Precision Medicine in Rheumatic Diseases: Unlocking the Potential of Antibody-Drug Conjugates.

In the era of precision medicine, antibody-drug conjugates (ADCs) have emerged as a cutting-edge therapeutic strategy. These innovative compounds combine the precision of monoclonal antibodies with the potent cell-killing or immune-modulating abilities of attached drug payloads. This unique strategy not only reduces off-target toxicity but also enhances the therapeutic effectiveness of drugs. Beyond their well established role in oncology, ADCs are now showing promising potential in addressing the unmet needs in the therapeutics of rheumatic diseases. Rheumatic diseases, a diverse group of chronic autoimmune diseases with varying etiologies, clinical presentations, and prognoses, often demand prolonged pharmacological interventions, creating a pressing need for novel, efficient, and low-risk treatment options. ADCs, with their ability to precisely target the immune components, have emerged as a novel therapeutic strategy in this context. This review will provide an overview of the core components and mechanisms behind ADCs, a summary of the latest clinical trials of ADCs for the treatment of rheumatic diseases, and a discussion of the challenges and future prospects faced by the development of next-generation ADCs. SIGNIFICANCE STATEMENT: There is a lack of efficient and low-risk targeted therapeutics for rheumatic diseases. Antibody-drug conjugates, a class of cutting-edge therapeutic drugs, have emerged as a promising targeted therapeutic strategy for rheumatic disease. Although there is limited literature summarizing the progress of antibody-drug conjugates in the field of rheumatic disease, updating the advancements in this area provides novel insights into the development of novel antirheumatic drugs.

Mid1 promotes synovitis in rheumatoid arthritis via ubiquitin-dependent post-translational modification.

INTRODUCTION: Current anti-rheumatic drugs are primarily modulating immune cell activation, yet their effectiveness remained suboptimal. Therefore, novel therapeutics targeting alternative mechanisms, such as synovial activation, is urgently needed. OBJECTIVES: To explore the role of Midline-1 (Mid1) in synovial activation. METHODS: NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were used to establish a subcutaneous xenograft model. Wild-type C57BL/6, Mid1-/-, Dpp4-/-, and Mid1-/-Dpp4-/- mice were used to establish a collagen-induced arthritis model. Cell viability, cell cycle, qPCR and western blotting analysis were used to detect MH7A proliferation, dipeptidyl peptidase-4 (DPP4) and Mid1 levels. Co-immunoprecipitation and proteomic analysis identified the candidate protein of Mid1 substrates. Ubiquitination assays were used to determine DPP4 ubiquitination status. RESULTS: An increase in Mid1, an E3 ubiquitin ligase, was observed in human RA synovial tissue by GEO dataset analysis, and this elevation was confirmed in a collagen-induced mouse arthritis model. Notably, deletion of Mid1 in a collagen-induced arthritis model completely protected mice from developing arthritis. Subsequent overexpression and knockdown experiments on MH7A, a human synoviocyte cell line, unveiled a previously unrecognized role of Mid1 in synoviocyte proliferation and migration, the key aspects of synovial activation. Co-immunoprecipitation and proteomic analysis identified DPP4 as the most significant candidate of Mid1 substrates. Mechanistically, Mid1 promoted synoviocyte proliferation and migration by inducing ubiquitin-mediated proteasomal degradation of DPP4. DPP4 deficiency led to increased proliferation, migration, and inflammatory cytokine production in MH7A, while reconstitution of DPP4 significantly abolished Mid1-induced augmentation of cell proliferation and activation. Additionally, double knockout model showed that DPP4 deficiency abolished the protective effect of Mid1 defect on arthritis. CONCLUSION: Overall, our findings suggest that the ubiquitination of DPP4 by Mid1 promotes synovial cell proliferation and invasion, exacerbating synovitis in RA. These results reveal a novel mechanism that controls synovial activation, positioning Mid1 as a promising target for therapeutic intervention in RA.

A novel adaptive filter with a heart-rate-based reference signal for esophageal pressure signal denoising.

Esophageal pressure (Peso) is one of the most common and minimally invasive methods used to assess the respiratory and lung mechanics in patients receiving mechanical ventilation. However, the Peso measurement is contaminated by cardiogenic oscillations (CGOs), which cannot be easily eliminated in real-time. The field of study dealing with the elimination of CGO from Peso signals is still in the early stages of its development. In this study, we present an adaptive filtering-based method by constructing a reference signal based on the heart rate and sine function to remove CGOs in real-time. The proposed technique is tested using clinical data acquired from 20 patients admitted to the intensive care unit. Lung compliance ( QUOTE ) and esophageal pressure swings (△Pes) are used to evaluate the performance and efficiency of the proposed technique. The CGO can be efficiently suppressed when the constructional reference signal contains the fundamental, and second and third harmonic frequencies of the heart rate signal. The analysis of the data of 8 patients with controlled mechanical ventilation reveals that the standard deviation/mean of the QUOTE is reduced by 28.4-79.2% without changing the QUOTE and the △Pes measurement is more accurate, with the use of our proposed technique. The proposed technique can effectively eliminate the CGOs from the measured Peso signals in real-time without requiring additional equipment to collect the reference signal.

Self-Assembly of Cluster-Mediated 3D Catenanes with Size-Specific Recognition Behavior.

Although interlocked three-dimensional molecules display unique properties associated with their spatial structures, their synthesis and study of their host-guest properties remain challenging. We report the formation of a novel [2]catenane, [Et4N]@[(Tp*WS3Cu3Cl)2(cis-bpype)3]2(OTf)5 ([Et4N][1](OTf)5), by self-assembly of the cluster node [Tp*WS3Cu3Cl]+ and the organic linker (Z)-1,2-diphenyl-1,2-bis(4-(pyridin-4-yl)phenyl)ethene (cis-bpype). Single-crystal X-ray and NMR analyses established that [1]4+ is formed by the interpenetration of two cluster-organic cages. Unique cation-in-cation host-guest complexes were observed with this catenane. The crystalline, empty catenane was formed by taking advantage of the electrostatic repulsion-induced weak binding of the host. Encapsulation experiments also reveal that the empty catenane can adaptively encapsulate cations such as [Et4N]+ and [Pr4N]+ in the cross cavity but is unable to encapsulate [Bu4N]+ and [Me4N]+, although the size of the latter is compatible with that of the cavity. Theoretical calculations and volume analysis allow to unravel the ingenious role of catenane structures and the interplay between electrostatic repulsion and attractive noncovalent interactions for size-specific recognition behavior in host-guest systems involving species with similar electric charges.

Batch Similarity Based Triplet Loss Assembled into Light-Weighted Convolutional Neural Networks for Medical Image Classification.

In many medical image classification tasks, there is insufficient image data for deep convolutional neural networks (CNNs) to overcome the over-fitting problem. The light-weighted CNNs are easy to train but they usually have relatively poor classification performance. To improve the classification ability of light-weighted CNN models, we have proposed a novel batch similarity-based triplet loss to guide the CNNs to learn the weights. The proposed loss utilizes the similarity among multiple samples in the input batches to evaluate the distribution of training data. Reducing the proposed loss can increase the similarity among images of the same category and reduce the similarity among images of different categories. Besides this, it can be easily assembled into regular CNNs. To appreciate the performance of the proposed loss, some experiments have been done on chest X-ray images and skin rash images to compare it with several losses based on such popular light-weighted CNN models as EfficientNet, MobileNet, ShuffleNet and PeleeNet. The results demonstrate the applicability and effectiveness of our method in terms of classification accuracy, sensitivity and specificity.

A comprehensive analysis of subclass-specific IgG glycosylation in colorectal cancer progression by nanoLC-MS/MS.

Colorectal cancer is associated with changed IgG glycosylation, but the alteration in specific subclasses of IgG is unknown. Initially, we optimized five common IgG glycopeptide enrichment methods to acquire a comprehensive profile of IgG glycopeptides. However, an incomplete tryptic digestion of IgG occurred when using an ordinary protease to protein ratio, which significantly impacted the final statistical analysis. Herein, we introduced a two-step enzymatic digestion, enabling the complete digestion of IgG glycopeptides and further improving the detection intensity of the target glycopeptides. In order to rapidly process and automatically integrate the MS data, we developed a simple and effective code using MATLAB. Following statistical analysis, we observed that IgG1_H3N4F1 and IgG1_H3N4 were substantially increased in CRC, while IgG1_H5N5F1, IgG1_H5N4F1S1 and IgG2_H5N4F1 were markedly decreased. A further evaluation of the diagnostic performance showed that they all achieved a fair performance in discriminating the patients from the normal. In terms of the glycan features, it was demonstrated that the CRC progression was associated with increased agalactosylation, and the decreased digalactosylation and galactosylation per antenna on the diantenna glycans of IgG1 and IgG2. Concurrently, the decreased sialylation of IgG1 was strongly correlated with CRC. Moreover, an analysis of tumor-specific glycosylation showed that the alterations of IgG glycosylation were more significant in colon cancer, and no obvious difference was observed between colon and rectal cancer. This study comprehensively optimized the glycopeptide enrichment methods, evaluated the enzymatic digestion effect, and explored the association between CRC progression and subclass-specific glycosylation.

Safety and use of pulmonary function tests: a retrospective study from a single center over seven years' clinical practice.

BACKGROUND: To promote the utilization of pulmonary function tests (PFT) through analyzing the data of PFT during the past seven years in one large teaching hospital in China. METHODS: Through a retrospective analysis, the allocation of full-time staff in PFT room, the demographic characteristics of patients, cost-effectiveness of PFT, positive rate and failure rate of PFT, adverse events were analyzed. RESULTS: 1) From 2012 to 2018, the numbers of PFT showed the trend of escalation year by year. The proportion of patients receiving PFT rose from 29.0/10,000 in 2012 to 34.7/10,000 in 2018. The best allocation of PFT room was 20-25/ person / day. 2) The number of PFT provided by Department of Pulmonary and Critical Care Medicine (PCCM) accounted for 97.2, 97.1, 97.3, 97.8, 97.8, 98.0, and 98.2% of the total cases of outpatient PFT in the same year. The top three departments in the inpatient department were Department of Thoracic Surgery, Department of General Surgery, and Department of Urinary Surgery, the total cases of PFT in these three departments accounted for 65.1, 64.4, 62.1, 63.5, 62.4, 65.3 and 69.1% of the total cases of inpatient PFT in the same year. 3) Data from 2018 showed that the revenue from PFT was about 3.7 million Chinese Yuan, and that the salary of personnel and expenditure on machine maintenance and wear were about 800,000 Chinese Yuan. 4) 58.2% of the patients who had undergone PFT had ventilatory dysfunction. 5) The average failure rate of PFT in the past seven years was 1.91%. 6) The main adverse events of PFT examination were dizziness, amaurosis, limb numbness, lip numbness and falls. The incidence rates were 0.49, 0.42, 0.41, 0.39, 0.44, 0.48, and 0.45% respectively, with an average of 0.44%. CONCLUSIONS: The number of PFT showed an upward trend in the past seven years, and the optimal staffing of PFT room was 20-25 cases per person per day. The positive rate of pulmonary dysfunction was 58.2%. The failure rate of PFT and the incidence of adverse events were very low, suggesting it is a simple and safe clinical examination. It's worthy of further popularization and promotion.

H19 promotes non-small-cell lung cancer (NSCLC) development through STAT3 signaling via sponging miR-17.

LncRNAs can exhibit crucial roles in the development of multiple cancers, including non-small cell lung cancer (NSCLC). Currently, we investigated the role of lncRNA H19 in NSCLC. In our study, it was found that H19 was upregulated in A549 and H1299 cells compared to normal lung epithelial BEAS-2B cells. Meanwhile, we observed that miR-17 was downregulated in NSCLC cell lines. Inhibited H19 can suppress the growth, migration, and invasion of NSCLC cells and bioinformatics search was performed to predict the correlation between H19 and miR-17. Overexpression of miR-17 was able to inhibit the progression of NSCLC cells while reversely miR-17 inhibitors reversed this process. In addition, signal transducers and activators of transcription (STAT3), as an mRNA target of miR-17, was presented in our research. Moreover, we discovered that H19 demonstrated its biological functions via regulating miR-17 and STAT3 in vitro. Silencing H19 greatly increased STAT3 expression by sponging miR-19 in vitro. It was hypothesized that H19 may serve as a competing endogenous RNA (ceRNA) to modulate STAT3 by attaching miR-17 in lung cancer. In summary, our findings indicated that H19/miR-17/STAT3 axis participated in NSCLC development. H19 could be regarded as a significant prognostic biomarker in NSCLC progression.

Long noncoding RNA LINC00961 inhibits cell proliferation and induces cell apoptosis in human non-small cell lung cancer.

Long noncoding RNAs (LncRNAs) have been identified in multiple human cancer types, including lung cancer. An increasing number of studies have indicated that lncRNAs can function as important gene regulators. However, the biological mechanism of LINC00961 in lung cancerremains poorly understood. In our current study, we recognized lncRNA LINC00961, and we observed that it was significantly reduced in human non-small cell lung cancer (NSCLC) tissues. LINC00961 was elevated by infecting LV-LINC00961, while decreased by LV-shLINC00961 in H226 and A549 cells. Furthermore, it was shown that LINC00961 overexpression greatly inhibited lung cancer cell proliferation, whereas downregulated LINC00961 induced cell proliferation. In addition, further experiments showed that restoration of LINC00961 could dramatically increase apoptotic ratios of NSCLC H226 and A549 cells, and knockdown of LINC00961 exhibited an opposite effect. Moreover, Western blot analysis showed that upregulation of LINC00961 repressed proliferating cell nuclear antigen expression and increased Bax expression, indicating that it acts as an important pro-apoptosis gene. Conversely, inhibition of LINC00961 induced proliferating cell nuclear antigen expression and restrained Bax protein levels. Taking these together, LINC00961 might play a tumor suppressive role in NSCLC progression, and it could serve as a novel prognostic biomarker in NSCLC diagnosis and treatment.