Regularity of density for SDEs driven by degenerate L\'evy noises

By using Bismut's approach about the Malliavin calculus with jumps, we study the regularity of the distributional density for SDEs driven by degenerate additive L\'evy noises. Under full H\"ormander's conditions, we prove the existence of distributional density and the weak continuity in the first variable of the distributional density. Under the uniform first order Lie's bracket condition, we also prove the smoothness of the density.Comment: 25 page

Genetic variants of p27 and p21 as predictors for risk of second primary malignancy in patients with index squamous cell carcinoma of head and neck

<p>Abstract</p> <p>Background</p> <p>Cell cycle deregulation is common in human cancer, and alterations of <it>p27 </it>and <it>p21</it>, two critical cell cycle regulators, have been implicated in the development of many human malignancies. Therefore, we hypothesize that <it>p27 </it>T109G polymorphism individually or in combination with <it>p21 </it>(C98A and C70T) polymorphisms modifies risk of second primary malignancy (SPM) in patients with index squamous cell carcinoma of head and neck (SCCHN).</p> <p>Methods</p> <p>A cohort of 1,292 patients with index SCCHN was recruited between May 1995 and January 2007 at the M.D. Anderson Cancer Center and followed for SPM occurrence. Patients were genotyped for the three polymorphisms. A log-rank test and Cox proportional hazards models were used to compare SPM-free survival and SPM risk.</p> <p>Results</p> <p>We found that patients with <it>p27 </it>109 TG/GG, <it>p21 </it>98 CA/AA and <it>p21 </it>70 CT/TT variant genotypes had a worse SPM-free survival and an increased SPM risk than those with the corresponding <it>p27</it>109 TT, <it>p21 </it>98 CC, and <it>p21 </it>70 CC common genotypes, respectively. After combining the three polymorphisms, there was a trend for significantly increased SPM risk with increasing number of the variant genotypes (<it>P</it>_trend= 0.0002). Moreover, patients with the variant genotypes had an approximately 2.4-fold significantly increased risk for SPM compared with those with no variant genotypes (HR, 2.4, 95% CI, 1.6-3.6).</p> <p>Conclusions</p> <p>These results suggest that <it>p27 </it>T109G polymorphism individually or in combination with <it>p21 </it>(C98A and C70T) polymorphisms increases risk of SPM in patients with index SCCHN.</p

Microbial metabolites are involved in tumorigenesis and development by regulating immune responses

The human microbiota is symbiotic with the host and can create a variety of metabolites. Under normal conditions, microbial metabolites can regulate host immune function and eliminate abnormal cells in a timely manner. However, when metabolite production is abnormal, the host immune system might be unable to identify and get rid of tumor cells at the early stage of carcinogenesis, which results in tumor development. The mechanisms by which intestinal microbial metabolites, including short-chain fatty acids (SCFAs), microbial tryptophan catabolites (MTCs), polyamines (PAs), hydrogen sulfide, and secondary bile acids, are involved in tumorigenesis and development by regulating immune responses are summarized in this review. SCFAs and MTCs can prevent cancer by altering the expression of enzymes and epigenetic modifications in both immune cells and intestinal epithelial cells. MTCs can also stimulate immune cell receptors to inhibit the growth and metastasis of the host cancer. SCFAs, MTCs, bacterial hydrogen sulfide and secondary bile acids can control mucosal immunity to influence the occurrence and growth of tumors. Additionally, SCFAs, MTCs, PAs and bacterial hydrogen sulfide can also affect the anti-tumor immune response in tumor therapy by regulating the function of immune cells. Microbial metabolites have a good application prospect in the clinical diagnosis and treatment of tumors, and our review provides a good basis for related research

Death-associated protein 3 in cancer-discrepant roles of DAP3 in tumours and molecular mechanisms

The article has a word count of 4657 as well as contains an image and a table Abstract: Cancer, ranks as the secondary cause of death, is a group of diseases that are characterized by uncontrolled tumor growth and distant metastasis, leading to increased mortality year-on-year. To date, targeted therapy to intercept the aberrant proliferation and invasion is crucial for clinical anticancer treatment, however, mutant expression of target genes often leads to drug resistance. Therefore, it is essential to identify more molecules that can be targeted to facilitate combined therapy. Previous studies showed that death associated protein 3 (DAP3) exerts a pivotal role in regulating apoptosis signaling of tumors, meanwhile, aberrant DAP3 expression is associated with the tumorigenesis and disease progression of various cancers. This review provides an overview of the molecule structure of DAP3 and the discrepant roles played by DAP3 in various types of tumors.Considering the molecular mechanism of DAP3-regulated cancer development, new potential treatment strategies might be developed in the future

Potential molecular mechanisms of Erlongjiaonang action in idiopathic sudden hearing loss: A network pharmacology and molecular docking analyses

BackgroundIdiopathic sudden hearing loss (ISHL) is characterized by sudden unexplainable and unilateral hearing loss as a clinically emergent symptom. The use of the herb Erlongjiaonang (ELJN) in traditional Chinese medicine is known to effectively control and cure ISHL. This study explored the underlying molecular mechanisms using network pharmacology and molecular docking analyses.MethodThe Traditional Chinese Medicine System Pharmacological database and the Swiss Target Prediction database were searched for the identification of ELJN constituents and potential gene targets, respectively, while ISHL-related gene abnormality was assessed using the Online Mendelian Inheritance in Man and Gene Card databases. The interaction of ELJN gene targets with ISHL genes was obtained after these databases were cross-screened, and a drug component–intersecting target network was constructed, and the gene ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes, and protein–protein interaction networks were analyzed. Cytoscape software tools were used to map the active components–crossover target–signaling pathway network and screened targets were then validated by establishing molecular docking with the corresponding components.ResultErlongjiaonang contains 85 components and 250 corresponding gene targets, while ISHL has 714 disease-related targets, resulting in 66 cross-targets. The bioinformatical analyses revealed these 66 cross-targets, including isorhamnetin and formononetin on NOS3 expression, baicalein on AKT1 activity, and kaempferol and quercetin on NOS3 and AKT1 activity, as potential ELJN-induced anti-ISHL targets.ConclusionThis study uncovered potential ELJN gene targets and molecular signaling pathways in the control of ISHL, providing a molecular basis for further investigation of the anti-ISHL activity of ELJN

A division-of-labor mode contributes to the cardioprotective potential of mesenchymal stem/stromal cells in heart failure post myocardial infarction

BackgroundTreatment of heart failure post myocardial infarction (post-MI HF) with mesenchymal stem/stromal cells (MSCs) holds great promise. Nevertheless, 2-dimensional (2D) GMP-grade MSCs from different labs and donor sources have different therapeutic efficacy and still in a low yield. Therefore, it is crucial to increase the production and find novel ways to assess the therapeutic efficacy of MSCs.Materials and methodshUC-MSCs were cultured in 3-dimensional (3D) expansion system for obtaining enough cells for clinical use, named as 3D MSCs. A post-MI HF mouse model was employed to conduct in vivo and in vitro experiments. Single-cell and bulk RNA-seq analyses were performed on 3D MSCs. A total of 125 combination algorithms were leveraged to screen for core ligand genes. Shinyapp and shinycell workflows were used for deploying web-server.Result3D GMP-grade MSCs can significantly and stably reduce the extent of post-MI HF. To understand the stable potential cardioprotective mechanism, scRNA-seq revealed the heterogeneity and division-of-labor mode of 3D MSCs at the cellular level. Specifically, scissor phenotypic analysis identified a reported wound-healing CD142+ MSCs subpopulation that is also associated with cardiac protection ability and CD142- MSCs that is in proliferative state, contributing to the cardioprotective function and self-renewal, respectively. Differential expression analysis was conducted on CD142+ MSCs and CD142- MSCs and the differentially expressed ligand-related model was achieved by employing 125 combination algorithms. The present study developed a machine learning predictive model based on 13 ligands. Further analysis using CellChat demonstrated that CD142+ MSCs have a stronger secretion capacity compared to CD142- MSCs and Flow cytometry sorting of the CD142+ MSCs and qRT-PCR validation confirmed the significant upregulation of these 13 ligand factors in CD142+ MSCs.ConclusionClinical GMP-grade 3D MSCs could serve as a stable cardioprotective cell product. Using scissor analysis on scRNA-seq data, we have clarified the potential functional and proliferative subpopulation, which cooperatively contributed to self-renewal and functional maintenance for 3D MSCs, named as “division of labor” mode of MSCs. Moreover, a ligand model was robustly developed for predicting the secretory efficacy of MSCs. A user-friendly web-server and a predictive model were constructed and available (https://wangxc.shinyapps.io/3D_MSCs/)

Death associated protein‑3 (DAP3) and DAP3 binding cell death enhancer‑1 (DELE1) in human colorectal cancer, and their impacts on clinical outcome and chemoresistance

Death associated protein‑3 (DAP3) was identified as a responsive protein to interferon‑gamma‑induced cell death which possibly exerts this regulation by interacting with DAP3 binding cell Death enhancer‑1 (DELE1), a newly discovered mitochondrial stress protein in response to cell stress signals. Whilst DAP3 has been shown to be aberrantly expressed in several cancer types (i.e. breast cancer), little is known about the relationship between DAP3 and DELE1 in cancers. The present study examined the expression levels of both DAP3 and DELE1 in clinical colorectal cancers (CRCs), as well as their implication on chemoresistance and mechanism behind the action. Firstly, transcript levels of both DAP3 and DELE1 were quantitatively assessed in a clinical cohort of CRC (n=94). Tumour tissues had significantly higher levels of DAP3, but not DELE1 compared with normal tissues. Levels of DAP3 and DELE1 had a significant association with patient's clinical outcomes and local recurrence. DAP3 and DELE1 significantly correlated in normal colorectal tissues but not in tumour tissues. Secondly, the protein levels of DAP3 and DELE1 were evaluated in both normal and tumour colon tissues which showed that both proteins were highly aberrant in CRC tissues. In addition, both DAP3 and DELE1 at transcript and protein levels were identified as prognostic factors for patient's clinical outcomes. Furthermore, in in vitro assays, knocking down DAP3 or DELE1, and in particular both DAP3 and DELE1 together rendered the CRC cells more sensitive to chemotherapy drugs, consistent with clinical findings of the TCGA‑COAD datasets. The acquisition of drug sensitivity following the genetic knockdown was independent of the mitochondrial metabolism, as neither DAP3 knockdown nor DELE1 knockdown showed a significant change. In summary, DAP3 and DELE1 are highly aberrant in CRCs, and both molecules are prognostic factors for patient's clinical outcomes and local recurrence, and are indicators for chemoresistance

Death associated protein-3 (DAP3) and DAP3 binding cell death enhancer-1 (DELE1) in human colorectal cancer, and their impacts on clinical outcome and chemoresistance

Death associated protein‑3 (DAP3) was identified as a responsive protein to interferon‑gamma‑induced cell death which possibly exerts this regulation by interacting with DAP3 binding cell Death enhancer‑1 (DELE1), a newly discovered mitochondrial stress protein in response to cell stress signals. Whilst DAP3 has been shown to be aberrantly expressed in several cancer types (i.e. breast cancer), little is known about the relationship between DAP3 and DELE1 in cancers. The present study examined the expression levels of both DAP3 and DELE1 in clinical colorectal cancers (CRCs), as well as their implication on chemoresistance and mechanism behind the action. Firstly, transcript levels of both DAP3 and DELE1 were quantitatively assessed in a clinical cohort of CRC (n=94). Tumour tissues had significantly higher levels of DAP3, but not DELE1 compared with normal tissues. Levels of DAP3 and DELE1 had a significant association with patient's clinical outcomes and local recurrence. DAP3 and DELE1 significantly correlated in normal colorectal tissues but not in tumour tissues. Secondly, the protein levels of DAP3 and DELE1 were evaluated in both normal and tumour colon tissues which showed that both proteins were highly aberrant in CRC tissues. In addition, both DAP3 and DELE1 at transcript and protein levels were identified as prognostic factors for patient's clinical outcomes. Furthermore, in in vitro assays, knocking down DAP3 or DELE1, and in particular both DAP3 and DELE1 together rendered the CRC cells more sensitive to chemotherapy drugs, consistent with clinical findings of the TCGA‑COAD datasets. The acquisition of drug sensitivity following the genetic knockdown was independent of the mitochondrial metabolism, as neither DAP3 knockdown nor DELE1 knockdown showed a significant change. In summary, DAP3 and DELE1 are highly aberrant in CRCs, and both molecules are prognostic factors for patient's clinical outcomes and local recurrence and are indicators for chemoresistance

Characterization of microRNAs Identified in a Table Grapevine Cultivar with Validation of Computationally Predicted Grapevine miRNAs by miR-RACE

BACKGROUND: Alignment analysis of the Vv-miRNAs identified from various grapevine cultivars indicates that over 30% orthologous Vv-miRNAs exhibit a 1-3 nucleotide discrepancy only at their ends, suggesting that this sequence discrepancy is not a random event, but might mainly derive from divergence of cultivars. With advantages of miR-RACE technology in determining precise sequences of potential miRNAs from bioinformatics prediction, the precise sequences of vv-miRNAs predicted computationally can be verified with miR-RACE in a different grapevine cultivar. This presents itself as a new approach for large scale discovery of precise miRNAs in different grapevine varieties. METHODOLOGY/PRINCIPAL FINDINGS: Among 88 unique sequences of Vv-miRNAs from bioinformatics prediction, 83 (96.3%) were successfully validated with MiR-RACE in grapevine cv. 'Summer Black'. All the validated sequences were identical to their corresponding ones obtained from deep sequencing of the small RNA library of 'Summer Black'. Quantitative RT-PCR analysis of the expressions levels of 10 Vv-miRNA/target gene pairs in grapevine tissues showed some negative correlation trends. Finally, comparison of Vv-miRNA sequences with their orthologs in Arabidopsis and study on the influence of divergent bases of the orthologous miRNAs on their targeting patterns in grapevine were also done. CONCLUSION: The validation of precise sequences of potential Vv-miRNAs from computational prediction in a different grapevine cultivar can be a new way to identify the orthologous Vv-miRNAs. Nucleotide discrepancy of orthologous Vv-miRNAs from different grapevine cultivars normally does not change their target genes. However, sequence variations of some orthologous miRNAs in grapevine and Arabidopsis can change their targeting patterns. These precise Vv-miRNAs sequences validated in our study could benefit some further study on grapevine functional genomics