C. elegans spermatocyte divisions show a weak spindle checkpoint response.

Male meiotic division exhibits two consecutive chromosome separation events without apparent pausing. Several studies have shown that spermatocyte divisions are not stringently regulated as in mitotic cells. In this study, we investigated the role of the canonical spindle assembly (SAC) pathway in Caenorhabditis elegans spermatogenesis. We found the intensity of chromosome-associated outer kinetochore protein BUB-1 and SAC effector MDF-1 oscillates between the two divisions. However, the SAC target securin is degraded during the first division and remains undetectable for the second division. Inhibition of proteasome-dependent protein degradation did not affect the progression of the second division but stopped the first division at metaphase. Perturbation of spindle integrity did not affect the duration of meiosis II, and only slightly lengthened meiosis I. Our results demonstrate that male meiosis II is independent of SAC regulation, and male meiosis I exhibits only weak checkpoint response.

PAFAH2 suppresses synchronized ferroptosis to ameliorate acute kidney injury.

Synchronized ferroptosis contributes to nephron loss in acute kidney injury (AKI). However, the propagation signals and the underlying mechanisms of the synchronized ferroptosis for renal tubular injury remain unresolved. Here we report that platelet-activating factor (PAF) and PAF-like phospholipids (PAF-LPLs) mediated synchronized ferroptosis and contributed to AKI. The emergence of PAF and PAF-LPLs in ferroptosis caused the instability of biomembranes and signaled the cell death of neighboring cells. This cascade could be suppressed by PAF-acetylhydrolase (II) (PAFAH2) or by addition of antibodies against PAF. Genetic knockout or pharmacological inhibition of PAFAH2 increased PAF production, augmented synchronized ferroptosis and exacerbated ischemia/reperfusion (I/R)-induced AKI. Notably, intravenous administration of wild-type PAFAH2 protein, but not its enzymatically inactive mutants, prevented synchronized tubular cell death, nephron loss and AKI. Our findings offer an insight into the mechanisms of synchronized ferroptosis and suggest a possibility for the preventive intervention of AKI.

Germline mutations of homologous recombination genes and clinical outcomes in pancreatic cancer: a multicenter study in Taiwan.

BACKGROUND: Cancer susceptibility germline mutations are associated with pancreatic ductal adenocarcinoma (PDAC). However, the hereditary status of PDAC and its impact on survival is largely unknown in the Asian population. METHODS: Exome sequencing was performed on 527 blood samples from PDAC individuals and analyzed for mutations in 80 oncogenic genes. Pathogenic and likely pathogenic (P/LP) germline variants were diagnosed according to the ACMG variant classification categories. The association between germline homologous recombination gene mutations (gHRmut, including BAP1, BRCA1, BRCA2, PALB2, ATM, BLM, BRIP1, CHEK2, NBN, MUTYH, FANCA and FANCC) and the treatment outcomes was explored in patients with stage III/IV diseases treated with first-line (1L) platinum-based versus platinum-free chemotherapy. RESULTS: Overall, 104 of 527 (19.7%) patients carried germline P/LP variants. The most common mutated genes were BRCA2 (3.60%), followed by ATR (2.66%) and ATM (1.9%). After a median follow-up duration of 38.3-months (95% confidence interval, 95% CI 35.0-43.7), the median overall survival (OS) was not significantly different among patients with gHRmut, non-HR germline mutations, or no mutation (P = 0.43). Among the 320 patients with stage III/IV disease who received 1L combination chemotherapy, 32 (10%) had gHRmut. Of them, patients receiving 1L platinum-based chemotherapy exhibited a significantly longer median OS compared to those with platinum-free chemotherapy, 26.1 months (95% CI 12.7-33.7) versus 9.6 months (95% CI 5.9-17.6), P = 0.001. However, the median OS of patients without gHRmut was 14.5 months (95% CI 13.2-16.9) and 12.6 months (95% CI 10.8-14.7) for patients receiving 1L platinum-based and platinum-free chemotherapy, respectively (P = 0.22). These results were consistent after adjusting for potential confounding factors including age, tumor stage, performance status, and baseline CA 19.9 in the multivariate Cox regression analysis. CONCLUSIONS: Our study showed that nearly 20% of Taiwanese PDAC patients carried germline P/LP variants. The longer survival observed in gHRmut patients treated with 1L platinum-based chemotherapy highlights the importance of germline testing for all patients with advanced PDAC at diagnosis.

Highly Efficient Photocatalytic Degradation of Organic Pollutants Using a Polyvinylidene Fluoride/Polyvinylpyrrolidone-Cuprous Oxide Composite Membrane.

Enhancing the efficiency of photocatalysts in the removal of organic pollutants is of vital importance in wastewater treatment. In this work, a set of composite membranes that can be used for efficient removal of the organic dyes, such as methyl orange (MO), methylene blue (MB), and Congo red (CR), were prepared through coblending/electrospinning techniques using polyvinylidene fluoride (PVDF) as the substrate, polyvinylpyrrolidone (PVP) as the dispersing agent and wettability regulator, and cuprous oxide (Cu2O) as the photocatalyst. The results showed that Cu2O particles were well encapsulated in the electrospun PVDF/PVP fibers, and the composite membranes exhibited apparently enhanced hydrophilicity. Furthermore, compared with the pure Cu2O particles, the composite membranes not only showed a higher photocatalytic degradation ratio for MO (93.6%) but also showed a much higher degradation rate (62.4 mg/(mg·h)) in comparison with the other reported Cu2O-based composite photocatalytic materials in the literature. In addition, the membrane sample also had excellent recycling stability, and the retention rate of its removal ability maintained 92.1% after 5 times of recycling. Furthermore, the composite membranes also showed high removal ability toward MB and CR, with photocatalytic degradation ratios of 81.4 and 76.1%, respectively. This work indicates that the prepared PVDF/PVP-Cu2O composite membranes possess promising application prospects in wastewater treatment.

Photosensitive and dual-targeted chromium nanoparticle delivering small interfering RNA YTHDF1 for molecular-targeted immunotherapy in liver cancer.

Tumor-associated macrophages (TAMs) are a promising target for cancer immunotherapy, but delivering therapeutic agents to TAMs within the tumor microenvironment (TME) is challenging. In this study, a photosensitive, dual-targeting nanoparticle system (M.RGD@Cr-CTS-siYTHDF1 NPs) was developed. The structure includes a shell of DSPE-modified RGD peptides targeting integrin receptors on tumor cells and carboxymethyl mannose targeting CD206 receptors on macrophages, with a core of chitosan adsorbing m6A reading protein YTHDF1 siRNA and chromium nanoparticles (Cr NPs). The approach is specifically designed to target TAM and cancer cells, utilizing the photothermal effect of Cr NPs to disrupt the TME and deliver siYTHDF1 to TAM. In experiments with tumor-bearing mice, M.RGD@Cr-CTS-siYTHDF1 NPs, when exposed to laser irradiation, effectively killed tumor cells, disrupted the TME, delivered siYTHDF1 to TAMs, silenced the YTHDF1 gene, and shifted the STAT3-STAT1 equilibrium by reducing STAT3 and enhancing STAT1 expression. This reprogramming of TAMs towards an anti-tumor phenotype led to a pro-immunogenic TME state. The strategy also suppressed immunosuppressive IL-10 production, increased expression of immunostimulatory factors (IL-12 and IFN-γ), boosted CD8 + T cell infiltration and M1-type TAMs, and reduced Tregs and M2-type TAMs within the TME. In conclusion, the dual-targeting M.RGD@Cr-CTS-siYTHDF1 NPs, integrating dual-targeting capabilities with photothermal therapy (PTT) and RNA interference, offer a promising approach for molecular targeted cancer immunotherapy with potential for clinical application.

Translational PK/PD framework for antibody-drug conjugates to inform drug discovery and development.

(171/200)ADCs represent a transformative class of medicine that combines the specificity of monoclonal antibodies with the potency of highly cytotoxic agents through linkers, aiming to enhance the therapeutic index of cytotoxic drugs. Given the complex molecular structures of ADCs, combining the molecular characteristics of small-molecule drugs and those of large-molecule biotherapeutics, there are several unique considerations when designing nonclinical-to-clinical PK/PD translation strategies.This complexity also demands a thorough understanding of the ADC's components-antibody, linker, and payload-to the overall toxicological, PK/PD, and efficacy profile. ADC development is a multidisciplinary endeavor requiring a strategic integration of nonclinical safety, pharmacology, and PK/PD modeling to translate from bench to bedside successfully.The ADC development underscores the necessity for a robust scientific foundation, leveraging advanced analytical and modeling tools to predict human responses and optimize therapeutic outcomes.This review aims to provide an ADC translational PK/PD framework by discussing unique aspects of ADC nonclinical to clinical PK translation, starting dose determination, and leveraging PK/PD modeling for human efficacious dose prediction and potential safety mitigation.

Associations between immune cell phenotypes and lung cancer subtypes: insights from mendelian randomization analysis.

INTRODUCTION: Lung cancer is a common malignant tumor, and different types of immune cells may have different effects on the occurrence and development of lung cancer subtypes, including lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD). However, the causal relationship between immune phenotype and lung cancer is still unclear. METHODS: This study utilized a comprehensive dataset containing 731 immune phenotypes from the European Bioinformatics Institute (EBI) to evaluate the potential causal relationship between immune phenotypes and LUSC and LUAD using the inverse variance weighted (IVW) method in Mendelian randomization (MR). Sensitivity analyses, including MR-Egger intercept, Cochran Q test, and others, were conducted for the robustness of the results. The study results were further validated through meta-analysis using data from the Transdisciplinary Research Into Cancer of the Lung (TRICL) data. Additionally, confounding factors were excluded to ensure the robustness of the findings. RESULTS: Among the final selection of 729 immune cell phenotypes, three immune phenotypes exhibited statistically significant effects with LUSC. CD28 expression on resting CD4 regulatory T cells (OR 1.0980, 95% CI: 1.0627-1.1344, p < 0.0001) and CD45RA + CD28- CD8 + T cell %T cell (OR 1.0011, 95% CI: 1.0007; 1.0015, p < 0.0001) were associated with increased susceptibility to LUSC. Conversely, CCR2 expression on monocytes (OR 0.9399, 95% CI: 0.9177-0.9625, p < 0.0001) was correlated with a decreased risk of LUSC. However, no significant causal relationships were established between any immune cell phenotypes and LUAD. CONCLUSION: This study demonstrates that specific immune cell types are associated with the risk of LUSC but not with LUAD. While these findings are derived solely from European populations, they still provide clues for a deeper understanding of the immunological mechanisms underlying lung cancer and may offer new directions for future therapeutic strategies and preventive measures.

Brominated Depsidones with Antibacterial Effects from a Deep-Sea-Derived Fungus Spiromastix sp.

Eleven new brominated depsidones, namely spiromastixones U-Z5 (1-11) along with five known analogues (12-16), were isolated from a deep-sea-derived fungus Spiromastix sp. through the addition of sodium bromide during fermentation. Their structures were elucidated by extensive analysis of the spectroscopic data including high-resolution MS and 1D and 2D NMR data. Compounds 6-10 and 16 exhibited significant inhibition against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE) with MIC values ranging from 0.5 to 2.0 µM. Particularly, tribrominated 7 displayed the strongest activity against MRSA and VRE with a MIC of 0.5 and 1.0 µM, respectively, suggesting its potential for further development as a new antibacterial agent.

RSPO2-associated mitochondrial metabolism defines molecular subtypes with distinct clinical and immune features in esophageal cancer.

BACKGROUND: Esophageal cancer is a highly aggressive malignancy with limited treatment options and poor prognosis. The identification of novel molecular subtypes and therapeutic targets is crucial for improving clinical outcomes. METHOD: In this study, we investigated the role of R-spondin 2 (RSPO2) in esophageal cancer and its association with mitochondrial metabolism. Using bioinformatics analysis of publicly available datasets, we identified a panel of RSPO2-related mitochondrial metabolism genes and their expression patterns in esophageal cancer. Based on these genes, we stratified esophageal cancer patients into distinct molecular subtypes with different survival rates, immune cell infiltration profiles, and drug sensitivities. RESULTS: Our findings suggest that RSPO2-related mitochondrial metabolism genes may serve as potential therapeutic targets and prognostic markers for esophageal cancer. These genes play an important role in the prognosis, immune cell infiltration and drug sensitivity of esophageal cancer. CONCLUSION: The identified molecular subtypes provide valuable insights into the underlying molecular mechanisms of esophageal cancer and could guide personalized treatment strategies in the future.

Experimental Observation of Highly Anisotropic Elastic Properties of Two-Dimensional Black Arsenic.

Anisotropic two-dimensional layered materials with low-symmetry lattices have attracted increasing attention due to their unique orientation-dependent mechanical properties. Black arsenic (b-As), with the puckered structure, exhibits extreme in-plane anisotropy in optical, electrical, and thermal properties. However, experimental research on mechanical properties of b-As is very rare, although theoretical calculations predicted the exotic elastic properties of b-As, such as the anisotropic Young's modulus and negative Poisson's ratio. Herein, experimental observations on highly anisotropic elastic properties of b-As were demonstrated using our developed in situ tensile straining setup based on the effective microelectromechanical system. The cyclic and repeatable load-displacement curves proved that Young's modulus along the zigzag direction was ∼1.6 times greater than that along the armchair direction, while the anisotropic ratio of ultimate strain reached ∼2.5, attributed to the hinge structure in the armchair direction. This study could provide significant insights into the design of novel anisotropic materials and explore their potential applications in nanomechanics and nanodevices.

Integrated Transcriptomic and Proteomic Study of the Mechanism of Action of the Novel Small-Molecule Positive Allosteric Modulator 1 in Targeting PAC1-R for the Treatment of D-Gal-Induced Aging Mice.

Small-molecule positive allosteric modulator 1 (SPAM1), which targets pituitary adenylate cyclase-activating polypeptide receptor 1 (PAC1-R), has been found to have a neuroprotective effect, and the underlying mechanism was explored in this study. First, using a D-galactose (D-gal)-induced aging mouse model, we confirmed that SPAM1 improves the structure of the hippocampal dentate gyrus and restores the number of neurons. Compared with D-gal model mice, SPAM1-treated mice showed up-regulated expression of Sirtuin 6 (SIRT6) and Lamin B1 and down-regulated expression of YinYang 1 (YY1) and p16. A similar tendency was observed in senescent RGC-5 cells induced by long-term culture, indicating that SPAM1 exhibits significant in vitro and in vivo anti-senescence activity in neurons. Then, using whole-transcriptome sequencing and proteomic analysis, we further explored the mechanism behind SPAM1's neuroprotective effects and found that SPAM is involved in the longevity-regulating pathway. Finally, the up-regulation of neurofilament light and medium polypeptides indicated by the proteomics results was further confirmed by Western blotting. These results help to lay a pharmacological network foundation for the use of SPAM1 as a potent anti-aging therapeutic drug to combat neurodegeneration with anti-senescence, neuroprotective, and nerve regeneration activity.

Biomarkers Screening and Mechanisms Analysis of the Restraint Stress-Induced Myocardial Injury in Hyperlipidemia ApoE-/- Mice.

OBJECTIVES: To explore the biomarkers and potential mechanisms of chronic restraint stress-induced myocardial injury in hyperlipidemia ApoE-/- mice. METHODS: The hyperlipidemia combined with the chronic stress model was established by restraining the ApoE-/- mice. Proteomics and bioinformatics techniques were used to describe the characteristic molecular changes and related regulatory mechanisms of chronic stress-induced myocardial injury in hyperlipidemia mice and to explore potential diagnostic biomarkers. RESULTS: Proteomic analysis showed that there were 43 significantly up-regulated and 58 significantly down-regulated differentially expressed proteins in hyperlipidemia combined with the restraint stress group compared with the hyperlipidemia group. Among them, GBP2, TAOK3, TFR1 and UCP1 were biomarkers with great diagnostic potential. KEGG pathway enrichment analysis indicated that ferroptosis was a significant pathway that accelerated the myocardial injury in hyperlipidemia combined with restraint stress-induced model. The mmu_circ_0001567/miR-7a/Tfr-1 and mmu_circ_0001042/miR-7a/Tfr-1 might be important circRNA-miRNA-mRNA regulatory networks related to ferroptosis in this model. CONCLUSIONS: Chronic restraint stress may aggravate myocardial injury in hyperlipidemia mice via ferroptosis. Four potential biomarkers are selected for myocardial injury diagnosis, providing a new direction for sudden cardiac death (SCD) caused by hyperlipidemia combined with the restraint stress.

The emergence of RAS mutations in patients with RAS wild-type mCRC receiving cetuximab as first-line treatment: a noninterventional, uncontrolled multicenter study.

ABSRTACT: BACKGROUND: Patients treated with anti-epidermal growth factor receptor (anti-EGFR) will ultimately develop acquired resistance promoted by clonal selection, mainly the emergence of mutations in the MAPK pathway (mostly RAS mutations). Baseline assessment of RAS mutations in the blood of patients correlates well with RAS tumour tissue testing and is currently an alternative option in routine clinical practice to guide first-line therapy. The aim of this study was the prevalence of acquired genomic alterations detected in the auxiliary tool of ctDNA testing and investigated the role of RAS ctDNA status for detecting tumour response and predicting benefit to anti-EGFR therapy. METHODS: Only patients with concordant wild-type formalin-fixed, paraffin-embedded (FFPE) tumour tissue and baseline ctDNA RAS wild-type were included. RAS mutations in plasma were evaluated using MassARRAY platform. Blood samples were collected at baseline, every 3 months during first-line treatment, and at disease progression. The primary endpoint was the detection rate of RAS mutations during cetuximab treatment. The correlation between response and survival outcomes and the emergence of circulating RAS mutations was also analysed. RESULTS: The detection rate of RAS mutations during treatment was 9.3% (10/108). RAS mutations detection occurred a median of 3 months prior to radiologic documentation. The subgroup of patients with RAS mutations exhibited significantly inferior progression-free survival and overall survival (P = 0.002 and 0.027, respectively) but the baseline characteristics, response rates, disease control rates, and metastatectomy were not significant (all P > 0.05). CONCLUSIONS: We demonstrated that RAS ctDNA status might be a valuable biomarker for detecting early tumour response and predicting benefit to anti-EGFR therapy. CLINICAL TRIAL REGISTRATION: NCT03401957 (January 17, 2018).

Growing Electrocatalytic Conjugated Microporous Polymers on Self-Standing Carbon Nanotube Films Promotes the Rate Capability of Li-S Batteries.

Lithium-sulfur (Li-S) batteries hold great promise for widespread application on account of their high theoretical energy density (2600 Wh kg-1 ) and the advantages of sulfur. Practical use, however, is impeded by the shuttle effect of polysulfides along with sluggish cathode kinetics. it is reported that such deleterious issues can be overcome by using a composite film (denoted as V-CMP@MWNT) that consists of a conjugated microporous polymer (CMP) embedded with vanadium single-atom catalysts (V SACs) and a network of multi-walled carbon nanotubes (MWNTs). V-CMP@MWNT films are fabricated by first electropolymerizing a bidentate ligand designed to coordinate to V metals on self-standing MWNT films followed by treating the CMP with a solution containing V ions. Li-S cells containing a V-CMP@MWNT film as interlayer exhibit outstanding performance metrics including a high cycling stability (616 mA h g-1 at 0.5 C after 1000 cycles) and rate capability (804 mA h g-1 at 10 C). An extraordinary area-specific capacity of 13.2 mA h cm-2 is also measured at a high sulfur loading of 12.2 mg cm-2 . The underlying mechanism that enables the V SACs to promote cathode kinetics and suppress the shuttle effect is elucidated through a series of electrochemical and spectroscopic techniques.

Dual role of sprouty2 as an inhibitor of RAS/ERK-driven proliferation and a promoter of cancer invasion in KRAS wild-type colorectal cancer.

Sprouty2 (SPRY2) is known to inhibit the RAS/MAPK/ERK pathway, and is a potential study target for cancer. The effect of SPRY2 in colorectal cancer (CRC) and whether it is influenced by KRAS mutation are not known. We manipulated SPRY2 gene expression and used an activating KRAS-mutant plasmid to determine its effect on CRC cell function in vitro and/or in vivo. We performed SPRY2 immunohistochemical staining in 143 CRC specimens and analyzed the staining results with various clinicopathological characteristics in relation to KRAS mutation status. SPRY2 knockdown in Caco-2 cells carrying the wild-type (WT) KRAS gene upregulated phosphorylated ERK (p-ERK) levels and increased cell proliferation in vitro, but inhibited cell invasion. However, SPRY2 knockdown in SW480 cells (activating KRAS mutant) or Caco-2 cells transfected with KRAS-mutant plasmid did not significantly alter p-ERK levels, cell proliferation, or invasion. The xenografts of SPRY2-knockdown Caco-2 cells were larger with less deep muscle invasion than those of control cells. The clinical cohort study revealed a positive association of SPRY2 protein expression with pT status, lymphovascular invasion, and perineural invasion in KRAS-WT CRCs. However, the associations were not observed in KRAS-mutant CRCs. Interestingly, high SPRY2 expression was related to shorter cancer-specific survival in both KRAS-WT and KRAS-mutant CRC patients. Our study demonstrated the dual role of SPRY2 as an inhibitor of RAS/ERK-driven proliferation and as a promoter of cancer invasion in KRAS-WT CRC. SPRY2 may promote the invasion and progression of KRAS-WT CRC, and might also enhance KRAS-mutant CRC progression through pathways other than invasion.

SUMO and PIAS repress NF-κB activation in a basal chordate.

Small ubiquitin-like modifier (SUMO) regulates various biological processes, including the MyD88/TICAMs-IRAKs-TRAF6-NF-κB pathway, one of the core immune pathways. However, its functions are inconsistent between invertebrates and vertebrates and have rarely been investigated in lower chordates, including amphioxus and fishes. Here, we investigated the SUMOylation gene system in the amphioxus, a living basal chordate. We found that amphioxus has a SUMOylation system that has a complete set of genes and preserves several ancestral traits. We proceeded to study their molecular functions using the mammal cell lines. Both amphioxus SUMO1 and SUMO2 were shown to be able to attach to NF-κB Rel and to inhibit NF-κB activation by 50-75% in a dose-dependent fashion. The inhibition by SUMO2 could be further enhanced by the addition of the SUMO E2 ligase UBC9. In comparison, while human SUMO2 inhibited RelA, human SUMO1 slightly activated RelA. We also showed that, similar to human PIAS1-4, amphioxus PIAS could serve as a SUMO E3 ligase and promote its self-SUMOylation. This suggests that amphioxus PIAS is functionally compatible in human cells. Moreover, we showed that amphioxus PIAS is not only able to inhibit NF-κB activation induced by MyD88, TICAM-like, TRAF6 and IRAK4 but also able to suppress NF-κB Rel completely in the presence of SUMO1/2 in a dose-insensitive manner. This suggests that PIAS could effectively block Rel by promoting Rel SUMOylation. In comparison, in humans, only PIAS3, but not PIAS1/2/4, has been reported to promote NF-κB SUMOylation. Taken together, the findings from amphioxus, together with those from mammals and other species, not only offer insights into the functional volatility of the animal SUMO system, but also shed light on its evolutionary transitions from amphioxus to fish, and ultimately to humans.

Enhancement of hair growth through stimulation of hair follicle stem cells by prostaglandin E2 collagen matrix.

Prostaglandin metabolism is involved in the regulation of the periodic process of hair follicles. Preliminary research data reported that prostaglandin E2 (PGE2) exhibits potential in hair growth. However, the relevant evidence is still insufficient. Herein, we prepared a PGE2 matrix by conjugating PGE2 with collagen via crosslinkers to avoid rapid degradation of PGE2 molecules in vivo. First, we measured the physical properties of the PGE2 matrix. A mouse model of hair loss was established, and PGE2 matrix subcutaneous injection was applied to evaluate hair growth. Under different treatments with the PGE2 matrix, the morphology of hair follicles, the dynamic expression of hair follicle stem cell markers and key regulators in the hair growth cycle were explored. Our data revealed that the PGE2 matrix increased the proportion of developing hair follicles at the early growth stage. Improvements in hair follicle stem cells, such as Sox9+ and Lgr5+ cells, have also been confirmed as therapeutic effects of PGE2 to stimulate hair follicle growth. Our study indicated that PGE2 exhibits effective roles in hair development during anagen. Furthermore, the results also highlight the potential of the PGE2 delivery system as a novel therapeutic strategy for the treatment of hair disorders in the future.

Delivery of Mir-196c-3p with NIR-II light-triggered gel attenuates cardiomyocyte ferroptosis in cardiac ischemia-reperfusion injury.

Ferroptosis plays an important role in ischemia-reperfusion (I/R)-induced cardiac injury and there are many defects in current targeted delivery of miRNAs for the treatment of ferroptosis. We herein report a unique hydrogel (Gel) that can be triggered by a near-infrared-II (NIR-II) light with deep tissue penetration and biocompatible maximum permissible exposure (MPE) value for in situ treatment after I/R. The mir-196c-3p mimic (mimics) and photothermal nanoparticles (BTN) were co-encapsulated in an injectable Gel (mimics + Gel/BTN) with NIR-II light-triggered release. Using 1064 nm light irradiation, local microenvironment photothermal-triggered on-demand noninvasive controllable delivery of miRNA was achieved, aiming to inhibit I/R-induced ferroptosis. Consequently, declined ferroptosis in cardiomyocytes and improved cardiac function, survival rate in rats was achieved through the controlled release of Gel/BTN mimics in I/R model to simultaneously inhibit ferroptosis hub genes NOX4, P53, and LOX expression.

Association of spinopelvic index with proximal junctional failure developing in adult spinal deformity after surgical treatment: an observational study.

BACKGROUND: Those pelvic parameters of sacral slope (SS) and pelvic tilt (PT) correlated significantly to lumbar spine and hip joints respectively. We proposed the match between SS and PT, namely spinopelvic index (SPI), in order to investigate whether the SPI correlated to proximal junctional failure (PJF) in adult spinal deformity (ASD) after correction surgery. METHODS: Ninety-nine ASD patients who had undergone long-fusion (≥ 5 vertebras) surgeries were reviewed retrospectively in two medical institutions from January 2018 to December 2019. Those SPI were calculated with the equation: SPI = SS/PT, and analyzed using the receiver operating characteristic curve (ROC) analysis. All participants were subdivided into the observational and control group. Comparisons of demographics, surgical and radiographic data between the two groups were performed. A Kaplan-Meier curve and log-rank test was used to analyze the differences in PJF-free survival time, and the 95% confidence intervals (CI) were recorded respectively. RESULTS: Nineteen patients suffering from PJF had much smaller postoperative SPI (P = 0.015), but much larger TK postoperatively (P < 0.001). ROC analysis determined the best cutoff value of 0.82 for SPI (sensitivity = 88.5%, specificity = 57.9%; AUC = 0.719, 95%CI: 0.612-0.864; P = 0.003). There were 19 and 80 cases in the observational (SPI ≤ 0.82) and control group (SPI > 0.82) respectively. The incidence of PJF in the observational group was much higher (11/19 VS 8/80, P < 0.001); further logistic regression analysis showed that SPI ≤ 0.82 was associated with increased odds of PJF (odds ratio: 12.375; 95%CI: 3.851-39.771). PJF-free survival time in the observational group decreased significantly (P < 0.001, log-rank test), moreover, multivariate analysis demonstrated that a value of SPI ≤ 0.82 (HR 6.626, 95%CI: 1.981-12.165) was significantly associated with PJF. CONCLUSIONS: For ASD patients underwent long-fusion surgeries, the SPI should be over 0.82. The incidence of PJF may increase by 12-fold in such individuals with the immediate SPI ≤ 0.82 postoperatively.

Sulforaphane suppresses skin squamous cell carcinoma cells proliferation through miR-199a-5p/Sirt1/CD44ICD signaling pathway.

BACKGROUND: The present study aimed to explore the impact of sulforaphane on the growth of sSCC cells, and the activation of miR-199a-5p/Sirt1 and CD44ICD signaling pathways. METHODS: Cell viability, count, apoptosis, and invasion assays were performed in the sSCC cell line (SCC-13) in which miR-199a-5p was over-expressed or under-expressed. The expression levels of miR-199a-5p, Sirt1 and CD44ICD mRNA were measured by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Sulforaphane significantly inhibited the cell growth and invasion of SCC-13 cells, and dramatically induced cell apoptosis. Additionally, sulforaphane also greatly increased miR-199a-5p expression and suppressed Sirt1 and CD44ICD mRNA levels. Moreover, miR-199a-5p overexpression considerably down-regulated the expressions of Sirt1 and CD44ICD mRNA, and promoted the ability of sulforaphane to represses cell growth and invasion, and to induce cell apoptosis. However, miR-199a-5p underexpression has the opposite effects. CONCLUSIONS: Sulforaphane appears to inhibit sCC progression by impacting its growth and invasion ability, and regulates miR-199a-5p/Sirt1 and CD44ICD signaling pathways, and may be utilized to develop a curative approach for sSCC.