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Let $(X,J,\omega)$ be a complete $2n$-dimensional almost K\"{a}hler manifold. First part of this article, we construct some identities of various Laplacians, generalized Hodge and Serre dualities, a generalized hard Lefschetz duality, and a Lefschetz decomposition, all on the space of $\ker{\Delta_{\partial}}\cap\ker{\Delta_{\bar{\partial}}}$ on pure bidegree. In the second part, as some applications of those identities, we establish some vanishing theorems on the spaces of $L^{2}$-harmonic $(p,q)$-forms on $X$ under some growth assumptions on the K\"{a}her form $\omega$. We also give some $L^{2}$-estimates to sharpen the vanishing theorems in two specific cases. At last of the article, as an application, we study the topology and geometry of the compact almost K\"{a}hler manifold with negative sectional curvature., Comment: 33 pages, Submitted. We have added some references. Since Proposition 4.5 can be obtained directly from Lemma 3.2 in [43], we remove its proof

Let $(X,J,ω)$ be a complete $2n$-dimensional almost Kähler manifold. First part of this article, we construct some identities of various Laplacians, generalized Hodge and Serre dualities, a generalized hard Lefschetz duality, and a Lefschetz decomposition, all on the space of $\ker{Δ_{\partial}}\cap\ker{Δ_{\bar{\partial}}}$ on pure bidegree. In the second part, as some applications of those identities, we establish some vanishing theorems on the spaces of $L^{2}$-harmonic $(p,q)$-forms on $X$ under some growth assumptions on the Käher form $ω$. We also give some $L^{2}$-estimates to sharpen the vanishing theorems in two specific cases. At last of the article, as an application, we study the topology and geometry of the compact almost Kähler manifold with negative sectional curvature., 33 pages, Submitted. We have added some references. Since Proposition 4.5 can be obtained directly from Lemma 3.2 in [43], we remove its proof

Supplementary Material 1

Communication between the maternal uterus and the embryo is vital for a successful pregnancy. Exosomes, subtypes of extracellular vesicles comprising many bioactive factors, regulate the early stages of pregnancy, specifically during embryo implantation. Nevertheless, the mechanism by which exosomal microRNAs (miRNAs) derived from placental trophoblasts regulate embryo implantation remains elusive. We isolated and identified exosomes derived from placental trophoblast cells (HTR8/SVneo). Subsequently, we evaluated the loading miRNA in exosomes by small RNA sequencing. Consequently, we showed that trophoblast cell-derived exosomes could transfer to endometrial epithelial cells. Besides, these exosomes promoted the epithelial-mesenchymal transition (EMT) as well as migration of endometrial cells and were implicated in the regulation of inflammation. Further, the specific miRNAs were screened in exosomes, and as a result, miRNA (miR)-1290 was enriched specifically in exosomes. miR-1290 promoted the expression of inflammatory factors (interleukin [IL]-6 and IL-8) and migration of endometrial epithelial cells. In addition, exosomal miR-1290 promoted angiogenesis in vitro. More importantly, by targeting LHX6, trophoblast HTR8/SVneo cell-derived exosomal miR-1290 promoted the EMT process of endometrial epithelial cell HEC-1-A. Altogether, our findings provide novel insights into the mechanism of trophoblast cell-derived exosomes during embryo implantation., Graphical abstract, Trophoblast cell-derived exosomal miR-1290 delivered to endometrial epithelial cells and target LHX6, thereby promoting the EMT process. This mechanism is important for successful embryo implantation.

Described here is a selective synthesis of 2,3-dihydropyrrole-fused N-glycosides through rhodium-catalyzed denitrogenative transannulation of N-sulfonyl-1,2,3-triazoles with glycals. A series of pyrroline-fused N-glycosides are afforded in moderate to excellent yields with exclusive regioselectivity and stereoselectivity. Functional application of such a resultant product by oxidative addition and epoxidation is also explored. Notably, the treatment of a pyrroline-fused N-glycoside (3a) with TMSOTf efficiently leads to an interesting unexpected C-nucleoside (9) via a TMSOTf-inducing ring opening/acetyl migration/ring closing reaction sequence.

Communication between maternal uterus and blastocyst occurs in the early stages of pregnancy, and the interaction influences the success of embryo implantation. Whereas small extracellular vesicles (sEVs) play an essential role in mediating intercellular communication in numerous biological processes, their role in embryo implantation during the window of implantation (WOI) remains poorly defined. Here, we report that endometrial epithelial cells (EECs) secrete sEVs during early pregnancy, which affects the trophoblast behaviors (migration, invasion, and proliferation), thus influencing embryo implantation. We show that microRNA (miR)-100-5p, sEVs containing microRNA (miRNA), activates both focal adhesion kinase (FAK) and c-Jun N-terminal kinase (JNK), as well as contributes to trophoblast migration and invasion. Furthermore, our findings indicate that the sEV miR-100-5p promotes angiogenesis during the implantation process. In conclusion, this study reveals a novel mechanism by which EEC-derived sEV miR-100-5p crosstalks with trophoblasts, leading to an enhanced ability for implantation., Graphical Abstract, The receptive endometrial cell-derived small extracellular vesicle miR-100-5p promotes the migration, invasion, and proliferation of trophoblast cells, as well as angiogenesis, thereby promoting embryo implantation in the early stage of pregnancy.

Embryo implantation plays a decisive role in pregnancy. While in the process of implantation, microRNA (miRNA) is an important regulatory factor in the post transcriptional level. However, the role of many miRNAs in embryo implantation remained unknown. In this study, microRNA-183 (miR-183) was found differentially expressed in mouse uterus during implantation. In vivo treatment of miR-183 agomir in the uterine horn before implantation could eliminate the number of implantation site. The localization of miR-183 in mouse uteri gradually changed from epithelial to stromal layer in early pregnancy. Mice implantation models demonstrated that the decrease of miR-183 was mainly caused by maternal factors. Loss and gain function of miR-183 in endometrial cell lines showed that miR-183 could inhibit cell migration, invasion and apoptosis. MiR-183 could inhibit embryo implantation by binding Heparin-Binding EGF-like growth factor (Hbegf) and Laminin gamma one (Lamc1), which were key genes in embryo apposition and penetration. All these evidences indicate that miR-183 plays an important role during embryo implantation. This study provides new insights into the functions of miR-183 during embryo implantation and the development of contraceptive drugs in early pregnancy.

Additional file 1. Statistical Results in Figures.

Additional file 2: Supplementary Results.

Additional file 3: Supplementary Figures. Figure S1. Mutation statistics of all curated samples. (A) Regimen combinations of the 14 NSCLC patients. (B) Chemotherapeutic drugs and immunotherapy agents used by each patient. (C) Neoadjuvant immunotherapy duration time distribution between MPR and Non-MPR groups. (D) Correlation between PD-L1 expression and percentage of viable tumor cells in patients. (E) Mutation number retained after filtrations. (F) Mutation number distribution on MPR/Non-MPR and FFPE/Frozen specimen. (G) Six substitution type spectrum plot in two patient groups. P-values were shown above each substitution category. (H) Exposures of three types of mutation signature to known database. SBS: single base substitution; ID: InDel; DBS: double base substitution. Either sum or log2 fold change of the absolute exposures was addedly depicted. (I) Percentage of altered tumor suppressor genes enriched in multiple DNA repair-related pathways in MPR and Non-MPR group. Figure S2. SCNA statistical and signature analyses results in groups with distinct therapeutic response. (A) Chromosome level CNV burden between MPR/Non-MPR groups. (B) Arm level CNV burden in two groups. (C) Chromosome level CNV burden between squamous cell carcinoma (SCC) MPR/Non-MPR patients. (D) Arm level CNV burden in two SCC patient groups. (E) Correlation between chromosome level CNV burden and percentage of viable tumor cells. (F) Correlation between arm level CNV burden and percentage of viable tumor cells. (G) Percentage of genome amplified in two groups. (H) Percentage of genome deleted in two groups. (I) Percentage of genome amplified in SCC patients. (J) Percentage of genome deleted in SCC patients. (K) SCNA heatmap only plotting copy number alternations exceeding the threshold +/-0.2. Two aneuploid samples were marked by pink circles. (L) Contributions of three SCNA signatures in all samples. Adenocarcinoma samples were marked with pink triangles. (M) Proportion of SCNA Signature 1 in patients. (N) Proportion of SCNA Signature 7 in patients. (O) Proportion of SCNA Signature 5 in patients. (P) Proportion of SCNA Signature 1 in SCC patients. (Q) Proportion of SCNA Signature 7 in SCC patients. (R) Proportion of SCNA Signature 5 in SCC patients. Figure S3. HRDscore in non-aneuploid SCC samples. (A) HRDscore calculated on non-aneuploid SCC samples. (B) Correlation between HRDscore and percentage of viable tumor cells in all non-aneuploid SCC samples. Figure S4. Multidimensional ITH comparison results between MPR/Non-MPR groups. (A) TMB value distribution in SCC samples. (B) Correlation between TMB and percentage of viable tumor cells in SCC samples. (C) Clonal TMB value in two groups, only selecting SCC patients. (D) Correlation between clonal TMB and percentage of viable tumor cells on SCC samples. (E) Germline HR pathway gene mutation number in MPR/Non-MPR groups. (F) Subclonal SCNA fragment number in two groups, only selecting SCC samples. (G) Correlation between subclonal SCNA fragment number and percentage of viable tumor cells, only selecting SCC samples. Figure S5. Investigation on the neoantigen load difference between patients with distinct outcomes. (A) TNB in two groups. (B) Correlation between TNB values and percentage of viable tumor cells. (C) TNB in two groups, only selecting SCC samples. (D) Correlation between TNB values and percentage of viable tumor cells, only selecting SCC samples. (E) Clonal TNB value distribution in two groups, only selecting SCC samples. (F) Correlation between clonal TNB and percentage of viable tumor cells, only selecting SCC samples. (G) HLA LOH frequency in MPR/Non-MPR groups. (H) TNB value on kept HLA alleles. (I) Correlation between TNB on kept HLA alleles and percentage of viable tumor cells. (J) TNB value on kept HLA alleles, only selecting SCC samples. (K) Correlation between TNB on kept HLA alleles and percentage of viable tumor cells, only selecting SCC samples. (L) Clonal TNB value on kept HLA alleles. (M) Correlation between clonal TNB on kept HLA alleles and percentage of viable tumor cells. (N) Clonal TNB value on kept HLA alleles, only selecting SCC samples. (O) Correlation between clonal TNB on kept HLA alleles and percentage of viable tumor cells, only selecting SCC samples. Figure S6. Comprehensive analysis on clonal neoantigen and SCNA bring insights to the function of SCNA on neoantigen generation. (A) Percentage of kept clonal neoantigens on SCNA regions in two groups. (B) Correlation between CNV-related neoantigen proportion and percentage of viable tumor cells. (C) Percentage of kept clonal neoantigens on SCNA regions in two groups, only selecting SCC samples. (D) Correlation between CNV-related neoantigen proportion and percentage of viable tumor cells, only selecting SCC samples. (E) Number of clonal neoantigen on kept HLA alleles and their distribution on 3 types of SCNAs. Adenocarcinoma samples were marked with pink triangles. The sample with ATR mutation was marked with arrow. (F) Correlation between clonal neoantigen number on amplified segments and percentage of viable tumor cells. (G) Correlation between clonal neoantigen number on amplified segments and percentage of viable tumor cells, only selecting SCC samples. (H) Correlation values on all 11 non-aneuploid and high purity samples, calculated by Spearman Correlation Coefficient (SCC). (I) Similar with (H), the correlation values were on MPR samples. (J) Similar with (H), the correlation values were on Non-MPR samples. Figure S7. Investigation on HR pathway gene alternation frequency in patients with distinct response from public cohorts. (A) HR pathway gene mutation frequency in J Immunother Cancer. 2020 neoadjuvant dataset. Left: in pCR patients. Middle: in other patients. Right: percentage of distinct mutant reads for each HR gene mutation detected. Mutations from pCR patients were marked with red color. (B) HR pathway gene mutation frequency in N Engl J Med. 2018 neoadjuvant dataset. Left: in MPR patients. Middle: in Non-MPR patients. Right: percentage of distinct mutant reads for each HR gene mutation detected. Mutations from MPR patients were marked with red color. (C) HR pathway gene mutation frequency in DCB patients from Nat Genet. 2018 dataset. Left: all and clonal HR gene mutations. Right: all and clonal HR core pathway mutations. (D) Similar with (C), but using non-DCB patients. (E) Similar with (C), but using J Clin Oncol. 2018 dataset. (F) Similar with (C), but using NDB patients. (G) HR pathway gene mutation frequency in patients achieved DCB in chemotherapy from Cancer Discov. 2017 dataset. (H) Similar with (G), but in NDB patients. (I) HR pathway gene SCNA frequency in patients achieved DCB in chemotherapy from Cancer Discov. 2017 dataset. Left: HR gene SCNAs. Right: HR core pathway gene SCNAs. (J) Similar with (I), but in NDB patients. (K) HR pathway gene mutation frequency in patients achieved CR and PR in chemotherapy from Nat Med. 2018 dataset. Left: all and clonal HR gene mutations. Right: all and clonal HR core pathway mutations. (L) Similar with (K), but in other patients. (M) Similar with (K), but using patients received immunotherapy. (N) Similar with (M), but in other patients. Figure S8. Comparisons on TMB values stratified by therapeutic response and HR pathway gene status from public cohorts. (A) TMB and clonal TMB value distribution between DCB and other patients in non-squamous population from Nat Genet. 2018 dataset. Left: TMB. Right: clonal TMB. (B) Similar with (A) but using HR pathway gene clonal mutations as the stratification strategy. (C) TMB value distribution between DCB and NDB patients in J Clin Oncol. 2018. (D) Similar with (C) but focusing on different histological subtypes. Left: in adenocarcinoma subgroup. Right: in squamous subgroup. (E) Similar with (D) but using HR pathway gene mutation as the classification strategy. (F) Clonal TMB value distribution between patients stratified by HRD event in J Clin Oncol. 2018 dataset. Left: between patients with and without HR pathway gene mutation. Right: between patients with and without HR pathway gene clonal mutation. (G) TMB value distribution between CR+PR and other immunotherapy patients in Nat Med. 2018 dataset. (H) Similar with (G) but focusing on different histological subtypes. Left: in non-squamous subgroup. Right: in squamous subgroup. (I) TMB value distribution between CR+PR patients with HRD and other CR+PR patients in Nat Med. 2018. (J) Similar with (F), but in Nat Med. 2018 dataset. Figure S9. Survival analyses and TMB comparisons on HRD event-stratified patients in multiple public cohorts. (A) PFS of patients stratified by HR gene mutational condition in Nat Genet. 2018 dataset. Left: between patients with and without HR gene mutation. Right: between patients with and without HR gene clonal mutation. (B) Similar with (A), but on OS data. (C) Similar with (A) but in all patients from J Clin Oncol. 2018 cohort. (D) Similar with (C) but in adenocarcinoma patients. (E) Similar with (C), but in squamous patients. (F) PFS and TMB of all DCB patients with and without HR gene mutations in Nat Genet. 2018 cohort. (G) Similar with (F) but on OS data. (H) Similar with (F) but using HR pathway gene clonal mutations as the classification strategy. (I) Similar with (H) but on OS data. (J) Similar with (F) but in patients from J Clin Oncol. 2018 cohort. Figure S10. Survival analyses and TMB comparisons conducted on Nat Med. 2018 blood cohort. (A) Survival and TMB of all chemo-treated non-squamous patients with and without HR gene mutations. Left: OS. Middle: PFS. Right: TMB distribution. (B) Similar with (A) but on squamous patients. (C) Similar with (A) but on patients received immunotherapy. (D) Similar with (C) but on squamous patients. (E) Survival and TMB of all HR pathway-mutant patients treated with immunotherapy and chemotherapy. Left: OS. Middle: PFS. Right: TMB distribution. (F) Similar with (E) but among patients with HR gene clonal mutations. Figure S11. Investigation on HR pathway gene alternation frequency and HRD events in multiracial untreated patients. (A) HR pathway gene mutation frequency in Sci Rep. 2015 dataset. Left: all and clonal HR gene mutations. Right: all and clonal HR core pathway mutations. (B) Similar with (A), but in J Thorac Oncol. 2020 cohort. (C) Similar with (A), but in TCGA-LUAD dataset. (D) Similar with (A), but in TCGA-LUSC dataset. (E) HR pathway gene alternation frequency in TCGA-LUAD dataset. (F) Similar with (E), but in TCGA-LUSC dataset. (G) Correlation between CNV burden and HRDscore in TCGA-LUAD dataset. (H) Similar with (G), but in TCGA-LUSC dataset.

Objectives Food and Drug Administration (FDA) approved crizotinib for advanced ROS1‐rearranged (ROS1+) non‐small‐cell lung cancer (NSCLC) patients due to a single‐arm study PROFILE 1001. However, there is no direct comparison between crizotinib and platinum‐pemetrexed chemotherapy. Materials and methods Clinical data of advanced ROS1+NSCLC patients treated with first‐line crizotinib or platinum‐pemetrexed chemotherapy between August 2010 and December 2017 were analyzed. Results Seventy‐seven patients were eligible, including 30 (39.0%) in the crizotinib group and 47 (61.0%) in the platinum‐pemetrexed chemotherapy group. The median follow‐up was 28.1 months (95% confidence interval [CI]: 19.2‐39.0). The objective response rate (ORR) of crizotinib (86.7%, 95% CI: 73.3‐96.7) was higher than that of platinum‐pemetrexed chemotherapy (44.7%, 95% CI: 29.8‐57.4, P, This is the first study to compare crizotinib with chemotherapy in ROS1+NSCLC. Crizotinib was superior to platinum‐pemetrexed chemotherapy as an initial treatment.

Objective To study the differential DNA methylation in the hippocampus of rats exposed to benzo(a)pyrene and explore the mechanism of benzo(a)pyrene-induced functional impairment of the hippocampus. Methods Twenty male SD rats (3 weeks old) were randomly divided into control group and benzo(a)pyrene exposure group (n=10), and in the latter group, the rats were exposed to benzo(a)pyrene delivered via gavage on a daily basis for 7 consecutive weeks. After the exposure, Morris water maze test was performed to assess the changes in the spatial memory and learning ability of rats; the brain tissues were dissected for morphological examination of the hippocampal neurons with HE staining. Reduced representation bisulfite sequencing (RRBS) of the genomic DNA from the hippocampus was performed, followed by GO and KEGG analyses of the sequencing data; qRT-PCR was used to detect the expression levels of Tnr and Pla2g2a mRNAs. Results Morris water maze test and HE staining showed that exposure to benzo(a)pyrene resulted in obvious impairment of the spatial learning and memory abilities and caused hippocampal injuries in rats. DNA methylation sequencing identified 32 differentially methylated regions; GO analysis enriched 871 GO items and KEGG analysis obtained 52 pathways, of which 145 GO items and 11 pathways were significantly enriched (P < 0.05). Compared with the control rats, the benzo(a)pyrene-exposed rats showed significantly decreased Tnr mRNA expression and increased Pla2g2a mRNA expressions in the hippocampus(P < 0.05). Conclusion A number of differentially methylated sites occur in the genomic DNA in rat hippocampus following benzo(a)pyrene exposure, and these sites may provide important clues in exploring the mechanism of benzo(a)pyrene-induced hippocampal injury.

MicroRNA-183(miR-183) is abnormally expressed in many kinds of tumors. It participates in the initiation and development of tumors. There are many pathways regulate the expression of miR-183. The action mechanism of miR-183 in cancer is very extensive, and contradictory conclusions are often drawn. It was upregulated in 18 kinds of cancer, downregulated in 6 kinds of cancer. In addition, there are seven types of cancer, both upregulated and downregulated reports can be found. Evidence showed that miR-183 can not only directly play the role of oncogene or antioncogene, but also regulate the expression of other oncogene or antioncogene in different cancer types. In this review, we discuss the regulator of miR-183 and summarized the expression of miR-183 in different cancers. We also counted the target genes of miR-183 and the functional roles they play. Furthermore, we focused on the roles of miR-183 in cell migration, cell invasion, epithelial-mesenchymal transition (EMT) and microangiogenesis, which play the most important roles in cancer processes. It sheds light on the likely reasons why miR-183 plays different roles in various cancers. In addition, miR-183 and its downstream effectors have the potential to be promising prognostic markers and therapeutic targets in cancer.

Objective To investigate the effect of astrocyte-microglia crosstalk mediated by complement C3/C3aR signaling on hydrocephalus after germinal matrix hemorrhage (GMH) in newborn rats. Methods GMH was induced in post-natal day 7 SD rats by collagenase Ⅶ-S injection into the ganglionic eminence. We detected the changes in the expression of periventricular C3 and C3aR over time after GMH, and observed the effect of intraperitoneal injection of C3aRA (a selective C3aR antagonist) on hydrocephalus using magnetic resonance imaging (MRI). The learning and memory functions of the rats were tested after the treatment using Morris water maze test, and the expression of interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1) and aquaporin 4 in the brain tissues were detected using Western blotting at different time points after GMH. Results The neonatal rats with GMH showed significantly up-regulated expression of C3 and C3aR around the cerebral ventricles and increased expression of IL-1β, IL-6, TNF-α and TGF-β1 in the brain, presenting also with obvious lateral ventricle dilation, compression of the cortex and hippocampus, and impairment of the learning and memory functions. Treatment of the rats with C3aRA obviously decreased C3 and C3aR expression, alleviated hydrocephalus, improved the neurological deficits, and reduced the expression of the inflammatory factors in the brain. GMH caused obvious ectopic expression of aquaporins 4 and increased its expression level on the astrocytes, and C3aRA treatment significantly improved the abnormal expression of aquaporins 4. Conclusion GMH causes the astrocytes to up-regulate and release C3, which binds to C3aR on the microglia to promote inflammation and aggravate hydrocephalus. The ectopic expression of aquaporin 4 in astrocytes may play an important role in the occurrence of hydrocephalus following GMH. rats newborn

During the process of DNA replication, insertions or deletions of repeat sequences easily occur in microsatellites due to DNA polymerase slippage in instances of defective mismatch repair; this phenomenon is known as microsatellite instability. Based on genetic profiling, microsatellite instability gastric cancer is regarded as a separate subtype of gastric cancer that is associated with old age, the female sex, a distal gastric location, and a lower number of lymph node metastases. According to numerous retrospective studies, microsatellite instability is a favourable predictive marker for prognosis. However, during the perioperative period, gastric cancer patients with microsatellite instability after chemotherapy often exhibit a poor and unfavourable prognosis. This result still remains controversial. The efficacy of adjuvant chemotherapy in microsatellite instability-high tumours ranges from detrimental to beneficial effects. Due to the widespread expression of immune checkpoint molecules (such as programmed death-1 and programmed death-ligand 1) in tumours with microsatellite instability, immune checkpoint inhibitors have been utilized to treat microsatellite instability gastric cancer and tremendously improve the efficacy of treatment and survival of microsatellite instability patients. In this review, we attempt to outline the definitions of microsatellites and microsatellite instability, the methods used to screen for microsatellite instability, the clinical characteristics of microsatellite instability gastric cancer, and its responses to chemotherapy and immune checkpoint inhibitor treatment. Overall, determining the status of microsatellites is essential before developing a tailored treatment strategy for patients with microsatellite instability gastric cancer.

Background: MicroRNAs (miRNAs) play key roles in posttranscriptional regulation during the window of implantation. However, which miRNA may play regulatory role during the window of implantation remains to be studied in depth. This paper aimed to explore the miRNAs that played regulatory roles during the process of implantation. Methods: RNA sequencing was performed to analyze mice uterus tissue in gestation day 1 (D1), gestation day 4 (D4) and gestation day5 (D5). The tissues in D5 were divided into embryo implantation sites (D5IMS) and inter-implantation sites (D5IIS). The differentially expressed miRNAs were screened and bioinformatics analyzed. Transfecting miR-183-5p mimics into HEC-1-A cells, genes regulated by miR-183-5p were analyzed by transcriptome sequencing. Result: Eleven differentially expressed miRNAs were identified during the window of implantation. KEGG enrichment analysis showed that the most differentially expressed miRNAs mainly related to binding and signaling transduction related pathways. Especially miR-183-5p, miR-182-5p, miR-199b-5p and miR-218-5p play a crucial role in regulating many important pathways. Transcriptome sequencing results showed that there were 19 up-regulated and 31 down-regulated genes in the miR-183-5p mimics group compared with the negative control (NC) group. This work laid a foundation for the study of miRNA in early pregnancy.

Endometrial cancer is one of the most prevalent tumors of the female reproductive system causing serious health effects to women worldwide. Although numerous studies, including analysis of gene expression profile and cellular microenvironment have been reported in this field, pathogenesis of this disease remains unclear. In this study, we performed a system bioinformatics analysis of endometrial cancer using the Gene Expression Omnibus (GEO) datasets (GSE17025, GSE63678, and GSE115810) to identify the core genes. In addition, exosomes derived from endometrial cancer cells were also isolated and identified. First, we analyzed the differentially expressed genes (DEGs) between endometrial cancer tissues and normal tissues in clinic samples. We found that HAND2-AS1, PEG3, OGN, SFRP4, and OSR2 were co-expressed across all 3 datasets. Pathways analysis showed that several pathways associated with endometrial cancer, including “p53 signaling pathway”, “Glutathione metabolism”, “Cell cycle”, and etc. Next, we selected DEGs with highly significant fold change and co-expressed across the 3 datasets and validated them in the TCGA database using Gene Expression Profiling Interactive Analysis (GEPIA). Finally, we performed a survival analysis and identified four genes (TOP2A, ASPM, EFEMP1, and FOXL2) that play key roles in endometrial cancer. We found up-regulation of TOP2A and ASPM in endometrial cancer tissues or cells, while EFEMP1 and FOXL2 were down-regulated. Furthermore, we isolated exosomes from the culturing supernatants of endometrial cancer cells (Ishikawa and HEC-1-A) and found that miR-133a, which regulates expression of FOXL2, were present in exosomes and that they could be delivered to normal endometrial cells. The common DEGs, pathways, and exosomal miRNAs identified in this study might play an important role in progression as well as diagnosis of endometrial cancer. In conclusion, our results provide insights into the pathogenesis and risk assessment of endometrial cancer. Even so, further studies are required to elucidate on the precise mechanism of action of these genes in endometrial cancer.

The establishment of uterine receptivity is a prerequisite for embryo implantation and begins with the transformation of the luminal epithelium. MicroRNAs (miRNAs) have been widely reported to be involved in the regulation of embryo implantation, but their roles in establishing uterine receptivity remain unclear. In this study, through small RNA sequencing analysis, we showed that a low level of miR-192-5p is essential for initiating implantation in mice, and transient upregulation of miR-192-5p led to implantation failure. In situ hybridization results revealed that miR-192-5p was primarily expressed in the endometrial epithelium, and dysregulation of miR-192-5p interfered with the performance of the luminal epithelium, resulting in inadequate receptivity. By manipulating miR-192-5p expression in mouse uterus and an endometrial epithelial cell line, we showed that miR-192-5p maintains cell polarity through stabilizing adherens junction protein E-cadherin, thereby preventing epithelial-mesenchymal transition. Furthermore, miR-192-5p preserved the pattern of microvilli as well as Muc1 expression on the apical membrane of epithelial cells, thereby avoiding embryo adhesion. Moreover, miR-192-5p was found to be regulated by ovarian steroids. Collectively, this study demonstrated that the physiological role of miR-192-5p in mouse uterus is to maintain the nonreceptive state of epithelial cells and prevent their transformation to the receptive state. Thus, a sustained high level of miR-192-5p is detrimental to embryo implantation. These findings help elucidate the mechanisms involved in miRNA-based regulation of uterine physiology in early pregnancy, and may even contribute to the diagnosis and treatment of infertility.

The concentration analyzer with high precision and wide range is the core device for monitoring the fermentation process. In this work, we designed and proposed a lowcost three-electrode glucose analyzer based on a self-made screen-printed enzyme biosensor chip, which has a Prussian blue (PB) nanocubic structure and leads to high sensitivity of 117.31 μAmM-1cm-2. The hardware design of the glucose analyzer can be divided into five critical parts, including digital, signal treatment system, power supply, motor-driven and the host computer. The signal treatment system is used to collect, convert and amplify the weak current signal generated by the biosensor. The digital circuit of the central processing unit of the analyzer is designed using the STM32F407ZET6. Besides, an external analog-to-digital converter is used to achieve high precision A/D conversion. The stability of the potentiostat is ensured by designing the precision power supply, hardware filtering, and algorithm filtering. The experimental results show that the glucose analyzer has a wide linear detection range from 1g/L to 120g/L and the coefficient of variation at 1g/L is 0.038, which exhibits excellent performance in stability and detection accuracy. The analyzer can be applied in the future for in-situ measurement of glucose concentration for its wide-range and high-precision detection capabilities.

Acquired respiratory-digestive tract fistulas occur with abnormal communication between the airways and digestive tract, causing the interflow of gas and liquid. Despite advances in surgical methods and the development of multimodal therapy in recent years, patients with acquired respiratory-digestive tract fistulas continue to exhibit unfavorable clinical outcomes. Therefore, in order to guide clinical practice in China, the Respiratory and Cancer Intervention Alliance of the Beijing Health Promotion Association organized a group of experienced experts in the field to develop this consensus document. Based on a study of clinical application and expert experience in the diagnosis and management of acquired respiratory-digestive tract fistulas at home and abroad, an Expert Consensus was developed. The panelists recruited comprised experts in pulmonology, oncology, thoracic surgery, interventional radiology, and gastroenterology. PubMed, Chinese Biology Abstract, Chinese Academic Journal, and Wanfang databases were used to identify relevant articles. The guidelines address etiology, classification, pathogenesis, diagnosis and management of acquired respiratory-digestive tract fistulas. The statements on treatment focus on the indications for different procedures, technical aspects, and preprocedural, post-procedural and complication management. The proposed guidelines for the diagnosis and management of acquired respiratory-digestive tract fistulas are the first to be published by Chinese experts. These guidelines provide an in-depth review of the current evidence and standard of diagnosis and management.

High-velocity/high-dynamic operation is the basic requirement of the permanent magnet linear synchronous motor (PMLSM)-driven application especially in semiconductor equipment. Predictive current control (PCC) can make sure superior current/thrust response. However, large inductance mismatch between the controller and the real plant will deteriorate the current performance significantly. This paper presents two different adaptive disturbance observer (ADO) design method to improve the inductance robustness of the PCC for the PMLSM. Firstly, the traditional constant-gain ADO based on the internal model is introduced and its drawback of large current overshoot and oscillations is presented. Secondly, to improve the current performance, two different types of ADO methods with discrete form are designed. Finally, the simulation and experimental results are given to verify the effectiveness of the newly design method.

Synchronous communication between the developing embryo and the receptive endometrium is crucial for embryo implantation. Thus, uterine receptivity evaluation is vital in managing recurrent implantation failure (RIF). The potential roles of small extracellular vesicle (sEV) miRNAs in pregnancy have been widely studied. However, the systematic study of sEVs derived from endometrium and its cargos during the implantation stage have not yet been reported. In this study, we isolated endometrium-derived sEVs from the mouse endometrium on D2 (pre-receptive phase), D4 (receptive phase), and D5 (implantation) of pregnancy. Herein, we reveal that multivesicular bodies (MVBs) in the endometrium increase in number during the window of implantation (WOI). Moreover, our findings indicate that CD63, a well-known sEV marker, is expressed in the luminal and glandular epithelium of mouse endometrium. The sEV miRNA expression profiles indicated that miR-34c-5p, miR-210, miR-369-5p, miR-30b, and miR-582-5p are enriched during WOI. Further, we integrated the RIF&rsquo, s database analysis results and found out that miR-34c-5p regulates growth arrest specific 1 (GAS1) for normal embryo implantation. Notably, miR-34c-5p is downregulated during implantation but upregulated in sEVs. An implication of this is the possibility that sEVs miR-34c-5p could be used to evaluate uterine states. In conclusion, these findings suggest that the endometrium derived-sEV miRNAs are potential biomarkers in determining the appropriate period for embryo implantation. This study also has several important implications for future practice, including therapy of infertility.

Piedmont tectonic belts are rich of oil and gas resources, however the intense tectonic stress and broken formation may cause great drilling problems in piedmont structures such as borehole collapse, lost circulation and gas cutting. Through analysis of in situ stress properties, bedding structure and mechanical characteristics, wellbore instability mechanism was expounded from rock mechanics, chemistry of drilling fluid and drilling technology. The high tectonic stress, formation strength decreasing and fluid pressure rising after mud filtrate seepage are main reasons for borehole collapse. The methods of calculating collapse and fracture pressure and determining drilling safety density window were put forward based on mechanical analysis. In order to reduce drilling problems in piedmont structures, some countermeasures should be taken from optimizing well track and casing program, using proper mud density, improving inhibitive and sealing ability of drilling fluid. Good sealing ability can reduce seepage and cut off pressure transmission, enhancing the effective support force. This is the key technology of maintaining wellbore stability in hard brittle shale in piedmont structures.

The cannabinoid receptor-2 (CB2R) was initially thought to be the "peripheral cannabinoid receptor." Recent studies, however, have documented CB2R expression in the brain in both glial and neuronal cells, and increasing evidence suggests an important role for CB2R in the central nervous system inflammatory response. Intracerebral hemorrhage (ICH), which occurs when a diseased cerebral vessel ruptures, accounts for 10-15% of all strokes. Although surgical techniques have significantly advanced in the past two decades, ICH continues to have a high mortality rate. The aim of this study was to investigate the therapeutic effects of CB2R stimulation in acute phase after experimental ICH in rats and its related mechanisms. Data showed that stimulation of CB2R using a selective agonist, JWH133, ameliorated brain edema, brain damage, and neuron death and improved neurobehavioral outcomes in acute phase after ICH. The neuroprotective effects were prevented by SR144528, a selective CB2R inhibitor. Additionally, JWH133 suppressed neuroinflammation and upregulated the expression of microglial M2-associated marker in both gene and protein level. Furthermore, the expression of phosphorylated cAMP-dependent protein kinase (pPKA) and its downstream effector, cAMP-response element binding protein (CREB), were facilitated. Knockdown of CREB significantly inversed the increase of M2 polarization in microglia, indicating that the JWH133-mediated anti-inflammatory effects are closely associated with PKA/CREB signaling pathway. These findings demonstrated that CB2R stimulation significantly protected the brain damage and suppressed neuroinflammation by promoting the acquisition of microglial M2 phenotype in acute stage after ICH. Taken together, this study provided mechanism insight into neuroprotective effects by CB2R stimulation after ICH.

This paper proves that on any tamed closed almost complex four-manifold $(M,J)$ whose dimension of $J$-anti-invariant cohomology is equal to the self-dual second Betti number minus one, there exists a new symplectic form compatible with the given almost complex structure $J$. In particular, if the self-dual second Betti number is one, we give an affirmative answer to a question of Donaldson for tamed closed almost complex four-manifolds. Our approach is along the lines used by Buchdahl to give a unified proof of the Kodaira conjecture.

Research on the flow low in the slot of the slotted screen used in the unconsolidated sand formation is conducted with computational fluid dynamics method. Research on the erosion and corrosion of the slotted screen is presented with the calculation of flow field and the introduction of erosion model established by the Erosion and Corrosion Research Center of Tula. Moreover, the slot erosion characters and the maximum erosion with different production pressure difference and sand content are given. The result shows that: (1) the maximum value of the flow rate and the erosion appears at the horn mouth of the slotted screen; If the production pressure difference is enlarged, the amount of sand that flows into the inner of the screen will increase and the flow rate of the sand will increase sharply, which worsens the erosion of the screen; (2) the degree of the erosion of the slotted screen grows exponentially with the increase of the production pressure difference and initially increases and then decreases with the increasing of the sand content; the degree of the erosion reaches the peak value when the sand content is ten percent; and (3) the main erosion region is the middle part of the slot, and this region widens with the increasing of production pressure difference. The lower part of the screen is more damaged than the upper part.

Shale gas reservoirs are characterized by tight matrix, well-developed micro-fissures, and laminations. The study about the failure of shale under compression is of great significance to safe drilling operation and the subsequent reservoir stimulation. The variation of rock mechanical properties with the angle between the axial stress and bedding plane normal (coring angle) is analyzed based on laboratory tests. A failure criterion is applied and verified to describe the strength of shale. Moreover, ultrasonic technology is used to study the damage characteristics of shale during the uniaxial compression process. The experimental results show that shale strength decreases initially and then increases with the increase of the coring angle. The Young’s modulus and Poisson’s ratio increase with the increase of coring angle. In a compression process, damage is essentially the development of new micro-cracks induced by the compression. Shale failure is the microscopical reflection of the process of the generation and expansion of axial micro-cracks, so it is the result of damage accumulation. The variation of the lateral p wave velocity can function as a monitor of the development process of shale damage. The damage factor will increase in the linear elastic stage and then enlarge rapidly after entering the stage of unstable micro-crack expansion.

In recent years, Extended reach well (ERW) drilling technology is widely used in the offshore oil & gas fields in order to reduce the number of the drilling platforms. As it has notable characteristics such as the high deviation angle, large horizontal displacement and long open borehole interval the borehole stability increases the drilling risk and cost dramatically. To research the ERW borehole stability, including mechanical model, shale hydration test and the effect of circulating pressure loss in this paper, rock mechanics theory and hydraulics principle were comprehensively applied . The results show that, the safer drilling azimuth of the ERW in normal fault lies in the minimum horizontal principle stress direction; hydration radius increases with the passage of time, and the hydration collapsed rock has important influence on cutting beds and circulating pressure loss in annulus; the upper limit value of safety mud density decreases with the well depth increases, and when it deceases to the equivalent mud density of collapse pressure, the limit depth of the ERW is obtained. The research results provide relevant guidance on the ERW drilling, which can be used to determine the upper and lower safety mud weight limits, the best well trajectory selections and the well structure design.

At present, many oilfields were placed in the middle and late development period and the reservoir pressure depleted usually, resulting in more serious differential pressure sticking and drilling mud leakage both in the reservoir and cap rock. In view of this situation, a systematic prediction method of safety mud density in depleted oilfields was established. The influence of reservoir depletion on stress and strength in reservoir and cap formation were both studied and taken into the prediction of safety mud density. The research showed that the risk of differential pressure sticking and drilling mud leakage in reservoir and cap formation were both increased and they were the main prevention object in depleted oilfields drilling. The research results were used to guide the practice drilling work, the whole progress gone smoothly.

This paper describes the method used in the depleted reservoir for analyzing horizontal in-situ stresses in order to define a stable mud weight window to maximize the efficiency of drilling process. The method combines wellbore sta- bility modeling, in-situ stress prediction, and pore pressure depletion during production process. In the presence of any hydraulically isolated fault blocks or other permeability barriers, the pore pressure depletion will cause horizontal stress changes in both magnitude and orientation. Furthermore, the changes of horizontal stress affect the wellbore stability of inclined wells. The results indicate that the reservoir depletion has notable effect on the safe mud weight window, espe- cially the fracture pressure. The fracture pressure may be overestimated in previous model, and the most stable well azi- muth is not static but varies over the lifetime of the oilfield. The research conclusions can provide significant reference for the mud weight design of directional well in depleted reservoir.

In this paper, we study the symplectic cohomologies and symplectic harmonic forms which introduced by Tseng and Yau. Based on this, we get if $(M^{2n},\omega)$ is a compact symplectic parabolic manifold which satisfies the hard Lefschetz property, then its Euler number satisfies the inequality $(-1)^n\chi(M)\geq 0$.

The properties of bedding shales are different from that of normal formations. Strength anisotropy is their outstanding feature. Experimental study and theoretical analysis show that this kind of anisotropy of bedding shales is the main reason of wellbore instability. W-2nd section shales in WZ12-1N oilfield are in typical bedding formation, and there were some problems such as severe borehole collapse and pipe sticking in drilling. Bedding shale formation was assumed to be a transversely isotropic material, and a collapse pressure calculating method was established. The calculation result of directional drilling collapse pressure in W-2nd bedding shales shows that if hole deviation exceeds a certain critical value, collapse pressure will increase sharply. This result was used in mud density design and well trajectory optimization, which solved the wellbore instability problems of the W-2nd formation. This research method has reference value to solve problems of wellbore instability and improve d...

Enzymatic hydrolysis of penicillin G for production of 6-amino-penicillanic-acid (6-APA) was achieved by using penicillin G acylase as catalyst in an aqueous-methylisobutyl ketone (MIBK) system. The optimization was carried out and it was found that the best conversion was improved 10% more than the aqueous system, which was obtained at the conditions: initial pH 8.0, 5.0% (W/V) substrate (penicillin G), and temperature at 35 degrees C, and the ratio of aqueous and organic phase was 3:1. The stability of the biocatalyst was studied at the operational conditions. After 5 cycles of semi-batch reactions, the residual activity of penicillin G acylase was 69.2% of the initial activity. There was no apparent loss of the yield of product. This process has a potential application in the industrial scale production of 6-APA because it simplifies the process effectively.

PurposeThe aim of the paper is to develop a method to block hydroxyl groups of epoxy acrylate (AAEP) in vinyl ester resin (VER) and to study the influence of modified VER on polyurethane/(VER) interpenetrating polymer network (PU/VER IPN).Design/methodology/approachThe hydroxyl groups of AAEP in VER were blocked via different methods. Infra‐red spectroscopy was adopted to study the influence of the reagents, reaction temperature and feed molar ratio on the blocking effect of hydroxyl groups and the optimised technological parameters were determined. The PU/VER IPN and PU/modified VER IPN were prepared by simultaneous interpenetrating of VER (mixture of AAEP and butyl methacrylate with the mass ratio of 2/1) or modified VER and synthesised PU in their laboratory. The microstructure, dynamic mechanical properties and mechanical properties of PU/VER IPN and PU/modified VER IPN were compared.FindingsThe results showed that compared to unmodified IPN, because the hydroxyl groups in VER were blocked and no chemical cross‐linked structure existed between the two networks, the modified IPN showed dual‐continuous microsturcture with larger phase domain sizes between 20 and 50 nm. The effect damping temperature range of modified IPN was broadened and its damping performance was improved. The mechanical strength of modified IPNs decreased and their break elongation increased evidently.Practical implicationsThe PU/modified VER IPN with excellent damping properties can be used in the applications where reduction of vibration and noise is desired.Originality/valueThe PU/modified VER IPN, in which no chemical cross‐linked structure existed between the two networks, was novel and its damping performance was improved and excellent.

Purpose: we aimed to investigate the receptor for advanced glycation end products (RAGE) -374T/A polymorphism and breast cancer risk in a Chinese population. Methods: The study subjects included 188 women with histologically confirmed breast cancer and 210 controls. The RAGE genotypes were determined using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) assay. Pearson’s χ2 test was used to test the association between cases and controls and genotype frequencies. The association between the polymorphism and risk of breast cancer was estimated by odds ratio (OR) and 95% confidence interval (95% CI). Results: The AA genotype was significantly higher in breast cancer patients than in controls (37.77% vs. 28.10%, P = 0.002). Furthermore, the A allele frequency was significantly higher in the case group than in the control group (55.32% vs. 42.14%, P < 0.001). With the TT genotype as reference, the adjusted OR for AA homozygous carriers reached to 0.36 (95% CI: 0.17-0.88; P = 0.03). Under the dominant model of inheritance, the TA+AA genotype was associated with significantly decreased risk for breast cancer (adjusted OR = 0.38, 95% CI = 0.27-0.87; P = 0.02). The A allele carriage also presented a lower risk for breast cancer (adjusted OR = 0.42; 95% CI, 0.33-0.91; P = 0.04). Conclusion: Our findings suggest that the polymorphic variants of RAGE-374T/A may have an influence on breast cancer risk among Chinese women.

For motor working in high load condition, such as electromagnetic launch motor, the phenomenon of the local overheating exists easily. It makes the thermal capacity of the motor itself reduce, and the efficiency of the traditional water cooling or forced air cooling systems in the iron decline. Against the issue, this paper researched a small proportion of tubular permanent magnet linear synchronous motor (TPMLSM). The temperature calculation model was established combing the methods of thermal circuit and temperature field. The heating and cooling process and their regularity were analyzed. And the optimization of thermal conductivity was obtained by optimizing the insulation to reduce the temperature gradient inside the motor and improve the cooling rate. The temperature rises of the TPMLSM when the methods of the optimization of thermal conductivity, forced cooling and reducing the loss were used. And the effect of reducing temperature rise were comparing, which were expected to be useful for the thermal optimization and reasonable application for the motor in different working condition.

In this paper, we calculate the dimension of the $J$-anti-invariant cohomology subgroup $H_J^-$ on $\mathbb{T}^4$. Inspired by the concrete example, $\mathbb{T}^4$, we get that: On a closed symplectic $4$-dimensional manifold $(M, \omega)$, $h^-_J=0$ for generic $\omega$-compatible almost complex structures., Comment: arXiv admin note: text overlap with arXiv:1112.0768

In this paper, we define the generalized Lejmi's $P_J$ operator on a compact almost K\"{a}hler $2n$-manifold. We get that $J$ is $C^\infty$-pure and full if $\dim\ker P_J=b^2-1$. Additionally, we investigate the relationship between $J$-anti-invariant cohomology introduced by T.-J. Li and W. Zhang and new symplectic cohomologies introduced by L.-S. Tseng and S.-T. Yau on a closed symplectic $4$-manifold.

In this paper, we investigate the relationship between J-anti-invariant cohomology of a closed symplectic 4-manifold introduced by T.-J. Li and W. Zhang and new symplectic cohomologies introduced by L.-S. Tseng and S.-T. Yau. We also prove that the dimension of J-anti-invariant cohomology is constant for almost structures J which are compatible with a fixed symplectic form., Sorry, we have made a mistake, the main theorem is incorrect

Based on recent work of T. Draghici, T.-J. Li and W. Zhang, we further investigate properties of the dimension h_J of the J-anti-invariant cohomology subgroup H_J of a closed almost Hermitian 4-manifold (M, g, J, F) using metric compatible and symplectic 2-form compatible almost complex structures. We prove that h_J = 0 for generic almost complex structures J on M., Comment: 13 pages. Important Note: The second the two main results of the previous version of this paper has been dropped; it has been dealt with in a different paper (arXiv:1307.1513)

Objective There are two types of endothelial progenitor cell (EPC) in bone marrow (BM) and circulation, BM-EPC and Circulation late endothelial progenitor cell (CL-EPC). Diabetes impairs the function of EPC, but it is not clear whether transplantation of EPC can rescue ischemic myocardium in diabetes. In this study, we compared the function of BM-EPC and CL-EPC in vitro. Then we administered BM-EPC and CL-EPC intramyocardially and compared their contribution to vasculogenesis in diabetic rabbits. Methods BM-EPC and CL-EPC from healthy and diabetic rabbits were isolated and subjected to in vitro proliferation, tube-forming, angiogenic cytokine assays. Exogenous BM-EPC and CL-EPC were analysed for therapeutic efficacy in an acute ischemia model of diabetic rabbits. LVfunction was assessed using echocardiography. The capillary density and fibrosis area were evaluated. mRNA expression of VEGF and bFGF was analysed using relative realtime quantitive PCR. Results Proliferation, tube-forming, secretion of VEGF and bFGF of diabetic EPC were significantly reduced compared with healthy EPC. In diabetic rabbits, healthy BM-EPC transplantation could increase capillary density and improve cardiac function, decrease fibrosis area compared with CL-EPC and the control group. Real time PCR indicated that mRNA expression of VEGF and bFGF were augmented more in the healthy BM-EPC group than those in the control and CL-EPC groups. Conclusions These findings suggest that diabetes impairs the function of EPC. Transplantation of healthy BM-EPC may rescue the ischemic myocardium by neovasculogenesis and paracrine effect in diabetic rabbits. However, autologous transplantation of CL-EPC could not enhance cardiac function.

European Journal of Cardio-Thoracic Surgery, 31 (5), ISSN:1010-7940

BACKGROUND Delayed revascularization process and substitute infection remain to be key challenges in tissue engineered (TE) airway reconstruction. We propose an "in-vivo bioreactor" design, defined as an implanted TE substitutes perfused with an intra-scaffold medium flow created by an extracorporeal portable pump system for in situ organ regeneration. The perfusate keeps pre-seeded cells alive before revascularization. Meanwhile the antibiotic inside the perfusate controls topical infection. METHODS A stage IIIA squamous lung cancer patient received a 5-cm TE airway substitute, bridging left basal segment bronchus to carina, with the in-vivo bioreactor design to avoid left pneumonectomy. Continuous intra-scaffold Ringer's-gentamicin perfusion lasted for 1 month, together with orthotopic peripheral total nucleated cells (TNCs) injection twice a week. RESULTS The patient recovered uneventfully. Bronchoscopy follow-up confirmed complete revascularization and reepithelialization four months postoperatively. Perfusate waste test demonstrated various revascularization growth factors secreted by TNCs. The patient received two cycles of chemotherapy and 30 Gy radiotherapy thereafter without complications related to the TE substitute. CONCLUSIONS In-vivo bioreactor design combines the traditionally separated in vitro 3D cell-scaffold culture system and the in vivo regenerative processes associated with TE substitutes, while treating the recipients as bioreactors for their own TE prostheses. This design can be applied clinically. We also proved for the first time that TE airway substitute is able to tolerate chemo-radiotherapy and suitable to be used in cancer treatment.