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.

Systematic identification and characterization of microRNAs with target genes involved in high night temperature stress at the filling stage of rice.

High night temperature stress is one of the main environmental factors affecting rice yield and quality. More and more evidence shows that microRNA (miRNA) plays an important role in various abiotic stresses. However, the molecular network of miRNA regulation on rice tolerance to high night temperatures remains unclear. Here, small RNA, transcriptome and degradome sequencing were integrated to identify differentially expressed miRNAs, genes, and key miRNA-target gene pairs in rice heat-sensitive and heat-tolerant lines at the filling stage suffering from high night temperature stress. It was discovered that there were notable differences in the relative expression of 102 miRNAs between the two rice lines under stress. Meanwhile, 5263 and 5405 mRNAs were differentially expressed in the heat-sensitive line and heat-tolerant line, and functional enrichment analysis revealed that these genes were involved in heat-related processes and pathways. The miRNAs-mRNAs target relationship was further verified by degradome sequencing. Eventually, 49 miRNAs-222 mRNAs target pairs with reverse expression patterns showed significant relative expression changes between the heat-tolerant and the heat-sensitive line, being suggested to be responsible for the heat tolerance difference of these two rice lines. Functional analysis of these 222 mRNA transcripts showed that high night temperature-responsive miRNAs targeted these mRNAs involved in many heat-related biological processes, such as transcription regulation, chloroplast regulation, mitochondrion regulation, protein folding, hormone regulation and redox process. This study identified possible miRNA-mRNA regulation relationships in response to high night temperature stress in rice and potentially contributed to heat resistance breeding of rice in the future.

Study on a Pig Vocalization Classification Method Based on Multi-Feature Fusion.

To improve the classification of pig vocalization using vocal signals and improve recognition accuracy, a pig vocalization classification method based on multi-feature fusion is proposed in this study. With the typical vocalization of pigs in large-scale breeding houses as the research object, short-time energy, frequency centroid, formant frequency and first-order difference, and Mel frequency cepstral coefficient and first-order difference were extracted as the fusion features. These fusion features were improved using principal component analysis. A pig vocalization classification model with a BP neural network optimized based on the genetic algorithm was constructed. The results showed that using the improved features to recognize pig grunting, squealing, and coughing, the average recognition accuracy was 93.2%; the recognition precisions were 87.9%, 98.1%, and 92.7%, respectively, with an average of 92.9%; and the recognition recalls were 92.0%, 99.1%, and 87.4%, respectively, with an average of 92.8%, which indicated that the proposed pig vocalization classification method had good recognition precision and recall, and could provide a reference for pig vocalization information feedback and automatic recognition.

Hyperoside ameliorates cerebral ischaemic-reperfusion injury by opening the TRPV4 channel in vivo through the IP3-PKC signalling pathway.

CONTEXT: Hyperoside (Hyp), one of the active flavones from Rhododendron (Ericaceae), has beneficial effects against cerebrovascular disease. However, the effect of Hyp on vasodilatation has not been elucidated. OBJECTIVE: To explore the effect of Hyp on vasodilatation in the cerebral basilar artery (CBA) of Sprague-Dawley (SD) rats suffering with ischaemic-reperfusion (IR) injury. MATERIALS AND METHODS: Sprague-Dawley rats were randomly divided into sham, model, Hyp, Hyp + channel blocker and channel blocker groups. Hyp (50 mg/kg, IC50 = 18.3 µg/mL) and channel blocker were administered via tail vein injection 30 min before ischaemic, followed by 20 min of ischaemic and 2 h of reperfusion. The vasodilation, hyperpolarization, ELISA assay, haematoxylin-eosin (HE), Nissl staining and channel-associated proteins and qPCR were analysed. Rat CBA smooth muscle cells were isolated to detect the Ca2+ concentration and endothelial cells were isolated to detect apoptosis rate. RESULTS: Hyp treatment significantly ameliorated the brain damage induced by IR and evoked endothelium-dependent vasodilation rate (47.93 ± 3.09% vs. 2.99 ± 1.53%) and hyperpolarization (-8.15 ± 1.87 mV vs. -0.55 ± 0.42 mV) by increasing the expression of IP3R, PKC, transient receptor potential vanilloid channel 4 (TRPV4), IKCa and SKCa in the CBA. Moreover, Hyp administration significantly reduced the concentration of Ca2+ (49.08 ± 7.74% vs. 83.52 ± 6.93%) and apoptosis rate (11.27 ± 1.89% vs. 23.44 ± 2.19%) in CBA. Furthermore, these beneficial effects of Hyp were blocked by channel blocker. DISCUSSION AND CONCLUSIONS: Although Hyp showed protective effect in ischaemic stroke, more clinical trial certification is needed due to the difference between animals and humans.

[Mechanism of total flavonoids of Rhododendra simsii in alleviating ischemic brain injury].

This study explores the effect of total flavonoids of Rhododendra simsii(TFR) on middle cerebral artery occlusion(MCAO)-induced cerebral injury in rats and oxygen-glucose deprivation/reoxygenation(OGD/R) injury in PC12 cells and the underlying mechanism. The MCAO method was used to induce focal ischemic cerebral injury in rats. Male SD rats were randomized into sham group, model group, and TFR group. After MCAO, TFR(60 mg·kg~(-1)) was administered for 3 days. The content of tumor necrosis factor-α(TNF-α), interleukin-1(IL-1), and interleukin-6(IL-6) in serum was detected by enzyme-linked immunosorbent assay(ELISA). The pathological changes of brain tissue and cerebral infarction were observed based on hematoxylin and eosin(HE) staining and 2,3,5-triphenyltetrazolium chloride(TTC) staining. RT-qPCR and Western blot were used to detect the mRNA and protein levels of calcium release-activated calcium channel modulator 1(ORAI1), stromal interaction molecule 1(STIM1), stromal intera-ction molecule 2(STIM2), protein kinase B(PKB), and cysteinyl aspartate specific proteinase 3(caspase-3) in brain tissues. The OGD/R method was employed to induce injury in PC12 cells. Cells were randomized into the normal group, model group, gene silencing group, TFR(30 µg·mL~(-1)) group, and TFR(30 µg·mL~(-1))+gene overexpression plasmid group. Intracellular Ca~(2+) concentration and apoptosis rate of PC12 cells were measured by laser scanning confocal microscopy and flow cytometry. The effect of STIM-ORAI-regulated store-operated calcium entry(SOCE) pathway on TFR was explored based on gene silencing and gene overexpression techniques. The results showed that TFR significantly alleviated the histopathological damage of brains in MCAO rats after 3 days of admini-stration, reduced the contents of TNF-α, IL-1, and IL-6 in the serum, down-regulated the expression of ORAI1, STIM1, STIM2, and caspase-3 genes, and up-regulated the expression of PKB gene in brain tissues of MCAO rats. TFR significantly decreased OGD/R induced Ca~(2+) overload and apoptosis in PC12 cells. However, it induced TFR-like effect by ORAI1, STIM1 and STIM2 genes silencing. However, overexpression of these genes significantly blocked the effect of TFR in reducing Ca~(2+) overload and apoptosis in PC12 cells. In summary, in the early stage of focal cerebral ischemia-reperfusion injury and OGD/R-induced injury in PC12 cells TFR attenuates ischemic brain injury by inhibiting the STIM-ORAI-regulated SOCE pathway and reducing Ca~(2+) overload and inflammatory factor expression, and apoptosis.

[Protective effect of total flavonoids of Rhododendron simsii on focal cerebral ischemia-reperfusion injury through SOCE pathway in rats].

This paper explored the protective effect of total flavonoids of Rhododendron simsii(TFR) on focal cerebral ischemia-reperfusion injury(CIRI) in rats and its relationship with the store-operated calcium entry(SOCE) pathway regulated by stromal intera-ction molecule(STIM) and calcium release-activated calcium modulator(Orai).Rats were randomly assigned into the sham group, model(middle cerebral artery occlusion, MCAO) group, TFR(60 mg·kg~(-1)) group, TFR(60 mg·kg~(-1))+SOCE pathway inhibitor 2-aminoethoxydiphenyl borate(2-APB, 2.5 mg·kg~(-1)) group, and 2-APB(2.5 mg·kg~(-1)) group.The rats in the sham group and MCAO group were administrated with normal saline, and those in the TFR group and TFR+2-APB group were administrated with TFR(60 mg·kg~(-1)) by gavage for 14 days until sampling.The rats in the 2-APB group and TFR+2-APB group were intraperitoneally injected with 2-APB(2.5 mg·kg~(-1)) after operation.The levels of interleukin-1(IL-1), interleukin-6(IL-6), and tumor necrosis factor-alpha(TNF-α) in serum were measured by ELISA.The cerebral infarction and the pathological status of ischemic brain tissue were detected via TTC staining and HE staining, respectively.The protein and mRNA levels of STIM1, STIM2, Orai1, cysteinyl aspartate specific proteinase 3(caspase-3), and protein kinase B(PKB) in brain tissue were respectively determined by Western blot and RT-qPCR.The growth of brain neurons in each group was observed via immunofluorescence method.The results showed that compared with the MCAO group, TFR lowered the levels of IL-1, IL-6 and TNF-α in serum and the score of neurological function, ameliorated the pathological injury of brain tissue, and decreased the infarct size.Moreover, TFR up-regulated the mRNA and protein levels of STIM1, STIM2, Orai1, and PKB, down-regulated those of caspase-3 in brain tissue, and increased the double-labeled positive cells under fluorescence microscope.However, the above effects were significantly weakened by the addition of 2-APB, a SOCE inhibitor.The results suggested that TFR may play a protective role against focal cerebral ischemia-reperfusion injury by up-regulating the expression of SOCE-related signal molecules, promoting neurogenesis around the ischemic area, improving the survival state of neurons, and redu-cing the activity of inflammatory mediators.

[Clinical Investigation of Key Parameter Range of AMG Muscle Relaxant Monitor].

The accelerometry(AMG) muscle relaxant monitor is the most widely used quantitative muscle relaxant monitor to assess the degree of neuromuscular at present. In this study, the ulnar nerve was stimulated by using train of four stimulation(TOF) mode of the AMG muscle relaxant monitor, and the movement of the adductor pollicis muscle was monitored. In this way, the distribution range of key parameters (acceleration peak value, response time, and TOF ratio) of the adductor pollicis muscle during the use of muscle relaxant in clinical practice is analyzed and will provide a practical basis for the development and improvement of the muscle relaxant monitor.

Induction chemotherapy with lobaplatin and fluorouracil versus cisplatin and fluorouracil followed by chemoradiotherapy in patients with stage III-IVB nasopharyngeal carcinoma: an open-label, non-inferiority, randomised, controlled, phase 3 trial.

BACKGROUND: Cisplatin-based induction chemotherapy plus concurrent chemoradiotherapy in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma has been recommended in the National Comprehensive Cancer Network Guidelines. However, cisplatin is associated with poor patient compliance and has notable side-effects. Lobaplatin, a third-generation platinum drug, has shown promising antitumour activity against several malignancies with less toxicity. In this study, we aimed to evaluate the efficacy of lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy over a cisplatin-based regimen in patients with locoregional, advanced nasopharyngeal carcinoma. METHODS: In this open-label, non-inferiority, randomised, controlled, phase 3 trial done at five hospitals in China, patients aged 18-60 years with previously untreated, non-keratinising stage III-IVB nasopharyngeal carcinoma; Karnofsky performance-status score of at least 70; and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either lobaplatin-based (lobaplatin 30 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1-5 and 22-26 for two cycles) or cisplatin-based (cisplatin 100 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1-5 and 22-26 for two cycles) induction chemotherapy, followed by concurrent lobaplatin-based (two cycles of intravenous lobaplatin 30 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) or cisplatin-based (two cycles of intravenous cisplatin 100 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) chemoradiotherapy. Total radiation doses of 68-70 Gy (for the sum of the volumes of the primary tumour and enlarged retropharyngeal nodes), 62-68 Gy (for the volume of clinically involved gross cervical lymph nodes), 60 Gy (for the high-risk target volume), and 54 Gy (for the low-risk target volume), were administered in 30-32 fractions, 5 days per week. Randomisation was done centrally at the clinical trial centre of Sun Yat-sen University Cancer Centre by means of computer-generated random number allocation with a block design (block size of four) stratified according to disease stage and treatment centre. Treatment assignment was known to both clinicians and patients. The primary endpoint was 5-year progression-free survival, analysed in both the intention-to-treat and per-protocol populations. If the upper limit of the 95% CI for the difference in 5-year progression-free survival between the lobaplatin-based and cisplatin-based groups did not exceed 10%, non-inferiority was met. Adverse events were analysed in all patients who received at least one cycle of induction chemotherapy. This trial is registered with the Chinese Clinical Trial Registry, ChiCTR-TRC-13003285 and is closed. FINDINGS: From June 7, 2013, to June 16, 2015, 515 patients were assessed for eligibility and 502 patients were enrolled: 252 were randomly assigned to the lobaplatin-based group and 250 to the cisplatin-based group. After a median follow-up of 75·3 months (IQR 69·9-81·1) in the intention-to-treat population, 5-year progression-free survival was 75·0% (95% CI 69·7-80·3) in the lobaplatin-based group and 75·5% (70·0 to 81·0) in the cisplatin-based group (hazard ratio [HR] 0·98, 95% CI 0·69-1·39; log-rank p=0·92), with a difference of 0·5% (95% CI -7·1 to 8·1; pnon-inferiority=0·0070). In the per-protocol population, the 5-year progression-free survival was 74·8% (95% CI 69·3 to 80·3) in the lobaplatin-based group and 76·4% (70·9 to 81·9) in the cisplatin-based group (HR 1·04, 95% CI 0·73 to 1·49; log-rank p=0·83), with a difference of 1·6% (-6·1 to 9·3; pnon-inferiority=0·016). 63 (25%) of 252 patients in the lobaplatin-based group and 63 (25%) of 250 patients in the cisplatin-based group had a progression-free survival event in the intention-to-treat population; 62 (25%) of 246 patients in the lobaplatin-based group and 58 (25%) of 237 patients in the cisplatin-based group had a progression-free survival event in the per-protocol population. The most common grade 3-4 adverse events were mucositis (102 [41%] of 252 in the lobaplatin-based group vs 99 [40%] of 249 in the cisplatin-based group), leucopenia (39 [16%] vs 56 [23%]), and neutropenia (25 [10%] vs 59 [24%]). No treatment-related deaths were reported. INTERPRETATION: Lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy resulted in non-inferior survival and fewer toxic effects than cisplatin-based therapy. The results of our trial indicate that lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy might be a promising alternative regimen to cisplatin-based treatment in patients with locoregional, advanced nasopharyngeal carcinoma. FUNDING: National Science and Technology Pillar Program, International Cooperation Project of Science and Technology Program of Guangdong Province, Planned Science and Technology Project of Guangdong Province, and Cultivation Foundation for the Junior Teachers at Sun Yat-sen University. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Two Metal Complexes: Selective Detection of Fe3+ Ion and Promotion Activity on Mesenchymal Stem Cells Differentiate Into Vascular Endothelial Cells.

With the aid of 1,2-bis(4-pyridyl)ethane (bpee), a nitrogen-donor ligand and 1,3,5-tris(carboxymethoxy)benzene (H3TCMB), a tripodal ether-connector tricarboxylate ligand, two novel transition metal coordination polymers (CPs) have been synthesized via the reaction of Zn(NO3)2·6H2O or Cu(NO3)2·3H2O with the ligands of H3TCMB and bpee ligands with similar reactions under slightly distinct temperatures (80℃ for 1 and 120℃ for 2), and their chemical formula are [Cu4(TCMB)2(bpee)2(µ3-OH)2(H2O)2]n·12nH2O (1) and [Zn4(TCMB)2(bpee)2(µ3-OH)2(H2O)2]n·12nH2O (2). Complex 2 can be utilized as a super sensitive fluorescence quenching sensor to determine the Fe3+ ions. The effect of these two compounds on the differentiation of mesenchymal stem cells (MSCs) into the cells of vascular endothelial was further explored.

Molecular epidemiology of Bordetella pertussis and analysis of vaccine antigen genes from clinical isolates from Shenzhen, China.

BACKGROUND: Although pertussis cases globally have been controlled through the Expanded Programme on Immunization (EPI), the incidence of pertussis has increased significantly in recent years, with a "resurgence" of pertussis occurring in developed countries with high immunization coverage. Attracted by its fast-developing economy, the population of Shenzhen has reached 14 million and has become one of the top five largest cities by population size in China. The incidence of pertussis here was about 2.02/100,000, far exceeding that of the whole province and the whole country (both < 1/100,000). There are increasing numbers of reports demonstrating variation in Bordetella pertussis antigens and genes, which may be associated with the increased incidence. Fifty strains of Bordetella pertussis isolated from 387 suspected cases were collected in Shenzhen in 2018 for genotypic and molecular epidemiological analysis. METHODS: There were 387 suspected cases of pertussis enrolled at surveillance sites in Shenzhen from June to August 2018. Nasopharyngeal swabs from suspected pertussis cases were collected for bacterial culture and the identity of putative Bordetella pertussis isolates was confirmed by real-time PCR. The immunization history of each patient was taken. The acellular pertussis vaccine (APV) antigen genes for pertussis toxin (ptxA, ptxC), pertactin (prn) and fimbriae (fim2 and fim3) together with the pertussis toxin promoter region (ptxP) were analyzed by second-generation sequencing. Genetic and phylogenetic analysis was performed using sequences publicly available from GenBank, National Institutes of Health, Bethesda, MD, USA ( https://www.ncbi.nlm.nih.gov/genbank/ ). The antimicrobial susceptibility was test by Kirby-Bauer disk diffusion. RESULTS: Fifty strains of Bordetella pertussis were successfully isolated from nasopharyngeal swabs of 387 suspected cases, with a positivity rate of 16.79%, including 28 males and 22 females, accounting for 56.0% and 44.0% respectively. Thirty-eight of the 50 (76%) patients were found to be positive for B. pertussis by culture. Among the positive cases with a history of vaccination, 30 of 42 (71.4%) cases had an incomplete pertussis vaccination history according to the national recommendation. Three phylogenetic groups (PG1-PG3) were identified each containing a predominant genotype. The two vaccines strains, CS and Tohama I, were distantly related to these three groups. Thirty-one out of fifty (62%) isolates belonged to genotype PG1, with the allelic profile prn2/ptxC2/ptxP3/ptxA1/fim3-1/fim2-1. Eighteen out of fifty (36%) isolates contained the A2047G mutation and were highly resistant to erythromycin, and all belonged to genotype PG3 (prn1/ptxA1/ptxP1/ptxC1/fim3-1/fim2-1), which is closely related to the recent epidemic strains found in northern China. CONCLUSIONS: The positive rate of cases under one-year-old was significantly higher than that of other age groups and should be monitored. The dominant antigen genotypes of 50 Shenzhen isolates are closely related to the epidemic strains in the United States, Australia and many countries in Europe. Despite high rates of immunization with APV, epidemics of pertussis have recently occurred in these countries. Therefore, genomic analysis of circulating isolates of B. pertussis should be continued, for it will benefit the control of whooping cough and development of improved vaccines and therapeutic strategies.

EGFR-PKM2 signaling promotes the metastatic potential of nasopharyngeal carcinoma through induction of FOSL1 and ANTXR2.

Nasopharyngeal carcinoma (NPC) is notorious for its aggressiveness and high metastatic potential. NPC patients with distant metastasis have a particularly poor prognosis; however, evaluating metastatic potential by expression profiles of primary tumors is challenging. This study aimed to investigate the association between activation of epidermal growth factor receptor (EGFR) signaling and NPC metastasis and the underlying mechanisms. We found an association between EGFR protein overexpression and intense EGFR immunostaining in NPC samples with advanced tumor node metastasis stage, clinical stage, and distant metastasis in NPC patients. Exogenous EGF stimulates NPC mobility and invasiveness in vitro. Activation of EGFR signaling prompted PKM2 translocation to the nucleus. Silencing either EGFR or PKM2 attenuates NPC cell aggressiveness in vitro and in vivo. Blocking EGFR signaling with cetuximab suppressed NPC cell invasiveness in vitro and metastatic potential in vivo. Comprehensive analyses of transcriptome profiles indicated that the EGFR-PKM2 axis activates a number of novel metastasis promoters, including F3, FOSL1, EPHA2, ANTXR2, and AKR1C2. Finally, we found that the metastasis-promoting function of the EGFR-PKM2 axis is dependent on nuclear PKM2 regulation of the transcription of metastasis-related genes, including FOSL1 and ANTXR2. Our study indicates that EGFR-PKM2 signaling promotes NPC cell invasion and metastasis through induction of FOSL1 and ANTXR2 and identifies EGFR as a promising biomarker for predicting the risk of distant metastasis.

Ulinastatin Inhibits the Formation and Progression of Experimental Abdominal Aortic Aneurysms.

AIMS: Aortic mural inflammatory damage takes a vital part in abdominal aortic aneurysm (AAA). Recently, ulinastatin (UTI) has attracted attention for its anti-inflammatory function. Our study aimed to evaluate potential influences of UTI on experimental AAA. METHODS: A mouse model of AAA was induced by infusion of porcine pancreatic elastase (PPE) into the abdominal aorta. Mice were treated with UTI (50,000 U/kg/day i.p.) beginning either immediately or on the 4th day after PPE infusion, with treatment being continued until the 14th day. UTI effects were assessed by aortic diameter measurements and aortic histopathological analysis. RESULTS: Significant and time-dependent aortic diameter enlargement persisted in the control mice from day 0. In the UTI group, aortic diameter increased, and depletion of aortic mural smooth muscle cells and elastin was significantly -attenuated. Simultaneously, mural CD68+ macrophages, CD8+ T-cell and B220+ B-cell density, as well as neoangiogenesis were suppressed by UTI. In addition, delayed UTI treatment could still effectively limit aneurysm expansion. CONCLUSIONS: UTI treatment limits the formation and growth of experimental AAA, and UTI may be a potential treatment for early AAA disease.

Feature Extraction and Mapping Construction for Mobile Robot via Ultrasonic MDP and Fuzzy Model.

This paper presents a modeling approach to feature classification and environment mapping for indoor mobile robotics via a rotary ultrasonic array and fuzzy modeling. To compensate for the distance error detected by the ultrasonic sensor, a novel feature extraction approach termed "minimum distance of point" (MDP) is proposed to determine the accurate distance and location of target objects. A fuzzy model is established to recognize and classify the features of objects such as flat surfaces, corner, and cylinder. An environmental map is constructed for automated robot navigation based on this fuzzy classification, combined with a cluster algorithm and least-squares fitting. Firstly, the platform of the rotary ultrasonic array is established by using four low-cost ultrasonic sensors and a motor. Fundamental measurements, such as the distance of objects at different rotary angles and with different object materials, are carried out. Secondly, the MDP feature extraction algorithm is proposed to extract precise object locations. Compared with the conventional range of constant distance (RCD) method, the MDP method can compensate for errors in feature location and feature matching. With the data clustering algorithm, a range of ultrasonic distances is attained and used as the input dataset. The fuzzy classification model-including rules regarding data fuzzification, reasoning, and defuzzification-is established to effectively recognize and classify the object feature types. Finally, accurate environment mapping of a service robot, based on MDP and fuzzy modeling of the measurements from the ultrasonic array, is demonstrated. Experimentally, our present approach can realize environment mapping for mobile robotics with the advantages of acceptable accuracy and low cost.

Down-regulation of TCF21 by hypermethylation induces cell proliferation, migration and invasion in colorectal cancer.

Epigenetic alteration induced loss function of the transcription factor 21 (TCF21) has been associated with different types of human cancers. However, the epigenetic regulation and molecular functions of TCF21 in colorectal cancer (CRC) remain unknown. In this study, TCF21 expression levels and methylation status of its promoter region in CRC cell lines (n = 5) and CRC tissues (n = 151) as well as normal colorectal mucosa (n = 30) were assessed by RTq-PCR and methylation analysis (methylation specific PCR, MSP and bisulfite sequencing PCR, BSP), respectively. The cellular functions of TCF21 on CRC cell proliferation, apoptosis, invasion and migration were investigated in vitro. Our data revealed that TCF21 was frequently silenced by promoter hypermethylation in both tested CRC cell lines and primary CRC, and correlation analysis between methylation status and clinicopathologic parameters found that TCF21 methylation was significantly correlated with lymph node invasion (P = 0.013), while no significant correlation was found in other parameters. In addition, demethylation treatment resulted in re-expression of TCF21 in CRC cell lines, and cellular function experiments revealed that restoration of TCF21 inhibited CRC cell proliferation, promoted apoptosis and suppressed cell invasion and migration, suggesting that TCF21 may function as a tumor suppressor gene, which is downregulated through promoter hypermethylation in CRC development.

Prognostic value of the distance between the primary tumor and brainstem in the patients with locally advanced nasopharyngeal carcinoma.

BACKGROUND: Brainstem dose limitations influence radiation dose reaching to tumor in the patients with locally-advanced nasopharyngeal cancer (NPC). METHODS: A retrospective analysis of the prognostic value of the distance between the primary tumor and brainstem (Dbs) in 358 patients with locally-advanced NPC after intensity-modulated radiation therapy (IMRT). Receiver operating characteristic (ROC) curves were used to identify the cut-off value to analyze the impact of Dbs on tumor dose coverage and prognosis. RESULTS: The three-year overall survival (OS), local relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and disease-free survival (DFS) were 88.8 vs. 78.4% (P = 0.007), 96.5 vs. 91.1% (P = 0.018), 87.8 vs. 79.3% (P = 0.067), and 84.1 vs. 69.6% (P = 0.002) for the patients with the Dbs > 4.7 vs. ≤ 4.7 mm, respectively. ROC curves revealed Dbs (4.7 mm) combined with American Joint Committee on Cancer (AJCC) T classification had a significantly better prognostic value for OS (P < 0.05). CONCLUSIONS: Dbs (≤ 4.7 mm) is an independent negative prognostic factor for OS/LRFS/DFS and enhances the prognostic value of T classification in the patients with locally-advanced NPC.

[Genetic abnormality in 101 cases of plasma cell dyscrasias by FISH technology and cytogenetic examination].

OBJECTIVE: To investigate several abnormal genes by the fluorescence in situ hybridization (FISH) in multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS) and reactive plasmacytosis (RP), and to increase the diagnosis and differential diagnosis levels for these common plasma diseases. 
 METHODS: The clinical manifestations, image and laboratory tests and the FISH detection were retrospectively analyzed in 61 cases of newly diagnosed MM, 20 cases of MGUS and 20 cases of RP from August, 2012 to February, 2015 in the Xiangya Hospital of Central South University. 
 RESULTS: Fifty cases among 61 MM patients showed genetic abnormality by FISH technology. The total positive rate was 81.9%. Among them, 19 cases (31.1%) had 1q21 amplification, 18 cases (29.5%) lacked D13S319, 10 cases (16.4%) missed RB1, 10 cases (16.4%) had IGH translocation and 7 cases (11.4%) lacked p53 gene. The positive rate for two or more genes abnormal was 19.8% in 12 cases. However, in 20 cases of MGUS patients, the positive detection rate was 25%, including 4 cases (20%) of 1q21 augmentation and 2 cases (10%) of IGH translocation. There were not two or more abnormal genes in one case. While in RP cases, only 1 case of patients had D13S319 abnormal gene, and the positive rate was only 5%. There was significant difference (P<0.05) among the 3 groups. 
 CONCLUSION: The positive detection rate is 81.9% in MM patients by FISH, which is significantly higher than that in patients with MGUS or RP. FISH technology can detect a variety of abnormal genes in MM. It is useful for the differential diagnosis and prognosis for MM, MGUS and RP.

Association of miR-146a gene polymorphism with risk of nasopharyngeal carcinoma in the central-southern Chinese population.

This case-control study focused on estimating the association between miR-146a polymorphism and risk of nasopharyngeal carcinoma (NPC) in central-south China. In total, 160 patients with NPC and 200 healthy controls in central-south China were genotyped using polymerase chain reaction-restriction fragment length polymorphism assay. Chi-square test was used to assess the different distribution of miR-146a polymorphism between NPC patients and controls; and logistic regression analysis was applied to analyze the associations between miR-146a polymorphism with cancer risk in different contrast models. Significant differences between NPC patients and controls were found in genotype (P=0.033 for GG versus CG versus CC; and odds ratio (OR)=0.568, 95% confidence interval (CI)=0.354-0.912, P=0.019 for CG versus CC; and OR=0.503, 95% CI=0.261-0.971, P=0.041 for CG versus CC; and OR=0.564, 95% CI=0.360-0.884, P=0.012 for GG+CG versus CC, respectively) and allelic analysis (P=0.025 for G versus C). Our findings suggested that polymorphism of mir-146a was associated with NPC in the central-southern Chinese population.

Intelligent wound dressing for simultaneous in situ detection and elimination of pathogenic bacteria.

Wound infections hinder the healing process and potentially result in life-threatening complications, which urgently require rapid and timely detection and treatment pathogens during the early stages of infection. Here, an intelligent wound dressing was developed to enable in situ detection and elimination of pathogenic bacteria through a combination of point-of-care testing and antibacterial photodynamic therapy technology. The dressing is an injectable hydrogel composed of carboxymethyl chitosan and oxidized sodium alginate, with addition of 4-methylumphulone beta-D-glucoside (MUG) and up-converted nanoparticles coated with titanium dioxide (UCNPs@TiO2). The presence of bacteria can be visually detected by monitoring the blue fluorescence of 4-methylumbellione, generated through the reaction between MUG and the pathogen-associated enzyme. The UCNPs@TiO2 photosensitizers were synthesized and demonstrated high antibacterial activity through the generation of reactive oxygen species when exposed to near-infrared irradiation. Meanwhile, a smartphone-based portable detection system equipped with a self-developed Android app was constructed for in situ detection of pathogens in mere seconds, detecting as few as 103 colony-forming unit. Additionally, the dressing was tested in a rat infected wound model and showed good antibacterial activity and pro-healing ability. These results suggest that the proposed intelligent wound dressing has potential for use in the diagnosis and management of wound infections. STATEMENT OF SIGNIFICANCE: An intelligent wound dressing has been prepared for simultaneous in situ detection and elimination of pathogenic bacteria. The presence of bacteria can be visually detected by tracking the blue fluorescence of the dressing. Moreover, a smartphone-based detection system was constructed to detect and diagnose pathogenic bacteria before reaching the infection limit. Meanwhile, the dressing was able to effectively eliminate key pathogenic bacteria on demand through antibacterial photodynamic therapy under NIR irradiation. The proposed intelligent wound dressing enables timely detection and treatment of infectious pathogens at an early stage, which is beneficial for wound management.