MedComm - Future medicine最新文献

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer, characterized by poor prognosis and limited therapeutic options. Although neoadjuvant chemotherapy (NACT) remains the established treatment approach, its suboptimal efficacy associated with TNBC highlight the urgent need for optimized treatment strategies to improve pathological complete response (pCR) rates. This review provides a comprehensive overview of recent advancements in neoadjuvant treatment for TNBC, emphasizing pivotal breakthroughs in therapeutic strategies and the ongoing pursuit of innovative approaches to enhance precision medicine. It emphasizes the clinical value of platinum-based agents, such as carboplatin and cisplatin, which have shown significant improvements in pCR rates, particularly in TNBC patients with BRCA mutations. Additionally, the review explores progress in targeted therapies, including PARP inhibitors, AKT inhibitors, and Antiangiogenic agents, showcasing their potential for personalized treatment approaches. The integration of immunotherapy, particularly immune checkpoint inhibitor like pembrolizumab and atezolizumab, with chemotherapy has demonstrated substantial efficacy in high-risk TNBC cases. Future research priorities include refining biomarker-driven strategies, optimizing therapeutic combinations, developing antibody-drug conjugates (ADCs) targeting TROP2 and other biomarkers, and reducing treatment-related toxicity to develop safer and highly personalized neoadjuvant therapies. Furthermore, artificial intelligence has also emerged as a transformative tool in predicting treatment response and optimizing therapeutic decision-making in TNBC. These advancements aim to improve long-term outcomes and quality of life for patients with TNBC.

In a recent study published in Nature Nanotechnology, You et al. describe how coating tumor autophagosomes with nanodots in situ offers a promising strategy for personalizing cancer vaccines in the treatment of tumors [1]. Here, we explore how titanium nitride-based MXene (Ti₂NX) nanodots help tumor autophagosomes escape fusion with lysosomes, allowing drainage to lymph nodes (LNs), and priming of T cells. This Research Highlight also summarizes the therapeutic effects of Ti₂NX nanodot-coated autophagosomes in different murine tumor models.

Autophagy is an essential intracellular process involving the formation of autophagosomes that degrade and recycle cellular components to maintain cellular homeostasis. Autophagosomes, double-membrane vesicles that engulf and transport intracellular material to lysosomes for degradation [2], are being exploited as vaccines in cancer immunotherapy based on their capacity to carry tumor antigens that can be taken up and cross-presented by antigen-presenting cells (APCs), such as dendritic cells (DCs). Autophagosomes are conventionally prepared intracellularly by increasing lysosomal pH, with compounds like Bafilomycin A1, chloroquine, hydroxychloroquine, or ammonium chloride [2], to prevent fusion with lysosomes and allow autophagosome isolation through cell disruption and gradient centrifugation. However, this conventional approach may reduce autophagosome immunogenicity as increasing lysosomal pH can promote the formation of multivesicular bodies (MVBs) that fuse with autophagosomes. You et al. developed 3 nm Ti₂NX nanodots that coat tumor-derived autophagosomes and inhibit autophagy by preventing autophagosome fusion with lysosomes or MVBs [1]. Unlike conventional autophagy inhibitors that affect autophagy in cancer and immune cells, Ti₂NX nanodots selectively target cancer cells and preserve immune cell function.

The fate of Ti₂NX nanodot-coated autophagosomes (NCAPs) follows a sophisticated and well-coordinated process (Figure 1) that begins with nanodots shielding phosphatidylinositol-4-phosphate (PI4P), expressed on the autophagosome surface, through molecular interactions (e.g., hydrogen bonding) with the phosphate groups of PI4P. This shielding prevents the recruitment of functional proteins, such as SNARE syntaxin 17, that mediate fusion of autophagosomes with lysosomes or MVBs. Subsequent accumulation of NCAPs within tumor cells induces intracellular stress, leading to inflammasome-associated pyroptosis and release of NCAPs from tumor cells for recognition and transport by migratory DCs to the LNs. The size range of NCAPs (200–700 nm) and presence of C-type lectin domains containing 9 A (CLEC9A) ligands on the surface of NCAPs enhance recognition by DCs.

Once in the LNs, NCAPs are processed by LN-resident and migratory DCs for cross-presentation. Tumor antigens carried

Coronary artery disease (CAD), the most common panvascular disease, can progress to chronic total occlusion (CTO). Drug-eluting stent (DES) is one of standard CAD treatments, but in-stent restenosis leading to CTO is challenging, with unclear optimal management. The efficacy of drug-coated balloons (DCB) for treating DES-related in-stent chronic total occlusion (IS-CTO) is undetermined. In this single-center retrospective cohort study of 198 patients with IS-CTO post-DES, 3-year outcomes of DCB, DES, and plain old balloon angioplasty (POBA) were compared, focusing on target vessel failure (TVF). DES showed the lowest TVF rate (DCB vs. DES vs. POBA: 31.8% vs. 17.1% vs. 51.6%, p < 0.01), mainly due to fewer revascularizations. Notably, the difference in TVF between DCB and DES became more apparent after the first year. DCB was an independent risk factor for late TVF (HR_adj = 6.51, 95% confidence interval [CI] = 2.45–18.84, p < 0.01), whereas POBA for early TVF compared to DCB (HR_adj = 5.01, 95% CI = 1.36–18.42, p = 0.02). While POBA-treated patients exhibited a higher target vessel myocardial infarction rate, the death rates were comparable across all cohorts. In conclusion, DES showed the lowest 3-year TVF rate, making it the most effective treatment for IS-CTO compared to DCB and POBA.

Immunotherapy has revolutionized cancer treatment in recent years, yet non-responsiveness of immunotherapy remains a challenge for cancer treatment. Therefore, the prediction method for potential clinical benefits of patients from immunotherapy is urgently needed. This study aims to develop an effective clinical practice assistance tool to evaluate the potential clinical benefits and therapy responsiveness of patients undergoing immunotherapy. We developed an immunotherapy resistance score (IRS), which performed well compared with conventional immunotherapy response indicators across different immunotherapy cohorts. Tumor microenvironment (TME) analysis showed that both immune and nonimmune features collectively impact immunotherapy responsiveness. Thus, IRS was constructed based on the TME features using machine learning approaches. The clinical application potential of IRS has been demonstrated in our in-house Harbin Medical University (HMU) cohort and an external validation cohort. Furthermore, we analyzed the correlation between IRS and pathways related to cancer therapy targets to explore the application potential of IRS in comprehensive cancer therapy. In conclusion, IRS is a robust tool for predicting patient immunotherapy prognosis, which has great potential to promote precise clinical therapy.

Most individuals with COVID-19, caused by SARS-CoV-2 infection, experience asymptomatic or mild-to-moderate symptoms, while a minority of patients may deteriorate to severe illness or fatal outcomes [1]. Severe COVID-19 can lead to critical complications, including respiratory distress and increased mortality rates [2]. One such complication is the development of “white lung” on chest radiographs (e.g., X-ray), characterized by extensive inflammation and fluid accumulation affecting 70%–80% of the lung area [3]. The appearance of white lung signals a critical stage in COVID-19 patients, profoundly impairing lung function, often requiring mechanical ventilation and ICU admission, and substantially increasing mortality risk [1, 2]. Despite extensive research into the pathophysiology of COVID-19, the mechanisms underlying “white lung” remain poorly understood.

Here, we performed single-cell RNA sequencing analysis of bronchoalveolar lavage fluid (BALF) to characterize the pathophysiology of “white lung” in COVID-19 (Figure 1A). BALF samples were collected from 16 patients with moderate (MO, n = 3), severe (SE, n = 6), and “white lung” (WL, n = 7) syndrome, as well as from 3 healthy controls (HC) (Figure 1A). After quality control filtering (Supporting Information S1: Figure S1A–C), we obtained transcriptome data sets from 136,015 cells (mean = 7159 cells/sample). Using uniform manifold approximation and projection (UMAP), we identified 7 major cell types (Supporting Information S1: Figure S1D) and, through sub-clustering, 44 distinct cell states representing diverse respiratory cell types (Supporting Information S1: Figure S1E). UMAP visualization (Supporting Information S1: Figure S1F) revealed substantial inter-group heterogeneity. The distribution of seven major clusters was portrayed through R_O/E (Supporting Information S1: Figure S1G) [1]. We observed an obvious expansion of NK and neutrophils in COVID-19 patients with “white lung” (Supporting Information S1: Figure S1G–J, Figure 1B). However, NK cells comprised < 0.5% of the total cell population in these patients (Supporting Information S1: Figure S1I), implying that their expansion is unlikely to be the primary driver of this complication. In contrast, neutrophils constituted up to 85% of BALF cells in COVID-19 patients with “white lung,” whereas this proportion did not exceed 25% in any other group (Figure 1B, Supporting Information S1: Figure S1H). PCA analysis clearly distinguished neutrophils from “white lung” patients from those in controls and patients with moderate and severe COVID-19 (Supporting Information S1: Figure S2A,B). Among BALF immune cells, neutrophils exhibited a significant association with “white lung” patients (Supporting Information S1: Figure S2C). These results suggested that neutrophil infiltration may be a key driver of “white lung” development in COVID-19.<

Muscle atrophy, characterized by the loss of muscle mass and function, is a hallmark of sarcopenia and cachexia, frequently associated with aging, malignant tumors, chronic heart failure, and malnutrition. Moreover, it poses significant challenges to human health, leading to increased frailty, reduced quality of life, and heightened mortality risks. Despite extensive research on sarcopenia and cachexia, consensus in their assessment remains elusive, with inconsistent conclusions regarding their molecular mechanisms. Muscle atrophy models are crucial tools for advancing research in this field. Currently, animal models of muscle atrophy used for clinical and basic scientific studies are induced through various methods, including aging, genetic editing, nutritional modification, exercise, chronic wasting diseases, and drug administration. Muscle atrophy models also include in vitro and small organism models. Despite their value, each of these models has certain limitations. This review focuses on the limitations and diverse applications of muscle atrophy models to understand sarcopenia and cachexia, and encourage their rational use in future research, therefore deepening the understanding of underlying pathophysiological mechanisms, and ultimately advancing the exploration of therapeutic strategies for sarcopenia and cachexia.

Cancer immunotherapies, developed on the basis of research into tumor escape mechanisms, manipulate the immune system to reactivate an antitumor immune response to recognize and attack cancer cells. Immunotherapy has demonstrated promising and exciting outcomes in the treatment of many cancers, yet not all patients experience favorable responses. The gut microbiota plays a critical role in modulating the host immune system, influencing responses to cancer immunotherapy. Research has increasingly demonstrated that specific microbial communities can increase the efficacy of immune checkpoint inhibitors, although the mechanisms involved remain under investigation. However, a clear gap exists in the understanding of how bacterial therapies can be further optimized for cancer treatment. This review provides an in-depth analysis of current bacterial therapies used in clinical trials as adjuncts to cancer immunotherapy, summarizing common research approaches and technologies utilized to investigate gut microbiota interactions with the immune system. Additionally, advanced strategies for modifying bacteria, including genetic engineering, surface modifications, and the development of bacterial derivatives, are discussed. By synthesizing these findings, this review highlights the potential of microbiota-based therapies to improve immunotherapy outcomes and offers future directions for improving clinical applications.

Acute kidney injury (AKI) is a significant global healthcare burden but lacks specific and effective treatment. Renal tubular cells damage is central to ischemia-reperfusion injury (IRI) induced AKI. It is critical to clarify the initiation mechanisms of renal IRI and develop early intervention targets of AKI. This study used label-free quantification proteomic analysis to identify new targets in AKI-related renal tubular injury and investigate the potential mechanisms. We discovered significant changes in cysteinyl-tRNA synthetase (CARS) in renal tubular cell during IRI. Considering the involvement of CARS in ATP metabolism and the close correlation between ATP and pyroptosis, we further explored pyroptosis phenotype with and without CARS intervention as well as the expression of CARS during pyroptosis activation and inhibition. Our findings suggest that CARS expression decreased over time and is linked to pyroptosis. Modifying CARS affects ATP metabolism and alters the expression of pyroptosis-related proteins during H/R and IRI treatments. Regulating pyroptosis may influence CARS expression during IRI treatment. Overall, CARS is associated with renal tubular damage from ischemia-reperfusion injury, possibly involving pyroptosis, though the regulatory mechanism remains unclear.

Vancomycin (VAN)-intermediate Staphylococcus aureus (VISA) is a critical cause of VAN treatment failure worldwide. Multiple genetic changes are reportedly associated with VISA formation, whereas VISA strains often present common phenotypes, such as reduced autolysis and thickened cell wall. However, how mutated genes lead to VISA common phenotypes remains unclear. Here, we show a metabolism regulatory cascade (CcpA-GlmS), whereby mutated two-component systems (TCSs) link to the common phenotypes of VISA. We found that ccpA deletion decreased VAN resistance in VISA strains with diverse genetic backgrounds. Metabolic alteration in VISA was associated with ccpA upregulation, which was directly controlled by TCSs WalKR and GraSR. RNA-sequencing revealed the crucial roles of CcpA in changing the carbon flow and nitrogen flux of VISA to promote VAN resistance. A gate enzyme (GlmS) that drives carbon flow to the cell wall precursor biosynthesis was upregulated in VISA. CcpA directly controlled glmS expression. Blocking CcpA sensitized VISA strains to VAN treatment in vitro and in vivo. Overall, this work uncovers a link between the formation of VISA phenotypes and commonly mutated genes. Inhibition of CcpA-GlmS cascade is a promising strategy to restore the therapeutic efficiency of VAN against VISA infections.