Real-World Experience among Elderly Metastatic Breast Cancer Patients Treated with CDK4/6 Inhibitor-Based Therapy.

The largest portion of breast cancer patients diagnosed after 70 years of age present with hormone receptor-positive (HR+) breast cancer subtypes. Cyclin-dependent kinase (CDK) 4/6 inhibitor treatment, in conjunction with endocrine therapy, has become standard-of-care for metastatic HR+ breast cancer. In total, 320 patients with metastatic breast cancer receiving CDK4/6 inhibitor combined with fulvestrant or an aromatase inhibitor were enrolled in an ongoing observational study or were included in an IRB-approved retrospective study. All patients receiving CDK4/6 inhibitor-based therapy that were ≥70 years of age (n = 111) displayed prolonged progression-free survival (27.6 months) as compared to patients <70 years of age (n = 209, 21.1 months, HR = 1.38, p < 0.05). Specifically, patients receiving a CDK4/6 inhibitor with an aromatase inhibitor who were ≥70 years of age (n = 79) displayed exceptionally prolonged progression-free survival (46.0 months) as compared to patients receiving the same treatment who were <70 years of age (n = 161, 21.8 months, HR = 1.71, p < 0.01). However, patients ≥70 years of age also experienced more frequent adverse responses to CDK4/6 inhibitor-based treatment leading to dose reduction, hold, or discontinuation than the younger cohort (69% and 53%, respectively). Treatment strategies that may decrease toxicity without affecting efficacy (such as dose titration) are worth further exploration.

Translational PET Imaging of Nectin-4 Expression in Multiple Different Cancers with 68Ga-N188.

Nectin cell adhesion molecule 4 (nectin-4) is a transmembrane protein overexpressed on a variety of cancers and plays an important role in oncogenic and metastatic processes. The nectin-4-targeted antibody-drug conjugate enfortumab vedotin has been approved for treating locally advanced or metastatic urothelial cancer, but the efficacy in other types of cancer remains to be explored. The aim of this study was to evaluate the feasibility of nectin-4-targeted PET imaging with 68Ga-N188 as a noninvasive method to quantify membranous nectin-4 expression in multiple tumor types-an approach that may provide insight for patient stratification and treatment selection. Methods: Sixty-two patients with 16 types of cancer underwent head-to-head 68Ga-N188 and 18F-FDG PET/CT imaging for initial staging or detection of recurrence and metastases. Correlation between lesion SUVmax and nectin-4 expression determined by immunohistochemistry staining was analyzed in 36 of 62 patients. Results: The SUVmax of 68Ga-N188 had a positive correlation with membranous nectin-4 expression in the various tumor types tested (r = 0.458; P = 0.005), whereas no association was observed between the SUVmax and cytoplasmic nectin-4 expression. The detection rates for patient-based analysis of 68Ga-N188 and 18F-FDG PET/CT examinations were comparable (95.00% [57/60] vs. 93.33% [56/60]). In patients with pancreatic cancer, 68Ga-N188 exhibited a potential advantage for detecting residual or locally recurrent tumors; this advantage may assist in clinical decision-making. Conclusion: The correlation between nectin-4-targeted 68Ga-N188 PET imaging and membranous nectin-4 expression indicates the potential of 68Ga-N188 as an effective tool for selecting patients who may benefit from enfortumab vedotin treatment. The PET imaging results provided evidence to explore nectin-4-targeted therapy in a variety of tumors. 68Ga-N188 may improve the restaging of pancreatic cancer but requires further evaluation in a powered, prospective setting.

Indirubin-3'-monoxime exhibits potent antiviral and anti-inflammatory effects against human adenoviruses in vitro and in vivo.

Human adenovirus (HAdV) infection is a major cause of respiratory disease, yet no antiviral drugs have been approved for its treatment. Herein, we evaluated the antiviral and anti-inflammatory effects of cyclin-dependent protein kinase (CDK) inhibitor indirubin-3'-monoxime (IM) against HAdV infection in cells and a transgenic mouse model. After evaluating its cytotoxicity, cytopathic effect reduction, antiviral replication kinetics, and viral yield reduction assays were performed to assess the anti-HAdV activity of IM. Quantitative real-time polymerase chain reaction (qPCR), quantitative reverse transcription PCR (qRT-PCR), and western blotting were used to assess the effects of IM on HAdV DNA replication, transcription, and protein expression, respectively. IM significantly inhibited HAdV DNA replication as well as E1A and Hexon transcription, in addition to significantly suppressing the phosphorylation of the RNA polymerase II C-terminal domain (CTD). IM mitigated body weight loss, reduced viral burden, and lung injury, decreasing cytokine and chemokine secretion to a greater extent than cidofovir. Altogether, IM inhibits HAdV replication by downregulating CTD phosphorylation to suppress viral infection and corresponding innate immune reactions as a promising therapeutic agent.

Study on heat transfer law of moving temperature variable gas in thermoacoustic plate stack.

Taking gas and the heat transfer process between gas and plate as the research object, the mathematical model of heat transfer in one working cycle by moving variable temperature air mass under the action of sound field is established, which provides a new idea for understanding thermoacoustic effect. The influence factors in the model are analyzed and it is found that the amplitude of the air mass has a significant influence on the heat transfer, and the heat transfer of the air mass in one working cycle is proportional to the square of the amplitude. In a certain working environment, the thermoacoustic refrigerator has a critical operating frequency, and only when the operating frequency is greater than the critical frequency can refrigeration be realized. The critical operating frequency is independent of the amplitude and increases with the increase of the stack temperature gradient. With the pressure belly point as the reference position, the greater the distance from the reference position, the greater the critical operating frequency. On this basis, the idea of short plate overlapping is put forward and the formation mechanism of temperature difference between two ends of plate overlapping is explained.

TripHLApan: predicting HLA molecules binding peptides based on triple coding matrix and transfer learning.

Human leukocyte antigen (HLA) recognizes foreign threats and triggers immune responses by presenting peptides to T cells. Computationally modeling the binding patterns between peptide and HLA is very important for the development of tumor vaccines. However, it is still a big challenge to accurately predict HLA molecules binding peptides. In this paper, we develop a new model TripHLApan for predicting HLA molecules binding peptides by integrating triple coding matrix, BiGRU + Attention models, and transfer learning strategy. We have found the main interaction site regions between HLA molecules and peptides, as well as the correlation between HLA encoding and binding motifs. Based on the discovery, we make the preprocessing and coding closer to the natural biological process. Besides, due to the input being based on multiple types of features and the attention module focused on the BiGRU hidden layer, TripHLApan has learned more sequence level binding information. The application of transfer learning strategies ensures the accuracy of prediction results under special lengths (peptides in length 8) and model scalability with the data explosion. Compared with the current optimal models, TripHLApan exhibits strong predictive performance in various prediction environments with different positive and negative sample ratios. In addition, we validate the superiority and scalability of TripHLApan's predictive performance using additional latest data sets, ablation experiments and binding reconstitution ability in the samples of a melanoma patient. The results show that TripHLApan is a powerful tool for predicting the binding of HLA-I and HLA-II molecular peptides for the synthesis of tumor vaccines. TripHLApan is publicly available at https://github.com/CSUBioGroup/TripHLApan.git.

High-sensitivity dual U-shaped PCF-SPR refractive index sensor for the detection of gas and liquid analytes.

A dual U-shaped photonic crystal fiber (PCF) biochemical sensor based on surface plasmon resonance (SPR) is designed for the simultaneous detection of gas and liquid analytes, and the properties are analyzed by the full vector finite element method (FEM). SPR is excited by placing gold nanowires on the inner surface of the U-shaped device. In this technique, the traditional metal deposition process can be replaced, subsequently reducing the difficulty and complexity of actual production and improving the phase matching between the basic mode and plasmonic modes. To improve the detection properties, the structural parameters of the sensor including the air hole diameter, spacing, gold nanowire diameter, and polishing depth are optimized, and to better evaluate and analyze the sensing properties, the wavelength and amplitude modulation inquiry method is adopted. The results show that the maximum wavelength sensitivity (WS), amplitude sensitivity (AS), minimum resolution (R), and optimal FOM are 35,000 nm/RIU, 438.08R I U -1, 2.86×10-6 R I U, and 165.16R I U -1, respectively. In addition, the sensor can detect analyte RIs between 1.00 and 1.36 for gas and liquid analytes simultaneously. Owing to the simple structure, low cost, and ambient-condition monitoring, the sensor has large potential in a myriad of applications including sewage treatment, food safety, humoral regulation, environmental and biological monitoring, and medical diagnosis.

Ginsenoside Rh2-Based Multifunctional Liposomes for Advanced Breast Cancer Therapy.

Background: Most solid tumors are not diagnosed and treated until the advanced stage, in which tumors have shaped mature self-protective power, leading to off-target drugs and nanomedicines. In the present studies, we established a more realistic large tumor model to test the antitumor activity of a multifunctional ginsenoside Rh2-based liposome system (Rh2-lipo) on advanced breast cancer. Methods: Both cholesterol and PEG were substituted by Rh2 to prepare the Rh2-lipo using ethanol-water system and characterized. The effects of Rh2-lipo on cell uptake, penetration of the tumor spheroid, cytotoxicity assay was investigated with 4T1 breast cancer cells and L929 fibroblast cells. The 4T1 orthotopic-bearing large tumor model was established to study the targeting effect of Rh2-lipo and inhibitory effect of paclitaxel loaded Rh2-lipo (PTX-Rh2-lipo) on advanced breast tumors. Results: Rh2-lipo exhibit many advantages that address the limitations of current liposome formulations against large tumors, such as enhanced uptake in TAFs and tumor cells, high targeting and penetration capacity, cytotoxicity against TAFs, normalization of the vessel network, and depletion of stromal collagen. In in vivo study, PTX-Rh2-lipo effectively inhibiting the growth of advanced breast tumors and outperformed most reported PTX formulations, including Lipusu® and Abraxane®. Conclusion: Rh2-lipo have improved drug delivery efficiency and antitumor efficacy in advanced breast cancer, which offers a novel promising platform for advanced tumor therapy.

MA-PEP: A novel anticancer peptide prediction framework with multimodal feature fusion based on attention mechanism.

AntiCancer Peptides (ACPs) have emerged as promising therapeutic agents for cancer treatment. The time-consuming and costly nature of wet-lab discriminatory methods has spurred the development of various machine learning and deep learning-based ACP classification methods. Nonetheless, current methods encountered challenges in efficiently integrating features from various peptide modalities, thereby limiting a more comprehensive understanding of ACPs and further restricting the improvement of prediction model performance. In this study, we introduce a novel ACP prediction method, MA-PEP, which leverages multiple attention mechanisms for feature enhancement and fusion to improve ACP prediction. By integrating the enhanced molecular-level chemical features and sequence information of peptides, MA-PEP demonstrates superior prediction performance across several benchmark datasets, highlighting its efficacy in ACP prediction. Moreover, the visual analysis and case studies further demonstrate MA-PEP's reliable feature extraction capability and its promise in the realm of ACP exploration. The code and datasets for MA-PEP are available at https://github.com/liangxiaodata/MA-PEP.

The radiological characteristics, tertiary lymphoid structures, and survival status associated with EGFR mutation in patients with subsolid nodules like stage I-II LUAD.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) recommended for the patients with subsolid nodule in early lung cancer stage is not routinely. The clinical value and impact in patients with EGFR mutation on survival outcomes is further needed to be elucidated to decide whether the application of EGFR-TKIs was appropriate in early lung adenocarcinoma (LUAD) stage appearing as subsolid nodules. MATERIALS AND METHODS: The inclusion of patients exhibiting clinical staging of IA-IIB subsolid nodules. Clinical information, computed tomography (CT) features before surgical resection and pathological characteristics including tertiary lymphoid structures of the tumors were recorded for further exploration of correlation with EGFR mutation and prognosis. RESULTS: Finally, 325 patients were enrolled into this study, with an average age of 56.8 ± 9.8 years. There are 173 patients (53.2%) harboring EGFR mutation. Logistic regression model analysis showed that female (OR = 1.944, p = 0.015), mix ground glass nodule (OR = 2.071, p = 0.003, bubble-like lucency (OR = 1.991, p = 0.003) were significant risk factors of EGFR mutations. Additionally, EGFR mutations were negatively correlated with TLS presence and density. Prognosis analysis showed that the presence of TLS was associated with better recurrence-free survival (RFS)(p = 0.03) while EGFR mutations were associated with worse RFS(p = 0.01). The RFS in patients with TLS was considerably excel those without TLS within EGFR wild type group(p = 0.018). Multivariate analyses confirmed that EGFR mutation was an independent prognostic predictor for RFS (HR = 3.205, p = 0.037). CONCLUSIONS: In early-phase LUADs, subsolid nodules with EGFR mutation had specific clinical and radiological signatures. EGFR mutation was associated with worse survival outcomes and negatively correlated with TLS, which might weaken the positive impact of TLS on prognosis. Highly attention should be paid to the use of EGFR-TKI for further treatment as agents in early LUAD patients who carrying EGFR mutation.

GraphPath: a graph attention model for molecular stratification with interpretability based on the pathway-pathway interaction network.

MOTIVATION: Studying the molecular heterogeneity of cancer is essential for achieving personalized therapy. At the same time, understanding the biological processes that drive cancer development can lead to the identification of valuable therapeutic targets. Therefore, achieving accurate and interpretable clinical predictions requires paramount attention to thoroughly characterizing patients at both the molecular and biological pathway levels. RESULTS: Here, we present GraphPath, a biological knowledge-driven graph neural network with multi-head self-attention mechanism that implements the pathway-pathway interaction network. We train GraphPath to classify the cancer status of patients with prostate cancer based on their multi-omics profiling. Experiment results show that our method outperforms P-NET and other baseline methods. Besides, two external cohorts are used to validate that the model can be generalized to unseen samples with adequate predictive performance. We reduce the dimensionality of latent pathway embeddings and visualize corresponding classes to further demonstrate the optimal performance of the model. Additionally, since GraphPath's predictions are interpretable, we identify target cancer-associated pathways that significantly contribute to the model's predictions. Such a robust and interpretable model has the potential to greatly enhance our understanding of cancer's biological mechanisms and accelerate the development of targeted therapies. AVAILABILITY AND IMPLEMENTATION: https://github.com/amazingma/GraphPath.

A review on gold nanoparticles as an innovative therapeutic cue in bone tissue engineering: Prospects and future clinical applications.

Bone damage is a complex orthopedic problem primarily caused by trauma, cancer, or bacterial infection of bone tissue. Clinical care management for bone damage remains a significant clinical challenge and there is a growing need for more advanced bone therapy options. Nanotechnology has been widely explored in the field of orthopedic therapy for the treatment of a severe bone disease. Among nanomaterials, gold nanoparticles (GNPs) along with other biomaterials are emerging as a new paradigm for treatment with excellent potential for bone tissue engineering and regenerative medicine applications. In recent years, a great deal of research has focused on demonstrating the potential for GNPs to provide for enhancement of osteogenesis, reduction of osteoclastogenesis/osteomyelitis, and treatment of bone cancer. This review details the latest understandings in regards to GNPs based therapeutic systems, mechanisms, and the applications of GNPs against various bone disorders. The present review aims to summarize i) the mechanisms of GNPs in bone tissue remodeling, ii) preparation methods of GNPs, and iii) functionalization of GNPs and its decoration on biomaterials as a delivery vehicle in a specific bone tissue engineering for future clinical application.

Draft genome sequence of Dietzia sp. strain CH92 isolated from oil reservoir.

We report the draft genome sequence of Dietzia sp. strain CH92, isolated from a high temperature oil well in Baolige oilfield, China. The estimated genome is 3.73 Mb, with 3,479 protein-coding sequences.

The genomic and evolutionary landscapes of anaplastic thyroid carcinoma.

Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs with differentiated thyroid cancers, yet the molecular origins of its aggressivity are unknown. We sequenced tumor DNA from 329 regions of thyroid cancer, including 213 from patients with primary anaplastic thyroid carcinomas. We also whole genome sequenced 9 patients using multi-region sequencing of both differentiated and anaplastic thyroid cancer components. Using these data, we demonstrate thatanaplastic thyroid carcinomas have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. Further, different cancer driver genes are mutated in anaplastic and differentiated thyroid carcinomas, even those arising in a single patient. Finally, we unambiguously demonstrate that anaplastic thyroid carcinomas share a genomic origin with co-occurring differentiated carcinomas and emerge from a common malignant field through acquisition of characteristic clonal driver mutations.

Clinical effect of the internal fixation for rib fracture with single utility port complete video-assisted thoracoscopic surgery.

BACKGROUNDS: The internal fixation for rib fracture with single-operation-port (two ports) complete video-assisted thoracoscopic surgery (VATS) is a promising surgical approach for treating multiple rib fractures. The study aimed to investigate the minimally invasive surgical procedure's clinical effect in treating multiple rib fractures. METHODS: Seventy-three patients with multiple rib fractures were divided into two groups according to surgical procedure. In the study group, 42 patients were operated on with the internal fixation of rib fracture with single-operation-port complete VATS. In the control group, this study performed the open operative internal fixation for rib fracture with traditional thoracotomy on 31 patients. The surgical-related indexes were retrospectively analyzed. These included the operative time, the intraoperative blood loss, the drainage amount of the chest tube, the placement time of the chest tube, the postoperative hospital stay, the incidence of postoperative complications, the imaging efficacy of rib fixation of rib fractures, and visual analog scale of pain scoring (VAS scoring). RESULTS: There was no difference in the operative time between the study and control groups (P = 0.806). The intraoperative blood loss, the chest tube drainage amount, the chest tube placement time, the postoperative hospital stay, and the incidence of postoperative complications in the study group were lower than those in the control group (P < 0.05). There was no significant difference in the imaging efficacy of rib fixation of rib fractures between the two groups (P = 0.806). VAS scores in the study group on the seventh postoperative day were significantly reduced compared with the control group (P = 0.026). CONCLUSION: The internal fixation for rib fractures with single-operation-port complete VATS is a feasible, safe, simple, and minimally invasive surgical procedure to treat multiple rib fractures, which is worthy of clinical application.

The Extracellular Niche and Tumor Microenvironment Enhance KRAS Inhibitor Efficacy in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that lacks effective treatment options, highlighting the need for developing new therapeutic interventions. Here, we assessed the response to pharmacologic inhibition of KRAS, the central oncogenic driver of PDAC. In a panel of PDAC cell lines, inhibition of KRASG12D with MRTX1133 yielded variable efficacy in suppressing cell growth and downstream gene expression programs in 2D cultures. On the basis of CRISPR-Cas9 loss-of-function screens, ITGB1 was identified as a target to enhance the therapeutic response to MRTX1133 by regulating mechanotransduction signaling and YAP/TAZ expression, which was confirmed by gene-specific knockdown and combinatorial drug synergy. Interestingly, MRTX1133 was considerably more efficacious in 3D cell cultures. Moreover, MRTX1133 elicited a pronounced cytostatic effect in vivo and controlled tumor growth in PDAC patient-derived xenografts. In syngeneic models, KRASG12D inhibition led to tumor regression that did not occur in immune-deficient hosts. Digital spatial profiling on tumor tissues indicated that MRTX1133-mediated KRAS inhibition enhanced IFNγ signaling and induced antigen presentation that modulated the tumor microenvironment. Further investigation of the immunologic response using single-cell sequencing and multispectral imaging revealed that tumor regression was associated with suppression of neutrophils and influx of effector CD8+ T cells. Together, these findings demonstrate that both tumor cell-intrinsic and -extrinsic events contribute to response to MRTX1133 and credential KRASG12D inhibition as a promising therapeutic strategy for a large percentage of patients with PDAC. SIGNIFICANCE: Pharmacologic inhibition of KRAS elicits varied responses in pancreatic cancer 2D cell lines, 3D organoid cultures, and xenografts, underscoring the importance of mechanotransduction and the tumor microenvironment in regulating therapeutic responses.

Preparation and Oil Adsorption of Cellulose-graft-poly(butyl acrylate-N,N'-methylene Bisacrylamide).

With the advancement of industrial economies, incidents involving spills of petroleum products have become increasingly frequent. The resulting pollutants pose significant threats to air, water, soil, plant and animal survival, as well as human health. In this study, microcrystalline cellulose served as the matrix and benzoyl peroxide (BPO) as the initiator, while butyl acrylate (BA) and N,N'-methylene bisacrylamide (MBA) were employed as graft monomers. Through free radical graft polymerization, cellulose-graft-poly(butyl acrylate-N,N'-methylene bisacrylamide) [Cell-g-P(BA-MBA)], possessing oil-adsorbing properties, was synthesized. The chemical structure, elemental composition, surface morphology and wetting properties of the graft polymerization products have been characterized, using infrared spectroscopy, elemental analysis, scanning electron microscopy and contact angle testing. The adsorption properties of Cell-g-P(BA-MBA) for various organic solvents and oils were then assessed. The experimental results demonstrated that Cell-g-P(BA-MBA) exhibited a maximum adsorption capacity of 37.55 g/g for trichloromethane. Adsorption kinetics experiments indicated a spontaneous and exothermic process involving physical adsorption, conforming to the Freundlich isotherm model. Furthermore, adsorption kinetics experiments revealed that Cell-g-P(BA-MBA) displayed favorable reuse and regeneration performance, maintaining its adsorption capacity essentially unchanged over fifteen adsorption-desorption cycles.

An injectable signal-amplifying device elicits a specific immune response against malignant glioblastoma.

Despite exciting achievements with some malignancies, immunotherapy for hypoimmunogenic cancers, especially glioblastoma (GBM), remains a formidable clinical challenge. Poor immunogenicity and deficient immune infiltrates are two major limitations to an effective cancer-specific immune response. Herein, we propose that an injectable signal-amplifying nanocomposite/hydrogel system consisting of granulocyte-macrophage colony-stimulating factor and imiquimod-loaded antigen-capturing nanoparticles can simultaneously amplify the chemotactic signal of antigen-presenting cells and the "danger" signal of GBM. We demonstrated the feasibility of this strategy in two scenarios of GBM. In the first scenario, we showed that this simultaneous amplification system, in conjunction with local chemotherapy, enhanced both the immunogenicity and immune infiltrates in a recurrent GBM model; thus, ultimately making a cold GBM hot and suppressing postoperative relapse. Encouraged by excellent efficacy, we further exploited this signal-amplifying system to improve the efficiency of vaccine lysate in the treatment of refractory multiple GBM, a disease with limited clinical treatment options. In general, this biomaterial-based immune signal amplification system represents a unique approach to restore GBM-specific immunity and may provide a beneficial preliminary treatment for other clinically refractory malignancies.

Centrifugal Extraction-Assisted Fiber-Enhanced Raman Spectroscopy for Online Detection of Trace Furfural in Oil Power Equipment.

Oil-paper insulated equipment is integral in power conversion and supports low-loss electricity transport. As a characteristic byproduct of the oil-paper insulation system, the realization of efficient detection of furfural in oil is crucial to the safe operation of the power grid. We proposed a novel approach using dual-enhanced Raman spectroscopy for sensing trace liquid components. This method employs a centrifugal extractor to separate and enrich the targeted components, achieving selective enhancement. The optimal phase ratio was determined to be 30:1. A liquid-core fiber was used to optimize the laser transmission efficiency and Raman signal collection efficiency, resulting in a nonselective signal enhancement of 44.86. It also investigated the impact of intermolecular interactions on the shift of Raman spectra, identifying the reasons for the differences in Raman signals between pure furfural, furfural in oil, and furfural in water. A batch of samples with furfural dissolved in insulation oil was measured using this system and achieved a limit of detection of 0.091 mg/L. The stability of the dual-enhanced Raman platform was experimentally verified with a spectral intensity fluctuation of 0.68%. This method is fast, stable, adaptable, and suitable for the detection of a wide range of liquid ingredients.

Determinants of response to CDK4/6 inhibitors in the real-world setting.

Despite widespread use and a known mechanism of action for CDK4/6 inhibitors in combination with endocrine therapy, features of disease evolution and determinants of therapeutic response in the real-world setting remain unclear. Here, a cohort of patients treated with standard-of-care combination regimens was utilized to explore features of disease and determinants of progression-free survival (PFS) and overall survival (OS). In this cohort of 280 patients, >90% of patients were treated with palbociclib in combination with either an aromatase inhibitor (AI) or fulvestrant (FUL). Most of these patients had modified Scarff-Bloom-Richardson (SBR) scores, and ER, HER2, and PR immunohistochemistry. Both the SBR score and lack of PR expression were associated with shorter PFS in patients treated with AI combinations and remained significant in multivariate analyses (HR = 3.86, p = 0.008). Gene expression analyses indicated substantial changes in cell cycle and estrogen receptor signaling during the course of treatment. Furthermore, gene expression-based subtyping indicated that predominant subtypes changed with treatment and progression. The luminal B, HER2, and basal subtypes exhibited shorter PFS in CDK4/6 inhibitor combinations when assessed in the pretreatment biopsies; however, they were not associated with OS. Using unbiased approaches, cell cycle-associated gene sets were strongly associated with shorter PFS in pretreatment biopsies irrespective of endocrine therapy. Estrogen receptor signaling gene sets were associated with longer PFS particularly in the AI-treated cohort. Together, these data suggest that there are distinct pathological and biological features of HR+/HER2- breast cancer associated with response to CDK4/6 inhibitors. Clinical trial registration number: NCT04526587.

Piezoelectric enhanced sulfur doped graphdiyne nanozymes for synergistic ferroptosis-apoptosis anticancer therapy.

Graphdiyne has excellent potential due to its enzymatic properties. Metal-free sulfur-doped Graphdiyne (S-GDY) has piezoelectric characteristics, and ultrasonic excitation of S-GDY enhances peroxidase activity. It can turn hydrogen peroxide into toxic hydroxyl radicals and induce apoptosis in 4T1 cells. More importantly, the ultrasound (US) enhanced nanozyme induced 4T1 cell ferroptosis by promoting an imbalanced redox reaction due to glutathione depletion and glutathione peroxidase 4 inactivation. S-GDY exhibited enhanced nanozyme activity in vitro and in vivo that may directly trigger apoptosis-ferroptosis for effective tumor therapy. Altogether, this study was expected to provide new insights into the design of piezoelectric catalytic nanozyme and expand their application in the catalytic therapy of tumors.