The Glasgow Prognostic Score Predicts Poor Survival in Cisplatin-Based Treated Patients with Metastatic Nasopharyngeal Carcinoma

Background

Several inflammation-based prognostic scoring systems, including Glasgow Prognostic Score (GPS), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) have been reported to predict survival in many malignancies, whereas their role in metastatic nasopharyngeal carcinoma (NPC) remains unclear. The aim of this study is to evaluate the clinical value of these prognostic scoring systems in a cohort of cisplatin-based treated patients with metastatic NPC.

Methods

Two hundred and eleven patients with histologically proven metastatic NPC treated with first-line cisplatin-based chemotherapy were retrospectively evaluated. Demographics, disease-related characteristics and relevant laboratory data before treatment were recorded. GPS, NLR and PLR were calculated as described previously. Response to first-line therapy and survival data were also collected. Survival was analyzed in Cox regressions and stability of the models was examined by bootstrap resampling. The area under the receiver operating characteristics curve (AUC) was calculated to compare the discriminatory ability of each scoring system.

Results

Among the above three inflammation-based prognostic scoring systems, GPS (P<0.001) and NLR (P = 0.019) were independently associated with overall survival, which showed to be stable in a bootstrap resampling study. The GPS consistently showed a higher AUC value at 6-month (0.805), 12-month (0.705), and 24-month (0.705) in comparison with NLR and PLR. Further analysis of the association of GPS with progression-free survival showed GPS was also associated independently with progression-free survival (P<0.001).

Conclusions

Our study demonstrated that the GPS may be of prognostic value in metastatic NPC patients treated with cisplatin-based palliative chemotherapy and facilitate individualized treatment. However a prospective study to validate this prognostic model is still needed.     

Gating of inward rectifier K+ channels by proton-mediated interactions of N- and C-terminal domains

Ion channels play an important role in cellular functions, and specific cellular activity can be produced by gating them. One important gating mechanism is produced by intra- or extracellular ligands. Although the ligand-mediated channel gating is an important cellular process, the relationship between ligand binding and channel gating is not well understood. It is possible that ligands are involved in the interactions of different protein domains of the channel leading to opening or closing. To test this hypothesis, we studied the gating of Kir2.3 (HIR) by intracellular protons. Our results showed that hypercapnia or intracellular acidification strongly inhibited these channels. This effect relied on both the N and C termini. The CO(2)/pH sensitivities were abolished or compromised when one of the intracellular termini was replaced. Using purified N- and C-terminal peptides, we found that the N and C termini bound to each other in vitro. Although their binding was weak at pH 7.4, stronger binding was seen at pH 6.6. Two short sequences in the N and C termini were found to be critical for the N/C-terminal interaction. Interestingly, there was no titratable residue in these motifs. To identify the potential protonation sites, we systematically mutated most histidine residues in the intracellular N and C termini. We found that mutations of several histidine residues in the C but not the N terminus had a major effect on channel sensitivities to CO(2) and pH(i). These results suggest that at acidic pH, protons appear to interact with the C-terminal histidine residues and present the C terminus to the N terminus. Consequentially, these two intracellular termini bound to each other through two short motifs and closed the channel. Thus, a novel mechanism for K(+) channel gating is demonstrated, which involves the N- and C-terminal interaction with protons as the mediator.     

Regeneration of <Emphasis Type="Italic">Aeschynanthus radicans</Emphasis> via direct somatic embryogenesis and analysis of regenerants with flow cytometry

Plant regeneration through direct somatic embryogenesis in Aeschynanthus radicans ‘Mona Lisa’ was achieved in this study. Globular somatic embryos were formed directly from cut edges of leaf explants and cut ends or on the surface of stem explants 4 wk after culture on Murashige and Skoog (MS) medium supplemented with N-phenyl-N′-1, 2, 3-thiadiazol-5-ylurea (TDZ) with α-naphthalene acetic acid (NAA), TDZ with 2,4-dichlorophenoxyacetic acid (2,4-D), or 6-benzylaminopurine (BA) or kintin (KN) with 2,4-D. MS medium containing 9.08 μM TDZ and 2.68 μM 2,4-D resulted in 71% of stem explants producing somatic embryos. In contrast, 40% of leaf explants produced somatic embryos when induced in medium containing 6.81 μM TDZ and 2.68 μM 2,4-D. Somatic embryos matured, and some germinated into small plants on the initial induction medium. Up to 64% of stem explants cultured on medium supplemented with 9.08 μM TDZ + 2.68 μM 2,4-D, 36% of leaf explants cultured on medium containing 6.81 μM TDZ and 2.68 μM 2,4-D had somatic embryo germination before or after transferring onto MS medium containing 8.88 μM BA and 1.07 μM NAA. Shoots elongated better and roots developed well on MS medium without growth regulators. Approximately 30–50 plantlets were regenerated from each stem or leaf explant. The regenerated plants grew vigorously after transplanting to a soil-less substrate in a shaded greenhouse with more than a 98% survival rate. Three months after their establishment in the shaded greenhouse, 500 plants regenerated from stem explants were morphologically evaluated, from which five types of variants that had large, orbicular, elliptic, small, and lanceolate leaves were identified. Flow cytometry analysis of the variants along with the parent showed that they all had one identical peak, indicating that the variant lines, like the parent, were diploid. The mean nuclear DNA contents of the variant lines and their parent ranged from 4.90 to 4.99 pg 2C⁻¹, which were not significantly different statistically. The results suggest that the regenerated plants have a stable ploidy level, and the regeneration method established in this study can be used for rapid propagation of ploidy-stable Aeschynanthus radicans.     

Ganglioside GD1a restores infectibility to mouse cells lacking functional receptors for polyomavirus

Recent investigations on the pathway of cell entry by polyomavirus (Py) and simian virus 40 (SV40) have defined specific gangliosides as functional receptors mediating virus binding and transport from the plasma membrane to the endoplasmic reticulum (B. Tsai et al., EMBO J. 22:4346-4355, 2003; Gilbert and Benjamin, in press). These studies were carried out with C6 rat glioma cells, a heterologous host chosen for its known deficiency in ganglioside biosynthesis. Here, a cell genetic approach was undertaken to identify components required for the early steps of infection using mouse cells as the natural host for Py. Receptor-negative (R-) mouse cells, screened based on resistance to Py infection, were shown to bind Py but failed to allow entry of the virus. R- cells were also found to be resistant to SV40. Infectibility was restored or enhanced by the addition of the same specific gangliosides found in earlier studies with C6 cells. In one R- line, overexpression of caveolin-1 also increased infectibility. These results support and extend findings on gangliosides in lipid rafts as functional receptors and mediators of internalization for Py and SV40.     

Renal localization, expression, and developmental regulation of P450 4F cytochromes in three substrains of spontaneously hypertensive rats

Cytochrome P450 4F isoforms have been shown to metabolize arachidonic acid to generate 20-hydroxyeicosatetraenoic acid (20-HETE), a potent eicosanoid that modulates vascular tone and renal tubular function. 20-HETE production in the kidney is implicated in the development of essential hypertension in the spontaneously hypertensive rat (SHR). In this study, we determined CYP4F mRNA localization and distribution in rat liver and kidney by in situ hybridization and real time quantitative PCR. CYP4Fs are regionally distributed in the kidney with CYP4F1, 4F4, and 4F5 being expressed more in the renal cortex than medulla while CYP4F6 shows higher medullary expression. We investigated developmental CYP4F gene expression in three different substrains of SHR. Distinct age-dependent patterns of expression were seen for individual CYP4F isoforms in Wistar-Kyoto (WKY) and three SHR substrains (B2, C, and A3). A steady increase in CYP4F1 expression with age was seen in each of the three substrains which correlate well with increased 20-HETE levels and elevated blood pressure seen in these animals. CYP4F4 expression increased significantly at 8 weeks followed by a precipitous fall in WKY and A3 strains at 12 weeks of age. In strains B2 and C, CYP4F4 levels started declining as early as 8 weeks of age. CYP4F5 and 4F6 levels fluctuated with age in a biphasic manner with a different profile for each sub-strain. Based on the expression profile and catalytic activity, CYP4F1 seems to be the most critical 4F isoform involved in the production of 20-HETE in the SHR kidney.     

Comparison of Risk Factor between Lacunar Stroke and Large Artery Atherosclerosis Stroke: A Cross-Sectional Study in China

Background

Stroke is the second most common cause of mortality in China. Although most subtypes of ischemic stroke share similar risk factors, they have different etiologies. Our study aimed to evaluate the different risk factor profiles between the stroke subtypes, lacunar infarcts (LI) and large-artery atherosclerosis (LAA), and clarify the characteristics of current acute ischemic stroke in China.

Methods

In this cross-sectional study, we analyzed the clinical characteristics of 1982 patients with acute ischemic stroke who were admitted to the neurology department at the Peking University First Hospital between 2007 and 2014. Ischemic stroke was further classified into LAA, LI, cardioembolism (CE) and undetermined causes of infarction (UDI) according to TOAST classification. Demographic characteristics, risk factors, as well as the findings of laboratory and imaging tests of 1773 patients with LAA and LI, were analyzed by univariate and multivariate logistic analysis.

Results

Of the 1982 ischemic stroke patients included in this study, 1207 were diagnosed with LAA, 566 with LI, 173 with cardioembolism (CE) and 36 with undetermined causes of infarction (UDI). By comparing the risk factors in multivariate logistic regression analysis, hypertension [odds ratio (OR) = 1.832] and white matter leukoaraiosis (WML) (OR = 1.865) were found to be more strongly correlated with LI than LAA. Low density lipoprotein- cholesterol (LDL-c) (OR = 0.774) were more strongly related to LAA than LI.

Conclusions

This study found that hypertension and WML were more strongly correlated with LI than LAA. LDL-c was more strongly related to LAA than LI.     

A New Glabrous Gene (csgl3) Identified in Trichome Development in Cucumber (Cucumis sativus L.)

Spines or trichomes on the fruit of cucumbers enhance their commercial value in China. In addition, glabrous mutants exhibit resistance to aphids and therefore their use by growers can reduce pesticide residues. Previous studies have reported two glabrous mutant plants containing the genes, csgl1 and csgl2. In the present study, a new glabrous mutant, NCG157, was identified showing a gene interaction effect with csgl1 and csgl2. This mutant showed the glabrous character on stems, leaves, tendrils, receptacles and ovaries, and there were no spines or tumors on the fruit surface. Inheritance analysis showed that a single recessive gene, named csgl3, determined the glabrous trait. An F₂ population derived from the cross of two inbred lines 9930 (a fresh market type from Northern China that exhibits trichomes) and NCG157 (an American processing type with glabrous surfaces) was used for genetic mapping of the csgl3 gene. By combining bulked segregant analysis (BAS) with molecular markers, 18 markers, including two simple sequence repeats (SSR), nine insertion deletions (InDel) and seven derived cleaved amplified polymorphism sequences (dCAPs), were identified to link to the csgl3 gene. All of the linked markers were used as anchor loci to locate the csgl3 gene on cucumber chromosome 6. The csgl3 gene was mapped between the dCAPs markers dCAPs-21 and dCAPs-19, at genetic distances of 0.05 cM and 0.15 cM, respectively. The physical distance of this region was 19.6 kb. Three markers, InDel-19, dCAPs-2 and dCAPs-11, co-segregated with csgl3. There were two candidate genes in the region, Csa6M514860 and Csa6M514870. Quantitative real-time PCR showed that the expression of Csa6M514870 was higher in the tissues of 9930 than that of NCG157, and this was consistent with their phenotypic characters. Csa6M514870 is therefore postulated to be the candidate gene for the development of trichomes in cucumber. This study will facilitate marker-assisted selection (MAS) of the smooth plant trait in cucumber breeding and provide for future cloning of csgl3.     

A Neural Network Model for K(λ) Retrieval and Application to Global K par Monitoring

Accurate estimation of diffuse attenuation coefficients in the visible wavelengths K _d(λ) from remotely sensed data is particularly challenging in global oceanic and coastal waters. The objectives of the present study are to evaluate the applicability of a semi-analytical K _d(λ) retrieval model (SAKM) and Jamet’s neural network model (JNNM), and then develop a new neural network K _d(λ) retrieval model (NNKM). Based on the comparison of K _d(λ) predicted by these models with in situ measurements taken from the global oceanic and coastal waters, all of the NNKM, SAKM, and JNNM models work well in K _d(λ) retrievals, but the NNKM model works more stable and accurate than both SAKM and JNNM models. The near-infrared band-based and shortwave infrared band-based combined model is used to remove the atmospheric effects on MODIS data. The K _d(λ) data was determined from the atmospheric corrected MODIS data using the NNKM, JNNM, and SAKM models. The results show that the NNKM model produces <30% uncertainty in deriving K _d(λ) from global oceanic and coastal waters, which is 4.88-17.18% more accurate than SAKM and JNNM models. Furthermore, we employ an empirical approach to calculate K _par from the NNKM model-derived diffuse attenuation coefficient at visible bands (443, 488, 555, and 667 nm). The results show that our model presents a satisfactory performance in deriving K _par from the global oceanic and coastal waters with 20.2% uncertainty. The K _par are quantified from MODIS data atmospheric correction using our model. Comparing with field measurements, our model produces ~31.0% uncertainty in deriving K _par from Bohai Sea. Finally, the applicability of our model for general oceanographic studies is briefly illuminated by applying it to climatological monthly mean remote sensing reflectance for time ranging from July, 2002- July 2014 at the global scale. The results indicate that the high K _d(λ) and K _par values are usually found around the coastal zones in the high latitude regions, while low K _d(λ) and K _par values are usually found in the open oceans around the low-latitude regions. These results could improve our knowledge about the light field under waters at either the global or basin scales, and be potentially used into general circulation models to estimate the heat flux between atmosphere and ocean.     

Development of genome-wide insertion/deletion markers in rice based on graphic pipeline platform

DNA markers play important roles in plant breeding and genetics.The Insertion/Deletion(InDel) marker is one kind of co-dominant DNA markers widely used due to its low cost and high precision.However,the canonical way of searching for InDel markers is time-consuming and laborintensive.We developed an end-to-end computational solution(InDel Markers Development Platform,IMDP) to identify genome-wide InDel markers under a graphic pipeline environment.IMDP constitutes assembled genome sequences alignment pipeline(AGA-pipe) and next-generation resequencing data mapping pipeline(NGS-pipe).With AGA-pipe we are able to identify 12,944 markers between the genome of rice cultivars Nipponbare and 93-11.Using NGS-pipe,we reported 34,794 InDels from re-sequencing data of rice cultivars Wu-Yun-Geng7 and Guang-Lu-Ai4.Combining AGApipe and NGS-pipe,we developed 205,659 InDels in eight japonica and nine indica cultivars and 2,681 InDels showed a subgroup-specific pattern.Polymerase chain reaction(PCR)analysis of subgroup-specific markers indicated that the precision reached 90%(86 of 95).Finally,to make them available to the public,we have integrated the InDels/markers information into a website(Rice InDel Marker Database,RIMD,http://202.120.45.71/).The application of IMDP in rice will facilitate efficiency for development of genome-wide InDel markers,in addition it can be used in other species with reference genome sequences and NGS data.     

Lily Cultivars Have Allelopathic Potential in Controlling Orobanche aegyptiaca Persoon

As a devastating holoparasitic weed, Orobanche aegyptiaca Persoon. (Egyptian broomrape) causes serious damage to agricultural production and threatens economic development, which has raised widespread concern. The present study was conducted to determine whether lilies have the potential to be used as ‘trap crops’ for controlling O. aegyptiaca Persoon. In the experiments, the ability of three popular lily cultivars (Lilium Oriental hybrids ‘Sorbonne’, Lilium LA (Longiflorum hybrids x Asiatic hybrids) hybrids ‘Ceb Dazzle’, and Lilium Longiflorum hybrids (L. formosanum x L. longiflorum) ‘L. formolongo’) to induce O. aegyptiaca Persoon. seed germination was assessed. Parts of the three lily cultivars, including the rhizosphere soil and underground and above-ground organs, all induced “suicidal germination” of parasitic O. aegyptiaca Persoon. seed at four growth stages. Specifically, Sorbonne and Ceb Dazzle behaved with similar allelopathy, and the bulb, scale leaf and aerial stem exhibited stronger allelopathic effects on O. aegyptiaca Pers. germination compared to other organs. Aqueous L. formolongo leaf extracts may contain more stable, effective stimulants given that they induced the highest germination rate at 76.7% even though the extracts were serially diluted. We speculate that these organs may be advantageous in further isolating and purifying economical active substances that can be substitutes for GR24. These results indicate that lilies have the potential to be used as a trap crops or can be processed into green herbicide formulations that can be applied in agriculture production to rapidly deplete the seed bank of O. aegyptiaca Persoon. parasitic weeds in soil.