Efficacy and safety of intrathecal pemetrexed for TKI-failed leptomeningeal metastases from EGFR+ NSCLC: an expanded, single-arm, phase II clinical trial.

BACKGROUND: This study aimed to evaluate the efficacy and safety of intrathecal pemetrexed (IP) for treating patients with leptomeningeal metastases (LM) from non-small-cell lung cancer (NSCLC) who progressed from epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment in an expanded, prospective, single-arm, phase II clinical study (ChiCTR1800016615). PATIENTS AND METHODS: Patients with confirmed NSCLC-LM who progressed from TKI received IP (50 mg, day 1/day 5 for 1 week, then every 3 weeks for four cycles, and then once monthly) until disease progression or intolerance. Objectives were to assess overall survival (OS), response rate, and safety. Measurable lesions were assessed by investigator according to RECIST version 1.1. LM were assessed according to the Response Assessment in Neuro-Oncology (RANO) criteria. RESULTS: The study included 132 patients; 68% were female and median age was 52 years (31-74 years). The median OS was 12 months (95% confidence interval 10.4-13.6 months), RANO-assessed response rate was 80.3% (106/132), and the most common adverse event was myelosuppression (n = 42; 31.8%), which reversed after symptomatic treatment. The results of subgroup analysis showed that absence of brain parenchymal metastasis, good Eastern Cooperative Oncology Group score, good response to IP treatment, negative cytology after treatment, and patients without neck/back pain/difficult defecation had longer survival. Gender, age, previous intrathecal methotrexate/cytarabine, and whole-brain radiotherapy had no significant influence on OS. CONCLUSIONS: This study further showed that IP is an effective and safe treatment method for the EGFR-TKI-failed NSCLC-LM, and should be recommended for these patients in clinical practice and guidelines.

Appropriate noise addition to metaheuristic algorithms can enhance their performance.

Nature-inspired swarm-based algorithms are increasingly applied to tackle high-dimensional and complex optimization problems across disciplines. They are general purpose optimization algorithms, easy to implement and assumption-free. Some common drawbacks of these algorithms are their premature convergence and the solution found may not be a global optimum. We propose a general, simple and effective strategy, called heterogeneous Perturbation-Projection (HPP), to enhance an algorithm's exploration capability so that our sufficient convergence conditions are guaranteed to hold and the algorithm converges almost surely to a global optimum. In summary, HPP applies stochastic perturbation on half of the swarm agents and then project all agents onto the set of feasible solutions. We illustrate this approach using three widely used nature-inspired swarm-based optimization algorithms: particle swarm optimization (PSO), bat algorithm (BAT) and Ant Colony Optimization for continuous domains (ACO). Extensive numerical experiments show that the three algorithms with the HPP strategy outperform the original versions with 60-80% the times with significant margins.

[Extraction treatment on orthodontic patients with Stage â £/Grade C periodontitis: a preliminary study].

Objective: To evaluate the effect of extraction treatment on orthodontic patients with Stage Ⅳ/Grade C periodontitis. Methods: Eight orthodontic patients with Stage Ⅳ/Grade C periodontitis (3 males, 5 females, 25~38 years old) who had finished extraction treatment during January 2003 and December 2013 were included in the study. The patients accepted periodontal treatment and extraction orthodontic treatment in the Department of Periodontology and Department of Orthodontics at Peking University School and Hospital of Stomatology. Clinical examination records and periapical films of 34 teeth adjacent to extraction sites (TAES) and 34 teeth non-adjacent to extraction sites (TNES) were evaluated and compared. Probing depth (PD) and relative bone height (RBH) before and after orthodontic treatment were also compared. Results: No significant difference was found between PD of TAES and that of TNES (P>0.05). After orthodontic treatment, RBH of TAES was increased by 8.19% (-3.36%,14.01%) (P<0.05). RBH of TAES far from extraction sites was elevated by 7.73% (-1.52%, 21.55%)(P<0.05). Tooth resorption rate of TAES was 13.1% (1.3%, 23.9%)and TNES was 4.3% (-8.19%, 12.5%) after orthodontic treatment, and the difference was statistically significant. Conclusions: Under proper combined periodontal and orthodontic treatment, stability of periodontal status in patients with Stage Ⅳ/Grade C periodontitis can be maintained. Relative bone height of extraction sites can be elevated after orthodontic treatment.

Long lifetime of bialkali photocathodes operating in high gradient superconducting radio frequency gun.

High brightness, high charge electron beams are critical for a number of advanced accelerator applications. The initial emittance of the electron beam, which is determined by the mean transverse energy (MTE) and laser spot size, is one of the most important parameters determining the beam quality. The bialkali photocathodes illuminated by a visible laser have the advantages of high quantum efficiency (QE) and low MTE. Furthermore, Superconducting Radio Frequency (SRF) guns can operate in the continuous wave (CW) mode at high accelerating gradients, e.g. with significant reduction of the laser spot size at the photocathode. Combining the bialkali photocathode with the SRF gun enables generation of high charge, high brightness, and possibly high average current electron beams. However, integrating the high QE semiconductor photocathode into the SRF guns has been challenging. In this article, we report on the development of bialkali photocathodes for successful operation in the SRF gun with months-long lifetime while delivering CW beams with nano-coulomb charge per bunch. This achievement opens a new era for high charge, high brightness CW electron beams.

High-Brightness Continuous-Wave Electron Beams from Superconducting Radio-Frequency Photoemission Gun.

Continuous-wave photoinjectors operating at high accelerating gradients promise to revolutionize many areas of science and applications. They can establish the basis for a new generation of monochromatic x-ray free electron lasers, high-brightness hadron beams, or a new generation of microchip production. In this Letter we report on the record-performing superconducting rf electron gun with CsK_{2}Sb photocathode. The gun is generating high charge electron bunches (up to 10 nC/bunch) and low transverse emittances, while operating for months with a single photocathode. This achievement opens a new era in generating high-power beams with a very high average brightness.

pUC18-CpG stimulates RAW 264.7 via TBK1-mediated pathway and presents adjuvanticity in mice.

Phosphorothioate CpG oligodeoxynucleotides (ODN) are reported to be recognized by the membrane-bound TLR9 and trigger the MyD88-dependent up-regulation of Type I interferons and pro-inflammatory cytokines. Whether plasmids containing multiple CpG motifs stimulate the same signaling pathway is yet to be determined. The present results show that the CpG motifs enrich plasmid pUC18-CpG stimulates RAW 264.7 in vitro, mainly through the TBK1-mediated signaling pathway, causing the up-regulation of IFN-ß, and pro-inflammatory cytokines TNF-α and IL-6. When pUC18-CpG is co-administered with the recombinant Echinococcus granulosus antigen, the antigen-specific antibody titers are markedly increased compared to the Quil-A adju- vanted group. Antigen specific cytokine quantification shows that cytokine profiles from the pUC18-CpG adjuvanted-group are switched to a Th1-biased immune response.

Isolation and sequence analysis of the complete VP2 gene of canine parvovirus from Chinese domestic pets and determination of the pathogenesis of these circulating strains in beagles.

Canine parvovirus (CPV) causes acute gastroenteritis in domestic dogs, cats, and several wild carnivore species. In this study, the full-length VP2 gene of 36 CPV isolates from dogs and cats infected between 2016 and 2017 in Beijing was sequenced and analyzed. The results showed that, in dogs, the new CPV-2a strain was the predominant variant (n = 18; 50%), followed by the new CPV-2b (n = 6; 16.7%) and CPV-2c (n = 3; 8.3%) strains, whereas, among cats, the predominant strain was still CPV-2 (n = 9; 25%). One new CPV-2a strain, 20170320-BJ-11, and two CPV-2c strains, 20160810-BJ-81 and 20170322-BJ-26, were isolated and used to perform experimental infections. Multiple organs of beagles that died tested PCR positive for CPV, and characteristic histopathological lesions were observed in organs, including the liver, spleen, lungs, kidneys, small intestines, and lymph nodes. Experimental infections showed that the isolates from the epidemic caused high morbidity in beagles, indicating their virulence in animals and suggesting the need to further monitor evolution of CPV in China.

Phospholipase C signaling is involved in porcine reproductive and respiratory syndrome virus infection in cell cultures.

The phospholipase C (PLC) is a family of kinases that hydrolyze phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] to generate two second messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), which stimulate distinct downstream signaling. Recently, it has been reported that PLC signaling is activated by multiple viruses for efficient replication and the virus-induced inflammatory response. In this study, we demonstrated that PLC-specific inhibitor U73122 strongly suppressed porcine reproductive and respiratory syndrome virus (PRRSV) productive infection in cell cultures. The inhibitor affected both viral post-binding cell entry and post-entry processes. The virus infection led to an early transient activation of PLCγ-1 at 0.5 h post-infection (hpi), and sustained event at a stage from 4 to 16 hpi in MARC-145 cells. In addition, U73122 inhibited the activation of p38 MAPK signaling stimulated by PRRSV infection, suggesting that PLC signaling may be associated with the virus infection-induced inflammatory response. Taken together, these studies suggested that PLC signaling played an important role in PRRSV infection or pathogenesis. Keywords: PRRSV; U73122; phospholipase C; PLCγ-1.

Genotyping and pathogenic characterization of canine distemper virus based on mutations in the hemagglutinin gene in Chinese domestic dogs.

Canine distemper virus (CDV) infects wild and domestic Canidae worldwide. The hemag- glutinin (H) gene has the highest genetic variation in the genome of this virus. Thus, the H gene is commonly used for lineage identification and genetic analyses. In order to study the genetic characteristics and pathogenicity of CDV strains prevalent in China, 132 samples were collected from domestic dogs with suspected CDV infection, 58 samples were confirmed to be positive, and the H gene was successfully amplified from 15 samples. The epidemic strain was identified as type Asia-1 and the novel mutations, A51T, V58I, R179K and D262N, were detected in this strain. Isolated strains, BJ16B53, BJ16B14, and BJ17B8, were used for an animal infection experiment in raccoon dogs. BJ16B53 and BJ16B14 were found to cause clinical symptoms, death, and exten- sive lesions in various organs. These results are expected to facilitate the development of effective strategies to monitor and control CDV infection in China.

Versatile mechanical properties of novel g-SiC x monolayers from graphene to silicene: a first-principles study.

Recently, a series of graphene-like binary monolayers (g-SiC x ), where Si partly substitutes the C positions in graphene, have been obtained by tailoring the band gaps of graphene and silicene that have made them a promising material for application in opto-electronic devices. Subsequently, evaluating the mechanical properties of g-SiC x has assumed great importance for engineering applications. In this study, we quantified the in-plane mechanical properties of g-SiC x (x = 7, 5, 3, 2 and 1) monolayers (also including graphene and silicene) based on density function theory. It was found that the mechanical parameters of g-SiC x , such as the ideal strength, Young's modulus, shear modulus, Poisson's ratio, as well as fracture toughness, are overall related to the ratio of Si-C to C-C bonds, which varies with Si concentration. However, for g-SiC7 and g-SiC3, the mechanical properties seem to depend on the structure because in g-SiC7, the C-C bond strength is severely weakened by abnormal stretching, and in g-SiC3, conjugation structure is formed. The microscopic failure of g-SiC x exhibits diverse styles depending on the more complex structural deformation modes introduced by Si substitution. We elaborated the structure-properties relationship of g-SiC x during the failure process, and in particular, found that the structural transformation of g-SiC3 and g-SiC is due to the singular symmetry of their structure. Due to the homogeneous phase, all the g-SiC x investigated in this study preserve rigorous isotropic Young's moduli and Poisson's ratios. With versatile mechanical performances, the family of g-SiC x may facilitate the design of advanced two-dimensional materials to meet the needs for practical mechanical engineering applications. The results offer a fundamental understanding of the mechanical behaviors of g-SiC x monolayers.

Radial forearm flaps with venous compromise: correlations between salvage techniques and their rates of success.

We retrospectively analysed the reliability of anastomosis of the deep venous system as a salvage technique for a free radial forearm flap that has developed venous compromise. The primary predictors were the salvage techniques, which comprised anastomosis of the deep venous system and a repeat of the original anastomosis, and the primary outcome measure was the rate of success. The potential confounders included original venous outflow, the original causes of the venous compromise, and the number of venous anastomoses. The chi squared test, Fisher's exact test, and the Cochran-Mantel-Haenszel test were used for statistical analysis as appropriate. The final sample comprised 42 patients who required re-exploration for venous compromise. The salvage rates were 15/18 when anastomosis of the deep venous system was chosen as a salvage technique and 9/24 and when the original anastomosis was done again (p=0.003, OR 2.222, 95% CI 1.274 to 3.876). The salvage rate of venous compromise was higher in patients who had anastomoses of the deep venous system than in those in whom the original anastomosis was repeated.

[Extraction-orthodontic treatment on patients with chronicperiodontitis: a preliminary study].

OBJECTIVE: To retrospectively evaluate clinical and radiographic records of chronic periodontitis patients who underwent extraction-orthodontic treatment, in order to determine the effect of the treatment on probing depth, alveolar bone height of teeth adjacent to the extraction sites. METHODS: In the study, 33 chronic periodontitis patients who had finished extraction-orthodontic treatment were selected, the periodontal examination system tables and panoramic tomography were recorded before treatment (T0) and after treatment (T1), and the periodontal probing depth (PD), residual alveolar bone height (RBH) of the teeth adjacent to extraction sites (TAES) and the non-teeth adjacent to extraction sites (NTAES) were measured at T0 and T1. RESULTS: There was insignificant difference in PD of TAES and NTAES at T0 [(2.40±0.51) mm vs. (2.42±0.55) mm,P>0.05], neither was that at T1 [(2.70±0.67) mm vs. (2.67±0.64) mm, P>0.05]; From T0 to T1, PD of TAES and NTAES had mean increases of 0.3 mm [(2.40±0.51) mm vs. (2.70±0.67) mm,P<0.01] and 0.25 mm [(2.42±0.55 mm vs. (2.67±0.64) mm, P<0.01], respectively. And PD of TAES and NTAES increased from T0 to T1 statistically in the same degree [(0.30±0.64) mm vs. (0.25±0.58) mm,P>0.05]; at T0, RBH of TAES was 0.024 smaller than that of NTAES (0.74±0.16 vs. 0.76±0.16,P<0.05), but there was no difference in RBH between the TAES and NTAES at T1 (0.78±0.14 vs. 0.79±0.12,P>0.05); From T0 to T1, RBH of TAES and NTAES had mean increases of 0.04 (0.74±0.16 vs.0.78±0.14,P<0.05) and 0.02 (0.76±0.16 vs. 0.79±0.12,P<0.05), respectively. And the change of RBH between TAES and NTAES from T0 to T1 had no statistical difference (0.04±0.11 vs. 0.02±0.08,P>0.05)RBH of TAES in the side close to extraction sites was as the same as that of TAES in the side away from the extraction sites at T0 (0.73±0.17 vs. 0.74±0.16,P>0.05). From T0 to T1, RBH of both sides of TAES had mean increases of 0.04 (0.73±0.11 vs. 0.77±0.11,P<0.05) and 0.04 (0.74±0.11 vs. 0.78±0.11,P<0.05), respectively. But for both sides of TAES, from T0 to T1, there was no significant difference in change of RBH (0.04±0.11 vs. 0.04±0.11,P>0.05). CONCLUSIONS: With strict control of periodontal inflammation and maintenance of oral hygiene, orthodontic treatment preserves the periodontal conditions in patients with chronic periodontitis, and the extraction-orthodontic treatment can preserve the bone height of the teeth adjacent to extraction sites.

Design of a high-bunch-charge 112-MHz superconducting RF photoemission electron source.

High-bunch-charge photoemission electron-sources operating in a continuous wave (CW) mode are required for many advanced applications of particle accelerators, such as electron coolers for hadron beams, electron-ion colliders, and free-electron lasers. Superconducting RF (SRF) has several advantages over other electron-gun technologies in CW mode as it offers higher acceleration rate and potentially can generate higher bunch charges and average beam currents. A 112 MHz SRF electron photoinjector (gun) was developed at Brookhaven National Laboratory to produce high-brightness and high-bunch-charge bunches for the coherent electron cooling proof-of-principle experiment. The gun utilizes a quarter-wave resonator geometry for assuring beam dynamics and uses high quantum efficiency multi-alkali photocathodes for generating electrons.

Expression Patterns of Three Genes Under Short and Long Term Cold Exposure in Thitarodes pui (Lepidoptera: Hepialidae), A Host of Ophiocordyceps sinensis.

　　BACKGROUND: Thitarodes larvae are the host of the caterpillar fungus Ophiocordyceps sinensis. Low temperature is the main environmental limitation for larvae growth. OBJECTIVE: To better understand the cold adaption process in T. pui larvae, the expression patterns of trehalose-6-phosphate synthase (TpTPS), heat shock protein 70 (TpHSP70), and heat shock protein 90 (TpHSP90) were investigated upon short and long-term exposure to 0°C. MATERIALS AND METHODS: The 6th instar T. pui larvae were collected in July 2013. TpTPS was firstly sequenced and expression patterns of TpTPS, TpHSP70 and TpHSP90 were investigated using quantitative PCR. RESULTS: Full-length cDNA of TpTPS was 3,012 bp, with an open reading frame of 2,472 bp and an encoding protein of 823 amino acids. TpTPS up-regulation was induced by cold exposure. TpHSP70 expression is altered by cold exposure, but remained low. TpHSP90 expression was obviously up regulated in long-term cold stimulation. CONCLUSION: All three genes (TpTPS, TpHSP70 and TpHSP90) have likely contributed to cold tolerance in T. pui larvae, TpTPS and TpHSP90 potentially being more important.

Correlation research on the protein expression (p75NTR, bax, bcl-2, and caspase-3) and cortical neuron apoptosis following mechanical injury in rat.

OBJECTIVE: In this study, we aimed to survey the role of p75NTR, bax, bcl-2, and caspase-3 in the progress of traumatic brain injury (TBI). MATERIALS AND METHODS: A mechanical trauma model of vital neurons was established by putting external pressure, contusion and centrifugal acceleration on neurons. Morphological change, survival rate, assay of LDH activity, and apoptosis rate were evaluated for mild, medium and severe injury models. The expression of bax, bcl-2, caspase-3, p75NTR, p75NTR mRNA was determined by immunohistochemistry, immunofluorescence, Western blotting and RT-PCR. RESULTS: There was a transient high level Bcl-2 protein within 2 h after injury to increase neuronal tolerance and avoid apoptosis. Subsequently p75NTR, Bax/Bcl-2, and Caspase-3 reached their peaks from 48 to 72 h accompanied with the maximum apoptosis rate. CONCLUSIONS: Our results suggest that apoptosis ratio in varying degree injury groups are correlated with the expression level of p75NTRmRNA, p75NTR, Caspase-3, Bax/Bcl-2 ratio.

Concrete ensemble Kalman filters with rigorous catastrophic filter divergence.

The ensemble Kalman filter and ensemble square root filters are data assimilation methods used to combine high-dimensional, nonlinear dynamical models with observed data. Ensemble methods are indispensable tools in science and engineering and have enjoyed great success in geophysical sciences, because they allow for computationally cheap low-ensemble-state approximation for extremely high-dimensional turbulent forecast models. From a theoretical perspective, the dynamical properties of these methods are poorly understood. One of the central mysteries is the numerical phenomenon known as catastrophic filter divergence, whereby ensemble-state estimates explode to machine infinity, despite the true state remaining in a bounded region. In this article we provide a breakthrough insight into the phenomenon, by introducing a simple and natural forecast model that transparently exhibits catastrophic filter divergence under all ensemble methods and a large set of initializations. For this model, catastrophic filter divergence is not an artifact of numerical instability, but rather a true dynamical property of the filter. The divergence is not only validated numerically but also proven rigorously. The model cleanly illustrates mechanisms that give rise to catastrophic divergence and confirms intuitive accounts of the phenomena given in past literature.

The ADAMTS1 Gene Is Associated with Familial Mandibular Prognathism.

Mandibular prognathism is a facial skeletal malocclusion. Until now, the genetic mechanism has been unclear. The goal of this study was to identify candidate genes or genomic regions directly associated with mandibular prognathism development, by employing whole genome sequencing. A large Chinese family was recruited, composed of 9 affected and 12 unaffected individuals, and the inheritance pattern of this family tends to be autosomal dominant. A single-nucleotide missense mutation in the ADAMTS1 gene (c. 742I>T) was found to segregate in the family, given that the affected individuals must be heterozygous for the mutation. For mutation validation, we screened this candidate mutation and 15 tag single-nucleotide polymorphisms in the coding sequence of ADAMTS1 among 230 unrelated cases and 196 unrelated controls using Sequenom Massarray and found that 3 in 230 cases carried this mutation and none of the controls did. Final results suggested that 2 single-nucleotide polymorphisms (rs2738, rs229038) of ADAMTS1 were significantly associated with mandibular prognathism.

High-resolution melting analysis for the detection of two erythromycin-resistant Bordetella pertussis strains carried by healthy schoolchildren in China.

Two erythromycin-resistant strains of Bordetella pertussis were isolated from nasopharyngeal specimens of two asymptomatic schoolchildren in China. High-resolution melting and sequencing analyses confirmed the homogeneous A2047G mutation in 23S rRNA genes of the two isolates. High-resolution melting (HRM) analysis is a useful assay for the rapid detection of erythromycin-resistant B. pertussis. The appearance of erythromycin-resistant B. pertussis strains in China is alarming.

Bmi-1 siRNA inhibited ovarian cancer cell line growth and decreased telomerase activity.

The knockdown of Bmi-1 could effectively suppress cancer cell proliferation and tumourigenicity in several cancers. This study aims to investigate whether or not Bmi-1 plays a causative role in the proliferation of ovarian epithelial cancer cells and telomerase activity. The messenger RNA (mRNA) and protein expression levels of Bmi-1 in the human ovarian carcinoma cell line OVCAR-3 were downregulated by Bmi-1 siRNA, as confirmed by real-time polymerase chain reaction (PCR) and Western blot. Cell viability was analysed by MTT assay, and telomerase activity was analysed by a modified telomeric repeat amplification protocol. Targeting Bmi-1 with siRNA inhibited Bmi-1 mRNA over five-fold compared with the control cells, and inhibited Bmi-1 protein expression over three-fold compared with control cells. The viability of the OVCAR-3 ovarian cancer cell line was reduced by Bmi-1 mRNA compared to control cells. Telomerase activity was decreased 22.73% (from 0.33 to 0.255) by Bmi-1 siRNA treatment compared to control cells. As Bmi-1 siRNA depressed telomerase activity, cell immortalisation may be prevented; thus, silencing Bmi-1 may be a potential therapy to manage ovarian cancer.

Emissions of EC, OC, and PAHs from cottonseed oil biodiesel in a heavy-duty diesel engine.

Biodiesel fuels, made from renewable resources, have emerged as viable alternatives to conventional diesel fuel, but their impact on emissions is not fully understood. This study examines elemental carbon (EC), organic carbon (OC), and polycyclic aromatic hydrocarbons (PAHs) emissions from cottonseed oil biodiesel (CSO-B100). Relative to normal diesel fuel, CSO-B100 reduced EC emissions by 64% (±16%). The bulk of EC emitted from CSO-B100 was in the fine particle mode (<1.4 µm), which is similar to normal diesel. OC was found in all size ranges, whereas emissions of OC(1.4-2.5) were proportionately higher in OC(2.5) from CSO-B100 than from diesel. The CSO-B100 emission factors derived from this study are significantly lower, even without aftertreatment, than the China-4 emission standards established in Beijing and Euro-IV diesel engine standards. The toxic equivalency factors (TEFs) for CSO-B100 was half the TEFs of diesel, which suggests that PAHs emitted from CSO-B100 may be less toxic.