Detection of metastatic lymph node and sentinel lymph node mapping ​using mannose receptor targeting in in vivo mouse footpad tumor models and rabbit uterine cancer models.

BACKGROUND: This study aimed to evaluate the effectiveness of neo-mannosyl human serum albumin-indocyanine green (MSA-ICG) for detecting metastatic lymph node (LN) and mapping sentinel lymph node (SLN) using mouse footpad uterine tumor models. Additionally, the authors assessed the feasibility of MSA-ICG in SLN mapping in rabbit uterine cancer models. MATERIALS AND METHODS: The authors compared the LN targeting ability of MSA-ICG with ICG. Six mouse footpad tumor models and two normal mice were each assigned to MSA-ICG and ICG, respectively. After the assigned tracers were injected, fluorescence images were taken, and the authors compared the signal-to-background ratio (SBR) of the tracers. A SLN biopsy was performed to confirm LN metastasis status and CD206 expression level. Finally, an intraoperative SLN biopsy was performed in rabbit uterine cancer models using MSA-ICG. RESULTS: The authors detected 14 groin LNs out of 16 in the MSA-ICG and ICG groups. The SBR of the MSA-ICG group was significantly higher than that of the ICG group. The metastatic LN subgroup of MSA-ICG showed a significantly higher SBR than that of ICG. CD206 was expressed at a high level in metastatic LN, and the signal intensity difference increased as the CD206 expression level increased. SLN mapping was successfully performed in two of the three rabbit uterine cancer models. CONCLUSIONS: MSA-ICG was able to distinguish metastatic LN for an extended period due to its specific tumor-associated macrophage-targeting property. Therefore, it may be a more distinguishable tracer for identifying metastatic LNs and SLNs during uterine cancer surgery. Further research is needed to confirm these results.

Determination of pharmacokinetics and tissue distribution of a novel lutetium-labeled PSMA-targeted ligand, 177Lu-DOTA-PSMA-GUL, in rats by using LC-MS/MS.

Prostate specific membrane antigen (PSMA) is known to be overexpressed in prostate cancer cells, providing as a diagnostic and therapeutic target for prostate cancer. A lutetium-labeled PSMA targeted ligand, 177Lu-DOTA-PSMA-GUL is a novel radiopharmaceutical, which has been developed for the treatment of prostate cancer. While the GUL domain of 177Lu-DOTA-PSMA-GUL binds to the antigen, the beta-emitting radioisotope, 177Lu-labeled DOTA, interacts with prostate cancer cells. However, the in vivo pharmacokinetics of intact 177Lu-DOTA-PSMA-GUL has never been characterized. This study aimed to evaluate the pharmacokinetics and tissue distribution of the radiopharmaceutical in rats by using its stable isotope-labeled analog, 175Lu-DOTA-PSMA-GUL. A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of 175Lu-DOTA-PSMA-GUL was developed and validated. Following intravenous injection, the plasma concentration-time profiles of 175Lu-DOTA-PSMA-GUL showed a multi-exponential decline with the average elimination half-life of 0.30 to 0.33 h. Systemic exposure increased with the dose and renal excretion is the major elimination route. Tissue distribution of 175Lu-DOTA-PSMA-GUL was most substantial in kidneys, followed by the prostate. The developed LC-MS/MS assay and the in vivo pharmacokinetic data of 175Lu-DOTA-PSMA-GUL would provide helpful information for further clinical studies to be developed as a novel therapeutic agent for prostate cancer.

The Risk Factors, Incidence and Prognosis of Postpartum Breast Cancer: A Nationwide Study by the SMARTSHIP Group.

The term 'pregnancy-associated breast cancer' is no longer used as it has been consistently reported that breast cancer during pregnancy and breast cancer after delivery (postpartum breast cancer) have different characteristics and prognosis. The purpose of this study is to define postpartum breast cancer by analyzing the incidence rate, related factors, and prognosis according to the timing of breast cancer. Data from the Korean National Health Insurance Service were used to analyze 1,292,727 women aged 20-49 years who birthed their first child between 2007 and 2012. The annual incidence rate of breast cancer after delivery increased every year (7.7 per 10,000 person-years after 5 years, 19.36 per 10,000 person-years after 10 years). The risk of breast cancer was significantly higher (hazard ratio 1.15, 95% CI 1.05-1.27, P=0.0037) in women diagnosed with gestational diabetes, but that was not associated with overall survival (OS). Patients diagnosed with breast cancer within 5 years of delivery had a poorer prognosis than those diagnosed later (5-year OS, <5 years: 91.1% vs. 5-10 years: 96.0%). In multivariate analysis of OS, the hazard ratio of patients diagnosed within 5 years after delivery was twice as high as of patients diagnosed between 5 and 10 years. Women diagnosed with gestational diabetes had an increased risk of breast cancer. Breast cancer patients diagnosed within 5 years of delivery had a poorer prognosis than those diagnosed later. In this regard, careful screening for early diagnosis of high-risk patients and intensive research on new treatment strategies are needed.

Work-Related Risk Factors of Knee Meniscal Tears in Korean Farmers: A Cross-Sectional Study.

BACKGROUND: Meniscal tears are among the major risk factors for knee osteoarthritis progression. This study aimed to investigate the relationship between meniscal tears and work-related factors in the farming occupation. METHODS: The participants included 486 farmers (238 men and 248 women), aged 40-69 years, who were among the 550 farmers registered in the Korea Farmer's Knee Cohort (KFKC). Data such as those on gender, age, body mass index (BMI), mechanical axis, cumulative heavy-lifting working time (CLWT), cumulative squatting working time (CSWT), and previous knee injury history were collected from the questionnaire, along with whole leg radiographic findings. Two radiologists assessed the magnetic resonance images of both knees to confirm the presence of meniscal tears. The factors related to meniscal tears were analyzed by multiple logistic regression. RESULTS: A total of 54.5% of the farmers (48.7% of men and 60.1% of women) had meniscal tears. These tears were associated with gender, age, and BMI. We also identified an association between meniscal tears and CSWT, an especially important factor in farming [10,000-19,999 working hours, odds ratio = 2.16, 95% confidence interval (CI): 1.14-4.07, ≥20,000 working hours, odds ratio = 2.35, 1.45-3.80]. However, mechanical axis, knee injury history, and CLWT were not significantly related to meniscal tears. CONCLUSION: This study's findings show that squatting for long periods, as an occupational factor, is related to meniscal tears.

Factors related to femoral bowing among Korean female farmers: a cross-sectional study.

BACKGROUND: Female farmers have a high prevalence of knee osteoarthritis (KOA) in South Korea. Femoral bowing has been reported to be related to KOA by increasing load on the mechanical axis. This study aimed to investigate factors related to femoral bowing in Korean female farmers. METHODS: We analyzed the legs of 264 female farmers registered with the Korea farmers' knee cohort of Jeonnam Center for Farmers' Safety and Health. A structured questionnaire was used to determine sociodemographic variables, agricultural career, cumulative squatting working time (CSWT), and cumulative heavy lifting working time. Femoral bone density was measured and Kellgren-Lawrence (KL) grades were obtained from the knee radiographs. Mechanical axis angle (MAA), femoral bowing angle (FBA), anatomical lateral distal femoral angle (aLDFA), anatomical medial proximal tibial angle (aMPTA), and condylar-plateau angle (CPA) were measured. We examined the relationship between the FBA and related factors by using multiple linear regression. RESULTS: The proportion of individuals with radiographic KOA (≥ KL grade 2) in this study was 37.9%. As KL grades increased, MAA, FBA, and CPA increased, whereas aLDFA and aMPTA decreased. FBA increased with age. Multiple linear regression analyses using FBA as a dependent variable showed relationship with higher age, lower height, higher BMI, lower bone mineral density, longer CSWT, and longer agricultural careers. CONCLUSIONS: The results of this study suggest that external factors related to agricultural work in female farmers was associated with femoral bowing, in addition to internal factors such as age, bone density, height, and obesity.

Work-related factors of knee osteoarthritis in Korean farmers: a cross-sectional study.

BACKGROUND: Several studies have reported a high prevalence of osteoarthritis (OA) of the knee among agricultural workers. We investigated work-related factors that increase the risk of knee OA among Korean farmers. METHODS: Data were extracted from the Jeonnam Center for Farmer's Safety and Health survey, conducted between 2013 and 2015. The sample included 489 farmers (man 240, woman 249). We defined knee OA as radiographic knee OA (≥ Kellgren-Lawrence grade 2) with symptoms (≥ Western Ontario and McMaster Universities Osteoarthritis, Korean version score 29.5). We considered covariates such as cumulative squatting working time (CSWT), cumulative heavy lifting working time (CLWT), body mass index (BMI), and history of knee injury. Odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated for knee OA and adjusted for relevant covariates. RESULTS: The results of multivariate logistic regression analysis indicated that knee OA was correlated by factors such as sex, age, BMI, history of knee injury, CSWT, and CLWT. Particularly, CSWT > 20,000 hours (OR: 2.83; 95% CI: 1.35-5.92; reference < 10,000 hours) and CLWT > 5,000 hours (OR: 2.62; 95% CI: 1.14-6.06; reference < 2,000 hours) were associated with an increased risk of knee OA after adjustment for covariates. CONCLUSIONS: Squatting posture and heavy lifting associated with farm work might increase the risk of knee OA among Korean farmers.

Sensitivity and specificity of the safe driving behavior measure and the driving habits questionnaire for older self-drivers.

[Purpose] To evaluate the sensitivity and specificity of the Safe Driving Behavior Measure and the Driving Habits Questionnaire in community-dwelling older self-drivers. [Subjects and Methods] Forty-five older participated in this study, to measure the Safe Driving Behavior Measure and the Driving Habits Questionnaire. Sensitivity and specificity were calculated along with cut-off values and overall accuracy of each measure as determined by the participants operating characteristic curve and the area under the curve. Multivariate logistic regression analysis was employed to identify predictors of driving abilities. [Results] The sensitivities were 0.538 for Safe Driving Behavior Measure, and 0.577, 0.423, and 0.615 for the difficulty, crash and citations, and driving space on domains of the Driving Habits Questionnaire, respectively. The specificities of the person-vehicle domain, person-environment domain, and person-vehicle-environment domain of the Safe Driving Behavior Measure were 0.474, 0.526, and 0.421, respectively, while the Driving Habits Questionnaire domains, the specificities of difficulty, crash and citations, and driving space were 0.526, 0.211, and 0.421, respectively. [Conclusion] The results of this study suggest that factors related to the accident history of older self-drivers were not well-explained, although the Safe Driving Behavior Measure and Driving Habits Questionnaire domains have the potential to determine driving-related accident history.

Atypical traumatic pneumorrhachis accompanied by paraparesis.

Pneumorrhachis, caused by intraspinal air, is an exceptional but important radiographic finding that is accompanied by different etiologies. Pneumorrhachis, by itself, is usually asymptomatic and gets reabsorbed spontaneously. Therefore, the patients with pneumorrhachis are mostly managed conservatively. We encountered a unique case of atypical traumatic pneumorrhachis accompanied by paraparesis.

Paraplegia due to Spinal Epidermoid Cyst Rupture at Asthma Attack.

Spinal epidermoid cyst is less than 1% of the entire spinal cord tumor and a rare tumor. It is a slowly proliferating benign tumor and can be a result of either congenital or acquired factors. In particular, reports of acute paraplegia due to spinal epidermoid cyst rupture are very rare. Since authors experienced paraplegia resulting from congenital spinal epidermoid cyst rupture during an asthma attack, it is reported with a review of literature.

Ape1/Ref-1 Stimulates GDNF/GFRalpha1-mediated Downstream Signaling and Neuroblastoma Proliferation.

We previously reported that glial cell line-derived neurotropic factor (GDNF) receptor alpha1 (GFRalpha1) is a direct target of apurinic/apyrimidinic endonuclease 1 (Ape1/Ref-1). In the present study, we further analyzed the physiological roles of Ape1/Ref-1-induced GFRalpha1 expression in Neuro2a mouse neuroblastoma cells. Ape1/Ref-1 expression caused the clustering of GFRalpha1 immunoreactivity in lipid rafts in response to GDNF. We also found that Ret, a downstream target of GFRalpha1, was functionally activated by GDNF in Ape1/Ref-1-expressing cells. Moreover, GDNF promoted the proliferation of Ape1/Ref-1-expressing Neuro2a cells. Furthermore, GFRalpha1-specific RNA experiments demonstrated that the downregulation of GFRalpha1 by siRNA in Ape1/Ref-1-expressing cells impaired the ability of GDNF to phosphorylate Akt and PLCgamma-1 and to stimulate cellular proliferation. These results show an association between Ape1/Ref-1 and GDNF/GFRalpha signaling, and suggest a potential molecular mechanism for the involvement of Ape1/Ref-1 in neuronal proliferation.

(-)-epigallocatechin gallate inhibits the pacemaker activity of interstitial cells of cajal of mouse small intestine.

The effects of (-)-epigallocatechin gallate (EGCG) on pacemaker activities of cultured interstitial cells of Cajal (ICC) from murine small intestine were investigated using whole-cell patch-clamp technique at 30 and Ca(2+) image analysis. ICC generated spontaneous pacemaker currents at a holding potential of -70 mV. The treatment of ICC with EGCG resulted in a dose-dependent decrease in the frequency and amplitude of pacemaker currents. SQ-22536, an adenylate cyclase inhibitor, and ODQ, a guanylate cyclase inhibitor, did not inhibit the effects of EGCG. EGCG-induced effects on pacemaker currents were not inhibited by glibenclamide, an ATP-sensitive K(+) channel blocker and TEA, a Ca(2+)-activated K(+) channel blocker. Also, we found that EGCG inhibited the spontaneous [Ca(2+)](i) oscillations in cultured ICC. In conclusion, EGCG inhibited the pacemaker activity of ICC and reduced [Ca(2+)](i) oscillations by cAMP-, cGMP-, ATP-sensitive K+ channel-independent manner.

Expeditious syntheses of conjugated allenyl esters and oxazoles through a cascade reaction of alpha-alkynyl malonates under alkaline conditions.

Diethyl alpha-alkynyl-alpha-methoxymalonates (2a--e) were smoothly hydrolyzed and then decarboxylated under alkaline conditions employing 1 N KOH in EtOH to give conjugated allenyl esters (6a--e) in high yields, and similar alkaline treatment of diethyl alpha-alkynyl-alpha-acetylaminomalonates (5a, b, d, e) furnished unexpectedly the oxazoles (7a, b, d, e) having three substituent groups in excellent yields.

Concentration-dependent collateral sensitivity of cisplatin-resistant gastric cancer cell sublines.

The cisplatin-resistant gastric cancer cell sublines, SNU-601/Cis2 and /Cis10, were 49 and >530 times more resistant to cisplatin, respectively, compared with the drug-sensitive cells, SNU-601/WT. The SNU-601/Cis2 showed cross-resistance to carboplatin, heptaplatin, doxorubicin, mitomycin C, and 5-fluorouracil compared with the SNU-601/WT whereas the SNU-601/Cis10 displayed collateral sensitivity to these drugs with the exception of cisplatin compared with the SNU-601/Cis2, suggesting that the cross-resistance and collateral sensitivity of cisplatin-resistant gastric cancer cells are dependent upon cisplatin concentrations. Altered expression of the antioxidant and transporter genes (metallothionein, catalase, superoxide dismutases, P-glycoprotein, and the breast cancer resistance protein) was involved in these phenotypes of the cisplatin-resistant gastric cancer cell lines.

Molecular mechanisms of heptaplatin effective against cisplatin-resistant cancer cell lines: less involvement of metallothionein.

BACKGROUND: Heptaplatin is a new platinum derivative with anticancer activity against various cancer cell lines, including cisplatin-resistant cancer cell lines (Cancer Chemother Pharmacol 1995; 35: 441). METHODS: Molecular mechanisms of heptaplatin effective against cisplatin-resistant cancer cell lines has been investigated in connection with metallothionein (MT). Cytotoxicity was determined by an MTT assay. MT mRNA, was determined by RT-PCR assay. Transfection study was carried out to examine the function of MT. RESULTS: Of various gastric cancer cell lines, SNU-638 and SNU-601 showed the highest and lowest levels of MT mRNA, respectively, showing 80-fold difference. The IC50 values of SNU-638 to cisplatin, carboplatin and heptaplatin were 11.2-fold, 5.1-fold and 2.0-fold greater than those of SNU-601, respectively. Heptaplatin was more effective against cisplatin-resistant and MT-transfected gastric cancer sublines than cisplatin or carboplatin was. In addition, heptaplatin attenuated cadmium, but not zinc, induction of MT. CONCLUSION: These results indicate that molecular mechanisms of heptaplatin effective against cisplatin-resistant gastric cancer sublines is at least in part due to the less involvement of MT in heptaplatin resistance as well as its attenuation of MT induction.

Differential induction of Mn-containing superoxide dismutase by paraquat in peripheral lymphocytes of normal subjects and gastric cancer patients.

Reactive oxygen species (ROS) cause macromolecular damage and may play an important role in tumor development. Superoxide dismutase (SOD) and metallothionein (MT) serve as initial and final defense mechanisms, respectively, against ROS. We hypothesized that the inducibility of Mn-SOD and MT mRNA by paraquat, an intracellular superoxide generator, might be altered in lymphocytes of gastric cancer patients. The inducibility of Mn-SOD mRNA by paraquat in lymphocytes of 19 normal subjects and the 14 gastric cancer patients was 162.4 +/- 16.7% and 87.9 +/- 9.5%, respectively (P = 0.001). The inducibility of MT mRNA by paraquat in the normal subjects and the gastric cancer patients was 126.7 +/- 15.8% and 115.4 +/- 12.9%, respectively. This suggests that the failure of Mn-SOD mRNA induction by oxidative stress in peripheral lymphocytes may be involved in the development of gastric cancer and may be of value in predicting the future occurrence of gastric cancer. In addition, the wide variation in Mn-SOD and MT mRNA levels among normal subjects may reflect different susceptibilities to diseases including cancer.