Obesity is a significant risk factor for cancer and is associated with breast cancer metastasis. Nevertheless, the mechanism by which alterations in systemic metabolism affect tumor microenvironment (TME) and consequently influence tumor metastasis remains inadequately understood. Herein, we found that perturbations in circulating metabolites induced by obesity promote metastasis-like phenotypes in breast cancer. Oleoylcarnitine (OLCarn) concentrations were elevated in the serum of obese mice and humans. Administration of exogenous OLCarn induces metastasis-like characteristics in breast cancer cells. Mechanistically, OLCarn directly interacts with the Arg176 site of adenylate cyclase 10 (ADCY10), leading to the activation of ADCY10 and enhancement of cAMP production. Mutations at Arg176 prevent OLCarn from binding to ADCY10, disrupting the ADCY10-mediated activation of cyclic adenosine monophosphate (cAMP) signaling pathway. This activation promotes transcription factor 4 (TCF4)-dependent kinesin family member C1 (KIFC1) transcription, thereby driving breast cancer metastasis. Conversely, the neutralization of both ADCY10 and KIFC1 through knockdown or pharmacological inhibition abrogates the oncogenic effects mediated by OLCarn. Hence, obesity-induced systemic environmental changes lead to the aberrant accumulation of OLCarn within the TME, making it a potential therapeutic target and biomarker for breast cancer.

Humans ; Consanguinity ; Exome Sequencing ; Mutation/genetics* ; Sequence Analysis, DNA ; Ciliary Motility Disorders ; Axonemal Dyneins/genetics*

Objective To explore the effect of 2-aminoethoxy-diphenyl borate(2-APB)on H2O2-induced chondro-cyte apoptosis and its mechanism.Methods The experiment was divided into control group,H2O2 group,2-APB group and H2O2+2-APB group.CCK-8 method was used to detect the cell viability of each group;The effect of 2-APB on the morphological changes of chondrocytes induced by H2O2 was observed under microscopy;TUNEL meth-od and flow cytometry were used to detect chondrocyte apoptosis;Flow cytometry was used to detect Lipid reactive oxygen species(ROS);Western blot was used to detect the protein expressions of Cleaved-PARP,p-PKCα and HIF-1α in H2O2-induced cells by 2-APB;Immunofluorescence was used to detect the fluorescent expression of HIF-1α in cells induced by H2O2 by PKCα inhibitor BIM-1.Results 2-APB inhibited H2O2-induced apoptosis in chon-drocytes,and the inhibitory effect was the most significant when the concentration of 2-APB was 100 pmol/L(F=235.80,P＜0.01);22-APB could inhibit the positive rate of H2O2-induced apoptosis of chondrocytes(F=114.80,P＜0.01)and the level of ROS(F=52.99,P＜0.01).and inhibited the expression of Cleaved-PARP(F=10.10,P＜0.05),p-PKCα(F=24.56,P＜0.05)and HIF-1α proteins(F=6.85,P＜0.05).The PKCα in-hibitor BIM-Ⅰ could inhibit the increase in HIF-1α fluorescence intensity caused by H2O2.Conclusion 2-APB can inhibit chondrocytes apoptosis induced by H2O2 through the PKCα/HIF-1α pathway and thus protect chondro-cytes.

Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attracting considerable attention in precise oncology therapy.Cetuximab(Cet)is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma(cSCC);however,its anti-tumor activity is limited to a single use.Cisplatin(CisPt)shows good curative effects;however,its adverse effects and non-tumor-targeting ability are major drawbacks.In this study,we designed and developed a new ADC based on a new cytotoxic platinum(Ⅳ)prodrug(C8Pt(Ⅳ))and Cet.The so-called antibody-platinum(Ⅳ)prodrugs conjugates,named Cet-C8Pt(Ⅳ),showed excellent tumor targeting in cSCC.Specifically,it accurately delivered C8Pt(Ⅳ)into tumor cells to exert the combined anti-tumor effect of Cet and CisPt.Herein,metabolomic analysis showed that Cet-C8Pt(Ⅳ)promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells,thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum(Ⅳ)prodrugs conjugates.

Lower cervical fracture and dislocation combined with facet interlocking is an acute spinal cord injury caused by flexion-distraction and rotational force. It can result in various degrees of quadriplegia and urinary and defecation disorders, with a high rate of disability, most of which requires surgical treatment. Surgical treatment options for lower cervical fracture and dislocation combined with facet interlocking include anterior approach, posterior approach and combined surgical approach. However, the optimal treatment option remains to be determined. The anterior approach, with the advantages of simple access, smaller trauma, fewer complications, and good sagittal balance, is currently the preferred treatment option for lower cervical fracture and dislocation combined with facet interlocking. Many methods of surgical repositioning and fixation are available in anterior approach, but the choice of surgical repositioning and fixation options in anterior approach is still controversial among scholars. For this purpose, the authors reviewed the progress of researches on anterior surgical approach for lower cervical fracture and dislocation combined with facet interlocking, aiming to provide a reference for its clinical treatment.

Objective:To analyze the hotspots and trends of the researches on artificial intelligence (AI) in the diagnosis and treatment of traumatic brain injury (TBI).Methods:Based on the core database of Web of Science, the studies over AI in the diagnosis and treatment of TBI published from January 2000 to June 2024 were obtained by searching with the subject headings. VOSviewer software was used to analyze the publication year trend, country publication volume, country cooperation network, author publication volume, author citation frequency and author cooperation network. CiteSpace software was also used to identify key words with a significant rise in frequency over a short period of time to obtain the research trends.Results:A total of 2 662 relevant studies were retrieved, from which 677 related with AI in the diagnosis and treatment of TBI were finally enrolled. The number of published studies per year generally showed a rapid growth from 2018 to 2023. The United States had the highest number of publications as a country (362 studies). The author Camarillo had the most publications (9 studies). Rehabilitation was the keyword with the highest frequency (133 times) and the clustering topics containing the three largest number of keywords were virtual reality (VR), mild TBI, and deep learning. The keywords of mobile application, mobile health and intracranial pressure showed a significant increase in frequency from January 2022 to June 2024.Conclusions:VR technology, mild TBI and deep learning technology are the research hotspots of AI in TBI diagnosis and treatment. Mobile apps, mobile health, and intracranial pressure may be new research trends for AI in the diagnosis and treatment of TBI.

The many-banded krait, Bungarus multicinctus, has been recorded as the animal resource of JinQianBaiHuaShe in the Chinese Pharmacopoeia. Characterization of its venoms classified chief phyla of modern animal neurotoxins. However, the evolutionary origin and diversification of its neurotoxins as well as biosynthesis of its active compounds remain largely unknown due to the lack of its high-quality genome. Here, we present the 1.58 Gbp genome of B. multicinctus assembled into 18 chromosomes with contig/scaffold N50 of 7.53 Mbp/149.8 Mbp. Major bungarotoxin-coding genes were clustered within genome by family and found to be associated with ancient local duplications. The truncation of glycosylphosphatidylinositol anchor in the 3'-terminal of a LY6E paralog released modern three-finger toxins (3FTxs) from membrane tethering before the Colubroidea divergence. Subsequent expansion and mutations diversified and recruited these 3FTxs. After the cobra/krait divergence, the modern unit-B of β-bungarotoxin emerged with an extra cysteine residue. A subsequent point substitution in unit-A enabled the β-bungarotoxin covalent linkage. The B. multicinctus gene expression, chromatin topological organization, and histone modification characteristics were featured by transcriptome, proteome, chromatin conformation capture sequencing, and ChIP-seq. The results highlighted that venom production was under a sophisticated regulation. Our findings provide new insights into snake neurotoxin research, meanwhile will facilitate antivenom development, toxin-driven drug discovery and the quality control of JinQianBaiHuaShe.

Objective:To investigate the clinical efficacy of oblique intervertebral fusion in the treatment of failed internal fixation of thoracolumbar fractures.Methods:A retrospective study was conducted to analyze the clinical data of 14 patients who had undergone revision surgery for failed internal fixation of thoracolumbar fracture at Department of Orthopedics, The First Hospital Affiliated to Zhengzhou University from January 2014 to December 2021. There were 6 men and 8 women with a mean age of 47.5 (42.0, 54.3) years. Fracture segments: T 12 in 2 cases, L 1 in 3 cases, L 2 in 4 cases, L 3 in 3 cases, and L 4 in 2 cases; AO classification: type A in 1 case, type B in 7 cases, and type C in 6 cases. Their prior surgical method was posterior internal fixation with pedicle screws. The revision surgery consisted of subtotal vertebral resection through the oblique lateral approach, bone column reconstruction and lateral screw-rod internal fixation for intervertebral fusion after posterior internal fixation reset. The operation time, intraoperative bleeding, postoperative hospital stay, and incidence of complications were recorded. Compared were visual analogue scale (VAS) and Oswestry disability index (ODI) scores for low back pain at preoperation, 3 days and 3 months postoperation, and the last follow-up, fusion at the last follow-up, and Frankel grading for neurological function at preoperation and postoperation. Results:All the 14 patients underwent surgery successfully and were followed up for 23 (18, 24) months. The operation time was (175.1±28.2) min, the intraoperative bleeding (300.4±122.6) mL, and the postoperative hospital stay 6 (6, 7) d. One case developed postoperative transient hip flexion weakness but was discharged after restoration of normal muscle strength by conservative treatment. Both VAS and ODI scores for low back pain at all postoperative time points were significantly improved compared with the preoperative values ( P<0.05), with a significant trend of 3 days postoperation >3 months postoperation > the last follow-up ( P<0.05). In the 12 patients with preoperative neurological damage, the Frankel grading rose by at least 1 level postoperatively ( Z=-3.110, P=0.002). The last follow-up revealed no loosening or fracture of the internal fixation. Complete bony fusion was visible in all CT sagittal reconstructions. Conclusion:For patients with thoracolumbar fracture undergoing failed internal fixation, oblique intervertebral fusion is an alternative minimally invasive surgical treatment due to its satisfactory overall outcomes.

Objective:To investigate the adhesion of polydopamine-modified collagen membrane composites to cartilage tissues and the effect on chondrocyte proliferation, and further explore the possibility of their application in autologous chondrocyte transplantation.Methods:Porous collagen membranes were prepared, and the polydopamine-modified collagen membrane composites were constructed by the adsorption method. The physical and chemical properties and structural characteristics of the membranes, such as thermal stability, thermal properties, porous structure, and surface element composition, were characterized by infrared spectroscopy, thermogravimetric analysis, differential thermal analysis, scanning electron microscopy, and X-ray photoelectron spectroscopy, respectively. The adhesion between the polydopamine-modified collagen membrane and fresh cartilage tissue was tested by a mechanical testing machine. The effects of the membranes on the adhesion and proliferation of rabbit chondrocytes were investigated by in vitro cell culture.Results:The structure and surface element composition of the membranes altered with the increase in the adsorption time of polydopamine, and the capacity of polydopamine increased with the increase in the adsorption time. The thermal stability and thermal properties of collagen membrane materials were not significantly affected by the adsorption of polydopamine. The adhesion of the membrane to cartilage tissue increased with the increase in the amount of absorbed polydopamine. The membranes showed a time-dependent promoting effect on the proliferation of the chondrocytes.Conclusions:The polydopamine-modified collagen membrane has potential application in articular cartilage repair, but more research is required to optimize the membrane before it is used in articular cartilage repair.

ObjectiveTo determine the therapeutic effect of Gegentang granules on a disease-syndrome mouse model combining human coronavirus 229E （hCoV-229E） pneumonia with Hanshi Yidu Xifei syndrome in vivo. MethodMice were randomly divided into normal group， infection group， cold-dampness group， model group， chloroquine phosphate group （0.18 g·kg^-1）， interferon-α2b （IFN-α2b） group （1.83×10⁶ U·kg^-1）， Gegentang granules high-dose and low-dose groups （6.6， 3.3 g·kg^-1） with 10 mice in each group. Cold-dampness environment and hCoV-229E infection were used for modeling， and the general status and lung index of mice in each group were observed. The viral load in lung tissue was detected by real-time fluorescent quantitative polymerase chain reaction （Real-time PCR）， the pathological changes in lung tissue were evaluated by hematoxylin-eosin （HE） staining， the levels of serum gastrointestinal hormones and inflammatory factors in lung tissue were detected by enzyme-linked immunosorbent assay （ELISA）， and the percentage of peripheral blood lymphocytes was detected by flow cytometry. ResultComparing with model group， Gegentang granules could significantly alleviate the physical signs of Hanshi Yidu Xifei syndrome， including listlessness， weakness of limbs， sticky stool， etc. Comparing with model group， Gegentang granules high-dose group significantly reduced lung index， histopathological score of interstitial lung and bronchus， and the level of serum motilin （P<0.05， P<0.01）， two doses of Gegentang granules could significantly increase the level of serum gastrin （P<0.05， P<0.01）， the percentage of CD4⁺， CD8⁺ T lymphocytes in peripheral blood （P<0.05， P<0.01）， and the level of tumor necrosis factor-α （TNF-α） in lung tissue was significantly decreased （P<0.01）， and the level of interleukin-6 （IL-6） showed decreasing tendency. ConclusionGegentang granules has therapeutic effect on model mice. It can improve the appearance and behavior characterization， regulate the level of gastrointestinal hormones， decrease lung index and histopathological score， and possibly play an immunomodulatory role by inhibiting the expression of inflammatory cytokines in lung tissue and restoring the percentage of peripheral blood lymphocytes.