HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation

Heat shock factor 1 (HSF1) initiates a broad transcriptional response to proteotoxic stress while also mediating a cancer-specific transcriptional program. HSF1 is thought to be regulated by molecular chaperones, including Heat Shock Protein 90 (HSP90). HSP90 is proposed to sequester HSF1 in unstressed cells, but visualization of this interaction in vivo requires protein crosslinking. In this report, we show that HSP90 binding to HSF1 depends on HSP90 conformation and is only readily visualized for the ATP-dependent, N-domain dimerized chaperone, a conformation only rarely sampled by mammalian HSP90. We have used this mutationally fixed conformation to map HSP90 binding sites on HSF1. Further, we show that ATP-competitive, N-domain targeted HSP90 inhibitors disrupt this interaction, resulting in the increased duration of HSF1 occupancy of the hsp70 promoter and significant prolongation of both the constitutive and heat-induced HSF1 transcriptional activity. While our data do not support a role for HSP90 in sequestering HSF1 monomers to suppress HSF1 transcriptional activity, our findings do identify a noncanonical role for HSP90 in providing dynamic modulation of HSF1 activity by participating in removal of HSF1 trimers from heat shock elements in DNA, thus terminating the heat shock response

Bulk organic δ13C and C/N as indicators for sediment sources in the Pearl River delta and estuary, southern China

Preservation of organic matter in estuarine and coastal areas is an important process in the global carbon cycle. This paper presents bulk d13C and C/N of organic matter from source to sink in the Pearl River catchment, delta and estuary, and discusses the applicability of d13C and C/N as indicators for sources of organic matter in deltaic and estuarine sediments. In addition to the 91 surface sediment samples, other materials collected in this study cover the main sources of organic material to estuarine sediment. These are: terrestrial organic matter (TOM), including plants and soil samples from the catchment; estuarine and marine suspended particulate organic carbon (POC) from both summer and winter. Results show that the average d13C of estuarine surface sediment increases from 25.0 1.3& in the freshwater environment to 21.0 0.2& in the marine environment, with C/N decreasing from 15.2 3.3 to 6.8 0.2. In the source areas, C3 plants have lower d13C than C4 plants (29.0 1.8& and 13.1 0.5& respectively). d13C increases from 28.3 0.8& in the forest soil to around 24.1& in both riverbank soil and mangrove soil due to increasing proportion of C4 grasses. The d13CPOC increases from 27.6 0.8& in the freshwater areas to 22.4 0.5& in the marine-brackish-water areas in winter, and ranges between 24.0& in freshwater areas and 25.4& in brackish-water areas in summer. Comparison of the d13C and C/N between the sources and sink indicates a weakening TOM and freshwater POC input in the surface sedimentary organic matter seawards, and a strengthening contribution from the marine organic matter. Thus we suggest that bulk organic d13C and C/N analysis can be used to indicate sources of sedimentary organic matter in estuarine environments. Organic carbon in surface sediments derived from anthropogenic sources such as human waste and organic pollutants from industrial and agricultural activities accounts for less than 10% of the total organic carbon (TOC). Although results also indicate elevated d13C of sedimentary organic matter due to some agricultural products such as sugarcane, C3 plants are still the dominant vegetation type in this area, and the bulk organic d13C and C/N is still an effective indicator for sources of organic matter in estuarine sediments

Free PSA and Clinically Significant and Fatal Prostate Cancer in the PLCO Screening Trial

INTRODUCTION: We studied whether adding percent free prostate-specific antigen (%fPSA) to total PSA improves prediction of clinically significant prostate cancer (csPCa) and fatal PCa.METHODS: 6727 men within the intervention arm of the Prostate, Lung, Colorectal and Ovarian Trial had baseline %fPSA. Of this cohort, 475 had csPCa and 98 had fatal PCa. Cumulative incidence and Cox analyses were conducted to evaluate the association between %fPSA/PSA and csPCa/fatal PCa. Harrell's concordance-index (C-index) evaluated predictive ability. Kaplan-Meier analysis assessed survival.RESULTS: Median follow-up was 19.7 years, median baseline PSA was 1.19 ng/mL, median %fPSA was 18%. Cumulative incidence of fatal PCa for men with baseline PSA≥2 ng/mL and %fPSA ≤10 was 3.2% and 6.1% at 15 and 25 years, compared to 0.03% and 1.1% for men with %fPSA >25%. In younger men (55-64 yr) with baseline PSA 2-10 ng/mL, C-index improved from 0.56 to 0.60 for csPCa and from 0.53 to 0.64 for fatal PCa with addition of %fPSA. In older men (65-74 yr), C-index improved for csPCa from 0.60 to 0.66, while no improvement in fatal PCa. Adjusting for age, digital rectal exam, family history of PCa, and total PSA, %fPSA was associated with csPCa (HR 1.05, P < .001) per 1% decrease. %fPSA improved prediction of csPCa and fatal PCA for all race groups. CONCLUSION: In a large US screening trial, the addition of %fPSA to total PSA in men with baseline PSA ≥2 ng/mL improved prediction of csPCa and fatal PCa. Free PSA should be used to risk-stratify screening and decrease unnecessary prostate biopsies

Gambogic acid identifies an isoform-specific druggable pocket in the middle domain of Hsp90β.

Because of their importance in maintaining protein homeostasis, molecular chaperones, including heat-shock protein 90 (Hsp90), represent attractive drug targets. Although a number of Hsp90 inhibitors are in preclinical/clinical development, none strongly differentiate between constitutively expressed Hsp90β and stress-induced Hsp90α, the two cytosolic paralogs of this molecular chaperone. Thus, the importance of inhibiting one or the other paralog in different disease states remains unknown. We show that the natural product, gambogic acid (GBA), binds selectively to a site in the middle domain of Hsp90β, identifying GBA as an Hsp90β-specific Hsp90 inhibitor. Furthermore, using computational and medicinal chemistry, we identified a GBA analog, referred to as DAP-19, which binds potently and selectively to Hsp90β. Because of its unprecedented selectivity for Hsp90β among all Hsp90 paralogs, GBA thus provides a new chemical tool to study the unique biological role of this abundantly expressed molecular chaperone in health and disease

Rising Serum Uric Acid Level Is Negatively Associated with Survival in Renal Cell Carcinoma.

Aim and Background: To investigate the association of serum uric acid (SUA) levels along with statin use in Renal Cell Carcinoma (RCC), as statins may be associated with improved outcomes in RCC and SUA elevation is associated with increased risk of chronic kidney disease (CKD). Methods: Retrospective study of patients undergoing surgery for RCC with preoperative/postoperative SUA levels between 8/2005-8/2018. Analysis was carried out between patients with increased postoperative SUA vs. patients with decreased/stable postoperative SUA. Kaplan-Meier analysis (KMA) calculated overall survival (OS) and recurrence free survival (RFS). Multivariable analysis (MVA) was performed to identify factors associated with increased SUA levels and all-cause mortality. The prognostic significance of variables for OS and RFS was analyzed by cox regression analysis. Results: Decreased/stable SUA levels were noted in 675 (74.6%) and increased SUA levels were noted in 230 (25.4%). A higher proportion of patients with decreased/stable SUA levels took statins (27.9% vs. 18.3%, p = 0.0039). KMA demonstrated improved 5- and 10-year OS (89% vs. 47% and 65% vs. 9%, p &lt; 0.001) and RFS (94% vs. 45% and 93% vs. 34%, p &lt; 0.001), favoring patients with decreased/stable SUA levels. MVA revealed that statin use (Odds ratio (OR) 0.106, p &lt; 0.001), dyslipidemia (OR 2.661, p = 0.004), stage III and IV disease compared to stage I (OR 1.887, p = 0.015 and 10.779, p &lt; 0.001, respectively), and postoperative de novo CKD stage III (OR 5.952, p &lt; 0.001) were predictors for increased postoperative SUA levels. MVA for all-cause mortality showed that increasing BMI (OR 1.085, p = 0.002), increasing ASA score (OR 1.578, p = 0.014), increased SUA levels (OR 4.698, p &lt; 0.001), stage IV disease compared to stage I (OR 7.702, p &lt; 0.001), radical nephrectomy (RN) compared to partial nephrectomy (PN) (OR 1.620, p = 0.019), and de novo CKD stage III (OR 7.068, p &lt; 0.001) were significant factors. Cox proportional hazard analysis for OS revealed that increasing age (HR 1.017, p = 0.004), increasing BMI (Hazard Ratio (HR) 1.099, p &lt; 0.001), increasing SUA (HR 4.708, p &lt; 0.001), stage III and IV compared to stage I (HR 1.537, p = 0.013 and 3.299, p &lt; 0.001), RN vs. PN (HR 1.497, p = 0.029), and de novo CKD stage III (HR 1.684, p &lt; 0.001) were significant factors. Cox proportional hazard analysis for RFS demonstrated that increasing ASA score (HR 1.239, p &lt; 0.001, increasing SUA (HR 9.782, p &lt; 0.001), and stage II, III, and IV disease compared to stage I (HR 2.497, p &lt; 0.001 and 3.195, p &lt; 0.001 and 6.911, p &lt; 0.001) were significant factors. Conclusions: Increasing SUA was associated with poorer outcomes. Decreased SUA levels were associated with statin intake and lower stage disease as well as lack of progression to CKD and anemia. Further investigation is requisite

Rising Serum Uric Acid Level Is Negatively Associated with Survival in Renal Cell Carcinoma

Aim and Background: To investigate the association of serum uric acid (SUA) levels along with statin use in Renal Cell Carcinoma (RCC), as statins may be associated with improved outcomes in RCC and SUA elevation is associated with increased risk of chronic kidney disease (CKD). Methods: Retrospective study of patients undergoing surgery for RCC with preoperative/postoperative SUA levels between 8/2005&#8211;8/2018. Analysis was carried out between patients with increased postoperative SUA vs. patients with decreased/stable postoperative SUA. Kaplan-Meier analysis (KMA) calculated overall survival (OS) and recurrence free survival (RFS). Multivariable analysis (MVA) was performed to identify factors associated with increased SUA levels and all-cause mortality. The prognostic significance of variables for OS and RFS was analyzed by cox regression analysis. Results: Decreased/stable SUA levels were noted in 675 (74.6%) and increased SUA levels were noted in 230 (25.4%). A higher proportion of patients with decreased/stable SUA levels took statins (27.9% vs. 18.3%, p = 0.0039). KMA demonstrated improved 5- and 10-year OS (89% vs. 47% and 65% vs. 9%, p &lt; 0.001) and RFS (94% vs. 45% and 93% vs. 34%, p &lt; 0.001), favoring patients with decreased/stable SUA levels. MVA revealed that statin use (Odds ratio (OR) 0.106, p &lt; 0.001), dyslipidemia (OR 2.661, p = 0.004), stage III and IV disease compared to stage I (OR 1.887, p = 0.015 and 10.779, p &lt; 0.001, respectively), and postoperative de novo CKD stage III (OR 5.952, p &lt; 0.001) were predictors for increased postoperative SUA levels. MVA for all-cause mortality showed that increasing BMI (OR 1.085, p = 0.002), increasing ASA score (OR 1.578, p = 0.014), increased SUA levels (OR 4.698, p &lt; 0.001), stage IV disease compared to stage I (OR 7.702, p &lt; 0.001), radical nephrectomy (RN) compared to partial nephrectomy (PN) (OR 1.620, p = 0.019), and de novo CKD stage III (OR 7.068, p &lt; 0.001) were significant factors. Cox proportional hazard analysis for OS revealed that increasing age (HR 1.017, p = 0.004), increasing BMI (Hazard Ratio (HR) 1.099, p &lt; 0.001), increasing SUA (HR 4.708, p &lt; 0.001), stage III and IV compared to stage I (HR 1.537, p = 0.013 and 3.299, p &lt; 0.001), RN vs. PN (HR 1.497, p = 0.029), and de novo CKD stage III (HR 1.684, p &lt; 0.001) were significant factors. Cox proportional hazard analysis for RFS demonstrated that increasing ASA score (HR 1.239, p &lt; 0.001, increasing SUA (HR 9.782, p &lt; 0.001), and stage II, III, and IV disease compared to stage I (HR 2.497, p &lt; 0.001 and 3.195, p &lt; 0.001 and 6.911, p &lt; 0.001) were significant factors. Conclusions: Increasing SUA was associated with poorer outcomes. Decreased SUA levels were associated with statin intake and lower stage disease as well as lack of progression to CKD and anemia. Further investigation is requisite