Intensity-modulated radiotherapy alone compared with intensity-modulated radiotherapy plus concurrent chemotherapy in intermediate-risk nasopharyngeal carcinoma : A prospective multicenter phase II trial.

BACKGROUND: This study aimed to investigate the clinical benefit of adding concurrent chemotherapy to intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC) patients with an intermediate risk (stage II and T3N0M0). METHODS: A multicenter phase II randomized trial was conducted in intermediate-risk NPC patients. Enrolled patients were previously untreated and aged ranged from 18 to 70 years without severe coexisting diseases. Patients were randomly assigned to receive IMRT alone or IMRT+concurrent chemotherapy (CC; three cycles of 80 mg/m2 cisplatin every 3 weeks). Primary endpoint was defined as 3­year progression-free survival (PFS). The secondary endpoints were distant metastasis-free survival (DMFS), locoregional relapse-free survival (LRRFS), overall survival (OS), and treatment-associated toxicity. We registered this study with Chinese Clinical Trial Registry (CliCTR1800017132; registered July 13, 2018, study start July 13, 2018). RESULTS: From November 2015 to July 2019, 42 patients with stage II and T3N0M0 NPC were enrolled; 20 patients received IMRT alone while 22 patients received IMRT+CC. After a median of 58 months of follow-up, we estimated the 3­year PFS rates as 90% (IMRT group) and 86.4% (IMRT+CC group; hazard ratio 1.387, 95% confidence interval 0.240-8.014; P = 0.719). The 3­year PFS, OS, and cumulative DMFS and LRRFS showed no significant differences between the two groups (P > 0.05). However, the IMRT group displayed a lower incidence of nausea/vomiting, leucopenia, and dry mouth than the IMRT+CC group. CONCLUSION: Adding CC to IMRT provided no survival benefit but increased treatment-associated toxicities in patients with intermediate-risk NPC.

Nomogram for distant metastasis-free survival in patients with locoregionally advanced nasopharyngeal carcinoma.

OBJECTIVE: To develop and validate a nomogram to predict distant metastasis-free survival of patients with locoregionally advanced nasopharyngeal carcinoma. METHODS: We collected the total clinical data of 820 nasopharyngeal carcinoma (NPC) patients, of whom 482 formed the training cohort from one hospital and 328 made up the validation cohort from another hospital. By analyzing the prognosis of all patients after intensity-modulated radiotherapy by univariate and multivariate Cox regression models, a nomogram related to DMFS was created in the training cohort. The discriminatory and calibration power of the nomogram was successively assessed in the training and validation cohorts by the C­index and calibration curve. The predictive ability for 3­year DMFS was compared between the nomogram and TNM stage using ROC curves. Patients were divided into different risk groups based on scores calculated from the nomogram. RESULTS: Age, lymph node gross tumor volume (GTVnd), and gross tumor volume of the nasopharynx (GTVnx) were the factors included in the nomogram. The C­index of the nomogram was 0.721 in the training cohort and 0.750 in the validation cohort. The calibration curves were satisfactory. Patients in the high-risk group were more likely to develop metastases. CONCLUSION: A nomogram incorporating age, GTVnd, and GTVnx showed good performance for predicting DMFS in patients with locoregionally advanced NPC.

Methylation-associated silencing of miR-9-1 promotes nasopharyngeal carcinoma progression and glycolysis via HK2.

Characteristically, cancer cells metabolize glucose through aerobic glycolysis, known as the Warburg effect. Accumulating evidence suggest that during cancer formation, microRNAs (miRNAs) could regulate such metabolic reprogramming. In the present study, miR-9-1 was identified as significantly hypermethylated in nasopharyngeal carcinoma (NPC) cell lines and clinical tissues. Ectopic expression of miR-9-1 inhibited NPC cell growth and glycolytic metabolism, including reduced glycolysis, by reducing lactate production, glucose uptake, cellular glucose-6-phosphate levels, and ATP generation in vitro and tumor proliferation in vivo. HK2 (encoding hexokinase 2) was identified as a direct target of miR-9-1 using luciferase reporter assays and Western blotting. In NPC cells, hypermethylation regulates miR-9-1 expression and inhibits HK2 translation by directly targeting its 3' untranslated region. MiR-9-1 overexpression markedly reduced HK2 protein levels. Restoration of HK2 expression attenuated the inhibitory effect of miR-9-1 on NPC cell proliferation and glycolysis. Fluorescence in situ hybridization results indicated that miR-9-1 expression was an independent prognostic factor in NPC. Our findings revealed the role of the miR-9-1/HK2 axis in the metabolic reprogramming of NPC, providing a potential therapeutic strategy for NPC.

[Analysis of clinical features of 3 201 cases of adult intertrochanteric fractures: a single center experience].

OBJECTIVE: To analyze the gender, age, fracture classification and variation trend of adult intertrochanteric fractures treated in a single-center hospital in ten years. METHODS: The data of adult (age ≥ 16 years) intertrochanteric fractures admitted to the Third Hospital of Hebei Medical University from January 2003 to December 2012 were collected retrospectively. All the fractures were acute and the pathological or periprosthetic fractures were excluded. The radiography of fracture were classified by same experienced orthopedic resident and verified by two orthopedic deans and one radiologist. The gender, age and fracture classification were analyzed and compared between January 2003 to December 2007 and January 2008 to December 2012. RESULTS: A total of 3 201 cases were collected. The adult intertrochanteric fractures accounted for 2.97% of all adult fractures and 43.76% of adult proximal femoral fractures. Of all fractures 64.98% were elderly ( ≥ 60 years) and 35.02% were middle-aged (16-59 years). In elderly, female were common (57.78%) while in middle-aged were male commonly (79.13%). According to Evans classification, instable fractures were more common (68.92%). According to AO classification, the most common type was A2 (49.67%) and the least was A3 (15.93%). Comparing between January 2003 to December 2012 and January 2008 to December 2012, the proportion of intertrochanteric fracture of adult fracture was decreased by 0.31% (χ² = 9.29, P = 0.002)and the proportion of intertrochanteric fracture of adult proximal femoral fractures was decreased by 3.15% (χ² = 7.35, P = 0.007). The proportion of elderly patients, female and stable fractures was increased by 14.35% (χ² = 71.98, P < 0.01), 4.04% (χ² = 8.16, P = 0.004) and 5.62% (χ² = 11.7, P = 0.001), respectively. The proportion of AO classification was not significantly verified (χ² = 3.24, P = 0.198). CONCLUSIONS: The intertrochanteric fractures are most common in elderly patients, A2-type of AO Classification and stable (Evans III, IV, V) in Evans classification. Compared with the previous five years, the proportions of female, elderly and stable (Evans I, II) fracture increase in last 5 years.

Systemic Inflammation Predict Neurological Functional Outcome in Patients with Tuberculous Meningitis: A Multicenter Retrospective Cohort Study in China.

Background: The predictors associated with clinical outcomes in patients with tuberculous meningitis (TBM) remain unclear. We aimed to analyse the relationship between systemic inflammation and clinical outcomes, as well as to explore whether systemic inflammation level influences the effectiveness of dexamethasone on treatment. Methods: Between January 2011 and December 2021, TBM patients admitted to five hospitals were observed consecutively. Baseline and post-treatment systemic inflammation levels were calculated using the neutrophil-lymphocyte-ratio (NLR). Generalized linear mixed models were employed to identify predictors of clinical outcomes. Propensity score matching and subgroup analyses were conducted to evaluate the effect of dexamethasone on treatment outcomes across different NLR levels. Results: A total of 1203 TBM patients were included in the study. During the follow-up, 144 (13.6%) participants experienced early neurological deterioration within 7 days after admission, and 345 (28.67%) exhibited poor functional outcome at the 12-month follow-up. Multivariate analysis revealed that post-treatment NLR was significantly associated with early neurological deterioration (OR=1.25; 95% CI, 1.14-1.33; P<0.001), and poor outcome (OR=1.34; 95% CI, 1.26-1.45; P<0.001). After propensity score matching, dexamethasone treatment was not associated with early neurological deterioration (OR=0.83; 95% CI, 0.42-1.66; P=0.610) or poor outcome (OR=1.22; 95% CI, 0.49-2.11; P=0.490) in the highest quartile of post-treatment NLR. The effect of dexamethasone on treatment outcomes did not significantly vary with disease severity stratification. Conclusion: Elevated systemic inflammation is an independent risk factor for neurological outcome in TBM patients. Further studies are required to investigate systemic inflammation in more severely affected population to better predict the outcomes following anti-inflammatory therapies.

Development and validation of an individualized angiogenesis and tumor-infiltrating lymphocytes prognostic signature in nasopharyngeal carcinoma.

In recent years, targeted therapy and immunotherapy have become ideal choices for the treatment of advanced, metastatic, recurrent, and drug-resistant nasopharyngeal carcinoma (NPC), but the lack of understanding of the relationship and mechanism between TILs and angiogenic factors hinders therapeutic development and optimization. In this study, the expression of angiogenesis-related markers (VEGF-A,VEGFR-2) and TILs (CD4+T,CD8+T) was studied by using immunohistochemistry (IHC). Then we constructed an immunohistochemical scoring model for the co-expression of angiogenesis-related markers and TILs (COV+TIL score)in the training (n = 124) and validated the accuracy and reliability of the scoring system in the validation cohorts (n = 114), respectively We established the COV+TIL score model and stratified patients into different risk level in the training cohorts according to COV+TIL score (cut-off value=28). Patients in the high-risk group had worse prognosis in the training cohorts five-year overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS) was lower than that of patients in the low-risk group, and this result was validated in the validation cohorts ( 5-year OS in the high-risk and the low-risk group 46.8% vs. 83.4%, HR: 3.42, 95%CI: 1.77-6.61, p < 0.001); ( 5-year PFS 45.9% vs. 81.2%, HR: 3.22, 95%CI: 1.71-6.06, p < 0.001); ( 5-year LRRFS 74.6% vs. 87.5%, HR: 3.22, 95%CI: 1.16-8.93, p = 0.027); and ( 5-year DMFS79.2% vs. 93.2%, HR: 2.22, 95%CI: 0.91-5.39, p = 0.086). Upon multivariable analysis, COV+TIL score emerged as an independent prognostic indicator for defining survival in the training cohorts and the validation cohorts. Combining the COV+TIL score and TNM stage improved the prediction ability of the survival. In conclusion, NPC patients with high COV+TIL score showed worse prognosis.

Acute ischemic stroke in tuberculous meningitis.

Background: The underlying mechanism for stroke in patients with tuberculous meningitis (TBM) remains unclear. This study aimed to investigate the predictors of acute ischemic stroke (AIS) in TBM and whether AIS mediates the relationship between inflammation markers and functional disability. Methods: TBM patients admitted to five hospitals between January 2011 and December 2021 were consecutively observed. Generalized linear mixed model and subgroup analyses were performed to investigate predictors of AIS in patients with and without vascular risk factors (VAFs). Mediation analyses were performed to explore the potential causal chain in which AIS may mediate the relationship between neuroimaging markers of inflammation and 90-day functional outcomes. Results: A total of 1,353 patients with TBM were included. The percentage rate of AIS within 30 days after admission was 20.4 (95% CI, 18.2-22.6). A multivariate analysis suggested that age ≥35 years (OR = 1.49; 95% CI, 1.06-2.09; P = 0.019), hypertension (OR = 3.56; 95% CI, 2.42-5.24; P < 0.001), diabetes (OR = 1.78; 95% CI, 1.11-2.86; P = 0.016), smoking (OR = 2.88; 95% CI, 1.68-4.95; P < 0.001), definite TBM (OR = 0.19; 95% CI, 0.06-0.42; P < 0.001), disease severity (OR = 2.11; 95% CI, 1.50-2.90; P = 0.056), meningeal enhancement (OR = 1.66; 95% CI, 1.19-2.31; P = 0.002), and hydrocephalus (OR = 2.98; 95% CI, 1.98-4.49; P < 0.001) were associated with AIS. Subgroup analyses indicated that disease severity (P for interaction = 0.003), tuberculoma (P for interaction = 0.008), and meningeal enhancement (P for interaction < 0.001) were significantly different in patients with and without VAFs. Mediation analyses revealed that the proportion of the association between neuroimaging markers of inflammation and functional disability mediated by AIS was 16.98% (95% CI, 7.82-35.12) for meningeal enhancement and 3.39% (95% CI, 1.22-6.91) for hydrocephalus. Conclusion: Neuroimaging markers of inflammation were predictors of AIS in TBM patients. AIS mediates < 20% of the association between inflammation and the functional outcome at 90 days. More attention should be paid to clinical therapies targeting inflammation and hydrocephalus to directly improve functional outcomes.

MFSD4A inhibits the malignant progression of nasopharyngeal carcinoma by targeting EPHA2.

DNA Methylation can lead to abnormal gene expression. In the present study, we investigated whether the expression of methylated MFSD4A (major facilitator superfamily domain containing 4 A) was downregulated in nasopharyngeal carcinoma (NPC) and whether it is associated with malignant progression and poor prognosis of NPC. Bioinformatic analysis, bisulfite pyrosequencing, quantitative real-time reverse transcription PCR, and western blotting assays were performed to explore the relationship between hypermethylation of MFSD4A and its expression in NPC. The role of MFSD4A in NPC was verified by Cell Cycle Kit 8, transwell assays and flow cytometry in vitro and by animal experiments in vivo. Mass spectrometry, co-immunoprecipitation, and immunofluorescence assays were applied to explore the mechanism by which MFSD4A inhibits NPC. The prognostic significance of MFSD4A or EPHA2 was investigated by immunohistochemical analysis of clinical specimens. Hypermethylation of the promoter region of MFSD4A led to decreased expression of MFSD4A. When MFSD4A expression was upregulated or downregulated, the proliferation, apoptosis, migration, and invasion abilities of NPC cells were altered accordingly. Mechanistically, MFSD4A could specifically bind to and degrade EPH receptor A2 (EPHA2) by recruiting ring finger protein 149 (RNF149), which led to alterations in the EPHA2-mediated PI3K-AKT-ERK1/2 pathway and epithelial-mesenchymal transition (EMT), thereby affecting NPC progression. Clinically, high MFSD4A expression or low-EPHA2 expression was associated with better prognosis for patients with NPC. In all, reduced MFSD4A expression in NPC is caused by promoter hypermethylation. MFSD4A or EPHA2 expression is associated with the malignant biological behavior and prognosis of NPC. MFSD4A is a promising potential therapeutic target for NPC.

Effects of soil resource availability on patterns of plant functional traits across spatial scales.

Identifying patterns and drivers of plant community assembly has long been a central issue in ecology. Many studies have explored the above questions using a trait-based approach; however, there are still unknowns around how patterns of plant functional traits vary with environmental gradients. In this study, the responses of individual and multivariate trait dispersions of 134 species to soil resource availability were examined based on correlational analysis and torus-translation tests across four spatial scales in a subtropical forest, China. Results indicated that different degrees of soil resource availability had different effects on trait dispersions. Specifically, limited resource (available phosphorus) showed negative relationships with trait dispersions, non-limited resource (available potassium) showed positive relationships with trait dispersions, and saturated resource (available nitrogen) had no effect on trait dispersions. Moreover, compared with the stem (wood density) and architectural trait (maximum height), we found that leaf functional traits can well reflect the response of plants to nutrient gradients. Lastly, the spatial scale only affected the magnitude but not the direction of the correlations between trait dispersions and environmental gradients. Overall, the results highlight the importance of soil resource availability and spatial scale in understanding how plant functional traits respond to environmental gradients.

Correction: The effects of Bidens alba invasion on soil bacterial communities across different coastal ecosystem land-use types in southern China.

[This corrects the article DOI: 10.1371/journal.pone.0238478.].

The effects of Bidens alba invasion on soil bacterial communities across different coastal ecosystem land-use types in southern China.

Environments in both biotic and abiotic ecosystems have been affected by the colonization of non-native flora. In this study, we examined the effect of Bidens alba invasion on different land-use types along a coastline in southern China. Bacterial communities in each site were determined using 16S rDNA sequencing, and soil physicochemical properties were analyzed using standard methods. Although our results indicated that B. alba invasion did not have a significant effect on the alpha diversity of bacteria, it caused significant differences in soil bacterial community composition between invaded and uninvaded soil across different land-use types. Beta diversity and several physicochemical properties in forest, orchard and waterfront environments were recorded to be more susceptible to B. alba invasion. A high proportion of the variation of bacterial communities can be explained by a combination of environmental variables, indicating that environmental selection rather than plant invasion is a more effective process in coastal microbial assemblages. By comparing topological roles of shared OTUs among invaded and uninvaded soil, keystone taxa in invaded soil were identified. Acidobacteria was the major phyla involved in the invasive process which could be driven by environmental selection. How key phyla react in our experiment should be verified by further studies.