Pin1 acts as a negative regulator of the G2/M transition by interacting with the Aurora-A-Bora complex.

Pin1 was the first prolyl isomerase identified that is involved in cell division. The mechanism by which Pin1 acts as a negative regulator of mitotic activity in G2 phase remains unclear. Here, we found that Aurora A can interact with and phosphorylate Pin1 at Ser16, which suppresses the G2/M function of Pin1 by disrupting its binding ability and mitotic entry. Our results also show that phosphorylation of Bora at Ser274 and Ser278 is crucial for binding of Pin1. Through the interaction, Pin1 can alter the cytoplasmic translocation of Bora and promote premature degradation by ß-TrCP, which results in a delay in mitotic entry. Together with the results that Pin1 protein levels do not significantly fluctuate during cell-cycle progression and Aurora A suppresses Pin1 G2/M function, our data demonstrate that a gain of Pin1 function can override the Aurora-A-mediated functional suppression of Pin1. Collectively, these results highlight the physiological significance of Aurora-A-mediated Pin1 Ser16 phosphorylation for mitotic entry and the suppression of Pin1 is functionally linked to the regulation of mitotic entry through the Aurora-A-Bora complex.

Malfunction endostapler trapped on renal vein - Nightmare scenario for surgeon.

The utilization of endostapler devices has become standard practice for renal vein ligation during laparoscopic nephroureterectomy. While exceptionally rare, malfunctions can occur in these devices. In the video, we present a malfunctioning endostapler that became trapped on the renal vein. Fortunately, this catastrophic event was successfully managed without conversion to open surgery or massive blood loss and was recorded on video. We propose a structured management flow chart for addressing GIA malfunction, aiming to assist surgeons in navigating through this potentially life-threatening situation.

Nephroscope-assisted single trocar peritoneal dialysis catheter insertion improves catheter survival compared with laparoscopic technique: Ten-year experience of a single-center.

BACKGROUND: An ideal technique for peritoneal dialysis (PD) catheter insertion should provide a long-term functioning catheter until permanent renal replacement therapy becomes available. We developed a technique using the nephroscope-assisted single-trocar approach in 2011. In this study, we report the outcomes, learning curve analysis and cost-effectiveness analysisof the nephroscopic approach compared with the traditional laparoscopic approach. METHOD: Between January 2005 and December 2020, we retrospectively reviewed 511 patients who received PD catheter insertions using the laparoscopic or nephroscopic approach. We compared the baseline characteristics of the patients, surgical outcomes, and complications of the two groups. We further analyzed the nephroscopic group to determine the cost-effectiveness analysis, learning curve and the complication frequency between the learning and mastery periods of the nephroscopic approach. RESULTS: A total of 208 patients underwent laparoscopic PD catheter insertion, whereas 303 patients received nephroscopic surgery. The median catheter survival in the nephroscopic group is significantly longer (43.1 vs. 60.5 months, p = 0.019). The incidence of peritonitis (29.3% vs.20.8%, p = 0.035) and exit site infection (12.5% vs. 6.6%, p = 0.019) were significantly lower in the nephroscopic group. The cost-effectiveness analysis showed a medical expense reduction of 16000 USD annually by using the nephroscopic technique. There was no difference in the frequency of surgical complications between the learning and mastery phases when examining the learning curve analysis for the nephroscopic technique. CONCLUSIONS: Compared with the traditional laparoscopic approach, the nephroscopic technique effectively prolonged catheter survival and reduces health care cost by reducing infectious complications. The low complication rate during the learning phase of surgery makes the procedure safe for patients and surgeons.

Conventional androgen deprivation therapy is associated with an increased risk of fracture in advanced prostate cancer, a nationwide population-based study.

PURPOSE: Androgen deprivation therapy (ADT) is the standard of care in advanced prostate cancer. We conducted a Taiwan National Health Insurance Research Database (NHIRD) study to evaluate the association between ADT and fracture risk in patient with prostate cancer in Taiwan. METHODS: Between 2001 and 2008, data from the Taiwan NHIRD was collected. We separated newly diagnosed prostate cancer patients into four groups: the injection of gonadotropin-releasing hormone agonists and antagonists group, the orchiectomy group, the oral antiandorgens group and the radical prostatectomy only group. A non-cancer matched control group was also assigned for comparison. T tests, chi-squared tests, multivariate Cox proportional hazard regression were performed. A subsequent fracture event was defined according to the appropriate diagnosis codes (ICD9-CM 800-829) with hospitalization. Patients with fracture before their diagnosis with prostate cancer were excluded. RESULTS: Overall, 22517 newly diagnosed patients with prostate cancer were enrolled in the study. After exclusion criteria were applied, 13321 patients were separated into the injection group (5020 subjects), the orchiectomy group (1193 subjects), the oral group (6059 subjects) and the radical prostatectomy only group (1049 subjects). The mean age of the overall study population was 74.4 years. Multi-variant analysis disclosed a significantly increased risk of fracture in the injection group, the orchiectomy group, and the oral group (hazard ratio [HR] = 1.55, 95%, confidence interval [CI] 1.36 to 1.76, p<0.001, HR = 1.95, 95%, CI 1.61 to 2.37, p<0.001, HR = 1.37, 95%, CI 1.22 to 1.53, p<0.001, respectively). In contrast, a significantly decreased fracture risk was noted in the radical prostatectomy only group (HR = 0.51, 95%, CI 0.35 to 0.74, p = 0.001). Patients receiving osteoporosis medication had a significantly decreased fracture risk (HR = 0.26, 95%, CI 0.19-0.37, p<0.001). CONCLUSIONS: ADT is associated with an increased risk of fracture. For patients receiving long-term prostate cancer castration therapy, doctors should always keep this complication in mind and arrange proper monitoring and provide timely osteoporosis medication.

Dioxin exposure and insulin resistance in Taiwanese living near a highly contaminated area.

BACKGROUND: Several epidemiologic studies suggest a slightly increased risk of type 2 diabetes in relation to background levels of dioxins. Little is known about how serum dioxins might affect insulin resistance, a hallmark of type 2 diabetes. We examined the association between exposure to dioxins and insulin resistance. METHODS: We investigated 1234 nondiabetic persons living near a deserted pentachlorophenol factory. Using high-resolution gas chromatography/high-resolution mass spectrometry and blood biochemistry tests, we measured serum dioxins, fasting glucose, and insulin. Finally, we examined associations between serum dioxin levels and the homoeostasis model assessments of insulin resistance and pancreatic beta-cell function. RESULTS: Participants with insulin resistance (index at or above the 75th percentile) had higher dioxin levels (24.3 vs. 19.8 pg WHO(98)-TEQ(DF)/g lipid) than those without insulin resistance. In both the crude and adjusted models, insulin resistance increased with serum polychlorinated dibenzo-p-dioxins and dibenzofuran (PCDD/F) levels. We found a slight monotonic increase in insulin resistance across the serum PCDD/F categories (P for the trend <0.001). Groups with serum dioxin levels higher than 20.5 pg WHO(98)-TEQ(DF)/g lipid had higher insulin resistance (adjusted odds ratios of 2.7, 3.5, and 5.0 for 50th to <75th, 75th to <90th, and >or=90th percentile, respectively) compared with the reference group (<9.6 pg WHO(98)-TEQ(DF)/g lipid [< 10th percentile]). CONCLUSIONS: After adjusting for confounding factors, we found a positive association between serum dioxins and the prevalence of insulin resistance.

Retzius-sparing Robotic-assisted Radical Prostatectomy Facilitates Early Continence Regardless of Neurovascular Bundle Sparing.

BACKGROUND/AIM: Retzius-sparing robotic-assisted radical prostatectomy (RARP) has had better results in early continence rate and comparable oncological safety compared to the retropubic approach. However, the role the neurovascular bundle (NVB) sparing plays in the rate of early continence after catheter removal remains unclear. In this study, we sought to compare the early continence rate between Retzius-sparing RARP and the retropubic approach RARP to assess whether NVB sparing affects the continence rate in patients with prostate cancer. PATIENTS AND METHODS: This was a retrospective case series of 133 patients who underwent RARP from 2004 to 2017. 92 patients underwent retropubic RARP and 41 patents underwent Retzius-sparing RARP. All procedures were performed by a single surgical team in a single institution. Baseline patient characteristics were recorded and analyzed. Continence results and oncological outcomes were compared between the two groups. Continence outcome of Retzius-sparing RARP with NVB sparing was also analyzed. RESULTS: No differences in age, prostate size, pathology T stage, PSA, and NVB sparing were found between the two groups. The oncological results including surgical margin and biochemical recurrence rate at one year showed no difference between the two groups. With respect to immediate continence results, the Retzius-sparing group showed a better continence result compared to the retropubic approach (75.6% vs. 26.1 %, respectively, p<0.001) after catheter removal. However, there was no difference between the two groups after 6 months. Furthermore, no significant difference in immediate continence result was found in the Retzius-sparing group between patients with NVB sparing (75 %) and those without (75 % vs. 78%, respectively, p=1.00). CONCLUSION: Retzius-sparing RARP may provide a better immediate continent result compared to retropubic RARP. In Retzius-sparing RARP, NVB sparing did not enhance immediate continence after the operation.

Relationship between insulin sensitivity and exposure to dioxins and polychlorinated biphenyls in pregnant women.

The aim of this study was to examine the relationship between insulin sensitivity and polychlorinated biphenyls (PCBs) exposure in non-diabetic pregnant women. Forty gravidas, 21-39 years of age and residing within the study area, were recruited. Seventeen 2,3,7,8-substituted dichloro-p-dioxin, dibenzofurans and 12 PCBs were measured using high-resolution gas chromatography/high-resolution mass spectrometry (HRGC/HRMS). Serum insulin and glucose were also measured. Insulin sensitivity and the quantitative insulin sensitivity check index (QUICKI) were calculated based on fasting glucose and insulin levels. Three specific congeners of PCBs (123, 126, and 169) were significantly associated with insulin activity (r=-0.34 approximately -0.36, p<0.05). Statistical analyses revealed that insulin sensitivity was significantly associated with age- and pre-pregnancy body mass indices (BMI)-adjusted for decreasing toxic equivalents (TEQ) of PCBs (p=0.02 for age- and BMI-adjusted). We also performed an insulin correlation for total TEQ and the TEQ of PCBs, and determined that insulin sensitivity was predicted by the TEQ of PCBs by a regression coefficient of -0.189 after adjustment for age and pre-pregnancy BMI. These findings suggest that PCBs may be associated with decreasing insulin sensitivity in non-diabetic pregnant women; however, the mechanism remains to be ascertained.

Toward a new insight of calcium oxalate stones in Drosophila by micro-computerized tomography.

We previously developed an animal model of calcium oxalate (CaOx) deposition on the Malphigian tubules of Drosophila melanogaster as a model of urolithiasis. Here, we introduce a new tool for the study of anatomical structure for Drosophila. As a consequence of technical development, the invention of micro-computerized tomography (CT) has been introduced to the small animal, such as rat and mice. We used Drosophila as a model organism and fed the flies 0.5% lithogenic agent ethylene glycol for 3 weeks. Samples were simply prepared for further scanned by micro-CT to scan samples at 800 nm resolution. CT scanning was performed at 40 kVp of voltage, 250 µA of current, and 1750 ms of exposure time and without filter. Reconstruction of sections was carried out with the GPU-based scanner software. Specific region of interests was further analyzed by DataViewer software. Area with high radiologic density level was defined as CaOx deposition for further 3D analysis. Image of whole lithogenic Drosophila was compared with control. High radiologic density level was detected in the region of Malphigian tubules which can be identified as CaOx stones. There was no stone image in the control group. The image was the same as human non-contrast CT for the diagnosis of stone disease. Micro-CT clearly demonstrated the calcium oxalate calcifications in the Malphigian tubules of fruit fly. The image system provides that a new vision on study animal will facilitate further study of stone disease. With the development of new technology on micro-CT, more delicate and advanced image will be presented in the future.

Treatment of Urolithiasis with Medicinal Plant Salvia miltiorrhiza: A Nationwide Cohort Study.

Salvia miltiorrhiza Bunge (Danshen), a common medicinal plant in traditional Chinese medicine, has been tested effectively to prevent urolithiasis in animals; nevertheless, the clinical application for urolithiasis remains unclear. We thus investigated the clinical effect of Danshen by analyzing the database from the Taiwan National Institute of Health. The cohort "Danshen-users" was prescribed Chinese herb medicine Danshen after the initial diagnosis of calculus. The control group (non-Danshen-users) was not given Danshen after the initial diagnosis of calculus. The date of first using Danshen after new diagnosis date of calculus was considered as index date. The outcome variables were categorized into two categories: the first category included calculus surgical treatment, including extracorporeal shock wave lithotripsy, ureteroscopy, percutaneous nephrostomy with fragmentation, and ureterolithotomy; the second category included any bleeding disorders, including gastrointestinal bleeding, intracranial hemorrhage, and blood transfusions. The incidence of calculus surgical treatment in the Danshen-users was less than that in the non-Danshen-users: 1.071% in 1,000 person-years (200 people followed up for 5 years) and 3.142% in 1,000 person-years, respectively. The adjusted hazard ratio for calculus surgical treatment in the Danshen-users was 0.34 (95% confidence intervals: 0.31-0.38) as compared to the non-Danshen-users. When stratified by sex, the incidence of calculus surgical treatment in Danshen-users was 0.685% in 1,000 person-years and 1.575% in 1,000 person-years for women and men, respectively, which was lower than that in non-Danshen-users. Danshen decreased the ratio of subsequent stone treatment after the first treatment in the study population; there was no increased bleeding risk due to long-term Danshen use.

Association of chronic obstructive pulmonary disease and hemorrhoids: A nationwide cohort study.

According to traditional Chinese medicine (TCM) theory, a specific physiological and pathological relationship exists between the lungs and the large intestine. The aim of this study is to delineate the association of chronic obstructive pulmonary disease (COPD) and hemorrhoids in order to verify the "interior-exterior" relationship between the lungs and the large intestine. A retrospective cohort study is conceived from the National Health Insurance Research Database, Taiwan. The 2 samples (COPD cohort and non-COPD cohort) were selected from the 2000 to 2003 beneficiaries of the NHI, representing patients age 20 and older in Taiwan, with the follow-up ending on December 31, 2011. The COPD cohort (n = 51,506) includes every patient newly diagnosed as having Chronic Obstructive Pulmonary Disease (COPD, ICD-9-CM: 490-492, 494, 496), who have made at least 2 confirmed visits to the hospital/clinic. The non-COPD cohort (n = 103,012) includes patients without COPD and is selected via a 1:2 (COPD: non-COPD) matching by age group (per 5 years), gender, and index date (diagnosis date of COPD for the COPD cohort). Compared with non-COPD cohorts, patients with COPD have a higher likelihood of having hemorrhoids and the age-, gender- and comorbidies-adjusted hazard ratio (HR) for hemorrhoids is 1.56 (95% confidence intervals [CI]:1.50-1.62). The adjusted HR of hemorrhoids for females is 0.79 (95% CI: 0.77-0.83), which is significantly less than that for males. The elderly groups, 40 to 59 years and aged 60 or above, have higher adjusted HRs than younger age groups (20-39 years), 1.19 (95% CI: 1.14-1.26), and 1.18 (95% CI: 1.12-1.24), respectively. Patients with COPD may have a higher likelihood to have hemorrhoids in this retrospective cohort study. This study verifies the fundamental theorem of TCM that there is a definite pathogenic association between the lungs and large intestine.

Association of congenital anomalies with fracture of spine, trunk, and upper and lower limbs among young people: A population-based matched cohort study in Taiwan.

According to the Traditional Chinese Medicine (TCM) theory, congenital anomalies are caused by kidney malfunctions, which decreased the bone quality, and may eventually result in bone fractures. This retrospective cohort study investigated the relationship between congenital anomalies and fracture of spine, trunk, and upper and lower limbs in young people. We utilized data from the National Health Insurance Research Database of Taiwan. This study included patients with congenital anomalies (International Classification of Diseases/ICD-9 code: 740-759) and a comparison group of patients without congenital anomalies. Cases evaluated were fracture of spine and trunk (ICD-9 codes: 805-809), fracture of upper limbs (ICD-9 codes: 810-819), and fracture of lower limbs (ICD-9 codes: 820-829). Our study shows that in comparison to the control group, patients with congenital anomalies are 1.11 times more likely to develop fractures. This is the first documented research study that supports the TCM theory that "the Kidney governs the bones, and healthy bones give the body stabilization and prevent fracture."

Body burden of dioxins and dioxin-like polychlorinated biphenyls in pregnant women residing in a contaminated area.

A large pentachlorophenol (PCP)-manufacturing plant located in southwestern Taiwan operated between 1965 and 1982. The present study was conducted to ascertain whether an increased body burden of dioxins existed in pregnant women living in an area of Tainan city contaminated by chemicals from this plant. Twenty-eight pregnant subjects, 21-39 years of age and residing in the study area between March and December of 2004 with a mean dwelling time of 6.07+/-6.11 years, were recruited. Concentrations of polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/Fs), and dioxin-like polychlorinated biphenyls (PCBs) in serum of recruited residents were determined. Pregnant women residing in the study area >3 years had significantly higher PCDD (7.48 versus 5.13 pg-toxic equivalents [TEQ]/g-lipid) and dioxin-like PCB (6.70 versus 3.74 pg-TEQ/g-lipid) values as compared to those residing < or = 3 years. Furthermore, dioxin concentrations increased with increasing dwelling time. Statistical analyses performed according to demographic characteristics and socioeconomic and dietary habits revealed that total TEQ values were significantly associated with fish consumption and smoking status. Dioxin congeners with greater degrees of chlorine substitution (e.g., HpCDD/F and OCDD/F) partitioned to greater degrees in the subjects of this study as compared to subjects in the general Taiwanese population. The findings of this study strongly implicate the activity of the PCP manufacturing plant in the observed increase in dioxin body burden. Investigation of the health consequences of this increased body burden is recommended.

Glycogen synthase kinase 3 ß activity is required for hBora/Aurora A-mediated mitotic entry.

The synthesis and degradation of hBora is important for the regulation of mitotic entry and exist. In G 2 phase, hBora can complex with Aurora A to activate Plk1 and control mitotic entry. However, whether the post-translational modification of hBora is relevant to the mitotic entry still unclear. Here, we used the LC-MS/MS phosphopeptide mapping assay to identify 13 in vivo hBora phosphorylation sites and characterized that GSK3ß can interact with hBora and phosphorylate hBora at Ser274 and Ser278. Pharmacological inhibitors of GSK3ß reduced the retarded migrating band of hBora in cells and diminished the phosphorylation of hBora by in vitro kinase assay. Moreover, as well as in GSK3ß activity-inhibited cells, specific knockdown of GSK3ß by shRNA and S274A/S278 hBora mutant-expressing cells also exhibited the reduced Plk1 activation and a delay in mitotic entry. It suggests that GSK3ß activity is required for hBora-mediated mitotic entry through Ser274 and Ser278 phosphorylation.

Predicting the risk of cardiovascular disease in people exposed to moderate to high levels of dioxin.

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide. Dioxins can cause cardiovascular toxicity in experimental animals. The potential role of dioxin exposure as a preventable risk factor has attracted the attention of public health services, especially because dioxin exposure is a ubiquitous problem. We aimed to investigate and clarify the effect on CVD risk of moderate-to-high exposure to dioxins. This cross-sectional study investigated 914 residents without CVD near a deserted pentachlorophenol factory. CVD-related factors were measured to examine their associations with serum dioxin. We also investigated associations between serum dioxins and the Framingham risk score. Serum PCDD/F levels were significantly positively associated with CVD risk in both genders (Men: b=0.023, P<0.001; Women: b=0.005, P<0.001; All: b=0.013, P<0.001). After adjusting for confounding factors, participants with higher serum PCDD/F levels had a higher risk for CVD than did the reference group (serum PCDD/levels<9.8 pg WHO(98)-TEQ(DF)/g lipid) (25th to <50th percentile, adjusted odds ratio (AOR)=2.96 [95% confidence interval (CI)=1.13-7.75]; 50th to<75th percentile, AOR=3.37 [1.32-8.59]; ≥75th percentile, AOR=6.22 [2.47-15.63]). We hypothesize that accumulated dioxins heightens the cardiovascular risk.

Simultaneous exposure of non-diabetics to high levels of dioxins and mercury increases their risk of insulin resistance.

Insulin resistance and the defective function of pancreatic ß-cells can occur several years before the development of type 2 diabetes. It is necessary to investigate and clarify the integrated effects of moderate-to-high exposure to dioxins and mercury on the pancreatic endocrine function. This cross-sectional study investigated 1449 non-diabetic residents near a deserted pentachlorophenol and chloralkali factory. Metabolic syndrome related factors were measured to examine associations with serum dioxin and blood mercury. We also investigated associations between insulin resistance (HOMA-IR > 75th percentile), defective pancreatic ß-cells function (HOMA ß-cell > 75th percentile), serum dioxins and blood mercury. After adjusting for confounding factors, we found that insulin resistance increased with serum dioxins (b = 0.13, P < 0.001) and blood mercury (b = 0.01, P < 0.001). Moreover, participants with higher serum dioxins or blood mercury were at a significantly increasing risk for insulin resistance (P(trend) < 0.001). The joint highest tertile of serum dioxins and blood mercury was associated with elevated HOMA-IR at 11 times the odds of the joint lowest tertile (AOR 11.00, 95% CI: 4.87, 26.63). We hypothesize that simultaneous exposure to dioxins and mercury heightens the risk of insulin resistance more than does individual exposure.