Advances in immunotherapy and targeted therapy of advanced pancreatic cancer / 临床外科杂志

Pancreatic cancer is a highly malignant tumor of the digestive system with poor prognosis.Due to the lack of effective early screening and diagnosis methods,the majority of patients with pancreatic cancer present with locally advanced or metastatic disease at diagnosis.For advanced pancreatic cancer,the major treatment strategy is still chemotherapy-based comprehensive treatment.The development of immunotherapy and targeted therapy gives us cause for optimism in our pursuit of better treatment.This article reviewed the advances in immunotherapy and targeted therapy of advanced pancreatic cancer.

Interpretations of the NCCN guidelines for breast cancer risk reduction (version 2023) / 中国胸心血管外科临床杂志

@#Breast cancer, the most common malignancy in the world, also causes the most death cases of women among malignancies. Breast cancer risk reduction guidelines (version 2023) was updated by National Comprehensive Cancer Network (NCCN). Based on high-level evidences from evidence-based medicine and the latest research progress, the guidelines provided standardized guidance for breast cancer risk assessment and risk reduction strategies for individuals without a history of invasive breast cancer or ductal carcinoma in situ, which has attracted widespread attention from clinicians worldwide. Breast cancer is also the most common malignancy in Chinese women, and the number of newly diagnosed breast cancer cases each year in China ranks first in the world due to the large population, so the breast cancer prevention has become a major public health challenge in China. Aimed to provide reference for breast cancer prevention in China, this article interpreted the guidelines (the new version) based on the characteristics of breast structure in Asian women and the epidemiological characteristics of breast cancer in China.

Discovery of novel covalent selective estrogen receptor degraders against endocrine-resistant breast cancer

Endocrine-resistance remains a major challenge in estrogen receptor α positive (ERα+) breast cancer (BC) treatment and constitutively active somatic mutations in ERα are a common mechanism. There is an urgent need to develop novel drugs with new mode of mechanism to fight endocrine-resistance. Given aberrant ERα activity, we herein report the identification of novel covalent selective estrogen receptor degraders (cSERDs) possessing the advantages of both covalent and degradation strategies. A highly potent cSERD 29c was identified with superior anti-proliferative activity than fulvestrant against a panel of ERα+ breast cancer cell lines including mutant ERα. Crystal structure of ERα‒ 29c complex alongside intact mass spectrometry revealed that 29c disrupted ERα protein homeostasis through covalent targeting C530 and strong hydrophobic interaction collied on H11, thus enforcing a unique antagonist conformation and driving the ERα degradation. These significant effects of the cSERD on ERα homeostasis, unlike typical ERα degraders that occur directly via long side chains perturbing the morphology of H12, demonstrating a distinct mechanism of action (MoA). In vivo, 29c showed potent antitumor activity in MCF-7 tumor xenograft models and low toxicity. This proof-of-principle study verifies that novel cSERDs offering new opportunities for the development of innovative therapies for endocrine-resistant BC.

The D614G mutation in SARS-CoV-2 Spike increases transduction of multiple human cell types

A novel isolate of the SARS-CoV-2 virus carrying a point mutation in the Spike protein (D614G) has recently emerged and rapidly surpassed others in prevalence. This mutation is in linkage disequilibrium with an ORF1b protein variant (P314L), making it difficult to discern the functional significance of the Spike D614G mutation from population genetics alone. Here, we perform site-directed mutagenesis to introduce the D614G variant and show that in multiple cell lines, including human lung epithelial cells, that the D614G mutation is up to 8-fold more effective at transducing cells than wild-type. We demonstrate increased infection using both Spike-pseudotyped lentivirus and intact SARS-CoV-2 virus. Although there is minimal difference in ACE2 receptor binding between the Spike variants, we show that the G614 variant is more resistant to proteolytic cleavage in vitro and in human cells, suggesting a possible mechanism for the increased transduction. This result has important implications for the efficacy of Spike-based vaccines currently under development in protecting against this recent and highly-prevalent SARS-CoV-2 isolate.