This study reports the subjective perceptions and mental state of employees working in the Erdaogou Mine, affiliated with Jiapigou Minerals Limited Corporation of China National Gold Group Corporation (CJEM); these employees are pioneers working at the deepest point below ground in China. The data represent a valuable baseline from which to assess the effects of the environmental factors in the deep-underground on human physiology, psychology, and pathology.The air pressure, relative humidity, temperature, total γ radiation dose-rate, and oxygen concentration in the CJEM in the aisles in goafs at 4 depths below ground were measured. Study subjects were administered a study-specific questionnaire that included items that targeted factors with potential to affect respondents' health and wellbeing and included the symptom checklist-90-revised (SCL-90-R).Air pressure, relative humidity, and temperature rose, total γ radiation dose-rate decreased, and there was no change in oxygen concentration with increasing depth below ground. Most (97.2%) respondents had a negative impression of the ambient conditions in the deep-underground space. The most commonly perceived adverse factors included moisture (74.9%), heat (33.5%), and poor ventilation (32.4%). 93.29% of respondents associated ≥1 self-reported negative physical symptom with working in the deep-underground space; the most frequent symptoms were being easily tired (48.7%), tinnitus (47.5%), and hearing loss (44.1%). Higher SCL-90-R scores were associated with the perception of >1 adverse factor in the deep-underground, spending >8 hours continuously in the deep-underground space, or working at a depth > 1000 m below ground. >1 perceived adverse factor in the deep-underground and continuously spending >8 hours in the deep-underground space were significant predictors of high SCL-90-R scores.Adverse factors, including high temperature, humidity, and dim light, may have negative impacts on the physical and psychological health of people who spend long periods of time living and/or working in the deep-underground space.
OBJECTIVE: The recombinant adenovirus vector carrying p14ARF gene was constructed for using in the interference therapy in signal transduction of laryngeal squamous cell carcinoma. METHODS: The total cDNA fragment of p14ARF was cloned into the shuttle plasmid pAdTrack-CMV, with the resultant plasmid and the backbone plasmid pAdEasy-1, the homologous recombination took place in the E.Coli BJ5183 and the recombinant adenoviral plasmid was generated. The adenoviruses were packaged and amplified in the 293 cells. Then the viral titer was checked by GFP. RESULTS: The recombinant adenovirus vector carrying p14ARF was constructed successfully. The viral titer was 2.3 x 10(9). CONCLUSION: The recombinant adenovirus vector could introduce p14ARF gene into the laryngeal squamous cell carcinoma line or tumor tissue effectively, which would provide experimental basis for the mechanisms and further study of the interference therapy in signal transduction of laryngeal squamous cell carcinoma.
Sensorineural hearing loss (SNHL), a highly prevalent sensory impairment, results from a multifaceted interaction of genetic and environmental factors. As we continually gain insights into the molecular basis of auditory development and the growing compendium of deafness genes identified, research on gene therapy for SNHL has significantly deepened. Adeno-associated virus (AAV), considered a relatively secure vector for gene therapy in clinical trials, can deliver various transgenes based on gene therapy strategies such as gene replacement, gene silencing, gene editing, or gene addition to alleviate diverse types of SNHL. This review delved into the preclinical advances in AAV-based gene therapy for SNHL, spanning hereditary and acquired types. Particular focus is placed on the dual-AAV construction method and its application, the vector delivery route of mouse inner ear models (local, systemic, fetal, and cerebrospinal fluid administration), and the significant considerations in transforming from AAV-based animal model inner ear gene therapy to clinical implementation.
Head and neck cancers (HNCs) are the sixth most common type of cancer in the world. Despite the development of refined surgical techniques and precise targeted radiation, patients with HNCs have a dismal prognosis. Here, we examine the expression profile of B7-H3 in HNCs and verify whether B7-H3 can serve as a novel therapeutic target for HNCs via anti-B7-H3×CD3 bispecific antibodies (biAbs). We analyzed the expression level of B7-H3 in 274 HNC samples and evaluated the association between B7-H3 expression and clinicopathological parameters. Anti-B7-H3×CD3 biAbs were constructed, and the efficacy of these biAbs in targeting HNCs was assessed in vitro and in vivo. As a result, high expression of B7-H3 was detected in 66.1% of clinical HNC samples and was correlated with poor survival. Specific antitumor effects of anti-B7-H3×CD3 biAbs were confirmed in vitro using HNC cell lines. In xenograft HNC mouse model, anti-B7-H3×CD3 biAbs delayed tumor growth and prolonged survival. In conclusion, B7-H3 is frequently overexpressed in HNCs and could be a promising therapeutic target for biAb therapy.
Ataxia-telangiectasia-mutated (ATM) is a radiosensitization gene. In the present study, we investigated the efficacy of poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles containing ATM antisense oligonucleotides (ASOs) for the radiosensitization of head and neck squamous-cell carcinoma in mice, using the SCCVII cell line. Nanoparticles containing ATM ASOs were prepared with PLGA by using a double-emulsion solvent evaporation method. The results showed that the nanoparticles were suitable for intracellular uptake, and ATM ASOs inhibited ATM expression when delivered by using nanoparticles or lipofectin, but not in their free form. Meanwhile, we found that ATM reduction sensitized SCCVII cells in vitro and tumors in vivo to irradiation. In conclusion, biodegradable PLGA nanoparticles, used as a delivery carrier, enhanced intracellular uptake of ATM ASOs into SCCVII cells and the inhibitory effect of ATM ASOs. These results demonstrated that antisense ATM therapy, using PLGA nanoparticles, might provide a therapeutic benefit to patients undergoing radiation therapy for head and neck squamous-cell carcinoma.
Abstract The aim of the present study was to reveal the physical symptom changes and their correlations with mental health status in deep underground miners. A total of 286 deep underground miners completed a cross-sectional questionnaire study at China Pingmei Shenma mine complex. The questionnaire included sociodemographics, self-reported physical symptoms, underground adverse environmental factors, and the Symptom Checklist-90-Revised (SCL-90-R). Five environmental parameters of 1 deep mine were also measured. Data from 266 valid questionnaires were analyzed. The 3 most frequent complaints about underground adverse conditions were moisture [62.03% (165/266)], dim light [45.86% (122/266)], and high temperature [42.11% (112/266)]. Fatigue [40.22% (107/266)], hearing loss [34.96% (93/266)], and tinnitus [31.58% (84/266)] were reported to be the three most common physical symptoms. Insomnia was reported in 204 participants (76.69%) mainly due to the difficulty of falling asleep [42.35% (84/204)] and dreams [39.70% (81/204)]. Mean scores of SCL-90-R subscales including somatization, anxiety, phobic anxiety, psychoticism, and paranoid ideation were elevated compared to Chinese norms, while there was diminished interpersonal sensitivity. Univariate analyses indicated that the 3 most common physical symptoms were associated with poorer SCL-90-R scores. With increasing depth below ground, air pressure, relative humidity, CO 2 concentration and temperature rose, while total gamma radiation dose-rate decreased. The physical and mental health status of deep underground miners was poorer than the general Chinese male population. Some adverse environmental factors were identified that may have influenced health status. Measures are suggested to improve the deep underground working environment.
Background Vault is the largest nonicosahedral cytosolic nucleoprotein particle, which is widely involved in induction of chemoresistance and lead to failure in long-term chemotherapy. Vault contains three different major vault proteins (MVPs) and four vault RNAs paralogues (vtRNAs, vtRNA1-1, vtRNA1-2, vtRNA1-3 and vtRNA2-1). Disruption of the MVPs do not induce hypersensitivity while expression of vtRNAs contributes to cells' drug resistance, indicates that vtRNAs, but not MVPs play an important role in causing drug resistance. Polypyrimidine tract binding protein associated splicing factor (PSF) contributes to cell sensitivity to chemotherapy by its transcriptional activity, promotes us to figure out its potential association with vtRNAs. Methods We investigate the interaction between PSF and vtRNAs by electrophoretic mobility shift assays (EMSA) and RNA-immunoprecipitation (IP), and showed the binding between PSF and vtRNAs. Chromatin Immunoprecipitation (ChIP) was performed to detect the effects of vtRNAs on the interaction of PSF with GAGE6 promoter. The role of vtRNAs on chemoresistance in MCF-7 was detected by CCK-8 and EdU staining. The independent role of vtRNAs with MVP is detected by MVP or vtRNAs knockdown. Results The complex with vtRNA1-1 releases PSF, allowing transcription of GAGE6 to proceed. Then we showed that induction of GAGE6 caused drug resistance by promoting cell proliferation and colony formation in soft agar. Ectopic expression of shRNA targets to vtRNA1-1 further confirmed the role of vtRNA1-1 in regulating PSF transcriptional activity independent with the expression of MVP. By vtRNA1-1 or MVP knockdown, it is revealed that vtRNA1-1 caused chemoresistance independent of MVP. Furthermore, knockdown of GAGE6 does not cause drug resistance, indicates the GAGE6 is directly involved in cell proliferation, but not the drug resistance. Conclusion These results suggest that vtRNAs regulates cell proliferation, drug resistance, and possibly other physiological processes of humans, by complex formation with PSF.
To examine the antitumour efficacy and investigate immunological mechanism of combination therapy of IL-2 gene and IL-12 gene transfer with radiation in an immunocompetent murine model that parallel more closely the clinical therapy of head and neck squamous cell carcinoma (HNSCC).Tumors were established in the floor of mouth in C3H/HeJ mice with SCCVII cell line. Lipid-DNA complexed (lipoplexes) by using polycationic liposome-Mediated transduction for HNSCC was transduced in tumor-bearing mouse by direct intratumoral gene transfer. The local tumor was radiated with a dose of 2 Gy in the second day. Tumor sizes were measured before and after the treatment as compared to the different single treatment groups and the controls. After tumors were subculture, the supernatants were collected for IL-2 and IL-12 expression by enzyme-linked immunosorbent assay (ELISA). Natural killer (NK) cell activity and cytotoxic T-lymphocyte (CTL) activity were also assayed by LDH method. CD4+ and CD8+ T-lymphocyte in tumor tissues were examined by immunohistochemistry.HNSCC tumor growth was significantly inhibited following combined IL-2 and IL-12 gene therapy with radiation as compared to IL-2 or IL-12 gene therapy with radiation, single IL-2 or IL-12 gene therapy, radiation alone and the controls. Increased secreted levels of IL-2 and IL-12 protein expression were found in combined and single IL-2 gene or IL-12 gene treated groups. The combination and single gene treated groups produced greater activation of CTL and NK than the controls of all concerned test. The significant CD4+ and CD8+ T lymphocyte infiltration was distributed and the numerous necrosis were seen in tumor tissues after combination therapy.Combined IL-2 gene and IL-12 gene therapy with radiation could significantly inhibited HNSCC tumor growth in the murine model and efficiently induced antitumor immunity of the host.
Background: There has been considerable concern about the potential harmful effects of radiation exposure inducing cancers. However, a few researches focused on the biological effect of below background radiation (BBR) in deep underground environment. To better understand the effect of BBR on cancer, we selected a well-differentiated laryngeal squamous cell carcinoma cell (FD-LSC-1) to observe the biological effect of the BBR in underground laboratory (DUGL). Methods: The growth curve, morphology and quantitative proteomics were performed on the FD-LSC-1 cells cultured in the DUGL and aboveground laboratory (AGL) respectively. Result: Compared with the AGL group, the proliferation of FD-LSC-1 cells of DUGL group was delayed. TEM scan of cells cultured in the DUGL showed that cells had obvious hypertrophic endoplasmic reticulum (ER) and increased number of ER. With a cutoff of∣fold change∣≥1.2 and p value < 0.05, a total of 807 DAPs (536 proteins up-regulated and 271 proteins down-regulated in cells cultured in the DUGL) were detected. KEGG pathway analysis of these DAPs revealed that seven pathways were enriched. These pathways were ribosome (p<0.0001), spliceosome (p=0.0001), oxidative phosphorylation (p=0.0001), Protein export (p=0.0001), Thermogenesis (p=0.0003), protein processing in endoplasmic reticulum (p=0.0108), and Non-alcoholic fatty liver disease (p=0.0421). Conclusion: BBR environment could inhibit proliferation of FD-LSC-1 cells. Additionally, the BBR environment induced the change of protein expression of FD-LSC-1 cells, which covered ribosome, gene spliceosome, RNA transport, energy metabolism etc. These changed proteins might be the molecular basis of the inhibition of proliferation and enhanced survival ability for cells adapting to the BBR in deep underground environment. RPL26, RPS27, ZMAT2, PRPF40A, SNRPD2, SLU7, SRSF5, SRSF3, SNRPF, WFS1, STT3B, CANX, ERP29, HSPA5, COX6B1, UQCRH, ATP6V1G1 were the core proteins in the BBR stress response of cells.
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