Modulating ß-catenin/BCL9 interaction with cell-membrane-camouflaged carnosic acid to inhibit Wnt pathway and enhance tumor immune response.

Introduction: Lung adenocarcinoma (LUAD) therapies are plagued by insufficient immune infiltration and suboptimal immune responses in patients, which are closely associated with the hyperactive Wnt/ß-catenin pathway. Suppressing this signaling holds considerable promise as a potential tumor therapy for LUAD, but Wnt suppressor development is hindered by concerns regarding toxicity and adverse effects due to insufficient targeting of tumors. Methods: We have synthesized a tumor-specific biomimetic Wnt pathway suppressor, namely CM-CA, by encapsulating carnosic acid within Lewis lung carcinoma (LLC) cell membranes. It possesses nano-size, allowing for a straightforward preparation process, and exhibits the ability to selectively target the Wnt/ß-catenin pathway in lung adenocarcinoma cells. To evaluate its in vivo efficacy, we utilized the LLC Lewis homograft model, and further validated its mechanism of action through immunohistochemistry staining and transcriptome sequencing analyses. Results: The findings from the animal experiments demonstrated that CM-CA effectively suppressed the Wnt/ß-catenin signaling pathway and impeded cellular proliferation, leading to notable tumor growth inhibition in a biologically benign manner. Transcriptome sequencing analyses revealed that CM-CA promoted T cell infiltration and bolstered the immune response within tumor tissues. Conclusion: The utilization of CM-CA presents a novel and auspicious approach to achieve tumor suppression and augment the therapeutic response rate in LUAD, while also offering a strategy for the development of Wnt/ß-catenin inhibitors with biosafety profile.

Remission from the 5-Fu-Based Chemotherapy to Gemcitabine-Based Chemotherapy-Based on the Pathological Classification of Periampullary Carcinoma: A Case Report and Literature Review.

Background: Periampullary carcinoma, which includes ampullary carcinoma, pancreatic head cancer, distal common bile duct cancer, and duodenal papillary cancer, is a relatively rare malignancy with uncertain therapeutic options. Although several studies have investigated the efficacy of multiple adjuvant chemotherapy regimens for periampullary carcinoma treatment, the optimal regimen remains to be determined. The inherent heterogeneity of the mucosal origin divides periampullary carcinoma into intestinal and pancreaticobiliary types. Therefore, the selection of chemotherapy regimens based on pathological type may have potential therapeutic significance. Case Presentation: A 72-year-old woman with moderately differentiated periampullary adenocarcinoma experienced disease progression after receiving FOLFOX regimen. Subsequently, the sample was subtyped first by H&E evaluation and then by the evaluation of an IHC panel composed of CK20, CDX2, MUC1, MUC2, and MUC5AC. The pathologists concluded that the patient's sample was of the pancreaticobiliary (PB) subtype. The subsequent change to gemcitabine plus S-1 adjuvant therapy achieved remission of liver metastases based on the pathological classification of the cancer. Conclusion: Based on the pathological classification, adjuvant chemotherapy with gemcitabine may be beneficial for patients with PB subtype periampullary carcinoma. 5-Fu-based adjuvant chemotherapy may be beneficial for patients with intestinal subtype periampullary carcinoma.

Adjuvant therapy for periampullary carcinoma and the significance of histopathological typing: A systematic review.

OBJECTIVE: This review investigates the role of adjuvant therapy (AT) and the importance of histopathological typing in periampullary carcinoma (PAC) treatment. BACKGROUND: PAC is a relatively rare gastrointestinal malignancy. The regimen and effect of AT in PAC are still controversial. However, there is a treatment based on histopathological types (pancreaticobiliary-type, PB-type or intestinal-type, IN-type), but there are no clear guidelines indicating that typing can be used to guide the selection of AT drugs. METHODS: A literature search of PubMed and Web of Science databases was conducted for studies published from January 2001 to August 2021 on the use of AT in PAC. RESULTS: A total of 75 studies were included in this review. According to existing studies, AT for PAC is mostly based on 5-FU or gemcitabine, but the effect is unknown. However, when PAC is classified into different histopathological types, AT with gemcitabine is beneficial for patients with the PB-type of PAC, while 5-FU-based AT is beneficial for patients with the IN-type of PAC. In addition, the benefits of AT are more pronounced in patients with a high-risk disease, such as patients with stage II/III, T3/T4 tumors, or positive lymph node involvement. There are few studies on targeted therapy and immunotherapy for PAC. CONCLUSIONS: This review suggests that AT has potential survival benefits, especially when based on the histopathologic type that helps the choice of drugs during AT in PAC patients.

Assembling BH3-mimic peptide into a nanocluster to target intracellular Bcl2 towards the apoptosis induction of cancer cell.

Bcl-2, an anti-apoptotic protein, is always overexpressed in tumor cells to suppress the pro-apoptotic function of Bax, thereby prolonging the life of the tumor. However, BH3 proteins could directly activate Bax via antagonizing Bcl-2 to induce apoptosis in response to the stimulation. Thus, mimicking BH3 proteins with a peptide is a potential strategy for anti-cancer therapy. Unfortunately, clinical translation of BH3-mimic peptide is hindered by its inefficacious cellular internalization and proteolysis resistance. Herein, we translated a BH3-mimic peptide into a peptide-auric spheroidal nanocluster (BH3-AuNp), in which polymeric BH3-Auric precursors [Au1+-S-BH3]narein situself-assembled on the surface of gold nanoparticles by a one-pot synthesis. Expectedly, this strategy could improve the anti-proteolytic ability and cytomembrane penetrability of the BH3 peptide. As a result, BH3-AuNp successfully induced the apoptosis of two cancer cell lines by an order of magnitude compared to BH3. This therapeutic and feasible peptide nano-engineering strategy will help peptides overcome the pharmaceutical obstacles, awaken its biological functions, and possibly revive the research about peptide-derived nanomedicine.

Chiral Protein Supraparticles for Tumor Suppression and Synergistic Immunotherapy: An Enabling Strategy for Bioactive Supramolecular Chirality Construction.

The design of bioactive supramolecular chirality is always hampered by the lack of feasible schemes to assigned specific biological activities. Herein, we developed a "mirror-image peptide grafting" method to graft the epitopes of bioactive d-peptide onto the miniprotein template to construct a self-assembled supraparticle. Grafting DPMIß, a 12-mer d-enantiomeric peptide functioned as the p53 agonist, onto Apamin, we successfully constructed a self-assembled d-enantiomeric miniprotein supermolecule nanoparticle, termed DMSN. This chiral supraparticle possesses a favorable pharmaceutical profile including the passive tumor targeting, cell membrane penetration, intracellular reductive responsiveness, and endosome escaping. DMSN showed in vitro and in vivo p53-dependent antiproliferative activity and augmented antitumor immunity elicited by anti-PD1 therapy. This enabling strategy will allow us to fabricate a class of peptide/protein-derived supramolecular chirality with predictable biological activities and will likely have a broad impact on the chiral nanotechnology at the service of prevention and treatment of human diseases.