Circ_0005015 upregulates BACH1 to promote aggressive behaviors in glioblastoma by sponging microRNA-382-5p.

To investigate the potential role and molecular mechanism of circ_0005015 in GBM progression. Circ_0005015, microRNA-382-5p (miR-382-5p), and BTB domain and CNC homolog 1 (BACH1) levels were measured by real-time quantitative polymerase chain reaction (RT-qPCR). Cell proliferation was determined by MTT, colony formation, and EdU assays. Cell apoptosis was analyzed using flow cytometry. Cell migration and invasion were assessed using wound healing and transwell assays. Glucose accumulation and lactate levels were examined by the corresponding kit. RNA pull-down and dual-luciferase reporter assays were performed to confirm the interaction between miR-382-5p and circ_0005015 or BACH1. Protein levels of MMP9, PCNA, and BACH1 were examined using western blot assay. Role of circ_0005015 on tumor growth in vivo was analyzed using a xenograft tumor model. Circ_0005015 content was up-regulated in GBM patients and cells, its knockdown restrained GBM cell proliferation, migration, invasion, glycolysis, and triggered apoptosis. Mechanistically, we found that circ_0005015 could directly interact with miR-382-5p and serve as a miRNA sponge to regulate BACH1 expression. In addition, circ_0005015 knockdown might repress tumor growth in vivo. Circ_0005015 boosted GBM progression via binding to miR-382-5p to up-regulate BACH1, which may offer new effective targets for GBM treatment.

Drug-tolerant persister cells in cancer: the cutting edges and future directions.

Drug-tolerant persister (DTP) cell populations were originally discovered in antibiotic-resistant bacterial biofilms. Similar populations with comparable features have since been identified among cancer cells and have been linked with treatment resistance that lacks an underlying genomic alteration. Research over the past decade has improved our understanding of the biological roles of DTP cells in cancer, although clinical knowledge of the role of these cells in treatment resistance remains limited. Nonetheless, targeting this population is anticipated to provide new treatment opportunities. In this Perspective, we aim to provide a clear definition of the DTP phenotype, discuss the underlying characteristics of these cells, their biomarkers and vulnerabilities, and encourage further research on DTP cells that might improve our understanding and enable the development of more effective anticancer therapies.

Immunotherapy for Recurrent Glioma-From Bench to Bedside.

Glioma is the most aggressive malignant tumor of the central nervous system, and most patients suffer from a recurrence. Unfortunately, recurrent glioma often becomes resistant to established chemotherapy and radiotherapy treatments. Immunotherapy, a rapidly developing anti-tumor therapy, has shown a potential value in treating recurrent glioma. Multiple immune strategies have been explored. The most-used ones are immune checkpoint blockade (ICB) antibodies, which are barely effective in monotherapy. However, when combined with other immunotherapy, especially with anti-angiogenesis antibodies, ICB has shown encouraging efficacy and enhanced anti-tumor immune response. Oncolytic viruses and CAR-T therapies have shown promising results in recurrent glioma through multiple mechanisms. Vaccination strategies and immune-cell-based immunotherapies are promising in some subgroups of patients, and multiple new tumor antigenic targets have been discovered. In this review, we discuss current applicable immunotherapies and related mechanisms for recurrent glioma, focusing on multiple preclinical models and clinical trials in the last 5 years. Through reviewing the current combination of immune strategies, we would like to provide substantive thoughts for further novel therapeutic regimes treating recurrent glioma.

Heat Shock Proteins in Non-Small-Cell Lung Cancer-Functional Mechanism.

Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers, which has the highest cancer-related mortality worldwide. Regardless of the therapeutic effects of chemotherapy or targeted therapy, drug resistance will occur after 1 year. Heat shock proteins (HSPs) are a class of molecular chaperones participated in protein stability and multiple intracellular signaling pathways. It has been widely reported that HSPs family is over expressed in non-small cell lung cancer, and these molecules are also associated with protein stability and multiple intracellular signaling pathways. The effect of chemotherapy drugs or targeted drugs on cancer cells is usually to induce apoptosis. It is necessary to explore the interaction between heat shock protein family and apoptosis pathway in NSCLC. Here we provide a brief review of how HSPs affect the apoptotic pathway in NSCLC.

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.

Lenalidomide bypasses CD28 co-stimulation to reinstate PD-1 immunotherapy by activating Notch signaling.

Programmed cell death protein 1 (PD-1) checkpoint blockade therapy requires the CD28 co-stimulatory receptor for CD8+ T cell expansion and cytotoxicity. However, CD28 expression is frequently lost in exhausted T cells and during immune senescence, limiting the clinical benefits of PD-1 immunotherapy in individuals with cancer. Here, using a cereblon knockin mouse model that regains in vivo T cell response to lenalidomide, an immunomodulatory imide drug, we show that lenalidomide reinstates the anti-tumor activity of CD28-deficient CD8+ T cells after PD-1 blockade. Lenalidomide redirects the CRL4Crbn ubiquitin ligase to degrade Ikzf1 and Ikzf3 in T cells and unleashes paracrine interleukin-2 (IL-2) and intracellular Notch signaling, which collectively bypass the CD28 requirement for activation of intratumoral CD8+ T cells and inhibition of tumor growth by PD-1 blockade. Our results suggest that PD-1 immunotherapy can benefit from a lenalidomide combination when treating solid tumors infiltrated with abundant CD28- T cells.

Impaction Bone Grafting Combined with Titanium Mesh for Acetabular Bone Defects Reconstruction in Total Hip Arthroplasty Revision: A Retrospective and Mini-Review Study.

OBJECTIVE: To investigate the application of impaction bone grafting (IBG) combined with Ti-alloy mesh for acetabular bone defect reconstruction in total hip arthroplasty (THA) revision and follow up the clinical outcomes and imaging findings. METHODS: The clinical and imaging data of patients who were admitted to our hospital from January 2000 to December 2020 and underwent acetabular bone defects reconstruction using IBG combined with titanium mesh were retrospectively analyzed. Preoperative and post-revision Oxford and Harris scores, and post-revision complications were evaluated. Radiographs were used to determine center of rotation (COR) of the hip joint, transparency line, bone graft fusion, and bone mineral density (BMD) around the hip joint. RESULTS: Significant improvement was observed in both Oxford and Harris scores (P < 0.05). The radiographs taken at the last follow-up examination showed no significant differences in the acetabulum COR, offsets, inclination angle, mean ratio of vertical value, and BMD analysis between the post-revision side and contralateral side (P > 0.05). The follow-up data showed restoration of the mesh implant and graft bone fusion. CONCLUSIONS: The application of IBG combined with titanium-alloy mesh in revision THA patients with acetabular defects was found to provide satisfactory outcomes. However, large-scale studies are still needed to further elucidate the long-term outcomes.

Multi-Component Nanofiber Composite Membrane Enabled High PM0.3 Removal Efficiency and Oil/Water Separation Performance in Complex Environment.

Currently, industrial waste gas and oily wastewater are usually at high temperature and contain corrosive components (e.g., acid, alkali, oxidant, or high salt, etc.), presenting great challenges on filtration/separation materials. Here, a multi-purpose Poly(m-phenylene isophthalamide)/polyacrylonitrile/silica (PMIA/PAN/SiO2) nanofiber composite membrane with a high yield was prepared simply via electrospinning to satisfy the demands of air filtration and oil/water separation in complex environments. Under the synergy of PMIA, PAN and SiO2, the composite membrane possesses high PM0.3 removal capacity of 99.69%, robust purification ability against real smoke PM2.5, effective oil/water separation performance of > 99.6%, superior high temperature stability (about 250 °C) and excellent chemical resistance, showing the potential application in filtration/separation process under complex conditions. Moreover, the influence mechanism of SiO2 NPs on mechanical properties and filtration performance was systematically investigated through experiments and simulations, paving the way for future intensive research. This study provides an option for the facile and effective preparation of high-performance filtration/separation membranes applied in the field of dust filtration and oily wastewater separation, even in harsh environments.

Development and Application of a Liquid Chromatography-Mass Spectrometry Method for Residual Iodixanol Quantification in AAV-Based Gene Therapy Product Development.

Adeno-associated viruses (AAVs) are nonenveloped viruses that have become popular gene transfer vectors to deliver DNA to target cells in clinical gene therapy. Iodixanol-based density gradient is one of the widely used purification methods for serotype-independent AAVs. However, residual iodixanol in AAV could be a safety concern, and further purification to remove this process-related impurity is typically needed. An analytical assay with high sensitivity is essential for the detection of residual iodixanol to ensure the safety of AAV products. We developed a liquid chromatography-mass spectrometry method with the limit of quantification of 0.01 µg/mL for residual iodixanol measurement in AAVs. The method also demonstrated linearity over four orders of magnitude that allows quantifying a high iodixanol concentration in in-process samples with excellent recovery and accuracy. In addition, we further explored a highly efficient purification method for removal of the residual iodixanol, to minimize the safety concern from iodixanol as a process impurity.

circ_0030018 promotes glioma proliferation and metastasis.

BACKGROUND: Circular RNA (circRNA) plays an essential role in tumor progression, including glioma. circ_0030018 is a newly discovered circRNA that is highly expressed in glioma. However, its role and mechanism in glioma need to be further elucidated. METHODS: The expression of circ_0030018, microRNA (miR)-194-5p, and tripartite motif containing 44 (TRIM44) was examined using quantitative real-time PCR. Cell proliferation, migration, invasion, and apoptosis were determined using MTT assay, colony formation assay, transwell assay, and flow cytometry. Moreover, dual-luciferase reporter assay and RNA pull-down assay were used to verify the interactions among circ_0030018, miR-194-5p, and TRIM44. The protein expression of TRIM44 was assessed by western blot analysis. Animal experiments were conducted to explore the role of circ_0030018 in glioma tumor growth in vivo. RESULTS: circ_0030018 was overexpressed in glioma tissues and cells, and its silencing could inhibit glioma cell proliferation, migration, invasion, and accelerate apoptosis. miR-194-5p could be sponged by circ_0030018, and its overexpression could hinder the progression of glioma cells. Further experiments revealed that miR-194-5p inhibitor reversed the negative regulation of circ_0030018 knockdown on glioma cell progression. In addition, TRIM44 was a target of miR-194-5p, and its downregulation could repress glioma cell progression. Overexpressed TRIM44 reversed the inhibition effect of miR-194-5p on glioma cell progression. Animal experiments suggested that circ_0030018 knockdown could reduce glioma tumor growth through regulating miR-194-5p and TRIM44. CONCLUSION: Our 8data showed that circ_0030018 enhanced glioma progression by sponging miR-194-5p to regulate TRIM44, indicating that circ_0030018 might be a potential treatment target for glioma.

Primary Mediastinal Nonseminomas: A Population-Based Surveillance, Epidemiology, and End Results Analysis.

BACKGROUND: This study aimed to determine the disease characteristics and prognosis of patients with primary mediastinal nonseminomas (PMNS) in a Surveillance, Epidemiology, and End Results (SEER) analysis. MATERIALS AND METHODS: Demographic, treatment, and survival outcome data of cases with PMNS from 1975 to 2016 were retrieved. Cases with unknown variables mentioned in the analysis were excluded. Relative statistical methods were applied to analyze clinical characteristics and prognosis. RESULTS: A total of 587 PMNS patients met the selection criteria, 526 of whom were men. The mean age of patients was 28 (1-85) y. A total of 511 PMNS patients had validated subtypes, including 172 mixed germ cell tumors, 117 yolk sac tumors, 111 malignant teratomas, 70 choriocarcinomas, and 41 embryonal carcinomas. Patients with yolk sac tumors had the highest 3-y cancer-specific survival (CSS) rate (66.9%), while those with choriocarcinoma and embryonal carcinoma showed the worst prognosis. Surgery + chemotherapy (46.2%) was the most common and effective treatment for each subtype of PMNS. Multivariate Cox proportional hazards analysis identified embryonal carcinoma, malignant teratoma, choriocarcinoma, tumor size >15 cm, nodal metastasis, and distant stage as risk factors. In contrast, surgery-based care and younger age were protective factors. Propensity score matching analysis revealed significant improvement in the 5-y CSS rate from 35.8% to 60.3% with surgery (P < 0.001). However, radiotherapy (P = 0.436) and chemotherapy (P = 0.978) showed no survival benefits. CONCLUSIONS: 10 percent of the PMNS patients were female. Choriocarcinomas and embryonal carcinomas had the worst prognosis. Surgery was demonstrated to be the only way to prolong survival time. Chemotherapy and radiotherapy had minimal effects on prognosis.

Repair of severe traumatic nasal alar defects with combined pedicled flap and conchal cartilage composite grafts: a retrospective study.

BACKGROUND: Repair of traumatic alar defect is challenging because poor blood supply is caused by contracture scars, which sometimes extend beyond the alar groove. However, few studies have investigated the reconstruction results of severe traumatic cases. This study aimed to examine the clinical outcomes of severe traumatic alar defect reconstruction using either pedicled nasolabial or forehead flaps combined with conchal cartilage. METHODS: This retrospective study investigated the clinical characteristics and treatment effects of 17 patients with severe traumatic alar defects treated in a single plastic surgery center from March 1, 2015, to September 1, 2018. All cases were scored and graded with regard to the size and depth of the alar defect and the surrounding scar according to the Alar Defect Severity Score (ADSS). Surgical outcomes were evaluated on the basis of the severity of defect before repair, donor site distortion, and postoperative nasal symmetry, especially shape and color. RESULTS: The average ADSS of the cases was 8.1±0.8 (highest score, 9.0). No flap necrosis or any complications were observed postoperatively. The symmetry of the bilateral alae was satisfactory. No color distinction between grafts and surrounding tissues, retraction, or inferior displacement of the ala was observed at an average follow-up of 24.2±10.4 months (range, 8-42 months). The average postoperative surgeon-based evaluation score was 4.3±0.2 (highest score, 5.0). Esthetic and functional results were satisfactory in all cases. CONCLUSIONS: A pedicled flap combined with conchal composite grafts should be considered for the treatment of severe traumatic alar defect. This is a reproducible technique that enables a predictably decent outcome for severe traumatic alar defect, especially in Asian patients.

Multifunctional composite membrane based on BaTiO3@PU/PSA nanofibers for high-efficiency PM2.5 removal.

In this study, a new barium titanate@polyurethane/polysulfonamide (BaTiO3@PU/PSA) composite nanofibrous membrane with comprehensive properties for high temperature filtration and robust PM2.5 removal was successfully fabricated through the blending spinning of PU and PSA and the introduction of BaTiO3. As a consequence, the BaTiO3@PU/PSA membrane achieved the high capture efficiency of 99.99 % for fine particulates, low pressure drop of 39.4 ± 0.2 Pa, good mechanical property (13.27 MPa), sufficient flexibility, high thermal stability (up to 300 °C), favorable flame-retardancy as well as superior chemical resistance against acid and alkali. Especially, to intuitively reveal the relationship between the fiber structure, high temperature environment, gas velocity and filtration performance of the composite membrane, the filtration processes were carefully investigated through the analog simulation. More importantly, the BaTiO3@PU/PSA membrane exhibited high-efficiency PM2.5 purification capacity, and the removal efficiency kept stable after high temperature, acid or alkali treatment, ascribing to the advantageous structure of PSA, PU and BaTiO3. Overall, the BaTiO3@PU/PSA nanofiber membranes with versatility are a promising high-efficiency candidate for dust removal, particularly in harsh conditions.

Thymic Squamous Cell Carcinoma: A Population-Based Surveillance, Epidemiology, and End Result Analysis.

OBJECTIVES: Thymic squamous cell carcinoma (TSCC) is a rare neoplasm that has been sparsely cited in the literature. The aim of this study was to determine disease characteristics and prognostic factors of patients in a Surveillance, Epidemiology, and End Results (SEER) analysis. METHODS: Cases from 1990-2016 were retrieved from the SEER database and demographics, treatments, and survival outcomes were analyzed. RESULTS: The TSCC accounted for 72.4% of the thymic carcinomas and 7.2% of thymic tumors. The 276 patients (165 men) selected for analysis had a median age of 65 (24-85) years, and 201 patients were diagnosed with Masaoka-Koga stage III/IV. The median survival of TSCC was 59 months with a 49.0% 5-year OS rate, a better prognosis than lymphoepithelioma-like carcinoma (32.1%) and undifferentiated carcinoma (33.3%). Multivariate analysis revealed the Masaoka-Koga stage (p = 0.003) and surgical types (complete resection, incomplete resection, and none; p < 0.001) were determinants of survival. Complete resection had the best prognosis with a 72.7% 5-year OS rate. Chemotherapy was an independent protective factor (HR = 0.555, 95% CI 0.347-0.886; p = 0.014) though poor survival was showed in univariate analysis. And the survival benefit of chemotherapy was validated in PSM analysis (3-year OS rate was 77.7% with chemotherapy vs. 52.8% without chemotherapy; p = 0.014). CONCLUSIONS: TSCC was frequently diagnosed in older patients with advanced Masaoka-Koga stage and had more favorable survival than other subtypes of thymic carcinomas. Complete resection is the preferred treatment. Masaoka-Koga stage and chemotherapy had a strong association with prognosis.

Electrospun Polymer Composite Membrane with Superior Thermal Stability and Excellent Chemical Resistance for High-Efficiency PM2.5 Capture.

To address the challenge of high-temperature air filtration, a novel electreted polysulfonamide/polyacrylonitrile-boehmite (PSA/PAN-B) composite nanofiber based filter was developed via electrospinning for effective high-temperature dust removal. In this study, the spinnability of PSA was greatly improved by adding a small amount of PAN as an auxiliary polymer, and the introduction of a boehmite electret further significantly reinforced the properties of PSA fibers. As a result, the PSA/PAN-B membrane exhibited a high filtration efficiency (up to 99.52 ± 0.32%), low pressure drop (45.16 ± 1.39 Pa), excellent flexibility, good mechanical properties, high thermal stability (up to approximately 300 °C), and superior chemical resistance. Through data analysis and 3D simulation, the important benefits of the boehmite electret in the optimization of the PSA fibrous membrane performance were determined: it increases the charge storage capacity, constructs a rough surface morphology, improves the specific surface area, and enhances the mechanical properties. More importantly, the PSA/PAN-B film possessed a robust PM2.5 purification capacity, and the particulate matter removal efficiency was kept unchanged after high-temperature, acid, or alkali treatment-a performance derived from the intrinsic molecular structure of PSA. The PSA/PAN-B composite fibrous membrane, with excellent comprehensive properties, is a promising candidate for air filters, especially in harsh environments, further broadening the applications of PSA and providing new insight into the design of high-performance filters with high-temperature and corrosion resistance.

Efficiency of Zoledronic Acid in Inhibiting Accelerated Periprosthetic Bone Loss After Cementless Total Hip Arthroplasty in Osteoporotic Patients: A Prospective, Cohort Study.

OBJECTIVE: To investigate the influence of preoperative osteopenia/osteoporosis on periprosthetic bone loss after total hip arthroplasty (THA) and the efficiency of zoledronate (ZOL) treatment in periprosthetic bone preservation. METHODS: This multicenter, prospective cohort study was conducted in four centers between April 2015 and October 2017. Patients were assigned to Normal BMD, Osteopenia, and Osteoporosis+ZOL groups. Patients with osteopenia received daily oral calcium (600 mg/d) and vitamin D (0.5 µg/d), while patients in the Osteoporosis+ZOL group received additional ZOL annually (5 mg/year). Periprosthetic bone mineral density (BMD) in seven Gruen zones, radiographic parameters, Harris hip score, EuroQol 5-Dimensions (EQ-5D) score, and BMD in hip and spine were measured within 7 days, 3 months, 12 months postoperation and annually thereafter. RESULTS: A total of 266 patients were enrolled, while 81 patients that completed the first year follow-up were involved in the statistical analysis. The mean follow-up time was 1.3 years. There were significant decreases of mean BMD in total Gruen zones (-4.55%, P < 0.05) and Gruen zone 1 (-10.22%, P < 0.01) in patients with osteopenia during the first postoperative year. Patients in the Osteoporosis+ZOL group experienced a marked increase in BMD in Gruen zone 1 (+16%) at the first postoperative year, which had a significant difference when compared with the Normal BMD group (P < 0.05) and the Osteopenia Group (P < 0.001). Low preoperative BMD in hip and spine was predictive of bone loss in Gruen zone 1 at 12 months after THA in patients with normal BMD (R2 = 0.40, P < 0.05). CONCLUSIONS: Patients with osteopenia are prone to higher bone loss in the proximal femur after cementless total hip arthroplasty (THA). ZOL, not solely calcium and vitamin D, could prevent the accelerated periprosthetic bone loss after THA in patients with osteopenia and osteoporosis.

[Analysis of Greenhouse Gas Emission Characteristics and Their Influencing Factors in the Algae Zone of Lake Taihu].

In order to identify CH4 and CO2 emission flux characteristics and their impact factors in the algal lake zone of Lake Taihu, CH4 and CO2 fluxes were observed by the improved closed chamber method in Meiliang Bay in Lake Taihu. The relationships between CH4 and CO2 flux and meteorological factors were analyzed. The results showed that CH4 and CO2 fluxes had obvious diurnal variations. The CH4 flux in the daytime was higher than that in the nighttime in spring; however, the CH4 flux in the nighttime was higher than that in the daytime in summer. The CO2 uptake flux in the daytime was higher than that in the nighttime in spring and summer. The algae zone of Lake Taihu was a CH4 source for the atmosphere. The average CH4 flux was 4.047 nmol ·(m2 ·s)-1 and 40.779 nmol ·(m2 ·s)-1 in spring and summer, respectively. The zone was the CO2 sink for the atmosphere in spring and summer. The average CO2 flux was -0.160 µmol ·(m2 ·s)-1 and -0.033 µmol ·(m2 ·s)-1 in spring and summer, respectively. On an hourly scale, the CH4 emission flux was positively correlated with air temperature and water temperature (r=0.20, P<0.01 and r=0.34, P<0.01, respectively). When wind speed was lower than 6 m ·s-1, the CH4 flux was positively correlated with wind speed (r=0.71, P<0.01). The CO2 uptake flux had a significant positive correlation with air temperature and wind speed (r=0.14, P<0.01 and r=0.33, P<0.05, respectively). However, the CO2 uptake flux was negatively correlated with air pressure and solar radiation (r=-0.41, P<0.01 and r=-0.35, P<0.01, respectively). The CO2 efflux had a significant positive correlation with wind speed (r=0.40, P<0.05). The CO2 efflux was negatively correlated with solar radiation (r=-0.35, P<0.01). On a daily scale, the CH4 emission flux had a significant positive correlation with air temperature and water temperature (r=0.83, P<0.01 and r=0.78, P<0.01, respectively).

Preparation of Polypropylene Micro and Nanofibers by Electrostatic-Assisted Melt Blown and Their Application.

In this paper, a novel electrostatic-assisted melt blown process was reported to produce polypropylene (PP) microfibers with a diameter as fine as 600 nm. The morphology, web structure, pore size distribution, filtration efficiency, and the stress and strain behavior of the PP nonwoven fabric thus prepared were characterized. By introducing an electrostatic field into the conventional melt-blown apparatus, the average diameter of the melt-blown fibers was reduced from 1.69 to 0.96 µm with the experimental setup, and the distribution of fiber diameters was narrower, which resulted in a filter medium with smaller average pore size and improved filtration efficiency. The polymer microfibers prepared by this electrostatic-assisted melt blown method may be adapted in a continuous melt blown process for the production of filtration media used in air filters, dust masks, and so on.