Glioma-Stem-Cell-Derived Exosomes Remodeled Glioma-Associated Macrophage via NEAT1/miR-125a/STAT3 Pathway.

Glioblastoma (GBM), as the most common primary brain tumor, usually results in an extremely poor prognosis, in which glioma stem cells (GSCs) and their immunosuppressive microenvironment prominently intervene in the resistance to radiotherapy and chemotherapy that directly leads to tumor recurrence and shortened survival time. The specific mechanism through which exosomes generated from GSCs support the creation of an immunosuppressive microenvironment remains unknown, while it is acknowledged to be engaged in intercellular communication and the regulation of the glioma immunosuppressive microenvironment. The elevated expression of LncRNA-NEAT1 was found in glioma cells after radiotherapy, chemotherapy, and DNA damage stimulation, and NEAT1 could promote the malignant biological activities of GSCs. Emerging evidence suggests that lncRNAs may reply to external stimuli or DNA damage by playing a role in modulating different aspects of tumor biology. Our study demonstrated a promotive role of the carried NEAT1 by GSC-derived exosomes in the polarization of M2-like macrophages. Further experiments demonstrated the mediative role of miR-125a and its target gene STAT3 in NEAT1-induced polarization of M2-like macrophages that promote glioma progression. Our findings elucidate the mechanism by which GSCs influence the polarization of M2-like macrophages through exosomes, which may contribute to the formation of immunosuppressive microenvironments. Taken together, our study reveals the miR-125a-STAT3 pathway through which exosomal NEAT1 from treatment-resistant GSCs contributes to M2-like macrophage polarization, indicating the potential of exosomal NEAT1 for treating glioma.

Treatment outcomes of surgery followed by short-course every other day radiotherapy in keloid.

BACKGROUND: Postoperative radiotherapy can significantly reduce keloid recurrence. However, consensus on the optimal radiotherapy dose and treatment schedule remains elusive. This study aims to evaluate the effectiveness of surgery followed by a short-course of radiotherapy administered every other day for keloid treatment. MATERIALS/METHODS: We conducted a retrospective analysis of 498 patients with keloids treated at our institution between January 2010 and December 2017. All patients underwent electron beam irradiation at a dose of 16 Gy, delivered in four fractions every other day, starting within 24 h post-surgery. The primary endpoint of the study was the local control rate. RESULTS: A total of 130 (26.5%) keloids recurred after a median follow-up of 68.1months (42.6-129.9 months). The local control rates at 1 year, 3 years and 5 years for all patients were 89.5%, 82.5% and 81%, respectively. The highest recurrence rate was observed in keloids located in the chest region (50.8%), followed by the suprapubic (47.8%), head and neck (38.8%), limbs (33.3%) and ear (14%). Both multivariate and univariate analyses identified the presence of pain and or pruritus as an independently prognostic factor for keloid recurrence (p<0.0001). The local control rates at 1-year, 3-years and 5-years for patients with or without symptom of pain or pruritus were 45% vs. 98.8%, 12.5% vs. 95.9%, and 8.8% vs. 95%, respectively (HR:37.829, 95%CI: 24.385-58.686, p<0.001). In the ear keloid subgroup, the 1-year, 3-year and 5-year local control rates for patients with pruritus were significantly lower than those without pain or pruritus (60.0% vs. 97.9%, 26.7% vs. 94.7%, 26.7% vs. 94.3%, HR:30.209, 95% CI:14.793-61.69, p<0.001). The same results were found in other location(p<0.001). During treatment and follow-up, two patients experienced infections, and one patient developed a cutaneous fibroblastoma. CONCLUSION: This study suggests that a combination of surgery followed by short-course, every-other-day radiotherapy can yield satisfactory local control rates for keloids. Pain and or pruritus symptom was an independently prognostic factors for recurrence of keloid. To further validate these results, a prospective randomized controlled trial is recommended.

Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Tricks and tracks of prevalence, occurrences, treatment technologies, and challenges of mixtures of emerging contaminants in the environment: With special emphasis on microplastic.

This paper aims to emphasize the occurrence of various emerging contaminant (EC) mixtures in natural ecosystems and highlights the primary concern arising from the unregulated release into soil and water, along with their impacts on human health. Emerging contaminant mixtures, including pharmaceuticals, personal care products, dioxins, polychlorinated biphenyls, pesticides, antibiotics, biocides, surfactants, phthalates, enteric viruses, and microplastics (MPs), are considered toxic contaminants with grave implications. MPs play a crucial role in transporting pollutants to aquatic and terrestrial ecosystems as they interact with the various components of the soil and water environments. This review summarizes that major emerging contaminants (ECs), like trimethoprim, diclofenac, sulfamethoxazole, and 17α-Ethinylestradiol, pose serious threats to public health and contribute to antimicrobial resistance. In addressing human health concerns and remediation techniques, this review critically evaluates conventional methods for removing ECs from complex matrices. The diverse physiochemical properties of surrounding environments facilitate the partitioning of ECs into sediments and other organic phases, resulting in carcinogenic, teratogenic, and estrogenic effects through active catalytic interactions and mechanisms mediated by aryl hydrocarbon receptors. The proactive toxicity of ECs mixture complexation and, in part, the yet-to-be-identified environmental mixtures of ECs represent a blind spot in current literature, necessitating conceptual frameworks for assessing the toxicity and risks with individual components and mixtures. Lastly, this review concludes with an in-depth exploration of future scopes, knowledge gaps, and challenges, emphasizing the need for a concerted effort in managing ECs and other organic pollutants.

Synthesis and characterization of microencapsulated paraffin with melamine-urea-formaldehyde shell modified with lignin.

The study aims to fabricate MUF/paraffin microcapsules with lignin nanoparticles (LNPs)/ melamine-urea-formaldehyde (MUF) resin as hybrid shell material with different LNPs addition were synthesized in oil-in-water emulsion stabilized synergistically by styrene/maleic anhydride (SMA) and LNPs. The morphological characterization of LNPs was observed by transmission electron microscopy (TEM). The particle size of LNPs, the mean particle size and ξ potentials of SMA/LNPs mixture at pH =4.5 were investigated by zeta potential measurement. Field emission scanning electron microscopy (FE-SEM), Fourier-transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), thermogravimetric analyzer (TGA), and differential scanning calorimetry (DSC) were characterized the morphologies, crystallography, chemical component, thermal stability and phase change properties of MUF/paraffin microcapsules with different LNPs addition. The results showed that MUF/paraffin microcapsules were spherical. The LNPs did not influence the chemical structure or crystal type of MUF/paraffin microcapsules. When the LNPs addition was 0.15 g, the melting enthalpy and crystallization enthalpy is respectively 130.03 and 121.92 J/g and the encapsulation efficiency of MicroC-15 is 61.04 %.

A blinded-endpoint, randomized controlled trial of Sanyrene with natural active ingredient for prophylaxis of radiation dermatitis in patients receiving radiotherapy.

BACKGROUND: Randomized controlled study was conducted to evaluate the efficacy of Sanyrene® vs. control intervention (DaBao®, a complex of hyaluronic acid and Vitamin E) for acute radiation dermatitis in patients receiving radiotherapy. METHODS: Patients with breast cancer or head and neck cancer undergoing radiotherapy (≥ 50 Gy) were eligible. Participants were randomly assigned to either Sanyrene arm or control intervention arm in a ratio of 1:1. The primary endpoint was incidence rate of ≥ grade 2 radiation induced dermatitis. (Trial Registration: ChiCTR2100050910, registration date: 9/7/2021) RESULTS: A total of 102 eligible patients were randomly assigned into the study. The rate of ≥ grade 2 radiation dermatitis was 22% in Sanyrene group, as compared with 67.3% in the control intervention group (P<0.001). The incidence of grade 3 radiation dermatitis was 20.4% and 8.0% in control intervention group and Sanyrene group, respectively (P = 0.076). Patients in Sanyrene group had a longer median time to reach ≥ grade 2 radiation dermatitis compared to these in control intervention group, with hazard ratio of 0.231 (95%CI:0.116-0.458, p < 0.001). Mean score of SD-16 were much higher in control intervention group than Sanyrene group at end of radiotherapy (25 vs.8.3), 2 weeks after radiotherapy (22.9 vs. 0.5) and 4 weeks after radiotherapy (4.2 vs.0), with significantly statistical difference between two groups. CONCLUSIONS: This trial suggests that Sanyrene is effective on preventing serious radiation dermatitis and improving skin related quality of life in patients with breast cancer or head and neck cancer receiving radiotherapy.

Effects of Processing Conditions on the Properties of Monoammonium Phosphate Microcapsules with Melamine-Formaldehyde Resin Shell.

To develop monoammonium phosphate (MAP) as a novel acid source for durable intumescent fire retardants (IFR), MAP microcapsules (MCMAPs) containing MAP as the internal core and melamine-formaldehyde (MF) as the external shell were prepared by in situ polymerization in this study. The influences of synthesis conditions (including reaction temperature, polymerization time, and reaction pH value) on the properties of obtained MCMAPs (MAP content, yield, morphologies, and thermal properties) were then investigated systematically. The morphologies, chemical structures, and thermal properties were characterized by optical microscopy, scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), Fourier transform infrared (FTIR) spectroscopy, and thermogravimetry analyzer (TGA). The results show that MAP was well encapsulated by MF resin. No microcapsules are obtained at <55 °C or with polymerization times <1 h. Optimal preparation conditions of reaction temperature, polymerization time, and reaction pH value are 75 °C, 3 h, and 5.5, respectively. Those results provide process reference and theoretical basis for preparing MCMAPs and could promote the application of MAP microcapsules in wood flame-retardant materials.

Characterization and commissioning of a new collaborative multi-modality radiotherapy platform.

TaiChi, a new multi-modality radiotherapy platform that integrates a linear accelerator, a focusing gamma system, and a kV imaging system within an enclosed O-ring gantry, was introduced into clinical application. This work aims to assess the technological characteristics and commissioning results of the TaiChi platform. The acceptance testing and commissioning were performed following the manufacturer's customer acceptance tests (CAT) and several AAPM Task Group (TG) reports/guidelines. Regarding the linear accelerator (linac), all applicable validation measurements recommended by the MPPG 5.a (basic photon beam model validation, intensity-modulated radiotherapy (IMRT)/volumetric-modulated arc therapy (VMAT) validation, end-to-end(E2E) tests, and patient-specific quality assurance (QA)) were performed. For the focusing gamma system, the absorbed doses were measured using a PTW31014 ion chamber (IC) and PTW60016 diode detector. EBT3 films and a PTW60016 diode detector were employed to measure the relative output factors (ROFs). The E2E tests were performed using PTW31014 IC and EBT3 films. The coincidences between the imaging isocenter and the linac/gamma mechanical isocenter were investigated using EBT3 films. The image quality was evaluated regarding the contrast-to-noise ratio (CNR), spatial resolution, and uniformity. All tests included in the CAT met the manufacturer's specifications. All MPPG 5.a measurements complied with the tolerances. The confidence limits for IMRT/VMAT point dose and dose distribution measurements were achieved according to TG-119. The point dose differences were below 1.68% and gamma passing rates (3%/2 mm) were above 95.1% for the linac E2E tests. All plans of patient-specific QA had point dose differences below 1.79% and gamma passing rates above 96.1% using the 3%/2 mm criterion suggested by TG-218. For the focusing gamma system, the differences between the calculated and measured absorbed doses were below 1.86%. The ROFs calculated by the TPS were independently confirmed within 2% using EBT3 films and a PTW60016 detector. The point dose differences were below 2.57% and gamma passing rates were above 95.3% using the 2%/1 mm criterion for the E2E tests. The coincidences between the imaging isocenter and the linac/gamma mechanical isocenter were within 0.5 mm. The image quality parameters fully complied with the manufacturer's specifications regarding the CNR, spatial resolution, and uniformity. The multi-modality radiotherapy platform complies with the CAT and AAPM commissioning criteria. The commissioning results demonstrate that this platform performs well in mechanical and dosimetry accuracy.

Therapeutic Evaluation of Induction Chemotherapy for Locoregionally Advanced Nasopharyngeal Carcinoma With Low-risk N Stage : A Multicenter Retrospective Study From Nonendemic Region of China.

OBJECTIVES: The role of induction chemotherapy (IC) remains ambiguous in a patient with T3-4N0-1 nasopharyngeal carcinoma (NPC) according to data from the endemic area of China. Here, we conducted a multicenter retrospective study to investigate the value of adding IC to concurrent chemoradiotherapy (CCRT) for T3-4N0-1 NPC from Northwest China. METHODS: Data were extracted in 3 hospitals from Northwest China between May 1, 2010 and August 30, 2018. The Kaplan-Meier method was used to estimate the endpoints. Survival curves were compared using the log-rank test. Initial propensity matching was conducted with a 1:1 match of IC + CCRT to CCRT. The primary endpoint of this study was overall survival (OS). RESULTS: A total of 108 patients with staging T3-4N0-1 were included in this study. The median follow-up time was 50 months (range: 6 to 118 months). IC followed by CCRT did not significantly improve OS compared with CCRT in the whole cohort (89.5% vs 77.6%, hazard ratio: 0.41, 95% CI: 0.16-1.04, P = 0.100). But significantly better OS was found when a well-balanced propensity score-matched cohort was analyzed. Adjusted 4-year OS was 89.5% for IC followed by CCRT versus 71.1% for CCRT (hazard ratio: 0.30, 95% CI: 0.11-0.80, P = 0.027). No significant differences were detected in side effects between the two groups. CONCLUSION: This study suggested IC followed by CCRT had the potential to further improve OS in patients with T3-4N0-1M0 NPC from Northwest China compared with CCRT. However, prospective studies with a large sample are warranted to confirm the results.

The epidemiological characteristics of neurogenic limb deformity disorder in China: a national-based study from Qin Sihe orthopedic center.

BACKGROUND: Neurogenic limb deformity disorder (NLDD) refers to limb deformity disorders caused by various neurogenic disorders. However, there are no studies to systematically summarize and analyze these diseases in China, and we first proposed the concept of NLDD. We describe the epidemiological characteristics of NLDD in China based on the largest case database of limb orthopedics in China. METHODS: This study analyzed parameters from the Qin Sihe Orthopedic Surgery Case Data (QSHOSCD). The database is based on the Rehabilitation Hospital affiliated to National Research Center for Rehabilitation, which has collected nearly 37,000 patients to date and includes a wide variety of limb deformities. The types of diseases are summarized and classified for all patients studied. Statistical analysis was based on the type of etiology, age, regional distribution, and historical surgical volume. Partial outcomes were statistically analyzed separately by common diseases (polio and cerebral palsy) and rare diseases (37 other diseases). RESULTS: From 1979 to 2019, 30,194 patients with NLDD were treated surgically for 39 neurogenic disorders. The male to female ratio was 1.48:1, the mean age was 19.65 years, and most patients (82.38%) were aged between 6 and 30 years. Patients included from 32 provinces and cities across China, mainly concentrated in populous central provinces and Heilongjiang Province. The peak of annual surgical procedures was from 1988 to 1994, and the number of annual surgical procedures for common diseases gradually decreased from 1994 onwards, but the trending is opposite for rare diseases. CONCLUSIONS: This study is the first to demonstrate the disease types, population characteristics and incidence trends of NLDD in China. It suggests that the prevention and treatment of NLDD should focus on the adolescent population and enhance the treatment of neurogenic diseases that cause limb deformities. The growth and adaption of the Ilizarov technique and its practice in Chinese orthopedic benefits the treatment of neurogenic limb deformity disorders.

Cadmium distribution and transformation in leaf cells involved in detoxification and tolerance in barley.

Barley is a diagnostic plant that often used in the research of soil pollution by heavy metals, our research explored the detoxification and tolerance mechanism of cadmium(Cd) in barley through pot experiment. We investigated subcellular distribution, chemical forms and oxidative damage of Cd in barley leaves, combing with the transmission electron microscopy and Fourier-transform infrared spectroscopy(FT-IR) to further understand the translocation, transformation characteristics and toxic effect of Cd in cells. The results showed that, the bioaccumulation factors in roots and shoots of barley were ranged of 4.03-7.48 and 0.51-1.30, respectively. Barley reduces the toxic effects by storing Cd in the roots and reducing its transport to the shoots. Compared to the control treatment (0 mg/kg), the percentage of Cd in the cell wall fractions of leaves in 300 mg/kg Cd treatment increased from 34.74 % to 38.41 %; the percentage of the organelle fractions increased from 24.47 % to 56.02 %; and the percentage of soluble fraction decreased from 40.80 % to 5.57 %. We found that 69.13 % of the highly toxic inorganic Cd and water-soluble Cd were converted to less toxic pectates and protein-integrated Cd (50.20 %) and undissolved Cd phosphates (18.93 %). This conversion of Cd was mainly due to its combination with -OH, -NH, -CN, -C-O-C, and -C-O-P groups. Excessive Cd induced a significant (P < 0.05) increase in the levels of peroxidase, malondialdehyde, and cell membrane permeability, which damaged the cell membrane and allowed Cd to enter the organelles. The chloroplasts and mitochondria were destroyed, and eventually the metabolism of intracellular substances was affected, resulting in symptoms of toxicity. Our research provides cellular-scale insight into the mechanisms of Cd tolerance in barley.

Low expression of microRNA-125b enhances the expression of STAT3 and contributes to cholesteatoma growth.

Introduction: MicroRNA-125b has been found to be down-regulated in many types of malignant tumours and diseases with excessive proliferation of keratinocytes, such as cutaneous squamous cell carcinoma and psoriasis. Cholesteatoma, which is mainly composed of keratinocytes, also has characteristics of abnormal proliferation similar to a malignant tumour. However, the expression and regulatory mechanisms of miR-125b and its downstream genes in cholesteatoma have not been clarified. Material and methods: Real time fluorescence quantitative PCR was applied to detect the expression of miR-125b in the cholesteatoma and corresponding retroauricular skin. Immunohistochemical staining and western blot were used to detect signal transducers and activators of transcription 3 (STAT3) and the downstream gene cyclin D1, survivin, and vascular endothelial growth factor (VEGF) in the cholesteatoma and corresponding retroauricular skin. The targeted regulatory relationship between miR-125b and STAT3 was confirmed by dual luciferase reporter assay. Proliferation and apoptosis of transfected HaCaT cells were detected by MTS, cell cycle, and apoptosis assays. Results: We observed down-regulation of miR-125b and up-regulation of STAT3, cyclin D1, survivin, and VEGF in cholesteatoma tissues. STAT3 was a direct target gene of miR-125b. Inhibition of miR-125b enhanced STAT3 and its downstream genes expression, promoted HaCaT cell proliferation, and inhibited apoptosis. Conclusions: The results of this study demonstrate that miR-125b can influence the growth of cholesteatoma by targeting STAT3 and its downstream genes, including cyclin D1, survivin, and VEGF, thus providing an opportunity to establish new medical therapy strategies and facilitating further study of the pathogenesis of cholesteatoma.

Final Overall Survival Analysis of Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma: A Multicenter, Randomized Phase III Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We previously reported significantly improved failure-free survival using gemcitabine plus cisplatin induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma. Here, we present the final overall survival (OS) analysis. In this multicenter, randomized trial, patients were assigned to be treated with concurrent chemoradiotherapy alone (standard therapy, n = 238) or gemcitabine and cisplatin induction chemotherapy before concurrent chemoradiotherapy (n = 242). With a median follow-up of 69.8 months, the induction chemotherapy group had a significantly higher 5-year OS (87.9% v 78.8%, hazard ratio, 0.51 [95% CI 0.34 to 0.78]; P = .001) and a comparable risk of late toxicities (≥ grade 3, 11.3% v 11.4%). Notably, the depth of the tumor response to induction chemotherapy correlated significantly and positively with survival (complete response v partial response v stable/progressive disease, 5-year OS, 100% v 88.4% v 61.5%, P = .005). Besides, patients with a low pretreatment cell-free Epstein-Barr virus DNA load (< 4,000 copies/mL) might not benefit from induction chemotherapy (5-year OS, 90.6% v 91.4%, P = .77). In conclusion, induction chemotherapy before concurrent chemoradiotherapy improved OS significantly in patients with locally advanced nasopharyngeal carcinoma, without increasing the risk of late toxicities. Tumor response to induction chemotherapy and pretreatment cell-free Epstein-Barr virus DNA might be useful to guide individualized treatment.

A New Nomogram for Predicting the Risk of Intracranial Hemorrhage in Acute Ischemic Stroke Patients After Intravenous Thrombolysis.

Background: We aimed to develop and validate a new nomogram for predicting the risk of intracranial hemorrhage (ICH) in patients with acute ischemic stroke (AIS) after intravenous thrombolysis (IVT). Methods: A retrospective study enrolled 553 patients with AIS treated with IVT. The patients were randomly divided into two cohorts: the training set (70%, n = 387) and the testing set (30%, n = 166). The factors in the predictive nomogram were filtered using multivariable logistic regression analysis. The performance of the nomogram was assessed based on the area under the receiver operating characteristic curve (AUC-ROC), calibration plots, and decision curve analysis (DCA). Results: After multivariable logistic regression analysis, certain factors, such as smoking, National Institutes of Health of Stroke Scale (NIHSS) score, blood urea nitrogen-to-creatinine ratio (BUN/Cr), and neutrophil-to-lymphocyte ratio (NLR), were found to be independent predictors of ICH and were used to construct a nomogram. The AUC-ROC values of the nomogram were 0.887 (95% CI: 0.842-0.933) and 0.776 (95% CI: 0.681-0.872) in the training and testing sets, respectively. The AUC-ROC of the nomogram was higher than that of the Multicenter Stroke Survey (MSS), Glucose, Race, Age, Sex, Systolic blood Pressure, and Severity of stroke (GRASPS), and stroke prognostication using age and NIH Stroke Scale-100 positive index (SPAN-100) scores for predicting ICH in both the training and testing sets (p < 0.05). The calibration plot demonstrated good agreement in both the training and testing sets. DCA indicated that the nomogram was clinically useful. Conclusions: The new nomogram, which included smoking, NIHSS, BUN/Cr, and NLR as variables, had the potential for predicting the risk of ICH in patients with AIS after IVT.

miR-139/PDE2A-Notch1 feedback circuit represses stemness of gliomas by inhibiting Wnt/ß-catenin signaling.

Rationale: The malignant phenotypes of glioblastomas (GBMs) are primarily attributed to glioma stem cells (GSCs). Our previous study and other reports have suggested that both miR-139 and its host gene PDE2A are putative antitumor genes in various cancers. The aim of this study was to investigate the roles and mechanisms of miR-139/PDE2A in GSC modulation. Methods: Clinical samples were used to determine miR-139/PDE2A expression. Patient-derived glioma stem-like cells (PD-GSCs) were stimulated for immunofluorescent staining, sphere formation assays and orthotopic GBM xenograft models. Bioinformatic analysis and further in vitro experiments demonstrated the downstream molecular mechanisms of miR-139 and PDE2A. OX26/CTX-conjugated PEGylated liposome (OCP) was constructed to deliver miR-139 or PDE2A into glioma tissue specifically. Results: We demonstrated that miR-139 was concomitantly transcribed with its host gene PDE2A. Both PDE2A and miR-139 indicated better prognosis of gliomas and were inversely correlated with GSC stemness. PDE2A or miR-139 overexpression suppressed the stemness of PD-GSCs. FZD3 and ß-catenin, which induced Wnt/ß-catenin signaling activation, were identified as targets of miR-139 and mediated the effects of miR-139 on GSCs. Meanwhile, PDE2A suppressed Wnt/ß-catenin signaling by inhibiting cAMP accumulation and GSK-3ß phosphorylation, thereby modulating the self-renewal of PD-GSCs. Notably, Notch1, which is also a target of miR-139, suppressed PDE2A/miR-139 expression directly via downstream Hes1, indicating that miR-139 promoted its own expression by the miR-139-Notch1/Hes1 feedback circuit. Expectedly, targeted overexpression miR-139 or PDE2A in glioma with OCP system significantly repressed the stemness and decelerated glioma progression. Conclusions: Our findings elaborate on the inhibitory functions of PDE2A and miR-139 on GSC stemness and tumorigenesis, which may provide new prognostic markers and therapeutic targets for GBMs.

Residual Volume of Lymph Nodes During Chemoradiotherapy Based Nomogram to Predict Survival of Nasopharyngeal Carcinoma Patient Receiving Induction Chemotherapy.

PURPOSE: To accurately stratify nasopharyngeal carcinoma (NPC) patients who were benefit from induction chemotherapy (IC) followed by chemoradiotherapy (CCRT), we established residual volume of lymph nodes during chemoradiotherapy based nomogram to predict survival for NPC patients. METHODS: Cox regression analysis were used to evaluate predictive effects of tumor volume parameters. Multivariate Cox regression analysis was used to identify the prognostic factors, and nomogram models were developed to predict survival of NPC patients receiving IC followed by CCRT. RESULTS: Compared with other tumor volumetric parameters, midRT GTVnd was the best predictive factor for OS (HR: 1.043, 95%CI: 1.031-1.055), PFS (HR: 1.040, 95%CI: 1.030- 1.051), and DMFS (HR: 1.046, 95%CI: 1.034 - 1.059) according to the HR of Cox regression analysis. Based on multivariate analysis, three nomograms included midRT GTVnd were constructed to predict 4-year survival. The C-index of nomograms for each survival endpoints were as follow (training cohort vs. validation cohort): 0.746 vs. 0.731 for OS; 0.747 vs. 0.735 for PFS; 0.768 vs. 0.729 for DMFS, respectively. AUC showed a good discriminative ability. Calibration curves demonstrated a consistence between actual results and predictions. Decision curve analysis (DCA) showed that the nomograms had better clinical predictive effects than current TNM staging system. CONCLUSION: We identified the best volumetric indicator associated with prognosis was the residual volume of lymph nodes at the fourth week of chemoradiotherapy for patients receiving IC followed by CCRT. We developed and validated three nomograms to predict specific probability of 4-year OS, PFS and DMFS for NPC patient receiving IC followed by CCRT.

Long-term survival outcomes and adverse effects of nasopharyngeal carcinoma patients treated with IMRT in a non-endemic region: a population-based retrospective study.

OBJECTIVES: To evaluate the long-term survival outcomes and adverse effects of intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC) and to summarise the experiences of IMRT in NPC in the past few decades in non-endemic northwest China. DESIGN: A population-based retrospective study. SETTING: An experience of using IMRT in non-endemic region of China. PARTICIPANTS: The study included 792 newly diagnosed and non-metastatic NPC patients who received IMRT from January 2006 to September 2018 in Xijing Hospital. OUTCOME MEASURES: The survival outcomes, adverse effects and failure patterns were evaluated by univariate, multivariate and subgroup analyses. RESULTS: With a median follow-up time of 46.2 months, the 5-year local recurrence-free survival, regional recurrence-free survival, distant metastasis-free survival, disease-free survival (DFS) and overall survival (OS) rates were 90.8%, 97.0%, 82.8%, 69.6% and 78.0%, respectively. Multivariate analysis showed that age, N stage, clinical stage, pathological type and primary tumour volume of more than 23 cm3 were the independent prognosis factors for DFS (all p<0.05); age, N stage, pathological type, cervical lymph node necrosis, and anaemia were significantly associated with OS (all p<0.05). The most common acute toxicities of IMRT were dermatitis, mucositis and dysphagia. Xerostomia and hearing impairment were the top two late toxicities. The main failure patterns were distant metastasis and local and/or regional relapses. CONCLUSIONS: Similar survival, toxicities and failure patterns have been observed in patients treated with IMRT in a non-endemic area of China when compared with that in endemic areas. Induction chemotherapy combined with concurrent chemoradiotherapy may benefit locally advanced NPC in non-endemic areas of China.

Detailed analysis of recovery process of cranial nerve palsy after IMRT-based comprehensive treatment in nasopharyngeal carcinoma.

BACKGROUND: Cranial nerve (CN) palsy due to cancer involvement has been considered as an unfavorable prognostic factor for patients with nasopharyngeal carcinoma (NPC). We assessed the role of IMRT based treatment on the recovery of CN palsy and investigated the prognostic value of complete recovery of CN palsy. METHODS: A total of 115 NPC patients with cancer-related CN palsy were included in the study. We referred CTCAE version 5.0 to evaluate the grade of CN palsy. RESULTS: All patients with grade 1 CN palsy recovered completely during the 2 years of follow-up after definite treatment. Most grade 2 palsy could change gradually to grade 1 palsy or complete recovery during 2 years of follow-up. Patients with more than 2 symptoms of CN palsy had poor 3-year disease-free survival (DFS) than these with 1 or 2 symptoms (60.3% vs. 84.9%, HR 0.25, 95% CI 0.07-0.89, P = 0.001). There were no significant differences for PFS, OS, DMFS and LRFS between patients with complete recovery and non-complete recovery from CN palsy after receiving IMRT based comprehensive treatment. CONCLUSIONS: IMRT based comprehensive treatment could effectively promote the recovery of tumor-related CN palsy for NPC patient. More than 2 symptoms of CN palsy was a poor prognostic factor for DFS of NPC patients. The prognostic role of complete recovery of CN palsy was not identified in our study.

Metronomic capecitabine as adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma: a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Patients with locoregionally advanced nasopharyngeal carcinoma have a high risk of disease relapse, despite a high proportion of patients attaining complete clinical remission after receiving standard-of-care treatment (ie, definitive concurrent chemoradiotherapy with or without induction chemotherapy). Additional adjuvant therapies are needed to further reduce the risk of recurrence and death. However, the benefit of adjuvant chemotherapy for nasopharyngeal carcinoma remains controversial, highlighting the need for more effective adjuvant treatment options. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was done at 14 hospitals in China. Patients (aged 18-65 years) with histologically confirmed, high-risk locoregionally advanced nasopharyngeal carcinoma (stage III-IVA, excluding T3-4N0 and T3N1 disease), no locoregional disease or distant metastasis after definitive chemoradiotherapy, an Eastern Cooperative Oncology Group performance status of 0 or 1, sufficient haematological, renal, and hepatic function, and who had received their final radiotherapy dose 12-16 weeks before randomisation, were randomly assigned (1:1) to receive either oral metronomic capecitabine (650 mg/m2 body surface area twice daily for 1 year; metronomic capecitabine group) or observation (standard therapy group). Randomisation was done with a computer-generated sequence (block size of four), stratified by trial centre and receipt of induction chemotherapy (yes or no). The primary endpoint was failure-free survival, defined as the time from randomisation to disease recurrence (distant metastasis or locoregional recurrence) or death due to any cause, in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of capecitabine or who had commenced observation. This trial is registered with ClinicalTrials.gov, NCT02958111. FINDINGS: Between Jan 25, 2017, and Oct 25, 2018, 675 patients were screened, of whom 406 were enrolled and randomly assigned to the metronomic capecitabine group (n=204) or to the standard therapy group (n=202). After a median follow-up of 38 months (IQR 33-42), there were 29 (14%) events of recurrence or death in the metronomic capecitabine group and 53 (26%) events of recurrence or death in the standard therapy group. Failure-free survival at 3 years was significantly higher in the metronomic capecitabine group (85·3% [95% CI 80·4-90·6]) than in the standard therapy group (75·7% [69·9-81·9]), with a stratified hazard ratio of 0·50 (95% CI 0·32-0·79; p=0·0023). Grade 3 adverse events were reported in 35 (17%) of 201 patients in the metronomic capecitabine group and in 11 (6%) of 200 patients in the standard therapy group; hand-foot syndrome was the most common adverse event related to capecitabine (18 [9%] patients had grade 3 hand-foot syndrome). One (<1%) patient in the metronomic capecitabine group had grade 4 neutropenia. No treatment-related deaths were reported in either group. INTERPRETATION: The addition of metronomic adjuvant capecitabine to chemoradiotherapy significantly improved failure-free survival in patients with high-risk locoregionally advanced nasopharyngeal carcinoma, with a manageable safety profile. These results support a potential role for metronomic chemotherapy as an adjuvant therapy in the treatment of nasopharyngeal carcinoma. FUNDING: The National Natural Science Foundation of China, the Key-Area Research and Development Program of Guangdong Province, the Natural Science Foundation of Guangdong Province, the Innovation Team Development Plan of the Ministry of Education, and the Overseas Expertise Introduction Project for Discipline Innovation. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

The miR-136-5p/ROCK1 axis suppresses invasion and migration, and enhances cisplatin sensitivity in head and neck cancer cells.

Laryngeal squamous cell carcinoma (LSCC) and hypopharyngeal squamous cell carcinoma (HPSCC) are two types of head and neck cancers with high incidence rates and relatively poor prognoses. The aim of the present study was to determine the effects of microRNA (miR/miRNA)-136-5p and its downstream target, Rho-associated coiled-coil containing protein kinase 1 (ROCK1), on LSCC and HPSCC progression and cisplatin sensitivity. The miRNA and protein expression levels in head and neck cancer cell lines were evaluated using reverse transcription-quantitative PCR and western blotting, respectively. MTT, wound healing assays, transwell assays and flow cytometry analysis were performed to measure cell properties. The binding between miR-136-5p and ROCK1 was detected using a dual-luciferase reporter assay. Autophagy double-labeled adenoviral infection assays were used to assess cell autophagy. The results showed that miR-136-5p was expressed in LSCC and HPSCC cells. Functional experiments showed that the expression of miR-136-5p in LSCC and HPSCC cells was negatively correlated with cell viability, invasion and migration. Additionally, miR-136-5p overexpression inhibited epithelial-mesenchymal transition, whereas miR-136-5p knockdown had the opposite effect. Dual-luciferase reporter assays confirmed the targeting relationship between miR-136-5p and ROCK1. miR-136-5p overexpression increased the cisplatin sensitivity of LSCC and HPSCC cells by reducing cell viability, as well as promoting cell apoptosis and autophagy. miR-136-5p overexpression decreased the expression levels of its downstream target ROCK1 and attenuated activity of the Akt/mTOR signaling pathway in cisplatin-treated LSCC and HPSCC cells. Conversely, miR-136-5p knockdown increased ROCK1 levels and decreased cisplatin sensitivity of the LSCC and HPSCC cells by increasing cell viability and inhibiting cell apoptosis, which was reversed by ROCK1 inhibition using the ROCK1 inhibitor, Y27632. Taken together, the results showed that the miR-136-5p/ROCK1 axis inhibits cell invasion and migration, and increases the sensitivity of LSCC and HPSCC cells to cisplatin.