Prediction of Acquired Taxane Resistance Using a Personalized Pathway-Based Machine Learning Method / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: This study was conducted to develop and validate an individualized prediction model for automated detection of acquired taxane resistance (ATR). MATERIALS AND METHODS: Penalized regression, combinedwith an individualized pathway score algorithm,was applied to construct a predictive model using publically available genomic cohorts of ATR and intrinsic taxane resistance (ITR). To develop a model with enhanced generalizability, we merged multiple ATR studies then updated the learning parameter via robust cross-study validation. RESULTS: For internal cross-study validation, the ATR model produced a perfect performance with an overall area under the receiver operating curve (AUROC) of 1.000 with an area under the precision-recall curve (AUPRC) of 1.000, a Brier score of 0.007, a sensitivity and a specificity of 100%. The model showed an excellent performance on two independent blind ATR cohorts (overall AUROC of 0.940, AUPRC of 0.940, a Brier score of 0.127). When we applied our algorithm to two large-scale pharmacogenomic resources for ITR, the Cancer Genome Project (CGP) and the Cancer Cell Line Encyclopedia (CCLE), an overall ITR cross-study AUROC was 0.70, which is a far better accuracy than an almost random level reported by previous studies. Furthermore, this model had a high transferability on blind ATR cohorts with an AUROC of 0.69, suggesting that general predictive features may be at work across both ITR and ATR. CONCLUSION: We successfully constructed a multi-study–derived personalized prediction model for ATR with excellent accuracy, generalizability, and transferability.

Development of second primary cancer in Korean breast cancer survivors

PURPOSE: Breast cancer survivors have slightly increased the risk of second primary cancers. Breast, colon, uterine, and ovarian cancers are common secondary cancers in breast cancer survivors. In this study, we assessed the development of second primary cancers of breast cancer survivors in Korea. METHODS: Medical records of patients with breast cancer in 3 tertiary medical institutions were reviewed retrospectively. We evaluated secondary malignancy diagnosed at least 2 months after the breast cancer diagnosis. Based on the International Classification of Disease-9 codes of malignancies, secondary primary breast cancer records were evaluated with person-year adjustment. The standardized incidence ratio (SIR) was assessed using national cancer incidence. RESULTS: A total of 3,444 treatment records were included from 3 medical centers. The cumulative incidence of overall second primary cancers was 2.8% (n = 93). The SIR was significantly higher in all sites (1.56; 95% confidence interval [CI], 1.26–1.91), endometrial cancer (5.65; 95% CI, 2.06–12.31), biliary tract cancer (3.96; 95% CI, 1.19–8.60), and thyroid cancer (2.29; 95% CI, 1.67–3.08). CONCLUSION: The incidence of cancer was higher in breast cancer survivors compared to general population. Surveillance of secondary cancer in this group should be recommended individually considering the benefit related to the prognosis of primary breast cancer.

Development of second primary cancer in Korean breast cancer survivors

PURPOSE: Breast cancer survivors have slightly increased the risk of second primary cancers. Breast, colon, uterine, and ovarian cancers are common secondary cancers in breast cancer survivors. In this study, we assessed the development of second primary cancers of breast cancer survivors in Korea. METHODS: Medical records of patients with breast cancer in 3 tertiary medical institutions were reviewed retrospectively. We evaluated secondary malignancy diagnosed at least 2 months after the breast cancer diagnosis. Based on the International Classification of Disease-9 codes of malignancies, secondary primary breast cancer records were evaluated with person-year adjustment. The standardized incidence ratio (SIR) was assessed using national cancer incidence. RESULTS: A total of 3,444 treatment records were included from 3 medical centers. The cumulative incidence of overall second primary cancers was 2.8% (n = 93). The SIR was significantly higher in all sites (1.56; 95% confidence interval [CI], 1.26–1.91), endometrial cancer (5.65; 95% CI, 2.06–12.31), biliary tract cancer (3.96; 95% CI, 1.19–8.60), and thyroid cancer (2.29; 95% CI, 1.67–3.08). CONCLUSION: The incidence of cancer was higher in breast cancer survivors compared to general population. Surveillance of secondary cancer in this group should be recommended individually considering the benefit related to the prognosis of primary breast cancer.

Diet control to achieve euglycemia induces significant loss of heart and liver weight via increased autophagy compared with ad libitum diet in diabetic rats

Intensive glucose control increases the all-cause mortality in type 2 diabetes mellitus (T2DM); however, the underlying mechanisms remain unclear. We hypothesized that strict diet control to achieve euglycemia in diabetes damages major organs, increasing the mortality risk. To evaluate effects on major organs when euglycemia is obtained by diet control, we generated a model of end-stage T2DM in 13-week-old Sprague-Dawley rats by subtotal pancreatectomy, followed by ad libitum feeding for 5 weeks. We divided these rats into two groups and for the subsequent 6 weeks provided ad libitum feeding to half (AL, n=12) and a calorie-controlled diet to the other half (R, n=12). To avoid hypoglycemia, the degree of calorie restriction in the R group was isocaloric (g per kg body weight per day) compared with a sham-operated control group (C, n=12). During the 6-week diet control period, AL rats ate three times more than rats in the C or R groups, developing hyperglycemia with renal hyperplasia. R group achieved euglycemia but lost overall body weight significantly compared with the C or AL group (49 or 22%, respectively), heart weight (39 or 23%, respectively) and liver weight (50 or 46%, respectively). Autophagy levels in the heart and liver were the highest in the R group (P<0.01), which also had the lowest pAkt/Akt levels among the groups (P<0.05 in the heart; P<0.01 in the liver). In conclusion, glycemic control achieved by diet control can prevent hyperglycemia-induced renal hyperplasia in diabetes but may be deleterious even at isocaloric rate when insulin is deficient because of significant loss of heart and liver mass via increased autophagy.

Spontaneous Recovery of Cavernous Nerve Crush Injury

PURPOSE: To investigate pathophysiological consequences and spontaneous recovery after cavernous nerve crush injury (CNCI) in a rat model. MATERIALS AND METHODS: Twenty 4-week-old male Sprague-Dawley rats were divided into the following groups: sham-operated group (n=10) and bilateral CNCI groups (n=10) for two different durations (12 and 24 weeks). At both time points, CN electrical stimulation was used to assess erectile function by measuring the intracavernous pressure. The expression of hypoxia inducible factor (HIF)-1alpha and sonic hedgehog (SHH) was examined in penile tissue. Immunohistochemical staining was performed for nerve growth factor (NGF), endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), and smooth muscle alpha-actin. RESULTS: CNCI significantly decreased erectile function at 12 weeks (51.7% vs. 71.9%, mean ICP/BP ratio, p<0.05) and increased the expression of HIF-1alpha and decreased the expression of eNOS, nNOS, and SHH. At 24 weeks, erectile function in the CNCI group was improved with no significant difference versus the sham group (70.5% vs. 63.3%, mean ICP/BP ratio, p<0.05) or the CN group at 12 weeks (51.7% vs. 63.3%, mean ICP/BP ratio, p<0.05). By RT-PCR, the increase in HIF-1alpha and decrease in SHH mRNA was restored at 24 weeks. By immunohistochemistry, the expression of eNOS and nNOS was increased at 24 weeks. CONCLUSIONS: CN injury induces significantly impaired erectile function and altered gene and protein expression, which suggests that local hypoxic and inflammatory processes may contribute to this change. Significant spontaneous recovery of erectile function was observed at 6 months after CN crush injury.

Spontaneous Recovery of Cavernous Nerve Crush Injury

PURPOSE: To investigate pathophysiological consequences and spontaneous recovery after cavernous nerve crush injury (CNCI) in a rat model. MATERIALS AND METHODS: Twenty 4-week-old male Sprague-Dawley rats were divided into the following groups: sham-operated group (n=10) and bilateral CNCI groups (n=10) for two different durations (12 and 24 weeks). At both time points, CN electrical stimulation was used to assess erectile function by measuring the intracavernous pressure. The expression of hypoxia inducible factor (HIF)-1alpha and sonic hedgehog (SHH) was examined in penile tissue. Immunohistochemical staining was performed for nerve growth factor (NGF), endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), and smooth muscle alpha-actin. RESULTS: CNCI significantly decreased erectile function at 12 weeks (51.7% vs. 71.9%, mean ICP/BP ratio, p<0.05) and increased the expression of HIF-1alpha and decreased the expression of eNOS, nNOS, and SHH. At 24 weeks, erectile function in the CNCI group was improved with no significant difference versus the sham group (70.5% vs. 63.3%, mean ICP/BP ratio, p<0.05) or the CN group at 12 weeks (51.7% vs. 63.3%, mean ICP/BP ratio, p<0.05). By RT-PCR, the increase in HIF-1alpha and decrease in SHH mRNA was restored at 24 weeks. By immunohistochemistry, the expression of eNOS and nNOS was increased at 24 weeks. CONCLUSIONS: CN injury induces significantly impaired erectile function and altered gene and protein expression, which suggests that local hypoxic and inflammatory processes may contribute to this change. Significant spontaneous recovery of erectile function was observed at 6 months after CN crush injury.

Biliverdin reductase A in the prevention of cellular senescence against oxidative stress

Biliverdin reductase A (BLVRA), an enzyme that converts biliverdin to bilirubin, has recently emerged as a key regulator of the cellular redox cycle. However, the role of BLVRA in the aging process remains unclear. To study the role of BLVRA in the aging process, we compared the stress responses of young and senescent human diploid fibroblasts (HDFs) to the reactive oxygen species (ROS) inducer, hydrogen peroxide (H2O2). H2O2 markedly induced BLVRA activity in young HDFs, but not in senescent HDFs. Additionally, depletion of BLVRA reduced the H2O2-dependent induction of heme oxygenase-1 (HO-1) in young HDFs, but not in senescent cells, suggesting an aging-dependent differential modulation of responses to oxidative stress. The role of BLVRA in the regulation of cellular senescence was confirmed when lentiviral RNAitransfected stable primary HDFs with reduced BLVRA expression showed upregulation of the CDK inhibitor family members p16, p53, and p21, followed by cell cycle arrest in G0-G1 phase with high expression of senescence-associated beta-galactosidase. Taken together, these data support the notion that BLVRA contributes significantly to modulation of the aging process by adjusting the cellular oxidative status.

ERRATUM: Expression of LDH-5 in Colorectal Carcinomas: Correlation with Prognosis and Tumor Angiogenesis

No abstract available.

A case of sideroblastic anemia caused by lead-containing herbal medication / 대한내과학회지

Although lead intoxication is commonly mentioned as a cause of sideroblastic anemia, no well-documented case exists in the literature. We encountered a patient with sideroblastic anemia caused by lead-containing herbal medicine. A 34-year-old woman was admitted to our hospital with abdominal pain. She had taken herbal medicine for her general health. Anemia, hyperbilirubinemia, and elevated lactic dehydrogenase were found from the laboratory data. Bone marrow biopsy showed pathological ringed sideroblasts. Her serum level of lead was high and the lead content of the tablet was higher than permitted. We diagnosed her with sideroblastic anemia secondary to lead poisoning caused by herbal medicine. We stopped her from taking herbal medicine and she gradually recovered from anemia.

Expression of LDH-5 in Colorectal Carcinomas: Correlation with Prognosis and Tumor Angiogenesis

PURPOSE: Lactate dehydrogenase-5 (LDH-5) is one of five isoenzymes and is the most important for anaerobic glycolysis. LDH-5 is transcriptionally regulated by hypoxia-inducible factor (HIF). HIF plays a role in the response to hypoxia by activating genes involved in vascular remodeling, cell proliferation, and erythropoiesis. In this study, we investigated the clinicopathologic significance and angiogenesis of LDH-5 expression in colorectal cancer. METHODS: We retrospectively reviewed the medical records of 83 patients with colorectal cancer who underwent a surgical resection at Soonchunhyang Cheonan Hospital from January 2001 to December 2003. LDH-5 and HIF-1alpha protein expressions were evaluated in 83 human colorectal cancer specimens. These factors were related to TNM stage, lymph node metastasis, vascular, neural, and lymphatic invasion, and prognosis. RESULTS: LDH-5 was positive in 66% (55 patients) of the tumors, and HIF-1alpha was positive in 66% (55 patients) of the tumors. LDH-5 expression was significantly associated with HIF-1alpha protein expression (P<0.001). Also, LDH-5 expression was significantly associated with TNM stage and lymph node metastasis (P<0.001) while HIF-1alpha expression was significantly associated with TNM stage (P<0.001), lymph node metastasis (P<0.001), vascular invasion (P=0.011), and lymphatic invasion (P=0.005). The survival of the patients with high LDH-5 expression was worse than that of patients with low LDH-5 expression (P=0.032). CONCLUSION: Our study shows a high expression of LDH-5 in colorectal cancer. The up-regulation of LDH-5 parallels an increase in HIF-1alpha expression. The immunohistochemical assessment of tissue LDH-5 and HIF-1alpha provides important prognostic information for colorectal carcinomas.

Expression Changes of the Phosphodiesterase 5 isoform in the Penis of Type 2 Diabetic Rat / 대한남성과학회지

PURPOSE: To investigate the tissue distribution of PDE5 isoforms in type 2 diabetic rat penile tissues. MATERIALS AND METHODS: We prepared ten male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which develop NIDDM naturally, and ten control male Long-Evans Tokushima Fatty (LETO) rats. An oral glucose tolerance test confirmed diabetes development in OLETF rats at 26 weeks. At 42 weeks, we checked serum glucose, testosterone, triglyceride, insulin, and adiponectin before sacrifice. We performed semi-quantitative multiplex RT-PCR for rat PDE5, PDE5A1, and PDE5A2. Immunohistochemistry was performed using mouse monoclonal anti-cGB-PDE5 and anti-smooth muscle alpha-actin. RESULTS: OLETF rats were significantly more hyperglycemic, hypogonadal, hyperinsulinemic, hypercholesterolemic, hypertriglycemic, and had lower adiponectin levels than LETO rats. Levels of PDE5 mRNA were decreased in OLETF rats, but there were no changes in PDE5A1 or PDE5A2 mRNA levels. CONCLUSION: Diabetes may contribute to decreased expression of PDE5 mRNA, but not PDE5A1 or PDE5A2, in rat penile tissue. Furthermore, serum free testosterone was decreased in diabetic rats. PDE5 has an important role in the development of diabetic erectile dysfunction, but it is not clear whether PDE5A1 and PDE5A2 gene have specific roles.

Expression Changes of the Phosphodiesterase 5 isoform in the Penis of Type 2 Diabetic Rat / 대한남성과학회지

PURPOSE: To investigate the tissue distribution of PDE5 isoforms in type 2 diabetic rat penile tissues. MATERIALS AND METHODS: We prepared ten male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which develop NIDDM naturally, and ten control male Long-Evans Tokushima Fatty (LETO) rats. An oral glucose tolerance test confirmed diabetes development in OLETF rats at 26 weeks. At 42 weeks, we checked serum glucose, testosterone, triglyceride, insulin, and adiponectin before sacrifice. We performed semi-quantitative multiplex RT-PCR for rat PDE5, PDE5A1, and PDE5A2. Immunohistochemistry was performed using mouse monoclonal anti-cGB-PDE5 and anti-smooth muscle alpha-actin. RESULTS: OLETF rats were significantly more hyperglycemic, hypogonadal, hyperinsulinemic, hypercholesterolemic, hypertriglycemic, and had lower adiponectin levels than LETO rats. Levels of PDE5 mRNA were decreased in OLETF rats, but there were no changes in PDE5A1 or PDE5A2 mRNA levels. CONCLUSION: Diabetes may contribute to decreased expression of PDE5 mRNA, but not PDE5A1 or PDE5A2, in rat penile tissue. Furthermore, serum free testosterone was decreased in diabetic rats. PDE5 has an important role in the development of diabetic erectile dysfunction, but it is not clear whether PDE5A1 and PDE5A2 gene have specific roles.

Expression of Hypoxia-inducible Factor-1alpha and Vascular Endothelial Growth Factor in Colon Cancer: Relationship to the Prognosis and Tumor Markers

PURPOSE: Angiogenesis is one of the key steps in solid tumor growth and metastasis. We investigated the prognostic significance of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1alpha (HIF-1alpha) expressions as markers of angiogenesis in colon cancer. METHODS: We retrospectively reviewed the medical records of 78 patients with colon or rectal cancer who underwent a surgical resection at Soonchunhyang University Hospital from January 2000 to December 2001, and we evaluated the expression of VEGF and HIF-1alpha in archival tumor tissues by using immunohistochemistry. We recorded the clinical and the pathological characteristics of the patients and analyzed their survival outcomes. RESULTS: Thirty-four (34) patients were male, and the mean age of all the patients was 66.7 years. HIF-1alpha and VEGF were positive in 56% (44 patients) and 53% (42 patients) of the tumors, respectively. HIF-1alpha expression was significantly associated with several pathological parameters, such as TNM stage (P=0.001), lymph node metastasis (P=0.001). HIF-1alpha expression was also associated with VEGF expression (P=0.032). The survival of patients with HIF-1alpha expression was worse than that of patients with no HIF-1alpha expression (P=0.036). However, VEGF expression was not associated with other pathological characteristics. CONCLUSIONS: We suggest that, in cases of colorectal cancer, HIF-1alpha expression may be associated with expression of VEGF, progression of tumors, and poor prognosis.

An in-vitro evaluation of sealer placement methods in simulated root canal extensions / 대한치과보존학회지

The aim of this study was to evaluate the effectiveness of sealer placement in simulated root canal extensions. Forty resin blocks were attained from the Endo-training Bloc. In each block, the simulated root canal was made with #20, 08taper GT file. After each block was longitudinally split into two halves, a standardized groove was prepared on one canal wall of two halves to simulate the canal extensions with various irregularities. The two halves of each block were assembled and all simulated root canals were obturated by single cone method with AH26 sealer. Four different methods of sealer placement were used: group A, #20 K-file; group B, ultrasonic file; group C, lentulo spiral; group D, EZ-Fill bi-directional spiral. All obturated blocks were stored in 100% humidity at 37degrees C for 1 week. Using a low speed saw, each block was sectioned horizontally. Images of the sections were taken using a stereomicroscope at x 30 magnification and a digital camera. The amount of the sealer in the groove was evaluated using a scoring system, a higher score indicated better sealing effectiveness. The data was statistically analysed by Fisher's Exact Test. The sealing score was the lowest, specially at the middle area of canal extensions in group A, and that was statistically significant difference from other groups. In conclusion, the ultrasonic file, lentulo spiral and EZ-Fill bi-directional spiral were effective methods of sealer placement in simulated canal extensions. The K file was the least effective method, specially at the middle area of canal extensions.

A Case of Neonatal Alloimmune Thrombocytopenia dut to Anti-HLA A2

Neonatal alloimmune thrombocytopenia(NAIT) is a rare disease caused by maternal alloimmunization against fetal platelet surface antigen, which is mainly platelet specific alloantigen or human leukocyte antigen(HLA). During routine hemotology, we accidentally discovered thrombocytopenia in a female fullterm newborn admitted due to jaundice. We excluded NAIT due to human platelet alloantigen(HPA), because the HPA of the mother and baby were the same on PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism). Mother's serum was tested for lyrnphocytotoxity against 36 donor lymphocytes, and anti-HLA A2, A24 and B58 were found. HLA typing of the father and baby revealed A2 antigen which was not present on the mothers lymphocytes. The patient received concentrated platelet and intravenous globulin. Her platelet count increased to 222,000/mm from 3,000/mm on the 11th day of life. We described a case of NAIT due to anti-HLA A2 antibody with a detailed clinical feature. (J Korean Pediatr Soc 1999;43:861-865)

Clinical Observation on Undescended Testis / 대한비뇨기과학회지

A clinical observation was made on 36 patients of cryptorchidism who had been admitted to the department of Urology, Cho sun University Medical School during the period from January, 1981 to February, 1984. The results were as follows: 1. The cryptorchidism had the highest incidence rate among the anomalies of the genitourinary tract (35%). 2. Age distribution ranged from 20 months to 40 years, and the most frequent age group was 6 to 10 years old. 3. Of the 47 undescended testes, the most popular location was inguinal type in 22 testes(45.8%), and bilateral cryptorchidism were found in 11 cases, right in 18 cases and left in 7 cases. 4, Hormonal therapy was done on 7 cases of bilateral cryptorchidism but only one case was respond with partial descent. 5. Orchiopexy was performed on all the cases of cryptorchidism.

A Case of Inverted Papilloma of Urinary Bladder / 대한비뇨기과학회지

Inverted papilloma of the urinary tract is a unique and uncommon tumor, characterized by an endophytic growth pattern. Recently, we experienced a case of inverted vesical papilloma in a 54-year-old women.