Programmable melanoma-targeted radio-immunotherapy via fusogenic liposomes functionalized with multivariate-gated aptamer assemblies.

Radio-immunotherapy exploits the immunostimulatory features of ionizing radiation (IR) to enhance antitumor effects and offers emerging opportunities for treating invasive tumor indications such as melanoma. However, insufficient dose deposition and immunosuppressive microenvironment (TME) of solid tumors limit its efficacy. Here we report a programmable sequential therapeutic strategy based on multifunctional fusogenic liposomes (Lip@AUR-ACP-aptPD-L1) to overcome the intrinsic radio-immunotherapeutic resistance of solid tumors. Specifically, fusogenic liposomes are loaded with gold-containing Auranofin (AUR) and inserted with multivariate-gated aptamer assemblies (ACP) and PD-L1 aptamers in the lipid membrane, potentiating melanoma-targeted AUR delivery while transferring ACP onto cell surface through selective membrane fusion. AUR amplifies IR-induced immunogenic death of melanoma cells to release antigens and damage-associated molecular patterns such as adenosine triphosphate (ATP) for triggering adaptive antitumor immunity. AUR-sensitized radiotherapy also upregulates matrix metalloproteinase-2 (MMP-2) expression that combined with released ATP to activate ACP through an "and" logic operation-like process (AND-gate), thus triggering the in-situ release of engineered cytosine-phosphate-guanine aptamer-based immunoadjuvants (eCpG) for stimulating dendritic cell-mediated T cell priming. Furthermore, AUR inhibits tumor-intrinsic vascular endothelial growth factor signaling to suppress infiltration of immunosuppressive cells for fostering an anti-tumorigenic TME. This study offers an approach for solid tumor treatment in the clinics.

Nanointegrative Glycoengineering-Activated Necroptosis of Triple Negative Breast Cancer Stem Cells Enables Self-Amplifiable Immunotherapy for Systemic Tumor Rejection.

Triple-negative breast cancer stem cells (TCSCs) are considered as the origin of recurrence and relapse. It is difficult to kill not only for its resistance, but also the lacking of targetable molecules on membrane. Here, it is confirmed that ST6 ß-galactoside alpha-2,6-sialyltransferase 1 (ST6Gal-1) is highly expressed in TCSCs that may be the key enzyme involved in glycoengineering via sialic acid (SA) metabolism. SA co-localizes with a microdomain on cell membrane termed as lipid rafts that enrich CSCs marker and necroptosis proteins mixed lineage kinase domain-like protein (MLKL), suggesting that TCSCs may be sensitive to necroptosis. Thus, the triacetylated N-azidoacetyl-d-mannosamine (Ac3ManNAz) is synthesized as the glycoengineering substrate and applied to introduce artificial azido receptors, dibenzocyclooctyne (DBCO)-modified liposome is used to deliver Compound 6i (C6), a receptor-interacting serine/threonine protein kinase 1(RIPL1)-RIP3K-mixed lineage kinase domain-like protein(MLKL) activator, to induce necroptosis. The pro-necroptosis effect is aggravated by nitric oxide (NO), which is released from NO-depot of cholesterol-NO integrated in DBCO-PEG-liposome@NO/C6 (DLip@NO/C6). Together with the immunogenicity of necroptosis that releases high mobility group box 1(HMGB1) of damage-associated molecular patterns, TCSCs are significantly killed in vitro and in vivo. The results suggest a promising strategy to improve the therapeutic effect on the non-targetable TCSCs with high expression of ST6Gal-1 via combination of glycoengineering and necroptosis induction.

Inhibition of glycolysis-driven immunosuppression with a nano-assembly enhances response to immune checkpoint blockade therapy in triple negative breast cancer.

Immune-checkpoint inhibitors (ICI) are promising modalities for treating triple negative breast cancer (TNBC). However, hyperglycolysis, a hallmark of TNBC cells, may drive tumor-intrinsic PD-L1 glycosylation and boost regulatory T cell function to impair ICI efficacy. Herein, we report a tumor microenvironment-activatable nanoassembly based on self-assembled aptamer-polymer conjugates for the targeted delivery of glucose transporter 1 inhibitor BAY-876 (DNA-PAE@BAY-876), which remodels the immunosuppressive TME to enhance ICI response. Poly ß-amino ester (PAE)-modified PD-L1 and CTLA-4-antagonizing aptamers (aptPD-L1 and aptCTLA-4) are synthesized and co-assembled into supramolecular nanoassemblies for carrying BAY-876. The acidic tumor microenvironment causes PAE protonation and triggers nanoassembly dissociation to initiate BAY-876 and aptamer release. BAY-876 selectively inhibits TNBC glycolysis to deprive uridine diphosphate N-acetylglucosamine and downregulate PD-L1 N-linked glycosylation, thus facilitating PD-L1 recognition of aptPD-L1 to boost anti-PD-L1 therapy. Meanwhile, BAY-876 treatment also elevates glucose supply to tumor-residing regulatory T cells (Tregs) for metabolically rewiring them into an immunostimulatory state, thus cooperating with aptCTLA-4-mediated immune-checkpoint inhibition to abolish Treg-mediated immunosuppression. DNA-PAE@BAY-876 effectively reprograms the immunosuppressive microenvironment in preclinical models of TNBC in female mice and provides a distinct approach for TNBC immunotherapy in the clinics.

Physical Activity Mediates the Relationship Between Sarcopenia and Cognitive Function Among Older Adults in Nursing Homes.

Purpose: Sarcopenia and physical activity are significant factors influencing cognitive function. However, few studies have examined their underlying mechanisms between the three conditions. The aim of the study is to examine the mediating role of physical activity in the relationship between sarcopenia and cognitive function in elderly nursing home residents. Materials and Methods: A total of 420 older adults aged 60 years and above in nursing homes participated in this study. Sarcopenia was defined following the Asian Sarcopenia Working Group (AWGS) 2019 criteria. Cognitive function was assessed by the Mini-Mental State Examination (MMSE). Multiple linear regression analysis was employed to explore the relationships between sarcopenia, cognitive function and physical activity. Mediation analyses were performed to examine whether physical activity moderates the relationship between sarcopenia and cognitive function, with the use of PROCESS macro version 4.0. Results: A total of 386 older adults were included in the analysis (mean age 80.30 years), 175 (45.3%) were assessed as cognitive impairment, and sarcopenia was more common in those with cognitive impairment (p < 0.01). The linear regression analysis indicated that there were significant associations between sarcopenia and physical activity (ß = -0.285, p = 0.012), physical activity and cognitive function (ß = 0.218, p < 0.001), and sarcopenia and cognitive function (ß = -0.245, p = 0.021). Mediating effects of physical activity on the association between sarcopenia and cognitive function were observed in participants, with 20.2% of partial mediating effect. Conclusion: The results of the study suggest physical activity may partially buffer the adverse effects of sarcopenia on cognitive impairment among the older adults in nursing homes. Accordingly, engagement in physical activity can help to preserve cognitive function among those with sarcopenia.

Engineered hydrochar from waste reed straw for peroxymonosulfate activation to degrade quinclorac and improve solanaceae plants growth.

Hydrochar from agricultural wastes is regarded as a prospective and low-cost material to activate peroxymonosulfate (PMS) for degrading pollutants. Herein, a novel in-situ N-doped hydrochar composite (RHCM4) was synthesized using montmorillonite and waste reed straw rich in nitrogen as pyrolysis catalyst and carbon source, respectively. The fabricated RHCM4 possessed excellent PMS activation performance for decomposing quinclorac (QC), a refractory herbicide, with a high removal efficiency of 100.0% and mineralization efficiency of 75.1%. The quenching experiments and electron spin resonance (ESR) detection disclosed free radicals (•OH, •SO4-, and •O2-) and non-radicals (1O2) took part in the QC degradation process. Additionally, the catalytic mechanisms were analyzed in depth with the aid of various characterizations. Moreover, the QC degradation intermediates and pathways were clarified by density functional theory calculations and HPLC-MS. Importantly, phytotoxicity experiments showed that RHCM4/PMS could efficaciously mitigate the injury of QC to Solanaceae crops (pepper, tomato, and tobacco). These findings give a new idea for enhancing the catalytic activity of hydrochar from agricultural wastes and broaden its application in the field of agricultural environment.

Mechanotransduction in response to ECM stiffening impairs cGAS immune signaling in tumor cells.

The tumor microenvironment (TME) plays decisive roles in disabling T cell-mediated antitumor immunity, but the immunoregulatory functions of its biophysical properties remain elusive. Extracellular matrix (ECM) stiffening is a hallmark of solid tumors. Here, we report that the stiffened ECM contributes to the immunosuppression in TME via activating the Rho-associated coiled-coil-containing protein kinase (ROCK)-myosin IIA-filamentous actin (F-actin) mechanosignaling pathway in tumor cells to promote the generation of TRIM14-scavenging nonmuscle myosin heavy chain IIA (NMHC-IIA)-F-actin stress fibers, thus accelerating the autophagic degradation of cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) to deprive tumor cyclic GMP-AMP (cGAMP) and further attenuating tumor immunogenicity. Pharmacological inhibition of myosin IIA effector molecules with blebbistatin (BLEB) or the RhoA upstream regulator of this pathway with simvastatin (SIM) restored tumor-intrinsic cGAS-mediated cGAMP production and enhanced antitumor immunity. Our work identifies that ECM stiffness is an important biophysical cue to regulate tumor immunogenicity via the ROCK-myosin IIA-F-actin axis and that inhibiting this mechanosignaling pathway could boost immunotherapeutic efficacy for effective solid tumor treatment.

Ferroptosis Nanomedicine: Clinical Challenges and Opportunities for Modulating Tumor Metabolic and Immunological Landscape.

Ferroptosis, a type of regulated cell death driven by iron-dependent phospholipid peroxidation, has captured much attention in the field of nanomedicine since it was coined in 2012. Compared with other regulated cell death modes such as apoptosis and pyroptosis, ferroptosis has many distinct features in the molecular mechanisms and cellular morphology, representing a promising strategy for treating cancers that are resistant to conventional therapeutic modalities. Moreover, recent insights collectively reveal that ferroptosis is tightly connected to the maintenance of the tumor immune microenvironment (TIME), suggesting the potential application of ferroptosis therapies for evoking robust antitumor immunity. From a biochemical perspective, ferroptosis is intricately regulated by multiple cellular metabolic pathways, including iron metabolism, lipid metabolism, redox metabolism, etc., highlighting the importance to elucidate the relationship between tumor metabolism and ferroptosis for developing antitumor therapies. In this review, we provide a comprehensive discussion on the current understanding of ferroptosis-inducing mechanisms and thoroughly discuss the relationship between ferroptosis and various metabolic traits of tumors, which offer promising opportunities for direct tumor inhibition through a nanointegrated approach. Extending from the complex impact of ferroptosis on TIME, we also discussed those important considerations in the development of ferroptosis-based immunotherapy, highlighting the challenges and strategies to enhance the ferroptosis-enabled immunostimulatory effects while avoiding potential side effects. We envision that the insights in this study may facilitate the development and translation of ferroptosis-based nanomedicines for tumor treatment.

Injectable microenvironment-responsive hydrogels with redox-activatable supramolecular prodrugs mediate ferroptosis-immunotherapy for postoperative tumor treatment.

Immunotherapy is an emerging antitumor modality with high specificity and persistence, but its application for resected tumor treatment is impeded by the low availability of tumor-specific antigens and strong immunosuppression in the wound margin. Here a nanoengineered hydrogel is developed for eliciting robust cooperative ferroptosis-immunotherapeutic effect on resected tumors. Specifically, ß-cyclodextrin (ß-CD) is first grafted onto oxidized sodium alginate (OSA) through Schiff base ligation, which could trap cRGD-modified redox-responsive Withaferin prodrugs (WA-cRGD) to obtain the hydrogel building blocks (Gel@WA-cRGD). Under Ca2+-mediated crosslinking, Gel@WA-cRGD rapidly forms physiologically stable hydrogels, of which the porous network is used to deliver programmed cell death ligand 1 antibodies (aPD-L1). After injection into the post-surgical wound cavity, the ß-CD-entrapped WA-cRGD is detached by the local acidity and specifically internalized by residual tumor cells to trigger ferroptosis, thus releasing abundant damage-associated molecular patterns (DAMPs) and tumor-derived antigens for activating the antigen-presenting cell-mediated cross-presentation and downstream cytotoxic T cell (CTL)-mediated antitumor responses. Furthermore, aPD-L1 could block PD-1/PD-L1 interaction and enhance the effector function of CTLs to overcome tumor cell-mediated immunosuppression. This cooperative hydrogel-based antitumor strategy for ferroptosis-immunotherapy may serve as a generally-applicable approach for postoperative tumor management. STATEMENT OF SIGNIFICANCE: To overcome the immunosuppressive microenvironment in resected solid tumors for enhanced patient survival, here we report a nanoengineered hydrogel incorporated supramolecular redox-activatable Withaferin prodrug and PD-L1 antibody, which could elicit robust cooperative ferroptosis-immunotherapeutic effect against residual tumor cells in the surgical bed to prevent tumor relapse, thus offering a generally-applicable approach for postoperative tumor management.

Coordination-driven FBXW7 DNAzyme-Fe nanoassembly enables a binary switch of breast cancer cell cycle checkpoint responses for enhanced ferroptosis-radiotherapy.

Radiotherapy is a mainstream modality for breast cancer treatment that employs ionizing radiation (IR) to damage tumor cell DNA and elevate ROS stress, which demonstrates multiple clinically-favorable advantages including localized treatment and low invasiveness. However, breast cancer cells may activate the p53-mediated cell cycle regulation in response to radiotherapy to repair IR-induced cellular damage and facilitate post-treatment survival. F-Box and WD Repeat Domain Containing 7 (FBXW7) is a promoter of p53 degradation and critical nexus of cell proliferation and survival events. Herein, we engineered a cooperative radio-ferroptosis-stimulatory nanomedicine through coordination-driven self-assembly between ferroptosis-inducing Fe2+ ions and FBXW7-inhibiting DNAzymes and further modification of tumor-targeting dopamine-modified hyaluronic acid (HA). The nanoassembly could be selectively internalized by breast cancer cells and disintegrated in lysosomes to release the therapeutic payload. DNAzyme readily abolishes FBXW7 expression and stabilizes phosphorylated p53 to cause irreversible G2 phase arrest for amplifying post-IR tumor cell apoptosis. Meanwhile, the p53 stabilization also inhibits the SLC7A11-cystine-GSH axis, which combines with the IR-upregulated ROS levels to amplify Fe2+-mediated ferroptotic damage. The DNAzyme-Fe-HA nanoassembly could thus systematically boost the tumor cell damaging effects of IR, presenting a simple and effective approach to augment the response of breast cancer to radiotherapy. STATEMENT OF SIGNIFICANCE: To overcome the intrinsic radioresistance in breast cancer, we prepared co-assembly of Fe2+ and FBXW7-targeted DNAzymes and modified surface with dopamine conjugated hyaluronic acid (HA), which enabled tumor-specific FBXW7-targeted gene therapy and ferroptosis therapy in IR-treated breast cancers. The nanoassembly could be activated in acidic condition to release the therapeutic contents. Specifically, the DNAzymes could selectively degrade FBXW7 mRNA in breast cancer cells to simultaneously induce accumulation of p53 and retardation of NHEJ repair, eventually inducing irreversible cell cycle arrest to promote apoptosis. The p53 stabilization would also inhibit the SLC7A11/GSH/GPX4 axis to enhance Fe2+ mediated ferroptosis. These merits could act in a cooperative manner to induce pronounced tumor inhibitory effect, offering new approaches for tumor radiosensitization in the clinics.

A bi-directional Mendelian randomization study of sarcopenia-related traits and type 2 diabetes mellitus.

Background: Previous studies have reported an association between sarcopenia and type 2 diabetes mellitus (T2DM), but causation was prone to confounding factors. A more robust research approach is urgently required to investigate the causal relationship between sarcopenia and T2DM. Methods: The bi-directional two-sample MR study was carried out in two stages: Sarcopenia-related traits were investigated as exposure while T2DM was investigated as an outcome in the first step, whereas the second step was reversed. The GWAS summary data for hand-grip strength (n = 256,523), appendicular lean mass (ALM, n = 450,243), and walking pace (n = 459,915) were obtained from the UK Biobank. T2DM data were obtained from one of the biggest case-control studies on diabetes (DIAGRAM; n = 180,834 cases and 492,191 controls), which was published in 2022. The inverse-variance weighted (IVW) approach was used to obtain MR estimates, and various sensitivity analysis was also performed. Results: Low hand-grip strength had a potential causal relationship with an increased incidence of T2DM (OR = 1.109; 95% CI, 1.008-1.222; p = 0.0350). T2DM risk was reduced by increasing ALM and walking pace: A 1 kg/m2 increase in ALM decreased the risk of T2DM by 10.2% (OR = 0.898; 95% CI, 0.830-0.952; p < 0.001). A 1 m/s increase in walking pace decreased the risk of T2DM by 90.0% (OR = 0.100; 95% CI, 0.053-0.186; p < 0.001). The relationship was bidirectional, with T2DM as a causative factor of sarcopenia-related traits (p < 0.05) except for ALM (ß = 0.018; 95% CI, -0.008 to -0.044; p = 0.168). Conclusions: Hand-grip strength and T2DM had a potential bidirectional causal relationship, as did walking pace and T2DM. We suggest that sarcopenia and T2DM may mutually have a significant causal effect on each other.

The Mutation of the DNA-Binding Domain of Fur Protein Enhances the Pathogenicity of Edwardsiella piscicida via Inducing Overpowering Pyroptosis.

Edwardsiella piscicida is an important fish pathogen with a broad host that causes substantial economic losses in the aquaculture industry. Ferric uptake regulator (Fur) is a global transcriptional regulator and contains two typical domains, the DNA-binding domain and dimerization domain. In a previous study, we obtained a mutant strain of full-length fur of E. piscicida, TX01Δfur, which displayed increased siderophore production and stress resistance factors and decreased pathogenicity. To further reveal the regulatory mechanism of Fur, the DNA-binding domain (N-terminal) of Fur was knocked out in this study and the mutant was named TX01Δfur2. We found that TX01Δfur2 displayed increased siderophore production and enhanced adversity tolerance, including a low pH, manganese, and high temperature stress, which was consistent with the phenotype of TX01Δfur. Contrary to TX01Δfur, whose virulence was weakened, TX01Δfur2 displayed an ascended invasion of nonphagocytic cells and enhanced destruction of phagocytes via inducing overpowering or uncontrollable pyroptosis, which was confirmed by the fact that TX01Δfur2 induced higher levels of cytotoxicity, IL-1ß, and p10 in macrophages than TX01. More importantly, TX01Δfur2 displayed an increased global virulence to the host, which was confirmed by the result that TX01Δfur2 caused higher lethality outcomes for healthy tilapias than TX01. These results demonstrate that the mutation of the Fur N-terminal domain augments the resistance level against the stress and pathogenicity of E. piscicida, which is not dependent on the bacterial number in host cells or host tissues, although the capabilities of biofilm formation and the motility of TX01Δfur2 decline. These interesting findings provide a new insight into the functional analysis of Fur concerning the regulation of virulence in E. piscicida and prompt us to explore the subtle regulation mechanism of Fur in the future.

Nutritional Status and Sarcopenia in Nursing Home Residents: A Cross-Sectional Study.

OBJECTIVE: This study aimed to assess the nutritional status and sarcopenia in older people living in nursing homes. METHODS: This cross-sectional study enrolled 386 older adults in nursing homes in Hunan Province, China. Assessments included the Mini Nutritional Assessment Short Form for nutrition risk, Dietary Diversity Score for dietary diversity and Mini Mental State Examination for cognitive status. Sociodemographic (e.g., age, sex and educational level), health-related characteristics (e.g., food intake, self-care status and medication), body composition (e.g., body mass index [BMI], protein, body fat mass [BFM], percent body fat [PBF], skeletal muscle index [SMI] and total body water [TBW]) and anthropometric parameters data (e.g., calf circumference [CC], upper arm circumference [UAC], handgrip and gait speed) were also collected. Malnutrition and their associated risk were analyzed by multivariable Poisson regression analysis. RESULTS: In total, 32.4% of participants (n = 125) were at risk of malnutrition and 49.7% (n = 192) suffered from sarcopenia. Nutritional status was positively associated with age (risk ratio [RR] = 1.03), sarcopenia (RR = 1.88), tooth loss affecting food intake (RR = 1.45), low self-care status (RR = 1.82) and moderate/inadequate dietary diversity (RR = 2.04) and negatively associated with one child (RR = 0.27), BMI (RR = 0.82), protein (RR = 0.76), BFM (RR = 0.91), PBF (RR = 0.94), SMI (RR = 0.65), TBW (RR = 0.94), CC (RR = 0.89) and UAC (RR = 0.86). CONCLUSIONS: Age, number of children, sarcopenia, food intake, self-care status, dietary diversity and body composition were associated with malnutrition among nursing home residents. For vulnerable groups, researchers should focus on raising the body composition indicators, such as BMI, protein, BFM, SMI and TBW and measuring CC and UAC for initial screening.

The Prevalence of Sarcopenia among Hunan Province Community-Dwelling Adults Aged 60 Years and Older and Its Relationship with Lifestyle: Diagnostic Criteria from the Asian Working Group for Sarcopenia 2019 Update.

Background and Objectives: This study aims to detect the prevalence of sarcopenia in community-dwelling older adults in Hunan Province, discuss factors related to lifestyle, and provide a reliable basis for the prevention and treatment of sarcopenia. Materials and Methods: In this study, a total of 1040 community-dwelling adults ≥ 60 years were examined for sarcopenia using a cluster stratified random sampling method, which was defined using the diagnostic criteria recommended by the Asian Working Group for Sarcopenia (AWGS) from September 2019 to March 2020. Multivariate logistic regression analysis was applied to determine the correlation between sarcopenia and smoking, drinking, nutritional status, physical activity, and sleep quality. Results: A total of 27.1% of the older adults were diagnosed with sarcopenia, with rates of 26.2% in men and 25.2% in women. Multiple logistic regression showed that advanced age (OR = 2.480, 95% CI: 1.730, 3.553), the risk of malnutrition (OR = 2.085, 95% CI: 1.440, 3.019), and malnutrition (OR = 1.212, 95% CI: 0.304, 4.834) were risk factors for sarcopenia. No falls in the previous year (OR = 0.616, 95% CI: 1.885, 1.209), normal weight (OR = 0.228, 95% CI: 0.109, 0.475), overweight (OR = 0.030, 95% CI: 0.013, 0.069), moderate physical activity (OR = 0.593, 95% CI: 0.377, 0.933), or high physical activity (OR = 0.417, 95% CI: 0.230, 0.755) were identified as protective factors for sarcopenia. Conclusions: The prevalence of sarcopenia was high among older adults in the community in Hunan Province. In addition, we found that lifestyle is an important factor in sarcopenia.

Increasing the Modulation Depth of GdIII-Based Pulsed Dipolar EPR Spectroscopy (PDS) with Porphyrin-GdIII Laser-Induced Magnetic Dipole Spectroscopy.

Distance determination with pulsed EPR has become an important technique for the structural investigation of biomacromolecules, with double electron-electron resonance spectroscopy (DEER) as the most important method. GdIII-based spin labels are one of the most frequently used spin labels for DEER owing to their stability against reduction, high magnetic moment, and absence of orientation selection. A disadvantage of GdIII-GdIII DEER is the low modulation depth due to the broad EPR spectrum of GdIII. Here, we introduce laser-induced magnetic dipole spectroscopy (LaserIMD) with a spin pair consisting of GdIII(PymiMTA) and a photoexcited porphyrin as an alternative technique. We show that the excited state of the porphyrin is not disturbed by the presence of the GdIII complex and that herewith modulation depths of almost 40% are possible. This is significantly higher than the value of 7.2% that was achieved with GdIII-GdIII DEER.

Modulating tumor physical microenvironment for fueling CAR-T cell therapy.

Chimeric antigen receptor (CAR) T cell therapy has achieved unprecedented clinical success against hematologic malignancies. However, the transition of CAR-T cell therapies for solid tumors is limited by heterogenous antigen expression, immunosuppressive microenvironment (TME), immune adaptation of tumor cells and impeded CAR-T-cell infiltration/transportation. Recent studies increasingly reveal that tumor physical microenvironment could affect various aspects of tumor biology and impose profound impacts on the antitumor efficacy of CAR-T therapy. In this review, we discuss the critical roles of four physical cues in solid tumors for regulating the immune responses of CAR-T cells, which include solid stress, interstitial fluid pressure, stiffness and microarchitecture. We highlight new strategies exploiting these features to enhance the therapeutic potency of CAR-T cells in solid tumors by correlating with the state-of-the-art technologies in this field. A perspective on the future directions for developing new CAR-T therapies for solid tumor treatment is also provided.

YTHDF1 upregulation mediates hypoxia-dependent breast cancer growth and metastasis through regulating PKM2 to affect glycolysis.

N6-methyladenosine modification is the most common RNA modification mechanism in mammals. YTHDF1, a m6A reader, can recognize the m6A of mRNAs to facilitate the interaction with the mRNA ribosome assembly and recruitment of translation initiators to promote translation. From a clinical perspective, YTHDF1 upregulation is frequently observed in breast cancer, but its involvement in those cancer-related events is still unclear. Here we report that YTHDF1 is a cancer driver capable of facilitating the proliferation and invasion of breast cancer cells as well as enhancing tumorigenicity and metastasis through promoting glycolysis. We found that tumor hypoxia can transcriptionally induce HIF1α and post-transcriptionally inhibit the expression of miR-16-5p to promote YTHDF1 expression, which could sequentially enhance tumor glycolysis by upregulating PKM2 and eventually increase the tumorigenesis and metastasis potential of breast cancer cells. Inhibiting YTHDF1 via gene knockdown or miR-16-5p would significantly abolish YTHDF1-dependent tumor growth and metastasis. In summary, we identified the role of the YTHDF1-PKM2 signal axis in the occurrence and development of breast cancer, which can be used as a potential target for breast cancer treatment.

Prevalence and diagnostic agreement of sarcopenic obesity with different definitions among Chinese community-dwelling older adults.

OBJECTIVE: this retrospective study aims to compare the prevalence and diagnostic agreement of sarcopenic obesity (SO) using different obesity diagnostic methods among Chinese community-dwelling older adults. METHODS: SO was diagnosed with sarcopenia and obesity diagnostic methods. Sarcopenia was defined using the Asian Working Group for Sarcopenia criteria 2019 (AWGS2019). Four widely used indicators were used to define obesity: body mass index (BMI), waist circumference (WC), percent of body fat (PBF) and visceral fat area (VFA). Cohen's kappa was used to analyse the diagnosis agreement of SO between different diagnostic methods. RESULTS: a total of 1,050 participants were included, including 347 men (71.3 ± 7.4 years) and 703 women (69.9 ± 7.5 years). The prevalence of sarcopenia was 25% in total participants, there was no difference between men (24.2%) and women (25.5%), (P = 0.705). With different obesity diagnostic methods, the obesity prevalence ranged from 4.1 to 42.2%, the SO prevalence was 0.1-7.9%. The diagnosis agreement of SO was poor-to-moderate (κ ranged from -0.002 to 0.682). Among the four diagnostic methods, AWGS combined with BMI had the poorest agreement (κ = -0.002 with other methods), AWGS combined with VFA had the best agreement (κ = 0.641 and 0.682 with AWGS combined with PBF and with AWGS combined with WC, respectively). CONCLUSION: the prevalence of SO vary considerably and the diagnostic agreement is poor-to-moderate with non-uniform diagnostic methods. BMI has the lowest sensitivity, whereas VFA has the highest sensitivity in diagnosis of SO, and VFA has a relatively good diagnostic agreement with other diagnostic methods.

Development and Validation of a Nomogram for Predicting Sarcopenia in Community-Dwelling Older Adults.

OBJECTIVE: To establish and validate a nomogram that predicts the risk of sarcopenia for community-dwelling older residents. DESIGN: Retrospective study. SETTING AND PARTICIPANTS: A total of 1050 community-dwelling older adults. METHODS: Data from a survey of community-dwelling older residents (≥60 years old) in Hunan, China, from June to September 2019 were retrospectively analyzed. The survey included general demographic information, diet, and exercise habits. Sarcopenia diagnosis was according to 2019 Asian Working Group for Sarcopenia criteria. Participants were randomly divided into the development group and validation groups. Independent risk factors were screened by multivariate logistic regression analysis. Based on the independent risk factors, a nomogram model was developed to predict the risk of sarcopenia for community-dwelling older adults. Both in the development and validation sets, the discrimination, calibration, and clinical practicability of the nomogram were verified using receiver operating characteristic curve analysis, Hosmer-Lemeshow test, and decision curve analysis, respectively. RESULTS: Sarcopenia was identified in 263 (25.0%) participants. Age, body mass index, marital status, regular physical activity habit, uninterrupted sedentary time, and dietary diversity score were significant contributors to sarcopenia risk. A nomogram for predicting sarcopenia in community-dwelling older adults was developed using these factors. Receiver operating characteristic curve analysis showed that the area under the curve was 0.827 (95% CI 0.792-0.860) and 0.755 (95% CI 0.680-0.837) in the development and validation sets, respectively. The Hosmer-Lemeshow test yielded P values of .609 and .565, respectively, for the 2 sets. The nomogram demonstrated a high net benefit in the clinical decision curve in both sets. CONCLUSIONS AND IMPLICATIONS: This study developed and validated a risk prediction nomogram for sarcopenia among community-dwelling older adults. Sarcopenia risk was classified as low (<11%), moderate (11%-70%), and high (>70%). This nomogram provides an accurate visual tool to medical staff, caregivers, and older adults for prediction, early intervention, and graded management of sarcopenia.

An ROS-Activatable Nanoassembly Remodulates Tumor Cell Metabolism for Enhanced Ferroptosis Therapy.

Ferroptosis is an emerging antitumor option and has demonstrated unique advantages against many tumor indications. However, its efficacy is potentially hindered by the endogenous lipid peroxide-scavenging mechanisms and the reliance on acidic pH. Herein, a nanointegrated strategy based on clinically-safe components to synergistically remodel glutathione and lactate metabolism in tumor cells for enhanced ferroptosis therapy is developed. First ferrocene is conjugated on PEGylated polyamidoamine dendrimers via reactive oxygen species (ROS)-cleavable thioketal linkage, which would further self-assemble with the glutathione (GSH)-depleting agent diethyl maleate (DEM) and monocarboxylate transporter 4-inhibiting siRNA (siMCT4) to afford biostable nanoassemblies (siMCT4-PAMAM-PEG-TK-Fc@DEM). The nanoassemblies can be activated by the elevated ROS levels in tumor intracellular environment and readily release the incorporated therapeutic contents, afterward DEM can directly conjugate to GSH to disrupt the glutathione peroxidase 4 (GPX4)-mediated antioxidant defense, while siMCT4 can block the MCT4-mediated efflux of lactic acid and acidify the intracellular milieu, both of which can improve the ferrocene-catalyzed lipid peroxidation and induce pronounced ferroptotic damage. The siMCT4-PAMAM-PEG-TK-Fc@DEM nanoplatform demonstrates high ferroptosis-based antitumor potency and good biocompatibility in vitro and in vivo, which may offer new avenues for the development of more advanced antitumor therapeutics with improved translatability.

Impact of Pricing and Product Information on Consumer Buying Behavior With Customer Satisfaction in a Mediating Role.

The relationship between product pricing and product packaging plays an important role in the buying behavior of consumers, whereas customer satisfaction plays a mediating role. To test these hypotheses, research was conducted on university students in China. Questionnaire-based convenience sampling was conducted on 500 students for data collection using online and offline sources. A total of 367 (73%) students responded, and 17 questionnaires were rejected due to missing information. SPSS and AMOS software were used for the data analysis. Product pricing and product information were independent variables in this study, whereas consumer buying behavior was a dependent variable. Customer satisfaction is mediated by one dependent and two independent variables. Confirmatory factor analysis, path analysis, and discriminant validity in structural equation modeling revealed that product pricing and packaging had a statistically significant relationship with the buyer decision process. The introduction of satisfaction as a mediating variable led to the observation of full mediation in the case of product pricing and partial mediation in product packaging. Given the results of this research, product managers should adopt pricing tactics along with product packaging to influence the buying intentions of consumers.