Purpose: DA-8010 is a novel muscarinic M3 receptor antagonist with significant selectivity for bladder over salivary gland in preclinical studies. We evaluated the clinical efficacy and safety of DA-8010 in overactive bladder (OAB) patients. Methods: This phase 2, randomized, double-blind, parallel-group, active reference- and placebo-controlled trial was conducted at 12 centers in South Korea (NCT03566134). Patients aged ≥19 years with OAB symptoms for ≥3 months were enrolled. Three hundred six patients (30.07% male) were randomized to 12 weeks of treatment among 4 groups; 2 experimental groups (DA-8010 2.5 or 5 mg), an active reference group (solifenacin 5 mg), and a placebo group. The change from the baseline of (=∆) 24-hour frequency at 12 weeks (primary endpoint), episodes of urgency, overall/urgency urinary incontinence, average/ maximum voided volume, nocturia, and patients’ subjective responses were analyzed. Results: In the full analysis set, the mean (standard deviation) [median] values for ∆ 24-hour frequency at 12 weeks were -1.01 (2.44) [-1.33] for placebo, -1.22 (2.05) [-1.33] for DA-8010 2.5 mg, and -1.67 (2.25) [-1.67] for DA-8010 5 mg; DA-8010 5 mg showed a significant decrease compared with placebo (P=0.0413). At 4 and 8 weeks, both DA-8010 2.5 mg (P=0.0391 at 4 weeks, P=0.0335 at 8 weeks) and DA-8010 5 mg (P=0.0001 at 4 weeks, P=0.0210 at 8 weeks) showed significant decrease in ∆ 24-hour frequency compared with placebo. DA-8010 5 mg achieved a significant decrease in ∆ number of urgency episodes, compared with placebo at 4 (P=0.0278) and 8 (P=0.0092) weeks. Adverse drug reactions (ADRs) were observed in 3.95% of placebo, 6.67% of DA-8010 2.5 mg, 18.42% of DA-8010 5 mg, and 17.33% of solifenacin 5 mg groups. No serious ADRs were observed in any patient. Conclusions Both DA-8010 2.5 mg and 5 mg showed therapeutic efficacy for OAB without serious ADRs. Therefore, both dosages of DA-8010 can advance to a subsequent large-scale phase 3 trial.

The therapeutic effects of mesenchymal stem cells (MSCs) in musculoskeletal diseases (MSDs) have been verified in many human and animal studies. Although some tissues contain MSCs, the number of cells harvested from those tissues and rate of proliferation in vitro are not enough for continuous transplantation. In order to produce and maintain stable MSCs, many attempts are made to induce differentiation from pluripotent stem cells (iPSCs) into MSCs. In particular, it is also known that the paracrine action of stem cell-secreted factors could promote the regeneration and differentiation of target cells in damaged tissue. MicroRNAs (miRNAs), one of the secreted factors, are small non-coding RNAs that regulate the translation of a gene. It is known that miRNAs help communication between stem cells and their surrounding niches through exosomes to regulate the proliferation and differentiation of stem cells. While studies have so far been underway targeting therapeutic miRNAs of MSDs, studies on specific miRNAs secreted from MSCs are still minimal. Hence, our ultimate goal is to obtain sufficient amounts of exosomes from iPSC-MSCs and develop them into therapeutic agents, furthermore to select specific miRNAs and provide safe cell-free clinical setting as a cell-free status with purpose of delivering them to target cells. This review article focuses on stem cell therapy on MSDs, specific microRNAs regulating MSDs and updates on novel approaches.

The therapeutic effects of mesenchymal stem cells (MSCs) in musculoskeletal diseases (MSDs) have been verified in many human and animal studies. Although some tissues contain MSCs, the number of cells harvested from those tissues and rate of proliferation in vitro are not enough for continuous transplantation. In order to produce and maintain stable MSCs, many attempts are made to induce differentiation from pluripotent stem cells (iPSCs) into MSCs. In particular, it is also known that the paracrine action of stem cell-secreted factors could promote the regeneration and differentiation of target cells in damaged tissue. MicroRNAs (miRNAs), one of the secreted factors, are small non-coding RNAs that regulate the translation of a gene. It is known that miRNAs help communication between stem cells and their surrounding niches through exosomes to regulate the proliferation and differentiation of stem cells. While studies have so far been underway targeting therapeutic miRNAs of MSDs, studies on specific miRNAs secreted from MSCs are still minimal. Hence, our ultimate goal is to obtain sufficient amounts of exosomes from iPSC-MSCs and develop them into therapeutic agents, furthermore to select specific miRNAs and provide safe cell-free clinical setting as a cell-free status with purpose of delivering them to target cells. This review article focuses on stem cell therapy on MSDs, specific microRNAs regulating MSDs and updates on novel approaches.

Clinical trials have not consistently supported the use of induction chemotherapy (IC) for locally advanced head and neck squamous cell cancer. Hypopharynx and base of tongue (BOT) cancer has shown relatively poor survival. We investigated the role of IC in improving outcome over current chemoradiotherapy (CRT) in patients with hypopharynx and BOT cancer. Methods: Treatment-naïve patients with stage III/IV (M0) hypopharynx or BOT cancer were randomly assigned to receive CRT alone (CRT arm: cisplatin 100 mg/m2 on D1 3-weekly, two times plus radiotherapy 68.4 Gy/30 fractions on weekdays) versus two 21-day cycles of IC with TPF (docetaxel & cisplatin 75 mg/m2 on D1, and fluorouracil 75 mg/m2 on D1-4) followed by the same CRT regimen (IC arm). The primary endpoint was progression-free survival (PFS). Results: This study closed early after enrollment of 36 patients (19 in the CRT arm, 17 in the IC arm). After a median follow-up of 47.2 months, there was no significant difference in PFS: the median PFS was 26.8 months for the CRT arm and was not reached for the IC arm (p = 0.13). However, the survival curves were widely separated with a plateau after 3 years, suggesting a potential survival benefit from IC: 3-year PFS rates were 45% and 68%, and 3-year overall survival rates were 56% and 86%, in the CRT and IC arms, respectively. Conclusions: This study failed to demonstrate that induction TPF chemotherapy improves survival in patients with BOT and hypopharynx cancer. However, it suggested a favorable outcome with IC to this population.

We evaluated the antibacterial, anti-inflammatory, and inhibitory effect of osteoclast differentiation of Brachypodium sylvaticum (BS) to find out the possibility of preventing periodontal disease. The inhibition of Porphyromonas gingivalis (P. gingivalis) growth by BS and the sustainability of the antibacterial activity was assessed. The production of pro-inflammatory cytokines from lipopolysaccharide (LPS)-induced RAW 264.7 cells were measured using enzyme-linked immunosorbent assays (ELISA), and the production of nitric oxide (NO) and cell viability were measured. Osteoclast differentiation was evaluated by Tartrate-resistant acid phosphatase (TRAP) staining, and TRAP activity. BS showed significant antibacterial activity and sustainable antibacterial activity in P. gingivalis. We also found out that the BS significantly decreased secretion of pro-inflammatory cytokines [tumor necrosis factor (TNF-α) and interleukin-6 (IL-6)] and NO production without cytotoxicity. Furthermore, BS inhibited the differentiation of bone marrow macrophages (BMMs) obtained from mouse bone marrow cells into osteoclasts without cytotoxicity. Taken together, BS can be a promising candidate for a preventive and improving agent of periodontal disease having antibacterial, anti-inflammatory, and inhibitory effects of osteoclast differentiation.

We evaluated the antibacterial, anti-inflammatory, and inhibitory effect of osteoclast differentiation of Brachypodium sylvaticum (BS) to find out the possibility of preventing periodontal disease. The inhibition of Porphyromonas gingivalis (P. gingivalis) growth by BS and the sustainability of the antibacterial activity was assessed. The production of pro-inflammatory cytokines from lipopolysaccharide (LPS)-induced RAW 264.7 cells were measured using enzyme-linked immunosorbent assays (ELISA), and the production of nitric oxide (NO) and cell viability were measured. Osteoclast differentiation was evaluated by Tartrate-resistant acid phosphatase (TRAP) staining, and TRAP activity. BS showed significant antibacterial activity and sustainable antibacterial activity in P. gingivalis. We also found out that the BS significantly decreased secretion of pro-inflammatory cytokines [tumor necrosis factor (TNF-α) and interleukin-6 (IL-6)] and NO production without cytotoxicity. Furthermore, BS inhibited the differentiation of bone marrow macrophages (BMMs) obtained from mouse bone marrow cells into osteoclasts without cytotoxicity. Taken together, BS can be a promising candidate for a preventive and improving agent of periodontal disease having antibacterial, anti-inflammatory, and inhibitory effects of osteoclast differentiation.

BACKGROUND: The perception of sleep time in obstructive sleep apnea (OSA) is not well understood, some studies have reported that subjects with OSA have abnormal sleep perception. We hypothesized that the severity of OSA would affect the sleep perception of patients with OSA and investigated the associated factors that affect the sleep perception in OSA. METHODS: Four hundred and sixty eight subjects with OSA were included in present study. Subjects with OSA were divided, depending upon their sleep perception. The first group included individuals who underestimated their time spent sleeping, the second group included those who did not underestimate their sleep time. The underestimation of sleep time is defined as the perceived total sleep time being less than 80% of that measured in polysomnography (PSG). All participants were analyzed their demographics, PSG parameter and questionnaires such as Beck Depression Inventory, Epworth Sleepiness Scale. RESULTS: Of 468 participants, 179 (38.2%) subjects were included in the group that underestimating sleep. Gender (female, odds ratio [OR]=2.01, 95% confidence interval [CI]=1.25–3.22), depression (OR=1.75, 95% CI=1.03–2.97) and proportion of slow wave sleep (OR=0.98, 95% CI=0.96–0.99) were related to the underestimation of sleep. CONCLUSIONS: The underestimation of sleep in OSA is not directly related to OSA severity. Gender, psychiatric disorder, and sleep architecture are associated with the underestimating sleep in OSA.
Demography ; Depression ; Humans ; Odds Ratio ; Polysomnography ; Retrospective Studies ; Sleep Apnea, Obstructive

BACKGROUND/AIMS: Carbohydrate antigen 125 (CA-125) is an emerging prognostic biomarker for heart failure. We aimed to test the long-term prognostic value of CA-125 in combination with N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with acute decompensated heart failure (ADHF). METHODS: This observational study included a total of 413 patients (64.1 ± 15.6 year-old, 214 men) with ADHF. All-cause mortality during the 2-year follow-up was investigated for the prognosis. RESULTS: During the follow-up (mean follow-up, 591 ± 233 days), 109 deaths (26.0%) were recorded. In the multivariable analysis model, CA-125 was an independent factor associated with all-cause mortality (log CA-125: hazard ratio, 1.23; 95% confidence interval, 1.02 to 1.48; p = 0.030) together with age, sex, New York Heart Association class, β-blocker, and NT-proBNP. The Kaplan-Meier survival analysis demonstrated that the group with both low marker levels showed the best 2-year survival (87.9%) followed by the group with low NT-proBNP and high CA-125 (76.1%), high NT-proBNP and low CA-125 (64.7%) and high NT-proBNP and high CA-125 levels (54.3%) (p < 0.001). Addition of CA-125 in combination with NT-proBNP and established risk factors further increased the predictive power for mortality in patients with ADHF. CONCLUSIONS CA-125 was an independent factor associated with all-cause mortality in patients with ADHF. Combination of CA-125 with NT-proBNP significantly improved the prediction of mortality in patients with ADHF.

Autoimmune pancreatitis (AIP) is rarely associated with pancreatic pseudocysts. AIP-associated pseudocysts requiring drainage despite steroid therapy are rather rare. We report a case of AIP with an infected pseudocyst requiring drainage despite steroid therapy. A 68-year-old male was diagnosed with AIP via pancreatic imaging, a high serum immunoglobulin G4 level, and steroid responsiveness. The AIP was accompanied by a pancreatic pseudocyst. Steroid therapy was prescribed, but the pancreatic pseudocyst became aggravated during steroid tapering. Endoscopic ultrasonography-guided cyst drainage was required; the pseudocyst then became completely resolved.
Aged ; Drainage* ; Humans ; Immunoglobulins ; Male ; Pancreatic Pseudocyst ; Pancreatitis* ; Steroids

PURPOSE: Papillary thyroid carcinomas (PTCs) frequently involve genetic alterations. The objective of this study was to investigate genetic alterations and further explore the relationships between these genetic alterations and clinicopathological characteristics in a high-recurrence risk (node positive, N1) PTC group. MATERIALS AND METHODS: Tumor tissue blocks were obtained from 240 surgically resected patients with histologically confirmed stage III/IV (pT3/4 or N1) PTCs. We screened gene fusions using NanoString’s nCounter technology and mutational analysis was performed by direct DNA sequencing. Data describing the clinicopathological characteristics and clinical courses were retrospectively collected. RESULTS: Of the 240 PTC patients, 207 (86.3%) had at least one genetic alteration, including BRAF mutation in 190 patients (79.2%), PIK3CA mutation in 25 patients (10.4%), NTRK1/3 fusion in six patients (2.5%), and RET fusion in 24 patients (10.0%). Concomitant presence of more than two genetic alterations was seen in 36 patients (15%). PTCs harboring BRAF mutation were associated with RET wild-type expression (p=0.001). RET fusion genes have been found to occur with significantly higher frequency in N1b stage patients (p=0.003) or groups of patients aged 45 years or older (p=0.031); however, no significant correlation was found between other genetic alterations. There was no trend toward favorable recurrence-free survival or overall survival among patients lacking genetic alterations. CONCLUSION: In the selected high-recurrence risk PTC group, most patients had more than one genetic alteration. However, these known alterations could not entirely account for clinicopathological features of high-recurrence risk PTC.
Gene Fusion ; Humans ; Retrospective Studies ; Sequence Analysis, DNA ; Thyroid Gland* ; Thyroid Neoplasms*