The Efficacy of Traumatic Brain Injury Treatment by Neurotrauma Specialists.

Objective: Since the establishment of Regional Trauma Centers (RTCs) in Korea, significant efforts have been made to improve the quality of care for patients with trauma. Simultaneously, the Department of Neurosurgery assigned neurotrauma specialists to RTCs to provide specialized care to patients with traumatic brain injury (TBI). In this study, we sought to determine whether neurotrauma specialists, compared to general neurosurgeons, could make a significant difference in treatment outcomes of patients with TBI. Methods: In total, 156 patients with acute TBI who required decompression were included. We reviewed their records and compared the characteristics, outcomes, and prognosis of those who received surgical treatment from either neurotrauma specialists or general neurosurgeons at our institution. Results: A significant difference was observed between treatment by trauma neurosurgery specialists and general neurosurgeons in time to surgery, with trauma specialists experiencing shorter surgical delays. However, no significant differences existed in mortality rates or Extended Glasgow Outcome Scale scores. Univariate and multivariable regression analyses revealed that lower Glasgow Coma Scale scores, an abnormal pupil reflex, larger transfusion volume, and prolonged time from emergency room admission to surgery were associated with high mortality rates. Conclusion: Neurotrauma specialists can provide prompt surgical treatment to patients with TBI compared to general neurosurgeons. Our study did not reveal a significant difference in outcomes between the two groups. However, it is clear that rapid decompression is effective in patients with impending brain herniation. Therefore, the effectiveness of neurotrauma specialists needs to be confirmed through further systematic studies.

Incidence and risk factors of hypoparathyroidism and hypocalcemia after hemithyroidectomy.

PURPOSE: The incidence and risk factors for hypoparathyroidism after total thyroidectomy is well-known. However, the characteristics of hypoparathyroidism and hypocalcemia after hemithyroidectomy have not been investigated well. In this study, we aimed to evaluate the incidence, characteristics, and risk factors of hypoparathyroidism and hypocalcemia after hemithyroidectomy. METHOD: We retrospectively analyzed the medical data of 321 patients who underwent hemithyroidectomy, with or without central neck dissection, from January 2012 to April 2019. We analyzed the serum intact parathyroid hormone (iPTH), calcium, and ionized calcium (iCa) levels serially (preoperatively and postoperatively on the operation day; days 1 and 3; and months 1, 3, 6, and 12) and evaluated risk factors for postoperative hypoparathyroidism and hypocalcemia. RESULTS: The mean iPTH and calcium levels decreased significantly after hemithyroidectomy on the operation day and postoperative days 1 and 3, and returned to the preoperative level at the postoperative 1-month follow-up. The mean iCa level decreased significantly on the operation day and postoperative day 1. Transient hypoparathyroidism and transient hypocalcemia occurred in 16 (5%) and 250 (78%) participants, and they recovered to normal levels postoperatively by 1 month. Eight (2.5%) patients had mild symptoms of hypocalcemia necessitating oral calcium supplementation. No permanent hypoparathyroidism or hypocalcemia was observed. Preoperatively low serum iPTH and calcium levels were associated with transient hypoparathyroidism and hypocalcemia after hemithyroidectomy. CONCLUSION: Approximately 5% and 2.5% of participants showed transient hypoparathyroidism and mild symptomatic hypocalcemia after hemithyroidectomy. The risk factors for transient hypoparathyroidism and hypocalcemia include preoperative low serum iPTH and calcium levels.

Higher Non-High-Density Lipoprotein Cholesterol Was Higher Associated With Cardiovascular Disease Comparing Higher LDL-C in Nine Years Follow Up: Cohort Study.

Objective: Non-high-density lipoprotein cholesterol (non-HDL-C) may be equivalent to or superior to low-density lipoprotein cholesterol (LDL-C) for the prediction of cardiovascular disease (CVD). However, studies comparing the predictive values of LDL-C and non-HDL-C levels for CVD have yielded conflicting results. In this study, we evaluated the relationship between non-HDL-C, LDL-C, and CVD using a large-scale population dataset from the National Health Information Database (NHID). Methods: We performed a retrospective observational cohort study of 3,866,366 individuals ≥ 20 years, from 2009 to 2018, using the NHID. The participants were divided into LDL-C and non-HDL-C quartiles. The outcome variables included stroke, myocardial infarction (MI), and both. All outcomes were analyzed using Cox proportional hazards regression analysis while controlling for baseline covariates (age, sex, smoking, drinking, regular exercise, body mass index, diabetes, hypertension, and statin use). Results: During 9.1 years of mean follow-up, stroke was diagnosed in 60,081 (1.55%), MI in 31,234 (0.81%), and both stroke and MI in 88,513 (2.29%) participants. Multivariate-adjusted hazard ratios (HRs) for patients in the highest non-HDL-C quartile demonstrated that these patients had a higher risk of stroke (HR, 1.254; 95% confidence interval [CI], 1.224-1.285), MI (HR, 1.918; 95% CI, 1.853-1.986), and both (HR, 1.456; 95% CI, 1.427-1.486) compared with participants in the lowest quartile. These were higher than the HRs for patients in the highest LDL-C quartile for stroke (HR, 1.134; 95% CI, 1.108-1.160), MI (HR, 1.601; 95% CI, 1.551-1.653), and both (HR, 1.281; 95% CI, 1.257-1.306). Conclusion: In our large population study, higher non-HDL-C levels were associated with CVD than LDL-C levels.

TOPK inhibits TNF-α-induced granulosa cell apoptosis via regulation of SIRT1/p53.

T-LAK cell originated protein kinase (TOPK) has been shown to regulate proliferation, invasion or migration of various cancer cells. However, the role of TOPK in follicle environments remains unknown. Here we reveal that TOPK inhibits TNF-α-induced human granulosa COV434 cell apoptosis. The expression of TOPK were increased in COV434 cells in response to TNF-α. TOPK inhibition also decreased TNF-α-induced SIRT1 expression but promoted TNF-α-induced p53 acetylation and expression of PUMA or NOXA. Accordingly, TOPK inhibition attenuated TNF-α-mediated SIRT1 transcriptional activity. In addition, SIRT1 inhibition augmented acetylation of p53 or expression of PUMA and NOXA in response to TNF-α, leading to COV434 cell apoptosis. We conclude that TOPK suppresses TNF-α-induced COV434 granulosa cell apoptosis via regulation of p53/SIRT1 axis, suggesting a potential role of TOPK in regulation of ovarian follicular development.

Evaluation and Treatment of Obesity and Its Comorbidities: 2022 Update of Clinical Practice Guidelines for Obesity by the Korean Society for the Study of Obesity.

The goal of the 8th edition of the Clinical Practice Guidelines for Obesity is to help primary care physician provide safe, effective care to patients with obesity by offering evidence-based recommendations to improve the quality of treatment. The Committee for Clinical Practice Guidelines comprised individuals with multidisciplinary expertise in obesity management. A steering board of seven experts oversaw the entire project. Recommendations were developed as the answers to key questions formulated in patient/problem, intervention, comparison, outcomes (PICO) format. Guidelines underwent multi-level review and cross-checking and received endorsement from relevant scientific societies. This edition of the guidelines includes criteria for diagnosing obesity, abdominal obesity, and metabolic syndrome; evaluation of obesity and its complications; weight loss goals; and treatment options such as diet, exercise, behavioral therapy, pharmacotherapy, and bariatric and metabolic surgery for Korean people with obesity. Compared to the previous edition of the guidelines, the current edition includes five new topics to keep up with the constantly evolving field of obesity: diagnosis of obesity, obesity in women, obesity in patients with mental illness, weight maintenance after weight loss, and the use of information and communication technology-based interventions for obesity treatment. This edition of the guidelines features has improved organization, more clearly linking key questions in PICO format to recommendations and key references. We are confident that these new Clinical Practice Guidelines for Obesity will be a valuable resource for all healthcare professionals as they describe the most current and evidence-based treatment options for obesity in a well-organized format.

Five-Year Oncologic Outcome and Surgical Completeness of Transoral Robotic Thyroidectomy for Papillary Thyroid Carcinoma: Comparison with Conventional Transcervical Thyroidectomy Using Propensity Score Matching.

OBJECTIVE: This study aimed to evaluate the oncological outcomes and surgical completeness of transoral robotic thyroidectomy (TORT) for papillary thyroid carcinoma (PTC) compared with conventional transcervical thyroidectomy. METHODS: We analyzed 489 patients with PTC who underwent thyroidectomy with or without central neck dissection (CND; 311 conventional thyroidectomy and 178 TORT) between January 2017 and December 2021. Patients with gross invasion of the surrounding structures, revision or completion thyroidectomy, and lateral neck dissection were excluded. Propensity score-matched analysis was performed using eight covariates, including age, sex, extent of thyroidectomy, tumor size, extrathyroidal extension (ETE), radioactive iodine (RAI) ablation, lymphovascular invasion (LVI), and CND. RESULTS: Before propensity score matching (PSM), age, male-to-female ratio, and body mass index were lower in the TORT group. The ratio of total thyroidectomy and CND, tumor size and bilaterality, LVI, and RAI ablation were higher in the conventional group. PSM generated two matched groups of 100 patients each. After PSM, significant differences between the two groups in the baseline analysis disappeared. In the matched samples, the recurrence rate (2% and 0% in the conventional and TORT groups, respectively) and recurrence-free survival curves did not differ between the two groups. The mean thyroid-stimulating hormone (TSH)-stimulated thyroglobulin level in the RAI group and TSH-suppressed thyroglobulin level in the non-RAI group were not different between the two groups. CONCLUSIONS: The 5-year oncologic outcomes and surgical completeness of TORT were comparable with those of conventional thyroidectomy in patients with small, localized, low-risk PTC when performed by experienced surgeons.

Protective effect of GK2 fused BLVRA protein against oxidative stress-induced dopaminergic neuronal cell damage.

It is well known that oxidative stress is highly associated with Parkinson's disease (PD), and biliverdin reductase A (BLVRA) is known to have antioxidant properties against oxidative stress. In this study, we developed a novel N-acetylgalactosamine kinase (GK2) protein transduction domain (PTD) derived from adenosine A2A and fused with BLVRA to determine whether the GK2-BLVRA fusion protein could protect dopaminergic neuronal cells (SH-SY5Y) from oxidative stress in vitro and in vivo using a PD animal model. GK2-BLVRA was transduced into various cells, including SH-SY5Y cells, without cytotoxic effects, and this fusion protein protected SH-SY5Y cells and reduced reactive oxygen species production and DNA damage after 1-methyl-4-phenylpyridinium (MPP+ ) exposure. GK2-BLVRA suppressed mitogen-activated protein kinase (MAPK) activation and modulated apoptosis-related protein (Bcl-2, Bax, cleaved Caspase-3 and -9) expression levels. In the PD animal model, GK2-BLVRA transduced into the substantia nigra crossed the blood-brain barrier and markedly reduced dopaminergic neuronal cell death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced animals. These results indicate that our novel PTD GK-2 is useful for the transduction of protein, and GK2-BLVRA exhibits a beneficial effect against dopaminergic neuronal cell death in vitro and in vivo, suggesting that BLVRA can be used as a therapeutic agent for PD.

Feasibility of transoral robotic selective neck dissection with or without a postauricular incision for papillary thyroid carcinoma: A pilot study.

Background: The study aimed to evaluate the feasibility of transoral robotic selective neck dissection (SND) with or without a postauricular incision for papillary thyroid carcinoma (PTC). Methods: We studied 14 patients with PTC who underwent robotic SND via the transoral or combined transoral and postauricular approaches. Results: The transoral approach was performed on 10 patients for dissection of levels III and IV. An additional postauricular incision was made on 4 patients for dissection of level II in addition to levels III, IV, and V. The operation was completed successfully in 13 patients, except 1 patient with the procedure conversion due to uncontrolled bleeding from the internal jugular vein. The mean numbers of removed lymph nodes in the lateral compartment were 23.1 ± 9.4 and 38.3 ± 8.5 in the transoral and combined groups. Transient recurrent laryngeal nerve palsy occurred in 1 patient, transient hypoparathyroidism in 3 patients, and chyle leakage in 1 patient. There were no hematomas, mental nerve injuries, surgical space infections, or CO2 embolisms. Conclusion: Transoral robotic SND is feasible with or without a postauricular incision.

Single-cell transcriptomics reveal cellular diversity of aortic valve and the immunomodulation by PPARγ during hyperlipidemia.

Valvular inflammation triggered by hyperlipidemia has been considered as an important initial process of aortic valve disease; however, cellular and molecular evidence remains unclear. Here, we assess the relationship between plasma lipids and valvular inflammation, and identify association of low-density lipoprotein with increased valvular lipid and macrophage accumulation. Single-cell RNA sequencing analysis reveals the cellular heterogeneity of leukocytes, valvular interstitial cells, and valvular endothelial cells, and their phenotypic changes during hyperlipidemia leading to recruitment of monocyte-derived MHC-IIhi macrophages. Interestingly, we find activated PPARγ pathway in Cd36+ valvular endothelial cells increased in hyperlipidemic mice, and the conservation of PPARγ activation in non-calcified human aortic valves. While the PPARγ inhibition promotes inflammation, PPARγ activation using pioglitazone reduces valvular inflammation in hyperlipidemic mice. These results show that low-density lipoprotein is the main lipoprotein accumulated in the aortic valve during hyperlipidemia, leading to early-stage aortic valve disease, and PPARγ activation protects the aortic valve against inflammation.

Silica-Capped and Gold-Decorated Silica Nanoparticles for Enhancing Effect of Gold Nanoparticle-Based Photothermal Therapy.

BACKGROUND: Various methods based on gold nanoparticles (AuNPs) have been applied to enhance the photothermal effect. Among these methods, combining gold nanoparticles and stem cells has been suggested as a new technique for elevating the efficiency of photothermal therapy (PT) in terms of enhancing tumor targeting effect. However, to elicit the efficiency of PT using gold nanoparticles and stem cells, delivering large amounts of AuNPs into stem cells without loss should be considered. METHODS: AuNPs, AuNPs-decorated silica nanoparticles, and silica-capped and AuNPs-decorated silica nanoparticles (SGSs) were synthesized and used to treat human mesenchymal stem cells (hMSCs). After evaluating physical properties of each nanoparticle, the concentration of each nanoparticle was estimated based on its cytotoxicity to hMSCs. The amount of AuNPs loss from each nanoparticle by exogenous physical stress was evaluated after exposing particles to a gentle shaking. After these experiments, in vitro and in vivo photothermal effects were then evaluated. RESULTS: SGS showed no cytotoxicity when it was used to treat hMSCs at concentration up to 20 µg/mL. After intravenous injection to tumor-bearing mice, SGS-laden hMSCs group showed significantly higher heat generation than other groups following laser irradiation. Furthermore, in vivo photothermal effect in the hMSC-SGS group was significantly enhanced than those in other groups in terms of tumor volume decrement and histological outcome. CONCLUSION: Our results suggest that additional silica layer in SGSs could protect AuNPs from physical stress induced AuNPs loss. The strategy applied in SGS may offer a prospective method to improve PT.

Discovery of dipeptidyl peptidase-4 inhibitor specific biomarker in non-alcoholic fatty liver disease mouse models using modified basket trial.

BACKGROUND/AIMS: We aimed to define an optimal target population and drug-specific biomarkers that may predict dipeptidyl peptidase (DPP)-4 inhibitor responses in non-alcoholic fatty liver disease (NAFLD). METHODS: An exploration study (study I) was performed using three different NAFLD models (basket study design; high-fat diet [HFD], methionine choline-deficient diet [MCD], and high-cholesterol Western diet [WD] models). RNA transcriptome analysis was performed on pre-studied liver tissues to identify biomarkers that could predict the response to DPP-4 inhibitors. In the validation study (study II), the HFD-induced NAFLD model was divided into high and low hepatic insulin-like growth factor binding protein 1 (Igfbp-1) groups based on the pre-study liver biopsy. RESULTS: DPP-4 inhibitor attenuated the NAFLD activity score and fibrosis stage in the HFD model but not in the WD and MCD models. The overall response rate was 19% across the modified basket NAFLD trial and 42%, 25%, and 0% in the HFD, WD, and MCD models. Hepatic Igfbp-1 expression was higher in the responder group than in the non-responder group in pre-study biopsy samples. In contrast, hepatic Igfbp-1 expression was lower in the responder group than in the non-responder group in the end-study biopsy samples. DPP-4 inhibitor response rates were 83% and 17% in the baseline hepatic high Igfbp-1 and low Igfbp-1 groups, respectively. Hepatic messenger RNA Igfbp-1 expression was positively correlated with serum IGFBP-1 levels. CONCLUSION: The DPP-4 inhibitor response was higher in the HFD phenotype and pre-treatment levels of hepatic or serum IGFBP-1 were high.

Metal Ion Releasing Gold Nanoparticles for Improving Therapeutic Efficiency of Tumor Targeted Photothermal Therapy.

BACKGROUND: Owing to the tumor-targeted migration capacity of human mesenchymal stem cells (hMSCs), they have been combined with nanoparticles for photothermal therapy. However, the low viability of hMSCs following transplantation remains a problem. Here, we developed iron (Fe) ion-releasing gold (Au) nanoparticles (IIAuNPs) for advanced tumor-targeted photothermal therapy using hMSCs. METHODS: IIAuNPs were designed to undergo degradation under low pH conditions, such as the endosomal microenvironment, for Fe ion release in hMSCs. After evaluating the properties of IIAuNP, the IIAuNP concentration for treating hMSCs was optimized in terms of cytotoxicity. In vitro cell migration and antiapoptotic factor secretion were observed in hMSCs. Additionally, IIAuNPs-treated hMSCs were intravenously injected into tumor-bearing mice, and enhanced tumor targeting based on improved cell viability and cell migration was evaluated. Three days after the injection, the mice were irradiated with 660 nm laser to confirm the enhanced photothermal effect. RESULTS: In vitro studies revealed that treating hMSCs with an optimum concentration of IIAuNPs enhanced cell migration and anti-apoptotic gene expression through intracellular Fe ion delivery. The viability of hMSCs under hypoxic cell culture conditions that mimic the in vivo microenvironment was also improved when hMSCs were treated with IIAuNPs, compared to hMSCs without IIAuNPs treatment. IIAuNPs-treated hMSCs showed significantly enhanced tumor-targeting efficiency and subsequent photothermal effect compared to hMSCs without IIAuNP treatment. CONCLUSION: Our results suggest that our metal-ion-releasing photothermal nanoparticles may provide a promising platform for future photothermal therapies and related applications.

Early Interferon-Gamma Response in Nonhuman Primate Recipients of Solid-Organ Xenotransplantation.

BACKGROUND: To understand changes in biological responses in nonhuman primate (NHP) recipients of xenotransplantation (XTP), we retrospectively investigated chronological changes in cytokine profiles of NHP recipients after solid-organ XTP. METHODS: Plasma samples were collected from 7 NHP recipients of pig heart or kidney XTP with α-1,3-galactosyltransferase gene knockout (GTKO) under anti-CD154-based immune suppression at the following time points: immediately before; 2 hours, 3 days, and 7 days after XTP; and weekly thereafter until the graft failed. The plasma levels of the following cytokines were measured: interleukin (IL)-1α, IL-1ß, IL-6, IL-12p70, IL-8, IL-10, IL-15, tumor necrosis factor, interferon gamma (IFN-γ), D-dimer, C3a, and histone-complexed DNA fragments. For in vitro experiments, human natural killer (NK) cells were cocultured with wild-type porcine endothelial cells (PECs), GTKO-PECs, and human umbilical vein endothelial cells, with or without anti-CD154 antibody. IFN-γ levels in the culture supernatants were compared. RESULTS: IFN-γ levels peaked on day 7 or 10 of XTP and then decreased to basal levels, whereas proinflammatory cytokine levels increased along with the elevation of histone-complexed DNA fragments and were sustained until xenograft failure. In vitro, human NK cells produced more IFN-γ when in contact with wild-type PECs than with human umbilical vein endothelial cells, which was not reduced by the use of GTKO-PECs or addition of anti-CD154 antibody to the mixture. CONCLUSIONS: In NHP recipients of XTP, the early peak of IFN-γ priming subsequent inflammatory responses may be attributed to NK cell activation in response to xenografts.

Clinical Characteristics of Patients with Adrenal Insufficiency and Fever.

BACKGROUND: Because persistent fever often occurs in adrenal insufficiency, it might be confused with infectious diseases. This study aimed to identify clinical characteristics and risk factors of patients with adrenal insufficiency and fever. METHODS: All adult patients (n = 150) admitted to a tertiary care hospital in South Korea and diagnosed with adrenal insufficiency between 1 March 2018, and 30 June 2019, were recruited. Patients were excluded if they had: 1) proven structural problems in the adrenal or pituitary gland; 2) a history of chemotherapy within 6 months prior to the diagnosis of adrenal insufficiency; and 3) other medical conditions that may cause fever. RESULTS: Among the included patients, 45 (30.0%) had fever at the time of the diagnosis of adrenal insufficiency. The mean C-reactive protein level was higher (11.25 ± 8.54 vs. 4.36 ± 7.13 mg/dL) in patients with fever than in those without fever. A higher proportion of patients with fever changed antibiotics (33.3% vs. 1.0%). On multivariate logistic regression analysis, female sex (odds ratio [OR], 0.32) lowered the risk of adrenal insufficiency with fever, while a history of surgery within 6 months (OR, 4.35), general weakness (OR, 7.21), and cough (OR, 17.29) were significantly associated with that. CONCLUSION: The possibility of adrenal insufficiency should be considered in patients with fever of unknown origin, especially those with risk factors.

Risk factors for hypothyroidism and thyroid hormone replacement after hemithyroidectomy in papillary thyroid carcinoma.

PURPOSE: Thyroid lobectomy is now preferred over total thyroidectomy to preserve thyroid function and reduce complications in patients with low-risk papillary thyroid carcinoma (PTC). One inevitable consequence of thyroidectomy includes hypothyroidism. This study aimed to evaluate the risk factors for hypothyroidism and thyroid hormone replacement after hemithyroidectomy in patients with PTC. METHODS: We retrospectively studied 353 patients with PTC who underwent hemithyroidectomy with or without central neck dissection from January 2012 to January 2019. We excluded patients who had hypo- or hyperthyroidism preoperatively and those who underwent total or subtotal thyroidectomy. We analyzed various risk factors related to postoperative hypothyroidism and thyroid hormone supplementation. RESULTS: Of the patients, 54.7% showed hypothyroidism after hemithyroidectomy (n=193 with n=157, subclinical hypothyroidism; n=36, overt hypothyroidism). Ninety-one percent of postoperative hypothyroidism cases developed within 7 months postoperatively. Eventually, 43.1% (n=152) of patients received levothyroxine after hemithyroidectomy. Preoperative high thyroid-stimulating hormone (TSH) level and low free thyroxine (fT4) level were significantly associated with postoperative hypothyroidism and the need for thyroid hormone supplementation postoperatively. CONCLUSION: Preoperative TSH and fT4 levels are predictive risk factors of hypothyroidism and need for supplementation of levothyroxine after hemithyroidectomy in patients with PTC. Finally, approximately 43% of patients need levothyroxine supplementation after hemithyroidectomy, and individual preoperative counseling is necessary for these patients.

Factors affecting drug survival of an alternative TNF inhibitor and secukinumab in patients with ankylosing spondylitis switching from the first TNF inhibitor.

BACKGROUND: To investigate factors associated with drug survival of an alternative tumour necrosis factor inhibitor (TNFi) and secukinumab (SEC) after switching from the first TNFi in patients with ankylosing spondylitis (AS). METHODS: We included a total of 78 patients with AS who switched to an alternative TNFi (n = 56) or SEC (n = 22) from the first TNFi. Patient characteristics at the time of switching and drug discontinuation rate were compared between the two groups. Cox regression analyses were performed to evaluate factors associated with the risk of discontinuing the alternative TNFi and SEC. RESULTS: The proportion of patients with syndesmophytes was numerically lower (28.6% versus 45.5%, p = 0.155) and the C-reactive protein (CRP) level was numerically higher [3.8 (1.0-15.4) mg/L versus 1.1 (0.5-3.5) mg/L, p = 0.060] in patients who received an alternative TNFi. The drug discontinuation rate (alternative TNFi: 35.7% versus SEC: 36.4%, p = 0.957) and reasons for discontinuation were similar (primary failure, p = 0.342; secondary failure, p > 0.999; and adverse events, p = 0.670) between the two groups. A higher CRP level at switching was associated with a lower risk (adjusted HR = 0.93, 95% CI = 0.87-0.99, p = 0.022) of discontinuing the alternative TNFi, and primary failure of the first TNFi was associated with a higher risk [adjusted HR (HR) = 5.20, 95% confidence interval (CI) = 1.91-14.11, p = 0.001]. Current smokers (adjusted HR = 5.77, 95% CI = 1.20-27.74, p = 0.029) and the presence of syndesmophytes (adjusted HR = 7.49, 95% CI = 1.39-40.23, p = 0.019) were associated with a higher risk of discontinuing SEC. CONCLUSION: When switching the drug from the first TNFi in patients with AS, an alternative TNFi could be preferable in patients with higher CRP levels or syndesmophytes, or current smokers, whereas SEC could be a better choice in patients who presented primary failure of the first TNFi in terms of drug survival.

Tumour necrosis factor inhibitor tapering in patients with ankylosing spondylitis at low disease activity: factors associated with flare.

BACKGROUND: To investigate factors associated with flare in patients with ankylosing spondylitis (AS) who tapered tumour necrosis factor inhibitors (TNFis) after achievement of low disease activity (LDA) with the standard dose of TNFis. METHODS: This retrospective cohort study included 101 patients with AS who tapered their first TNFis after achievement of LDA. The proportion of reduced versus standard doses of TNFi throughout the follow up in each patient was quantified using the time-averaged dose quotient (DQ). Clinical characteristics were compared between patients who did and did not experience flare after TNFi tapering. Multivariable Cox regression analysis was performed to identify factors associated with flare. Receiver operating characteristic curve analysis was performed to determine the cut-offs of these covariates that best predicted flare. RESULTS: Of the total 101 patients, 45 (44.6%) patients experienced flare after TNFi tapering. Compared with patients who did not experience flare, those who experienced flare had a shorter disease duration (p = 0.006), shorter LDA duration before TNFi tapering (p < 0.001) and lower time-averaged DQ (p < 0.001). In multivariable Cox regression analysis, the LDA duration [adjusted hazard ratio (HR): 0.944, 95% confidence interval (CI): 0.906-0.983, p = 0.006] and time-averaged DQ (adjusted HR: 0.978, 95% CI: 0.959-0.998, p = 0.032) were inversely associated with flare. The cut-off values of the LDA duration and time-averaged DQ that best predicted flares were <5.3 months and <60.6%, respectively. CONCLUSION: Shorter LDA duration (cut-off value: 5.3 months) and lower time-averaged DQ (cut-off value: 60.6%) were associated with a higher risk of flare after tapering TNFi.

Role of the SIRT1/p53 regulatory axis in oxidative stress­mediated granulosa cell apoptosis.

Oxidative stress has been suggested to induce granulosa cell apoptosis, which contributes to follicular atresia. However, the mechanism via which oxidative stress mediates granulosa cell apoptosis remains elusive. Therefore, the aim of this study was to elucidate the molecular mechanisms regulating oxidative stress­induced granulosa cell apoptosis. The present study demonstrated that reactive oxygen species induced by H2O2 resulted in human granulosa COV434 cell apoptosis via the regulation of sirtuin 1 (SIRT1)­mediated p53 activity. Endogenous SIRT1 expression was alleviated by H2O2 treatment of COV434 cells in a time­dependent manner. In addition, knockdown or inhibition of SIRT1 promoted H2O2­induced poly(ADP­ribose) polymerase (PARP) cleavage and p53 acetylation, which led to an increase in COV434 cell apoptosis. Treatment with H2O2 enhanced the expression levels of the p53­dependent proteins, p53­upregulated modulator of apoptosis (PUMA) and phorbol­12­myristate­13­acetate­induced protein 1 (PMAIP1), as well as those of p53; however, knockdown of p53 decreased cleaved PARP, PUMA and PMAIP1 expression levels induced by H2O2 treatment. Moreover, knockdown of PUMA or PMAIP1 attenuated the H2O2 induction of PARP cleavage and COV434 cell apoptosis. In conclusion, the present findings suggested that H2O2­induced oxidative stress causes granulosa COV434 cell apoptosis via the upregulation of p53 activity by SIRT1 suppression, indicating a mechanistic role of the SIRT1/p53 axis in H2O2­induced granulosa cell apoptosis.

TOPK mediates hypoxia-induced epithelial-mesenchymal transition and the invasion of nonsmall-cell lung cancer cells via the HIF-1α/snail axis.

Hypoxia has been suggested to induce epithelial-mesenchymal transition (EMT) in various cancer types via the transcription factor hypoxia-inducible factor-1 alpha (HIF-1α). Here, we demonstrated that TOPK upregulates EMT and the invasion of H460 nonsmall-cell lung cancer cells through the induction of the HIF-1α/Snail axis and hypoxic signaling. The expression of endogenous TOPK, phosphorylated TOPK, HIF-1α and Snail was significantly increased upon hypoxia exposure, but TOPK depletion markedly abrogated the induced mRNA and protein levels of HIF-1α and Snail. Interestingly, TOPK knockdown restored the hypoxia-induced suppression of E-cadherin and diminished hypoxia-induced N-cadherin expression. In addition, Snail depletion suppressed hypoxia-induced N-cadherin expression, which was attenuated by TOPK knockdown. Moreover, knockdown of Snail decreased hypoxia-induced nonsmall-cell lung cancer cell migration and invasion, which were suppressed by TOPK depletion. In summary, we conclude that TOPK positively regulates HIF-1α expression through hypoxia signaling and thereby promotes Snail expression, leading to EMT and the invasion of nonsmall-cell lung cancer cells. These findings suggest that TOPK plays a critical role as a novel mediator of hypoxia signaling that regulates nonsmall-cell lung cancer development.