Formation of the androgen receptor splicing variant 7 (AR-V7) is one of the major mechanisms by which resistance of prostate cancer to androgen deprivation therapy occurs. The histone demethylase ...JMJD1A (Jumonji domain containing 1A) functions as a key coactivator for AR by epigenetic regulation of H3K9 methylation marks. Here, we describe a role for JMJD1A in AR-V7 expression. While JMJD1A knockdown had no effect on full-length AR (AR-FL), it reduced AR-V7 levels in prostate cancer cells. Reexpression of AR-V7 in the JMJD1A-knockdown cells elevated expression of select AR targets and partially rescued prostate cancer cell growth in vitro and in vivo. The AR-V7 protein level correlated positively with JMJD1A in a subset of human prostate cancer specimens. Mechanistically, we found that JMJD1A promoted alternative splicing of AR-V7 through heterogeneous nuclear ribonucleoprotein F (HNRNPF), a splicing factor known to regulate exon inclusion. Knockdown of JMJD1A or HNRNPF inhibited splicing of AR-V7, but not AR-FL, in a minigene reporter assay. JMJD1A was found to interact with and promote the recruitment of HNRNPF to a cryptic exon 3b on AR pre-mRNA for the generation of AR-V7. Taken together, the role of JMJD1A in AR-FL coactivation and AR-V7 alternative splicing highlights JMJD1A as a potentially promising target for prostate cancer therapy.
This study aims to analyze the clinical characteristics and treatment outcomes of 590 patients with brucellosis in Xinjiang, China.
The clinical characteristics, laboratory findings, complications ...and prognosis of 590 patients infected with brucellosis were retrospectively analyzed. These patients had a mean age of 44.24 ± 15.83 years with 60.5% having a history of close contacting with cattle and sheep. Of them, 53.6% (316 /590) were in acute phase and 21.5% were in chronic phase. Agglutination test showed 98.5% positive with 34% blood culture positive of Brucella. The major symptoms were fatigue (91%), hyperhidrosis(88.1%), fever(86.9%), and joint pain(81%) with 29.8% having enlarged liver, 26.1% having enlarged spleen and 23.2% having osteoarticular complications. Combination of doxycycline plus rifampicin for 12 weeks was an effective regimen for patients without complications. The 3-drug regimen (doxycycline+rifampicin+levofloxacin) for 12 weeks was recommended for these with complications. There were 6 patients died (1.02%) with overall relapse rate of 5.98%.
Brucellosis is mostly associated with contacting with domestic animal production in Xinjiang, China. Clinical symptoms include fever, fatigue, hyperhidrosis, and joint pain with common complication of osteoarticular involvement. Three-drug-regimen of doxycycline+rifampicin+levofloxacin for 12 weeks was effective for these patients with complications.
Abstract
Brucella is a typical facultative intracellular bacterium that can cause zoonotic infections. For Brucella, it is difficult to eliminate with current medical treatment. Therefore, a ...multi-epitope vaccine (MEV) should be designed to prevent Brucella infection. For this purpose, we applied the reverse vaccinology approach from Omp10, Omp25, Omp31 and BtpB. Finally, we obtained 13 cytotoxic T lymphocyte (CTL) epitopes, 17 helper T lymphocyte (HTL) epitopes, 9 linear B cell epitopes, and 2 conformational B cell epitopes for further study. To keep the protein folded normally, we linked AAY, GPGPG, and KK to CTL epitopes, HTL epitopes, and B cell epitopes, respectively. The N-terminal of the vaccine peptide is supplemented with appropriate adjuvants to enhance immunogenicity. To evaluate its immunogenicity, stability, safety, and feasibility, a final MEV containing 806 amino acids was constructed by linking linkers and adjuvants. In addition, molecular docking and molecular dynamics simulations were performed to verify the affinity and stability of the MEV-TLR4. Then, codon adaptation and in silico cloning studies were carried out to identify the possible codons for expressing the MEV. In animal experiments, the results demonstrated that the MEV had high immunogenicity. Collectively, this study provided a theoretical basis for the development of a Brucella vaccine.
Objective To compare the clinical outcomes between thulium laser transurethral enucleation of the prostate (ThuLEP) (70 W) and holmium laser transurethral enucleation of the prostate (HoLEP) (90 W) ...in a prospective randomized trial with 18 months of follow-up. Both ThuLEP and HoLEP effectively relieve the obstructive symptoms due to benign prostatic hyperplasia (BPH). Methods A total of 133 consecutive patients with BPH were randomized to either ThuLEP (n = 71) or HoLEP (n = 62). An energy setting of 70 W and 90 W was used for the thulium and holmium laser in the enucleation procedure, respectively. The mushroom technique was used to fragment the enucleated lobes with the resection loop. The preoperative and postoperative parameters were compared. Results ThuLEP required a longer operation time (72.4 vs 61.5 minutes, P = .034) but resulted in less blood loss than HoLEP (130.0 vs 166.6 mL, P = .045). The catheterization time was comparable. At 18 months, the lower urinary tract symptom indexes were improved significantly in both groups compared with the baseline values. The International Prostate Symptom Score decreased to 5.2 in the ThuLEP group and 6.2 in the HoLEP group. The quality of life score and peak urinary flow rate were similar between the 2 groups (1.3 vs 1.2 and 23.4 vs 24.2 mL/s) and the postvoid residual urine volume decreased by 82.50% and 81.73% in the ThuLEP and HoLEP groups, respectively. The mean prostate-specific antigen decrease after HoLEP and ThuLEP was 30.43% and 43.36%, respectively. No urethral or bladder neck stricture were found in either group. Conclusion Both ThuLEP (70 W) and HoLEP (90 W) relieve lower urinary tract symptoms equally with high efficacy and safety. ThuLEP was statistically superior to HoLEP in blood loss and inferior to HoLEP in operation time, although the differences were clinically negligible. The mushroom technique could be adequate, without an additional mechanical tissue morcellator.
Brucella, a gram-negative intracellular bacterium, causing Brucellosis, a zoonotic disease with a range of clinical manifestations, from asymptomatic to fever, fatigue, loss of appetite, joint and ...muscle pain, and back pain, severe patients have developed serious diseases affecting various organs. The mRNA vaccine is an innovative type of vaccine that is anticipated to supplant traditional vaccines. It is widely utilized for preventing viral infections and for tumor immunotherapy. However, research regarding its effectiveness in preventing bacterial infections is limited. In this study, we analyzed the epitopes of two proteins of brucella, the TonB-dependent outer membrane receptor BtuB and the LPS assembly protein LptD, which is involved in nutrient transport and LPS synthesis in Brucella. In order to effectively stimulate cellular and humoral immunity, we utilize a range of immunoinformatics tools such as VaxiJen, AllergenFPv.1.0 and SignalP 5.0 to design proteins. Finally, five cytotoxic T lymphocyte (CTL) cell epitopes, ten helper T lymphocyte (HTL) cell epitopes, and eight B cell epitopes were selected to construct the vaccine. Computer simulations are also used to verify the immune response of the vaccine. The codon optimization, in silico cloning showed that the vaccine can efficiently transcript and translate in E. coli. The secondary structure of mRNA vaccines and the secondary and tertiary structures of vaccine peptides were predicted and then docked with TLR-4. Finally, the stability of the developed vaccine was confirmed through molecular dynamics simulation. These analyses showed that the design the multi-epitope mRNA vaccine could potentially target extracellular protein of prevalent Brucella, which provided novel strategies for developing the vaccine.
Well-defined ethyl cellulose-graft-poly(ε-caprolactone) (EC-g-PCL) graft copolymers were successfully synthesized via ring-opening polymerization (ROP) of ε-caprolactone (CL) with an ethyl cellulose ...(EC) initiator and a tin 2-ethylhexanoate (Sn(Oct)2) catalyst in xylene at 120 °C. Then, novel ethyl cellulose-graft-poly(ε-caprolactone)-block-poly(l-lactide) (EC-g-PCL-b-PLLA) graft-block copolymers were prepared by ROP of l-lactide (L-LA) with a hydroxyl-terminated EC-g-PCL macroinitiator and Sn(Oct)2 catalyst in bulk at 120 °C. Various graft and block lengths of EC-g-PCL and EC-g-PCL-b-PLLA copolymers were obtained by adjusting the molar ratios of CL monomer to EC and the L-LA monomer to CL. The thermal properties and crystalline morphologies of EC-g-PCL and EC-g-PCL-b-PLLA copolymers were different from those of linear PCL. The in vitro degradation rate of EC-g-PCL-b-PLLA was faster than those of linear PCL and EC-g-PCL due to the presence of PLLA blocks.
The development of an effective multivalent vaccine against SARS-CoV-2 variants is an important means to improve the global public health situation caused by COVID-19. In this study, we identified ...the antigen epitopes of the main global epidemic SARS-CoV-2 and mutated virus strains using immunoinformatics approach, and screened out 8 cytotoxic T lymphocyte epitopes (CTLEs), 17 helper T lymphocyte epitopes (HTLEs), 9 linear B-cell epitopes (LBEs) and 4 conformational B-cell epitopes (CBEs). The global population coverage of CTLEs and HTLEs was 93.16% and 99.9% respectively. These epitopes were spliced together by corresponding linkers and recombined into multivalent vaccine. In silico tests, the vaccine protein was a non-allergen and the docking with TLR-3 molecule showed a strong interaction. The results of immune simulation showed that the vaccine may be helpful to initiate both cellular and humoral immunity against all VOC. The optimistic immunogenicity of the vaccine was confirmed
and
finally. Therefore, our vaccine may have potential protection against SARS-CoV-2 and its variants.
This study is to investigate the role of regulatory B (Breg) cells in cervical cancer. In total, 70 cases of cervical cancer, 52 cases of cervical intraepithelial neoplasia (CIN), and 40 normal ...controls were enrolled. The percentage of Breg cells was detected by flow cytometry. Serum levels of IL-10 were measured by ELISA. The correlation between Breg cells and the clinical characterizations of cervical cancer was analyzed. The inhibition effect of Breg cells on CD8+ T cells was tested by blocking IL-10 in vitro. The percentage of CD19+CD5+CD1d+ Breg cells and the level of IL-10 of patients with cervical cancer or CIN were significantly higher than those in the control group (P<0.05). And the postoperative levels of Breg cells and IL-10 were significantly lower than the preoperative levels (P<0.05). Breg cells and the IL-10 level were positively correlated in cervical cancer patients (r=0.516). In addition, the Breg cell percentage was closely related to the FIGO stages, lymph node metastasis, tumor differentiation, HPV infection, and the tumor metastasis of cervical cancer (P<0.05). The Breg cell percentage was negatively correlated with CD8+ T cells of cervical cancer patients (r=‐0.669). The level of IL-10 in the culture supernatant of Bregs treated with CpG was significantly higher than that of non-Bregs (P<0.05). After coculture with Bregs, the quantity of CD8+ T cells to secrete perforin and Granzyme B was significantly decreased, and this effect was reversed after blocking IL-10 by a specific antibody. Breg cells are elevated in cervical cancer and associated with disease progression and metastasis. Moreover, they can inhibit the cytotoxicity of CD8+ T cells.
All the time, echinococcosis is a global zoonotic disease which seriously endangers public health all over the world. In order to speed up the development process of anti-
vaccine, at the same time, ...it can also save economic cost. In this study, immunoinformatics tools and molecular docking methods were used to predict and screen the antigen epitopes of
, to design a multi-epitope vaccine containing B- and T-cell epitopes. The multi-epitope vaccine could activate B lymphocytes to produce specific antibodies theoretically, which could protect the human body against
infection. It also could activate T lymphocytes and clear the infected parasites in the body. In this study, four CD8
T-cell epitopes, three CD4
T-cell epitopes and four B-cell epitopes of Protein EgTeg were identified by immunoinformatics methods. Meanwhile, three CD8
T-cell epitopes, two CD4
T-cell epitopes and four B-cell epitopes of Protein EgFABP1 were identified. We constructed the multi-epitope vaccine using linker proteins. The study based on the traditional methods of antigen epitope prediction, further optimized the prediction results combined with molecular docking technology and improved the precision and accuracy of the results. Finally,
and
experiments had verified that the vaccine designed in this study had good antigenicity and immunogenicity.
Chronic obstructive pulmonary disease (COPD), a common respiratory disease, can be divided into stable phase and acute exacerbation phase (AECOPD) and is characterized by inflammation and ...hyper-immunity. Methylation of N6-methyladenosine (m6A) is an epigenetic modification that regulates the expression and functions of genes by influencing post-transcriptional RNA modifications. Its influence on the immune regulation mechanism has attracted great attention. Herein, we present the m6Amethylomic landscape and observe how the methylation of m6A participates in the pathological process of COPD. The m6A modification of 430 genes increased and that of 3995 genes decreased in the lung tissues of mice with stable COPD. The lung tissues of mice with AECOPD exhibited 740 genes with hypermethylated m6A peak and 1373 genes with low m6A peak. These differentially methylated genes participated in signaling pathways related to immune functions. To further clarify the expression levels of differentially methylated genes, RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-sequencing data were jointly analyzed. In the stable COPD group, 119 hypermethylated mRNAs (82 upregulated and 37 downregulated mRNAs) and 867 hypomethylated mRNAs (419 upregulated and 448 downregulated mRNAs) were differentially expressed. In the AECOPD group, 87 hypermethylated mRNAs (71 upregulated and 16 downregulated mRNAs) and 358 hypomethylated mRNAs (115 upregulated and 243 downregulated mRNAs) showed differential expression. Many mRNAs were related to immune function and inflammation. Together, this study provides important evidence on the role of RNA methylation of m6A in COPD.
PDF
