Purpose: A widely distributed cell cycle inhibitor, p27, regulates cyclin-dependent kinase-cyclin complexes. Although the prognostic value of p27 has been established for various types of carcinomas, its role in luminal breast cancer remains poorly understood. This study aimed to explore the functional enrichment of p27 and identify potential drug targets in patients with luminal-type breast cancer. Methods: Clinicopathological data were collected from 868 patients with luminal-type breast cancer. Additionally, publicly available data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset (1,500 patients) and the Gene Expression Omnibus database (855 patients) were included in the analysis. Immunohistochemical staining for p27, differential gene expression analysis, disease ontology analysis, survival prediction modeling using machine learning (ML), and in vitro drug screening were also performed. Results: Low p27 expression correlated with younger age, advanced tumor stage, estrogen receptor/progesterone receptor negativity, decreased cluster of differentiation 8+ T cell count, and poorer survival outcomes in luminal-type breast cancer. The METABRIC data revealed that reduced cyclin-dependent kinase inhibitor 1B (CDKN1B) expression (encoding p27) was associated with cell proliferation-related pathways and epigenetic polycomb repressive complex 2. Using ML, p27 emerged as the second most significant survival factor after N stage, thereby enhancing survival model performance. Additionally, luminal-type breast cancer cell lines with low CDKN1B expression demonstrated increased sensitivity to specific anticancer drugs such as voxtalisib and serdemetan, implying a potential therapeutic synergy between CDKN1B-targeted approaches and these drugs. Conclusion The integration of ML and bioinformatic analyses of p27 has the potential to enhance risk stratification and facilitate personalized treatment strategies for patients with breast cancer.

Purpose: A widely distributed cell cycle inhibitor, p27, regulates cyclin-dependent kinase-cyclin complexes. Although the prognostic value of p27 has been established for various types of carcinomas, its role in luminal breast cancer remains poorly understood. This study aimed to explore the functional enrichment of p27 and identify potential drug targets in patients with luminal-type breast cancer. Methods: Clinicopathological data were collected from 868 patients with luminal-type breast cancer. Additionally, publicly available data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset (1,500 patients) and the Gene Expression Omnibus database (855 patients) were included in the analysis. Immunohistochemical staining for p27, differential gene expression analysis, disease ontology analysis, survival prediction modeling using machine learning (ML), and in vitro drug screening were also performed. Results: Low p27 expression correlated with younger age, advanced tumor stage, estrogen receptor/progesterone receptor negativity, decreased cluster of differentiation 8+ T cell count, and poorer survival outcomes in luminal-type breast cancer. The METABRIC data revealed that reduced cyclin-dependent kinase inhibitor 1B (CDKN1B) expression (encoding p27) was associated with cell proliferation-related pathways and epigenetic polycomb repressive complex 2. Using ML, p27 emerged as the second most significant survival factor after N stage, thereby enhancing survival model performance. Additionally, luminal-type breast cancer cell lines with low CDKN1B expression demonstrated increased sensitivity to specific anticancer drugs such as voxtalisib and serdemetan, implying a potential therapeutic synergy between CDKN1B-targeted approaches and these drugs. Conclusion The integration of ML and bioinformatic analyses of p27 has the potential to enhance risk stratification and facilitate personalized treatment strategies for patients with breast cancer.

Purpose: A widely distributed cell cycle inhibitor, p27, regulates cyclin-dependent kinase-cyclin complexes. Although the prognostic value of p27 has been established for various types of carcinomas, its role in luminal breast cancer remains poorly understood. This study aimed to explore the functional enrichment of p27 and identify potential drug targets in patients with luminal-type breast cancer. Methods: Clinicopathological data were collected from 868 patients with luminal-type breast cancer. Additionally, publicly available data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset (1,500 patients) and the Gene Expression Omnibus database (855 patients) were included in the analysis. Immunohistochemical staining for p27, differential gene expression analysis, disease ontology analysis, survival prediction modeling using machine learning (ML), and in vitro drug screening were also performed. Results: Low p27 expression correlated with younger age, advanced tumor stage, estrogen receptor/progesterone receptor negativity, decreased cluster of differentiation 8+ T cell count, and poorer survival outcomes in luminal-type breast cancer. The METABRIC data revealed that reduced cyclin-dependent kinase inhibitor 1B (CDKN1B) expression (encoding p27) was associated with cell proliferation-related pathways and epigenetic polycomb repressive complex 2. Using ML, p27 emerged as the second most significant survival factor after N stage, thereby enhancing survival model performance. Additionally, luminal-type breast cancer cell lines with low CDKN1B expression demonstrated increased sensitivity to specific anticancer drugs such as voxtalisib and serdemetan, implying a potential therapeutic synergy between CDKN1B-targeted approaches and these drugs. Conclusion The integration of ML and bioinformatic analyses of p27 has the potential to enhance risk stratification and facilitate personalized treatment strategies for patients with breast cancer.

Background: Tumor spread through air spaces (STAS) is a recently discovered risk factor for lung adenocarcinoma (LUAD). The aim of this study was to investigate specific genetic alterations and anticancer immune responses related to STAS. By using a machine learning algorithm and drug screening in lung cancer cell lines, we analyzed the effect of Janus kinase 2 (JAK2) on the survival of patients with LUAD and possible drug candidates. Methods: This study included 566 patients with LUAD corresponding to clinicopathological and genetic data. For analyses of LUAD, we applied gene set enrichment analysis (GSEA), in silico cytometry, pathway network analysis, in vitro drug screening, and gradient boosting machine (GBM) analysis. Results: The patients with STAS had a shorter survival time than those without STAS (P < 0.001). We detected gene set-related downregulation of JAK2 associated with STAS using GSEA. Low JAK2 expression was related to poor prognosis and a low CD8+ T-cell fraction. In GBM, JAK2 showed improved survival prediction performance when it was added to other parameters (T stage, N stage, lymphovascular invasion, pleural invasion, tumor size). In drug screening, mirin, CCT007093, dihydroretenone, and ABT737 suppressed the growth of lung cancer cell lines with low JAK2 expression. Conclusion In LUAD, low JAK2 expression linked to the presence of STAS might serve as an unfavorable prognostic factor. A relationship between JAK2 and CD8+ T cells suggests that STAS is indirectly related to the anticancer immune response. These results may contribute to the design of future experimental research and drug development programs for LUAD with STAS.

PURPOSE: Many studies have proposed predictive models for type 2 diabetes mellitus (T2DM). However, these predictive models have several limitations, such as user convenience and reproducibility. The purpose of this study was to develop a T2DM predictive model using electronic medical records (EMRs) and machine learning and to compare the performance of this model with traditional statistical methods. MATERIALS AND METHODS: In this study, a total of available 8454 patients who had no history of diabetes and were treated at the cardiovascular center of Korea University Guro Hospital were enrolled. All subjects completed 5 years of follow up. The prevalence of T2DM during follow up was 4.78% (404/8454). A total of 28 variables were extracted from the EMRs. In order to verify the cross-validation test according to the prediction model, logistic regression (LR), linear discriminant analysis (LDA), quadratic discriminant analysis (QDA), and K-nearest neighbor (KNN) algorithm models were generated. The LR model was considered as the existing statistical analysis method. RESULTS: All predictive models maintained a change within the standard deviation of area under the curve (AUC) < 0.01 in the analysis after a 10-fold cross-validation test. Among all predictive models, the LR learning model showed the highest prediction performance, with an AUC of 0.78. However, compared to the LR model, the LDA, QDA, and KNN models did not show a statistically significant difference. CONCLUSION: We successfully developed and verified a T2DM prediction system using machine learning and an EMR database, and it predicted the 5-year occurrence of T2DM similarly to with a traditional prediction model. In further study, it is necessary to apply and verify the prediction model through clinical research.
Area Under Curve ; Diabetes Mellitus ; Diabetes Mellitus, Type 2 ; Electronic Health Records ; Follow-Up Studies ; Humans ; Korea ; Learning ; Logistic Models ; Machine Learning ; Methods ; Prevalence

PURPOSE: Angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) are associated with a decreased incidence of new-onset diabetes mellitus (NODM). The aim of this study was to compare the protective effect of ACEI versus ARBs on NODM in an Asian population. MATERIALS AND METHODS: We investigated a total of 2817 patients who did not have diabetes mellitus from January 2004 to September 2009. To adjust for potential confounders, a propensity score matched (PSM) analysis was performed using a logistic regression model. The primary end-point was the cumulative incidence of NODM, which was defined as having a fasting blood glucose > or =126 mg/dL or HbA1c > or =6.5%. Multivariable cox-regression analysis was performed to determine the impact of ACEI versus ARB on the incidence of NODM. RESULTS: Mean follow-up duration was 1839+/-1019 days in all groups before baseline adjustment and 1864+/-1034 days in the PSM group. After PSM (C-statistics=0.731), a total 1024 patients (ACEI group, n=512 and ARB group, n=512) were enrolled for analysis and baseline characteristics were well balanced. After PSM, the cumulative incidence of NODM at 3 years was lower in the ACEI group than the ARB group (2.1% vs. 5.0%, p=0.012). In multivariate analysis, ACEI vs. ARB was an independent predictor of the lower incidence for NODM (odd ratio 0.37, confidence interval 0.17-0.79, p=0.010). CONCLUSION: In the present study, compared with ARB, chronic ACEI administration appeared to be associated with a lower incidence of NODM in a series of Asian cardiovascular patients.
Adult ; Aged ; Angiotensin Receptor Antagonists/*therapeutic use ; Angiotensin-Converting Enzyme Inhibitors/*therapeutic use ; Asian Continental Ancestry Group/*statistics & numerical data ; Blood Glucose/analysis ; Diabetes Mellitus/*diagnosis/*epidemiology ; Dose-Response Relationship, Drug ; Drug Monitoring/methods ; Female ; Follow-Up Studies ; Humans ; Hypertension/*drug therapy ; Incidence ; Kaplan-Meier Estimate ; Logistic Models ; Male ; Middle Aged ; Multivariate Analysis ; Propensity Score ; Republic of Korea/epidemiology ; Risk Factors

Renal artery stenosis may be a cause of hypertension and a potential contributor to progressive renal insufficiency. However, the prevalence of renal artery disease in a general population is poorly defined. The purposes of this study were to evaluate the prevalence of angiographically-determined renal artery narrowing in a patient population undergoing routine cardiac catheterization, and to identify the risk factors for renal artery stenosis. After left ventriculography, abdominal aortography was performed to screen for the presence of renal artery stenosis. A total of 427 patients (274 males, 153 females) were studied and the mean age was 59 years. Renal artery narrowing was identified in 10.5% of patients. Significant (> or = 50% diameter narrowing) renal artery stenosis was found in 24 patients (5.6%) and insignificant stenosis was found in 21 patients (4.9%). Significant unilateral stenosis was present in 4.2% of patients and bilateral stenosis was present in 1.4%. The stem of the renal artery was a more common site of stenosis in 62.2% of patients than in the ostium (37.8%), but the severity of stenosis was not significantly different according to the site of stenosis. By univariate and multivariate logistic regression analysis, the association of clinical variables with renal artery stenosis was assessed. Multivariable predictors included age, hypertension and peripheral vascular disease (p < 0.05). The variables such as sex, smoking history, hyperlipidemia, renal insufficiency, as well as the presence of obesity, severity of coronary heart disease and D.M., were not associated. In conclusion, the prevalence of angiographically-determined renal artery narrowing in a patient population undergoing cardiac catheterization is 10.5%. Old age, hypertension and evidence of peripheral vascular disease represent the predictors of renal artery stenosis.
Adult ; Aged ; Female ; Heart Catheterization* ; Human ; Hypertension/etiology ; Male ; Middle Age ; Multivariate Analysis ; Prevalence ; Renal Artery Obstruction/etiology ; Renal Artery Obstruction/epidemiology* ; Risk Factors

A multicenter prospective study was done in four-university hospital to evaluate the efficacy and safety of cyclosporin A(CyA, Cipol-N(R)) in 64 patients with adult nephrotic syndrome mean age 34.8 years, male:female 2.4:1, duration of disease 38.0+/-40.9months, 31 patients with MCD, 33 patients with Non-MCD (8 FSGS, 14 MGN, 7 MPGN, 2 lupus nephritis, 1 HBsAg associated GN)]. The prior steroid responses of these patients were 17 steroid dependent, 9 frequent relapser, 4 steroid resistant and 1 other in MCD patients, and 5 steroid dependent, 5 frequent relapser, 22 steroid resistant and 1 other in Non-MCD patients. After a 2-week steroid (predni-solon 10mg/day or deflazacort 12mg/day) run-in period, CyA 5mg/kg/day and prednisolone 10mg/day (or deflazacort 12mg/day) were administered for up to 16 weeks. Of the 64 patients enrolled, ll patients were dropped out prematurely due to adverse events or protocol violation. Of the 53 patients who completed the study, 27 had MCD and 26 had Non- MCD. High response (CR and PR) rate of 68% (36/53) were obtained with CyA treatment in all patients. Although the response rate in MCD was significantly higher than that in Non-MCD (89 vs. 46%, p<0.05) and response rates were significantly different according to the previous steroid responses by univariate analysis, only previous steroid responses affected the response to CyA significantly by Logistic multiple regression analysis (p=0.03, RR 7.08); responses were 84% (27/32) in steroid dependent and frequent relapser patients, and 37% (7/19) in steroid resistant patients. 24-hr proteinuria significantly decreased after 2 weeks and serum albumin and cholesteroi increased significantly after 4 weeks of treatment compared to baseline level. The serum creatinine level was not changed during the study. No serious and unexpected side event was observed. In conclusion, cyclosporine therapy is a safe and effective mode of treatment in patients with ne-phrotic syndrome, especially in those who need prolonged administration of steroids with resulting in unavoidable steroid complications such as frequent relapser and steroid dependent type. The patients with steroid resistant type and contraidications of steroid administration such as DM, aseptic bone neerosis etc. can also be candidates for this treatment.
Adult* ; Creatinine ; Cyclosporine* ; Glomerulonephritis, Membranoproliferative ; Hepatitis B Surface Antigens ; Humans ; Lupus Nephritis ; Nephrotic Syndrome ; Prednisolone ; Prospective Studies ; Proteinuria ; Serum Albumin ; Steroids

The most widely used method for treatment of secondary hyperparathyroidism(SH) in CAPD patients has been the administration of calcitriol by oral route. In this study, we compared the efficacy and safety of daily low dose calcitriol therapy with those of intermittent high dose pulse therapy. The study group consisted of 38 patients undergoing CAPD with serum intact PTH level of more than 200pg/ mL. Twenty patients were randomly administered daily low dose calcitriol(0.25 microgram/day for 1 month followed by 0.5 microgram daily dose for the next 3 mon-ths) while 18 patients were given intermittent pulse therapy (0.5 microgram-0.5 microgram-0.75 microgram 3 times a week for 1 month, increased to 1.0 microgram-1.25 microgram-1.25 microgram 3 times a week for the next 3 months). Thirty five patients completed the study : 17 on daily oral calcitriol (M: F=0.7:1, mean age=47.3+/-10.6 years, mean duration of CAPD=48.9+/-41.1 months), and 18 on oral pulse calcitriol (M:F=1.6:1, mean age=41.5+/-12.7 years, mean duration of CAPD=49.2+/-41.6 months). The baseline serum levels of calcium, phosphorus, i-PTH, alkaline phosphatase, and total CO2 were not different between daily and pulse group(9.5+/-0.8 vs 9.3+/-0.9mg/dL, 5.8+/-1.3 vs 5.1+/-1.2mg/dL, 443.1+/-162.5 vs 546+/-385.9pg/mL, 91.8+/-47.7 vs 108.9+/-66.5IU/L, 23.7+/-1.9 vs 25.5+/-2.0mEq/L, p>0.05, respectively). The i-PTH level decreased significantly in daily calcitriol group after 1 month (332.8+/-214.8pg/mL, p<0.01), and at final evaluation (180.4+/-254.8pg/mL, p<0.01). In pulse calcitriol group, i-PTH level also decreased significantly to 400,4+/-225.8pg/mL(p<0.05), 89.4+/-122.6 pg/mL(p<0.01), respectively. The rate of decline in i-PTH level from baseline were similar(daily=25.4+/-22.7 vs pulse=19.5+/-12.6%decline/month, p>0.05). The serum calcium increased similarly in both groups after treatment (daily=10.6+/-0.8 vs pulse=l0.1+/-1.0mg/dL, p>0.05). Hypercalcemia(>11.0mg/dL) was rarely observed in all patients (daily=5, pulse=8 episodes). In conclusion, both daily and pulse calcitriol therapy were similarly effective and safe in control of SH.
Alkaline Phosphatase ; Calcitriol* ; Calcium ; Humans ; Hyperparathyroidism, Secondary* ; Peritoneal Dialysis* ; Peritoneal Dialysis, Continuous Ambulatory ; Phosphorus

Calcitriol therapy is an important treatment for the prevention and control of secondary hyperparathyroidism in continuous ambulatory peritoneal dialysis (CAPD) patients. However, this often has been limited by the associated hypercalcemia and hyperphosphatemia due to increase in intestinal calcium and phosphorus absorption. Many studies reported that these limitations could be avoided by changing routes, frequency and dose of calcitriol treatment. But, there are still controversy about each methods and the results on the PTH response to conventional calcitriol treatment in CAPD patients. This study was performed to evaluate the factors affecting the response to oral calcitriol in CAPD patients. A retrospective study was done in 92 CAPD patients with secondary hyperparathyroidism(intact PTH level >200pg/ml) on oral calcitriol treatment. After baseline study of serum calcium, phosphorus, alkaline phosphatase, BUN, creatinine and intact PTH, calcitriol therapy was begun via oral rou- te, daily. Serum calcium, phosphorus, alkaline phosphatase, BUN, creatinine, intact FI'H and other bio- chemical markers were checked at 3 month, 6 month after treatment. Parathyroid gland ultrasonography was performed to detect parathyroid hypertrophy and nodule and to measure the diameter of parathymid gland. All the patients were divided into two groups according to percent reduetion of i-PTH(initial PTH PTH after 3, 6 months)X100/initial PTH(%),deltaPTH during oral calcitriol therapy for 3 and 6 months(group I ; delta PTH >30%, group II ; delta PTH <30%). RESULT: 1) All 92 patients(mean age 46.5 11.3yr, M: F 45: 47, mean CAPD duration 51.3 39.4 months) were administered oral calcitriol, daily. Mean calcitriol dose during 3 month was 0.43 0.22Mg and during 6month 0.43 0.24Mg. 2) After 3-month treament, there were significant differences in initial i-PTH, the diameter of parathyroid gland, initial phosphorus, intial total alkaline phosphatase and duration of CAPD between group I and II(406.7+/-196.5 vs. 871.0+/-478Apglml, 6.2+/-2.6 vs. 13.1+/-5.2mm, 5.0+/-1.3 vs. 5.7+/-1.3mg/dl, 93.7+/-4L1 vs. 171.9+/-137.6IU/L, 40.1+/-34.9 vs. 73.5+/-37.8months, p< 0.05, respectively). 4) After 6-month treament, there were significant differences in initial i-PTH, the diameter of parathyroid gland, intial total alkaline phosphatase and duration of CAPD between group I and II(474.1+/-266.6 vs. 889.7+/-485.4pg/ml, 6.4+/-2.7 vs. 14.5+/-5.1mm, 107.9+/-80.1 vs. 180.7+/-121.5IU/L, 40.5+/- 32.9 vs. 81.8+/-35.3months, p<0.05, respectively). 5) The significant negative correlation was shown between deltaPTH and the duration of peritoneal dialysis, the diameter of parathyroid gland, initial PTH level and PTH response during 3-month and 6-month oral calcitriol treatment. The response to oral calcitriol was poor when i-PTH level more than 500pg/ml(kappa 0.429, p value <0.01), the diameter of parathyroid gland more than 10.0mm(kappa 0.641, p value<0.01), the duration of CAPD more than 55months(kappa 0.524, p value< 0.01). These data suggested that initial i-PTH level, the diameter of parathyroid gland size and the duration of CAPD were independent risk factors of the poor response to oral calcitriol therapy in CAPD patients with secondary hyperparathyroidism.
Absorption ; Alkaline Phosphatase ; Calcitriol* ; Calcium ; Creatinine ; Humans ; Hypercalcemia ; Hyperparathyroidism, Secondary* ; Hyperphosphatemia ; Hypertrophy ; Parathyroid Glands ; Peritoneal Dialysis ; Peritoneal Dialysis, Continuous Ambulatory* ; Phosphorus ; Retrospective Studies ; Risk Factors ; Ultrasonography