Feasibility and tolerability of sintilimab plus anlotinib as the second-line therapy for patients with advanced biliary tract cancers: An open-label, single-arm, phase II clinical trial.

Patients with biliary tract cancer (BTC) were associated with poor prognosis and limited therapeutic options after first-line therapy currently. In this study, we sought to evaluate the feasibility and tolerability of sintilimab plus anlotinib as the second-line treatment for patients with advanced BTC. Eligible patients had histologically confirmed locally advanced unresectable or metastatic BTC and failed after the first-line treatment were recruited. The primary endpoint was overall survival (OS). Simultaneously, association between clinical outcomes and genomic profiling and gut microbiome were explored to identify the potential biomarkers for this regimen. Twenty patients were consecutively enrolled and received study therapy. The trail met its primary endpoint with a median OS of 12.3 months (95% CI: 10.1-14.5). Only four (20%) patients were observed of the grade 3 treatment-related adverse events (TRAEs) and no grade 4 or 5 TRAEs were detected. Mutation of AGO2 was correlated with a significantly longer OS. Abundance of Proteobacteria was associated with inferior clinical response. Therefore, sintilimab plus anlotinib demonstrated encouraging anti-tumor activity with a tolerable safety profile and deserved to be investigated in larger randomized trials for patients with advanced BTC subsequently.

Phthalates promote the invasion of hepatocellular carcinoma cells by enhancing the interaction between Pregnane X receptor and E26 transformation specific sequence 1.

Phthalates (PAEs) are considered endocrine-disrupting chemicals (EDCs), a series of compounds able to disrupt the normal regulation of the human endocrine-system. In the present study, we investigated the roles of four PAEs, butyl benzyl phthalate (BBP), dibutyl phthalate (DBP), dimethyl phthalate (DMP), and diethyl phthalate (DEP), in hepatocellular carcinoma (HCC) cells. We define novel roles for the PAEs on the migration of HCC cells via their enhancing of the interaction between the pregnane X receptor (PXR) and E26 transformation specific sequence 1 (ETS-1). Our results indicate that PAEs induced the transcriptional activation of ETS-1 and PXR. PXR activated by PAEs could bind to ETS-1 directly and enhanced the activity of ETS-1, which resulted in the induction of invasion-related ETS-1 target genes. The "LXXLL" motif in the ETS-1C-terminal was essential for the interaction between PXR and ETS-1 induced by PAEs. Treatment of PAEs promoted the nuclear accumulation of ETS-1 or the recruitment of ETS-1, but not in cells expressing ETS-1 with a mutated LXXLL motif in its downstream gene promoter region, or following transfection of PXR siRNA. Treatment with the PXR antagonist ketoconazole almost completely inhibited the effects of PAEs. Moreover, PAEs enhanced the in vitro or in vivo invasion of HCC cells via PXR/ETS-1. Therefore, our results not only contribute to a better understanding of HCC, but also extended the roles of EDCs regulating human malignancies.

Targeting HOX/PBX dimer formation as a potential therapeutic option in esophageal squamous cell carcinoma.

Homeobox genes are known to be classic examples of the intimate relationship between embryogenesis and tumorigenesis, which are a family of transcriptional factors involved in determining cell identity during early development, and also dysregulated in many malignancies. Previously, HOXB7, HOXC6 and HOXC8 were found abnormally upregulated in esophageal squamous cell carcinoma (ESCC) tissues compared with normal mucosa and seen as poor prognostic predictors for ESCC patients, and were shown to promote cell proliferation and anti-apoptosis in ESCC cells. These three HOX members have a high level of functional redundancy, making it difficult to target a single HOX gene. The aim of the present study was to explore whether ESCC cells are sensitive to HXR9 disrupting the interaction between multiple HOX proteins and their cofactor PBX, which is required for HOX functions. ESCC cell lines (KYSE70, KYSE150, KYSE450) were treated with HXR9 or CXR9, and coimmunoprecipitation and immunofluorescent colocalization were carried out to observe HOX/PBX dimer formation. To further investigate whether HXR9 disrupts the HOX pro-oncogenic function, CCK-8 assay and colony formation assay were carried out. Apoptosis was assessed by flow cytometry, and tumor growth in vivo was investigated in a xenograft model. RNA-seq was used to study the transcriptome of HXR9-treated cells. Results showed that HXR9 blocked HOX/PBX interaction, leading to subsequent transcription alteration of their potential target genes, which are involved in JAK-signal transducer and activator of transcription (STAT) activation and apoptosis inducement. Meanwhile, HXR9 showed an antitumor phenotype, such as inhibiting cell proliferation, inducing cell apoptosis and significantly retarding tumor growth. Therefore, it is suggested that targeting HOX/PBX may be a novel effective treatment for ESCC.

Long noncoding RNA DIO3OS interacts with miR-122 to promote proliferation and invasion of pancreatic cancer cells through upregulating ALDOA.

BACKGROUND: Long noncoding RNA (lncRNA) has been implicated in numerous tumors, including pancreatic cancer (PC). However, the precise cellular roles and molecular mechanisms of lncRNA DIO3OS on PC development remains to be fully clarified. METHODS: We performed the meta-analysis on PC samples and non-tumor samples retrieved from the TCGA database, and measured the levels of DIO3OS in PC cell lines and a normal pancreatic duct epithelial cell line HPDE6-C7. Cell proliferation was evaluated via CCK-8 assay. Cell invasion in vitro was investigated by transwell assay. The RNA immunoprecipitation assay and luciferase reporter assay was utilized to confirm the putative miR-122-binding site in DIO3OS. The effects of DIO3OS on PC progression were tested using in vivo subcutaneous xenografts. RESULTS: Our results showed that DIO3OS was highly expressed in human PC tissues and PC cell lines. DIO3OS exhibited oncogenic properties in stimulating PC cell proliferation and invasion in vitro and promoting cancer growth in vivo. Through online predictive tools and functional experiments, we found that DIO3OS could bind directly to microRNA-122 (miR-122) and inhibited its expression, which functioned as a tumor suppressor in PC cells. We also verified that ALDOA was the direct target of miR-122, and the tumor suppressive effects caused by DIO3OS knockdown or miR-122 overexpression could be rescued by re-expression of ALDOA in PC cells. CONCLUSIONS: Overall, our study suggested that lncRNA DIO3OS promotes PC cell growth and invasion by competing for miR-122 to modulate the expression of ALDOA. These findings yield a better understanding of the potential mechanisms by which gain of DIO3OS expression accelerates PC progression.

The survival predictive significance of HOXC6 and HOXC8 in esophageal squamous cell carcinoma.

BACKGROUND & AIM: Esophageal squamous cell carcinoma (ESCC), a common disease in China, is mainly treated surgically. We established a prospective database of patients with esophageal cancer between January 2000 and December 2010, including 486 subjects with ESCC who underwent surgical treatment. In this study, we explored the prognostic significance of the expressions of HOXC6 and HOXC8, responsible for embryonic development, by studying the specimens collected from clinical subjects during strict follow-up periods. MATERIALS & METHODS: Immunohistochemistry was used to detect the expressions of HOXC6 and HOXC8 in 274 ESCC subjects including 138 ESCC subjects treated with surgery alone and 136 ESCC subjects treated with neoadjuvant chemotherapy. Survival analysis was performed from the day of surgery to August 2013. RESULTS: The 5-y survival rate of the 274 ESCC subjects was 44.2%, with a median survival time of 44.12 mo. For the 274 ESCC subjects involved in the investigation of HOXC6 and HOXC8 expressions, the median survival time of subjects with high-level expressions of HOXC6 and HOXC8 was shorter than that for subjects with low-level expressions (P = 0.001, P < 0.001, respectively). Similar results were obtained from the analysis of the prognostic value of HOXC6 and HOXC8 in the group treated with surgery alone and the group treated with neoadjuvant chemotherapy. Multivariate analysis demonstrated that HOXC6 and HOXC8 expressions were independent prognostic factors in patients with ESCC. CONCLUSIONS: The HOXC6 and HOXC8 genes can be used as prognostic markers in patients with ESCC, but prospective studies are still needed to confirm.

Surface enhanced fluorescence from silver film substrate decorated with nanohole arrays.

The fluorescence enhancement effect of Rh6G molecules deposited on the silver film substrate decorated with nanohole arrays was investigated in this paper. The prepared substrate, decorated with nanohole arrays, was fabricated with the deposition of silver films onto the anodic aluminum oxide templates through magnetron sputtering method. Compared with the conventional continuous silver film substrate, the prepared substrate shows better enhanced effect. Particularly, the fluorescence enhancement factor has a relationship with the size and period of the nanohole arrays. The experimental observations were analyzed with local surface plasmon resonance model. The results of current work highlight the importance of strong electromagnetic coupling effect in surface enhanced fluorescence.

Baseline neutrophil-to- ratio combined with the change during treatment provides risk stratification for metastatic malignant melanoma patients treated with PD-1 inhibitors in a Chinese population.

Background: Previous studies have suggested that an elevated baseline neutrophil-to-lymphocyte ratio (BLNLR) and elevated relative change of NLR (ΔNLR%) is associated with worse outcomes in patients with a variety of cancers. This study aims to investigate the value of BLNLR and ΔNLR% before the third cycle of treatment on the prognosis of patients with metastatic malignant melanoma treated with PD-1 inhibitors. Methods: A total of 63 patients with metastatic malignant melanoma treated with PD-1 inhibitors in the First Affiliated Hospital of Zhengzhou University from January 2017 to December 2021 were retrospectively analyzed. BLNLR and ΔNLR% before the third cycle of treatment were collected. The Kaplan-Meier method was used to draw survival curves and Log-Rank test was used for survival analysis. Univariate and multivariate Cox regression analysis were used to analyze the relationship between BLNLR, ΔNLR% and clinical characteristics with progression-free survival (PFS) and overall survival (OS). Results: Univariate analysis showed that PFS and OS were associated with BLNLR, ΔNLR%, BMI and number of metastatic organs (P < 0.05). Multivariate analysis showed that BLNLR, ΔNLR%, BMI and number of metastatic organs were independent predictors of OS and BLNLR and ΔNLR% were independent predictors of PFS. Patients were divided into four groups according to BLNLR (<3, ≥3) and ΔNLR% (< 30%, ≥30%): low-BLNLR + low-ΔNLR% group, low-BLNLR + high-ΔNLR% group, high-BLNLR + low-ΔNLR% group, high-BLNLR + high-ΔNLR% group. The median OS was 20 months, 8 months, 9 months, 5 months and the median PFS was 8 months, 3 months, 2 months, 2 months, respectively. Conclusion: BLNLR combined with ΔNLR% can be used to predict the prognosis of PD-1 inhibitors in patients with metastatic malignant melanoma.

Exopolysaccharide from Weissella confusa J4-1 inhibits colorectal cancer via induction of cell cycle arrest.

Exopolysaccharide (EPS), a bioproduct of lactic acid bacteria (LAB), has various health-promoting biological activities that may be beneficial for cancer therapy. This in vivo and in vitro study aimed to elucidate the anti-colorectal cancer (CRC) capacity of a homopolysaccharide EPS obtained from Weissella confusa J4-1 (EPSJ4-1) isolated from the faeces of healthy infants. We confirmed that EPSJ4-1 contained glucose and effectively suppressed the proliferation, migration, and invasion of CRC cells. EPSJ4-1 treatment significantly retarded the growth of HT-29 tumour xenografts without causing cytotoxicity to normal organs. EPSJ4-1 exerts an inhibitory effect on cell proliferation by inducing G0/G1 phase cell cycle arrest in CRC cells. Furthermore, EPSJ4-1 upregulated p21 levels and downregulated mutant p53 and cyclin kinase 2 levels. This is the first study to demonstrate the antitumour effects of EPS from W. confusa on CRC via cell cycle arrest and inhibition of cell migration and invasion, suggesting that EPSJ4-1 has the potential to be developed as a nutraceutical or pharmaceutical drug to prevent and treat CRC.

The anticancer mechanisms of exopolysaccharide from Weissella cibaria D-2 on colorectal cancer via apoptosis induction.

Exopolysaccharide (EPS) from Weissella cibaria has been devoted to the study of food industry. However, the anticancer activity of W. cibaria derived EPS has not yet been investigated. In this study, we obtained the EPS from W. cibaria D-2 isolated from the feces of healthy infants and found that D-2-EPS, a homopolysaccharide with porous web like structure, could effectively inhibit the proliferation, migration, invasion and induce cell cycle arrest in G0/G1 phase of colorectal cancer (CRC) cells. In HT-29 tumor xenografts, D-2-EPS significantly retarded tumor growth without obvious cytotoxicity to normal organs. Furthermore, we revealed that D-2-EPS promoted the apoptosis of CRC cells by increasing the levels of Fas, FasL and activating Caspase-8/Caspase-3, indicating that D-2-EPS might induce apoptosis through the extrinsic Fas/FasL pathway. Taken together, the D-2-EPS has the potential to be developed as a nutraceutical or drug to prevent and treat colorectal cancer.

Characterization of tumor immune microenvironment and cancer therapy for head and neck squamous cell carcinoma through identification of a genomic instability-related lncRNA prognostic signature.

Head and neck squamous cell carcinoma (HNSCC) represents one of the most prevalent and malignant tumors of epithelial origins with unfavorable outcomes. Increasing evidence has shown that dysregulated long non-coding RNAs (lncRNAs) correlate with tumorigenesis and genomic instability (GI), while the roles of GI-related lncRNAs in the tumor immune microenvironment (TIME) and predicting cancer therapy are still yet to be clarified. In this study, transcriptome and somatic mutation profiles with clinical parameters were obtained from the TCGA database. Patients were classified into GI-like and genomic stable (GS)-like groups according to the top 25% and bottom 25% cumulative counts of somatic mutations. Differentially expressed lncRNAs (DElncRNAs) between GI- and GS-like groups were identified as GI-related lncRNAs. These lncRNA-related coding genes were enriched in cancer-related KEGG pathways. Patients totaling 499 with clinical information were randomly divided into the training and validation sets. A total of 18 DElncRNAs screened by univariate Cox regression analysis were associated with overall survival (OS) in the training set. A GI-related lncRNA signature that comprised 10 DElncRNAs was generated through least absolute shrinkage and selection operator (Lasso)-Cox regression analysis. Patients in the high-risk group have significantly decreased OS vs. patients in the low-risk group, which was verified in internal validation and entire HNSCC sets. Integrated HNSCC sets from GEO confirmed the notable survival stratification of the signature. The time-dependent receiver operating characteristic curve demonstrated that the signature was reliable. In addition, the signature retained a strong performance of OS prediction for patients with various clinicopathological features. Cell composition analysis showed high anti-tumor immunity in the low-risk group which was evidenced by increased infiltrating CD8+ T cells and natural killer cells and reduced cancer-associated fibroblasts, which was convinced by immune signatures analysis via ssGSEA algorithm. T helper/IFNγ signaling, co-stimulatory, and co-inhibitory signatures showed increased expression in the low-risk group. Low-risk patients were predicted to be beneficial to immunotherapy, which was confirmed by patients with progressive disease who had high risk scores vs. complete remission patients. Furthermore, the drugs that might be sensitive to HNSCC were identified. In summary, the novel prognostic GILncRNA signature provided a promising approach for characterizing the TIME and predicting therapeutic strategies for HNSCC patients.

Identification of Immune-Related Breast Cancer Chemotherapy Resistance Genes via Bioinformatics Approaches.

Chemotherapy resistance in breast cancer is an important factor affecting the prognosis of breast cancer patients. We computationally analyzed the differences in gene expression before and after chemotherapy in breast cancer patients, drug-sensitive groups, and drug-resistant groups. Through functional enrichment analysis, immune microenvironment analysis, and other computational analysis methods, we identified PRC1, GGTLC1, and IRS1 as genes that may mediate breast cancer chemoresistance through the immune pathway. After validation of certain other clinical datasets and in vitro cellular assays, we found that the above three genes influenced drug resistance in breast cancer patients and were closely related to the tumor immune microenvironment. Our finding that chemoresistance in breast cancer could be influenced by the mediation of tumor immunity expanded our knowledge of how to address this problem and could guide future research involving chemoresistance.

Folate receptor-positive circulating tumor cell count, lymphocyte count and derived neutrophil-to- lymphocyte ratio for diagnosing lung cancer relapse.

The folate receptor-positive circulating tumor cell (FR+-CTC) count can be used to improve the diagnosis rate of lung cancer. The lymphocyte count (LC) and derived neutrophil-to-lymphocyte ratio (dNLR) are involved in inflammatory processes. Whether the FR+-CTC count combined with the dNLR or LC is helpful for diagnosing lung cancer recurrence is not clear. Sixty-eight patients who were initially diagnosed with lung cancer and received first-line treatment were included. The clinicopathological characteristics, routine blood examination results and CTC examination results of the patients were collected. The role of the complete blood count and FR+-CTC count in lung cancer treatment response and prognosis was analyzed. The FR+-CTC count after treatment was significantly correlated with the T stage (p=0.005). Multivariate analysis showed that the pathological type and FR+-CTC count were independent predictors of disease-or progression-free survival (DFS/PFS) in patients with lung cancer (p=0.010 and p=0.030, respectively). The FR+-CTC count, LC and dNLR predicted the recurrence of lung cancer (sensitivity and specificity of the FR+-CTC count, 69.2% and 71.4%; the LC, 50.0% and 88.5%; and the dNLR, 50.0% and 88.1%, respectively). The FR+-CTC count combined with the LC or dNLR improved the diagnostic rate of lung cancer recurrence (sensitivity and specificity of the FR+-CTC count plus the LC, 53.8% and 90.5%, and the FR+-CTC count plus the dNLR, 73.1% and 73.8%, respectively). When these three indicators were combined to predict lung cancer recurrence, the AUC value was 0.817. The FR+-CTC count combined with the dNLR and/or LC after treatment can improve the diagnostic rate of lung cancer recurrence. A higher FR+-CTC count predicts worse DFS/PFS in patients with lung cancer.

Oral nanozyme-engineered probiotics for the treatment of ulcerative colitis.

Probiotic-based therapy for ulcerative colitis (UC) is a novel and promising approach that has gained much popularity in recent years. However, probiotics may be easily captured and destroyed by the harsh in vivo environment, which limits their application prospects to a large extent. This work introduces a versatile facile approach for decorating individual probiotics with nanozyme coatings, named Pt-Lipid@EcN. A bimolecular lipid coating is deposited on the surface of probiotics used in the oral treatment of UC using simple self-assembly with a liposome under cytocompatible conditions, and it acts as armor to effectively protect the probiotics from strong digestive acids and enzymes. The obtained results indicated that the liposome-coated Escherichia coli Nissle (EcN) 1917 could significantly improve the colonization rate of the microorganisms in the intestinal tract. We also explored the specific mechanism of Pt-Lipid@EcN to improve the behavior of murine UC models, including reduction of inflammatory effects and histological injury, and regulation of epithelial barrier homeostasis in the intestine. The nanozyme-shielded probiotic exhibited enhanced anti-inflammatory ability in vivo, introducing novel strategies for the application of nanozyme biomedicine in the treatment of colonic inflammatory diseases.

B4GALNT2 Gene Promotes Proliferation, and Invasiveness and Migration Abilities of Model Triple Negative Breast Cancer (TNBC) Cells by Interacting With HLA-B Protein.

B4GALNT2 gene encodes the enzyme ß1,4-N-acetylgalactosaminyltransferase 2 that biosynthesizes the histo-blood group antigen Sda, which is expressed on the surface of erythrocytes and in body secretions. Analysis of The Cancer Genome Atlas (TCGA) database revealed that this gene was highly expressed in breast cancer tissues in comparison with adjacent healthy ones. In-vitro lentivirus-assisted B4GALNT2 gene knockdown experiments in model triple negative breast cancer (TNBC) cell lines (HCC1937 and MDA-MB-231) showed inhibition in cell proliferation, decrease in cell viability, promotion of cell apoptosis and inhibitions in cell migration and invasiveness abilities in comparison with empty lentivirus transfectant controls. Also, in cell cycle tests, the number of cells in the G1 phase increased, in the S phase decreased and did not change in the G2/M phase (indicative of the presence of a block in the G1 phase). In-vivo tumor formation experiments in mice revealed that knockdown of the B4GALNT2 gene in MDA-MB-231 cells inhibited their proliferation. Using co-immunoprecipitation (Co-IP) mass spectroscopy-assisted analysis, it was found that HLA-B protein [a product of the human leukocyte antigen (HLA) class I gene] interacts with B4GALNT2 protein. In-vitro overexpression of HLA-B in B4GALNT2-knocked down MDA-MB-231 cell lines significantly recovered the cell proliferation, viability and migration ability of B4GALNT2 gene. These indicate that HLA-B is one of the interaction proteins in the downstream pathway of the B4GALNT2 gene.

A panel of 8-lncRNA predicts prognosis of breast cancer patients and migration of breast cancer cells.

BACKGROUND: Breast cancer (BCa) is the most commonly diagnosed cancer and the leading cause of cancer death among females around the world. Recent studies have indicated that long non-coding RNAs (lncRNAs) can serve as an independent biomarker for diagnosis and prognosis in many types of cancer, including pancreatic adenocarcinoma, gastric cancer, liver cancer, and lung cancer. Previous studies have shown that many lncRNAs are associated with the occurrence and development of BCa. However, few studies have combined multiple lncRNAs to predict the prognosis of early-stage BCa patients. METHODS: Systematic and comprehensive analysis of data from The Cancer Genome Atlas (TCGA) was conducted to identify lncRNA signatures with prognostic value in BCa. Additionally, the relative expression levels of the 8 lncRNA of several BCa cell lines were detected by quantitative real-time PCR (qPCR) and the results were substituted into a risk score formula. Finally, migration assays were used to verify the result from prognostic analysis according to the risk scores among cell lines with different risk scores. RESULTS: Our study included 808 BCa patients with complete clinical data. A panel of 8 lncRNAs was identified using Wilcox tests as different between normal and tumor tissue of the BCa patients. This panel was used to analyze the survival of BCa patients. Patients with low risk scores had greater overall survival (OS) than those with high risk scores. Multivariate Cox regression analyses demonstrated that the lncRNA signature was an independent prognostic factor. Gene Set Enrichment Analysis (GSEA) suggested that the lncRNAs might be involved in several molecular signaling pathways implicated in BCa such as the DNA replication pathway, the cell cycle pathway, and the pentose phosphate pathway. Validation experiments in breast cancer cells to test cell migration by using wound-healing assays supported the results of the model. CONCLUSION: Our study demonstrated that a panel of 8 lncRNAs has the potential to be used as an independent prognostic biomarker of BCa.

An interactive network of alternative splicing events with prognostic value in geriatric lung adenocarcinoma via the regulation of splicing factors.

Alternative splicing (AS), an essential process for the maturation of mRNAs, is involved in tumorigenesis and tumor progression, including angiogenesis, apoptosis, and metastasis. AS changes can be frequently observed in different tumors, especially in geriatric lung adenocarcinoma (GLAD). Previous studies have reported an association between AS events and tumorigenesis but have lacked a systematic analysis of its underlying mechanisms. In the present study, we obtained splicing event information from SpliceSeq and clinical information regarding GLAD from The Cancer Genome Atlas. Survival-associated AS events were selected to construct eight prognostic index (PI) models. We also constructed a correlation network between splicing factors (SFs) and survival-related AS events to identify a potential molecular mechanism involved in regulating AS-related events in GLAD. Our study findings confirm that AS has a strong prognostic value for GLAD and sheds light on the clinical significance of targeting SFs in the treatment of GLAD.

Thymosin alpha-1 blocks the accumulation of myeloid suppressor cells in NSCLC by inhibiting VEGF production.

BACKGROUND: Thymosin alpha-1 (TA) has been reported to inhibit tumor growth as an immunomodulator. However, its mechanism of action in immunosuppressive cells is unclear. The purpose of this study was to investigate whether TA can reshape the immune microenvironment by inhibiting the function of myeloid-derived suppressor cells (MDSCs) in non-small cell lung carcinoma (NSCLC). METHODS: The effects of TA on peripheral blood monocytic MDSCs (M-MDSCs) in patients with NSCLC and on the apoptosis and migration of M-MDSCs were studied. A mouse subcutaneous xenograft tumor model was constructed, and the effect of TA on M-MDSC migration was evaluated. Quantitative real-time PCR, Western blotting, flow cytometry and immunohistochemistry were used to examine the mechanism by which TA affects M-MDSCs. RESULTS: TA not only promoted the apoptosis of M-MDSCs by reducing the Bcl-2/BAX ratio but also and more importantly inhibited the migration of MDSCs to the tumor microenvironment by suppressing the production of vascular endothelial growth factor (VEGF) through the downregulation of hypoxia-inducible factor (HIF)-1α in tumor cells. CONCLUSIONS: TA may have a novel antitumor effect mediated by decreasing M-MDSC accumulation in the tumor microenvironment through reduced VEGF production.

Corrigendum: Modularized Perturbation of Alternative Splicing Across Human Cancers.

[This corrects the article DOI: 10.3389/fgene.2019.00246.].

Modularized Perturbation of Alternative Splicing Across Human Cancers.

Splicing perturbation in cancers contribute to different aspects of cancer cell progression. However, the complete functional impact of cancer-associated splicing have not been fully characterized. Comprehensive large-scale studies are essential to unravel the dominant patterns of cancer-associated splicing. Here we analyzed the genome-wide splicing data in 16 cancer types with normal samples, identified differential splicing events in each cancer type. Then we took a network-based and modularized approach to reconstruct cancer-associated splicing networks, determine the module structures, and evaluate their prognosis relevance. This approach in total identified 51 splicing modules, among which 10/51 modules are related to patient survival, 8/51 are related to progression-free interval, and 5/51 are significant in both. Most of the 51 modules show significant enrichment of important biological functions, such as stem cell proliferation, cell cycle, cell growth, DNA repair, receptor or kinase signaling, and VEGF vessel development. Module-based clustering grouped cancer types according to their tissue-of-origins, consistent with previous pan-cancer studies based on integrative clustering. Interestingly, 13/51 modules are highly common across different cancer types, suggesting the existence of pan-cancer splicing perturbations. Together, modularized perturbation of splicing represents an functionally important and common mechanism across cancer types.

[Study on vibrational spectra of ethyl hexanoate molecule].

The vibrational spectra of ethyl hexanoate were calculated by the density functional theory (DFT) with B3LYP complex function, diffuse function and polarization function added to heavy atoms and light atoms. On the base of this, the normal Raman spectrum (NRS) and the infrared spectrum (IR) were assigned in detail in the present paper. Comparing the calculated results with the experimental data, the calculated results are in good agreement with the experimental results. The comparison of the experimental Raman and infrared spectra shows that in the experimental Raman spectrum, the strongest bands appear at the frequencies of 2600-3100 cm(-1), while the strongest band is not 1734 cm(-1) but 1444 cm(-1) at the frequencies of 400-2000 cm(-1). The band 1734 cm(-1) attributed to the C=O stretch vibration is the distinctive mark of organic ester compounds, and the band 1444 cm(-1) is related to the symmetric and anti-symmetric scissors vibration of C-H. In the experimental infrared spectrum, the strongest vibrational band is 1739 cm(-1), which is related to C=O stretch vibration; At the frequencies of 400-2000 cm(-1), the relative intensity of the infrared spectrum is distinctively stronger than that of the Raman spectrum, but the relative intensity of infrared spectrum is weaker than that of the Raman spectrum at the frequencies of 2600-3100 cm(-1). In the frequencies of 2600-2800 cm(-1), the vibrational bands 2762 and 2732 cm(-1) do not appear in the experimental spectra, which may originate from two reasons: (1) the weak interaction of molecules. Also, the relative intensity of these vibrational bands is very weak in the experimental spectra, and this may testify that the interaction of molecules is rather weak; (2) the vibrational bands may belong to second order vibrational mode at the frequencies of 2600-2800 cm(-1). The relative intensity of infrared bands is weaker than that of the Raman bands at the frequencies of 2600-2800 cm(-1). At the end, the stronger bands appearing in Raman and infrared experimental spectra are assigned as characteristic marks, respectively. The study on vibrational spectra of ethyl hexanoate molecule may have great application value in detection of liquor flavor, chemical industry and biology fields, providing important reference value for the related basic research field.