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Q: youtube iframe events I try to catch the events of a youtube iframe:
http://lab.joergpfeiffer.de/videofull/youtube.php
So I call first the api

I set the iframe

and try to set the events later in
var ytfullplayer;
    function onYouTubePlayerAPIReady() {
        console.log('onYouTubePlayerAPIReady');
        ytfullplayer = new YT.Player('ytfullplayer', {
            events: {
              'onReady': testfunc,
              'onPlaybackQualityChange': testfunc,
              'onStateChange': testfunc,
              'onError': testfunc
            }
        });

    }
    function testfunc(){ alert('hello'); }

Whatever I do, there are no events fired. And I read the iframe api 10 times. it should work actually.
Any idea?

A: Execute these routines before onYouTubePlayerAPIReady()
// This code loads the IFrame Player API code asynchronously.
var tag = document.createElement('script');
tag.src = "http://www.youtube.com/player_api";
var firstScriptTag = document.getElementsByTagName('script')[0];
firstScriptTag.parentNode.insertBefore(tag, firstScriptTag);

if stil have confusion then visit http://code.google.com/apis/youtube/iframe_api_reference.html

A: I did the following.
Started with the example code found at https://developers.google.com/youtube/iframe_api_reference#Loading_a_Video_Player
I then replaced:

with

(iframe markup found at the same URL)
Then I got rid of the origin parameter in the above - that seemed to make things work. BTW, I found that step 2 can be replaced by markup:

A: Adeel's answer should fix your problem.
Google recommend you load the player API script asynchronously, ie, letting the rest of your page load while the script is simultaneously loading.
Because you're placing the script tag in your markup early on, the rest of the page isn't executed until that script has been loaded.  So when the call is made to onYouTubePlayerAPIReady(), your function hasn't yet been defined.

A: I have the same problem.  It seems to relate to putting the iframe in manually instead of using the div tag substitution.  If I use the div method it works fine, manual iframe, no.
Async load of the API script, or including it in the head manually didn't make any difference.
I have just gone with the div substitution for now, and stopped fighting it.

A: There is also &enablejsapi=1 which needs to be done in creating the embedded player- otherwise the API will ignore your JS side.

redpajama_set_name: RedPajamaStackExchange


text:
Q: Building a CMS admin panel I would like to build a CMS/backend in PHP for my websites to manage different things like photos, albums, news and in general creating dynamic content.
For example I would like to make a website where the owner can create a list of all his products with different attributes (text, images etc).
I know I could make my own CMS with an admin panel and I will have all the problems like users manage, CRUD functions for objects etc.
What I'm looking for is something between a CMS (like drupal or Wordpress) and Yii or Zend Framework.
I don't want to use this (CMS) to build frontend pages in total, like how drupal and wordpress do, because when i will create the frontend i just want to include my cms and use his functions like include_once(cms.php) and then use objects created by this CMS like echo $object->title etc.
What is the best and fastest way to create this?
I like how drupal creates content types where you can choose how to build this content like insert an image field or a text field etc but I think I can't just include Drupal in my frontend and use echo $object->title and also I like how Yii creates modules with CRUD functions.
What do you suggest?
Should I start from Yii or Zend and then use this as an admin panel or should I start from drupal and then try to include and use its functions in "external" pages?

A: IMHO Fastest way is to get a working system and try to manipulate to make act like you want, add code to your needs. this way you don't have to worry about some common tasks but there is a little learning of how that system works part.
but if you have time, you can always start from the ground up and make your own, just add what you need is making a faster system, but there is a difference between a system that has small team of developers (or you alone), and a system that has large number of users and a community of developers behind it.

for starters I would suggest to work on a reliable system, and build on top of that.


text:
Two vie for Fort Smith School Board seat
By SD News	 On May 8, 2021
FORT SMITH – The president of the school council has a challenger in the annual school election on May 18.
Incumbent Bill Hanesworth and Matt Blaylock compete for the big seat of the board in Position 4. The winner will be given a three-year term in the unpaid position.
Hanesworth has held this seat since 2015. He has served as Chairman of the Board for approximately one year.
A former high school teacher, Hanesworth is the chief operating officer of the Littlefield Oil Co. in Fort Smith. He is a member of the Dean's Leadership Council of the University of Arkansas – Fort Smith College of Business.
Blaylock is president of Blaylock Heating, Air Conditioning, & Plumbing Services in Fort Smith. He is also a member of the city's plumbing advisory board.
Hanesworth said he was initially running for the board after hearing from others that the school district had reportedly "fallen far behind in areas such as technology and infrastructure." He ran to find out what those people meant and to be part of the solution. He also wants to see Vision 2023, the district's five-year plan approved by the board in 2017.
Fort Smith and Barling voters approved an increase in property tax from 36.5 to 42 mills in May 2018 to pay for projects in the Vision 2023 capital improvement program. The additional millage – the district's first increase in 31 years – generated about $ 120 million for capital improvements, including new, safe access to schools.
Hanesworth said one of the issues he originally stood up for the board of directors was to provide "a safe learning environment for all students and teachers."
He said he voted to establish the district's own police department, which started in 2019. This consists of five full-time certified police officers, a part-time officer and three additional officers provided by the Fort Smith Police Department. It is run by Bill Hollenbeck, a former Sebastian County sheriff.
Hanesworth also said the district should standardize its curriculum across grades and schools and review certain teaching methods.
"We also have to take into account that many things have been learned during COVID that will allow us to get better in the future," said Hanesworth. "Using Zoom forced us to evaluate some other possibilities we could do with virtual schooling children."
Hanesworth said his experiences in key management roles at various companies give him a broad perspective on how to evaluate strategies. His time on the board included the hiring of two superintendents: Doug Brubaker in 2016 and Terry Morawski last year.
Blaylock said several decisions taken by the administration and the district in recent years have prompted him to flee. He declined to specify what the decisions were, except that some were staff-related, while others were financial decisions with the millage. He believes some of the millage revenue that went into construction projects has left Fort Smith's economy when it should have stayed there, he said.
According to Blaylock, the top three priorities of the board should be students, teachers and staff, and sound financial management.
"I think that is sometimes forgotten, and I think there are some board members who think that everyone among them works for them, when the board should really work for everyone: the people they represent and the employees of Fort Smith. Public School District, "said Blaylock.
Blaylock said he has worked with the district for more than 20 years, including as a contractor and with the district's Partners in Education program, which connects its schools with businesses in the community, according to the district website. It is important for Blaylock to have more participants in that program.
"To be fair, I think they could use those resources a lot more than they do," he said. "I have tried to offer them more help. They are not always taken advantage of, the opportunities that are offered."
"Simply put, if you're happy with the leadership of the Fort Smith Public Schools, you should vote for Mr. Hanesworth," Blaylock said. 'If you are not satisfied, then I am your candidate. I am sure of one thing: if nothing changes, nothing will change. '
Hanesworth has two children, one of whom is a freshman in the district. Blaylock has two children – a junior and an eighth-grader – enrolled in the district.
The early vote for the election starts on Tuesday.
Bill Hanesworth
• Hometown: Fort Smith; has lived in the school district for about 20 years
• Employment: Chief Operating Officer, Littlefield Oil Company, Fort Smith
• Education: Bachelor's Degree in Secondary Education from Louisiana Tech University, Ruston, La.
• Political Experience: Fort Smith School Board since 2015
Matt Blaylock
• Hometown: Fort Smith; lifelong resident of the school district
• Employment: President of Blaylock Heating, Air Conditioning, & Plumbing Services, Fort Smith
• Education: Bachelor's Degree in Professional Studies with a Concentration in Community Range from Arkansas Tech University, Russellville
• Political experience: none
HVAC Excellence to Offer Hybrid Event in 2022
Daum helps roofing company expand to Glendale | Business | glendalestar.com – Glendale Star

redpajama_set_name: RedPajamaCommonCrawl


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Neu-Ulm is a city known for its historic myths and traditions, scenic beauty, cooperative people and luxurious hotels and cottages. Neu-Ulm is one of the favorite holiday destinations for most of the vacation lovers.


What Are Some of the Most Highly Rated Marcy Jo's Mealhouse Recipes?
Two of the most well-reviewed recipes from Marcy Jo's Mealhouse are the ever-popular Angel Biscuits and Sausage Gravy (listed as separate recipes). Find these and most of the other Marcy Jo's Mealhouse recipes on the Joey+Rory website as of 2015.
Some of the other well-liked savory recipes from Marcy Jo's Mealhouse include Catfish and Hush Puppies, Mom's Meatloaf, Chicken Salad (and Chicken Salad Sandwiches), Barbecue Ribs, Pork Chops and fresh baked Wheat Bread. Among the most popular desserts or sweet breakfast recipes are Cinnamon Rolls, Pecan Sticky Buns, Chocolate Banana Peanut Butter Pie and the highly praised Marcy Jo's Stuffed French Toast.


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Counselling can help us to understand what triggers our anger and manage our response to it effectively, helping us to regain control and keep ourselves and others safe.
Anger is a natural emotion and part of our "fight or flight" system that can protect us when we are under threat. Like many of our emotions it triggers physical changes within our bodies; our hearts beat faster, our blood pressure increases, our digestive system and other processes shut down.
In everyday life we can usually recover from our feelings of anger fairly quickly and resume our ordinary behaviour. However, if we feel angry a lot of the time this can cause real problems with our physical and mental health as well as damage our relationships. It can leave us feeling out of control and can lead us to harm ourselves and others. At the other end of the scale, feeling angry but not expressing ourselves can leave us feeling depressed and anxious.
Problems with anger can be the result of a reaction to the environment or situation we find ourselves in, such as a highly pressurized and stressful job, money worries, being bullied or a victim of crime or feeling frightened, powerless, humiliated or overwhelmed. We learn to express our emotions largely through our experiences growing up as children, what was acceptable or not acceptable, and as a result we may learn to respond in an angry or threatening way to get our needs met. We may also have experienced anger and violence within our families or learnt that it was not acceptable to express anger. All this can leave us unable to manage or express our anger effectively as adults.
Anger management counselling is about increasing our self-awareness, helping to understand the origins of our anger and what triggers it. It enables us to manage the frustrations we encounter in life without recourse to aggression or angry outbursts.
"Feeling real is more than existing; it is finding a way to exist as oneself, and to relate to others as oneself, and to have a self into which to retreat for relaxation" DW Winnicott (1971) "Playing and Reality"


We can often see tell that an argument is unconvincing - or just plain wrong - but it's not always easy to work out why.
This workshop will focus on the vices that often accompany our modes of thought. Although these vices can best be understood as slippages or mistakes in our faculty to draw inferences, they are not always easy to spot. Thus, in learning how to formally identify these slippages or mistakes, you will also learn how to avoid making them when developing an argument of your own.


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text:
Q: How do I get Bluetooth working on Fedora Linux 20? I am trying to get a HP Office 100 printer to work over Bluetooth from my LinuxFedora 20 PC. I have installed "blueman-0.19-all.tar.gz", I tried to install bluez... but got  "Package bluez-5.18-1.fc20.i686 is already installed. " but "ddnf istall bluez-utils gave "No package bluez-utils available"
I have a link under Applications>Accessories  that is "blueman bluetooth manager" but when I click on it I get an "Error" window that says "No module named bluetooth. Make sure all dependencies are satisfied" Please what do I do to get out of this?


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Besides setting the brightness, choosing a pleasing color or neutral light, you can also pick one of the multiple effect modes. The RGBW WiFi ledstrip kit is very complete with the additional RF Color Touch remote.


text:
Home » Electronic Linguistics: Taka Iimura
Electronic Linguistics: Taka Iimura
Collins,Dan
ArtWeek, Cecile N McCann, Volume 11, Issue 41, Los Angeles, CA (1980)
people-text
Taka Iimura, the Japanese film and video artist is widely known for his work in film where he has concentrated on our perception of time and duration. As in his filmmaking, which seeks to arrive at the "fundamental components" of the medium, Iimura's videotapes, screened recently at the Long Beach Post-Production Studio, investigate the basic vocabulary of television.
For the past few years, Iimura has explored the structural relationships of language, using a closed-circuit video system. In a "self-referential" network of equipment where the image of a VTR camera ("observer") is fed back through a monitor ("observed"), a series of images is created which parallel in structure the syntax of the English language. Physically, the arrangements he favors utilize a basic VTR unit routed through a "switcher," two cameras and two monitors. Each camera is the focus on a monitor which, in turn, can display either live or prerecorded information.
In Iimura's attempt to relate image to language, the observer/camera(subject) becomes an integral part of both system and "sentence." He writes, "Unlike film, in closed-circuit video one can see the'observer' (subject) and the 'observed' (object) at the same time." The artist considers this subject/object relation to be "sentence-like." In 1976 Iimura began using a linguistic model where the subject/camera ("I") can "see" the object/monitor ("you"), i.e.,"I see you." By using this basic syntactical unit as a departure point for increasingly complex "sentences,"
the structural relationships between words, both written and spoken, and
hardware could be explored.
In Iimura's work, the roles of observer and observed shift according to the description of the words seen and/or heard by the percipient. For example, if the picture reads "I" and an off-screen voice says "you," one's mode of perception is affected differently than if the picture reads "you" and an off-screen voice says "I." A Given image, whether considered linguistically or in terms of the hardware employed, is expanded to include the functions of both observer and observed.
Norman Yonemoto, an LA video artist, feels that the primary concern of Iimura's work is "educational," i.e., it provides "lessons in a visual language." The point of these lessons, besides refining a viewer's capacity for processing audiovisual information, is, in Yonemoto's estimation, to put oneself into a contextual framework where there is the possibility of "total self-referencing."
Traditionally, the West has effected a clear separation of the concept of "subject" and "object," i.e., Western man (subject) has chosen to dominate and restructure his environment (object) to suit his most immediate needs. In contrast, the East has been characterized for generations by a fluid interchange between "subject" and "object," i.e., an individual schooled in the ways of the East has little trouble assimilating objects into the self.
Iimura, a native of Japan, is challenging our basic assumptions about how we perceive the world around us - as expressed in the simple arrangements of words and images. While the structures employed by the artist would be nothing new to those interested in language and its veiled functions, the work seen as a whole reflects a personality committed to expressing the universal through the subtle relationships which, from moment to moment, escape us all.


text:
$(document).ready(function() {
	// Tab
	tabsLoad("systemConfiguration");

	var current_case			= "";
	var import_modal_label 		= $("#import_modal_label");
	var verification_message 	= $("#verification_message");
	var user_verification_link 	= $(".user_verification_link");
	var btn_verify 				= $("#btn_verify");
	var btn_close 				= $('#btn_close');

	$("#btn_close").on("click", function(){
		btn_close.text("Cancel");
		btn_verify.removeClass("hide");
		btn_verify.removeClass("disabled");
		btn_verify.removeAttr('disabled');
		btn_verify.text('Yes');
	});

	$(".btn_import").on("click", function(){
		current_case 	= $(this).attr("data-case"); 	// update modal case (case_clinic / case_clinic_reminder / case_note)
		current_content = $(this).attr("data-content"); // update modal content
		current_title 	= $(this).attr("data-title");	// update modal title
		//alert(current_case);
		$("#btn_verify").attr("data-case", current_case);
		import_modal_label.text(current_title);
		verification_message.text(current_content);
	});

	$('#verifyForm').submit(function(e){
	e.preventDefault();

	btn_verify.button();
	btn_verify.button('loading');

	switch(current_case) {
		case "case_clinic":
			current_url = 'importData/clinics/refresh';
			break;
		case "case_clinic_reminder":
			current_url = 'importData/clinicalReminders/refresh';
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redpajama_set_name: RedPajamaGithub


text:
NIA takes over reins of suspected JMB operative case from Tripura cops
The JMB cadre has been charged with 'conspiracy to commit terrorist acts in India'
GUWAHATI , March 23, 2019 1:00 pm
NOOSE TIGHTENS: File Image of JMB operative Nazir Sheikh being taken into custody by Tripura Police on March 6 last.
The National Investigation Agency (NIA) took over from the Tripura Police a case 'involving' Nazir Sheikh, a suspected cadre of the terrorist outfit Jamaat-ul-Mujahideen Bangladesh (JMB).
As per reports, NIA was quoted as saying in a statement, "Case FIR No 019 dated 6.3.2019 under Sections 120B, 121, 121A, 122 and 123 of the IPC and Sections 18 and 20 of the Unlawful Activities (Prevention) Act, Police Station AD Nagar, West Tripura District has been taken over by NIA as Case No RC-01/2019/NIA-GUW (JMB Case of Tripura) on 22.03.2019 and investigation started."
NIA further added that the case relates to the arrest of a JMB cadre Nazir Sheikh who is a resident of Murshidabad in West Bengal who has been charged with "conspiracy to commit terrorist acts in India".
Sheikh was arrested by the Tripura Police earlier this month for having links with the terrorist outfit JMB. The police arrested him after receiving intelligence inputs and conducting a number of search operations.
Sheikh who is an expert in making Improvised Explosive Device (IED) told the police that "deadly attacks were being planned" in Assam and Bangladesh to "terrify the enemies of Islam".
His confessions echoes those of Mujibur Rahman, who, after his arrest by Bangladesh Police, confessed to working closely with Mazhar Khan, an ISI officer working under consular cover as assistant visa officer in the Pakistani Embassy in Dhaka.
Rahman confessed that he had been to Pakistan at least 20 times, to India 11 times and to Thailand to meet ISI officers and gun-runners 22 times, all in the past 18 months.
He told Bangladesh Police that the ISI officers were funding and arming the neo-JMB elements and the Bangkok meetings were part of the "third-country contacts" to facilitate peddling of weapons to the jihadis inside Bangladesh and Northeast India.
Since Rahman's confessions, Bangladesh Police has tightened its surveillance of the Pakistan Embassy in Dhaka and the Hasina Government has even refused to accept the credentials of Pakistan's ambassdor designate in Dhaka, Syedah Saqlain.


text:
FGFR3
Gene: FGFR3; fibroblast growth factor receptor 3
Aliases: ACH, CEK2, JTK4, CD333, HSFGFR3EX
Summary: This gene encodes a member of the fibroblast growth factor receptor (FGFR) family, with its amino acid sequence being highly conserved between members and among divergent species. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein would consist of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member binds acidic and basic fibroblast growth hormone and plays a role in bone development and maintenance. Mutations in this gene lead to craniosynostosis and multiple types of skeletal dysplasia. [provided by RefSeq, Aug 2017]
Protein: fibroblast growth factor receptor 3
Source: NCBIAccessed: 01 September, 2019
FGFR3 is implicated in:
- alveolar secondary septum development
- apoptotic process
- axonogenesis involved in innervation
- bone maturation
- bone morphogenesis
- central nervous system myelination
- chondrocyte differentiation
- chondrocyte proliferation
- cochlea development
- cytoplasmic membrane-bounded vesicle
- digestive tract morphogenesis
- endochondral bone growth
- endochondral ossification
- endoplasmic reticulum
- epithelial cell fate commitment
- fibroblast growth factor binding
- fibroblast growth factor receptor signaling pathway
- fibroblast growth factor-activated receptor activity
- focal adhesion
- inner ear receptor cell differentiation
- insulin receptor signaling pathway
- integral to membrane
- integral to plasma membrane
- internal side of plasma membrane
- JAK-STAT cascade
- lens fiber cell development
- lens morphogenesis in camera-type eye
- lysosome
- MAPK cascade
- morphogenesis of an epithelium
- negative regulation of astrocyte differentiation
- negative regulation of developmental growth
- negative regulation of epithelial cell proliferation
- negative regulation of mitosis
- negative regulation of smoothened signaling pathway
- peptidyl-tyrosine phosphorylation
- perinuclear region of cytoplasm
- positive regulation of apoptotic process
- positive regulation of canonical Wnt receptor signaling pathway
- positive regulation of cell differentiation
- positive regulation of cell proliferation
- positive regulation of endothelial cell proliferation
- positive regulation of ERK1 and ERK2 cascade
- positive regulation of MAPK cascade
- positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway
- positive regulation of phosphatidylinositol 3-kinase activity
- positive regulation of phospholipase activity
- positive regulation of protein ubiquitination
- positive regulation of tyrosine phosphorylation of Stat1 protein
- protein autophosphorylation
- protein tyrosine kinase activity
- regulation of apoptotic process
- response to axon injury
- skeletal system development
- somatic stem cell maintenance
- substantia nigra development
FGFR3 is involved in:
- MAPK signaling pathway KEGG
- Regulation of actin cytoskeleton KEGG
High-Throughput Nucleotide Sequencing
DNA Mutational Analysis
Transcription Factor TFIIIA
Oncogene Fusion Proteins
Neoplasm Invasiveness
DNA Sequence Analysis
Xanthomatosis
Neoplasm Recurrence, Local
Microtubule-Associated Proteins
Receptors, Fibroblast Growth Factor
Neoplasm Grading
Phosphatidylinositol 3-Kinases
Urinary System Cancers
Wnt Proteins
Urothelium
Class I Phosphatidylinositol 3-Kinases
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex
Urinary System Cancers FGFR3 and Urinary System Cancers View Publications 268
Bladder Cancer FGFR3 and Bladder Cancer View Publications 245
Multiple Myeloma FGFR3 and Multiple Myeloma View Publications 140
Transitional Cell Cancer of the Renal Pelvis and Ureter FGFR3 and Transitional Cell Cancer of the Renal Pelvis and Ureter View Publications 70
Skin Cancer FGFR3 and Skin Cancer View Publications 38
Lung Cancer FGFR3 and Lung Cancer View Publications 43
Cervical Cancer FGFR3 and Cervical Cancer View Publications 7
Testicular Cancer FGFR3 and Testicular Cancer View Publications 6
Latest Publications: FGFR3 (cancer-related)
Tsujino T, Sugito N, Taniguchi K, et al.
MicroRNA-143/Musashi-2/KRAS cascade contributes positively to carcinogenesis in human bladder cancer.
Cancer Sci. 2019; 110(7):2189-2199 [PubMed] Free Access to Full Article Related Publications
It has been well established that microRNA (miR)-143 is downregulated in human bladder cancer (BC). Recent precision medicine has shown that mutations in BC are frequently observed in FGFR3, RAS and PIK3CA genes, all of which correlate with RAS signaling networks. We have previously shown that miR-143 suppresses cell growth by inhibiting RAS signaling networks in several cancers including BC. In the present study, we showed that synthetic miR-143 negatively regulated the RNA-binding protein Musashi-2 (MSI2) in BC cell lines. MSI2 is an RNA-binding protein that regulates the stability of certain mRNAs and their translation by binding to the target sequences of the mRNAs. Of note, the present study clarified that MSI2 positively regulated KRAS expression through directly binding to the target sequence of KRAS mRNA and promoting its translation, thus contributing to the maintenance of KRAS expression. Thus, miR-143 silenced KRAS and MSI2, which further downregulated KRAS expression through perturbation of the MSI2/KRAS cascade.
Related: MicroRNAs Bladder Cancer Bladder Cancer - Molecular Biology KRAS MSI2
Grodzik M, Szczepaniak J, Strojny-Cieslak B, et al.
Diamond Nanoparticles Downregulate Expression of
Molecules. 2019; 24(8) [PubMed] Free Access to Full Article Related Publications
Our previous studies have shown that diamond nanoparticles (NDs) exhibited antiangiogenic and proapoptotic properties in vitro in glioblastoma multiforme (GBM) cells and in tumors in vivo. Moreover, NDs inhibited adhesion, leading to the suppression of migration and invasion of GBM. In the present study, we hypothesized that the NDs might also inhibit proliferation and cell cycle in glioma cells. Experiments were performed in vitro with the U87 and U118 lines of GBM cells, and for comparison, the Hs5 line of stromal cells (normal cells) after 24 h and 72 h of treatment. The analyses included cell morphology, cell death, viability, and cell cycle analysis, double timing assay, and gene expression (
Mao W, Huang X, Wang L, et al.
Circular RNA hsa_circ_0068871 regulates FGFR3 expression and activates STAT3 by targeting miR-181a-5p to promote bladder cancer progression.
BACKGROUND: FGFR3 plays an important role in the development of bladder cancer (BCa). Hsa_circ_0068871 is a circRNA generated from several exons of FGFR3. However, the potential functional role of hsa_circ_0068871 in BCa remains largely unknown. Here we aim to evaluate the role of hsa_circ_0068871 in BCa.
METHODS: We selected miR-181a-5p as the potential target miRNA of hsa_circ_0068871. The expression levels of hsa_circ_0068871 and miR-181a-5p were examined in BCa tissues and paired adjacent normal tissues by quantitative real-time PCR. To characterize the function of hsa_circ_0068871, BCa cell lines were stably infected with lentivirus targeting hsa_circ_0068871, followed by examinations of cell proliferation, migration and apoptosis. In addition, xenografts experiment in nude mice were performed to evaluate the effect of hsa_circ_0068871 in BCa. Biotinylated RNA probe pull-down assay, fluorescence in situ hybridization and luciferase reporter assay were conducted to confirm the relationship between hsa_circ_0068871, miR-181a-5p and FGFR3.
RESULTS: Hsa_circ_0068871 is over-expressed in BCa tissues and cell lines, whereas miR-181a-5p expression is repressed. Depletion of has_circ_0068871 or upregulation of miR-181a-5p inhibited the proliferation and migration of BCa cells in vitro and in vivo. Mechanistically, hsa_circ_0068871 upregulated FGFR3 expression and activated STAT3 by targeting miR-181a-5p to promote BCa progression.
CONCLUSIONS: Hsa_circ_0068871 regulates the miR-181a-5p/FGFR3 axis and activates STAT3 to promote BCa progression, and it may serve as a potential biomarker.
Related: Apoptosis MicroRNAs Bladder Cancer Bladder Cancer - Molecular Biology STAT3
Lin JF, Tsai TF, Lin YC, et al.
Benzyl isothiocyanate suppresses IGF1R, FGFR3 and mTOR expression by upregulation of miR-99a-5p in human bladder cancer cells.
Int J Oncol. 2019; 54(6):2106-2116 [PubMed] Related Publications
Benzyl isothiocyanate (BITC) is known for its pharmacological properties against malignant neoplasm, including bladder cancer (BC). The current study investigated microRNAs (miRNA or miR) expression profiles with an emphasis on the role of miR‑99a‑5p in BITC‑treated BC cells. A quantitative polymerase chain reaction (qPCR) microarray containing 79 aberrantly expressed miRNAs in BC was used to detect miRNA expression in BITC‑treated cells. Several dysregulated miRNAs were identified and further confirmed using miRNA stem‑loop reverse transcription (RT)‑qPCR in 5637 cells. Insulin‑like growth factor 1 receptor (IGF1R), fibroblast growth factor receptor 3 (FGFR3) and mammalian target of rapamycin (mTOR) expression were determined by RT‑qPCR and western blotting. Cell viability was evaluated using WST‑1 reagent and apoptosis was monitored by determining the levels of cleaved‑poly ADP‑ribose polymerase and cleaved‑caspase‑3. BITC treatment significantly upregulated miR‑99a‑5p levels in a dose‑dependent manner. miR‑99a‑5p overexpression decreased IGF1R, mTOR and FGFR3 expression, predicted targets of miR‑99a‑5p. In addition, antisense miR‑99a‑5p sequences inhibited BITC‑induced miR‑99a‑5p overexpression, resulting in the restoration of protein expression and decreased cell viability. The current study identified multiple miRNAs responsive to BITC treatment, including miR‑99a‑5p. In addition, the induction of miR‑99a‑5p decreased IGF1R, mTOR and FGFR3 expression in BITC‑treated BC cells. The current study provided novel insight into the antitumor mechanism by which BITC restores miR‑99a‑5p expression and decreases cancer cell survival.
Related: Apoptosis MicroRNAs Bladder Cancer Bladder Cancer - Molecular Biology MTOR
Hayashi Y, Fujita K, Matsuzaki K, et al.
Diagnostic potential of TERT promoter and FGFR3 mutations in urinary cell-free DNA in upper tract urothelial carcinoma.
Most upper tract urothelial carcinomas (UTUC) are muscle invasive at the time of diagnosis. Current standard methods for the diagnosis of UTUC are invasive. Urine cytology is the only non-invasive test for detecting UTUC, but its sensitivity is low. A novel non-invasive assay for UTUC detection would improve patient outcome. This study aimed to investigate the mutation of cell-free DNA (cfDNA) in urine supernatant to develop a reliable diagnostic biomarker for UTUC patients. We studied urinary cfDNA from 153 individuals, including 56 patients with localized UTUC, and carried out droplet digital PCR assay for TERT promoter and FGFR3 hotspot mutations. We could detect mutations of TERT C228T in 22/56 (39.3%), TERT C250T in 4/56 (7.1%), and FGFR3 S249C in 9/56 (16.1%) patients. FGFR3 mutation was detected only in ≤pT1 tumors (positive predictive value: 100.0%). In combination with cytology results, the sensitivity was 78.6%, and the specificity was 96.0%. Although these data need to be validated in a larger-scale cohort, mutation analysis of TERT promoter and FGFR3 in urinary cfDNA has the potential to be a non-invasive diagnostic marker and reliable factor for tumor staging.
Related: Transitional Cell Cancer of the Renal Pelvis and Ureter Bladder Cancer Bladder Cancer - Molecular Biology TERT
Quaas A, Heydt C, Waldschmidt D, et al.
Alterations in ERBB2 and BRCA and microsatellite instability as new personalized treatment options in small bowel carcinoma.
BMC Gastroenterol. 2019; 19(1):21 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Carcinomas of the small bowel are rare tumors usually with dismal prognosis. Most recently, some potentially treatable molecular alterations were described. We emphasize the growing evidence of individualized treatment options in small bowel carcinoma.
METHODS: We performed a DNA- based multi-gene panel using ultra-deep sequencing analysis (including 14 genes with up to 452 amplicons in total; KRAS, NRAS, HRAS, BRAF, DDR2, ERBB2, KEAP1, NFE2L2, PIK3CA, PTEN, RHOA, BRCA1, BRCA2 and TP53) as well as an RNA-based gene fusion panel including ALK, BRAF, FGFR1, FGFR2, FGFR3, MET, NRG1, NTRK1, NTRK2, NTRK3, RET and ROS1 on eleven formalin fixed and paraffin embedded small bowel carcinomas. Additionally, mismatch-repair-deficiency was analyzed by checking the microsatellite status using the five different mononucleotide markers BAT25, BAT26, NR-21, NR-22 and NR-27 and loss of mismatch repair proteins using four different markers (MLH1, MSH6, MSH2, PMS2).
RESULTS: In five out of eleven small bowel carcinomas we found potentially treatable genetic alterations. Three patients demonstrated pathogenic (class 5) BRCA1 or BRCA2 mutations - one germline-related in a mixed neuroendocrine-non neuroendocrine neoplasm (MiNEN). Two additional patients revealed an activating ERBB2 mutation or PIK3CA mutation. Furthermore two tumors were highly microsatellite-instable (MSI-high), in one case associated to Lynch-syndrome. We did not find any gene fusions.
CONCLUSION: Our results underscore, in particular, the relevance of potentially treatable molecular alterations (like ERBB2, BRCA and MSI) in small bowel carcinomas. Further studies are needed to proof the efficacy of these targeted therapies in small bowel carcinomas.
Na K, Kim HS, Shim HS, et al.
Targeted next-generation sequencing panel (TruSight Tumor 170) in diffuse glioma: a single institutional experience of 135 cases.
J Neurooncol. 2019; 142(3):445-454 [PubMed] Related Publications
PURPOSE: The TruSight Tumor 170 (TST-170) panel consists of a DNA workflow for the identification of single-nucleotide variants, small insertions and deletions, and copy number variation, as well as a panel of 55 genes for a RNA workflow for the identification of splice variants and gene fusions. To date, the application of TST-170 in diffuse gliomas (DGs) has not been described.
METHODS: We analyzed 135 samples of DG, which were diagnosed by WHO criteria based on histological features and conventional molecular tests including immunostaining, 1p/19q FISH, and analysis of MGMT methylation and TERT promoter mutation.
RESULTS: A total of 135 cases consisted of 38 IDH-mutant [17 astrocytoma (AC), 13 oligodendroglioma (OD) and eight glioblastoma (GBM)], 87 IDH-wildtype (six AC, three OD and 78 GBM), and 10 diffuse midline glioma, H3K27M-mutant. DNA analysis enabled the detection of all mutations identified in these samples by conventional techniques, and the results were highly comparable to the known mutations in each subtype. RNA analysis detected four fusion genes including PTPRZ1-MET, FGFR3-TACC3, FAM131B-BRAF, and RET-CCDC6 and one splicing variant (EGFR vIII mutant). Clustered copy number loss in 1p and 19q loci genes were detected in 1p/19q-codeleted OD.
CONCLUSIONS: The application of TST-170 panel based NGS in clinical and laboratory setting is expected to improve diagnostic accuracy and prognostication. Most benefits are expected in IDH-wildtype DG, a group of genetically heterogenous tumors harboring DNA sequence changes, copy number alterations, and fusions in a large number of oncogenes and tumor suppressor genes.
Liu GC, Zhou YF, Su XC, Zhang J
Interaction between TP53 and XRCC1 increases susceptibility to cervical cancer development: a case control study.
BACKGROUND: Cervical cancer is the 4th highest cause of female reproductive tract malignancies. Multiple loci have been identified as important determinant factors for tumor susceptibility. In this report, we aimed to explore the roles of gene polymorphisms affecting x-ray repair cross complementing 1 (XRCC1), the tumor protein p53 (TP53), and fibroblast growth factor receptor 3 (FGFR3) in the context of susceptibility to cervical cancer. Additionally, we assessed the impact of single nucleotide polymorphism-single nucleotide polymorphism (SNP-SNP) interaction of these three genes in the context of cervical cancer risk in Chinese women.
METHODS: A case-control study consisted of 340 women located in Chongqing. Of these women, 121 were diagnosed with cervical cancer, 118 served as healthy controls, and 101 were specifically recruited elderly patients above the age of 80 who showed no history of cervical cancer. Three SNPs (XRCC1 rs25487, TP53 rs1042522, and FGFR3 rs121913483) were examined using mutation analysis of mismatch amplification PCR (MAMA-PCR) on samples obtained from peripheral blood.
RESULTS: Our results indicated that females from southwestern China all exhibited a wild-type phenotype at FGFR3 rs121913483. We also observed that the rs25487 mutation was significantly increased within the cervical cancer population. A 2-locus SNP-SNP interaction pattern (rs25487 and rs1042522) was significantly associated with cervical cancer risk (cases vs. negative controls: OR = 4.63, 95% CI = 1.83-11.75; cases vs. elderly group: OR = 17.61, 95% CI = 4.34-71.50).
CONCLUSIONS: This is the first study to identify a novel interaction between the XRCC1 and TP53 genes that is highly associated with susceptibility to cervical cancer risk in a female population in southwestern China.
Related: TP53 Cervical Cancer
Gao XH, Yu GY, Hong YG, et al.
Clinical significance of multiple gene detection with a 22-gene panel in formalin-fixed paraffin-embedded specimens of 207 colorectal cancer patients.
Int J Clin Oncol. 2019; 24(2):141-152 [PubMed] Related Publications
BACKGROUND: Simultaneous detection of multiple molecular biomarkers is helpful in the prediction of treatment response and prognosis for colorectal cancer (CRC) patients.
METHODS: A 22-gene panel consisting of 103 hotspot regions was utilized in the formalin-fixed paraffin-embedded (FFPE) tissue samples of 207 CRC patients, using the next-generation sequencing (NGS)-based multiplex PCR technique. Those 22 genes included AKT1, ALK, BRAF, CTNNB1, DDR2, EGFR, ERBB2, ERBB4, FBXW7, FGFR1, FGFR2, FGFR3, KRAS, MAP2K1, MET, NOTCH1, NRAS, PIK3CA, PTEN, SMAD4, STK11, and TP53.
RESULTS: Of the 207 patients, 193 had one or more variants, with 170, 20, and 3 having one, two, and three mutated genes, respectively. Of the total 414 variants identified in this study, 384, 25, and 5 were single-nucleotide variants, deletion, and insertion. The top four frequently mutated genes were TP53, KRAS, PIK3CA, and FBXW7. There was high consistency between the results of NGS-PCR technique and routine ARMS-PCR in KRAS and BRAF mutation detection. Univariate and multivariate analyses demonstrated that advanced TNM stage, elevated serum CEA, total variants number ≥ 2, AKT1 and PTEN mutation were independent predictors of shorter DFS; poor differentiation, advanced TNM stage, total variants number ≥ 2, BRAF, CTNNB1 and NRAS mutation were independent predictors of shorter OS.
CONCLUSIONS: It is feasible to detect multiple gene mutations with a 22-gene panel in FFPE CRC specimens. TNM stage and total variants number ≥ 2 were independent predictors of DFS and OS. Detection of multiple gene mutations may provide additional prognostic information to TNM stage in CRC patients.
Related: Colorectal (Bowel) Cancer
Gillison ML, Akagi K, Xiao W, et al.
Human papillomavirus and the landscape of secondary genetic alterations in oral cancers.
Genome Res. 2019; 29(1):1-17 [PubMed] Free Access to Full Article Related Publications
Human papillomavirus (HPV) is a necessary but insufficient cause of a subset of oral squamous cell carcinomas (OSCCs) that is increasing markedly in frequency. To identify contributory, secondary genetic alterations in these cancers, we used comprehensive genomics methods to compare 149 HPV-positive and 335 HPV-negative OSCC tumor/normal pairs. Different behavioral risk factors underlying the two OSCC types were reflected in distinctive genomic mutational signatures. In HPV-positive OSCCs, the signatures of APOBEC cytosine deaminase editing, associated with anti-viral immunity, were strongly linked to overall mutational burden. In contrast, in HPV-negative OSCCs, T>C substitutions in the sequence context 5'-ATN-3' correlated with tobacco exposure. Universal expression of HPV
Cui M, Hu Y, Bi Y, et al.
Preliminary exploration of potential molecular therapeutic targets in recurrent and metastatic parathyroid carcinomas.
Int J Cancer. 2019; 144(3):525-532 [PubMed] Related Publications
Parathyroid carcinoma (PC) is a rare endocrine malignancy. Surgical resection is curative for local lesions, while effective therapies are lacking for recurrent or metastatic PCs. To study whether targeted therapies could be applied in recurrent or metastatic PCs, potential therapeutic targets were identified with next-generation sequencing (NGS). DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) sections from 19 recurrent or metastatic PC samples. A panel of 560 genes was sequenced with NGS to identify genomic alterations at an average sequencing depth of 581×. In total, 190 genomic alterations were identified. Nine PC samples (47%) harbored at least one potentially actionable genomic alteration including in the after genes: ROS1 (5/19; 26%), PTEN (3/19; 16%), TSC1 (2/19; 11%), PIK3CA (1/19; 5%), AKT1 (1/19; 5%), MTOR (1/19; 5%), ERBB2 (1/19; 5%), NTRK1 (1/19; 5%), IDH1 (1/19; 5%) and FGFR3 (1/19; 5%). CDC73 mutations were detected in 9/19 (47%) PC samples. Additional recurrent genomic alterations were identified in MSH2 (15/19; 79%), AR (9/19; 47%), BCR (8/19; 42%), SLC45A3 (6/19; 32%), MAGI1 (5/19; 26%), ZNF521 (4/19; 21%), KMT2C (4/19; 21%) and NOTCH4 (4/19; 21%). Our study identified a relatively high frequency of potentially actionable genomic alterations in PC patients in a Chinese population for the first time. A series of recurrent mutant genes was detected as well. Our study contributes to both the selection of novel targeted therapies for PC and further molecular understanding of this refractory malignancy.
Related: Parathyroid Cancer CDC73
Youssef O, Knuuttila A, Piirilä P, et al.
Hotspot Mutations Detectable by Next-generation Sequencing in Exhaled Breath Condensates from Patients with Lung Cancer.
Anticancer Res. 2018; 38(10):5627-5634 [PubMed] Related Publications
BACKGROUND: Genetic alterations occurring in lung cancer are the basis for defining molecular subtypes and essential for targeted therapies. Exhaled breath condensate (EBC) is a form of non-invasive sample that, amongst components, contains DNA from pulmonary tissue. Next-generation sequencing (NGS) was herein used to analyze mutations in EBC from patients with lung cancer.
MATERIALS AND METHODS: EBC was collected from 26 patients with cancer and 20 healthy controls. Amplicon-based sequencing using Ion Ampliseq Colon and Lung Cancer gene panel v2 was applied.
RESULTS: The sequencing was successful in 17 patients and 20 controls. EBC from patients revealed 39 hotspot mutations occurring in: adenomatous polyposis coli (APC), v-raf murine sarcoma viral oncogene homolog B (BRAF), discoidin domain receptor tyrosine kinase 2 (DDR2), epidermal growth factor receptor (EGFR), erb-b2 receptor tyrosine kinase 4 (ERBB4), F-box and WD repeat domain containing 7 (FBXW7), fibroblast growth factor receptor 1 (FGFR1), FGFR3 (fibroblast growth factor receptor 3), Kirsten rat sarcoma viral oncogene homolog (KRAS), mitogen-activated protein kinase kinase 1 (MAP2K1), met proto-oncogene (MET), neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphatase and tensin homolog (PTEN), ret proto-oncogene (RET), SMAD family member 4 (SMAD4), serine/threonine kinase 11 (STK11), and tumor protein p53 (TP53) genes. EBC from controls revealed 35 hotspot mutations. The average mutant allele fraction was higher in patients than controls.
CONCLUSION: NGS can identify mutations in EBCs from patients with lung cancer. This could provide a promising non-invasive method for the assessment of gene mutations in lung cancer.
Related: Non-Small Cell Lung Cancer Small Cell Lung Cancer
Koh J, Nam SK, Roh H, et al.
Somatic mutational profiles of stage II and III gastric cancer according to tumor microenvironment immune type.
Genes Chromosomes Cancer. 2019; 58(1):12-22 [PubMed] Related Publications
We aimed to determine somatic mutational profiles of stage II/III gastric cancers (GCs) according to their tumor microenvironment immune types (TMITs), which classify cancer based on co-assessment of PD-L1 expression and CD8
Bellmunt J, Lalani AA, Jacobus S, et al.
Everolimus and pazopanib (E/P) benefit genomically selected patients with metastatic urothelial carcinoma.
Br J Cancer. 2018; 119(6):707-712 [PubMed] Related Publications
BACKGROUND: Metastatic urothelial carcinoma (mUC) is a genomically diverse disease with known alterations in the mTOR pathway and tyrosine kinases including FGFR. We investigated the efficacy and safety of combination treatment with everolimus and pazopanib (E/P) in genomically profiled patients with mUC.
METHODS: mUC patients enrolled on a Phase I dose escalation study and an expansion cohort treated with E/P were included. The primary end point was objective response rate (ORR); secondary end points were safety, duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Patients were assessed for mutations and copy number alterations in 300 relevant cancer-associated genes using next-generation sequencing and findings were correlated with outcomes. Time-to-event data were estimated with Kaplan-Meier methods.
RESULTS: Of the 23 patients enrolled overall, 19 had mUC. ORR was 21% (one complete response (CR), three partial responses (PR), eight with stable disease (SD). DOR, PFS and OS were 6.5, 3.6, and 9.1 months, respectively. Four patients with clinical benefit (one CR, two PR, one SD) had mutations in TSC1/TSC2 or mTOR and a 5th patient with PR had a FGFR3-TACC3 fusion.
CONCLUSIONS: Combination therapy with E/P is safe in mUC and select patients with alterations in mTOR or FGFR pathways derive significant clinical benefit.
Related: Transitional Cell Cancer of the Renal Pelvis and Ureter Everolimus (Afinitor) Kidney Cancer TACC3 Pazopanib (Votrient)
Tan TZ, Rouanne M, Tan KT, et al.
Molecular Subtypes of Urothelial Bladder Cancer: Results from a Meta-cohort Analysis of 2411 Tumors.
Eur Urol. 2019; 75(3):423-432 [PubMed] Related Publications
BACKGROUND: Previous molecular subtyping for bladder carcinoma (BLCA) involved <450 samples, with diverse classifications.
OBJECTIVE: To identify molecular subtypes by curating a large BLCA dataset.
DESIGN, SETTING, AND PARTICIPANTS: Gene expression publicly available were combined and reanalyzed. The dataset contained 2411 unique tumors encompassing non-muscle-invasive (NMIBC) and muscle-invasive BLCA (MIBC). Subtypes were reproduced on The Cancer Genome Atlas, UROMOL, and IMvigor210.
INTERVENTION: Subtypes were assigned by gene expression.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier analyses were performed for subtype-clinical outcome correlations; Chi-square/Fisher exact tests were used for subtype-clinicopathological parameters associations.
RESULTS AND LIMITATIONS: We identified six molecular subtypes with different overall survival (OS) and molecular features. Subtype Neural-like (median OS, 87 mo) is prevalent in MIBC and characterized by high WNT/β-catenin signaling. HER2-like (107.7 mo) is distributed evenly across NMIBC and MIBC, with higher ERBB2 amplification and signaling. Papillary-like (>135 mo), an NMIBC subtype enriched in urothelial differentiation genes, shows a high frequency of actionable FGFR3 mutations, amplifications, and FGFR3-TACC3 fusion. Luminal-like (91.7 mo), predominantly NMIBC, has higher MAPK signaling and more KRAS and KMT2C/D mutations than other subtypes. Mesenchymal-like (MES; 86.6 mo) and Squamous-cell carcinoma-like (SCC; 20.6 mo) are predominant in MIBC. MES is high in AXL signaling, whereas SCC has elevated PD1, CTLA4 signaling, and macrophage M2 infiltration. About 20% of NMIBCs show MIBC subtype traits and a lower 5-yr OS rate than Papillary-like NMIBC (81% vs 96%). The main limitations of our study are the incomplete clinical annotation, and the analyses were based on transcriptome subset due to comparisons across gene expression quantification technologies.
CONCLUSIONS: BLCA can be stratified into six molecular subtypes. NMIBC, with a high risk of progression, displays the molecular features of MIBC.
PATIENT SUMMARY: Biomarkers are urgently needed to guide patient treatment selection and avoid unnecessary toxicities in those who fail to respond. We believe molecular subtyping is a promising way to tailor disease management for those who will benefit most.
Related: Bladder Cancer Bladder Cancer - Molecular Biology
Liang X, Vacher S, Boulai A, et al.
Targeted next-generation sequencing identifies clinically relevant somatic mutations in a large cohort of inflammatory breast cancer.
Breast Cancer Res. 2018; 20(1):88 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Inflammatory breast cancer (IBC) is the most aggressive form of primary breast cancer. Using a custom-made breast cancer gene sequencing panel, we investigated somatic mutations in IBC to better understand the genomic differences compared with non-IBC and to consider new targeted therapy in IBC patients.
METHODS: Targeted next-generation sequencing (NGS) of 91 candidate breast cancer-associated genes was performed on 156 fresh-frozen breast tumor tissues from IBC patients. Mutational profiles from 197 primary breast tumors from The Cancer Genome Atlas (TCGA) were used as non-IBC controls for comparison analysis. The mutational landscape of IBC was correlated with clinicopathological data and outcomes.
RESULTS: After genotype calling and algorithmic annotations, we identified 392 deleterious variants in IBC and 320 variants in non-IBC cohorts, respectively. IBC tumors harbored more mutations than non-IBC (2.5 per sample vs. 1.6 per sample, p < 0.0001). Eighteen mutated genes were significantly different between the two cohorts, namely TP53, CDH1, NOTCH2, MYH9, BRCA2, ERBB4, POLE, FGFR3, ROS1, NOTCH4, LAMA2, EGFR, BRCA1, TP53BP1, ESR1, THBS1, CASP8, and NOTCH1. In IBC, the most frequently mutated genes were TP53 (43.0%), PIK3CA (29.5%), MYH9 (8.3%), NOTCH2 (8.3%), BRCA2 (7.7%), ERBB4 (7.1%), FGFR3 (6.4%), POLE (6.4%), LAMA2 (5.8%), ARID1A (5.1%), NOTCH4 (5.1%), and ROS1 (5.1%). After grouping 91 genes on 10 signaling pathways, we found that the DNA repair pathway for the triple-negative breast cancer (TNBC) subgroup, the RTK/RAS/MAPK and cell cycle pathways for the HR
CONCLUSIONS: Breast cancer-specific targeted NGS uncovered a high frequency of deleterious somatic mutations in IBC, some of which may be relevant for clinical management.
Kim YS, Kim K, Kwon GY, et al.
Fibroblast growth factor receptor 3 (FGFR3) aberrations in muscle-invasive urothelial carcinoma.
BMC Urol. 2018; 18(1):68 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Recent studies suggest that FGFR3 is a potential therapeutic target in urothelial carcinoma (UC). The purpose of this study was to evaluate the rates and types of FGFR3 aberrations in patients with muscle-invasive UC who received radical resection.
METHODS: We analyzed surgical tumor samples from 74 UC patients who had received radical cystectomy (n = 40) or ureteronephrectomy (n = 34). Ion AmpliSeq Cancer Hotspot Panel v2 and nCounter Copy Number Variation Assay were used to detect FGFR3 aberrations.
RESULTS: Fifty-four patients (73%) had high-grade tumors, and 62% had lymph node involvement. Sixteen patients (22%) harbored FGFR3 alterations, the most common of which was FGFR3 mutations (n = 13): Y373C (n = 3), N532D (n = 3), R248C (n = 2), S249C (n = 1), G370C (n = 1), S657S (n = 1), A797P (n = 1), and 746_747insG (n = 1). Three additional patients had a FGFR3-TACC3 rearrangement. The frequency of FGFR3 aberrations was higher in bladder UC (25%) than in UC of the renal pelvis and ureter (18%) but the difference was not statistically significant (P = 0.444). Genes that were co-aberrant with FGFR3 included APC (88%), PDGFRA (81%), RET (69%), and TP53 (69%).
CONCLUSIONS: We report the frequency and types of FGFR3 aberrations in Korean patients with UC. Patients with FGFR3 mutations or FGFR3-TACC3 fusion may constitute potential candidates for a novel FGFR-targeted therapy in the perioperative setting.
Related: Transitional Cell Cancer of the Renal Pelvis and Ureter Bladder Cancer Bladder Cancer - Molecular Biology
Fujino M
The histopathology of myeloma in the bone marrow.
J Clin Exp Hematop. 2018; 58(2):61-67 [PubMed] Free Access to Full Article Related Publications
Myeloma is characterized by the neoplastic proliferation of monoclonal plasma cells. A diagnosis of myeloma is based on the criteria proposed by the International Myeloma Working Group and the pathological findings.Myeloma cells are classified into four types: mature, immature, pleomorphic, and plasmablastic. There are three patterns in which myeloma infiltrates bone marrow - nodular, interstitial, and diffuse. Dutcher bodies are highly specific to neoplastic myeloma cells. On immunohistochemical staining, the specificity of CD138 is high for plasma cells. As a clear image is often not obtained from the immunohistochemical staining of the immunoglobulin light chain, in situ hybridization is recommended. Abnormal expression of CD56 is seen in 70-80% of cases by flow cytometry analysis. CD56 expression definitively indicates myeloma, suggesting its high diagnostic value. Evaluation of the infiltration pattern, monoclonality, and abnormal antigen expression of plasma cells is more important than the plasmocytic ratio to determine whether a case is reactive or neoplastic.Multiple gene abnormalities function in the onset and progression of myeloma. In our department, we analyze CCND1, FGFR3, MAF, and del (17p13) by FISH for all myeloma cases. None of the cases with genetic abnormalities were recognized by G-banding. Therefore, FISH is more effective than G-banding for the evaluation of genetic abnormalities in myeloma.
Best SA, Harapas CR, Kersbergen A, et al.
FGFR3-TACC3 is an oncogenic fusion protein in respiratory epithelium.
Oncogene. 2018; 37(46):6096-6104 [PubMed] Free Access to Full Article Related Publications
Structural rearrangements of the genome can drive lung tumorigenesis through the generation of fusion genes with oncogenic properties. Advanced genomic approaches have identified the presence of a genetic fusion between fibroblast growth factor receptor 3 (FGFR3) and transforming acidic coiled-coil 3 (TACC3) in non-small cell lung cancer (NSCLC), providing a novel target for FGFR inhibition. To interrogate the functional consequences of the FGFR3-TACC3 fusion in the transformation of lung epithelial cells, we generated a novel transgenic mouse model that expresses FGFR3-TACC3 concomitant with loss of the p53 tumor suppressor gene. Intranasal delivery of an Ad5-CMV-Cre virus promoted seromucinous glandular transformation of olfactory cells lining the nasal cavities of FGFR3-TACC3 (LSL-F3T3) mice, which was further accelerated upon loss of p53 (LSL-F3T3/p53). Surprisingly, lung tumors failed to develop in intranasally infected LSL-F3T3 and LSL-F3T3/p53 mice. In line with these observations, we demonstrated that intranasal delivery of Ad5-CMV-Cre induces widespread Cre-mediated recombination in the olfactory epithelium. Intra-tracheal delivery of Ad5-CMV-Cre into the lungs of LSL-F3T3 and LSL-F3T3/p53 mice, however, resulted in the development of lung adenocarcinomas. Taken together, these findings provide in vivo evidence for an oncogenic function of FGFR3-TACC3 in respiratory epithelium.
Related: Non-Small Cell Lung Cancer Lung Cancer TACC3
Zięba S, Kowalik A, Zalewski K, et al.
Somatic mutation profiling of vulvar cancer: Exploring therapeutic targets.
Gynecol Oncol. 2018; 150(3):552-561 [PubMed] Related Publications
BACKGROUND: Vulvar squamous cell carcinoma (VSCC) constitutes over 90% of vulvar cancer. Its pathogenesis can follow two different pathways; high risk human papillomavirus (hrHPV)-dependent and HPV-independent. Due to the rarity of VSCC, molecular mechanisms underlying VSCC development remain largely unknown. The study aimed to identify pathogenic mutations implicated in the two pathways of VSCC development.
METHODS: Using next generation sequencing, 81 VSCC tumors, 52 hrHPV(+) and 29 hrHPV(-), were screened for hotspot mutations in 50 genes covered by the Ion AmpliSeq Cancer Hotspot Panel v2 Kit (Thermo Fisher Scientific).
RESULTS: Mutations of TP53 (46% and 41%, of hrHPV(+) and hrHPV(-) cases respectively) and CDKN2A (p16) (25% and 21%, of hrHPV(+) and hrHPV(-) cases respectively) were the most common genetic alterations identified in VSCC tumors. Further mutations were identified in PIK3CA, FBXW7, HRAS, FGFR3, STK11, AKT1, SMAD4, FLT3, JAK3, GNAQ, and PTEN, albeit at low frequencies. Some of the identified mutations may activate the PI3K/AKT/mTOR pathway. The activation of mTOR was confirmed in the vast majority of VSCC samples by immunohistochemical staining.
CONCLUSIONS: Detecting pathogenic mutations in 13/50 genes examined at comparable frequencies in hrHPV(+) and hrHPV(-) tumors suggest that genetic mechanisms of the two routes of VSCC pathogenesis may be similar, despite being initiated from different premalignant lesions. Importantly, our data provide a rationale for new anti-VSCC therapies targeting the PI3K/AKT/mTOR pathway.
Related: Everolimus (Afinitor) PTEN AKT1 Signal Transduction MADH4 TP53 Vulva Cancer FBXW7 GNAQ STK11 MTOR FLT3 HRAS
Yang Z, Zhang R, Ge Y, et al.
Somatic FGFR3 Mutations Distinguish a Subgroup of Muscle-Invasive Bladder Cancers with Response to Neoadjuvant Chemotherapy.
EBioMedicine. 2018; 35:198-203 [PubMed] Free Access to Full Article Related Publications
The administration of neoadjuvant chemotherapy (NAC) preceding radical cystectomy benefits overall survival for patients with muscle-invasive bladder cancer (MIBC). However, the relationship between the genetic profiling of MIBC and NAC response remains unclear. Here, a mutation panel of six cancer-associated genes (TSC1, FGFR3, TERT, TP53, PIK3CA and ERBB2) and an immunohistochemistry (IHC) panel containing eight bladder cancer (BC) biomarkers (EGFR, RRM1, PD-L1, BRCA1, TUBB3, ERCC, ERCC1, aberrantly glycosylated integrin α3β1 (AG) and CK5/6) were developed. BC samples from patients who showed a pathologic response (n = 39) and non-response (n = 13) were applied to the panel analysis. ERBB2, FGFR3 and PIK3CA exclusively altered in the responders group (19/39, 48.7%), in which FGFR3 mutations were significantly enriched in patients with a response in the cohort (14/39, 35.9%; P = 0.01). Additionally, strong expression of ERCC1 was associated with a pathologic response (P = 0.01). However, positive lymph node metastasis (P < 0.01) and lymph-vascular invasion (LVI) (P = 0.03) were correlated with a non-response. Overall, the data show that FGFR3 mutations and elevated expression of ERCC1 in MIBCs are potential predictive biomarkers of the response to NAC.
Related: Cisplatin Bladder Cancer Bladder Cancer - Molecular Biology
Walker BA, Mavrommatis K, Wardell CP, et al.
Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma.
Understanding the profile of oncogene and tumor suppressor gene mutations with their interactions and impact on the prognosis of multiple myeloma (MM) can improve the definition of disease subsets and identify pathways important in disease pathobiology. Using integrated genomics of 1273 newly diagnosed patients with MM, we identified 63 driver genes, some of which are novel, including
Jing P, Zhao N, Xie N, et al.
miR-24-3p/FGFR3 Signaling as a Novel Axis Is Involved in Epithelial-Mesenchymal Transition and Regulates Lung Adenocarcinoma Progression.
J Immunol Res. 2018; 2018:2834109 [PubMed] Free Access to Full Article Related Publications
Our previous studies showed that Fibroblast growth factor receptor 3 (FGFR3) contributed to cell growth in lung cancer. However, the correlation between FGFR3 and tumor progression, coupled with the underlying mechanisms, are not fully understood. The clinical significance of FGFR3 was determined in two cohorts of clinical samples (
Related: Lung Cancer MicroRNAs Signal Transduction
Tauziède-Espariat A, Saffroy R, Pagès M, et al.
Cerebellar high-grade gliomas do not present the same molecular alterations as supratentorial high-grade gliomas and may show histone H3 gene mutations.
Clin Neuropathol. 2018 Sep/Oct; 37(5):209-216 [PubMed] Related Publications
Numerous molecular alterations have been described in supratentorial high-grade gliomas (1p19q co-deletion, IDH1/2, histone H3, hTERT promotor mutations, loss of ATRX) which have led to a new histomolecular classification of diffuse gliomas. We aimed at describing these alterations in a series of 19 adults with pure cerebellar high-grade gliomas. Systematic immunohistochemical analyses, including that of IDH1R132H, ATRX, p53, PTEN, EGFR, p16, FGFR3, BRAFV600E, mismatch repair proteins, H3K27me3, H3K36me3, and H3K27M; molecular analyses of IDH1/2, hTERT, BRAF, H3F3A, and HIST1H3B mutation hotspots; and EGFR, PTEN FISH were retrospectively performed in a multicentric study. We histopathologically identified 14 glioblastomas, 4 grade III astrocytomas and 1 gliosarcoma. Two cases showed a H3F3A K27M mutation. Only one case harbored a classical profile of glioblastoma with hTERT mutation, EGFR gain and 10q loss. The most frequent alteration was the absence of p16 immunoexpression. We report a histomolecular analysis of pure cerebellar high grade gliomas. The histomolecular profile appears to be different from that of supratentorial gliomas, with no IDH1/2 gene mutations and only 1 case with a classic profile of de novo glioblastoma. In 2 cases, we identified H3F3A K27M mutation, classically described in pediatric midline gliomas.
.
Ryland GL, Jones K, Chin M, et al.
Novel genomic findings in multiple myeloma identified through routine diagnostic sequencing.
J Clin Pathol. 2018; 71(10):895-899 [PubMed] Related Publications
AIMS: Multiple myeloma is a genomically complex haematological malignancy with many genomic alterations recognised as important in diagnosis, prognosis and therapeutic decision making. Here, we provide a summary of genomic findings identified through routine diagnostic next-generation sequencing at our centre.
METHODS: A cohort of 86 patients with multiple myeloma underwent diagnostic sequencing using a custom hybridisation-based panel targeting 104 genes. Sequence variants, genome-wide copy number changes and structural rearrangements were detected using an inhouse-developed bioinformatics pipeline.
RESULTS: At least one mutation was found in 69 (80%) patients. Frequently mutated genes included
CONCLUSIONS: Our results demonstrate that many clinically relevant genomic findings remain in multiple myeloma which have not yet been identified through large-scale sequencing efforts, and provide important mechanistic insights into plasma cell pathobiology.
Ferguson SD, Zhou S, Huse JT, et al.
Targetable Gene Fusions Associate With the IDH Wild-Type Astrocytic Lineage in Adult Gliomas.
J Neuropathol Exp Neurol. 2018; 77(6):437-442 [PubMed] Free Access to Full Article Related Publications
Gene fusions involving oncogenes have been reported in gliomas and may serve as novel therapeutic targets. Using RNA-sequencing, we interrogated a large cohort of gliomas to assess for the incidence of targetable genetic fusions. Gliomas (n = 390) were profiled using the ArcherDx FusionPlex Assay. Fifty-two gene targets were analyzed and fusions with preserved kinase domains were investigated. Overall, 36 gliomas (9%) harbored a total of 37 potentially targetable fusions, the majority of which were found in astrocytomas (n = 34). Within this lineage 11% (25/235) of glioblastomas, 12% (5/42) of anaplastic astrocytomas, 8% (2/25) of grade II astrocytomas, and 33% (2/6) of pilocytic astrocytoma harbored targetable fusions. Fusions were significantly more frequent in IDH wild-type tumors (12%, n = 31/261) relative to IDH mutants (4%; n = 4/109) (p = 0.011). No fusions were seen in oligodendrogliomas. The most frequently observed therapeutically targetable fusions were in FGFR (n = 12), MET (n = 11), and NTRK (n = 8). Several additional novel fusions that have not been previously described in gliomas were identified including EGFR:VWC2 and FGFR3:NBR1. In summary, targetable gene fusions are enriched in IDH wild-type high-grade astrocytic tumors, which will influence enrollment in and interpretation of clinical trials of glioma patients.
Related: Childhood Astrocytoma Childhood Brain Tumours Childhood Brain Tumors Brain Stem Glioma - Childhood
Jing P, Zhao N, Ye M, et al.
Protein arginine methyltransferase 5 promotes lung cancer metastasis via the epigenetic regulation of miR-99 family/FGFR3 signaling.
Protein arginine methyltransferase 5 (PRMT5) functions as a tumor initiator to regulate several cancer progressions, such as proliferation and apoptosis, by catalyzing the symmetrical dimethylation (me2s) of arginine residues within targeted molecules. However, the exact role of PRMT5-mediated metastasis in lung cancer is not fully understood. Here, we illustrated its potential effects in lung cancer metastasis in vivo and vitro. PRMT5 was frequently overexpressed in lung tumors, and its expression was positively related to tumor stages, lymphatic metastasis and poor outcome. In this model, PRMT5 repressed the transcription of the miR-99 family by symmetrical dimethylation of histone H4R3, which increased FGFR3 expression and in turn activated Erk1/2 and Akt, leading to cell growth and metastasis in lung cancer. Furthermore, loss of PRMT5 exerted anti-metastasis effects on lung cancer progression by blocking histone-modification of miR-99 family. Overall, this study provides new insights into the PRMT5/miR-99 family/FGFR3 axis in regulating lung cancer progression and identifies PRMT5 as a promising prognostic biomarker and therapeutic target.
Jungels C, Martinez Chanza N, Albisinni S, et al.
Interest of next-generation sequencing in BCG-treated high-risk bladder cancer.
Prog Urol. 2018; 28(6):344-350 [PubMed] Related Publications
OBJECTIVES: There are only few predictive factors for response of non-musculo-invasive bladder cancer (NMIBC) to Bacillus Calmette-Guérin (BCG) therapy. Our study analyzed the results of the sequencing of new generation (NGS) targeted on 50 genes of oncological interest obtained on bladder resection parts in high-risk NMIBC patients treated with BCG, to describe this population from a molecular point of view and try to correlate these results in patients who present or not recurrence after BCG.
METHODS: We reviewed 63 patients with high grade NMIBC treated between 2014 and 2016 with BCG after endoscopic resection. Each one had NGS analysis. Association tests between mutations detected by NGS and recurrence or progression were realized.
RESULTS: The 45 remaining patients were fully analysed. For 73% of cases a mutation has been found, most frequent one's being FGFR3, TP53 and PIK3CA. With a median follow-up of 24 months (4-40), recurrence was present in 15 patients (33.3%), with 10 NMIBC (22.2%) and 5 progressions to muscular-invasive cancer (11.1%). If some mutations were more frequent in different prognostic groups no significant association has been found. No patient presenting CIS had FGFR3 mutation (P<0.0001).
CONCLUSION: Next generation sequencing in NMIBC could be a supplementary aid in treatment decision making in the future. In an area where personalized medicine is rapidly growing in importance we need larger studies to define molecular characteristics in tumours to detect genomic associations between clinical phenotypes and recurrence or progression of the disease.
LEVEL OF EVIDENCE: 3.
Bockorny B, Rusan M, Chen W, et al.
RAS-MAPK Reactivation Facilitates Acquired Resistance in
The FGFR kinases are promising therapeutic targets in multiple cancer types, including lung and head and neck squamous cell carcinoma, cholangiocarcinoma, and bladder cancer. Although several FGFR kinase inhibitors have entered clinical trials, single-agent clinical efficacy has been modest and resistance invariably occurs. We therefore conducted a genome-wide functional screen to characterize mechanisms of resistance to FGFR inhibition in a
Related: Lung Cancer FGFR1 Signal Transduction
Dhami J, Hirshfield KM, Ganesan S, et al.
Comprehensive genomic profiling aids in treatment of a metastatic endometrial cancer.
Cold Spring Harb Mol Case Stud. 2018; 4(2) [PubMed] Free Access to Full Article Related Publications
Related: Endometrial (Uterus) Cancer Endometrial Cancer
Cite this page: Cotterill SJ. FGFR3, Cancer Genetics Web: http://www.cancer-genetics.org/FGFR3.htm Accessed:
[Home] Page last revised: 01 September, 2019 Cancer Genetics Web, Established 1999


text:
Sports Barça out of Valverde and into the hands of...
Barça out of Valverde and into the hands of Quique Setién
Ernesto Valverde leaves Barça and will be replaced by Quique Setién after a day in the club's annals. The day was a bizarre end to an almost comical scene at the same hotel where Josep Maria Bartomeu could not sign Valverde's contract settlement, just meters from the room where he was negotiating the contract with the new coach, Quique Setién. The arrangements came at 11:15 pm. The new coach will be unveiled this afternoon, with a press conference at 2:30 PM. In fact, Setién will already be heading the morning training, at which point he will introduce himself to the players.
Shortly before eight o'clock in the evening, Bartomeu informed Valverde's agent Iñaki Ibáñez of the end of an announced death. But Ibáñez, who went by Bartomeu's car from Camp Nou to the hotel where he would negotiate, left without signing any paper: "I suppose we will reach an agreement tomorrow. He has been fired, or he will be fired, this is not a good time, "he explained. The deal, however, was closed an hour later, as Barça did not want to wait another day. It is destitution that leaves wounds, not so much because of changing techniques or ways.
⚠ LAST TIME
Ique Quique Setién will be the new coach of FC Barcelona. Welcome!
🔵🔴
– FC Barcelona (@FCBarcelona_cat) January 13, 2020
Barça wanted to make a statement at 9pm, but the hours went by without agreement. And nerves seized a club that fired a mid-season coach for the first time in seventeen years. Although unlike the dismissal of Louis van Gaal in the 2002/03 season, Barça currently occupy the top spot in the league. Seventeen years ago, Radomir Antic, on the other hand, came to a team three points downhill. If then Barça were specialized in shooting foot shots, now it was three quarters, because announcing what you would do before signing the contracts only made your life more difficult because you could not easily reach an agreement with Valverde's representative over the farewell.
The coach raised in Vitoria leaves after winning two leagues, two Super Cups and a Copa del Rey. But he will always be remembered for the defeats of Rome and Liverpool, defeats in which his end was written. President Josep Maria Bartomeu and sports director Eric Abidal will explain the reasons for this move today, after deciding that the new coach would be the Cantabrian Quique Setién. A 61-year-old coach, romantic in his game proposal but with a resume in which the biggest club he has run is Betis. Before that he had worked in clubs such as Racing de Santander, Lugo, Las Palmas and Logroño. Setién will have a great opportunity, but also pressure to win. His representative, Edoardo Crnjar, came from Italy, where he lives, to close the contract, and met with Ibáñez, who was negotiating for Valverde's farewell papers. Both got Barça in trouble. Ibáñez to defend Valverde and Crnjar for more than six months offered by the club. And he succeeded, as the contract officially is until the season 2021/22, but with a nuance. At the end of each season the contract could be broken, starting this summer.
The sports area thinks Setién can lead the project now, but having given him a short contract he would have expressed doubts as to whether he was the ideal coach for a longer period of time. His name was defended at a board meeting by sports officials Eric Abidal and Ramón Planes. Betting on a six-month contract, the door was open to negotiate with Xavi Hernández or Ronald Koeman for next season. That is to say, the two technicians who these days, have refused to be in the place of Setién right now. But with that contract, Setién would be closing the door this summer for names like Xavi and Koeman. The manager has left with a contract until after the election of 2021, which moves Xavi away from the current directive.
The board meeting at which it was decided lasted more than four hours. A meeting in which it was clear that there were different points of view, as more than one manager proposed the subsidiary's manager, García Pimienta, or the Argentine Mauricio Pochettino. Pochettino's past with Espanyol was key to dismissing the Tottenham manager, who equally would not have accepted. Some executives, in fact, were not happy with Bartomeu because of the way Valverde's farewell was handled, which saw everyone talking about his farewell when Barça had not informed him.
The day started when the president, Josep Maria Bartomeu, met with Valverde at the Joan Gamper Sports City after the last training run by Valverde. The meeting was not to be dismissed but Bartomeu apologized for the ways Barça have negotiated with other coaches, such as Xavi and Koeman. And to warn him that within a few hours he should pack his bags.
In the past, the board had valued Valverde out on several occasions, but footballers had always saved him. However, after last Thursday's loss against Atletico, the players dropped the coach. Some came to call Xavi Hernández personally to ask him to be their new manager. Xavi, however, preferred to follow Qatar and not go down in history as the out-coach Valverde. A movie villain who will not occupy Setién, who will arrive to take the place of a coach destined to leave.
The board had lost trust in Valverde some time ago. This season Bartomeu was especially disappointed after the team's loose game against Real Madrid at home (0-0). Watching the Super Cup slip away, all parties agreed to take it out for a reaction before the key phase of the season. In the end the chosen one is Setién, who will be presented on the day when Bartomeu will have to defend the change. And especially justify the manner in which such an improvised relief was managed, which ended in nerves and an early morning statement.
. (tagsToTranslate) Barça (t) Guardiola (t) football (t) first division (t) league BBVA (t) minority sports (t) women's sport (t) athlete (t) Olympic Games
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Can I Get a Car Loan If I've Been Bankrupt?
home|FAQs|What If I've Been Bankrupt?
If you've been discharged from a bankruptcy or consumer proposal there is a strong chance of getting approved for a subprime auto loan. If you're currently active within a bankruptcy there is a step involving the trustee contacting the lender that you are in a good position to go ahead with vehicle financing.