A case report of Transnasal Endoscopic Drainage for Upper Parapharyngeal Abscess.

We report a case of upper parapharyngeal abscess arising from progression of a central skull base osteomyelitis, in a patient with poorly controlled diabetes mellitus. Our case is unusual for its presentation in an upper parapharyngeal location, involvement of the skull base, and poor response to medical treatment, hence requiring transnasal endoscopic surgical drainage to achieve definitive treatment. Here, we share our experience with a safe and effective technique of transnasal endoscopic drainage of a parapharyngeal abscess. Laryngoscope, 2024.

Black porous silicon as a photothermal agent and immunoadjuvant for efficient antitumor immunotherapy.

Photothermal therapy (PTT) in combination with other treatment modalities has shown great potential to activate immunotherapy against tumor metastasis. However, the nanoparticles (NPs) that generate PTT have served as the photothermal agent only. Moreover, researchers have widely utilized highly immunogenic tumor models to evaluate the immune response of these NPs thus giving over-optimistic results. In the present study black porous silicon (BPSi) NPs were developed to serve as both the photothermal agent and the adjuvant for PTT-based antitumor immunotherapy. We found that the poorly immunogenic tumor models such as B16 are more valid to evaluate NP-based immunotherapy than the widely used immunogenic models such as CT26. Based on the B16 cancer model, a cocktail regimen was developed that combined BPSi-based PTT with doxorubicin (DOX) and cytosine-phosphate-guanosine (CpG). BPSi-based PTT was an important trigger to activate the specific immunotherapy to inhibit tumor growth by featuring the selective upregulation of TNF-α. Either by adding a low dose DOX or by prolonging the laser heating time, a similar efficacy of immunotherapy was evoked to inhibit tumor growth. Moreover, BPSi acted as a co-adjuvant for CpG to significantly boost the immunotherapy. The present study demonstrates that the BPSi-based regimen is a potent and safe antitumor immunotherapy modality. Moreover, our study highlighted that tuning the laser heating parameters of PTT is an alternative to the toxic cytostatic to evoke immunotherapy, paving the way to optimize the PTT-based combination therapy for enhanced efficacy and decreased side effects. STATEMENT OF SIGNIFICANCE: Tumor metastasis causes directly or indirectly more than 90% of cancer deaths. Combination of photothermal therapy (PTT), chemotherapy and immunotherapy based on nanoparticles (NPs) has shown great potential to inhibit distant and metastatic tumors. However, these NPs typically act only as photothermal agents and many of them have been evaluated with immunogenic tumor models. The present study developed black porous silicon working as both the photothermal conversion agent and the immunoadjuvant to inhibit distant tumor. It was recognized that the poorly immunogenic tumor model B16 is more appropriate to evaluate immunotherapy than the widely used immunogenic model CT26. The coordination mechanism of the PTT-based combination therapy regimen was discovered in detail, paving the way to optimize cancer immunotherapy for enhanced efficacy and decreased side effects.

Downregulation of Methyltransferase-Like 14 Promotes Ovarian Cancer Cell Proliferation Through Stabilizing TROAP mRNA.

Altered expression levels of the proteins that regulate N6-methyladenosine (m6A) RNA methylation, including methyltransferase-like 14 (METTL14), are associated with cancer development. Based on our analysis of m6A methylation regulators using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, we focused on the regulatory role of METTL14 in ovarian cancer. We performed bioinformatics and survival analyses with these datasets and also used METTL14-overexpressing SKOV-3 ovarian cancer cells for in vitro studies. Trophinin associated protein (TROAP) siRNA and treatment with or without actinomycin D was used in the cells for qRT-PCR, western blot, cDNA microarray, cell viability, colony formation, luciferase gene reporter, methylated RNA immunoprecipitation (MeRIP)-qPCR, total RNA methylation, and RNA stability assays. Additionally, ovarian cancer and normal tissue samples were analyzed by immunohistochemistry, qRT-PCR, and western blot assays. The TCGA and GEO data confirmed copy number variations (CNVs) of these m6A RNA methylation regulators in ovarian cancer tissues. Furthermore, reduced METTL14 expression was associated with alterations in CNVs as well as poor patient survival in ovarian cancer. Moreover, the METTL14 and m6A RNA methylation levels were both significantly reduced in ovarian cancer tissues than in normal tissues. Restoration of METTL14 expression suppresses ovarian cancer cell proliferation by inhibition of TROAP expression. Further in vivo and in vitro experiments confirmed that METTL14 is a negative regulator of ovarian cancer cell proliferation via TROAP expression and that m6A RNA methylation regulates TROAP mRNA stability. In conclusion, METTL14 overexpression decreased ovarian cancer proliferation by inhibition of TROAP expression via an m6A RNA methylation-dependent mechanism.

The Establishment and Application Studies on Precise Lysosome pH Indicator Based on Self-Decomposable Nanoparticles.

Acidic pH of lysosomes is closely related to autophagy; thus, well known of the precise lysosomes, pH changes will give more information on the autophagy process and status. So far, however, only pH changes in a relatively broad range could be indicated, the exact lysosomes pH detection has never arrived. In our study, we established an endo/lysosome pH indicator based on the self-decomposable SiO2 nanoparticle system with specific synthesis parameters. The central concentrated methylene blue (MB) in the central-hollow structural nanoparticles presented sensitive release as a function of pH values from pH 4.0-4.8, which is exactly the pH range of lysosomes. The linear correlation of the optical density (OD) values and the pH values has been built up, which has been used for the detection of lysosomes pH in 6 different cell lines. Moreover, by this system, we succeeded in precisely detecting the pH average changes of lysosomes before and after black mesoporous silicon (BPSi) NP endocytosis, clarifying the mechanism of the autophagy termination after BPSi endocytosis. So, the self-decomposable nanoparticle-based luminal pH indicator may provide a new methodology and strategy to know better of the lysosome pH, then indicate more details on the autophagy process or other important signaling about metabolisms.

Supramolecular Drug-Drug Complex Vesicles Enable Sequential Drug Release for Enhanced Combination Therapy.

Drug-drug self-delivery systems serving as both carriers and cargos have been explored as advanced combination chemotherapy strategies to overcome the limitations of the traditional single-drug chemotherapy. However, most known drug-drug self-delivery systems may cause a rapid increase in drug concentration when the single covalent bond is broken, thus leading to high toxicity to organs and low therapeutic efficiency against tumors. To address the above problem, in this study, a novel supramolecular drug-drug complex (SDDC) simultaneously containing both covalent and noncovalent bonds was proposed to realize the sequential release of two drugs in tumor cells for enhanced combination therapy. The SDDC could self-assemble into uniform bilayer supramolecular vesicles (SVs) with a remarkable drug loading capacity and stable drug transport. Notably, the SVs with controlled sequential release ability in tumor cells exhibited a superior synergistic effect and significantly improved therapeutic efficiency with reduced toxicity in in vivo antitumor activity and histological analyses in comparison to either individual free drugs or a mixture of two free drugs. Therefore, by combining the advantages of noncovalent interactions with the dynamic nature and stable covalent bonds, this study opens a new way for cancer therapy.

Low-Dose X-ray Excited Photodynamic Therapy Based on NaLuF4:Tb3+-Rose Bengal Nanocomposite.

X-ray excited photodynamic therapy (X-PDT), which utilizes X-rays as the energy source and X-ray luminescent nanoparticles (XLNPs) as the transducer to excite photosensitizers (PS), resolves the penetration problem of light in traditional PDT to enable the treatment of deep-seated tumors. Nevertheless, the high X-ray dosage used in X-PDT hampers its potential applications in clinics. In this study, to alleviate the dose problem, ß-NaLuF4:Tb3+ spherical nanoparticles (NPs) with ultrastrong green X-ray excited optical luminescence (XEOL) due to the less nonradiative relaxation probability and high X-ray absorption mass coefficient, which perfectly matches the absorption spectrum of a photosensitizer named rose bengal (RB), were synthesized and employed as the energy transducer for X-PDT. After covalent conjugation of NPs with RB, high Förster resonant energy transfer (FRET) efficiency up to 94.29% was achieved, leading to high production of singlet oxygen. In vivo X-PDT efficacy was evaluated by nude mice with a HepG2 tumor xenograft. With excellent biocompatibility, the synthesized NPs-RB nanocomposite showed significant antitumor efficiency up to 80 ± 12.3% with a total X-ray dose of only 0.19 Gy, demonstrating the feasibility of low-dose X-PDT in vivo for the first time. The present work provides a promising platform for X-PDT in deep-seated tumors.

Serum long noncoding RNA urothelial carcinoma-associated 1: A novel biomarker for diagnosis and prognosis of hepatocellular carcinoma.

Objective Long noncoding RNAs (lncRNAs) offer great potential as cancer biomarkers. This study was performed to assess the applicability of serum lncRNA urothelial carcinoma-associated 1 (UCA1) as a diagnostic and/or prognostic biomarker for hepatocellular carcinoma (HCC). Methods We examined UCA1 expression in serum samples from 105 patients with HCC, 105 patients with benign liver disease (BLD), and 105 healthy volunteers using reverse-transcription polymerase chain reaction and analyzed the relationship between serum UCA1 and clinicopathological parameters of HCC as well as survival. Results Expression of serum UCA1 was significantly higher in patients with HCC and allowed for discrimination of HCC from BLD and healthy controls. High expression of serum UCA1 was significantly associated with a high tumor grade, large tumor size, positive vascular invasion, and advanced TNM stage. Multivariate analysis revealed that a high serum UCA1 level was an independent unfavorable prognostic factor for HCC. Conclusions Our results confirm the upregulation of serum UCA1 expression in HCC and indicate its clinical value as a noninvasive biomarker for HCC screening and prognostic prediction.

Inhibitory effects of CIK on lung cancer A549 cells intensified by chemotherapyinduced damaged associated molecular pattern / 中国肿瘤生物治疗杂志

@# Objective: To investigate the effect of DAMP (damaged associated molecular pattern) on the inhibition of RAS-mutant A549 lung adenocarcinoma cells by CIK cells and its mechanism. Methods: Human peripheral blood mononuclear cells were isolated in vitro and CIK cells were cultured. A549 cells were treated with cisplatin (DDP) and doxorubicin (ADM) alone or in combination, and the morphology of A549 cells was observed under a microscope. The supernatant of A549 cells was co-cultured with CIK cells. Flow cytometry was used to detect the CIK cell immunophenotype after co-culture. MTT assay was used to detect the inhibition of A549 lung cancer cell proliferation induced by A549 cell supernatant. The concentration of chemotherapeutic drugs kills A549 cell supernatant CRT, ATP, HMGB1 content. Results: Low-level chemotherapeutic drugs showed more immunogenic death characteristics after killingA549 cells. The ratio of CD8+ and CD56+ in CIK cells was significantly higher than that in control CIK cells (P<0.05). The inhibition rate of CIK cells induced byA549 cells after injury onA549 lung adenocarcinoma cells was significantly higher than that of the same dose chemotherapy group [DDP group (31.34±1.51)% vs (5.97±1.74)%, ADM group (45.46±1.78)% vs (6.22±1.34)%, DDP+ ADM group (45.78±1.14)% vs (11.94±3.11)%, all P<0.05], and low-mass chemotherapeutic agents killed C549 induced by A549 cell supernatant on A549 The inhibition rate of the cells was higherthan that of the supernatant induced by the higher concentration of chemotherapeutic drugs (all P<0.05). The level of CRT,ATP, and HMGB1 in immunogenicity-related molecules in the supernatant ofA549 cells was significantly increased by low-concentration chemotherapy drugs (all P<0.05). In the low-concentration group, the supernatant-induced inhibition of the proliferation of A549 lung adenocarcinoma cells increased with the increase of CRT, ATP, and HMGB1 levels. Conclusion: The combination of lower concentration of DDP and ADM alone or in combination could more easily induce the immunogenic death of A549 cells and release higher levels of DAMP molecules, which could promote the inhibitory effect of CIK on lung cancerA549 cells.

Overexpression of PAD4 suppresses drug resistance of NSCLC cell lines to gefitinib through inhibiting Elk1-mediated epithelial-mesenchymal transition.

It is reported that epithelial-to-mesenchymal transition (EMT) could induce resistance in tumor cells, and knockdown of peptidylarginine deiminase IV (PAD4) induces the activity of EMT. However, the role of PAD4 in gefitinib­acquired resistance in non-small cell lung cancer (NSCLC) remains unclear. In this study, we aimed to investigate the role of PAD4 in the resistance of NSCLC to gefitinib. The cells resistant to gefitinib were established in accordance with the literature, and were derived from NSCLC cell lines HCC827 and H1650. Real-time quantitative PCR and western blot results showed that PAD4 was obviously downregulated in the cells resistant to gefitinib. Overexpression of PAD4 distinctly inhibited gefitinib resistance, whereas PAD4 downregulation had the opposite effect. Further data indicated that PAD4 upregulation could restrain EMT activity via controlling the expression of ETS-domain containing protein (Elk1). Conversely, inhibition of PAD4 showed the reverse function compared with PAD4 upregulation. Above all, our study showed that overexpression of PAD4 constrains the activity of EMT via suppressing Elk1 expression, and inhibits resistance of NSCLC to gefitinib.

The expression and crystallization of Cry65Aa require two C-termini, revealing a novel evolutionary strategy of Bacillus thuringiensis Cry proteins.

The insecticidal crystal protein (Cry) genes of Bacillus thuringiensis are a key gene resource for generating transgenic crops with pest resistance. However, many cry genes cannot be expressed or form crystals in mother cells. Here, we report a novel Cry protein gene, cry65Aa1, which exists in an operon that contains a downstream gene encoding a hypothetical protein ORF2. We demonstrated that ORF2 is required for Cry65Aa1 expression and crystallization by function as a C-terminal crystallization domain. The orf2 sequence is also required for Cry65Aa expression, because orf2 transcripts have a stabilizing effect on cry65Aa1 transcripts. Furthermore, we found that the crystallization of Cry65Aa1 required the Cry65Aa1 C-terminus in addition to ORF2 or a typical Cry protein C-terminal region. Finally, we showed that Cry65Aa1 has a selective cytotoxic effect on MDA-MB231 cancer cells. This report is the first description of a 130-kDa mass range Cry protein requiring two C-termini for crystallization. Our findings reveal a novel evolutionary strategy of Cry proteins and provide an explanation for the existence of Cry protein genes that cannot form crystals in B. thuringiensis. This study also provides a potential framework for isolating novel cry genes from "no crystal" B. thuringiensis strains.

Synthesis and in vitro cytotoxic effect of 6-amino-substituted 11H- and 11Me-indolo[3,2-c]quinolines.

A series of 6-amino-11H- indolo[3,2-c]quinoline derivatives with various substituents on the quinoline ring were synthesized. A methyl group introduced to N-11 of the intermediate 4 to elaborate novel analog 7. The cytotoxic effect of these 6-amino-substituted 11H- and 11-methyl-indolo[3,2-c]quinoline derivatives in vitro were tested against MV4-11 (human leukemia), A549 (non-small cell lung cancer) and HCT116 (colon cancer) and BALB/3T3 (normal murine fibroblasts). All the N-11 methylated compounds significantly increased the cytotoxicity. Compound 7p was most active with the IC50 value of 0.052 µM against the MV4-11 cell line, and also exhibited a selective activity against A549, HCT116 and BALB/3T3 cell line, with the respective IC50 values of 0.112, 0.007 and 0.083 µM, which were higher or comparable to those of the anticancer drug doxorubicin HCl. The binding constants of 5g and 7h to salmon fish sperm DNA were also evaluated using UV-vis absorption spectroscopy, indicating intercalation binding with constants of 1.05 × 10(6) L/mol and 4.84 × 10(6) L/mol.

Synthesis and in vitro antimalarial testing of neocryptolepines: SAR study for improved activity by introduction and modifications of side chains at C2 and C11 on indolo[2,3-b]quinolines.

To obtain a high antimalarial activity with neocryptolepine derivatives, modifying and changing the side chains at the C11 position with varying the substituents of an electron-withdrawing or electron-donating nature at the C2 position for a SAR study were executed. Installation of alkylamino and ω-aminoalkylamino groups at the C11 position of the neocryptolepine core was successful. For further variation, the aminoalkylamino substituents were transformed into the corresponding acyclic or cyclic carbamides or thiocarbamides. These side chain modified neocryptolepine derivatives were tested for antimalarial activity against CQR (K1) and CQS (NF54) of Plasmodium falciparum in vitro and for cytotoxicity toward mammalian L6 cells. Among the tested compounds, the compound 17f showed an IC50 of 2.2 nM for CQS (NF54) and a selectivity index of 1400, and 17i showed an IC50 of 2.2 nM for CQR (K1), a selectivity index of 1243, and a resistance index of 0.5.

Synthesis and in vitro antiproliferative activity of new 11-aminoalkylamino-substituted chromeno[2,3-b]indoles.

To search for new biological activities of the chromeno[2,3-b]indoles, the 5-oxa analog of the indolo[2,3-b]quinolines that are known to have a potent antitumor activity, a series of 11-amino derivatives with various substituents at the C-2 position were prepared. The synthesis of the chromeno[2,3-b]indole structure involves the cyclization of 2-phenoxy-3-indolecarboxylates 3, accessible from the indole-3-carboxylate 1 and phenols 2, producing the chromeno[2,3-b]indol-11(6H)-ones 4, which is followed by dehydroxychlorination with phosphorus oxychloride to afford the 11-chlorochromeno[2,3-b]indoles 5. The treatment of 5 with various amines produced the corresponding 11-aminated chromeno[2,3-b]indoles 6, while some of the 11-ω-aminoalkylamino derivatives 6 were transformed into the 11-ω-sulfonylaminoalkylamino derivatives 8. The antiproliferative activity of these 11-aminochromeno[2,3-b]indoles 6 and 8 in vitro were tested using MV4-11 (human leukemia), A549 (lung cancer), HCT116 (colon cancer), and the normal mice fibroblast (BALB/3T3) and their potencies were described.

[The variation trend of fluorescence characteristics of DOM in the acetophenone degradation process by electro-Fenton].

In the acetophenone degradation process by electro-Fenton, the variation trend of fluorescence characteristics of dissolved organic matter (DOM) in acetophenone synthetic wastewater was detected by excitation-emission matrix (EEM) fluorescence spectra. The fluorescence spectra characteristics of acetophenone were studied, and the fitting line of fluorescence intensity and acetophenone removal efficiency was discussed in detail. The results show that the locations of the two fluorescence centers of acetophenone synthetic wastewater are at lambda(Ex/Em) = 270/305 nm (Peak A) and lambda(Ex/Em) = 215/305 nm (Peak B), respectively, and the ratio of Peak A/Peak B is 1.22. In the electro-Fenton treatment process, firstly, acetophenone was decomposed into unsaturated fatty acid which had stronger fluorescence intensity, further, it was degraded into short-chain small molecular compounds which have weaker fluorescence intensity. Therefore, the fluorescence intensity of synthetic wastewater was increased at first and decreased afterwards in the entire 180 min electro-Fenton treatment process. The two-dimensional fluorescence peak at 285-375 nm of emission wavelength (at lambda(Ex) = 250 nm) had a good linear relationship with the removal efficiency of acetophenone, therefore, it could reflect effectively the removal efficiency of acetophenone in the whole electro-Fenton treatment process.