Abstract
MicroRNAs (miRNAs) are noncoding RNAs with 18–26 nucleotides; they pair with target mRNAs to regulate gene expression and produce significant changes in various physiological and ...pathological processes. In recent years, the interaction between miRNAs and their target genes has become one of the mainstream directions for drug development. As a large-scale biological database that mainly provides miRNA–target interactions (MTIs) verified by biological experiments, miRTarBase has undergone five revisions and enhancements. The database has accumulated >2 200 449 verified MTIs from 13 389 manually curated articles and CLIP-seq data. An optimized scoring system is adopted to enhance this update’s critical recognition of MTI-related articles and corresponding disease information. In addition, single-nucleotide polymorphisms and disease-related variants related to the binding efficiency of miRNA and target were characterized in miRNAs and gene 3′ untranslated regions. miRNA expression profiles across extracellular vesicles, blood and different tissues, including exosomal miRNAs and tissue-specific miRNAs, were integrated to explore miRNA functions and biomarkers. For the user interface, we have classified attributes, including RNA expression, specific interaction, protein expression and biological function, for various validation experiments related to the role of miRNA. We also used seed sequence information to evaluate the binding sites of miRNA. In summary, these enhancements render miRTarBase as one of the most research-amicable MTI databases that contain comprehensive and experimentally verified annotations. The newly updated version of miRTarBase is now available at https://miRTarBase.cuhk.edu.cn/.
Aim
To summarize HBV‐related biomarkers predicting nucleos(t)ide analogs (NAs) discontinuation and hepatitis B virus (HBV) recurrence after drug withdrawal in chronic hepatitis B (CHB) patients, ...providing references for clinical medication, so as to manage CHB patients more scientifically.
Methods
Related pieces of literature were retrieved in PubMed and the results were sorted out. We then analyzed and summarized these articles.
Results
We found that HBV related biomarkers maybe could predict NAs withdrawal safely and the possibility of relapse after treatment cessation, including hepatitis B e antigen (HBeAg), hepatitis B surface antigen (HBsAg), HBV DNA, HBV RNA, pregenomic‐RNA (pgRNA), hepatitis B core‐related antigen (HBcrAg), hepatitis B core antibody (anti‐HBc), and models containing several indicators for predicting the effectiveness of treatment.
Conclusions
HBV DNA, HBV RNA, pgRNA, HBcrAg, anti‐HBc, as well as the prediction models formed by several biomarkers could predict the safe discontinuation of NAs before HBsAg loss and recurrence.
Traditional drug design requires a great amount of research time and developmental expense. Booming computational approaches, including computational biology, computer-aided drug design, and ...artificial intelligence, have the potential to expedite the efficiency of drug discovery by minimizing the time and financial cost. In recent years, computational approaches are being widely used to improve the efficacy and effectiveness of drug discovery and pipeline, leading to the approval of plenty of new drugs for marketing. The present review emphasizes on the applications of these indispensable computational approaches in aiding target identification, lead discovery, and lead optimization. Some challenges of using these approaches for drug design are also discussed. Moreover, we propose a methodology for integrating various computational techniques into new drug discovery and design.
Lymphangioleiomyomatosis (LAM) is a rare, low-grade multisystem neoplastic disease. Most LAM patients are at a high risk of losing lung function at an accelerated rate and developing progressive ...dyspnea. Recently, several studies have reported their experience with pharmacological treatments for LAM. Therefore, we conducted a systematic review and meta-analysis to assess the efficacy and safety of these therapies.
PubMed (Medline), EMBASE, Cochrane Library, Web of Science and EBSCO Host were searched (until March 31, 2019) for eligible prospective studies regarding LAM patients treated with pharmacological treatments. Random effect models were used for quantitative analysis.
Fourteen prospective studies regarding five pharmacological treatments (including sirolimus, everolimus, doxycycline, triptorelin, and a combination therapy of sirolimus and hydroxychloroquine) were enrolled in our systematic review, and ten of them were used for the meta-analysis. Seven prospective studies reported that sirolimus was effective at improving or stabilizing lung function and alleviating renal angiomyolipoma (AML) in LAM patients. Subsequent quantitative analyses showed that during sirolimus treatment, the pooled values of lung function and 6-min walk distance (6MWD) were not significantly changed (P > 0.05), with the pooled response rate of AML being 0.62 (95% confidence intervals CIs: 0.43 to 0.82, I
= 65%). Regarding everolimus, three prospective studies reported similar effects to those of sirolimus with regard to preserving lung function and reducing AMLs. The meta-analysis showed that the changes in lung function during everolimus treatment were not statistically significant (P > 0.05), while the pooled response rate of AML was 0.78 (95% CI: 0.68 to 0.88, I
= 8%). Neither the qualitative nor the quantitative results confirmed the benefits of doxycycline or triptorelin treatment, and the effects of the combination therapy were unclear in LAM patients. Most of the adverse events during pharmacological treatments were low or moderate grade and tolerable.
Overall, sirolimus and everolimus were recommended for the treatment of LAM because they could stabilize lung function and alleviate renal AML. Doxycycline and triptorelin were not recommended for the treatment of LAM because no beneficial outcomes were consistently observed. The efficacy and safety of combination therapy remain to be further explored.
Abstract
Background
Ubiquitylation is an important post-translational modification of proteins that not only plays a central role in cellular coding, but is also closely associated with the ...development of a variety of diseases. The specific selection of substrate by ligase E3 is the key in ubiquitylation. As various high-throughput analytical techniques continue to be applied to the study of ubiquitylation, a large amount of ubiquitylation site data, and records of E3-substrate interactions continue to be generated. Biomedical literature is an important vehicle for information on E3-substrate interactions in ubiquitylation and related new discoveries, as well as an important channel for researchers to obtain such up to date data. The continuous explosion of ubiquitylation related literature poses a great challenge to researchers in acquiring and analyzing the information. Therefore, automatic annotation of these E3-substrate interaction sentences from the available literature is urgently needed.
Results
In this research, we proposed a model based on representation and attention mechanism based deep learning methods, to automatic annotate E3-substrate interaction sentences in biomedical literature. Focusing on the sentences with E3 protein inside, we applied several natural language processing methods and a Long Short-Term Memory (LSTM)-based deep learning classifier to train the model. Experimental results had proved the effectiveness of our proposed model. And also, the proposed attention mechanism deep learning method outperforms other statistical machine learning methods. We also created a manual corpus of E3-substrate interaction sentences, in which the E3 proteins and substrate proteins are also labeled, in order to construct our model. The corpus and model proposed by our research are definitely able to be very useful and valuable resource for advancement of ubiquitylation-related research.
Conclusion
Having the entire manual corpus of E3-substrate interaction sentences readily available in electronic form will greatly facilitate subsequent text mining and machine learning analyses. Automatic annotating ubiquitylation sentences stating E3 ligase-substrate interaction is significantly benefited from semantic representation and deep learning. The model enables rapid information accessing and can assist in further screening of key ubiquitylation ligase substrates for in-depth studies.
The formation of anti-drug antibodies (ADAs) during anti-tumor necrosis factor (anti-TNF) therapy is reported to lead to reducing serum drug levels, which may bring about a loss of response to ...treatment. Previous research has suggested an association between specific antibiotic classes and ADA formation during anti-TNF therapy. However, there are few studies specifically examining this association in Chinese inflammatory bowel disease (IBD) patients. Therefore, our study aimed to evaluate the possible effect of antibiotic use on ADA formation to anti-TNF therapy in Chinese patients with IBD.
A total of 166 patients with IBD, including 149 with Crohn's disease (CD) and 17 with ulcerative colitis (UC), were included in this retrospective analysis. These patients were initially treated with anti-TNF therapy (infliximab or adalimumab) after January 2018 and reviewed with available ADA levels before October 2023. After univariable analysis of all the variables, a multivariate Cox proportional hazards model was used to assess the association between antibiotic use and ADA development.
Among 166 IBD patients treated with infliximab (108/166, 65.1%) or adalimumab (58/166, 34.9%), 31 patients (18.7%) were measured as positive ADA levels. Cox proportional hazard model demonstrated an increased risk of ADA formation in IBD patients who used β-lactam-β-lactamase inhibitor combinations (BL-BLIs) (HR = 5.143, 95%CI 1.136-23.270,
= 0.033), or nitroimidazoles (HR = 4.635, 95%CI 1.641-13.089,
= 0.004) during 12 months before the ADA test. On the contrary, a reduced risk was noted in patients treated with fluoroquinolones (HR = 0.258, 95% CI 0.072-0.924,
= 0.037). Moreover, the median serum infliximab or adalimumab concentration in patients with positive ADA levels was significantly lower than that in patients with negative ADA levels (infliximab: 0.30 vs. 1.85 μg/mL,
< 0.0001; adalimumab: 0.45 vs. 7.55 μg/mL,
= 0.0121).
ADA development is associated with various antibiotic classes. BL-BLIs and nitroimidazoles might increase the risk of ADA formation during anti-TNF therapy in Chinese IBD patients, while the treatment with fluoroquinolones could probably reduce such risk. There were certain limitations in the retrospective analysis of the study, therefore, the results are just for reference, and other studies are needed to further confirm our findings.
Inflammatory bowel disease (IBD) has been associated with lipid-lowering drugs in observational studies. Drug-target Mendelian randomization (MR) was utilized in this study to examine the causal ...relationship between lipid-lowering drugs and incidence of IBD, aiming to identify new preventive uses for the drugs.
We identified instrumental variables for three classes of lipid-lowering drugs: HMGCR inhibitors, PCSK9 inhibitors, and NPC1L1 inhibitors, using data from the Global Lipids Genetics Consortium. Summary statistics of IBD were obtained from UK Inflammatory Bowel Disease Genetics. The summary-data-based MR (SMR) and the inverse-variance weighted (IVW) MR were used for analysis. Sensitivity analyses were performed by conventional MR methods.
The SMR analysis showed no significant genetic association between increased gene expression of HMGCR, PCSK9, and NPC1L1 and IBD, Crohn's disease (CD) and ulcerative colitis (UC). According to IVW-MR analysis, increased HMGCR expression is associated with a reduced risk of IBD (OR = 0.73, 95% confidence interval (CI) 0.59-0.90, P = 0.003) and CD (OR = 0.75, 95% CI 0.57-0.97, P = 0.03), but not with UC. Additionally, increased NPC1L1 gene expression was associated with elevated risk of IBD (OR = 1.60, 95% CI 1.07-2.40, P = 0.023), but not with CD and UC. However, no significant causal relationships were found between PCSK9 gene expression and IBD, CD, and UC. The sensitivity analysis demonstrated no evidence of heterogeneity or pleiotropy among the reported results.
The heightened expression of genetic variations in HMGCR inhibitor targets could potentially reduce the risk of IBD and CD, while genetic variation in the expression of NPC1L1 targets was positively associated with IBD.
Monoclonal immunoglobulin produced by clonal plasma cells is the main cause in multiple myeloma and monoclonal gammopathy of renal significance. Because of the complicated purification method and the ...low stoichiometry of purified protein and glycans, site-specific N-glycosylation characterization for monoclonal immunoglobulin is still challenging. To profile the site-specific N-glycosylation of monoclonal immunoglobulins is of great interest. Therefore, in this study, we presented an integrated workflow for micro monoclonal IgA and IgG purification from patients with multiple myeloma in the HYDRASYS system, in-agarose-gel digestion, LC-MS/MS analysis without intact N-glycopeptide enrichment, and compared the identification performance of different mass spectrometry dissociation methods (EThcD-sceHCD, sceHCD, EThcD and sceHCD-pd-ETD). The results showed that EThcD-sceHCD was a better choice for site-specific N-glycosylation characterization of micro in-agarose-gel immunoglobulins (~2 μg) because it can cover more unique intact N-glycopeptides (37 and 50 intact N-glycopeptides from IgA1 and IgG2, respectively) and provide more high-quality spectra than sceHCD, EThcD and sceHCD-pd-ETD. We demonstrated the benefits of the alternative strategy in site-specific N-glycosylation characterizing micro monoclonal immunoglobulins obtained from bands separated by electrophoresis. This work could promote the development of clinical N-glycoproteomics and related immunology.
Objective: To compare the Duhamel and transanal endorectal pull-through (TERPT) procedures in the treatment of children with Hirschsprung’s disease. Methods: Studies comparing the Duhamel and TERPT ...procedures were included until 22 July 2023. R software (version 4.3.0) was used to perform the meta-analysis. Results: Ten studies with a sum of 496 patients were included. The length of postoperative hospital stay and incidence of postoperative constipation were longer and higher after the Duhamel procedure than the TERPT procedure (p < 0.0001 and p = 0.0041, respectively). The incidence of postoperative anastomotic stricture was higher after the TERPT procedure than the Duhamel procedure (p = 0.0015). No significant differences were found in the incidence of postoperative fecal continence, fecal incontinence/soiling, anastomotic leak, or ileus between these two procedures. The operation time seemed to be similar for both procedures, but it became longer for the Duhamel procedure than the TERPT procedure after sensitivity analysis. While the incidence of postoperative enterocolitis seemed to be higher after the TERPT procedure, it became similar for both procedures in the subgroup analysis. Conclusions: The Duhamel procedure seems to be associated with a longer length of postoperative hospital stay, a higher incidence of postoperative constipation, and a lower incidence of postoperative anastomotic stricture than the TERPT procedure. However, the effect of these two procedures on the operation time and the incidence of postoperative enterocolitis remains unclear.
To study the dentoskeletal characteristics and the degree of compensations in skeletal Class I adults with unilateral posterior crossbite (UPCB).
A sample of 40 adults was chosen for this ...cross-sectional study. 20 skeletal Class I adults with UPCB (mean age: 22.20 ± 2.88 years), were compared to 20 skeletal Class I adults with normal occlusion (mean age: 27.56 ± 5.76 years). The respective dentoskeletal measurements were made on cross-sectional images from cone-beam computed tomography scans.
Skeletally, both groups showed significant differences (P < 0.05) in mandibular corpus length and menton deviation with the UPCB group showing the greatest displacement. Maxillomandibular vertical asymmetry and condylar positional asymmetry were not significant in both groups (P > 0.05). For dental variables on the second premolar and first molar, the UPCB group showed greater linear and angular differences when compared to the control group (P < 0.05). On the crossbite side, maxillary posterior teeth were more buccally inclined, and mandibular posterior teeth were more lingually inclined. However, on the non-crossbite side, both maxillary and mandibular posterior teeth were lingually inclined.
Adults with UPCB showed distinct transverse dentoskeletal asymmetry. No asymmetry was found in the condylar position and the mandibular height in UPCB adults.
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