We have previously shown that broadly neutralizing antibodies reactive to the conserved stem region of the influenza virus hemagglutinin (HA) were generated in people infected with the 2009 pandemic ...H1N1 strain. Such antibodies are rarely seen in humans following infection or vaccination with seasonal influenza virus strains. However, the important question remained whether the inactivated 2009 pandemic H1N1 vaccine, like the infection, could also induce these broadly neutralizing antibodies. To address this question, we analyzed B-cell responses in 24 healthy adults immunized with the pandemic vaccine in 2009. In all cases, we found a rapid, predominantly IgG-producing vaccine-specific plasmablast response. Strikingly, the majority (25 of 28) of HA-specific monoclonal antibodies generated from the vaccine-specific plasmablasts neutralized more than one influenza strain and exhibited high levels of somatic hypermutation, suggesting they were derived from recall of B-cell memory. Indeed, memory B cells that recognized the 2009 pandemic H1N1 HA were detectable before vaccination not only in this cohort but also in samples obtained before the emergence of the pandemic strain. Three antibodies demonstrated extremely broad cross-reactivity and were found to bind the HA stem. Furthermore, one stem-reactive antibody recognized not only H1 and H5, but also H3 influenza viruses. This exceptional cross-reactivity indicates that antibodies capable of neutralizing most influenza subtypes might indeed be elicited by vaccination. The challenge now is to improve upon this result and design influenza vaccines that can elicit these broadly cross-reactive antibodies at sufficiently high levels to provide heterosubtypic protection.
Weaning is the gradual process of introducing solids or semisolid foods into an infant's diet, in order to ensure their healthy growth. This study developed two kinds of formula weaning food based on ...roasted or extruded quinoa and millet flour, and evaluated their quality. A fructo‐oligosaccharide (FOS)/galacto‐oligosaccharide (GOS) mix was added to provide the prebiotic potential. The protein contents of the roasted quinoa‐millet complementary food (RQMCF) and extruded quinoa‐millet complementary food (EQMCF) were 16.7% and 17.74% higher, respectively, than that of commercial millet complementary food (CMCF). Both RQMCF and EQMCF provided sufficient levels of energy and minerals. Extrusion provided the foods with a lower viscosity, and higher solubility and water absorption ability than roasting. In vitro digestion results showed that EQMCF exhibited the highest starch and protein digestibility (89.76% and 88.72%, respectively) followed by RQMCF (87.75% and 86.63%) and CMCF (83.35% and 81.54%). The digestas of RQMCF and EQMCF after in vitro digestion exhibited prebiotic effects by promoting the growth of the probiotics (Lactobacillus plantarum and Lactobacillus delbrueckii). These results will contribute to developing complementary weaning foods for infants.
Practical Application
This study has shown that extrusion is an efficient and stable processing method for producing infant complementary foods with low density, balanced nutrition, and high levels of starch and protein digestibility. Extruded quinoa‐millet prebiotic complementary food can also promote the proliferation of probiotics. This will provide a new direction for developing novel infant formula weaning foods.
One new ionic penta-nuclear Fe
III
cluster, HN(Et)
3
·Fe
5
(L
3
)
4
(ATZ)
4
(μ
3
-O)
2
·(H
2
O) (1), (H
2
L is 2-(((1H-tetrazol-5-yl)imino)methyl)-6-methoxyphenol; HATZ is 5-amino-1,2,3,4- ...tetrazole), was synthesized through a micro-vial reaction. Complex 1 was characterized by elemental analysis, FT-IR spectra, X-ray single crystal diffraction, thermogravimetric analysis. Complex 1 reveals high thermal stability, and displays intracluster antiferromagnetic coupling between the Fe(III) ions through μ
3
-O bridges. In 1, HATZ was synthesized through in situ decomposition reaction of H
2
L. The Hirshfeld surface analysis results indicate that the N···H interaction is one of the most significant contacts for the complex.
Identification of high-risk localised renal cell carcinoma is key for the selection of patients for adjuvant treatment who are at truly higher risk of reccurrence. We developed a classifier based on ...single-nucleotide polymorphisms (SNPs) to improve the predictive accuracy for renal cell carcinoma recurrence and investigated whether intratumour heterogeneity affected the precision of the classifier.
In this retrospective analysis and multicentre validation study, we used paraffin-embedded specimens from the training set of 227 patients from Sun Yat-sen University (Guangzhou, Guangdong, China) with localised clear cell renal cell carcinoma to examine 44 potential recurrence-associated SNPs, which were identified by exploratory bioinformatics analyses of a genome-wide association study from The Cancer Genome Atlas (TCGA) Kidney Renal Clear Cell Carcinoma (KIRC) dataset (n=114, 906 600 SNPs). We developed a six-SNP-based classifier by use of LASSO Cox regression, based on the association between SNP status and patients' recurrence-free survival. Intratumour heterogeneity was investigated from two other regions within the same tumours in the training set. The six-SNP-based classifier was validated in the internal testing set (n=226), the independent validation set (Chinese multicentre study; 428 patients treated between Jan 1, 2004 and Dec 31, 2012, at three hospitals in China), and TCGA set (441 retrospectively identified patients who underwent resection between 1998 and 2010 for localised clear cell renal cell carcinoma in the USA). The main outcome was recurrence-free survival; the secondary outcome was overall survival.
Although intratumour heterogeneity was found in 48 (23%) of 206 cases in the internal testing set with complete SNP information, the predictive accuracy of the six-SNP-based classifier was similar in the three different regions of the training set (areas under the curve AUC at 5 years: 0·749 95% CI 0·660–0·826 in region 1, 0·734 0·651–0·814 in region 2, and 0·736 0·649–0·824 in region 3). The six-SNP-based classifier precisely predicted recurrence-free survival of patients in three validation sets (hazard ratio HR 5·32 95% CI 2·81–10·07 in the internal testing set, 5·39 3·38–8·59 in the independent validation set, and 4·62 2·48–8·61 in the TCGA set; all p<0·0001), independently of patient age or sex and tumour stage, grade, or necrosis. The classifier and the clinicopathological risk factors (tumour stage, grade, and necrosis) were combined to construct a nomogram, which had a predictive accuracy significantly higher than that of each variable alone (AUC at 5 years 0·811 95% CI 0·756–0·861).
Our six-SNP-based classifier could be a practical and reliable predictor that can complement the existing staging system for prediction of localised renal cell carcinoma recurrence after surgery, which might enable physicians to make more informed treatment decisions about adjuvant therapy. Intratumour heterogeneity does not seem to hamper the accuracy of the six-SNP-based classifier as a reliable predictor of recurrence. The classifier has the potential to guide treatment decisions for patients at differing risks of recurrence.
National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Provincial Science and Technology Foundation of China, and Guangzhou Science and Technology Foundation of China.
Background The molecular pathogenesis of endometrial cancer is not completely understood. CypB upregulated in many cancers, however, its role in endometrial carcinoma has not been studied. Here, we ...determine the effect of CypB on the growth of endometrial cancer. Methods In this study, we examined the expression of CypB in endometrial cancer tissues using immunohistochemistry. CypB silenced in HEC-1-B cell line by shRNA. CCK-8, colony formation assays, wound healing assays, and transwell analysis were performed to assess its effect on tumor cell proliferation and metastasis. Furthermore, microarray analysis was carried out to compare the global mRNA expression profile between the HEC-1-B and CypB-silenced HEC-1-B cells. Gene ontology and KEGG pathway enrichment analysis were performed to determine the potential function of differentially expressed genes related to CypB. Results We found that CypB was upregulated in endometrial cancer, inhibit CypB expression could significantly suppress cell proliferation, metastasis, and migration. We identified 1536 differentially expressed genes related to CypB (onefold change, p < 0.05), among which 652 genes were upregulated and 884 genes were downregulated. The genes with significant difference in top were mainly enriched in the cell cycle, glycosphingolipid biosynthesis, adherens junctions, and metabolism pathways. Conclusion The results of our study suggest that CypB may serve as a novel regulator of endometrial cell proliferation and metastasis, thus representing a novel target for gene-targeted endometrial therapy. Trial registration YLYLLS 2018 008. Registered 27 November 2017. Keywords: Endometrial cancer, Cyclophilin B, Proliferation, Microarray
Biomonitoring studies have demonstrated extensive exposure of infants, children, and pregnant women to phthalates, but data on phthalate exposure and their determinants in Chinese older adults remain ...insufficient. This study aims to assess urinary phthalate metabolite levels, individual and cumulative exposure risk, and their determinants in Chinese community-dwelling older adults.
A total of 987 individuals aged 60 years or over were included in this study. The urinary levels of seven phthalate metabolites were measured using high-performance liquid chromatography-tandem mass spectrometry. The estimated daily intake (EDI), hazard quotient (HQ), and hazard index (HI) of phthalates were calculated based on urinary metabolite levels. The associations between phthalate metabolite levels and potential determinants were examined using multiple linear regressions.
Detection rates of seven phthalate metabolites from the study population ranged from 63.83% to 99.39%. The highest median concentration was 43.64 μg/L (42.59 μg/g creatinine) for mono-butyl phthalate (MBP). The highest median EDI was 1.55 μg/kg-bw/day for diethyl phthalate (DBP). Nearly 5% of participants had high HI values exceeding 1, mainly attributed to DBP and di-2-ethylhexyl phthalate (DEHP). Furthermore, we found that females, higher body mass index (BMI), smoking, having two or more chronic diseases, and vegetable-based diets were significantly associated with higher levels of parts of phthalate metabolites. More interestingly, higher urine levels of high-molecular-weight (HMW) phthalate metabolites and lower urine levels of low-molecular-weight (LMW) phthalate metabolites were found in rural older adults than in urban older adults.
Chinese community-dwelling older adults are extensively exposed to phthalates, especially to DBP and DEHP. More attention should be paid to urban-rural differences in exposure to HMW and LMW phthalates and to phthalate exposure among older adults with overweight/obesity, females, and individuals who are current heavy smokers, have two or more chronic diseases, and consume vegetable-based diets.
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•Chinese community-dwelling older adults are widely exposed to phthalates, especially DEHP and DBP.•Urban-rural difference in exposures to HMW and LMW phthalates should be tightly concerned.•Females were significantly associated with higher levels of MBP and MEP.•BMI was positively associated with MMP, MEP, MBP, and DEHP metabolites.•Higher exposure levels to phthalates were found in individuals with smoking, chronic diseases, and vegetable-based diets.
Abstract Integrating genomics and histology for cancer prognosis demonstrates promise. Here, we develop a multi-classifier system integrating a lncRNA-based classifier, a deep learning ...whole-slide-image-based classifier, and a clinicopathological classifier to accurately predict post-surgery localized (stage I–III) papillary renal cell carcinoma (pRCC) recurrence. The multi-classifier system demonstrates significantly higher predictive accuracy for recurrence-free survival (RFS) compared to the three single classifiers alone in the training set and in both validation sets (C-index 0.831-0.858 vs. 0.642-0.777, p < 0.05). The RFS in our multi-classifier-defined high-risk stage I/II and grade 1/2 groups is significantly worse than in the low-risk stage III and grade 3/4 groups (p < 0.05). Our multi-classifier system is a practical and reliable predictor for recurrence of localized pRCC after surgery that can be used with the current staging system to more accurately predict disease course and inform strategies for individualized adjuvant therapy.
Through analysis and summarization of clinicopathological features, immunohistochemical expression, pathological diagnostic criteria, prognostic and other factors in patients suffering from bladder ...neuroendocrine carcinoma (BNEC), a better understanding of BNEC could be achieved to provide solid evidence for clinicopathology and prognosis.
The clinicopathological data of 39 cases of BNEC with up to 5-year follow-up data (median follow-up=650 days) were analyzed retrospectively based on immunohistochemical staining. Survival analyses were carried out using the Kaplan-Meier method and tested with the log-rank method. Multivariate Cox regression analysis was adopted to screen independent risk factors affecting patients' survival. In these 39 cases of BNEC, there were 26 cases of male patients, 13 female, with the proportion of male to female being 2:1. The ages of onset ranged from 44 to 86, with the median age being 62 and the average age 61.97 years, respectively. Histologically, referring to the WHO standard of neuroendocrine lung tumor classification, there were 7 cases of typical carcinoid tumors, 8 atypical carcinoid, 12 small-cell carcinomas and 12 large-cell carcinomas. In these cases there were 11 cases of featured urothelium carcinomas and 9 cases of adenocarcinomas.
Immunohistochemical staining showed that, in these 39 cases of BNEC, the positive expression for the neuroendocrinic markers, including neural cell adhesion molecule 56 (CD56), synaptophysin (Syn), chromogranin A (CgA), neuron-specific enolase (NSE), thyroid transcription factor-1 (TTF-1), cytokeratin (CK) and cytokeratin 7 (CK7), accounted for 39/39, 27/39, 18/39, 39/39, 19/39, 10/39 and 8/39, respectively. In contrast, cytokeratin 20 (CK20), protein 63 (P63), human melanoma black 45 (HMB45), S-lfln protein 100 (S-100) and leukocyte common antigen (LCA) were all negatively expressed. During the follow-up period, 12 patients died. The 1-, 3- and 5-year overall survival (OS) rates were 76.92%, 74.36% and 69.23%.
BNEC is one of the most malignant tumors with severe invasiveness and poor prognosis. Immunohistochemistry revealed that CD56, Syn, CgA, NSE, TTF-1, CK, CK7, CK20, P63, HMB45, S-100 protein and LCA immune markers play important roles in diagnosis and differentiation. Many factors, including the patient's age, size and shape of the tumor, operative method, perineuronal invasion, vascular invasion, distant organ metastasis and pathological type, show great difference in influencing OS time of patients, among which the size of the tumor, no invasion, vascular invasion and distant organ metastasis are independent risk factors affecting prognosis (survival time). Radical cystectomy is the prior alternative to treat this tumor.
Improved markers for predicting recurrence are needed to stratify patients with localised (stage I–III) renal cell carcinoma after surgery for selection of adjuvant therapy. We developed a novel ...assay integrating three modalities—clinical, genomic, and histopathological—to improve the predictive accuracy for localised renal cell carcinoma recurrence.
In this retrospective analysis and validation study, we developed a histopathological whole-slide image (WSI)-based score using deep learning allied to digital scanning of conventional haematoxylin and eosin-stained tumour tissue sections, to predict tumour recurrence in a development dataset of 651 patients with distinctly good or poor disease outcome. The six single nucleotide polymorphism-based score, which was detected in paraffin-embedded tumour tissue samples, and the Leibovich score, which was established using clinicopathological risk factors, were combined with the WSI-based score to construct a multimodal recurrence score in the training dataset of 1125 patients. The multimodal recurrence score was validated in 1625 patients from the independent validation dataset and 418 patients from The Cancer Genome Atlas set. The primary outcome measured was the recurrence-free interval (RFI).
The multimodal recurrence score had significantly higher predictive accuracy than the three single-modal scores and clinicopathological risk factors, and it precisely predicted the RFI of patients in the training and two validation datasets (areas under the curve at 5 years: 0·825–0·876 vs 0·608–0·793; p<0·05). The RFI of patients with low stage or grade is usually better than that of patients with high stage or grade; however, the RFI in the multimodal recurrence score-defined high-risk stage I and II group was shorter than in the low-risk stage III group (hazard ratio HR 4·57, 95% CI 2·49–8·40; p<0·0001), and the RFI of the high-risk grade 1 and 2 group was shorter than in the low-risk grade 3 and 4 group (HR 4·58, 3·19–6·59; p<0·0001).
Our multimodal recurrence score is a practical and reliable predictor that can add value to the current staging system for predicting localised renal cell carcinoma recurrence after surgery, and this combined approach more precisely informs treatment decisions about adjuvant therapy.
National Natural Science Foundation of China, and National Key Research and Development Program of China.
The innate physiological dormancy of Tulipa thianschanica seeds ensures its survival and regeneration in the natural environment. However, the low percentage of germination restricts the ...establishment of its population and commercial breeding. To develop effective ways to break dormancy and improve germination, some important factors of seed germination of T. thianschanica were tested, including temperature, gibberellin (GA3) and/or kinetin (KT), cold stratification and sowing depth. The percentage of germination was as high as 80.7% at a constant temperature of 4 °C, followed by 55.6% at a fluctuating temperature of 4/16 °C, and almost no seeds germinated at 16 °C, 20 °C and 16/20 °C. Treatment with exogenous GA3 significantly improved the germination of seeds, but KT had a slight effect on the germination of T. thianschanica seeds. The combined treatment of GA3 and KT was more effective at enhancing seed germination than any individual treatment, and the optimal hormone concentration for the germination of T. thianschanica seeds was 100 mg/L GA3 + 10 mg/L KT. In addition, it took at least 20 days of cold stratification to break the seed dormancy of T. thianschanica. The emergence of T. thianschanica seedlings was the highest with 82.4% at a sowing depth of 1.5 cm, and it decreased significantly at a depth of >3.0 cm. This study provides information on methods to break dormancy and promote the germination of T. thianschanica seeds.
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