PUM1-TRAF3 fusion protein activates non-canonical NF-κB signaling via rescued NIK in biliary tract cancer.

Discovery and verification of diagnostic or therapeutic biomarkers for biliary tract cancer (BTC) is challenging owing to the low prevalence of the disease. Here, we identified and investigated the clinical impact of a fusion gene, Pumilio1-tumor necrosis factor receptor-associated factor 3 (PUM1-TRAF3), caused by 1;14 chromosomal translocation in BTC. PUM1-TRAF3 was initially identified in the RNA-sequencing of five BTC surgical tissues and confirmed by fluorescence in situ hybridization. Expression of the fusion gene was validated in an expanded cohort (5/55, 9.1%). Establishment and molecular assessment of PUM1-TRAF3 expressing BTC cells revealed that PUM1-TRAF3 activates non-canonical NF-κB signaling via NF-κB-inducing kinase (NIK). Abnormal TRAF3 activity, driven by competitive binding of PUM1-TRAF3 and TRAF3 to NIK, led to NIK rescue followed by P52/RelB nuclear translocation, all of which were reverted by an NIK inhibitor. The elevated expression of NIK and activated NF-κB signaling was observed in the PUM1-TRAF3-expressing regions of patient tissues. Expression of the PUM1-TRAF3 fusion was significantly correlated with strong NIK expression, which is associated with a poorer prognosis for patients with BTC. Overall, our study identifies a new fusion gene, PUM1-TRAF3, that activates NIK and non-canonical NF-κB signaling, which may be beneficial for developing precise treatment strategies for BTC.

Lazertinib in EGFR-Variant Non-Small Cell Lung Cancer With CNS Failure to Prior EGFR Tyrosine Kinase Inhibitors: A Nonrandomized Controlled Trial.

Importance: EGFR-variant non-small cell lung cancer (NSCLC) is associated with a high rate of central nervous system (CNS) metastases, even with treatment with first-generation or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Objective: To investigate CNS activity with lazertinib, a third-generation EGFR TKI. Design, Setting, and Participants: This multicenter single-arm, phase 2 nonrandomized controlled trial was conducted in South Korea and included patients with EGFR-variant NSCLC who had asymptomatic or mildly symptomatic brain metastases after unsuccessful treatment with first-generation or second-generation EGFR TKIs. Data were collected from June 2021 to April 2022, with a data cutoff date of December 15, 2022. Exposure: Lazertinib, 240 mg, once daily. Main Outcomes and Measures: The primary end point was intracranial objective response rate (iORR) in the evaluable population according to the Response Evaluation Criteria in Solid Tumours version 1.1 assessed by the investigators. Secondary end points included intracranial progression-free survival (iPFS) and iORR in patients with T790M-negative disease and isolated CNS progression as well as overall ORR, duration of response, intracranial duration of response, disease control rate, overall survival, cerebrospinal fluid penetration of lazertinib, and safety. Results: Among 40 included patients, 25 (63%) were women, and the median (range) age was 63 (29-85) years. A total of 38 patients were evaluable for tumor response, including 12 patients with leptomeningeal metastases. At data cutoff, the median (range) follow-up was 13.6 (2.9-17.7) months. The iORR for the evaluable population was 55% (21 of 38; 95% CI, 38.3-71.4); for patients with T790M-positive disease, 80% (4 of 5; 95% CI, 28.4-99.5); for patients with T790M-negative disease, 43% (9 of 21; 95% CI, 21.8-66.0); and for patients with T790M-unknown disease, 67% (8 of 12; 95% CI, 34.9-90.1). The median iPFS was 15.8 months (95% CI, 15.2-not reached) for the evaluable population, 15.2 months (95% CI, 4.2-not reached) for the T790M-positive subgroup, 15.4 months (95% CI, 7.9-not reached) for the T790M-negative subgroup, and 18.0 months (95% CI, 3.9-not reached) for the T790M-unknown subgroup. The cerebrospinal fluid penetration rate of lazertinib was 46.2% (95% CI, 10.0-49.6), providing further support for its mechanism of intracranial response. Most adverse events were grade 1 or 2. Conclusions and Relevance: In this study, lazertinib had substantial CNS activity, regardless of T790M status, against the progression of intracranial metastases with or without leptomeningeal metastases after unsuccessful treatment with first-generation or second-generation EGFR TKIs in patients with metastatic EGFR-variant NSCLC. These results suggest that using lazertinib instead of brain local treatment could be a potential strategy in patients with EGFR-variant NSCLC whose CNS metastases progressed after prior EGFR TKI treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT05326425.

CLEMENT: genomic decomposition and reconstruction of non-tumor subclones.

Genome-level clonal decomposition of a single specimen has been widely studied; however, it is mostly limited to cancer research. In this study, we developed a new algorithm CLEMENT, which conducts accurate decomposition and reconstruction of multiple subclones in genome sequencing of non-tumor (normal) samples. CLEMENT employs the Expectation-Maximization (EM) algorithm with optimization strategies specific to non-tumor subclones, including false variant call identification, non-disparate clone fuzzy clustering, and clonal allele fraction confinement. In the simulation and in vitro cell line mixture data, CLEMENT outperformed current cancer decomposition algorithms in estimating the number of clones (root-mean-square-error = 0.58-0.78 versus 1.43-3.34) and in the variant-clone membership agreement (∼85.5% versus 70.1-76.7%). Additional testing on human multi-clonal normal tissue sequencing confirmed the accurate identification of subclones that originated from different cell types. Clone-level analysis, including mutational burden and signatures, provided a new understanding of normal-tissue composition. We expect that CLEMENT will serve as a crucial tool in the currently emerging field of non-tumor genome analysis.

Ajania pacifica (Nakai) K. Bremer and Humphries Extract Limits MYC Expression to Induce Apoptosis in Diffuse Large B Cell Lymphoma.

The proto-oncogene MYC is frequently dysregulated in patients with diffuse large B-cell lymphoma (DLBCL) and plays a critical role in disease progression. To improve the clinical outcomes of patients with DLBCL, the development of strategies to target MYC is crucial. The use of medicinal plants for developing anticancer drugs has garnered considerable attention owing to their diverse mechanisms of action. In this study, 100 plant extracts of flora from the Republic of Korea were screened to search for novel agents with anti-DLBCL effects. Among them, Ajania pacifica (Nakai) K. Bremer and Humphries extract (APKH) efficiently suppressed the survival of DLBCL cells, while showing minimal toxicity toward normal murine bone marrow cells. APKH suppressed the expression of anti-apoptotic BCL2 family members, causing an imbalance between the pro-apoptotic and anti-apoptotic BCL2 members. This disrupted mitochondrial membrane potential, cytochrome c release, and pro-caspase-3 activation and eventually led to DLBCL cell death. Importantly, MYC expression was markedly downregulated by APKH and ectopic expression of MYC in DLBCL cells abolished the pro-apoptotic effects of APKH. These results demonstrate that APKH exerts anti-DLBCL effects by inhibiting MYC expression. Moreover, when combined with doxorubicin, an essential component of the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone), APKH synergistically enhanced the therapeutic effect of doxorubicin. This indicates that APKH may overcome drug resistance, which is common in patients with refractory/relapsed DLBCL. To identify compounds with anti-DLBCL activities in APKH, the chemical profile analysis of APKH was performed using UPLC-QTOF/MSe analysis and assessed for its anticancer activity. Based on the UPLC-QTOF/MSe chemical profiling, it is conceivable that APKH may serve as a novel agent targeting MYC and sensitizing drug-resistant DLBCL cells to CHOP chemotherapy. Further studies to elucidate how the compounds in APKH exert tumor-suppressive role in DLBCL are warranted.

Long-term cardiovascular risk reduction after gastric cancer surgery: a nationwide cohort study.

BACKGROUND: Gastrectomy for gastric cancer is associated with postoperative changes in cardiovascular risk factors, however, the impact of gastrectomy on cardiovascular events remains unclear. The authors assessed the incidence of cardiovascular events between patients undergoing gastrectomy or endoscopic resection for gastric cancer, and the general population. MATERIALS AND METHODS: This retrospective nationwide cohort study included patients with gastric cancer undergoing gastrectomy ( n =37 698), endoscopic resection ( n =2773), and matched control population ( n =161 887) between 2004 and 2013. The authors included patients without a history of cancer other than gastric cancer, myocardial infarction, or ischemic stroke. The primary outcome was the incidence of major adverse cardiovascular events (MACE) such as acute myocardial infarction, revascularization, or acute ischemic stroke, in patients with gastric cancer. RESULTS: Among patients who underwent gastrectomy for gastric cancer, 2.9% (4.69 per 1000 person-years) developed novel MACE within the 1-year follow-up period. The gastrectomy group demonstrated a significantly decreased risk for MACE than the control population [hazard ratio (HR), 0.65; 95% CI: 0.61-0.69; P <0.001). Among the patients undergoing endoscopic resection for gastric cancer, 5.4% (8.21 per 1000 person-years) developed novel MACE within the 7-year follow-up period. The risk for MACE in the endoscopic resection group was not significantly different from the control population. CONCLUSION: Patients with gastric cancer who have undergone gastrectomy exhibit a reduced risk of cardiovascular diseases in comparison to the general population. In contrast, the risk for cardiovascular diseases in patients with gastric cancer who underwent endoscopic resection did not demonstrate a significant difference in cardiovascular risk in comparison to the general population.

Evaluation of Lipopolysaccharide and Interleukin-6 as Useful Screening Tool for Chronic Endometritis.

Universal diagnostic criteria for chronic endometritis (CE) have not been established due to differences in study design among researchers and a lack of typical clinical cases. Lipopolysaccharides (LPSs) have been reported to cause inflammation in the reproductive systems of several animals. This study aimed to elucidate the influence of LPS in the pathogenesis of CE in humans. We investigated whether LPS affected cytokine production and cell proliferation in the endometrium using in vivo and in vitro experiments. LPS concentrations were analyzed between control and CE patients using endometrial tissues. LPS administration stimulated the proliferation of EM-E6/E7 cells derived from human endometrial cells. High LPS concentrations were detected in CE patients. LPS concentration was found to correlate with IL-6 gene expression in the endometrium. Inflammation signaling evoked by LPS led to the onset of CE, since LPS stimulates inflammatory responses and cell cycles in the endometrium. We identified LPS and IL-6 as suitable candidate markers for the diagnosis of CE.

Effect of gas temperature on carbon soot oxidation via non-thermal plasma: two-dimensional numerical study integrating reactive flow and discharge models.

Non-thermal plasma (NTP) efficiently regenerates diesel particulate filters by oxidizing carbon soot (CS) at low temperatures. However, numerical studies on the spatial characteristics of CS oxidation by NTP are scarce. In addition, the influence of background gas heating on the CS-oxidizing performance by NTP remains inadequately understood. This research investigates the impact of gas temperature (323-573 K) on heterogeneous CS oxidation using NTP in a two-dimensional configuration. The results indicate that CS is mainly oxidized by [Formula: see text], [Formula: see text], and [Formula: see text] during NTP treatment. The energy efficiency of CS removal by NTP ranges from 0.1 to 2.6 g kWh-1 for varying gas temperature and applied voltage, consistent with previous research. Higher gas temperatures enhance both CS removal rate and efficiency, whereas higher applied voltages enhance rate at the expense of efficiency. The study also assesses energy conversion efficiency from electrical power input to chemical bonding energy during CS oxidation by NTP, yielding 0.03 to 0.23% efficiency for the considered gas temperature and voltage ranges, with higher temperatures leading to better efficiency.

Failure after intramedullary nailing for geriatric trochanteric fracture: does quality of fracture reduction on the AP and lateral planes show the same results?

PURPOSE: This study aimed to investigate the failure of trochanteric fracture fixation according to the quality of fracture reduction on the anteroposterior (AP) and lateral views. METHODS: Data from 340 female and 152 male patients ≥ 60 years of age who underwent intramedullary nailing for a trochanteric fracture between 2016 and 2020 were analysed retrospectively. The quality of fracture reduction was classified as type A, type E, and type I on the AP view and type N, type A, and type P on the lateral view according to the relative position of the proximal and distal fragments. The failure rate was evaluated and compared according to the quality of fracture reduction. The risk factors of the fixation failure were investigated by comparison of variables between patients with and without failure and by regression analysis. RESULTS: Patients with poor reduction, type I and type P had higher failure rates. However, a statistically significant difference was found only for patients with poor reduction (type P) on the lateral view (p < 0.001). Patients with failure showed significantly higher rates of poor reduction on the lateral view and AO/OTA type A3 fractures. The regression analysis also showed that poor reduction on the lateral view (odds ratio [OR] 12.70; 95% confidence interval [CI] 4.0-40.6; p < 0.001) and AO/OTA type A3 fractures (OR 5.40; 95% CI 1.24-23.49, p = 0.025) were risk factors for failure. CONCLUSION: Poor reduction such as type P reduction was associated with failure after intramedullary nailing for trochanteric fractures. Surgeons should check the quality of fracture reduction carefully with the proper fluoroscopic view to prevent failure in geriatric patients with trochanteric fractures.

Immunological subtyping of salivary gland cancer identifies histological origin-specific tumor immune microenvironment.

Gene expression analysis enhances proper cancer subtyping, a better understanding of the molecular characteristics of cancer, and strategies for precision medicine. However, salivary gland cancer (SGC) subtyping remains largely unexplored because of its rarity and diverse histopathological and immunological characteristics. This study aimed to determine whether the histological origin and immunological characteristics of SGC subtypes are intrinsic tumor immunity factors. We performed immune profiling of 94 RNA-seq of SGC tissues and found that the SGCs that originated from the excretory duct (ED), such as the salivary duct and mucoepidermoid carcinomas, exhibit higher immunity than those from the intercalated duct (ID), such as the adenoid cystic and myoepithelial carcinomas, based on the computationally predicted immune score (p < 0.001), immune cell enrichment in the tumor immune microenvironment (TIME) (p < 0.001), T-cell receptor diversity (p < 0.001), and expression of signal I (major histocompatibility complex, MHC, p < 0.001) and signal II (co-stimulatory, p < 0.001 and co-inhibitory, p < 0.001) genes. Further analysis revealed that tolerogenic dendritic cell-induced dysfunctional T-cell populations and T-cell exclusion in the TIME are the major immune evasive mechanisms of the ED-and ID-derived SGCs, respectively.

Early Improved Functional Outcomes in Head and Neck Cancer Patients with Primary Tumor Detection.

OBJECTIVES: We characterize functional outcomes in head and neck cancer of unknown primary (CUP) based on primary site identification. METHODS: In this retrospective study, CUP cases were categorized as known primaries (KP) if a tumor was localized after diagnostic workup or persisting unknown primaries (UP). Age, sex, HPV status, diagnostic methods, and treatments regimens were collected. Pretreatment and short-term posttreatment (3-6 months after completion of treatment) weights, PHQ-9, Eating Assessment Tool (EAT-10), and Voice Handicap Index (VHI-10) scores were compared between UP and KP. RESULTS: Among 67 CUP patients, 35 (52.2%) had identified primaries (91.4% oropharyngeal and 8.6% nasopharyngeal). KP patients were younger (58 vs. 64, p = 0.04) and more likely to be HPV-positive (88.6% vs. 50%, p = 0.002). Overall detection rates were 16.7% for PET/CT, 34.7% for direct laryngoscopy, and 46.6% for transoral robotic oropharyngectomy. Diagnostic workup was not significantly different between groups. Patients with KP received smaller intermediate radiation dose volumes (436.5 vs. 278.9 cc, p = 0.03) and lower doses to the cricopharyngeal muscle (41.6 vs. 24.6 Gy, p = 0.03).Pretreatment weights, PHQ-9, EAT-10, and VHI-10 scores did not differ between groups. However, posttreatment, UP had greater relative weight loss (-14.1% vs. -7.6%, p = 0.032), higher EAT-10 scores (12.5 vs. 3, p = 0.004), and higher PHQ-9 scores (6 vs. 1.4, p = 0.017). Specifically, UP reported more stressful swallowing, difficulty swallowing solids and pills, and swallowing affecting public eating. CONCLUSION: KP patients experienced less weight loss, depression, and reduced swallowing dysfunction, highlighting an early functional benefit of primary tumor identification likely driven by reduced radiation treatment volumes. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:701-707, 2024.

Personalized Biomarker-Based Umbrella Trial for Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: KCSG HN 15-16 TRIUMPH Trial.

PURPOSE: A precise oncologic approach for head and neck squamous cell carcinoma (HNSCC) is necessary. We performed a genomic profile-based umbrella trial for the patients with platinum-refractory recurrent and/or metastatic HNSCC. METHODS: In this multicenter, open-label, single-arm phase II trial, we performed targeted next-generation sequencing (NGS). Patients were assigned to each treatment arm on the basis of their matching genomic profiles: arm 1, alpelisib, a PIK3CA inhibitor; arm 2, poziotinib, an epidermal growth factor receptor/HER2 inhibitor; arm 3, nintedanib, an fibroblast growth factor receptor inhibitor; and arm 4, abemaciclib, a CDK4/6 inhibitor. If there was no matching target, patients were allocated to arm 5, duvalumab ± tremelimumab, anti-PD-L1/cytotoxic T-cell lymphocyte-4 inhibitor. When progressive disease (PD) occurred in arms 1-4, cross over to arm 5 was allowed. The primary end point was disease control rate (DCR) in arm 1 and overall response rate (ORR) in arms 2-5 by investigator assessment. RESULTS: Between October 2017 and August 2020, 203 patients were enrolled, including crossover. In arm 1, the ORR was 21.2% and DCR was 65.6%. The ORR was 0% for arm 2, 42.9% for arm 3, 0% for arm 4, and 15.6% for arm 5. In the case of PD with durvalumab, tremelimumab was added, and the ORR for durvalumab + tremelimumab was 2.2%. The median progression-free survival was 3.4, 3.2, 5.6, 1.6, and 1.7 months for each arm, respectively. The median overall survival was 12.4, 6.1, 11.1, 9.1, and 12.7 months, respectively. Overall, the toxicity profiles were manageable, and there were no treatment-related deaths. CONCLUSION: To our knowledge, this study is the first biomarker-driven umbrella trial for platinum-refractory HNSCC using matched molecular targeted agents. We found that NGS-based genomic phenotyping was methodologically feasible and applicable.

Experimental and Numerical Study on the Perforation Behavior of an Aluminum 6061-T6 Cylindrical Shell.

The modified Johnson-Cook (MJC) material model is widely used in simulation under high-velocity impact. There was a need to estimate a strain rate parameter for the application to the impact analysis, where the method typically used is the Split Hopkinson bar. However, this method had a limit to the experiment of strain rate. This study proposed to estimate the strain rate parameter of the MJC model based on the impact energy and obtained a parameter. The proposed method of strain rate parameter calculation uses strain parameters to estimate from the drop weight impact and high-velocity impact experiments. Then, the ballistic experiment and analysis were carried out with the target of the plate and cylindrical shape. These analysis results were then compared with those obtained from the experiment. The penetration velocities of plates could be predicted with an error of a maximum of approximately 3.7%. The penetration shape of the cylindrical target has a similar result shape according to impact velocity and had an error of approximately 6%.

CanISO: a database of genomic and transcriptomic variations in domestic dog (Canis lupus familiaris).

BACKGROUND: The domestic dog, Canis lupus familiaris, is a companion animal for humans as well as an animal model in cancer research due to similar spontaneous occurrence of cancers as humans. Despite the social and biological importance of dogs, the catalogue of genomic variations and transcripts for dogs is relatively incomplete. RESULTS: We developed CanISO, a new database to hold a large collection of transcriptome profiles and genomic variations for domestic dogs. CanISO provides 87,692 novel transcript isoforms and 60,992 known isoforms from whole transcriptome sequencing of canine tumors (N = 157) and their matched normal tissues (N = 64). CanISO also provides genomic variation information for 210,444 unique germline single nucleotide polymorphisms (SNPs) from the whole exome sequencing of 183 dogs, with a query system that searches gene- and transcript-level information as well as covered SNPs. Transcriptome profiles can be compared with corresponding human transcript isoforms at a tissue level, or between sample groups to identify tumor-specific gene expression and alternative splicing patterns. CONCLUSIONS: CanISO is expected to increase understanding of the dog genome and transcriptome, as well as its functional associations with humans, such as shared/distinct mechanisms of cancer. CanISO is publicly available at https://www.kobic.re.kr/caniso/ .

Pluronic F-68 and F-127 Based Nanomedicines for Advancing Combination Cancer Therapy.

Pluronics are amphiphilic triblock copolymers composed of two hydrophilic poly (ethylene oxide) (PEO) chains linked via a central hydrophobic polypropylene oxide (PPO). Owing to their low molecular weight polymer and greater number of PEO segments, Pluronics induce micelle formation and gelation at critical micelle concentrations and temperatures. Pluronics F-68 and F-127 are the only United States (U.S.) FDA-approved classes of Pluronics and have been extensively used as materials for living bodies. Owing to the fascinating characteristics of Pluronics, many studies have suggested their role in biomedical applications, such as drug delivery systems, tissue regeneration scaffolders, and biosurfactants. As a result, various studies have been performed using Pluronics as a tool in nanomedicine and targeted delivery systems. This review sought to describe the delivery of therapeutic cargos using Pluronic F-68 and F-127-based cancer nanomedicines and their composites for combination therapy.

Highly Water-Dispersed and Stable Deinoxanthin Nanocapsule for Effective Antioxidant and Anti-Inflammatory Activity.

Introduction: Deinoxanthin (DX), a carotenoid, has excellent antioxidant and anti-inflammatory properties. However, owing to its lipophilicity, it is unfavorably dispersed in water and has low stability, limiting its application in cosmetics, food, and pharmaceuticals. Therefore, it is necessary to study nanoparticles to increase the loading capacity and stability of DX. Methods: In this study, DX-loaded nanocapsules (DX@NCs) were prepared by nanoprecipitation by loading DX into nanocapsules. The size, polydispersity index, surface charge, and morphology of DX@NCs were confirmed through dynamic light scattering and transmission electron microscopy. The loading content and loading efficiency of DX in DX@NCs were analyzed using high-performance liquid chromatography. The antioxidant activity of DX@NCs was evaluated by DPPH assay and in vitro ROS. The biocompatibility of DX@NCs was evaluated using an in vitro MTT assay. In vitro NO analysis was performed to determine the effective anti-inflammatory efficacy of DX@NCs. Results: DX@NCs exhibited increased stability and antioxidant efficacy owing to the improved water solubility of DX. The in situ and in vitro antioxidant activity of DX@NCs was higher than that of unloaded DX. In addition, it showed a strong anti-inflammatory effect by regulating the NO level in an in vitro cell model. Conclusion: This study presents a nanocarrier to improve the water-soluble dispersion and stability of DX. These results demonstrate that DX@NC is a carrier with excellent stability and has a high potential for use in cosmetic and pharmaceutical applications owing to its antioxidant and anti-inflammatory effects.

Acetabular, Femoral, and Combined Anteversion in a Province in South Korea: Computed Tomography-Based Study.

Background: The purpose of this study was to investigate the femoral, acetabular, and combined anteversion of the hip joint in South Koreans using computed tomography (CT). Methods: We measured anteversion using CT venograms taken from 2016 to 2020. Of the total 1,073 patients, 952 patients were included in the study except for those with pelvic fractures, previous femoral fractures, childhood hip joint disease, osteoarthritis, or hip dysplasia (lateral center-edge angle, < 20), foreigners, and hip and knee replacement patients. Measurements were taken twice by two orthopedic surgeons. Results: The femoral anteversion in women was 10.64° ± 10.26° (≤ 49 years), 15.75° ± 9.40° (50-59 years), 10.81° ± 9.14° (60-69 years), 12.38° ± 8.55° (70-79 years), and 11.23° ± 8.44° (≥ 80 years). The femoral anteversion in men was 12.02° ± 11.38° (≤ 49 years), 10.62° ± 9.11° (50-59 years), 6.09° ± 9.95° (60-69 years), 6.57° ± 9.51° (70-79 years), and 5.53° ± 9.29° (≥ 80 years). The acetabular anteversion in women was 17.65° ± 6.58° (≤ 49 years), 19.24° ± 6.42° (50-59 years), 20.30° ± 6.25° (60-69 years), 22.38° ± 7.36° (70-79 years), and 23.34° ± 6.98° (≥ 80 years). The acetabular anteversion in men was 15.21° ± 8.14° (≤ 49 years), 17.68° ± 6.00° (50-59 years), 17.54° ± 5.93° (60-69 years), 18.68° ± 6.62° (70-79 years), and 18.19° ± 6.94° (≥ 80 years). The combined anteversion in women was 28.29° ± 14.30° (≤ 49 years), 34.99° ± 10.62° (50-59 years), 31.11° ± 11.52° (60-69 years), 34.76° ± 10.86° (70-79 years), and 34.57° ± 11.45° (≥ 80 years). The combined anteversion in men was 27.23° ± 15.11° (≤ 49 years), 28.30° ± 11.23° (50-59 years), 23.63° ± 11.77° (60-69 years), 25.25° ± 12.02° (70-79 years), and 23.72° ± 11.88° (≥ 80 years). Conclusions: Femoral anteversion tended to decrease with age in men and acetabular anteversion tended to increase in both men and women. Combined anteversion showed a tendency to increase slightly in women.

Targeting Wnt/ß-catenin-mediated upregulation of oncogenic NLGN3 suppresses cancer stem cells in glioblastoma.

Glioblastoma (GBM) is the most malignant tumor in brain and is highly resistant to therapy. Clinical evidence suggests increased number of cancer stem cells (CSCs) may contribute to the failure of conventional therapies, but the mechanisms associated with acquisition of CSC properties in GBM are not fully understood. We found that DAB2IP suppresses CSC properties by targeting the synaptic proteins neuroligin 3 (NLGN3) in GBM. Furthermore, we showed that GBM-derived NLGN3 has an oncogenic function by inducing CSC properties within GBM. Moreover, elevated NLGN3 transcription mediated by Wnt/ß-catenin signaling pathway resulted in increased secretion of NLGN3 into the surrounding tumor microenvironment. Both condition media containing NLGN3 and recombinant NLGN3 transformed neighboring cells to CSCs, suggesting NLGN3 as a critical component inducing CSC properties. Furthermore, targeting NLGN3-bearing CSCs using upstream Wnt/ß-catenin inhibitors synergistically enhances the efficacy of conventional treatment. Hence, we unveiled the series of regulatory mechanisms for acquisition of CSC properties in GBM progression by Wnt/ß-catenin-mediated NLGN3. These results may provide a new targeting strategy to improve the therapeutic efficacy of GBM treatments.

Transcriptomic analysis of neutrophil apoptosis induced by diffuse large B-cell lymphoma unveils a potential role in neutropenia.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma that arises from malignant transformation of B lymphocytes. Outcome of patients with DLBCL has been significantly improved by rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy, which is regarded "gold standard" of DLBCL therapy. It is unfortunate that febrile neutropenia, a decrease of the neutrophil count in the blood accompanying fever, is one of the most common complications that DLBCL patients receiving R-CHOP regimen experience. Given the critical role of neutrophils against bacterial and fungal infections, neutropenia could be deadly. While the association between R-CHOP therapy and neutropenia has been well-established, the negative effect of DLBCL cells on the survival of neutrophils has not been clearly understood. Our previous study have shown that conditioned medium (CM) derived from Ly1 DLBCL cells induces apoptosis in murine neutrophils ex vivo. Additionally, Ly1 CM and doxorubicin synergize to further enhance apoptotic rate in neutrophils, possibly contributing to neutropenia in DLBCL patients. OBJECTIVE: We investigated the mechanism and genes that regulate neutrophil apoptosis induced by secretome of DLBCL cells, which would give insight into the potential role of DLBCL in neutropenia. METHOD: Murine neutrophils were isolated from bone marrow in C57BL6/J mice using flow cytometry. QuantSeq 3' mRNA-sequencing was conducted on neutrophils following exposure to CM derived from Ly1 DLBCL cells or murine bone marrow cells (control). Quantseq 3'mRNA sequencing data were aligned to identify differentially expressed mRNAs. Next, the expression of genes related to neutrophil apoptosis and proliferation were analyzed and Gene classification and ontology were analyzed. RESULT: We identified 1196 (198 upregulated and 998 downregulated) differentially expressed genes (DEGs) in Ly1 DLBCL co-culture group compared to the control group. The functional enrichment analyses of DEGs in co-culture group revealed significant enriched in apoptosis process, and immune system process in gene ontology and the highly enriched pathway of various bacterial infection, leukocyte transendothelial migration, apoptosis, and cell cycle in KEGG pathway. Importantly, Bcl7b, Bnip3, Bmx, Mcl1, and Pim1 were identified as critical regulators of neutrophil apoptosis, which may be potential drug targets for the treatment of neutropenia. We are currently testing the efficacy of the activators/inhibitors of the proteins encoded by these genes to investigate whether they would block DLBCL-induced neutrophil apoptosis. CONCLUSION: In the present study, bioinformatic analyses of gene expression profiling data revealed the crucial genes involved in neutrophil apoptosis and gave insight into the underlying mechanism. Given our data, it may be likely that novel opportunities for the treatment of neutropenia, and eventually improvement of prognosis of DLBCL patients, might emerge.

Anti-Leukemic Effects of Idesia polycarpa Maxim Branch on Human B-Cell Acute Lymphoblastic Leukemia Cells.

Patients with pediatric B-cell acute lymphoblastic leukemia (B-ALL) have a high survival rate, yet the prognosis of adults and patients with relapsed/refractory disease is relatively poor. Therefore, it is imperative to develop new therapeutic strategies. Here, we screened 100 plant extracts from South Korean Flora and investigated their anti-leukemic effect using CCRF-SB cells as a B-ALL model. The top cytotoxic extract identified in this screening was the Idesia polycarpa Maxim. branch (IMB), which efficiently inhibited the survival and proliferation of CCRF-SB cells, while having minimal to no impact on normal murine bone marrow cells. Mechanistically, the IMB-induced proapoptotic effect involves the increase of caspase 3/7 activity, which was shown to be associated with the disruption of the mitochondrial membrane potential (MMP) through the reduction in antiapoptotic Bcl-2 family expression. IMB also promoted the differentiation of CCRF-SB cells via the upregulation of the expression of differentiation-related genes, PAX5 and IKZF1. Given that resistance to glucocorticoid (GC) is often found in patients with relapsed/refractory ALL, we investigated whether IMB could restore GC sensitivity. IMB synergized GC to enhance apoptotic rate by increasing GC receptor expression and downmodulating mTOR and MAPK signals in CCRF-SB B-ALL cells. These results suggest that IMB has the potential to be a novel candidate for the treatment of B-ALL.

Mesoporous Silica Nanoparticles as a Gene Delivery Platform for Cancer Therapy.

Cancer remains a major global health challenge. Traditional chemotherapy often results in side effects and drug resistance, necessitating the development of alternative treatment strategies such as gene therapy. Mesoporous silica nanoparticles (MSNs) offer many advantages as a gene delivery carrier, including high loading capacity, controlled drug release, and easy surface functionalization. MSNs are biodegradable and biocompatible, making them promising candidates for drug delivery applications. Recent studies demonstrating the use of MSNs for the delivery of therapeutic nucleic acids to cancer cells have been reviewed, along with their potential as a tool for cancer therapy. The major challenges and future interventions of MSNs as gene delivery carriers for cancer therapy are discussed.