Sagittal en bloc resection of thoracolumbar tumours: a report of thirty one cases.

PURPOSE: To develop a novel classification of sagittal en bloc resection (SEBR) based on anatomical locations for thoracolumbar spine tumors and assess the clinical outcomes of this surgical procedure. METHODS: 31 patients with thoracolumbar tumours treated with SEBR were enrolled in this study. The individualized surgical strategy was adopted based on our surgical classification. Demographics, perioperative outcomes, complications and postoperative outcomes were assessed. RESULTS: Based on our surgical classifications, patients were divided into four types. All bony resection margins were negative, wide resection was achieved in 25 patients, marginal resection in four, and intralesional resection in two. 18 patients underwent anterior reconstruction. Complications were encountered in five patients, and instrumentation failure occurred in one patient. The median follow-up was 24 (range, 6-72) months and recurrence was found in only one patient. CONCLUSION: SEBR is a safe and effective surgical procedure for patients with thoracolumbar spinal tumours in specific anatomical locations. The proposed surgical classification covers all SEBR types and is easy to apply, it may assist surgical decision-making in patients with spinal tumours.

3D-printed modular prostheses for reconstruction of intercalary bone defects after joint-sparing limb salvage surgery for femoral diaphyseal tumours.

Aims: The aim of this study was to investigate the safety and efficacy of 3D-printed modular prostheses in patients who underwent joint-sparing limb salvage surgery (JSLSS) for malignant femoral diaphyseal bone tumours. Methods: We retrospectively reviewed 17 patients (13 males and four females) with femoral diaphyseal tumours who underwent JSLSS in our hospital. Results: In all, 17 patients with locally aggressive bone tumours (Enneking stage IIB) located in the femoral shaft underwent JSLSS and reconstruction with 3D-printed modular prostheses between January 2020 and June 2022. The median surgical time was 153 minutes (interquartile range (IQR) 117 to 248), and the median estimated blood loss was 200ml (IQR 125 to 400). Osteosarcoma was the most common pathological type (n = 12; 70.6%). The mean osteotomy length was 197.53 mm (SD 12.34), and the median follow-up was 25 months (IQR 19 to 38). Two patients experienced local recurrence and three developed distant metastases. Postoperative complications included wound infection in one patient and screw loosening in another, both of which were treated successfully with revision surgery. The median Musculoskeletal Tumor Society score at the final follow-up was 28 (IQR 27 to 28). Conclusion: The 3D-printed modular prosthesis is a reliable and feasible reconstruction option for patients with malignant femoral diaphyseal tumours. It helps to improve the limb salvage rate, restore limb function, and achieve better short-term effectiveness.

DNA Image Cytometry for Screening the Carcinogenetic Risk of Oral Potential Malignant Disorders.

Background: Oral Submucosal Fibrosis (OSF) and Oral Leukoplakia (OLK) are well-known oral potentially malignant disorders, and cases of Oral Submucosal Fibrosis concomitant Oral Leukoplakia (OSF+OLK) are now being reported clinically. DNA image cytometry is an objective and non-invasive method for monitoring the risk of precancerous lesions in the oral cavity. Methods: A total of 111 patients with clinically characterized oral mucosal lesions underwent simultaneous and independent histopathological and DNA imaging cytometry assessments. Clinical data were also collected for each patient. Results: The frequency of DNA content abnormality was higher in the tongue than in other oral sites (P = 0.003) for OLK. The frequency of DNA content abnormality was higher in the tongue than in other oral sites (P = 0.035) for OSF+OLK. The differences of DNA content abnormality in age, sex, dietary habit, smoking, and alcohol intake were not observed in OLK and OSF+OLK. The study indicates an association between DNA content abnormality and pathological examination in OSF+OLK ( χ2 test, P = 0.007). OLK showed higher sensitivity and specificity than OSF, while the sensitivity and specificity of OSF+OLK are higher than OLK only and OSF only. Conclusion: DNA image cytometry can be utilized as an adjunctive device for the initial detection of oral potentially malignant disorders that require further clinical management.

SRCAP complex promotes lung cancer progression by reprograming the oncogenic transcription of Hippo-YAP/TAZ signaling pathway.

The activation of YAP/TAZ, a pair of paralogs of transcriptional coactivators, initiates a dysregulated transcription program, which is a key feature of human cancer cells. However, it is not fully understood how YAP/TAZ promote dysregulated transcription for tumor progression. In this study, we employed the BioID method to identify the interactome of YAP/TAZ and discovered that YAP/TAZ interact with multiple components of SRCAP complex, a finding that was further validated through endogenous and exogenous co-immunoprecipitation, as well as immunofluorescence experiments. CUT&Tag analysis revealed that SRCAP complex facilitates the deposition of histone variant H2A.Z at target promoters. The depletion of SRCAP complex resulted in a decrease in H2A.Z occupancy and the oncogenic transcription of YAP/TAZ target genes. Additionally, the blockade of SRCAP complex suppressed YAP-driven tumor growth. In a genetically engineered lung adenocarcinoma mouse model and non-small cell lung cancer patients, SRCAP complex and H2A.Z deposition were found to be upregulated. This upregulation was statistically correlated with YAP expression, pathological stages, and poor survival in lung cancer patients. Together, our study uncovers that SRCAP complex plays a critical role in YAP/TAZ oncogenic transcription by coordinating H2A.Z deposition during cancer progression, providing potential targets for cancer diagnosis and prevention.

LATS2 condensates organize signalosomes for Hippo pathway signal transduction.

Biomolecular condensates have been proposed to mediate cellular signaling transduction. However, the mechanism and functional consequences of signal condensates are not well understood. Here we report that LATS2, the core kinase of the Hippo pathway, responds to F-actin cytoskeleton reduction and forms condensates. The proline-rich motif (PRM) of LATS2 mediates its condensation. LATS2 partitions with the main components of the Hippo pathway to assemble a signalosome for LATS2 activation and for its stability by physically compartmentalizing from E3 ligase FBXL16 complex-dependent degradation, which in turn mediates yes-associated protein (YAP)-transcriptional coactivator with PDZ-binding motif (TAZ) recruitment and inactivation. This oncogenic FBXL16 complex blocks LATS2 condensation by binding to the PRM region to promote its degradation. Disruption of LATS2 condensation leads to tumor progression. Thus, our study uncovers that the signalosomes assembled by LATS2 condensation provide a compartmentalized and reversible platform for Hippo signaling transduction and protein stability, which have potential implications in cancer diagnosis and therapeutics.

Mass Spectrometry-Based Proteomics Identifies Serpin B9 as a Key Protein in Promoting Bone Metastases in Lung Cancer.

Bone metastasis (BM) is one of the most common complications of advanced cancer. Immunotherapy for bone metastasis of lung cancer (LCBM) is not so promising and the immune mechanisms are still unknown. Here, we utilized a model of BM by injecting cancer cells through caudal artery (CA) to screen out a highly bone metastatic derivative (LLC1-BM3) from a murine lung cancer cell line LLC1. Mass spectrometry-based proteomics was performed in LLC1-parental and LLC1-BM3 cells. Combining with prognostic survival information from patients with lung cancer, we identified serpin B9 (SB9) as a key factor in BM. Molecular characterization showed that SB9 overexpression was associated with poor prognosis and high bone metastatic burden in lung cancer. Moreover, SB9 could increase the ability of lung cancer cells to metastasize to the bone. The mechanistic studies revealed that tumor-derived SB9 promoted BM through an immune cell-dependent way by inactivating granzyme B, manifesting with the decreased infiltration of cytotoxic T cells and increased expression level of exhausted markers. A specific SB9-targeting inhibitor [1,3-benzoxazole-6-carboxylic acid (BTCA)] significantly suppressed LCBM in the CA mouse model. This study reveals that SB9 may serve as a therapeutic target and potential prognostic marker for patients with LCBM. IMPLICATIONS: SB9 as a therapeutic target for LCBM.

A nanodrug combining CD47 and sonodynamic therapy efficiently inhibits osteosarcoma deterioration.

Treatments for osteosarcoma (OS) with pulmonary metastases reach a bottleneck with a survival rate of 10-20%. The suppressive tumor associated macrophages(TAMs) and CD47 over-expression greatly lead to the treatment failure. Sonodynamic therapy (SDT) can generate ROS with deep tumor penetration to induce tumor cell apoptosis, which is reported to further induce M1 macrophage polarization. CD47 inhibition combined with SDT to synergistically modulate TAMs may induce superior effects for OS treatment. In this work, for the first time, a biomimetic nanodrug named MPIRx was deveploped by loading IR780 (a sonosensitizer) and RRx-001 (a CD47 inhibitor) in PEG-PCL nanomicelles and then coating with OS cell membranes. After ultrasound activation, the nanodrug significantly inhibited OS proliferation and migration, induced apoptosis and immunogenic cell death in OS cells. Furthermore, MPIRx could guide macrophage migrating towards tumor cells and promote M1-type polarization while increasing the phagocytosis activity of macrophages on OS cells. Ultimately, MPIRx showed good tumor accumulation in vivo and successfully inhibited subcutaneous OS and orthotopic tumor with deterioration of pulmonary metastasis. Overall, by creating a local oxidative microenvironment and modulating the TAMs/CD47 in tumor tissue, the MPIRx nanodrug presents a novel strategy for macrophage-related immunotherapy to successfully eliminate OS and inhibit the intractable pulmonary metastasis.

Minimally invasive separation surgery for the treatment of spinal metastases with small incision and freehand pedicle screw fixation: the surgical learning curve.

BACKGROUND: Minimally invasive separation surgery (MISS) is a safe and effective surgical technique, the current optimal treatment for spinal metastases. However, the learning curve for this technique has not been analyzed. This study aimed to define and analyze the surgical learning curve of MISS for the treatment of spinal metastases with small incision and freehand pedicle screw fixation. METHODS: A continuous series of 62 patients with spinal metastases who underwent MISS were included. Each patient's operative data were accurately counted. The improvement of the patients' neurological function was followed up after surgery to evaluate the surgical treatment effect. Logarithmic curve-fit regression was used to analyze the surgical learning curve of MISS. The number of cases needed to achieve proficiency was analyzed. Based on this cut-off point, this series of cases was divided into the early phase and later phase groups. The influence of the time sequence of MISS on surgical data and surgical efficacy was analyzed. RESULTS: The operative time decreased gradually with the number of surgical cases increasing and stabilized after the 20th patient. There was no statistical difference in demographic characteristics and preoperative characteristics between the two groups. The mean operative time in the later phase group was about 39 min shorter than that in the early phase group (mean 227.95 vs. 189.02 min, P = 0.027). However, it did not affect other operative data or the surgical treatment effect. CONCLUSION: The learning curve of MISS for spinal metastases is not steep. With the increase of surgeons' experience, the operative time drops rapidly and stabilizes within a certain range. MISS can be safely and effectively performed at the beginning of a surgeon's caree.

Rare isolated extra-hepatic bile duct injury: A case report.

BACKGROUND: Extra-hepatic bile duct injury (EHBDI) is very rare among all blunt abdominal injuries. According to literature statistics, it only accounts for 3%-5% of abdominal injuries, most of which are combined injuries. Isolated EHBDI is more rare, with a special injury mechanism, clinical presentation and treatment strategy, so missed diagnosis easily occurs. CASE SUMMARY: We report a case of unexplained abdominal effusion and jaundice following blunt abdominal trauma in our department. Of which, surgical exploration of the case was performed and a large amount of bile leakage in the abdominal cavity was found. No obvious abdominal organ damage or bile duct rupture was found. Surgery was terminated after the common bile duct indwelled with a T tube. After 2 wk, a T-tube angiography revealed the lesion in the common bile duct pancreatic segment, confirming isolated EHBDI. And 2 mo later, the T tube was pulled out with re-examined magnetic resonance cholangiopancreatography, indicating narrowing of the common bile duct injury, with no special treatment due to no clinical symptoms and no abnormality in the current follow-up. CONCLUSION: This case was featured by intraoperative bile leakage and no EHBDI. This type of rare isolated EHBDI is prone to missed and delayed diagnosis due to its atypical clinical manifestations and imaging features. Surgery is still the main treatment, and the indications and principles of bile duct injury repair must be followed.

Protocol to establish a lung adenocarcinoma immunotherapy allograft mouse model with FACS and immunofluorescence-based analysis of tumor response.

Anti-PD-1/PD-L1 therapy shows long-term effects in many cancer types, but resistance and relapse remain the main limitations of this therapy. Here, we describe a protocol to evaluate the tumor response to immunotherapy in a mouse lung cancer model. The protocol includes the establishment of the lung cancer mouse model, anti-PD-1 treatment, tumor-infiltrating lymphocyte isolation, immunofluorescence, and flow cytometry analysis. This protocol can also be applied to other cancer types and immunotherapies. For complete details on the use and execution of this protocol, please refer to Yu et al. (2021).

Radix Pseudostellariae protein-curcumin nanocomplex: Improvement on the stability, cellular uptake and antioxidant activity of curcumin.

Radix Pseudostellariae protein (RPP) with satisfactory antioxidant activity and self-assembled ability was extracted from dried Radix Pseudostellariae. In this study, RPP-curcumin nanocomplex (RPP-Cur) was fabricated, and its improvement on the stability, cellular uptake and antioxidant activity of curcumin was investigated. RPP-Cur with homogeneously spherical structure exhibited good stability, which could maintain the morphology against simulated gastrointestinal digestion and up to 300 mM ionic concentration. After RPP nanoparticles encapsulation, the retention of curcumin increased 1.45 times under UV irradiation for 6 h. Besides, RPP-Cur exhibited additive reducing power of curcumin and RPP. The transport efficiency of hydrophobic curcumin across Caco-2 cells monolayer was greatly improved by RPP nanoparticle by 3.7 folds. RPP-Cur was able to be internalized by Caco-2 cells dose-dependently via macropinocytosis and clathrin-mediated endocytosis. The cellular uptake efficiency of embedded curcumin in RPP nanoparticles by Caco-2 cells was significantly higher than that of free curcumin, which might contribute to the enhanced intracellular antioxidant activity of RPP-Cur. These findings suggest that the proteins from Radix Pseudostellariae have potential to be developed into novel delivery system with intrinsic antioxidant activity for the hydrophobic active molecules in healthy food field.

Interferon-γ induces tumor resistance to anti-PD-1 immunotherapy by promoting YAP phase separation.

Interferon-γ (IFN-γ)-mediated adaptive resistance is one major barrier to improving immunotherapy in solid tumors. However, the mechanisms are not completely understood. Here, we report that IFN-γ promotes nuclear translocation and phase separation of YAP after anti-PD-1 therapy in tumor cells. Hydrophobic interactions of the YAP coiled-coil domain mediate droplet initiation, and weak interactions of the intrinsically disordered region in the C terminus promote droplet formation. YAP partitions with the transcription factor TEAD4, the histone acetyltransferase EP300, and Mediator1 and forms transcriptional hubs for maximizing target gene transcriptions, independent of the canonical STAT1-IRF1 transcription program. Disruption of YAP phase separation reduced tumor growth, enhanced immune response, and sensitized tumor cells to anti-PD-1 therapy. YAP activity is negatively correlated with patient outcome. Our study indicates that YAP mediates the IFN-γ pro-tumor effect through its nuclear phase separation and suggests that YAP can be used as a predictive biomarker and target of anti-PD-1 combination therapy.

Dcaf11 activates Zscan4-mediated alternative telomere lengthening in early embryos and embryonic stem cells.

Telomeres play vital roles in ensuring chromosome stability and are thus closely linked with the onset of aging and human disease. Telomeres undergo extensive lengthening during early embryogenesis. However, the detailed molecular mechanism of telomere resetting in early embryos remains unknown. Here, we show that Dcaf11 (Ddb1- and Cul4-associated factor 11) participates in telomere elongation in early embryos and 2-cell-like embryonic stem cells (ESCs). The deletion of Dcaf11 in embryos and ESCs leads to reduced telomere sister-chromatid exchange (T-SCE) and impairs telomere lengthening. Importantly, Dcaf11-deficient mice exhibit gradual telomere erosion with successive generations, and hematopoietic stem cell (HSC) activity is also greatly compromised. Mechanistically, Dcaf11 targets Kap1 (KRAB-associated protein 1) for ubiquitination-mediated degradation, leading to the activation of Zscan4 downstream enhancer and the removal of heterochromatic H3K9me3 at telomere/subtelomere regions. Our study therefore demonstrates that Dcaf11 plays important roles in telomere elongation in early embryos and ESCs through activating Zscan4.

Biomechanical effect of anterior talofibular ligament injury in Weber B lateral malleolus fractures after lateral plate fixation: A finite element analysis.

OBJECTIVE: To determine the biomechanical effect of anterior talofibular ligament injury in Weber B lateral malleolus fractures after lateral plate fixation. METHOD: A three-dimensional model was established based on CT images from a healthy volunteer. The simulation of lateral malleolus fracture, and the modeling and assembly of plate were completed by referring to characteristics of Weber B lateral malleolus fractures, as well as the technical characteristics of open reduction and internal fixation of lateral plate. Operating conditions were set up for groups A-D. The proximal end of the model was restrained in all four groups, 200N of upward force and 100N of backward force were applied at anterior of talus head in order to simulate the dorsiflexion of ankle joint. Biomechanical differences of the lateral plate were observed under various conditions of different ligament ruptures. RESULTS: The maximum stress value of group A was the smallest, approximately 78.47N, while that of group C was the largest, approximately 238.83N. The maximum stress value of group B was about 91.69N; and that of group D was about 184.08N. Importantly, location of the maximum stress in group D (CUT ATaF) was displaced from the posterior edge to the anterior edge of the plate, which was different from those of the other three groups. CONCLUSIONS: The anterior talofibular ligament injury may be a major contributing factor to the stress of lateral plate fixation following Weber B lateral malleolus fracture. It should be considered as an essential risk factor for evaluation of the stability in these fractures.

Cancer risk assessment for occupational exposure to chromium and nickel in welding fumes from pipeline construction, pressure container manufacturing, and shipyard building in Taiwan.

OBJECTIVE: We assessed the cancer risks resulting from the exposure to chromium, hexavalent chromium (Cr (VI) ), oxidic nickel (Ni), and soluble Ni in welding fumes during pipeline and shipyard construction and pressure container manufacturing in Taiwan. We also determined the roles of welding performance and demographic characteristics during the exposure to Cr and Ni. METHODS: Personal air samples were collected for the analysis of Cr and Ni, and the concentrations of Cr (VI), oxidic Ni, and soluble Ni were quantified. We assessed cancer slope factors for Cr, Cr (VI), oxidic Ni, and soluble Ni, and we used the Incremental Lifetime Cancer Risk model proposed by the United States Environmental Protection Agency to calculate excess risk. RESULTS: The risks of exposure to Cr and Cr (VI) in welding fumes exceeded the acceptable level of occupational exposure (10-3). We ranked the excess cancer risk in three industries in decreasing order as follows: pipeline construction, shipyard construction, and pressure container manufacturing. The most sensitive parameters for the risk assessment were Cr and Ni concentrations. Statistically significant determinants of Cr (VI), oxidic Ni, and soluble Ni concentrations were the following: stainless steel as the base metal and the filler metals of shielded metal arc welding (SMAW) and of gas tungsten arc welding (GTAW). CONCLUSION: The study revealed that welders belong to a high cancer-risk group. Furthermore, we demonstrated the roles of filler metals and stainless steel in exposure to Cr and Ni.

Etiologic factors of gastric cardiac adenocarcinoma among men in Taiwan.

AIM: To elucidate etiologic associations between Helicobacter pylori (H pylori), lifestyle, environmental factors and gastric cardiac adenocarcinoma (GCA) among men. METHODS: A hospital-based case-control study was conducted in Taiwan from 2000 to 2009. All cases were newly confirmed as primary GCA. Five controls were selected matching with age, sex, and admission date to each case. Participants were informed of potential risk factors with a structured questionnaire by trained interviewers during hospitalization and provided a blood sample for the determination of H pylori infection. Odds ratio (OR) and 95% confidence interval (95% CI) were used to evaluate risk, and a multivariate conditional logistic regression model was performed. RESULTS: All participants recruited for this study were men, consisting of 41 cases and 205 controls. Results of the univariate analysis showed that significant factors associated with the etiology of GCA included H pylori (OR = 2.69, 95% CI = 1.30-5.53), cigarette smoking (OR = 2.28, 95% CI = 1.05-4.96), working or exercising after meals (OR = 3.26, 95% CI = 1.31-8.11), salted food (OR = 2.51, 95%CI = 1.08-6.11), fresh vegetables (OR = 0.28, 95% CI = 0.09-0.80), fruits (OR = 0.19, 95% CI = 0.04-0.89), and rice as principal food (OR = 0.53, 95% CI = 0.30-0.85). Multivariate conditional logistic regression models indicated that a significantly elevated risk of contracting GCA was associated with working or exercising after meals (OR = 3.18, 95% CI = 1.23-9.36) and H pylori infection (OR = 2.93, 95% CI = 1.42-6.01). In contrast, the consumption of fresh vegetables (OR = 0.22, 95% CI = 0.06-0.83), fruits (OR = 0.28, 95% CI = 0.09-0.79) and rice as principal food (OR = 0.48, 95% CI = 0.24-0.93) remained as significant beneficial factor associated with GCA. CONCLUSION: Working or exercising after meals and H pylori infection increase the risk of GCA, but higher intakes of rice, fresh vegetables and fruits reduce the risk.

Terminal nickel(ii) amide, alkoxide, and thiolate complexes containing amido diphosphine ligands of the type [N(o-C6H4PR2)2]- (R = Ph, (i)Pr, Cy).

A series of nickel(ii) complexes of the type [R-PNP]Ni(ER') ([R-PNP](-) = [N(o-C(6)H(4)PR(2))(2)](-); R = Ph, (i)Pr, Cy; E = NH, O, S; R' = Ph, (t)Bu) featuring unsupported, covalently bound pi-donor ligands have been prepared and characterized. The metathetical reactions of [R-PNP]NiCl (R = Ph, (i)Pr, Cy) with LiNHPh, NaOPh, or NaSPh, respectively, produced the corresponding anilide [R-PNP]Ni(NHPh), phenolate [R-PNP]Ni(OPh), and thiophenolate [R-PNP]Ni(SPh) derivatives. Treatment of [Ph-PNP]NiCl with either LiNH(t)Bu or NaO(t)Bu generated tert-butyl amide [Ph-PNP]Ni(NH(t)Bu) and tert-butoxide [Ph-PNP]Ni(O(t)Bu), respectively. In contrast, attempts to prepare analogous tert-butyl amide and tert-butoxide complexes of [(i)Pr-PNP](-) or [Cy-PNP](-) were not successful. Protonolysis studies of these nickel(ii)-heteroatom complexes revealed the basic reactivity of these pi-donor ligands. The basicity follows the order NH(t)Bu > O(t)Bu > NHPh > OPh > SPh. In addition to solution NMR spectroscopic data for all new compounds, X-ray structures of [(i)Pr-PNP]Ni(NHPh) and [(i)Pr-PNP]Ni(OPh) are presented.

Benzene C-H activation by platinum(II) complexes of bis(2-diphenylphosphinophenyl)amide.

The amido diphosphine complexes [PNP]PtMe and [PNP]PtOTf, where [PNP]- is bis(2-diphenylphosphinophenyl)amide, effectively activate the benzene C-H bond in the presence of an appropriate Lewis acid or base, leading to the formation of [PNP]PtPh quantitatively.