A case report of chyle leakage after axillary node clearance in a patient with breast cancer.

Key Clinical Message: Chyle leakage is a rare postoperative complication of breast cancer, and conservative treatments should be prioritized, with careful monitoring of drainage volume and timely surgical intervention when conservative treatments are ineffective. Abstract: Chyle leaks following surgery for breast cancer are seldom encountered. Management varies with no consensus in the literature. This paper reports a case of a chylous leak after axillary dissection in a patient with breast cancer eventually cured with conservative treatment and discusses management options varied with both conservative and surgical options available to clinicians.

When will the immune-stimulating antibody conjugates (ISACs) be transferred from bench to bedside?

Immunostimulatory antibody conjugates (ISACs) as a promising new generation of targeted therapeutic antibody-drug conjugates (ADCs), that not only activate innate immunity but also stimulate adaptive immunity, providing a dual therapeutic effect to eliminate tumor cells. However, several ISACs are still in the early stages of clinical development or have already failed. Therefore, it is crucial to design ISACs more effectively to overcome their limitations, including high toxicity, strong immunogenicity, long development time, and poor pharmacokinetics. This review aims to summarize the composition and function of ISACs, incorporating current design considerations and ongoing clinical trials. Additionally, the review delves into the current issues with ISACs and potential solutions, such as adjusting the drug-antibody ratio (DAR) to improve the bioavailability of ISACs. By leveraging the affinity and bioavailability-enhancing properties of bispecific antibodies, the utility between antibodies and immunostimulatory agents can be balanced. Commonly used immunostimulatory agents may induce systemic immune reactions, and BTK (Bruton's tyrosine kinase) inhibitors can regulate immunogenicity. Finally, the concept of grafting ADC's therapeutic principles is simple, but the combination of payload, linker, and targeted functional molecules is not a simple permutation and combination problem. The development of conjugate drugs faces more complex pharmacological and toxicological issues. Standing on the shoulders of ADC, the development and application scenarios of ISAC are endowed with broader space.

Advancement of anti-LAG-3 in cancer therapy.

Immune checkpoint inhibitors have effectively transformed the treatment of many cancers, particularly those highly devastating malignancies. With their widespread popularity, the drawbacks of immune checkpoint inhibitors are also recognized, such as drug resistance and immune-related systematic side effects. Thus, it never stops investigating novel immune checkpoint inhibitors. Lymphocyte Activation Gene-3 (LAG-3) is a well-established co-inhibitory receptor that performs negative regulation on immune responses. Recently, a novel FDA-approved LAG-3 blocking agent, together with nivolumab as a new combinational immunotherapy for metastatic melanoma, brought LAG-3 back into focus. Clinical data suggests that anti-LAG-3 agents can amplify the therapeutic response of other immune checkpoint inhibitors with manageable side effects. In this review, we elucidate the intercellular and intracellular mechanisms of LAG-3, clarify the current understanding of LAG-3 in the tumor microenvironment, identify present LAG-3-associated therapeutic agents, discuss current LAG-3-involving clinical trials, and eventually address future prospects for LAG-3 inhibitors.

An evidence update to explore molecular targets and protective mechanisms of apigenin against abdominal aortic aneurysms based on network pharmacology and experimental validation.

Abdominal aortic aneurysms (AAA) is a life-threatening disease and the incidence of AAA is still on the rise in recent years. Numerous studies suggest that dietary moderate consumption of polyphenol exerts beneficial effects on cardiovascular disease. Apigenin (API) is a promising dietary polyphenol and possesses potent beneficial effects on our body. Although our previous study revealed protective effects of API on experimental AAA formation, up till now few studies were carried out to further investigate its involved molecular mechanisms. In the present study, network pharmacology combined molecular docking and experimental validation was used to explore API-related therapeutic targets and mechanisms in the treatment of AAA. Firstly, we collected 202 API-related therapeutic targets and 2475 AAA-related pathogenetic targets. After removing duplicates, a total of 68 potential therapeutic targets were obtained. Moreover, 5 targets with high degree including TNF, ACTB, INS, JUN, and MMP9 were identified as core targets of API for treating AAA. In addition, functional enrichment analysis indicated that API exerted pharmacological effects in AAA by affecting versatile mechanisms, including apoptosis, inflammation, blood fluid dynamics, and immune modulation. Molecular docking results further supported that API had strong affinity with the above core targets. Furthermore, protein level of core targets and related pathways were evaluated in a Cacl2-induced AAA model by using western blot and immunohistochemistry. The experimental validation results demonstrated that API significantly attenuated phosphorylation of JUN and protein level of predicted core targets. Taken together, based on network pharmacological and experimental validation, our study systematically explored associated core targets and potential therapeutic pathways of API for AAA treatment, which could supply valuable insights and theoretical basis for AAA treatment.

Peptide-drug conjugates (PDCs): a novel trend of research and development on targeted therapy, hype or hope?

Peptide-drug conjugates (PDCs) are the next generation of targeted therapeutics drug after antibody-drug conjugates (ADCs), with the core benefits of enhanced cellular permeability and improved drug selectivity. Two drugs are now approved for market by US Food and Drug Administration (FDA), and in the last two years, the pharmaceutical companies have been developing PDCs as targeted therapeutic candidates for cancer, coronavirus disease 2019 (COVID-19), metabolic diseases, and so on. The therapeutic benefits of PDCs are significant, but poor stability, low bioactivity, long research and development time, and slow clinical development process as therapeutic agents of PDC, how can we design PDCs more effectively and what is the future direction of PDCs? This review summarises the components and functions of PDCs for therapeutic, from drug target screening and PDC design improvement strategies to clinical applications to improve the permeability, targeting, and stability of the various components of PDCs. This holds great promise for the future of PDCs, such as bicyclic peptide‒toxin coupling or supramolecular nanostructures for peptide-conjugated drugs. The mode of drug delivery is determined according to the PDC design and current clinical trials are summarised. The way is shown for future PDC development.

Cell adhesion molecules and immunotherapy in advanced non-small cell lung cancer: Current process and potential application.

Advanced non-small cell lung cancer (NSCLC) is a severe disease and still has high mortality rate after conventional treatment (e.g., surgical resection, chemotherapy, radiotherapy and targeted therapy). In NSCLC patients, cancer cells can induce immunosuppression, growth and metastasis by modulating cell adhesion molecules of both cancer cells and immune cells. Therefore, immunotherapy is increasingly concerned due to its promising anti-tumor effect and broader indication, which targets cell adhesion molecules to reverse the process. Among these therapies, immune checkpoint inhibitors (mainly anti-PD-(L)1 and anti-CTLA-4) are most successful and have been adapted as first or second line therapy in advanced NSCLC. However, drug resistance and immune-related adverse reactions restrict its further application. Further understanding of mechanism, adequate biomarkers and novel therapies are necessary to improve therapeutic effect and alleviate adverse effect.

Discovery and Rational Design of a Novel Bowman-Birk Related Protease Inhibitor.

Anuran amphibian skin secretions are a rich source of peptides, many of which represent novel protease inhibitors and can potentially act as a source for protease inhibitor drug discovery. In this study, a novel bioactive Bowman-Birk type inhibitory hexadecapeptide of the Ranacyclin family from the defensive skin secretion of the Fukien gold-striped pond frog, Pelophlax plancyi fukienesis, was successfully isolated and identified, named PPF-BBI. The primary structure of the biosynthetic precursor was deduced from a cDNA sequence cloned from a skin-derived cDNA library, which contains a consensus motif representative of the Bowman-Birk type inhibitor. The peptide was chemically synthesized and displayed a potent inhibitory activity against trypsin (Ki of 0.17 µM), as well as an inhibitory activity against tryptase (Ki of 30.73 µM). A number of analogues of this peptide were produced by rational design. An analogue, which substituted the lysine (K) at the predicted P1 position with phenylalanine (F), exhibited a potent chymotrypsin inhibitory activity (Ki of 0.851 µM). Alternatively, a more potent protease inhibitory activity, as well as antimicrobial activity, was observed when P16 was replaced by lysine, forming K16-PPF-BBI. The addition of the cell-penetrating peptide Tat with a trypsin inhibitory loop resulted in a peptide with a selective inhibitory activity toward trypsin, as well as a strong antifungal activity. This peptide also inhibited the growth of two lung cancer cells, H460 and H157, demonstrating that the targeted modifications of this peptide could effectively and efficiently alter its bioactivity.