Multi-omic Analysis of Uterine Leiomyomas in Self-Described Black and White Women: Molecular Insights into Health Disparities.

BACKGROUND: Black women are at an increased risk to develop uterine leiomyomas (ULMs) and to experience worse disease prognosis compared to White women. Epidemiological and molecular factors have been identified as underlying these disparities, but there remains a paucity of deep, multi-omic analysis investigating molecular differences in ULMs from Black and White patients. OBJECTIVE: To identify molecular alterations within ULM tissues correlating with patient race by multi-omic analyses of ULMs collected from cohorts of Black and White women. STUDY DESIGN: We performed multi-omic analysis of ULMs from Black (42) and White (47) women undergoing hysterectomy for symptomatic uterine leiomyomata. Our analysis also included application of orthogonal methods to evaluate fibroid biomechanical properties, such as second harmonic generation microscopy, uniaxial compression testing, as well as sheer wave ultrasonography analyses. RESULTS: We found a greater proportion of mediator complex subunit 12 (MED12) mutant ULMs from Black women (>35% increase, Mann Whitney U p = 7E-4). MED12 mutant tumors exhibited elevated abundance of extracellular matrix proteins, including several collagen isoforms, involved in regulation of the core matrisome. Histological analysis of tissue fibrosis using trichrome staining and secondary harmonic generation microscopy confirmed that MED12 mutant tumors are more fibrotic than MED12 wildtype tumors. Using Sheer Wave ultrasonography in a prospectively collected cohort, Black patients had fibroids that were firmer when compared to White patients, even when similar in size. These analyses also uncovered expression quantitative trait loci (eQTL) associated with altered allele frequencies in African and European populations that correlated with differential abundance of several proteins in ULM that are independent of MED12 mutational status, including multiple eQTL mapping to tetratricopeptide repeat protein 38. CONCLUSIONS: Our study shows that Black women have a higher prevalence of ULMs harboring mutations in MED12 and that this mutational status correlates with increased tissue fibrosis in comparison with wildtype ULMs. Our study provides insights into molecular alterations underlying racial disparities in ULMs and improves our understanding of the molecular etiology underlying ULM development within these populations.

Protein lipoylation: mitochondria, cuproptosis, and beyond.

Protein lipoylation, a crucial post-translational modification (PTM), plays a pivotal role in mitochondrial function and emerges as a key player in cell death through cuproptosis. This novel copper-driven cell death pathway is activated by excessive copper ions binding to lipoylated mitochondrial proteins, disrupting energy production and causing lethal protein aggregation and cell death. The intricate relationship among protein lipoylation, cellular energy metabolism, and cuproptosis offers a promising avenue for regulating essential cellular functions. This review focuses on the mechanisms of lipoylation and its significant impact on cell metabolism and cuproptosis, emphasizing the key genes involved and their implications for human diseases. It offers valuable insights into targeting dysregulated cellular metabolism for therapeutic purposes.

Adherence to a healthy lifestyle including sleep and sedentary behaviors and risk of metabolic dysfunction-associated steatotic liver disease in Chinese adults.

OBJECTIVE: Various lifestyle factors including smoking, alcohol, physical activity, sedentary behavior, diet quality, sleep behavior, and overweight have been related to metabolic dysfunction-associated steatotic liver disease (MASLD); however, their joint impact on risk of MASLD is not well known. We prospectively investigated the association between a combination of lifestyle factors and risk of MASLD. METHODS: This prospective cohort study included 13,303 participants (mean age: 39.1 ± 11.3 years, female: 60.1%) in China. A novel healthy lifestyle score was created combining seven healthy factors: not smoking, no alcohol intake, regular physical activity, short sedentary time, healthy diet, healthy sleep, and healthy weight. Incident MASLD cases were ascertained annually by liver ultrasound and cardiometabolic risk factors. Multivariable Cox proportional hazards regression models were used to estimate the association of healthy lifestyle score with risk of MASLD. RESULTS: Within 48,036 person-years of follow-up, 2823 participants developed MASLD. After adjusting for age, sex, education, occupation, household income, personal and family history of disease, and total energy intake, compared with participants with 0-2 healthy lifestyle factors, the multivariable hazard ratios (95% confidence interval) of MASLD were 0.81 (0.73, 0.89), 0.67 (0.61, 0.75), and 0.55 (0.49, 0.62) for healthy lifestyle score of 3, 4, and 5-7, respectively (P for trend <0.0001). Such associations were consistent across subgroup and sensitivity analyses. CONCLUSION: Our results indicate that a higher healthy lifestyle score is associated with a lower risk of MASLD.

[Application of antibiotic bone cement-coated plates internal fixation for primary treating Gustilo type â ¢B tibiofibular open fracture].

Objective: To explore the effectiveness of using antibiotic bone cement-coated plates internal fixation technology as a primary treatment for Gustilo type ⅢB tibiofibular open fractures. Methods: The clinical data of 24 patients with Gustilo type ⅢB tibiofibular open fractures who were admitted between January 2018 and December 2021 and met the selection criteria was retrospectively analyzed. Among them, there were 18 males and 6 females, aged from 25 to 65 years with an average age of 45.8 years. There were 3 cases of proximal tibial fracture, 6 cases of middle tibial fracture, 15 cases of distal tibial fracture, and 21 cases of fibular fracture. The time from injury to emergency surgery ranged from 3 to 12 hours, with an average of 5.3 hours. All patients had soft tissue defects ranging from 10 cm×5 cm to 32 cm×15 cm. The time from injury to skin flap transplantation for wound coverage ranged from 1 to 7 days, with an average of 4.1 days, and the size of skin flap ranged from 10 cm×5 cm to 33 cm×15 cm. Ten patients had bone defects with length of 2-12 cm (mean, 7.1 cm). After emergency debridement, the tibial fracture end was fixed with antibiotic bone cement-coated plates, and the bone defect area was filled with antibiotic bone cement. Within 7 days, the wound was covered with a free flap, and the bone cement was replaced while performing definitive internal fixation of the fracture. In 10 patients with bone defect, all the bone cement was removed and the bone defect area was grafted after 7-32 weeks (mean, 11.8 weeks). The flap survival, wound healing of the affected limb, complications, and bone healing were observed after operation, and the quality of life was evaluated according to the short-form 36 health survey scale (SF-36 scale) [including physical component summary (PCS) and mental component summary (MCS) scores] at 1 month, 6 months after operation, and at last follow-up. Results: All 24 patients were followed up 14-38 months (mean, 21.6 months). All the affected limbs were successfully salvaged and all the transplanted flaps survived. One case had scar hyperplasia in the flap donor site, and 1 case had hypoesthesia (grade S3) of the skin around the scar. There were 2 cases of infection in the recipient area of the leg, one of which was superficial infection after primary flap transplantation and healed after debridement, and the other was sinus formation after secondary bone grafting and was debrided again 3 months later and treated with Ilizarov osteotomy, and healed 8 months later. The bone healing time of the remaining 23 patients ranged from 4 to 9 months, with an average of 6.1 months. The scores of PCS were 44.4±6.5, 68.3±8.3, 80.4±6.9, and the scores of MCS were 59.2±8.2, 79.5±7.8, 90.0±6.6 at 1 month, 6 months after operation, and at last follow-up, respectively. The differences were significant between different time points ( P<0.05). Conclusion: Antibiotic bone cement-coated plates internal fixation can be used in the primary treatment of Gustilo type ⅢB tibiofibular open fractures, and has the advantages of reduce the risk of infection in fracture fixation, reducing complications, and accelerating the functional recovery of patients.

Validation of Core Ingredients and Molecular Mechanism of Cinobufotalin Injection Against Liver Cancer.

Purpose: Cinobufotalin injection has obvious curative effects on liver cancer patients with less toxicity and fewer side effects than other therapeutic approaches. However, the core ingredients and mechanism underlying these anti-liver cancer effects have not been fully clarified due to its complex composition. Methods: Multidimensional network analysis was used to screen the core ingredients, key targets and pathways underlying the therapeutic effects of cinobufotalin injection on liver cancer, and in vitro and in vivo experiments were performed to confirm the findings. Results: By construction of ingredient networks and integrated analysis, eight core ingredients and ten key targets were finally identified in cinobufotalin injection, and all of the core ingredients are tightly linked with the key targets, and these key targets are highly associated with the cell cycle-related pathways, supporting that both cinobufotalin injection and its core ingredients exert anti-liver cancer roles by blocking cell cycle-related pathways. Moreover, in vitro and in vivo experiments confirmed that either cinobufotalin injection or one of its core ingredients, cinobufagin, significantly inhibited cell proliferation, colony formation, cell cycle progression and xenograft tumor growth, and the key target molecules involved in the cell cycle pathway such as CDK1, CDK4, CCNB1, CHEK1 and CCNE1, exhibit consistent changes in expression after treatment with cinobufotalin injection or cinobufagin. Interestingly, some key targets CDK1, CDK4, PLK1, CHEK1, TTK were predicted to bind with multiple of core ingredients of cinobufotalin injection, and the affinity between one of the critical ingredients cinobufagin and key target CDK1 was further confirmed by SPR assay. Conclusion: Cinobufotalin injection was confirmed to includes eight core ingredients, and they play therapeutic effects in liver cancer by blocking cell cycle-related pathways, which provides important insights for the mechanism of cinobufotalin injection antagonizing liver cancer and the development of novel small molecule anti-cancer drugs.

CircCDYL2 bolsters radiotherapy resistance in nasopharyngeal carcinoma by promoting RAD51 translation initiation for enhanced homologous recombination repair.

BACKGROUND: Radiation therapy stands to be one of the primary approaches in the clinical treatment of malignant tumors. Nasopharyngeal Carcinoma, a malignancy predominantly treated with radiation therapy, provides an invaluable model for investigating the mechanisms underlying radiation therapy resistance in cancer. While some reports have suggested the involvement of circRNAs in modulating resistance to radiation therapy, the underpinning mechanisms remain unclear. METHODS: RT-qPCR and in situ hybridization were used to detect the expression level of circCDYL2 in nasopharyngeal carcinoma tissue samples. The effect of circCDYL2 on radiotherapy resistance in nasopharyngeal carcinoma was demonstrated by in vitro and in vivo functional experiments. The HR-GFP reporter assay determined that circCDYL2 affected homologous recombination repair. RNA pull down, RIP, western blotting, IF, and polysome profiling assays were used to verify that circCDYL2 promoted the translation of RAD51 by binding to EIF3D protein. RESULTS: We have identified circCDYL2 as highly expressed in nasopharyngeal carcinoma tissues, and it was closely associated with poor prognosis. In vitro and in vivo experiments demonstrate that circCDYL2 plays a pivotal role in promoting radiotherapy resistance in nasopharyngeal carcinoma. Our investigation unveils a specific mechanism by which circCDYL2, acting as a scaffold molecule, recruits eukaryotic translation initiation factor 3 subunit D protein (EIF3D) to the 5'-UTR of RAD51 mRNA, a crucial component of the DNA damage repair pathway to facilitate the initiation of RAD51 translation and enhance homologous recombination repair capability, and ultimately leads to radiotherapy resistance in nasopharyngeal carcinoma. CONCLUSIONS: These findings establish a novel role of the circCDYL2/EIF3D/RAD51 axis in nasopharyngeal carcinoma radiotherapy resistance. Our work not only sheds light on the underlying molecular mechanism but also highlights the potential of circCDYL2 as a therapeutic sensitization target and a promising prognostic molecular marker for nasopharyngeal carcinoma.

Bone marrow CD8+ Trm cells induced by IL-15 and CD16+ monocytes contribute to HSPC destruction in human severe aplastic anemia.

Idiopathic severe aplastic anemia (SAA) is a disease of bone marrow failure caused by T-cell-induced destruction of hematopoietic stem and progenitor cells (HSPCs), however the mechanism remains unclear. We performed single-cell RNA sequencing of PBMCs and BMMCs from SAA patients and healthy donors and identified a CD8+ T cell subset with a tissue residency phenotype (Trm) in bone marrow that exhibit high IFN-γ and FasL expression and have a higher ability to induce apoptosis in HSPCs in vitro through FasL expression. CD8+ Trm cells were induced by IL-15 presented by IL-15Rα on monocytes, especially CD16+ monocytes, which were increased in SAA patients. CD16+ monocytes contributed to IL-15-induced CD38+CXCR6+ pre-Trm differentiation into CD8+ Trm cells, which can be inhibited by the CD38 inhibitor 78c. Our results demonstrate that IL-15-induced CD8+ Trm cells are pathogenic cells that mediate HSPC destruction in SAA patients and are therapeutic targets for future treatments.

Clinical translation of a novel FAPI dimer [68Ga]Ga-LNC1013.

Fibroblast activation protein (FAP) has emerged as a highly promising target for cancer diagnostic imaging and targeted radionuclide therapy. To exploit the therapeutic potential of suitably radiolabeled FAP inhibitors (FAPIs), this study presents the design and synthesis of a series of FAPI dimers to increase tumor uptake and retention. Preclinical evaluation and a pilot clinical PET imaging study were conducted to screen the lead compound with the potential for radionuclide therapy. METHODS: Three new FAPI dimers were synthesized by linking two quinoline-based FAPIs with different spacers. The in vitro binding affinity and preclinical small animal PET imaging of the compounds were compared with their monomeric counterparts, FAPI-04 and FAPI-46. The lead compound, [68Ga]Ga -LNC1013, was then evaluated in a pilot clinical PET imaging study involving seven patients with gastrointestinal cancer. RESULTS: The three newly synthesized FAPI homodimers had high binding affinity and specificity in vitro and in vivo. Small animal PET imaging and biodistribution studies showed that [68Ga]Ga-LNC1013 had persistent tumor retention for at least 4 h, also higher uptake than the other two dimers and the monomer counterparts, making it the lead compound to enter clinical investigation. In the pilot clinical PET imaging study, seven patients were enrolled. The effective dose of [68Ga]Ga-LNC1013 was 8.24E-03 mSv/MBq. The human biodistribution of [68Ga]Ga-LNC1013 demonstrated prominent tumor uptake and good tumor-to-background contrast. [68Ga]Ga-LNC1013 PET imaging showed potential in capturing primary and metastatic lesions and outperforming 18F-FDG PET in detecting pancreatic and esophageal cancers. The SUVmax for lesions with [68Ga]Ga-FAPI-46 decreased over time, whereas [68Ga]Ga-LNC1013 exhibited persistently high tumor uptake from 1 to 4 h post-injection. CONCLUSION: Dimerization is an effective strategy to produce FAPI derivatives with favorable tumor uptake, long tumor retention, and imaging contrast over its monomeric counterpart. We demonstrated that [68Ga]Ga-LNC1013, the lead compound without any piperazine moiety, had superior diagnostic potential over [68Ga]Ga-FAPI-46 and 18F-FDG, suggesting the future potential of LNC1013 for radioligand therapy of FAP-positive cancers.

CircPHGDH downregulation decreases papillary thyroid cancer progression through miR-122-5p/PKM2 axis.

BACKGROUND: Although papillary thyroid carcinoma (PTC) has a favorable prognosis, it could affect patient life quality and become a serious threat because of invasion and metastasis. Many investigations have suggested that circular RNAs (circRNAs) are involved in different cancer regulations. Nevertheless, circRNAs role in invasive PTC remains unclear. METHODS: In the present investigation, next-generation sequencing was applied to explore abnormal circRNA expression. The expression of circRNA phosphoglycerate dehydrogenase (circPHGDH) in PTC cell lines and tissues were examined. Then, we investigated regulatory mechanism and circPHGDH downstream targets using bioinformatics analysis and luciferase reporting analysis. Then transwell migration, Cell Counting Kit-8 (CCK8) and 5-ethynyl-2'-deoxyuridine (EdU) assays were used for cells migration and proliferation analysis. In vivo metastasis and tumorigenesis assays were also employed to evaluate the circPHGDH role in PTC. RESULTS: The data showcased that circPHGDH expression increased in both PTC cell lines and tissues, which suggested that circPHGDH functions in PTC progression. circPHGDH downregulation suppressed PTC invasion and proliferation in both in vivo and in vitro experiments. Bioinformatics and luciferase reporter results confirmed that both microRNA (miR)-122-5p and pyruvate kinase M2 subtype (PKM2) were downstream targets of circPHGDH. PKM2 overexpression or miR-122-5p suppression reversed PTC cell invasion and proliferation post silencing circPHGDH by restoring aerobic glycolysis. CONCLUSION: Taken together, our research found that circPHGDH downregulation reduced PTC progression via miR-122-5p/PKM2 axis regulation mediated by aerobic glycolysis.

Fibromodulin facilitates the osteogenic effect of Masquelet's induced membrane by inhibiting the TGF-ß/SMAD signaling pathway.

Masquelet's induced membrane (IM) technique is a promising treatment strategy for the repair of substantial bone defects. The formation of an IM around polymethylmethacrylate bone cement plays a crucial role in this technique. Several studies have indicated that IMs have bioactivity because they contain abundant blood vessels, a variety of cells, and biological factors. The bioactivity of an IM increases during the initial stages of formation, thereby facilitating bone regeneration and remodeling. Nevertheless, the precise mechanisms underlying the enhancement of IM bioactivity and the promotion of bone regeneration necessitate further investigation. In this study, we successfully developed a Masquelet IM model of critical femur defects in rats. By employing proteomics analysis and biological detection techniques, we identified fibromodulin (FMOD) as a pivotal factor contributing to angiogenesis and the enhanced bioactivity of the IM. A significant increase in angiogenesis and the expression of bioactive factors in the IM was also observed with the upregulation of FMOD expression. Furthermore, this effect is mediated through the inhibition of the transforming growth factor beta (TGF-ß)/SMAD signaling pathway. We also demonstrated that administering recombinant human FMOD enhanced osteogenesis in rat bone marrow mesenchymal stem cells and angiogenesis in human umbilical vein endothelial cells in vitro. Furthermore, the negative regulatory effect of the TGF-ß signaling pathway was verified. In conclusion, this study provides a novel theoretical basis for the application of IMs in bone-defect reconstruction and explores possible new mechanisms that may play an important role in promoting the bioactivity and osteogenic potential of IMs.

Neuroinvasive virus facilitates viral replication by employing lipid droplets to reduce arachidonic acid-induced ferroptosis.

Lipids have been previously implicated in the lifecycle of neuroinvasive viruses. However, the role of lipids in programmed cell death and the relationship between programmed cell death and lipid droplets (LDs) in neuroinvasive virus infection remains unclear. Here, we found that the infection of neuroinvasive virus, such as rabies virus and encephalomyocarditis virus could enhance the LD formation in N2a cells, and decreasing LDs production by targeting diacylglycerol acyltransferase could suppress viral replication. The lipidomics analysis revealed that arachidonic acid (AA) was significantly increased after reducing LD formation by restricting diacylglycerol acyltransferase, and AA was further demonstrated to induce ferroptosis to inhibit neuroinvasive virus replication. Moreover, lipid peroxidation and viral replication inhibition could be significantly alleviated by a ferroptosis inhibitor, ferrostatin-1, indicating that AA affected neuroinvasive virus replication mainly through inducing ferroptosis. Furthermore, AA was demonstrated to activate the acyl-CoA synthetase long-chain family member 4-lysophosphatidylcholine acyltransferase 3-cytochrome P450 oxidoreductase axis to induce ferroptosis. Our findings highlight novel cross-talks among viral infection, LDs, and ferroptosis for the first time, providing a potential target for antiviral drug development.

Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4+ T cells.

HIV-1 infection elevates the risk of developing various cancers, including T-cell lymphoma. Whether HIV-1-encoded proteins directly contribute to oncogenesis remains unknown. We observe that approximately 1-5% of CD4+ T cells from the blood of people living with HIV-1 exhibit over-duplicated centrioles, suggesting that centrosome amplification underlies the development of HIV-1-associated cancers by driving aneuploidy. Through affinity purification, biochemical, and cellular analyses, we discover that Vpr, an accessory protein of HIV-1, hijacks the centriole duplication machinery and induces centrosome amplification and aneuploidy. Mechanistically, Vpr forms a cooperative ternary complex with an E3 ligase subunit, VprBP, and polo-like kinase 4 (Plk4). Unexpectedly, however, the complex enhances Plk4's functionality by promoting its relocalization to the procentriole assembly and induces centrosome amplification. Loss of either Vpr's C-terminal 17 residues or VprBP acidic region, the two elements required for binding to Plk4 cryptic polo-box, abrogates Vpr's capacity to induce these events. Furthermore, HIV-1 WT, but not its Vpr mutant, induces multiple centrosomes and aneuploidy in human primary CD4+ T cells. We propose that the Vpr•VprBP•Plk4 complex serves as a molecular link that connects HIV-1 infection to oncogenesis and that inhibiting the Vpr C-terminal motif may reduce the occurrence of HIV-1-associated cancers.

Healthy Lifestyle and the Risk of Metabolic Dysfunction-Associated Fatty Liver Disease: A Large Prospective Cohort Study.

Background: The incidence density of metabolic dysfunction-associated fatty liver disease (MAFLD) and the effect of a healthy lifestyle on the risk of MAFLD remain unknown. We evaluated the prevalence and incidence density of MAFLD and investigated the association between healthy lifestyle and the risk of MAFLD. Methods: A cross-sectional analysis was conducted on 37,422 participants to explore the prevalence of MAFLD. A cohort analysis of 18,964 individuals was conducted to identify the incidence of MAFLD, as well as the association between healthy lifestyle and MAFLD. Cox proportional hazards regression was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) with adjustments for confounding factors. Results: The prevalence of MAFLD, non-alcoholic fatty liver disease, and their comorbidities were 30.38%, 28.09%, and 26.13%, respectively. After approximately 70 thousand person-years of follow-up, the incidence densities of the three conditions were 61.03, 55.49, and 51.64 per 1,000 person-years, respectively. Adherence to an overall healthy lifestyle was associated with a 19% decreased risk of MAFLD (HR, 0.81; 95% CI, 0.72 to 0.92), and the effects were modified by baseline age, sex, and body mass index (BMI). Subgroup analyses revealed that younger participants, men, and those with a lower BMI experienced more significant beneficial effects from healthy lifestyle. Conclusion: Our results highlight the beneficial effect of adherence to a healthy lifestyle on the prevention of MAFLD. Health management for improving dietary intake, physical activity, and smoking and drinking habits are critical to improving MAFLD.

Integrated neutrophil-to-lymphocyte ratio and handgrip strength better predict survival in patients with cancer cachexia.

OBJECTIVES: Systemic inflammation and skeletal muscle strength play crucial roles in the development and progression of cancer cachexia. In this study we aimed to evaluate the combined prognostic value of neutrophil-to-lymphocyte ratio (NLR) and handgrip strength (HGS) for survival in patients with cancer cachexia. METHODS: This multicenter cohort study involved 1826 patients with cancer cachexia. The NLR-HGS (NH) index was defined as the ratio of neutrophil-to-lymphocyte ratio to handgrip strength. Harrell's C index and receiver operating characteristic (ROC) curve analysis were used to assess the prognosis of NH. Kaplan-Meier analysis and Cox regression models were used to evaluate the association of NH with all-cause mortality. RESULTS: Based on the optimal stratification, 380 women (NH > 0.14) and 249 men (NH > 0.19) were classified as having high NH. NH has shown greater predictive value compared to other indicators in predicting the survival of patients with cancer cachexia according to the 1-, 3-, and 5-y ROC analysis and Harrell's C index calculation. Multivariate survival analysis showed that higher NH was independently associated with an increased risk of death (hazard ratio = 1.654, 95% confidence interval = 1.389-1.969). CONCLUSION: This study demonstrates that the NH index, in combination with NLR and HGS, is an effective predictor of the prognosis of patients with cancer cachexia. It can offer effective prognosis stratification and guidance for their treatment.

[Analysis of the outcome of 12 cases of facial nerve tumors].

Objective:This study aims to provide a comprehensive summary of the pathogenesis, screening modalities, treatment strategies, repair modalities and preliminary results associated with facial nerve tumors. Methods:A retrospective analysis was conducted on the clinical data of 12 patients with facial nerve tumors who were admitted to our department between May 2018 and February 2023. The study population consisted of 5 males and 7 females, with ages ranging from 35 to 90 years. Clinical symptoms observed in these patients included facial nerve palsy, hearing loss, tinnitus, headache, and otalgia, etc. The severity of facial nerve dysfunction was assessed using the House-Brackmann（H-B） facial nerve function classification, with 3 cases classified as grade Ⅰ, 4 cases as grade Ⅲ, 2 cases as grade Ⅳ, and 3 cases as grade Ⅴ. There was a total of 11 patients who presented with hearing loss. Among these patients, 7 cases were diagnosed with conductive hearing loss, 2 cases with sensorineural hearing loss, and 2 cases with mixed hearing loss. The selection of the observation or surgical route for tumor localization was based on clinical symptoms, facial nerve function grading, and imaging examination results including temporal bone CT and enhanced MRI. Specifically, the location of the tumor was selected for observation or the best surgical route: 2 cases were followed up for observation, 1 case underwent biopsy, and 9 cases underwent tumor resection（7 cases of trans-mastoid approach, 2 cases of combined parotid-mastoidal approach）, concurrent repair of the facial nerve（4 cases of auricular nerve grafting, 3 cases of facial nerve diversion anastomosis, 2 cases of peroneal nerve grafting）. （4 cases of auricular nerve graft, 3 cases of facial nerve diversion anastomosis and 2 cases of peroneal nerve grafting）. Periodic postoperative evaluation of facial nerve function was conducted. Results:1-year follow-up was available. Intraoperatively, it was observed that 66.7%（6 out of 9） of the facial nerve tumors were present in multiple segments. Among these segments, the vertical segment had the highest proportion, accounting for 77.8%（7 out of 9）, followed by the labyrinthine segment/geniculate ganglion with 66.7%（6 out of 9） and the horizontal segment with 55.6%（5 out of 9）. Postoperative pathology confirmed 8 cases with nerve sheath meningioma, Ⅰ with seminal fibroma and 1 with hemangioma. Postoperative facial nerve function was graded as H-B grade I in one patient）, grade Ⅲ in three, grade Ⅳ in four, grade Ⅴ in 2, and grade Ⅵ in 2 patients. The auditory outcomes following surgery are as follows: 8 individuals experienced postoperative hearing loss, while 2 individuals demonstrated postoperative hearing preservation. Conclusion:In the case of patients presenting with facial nerve palsy as their initial symptom, it is imperative to consider the potential presence of a facial nerve tumor. To determine the appropriate course of action, it is necessary to ascertain the size and location of the tumors through imaging examinations. This information will aid in the decision making process regarding whether surgical intervention is warranted, and so, the most suitable approach. Additionally, the choice of repair method during the operation should be guided by the extent of facial nerve defect.

Extraction of Tooth Cusps based on DBSCAN Density Clustering and Neighborhood Search Algorithm.

A good tooth cusp extraction is helpful in evaluating the effect of cosmetic dental work in virtual tooth surgery. We propose a new tooth cusp extraction, which integrates the DBSCAN (density-based spatial clustering of applications with noise) clustering algorithm with the neighborhood search algorithm to extract tooth cusp from a three-dimensional cloud-point tooth model. This method used the point cloud height and curvature to screen out the dented point set. Then we employ the DBSCAN clustering algorithm to segment different feature regions of the tooth surface and generate the candidate point set. Finally, the candidate point set was accurately located at the tooth apex through the neighborhood search algorithm and the traversal search method of non-maximum suppression. The experimental results show that the proposed method is superior to the traditional watershed algorithm-based methods by calculating the recall rate and accuracy rate, and also has higher extraction speed and extraction precision than manual extraction methods.

Pediatric Pterygopalatine Fossa Schwannoma Presenting as Vision Loss: A Case Report and Literature Review.

Neurosynovial tumors, originating from Schwann cells within nerve sheaths, are benign entities, with 25% to 45% manifesting in the head and neck region. However, occurrences in the pterygopalatine fossa (PPF) are exceptionally rare, and only a handful of cases have been documented. In this report, we present the unique case of a 6-year-old child exhibiting a sizable soft tissue mass in the left PPF, extending into the inferior orbital fissure. The patient underwent successful intranasal endoscopic removal of PPF schwannoma utilizing the prelacrimal recess approach, with postoperative pathology confirming the diagnosis of schwannoma. Schwannomas within the PPF are particularly uncommon, and instances of such tumors in pediatric patients are even more exceptional. This case highlights the diagnostic and therapeutic challenges associated with PPF schwannomas in children, emphasizing the significance of a multidisciplinary approach for optimal management. In addition, a comprehensive literature review is presented to provide insights into the existing knowledge on this rare entity, further contributing to the understanding of pediatric PPF schwannomas.

Lyssavirus M protein degrades neuronal microtubules by reprogramming mitochondrial metabolism.

Infection with neurotropic viruses may result in changes in host behavior, which are closely associated with degenerative changes in neurons. The lyssavirus genus comprises highly neurotropic viruses, including the rabies virus (RABV), which has been shown to induce degenerative changes in neurons, marked by the self-destruction of axons. The underlying mechanism by which the RABV degrades neuronal cytoskeletal proteins remains incomplete. In this study, we show that infection with RABV or overexpression of its M protein can disrupt mitochondrial metabolism by binding to Slc25a4. This leads to a reduction in NAD+ production and a subsequent influx of Ca2+ from the endoplasmic reticulum and mitochondria into the cytoplasm of neuronal cell lines, activating Ca2+-dependent proteinase calpains that degrade α-tubulin. We further screened the M proteins of different lyssaviruses and discovered that the M protein of the dog-derived RABV strain (DRV) does not degrade α-tubulin. Sequence analysis of the DRV M protein and that of the lab-attenuated RABV strain CVS revealed that the 57th amino acid is vital for M-induced microtubule degradation. We generated a recombinant RABV with a mutation at the 57th amino acid position in its M protein and showed that this mutation reduces α-tubulin degradation in vitro and axonal degeneration in vivo. This study elucidates the mechanism by which lyssavirus induces neuron degeneration.IMPORTANCEPrevious studies have suggested that RABV (rabies virus, the representative of lyssavirus) infection induces structural abnormalities in neurons. But there are few articles on the mechanism of lyssavirus' effect on neurons, and the mechanism of how RABV infection induces neurological dysfunction remains incomplete. The M protein of lyssavirus can downregulate cellular ATP levels by interacting with Slc25a4, and this decrease in ATP leads to a decrease in the level of NAD+ in the cytosol, which results in the release of Ca2+ from the intracellular calcium pool, the endoplasmic reticulum, and mitochondria. The presence of large amounts of Ca2+ in the cytoplasm activates Ca2+-dependent proteases and degrades microtubule proteins. The amino acid 57 of M protein is the key site determining its disruption of mitochondrial metabolism and subsequent neuron degeneration.

Dissecting the genome sequence of a clinical isolated Cunninghamella bertholletiae Z2 strain with rich cytochrome P450 enzymes (Article).

Mucormycosis is receiving much more attention because of its high morbidity and extremely high mortality rate in immunosuppressed populations. In this study, we isolated a Cunnignhamella bertholletiae Z2 strain from a skin lesion of a 14 year, 9 months old girl with acute lymphoblastic leukemia who die of infection from the Z2 strain. Genome sequencing was performed after isolation and amplification of the Z2 strain to reveal potential virulence factors and pathogenic mechanisms. The results showed that the genome size of the Z2 strain is 30.9 Mb with 9213 genes. Mucoral specific virulence factor genes found are ARF, CalN, and CoTH, while no gliotoxin biosynthesis gene cluster was found, which is a known virulence factor in Aspergillus fumigatus adapted to the environment. The Z2 strain was found to have 69 cytochrome P450 enzymes, which are potential drug resistant targets. Sensitivity testing of Z2 showed it was only inhibited by amphotericin B and posaconazole. Detailed genomic information of the C. bertholletiae Z2 strain may provide useful data for treatment.