To identify novel hypoxia-associated long non-coding RNAs (lncRNAs) as potential biomarkers, we developed a risk stratification signature and constructed a prognosis prediction nomogram of clear cell renal cell carcinoma (ccRCC). Hypoxia-related lncRNAs were identified through Pearson correlation analysis between the expression profiles of hypoxia-related differentially expressed genes and lncRNAs from The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) dataset. Then, a signature of four key lncRNAs ( COMETT , EMX2OS , AC026462.3 , and HAGLR ) was developed. The four lncRNAs were downregulated in high-grade, advanced stage, and high-risk ccRCC. The signature had an independent and long-standing prognosis prediction ability up to a 10-year follow-up. Notably, the risk score was significantly positively correlated with the infiltration abundances of six immune cells from the Tumor IMmune Estimation Resource (TIMER). The gene set enrichment analysis (GSEA) also suggested that the signature was involved in metabolism and tumorigenesis, which were closely related to the hypoxic tumor microenvironment. Ultimately, a nomogram of signature, age, stage, and grade, was built to predict the individual long-term survival possibility. Finally, the expressions of four lncRNAs were validated by quantitative real-time PCR (qRT-PCR). Our study identified a four-lncRNA signature and established a prognostic nomogram that reliably predicts survival in ccRCC. The findings may be beneficial to therapeutic customization and medical decision-making.
Background: PD-L1 expression and TMB have not been approved as response biomarkers in the neoadjuvant anti-PD-(L)1 setting for resectable NSCLC, with result been discrepant across clinical trials. Previous heterogenous results are urging a meta-analysis to delineate the prediction efficiency of PD-L1 expression and TMB on pathological response in neoadjuvant PD-1/PD-L1 blockades setting. Methods: Databases including PubMed, Embase, ClinicalTrials.gov and Conference abstracts were searched for clinical trials of neoadjuvant ICIs for resectable NSCLC. Data regarding major pathological response (MPR) and pathological complete response (pCR) in patients with different pretreatment PD-L1 expression (measures by Tumor Proportion Score, TPS) and TMB were synthesized using a fixed-model meta-analysis and evaluated by odds ratio (OR) with 95% confidence interval (CI). (Registration: PROSPERO CRD42020206059) Results: This analysis included 10 studies involving 461 NSCLC patients. Compared with low PD-L1 expression (TPS<1%), PD-L1 expression≥1% was associated with higher rate of MPR (OR = 2.62, 95% CI: 1.51–4.56; P =0.0006) and pCR (OR = 2.94, 95% CI: 1.69–5.09; P = 0.0001). High-TMB (cut-off varied from 10.0 to 12.3 muts/mb) was also associated with pathological response with the pooled OR of 3.40 (95% CI: 1.33–8.70; P = 0.0109) for MPR and 1.98 (95% CI: 1.08–3.63; P = 0.0265) for pCR. Similar findings could be observed in subgroup analyses despite mono-ICI or combination with chemotherapy. Notably, TPS of 50% as cutoff value for PD-L1 expression demonstrated a better prediction efficacy for MPR [50%: OR: 3.57 (95%CI: 1.75-7.29)] than TPS of 1%. Interpretation: PD-L1 expression and TMB could be effective biomarkers for predicting pathological response in the neoadjuvant immunotherapy setting for resectable NSCLC. Funding: None to declare. Declaration of Interest: None to declare.
Ovarian cells that transcribe and translate the gene for tumor necrosis factor alpha (TNFα) were identified in the adult cyclic mouse by using in situ hybridization and immunocytochemistry. TNFα mRNA was observed in > 97% and protein was contained in ∼53% of the oocytes of healthy follicles with two or more layers of granulosa cells, but neither was detectable in oocytes of primordial follicles and follicles with a single layer of granulosa cells. In early atretic follicles, only 13% contained TNFα protein and 40% contained TNFα mRNA. In late stages of atresia, intense immunoreactive TNFα was observed in all of the oocytes, but TNFα mRNA was present in only 13%. In ∼85% of follicles, theca and/or granulosa cells exhibited TNFα mRNA hybridization signals. Macrophage-like cells within the interstitium were positive for TNFα mRNA and protein. In corpora lutea, luteal cells and macrophage-like cells contained TNFα message, while only the latter lineage contained immunoreactive TNFα. Hybridization signals and immunoreactivity were more intense in older corpora lutea than in corpora lutea of the present cycle. Northern blot analysis revealed a 2.2-kb TNFα mRNA in the ovary that was unchanged relative to 28S rRNA (constitutive RNA) during the cycle. Similarly, TNFα hybridization signals and immunoreactivity did not appear to change throughout the cycle. These results indicate that TNFα gene transcription in the oocyte coincides with the synthesis of immunoreactive TNFα and that these complex biochemical processes occur at distinct steps of follicular development in the mouse. The formation of the second layer of granulosa cells is coupled with the initial phase of TNFα gene transcription in the oocyte since TNFα mRNA and protein appear at this stage. Our findings also suggest that TNFα may be involved in various phases of follicular development, atresia, and luteal function in the mouse.
Considering the striking evidence revealed by immunotherapy in advanced or metastatic bladder cancer, investigators have explored neoadjuvant immunotherapy and chemoimmunotherapy in muscle-invasive bladder cancer (MIBC). Currently, there have been a large number of studies reporting varied efficacy and safety of these approaches. Herein, we pooled the available evidence in terms of oncological outcomes (pathological complete response [pCR] and pathological partial response [pPR]) and safety outcomes (immune-related adverse events [irAEs], treatment-related adverse events [TRAEs]), through a systematic review and meta-analysis.
Objective: To investigate the safety, feasibility and operation key points of whole lung lavage in infants with pulmonary alveolar proteinosis. Methods: The clinical manifestations, genetic screening, therapeutic interventions and outcome of an infant with pulmonary alveolar proteinosis complicated with respiratory failure who received whole lung lavage in November 2018 in Shanghai Children's Medical Center Affiliated to Shanghai Jiaotong University School of Medicine were reported. Websites including PubMed, Springer Link, China National Knowledge Infrastructure (CNKI), Weipu Database, and Wanfang Database were searched using the key words of "whole lung lavage" "pediatric" and "pulmonary alveolar proteinosis" for articles published from their establishments to April 2019. Relevant literature was reviewed. Results: A 3-month-old boy had experienced cough, shortness of breath and cyanosis for 1 week prior to admission to pediatric intensive care unit. Physical examination showed hepatosplenomegaly. Complete blood cell count showed mild anemia (hemoglobin 96 g/L) and normal white blood cells. The patient had normal C-reactive protein and normal blood platelet. Biochemical panel showed hypoalbuminemia (31 g/L), mildly elevated glutamic oxaloacetic transaminase (115 U/L) and blood ammonia (165 μmol/L), extremely elevated lactate dehydrogenase (>6 600 U/L) and hyperferritinemia (>4 500 μg/L). Chest computed tomography (CT) revealed decreased transmittance of both lungs, patchy high density shadow and ground glass opacity. Genetic testing revealed a mutation of c.625+1G>A in SLC7A7. Schiff reaction (PAS staining) in bronchoalveolar lavage fluid was positive. The patient was diagnosed with severe pneumonia, respiratory failure, lysinuria urinary protein intolerance, and pulmonary alveolar proteinosis. The patient received sequential unilateral whole lung lavage in 2 days and was successfully weaned from ventilator. He was discharged home breathing room air. Eleven articles (11 in English and non in Chinese) were reviewed. Twenty-one patients were included. After whole lung lavage, 76% (16/21) of the patients had improvement in respiratory function. Conclusions: Whole lung lavage can effectively improve respiratory failure caused by pulmonary alveolar proteinosis in infant patients. The procedure is feasible and safe.目的： 探讨婴儿全肺灌洗治疗肺泡蛋白沉积症的安全性、可行性及操作要点。 方法： 报道2018年11月上海交通大学医学院附属上海儿童医学中心重症医学科收治的1例肺泡蛋白沉积导致呼吸衰竭的患儿的临床表现、基因检查及全肺灌洗治疗方法；并以"whole lung lavage" "pediatric" "pulmonary alveolar proteinosis" "全肺灌洗" "儿童" "肺泡蛋白沉积"为检索词，检索PubMed、Springer Link、中国知网、维普、万方数据库建库至2019年4月相关文献并进行总结。 结果： 患儿男，3月龄，因"咳嗽、气促伴口唇青紫1周"入院。查体示肝脾肿大。血常规示轻度贫血（血红蛋白96 g/L），白细胞、血小板及C反应蛋白正常。白蛋白偏低（31 g/L），天冬氨酸转氨酶轻度升高（115 U/L）；乳酸脱氢酶显著升高（>6 600 U/L），铁蛋白显著升高（>4 500 μg/L），血氨轻度升高（165 μmol/L）。胸部CT显示两肺透光度减低，斑片状高密度影及磨玻璃样影。基因检查显示SLC7A7基因存在突变（c.625+1G>A）。支气管肺泡灌洗液过碘酸希夫反应（PAS染色）阳性。患儿诊断为重症肺炎、呼吸衰竭、赖氨酸尿性蛋白耐受不良、肺泡蛋白沉积症。行左右肺全肺灌洗治疗后患儿顺利撤机，脱离吸氧并出院。文献检索共11篇，中文0篇、英文11篇，纳入21例患者，进行全肺灌洗后呼吸功能好转者占76%（16/21）。 结论： 全肺灌洗可有效改善婴儿肺泡蛋白沉积导致的呼吸衰竭，改善患儿呼吸功能；且操作具有可行性及安全性。.
Intracerebral hemorrhage (ICH) is a severe stroke subtype with limited therapeutic options.Programmed cell death (PCD) is crucial for immunological balance, and includes necroptosis, pyroptosis, apoptosis, ferroptosis, and necrosis.However, the distinctions between these programmed cell death modalities after ICH remain to be further investigated.We used single-cell transcriptome (single-cell RNA sequencing) and spatial transcriptome (spatial RNA sequencing) techniques to investigate PCD-related gene expression trends in the rat brain following hemorrhagic stroke.Ferroptosis was the main PCD process after ICH, and primarily affected mature oligodendrocytes.Its onset occurred as early as 1 hour post-ICH, peaking at 24 hours post-ICH.Additionally, ferroptosis-related genes were distributed in the hippocampus and choroid plexus.We also elucidated a specific interaction between lipocalin-2 (LCN2)-positive microglia and oligodendrocytes that was mediated by the colony stimulating factor 1 (CSF1)/CSF1 receptor pathway, leading to ferroptosis induction in oligodendrocytes and subsequent neurological deficits.In conclusion, our study highlights ferroptosis as the primary PCD mechanism, emerging as early as 1 hour post-ICH.Early therapeutic intervention via the suppression of microglial LCN2 expression may alleviate ferroptosis-induced damage in oligodendrocytes and associated neurological deficits, thus offering a promising neuroprotective strategy following ICH.
Background: Immunosuppressive cell interactions are responsible for tumor progression and metastasis, as well as anti-tumor immune dysfunction. However, the communication pattern remains unclear. Methods: We first integrated two single-cell RNA-seq datasets (GSE72056 and GSE103322) of different tumor types to increase the diversity of immunosuppressive cells. Then, based on the analysis results of the communication network, gene regulatory network (GRN), and highly activated pathways, we identified the hub gene in the immunosuppressive tumor microenvironment (TME). To further explore the molecular features of the identified gene, we performed several in silico analysis and in vitro experiments including qRT-PCR and CCK-8 assay. Results: Four types of immunosuppressive cells were identified, including cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), and regulatory T cells (Tregs). Based on GRNs and the interactions of immunosuppressive cells and tumor cells, we constructed an intercellular communication signature that divided the pan-cancer TME into two clusters with distinct immunological features and different responses to immunotherapy. In combination with pathway analysis, JunB proto-oncogene (JUNB) was identified as the hub gene of the immunosuppressive TME, and it designed a non-inflamed TME of bladder cancer according to evidence that JUNB was negatively correlated with immunomodulators, chemokines, major histocompatibility complex molecules, immune cell infiltration abundances, anti-cancer immune response, and immune checkpoint inhibitors. Moreover, JUNB may predict an unfavorable response to immunotherapy. The signaling network of the four types of cells demonstrated the dominant roles of CAFs and TAMs in the TME. Further investigation uncovered that the complement signal was highly activated in the interactions between subpopulations of the inflammatory phenotype of CAFs and TAMs. Functional experiment results demonstrated the upregulated JUNB in bladder cancer tissues and low-immunity-score tissues. In addition, CAFs showed a pro-tumor proliferation effect via JUNB. Conclusion: Our findings gave insights into the immunosuppressive TME communication network and provided potential therapeutic targets.
A 19-year-old man complaining of anuria for 1 day was presented. A ureteral stent was indwelled 3 months ago for preventing ureteral obstruction and protecting kidney function. Abdominopelvic computed tomography (CT) scan revealed a solitary pelvic ectopic kidney (PEK) and severe hydronephrosis. And the ureteral stent was covered by encrustations which caused ureteral obstruction. The stent had been retained in his ureter for more than 3 months until he was admitted. It couldn't be removed after shock wave lithotripsy (SWL) or flexible ureteroscope laser lithotripsy (f-URS). Finally, we had to conduct open surgery which was an alternative option. The stent was replaced by a new one successfully. The patient was discharged safely without postoperative complications. After 2 months of follow-up, the patient's renal function remained stable.Es wurde ein 19-jähriger Patient vorgestellt, der seit einem Tag über Anurie klagte. 3 Monate zuvor war ihm zur Prävention einer Harnleiterobstruktion und zum Schutz der Nierenfunktion ein Harnleiter-Stent eingesetzt worden. Eine abdominopelvine Computertomografie (CT) zeigte eine solitäre Beckenniere und eine schwere Hydronephrose. Der Harnleiter-Stent war mit Inkrustationen bedeckt, die eine Harnleiterobstruktion verursachten. Bei Aufnahme des Patienten lag der Stent seit mehr als 3 Monaten im Harnleiter ein. Er konnte weder nach Stoßwellenlithotripsie (SWL) noch nach flexibler ureteroskopischer Laserlithotripsie (f-URS) entfernt werden. Schließlich mussten wir eine offene Operation durchführen, was eine alternative Option darstellte. Der Stent wurde erfolgreich durch einen neuen ersetzt. Der Patient wurde wohlbehalten und ohne postoperative Komplikationen entlassen. Nach zweimonatiger Nachbeobachtung war die Nierenfunktion des Patienten nach wie vor stabil.
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