In the 1980s the Orient Express was used intensely by the Ex-Iraq government for military purposes, to transport military equipment for the Iraqi Army during the Iraq-Iran war. The transportation of tanks and other heavy military equipment inflicted severe damages on the railroad tracks. Partly due to this reason, the passenger trains had nearly stopped during that era.
During the 1990s the international sanctions regime prevented Iraq from continuing their international trains and the travel of trains across Iraq's borders. It was well known that the trains during Saddam's regime were used for transporting soldiers and construction materials. People used to prefer travelling in their cars rather than the trains, due to the poor service and deteriorating conditions of the Iraqi railway.
When the United States bombing campaign began in 2003, many of the railroad tracks were destroyed, the train stations were looted and many key elements of the locomotives were stolen. The Iron used in constructing the trains provided a valuable commodity encouraging many thieves. Stations such as the Baghdad International Train Station were looted by individuals who stole everything down to the spare parts. That prevented the Iraqi Republic Railways company from fixing many trains and keep them in the stations without any news.
Now the Iraqi Republic Railways company is trying to fix the trains and is working on improving the old Orient Express, hoping the railroads will be modernized and good enough for passengers to use regularly in the near future.
This week our correspondent Nabeel Kamal visited the Iraqi Republic Railways company in Baghdad to see how the progress is going with this old company that is in fact older than Iraq itself.


How the Universe Works is a documentary science television series that originally aired on the Discovery Channel in 2010. The first, fourth, fifth and sixth seasons were narrated by Mike Rowe and the second and third by Erik Todd Dellums. The first season, broadcast from April 25 to May 24, 2010, was released on Blu-ray on February 28, 2012. Since its second season, consisting of eight episodes broadcast between July 11 and August 29, 2012, the show has aired on The Science Channel. The third season aired between July 9 and September 3, 2014. The fourth season premiered on July 14, 2015, as part of the Science Channel's "Space Week," in honor of New Horizons′ flyby of Pluto that day; the season ran through September 1, 2015. The show′s fifth season aired from November 22, 2016, through February 7, 2017. The sixth season premiered on January 9, 2018 through March 13, 2018. The seventh season premiered on January 8, 2019 through March 12, 2019.
New discoveries reveal that Earth and the planets were formed from the destruction of strange alien worlds.
Mercury is a deadly world, facing attacks from the Sun, comets, and other planets, and even though it's the smallest planet in our solar system, it has a dangerous secret that might one day threaten life on Earth.
Neutron stars are strange and violent phenomena that defy the laws of physics, and new discoveries reveal that these bizarre nightmares are far more deadly than we ever thought, with the power to destroy planets and even other stars.
Interstellar space is the space between the universe's stars and new discoveries reveal that it's not empty and unremarkable as previously thought, but filled with weird objects and strange phenomena that might hold the darkest secrets of our cosmos.
Black holes aren't the violent monsters we think they are, and new discoveries reveal that they might have been essential to creating stars, giving light, and building the universe itself.
New discoveries are causing astronomers to question if the Big Bang really happened, and using the latest science, they investigate if it wasn't just the start of our universe but many mysterious multiverses.
Dark matter and dark energy are locked in an epic battle for control of the cosmos, and the winner will determine the fate of the universe. New discoveries might reveal which force will emerge victorious.
The latest discoveries suggest that we might be on the verge of discovering life beyond our planet, and scientists are investigating if earth's life began elsewhere in the universe, and whether we need to evolve to know for sure.
For twenty years, NASA's Cassini spacecraft revealed the strange secrets of Saturn until it vaporized in its atmosphere in a blaze of glory. But today its legacy lives on, as fresh data from the probe helps scientists make brand-new discoveries.
^ "How the Universe Works Videos". Discovery Channel. Archived from the original on August 22, 2010. Retrieved September 3, 2010.
^ "How the Universe Works Blu-ray". Amazon.com. Retrieved April 8, 2012.
^ "How the Universe Works Season 2". The Science Channel. Retrieved July 14, 2012.
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^ "Extinction". 13 August 2014. Retrieved 15 November 2016.
^ "Watch Online How the Universe Works Season 3 Episode 6 - Weapons of Mass Extinction". Retrieved 15 November 2016.
^ " "Did a Black Hole Build the Milky Way?". Retrieved 6 March 2018.
^ Mitch Metcalf. "Top 150 Tuesday Cable Originals: 1.9.2018". Showbuzz Daily. Retrieved January 9, 2018.
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^ Mitch Metcalf. "Top 150 Tuesday Cable Originals: 3.06.2018". Showbuzz Daily. Retrieved March 6, 2018.
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^ Mitch Metcalf. "Top 150 Tuesday Cable Originals: 1.8.2019". Showbuzz Daily. Retrieved Jan 8, 2019.
^ Mitch Metcalf. "Top 150 Tuesday Cable Originals: 1.15.2019". Showbuzz Daily. Retrieved Jan 15, 2019.
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^ Mitch Metcalf. "Top 150 Tuesday Cable Originals: 2.12.2019". Showbuzz Daily. Retrieved Feb 12, 2019.
^ Mitch Metcalf. "Top 150 Tuesday Cable Originals: 2.19.2019". Showbuzz Daily. Retrieved Feb 19, 2019.
^ Mitch Metcalf. "Top 150 Tuesday Cable Originals: 2.26.2019". Showbuzz Daily. Retrieved Feb 26, 2019.
^ Mitch Metcalf. "Top 150 Tuesday Cable Originals: 3.5.2019". Showbuzz Daily. Retrieved Mar 5, 2019.
^ Mitch Metcalf. "Top 150 Tuesday Cable Originals: 3.12.2019". Showbuzz Daily. Retrieved Mar 12, 2019.


text:
Running from the Wolves
Adolf (Constantin) Baumgartner-Stoiloff
Period 1850-1900, 19th century, 20th century
Origin Austria, Bulgaria
Medium Oil on canvas
Dimensions 80 x 106.8 cm (31¹/₂ x 42 inches)
Gallery Sphinx Fine Art
This is a lively depiction of a typically Russian winter scene: a small sleigh, drawn by six frightened horses, speeds along in a flurry of snow in an attempt to escape the wolves that are hard on its heels. The sleigh and horses occupy almost the entire field of the composition: the white horse nearest to the viewer and which turns its head in panic towards us, blends in with the white snow and blizzard-filled sky, in a white whirlwind. The other, darker animals provide the landscape with a sense of depth within the churning snowy mass and give relief to the composition.
Adolf Baumgartner-Stoiloff explores, within a quasi-monochrome palette, the difference in texture between the crisp snow underfoot, the clouds and blizzard in the sky, and the powdery, snow-laden trees in the forest. The snow, trampled by the terrified horses, and raised by the blades of the sleigh, is highlighted with small, sharp strokes of black paint, which emphasise its crispness. The sky itself resembles a snow-drift, with an infinite variety of pale shades of white and grey: Baumgartner-Stoiloff uses oil like watercolour in this section of his work, creating almost the effect of a wash. The frontier between the clouds and trees is defined solely by the forest's slightly darker tonality, and the more defined shapes. The grey frothy masses are highlighted with light touches of white; few trunks are visible in the swirling blizzard, and the forest itself melts rapidly into the snowy distance.
The forest and snow-storm concealed the predatory wolves from the eyes of the travellers until the moment was ripe for the attack: their onslaught has visibly startled and terrified the horses, which attempt to career off in different directions, and are barely held in check by their harness and the driver, who is astride one of them. Of the pursuing wolves, one has been shot by the passenger in the sleigh, and is depicted in the act of falling to the hoary ground. The anatomical imprecision of Baumgartner-Stoiloff's depiction of the wolves and the sketchy treatment of the figures emphasise the fact that the main focus of the work is the study of horses. This focus is a common trait in many of his works, such as Russian Caravan Racing in the Snow. Indeed Baumgartner-Stoiloff was renowned particularly as a horse painter.
Adolf Baumgartner-Stoiloff was a Bulgarian artist, born in 1850. According to Russian sources, he studied at the St. Petersburg Academy of Fine Arts in the 1880s. From around 1890 to the early 1900s his Russian scenes with Cossacks and hunters were frequently reproduced in various European magazines. He is known to have worked under various pseudonyms, signing his paintings "A.Baumgartner-Stoiloff" , "Stoiloff", "Constantin Stoiloff" or "C.Stoiloff".
Period: 1850-1900, 19th century, 20th century
Origin: Austria, Bulgaria
Signature: Signed 'C. Stoiloff' (lower left)
Dimensions: 80 x 106.8 cm (31¹/₂ x 42 inches)
Categories: Paintings, Drawings & Prints
Sphinx Fine Art
Old Master & Russian Paintings
A Desert Fort
Aleksandr Evgen'evich Yakovlev (St. Petersburg, 1887 - Paris, 1938)
Portrait of a Gentleman, Probably a Self-Portrait
Carel de Moor (Leiden, 1656 - Warmond, 1738)
A River Scene with Rowing Boats, Cottages on the Shore and a Windmill in the Distance
Esaias van de Velde (Amsterdam, 1587 - The Hague, 1630)
The Sermon on the Mount
Sebastiano Ricci (Belluno, 1659 - Venice, 1734)
Portrait of a Man, Half-Length, in a Grey Coat
Henri-Pierre Danloux (Paris, 1753 - Paris, 1809)
A Winter Landscape with a Troika on a Track
Feodor Karlovich Burhardt (St. Petersburg, 1854 - 1918)

redpajama_set_name: RedPajamaCommonCrawl


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The Princeton Club of Chicago invites you to join Princeton alumni currently working at Citadel to discuss career and growth opportunities across data science, technology and finance today and over the next 3-5 years. Please scroll down to see group of panelists and bios below. Please note that all guests MUST be registered and on the security list. BRING ID. No walk-ins. Thank you!
Many thanks to James Yeh '87 for graciously hosting this event!
Click HERE to reserve by Sunday, November 12th!
Solomon Barnett '05 leads the systematic equities trading desk for the Americas within the core quantitative market making unit at Citadel Securities. He is a licensed financial service professional with a degree in Economics from Princeton University. His central role in the core quantitative trading business over the last decade has exposed him to a broad array of problem solving opportunities around quantitative trading systems, portfolio risk management, low latency technology development and management, business development and managing daily trading operations for the largest market maker in US equity markets.
Lucy DeStefano '99 is the Head of Trading at Aptigon Capital. She joined Citadel in 2016 to lead the buildout of the trading function at Aptigon Capital, Citadel's newest equity investment business. She manages a team of multiple traders that she has built over the past 12 months and develops the trading strategy for the business. Prior to joining Citadel, she was formerly Head of Listed Securities and Co-Portfolio Manager of the Liquid Alternatives business at Pine River Capital Management, and Managing Director and Head of International Equity Trading at Morgan Stanley. She began her career at Goldman Sachs, eventually becoming a Vice President in the firm's Securities division. Lucy and her husband, Chris '94, have three children and also serve as a host family for Right to Dream.
Anna Huang '07 is a member of the Global Trading and Equity Quantitative Research COO team at Citadel. She works across multiple functional teams and businesses in the Asset Manager, primarily focusing on Citadel's equities businesses. She earned a BSE from Princeton majoring in Operations Research and Financial Engineering and a MBA from Kellogg School of Management. Prior to joining Citadel, she was a senior consultant with L.E.K. Consulting and began her career at Morgan Stanley in Fixed Income.
Jack Jablonski '16 is an options trader at Citadel Securities. He earned a BSE from Princeton majoring in Operations Research and Financial Engineering. He was a member of the Men's Lightweight Rowing Team, a Residential College Advisor in Mathey College and a member of the Cap and Gown Club. Jack attended high school at the American School of London and graduated from Pine Crest School in Fort Lauderdale, Florida.
Scott Rickard *03 is Chief Data Scientist and joined Citadel in 2016. He was formerly a professor at University College Dublin, where he founded the Complex & Adaptive Systems Laboratory, where biologists, geologists, mathematicians, computer scientists, social scientists and economists worked together on problems that impact society. He is also the founder of ScienceWithMe!, an online community dedicated to engaging youth through science and math. He received a Bachelor's degree in Mathematics in 1992, a Bachelor's degree in Computer Science and Engineering in 1993, and a Master's degree in Electrical Engineering and Computer Science also in 1993 from M.I.T. He received M.A. and Ph.D. degrees in Applied and Computational Mathematics from Princeton University in 2000 and 2003 respectively.
James Yeh '87 is Senior Managing Director and a member of Citadel's Portfolio Committee. He joined Citadel in 1993 and was the original architect of Citadel's quantitative businesses. He has held a number of senior leadership roles across quantitative and fundamental strategies, including serving as Head of Global Equities. He serves as a Charter Trustee of Princeton University and as a Director of the Princeton University Investment Company. He received an A.B. from Princeton University and a Ph.D. in Physics from the University of California, Berkeley.


If you would like to shadow a PA, OAPA maintains lists of PA volunteers by region. Unfortunately, due to the high demand, undergraduate college students will be given priority for shadowing opportunities. Please contact oapa@ohiopa.com for more information.
OAPA will find a mentor for students and recent grads. You must be a current member of OAPA. Mentors can be assigned by region, specialty or specialty within a region. Contact the OAPA office at oapa@ohiopa.com to be assigned a mentor.


text:
Torah unto all Nations – A Response to the Message of Isaiah 56
Rabbi Avraham Feld Blog, Commentaries, Return and Ingathering of the Lost Ten Tribes of Israel 1
Not only Isaiah 56 but all of the Torah cries out to us to reach out to our fellow Jews, Hebrews (incl. those lost souls of Judah and the House of 10-Israel) and all the nations.
We need to be an educative 'Light to the Nations'.
Here is but a small sampling of the exhaustive sources that are available in the vast library of Jewish Writings.
Our Giants of mind and soul, the Jewish Sages, and our current remnant covenantal faith action community have much to say on the above.
We know that there were three waves of refugees from the North that fled into the bracing arms of Judah, under King Hezekiah and Isaiah. At the same time parts of Judah, Binyamin and Levi were forcibly taken into exile with the Northern Kingdom of 10-Israel. Over the years much of Judah fell into assimilation and hiding among the nations where they still are today. Many Jews and Israelites throughout the ages also intermarried with the nations. In Oral Torah this is called 'Judah in captivity'. Only a small percentage of 10-Israel returned to join with the House of Judah. The Scriptures refer to a giant Ingathering of the exiles as part of the End of Days scenario.
Mazel Tov, Marbruk, Congratulations we have arrived, finally, in the beginning of the Messiah Age. In addition to our own lost family, we have been charged with outreach to the Family of Humankind. One reason for so many religions in the World today was our failure to properly instruct and guide the World. Hey, we were not completely at fault. Severe Exile conditions and being executed by the Roman Empire for making Roman converts to Judaism were inhibiting. It drove Judaism into self-protection mode to keep the Torah just for ourselves. It drove the nations to hatred of Jews simply because we believed in and developed the Torah instructions for Life.
But now we are on a new Dawn of strength, G-D given and driven, so let's get to work. Our Sages have spoken extensively of this Our Divine Mandate and it's high time to listen more in depth. To mention but a few: Iben Ezra, Radak, Nachmanides, Arbarbenel. Chatam Sofer, Rashi and others.
Hey, what is the greatness of Rashi? He was able to learn Chumash (Five Books of Moses) without Rashi. Who was the first to actually learn Chumash with Rashi? Why, his illustrious father, of course! Targum Yonatan, Medrash Tan chuma, Yalket Shmome and on and on.
Please check out KOL HATOR Vision and BRIT AM for more details. BRITAM is presented by well informed commentator and researcher, Yair Davidy.
There will be no complete Redemption for Judah without the return of Ten Israel (Isaiah 11: 12-13; Ezekiel 37; Ezekiel 16: 53, 55,61). We of Judah need to realize and appreciate our obligation to reach out and help bring them back Home (Jeremiah 3: 18; 32:8).The Tribes are called to return to their ancestry (Jeremiah 31: 9-10, 21).
We have hints that the exiles will return to the land and WILL put away their false versions of HaShem and keep Torah as we have received and transmitted it's holiness (Ezekiel 11:20).
It was foretold by our Sages and Prophets that a part of Judah would first return and successfully build up the Land. Then Ten Israel will pitch in and come on home in two stages .First, with a remnant of Judah (Isaiah 56:8; Hosea 6). The Gomorrah in Yevamos and Hosea 1 predicted that Ten Israel would be considered as non-Israelites and as being distinct from Judah – in need of a renewal (Hosea 7:8; Isaiah 11:11, 49:21).
So, along with all the hand washing brought about by Corona, both for cleanliness and ritual purposes, just remember that HaShem got us all in His Hands. He's got the whole wide world in His Hands, so to speak.
Rabbi Avraham Feld
Co-Founder of the Kol HaTor-Project.
His association with the Kol HaTor Vision and Project draws from his passion for the Biblical Prophetical Promise of the Restoration of the House of Israel. Read more.
Redemption - the Main Theme of the Bible - and foundational pillar of two contending religions
The Price for preparing the Promised Land for its ultimate Divine Purpose
Where Is God to Be Found in Exile?
Parashat Lech Lecha (Get yourself going) - Weekly Parashah
Standing at the Gates of the Promised Land in the Second Exodus at the culmination of the Ages
Rabbi Machlis: Haftarah of Parshat Ekev
Parashat Yithro (Abundance) - Weekly Parashah
Yaakov Coetzee
May 15, 2020 @ 12:48 pm
Marvelous stuff, I am absolutely enjoying all the good teachings.
"The Servant of G-d" – Who is this? The true interpretation of 'The Servant of G-d' holds a bold Reawakening Messag... under End Time, Reconciliation, Return and Ingathering of the Lost Ten Tribes of Israel, The Mashiach
Judah – The Lawgiver of God (Hebrew: Mechoqeck) by OvadYah Avrahami co-founder of KOL HATOR Vision for the Resto... under 10-Israel Source, Commentaries


text:
The US Should Get Ready for King Mohammed bin Salman
Since the murder of Jamal Khashoggi in the Saudi consulate in Istanbul on Oct. 2, some American lawmakers have assumed the right and moral authority to dictate the Kingdom of Saudi Arabia's succession line-up. In November, Republican Sen. Lindsey Graham accused Saudi Crown Prince Mohammed bin Salman (MbS) of being "crazy" and asserted that "he needs to go." Such rhetoric is significant given that the U.S. has not meddled in the Al Saud family's internal power struggles since the 1960s. But regardless of the preferences that some politicians in Washington may have regarding Saudi Arabia's succession, the U.S. will likely have to accept dealing with a King Mohammed.
MbS's ascendancy, which began in 2015, has transformed Saudi Arabia. Gone is Saudi Arabia's traditional model of leadership of the pre-MbS era that was based on collective decision-making and consensus building among a large group of princes. By virtue of how much power MbS possesses, it is difficult to imagine any credible challenge to his rule, or position in the succession lineup, no matter the pressure Washington might try to impose.
Even before the Khashoggi affair, MbS's power in Riyadh was so consolidated that the millennial prince faced virtually no constraints from other members of the Al Saud family. In recent months, MbS has only further consolidated his power in the Kingdom despite all the criticisms that MbS has received from lawmakers in the U.S. following the CIA's conclusion that he ordered Khashoggi's murder. Not even the political fallout of the journalist's slaying last year has caused MbS to ease his internal crackdown, or even his targeting of Saudi dissidents overseas with efforts to lure them back to the Kingdom.
Thus, given that the Saudi security apparatus and all the dominant state institutions are under MbS's consolidated control, it is extremely difficult to imagine any successful opposition to the millennial prince from within. While many in the House of Saud dislike MbS, they lack the ability to collectively stop him.
As the Kingdom is an absolute monarchy, the decision to change the succession order can only be made by King Salman. Although Salman, since he became the Saudi monarch in January 2015, has twice dismissed/forced out two other crown princes — Prince Muqrin (in April 2015) and Prince Mohammed bin Nayef (in June 2017) — he has shown no signs of removing his son from succession.
Riyadh: Butt Out
From Riyadh's perspective, foreign powers need to butt out and stop naively pretending they can influence the process. Furthermore, outside pressure on King Salman to fire his son could backfire and give the Saudi leadership more interest in standing by MbS. As Prince Turki al-Faisal, a former chief of Saudi intelligence and a former ambassador to Washington, put it: "The more [foreign] criticism there is of the crown prince, the more popular he is in the kingdom."
Indeed, officials in Riyadh find it outrageous that American lawmakers are trying to weigh in on Saudi Arabia's succession question — a redline for the Kingdom's leadership. For Saudi Arabia's ruling family, changing the succession lineup under pressure from the U.S. government would signal weakness and subservience to the world's superpower at a time when Riyadh is working to project Saudi dominance in the Middle East and greater autonomy from the West as the world becomes more multipolar.
Such pressure from the U.S. would likely accelerate Riyadh's eastward geopolitical pivot which has led to Saudi Arabia investing in deeper ties with China, India, Pakistan, and Russia. With the Saudi leadership questioning the long-term commitment of the U.S. to the Kingdom's security, Riyadh is attempting to diversify its global alliances and partnerships in order to gain greater geopolitical independence from Saudi Arabia's traditional Western allies. The silence from these non-Western governments on the Khashoggi file underscores such non-Western states' keenness to avoid criticizing Saudi Arabia on human rights grounds—a factor that has earned them goodwill with MbS—in order to capitalize on all that deeper ties with Riyadh can offer. In the case of both China and Russia, the Khashoggi case has provided an opportunity to drive a greater wedge between the U.S. and its main ally in the Persian Gulf.
Bilateral Risk
If Trump's successor shares Sen. Graham's view that MbS should never become the King of Saudi Arabia, Riyadh's alliance with Washington could face an unprecedented bilateral crisis. Already, with MbS' reputation among American lawmakers and members of the DC establishment having suffered immense damage following Khashoggi's killing, the Crown Prince simply cannot make a visit to Washington. While for the time being MbS can continue working with a U.S. president whose administration has taken pains to give the crown prince the benefit of the doubt on the Khashoggi file, questions about Saudi-U.S. relations in the post-Trump era must unsettle the Saudi leadership. Given the rhetoric about Saudi Arabia and the Saudi-U.S. alliance coming from some Democratic presidential hopefuls, such as Sen. Bernie Sanders and Rep. Tulsi Gabbard, such concerns cannot be dismissed by MbS.
Of course, there is a potential scenario whereby MbS is targeted internally, possibly meeting the same fate as Anwar Sadat, the Egyptian president who was assassinated. This would prevent the crown prince from becoming custodian of the two holy mosques (the Saudi king's official title since 1986). But such a scenario appears unlikely. What is far more probable is that MbS will become Saudi Arabia's next king, even if this fuels rage in the U.S. Senate. As much as many officials in Washington take major issue with MbS, accepting the unacceptable will likely be necessary. The U.S. will have to contend, one way or another, with a King Mohammed ruling Washington's most important Arab ally and the country that leads globally in oil production and exports.
Doubtless, the implications of MbS becoming the next Saudi king will be felt across the greater MENA region and beyond. As evidenced by the war in Yemen, the blockade of Qatar, the Saudi-Canadian diplomatic spat of August 2018, the Ritz Carlton arrests and Saad Hariri saga of 2017, the millennial prince has made foreign policy decisions that reflect his brashness and impulsive thinking. If MbS has already created such crises for Saudi Arabia and its relationship with Washington over the course of the past four years, it is truly mind boggling to think about what he, as the next king of Saudi Arabia, could do to change the Kingdom and the greater Middle East during the upcoming four or five decades if he rules until his natural death.
By Giorgio Cafiero
Source: Consortium News
Post Tags: #MbS#Saudi Arabia#US
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text:
bims-pimaco Biomed News
on PI3K and MAPK signalling in colorectal cancer
fifteen papers selected by
Lucas B. Zeiger
Beatson Institute for Cancer Research
MNK inhibition sensitizes KRAS-mutant colorectal cancer to mTORC1 inhibition by reducing eIF4E phosphorylation and c-MYC expression.
SIRT4 is the molecular switch mediating cellular proliferation in colorectal cancer through GLS mediated activation of AKT/GSK3β/Cyclin D1 pathway.
KRAS Codon 12 Mutation is Associated with More Aggressive Invasiveness in Synchronous Metastatic Colorectal Cancer (mCRC): Retrospective Research.
Hexameric procyanidins inhibit colorectal cancer cell growth through both redox and non-redox regulation of the epidermal growth factor signaling pathway.
ORAI2 Promotes Gastric Cancer Tumorigenicity and Metastasis Through PI3K/Akt Signaling and MAPK-dependent Focal Adhesion Disassembly.
Impact of early tumor shrinkage and depth of response on the outcomes of panitumumab-based maintenance in patients with RAS wild-type metastatic colorectal cancer.
ROS and Lipid Droplet accumulation induced by high glucose exposure in healthy colon and Colorectal Cancer Stem Cells.
Visualizing cellular heterogeneity by quantifying the dynamics of MAPK activity in live mammalian cells with synthetic fluorescent biosensors.
Ibuprofen disrupts a WNK1/GSK3β/SRPK1 protein complex required for expression of tumor-related splicing variant RAC1B in colorectal cells.
Clinicopathologic Features and Prognosis of BRAF Mutated Colorectal Cancer Patients.
Discoveries in the redox regulation of KRAS.
Mutational inactivation of Apc in the intestinal epithelia compromises cellular organisation.
Hypoxia Correlates With Poor Survival and M2 Macrophage Infiltration in Colorectal Cancer.
Clinicopathological, molecular features and prognosis of colorectal cancer with mucinous component.
The spectrum of serrated colorectal lesions - new entities and unanswered questions.
Cancer Discov. 2020 Dec 16. pii: CD-20-0652. [Epub ahead of print]
Knight JRP, Alexandrou C, Skalka GL, Vlahov N, Pennel K, Officer L, Teodosio A, Kanellos G, Gay DM, May-Wilson S, Smith EM, Najumudeen AK, Gilroy K, Ridgway RA, Flanagan DJ, Smith RCL, McDonald L, MacKay C, Cheasty A, McArthur K, Stanway E, Leach JDG, Jackstadt R, Waldron JA, Campbell AD, Vlachogiannis G, Valeri N, Haigis KM, Sonenberg N, Proud CG, Jones NP, Swarbrick ME, McKinnon HJ, Faller WJ, Le Quesne J, Edwards J, Willis AE, Bushell M, Sansom OJ.
KRAS-mutant colorectal cancers (CRC) are resistant to therapeutics, presenting a significant problem for ~40% of cases. Rapalogs, which inhibit mTORC1 and thus protein synthesis, are significantly less potent in KRAS-mutant CRC. Using Kras-mutant mouse models and mouse- and patient-derived organoids we demonstrate that KRAS with G12D mutation fundamentally rewires translation to increase both bulk and mRNA-specific translation initiation. This occurs via the MNK/eIF4E pathway culminating in sustained expression of c-MYC. By genetic and small molecule targeting of this pathway, we acutely sensitize KRASG12D models to rapamycin via suppression of c-MYC. We show that 45% of CRCs have high signaling through mTORC1 and the MNKs, with this signature correlating with a 3.5-year shorter cancer-specific survival in a subset of patients. This work provides a c-MYC-dependent co-targeting strategy with remarkable potency in multiple Kras-mutant mouse models and metastatic human organoids and identifies a patient population who may benefit from its clinical application.
DOI: https://doi.org/10.1158/2159-8290.CD-20-0652
Carcinogenesis. 2020 Dec 14. pii: bgaa134. [Epub ahead of print]
Cui Y, Bai Y, Yang J, Yao Y, Zhang C, Liu C, Shi J, Li Q, Zhang J, Lu X, Zhang Y.
Mitochondria-localized sirtuin 4 (SIRT4) is associated with malignant phenotypes in colorectal cancer. However, the molecular mechanisms that drive SIRT4-mediated carcinogenesis are unclear. Initially, we confirmed expression of SIRT4 in colorectal cancer through public database and in colorectal cancer patient tissues using quantitative real-time reverse transcription PCR. We established HCT116 colorectal cells that overexpressed SIRT4 and HT29 cells were transfected with plasmids bearing a small interfering RNA siRNA construct to silence SIRT4. Assays to determine the malignant phenotypes (proliferation, invasion and migration) were performed. Xenograft in-vivo models were also constructed. A protein interactome network was built using differentially expressed proteins identified using the liquid chromatography/tandem mass spectrophotometry, the findings of which were confirmed using coimmunoprecipitation, western blotting, and phenotype rescue experiments. Decreased SIRT4 expression was associated with malignant phenotypes in vitro and in vivo. The ribosomal biogenesis pathway was enriched in the interactome network. SIRT4 suppression activated glutaminase, thereby initiating AKT activation. Our research provided novel insights into the molecular mechanisms underlying colorectal cancer, and identified that SIRT4 exerts its antitumor activity in colorectal cancer possibly dependent on glutaminase to inhibit proliferation, migration, and invasion via the AKT/GSK3β/CyclinD1 pathway.
DOI: https://doi.org/10.1093/carcin/bgaa134
Onco Targets Ther. 2020 ;13 12601-12613
He K, Wang Y, Zhong Y, Pan X, Si L, Lu J.
Objective: To investigate the connection between mutant KRAS/NRAS/BRAF and clinicopathological characteristics in therapy-naïve synchronous metastatic colorectal cancer (mCRC) in Chinese populations when compared with all wild type (KRAS/NRAS/BRAF wild type).Patients and Methods: A total of 200 patients with therapy-naïve synchronous mCRC (TNM stage: TanyNanyM1) were retrospectively collected as study objects. Primary tumor tissues from 200 mCRC patients were analyzed through next-generation sequencing panel to assess the mutated regions of KRAS/NRAS/BRAF.
Results: The distribution frequency of gene mutation in our study was 41% KRAS, 4% NRAS, 11.5% BRAF, 0.5% both KRAS and BRAF. Tumors with any gene mutations (any gene mutations in KRAS/NRAS/BRAF), KRAS and KRAS codon 12 mutation were more likely to be located in right-sided colon (P=0.007, P=0.008, P=0.026, respectively). For metastasis, tumors with any gene mutations, KRAS and KRAS codon 12 mutation were significantly correlated with peritoneal metastasis (P=0.019, P=0.017, P=0.014, respectively), liver-peritoneum metastases (P=0.004, P=0.003, P=0.002, respectively) and multi-organ metastases (P=0.002, P=0.008, P=0.001, respectively). Tumors with all wild type were significantly correlated with distant lymph node-only metastasis. No statistically significant differences were found between clinicopathological characteristics and KRAS codon 13 and NRAS mutations.
Conclusion: Our study suggests that clinicopathological characteristics (specifically for metastasis) are related to KRAS/NRAS/BRAF mutations in therapy-naïve synchronous mCRC population in China. We demonstrated that distant lymph node-only metastasis is visibly linked to all wild-type tumors. We found that patients with any gene mutations, KRAS mutation are more likely to carry peritoneal metastasis, liver-peritoneum metastases and multi-organ metastases than those with all wild type. After stratification, KRAS codon 12 mutation, but not codon 13 mutation, was remarkably associated with peritoneal metastasis, liver-peritoneum metastases, and multi-organ metastases compared to all wild type. These results may be useful for aiding in the prediction of prognosis and choosing the appropriate regimens for therapy.
Keywords: BRAF mutation; KRAS codon 12 mutation; KRAS codon 13 mutation; KRAS mutation; NRAS mutation; synchronous metastatic colorectal cancer
DOI: https://doi.org/10.2147/OTT.S279312
Redox Biol. 2020 Dec 10. pii: S2213-2317(20)31035-1. [Epub ahead of print]38 101830
Daveri E, Adamo AM, Alfine E, Zhu W, Oteiza PI.
Dietary proanthocyanidins (PAC) consumption is associated with a decreased risk for colorectal cancer (CRC). Dysregulation of the epidermal growth factor (EGF) receptor (EGFR) signaling pathway is frequent in human cancers, including CRC. We previously showed that hexameric PAC (Hex) exert anti-proliferative and pro-apoptotic actions in human CRC cells. This work investigated if Hex could exert anti-CRC effects through its capacity to regulate the EGFR pathway. In proliferating Caco-2 cells, Hex acted attenuating EGF-induced EGFR dimerization and NADPH oxidase-dependent phosphorylation at Tyr 1068, decreasing EGFR location at lipid rafts, and inhibiting the downstream activation of pro-proliferative and anti-apoptotic pathways, i.e. Raf/MEK/ERK1/2 and PI3K/Akt. Hex also promoted EGFR internalization both in the absence and presence of EGF. While Hex decreased EGFR phosphorylation at Tyr 1068, it increased EGFR Tyr 1045 phosphorylation. The latter provides a docking site for the ubiquitin ligase c-Cbl and promotes EGFR degradation by lysosomes. Importantly, Hex acted synergistically with the EGFR-targeted chemotherapeutic drug Erlotinib, both in their capacity to decrease EGFR phosphorylation and inhibit cell growth. Thus, dietary PAC could exert anti-CRC actions by modulating, through both redox- and non-redox-regulated mechanisms, the EGFR pro-oncogenic signaling pathway. Additionally, Hex could also potentiate the actions of EGFR-targeted drugs.
Keywords: Colorectal cancer; Epidermal growth factor receptor; NADPH oxidase; Proanthocyanidins; Redox regulation
DOI: https://doi.org/10.1016/j.redox.2020.101830
Cancer Res. 2020 Dec 11. pii: canres.0049.2020. [Epub ahead of print]
Wu S, Chen M, Huang J, Zhang F, Lv Z, Jia Y, Cui YZ, Sun LZ, Wang Y, Tang Y, Verhoeft KR, Li Y, Qin Y, Lin X, Guan XY, Lam KO.
The ubiquitous second messenger Ca2+ has long been recognized as a key regulator in cell migration. Locally confined Ca2+, in particular, is essential for building front-to-rear Ca2+ gradient which serves to maintain the morphological polarity required in directionally migrating cells. However, little is known about the source of the Ca2+ and the mechanism by which they crosstalk between different signaling pathways in cancer cells. Here, we report that Calcium Release-Activated Calcium Modulator 2 (ORAI2), a poorly characterized store-operated calcium (SOC) channel subunit, is predominantly upregulated in the lymph node (LN) metastasis of gastric cancer (GC), supporting cell proliferation and migration. Clinical data reveal that a high frequency of ORAI2-positive cells in GC tissues significantly correlated with poor differentiation, invasion, LN metastasis and worse prognosis. Gain- and loss-of-function showed that ORAI2 promotes cell motility, tumor formation and metastasis in both GC cell lines and mice. Mechanistically, ORAI2 mediated SOC activity and regulated tumorigenic properties through the activation of the PI3K/Akt signaling pathways. Moreover, ORAI2 enhanced the metastatic ability of GC cells by inducing FAK-mediated mitogen-activated protein kinase (MAPK)/ERK activation and promoted focal adhesion disassembly at rear-edge of the cell. Collectively, our results demonstrate that ORAI2 is a novel gene that plays an important role in the tumorigenicity and metastasis of GC.
DOI: https://doi.org/10.1158/0008-5472.CAN-20-0049
Eur J Cancer. 2020 Dec 12. pii: S0959-8049(20)31349-6. [Epub ahead of print]144 31-40
Manca P, Corallo S, Randon G, Lonardi S, Cremolini C, Rimassa L, Bergamo F, Antoniotti C, Smiroldo V, Zaniboni A, Murialdo R, Tampellini M, Tomasello G, Clavarezza M, Racca P, Antista M, Raimondi A, Prisciandaro M, Pagani F, Palermo F, Greco FG, Vaiani M, Di Bartolomeo M, de Braud F, Calareso G, Morano F, Pietrantonio F.
BACKGROUND: In patients with metastatic colorectal cancer (mCRC) receiving highly active first-line combination treatments, early tumor shrinkage (ETS) and depth of response (DoR) are associated with survival, but their influence on outcomes during maintenance therapy is unknown. The Valentino study showed inferior PFS in 229 RAS wild-type mCRC patients randomized to panitumumab plus FOLFOX followed by maintenance with panitumumab vs. panitumumab + 5-FU/LV.PATIENTS AND METHODS: After blinded independent central review of ETS (≥20% reduction of the sum of target lesions) and DoR in patients enrolled in Valentino, the prognostic and predictive role of such parameters was investigated, along with their combination with PRESSING panel (uncommon genomic alterations associated with anti-EGFRs resistance beyond RAS and BRAF).
RESULTS: One hundred and ninety-six patients were included (ETS in 132 [67.3%], median DoR: 44.1%). Both ETS and DoR ≥34% were associated with longer mPFS (p = 0.010 and p < 0.001) and mOS (p = 0.006 and p < 0.001). The PFS benefit of 5-FU/LV added to panitumumab maintenance, reported in the study, was independent from ETS and DoR status (interaction tests NS for both PFS and OS). However, outcomes were extremely poor in patients who received single-agent panitumumab and had no-ETS (mPFS and mOS: 7.7 and 18.7 months) or DoR < 34% (mPFS and mOS: 6.5 and 18 months). Combining PRESSING panel ('molecular hyperselection') and response dynamics allowed to stratify both PFS (p < 0.001 and p < 0.001 for ETS and DoR, respectively) and OS (p < 0.001 and p = 0.017 for ETS and DoR, respectively).
CONCLUSIONS: ETS and DoR allow on-treatment anticipation of outcomes following an anti-EGFR-based strategy planning de-escalation, and poor radiological response may guide enrolment in crossover strategy trials. As in vivo markers of drug sensitivity, ETS and DoR may be integrated with several patient- and tumor-related factors to wisely drive decision-making on upfront treatment duration and intensity.
Keywords: Depth of response; Early tumor shrinkage; Maintenance therapy; Metastatic colorectal cancer; Molecular hyper-selection; Panitumumab; RAS wild-type
DOI: https://doi.org/10.1016/j.ejca.2020.11.017
Genes Dis. 2020 Dec;7(4): 620-635
Tirinato L, Pagliari F, Di Franco S, Sogne E, Marafioti MG, Jansen J, Falqui A, Todaro M, Candeloro P, Liberale C, Seco J, Stassi G, Di Fabrizio E.
Lipid Droplets (LDs) are emerging as crucial players in colon cancer development and maintenance. Their expression has been associated with high tumorigenicity in Cancer Stem Cells (CSCs), so that they have been proposed as a new functional marker in Colorectal Cancer Stem Cells (CR-CSCs). They are also indirectly involved in the modulation of the tumor microenvironment through the production of pro-inflammatory molecules. There is growing evidence that a possible connection between metabolic alterations and malignant transformation exists, although the effects of nutrients, primarily glucose, on the CSC behavior are still mostly unexplored. Glucose is an essential fuel for cancer cells, and the connections with LDs in the healthy and CSC populations merit to be more deeply investigated. Here, we showed that a high glucose concentration activated the PI3K/AKT pathway and increased the expression of CD133 and CD44v6 CSC markers. Additionally, glucose was responsible for the increased amount of Reactive Oxygen Species (ROS) and LDs in both healthy and CR-CSC samples. We also investigated the gene modulations following the HG treatment and found out that the healthy cell gene profile was the most affected. Lastly, Atorvastatin, a lipid-lowering drug, induced the highest mortality on CR-CSCs without affecting the healthy counterpart.
Keywords: Cholesterol metabolism; Colorectal cancer stem cells; Fatty acid metabolism; High glucose; Lipid droplets; Oncogenes; Oxidative stress; PI3K-AKT
DOI: https://doi.org/10.1016/j.gendis.2019.09.010
Heliyon. 2020 Dec;6(12): e05574
Ma M, Bordignon P, Dotto GP, Pelet S.
Mitogen-Activated Protein Kinases (MAPKs) control a wide array of cellular functions by transducing extracellular information into defined biological responses. In order to understand how these pathways are regulated, dynamic single cell measurements are highly needed. Fluorescence microscopy is well suited to perform these measurements. However, more dynamic and sensitive biosensors that allow the quantification of signaling activity in living mammalian cells are required. We have engineered a synthetic fluorescent substrate for human MAPKs (ERK, JNK and p38) that relocates from the nucleus to the cytoplasm when phosphorylated by the kinases. We demonstrate that this reporter displays an improved response compared to other relocation biosensors. This assay allows to monitor the heterogeneity in the MAPK response in a population of isogenic cells, revealing pulses of ERK activity upon a physiological EGFR stimulation. We show applicability of this approach to the analysis of multiple cancer cell lines and primary cells as well as its application in vivo to developing tumors. Using this ERK biosensor, dynamic single cell measurements with high temporal resolution can be obtained. These MAPK reporters can be widely applied to the analysis of molecular mechanisms of MAPK signaling in healthy and diseased state, in cell culture assays or in vivo.
Keywords: Biochemistry; Cancer research; Cell biology; Fluorescent biosensor; Live-cell imaging; MAPK signaling; Single cells; Systems biology
DOI: https://doi.org/10.1016/j.heliyon.2020.e05574
Oncotarget. 2020 Nov 24. 11(47): 4421-4437
Gonçalves V, Henriques AFA, Matos P, Jordan P.
A major risk factor promoting tumor development is chronic inflammation and the use of nonsteroidal anti-inflammatory drugs (NSAID), including ibuprofen, can decrease the risk of developing various types of cancer, including colorectal cancer (CRC). Although the molecular mechanism behind the antitumor properties of NSAIDs has been largely attributed to inhibition of cyclooxygenases (COXs), several studies have shown that the chemopreventive properties of ibuprofen also involve multiple COX-independent effects. One example is its ability to inhibit the alternative splicing event generating RAC1B, which is overexpressed in a specific subset of BRAF-mutated colorectal tumors and sustains cell survival. Here we describe the mechanism by which ibuprofen prevents RAC1B alternative splicing in a BRAF mutant CRC cell line: it leads to decreased translocation of SRPK1 and SRSF1 to the nucleus and is regulated by a WNK1/GSK3β/SRPK1 protein kinase complex. Surprisingly, we demonstrate that ibuprofen does not inhibit the activity of any of the involved kinases but rather promotes disassembly of this regulatory complex, exposing GSK3β serine 9 to inhibitory phosphorylation, namely by AKT, which results in nuclear exclusion of SRPK1 and SRSF1 hypophosphorylation. The data shed new light on the biochemical mechanisms behind ibuprofen's action on alternative spliced RAC1B and may support its use in personalized approaches to CRC therapy or chemoprevention regimens.
Keywords: RAC1B; alternative splicing; colorectal cancer cells; ibuprofen; protein kinase
DOI: https://doi.org/10.18632/oncotarget.27816
Front Oncol. 2020 ;10 563407
Guan WL, Qiu MZ, He CY, Yang LQ, Jin Y, Wang ZQ, Li YH, Xu RH, Wang FH.
Background: BRAF V600E mutation is associated with poor prognosis of colorectal cancer (CRC) patients, but the comparison of clinic-pathologic features between V600E and non-V600E mutation was not well-known in CRC patients. The aim of this study is to evaluate the clinical and pathological features, prognostic value of BRAF mutations in CRC. Methods: We conducted a retrospective study to characterize the clinical and pathological features and survival of patients with BRAF mutated CRC. Patients were classified according to BRAF status as BRAF V600E mutation and non-V600E mutations. Difference of characteristics and survival between the two groups was analyzed. Results: There was no significant difference in gender, family history, location of primary tumor, metastatic sites between patients with BRAF-V600E mutation and non-V600E mutations. Patients with V600E mutation were younger than those with non-V600E mutations (p = 0.002). Patients with BRAF V600E mutation showed a poorer outcome than those with non-V600E mutations (23.1 vs. 49.9 months, respectively, p = 0.0024). Lack of CDX2 expression was associated with worse prognosis (mOS: 9.4 m vs. not reached, respectively, p = 0.016). Status of V600E mutation did not affect the mPFS and ORR of first-line or second-line treatment. Conclusion: BRAF V600E mutation defines a distinct subgroup of CRC with worse prognosis. Lack of CDX2 expression is associated with poor OS. Status of V600E mutation did not affect the mPFS of first-line or second-line treatment.
Keywords: BRAF; CDX2; V600E; colorectal cancer; prognosis
DOI: https://doi.org/10.3389/fonc.2020.563407
Int J Biochem Cell Biol. 2020 Dec 10. pii: S1357-2725(20)30218-1. [Epub ahead of print] 105901
Kramer-Drauberg M, Ambrogio C.
Oncogenic KRAS is one of the most common drivers of human cancer. Despite intense research, no effective therapy to directly inhibit oncogenic KRAS has yet been approved and KRAS mutant tumors remain associated with a poor prognosis. This short review discusses the current knowledge of the redox regulation of RAS and examines the newest findings on cysteine 118 (C118) as a potential novel target for KRAS inhibition.
Keywords: Cysteine modification; RAS; Redox regulation
DOI: https://doi.org/10.1016/j.biocel.2020.105901
J Cell Sci. 2020 Dec 17. pii: jcs.250019. [Epub ahead of print]
Rannikmae H, Peel S, Barry S, Senda T, de la Roche M.
The adenomatous polyposis coli (Apc) protein regulates diverse effector pathways essential for tissue homeostasis. Truncating oncogenic mutations in Apc removing its Wnt pathway and microtubule regulatory domains drives intestinal epithelia tumorigenesis. Exuberant cell proliferation is one well-established consequence of oncogenic Wnt pathway activity however, the contribution of other de-regulated molecular circuits to tumorigenesis has not been fully examined.Using in vivo and organoid models of intestinal epithelial tumorigenesis we find that Wnt pathway activity controls intestinal epithelial villi and crypt structure, morphological features lost upon Apc inactivation. While the Wnt pathway target gene c-Myc has critical roles in regulating cell proliferation and tumorigenesis, Apc specification of intestinal epithelial morphology is independent of the Wnt-responsive Myc-335 regulatory element.We further demonstrate that Apc inactivation disrupts the microtubule cytoskeleton and consequently localisation of organelles without affecting the distribution of the actin cytoskeleton and associated components. Our data indicates direct control over microtubule dynamics by Apc through an independent molecular circuit.Our study stratifies three independent Apc effector pathways in the intestinal epithelial controlling: (i) proliferation, (ii) microtubule dynamics and (iii) epithelial morphology.
Keywords: Adenomatous polyposis coli (APC); Intestinal epithelia; Microtubule cytoskeleton; Organoids; Wnt pathway
DOI: https://doi.org/10.1242/jcs.250019
Qi L, Chen J, Yang Y, Hu W.
Background: It is widely accepted that the oxygen level in tumor tissue is significantly lower than the adjacent normal tissue, thus termed hypoxia. Intratumoral hypoxia represents a major driving force in cancer progression, recurrence, metastasis, and decreased survival. Though multiple gene signatures reflect the complex cellular response to hypoxia have been established in several cancer types such as head and neck, breast, and lung cancers, the hypoxic panorama in colorectal cancer (CRC) remains poorly understood.Methods: A hypoxic signature constituted by a total of 356 genes, including canonical hypoxia-responsive ADM, ANGPTL4, CA9, and VEGFA, was established based on systemic literature search. A total of 1,730 CRC samples across four independent cohorts were used for nonnegative matrix factorization clustering and subtyping. Prognosis, molecular signatures, pathways, and tumor-infiltrating lymphocytes were compared between the subtypes.
Results: CRCs mainly fell into two subgroups, one indicated as hypoxia and the other one designated as normoxia. Hypoxia was correlated with poor outcomes in CRC and will increase the risk of a subset of stage II patients to the level of normoxic stage III. Additionally, hypoxia was closely associated with activation of RAS signaling pathway independent of KRAS mutation. More M2 macrophage infiltration was another hypoxic marker indicated that subsets of patients with high M2 macrophages may benefit from macrophage-targeting therapy.
Conclusions: These findings will facilitate the development of a hypoxia-oriented therapy strategy to enhance the treatment effect in the near future.
Keywords: HIF-1; KRAS mutation; M2 macrophages; colorectal cancer; hypoxia
Future Oncol. 2020 Dec 17.
Li J, Yang L, Bai F, Cai Y, Zhang J, Wu Z, Fu Y, Deng Y.
Background: Colorectal cancer (CRC) with mucinous component is associated with distinct characteristics and controversial prognosis. Patients & methods: A total of 1800 CRC patients were retrospectively enrolled and grouped by the mucinous content of the primary tumors. The clinicopathological characteristics and overall survival rate were compared between groups. Results: Mucinous adenocarcinoma (MAC) and adenocarcinoma with mucinous component (AMC) had higher frequencies of DNA mismatch repair protein deficiency, KRAS, BRAF and PIK3CA mutations as compared to those of conventional adenocarcinoma (CAC). MAC had worse prognosis than CAC. However, MAC was not an independent prognostic factor in multivariable analysis. Conclusion: Molecular features of AMC and MAC were similar, which were different from those of CAC. Neither MAC nor AMC were independent prognostic factors for CRC.
Keywords: DNA mismatch repair protein deficiency; colorectal cancer; mucinous; mutation; prognosis
DOI: https://doi.org/10.2217/fon-2020-1055
Histopathology. 2020 Dec 17.
Bateman AC.
Hyperplastic polyps (HPs) of the colon and rectum were historically thought not to be associated with an increased risk of development of colorectal cancer (CRC). The recognition of variants of serrated colorectal lesions that possessed relatively subtle but significant morphological differences to those of HPs and that could be associated with epithelial dysplasia and CRC led to the characterisation of sessile serrated lesions (SSLs) and traditional serrated adenomas (TSAs). These links were supported by the identification of genetic alterations that are commonly found in HPs, SSLs, TSAs and CRC e.g. BRAF and KRAS mutations. The 'serrated pathway' to CRC may progress faster than the traditional 'adenoma-carcinoma sequence', underlining the importance of identifying these lesions. The diagnostic histological criteria for SSLs have since been more clearly defined, in parallel with a drive to increase the recognition of these lesions at endoscopy. The existence of lesions showing overlapping morphological and molecular features to those of HPs, SSLs and TSAs has most recently been highlighted - including the mucin-rich TSA, the serrated tubulovillous adenoma and those showing mixed histological features e.g. comprising differing combinations of HP, SSL and TSA. Morphological and molecular study of this range of lesions is providing insights into the relationship of serrated colorectal lesions to each other and with CRC. This article provides an overview of the current understanding of serrated colorectal lesions, including a discussion of those with 'overlapping' and 'mixed' features.
Keywords: bowel cancer screening; colorectal cancer; molecular; serrated polyp
DOI: https://doi.org/10.1111/his.14305


text:
Advising and Planning
Coherent Supports
Diverse Learning Options
Evidence-Based Policies
Responsive Systems
Lauren Miller
Senior Associate Partner
Strategic Advising
lauren.miller@bellwether.org
Lauren Miller is a senior associate partner with Bellwether in the Strategic Advising practice area. Since joining Bellwether in 2013, Lauren has advised leaders across the sector on ways to grow and deepen their impact. Lauren brings experience in growth planning, organizational development, and implementation support to the team. In addition to state- and school-level strategic planning, Lauren has worked to develop new organization business plans as well as to scale initiatives that aim to elevate and center student voices nationally. Prior to joining Bellwether, Lauren spent more than three years in the Insights and Planning department at POSSIBLE, a digital advertising agency. In 2012, Lauren developed a strategic plan and designed a new organizational structure for the Education Writers Association as an Education Pioneers Fellow.
Lauren holds an MBA from Georgetown University and a bachelor's degree from Brandeis University, where she double-majored in international relations and politics. She lives in Maryland with her husband and two daughters.
Why I do this work:
My commitment to equity and education comes from my experience growing up — both in attending public schools that fell short of my vision, as well as being active in my religious community. I do this work because I deeply believe that all children, regardless of their background, should have access to a high-quality education so they can achieve their dreams.
Experience at Bellwether:
Strategic Planning; Business Plan Development; Growth and Expansion Strategy; Human Capital/Organizational Design; Performance Improvement/Sustainability; Implementation Planning; Project Management
Client segments served:
K-12 Schools; CMO/Charter Schools; State Education Agencies; Nonprofit Organizations; Advocacy Groups
Sample clients:
The Opportunity Project, Higher Achievement, Education Forward D.C., Partners for Education at Berea College, the Greater Tacoma Community Foundation, the Office of the State Superintendent of Education in D.C.
We've partnered with a diverse group of equity-focused clients, from large-scale foundations, to school districts, to nonprofits and mission-drive companies, and more. Let's transform education together.
© Bellwether 2022


text:
Q: Vim + tmux: background with different colors Does anyone know why when I'm within tmux, the background is darker on the right side and lighter on the left side?

A: Put
set -g default-terminal "screen-256color" in .tmux.conf
and
xterm-256color in the iTerm 2 settings.

redpajama_set_name: RedPajamaStackExchange


text:
Weapons seized during warrant in South Oxhey
A samurai sword and six knives were seized from an address in South Oxhey after officers from Three Rivers executed a warrant.
They forced entry to the address on Prestwick Road at 6.30am on Friday 29 November.
They conducted a search of the property before recovering the samurai sword, six further knives, a quantity of cash and suspected class B drugs (cannabis).
Operation Scorpion officers, supported by colleagues from both Rickmansworth and Oxhey Safer Neighbourhood Teams, forced entry to the address on Prestwick Road at 6.30am on Friday 29 November.
They conducted a search of the address under Section 23 of the Misuse of Drugs Act before recovering the samurai sword, six further knives, a quantity of cash and suspected class B drugs (cannabis).
A 16-year-old boy from South Oxhey has been reported for possession with intent to supply class B drugs. Intelligence has been recorded and enquiries remain ongoing.
PC Marcus Zost, from the Three Rivers Operation Scorpion team, said: "We are pleased to have removed six weapons from the street, and are satisfied that they will not be used to threaten or hurt anyone.
"We took this overt action after receiving information to suggest the address was being used as a location for suspected drug dealing and criminality.
"We hope residents take this as reassurance that we will robustly act on information given to us, so we want to encourage the public to continue to submit this.
"Everyone has the right to live in peace and that is why we do not tolerate drug crime in our neighbourhoods."
You can submit information online or speak to an operator in our Force Communications Room via web chat here.
You can also call the non-emergency number 101, and ask for Herts Police.
Alternatively, you can stay 100% anonymous by contacting the independent charity Crimestoppers on 0800 555 111 or via their untraceable online form.
Police investigating a series of assaults across the St Albans district have arrested four people this morning (Friday 17 January) as part of their ongoing enquiries.
Working together to Keep Safe in Hemel
Hemel Hempstead's Liberty Tea Rooms and Community Hub has joined the 'Keep Safe' community safety scheme.
Welwyn Hatfield police officer receives Royal Humane Society Award
A Welwyn Hatfield police officer has received a Royal Humane Society Award after administering life-saving CPR to a member of the public.


text:
/*

Copyright 2008-2014 TOPdesk, the Netherlands

Licensed under the Apache License, Version 2.0 (the "License");
you may not use this file except in compliance with the License.
You may obtain a copy of the License at

http://www.apache.org/licenses/LICENSE-2.0

Unless required by applicable law or agreed to in writing, software
distributed under the License is distributed on an "AS IS" BASIS,
WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
See the License for the specific language governing permissions and
limitations under the License.

*/

package org.kordamp.jipsy.processor.testutils;

import org.kordamp.jipsy.processor.LogLocation;
import org.kordamp.jipsy.processor.Logger;

import javax.tools.Diagnostic.Kind;
import java.util.ArrayList;
import java.util.Collections;
import java.util.List;

public class TestLogger implements Logger {
    private final List<TestLogger.Record> records = new ArrayList<TestLogger.Record>();

    @Override
    public String getFileContent() {
        StringBuilder result = new StringBuilder();
        for (TestLogger.Record r : records) {
            if (r.location.toLogFile()) {
                if (r.kind == Kind.WARNING) {
                    result.append("warning: ");
                }
                result.append(r.message).append("\n");
            }
        }
        return result.toString();
    }

    @Override
    public void note(LogLocation location, String message) {
        records.add(new Record(Kind.NOTE, location, message));
    }

    @Override
    public void warning(LogLocation location, String message) {
        records.add(new Record(Kind.WARNING, location, message));
    }

    public List<TestLogger.Record> records() {
        return Collections.unmodifiableList(records);
    }

    public void reset() {
        records.clear();
    }

    public static final class Record {
        final Kind kind;
        final LogLocation location;
        final String message;

        public Record(Kind kind, LogLocation location, String message) {
            this.kind = kind;
            this.location = location;
            this.message = message;
        }

        @Override
        public String toString() {
            final StringBuilder sb = new StringBuilder("Record{");
            sb.append("kind=").append(kind);
            sb.append(", location=").append(location);
            sb.append(", message='").append(message).append('\'');
            sb.append('}');
            return sb.toString();
        }
    }
}

redpajama_set_name: RedPajamaGithub


We thank all Exhibitors, Visitors, Attendees, Sponsors and Partners!
Intersolar South America, Latin America's largest exhibition and conference for the solar industry, has a focus on the areas of photovoltaics, PV production and solar thermal technologies. At the accompanying Intersolar South America Conference, renowned experts shed light on hot topics in the industry.
In 2018 Intersolar South America welcomes more than 20,000 visitors and over 1,500 conference attendees at São Paulo's Expo Center Norte. 250+ exhibitors showcased their products – an increase of more than 40% over the last two years.
As a visitor, you will find the complete value chain of PV and ST at the show floor, from PV Cells and Modules manufactures, BOS, components, tracking, applications, distributors. Global brands and local heroes present their latest technologies and show possibilities to earn money, to save money, and to be up-to-date on solar developments.


Richard Stallman originated free software and the GFDL license used by the R&D wiki. He is a major influence on many debates on patent law as applied to software, and an opponent of both open source and shared source. He grumbles also about the consortium approach.
He created the GFDL and the "open patent" pool.
This page was last edited on 24 November 2003, at 23:35.


Thanks to Kathie and helpers for a delicious laying up lunch. Greatly appreciated after a chilly morning's racing. It was good to see so many boats out on the water and a full clubhouse. Rob Matthews showed everyone the way around the race course - blazing across the lake in his Comet to end the season.


text:
Q: Android WebView does not display web page even though the page has successfully finished loading I have added internet-permissions and I also used the WebViewClient.onPageFinished method to check whether the page has loaded which turns out it did. JavaScript is also enabled for my WebView.
The code I use to set up my web view
webView.webChromeClient = KeplerWebChromeClient(progressBar)
webView.webViewClient = keplerWebViewClient

webView.settings.javaScriptEnabled = true
webView.settings.useWideViewPort = true
webView.settings.loadWithOverviewMode = true
webView.settings.setSupportZoom(true)
webView.settings.setSupportMultipleWindows(true)
webView.scrollBarStyle = View.SCROLLBARS_INSIDE_OVERLAY
webView.setBackgroundColor(Color.WHITE)

I am using KeplerWebChromeClient to display web page loading progress.
keplerWebViewClient is an object of WebViewClient class which I use to load webpages and to track for whether the webpage has finished loading or not.
And I must mention that this issue doesn't always arise. Sometimes when I run my app, the WebView does work and it does load and display the web page correctly and other times it doesn't. I have found the below stated logcat entries to be unique to when the web page isn't displayed.

E/chromium: [ERROR:tile_manager.cc(778)] WARNING: tile memory limits exceeded, some content may not draw
[ERROR:tile_manager.cc(778)] WARNING: tile memory limits exceeded, some content  may not draw
E/chromium: [ERROR:tile_manager.cc(778)] WARNING: tile memory limits exceeded, some content may not draw
E/chromium: [ERROR:tile_manager.cc(778)] WARNING: tile memory limits exceeded, some content may not draw

What is the issue here and how do I fix it? Thanks in advance.
Edit:
I cleared all the app data from my phone and then I restarted my app. After doing so, everything was working just fine. I was able to browse using the WebView but after using the app a few more times i.e. closing and opening it, the problem reappeared. Clearing all data solves the problem temporarily. What aid can this be in solving the problem?

A: I have to try and it's working fine for me.
private fun setupWebView(url: String) {
        webView.settings.javaScriptEnabled = true
        webView.settings.domStorageEnabled = true
        webView.settings.setPluginState(WebSettings.PluginState.ON);
        webView.settings.allowFileAccess = true;
        webView.webViewClient = WebClient()
        webView.webChromeClient = CustomWebChromeClient()
        webView.loadUrl(url)
    }

    private inner class WebClient : WebViewClient() {

        override fun onPageStarted(view: WebView, url: String, favicon: Bitmap?) {
            super.onPageStarted(view, url, favicon)
        }

        override fun onPageCommitVisible(view: WebView, url: String) {
            super.onPageCommitVisible(view, url)
        }

        override fun shouldOverrideUrlLoading(
            view: WebView,
            url: String
        ): Boolean {
            view.loadUrl(url)
            return true
        }

        override fun onPageFinished(view: WebView, url: String) {
            super.onPageFinished(view, url)
        }
    }

    private inner class CustomWebChromeClient : WebChromeClient() {
        override fun onJsAlert(
            view: WebView,
            url: String,
            message: String,
            result: JsResult
        ): Boolean {
            return false
        }
    }

I hope it's work for you!


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text:
Q: AWS static ip address I am using AWS code deploy agent and deploying my project to the server through bitbucket plugin.
The code deployment agent first executes the script files which has the command to execute my spring-boot project.
Since I have two environments one development and another production. I want the script to do things differently based on the environment i.e two different instances.
My plan is to fetch the aws static ip-address which is mapped and from that determine the environment
(production or stage).
How to fetch the elastic ip address through sh commands.
edited

A: Static IP will work.
Here is a more nature CodeDeploy way to solve this is - set up 2 CodeDeploy deployment groups, one for your development env and the other for your production env. Then in your script, you can use environment variables that CodeDeploy will set during the deployment to understand which env you are deploying to.
Here is a blog post about how to use CodeDeploy environment variables: https://aws.amazon.com/blogs/devops/using-codedeploy-environment-variables/

A: You could do the following:
id=$( curl http://169.254.169.254/latest/meta-data/instance-id )
eip=$( aws ec2 describe-addresses --filter Name=instance-id,Values=${id} | aws ec2 describe-addresses | jq .Addresses[].PublicIp --raw-output )

The above gets the instance-id from metadata, then uses the aws cli to look for elastic IPs filtered by the id from metadata. Using jq this output can then be parsed down to the IP you are looking for.

A: Query the metadata server
eip=`curl -s 169.254.169.254/latest/meta-data/public-ipv4`
echo $eip

A: The solution is completely off tangent to what I originally asked but it was enough for my requirement.
I just needed to know the environment I am in to do certain actions. So what I did was to set an environment variable in an independent script file where the environment variable is set and the value is that of the environment.
ex: let's say in a file env-variables.sh
export profile= stage
In the script file where the commands have to be executed based on the environment I access it this way
 source /test/env-variables.sh
    echo current profile is $profile
    if [ $profile = stage ]
    then
        echo stage
    elif [ $profile = production ]
    then
        echo production
else
        echo failure
    fi

Hope some one finds it useful


text:
Losses in Good-Will Values Compound Bank Troubles
JACK HEALY
Write-downs for good-will losses have already been in the tens of billions of dollars, and analysts say they are likely to continue as companies reassess the value of old deals.
When times were flush, businesses bought up rivals and absorbed smaller companies to grow as big as possible as fast as possible. But now, those purchases are starting to look a lot like housing bought at the peak of the bubble — overpriced and losing value fast.
Companies are taking billions of dollars in losses as they write down the value of assets known as good will — the amount they overpaid for a business compared with the sum of its parts. As the economy sinks lower and businesses struggle, that good will is going bad.
The losses from these write-downs have already been in the tens of billions of dollars, and analysts say they are likely to continue as companies reassess the value of old deals in the light of faltering stock markets, declines in real estate and weak corporate revenues.
"It's not the end of the tragedy," said Feng Gu, an assistant professor at the State University of New York at Buffalo and an author of a paper on good-will impairments with Baruch Lev, a professor at New York University. "Things continue to get worse."
For the nation's banks, which are already bracing for another spate of big losses from commercial real estate loans and credit card businesses, the rapid declines in good will represent another potential source of losses.
Banks wrote down more than $25 billion in good will in 2008, up sharply from $790 million a year earlier, according to data compiled by Frank Schiraldi of Sandler O'Neill & Partners. By the end of the year, banks still had $291 billion worth of good will on their books. An incomplete tally of write-downs from the first quarter showed that banks had taken a $3.5 billion hit to good-will values.
For some companies, the losses will be staggering.
Before it was scooped up in a merger with Wells Fargo last year, the Wachovia Corporation cut the value of its good will by $18.7 billion, largely from its purchase of the troubled mortgage lender Golden West Financial and other acquisitions that took on water as housing markets sank and the economy hurtled lower.
Macy's took a good-will charge of $5.4 billion in 2008. In February 2008, the cellular carrier Sprint Nextel wrote down $30 billion from Sprint's purchase of Nextel.
Companies characterize the hits as nothing more than accounting losses, a revaluing of assets that were not tangible to begin with. And they say the write-downs do not threaten their credit, their cash flow or their long-term health.
"It was just a paper entry sitting on your balance sheet," said Rex S. Schuette, chief financial officer of United Community Banks, which wrote down $70 million of good will in the first quarter.
But the losses take a real bite out of corporate earnings, like a first-quarter good-will charge of $2.6 billion at Huntington Bancshares that contributed to its $2.4 billion first-quarter loss. And they could lead to more declines in company share prices as many are grappling with declining market value, crumbling real estate portfolios and lower revenues.
"Investors will have to be wary of these things," said J. Edward Ketz, an associate professor of accounting at the Pennsylvania State University, who has studied good will. "You never know when an intangible asset is going to be written off."
If nothing else, the decline in the value of good will shows that corporations across the spectrum spent far too much during the merger mania of the last decade, analysts said. As the markets roared higher, companies looked at their rising share prices like lottery money, and deployed their stock to go on a buying binge, eager to show shareholders growth and expanding sources of revenue.
If the mergers were lavish wedding ceremonies, the slumping value of the good will has been the rocky marriages that followed.
"If they overpaid for it and they have to take a write-down, that definitely is an indicator that they overpaid, and that the corporate acquisition group is not doing its job that well," said William Hughes, managing director of the Valuation Research Corporation.
The value of good will represents intangible qualities like the value of a company's brand name, its customer base and reputation. Every year, companies that list good will as a leftover asset from mergers have to test its value to see whether it has held up.
SunTrust Banks, based in Atlanta, had been monitoring its $7 billion in good will every quarter since the end of 2007, and cut its value by $715 million this spring. The bank said it had made the write-down because economic declines had continued to hammer its mortgage and commercial real estate assets.
"There's been some erosion in financial performance, but the uncertainty and sentiment in the marketplace has also had a meaningful effect," said the bank's controller, Thomas E. Panther.
For the quarter, SunTrust reported a net loss of $815 million but said the good-will charge had no effect on its levels of capital required by government regulators. It also said that some signs of improvement in deposits and mortgage lending were emerging and that it thought it had revalued its good will to match current conditions.
Although SunTrust played down the significance of the write-down, the analysis of good-will losses by Mr. Gu and Mr. Lev found that they often presaged rough waters ahead. If the write-downs mount, they can lead businesses to cut jobs, reduce capital investments, slash budgets and close plants.
Still, the losses don't mean that businesses have less money to pay off their debts, or that they are on the brink of insolvency. And with investors already bracing for the worst, some analysts said the good-will write-downs did not provide much additional shock.
"You're pushed down so low anyhow," Mr. Hughes said. "What's more bad news on top of bad news?"