Spatial patterns of the cap-binding complex eIF4F in human melanoma cells.

As a central node of protein synthesis, the cap-binding complex, eukaryotic translation initiation factor 4 F (eIF4F), is involved in cell homeostasis, development and tumorigenesis. A large body of literature exists on the regulation and function of eIF4F in cancer cells, however the intracellular localization patterns of this complex are largely unknown. Since different subsets of mRNAs are translated in distinct subcellular compartments, understanding the distribution of translation initiation factors in the cell is of major interest. Here, we developed an in situ detection method for eIF4F at the single cell level. By using an image-based spot feature analysis pipeline as well as supervised machine learning, we identify five distinct spatial patterns of the eIF4F translation initiation complex in human melanoma cells. The quantity of eIF4F complex per cell correlated with the global mRNA translation activity, and its variation is dynamically regulated by cell state or extracellular stimuli. In contrast, the spatial patterns of eIF4F complexes at the single cell level could distinguish melanoma cells harboring different oncogenic driver mutations. This suggests that different tumorigenic contexts differentially regulate the subcellular localization of mRNA translation, with specific localization of eIF4F potentially associated with melanoma cell chemoresistance.

Electrocautery vs. Stapler in Comparing Safety for Segmentectomy of Lung Cancer: A Meta-Analysis.

Background: Electrocautery and staplers are regarded as the two most common surgical instruments for dissecting the intersegmental plane in segmentectomy. We performed a meta-analysis to compare electrocautery and staplers in terms of their safety and effects. Methods: A systematic search strategy was performed using PubMed, and the retrieval time was up to April 1, 2020. Odds ratio (OR) and mean differences (MDs) with 95% CI were applied to determine the effectiveness of dichotomous or continuous variables, respectively. Results: Six studies including 385 patients were included. The electrocautery had a higher incidence rate of postoperative complication [OR= 1.92, 95% CI (1.12, 3.28), P = 0.02)] and air leak [OR: 3.91, 95% CI (1.64, 9.35), P = 0.002)]. No significant difference was found in the comparison of surgery time, blood loss, and duration of tube days or hospitality days. Conclusions: Our study indicated that patients under segmentectomy were associated with better safety by using stapler than electrocautery in the reduction of postoperative complications.

Knockdown of miR-15b partially reverses the cisplatin resistance of NSCLC through the GSK-3ß/MCL-1 pathway.

BACKGROUND: Induction of acquired drug resistance occurs frequently with cisplatin-based therapy for non-small cell lung cancer (NSCLC). As recent studies have demonstrated that deregulation of microRNAs (miRNAs) is associated with drug resistance in cancers, correcting the deregulation of miRNAs represents a promising strategy to reverse acquired resistance in NSCLC. OBJECTIVES: This study investigated the functional role of miR-15b in cisplatin resistance in NSCLC. MATERIAL AND METHODS: Cisplatin-resistant PC9 and A549 NSCLC cell lines (PC9-R and A549-R) were established through long-term exposure to cisplatin. Differences in miR-15b expression between cisplatin-resistant NSCLC cell lines and their parental cell lines were identified through quantitative real-time polymerase chain reaction (qRT-PCR). The effect of anti-miR-15b on the sensitivity of PC9-R and A549-R to cisplatin-induced cytotoxicity was evaluated using Cell Counting Kit-8 (CCK-8) assays. Regulation of GSK-3ß by miR-15b was confirmed with luciferase reporter assays. Cell apoptosis and mitochondrial membrane potential (MMP) were measured using flow cytometry analysis. RESULTS: In PC9-R and A549-R cells, miR-15b was significantly overexpressed. However, knockdown of miR-15b clearly reduced cisplatin resistance in PC9-R and A549-R cells. Researching the mechanism, we proved that GSK-3ß was the target of miR-15b. Knockdown of miR-15b significantly increased the expression GSK-3ß and thus promoted the degradation of MCL-1, which is a key anti-apoptosis protein. As a result, anti-miR-15b expanded the cisplatin-induced apoptosis in cisplatin-resistant NSCLC cells. CONCLUSIONS: Knockdown of miR-15b partially reversed cisplatin resistance in NSCLC cells through the GSK-3ß/MCL-1 pathway.

Thermal Volume Reduction Surgery for Surgical Treatment of Pulmonary Bullae: A Single-Center Treatment Experience of 276 Cases Accompany With Primary Lung Cancer.

Objective: Lung volume reduction surgery (LVRS) has been regarded as an effective surgical procedure for severe emphysema (including pulmonary bullae). However, there still remain controversial that its applications limited that only patients with a specific clinical situation may benefit from LVRS, and so did other non-surgical treatments. The current study aims to introduce some initial experience of new technique for treating pulmonary bullae, including using thermal surgical instruments to reduce enlargement of lung tissue in a specific group that diagnosed with lung cancer accompany with pulmonary bullae. Methods: This retrospective study included 276 patients undergoing emphysema reducing surgery between 2010 and 2020. All procedure were performed by thermal volume reduction surgery of using thermal surgical instruments to reduce pulmonary bullae. Results: The average time required for operating single pulmonary bullae was <10 min. Median operative time was 106 min (range 85 to 191 min). No intraoperative air leak, massive blood loss, or other severe complications occurred. The estimated blood loss for TVRS was about 40 ml (range 15 to 120 ml). Postoperative complications included atelectasis (n = 8), pulmonary infection (n = 17), bleeding (n = 5), delayed air leak (n = 7) among the cohort. The postoperative lung function at 1-year post surgery in TVRS group recovered faster with a better recovery that achieving an FEV1 of 1.95 ± 0.46 L, TLC of 6.36 ± 0.79 L, RV of 3.56 ± 0.81 L, PO2 of 60 ± 8 mmHg, PCO2 of 37 ± 6 mmHg, and 6 MWD (6-min walk distant) of 305 ± 22 m. The 1-year QOL score was elevated comparing with preoperative period. Conclusion: This single-center study reported a new thermal-based surgical approach to treat pulmonary bullae by reducing abnormally enlarged lung tissue in specific patients diagnosed with lung cancer accompany with pulmonary bullae.

Eriodictyol inhibits high glucose-induced oxidative stress and inflammation in retinal ganglial cells.

Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes mellitus and is considered as a leading cause of blindness. Oxidative stress and inflammation are significant drivers for the development of DR. Eriodictyol, a flavonoid compound, was proved to possess anti-inflammatory, antioxidative, and antidiabetic activities. However, the role of eriodictyol in DR has not been unveiled. In the current study, we explored the protective effects of eriodictyol on high glucose (HG)-induced rat retinal ganglial cells (RGCs). The results suggested that eriodictyol improved cell viability of HG-induced rat RGC-5 cells in a dose-dependent manner. Eriodictyol reduced the reactive oxygen species production and increased the activities of superoxide dismutase, glutathione peroxidase and catalase in rat RGC-5 cells in response to HG stimulation. The production of proinflammatory cytokines including tumor necrosis factor alpha and interleukin-8 was diminished after eriodictyol treatment. Eriodictyol also suppressed cell apoptosis induced HG in rat RGC-5 cells. Furthermore, eriodictyol enhanced the nuclear translocation of nuclear factor erythroid-2 (E2)-related factor 2 (Nrf2) and elevated the expression of antioxidant enzyme heme-oxygenase-1 (HO-1). These findings suggested that eriodictyol protects the RGC-5 cells from HG-induced oxidative stress, inflammation, and cell apoptosis through regulating the activation of Nrf2/HO-1 pathway.

Clinical characteristics and outcomes of lung cancer patients with combined pulmonary fibrosis and emphysema: a systematic review and meta-analysis of 13 studies.

BACKGROUND: The characteristic and outcomes of lung cancer patients with combined pulmonary fibrosis and emphysema (CPFE) have long been assessed, but results were controversial. Therefore, we performed a meta-analysis to assess the clinical features and prognosis of lung cancer patients with CPFE. METHODS: The databases PubMed, Embase, and Web of Science (updated to October 1, 2017) were searched for eligible studies. Pooled odds ratios (ORs), weighted mean differences (WMD) or hazard ratios (HRs) with 95% confidence intervals (95% CIs) were used to evaluate the clinicopathological characteristics, the short-term outcome after operation and long-term survival of lung cancer patients with CPFE compared with lung cancer patients without CPFE (fibrosis, emphysema, and normal). RESULTS: Thirty original studies with 8,050 patients were included in this meta-analysis. The pooled results indicated that lung cancer patients with CPFE were associated with higher age (MD =3.39; 95% CI: 2.12-4.67, P<0.001), male (OR =8.46; 95% CI: 6.36-11.26, P<0.001), ex- or current smoker (OR =39.65; 95% CI: 15.64-100.5, P<0.001), longer smoking history (MD =15.56; 95% CI: 3.73-27.39, P=0.01), lower DLCO% (MD =-13.82; 95% CI: -21.4 to -6.24, P<0.001), squamous cell carcinoma histology (OR =3.55; 95% CI: 2.49-5.05, P<0.001), the lower lobes (OR =1.92; 95% CI: 1.52-2.43, P<0.001), advanced pathological stage (OR =1.55; 95% CI: 1.22-1.96, P<0.001). Lung cancer patients with CPFE had higher 30-day mortality (OR =4.72, 95% CI: 2.06-10.85, P<0.001), 90-day mortality (OR =5.33; 95% CI: 1.39-20.42, P=0.01), and incidence of postoperative complications (OR =5.25, 95% CI: 2.38-11.57, P<0.001). In addition, the lung cancer patients with CPFE had a poorer OS (HR =2.006, 95% CI: 1.347-2.986, P=0.001) than lung cancer patients without CPFE. CONCLUSIONS: This meta-analysis demonstrated that lung cancer patients with CPFE have more aggressive clinical characteristic and a poor prognosis, suggesting that lung cancer patients with CPFE should be early detected, treated reasonably and be taken good care of.

Molecular analysis of interactions between a PAMAM dendrimer-paclitaxel conjugate and a biomembrane.

Understanding the underlying mechanism of nanomedicine-biomembrane interactions is important for the design and optimization of payload delivery systems. This study investigates the interactions between polyamidoamine (PAMAM) dendrimer-paclitaxel conjugates and biomembranes using coarse-grained molecular dynamics simulations. We found that acidic conditions (e.g., pH ∼ 5) and membrane asymmetry can improve the conjugate penetration. Paclitaxel (PTX) distributions on a G4 PAMAM dendrimer can affect interactions via the penetration mechanism, although they have no significant effect on interactions via the adsorption mechanism. The random distribution of PTX can enhance the ability of PTX molecules to pass through asymmetric membranes. Furthermore, the penetration process becomes more difficult with increasing paclitaxel loading ratios. These results provide molecular insights into the precise translocation mechanism of dendrimer-drug conjugates and thus provide suggestions for drug design and delivery.

Enhancement of Cerenkov luminescence imaging by dual excitation of Er(3+),Yb(3+)-doped rare-earth microparticles.

UNLABELLED: Cerenkov luminescence imaging (CLI) has been successfully utilized in various fields of preclinical studies; however, CLI is challenging due to its weak luminescent intensity and insufficient penetration capability. Here, we report the design and synthesis of a type of rare-earth microparticles (REMPs), which can be dually excited by Cerenkov luminescence (CL) resulting from the decay of radionuclides to enhance CLI in terms of intensity and penetration. METHODS: Yb(3+)- and Er(3+)- codoped hexagonal NaYF4 hollow microtubes were synthesized via a hydrothermal route. The phase, morphology, and emission spectrum were confirmed for these REMPs by power X-ray diffraction (XRD), scanning electron microscopy (SEM), and spectrophotometry, respectively. A commercial CCD camera equipped with a series of optical filters was employed to quantify the intensity and spectrum of CLI from radionuclides. The enhancement of penetration was investigated by imaging studies of nylon phantoms and nude mouse pseudotumor models. RESULTS: the REMPs could be dually excited by CL at the wavelengths of 520 and 980 nm, and the emission peaks overlaid at 660 nm. This strategy approximately doubled the overall detectable intensity of CLI and extended its maximum penetration in nylon phantoms from 5 to 15 mm. The penetration study in living animals yielded similar results. CONCLUSIONS: this study demonstrated that CL can dually excite REMPs and that the overlaid emissions in the range of 660 nm could significantly enhance the penetration and intensity of CL. The proposed enhanced CLI strategy may have promising applications in the future.

[Regulation of chondrosarcoma cell growth using synthesized hydrogels with different electric charges].

To develop standard in vitro chondrosarcoma models, we synthesized three hydrogels (i. e., PDMAAm, PNaAMPS and PMETAC) and investigated the influence of Young's modulus, swelling ratio and electric charges on the behavior of chondrosarcoma cells seeded on the hydrogels, including morphology, adhesion and aggregation. Results showed that the morphology of chondrosarcoma cells at 6h was dependent on the charges of hydrogels; cells present spindle-shaped and round-shaped morphology on negative charged and neutral hydrogel, respectively, while no cells spreaded on positive charged hydrogel. Chondrosarcoma cells formed aggregates on neutral PDMAAm after further culture. The hydrogels can be synthesized easily and has the characteristics of ease at use with defined components, which holds great potential for developing standard chondrosarcoma models in vitro.

Potential application of titanium dioxide nanoparticles in the prevention of osteosarcoma and chondrosarcoma recurrence.

Osteosarcoma and chondrosarcoma are malignant bone tumors, and they significantly affect the life quality of patients including children and adults. The main treatment method is surgical amputation of the malignant lesion, despite that recurrence often occurs. Recently, it has been observed that TiO2 NPs killed HeLa cells effectively via photocatalysis in vitro, which indicates titanium dioxide (TiO2) nanoparticles (NPs) might be used to reduce the recurrence of osteosarcoma and chondrosarcoma by inducing cytotoxicity to bone tumor cells. In this study, we investigated the potential effects of TiO2 NPs in two cancer cell lines in vitro: U-2 OS (osteosarcoma) and SW 1353 (chondrosarcoma). We assessed cell viability, the levels of reactive oxygen species (ROS) and glutathione (GSH) after exposure to TiO2 NPs at different concentrations (0.1-100 microg/ml) for varying exposure periods (12-48 hours). Compared to the NP-free control, TiO2 NPs induced cell death in a dosage-dependent and time-dependent manner. The median inhibitory concentration (IC50) of TiO2 NPs at 24 hours was 211.3 +/- 15.2 microg/ml and 5408.8 +/- 45.9 microg/ml for SW 1353 and U-2 OS cell lines, respectively. TiO2 NPs concentrations above 1 microg/ml were more efficient to reduce the cell viability of SW 1353 than U-2 OS of NPs at all exposure times. The increased ROS and reduced GSH levels indicated that TiO2 NPs killed cancer cells through oxidative stress. These results suggested that the TiO2 NPs can be potentially used to minimize/prevent the recurrence of osteosarcoma and chondrosarcoma.

Interleukin-6 signaling pathway in targeted therapy for cancer.

Interleukin-6 (IL-6) is a multifunctional cytokine which plays an important role in a wide range of biologic activities in different types of cell including tumor cells. IL-6 is involved in the host immune defense mechanism as well as the modulation of growth and differentiation in various malignancies. These effects are mediated by several signaling pathways, in particular the signal transducer and transcription activator 3 (Stat3). There exists abundant evidence demonstrating that deregulated overexpression of IL-6 was associated with tumor progression through inhibition of cancer cell apoptosis, stimulation of angiogenesis, and drug resistance. Clinical studies have revealed that increased serum IL-6 concentrations in patients are associated with advanced tumor stages of various cancers (e.g., multiple myeloma, non-small cell lung carcinoma, colorectal cancer, renal cell carcinoma, prostate cancer, breast cancer and ovarian cancer) and short survival in patients. Therefore, blocking IL-6 signaling is a potential therapeutic strategy for cancer (i.e., anti-IL-6 therapy) characterized by pathological IL-6 overproduction. Preliminary clinical evidence has shown that antibody targeted IL-6 therapy was well tolerated in cancer patients. In this review, we detail the progress of the current understanding of IL-6 signaling pathway in cancer as well as an antibody targeted IL-6 therapy for human cancer.

Recent advances in synthesis and surface modification of lanthanide-doped upconversion nanoparticles for biomedical applications.

Lanthanide (Ln)-doped upconversion nanoparticles (UCNPs) with appropriate surface modification can be used for a wide range of biomedical applications such as bio-detection, cancer therapy, bio-labeling, fluorescence imaging, magnetic resonance imaging and drug delivery. The upconversion phenomenon exhibited by Ln-doped UCNPs renders them tremendous advantages in biological applications over other types of fluorescent materials (e.g., organic dyes, fluorescent proteins, gold nanoparticles, quantum dots, and luminescent transition metal complexes) for: (i) enhanced tissue penetration depths achieved by near-infrared (NIR) excitation; (ii) improved stability against photobleaching, photoblinking and photochemical degradation; (iii) non-photodamaging to DNA/RNA due to lower excitation light energy; (iv) lower cytotoxicity; and (v) higher detection sensitivity. Ln-doped UCNPs are therefore attracting increasing attentions in recent years. In this review, we present recent advances in the synthesis of Ln-doped UCNPs and their surface modification, as well as their emerging applications in biomedicine. The future prospects of Ln-doped UCNPs for biomedical applications are also discussed.