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Nucleic acid therapeutics have attracted recent attention as promising preventative solutions for a broad range of diseases. Nonviral delivery vectors, such as cationic polymers, improve the cellular uptake of nucleic acids without suffering the drawbacks of viral delivery vectors. However, these delivery systems are faced with a major challenge for worldwide deployment, as their poor thermal stability elicits the need for cold chain transportation. Here, we demonstrate a biomaterial strategy to drastically improve the thermal stability of DNA polyplexes. Importantly, we demonstrate long-term room temperature storage with a transfection efficiency maintained for at least 9 months. Additionally, extreme heat shock studies show retained luciferase expression after heat treatment at 70 °C. We therefore provide a proof of concept for a platform biotechnology that could provide long-term room temperature storage for temperature-sensitive nucleic acid therapeutics, eliminating the need for the cold chain, which in turn would reduce the cost of distributing life-saving therapeutics worldwide.

Treatment with anti-programmed cell death protein 1 (PD-1) therapy and chemotherapy prolongs the survival of patients with unresectable advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The benefit from anti-PD-1 therapy is enriched in patients with programmed cell death 1 ligand 1 (PD-L1) combined positive score (CPS)-positive or CPS-high tumors compared with patients with PD-L1 CPS-negative or CPS-low tumors. In this phase 1b/2 study, we evaluated the efficacy and safety of cadonilimab, a bispecific antibody targeting PD-1 and cytotoxic T-lymphocyte antigen-4, plus chemotherapy as first-line treatment in patients with human epidermal growth factor receptor 2-negative unresectable advanced or metastatic gastric or GEJ adenocarcinoma. The primary endpoint was the recommended phase 2 dose (RP2D) for phase 1b and the objective response rate for phase 2. Secondary endpoints included disease control rate, duration of response, time to response, progression-free survival, overall survival (OS) and safety. The primary endpoint was met. No dose-limiting toxicities were observed during dose escalation in phase 1b; the recommended phase 2 dose was determined as 6 mg kg−1every 2 weeks. The objective response rate was 52.1% (95% confidence interval (CI) = 41.6–62.5), consisting of complete and partial responses in 4.3% and 47.9% of patients, respectively. The median duration of response, progression-free survival and OS were 13.73 months (95% CI = 7.79–19.12), 8.18 months (95% CI = 6.67–10.48) and 17.48 months (95% CI = 12.35–26.55), respectively. The median OS in patients with a PD-L1 CPS ≥ 5 was 20.32 months (95% CI = 4.67–not estimable); in patients with a PD-L1 CPS < 1, the median OS reached 17.64 months (95% CI = 11.63–31.70). The most common treatment-related grade 3 or higher adverse events were decreased neutrophil count (19.1%), decreased platelet count (16.0%), anemia (12.8%) and decreased leukocyte count (8.5%). No new safety signal was identified. The current regimen showed promising clinical activity and manageable safety in patients with gastric or GEJ adenocarcinoma regardless of PD-L1 expression. Chinadrugtrials.org.cn registration: CTR20182027

Excessive fructose absorption and its subsequent metabolisms are implicated in nonalcoholic fatty liver disease, obesity, and insulin resistance in humans. Ketohexokinase (KHK) is a primary enzyme involved in fructose metabolism via the conversion of fructose to fructose-1-phosphate. KHK inhibition might be a potential approach for the treatment of metabolic disorders. Herein, a series of novel KHK inhibitors were designed, synthesized, and evaluated. Among them, compound 14exhibited more potent activity than PF-06835919based on the rat KHK inhibition assay in vivo, and higher drug distribution concentration in the liver. Its good absorption, distribution, metabolism, and excretion and pharmacokinetic properties make it a promising clinical candidate.

Pyrotinib is a novel epidermal growth factor receptor/human epidermal growth factor receptor-2 (HER2) tyrosine kinase inhibitor that exhibited clinical efficacy in patients with HER2-positive breast cancer and HER2-mutant/amplified lung cancer. However, severe diarrhea adverse responses preclude its practical use. At present, the mechanism of pyrotinib-induced diarrhea is unknown and needs further study. First, to develop a suitable and reproducible animal model, we compared the effects of different doses of pyrotinib (20, 40, 60 and 80 mg/kg) in Wistar rats. Second, we used this model to examine the intestinal toxicity of pyrotinib. Finally, the mechanism underlying pyrotinib-induced diarrhea was fully studied using gut microbiome and host intestinal tissue metabolomics profiling. Reproducible diarrhea occurred in rats when they were given an 80 mg/kg daily dose of pyrotinib. Using the pyrotinib-induced model, we observed that Lachnospiraceae and Acidaminococcaceae decreased in the pyrotinib groups, whereas Enterobacteriaceae, Helicobacteraceae and Clostridiaceae increased at the family level by 16S rRNA gene sequence. Multiple bioinformatics methods revealed that glycocholic acid, ursodeoxycholic acid and cyclic AMP increased in the pyrotinib groups, whereas kynurenic acid decreased, which may be related to the pathogenesis of pyrotinib-induced diarrhea. Additionally, pyrotinib-induced diarrhea may be associated with a number of metabolic changes mediated by the gut microbiome, such as Primary bile acid biosynthesis. We reported the establishment of a reproducible pyrotinib-induced animal model for the first time. Furthermore, we concluded from this experiment that gut microbiome imbalance and changes in related metabolites are significant contributors to pyrotinib-induced diarrhea.

In this paper, we consider the existence of solutions for nonlinear elliptic equations of the form (0.1)−Δu+V(x)u=f(x,u)+λa(x)∣u∣q−2u,x∈R2,-\Delta u+V\left(x)u=f\left(x,u)+\lambda a\left(x)| u{| }^{q-2}u,\hspace{1em}x\in {{\mathbb{R}}}^{2},where λ>0\lambda \gt 0, q∈(1,2)q\in \left(1,2), a∈L2/(2−q)(R2)a\in {L}^{2\text{/}\left(2-q)}\left({{\mathbb{R}}}^{2}), V(x)V\left(x), and f(x,t)f\left(x,t)are 1-periodic with respect to xx, and f(x,t)f\left(x,t)has critical exponential growth at t=∞t=\infty . By combining the variational methods, Trudinger-Moser inequality, and some new techniques with detailed estimates for the minimax level of the energy functional, we prove the existence of a nontrivial solution for the aforementioned equation under some weak assumptions. Our results show that the presence of the concave term (i.e. λ>0\lambda \gt 0) is very helpful to the existence of nontrivial solutions for equation (0.1) in one sense.

Lithium (Li) metal is the most promising anode for improving the energy density of currently commercialized Li-ion batteries. However, its practical application is limited due to its high reactivity to electrolytes, which induces severe electrolyte decomposition and Li-dendrite growth. Interphases are usually constructed on Li anode to address the above issue. Meanwhile, it is a big challenge to balance the stability and plating/stripping overpotential of Li anode. In this work, we report a novel strategy for constructing a highly stable and lowly polarized surface film on Li anode. A chemically and structurally unique film is formed by simply dropping a zinc trifluoromethanesulfonate [Zn(OTF)2] and fluoroethylene carbonate (FEC)-containing solution onto Li anode. This unique film consists of inner nucleation sites and outer protection textures, mainly containing Li-Zn alloy and LiF/polymer, respectively. The former results from the preferential reduction of Zn(OTF)2, providing nucleation sites with low polarization for Li plating/stripping. In contrast, the latter arises from the subsequent reduction of FEC, providing protection for the underneath Li-Zn alloy and Li metal and ensuring the stability of Li anode. The Li anode with such a unique surface film exhibits excellent cycling stability and low plating/stripping overpotentials, which have been demonstrated using Li//Li symmetric and Li//LiFePO4full cells.

Oil-water emulsion separation could improve the efficiency of oil resources and reduce environmental pollution. The efficiency of oil-water separation was directly affected by the surface hydrophobicity of the membrane and its reliability and reusability. Therefore, the construction of a reliable and reusable super-hydrophobic surface was very important. In this research, the EFM with sandwich structure of PS-SiO2-PVAc-SiO2was easily fabricated by a three times liquid phase induction process and heat treatment. The PS-SiO2-PVAc-SiO2EFM was first formed by a triple liquid phase induction process, then the EFM was heat-treated, the PVAc, which is a heat-sensitive material, resulting in SiO2nanoparticles being welded onto PS fibers. The rolling contact angle experiment at an inclination of 8° proved that the PS-SiO2-PVAc-SiO2EFM has super-hydrophobic properties. Meanwhile, the PS-SiO2-PVAc-SiO2EFM showed excellent stability and reliability of super-hydrophobic properties after the EFM was washed or taped. In addition, the PS-SiO2-PVAc-SiO2EFM had self-cleaning function and fine oil-water separation property. The oil-water separation efficiency was over 99.50 % and the flow rate was 68 L/m2h. After 5 times of oil-water separation, the flux and separation efficiency did not decrease significantly, which proved that the PS-SiO2-PVAc-SiO2EFM could be reusable.

ABSTRACTGlioblastoma multiforme (GBM) is a malignant cancer with severely poor survival, and the cells continue to thrive during hypoxia and toxic stress through autophagy. To validate the oncogenic role of long noncoding RNA H19 in GBM progression and examine whether autophagy and/or miR-491-5p participate in the process. The expression of H19 and autophagy-related genes in GBM and healthy control tissues was assessed via quantitative polymerase chain reaction. In addition, cell viability, proliferation, apoptosis and autophagy were respectively determined via cell counting kit-8 assay, clone formation assay, flow cytometry, western blotting and green fluorescent protein–microtubule-associated protein 1 light chain 3 alpha fluorescence analysis in vitro. Furthermore, a rescue assay was performed using rapamycin or miR-491-5p antagomir to examine the role of autophagy or miR-491-5p in H19-mediated regulation of proliferation and apoptosis. RNA pull-down and dual-luciferase reporter assays were employed to analyze the interaction between H19 and miR-491-5p. Additionally, tumor growth in a xenograft-bearing mouse model and autophagy in tumor mass were analyzed in vivo. The expression H19 was increased in GBM and was positively correlated with LC3 or Beclin-1. Silencing H19 inhibited growth and promoted apoptosis in GBM cells both in vitroand in vivo, and miR-491-5p was identified as one of the important mediators. H19 regulated the autophagy signaling pathway at least partly via miR-491-5p. Increased H19 expression in GBM exerts oncogenic effects by sponging miR-491-5p and enhancing autophagy. Therefore, H19 may be explored as a target for GBM therapy.

The goal of this study was to describe the current status of oncology nurses' behaviors toward end of life (EOL) care in China and to explore the factors associated with oncology nurses’ behaviors toward EOL care.

Background Allergic rhinitis (AR) is one of the most common noninfectious respiratory diseases caused by immunoglobulin E (IgE) response.Objective The study sought to explore the relationship between lncRNA MIAT and miR-10b-5p and their interaction in the regulation of allergic phenotypes in allergic rhinitis (AR) mice.Methods A mice model of AR was constructed using ovalbumin (OVA) sensitization. AR mice were treated with miR-10b-5p agomiR and LNA mediated lncRNA MIAT. The targeting relationship between MIAT and miR-10b-5p was analyzed by the ENCORI website and dual-luciferase reporter assay. The numbers of rubbing and sneezing of mice were counted. Hematoxylin-eosin (HE) staining visualized the eosinophils infiltration in nasal mucosa tissues of mice. The percentage of Th17 cells was quantitated by flow cytometry analysis. ELISA was used to detect the levels of serum OVA-specific IgE, the Th12 cytokine IL-4, and in?ammatory cytokines (IL-6, IL-17).Results MIAT was up-regulated in the nasal mucosa of AR mice, while miR-10b-5p was down-regulated. MIAT directly suppressed miR-10b-5p expression in AR mice. The numbers of rubbing and sneezing, the percentage of Th17 cells, and the levels of OVA-specific IgE, IL-4, IL-6, and IL-17 in AR mice were decreased by miR-10b-5p overexpression, which was reversed by MIAT overexpression. The eosinophils infiltration in AR mice was inhibited by miR-10b-5p overexpression, which was also reversed by MIAT overexpression.Conclusion The present study demonstrates that MIAT overexpression Promotes allergic inflammation and symptoms by activating Th17 immune response via miR-10b-5p inhibition.

Introduction:In a multicenter, open-label, parallel-group, randomized, phase 2 study for pretreated advanced hepatocellular carcinoma (HCC), camrelizumab showed potent antitumor activity and acceptable safety profile. The aim of this report was to provide long-term data and evaluate potential benefit of treatment with camrelizumab beyond progression. Methods:From November 15, 2016, to November 16, 2017, 217 patients received camrelizumab 3 mg/kg intravenously every 2 or 3 weeks. Treatment beyond first Response Evaluation Criteria in Solid Tumors (RECIST)-defined progression (TBP) with camrelizumab was allowed. Results:At data cutoff of December 16, 2019 (>2 years after the last patient enrollment; median duration of follow-up, 13.2 months [IQR 5.7–25.8]), 14 (43.8%) of the 32 responses per blinded independent central review were ongoing. The median duration of response was not reached (range 2.5–30.5 + months). The ongoing response rates at 12, 18, and 24 months were 68.3% (95% confidence interval [CI] 47.7–82.2), 59.8% (95% CI 38.8–75.6), and 53.1% (95% CI 31.0–71.0), respectively. The median overall survival (OS) was 14.2 months (95% CI 11.5–16.3). The 18- and 24-month OS rates were 41.3% (95% CI 34.6–47.9) and 33.7% (95% CI 27.3–40.2), respectively. Of the 172 patients who experienced RECIST-defined progression per investigator, 102 received TBP, while 70 did not (non-TBP). The median OS was 16.9 months (95% CI 13.3–22.6) in the TBP group versus 9.4 months (95% CI 5.8–14.8) in the non-TBP group, and the 18- and 24-month OS rates were 47.5% (95% CI 37.3–56.9) versus 33.1% (95% CI 22.3–44.3) and 38.8% (95% CI 29.2–48.4) versus 23.2% (95% CI 13.8–34.1), respectively. No new safety signals of camrelizumab were observed. Conclusions:With prolonged follow-up, camrelizumab continues to demonstrate the durable response and long survival in pretreated advanced HCC patients with manageable toxicities, especially in those who continued the treatment beyond first RECIST-defined progression.

In this article, we consider the existence of solutions for nonlinear elliptic equations of the form −Δu+V(∣x∣)u=Q(∣x∣)f(u),x∈R2,-\Delta u+V\left(| x| )u=Q\left(| x| )f\left(u),\hspace{1em}x\in {{\mathbb{R}}}^{2},where the nonlinear term f(s)f\left(s)has critical exponential growth which behaves like eαs2{e}^{\alpha {s}^{2}}, the radial potentials V,Q:R+→RV,Q:{{\mathbb{R}}}^{+}\to {\mathbb{R}}are unbounded, singular at the origin or decaying to zero at infinity. By combining the variational methods, Trudinger-Moser inequality, and some new approaches to estimate precisely the minimax level of the energy functional, we prove the existence of a Mountain-pass-type solution for the above problem under some weak assumptions.

Immunotherapy combined with chemotherapy has been shown to be efficacious as treatment for advanced non-squamous non-small-cell lung cancer (NSCLC) without targetable genetic aberrations; however, there is scarce evidence of the effectiveness of the combinations in the Asian population. We evaluated camrelizumab plus chemotherapy against non-squamous NSCLC in China.

Treatment options in the second-line extensive-stage SCLC (ED-SCLC) setting are limited. The PASSION study (ClinicalTrials.govidentifier: NCT03417895) was a phase 2 study of camrelizumab plus apatinib in ED-SCLC after platinum-based chemotherapy.

Gemcitabine-cisplatin (GP) chemotherapy is the standard first-line systemic treatment for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). In this international, double-blind, phase 3 trial (ClinicalTrials.gov identifier: NCT03581786), 289 patients with RM-NPC and no previous chemotherapy for recurrent or metastatic disease were randomized (1/1) to receive either toripalimab, a monoclonal antibody against human programmed death-1 (PD-1), or placebo in combination with GP every 3 weeks for up to six cycles, followed by monotherapy with toripalimab or placebo. The primary endpoint was progression-free survival (PFS) as assessed by a blinded independent review committee according to RECIST v.1.1. At the prespecified interim PFS analysis, a significant improvement in PFS was detected in the toripalimab arm compared to the placebo arm: median PFS of 11.7 versus 8.0 months, hazard ratio (HR) = 0.52 (95% confidence interval (CI): 0.36–0.74), P= 0.0003. An improvement in PFS was observed across key subgroups, including PD-L1 expression. As of 18 February 2021, a 40% reduction in risk of death was observed in the toripalimab arm compared to the placebo arm (HR = 0.603 (95% CI: 0.364–0.997)). The incidence of grade ≥3 adverse events (AEs) (89.0 versus 89.5%), AEs leading to discontinuation of toripalimab/placebo (7.5 versus 4.9%) and fatal AEs (2.7 versus 2.8%) was similar between the two arms; however, immune-related AEs (39.7 versus 18.9%) and grade ≥3 infusion reactions (7.5 versus 0.7%) were more frequent in the toripalimab arm. In conclusion, the addition of toripalimab to GP chemotherapy as a first-line treatment for patients with RM-NPC provided superior PFS compared to GP alone, and with a manageable safety profile.

The present study aimed to research the effects of cyclic heat environment on the microbial diversity and structure of respiratory tract and cecum of chicken. A total of 360 layer-type pullets at 11 wk of age were subjected to different temperature treatments for 10 wk: constant 22°C; cyclic temperature 22°C to 24°C, 22°C to 26°C, 22°C to 28°C, 22°C to 30°C; the ambient temperature increased from 10:00, reached the set point within 1 h, and maintained until 18:00, thereafter the temperature was restored to 22°C; and the relative humidity was maintained at 60%. The result showed that feed intake of the chickens on ambient temperature 30°C group was significantly lower than that of the chickens on ambient temperature 24°C. The white blood cell, red blood cell, lymphocyte, hemoglobin, and pecked-cell volume content were highest at 24°C on 14, 16, and 18 wk. The ratio of CD3+CD4+/CD3+CD8+T cells was lowest at 30°C. Meanwhile, the abundance of cecum bacteria in chickens at 30°C was lower than that at 24°C. Cyclic heat environment temperature treatment did not significantly affect the concentration of secretory immunoglobulin A in chicken bronchoalveolar lavage fluid (BALF) levels during 10 wk of trial. The diversity index analysis showed that the effect of 24°C on the cecum flora of chickens was optimal. Abundance of Firmicutes bacteria in the lung flora and cecum flora was lower at 30°C than at 24°C group. Similarly, the microorganism, Brevibacillusin the BALF was also significantly lower at 24°C. In conclusion, cyclic 24°C treatment was beneficial for the feed intake, blood routine indexes, microflora structure of the cecum, and respiratory tract in laying pullets.

A visible‐light‐catalyzed radical N‐acylation of amines with carboxylic acids was achieved by means of eosin Y as the photocatalyst under aqueous medium without any transition‐metal‐based catalytic systems. The new method takes advantages of visible‐light photocatalysis to generate the amides under mild conditions. A variety of amides have been synthesized in good to excellent yields. Moreover, the strategy was successfully applied in the preparation of paracetamol. A visible‐light‐catalyzedradical N‐acylation of amines with carboxylic acids was achieved by means of eosin Y as the photocatalyst under aqueous medium without any transition‐metal‐based catalytic systems.

AbstractObjectives:To describe direct medical costs associated with each line of treatment among metastatic colorectal cancer (mCRC) patients in China.Methods:Electronic medical records between 2011 and 2016 were extracted from 12 tertiary hospitals in China for adult patients who initiated third-line treatment at least nine months before the end of data collection. Direct medical costs included costs of wards, diagnostic tests, surgical procedures, special materials, drugs and others. Costs were assessed by line of treatment, and drug costs were further breakdown for patients receiving chemotherapy alone and those receiving chemo- and biologics-combined therapy.Results:Of the 404 mCRC patients, the mean age was 55 years old and 62% were male. Oxaliplatin- and irinotecan-based regimens dominated first- and second-line treatment, respectively (44 and 37%). From first- to second- to third-line, the proportion of patients receiving targeted biologics increased from 18% at first-line and 12% at second-line to 34% at third-line; median number of treatment cycles reduced from 6 to 4 and to 2. The corresponding mean direct medical costs per person per cycle increased from $2,514 to $2,678 to $5,121. Mean drug costs per cycle increased from $2,314 to $2,673 to $4,316 among patients receiving chemotherapy alone and from $3,245 to $2,717 to $6,533 among patients receiving chemo- and biologics-combined therapy.Conclusions:Before 2017, mCRC patients in China did not receive the maximum benefits of precision medicine breakthroughs. Reduced treatment cycles and increased costs per cycle from first- to third-line suggested poor healthcare resource utilization. With earlier initiation and more treatment cycles, targeted biologics may better demonstrate their effectiveness among Chinese patients. Our findings reflected the urgent need to increase drug accessibility in China before 2017 and underscore that including innovative biologics into Chinese health insurance plans can reduce patients’ economic burden and improve the management of mCRC.

In poultry production, vaccination is an effective measure to protect chickens from diseases. Vaccination, however, is a stressor that may induce stress responses that interfere with the growth and development of chickens. The interaction between the skeletal and immune systems on bone quality has gained more attention. In the present study, the influence of high frequency vaccinations on the bone development of layer pullets was investigated. Thirty 35-day-old SPF White Leghorn layer pullets were obtained and randomly subjected to the following treatments: vaccinated against Newcastle disease (ND) with LoSota vaccine once at 35-day-old (V1, control); 4 times at 35, 49, 63, and 77 d of age (V4); and 7 times at 35, 42, 49, 56, 63, 70, and 77 d of age (V7). The body weight and organ index of the spleen, thymus, and tibia were recorded. The antibody titer and serum and the tibia calcium and phosphorus concentrations were measured. The transcription levels of the IL-6, IL-17, TNF-α, receptor activator of NF-κB ligand (RANKL), and osteoprotegerin (OPG) genes were determined in spleen, thymus, and the tibia. The results showed that V7 decreased body weight and increased the ND antibody titer, compared to V1-chickens. The expression levels of IL-6, IL-17, and TNF-α were upregulated in spleen, thymus, and the tibia of V7 chickens. In the tibia, RANKL was upregulated, while OPG was downregulated by V7 treatment. The results indicate that high frequency vaccination induces immune stress and impairs bone development. The results suggest that the augmented cytokine expression in immune organs and the tibia is associated with activation of the OPG/RANKL pathway, which, in turn, enhances osteoclastogenesis. The appropriate frequency of vaccination should support optimal bone development and full immunoprotection in layer pullets.

Cannabinoid 1 receptor (CB1R) allosteric ligands hold a far-reaching therapeutic promise. We report the application of fluoro- and nitrogen-walk approaches to enhance the drug-like properties of GAT211, a prototype CB1R allosteric agonist-positive allosteric modulator (ago-PAM). Several analogs exhibited improved functional potency (cAMP, β-arrestin 2), metabolic stability, and aqueous solubility. Two key analogs, GAT591 (6r) and GAT593 (6s), exhibited augmented allosteric-agonist and PAM activities in neuronal cultures, improved metabolic stability, and enhanced orthosteric agonist binding (CP55,940). Both analogs also exhibited good analgesic potency in the CFA inflammatory-pain model with longer duration of action over GAT211 while being devoid of adverse cannabimimetic effects. Another analog, GAT592 (9j), exhibited moderate ago-PAM potency and improved aqueous solubility with therapeutic reduction of intraocular pressure in murine glaucoma models. The SAR findings and the enhanced allosteric activity in this class of allosteric modulators were accounted for in our recently developed computational model for CB1R allosteric activation and positive allosteric modulation.

This paper is dedicated to studying the following elliptic system of Hamiltonian type: {−ε2Δu+u+V(x)v=Q(x)Fv(u,v),x∈RN,−ε2Δv+v+V(x)u=Q(x)Fu(u,v),x∈RN,|u(x)|+|v(x)|→0,as|x|→∞where N⩾ 3, V, Q∈C(RN,R), V(x) is allowed to be sign-changing and inf Q> 0, and F∈C1(R2,R)is superquadratic at both 0 and infinity but subcritical. Instead of the reduction approach used in Ding et al. (2014), we develop a more direct approach—non-Nehari manifold approach to obtain stronger conclusions but under weaker assumptions than those in Ding et al. (2014). We can find an ε0> 0 which is determined by terms of N, V, Qand F, and then we prove the existence of a ground state solution of Nehari-Pankov type to the coupled system for all ε∈ (0, ε0].

Purpose: To investigate the efficacy of paclitaxel combined with a leucovorin and 5-fluorouracil regimen (PLF regimen; q2w) as neoadjuvant chemotherapy (NCT) for advanced gastric cancer.Methods: A total of 183 patients with advanced gastric cancer who underwent 3 cycles of PLF regimen chemotherapy before surgery and received surgery 2 weeks after chemotherapy were enrolled as a treatment group. A total of 184 patients with advanced gastric cancer and no NCT during the same period were enrolled as the controls and treated with surgery. Both groups underwent a D2 radical gastrectomy and the standard postoperative adjuvant chemotherapy.Results: In the NCT group, there were 19 cases of complete remission, 86 cases of partial remission, 72 cases of stable disease, and 6 cases of progressive disease, with an overall response rate of 57.4%. The R0 resection rate was higher than in the control group (85.2% vs 61.4%, p< .05). In the NCT group, 12 cases of esophagogastric cancer (20.7%) showed complete remission and 32 cases (55.2%) showed partial remission, while 7 cases of distal gastric cancer (5.6%) showed complete remission and 54 cases (43.2%) showed partial remission. Pathologic complete remission was higher for esophagogastric cancer than for distal gastric cancer (20.7% vs 3.2%, p< .05). Differences were found between the NCT and control groups in terms of 1-year, 3-year, and 5-year overall and disease-free survival.Conclusion: The PLF regimen showed good tolerability and a high response rate, especially for esophagogastric cancer. This regimen reduced the tumor size, lowered the tumor stage, and improved the R0 resection rate and survival rate.

A novel adsorbent of mesoporous carbon with high specific surface area was successfully prepared by hydrothermal and template method, using sodium lignosulfonate (LSs) as a raw material and cetyltrimethylammonium bromide (CTAB) as a template agent. The mesoporous carbon was characterized by SEM, TEM, BET, FTIR, and XPS. The formation mechanism of the mesoporous carbon was analyzed. The adsorption of uranium(VI) on the mesoporous carbon from the simulated aqueous solution and actual radioactive wastewater was respectively investigated. The optimum conditions for U(VI) adsorption were determined by studying experimental variables including pH, contact time, sorbent dose, initial concentration, and temperature. The results indicated that the maximum adsorption capacity of the mesoporous carbon for U(VI) in the simulated aqueous solution and actual radioactive wastewater was respectively 109.46 mg/g at pH 5.5 and 328.15 K and 195.6 mg/g at pH 5.5 and the initial U(VI) concentration of 189.75 mg/L. The adsorption data could be well described by the pseudo-second-order model and Freundlich isotherm model. The adsorption of U(VI) on the mesoporous carbon was an endothermic and spontaneous process. The adsorption mechanism may be a complex chemical reaction between uranium and the oxygen-containing functional groups on the mesoporous carbon.

In view of the advantageous merits of LiNi0.8Co0.15Al0.05O2(NCA), i.e., high voltage and decent specific capacity, an impressive electrolyte film-forming additive, methyl-3-fluorothiophene-2-carboxylate (MFC), is put forward to remarkably improve the cycle performance of NCA cathodes toward high energy density lithium-ion batteries (LIBs). Theoretical calculation and experimental investigation both reveal that MFC is more readily oxidized to construct a cathode electrolyte interphase (CEI) on the surface of NCA cathode. Spectroscopy and microscopy data display that a MFC-derived CEI layer is thin, homogeneous, and conformally covers on the NCA surface, maintains the NCA structural integrity without visible microcracks, and protects the NCA cathode from electrolyte corrosion with alleviated dissolution of Ni and Co. Electrochemical properties show that the NCA/Li half-cell with a 5 wt % MFC-containing electrolyte delivers a higher discharge capacity with a much superior capacity retention of 148.6 mA h g–1/85.5% than that of base electrolyte (121.2 mA h g–1/71.0%) after 150 cycles at 1 C. This work indicates that MFC can work as an effective film-forming additive for high-voltage NCA and provides precious insights and theoretical guidance to the development of advanced electrolyte additives for high energy density LIBs.

A novel nanospherical hydrous titanium oxide adsorbent (hydrous titanium oxide-immobilized bovine serum albumin nanospheres, HTO-BSA-NSs) was prepared by immobilizing HTOs with a manipulated molecular mass and number of active sites for uranium on the surface of BSA-NSs. The adsorption performances of HTO-BSA-NSs were investigated in spiked natural seawater with extra 8 ppm uranium. The results demonstrated that HTO-BSA-NSs are capable of uranium capture from a complex aqueous matrix with a low uranium concentration. Meanwhile, the microbial stability of HTO-BSA-NSs in sterilized natural seawater with Marinobactersp. was investigated and observed through an optical microscope and TEM, revealing that the wrapped HTOs could protect the BSA-NSs from the decomposition of microorganisms, and the structure and functional groups of HTO-BSA-NSs remain stable compared with the BSA-NSs. In addition, the uranium adsorption mechanism of HTO-BSA-NSs is mainly recognized as dehydrated complexation, which was concluded from characterization analysis, adsorption model fitting, and theoretical calculations based on density functional theory. The remarkable uranium adsorption performance and microbial stability of HTO-BSA-NSs indicated that they have the potential to be a low-cost and environmentally friendly adsorbent for uranium extraction from complex environments such as seawater or uranium-containing industrial wastewater.

Protein aggregation is associated with neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. The poorly understood pathogenic mechanism of amyloid diseases makes early stage diagnostics or therapeutic intervention a challenge. Seeded polymerization that reduces the duration of the lag phase and accelerates fibril growth is a widespread model to study amyloid formation. Seeding effects are hypothesized to be important in the “infectivity” of amyloids and are linked to the development of systemic amyloidosis in vivo. The exact mechanism of seeding is unclear yet critical to illuminating the propagation of amyloids. Here we report on the lateral and axial fragmentation of seed fibrils in the presence of lysozyme monomers at short time scales, followed by the generation of oligomers and growth of fibrils.

Three-dimensional microfocus x-ray fluorescence technology has been used to determine surface topography. The surface scanning technique initially facilitated surface topography reconstruction of the sample. This paper demonstrates the improved performance of its infrastructure, including a higher-precision translation platform, an ultrabright microfocus x-ray source and a rewritten scanning algorithm, leading to a new scanning technology that can depict the surface topography of samples with complex internal structures. The improved scanning technology can analyze the metal element information of layers at different depths. This paper presents studies of the surface and depth of coins and porcelain bottles from ancient times using this technique.

Menopause is associated with dyslipidemia and an increased risk of cardio-cerebrovascular disease. The classic view assumes that the underlying mechanism of dyslipidemia is attributed to an insufficiency of estrogen. In addition to a decrease in estrogen, circulating follicle-stimulating hormone (FSH) levels become elevated at menopause. In this study, we find that blocking FSH reduces serum cholesterol via inhibiting hepatic cholesterol biosynthesis. First, epidemiological results show that the serum FSH levels are positively correlated with the serum total cholesterol levels, even after adjustment by considering the effects of serum estrogen. In addition, the prevalence of hypercholesterolemia is significantly higher in peri-menopausal women than that in pre-menopausal women. Furthermore, we generated a mouse model of FSH elevation by intraperitoneally injecting exogenous FSH into ovariectomized (OVX) mice, in which a normal level of estrogen (E2) was maintained by exogenous supplementation. Consistently, the results indicate that FSH, independent of estrogen, increases the serum cholesterol level in this mouse model. Moreover, blocking FSH signaling by anti-FSHβ antibody or ablating the FSH receptor(FSHR) gene could effectively prevent hypercholesterolemia induced by FSH injection or high-cholesterol diet feeding. Mechanistically, FSH, via binding to hepatic FSHRs, activates the Gi2α/β-arrestin-2/Akt pathway and subsequently inhibits the binding of FoxO1 with the SREBP-2promoter, thus preventing FoxO1 from repressing SREBP-2gene transcription. This effect, in turn, results in the upregulation of SREBP-2, which drives HMGCRnascent transcription and de novo cholesterol biosynthesis, leading to the increase of cholesterol accumulation. This study uncovers that blocking FSH signaling might be a new strategy for treating hypercholesterolemia during menopause, particularly for women in peri-menopause characterized by FSH elevation only.

AM1710 (3-(1,1-dimethyl-heptyl)-1-hydroxy-9-methoxy-benzo(c) chromen-6-one), a cannabilactone cannabinoid receptor 2 (CB2) agonist, suppresses chemotherapy-induced neuropathic pain in rodents without producing tolerance or unwanted side effects associated with CB1 receptors; however, the signaling profile of AM1710 remains incompletely characterized. It is not known whether AM1710 behaves as a broad-spectrum analgesic and/or suppresses the development of opioid tolerance and physical dependence. In vitro, AM1710 inhibited forskolin-stimulated cAMP production and produced enduring activation of extracellular signal-regulated kinases 1/2 phosphorylation in human embryonic kidney (HEK) cells stably expressing mCB2. Only modest species differences in the signaling profile of AM1710 were observed between HEK cells stably expressing mCB2 and hCB2. In vivo, AM1710 produced a sustained inhibition of paclitaxel-induced allodynia in mice. In paclitaxel-treated mice, a history of AM1710 treatment (5 mg/kg per day × 12 day, i.p.) delayed the development of antinociceptive tolerance to morphine and attenuated morphine-induced physical dependence. AM1710 (10 mg/kg, i.p.) did not precipitate CB1 receptor–mediated withdrawal in mice rendered tolerant to Δ9-tetrahydrocannabinol, suggesting that AM1710 is not a functional CB1 antagonist in vivo. Furthermore, AM1710 (1, 3, 10 mg/kg, i.p.) did not suppress established mechanical allodynia induced by complete Freund’s adjuvant (CFA) or by partial sciatic nerve ligation (PSNL). Similarly, prophylactic and chronic dosing with AM1710 (10 mg/kg, i.p.) did not produce antiallodynic efficacy in the CFA model. By contrast, gabapentin suppressed allodynia in both CFA and PSNL models. Our results indicate that AM1710 is not a broad-spectrum analgesic agent in mice and suggest the need to identify signaling pathways underlying CB2 therapeutic efficacy to identify appropriate indications for clinical translation.

Immunotherapy with immune checkpoint inhibitors combined with an anti-angiogenic tyrosine-kinase inhibitor (TKI) has been shown to improve overall survival versus anti-angiogenic therapy alone in advanced solid tumours, but not in hepatocellular carcinoma. Therefore, a clinical study was conducted to compare the efficacy and safety of the anti-PD-1 antibody camrelizumab plus the VEGFR2-targeted TKI rivoceranib (also known as apatinib) versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma.