Clinical benefit and safety profile of cross-line therapy with CDK4/6 inhibitors: a retrospective study of HR+/HER2- advanced breast cancer.

OBJECTIVE: CDK4/6 inhibitors (CDK4/6is) in combination with endocrine therapy have secured a central role in the treatment of hormone receptor (HR)-positive advanced breast cancer (ABC) and have transformed the therapeutic landscape. Cross-line CDK4/6i therapy in which another CDK4/6i is continued after progression on a prior CDK4/6i may still offer advantageous therapeutic effects. Cross-line CDK4/6i therapy is an area of active investigation in the ongoing pursuit to improve outcomes for patients with HR+/human epidermal growth factor receptor 2 (HER2)- ABC. METHODS: This retrospective study enrolled 82 patients with HR+/HER2- ABC who were treated with cross-line CDK4/6is (abemaciclib, palbociclib, ribociclib, and dalpiciclib) after progression with another CDK4/6i. The primary endpoint was progression-free survival (PFS) according to version 1.1 of the Response Evaluation Criteria in Solid Tumors. Secondary endpoints included toxicity, objective response rate, disease control rate, and overall survival. Adverse events (AEs) were graded according to version 5.0 of the Common Terminology Criteria for Adverse Events, as promulgated by the U.S. Department of Health and Human Services. RESULTS: Eighty-two HR+/HER2- ABC patients who received cross-line CDK4/6i therapy from January 2022 to February 2024 were enrolled. The median age of the patients was 60 years. The median PFS of all patients was 7.6 months (95% CI, 5.9-9.2). Cox regression analysis identified lung metastasis and a switch to endocrine therapy following prior CDK4/6i therapy as independent predictive factors for PFS. Notably, patients who previously received abemaciclib and switched to palbociclib upon disease progression had a median PFS of 10.7 months. The strategy of transitioning to chemotherapy after progression on a prior CDK4/6i, then to a subsequent CDK4/6i merits further investigation. Hematologic toxicity was the most common grade ≥ 3 AEs. No instances of fatal safety events were observed. CONCLUSIONS: Cross-line CDK4/6i therapy is associated with significant clinical benefits and manageable safety profiles in patients with HR+/HER2- ABC, which underscores cross-line CDK4/6i therapy potential as an effective treatment strategy.

Inetetamab-based therapy in real-world treatment patterns with HER2-positive advanced breast cancer patients: a retrospective single-center study.

Background: Inetetamab is a novel antibody targeting human epidermal growth factor receptor 2 (HER2) developed in China. Due to its optimized antibody-dependent cell-mediated cytotoxicity effect compared with trastuzumab, it has shown good efficacy and safety in the treatment of HER2-positive advanced breast cancer (ABC). Objectives: This study aimed to investigate the efficacy and safety of inetetamab combination therapy in the treatment of HER2-positive ABC in real-world clinical practice. Design: Retrospective study. Methods: A total of 133 patients with HER2-positive ABC who were treated with inetetamab-based regimens between March 2020 and January 2024 were retrospectively included in this study. The main endpoint was median progression-free survival (mPFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. Results: The study included 133 HER2-positive ABC patients, and the median age was 55 years. The mPFS was 8.0 (6.7-9.3) months. The ORR was 50.4%, while the DCR was 88.7%. The mPFS for patients receiving inetetamab-based therapy as first to second, third to fourth, and later lines of metastatic treatment were 14.0, 7.0, and 6.0 months, respectively. Patients treated with inetetamab plus pyrotinib plus chemotherapy, especially with capecitabine, had the best outcomes (mPFS = 14.0 months). Multivariate analysis revealed that prior HER2-TKI treatment was significantly associated with worse PFS (hazard ratios 2.829, 95% confidence interval 1.265-6.328, p = 0.011). Subgroup analysis indicated that patients without visceral metastases had significantly better PFS (14.0 months vs 8.0 months, p = 0.003). The overall incidence of any grade adverse events (AEs) was 100%, with most being grades 1-2. Severe complications included neutropenia (37.6%) and leukopenia (33.1%). Conclusions: Inetetamab-based combination therapy shows promising efficacy and good safety in patients with HER2-positive ABC. It is one of the late-line treatment options for Chinese patients with HER2-positive ABC.

Mechanism of Yishen Chuchan decoction intervention of Parkinson's disease based on network pharmacology and experimental verification.

The incidence of Parkinson's disease (PD) rises rapidly with the increase of age. With the advent of global aging, the number of patients with PD is rising along with the elderly population, especially in China. Previously, we found that Yishen chuchan decoction (YCD), prescribed based on clinical experience, has the potential of alleviating symptoms, delaying the progression, and controlling the development of PD. Nonetheless, the underlying mechanistic role is yet to be explored. Aim: This research examined the possible therapeutic effects of YCD in alleviating PD via a systematic approach with network pharmacology and experimental validation, aiming at providing a new understanding of traditional Chinese medicine management regarding PD. Methods: The chemical structure and properties of YCD were adopted from Traditional Chinese Medicine System Pharmacology Database (TCMSP), SwissADME, PubChem, and PubMed. The potential targets for YCD and PD were identified using Swiss Target Prediction, GeneCard, PubChem, and UniProt. The herbal-component-target network was created via the Cytoscape software. Moreover, by using the STRING database, the protein-protein interaction (PPI) network was screened. Gene function GO and KEGG pathway enrichment analyses were performed via the Metascape database. YCD-medicated Rat Serum from Sprague-Dawley (SD) Rats was prepared, and SH-SY5Y cells were preconditioned with rotenone to develop the PD model. To examine the impact of YCD on these cells and explore the mechanistic role of the p38 mitogen-activated protein kinase (MAPK) pathway, the cells were pretreated with either serum or a p38 MAPK pathway inhibitor. This study employed the Cell Counting Kit (CCK)-8 assay and Hoechst 33,342 staining to evaluate the viability and morphological changes induced by the YCD-medicated rat serum on rotenone-treated SH-SY5Y cells. Apoptosis was assessed by Flow cytometry. Immunofluorescence staining assessed the microtubule-associated protein 2 (MAP2) level. Enzyme-linked immunosorbent assay (ELISA) was employed to quantify the concentrations of inflammatory mediators interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Also, reactive oxygen species (ROS) and superoxide dismutase (SOD) levels were determined. Western Blotting measured the expression of total and phospho-p38 MAPK (p-p38). Results: This study identified 65 active components in YCD, which were found to target 801 specific genes. By screening, 63 potential core targets were identified from a pool of 172 overlapping targets between PD and YCD. These targets were examined by GO and KEGG analyses revealing their substantial correlation to MAPK, PI3K-Akt signaling pathways, positively controlling protein phosphorylation, and pathways of neurodegenerative diseases. SH-SY5Y cells were treated with 2 µM rotenone for 48 h, which reduced cell viability to 50 %, and reduced MAP2 expression, increased the rate of apoptosis, oxidative stress, inflammation, and p-p38 expressions. YCD-medicated rat serum significantly improved the viability, reduced the apoptosis rate, and increased the MAP2 expression. YCD-medicated serum increased SOD, reduced ROS and suppressed IL-6, IL-1ß and TNF-α levels, thus inhibiting oxidative stress and inflammation in rotenone-treated SH-SY5Y cells. Moreover, YCD-medicated serum substantially lowered the p-p38 expression induced by rotenone. SB203580, a specific inhibitor of p38 MAPK, could also inhibit the p-p38 expression, apoptosis, and restore morphological damage of cells, also improve inflammation and oxidative stress. Conclusion: YCD enhanced cell viability and reduced apoptosis rate, inflammation, and oxidative stress in vitro. These beneficial effects could potentially involve the suppression of p38 pathway and suppressed the phosphorylation of p38 MAPK.

Neoadjuvant inetetamab and pertuzumab with taxanes and carboplatin (TCbIP) In locally advanced HER2-positive breast cancer: a prospective cohort study with propensity-matched analysis.

BACKGROUND: Inetetamab is the first domestically developed innovative anti-HER2 monoclonal antibody in China, proven effective and safe in HER2-positive advanced breast cancer. However, its efficacy and safety in neoadjuvant treatment of HER2-positive locally advanced breast cancer (LABC) remain to be validated. METHODS: This prospective cohort study aimed to evaluate the efficacy and safety of inetetamab combined with pertuzumab, taxanes, and carboplatin (TCbIP) in neoadjuvant therapy for HER2-positive LABC, comparing it to data from patients treated with the TCbHP regimen (trastuzumab combined with pertuzumab, taxanes, and carboplatin) using propensity score matching (PSM). The primary endpoint was total pathological complete response (tpCR). Adverse events (AEs), objective response rate (ORR), and near-pCR were key secondary endpoints. RESULTS: Forty-four patients with clinical stage IIA-IIIC HER2-positive LABC were prospectively enrolled and treated with the TCbIP regimen. The tpCR rate among 28 patients who completed surgery was 60.7%, comparable to and slightly higher than the TCbHP group in PSM (60.7% vs. 53.6%, P = 0.510). The ORR was 96.4%, and the DCR reached 100.0%. The most common ≥ grade 3 AE was neutropenia (21.4% vs. 11.9%, P = 0.350). No significant reduction in left ventricular ejection fraction was observed, and no patient withdrew from treatment due to AEs. CONCLUSION: Neoadjuvant therapy with TCbIP showed good efficacy and safety in patients with HER2-positive LABC and might be another promising option for neoadjuvant treatment. TRIAL REGISTRATION: NCT05749016 (registration date: Nov 01, 2021).

Indium oxide-based Z-scheme hollow core-shell heterostructure with rich sulfur-vacancy for highly efficient light-driven splitting of water to produce clean energy.

Crafting an inorganic semiconductor heterojunction with defect engineering and morphology modulation is a strategic approach to produce clean energy by the highly efficient light-driven splitting of water. In this paper, a novel Z-scheme sulfur-vacancy containing Zn3In2S6 (Vs-Zn3In2S6) nanosheets/In2O3 hollow hexagonal prisms heterostructrue (Vs-ZIS6INO) was firstly constructed by an oil bath method, in which Vs-Zn3In2S6 nanosheets grew on the surfaces of In2O3 hollow hexagonal prisms to form a hollow core-shell structure. The obtained Vs-ZIS6INO heterostructrue exhibited much enhanced activity of the production of H2 and H2O2 by the light-driven water splitting. In particular, under visible light irradiation (λ > 420 nm), the rate of generation of H2 of Vs-ZIS6INO sample containing 30 wt% Vs-Zn3In2S6 (30Vs-ZIS6INO) could reach 3721 µmol g-1h-1, which was 87 and 6 times higher than those of Zn3In2S6 (43 µmol g-1h-1) and Vs-Zn3In2S6 (586 µmol g-1h-1), respectively. Meanwhile, 30Vs-ZIS6INO could exhibit the rate of H2O2 production of 483 µmol g-1h-1 through the dual pathways of indirect 2e- oxygen reduction (ORR) and water oxidation (WOR) without adding any sacrifice agents, far exceeding In2O3 (7 µmol g-1h-1) and Vs-Zn3In2S6 (58 µmol g-1h-1). The excellent photocatalytic activities of H2 and H2O2 generations of Vs-ZIS6INO sample might result from the synergistic effect of the sulfur vacancy, hollow core-shell structure, and Z-scheme heterostructure, which accelerated the electron delocalization, enhanced the absorption and conversion of solar energy, reduced the carrier diffusion distance, and ensured high REDOX ability. In addition, the possible photocatalytic mechanisms for the production of H2 and H2O2 were discussed in detail. This study provided a new idea and reference for constructing the novel and efficient inorganic semiconductor heterostructures by coordinating vacancy defect and morphology design to adequately utilize water splitting for the production of clean energy.

fosA11, a novel chromosomal-encoded fosfomycin resistance gene identified in Providencia rettgeri.

This study investigated resistance genes corresponding to the fosfomycin resistance phenotype in clinical isolate Providencia rettgeri W986, as well as characterizing the enzymatic activity of FosA11 and the genetic environment. Antimicrobial susceptibility testing was performed using the agar microdilution method based on the Clinical and Laboratory Standards Institute guidelines. The whole genomic sequence of Providencia rettgeri W986 was obtained using Illumina sequencing and the PacBio platform. The fosA-11 gene was amplified by PCR and cloned into the pUCP20 vector. The recombinant strain pCold1-fosA11-BL21 was expressed to extract the target protein, and absorbance photometry was applied for enzymatic parameter determination. Minimal inhibitory concentration (MIC) tests showed that W986 conferred fosfomycin resistance and was inhibited by phosphonoformate, thereby indicating the presence of a FosA protein. A novel resistance gene designated as fosA11 was identified by whole-genome sequencing and bioinformatics analysis, and it shared 54.41%-64.23% amino acid identity with known FosA proteins. Cloning fosA11 into Escherichia coli obtained a significant increase (32-fold) in the MIC with fosfomycin. Determination of the enzyme kinetics showed that FosA11 had a high catalytic effect on fosfomycin, with Km = 18 ± 4 and Kcat = 56.1 ± 3.2. We also found that fosA11 was located on the chromosome, but the difference in the GC content between the chromosome and fosA11 was dubious, and thus further investigation is required. In this study, we identified and characterized a novel fosfomycin inactivation enzyme called FosA11. The origin and prevalence of the fosA11 gene in other bacteria require further investigation.IMPORTANCEFosfomycin is an effective antimicrobial agent against Enterobacterales strains. However, the resistance rate of fosfomycin is increasing year by year. Therefore, it is necessary to study the deep molecular mechanism of bacterial resistance to fosfomycin. We identified a novel chromosomal fosfomycin glutathione S-transferase, FosA11 from Providencia rettgeri, which shares a very low identity (54.41%-64.23%) with the previously known FosA and exhibits highly efficient catalytic ability against fosfomycin. Analysis of the genetic context and origin of fosA11 displays that the gene and its surrounding environments are widely conserved in Providencia and no mobile elements are discovered, implying that FosA11 may be broadly important in the natural resistance to fosfomycin of Providencia species.

ZeXieYin Formula alleviates TMAO-induced cognitive impairment by restoring synaptic plasticity damage.

ETHNOPHARMACOLOGICAL RELEVANCE: Treating cognitive impairment is a challenging and necessary research topic. ZeXieYin Formula (ZXYF), is a traditional herbal formula documented in the book of HuangDiNeiJing. Our previous studies demonstrated the ameliorative effects of ZXYF on atherosclerosis by reducing the plasma trimethylamine oxide (TMAO) level. TMAO is a metabolite of gut microorganisms, our recent research found that the increasing level of TMAO may have adverse effects on cognitive functions. AIM OF THE STUDY: Our study mainly focused on the therapeutic effects of ZXYF on TMAO-induced cognitive impairment in mice and explored its underlying mechanism. MATERIALS AND METHODS: After the TMAO-induced cognitive impairment mice models were established, we applied behavioral tests to estimate the learning and memory ability of the ZXYF intervention mice. Liquid chromatography-mass spectrometry (LC-MS) was used to quantify the TMAO levels in plasma and the brain. The effects of ZXYF on the hippocampal synaptic structure and the neurons were observed by transmission electron microscopy (TEM) and Nissl staining. In addition, western-blotting (WB) and immunohistochemical (IHC) staining were used to detect the level of related proteins in the synaptic structure and further verify the changes in synaptic plasticity and the mTOR pathway after ZXYF administration. RESULTS: Behavioral tests showed that the learning and memory ability of mice impaired after a period of TMAO intervention and ZXYF could alleviate these changes. A series of results showed that ZXYF partly restored the damage of hippocampal synapse and neurons in TMAO-induced mice, at the same time, the expression of synapse-related proteins and mTOR pathway-related proteins were significantly regulated compared with the damage caused by TMAO. CONCLUSION: ZXYF could alleviate TMAO-induced cognitive impairment by improving synaptic function, reducing neuronal damage, regulating synapse-associated proteins, and regulating the mTOR signaling pathway.

Dietary choline metabolite TMAO impairs cognitive function and induces hippocampal synaptic plasticity declining through the mTOR/P70S6K/4EBP1 pathway.

Mild cognitive impairment (MCI) is an intermediate state between "healthy" and "dementia", which affects memory and cognitive function. Timely intervention and treatment of MCI can effectively prevent it from developing into an incurable neurodegenerative disease. Lifestyle factors, such as dietary habits, were highlighted as risk factors for MCI. The effect of a high-choline diet on cognitive function is contentious. In this study, we focus our attention on the choline metabolite trimethylamine-oxide (TMAO), an acknowledged pathogenic molecule of cardiovascular disease (CVD). With recent studies indicating that TMAO also plays a potential role in the central nervous system (CNS), we aim to explore the effect of TMAO on synaptic plasticity in the hippocampus, the basic structure of studying and memory. Using various hippocampal-dependent spatial references or working memory-related behavioral texts, we found that TMAO treatment caused both long-term memory (LTM) and short-term memory (STM) deficits in vivo. Simultaneously, the plasm and whole brain levels of choline and TMAO were measured by employing liquid phase mass spectrometry (LC/MS). Furthermore, the effects of TMAO on the hippocampus were further explored by applying Nissl staining and transmission electron microscopy (TEM). Moreover, the expression of synaptic plasticity-related proteins, including synaptophysin (SYN), postsynaptic density protein95 (PSD95), and N-methyl-aspartate receptor (NMDAR), was examined by western blotting and immunohistochemical (IHC). The results showed that TMAO treatment contributes to neuron loss, synapse ultrastructure alteration, and synaptic plasticity impairments. In mechanism, the mammalian target of rapamycin (mTOR) regulates synaptic function, and the activation of the mTOR signaling pathway was observed in TMAO groups. In conclusion, this study confirmed that the choline metabolite TMAO can induce hippocampal-dependent learning and memory ability impairment with synaptic plasticity deficits by activating the mTOR signaling pathway. The effects of choline metabolites on cognitive function may provide a theoretical basis for establishing the daily reference intakes (DRIs) of choline.

Single-cell RNA landscape of the special fiber initiation process in Bombax ceiba.

As a new source of natural fibers, the Bombax ceiba tree can provide thin, light, extremely soft and warm fiber material for the textile industry. Natural fibers are an ideal model system for studying cell growth and differentiation, but the molecular mechanisms that regulate fiber initiation are not fully understood. In B. ceiba, we found that fiber cells differentiate from the epidermis of the inner ovary wall. Each initiated cell then divides into a cluster of fiber cells that eventually develop into mature fibers, a process very different from the classical fiber initiation process of cotton. We used high-throughput single-cell RNA sequencing (scRNA-seq) to examine the special characteristics of fiber initiation in B. ceiba. A total of 15 567 high-quality cells were identified from the inner wall of the B. ceiba ovary, and 347 potential marker genes for fiber initiation cell types were identified. Two major cell types, initiated fiber cells and epidermal cells, were identified and verified by RNA in situ hybridization. A developmental trajectory analysis was used to reconstruct the process of fiber cell differentiation in B. ceiba. Comparative analysis of scRNA-seq data from B. ceiba and cotton (Gossypium hirsutum) confirmed that the additional cell division process in B. ceiba is a novel species-specific mechanism for fiber cell development. Candidate genes and key regulators that may contribute to fiber cell differentiation and division in B. ceiba were identified. This work reveals gene expression signatures during B. ceiba fiber initiation at a single-cell resolution, providing a new strategy and viewpoint for investigation of natural fiber cell differentiation and development.

Comparative proteomic analysis identified proteins and the phenylpropanoid biosynthesis pathway involved in the response to ABA treatment in cotton fiber development.

Abscisic acid (ABA) is a plant hormone that plays an important role in cotton fiber development. In this study, the physiological changes and proteomic profiles of cotton (Gossypium hirsutum) ovules were analyzed after 20 days of ABA or ABA inhibitor (ABAI) treatment. The results showed that compared to the control (CK), the fiber length was significantly decreased under ABA treatment and increased under ABAI treatment. Using a tandem mass tags-based quantitative technique, the proteomes of cotton ovules were comprehensively analyzed. A total of 7321 proteins were identified, of which 365 and 69 differentially accumulated proteins (DAPs) were identified in ABA versus CK and ABAI versus CK, respectively. Specifically, 345 and 20 DAPs were up- and down-regulated in the ABA group, and 65 and 4 DAPs were up- and down-regulated in the ABAI group, respectively. The DAPs in the ABA group were mainly enriched in the biosynthesis of secondary metabolites, phenylpropanoid biosynthesis and flavonoid secondary metabolism, whereas the DAPs in the ABAI group were mainly enriched in the indole alkaloid biosynthesis and phenylpropanoid biosynthesis pathways. Moreover, 9 proteins involved in phenylpropanoid biosynthesis were upregulated after ABA treatment, suggesting that this pathway might play important roles in the response to ABA, and 3 auxin-related proteins were upregulated, indicating that auxin might participate in the regulation of fiber development under ABAI treatment.

Subjective Exercise Experience and Group Cohesion among Chinese Participating in Square Dance: A Moderated Mediation Model of Years of Participation and Gender.

(1) Background: This study aimed to explore the relationship between years of participation, subjective exercise experience, and group cohesion among gender-specific square dance practitioners. (2) Methods: The Subjective Exercise Experience Questionnaire (SEEQ) and Group Environment Questionnaire (GEQ) were used to evaluate Subjective Exercise Experience (SEE) and group cohesion (GC). An analysis was conducted on 130 Chinese (63 males and 67 females) using multiple group analysis within a structural equation model. (3) Results: (a) The positive aspects of Subjective Exercise Experience (SEE) and Positive Well-Being (PWB), had a strongly positive effect on GC in both groups. The negative aspects of SEE, Psychological Fatigue (PF), and Psychological Distress (PD), had negative effects on GC. (b) Only for the male group was there an indirect effect of participation years on the association between SEE and GC in the model (a × b = 0.062, 95% CI [0.001, 0.181]; standard error (SE) = 0.062, p = 0.048). (c) The significant differences between paths coefficients were noticed in the association of years of participation with SEE (t = -2.043) and GC (t = -1.962). (4) Conclusion: Based on these results, gender differences in terms of the partial mediating role of adherence in the relationship of SEE and GC were presented for future research, fitness popularization, and society.