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

Funding structures for Build-to-Suit developments in Brazil: advantages and risks

Empreendimentos build-to-suit são aqueles em que o locador desenvolve um imóvel sob medida para o locatário, que o ocupará pelo prazo previsto em contrato. Dadas as peculiaridades desse tipo de contrato no contexto do real estate, o objetivo deste artigo é analisar as diferentes origens de recursos (fontes de funding) e a forma como eles são empregados (estruturas de funding) para desenvolver os empreendimentos, e discutir as vantagens e riscos dessas estruturas de funding do ponto de vista do empreendedor, que também é o locador. De forma a desenvolver este estudo e formatar as estruturas de funding apresentadas, parte-se de uma revisão das\ud práticas atuais do mercado imobiliário brasileiro (através de notícias veiculadas\ud na mídia e de prospectos de negócios realizados), da literatura brasileira sobre o tema e do conhecimento gerado no Grupo de Real Estate da Escola Politécnica da USP. De maneira a verificar a validade legal das soluções, é realizada uma checagem com\ud base na legislação brasileira e nas normas da Comissão de Valores Mobiliários.\ud Considera-se fontes de funding aquelas tratadas (1) como equity: capital próprio do empreendedor, capital de parceiros (e sócios) no empreendimento na forma de dinheiro ou imóveis (notadamente, o terreno onde será construído o empreendimento), ou investimento de Fundo de Investimento Imobiliário (FII); e (2) como dívida: financiamento bancário, securitização dos recebíveis de aluguéis com CRI ou debêntures. As estruturas de funding apresentadas serão combinações dessas fontes. A análise evidencia que estruturas com financiamento por securitização e emissão de CRI são as mais adequadas de forma geral para os negócios, assim como o investimento completo por FII para negócios de maior porte e nos quais o FII é proprietário direto do empreendimento. \ud Palavras-chave: real estate, build-to-suit, locação, funding, project financeBuild-to-suit real estate assets are tailor made developments for the tenant purposes, who occupies and operates the property for the duration agreed. Given the peculiarities of these contracts and the specificities of the property, this article aims at analyzing the sources of capital and how these funds are mixed and structured for the developments. The article discusses the risks and benefits of each of these funding\ud structures assuming the role of developer. In order to do this study and establish the funding structures shown, the research starts with a review of the current practices in Brazilian real estate market (based on press releases and prospects of deals), of local research papers, and will use the knowledge created at the Real Estate Research Group at Escola Politécnica at Universidade de São Paulo. Since it’s necessary to validate\ud the solutions proposed, Brazilian laws and Comissão de Valores Mobiliários (CVM) norms\ud are reviewed. Funding sources considered will be treated as (1) equity: developers own funds, partnership (via capital or real state – mainly land – investment), or Fundo de Investimento Imobiliário (Brazilian investment structure comparable to REITs); or as (2) debt: banks traditional credit lines, securitization of receivables with CRI emissions\ud , and debt bond emissions. The funding structures presented are mixes of these sources. The analysis shows that the structures best suited for this purpose are those with debt by securitization with CRI emissions, along with the complete investment by a FII but only with large emissions and having the FII as the sole owner of the real estate. \ud Keywords: real estate, build-to-suit, rent, funding, project financ

PI3K-mTOR-S6K Signaling Mediates Neuronal Viability via Collapsin Response Mediator Protein-2 Expression

Collapsin response mediator protein (CRMP)-2 and the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway are associated with common physiological functions such as neuronal polarity, axonal outgrowth and synaptic strength, as well as various brain disorders including epilepsy. But, their regulatory and functional links are unclear. Alterations in CRMP-2 expression that lead to its functional changes are implicated in brain disorders such as epilepsy. Here, we investigate whether changes in CRMP-2 expression, possibly regulated by mTOR-related signaling, correlates with neuronal growth and viability. Inhibition of mTOR and/or phosphoinositol-3-kinase (PI3K) led to deceased p-S6K, and p-S6 signals also reduced CRMP-2 expression. These changes corresponded to inhibition of neuronal viability and proliferation in cultured hippocampal HT-22 cells under both basal serum-free and serum- or insulin-induced mTOR pathway-activated conditions. CRMP-2 expression tended to be increased by mTOR activation, indicated by an increase in p-S6/S6 level, in pentylentetrazole (PTZ)-induced epileptic rat hippocampal tissues was also significantly reduced by mTOR inhibition. Knockdown of CRMP-2 by si-RNA reduced the neuronal viability without changes in mTOR signaling, and overexpression of CRMP-2 recovered the glutamate-induced neurotoxicity and decrease of mTOR signaling in HT-22 cells. In conclusion, CRMP-2 protein expression controlled by the PI3K-mTOR-S6K signaling axis exerts its important functional roles in neuronal growth and survival

Immunohistochemical and Molecular Characteristics of Follicular Patterned Thyroid Nodules with Incomplete Nuclear Features of Papillary Thyroid Carcinoma

Background : Follicular patterned thyroid nodules with incomplete nuclear features of papillary thyroid carcinoma (FTN-INPTCs) are difficult to diagnose, and their biological behavior and association with follicular variants of PTC (FVPTCs) have not yet been established. The aim of this study is to determine immunohistochemical and molecular characteristics of FTN-INPTCs. Methods : We investigated immunohistochemical features (galectin-3, HBME-1, CK19, fibronectin-1, CITED1), BRAF V600E mutation and RASSF1A promoter methylation status in 30 FTN-INPTC cases, along with 26 FVPTCs, 21 follicular adenomas (FAs) and 14 nodular hyperplasias (NHs). Results : Expression of galectin-3, HBME-1, CK19 and CITED1 was significantly higher in FTN-INPTCs than in FAs or NHs, but expression of galectin-3, CK19 and fibronectin-1 was lower in FTN-INPTCs than in FVPTCs. The BRAF V600E mutation was not detected in the benign nodules or FTN-INPTCs, whereas 57% of FVPTCs had the mutation. RASSF1A promoter methylation was higher in FTN-INPTCs than in benign nodules but there was no difference between FTN-INPTCs and FVPTCs. Conclusions : Our results represent the borderline immunohistochemical and molecular characteristics of FTN-INPTC. We conclude that FTN-INPTC is an intermediate lesion between a benign nodule and a FVPTC, and that it is pathogenetically related to FVPTC.This work was supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD) (KRF-2006- 331-E00050).Arora N, 2008, WORLD J SURG, V32, P1237, DOI 10.1007/s00268-008-9484-1Park YJ, 2007, J KOREAN MED SCI, V22, P621CHAN JKC, 2007, DIAGNOSTIC HISTOPATH, P997Rhoden KJ, 2006, J CLIN ENDOCR METAB, V91, P2414, DOI 10.1210/jc.2006-0240de Matos PS, 2005, HISTOPATHOLOGY, V47, P391, DOI 10.1111/j.1365-2559.2005.02221.xNakamura N, 2005, LAB INVEST, V85, P1065, DOI 10.1038/labinvest.3700306Xing M, 2005, ENDOCR-RELAT CANCER, V12, P245, DOI 10.1677/erc.1.0978Papotti M, 2005, MODERN PATHOL, V18, P541, DOI 10.1038/modpathol.3800321Prasad ML, 2005, MODERN PATHOL, V18, P48, DOI 10.1038/modpathol.3800235Weisenberger DJ, 2005, NUCLEIC ACIDS RES, V33, P6823, DOI 10.1093/nar/gki987Vasko VV, 2004, EUR J ENDOCRINOL, V151, P779Kim KH, 2004, YONSEI MED J, V45, P818Gasbarri A, 2004, BRIT J CANCER, V91, P1096, DOI 10.1038/sj.bjc.6602097Xing MZ, 2004, CANCER RES, V64, P1664Kimura ET, 2003, CANCER RES, V63, P1454Hirokawa M, 2002, AM J SURG PATHOL, V26, P1508Schagdarsurengin U, 2002, CANCER RES, V62, P3698Fusco A, 2002, AM J PATHOL, V160, P2157Shivakumar L, 2002, MOL CELL BIOL, V22, P4309, DOI 10.1128/MCB.22.12.4309-4318.2002Coli A, 2002, HISTOPATHOLOGY, V40, P80Bartolazzi A, 2001, LANCET, V357, P1644Eads CA, 2001, CANCER RES, V61, P3410Williams ED, 2000, INT J SURG PATHOL, V8, P181Orlandi F, 1998, CANCER RES, V58, P3015Sack MT, 1997, MODERN PATHOL, V10, P668Herman JG, 1996, P NATL ACAD SCI USA, V93, P9821OKAYASU I, 1995, CANCER, V76, P2312BERHO M, 1995, ANN CLIN LAB SCI, V25, P513RAPHAEL SJ, 1994, MODERN PATHOL, V7, P295ROSAI J, 1992, ATLAS TUMOR PATHOL, P65

Evaluation of the transporter-mediated herb-drug interaction potential of DA-9801, a standardized dioscorea extract for diabetic neuropathy, in human in vitro and rat in vivo

BACKGROUND: Drug transporters play important roles in the absorption, distribution, and elimination of drugs and thereby, modulate drug efficacy and toxicity. With a growing use of poly pharmacy, concurrent administration of herbal extracts that modulate transporter activities with drugs can cause serious adverse reactions. Therefore, prediction and evaluation of drug-drug interaction potential is important in the clinic and in the drug development process. DA-9801, comprising a mixed extract of Dioscoreae rhizoma and Dioscorea nipponica Makino, is a new standardized extract currently being evaluated for diabetic peripheral neuropathy in a phase II clinical study. METHOD: The inhibitory effects of DA-9801 on the transport functions of organic cation transporter (OCT)1, OCT2, organic anion transporter (OAT)1, OAT3, organic anion transporting polypeptide (OATP)1B1, OATP1B3, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) were investigated in HEK293 or LLC-PK1 cells. The effects of DA-9801 on the pharmacokinetics of relevant substrate drugs of these transporters were also examined in vivo in rats. RESULTS: DA-9801 inhibited the in vitro transport activities of OCT1, OCT2, OAT3, and OATP1B1, with IC(50) values of 106, 174, 48.1, and 273 μg/mL, respectively, while the other transporters were not inhibited by 300 μg/mL DA-9801. To investigate whether this inhibitory effect of DA-9801 on OCT1, OCT2, and OAT3 could change the pharmacokinetics of their substrates in vivo, we measured the pharmacokinetics of cimetidine, a substrate for OCT1, OCT2, and OAT3, and of furosemide, a substrate for OAT1 and OAT3, by co-administration of DA-9801 at a single oral dose of 1,000 mg/kg. Pre-dose of DA-9801 5 min or 2 h prior to cimetidine administration decreased the C(max) of cimetidine in rats. However, DA-9801 did not affect the elimination parameters such as half-life, clearance, or amount excreted in the urine, suggesting that it did not inhibit elimination process of cimetidine, which is governed by OCT1, OCT2, and OAT3. Moreover, DA-9801 did not affect the pharmacokinetic characteristics of furosemide, as evidenced by its unchanged pharmacokinetic parameters. CONCLUSION: Inhibitory effects of DA-9801 on OCT1, OCT2, and OAT3 observed in vitro may not necessarily translate into in vivo herb-drug interactions in rats even at its maximum effective dose

Effect Modification of Kidney Function on the Non-linear Association Between Serum Calcium Levels and Cardiovascular Mortality in Korean Adults

Objectives This study aimed to evaluate the potential interaction between kidney function and the non-linear association between serum calcium levels and cardiovascular disease (CVD) mortality. Methods This study included 8927 participants enrolled in the Dong-gu Study. Albumin-corrected calcium levels were used and categorized into 6 percentile categories: 97.5th. Restricted cubic spline analysis was used to examine the non-linear association between calcium levels and CVD mortality. Cox proportional hazard regression was used to estimate hazard ratios (HRs) for CVD mortality according to serum calcium categories. All survival analyses were stratified by the estimated glomerular filtration rate. Results Over a follow-up period of 11.9±2.8 years, 1757 participants died, of whom 219 died from CVD. A U-shaped association between serum calcium and CVD mortality was found, and the association was more evident in the low kidney function group. Compared to the 25.0-50.0th percentile group for serum calcium levels, both low and high serum calcium tended to be associated with CVD mortality (97.5th: HR, 2.56; 95% CI, 0.76 to 8.66) in the low kidney function group. In the normal kidney function group, a similar association was found between serum calcium levels and CVD mortality (97.5th: HR, 1.65; 95% CI, 0.70 to 3.93). Conclusions We found a non-linear association between serum calcium levels and CVD mortality, suggesting that calcium dyshomeostasis may contribute to CVD mortality, and kidney function may modify the association

Real-time interactive digital healthcare system for post-operative breast cancer patients: study protocol for a randomized controlled trial

Background After receiving breast cancer surgery or reconstruction, shoulder dysfunctions including weakness, post-operative pain, shoulder joint instability, and limited range of motion (ROM) often occur. Due to limited ROM, patients may suffer difficulty in activities of daily living, and quality of life may be reduced. The objective of this study is to compare the effects on shoulder ROM of a real-time interactive digital healthcare system and brochure-based home rehabilitation program in post-operative breast cancer patients. Methods This study is a prospective, multi-center, assessor-blinded randomized controlled trial. The study aims to recruit 100 breast cancer patients exhibiting limited shoulder ROM after undergoing axillary lymph node dissection or breast reconstruction following mastectomy. Patients will be randomly assigned to two groups for 8 weeks of rehabilitation: a digital healthcare system rehabilitation (intervention) group and a brochure-based rehabilitation (control) group. The primary outcome is the change in ROM of the affected shoulder between baseline and 12 weeks after enrollment. Secondary outcomes include pain in the affected shoulder, as measured using a numerical rating scale, functional outcomes (QuickDASH scores), and quality of life (FACT-B and EQ-5D-5L scores), all of which will be measured on enrollment and 4, 8, and 12 weeks thereafter. Discussion This study will compare the effectiveness of a newly developed, augmented reality-based real-time interactive digital healthcare system with that of brochure-based home rehabilitation for improving the shoulder ROM, pain, functional outcomes, and quality of life of post-operative breast cancer patients. Trial registration ClinicalTrials.gov NCT04316156 . Registered on 20 March 2020.This study is being financially supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI19C0781)

Pregnancy-related knowledge, risk perception, and reproductive decision making of women with epilepsy in Korea

AbstractPurposeTo determine the influence of pregnancy-related knowledge and the risk perception on reproductive decision making in women with epilepsy.MethodsWe enrolled women with epilepsy, who were of reproductive age and were considering having children in the future. A questionnaire was used to assess the level of pregnancy-related knowledge, perception of the offspring's risk for developing epilepsy or for having a congenial anomaly, and discussion with a physician concerning pregnancy-related issues. We evaluated the following outcome variables: (1) the decision to discontinue anti-epileptic drug (AED) during a future pregnancy regardless of the medical indication; and (2) the decision to have fewer children because of epilepsy.ResultsWe enrolled a total of 186 women with epilepsy. (1) Fifty-eight percent of the women were considering discontinuing AED during a future pregnancy regardless of the medical indication, and 25% of the women decided to have fewer children because of epilepsy. (2) The decision to discontinue AED during a future pregnancy was associated with low-level pregnancy-related knowledge. (3) The decision to have fewer children because of epilepsy was associated with an exaggerated perception of the offspring's risk for developing epilepsy. (4) The women who had ever discussed pregnancy-related issues with their physician were less likely to decide to discontinue AED during a future pregnancy; however, a discussion on this issue had no impact on their decision to have fewer children because of epilepsy.ConclusionMore than 50% of the women would decide to discontinue AED during a future pregnancy, and 25% of the women stated that they would have fewer children because of epilepsy. These data highlight the importance of education on pregnancy-related issues and genetic risk counseling

Tlr2 and the nlrp3 inflammasome mediate il-1β production in prevotella nigrescens-infected dendritic cells

Prevotella nigrescens is an oral pathogen that is frequently observed in the subgingival plaque of periodontitis patients. Interleukin-1β (IL-1β) is known to be involved in the immunopathology of periodontal diseases and has been implicated in the destruction of bone. In this study, we investigated the mechanism of IL-1β production by P. nigrescens in murine bone marrow-derived dendritic cells (BMDCs). Our results showed that a host receptor, Toll-like receptor 2 (TLR2), but not TLR4 is required for pro-IL-1β induction and nucleotide-binding oligomerization domain like receptor pyrin domain containing 3 (NLRP3) priming in BMDCs in response to P. nigrescens and activation of the NLRP3 inflammasome is necessary for processing of pro-IL-1β into mature IL-1β. In addition, an inhibitor assay revealed that production of reactive oxygen species, P2X7R activity, and release of cathepsin B are involved in IL-1β production in BMDCs in response to P. nigrescens. © The author(s).1

A study of consumers' perceptions and prediction of consumption patterns for generic health functional foods

The Korea Food and Drug Administration (KFDA) revised the Health Functional Food Act in 2008 and extended the form of health functional foods to general food types. Therefore, this study was performed to investigate consumers' perceptions of the expanded form of health functional food and to predict consumption patterns. For this study, 1,006 male and female adults aged 19 years and older were selected nationwide by multi-stage stratified random sampling and were surveyed in 1:1 interviews. The questionnaire survey was conducted by Korea Gallup. The subjects consisted of 497 (49.4%) males and 509 (50.6%) females. About 57.9% of the subjects recognized the KFDA's permission procedures for health functional foods. Regarding the health functional foods that the subjects had consumed, red ginseng products were the highest (45.3%), followed by nutritional supplements (34.9%), ginseng products (27.9%), lactobacillus-containing products (21.0%), aloe products (20.3%), and Japanese apricot extract products (18.4%). Opinions on expanding the form of health functional foods to general food types scored 4.7 points on a 7-point scale, showing positive responses. In terms of the effects of medicine-type health functional foods versus generic health functional foods, the highest response was 'same effects if the same ingredients are contained' at a rate of 34.7%. For intake frequency by food type, the response of 'daily consistent intake' was 31.7% for capsules, tablets, and pills, and 21.7% for extracts. For general food types, 'daily consistent intake' was 44.5% for rice and 22.8% for beverages, which were higher rates than those for medicine types. From the above results, consumers had positive opinions of the expansion of health functional foods to generic forms but are not expected to maintain accurate intake frequencies or amounts. Thus, continuous promotion and education are needed for proper intake of generic health functional foods