text:
Q: Mongoose await doc.save() Incomplete I fetch a JSON object from a remote server successfully. The JSON file is an array of objects. I loop over them and during the loop I try to save each document object with mongoose as below. But only 50 records are saved out of 500. So obviously I am doing something wrong with async/await. Your help is appreciated.
Edit: Added more of the code upon request from users.
const mongoose = require('mongoose')
const fetch = require('fetch-json')
const PriceModel = mongoose.model('Price', priceSchema);

getPrices = async () => {
  try {
    const url = 'https://api.binance.com/api/v3/ticker/price'
    const params = ''
    const jsonData = await fetch.get(url, params)
    return jsonData

  } catch (e) {
    console.log('Error caught during getPrices: ', e.message)
  }
}

mongoose.connect('mongodb://localhost/prices', { useNewUrlParser: true });

const db = mongoose.connection;
db.on('error', console.error.bind(console, 'connection error:'));
db.once('open', function () {
  console.log('we\'re connected')
});

const priceSchema = new mongoose.Schema({
  timestamp: Date,
  symbol: String,
  price: Number
});

    persistData = async () => {

      try {
        const timestamp = Date.now()
        const allPrices = await getPrices()

        for (const element of allPrices) {
          let doc = new PriceModel()
          doc.timestamp = timestamp
          doc.symbol = element.symbol
          doc.price = element.price
          await doc.save()
        }
      } catch (e) {
        console.log('Error caught during db save: ', e.message)
      }
    }

A: As from version 4.4 mongoose does support insertMany operation. So a much faster algorithm will be to prepare your needed data:
const priceModels = [];

for (const element of allPrices) {
  let doc = {
     timestamp,
     ...element,
  }
  priceModels.push(doc)
}

And after you prepared all the objects, you make one insert to the database:
await PriceModel.insertMany(priceModels);


Conversion from 0.22 Zcash to Yen with latest exchange rate and cryptocurrency price. Also, view 0.22 ZEC to JPY result in ZEC-JPY overview table and ZEC/JPY chart. This is real-time market price of Zcash in Japan. Calculate how much is 0.22 Zcash in Yen with a conversion calculator.


text:
NavigationLifestyleHealthTravelCelebsHappeningsPress
Egyptian singer banned after claiming lack of free speech
In this Dec. 31, 2018 photo, Egyptian singer Sherine Abdel-Wahab performs during New Years' Eve, in Cairo, Egypt. Abdel-Wahab has been banned from performing in her home country after suggesting that it does not respect free speech. (AP Photo/Mahmoud Abdel Nasser)
CAIRO — An Egyptian singer has been banned from performing in her home country after suggesting that it does not respect free speech.
A video clip circulated online shows Sherine Abdel-Wahab, during a performance in Bahrain, saying: "Here I can say whatever I want. In Egypt, anyone who talks gets imprisoned."
Egypt's Musicians Union responded late Friday by barring the singer, popularly known by her first name, from performing. It also summoned her for questioning.
Samir Sabry, a pro-government lawyer with a reputation for moral vigilantism and suing celebrities, filed a complaint against the singer accusing her of "insulting Egypt and inviting suspicious rights groups to interfere in Egypt's affairs."
Last year, Sherine was sentenced to six months in prison over a similar clip from a concert in which she joked that the Nile is polluted. The sentence was suspended upon appeal. She apologized for the remark, calling it a "bad joke."
The singer, who hosts the Arabic version of "The Voice," apologized again after the latest remarks in a TV interview aired late Friday, saying she was joking.
"I am very tired. I made a mistake. I am sorry. I appeal the president of the Arab Republic of Egypt, who is our father. I feel that I was persecuted. I did nothing. I love Egypt," she said.
Egyptian authorities have waged an unprecedented crackdown on dissent since President Abdel-Fattah el-Sissi led the military overthrow of an elected but divisive Islamist president in 2013. The local media is dominated by pro-government outlets that attack anyone seen as criticizing the country or its leaders, and several people have been jailed or fined for violating vaguely written laws outlawing such criticism.
Thousands of people have been jailed or forced to leave the country since el-Sissi came to power, mainly Islamists but also a large number of secular activists, politicians and artists.
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Month of Ramadan fasting for many Muslims begins...
Originally founded in 2015, Voyage Times publishes articles on travel and lifestyle for travelers, leisure seekers, and culture hunters from around the world.
Contact us: sales[at]voyagetimes.com
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Copyright © 2015 - 2020 Voyage Times. All Rights Reserved.

redpajama_set_name: RedPajamaCommonCrawl


Falso Service Experts in East Syracuse has been ahead of the pack in the installation and repair of all major commercial HVAC systems across North America, including top manufacturers, like Lennox, Carrier, Trane, Goodman, Rheem, York and many more. With a depth of skill, experience and technical expertise across all major HVAC brands, we can solve any comfort problem your company may encounter.
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Nancy Gillman is a senior attorney in the Capital Markets Practice in Cadwalader's New York office. Nancy's practice is concentrated in the area of commercial mortgage-backed securitization, representing financial institutions as mortgage loan sellers in CMBS transactions. Prior to joining Cadwalader, Nancy's practice focused on commercial real estate loans, acquisitions, dispositions and REITs.
Nancy received her J.D. from Suffolk University School of Law and her undergraduate degree from Brown University. She is admitted to practice in the States of New York and Massachusetts.


The Screaming Penny: Breastmilk Storage Bags, 25-Count Boxes (Pack of 3) under $9!
Breastmilk Storage Bags, 25-Count Boxes (Pack of 3) under $9!
Amazon has Lansinoh 20435 Breastmilk Storage Bags, 25-Count Boxes (Pack of 3) for $9.70--but use Subscribe and Save and only pay $8.24! Be sure to cancel right after you order if you don't want more.


text:
TODAY: Norway, Russia and Security in the Arctic Briefing
/Armed Services /Foreign Affairs /Administrative / TH2 / TODAY: Norway, Russia and Security in the Arctic Briefing
Armed Services/ Foreign Affairs/ TH2
Sending Office: Honorable Juan Vargas
Aaron.Allen@mail.house.gov
Norway, Russia and Security in the Arctic
*Lunch will be provided*
Click Here to RSVP
Please join the Foreign Affairs Congressional Staff Association (FACSA) and the Embassy of Norway for an informational briefing on Norway, Russia and security in the Artic. How do we deal with an increasingly assertive Russia along NATO's Northern flank?
As Russia's neighbor and NATO's eyes and ears in the North, Norway has a unique perspective on security in the Arctic and the North Atlantic. Join us for a discussion with Norway's incoming Ambassadors to Moscow and NATO about Russia, NATO and transatlantic
security.
Mr. Rune Resaland is Director General in the Department for Security Policy and the High North in the Norwegian Ministry of Foreign Affairs. In this capacity, he is lead adviser to the Norwegian Foreign Minister on transatlantic relations
and Norway's relations to Russia. As of August, Mr. Resaland will be Norway's Ambassador to Moscow. Mr. Resaland has previously been Deputy Chief of Mission at the Norwegian Embassy in Washington, D.C., and Head of the International Department at the Storting
(Norwegian Parliament).
Mr. Øystein Bø served as Norway's Deputy Minister of Defence from 2013 to 2017. In August, he will take up his duties as Norway's Ambassador to NATO in Brussels. Mr. Bø was Head of the International Department at the Storting from 2010 to
2013. He has previously served as Deputy Chief of Mission in the Norwegian NATO delegation in Brussels, and Director General in the Secretariat of the Minister of Foreign Affairs.
FACSA is an officially recognized, bipartisan and bicameral organization tasked with providing networking opportunities, career guidance, briefings on key topics and other engagements for staffers to learn and grow as foreign
policy professionals.
Selected legislative information: Armed Services, Foreign Affairs
Tagged:Juan Vargas
Stand up for our Servicemembers who have been Victims of Domestic Violence: Support the Violence Against Women's Veterans Act of 2019
Co-Sponsor Veterans Health Savings Account Act of 2019
Cosponsor H.R. 3456, the Peace Corps Reauthorization Act of 2019


This web based application not only bridges Tekbox RTU with 3rd party IoT platforms but can also be used for monitoring purpose.
This is an optional service that aims to speed up the integration of TEKBOX RTUs into 3rd party IoT platforms.
For LoRaWAN RTU (TBS12B, TBS12S and TBSL1/RFB-LoRa) packets are collected from the LoRaWAN server and for the cellular version (TBSL1/RFB-4G) packets are directly retrieved over the MQTT interface. Automatic export functions over FTP or MQTT can be configured resulting in the export of JSON data and meta-data files.
Thanks to their comprehensive tags based structures, these JSON file can be easily manipulated by any IoT platform. TEKBOX IoT broker also provides basic monitoring and graph capabilities.
Optimised data and meta-data JSON structures for an easy integration into 3rd party IoT platform.
Other Import/Export features: contact Tekbox Digital Solutions sales.


text:
Q: how to save pdf files using html-pdf-node I am trying to save pdf file in current directory but its not.
its creating buffer but not saving file.

var html_to_pdf = require('html-pdf-node');

let options = { format: 'A4' };
let file = { content: "
Welcome to html-pdf-node
" };
html_to_pdf.generatePdf(file, options).then(pdfBuffer => {
  console.log("PDF Buffer:-", pdfBuffer);
});

A: Checkout the html-pdf-node documentation: Html-pdf-node
The documentation says this:
path  The file path to save the PDF to. If path is a relative path, then it is resolved to current working directory. If no path is provided, the PDF won't be saved anywhere.
The file parameter serves as an object you can specify the file.path to save the pdf to a specific path.
let options = { format: 'A4' };
let file = [{
  url: "https://example.com", name: 'example.pdf', path: 'path/to/save/file'
}];

html_to_pdf.generatePdfs(file, options).then(output => {
  console.log("PDF Buffer:-", output); // PDF Buffer:- [{url: "https://example.com", name: "example.pdf", buffer: <PDF buffer>}]
});

redpajama_set_name: RedPajamaStackExchange


Yael offers a variety of meditation and learning opportunities for people of all levels and skill-sets. If you do not see an opportunity that is right for you, please get in touch.
Yael writes about topics involving meditation, religion, and spirituality and has been published in a variety of publications from the Harvard Business Review to the Huffington Post. She is also the author of the forthcoming book, What Now? Meditation for Your Twenties and Beyond (Parallax, November 2017).


text:
Sun Signs(current)
Sarah Jessica Parker Biography, Life, Interesting Facts
Also Known For :
Film Actress, Producer, Television Actress, Theater Actress
Nelsonville, Ohio, United States of America
Zodiac Sign :
Chinese Zodiac :
Birth Element :
Sarah Jessica Parker is an American actress born on March 25th, 1965. She is best known for her role on Sex and the City as Carrie Bradshaw. In fact, her great efforts to the role earned her a two Emmy Awards and four Golden Globe Awards. She has also acted in other films like Ed Wood, Hocus Pocus, and Failure to Launch.
Growing up, Sarah Jessica Parker took both singing and Ballet classes before moving to New York where she continued her passion for acting. She realized her talent at such a young age and nurtured it. In 200, she was the MTV Movie Awards host. The talented actress also appeared in Glee in its fourth season four alongside Jane Lynch.
Sarah Jessica Parker was born on March 25th, 1965. Her place of birth is in Nelsonville, Ohio in the United States. She is among the eight kids of Stephen Parker and Barbara Parker. Stephen worked as a journalist and entrepreneur while Barbra was a teacher and nursery school operator. Among her siblings are actors Pippin Parker and Timothy Parker. At a young age, her parents divorced, and Paul Forste married her mother. He was an account executive and a truck driver as well.
From a young age, Sarah Jessica Parker took Ballet lessons along with singing classes. Her family later relocated to Cincinnati before settling in near New York City. This is where she would have proper exposure for her passion in acting in singing. The family then relocated sometimes and finally settled once again in Englewood, New Jersey. This is where Parker enrolled at Dwight Morrow High School.
Subsequently, she went to New York City to study in School of American Ballet. She also attended Professional Children's School still in New York. Later, she studied in School for Creative and Performing Arts situated in Cincinnati. While at Los Angeles, she took classes in Hollywood High School.
After Sarah Jessica Parker won her debut role on Broadway in The Innocents, her family relocated to New Jersey. This was a career move since they wanted her to explore more in acting. In the following years, she went on tour with The Sound of Music along with her four siblings.
Her first role in film premiered in 1979 with her role in Rich Kids. Later in 1982, her role in Square Pegs sitcom made her quite famous among Television audiences. She became even more famous for her role in the hit movie Footloose in 1984.
In 1985, she starred in Girls Just Want to Have Fun along with very young Helen Hunt. She also featured in L.A. Story in 1991 and Honeymoon in Vegas the following year. Later in 1996, she acted supporting role in Miami Rhapsody. In 2016, Parker was the executive producer of the comedy Divorce by HBO. She is also starred in the film.
Fashion Career
In 1998, Sarah Jessica Parker was given a starring role in Sex and the City. She became a legend in the fashion world with this role. Parker wasted no time utilizing this new side of her to be a style icon.
In 2003, she became Garnier hair products' spokesperson. Subsequently, in 2005, she launched Lovely, her first perfume.
She also owns SJP Beauty Company. She sells most of her perfumes through this company. Additionally, Parker launched her line of shoes in 2014. It is called SJP Collection
Between 1984 and 1991, Sarah Jessica Parker dated Robert Downey, Jr., an actor. Their relationship ended following Downey's drug addiction. She also dated John F. Kennedy Jr. for a while.
Later in 1997, Sarah Jessica Parker wedded Matthew Broderick exchanged wedding vows. Together they were blessed with three kids, James Wilkie followed by twin daughters (Marion and Tabitha).
March 25 Horoscope
More Actresses
Molly Shannon
More People From Ohio
Allicattt
Dr. Oz
Lillian D. Wald
More People From United States of America
Joseph Jackson
Percy Sutton
More Aries People
Melvin Ellis Calvin
Lucy Craft Laney
Ranil Wickremasinghe
More Chinese Snake People
Fred West
© 2017 SunSigns.Org


text:
Targeting the PI3K/AKT/mTOR signaling pathway as an effectively radiosensitizing strategy for treating human oral squamous cell carcinoma in vitro and in vivo
Chih-Chia Yu, Shih-Kai Hung, Hon-Yi Lin, Wen-Yen Chiou, Moon-Sing Lee, Hui-Fen Liao, Hsien-Bin Huang, Hsu-Chueh Ho and Yu-Chieh Su _
Chih-Chia Yu1,2,*, Shih-Kai Hung2,3,*, Hon-Yi Lin2,3, Wen-Yen Chiou2,3, Moon-Sing Lee2,3, Hui-Fen Liao4, Hsien-Bin Huang1, Hsu-Chueh Ho5 and Yu-Chieh Su6,7
1Department of Life Science and Institute of Molecular Biology, National Chung Cheng University, Chia-Yi, Taiwan, R.O.C
2Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taiwan, R.O.C
3School of Medicine, Tzu Chi University, Hualian, Taiwan, R.O.C
4Department of Biochemical Science and Technology, National Chiayi University, Chia-Yi, Taiwan, R.O.C
5Department of Otolaryngology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taiwan, R.O.C
6Division of Hematology and Oncology, E-Da Hospital, Kaohsiung, Taiwan
7School of Medicine, I-Shou University, Kaohsiung, Taiwan, R.O.C
*These authors (Chih-Chia Yu and Shih-Kai Hung) contributed equally to this work
Yu-Chieh Su, email: [email protected]
Keywords: PI3K/mTOR pathway, radiation, radiosensitization, radioresistant, oral cancer
Received: September 23, 2016 Accepted: June 20, 2017 Published: August 02, 2017
Radiation therapy (RT) is the current standard adjuvant approach for oral squamous cell carcinoma (OSCC) patients. Radioresistance is a major contributor to radiotherapy failure. In this study, we used patient-derived cells and a radiation-resistant cell line in vitro and in vivo for two purposes: evaluate the anti-tumor effects and understand the mechanisms in the dual PI3K/mTOR signaling pathway regulation of radiosensitization. Our findings indicate that in OML1-R cells, the radioresistance phenotype is associated with activation of the PI3K/AKT/mTOR signaling pathway. Compared to a combination of PI3K or mTOR inhibitors and radiation, dual blockade of the PI3K and mTOR kinases significantly improved radiation efficacy in oral cancer and patient-derived OSCC cells. Dual PI3K/mTOR inhibition enhanced the effect of radiation by inhibiting AKT/mTOR signaling pathways and caused G1 phase arrest, which is associated with downregulation of cyclin D1/CDK4 activity, leading to growth inhibition. In nude mice xenografted with radioresistant OML1-R cells, the combined treatment was also more effective than RT alone in reducing tumor growth. This treatment was also demonstrated to be dependent on the inhibition of protein kinase-dependent S6 kinase pathway and eIF4E-mediated cap-dependent translation. These findings indicate that activation of the PI3K/AKT/mTOR signaling pathway has a role in radioresistance of OSCC. We determined that a PI3K/mTOR inhibitor combined with radiation exhibits synergistic inhibition of the AKT/mTOR axis and induces cell cycle arrest. Our results show the therapeutic potential of drugs targeting the PI3K/AKT/mTOR signaling pathway should be new candidate drugs for radiosensitization in radiotherapy.
In Taiwan, oral cancer is the fourth leading cause of cancer death for males. Radiation therapy (RT) is an important and potential treatment modality for oral squamous cell carcinoma (OSCC). However, tumor radioresistance is a major contributor to radiotherapy failure. Although cisplatin and 5-flurouracil (5-FU) are common potent radiosensitizers and combined RT could improve the outcome in locoregionally advanced OSCC [1-3], clinical outcomes clearly show that these advanced approaches cannot completely overcome radioresistance in OSCC. Moreover, toxicities of these drugs not only decrease patients' quality of life, but also limit overall treatment response. Thus, identifying novel strategies for sensitizing OSCC cells to the effects of ionizing radiation (IR) will improve potency or decrease the toxicity in these patients.
The PI3K/AKT/mTOR signaling pathway has been extensively studied owing to growing evidence supporting its critical role in cancer progression; it influences metabolism, tumor growth, survival, and the development of metastases [4]. Recently, therapeutic compounds that target this pathway have been developed and are currently being evaluated in clinical trials for several malignancies [5] including OSCC cancers [6]. The PI3K/AKT/mTOR signaling pathway is also known to be overstimulated in cancer cells or in tumors resistant to treatments such as chemotherapy, radiation, as well as hormone therapy [3]. Recent findings suggest that dual targeting of PI3K and mTOR has the ability to overcome resistance to IR and improve the anticancer efficacy of the treatment in various cancer cell types in vitro and in in vivo xenograft models of cancer [7-9].
Although radioresensitizing using dual PI3K/mTOR inhibitors has been reported in head and neck cancer cell lines [10], these results only reflect the OSCC tumor subtype and do not truly represent the clinical situation. In the present study, we used a human radioresistant OSCC cell line that was established by Hon-Yi Lin and Michael W.Y. Chan et al. [11] to examine the radiosensitizing effects of single and dual PI3K/AKT/mTOR inhibitors by using both in vitro and in vivo models. Particularly, we established a patient-derived OSCC cell culture isolation of tumor tissues that served as a preclinical model. This model could be of clinical value and provide insights into the effects of combination treatments with PI3K/mTOR inhibitors and RT, as well as the putative mechanisms through which they act. Furthermore, our findings showed that dual a PI3K/mTOR inhibitor could efficiently overcome radioresistance in oral cells and sensitized oral carcinoma cells to IR. Therefore, this is a promising therapeutic approach that may replace cisplatin, a drug with known considerable toxicity, to improve treatment results.
Inhibition of the PI3K/AKT/mTOR signaling pathway sensitizes radioresistant cells to IR
To confirm the radioresistant phenotype of the OML1-R cell line, we determined the plating efficiency of the parental OML1 and the radioresistant OML1-R subline cells that were cultured after a high-dose fractionated IR exposure (10 Gy), and then examined using the clonogenic survival assay. OML1-R cells demonstrated significantly higher levels of clonal survival after IR in comparison with that of the parental cells (Figure 1A). We also analyzed the expression profiles of AKT/mTOR signaling pathway-related proteins; both p110 and p85 PI3K showed high expression levels in OML1-R cells. Additionally, phospho-AKT and mTOR downstream effectors, phospho-4EBP1 and eIF4E, displayed significantly higher expression levels in OML1-R cells (Figure 1B). Next, we determined that dual PI3K/mTOR inhibition with 100 nM BEZ235 in combination with IR dramatically inhibited the proliferation of OML1 and OML1-R cells compared to that by the mTORC1 inhibitor RAD001 with IR, or IR alone(Figure 1C). Thus, our findings suggest that the PI3K/Akt/mTOR signaling pathway is actively involved in OSCC radioresistance and that disruption of the PI3K/AKT/mTOR signaling pathway using the dual PI3K/mTOR inhibitor sensitizes cells to RT and overcomes OSCC radioresistance.
Figure 1: The dual PI3K/mTOR inhibitor reduces radiation survival of OML1-R and parental cells. (A) Clonogenic assay in radioresistant OML1-R and parental OML1 cells using a single 10 Gy IR. Cells were allowed to recover for 14 days and then stained with 0.4% crystal violet. (B) Expression of AKT and mTOR signaling pathway molecules in OML1-R and OML1 cells. Cells were lysed and processed for western blot analysis. (C) The radiosensitizing effect of an mTORC1 inhibitor and BEZ235, a dual PI3K/mTOR inhibitor, in both cell lines. Cells were exposed to IR (4 Gy) with and without RAD001 (300 nM) or BEZ235 (100 nM). The colonies were imaged at 14 days. The number of colonies in each well was counted. Data represent the mean ± SD of three independent experiments performed in triplicate. SD = standard deviation.
Inhibiting the PI3K/AKT/mTOR signaling pathway enhances radiosensitization in OSCC cell lines and patient-derived cells
We investigated whether targeting the PI3K/AKT/mTOR signaling pathway could sensitize OSCC cells to IR and reduce IR-induced radioresistance. For this purpose, we treated OSCC (SCC4, SCC25) and OML1-R cell lines with NVP-BEZ235 (50 or 100 nM) for 14 days, followed by IR (0–4 Gy). The combination of NVP-BEZ235 and IR clearly reduced proliferation of OSCC and radioresistant OSCC cell lines (Figure 2A). To confirm the clinical effectiveness of the dual PI3K/mTOR inhibitor, we isolated and expanded four primary tumor cells from OSCC patients and then treated them with NVP-BEZ235 with and without IR. Four cell lines derived from human OSCCs had been demonstrated for their different radiosensitivity. Cells derived from patients who had lymph node metastasis (N+) or local recurrence after radiotherapy revealed a higher colony growth after exposure to 4 Gy of IR when compared with those cells derived from the Patient 1 and 4. Consistently, the combination treatment of BEZ235 and IR significantly reduced colony formation in all primary OSCC cells (Figure 2B and Table 1). Thus, inhibition of the PI3K/AKT/mTOR signaling pathway enhances radiosensitivity in OSCC cells by repressing their colony formation ability.
Figure 2: The dual PI3K/mTOR inhibitor enhances the radiosensitization of OSCC cells and patient-derived cells. Effect of BEZ235 and IR on OSCC colony formation. (A) SCC4 and SCC25 cells were treated with AZD2014, IR, or the two treatments in combination to then perform a colony formation assay. Data represent the mean ± SD of three independent experiments (B) Patient-derived cells were established from four individual patients with OSCC. Typical images of colony growth for the different treatments are shown. The clinical and pathologic characteristics of patients are listed in Table 1.
Table 1: Information of patients and corresponding patient-derived cell models
Age/sex
Tumor location
Left upper lip
Left buccal
Left cheek
Right tongue
Tumor differentiation
Moderately to pooly
Image staging
cT2N0M0
rcT4aN0
cT4aN0M0
Pathological Staging
pT3N0
rpT4aN0
pT4aN0
Patient has received radiation therapy
Combining a PI3K/mTOR signaling pathway inhibitor with radiation therapy is an effective anticancer strategy
Cisplatin has demonstrated radiosensitizing abilities of platinum-based compounds for the control of locoregional diseases in locally advanced head and neck cancers [3]; thus, we evaluated and compared the effects of the dual PI3K/mTOR inhibitor BEZ235, the pan-PI3K inhibitor BKM120, the mTORC1/mTORC2 inhibitor AZD2014, and Cisplatin with and without IR on SCC25, OML1-R, and primary OSCC cells. The combination treatment of BEZ235 and 4-Gy IR consistently showed a significant reduction in colony formation compared with that by each single PI3K or mTOR inhibitor (BKM120 or AZD2014) with or without IR. However, no significant differences were seen after cisplatin plus IR (Figure 3A) treatment in these three cell lines. In addition, we also found that AZD2014 was more effective than BKM120 in reducing clonogenic survival of SCC25 and primary OSCC cells.
Figure 3: Comparison of the radiosensitizing effects of PI3K/mTOR inhibitors and Cisplatin in OSCC cells. (A) SCC25, OML1-R, and patient-derived cells were treated with a dual PI3K/mTOR inhibitor, Cisplatin, and a single inhibitor (AZD2014 or BKM120) with or without IR for performing colony formation assays. Typical images of colony growth for the different treatments are shown. Quantitative analysis of individual colonies, stained cells were lysed and measured by a spectrophotometer, and the relative number of cells was expressed as OD580. Data were expressed as means ± SD (n=3). (B) Cells were treated with BEZ235 (100nM), cisplatin (0.5 mg/mL), and/or IR for 7 days. Cell viability was then analyzed by using MTT method. Values represent averages of three experiments, and bars indicate means ± SD. Graph shows fold change: BEZ235 combined with IR versus BEZ235 alone, and cisplatin combined with IR versus cisplatin alone.
In order to further confirm the PI3K/mTOR inhibitor to enhance IR-induced cytotoxicity more effectively, we examined cytotoxic effects of IR plus BEZ235 or cisplatin on cancer cells growth. We found that treatment of BEZ235 alone for oral cancer cell lines showed a 57%–77% survival rate, when combined with RT, significantly viability was reduced to 21%-32% in all cells. BEZ235 in combination with IR increased cell growth inhibition rates of 2.4 to 6.3 fold when compared with BEZ235 alone (Figure 3B). On the other hand, the addition of cisplatin obviously decreased the cell viability of OML1-R, SCC25 cells, and primary OSCC cells by 23.1%, 28.0% and 21.1%, and significantly reduced cell growth by 19.6%, 8.7% and 6.9% when combined with IR, respectively. When compared with cisplatin alone, combined IR increased a maximal 3-fold cell growth inhibition.
The above results showed that BEZ235 had a lower toxicity than cisplatin. More notably, when the cell lines were exposed to BEZ235 in conjunction with IR, cytotoxicity was obviously augmented. The tumor-killing effects of radiation were enhanced by adding BEZ235 in both radiosensitive and radioresistant OSCC cells.Our results suggested that inhibiting the PI3K/AKT/mTOR signaling pathway acts additively with IR, decreases proliferation of OSCC cells, and re-sensitizes resistant cells to IR obviously.
Inhibition of the PI3K/AKT/mTOR signaling pathway sensitizes OSCCs to radiation by down-regulating the AKT/mTOR axis and inducing autophagic activity
To investigate the involvement of the AKT/mTOR signaling pathway in the radiosensitization conferred by dual inhibition of the PI3K/mTOR signaling pathway, cells were treated with BEZ235 and/or exposed to 4 Gy of IR. Western blotting analyses revealed that treatment with BEZ235 diminished expression levels of phosphorylated AKT (phospho-AKT) in all OSCC cells. Consistently, we found that BEZ235-treated OSCC cells exposed to IR showed reduced levels of mTOR effectors including S6 kinase, 4EBP1, and eIF4E (Figure 4A). Therefore, inhibition of the PI3K/mTOR signaling pathway efficiently attenuated phosphorylation of AKT and mTOR signaling cascades, concomitantly blocking proliferation of OSCC cell lines, primary OSCCs, and radioresistant cells. We further examined whether cell death pathways (apoptosis and autophagy) were associated with OSCCs radiosensitivity after combination treatment of BEZ235 with IR. LC3 expression levels were increased after the combination treatment of BEZ235 and IR; however, neither apoptosis markers (Caspase 3, Bax, Bak) nor γ-H2AX, a sensitive marker of DNA damage response, showed significant differences after combination treatment (Figure 4B). Thus, these findings indicate that BEZ235 may be effective as a radiosensitizing agent against OSCC cell growth through enhanced inhibition of the AKT/mTORC axis and induction of autophagy activity.
Figure 4: The dual PI3K/mTOR inhibitor sensitized OSCC cells to radiation, which led to reduced clonogenic survival by inhibiting AKT/mTOR signaling and inducing autophagy. Cells were treated with IR alone or in combination with BEZ235. AKT/mTOR signaling pathway- (A) apoptosis-, autophagy-, and DNA damage pathway-related proteins (B) were analyzed by western blotting.
Inhibition of the PI3K/AKT/mTOR signaling pathway promotes G1 phase arrest by altering cell cycle-related proteins
The PI3K/AKT/mTOR signaling pathway has been shown to play a distinct role in the regulation of the cell cycle [13]. Moreover, radiosensitization due to inhibition of the PI3K/AKT/mTOR signaling pathway has been shown to cause cell cycle arrest [14, 15]. Based on these findings, we demonstrated that BEZ235 significantly increased the proportion of OSCC cells (SCC4 and SCC25) and IR-resistant cells (OML1-R) in the G1 phase. Similar results were observed for three primary OSCC cell lines, which had a higher ratio of cells in the G1 phase after treatment with BEZ235. Additionally, the proportion of G2/M phase cells increased in IR-treated cells, whereas cells in the S phase decreased, indicating a G1/G2/M block (Figure 5A). In order to understand the molecular basis of the BEZ235-induced G1 arrest in cell growth inhibition, we investigated the probability of changes in expression levels of diverse regulators of the cell cycle, particularly those associated with G1 checkpoints such as cyclin D1, and CDK4 [16]. In the presence of BEZ235, cyclin D1 and CDK4 were significantly decreased; however, there were no obvious changes in the expression levels of these molecules in neither control nor IR-treated cells (Figure 5B). In agreement with the cell-cycle distribution analysis, inhibition of the PI3K/mTOR signaling pathway significantly reduced the expression of cyclin D1 and CDK4, causing cell cycle G1 arrest, thus contributing to the growth-inhibitory effects in all OSCC cells.
Figure 5: Combination treatment with the dual PI3K/mTOR inhibitor and IR causes G1 cell cycle arrest in OSCC cells by regulating cell cycle-related proteins. (A) Cells were treated with BEZ235 with or without IR for 48 h. The cell cycle distributions were then evaluated. Data are representative of three independent experiments. (B) Expression of Cyclin D1 and CDK4 cell-cycle-related proteins in OSCC cells as determined by western blotting.
Combination of PI3K/AKT/mTOR pathway inhibitors and RT enhanced growth inhibition in an in vivo tumor model
Next, we tested the role of the dual PI3K/mTOR inhibitor in tumor growth and radiosensitivity of an OML1-R xenografted mouse model. Mice bearing subcutaneous OML1-R tumors were randomized into three groups to receive: 1) IR alone (4 Gy fraction, thrice each week), 2) IR combined with BEZ235 (25 mg/kg BEZ235 twice weekly p.o.) or 3) sham treatment. IR treatment enhanced the suppression of OML1-R tumor growth compared to that by the control. IR in combination with BEZ235 significantly suppressed the growth of xenografted tumors to a greater extent than IR alone (p = 0.00017) (Figure 6A). The combination treatment did not significantly reduce mouse body weight (Figure 6B). To further confirm the biological significance of PI3K/mTOR inhibition in vivo, we examined the expression profile of mTOR signaling pathway-related molecules in tissue specimens of OML1-R xenografted tumors, three weeks after treatment. Immunohistochemistry analysis revealed a significant reduction in phospho-S6 and eIF4E levels in tumor-bearing radioresistant OML1-R mice treated with BEZ235 compared with that by either IR or control treatments (Figure 6C).
Figure 6: Treatment with a dual PI3K/mTOR inhibitor in combination with IR inhibits tumor growth of OML1-R xenografted tumor. After subcutaneous injection of OML1-R oral cancer cells, athymic nude mice were treated with vehicle, IR alone (4 Gy), or with a combination of BEZ235 and IR. (A) As represented on the graph, tumor growth measurements were followed from 1 to 21 days as tumor volume. Tumors were measured after animals were sacrificed. (B) Body weight assessment after treatments. (C) Immunohistochemical analysis of phospho-S6 and eIF4E in xenograft tumors.
Although RT is a powerful tool to treat oral cancer, resistance of tumor cells to this treatment remains a serious concern. Therefore, understanding the molecular mechanisms involved in the sensitivity of tumors to IR that lead to the acquisition of radioresistance and the identification of targets for its therapeutic use are important to improve RT and overcome radioresistance. The PI3K/AKT/mTOR signaling pathway has been extensively studied and demonstrated to be critical for RT resistance in various cancer types [17-19]. Although prior studies observed radiosensitization in response to treatment with dual PI3K/mTOR inhibitors (in other cancer cell lines both in vitro and in vivo) [20, 21], an in vitro condition does not truly represent clinical scenarios. Combining dual PI3K/mTOR inhibitors and IR treatment exhibits a synergistic anticancer effect on OSCC; however, this has only been partially explored and remains largely unknown. In this study, we used a radioresistant cell line and patient-derived OSCC cells to improve the understanding of radioresistance of oral cancer cells and the role of the PI3K/AKT/mTOR signaling pathway in radiosensitization.
The PI3K/AKT/mTOR signaling pathway is one of the most frequently dysregulated signaling cascades in human malignancies [13, 22] and has been known to play a pivotal role in the initiation and progression of malignancies, enhancement of cell survival, proliferation, and cellular metabolism. Moreover, this pathway has been implicated in radioresistance [17-19]. Drugs that target PI3K, or mTOR have been extensively developed and are being tested in clinical trials demonstrated that combined with radiation improved the anticancer effect. However, signaling events elicited by PI-3K and mTOR are complex and although overlapping, have non-identical functions that regulate cell survival and therapeutic resistance. We found higher expression levels of PI3K/AKT/mTOR-related proteins in radioresistant OSCC cell lines compared with that in the parental cell lines, suggesting that the PI3K/AKT/mTOR signaling pathway contributes to OSCC radioresistance. Numerous small molecular drugs targeting individual PI3K, AKT, or mTOR signaling proteins or dual blockade of PI3K and mTOR have been reported to induce a radiosensitizing effect. However, the key molecular acts in this pathway contributing to sensitize cells to IR still not clarified. We compared the inhibitory effects of these drugs and found that combining PI3K/AKT/mTOR inhibition with IR resulted in decreased survival of IR-resistant cells, patient-derived OSCC cells, and other OSCC cell lines. However, an mTORC1 inhibitor or PI3K inhibitor with or without IR could not repress tumor cell growth.
These data are consistent with previous our findings [23], Everolimus (RAD001) allosterically inhibits only mTORC1 but not mTORC2 causing feedback activation of AKT signaling due to not directly inhibit mTORC2 function, which can attenuate their antitumor activity. Conversely, dual mTORC1/mTORC2 inhibition increased the IR-induced inhibition of survival in both OSCC cell lines and patient-derived cells. Nevertheless, AZD2014 treatment did not affect radioresistant cells; results consistent with a previous study [12, 23]. BKM120 is a highly specific, orally available pan-Class I PI3K inhibitor that exhibits potent antiproliferative and synergistic radiosensitization in tumor cell lines [24, 25]. Our results demonstrated that NVP-BKM120 did not significantly enhance cell killing after IR exposure. Importantly, the combination of dual PI3K/AKT/mTOR inhibitors with IR significantly enhanced IR-induced regression of OSCC cells as efficiently as Cisplatin with IR treatment, indicating that dual PI3K/mTOR inhibition is a promising therapy that can potentially enhance the tumor response to radiation therapy in the clinic. These results provide a strong rationale for dual targeting of PI3K and mTOR activity to completely overcome radioresistance in OSCC and enhance radiosensitivity of OSCC cells, resulting in cell growth inhibition.
The PI3K/AKT/mTOR axis plays a crucial role in the regulation of cell growth migration, survival, and protein synthesis. Specifically, mTOR is a key regulator in mRNA translation and cell cycle progression via regulation of p70S6K and 4EBP1/eIF4E cascades [26, 27]. Moreover, mTOR signaling is often found activated and plays an important role in development of OSCC. It has been previously shown that inhibition of S6 phosphorylation via blocking of mTOR effectively suppressed, but did not completely prevent 4EBP1/eIF4E cascades, which may limit the utility of this therapeutic drug. Remarkably, although treatment with a dual PI3K/mTOR inhibitor led to efficient AKT inhibition and complete inhibition of both p70S6K and 4EBP1/eIF4E signaling, it showed a marked inhibitory effect on OSCC growth. These results support the finding that the anti-tumor effects of OSCC are required for effective inhibition of both PI3K and mTOR signaling pathways.
The S6K1 and 4EBP1/eIF4E signaling pathways have been shown to be critical for mTOR-mediated cell cycle progression. Both S6K1 and 4EBP1/eIF4E have been implicated in rapamycin-induced retardation of G1 cell cycle progression [28]. The eukaryotic initiation factor 4E (eIF4E) plays an important role in mRNA translation by binding the 5′-cap structure of the mRNA and promoting the formation of the translation initiation complex and ribosome binding. Expression of eIF4E is commonly elevated in human and experimental cancers and has been associated with promoting angiogenesis and tumor growth. Elevated eIF4E expression levels selectively elevate the expression of the oncogenes, c-myc and cyclin D1, which are involved in cell-cycle processes [29]. The previous results strongly suggested that suppression of eIF4E is also important for complete G1 cell cycle arrest. To further assess the synergistic effects of these proteins in the all tested OSCC cells after IR or combined drug-IR treatment, we analyzed the cell cycle phase distributions. We found that inhibition of the PI3K/AKT/mTOR signaling pathway causes cell cycle arrest in the G1 phase. Additionally, expression levels of cyclin D1 and CDK4, regulators of the G1 phase, were significantly downregulated. It was also reported that inhibition of mTOR can cause G1 arrest in a manner that could be suppressed through 4EBP1 phosphorylation; however, mTOR inhibition is not sufficient to suppress eIF4E in most cells [12, 23, 30].
Although de-repression of eIF4E was observed in BEZ235-treated OSCC cells, the inhibition of the cyclin D1/CDK4 complex activity leads to G1 cell cycle progression. These data demonstrate synergistic effects of combining a dual PI3K/mTOR inhibitor with IR to repress both S6K and 4EBP1/eIF4E signaling pathways and induce G1 arrest by inhibiting cyclinD1 and CDK4 activities, resulting in increased sensitivity towards IR. These data suggest that eIF4E represents a logical therapeutic target to increase tumor cell radiosensitivity and overcome cancer radioresistance that may support potential clinical value of eIF4E-targeting strategies for oral cancer treatment. Additionally, we examined the effect of combination treatment with dual or single IR on the induction of apoptosis and autophagy. Treatment with BEZ235 in combination with IR caused a slight induction of autophagy, whereas it had no relevant effect in apoptosis of OSCC cells for any of the treatments. γ-H2AX formation has normally been associated with the induction of double-strand breaks after exposure to IR or other DNA-damaging agents [31], and has been previously shown to be associated with radiosensitization after mTOR inhibition [32]. However, we did not observe any notable differences in phosphorylation of γ-H2AX for any treatment.
Finally, we confirmed the safety and efficacy of dual PI3K/mTOR inhibition in vivo. BEZ235 displayed a statistically significant anti-tumor activity and synergy with IR against OML1-R xenografts and an attenuation effect of eIF4E and S6K phosphorylation. No significant weight loss or illness was observed during the study period, suggesting that this therapy may have a promising safety profile. Furthermore, combination treatment of BEZ235 and IR in vivo is a safe and effective treatment that offered a greater therapeutic gain than that of RT alone.
In summary, this study confirmed that PI3K/AKT/mTOR signaling pathway activation has a role in radioresistance of oral cancers. More notably, the present study declared that combining a novel agent of BEZ235 to inhibit the PI3K/mTOR signaling pathway is a potential therapeutic strategy for irradiating OSCC, including patient-derived cells, OSCC radioresistant cell lines, and xenografts. The radiosensitization efficiency of BEZ235 is achieved by impairing S6K1 and 4EBP1/eIF4E signaling pathways, inducing cell-cycle arrest, and inducing autophagic cell death that causes cell proliferation or cell growth inhibition. These data suggested that an inhibitor of the PI3K/AKT/mTOR signaling pathway appears to be a potential therapeutic drug candidate for restoring radiosensitivity in oral cancers that were intrinsically or consequently resistant to RT. More importantly, it demonstrates a potential to replace the standard cisplatin-based RT, which has serious secondary effects such as toxicity, and provide useful information to predict therapeutic efficacy of OSCC.
This study was initiated after a formal approval of the institutional review board (IRB) of the Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taiwan (approved number, B10302008). All experiments involved human samples were obtained from patients who had surgical tumor resection and signed an informed consent.
Reagents and chemicals
BEZ235, RAD001, and BKM120 were provided by Novartis Pharmaceuticals Corporation (East Hanover, NJ, USA). AZD2014 was obtained from AstraZeneca (London, United Kingdom). Cisplatin was obtained from Fresenius-Kabi (Bad Homburg, Germany). Stock solution were prepared in DMSO, stored at −20 °C, and diluted in fresh medium for each experiment.
Cell lines and cell culture
SCC4 and SCC25, which were derived from a squamous cell carcinoma of the tongue, were purchased from the American Type Culture Collection (ATCC; Manassas, VA, USA), and cultured in DMEM/F12 containing 10% fetal bovine serum (FBS), 1% penicillin-streptomycin and 2 mM l-glutamine. OML1 and OML1-R (Radioresistant) cells were established by Hon-Yi Lin and Michael W.Y. Chan et al. [11] and maintained in RPMI1640 containing 10% FBS, 1% penicillin-streptomycin, and 2 mM l-glutamine. Cells were cultured at 37 °C under a humidified atmosphere of 5% CO2 and 95% air.
Tissue specimens and initial cell culture
The establishment of primary cultures was successfully attained from four tumor tissues of patients with oral squamous cell carcinoma (including the lips, buccal mucosa, cheek tissue, and tongue). The cells were maintained in keratinocyte growth media (KGM; ScienCell Research Laboratories, Carlsbad, CA) with 15% FBS. All patient-derived cells were isolated according to a protocol previously described [12].
Clonogenic assay
The OSCC cell lines, radioresistant OSCC cells, and patient-derived cells were pre-treated with RAD001, BEZ235, BKM120, or cisplatin and irradiated at 0, 2, or 4 Gy. After 14 days, colonies (defined as groups of > 50 cells) were stained with 0.05% crystal violet and counted. Pictures were acquired using a digital camera to count the colonies.
Cell cycle profiling
The effects on the cell cycle in OSCC cell lines, radioresistant OSCC cells, and patient-derived cells exposed to BEZ235 (100 nM) and/or IR for 48 h were assessed with the NucleoCounter NC-3000 (ChemoMetec, Allerød, Denmark), which is based on the analysis of DAPI-stained cells.
After treatment, cells were harvested and lysed, and protein concentrations were measured using the Bio-Rad protein assay kit (Bio-Rad, Richmond, CA, USA). Fifty micrograms of protein from each sample were separated by SDS-PAGE and transferred to a PVDF membrane (Millipore, Billerica, MA, USA). After blocking with non-fat dry milk for 1 h, membranes were incubated with the corresponding primary antibodies [PI3K p110α, PI3K p110β, PI3K p85β, phospho-mTOR (Ser2448), Rictor, phospho-AKT (Ser473), phospho-S6 (Ser235/236), phospho-4EBP1(Ser65), eIF4E, BAK, BAX, cleaved Caspase3, LC3, CyclinD1, CDK4, and γ-H2AX] and secondary antibodies for 1 h. All antibodies used in this study were obtained from Cell Signaling Technology (Beverly, MA, USA). Reactive bands were visualized using a chemiluminescence (ECL) detection kit (Millipore).
In vivo radioresistance of mouse xenografts
Radioresistance of OML1-R transplanted xenografts in nude mice was established according to an already established method [11]. Male 3-week-old athymic nude mice (BALB/cAnN.Cg-Foxn1nu/CrlNarl) were obtained from the National Laboratory Animal Center, Taiwan. OML1-R cells (2 x 106 cells) were injected subcutaneously into the flank of each mouse. When tumors reached a size of approximately 100 mm3, mice were randomized into three groups: Vehicle control, RT, and BEZ235+RT. BEZ235 was formulated in DMSO and intraperitoneally injected at a dose of 25 mg/kg three times in one week. Mice in IR groups were irradiated with a single dose of 4 Gy fractions two times in one week. Tumor volume was monitored and presented as the tumor volume growth ratio (final volume/initial volume).
Tumor specimens from mice were fixed with 10% formaldehyde and embedded in paraffin. Five micrometer sections were cut, deparaffinized, and stained using a mouse monoclonal antibody for phospho-S6 (Ser235/236) and eIF4E (1:50, Cell Signaling Technology).
All data were presented as the mean ± standard deviation. Significance levels were calculated by using Student's t-test, and p-values of less than 0.05 were considered statistically significant.
RT: radiation therapy
OSCC: oral squamous cell carcinoma
IR: ionizing radiation
Conception and design: YC Su, SK Hung, HF Liao, Hb Huang
Acquisition of data: CC Yu, HC Ho, HY Lin, HF Liao
Analysis and interpretation of data: YC Su, SK Hung, WY Chiou, MS Lee, Hb Huang
Writing, review, and/or revision of the manuscript: CC Yu, SK Hung, HY Lin
The present study was supported by research grants from: 1). Buddhist Dalin Tzu Chi Hospital (DTCRD102(2)-I-15 and DTCRD103(2)-I-02; 2). Department of Life Science and Institute of Molecular Biology, National Chung Cheng University (IACUC no.1040602).
Nothing to declare.
All funding sources provided study budgets only.
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I am a registered nurse working in my community ED. I am a BIG geek, former ballerina, and most importantly traveler. I was bitten by the travel bug at a young age and have been traveling ever since. I am a bit type A, and most of my trips are planned almost to the minute. However, I do know about the importance of impromptu travels. I love walking my way through a city, including getting lost at times. I also love to eat my way thru a city. Food is such an important part of a culture and can tell you a lot about the people and their history. Plus it's supper yummy!


text:
Luke James - I.O.U
It's easy to see why Luke James was chosen as the support act for Beyoncé on the UK leg of her current world tour. Audience full of screaming girls? Give them a singing torso.
But is there more to James than this shallow attempt at winning over a female audience? As well as his six-pack, James showcased his impressive vocal abilities – ranging from a smooth tenor to a piercing, bright falsetto. And strutting around the stage, he performed with a confidence far beyond his 'support act' status.
Yet his voice doesn't impress half as much on the record of I.O.U, his latest single. Largely, this is due to the quality of the music. I.O.U quickly settles into a mid-tempo R&B groove that fails to excite, with a limited melody and soppy, clichéd lyrics ("just like my favourite wine it gets better every time", "Baby ain't nobody else in my vision, only loving you is my mission"). It might have a sexy feel and funky, syncopated bassline, but it lacks the invention of his contemporaries.
A voice like this deserves better. Instead, James comes across as a poor man's Miguel.
Listen: I.O.U is available now.
Labels: Beyonce, I.O.U, Luke James, Music, The Mrs Carter Show
Haim @ Koko, London
When Saints Go Machine - Infinity Pool
Jessie J feat. Big Sean & Dizzee Rascal - Wild
Muse @ The Emirates Stadium
Field Day 2013 - Highlights
Prides - Out Of The Blue
Wozzeck - ENO @ The Coliseum
The Great Gatsby (2013) - Baz Luhrmann
Robin Thicke feat. T.I. & Pharrell - Blurred Lines
30 Seconds To Mars - Love Lust Faith + Dreams
Loreen - We Got The Power
Dizzee Rascal feat. Robbie Williams - Goin' Crazy
Daft Punk - Random Access Memories
Savages - Silence Yourself
Gabrielle Aplin - English Rain
Cloud Boat - Book of Hours
!!! - Thr!!!er
The best of Eurovision 2013
Star Trek Into Darkness (2013) - J.J. Abrams
Editors - A Ton of Love
Demi Lovato - Demi
Beyoncé - The Mrs Carter Show @ The O2
Little Boots - Nocturnes
Benga - Chapter II
Viva Forever @ The Piccadilly Theatre


Below is a selection of articles by programme faculty members which were recently published or are forthcoming. Appearing are representative articles in scientific journals co-authored by faculty members publishing under their EDHEC Business School affiliation.
* Matt Lanfaer and Mark Siebert are graduates of the EDHEC PhD in Finance programme.
Macroeconomic Environment, Money Demand and Portfolio Choice, Abraham Lioui and Andrea Tarelli*, European Journal of Operational Research, , 1 April 2019, Volume 274, Issue 1, Pages 357-374.
*Andrea Tarelli is a graduate of the EDHEC PhD in Finance programme.
Does Household Finance Matter? Small Financial Errors with Large Social Costs, Harjoat Bhamra and Raman Uppal, American Economic Review, March 2019, Volume 109(3), Pages 1116-54.
A Factor- and Goal-Driven Model for Defined Benefit Pensions: Setting Realistic Benefits, John M. Mulvey, Lionel Martellini, Han Hao and Nongchao Li, The Journal of Portfolio Management Quantitative Special Issue, March 2019, Volume 45, Issue 3, Pages 165-177.
Predicting Returns in US Treasuries: Do Tents Matter?, Riccardo Rebonato, International Journal of Theoretical and Applied Finance, 2018, Vol. 21, No. 07, 1850047.
Aggregation of Heterogenous Beliefs, Asset Pricing, and Risk Sharing in Complete Financial Markets, Laurent E. Calvet, Jean-Michel Grandmont and Isabelle Lemaire, Research in Economics, 2018, Volume 72, Pages 117-146.
Life-Cycle Asset Allocation with Ambiguity Aversion and Learning, Kim Peijnenburg, Journal of Financial and Quantitative Economics, October 2018, Volume 53, Issue 5, Pages 1963-1994.
A Reinterpretation of the Optimal Demand for Risky Assets in Fund Separation Theorems, Romain Deguest, Lionel Martellini, Vincent Milhau, Management Science, September 2018, Volume 64, Issue 9, Pages 3971-4470.
Sovereign to Corporate Risk Spillovers, Patrick Augustin, Hamid Boustanifar, Johannes H. Breckenfelder, and Jan Schnitzler, Journal of Money, Credit, and Banking, August 2018, Volume 50 (5), Pages 857-891.
Bond Portfolio Optimization in the Presence of Duration Constraints, Romain Deguest, Frank Fabozzi, Lionel Martellini and Vincent Milhau, Journal of Fixed Income, Summer 2018, Voume 28, Issue 1.
Another Look at the Ho-Lee Bond Option Pricing Model, Young Shin Kim, Stoyan V. Stoyanov, Svetlozar T. Rachev and Frank J. Fabozzi, The Journal of Derivatives, Summer 2018, 25 (4), Pages 48-53.
Recent advancements in robust optimization for investment management, Jang Ho Kim, Woo Chang Kim and Frank J. Fabozzi, Annals of Operations Research, July 2018, Volume 266, Issue 1–2, Pages 183–198.
Local Volatility and the Recovery Rate of Credit Default Swaps, Jeroen Jansen*, Sanjiv Das and Frank J. Fabozzi, Journal of Economic Dynamics and Control, July 2018, Volume 92, Pages 1-29.
*Jeroen Jansen is a graduate of the EDHEC PhD in Finance programme.
Staying on top of the curve: A cascade model of term structure dynamics, Laurent E. Calvet, Adlai Fisher and Liuren Wu, Journal of Financial and Quantitative Analysis, April 2018, Volume 53, Issue 2, Pages 937-963.
Macroeconomic Variable Selection for Creditor Recovery Rates, Abdolreza Nazemi and Frank J. Fabozzi, Journal of Banking & Finance, April 2018, Volume 89, Pages 14-25.
Capital Structure Decesions and the Optimal Design of Corporate Market Debt Programs, Lionel Martellini, Vincent Milhau and Andrea Tarelli, Journal of Corporate Finance, April 2018, Volume 49, Pages 141-167.
A Financially Motivated Extension of the Heston Model for a Joint ℙ- and ℚ-Dynamics Analysis of Variance, Riccardo Rebonato and Chu Ming Ng, Spring 2018, Journal of Derivatives, Volume 25, Issue 3.
Wages and Human Capital in Finance: International Evidence 1970-2011, Hamid Boustanifar, Everett. Grant and Ariell Reshef, Review of Finance, March 2018, Volume 22, Issue 2, 1, Pages 699-745.
Calibrating the Italian Smile with Time-Varying Volatility and Heavy-Tailed Models, Michele Leonardo Bianchi, Svetlozar T. Rachev and Frank J. Fabozzi, Computational Economics, March 2018, Volume 51, Issue 3, Pages 339-378.
The Quickest Way to Lose the Money You Could Not Afford To Lose - Reverse Stress Testing and Other Problems with Maximum-Entropy, Riccardo Rebonato, Journal of Risk, February 2018, Volume 20, No. 3.
Threat of Entry and Debt Maturity: Evidence from Airlines, Gianpaolo Parise, Journal of Financial Economics, February 2018, Volume 127, Issue 2, Pages 226-247.
Proverbial Baskets are Uncorrelated Risk Factors! A Factor-Based Framework for Measuring and Managing Diversification in Multi-Asset Investment Solutions, Lionel Martellini and Vincent Milhau, Journal of Portfolio Management, January 2018, Volume 44, Issue 2, Multi-Asset Special.
Equity Portfolios with Improved Liability-Hedging Benefits, Guillaume Coqueret, Lionel Martellini and Vincent Milhau, Journal of Portfolio Management, Winter 2017, Volume 43, Issue 2, Pages 37-49.
Explosive Rent During Housing Market Exuberance, Frank J. Fabozzi and Keli Xiao, The Quarterly Review of Economics and Finance, November 2017, Volume 66, Pages 100-107.
Fuzzy Decision Fusion Approach for Loss-Given-Default Modeling, Abdolreza Nazemi, Farnoosh Fatemipour, Konstantin Heidenreich, and Frank J. Fabozzi, European Journal of Operational Research, October 2017, Volume 262, Issue 2, Pages 780-791.
How much do means-tested benefits reduce the demand for annuities? Butler, M., Peijnenburg, K. and Staubli, S., Journal of Pension Economics & Finance, October 2017, Volume 16, Issue 4, Pages 419-449.
"Who Internationalizes? Managerial Risk-Taking and Cross Border M&As", Hamid Boustanifar and Flladina Zilja, Academy of Management Proceedings, 2017, No.1.
Sin Stocks Revisited: Resolving the Sin Stock Anomaly, David Blitz and Frank J. Fabozzi, The Journal of Portfolio Management, Fall 2017, Volume 44, Issue 1.
The Market Price of Volatility Risk and the Dynamics of Market and Actuarial Implied Volatilities, Riccardo Rebonato, Journal of Derivatives, Summer 2017, Volume 24, Issue 4, Pages 21-51.
Effects of Spot Market Short-Sale Constraints on Index Futures Trading, Frank J. Fabozzi, Ahmet K. Karagozoglu, and Na Wang, Review of Finance, August 2017, Volume 21, Issue 5, Pages 1975-2005.
Health Cost Risk: A Potential Solution to the Annuity Puzzle, Kim Peijnenburg, The Economic Journal, August 2017, Volume 127, Issue 603, Pages 1598-1625.
The value of convexity: a theoretical and empirical investigation, Riccardo Rebonato, Vladislav Putyatin, Quantitative Finance, July 2017, Pages 11-30.
A Reinterpretation of the Optimal Demand for Risky Assets in Fund Separation Theorems, Romain Deguest, Lionel Martellini, and Vincent Milhau, Management Science, June 2017.
CDS Implied Credit Ratings, Jeroen Jansen* and Frank J. Fabozzi, Journal of Fixed Income, Spring 2017, Volume 26, Issue 4, Pages 25-52.
Who are the value and growth investors?, Sebastien Betermier, Laurent Calvet and Paolo Sodini, Journal of Finance, February 2017, Volume 72, Issue 1, Pages 5-46.
Skillful Hiding: Evaluating Hedge Fund Managers' Performance Based On What They Hide, Rama Malladi* and Frank J. Fabozzi, Applied Economics, 2017, Volume 49, Issue 7, Pages 664-676.
*Rama Malladi is a graduate of the EDHEC PhD in Finance programme.
Penalizing Variances for Higher Dependency on Factors, Frank J. Fabozzi, Jang Ho Kim and Woo Chang Kim, and Frank J. Fabozzi, and Radu Tunaru, Quantitative Finance, 2017, Issue 4, Volume 17, Pages 479-489 (lead article).
Factor Investing and Risk Allocation: From Traditional to Alternative Risk Premia Harvesting, Jean-Michel Maeso and Lionel Martellini, Journal of Alternative Investments, 2017, 20, 1, Pages 27-42.
Calibrating Short Interest Rate Models in a Negative Rate Environment, Frank J. Fabozzi and Vincenzo Russo, Journal of Derivatives, 2017, Volume 24, Issue 4, Pages 80-92.
Exploring Rating Shopping For European Triple A Senior Structured Finance Securities. Frank J. Fabozzi, Mike Nawas, and Dennis Vink, Finance Research Letters, 2017, Volume 20, Pages 35-39.
An Improved Method Least Squares Monte Carlo Valuation Method Based on Heteroscedasticity, Frank J. Fabozzi, Tommaso Paletta, Silvia Stanescu, and Radu Tunaru, European Journal of Operational Research, 2017, Volume 263, Pages 698-706.
Predictability Dynamics of Emerging Sovereign CDS Markets, Ahmet Sensoy, Frank J. Fabozzi, and Veysel Eraslanc, Economics Letters, 2017, Volume 161, Pages 5-9.
Understanding Dynamic Mean Variance Asset Allocation, Abraham Lioui and Patrice Poncet, European Journal of Operational Research, October 2016, Volume 254, Issue 1, Pages 320-337.
The Annuity Puzzle Remains a Puzzle, Kim Peijnenburg, Theo Nijman, Bas Werker, Journal of Economic Dynamics and Control, September 2016, Volume 70, Pages 18-35.
The Intended and Unintended Consequences of Financial-Market Regulations: A General Equilibrium Analysis, Adrian Buss, Bernard Dumas, Raman Uppal, and Grigory Vilkov. Journal of Monetary Economics, August 2016, Volume 81, Pages 25-43.
Ambiguity Aversion and Household Portfolio Choice Puzzles: Empirical Evidence, Kim Peijnenburg, Steve Dimmock, Roy Kouwenberg, Olivia Mitchell, Journal of Financial Economics, March 2016, Volume 119, Issue 3, Pages 559-577.
Bridging the gap: the design of bank loan contracts and distance. Arnt Verriest, Journal of Financial Economics, February 2016, Volume 119, Issue 2, Pages 399-419.


This year Playing Arts make step back a bit and jump further at the same time ) Let me explain why. So if you are a fan of this great collaborative art project, you probably saw earlier created Zero One Edition with really cool illustrated cards. This time Playing Arts team with Aria send an invitation to motion graphics artists to make animated version of this series without limitation of his vision or tools for create it. And here it is, my motion version of eight of diamonds card from Zero One Edition.
Original idea of this illustration came from Valp Maciej Hajnrich.


text:
Welcome, stranger
A Tiger in Eden
Text Publishing (2012)
Beautiful beaches, sexy young backpackers, cheap drinks: southern Thailand in the mid- 1990s is the perfect place for a holiday.
It's also the perfect place for Billy, on the run from the Belfast police—to lie low. He's turning away from a life of crime, but isn't sure where to go.
A series of fights and one-night stands helps put his troubles out of mind for a while. But when Billy ends up in a Buddhist retreat he learns that no matter how far you travel, your past will always catch up with you.
"If ever Irvine Welsh and Elizabeth Gilbert had a love child, then A Tiger in Eden would be the result. The debut novel from Melbourne journalist Chris Flynn is brutal, hilarious and wholly surprising."
"A Tiger in Eden is not for the faint-hearted, but persevere because the journey is more than worth the effort. Flynn's deft characterization of Billy and his eye for contrasting beauty with ugliness takes this novel to a higher level. [It] will leave the reader both inspired and breathless."
"Illuminating mayhem. A wild whirl of Roddy Doyle, James Kelman and Irvine Welsh, with no punches pulled… full of vibrant energy, pulse and earthily scatological humour. As a debut, A Tiger in Eden is impressive – hilarious, terrifying and raunchy."
Sunday Star Times
The weird thing is, right, apart from the fact a good book can take your mind off of things like the past and that, is that I starts speaking different. I could hear myself using words I'd never said before and I was thinking fuck me, I sound all educated or something. Just goes to show you like, I always thought you could never learn nothing from books but I was telling this Scottish lad about it one night at the bar, he was a good Prod so he was, he'd seen Rangers play loads of times, and he says to me sure reading books improves your vocabulary, everyone knows that.
Fuck me, I says, I must of missed the memo.


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text:
package de.jarnbjo.ogg;

import java.io.*;

import de.jarnbjo.util.io.*;

/**
 *
An instance of this class represents an ogg page read from an ogg file
 * or network stream. It has no public constructor, but instances can be
 * created by the create methods, supplying a JMF stream or
 * a RandomAccessFile
 * which is positioned at the beginning of an Ogg page.

 *
 *
Furtheron, the class provides methods for accessing the raw page data,
 * as well as data attributes like segmenting information, sequence number,
 * stream serial number, chechsum and wether this page is the beginning or
 * end of a logical bitstream (BOS, EOS) and if the page data starts with a
 * continued packet or a fresh data packet.

 */

public class OggPage {

   private int version;
   private boolean continued, bos, eos;
   private long absoluteGranulePosition;
   private int streamSerialNumber, pageSequenceNumber, pageCheckSum;
   private int[] segmentOffsets;
   private int[] segmentLengths;
   private int totalLength;
   private byte[] header, segmentTable, data;

   protected OggPage() {
   }

   private OggPage(
      int version,
      boolean continued,
      boolean bos,
      boolean eos,
      long absoluteGranulePosition,
      int streamSerialNumber,
      int pageSequenceNumber,
      int pageCheckSum,
      int[] segmentOffsets,
      int[] segmentLengths,
      int totalLength,
      byte[] header,
      byte[] segmentTable,
      byte[] data) {

      this.version=version;
      this.continued=continued;
      this.bos=bos;
      this.eos=eos;
      this.absoluteGranulePosition=absoluteGranulePosition;
      this.streamSerialNumber=streamSerialNumber;
      this.pageSequenceNumber=pageSequenceNumber;
      this.pageCheckSum=pageCheckSum;
      this.segmentOffsets=segmentOffsets;
      this.segmentLengths=segmentLengths;
      this.totalLength=totalLength;
      this.header=header;
      this.segmentTable=segmentTable;
      this.data=data;
   }

	/**
	 *  this method equals to create(RandomAccessFile source, false)
	 *
	 *  @see #create(RandomAccessFile, boolean)
	 */

   public static OggPage create(RandomAccessFile source) throws IOException, EndOfOggStreamException, OggFormatException  {
      return create(source, false);
   }

   /**
    * This method is called to read data from the current position in the
    * specified RandomAccessFile and create a new OggPage instance based on the data
    * read. If the parameter skipData is set to true,
    * the actual page segments (page data) is skipped and not read into
    * memory. This mode is useful when scanning through an ogg file to build
    * a seek table.
    *
    * @param source the source from which the ogg page is generated
    * @param skipData if set to true, the actual page data is not read into memory
    * @return an ogg page created by reading data from the specified source, starting at the current position
    * @throws FormatException if the data read from the specified source is not matching the specification for an ogg page
    * @throws EndOfStreamException if it is not possible to read an entire ogg page from the specified source
    * @throws IOException if some other I/O error is detected when reading from the source
    *
    * @see #create(RandomAccessFile)
    */

   public static OggPage create(RandomAccessFile source, boolean skipData) throws IOException, EndOfOggStreamException, OggFormatException  {
      return create((Object)source, skipData);
   }

	/**
	 *  this method equals to create(InputStream source, false)
	 *
	 *  @see #create(InputStream, boolean)
	 */

   public static OggPage create(InputStream source) throws IOException, EndOfOggStreamException, OggFormatException  {
      return create(source, false);
   }

   /**
    * This method is called to read data from the current position in the
    * specified InpuStream and create a new OggPage instance based on the data
    * read. If the parameter skipData is set to true,
    * the actual page segments (page data) is skipped and not read into
    * memory. This mode is useful when scanning through an ogg file to build
    * a seek table.
    *
    * @param source the source from which the ogg page is generated
    * @param skipData if set to true, the actual page data is not read into memory
    * @return an ogg page created by reading data from the specified source, starting at the current position
    * @throws FormatException if the data read from the specified source is not matching the specification for an ogg page
    * @throws EndOfStreamException if it is not possible to read an entire ogg page from the specified source
    * @throws IOException if some other I/O error is detected when reading from the source
    *
    * @see #create(InputStream)
    */

   public static OggPage create(InputStream source, boolean skipData) throws IOException, EndOfOggStreamException, OggFormatException  {
      return create((Object)source, skipData);
   }

	/**
	 *  this method equals to create(byte[] source, false)
	 *
	 *  @see #create(byte[], boolean)
	 */

   public static OggPage create(byte[] source) throws IOException, EndOfOggStreamException, OggFormatException  {
      return create(source, false);
   }

   /**
    * This method is called to
    * create a new OggPage instance based on the specified byte array.
    *
    * @param source the source from which the ogg page is generated
    * @param skipData if set to true, the actual page data is not read into memory
    * @return an ogg page created by reading data from the specified source, starting at the current position
    * @throws FormatException if the data read from the specified source is not matching the specification for an ogg page
    * @throws EndOfStreamException if it is not possible to read an entire ogg page from the specified source
    * @throws IOException if some other I/O error is detected when reading from the source
    *
    * @see #create(byte[])
    */

   public static OggPage create(byte[] source, boolean skipData) throws IOException, EndOfOggStreamException, OggFormatException  {
      return create((Object)source, skipData);
   }

   private static OggPage create(Object source, boolean skipData) throws IOException, EndOfOggStreamException, OggFormatException  {

      try {
         int sourceOffset=27;

         byte[] header=new byte[27];
         if(source instanceof RandomAccessFile) {
            RandomAccessFile raf=(RandomAccessFile)source;
            if(raf.getFilePointer()==raf.length()) {
               return null;
            }
            raf.readFully(header);
         }
         else if(source instanceof InputStream) {
            readFully((InputStream)source, header);
         }
         else if(source instanceof byte[]) {
            System.arraycopy((byte[])source, 0, header, 0, 27);
         }

         BitInputStream bdSource=new ByteArrayBitInputStream(header);

         int capture=bdSource.getInt(32);

         if(capture!=0x5367674f) {
            //throw new FormatException("Ogg page does not start with 'OggS' (0x4f676753)");

            /*
            ** This condition is IMHO an error, but older Ogg files often contain
            ** pages with a different capture than OggS. I am not sure how to
            ** manage these pages, but the decoder seems to work properly, if
            ** the incorrect capture is simply ignored.
            */

            String cs=Integer.toHexString(capture);
            while(cs.length()<8) {
               cs="0"+cs;
            }
            cs=cs.substring(6, 8)+cs.substring(4, 6)+cs.substring(2, 4)+cs.substring(0, 2);
            char c1=(char)(Integer.valueOf(cs.substring(0, 2), 16).intValue());
            char c2=(char)(Integer.valueOf(cs.substring(2, 4), 16).intValue());
            char c3=(char)(Integer.valueOf(cs.substring(4, 6), 16).intValue());
            char c4=(char)(Integer.valueOf(cs.substring(6, 8), 16).intValue());
            System.out.println("Ogg packet header is 0x"+cs+" ("+c1+c2+c3+c4+"), should be 0x4f676753 (OggS)");
         }

         int version=bdSource.getInt(8);
         byte tmp=(byte)bdSource.getInt(8);
         boolean bf1=(tmp&1)!=0;
         boolean bos=(tmp&2)!=0;
         boolean eos=(tmp&4)!=0;
         long absoluteGranulePosition=bdSource.getLong(64);
         int streamSerialNumber=bdSource.getInt(32);
         int pageSequenceNumber=bdSource.getInt(32);
         int pageCheckSum=bdSource.getInt(32);
         int pageSegments=bdSource.getInt(8);

         //System.out.println("OggPage: "+streamSerialNumber+" / "+absoluteGranulePosition+" / "+pageSequenceNumber);

         int[] segmentOffsets=new int[pageSegments];
         int[] segmentLengths=new int[pageSegments];
         int totalLength=0;

         byte[] segmentTable=new byte[pageSegments];
         byte[] tmpBuf=new byte[1];

         for(int i=0; i<pageSegments; i++) {
            int l=0;
            if(source instanceof RandomAccessFile) {
               l=((int)((RandomAccessFile)source).readByte()&0xff);
            }
            else if(source instanceof InputStream) {
               l=(int)((InputStream)source).read();
            }
            else if(source instanceof byte[]) {
               l=(int)((byte[])source)[sourceOffset++];
               l&=255;
            }
            segmentTable[i]=(byte)l;
            segmentLengths[i]=l;
            segmentOffsets[i]=totalLength;
            totalLength+=l;
         }

         byte[] data=null;

         if(!skipData) {

            //System.out.println("createPage: "+absoluteGranulePosition*1000/44100);

            data=new byte[totalLength];
            //source.read(data, 0, totalLength);
            if(source instanceof RandomAccessFile) {
               ((RandomAccessFile)source).readFully(data);
            }
            else if(source instanceof InputStream) {
               readFully((InputStream)source, data);
            }
            else if(source instanceof byte[]) {
               System.arraycopy(source, sourceOffset, data, 0, totalLength);
            }
         }

         return new OggPage(version, bf1, bos, eos, absoluteGranulePosition, streamSerialNumber, pageSequenceNumber, pageCheckSum, segmentOffsets, segmentLengths, totalLength, header, segmentTable, data);
      }
      catch(EOFException e) {
         throw new EndOfOggStreamException();
      }
   }

   private static void readFully(InputStream source, byte[] buffer) throws IOException {
      int total=0;
      while(total<buffer.length) {
         int read=source.read(buffer, total, buffer.length-total);
         if(read==-1) {
            throw new EndOfOggStreamException();
         }
         total+=read;
      }
   }

   /**
    * Returns the absolute granule position of the last complete
    * packet contained in this Ogg page, or -1 if the page contains a single
    * packet, which is not completed on this page. For pages containing Vorbis
    * data, this value is the sample index within the Vorbis stream. The Vorbis
    * stream does not necessarily start with sample index 0.
    *
    * @return the absolute granule position of the last packet completed on
    *         this page
    */

   public long getAbsoluteGranulePosition() {
      return absoluteGranulePosition;
   }

   /**
    * Returns the stream serial number of this ogg page.
    *
    * @return this page's serial number
    */

   public int getStreamSerialNumber() {
      return streamSerialNumber;
   }

   /**
    * Return the sequnce number of this ogg page.
    *
    * @return this page's sequence number
    */

   public int getPageSequenceNumber() {
      return pageSequenceNumber;
   }

   /**
    * Return the check sum of this ogg page.
    *
    * @return this page's check sum
    */

   public int getPageCheckSum() {
      return pageCheckSum;
   }

   /**
    * @return the total number of bytes in the page data
    */

   public int getTotalLength() {
      if(data!=null) {
         return 27+segmentTable.length+data.length;
      }
      else {
         return totalLength;
      }
   }

   /**
    * @return a ByteBuffer containing the page data
    */

   public byte[] getData() {
      return data;
   }

   public byte[] getHeader() {
      return header;
   }

   public byte[] getSegmentTable() {
      return segmentTable;
   }

   public int[] getSegmentOffsets() {
      return segmentOffsets;
   }

   public int[] getSegmentLengths() {
      return segmentLengths;
   }

   /**
    * @return true if this page begins with a continued packet
    */

   public boolean isContinued() {
      return continued;
   }

   /**
    * @return true if this page begins with a fresh packet
    */

   public boolean isFresh() {
      return !continued;
   }

   /**
    * @return true if this page is the beginning of a logical stream
    */

   public boolean isBos() {
      return bos;
   }

   /**
    * @return true if this page is the end of a logical stream
    */

   public boolean isEos() {
      return eos;
   }

}

redpajama_set_name: RedPajamaGithub