Inhibition of PAD4 enhances radiosensitivity and inhibits aggressive phenotypes of nasopharyngeal carcinoma cells.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a tumor deriving from nasopharyngeal epithelium. Peptidyl-arginine deiminase 4 (PAD4) is a vital mediator of histone citrullination and plays an essential role in regulating disease process. Radiotherapy is an essential method to treat NPC. In this research, we explored the effect of PAD4 on NPC radiosensitivity. METHODS: We enrolled 50 NPC patients, established mice xenograft model, and purchased cell lines for this study. Statistical analysis and a series of experiments including RT-qPCR, clonogenic survival, EdU, Transwell, and wound healing assays were done. RESULTS: Our data manifested that PAD4 (mRNA and protein) presented a high expression in NPC tissues and cells. GSK484, an inhibitor of PAD4, could inhibit activity of PAD4 in NPC cell lines. PAD4 overexpression promoted the radioresistance, survival, migration, and invasion of NPC cells, whereas treatment of GSK484 exerted inhibitory effects on radioresistance and aggressive phenotype of NPC cells. Additionally, GSK484 could attenuate the effect of PAD4 of NPC cell progression. More importantly, we found that GSK484 significantly inhibited tumor size, tumor weight and tumor volume in mice following irradiation. CONCLUSIONS: PAD4 inhibitor GSK484 attenuated the radioresistance and cellular progression in NPC.

PAD4 inhibitor promotes DNA damage and radiosensitivity of nasopharyngeal carcinoma cells.

Peptidylarginine deiminases 4 (PAD4), a kind of enzyme capable of converting protein arginine or mono-methylarginine into citrulline, has been identified to display a key role in diverse diseases. Radiotherapy is frequently used in nasopharyngeal carcinoma (NPC) treatment and induces DNA double strand breaks. In this study, whether PAD4 inhibitor YW3-56 affects the radiosensitivity of NPC cells was explored. RT-qPCR, immunofluorescence, western blot, clonogenic survival, and flow cytometry assays were used to assess the function of PAD4 and YW3-56 in NPC. We found the upregulation of PAD4 expression in NPC cells. PAD4 overexpression suppressed NPC cell apoptosis and promoted cell cycle, while PAD4 depletion had an opposite result. Moreover, the survival of NPC cells after irradiation was increased by overexpression of PAD4. PAD4 overexpression inhibited DNA damage and sensitivity of NPC cells to irradiation. Functional assays showed that YW3-56 treatment promoted DNA damage, apoptosis, and radiosensitivity of NPC cells. Importantly, YW3-56 treatment inhibited tumor growth in vivo. Overall, this study revealed the efficacy of PAD4 inhibitor YW3-56 in promoting sensitivity of NPC cells to irradiation.

Administration of nimotuzumab combined with cisplatin plus 5-fluorouracil as induction therapy improves treatment response and tolerance in patients with locally advanced nasopharyngeal carcinoma receiving concurrent radiochemotherapy: a multicenter randomized controlled study.

BACKGROUND: Nimotuzumab (NTZ) is an anti-EGFR monoclonal antibody. However,the effect of targeted drugs combined with induction therapy in locally advanced nasopharyngeal carcinoma remains unclear. The aim of this study is to investigate the safety and efficacy of NTZ combined with cisplatin plus 5-fluorouracil (PF) as induction regimen in locally advanced nasopharyngeal carcinoma (NPC) patients receiving concurrent radiochemotherapy. METHODS: This was a multicenter randomized controlled study performed in eight Guangxi hospitals in 2015-2017. Eligible patients with NPC were randomized into nimotuzumab/PF (NPF group) and docetaxel/PF (DPF group) regimens, respectively, as induction therapy. After 2 cycles of induction therapy, all patients received cisplatin and concurrent intensity modulated radiation therapy (IMRT). Then, the two groups were compared for safety and efficacy. RESULTS: A total of 118 patients with stage III-IVa NPC were assessed, with 58 and 60 in the NPF and DPF groups, respectively. Compared with DPF treatment, NPF induction therapy showed a more pronounced effect on cervical lymph nodes (P = 0.036), with higher response rate (RR) (81% vs 60%). Compared with the DPF group, the NPF group showed significantly reduced leukopenia, neutropenia and gastrointestinal reactions (all P < 0.05); rash only appeared in the NPF group, but all cases were grade 1. During concurrent treatment with radiotherapy and chemotherapy, the NPF group showed better tolerance to radiotherapy and chemotherapy; neutropenia, anemia, gastrointestinal reactions, oral mucositis and radiation dermatitis in the NPF group were significantly reduced (P < 0.05). The expression rate of EGFR was 94.9% (112/118). Compared with the DPF group, patients with EGFR expression in the NPF group showed better response (77.8% vs 63.0%, P = 0.033). CONCLUSION: For locally advanced NPC patients receiving follow-up cisplatin and IMRT, nimotuzumab/PF for induction therapy has better lymph node response rate and milder adverse reactions than the DPF regimen. In addition, the patients have better tolerance in subsequent concurrent radiotherapy and chemotherapy; however, long-term efficacy needs further follow-up evaluation. TRIAL REGISTRATION: The registration number of the clinical trial is ChiCTR-OIC-16008201 and retrospectively registered on March 31, 2016.

Binder assisted graphene derivatives as lubricants in copper: Improved tribological performance for industrial application.

Originally derived from graphite, high-quality single-layer graphene is an excellent anti-wear and -friction additive in metal matrix. Here, the tribological performance of 3 different commercialized graphene derivatives (e.g., graphene oxide [GO], reduced graphene oxide [RGO], and graphene nanoplatelet [GNP]) as additives in a Cu matrix, were investigated from an industrial perspective. To increase the interaction of graphene derivatives with Cu particles, and addressing the aggregation problem of the graphene derivatives, different binders (polyvinyl alcohol [PVA] and cellulose nanocrystals [CNC]) were introduced into the system. Benefiting from such a strategy, a uniform distribution of the graphene derivatives in Cu matrix was achieved with graphene loading up to 5 wt %. After high-temperature sintering, the graphene is preserved and well distributed in the Cu matrix. It was found that the GNP-containing sample shows the most stable friction coefficient behavior. However, GO and RGO also improve the tribological performance of Cu under different circumstances.

Maintenance therapy improves the survival outcomes of patients with metastatic nasopharyngeal carcinoma responding to first-line chemotherapy: a multicentre, randomized controlled clinical study.

PURPOSE: To explore the safety and role of tegafur/gimeracil/oteracil (S1) maintenance therapy (MT) in metastatic nasopharyngeal carcinoma (NPC) patients after response to first-line chemotherapy and to assess outcome-associated biomarkers. METHODS: This was a multicentre, open-label, randomized controlled study involving metastatic NPC patients recruited (from May 2015 to May 2019) at five hospitals in China. The participants were randomized to S1-MT (receiving S1 MT until disease progression or intolerance) or non-MT (followed up until disease progression) groups. The primary endpoint was the progression-free survival (PFS). The secondary endpoints were the overall survival (OS), the correlation between EBV-DNA, serum amyloid A (SAA) status, and outcomes after the first-line chemotherapy, and safety. RESULTS: The median follow-up was 24.3 months; 88 and 95 participants were evaluable in the S1-MT and non-MT groups, respectively. Compared with non-MT, S1-MT prolonged PFS (16.9 vs. 9.3 months, P < 0.001) and OS (33.6 vs. 20.6 months, P < 0.001). Regardless of their EBV-DNA status after first-line chemotherapy, participants were able to benefit from S1 MT, but EBV-DNA-positive participants benefited more significantly (PFS: HR = 0.600, 95% CI = 0.373-0.965, P = 0.035; OS: HR = 0.393, 95% CI = 0.227-0.681, P = 0.001). MT only improved PFS and OS in patients with an SAA decline after first-line chemotherapy (PFS: HR = 0.570, 95% CI = 0.350-0.919, P = 0.021; OS: HR = 0.404, 95% CI = 0.230-0.709, P = 0.002). The median S1 treatment was 23 cycles. Grade 1-2 skin pigmentation, oral mucositis, and hand and foot syndrome were the main adverse reactions. CONCLUSION: For metastatic NPC patients with first-line chemotherapy response, S1 MT can improve PFS and OS, with good tolerability. EBV-DNA and SAA can better help us identify patients who can benefit from MT after standard treatment. TRIAL REGISTRATION: The study protocol was registered at the Chinese Clinical Trial Registry (ChiCTR-IOR-16007939).

Construction of a 5 immune-related lncRNA-based prognostic model of NSCLC via bioinformatics.

ABSTRACT: Participate in tumorigenic, oncogenic, and tumor suppressive pathways through gene expression regulation. We aimed to build an immune-related long noncoding RNA (lncRNA) prognostic model to enhance nonsmall cell lung cancer (NSCLC) prognostic prediction.The original data were collected from the cancer genome atlas database. Perl and R software were used for statistical analysis. The effects of lncRNAs expression on prognosis were analyzed by Gene Expression Profiling Interactive Analysis. Silico functional analysis were performed by DAVID Bioinformatics Resources.The median risk score as a dividing value separated patients into high- and low-risk groups. These 2 groups had different 5-year survival rates, median survival times, and immune statuses. The 5-lncRNA signature was validated as an independent prognostic factor with high accuracy (area under the receiver operating characteristic = 0.722). Silico functional analysis connected the lncRNAs with immune-related biological processes and pathways in carcinogenesis.The novel immune-related lncRNA prognostic model had significant clinical implication for enhancing lung adenocarcinoma outcome prediction and guiding the choice of treatment.

The PAD4 inhibitor GSK484 enhances the radiosensitivity of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) accounts for approximately 10-20% of all breast cancers and is one of the leading causes of mortality among females. Radiotherapy is essential during the treatment of breast cancer. Growing evidence has indicated that peptidyl arginine deiminase-4 (PAD4) inhibitor can alleviate the development of multiple cancers, including breast cancer, through inhibiting cell proliferation. GSK484 is considered to be a highly potent PAD4-selective inhibitors. However, the potential role and mechanism of GSK484 in TNBC remain unclear. In this study, we intended to explore the effects of GSK484 on the radiosensitivity of TNBC cell lines (MDA-MB-231 and BT-549). We found that the pretreatment of GSK484 enhanced irradiation (IR)-induced inhibitory effects on cell proliferation, migration and invasion. Besides, our findings revealed that GSK484 facilitated TNBC cell apoptosis. IR treatment-induced increase of the protein level of ATG5 and ATG7, and decrease of p62 protein level were countervailed by GSK484. In addition, GSK484 enhanced DNA damage induced by IR. Moreover, in vivo experiments demonstrated that the combined treatment of IR and GSK484 showed an obvious decline of tumor growth in contrast to IR-alone or GSK484-alone treatment. Overall, GSK484 may serve as a radiosensitizer of TNBC through inhibiting IR-induced autophagy.

Plasma lncRNA FEZF1-AS1 as a potential biomarker for diagnosis of non-small-cell lung carcinoma.

Diagnosis of numerous cancers has been closely linked to the expression of certain long non-coding RNAs. This study aimed to evaluate levels of plasma FEZ family zinc finger 1 antisense RNA 1 (FEZF1-AS1) relative to non-small-cell lung carcinoma (NSCLC) diagnosis.The level of FEZF1-AS1 in the blood plasma of 126 NSCLC patients and 62 healthy controls was examined by quantitative real-time polymerase chain reaction.Plasma FEZF1-AS1 of the NSCLC group was increased compared with that in the control group (P < .0001). Plasma FEZF1-AS1 could distinguish patients with NSCLC from healthy individuals via the area under the ROC curve (AUC) of 0.855 (95% CI = 0.800-0.909; P = .000). FEZF1-AS1 combined with neuron-specific enolase increased the area under the (ROC) curve to 0.932 (95% CI = 0.897-0.968; P = .018). A high expression level of plasma FEZF1-AS1 was associated with some clinical features of NSCLC. Increased expression of FEZF1-AS1 greatly improved the risk of NSCLC (adjusted OR = 2.42; 95% CI = 1.23-4.76). A significant concentration-dependent relationship was noted between risk of NSCLC and higher FEZF1-AS1 expression (P for trend <.001).Plasma FEZF1-AS1 could potentially be used as a biomarker for NSCLC diagnosis.

Prognostic implications of survivin and lung resistance protein in advanced non-small cell lung cancer treated with platinum-based chemotherapy.

Platinum-based chemotherapy is the first-line treatment for non-small cell lung cancer (NSCLC), but the chemotherapy often results in the development of chemoresistance. The present study aimed to explore the prognostic implications of survivin and lung resistance protein (LRP) in advanced NSCLC treated with platinum-based chemotherapy. Tumor samples were collected from 61 hospitalized patients with stage IIIB-IV NSCLC that underwent platinum-based chemotherapy. All patient samples were collected in the Oncology Department of the Third Affiliated Hospital of Guangxi Medical University between January 2006 and January 2011. Cytoplasmic survivin and LRP expression were evaluated using immunohistochemistry. The expression of LRP and survivin reached 77% (47/61) and 76% (45/61), respectively. Positive expression of survivin was associated with a lower median progression-free survival (PFS) time (4 vs. 9 months; P=0.038) and a lower median overall survival (OS) time compared with the absence of survivin expression (9 vs. 16 months; P=0.039). Patients with LRP and survivin expression (n=41) demonstrated a median PFS time of 4 months. However, patients with either LRP or survivin expression (n=10) demonstrated a median PFS time of 8 months, which is similar to the median PFS time of the 10 patients with no expression of LRP and survivin (9 months; P=0.022). Either the expression of survivin or the combined expression of LRP and survivin is associated with a poor prognosis in advanced NSCLC treated with platinum-based chemotherapy.

[Combination of gemcitabine and carboplatin in the treatment of advanced non-small cell lung cancer].

BACKGROUND: To evaluate the efficacy and toxicity of the combination of gemcitabine and carboplatin in the treatment of patients with advanced non-small cell lung cancer (NSCLC). METHODS: Forty-one patients with locally advanced (stage IIIB) or metastatic (stage IV) NSCLC were enrolled into the study. The patients received gemcitabine 1 000 mg/m² on days l, 8 and 15, and carboplatin AUC 5 on day 1, with 28 days as a cycle. Each patient received at least two cycles. RESULTS: Of the 41 patients, 2 cases got complete response, 18 got partial response, 15 had stable disease, and 6 had progressive disease, with an overall response rate of 48.8%. The response rate was 55.6% (10/18) in the initial patients, and 43.5% (10/23) in the retreated patients (P > 0.05). The median survival duration was 11.8 months. The 1-year survival rate was 49%. There were 29 patients whose KPS score increased. The main toxicities were leukopenia (incidence of 34.1% for grade III+IV) and thrombocytopenia (incidence of 29.3% for grade III+IV). CONCLUSIONS: The combination of gemcitabine and carboplatin is a feasible, well-tolerated and active scheme in either first-line or second-line treatment of advanced NSCLC.

[Clinical application of lung biopsy through CT-guided percutaneous paracentesis].

BACKGROUND: To explore the significance of lung biopsy through CT-guided percutaneous paracentesis in the diagnosis of space-occupying lesions of the lung. METHODS: Thirty-five patients with space occupying lesions of the lung underwent lung biopsy through CT-guided percutaneous paracentesis and DLTRA-CUT 16G, 18G or 20G soft-tissue-cutting biopsy needles and PICKER IQ computerized tomograph were used. RESULTS: Of the 35 patients, 26 were confirmed by pathological examination to suffer from primary malignant tumor, 1 from metastatic carcinoma, 3 from tuberculosis and 3 from inflammatory pseudotumor. No definite diagnosis was made in two patients. The diagnostic rate was 94.3%. After operation, minor pneumothorax occurred in 5 cases and traces of blood in sputum in 2 cases, however, they didn't need any treatment. CONCLUSIONS: Lung biopsy through CT-guided percutaneous paracentesis is a safe and practical technique and may be widely used in hospitals if conditions permit.

Is ftsH the key to plastid longevity in sacoglossan slugs?

Plastids sequestered by sacoglossan sea slugs have long been a puzzle. Some sacoglossans feed on siphonaceous algae and can retain the plastids in the cytosol of their digestive gland cells. There, the stolen plastids (kleptoplasts) can remain photosynthetically active in some cases for months. Kleptoplast longevity itself challenges current paradigms concerning photosystem turnover, because kleptoplast photosystems remain active in the absence of nuclear algal genes. In higher plants, nuclear genes are essential for plastid maintenance, in particular, for the constant repair of the D1 protein of photosystem II. Lateral gene transfer was long suspected to underpin slug kleptoplast longevity, but recent transcriptomic and genomic analyses show that no algal nuclear genes are expressed from the slug nucleus. Kleptoplast genomes themselves, however, appear expressed in the sequestered state. Here we present sequence data for the chloroplast genome of Acetabularia acetabulum, the food source of the sacoglossan Elysia timida, which can maintain Acetabularia kleptoplasts in an active state for months. The data reveal what might be the key to sacoglossan kleptoplast longevity: plastids that remain photosynthetically active within slugs for periods of months share the property of encoding ftsH, a D1 quality control protease that is essential for photosystem II repair. In land plants, ftsH is always nuclear encoded, it was transferred to the nucleus from the plastid genome when Charophyta and Embryophyta split. A replenishable supply of ftsH could, in principle, rescue kleptoplasts from D1 photodamage, thereby influencing plastid longevity in sacoglossan slugs.