[Therapeutic effect of nivolumab on non-small-cell lung cancer patients with brain metastases: a retrospective study].

Objective: To preliminarily explore the treatment effect of nivolumab on Chinese non-small-cell lung cancer (NSCLC) patients with brain metastases, and further enrich the evidences of programmed death-ligand 1 (PD-1) monoclonal antibody in the treatment of NSCLC patients with brain metastases. Methods: The clinical and pathological data of 22 NSCLC patients with brain metastases treated with nivolumab were collected. The electronic imaging data were collected to confirm the treatment effect and time point of disease progression, and the survival data of the patients were obtained through follow-up. Results: Twenty-one patients were evaluated for the intracranial treatment effect. The intracerebral objective response rate (IORR) was 28.6%, the intracranial disease control rate (IDCR) was 47.6%. The median intracranial progression-free-survival (iPFS) of all the 22 patients was 5.2 months. Both the 1-year and 2-year survival rates were 56.7%. Conclusions: The treatment effect of PD-1 monoclonal antibody on NSCLC patients with brain metastases is similar as those without brain metastases.

Let-7 derived from endometrial extracellular vesicles is an important inducer of embryonic diapause in mice.

Embryonic diapause is a maternally controlled phenomenon. The molecule controlling the onset of the phenomenon is unknown. We demonstrated that overexpression of microRNA let-7a or incubation with let-7g-enriched extracellular vesicles from endometrial epithelial cells prolonged the in vitro survival of mouse blastocysts, which developed into live pups after having been transferred to foster mothers. Similar to in vivo dormant blastocysts, let-7-induced dormant blastocysts exhibited low level of proliferation, apoptosis, and nutrient metabolism. Let-7 suppressed c-myc/mTORC1 and mTORC2 signaling to induce embryonic diapause. It also inhibited ODC1 expression reducing biosynthesis of polyamines, which are known to reactivate dormant embryos. Furthermore, the overexpression of let-7 blocked trophoblast differentiation and implantation potential of human embryo surrogates, and prolonged survival of human blastocysts in vitro, supporting the idea that embryonic diapause was an evolutionary conserved phenomenon. In conclusion, let-7 is the main factor inducing embryonic diapause.

[Influence of genetic variation of programmed death-ligand 1 (PD-L1) on the prognosis of patients with non-small cell lung cancer who received platinum-based adjuvant chemotherapy].

Objective: The aim of present study was to investigate the influence of genetic variation of programmed death-ligand 1 (PD-L1) on the prognosis of patients with non-small cell lung cancer (NSCLC) who received platinum-based adjuvant chemotherapy. Methods: This study was designed as a retrospective analysis, and a total of 278 patients with postoperative NSCLC who received platinum-based adjuvant chemotherapy from January 2012 to December 2018 in the Department of Respiratory Medicine of the First affiliated Hospital of Zhengzhou University were included in this study. Biological specimens of the patients were collected during hospitalization. Recurrence status and adverse reactions were evaluated in the hospital during adjuvant chemotherapy. Survival data of the patients were obtained through telephone follow-up after completing the fixed cycle of adjuvant chemotherapy. DNA extracted from the collected hematological specimens was genotyped for PD-L1 gene polymorphism. Additionally, postoperative cancer tissue specimens from 68 patients were collected for RNA extraction in order to perform the PD-L1 mRNA expression analysis. The univariate analysis of genotypes and prognosis was carried out by Kaplan-Meier survival analysis. Results: Prognostic results indicated that the median disease-free survival (DFS) of the 278 patients with NSCLC was 3.2 years and the median overall survival (OS) was 4.9 years. The prevalence of -1813G>C polymorphism were: GG genotype 173 cases (62.23%), GC genotype 92 cases (33.09%), CC genotype 13 cases (4.68%), the minor allele frequency was 0.21, the distribution of the three genotypes was in accordance with Hardy-Weinberg Equilibrium (P=0.864). In view of the rare frequency of CC genotype, GC and CC genotype were merged in the following analysis. The survival analysis results of the two genotype groups suggested that the median DFS of patients with GG and GC/CC genotype was 2.7 and 4.0 years, which was statistically significant (P=0.013). Furthermore, the median OS of patients with GG and GC/CC was 4.0 and 5.4 years respectively, which was statistically significant as well (P=0.009). However, the safety analysis failed to find the significant association between the polymorphism and adverse events (P>0.05). Interestingly, expression analysis of RNA extracted from cancer tissues specimens indicated that the PD-L1 mRNA expression of the patients with GG genotype were significantly higher than those of the GC/CC genotype (3.67±0.65 vs 2.69±0.78, P<0.001). Conclusion: The prognosis of patients with postoperative non-small cell lung cancer who received platinum-based adjuvant chemotherapy is influenced by -1813G>C polymorphism of PD-L1 gene.

Treatment of bone loss in proximal femurs of postmenopausal osteoporotic women with AGN1 local osteo-enhancement procedure (LOEP) increases hip bone mineral density and hip strength: a long-term prospective cohort study.

This first-in-human study of AGN1 LOEP demonstrated that this minimally-invasive treatment durably increased aBMD in femurs of osteoporotic postmenopausal women. AGN1 resorption was coupled with new bone formation by 12 weeks and that new bone was maintained for at least 5-7 years resulting in substantially increased FEA-estimated femoral strength. INTRODUCTION: This first-in-human study evaluated feasibility, safety, and in vivo response to treating proximal femurs of postmenopausal osteoporotic women with a minimally-invasive local osteo-enhancement procedure (LOEP) to inject a resorbable triphasic osteoconductive implant material (AGN1). METHODS: This prospective cohort study enrolled 12 postmenopausal osteoporotic (femoral neck T-score ≤ - 2.5) women aged 56 to 89 years. AGN1 LOEP was performed on left femurs; right femurs were untreated controls. Subjects were followed-up for 5-7 years. Outcomes included adverse events, proximal femur areal bone mineral density (aBMD), AGN1 resorption, and replacement with bone by X-ray and CT, and finite element analysis (FEA) estimated hip strength. RESULTS: Baseline treated and control femoral neck aBMD was equivalent. Treated femoral neck aBMD increased by 68 ± 22%, 59 ± 24%, and 58 ± 27% over control at 12 and 24 weeks and 5-7 years, respectively (p < 0.001, all time points). Using conservative assumptions, FEA-estimated femoral strength increased by 41%, 37%, and 22% at 12 and 24 weeks and 5-7 years, respectively (p < 0.01, all time points). Qualitative analysis of X-ray and CT scans demonstrated that AGN1 resorption and replacement with bone was nearly complete by 24 weeks. By 5-7 years, AGN1 appeared to be fully resorbed and replaced with bone integrated with surrounding trabecular and cortical bone. No procedure- or device-related serious adverse events (SAEs) occurred. CONCLUSIONS: Treating femurs of postmenopausal osteoporotic women with AGN1 LOEP results in a rapid, durable increase in aBMD and femoral strength. These results support the use and further clinical study of this approach in osteoporotic patients at high risk of hip fracture.

Connecting the Sequence-Space of Bacterial Signaling Proteins to Phenotypes Using Coevolutionary Landscapes.

Two-component signaling (TCS) is the primary means by which bacteria sense and respond to the environment. TCS involves two partner proteins working in tandem, which interact to perform cellular functions whereas limiting interactions with non-partners (i.e., cross-talk). We construct a Potts model for TCS that can quantitatively predict how mutating amino acid identities affect the interaction between TCS partners and non-partners. The parameters of this model are inferred directly from protein sequence data. This approach drastically reduces the computational complexity of exploring the sequence-space of TCS proteins. As a stringent test, we compare its predictions to a recent comprehensive mutational study, which characterized the functionality of 204 mutational variants of the PhoQ kinase in Escherichia coli We find that our best predictions accurately reproduce the amino acid combinations found in experiment, which enable functional signaling with its partner PhoP. These predictions demonstrate the evolutionary pressure to preserve the interaction between TCS partners as well as prevent unwanted cross-talk. Further, we calculate the mutational change in the binding affinity between PhoQ and PhoP, providing an estimate to the amount of destabilization needed to disrupt TCS.

Novel laryngoscopic strategies to improve evaluation of the site and extent of primary hypopharyngeal tumours.

OBJECTIVE: To investigate different strategies for displaying the hypopharynx and oesophageal entrance during laryngoscopy for hypopharyngeal cancer. PATIENTS AND METHODS: A total of 113 patients with hypopharyngeal cancer underwent laryngoscopy prior to surgery. The hypopharynx was displayed by: (1) pulling the anterior cervical skin; (2) having the patient perform the Valsalva balloon-blowing manoeuvre; and (3) injecting oxygen through the biopsy channel to expose the oesophageal entrance. The effect of these methods on visualisation of primary tumour size and extent was assessed. RESULTS: During pronunciation of the letter 'e', the hypopharynx was displayed in only 33 patients (29.2 per cent); with anterior cervical skin traction plus the balloon-blowing manoeuvre, the hypopharynx was displayed in 106 patients (93.8 per cent; p < 0.001). The combined strategy was superior especially when judging the extent of posterior pharyngeal wall and postcricoid invasion. Oesophageal entrance involvement was visible in 33 patients upon injecting oxygen through the laryngoscopic biopsy channel, and in 25 patients during radiological examination; laryngoscopy was superior to radiological examination in determining the extent of oesophageal entrance invasion (p = 0.003). CONCLUSION: Adequate laryngoscopic display of the hypopharynx could increase the accuracy of pre-treatment hypopharyngeal cancer staging.