Development of injectable in situ hydrogels based on hyaluronic acid via Diels-Alder reaction for their antitumor activities studies.

The objective of this study was to develop an injectable hydrogel based on furfuryl amine-conjugated hyaluronic acid (FA-conj-HA) and evaluate the in vivo anti-4 T1 tumor activity of doxorubicin-loaded hydrogel (DOX@FA-conj-HAgel). The cargo-free hydrogel (FA-conj-HAgel) was fabricated through a Diels-Alder reaction at 37 °C with FA-conj-HA as a gel material and four armed poly(ethylene glycol)2000-maleimide (4-arm-PEG2000-Mal) as a cross-linker. The bio-safety of FA-conj-HAgel were assessed, and the in vivo antitumor activity of DOX@FA-conj-HAgel was also investigated. Many 3D network structures were observed from scanning electron microscope (SEM) photograph, confirming the successful preparation of FA-conj-HAgel. The absence of cytotoxicity from FA-conj-HAgel was proved by the high viability of 4 T1 cells. In vivo bio-safety studies suggested that the obtained FA-conj-HAgel did not induce acute toxicity or other lesions in treated mice, confirming its high bio-safety. The reduced tumor volumes, hematoxylin-eosin staining (H&E), and TdT-mediated dUTP-biotin nick end labeling (TUNEL) analysis indicated the potent in vivo anti-4 T1 tumor effects of DOX@FA-conj-HAgel. In conclusion, the favorable bio-safety and potent antitumor activity of DOX@FA-conj-HAgel highlighted its potential application in oncological therapy.

Synthesis of the pH-sensitive nanoparticles based on the acylhydrazone bonds conjugated doxorubicin and studies on their in vivo anti-tumor effects.

The purpose of this study was to synthesize DHPD polymers through the conjugation of doxorubicin (DOX) molecules onto poly(ethylene glycol) (PEG) chains via acylhydrazone bonds, and to fabricate pH-responsive DHPD nanoparticles (NPs) for investigation of their biosecurity and in vivo anti-tumor activity. The morphology, size distribution, stability, pH-responsiveness, biosecurity, and in vivo anti-tumor effects of the DHPD NPs were evaluated. Characterization of the DHPD polymers using 1H NMR, FTIR, and Raman spectra confirmed their successful synthesis. The DHPD NPs exhibited a round morphology with an average diameter of 144.4 ± 1.7 nm and a polydispersity index (PDI) of 0.23 ± 0.02. Biosecurity studies indicated that the DHPD NPs were non-toxic to treated mice, and in vitro cell tests demonstrated their ability to be taken up by 4T1 cells. Under the acidic microenvironment of 4T1 cells, the acylhydrazone bonds were cleaved, resulting in increased DOX delivery to tumor cells and improved in vivo anti-tumor effects. Animal experiments confirmed that the DHPD NPs reduced DOX toxicity while enhancing its anti-tumor activity. Furthermore, results from the analysis of γ-interferon (INF-γ), tumor necrosis factor-α (TNF-α), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF) indicated that the DHPD NPs improved the anti-4T1 tumor effect of DOX, suggesting their potential application in the treatment of breast cancer.

Part of speech tagging of grammatical features related to L2 Chinese development: A case analysis of Stanza in the L2 writing context.

Grammatical complexity has received extensive attention in second language acquisition. Although computational tools have been developed to analyze grammatical complexity, most relevant studies investigated this construct in the context of English as a second language. In response to an increasing number of L2 Chinese learners, it is important to extend the investigation of grammatical complexity in L2 Chinese. To promote relevant research, we evaluated the new computational tool, Stanza, on its accuracy of part-of-speech tagging for L2 Chinese writing. We particularly focused on eight grammatical features closely related to L2 Chinese development. Then, we reported the precisions, recalls, and F-scores for the individual grammatical features and offered a qualitative analysis of systematic tagging errors. In terms of the precision, three features have high rates, over 90% (i.e., ba and bei markers, classifiers, -de as noun modifier marker). For recall, four features have high rates, over 90% (i.e., aspect markers, ba and bei markers, classifiers, -de as noun modifier marker). Overall, based on the F-scores, Stanza has a good tagging performance on ba and bei markers, classifiers, and -de as a noun modifier marker. This evaluation provides research implications for scholars who plan to use this computational tool to study L2 Chinese development in second language acquisition or applied linguistics in general.

Application of tumoroids derived from advanced colorectal cancer patients to predict individual response to chemotherapy.

Therapeutic approaches of advanced colorectal cancer are more complex, here we present a living biobank of patient-derived tumoroids from advanced colorectal cancer patients and show examples of how these tumoroids can be used to to simulate cancer behavior ex vivo and provide more evidence for tumoroids could be utilized as a predictive platform during chemotherapy treatment to identify the chemotherapy response. Morphological, histological and genomic characterization analysis of colorectal cancer tumoroids was conducted. Further, we treated colorectal cancer tumoroids with different drugs to detect cellular activities to evaluate drug sensitivity using CellTiter-Glo 3 D cell viability assay. Then the drug sensitivity of tumoroids was compared with clinical outcomes. Our results implied that tumoroids recapitulated the histological features of the original tumours and genotypic profiling of tumoroids showed a high-level of similarity to the matched primary tumours. Dose-response curves, area under the curve and tumour inhibitory rate of each therapeutic profiling calculations in tumoroids demonstrated a great diversity and we gained 88.24% match ratio between the sensitivity data of tumoroids with their paired patients' clinical outcomes. tumour inhibitory rate of each treatment parameters in tumoroids performed positive correlation with progression-free survival while area under the curve of each treatment parameters performed negative correlation with progression-free survival of the corresponding patients. In summary, We presented a living biobank of tumoroids from advanced colorectal cancer patients and show tumoroids got great potential for predicting clinical responses to chemotherapy treatment of advanced colorectal cancer.

Targeted delivery of doxorubicin into tumor cells to decrease the in vivo toxicity of glutathione-sensitive prodrug-poloxamer188-b-polycaprolactone nanoparticles and improve their anti-tumor activities.

Doxorubicin (DOX) is widely used in the treatment of many tumors, but the dose-dependent toxicity limits its further application. In this study, a unique strategy was developed to improve the anti-tumor effects of free DOX and lower its in vivo toxicity by constructing novel glutathione (GSH)-sensitive poloxamer188-b-polycaprolactone-S-S-doxorubicin nanoparticles (PPSSD NPs). After uptake by tumor cells, the disulfide bonds in the PPSSD NPs would be cloven by reacting with GSH. Then, a lethal dose of DOX was released in tumor cells. The uptake of PPSSD NPs by 4T1 cells was proved using fluorescence microscopy by co-localization of PPSSD NPs and 4', 6-diamidino-2-phenylindole (DAPI). Cell tests suggested that the PPSSD NPs showed high anti-tumor cells (4T1) activity but low cytotoxicity against normal cells (293 t). The in vivo toxicity and anti-tumor effects of the PPSSD NPs were studied with Kunming and Balb/c mice as models, respectively. The H&E slices, blood routine and biochemistry indexes of the PPSSD NPs treated mice indicated that the PPSSD NPs did not induce obvious in vivo toxicity. The PPSSD NPs showed higher in vitro anti-4T1 cells activity than free DOX. Furthermore, the in vivo anti-tumor study, TUNEL and H&E slices suggested that the PPSSD NPs exhibited excellent anti-tumor effects. In a word, the novel PPSSD NPs did not only improve the anti-tumor effect of DOX, but also decrease its cytotoxicity to normal tissues.

Effect of Insoles Treatment on School-Age Children with Symptomatic Flexible Flatfoot: A 2-Year Follow-Up Study.

Background: Flatfoot is common among children. Symptomatic flexible flatfoot is one of the various types which needs treatment. Wearing insoles is considered one of the conservative therapies, but its effects are still uncertain. This study aims to provide evidence for the efficacy of insoles treatment among school-aged children with symptomatic flexible flatfoot. Methods: Patient who were Children who were diagnosed with symptomatic flexible flatfoot and received insoles treatment in authors' institute were retrospectively included. Their ages, body mass index, pain positions, pain frequency, valgus angle, arch index and visual analogue scale (VAS) score were collected before and after insole treatment. Results: A total of 32 children were included in this study. The results showed that wearing insoles for 2 years caused a significant improvement in pain frequency, valgus angle, arch index and VAS score. Conclusions: This study indicated that pediatric symptomatic flexible flatfoot could be relieved by wearing insoles for 2 years. Insole treatment might be a workable option for pediatric symptomatic flexible flatfoot in children older than 6 years old.

Docetaxel-loaded redox-sensitive nanoparticles self-assembling from poly(caprolactone) conjugates with disulfide-linked poly(ethylene glycol).

In this study, novel redox-sensitive nanoparticles (NPs) were fabricated from the poly(caprolactone) conjugates with disulfide-linked poly(ethylene glycol) (DDMAT- mPEG-S-S-PCL, DPSP). The DPSP polymer was synthesized by ring-opening polymerization (ROP) and reversible addition-fragmentation chain transfer (RAFT) polymerization. The obtaining of the DPSP polymer was confirmed by the 1H nuclear magnetic resonance (1H NMR) and Fourier transform infrared spectroscopy (FTIR) spectra. The DPSP NPs were fabricated with the solvent-evaporation method. Docetaxel (DTX) was employed as a model drug and encapsulated into the DPSP NPs. The in vitro anti-tumor activity of the DTX-loaded DPSP NPs and free DTX against the breast cancer cells (4T1) were evaluated by MTT assay. The cargo-free DPSP NPs were in circular shapes with an average diameter of 107.8 ± 0.4 nm. These NPs displayed redox-responsive behavior in the presence of glutathione. Animal experiments indicated that the DPSP NPs showed excellent blood compatibility and good bio-security. Cell tests suggested that the DPSP NPs could be taken in by 4T1 cells, smoothly, which improved the anti-tumor activity of free DTX.

The impact of flooding on firm performance and economic growth.

Using comprehensive flood data from China, we find a significant, negative impact of flooding on firm performance, which is mainly driven by unexpected flooding. We use multiple identification strategies to address endogeneity concerns and find that the documented impact of flooding on firm performance is likely causal. The impact is more pronounced for firms with more tangible asset investment, firms located in cities with low government quality, firms facing tight financial constraints, firms controlled by non-government entities and firms with low geographic diversification. Flood-exposed firms react to the threat by altering their investment, financial, cash, payout and executive compensation policies. Finally, flooding also exerts a significant impact on local economic and employment growth.

Controlled Decompression Alleviates Brain Injury via Attenuating Oxidative Damage and Neuroinflammation in Acute Intracranial Hypertension.

BACKGROUND: The benefits of controlled decompression (CDC) for patients with acute intracranial hypertension especially in terms of alleviating the complications caused by rapid decompression (RDC) have been confirmed by clinical studies. This study is aimed at evaluating the therapeutic potency of CDC with ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) by investigating the potential molecular mechanism in the acute intracranial hypertension (AICH) rabbit model. METHODS: Male New Zealand white rabbits were randomly subdivided into the sham-operated (SH) group, CDC group, and RDC group. Blood plasma samples and brain tissue were collected 2 days before operation (baseline) and at 3, 6, 24, and 72 hours after operation to measure the levels of UCH-L1, GFAP, oxidative stress indicators, and inflammatory cytokines by performing ELISA or Western blot. The neurological score of the rabbits and brain water content was graded 24 h after surgery. qPCR, immunofluorescence, and FJ-C staining were conducted. RESULTS: CDC improved neurological function, lowered brain water content, ameliorated neuronal degeneration, attenuated oxidative damage, and inflammatory responses to a greater extent than RDC. Plasma UCH-L1 level was significantly lower in the CDC group at 3 h postoperatively than in the RDC group. CDC reduced plasma GFAP levels to various degrees at 3 h, 6 h, and 24 h postoperatively compared with RDC. Immunofluorescence confirmed that the expression of UCH-L1 and GFAP in the cortex of the CDC group was lower than that of the RDC group. CONCLUSIONS: Our data collectively demonstrate that CDC could attenuate oxidative damage and inflammatory responses, downregulate UCH-L1 and GFAP levels, and contribute to an improved neuroprotective effect compared with RDC.

Fabrication of poly(t-butyl betaine carboxylate)-based nanoparticles and study on their in vivo biosecurity.

The purpose of this article was to fabricate the novel poly(t-butyl betaine carboxylate)-S-S-poly (1, 3-dioxan-2-one) nanoparticles (PCB-tBU-S-S-PDI NPs) and study their in vivo biosecurity. The poly(t-butyl betaine carboxylate) (PCB-tBU) segment was conjugated to the poly(1, 3-dioxan-2-one)(PDI) moity with a disulfide bond to obtain the copolymer PCB-tBU-S-S-PDI. Hydrogen nuclear magnetic resonance (1H NMR) and Fourier transform infrared spectroscopy (FTIR) spectra were applied to study the structure of PCB-tBU-S-S-PDI. The cargo-free NPs were administrated to Sprague-Dawley (SD) rats by intraperitoneal injection every 3 days for 30 days. Then, the blood routine examination, blood biochemistry, and histologic slides of rat's organs were carried out to monitor the in vivo biosecurity of cargo-free PCB-tBU-S-S-PDI NPs. 1H NMR and FTIR spectra confirmed the successfully synthesis of PCB-tBU-S-S-PDI. The cargo-free NPs showed spherical morphology with an average of 139.8 ± 0.26 nm. The results of blood biochemistry and blood routine examination suggested that the cargo-free PCB-tBU-S-S-PDI NPs did not show any influence on the liver and renal functions of treated rats. Significantly, the physiological slides of treated rat's organs did not show any physiological and pathological changes. These phenomena suggested that the PCB-tBU-S-S-PDI NPs had good biosecurity, and it could be used as a vehicle for antineoplastic drug delivery.

Identification of RORγ as a favorable biomarker for colon cancer.

OBJECTIVE: To evaluate the expression of retinoid-related orphan receptor gamma (RORγ) and its potential role in the prognosis of colon cancer. METHODS: The Cancer Genome Atlas and GSE117606 were used to evaluate to RORγ levels in colon cancer, and real-time quantitative polymerase chain reaction was applied for validation. UALCAN and MEXPRESS were used to analyze the associations of RORγ expression with clinical parameters. The survival analysis was conducted in GEPIA. RESULTS: RORγ expression was significantly lower in colon tumors than in adjacent normal mucosa tissues. RORγ expression was significantly associated with tumor stage, lymph node metastasis, and liver metastasis. The area under the curve for diagnosis was 0.71. Decreased RORγ expression was positively correlated with the incidence of lymphatic invasion, microsatellite instability, the presence of residual tumor, venous invasion, and copy number variation. Overall survival was longer in patients with higher RORγ expression, especially those with microsatellite instability-high features. Methylation analysis revealed that hypermethylation of the RORγ promoter was associated with the colon cancer stage. CONCLUSIONS: RORγ downregulation could be a potential biomarker for colon cancer, especially for predicting prognosis. Decreased RORγ expression in colon tumor may be associated with promoter hypermethylation.

FGF-2 suppresses neuronal autophagy by regulating the PI3K/Akt pathway in subarachnoid hemorrhage.

The degree of early brain injury (EBI) is a significant factor that affects the prognosis of patients with subarachnoid hemorrhage (SAH). Evidence has shown that fibroblast growth factor-2 (FGF-2) may alleviate the serious consequences of EBI after SAH. The objective of the current study was to investigate the underlying mechanism that mediates the neuroprotective effects of FGF-2 in the SAH rat model. Sprague-Dawley (SD) rats that underwent different treatments were divided into various groups. FGF-2 was administered intranasally to rats in the treatment group within 30 min after modeling. Rapamycin (an autophagy activator) or LY294002 (a PI3K/Akt pathway inhibitor) was administered intracerebroventricularly (i.c.v.) 30 min before modeling. Neurological scale and brain water content were measured in the brain tissue of the rats. TUNEL staining, Western blot, and immunofluorescence staining were performed to examine and compare the diverse effects of FGF-2 treatment, activated autophagy, and inhibited the PI3K/Akt pathway. We found that FGF-2 treatment effectively reduced the number of TUNEL-positive cells, decreased the brain water content, and improved the neurological function of rats after SAH. Additionally, the expression levels of autophagy-related proteins (LC3 and Beclin-1) were obviously decreased in the FGF-2 treatment group compared with the SAH + vehicle group. The therapeutic effects of FGF-2 in the SAH + FGF-2+rapamycin group were weakened compared with that in the SAH + FGF-2+DMSO group. In the event of the PI3K/Akt pathway inhibition, the expression levels of LC3 and Beclin-1 were enhanced, and the therapeutic effects of FGF-2 were compromised. In summary, our data collectively demonstrated that FGF-2 may suppress autophagy levels to play a neuroprotective role, at least partially by activating the PI3K/Akt pathway. These results highlight FGF-2 as a promising solution to the clinical intervention of SAH.

[Voice analysis of early glottic carcinoma treated by carbon dioxide laser].

Objective:The aim of this study is to investigate the effect of CO2 laser cordectomy on the voice of early glottic carcinoma. Method:A retrospective analysis of 40 patients who underwent CO2 laser treatment early glottis preoperative clinical data of postoperative laryngeal cancer patients, patients with postoperative recurrence rate, survival rate, and the postoperative complications of patients with preoperative and postoperative laryngoscopy, voice disorders index（voice handicap index, VHI） simplified Chinese version（VHI 13） rating scale, affecting the stability sound quality postoperatively in patients with laryngeal cancer were discussed. Result:All patients underwent voice reexamination 8-97 months after surgery, and the survival rate was 100%, no local recurrence and no obvious postoperative complications. Compared with the healthy control group, there were statistically significant differences in the four indicators F0（fundamental frequency）, Jitter（fundamental frequency perturbation）, Shimmer（amplitude perturbation） and MPT（maximum pronunciation time）, suggesting that CO2 laser surgery resulted in significant changes in acoustic parameters. Jitter and Shimmer indexes in the pre involved combined group were statistically significant different from those in the non involved combined group, suggesting that the sound quality of the pre involved combined group was worse in the postoperative stability period. The VHI score indicated that most patients with early glottic cancer were in severe voice disorder before operation and most were in moderate voice disorder after operation. Compared with the healthy control group, the VHI score and total score of the healthy control group were lower in terms of physiology, psychology and emotion. Compared with the healthy control group, the VHI score and physiology of the early glottic laryngeal cancer patients were lower in the early glottic laryngeal cancer patients before and after surgery, and they were statistically significant. Conclusion:CO2 laser surgery for early glottic cancer, the overall survival rate of patients, low recurrence rate, fewer complications, CO2 laser surgery led to significant changes in acoustic parameters, postoperative sound quality and whether the involvement of pre-associated factors; The total score of VHI and physiological score of early glottic carcinoma patients after CO2 laser operation were better than those before operation.

Abnormal Activation of Myeloid Dendritic Cells in JORRP Patients and Associated with Disease Activity.

BACKGROUND: Representing the first line of host defense against virus infections and an essential link between innate and adaptive immune response, the role of dendritic cells (DCs) in peripheral blood of juvenile-onset recurrent respiratory papillomatosis (JORRP) patients and association with disease activity were still not established. MATERIALS AND METHODS: In our present study, 28 JORRP patients and 28 age and sex matched healthy controls were enrolled. The percentage, phenotype and cytokine secretion of DC and was measured by flow cytometry. Plasma cytokine were detected by the enzyme-linked immunosorbent assay (ELISA). RESULTS: We found that the percentage of myeloid DC (mDC) was significantly lower in JORRP patients compared to healthy controls and was negatively correlated with interval times, but not surgical times or disease onset. Moreover, the activation marker, CD40 and CD86 was significantly up-regulated on the surfaces of mDC in JORRP patients compared with healthy controls. Neither the percentage nor activation of plasmacytoid DC (pDC) showed statistical difference between JORRP patients and healthy controls. HLA-DR expression on both mDC and pDC was down-regulated in JORRP group and negatively correlated with surgical times. Antigen presenting ability of DC was greatly impaired in JORRP patients of higher number of operations and shorter interval time. Plasma IL-10 as well as IL-10 secreted by mDC was higher in JORRP patients compared with healthy control. Finally, we detected an up-regulated TLR2 and TLR4 expression on mDCs and TLR4 expression was positively correlated with HLA-DR expression on mDC of JORRP patients. CONCLUSION: Our results demonstrate an abnormal TLR2 and TLR4 expression in mDCs may contribute to suppressive immune response to HPV6 or HPV11 infection and associated with disease activity in JORRP patients.

A parallel decoding algorithm for short polar codes based on error checking and correcting.

We propose a parallel decoding algorithm based on error checking and correcting to improve the performance of the short polar codes. In order to enhance the error-correcting capacity of the decoding algorithm, we first derive the error-checking equations generated on the basis of the frozen nodes, and then we introduce the method to check the errors in the input nodes of the decoder by the solutions of these equations. In order to further correct those checked errors, we adopt the method of modifying the probability messages of the error nodes with constant values according to the maximization principle. Due to the existence of multiple solutions of the error-checking equations, we formulate a CRC-aided optimization problem of finding the optimal solution with three different target functions, so as to improve the accuracy of error checking. Besides, in order to increase the throughput of decoding, we use a parallel method based on the decoding tree to calculate probability messages of all the nodes in the decoder. Numerical results show that the proposed decoding algorithm achieves better performance than that of some existing decoding algorithms with the same code length.

Cooperation during cultural group formation promotes trust towards members of out-groups.

People often cooperate with members of their own group, and discriminate against members of other groups. Previous research establishes that cultural groups can form endogenously, and that these groups demonstrate in-group favouritism. Given the presence of cultural groups, the previous literature argues that cultural evolution selects for groups that exhibit parochial altruism. The source of initial variation in these traits, however, remains uninformed. We show here that a group's economic production environment may substantially influence parochial tendencies, with groups formed around more cooperative production (CP) displaying less parochialism than groups formed around more independent production (IP) processes. Participants randomized into CP and IP production tasks formed cultural groups, and subsequently played hidden-action trust games with in-group and out-group trustees. We found CP to be associated with significantly greater sharing and exchanging behaviours than IP. In trust games, significant parochial altruism (in-group favouritism combined with out-group discrimination) was displayed by members of IP groups. By contrast, members of CP groups did not engage in either in-group favouritism or out-group discrimination. Further, we found the absence of out-group discrimination in CP to persist even following 'betrayal'. Finally, belief data suggest that members of CP are not more intrinsically generous than IP members, but rather more likely to believe that out-group trustees will positively reciprocate. Our results have important implications for anyone interested in building cooperative teams, and shed new light on connections between culture and cooperation.

The causal effect of market priming on trust: an experimental investigation using randomized control.

We report data from laboratory experiments where participants were primed using phrases related to markets and trade. Participants then participated in trust games with anonymous strangers. The decisions of primed participants are compared to those of a control group. We find evidence that priming for market participation affects positively the beliefs regarding the trustworthiness of anonymous strangers and increases trusting decisions.

Competition for trophies triggers male generosity.

BACKGROUND: Cooperation is indispensable in human societies, and much progress has been made towards understanding human pro-social decisions. Formal incentives, such as punishment, are suggested as potential effective approaches despite the fact that punishment can crowd out intrinsic motives for cooperation and detrimentally impact efficiency. At the same time, evolutionary biologists have long recognized that cooperation, especially food sharing, is typically efficiently organized in groups living on wild foods, even absent formal economic incentives. Despite its evident importance, the source of this voluntary compliance remains largely uninformed. Drawing on costly signaling theory, and in light of the widely established competitive nature of males, we hypothesize that unique and displayable rewards (trophies) out of competition may trigger male generosity in competitive social environments. PRINCIPAL FINDINGS: Here, we use a controlled laboratory experiment to show that cooperation is sustained in a generosity competition with trophy rewards, but breaks down in the same environment with equally valuable but non-unique and non-displayable rewards. Further, we find that males' competition for trophies is the driving force behind treatment differences. In contrast, it appears that female competitiveness is not modulated by trophy rewards. SIGNIFICANCE: Our results suggest new approaches to promoting cooperation in human groups that, unlike punishment mechanisms, do not sacrifice efficiency. This could have important implications in any domain where voluntary compliance matters--including relations between spouses, employers and employees, market transactions, and conformity to legal standards.