Urine-Derived Stem Cells Reverse Bleomycin­Induced Experimental Pulmonary Fibrosis by Inhibition of the TGF-ß1-Smad2/3 Pathway.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung interstitial lesions with the disease pathophysiology incompletely understood, which is a serious and fatal disorder with limited treatment options. Mesenchymal stem cells (MSCs) have exhibited promising therapeutic capability for IPF. While most types of MSCs are obtained invasively, urine-derived stem cells (USCs) can be gained in a safe, noninvasive, and inexpensive procedure, which are readily available and reported to exhibit no risk of teratoma formation or oncogenic potential in vivo, sounding alternative to other MSCs. This study aims to investigate the therapeutic effect and mechanism of USCs on IPF, using a bleomycin (BLM)-induced IPF model in mice. METHODS: Cell surface marker examination by flow cytometry analysis and cell differentiation culture were used to characterize USCs obtained from healthy individuals. BLM was instilled endotracheally in adult C57BL/6 mice, followed by USCs or human bone marrow-derived mesenchymal stem cells (BMSCs) treatment by tail vein injection on day 14. Mice were euthanized on day 14 before administration or day 21 for the evaluation of pulmonary histopathology and hydroxyproline (HYP) content. Inflammatory factors of the lung, including transforming growth factor (TGF)-ß1, TNF-α, IL-6, MMP2 were analyzed by quantitative real-time PCR (qRT-PCR). Additionally, immunohistochemistry (IHC) and western blotting (WB) were applied to evaluate the expression of α-SMA and activation of TGF-ß1-Smad2/3 in lung. RESULTS: USCs highly expressed CD29 and CD90, showing negative expression of hematopoietic stem cell markers (CD45, CD34) and could differentiate into, at least, bone and fat in vitro. In mice challenged with BLM, septal thickening and prominent fibrosis were observed on day 14, with higher HYP content and mRNA levels of TGF-ß1, TNF-α and IL-6 exhibited, compared to untreated mice. USCs could migrate to lung and accumulate there in mouse model after intravenous injection. Transplantation of USCs into BLM-induced mice improved their pulmonary histopathology, decreasing Ashcroft score, Szapiel score, HYP content and mRNA levels of TGF-ß1 and MMP2 of lung, similar to the effects of BMSCs. IHC and WB further revealed that USCs could inhibit activation of the TGF­ß1-Smad2/3 pathway of lung in vivo. CONCLUSIONS: Transplantation of USCs effectively reverses pulmonary fibrotic phenotype in an experimental IPF model, inhibiting the TGF-ß1-Smad2/3 pathway, a key driver of fibrosis. These results suggest the therapeutic application of USCs for IPF, instead of other types of MSCs obtained invasively.

Engineering Co-N-Cr Cross-Interfacial Electron Bridges to Break Activity-Stability Trade-Off for Superdurable Bifunctional Single Atom Oxygen Electrocatalysts.

Atomically dispersed metal-nitrogen-carbon (M-N-C) catalysts have exhibited encouraging oxygen reduction reaction (ORR) activity. Nevertheless, the insufficient long-term stability remains a widespread concern owing to the inevitable 2-electron byproducts, H2O2. Here, we construct Co-N-Cr cross-interfacial electron bridges (CIEBs) via the interfacial electronic coupling between Cr2O3 and Co-N-C, breaking the activity-stability trade-off. The partially occupied Cr 3d-orbitals of Co-N-Cr CIEBs induce the electron rearrangement of CoN4 sites, lowering the Co-OOH* antibonding orbital occupancy and accelerating the adsorption of intermediates. Consequently, the Co-N-Cr CIEBs suppress the two-electron ORR process and approach the apex of Sabatier volcano plot for four-electron pathway simultaneously. As a proof-of-concept, the Co-N-Cr CIEBs is synthesized by the molten salt template method, exhibiting dominant 4-electron selectively and extremely low H2O2 yield confirmed by Damjanovic kinetic analysis. The Co-N-Cr CIEBs demonstrates impressive bifunctional oxygen catalytic activity (▵E=0.70 V) and breakthrough durability including 100 % current retention after 10 h continuous operation and cycling performance over 1500 h for Zn-air battery. The hybrid interfacial configuration and the understanding of the electronic coupling mechanism reported here could shed new light on the design of superdurable M-N-C catalysts.

Silencing GMPPB Inhibits the Proliferation and Invasion of GBM via Hippo/MMP3 Pathways.

Glioblastoma multiforme (GBM) is a highly aggressive malignancy and represents the most common brain tumor in adults. To better understand its biology for new and effective therapies, we examined the role of GDP-mannose pyrophosphorylase B (GMPPB), a key unit of the GDP-mannose pyrophosphorylase (GDP-MP) that catalyzes the formation of GDP-mannose. Impaired GMPPB function will reduce the amount of GDP-mannose available for O-mannosylation. Abnormal O-mannosylation of alpha dystroglycan (α-DG) has been reported to be involved in cancer metastasis and arenavirus entry. Here, we found that GMPPB is highly expressed in a panel of GBM cell lines and clinical samples and that expression of GMPPB is positively correlated with the WHO grade of gliomas. Additionally, expression of GMPPB was negatively correlated with the prognosis of GBM patients. We demonstrate that silencing GMPPB inhibits the proliferation, migration, and invasion of GBM cells both in vitro and in vivo and that overexpression of GMPPB exhibits the opposite effects. Consequently, targeting GMPPB in GBM cells results in impaired GBM tumor growth and invasion. Finally, we identify that the Hippo/MMP3 axis is essential for GMPPB-promoted GBM aggressiveness. These findings indicate that GMPPB represents a potential novel target for GBM treatment.

Design, Synthesis, and Biomedical Application of Multifunctional Fluorescent Polymer Nanomaterials.

Luminescent polymer nanomaterials not only have the characteristics of various types of luminescent functional materials and a wide range of applications, but also have the characteristics of good biocompatibility and easy functionalization of polymer nanomaterials. They are widely used in biomedical fields such as bioimaging, biosensing, and drug delivery. Designing and constructing new controllable synthesis methods for multifunctional fluorescent polymer nanomaterials with good water solubility and excellent biocompatibility is of great significance. Exploring efficient functionalization methods for luminescent materials is still one of the core issues in the design and development of new fluorescent materials. With this in mind, this review first introduces the structures, properties, and synthetic methods regarding fluorescent polymeric nanomaterials. Then, the functionalization strategies of fluorescent polymer nanomaterials are summarized. In addition, the research progress of multifunctional fluorescent polymer nanomaterials for bioimaging is also discussed. Finally, the synthesis, development, and application fields of fluorescent polymeric nanomaterials, as well as the challenges and opportunities of structure-property correlations, are comprehensively summarized and the corresponding perspectives are well illustrated.

Driver mutations in ADGRL3 are involved in the evolution of ependymoma.

Although there have been recent advances in the molecular pathology of ependymomas, little is known about the underlying molecular evolution during its development. Here, we assessed the clinical, pathological and molecular evolutionary process of ependymoma recurrence in a 9-year-old patient who had seven recurrences of supratentorial ependymoma and died from intracranial multiregional recurrences at the age of 19 years old. Whole-genome sequencing (WGS) of 7 tumor samples (1 primary and 6 subsequent recurrent tumors) was performed to elucidate the mutation landscape and identify potential driver mutations for tumor evolution. The genetic profiles of the seven tumor specimens showed significant heterogeneity and suggested a highly branched evolutionary pattern. The mutational signatures and chromothripsis changed with treatments. Strikingly, adhesion G protein-coupled receptor L3 (ADGRL3, also known as Latrophilins 3, LPNH3) was found to be consistently mutated during the entire disease process. However, Sanger sequencing of other 78 ependymoma patients who underwent surgery at our institution showed no genetic alteration of ADGRL3, as found in the present case. The mRNA levels of ADGRL3 were significantly lower in ependymomas (n = 36), as compared with normal brain tissue (n = 3). Grade III ependymomas had the lowest ADGRL3 expression. Moreover, ependymomas with lower mRNA level of ADGRL3 had shorter overall survival. Our findings, therefore, demonstrate a rare evolutionary process of ependymoma involving ADGRL3.

Better preservation of erectile function in localized prostate cancer patients with modern proton therapy: Is it cost-effective?

BACKGROUND: Stereotactic body radiation therapy (SBRT) has gradually been recognized as favorable curative treatment for localized prostate cancer (PC). However, the high rate of erectile dysfunction (ED) after traditional photon-based SBRT remains an ongoing challenge that greatly impacts the quality of life of PC survivors. Modern proton therapy allows higher conformal SBRT delivery and has the potential to reduce ED occurrence but its cost-effectiveness remains uninvestigated. METHODS: A Markov decision model was designed to evaluate the cost-effectiveness of proton SBRT versus photon SBRT in reducing irradiation-related ED. Base-case evaluation was performed on a 66-year-old (median age of PC) localized PC patient with normal pretreatment erectile function. Further, stratified analyses were performed for different age groups (50, 55, 60, 65, 70, and 75 years) and threshold analyses were conducted to estimate cost-effective scenarios. A Chinese societal willingness-to-pay (WTP) threshold (37,653 US dollars [$])/quality-adjusted life-year [QALY]) was adopted. RESULTS: For the base case, protons provided an additional 0.152 QALY at an additional cost of $7233.4, and the incremental cost-effectiveness ratio was $47,456.5/QALY. Protons was cost-effective for patients ≤62-year-old at the WTP of China (≤66-year-old at a WTP of $50,000/QALY; ≤73-year-old at a WTP of $100,000/QALY). For patients at median age, once the current proton cost ($18,000) was reduced to ≤$16,505.7 or the patient had a life expectancy ≥88 years, protons were cost-effective at the WTP of China. CONCLUSIONS: Upon assumption-based modeling, the results of current study support the use of proton SBRT in younger localized PC patients who are previously potent, for better preservation of erectile function. The findings await further validation using data from future comparative clinical trials.

Addition of chemoradiotherapy to palliative chemotherapy in de novo metastatic nasopharyngeal carcinoma: a real-world study.

BACKGROUND: To determine whether concurrent chemotherapy is necessary during locoregional radiotherapy (RT) after palliative chemotherapy (PCT) in patients with de novo metastatic nasopharyngeal carcinoma (mNPC). METHODS: A total of 746 patients with mNPC from 2000 to 2017 at our hospital were retrospectively reviewed. Among them, 355 patients received PCT followed by RT. Overall survival (OS) and progression-free survival (PFS), including locoregional progression-free survival (LRPFS) and distant progression-free survival (DPFS) were estimated with the Kaplan-Meier method and log-rank test. Cox proportional-hazards models, landmark analyses, propensity score matching, and subgroup analyses were used to address confounding. RESULTS: Of the patients included in our study, 192 received radiotherapy alone after PCT (PCT + RT), and 163 received concurrent chemoradiotherapy after PCT (PCT + CCRT). The prognosis of PCT + CCRT was significantly better than that of PCT + RT (5 year OS, 53.0 vs 36.2%; P = 0.004). After matching, the 5 year OS rates of the two groups were 55.7 and 39.0%, respectively (P = 0.034) and the median DPFS were 29.4 and 18.7 months, respectively (P = 0.052). Multivariate Cox regression analysis indicated that PCT + CCRT was an independent favorable prognostic factor (P = 0.009). In addition, conducting concurrent chemoradiotherapy after 4-6 cycles of PCT or conducting concurrent chemotherapy with single-agent platinum was associated with significant survival benefit in the matched cohort (5 year OS rate, 60.4 or 57.4%, respectively). The survival difference between groups remained significant when evaluating patients who survived for ≥ 1 year (P = 0.028). CONCLUSIONS: The optimal treatment strategy of mNPC is the combination of PCT followed by concurrent chemoradiotherapy. More specifically, concurrent chemoradiotherapy with single-agent platinum after 4-6 cycles of PCT is suggested.

Optimizing oropharyngeal cancer management by using proton beam therapy: trends of cost-effectiveness.

BACKGROUND: Proton beam therapy (PBT) is a new-emerging cancer treatment in China but its treatment costs are high and not yet covered by Chinese public medical insurance. The advanced form of PBT, intensity-modulated proton radiation therapy (IMPT), has been confirmed to reduce normal tissue complication probability (NTCP) as compared to conventional intensity-modulated photon-radiation therapy (IMRT) in patients with oropharyngeal cancer (OPC). Herein, we evaluated the cost-effectiveness and applicability of IMPT versus IMRT for OPC patients in China, aiming at guiding the proper use of PBT. METHODS: A 7-state Markov model was designed for analysis. Base-case evaluation was performed on a 56-year-old (median age of OPC in China) patient under the assumption that IMPT could provide a 25% NTCP-reduction in long-term symptomatic dysphagia and xerostomia. Model robustness was examined using probabilistic sensitivity analysis, cohort analysis, and tornado diagram. One-way sensitivity analyses were conducted to identify the cost-effective scenarios. IMPT was considered as cost-effective if the incremental cost-effectiveness ratio (ICER) was below the societal willingness-to-pay (WTP) threshold. RESULTS: Compared with IMRT, IMPT provided an extra 0.205 quality-adjusted life-year (QALY) at an additional cost of 34,926.6 US dollars ($), and had an ICER of $170,082.4/ QALY for the base case. At the current WTP of China ($33,558 / QALY) and a current IMPT treatment costs of $50,000, IMPT should provide a minimum NTCP-reduction of 47.5, 50.8, 55.6, 63.3 and 77.2% to be considered cost-effective for patient age levels of 10, 20, 30, 40 and 50-year-old, respectively. For patients at the median age level, reducing the current IMPT costs ($50,000) to a $30,000 level would make the minimum NTCP-reduction threshold for "cost-effective" decrease from 91.4 to 44.6%, at the current WTP of China (from 69.0 to 33.5%, at a WTP of $50,000 / QALY; and from 39.7 to 19.1%, at a WTP of $100,000 / QALY). CONCLUSIONS: Cost-effective scenarios of PBT exist in Chinese OPC patients at the current WTP of China. Considering a potential upcoming increase in PBT use in China, such cost-effective scenarios may further expand if a decrease of proton treatment costs occurs or an increase of WTP level.

Nasopharyngeal Epstein-Barr virus DNA loads in high-risk nasopharyngeal carcinoma families: Familial aggregation and host heritability.

Nasopharyngeal carcinoma (NPC), the most common head and neck cancer, is characterized by distinct geographic distribution and familial aggregation. Multiple risk factors, including host genetics, environmental factor, and EBV infection, have been linked to the development of NPC, particularly in the familial clustering cases. However, the cause of NPC endemicity remains enigmatic due possibly to the complicated interplay between these risk factors. Recently, positive Epstein-Barr virus (EBV) DNA loads at nasopharyngeal (NP) cavity has been found to reflect NPC development and applied in NPC screening. To examine whether the increased NP EBV loads could aggregate in the families and be affected by host genetics and environmental factor, EBV loads were obtained by 510 NP brushing samples from eligible unaffected individuals, who have two or more relatives affected with NPC, in 116 high-risk NPC families. The correlation of relative pairs was estimated using S.A.G.E. (version 6.4, 2016), and host heritability of NP EBV loads was calculated with variance component models using SOLAR (version 8.4.2, 2019). In result, significant correlations of EBV loads were observed between parent-offspring pairs and sibling-sibling pairs (P < .001), but not in distant kin relationship pairs. Interestingly, after excluding the shared environmental factor within families, host genetics contributes significantly to NP EBV loads with a heritability of 56.41% (P = 1.00 × 10-7 ), and its effect was slightly elevated (68.86%, P = 3.40 × 10-6 ) in families with more NPC cases (≥3). These findings indicate that additional host-genetic variants involved in the EBV local NP mucosal behavior may be especially important for the development of NPC.

Cost-effectiveness analysis of proton beam therapy for treatment decision making in paranasal sinus and nasal cavity cancers in China.

BACKGROUND: Cost-effectiveness is a pivotal consideration for clinical decision making of high-tech cancer treatment in developing countries. Intensity-modulated proton radiation therapy (IMPT, the advanced form of proton beam therapy) has been found to improve the prognosis of the patients with paranasal sinus and nasal cavity cancers compared with intensity-modulated photon-radiation therapy (IMRT). However, the cost-effectiveness of IMPT has not yet been fully evaluated. This study aimed at evaluating the cost-effectiveness of IMPT versus IMRT for treatment decision making of paranasal sinus and nasal cavity cancers in Chinese settings. METHODS: A 3-state Markov model was designed for cost-effectiveness analysis. A base case evaluation was performed on a patient of 47-year-old (median age of patients with paranasal sinus and nasal cavity cancers in China). Model robustness was examined by probabilistic sensitivity analysis, Markov cohort analysis and Tornado diagram. Cost-effective scenarios of IMPT were further identified by one-way sensitivity analyses and stratified analyses were performed for different age levels. The outcome measure of the model was the incremental cost-effectiveness ratio (ICER). A strategy was defined as cost-effective if the ICER was below the societal willingness-to-pay (WTP) threshold of China (30,828 US dollars ($) / quality-adjusted life year (QALY)). RESULTS: IMPT was identified as being cost-effective for the base case at the WTP of China, providing an extra 1.65 QALYs at an additional cost of $38,928.7 compared with IMRT, and had an ICER of $23,611.2 / QALY. Of note, cost-effective scenarios of IMPT only existed in the following independent conditions: probability of IMPT eradicating cancer ≥0.867; probability of IMRT eradicating cancer ≤0.764; or cost of IMPT ≤ $52,163.9. Stratified analyses for different age levels demonstrated that IMPT was more cost-effective in younger patients than older patients, and was cost-effective only in patients ≤56-year-old. CONCLUSIONS: Despite initially regarded as bearing high treatment cost, IMPT could still be cost-effective for patients with paranasal sinus and nasal cavity cancers in China. The tumor control superiority of IMPT over IMRT and the patient's age should be the principal considerations for clinical decision of prescribing this new irradiation technique.

The prognostic significance of PD-L1 and PD-1 expression in patients with nasopharyngeal carcinoma: a systematic review and meta-analysis.

BACKGROUND: Whether PD-L1/PD-1 expression plays a significant role in the prognosis of NPC is still controversial. The present study mainly aimed to investigate the prognostic significance of PD-L1/PD-1 expression in patients with NPC. METHODS: A systematical research was performed in the PubMed, Web of Science, EMBASE, and the Cochrane Library databases up to January 06, 2019. Eighteen studies met eligible criteria were included in the meta-analysis. Quality assessment of included articles was evaluated by Newcastle-Ottawa quality assessment scale (NOS). Pooled hazard ratios (HRs) and their corresponding 95% confidence intervals (95% CIs) were used to elucidated the primary endpoint, overall survival (OS), and the secondary endpoints. Furthermore, the relationship between clinicopathological features of NPC and PD-L1/PD-1 expression was estimated by relative ratios (RRs) and 95% CIs. RESULTS: A total of 1836 patients from 15 included studies concerning PD-L1 and 678 patients from six studies regarding PD-1 were included in the meta-analysis. Pooled results revealed that PD-L1 expression in NPC did not correlate with OS (HR 1.34 95% CI 0.93-1.93, p = 0.11), DFS (HR 1.82, 95% CI 0.86-3.85, p = 0.12), PFS (HR 1.19, 95% CI 0.46-3.08, p = 0.72), and DMFS (HR 2.26, 95% CI 0.60-8.56, p = 0.23). Meanwhile, no statistically significant differences existed between the expression level of PD-1 in tumor infiltrating lymphocytes (TILs) and the OS in NPC, with the pooled HR 1.29 (95% CI 0.68-2.42, p = 0.44). In subgroup analysis, higher expression of PD-L1 in immune cells correlated with better OS in patients with NPC, with a pooled HR 0.68 (95% CI 0.47-0.99, p = 0.04). Among the clinicopathological features included in our study, we found that the positive expression of PD-L1 in NPC associated with the higher expression of PD-1 (RR 1.25, 95% CI 1.02-1.52, p = 0.03). CONCLUSIONS: Our meta-analysis indicated that higher/positive expression of PD-L1/PD-1 may not serve as suitable biomarkers for the prognosis of NPC, which was not in consistent with some previous studies about the prognostic value of PD-L1/PD-1 in other types of tumors. Despite the positive results in subgroup analysis and study about clinicopathological features, it may still need corroboration of prospective and large-scale studies.

An extended genome-wide association study identifies novel susceptibility loci for nasopharyngeal carcinoma.

To further identify novel susceptibility loci of nasopharyngeal carcinoma (NPC), we here extended our previous genome-wide association study (GWAS) by boosting statistical power with larger sample size and validating more SNPs in the ranking list based on the GWAS P-values. The discovery stage consisting of 463,250 SNPs in 1,583 cases and 2,979 controls of southern Chinese ancestry revealed 1,257 top SNPs to be associated with NPC, which were brought forward for validation in 1,925 cases and 1,947 controls of southern Chinese. Further, 11 SNPs were selected for another independent validation in 3,538 cases and 3,644 controls of southern Chinese. The joint analysis with 7,046 cases and 8,570 controls resulted in two associations surpassing genome-wide significance (P < 5 × 10-8), including TERT-CLPTM1L at chromosome 5p15 (rs401681; P = 2.65 × 10-14; odds ratio, OR = 0.82) and CIITA at chromosome 16p13 (rs6498114; P = 4.01 × 10-9; OR = 0.87). Conditional analysis revealed that rs401681 accounts for all the tested associations at TERT-CLPTM1L locus, which has been linked with multiple cancers' susceptibilities. Moreover, bioinformatics analyses showed that both SNPs are located in the regulatory regions and correlated with the expression of nearby genes (rs401681 for CLPTM1L and TERT, and rs6498114 for CIITA). CLPTM1L and TERT have been implicated in cancers, and CIITA is considered as the "master control factor" for the expression of NPC-associated MHC class II genes. These suggested that both SNPs might be functional. Altogether, our findings expand our understanding of the genetic contribution to NPC risk and provide novel biological insights into NPC pathogenesis.

Motion analysis of the wrist joints in Chinese rheumatoid arthritis patients: a cross-sectional study.

BACKGROUND: The wrist is often severely affected in rheumatoid arthritis (RA) patients; however, little is known about the potential risk factors of the reduced wrist range of motion. In this study, we explored a broad range of possible risk factors of wrist range of motion in RA patients. We also determined whether measurements of wrist range of motion reflect Sharp score for the wrists. METHODS: Active wrist volar flexion, dorsal flexion, radial deviation and ulnar deviation were assessed using a goniometer. RA patients underwent standardized laboratory and radiographic examinations and completed several questionnaires. A linear regression model was used to study association between the wrist range of motion and independent variables. In addition, Spearman and Pearson correlation analysis were used to compare influence factors and outcome measurements between the measurements of wrist range of motion and Sharp score for the wrists. RESULTS: In this study, lower socioeconomic status, longer disease duration, severe pain, higher disease activity and drug treatments were associated with reduced wrist range of motion in RA patients (n = 102, 86.3% female, mean ± SD age, 55.0 ± 11.7 years, and mean ± SD disease duration, 8.4 ± 8.7 years). Furthermore, wrist range of motion was highly correlated with Sharp score for the wrists (P < 0.05). CONCLUSIONS: Socioeconomic status and disease-specific factors were significantly associated with wrist range of motion in RA patients. The results indicated that rheumatologists and nurses should note the measurements of wrist range of motion in RA patients, especially those with a low socioeconomic status, a long disease duration, severe pain, and high disease activity to develop strategies to improve their quality of life.

Effectiveness and safety of different amifostine regimens: Preliminary results of a phase II multicenter randomized controlled trial.

OBJECTIVE: The radioprotective effects of amifostine remain uncertain in patients with nasopharyngeal carcinoma (NPC), and adverse effects and cost limit generalization of its classical everyday regimen. This phase II multicenter randomized controlled trial aimed to explore whether amifostine could ameliorate the toxicities of NPC patients in the era of intensity-modulated radiotherapy (IMRT), and to compare different regimens of amifostine on effectiveness and safety. METHODS: Patients with stage I-IVB NPC were involved prospectively from January 1st, 2013. All patients received radical treatment based on IMRT. After a randomization stratified by their stage, these patients were allocated into 3 groups: the group treated without amifostine, the group treated with the everyday regimen of amifostine, and the group treated with the every-other-day regimen. The 3 groups of patients were compared on radiotherapy-related acute toxicities, treatment effects of NPC, and amifostine-related complications. This trial was registered on the clinicaltrials.gov (ID: NCT01762514). RESULTS: Until August 31st, 2017, totally 187 patients completed experimental intervention. Only amifostine of everyday regimen appeared to reduce the patient proportion of mucositis (79.1% vs. 96.8%, P=0.002). Hypocalcemia was less common in patients treated without amifostine than in those treated with amifostine (22.6% vs. 53.4% vs. 41.8%, P=0.002). Neither complete remission rates nor the survivals were affected by amifostine. CONCLUSIONS: Amifostine of everyday regimen could reduce mucositis in NPC patients who received IMRT, though it also had the possibility to cause more hypocalcemia.

RPA3 is a potential marker of prognosis and radioresistance for nasopharyngeal carcinoma.

Radioresistance-induced residual and recurrent tumours are the main cause of treatment failure in nasopharyngeal carcinoma (NPC). Thus, the mechanisms of NPC radioresistance and predictive markers of NPC prognosis and radioresistance need to be investigated and identified. In this study, we identified RPA3 as a candidate radioresistance marker using RNA-seq of NPC samples. In vitro studies further confirmed that RPA3 affected the radiosensitivity of NPC cells. Specifically, the overexpression of RPA3 enhanced radioresistance and the capacity for DNA repair of NPC cells, whereas inhibiting RPA3 expression sensitized NPC cells to irradiation and decreased the DNA repair capacity. Furthermore, the overexpression of RPA3 enhanced RAD51 foci formation in NPC cells after irradiation. Immunohistochemical assays in 104 NPC specimens and 21 normal epithelium specimens indicated that RPA3 was significantly up-regulated in NPC tissues, and a log-rank test suggested that in patients with NPC, high RPA3 expression was associated with shorter overall survival (OS) and a higher recurrence rate compared with low expression (5-year OS rates: 67.2% versus 86.2%; 5-year recurrence rates: 14.8% versus 2.3%). Moreover, TCGA data also indicated that high RPA3 expression correlated with poor OS and a high recurrence rate in patients with head and neck squamous cell carcinoma (HNSC) after radiotherapy. Taken together, the results of our study demonstrated that RPA3 regulated the radiosensitivity and DNA repair capacity of NPC cells. Thus, RPA3 may serve as a new predictive biomarker for NPC prognosis and radioresistance to help guide the diagnosis and individualized treatment of patients with NPC.

JAK-STAT signaling mediates the senescence of bone marrow-mesenchymal stem cells from systemic lupus erythematosus patients.

Previous studies have revealed that bone marrow-mesenchymal stem cells (BM-MSCs) from systemic lupus erythematosus (SLE) patients exhibited early signs of senescence, which may participate in the development of SLE. However, the molecular mechanisms about this phenomenon have not been fully elucidated. In the current study, we aimed to investigate whether Janus kinase (JAK)-signaling transducers and activators of transcription (STAT) signaling mediated the senescence of BM-MSCs from SLE patients. Twelve female SLE patients and healthy subjects were enrolled in the study. All BM-MSCs were isolated by density gradient centrifugation. Western blot analysis was used to test the expression of JAK-STAT signaling molecules. We observed the activity of ß-gal of cells, the changes of cytoskeletal structure by F-actin staining, and the distribution of cell cycle by flow cytometry. BM-MSCs from SLE patients showed prominent features of senescence, and abnormal activation of JAK-STAT signaling transduction, high level of phosphorylated JAK2, and STAT3. After stimulation of IFN-γ in normal MSCs, JAK-STAT signaling was activated. The cell volume and the number of senescence-associated ß-galactosidase (SA-ß-gal) positive in SLE BM-MSCs were increased. The organization of cytoskeleton was nearly disordered. The rate of cell proliferation was decreased. AG490, the inhibitor of JAK2, and knockdown of STAT3 in BM-MSCs, could significantly reverse the senescence. In summary, our study indicated that JAK-STAT signaling pathway may play a critical role in the senescence of SLE BM-MSCs.

The correlations of socioeconomic status, disease activity, quality of life, and depression/anxiety in Chinese patients with rheumatoid arthritis.

This study aimed (i) to investigate the relationships among socioeconomic status, disease activity, quality of life, and the psychological status in Chinese rheumatoid arthritis (RA) patients; (ii) to explore the possible risk factors of anxiety and depression. A total of 160 RA patients underwent standardized laboratory examinations and completed several questionnaires. Independent samples t-tests, χ2 analyses, and logistic regression modeling were used to analyze the data. We found 30.6% RA patients were anxiety, and 27.5% had depression, which were significantly higher than the control group (7.8 and 11.7%, respectively). And there were significant correlations among education, pain, disease activity, medication adherence, functional capacity, quality of life, and anxiety/depression. Meanwhile, logistic regression analysis revealed that poor quality of life and low education level were significantly associated with anxiety/depression in RA patients. In conclusion, there were significant relationships among education, quality of life, and anxiety/depression in Chinese RA patients.

Image-based Multilevel Subdivision of M1 Category in TNM Staging System for Metastatic Nasopharyngeal Carcinoma.

Purpose To establish an image-based M1 category subdivision system for personalized prognosis prediction and treatment planning in patients with metastatic nasopharyngeal carcinoma (NPC). Materials and Methods A total of 1172 patients with metachronous metastasic NPC were retrospectively enrolled (the dataset is from Sun Yat-sen University Cancer Center for derivation, and the combined datasets are from Guangzhou Medical University Cancer Center and the Fifth Affiliated Hospital of Sun Yat-sen University for validation). The Ethics Committee of the three centers approved this study. A general subdivision system of the M1 category was established on the basis of the most influential metastatic features for overall survival (OS). The following multilevel subdivision system for precise subdivision of the M1 category was designed: M [number of locations]-Location [number of lesions], with B indicating bone, L indicating the lung, H indicating the liver, and N indicating a node. The correlation of the M1 subdivisions with OS was determined with Cox regression. The best treatment response was assessed with Response Evaluation Criteria in Solid Tumors 1.1 guidelines and modified Response Evaluation Criteria in Solid Tumors criteria. Results Multivariate analysis in the derivation cohort showed that the number of metastatic lesions (multiple or single), the number of metastatic locations (multiple or single), liver involvement, and bone involvement were independent prognostic factors for OS. In general, subdividing the cohort by the number of metastatic lesions and the number of metastatic locations resulted in three subcategories of differential OS: M1a, a single lesion in a single organ or location; M1b, multiple lesions in a single organ or location; and M1c, metastases in multiple locations (for M1b vs M1a, hazard ratio [HR] = 2.28, 95% confidence interval [CI]: 1.71, 3.05; for M1c vs M1a, HR = 3.65, 95% CI: 2.75, 4.85); these subdivisions were externally validated. The multilevel subdivision system could be further used to discriminate among subgroups of differential OS under the M1b subcategory. Findings from analysis of multilevel subgroups suggested that patients with a single metastatic lesion (M1-B1, M1-L1, M1-H1, M1-N1) or two lesions in the liver only (M1-H2) had high rates of complete response (CR) or complete surgical resection (CSR) and 3-year OS after treatment (CR plus CSR rates >30%, and 3-year OS rates >50%); there were high 3-year OS rates (>50%) in patients with stage M1-B2, M1-L2, or M1-H3 disease but relatively low rates of CR or CSR. Conclusion Use of the multilevel M1 subdivision system in patients with NPC could facilitate more precise prognosis prediction and better identification of patients who will respond well to treatment than the conventional subdivision strategy. (©) RSNA, 2016 Online supplemental material is available for this article.

Association between XRCC3 Thr241Met polymorphism and nasopharyngeal carcinoma risk: evidence from a large-scale case-control study and a meta-analysis.

The X-ray repair cross-complementing group 3 (XRCC3) Thr241Met polymorphism (rs861539, C > T) has drawn wide attentions as its association with cancer risk and its involvement in DNA repair. Several studies have attempted to link rs861539 to nasopharyngeal cancer (NPC) risk; however, the sample sizes of these studies are small and the results are controversial. To investigate the relationship of rs861539 and NPC susceptibility, we conducted a large-scale case-control study involving 4001 NPC cases and 2967 controls of southern Chinese. Logistic regression analysis revealed significant association for rs861539 and NPC risk under the recessive model (TT vs. CT + CC) with adjustment of age and gender (odds ratio, OR = 2.72; 95 % CI 1.10-6.72; P = 0.03). Further, meta-analysis involving 4457 NPC cases and 4132 controls from four studies showed consistent association of TT carriers and NPC risk (OR = 3.12; 95 % CI 1.58-6.13; P = 0.001). Taken together, our findings based on large-scale sample size suggested rs861539 at XRCC3 to be associated with NPC risk through recessive model.

Sleep quality in Chinese patients with rheumatoid arthritis: contributing factors and effects on health-related quality of life.

BACKGROUND: Poor sleep quality is common in rheumatoid arthritis (RA) patients and may lead to disease aggravation and decreased health-related quality of life (HRQoL). The increasing prevalence of poor sleep in RA patients is associated with adverse demographic, clinical, and psychological characteristics. However, there are currently no known reported studies related to the effects of sleep quality on HRQoL in RA patients from China. This cross-sectional study aims to evaluate the contributors of poor sleep and the effects of sleep quality on HRQoL in Chinese RA patients. METHODS: A self-report survey was administered to 131 RA patients and 104 healthy individuals using the Pittsburgh Sleep Quality Index (PSQI) for sleep quality. RA patients completed the Hospital Anxiety and Depression Scale for anxiety and depression, the 28-joint Disease Activity Score for disease activity, the 10 cm Visual Analog Scale for pain, the Health Assessment Questionnaire-Disability Index for functional capacity and the Short Form 36 health survey for HRQoL. Blood samples were taken to gain some biochemical indicators (e.g., erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, and anti-cyclic citrullinated peptide). Independent samples t-tests, Chi square analysis, logistic regression modeling and linear regression were used to analyze these data. RESULTS: Our results found that the prevalence of poor sleep (PSQI ≥ 5) was 78.6% and the mean global score of PSQI was 7.93 (SD 3.98) in patients, which were significantly higher than the controls (18.7% and 3.88 (SD 1.89), respectively). There were significant correlations among synthetic disease-modifying antirheumatic drugs, erythrocyte sedimentation rate, pain, disease activity, functional capacity, anxiety/depression and sleep quality in RA patients. Meanwhile, logistic regression models identified disease activity and depression as predictors of poor sleep quality. Poor RA sleepers had impaired HRQoL than good RA sleepers, and sleep quality was independently and significantly associated with social function and mental components summary. CONCLUSIONS: The majority of Chinese RA patients suffered from poor sleep, which significantly impairs their HRQoL. The data suggested the need for holistic assessment and management of RA patients and the importance of objective interventions to improve their sleep quality and finally to improve their HRQoL.