Physiological, molecular, and environmental insights into plant nitrogen uptake, and metabolism under abiotic stresses.

Nitrogen (N) as an inorganic macronutrient is inevitable for plant growth, development, and biomass production. Many external factors and stresses, such as acidity, alkalinity, salinity, temperature, oxygen, and rainfall, affect N uptake and metabolism in plants. The uptake of ammonium (NH4 +) and nitrate (NO3 -) in plants mainly depends on soil properties. Under the sufficient availability of NO3 - (>1 mM), low-affinity transport system is activated by gene network NRT1, and under low NO3 - availability (<1 mM), high-affinity transport system starts functioning encoded by NRT2 family of genes. Further, under limited N supply due to edaphic and climatic factors, higher expression of the AtNRT2.4 and AtNRT2.5T genes of the NRT2 family occur and are considered as N remobilizing genes. The NH4 + ion is the final form of N assimilated by cells mediated through the key enzymes glutamine synthetase and glutamate synthase. The WRKY1 is a major transcription factor of the N regulation network in plants. However, the transcriptome and metabolite profiles show variations in N assimilation metabolites, including glycine, glutamine, and aspartate, under abiotic stresses. The overexpression of NO3 - transporters (OsNRT2.3a and OsNRT1.1b) can significantly improve the biomass and yield of various crops. Altering the expression levels of genes could be a valuable tool to improve N metabolism under the challenging conditions of soil and environment, such as unfavorable temperature, drought, salinity, heavy metals, and nutrient stress.

Learning With Noisy Labels Over Imbalanced Subpopulations.

Learning with noisy labels (LNL) has attracted significant attention from the research community. Many recent LNL methods rely on the assumption that clean samples tend to have a "small loss." However, this assumption often fails to generalize to some real-world cases with imbalanced subpopulations, that is, training subpopulations that vary in sample size or recognition difficulty. Therefore, recent LNL methods face the risk of misclassifying those "informative" samples (e.g., hard samples or samples in the tail subpopulations) into noisy samples, leading to poor generalization performance. To address this issue, we propose a novel LNL method to deal with noisy labels and imbalanced subpopulations simultaneously. It first leverages sample correlation to estimate samples' clean probabilities for label correction and then utilizes corrected labels for distributionally robust optimization (DRO) to further improve the robustness. Specifically, in contrast to previous works using classification loss as the selection criterion, we introduce a feature-based metric that takes the sample correlation into account for estimating samples' clean probabilities. Then, we refurbish the noisy labels using the estimated clean probabilities and the pseudo-labels from the model's predictions. With refurbished labels, we use DRO to train the model to be robust to subpopulation imbalance. Extensive experiments on a wide range of benchmarks demonstrate that our technique can consistently improve state-of-the-art (SOTA) robust learning paradigms against noisy labels, especially when encountering imbalanced subpopulations. We provide our code in https://github.com/chenmc1996/LNL-IS.

Deep Trans-Omic Network Fusion for Molecular Mechanism of Alzheimer's Disease.

Background: There are various molecular hypotheses regarding Alzheimer's disease (AD) like amyloid deposition, tau propagation, neuroinflammation, and synaptic dysfunction. However, detailed molecular mechanism underlying AD remains elusive. In addition, genetic contribution of these molecular hypothesis is not yet established despite the high heritability of AD. Objective: The study aims to enable the discovery of functionally connected multi-omic features through novel integration of multi-omic data and prior functional interactions. Methods: We propose a new deep learning model MoFNet with improved interpretability to investigate the AD molecular mechanism and its upstream genetic contributors. MoFNet integrates multi-omic data with prior functional interactions between SNPs, genes, and proteins, and for the first time models the dynamic information flow from DNA to RNA and proteins. Results: When evaluated using the ROS/MAP cohort, MoFNet outperformed other competing methods in prediction performance. It identified SNPs, genes, and proteins with significantly more prior functional interactions, resulting in three multi-omic subnetworks. SNP-gene pairs identified by MoFNet were mostly eQTLs specific to frontal cortex tissue where gene/protein data was collected. These molecular subnetworks are enriched in innate immune system, clearance of misfolded proteins, and neurotransmitter release respectively. We validated most findings in an independent dataset. One multi-omic subnetwork consists exclusively of core members of SNARE complex, a key mediator of synaptic vesicle fusion and neurotransmitter transportation. Conclusions: Our results suggest that MoFNet is effective in improving classification accuracy and in identifying multi-omic markers for AD with improved interpretability. Multi-omic subnetworks identified by MoFNet provided insights of AD molecular mechanism with improved details.

Full-length transcriptome profiling of Acanthopanax gracilistylus provides new insight into the kaurenoic acid biosynthesis pathway.

Acanthopanax gracilistylus is a deciduous plant in the family Araliaceae, which is commonly used in Chinese herbal medicine, as the root bark has functions of nourishing the liver and kidneys, removing dampness and expelling wind, and strengthening the bones and tendons. Kaurenoic acid (KA) is the main effective substance in the root bark of A. gracilistylus with strong anti-inflammatory effects. To elucidate the KA biosynthesis pathway, second-generation (DNA nanoball) and third-generation (Pacific Biosciences) sequencing were performed to analyze the transcriptomes of the A. gracilistylus leaves, roots, and stems. Among the total 505,880 isoforms, 408,954 were annotated by seven major databases. Sixty isoforms with complete open reading frames encoding 11 key enzymes involved in the KA biosynthesis pathway were identified. Correlation analysis between isoform expression and KA content identified a total of eight key genes. Six key enzyme genes involved in KA biosynthesis were validated by real-time quantitative polymerase chain reaction. Based on the sequence analysis, the spatial structure of ent-kaurene oxidase was modeled, which plays roles in the three continuous oxidations steps of KA biosynthesis. This study greatly enriches the transcriptome data of A. gracilistylus and facilitates further analysis of the function and regulation mechanism of key enzymes in the KA biosynthesis pathway. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-024-01436-7.

A signaling cascade mediating fruit trait development via phosphorylation-modulated nuclear accumulation of JAZ repressor.

It is generally accepted that jasmonate-ZIM domain (JAZ) repressors act to mediate jasmonate (JA) signaling via CORONATINE-INSENSITIVE1 (COI1)-mediated degradation. Here, we report a cryptic signaling cascade where a JAZ repressor, FvJAZ12, mediates multiple signaling inputs via phosphorylation-modulated subcellular translocation rather than the COI1-mediated degradation mechanism in strawberry (Fragaria vesca). FvJAZ12 acts to regulate flavor metabolism and defense response, and was found to be the target of FvMPK6, a mitogen-activated protein kinase that is capable of responding to multiple signal stimuli. FvMPK6 phosphorylates FvJAZ12 at the amino acid residues S179 and T183 adjacent to the PY residues, thereby attenuating its nuclear accumulation and relieving its repression for FvMYC2, which acts to control the expression of lipoxygenase 3 (FvLOX3), an important gene involved in JA biosynthesis and a diverse array of cellular metabolisms. Our data reveal a previously unreported mechanism for JA signaling and decipher a signaling cascade that links multiple signaling inputs with fruit trait development.

Synthesis of Spiro Polycyclic N-Heterocycles and Indolecarbazoles via Merging Oxidative Coupling and Cascade Palladium-Catalyzed Intramolecular Oxidative Cyclization.

We report a step-economic strategy for the direct synthesis of spiro polycyclic N-heterocycles and indolecarbazole-fused naphthoquinones by merging oxidative coupling and cascade palladium-catalyzed intramolecular oxidative cyclization. In the protocol, bi-indolylnaphthoquinones were first synthesized by oxidative coupling of indoles and naphthoquinones. Subsequent cascade palladium-catalyzed intramolecular oxidative cyclization of bi-indolylnaphthoquinones gave spiro polycyclic N-heterocycles and indolecarbazoles. The intramolecular oxidative cyclization approach could also be realized by the presence or absence of iron catalysts under standard conditions. This protocol is featured with moderate to excellent yields, a wide substrate scope, and divergent structures of products.

Efficiency of Protective Interventions on Irinotecan-Induced Diarrhea: A Systematic Review and Meta-Analysis.

BACKGROUND: Irinotecan is widely used in the treatment of various solid tumors, but the adverse effects from it, especially diarrhea, limit its use. Several clinical trials of prophylactic treatment of irinotecan-induced diarrhea (IID) have been ongoing, and some of the data are controversial. This encouraged us to conduct a meta-analysis of the effects of interventions on preventing IID. METHOD: This systematic review was conducted based on the PRISMA statement. We performed literature searches from PubMed, Web of Science, Embase, and Cochrane Library. The number registered in PROSPERO is CRD42022368633. After searching 1034 articles in the database and references, 8 studies were included in this meta-analysis. RESULT: The RR of high-grade diarrhea and all-grade diarrhea were 0.31 (I2 = 51%, 95% CI: 0.14-0.69; P = .004) and .76 (I2 = 65%, 95% CI: 0.62-0.93; P < .008) respectively, thus the use of intervention measures for preventing IID is effective, and the risk reduction of high-grade diarrhea was more significant. Subgroup analysis revealed that the monotherapy group (RR: 0.48, 95% CI: 0.21-1.13, I2 = 0%) and combination therapy group (RR: 0.14, 95% CI: 0.06-0.32, I2 = 0%) in the risk of high-grade diarrhea had no significant heterogeneity within the groups, and traditional herbal medicines (Kampo medicine Hangeshashin-to, PHY906 and hot ironing with Moxa Salt Packet on Tianshu and Shangjuxu) were effective preventive measures (RR:0.20, 95% CI: 0.07-0.60, I2 = 0%). The Jadad scores for traditional herbal medicines studies were 3, and the follow-up duration was only 2 to 6 weeks. CONCLUSION: This systematic review and meta-analysis suggest that preventive treatments significantly reduced the risk of high-grade and all-grade diarrhea, confirming the efficacy in the incidence and severity of IID, among which traditional herbal medicines (baicalin-containing) provided a protective effect in reducing the severity of IID. However, the traditional herbal medicines studies were of low quality. Combined irinotecan therapy can obtain better preventive effects than monotherapy of IID. These would be helpful for the prevention of IID in clinical practice.

The genetic regulatory architecture and epigenomic basis for age-related changes in rattlesnake venom.

Developmental phenotypic changes can evolve under selection imposed by age- and size-related ecological differences. Many of these changes occur through programmed alterations to gene expression patterns, but the molecular mechanisms and gene-regulatory networks underlying these adaptive changes remain poorly understood. Many venomous snakes, including the eastern diamondback rattlesnake (Crotalus adamanteus), undergo correlated changes in diet and venom expression as snakes grow larger with age, providing models for identifying mechanisms of timed expression changes that underlie adaptive life history traits. By combining a highly contiguous, chromosome-level genome assembly with measures of expression, chromatin accessibility, and histone modifications, we identified cis-regulatory elements and trans-regulatory factors controlling venom ontogeny in the venom glands of C. adamanteus. Ontogenetic expression changes were significantly correlated with epigenomic changes within genes, immediately adjacent to genes (e.g., promoters), and more distant from genes (e.g., enhancers). We identified 37 candidate transcription factors (TFs), with the vast majority being up-regulated in adults. The ontogenetic change is largely driven by an increase in the expression of TFs associated with growth signaling, transcriptional activation, and circadian rhythm/biological timing systems in adults with corresponding epigenomic changes near the differentially expressed venom genes. However, both expression activation and repression contributed to the composition of both adult and juvenile venoms, demonstrating the complexity and potential evolvability of gene regulation for this trait. Overall, given that age-based trait variation is common across the tree of life, we provide a framework for understanding gene-regulatory-network-driven life-history evolution more broadly.

Strong Interactions between Au Nanoparticles and BiVO4 Photoanode Boosts Hole Extraction for Photoelectrochemical Water Splitting.

Strong metal-support interaction (SMSI) is widely proposed as a key factor in tuning catalytic performances. Herein, the classical SMSI between Au nanoparticles (NPs) and BiVO4 (BVO) supports (Au/BVO-SMSI) is discovered and used innovatively for photoelectrochemical (PEC) water splitting. Owing to the SMSI, the electrons transfer from V4+ to Au NPs, leading to the formation of electron-rich Au species (Auδ-) and strong electronic interaction (i.e., Auδ--Ov-V4+), which readily contributes to extract photogenerated holes and promote charge separation. Benefitted from the SMSI effect, the as-prepared Au/BVO-SMSI photoanode exhibits a superior photocurrent density of 6.25 mA cm-2 at 1.23 V versus the reversible hydrogen electrode after the deposition of FeOOH/NiOOH cocatalysts. This work provides a pioneering view for extending SMSI effect to bimetal oxide supports for PEC water splitting, and guides the interfacial electronic and geometric structure modulation of photoanodes consisting of metal NPs and reducible oxides for improved solar energy conversion efficiency.

Antigen-Clustered Nanovaccine Achieves Long-Term Tumor Remission by Promoting B/CD 4 T Cell Crosstalk.

Current cancer vaccines using T cell epitopes activate antitumor T cell immunity through dendritic cell/macrophage-mediated antigen presentation, but they lack the ability to promote B/CD4 T cell crosstalk, limiting their anticancer efficacy. We developed antigen-clustered nanovaccine (ACNVax) to achieve long-term tumor remission by promoting B/CD4 T cell crosstalk. The topographic features of ACNVax were achieved using an iron nanoparticle core attached with an optimal number of gold nanoparticles, where the clusters of HER2 B/CD4 T cell epitopes were conjugated on the gold surface with an optimal intercluster distance of 5-10 nm. ACNVax effectively trafficked to lymph nodes and cross-linked with BCR, which are essential for stimulating B cell antigen presentation-mediated B/CD4 T cell crosstalk in vitro and in vivo. ACNVax, combined with anti-PD-1, achieved long-term tumor remission (>200 days) with 80% complete response in mice with HER2+ breast cancer. ACNVax not only remodeled the tumor immune microenvironment but also induced a long-term immune memory, as evidenced by complete rejection of tumor rechallenge and a high level of antigen-specific memory B, CD4, and CD8 cells in mice (>200 days). This study provides a cancer vaccine design strategy, using B/CD4 T cell epitopes in an antigen clustered topography, to achieve long-term durable anticancer efficacy through promoting B/CD4 T cell crosstalk.

[Occurrence Characteristic and Risk Assessment of Microplastics in Sishui River (Xingyang Section)].

Urban rivers are the main receptors and transporters of microplastic pollution. Understanding the occurrence and environmental risk of microplastics in urban rivers can provide theoretical basis for further control of microplastic pollution. The Sishui River, a tributary of the Yellow River, was selected as the research object. A total of nine water samples were collected from sewage outlets of the Sishui River (Xingyang section). The microplastics in the collected samples were characterized by their sizes, shapes, and colors using a microscope. It was found that microplastics were mostly in the form of transparent fibers and fragments in the water body of sewage outlets, of which the size below 500 µm was relatively high. In addition, PET and PE polymers were identified as the main types using a laser infrared imager. The correlation analysis showed that there was a significant correlation between the PET and PE, indicating that they were similar in origin. The results of the environmental risk assessment showed that the type of microplastics was the main factor affecting the assessment results, whereas the risk values of six sewage samples containing PVC were high. However, the value of pollution load index revealed a low risk level of pollutants in the study area.

Theoretical study of filtered and amplified PRBS phase modulation for SBS suppression in a 2.5†kW, 10†GHz monolithic fiber amplifier.

We report a theoretical and experimental study on stimulated Brillouin scattering (SBS) suppression in a monolithic fiber amplifier with filtered and amplified pseudo-random binary sequence (PRBS) phase modulation. Theoretically, we use a time-dependent three-wave coupled nonlinear system considering both active fiber and passive fiber to describe the acoustic phonon, laser, and Stokes characteristics in a fiber amplifier. The SBS threshold power after filtered PRBS phase modulation is numerically evaluated to obtain the optimal parameters, and the time-averaged distributions of the counter-pump power, laser power, and Stokes power at different positions along the fiber length of the fiber system are simulated. Also, we established a four-stage fiber amplifier system to verify our theory. The configuration of the fiber amplifier system includes a filtered and amplified PRBS phase-modulated single-frequency fiber laser, a three-stage pre-amplifier, and a counter-pumping main stage, subsequently. 2.5 kW output power with an FWHM linewidth of 9.63 GHz is accomplished by a domestic ytterbium-doped double-clad fiber with core/cladding diameters of 20.2/400  µm. The reflectivity of the main stage is 0.049‰ at the maximum output power, which indicates the proposed architecture is under the SBS threshold. The experiments verify the accuracy of the theoretical model, which provides a reliable reference for evaluating the SBS suppression capability of the high-power narrow-linewidth fiber amplifier phase modulated by the filtered and amplified PRBS signal.

ZmARF1 positively regulates low phosphorus stress tolerance via modulating lateral root development in maize.

Phosphorus (P) deficiency is one of the most critical factors for plant growth and productivity, including its inhibition of lateral root initiation. Auxin response factors (ARFs) play crucial roles in root development via auxin signaling mediated by genetic pathways. In this study, we found that the transcription factor ZmARF1 was associated with low inorganic phosphate (Pi) stress-related traits in maize. This superior root morphology and greater phosphate stress tolerance could be ascribed to the overexpression of ZmARF1. The knock out mutant zmarf1 had shorter primary roots, fewer root tip number, and lower root volume and surface area. Transcriptomic data indicate that ZmLBD1, a direct downstream target gene, is involved in lateral root development, which enhances phosphate starvation tolerance. A transcriptional activation assay revealed that ZmARF1 specifically binds to the GC-box motif in the promoter of ZmLBD1 and activates its expression. Moreover, ZmARF1 positively regulates the expression of ZmPHR1, ZmPHT1;2, and ZmPHO2, which are key transporters of Pi in maize. We propose that ZmARF1 promotes the transcription of ZmLBD1 to modulate lateral root development and Pi-starvation induced (PSI) genes to regulate phosphate mobilization and homeostasis under phosphorus starvation. In addition, ZmERF2 specifically binds to the ABRE motif of the promoter of ZmARF1 and represses its expression. Collectively, the findings of this study revealed that ZmARF1 is a pivotal factor that modulates root development and confers low-Pi stress tolerance through the transcriptional regulation of the biological function of ZmLBD1 and the expression of key Pi transport proteins.

Metformin versus metformin plus pioglitazone on gonadal and metabolic profiles in normal-weight women with polycystic ovary syndrome: a single-center, open-labeled prospective randomized controlled trial.

OBJECTIVE: To investigate the effects of metformin (MET) monotherapy and pioglitazone plus MET (PIOMET) therapy on gonadal and metabolic profiles in normal-weight women with polycystic ovary syndrome (PCOS). METHODS: Sixty normal-weight women with PCOS were recruited between January and September 2022 at the Shengjing Hospital of China Medical University. They were randomly assigned to the MET or PIOMET groups for 12 weeks of MET monotherapy or PIOMET therapy. Anthropometric measurements, menstrual cycle changes, gonadal profiles, and the oral glucose insulin-releasing test (OGIRT) were performed at baseline and after the 12-week treatment. RESULTS: Thirty-six participants completed the trial. MET and PIOMET therapies improved menstrual cycles after the 4- and 12-week treatments; however, there was no statistical difference between the two groups. PIOMET therapy improved luteinizing hormone (LH), luteinizing hormone/follicle stimulating hormone (LH/FSH) ratio, and free androgen index (FAI) levels after the 4-week treatment, whereas MET monotherapy only improved total testosterone (TT) levels compared to baseline (P < 0.05). Both MET and PIOMET therapies improved TT and anti-Mullerian hormone (AMH) levels after the 12-week treatment (P < 0.05). In addition, only PIOMET therapy significantly improved sex hormone-binding globulin (SHBG), FAI, and androstenedione (AND) levels than the baseline (P < 0.05). PIOMET therapy improved SHBG and AMH levels more effectively than MET monotherapy (P < 0.05). Furthermore, PIOMET treatment was more effective in improving blood glucose levels at 120 and 180 min of OGIRT compared to MET monotherapy (P < 0.05). CONCLUSIONS: In normal-weight women with PCOS, PIOMET treatment may have more benefits in improving SHBG, AMH, and postprandial glucose levels than MET monotherapy, and did not affect weight. However, the study findings need to be confirmed in PCOS study populations with larger sample sizes.

Predictive performance of the variation rate of the driving pressure on the outcome of invasive mechanical ventilation in patients with acute respiratory distress syndrome.

PURPOSE: To assess the value of the driving pressure variation rate (ΔP%) in predicting the outcome of weaning from invasive mechanical ventilation in patients with acute respiratory distress syndrome. METHODS: In this case-control study, a total of 35 patients with moderate-severe acute respiratory distress syndrome were admitted to the intensive care unit between January 2022 and December 2022 and received invasive mechanical ventilation for at least 48 h were enrolled. Patients were divided into successful weaning group and failed weaning group depending on whether they could be removed from ventilator support within 14 days. Outcome measures including driving pressure, PaO2:FiO2, and positive end-expiratory pressure, etc. were assessed every 24 h from day 0 to day 14 until successful weaning was achieved. The measurement data of non-normal distribution were presented as median (Q1, Q3), and the differences between groups were compared by Wilcoxon rank sum test. And categorical data use the Chi-square test or Fisher's exact test to compare. The predictive value of ΔP% in predicting the outcome of weaning from the ventilator was analyzed using receiver operating characteristic curves. RESULTS: Of the total 35 patients included in the study, 17 were successful vs. 18 failed in weaning from a ventilator after 14 days of mechanical ventilation. The cut-off values of the median ΔP% measured by Operator 1 vs. Operator 2 in the first 4 days were ≥ 4.17% and 4.55%, respectively (p < 0.001), with the area under curve of 0.804 (sensitivity of 88.2%, specificity of 64.7%) and 0.770 (sensitivity of 88.2%, specificity of 64.7%), respectively. There was a significant difference in mechanical ventilation duration between the successful weaning group and the failure weaning group (8 (6, 13) vs. 12 (7.5, 17.3), p = 0.043). The incidence of ventilator-associated pneumonia in the successful weaning group was significantly lower than in the failed weaning group (0.2‰ vs. 2.3‰, p = 0.001). There was a significant difference noted between these 2 groups in the 28-day mortality (11.8% vs. 66.7%, p = 0.003). CONCLUSION: The median ΔP% in the first 4 days of mechanical ventilation showed good predictive performance in predicting the outcome of weaning from mechanical ventilation within 14 days. Further study is needed to confirm this finding.

Molecular Mechanisms of Intracellular Delivery of Nanoparticles Monitored by an Enzyme-Induced Proximity Labeling.

Achieving increasingly finely targeted drug delivery to organs, tissues, cells, and even to intracellular biomacromolecules is one of the core goals of nanomedicines. As the delivery destination is refined to cellular and subcellular targets, it is essential to explore the delivery of nanomedicines at the molecular level. However, due to the lack of technical methods, the molecular mechanism of the intracellular delivery of nanomedicines remains unclear to date. Here, we develop an enzyme-induced proximity labeling technology in nanoparticles (nano-EPL) for the real-time monitoring of proteins that interact with intracellular nanomedicines. Poly(lactic-co-glycolic acid) nanoparticles coupled with horseradish peroxidase (HRP) were fabricated as a model (HRP(+)-PNPs) to evaluate the molecular mechanism of nano delivery in macrophages. By adding the labeling probe biotin-phenol and the catalytic substrate H2O2 at different time points in cellular delivery, nano-EPL technology was validated for the real-time in situ labeling of proteins interacting with nanoparticles. Nano-EPL achieves the dynamic molecular profiling of 740 proteins to map the intracellular delivery of HRP (+)-PNPs in macrophages over time. Based on dynamic clustering analysis of these proteins, we further discovered that different organelles, including endosomes, lysosomes, the endoplasmic reticulum, and the Golgi apparatus, are involved in delivery with distinct participation timelines. More importantly, the engagement of these organelles differentially affects the drug delivery efficiency, reflecting the spatial-temporal heterogeneity of nano delivery in cells. In summary, these findings highlight a significant methodological advance toward understanding the molecular mechanisms involved in the intracellular delivery of nanomedicines.

Theory of soliton self-frequency shift in silica optical microresonators with a modified Raman response by the Boson peak.

We theoretically study the Raman-induced self-frequency shift of dissipative Kerr soliton in silica optical resonators by taking into consideration the Boson peak. We find that the Boson peak will greatly increase the soliton self-frequency shift and contribute even more than the shift induced by the Lorentzian response for certain pulse durations. We also show that the revised Raman shock time is associated with the pulse width even for a relatively long pulse. Moreover, we demonstrate that the background continuous wave decreases the self-frequency shift of the soliton via the interference with the soliton. Our theoretical and simulated results display excellent agreement with the previous experimental values in the silica-based Kerr-soliton microcomb.

Boosting synergism of chemo- and immuno-therapies via switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis by bisphosphonate coordination lipid nanogranules.

Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted drugs. It is critical to inspire new potential to remodel the value of this classical therapeutic strategy. Here, we fabricate bisphosphonate coordination lipid nanogranules (BC-LNPs) and load paclitaxel (PTX) to boost the chemo- and immuno-therapeutic synergism of cytotoxic drugs. Alendronate in BC-LNPs@PTX, a bisphosphonate to block mevalonate metabolism, works as both the structure and drug constituent in nanogranules, where alendronate coordinated with calcium ions to form the particle core. The synergy of alendronate enhances the efficacy of paclitaxel, suppresses tumor metastasis, and alters the cytotoxic mechanism. Differing from the paclitaxel-induced apoptosis, the involvement of alendronate inhibits the mevalonate metabolism, changes the mitochondrial morphology, disturbs the redox homeostasis, and causes the accumulation of mitochondrial ROS and lethal lipid peroxides (LPO). These factors finally trigger the ferroptosis of tumor cells, an immunogenic cell death mode, which remodels the suppressive tumor immune microenvironment and synergizes with immunotherapy. Therefore, by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis, BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.

Ixazomib-based frontline therapy followed by ixazomib maintenance in frail elderly newly diagnosed with multiple myeloma: a prospective multicenter study.

Background: Frail elderly patients with newly diagnosed multiple myeloma (NDMM) have inferior survival and less benefit from high-dose therapies. This prospective study aimed to investigate the efficacy, safety, and quality of life (QoL) of induction treatment of ixazomib/lenalidomide/dexamethasone (IRd) and ixazomib/pegylated liposomal doxorubicin/dexamethasone (IDd) followed by ixazomib/dexamethasone (Id) maintenance therapy in frail, elderly patients with NDMM. Methods: From July 2019 to December 2021, this non-randomized concurrent controlled clinical study enrolled 120 NDMM patients aged ≥65 years with frailty defined by the International Myeloma Working Group (IMWG) frailty score or Mayo geriatric scoring system. The enrolled patients received 6-8 cycles of IRd or IDd followed by Id maintenance therapy for a minimum of 2 years at the discretion of physicians based on patient's clinical characteristics (chiCTR1900024917). Findings: The median age was 71 years and 55% of the patients were males. The overall response rate (ORR) was 82% and 77%, complete response (CR) rate was 25% and 12% for IRd and IDd groups, respectively. The difference in ORR of the Idd group minus the IRd group was -5.36% (95% CI: -18.9% to 8.19%), indicating that the ORR of the IDd group was neither inferior nor non-inferior to the IRd group. After a median follow-up of 34.3 months, the median progression-free survival (PFS) was 21.6 and 13.9 months, OS was not reached and 29.2 months in IRd and IDd groups, respectively. 28 and 33 patients discontinued induction therapy, 20 and 19 discontinued maintenance therapy in IRd and IDd groups, respectively. Cumulative Grade 3 or higher hematological adverse events (AEs) occurred in 10 of the 60 patients (17%) and non-hematological AEs occurred in 15 of the 60 patients (25%) in the IRd group, while 13 of the 60 patients (22%) and 21 of the 60 patients (35%) in the IDd group. Patients were observed with clinically significant improvement in QoL when compared with that at baseline in both IRd and IDd groups by evaluation per cycle (P < 0.0001). Interpretation: The results demonstrated that compared with IRd regimen, IDd regimen showed no significant advantage, but the survival of the IDd group was shorter than that of the IRd group, indicating an all-oral outpatient triplet regimen with IRd, which has low toxicity and has improved QoL, could be the viable first-line treatment option for frail NDMM patients. Funding: The Young Elite Scientist sponsorship program by bast of Beijing Association for Science and Technology (No. BYESS2023116) and Beijing Medical Award Foundation (No. YXJL-2018-0539-0073).