The correlation of the intestinal with pharyngeal microbiota in early neonates

IntroductionThe gut-lung axis has long been recognized as an important mechanism affecting intestinal and lung immunity. Still, few studies have examined the correlation between the intestinal and pharyngeal microbiota in early neonates, especially when feeding patterns are one of the main drivers of microbiota development.MethodsTo explore the composition and function of intestinal and pharyngeal microbiota and to analyze the effect of limited formula feeding on the initial microbiota colonization in early full-term neonates, we characterized the stool and oropharyngeal microbiota of 20 healthy full-term newborns sampled on days 0 and 5–7 after birth using 16S rRNA gene sequencing. Based on the sequencing results, a comparison was made of the compositions and functions of the intestinal and oropharyngeal microbiota for analysis.Results and discussionAt the phylum level, Firmicutes, Actinobacteria, Proteobacteria, and Bacteroidetes were the most abundant in both niches. At the genus level, the species of pioneer bacteria were rich in the intestine and oropharynx but low in abundance on day 0. On days 5–7, Bifidobacterium (25.40%) and Escherichia-Shigella (22.16%) were dominant in the intestine, while Streptococcus (38.40%) and Staphylococcus (23.13%) were dominant in the oropharynx. There were eight core bacteria genera in the intestine and oropharynx on days 5–7, which were Bifidobacterium, Escherichia-Shigella, Staphylococcus, Streptococcus, Bacteroides, Parabacteroides, Rothia, and Acinetobacter. As indicated by PICRUSt analysis, on days 5–7, the intestinal microbiota was more predictive than the oropharyngeal microbiota in transcription, metabolism, cell motility, cellular processes and signaling, and organismal system function in the KEGG pathway. Compared to exclusive breastfeeding, limited formula feeding (40–60%) had no significant effect on the neonatal intestinal and oropharyngeal microbiota composition during the initial colonization period. Our results suggest that the initial colonization of microbiota is closely related to the ecological niche environment in the intestine and oropharynx, with their core microbiota being closely correlated. We found that early limited formula feeding could not significantly affect the initial colonization of microbiota in the intestine and oropharynx

Pyrotinib and chrysin synergistically potentiate autophagy in HER2-positive breast cancer

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has been the most challenging subtype of BC, consisting of 20% of BC with an apparent correlation with poor prognosis. Despite that pyrotinib, a new HER2 inhibitor, has led to dramatic improvements in prognosis, the efficacy of pyrotinib monotherapy remains largely restricted due to its acquired resistance. Therefore, identifying a new potential antitumor drug in combination with pyrotinib to amplify therapeutic efficacy is a pressing necessity. Here, we reported a novel combination of pyrotinib with chrysin and explored its antitumor efficacy and the underlying mechanism in HER2-positive BC. We determined that pyrotinib combined with chrysin yielded a potent synergistic effect to induce more evident cell cycle arrest, inhibit the proliferation of BT-474 and SK-BR-3 BC cells, and repress in vivo tumor growth in xenograft mice models. This may be attributed to enhanced autophagy induced by endoplasmic reticulum stress. Furthermore, the combined treatment of pyrotinib and chrysin induced ubiquitination and glucose-6-phosphate dehydrogenase (G6PD) degradation by upregulating zinc finger and BTB/POZ domain-containing family protein 16 (ZBTB16) in tumorigenesis of BC. Mechanistically, we identified that miR-16-5p was a potential upstream regulator of ZBTB16, and it showed a significant inverse correlation with ZBTB16. Inhibition of miR-16-5p overexpression by restoring ZBTB16 significantly potentiated the overall antitumor efficacy of pyrotinib combined with chrysin against HER2-positive BC. Together, these findings demonstrate that the combined treatment of pyrotinib and chrysin enhances autophagy in HER2-positive BC through an unrecognized miR-16-5p/ZBTB16/G6PD axis.</p

Four novel variants identified in primary hyperoxaluria and genotypic and phenotypic analysis in 21 Chinese patients

Background: Primary hyperoxaluria (PH) is a rare genetic disorder characterized by excessive accumulation of oxalate in plasma and urine, resulting in various phenotypes due to allelic and clinical heterogeneity. This study aimed to analyze the genotype of 21 Chinese patients with primary hyperoxaluria (PH) and explore their correlations between genotype and phenotype.Methods: Combined with clinical phenotypic and genetic analysis, we identified 21 PH patients from highly suspected Chinese patients. The clinical, biochemical, and genetic data of the 21 patients were subsequently reviewed.Results: We reported 21 cases of PH in China, including 12 cases of PH1, 3 cases of PH2 and 6 cases of PH3, and identified 2 novel variants (c.632T &gt; G and c.823_824del) in AGXT gene and 2 novel variants (c.258_272del and c.866-34_866-8del) in GRHPR gene, respectively. A possible PH3 hotspot variant c.769T &gt; G was identified for the first time. In addition, patients with PH1 showed higher levels of creatinine and lower eGFR than those with PH2 and PH3. In PH1, patients with severe variants in both alleles had significantly higher creatinine and lower eGFR than other patients. Delayed diagnosis still existed in some late-onset patients. Of all cases, 6 had reached to end-stage kidney disease (ESKD) at diagnosis with systemic oxalosis. Five patients were on dialysis and three had undergone kidney or liver transplants. Notably, four patients showed a favorable therapeutic response to vitamin B6, and c.823_824dup and c.145A &gt; C may be identified as potentially vitamin B6-sensitive genotypes.Conclusion: In brief, our study identified 4 novel variants and extended the variant spectrum of PH in the Chinese population. The clinical phenotype was characterized by large heterogeneity, which may be determined by genotype and a variety of other factors. We first reported two variants that may be sensitive to vitamin B6 therapy in Chinese population, providing valuable references for clinical treatment. In addition, early screening and prognosis of PH should be given more attention. We propose to establish a large-scale registration system for rare genetic diseases in China and call for more attention on rare kidney genetic diseases

Maintenance of Self-Renewal and Pluripotency in J1 Mouse Embryonic Stem Cells through Regulating Transcription Factor and MicroRNA Expression Induced by PD0325901

Embryonic stem cells (ESCs) have the ability to grow indefinitely and retain their pluripotency in culture, and this self-renewal capacity is governed by several crucial molecular pathways controlled by specific regulatory genes and epigenetic modifications. It is reported that multiple epigenetic regulators, such as miRNA and pluripotency factors, can be tightly integrated into molecular pathways and cooperate to maintain self-renewal of ESCs. However, mouse ESCs in serum-containing medium seem to be heterogeneous due to the self-activating differentiation signal of MEK/ERK. Thus, to seek for the crucial miRNA and key regulatory genes that establish ESC properties in MEK/ERK pathway, we performed microarray analysis and small RNA deep-sequencing of J1 mESCs treated with or without PD0325901 (PD), a well-known inhibitor of MEK/ERK signal pathway, followed by verification of western blot analysis and quantitative real-time PCR verification; we found that PD regulated the transcript expressions related to self-renewal and differentiation and antagonized the action of retinoic acid- (RA-) induced differentiation. Moreover, PD can significantly modulate the expressions of multiple miRNAs that have crucial functions in ESC development. Overall, our results demonstrate that PD could enhance ESC self-renewal capacity both by key regulatory genes and ES cell-specific miRNA, which in turn influences ESC self-renewal and cellular differentiation

A Constitutive Model of Plate-Like Entangled Metallic Wire Material in Wide Temperature Range

Entangled metallic wire material (EMWM) is a kind of porous damping material. To promote the engineering application of EMWM, it is necessary to establish the constitutive model of EMWM to estimate its mechanical properties. In this paper, a series of quasi-static compression experiments for plate-like EMWM specimens made of austenitic stainless steel wire (06Cr19Ni10) with different densities were carried out in the temperature range of 20&ndash;500 &deg;C. It was found that the stiffness of the plate-like EMWM would increase with the increases in the ambient temperature. The non-linear characteristics of the force&ndash;displacement curve of the plate-like EMWM would be weakened. Taking the spatial structural characteristics of the plate-like EMWM and the influence of the thermal expansion of the structure into account, a new constitutive model for plate-like EMWM was presented by the combination of the Johnson&ndash;Cook model and the Sherwood&ndash;Frost constitutive framework model. The accuracy of the model was verified by the experimental data under different temperatures. The results show that the calculated results of the model are consistent with the experimental results. This model can provide an effective theoretical basis for predicting the mechanical properties of plate-like EMWM and guiding its design

Neoadjuvant chemotherapy in triple negative breast cancer:An observational study

Triple negative breast cancer (TNBC) is a phenotype of breast cancer with aggressive clinical behavior. Because of the absence of optimal treatment, the prognosis of this disease is poor. The main purpose of this study was to detect the response to neoadjuvant chemotherapy (NACT) in a TNBC cohort and compare the long-term survival between patients with and without pathological complete response (pCR). A total of 53 patients diagnosed with TNBC from 2005 to 2013 who received NACT at the University Hospital Birmingham were enrolled in this study. Overall survival (OS) and progression-free survival (PFS) were compared between the pCR group and non-pCR group. Demographic information and clinical or pathologic parameters were also analyzed to explore potential predictive and prognostic factors. Fourteen patients (26.4%) achieved pCR to NACT. In univariate analysis, patients with pCR had longer PFS time (p = 0.013) and OS time (p = 0.054) compared with their counterparts without pCR. In multivariate analysis, the existence of lymphovascular invasion (LVI) significantly reduced OS (HR = 17.404, 95% CI = 2.923‐103.644) and PFS (HR = 7.776, 95% CI = 1.645‐36.753). The achievement of pCR to NACT can significantly postpone the incidence of disease progression in patients with TNBC. There is not enough evidence showing its influence on ultimate survival. LVI may be a more potent prognostic factor than pCR in the TNBC cohort.</jats:p

Novel immunotherapy approaches for metastatic urothelial and renal cell carcinoma

The treatment of metastatic renal cell carcinoma (RCC) and urothelial carcinoma (UC) remains a major challenge. Past research has implicated the immune system in tumor surveillance of both malignancies, leading to the application of immunotherapy agents for both cancers. Among them, the most promising agents are the checkpoint blockade drugs, such as antibodies targeting the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death receptor 1 (PD-1), and PD-1 ligand (PD-L1). In normal physiology, these immune checkpoints act as inhibitory signals to fine-tune the duration and strength of immune reactions, which is pivotal for maintaining self-tolerance. However, tumor cells also utilize immune checkpoint pathways to evade anti-tumor immune response, leading to disease progression and metastasis. Thus, there has been intense preclinical and clinical effort focused on the application of checkpoint inhibitors in metastatic RCC and UC. To date, nivolumab (anti-PD-1) and atezolizumab (anti-PD-L1) have been approved for the treatment of metastatic RCC and UC, respectively. Despite these successes, challenges remain in how to further improve response rates to immunotherapy and how to select patients that will benefit from this approach. In this report, we review existing data and research on immunotherapy in metastatic RCC and UC. Keywords: Immune checkpoint inhibitors, Nivolumab, Atezolizumab, Pembrolizumab, Renal cell carcinoma, Urothelial carcinom

Effects of water temperature and light intensity on the performance of gravity-driven membrane system

The selection of favorable environmental conditions for gravity-driven membrane (GDM) systems is crucial to their widespread application. In this study, GDM systems operated under different light intensities (illuminance levels of 0, 200, and 3000 Lux) and water temperatures (10, 20, and 30 degrees C) were investigated for their performance and fouling layer characteristics. The results showed that indoor light (200 Lux) had limited effects on the performance of the GDM system. However, full daylight (3000 Lux) led to algal growth; these algae increased fouling resistance and deteriorated permeate water by releasing algogenic organic matter, although they could also enhance the heterogeneity of the biofouling layer by increasing the microbial activity. Water temperature rarely influenced the total organic matter removal. The fouling layers had different thicknesses and heterogeneity, but the same level of EPS; therefore, the hydraulic resistances of these fouling layer were almost the same at different water temperatures. These findings suggest that GDM system could be operated at low water temperature and indoor light conditions, and that strong light should be avoided during the operation of GDM systems. (C) 2018 Elsevier Ltd. All rights reserved