Production and engineering of nanobody-based quenchbody sensors for detecting recombinant human growth hormone and its isoforms.

Due to athletes' misuse of recombinant human growth hormone (rhGH) for performance improvement, the World Anti-Doping Agency has designated rhGH as a prohibited substance. This study focuses on the development and improvement of a simple and fast rhGH detection method using a fluorescence-incorporated antibody sensor "Quenchbody (Q-body)" that activates upon antigen binding. Camelid-derived nanobodies were used to produce stable Q-bodies that withstand high temperatures and pH levels. Notably, pituitary human growth hormone (phGH) comprises two major isoforms, namely 22 and 20 kDa GH, which exist in a specific ratio, and the rhGH variant shares the same sequence as the 22 kDa GH isoform. Therefore, we aimed to discriminate rhGH abuse by analyzing its specific isoform ratio. Two nanobodies, NbPit (recognizing phGH) and NbRec (preferentially recognizing 22 kDa rhGH), were used to develop the Q-bodies. Nanobody production in Escherichia coli involved the utilization of a vector containing 6xHis-tag, and Q-bodies were obtained using a maleimide-thiol reaction between the N-terminal of the cysteine tag and a fluorescent dye. The addition of tryptophan residue through antibody engineering resulted in increased fluorescence intensity (FI) (from 2.58-fold to 3.04-fold). The limit of detection (LOD) was determined using a fluorescence response, with TAMRA-labeled NbRec successfully detecting 6.38 ng/ml of 22 kDa rhGH while unable to detect 20 kDa GH. However, ATTO520-labeled NbPit detected 7.00 ng/ml of 20 kDa GH and 2.20 ng/ml 22 kDa rhGH. Q-bodies successfully detected changes in the GH concentration ratio from 10 to 40 ng/ml in human serum within 10 min without requiring specialized equipment and kits. Overall, these findings have potential applications in the field of anti-doping measures and can contribute to improved monitoring and enforcement of rhGH misuse, ultimately enhancing fairness and integrity in competitive sports.

BILATERAL MACULAR CHOROIDAL ABNORMALITIES WITH DRUSENOID DEPOSITS IN PATIENTS WITH UNILATERAL PERIPHERAL EXUDATIVE HEMORRHAGIC CHORIORETINOPATHY.

PURPOSE: To investigate bilateral macular features on optical coherence tomography in patients with unilateral peripheral exudative hemorrhagic chorioretinopathy (PEHCR). METHODS: In this cross-sectional study, optical coherence tomography features of affected eyes (PEHCR group, n = 30) and unaffected contralateral eyes (contralateral group, n = 30) were investigated. Age-matched and sex-matched patients with polypoidal choroidal vasculopathy (PCV group, n = 51) and healthy controls (normal group, n = 50) were included to compare choroidal thickness, measured at six points apart from the fovea, with the PEHCR group. RESULTS: Subretinal drusenoid deposits were the most common feature in the PEHCR (20%) and contralateral (23%) groups, followed by soft drusen. Although the macular choroid was comparably thin in both the PEHCR and contralateral groups, pachyvessels were also observed. The choroids of the PEHCR group were significantly thinner than those of the normal group at the subfovea and 1-mm temporal to the fovea and considerably thinner than those of the polypoidal choroidal vasculopathy group from 3-mm nasal to 3-mm temporal to the fovea. CONCLUSION: In patients with unilateral PEHCR, bilateral choroidal thinning and drusenoid deposit accumulation were noted in the macula. The pathophysiology of PEHCR may be a rare peripheral complication of age-related macular degeneration with pathologic choroid.

Functional Constipation is Associated with a Decline in Word Recognition 2 Years Later in Community-Dwelling Older Adults: The Korean Frailty and Aging Cohort Study.

BACKGROUND: Consumption and cognitive impairment are the most common health problems among older adults. This study aimed to determine the effects of functional constipation on cognitive decline in community-dwelling older adults. METHODS: This was a 2-year longitudinal analysis of Korean Frailty and Aging Cohort Study data, including 851 community-dwelling residents who participated in both the baseline and follow-up surveys. A neuropsychological test, the Consortium to Establish a Registry for Alzheimer's Disease Assessment Battery (CERAD-K), and the Korean version of the Frontal Assessment Battery (FAB) were used to evaluate cognitive function. Functional constipation was defined according to the ROME IV criteria. An analysis of covariance was used to identify the association between functional constipation and cognitive decline. RESULTS: Among the 851 participants, 8.9% had functional constipation. The patients in the constipation group were more likely to have low physical activity (15.8% vs. 8.8%), polypharmacy (61.8% vs. 45.5%), and depression (30.3% vs. 17.4%) than the non-constipation group. After adjusting for potential confounding factors, including age, sex, education years, low physical activity, polypharmacy, type 2 diabetes mellitus, depression, and baseline Cognitive Function Test score, the mean changes in Word Recognition test scores from 2018 to 2020 were -0.07 and -0.54 in the non-constipation and constipation groups, respectively (p=0.007). Other cognitive function tests (Mini-Mental State Examination, word list memory, word list recall, digit span, trail-making test, and FAB) did not show any difference in decline between the two groups (p>0.05). CONCLUSIONS: Functional constipation at baseline was associated with a decline in word recognition after 2 years.

Discovery of pyrazole-1-carboxamide derivatives as novel Gi-biased µ-opioid receptor agonists.

µ-Opioid receptor (MOR) Gi-biased agonists with no recruitment of ß-arrestin were introduced as a new analgesic strategy to overcome the conventional undesirable side effects of opioid receptor-targeted drugs, such as tolerance, addiction, respiratory depression, and constipation. For the development of novel Gi-biased MOR agonists, the design, synthesis, and structure-activity relationship (SAR) analysis of the aminopyrazole core skeleton were conducted according to the current SAR data of PZM21 (2a) and its derivatives. New derivatives were biologically evaluated for their agonistic effects on cyclic adenosine monophosphate (cAMP) levels for the Gi pathway and ß-arrestin recruitment in MOR/κ-opioid receptor/δ opioid receptor. An optimized selective Gi-biased agonist, Compound 17a, was discovered with potent cAMP inhibitory activities, with a 50% efficacy concentration value of 87.1 nM and no activity in the MOR ß-arrestin pathway and other subtypes. The in vivo pain relief efficacy of Compound 17a was confirmed in a dose-dependent manner with spinal nerve ligation and cisplatin-induced peripheral neuropathy rodent neuropathic pain models.

Involvement of inflammatory lipoproteinemia with idiopathic adhesive capsulitis accompanying subclinical hypothyroidism.

BACKGROUND: Thyroid functional abnormalities are considered risk factors for idiopathic adhesive capsulitis (IAC) though that relationship remains uncertain. Although dyslipidemias are associated with IAC, no readily accessible study has reported associations between dyslipidemias and IAC patients with subclinical hypothyroidism. The purposes of this study were to investigate whether subclinical hypothyroidism is an independently associated factor for IAC and to determine the differences in prevalence of dyslipidemias between two groups of persons with subclinical hypothyroidism: one composed of IAC patients and the other of individuals without IAC. METHODS: This case-control study included a case group of 412 IAC patients without intrinsic shoulder lesions, extrinsic causes, or medication for thyroid dysfunction. The control group comprised 1236 age- and sex-matched persons seeking general checkups at the authors' health promotion center during the same period as the case group. Control subjects had normal shoulder function and no previously diagnosed adhesive capsulitis, no medication for thyroid dysfunction, and no history of trauma or of shoulder surgery. The studied variables were age, gender, obesity, diabetes, dyslipidemias, subclinical hypothyroidism, hypothyroidism, and hyperthyroidism. A conditional logistic regression analysis evaluated the matched sets of subjects to determine odds ratios and 95% confidence intervals for the studied variables. The differences in the prevalence of dyslipidemias between IAC patients with subclinical hypothyroidism and individuals with subclinical hypothyroidism but without IAC were determined with generalized estimating equations, using covariates of age, sex, and diabetes. The P values were set at < 0.05. RESULTS: Subclinical hypothyroidism (odds ratio, 2.10; 95% confidence interval, 1.36-3.15; P = .001) was significantly associated with IAC. Patients with IAC and subclinical hypothyroidism had a significantly higher prevalence of hyper-low-density lipoproteinemia, an inflammatory lipoproteinemia, than individuals with subclinical hypothyroidism but without IAC (P = .002). CONCLUSIONS: Subclinical hypothyroidism is significantly associated with IAC. Hyper-low-density lipoproteinemia, an inflammatory lipoproteinemia, is involved in IAC accompanied by subclinical hypothyroidism.

Near-infrared autofluorescence-based parathyroid glands identification in the thyroidectomy or parathyroidectomy: a systematic review and meta-analysis.

PURPOSE: To evaluate the diagnostic accuracy of near-infrared autofluorescence-based identification in the identification of parathyroid glands during thyroidectomy or parathyroidectomy. METHODS: The clinical studies were retrieved from PubMed, the Cochrane Central Register of Controlled Trials, Embase, Web of Science, SCOPUS, and Google Scholar. The study protocol was registered on Open Science Framework ( https://osf.io/um8rj/ ). The search period ranged from the date of each database's inception to May 2021. Cohort studies dealing with patients of whom parathyroid glands were detected by near-infrared autofluorescence and confirmed clinically or pathologically during thyroidectomy or parathyroidectomy were included. Editorials, letters, "how-I-do-it" descriptions, other site head and neck tumors, and articles with lack of diagnostic identification data were excluded. True positive, true negative, false positive, and false negative were extracted. The QUDAS ver. 2 was used to evaluate the methodological quality. RESULTS: Seventeen studies with 1198 participants were evaluated in this analysis. Near-infrared autofluorescence-based identification of parathyroid glands showed a diagnostic odds ratio of 228.8759 (95% confidence interval, 134.1099; 390.6063). The area under the summary receiver operating characteristic curve was 0.967. The sensitivity, specificity, negative predictive value, and positive predictive value were 0.9693 (0.9491; 0.9816), 0.9248 (0.8885; 0.9499), 0.9517 (0.8981; 0.9778), and 0.9488 (0.9167; 0.9689), respectively. Subgroup analyses were performed to compare two autofluorescence detection methods, because there was high heterogeneity in the outcomes. The diagnostic accuracy was higher in probe-based detection than in image-based detection. CONCLUSIONS: Near-infrared autofluorescence-based identification is valuable for identifying the parathyroid glands of patients during thyroidectomy or parathyroidectomy.

Effectiveness of the Endoscopic Prelacrimal Recess Approach for Maxillary Sinus Inverted Papilloma Removal: A Systematic Review and Meta-Analysis.

BACKGROUND: Conventional minimally invasive surgery has a high recurrence rate, and nasal morbidity can occur if the scope of surgery is expanded to complete removal of maxillary sinus inverted papilloma. OBJECTIVE: To analyze the efficacy of the endoscopic prelacrimal recess approach (EPLRA) for maxillary sinus inverted papilloma removal. METHODS: Eighteen studies were included in this meta-analysis. Articles comparing the prelacrimal recess approach with conventional surgery (endoscopic surgery or the Caldwell-Luc operation) for inverted papilloma removal were included. Outcomes of interest included recurrence and postoperative morbidities. The methodological quality was assessed using the Newcastle-Ottawa scale. RESULTS: The recurrence rates of inverted papilloma, postoperative facial or gingival numbness, and alar collapse were 3.13% (95% confidence interval [CI]: 1.32, 7.27), 9.02% (95% CI: 3.70, 20.39), and 3.39% (95% CI: 1.28, 8.68), respectively. The recurrence rate of inverted papilloma was significantly lower after the EPLRA than after conventional surgery (odds ratio [OR] = 0.2290; 95% CI: 0.0808, 0.6489). However, there were no significant differences between the procedures in the rates of facial or gingival numbness (OR = 0.4567; 95% CI: 0.1497, 1.3933), epistaxis (OR = 0.3150; 95% CI: 0.0471, 2.1044), or periorbital swelling (OR = 1.2405; 95% CI: 0.1205, 12.7731). CONCLUSIONS: The EPLRA can preserve the lacrimal system and is useful for maxillary sinus inverted papilloma removal due to a lower recurrence rate compared with conventional surgeries.

Indocyanine green fluorescence for parathyroid gland identification and function prediction: Systematic review and meta-analysis.

BACKGROUND: To evaluate the diagnostic accuracies of indocyanine green (ICG) fluorescence for identifying parathyroid glands during surgery and predicting the postoperative function. METHODS: From six databases, 21 studies were finally included in the study. True-positive, true-negative, false-positive, and false-negative data were extracted for the analysis. The quality of each study was analyzed using the QUADAS-2 tool. RESULTS: The sensitivity of ICG-based parathyroid gland identification was 0.9380 (95% CI [0.9003, 0.9621]). The diagnostic odds ratio for ICG-based prediction of parathyroid gland function was 54.5652 [13.2059, 225.4570]. The area under the summary receiver operating characteristic curve was 0.909. Fluorescence intensity-based prediction presented higher diagnostic accuracy than that of score-based prediction. The incidence of postoperative hypoparathyroidism was higher in the group with a zero ICG score compared to the high scored group. CONCLUSIONS: Identification of parathyroid gland and prediction of postoperative function using ICG are valuable to patients undergoing thyroidectomy or parathyroidectomy.

Pattern analysis for prognosis of differentiated thyroid cancer according to preoperative serum thyrotropin levels.

Serum thyrotropin (TSH) level after thyroid surgery affects the prognosis of differentiated thyroid cancer (DTC). However, the effects of preoperative serum TSH levels on the prognosis of DTC remain contradictory. In this study, to better understand the relationship between preoperative TSH levels and the prognosis of DTC, we performed pattern analysis of prognostic factors of DTC according to preoperative serum TSH levels. We retrospectively reviewed the clinical records of patients who were diagnosed and treated for DTC at the Samsung Medical Center, between 1994 and 2016. We reviewed preoperative serum TSH levels and performed a pattern analysis with prognostic risk factors for DTC. For pattern analysis, TSH was divided into 10 groups of equal fractions (TSH decile). We found a linear association between preoperative TSH levels and extra-thyroidal extension and lymph node metastasis. However, primary tumor size and initial distant metastasis showed a bimodal peak, which was similar to the pattern of overall and disease-specific death. We found that preoperative TSH range which showed the lowest mortality rate was about 0.8 to 1.59 mIU/L, which are slightly lower normal TSH levels. Although there was no linear trend, the primary tumor size, initial distant metastasis, and mortality of DTC were closely related with preoperative TSH decile and they showed a bimodal pattern. The results obtained in this study provide additional information for understanding the association between preoperative TSH levels and DTC prognosis.

Light-emitting diode irradiation induces AKT/mTOR-mediated apoptosis in human pancreatic cancer cells and xenograft mouse model.

The beneficial effects of light-emitting diode (LED) irradiation have been reported in various pathologies, including cancer. However, its effect in pancreatic cancer cells remains unclear. Herein, we demonstrated that blue LED of 460 nm regulated pancreatic cancer cell proliferation and apoptosis by suppressing the expression of apoptosis-related factors, such as mutant p53 and B-cell lymphoma 2 (Bcl-2), and decreasing the expression of RAC-ß serine/threonine kinase 2 (AKT2), the phosphorylation of protein kinase B (AKT), and mammalian target of rapamycin (mTOR). Blue LED irradiation also increased the levels of cleaved poly-(ADP-ribose) polymerase (PARP) and caspase-3 in pancreatic cancer cells, while it suppressed AKT2 expression and inhibited tumor growth in xenograft tumor tissues. In conclusion, blue LED irradiation suppressed pancreatic cancer cell and tumor growth by regulating AKT/mTOR signaling. Our findings indicated that blue LEDs could be used as a nonpharmacological treatment for pancreatic cancer.

A prion-like domain in ELF3 functions as a thermosensor in Arabidopsis.

Temperature controls plant growth and development, and climate change has already altered the phenology of wild plants and crops1. However, the mechanisms by which plants sense temperature are not well understood. The evening complex is a major signalling hub and a core component of the plant circadian clock2,3. The evening complex acts as a temperature-responsive transcriptional repressor, providing rhythmicity and temperature responsiveness to growth through unknown mechanisms2,4-6. The evening complex consists of EARLY FLOWERING 3 (ELF3)4,7, a large scaffold protein and key component of temperature sensing; ELF4, a small α-helical protein; and LUX ARRYTHMO (LUX), a DNA-binding protein required to recruit the evening complex to transcriptional targets. ELF3 contains a polyglutamine (polyQ) repeat8-10, embedded within a predicted prion domain (PrD). Here we find that the length of the polyQ repeat correlates with thermal responsiveness. We show that ELF3 proteins in plants from hotter climates, with no detectable PrD, are active at high temperatures, and lack thermal responsiveness. The temperature sensitivity of ELF3 is also modulated by the levels of ELF4, indicating that ELF4 can stabilize the function of ELF3. In both Arabidopsis and a heterologous system, ELF3 fused with green fluorescent protein forms speckles within minutes in response to higher temperatures, in a PrD-dependent manner. A purified fragment encompassing the ELF3 PrD reversibly forms liquid droplets in response to increasing temperatures in vitro, indicating that these properties reflect a direct biophysical response conferred by the PrD. The ability of temperature to rapidly shift ELF3 between active and inactive states via phase transition represents a previously unknown thermosensory mechanism.

Association between fasting glucose levels and adhesive capsulitis in a normoglycemic population: a case-control study.

BACKGROUND: Hyperglycemia is the most commonly cited risk factor for adhesive capsulitis. However, no study has established whether fasting glucose levels within the normoglycemic range are associated with idiopathic adhesive capsulitis (IAC). This study hypothesized that increments of fasting glucose levels within the normoglycemic range would be linked to IAC. This study investigated any association between normoglycemic fasting glucose levels and IAC. METHODS: This case-control study comprised a group of 151 patients with IAC without intrinsic shoulder lesions, extrinsic causes, or known metabolic risk factors such as diabetes, dyslipidemia, and thyroid dysfunction. The control group comprised 453 age- and sex-matched persons seeking general check-ups at the authors' health promotion center during the same period as the case group. Control subjects had normal shoulder function, no previous diagnosis of adhesive capsulitis or of metabolic disease, and no history of trauma or of shoulder surgery. The studied variables were body mass index, serum lipid profiles, thyroid hormone levels, fasting glucose levels, glycosylated hemoglobin A1c, and high-sensitivity C-reactive protein. Fasting glucose levels were studied as scale data and categorical data (<85, 85-89, 90-94, and 95-99 mg/dL). Multivariable conditional logistic regression analysis evaluated the matched sets of subjects. Odds ratios and 95% confidence intervals were determined for various potentially associated factors. RESULTS: Fasting glucose level, hypercholesterolemia, and high-sensitivity C-reactive protein were significantly associated with IAC (P ≤ .030). Fasting glucose levels in the <85 mg/dL quartile were significantly negatively associated with IAC (P ≤ .001). In contrast, fasting glucose levels in the 90-94 mg/dL quartile or higher were significantly positively associated with IAC (P ≤ .034). CONCLUSION: IAC is positively associated with fasting glucose levels of 90-99 mg/dL, which are currently considered normoglycemic.

Association Between High-Sensitivity C-Reactive Protein and Idiopathic Adhesive Capsulitis.

BACKGROUND: Chronic inflammation is implicated in the development of idiopathic adhesive capsulitis (IAC), whose association with high-sensitivity C-reactive protein (CRP), an inflammation marker, is undetermined. This study's purposes were to investigate the association between high-sensitivity CRP levels and IAC and to determine the metabolic factors associated with high-sensitivity CRP. METHODS: This case-control study examined a group of 202 patients with IAC and without intrinsic shoulder lesions or extrinsic causes and a control group of 606 age and sex-matched persons seeking general check-ups at our health promotion center during the same period as the case group. Control subjects had normal shoulder function and no previously diagnosed adhesive capsulitis; no medication for diabetes, dyslipidemia, and thyroid abnormalities; and no history of trauma or of shoulder surgery. The studied variables were body mass index; diabetes; thyroid abnormalities; dyslipidemias; triglyceride/high-density lipoprotein (TG/HDL) >3.5; serum levels of thyroid hormone, fasting glucose, and glycosylated hemoglobin A1c (HbA1c); and high-sensitivity CRP >1.0 mg/L. Multivariable conditional logistic regression analysis evaluated the matched sets of subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined for the studied variables possibly affecting IAC. RESULTS: Serum high-sensitivity CRP >1.0 mg/L was significantly associated with IAC (OR, 2.47 [95% CI, 1.65 to 3.70]) after adjusting for diabetes, fasting glucose level, HbA1c, dyslipidemia, TG/HDL >3.5, and thyroid-stimulating hormone (p ≤ 0.031). Diabetes (OR, 1.71 [95% CI, 1.09 to 3.33]), fasting glucose level (OR, 1.54 [95% CI, 1.12 to 2.12]), HbA1c (OR, 2.00 [95% CI, 1.25 to 3.22]), hypertriglyceridemia (OR, 1.70 [95% CI, 1.03 to 3.41]), hypo-high-density lipoproteinemia (OR, 1.98 [95% CI, 1.04 to 3.79]), and TG/HDL >3.5 (OR, 1.37 [95% CI, 1.06 to 1.88]) were significantly associated with high-sensitivity CRP >1.0 mg/L in patients with IAC (p ≤ 0.039). CONCLUSIONS: Serum high-sensitivity CRP >1.0 mg/L is an independent associated marker for IAC. Dyslipidemia, insulin resistance, and hyperglycemia, which are recognized factors associated with IAC, are also associated with high-sensitivity CRP >1.0 mg/L in these patients, supporting the interaction of chronic systemic inflammation in IAC. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Hypo-High-Density Lipoproteinemia Is Associated With Preoperative Tear Size and With Postoperative Retear in Large to Massive Rotator Cuff Tears.

PURPOSE: To evaluate any association of specific subtypes of dyslipidemia with increments of preoperative tear size and with structural integrity after arthroscopic rotator cuff repair (ARCR). METHODS: One surgeon's consecutive patients who underwent ARCR from January 2011 to June 2018 were reviewed. The inclusion criteria were minimum 1-year follow-up ultrasonography, blood tests, physical examination, and provision of informed consent. The exclusion criteria were incomplete laboratory tests, history of acute trauma, previous shoulder surgery, isolated subscapularis tendon tear, inappropriate radiographs, no 1-year follow-up ultrasonography, and medication with lipid-lowering drugs. Associated preoperative factors for the increments of tear size and for retear after ARCR were determined using logistic regression analysis. Statistical significance was set at P < .05. RESULTS: Of the 502 ARCR patients from the study period, 195 patients (195 shoulders), with a mean age of 60.5 ± 7.5 years, met the inclusion and exclusion criteria. Age (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.1-1.3), diabetes (OR, 3.6; 95% CI, 1.7-7.5), and hypo-high-density lipoproteinemia (hypo-HDLemia) (OR, 2.9; 95% CI, 1.5-5.6) were significantly associated with increments of preoperative tear size (P ≤ .01). Diabetes (OR, 3.0; 95% CI, 1.3-6.6), critical shoulder angle (OR, 2.0; 95% CI, 1.4-3.0), and tear size (OR, 2.1; 95% CI, 1.3-3.4) were significantly associated with retear after ARCR in overall study subjects (P = .01). Diabetes (OR, 3.8; 95% CI, 1.3-11.4), hypo-HDLemia (OR, 3.0; 95% CI, 1.1-8.8), and critical shoulder angle (OR, 1.5; 95% CI, 1.1-2.3) had significant associations with retear after ARCR in patients with a large to massive preoperative tear size (P ≤ .04). CONCLUSIONS: Preoperative hypo-HDLemia (high-density lipoprotein level < 40 mg/dL in male patients and < 50 mg/dL in female patients) has a significant association with the increments of preoperative tear size and with retear after ARCR in large- to massive-sized rotator cuff tears. LEVEL OF EVIDENCE: Level IV, case series.

A Comparison of Embryonic Development and Clinical Outcomes between In vitro Oocytes Maturation Using Micro-Vibration System and In vivo Oocytes Maturation in Polycystic Ovarian Syndrome Patients.

BACKGROUND/OBJECTIVES: Mechanical micro-vibration remains insufficient for improving embryo culture conditions in human immature oocytes. This study compared the clinical outcomes and embryo development between germinal vesicle (GV) oocytes with the micro-vibration culture (MVC) system in in vitro maturation (IVM) cycles and in vivo-matured oocytes in controlled ovarian hyperstimulation (COH) cycles in polycystic ovarian syndrome (PCOS) patients. METHODS: This study investigated 152 PCOS patients who underwent 159 fresh embryo transfer cycles, including IVM cycles with embryos derived from GV oocytes and the COH cycles with embryos derived from in vivo-matured oocytes. The IVM cycles were divided into groups according to the culture system used: static culture (SC) and MVC: In the IVM-S group (n = 47), SC was applied during both IVM and in vitro culture (IVC), whereas in the IVM-MV group (n = 44), MVC was applied during both IVM and IVC. For the COH cycles, in the COH-S group (n = 68), SC was applied during IVC. RESULTS: The number of in vitro-matured oocytes was similar in the IVM-S and IVM-MV groups, but the good-quality embryo (GQE; ≥6-cells) rate was significantly higher in the IVM-MV group (p < 0.01). The GQE rate and clinical outcomes of the COH-S group were significantly better than those of the IVM-S group (p < 0.05) but similar to those of the IVM-MV group. CONCLUSION: Compared with the SC system, the MVC system in IVM cycles improves the embryonic quality of GV oocytes and clinical outcomes, resulting in development of potential equivalent to in vivo-matured oocytes.

Preoperative Serum Thyroglobulin and Its Correlation with the Burden and Extent of Differentiated Thyroid Cancer.

Lymph node metastasis (LNM) in differentiated thyroid cancer (DTC) is usually detected with preoperative ultrasonography; however, this has limited sensitivity for small metastases, and there is currently no predictive biomarker that can help to inform the extent of surgery required. We evaluated whether preoperative serum thyroglobulin levels can predict tumor burden and extent. We retrospectively reviewed the clinical records of 4029 DTC cases diagnosed and treated at a Samsung Medical Center between 1994 and 2016. We reviewed primary tumor size, number and location of LNM, and presence of distant metastases to reveal relationships between tumor burden and extent and preoperative serum thyroglobulin levels. We found a linear association between increasing preoperative thyroglobulin levels, the size of the primary tumor, and the number of LNM (r = 0.34, p < 0.001, r = 0.20, p < 0.001, respectively). Tumor extent also increased with each decile of increasing preoperative thyroglobulin level (r = 0.18, p < 0.001). Preoperative thyroglobulin levels of 13.15 ng/mL, 30.05 ng/mL, and 62.9 ng/mL were associated with the presence of ipsilateral lateral LNM, contralateral lateral LNM, and distant metastasis, respectively. Our results suggest that preoperative measurement of serum thyroglobulin may help to predict LNM and help to tailor surgery.

Improved survival after early detection of asymptomatic distant metastasis in patients with thyroid cancer.

The incidence of thyroid cancer (TC) has been increasing in many countries and concerns about overdiagnosis are also widely shared. However, early detection may be helpful in some high-risk TC patients, such as those with initial distant metastasis. We conducted this study to evaluate the usefulness of early detection in TC patients with initial distant metastasis. We retrospectively reviewed the clinical data of 13,249 TC patients, and found 127 patients with initial distant metastasis. Enrolled patients were divided into two groups according to the diagnostic periods; before and after 2004, when the early detection of TC by ultrasonography began in earnest in Korea. Patients were also divided into two groups according to the presence of symptoms. Prior to 2004, 33 patients (1.7% of TC patients) were diagnosed with TC with initial distant metastasis and 16 (48.5%) of them died. After 2004, 94 patients (0.8% of TC patients) were diagnosed with TC with initial distant metastasis and 29 (30.9%) of them died. Prior to 2004, the disease-specific death rates were similar between the asymptomatic and symptomatic groups (46.2% vs. 50.0%, P = 0.566). Conversely, after 2004, the asymptomatic group showed a significantly lower disease-specific death rate as compared with that of the symptomatic groups (17.2% vs. 60.0%; P < 0.001). Early detection had a significant positive impact on survival outcomes only after 2004, especially in asymptomatic TC patients with initial distant metastasis.

Anti-oxidant and Anti-inflammatory Effects of Aquatic Exercise in Allergic Airway Inflammation in Mice.

Oxidative stress and inflammation are key pathways responsible for the pathogenesis of asthma. Aquatic exercise (AE) has been proven to elicit a variety of biological activities such as anti-oxidant and anti-inflammatory effects. However, although proper forms of AE provide beneficial health effects, incorrect forms and types of AE are potentially injurious to health. Several studies have investigated AE, but the relationship between types of AE and asthma has not been fully elucidated. This study evaluated the effects of two types of AE according to resistance on ovalbumin (OVA)-induced allergic airway inflammation in mice. BALB/c mice were subjected to OVA sensitization and challenge, and then to different types of AE including, walking and swimming, in a pool filled with water to a height of 2.5 and 13 cm for 30 min, respectively. AE reduced OVA-induced eosinophilic inflammation, airway hyperresponsiveness, and serum immunoglobulin E level. AE significantly inhibited increases in interleukin (IL)-4, IL-5, IL-13, histamine, leukotriene D4, and tryptase levels in bronchoalveolar lavage fluid (BALF). AE also effectively suppressed mucus formation, lung fibrosis, and hypertrophy of airway smooth muscle within the lung tissues. This exercise markedly reduced the levels of malondialdehyde while increased glutathione and superoxide dismutase (SOD) activity in lung tissues. Furthermore, AE significantly decreased tumor necrosis factor-α, IL-6 levels, and prostaglandin E2 production in BALF. The inhibitory effects of swimming on the levels of biomarkers related to oxidative stress and inflammation were greater than that of walking. These effects may have occurred through upregulation of NF-E2-related factor 2/heme oxygenase-1 signaling and suppression of mitogen-activated protein kinase/nuclear factor-κB pathway. Cumulative results from this study suggest that AE might be beneficial in mitigating the levels of biomarkers related to oxidative stress and inflammation. Thus, this therapy represents a crucial non-pharmacological intervention for treatments of allergic airway inflammation.

Heterometallic BODIPY-Based Molecular Squares Obtained by Self-Assembly: Synthesis and Biological Activities.

Metal-based multinuclear supramolecules with different functionalities designed by self-assembly represent a growing area of research due to their versatile applications, particularly as anticancer agents. Four novel boron dipyrromethene (BODIPY)-based octacationic heterometallic molecular squares, 3-6 were synthesized by self-assembly via reaction of dipyridyl BODIPY ligands with suitable 90° palladium and platinum acceptors. The formation of the as-synthesized molecular squares was confirmed by multinuclear NMR spectroscopy, elemental analysis, high resolution electrospray mass spectrometry, UV-vis spectroscopy, and fluorescence spectroscopy. The square molecular structures of 4 and 6 were further rationalized theoretically using the PM7 semi-empirical method. The activities of the supramolecules against cancer cells were tested using cell lines of various malignant and nonmalignant origins. Complexes 3-6 showed high cytotoxicity toward cancer cells but 7.0 to 15.2 times lower cytotoxic effects were observed against nonmalignant human kidney epithelial cells (HEK-293). Particularly, complexes 3-6 provided 2.1-6.0 times lower IC50 values as compared to cisplatin in HCT116 cells. Interestingly, BDP ligand-containing complexes (3 and 4) induced cytotoxicity through apoptosis, whereas BDPCC-based complexes (5 and 6) induced cell death by necrosis. This study presents a novel series of iron-based heteroatomic palladium and platinum complexes that exhibit substantial potential as drug candidates for anticancer therapy.

Improvement of embryonic development and clinical outcomes of germinal vesicle stage oocytes using a microvibration culture system.

In vitro maturation (IVM) has evolved as a clinical treatment option in assisted reproductive technology. However, the poor developmental potential of germinal vesicle (GV)-stage oocytes is still suboptimal. This study's objective was to evaluate the effect of a microvibration culture system (MVC) during IVM and/or in vitro culture (IVC) on the clinical outcomes and the embryonic development potential of human GV-stage oocytes collected from human chorionic gonadotropin (HCG)-primed IVM and fertilization-embryo transfer (IVM/F-ET) cycles of patients with polycystic ovaries (PCO). A total of 206 HCG-primed IVM/F-ET cycles were divided into four groups according to the microvibration and static culture system applied during IVM and/or IVC: Group SS (static system during both IVM and IVC); Group SV (static system during IVM alternated with microvibration system during IVC); Group VS (microvibration system during IVM alternated with static system during IVC), and Group VV (microvibration system during both IVM and IVC). The results indicate that the rates of in vitro MII oocytes per cycle, fertilization, and cleavage were not significantly different between the groups. The rate of good-quality embryos in Group SV tended to be higher than the rate in Groups SS and VS, but there was no significant difference between Group SS and Group SV. Clinical pregnancy, implantation, and live birth rates of Groups SV and VS were slightly higher than those of Group SS. However, the rate of good-quality embryos with at least six cells on day 4, the clinical pregnancy, implantation, and live births in Group VV were significantly higher than those in Group SS. These results indicate that, compared with the static culture system, the MVC system applied for both IVM and IVC seems to improve the clinical outcomes and the quality of embryos of GV oocytes derived from HCG-primed IVM/F-ET cycles in PCO patients. Abbreviations: PCO: polycystic ovaries; HCG: human chorionic gonadotropin; GV: germinal vesicle; MII: metaphase II; IVM: in vitro maturation; IVF: in vitro fertilization; IVC: in vitro culture: MVC: microvibration culture; SC: static culture; ICSI: intracytoplasmic sperm injection; IVM/F-ET: IVM and fertilization-embryo transfer; AMH: anti-Mullerian hormone; OHSS: ovarian hyperstimulation syndrome.