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Air Cairo is een Egyptische chartermaatschappij met haar thuisbasis in Caïro.

Geschiedenis
Air Cairo werd opgericht in 2003 en is een volledige dochter van EgyptAir. Het is lid van de Arab Air Carriers Organization.

Vloot
In juli 2016 bestond de vloot van Air Cairo uit:
6 Airbus A320-200's

Egyptische luchtvaartmaatschappij
Economie in Caïro


text:
Ulm Corpus
Andrea Haege
Department of Phoniatrics and Pedaudiology
University of Ulm
andrea.haege@uniklinik-ulm.de
Participants: 94 (+ 46)
Type of Study: clinical
Location: Ulm
Media type: no longer available
DOI: doi:10.21415/T5GP4T
Browsable transcripts
Download transcripts
Publications using these data should cite one of these articles:
Haege, A. (1995). Cognitive abilities and interactional variables in young stutterers – first cross-sectional results of a five year longitudinal study. In C. W. Starkweather & H. F. M. Peters. Stuttering: Proceedings of the first world congress on fluency disorders, Munich, Vol.1. The International Fluency Association, Nijmegen, The Netherlands1995.
Haege, A., Rommel, D., Johannsen, H. S., & Schulze, H. (1997). Cognitive and linguistic abilities of stuttering children. In W. Hulstijn, H. F. M. Peters, & P. H. H. M. Van Lieshout (Eds.) Speech production: Motor control, brain research and fluency disorders. Elsevier, Amsterdam.
Haege, A., Rommel, D., Schulze, H., & Johannsen, H. S. (1994). Kindliches Stottern: Ätiologie und Laufsbedingungen. Erste Ergebnisse einer fünfjährigen Längsschittstudie. Folia Phoniatrica, 46, 298–304.
Johannsen, H. S., Schulze, H., Rommel, D., & Haege, A. (1994). Stuttering in childhood: A five-year longitudinal study in progress. Folia Phoniatrica, 46, 241–249.
Rommel, D., Haege, A., Johannsen, H. S., & Schulze, H. (1997) Linguistic aspects of stuttering in childhood. In W. Hulstijn, H. F. M. Peters, & P. H. H. M. Van Lieshout (Eds.). Speech production: Motor control, brain research and fluency disorders. Elsevier, Amsterdam 1997.
In accordance with TalkBank rules, any use of data from this corpus must be accompanied by at least one of the above references.
These transcript data were contributed by Helge S. Johannsen, Hartmut Schulze, Dieter Rommel, and Andrea Haege from the phoniatric outpatients department of the University of Ulm in Germany. The data are a set of protocols taken from preschool and primary school children in the context of an experimental playing situation in which the children play half an hour with their mothers in the phoniatric clinic laboratory. The playing material is a farm building kit, a zoo kit, or a knight's castle. The transcribed language is not standard German but a Swabian dialect spoken in the region around Ulm. All assessed children came to the phoniatric clinic because of more or less severe stuttering and took part in a longitudinal study of the relations between different variables and the development of stuttering in childhood using CLAN. Transcripts of playing situations were taken in 6-months-intervals provided that the children's stuttering persisted. For example david1.cha is the transcript from the first contact, david2.cha is taken 6 months later, and so on. If the children recovered from their stuttering, they were withdrawn from further follow-ups. There are140 transcripts in the corpus, in which 94 protocols come from the first contact with the stuttering children and 46 from the fourth contact 18 months later. In order to protect privacy, all names were replaced with pseudonyms. Please inform the authors when using these data. In case of interest more details about the data and their context can be requested.

redpajama_set_name: RedPajamaCommonCrawl


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Bober Markey Fedorovich Promotes Six Associates
Bober Markey Fedorovich (BMF), a top 20 regional CPA and advisory firm, is pleased to announce the promotions of six associates within Northeast Ohio.
Dana E. Mountjoy, CPA, to Senior Manager, Assurance and Advisory Services. Mountjoy brings nine years of experience at both a Big 4 and national firm, with extensive experience with U.S. GAAP and IFRS procedures, internal controls and small business services, SOX compliance readiness, and technical accounting research for clients in diverse industries, including construction, manufacturing, and employee benefit plans. She works closely with clients to offer recommendations and implement best practices to enhance their operations. Mountjoy serves as a board member at The Blick Center, and holds the position of Chair of BMFs annual United Way Campaign.
Nathan A Lieb, CPA, MSA, to Manager, Taxation Services. Lieb serves a variety of multi-state companies in taxation including public and private C-corporations, S-corporations, limited liability companies, and partnerships. His experience includes providing tax compliance in multiple taxing jurisdictions, consulting and various tax planning strategies, tax due diligence, and compliance with ASC 740 (FAS 109/FIN 48) Accounting for Income Taxes. Lieb is part of the 2018 Class of Akron Torchbearers and is a member of the Junior Advisory Board for the University of Akrons School of Accountancy, in which he served as the Secretary for the 2017/2018 school year.
Also receiving promotions:
Jonathan Palay " to Senior Accountant, Assurance and Advisory Services
Travis Werner " to Senior Accountant, Assurance and Advisory Services
Geoffrey Zion " to Supervisor, Taxation Services
Kurtis Thomson " to Senior Accountant, Taxation Services
About Bober Markey Fedorovich
Founded in 1959, Bober Markey Fedorovich is a Top 20 independent CPA and business advisory firm in Northeast Ohio serving greater Akron, Cleveland and surrounding regions. Our clients span a variety of industries, many with multi-state and global operations. We specialize in accounting, audit, tax, litigation support, valuation and transaction advisory services, with focus on privately held businesses, private equity groups and SEC companies. BMF is a member of Allinial Global, Financial Consulting Group, and is registered with the Public Company Accounting Oversight Board. For more information, visit www.bmfcpa.com.
For high resolution images click here:
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Optiv Security Announces [email protected] to Drive Holistic and Risk-Centric Security Across the Entire Payment Lifecycle; Further Helps Organizations Rationalize and Optimize Cyber Security
Poland Freight Forwarding Market Outlook to 2022 – ResearchAndMarkets.com
"This donation exemplifies our support of front-line community health care workers in the fight against COVID-19. We are proud that we can do our part to help provide much needed equipment and technology in the fight against the pandemic," said Corning Painter, chief executive officer of Orion Engineered Carbons.
In commenting on the funding Jarrett Stull, Executive Director Memorial Health Foundation said, In three short weeks, our community has come together to raise more than $530,000 to help our local health care system continue the fight against COVID-19 and prepare for a vaccination clinic that will be significant in moving the Mid-Ohio Valley through this virus. Orions gift demonstrates the thoughtful leadership this company has to ensure the health and safety of our community.
The donation is a continuation of Orions commitment to supporting the global communities that the company serves as a responsible corporate citizen working towards a sustainable future for all of its stakeholders.
About Orion Engineered Carbons S.A.
Orion is a worldwide supplier of carbon black. We produce a broad range of carbon blacks that include high-performance specialty gas blacks, acetylene blacks, furnace blacks, lamp blacks, thermal blacks and other carbon blacks that tint, colorize and enhance the performance of polymers, plastics, paints and coatings, inks and toners, textile fibers, adhesives and sealants, tires, and mechanical rubber goods such as automotive belts and hoses. Orion operates 14 global production sites and has approximately 1,425 employees worldwide. For more information, please visit our website www.orioncarbons.com.
About Memorial Health System
Memorial Health System is a not-for-profit integrated health system lead by a volunteer board of community members committed to providing comprehensive care services that meet the needs of our region. We are comprised of a network of locations and specialties provided by over 3,000 employees that include three hospitals (Marietta Memorial Hospital, Selby General Hospital and Sistersville General Hospital), outpatient service sites, and provider clinics. Memorial Health System strives to deliver quality care and service with an additional focus on medical education and community service. We invest in the most advanced technologies and treatments today, giving our patients the care that they need, so they can stay close to home.
Orion Engineered Carbons S.A.
Wendy Wilson, Investor Relations +1 281-974-0155
Memorial Health System
Jennifer Offenberger, Associate Vice President of Service Excellence +1 740-374-1797
Kofax, a leading supplier of Intelligent Automation software for digital workflow transformation, today announces TrustRadius has recognized Kofax Power PDFTM with its 2021 Best Feature Set and Best Customer Support Awards. These awards highlight companies with outstanding feature sets and customer support that have gone above and beyond to delight their users. Kofax finished in first place in both categories.
To win the Feature Set and Customer Support Awards, winners had to rank in the top three positions of their category in terms of what percentage of positive responses they earned this year. Additional vetting via textual review analysis was also performed by the TrustRadius research team.
These honors are particularly meaningful because theyre based on reviews from users of Kofax Power PDF and its extensive capabilities every day. Giving customers the best set of features alongside world-class support has always been a top priority for Kofax, says Kathleen Delaney, Chief Marketing Officer at Kofax. Were committed to continued product innovation and will keep giving our customers the outstanding support they deserve.
Kofax Power PDF 4 provides powerful PDF capabilities built for business users. Its designed to meet simple-to-complex needs with a single tool integrating virtually any enterprise document management system for collaboration and faster workflows, including integrations with Kofax SignDoc for e-signature capabilities. Additionally, Kofax Power PDF users gain improved searching and redaction accuracy with Kofaxs award-winning optical character recognition (OCR) technology.
Lets face it: not all products are created equal, and neither are all technology buyers, says Vinay Bhagat, Chief Executive Officer at TrustRadius. Thats why at TrustRadius were always looking for new ways to help buyers make great decisions. By highlighting products that have first-class feature sets, we can help more buyers navigate to products that will meet their unique needs.
Especially during this difficult year, software companies and tech buyers alike are facing new challenges, says Megan Headley, Vice President of Research at TrustRadius. The Best Feature Set and Customer Support Awards help both parties address those challenges through the power of trusted reviews on TrustRadius."
Last August, Kofax released Power PDF 4, the latest edition of the No. 1 global alternative to Adobe Acrobat with over two million users. Formerly Nuance Power PDF, Kofax Power PDF 4 increases worker productivity with improved digital accuracy and the integrated e-signature capabilities of Kofax SignDoc.
About TrustRadius
TrustRadius helps technology buyers make better decisions and helps vendors tell their unique story, improve conversion, engage high-intent buyers, and gain customer insights. Each month over 1 million B2B technology buyers, over 50% from large enterprises, use verified reviews and ratings on TrustRadius.com to make informed purchasing decisions. Headquartered in Austin, TX, TrustRadius was founded by successful entrepreneurs and is backed by Mayfield Fund, LiveOak Venture Partners and Next Coast Ventures.
About Kofax
Kofax enables organizations to Work Like Tomorrow"¢today. Kofaxs Intelligent Automation software platform and solutions digitally transform document-intensive workflows. Customers realize greater agility and resiliency by combining our process orchestration, cognitive capture, RPA, output management, analytics and mobile capabilities to speed time-to-value and increase competitiveness, growth and profitability while mitigating compliance risk. For more information, visit kofax.com.
2021 Kofax, Inc. Kofax is a registered trademark of Kofax Limited.
Amanda Ingalls


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Praying "Thy Kingdom Come" - launch of the 40-Day Fast and Prayer
THY KINGDOM COME. This prayer that Jesus prayed is the theme of the 2013 40-Day Fast and Prayer which began on 7 August.
Helping us to understand how this theme can impact our prayers for the nation are Pastor Dr Chew Weng Chee of SIB KL and Rev Esther Kong of GA611 Bread of Life Centre. They spoke at the launching of the fast and prayer on 31 July which was held simultaneously in FGA KL and GA611. Here are some gleanings from their inspiring sermons:
Rev Esther Kong: How is God's Kingdom going to come?
Praying in groups at the launch at GA611
Only the Spirit of God can open our eyes to the sin upon our land and move our hearts to action. Ezekiel 36: 17 notes how the people of Israel defiled their own land through their conduct and actions. It took Ezekiel, a man of God, to recognise their sin and proclaim the Lord's judgement. Likewise, we need to ask the Spirit of God to help us pray with focus and direction.
The eyes of the Church in Malaysia need to open before we can gain Ezekiel's discernment. We are reminded to:
Return to the Word, reading it voraciously so that we can discern truth from deceit.
Repent, by acknowledging our sins and turning away from selfish ways.
Be humble in prayer.
"Map" the strongholds in our nation through research and study, keeping abreast of current issues and understanding their significance to the nation.
Be faithful in evangelism, constantly proclaiming the Gospel of salvation.
Stay united in line with Ephesians 4: 3, "Make every effort to keep the unity of the Spirit through the bond of peace".
God looks for vessels that can be used by Him - people who love Him and who love the nation as well. Be the vessel that makes God's Kingdom a reality on earth!
Pr Chew at the launch at FGA KL
Pastor Dr Chew Weng Chee: How to advance God's Kingdom to overcome darkness in a nation.
Drawing from the life of Jehu in 2 Kings 9, Pastor Chew spoke on five points that churches and Christians can adopt for effective prayer and action:
Focus - As Jehu rode his chariot "like a maniac" (vs 20), so the Church must ride furiously with only one focus during this 40-day fast and prayer - God and His will for the nation.
Repentance - Jehu told each of King Joram's horsemen who rode up to him to "Fall in behind me". We need to pray for this kind of turn-around in the allegiance of Malaysia's people, to "fall in behind" truth and righteousness.
Wisdom and discernment - With each of the enemy horsemen who asked "Do you come in peace?", Jehu was able to discern the falsehood behind their request. An invitation to peace is often an invitation to compromise. Jehu knew, as he later told Joram in vs 22, that there could never be peace "as long as all the idolatry and witchcraft of your mother Jezebel abound".
Speak boldly - When Jehu shouted in vs 32 "Who is on my side?", those who responded were the eunuchs. These emasculated men were ultimately the ones who killed Jezebel. The Church must sound the war cry and be prepared for God to move not through the strong and mighty, but the small, weak and unlikely.
Empower the young - The prophet who anointed Jehu as Israel's new King was not Elisha, but a young, unnamed prophet (vs 4). Is the Church equipping its young and letting them rise to lead?
What does the story of Jehu have to do with praying "Thy Kingdom come, thy will be done?" What does 2 Kings 9 have to do with our prayers for Malaysia?
As Pastor Chew noted, this chapter records the defining moment in Israel's history when Jezebel and Ahab's reign of evil over Israel was finally broken. Ahab was already dead, but Jezebel had been the power behind his throne and his son Joram's. Jehu, aided by a handful of eunuchs, were God's instruments to bring Jezebel's downfall. Can the larger, urban, resource-rich churches be like Jehu to lead and partner the smaller, rural churches in bringing about Kingdom transformation?
The crowd at FGA KL


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passive euthanasia
passive euthanasia News
Person in persistent vegetative state shouldn't be made experimental object: Ex-CJI Misra
Justice (retd) Misra said if a person cannot die with dignity, it was akin to affecting his or her identity.
Dignity, but for whom?
Verdict on living wills does not take into account socioeconomic realities.
Kanpur woman, daughter write to President Kovind for passive euthanasia
Since 2014, Anamika has been writing to the President, Prime Minister Narendra Modi and the Chief Justice of India, stating that if arrangements could not be made for their treatment, they should be told how to end their lives.
UP woman, daughter write to President for passive euthanasia
Anamika Mishra contracted muscular dystrophy, a genetic disease which leads to increasing weakening and breakdown of skeletal muscles, six years ago.
'We want to go while our organs are still working', says Mumbai couple
Lavate wanted to end his life along with his wife Iravati (78), a former school principal. The couple does not have children and are "as healthy as old age lets them be", they claim.
The living will guarantee freedom and dignity, but it faces complex issues, which must be ironed out in use.
Passive euthanasia now legal: Health experts hail SC ruling, say it was long due
In a landmark judgment, the Supreme Court today recognized that a terminally-ill patient can write a 'living will' that permits doctors to withdraw life support, saying a person with no will to live shouldn't suffer in a comatose state.
What is active, passive euthanasia and 'living will'?
The Supreme Court, in a landmark judgement on Friday, decided that passive euthanasia will be legally allowed henceforth in India.
Passive euthanasia now legal: Here's everything you need to know about Supreme Court guidelines for 'living will'
It defined passive euthanasia as, "a decision to withdraw life-saving treatment by a patient who is competent to take decision as well as with regard to a patient who is not competent to take decision can be termed as passive euthanasia, which is lawful and legally permissible in this country."
Author Pinki Virani hails SC ruling on passive euthanasia
Virani had approached the Supreme Court in 2009 as the "next friend" of Shanbaug, who was in a vegetative state after being assaulted and raped by a wardboy-cum-sweeper at the KEM Hospital in Mumbai in 1973.


Amends the Laws N° 127(I) of 2000, 57(I) of 2004, 72(I) and 102(I) of 2007 and 63(I) of 2014 on Persons with Disabilities, by amending article 7A and by replacing the Annex on the parking card and privileges of persons with disabilities.
Introduces amendments to article 9, concerning the principle of reasonable normalization, and article 9C of the Laws N° 127(I) of 2000, 57(I) of 2004, 72(I) and 102(I) of 2007 on Persons with Disabilities.
Ratification of the UN Convention on the Rights of Persons with Disabilities.
Article 2: substituting the word "Medical Council" with the word "Mutlithematic Commission"
Article 3: adds "Labour and Social Security"
- article 2, replacing the words "the competent authority of the Labour Department" with the words "the Centre of Social Integration of Persons with Disabilities".
- article 6, replacing the words "Occupation" and "the Foreman of the Competent Authority of Labour Department" in section 1, with the words "of Social Integration of Persons with Disabilities" and "one Social Worker of the Department of Social Integration of Persons with Disabilities" respectively, and replacing the words "Occupation" and "Foreman of the Competent Authority of Labour Department in section 2, with the words "of Social Integration of Persons with Disabilities" and "Social Worker of the Department of Social Integration of Persons with Disabilities" respectively.
Law No. 57(I) of 2004 implementing Directive 2000/78/EC to amend Law No. 127 (I) of 2000 concerning persons with disabilities.
Prohibits all forms of direct or indirect discrimination against persons with disabilities as regards employment, selection criteria, promotion, vocational guidance and training, working conditions, including pay and termination of employment, as well as membership and participation in professional organizations. Establishes the liability of legal persons and of the executive personnel of legal persons for instances of discrimination which occur with the consent, collaboration or acceptance of the latter. Provides for the right of recourse to judicial and administrative remedies.
Law No. 74(I) of 2003 to amend Law No. 8 of 1991 and Law No. 97(I) of 1994 concerning public assistance and services.
Introduces a new definition of the term "disabled person" and extends the grant of public assistance to disabled persons residing temporarily outside the Republic of Cyprus for educational or medical treatment purposes.
Act No 127(I) of 2000 to make provisions for persons with disabilities.
Defines dispositions concerning the rights of disabled persons to work, just working conditions, and equal treatment in the working environment. Creates the Council for disabled persons and the Fund for persons with disabilities, and provides for their administration and management. Also provides for codes of practice and for the associated regulations.
Act No. 113(I) of 28 July 1999 concerning the education and culture of children with special needs.
Provides for the organization and monitoring of education and cultural activities of children with special needs.


0:05Skip to 0 minutes and 5 secondsThroughout the five weeks of this course, we hope that you've developed and deepened your understanding of how you can use assessment to differentiate and support the learning of all your students. Changing your practice in this way allows you to be responsive to learning and more aware of your learner's needs. This day-to-day use of assessment can be used to tailor teaching to develop approaches that different students' knowledge and understanding. Research shows that it's high-quality, formative assessment like this that goes the very heart of good teaching. We would like to encourage you to keep on implementing, adapting, and developing ideas that we've introduced in this course.
0:44Skip to 0 minutes and 44 secondsNone of this is easy to do, and all of it takes practice, resilience, and a growth mindset from us as educators. However, it is worth persevering with. So from myself and from Chris and Andrea, thank you for taking part in the course.
In this short video Chris and Dylan bid farewell and encourage you to persist in developing your use of assessment in order to differentiate and support all learners.
None of this is easy to do, and all of it takes practice, resilience, and a growth mindset from us as educators. However, it is worth persevering with.
As an endnote here is a list of Dylan, Chris, and Andrea's 'top picks'. These are links and resources that you may find helpful as you continue to deepen your understanding of Differentiating for Learning.
If you've your own recommendations to make then please feel free to post suggestions and links via the comments on this step.


I experienced a strange event in the summer 1970. I was 15-years-old and lived on a farm with my parents, grandparents & siblings. We lived near the town of Geneseo, IL. Our house was almost completely surrounded by woods.
One night, about 2 AM, I awoke and became aware that I was not in bed in the basement of the house. But rather I was sitting on a bench in an unknown room with one young adult male. The room was constructed of white-colored metal with benches. There was a door in the room and on either side of the door were windows from which I could see a passageway going to the left and right. The other person in the room with me sat on the bench to the left side of the door and completely ignored me even when I shook him and tried to get him to look at me. He just sat on the bench with his elbows on his knees gazing downward between his legs at the floor. He was oblivious of me. I tried to open the door but it was locked and I got up on the bench to the right side of the door and leaned against the glass trying to see something. It was just an empty passageway. The room was brightly lit, but no source of light was noticed.
I again tried to get the man in the room to pay attention to me and help me understand what was happening...but still he just sat there. I looked up at the window and saw a bizarre 'creature' about 4 feet tall, covered with reddish-colored long hair, but the face looked human-like. It did not pay any attention to us in the room, slowly walking by the window. I was very scared. I jumped on to the bench and them beat on the plexiglass and screamed. The being just kept walking by. That was the last thing I remember.


text:
High-grade serous carcinoma with discordant p53 signature: report of a case with new insight regarding high-grade serous carcinogenesis
Yuichiro Hatano1Email authorView ORCID ID profile,
Shinya Fukuda1,
Hiroshi Makino2,
Hiroyuki Tomita1,
Ken-ichirou Morishige2 and
Akira Hara1
Diagnostic Pathology201813:24
Received: 9 February 2018
Although p53 signature, benign-appearing epithelial cells with p53 diffuse expression, is frequently found in the fallopian tubes, the clinical and pathological significance of this lesion in the case of high-grade serous carcinoma (HGSC) patients still remains unclear.
A 56-year-old woman was referred to the gynecologist on account of abdominal distention. Since radiological and serological workup suggested that her illness was due to advanced ovarian cancer (FIGO Stage IVB), she received neoadjuvant chemotherapy, and the clinical evaluation of the chemotherapeutic response was a partial response. She underwent total hysterectomy with bilateral salpingo-oophorectomy, omentectomy, and intra-pelvic and para-aortic lymphadenectomy. Histologically, the cancer cells showed high-grade nuclear atypia and spread into the bilateral ovaries, omentum, uterine serosa, and left fallopian tube. The cancer cells showed complete absence of p53 but overexpressed p16, whereas some of benign-appearing tubal epithelial cells overexpressed p53 but lacked p16 expression. The results of direct sequence analysis revealed that the ovarian cancer contains a 1 bp deletion in exon 8 of TP53. Finally, the histological diagnosis of HGSC with discordant p53 signature was made. Interestingly, nuclear expression of γ-H2AX, a well-known marker of DNA damage, was not only observed in both p53 aberrantly-expressing lesions but also the benign-appearing tubal epithelium without p53 overexpression. After the histological confirmation, she received adjuvant chemotherapy and has been in disease-free condition without any detectable tumor for 5 months.
Recent evidence suggests that p53 signature is the putative precursor of p53 overexpression-type HGSC. Because the putative precursors of the other p53 immunophenotypical HGSC are not proposed, we presume γ-H2AX-expressing cells without p53 overexpression may be a potent candidate of null-type TP53-mutated tubal cells, which are named "γ-H2AX responsive foci."
Fallopian tube
High-grade serous carcinoma
p53 signature
γ-H2AX
Extra-uterine high-grade serous carcinoma (HGSC) is one of the most lethal malignancies of the female genital tract, and almost always harbors TP53 mutation [1–4]. Recent evidence indicates that most HGSC cases arise from serous tubal intraepithelial carcinoma (STIC), which is particularly found in the distal fallopian tube [5, 6]. Concurrent STIC and HGSC likely share a common TP53 mutation and/or p53 expression pattern, indicating that these two serous cancers originate from a single TP53-mutated clone [7, 8]. In addition, no intra-tumoral heterogeneity of TP53 mutation is found in primary untreated HGSC cases [9]. Consistent with this notion, demonstration of identical TP53 mutation is a useful clue of synchronous lesions [10] and late recurrence [11] of HGSC, and vice versa [12]. Therefore, routine pathological diagnosis of HGSC requires at least p53 immunostaining and extensive investigation of the fallopian tubes, which is based on the SEE-FIM (Sectioning and Extensively Examining of the Fimbriated end) protocol [13].
Such careful pathological examination of the fallopian tubes incidentally detects the p53 signature, which comprises continuous normal-looking tubal epithelium with p53 overexpression. These aberrant p53-expressing cells are occasionally found in asymptomatic healthy women regardless of BRCA germline mutation status, and more frequently in women with tubal intraepithelial carcinoma [14]. Interestingly, some of these benign-appearing lesions possess TP53 mutation identical to the coexisting tubal intraepithelial carcinoma. Considering that p53 dysregulation is believed to be the initiating event for high-grade serous carcinogenesis, the p53 signature is a potent precursor of STIC and/or HGSC.
We herein report the case of a patient with two distinctive p53 aberrantly-expressing lesions that suggest some new insight into the understanding of high-grade serous carcinogenesis.
Clinical history
A 56-year-old woman, gravida 2, para 2, was referred to the gynecologist on account of abdominal distention. She had a past medical history of acute pancreatitis, but she had never experienced similar symptoms before. She was on no medications at the time of presentation. She denied familial history of ovarian and/or breast cancer. Blood tests revealed that serum CA125 was high (1520.5 U/mL). Abdominopelvic magnetic resonance imaging showed massive ascites, ovarian masses and numerous nodules in the abdominal and pelvic cavities. In addition, chest computed tomography (CT) scan showed left-supraclavicular lymphadenopathy. Consistent with these radiological findings, positron emission tomography-CT detected fluorodeoxyglucose accumulation within bilateral ovarian masses and left-supraclavicular, peritoneal, para-aortic and intra-pelvic nodules, which were suggestive of distant metastases and peritoneal dissemination from ovarian cancer. Since the clinical diagnosis of advanced ovarian cancer, FIGO Stage IVB (cT3N1M1) was made, three cycles of neoadjuvant chemotherapy (NAC) with paclitaxel/carboplatin were administered. Following NAC, serum CA125 was reduced (97.6 U/mL) on blood tests, all the suspicious tumoral lesions had decreased in size, and the ascites had diminished on radiological re-assessment. The clinical evaluation of chemotherapeutic response yielded a partial response; total hysterectomy with bilateral salpingo-oophorectomy, omentectomy, intra-pelvic and para-aortic lymphadenectomy were performed.
Upon histological assessment of the surgical specimen the ovarian cancer was classified as FIGO Stage IIIB (ypT3bN1MX) [15] and the chemotherapy response score was estimated as 1 (minimal tumor response) [16]. She underwent six cycles of adjuvant chemotherapy with bevacizumab and/or paclitaxel/carboplatin, and has been disease-free without any detectable tumor for 5 months.
Pathological findings
Histologically, the cancer cells showed high-grade nuclear atypia and spread into both ovaries, the omentum, uterine serosa, and left fallopian tube. In the left distal fallopian tube (Fig. 1a-c), these cancer cells (Fig. 1d) showed complete absence of p53 (clone: DO-7; Figs. 1e and 2a), but overexpressed p16 (Figs. 1f and 2b). Interestingly, the benign-appearing tubal epithelium adjacent to the high-grade cancer cells (Fig. 1g) showed an overexpression of p53 (Figs. 1h and 2a), but lacked p16 expression (Figs. 1i and 2b). In addition, nuclear expression of γ-H2AX (clone: ab11174, Abcam, Fig. 2c), was found in both p53 aberrantly-expressing lesions. The Ki-67 labeling index of p53-positive benign-appearing epithelial cells was < 5% (Fig. 2d), whereas that of high grade tumor cells was approximately 15% (Fig. 2e). Finally, we diagnosed these lesions as HGSC with discordant p53 signature.
Two distinctive p53 aberrantly-expressing lesions. (a)-(c) Representative hematoxylin and eosin stained (a), p53 (b) and p16 (c) immunostained images of the left fallopian tube, which contains high-grade serous carcinoma (right) and p53 signature (left, arrowhead). (d)-(f) Representative hematoxylin and eosin stained (d), p53 (e) and p16 (f) immunostained images of high-grade serous carcinoma. (g)-(i) Representative hematoxylin and eosin stained (g), p53 (h) and p16 (i) immunostained images of p53 signature
γ-H2AX expression in the distal fallopian tube. (a)-(c) Representative immunostained images of the p53 (a), p16 (b) and γ-H2AX (c) protein expressions in the high-grade serous carcinoma (right) and p53 signature (left). (d)(e) Representative Ki-67 immunostained images of p53 signature (d) and high-grade serous carcinoma (e)
We also performed TP53 mutation analysis of HGSC by direct sequencing according to the International Agency for Research on Cancer protocol (http://p53.iarc.fr/Download/TP53_DirectSequencing_IARC.pdf Accessed 22 Dec 2017) with minor modification. Briefly, genomic DNA was extracted from formalin-fixed, paraffin-embedded samples of the ovarian tumor and normal tissue, respectively, using NucleoSpin DNA FFPE XS (Macherey-Nagel, Germany). Exons 4–8 of TP53 were amplified by polymerase chain reaction and the products were analyzed at the Division of Genomics Research, Life Science Research Center, Gifu University. The results showed that the ovarian cancer contains a 1 bp deletion (c.792del1), which is interpreted as a frameshift mutation, in exon 8 of TP53, whereas normal tissue lacked this alteration (Fig. 3).
TP53 mutation analysis of HGSC. A DNA sequence analysis of TP53 exon 8 from the ovarian and normal tissue with the reverse primer. The sequence of the ovarian tumor shows biallelic pattern from the coding DNA reference number 792, indicating that HGSC harbors a 1 bp deletion (c.792del1) in the TP53 gene
The patterns of p53 aberrant expression, which is a high-precision predictor of TP53 mutation, have been traditionally divided into diffuse positive (also known as overexpression), and complete absence (also called as null, diffuse negative) [9]. Intriguingly, the pattern of p53 aberrant expression also predicts the TP53 mutation status. The overexpression and null patterns are mainly associated with gain-of-function and loss-of-function type TP53 mutations, respectively. Recently, Kobel et al. reported the cytoplasmic p53 staining, which is the rare third pattern of p53 aberrant expression that arises from genetic mutation in the nuclear localization signaling domain [3]. Collectively, abnormal patterns of p53 expression reflect TP53 mutation types in HGSC.
In this case, two distinctive p53 aberrantly-expressing lesions were confirmed in the fallopian tube section. Direct sequencing revealed that HGSC harbored a 1 bp deletion in exon 8 of TP53. This alteration leads to disruption of the p53 DNA binding domain, which is consistent with the complete absence of p53 expression in HGSC. On the other hand, we failed to investigate TP53 mutation status of p53 signature because of the insufficient quantity. Given that TP53 mutation is an initial and central factor in the pathogenesis of HGSC, different TP53 mutation types likely determine the biological properties of neoplastic cells, including the p53 expression pattern. Thus, discordant p53 aberrantly-expressing patterns are interpreted as the p53 signature being unrelated to the coincident p53 null-type HGSC.
The various p53 immunophenotypes in HGSC implicate the existence of corresponding p53 immunophenotypical precursors. In other words, benign-looking tubal epithelium with abnormal p53 expression includes not only conventional overexpression-type p53 signature but also null- or cytoplasmic staining-type p53 signature (Table 1). Although the conventional p53 signature is detected by routine diagnostic immunohistochemistry, cytoplasmic staining-type p53 signature is probably misdiagnosed as the overexpression-type because of the rare and unknown abnormal pattern. Besides, the other speculative "null-type" p53 signature must be undetectable in the lesion by the same immunohistochemical analysis. Conceptually, these p53 null-type normal-looking tubal epithelial cells should be distinguished from secretory cell outgrowth (SCOUT) [17], which lacks TP53 mutation.
Summary of relationship between high-grade serous carcinogenesis and p53 immunophenotype
p53 immunophenotype
Precursor lesion
Malignant form
Diffuse positive (also called overexpression)
p53 signature [14]
HGSC with p53 overexpression, which may reflect GOF p53
Diffuse negative (also called as null, complete absence)
γ-H2AX responsive foci, see Discussion section
HGSC without p53 expression, which may reflect LOF p53
Cytoplasmic staining
Not proposed, but probably misinterpreted as a p53 signature
HGSC with p53 cytoplasmic expression, which is a rare immunophenotype with uncertain clinicopathological significance
Wild-type
SCOUT [17]
HGSC NOS, which shows any p53 immunophenotype
HGSC high-grade serous carcinoma, GOF gain-of-function, LOF loss-of-function, SCOUT secretory cell outgrowth, NOS not otherwise specified
To demonstrate invisible p53 mutants, we performed additional immunohistochemical analysis of γ-H2AX, a well-known marker of DNA damage [18, 19]. Since the orthodox function of wild-type p53 is activation of the DNA repair system, foci of γ-H2AX-expressing cells may reflect p53 dysfunction and/or TP53 mutations in the cells. Consistent with a previous report, [14] both the p53 signature and HGSC expressed γ-H2AX. Noteworthy, nuclear expression of γ-H2AX was also detected in the benign-appearing tubal epithelium without p53 overexpression (Fig. 2c). Similarly, Staff et al. reported that γ-H2AX-expressing cells were often found in the fallopian tube but that not all cells overlapped with p53 expression [20]. We speculate that these γ-H2AX-expressing cells without p53 overexpression may be potent candidates for null-type TP53 mutations, and therefore, named them "γ-H2AX responsive foci." Interestingly, the Ki-67 labeling index of these cells was almost the same as that of p53 signature. However, it is very difficult to determine whether these candidate cells harbor TP53 mutation by immunohistochemistry alone, unlike the p53 signature. To identify the hidden precursors of null-type p53 HGSC, other efficient markers of loss-of-function p53 and TP53 mutation analysis are desired. Taken together, the detection of null-type TP53 mutation in benign-appearing tubal epithelial cells can help elucidate unknown precursors of STIC and/or HGSC and certainly improve our understanding of microscopic TP53-mutated intraepithelial lesions.
Molecular characteristics of HGSC are classified as inevitable TP53 mutations and diverse gene expression profiles. TP53-mutated cells variously evolve by genomic instability, and result in intra- and inter-tumoral heterogeneity in HGSC. These heterogeneities often become a problem in medical practice today [21]. To understand the heterogeneities of prognoses and therapeutic response, molecular classification of HGSC based on gene expression profiles has been attempted [2, 22, 23]. Similarly, p53 expression/TP53 mutation type in HGSC has shown promise in the classification of the biological characteristics of this lethal high-grade malignancy.
Recent evidence suggests the precise prediction of TP53 mutation status solely by p53 immunohistochemistry. This suggestion is also a modest clue to investigate the microscopic lesion, p53 signature. If p53 dysfunction is visualized by other immunohistochemical markers, speculative "null-type" p53 signature could be detected. Therefore, we propose "γ-H2AX responsive foci" as a hidden precursor of null-type p53 HGSC. To progress in the study of the initial genetic event in high-grade serous carcinogenesis, identification of the null- and/or cytoplasmic staining-type TP53-mutated normally-appearing cells is required in the future.
FIGO:
The International Federation of Gynecology and Obstetrics
HGSC:
IARC:
International Agency for Research on Cancer
NAC:
Neoadjuvant chemotherapy
SCOUT:
Secretory cell outgrowth
STIC:
Serous tubal intraepithelial carcinoma
This work was supported by JSPS KAKENHI (18K15207)
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
YH: conception, pathological diagnosis, and writing of manuscript. YH, SF: TP53 mutation analysis. HM: collection of clinical data. YH, HT: immunohistochemical analysis. KM, AH: revision of manuscript. All authors read and approved the final manuscript prior to submission.
Written informed consent was obtained from the patient for the publication of this case report. A copy of the consent form is available for review by the Editor of this journal.
Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan
Department of Obstetrics and Gynecology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
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Great Job! Here's a Seat Belt!
Here is the story of Latoya Gardner, a seat belt, and what happened when a KFC in Louisville, Kentucky, ran out of crispy strips.
When the strips sold out that day, a customer had to wait while employees cooked up a fresh batch. Gardner, working the lunch shift, apologized for the delay and offered the man a free side item so he wouldn't go hungry. She and her team members "were just so attentive to me," the customer recalls.
It was no ordinary customer experience–and the man, it turned out, was no ordinary customer. As senior VP of public affairs at Yum Brands Inc. (formerly Tricon Global Restaurants), KFC's parent company, Jonathan Blum was in a position to recognize employees going the extra mile. Blum hurried back to nearby Yum headquarters, grabbed one of his signature awards–a seat belt on a plaque, symbolizing the "roller coaster" nature of the restaurant business–and returned to the KFC to fete Gardner. "In front of all her peers, I said, 'You didn't know that I work at Yum. I want you to know how proud I am of you.' " Today, a photo of a beaming Gardner hangs in Blum's office.
In Yum parlance, they call it "catching people doing things right"–taking time to notice and publicly reward employees who exceed expectations. "People innately want to be recognized for their hard work," says Yum chairman and CEO David Novak. It's something Novak learned in 1993 as chief operating officer of Pepsi-Cola North America. At a meeting with salespeople in St. Louis, Novak found that everyone kept mentioning a merchandising star named Bob.
"This guy starts crying," Novak recalls. "He says, 'I've been in this company 42 years, and I didn't know anybody thought this way about me.' I thought, if I ever run a company, I'm going to make sure people are recognized." Novak became president of KFC and of Pizza Hut, where he recognized stellar employees with floppy chickens and cheese heads. And when Tricon spun off from PepsiCo in 1997, Novak made recognition one of the new company's core principles.
Today at Yum headquarters, you can't turn a corner without bumping into an award of some sort. There are index-card-sized write-ups that workers post when they see a colleague Walking the Talk. There's the employee Roving Recognition Band, whose members, outfitted with tubas and tambourines, descend on workers' offices. There are Wow stickers, pins, and–most coveted of all–the idiosyncratic prizes, such as Blum's seat belt, that company leaders give out individually and display in Yum's halls.
Yum thinks the results are a big deal, too. Turnover among its 840,000 employees is down to 115% from 181% three years ago. Profit margins are up, too, from 11.5% in 1997 to a projected 14.5% in 2003. It's common sense, Novak says. "If you can get your people smiling and feeling good about themselves, that's fundamental to customer satisfaction." Employees are more likely to stay put longer–and customers come back for seconds.


text:
Sex predator who raped sleeping girl jailed for five years
Luke Brownlie, 19, attacked the 17-year-old and later texted her "I guess police will be at my door".
Grant McCabe
High Court, Glasgow (Image: Getty)
A sex predator who raped a sleeping girl has been locked up for five years.
Luke Brownlie attacked the 17 year-old – then later texted her: "I guess police will be at my door".
The 19 year-old denied the crime which occurred at a house in Kilsyth, Lanarkshire in July 2018.
But, jurors heard of the "damning" messages which helped snare Brownlie.
All-girls Notre Dame High School to admit boys for the first time from 2021
He returned to the High Court in Glasgow today having earlier been convicted of rape.
The hearing was told Brownlie – who had claimed consent – continues to protest his innocence.
Lord Armstrong told him: "The crime that you have been convicted of is a grave offence against which all women should be protected."
Brownlie, of Coatbridge, Lanarkshire, was also placed on the sex offenders list indefinitely.
The trial heard how victim had gone to the house in Kilsyth where Brownlie also was.
She ended up falling asleep on a bed – but awoke to find Brownlie having sex with her.
The traumatised teenager got up and left – Brownlie asked did he want him to walk her home.
She was described as "freaking out" and crying. The victim was not able to tell her own mum "face to face" and instead messaged her.
Brownlie later texted the teenager asking had she fallen out with him.
Appeal launched to trace vulnerable man missing from Shettleston
She stated at one stage: "Why did you do it?"
He replied: "I don't know. I promise it won't happen again."
In his closing speech, prosecutor Paul Kearney said: "His apologies you may think were designed to persuade her not to take the action that he knew she was entitled to."
Brownlie also stated: "I guess police will be at my door."
In another, he whined: "My life will be ended. I need my family. They are all I have got."
But, his victim replied: "What about me? This is going to f*** with my head."
Brownlie claimed he knew what happened was "wrong" and that he would "kill" himself.
The teenage girl gathered screenshots of the texts before going to police.
Mr Kearney said the testimony was "utterly compelling".
He told jurors: "I suggest when you look at all the evidence you can have absolutely no doubt at all that she was telling you the truth."
For more news and all that's going on in your city, head to the Glasgow Live homepage - or you can check us out on Facebook , Twitter and Instagram .


text:
Call To Freedom Placing Posters Ahead Of Sturgis Rally
by: Matt Holsen
Posted: Jul 27, 2018 / 10:09 PM CDT / Updated: Jul 27, 2018 / 10:09 PM CDT
The Sturgis Motorcycle Rally starts next week. While tourists will be coming in from all over the country to visit the state, a local organization says human traffickers will also be dropping by. Call To Freedom is organizing "ambassador teams" to go out and spread the word about trafficking.
Visitors are already rolling into the state on Interstates 29 and 90 for the Sturgis Rally.
"There are wonderful people coming into our state. They're supporting our state. We want that. Tourism is something we want but along with tourism, you will get those who will prey upon innocence," Volunteer Chair of the Ambassador Team for Call To Freedom Denise Austad said.
She's known several victims of trafficking and hopes putting up posters in hotels, restaurants, gas stations and businesses will help prevent future tragedies.
"The headline, 'Can You See Her?' These are faces that sometimes you are not going to readily identify," Austad said.
Ambassador Grant Washnok has been calling around Sioux Falls to see who'd like a poster. More than 500 have been ordered from the "Blue Campaign" and delivered to east river locations.
"To get out to the public so people know about this. It is around here. Just to get education out there and awareness," Washnok said.
On top of two phone numbers on the posters, Washnok is also handing out cards with tips on how to spot a victim.
"Some of the items are if the victim is being coached. They don't know what state they're in. They don't have money themselves are some examples," Washnok said.
It's all in an effort to stop trafficking. Austad says victims are left broken after the abuse.
"All these wonderful things that we think about that they should experience in school, in childhood, in friendship, going to games. They lose that," Austad said.
And she wants to stop it before it takes place.
Many Bikers will pass through Sioux Falls on their way to Sturgis. Call To Freedom is also putting up posters in Sioux City, Watertown, Worthington, Mitchell and Chamberlain.
WASHINGTON (AP) — Civil liberties groups are asking a federal judge for a temporary restraining order blocking the Trump administration's effort to effectively end asylum at the U.S.-Mexico border.
The American Civil Liberties Union and others filed the request Wednesday, seeking a Thursday hearing in San Francisco. The groups sued Tuesday and want the judge to block the policy while the case is heard.
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