A possible correlation between facet orientation and development of degenerative cervical spinal stenosis.

BACKGROUND: Previous studies have demonstrated the relationship between sagittal facet orientation and cervical degenerative spondylolisthesis. However, the associations between facet orientation and cervical spinal stenosis (CSS) have rarely been studied. METHODS: One hundred twenty patients with CSS (CSS group) and 120 healthy participants (control group) were consecutively enrolled. The cervical facet angles and anteroposterior diameter (A-P diameter) of spinal canal at each subaxial cervical levels were measured using axial magnetic resonance imaging. The intersection angle of the midsagittal line of the vertebra to the facet line represents the orientation of the facet joint. RESULTS: The facet angles on the right side at C2- C3 and C3-C4 in CSS group and at C2- C3 in control group had significantly higher values than those of the other sides. Besides, the facet angles and A-P diameter of spinal canal in CSS group were significantly smaller than those in control group at all levels (p < 0.05). CONCLUSIONS: Our study demonstrated that patients with CSS have smaller axial cervical facet joint angles compared to the healthy individuals. Further studies are needed to elicit the specific underlying mechanism between sagittalization of the cervical facet joints and the pathology of CSS.

Rehabilitation Program for Postlaryngectomy Patients Following Ileocolon Flap Transfer for Voice Reconstruction: An Essential Part of Success.

BACKGROUND: Speech restoration is important for communication and social activities after pharyngolaryngectomy in head and neck cancer or corrosive injury. Several techniques of voice restoration have been developed to improve life quality. The aim of this paper was to focus on the microsurgical transfer of ileocolon flap and outcome of further voice rehabilitation. PATIENTS AND METHODS: From 2010 to 2022, 69 patients had ileocolon flap at our hospital with postoperative speech training and regular follow-up for over 1 year. The patients received deglutition training first, followed by voice rehabilitation. Voice outcomes were evaluated at an interval of 3 months and finally at 12 months of voice training rehabilitation. Among other examinations, the speech function was evaluated using a 4-point Likert scale and senior surgeon (H-c.C.) scoring system. RESULTS: The results showed that speech function reached 13.1% of excellent voice, 65.1% of good voice, 13.1% of fair result, and 8.7% of poor result by Likert scales. Meanwhile, the senior surgeon (H-c.C.) score showed 17.4% of excellent, 63.8% of moderate, and 18.8% of poor results. About voice laboratory results, maximal phonation time was 11.0 seconds, and the average number counted in one breath was 15. Loudness and frequency showed 56.0 dB and 105.0 Hz, respectively. CONCLUSION: The study showed that after voice reconstruction with ileocolon flap followed by the voice rehabilitation program, the patients would have a better understanding of the altered anatomical structures and practice in a more efficient way. Adequate recommendation by the therapists to plastic surgeons for revision surgeries optimized voice function of the patients.

Coenzyme Q0 defeats NLRP3-mediated inflammation, EMT/metastasis, and Warburg effects by inhibiting HIF-1α expression in human triple-negative breast cancer cells.

Coenzyme Q0 (CoQ0) is a derivative quinone from Antrodia camphorata (AC) that exerts anticancer activities. This study examined the anticancer attributes of CoQ0 (0-4 µM) on inhibited anti-EMT/metastasis and NLRP3 inflammasome, and altered Warburg effects via HIF-1α inhibition in triple-negative breast cancer (MDA-MB-231 and 468) cells. MTT assay, cell migration/invasion assays, Western blotting, immunofluorescence, metabolic reprogramming, and LC-ESI-MS were carried out to assess the therapy potential of CoQ0. CoQ0 inhibited HIF-1α expression and suppressed the NLRP3 inflammasome and ASC/caspase-1 expression, followed by downregulation of IL-1ß and IL-18 expression in MDA-MB-231 and 468 cells. CoQ0 ameliorated cancer stem-like markers by decreasing CD44 and increasing CD24 expression. Notably, CoQ0 modulated EMT by upregulating the epithelial marker E-cadherin and downregulating the mesenchymal marker N-cadherin. CoQ0 inhibited glucose uptake and lactate accumulation. CoQ0 also inhibited HIF-1α downstream genes involved in glycolysis, such as HK-2, LDH-A, PDK-1, and PKM-2 enzymes. CoQ0 decreased extracellular acidification rate (ECAR), glycolysis, glycolytic capacity, and glycolytic reserve in MDA-MB-231 and 468 cells under normoxic and hypoxic (CoCl2) conditions. CoQ0 inhibited the glycolytic intermediates lactate, FBP, and 2/3-PG, and PEP levels. CoQ0 increased oxygen consumption rate (OCR), basal respiration, ATP production, maximal respiration, and spare capacity under normoxic and hypoxic (CoCl2) conditions. CoQ0 increased TCA cycle metabolites, such as citrate, isocitrate, and succinate. CoQ0 inhibited aerobic glycolysis and enhanced mitochondrial oxidative phosphorylation in TNBC cells. Under hypoxic conditions, CoQ0 also mitigated HIF-1α, GLUT1, glycolytic-related (HK-2, LDH-A, and PFK-1), and metastasis-related (E-cadherin, N-cadherin, and MMP-9) protein or mRNA expression in MDA-MB-231 and/or 468 cells. Under LPS/ATP stimulation, CoQ0 inhibited NLRP3 inflammasome/procaspase-1/IL-18 activation and NFκB/iNOS expression. CoQ0 also hindered LPS/ATP-stimulated tumor migration and downregulated LPS/ATP-stimulated N-cadherin and MMP-2/-9 expression. The present study revealed that suppression of HIF-1α expression caused by CoQ0 may contribute to inhibition of NLRP3-mediated inflammation, EMT/metastasis, and Warburg effects of triple-negative breast cancers.

Antrodia camphorata and coenzyme Q0 , a novel quinone derivative of Antrodia camphorata, impede HIF-1α and epithelial-mesenchymal transition/metastasis in human glioblastoma cells.

Antrodia camphorata (AC) and Coenzyme Q0 (CoQ0 ), a novel quinone derivative of AC, exhibits antitumor activities. The present study evaluated EMT/metastasis inhibition and autophagy induction aspects of AC and CoQ0 in human glioblastoma (GBM8401) cells. Our findings revealed that AC treatment (0-150 µg/mL) hindered tumor cell proliferation and migration/invasion in GBM8401 cells. Notably, AC treatment inhibited HIF-1α and EMT by upregulating epithelial marker protein E-cadherin while downregulating mesenchymal proteins Twist, Slug, Snail, and ß-catenin. There was an appearance of the autophagy markers LC3-II and p62/SQSTM1, while ATG4B was downregulated by AC treatment. We also found that CoQ0 (0-10 µM) could inhibit migration and invasion in GBM8401 cells. In particular, E-cadherin was elevated and N-cadherin, Vimentin, Twist, Slug, and Snail, were reduced upon CoQ0 treatment. In addition, MMP-2/-9 expression and Wnt/ß-catenin pathways were downregulated. Furthermore, autophagy inhibitors 3-MA or CQ reversed the CoQ0 -elicited suppression of migration/invasion and metastasis-related proteins (Vimentin, Snail, and ß-catenin). Results suggested autophagy-mediated antiEMT and antimetastasis upon CoQ0 treatment. CoQ0 inhibited HIF-1α and metastasis in GBM8401 cells under normoxia and hypoxia. HIF-1α knockdown using siRNA accelerated CoQ0 -inhibited migration. Finally, CoQ0 exhibited a prolonged survival rate in GBM8401-xenografted mice. Treatment with Antrodia camphorata/CoQ0 inhibited HIF-1α and EMT/metastasis in glioblastoma.

Magnetic resonance imaging and dynamic X-ray's correlations with dynamic electrophysiological findings in cervical spondylotic myelopathy: a retrospective cohort study.

BACKGROUND: Dynamic somatosensory evoked potentials (DSSEP) can be used to disclose abnormalities of ascending sensory pathways at dynamic positions and diagnose cervical spondylotic myelopathy (CSM). However, radiographic tests including magnetic resonance imaging (MRI) and dynamic X-ray are used much more widely in the management of CSM. Our study aims to clarify the correlations between several radiographic parameters and the DSSEP results, and further determine their reliability with clinical data. METHODS: We retrospectively enrolled 38 CSM patients with surgical intervention. DSSEP tests were performed before surgery. Amplitude ratios of DSSEP N13 and N20 waves at extension and flexion were calculated and recorded as N13_E, N20_E, N13_F, N20_F, respectively. Baseline severity was evaluated with the modified Japanese Orthopedic Association (mJOA) score and the Nurick grades. Prognosis was evaluated based on the 2-year recovery rate. Sagittal diameter and transverse areas of the cord and canal were measured and the the compressive ratios at the compressed site (Compression_Ratio), central (Central_Ratio), and 1/4-lateral points (1/4-Lateral_Compression_Ratio), and spinal cord/Canal Area Ratio were calculated. The intramedullary T2 hyperintensity patterns (Ax-CCM types) were also collected from MRI axial images. Dynamic X-rays were used to test for segmental instability of the cervical spine. The correlations between radiologic findings, DSSEP data, and clinical assessments were investigated. RESULTS: We found that DSSEP N13_E and N13_F correlated with the Compression_Ratio, Central_Ratio, 1/4-Lateral_Compression_Ratio (Pearson, p < 0.05) and Ax-CCM types (ANOVA, p < 0.05) in MRI axial images and cervical segmental instability in dynamic X-ray (t-test, p < 0.05). Apart from the 1/4-Lateral_Compression_Ratio, these radiographic parameters above also correlated with the baseline clinical assessments (Spearman or ANOVA or t-test, p < 0.05) and postoperative recovery rate (Pearson or ANOVA or t-test, p < 0.05). CONCLUSIONS: We found that the preoperative Compression_Ratio, Central_Ratio and 1/4-Lateral_Compression_Ratio in MRI and cervical segmental instability in dynamic X-ray could reflect the dynamic neural dysfunction of the spinal cord. Different Ax-CCM types corresponded to different DSSEP results at extension and flexion, suggesting divergent pathophysiology. These radiographic parameters could help evaluate disease severity and predict postoperative prognosis.

Anticancer activities of chalcone flavokawain B from Alpinia pricei Hayata in human lung adenocarcinoma (A549) cells via induction of reactive oxygen species-mediated apoptotic and autophagic cell death.

Chalcones found in fruits and vegetables have promising cancer chemopreventive properties. This study attempts to identify the anticancer efficacies of chalcone flavokawain B (FKB) in the rhizomes of Alpinia pricei Hayata by examining key molecular events in non-small-cell lung cancer (A549) cells. Our results indicated that in human A549 cells, FKB (0-15 µg/ml) decreases cell viability and colony formation, dysregulates the Bax:B-cell lymphoma 2 ratio and increases apoptotic DNA fragmentation. Mitochondrial (caspase-9/-3 and poly ADP ribose polymerase [PARP]) signaling was found to be involved in FKB-induced apoptosis. In addition, FKB-induced reactive oxygen species (ROS) generation, and N-acetylcysteine attenuated FKB-induced apoptotic cell death. Moreover, FKB triggered autophagy, as evidenced by the improved acidic vesicular organelle formation, lipidated light chain 3 (microtubule-related light chain 3) accumulation, and ATG7 expression and the decreased mammalian target of rapamycin phosphorylation. Furthermore, FKB suppressed ROS-mediated ATG4B expression. Inhibiting autophagy using 3-methyladenine/chloroquine diminished FKB-induced cell death, indicating that autophagy is triggered as a death mechanism by FKB. In summary, FKB has a crucial role in the execution and propagation of ROS-mediated apoptotic and autophagic cell death of lung adenocarcinoma cells.

Does Resection of the Primary Tumor Improve Survival in Patients With Metastatic Chondrosarcoma?

BACKGROUND: Although surgical resection or amputation has been the mainstay of localized chondrosarcoma management for many decades, its efficacy in patients with metastatic chondrosarcoma remains unknown, and likewise we do not know whether there are any tumor- or patient-related factors associated with better survival after surgery for metastatic chondrosarcoma. QUESTIONS/PURPOSES: (1) Is resection of the primary tumor associated with improved survival in patients with metastatic chondrosarcoma? (2) Which subgroups of patients with chondrosarcoma benefit more from resection in terms of survival? METHODS: We identified 200 of 222 patients with metastatic chondrosarcoma in the Surveillance, Epidemiology, and End Results (SEER) database between 1988 and 2014 based on the exclusion criteria. Among those patients, 107 (53.5%) underwent primary tumor resection or amputation. Patient information, including demographics (patient age, gender, race, year of diagnosis), tumor characteristics (primary site, histologic subtype, tumor grade, tumor size), and treatment (record of operation and radiation), was collected and included in the study. Kaplan-Meier analyses, log-rank tests, competing risks framework, multivariable Cox regression modeling, and interaction tests were conducted to assess the association of primary tumor resection and survival in the overall cohort and subgroups. RESULTS: Resection of the primary tumor was associated with improved overall survival (hazard ratio [HR], 0.481; 95% confidence interval [CI], 0.340-0.680; p < 0.001) and cancer-specific survival (HR, 0.493; 95% CI, 0.343-0.709; p < 0.001) after controlling for confounding variables. After controlling further for age, histologic subtype, and grade, primary tumor resection was associated with a survival advantage in patients with conventional subtype and Grade II chondrosarcoma (conventional subtype: HR, 0.403; 95% CI, 0.260-0.623 for overall survival and HR, 0.396; 95% CI, 0.250-0.627 for cancer-specific survival). However, primary tumor resection was not associated with increased survival in patients with metastatic chondrosarcoma who had the dedifferentiated subtype and Grade III malignancy. CONCLUSIONS: The present study demonstrates a possible favorable association between primary tumor resection and survival in some patients with metastatic chondrosarcoma at initial diagnosis. Specifically, patients with conventional subtypes and Grade II malignancies who underwent primary tumor resection had better survival compared with those patients who did not have primary tumor resection. Thus, there might be a benefit from primary tumor resection in these patients, but given the limitations of this database, further prospective studies or randomized trials are needed to confirm our findings. In the meantime, this information might be helpful to consider when discussing surgical options with patients who have conventional, Grade 2 metastatic chondrosarcoma at diagnosis. LEVEL OF EVIDENCE: Level III, therapeutic study.

Survival analysis of patients with metastatic osteosarcoma: a Surveillance, Epidemiology, and End Results population-based study.

PURPOSE: The present study is aimed at investigating whether (1) primary tumour surgery confers an improved survival on patients with metastatic osteosarcoma and (2) primary tumour surgery influences survival of patients with metastatic osteosarcoma differently according to primary tumour site. METHODS: We retrospectively identified 517 patients with high-grade, metastatic osteosarcoma in the Surveillance, Epidemiology, and End Results (SEER) database between 1994 and 2013. The effect of primary tumour surgery on survival was assessed using Kaplan-Meier analyses, log-rank tests, and multivariate Cox proportional hazard regression modeling. RESULTS: Of those 517 patients with metastatic osteosarcoma in the cohort, 351 patients (68%) underwent primary surgery, and 166 patients (32%) did not undergo surgery. Primary tumour surgery was associated with increased overall survival (hazard ratio (HR) = 0.457, 95% CI 0.354-0.590, p < 0.001) and cancer-specific survival (HR = 0.422, 95% CI 0.325-0.550, p < 0.001). When we focused on different primary tumour sites, receipt of primary tumour surgery significantly prolonged the survival of patients with extremity osteosarcoma (p < 0.05 for overall and cancer-specific survival). However, for patients with pelvis/spine osteosarcoma, both univariate and multivariate analyses indicated that primary tumour surgery might not be associated with improved survival (p > 0.05 for overall and cancer-specific survival). CONCLUSIONS: Our study is the first population-based analysis to provide evidence of a favourable prognostic impact of primary tumour surgery on metastatic extremity osteosarcoma patients but not metastatic axial (pelvis/spine) osteosarcoma patients. Moreover, we found that surgery type (resection of the primary tumor without amputation vs. amputation) did not influence survival in patients with metastatic osteosarcoma.

Ubiquitin-specific protease 3 overexpression promotes gastric carcinogenesis and is predictive of poor patient prognosis.

Although gastric cancer (GC) is one of the most common cancers, knowledge of its development and carcinogenesis is limited. To date, expression of ubiquitin-specific protease 3 (USP3) in all types of cancer, including GC, is still unknown. The present study explored the involvement of USP3 in the carcinogenesis and prognosis of GC. We measured USP3 expression in normal and GC tissues and cell lines. Correlations between USP3 protein level and clinicopathological parameters, as well as the significance of USP3 protein level for disease-free survival were assessed. Small hairpin RNA technology and transfection were used to investigate the effect of USP3 manipulation on cell proliferation and spreading. Moreover, xenograft proliferation and metastasis were used to explore the influence of USP3 on tumor growth and metastasis in animals. An increase in USP3 expression was observed in GC cells and tissues. The overexpression of USP3 was significantly correlated with several clinicopathological parameters and poor disease-free survival. Multivariate Cox regression analysis showed that the overexpression of USP3 was an independent prognostic biomarker. Silencing of USP3 suppressed GC cell proliferation and spreading in vitro as well as xenograft proliferation and metastasis in vivo; however, opposite results were obtained when USP3 was overexpressed. Further studies showed that USP3 influenced cell proliferation and spreading by regulating the cell cycle control- and epithelial-mesenchymal transition-related molecules. This study suggests that USP3 overexpression can be a useful biomarker for predicting the outcomes of GC patients and that USP3 targeting represents a potential modality for treating GC.

Ceramide synthase 6 predicts the prognosis of human gastric cancer: It functions as an oncoprotein by dysregulating the SOCS2/JAK2/STAT3 pathway.

Although gastric cancer (GC) is one of the most common cancers, knowledge of its development, and carcinogenesis is limited. The present study explored the involvement of ceramide synthase 6 (CERS6) in GC carcinogenesis and prognosis. RT-PCR, immunoblotting, and immunohistochemistry were used to examine the expression of CERS6. Transfection and small hairpin RNA technology were used to investigate the effect of CERS6 manipulation on cell proliferation and spread as well as the underlying mechanism. Moreover, xenograft proliferation was employed to explore the influence of CERS6 on tumor growth in animals. It was found that overexpression of CERS6 was significantly correlated with several clinicopathologic parameters and poor disease-free survival. The overexpression and silencing of CERS6 in GC cells facilitated and suppressed cell proliferation and spread as well as xenograft proliferation, respectively. Mechanistic studies further revealed that CERS6 influenced cell proliferation and spread by regulating cell cycle control and metastasis-related protein through the SOCS2/JAK2/STAT3 signaling pathway. Collectively, this study suggests that CERS6 overexpression could be a useful biomarker for predicting the outcomes of GC patients and that CERS6 targeting represents a potential modality for treating GC.

Application of transoral continuous intraoperative neuromonitoring in natural orifice transluminal endoscopic surgery for thyroid disease: a preliminary study.

BACKGROUND: The novel concept of continuous intraoperative neuromonitoring (Cont-IONM) through stimulation of the vagal nerve has been used in thyroidectomies to prevent imminent injury of the recurrent laryngeal nerve (RLN). This article reports on this technology and the results of using transoral Cont-IONM in natural orifice transluminal endoscopic surgery for thyroid disease. METHODS: Cont-IONM of the RLN was achieved through automatic cyclical stimulation of the vagal nerve using a C2 monitor and delta stimulating electrode. During the operation, three vestibular incisions were made, and the stimulating electrode was transorally inserted, with its cable line lying outside the trocar. The vagal nerve was gently dissected, looped, and then enveloped by the electrode cuff. Electromyography (EMG) of the vocalis muscle was performed, and the alarm was set to activate when the EMG amplitude reduced by 50% and latency was prolonged by 10%. Demographic data and outcome variables, including incremental time required to achieve Cont-IONM, were obtained. RESULTS: A total of 20 patients (28 nerves at risk) undergoing a transoral endoscopic thyroidectomy vestibular approach were enrolled in this study. All Cont-IONM procedures were successfully completed. In all patients, the stimulation was set at 0.7 milliamps every 1 s, and Cont-IONM use was unassociated with any untoward neural, cardiovascular, or gastrointestinal sequelae. On average, the ipsilateral Cont-IONM procedure required 10.33 ± 2.57 min to complete. Except for one instance, no significant problems occurred with electrode displacement. In one patient, a combined EMG event occurred, which improved after releasing the thyroid retractor, and the patient had no vocal cord paralysis postoperatively. CONCLUSION: Cont-IONM is feasible and safe to use during transoral endoscopic thyroidectomies and may assist in the early detection of adverse EMG changes, thereby preventing paralysis of the RLNs.

Chalcone flavokawain B induces autophagic-cell death via reactive oxygen species-mediated signaling pathways in human gastric carcinoma and suppresses tumor growth in nude mice.

Flavokawain B (FKB), a naturally occurring chalcone in kava extracts, has been reported to possess anticancer activity. However, the effect of FKB on gastric cancer remains unclear. We examined the in vitro and in vivo anticancer activity and autophagy involvement of FKB and determined the underlying molecular mechanisms. FKB is potently cytotoxic to human gastric cancer cells (AGS/NCI-N87/KATO-III/TSGH9201) and mildly toxic towards normal (Hs738) cells and primary mouse hepatocytes. FKB-induced AGS cell death was characterized by autophagy, not apoptosis, as evidenced by increased LC3-II accumulation, GFP-LC3 puncta and acidic vesicular organelles (AVOs) formation, without resulting procaspase-3/PARP cleavage. FKB further caused p62/SQSTM1 activation, mTOR downregulation, ATG4B inhibition, and Beclin-1/Bcl-2 dysregulation. Silencing autophagy inhibitors CQ/3-MA and LC3 (shRNA) significantly reversed the FKB-induced cell death of AGS cells. FKB-triggered ROS generation and ROS inhibition by NAC pre-treatment diminished FKB-induced cell death, LC3 conversion, AVO formation, p62/SQSTM1 activation, ATG4B inhibition and Beclin-1/Bcl-2 dysregulation, which indicated ROS-mediated autophagy in AGS cells. Furthermore, FKB induces G2/M arrest and alters cell-cycle proteins through ROS-JNK signaling. Interestingly, FKB-induced autophagy is associated with the suppression of HER-2 and PI3K/AKT/mTOR signaling cascades. FKB inhibits apoptotic Bax expression, and Bax-transfected AGS cells exhibit both apoptosis and autophagy; thus, FKB-inactivated Bax results in apoptosis inhibition. In vivo data demonstrated that FKB effectively inhibited tumor growth, prolonged the survival rate, and induced autophagy in AGS-xenografted mice. Notably, silencing of LC3 attenuated FKB-induced autophagy in AGS-xenografted tumors. FKB may be a potential chemopreventive agent in the activation of ROS-mediated autophagy of gastric cancer cells.

High expression of mitochondrial intermembrane chaperone TIMM9 represents a negative prognostic marker in gastric cancer.

BACKGROUND/PURPOSE: Gastric cancer (GC) is one of the most common malignant cancers worldwide. However, little is known about the molecular process underlying this disease and its progression. This study investigated correlations between the expression of a mitochondrial inner membrane protein translocase of inner mitochondrial membrane 9 homolog (TIMM9) and various clinicopathologic parameters as well as patients' survival. METHODS: Gastric tissue samples were obtained from 140 patients with GC and expression levels of TIMM9 were analyzed through immunohistochemistry. Paired t tests were used to analyze the differences in the expression levels of TIMM9 in both tumor and nontumor tissues for each patient. Two-tailed χ2 tests were performed to determine whether the differences in TIMM9 expression and clinicopathologic parameters were significant. Time-to-event endpoints for clinicopathologic parameters were plotted using the Kaplan-Meier method, and statistical significance was determined using univariate log-rank tests. Cox proportional hazard model was used for multivariate analysis to determine the independence of prognostic effects of TIMM9 expression. RESULTS: A borderline association was found between overexpression of TIMM9 and vascular invasion (p = 0.0887). Patients with high expression levels of TIMM9 achieved a significantly lower disease-free survival rate compared with those with low expression levels (p = 0.005). Multivariate Cox regression analysis showed that overexpression of TIMM9 was an independent prognostic marker for GC (p = 0.011). CONCLUSION: Overexpression of TIMM9 can be used as a marker to predict the outcome of patients with GC.

Frequent DNA methylation of MiR-129-2 and its potential clinical implication in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a highly malignant tumor with poor prognosis and high mortality due to a lack of effective medical treatment and apparent early stage symptoms. Understanding molecular mechanism of cancer development is crucial for HCC diagnosis, prognosis, and treatment. Recently, microRNAs have been shown to play an important role in carcinogenesis, being regulated by DNA methylation in several cases. In this study, a whole genome approach was used to identify methylation-regulated miRNAs in HCC, finally focusing on miR-129-2. MiR-129-2 methylation and reduced expression were observed in all examined HCC cell lines but not in normal liver cells and tissues. In 39 (93%) of 42 HCC, the methylation levels of miR-129-2 were significantly increased in tumor tissues compared with adjacent normal tissues. Furthermore, miR-129-2 methylation was detectable in plasma samples from HCC patients, but not in plasma samples from healthy individuals or patients with liver cirrhosis. At a cut-off value of -2.36 (log2 transformation of methylation level), it was possible to distinguish HCC from healthy and cirrhotic controls with sensitivity and specificity of 88% and 100%, respectively. This study indicates that miR-129-2 methylation is highly accurate in distinguishing HCC patients from cirrhosis patients and healthy individuals, implying its potential utility as an early diagnostic marker for HCC.

Emerging insights into the role of IL-1 inhibitors and colchicine for inflammation control in type 2 diabetes.

Type 2 diabetes mellitus (T2DM), a prevalent chronic metabolic disorder, is closely linked to persistent low-grade inflammation, significantly contributing to its development and progression. This review provides a comprehensive examination of the inflammatory mechanisms underlying T2DM, focusing on the role of the NLRP3 inflammasome and interleukin-1ß (IL-1ß) in mediating inflammatory responses. We discuss the therapeutic potential of IL-1 inhibitors and colchicine, highlighting their mechanisms in inhibiting the NLRP3 inflammasome and reducing IL-1ß production. Recent studies indicate that these agents could effectively mitigate inflammation, offering promising avenues for the prevention and management of T2DM. By exploring the intricate connections between metabolic disturbances and chronic inflammation, this review underscores the need for novel anti-inflammatory strategies to address T2DM and its complications.

Preoperative MRI-based endplate quality: a novel tool for predicting cage subsidence after anterior cervical spine surgery.

PURPOSE: The objective of this study was to examine the predictive value of a newly developed MRI-based Endplate Bone Quality (EBQ) in relation to the development of cage subsidence following anterior cervical discectomy and fusion (ACDF). METHODS: Patients undergoing ACDF for degenerative cervical diseases between January 2017 and June 2022 were included. Correlation between EBQ scores and segmental height loss was analyzed using Pearson's correlation. ROC analyses were employed to ascertain the EBQ cut-off values that predict the occurrence of cage subsidence. Multivariate logistic regression analyses were conducted to identify the risk factors associated with postoperative cage subsidence. RESULTS: 23 individuals (14.56%) exhibited the cage subsidence after ACDF. In the nonsubsidence group, the average EBQ and lowest T-score were determined to be 4.13 ± 1.14 and - 0.84 ± 1.38 g/cm2 respectively. In contrast, the subsidence group exhibited a mean EBQ and lowest T-score of 5.38 ± 0.47 (p < 0.001) and - 1.62 ± 1.34 g/cm2 (p = 0.014), respectively. There was a significant positive correlation (r = 0.798**) between EBQ and the segmental height loss. The EBQ threshold of 4.70 yielded optimal sensitivity (73.9%) and specificity (93.3%) with AUC of 0.806. Furthermore, the lowest T-score (p = 0.045, OR 0.667) and an elevated cervical EBQ score (p < 0.001, OR 8.385) were identified as significant risk factors for cage subsidence after ACDF. CONCLUSIONS: The EBQ method presents itself as a promising and efficient tool for surgeons to assess patients at risk of cage subsidence and osteoporosis prior to cervical spine surgery, utilizing readily accessible patient data.

Punicalagin Restricts Growth, Promotes Apoptosis, and Reduces Invasion in Human Gastric Cancer Cells.

This research investigated the anticancer properties of punicalagin, a prominent bioactive polyphenol extracted from Punica granatum L, in human gastric cancer cell lines. Normal and gastric cancer cells were exposed to different doses of punicalagin for various durations. Punicalagin exhibited cytotoxic effects on gastric cancer cells in a dose- and time-dependent fashion, while sparing normal gastric epithelial cells. It is noteworthy that among the 3 gastric cancer cells, HGC-27 cells were more resistant to punicalagin than 23,132/87 and AGS cells. Furthermore, punicalagin triggered apoptosis in gastric cancer cells, evidenced by a rise in both early and late apoptotic cell percentages. Western blot analysis further revealed that punicalagin elevated the levels of activated caspase-3. Conversely, punicalagin curtailed cell invasion and reduced the expression of MMP-2, MMP-9, Snail, and Slug. From a mechanistic standpoint, Western blotting indicated that punicalagin might inhibit the Erk and NF-κB pathways, leading to apoptosis induction and the inhibition of cell invasion in gastric cancer cells. These results indicate that punicalagin promotes apoptosis and inhibits cell invasion in gastric cancer cells by activating caspase-3 and suppressing MMP-2, MMP-9, Snail, and Slug through the inhibition of the Erk and NF-κB pathways.

Comparison of the effectiveness of zero-profile device and plate cage construct in the treatment of one-level cervical disc degenerative disease combined with moderate to severe paraspinal muscle degeneration.

Objective: Recent evidence indicates that cervical paraspinal muscle degeneration (PMD) is a prevalent and age-related condition in patients with cervical disc degenerative disease (CDDD). However, the relationship between surgery selection and post-operative outcomes in this population remains unclear. Consequently, this study aims to investigate the disparities in clinical outcomes, radiological findings, and complications between two frequently utilized anterior cervical surgical procedures. The objective is to offer guidance for the management of PMD in conjunction with CDDD. Methods: A total of 140 patients who underwent single-level anterior cervical discectomy and fusion (ACDF) at our department were included in this study. The patients were divided into three groups based on the severity of PMD: mild (n=40), moderate (n=54), and severe (n=46), as determined by Goutalier fat infiltration grade. The subjects of interest were those with moderate-severe PMD, and their clinical outcomes, radiological parameters, and complications were compared between those who received a stand-alone zero-profile anchored cage (PREVAIL) and those who received a plate-cage construct (PCC). Results: The JOA, NDI, and VAS scores exhibited significant improvement at all postoperative intervals when compared to baseline, and there were no discernible differences in clinical outcomes between the two groups. While the PCC group demonstrated more pronounced enhancements and maintenance of several sagittal alignment parameters, such as the C2-7 angle, FSU angle, C2-7 SVA, and T1 slope, there were no statistically significant differences between the two groups. The incidence of dysphagia in the zero-profile group was 22.41% at one week, which subsequently decreased to 13.79% at three months and 3.45% at the final follow-up. In contrast, the plate cage group exhibited a higher incidence of dysphagia, with rates of 47.62% at one week, 33.33% at three months, and 11.90% at the final follow-up. Notably, there were significant differences in the incidence of dysphagia between the two groups within the first three months. However, the fusion rate, occurrence of implant subsidence, and adjacent segment degeneration (ASD) were comparable at the final follow-up. Conclusion: For patients with one-level cervical disc degenerative disease combined with paraspinal muscle degeneration, both the zero-profile technique and PCC have demonstrated efficacy in ameliorating clinical symptoms and maintaining the postoperative sagittal balance. Although no significant disparities were observed between these two technologies in terms of complications such as adjacent segment degeneration and implant subsidence, the zero-profile technique exhibited superior performance over PCC in relation to dysphagia during the early stages of postoperative recovery. To validate these findings, studies with longer follow-up periods and evaluations of multilevel cervical muscles are warranted.

BHLHE22 drives the immunosuppressive bone tumor microenvironment and associated bone metastasis in prostate cancer.

BACKGROUND: The molecular characteristics of prostate cancer (PCa) cells and the immunosuppressive bone tumor microenvironment (TME) contribute to the limitations of immune checkpoint therapy (ICT). Identifying subgroups of patients with PCa for ICT remains a challenge. Herein, we report that basic helix-loop-helix family member e22 (BHLHE22) is upregulated in bone metastatic PCa and drives an immunosuppressive bone TME. METHODS: In this study, the function of BHLHE22 in PCa bone metastases was clarified. We performed immunohistochemical (IHC) staining of primary and bone metastatic PCa samples, and assessed the ability to promote bone metastasis in vivo and in vitro. Then, the role of BHLHE22 in bone TME was determined by immunofluorescence (IF), flow cytometry, and bioinformatic analyses. RNA sequencing, cytokine array, western blotting, IF, IHC, and flow cytometry were used to identify the key mediators. Subsequently, the role of BHLHE22 in gene regulation was confirmed using luciferase reporter, chromatin immunoprecipitation assay, DNA pulldown, co-immunoprecipitation, and animal experiments. Xenograft bone metastasis mouse models were used to assess whether the strategy of immunosuppressive neutrophils and monocytes neutralization by targeting protein arginine methyltransferase 5 (PRMT5)/colony stimulating factor 2 (CSF2) could improve the efficacy of ICT. Animals were randomly assigned to treatment or control groups. Moreover, we performed IHC and correlation analyses to identify whether BHLHE22 could act as a potential biomarker for ICT combination therapies in bone metastatic PCa. RESULTS: Tumorous BHLHE22 mediates the high expression of CSF2, resulting in the infiltration of immunosuppressive neutrophils and monocytes and a prolonged immunocompromised T-cell status. Mechanistically, BHLHE22 binds to the CSF2 promoter and recruits PRMT5, forming a transcriptional complex. PRMT5 epigenetically activates CSF2 expression. In a tumor-bearing mouse model, ICT resistance of Bhlhe22+ tumors could be overcome by inhibition of Csf2 and Prmt5. CONCLUSIONS: These results reveal the immunosuppressive mechanism of tumorous BHLHE22 and provide a potential ICT combination therapy for patients with BHLHE22+ PCa.

Punicalagin is cytotoxic to human colon cancer cells by modulating cell proliferation, apoptosis, and invasion.

Purpose: The purpose of this study was to explore the anticancer effect of punicalagin, an abundant bioactive tannin compound isolated from Punica granatum L., on three colon cancer cell lines, namely, HCT 116, HT-29, and LoVo.Research Design: Normal and colon cancer cells were treated with different concentrations of punicalagin for different periods. Data Collection and Analysis: Cell viability was measured with a CCK-8 assay. Programmed cell death and invasion were analyzed using an annexin V and cell death kit and a cell invasion analysis kit. The expression of active caspase-3, MMP-2, MMP-9, Snail, and Slug were measured by Western blot.Results: The results of the cell viability analysis showed that punicalagin was cytotoxic to colon cancer cells, but it was not to normal cells in a dose- and time-dependent manner. Additionally, punicalagin induced apoptosis in colon cancer cells (shown by the cumulative percentage of colorectal cancer cells in early and late apoptosis). It was found that caspase-3 activity increased following punicalagin treatment. Western blot results also showed that punicalagin increased the expression of activated caspase-3. In contrast, punicalagin inhibited the invasion of colon cancer cells. Further, treatment of colon cancer cells with punicalagin suppressed the expression of MMP-2, MMP-9, Snail, and Slug. Conclusions: These results showed that the activation of caspase-3 and the inhibition of MMP-2, MMP-9, Snail and Slug were involved in the effects of punicalagin on colon cancer cells.