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Journal articles on the topic 'Kon sanoati'
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1
Usmonov, Shohijahon Ulug`bek o`g`li. "XALQARO INVESTITSIYA HUQUQIDA TOG`-KON SANOATIGA IJTIMOIY MAS`ULIYATLI INVESTITSIYALAR TO`G`RISIDA." EURASIAN JOURNAL OF LAW, FINANCE AND APPLIED SCIENCES 3, no. 4 (2023): 202–7. https://doi.org/10.5281/zenodo.7854903.
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Mazkur maqola tog`-kon sanoatiga ijtimoiy mas`uliyatli investitsiyalar kiritish,tog`-kon kompaniyalari tomonidan qabul qilingan korporativ ijtimoiy mas`uliyatga zamonaviy yondashuvlarni,shuningdek, ijtimoiy mas`uliyatning to`rtta asosiy yo`nalishi:atrof-muhitni muhofaza qilish,salomatlik va xavfsizlik bo`yicha konchilik kompaniyalarining amaliyotlarini, xodimlar bilan munosabatlar va jamiyatning rivojlanishini baholaydi.Mazkur maqolada ijtimoiy mas`uliyat tushunchasining kelib chiqishi va evolyutsiyasi hamda uning tog`-kon sanoati uchun ahamiyatini,shuningdek,tog`-kon sanoatining atrof-muhitga tasirini va tog`-kon sanoatida ijtimoiy mas`uliyatning o`ziga xos xususiyatlarini va bir qator tegishli masalalarni ko`rib chiqadi.
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Abdusamad, Poyonov. "O'zbekistonning iqtisodiy rivojlanish tarixida tog'-kon metallurgiya sanoatining transformatsiyasi." «Maktabgacha va maktab ta'limi» jurnali 3, no. 2 (2025): 7–9. https://doi.org/10.5281/zenodo.14959498.
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Ushbu maqola O‘zbekistondagi eng muhim sanoat majmualaridan biri bo‘lgan tog‘-kon sanoatining rivojlanishtarixiga bag‘ishlangan. Tog‘-kon sanoati kompleksining kengayishi, yangi quvvatlarning ishga tushirilishi va mavjudkorxonalarning rekonstruksiya qilinishi sanoat-texnik bazaning modernizatsiya bosqichlariga qaratilgan.
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Abdusamad, Poyonov. "Yangi O'zbekistonning iqtisodiy rivojlanish tarixida tog'-kon metallurgiya sanoati ." «Maktabgacha va maktab ta'limi» jurnali 3, no. 1 (2025): 12–14. https://doi.org/10.5281/zenodo.15149797.
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Ushbu maqola O‘zbekistonning eng muhim sanoat majmualaridan biri bo‘lgan tog‘-kon sanoatining rivojlanishi, uning tarmoqlarining tabiiy joylashuvi va ijtimoiy-iqtisodiy tarixi masalalariga bag‘ishlangan. Tog‘-kon sanoati kompleksining kengayishi, yangi quvvatlarning ishga tushirilishi va mavjud korxonalarning rekonstruksiya qilinishi natijasida majmuaning sanoat-texnik bazasi hamda uning respublika sanoatidagi ahamiyati haqida qisqacha ma’lumotlar keltirilgan
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Meyliyev, To'lqin Meyli o'g'li, and Samandarbek Alisher o'g'li Absalomov. "METALLURGIYA SANOATIDA SUYUQ CHIQINDILARIDAN QIMMATLI KOMPONENTLARNI OLISH IMKONIYATLARI." SCHOLAR 1, no. 13 (2023): 153–57. https://doi.org/10.5281/zenodo.7954859.
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<em>Zaminimizning mineral resurslarga boyligiga qaramasdan, ishlab chiqarishga kon-metallurgiya sanoati korxonalarining chiqindilarini jalb qilinishi davlat iqtisodiyotining yanada samarali rivojlanishini ta’minlaydi. Kon-metallurgiya sanoati korxonalari ayrim chiqindilarining tarkibidagi qimmatli komponentlarning miqdori birlamchi xom ashyo tarkibidagi qimmatli komponentlarning miqdoridan yuqoriligi bilan ajralib turadi. Kon-metallurgiya sanoati korxonalarining chiqindilarini qayta ishlashga jalb qilinishi chiqindilar turgan yerlarni bo‘shatish, va chiqindi mahsulotlarini qayta ishlash chora tadbirlari o‘rganildi.</em>
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Hamro TOSHNIYOZOV and Bobir JONIBEKOV. "BESHBULOQ OHAKTOSH KONINING GEOLOGIK-SRTUKTURAVIY JOYLASHUVI." UzMU xabarlari 3, no. 3.1 (2024): 2301–304. http://dx.doi.org/10.69617/uzmu.v3i3.1.1816.
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Tog‘-kon sanoatiga yer qa’ridan foydali qazilmalarni qazib olish va qurulish sanoati uchun ishlatiladigan mahsulotni olishning asosiy bo‘g‘ini bo‘lgan qazib olingan rudalarni birlamchi qayta ishlash bilan shug‘ullanuvchi tarmoqlar kiradi. Tabiiy resurslardan oqilona foydalanish va atrof-muhitni muhofaza qilish ko‘p jihatdan rudani birlamchi qayta ishlash texnologiyasiga bog‘liq. Shuning uchun foydali komponentlar qazib olishni ko‘paytirish, qazib olingan rudalardan kompleks foydalanish bilan bir qatorda, tog‘-kon sanoatining eng muhim vazifalaridan biri hisoblanadi.
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Hamro TOSHNIYOZOV and Bobir JONIBEKOV. "BESHBULOQ OHAKTOSH KONINING GEOLOGIK-SRTUKTURAVIY JOYLASHUVI." UzMU xabarlari 3, no. 3.1 (2024): 2301–304. https://doi.org/10.69617/nuuz.v3i3.1.1816.
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Tog‘-kon sanoatiga yer qa’ridan foydali qazilmalarni qazib olish va qurulish sanoati uchun ishlatiladigan mahsulotni olishning asosiy bo‘g‘ini bo‘lgan qazib olingan rudalarni birlamchi qayta ishlash bilan shug‘ullanuvchi tarmoqlar kiradi. Tabiiy resurslardan oqilona foydalanish va atrof-muhitni muhofaza qilish ko‘p jihatdan rudani birlamchi qayta ishlash texnologiyasiga bog‘liq. Shuning uchun foydali komponentlar qazib olishni ko‘paytirish, qazib olingan rudalardan kompleks foydalanish bilan bir qatorda, tog‘-kon sanoatining eng muhim vazifalaridan biri hisoblanadi.
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I.E., Karimov, and B. Umarova X. "QISHLOQ XO'JALIGIDA RELYEFNI TEXNOGEN BUZILISHI SABABLARI VA ULARNI BARTARAF ETISH MUAMMOLARI." Oriental Journal of Geography 02, no. 02 (2022): 68–72. https://doi.org/10.5281/zenodo.7482322.
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Ushbu maqolada Qishloq xo‘jaligida relyefni texnogen buzilishi sabablari va ularni bartaraf etish muammolari, antropogen relyef formalarini melioratsiyalashda ularni genezisini o‘rganish katta amaliy ahamiyati, tog‘ kon sanoati bilan, qurilish materiallari qazib olish bilan sanoat korxonalari ta’sir doirasidagi jarayonlar bilan bog‘liqligi tahlil qilingan.
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Muhammedova, Nazokat Jurayevna, and Mohinabonu Talabboyeva. "NAMANGAN VILOYATI SANOATI." JOURNAL OF SCIENCE-INNOVATIVE RESEARCH IN UZBEKISTAN 2, no. 3 (2024): 76–78. https://doi.org/10.5281/zenodo.10801277.
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B Mamatqulov, O., U. U To‘xtayev, B. S Tog‘ayev, et al. "JIZZAX VILOYATI QO‘YTOSH TOG‘ TIZMASINING TABIIY RADIOAKTIVLIGI TO‘G‘RISIDA." 2022-yil, 3-son (133/1) ANIQ FANLAR SERIYASI 5, no. 135/1 (2022): 1–11. http://dx.doi.org/10.59251/2181-1296.v5.1351.1140.
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Nurota tog‘-kon sanoati Respublikamizning rangli metallurgiya hamda kamyob yer metallari qazib olish sanoati uchun eng istiqbolli hududlardan biri hisoblanadi. XX asrning ikkinchi yarmida Qo‘ytoshda molibden va volframni qazib olish va boyitish boshlandi. Hozirgi kunda ochiq va yopiq kon karyerlari va burg‘ulagan joylarning radioaktiv holatini monitoring qilish taqdim etilayotgan ishning asosiy maqsadi hisoblanadi. Ishda Qo‘ytosh hududidan olingan tuproq namunalarining TRN miqdori NaI(Tl) kristalli ssintillyatsion gamma-spektrometrda tadqiq etildi. Hududning tuproq va tog‘etaklaridagi maydonlarning yer yuzasidagi ROZ (radonning oqim zichligi) miqdori aniqlandi.
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Oxunjonova, Dildora Komiljon qizi. "TOG'-KON SANOATINING ATROF MUHITGA TA'SIRI (OLMALIQ TOG'-KON METALLURGIYA KOMBINATI MISOLIDA)." Innovative Development in Educational Activities 2, no. 22 (2023): 265–70. https://doi.org/10.5281/zenodo.10225484.
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<i>Bugungi kunda respublikada rivojlanib borayotgan tarmoqlardan biri tog'-kon sanoati bo'lib, u atrof muhit holatini o'zgarishiga ham kuchli ta'sir etmoqda. Konlarni qazib olish va ma'danlarni qayta ishlash jarayonida atrof muhitga, jumladan har bir tabiat komponentiga o'z ta'sirini ko'rsatmoqda. Mazkur maqola respublikada tog'-kon sanoatining vujudga kelishi va rivojlanishi, konchilik yaxshi rivojlangan hudud, ya'ni Olmaliq tog'-kon metallurgiya kombinati faoliyati natijasida tabiiy muhit holatining o'zgarishini tahlil qilishga bag'ishlangan. </i>
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RAUPOV, Xolmamat, and Rustam QARSHIYEV. "O‘ZBEKISTON KON-METALLURGIYA SANOATI KORXONALARI JOYLASHGAN SHAHARLARDAGI EKOLOGIK MASALALAR TARIXIDAN (XX ASR 70-80-YILLARIDA)." UzMU xabarlari 1, no. 1.5 (2025): 25–27. https://doi.org/10.69617/nuuz.v1i1.5.7672.
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Ushbu maqolada o‘tgan asrning 70-80 yillarida O‘zbekistonda faoliyat olib borgan kon-metallurgiya sanoati korxonlari joylashgan shaharlarda vujudga kelgan ekologik muammolar yoritilgan. Shuningdek, hududlarda qazilma boyliklarini o‘zlashtirish jarayonlarining tabiatga, odamlar sog‘ligiga salbiy ta’siri va uning oqibatlari keltirib o‘tilgan.
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Baychayev, F. X. "МЕТОДИКА ВЫБОРА ПРОФЕССИОНАЛЬНО ОРИЕНТИРОВАННЫХ ЗАДАЧ НА ПРАКТИЧЕСКИХ ЗАНЯТИЯХ ПО ФИЗИКЕ ДЛЯ БУДУЩИХ СПЕЦИАЛИСТОВ ГОРНО-МЕТАЛЛУРГИЧЕСКОЙ ПРОМЫШЛЕННОСТИ". Education and innovative research, № 4 (5 серпня 2021): 96–103. http://dx.doi.org/10.53885/edinres.2021.23.53.015.
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Kon-metallurgiya sanoati tizimi bo‘lajak mutaxassislari uchun fizikadan amaliyot darslarida kasbiy yo‘naltirilgan masalalarni saralash metodikasi yoritilgan. Освещено методика выбора профессионально ориентированных задач на практических занятиях по физике для будущих специалистов горно-металлургической промышленности The method of choosing professionally oriented problems in practical physics lessons for future specialists of the mining and metallurgical industry is highlighted.
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ABDURASULOV, Sherzamin Xayitbayevich, and Nuriddin Savranbek o'g'li ZAYNIDDINOV. "PE2M VA PE2U TORTISH AGREGATLARI RAMA KONSTRUKSIYALARI PARAMETRLARI VA O'ZIGA XOSLIKLARINING TAHLILI." ТАДҚИҚОТ ВА ИННОВАЦИЯЛАР ЖУРНАЛИ 1, no. 10 (2023): 8–19. https://doi.org/10.5281/zenodo.8405080.
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Ushbu maqola bugungi kunda O‘zbekiston Respublikasi tog‘-kon sanoati korxonalarida qo‘llanilib kelinayotgan PE2M, PE2U va MPE2U turidagi sanoat tortish agregatlarining rama konstruksiyalarining parametrlari va o‘ziga xosliklarini o‘rganish natijalarini o‘z ichiga olgan. Tortish agregati rama konstruksiyalarining parametrlari va o‘ziga xosliklari, adabiyotlar, konstruktorlik-texnologik texnik hujjatlar tahlili va haqiqiy namunalarini o‘rganish orqali amalga oshirilgan. Rama konstruksiyalarining tuzilishi, ularga foydalanish davomida ta’sir etadigan kuchlar va hosil bo‘ladigan kuchlanishlar haqida ma’lumotlar keltirilgan.
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To'xtashev, Alisher Bahodirovich, Samandar Shodmon o'g'li Abruyev, Sabina Zaynitdin qizi Xakimova, and Gulchehra Jurabek qizi Davronova. "KELAJAKDA QAYTA TIKLANADIGAN ENERGIYA." Innovative Development in Educational Activities 2, no. 7 (2023): 697–99. https://doi.org/10.5281/zenodo.7832400.
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<em>"Iqlim o‘zgarishining dahshatli oqibatlarini yumshatish chaqiriqlari yanada yashil ta’minot zanjirlariga o‘tishga va tog‘-kon sanoati kabi "Zaharli" deb hisoblangan sohalarga nisbatan nafratlanishga olib keldi."</em>
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Kurbanova, Mehriniso Nematjanovna. "Konchilik sanoati korxonalarining innovatsion jarayonlarni rivojlantirish xususiyatlari." Yashil iqtisodiyot va taraqqiyot 2, no. 6 (2024): 9–13. https://doi.org/10.5281/zenodo.12787217.
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Maqolada konchilik sanoati korxonalarining innovatsion jarayonlarni rivojlantirish xususiyatlari haqida fikryuritilgan. Ta’kidlanishicha, tog‘-kon korxonalarida innovatsion faoliyatni boshlash va rivojlantirishning mumkin bo‘lganyo‘nalishlaridan biri konlarni o‘zlashtirishning barcha bosqichlarida qazib olingan maydonni to‘ldirish bilan turli xil kontexnologiyasi variantlarini qo‘llash bilan bog‘liq bo‘lib, bu qazib olingan xom ashyo va chiqindi jinslarni qazib olingan maydongaqaytarish bilan boj’liq foydali komponentni to‘liq olish imkonini beradi. Bu konlarni dastlabki qo‘shimcha qidirishni,sifat va miqdoriy ko‘rsatkichlarni nazorat qilishni, ishlab chiqarish jarayoni strukturasini saqlashni, korxonaning raqobatbardoshliginiqo‘llab-quvvatlovchi va yakuniy ishlab chiqarish ko‘rsatkichlariga ta’sir ko‘rsatadigan zaxiralarni yaratishnita’minlaydi. Bunday texnologiya universaldir va qayta ko‘rib chiqishni talab qilmaydi va bu holda innovatsion faoliyatasosan mehnat unumdorligini boshqarish bilan bog‘liq bo‘ladi.
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Bobomurodov, Azamat Yo'ldosh o'g'li. "KALIY KONLARINI QAZIB OLISHDA QO'LLANILADIGAN MASHINALAR VA KOMPLEKSLAR." Innovative Development in Educational Activities 2, no. 22 (2023): 9–15. https://doi.org/10.5281/zenodo.10222717.
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<i>Ushbu maqolada kon sanoati korxonalari faoliyatida hamda jahonda<strong> </strong>kaliy rudalarini ishlab chiqarish va o'zlashtirish muamolari aniqlash, kaliy tuzlari konida silvinit qatlamlarini kombaynlar yordamida qazishning samarali texnologiyasini ishlab chiqish ishlari yoritib berilgan</i>
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Bobomurodov, Azamat Yo'ldosh o'g'li. "SHARG'UN KO'MIR KONIDA QAZIB-YUKLASH ISHLARI TEXNIKASI VA TEXNOLOGIYASINING TAHLILI." RESEARCH AND EDUCATION 3, no. 5 (2024): 84–87. https://doi.org/10.5281/zenodo.11518018.
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<em>Mazkur</em><em> maqolada kon sanoati korxonalari faoliyatida </em><em>hamda jahonda Sharg‘un ko‘mir konida qazib – yuklash ishlari texnikasi va texnologiyasining taxlil qilish, ko‘mir qatlamlarini ekskavatorlar yordamida qazib – yuklash ishlarida yuqori unumdorlikka ega bo‘lgan ekskavatorlardan foydalanilgan va Karyerdagi qazib-yuklash ishlarining samaradorligini oshirish va kamchiliklarni bartaraf qilish</em><em> ishlari yoritib berilgan.</em>
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O.Sh., Yormatov, та Toshtemirov U.T. "SHAXTA VA RUDNIKLARDAGI YER OSTI KON ISHLARI HOLATINI KOʻRISH UCHUN OLIY TA'LIM DARGOHLARIDA VIRTUAL SAYOHAT AUDITORIYASINI TASHKIL QILISH". Journal of Science-Innovative Research in Uzbekistan 1, № 2 (2023): 126–28. https://doi.org/10.5281/zenodo.8039387.
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O`zbekistonning iqtisodiy rivojlanish sur`atini har tomonlama tezlatish uchun asosan og`ir sanoatning butun xalq xo`jaligini yanada yuksalishiga yordam beradigan tarmoqlarini rivojlantirish katta ahamiyatga ega bo`ladi. Bunday tarmoqlardan biri hozirgi zamonda konchilik sanoatidir. Hozirda O`zbekiston konchilik sanoati rivojlangan mamlakatlar qatoriga kiradi. Har yili Respublikamiz konlarida taxminan 5.5 mlrd dollarlik miqdorida foydali qazilmalar qazib olinmoqda va ular yoniga 6.0-7.0 mlrd dollarlik zahiralar qo`shilmoqda. Shu ishlarning asosiy mutaxassislari bo`lib ishlayotgan hodimlar konchilardir
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Mirzoyeva, I.E, and SaydullayevaA. "O'ZBEKISTONDA KO'MIR KONLARI VA UNING ATROF- MUHITGA TA'SIRINING GEOGRAFIK JIHATLARI." PEDAGOGS international research journal 1, no. 1 (2022): 105–10. https://doi.org/10.5281/zenodo.5837489.
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<strong><em>Annotatsiya: </em></strong><em>Ushbu maqolada O‘zbekistondagi ko‘mir konlari va ularning tarqalish geografiyasi hamda ko‘mir konlarining ekologik ahvoli to‘g‘risida ma’lumot berilgan.</em> <strong><em>Аннотация:</em></strong><em> В статье представлена информация об угольных месторождениях Узбекистана и географии их распространения, а также об экологической ситуации на угольных месторождениях.</em> <strong><em>Annotation:</em></strong><em> This article provides information on coal deposits in Uzbekistan and the geography of their distribution, as well as the environmental situation of coal deposits.</em> Inson tabiat bilan hamisha uzviy aloqadorlikda yashaydi.Uning hayotini tabiatdan, tabiiy boyliklardan ayrilgan holda tasavvur etish mumkin emas. Nafas olinadigan havo, ichiladigan suv, sanoat va qishloq xo‘jaligi uchun zarur bo‘lgan tabiiy zaxiralar-neft, gaz, ko’mir, yoqilg‘i, har xil ma’danlar bo‘lmasa, inson yashay olmaydi. Jumladan, Respublikamiz zaminining geologik jihatdan qadimdan juda murakkab paleogeografik rivojlanish jarayonlarni boshdan kechirganligi murakkab burmalanish hodisalari dengiz havzalarining vaqt-vaqti bilan quruqlikka bostirib kirganligi nurashning kuchli tarzda ro`y berganligi vulqon harakatlari va boshqalar natijasida xilma-xil tabiiy boyliklar tarkib topgan. Hozirgi kunga kelib, O`zbekistonda 2700 dan ortiq qazilma boyliklar konlari va istiqbolda ochilishi mumkin bo`lgan yangi konlar aniqlangan. Ularning 60 xilidan xalq xo`jaligida foydalanilmoqda. Shundan ko`mir xomashyo zaxirasi 2 mlrd tonnani tashkil qiladi. O`zbekistonda 20 dan ortiq ko`mir konlari va ko`mirli havzalar aniqlangan. Mamlakatimizda yiliga 3,5mln tonna ko`mir qazib olinmoqda.[1] Ko`mir sanoatining geografiyasi neft yoki gaz sanoatiga nisbatan keng emas, u faqat Toshkent (Angren) va Surxondaryo (Sharg`un va Boysun) viloyatlarida birmuncha rivojlangan xolos. Shu o`rinda ta`kidlash joizki, qo`ng`ir ko`mirning iqtisodiy ahamiyati toshko`mirga nisbatan ancha past. Turli sabablarga ko`ra, bu ko`mir turidan qora metallurgiyada foydalanib bo`lmaydi; boz ustiga, qo`ng`ir ko`mirni, odatda ko`p saqlab bo`lmaydi. Binobarin, Angren qo`ng`ir ko`miridan asosan IESlarda foydalaniladi.[2] Mutaxassislarning fikriga ko`ra, bu yerdagi mahalliy jigarrang ko`mir boshqa konlarning xomashyosiga o`xshamaydi. Uning afzalligi ko`mirdan tashqari, boshqa foydali qazilmalar, jumladan kaolin (oq gil) ham qazib olinishidadir. Birlamchi kaolin esa ko`mir qatlamlarining ustki qismida joylashgan. Hozirda bu kondan yiliga o`rtacha 1 mln tonna kaolin qazib olinib, bu mamlakatning ushbu cho`kindi mineralga bo`lgan ehtiyojini qoplaydi. Qalinligi 60 m, chuqurligi 130-150 m gacha bo`lgan ko`mir konining ko`mir qatlamlariga yetish uchun esa barcha xavfsizlik choralariga rioya etgan holda to`g`ri harakatlanish kerak. Angren ko`mirini qazib olish, uni gazga aylantirish jarayoni bilan bog`liq bo`lgan ishlar natijasida ham Qurama tog` etaklaridagi konlar atrofida ko`plab surilmalar paydo bo`lgan. Ularning ichida eng kattasi Atchi surilmasidir. Uning hajmi 700 mln m<sup>3</sup>, sathi 12 km<sup>2 </sup>bo`lib, 80-170 m qalinlikdagi tog` jinslari qatlamlarining surilishi 1975 yildan beri davom etmoqda. Bunday surilmalar atrofidagi inshootlarni shikastlab, konga ham xavf tug`dirmoqda. Angren ko`mir koni- Toshkent viloyati Ohangaron vodiysidagi qo`ng`ir ko`mir koni.Qurama va Chotqol tog` etaklarida joylashgan bo’lib 1940 yilga ishga tushirilgan. Havza maydoni qariyb 70 km<sup>2</sup>.Aniqlangan zaxirasi 860 ming, chuqurlikkacha 1,9 mlrd tonna. Ko`mir yura davri yotqiziqlari orasida.Yonish issiqligi 13,9 mj/ kg. Boysun toshko`mir koni- Boysun tog`ining janubi-g`arbiy tarmog`i bo`lgan Ketmonchopti tizmasining janubiy yonbag`rida 1940-yildan o`zlashtirila boshlagan. Ko`mir qatlamlari assimetrik ko`tarilgan Ketmonchopti tog’ida taxminan 25 km² maydonni egallagan.Kon geomorfologik va tektonik jihatdan 3 qismdan iborat. Quyi, o`rta yura jinslari orasidan 22 ta ko`mir qatlami topilgan, shuning ikkitasidan ko`mir qazib olinadi. Sharg`un ko`mir koni - Hisor tog`tizmasining janubi-g`arbiy tarmog`ida joylashgan bo’lib, 1941- yilda ochilgan Surxondaryo viloyatidagi kon. Sharg`un ko`mir koni quyi va o`rta yura davriga mansub ko`mirli yotqiziqlar ichida topilgan. Ko`mir yotqiziqlarining umumiy qalinligi 26 m. Ko`mir qatlami Guliob soyidan Obizarang soyigacha – g`arbdan sharqqa 10 km ga cho`zilgan. Sharg`un ko`mir koni eng yirik qatlamining qalinligi 12,5 m;qatlamlarning o`rtacha qalinligi 4,6 m Sharg`un ko`miri – toshko`mir bo`lsa ham maydaroq va yumshoqroq, yengil tozalanadi, fabrikada briketlanib, iste`molchilarga yuboriladi. Sharg`un ko`mir koninining zaxirasi 36 mln. t. yiliga 50 ming t ko`mir qazib olinadi. Sharg`un ko`miri karbid olish uchun xomashyo hisoblanadi.“Sharg`un ko`mir” konining yillik quvvati 100 ming tonnani tashkil etadi. Hozirgi vaqtda foydali qazilmalarni (ko`mir, temir va marganets rudalari, metall bo`lmagan xomashyo, torf va boshqalarni) qazib olish paytida kon chiqindilari egallagan yerlarning umumiy maydoni 2 million gektardan oshadi. Tuproq qazib olish, ayniqsa, ochiq usulda qazib olishda, yer yuzasi va yer osti qatlamlariga eng katta ta'sir ko'rsatadi.Yuqorida ta'kidlab o`tilganidek, ushbu usul bilan yerning muhim maydonlari tortib olinadi, atrof-muhit har xil toksikantlar (ayniqsa og`ir metallar) bilan ifloslangan. Bilvosita ta`sirlar yer osti suvlari rejimining o`zgarishi, havo havzasi, yer usti suv oqimlari va yer osti suvlarining ifloslanishida namoyon bo'ladi, shuningdek suv toshqini va botqoqlanishni keltirib chiqaradi, bu esa oxir-oqibat mahalliy aholi kasalliklari bilan kasallanishning ko`payishiga olib keladi.Havoni ifloslantiruvchi moddalar orasida eng ko`zga ko`ringanlari chang va gaz bilan ifloslanishdir. Hisob-kitoblarga ko'ra, har yili konlar va konlarning yer osti qazib olish ishlaridan taxminan 200 ming tonna chang olinadi; dunyoning turli mamlakatlaridagi 4000 ga yaqin konlardan yiliga 2 milliard tonna ko`mir qazib olish atmosferaga 27 milliard m<sup>3</sup> metan va 17 milliard m<sup>3</sup> karbonat angidridning chiqishi bilan birga keladi. Mamlakatimizda ko`mir konlarini yer osti usuli bilan o`zlashtirish jarayonida havo havzasiga tushgan metan va karbonat angdrid miqdori ham har yili qayd etiladi:har yili Donbass (364 kon) va Kuzbass (78 kon) da 3870 va 680 million m<sup>3</sup> metan va karbonat angidrid chiqariladi.Qazib olish mexanik aralashmalar va mineral tuzlar bilan juda ifloslangan yer usti suv oqimlari va yer osti suvlariga salbiy ta'sir ko`rsatadi. Har yili ko`mir konlaridan taxminan 2,5 milliard m<sup>3</sup> ifloslangan kon suvlari yer yuziga quyiladi. Ochiq usulda qazib olish, birinchi navbatda, yuqori sifatli toza suv resurslarini kamaytiradi.Sanoat korxonalari, ijtimoiy va kommunal xo`jalik sohasi, aholi ham qattiq yonilg`iga talabni yuzaga keltiradi.Ichki bozorda elektr energiyani ishlab chiqarishda foydalaniladigan tabiiy gaz va neft mahsulotlari kabi energetik resurslar o`rniga ishlatish maqsadga muvofiqligi, O`zbekiston energetik balansi tarkibida ko`mir ulushining oshirilishi ko`mir sanoati ustuvor rivojlanishining asosiy omili hisoblanadi. Ko`mir sanoati korxonalarining iqtisodiy faolligi shuni ko`rsatadiki, konlarda va ochiq konlarda asosiy ifloslantiruvchi moddalar ko`mir-tosh zarralari bo`lib, ular suv havzalariga chiqindi suv bilan kirib, suvning shaffofligini pasaytiradi, tubini va qirg`oqlarini suv bosadi. Botqoqlanish, suv omborlari hajmining kamayishi va ulardagi biologik muvozanatning buzilishiga olib keladi. Natijada baliqlar va barcha tirik mavjudotlar asta-sekin yo`q bo`lib ketmoqda. Bu turdagi ifloslanish ayniqsa Qarag`anda ko`mir havzasi uchun xosdir. Ko`mir korxonalarining chiqindi suvlari, shuningdek, konlar, ochiq konlar va qayta ishlash zavodlari, transport kommunikatsiyalari va boshqa kon ob`ektlarining yer usti oqimi suvlarini o`z ichiga oladi. Ko`mir qazib oluvchi korxonalar faoliyati tahlili shuni ko`rsatadiki, ularning suv havzalariga zararli ta`sirini cheklashning samarali chorasi - bu konlarning va konlarning kon ishlariga suv oqimini kamaytirish choralarini ko`rishdir, bu nafaqat hajmini kamaytiradi. oqova suvlar va tashish va tozalash xarajatlari, shuningdek, tabiiy zaxiralar va yer osti suvlarining sifat tarkibini saqlab qolish.Tog`- kon sanoati foydali qazilmalarni olishning 3 asosiy usulini o'z ichiga oladi: shaxtali, ochiq usulda, quduq.Ularning har birining o`ziga xos ekologik muammolari bor. Katta hajmli karerlar va ochiq konlar, bu kuchli yer usti uskunalari paydo bo`lishi bilan mumkin bo`ldi. Ochiq yo`l u yanada progressiv hisoblanadi, chunki u sharoitni sezilarli darajada yaxshilaydi va mehnat unumdorligini oshiradi va foydali qazilmalarni qazib olishga imkon beradi.Ochiq konlar ko`mirning 38%, temir rudasining 88%, xromitning 96% va qurilish materiallarining deyarli 100% ni tashkil qiladi. Ko`mir konlarida atmosfera ifloslanishi muammosi ko`pincha chiqindilarga tushadigan sanoat bo`lmagan qatlamlardan ma`lum turdagi ko`mirning qobiliyati tufayli og`irlashadi. Katta ochiq konlar yaqinida havo mavjud bo`lganda, o`z –o`zidan yonish uchun, chuqurlik voronkalari hosil bo`ladi, ularning ichida yer osti suvlari sathining sezilarli pasayishi kuzatiladi, bu esa buloq va quduqlarning drenajlanishiga olib keladi. Qattiq foydali qazilmalarni kon va ochiq usulda qazib olishning ekologik muammolari melioratsiya yordamida hal qilinadi - buzilgan yerlarning hosildorligi va iqtisodiy qiymatini tiklash, shuningdek, ekologik sharoitni yaxshilashga qaratilgan ishlar majmui. Tabiiy resurslarni iste`mol qilishning tez o`sishi nafaqat antropogen ta`sirning miqdoriy ko`lamining o`zgarishi, balki tabiatga ta`siri ilgari ahamiyatsiz bo`lgan yangi omillarning paydo bo`lishi bilan hamroh bo`ladi. Tabiiy komponentlarga yetkazilgan zarar aniq oqibatlarga olib keladi va "zamonaviy ekologik vaziyat" tushunchasi bilan umumlashtirilgan bu ta`sirning (jamiyat uchun salbiy) teskari reaktsiyasini aks ettiradi. Mamlakatimizda tog`-kon ishlarining atrof-muhitga salbiy ta`sirini oldini olish maqsadida keng ko`lamli tadqiqotlar olib borilmoqda. Xulosa o`rnida aytish joizki, tabiatni muhofaza qilish, tabiiy resurslardan oqilona foydalanish har qanday davlatning kelajakda iqtisodiy-ijtimoiy rivojlanishining ustuvor yo`nalishlaridan hisoblanadi.Atrof-muhit tarkibiy qismlarining sifatini saqlab qolish va yaxshilash inson salomatligini muhofaza qilish uchun atrof-muhitni boshqarish samaradorligini oshirish imkoniyatlarni aniqlash atrof-muhitni boshqarish tizimini doimiy ravishda tahlil qilib, baholab borish lozim.
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Negmatov, Samariddin Qarshiboyevich Eshmonova Bahoroy. "O`ZBEKISTONNING YIRIK FOYDALI QAZILMA KONLARI." ZDTF 2, no. 7 (2023): 4–5. https://doi.org/10.5281/zenodo.8134133.
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Yer po`stida qattiq, suyuq, gazsimon holatlarda uchraydigan turli geologik jarayonlar natijasida qadimdan boshlab to`plangan, miqdori, sifati shart-sharoitiga ko`ra sanoatda ishlatishga yaroqli bo`lgan tabiiy mineral moddalar to`plangan. Foydali qazilmalar turli konlarning hosil bo`ishi natijasida paydo bo`lgan. Foydali qazilmalar kon qazib olishga ko`ra bir-biridan farqlanadi. Misol tariqasida foydali qazilma konlari ultiraabissal (10-15km, chuqurlikda), abissal (3-5.km), gipabissal (1,5 km chuqurlikda) joylashgan. O`zbekiston Respublikasida joylashgan sanoat ahamiyatiga ega bo`lgan bir necha yirik konlar haqida to`xtalib o`tamiz.
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Xaydaraliyev, Elbek Farxod o'g'li. "TOG'-KON SANOATINI RAQAMLASHTIRISH ORQALI IQTISODIY SAMARADORLIGINI OSHIRISH." SCHOLAR 3, no. 6 (2025): 41–45. https://doi.org/10.5281/zenodo.15254400.
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<em>Mazkur maqolada tog‘-kon sanoatida raqamlashtirish jarayonlari va ularning iqtisodiy samaradorlikka ta’siri tahlil qilinadi. Raqamli texnologiyalar, xususan, avtomatlashtirish, IoT, katta ma’lumotlar tahlili va sun’iy intellekt orqali ishlab chiqarish samaradorligi, xavfsizlik darajasi va xarajatlarni optimallashtirish imkoniyatlari o‘rganilgan. SWOT tahlil asosida kuchli va zaif tomonlar bilan birga tahdidlar va imkoniyatlar tahlil qilinadi. O‘zbekiston misolida raqamlashtirishdan keyingi ijobiy o‘zgarishlar grafiklar asosida yoritilgan. Maqola natijalari tog‘-kon sohasida raqamli transformatsiyani jadallashtirish uchun amaliy tavsiyalarni taklif etadi.</em>
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ABDURASULOV, Sherzamin Xayitbayevich, Nuriddin Savranbekovich ZAYNIDDINOV, and Abdulaziz Maxamadali o'g'li YUSUFOV. "O'ZBEKISTON RESPUBLIKASI TOG'-KON SANOATIDA FOYDALANILAYOTGAN TORTISH AGREGATLARI PARKINING TAHLILI." ТАДҚИҚОТ ВА ИННОВАЦИЯЛАР ЖУРНАЛИ 1, no. 9 (2023): 16–24. https://doi.org/10.5281/zenodo.8337067.
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Ushbu maqolada sanoat sohasidagi tortish agregatlari parkining bugungi kundagi holati o‘rganilgan. Tadqiqot ishidan maqsad O‘zbekiston Respublikasi sanoat korxonalarida foydalanilayotgan sanoat tortish agregatlari parkining holati, ularning xizmat muddatlari haqida ma’lumotlarga ega bo‘lish. Bugungi kunda O‘zbekiston Respublikasi sanoat korxonalarida 70 dan ortiq PE2M, PE2U, MPE2U turidagi tortish agregatlaridan foydalanilmoqda va ularning 50% dan ortiq qismi o‘z xizmat muddatini o‘tab bo‘lgan. Ushbu turdagi tortish agregatlaridan “Olmaliq kon-metallurgiya kombinati” AJ, “O‘zbekko‘mir” AJ korxonalarida foydalaniladi. Ushbu korxonalar yaqin kelajakda o‘zlarining sanoat tortish agregatlari parkini yangilash yoki xizmat muddatini uzaytirish yo‘li orqali mavjud parkdan foydalanishlari mumkin bo‘ladi.
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Eshonkulov, Uchkun. "TEMIR TARKIBLI XOM ASHYODAN VA MA'DANLARDAN TEMIRNI AJRATIB OLISHNING TEXNOLOGIK O'LCHAMLARINI TADQIQ QILISH VA ANIQLASH." "Sanoatda raqamli texnologiyalar" ilmiy-texnik jurnal 1, no. 2 (2023): 64–69. https://doi.org/10.5281/zenodo.10333379.
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<i>Tajriba sanoat sinovlarida Olmaliq kon-metallurgiya kombinati aksiyadorlik jamiyati Mis boyitish fabrikasi chiqindilarini tiklovchi kuydirish orqali FeO, Fe2O3 va Fe3O4 minerallarini Fe gacha qaytarish, kuyindidan temirni magnitli separator yordamida ajratib olish hamda pirit boyitasini oksidlovchi kuydirib, magnitli separator yordamida magnitli zarralarni ajratib olish jarayoni amalga oshirildi.</i>
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Xudoyqulov, Sunnatjon Muxammad o'g'li. "KARYER VA XALQ XO'JALIGI AVTOMOBIL YO'LLARIDAGI CHANGLARNI BOSTIRUVCHI PREPARAT ISHLAB CHIQISH VA AMALIYOTGA QO'LLASH." Innovative Development in Educational Activities 2, no. 5 (2023): 377–85. https://doi.org/10.5281/zenodo.7743322.
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<em>Ushbu maqolada hozirgi kunda butun dunyoda ayniqsa kon – metallurgiya sanoatida avtomobil yo‘llaridagi asosiy muammolardan biri hisoblangan changlar, ularni bartaraf etish uchun mahalliy xomashyolar asosida chang bostiruvchi preparat ishlab chiqish va amalda qo‘llash natijalari keltirilgan.</em>
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Bakirov, Gayrat. "RUDA KONLARINI QAZIB OLISHDA RUDA YOQOTILISHINING SABABLAR, IQTISODIY AHAMYATI VA TASNIFI." "Sanoatda raqamli texnologiyalar" ilmiy-texnik jurnal 1, no. 2 (2023): 107–11. https://doi.org/10.5281/zenodo.10411902.
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<em>Maqolada foydali qazilma konlarini qazib olishda sanoat zaxirasining yo‘qotilishiga olib keladigan sabablar, yo‘qotilishining iqtisodiy ahamyati va uning konchilik korxonasining xizmat muddatiga ta’siri kabi omillar ko‘rib chiqilgan.</em>
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Abdullayev, Farxod. "QIZIL-OLMA SHAXTASIDA BURGALASH PORTLATISH ISHLARI." Results of National Scientific Research 1, no. 1 (2022): 276–81. https://doi.org/10.5281/zenodo.6509588.
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<em>Konchilik ishi insoniyat faoliyatining asosiy ko‘rinishlaridan biri bo‘lib, hayot darajasi va sivilizatsiyaning o‘sishini ta’minlaydi.</em> <em>Qazib olish tizimining yuqori unumdorligini va kon ishlari xavfsizligini tashkil etish uchun ishlar ketma –ketligining tug`ri tashkil etilishi, kesuvchi, ochuvchi va tajribaviy qidiruv kon laximlarini tugri olib borish natijasida maksimal unumdorlikga erishish mumkin.</em>
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Mavlonov, J. A., and D. Sh Mardonov. "RUDANI YANCHUVCHI TEGIRMONLARNI ELEKTR ENERGIYA SAMADORLIGINI OSHIRISH USULLARI." Gorniy vestnik Uzbekistana, no. 3(90) (August 31, 2022): 102–5. http://dx.doi.org/10.54073/gv.2022.3.90.025.
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Ushbu ishda sharli tegirmonlarning koʹp yillar davomida xom-ashyoni yanchishda kon-korxonalari va boyitish fabrikalarida togʹ jinsi oʹlchamlari uchun optimal boʹlaklar olishda ishlatilib kelinmoqda. Rudani tegirmon bilan yanchish jarayonida ko'plab kamchiliklar uchraydi. Masalan yanchishda har xil zichlikdagi rudalarni kelishi, yanchish vaqtining koʹpayishi va shunga oʹxshash bir qancha kam- chiliklar mavjud. Ularni bartaraf etish uchun yangi modernizatsiyalangan modellar va nazorat qilish tizimlari bilan jarayonni optimal- lashtirish, energiya isteʹmolini kamaytirish uchun eng maʹqul yechim hisoblanadi. Togʹ jinslariga ishlov berishda klassik texnologik usullar sanoat tomonidan yaxshi qabul qilingan boʹlsada, bugungi kundagi tadqiqotlar tegirmonlarning ichki dinamikasini tahlil qilish va nazorat qilishning yangi usullariga qaratilgan.
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Akbar, Shavkatovich Jurayev, Zuxra Muzaffar qizi Raxmatova, and Fotima Muzaffar qizi Raxmatova. "GIDRAVLIK TIZIMLARGA QULANILADIGAN G'OVAKLI FILTRNI EKSPEREMENT NATIJALARI." EURASIAN JOURNAL OF SOCIAL SCIENCES, PHILOSOPHY AND CULTURE 2, no. 4 (2022): 140–46. https://doi.org/10.5281/zenodo.6512307.
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Bugungi kunda tog’-kon sanoatida hamda qurilish sohasida ekspluatasiya qilinayotgan gidravlik ekskavatorlar ishchi suyuqligini g'ovakli filtrdan tozalash ishlarini chuqur o'rganish talab qilinmoqda.G’ovakli filtr bilan gidravlik ishchi suyuqlikni qatlamli tozalash va ishchi suyuqlikni qatlamsiz tozalash usullari ustida ishlab kelinmoqda.Gidravlik ekskavatorlarning samarali ishlashini taminlash uchun ekskavatorning ishchi suyuqligi muhim ahamiyatga ega. Bu maqolada dunyoda ekspluatasiya qilinayotgan gidravlik ekskavatorlarning ishchi suyuqligini fiktrlashni qatlamli va qatlamsiz usullari atroflicha taqqoslanib tadqiqod tahlilari qilingan. Respublikamizda ishlatilayotgan gidravlik ekskavatorlarning ishchi suyuqligini tozaligini ta’minlash uchun yuqoridagi natijalariga erishishning iqtisodiy samarasini ko`rish uchun filtrlarni mahalliylashtirishga doir ishlar olib borilgan.
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Raxmatova, Zuxra Muzaffar qizi, Fotima Muzaffar qizi Raxmatova, and Shavkatovich Jurayev Akbar. "GIDRAVLIK TIZIMLARNING EKSPLUATATSIYASI GIDRAVLIK EKSKAVATORINING UMUMIY ISHLASHIGA TA'SIRINI O'RGANISH." Zamonaviy dunyoda pedagogika va psixologiya 2, no. 17 (2022): 1–6. https://doi.org/10.5281/zenodo.6613120.
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Bugungi kunda konchilik sanoatida hamda qurilish sohasida ekspluatasiya qilinayotgan gidravlik ekskavatorlar ish unumdorligini chuqur o'rganish talab qilinmoqda. Gidravlik ekskavatorning 3 holatdagi unumdorligini alohida o`rganib taxlil qilish lozim. Nazariy, texnikaviy, ekspluatasiyali unumdorligi hisoblab ko`rish, unumdorligni oshirish foydalishi ishning oshishiga ta`sir ko`rsatadi. Gidravlik ekskavatorning ish qurilmalarining quvvatini effektiv ishlashi manba agregati va gidravlik yuritmaning to`g’ri tanlaganligiga bog’liq bo’ladi. Gidravlik ekskavatorlarning samarali ishlashini taminlash uchun umumiy ish holatiga asosiy ko’rsatgichi bilish zarur. Bu maqolada dunyoda ekspluatasiya qilinayotgan gidravlik kon ekskavatorlarga gidravlik tizimlar ekspluatatsiyasining tasirini atroflicha taqqoslanib tadqiqod tahlilari qilingan.
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Kurbonov, Faxriddin Bobomuratovich, Ro'zigul To'xtayevna Safarova, Zulxumor Ergashevna Jumaeva, and Hulkar Eshonqulova. "Surxondaryo viloyati ochik suv xavzalarini ifloslanish manbalari va suv manbalarining xozirgi ekologik xolati." JOURNAL OF UNIVERSAL SCIENCE RESEARCH 1, no. 4 (2023): 368–72. https://doi.org/10.5281/zenodo.7838784.
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Sanoat korxonlarning oqova suvlarini o‘rganish juda muhim chunki, tabiiy suvlar ifloslanishi tirik organizmlar va atrof-muhitga salbiy ta'siri ortib bormoqda. Surxondaryo viloyatidagi Xandiza koni oqova suvlari tarkibidagi mikroelementlar, og‘ir metallar va uning muhiti spektrofotometrik usulda o‘rganildi. Suvlarning tarkibida temir, qo‘rg‘oshin, rux, mis metallari ionlarining miqdori yuqori ekanligi aniqlandi. Aniqlangan ko‘rsatgichlarga asoslanib keyingi ishlarni amalga oshirish uchun vazifalar belgilanib olindi.
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Raxmatova, Fotima Muzaffar qizi, and Shavkatovich Jurayev Akbar. "GIDRAVLIK EKSKAVATORNING GIDRAVLIK TIZIMIDAGI BOSIM YO'QOTILISHLARNING NAZARIY TAXLILI." Zamonaviy dunyoda pedagogika va psixologiya 2, no. 17 (2022): 7–14. https://doi.org/10.5281/zenodo.6613148.
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Bugungi kunda konchilik sanoatida hamda qurilish sohasida ekspluatasiya qilinayotgan gidravlik ekskavatorlar ish unumdorligini chuqur o'rganish talab qilinmoqda.Gidravlik ekskavator kovushning harakatida rukoyat gidrosilindirining harakatidagi gidravlik tizimida ishtirok etgan barcha qismlar, uchastkalarning umumiy bosim yo’qotolishini nosozliklar daraxti bilan ta’sir etish ehtimolini tadqiqodini natijasida asoslash gidravlik ekskavatorning umumiy ish ko’rsatgichiga gidravlik tizimning ta’siri tadqiqod qilishda gidro tizimning uzida salbiy faktorlar ta’sir qilmasdan o’zida bo’ladigan yo’qotilishdagi jarayonlarni o’rganiladi.Gidravlik ekskavatorning ish qurilmalarining quvvatini effektiv ishlashi manba agregati va gidravlik yuritmaning to`g’ri tanlaganligiga bog’liq bo’ladi. Gidravlik ekskavatorlarning samarali ishlashini taminlash uchun umumiy ish holatiga asosiy ko’rsatgichi bilish zarur. Bu maqolada dunyoda ekspluatasiya qilinayotgan gidravlik kon ekskavatorlarga gidravlik tizimlar ekspluatatsiyasining tasirini atroflicha taqqoslanib tadqiqod tahlilari qilingan.
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Umarova, Munavvarxon, Mirzoqulova Xushnoza, Yoldashaliyeva Dinara, and Maftuna Sodiqova. "PAXTA TOZALASH KORXONALARIDA ZAMONAVIY AXBOROT KOMMUNIKATSION TEXNOLOGIYALARNI JORIY ETISHDAGI TAJRIBALAR TAHLILI." Journal of Science-Innovative Research in Uzbekistan 3, no. 5 (2025): 393–98. https://doi.org/10.5281/zenodo.15508984.
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Mazkur maqolada paxta tozalash korxonalarining ishlab chiqarish jarayoniga zamonaviy axborot-kommunikatsiya texnologiyalarini (AKT) joriy etish borasidagi amaliy tajribalar tahlil qilinadi. Jumladan, xom ashyo qabul qilish, og‘irlikni aniqlash, namlikni baholash va tashkiliy boshqaruv bosqichlarida ID plastik kartalardan foydalanish, operator va dispetcher o‘rtasidagi ma’lumotlar almashinuvi, avtomatlashtirilgan "KOD" tizimi, "Brutto" ko‘rsatkichlarini real vaqt rejimida qayd etuvchi elektron tarozilarni qo‘llash kabi yechimlarning samaradorligi yoritilgan. Shuningdek, mazkur texnologiyalarni joriy etish natijasida korxonalarda mehnat unumdorligi, hisob-kitob aniqligi va inson omiliga bog‘liq xatoliklarning kamayishi holatlari muayyan misollar asosida tahlil qilingan. Tadqiqotda mavjud tizimning axborot xavfsizligi, operatorlar malakasini oshirish va texnik infratuzilmani takomillashtirish masalalari ham ko‘rib chiqilgan. Ushbu texnologik yondashuv paxta sanoatida raqamli transformatsiyaning muhim bosqichi sifatida baholanadi.
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Yang, Guang, Jinhua Wang, Xia Liu, et al. "A Novel HCK and BTK Dual Inhibitor Kin-8194 Shows Superior Activity over Ibrutinib and Overcomes BTKC481S Mediated Ibrutinib Resistance in Vitro and In Vivo in MYD88 Mutated B-Cell Lymphomas." Blood 134, Supplement_1 (2019): 394. http://dx.doi.org/10.1182/blood-2019-130636.
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Activating mutations in MYD88 promote malignant cell growth and survival through multiple pathways that include BTK and HCK. HCK is transcriptionally upregulated and activated by mutated MYD88 and in turn activates BTK itself, as well as ERK and AKT. Ibrutinib is a covalent inhibitor that binds to BTKCys481 and shows activity in MYD88 mutated B-cell malignancies, including WM, MZL, ABC DLBCL, and PCNSL. Resistance to ibrutinib on the basis of BTKCys481 as well as downstream mutations is increasingly being recognized. We therefore sought to develop potent and selective inhibitors that target HCK. We developed a non-covalent dual inhibitor, KIN-8194, of HCK and BTK following a screen &gt;220 clinical and preclinical kinase inhibitors, and lead optimization following synthesis &gt;400 analogs. Dual HCK and BTK inhibition was confirmed by both KINOMEscan® and live-cell target engagement studies (KiNativ™ profiling and live cell ATP-biotin competition assay). KIN-8194 showed robust suppression of HCK (IC50&lt;0.495nM) and BTK (IC50=0.915nM) in these studies, and blocked pHCK and pBTK in both wild-type and mutated BTKCys481 WM and ABC DLBCL cells, and primary WM cells. Importantly, KIN-8194 showed selective killing of MYD88 mutated WM and ABC DLBCL cells and overcame resistance to ibrutinib in WM and ABC DLBCL cells engineered to express mutated BTKCys481. KIN-8194 showed excellent microsomal stability across multiple species including human (T1/2=49.5 minutes). Pharmacokinetic studies in mice showed excellent bioavailability (F=55%), serum half-life (T1/2=15.1 hours) and drug clearance (CL=17.4mL/min/kg) amenable to once daily oral dosing. The compounds exhibited an excellent in vitro safety profiling including no relevant inhibition observed against a panel of 100 other receptor targets, including hERG, AMES was negative up to 50 µM, and Cyp inhibition studies showed acceptable inhibition up to 10 µM. Pharmacodynamic studies following oral administration showed that KIN-8194 blocked both pHCK and pBTK in wild-type and mutated BTKCys481 expressing TMD8 ABC DLBCL cells engrafted in NOD SCID mice. Continuous dosing up to 100 mg/kg was well tolerated in these mice. KIN-8194 treated NOD SCID mice xenografted with either wild-type (A) or mutated (B) BTKCys481 TMD cells (N=8/cohort) showed superior tumor growth suppression and survival over vehicle control or ibrutinib treated mice at 50 mg/kg. Among wild-type BTKCys481 TMD8 xenografted mice treated for 6 weeks, elimination of tumor was observed in half the mice with no subsequent growth following 12 additional weeks of observation, consistent with a cure. We therefore describe a novel, highly potent non-covalent dual HCK and BTK inhibitor that is well tolerated in mice, shows selective killing of MYD88 mutated WM and ABC DLBCL cells, and can overcome mutated BTKCys481 related ibrutinib resistance. Disclosures Hunter: Janssen: Consultancy. Castillo:Beigene: Consultancy, Research Funding; TG Therapeutics: Research Funding; Abbvie: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Gray:Gatekeeper, Syros, Petra, C4, B2S and Soltego.: Equity Ownership; Novartis, Takeda, Astellas, Taiho, Janssen, Kinogen, Voronoi, Her2llc, Deerfield and Sanofi.: Equity Ownership, Research Funding. Treon:Pharmacyclics: Research Funding; BMS: Research Funding; Janssen: Consultancy.
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Qayumova, Nargiza Abdurasul qizi. "SUG'ORISH NASOS STANSIYALARINING ENERGETIK SAMARADORLIGINI OSHIRISH USULLARI." Innovative Development in Educational Activities 1, no. 8 (2022): 317–22. https://doi.org/10.5281/zenodo.7397207.
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Ushbu maqolada, adabiyotlarni tahlil qilish natijasida energiyani tejash va nasos agregatlarining elektr yuritmalarining elektr energiyasidan foydalanish samaradorligini oshirish tartibga solinmagan elektr yuritmadan tartibga solinadiganga o‘tish va chastota bilan boshqariladigan elektr yuritmani joriy etish eng oqilona ekanligi ko‘rsatilgan.
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Munshi, Manit, Xia Liu, Amanda Kofides, et al. "A New Role for the SRC Family Member HCK As a Driver of BCR/SYK Signaling in MYD88 Mutated Lymphomas." Blood 138, Supplement 1 (2021): 3512. http://dx.doi.org/10.1182/blood-2021-153610.
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Abstract Activating mutations in MYD88 (MYD88 Mut) are common in B-cell malignancies including Waldenstrom Macroglobulinemia (WM) and ABC subtype of diffuse B-cell lymphoma (ABC DLBCL). MYD88 is a component of the Toll-like receptor (TLR) pathway. We and others previously showed that MYD88 Mut triggers assembly of a "Myddosome" complex that leads to downstream pro-survival signaling that includes IRAK4/IRAK1 and BTK triggered NF-κB (Ngo et al, Nature 2011; Treon et al, NEJM 2012; Yang et al, Blood 2013) and HCK mediated BTK/NF-κB, PI3K/AKT, and MAPK/ERK signaling (Yang et al, Blood 2016; Liu et al Blood Adv. 2020). The activation of the B-cell receptor (BCR) signaling component SYK has also been observed in MYD88 Mut WM (Argyropoulos et al, Leukemia 2016). In ABC DLBCL, chronic active BCR signaling underlies SYK activation that is triggered by the SRC family member LYN (Davis et al, Nature 2010). These observations led us to explore potential drivers of BCR/SYK activation in WM. We previously reported that MYD88 Mut triggered activation of SYK in WM and ABC DLBCL cells (Munshi et al, BCJ 2020). Herein, we investigated if HCK, a SRC family member that is transcriptionally upregulated and activated by MYD88 Mut could trigger the BCR pathway through SYK activation. Since LYN is an integral part of BCR signaling, we first examined its expression and activation state in MYD88 Mut WM and ABC DLBCL cells. While MYD88 Mut TMD8, HBL-1 and OCI-Ly3 ABC DLBCL cells showed strong expression of p-LYN, such expression was absent or low in MYD88 Mut BCWM.1 and MWCL-1 cells, as well as CD19-selected bone marrow derived primary lymphoplasmacytic cells (LPCs) from WM patients. In view of the above findings, we next interrogated a direct role for HCK in mediating SYK activation. We over-expressed wild-type HCK (HCK WT) or gatekeeper mutated HCK (HCK T333M) in MYD88 Mut BCWM.1 and MWCL-1 WM cell lines, and TMD8 ABC DLBCL cells. In all these cell lines, over-expression of HCK WT or HCK T333M triggered a robust increase in phosphorylation of SYK Y525/Y526 in comparison to vector only transduced cells. Moreover, using an inducible vector system, knockdown of HCK showed a marked reduction in phosphorylation of SYK Y525/Y526 in MYD88 Mut BCWM.1 WM and TMD8 ABC DLBCL cells. We next sought to clarify if HCK and activated SYK were present in the same signaling complex. We performed co-immunoprecipitation experiments using an HCK antibody in MYD88 Mut BCWM.1, TMD8 and wild-type MYD88 (MYD88 WT) Ramos cells. The HCK antibody effectively pulled down p-SYK in MYD88 Mut BCWM.1 and TMD8 cells, but not in MYD88 WT Ramos cells. To confirm whether SYK activation was a result of HCK kinase activity, we next performed rescue experiments with the HCK inhibitors A419259 and KIN-8194 in MYD88 Mut BCWM.1 and MWCL-1 WM and TMD8 ABC DLBCL cells expressing either HCK WT or the HCK T333M protein that abrogated the activity of these inhibitors against HCK. Expression of the HCK T333M protein produced marked resistance to A419259 as well as KIN-8194 versus vector or HCK WT transduced BCWM.1 and MWCL-1 cells. By PhosFlow analysis, we observed that expression of HCK T333M but not HCK WT led to persistent activation of HCK and SYK in the presence of A419259 or KIN-8194 in BCWM.1 and MWCL-1 WM cells, and TMD8 ABC DLBCL cells. Consistent with these observations, treatment of primary MYD88 mutated WM LPCs cells with either A419259 or KIN-8194 also showed marked reduction in both p-HCK and p-SYK expression by PhosFlow analysis. Taken together, our findings show that SYK is activated by HCK in MYD88 Mut B-cell lymphomas cells; broaden the pro-survival signaling generated by aberrant HCK expression in response to MYD88 Mut; and help further establish HCK as an important therapeutic target in MYD88 Mut B-cell lymphomas. Disclosures Palomba: Juno: Patents & Royalties; Rheos: Honoraria; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Notch: Honoraria, Other: Stock; Kite: Consultancy; Novartis: Consultancy; BeiGene: Consultancy; Priothera: Honoraria; Nektar: Honoraria; PCYC: Consultancy; Wolters Kluwer: Patents & Royalties; WindMIL: Honoraria; Magenta: Honoraria; Pluto: Honoraria; Lygenesis: Honoraria; Ceramedix: Honoraria. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding. Gray: Syros, C4, Allorion, Jengu, B2S, Inception, EoCys, Larkspur (board member) and Soltego (board member: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Takeda, Astellas, Taiho, Jansen, Kinogen, Arbella, Deerfield and Sanofi: Research Funding. Munshi: Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Abbvie: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy; Adaptive Biotechnology: Consultancy; Novartis: Consultancy; Legend: Consultancy; Pfizer: Consultancy. Anderson: Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees. Yang: Blueprint Medicines Corporations: Current Employment, Current holder of individual stocks in a privately-held company. Treon: BeiGene: Consultancy, Research Funding; Eli Lily: Research Funding; Abbvie/Pharmacyclics: Consultancy, Research Funding.
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Taylor, P. C., A. Kavanaugh, P. Nash, et al. "AB0290 EFFECT OF FILGOTINIB ON PAIN IN PATIENTS WITH RHEUMATOID ARTHRITIS IN THE PHASE 3 FINCH 1, 2 AND 3 STUDIES." Annals of the Rheumatic Diseases 82, Suppl 1 (2023): 1326.2–1327. http://dx.doi.org/10.1136/annrheumdis-2023-eular.1316.
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BackgroundPatients (pts) with rheumatoid arthritis (RA) often experience substantial pain despite treatment, and pain control is considered an important treatment outcome. The FINCH 1–3 studies demonstrated the efficacy and acceptable safety of the preferential Janus kinase (JAK) 1 inhibitor filgotinib (FIL) in pts living with RA.ObjectivesThispost-hocanalysis of the FINCH studies assessed specific effects of FIL on pain.MethodsFINCH 1–3 (NCT02889796,NCT02873936,NCT02886728) were Phase 3, randomized, double-blind trials of FIL 100 mg and 200 mg (FIL100/200). In FINCH 1, pts with an inadequate response (IR) to methotrexate (MTX) received FIL, adalimumab (ADA) or placebo (PBO) + MTX for 52 weeks. In FINCH 2, pts with an IR to biologic disease-modifying anti-rheumatic drugs (DMARDs) received FIL or PBO + conventional synthetic DMARDs for 24 weeks. In FINCH 3, MTX-naïve pts received FIL ± MTX or MTX for 52 weeks.For each treatment group, pts reported pain on a 100-mm visual analog scale (VAS). Scores of ≤10 mm reflected limited to no pain; scores of ≤20 mm indicated health status was not negatively affected by pain.[1]Time to first VAS score of ≤10 mm was assessed. The proportion of pts who achieved remission (as per Disease Activity Score 28 with C-reactive protein [DAS28-CRP] <2.6 or Clinical Disease Activity Index [CDAI] ≤2.8) at Week 24 was evaluated. Of pts who achieved DAS28-CRP or CDAI remission, the proportion who also reported VAS pain scores of ≤10 mm or ≤20 mm was determined.ResultsIn FINCH 1, there was a higher probability of achieving a VAS pain score of ≤10 mm with FIL200, vs ADA + MTX or PBO + MTX; responses were better or comparable with FIL100 vs other treatment arms (Figure 1). Similar findings were observed in FINCH 2 and 3 for FIL vs PBO and MTX, respectively. In FINCH 1, the proportion of pts achieving DAS28-CRP remission was greater with FIL200 + MTX (48.4%) and comparable for the FIL100 + MTX (35.2%) vs ADA + MTX arms (35.7%;Table 1). Further, the proportion of pts who achieved VAS pain scores of ≤10 mm and ≤20 mm in addition to DAS28-CRP remission was 26.3% and 35.8%, respectively, in the FIL200 + MTX group, compared with 17.2% and 24.6% in the ADA + MTX group (Table 1). In FINCH 2 and 3, a greater proportion of pts in the FIL groups achieved remission vs the PBO or MTX arms, respectively. A greater proportion of pts achieved pain responses in addition to DAS28-CRP remission in the FIL groups of FINCH 2 and FINCH 3 compared with PBO or MTX, respectively. Findings were similar when CDAI remission was assessed.ConclusionFIL positively affected pain parameters across the FINCH studies as early as Week 2, with responses sustained over time (up to Week 52 [FINCH 1 and 3] and Week 24 [FINCH 2]). In FINCH 1, FIL200 had a particularly favorable impact when pain response and remission were assessed together. Similar findings were seen with FIL compared with PBO and MTX in FINCH 2 and 3, respectively. These findings suggest that JAK inhibition may offer potential added value with respect to patient-reported pain outcomes when treat-to-target goals are met.Reference[1] Taylor PC, et al. J Clin Med 2019;8:831Table 1.Disease response and improvement in VAS pain score (up to Week 24)FINCH 1FIL200 + MTX (n=475)FIL100 + MTX (n=480)ADA + MTX (n=325)PBO + MTX (n=475)DAS28-CRP remission230 (48.4)169 (35.2)116 (35.7)77 (16.2) With VAS ≤10 mm125 (26.3)86 (17.9)56 (17.2)36 (7.6) With VAS ≤20 mm170 (35.8)120 (25.0)80 (24.6)55 (11.6)FINCH 2FIL200 + MTX (n=147)FIL100 + MTX (n=153)PBO (n=148)DAS28-CRP remission45 (30.6)40 (26.1)18 (12.2) With VAS ≤10 mm23 (15.6)19 (12.4)8 (5.4) With VAS ≤20 mm32 (21.8)27 (17.6)10 (6.8)FINCH 3FIL200 + MTX (n=416)FIL100 + MTX (n=207)FIL200 (n=210)MTX (n=416)DAS28-CRP remission225 (54.1)88 (42.5)89 (42.4)121 (29.1) With VAS ≤10 mm138 (33.2)57 (27.5)49 (23.3)62 (14.9) With VAS ≤20 mm169 (40.6)64 (30.9)68 (32.4)79 (19.0)ADA, adalimumab; DAS28-CRP, Disease Activity Score-28 with C-reactive protein; FIL(100/200), filgotinib (100/200 mg); MTX, methotrexate; PBO, placebo; VAS, visual analog scale.AcknowledgementsThe authors thank the physicians and patients who participated in the studies. The studies were funded by Gilead Sciences (Foster City, CA, USA) and Galapagos NV (Mechelen, Belgium). Publication coordination was provided by Fabien Debailleul, PhD, of Galapagos NV. Writing support was provided by Debbie Sherwood, BSc, CMPP (Aspire Scientific, Bollington, UK), and was funded by Galapagos NV.Disclosure of InterestsPeter C. Taylor Speakers bureau: AbbVie, Consultant of: AbbVie, Biogen, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, Nordic Pharma, Pfizer, Sanofi, UCB Pharma, Grant/research support from: Galapagos, Arthur Kavanaugh Consultant of: AbbVie, Amgen, BMS, Janssen, Novartis, Pfizer, UCB, Peter Nash Speakers bureau: AbbVie, Amgen, BMS, Celgene, Gilead/Galapagos, Janssen, Lilly, Novartis, Pfizer, Consultant of: AbbVie, Amgen, BMS, Celgene, Gilead/Galapagos, Janssen, Lilly, Novartis, Pfizer, Grant/research support from: AbbVie, Amgen, BMS, Celgene, Gilead/Galapagos, Janssen, Lilly, Novartis, Pfizer, Janet Pope: None declared, Georg Pongratz Speakers bureau: AbbVie, Boehringer, Lilly, Pfizer, Roche, Sanofi, Paid instructor for: Lilly, Roche, Consultant of: AbbVie, Boehringer, Galapagos, Lilly, Pfizer, Roche, Bruno Fautrel Consultant of: AbbVie, Amgen, Biogen, BMS, Celgene, Celltrion, Fresenius Kabi, Gilead, Janssen, Lilly, Medac, MSD, Mylan, Nordic Pharma, Novartis, Pfizer, Roche, Sandoz, Sanofi-Genzyme, Sobi, UCB, Grant/research support from: AbbVie, Lilly, MSD, Pfizer, Rieke Alten Consultant of: AbbVie, Amgen, Biogen, BMS, Celltrion, Gilead, Janssen, Lilly, Medac, MSD, Mylan, Novartis, Pfizer, Roche, Sandoz, Sanofi-Genzyme, UCB, Viatris, Ken Hasegawa Shareholder of: Gilead, Employee of: Gilead, Shangbang Rao Employee of: Gilead, Dick de Vries Shareholder of: Galapagos, Employee of: Galapagos, Pieter-Jan Stiers Employee of: Galapagos, Chris Watson Shareholder of: Galapagos, Employee of: Galapagos, Rene Westhovens Speakers bureau: Celltrion, Galapagos, Gilead, Consultant of: Celltrion, Galapagos, Gilead.
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Baraliakos, X., S. Tsiami, C. Rischpler, et al. "SAT0365 EFFECTS OF ANTI-TNF-THERAPY ON OSTEOBLASTIC ACTIVITY IN ANKYLOSING SPONDYLITIS – RESULTS FROM A PROSPECTIVE STUDY USING PET-MRI OF SIJ AND SPINE." Annals of the Rheumatic Diseases 79, Suppl 1 (2020): 1129.2–1130. http://dx.doi.org/10.1136/annrheumdis-2020-eular.5573.
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Background:The clinical efficacy of tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (axSpA) is well established but its effect on new bone formation is still unclear (1). Positron emission tomography (PET) using bone-seeking18F-Fluoride [18F]F in combination with magnetic resonance imaging ([18F]F /MRI) has been shown to depict not only bone marrow edema (BME) but also shows the quantity of tracer uptake in the late phase of perfusion suggestive of remodeling and osteoblastic activity, not only in radiographic axSpA (r-axSpA) (2).Objectives:Assess the effect of TNFi on bone remodeling processes in the axial skeleton of r-axSpA patients using [18F]F/MRI prior (baseline, BL) and 4 months after (follow-up, FU) treatment.Methods:Patients (11 male, 5 female, mean age 38.6±12.0 years) with clinically active r-axSpA (BASDAI>4, failure of NSAIDs, no previous biologics) prospectively underwent 3-Tesla and [18F]F PET/MRI (40 minutes after injection of a mean activity of 157 MBq [18F]F). Images of the SIJ (n=16 patients) and the whole spine (n=10 patients) were performed at BL and FU. Three readers (1 for [18F]F/MRI and 2 for conventional MRI) evaluated all images independently and blinded to timepoint allocation. Only lesions on which all readers agreed on were used for further analyses. Inflammation (bone marrow edema, BME), structural lesions (fat deposition (FD), sclerosis, erosions and ankylosis) and focal [18F]F uptake were recorded on the level of SIJ (SIJ-Q) and vertebral quadrants (V-Q), with each SIJ or vertebral body consisting of 4 VQs (superior and inferior sacral and iliac for the SIJ, and superior and inferior, anterior and posterior for the vertebral bodies).Results:A total of 128 SIJ-Q and 920 VQs were analyzed at both BL and FU. In the SIJs, 75 (58.6%), 120 (93.8%), 69 (53.9%), 99 (77.3%) and 16 (12.5%) SIJ-Q showed BME, FD, sclerosis, erosions and ankylosis, while 111 (86.7%) SIJ-Q showed focal [18F]F-uptake at BL. Association with increased [18F]F-uptake was found most frequently in SIJ-Q with BME (70/75 SIJ-Q, 93.3%), sclerosis (65/69 SIJ-Q, 94.2%) and FD (105/120 SIJ-Q, 87.5%). At FU, 37 SIJ-Q still showed BME (improvement by 50.7%), while almost no changes were observed in chronic lesions. In comparison, improvement of focal [18F]F-uptake was found in all lesion combinations, with improvement of focal [18F]F-lesions associated with BME by 62.9%, with sclerosis by 33.8% and with FD by 22.9% of SIJ-Q.In the spine, only 41 (4.5%), 61 (6.6%), 14 (1.5%) V-Q showed BME, FD and sclerosis, respectively, while 77 V-Q (8.4%) showed focal [18F]F-uptake. An association to increased [18F]F-uptake was found most frequently with sclerosis (7/14 V-Q, 50%) and FD (25/61 V-Q, 41%). At FU, 12 V-Q still showed BME (improvement by 70.7%), while, similar to SIJ, almost no changes were observed in the chronic lesions. The largest improvement was found in focal [18F]F-lesions associated with BME 81.8% and with FD by 22.9% of V-Q.Conclusion:In this first prospective study on whole spine and SIJ [18F]F/MRI in patients with r-axSpA, a significant decrease of osteoblastic activity was observed over 4 months of continuous anti-TNF treatment. The effect of treatment was observed not only at sites with inflammatory lesions (BME) but also at sites with pre-existing chronic structural lesions, while some osteoblastic activity remained visible at 4 months. These data support a short-term effect of anti-TNF treatment on osteoblastic activity, while the long-term effects need to be further studied.References:[1]Van der Heijde D et al, Ann Rheum Dis 2017[2]Buchbender C et al, J Rheumatol 2015This work was supported by an unrestricted Grant by MSD GmbH, GermanyDisclosure of Interests:Xenofon Baraliakos Grant/research support from: Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Consultant of: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Styliani Tsiami: None declared, Christoph Rischpler: None declared, Nils-Martin Bruckmann: None declared, Wolfgang Fendler: None declared, Julian Kirchner: None declared, Ken Hermann: None declared, Lino Sawicki: None declared, Juergen Braun Grant/research support from: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, Eli Lilly and Company, Medac, MSD (Schering Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi- Aventis, and UCB Pharma, Consultant of: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Eli Lilly and Company, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, and UCB Pharma, Speakers bureau: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Eli Lilly and Company, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, and UCB Pharma
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Markman, J., S. Perrot, S. Ohtori, et al. "OP0090 EFFICACY OF SUBCUTANEOUS TANEZUMAB FOR THE TREATMENT OF CHRONIC LOW BACK PAIN: AN ANALYSIS OF BRIEF PAIN INVENTORY-SHORT FORM SCORES FROM A 56-WEEK, RANDOMIZED, PLACEBO- AND TRAMADOL-CONTROLLED, PHASE 3 TRIAL." Annals of the Rheumatic Diseases 79, Suppl 1 (2020): 59.1–60. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2970.
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Background:Tanezumab, a monoclonal antibody against nerve growth factor, was recently evaluated in an 80 week placebo and tramadol-controlled trial in patients with chronic low back pain (CLBP) and a history of inadequate response to standard-of-care analgesics (NSAIDs, opioids, etc). Primary endpoint was change in Low Back Pain Intensity (LBPI) at week 16 vs placebo. Key secondary endpoints were the proportion of patients with ≥50% improvement in LBPI at week 16, change in Roland Morris Disability Questionnaire score at week 16, and change in LBPI at week 2 (all vs placebo). Tanezumab 10mg met the primary and all key secondary endpoints. Tanezumab 5mg did not meet the primary endpoint, but improved 2 of 3 key secondary endpoints. Due to the primary endpoint result and the statistical gate-keeping approach to control for multiple comparisons, a conclusion of superiority over placebo could not be made for the 5mg dose.Objectives:To further characterize tanezumab’s effects on pain and function in this trial through analysis of Brief Pain Inventory-short form (BPI-sf) scores.Methods:Patients received placebo (n=406), subcutaneous (SC) tanezumab 5mg (every 8 weeks; n=407), SC tanezumab 10mg (every 8 weeks; n=407) or oral tramadol prolonged-release (100-300mg/day; n=605). Pre-specified secondary endpoints included BPI-sf worst pain, average pain, the overall pain interference index, and selected individual domains of the index (general activity, walking ability, sleep, and normal work). Least squares (LS) mean (standard error [SE]) changes from baseline in BPI-sf scores were compared between groups (unadjusted for multiplicity) at week 16 using an analysis of covariance model. Scores range from 0-10 with higher scores indicating greater pain severity or functional impairment.Results:LS mean (SE) differences from placebo for worst pain were -0.52 (0.19) for tanezumab 5mg (p≤0.01), -0.54 (0.19) for tanezumab 10mg (≤0.01), and -0.24 (0.17) for tramadol (p=0.17). LS mean (SE) differences from placebo for average pain were -0.37 (0.18) for tanezumab 5mg (p=0.04), -0.46 (0.18) for tanezumab 10mg (≤0.01), and -0.17 (0.16) for tramadol (p=0.29). LS mean (SE) differences from placebo for the pain interference index were -0.41 (0.18) for tanezumab 5mg (p=0.03), -0.58 (0.18) for tanezumab 10mg (≤0.01), and -0.15 (0.17) for tramadol (p=0.39). Effects of tanezumab were not statistically different (p>0.05) from tramadol for worst pain, average pain, and the pain interference index, with exception of the pain interference index for tanezumab 10mg (p=0.01). Mean dose of tramadol was 203mg/day at week 16.Tanezumab 10mg significantly (p<0.05) improved individual domains of the pain interference index (general activity, walking ability, sleep, and normal work) vs placebo and vs tramadol. Tanezumab 5mg significantly (p<0.05) improved pain interference with general activity and normal work vs placebo, and sleep vs placebo and vs tramadol. No statistical differences in any domain was observed for tramadol vs placebo.Conclusion:Tanezumab 5mg and 10mg significantly improved worst pain, average pain, and overall pain interference index scores vs placebo in patients with CLBP. Tanezumab 10mg also significantly improved the overall pain interference index vs tramadol. Tanezumab 5mg significantly improved most individual domains of the pain interference index vs placebo, while tanezumab 10mg significantly improved all domains assessed vs placebo and vs tramadol.Disclosure of Interests:John Markman Consultant of: Consultant: Trigemina, Editas Medicine, and Plasma Surgical; Advisory board: Clexio Biosciences, Flexion Therapeutics, Quark Pharmaceuticals, Quartet Medicine, Collegium Pharmaceutical, Purdue Pharma, Biogen, Novartis, Aptinyx, Nektar, Allergan, Grünenthal, Eli Lilly and Company, Depomed, Janssen Pharmaceuticals, Teva Pharmaceutical Industries, KemPharm, Abbott Laboratories, Plasma Surgical, Chromocell, Convergence Pharmaceuticals, Inspirion, Pfizer, Sanofi, Daiichi Sankyo, and Trevena; Data safety monitoring boards for Novartis and Allergan, Serge Perrot Consultant of: Grunenthal, Pfizer, Lilly, MSD, Sanofi, Menarini, Seiji Ohtori: None declared, Thomas Schnitzer Consultant of: Pfizer, Lilly, AstraZeneca, GSK, Said Beydoun Grant/research support from: Argenx, Catalyst Pharma, Mallinckrodt, Pfizer, UCB, Consultant of: Alexion, Akcea, Alnylam, CSL, Takeda, Mitsubishi Tanabe, Speakers bureau: Alexion, Akcea, Alnylam, CSL, Takeda, Mitsubishi Tanabe, Lars Viktrup Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Ruoyong Yang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Candace Bramson Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Christine West Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ken Verburg Shareholder of: Pfizer Inc, Employee of: Pfizer Inc
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Saiki, Ryunosuke, Yusuke Shiozawa, Tetsuichi Yoshizato, et al. "Integrated Analysis of Copy-Number Alterations and Gene Mutations in 2,000 Patients with Myeloid Neoplasms." Blood 134, Supplement_1 (2019): 4216. http://dx.doi.org/10.1182/blood-2019-132174.
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Background Copy-number alterations (CNAs) and gene mutations are hallmarks of cancer genomes, and they are implicated in the development of myeloid neoplasm. However, their relationships have not been fully examined. To address this issue, we have recently developed a novel, next-generation sequencing-based platform for copy-number analysis, which enabled us to detect mutations and CNAs simultaneously. We applied this platform to around 2,000 cases with myeloid neoplasms. Aims We aimed at delineating the landscape of CNAs and their relationships with gene mutations in myeloid neoplasms. Methods We examined 2,101 cases with myeloid neoplasms by whole-exome sequencing (WES) or targeted deep sequencing. Excluding 116 samples showing low qualities of copy-number signals, we performed subsequent analysis on the remaining 1,985 cases with myelodysplastic syndromes (MDS, n = 1,102), myelodysplastic/myeloproliferative neoplasms (MDS/MPN, n = 140), de novo acute myeloid leukemia (de novo AML, n = 448), and secondary AML (sAML, n = 295). In copy-number analysis, total copy numbers and allele-specific copy numbers (ASCNs) were quantified based on sequencing depths and allelic ratios on genome-wide probes. Copy-number signals were corrected for multiple biases (e.g. GC content, ASCN, and fragment length). We also validated the performance of this platform through comparison with SNP-array karyotyping data in 115 de novo AML cases. CNAs longer than 5 Mb were regarded as arm-level CNAs, and those shorter than 5 Mb were regarded as focal CNAs. Results In total, we identified 4,141 CNAs (52.9 % of cases with at least one CNA), and 3,863 mutations (73.9 % of cases with at least one mutation). Most frequent alterations included -7/del(7q) (13.2 %), del(5q) (11.4 %), trisomy 8 (7.2 %), and del(20q) (5.2 %), and mutations of TET2 (12 .3 %), TP53 (11.3 %), ASXL1 (10.1%), and DNMT3A (9.9 %). To evaluate the difference of copy-number landscapes between de novo AML and myelodysplasia (MDS, MDS/MPN, and sAML), we compared the frequencies of CNAs between them. Uni-parental disomy (UPD) of 13q (FLT3) and 11p (WT1), and amplifications of 11q, 13q, and 21q (ERG) were more enriched in de novo AML, while der(1;7), UPD of 11q (CBL), and del(20q) were enriched in myelodysplasia, suggesting differential involvements of CNAs. We next analyzed the correlations between CNA profiles and prognosis in cases with myelodysplasia. Since TP53 status implies a large impact on both patients' prognosis and CNA profiles, we separately analyzed TP53-positive (n = 53) and negative (n = 686) cases with available survival data. In TP53-negative cases, -7/7qLOH (Hazard ratio(HR): 2.28, q < 0.001), and UPD of 11q (CBL) (HR: 2.60, q = 0.0034) significantly correlated with shorter overall survivals (OS), while, in TP53-positive cases, amp(11q), +19, and amp(21q) were marginally associated with shorter OS. To delineate the relationships between CNAs and mutations, we interrogated correlations between both lesions among MDS cases without TP53 alterations (n = 937). A number of significant correlations were detected, such as those between trisomy 8 and del(20q) with U2AF1 mutations (q < 0.05, for each), and monosomy 7 and amp(21q) with mutations of RUNX1 and NRAS (q < 0.01, for each). These correlations were also revealed in clustering analysis based on CNA and mutation profiles, which identified 5 unique clusters: Cluster 1 (n = 171) with trisomy 8, del(20q), and mutations of U2AF1 and ETV6, Cluster 2 (n = 43) with monosomy 7, amp(21q), and mutations of NRAS, SETBP1, and RUNX1, Cluster 3 (n = 19) with amp(1q) and amp(3q), Cluster 4 (n = 127) with those of SF3B1, TET2, and DNMT3A, and Cluster 5 (n = 50) with those of SRSF2, STAG2, ASXL1, and RUNX1. The remaining 527 cases were not assigned into any cluster due to lack of significantly correlated alterations. Finally, the temporal relationships of coexisting alterations were estimated based on their cell fractions; monosomy 7 had significantly greater cell fractions (P = 0.031) and is predicted to precede NRAS mutations, while the cell fractions of U2AF1 mutations tended to be greater than those of trisomy 8 (P = 0.063), suggesting their implications in different stages of disease progression. Conclusion An integrated analysis of CNAs and mutations in >2,000 cases revealed the impacts of CNAs on disease characteristics and provided novel insight into the interplay between CNAs and mutations in the pathogenesis of MDS. Figure Disclosures Atsuta: CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria. Kanda:Celgene: Consultancy, Research Funding; Novartis: Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Taiho: Research Funding; Asahi-Kasei: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; CSL Behring: Research Funding; Taisho-Toyama: Research Funding; Tanabe Mitsubishi: Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Takara-bio: Consultancy, Honoraria; Novartis: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Pfizer: Research Funding; Asahi-Kasei: Research Funding; Alexion: Consultancy, Honoraria; CSL Behring: Research Funding; Takara-bio: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Taiho: Research Funding; Celgene: Consultancy, Research Funding; Tanabe Mitsubishi: Research Funding; Taisho-Toyama: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Otsuka: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Saunthararajah:EpiDestiny: Consultancy, Equity Ownership, Patents & Royalties; Novo Nordisk: Consultancy. Miyazaki:Chugai: Research Funding; Otsuka: Honoraria; Novartis: Honoraria; Nippon-Shinyaku: Honoraria; Dainippon-Sumitomo: Honoraria; Kyowa-Kirin: Honoraria. Usuki:Boehringer-Ingelheim Japan: Other: Received Research ; Daiichi Sankyo: Other: Received Research ; SymBio Pharmaceuticals Limited.,: Other: Received Research ; Novartis: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau; Takeda Pharmaceutica: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Mochida Pharmaceutical: Speakers Bureau; MSD K.K.: Speakers Bureau; Celgene Corporation: Other: Received Research , Speakers Bureau; Sumitomo Dainippon Pharma: Other: Received Research , Speakers Bureau; Pfizer Japan: Other: Received Research ; Stellas Pharma: Other: Received Research ; Otsuka: Other: Received Research ; Kyowa Kirin: Other: Received Research ; GlaxoSmithKline K.K.: Other: Received Research ; Sanofi K.K.: Other: Received Research ; Shire Japan: Other: Received Research ; Janssen Pharmaceutical K.K: Other: Received Research . Imada:Bristol-Meyer Squibb K.K.: Honoraria; Celgene K.K.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Kyowa Hakko Kirin Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Novartis Pharma K.K.: Honoraria; Takeda Pharmaceutical Co.,LTD.: Honoraria; Nippon Shinyaku Co.,Ltd.: Honoraria. Takaori-Kondo:Kyowa Kirin: Research Funding; Pfizer: Honoraria; Janssen: Honoraria; Chugai: Research Funding; Takeda: Research Funding; Ono: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria, Research Funding. Kiguchi:Celltrion, Inc.: Research Funding; Astellas Pharmaceutical Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; MSD CO., Ltd.: Research Funding; Novartis Pharmaceutical Co., Ltd.: Research Funding; Sumitomo Dainippon Pharmaceutical Co., Ltd.: Research Funding; Bristol-Myeres Squibb Co., Ltd.: Research Funding; Janssen Pharmaceutical Co., Ltd.: Research Funding; Celgene Co., Ltd.: Research Funding; SymBio Pharmaceutical Co., Ltd.: Research Funding; Taiho Pharmaceutical Co., Ltd.: Research Funding; Tejin Co., Ltd.: Research Funding; Sanofi K.K., Ltd.: Research Funding. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. Ogawa:Asahi Genomics: Equity Ownership; Qiagen Corporation: Patents & Royalties; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding; RegCell Corporation: Equity Ownership; ChordiaTherapeutics, Inc.: Consultancy, Equity Ownership; Kan Research Laboratory, Inc.: Consultancy.
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Mitra, Amit Kumar, Ujjal Mukherjee, Taylor Harding, et al. "Scattome: A Single-Cell Analysis of Targeted Transcriptome Program to Predict Drug Sensitivity of Single Cells within Human Myeloma Tumors." Blood 126, no. 23 (2015): 4249. http://dx.doi.org/10.1182/blood.v126.23.4249.4249.
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Abstract Multiple myeloma (MM) is characterized by significant genetic diversity at subclonal levels that likely plays a defining role in the heterogeneity of tumor progression, clinical aggressiveness and drug sensitivity. Such heterogeneity is a driving factor in the evolution of MM, from founder clones through outgrowth of subclonal fractions. DNA Sequencing studies on MM samples have indeed demonstrated such heterogeneity in subclonal architecture at diagnosis based on recurrent mutations in pathologically relevant genes that may ultimately to lead to relapse. However, no study so far has reported a predictive gene expression signature that can identify, distinguish and quantify drug sensitive and drug-resistant subpopulations within a bulk population of myeloma cells. In recent years, our laboratory has successfully developed a gene expression profile (GEP)-based signature that could not only distinguish drug response of MM cell lines, but also was effective in stratifying patient outcomes when applied to GEP profiles from MM clinical trials using proteasome inhibitors (PI) as chemotherapeutic agents. Further, we noted myeloma cell lines that responded to the drug often contained residual sub-population of cells that did not respond, and likely were selectively propagated during drug treatment in vitro, and in patients. In this study, we performed targeted qRT-PCR analysis of single cells using a gene panel that included PI sensitivity genes and gene signatures that could discriminate between low and high-risk myeloma followed by intensive bioinformatics and statistical analysis for the classification and prediction of PI response in individual cells within bulk multiple myeloma tumors. Fluidigm's C1 Single-Cell Auto Prep System was used to perform automated single-cell capture, processing and cDNA synthesis on 576 pre-treatment cells from 12 cell lines representing a wide range of PI-sensitivity and 370 cells from 7 patient samples undergoing PI treatment followed by targeted gene expression profiling of single cells using automated, high-throughput on-chip qRT-PCR analysis using 96.96 Dynamic Array IFCs on the BioMark HD System. Probability of resistance for each individual cell was predicted using a pipeline that employed the machine learning methods Random Forest, Support Vector Machine (radial and sigmoidal), LASSO and kNN (k Nearest Neighbor) for making single-cell GEP data-driven predictions/ decisions. The weighted probabilities from each of the algorithms were used to quantify resistance of each individual cell and plotted using Ensemble forecasting algorithm. Using our drug response GEP signature at the single cell level, we could successfully identify distinct subpopulations of tumor cells that were predicted to be sensitive or resistant to PIs. Subsequently, we developed a R Statistical analysis package (http://cran.r-project.org), SCATTome (Single Cell Analysis of Targeted Transcriptome), that can restructure data obtained from Fluidigm qPCR analysis run, filter missing data, perform scaling of filtered data, build classification models and successfully predict drug response of individual cells and classify each cell's probability of response based on the targeted transcriptome. We will present the program output as graphical displays of single cell response probabilities. This package provides a novel classification method that has the potential to predict subclonal response to a variety of therapeutic agents. Disclosures Kumar: Skyline: Consultancy, Honoraria; BMS: Consultancy; Onyx: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.
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Hanamoto, Hitoshi, Yasuyoshi Morita, Motoshi Ichikawa, et al. "ASXL1 Mutations Predict a Poor Response to Darbepoetin Alfa in Anemic Patients with Low-Risk MDS: A Multicenter, Phase II Study." Blood 136, Supplement 1 (2020): 28–29. http://dx.doi.org/10.1182/blood-2020-134483.
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Introduction: Myelodysplastic syndromes (MDS) is thought to develop and progress as a result of accumulation of genetic mutations. This multicenter, open-label, phase II study examined impact of gene mutations on the effect of darbepoetin alfa (DA) for anemia. Death within 1 year and progression to acute myeloid leukemia (AML) were also examined. Methods: DA ≤240 μg was administered once weekly for 16 weeks to DA-naive, low-risk MDS (low or Intermediate-1 [Int-1] risk defined by the International Prognostic Scoring System [IPSS] risk classification) patients with anemia. DNA was extracted from the peripheral blood of patients, and presence of previously reported high-frequency gene mutations in MDS (SF3B1, TET2, SFRS2, ASXL1, DNMT3A, etc.) was analyzed by next-generation sequencing. Primary endpoint was association between frequently observed mutated genes and therapeutic effect of DA (IWG criteria 2006 (HIE)) at 16 weeks. A secondary endpoint was survival analysis results for death and progression to AML within one year after 16 weeks of treatment, with the date of first treatment as the starting date. For AML, progression to AML and subsequent death were stated as events, and the patients without confirmed progression to AML were censored at the date of last known survival. For overall survival, death from any cause was considered an event, and for the survival cases, the study was terminated at the date of last known survival. For the primary endpoint, relative risk and 95% confidence intervals (CI) were calculated using Wilson's score method; statistical significance was assessed using Pearson's chi-square test. Multivariate analysis was performed by adding baseline erythropoietin (EPO) levels (low: &lt;91.8, high: 91.8+ [mIU/mL]) to the explanatory variables, and odds ratio was calculated using logistic regression model. Survival curve was estimated using Kaplan-Meier method and median survival time (MST) was calculated using Brookmeyer and Crowley method. Results: Of the 85 patients enrolled between August 2016 and May 2019, 4 patients who were judged ineligible and 2 patients who discontinued the study prior to the start of treatment were excluded, and 79 subjects were included in the analysis (full analysis set). Of 79 subjects, 52 (65.8%) were male (median age 77.0 [29-90] years). IPSS risk was low in 27 (36.7%) and Int-1 in 50 (63.3%) subjects. The frequently mutated genes (³10%) were SF3B1 (24, 30.4%), TET2 (20, 25.3%), SRSF2 (10 cases, 12.7%), ASXL1 (9, 11.4%), and DNMT3A (8, 10.1%). Overall response rate was 70.9%. Univariate logistic regression analaysis did not show any significant association between these mutations and therapeutic efficacy of DA. The same results were obtained when the analysis was limited to red blood cell transfusion-dependent subjects (n=15). After adjusting against baseline EPO values, mutations of ASXL1 gene were associated with significantly worse response (odds ratio 0.180 [0.035-0.928], p = 0.040). Six (7.6%) confirmed cases of AML and 17 (21.5%) deaths (death before confirmed AML) were observed. Overall, 21 deaths were observed including 4 deaths after progression to AML. The median survival time (95% confidence interval) from the start of treatment to confirmed AML or death was 41.3 months (30.6 months - Not reached). Conclusions: The results of this exploratory study suggest that the presence of ASXL1 gene mutations may result in poor response to the anemic treatment with DA in low-risk MDS. The current analysis of progression to AML and death included subjects whose observation period did not reach the prespecified number of days. For such cases, the outcome research will be conducted around October 2020 and updated results will be presented at the ASH 2020 conference. Disclosures Ichikawa: Novartis, Takeda: Honoraria. Shibayama:Taiho: Research Funding; Shionogi: Research Funding; Ono: Honoraria, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Takeda: Honoraria, Research Funding; Merck Sharp & Dohme: Research Funding; Sumitomo Dainippon: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Kirin: Honoraria; Otsuka: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Fujimoto: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Teijin: Research Funding; Mundi Pharma: Honoraria. Maeda:Kyowa Kirin Co.Ltd.: Honoraria, Research Funding. Kawabata:Celgene Corporation: Consultancy; Celgene Corporation: Honoraria; Sanofi K. K: Honoraria; Novartis Pharma K. K.: Honoraria; Chugai Pharmaceutical Co., Ltd: Honoraria. Matsumura:Shionogi & Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Kyowa Kirin Co., Ltd.: Research Funding; ONO PHARMACEUTICAL CO., LTD.: Research Funding; Eisai Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Janssen Pharmaceutical K.K: Speakers Bureau; Amgen K.K.: Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; DAIICHI SANKYO COMPANY, LIMITED.: Speakers Bureau; Pfizer Japan Inc.: Speakers Bureau; Novartis Pharma KK: Speakers Bureau; Bristol-Myers Squibb Company: Speakers Bureau. Ogawa:Eisai Co., Ltd.: Research Funding; KAN Research Institute, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chordia Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Asahi Genomics Co., Ltd.: Current equity holder in private company; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding. Mitani:CHUGAI: Research Funding; Takeda: Research Funding; KYOWA KIRIN: Consultancy, Research Funding.
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Verstappen, G. M., J. C. Tempany, H. Cheon, et al. "AB0144 STRATIFICATION OF PATIENTS WITH PRIMARY SJÖGREN’S SYNDROME BY MEASURING B-CELL HEALTH." Annals of the Rheumatic Diseases 79, Suppl 1 (2020): 1372–73. http://dx.doi.org/10.1136/annrheumdis-2020-eular.3507.
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Background:Primary Sjögren’s syndrome (pSS) is a heterogeneous immune disorder with broad clinical phenotypes that can arise from a large number of genetic, hormonal, and environmental causes. B-cell hyperactivity is considered to be a pathogenic hallmark of pSS. However, whether B-cell hyperactivity in pSS patients is a result of polygenic, B cell-intrinsic factors, extrinsic factors, or both, is unclear. Despite controversies about the efficacy of rituximab, new B-cell targeting therapies are under investigation with promising early results. However, for such therapies to be successful, the etiology of B-cell hyperactivity in pSS needs to be clarified at the individual patient level.Objectives:To measure naïve B-cell function in pSS patients and healthy donors using quantitative immunology.Methods:We have developed standardised, quantitative functional assays of B-cell responses that measure division, death, differentiation and isotype switching, to reveal the innate programming of B cells in response to T-independent and dependent stimuli. This novel pipeline to measure B-cell health was developed to reveal the sum total of polygenic defects and underlying B-cell dysfunction at an individual level. For the current study, 25 pSS patients, fulfilling 2016 ACR-EULAR criteria, and 15 age-and gender-matched healthy donors were recruited. Standardized quantitative assays were used to directly measure B cell division, death and differentiation in response to T cell-independent (anti-Ig + CpG) and T-cell dependent (CD40L + IL-21) stimuli. Naïve B cells (IgD+CD27-) were sorted from peripheral blood mononuclear cells and were labeled with Cell Trace Violet at day 0 to track cell division until day 6. B cell differentiation was measured at day 5.Results:Application of our standardized assays, and accompanying parametric models, allowed us to study B cell-intrinsic defects in pSS patients to a range of stimuli. Strikingly, we demonstrated a hyperresponse of naïve B cells to combined B cell receptor (BCR) and Toll-like receptor (TLR)-9 stimulation in pSS patients. This hyperresponse was revealed by an increased mean division number (MDN) at day 5 in pSS patients compared with healthy donors (p=0.021). A higher MDN in pSS patients was observed at the cohort level and was likely attributed to an increased division burst (division destiny) time. The MDN upon BCR/TLR-9 stimulation correlated with serum IgG levels (rs=0.52; p=0.011). No difference in MDN of naïve B cells after T cell-dependent stimulation was observed between pSS patients and healthy donors. B cell differentiation capacity (e.g., plasmablast formation and isotype switching) after T cell-dependent stimulation was also assessed. At the cohort level, no difference in differentiation capacity between groups was observed, although some pSS patients showed higher plasmablast frequencies than healthy donors.Conclusion:Here, we demonstrate defects in B-cell responses both at the cohort level, as well as individual signatures of defective responses. Personalized profiles of B cell health in pSS patients reveal a group of hyperresponsive patients, specifically to combined BCR/TLR stimulation. These patients may benefit most from B-cell targeted therapies. Future studies will address whether profiles of B cell health might serve additional roles, such as prediction of disease trajectories, and thus accelerate early intervention and access to precision therapies.Disclosure of Interests:Gwenny M. Verstappen: None declared, Jessica Catherine Tempany: None declared, HoChan Cheon: None declared, Anthony Farchione: None declared, Sarah Downie-Doyle: None declared, Maureen Rischmueller Consultant of: Abbvie, Bristol-Meyer-Squibb, Celgene, Glaxo Smith Kline, Hospira, Janssen Cilag, MSD, Novartis, Pfizer, Roche, Sanofi, UCB, Ken R. Duffy: None declared, Frans G.M. Kroese Grant/research support from: Unrestricted grant from Bristol-Myers Squibb, Consultant of: Consultant for Bristol-Myers Squibb, Speakers bureau: Speaker for Bristol-Myers Squibb, Roche and Janssen-Cilag, Hendrika Bootsma Grant/research support from: Unrestricted grants from Bristol-Myers Squibb and Roche, Consultant of: Consultant for Bristol-Myers Squibb, Roche, Novartis, Medimmune, Union Chimique Belge, Speakers bureau: Speaker for Bristol-Myers Squibb and Novartis., Philip D. Hodgkin Grant/research support from: Medimmune, Vanessa L. Bryant Grant/research support from: CSL
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Okuda, Rurika, Yasuhito Nannya, Yotaro Ochi, et al. "Der(1;7)(q10;p10) Presents with a Unique Genetic Profile and Frequent ETNK1 Mutations in Myeloid Neoplasms." Blood 138, Supplement 1 (2021): 1513. http://dx.doi.org/10.1182/blood-2021-149556.
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Abstract Background Der(1;7)(q10;p10) (der(1;7) is an unbalanced translocation recurrently found in myeloid neoplasms, particularly in myelodysplastic syndromes (MDS) and related disorders. Caused by a recombination between two homologous alphoid sequencing D1Z7 and D7Z1 on chromosomes 1 and 7, respectively, it results in monosomy 7q and trisomy 1q, which is implicated in the pathogenesis of der(1;7)-positive myeloid neoplasms. Previous studies reported frequent co-occurrence of +8 and del(20q), as well as RUNX1 mutations, the genetic and clinical characteristics of this abnormality has not fully been elucidated. Methods In this study, we enrolled a total of 153 cases myeloid neoplasms positive for der(1;7) from Japanese and German cohorts, in which co-occurring genetic lesions were analyzed using whole exome and/or targeted-capture sequencing. An additional 3,223 MDS and related neoplasm cases were also analyzed using targeted-capture sequencing to identify der(1;7)-specific genomic features. Results Ethnicity was evaluated comparing the frequency of der(1;7) in 944 German MDS cases and 763 Japanese MDS cases. Der(1;7) cases were observed at a higher frequency in Japanese MDS cohort compared to German MDS cohort (73/763 cases versus 4/944 cases, p &lt; 0.00001). Der(1;7) cases showed a strong male predominance (86.3%) (p&lt;0.001). Of 153 myeloid neoplasm patients harboring der(1;7), 114 were diagnosed with MDS, 28 with AML, 5 with MDS-MPN and 1 with MPN. Targeted-capture sequencing revealed mutations in common myeloid drivers (n=61) in 96% of der(1;7) cases. The most frequently mutated gene was RUNX1 with 46%, followed by ETNK1 (24.5%) and EZH2 (24.5%). Of interest, ETNK1 mutation was identified as the most unique to der(1;7) when compared to myeloid neoplasm cases without der(1;7) (n=3,066) [odds ratio (OR)=15.06], followed by ETV6 (OR=9.35) and EZH2 (OR=6.52). To further examine the uniqueness of this mutation profile, the mutational profile of der(1;7) was compared to those myeloid neoplasm cases harboring amp(1q) (n=52) and monosomy 7 (n=105). Highly frequent ETV6 and ETNK1 mutations were highly unique to der(1;7) cases when compared to amp(1q) cases (OR=3.72, OR=2.57, respectively). BCOR and ETNK1 mutations were highly unique to der(1;7) cases when compared to monosomy 7 cases (OR=35.88, OR=4.29, respectively). Both amp(1q) and monosomy 7 cases showed a higher mutation rate in TP53 compared to der(1;7) cases (49.1% and 51%, respectively, vs 3.5 %) . From these mutational characteristics, ETNK1 was identified as being the most unique to der(1;7) when compared to amp(1q), monosomy 7 and other myeloid neoplasm cases. ETNK1-mutated der(1;7) cases were featured with eosinophilia (p &lt; 0.0005), a lack of RAS pathway mutations and trisomy 8 when compared to ETNK1-wild type der(1;7) cases. Survival analysis was conducted to elucidate the difference in survival in der(1;7) cases (n=65) versus myeloid neoplasm cases (n=2066). Der(1;7)-harboring myeloid neoplasm cases had a median overall survival of 6.8 months (95% CI, 3.5 to 11.9) and non-der(1;7) harboring myeloid neoplasm cases were 11.8 months (95% CI, 10.5 to 12.6). Thus, der(1;7)-harboring myeloid neoplasm cases had poorer prognosis (p&lt;0.001). Conclusion In conclusion, der(1;7) is an unbalanced translocation that occurs predominantly in males and is seen more frequently in Japanese than Caucasian populations. Der(1;7) cases present with a mutational profile that is distinct from other myeloid neoplasm cases such as those with amp(1q) and monosomy7/del(7q), showing frequency of ETNK1 mutations. Disclosures Nannya: Otsuka Pharmaceutical Co., Ltd.: Consultancy, Speakers Bureau; Astellas: Speakers Bureau. Kern: MLL Munich Leukemia Laboratory: Other: Part ownership. Haferlach: MLL Munich Leukemia Laboratory: Other: Part ownership. Atsuta: Astellas Pharma Inc.: Speakers Bureau; Mochida Pharmaceutical Co., Ltd.: Speakers Bureau; AbbVie GK: Speakers Bureau; Kyowa Kirin Co., Ltd: Honoraria; Meiji Seika Pharma Co, Ltd.: Honoraria. Handa: Ono: Honoraria; BMS: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Research Funding; Celgene: Honoraria, Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Abbvie: Honoraria; MSD: Research Funding; Shionogi: Research Funding. Ohyashiki: Novartis Pharma: Other: chief clinical trial; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Haferlach: MLL Munich Leukemia Laboratory: Other: Part ownership. Ogawa: Otsuka Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Kan Research Laboratory, Inc.: Consultancy, Research Funding; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding; ChordiaTherapeutics, Inc.: Consultancy, Research Funding; Ashahi Genomics: Current holder of individual stocks in a privately-held company.
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Talaulikar, Dipti, Tara Cochrane, John Gibson, et al. "Bing Neel Syndrome: Retrospective Australasian Experience of a Rare Treatable Complication of Waldenström Macroglobulinaemia/ Lymphoplasmacytic Lymphoma." Blood 132, Supplement 1 (2018): 5325. http://dx.doi.org/10.1182/blood-2018-99-113969.
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Abstract Introduction and aims:Bing Neel syndrome (BNS) is a rare complication of Waldenström Macroglobulinaemia (WM)/ Lymphoplasmacytic Lymphoma (LPL). It is a clinicopathological entity characterised by central nervous system involvement with malignant cells. It presents with diverse symptoms and can be difficult to recognise. However, it is a treatable condition amenable to systemic and intrathecal treatment. We present the Australasian experience of this rare entity. Methods:Inclusion in the study was based on cytologically or histologically confirmed presence of lymphoplasmacytic cells in the CSF or brain biopsy. Ten patients were included from 9 sites in Australia and New Zealand. Relevant retrospective data was extracted after obtaining consent from patients or next of kin. Results: Seven of the 10 patients were males with overall mean age of 63.5 years (range: 49-78 years); 4 patients were < 60 years old. Four patients (40%) did not have a prior diagnosis of WM; the remaining 6 patients were diagnosed ~ 11 years post diagnosis of WM (range: 3 -26 years) and received 1 line of treatment (except for 2 patients who received 2 lines of treatment). Treatment regimens received included R-CVP, chlorambucil-prednisolone, DRC, FCR, oral fludarabine, and RFM. At diagnosis of BNS, IgM and/or PP levels ranged between 3 - 70 g/L with 6 (60%) patients having levels < 10 g/L. One patient had a diagnosis of lymphoplasmacytic lymphoma with IgG paraprotein. Symptoms at presentation of BNS varied from headache, ptosis/ophthalmoplegia, memory loss, subacute hemiplegia, cognitive defects, hearing loss, and sensory or motor neuropathy. None of the patients had B symptoms. Lymphadenopathy was noted in 4 (40%) cases, splenomegaly in 1 (10%) and ECOG performance status ranged from 0-4 with 3 (30%) patients having an ECOG of > 2. Brain +/- spine MRI was done in all cases with 5 (50%) showing leptomeningeal involvement. Orbital infiltration or enhancement of optic or ophthalmic nerves was noted in 3 cases (30%), and 3 patients (30%) had focal signs/masses. 1 had cortical atrophy, and 3 had normal MRI. CSF analysis was abnormal in all cases on cytology with demonstration of abnormal lymphocytes. Where immunophenotyping was performed, it showed presence of CD5, CD10 negative B cells. MYD88 L265P was detected in 3 patients (30%). Treatment of BNS included systemic chemoimmunotherapy in 30%, CNS penetrating intravenous agents in 40%, Ibrutinib in 50%, intrathecal chemotherapy in 30%, and radiotherapy in 10%. More than 1 modality of treatment was used in 40% of patients. Ibrutinib was administered as frontline treatment in combination with high dose MTX or IT chemotherapy in 3 patients, and as single agent monotherapy in 1 patient. Ibrutinib was used as second line treatment in 2 patients with both achieving CR. The number of cycles administered were 2.6 (range 1-9). Response data was available in 9 patients with ORR in 6 (1 CR, 5 PR) and non-response in 3. All patients except the one treated with Ibrutinib monotherapy had at least PR. With a median follow-up time of 20 months, 3 patients have died. The median overall survival of patients was not reached. The 1-year and 3-year OS rates were 80% (95% CI 41-95%) and 60% (16-87%), respectively (Figure 1). Conclusion:BNS should be suspected in WM patients who develop focal or nonspecific neurological symptoms. It can be readily diagnosed on radiological scans i.e. brain and spinal MRI, and/or on CSF analysis. It can be treated with a number of systemic and intrathecal drugs including Ibrutinib, which crosses the blood brain barrier. Fig 1 legend:Kaplan Meir curve demonstrating median overall survival of patients (not reached) and 1-year and 3-year OS rates of 80% (95% CI 41-95%) and 60% (16-87%), respectively. Disclosures Talaulikar: Takeda: Research Funding; Novartis: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria; Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau. Ho:Celgene: Other: Travel to meeting ; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel to meeting; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Simpson:Roche: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Acerta: Research Funding; Merck: Honoraria, Research Funding; BeiGene: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Novartis: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; MSD: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Research Funding, TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria, Research Funding. Tam:AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Beigene: Honoraria. Castillo:Pharmacyclics: Consultancy, Research Funding; Millennium: Research Funding; Janssen: Consultancy, Research Funding; Genentech: Consultancy; Beigene: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding.
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Makishima, Hideki, Yasuhito Nannya, June Takeda, et al. "Clinical Impacts of Germline DDX41 Mutations on Myeloid Neoplasms." Blood 136, Supplement 1 (2020): 38–40. http://dx.doi.org/10.1182/blood-2020-140174.
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DDX41 was identified as a causative gene for late-onset familial myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). While DDX41 is thought to be one of the most frequent targets of germline mutations responsible for sporadic cases with AML/MDS and other myeloid neoplasms, the entire spectrum of pathogenic DDX41 variants and their effect size therein are still to be elucidated, and so was the clinical picture of DDX41-mutated myeloid neoplasms. In this study, through an international collaboration, we investigated DDX41 variants in a total of 5,609 sporadic cases with different myeloid neoplasms from different ethnicities, using next generation sequencing. Mutations in the major driver genes commonly mutated in AML/MDS were also examined. Frequencies of germline DDX41 variants were compared between sporadic cases with myeloid neoplasms and healthy individuals (n=13,906). We also characterized genetic/clinical features of DDX41-mutated myeloid neoplasms. We identified a total of 208 (3.6%) patients with DDX41 variants, of whom approximately 50% had both germline and somatic mutations, whereas 37% and 13% had either germline or somatic mutations alone, respectively. Somatic mutations were found in 58% of patients with germline mutation, which was significantly higher than those without (0.21%) (P&lt;0.0001). No somatic mutation was identified in healthy individuals. Among 174 germline variants, truncating and missense mutations were found in 93 and 81 cases, respectively, whereas only 1.9% of somatic mutations were truncating (P&lt;0.0001). Among 21 cases with somatic mutations alone, 4 had multiple somatic mutations and an additional 4 had loss-of-heterozygosity of the DDX41 locus (5q35.3), including 3 with uniparental disomy and 1 with deletion. Thus, 8 out of 21 cases with somatic mutation alone were suspected to have biallelic DDX41 mutations. Germline DDX41 variants showed a conspicuous ethnic diversity; the most frequent germline variants were A500fs in Japan, D140fs in USA, Q41* in Germany, G218D in Italy, M1I in Sweden, S21fs in Thailand. The M1I variant was also seen in other European countries, but not in Japan or Thailand, while no A500fs mutation was found in Europe. Among the Japanese population, significant enrichment in myeloid neoplasms was observed not only for truncating variants, such as A500fs (odds ratio (OR)=12.1) and E7X (OR=11.0) but also for missense variants, including Y259C (OR 14.3) and E256K (OR 7.81), frequently accompanied by a somatic DDX41 mutation (Figure 1). Patients with germline and/or somatic DDX41 variants were significantly older than those without (P=0.00076) and more prevalent in male than female (OR=3.14; P&lt;0.0001). DDX41 variants were significantly more frequent in MDS (4.7%) and AML (2.9%), compared with other myeloid neoplasms (0.58%). Among AML, mutations were more frequent in AML with myelodysplasia-related changes (P&lt;0.00001). Patients with MDS having both germline and somatic mutations were more likely to classified in refractory anemia with excess blasts (RAEB), compared with those with germline or somatic alone (P=0.029). DDX41 variants were significantly associated with lower WBC and granulocyte counts. Most frequently co-occurring mutations included those in ASXL1, SRSF2, TET2, CUX1, and DNMT3A, of which only CUX1 mutations were statistically significant. Overall, no difference was observed in overall survival (OS) between DDX41-mutated and unmutated cases. However, among RAEB cases, DDX41 variants were associated with a significantly longer OS (P=0.0039). In summary, the majority of DDX41-mutated cases had a germline variant, although a minority had somatic mutations alone. Pathogenic DDX41 alleles have a large ethnic diversity, where not only truncating variants but also missense variants are associated with an increased risk of the development of myeloid neoplasms. Disclosures Kanda: Chugai Pharma: Honoraria, Research Funding; Merck Sharp & Dohme: Honoraria; Mundipharma: Honoraria; Ono Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Takeda Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Honoraria; Shire: Honoraria; Mochida Pharmaceutical: Honoraria; Daiichi Sankyo: Honoraria; Shionogi: Research Funding; Meiji Seika Kaisha: Honoraria; Sanofi: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Janssen: Honoraria; Pfizer: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Novartis: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding. Miyazaki:NIPPON SHINYAKU CO.,LTD.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Novartis Pharma KK: Honoraria; Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Celgene: Honoraria. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria. Ogawa:Otsuka Pharmaceutical Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; KAN Research Institute, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Asahi Genomics Co., Ltd.: Current equity holder in private company; Chordia Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai Co., Ltd.: Research Funding.
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Ochi, Yotaro, Kenichi Yoshida, Ying-Jung Huang, et al. "Prognostic Relevance of Genetic Abnormalities in Blastic Transformation of Chronic Myeloid Leukemia." Blood 136, Supplement 1 (2020): 3–4. http://dx.doi.org/10.1182/blood-2020-140629.
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Background Chronic myeloid leukemia (CML) is characterized by the BCR-ABL1 fusion gene. Despite the use of tyrosine kinase inhibitors (TKIs), a minority of chronic phase (CP) CML patients fail TKI therapies and progress to blast crisis (BC), showing dismal outcomes. Although genetic studies have revealed that CML-BC frequently carries not only ABL1 mutations but other driver mutations, our knowledge about the mechanism of TKI resistance and progression to BC is still limited by a relatively small number of patients and/or genes analyzed in each study. Moreover, it remains elusive whether mutations can predict clinical outcomes of BC patients, in which few biomarkers are known. Here, we investigated a large cohort of CML patients to reveal the landscape of genetic lesions and those predicting clinical outcomes in CML. Methods We performed whole-exome sequencing (WES) of paired CP and BC samples from 52 patients and targeted-capture sequencing that covered myeloid driver genes in 32 BC and 19 CP samples. Combined with public WES data for 24 BC and 77 CP, we analyzed a total of 108 BC and 148 CP samples. Results In WES analysis of paired CP and BC samples, an average of 5.3 nonsynonymous mutations were acquired during disease progression from CP to BC. Notably, a Poisson regression model revealed that the number of acquired mutations was positively correlated with time to progression from CP to BC (P &lt; 0.001) and negatively with TKI therapy after CP diagnosis (P = 0.0093), although the correlation of the number of driver mutations in CML-BC with time to progression was not clear. These results suggest that the use of TKI effectively reduces the size of tumor populations at risk for clonal evolution by acquiring random mutations, by which prevents BC. In CML-BC, we found frequent mutations not only in known mutational targets in other hematological malignancies, such as RUNX1, ABL1, ASXL1, BCOR/BCORL1, TP53, and WT1, but also in other genes recently reported in BC (UBE2A and SETD1B) and previously unreported mutational targets in cancer (KLC2 and NBEAL2). Deep amplicon-sequencing revealed that ASXL1 mutations were already present at the time of CP diagnosis in most cases, whereas others such as RUNX1, ABL1, and TP53 mutations were absent in CP and newly emerged during progression to BC. Some abnormalities, such as +21, +8, and ASXL1 mutations, were more enriched in myeloid than lymphoid crisis, while others, including CDKN2A/B and IKZF1 deletions, -7/del(7p), -9/del(9p), and ABL1 mutations, vice versa. By contrast, abnormalities such as RUNX1 mutations and double Ph were almost equally observed in both crises. In univariate analysis of clinical factors for overall survival (OS) in 77 CML-BC cases for whom survival information was available, TKI-containing therapy for BC was significantly associated with a better OS, whereas genetic lesions including ASXL1 and TP53 mutations, del(17p), amp(17q), +19, and +21 had a negative impact on OS. Conspicuously, patients with TP53 mutations, del(17p), and amp(17q) showed an especially dismal outcome. We then performed a multivariate analysis using a Cox proportional hazard regression model, focusing on 36 TKI-treated patients, because TKI-containing therapy has been shown to improve OS and therefore, is a standard choice of therapy. We found that ASXL1 and BCOR mutations, complex copy-number alterations, amp(17q), and +21 were independent predictors for worse prognosis. Based on the number of these unfavorable factors, patients were classified into three subgroups showing distinct prognosis, where the 2-year OS rate was 71.8%, 15.6%, and 0% for patients with 0, 1, and ≥2 risk factors, respectively (P &lt; 0.001). Finally, we explored the genetic abnormalities and clinical outcomes in CML-CP. In CP, only ASXL1 was mutated at a frequency comparable to that in BC, while others, including TET2, KMT2D, PTPN11, RUNX1, and WT1, were mutated at much lower frequencies. Of interest, patients who later developed BC more frequently had at least one genetic abnormality, suggesting that mutations found at the time of CP might play a role in driving CML cells to BC under the pressure of TKI treatment. Conclusion Our study clarified a comprehensive registry of genetic lesions in BC in a large cohort of CML patients and their prognostic impact, which should provide a clue to the development of better therapy/management for patients with CML. Disclosures Takaori-Kondo: Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Ono Pharmaceutical: Research Funding; Thyas Co. Ltd.: Research Funding; Takeda: Research Funding; CHUGAI: Research Funding; Eisai: Research Funding; Nippon Shinyaku: Research Funding; Otsuka Pharmaceutical: Research Funding; Pfizer: Research Funding; OHARA Pharmaceutical: Research Funding; Sanofi: Research Funding; Novartis Pharma: Honoraria; MSD: Honoraria. Mitani:CHUGAI: Research Funding; Takeda: Research Funding; KYOWA KIRIN: Consultancy, Research Funding. Ogawa:Chordia Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Asahi Genomics Co., Ltd.: Current equity holder in private company; Eisai Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; KAN Research Institute, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding. Shih:Novartis: Research Funding; Celgene: Research Funding; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees.
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Takeda, June, Kenichi Yoshida, Akinori Yoda, et al. "Genotype-Phenotype Relationships and Therapeutic Targets in Acute Erythroid Leukemia." Blood 136, Supplement 1 (2020): 17–18. http://dx.doi.org/10.1182/blood-2020-141750.
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Background: Acute erythroid leukemia (AEL) is a rare subtype of AML characterized by erythroid predominant proliferation and classified into two subtypes with pure erythroid (PEL) and myeloid/erythroid (MEL) phenotypes. Although gene mutations in AEL have been described in several reports, genotype phenotype correlations are not fully understood with little knowledge about the feasible molecular targets for therapy. Methods: To understand the mechanism of the erythroid dominant phenotype of AEL and identify potential therapeutic targets for AEL, we analyzed a total of 105 AEL cases with the median age of 60 (23-86), using targeted-capture sequencing of commonly mutated genes in myeloid neoplasms, together with 1,279 SNPs for copy number measurements. Among these 105 cases, 13 were also analyzed by RNA sequencing. Genetic profiles of these 105 AEL cases were compared to those of 775 cases with non-erythroid AML (NEL) including 561 cases from The Cancer Genome Atlas and Beat AML study. An immature erythroid cell line (TF1) and three patient-derived xenografts (PDX) established from AEL with JAK2 and/or EPOR amplification. Cell line and samples from patients were inoculated into immune-deficient mice and tested for their response to JAK1/2 inhibitor. Results: According to unique genetic alterations, AEL was classified into 4 subgroups (A-D). Characterized by TP53 mutations and complex karyotype, Group A was the most common subtype and showed very poor prognosis. Remarkably, all PEL cases were categorized into Group A. Conspicuously, 80% of PEL cases had amplifications of JAK2 (6/10; 60%), EPOR (7/10;70%), and ERG (6/10;60%) loci on chromosomes 9p, 19q, and 21q, respectively, frequently in combination, although they were rarely seen in NEL cases. All cases in Group B (n=19, 18%), another prevalent form of AEL, had STAG2 mutations and classified in MEL. To further characterize this subgroup, we compared genetic profiles of STAG2-mutated AEL and NEL. Prominently, 70% (14/20) of STAG2-mutated cases in AEL had KMT2A-PTD, whereas it was found only in 8.8% (3/34) of NEL. CEBPA mutations were also more common in AEL (6/21; 29%) than NEL (4/34; 12%). While Group C was characterized by frequent NPM1 mutations, in contrast to the frequent co-mutation of FLT3 in the corresponding subgroup of NPM1-mutated cases in NEL, NPM1-mutated patents in this subgroup lacked FLT3 mutations but had frequent PTPN11 mutations (8/16; 50%), which were much less common in NEL (25/209; 12%). The remaining cases were categorized into Group D, which was enriched for mutations in ASXL1, BCOR, PHF6, U2AF1 and KMT2C. Recurrent loss-of-function mutations in USP9X were unique to this subtype, although USP9X mutations have been reported in ALL with upregulation of JAK-STAT pathway. In RNA sequencing analysis, AEL cases exhibited gene expression profiles implicated in an upregulated STAT5 signaling pathway, which was seen not only those cases with JAK2 or EPOR amplification, but also those without, suggesting that aberrantly upregulated STAT5 activation might represent a common defect in AEL. Based on this finding, we evaluated the effect of a JAK inhibitior, ruxolitinib, on an AEL-derived cell line and three PDX models established from AEL having TP53 mutations and JAK2 and EPOR mutation/amplification. Of interest, ruxolitinib significantly suppressed cell growth and prolonged overall survival in mice engrafted with TF1 and 2 PDX models with STAT5 downregulation, although the other model was resistant to JAK2 inhibition with persistent STAT5 activation. Conclusion: AEL is a heterogeneous group of AML, of which PEL is characterized by frequent amplifications/mutations in JAK2, EPOR and/or ERG. Frequent involvement of EPOR/JAK/STAT pathway is a common feature of AEL, in which a role of JAK inhibition was suggested. Disclosures Yoda: Chordia Therapeutics Inc.: Research Funding. Shih:Novartis: Research Funding; Celgene: Research Funding; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ishiyama:Alexion: Research Funding; Novartis: Honoraria. Miyazaki:Astellas Pharma Inc.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; NIPPON SHINYAKU CO.,LTD.: Honoraria; Celgene: Honoraria; Otsuka Pharmaceutical: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Novartis Pharma KK: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria. Nakagawa:Sumitomo Dainippon Pharma Co., Ltd.: Research Funding. Takaori-Kondo:Celgene: Honoraria, Research Funding; Ono Pharmaceutical: Research Funding; Thyas Co. Ltd.: Research Funding; Takeda: Research Funding; CHUGAI: Research Funding; OHARA Pharmaceutical: Research Funding; Sanofi: Research Funding; Novartis Pharma: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Research Funding; Otsuka Pharmaceutical: Research Funding; Eisai: Research Funding; Astellas Pharma: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Nippon Shinyaku: Research Funding; MSD: Honoraria. Kataoka:Asahi Genomics: Current equity holder in private company; Otsuka Pharmaceutical: Research Funding; Takeda Pharmaceutical Company: Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding. Usuki:Alexion: Research Funding, Speakers Bureau; Apellis: Research Funding; Novartis: Research Funding, Speakers Bureau; Chugai: Research Funding. Maciejewski:Novartis, Roche: Consultancy, Honoraria; Alexion, BMS: Speakers Bureau. Ganser:Novartis: Consultancy; Celgene: Consultancy. Thol:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Ogawa:Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Asahi Genomics Co., Ltd.: Current equity holder in private company; Eisai Co., Ltd.: Research Funding; Chordia Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; KAN Research Institute, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Ruxolitinib is used for drug efficacy test using patient-derived xenografts established from acute erythroid leukemia.
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Ebina, K., Y. Etani, Y. Maeda, et al. "POS0051 DRUG RETENTION AND REASONS FOR DISCONTINUATION OF BIOLOGICS AND JAK INHIBITORS IN PATIENTS WITH RHEUMATOID ARTHRITIS – THE ANSWER COHORT STUDY." Annals of the Rheumatic Diseases 82, Suppl 1 (2023): 234.1–235. http://dx.doi.org/10.1136/annrheumdis-2023-eular.1135.
Full textAbstract:
Background2022 EULAR recommendation announced that both biological disease-modifying antirheumatic drugs (bDMARDs) and janus kinase inhibitors (JAKi) are considered in the phase Ⅱ treatment of rheumatoid arthritis (RA). However, we still lack reliable evidence of direct comparison between these agents’ retention, which may reflect effectiveness and safety.ObjectivesThe aim of this multi-center (7 university-related hospitals)[1]-[3], retrospective study is to clarify the factors affecting treatment retention of bDMARDs and JAKi in a real-world setting.MethodsThis study assessed 6,666 treatment courses of bDMARDs and JAKi introduced from 2001 to 2022 (TNF inhibitors [TNFi]=3,577, anti-IL-6 receptor antibody [aIL-6R]=1,497, cytotoxic T lymphocyte-associated antigen-4-Ig [CTLA4-Ig]=1,139, JAKi=453; Bio/JAK naive cases 55.4%, baseline age 58.8 years, female 82.6%, disease duration 9.7 years, DAS28-ESR 4.3, concomitant methotrexate [MTX] [52.8%], other csDMARDs [26.0%], and oral glucocorticoid [GC] [36.4%]). Reasons for discontinuation were classified into four categories by each attending physician: 1) lack of effectiveness (primary and secondary), 2) toxic adverse events (infection, malignancies, and cardiovascular events, et al.), 3) non-toxic reasons (patient preference, change in hospital, and pregnancy, et al.), and 4) remission. Retention rates of each discontinuation reason were estimated at 36 months using the Kaplan-Meier method and adjusted for potential clinical confounders (age, sex, concomitant GC, MTX, and other csDMARDs, switched number of bDMARDs or JAKi, and prior use of TNFi, aIL-6R, CTLA4-Ig, or JAKi) using Cox proportional hazards modeling.ResultsAdjusted retention rates for each discontinuation reason were as follows: due to lack of effectiveness was aIL-6R=80.9%, JAKi=75.2%, CTLA4-Ig=73.6%, and TNFi=66.1% (Cox P<0.001 between 4 groups) (figure 1a), due to toxic adverse events was CTLA4-Ig=88.0%, JAKi=86.4%, aIL-6R=84.1%, and TNFi=83.6% (Cox P=0.052) (figure 1b), due to non-toxic reasons was aIL-6R=86.9%, TNFi=85.9%, JAKi=85.9%, and CTLA4-Ig=82.6% (Cox P=0.064), and due to remission was JAKi=97.1%, CTLA4-Ig=96.7%, aIL-6R=96.0%, and TNFi=94.9% (Cox P=0.18). Compared to TNFi, aIL-6R (hazard ratio [HR]=0.54, 95%CI=0.47–0.61, P<0.001), JAKi (HR=0.69, 95%CI=0.56–0.85, P<0.001), and CTLA4-Ig (HR=0.75, 95%CI=0.66–0.86, P<0.001) showed lower discontinuation rate due to lack of effectiveness. Compared to TNFi, CTLA4-Ig showed lower discontinuation rate due to toxic adverse events (HR=0.77, 95%CI=0.63–0.93, P=0.008) and remission (HR=0.67, 95%CI=0.46–0.98, P=0.041). Other factors increasing drug discontinuation due to lack of effectiveness was switched number of bDMARDs or JAKi (HR=1.42, 95%CI=1.24–1.63, P<0.001), concomitant GC (HR=1.17, 95%CI=1.06–1.29, P=0.0018), and prior aIL-6R use (HR=1.24, 95%CI=1.05–1.45, P=0.011). On the other hand, higher age (HR=1.01, 95%CI=1.00–1.02, P<0.001) and concomitant GC (HR=1.29, 95%CI=0.47–0.61, P<0.001) increased drug discontinuation due to toxic adverse events.ConclusionAdjusted by potential confounders, aIL-6R showed lowest discontinuation due to lack of effectiveness, and CTLA4-Ig showed lowest discontinuation due to toxic adverse events. Besides the difference of bDMARDs and JAKi, concomitant GC increased drug discontinuation due to lack of effectiveness and toxic adverse events.References[1]Ebina K, et al. Drug tolerability and reasons for discontinuation of seven biologics in 4466 treatment courses of rheumatoid arthritis-the ANSWER cohort study. Arthritis Res Ther. Apr 11 2019;21(1):91.[2]Ebina K, et al. Drug retention of 7 biologics and tofacitinib in biologics-naive and biologics-switched patients with rheumatoid arthritis: the ANSWER cohort study. Arthritis Res Ther. Jun 15 2020;22(1):142.[3]Ebina K, et al. Factors affecting drug retention of Janus kinase inhibitors in patients with rheumatoid arthritis: the ANSWER cohort study. Sci Rep. Jan 7 2022;12(1):134.Figure 1.Acknowledgements:NIL.Disclosure of InterestsKosuke Ebina Speakers bureau: AbbVie, Amgen, Asahi-Kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Janssen, Mitsubishi-Tanabe, Ono Pharmaceutical, Pfizer, Sanofi, Taisho, and UCB Japan., Consultant of: Asahi-Kasei and Taisho., Grant/research support from: AbbVie, Asahi-Kasei, Eisai, Mitsubishi-Tanabe, and Teijin Pharma. Affiliated with the Department of Musculoskeletal Regenerative Medicine, Osaka University, Graduate School of Medicine, which is supported by Taisho., Yuki Etani Grant/research support from: Eli Lilly, Yuichi Maeda Speakers bureau: Eli Lilly Japan K.K., Chugai Pharmaceutical Co. Ltd., Pfizer Inc., Bristol Myers Squibb, and Mitsubishi Tanabe Pharma Corporation, Grant/research support from: Eli Lilly, Yasutaka Okita Speakers bureau: Chugai Pharmaceutical, Pfizer, and Ono, Makoto Hirao Speakers bureau: Astellas, Ono Pharmaceutical, Eli Lilly, Mitsubishi-Tanabe, Pfizer, Ayumi, and Takeda, Wataru Yamamoto: None declared, Motomu Hashimoto Speakers bureau: Mitsubishi-Tanabe, Eisai, Eli Lilly, Bristol-Myers Squibb, and Novartis Pharma, Grant/research support from: Mitsubishi-Tanabe, Eisai, Eli Lilly, Bristol-Myers Squibb, and Novartis Pharma, Koichi Murata Speakers bureau: AbbVie GK, Eisai Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Bristol-Myers Squibb, Daiichi Sankyo Co. Ltd., and Asahi Kasei Pharma Corp., Grant/research support from: Daiichi Sankyo, Ryota Hara Speakers bureau: AbbVie and Eisai, Koji Nagai: None declared, Yuri Hiramatsu: None declared, Yonsu Son: None declared, Hideki Amuro: None declared, Takayuki Fujii Speakers bureau: Asahi Kasei Pharma, Abbvie, Jansen, Tanabe Mitsubishi Pharma, and Eisai, Takaichi Okano: None declared, Yo Ueda: None declared, Masaki Katayama: None declared, Tadashi Okano Speakers bureau: Abbvie, Chugai, Eli Lilly, Janssen and Novartis Pharma., Grant/research support from: Abbvie, Asahi Kasei, Chugai, Eisai, Eli Lilly and Tanabe Mitsubishi., Atsushi Kumanogoh Speakers bureau: Chugai, Eisai, Tanabe-Mitsubishi, Abbvie, and Ono, Grant/research support from: Chugai, Seiji Okada: None declared, Ken Nakata Grant/research support from: Astellas.
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Takeda, June, Kenichi Yoshida, Masahiro Marshall Nakagawa, et al. "EPOR/JAK/STAT Signaling Pathway As Therapeutic Target of Acute Erythroid Leukemia." Blood 138, Supplement 1 (2021): 610. http://dx.doi.org/10.1182/blood-2021-152800.
Full textAbstract:
Abstract Background: Acute erythroid leukemia (AEL) is a rare subtype of AML characterized by erythroid predominant proliferation and classified into two subtypes with pure erythroid (PEL) and myeloid/erythroid (MEL) phenotypes. Although several reports described gene mutations in AEL, genotype phenotype correlations have not fully been elucidated with little knowledge about feasible molecular targets for therapy. Methods: To understand the mechanism of the erythroid dominant phenotype of AEL and identify potential therapeutic targets for AEL, we analyzed a total of 121 adult AEL cases with the median age of 60 (23-87), using whole genome/exome sequencing of 35 cases, followed by targeted-capture sequencing of 387 genes together with 1,279 SNP loci for copy number measurements in all cases. Among these, 21 were also analyzed by RNA sequencing. Genetic profiles of these AEL cases were compared to those of 409 cases with non-erythroid AML (non-AEL) including 195 cases from The Cancer Genome Atlas. Six patient-derived xenografts (PDX) were established from AEL with JAK2 and/or EPOR focal gain/amplification/mutation. PDX cells were inoculated into immune-deficient mice and tested for their response to JAK1/2 inhibitor. Results: According to unique genetic alterations, AEL was classified into 4 genomic groups (A-D). Characterized by TP53 mutations and complex karyotype, Group A was the most common subtype (48/121; 40%) and showed very poor prognosis. Remarkably, almost all the PEL cases (12/13; 92%) were categorized into Group A. Conspicuously, 75% of PEL cases with TP53 mutation had focal gain/amplifications/mutations of JAK2 (5/12; 42%), EPOR (7/12; 58%), and ERG/ETS2 (1/12; 8%) loci on chromosomes 9p, 19q, and 21q, respectively, while 34% of MEL cases with TP53 mutation had focal gain/amplifications/mutations of JAK2 (2/29; 7%), EPOR (7/29;24%), and ERG/ETS2 (7/29;24%) loci, frequently in combination. Group B was characterized by frequent NPM1 mutations, in contrast to the frequent co-mutation of FLT3 in the corresponding subgroup of NPM1-mutated cases in non-AEL, whereas NPM1-mutated patents in this group lacked FLT3 mutations but had frequent PTPN11 mutations (8/16; 50%), which were much less common in non-AEL (15/101; 15%). All cases in Group C (n=22, 18%), another prevalent form of AEL, had STAG2 mutations and classified in MEL. Prominently, 68% (17/25) of STAG2-mutated AEL cases had KMT2A-PTD, which was rarely found in non-AEL cases. The remaining cases were categorized into Group D, which was enriched for mutations in ASXL1, BCOR, PHF6, RUNX1 and TET2. We also identified recurrent loss-of-function USP9X mutations in this group, which were previously reported in ALL with an upregulated JAK-STAT pathway. In RNA sequencing analysis, AEL cases exhibited gene expression profiles implicated in an upregulated STAT5 signaling pathway, which was seen not only in those cases with JAK2 or EPOR focal gain/amplification/mutation, but also in AEL without these amplifications, suggesting that aberrantly upregulated STAT5 activation might represent a common molecular signature of AEL. Survival analysis revealed that TP53 mutation is a poor prognostic factor in AEL and non-AEL and no statistically significant difference between AEL and non-AEL with TP53 mutation. Intriguingly, 19p gains/amplifications were associated with a significantly poor prognostic prognosis in TP53-mutated AEL cases. Based on this finding, we evaluated the effect of a JAK inhibitor, ruxolitinib, on 6 PDX models established from AEL having TP53 mutations and JAK2 and EPOR mutation/amplification. Of interest , ruxolitinib significantly suppressed cell growth and prolonged overall survival in mice engrafted with 4 PDX models with STAT5 downregulation, although the other 2 models were resistant to JAK2 inhibition with persistent STAT5 activation. Conclusion: AEL is a heterogeneous group of AML, of which PEL is characterized by frequent amplifications/mutations in JAK2 and/or EPOR. Frequent involvement of EPOR/JAK/STAT pathway is a common feature of AEL, in which a therapeutic role of JAK inhibition was suggested. Disclosures Nakagawa: Sumitomo Dainippon Pharma Oncology, Inc.: Research Funding. Yoda: Chordia Therapeutics Inc.: Research Funding. Morishita: Chordia Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Miyazaki: Sumitomo-Dainippon: Honoraria, Research Funding; Astellas: Honoraria; Chugai: Honoraria; Abbvie: Honoraria; Novartis: Honoraria; Nippon-Shinyaku: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Daiichi-Sankyo: Honoraria; Kyowa-Kirin: Honoraria; Eisai: Honoraria; Janssen: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria. Usuki: Alexion: Speakers Bureau; Eisai: Speakers Bureau; MSD: Speakers Bureau; PharmaEssentia: Speakers Bureau; Yakult: Speakers Bureau; Mundipharma: Research Funding; Astellas-Amgen-Biopharma: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Takeda: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Janssen: Research Funding; Ono: Research Funding, Speakers Bureau; Otsuka: Research Funding, Speakers Bureau; Sumitomo Dainippon: Research Funding; Daiichi Sankyo: Research Funding, Speakers Bureau; Symbio: Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Nippon shinyaku: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Pfizer: Research Funding; Kyowa Kirin: Research Funding, Speakers Bureau; Brisol-Myers Squibb: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau. Maciejewski: Bristol Myers Squibb/Celgene: Consultancy; Regeneron: Consultancy; Novartis: Consultancy; Alexion: Consultancy. Ohyashiki: Novartis Pharma: Other: chief clinical trial; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Ganser: Celgene: Honoraria; Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria. Heuser: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; Karyopharm: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; BergenBio: Research Funding; Janssen: Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolremo: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Thol: Astellas: Honoraria; Abbvie: Honoraria; Novartis: Honoraria; Jazz: Honoraria; BMS/Celgene: Honoraria, Research Funding; Pfizer: Honoraria. Shih: PharmaEssentia Co: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Ltd: Research Funding; Ltd: Research Funding; Novartis: Research Funding. Takaori-Kondo: Celgene: Research Funding; Bristol-Myers K.K.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Research Funding. Ogawa: Otsuka Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Kan Research Laboratory, Inc.: Consultancy, Research Funding; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding; ChordiaTherapeutics, Inc.: Consultancy, Research Funding; Ashahi Genomics: Current holder of individual stocks in a privately-held company.
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Kogure, Yasunori, Takuro Kameda, Junji Koya, et al. "Whole-Genome Analysis of Adult T-Cell Leukemia/Lymphoma." Blood 136, Supplement 1 (2020): 29–30. http://dx.doi.org/10.1182/blood-2020-134360.
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Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell malignancy with a dismal prognosis, caused by HTLV-1. Although our previous study, mainly using whole-exome sequencing and SNP array karyotyping, discovered many driver mutations and copy number alterations (CNAs), the whole-genome landscape of ATL still remains elusive. To this end, we have performed high-depth whole-genome sequencing (WGS) of 155 ATL cases with a median sequencing depth of 96-fold for tumors. Among them, 75 cases were also analyzed by RNA sequencing (RNA-seq). In total, we detected 1,952,490 single nucleotide variants (SNVs) and 159,141 insertion-deletions (4.0 SNVs and 0.3 indels/Mb/case), 10,279 SVs (66.3 SVs/case), and 3,975 CN altered segments (25.7 segments/case). Using several driver discovery algorithms (dNdScv, MutSig2CV, and DriverPower), we identified 47 significantly mutated genes, 19 of which were mutated in more than 10% of cases. These included several novel mutations, such as those affecting XPO1 (7.1%), ZNF292 (6.5%), and ITGB1 (5.2%). Using GISTIC2.0, we identified 13 significant CNAs, such as IRF4 amplifications and CDKN2A deletions, consistent with previous SNP array data. To detect significantly recurrent SVs, we calculated SV breakpoint frequency and identified 13 genes affected by SVs, including the previously identified genes (such as CARD11, CD274, and TP73). In addition, we investigated recurrent mutations in non-coding elements by DriverPower and LARVA and discovered 12 recurrently mutated elements. Among them, the most frequent were splice site mutations, including those of HLA-A and HLA-B, most of which caused loss of function as revealed by RNA-seq. By contrast, we found recurrent mutations in TP73 splice site, which induced skipping of exons 2 and 3, generating a dominant-negative variant similar to their SVs. In addition, recurrent non-coding elements contained several novel regions, such as 3´-untranslated region (UTR) of NFKBIZ and 5´- UTR of TMSB4X. Altogether, a total of 56 genes were recurrently altered. The median number of driver alterations was eight per case, and at least one driver alteration was found in 149 cases (96.1%). Among 56 driver genes, 40 (71.4%) genes were affected by more than one alteration class. Some drivers, such as CDKN2A, IKZF2, and CD274, were affected almost exclusively by CNAs and/or SVs, while showing quite high alteration frequencies (11.6-29.0%). These observations suggest that WGS presented a substantially different overview of driver alterations from our previous study. The overall numbers of mutations and SVs were linked to these driver alterations, suggesting their etiology. In particular, inactivation of EP300 and immune-related molecules, such as HLA-A, HLA-B, and CD58, were associated with an increased number of mutations and SVs, especially deletions and tandem duplications. By contrast, cases with TP53-altered cases harbored more inversions and translocations. These results emphasize a pivotal role of immune evasion for acquiring genetic alterations to drive ATL progression. To define molecular subgroups in ATL, we integrated the 56 identified genetic drivers using non-negative matrix factorization clustering and identified two robust subgroups with discrete clinical and genetic characteristics. Group 1 was enriched with alterations affecting distal components of T-cell receptor (TCR)/NF-κB signaling (such as CARD11, PRKCB, and IRF4) and immune-related molecules (HLA-A, HLA-B, and CD58), whereas proximal regulators of TCR/NF-κB signaling (PLCG1, VAV1, and CD28) and a JAK/STAT signaling molecule (STAT3) were more frequently altered in group 2. In addition, group 1 cases had a larger number of mutations, SVs, and CNAs than group 2 cases. Clinically, most cases with lymphoma subtype were classified into group 1, whereas group 2 mainly consisted of cases with leukemic subtypes. Moreover, group1 cases showed a worse overall survival than group 2, independently of clinical subtype. These results suggest the biological and clinical relevance of the molecular classification of ATL. In summary, our WGS analysis not only identifies novel somatic alterations but also extends the overview of ATL genome. We also propose a new molecular classification of ATL, with its clinical relevance, which can lead to the future improvement of patient management. Disclosures Kogure: Takeda Pharmaceutical Company Limited.: Honoraria. Nosaka:Kyowa Kirin Co.Ltd: Honoraria; Chugai pharmaceutical Co. Ltd: Honoraria; Novartis international AG: Honoraria; Celgene K.K: Honoraria; Eisai Co., Ltd: Honoraria; Merck Sharp & Dohme K.K.: Honoraria; Bristol-Myer Squibb: Honoraria. Imaizumi:Kyowa Kirin Co. Ltd.: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Eisai: Honoraria. Utsunomiya:Kyowa Kirin: Honoraria; Celgene: Honoraria. Shah:Celgene: Research Funding; BMS: Research Funding; Physicians Education Resource: Honoraria. Janakiram:Takeda, Fate, Nektar: Research Funding. Ramos:NIH: Research Funding. Takaori-Kondo:Astellas Pharma: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Ono Pharmaceutical: Research Funding; Thyas Co. Ltd.: Research Funding; Takeda: Research Funding; CHUGAI: Research Funding; Eisai: Research Funding; Nippon Shinyaku: Research Funding; Otsuka Pharmaceutical: Research Funding; Pfizer: Research Funding; OHARA Pharmaceutical: Research Funding; Sanofi: Research Funding; Novartis Pharma: Honoraria; MSD: Honoraria. Miyazaki:Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Celgene: Honoraria; NIPPON SHINYAKU CO.,LTD.: Honoraria; Otsuka Pharmaceutical: Honoraria; Novartis Pharma KK: Honoraria; Astellas Pharma Inc.: Honoraria. Matsuoka:Chugai Pharmaceutical Co. Ltd: Research Funding; Bristol-Myers Squibb: Research Funding; Kyowa Kirin Co. Ltd.: Research Funding. Ishitsuka:Takeda: Other: Personal fees, Research Funding; mundiharma: Other: Personal fees; Taiho Pharmaceuticals: Other: Personal fees, Research Funding; Janssen Pharmaceuticals: Other: Personal fees; Novartis: Other: Personal fees; Pfizer: Other: Personal fees; Astellas Pharma: Other, Research Funding; Genzyme: Other; Sumitomo Dainippon Pharma: Other, Research Funding; Eisai: Other, Research Funding; Mochida: Other, Research Funding; Shire: Other; Otsuka Pharmaceutical: Other; Ono Pharmaceutical: Other, Research Funding; Teijin Pharma: Research Funding; MSD: Research Funding; Asahi kasei: Research Funding; Eli Lilly: Research Funding; Daiichi Sankyo: Other; Huya Japan: Other; Celgene: Other: Personal Fees; Kyowa Hakko Kirin: Other: Personal fees, Research Funding; BMS: Other: Personal fees; Chugai Pharmaceutical: Other: Personal fees, Research Funding. Ogawa:Asahi Genomics Co., Ltd.: Current equity holder in private company; Chordia Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; KAN Research Institute, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding. Shimoda:Takeda Pharmaceutical Company: Honoraria; Bristol-Myers Squibb: Honoraria; Shire plc: Honoraria; Celgene: Honoraria; Perseus Proteomics: Research Funding; PharmaEssentia Japan: Research Funding; AbbVie Inc.: Research Funding; Astellas Pharma: Research Funding; Merck & Co.: Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Pfizer Inc.: Research Funding; Otsuka Pharmaceutical: Research Funding; Asahi Kasei Medical: Research Funding; Japanese Society of Hematology: Research Funding; The Shinnihon Foundation of Advanced Medical Treatment Research: Research Funding; Novartis: Honoraria, Research Funding. Kataoka:CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Takeda Pharmaceutical Company: Research Funding; Otsuka Pharmaceutical: Research Funding; Asahi Genomics: Current equity holder in private company.