ncRNA-mediated overexpression of ubiquitin-specific proteinase 13 contributes to the progression of prostate cancer via modulating AR signaling, DNA damage repair and immune infiltration.

Metastatic castration-resistant prostate cancer (mCRPC) is a lethal form of prostate cancer, and the molecular mechanism driving mCRPC progression has not yet been fully elucidated. Immunotherapies such as chimeric antigen receptor, T-cell therapy and immune checkpoint blockade have exerted promising antitumor effects in hematological and solid tumor malignancies; however, no encouraging responses have been observed against mCRPC. The deubiquitinase USP13 functions as a tumor suppressor in many human cancers, as it sustains the protein stability of PTEN and TP53; however, its role in prostate cancer (PCa) and involvement in DNA damage and AR signaling remain unclear. In the current study, we explored the prognostic value of USP13 in PCa based on the TCGA database, and we analyzed the expression of USP13 in PCa tissues and adjacent normal tissues based on TCGA and our cohort. The results suggested that USP13 is overexpressed in PCa tumors and has the potential to be an independent biomarker for the overall survival of PCa patients. Additionally, enrichment analysis indicated that USP13 may participate in the AR pathway and PI3k/Wnt signaling, which are closely related to PCa progression. We also observed a significant correlation between the expression of USP13 and AR-related genes, DDR genes and mismatch repair genes based on the TCGA_PRAD dataset, which further supported the critical role of USP13 in AR activation and the DNA damage response of PCa. USP13 was also found to be enriched in protein neddylation, and expression of USP13 was significantly associated with infiltration of immune cells and expression of immunomodulators. Taken together, our study revealed a key role of USP13 in contributing to PCa progression by participating in multiple oncogenic signaling pathways, the DNA damage response and the immunosuppressive tumor microenvironment. Targeting USP13 may inhibit tumor growth and provide additional benefits in cooperation with DDR inhibitors and immunotherapy.

Integrative Analysis and Experimental Validation Indicated That SNHG17 Is a Prognostic Marker in Prostate Cancer and a Modulator of the Tumor Microenvironment via a Competitive Endogenous RNA Regulatory Network.

The incidence of prostate cancer (PC) is growing rapidly worldwide, and studies uncovering the molecular mechanisms driving the progression and modulating the immune infiltration and antitumor immunity of PC are urgently needed. The long noncoding RNA SNHG family has been recognized as a prognostic marker in cancers and contributes to the progression of multiple cancers, including PC. In this study, we aimed to clarify the prognostic values and underlying mechanisms of SNHGs in promoting the progression and modulating the tumor microenvironment of PC through data mining based on The Cancer Genome Atlas (TCGA) database. We identified that within the SNHG family, SNHG17 was most correlated with the overall survival of PC patients and could act as an independent predictor. Moreover, we constructed a competitive endogenous RNA (ceRNA) network by which SNHG17 promotes progression and potentially inhibits the immune infiltration and immune response of prostate cancer. By interacting with miR-23a-3p/23b-3p/23c, SNHG17 upregulates the expression of UBE2M and OTUB1, which have been demonstrated to play critical roles in the tumorigenesis of human cancers, more importantly promoting cancer cell immunosuppression and resistance to cytotoxic stimulation. Finally, we examined the correlation between SNHG17 expression and the clinical progression of PC patients based on our cohort of 52 PC patients. We also verified the SNHG17/miR-23a/OTUB1 axis in RV-1 and PC-3 cells by dual luciferase and RIP assays, and we further identified that SNHG17 promoted cellular invasive capacity by modulating OTUB1. In summary, the current study conducted a ceRNA-based SNHG17-UBE2M/OTUB1 axis and indicated that SNHG17 might be a novel prognostic factor associated with the progression, immunosuppression, and cytotoxic resistance of PC.

Mariana-type ophiolites constrain the establishment of modern plate tectonic regime during Gondwana assembly.

Initiation of Mariana-type oceanic subduction zones requires rheologically strong oceanic lithosphere, which developed through secular cooling of Earth's mantle. Here, we report a 518 Ma Mariana-type subduction initiation ophiolite from northern Tibet, which, along with compilation of similar ophiolites through Earth history, argues for the establishment of the modern plate tectonic regime by the early Cambrian. The ophiolite was formed during the subduction initiation of the Proto-Tethys Ocean that coincided with slab roll-back along the southern and western Gondwana margins at ca. 530-520 Ma. This global tectonic re-organization and the establishment of modern plate tectonic regime was likely controlled by secular cooling of the Earth, and facilitated by enhanced lubrication of subduction zones by sediments derived from widespread surface erosion of the extensive mountain ranges formed during Gondwana assembly. This time also corresponds to extreme events recorded in climate and surface proxies that herald formation of the contemporary Earth.

Exploring the five different genes associated with PKCα in bladder cancer based on gene expression microarray.

Much progress has been made in understanding the mechanism of bladder cancer (BC) progression. Protein kinase C-α (PKCα) is overexpressed in many kinds of cancers. Additionally, PKCα is considered an oncogene that regulates proliferation, invasion, migration, apoptosis and cell cycle in multiple cancers. However, the mechanism underlying how these cellular processes are regulated by PKCα remains unknown. In the present study, we used PKCα siRNA to knock down PKCα gene expression and found that down-regulation of PKCα could significantly inhibit cell proliferation, migration and invasion and induce apoptosis and G1/S cell cycle arrest in vitro. Overexpression of PKCα promotes tumour growth in vivo. We applied cDNA microarray technology to detect the differential gene expression in J82 cells with PKCα knockdown and found that five key genes (BIRC2, BIRC3, CDK4, TRAF1 and BMP4) were involved in proliferation and apoptosis according to GO analysis and pathway analyses. Correlation analysis revealed a moderate positive correlation between PKCα expression and the expression of five downstream genes. BIRC2 and BIRC3 inhibit apoptosis, whereas CDK4, TRAF1 and BMP4 promote proliferation. Essentially, all five of these target genes participated in proliferation, and apoptosis was regulated by PKCα via the NF-kB signalling pathway.

Differential diagnosis of coronavirus disease 2019 from community-acquired-pneumonia by computed tomography scan and follow-up.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is currently the most serious infectious disease in the world. An accurate diagnosis of this disease in the clinic is very important. This study aims to improve the differential ability of computed tomography (CT) to diagnose COVID-19 and other community-acquired pneumonias (CAPs) and evaluate the short-term prognosis of these patients. METHODS: The clinical and imaging data of 165 COVID-19 and 118 CAP patients diagnosed in seven hospitals in Anhui Province, China from January 21 to February 28, 2020 were retrospectively analysed. The CT manifestations of the two groups were recorded and compared. A correlation analysis was used to examine the relationship between COVID-19 and age, size of lung lesions, number of involved lobes, and CT findings of patients. The factors that were helpful in diagnosing the two groups of patients were identified based on specificity and sensitivity. RESULTS: The typical CT findings of COVID-19 are simple ground-glass opacities (GGO), GGO with consolidation or grid-like changes. The sensitivity and specificity of the combination of age, white blood cell count, and ground-glass opacity in the diagnosis of COVID-19 were 92.7 and 66.1%, respectively. Pulmonary consolidation, fibrous cords, and bronchial wall thickening were used as indicators to exclude COVID-19. The sensitivity and specificity of the combination of these findings were 78.0 and 63.6%, respectively. The follow-up results showed that 67.8% (112/165) of COVID-19 patients had abnormal changes in their lung parameters, and the severity of the pulmonary sequelae of patients over 60 years of age worsened with age. CONCLUSIONS: Age, white blood cell count and ground-glass opacity have high accuracy in the early diagnosis of COVID-19 and the differential diagnosis from CAP. Patients aged over 60 years with COVID-19 have a poor prognosis. This result provides certain significant guidance for the diagnosis and treatment of new coronavirus pneumonia.

CT manifestations of coronavirus disease-2019: A retrospective analysis of 73 cases by disease severity.

PURPOSE: To report CT features of coronavirus disease-2019 (COVID-19) in patients with various disease severity. METHODS: The CT manifestations and clinical data of 73 patients with COVID-19 were retrospectively collected in 6 hospitals from Jan 21 to Feb 3, 2020. We analyzed the initial and follow-up CT features of patients with disease severity, according to the Guidelines for the Diagnosis and Treatment of New Coronavirus Pneumonia. RESULTS: Six patients (8%) were diagnosed as mild type pneumonia; these patients had no obvious abnormal CT findings or manifested mild changes of lung infection. All 43 patients (59 %) with common type presented unique or multiple ground-glass opacities (GGO) in the periphery of the lungs, with or without interlobular septal thickening. In the 21 patients (29 %) with severe type, extensive GGO and pulmonary consolidation were found in 16 cases (16/21, 76 %) and 5 cases (24 %), respectively. An extensive "white lung", with atelectasis and pleural effusion were found in critical type patients (3, 4%). On the resolutive phase of the disease, CT abnormalities showed complete resolution, or demonstrated residual linear opacities. CONCLUSIONS: Different CT features are seen according to disease severity, which can help COVID-19 stratification.

Anti-inflammatory diterpenes from the fruits of Vitex trifolia L. var. simplicifolia Cham.

Two new labdane-type diterpenes, named viterotulin C (1) and vitexilactone D (2), together with five known diterpenes (3-7), were isolated from the fruits of Vitex trifolia L. var. simplicifolia Cham. Their structures were elucidated by detailed analysis of spectroscopic data. All the compounds were evaluated for their inhibitory effects on nuclear factor-kappa B (NF-κB) pathway in HEK 293 cell line. These compounds presented inhibition on TNF-α-induced NF-κB activation, with inhibition rates ranging from 42.52 ± 10.69% to 68.86 ± 10.76% at the concentration of 50 µM.

A Review on the Terpenes from Genus Vitex.

The genus Vitex, which belongs to the Verbenaceae family, includes approximately 250 species. Some species of the genus Vitex have traditionally been used for the treatment of headaches, ophthalmodynia, coughs, asthma, premenopausal syndrome, etc. Chemical investigations indicate that the characteristic constituents of the genus Vitex are terpenes, and 210 of these compounds, including monoterpenoids, sesquiterpenoids, diterpenoids and triterpenoids, have been obtained from 12 species. Pharmacological studies had shown that these terpenes possess anti-inflammatory, antitumor, antibacterial, antioxidant activities, and so on. In this paper, the identity of these terpenes and their pharmacological effects are reviewed, which can provide references for further research regarding the chemistry and utilization of the Vitex species.

Structure-activity study of endomorphin-2 analogs with C-terminal modifications by NMR spectroscopy and molecular modeling.

Endomorphin-2 (EM-2) is a putative endogenous mu-opioid receptor ligand. To get insight into the important role of C-terminal amide group of EM-2, we investigated herein a series of EM-2 analogs by substitution of the C-terminal amide group with -NHNH(2), -NHCH(3), -N(CH(3))(2), -OCH(3), -OCH(2)CH(3), -OC(CH(3))(3), and -CH(2)-OH. Their binding affinity and bioactivity were determined and compared. Despite similar (analogs 1, 4, and 7) or decreased (analogs 2, 3,5, and 6) mu affinity in binding assays, all analogs showed low guinea pig ileum (GPI) and mouse vas deferens (MVD) potencies compared to their parent peptide. Interestingly, as for analogs 2 and 3 (a single and double N-methylation of C-terminal amide), the potency order with the K(i) (mu) values was 2>3; for the C-terminal esterified analogs 4-6, the potency order with the K(i) (mu) values was 4>5>6. Thus, we concluded that the steric hindrance of C-terminus might play an important role in opioid receptor affinity. We further investigated the conformational properties of these analogs by 1D and 2D (1)H NMR spectroscopy and molecular modeling. Evaluating the ratios of cis- and trans-isomers, aromatic interactions, dihedral angles, and stereoscopic views of the most convergent conformers, we found that modifications at the C-terminal amide group of EM-2 affected these analog conformations markedly, therefore changed the opioid receptor affinity and in vitro bioactivity.

Conformational analysis of endomorphin-2 analogs with phenylalanine mimics by NMR and molecular modeling.

We investigated a series of conformations of endomorphin-2 (EM-2) analogs substituted by phenylglycine (Phg) and homophenylalanine (Hfe) in the position 3 or 4 by two-dimensional (1)H NMR spectroscopy and molecular modeling. Evaluating the aromatic interactions and the dihedral angles in these phenylalanine mimics, we have observed that the conformations in trans isomer have varied from extended to folded as bioactivity decreases. It is suggested that the flexibility of aromatic side chain affects the backbone of EM-2 to adopt folded structures, which may block the ligands in binding to micro-opioid receptor.

Utilization of combined chemical modifications to enhance the blood-brain barrier permeability and pharmacological activity of endomorphin-1.

The endogenous mu-opioid receptor agonist, endomorphin (EM)-1, cannot be delivered into the central nervous system (CNS) in sufficient quantity to elicit analgesia when given systemically because it is severely restricted by the blood-brain barrier (BBB). To improve the physicochemical characteristics of EM-1 and subsequently achieve greater BBB permeation, we synthesized a series of EM-1 analogs by combining successful chemical modifications, including N-terminal cationization, C-terminal chloro-halogenation, and unnatural amino acid (d-Ala, Sar, and d-Pro-Gly) substitutions in position 2. Presently, their binding and bioassay activity, lipophilicity, stability, and antinociceptive activity were determined and compared. Guanidino-addition and chloro-halogenation attenuated the mu-receptor affinity to some extent, but they demonstrated differences in the influence on stability. It appeared that guanidino-addition contributed to brain stability enhancement for the greater part, whereas chloro-halogenation together with amino acid substitutions in position 2 was of more importance for the stability enhancement in serum than in brain. Determination of the octanol/buffer coefficient revealed that chloro-halogenation did compromise the decreased lipophilicity caused by guanidino-addition, and introduction of d-Ala as well as d-Pro-Gly, but not Sar, in place of l-Pro(2), also increased the overall lipophilicity to some extent. Among the peptides tested, intracerebroventricular injection of guanidino-[d-Ala(2), p-Cl-Phe(4)]EM-1 showed the strongest analgesia, being 3 times more potent than the parent peptide. We also found that in comparison with EM-1, the four d-Ala-containing tetrapeptides and the chloro-halogenated d-Pro-Gly-containing pentapeptide elicited significant and prolonged central-mediated analgesia upon subcutaneous administration, indicating that more peptides reached the CNS, eliciting greater analgesic effect.