-486-5p on NSCLC cell proliferation and migration invasiveness. For target gene prediction and screening, luciferase reporter assays were used to verify downstream target genes for lncRNA LINC01194 and miR-486-5p. The protein expression of CDK4 was detected using Western blotting. The tumor changes in mice were detected by in vivo experiments in nude mice. RESULTS: LncRNA LINC01194 was highly expressed in NSCLC tissues and NSCLC lines (A549, H1299, H460 cells, H1975), and lncRNA LINC01194 significantly promoted cell proliferation and migration of NSCLC cells. MiR-486-5p was identified as a potential target for LINC01194, and miR-486-5p was expressed at a low level in NSCLC tissues and NSCLC lines (A549, H1299, H460 cells, H1975). CDK4 was identified as a potential target for miR-486-5p. LncRNA LINC01194 was able to inhibit miR-486-5p expression and upregulate the expression level of CDK4. Finally, the results of in vivo animal models confirmed that lncRNA LINC01194 promoted NSCLC progression by modulating the miR-486-5p/CDK4 axis. CONCLUSION: LncRNA LINC01194 promoted the progression of NSCLC by modulating the miR-486-5p/CDK4 axis.

Influenza vaccination in early Alzheimer's disease rescues amyloidosis and ameliorates cognitive deficits in APP/PS1 mice by inhibiting regulatory T cells.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder strongly correlated with a dysfunctional immune system. Our previous results demonstrated that inactivated influenza vaccine (IIV) facilitates hippocampal neurogenesis and blocks lipopolysaccharide (LPS)-induced cognitive impairment. However, whether IIV improves cognitive deficits in an AD mouse model remains unclear. In addition, early interventions in AD have been encouraged in recent years. Here, we investigated whether IIV immunization at the preclinical stage of AD alters the brain pathology and cognitive deficits in an APP/ PS1 mouse model. METHODS: We assessed spatial learning and memory using Morris water maze (MWM). The brain ß-amyloid (Aß) plaque burden and activated microglia were investigated by immunohistochemistry. Furthermore, flow cytometry was utilized to analyze the proportions of Treg cells in the spleen. A cytokine antibody array was performed to measure the alteration of cytokines in the brain and peripheral immune system. RESULTS: Five IIV immunizations activated microglia, reduced the Aß burden and improved the cognitive impairment. Simultaneously, the IIV-induced immune response broke peripheral immunosuppression by reducing Foxp3+ regulatory T cell (Treg) activities, whereas the restoration of Treg level in the periphery using all-trans retinoic acid (ATRA) blunted the protective effects of IIV on Aß burden and cognitive functions. Interestingly, IIV immunization might increase proinflammatory and anti-inflammatory cytokine expression in the brain of APP/PS1 mice, enhanced microglial activation, and enhanced the clustering and phagocytosis of Aß, thereby creating new homeostasis in the disordered immune microenvironment. CONCLUSIONS: Altogether, our results suggest that early multiple IIV immunizations exert a beneficial immunomodulatory effect in APP/PS1 mice by breaking Treg-mediated systemic immune tolerance, maintaining the activation of microglia and removing of Aß plaques, eventually improving cognitive deficits.

IL-4 mediates the delayed neurobehavioral impairments induced by neonatal hepatitis B vaccination that involves the down-regulation of the IL-4 receptor in the hippocampus.

We have previously verified that neonatal hepatitis B vaccination induced hippocampal neuroinflammation and behavior impairments in mice. However, the exact mechanism of these effects remain unclear. In this study, we observed that neonatal hepatitis B vaccination induced an anti-inflammatory cytokine response lasting for 4-5 weeks in both the serum and the hippocampus, primarily indicated by elevated IL-4 levels. Three weeks after the vaccination schedule, however, hepatitis B vaccine (HBV)-mice showed delayed hippocampal neuroinflammation. In periphery, IL-4 is the major cytokine induced by this vaccine. Correlation analyses showed a positive relationship in the IL-4 levels between serum and hippocampus in HBV-mice. Thus, we investigated whether neonatal over-exposure to systemic IL-4 influences brain and behavior. We observed that mice injected intraperitoneally with recombinant mouse IL-4 (mIL-4) during early life had similar neuroinflammation and cognition impairment similar to those induced by neonatal hepatitis B vaccination. Next, the mechanism underlying the effects of IL-4 on brain in mice was explored using a series of experiments. In brief, these experiments showed that IL-4 mediates the delayed neurobehavioral impairments induced by neonatal hepatitis B vaccination, which involves the permeability of neonatal blood-brain barrier and the down-regulation of IL-4 receptor. This finding suggests that clinical events concerning neonatal IL-4 over-exposure, including neonatal hepatitis B vaccination and allergic asthma in human infants, may have adverse implications for brain development and cognition.

Congestion Pricing for Aircraft Pushback Slot Allocation.

In order to optimize aircraft pushback management during rush hour, aircraft pushback slot allocation based on congestion pricing is explored while considering monetary compensation based on the quality of the surface operations. First, the concept of the "external cost of surface congestion" is proposed, and a quantitative study on the external cost is performed. Then, an aircraft pushback slot allocation model for minimizing the total surface cost is established. An improved discrete differential evolution algorithm is also designed. Finally, a simulation is performed on Xinzheng International Airport using the proposed model. By comparing the pushback slot control strategy based on congestion pricing with other strategies, the advantages of the proposed model and algorithm are highlighted. In addition to reducing delays and optimizing the delay distribution, the model and algorithm are better suited for use for actual aircraft pushback management during rush hour. Further, it is also observed they do not result in significant increases in the surface cost. These results confirm the effectiveness and suitability of the proposed model and algorithm.

Anticancer bioactive peptide-3 inhibits human gastric cancer growth by targeting miR-338-5p.

BACKGROUND: Cancer incidence and mortality have been increasing in China, making cancer the leading cause of death since 2010 and a major public health concern in the country. Cancer stem cells have been studied in relation to the treatment of different malignancies, including gastric cancer. Anticancer bioactive peptide-3 (ACBP-3) can induce the apoptosis of gastric cancer stem cells (GCSCs) and reduce their tumorigenicity. In the present study, for the first time, we used a miRNA microarray and bioinformatics analysis to identify differentially expressed miRNAs in ACBP-3-treated GCSCs and GCSC-derived tumors in a xenograft model and functionally verified the identified miRNAs. miR-338-5p was selected based on its significant upregulation by ACBP-3 both in cultured GCSCs and in tumor tissues. RESULTS: miR-338-5p was downregulated in GCSCs compared with normal gastric epithelial cells, and the ectopic restoration of miR-338-5p expression in GCSCs inhibited cell proliferation and induced apoptosis, which correlated with the upregulation of the pro-apoptotic Bcl-2 proteins BAK and BIM. We also found that ACBP-3-treated GCSCs could respond to lower effective doses of cisplatin (DDP) or 5-fluorouracil (5-FU), possibly because ACBP-3 induced the expression of miR-338-5p and the BAK and BIM proteins and promoted GCSC apoptosis. CONCLUSIONS: Our data indicate that miR-338-5p is part of an important pathway for the inhibition of human gastric cancer stem cell proliferation by ACBP-3 combined with chemotherapeutics. ACBP-3 could suppress GCSC proliferation and lower the required effective dose of cisplatin or 5-fluorouracil. Therefore, this study provides not only further evidence for the remarkable anti-tumor effect of ACBP-3 but also a possible new approach for the development of GCSC-targeting therapies.