PELP1 signaling contributes to medulloblastoma progression by regulating the NF-κB pathway

Medulloblastoma (MB) is the most common and deadliest brain tumor in children. Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) is a scaffolding protein and its oncogenic signaling is implicated in the progression of several cancers. However, the role of PELP1 in the progression of MB remains unknown. The objective of this study is to examine the role of PELP1 in the progression of MB. Immunohistochemical analysis of MB tissue microarrays revealed that PELP1 is overexpressed in the MB specimens compared to normal brain. Knockdown of PELP1 reduced cell proliferation, cell survival, and cell invasion of MB cell lines. The RNA-sequencing analysis revealed that PELP1 knockdown significantly downregulated the pathways related to inflammation and extracellular matrix. Gene set enrichment analysis confirmed that the PELP1-regulated genes were negatively correlated with nuclear factor-κB (NF-κB), extracellular matrix, and angiogenesis gene sets. Interestingly, PELP1 knockdown reduced the expression of NF-κB target genes, NF-κB reporter activity, and inhibited the nuclear translocation of p65. Importantly, the knockdown of PELP1 significantly reduced in vivo MB progression in orthotopic models and improved the overall mice survival. Collectively, these results suggest that PELP1 could be a novel target for therapeutic intervention in MB.     

间歇性断食对老年前期肥胖大鼠肠道菌群及代谢的影响

目的 研究间歇性断食对老年前期肥胖大鼠代谢和肠道菌群的影响.方法 雌性Wistar大鼠经42周高脂高糖饲料饲养造模,根据体质量选取模型鼠进行间歇性断食干预.干预方法为每2周断食72 h,总干预时间18周.干预后进行口服葡萄糖耐量试验、血脂4项检测.收集粪便,通过Illumina高通量测序检测16S rRNA基因V4可变区,运用QIIME及LEfSe分析肠道菌群.结果 间歇性断食组体质量相对于模型对照组显著下降(P<0.01);高密度脂蛋白胆固醇和低密度脂蛋白胆固醇均显著下降(P<0.05);空腹血糖显著上升(P<0.01);葡萄糖耐量测试曲线下面积显著高于模型对照组,糖耐量减退(P<0.05);HE染色显示间歇性断食轻度减少肝脏脂肪变性.肠道菌群结果显示,断食组肠道菌群得到显著改善,具体表现为YS2、RF32、Helicobacteraceae(螺杆菌科)增加,Lactobacillus(乳杆菌属)、Roseburia(罗氏菌属)、Erysipelotrichaceae(韦荣球菌科)、Ralstonia(青枯菌属)、Bradyrhizobiaceae(慢生根瘤菌科)和RF39减少.Spearman相关性分析发现Bradyrhizobiaceae与总胆固醇、高密度脂蛋白胆固醇呈正相关;大鼠体质量与RF39呈负相关.结论 间歇性断食能改善肠道菌群,降低老年前期肥胖大鼠体质量和血脂水平,但对糖代谢有不良影响.     

Is the modified Mallampati test performed in supine position a reliable predictor of difficult tracheal intubation?

Management of the airway is central to the practice of anesthesia. Several bedside airway assessment methods have been proposed for preoperative identification of patients who are difficult to intubate. The modified Mallampati test (MMT) remains a time-tested technique to date for recognizing an anticipated difficult tracheal intubation as assessed by Cormack–Lehane grade. Both Mallampati and its further modification by Samsoon and Young evaluate patients in the seated position. Recently a study mentioned a change in MMT score from sitting to supine position toward the higher side. However, there is a lack of data regarding the relationship of positional change in MMT with Cormack–Lehane grade. The aim of this prospective study was to assess if MMT score observed in sitting or supine position is a better predictor of difficult tracheal intubation. One hundred and twenty-three patients of ASA physical status I and II, aged 18–60 years, who were scheduled to undergo various neurosurgical procedures were enrolled for the study. We found that the MMT in supine position has a higher positive predictive value and is associated with more true positives as compared to MMT in the sitting position.     

Discovery of Imidazopyridines as Potent Inhibitors of Indoleamine 2,3-Dioxygenase 1 for Cancer Immunotherapy

Indoleamine 2,3-dioxygenase 1 (IDO1) has been identified as a target for small-molecule immunotherapy for the treatment of a variety of cancers including renal cell carcinoma and metastatic melanoma. This work focuses on the identification of IDO1 inhibitors containing replacements or isosteres for the amide found in BMS-986205, an amide-containing, IDO1-selective inhibitor currently in phase III clinical trials. Detailed subsequently are efforts to identify a structurally differentiated IDO1 inhibitor via the pursuit of a variety of heterocyclic isosteres, leading to the discovery of highly potent, imidazopyridine-containing IDO1 inhibitors.     

H2S mediates O2 sensing in the carotid body

Gaseous messengers, nitric oxide and carbon monoxide, have been implicated in O₂ sensing by the carotid body, a sensory organ that monitors arterial blood O₂ levels and stimulates breathing in response to hypoxia. We now show that hydrogen sulfide (H₂S) is a physiologic gasotransmitter of the carotid body, enhancing its sensory response to hypoxia. Glomus cells, the site of O₂ sensing in the carotid body, express cystathionine γ-lyase (CSE), an H₂S-generating enzyme, with hypoxia increasing H₂S generation in a stimulus-dependent manner. Mice with genetic deletion of CSE display severely impaired carotid body response and ventilatory stimulation to hypoxia, as well as a loss of hypoxia-evoked H₂S generation. Pharmacologic inhibition of CSE elicits a similar phenotype in mice and rats. Hypoxia-evoked H₂S generation in the carotid body seems to require interaction of CSE with hemeoxygenase-2, which generates carbon monoxide. CSE is also expressed in neonatal adrenal medullary chromaffin cells of rats and mice whose hypoxia-evoked catecholamine secretion is greatly attenuated by CSE inhibitors and in CSE knockout mice.     

Segment-2 sequence analysis and cross-neutralization studies on some Indian bluetongue viruses suggest isolates are VP2-variants of serotype 23

Sequence analysis of segment 2 (seg-2) of three Indian bluetongue virus (BTV) isolates, Dehradun, Rahuri and Bangalore revealed 99% nucleotide identity amongst them and 96% with the reference BTV 23. Phylogenetic analysis grouped the isolates in ‘nucleotype D’. The deduced amino acid (aa) sequence of the Bangalore isolate showed a high variability in a few places compared to other isolates. B-cell epitope analyses predicted an epitope that is present exclusively in the Bangalore isolate. Two-way cross serum neutralization confirmed that Bangalore isolate is antigenically different from the other two isolates. The results of this study suggest that these three isolates are VP2 variants of BTV 23. This signifies that non-cross-neutralizing variants of the same BTV serotype should be included in vaccine preparation.     

A clinical study assessing the tolerability and biological effects of infliximab, a TNF-alpha inhibitor, in patients with advanced cancer

BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) is an important regulator of the chronic inflammation contributing to tumour progression. Infliximab, an anti-TNF-alpha monoclonal antibody was investigated in this trial of patients with advanced cancer. The primary objectives were to determine the safety profile and biological response of infliximab in a cancer population. Clinical response was a secondary objective. PATIENTS AND METHODS: Forty-one patients received infliximab at 5 mg/kg (n = 21) or 10 mg/kg (n = 20) i.v. at 0 and 2 weeks and then every 4 weeks. Post-treatment samples were measured for changes in plasma and serum TNF-alpha, CCL2, IL-6 and C-reactive protein (CRP). RESULTS: Infliximab was well tolerated with no dose-limiting toxic effects. At both doses of infliximab, neutralisation of serum TNF-alpha was observed after 1 h while plasma CCL2, IL-6 and serum CRP were decreased 24 and 48 h following infliximab administration. Seven patients experienced disease stablisation (range 10-50+ weeks). There was no evidence of disease acceleration in any patient. CONCLUSIONS: Infliximab treatment was safe and well tolerated in patients with advanced cancer. There was evidence of biological activity with baseline TNF-alpha and CCL2 being correlated with infliximab response.