Profiling targets and potential target pairs of CAR-T cell therapy in clinical trials.

Since the approval of the first chimeric antigen receptor (CAR)-T product in 2017, the number of new CAR-T clinical trials worldwide exceeds 100 per year. 1649 clinical studies have been conducted to explore possible future clinical applications of targets or target pairs through different biotechnologies. In this study, we aim to take a data-driven analytical approach to explore potential dual-target pairs based on clinical trial information. We screened 1283 non-withdrawal interventional CAR-T clinical trials spanning 96 different targets and 74 target pairs from clinicaltrials.gov. Through the Circos plot and temporal network plots, the information between targets and indications was visualized. Based on the assumption that two targets of a target pair must target the same indication, five new target pairs were inferred, including CD19/CD7, CD19/CD5, CD19/CD37, and CD19/BAFFR and validated by expression pattern, literature and patent information. This study provides novel support for target profiling of CAR-T from the perspective of clinical trials and also provides a reference for researchers and developers to select new targets or target pairs of CAR-T cell therapy.

A target map of clinical combination therapies in oncology: an analysis of clinicaltrials.gov.

Combination therapies have taken center stage for cancer treatment, however, there is a lack of a comprehensive portrait to quantitatively map the current clinical combination progress. This study aims to capture clinical combination therapies of the validated FDA-approved new oncology drugs by a macro data analysis and to summarize combination mechanisms and strategies in the context of the existing literature. A total of 72 new molecular entities or new therapeutic biological products for cancer treatment approved by the FDA from 2017 to 2021 were identified, and the data on their related 3334 trials were retrieved from the database of ClinicalTrials.gov. Moreover, these sampled clinical trials were refined by activity status and combination relevance and labeled with the relevant clinical arms and drug combinations, as well as drug targets and target pairs. Combination therapies are increasingly prevalent in clinical trials of new oncology drugs. From retrospective work, existing clinical combination therapies in oncology are driven by different patterns (i.e., rational design and industry trends). The former can be represented by mechanism-based or structure-based combinations, such as targeting different domains of HER2 protein or in-series co-targeting in RAF plus MEK inhibitors. The latter is an empirically driven strategy, including redundant combinations in hot targets, such as PD-1/PD-L1, PI3K, CDK4/6, and PARP. Because of an explosion in the number of clinical trials and the resultant shortage of available patients, it is essential to rationally design drug combinations.

Expanding potential targets of herbal chemicals by node2vec based on herb-drug interactions.

BACKGROUND: The identification of chemical-target interaction is key to pharmaceutical research and development, but the unclear materials basis and complex mechanisms of traditional medicine (TM) make it difficult, especially for low-content chemicals which are hard to test in experiments. In this research, we aim to apply the node2vec algorithm in the context of drug-herb interactions for expanding potential targets and taking advantage of molecular docking and experiments for verification. METHODS: Regarding the widely reported risks between cardiovascular drugs and herbs, Salvia miltiorrhiza (Danshen, DS) and Ligusticum chuanxiong (Chuanxiong, CX), which are widely used in the treatment of cardiovascular disease (CVD), and approved drugs for CVD form the new dataset as an example. Three data groups DS-drug, CX-drug, and DS-CX-drug were applied to serve as the context of drug-herb interactions for link prediction. Three types of datasets were set under three groups, containing information from chemical-target connection (CTC), chemical-chemical connection (CCC) and protein-protein interaction (PPI) in increasing steps. Five algorithms, including node2vec, were applied as comparisons. Molecular docking and pharmacological experiments were used for verification. RESULTS: Node2vec represented the best performance with average AUROC and AP values of 0.91 on the datasets "CTC, CCC, PPI". Targets of 32 herbal chemicals were identified within 43 predicted edges of herbal chemicals and drug targets. Among them, 11 potential chemical-drug target interactions showed better binding affinity by molecular docking. Further pharmacological experiments indicated caffeic acid increased the thermal stability of the protein GGT1 and ligustilide and low-content chemical neocryptotanshinone induced mRNA change of FGF2 and MTNR1A, respectively. CONCLUSIONS: The analytical framework and methods established in the study provide an important reference for researchers in discovering herb-drug interactions, alerting clinical risks, and understanding complex mechanisms of TM.

[Mutational Spectrum and Prognosis Analysis of Young Patients with Diffuse Large B-Cell Lymphoma Based on Next-Generation Sequencing].

OBJECTIVE: To investigate the mutational spectrum in young patients with diffuse large B-cell lymphoma (DLBCL) based on next generation sequencing (NGS), and to provide a basis for in-depth understanding of the molecular biological characteristics and accurate prognosis of young DLBCL. METHODS: From March 2009 to March 2021, 68 young DLBCL patients with complete initial diagnosis data from the Department of Hematology, The People's Hospital Xinjiang Uygur Autonomous Region were retrospectively analyzed, and their paraffin-embedded tissues were subjected to targeted sequencing analysis by NGS technology (including 475 Target genes), and the differences in gene mutation profiles and signaling pathways between high-risk patients with aaIPI ≥2 and low-intermediate risk patients with aaIPI <2 were compared. RESULTS: A total of 44 high-frequency mutation genes were detected in 68 young DLBCL patients. By comparing the high-frequency mutation genes in aaIPI high-risk group and low-intermediate risk group, it was found that CARD11 mutation in aaIPI high-risk group was significantly higher than that in low-intermediate risk group (P =0.002), while MGA mutation (P =0.037) only appeared in the aaIPI high-risk group, and SPEN mutation (P =0.004) only appeared in the aaIPI low-intermediate risk group. The high-frequency mutation genes and clinical indicators of the aaIPI high-risk group were included in the survival analysis, and the results showed that TP53 (P =0.009, P =0.027), POU2AF1 (P =0.003, P =0.006) and CCND3 (P =0.040, P =0.014) genes mutations were associated with worse PFS and OS, while B2M was associated with better PFS (P =0.014) and OS (P =0.013). Multivariate COX regression analysis showed that the TP53, POU2AF1 and CCND3 were independent risk factors for PFS（P ＝0.021，P =0.005，P =0.020） and OS（P ＝0.042，P =0.010，P =0.013）. CONCLUSION: The aaIPI staging combination with molecular biology markers is more conducive to accurately judging the prognosis of young DLBCL patients. TP53, POU2AF1 and CCND3 mutations predict worse survival in the patients with the aaIPI high-risk group.

A network pharmacology-based study on the quality control markers of antithrombotic herbs: Using Salvia miltiorrhiza - Ligusticum chuanxiong as an example.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza (Danshen, DS), the dried root and rhizome of Salvia miltiorrhiza Bunge and Ligusticum chuanxiong (Chuanxiong, CX), the dried rhizomes of Ligusticum striatum DC are effective in invigorating blood circulation and eliminating stasis which is highly related with cardiovascular disease (CVD). AIM OF STUDY: The identification of activity-based chemical markers is very important, but the complex mechanism of "multi-component, multi-target, and multi-effect" within traditional Chinese medicine (TCM) poses a great challenge to this work. In this study, we combined network pharmacological prediction with experimental validation of the DS and CX to explore an effective method for discovering quality control (QC) of antithrombotic herbs by clarifying the intermediate layer "module/cluster" between the whole complex system and a single component. MATERIALS AND METHODS: Based on structural similarity analysis of compound and the thrombosis network published before, we firstly modularized two layers called chemical cluster (CC) network and functional module (FM) network respectively and linked them into one bilayer modularized compound target (BMCT) network. "Two-step" calculation was applied on identifying the significant compounds as the potential QC markers from CC. The in vitro inhibitory activity of selected QC marker compounds on thrombin was evaluated to partially verify their pharmacological activities. HPLC was used to determine contents. RESULTS: According to the network-based analysis, nine compounds with great importance in the BMCT network were identified as QC markers of DS-CX, including tanshinone I, tanshinone IIA, cryptotanshinone, salvianolic acid B, ferulic acid, salvianolic acid A, rosmarinic acid, chlorogenic acid, and coniferyl ferulate. Enzyme inhibitory test partially verified the activity of tanshinone I and tanshinone IIA. Chemical profiling indicated that the nine marker compounds are the main components in the herbal pair. CONCLUSIONS: This study identified activity-based QC markers of DS-CX herbal pair and provided a new methodology that can be used in the QC of other herbs, herbal pairs, or formulas.

The internationalization of TCM towards Portuguese-speaking countries.

With the increasing demand for traditional Chinese medicine (TCM) in Portuguese-speaking countries (PSC), local regulatory systems and relevant legislation are still insufficient and lagging, even blank in some of them. This kind of unbalanced pace either makes users of TCM exposed in potential risk or eventually obstructs the long-term development of TCM in PSC. Despite existing tremendous studies on the internationalization of TCM, there are few studies specific to PSC. Thus, by a comprehensive desk review and typical case study, this article aims to summarize current situation of TCM in PSC by a cross-regional comparison, to identify various critical challenges, and further to provide an insightful reference to impel the development of TCM in PSC.

A review of cutting-edge therapies for hepatocellular carcinoma (HCC): Perspectives from patents.

Rationale: Hepatocellular carcinoma (HCC) is a challenging disease due to its heterogenous etiology. Several breakthroughs have occurred in treatment of HCC, associated with an enormous number of patent publications for a variety of HCC treatment modalities. As patents can provide valuable information for academic research and commercial development, this study aims to unravel the cutting-edge therapies for HCC by using patents as an indicator. The outcome from this analysis may offer meaningful insights for respective policymaking, strategic plan and research and development (R&D) prioritization. Methods: Derwent Innovation platform was employed to collect the sample data of patents related to HCC treatment technologies worldwide as of December 31, 2019. Data inclusion, screening and exclusion were according to the rules of preferred reporting items for systematic reviews and meta-analyses (PRISMA). Technologies were classified based on Barcelona Clinic Liver Cancer (BCLC) staging system and recent clinical publications. Patent citation network analysis was carried out to identify and understand HCC therapeutic technology flow. Results: A dataset of 2543 patent documents and 528 patent families was generated. 11 technological categories were classified. Numerous researches were focalized on refinements in technologies and innovations within the field of HCC therapy, and the major achievements are technology advancement on molecular target therapy, chemotherapy, locoregional therapy, combination therapy and immunotherapy with demonstrated clinical benefits. In patent citation network, Notch pathway investigation, antibody drug conjugate (ADC) technology development and drug eluting beads trans artery chemoembolization (DEB-TACE) advancement are the major technological communities involving patents with the greatest future exploratory potential. Conclusion: Numerous emerging technologies have been identified in this study, in which exploring novel therapeutic targets in molecular target therapy, more localized and visible locoregional therapy and combination of immunotherapy with target therapy or other traditional therapies are highlighted as the future trends in treating HCC.