Cell-specific IL-1R1 regulates the regional heterogeneity of microglial displacement of GABAergic synapses and motor learning ability.

Microglia regulate synaptic function in various ways, including the microglial displacement of the surrounding GABAergic synapses, which provides important neuroprotection from certain diseases. However, the physiological role and underlying mechanisms of microglial synaptic displacement remain unclear. In this study, we observed that microglia exhibited heterogeneity during the displacement of GABAergic synapses surrounding neuronal soma in different cortical regions under physiological conditions. Through three-dimensional reconstruction, in vitro co-culture, two-photon calcium imaging, and local field potentials recording, we found that IL-1ß negatively modulated microglial synaptic displacement to coordinate regional heterogeneity in the motor cortex, which impacted the homeostasis of the neural network and improved motor learning ability. We used the Cre-Loxp system and found that IL-1R1 on glutamatergic neurons, rather than that on microglia or GABAergic neurons, mediated the negative effect of IL-1ß on synaptic displacement. This study demonstrates that IL-1ß is critical for the regional heterogeneity of synaptic displacement by coordinating different actions of neurons and microglia via IL-1R1, which impacts both neural network homeostasis and motor learning ability. It provides a theoretical basis for elucidating the physiological role and mechanism of microglial displacement of GABAergic synapses.

MOINER: A Novel Multiomics Early Integration Framework for Biomedical Classification and Biomarker Discovery.

In the context of precision medicine, multiomics data integration provides a comprehensive understanding of underlying biological processes and is critical for disease diagnosis and biomarker discovery. One commonly used integration method is early integration through concatenation of multiple dimensionally reduced omics matrices due to its simplicity and ease of implementation. However, this approach is seriously limited by information loss and lack of latent feature interaction. Herein, a novel multiomics early integration framework (MOINER) based on information enhancement and image representation learning is thus presented to address the challenges. MOINER employs the self-attention mechanism to capture the intrinsic correlations of omics-features, which make it significantly outperform the existing state-of-the-art methods for multiomics data integration. Moreover, visualizing the attention embedding and identifying potential biomarkers offer interpretable insights into the prediction results. All source codes and model for MOINER are freely available https://github.com/idrblab/MOINER.

Application of Northern Goshawk Back-Propagation Artificial Neural Network in the Prediction of Monohydroxycarbazepine Concentration in Patients with Epilepsy.

INTRODUCTION: A northern goshawk back-propagation artificial neural network (NGO-BPANN) model was established to predict monohydroxycarbazepine (MHD) concentration in patients with epilepsy. METHODS: The data were collected from 108 Han Chinese patients with epilepsy on oxcarbazepine monotherapy. The results of 14 genotype variates were selected as the input layer in the first BPANN model, and the variables that had a more significant impact on the plasma concentration of MHD were retained. With demographic characteristics and clinical laboratory test results, the genotypes of SCN1A rs2298771 and SCN2A rs17183814 were used to construct the BPANN model. The BPANN model was comprehensively validated and used to predict the MHD plasma concentration of five patients with epilepsy in our hospital. RESULTS: The model demonstrated favorable fitness metrics, including a mean squared error of 0.00662, a gradient magnitude of 0.00753, an absence of validation tests amounting to zero, and a correlation coefficient of 0.980. Sex, BMI, and the genotype SCN1A rs2298771 were ranked highest by the absolute mean impact value (MIV), which is primarily associated with the concentration of MHD. The test group exhibited a range of - 20.84% to 31.03% bias between the predicted and measured values, with a correlation coefficient of 0.941 between the two. With BPANN, the MHD nadir concentration could be predicted precisely. CONCLUSION: The NGO-BPANN model exhibits exceptional predictive capability and can be a practical instrument for forecasting MHD concentration in patients with epilepsy. CLINICAL TRIAL REGISTRATION: www.chiCTR-OOC-17012141 .

Prevalence and clinical significance of potential drug-drug interactions among lung transplant patients.

Background: Drug-drug interactions (DDIs) are a major but preventable cause of adverse drug reactions. There is insufficient information regarding DDIs in lung transplant recipients. Objective: This study aimed to determine the prevalence of potential DDIs (pDDIs) in intensive care unit (ICU) lung transplant recipients, identify the real DDIs and the most frequently implicated medications in this vulnerable population, and determine the risk factors associated with pDDIs. Methods: This retrospective cross-sectional study included lung transplant recipients from January 2018 to December 2021. Pertinent information was retrieved from medical records. All prescribed medications were screened for pDDIs using the Lexicomp® drug interaction software. According to this interaction software, pDDIs were classified as C, D, or X (C = monitor therapy, D = consider therapy modification, X = avoid combination). The Drug Interaction Probability Scale was used to determine the causation of DDIs. All statistical analysis was performed in SPSS version 26.0. Results: 114 patients were qualified for pDDI analysis, and total pDDIs were 4051. The most common type of pDDIs was category C (3323; 82.0%), followed by D (653; 16.1%) and X (75; 1.9%). Voriconazole and posaconazole were the antifungal medicine with the most genuine DDIs. Mean tacrolimus concentration/dose (Tac C/D) before or after co-therapy was considerably lower than the Tac C/D during voriconazole or posaconazole co-therapy (p < 0.001, p = 0.027). Real DDIs caused adverse drug events (ADEs) in 20 patients. Multivariable logistic regression analyses found the number of drugs per patient (OR, 1.095; 95% CI, 1.048-1.145; p < 0.001) and the Acute Physiology and Chronic Health Evaluation II (APACHE Ⅱ) score (OR, 1.097; 95% CI, 1.021-1.179; p = 0.012) as independent risk factors predicting category X pDDIs. Conclusion: This study revealed a high incidence of both potential and real DDIs in ICU lung transplant recipients. Immunosuppressive drugs administered with azole had a high risk of causing clinically significant interactions. The number of co-administered drugs and APACHE Ⅱ score were associated with an increased risk of category × drug interactions. Close monitoring of clinical and laboratory parameters is essential for ensuring successful lung transplantation and preventing adverse drug events associated with DDIs.

SingPro: a knowledge base providing single-cell proteomic data.

Single-cell proteomics (SCP) has emerged as a powerful tool for detecting cellular heterogeneity, offering unprecedented insights into biological mechanisms that are masked in bulk cell populations. With the rapid advancements in AI-based time trajectory analysis and cell subpopulation identification, there exists a pressing need for a database that not only provides SCP raw data but also explicitly describes experimental details and protein expression profiles. However, no such database has been available yet. In this study, a database, entitled 'SingPro', specializing in single-cell proteomics was thus developed. It was unique in (a) systematically providing the SCP raw data for both mass spectrometry-based and flow cytometry-based studies and (b) explicitly describing experimental detail for SCP study and expression profile of any studied protein. Anticipating a robust interest from the research community, this database is poised to become an invaluable repository for OMICs-based biomedical studies. Access to SingPro is unrestricted and does not mandate a login at: http://idrblab.org/singpro/.

Discovery of a potent and selective PARP1 degrader promoting cell cycle arrest via intercepting CDC25C-CDK1 axis for treating triple-negative breast cancer.

PARP1 is a multifaceted component of DNA repair and chromatin remodeling, making it an effective therapeutic target for cancer therapy. The recently reported proteolytic targeting chimera (PROTAC) could effectively degrade PARP1 through the ubiquitin-proteasome pathway, expanding the therapeutic application of PARP1 blocking. In this study, a series of nitrogen heterocyclic PROTACs were designed and synthesized through ternary complex simulation analysis based on our previous work. Our efforts have resulted in a potent PARP1 degrader D6 (DC50 = 25.23 nM) with high selectivity due to nitrogen heterocyclic linker generating multiple interactions with the PARP1-CRBN PPI surface, specifically. Moreover, D6 exhibited strong cytotoxicity to triple negative breast cancer cell line MDA-MB-231 (IC50 = 1.04 µM). And the proteomic results showed that the antitumor mechanism of D6 was found that intensifies DNA damage by intercepting the CDC25C-CDK1 axis to halt cell cycle transition in triple-negative breast cancer cells. Furthermore, in vivo study, D6 showed a promising PK property with moderate oral absorption activity. And D6 could effectively inhibit tumor growth (TGI rate = 71.4 % at 40 mg/kg) without other signs of toxicity in MDA-MB-321 tumor-bearing mice. In summary, we have identified an original scaffold and potent PARP1 PROTAC that provided a novel intervention strategy for the treatment of triple-negative breast cancer.

Initial therapeutic target attainment of perampanel in pediatric patients with epilepsy.

Perampanel is a promising option for the treatment of pediatric epilepsy, but its plasma concentration varies among patients. This retrospective study aimed to investigate the initial target attainment of perampanel plasma concentration in pediatric patients with epilepsy in China. Inpatients admitted from January 2020 to December 2021 in a tertiary hospital were retrospectively included according to pre-set criteria. Demographic characteristics of patients and dosing strategies and therapeutic drug monitoring results were collected. A total of 137 pediatric patients (84 females and 53 males, aged from 0.6 to 16.4 years) were include for analysis. The perampanel concentrations varied greatly from 60 to 1,560 mg/L among patients, but 89.8% had suitable perampanel concentrations (100-1,000 ng/mL). The concomitant use of enzyme-inductive antiepileptic drugs (AEDs) was the only identified risk factor associated with target nonattainment (OR = 5.92, 95% confidence interval 1.68-20.9). Initial perampanel target attainment in pediatric patients is satisfactory. Routine therapeutic drug monitoring to achieved the suggested concentration range for these patients may be unnecessary, except for those receiving combined enzyme inductive AEDs.

An interpretable ensemble learning model facilitates early risk stratification of ischemic stroke in intensive care unit: Development and external validation of ICU-ISPM.

Ischemic stroke (IS) is a common and severe condition that requires intensive care unit (ICU) admission, with high mortality and variable prognosis. Accurate and reliable predictive tools that enable early risk stratification can facilitate interventions to improve patient outcomes; however, such tools are currently lacking. In this study, we developed and validated novel ensemble learning models based on soft voting and stacking methods to predict in-hospital mortality from IS in the ICU using two public databases: MIMIC-IV and eICU-CRD. Additionally, we identified the key predictors of mortality and developed a user-friendly online prediction tool for clinical use. The soft voting ensemble model, named ICU-ISPM, achieved an AUROC of 0.861 (95% CI: 0.829-0.892) and 0.844 (95% CI: 0.819-0.869) in the internal and external test cohorts, respectively. It significantly outperformed the APACHE scoring system and was more robust than individual models. ICU-ISPM obtained the highest performance compared to other models in similar studies. Using the SHAP method, the model was interpretable, revealing that GCS score, age, and intubation were the most important predictors of mortality. This model also provided a risk stratification system that can effectively distinguish between low-, medium-, and high-risk patients. Therefore, the ICU-ISPM is an accurate, reliable, interpretable, and clinically applicable tool, which is expected to assist clinicians in stratifying IS patients by the risk of mortality and rationally allocating medical resources. Based on ICU-ISPM, an online risk prediction tool was further developed, which was freely available at: http://ispm.idrblab.cn/.

Prevalence and influencing factors of probiotic usage among colorectal cancer patients in China: A national database study.

Probiotics have become increasingly popular among cancer patients. However, there is limited data from a real-world setting. This study aims to conduct a retrospective analysis to understand the trend of probiotic prescriptions in Chinese colorectal cancer patients. The Mann-Kendall and Cochran-Armitage trend test was applied to estimate the trend significance. Gephi software identified the combination of probiotic strains. The binary logistic regression investigated influence factors, and Spearman's rank correlation coefficient calculated correlations between probiotics and antitumor drug usage. The probiotic prescription percentage increased from 3.3% in 2015 to 4.2% in 2021 (Z = 12.77, p < 0.001). Although 48.3% of probiotic prescriptions had no indication-related diagnosis, diarrhea (OR 10.91, 95% CI 10.57-11.26) and dyspepsia (3.97, 3.82-4.12) included prescriptions most likely to contain probiotics. Prescriptions from the tertiary hospital (1.43,1.36-1.50), clinics (1.30, 1.28-1.33), and senior patients (1.018 per year, 1.017-1.019) were more likely to contain probiotics. Most probiotic prescriptions (95.0%) contained one probiotic product but multiple strains (69.3%). Enterococcus faecalis (49.7%), Lactobacillus acidophilus (39.4%), and Clostridium butyricum (27.9%) were the most prescribed strains. The probiotics co-prescribed with antitumor agents increased rapidly from 6.6% to 13.8% in seven years (Z = 15.31, p < 0.001). Oral fluorouracil agents (2.35, 2.14-2.59), regorafenib (1.70,1.27-2.26), and irinotecan (1.27,1.15-1.41) had a higher probability to co-prescribed with probiotics. There was no correlation between probiotic strain selection and specific antitumor drug use. The increasing prescription of probiotics in colorectal cancer patients in China may be related to treating the gastrointestinal toxicity of anti-cancer drugs. With unapproved indications and a lack of strain selectivity, evidence-based guidelines are urgently needed to improve probiotic use in this population.

Upregulation of HDAC9 in hippocampal neurons mediates depression-like behaviours by inhibiting ANXA2 degradation.

Major depressive disorder (MDD) is a pervasive and devastating mental disease. Broad spectrum histone deacetylase (HDAC) inhibitors are considered to have potential for the treatment of depressive phenotype in mice. However, due to its non-specific inhibition, it has extensive side effects and can not be used in clinical treatment of MDD. Therefore, finding specific HDAC subtypes that play a major role in the etiology of MDD is the key to develop corresponding specific inhibitors as antidepressants in the future. Copy number variation in HDAC9 gene is thought to be associated with the etiology of some psychiatric disorders. Herein, we found that HDAC9 was highly expressed in the hippocampus of chronic restraint stress (CRS) mouse model of depression. Upregulation of HDAC9 expression in hippocampal neurons of mice induced depression-like phenotypes, including anhedonia, helplessness, decreased dendritic spine density, and neuronal hypoexcitability. Moreover, knockdown or knockout of HDAC9 in hippocampal neurons alleviated depression-like phenotypes caused by chronic restraint stress (CRS) in WT mice. Importantly, using immunoprecipitation-mass spectrometry (IP-MS), we further found that Annexin A2 (ANXA2) was coupled to and deacetylated by HDAC9. This coupling resulted in the inhibition of ubiquitinated ANXA2 degradation and then mediates depression-like behavior. Overall, we discovered a previously unrecognized role for HDAC9 in hippocampal neurons in the pathogenesis of depression, indicating that inhibition of HDAC9 might be a promising clinical strategy for the treatment of depressive disorders.

Salvianolic acid B ameliorates neuroinflammation and neuronal injury via blocking NLRP3 inflammasome and promoting SIRT1 in experimental subarachnoid hemorrhage.

The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated immuno-inflammatory response plays a critical role in exacerbating early brain injury (EBI) after subarachnoid hemorrhage (SAH). Salvianolic acid B (SalB) has previously been shown to suppress neuroinflammatory responses in many disorders. Meanwhile, a previous study has demonstrated that SalB mitigated oxidative damage and neuronal degeneration in a prechiasmatic injection model of SAH. However, the therapeutic potential of SalB on immuno-inflammatory responses after SAH remains unclear. In the present study, we explored the therapeutic effects of SalB on neuroinflammatory responses in an endovascular perforation SAH model. We observed that SalB ameliorated SAH-induced functional deficits. Additionally, SalB significantly mitigated microglial activation, pro-inflammatory cytokines release, and neuronal injury. Mechanistically, SalB inhibited NLRP3 inflammasome activation and increased sirtuin 1 (SIRT1) expression after SAH. Administration of EX527, an inhibitor of SIRT1, abrogated the anti-inflammatory effects of SalB against SAH and further induced NLRP3 inflammasome activation. In contrast, MCC950, a potent and selective NLRP3 inflammasome inhibitor, reversed the detrimental effects of SIRT1 inhibition by EX527 on EBI. These results indicated that SalB effectively repressed neuroinflammatory responses and neuronal damage after SAH. The action of SalB appeared to be mediated by blocking NLRP3 inflammasome and promoting SIRT1 signaling.

RNAenrich: a web server for non-coding RNA enrichment.

MOTIVATION: With the rapid advances of RNA sequencing and microarray technologies in non-coding RNA (ncRNA) research, functional tools that perform enrichment analysis for ncRNAs are needed. On the one hand, because of the rapidly growing interest in circRNAs, snoRNAs, and piRNAs, it is essential to develop tools for enrichment analysis for these newly emerged ncRNAs. On the other hand, due to the key role of ncRNAs' interacting target in the determination of their function, the interactions between ncRNA and its corresponding target should be fully considered in functional enrichment. Based on the ncRNA-mRNA/protein-function strategy, some tools have been developed to functionally analyze a single type of ncRNA (the majority focuses on miRNA); in addition, some tools adopt predicted target data and lead to only low-confidence results. RESULTS: Herein, an online tool named RNAenrich was developed to enable the comprehensive and accurate enrichment analysis of ncRNAs. It is unique in (i) realizing the enrichment analysis for various RNA types in humans and mice, such as miRNA, lncRNA, circRNA, snoRNA, piRNA, and mRNA; (ii) extending the analysis by introducing millions of experimentally validated data of RNA-target interactions as a built-in database; and (iii) providing a comprehensive interacting network among various ncRNAs and targets to facilitate the mechanistic study of ncRNA function. Importantly, RNAenrich led to a more comprehensive and accurate enrichment analysis in a COVID-19-related miRNA case, which was largely attributed to its coverage of comprehensive ncRNA-target interactions. AVAILABILITY AND IMPLEMENTATION: RNAenrich is now freely accessible at https://idrblab.org/rnaenr/.

Effects of 101BHG-D01, a novel M receptor antagonism, on allergic rhinitis in animal models and its mechanism.

Allergic rhinitis (AR) is a nasal mucosal disease with sneezing and nasal itching as the main symptoms. Although AR treatment continues to improve, there remains a lack of effective drugs. There are still controversies regarding whether anticholinergic drugs can effectively and safely relieve the symptoms of AR and reduce inflammation in the nasal mucosa. Here, we synthesized 101BHG-D01, which is a novel anticholinergic drug that mainly targets the M3 receptor and may reduce the adverse effects of other anticholinergic drugs on the heart. We evaluated the effects of 101BHG-D01 on AR and investigated the potential molecular mechanism of anticholinergic therapy for AR. We found that 101BHG-D01 effectively alleviated AR symptoms, reduced the infiltration of inflammatory cells and attenuated the expression of inflammatory factors (IL-4, IL-5, IL-13, etc.) in various AR animal models. In addition, 101BHG-D01 reduced the activation of mast cells and the release of histamine from rat peritoneal mesothelial cells (RPMCs) challenged by IgE. Moreover, 101BHG-D01 reduced the expression of MUC5AC in IL-13-challenged rat nasal epithelial cells (RNECs) and human nasal epithelial cells (HNEpCs). Furthermore, IL-13 stimulation significantly increased JAK1 and STAT6 phosphorylation, which was suppressed by 101BHG-D01. We demonstrated that 101BHG-D01 reduced mucus secretion and inflammatory cell infiltration in the nasal mucosa, which may occur through a reduction in activation of the JAK1-STAT6 signaling pathway, indicating that 101BHG-D01 is a potent and safe anticholinergic therapy for AR.

Qualitative and quantitative evaluation of a standardized training model for improving patients' ability to use inhalers.

Objective: Training contributes to the effectiveness of aerosol inhalation therapy. However, qualitative and quantitative evaluation of effective training methods is rarely reported. This study aimed to evaluate the effectiveness of a standardized training model by pharmacists based on verbal instruction and physical demonstration in improving patients' ability to use inhalers using qualitative and quantitative methods. Risk or protective factors affecting correct inhaler use were also explored. Methods: 431 Outpatients with asthma or COPD were recruited and randomly divided into a standardized training group (n = 280) and a usual training group (control group, n = 151). A framework of qualitative (e.g., multi-criteria analysis) and quantitative comparisons [percentage of correct use (CU%), percentage of complete error (CE%), and percentage of partial error (PE%)] was established to evaluate the two training models. In addition, the changes of key factors (age, education level, adherence, device type, etc.) influencing patients' ability to use inhalers of two models were observed. Results: The multi-criteria analysis showed that the standardized training model had comprehensive advantages in qualitative indicators. The average correct use percentage (CU%) of the standardized training group was significantly higher than that of the usual training group (77.6% vs. 35.5%). A stratified analysis further demonstrated that the ORs (95%CI) in the usual training group of age and educational level was 2.263 (1.165-4.398) and 0.556 (0.379-0.815), while in the standardized training group, age and educational level were not the key factors influencing the ability to use inhaler devices (P > 0.05). Logistic regression analysis demonstrated that standardized training was a protective factor for inhalation ability. Conclusion: These findings indicate that the framework of qualitative and quantitative comparisons could be used to evaluate training models, and the standardized training model by pharmacists can significantly improve patients' ability to use inhalers correctly and address the influence of older age and lower education because of its methodological advantages. Further studies with more extended follow-up are needed to validate the role of the standardized training model by pharmacists in the correct use of inhalers. Clinical trial registration: chictr.org.cn, ChiCTR2100043592 (23-02-2021).

Pre-operative prognostic nutrition index and post-operative pneumonia in aneurysmal subarachnoid hemorrhage patients.

Background and objective: Post-operative pneumonia (POP), a common complication, may be associated with prolonged hospitalization and long-term mortality in aneurysmal subarachnoid hemorrhage (aSAH) patients. This study aimed to explore the association between pre-operative prognostic nutrition index (PNI) and POP in aSAH patients. Methods: A total of 280 aSAH patients were enrolled from Nanjing Drum Tower Hospital. PNI was calculated as follows: [10 × albumin(gr/dl)] + [0.005 × absolute pre-operative lymphocyte count (per mm3)]. We utilized multivariate analyses, restricted cubic spline, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) to elucidate the role of PNI in POP. Results: Pre-operative PNI levels in the POP group were higher, compared with the non-POP group (41.0 [39.0, 45.4] vs. 44.4 [40.5, 47.3], P = 0.001). When we included PNI as a categorical variable in the multivariate analysis, the levels of PNI were associated with POP (odds ratio, 0.433; 95% confidence interval, 0.253-0.743; P=0.002). In addition, when we included PNI as a continuous variable in the multivariate analysis, the PNI levels were also associated with POP (odds ratio, 0.942; 95% confidence interval, 0.892-0.994; P = 0.028). The level of albumin was also a predictor of the occurrence of POP, with a lower diagnostic power than PNI [AUC: 0.611 (95% confidence interval, 0.549-0.682; P = 0.001) for PNI vs. 0.584 (95% confidence interval, 0.517-0.650; P = 0.017) for albumin]. Multivariable-adjusted spline regression indicated a linear dose-response association between PNI and POP in aSAH participants (P for linearity = 0.027; P for non-linearity = 0.130). Reclassification assessed by IDI and NRI was significantly improved with the addition of PNI to the conventional model of POP in aSAH patients (NRI: 0.322 [0.089-0.555], P = 0.007; IDI: 0.016 [0.001-0.031], P = 0.040). Conclusion: The lower levels of pre-operative PNI may be associated with the higher incidence of POP in aSAH patients. Neurosurgeons are supposed to pay more attention to pre-operative nutrition status in aSAH patients.

The role of class IIa histone deacetylases in regulating endothelial function.

Vascular endothelial cells (ECs) are monolayer cells located in the inner layer of the blood vessel. Endothelial function is crucial in maintaining local and systemic homeostasis and is precisely regulated by sophisticated signaling pathways and epigenetic regulation. Endothelial dysfunctions are the main factors for the pathophysiological process of cardiovascular and cerebrovascular diseases like atherosclerosis, hypertension, and stroke. In these pathologic processes, histone deacetylases (HDACs) involve in epigenetic regulation by removing acetyl groups from lysine residues of histones and regulating downstream gene expression. Among all HDACs, Class IIa HDACs (HDAC4, 5, 7, 9) contain only an N-terminal regulatory domain, exert limited HDAC activity, and present tissue-specific gene regulation. Here, we discuss and summarize the current understanding of this distinct subfamily of HDACs in endothelial cell functions (such as angiogenesis and immune response) with their molecular underpinnings. Furthermore, we also present new thoughts for further investigation of HDAC inhibitors as a potential treatment in several vascular diseases.

Human PARP1 substrates and regulators of its catalytic activity: An updated overview.

Poly (ADP-ribose) polymerase 1 (PARP1) is a key DNA damage sensor that is recruited to damaged sites after DNA strand breaks to initiate DNA repair. This is achieved by catalyzing attachment of ADP-ribose moieties, which are donated from NAD+, on the amino acid residues of itself or other acceptor proteins. PARP inhibitors (PARPi) that inhibit PARP catalytic activity and induce PARP trapping are commonly used for treating BRCA1/2-deficient breast and ovarian cancers through synergistic lethality. Unfortunately, resistance to PARPi frequently occurs. In this review, we present the novel substrates and regulators of the PARP1-catalyzed poly (ADP-ribosyl)ation (PARylatison) that have been identified in the last 3 years. The overall aim is the presentation of protein interactions of potential therapeutic intervention for overcoming the resistance to PARPi.

MecDDI: Clarified Drug-Drug Interaction Mechanism Facilitating Rational Drug Use and Potential Drug-Drug Interaction Prediction.

Drug-drug interactions (DDIs) are a major concern in clinical practice and have been recognized as one of the key threats to public health. To address such a critical threat, many studies have been conducted to clarify the mechanism underlying each DDI, based on which alternative therapeutic strategies are successfully proposed. Moreover, artificial intelligence-based models for predicting DDIs, especially multilabel classification models, are highly dependent on a reliable DDI data set with clear mechanistic information. These successes highlight the imminent necessity to have a platform providing mechanistic clarifications for a large number of existing DDIs. However, no such platform is available yet. In this study, a platform entitled "MecDDI" was therefore introduced to systematically clarify the mechanisms underlying the existing DDIs. This platform is unique in (a) clarifying the mechanisms underlying over 1,78,000 DDIs by explicit descriptions and graphic illustrations and (b) providing a systematic classification for all collected DDIs based on the clarified mechanisms. Due to the long-lasting threats of DDIs to public health, MecDDI could offer medical scientists a clear clarification of DDI mechanisms, support healthcare professionals to identify alternative therapeutics, and prepare data for algorithm scientists to predict new DDIs. MecDDI is now expected as an indispensable complement to the available pharmaceutical platforms and is freely accessible at: https://idrblab.org/mecddi/.

Multidisciplinary Guidelines for the Rational Use of Topical Non-Steroidal Anti-Inflammatory Drugs for Musculoskeletal Pain (2022).

(1) Background: Topical non-steroidal anti-inflammatory drugs (NSAIDs) are one of the primary drugs for treating musculoskeletal pain. However, there are currently no evidence-based recommendations about drug selection, drug administration, drug interactions, and use in special populations or other pharmacology-related content of such medications. To this end, the Chinese Pharmaceutical Association Hospital Pharmacy Professional Committee developed multidisciplinary guidelines on using topical NSAIDs to treat musculoskeletal pain. (2) Methods: The guidelines development process followed the World Health Organization guideline development handbook, the GRADE methodology, and the statement of Reporting Items for Practice Guidelines in Healthcare. The guideline panel used the Delphi method to identify six clinical questions to be addressed in the guidelines. An independent systematic review team conducted a systematic search and integration of evidence. (3) Results: Based on the balance between the benefits and harms of an intervention, the quality of the evidence, patient preferences and values, and resource utilization, the guideline panel developed 11 recommendations and nine expert consensuses on using topical NSAIDs to treat acute and chronic musculoskeletal pain. (4) Conclusions: Based on the effectiveness and overall safety of topical NSAIDs, we recommend patients with musculoskeletal pain use topical NSAIDs and suggest high-risk patients use topical NSAIDs, such as those with other diseases or receiving other concurrent treatments. The evidenced-based guidelines on topical NSAIDs for musculoskeletal pain incorporated a pharmacist perspective. The guidelines have the potential to facilitate the rational use of topical NSAIDs. The guideline panel will monitor the relevant evidence and update the recommendations accordingly.