![]() ![]() 5 In addition, being a potential ALL biomarker, miR128a was characterized as a regulator of stemness and differentiation of leukemic cells. Notably, some miRNAs seem to control expression of the MLL-AF4 fusion protein, but no miRNA has been functionally validated as a critical fusion protein downstream target. ![]() Previous studies identified several aberrantly expressed miRNAs in MLL-AF4 + ALL. Collectively, Malouf et al identified 2 MLL-AF4–regulated and functionally relevant miRNAs (miR-128a, miR-130b) targeting 2 critical downstream effectors that contribute to malignant transformation of fetal liver–derived hematopoietic cells. ![]() Transplant experiments in which miRNA knockdown was combined with target overexpression suggest that induction, as well as maintenance, of the disease phenotype is miRNA dependent and involves downregulation of NR2F6 and SGMS1. NR2F6 and SGMS1 expression was downregulated in tumor cells of pMIRH-128a and pMIRH-130b mice overexpression of these genes decreased proliferation or induced apoptosis of human MLL-AF4 + ALL cell lines, respectively. Malouf et al also identified several candidate target genes that may mediate the leukemic activity of miR-128 (including the nuclear orphan receptor NR2F6 gene), miR-130b, or both (including the sphingomyelin synthase 1 gene). Further transplantation experiments demonstrated that lympho-myeloid progenitors (LMPPs) allowed the propagation of pMIRH-130b mixed B-cell/myeloid leukemia, whereas Lin-Sca1 +/−Il7 +Kit + blasts maintained pro–B-ALL disease of pMIRH-128a mice. Knockdown experiments showed that, although miR-128a seemed to be critical for initiation of the disease, miR-130b was essential for its maintenance. Comparative transcriptomic analysis of tumor cells from diseased mice revealed the expression of several well-known MLL-rearranged leukemia-associated target genes, including Meis1, Runx1 ( pMIRH-128a mice), HoxA9, Flt3 ( pMIRH-130b mice), Cdk6, and Bcl2. Similar to MLL-AF4 + human ALL, pMIRH-128a– and pMIRH-130b–transplanted mice showed significant leptomeningeal tumor cell infiltration. pMIRH-130b mice presented with a mixed B-cell/myeloid malignancy, whereas pMIRH-128a mice developed pro–B-cell ALL. Transplantation of Mll-AF4 + LSK cells virally expressing miR-128a ( pMIRH-128a) or miR-130b ( pMIRH-130b) induced a hematologic malignancy in mice with increasing penetrance upon propagation into secondary and tertiary recipients. Both miRNAs increased the clonogenic B-cell potential of Mll-AF4 + cells. To address the role of these miRNAs in transformation, the investigators overexpressed them in lineage-marker–depleted Sca1 +Kit + (LSK) fetal liver cells from targeted Mll-AF4 invertor mice (see figure). Knockdown of miR-128a and/or miR-130b significantly impaired proliferation of human MLL-AF4 + cell lines, and inhibition of miR-130a significantly impaired disease initiation by the pediatric MLL-AF4 + SEM ALL cell line in immunodeficient NOD- scid IL2Rgamma null (NSG) mice. 1 MLL-AF4 binding upstream of the miR-128a and miR-130b transcriptional start sites suggested direct regulation. ![]() Malouf et al found 2 miRNAs (miR-128a, miR-130b) that were significantly upregulated in tumor cells from pediatric MLL-AF4 + ALL patients. Targeting of Mll-AF4 in early fetal HSPCs enhanced the lymphoid potential of primed multipotent cells but was insufficient by itself to induce leukemia. In an earlier study, Barrett et al used a conditional invertor mouse line for cell-specific expression of an Mll-AF4 fusion protein. 3 Detection of the MLL-AF4 fusion protein in CD34 +/CD19 − fetal hematopoietic stem or progenitor cells or in fetal cells before hematologic specification suggests that there is a window of opportunity during development for the MLL-AF4 fusion protein to immortalize hematopoietic stem and progenitor cells (HSPCs). The small number of potentially cooperating genetic lesions suggests that MLL-AF4 is sufficient to induce infant ALL. 2 Detection of the gene fusion in neonatal blood spots indicates that MLL-rearranged infant ALL originates in utero. 1 Mixed lineage leukemia (MLL) gene fusions are the molecular hallmark of infant acute lymphoblastic leukemia (ALL) and are present in tumor cells in up to 80% of patients. In this issue of Blood, Malouf et al characterize 2 microRNAs (miRNAs) that are effectors of malignant transformation by the MLL-AF4 fusion protein. ![]()
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I’ve seen teachers jump into spelling before their students were really ready and it can cause a significant set back. I’d feel bad if I didn’t start with a quick reminder. I’ve got 10 years of students who benefited from it. So I’d also like to show you how I did it.It’s worth saying again, my schedule could vary from other schedules you’ve seen but this is what I know works. #The ultimate spelling and vocabulary reference freeIt also includes a super cute spelling Bingo homework sheet, spelling inventory assessments, and some free (&adorable) Spelling Test Sheets. It’s the culmination of years of work and experience already done for you and made ultra affordable! I’m a Mom and teacher myself, and I understand the need to stretch a budget, so I price all my products accordingly and try to give away a ton of freebies in the process (& throughout this post)!This instructional unit comes with 48 weeks of spelling words following my recommended schedule. You can grab that at the end of the post.If you’re a teacher or homeschooling Mama, and crunched for time, you can check out my 48 Weeks of Spelling Lists packet on TPT. This schedule, done daily with supporting word study activities gives beginning readers the foundation they need to become independent readers.So if you’re in search of an order to teach spelling using patterns, you’ve hit the jackpot! I’ve got 47 weeks of spelling instruction summed up in one blog post I’ve also condensed the highlights into a handy reference sheet for you. In fact, I was able to take what I learned in graduate school, what I saw working from the various phonics programs that came and went, and my own observations about how students learned and devise a schedule that complimented my beginning readers perfectly.This spelling schedule served me in grades Kindergarten through mid year 2nd grade and helped hundreds of beginning readers grow in confidence and ability. ![]() Through the years my grade level changed several times, the curriculum changed practically year by year, but my spelling methodology did not. Today though, I wanted to share the order in which I teach these spelling patterns and explain why I chose this order. #The ultimate spelling and vocabulary reference seriesIn fact, I’ve got an entire series on Word Sorts coming very soon. By learning to isolate these patterns in spelling, students simultaneously become better writers and better readers.I could go on and on about the importance of Word study. I got to work creating an entire series of spelling words that follow increasingly difficult spelling patterns. #The ultimate spelling and vocabulary reference how toAfter returning to school and getting my own M.Ed in Reading, I saw the research and understood how to make it work best for my students year after year. She taught me so much, but perhaps the most valuable tool she gave me was teaching me about Word Study. Some taught spelling and site words together, some used words from the outdated Reading series, some used vocabulary words, and some didn’t really do it at all.When I first started teaching I was lucky enough to have a wonderful mentor who’d gotten her Masters in Reading. Teachers in my school used a variety of methods. Be sure you know the meaning of each word you learn to spell.When I first started teaching, spelling was a bit of a mystery. Students, get a jump on your learning by studying this word list. ![]() Or perhaps you'll need to add more challenging words from my sixth or seventh grade list. For some, you will need to supplement with easier words from my fourth grade list. Remember these words will be about right for most students. Teachers, refer to this list when you're looking for words to use in your own worksheets, spelling games and other language activities. ![]() ![]() The autumn school cultural festival arrives and Rikako becomes more distant from the other girls, many of whom openly dislike her. She responds by slapping him and he slaps her in return. Taku confronts Rikako in class for hurting his best friend. After catching up on sleep at the hotel, Taku receives a call from Rikako asking to be rescued from her former boyfriend, Okada.īack home, Rikako ignores Taku, but tells her friends that they spent a night together. The next morning, Rikako kicks Taku out so that she can change clothes to meet a friend for lunch. Taku offers his bed and attempts to sleep in the bathtub. Rikako explains that when her parents were fighting, she had always sided with her father, but had now discovered he was not on her side. Rikako's father thanks Taku, repays the loan and arranges a room at the Hyatt Regency. Out of the blue, a distressed Yumi calls Taku, explaining that Rikako had tricked her into coming to the airport on the pretense of a concert trip, only to discover that their real destination is Tokyo, tickets paid for with Taku's money. Rikako has not returned Taku's money and he wonders if she has forgotten. Promising to repay him, she warns him not to tell anyone.īack in Kōchi, the third year begins with Rikako making a friend, Yumi Kohama. As Taku has a part-time job, he lends her ¥60,000. On a school trip to Hawaii, Rikako asks Taku to lend her money, as she has lost her own. Taku believes she is unhappy about leaving Tokyo. Rikako is academically gifted and good at sports, but also arrogant. He finds Yutaka with an attractive female transfer student, Rikako Muto, whom Yutaka was asked to show around. In Kōchi, Taku Morisaki receives a call from his friend, Yutaka Matsuno, asking to meet at their high school. Obiyamachi Shopping Arcade is a frequent film backdrop. OCEAN WAVES RESTAURANT TVIn the same year, a TV drama was produced mainly based on this work starring Shinji Takeda and Hitomi Satō. In 1995, a sequel to the novel, I Can Hear the Sea II: Because There Is Love, was published. However, it ended up going both over budget and over schedule. Ocean Waves was an attempt by Studio Ghibli to allow their younger staff members to make a film reasonably cheaply. The film is set in the city of Kōchi, and follows a love triangle that develops between two good friends and a new girl who transfers to their high school from Tokyo. Animated by Studio Ghibli for Tokuma Shoten and the Nippon Television Network, Ocean Waves first aired on on Nippon TV. Ocean Waves, known in Japan as I Can Hear the Sea ( Japanese: 海がきこえる, Hepburn: Umi ga Kikoeru), is a 1993 Japanese anime television film directed by Tomomi Mochizuki and written by Kaori Nakamura based on the 1990–1992 novel of the same name by Saeko Himuro. Tetsuya Kuroda (TV Asahi), Masayuki Morikawa ( Horipro) I Can Hear the Sea II: Because There Is Love ![]() ![]() ![]() ![]() #Food smooze tvA study from 2005 found that patients were more than twice as likely to get prescriptions for an antidepressant or adjustment-disorder drug if they merely said to their doctor, “I was watching this TV program about depression wondering if you thought a medicine might help me” than if they didn’t say something like that (76 percent vs 31 percent). As examples, they note the websites of the weight-loss drug Contrave and the hypoactive sexual desire drug Addyi, which prod would-be patients to schedule telemedicine visits to “complete your doctor consultation from the privacy of your own home.” AdvertisementĮven without such clear ties between doctors and companies, DTC marketing and awareness campaigns have obvious sway on patients and prescribing practices, Schwartz and Woloshin note. These features “help consumers locate prescribers, an approach that has raised ethical questions by creating a conflict of interest as to whether prescribers serve patients or companies,” they write. The authors of the analysis-Lisa Schwartz and Steven Woloshin, health policy experts at Dartmouth-highlight a particularly concerning practice of the “find-a-doctor” feature in some advertisements. Ultimately, “trust in physicians and health care institutions may be at stake if medical marketing… continues to increase unchecked,” they conclude. This “suggests that professionals may need further education or support to serve as the arbiter of deceptive marketing,” they write. In an accompanying editorial in JAMA, the pair notes that this increased reliance on doctors can be fraught with pitfalls because doctors can be biased and misled by marketing just like consumers, earlier research found. That boom in DTC ads “increases the need for clinicians to help patients understand product claims, medical need, cost, and nonmedical alternatives,” according to health policy experts Selena Ortiz, of Pennsylvania State University, and Meredith Rosenthal, of Harvard. And of that $9.6 billion, about $6 billion was for marketing prescription drugs, the analysis found. That is, money spent on DTC-mostly TV commercials and glossy magazine ads-went from $2.1 billion in 1997 to $9.6 billion in 2016. DTC advertising more than quadrupled in the timeframe of the analysis. What’s new-and why this is now a shadier situation-is the explosion of direct-to-consumer (DTC) marketing that couples with those efforts for a one-two marketing punch. #Food smooze freeThey largely do so by sending sales representatives to doctors’ offices for face-to-face visits, providing free drug samples and other swag, offering payments for speeches, food and beverages, travel, and hosting disease “education.” Advertisement And the way in which drug companies woo doctors hasn’t changed much either. In 1997, a whopping 88 percent ($15.6 billion of their total $17.7 billion) of medical marketing went to swaying doctors, according to the analysis. ![]() The finding that pharmaceutical companies spend most of their marketing oomph on charming doctors isn’t surprising, though. Meanwhile, US healthcare spending hit $3.3 trillion, or 17.8 percent of the GDP, in 2016. In that time, health companies went from spending $17.7 billion to $29.9 billion on medical marketing. The study broke down exactly how health companies convinced us to spend enormous sums on our care between 19. That’s according to an in-depth analysis published in JAMA this week. ![]() Of the nearly $30 billion that health companies now spend on medical marketing each year, around 68 percent (or about $20 billion) goes to persuading doctors and other medical professionals-not consumers-of the benefits of prescription drugs. The drug company likely got to your doctor first. You shouldn’t just take the word of the drug company behind that drug ad or awareness campaign, of course.īut the suggestion to consult with your doctor may not be as innocent as it seems. Talking with your own trusted doctor can help determine if a new drug really is right for you or if you may be suffering from an undiagnosed disease. Ostensibly, it seems like a responsible suggestion. Talk with your doctor… It’s a common refrain at the end of any drug advertisement or disease awareness campaign. ![]() ![]() The relevant price for sale by the merchant is the actual price of the product as displayed on the merchant's website at the time of purchase. EasyFind is easy to use and fast Highly recommended. #Easyfind flat tv4G-DTV Combined TV Antenna + 4G Internet. RangeMaster Long Range WiFi antenna and router. #Easyfind flat 1080pMerchants have no ability to directly influence the display of prices or to initiate immediate changes on our site. Solid 5 star app from one of the most reliable, longtime Mac developers, Devon Technologies. EASYFIND FLAT SAT 1080P 1080P Full HD Front and Rear Recording / Reversing Camera Systemor UK TV reception in the far south of France and into Spain the QuickSAT EZ65 with its space saving flat dish is what you need. Note that this kit includes the Easyfind System including the HD receiver. In particular, price increases are possible between the time we accept the price and the time you later visit this website. The key feature to this caravan satellite dish kit is the compact size of only 44cm in diameter yet it is as powerful as and equivalent to a 65cm satellite dish size. And theres no need to worry about finding perfect Christmas trees. Please note that the prices listed are periodically generated snapshots and may be partially out of date for technical reasons. the corner of your small apartment, we have the Christmas trees youre looking for. When sorting by a currency other than the currency of the merchant, the conversion is based on a daily exchange installment determined by us, which may not exactly match the price stated in the shop. For costs not listed for other countries, please check the merchant's website. shipping" to UK, the price includes the costs for shipping and payment. ![]() The listed offers do not constitute legally binding advertising claims of the merchants. The EasyFind function is ideal for camper, for assembly and dismantling are fast and easily done. ![]() This nearly invisible EasyFind Flat Antenna impresses with its flat and elegant design. #Easyfind flat manualNo responsibility is taken for the correctness of this information. The newer version, Easyfind Flat, is also a manual method of adjusting elevation and azimuth but replaces the traffic light system with a 2 digit display. This is the Tripod Mounted version which is fully working and complete. ![]() ![]() ![]()
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