Assessing the Benefits and Harms of Pharmacotherapy in Older Adults with Frailty: Insights from Pharmacoepidemiologic Studies of Routine Health Care Data.

The objective of this review is to summarize and appraise the research methodology, emerging findings, and future directions in pharmacoepidemiologic studies assessing the benefits and harms of pharmacotherapies in older adults with different levels of frailty. Older adults living with frailty are at elevated risk for poor health outcomes and adverse effects from pharmacotherapy. However, current evidence is limited due to the under-enrollment of frail older adults and the lack of validated frailty assessments in clinical trials. Recent advancements in measuring frailty in administrative claims and electronic health records (database-derived frailty scores) have enabled researchers to identify patients with frailty and to evaluate the heterogeneity of treatment effects by patients' frailty levels using routine health care data. When selecting a database-derived frailty score, researchers must consider the type of data (e.g., different coding systems), the length of the predictor assessment period, the extent of validation against clinically validated frailty measures, and the possibility of surveillance bias arising from unequal access to care. We reviewed 13 pharmacoepidemiologic studies published on PubMed from 2013 to 2023 that evaluated the benefits and harms of cardiovascular medications, diabetes medications, anti-neoplastic agents, antipsychotic medications, and vaccines by frailty levels. These studies suggest that, while greater frailty is positively associated with adverse treatment outcomes, older adults with frailty can still benefit from pharmacotherapy. Therefore, we recommend routine frailty subgroup analyses in pharmacoepidemiologic studies. Despite data and design limitations, the findings from such studies may be informative to tailor pharmacotherapy for older adults across the frailty spectrum.

Postoperative use of sleep aids and delirium in older adults after major surgery: A retrospective cohort study.

BACKGROUND: Sleep aids are commonly prescribed to treat sleep disturbance, a modifiable risk factor for postoperative delirium in older patients. The use of melatonin receptor agonists in the postoperative period has been increasing. The comparative safety of melatonin receptor agonists, zolpidem, and temazepam remains uncertain. METHODS: This retrospective study included 22,083 patients ≥65 years old who initiated melatonin receptor agonists, zolpidem, or temazepam after major surgery in the Premier Healthcare Database 2009-2018. We performed propensity score-based overlap weighting and estimated the risk ratio (RR) and risk difference (RD) of postoperative delirium as the primary outcome and a composite of delirium or new antipsychotic initiation, pneumonia, and in-hospital mortality as secondary outcomes. RESULTS: The mean age of the study population was 78 (SD, 7) years and 50% were female. There was no significant difference in the risk of postoperative delirium among patients treated with melatonin receptor agonists (3.4%, reference group), zolpidem (2.9%; RR [95% CI], 0.9 [0.7-1.2]; RD [95% CI] per 100 persons, -0.3 [-1.1 to 0.6]), and temazepam (3.1%; 0.9 [0.7-1.1]; RD [95% CI] per 100 persons, -0.5 [-1.2 to 0.3]). The risks of delirium or new antipsychotic initiation, pneumonia, and in-hospital mortality were also similar among all groups. CONCLUSIONS: Melatonin receptor agonists were not associated with a lower risk of postoperative delirium and other adverse outcomes compared with zolpidem and temazepam in older adults after major surgery.

Epoxidation of perillyl alcohol by engineered bacterial cytochrome P450 BM3.

Perillyl alcohol (POH) is a secondary metabolite of plants. POH and its derivatives are known to be effective as an anticancer treatment. In this study, oxidative derivatives of POH, which are difficult to synthesize chemically, were synthesized using the engineered bacterial cytochrome P450 BM3 (CYP102A1) as a biocatalyst. The activity of wild-type (WT) CYP102A1 and 29 engineered enzymes toward POH was screened using a high-performance liquid chromatography. They produced one major product. Among them, the engineered CYP102A1 M601 mutant with seven mutations (R47L/F81I/F87V/E143G/L150F/L188Q/E267V) showed the highest conversion, 6.4-fold higher than the WT. Structure modeling using AlphFold2 and PyMoL suggests that mutations near the water channel may be responsible for the increased catalytic activity of the M601 mutant. The major product was identified as a POH-8,9-epoxide by gas chromatography-mass spectrometry and nuclear magnetic resonance analysis. The optimal temperature and pH for the product formation were 35 °C and pH 7.4, respectively. The kcat and Km of M601 were 540 min-1 and 2.77 mM, respectively. To improve POH-8,9-epoxide production, substrate concentration and reaction time were optimized. The optimal condition for POH-8,9-epoxide production by M601 was 5.0 mM POH, pH 7.4, 35 ℃, and 6 h reaction, which produced the highest concentration of 1.72 mM. Therefore, the biosynthesis of POH-8,9-epoxide using M601 as a biocatalyst is suggested to be an efficient and sustainable synthetic process that can be applied to chemical and pharmaceutical industries.

Impact of peri-operative frailty and operative stress on post-discharge mortality, readmission and days at home in Medicare beneficiaries.

BACKGROUND: Understanding how patients' frailty and the physiological stress of surgical procedures affect postoperative outcomes may inform risk stratification of older patients undergoing surgery. The objective of the study was to examine the association of peri-operative frailty with mortality, 30-day readmission and days at home after non-cardiac surgical procedures of different physiological stress. METHODS: This retrospective study used Medicare claims data from a 7.125% random sample of Medicare fee-for-service beneficiaries from 2015 to 2019 who were aged ≥ 65 years and underwent non-cardiac surgical procedure listed in the Operative Stress Score categories. The exposure of the study was claims-based frailty index (robust, < 0.15; pre-frail, 0.15 to < 0.25; mildly frail, 0.25 to < 0.35; and moderate-to-severely frail, ≥ 0.35) with Operative Stress Score categories being 1, very low stress to 5, very high stress. The primary outcome was all-cause mortality at 30 days and 365 days after the surgical procedure. RESULTS: In total, 1,019,938 patients (mean (SD) age of 76.1 (7.3) years; 52.3% female; 16.8% frail) were included. The cumulative incidence of mortality generally increased with Operative Stress Score category, ranging from 5.0% (Operative Stress Score 2) to 24.9% (Operative Stress Score 4) at 365 days. Within each category, increasing frailty was associated with mortality at 30 days (hazard ratio comparing moderate-to-severe frailty vs. robust ranged from 1.59-3.91) and at 365 days (hazard ratio 1.30-4.04). The variation in postoperative outcomes by patients' frailty level was much greater than the variation by the operative stress category. CONCLUSIONS: These results emphasise routine frailty screening before major and minor non-cardiac procedures and the need for greater clinician awareness of postoperative outcomes beyond 30 days in shared decision-making with older adults with frailty.

Trends in use of antipsychotics and psychoactive drugs in older patients after major surgery.

BACKGROUND: Professional society guidelines recommend limiting the use of antipsychotics in older patients with postoperative delirium. How these recommendations affected the use of antipsychotics and other psychoactive drugs in the postoperative period has not been studied. METHODS: This retrospective cohort study included patients 65 years or older without psychiatric diagnoses who underwent major surgery in community hospitals (CHs) and academic medical centers (AMCs) in the United States. The outcome was the rate of hospital days exposed to antipsychotics, antidepressants, antiepileptics, benzodiazepines, hypnotics, and selective alpha-2 receptor agonist dexmedetomidine in the postoperative period by hospital type. RESULTS: The study included 4,098,431 surgical admissions from CHs (mean age 75.0 [standard deviation, 7.1] years; 50.8% female) during 2008-2018 and 2,310,529 surgical admissions from AMCs (75.0 [7.4] years; 49.4% female) during 2009-2018. In the intensive care unit (ICU) setting, the number of exposed days per 1000 hospital-days declined for haloperidol (CHs: 33-21 days [p < 0.01]; AMCs: 24-15 days [p < 0.01]) and benzodiazepines (CHs: 261-136 days [p < 0.01]; AMCs: 150-77 days [p < 0.01]). The use of atypical antipsychotics, antidepressants, antiepileptics, and dexmedetomidine increased, while hypnotic use varied by the hospital type. In the non-ICU setting, the rate declined for haloperidol in CHs but not in AMCs (CHs: 10-6 days [p < 0.01]; AMCs: 4-3 days [p = 0.52]) and for benzodiazepines in both settings (CHs: 126-56 days [p < 0.01]; AMCs: 30-27 days [p < 0.01]). The use of antiepileptics and antidepressants increased, while the use of atypical antipsychotics and hypnotics varied by the hospital type. CONCLUSIONS: The use of haloperidol and benzodiazepines in the postoperative period declined at both CHs and AMCs. These trends coincided with the increasing use of other psychoactive drugs.

Comparative Safety Analysis of Oral Antipsychotics for In-Hospital Adverse Clinical Events in Older Adults After Major Surgery : A Nationwide Cohort Study.

BACKGROUND: Antipsychotics are commonly used to manage postoperative delirium. Recent studies reported that haloperidol use has declined, and atypical antipsychotic use has increased over time. OBJECTIVE: To compare the risk for in-hospital adverse events associated with oral haloperidol, olanzapine, quetiapine, and risperidone in older patients after major surgery. DESIGN: Retrospective cohort study. SETTING: U.S. hospitals in the Premier Healthcare Database. PATIENTS: 17 115 patients aged 65 years and older without psychiatric disorders who were prescribed an oral antipsychotic drug after major surgery from 2009 to 2018. INTERVENTIONS: Haloperidol (≤4 mg on the day of initiation), olanzapine (≤10 mg), quetiapine (≤150 mg), and risperidone (≤4 mg). MEASUREMENTS: The risk ratios (RRs) for in-hospital death, cardiac arrhythmia events, pneumonia, and stroke or transient ischemic attack (TIA) were estimated after propensity score overlap weighting. RESULTS: The weighted population had a mean age of 79.6 years, was 60.5% female, and had in-hospital death of 3.1%. Among the 4 antipsychotics, quetiapine was the most prescribed (53.0% of total exposure). There was no statistically significant difference in the risk for in-hospital death among patients treated with haloperidol (3.7%, reference group), olanzapine (2.8%; RR, 0.74 [95% CI, 0.42 to 1.27]), quetiapine (2.6%; RR, 0.70 [CI, 0.47 to 1.04]), and risperidone (3.3%; RR, 0.90 [CI, 0.53 to 1.41]). The risk for nonfatal clinical events ranged from 2.0% to 2.6% for a cardiac arrhythmia event, 4.2% to 4.6% for pneumonia, and 0.6% to 1.2% for stroke or TIA, with no statistically significant differences by treatment group. LIMITATION: Residual confounding by delirium severity; lack of untreated group; restriction to oral low-to-moderate dose treatment. CONCLUSION: These results suggest that atypical antipsychotics and haloperidol have similar rates of in-hospital adverse clinical events in older patients with postoperative delirium who receive an oral low-to-moderate dose antipsychotic drug. PRIMARY FUNDING SOURCE: National Institute on Aging.

Factors associated with recurrent appendicitis after nonoperative management.

BACKGROUND: The objective of this study is to identify predictors for recurrent appendicitis in patients with appendicitis previously treated nonoperatively. METHODS: This is a prospective cohort study of all adult patients with appendicitis treated at a tertiary care hospital. Patient demographics, radiographic information, management, and clinical outcomes were recorded. The primary outcome was recurrent appendicitis within 6 months after discharge from the index admission. Given the competing risk of interval appendectomy, a time-to-event competing-risk analysis was performed. RESULTS: Of the 699 patients presenting with appendicitis, 74 were treated nonoperatively (35 [47%] were women; median [IQR] age, 48 [33,64] years), and 21 patients (29%) had recurrent appendicitis. On univariate and multivariate analysis, presence of an appendicolith on imaging was the only factor associated with a higher risk of recurrent appendicitis (p = 0.02). CONCLUSIONS: The presence of appendicolith was associated with an increased risk of developing recurrent appendicitis within 6 months.

Total Knee Replacement After Arthroscopic Meniscectomy in Knee Osteoarthritis: A Nationwide Population-Based Cohort Study.

BACKGROUND: Recent studies raise concerns that arthroscopic meniscectomy (AM) for degenerative tear may be detrimental to the maintenance of the joint structure. This study was performed to examine the rate of total knee replacement (TKR) among patients with knee osteoarthritis (OA) who underwent AM for meniscal tears and compare this rate with those who did not. METHODS: A retrospective cohort study was conducted using the National Health Insurance Database of South Korea. Among knee OA patients aged 50-79, those who were treated with AM due to meniscal damage from 2007 to 2009 were selected as the AM group while those not treated with AM despite the presence of meniscal damage were selected as control group. Both were matched based on a propensity score and followed-up until the earliest occurrence of: TKR, death, or 10 years. Cox proportional hazards models were used to compare the outcome. RESULTS: A total of 36,974 patients were included in AM groups and non-AM group after 1:1 matching. TKR occurred in 9.62% and 7.64% in AM and non-AM groups with the average duration after meniscectomy of 5.88 ± 2.77 and 5.50 ± 2.94 years, respectively. After adjustment for baseline confounders, the TKR rate in the AM group was calculated to be 25% higher than that in the non-AM group (subdistribution hazard ratio, 1.25; 95% confidence interval, 1.16-1.34). The mortality rate was 5.20%, which did not significantly differ between groups. CONCLUSION: OA patients who underwent AM for the meniscal injury had higher incidence of TKR up to 10 years of follow-up than the non-operated group. The greater TKR utilization observed in patients undergoing AM merits caution when treating OA patients with meniscal injury.

Perioperative Gabapentin Use and In-Hospital Adverse Clinical Events Among Older Adults After Major Surgery.

Importance: Gabapentin has been increasingly used as part of a multimodal analgesia regimen to reduce opioid use in perioperative pain management. However, the safety of perioperative gabapentin use among older patients remains uncertain. Objective: To examine in-hospital adverse clinical events associated with perioperative gabapentin use among older patients undergoing major surgery. Design, Setting, and Participants: This retrospective cohort study using data from the Premier Healthcare Database included patients aged 65 years or older who underwent major surgery at US hospitals within 7 days of hospital admission from January 1, 2009, to March 31, 2018, and did not use gabapentin before surgery. Data were analyzed from June 14, 2021, to May 23, 2022. Exposures: Gabapentin use within 2 days after surgery. Main Outcomes and Measures: The primary outcome was delirium, identified using diagnosis codes, and secondary outcomes were new antipsychotic use, pneumonia, and in-hospital death between postoperative day 3 and hospital discharge. To reduce confounding, 1:1 propensity score matching was performed. Risk ratios (RRs) and risk differences (RDs) with 95% CIs were estimated. Results: Among 967 547 patients before propensity score matching (mean [SD] age, 76.2 [7.4] years; 59.6% female), the rate of perioperative gabapentin use was 12.3% (119 087 patients). After propensity score matching, 237 872 (118 936 pairs) gabapentin users and nonusers (mean [SD] age, 74.5 [6.7] years; 62.7% female) were identified. Compared with nonusers, gabapentin users had increased risk of delirium (4040 [3.4%] vs 3148 [2.6%]; RR, 1.28 [95% CI, 1.23-1.34]; RD, 0.75 [95% CI, 0.75 [0.61-0.89] per 100 persons), new antipsychotic use (944 [0.8%] vs 805 [0.7%]; RR, 1.17 [95% CI, 1.07-1.29]; RD, 0.12 [95% CI, 0.05-0.19] per 100 persons), and pneumonia (1521 [1.3%] vs 1368 [1.2%]; RR, 1.11 [95% CI, 1.03-1.20]; RD, 0.13 [95% CI, 0.04-0.22] per 100 persons), but there was no difference in in-hospital death (362 [0.3%] vs 354 [0.2%]; RR, 1.02 [95% CI, 0.88-1.18]; RD, 0.00 [95% CI, -0.04 to 0.05] per 100 persons). Risk of delirium among gabapentin users was greater in subgroups with high comorbidity burden than in those with low comorbidity burden (combined comorbidity index <4 vs ≥4: RR, 1.20 [95% CI, 1.13-1.27] vs 1.40 [95% CI, 1.30-1.51]; RD, 0.41 [95% CI, 0.28-0.53] vs 2.66 [95% CI, 2.08-3.24] per 100 persons) and chronic kidney disease (absence vs presence: RR, 1.26 [95% CI, 1.19-1.33] vs 1.38 [95% CI, 1.27-1.49]; RD, 0.56 [95% CI, 0.42-0.69] vs 1.97 [95% CI, 1.49-2.46] per 100 persons). Conclusion and Relevance: In this cohort study, perioperative gabapentin use was associated with increased risk of delirium, new antipsychotic use, and pneumonia among older patients after major surgery. These results suggest careful risk-benefit assessment before prescribing gabapentin for perioperative pain management.

BAP1 functions as a tumor promoter in prostate cancer cells through EMT regulation.

BRCA1-associated protein 1 (BAP1) is a deubiquitinating enzyme that has long been considered to be a tumor suppressor in various tumors, including renal cell carcinoma, uveal melanoma, mesothelioma, and cutaneous melanoma. However, the involvement of BAP1 in the progression of prostate cancer has not been studied until recently. Herein, we investigated the tumor promoting function of BAP1 in the context of prostate cancer. Analysis of The Cancer Genome Atlas (TCGA) data set showed that prostate cancer patients express high levels of BAP1 mRNA. High BAP1 expression is inversely correlated with disease-free survival in patients with prostate cancer. Among the prostate cell lines tested, BAP1 expression was high in tumorigenic and metastatic cell lines, but was low in normal prostate cell line. Knockdown of BAP1 in PC3 or DU145 cells induced mesenchymal-to-epithelial transition (MET). Further, BAP1-knockdown resulted in decreased migration and invasion of PC3 and DU145 cells. Conversely, overexpression of BAP1 in RWPE1, a normal prostate cell line, induced the migratory and invasive properties. Collectively, our findings identified that BAP1 has a tumor promoting function in prostate cancer cells, and suggest that BAP1 can serve as a potential therapeutic target for prostate cancer.

USP7 deubiquitinates and stabilizes EZH2 in prostate cancer cells.

Regulation of target proteins by the ubiquitin-proteasome system (UPS) is common in a wide range of cellular events, including transcriptional regulation, cell cycle progression, differentiation, and tumorigenesis. Ubiquitin-specific protease 7 (USP7) has been implicated in tumor development and metastasis in various malignancies through the regulation of target protein stability. In this study, we found that the enhancer of zeste homolog 2 (EZH2), which catalyzes the methylation at lysine 27 of histone H3, is a target of USP7 and is stabilized by USP7-mediated deubiquitination. In prostate cancer cells, the transcriptional repression function of EZH2 was inhibited by USP7-knockdown. Furthermore, ectopic introduction of EZH2 restored the cell migration, invasion, and sphere-forming potential of prostate cancer cells, which had been decreased by USP7-knockdown. Moreover, combined treatment with the USP7-specific inhibitor P5091 and EZH2 inhibitors, such as GSK126, EPZ6438, and DZNep, induced synergistic inhibitory effects on cell migration, invasion, and sphere-forming potential in prostate cancer cells. Collectively, our findings revealed that the promotion of the malignancy-associated characteristics of prostate cancer cells by USP7 was in part due to EZH2 stabilization. Thus, we suggest that simultaneous treatment with a USP7 inhibitor and an EZH2 inhibitor could be a rational strategy for treating EZH2-dependent cancers.

USP44 Promotes the Tumorigenesis of Prostate Cancer Cells through EZH2 Protein Stabilization.

Ubiquitin-specific protease 44 (USP44) has been implicated in tumor progression and metastasis across various tumors. However, the function of USP44 in prostate cancers and regulatory mechanism of histone-modifying enzymes by USP44 in tumors is not well-understood. Here, we found that enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 methyltransferase, is regulated by USP44. We showed that EZH2 is a novel target of USP44 and that the protein stability of EZH2 is upregulated by USP44-mediated deubiquitination. In USP44 knockdown prostate cancer cells, the EZH2 protein level and its gene silencing activity were decreased. Furthermore, USP44 knockdown inhibited the tumorigenic characteristics and cancer stem cell-like behaviors of prostate cancer cells. Inhibition of tumorigenesis caused by USP44 knockdown was recovered by ectopic introduction of EZH2. Additionally, USP44 regulates the protein stability of oncogenic EZH2 mutants. Taken together, our results suggest that USP44 promotes the tumorigenesis of prostate cancer cells partly by stabilizing EZH2 and that USP44 is a viable therapeutic target for treating EZH2-dependent cancers.

Current status of endoscopic submucosal dissection for early gastric cancer in Korea: role and benefits.

BACKGROUND/AIMS: This study was aimed to investigate the current clinical status of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) in Korea based on a National Health Insurance (NHI) database between 2011 and 2014. METHODS: The claims data of ESD for EGC in Korean NHI were reviewed using material codes of Health Insurance Review and Assessment Service between November 2011 and December 2014. The current clinical status was analyzed in terms of treatment pattern, in-hospital length of stay (LOS), total medical costs, and en bloc resection rate according to the hospital type. RESULTS: A total of 23,828 cases of ESD for EGC were evaluated. ESD was performed in 67.4% of cases in tertiary care hospitals, 31.8% in general hospitals, and 0.8% in hospitals, respectively. The median LOS was 5 days, and total median medical costs was approximately 1,300 US dollars. En bloc resection rate was 99%; 8.5% of cases underwent additional treatment within 90 days ESD, and 5.5% in 91 to 365 days after ESD. The clinical status was not significantly different according to the year and hospital type. CONCLUSION: A majority of ESD for EGC were performed in tertiary care hospitals in Korea. The clinical status showed excellent clinical outcomes and did not differ by the year and between the types of hospitals in Korea.

Long-Term Clinical Outcomes of Endoscopic Submucosal Dissection in Patients with Early Gastric Cancer: A Prospective Multicenter Cohort Study.

Background/Aims: Endoscopic submucosal dissection (ESD) has been regarded as a curative treatment for early gastric cancer (EGC) in indicated cases. The aim of this study was to evaluate the nationwide long-term clinical outcomes of ESD for EGC in Korea. Methods: A prospective multicenter cohort study was performed to evaluate the long-term efficacy of ESD for EGC within pre-defined indications at 12 institutes in Korea. The cases that met the expanded criteria upon pathological review after ESD were followed for 5 years. The primary outcome was 5-year disease specific free survival. Results: Six hundred ninety-seven patients with 722 EGCs treated with ESD were prospectively enrolled and followed for 5 years. Complete resection was achieved in 81.3% of the cases, and curative resection was achieved in 86.1%. During the 5-year follow-up, the overall survival rate was 96.6%, and the disease specific free survival rate was 90.6%. Local recurrence developed in 0.9%, and metachronous tumor development occurred in 7.8%; both conditions were treated by endoscopic or surgical treatment. Distant metastasis developed in 0.5% during follow-up. Conclusions: ESD showed excellent long-term clinical outcomes and can be accepted as a curative treatment for patients with EGC who meet the expanded criteria in final pathology studies.

Structural and biochemical analyses reveal ubiquitin C-terminal hydrolase-L1 as a specific client of the peroxiredoxin II chaperone.

Peroxiredoxins (Prxs) play dual roles as both thiol-peroxidases and molecular chaperones. Peroxidase activity enables various intracellular functions, however, the physiological roles of Prxs as chaperones are not well established. To study the chaperoning function of Prx, we previously sought to identify heat-induced Prx-binding proteins as the clients of a Prx chaperone. By using His-tagged Prx I as a bait, we separated ubiquitin C-terminal hydrolase-L1 (UCH-L1) as a heat-induced Prx I binding protein from rat brain crude extracts. Protein complex immunoprecipitation with HeLa cell lysates revealed that both Prx I and Prx II interact with UCH-L1. However, Prx II interacted considerably more favorably with UCH-L1 than Prx I. Prx II exhibited more effective molecular chaperone activity than Prx I when UCH-L1 was the client. Prx II interacted with UCH-L1 through its C-terminal region to protect UCH-L1 from thermal or oxidative inactivation. We found that chaperoning via interaction through C-terminal region (specific-client chaperoning) is more efficient than that involving oligomeric structural change (general-client chaperoning). Prx II binds either thermally or oxidatively unfolding early intermediates of specific clients and thereby shifted the equilibrium towards their native state. We conclude that this chaperoning mechanism provides a very effective and selective chaperoning activity.

Anticancer activity of a novel small molecule tubulin inhibitor STK899704.

We have identified the small molecule STK899704 as a structurally novel tubulin inhibitor. STK899704 suppressed the proliferation of cancer cell lines from various origins with IC50 values ranging from 0.2 to 1.0 µM. STK899704 prevented the polymerization of purified tubulin in vitro and also depolymerized microtubule in cultured cells leading to mitotic arrest, associated with increased Cdc25C phosphorylation and the accumulation of both cyclin B1 and polo-like kinase 1 (Plk1), and apoptosis. Unlike many anticancer drugs such as Taxol and doxorubicin, STK899704 effectively displayed antiproliferative activity against multidrug-resistant cancer cell lines. The proposed binding mode of STK899704 is at the interface between αß-tubulin heterodimer overlapping with the colchicine-binding site. Our in vivo carcinogenesis model further showed that STK 899704 is potent in both the prevention and regression of tumors, remarkably reducing the number and volume of skin tumor by STK899704 treatment. Moreover, it was significant to note that the efficacy of STK899704 was surprisingly comparable to 5-fluorouracil, a widely used anticancer therapeutic. Thus, our results demonstrate the potential of STK899704 to be developed as an anticancer chemotherapeutic and an alternative candidate for existing therapies.

Association between metformin use and mortality in patients with type 2 diabetes mellitus and localized resectable pancreatic cancer: a nationwide population-based study in korea.

BACKGROUND: Preclinical studies support an antitumor effect of metformin. However, clinical studies have conflicting results and metformin's effect remains controversial. The aim of this study was to evaluate metformin's effect on clinical outcomes in diabetic patients with pancreatic cancer treated with curative resection. RESULTS: A total of 764 patients underwent curative resection, met none of the exclusion criteria, and were prescribed oral hypoglycemic agents. The cancer-specific survival (5-year, 31.9% vs. 22.2%, p < 0.001) was significantly higher in the 530 metformin users than in the 234 diabetic metformin non-users. After multivariable adjustments, metformin users had significantly lower cancer-specific mortality as compared with metformin non-users (hazard ratio, 0.727; 95% confidence interval, 0.611-0.868). Cubic spline regression analysis demonstrated significantly decreased cancer-specific mortality with increasing dose of metformin (p = 0.0047). MATERIALS AND METHODS: Data were provided from the Korea Central Cancer Registry and the National Health Insurance Service in the Republic of Korea. The study cohort consisted of 28,862 patients newly diagnosed with pancreatic cancer between 2005 and 2011. Metformin exposure was determined from prescription information from 6 months before the first diagnosis of pancreatic cancer to last follow-up. The main outcome was cancer-specific survival. CONCLUSIONS: This large study indicates that metformin might decrease cancer-specific mortality rates in localized resectable pancreatic cancer patients with pre-existing diabetes, independently of other factors, with a dose-response relationship.

Association between Metformin Use and Survival in Nonmetastatic Rectal Cancer Treated with a Curative Resection: A Nationwide Population Study.

PURPOSE: Metformin is associated with an anticancer effect. However, the effects of metformin in rectal cancer are controversial. This study investigated the impact of metformin on the survival of patients with diabetes mellitus and nonmetastatic rectal cancer who underwent curative surgery. MATERIALS AND METHODS: The database was provided by the Korea Center Cancer Registry and National Health Insurance Service of the Republic of Korea. A cohort of patients with newly diagnosed rectal cancer between 2005 and 2011 was identified. Drug exposure was defined as receiving the oral hypoglycemic agent for at least 90 days over the period from 6 months before the initial diagnosis of rectal cancer to the last follow-up. RESULTS: A total of 4,503 patients were prescribed oral hypoglycemic agents and classified as the diabetic group, of which 3,694 patients received metformin for at least 90 days. Unadjusted analyses showed a significantly higher overall survival (hazard ratio, 0.596; 95% confidence interval, 0.506 to 0.702) and rectal cancer-specific survival (hazard ratio, 0.621; 95% confidence interval, 0.507 to 0.760) in the metformin group than in the nonmetformin group. The adjusted overall survival (hazard ratio, 0.631; 95% confidence interval, 0.527 to 0.755) and cancer-specific survival (hazard ratio, 0.598; 95% confidence interval, 0.479 to 0.746) in the group with a medication possession ratio of 80% or greater was significantly higher than in the group with a medication possession ratio of less than 80%. CONCLUSION: Metformin use is associated with overall and cancer-specific survival in diabetic patients with a nonmetastatic rectal cancer treated with a curative resection.

Ginsenoside Re Promotes Osteoblast Differentiation in Mouse Osteoblast Precursor MC3T3-E1 Cells and a Zebrafish Model.

Bone homeostasis is tightly regulated to balance bone formation and bone resorption. Many anabolic drugs are used as bone-targeted therapeutic agents for the promotion of osteoblast-mediated bone formation or inhibition of osteoclast-mediated bone resorption. Previous studies showed that ginsenoside Re has the effect of the suppression of osteoclast differentiation in mouse bone-marrow derived macrophages and zebrafish. Herein, we investigated whether ginsenoside Re affects osteoblast differentiation and mineralization in in vitro and in vivo models. Mouse osteoblast precursor MC3T3-E1 cells were used to investigate cell viability, alkaline phosphatase (ALP) activity, and mineralization. In addition, we examined osteoblastic signaling pathways. Ginsenoside Re affected ALP activity without cytotoxicity, and we also observed the stimulation of osteoblast differentiation through the activation of osteoblast markers including runt-related transcription factor 2, type 1 collagen, ALP, and osteocalcin in MC3T3-E1 cells. Moreover, Alizarin red S staining indicated that ginsenoside Re increased osteoblast mineralization in MC3T3-E1 cells and zebrafish scales compared to controls. These results suggest that ginsenoside Re promotes osteoblast differentiation as well as inhibits osteoclast differentiation, and it could be a potential therapeutic agent for bone diseases.

Ginsenoside Re Inhibits Osteoclast Differentiation in Mouse Bone Marrow-Derived Macrophages and Zebrafish Scale Model.

Ginsenosides, which are the active materials of ginseng, have biological functions that include anti-osteoporotic effects. Aqueous ginseng extract inhibits osteoclast differentiation induced by receptor activator of NF-κB ligand (RANKL). Aqueous ginseng extract produces chromatography peaks characteristic of ginsenosides. Among these peaks, ginsenoside Re is a major component. However, the preventive effects of ginsenoside Re against osteoclast differentiation are not known. We studied the effect of ginsenoside Re on osteoclast differentiation, RANKL-induced tartrate-resistant acid phosphatase (TRAP) activity, and formation of multinucleated osteoclasts in vitro. Ginsenoside Re hampered osteoclast differentiation in a dose-dependent manner. In an in vivo zebrafish model, aqueous ginseng extract and ginsenoside Re had anti-osteoclastogenesis effects. These findings suggest that both aqueous ginseng extract and ginsenoside Re prevent bone resorption by inhibiting osteoclast differentiation. Ginsenoside Re could be important for promoting bone health.