Cost-utility analysis of add-on vericiguat for the treatment of chronic heart failure with reduced ejection fraction in China.

OBJECTIVE: This study aimed to evaluate the cost-utility of the addition of vericiguat for treating chronic heart failure (CHF) in China from the healthcare payer's perspective. METHODS: A Markov model was built to estimate the cost and utility of treating CHF using vericiguat plus standard treatment (vericiguat group) vs. standard treatment alone (standard treatment group). The clinical parameters (mortality of cardiovascular and hospitalization rate of HF) were calculated according to the VICTORIA clinical trial. The HF cost and utility data were obtained from the literature published in China. One-way sensitivity analysis and probability sensitivity analysis were performed. RESULTS: According to the 13-year model, vericiguat was more expensive (155599.07 CNY vs. 259396.83 CNY) and more effective (4.41 QALYs vs. 4.54 QALYs). The incremental cost-utility ratio (ICUR) was 802389.27 CNY per QALY. One-way sensitivity analysis revealed that cardiovascular mortality in the two groups was the parameter that had the greatest impact on the results. The GDP per capita in 2022 in China was 85,700 CNY. The probability sensitivity analysis (PSA) showed that the probability of vericiguat being cost-effective was only 41.7% at the willingness-to-pay (WTP) threshold of 3 times GDP per capita (257,100 CNY). CONCLUSIONS: In China, the treatment of CHF with vericiguat is not cost-effective. The drug price could decrease to 145.8 CNY, which could be considered cost-effective.

Triune Nanomodulator Enables Exhausted Cytotoxic T Lymphocyte Rejuvenation for Cancer Epigenetic Immunotherapy.

Oncogene activation and epigenome dysregulation drive tumor initiation and progression, contributing to tumor immune evasion and compromising the clinical response to immunotherapy. Epigenetic immunotherapy represents a promising paradigm in conquering cancer immunosuppression, whereas few relevant drug combination and delivery strategies emerge in the clinic. This study presents a well-designed triune nanomodulator, termed ROCA, which demonstrates robust capabilities in tumor epigenetic modulation and immune microenvironment reprogramming for cancer epigenetic immunotherapy. The nanomodulator is engineered from a nanoscale framework with epigenetic modulation and cascaded catalytic activity, which self-assembles into a nanoaggregate with tumor targeting polypeptide decoration that enables loading of the immunogenic cell death (ICD)-inducing agent. The nanomodulator releases active factors specifically triggered in the tumor microenvironment, represses oncogene expression, and initiates the type 1 T helper (TH1) cell chemokine axis by reversing DNA hypermethylation. This process, together with ICD induction, fundamentally reprograms the tumor microenvironment and significantly enhances the rejuvenation of exhausted cytotoxic T lymphocytes (CTLs, CD8+ T cells), which synergizes with the anti-PD-L1 immune checkpoint blockade and results in a boosted antitumor immune response. Furthermore, this strategy establishes long-term immune memory and effectively prevents orthotopic colon cancer relapse. Therefore, the nanomodulator holds promise as a standalone epigenetic immunotherapy agent or as part of a combination therapy with immune checkpoint inhibitors in preclinical cancer models, broadening the array of combinatorial strategies in cancer immunotherapy.

Gfi-1 modulates HMGB1-Mediated autophagy to overcome oxaliplatin resistance in colorectal cancer.

Background: Resistance to oxaliplatin (L-OHP) is a major barrier in the treatment of colorectal cancer (CRC). Autophagy is the main cause of L-OHP tolerance in CRC cells. Method: The human colon cancer cell lines HCT116 and SW480 were treated with L-OHP to obtain the drug-resistant cell lines HCT116/L-OHP and SW480/L-OHP, respectively. To probe the relationship between autophagy and L-OHP tolerance of growth factor independent 1 (Gfi-1) and high-mobility group protein 1 (HMGB1) in CRC cells, gene knockout or overexpression was performed, and Western blotting was used to determine the levels of drug tolerance interrelated proteins. Transwell and CCK-8 assays were employed to analyze the proliferation of cancer cells. Immunofluorescence detection of LC3 reflected autophagy levels. Finally, the relationship between Gfi-1 and HMGB1 was detected by chromatin immunoprecipitation (ChIP). Result: Compared to normal CRC cells, L-OHP-tolerant CRC cells exhibited greater autophagy (8.2 times greater in HCT116/L-OHP cells and 7.4 times greater in SW480/L-OHP cells). In addition, we detected low levels of Gfi-1 (0.6-fold for HCT116/L-OHP cells and 0.4-fold for SW480/L-OHP cells), and OE-Gfi-1 decreased HMGB1 levels (0.6-fold for HCT116/L-OHP + OE-Gfi-1 cells and 0.5-fold for SW480/L-OHP + OE-Gfi-1 cells). The inhibition of Gfi-1 further enhanced cell viability (1.7 times in HCT116+sh-Gfi-1 cells and 1.2 times in SW480+sh-Gfi-1 cells) and invasion (1.8 times in HCT116+sh-Gfi-1 cells and 2.1 times in SW480+sh-Gfi-1 cells) in CRC cells, thus promoting oxaliplatin resistance in these cells. The autophagy inhibitor 3-MA reversed the above effects. Furthermore, we noted that Gfi-1 can restrain HMGB1 expression by binding to its promoter (0.5 times in HCT116+OE-Gfi-1 cells and 0.5 times in SW480+OE-Gfi-1 cells). The inhibitory influence of 3-MA on HMGB1 reversed the influence of Gfi-1 on autophagy and malignant progression in CRC cells. Conclusion: Our study suggested that Gfi-1 inhibited HMGB1 to reduce CRC autophagy levels, increasing CRC sensitivity to L-OHP.

Foliar uptake screening: A promising strategy for identifying wheat varieties with low lead accumulation.

Lead (Pb) contamination in wheat grain is of great concern, especially in North China. Atmospheric deposition is a major contributor to Pb accumulation in wheat grain. Screening low Pb accumulating wheat varieties has been an effective method for addressing Pb contamination in wheat grain. However, identifying wheat varieties with low Pb accumulation based on foliar uptake of atmospheric Pb has been neglected. Therefore, two field trials with distinct atmospheric Pb deposition were conducted to screen for stable varieties with low Pb accumulation. It was verified that YB700 and CH58, which have high thousand-grain weights and stable low Pb accumulation in field 1 (0.19 and 0.13 mg kg-1) and field 2 (0.17 and 0.20 mg kg-1), respectively, were recommended for cultivation in atmospheric Pb contaminated farmlands in North China. Furthermore, indoor experiments were conducted to investigate Pb uptake by the roots and leaves of different wheat varieties. Our findings indicate that Pb accumulation in different wheat varieties is primarily influenced by foliar Pb uptake rather than root Pb uptake. Interestingly, there was a positive correlation (p < 0.05) between the Pb concentrations in leaves and the stomatal width and trichome length of the adaxial epidermal surface. Additionally, there is a positive correlation (p < 0.01) between the Pb concentration in the wheat grain and trichome length. In conclusion, the screening of wheat varieties with narrower stomatal widths or shorter trichomes based on foliar uptake pathways is an effective strategy for ensuring food safety in areas contaminated by atmospheric Pb.

A lipid/PLGA nanocomplex to reshape tumor immune microenvironment for colon cancer therapy.

Immune checkpoint blockade therapy provides a new strategy for tumor treatment; however, the insufficient infiltration of cytotoxic T cells and immunosuppression in tumor microenvironment lead to unsatisfied effects. Herein, we reported a lipid/PLGA nanocomplex (RDCM) co-loaded with the photosensitizer Ce6 and the indoleamine 2,3-dioxygenase (IDO) inhibitor 1MT to improve immunotherapy of colon cancer. Arginine-glycine-aspartic acid (RGD) as the targeting moiety was conjugated on 1,2-distearoyl-snglycero-3-phosphoethanolamine lipid via polyethylene glycol (PEG), and programmed cell death-ligand 1 (PD-L1) peptide inhibitor DPPA (sequence: CPLGVRGK-GGG-d(NYSKPTDRQYHF)) was immobilized on the terminal group of PEG via matrix metalloproteinase 2 sensitive peptide linker. The Ce6 and 1MT were encapsulated in PLGA nanoparticles. The drug loaded nanoparticles were composited with RGD and DPPA modified lipid and lecithin to form lipid/PLGA nanocomplexes. When the nanocomplexes were delivered to tumor, DPPA was released by the cleavage of a matrix metalloproteinase 2-sensitive peptide linker for PD-L1 binding. RGD facilitated the cellular internalization of nanocomplexes via avß3 integrin. Strong immunogenic cell death was induced by 1O2 generated from Ce6 irradiation under 660 nm laser. 1MT inhibited the activity of IDO and reduced the inhibition of cytotoxic T cells caused by kynurenine accumulation in the tumor microenvironment. The RDCM facilitated the maturation of dendritic cells, inhibited the activity of IDO, and markedly recruited the proportion of tumor-infiltrating cytotoxic T cells in CT26 tumor-bearing mice, triggering a robust immunological memory effect, thus effectively preventing tumor metastasis. The results indicated that the RDCM with dual IDO and PD-L1 inhibition effects is a promising platform for targeted photoimmunotherapy of colon cancer.

[Efficacy analysis of OLIF combined with posterior percutaneous internal fixation in patients with lumbar spinal stenosis with or without redundant nerve roots].

OBJECTIVE: To investigate the clinical efficacy of oblique lumbar interbody fusion(OLIF) combined with posterior percutaneous internal fixation in patients with lumbar spinal stenosis with or without redundant nerve roots(RNRs). METHODS: A retrospective analysis of 92 patients with lumbar spinal stenosis treated by oblique lateral lumbar interbody fusion combined with posterior percutaneous internal fixation from June 2019 to June 2022 was performed. There were 32 males and 60 females, aged from 44 to 82 years old with an average of (63.67±9.93) years old. All patients were divided into RNRs positive group and RNRs negative group according to redundancy or not before operation. There were 38 patients in RNRs positive group, including 15 males and 23 females. The age ranged from 45 to 82 years old with an average of (65.45±10.37) years old. The disease duration was 24.00(12.00, 72.00) months. There were 54 patients in RNRs negative group, including 17 males and 37 females. The age ranged from 44 to 77 years old with an average of (62.42±9.51) years old. The disease duration was 13.50(9.00, 36.00) months. The general data of patients were recorded, including operation time, intraoperative blood loss and complications. The imaging parameters before and after operation were observed, including the number of stenosis segments, intervertebral space height, lumbar lordosis angle and dural sac area. The visual analogue scale (VAS) was used to evaluate the back and lower extremity pain, and the Oswestry disability index (ODI) was used to evaluate the activities of daily living. RESULTS: All patients were followed up for 8 to 18 months with an average of (11.04±3.61) months, and no complications were found during the follow-up period.The number of stenosis segments in RNRs positive group (1.71±0.46) was more than that in RNRs negative group(1.17±0.38). In RNRs positive group, intervertebral space height, dural sac area, low back pain VAS, lower extremity pain VAS, ODI score were (1.11±0.19) cm, (0.46±0.17) cm2, (5.39±1.00) scores, (5.05±1.01) points, (55.74±4.05) points, respectively. RNRs negative groups respectively (0.97±0.23) cm, (0.69±0.26) cm2, (4.50±0.77) scores, (4.00±0.58) scores, (47.33±3.43) %. In RNRs positive group, intervertebral space height, dural sac area, low back pain VAS, leg pain VAS, ODI score were (1.60±0.19) cm, (0.74±0.36) cm2, (3.39±0.72) scores, (3.05±1.01) scores, (46.74±4.82) scores, respectively. RNRs negative groups respectively (1.48±0.25) cm, (1.12±0.35) cm2, (3.00±0.82) scores, (3.00±0.82) scores, (37.67±3.58) %. The postoperative intervertebral space height, dural sac area, low back pain VAS score, lower extremity pain VAS and ODI score of the patients in the RNRs positive group and the negative group were significantly improved compared with those before operation, and the differences were statistically significant (P<0.05). There were statistically significant differences in the number of stenosed segments, preoperative intervertebral space height, dural sac area, low back pain VAS, lower extremity pain VAS, and ODI between the two groups(P<0.05). There were significant differences in postoperative intervertebral space height and postoperative ODI between the two groups(P<0.05), but there was no significant difference in intervertebral space height before and after operation and ODI score before and after operation(P>0.05). There were significant differences in operation time, intraoperative blood loss, postoperative dural sac area, difference of dural sac area before and after operation, postoperative low back pain VAS, difference of low back pain VAS score before and after operation, difference of lower extremity pain VAS before and after operation between the two groups(P<0.05). CONCLUSION: OLIF combined with posterior percutaneous internal fixation has a good effect on patients with or without RNRs. Multi-segmental lumbar spinal stenosis and decreased dural sac area may lead to the occurrence of RNRs, and LSS patients with RNRs have more severe symptoms. LSS patients with RNRs have worse surgical outcomes than those without RNRs.

In Situ Atomic Reconstruction Engineering Modulating Graphene-Like MXene-Based Multifunctional Electromagnetic Devices Covering Multi-Spectrum.

With the diversified development of big data, detection and precision guidance technologies, electromagnetic (EM) functional materials and devices serving multiple spectrums have become a hot topic. Exploring the multispectral response of materials is a challenging and meaningful scientific question. In this study, MXene/TiO2 hybrids with tunable conduction loss and polarization relaxation are fabricated by in situ atomic reconstruction engineering. More importantly, MXene/TiO2 hybrids exhibit adjustable spectral responses in the GHz, infrared and visible spectrums, and several EM devices are constructed based on this. An antenna array provides excellent EM energy harvesting in multiple microwave bands, with |S11| up to - 63.2 dB, and can be tuned by the degree of bending. An ultra-wideband bandpass filter realizes a passband of about 5.4 GHz and effectively suppresses the transmission of EM signals in the stopband. An infrared stealth device has an emissivity of less than 0.2 in the infrared spectrum at wavelengths of 6-14 µm. This work can provide new inspiration for the design and development of multifunctional, multi-spectrum EM devices.

Clinical Significance of Upregulation of EZH1 Expression in Hepatocellular Carcinoma Tissues.

BACKGROUND AND AIMS: The incidence and mortality of hepatocellular carcinoma (HCC) are increasing. It is urgent to develop more effective HCC biomarkers for diagnosis and treatment. This project intends to verify the expression of enhancer of zeste 1 polycomb repressive complex 2 subunit (EZH1) and its mechanism in HCC. METHODS: This study integrates global microarray and high-throughput sequencing datasets, combined with internal immunohistochemistry, to analyze the expression and prognostic value of EZH1 in HCC. Functional enrichment analysis was conducted to investigate transcriptional targets, which were achieved by intersecting HCC over-expressed genes, EZH1 co-expressed genes and putative transcriptional targets. The relationship between EZH1 and anticancer drugs was detected by drug sensitivity analysis. RESULTS: In this study, 84 datasets from 40 platforms (3,926 HCC samples and 3,428 non-cancerous liver tissues) were included to show the high expression of EZH1 in HCC. Immunohistochemistry with 159 HCC samples and 62 non-HCC samples confirmed the high expression level. HCC patients with high EZH1 expression had worse survival prognoses. Gene ontology and Reactome analysis revealed that metabolism-related pathways, including autophagy, are critical for HCC. Interestingly, as one of the EZH1 potential transcriptional targets, autophagy-related 7 (ATG7) appeared in the above pathways. ATG7 was positively correlated with EZH1, upregulated in HCC, and mediated poor prognosis. Upregulation of EZH1 was found to be in contact with HCC anti-tumor drug resistance. CONCLUSIONS: The upregulation of EZH1 expression can promote the occurrence of HCC and lead to poor clinical progression and drug resistance; these effects may be mediated by regulating ATG7.

Global prevalence and risk factors associated with Toxoplasma gondii infection in wild birds: A systematic review and meta-analysis.

A systematic review and meta-analysis were performed to identify the global prevalence and factors associated with Toxoplasma gondii infection in wild birds. Six bibliographic databases (Chinese National Knowledge Infrastructure, VIP Chinese Journal Database, Wanfang Data, PubMed, Web of science and ScienceDirect) were searched from inception to February 2023. The search yielded 1220 records of which 659 articles underwent full-text evaluation, which identified 49 eligible articles and 16,030 wild bird samples that were included in the meta-analysis. The estimated pooled global prevalence of T. gondii infection in wild birds was 16.6%. Out of the variables tested, publication year after 2020 and climate type were significantly associated with T. gondii infection (P<0.01). Our data indicate that the prevalence of T. gondii in wild birds can be influenced by epidemiological variables. Further research is needed to identify the biological, environmental, anthropogenic, and geographical risk factors which impact the ecology and prevalence of T. gondii in wild birds.

[Blocking Effects of Foliar Conditioners on Cadmium, Arsenic, and Lead Accumulation in Wheat Grain in Compound-contaminated Farmland].

Heavy metal contamination of soil has become a hot issue of social concern due to its impact on the safety of agricultural products in recent years. Wheat is one of the most dominant staple food crops worldwide and has become a major source of toxic metals in human diets. Foliar application was considered to be a more efficient and economical method of heavy metal remediation. Field experiments were carried out in Cd-, As-, and Pb-contaminated farmland soils. The effects of foliar conditioners on the accumulation of Cd, As, and Pb in wheat grains were investigated after being sprayed with Zn (0.2% ZnSO4), Mg (0.4% MgSO4), and Mn (0.2% MnSO4) separately and in combination. Thus, the effective foliar conditioners were selected to block the accumulation of Cd, As, and Pb in wheat grains grown in combined heavy metal-contaminated farmland in north China. The results showed that, compared with that in the control, the Cd, As, and Pb contents in wheat grains of the Zn+Mg+Mn foliar treatment were significantly decreased by 18.96%, 23.87%, and 51.31%, respectively, and TFgrain/straw decreased by 14.62%, 27.73%, and 47.70%, respectively. Thus, spraying the compound foliar conditioner of Zn+Mg+Mn could effectively reduce heavy metal accumulation in wheat grains through inhibition translocation of those metals from stem leaves to grain. In addition, the results indicated that Cd and As were mainly distributed at the central endosperm (34.08%-37.08%), whereas Pb was primarily distributed at the pericarp and seed coat (27.78%) of the wheat grain. Compared with that in the control, spraying the compound foliar conditioner of Zn+Mg+Mn extremely decreased Cd and As accumulation in the aleurone layer of the wheat grain by 81.10% and 82.24%, respectively. Except for the pericarp, seed coat, and central endosperm layers, the Pb content in each grain layer was dramatically decreased by 42.85% to 91.15%. There was only a significant negative correlation between heavy metal content and Zn content in the aleurone layer (P2) of wheat flour. In summary, the accumulation of Cd, As, and Pb in wheat grains, especially in the aleurone layer, could be effectively reduced by foliar conditioner application at the jointing, booting, and early filling stages of wheat, separately. Furthermore, besides the foliar treatment, removing wheat bran to reduce Cd contamination in wheat grains is highly recommended to ensure the safe production of wheat.

High quality repair of osteochondral defects in rats using the extracellular matrix of antler stem cells.

BACKGROUND: Cartilage defects are some of the most common causes of arthritis. Cartilage lesions caused by inflammation, trauma or degenerative disease normally result in osteochondral defects. Previous studies have shown that decellularized extracellular matrix (ECM) derived from autologous, allogenic, or xenogeneic mesenchymal stromal cells (MSCs) can effectively restore osteochondral integrity. AIM: To determine whether the decellularized ECM of antler reserve mesenchymal cells (RMCs), a xenogeneic material from antler stem cells, is superior to the currently available treatments for osteochondral defects. METHODS: We isolated the RMCs from a 60-d-old sika deer antler and cultured them in vitro to 70% confluence; 50 mg/mL L-ascorbic acid was then added to the medium to stimulate ECM deposition. Decellularized sheets of adipocyte-derived MSCs (aMSCs) and antlerogenic periosteal cells (another type of antler stem cells) were used as the controls. Three weeks after ascorbic acid stimulation, the ECM sheets were harvested and applied to the osteochondral defects in rat knee joints. RESULTS: The defects were successfully repaired by applying the ECM-sheets. The highest quality of repair was achieved in the RMC-ECM group both in vitro (including cell attachment and proliferation), and in vivo (including the simultaneous regeneration of well-vascularized subchondral bone and avascular articular hyaline cartilage integrated with surrounding native tissues). Notably, the antler-stem-cell-derived ECM (xenogeneic) performed better than the aMSC-ECM (allogenic), while the ECM of the active antler stem cells was superior to that of the quiescent antler stem cells. CONCLUSION: Decellularized xenogeneic ECM derived from the antler stem cell, particularly the active form (RMC-ECM), can achieve high quality repair/reconstruction of osteochondral defects, suggesting that selection of decellularized ECM for such repair should be focused more on bioactivity rather than kinship.

A Biodegradable Janus Sponge for Negative Pressure Wound Therapy.

Negative pressure wound therapy (NPWT) is effective in repairing serious skin injury. The dressing used in the NPWT is important for wound healing. In this paper, we develop biodegradable amphiphilic polyurethanes (PUs) and fabricate the PUs into sponges as wound dressings (Bi@e) with Janus pore architectures for NPWT. The Bi@e is adaptive to all the stages of the wound healing process. The Janus Bi@e sponge consists of two layers: the dense hydrophobic upper layer with small pores provides protection and support during negative pressure drainage, and the loose hydrophilic lower layer with large pores absorbs large amounts of wound exudate and maintains a moist environment. Additionally, antibacterial agent silver sulfadiazine (SSD) is loaded into the sponge against Escherichia coli and Staphylococcus aureus with a concentration of 0.50 wt%. The Janus sponge exhibits a super absorbent capacity of 19.53 times its own water weight and remarkable resistance to compression. In a rat skin defect model, the Janus Bi@e sponge not only prevents the conglutination between regenerative skin and dressing but also accelerates wound healing compared to commercially available NPWT dressing. The Janus Bi@e sponge is a promising dressing for the NPWT.

A High Working Temperature Multiferroic Induced by Inverse Temperature Symmetry Breaking.

Molecular-based multiferroic materials that possess ferroelectric and ferroelastic orders simultaneously have attracted tremendous attention for their potential applications in multiple-state memory devices, molecular switches, and information storage systems. However, it is still a great challenge to effectively construct novel molecular-based multiferroic materials with multifunctionalities. Generally, the structure of these materials possess high symmetry at high temperatures, while processing an obvious order-disorder or displacement-type ferroelastic or ferroelectric phase transition triggered by symmetry breaking during the cooling processes. Therefore, these materials can only function below the Curie temperature (Tc), the low of which is a severe impediment to their practical application. Despite great efforts to elevate Tc, designing single-phase crystalline materials that exhibit multiferroic orders above room temperature remains a challenge. Here, an inverse temperature symmetry-breaking phenomenon was achieved in [FPM][Fe3(µ3-O)(µ-O2CH)8] (FPM stands for 3-(3-formylamino-propyl)-3,4,5,6-tetrahydropyrimidin-1-ium, which acts as the counterions and the rotor component in the network), enabling a ferroelastoelectric phase at a temperature higher than Tc (365 K). Upon heating from room temperature, two-step distinct symmetry breaking with the mm2Fm species leads to the coexistence of ferroelasticity and ferroelectricity in the temperature interval of 365-426 K. In the first step, the FPM cations undergo a conformational flip-induced inverse temperature symmetry breaking; in the second step, a typical ordered-disordered motion-induced symmetry breaking phase transition can be observed, and the abnormal inverse temperature symmetry breaking is unprecedented. Except for the multistep ferroelectric and ferroelastic switching, this complex also exhibits fascinating nonlinear optical switching properties. These discoveries not only signify an important step in designing novel molecular-based multiferroic materials with high working temperatures, but also inspire their multifunctional applications such as multistep switches.

Activating nickel foam with trace titanium oxide for enhanced water oxidation.

Nickel-based electrocatalysts for water oxidation suffer from low activity and poor stability. In this work, 0.015 mg cm-2 TiO2 nanosheets anchored on Ni foam addressed these problems after electrochemical activation. In situ investigations, including Raman spectra, corroborated the enhanced generation of highly active Ni(III)-O-O species on Ni foam in the presence of trace TiO2.

A modified natural small molecule inhibits triple-negative breast cancer growth by interacting with Tubb3.

BACKGROUND: Triple-negative breast cancer (TNBC) is a malignant tumor without specific therapeutic targets and a poor prognosis. Chemotherapy is currently the first-line therapeutic option for TNBC. However, due to the heterogeneity of TNBC, not all of TNBC patients are responsive to chemotherapeutic agents. Therefore, the demand for new targeted agents is critical. ß-tubulin isotype III (Tubb3) is a prognostic factor associated with cancer progression, including breast cancer, and targeting Tubb3 may lead to improve TNBC disease control. Shikonin, the active compound in the roots of Lithospermun erythrorhizon suppresses the growth of various types of tumors, and its efficacy can be improved by altering its chemical structure. PURPOSE: In this work, the anti-TNBC effect of a shikonin derivative (PMMB276) was investigated, and its mechanism was also investigated. STUDY DESIGN/METHODS: This study combines flow cytometry, immunofluorescence staining, immunoblotting, immunoprecipitation, siRNA silencing, and the iTRAQ proteomics assay to analyze the inhibition potential of PMMB276 on TNBC. In vivo study was performed, Balb/c female murine models with or without the small molecule treatments. RESULTS: Herein, we screened 300 in-house synthesized analogs of shikonin against TNBC and identified a novel small molecule, PMMB276; it suppressed cell proliferation, induced apoptosis, and arrested the cell cycle at the G2/M phase, suggesting that it could have a tumor suppressive role in TNBC. Tubb3 was identified as the target of PMMB276 using proteomic and biological activity analyses. Meanwhile, PMMB276 regulated microtubule dynamics in vitro by inducing microtubule depolymerization and it could act as a tubulin stabilizer by a different process than that of paclitaxel. Moreover, suppressing or inhibiting Tubb3 with PMMB276 reduced the growth of breast cancer in an experimental mouse model, indicating that Tubb3 plays a significant role in TNBC progression. CONCLUSION: The findings support the therapeutic potential of PMMB276, a Tubb3 inhibitor, as a treatment for TNBC. Our findings might serve as a foundation for the utilization of shikonin and its derivatives in the development of anti-TNBC.

NatD epigenetically activates FOXA2 expression to promote breast cancer progression by facilitating MMP14 expression.

N-α-acetyltransferase D (NatD) mediates N-α-terminal acetylation of histone H4 (Nt-Ac-H4), but its role in breast cancer metastasis remains unknown. Here, we show that depletion of NatD directly represses the expression of FOXA2, and is accompanied by a significant reduction in Nt-Ac-H4 enrichment at the FOXA2 promoter. We show that NatD is commonly upregulated in primary breast cancer tissues, where its expression level correlates with FOXA2 expression, enhanced invasiveness, and poor clinical outcomes. Furthermore, we show that FOXA2 promotes the migration and invasion of breast cancer cells by activating MMP14 expression. MMP14 is also upregulated in breast cancer tissues, where its expression level correlates with FOXA2 expression and poor clinical prognosis. Our study shows that the NatD-FOXA2-MMP14 axis functions as a key signaling pathway to promote the migratory and invasive capabilities of breast cancer cells, suggesting that NatD is a critical epigenetic modulator of cell invasion during breast cancer progression.

The expression levels of chemotaxis-related molecules CXC chemokine receptor 1, interleukin-8, and pro-platelet basic protein in gingival tissues.

Background/purpose: Excessive host immune response is thought to be an important cause of periodontal tissue damage during periodontitis. The potent chemotaxis produced by locally released chemokines is the key signal to trigger this response. Here, we aimed to investigate the expression of CXC chemokine receptor 1 (CXCR1), and chemokines interleukin-8 (IL-8) and pro-platelet basic protein (PPBP) in human inflammatory gingival tissues compared with healthy tissues. Materials and methods: A total of 54 human gingival tissues, 27 healthy and 27 inflammatory samples, were collected. Fifteen specimens of each group were employed for quantitative reverse transcription polymerase chain reaction to determine the mRNA levels of CXCR1, IL-8, and PPBP. Six samples of each group were used for Western blotting to investigate the protein expression of CXCR1 and for enzyme-linked immunosorbent assay to evaluate the protein levels of IL-8 and PPBP, respectively. Results: The mRNA levels of chemokine receptor CXCR1, chemokine IL-8, and PPBP in inflammatory gingival tissues were significantly higher than those in healthy controls (P < 0.05). The protein levels of CXCR1, IL-8, and PPBP in inflammatory gingival tissues were also significantly higher than those in healthy gingival tissues (P < 0.05). Conclusion: When compared to healthy gingival tissues, the expression of CXCR1, IL-8, and PPBP in inflammatory gingival tissues is higher.

High-toughness, extensile and self-healing PDMS elastomers constructed by decuple hydrogen bonding.

Elastomers are widely used in traditional industries and new intelligent fields. However, they are inevitably damaged by electricity, heat, force, etc. during the working process. With the continuous improvement of reliability and environmental protection requirements in human production and living, it is vital to develop elastomer materials with good mechanical properties that are not easily damaged and can self-heal after being damaged. Nevertheless, there are often contradictions between mechanical properties and self-healing as well as toughness, strength, and ductility. Herein, a strong and dynamic decuple hydrogen bonding based on carbon hydrazide (CHZ) is reported, accompanied with soft polydimethylsiloxane (PDMS) chains to prepare self-healing (efficiency 98.7%), recyclable, and robust elastomers (CHZ-PDMS). The strategy of decuple hydrogen bonding will significantly impact the study of the mechanical properties of elastomers. High stretchability (1731%) and a high toughness of 23.31 MJ m-3 are achieved due to the phase-separated structure and energy dissipation. The recyclability of CHZ-PDMS further supports the concept of environmental protection. The application of CHZ-PDMS as a flexible strain sensor exhibited high sensitivity.

Global prevalence of Plasmodium infection in wild birds: A systematic review and meta-analysis.

Avian malaria is a vector-borne parasitic disease caused by Plasmodium infection transmitted to birds by mosquitoes. The aim of this systematic review was to analyze the global prevalence of malaria and risk factors associated with infection in wild birds. A systematic search of the databases CNKI, WanFang, VIP, PubMed, and ScienceDirect was performed from database inception to 24 February 2023. The search identified 3181 retrieved articles, of which 52 articles met predetermined inclusion criteria. Meta-analysis was performed using the random-effects model. The estimated pooled global prevalence of Plasmodium infection in wild birds was 16%. Sub-group analysis showed that the highest prevalence was associated with adult birds, migrant birds, North America, tropical rainforest climate, birds captured by mist nets, detection of infection by microscopy, medium quality studies, and studies published after 2016. Our study highlights the need for more understanding of Plasmodium prevalence in wild birds and identifying risk factors associated with infection to inform future infection control measures.

FOXA2 activates HIF2α expression to promote tumor progression and is regulated by the E3 ubiquitin ligase VHL in renal cell carcinoma.

Renal cell carcinoma (RCC) is a frequent malignancy of the urinary system with high mortality and morbidity. However, the molecular mechanisms underlying RCC progression are still largely unknown. In this study, we identified FOXA2, a pioneer transcription factor, as a driver oncogene for RCC. We show that FOXA2 was commonly upregulated in human RCC samples and promoted RCC proliferation, as evidenced by assays of cell viability, colony formation, migratory and invasive capabilities, and stemness properties. Mechanistically, we found that FOXA2 promoted RCC cell proliferation by transcriptionally activating HIF2α expression in vitro and in vivo. Furthermore, we found that FOXA2 could interact with VHL (von Hippel‒Lindau), which ubiquitinated FOXA2 and controlled its protein stability in RCC cells. We showed that mutation of lysine at position 264 to arginine in FOXA2 could mostly abrogate its ubiquitination, augment its activation effect on HIF2α expression, and promote RCC proliferation in vitro and RCC progression in vivo. Importantly, elevated expression of FOXA2 in patients with RCC positively correlated with the expression of HIF2α and was associated with shorter overall and disease-free survival. Together, these findings reveal a novel role of FOXA2 in RCC development and provide insights into the underlying molecular mechanisms of FOXA2-driven pathological processes in RCC.