Pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer and brain metastases (PERMEATE trial): overall survival results from a multicenter, single-arm, two-cohort, phase 2 trial.

Background: The phase 2 PERMEATE study has shown the antitumor activity and safety of pyrotinib plus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer and brain metastases. In this report, survival results were updated with extended follow-up. Methods: Between January 29, 2019 and July 10, 2020, adult patients with HER2-positive metastatic breast cancer who had radiotherapy-naïve brain metastases (cohort A, n = 59) or progressive disease after radiotherapy (cohort B, n = 19) were enrolled and received pyrotinib (400 mg once daily) and capecitabine (1000 mg/m2 twice daily on days 1-14 of each 21-day cycle) until disease progression or unacceptable toxicity. Secondary endpoints progression-free survival (PFS) and overall survival (OS) were updated, and post-hoc central nervous system (CNS)-PFS was analyzed. This study is registered with ClinicalTrials.gov (NCT03691051). Findings: As of February 2, 2023, the median follow-up duration was 30.9 months (interquartile range, 16.1-39.8). Median PFS was 10.9 months (95% confidence interval [CI], 7.6-14.6) in cohort A and 5.7 months (95% CI, 3.4-11.5) in cohort B. Median OS was 35.9 months (95% CI, 24.4-not reached) in cohort A and 30.6 months (95% CI, 12.6-33.3) in cohort B. Median CNS-PFS was 13.6 months (95% CI, 9.0-15.8) in cohort A and 5.7 months (95% CI, 3.4-11.5) in cohort B. Median OS was 34.1 months (95% CI, 21.7-not reached) for 14 patients with intracranial progression only in cohort A who restarted pyrotinib plus capecitabine after local radiotherapy. Interpretation: These data support further validation in a randomized controlled trial for the assessment of pyrotinib in combination with capecitabine as systemic therapy for patients with HER2-positive breast cancer and brain metastases. Funding: National Cancer Center Climbing Foundation Key Project of China, Jiangsu Hengrui Pharmaceuticals.

Columbianadin ameliorates rheumatoid arthritis by attenuating synoviocyte hyperplasia through targeted vimentin to inhibit the VAV2/Rac-1 signaling pathway.

INTRODUCTION: Rheumatoid arthritis (RA) is an autoimmune disease pathologically characterized by synovial inflammation. The abnormal activation of synoviocytes seems to accompany the progression of RA. The role and exact molecular mechanism in RA of columbianadin (CBN) which is a natural coumarin is still unclear. OBJECTIVES: The present research aimed to investigate the effect of vimentin on the abnormal growth characteristics of RA synoviocytes and the targeted regulatory role of CBN. METHODS: Cell migration and invasion were detected using the wound healing and transwell method. Mechanistically, the direct molecular targets of CBN were screened and identified by activity-based protein profiling. The expression of relevant proteins and mRNA in cells and mouse synovium was detected by western blotting and qRT-PCR. Changes in the degree of paw swelling and body weight of mice were recorded. H&E staining, toluidine blue staining, and micro-CT were used to visualize the degree of pathological damage in the ankle joints of mice. Small interfering RNA and plasmid overexpression of vimentin were used to observe their effects on MH7A cell proliferation, migration, apoptosis, and downstream molecular signaling. RESULTS: The TNF-α-induced proliferation and migration of MH7A cells could be significantly repressed by CBN (25,50 µM), and the expression of apoptosis and autophagy-associated proteins could be modulated. Furthermore, CBN could directly bind to vimentin and inhibit its expression and function in synoviocytes, thereby ameliorating foot and paw swelling and joint damage in CIA mice. Silencing and overexpression of vimentin might be involved in developing RA synovial hyperplasia and invasive cartilage by activating VAV2 phosphorylation-mediated expression of Rac-1, which affects abnormal growth characteristics, such as synoviocyte invasion and migration. CONCLUSION: CBN-targeted vimentin restrains the overactivation of RA synoviocytes thereby delaying the pathological process in CIA mice, which provides valuable targets and insights for understanding the pathological mechanisms of RA synovial hyperplasia.

Molecular diagnosis of patients with syndromic short stature identified by trio whole-exome sequencing.

Background: Short stature is a complex disorder with phenotypic and genetic heterogeneity. This study aimed to investigate clinical phenotypes and molecular basis of a cohort of patients with short stature. Methods: Trio whole-exome sequencing (Trio-WES) was performed to explore the genetic aetiology and obtain a molecular diagnosis in twenty Chinese probands with syndromic and isolated short stature. Results: Of the twenty probands, six (6/20, 30%) patients with syndromic short stature obtained a molecular diagnosis. One novel COMP pathogenic variant c.1359delC, p.N453fs*62 and one LZTR1 likely pathogenic variant c.509G>A, p.R170Q were identified in a patient with short stature and skeletal dysplasia. One novel de novo NAA15 pathogenic variant c.63T>G, p.Y21X and one novel de novo KMT2A pathogenic variant c.3516T>A, p.N1172K was identified in two probands with short stature, intellectual disability and abnormal behaviours, respectively. One patient with short stature, cataract, and muscle weakness had a de novo POLG pathogenic variant c.2863 T>C, p.Y955H. One PHEX pathogenic variant c.1104G>A, p.W368X was identified in a patient with short stature and rickets. Maternal uniparental disomy 7 (mUPD7) was pathogenic in a patient with pre and postnatal growth retardation, wide forehead, triangular face, micrognathia and clinodactyly. Thirteen patients with isolated short stature had negative results. Conclusion: Trio-WES is an important strategy for identifying genetic variants and UPD in patients with syndromic short stature, in which dual genetic variants are existent in some individuals. It is important to differentiate between syndromic and isolated short stature. Genetic testing has a high yield for syndromic patients but low for isolated patients.

Berbamine inhibits porcine epidemic diarrhea virus in vitro and in vivo.

Porcine epidemic diarrhea virus (PEDV) is a significant contributor to high mortality rates in piglets, posing a serious threat to the global pig industry. The absence of effective control measures and vaccines against circulating PEDV variants underscores the urgent need for new treatment strategies. In this study, we screened a compound library and identified Berbamine as a potential anti-PEDV drug through molecular docking techniques. In vitro experiments demonstrated that Berbamine significantly inhibits PEDV proliferation in Vero and IPEC-J2 cells in a dose-dependent manner, primarily targeting the replication phase of the PEDV life cycle. Furthermore, in vivo experiments revealed that Berbamine effectively alleviates intestinal damage caused by PEDV infection in piglets, leading to a reduction in viral load and cytokine levels, including IL-6, IL-8, IL-1ß, and TNF-α. Additionally, autodock predictions indicate that viral non-structural proteins 3 and 16 (Nsp3 and Nsp16) are potential targets for Berbamine. Consequently, Berbamine holds significant promise for application and development as an antiviral treatment against PEDV.

Genetic evolutionary analysis of a strain of Senecavirus A in Anhui and the establishment of its detection method.

BACKGROUND: Senecavirus A (SVA) is the only member of the genus Senecavirus in the family Picornaviridae, and is one of the pathogens of porcine blistering disease. SVA has been reported in the United States, Canada, China, Thailand, and Colombia. METHODS: In this study, positive SVA infection was detected by RT-PCR in sick materials collected from pig farms of different sizes in Anhui Province. RESULTS: In this study, a virulent strain of SVA was successfully obtained by viral isolation on BHK21 cells and named SVA-CH-AHAU-1. Meanwhile, a simple, rapid and accurate nano-PCR method for the detection of SVA infection was established in this study, using the recombinant plasmid pClone-SVA-3D as a template. CONCLUSIONS: The complete genome of SVA-CH-AHAU-1 is 7286 bp, including a 5' non-coding region (UTR), an open reading frame (ORF) of 6546 nucleotides, encoding 2182 amino acids (aa), and a 3' UTR with Poly(A) features, and phylogenetic analysis showed that this isolate had the highest nucleotide homology (97.9 %) with the US isolate US-15-41901SD. In this study, the virulent strain SVA-CH-AHAU-1 was found to recombine in the ORF region with isolates SVA-CH-SDGT-2017 and SVA/Canada/ON/FMA-2015-0024 T2/2015. The complete genome has been submitted to GeneBank with the accession number OM654411. In addition, our results suggest that the established nano-PCR assay can be used as an economical, reliable and sensitive method for the field diagnosis of SVA method, especially in resource-limited areas.

Azobenzene-Bridged Covalent Organic Frameworks Boosting Photocatalytic Hydrogen Peroxide Production from Alkaline Water: One Atom Makes a Significant Improvement.

Covalent organic frameworks (COFs) have been demonstrated as promising photocatalysts for hydrogen peroxide (H2O2) production. However, the construction of COFs with new active sites, high photoactivity, and wide-range light absorption for efficient H2O2 production remains challenging. Herein, we present the synthesis of a novel azobenzene-bridged 2D COF (COF-TPT-Azo) with excellent performance on photocatalytic H2O2 production under alkaline conditions. Notably, although COF-TPT-Azo differs by only one atom (-N=N- vs. -C=N-) from its corresponding imine-linked counterpart (COF-TPT-TPA), COF-TPT-Azo exhibits a significantly narrower band gap, enhanced charge transport, and prompted photoactivity. Remarkably, when employed as a metal-free photocatalyst, COF-TPT-Azo achieves a high photocatalytic H2O2 production rate up to 1498 µmol g-1 h-1 at pH = 11, which is 7.9 times higher than that of COF-TPT-TPA. Further density functional theory (DFT) calculations reveal that the -N=N- linkages are the active sites for photocatalysis. This work provides new prospects for developing high-performance COF-based photocatalysts.

Design and optimization of handheld alloy analysis instrument based on microjoule high pulse repetition frequency LIBS.

We briefly describe the design of a handheld metal detection instrument based on microjoule high repetition frequency laser-induced breakdown spectroscopy. The instrument uses a Raspberry Pi as the control core and a laser with a frequency of 10 kHz and a single pulse energy of 100 µJ as the excitation source. In addition, a mini-putter is built into the instrument to move the laser, allowing the ablation of the sample surface line area without external auxiliary equipment. The excitation-generated plasma radiation is collected by a simple optical path and transmitted directly to the spectrometer. We also constructed and trained a Backpropagation Artificial Neural Network (BP-ANN) model based on 12 different grades of alloys and transplanted the feedback process of the BP-ANN to the Raspberry Pi, which realized the rapid classification of the 12 alloys with >95% classification accuracy on the handheld instrument.

Blurred interface induced control of electrical transport properties in Josephson junctions.

The interfacial microstructures of Josephson junctions are vital for understanding the microscopic mechanism to improve the performance of superconducting qubits further. However, there remain significant concerns about well understanding the correlation between atomic structures and electrical behaviors. Here, we propose a new method to define the interface of the barrier in Josephson junctions, and investigate the factors that affect the electrical properties of junctions using material analysis techniques and first principles. We find that the aluminium-oxygen ratio of the interface contributes greatly to the electrical properties of junctions, which is consistent with the conclusions obtained by utilizing the generative adversarial network for data augmentation. When the aluminium-oxygen ratio of the interface is 0.67-1.1, the model exhibits a lower barrier height and better electrical properties of the junction. Moreover, when the thickness of the barrier is fixed, the impact of the aluminium-oxygen ratio becomes prominent. A detailed analysis of Josephson junctions using a microscopic model has led to identifying of process defects that can enhance the yield rate of chips. It has a great boost for determining the relationship between microstructures and macroscopic performances.

[The Application Study of Voriconazole and Its Metabolites Concentration Monitoring in Allogeneic Hematopoietic Stem Cell Transplantation Patients].

OBJECTIVE: To explore the application value of simultaneous monitoring of voriconazole (VRCZ) and voriconazole N-oxide (VNO) in efficacy and safety of VRCZ in the prevention and treatment of fungal infections in allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients before engraftment (i.e., days +1 to +30 after transplantation). METHODS: The influencing factors of VRCZ, VNO concentration and MR (CVNO/CVRCZ) and the difference of VRCZ in the prevention and treatment of fungal infection and liver and kidney injury were analyzed. The receiver operating characteristic curve (ROC) was used to analyze the differences (the corresponding to the maximum of the Youden index on the curve was set as the cut-off value) to confirm the critical value. RESULTS: The factors affecting VRCZ concentration (CVRCZ), VNO concentration (CVNO) and MR were patient weight, VRCZ daily dose, and transplantation type (all P < 0.05). CVRCZ and CVNO in the effective group were higher than those in the ineffective group (P < 0.001), the opposite of MR (P < 0.001); the liver and renal injury group had lower MR than the normal group (P < 0.05). ROC showed that CVRCZ, C VNO and MR had important value in predicting VRCZ in the prevention and treatment of invasive fungal infections in allo-HSCT patients before engraftment, and their cutoff of concentrations were 0.95 µg/ml, 1.35 µg/ml and 1.645, respectively (AUC: 0.9677, 0.7634, 0.9564). CVRCZ and MR can assist in indicating liver ï¼»cutoff values: 0.65 µg/ml, 1.96 (AUC: 0.5971, 0.6663)ï¼½ and renal injury ï¼»cutoff values: 0.95 µg/ml, 1.705 (AUC: 0.6039, 0.6164)ï¼½. CONCLUSION: The great value of simultaneous monitoring of VRCZ, VNO and MR can predict in the efficacy and safety of VRCZ in allo-HSCT patients before engraftment. The prediction accuracy of CVRCZ was higher than that of MR, followed by that of CVNO. Increased CVRCZ and decreased MR increase the risk of liver and kidney injury.

Clinical outcomes of endoscopic resection for the treatment of intermediate- or high-risk gastric small gastrointestinal stromal tumors: a multicenter retrospective study.

BACKGROUND AND AIMS: Many studies of gastric gastrointestinal stromal tumors (g-GISTs) following endoscopic resection (ER) have typically focused on tumor size, with most tumors at low risk of aggressiveness after risk stratification. There have been few systematic studies on the oncologic outcomes of intermediate- or high-risk g-GISTs after ER. METHODS: From January 2014 to January 2020, we retrospectively collected patients considered at intermediate- or high-risk of g-GISTs according to the modified NIH consensus classification system. The primary outcome was overall survival (OS). RESULTS: Six hundred and seventy nine (679) consecutive patients were diagnosed with g-GISTs and treated by ER between January 2014 and January 2020 in three hospitals in Shanghai, China. 43 patients (20 males and 23 females) were confirmed at intermediate-or high-risk. The mean size of tumors was 2.23 ± 1.01 cm. The median follow-up period was 62.02 ± 15.34 months, with a range of 28 to 105 months. There were no recurrences or metastases, even among patients having R1 resections. The 5-year OS rate was 97.4% (42/43). CONCLUSION: ER for intermediate- or high-risk gastric small GISTs is a feasible and safe method, which allows for a wait-and-see approach before determining the necessity for imatinib adjuvant or surgical treatment. This approach to g-GISTs does require that patients undergo close follow-up.

A review on recent taxonomic updates of gut bacteria associated with social bees, with a curated genomic reference database.

Honeybees and bumblebees play a crucial role as essential pollinators. The special gut microbiome of social bees is a key factor in determining the overall fitness and health of the host. Although bees harbor relatively simple microbial communities at the genus level, recent studies have unveiled significant genetic divergence and variations in gene content within each bacterial genus. However, a comprehensive and refined genomics-based taxonomic database specific to social bee gut microbiomes remains lacking. Here, we first provided an overview of the current knowledge on the distribution and function of social bee gut bacteria, as well as the factors that influence the gut population dynamics. We then consolidated all available genomes of the gut bacteria of social bees and refined the species-level taxonomy, by constructing a maximum-likelihood core genome phylogeny and calculating genome-wide pairwise average nucleotide identity. On the basis of the refined species taxonomy, we constructed a curated genomic reference database, named the bee gut microbe genome sequence database (BGM-GDb). To evaluate the species-profiling performance of the curated BGM-GDb, we retrieved a series of bee gut metagenomic data and inferred the species-level composition using metagenomic intra-species diversity analysis system (MIDAS), and then compared the results with those obtained from a prebuilt MIDAS database. We found that compared with the default database, the BGM-GDb excelled in aligned read counts and bacterial richness. Overall, this high-resolution and precise genomic reference database will facilitate research in understanding the gut community structure of social bees.

Improvement of the catalytic performance of chitosanase Csn-PD from Paenibacillus dendritiformis by semi-rational design.

Chitooligosaccharides (COS) possess versatile functional properties that have found extensive applications across various fields. Chitosanase can specifically hydrolyze ß-1,4 glycosidic bonds in chitosan to produce COS. In this study, Csn-PD, a glycoside hydrolase family 46 chitosanase from Paenibacillus dendritiformis, which produces (GlcN)2 as its main product, was rationally redesigned aiming to improve its catalytic performance. Based on the results of molecular docking analysis and multiple sequence alignment, four amino acid residues in Csn-PD (I101, T120, T220, and Y259) were pinpointed for targeted mutations. Beneficial mutations in terms of enhanced catalytic activity were then combined by site-directed mutagenesis. Notably, the most promising variant, Csn-PDT6 (Csn-PD I101M/T120E/T220G), exhibited an impressive eight-fold surge in activity compared to the wild-type Csn-PD. This heightened enzymatic activity was complemented by an enhanced pH stability profile. A compelling feature of Csn-PDT6 is its preservation of the hydrolytic product profile observed in Csn-PD. This characteristic further accentuates its candidacy for the targeted production of (GlcN)2. The success of our strategic approach is vividly illustrated by the significant improvements achieved in the catalytic performance of the chitosanase, encompassing both its activity and stability. These developments offer a valuable model that may have implications for the semi-rational design of other enzymes.

Genome-wide analyses reveal the regulatory roles of DNA methylation-regulated alternative promoter transcripts in breast cancer.

A certain proportion of genes are regulated by multiple, distinct promoters, revealing a dynamic landscape of the cancer transcriptome. However, the contribution of alternative promoters (APs) in breast cancer (BRCA) remains largely unexplored. Here, we identified 3654 genes with multiple promoters in BRCA patients, and 53 of them could generate distinct AP transcripts that are dysregulated and prognosis-related in BRCA, namely prognosis-related dysregulated AP (prdeAP) transcripts. Interestingly, when we searched for the genomic signatures of these prdeAP genes, we found that the promoter regions of 92% of the prdeAP genes were enriched with abundant DNA methylation signals. Through further bioinformatic analysis and experimental validation, we showed that AP selections of TANK, UNKL, CCL28, and MAP1LC3A were regulated by DNA methylation upon their corresponding promoter regions. Functionally, by overexpressing AP variants of TANK, we found that TANK|55731 could dramatically suppress MDA-MB-231 cell proliferation and migration. Meanwhile, pan-cancer survival analyses suggested that AP variants of TANK provided more accurate prognostic predictive ability than TANK gene in a variety of tumor types, including BRCA. Together, by uncovering the DNA methylation-regulated AP transcripts with tumor prognostic features, our work revealed a novel layer of regulators in BRCA progression and provided potential targets that served as effective biomarkers for anti-BRCA treatment.

Human papillomavirus-16 E6 activates the pentose phosphate pathway to promote cervical cancer cell proliferation by inhibiting G6PD lactylation.

High-risk human papillomaviruses (HPVs) are the causative agents of cervical cancer. Here, we report that HPV16 E6E7 promotes cervical cancer cell proliferation by activating the pentose phosphate pathway (PPP). We found that HPV16 E6 activates the PPP primarily by increasing glucose-6-phosphate dehydrogenase (G6PD) enzyme activity. Mechanistically, HPV16 E6 promoted G6PD dimer formation by inhibiting its lactylation. Importantly, we suggest that G6PD K45 was lactylated during G6PD-mediated antioxidant stress. In primary human keratinocytes and an HPV-negative cervical cancer C33A cells line ectopically expressing HPV16 E6, the transduction of G6PD K45A (unable to be lactylated) increased GSH and NADPH levels and, correspondingly, decreasing ROS levels. Conversely, the re-expression of G6PD K45T (mimicking constitutive lactylation) in HPV16-positive SiHa cells line inhibited cell proliferation. In vivo, the inhibition of G6PD enzyme activity with 6-aminonicotinamide (6-An) or the re-expression of G6PD K45T inhibited tumor proliferation. In conclusion, we have revealed a novel mechanism of HPV oncoprotein-mediated malignant transformation. These findings might provide effective strategies for treating cervical and HPV-associated cancers.

Bioactive Components of Areca Nut: An Overview of Their Positive Impacts Targeting Different Organs.

Areca catechu L. is a widely cultivated tropical crop in Southeast Asia, and its fruit, areca nut, has been consumed as a traditional Chinese medicinal material for more than 10,000 years, although it has recently attracted widespread attention due to potential hazards. Areca nut holds a significant position in traditional medicine in many areas and ranks first among the four southern medicines in China. Numerous bioactive compounds have been identified in areca nuts, including alkaloids, polyphenols, polysaccharides, and fatty acids, which exhibit diverse bioactive functions, such as anti-bacterial, deworming, anti-viral, anti-oxidant, anti-inflammatory, and anti-tumor effects. Furthermore, they also display beneficial impacts targeting the nervous, digestive, and endocrine systems. This review summarizes the pharmacological functions and underlying mechanisms of the bioactive ingredients in areca nut. This helps to ascertain the beneficial components of areca nut, discover its medicinal potential, and guide the utilization of the areca nut.

Overexpression of EphB2 in the basolateral amygdala is crucial for inducing visceral pain sensitization in rats subjected to water avoidance stress.

AIMS: Basolateral amygdala (BLA), as a center for stress responses and emotional regulation, is involved in visceral hypersensitivity of irritable bowel syndrome (IBS) induced by stress. In the present study, we aimed to investigate the role of EphB2 receptor (EphB2) in BLA and explore the underlying mechanisms in this process. METHODS: Visceral hypersensitivity was induced by water avoidance stress (WAS). Elevated plus maze test, forced swimming test, and sucrose preference test were applied to assess anxiety- and depression-like behaviors. Ibotenic acid or lentivirus was used to inactivate BLA in either the induction or maintenance stage of visceral hypersensitivity. The expression of protein was determined by quantitative PCR, immunofluorescence, and western blot. RESULTS: EphB2 expression was increased in BLA in WAS rats. Inactivation of BLA or downregulation of EphB2 in BLA failed to induce visceral hypersensitivity as well as anxiety-like behaviors. However, during the maintenance stage of visceral pain, visceral hypersensitivity was only partially relieved but anxiety-like behaviors were abolished by inactivation of BLA or downregulation of EphB2 in BLA. Chronic WAS increased the expression of EphB2, N-methyl-D-aspartate receptors (NMDARs), and postsynaptic density protein (PSD95) in BLA. Downregulation of EphB2 in BLA reduced NMDARs and PSD95 expression in WAS rats. However, activation of NMDARs after the knockdown of EphB2 expression still triggered visceral hypersensitivity and anxiety-like behaviors. CONCLUSIONS: Taken together, the results suggest that EphB2 in BLA plays an essential role in inducing visceral hypersensitivity. In the maintenance stage, the involvement of EphB2 is crucial but not sufficient. The increase in EphB2 induced by WAS may enhance synaptic plasticity in BLA through upregulating NMDARs, which results in IBS-like symptoms. These findings may give insight into the treatment of IBS and related psychological distress.

Are Sandwich Vertebrae Prone to Refracture After Percutaneous Vertebroplasty or Kyphoplasty? A Meta-Analysis.

BACKGROUND: The formation of sandwiched vertebrae (SDVs) after percutaneous vertebroplasty (PVP) or percutaneous kyphoplasty (PKP) has become a common phenomenon. Whether SDVs are more likely to fracture is still controversial. Therefore, we conducted a meta-analysis to provide medical evidence for whether SDVs are more prone to refracture than non-SDVs (NSDVs) after PVP or PKP. METHODS: This study was conducted in accordance with the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Several databases, including PubMed, Embase, Medline databases, China National Knowledge Infrastructure, Wanfang, and Weipu, were thoroughly searched for relevant studies included from any point up until June 2022. Statistical analyses were performed using Revman 5.4. RESULTS: A total of 4052 individuals from 9 studies were enrolled. Overall, patients with SDV presented more risk to have refracture than patients with NSDV (OR = 1.57, P = 0.04). The incidences of refracture were comparable between the 2 cohorts in studies with a follow-up time less than 3 years (OR = 1.28, P = 0.49). However, patients with SDV were more prone to have refracture than patients with NSDV in studies with a follow-up time longer than 3 years (OR = 1.92, P = 0.009). Moreover, patients with SDV were more likely to have refracture than patients with NSDV in studies that involved both PVP and PKP (OR = 1.62, P = 0.002). In addition, age, low bone density, and postoperative kyphosis angle of sandwich fracture segments >10° were independent factors to predict refracture. CONCLUSIONS: Patients with SDV were more likely to have refracture after PVP or PKP, especially when the follow-up time was longer than 3 years.

Lactylation stabilizes DCBLD1 activating the pentose phosphate pathway to promote cervical cancer progression.

BACKGROUND: Discoidin, CUB, and LCCL domain-containing type I (DCBLD1) is identified as an oncogene involved in multiple regulation of tumor progression, but specific mechanisms remain unclear in cervical cancer. Lactate-mediated lactylation modulates protein function. Whether DCBLD1 can be modified by lactylation and the function of DCBLD1 lactylation are unknown. Therefore, this study aims to investigate the lactylation of DCBLD1 and identify its specific lactylation sites. Herein, we elucidated the mechanism by which lactylation modification stabilizes the DCBLD1 protein. Furthermore, we investigated DCBLD1 overexpression activating pentose phosphate pathway (PPP) to promote the progression of cervical cancer. METHODS: DCBLD1 expression was examined in human cervical cancer cells and adjacent non-tumorous tissues using quantitative reverse transcription-polymerase chain reaction, western blotting, and immunohistochemistry. In vitro and in vivo studies were conducted to investigate the impact of DCBLD1 on the progression of cervical cancer. Untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomics studies were used to characterize DCBLD1-induced metabolite alterations. Western blot, immunofuorescence and transmission electron microscopy were performed to detect DCBLD1 degradation of G6PD by activating autophagy. Chromatin immunoprecipitation, dual luciferase reporter assay for detecting the mechanism by which lactate increases DCBLD1 transcription. LC-MS/MS was employed to verify specific modification sites within the DCBLD1 protein. RESULTS: We found that lactate increased DCBLD1 expression, activating the PPP to facilitate the proliferation and metastasis of cervical cancer cells. DCBLD1 primarily stimulated PPP by upregulating glucose-6-phosphate dehydrogenase (G6PD) expression and enzyme activity. The mechanism involved the increased enrichment of HIF-1α in the DCBLD1 promoter region, enhancing the DCBLD1 mRNA expression. Additionally, lactate-induced DCBLD1 lactylation stabilized DCBLD1 expression. We identified DCBLD1 as a lactylation substrate, with a predominant lactylation site at K172. DCBLD1 overexpression inhibited G6PD autophagic degradation, activating PPP to promote cervical cancer progression. In vivo, 6-An mediated inhibition of G6PD enzyme activity, inhibiting tumor proliferation. CONCLUSIONS: Our findings revealed a novel post-translational modification type of DCBDL1, emphasizing the significance of lactylation-driven DCBDL1-mediated PPP in promoting the progression of cervical cancer.

Nanoenabled Intracellular Metal Ion Homeostasis Regulation for Tumor Therapy.

Endogenous essential metal ions play an important role in many life processes, especially in tumor development and immune response. The approval of various metallodrugs for tumor therapy brings more attention to the antitumor effect of metal ions. With the deepening understanding of the regulation mechanisms of metal ion homeostasis in vivo, breaking intracellular metal ion homeostasis becomes a new means to inhibit the proliferation of tumor cells and activate antitumor immune response. Diverse nanomedicines with the loading of small molecular ion regulators or metal ions have been developed to disrupt metal ion homeostasis in tumor cells, with higher safety and efficiency than free small molecular ion regulators or metal compounds. This comprehensive review focuses on the latest progress of various intracellular metal ion homeostasis regulation-based nanomedicines in tumor therapy including calcium ion (Ca2+ ), ferrous ion (Fe2+ ), cuprous ion (Cu+ ), managanese ion (Mn2+ ), and zinc ion (Zn2+ ). The physiological functions and homeostasis regulation processes of ions are summarized to guide the design of metal ion regulation-based nanomedicines. Then the antitumor mechanisms of various ions-based nanomedicines and some efficient synergistic therapies are highlighted. Finally, the challenges and future developments of ion regulation-based antitumor therapy are also discussed, hoping to provide a reference for finding more effective metal ions and synergistic therapies.