Unleashing the full potential of Hsp90 inhibitors as cancer therapeutics through simultaneous inactivation of Hsp90, Grp94, and TRAP1

Cancer therapeutics: Extending a drug's reach A new drug that blocks heat shock proteins (HSPs), helper proteins that are co-opted by cancer cells to promote tumor growth, shows promise for cancer treatment. Several drugs have targeted HSPs, since cancer cells are known to hijack these helper proteins to shield themselves from destruction by the body. However, the drugs have had limited success. Hye-Kyung Park and Byoung Heon Kang at Ulsan National Institutes of Science and Technology in South Korea and coworkers noticed that the drugs were not absorbed into mitochondria, a key cellular compartment, and HSPs in this compartment were therefore not being blocked. They identified a new HSP inhibitor that can reach every cellular compartment and inhibit all HSPs. Testing in mice showed that this inhibitor effectively triggered death of tumor cells, and therefore shows promise for anti-cancer therapy. The Hsp90 family proteins Hsp90, Grp94, and TRAP1 are present in the cell cytoplasm, endoplasmic reticulum, and mitochondria, respectively; all play important roles in tumorigenesis by regulating protein homeostasis in response to stress. Thus, simultaneous inhibition of all Hsp90 paralogs is a reasonable strategy for cancer therapy. However, since the existing pan-Hsp90 inhibitor does not accumulate in mitochondria, the potential anticancer activity of pan-Hsp90 inhibition has not yet been fully examined in vivo. Analysis of The Cancer Genome Atlas database revealed that all Hsp90 paralogs were upregulated in prostate cancer. Inactivation of all Hsp90 paralogs induced mitochondrial dysfunction, increased cytosolic calcium, and activated calcineurin. Active calcineurin blocked prosurvival heat shock responses upon Hsp90 inhibition by preventing nuclear translocation of HSF1. The purine scaffold derivative DN401 inhibited all Hsp90 paralogs simultaneously and showed stronger anticancer activity than other Hsp90 inhibitors. Pan-Hsp90 inhibition increased cytotoxicity and suppressed mechanisms that protect cancer cells, suggesting that it is a feasible strategy for the development of potent anticancer drugs. The mitochondria-permeable drug DN401 is a newly identified in vivo pan-Hsp90 inhibitor with potent anticancer activity

A Structural Equation Modeling on Reproductive Health Promoting Behavior of Unmarried Women: Based on the Theory of Planned Behavior

PURPOSE: The purpose of this study was to construct and test a structural equation modeling on the reproductive health behavior of single women with sexual experiences. This study employed Ajzen's Theory of Planned Behavior (TPB). METHODS: The data were collected after receipt of consent from 250 single women with sexual experiences, and analyzed using SPSS 18.0 and AMOS 18.0. RESULTS: Model fit indices for the hypothetical model were suitable for the recommended level: x²=362.407, RMR=0.065, RMSEA=0.070, GFI=0.867. TLI=0.927, CFI=0.938, IFI=0.939, and x²/dF=2.237. Intention showed direct effect with the biggest effect being on reproductive health behavior. Attitude, subjective norm and perceived behavioral control were found to have a direct effect on intention. Among them, perceived behavioral control revealed the largest influence. CONCLUSION: This study suggests that the TPB is a suitable model in explaining the reproductive health behavior of single women with sexual experience. Strategic plans for educational and intervention programs should be aimed to encourage single women to engage in reproductive health behavior

Association of type 2 diabetes mellitus with lung cancer in patients with chronic obstructive pulmonary disease

BackgroundPatients with chronic obstructive pulmonary disease (COPD) have an increased risk of developing lung cancer. Some studies have also suggested that diabetes mellitus (DM) may increase the risk of developing lung cancer. This study aimed to investigate whether type 2 DM (T2DM) is associated with an increased risk of lung cancer in patients with COPD.Materials and methodsWe conducted a retrospective analysis on two cohorts: the National Health Insurance Service-National Sample Cohort (NHIS-NSC) of Korea and the Common Data Model (CDM) database of a university hospital. Among patients newly diagnosed with COPD in each cohort, those with a lung cancer diagnosis were included, and a control group was selected through propensity score matching. We used the Kaplan–Meier analysis and Cox proportional hazard models to compare lung cancer incidence between patients with COPD and T2DM and those without T2DM.ResultsIn the NHIS-NSC and CDM cohorts, we enrolled 3,474 and 858 patients with COPD, respectively. In both cohorts, T2DM was associated with an increased risk of lung cancer [NHIS-NSC: adjusted hazard ratio (aHR), 1.20; 95% confidence interval (CI), 1.02–1.41; and CDM: aHR, 1.45; 95% CI, 1.02–2.07). Furthermore, in the NHIS-NSC, among patients with COPD and T2DM, the risk of lung cancer was higher in current smokers than in never-smokers (aHR, 1.45; 95% CI, 1.09–1.91); in smokers with ≥30 pack-years than in never-smokers (aHR, 1.82; 95% CI, 1.49–2.25); and in rural residents than in metropolitan residents (aHR, 1.33; 95% CI, 1.06–1.68).ConclusionOur findings suggest that patients with COPD and T2DM may have an increased risk of developing lung cancer compared to those without T2DM

Acanthopanax koreanum Fruit Waste Inhibits Lipopolysaccharide-Induced Production of Nitric Oxide and Prostaglandin E2 in RAW 264.7 Macrophages

The Acanthopanax koreanum fruit is a popular fruit in Jeju Island, but the byproducts of the alcoholic beverage prepared using this fruit are major agricultural wastes. The fermentability of this waste causes many economic and environmental problems. Therefore, we investigated the suitability of using A. koreanum fruit waste (AFW) as a source of antiinflammatory agents. AFWs were extracted with 80% EtOH. The ethanolic extract was then successively partitioned with hexane, CH2Cl2, EtOAc, BuOH, and water. The results indicate that the CH2Cl2 fraction (100 μg/mL) of AFW inhibited the LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production in RAW 264.7 cells by 79.6% and 39.7%, respectively. These inhibitory effects of the CH2Cl2 fraction of AFWs were accompanied by decreases in the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins and iNOS and COX-2 mRNA in a dose-dependent pattern. The CH2Cl2 fraction of AFWs also prevented degradation of IκB-α in a dose-dependent manner. Ursolic acid was identified as major compound present in AFW, and CH2Cl2 extracts by high performance liquid chromatography (HPLC). Furthermore using pure ursolic acid as standard and by HPLC, AFW and CH2Cl2 extracts was found to contain 1.58 mg/g and 1.75 mg/g, respectively. Moreover, we tested the potential application of AFW extracts as a cosmetic material by performing human skin primary irritation tests. In these tests, AFW extracts did not induce any adverse reactions. Based on these results, we suggest that AFW extracts be considered possible anti-inflammatory candidates for topical application

Revascularization of immature retinas with retinopathy of prematurity using combination therapy of deferred laser treatment after a single intravitreal bevacizumab injection

Background This study aimed to observe the extent of retinal vascularization in patients with retinopathy of prematurity (ROP) who underwent deferred laser treatment (LT) after a single intravitreal bevacizumab injection (IVB). Methods This study retrospectively evaluated 40 consecutive eyes in 21 infants who received a single IVB or LT. Deferred LT was performed in cases of ROP recurrence after a single IVB. To assess the amount of retinal vascularization between the initial IVB and deferred LT, the cases were divided into three groups based on treatment: single IVB, deferred LT after a single IVB, and prompt LT. The growth and associated complications were compared between groups. Results There were 12, 16, and 12 eyes in the single IVB, deferred LT, and prompt LT groups, respectively. Deferred LT was performed at an average of 7.9 weeks after a single IVB. In the single IVB group, retinal vascularization proceeded to zone III, whereas the prompt LT group did not show any growth of vascularization beyond the laser scars. In the deferred LT group, during the window period before LT, retinal vascularization progressed from zone I to zone II posterior and from zone II posterior to zone II anterior, respectively, without further ROP recurrence. Conclusions Retinal vascularization progressed during the deferred window period, thereby reducing the area of the retina ablated by LT. A single IVB followed by deferred LT can be an alternative treatment option to prevent ablation of zone I or multiple IVBs

Therapeutic Co-targeting of WEE1 and ATM Downregulates PD-L1 Expression in Pancreatic Cancer

Purpose Pancreatic cancer (PC) is one of the most lethal cancers worldwide, but there are currently no effective treatments. The DNA damage response (DDR) is under investigation for the development of novel anti-cancer drugs. Since DNA repair pathway alterations have been found frequently in PC, the purpose of this study was to test the DDR-targeting strategy in PC using WEE1 and ATM inhibitors. Materials and Methods We performed in vitro experiments using a total of ten human PC cell lines to evaluate antitumor effect of AZD1775 (WEE1 inhibitor) alone or combination with AZD0156 (ATM inhibitor). We established Capan-1-mouse model for in vivo experiments to confirm our findings. Results In our research, we found that WEE1 inhibitor (AZD1775) as single agent showed anti-tumor effects in PC cells, however, targeting WEE1 upregulated p-ATM level. Here, we observed that co-targeting of WEE1 and ATM acted synergistically to reduce cell proliferation and migration, and to induce DNA damage in vitro. Notably, inhibition of WEE1 or WEE1/ATM downregulated programmed cell death ligand 1 expression by blocking glycogen synthase kinase-3 beta serine 9 phosphorylation and decrease of CMTM6 expression. In Capan-1 mouse xenograft model, AZD1775 plus AZD0156 (ATM inhibitor) treatment reduced tumor growth and downregulated tumor expression of programmed cell death ligand 1, CMTM6, CD163, and CXCR2, all of which contribute to tumor immune evasion. Conclusion Dual blockade of WEE1 and ATM might be a potential therapeutic strategy for PC. Taken together, our results support further clinical development of DDR-targeting strategies for PC.

Relationship of Vertigo and Postural Instability in Patients With Vestibular Schwannoma

Objectives Growth of vestibular schwannomas (VS) causes progressive vestibular symptoms and postural instability. Since the tumor grows slowly, compensation of decaying vestibular input may decrease subjective symptoms of dizziness. This study aims to estimate the relationship of subjective vestibular symptoms and objective postural instability in patients with VS. Methods A retrospective review of 18 patients newly diagnosed with VS and with subjective vertigo symptoms was performed. The results of vestibular function tests including the sensory organization test (SOT) using computerized dynamic posturography, caloric test, and self-report measures of subjective dizziness handicap (Dizziness Handicap Inventory) and visual analogue scale were compared according to the onset of vertigo symptoms. Results In VS patients, SOT showed decreased equilibrium score for all vestibular function related conditions, condition (C) 5 and 6, and composite (COMP) score. COMP scores were not correlated with visual analogue scale or Dizziness Handicap Inventory scores. Acute onset group included six patients and insidious onset group, 12 patients. Equilibrium scores for C5 and C6, and COMP scores were lower for insidious onset group, but the difference was not statistically significant. Conclusion Our findings confirmed postural instability is prevalent in VS patients. SOT parameters did not differ significantly between acute onset and insidious onset groups, but increased tumor size and canal weakness were noted in the insidious onset group. Clinicians should consider that postural instability is likely present even in patients who do not complain of acute vertigo, and appropriate counseling should be discussed with the patients

PPM1A Controls Diabetic Gene Programming through Directly Dephosphorylating PPAR?? at Ser273

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a master regulator of adipose tissue biology. In obesity, phosphorylation of PPAR gamma at Ser273 (pSer273) by cyclin-dependent kinase 5 (CDK5)/extracellular signal-regulated kinase (ERK) orchestrates diabetic gene reprogramming via dysregulation of specific gene expression. Although many recent studies have focused on the development of non-classical agonist drugs that inhibit the phosphorylation of PPAR gamma at Ser273, the molecular mechanism of PPAR gamma dephosphorylation at Ser273 is not well characterized. Here, we report that protein phosphatase Mg2+/Mn2+-dependent 1A (PPM1A) is a novel PPAR gamma phosphatase that directly dephosphorylates Ser273 and restores diabetic gene expression which is dysregulated by pSer273. The expression of PPM1A significantly decreases in two models of insulin resistance: diet-induced obese (DIO) mice and db/db mice, in which it negatively correlates with pSer273. Transcriptomic analysis using microarray and genotype-tissue expression (GTEx) data in humans shows positive correlations between PPM1A and most of the genes that are dysregulated by pSer273. These findings suggest that PPM1A dephosphorylates PPAR gamma at Ser273 and represents a potential target for the treatment of obesity-linked metabolic disorders