The Role of Measuring Preoperative Social Maturation Score in Children With Additional Needs Who Underwent Cochlear Implantation.

BACKGROUND AND OBJECTIVES: Additional needs refer to specific requirements or support for individuals with disabilities or syndromes. Intellectual ability is a crucial outcome determinant of a cochlear implant. The social quotient (SQ) is an indirect predictor of intellectual capacity and social skills. This study aimed to investigate the clinical significance of the SQ on children with additional needs who received cochlear implants. Subjects and. METHODS: This study included 24 patients with diagnosed developmental delays and syndromes, who demonstrated SQ scores of <70. Preoperative social skills were evaluated using the SQ. All patients underwent cochlear implantation (CI) surgery before 7 years of age. Outcomes were evaluated using the Infant-Toddler Meaningful Auditory Integration Scale (IT-MAIS) and Categories of Auditory Performance (CAP) scores. Data were collected through a retrospective chart review. RESULTS: Children were categorized into three groups based on their SQ. There were no correlations between the preoperative SQ and IT-MAIS or CAP scores at 2 and 5 years of follow-up postoperatively. The CI outcomes of children with low SQ (<70) differed from those with normal development (SQ>70). In the low-SQ group, inner ear anomalies were observed in 10 (41.7%) patients. Although not statistically significant, these children exhibited a trend of lower average outcomes than children without inner ear anomalies. CONCLUSIONS: CI outcomes in children with additional needs positively affected auditory performance. Postoperative auditory and language skills tended to improve slowly in children with additional needs and a lower SQ. Over time, development gradually became more comparable to the other groups of children. However, this improvement was less than that observed in children without additional needs. Our findings support CI for children with additional needs as part of long-term auditory rehabilitation following surgery.

Acetyl-CoA synthetase 2 contributes to a better prognosis for liver cancer by switching acetate-glucose metabolism.

Acetyl-CoA synthetase 2 (ACSS2)-dependent acetate usage has generally been associated with tumorigenesis and increased malignancy in cancers under nutrient-depleted conditions. However, the nutrient usage and metabolic characteristics of the liver differ from those of other organs; therefore, the mechanism of ACSS2-mediated acetate metabolism may also differ in liver cancer. To elucidate the underlying mechanisms of ACSS2 in liver cancer and acetate metabolism, the relationships between patient acetate uptake and metabolic characteristics and between ACSS2 and tumor malignancies were comprehensively studied in vitro, in vivo and in humans. Clinically, we initially found that ACSS2 expression was decreased in liver cancer patients. Moreover, PET-CT imaging confirmed that lower-grade cancer cells take up more 11C-acetate but less 18F-fluorodeoxyglucose (18F-FDG); however, this trend was reversed in higher-grade cancer. Among liver cancer cells, those with high ACSS2 expression avidly absorbed acetate even in a glucose-sufficient environment, whereas those with low ACSS2 expression did not, thereby showing correlations with their respective ACSS2 expression. Metabolomic isotope tracing in vitro and in vivo revealed greater acetate incorporation, greater lipid anabolic metabolism, and less malignancy in high-ACSS2 tumors. Notably, ACSS2 downregulation in liver cancer cells was associated with increased tumor occurrence in vivo. In human patient cohorts, patients in the low-ACSS2 subgroup exhibited reduced anabolism, increased glycolysis/hypoxia, and poorer prognosis. We demonstrated that acetate uptake by ACSS2 in liver cancer is independent of glucose depletion and contributes to lipid anabolic metabolism and reduced malignancy, thereby leading to a better prognosis for liver cancer patients.

Water Extract of Desalted Salicornia europaea Inhibits RANKL-Induced Osteoclast Differentiation and Prevents Bone Loss in Ovariectomized Mice.

Osteoporosis, which is often associated with increased osteoclast activity due to menopause or aging, was the main focus of this study. We investigated the inhibitory effects of water extract of desalted Salicornia europaea L. (WSE) on osteoclast differentiation and bone loss in ovariectomized mice. Our findings revealed that WSE effectively inhibited RANKL-induced osteoclast differentiation, as demonstrated by TRAP staining, and also suppressed bone resorption and F-actin ring formation in a dose-dependent manner. The expression levels of genes related to osteoclast differentiation, including NFATc1, ACP5, Ctsk, and DCSTAMP, were downregulated by WSE. Oral administration of WSE improved bone density and structural parameters in ovariectomized mice. Dicaffeoylquinic acids (DCQAs) and saponins were detected in WSE, with 3,4-DCQA, 3,5-DCQA, and 4,5-DCQA being isolated and identified. All tested DCQAs, including the aforementioned types, inhibited osteoclast differentiation, bone resorption, and the expression of osteoclast-related genes. Furthermore, WSE and DCQAs reduced ROS production mediated by RANKL. These results indicate the potential of WSE and its components, DCQAs, as preventive or therapeutic agents against osteoporosis and related conditions.

Treatment outcomes of the external auditory canal and temporal bone malignancy with dura invasion.

Objectives: This study aimed to evaluate the characteristics and surgical outcomes of patients with external auditory canal (EAC) and temporal bone (TB) malignancy with dura invasion. Methods: The medical records of patients with EAC and TB malignancy with dura invasion were retrospectively reviewed. Survival outcomes (overall survival [OS], disease-specific survival [DSS], recurrence-free survival [RFS], and distant metastasis-free survival [DMFS]) were analyzed using the Kaplan-Meier method. Results: A total of eight patients were included in this study. The median age at diagnosis was 49.5 years (range 12-74 years). The median follow-up periods were 46.5 months. Histologically, four out of eight patients were diagnosed with squamous cell carcinoma (SCC; 50%). The 2-year OS and DSS rates of all patients were 62.5%, and those of EAC SCC patients were 50% and 66.7%, respectively; while the 2-year RFS and DMFS rates of all patients were 37.5%. There was one local recurrence at the resection site (12.5%), two regional neck nodal recurrences (25%), and two distant metastases (25%). Dura resection and duroplasty areas were not involved in the local recurrence case. Conclusion: In EAC and TB cancer with dura invasion, radical surgery with dura resection may show similar survival outcomes to previous studies without recurrence at the dura resection site.Level of evidence: IV.

Oral Administration of Lactobacillus sakei CVL-001 Improves Recovery from Dextran Sulfate Sodium-Induced Colitis in Mice by Microbiota Modulation.

Inflammatory bowel disease (IBD) is an intestinal chronic inflammatory disease, and its incidence is steadily increasing. IBD is closely related to the intestinal microbiota, and probiotics are known to be a potential therapeutic agent for IBD. In our study, we evaluated the protective effect of Lactobacillus sakei CVL-001, isolated from Baechu kimchi, on dextran sulfated sodium (DSS)-induced colitis in mice. The oral administration of L. sakei CVL-001 according to the experimental schedule alleviated weight loss and disease activity in the mice with colitis. Furthermore, the length and histopathology of the colon improved. The expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß genes decreased in the colons of mice that were administered L. sakei CVL-001, whereas that of IL-10 increased. The expressions of genes coding for E-cadherin, claudin3, occludin, and mucin were also restored. In co-housed conditions, L. sakei CVL-001 administration did not improve disease activity, colon length, and histopathology. Microbiota analysis revealed that L. sakei CVL-001 administration increased the abundance of microbiota and altered Firmicutes/Bacteroidetes ratio, and decreased Proteobacteria. In conclusion, L. sakei CVL-001 administration protects mice from DSS-induced colitis by regulating immune response and intestinal integrity via gut microbiota modulation.

Anatomical Features of Children With Mondini Dysplasia: Influence on Cochlear Implantation Performance.

OBJECTIVE: To analyze the long-term auditory performance after cochlear implantation (CI) and identify anatomical features of Mondini dysplasia associated with post-CI outcomes. STUDY DESIGN: Retrospective study. SETTING: Tertiary care academic center. PATIENTS: We enrolled 49 ears with Mondini dysplasia who underwent CI with more than 7 years of follow-up and age at CI- and sex-matched control group with radiologically normal inner ears. MAIN OUTCOMES AND MEASURES: The development of auditory skills after CI was evaluated using word recognition scores (WRSs). The anatomical features were measured based on temporal bone computed tomography and magnetic resonance imaging, involving the width of the bony cochlear nerve canal (BCNC), cochlear basal turn, enlarged vestibular aqueduct, cochlear height, and diameter of the cochlear nerve (CN). RESULTS: CI in ears with Mondini dysplasia showed comparable benefits and improvement of auditory performance to controls during the 7 years of follow-up. In Mondini dysplasia, four (8.2%) ears showed narrow BCNC (<1.4 mm) with poorer WRS (58 ± 17%) than those with normal-sized BCNC, which had WRS (79 ± 10%) comparable to that of the control group (77 ± 14%). In Mondini dysplasia, the maximum ( r = 0.513, p < 0.001) and minimum ( r = 0.328, p = 0.021) CN diameters had positive correlations with post-CI WRS. The maximum CN diameter ( ß = 48.347, p < 0.001) and BCNC width ( ß = 12.411, p = 0.041) were significant factors that influence the post-CI WRS in multiple regression analysis. CONCLUSIONS: Preoperative anatomical evaluation, especially BCNC status and CN integrity, may serve as predictive markers for post-CI performance.

Vactosertib, TGF-ß receptor I inhibitor, augments the sensitization of the anti-cancer activity of gemcitabine in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) exhibits a pronounced extracellular matrix (ECM)-rich response, which is produced by an excessive amount of transforming growth factor ß (TGF-ß), resulting in tumor progression and metastasis. In addition, TGF-ß signaling contributes to rapidly acquired resistance and incomplete response to gemcitabine. Recently, selective inhibitors of the TGF-ß signaling pathway have shown promise in PDAC treatment, particularly as an option for augmenting responses to chemotherapy. Here, we investigated the synergistic anticancer effects of a small-molecule TGF-ß receptor I kinase inhibitor (vactosertib/EW-7197) in the presence of gemcitabine, and its mechanism of action in pancreatic cancer. Vactosertib sensitized pancreatic cancer cells to gemcitabine by synergistically inhibiting their viability. Importantly, the combination of vactosertib and gemcitabine significantly attenuated the expression of major ECM components, including collagens, fibronectin, and α-SMA, in pancreatic cancer compared with gemcitabine alone. This resulted in potent induction of mitochondrial-mediated apoptosis, gemcitabine-mediated cytotoxicity, and inhibition of tumor ECM by vactosertib. Additionally, the combination decreased metastasis through inhibition of migration and invasion, and exhibited synergistic anti-cancer activity by inhibiting the TGF-ß/Smad2 pathway in pancreatic cancer cells. Furthermore, co-treatment significantly suppressed tumor growth in orthotopic models. Therefore, our findings demonstrate that vactosertib synergistically increased the antitumor activity of gemcitabine via inhibition of ECM component production by inhibiting the TGF-ß/Smad2 signaling pathway. This suggests that the combination of vactosertib and gemcitabine may be a potential treatment option for patients with pancreatic cancer.

A combination of BR101801 and venetoclax enhances antitumor effect in DLBCL cells via c-Myc/Bcl-2/Mcl-1 triple targeting.

Double hit diffuse large B-cell lymphoma (DLBCL) with rearrangement and overexpression of both c-Myc and Bcl-2 responds poorly to standard R-CHOP therapy. In a recent phase I study, Venetoclax (ABT-199) targeting Bcl-2 also exhibited disappointing response rates in patients with relapsed/refractory DLBCL, suggesting that targeting only Bcl-2 is not sufficient for achieving successful efficacy due to the concurrent oncogenic function of c-Myc expression and drug resistance following an increase in Mcl-1. Therefore, co-targeting c-Myc and Mcl-1 could be a key combinatorial strategy to enhance the efficacy of Venetoclax. In this study, BR101801 a novel drug for DLBCL, effectively inhibited DLBCL cell growth/proliferation, induced cell cycle arrest, and markedly inhibited G0/G1 arrest. The apoptotic effect of BR101801 was also observed by increased Cytochrome C, cleaved PARP, and Annexin V-positive cell populations. This anti-cancer effect of BR101801 was confirmed in animal models, where it effectively inhibited tumor growth by reducing the expression of both c-Myc and Mcl-1. Furthermore, BR101801 exhibited a significant synergistic antitumor effect even in late xenograft models when combined with Venetoclax. Our data strongly suggest that c-Myc/Bcl-2/Mcl-1 triple targeting through a combination of BR101801 and Venetoclax could be a potential clinical option for double-hit DLBCL.

A novel DDR1 inhibitor enhances the anticancer activity of gemcitabine in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an extracellular matrix (ECM)-rich carcinoma, which promotes chemoresistance by inhibiting drug diffusion into the tumor. Discoidin domain receptor 1 (DDR1) increases tumor progression and drug resistance by binding to collagen, a major component of tumor ECM. Therefore, DDR1 inhibition may be helpful in cancer therapeutics by increasing drug delivery efficiency and improving drug sensitivity. In this study, we developed a novel DDR1 inhibitor, KI-301690 and investigated whether it could improve the anticancer activity of gemcitabine, a cytotoxic agent widely used for the treatment of pancreatic cancer. KI-301690 synergized with gemcitabine to suppress the growth of pancreatic cancer cells. Importantly, its combination significantly attenuated the expression of major tumor ECM components including collagen, fibronectin, and vimentin compared to gemcitabine alone. Additionally, this combination effectively decreased mitochondrial membrane potential (MMP), thereby inducing apoptosis. Further, the combination synergistically inhibited cell migration and invasion. The enhanced anticancer efficacy of the co-treatment could be explained by the inhibition of DDR1/PYK2/FAK signaling, which significantly reduced tumor growth in a pancreatic xenograft model. Our results demonstrate that KI-301690 can inhibit aberrant ECM expression by DDR1/PYK2/FAK signaling pathway blockade and attenuation of ECM-induced chemoresistance observed in desmoplastic pancreatic tumors, resulting in enhanced antitumor effect through effective induction of gemcitabine apoptosis.

Lidocaine enhances the efficacy of palbociclib in triple-negative breast cancer.

The use of anesthetics in the surgical resection of tumors may influence the prognosis of cancer patients. Lidocaine, a local anesthetic, is known to act as a chemosensitizer and relieve pain in some cancers. In addition, palbociclib, a potent cyclin-dependent kinase (CDK) 4/6 inhibitor, has been approved for chemotherapy of advanced breast cancer. However, recent studies have revealed the acquired resistance of breast cancer cells to palbociclib. Therefore, the development of combination therapies that can extend the efficacy of palbociclib or delay resistance is crucial. This study investigated whether lidocaine would enhance the efficacy of palbociclib in breast cancer. Lidocaine synergistically suppressed the growth and proliferation of breast cancer cells by palbociclib. The combination treatment showed an increased cell cycle arrest in the G0/G1 phase by decreasing retinoblastoma protein (Rb) and E2F1 expression. In addition, it increased apoptosis by loss of mitochondrial membrane potential as observed by increases in cytochrome c release and inhibition of mitochondria-mediated protein expression. Additionally, it significantly reduced epithelial-mesenchymal transition and PI3K/AKT/GSK3ß signaling. In orthotopic breast cancer models, this combination treatment significantly inhibited tumor growth and increased tumor cell apoptosis compared to those treated with a single drug. Taken together, this study demonstrates that the combination of palbociclib and lidocaine has a synergistic anti-cancer effect on breast cancer cells by the inhibition of the PI3K/AKT/GSK3ß pathway, suggesting that this combination could potentially be an effective therapy for breast cancer.

Endoscopic Transcanal Labyrinthectomy for Intractable Meniere's Disease: An Alternative to Transmastoid Labyrinthectomy?

OBJECTIVE: To describe a novel approach for intractable Ménière's disease exclusively through a transcanal endoscopic ear surgery (TEES) approach. PATIENT: A 56-year-old male with intractable Ménière's disease despite conservative treatment and chemical labyrinthectomy. INTERVENTIONS: Transcanal endoscopic labyrinthectomy. MAIN OUTCOME MEASURE: Subjective vertigo control, surgical morbidity. RESULTS: The TEES approach provided a wide exposure of the oval window. This facilitated removal of stapes crura and footplate. After widening of the oval window, the perilymph was suctioned, and gentamicin was injected through the oval window. The oval window was obliterated using the perichondrium of the tragal cartilage and fibrin glue. After 2 years of follow-up, there was no recurrence of vertigo. CONCLUSIONS: As a compelling alternative to the transmastoid approach, we propose endoscopic labyrinthectomy as an option for patients with intractable MD without functional hearing who have failed chemical labyrinthectomy. Additional studies are needed to determine the risk-benefit profile of this technique.

Kushenol C Prevents Tert-Butyl Hydroperoxide and Acetaminophen-Induced Liver Injury.

Sophora flavescens, also known as Kushen, has traditionally been used as a herbal medicine. In the present study we evaluated the ameliorative effects of kushenol C (KC) from S. flavescens against tBHP (tert-Butyl hydroperoxide)-induced oxidative stress in hepatocellular carcinoma (HEPG2) cells and acetaminophen (APAP)-induced hepatotoxicity in mice. KC pretreatment protected the HEPG2 cells against oxidative stress by reducing cell death, apoptosis and reactive oxygen species (ROS) generation. KC pretreatment also upregulated pro-caspase 3 and GSH (glutathione) as well as expression of 8-Oxoguanine DNA Glycosylase (OGG1) in the HEPG2 cells. The mechanism of action was partly related by KC's activation of Akt (Protein kinase B (PKB)) and Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) in the HepG2 cells. In in vivo investigations, coadministration of mice with KC and APAP significantly attenuated APAP-induced hepatotoxicity and liver damage, as the serum enzymatic activity of aspartate aminotransferase and alanine aminotransferase, as well as liver lipid peroxidation and cleaved caspase 3 expression, were reduced in APAP-treated mice. Coadministration with KC also up-regulated antioxidant enzyme expression and prevented the production of proinflammatory mediators in APAP-treated mice. Taken together, these results showed that KC treatment has potential as a therapeutic agent against liver injury through the suppression of oxidative stress.

Receptor-interacting protein kinase 2 contributes to host innate immune responses against Fusobacterium nucleatum in macrophages and decidual stromal cells.

PROBLEM: Chorioamnionitis is caused by a bacterial infection that ascends from the vagina and can cause adverse pregnancy outcomes (APOs). Fusobacterium nucleatum (F. nucleatum) is a periodontal pathogen associated with the occurrence of APOs. In this study, we evaluated whether receptor-interacting protein kinase 2 (Ripk2), an adaptor protein of the cytosolic receptors nucleotide-binding oligomerization domain (NOD)1 and NOD2, in macrophages and human decidual stromal cells (hDSCs) contributes to immune responses against F. nucleatum. METHOD OF STUDY: Bone marrow-derived macrophages (BMDMs) isolated from wild-type (WT) and Ripk2-deficient mice and hDSCs were cultured with F. nucleatum (MOI 1, 10, 100). BMDMs and hDSCs were assessed using enzyme-linked immunosorbent assay, Western blot analysis, real-time PCR, and nitrite assay. RESULTS: Fusobacterium nucleatum-induced production of IL-6, but not of TNF-α and IL-10, was lower in Ripk2-deficient BMDMs than in WT cells. Western blotting revealed a decrease in F. nucleatum-induced p65 phosphorylation in Ripk2-deficient macrophages, whereas mitogen-activated protein kinases activation was comparable between WT and Ripk2-deficient cells. The production of nitric oxide (NO) in response to F. nucleatum and the gene and protein expression of inducible NO synthase was impaired in Ripk2-deficient BMDMs. In hDSCs, F. nucleatum upregulated the gene and protein expression of NOD1, NOD2, and Ripk2 in a time-dependent manner. F. nucleatum also increased the production of IL-6, CXCL8, and CCL2, whereas this production was decreased by the Ripk2 inhibitors SB203580 and PP2. CONCLUSIONS: In conclusion, Ripk2 signaling appears to contribute to the F. nucleatum-induced immune response and can be a preventive and therapeutic target against APOs.

Efficacy of bevacizumab injection after pterygium excision and limbal conjunctival autograft with limbal fixation suture.

PURPOSE: To determine the efficacy of subconjunctival bevacizumab injection after pterygium excision with limbal conjunctival autograft and limbal fixation suture. METHODS: This retrospective study included a total of 150 eyes of 150 patients with primary pterygium who received three different procedures after pterygium excision, i.e., 49 eyes with limbal conjunctival graft (group A), 48 eyes with limbal conjunctival autograft with limbal fixation suture (group B), and 53 eyes with limbal conjunctival autograft with limbal fixation suture followed by bevacizumab injection (group C). Image analysis was performed using preoperative anterior segment photographs to measure parameters including relative length, relative width, relative area, and vascularity index of pterygium. Recurrence of pterygium was determined at 1 year after surgery, and outcomes were compared between the 3 groups. Risk factors related to recurrence were evaluated using univariate and multivariate analyses. RESULTS: Recurrence rates after 1 year were 18.4% (9/49), 8.3% (4/48), and 1.9% (1/53) in groups A, B, and C, respectively (P = 0.004). Multivariate analysis showed that patients in group C had significantly reduced risk of recurrence compared with those in group A (P = 0.009), whereas the risk of recurrence was not significantly different between groups A and B (P = 0.227) and groups B and C (P = 0.068), respectively. Among various parameters, higher vascularity index had significant correlation with increased risk of recurrence (P = 0.008). CONCLUSIONS: Bevacizumab injection after limbal conjunctival autograft and limbal fixation suture may effectively reduce recurrence after pterygium excision. The vascularity of pterygium was associated with a higher risk of recurrence.

Immune-Enhancing Effects of a High Molecular Weight Fraction of Cynanchum wilfordii Hemsley in Macrophages and Immunosuppressed Mice.

The objective of this study was to investigate the immune-enhancing activity of a high molecular weight fraction (HMF) of Cynanchum wilfordii in RAW 264.7 macrophages and the cyclophosphamide (CYC)-induced mouse model of immunosuppression. To identify the bioactive substances of HMF, a crude polysaccharide (HMFO) was obtained and treated with sodium periodate (an oxidation agent) or digested with protease. In macrophages, HMF treatment enhanced the production of nitric oxide (NO) and cytokines (tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interleukin 1ß (IL-1ß)), as well as phagocytic ability. In CYC-immunosuppressed mice, HMF improved relative spleen and thymus weights, natural killer (NK) cell activity, and splenic lymphocyte proliferation. These increases in NO and cytokines were mediated by up-regulation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Periodate treatment, but not protease treatment, decreased the immune-enhancing activity of HMFO, suggesting that polysaccharides are the active ingredients in C. wilfordii extract.