Wenhao Shi

Targeted drug discovery has enabled the development of effective therapies for many diseases. However, a fundamental challenge remains in translating molecular binding into functional performance for the development of novel targeted drugs. Here, we present a programmable DNA nanoframe (NF) strategy that converts ligand binding into robust biological functions through precise spatial organization of multiple ligands. By encoding target dimensions and binding geometry, we have successfully constructed potential targeted nanodrugs against diverse proteins, which exhibit high avidity with markedly enhanced binding affinity and selectivity. A design-driven blockade of VEGF has also been translated into marked antiangiogenic efficacy both in vitro and in vivo. Overall, the programmable DNA NFs establish a modular and generalizable paradigm for targeted drug design, upgrading weak or non-functional binders into effective inhibitors through rational spatial programming.

Background Cytidine triphosphate synthase 1 (CTPS1), a rate-limiting enzyme in nucleotide biosynthesis, is frequently upregulated in cancers. However, its functional role and therapeutic potential in lung adenocarcinoma (LUAD) remain poorly defined. Methods We integrated proteomic analyses, tissue microarrays, and functional assays to evaluate CTPS1 expression and clinical significance in LUAD. Genetic knockdown and pharmacological inhibition with the selective inhibitor STP938 assessed malignant phenotypes. The therapeutic efficacy of STP938, alone or combined with osimertinib, was evaluated in xenograft models. Integrated proteomic and transcriptomic analyses explored underlying mechanisms. Results CTPS1 was significantly upregulated in LUAD and associated with lymph node metastasis and poor overall survival (OS), serving as an independent prognostic factor. CTPS1 promoted proliferation, migration, and invasion while suppressing apoptosis. STP938 inhibited tumour growth in vitro and in vivo, and enhanced the efficacy of osimertinib in EGFR-mutant models. Multi-omics analyses identified MX1-associated interferon signalling as a downstream pathway, with MX1 expression positively correlating with CTPS1 and poor prognosis. Conclusions CTPS1 drives LUAD progression and is linked to MX1-associated interferon signalling. Targeting CTPS1 with STP938, alone or in combination with osimertinib, represents a promising therapeutic strategy and supports CTPS1 as a targetable vulnerability in LUAD.

Diffuse-type gastric cancer (DGC) and intestinal-type gastric cancer (IGC) are the major histological types of gastric cancer (GC). The molecular mechanism underlying DGC and IGC differences are poorly understood. In this research, we carry out multilevel proteomic analyses, including proteome, phospho-proteome, and transcription factor (TF) activity profiles, of 196 cases covering DGC and IGC in Chinese patients. Integrative proteogenomic analysis reveals ARIDIA mutation associated with opposite prognostic effects between DGC and IGC, via diverse influences on their corresponding proteomes. Systematical comparison and consensus clustering analysis identify three subtypes of DGC and IGC, respectively, based on distinct patterns of the cell cycle, extracellular matrix organization, and immune response-related proteins expression. TF activity-based subtypes demonstrate that the disease progressions of DGC and IGC were regulated by SWI/SNF and NFKB complexes. Furthermore, inferred immune cell infiltration and immune clustering show Th1/Th2 ratio is an indicator for immunotherapeutic effectiveness, which is validated in an independent GC anti-PD1 therapeutic patient group. Our multilevel proteomic analyses enable a more comprehensive understanding of GC and can further advance the precision medicine.

Dexamethasone is the first and an important therapy that significantly reduces the risk of death in patients with severe COVID-19 disease. Nevertheless, a lot of studies have revealed that it has adverse impacts on multiple systems of the body especially the reproductive system, and dexamethasone exposure during the human foetal period may be associated with various diseases. In this paper, we reviewed the literature regarding the adverse effects of COVID-19 and dexamethasone administration on the reproductive system as well as related disease pathogenesis, in an attempt to clarify the potential harms of dexamethasone treatment in COVID-19 patients. Overall, we strongly support the application of dexamethasone as a pharmaceutical therapy in critical COVID-19 patients before a better therapy is developed, but the adverse side effects that may arise cannot be ignored. Our review will help medical professionals in the prognosis and follow-up of patients treated with dexamethasone. In addition, given that a considerable amount of uncertainty, confusion and even controversy that still remains, further studies and more clinical trials are urgently needed to improve the understanding of the parameters and the effects of dexamethasone on reproductive function of patients with severe acute respiratory syndrome coronavirus 2 infection.