Authors thank Jeffrey Sellers to assist orthotopic pancreatic cancer mouse modeling. This work was supported by Research Initiative Pilot Awards from the Department of Radiology at UAB and NIH grants 2P30CA013148 and P50CA101955.

Tüm işlemler Birmingham Alabama Üniversitesi Kurumsal Hayvan Bakım ve Kullanım Kurulu tarafından kabul edildi. 1. Ortotopik Pankreas Tümör Fare Modelleme <ol><li> Dulbecco tadil edilmiş Eagle ortamı (DMEM) içinde kültür standart insan pankreatik kanser hücre çizgileri% 10 cenin sığır serumu ile takviye edilmiştir. % 5 CO2 ile nemli bir atmosferde 37 ° C &#39;de, tüm kültür muhafaza edin. </li><li> 8-10 haftalık dişi şiddetli kombine immunodefisiyan fareler kullanın. 12 saat ışık ve 12 saat karanlık çevrimi oda sıcaklığında (21 ± 2 ° C) ve% 60 nemde bir hayvan kafesleri yerleştirin. </li><li> Ameliyat boyunca oksijen (/ dk 2 L) ile karıştırılmıştır izofluran% 2 ile havalandırma ile tüm hayvanlar anestezisi. Ayak tutam refleks ile anestezi derinliği onaylayın. Bir ısıtma yastığı (37 ° C) yerleştirin hayvanlar vücut ısısını korumak için. Anestezi altında iken kuruluğu önlemek için göze veteriner oftalmik merhem sürün. &amp;# 160; </li><li> Her fare karnın sol üst kadranda saç çıkarın ve bir analjezik ilaç vermek alana (5 mg / vücut ağırlığı kg subkutan carpofen). Maruz kalan cilde betadin çözümü uygulayın. Otoklava cerrahi aletler hazırlayın. </li><li> Deride 1 cm&#39;lik kesi yapmak ve iris düz makas kullanarak periton. Yavaşça cerrahi cımbız kullanarak karın pankreas kaldırmak. </li><li> Pankreas kuyruğa, 0.5 ml insülin şırınga 28 G iğne takın ve daha sonra yavaş yavaş, DMEM, 30 ul 2.500.000, insan pankreas kanser hücrelerinin bir çözelti aşılamak. Küçük bir kabarcık çözeltisi ile pankreas başında oluşturulan olduğunu doğrulayın. </li><li> Yavaşça geri cerrahi cımbız kullanarak karın içine pankreas yerleştirin. 2 5-0 Prolen sütür kesintiye 1 katmanda periton ve cilt kapatın ve sonra anestezi sonlandırmak. Tamamen iyileşene kadar diğer hayvanların şirkete ameliyat geçirmiş bir hayvan iade etmeyin.60; 7 ~ 10 gün sonrası ameliyat sırasında sütür çıkarın. </li><li> Ameliyattan 24 saat sonra (carpofen 5 mg / vücut ağırlığı deri altından kg) bir ilaç bir doz ver. </li><li> İki parmağınızı kullanarak cerrahi alan palpe tümör boyutunu kontrol edin. Tümörler genellikle çevredeki dokulara ve organlara göre daha yoğun ve bumpier hissediyorum. Bir tümör duygu başlamak için 2 hafta - Genellikle ~ 1 sürer. </li><li> Hastalık belirtileri günlük hayvanları izleyin. Hayvanlar hasta (eksikliği, normal bakım ve kaçınma davranışları) göründüğünde, biz anestezi altında iken servikal dislokasyon kullanarak sonlandırıldı. </li></ol> 2. Manyetik Rezonans Görüntüleme <ol><li> Hücre implantasyonu sonrası, genellikle 2 ila 4 hafta sonra, çapı 7 mm - tümör boyutu yaklaşık 5 olduğu zaman MRI uygulanır. Küçük hayvan görüntüleme veya küçük hayvan görüntüleme için özel bir bobin ile donatılmış bir klinik MR tarayıcı adanmış bir MR tarayıcı kullanın. NOT: 1 lH hacim rezonatörün bir kombinasyonu ile bir 9.4T küçük hayvan MR tarayıcı kullanılır/ Verici ve bir yüzey bobin yuvası (çapı 30 mm) (Bruker BioSpin Corp., Billerica, MA). Bir yüzey bobin daha iyi sinyal-gürültü oranı (SNR) 14 sağlamaktadır. </li><li> 0.2 ml PBS (fosfat tamponlu tuzlu su) - 0.1, her bir hayvana, 0.2 mg / kg - 0.1 enjekte etmek için bir gadolinyum göre MRT-kontrast maddesinin hazırlanması. NOT: gadoteridol kullanılır ve 15 saniyelik bir süre (0,1 ml / sn) üzerinde 0.15 mi, PBS içinde 0.2 mg / kg enjekte edildi. </li><li> Bir mikro-polietilen tüp (7.62 mm iç çap: 0.28 mm, dış çap: 0.64 mm uzunluk) hazırlayın. Bir borunun ucuna, diğer ucunu bir 30 G künt ucu iğne (9.5 mm uzunluk) içine 30 G iğne (12.7 mm uzunluk) takın. Künt ucu iğne MR kontrast madde içeren 1 ml şırınga bağlayın ve yavaşça MR kontrast madde ile tüm tüp doldurmak için şırınga itin. </li><li> Hazırlanması ve görüntüleme boyunca oksijen (2 L / dk) ile karışık izofluran% 2 - ~ 1 ile havalandırma kullanarak hayvanları uyutmak. ANEST derinliğini teyitayak tutam refleks ile zi. Anestezi altında iken kuruluğu önlemek için göze veteriner oftalmik merhem sürün. İğne yerleştirilmeden önce bir ısı lambası kullanarak ven kuyruk genişletmek. Kelly forseps kullanarak 30 G iğne ortasında tut, ve kuyruk ven içine yerleştirin. Plastik veya karton kağıt (10 mm genişlik x 100 mm uzunluk) bir parça üzerine bant hem kuyruk ve tüp kuyruğu dik tutmak için. </li><li> Görüntüleme sırasında vücut ısısını düzenlemek için ılık su (ya da sıcak hava) dolaşan ile donatılmış bir hayvan yatakta sırtüstü pozisyonda hayvan yerleştirin. 37 ° C yatakta sıcaklığını ayarlayın. Görüntüleme sırasında vücut sıcaklığını izlemek için bir rektal sıcaklık probu yerleştirin. </li><li> Karın alana bir dik bükülmüş plastik kurulu uygulayın. Tümör kurulu üst ucunun arkasında bulunduğundan emin olun, ve sonra hafifçe tahta aşağı çekin (~ 2 mm) tümörü sağlamak için yönetim kurulu tarafından yakalandı. Sıkıca hayvan yatağına kurulu Teyp. </li><li> Bir solunum ped transduce Teypgöğüs bölgesine r (SA Enstrüman, Inc., Stony Brook, NY) görüntüleme sırasında hayvan solunumu izlemek için. Tümörlü bölgede üst yüzey bobin yerleştirin ve sıkı bir şekilde bir hayvan yatağa bantlayın. (: 72 mm iç çap) hacim bobin merkezine tümör bölgesini yerleştirmek için MR tarayıcı içine hayvan yatak itin. </li><li> Alıcı ve verici hem de eşleştirme ve ayarlama yapın, shimming ile izledi. </li><li> Tümör bulmak için bir anatomik MR dizisi ile başlayın. Aşağıdaki satın alma parametreleri ile eksenel görüntüler elde etmek için bir T2 ağırlıklı (T2A) turbo spin-eko sekansı kullanın. Tekrarlama zamanı (TR) / eko zamanı (TE) = 3,000 / 34 msn, 128 x 128 matris, görüş 30 x 30 mm alan ortalamalar sayısı = 1, eko tren uzunluğu = 4, ve 20 bitişik 1 mm kalınlığında dilimler halinde Bir geçmeli modu tüm tümör bölgesini (: 1.6 dk, toplam tarama süresi) kapsayacak. Not: ortotopik pankreatik tümörler subkutan olanlardan daha bulunduğu için daha zor olduğu için, geleneksel localiAlt çözünürlüğe sahip zer görüntüleri yararlı olmayabilir. </li><li> T1 haritasını almak için çeşitli flip açıları ile T1 ağırlıklı (T1A) görüntüler elde. Ortalamaların tekrar zamanı (TR) / eko zamanı (TE) = 115/3 msn, 128 x 128 matrisi, görüş 30 x 30 mm alanını, sayı: Bu amaçla, aşağıdaki parametrelerin ile multiflip açı yaklaşımı yankı degrade kullanın = 4, ~ 5 - tümör bölgesini kapsayacak bir geçmeli modda 7 bitişik 1 mm kalınlığında dilimler ve 10 yedi çevirme açıları, 20, 30, 40, 50, 60, ve çevirme açısı başına 70 (toplam tarama süresi: 1 dakika). NOT: Ancak, multiflip açı yaklaşımı B1 alan homojenliği yüksek olduğu zaman etkilidir. Değilse, T1 harita birden TR yaklaşımı yerine, 15 ile elde edilebilir. </li><li> Öncesi ve gadolinyum bazlı MR kontrast enjeksiyonundan sonra T1A görüntüler elde. Esp, k-uzay merkezi elde edildiğinde sabit durumu sağlamak için T1 haritalama için ama 30. kullanın doğrusal kodlama sabit kapak açısı ile aynı satın alma parametreleri ve geometri kullanınKısa bir TR ve düşük derece çevirme açısı kullanılır ecially zaman. Kontrast verilmeden önce 5 temel görüntü elde. (: 45 dk, toplam tarama zamanında) Sonra kontrast enjeksiyonu sonrası 40 görüntüler elde. Sabit bir oranda (0.01 mi / saniye) kontrast ajanı enjekte etmek için bir şırınga pompası kullanın. </li><li> Sürekli hayvan nefes Monitör ve 50 solunum hızı tutmak için izofluran konsantrasyonunu ayarlamak - dakika başına 100 nefesten. Görüntüleme boyunca hayvan vücut sıcaklığını izlemek. </li><li> DCE-MRI tamamladıktan sonra, iğne ve diğer sondalar çıkarmak ve kağıt havlu ile tabakalı bir boş kafes içinde hayvan yerleştirin. Usulca alt karın bölgesine masaj. Kafes o kurtarır hayvan ısı degrade ve dışarı taşımak için izin vermek için bir ısı lambası altında yarısı konulmalıdır. Sternal yatma korumak için yeterli bilinci yerine kadar gözetimsiz bir hayvan bırakmayın. </li></ol> 3. Görüntü İşleme ve Analiz <ol><li> Segment tümör regi<html> T2A görüntülerde üzerinde. T2A görüntülerde, tümör bölgesinde sinyal yoğunluğu çevre dokulara daha parlak, yani tümör sınır çizilmiştir edilebilir. NOT: Bu tür küresel eşikleme veya aktif şekillendirme gibi yarı-otomatik segmentasyon teknikleri 16,17 kullanılabilir, ancak düzensiz arka plan yoğunluğu yüzey bobin kullanıldığında özellikle düzeltilmelidir. </li><li> T1 ve proton yoğunluğu haritaları oluşturun. O yankı zamanı (TE) varsayarak bir gradyan eko sekansı ile elde edilen T1A görüntülerde, T2 * değeri, piksel değeri tarafından belirlenir çok daha azdır <img alt="Denklem 1" fo:content-width="3in" src="/files/ftp_upload/52641/52641eq1.jpg" /> S 0 proton yoğunluğu olduğu, T 1 TR tekrarlama zamanı, T 1 gevşeme zamanı sabittir, ve θ bir flip açısıdır. Denklem (1) ile yazılabilir 641eq2.jpg &quot;/&gt; S (θ) / sinθ Y ile ikame edilir, ve S (θ) zaman / tanθ X ile değiştirilir. Denklem (2) bir lineer denklem ve onun eğim ve kesişim sırasıyla T1 ve S 0 değerleri almak için kullanılabilir. </li><li> DCE-MR görüntüleri MR kontrast konsantrasyonunu hesaplayın. Gadolinyum bazlı MR kontrast madde enjekte edildiğinde, T 1 gevşeme zamanı sabiti zamanla değişti. Yani, denklem (1) için yeniden olabilir <img alt="Denklem 3" fo:content-width="3in" src="/files/ftp_upload/52641/52641eq3.jpg" /> Aşağıdaki gibi, T 1 (t), MR kontrast konsantrasyonu, C (t) ile ilgilidir <img alt="Denklem 4" fo:content-width="3in" src="/files/ftp_upload/52641/52641eq4.jpg" /> burada r, 1 MR kontrast madde uzunlamasına relaksivitesi olup. Yani, birleştirerek denklemler (3) ve (4), MR kontrast konsantrasyonu ile belirlenir <img alt = &quot;Denklem 5&quot; fo: içerik width = &quot;3in&quot; src = &quot;/ files / ftp_upload / 52.641 / 52641eq5.jpg&quot; /&gt; </li><li> Kontrast enjeksiyonu başlatıldıktan sonra t MR kontrast ajan. C p (t) kan plazması MR kontrast konsantrasyonunu sunuyor farmakokinetik parametreleri ölçmek. C p (t) arteriyel giriş fonksiyonu (AIF) denir. AIF varsa, MR kontrast maddenin farmakokinetik parametreler hesaplanabilir <img alt="Denklem 6" fo:content-width="4in" src="/files/ftp_upload/52641/52641eq6.jpg" /> Cı t (t), MR kontrast konsantrasyonu, hedef dokuda etkinin ortaya çıkışıdır ve v s, h e fraksiyonel ekstravasküler ekstrasellüler hacim fraksiyonel kan plazma hacmi ve K, trans ses aktarma sabittir. Akı, k oran sabiti ep K tran eşittirv e bölünür s. AIF mevcut değilse, o zaman bir referans bölgesi, bir model yerine 18,19 kullanılabilir. Referans bölge modeli akış sınırlı Kety modeli 20 ve dayalı şöyle AIF ihtiyacını kaldırmak için bir referans bölgedeki kontrast konsantrasyonunu kullanır, <img alt="Denklem 7" fo:content-width="5in" src="/files/ftp_upload/52641/52641eq7.jpg" /> burada C t, ROI (t), K trans, YG ve v e ROI, ilgi (ROI) bölgede sırasıyla kontrast konsantrasyonu, hacim transferi sabit ve fraksiyonel ekstravasküler-dışı hacim, vardır C t iken, RR (t); K, trans, RR ve v, e, RR referans bölgesinin olanlardır. Paravertebral kas genellikle kemirgen pa v e RR referans bölge olarak seçilen veravertebral kas 0.08 21 sabit olduğu varsayılır. Biz referans bölge modeli kullanılır. </li></ol>

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S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Estimating+kinetic+parameters+from+dynamic+contrast-enhanced+T(1)-weighted+MRI+of+a+diffusable+tracer:+standardized+quantities+and+symbols.">Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer: standardized quantities and symbols.</a> J Magn Reson Imaging. 10 (3), 223-232 (1999).</li><li>Yankeelov, T. E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Comparison+of+a+reference+region+model+with+direct+measurement+of+an+AIF+in+the+analysis+of+DCE-MRI+data.">Comparison of a reference region model with direct measurement of an AIF in the analysis of DCE-MRI data.</a> Magn Reson Med. 57 (2), 353-361 (2007).</li><li>Cao, R. Y., Amand, T., Ford, M. D., Piomelli, U., Funk, C. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+Murine+Angiotensin+II-Induced+Abdominal+Aortic+Aneurysm+Model:+Rupture+Risk+and+Inflammatory+Progression+Patterns.">The Murine Angiotensin II-Induced Abdominal Aortic Aneurysm Model: Rupture Risk and Inflammatory Progression Patterns.</a> Front Pharmacol. 1 (9), (2010).</li><li>Parker, G. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Experimentally-derived+functional+form+for+a+population-averaged+high-temporal-resolution+arterial+input+function+for+dynamic+contrast-enhanced+MRI.">Experimentally-derived functional form for a population-averaged high-temporal-resolution arterial input function for dynamic contrast-enhanced MRI.</a> Magn Reson Med. 56 (5), 993-1000 (2006).</li><li>Tseng, W., Leong, X., Engleman, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Orthotopic+mouse+model+of+colorectal+cancer.">Orthotopic mouse model of colorectal cancer.</a> J Vis Exp. (10), 484 (2007).</li><li>Bhullar, J. S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+true+orthotopic+gastric+cancer+murine+model+using+electrocoagulation.">A true orthotopic gastric cancer murine model using electrocoagulation.</a> J Am Coll Surg. 217 (1), 64-70 (2013).</li></ol>

Authors do not have any conflicts of interest to declare.

Bu immunodefisiyan fareler, fare abdominal tümörlerin DCE MRG ve kinetik parametrelerinin ölçümü ile ortotopik pankreas tümörü modelleme ayrıntılı olacak şekilde kullanılır. Pankreas kuyruk içine bir iğne takarken ortotopik pankreas tümörü modellemede, dikkatli olunmalıdır. Eğer başarılı olursa, hücreler, küçük bir kabarcık oluşturma pankreas başı transfer edilecek. Bir dik bükülmüş plastik kurulu uygularken, tümör kurulu üst ucunun altında bulunduğunu doğrulamak için kritik ...

Bu yöntemin genel amacı farelerde ortotopik pankreas tümörü xenografts için dinamik kontrastlı manyetik rezonans görüntüleme (DCE-MRI) uygulamaktır. DCE MR enjeksiyonundan sonra belli bir süre boyunca MR kontrast değişiklik izlenerek veya hedeflenen bir dokuda mikrovaskuleterini değerlendirmek için invazif olmayan bir yöntemdir. DCE-MRI habis tümörler teşhis etmek ve çeşitli terapiler 1-4 tümör yanıtı değerlendirmek için kullanılmıştır. Kantitatif DCE-MRG yüksek tekrarlanabilirlik 5 sunmuştur. Bir hedef dokuda bir MR kontrast maddenin farmakokinetik parametrelerini ölçmek için, kontrast madde önce elde edilen farklı zaman noktalarında, T1 haritasına alınan tüm DCE MR görüntüleri 6 coregistered gerekir. Ancak, karın bölgesinde solunum ve peristaltik hareketlere, kantitatif DCE-MRI, gastrointestinal tümörler için sınırlı bir uygulama olmuştur. Ortotopik pankreatik tümör modelleri değerlendirmek için kullanılmıştırBiyolojik tedaviler ve kemoterapi 7,8 aşağıdaki pankreas-tümör yanıtı. Orijinal tümör sitesinde mikroçevresinin yansır ve tedaviye böylece insan tümör yanıtı daha doğru tahmin edilebilir çünkü Ortotopik tümör modelleri, klasik subkutan modellere üstün kabul edilir. Ancak, fare pankreas karnın sol üst kadranda bulunan, farelerde ortotopik pankreas tümörü ksenograftlarının nedenle nicel DCE-MRI kolayca uygulamaya konmamıştır. Biz göğüs bölgesi 9 dan hareket transferini engellemek için bir dik bükülmüş plastik tahta kullanarak tümörleri tespit farelerde tümörlerin karın DCE-MRI bir protokol kurduk. Bu kurul tarafından uygulanan basınç karın bölgesinde lokalize edilmiş ve solunum güçlüğü sonuçlandı değil. Otomatik görüntü coregistration tekniği serbest nefes modunda karın içi organların DCE-MRI valide edilmiş, ancak effectivel gerçekleştiriry sadece hedef bölgeleri yavaş yavaş ve düzenli 10 taşıdığınızda. Hayvanların Solunum hızı görüntüleme sırasında değişkendir, karın bölgesinde çok fiziksel kısıtlama ortotopik pankreas tümörü fare modellerinde güvenilir farmakokinetik parametrelerini almak için gerekli olacaktır. Biz başarıyla DCE-MRI 11-13 yılında dik bükülmüş plastik tahta kullanarak ortotopik pankreas tümörü ksenograftlarda bir MR kontrast maddenin farmakokinetik parametreleri quantitated var. Burada ortotopik pankreas tümörü modelleme ayrıntılı prosedürü sunmak, tümör farelerde xenografts ve farmakokinetik parametrelerin ölçümü ve DCE-MRI.

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			<td height="21" style="height:21px;width:245px;">Name of Material/ Equipment</td>
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			<td style="width:712px;">Comments/Description</td>
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			<td height="21" style="height:21px;">DMEM</td>
			<td>Invitrogen</td>
			<td>11965-118</td>
			<td></td>
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			<td height="21" style="height:21px;">Fetal bovine serum</td>
			<td>Harlan Laboratories</td>
			<td>BT-9501</td>
			<td></td>
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			<td height="21" style="height:21px;">Betadine</td>
			<td style="width:199px;">Purdue products</td>
			<td style="width:119px;">67618-153-01</td>
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			<td height="21" style="height:21px;">5-0 Prolene sutures</td>
			<td style="width:199px;">Ethicon</td>
			<td style="width:119px;">8720H</td>
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			<td height="42" style="height:42px;">9.4T MR scanner</td>
			<td>Bruker Biospin Corporation</td>
			<td style="width:119px;">BioSpec 94/20 USR</td>
			<td></td>
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			<td height="42" style="height:42px;">Gadoteridol</td>
			<td>Bracco Diagnostics Inc</td>
			<td style="width:119px;">NDC 0270-1111-03</td>
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			<td height="21" style="height:21px;">Micro-polyethelene tube</td>
			<td style="width:199px;">Strategic Applications, Inc</td>
			<td style="width:119px;">#PE-10-25</td>
			<td></td>
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			<td height="21" style="height:21px;">30G blunt tip needle</td>
			<td style="width:199px;">Strategic Applications, Inc</td>
			<td style="width:119px;">89134-194</td>
			<td></td>
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		<tr height="21">
			<td height="21" style="height:21px;">Monitoring and gating system</td>
			<td style="width:199px;">SA instruments, Inc</td>
			<td style="width:119px;">Model 1030</td>
			<td>This is an MR compatiable system to measure resiratory rating and body temperature of small animals at the same time.</td>
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			<td height="21" style="height:21px;">Syringe pump</td>
			<td>New Era Pump Systems, Inc.</td>
			<td>NE-1600</td>
			<td></td>
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dynamic contrast enhanced magnetic resonance imaging of an orthotopic pancreatic cancer mouse model

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has been limitedly used for orthotopic pancreatic tumor xenografts due to severe respiratory motion artifact in the abdominal area. Orthotopic tumor models offer advantages over subcutaneous ones, because those can reflect the primary tumor microenvironment affecting blood supply, neovascularization, and tumor cell invasion. We have recently established a protocol of DCE-MRI of orthotopic pancreatic tumor xenografts in mouse models by securing tumors with an orthogonally bent plastic board to prevent motion transfer from the chest region during imaging. The pressure by this board was localized on the abdominal area, and has not resulted in respiratory difficulty of the animals. This article demonstrates the detailed procedure of orthotopic pancreatic tumor modeling using small animals and DCE-MRI of the tumor xenografts. Quantification method of pharmacokinetic parameters in DCE-MRI is also introduced. The procedure described in this article will assist investigators to apply DCE-MRI for orthotopic gastrointestinal cancer mouse models.

Insan pankreas tümörü hücreleri, fare pankreası bir katı tümör oluşturma başarılı bir şekilde büyür. 1, (A), tümör hücre solüsyonu enjekte edilir bir normal pankreas, ve (B) fotoğraflarını göstermektedir ortotopik pankreas tümörü xenograft taşıyan bir temsili fare (MIA PaCa-2 ). Tümör yanında dalak, karın sol üst kadranda yer almaktadır. Hücre implantasyon sonrası çapı 7 mm - tümörler 5 büyümek için 4 hafta - Genellikle 2 sürer. <p class="...

Watch this Scientific Journal Video about Dynamic Contrast Enhanced Magnetic Resonance Imaging of an Orthotopic Pancreatic Cancer Mouse Model at JoVE.com

Dynamic Contrast Enhanced Magnetic Resonance Imaging of an Orthotopic Pancreatic Cancer Mouse Model

The goal of this protocol is to apply dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) for orthotopic pancreatic tumor xenografts in mice. DCE-MRI is a non-invasive method to analyze microvasculature in a target tissue, and useful to assess vascular response in a tumor following a novel therapy.

Ortotopik Pankreas Kanseri Fare Modeli Dinamik Kontrast Geliştirilmiş Manyetik Rezonans Görüntüleme

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has been limitedly used for orthotopic pancreatic tumor xenografts due to severe ...

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Research

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Medicine

15.0K Görüntüleme.  University of Alabama at Birmingham. The goal of this protocol is to apply dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) for orthotopic pancreatic tumor xenografts in mice. DCE-MRI is a non-invasive method to analyze microvasculature in a target tissue, and useful to assess vascular response in a tumor following a novel therapy. 

Video: Dynamic Contrast Enhanced Magnetic Resonance Imaging of an Orthotopic Pancreatic Cancer Mouse Model

Contrast Enhanced Vessel Imaging using MicroCT

Microscopic computed tomography (microCT) offers high-resolution volumetric imaging of the anatomy of living small animals. However, the contrast between different soft tissues and body fluids is inherently poor in micro-CT images 1. Under these circumstances, visualization of blood vessels becomes a nearly impossible task. To overcome this and to improve the visualization of blood vessels exogenous contrast agents can be used. Herein, we present a methodology for visualizing the vascular network in a rodent model. By using a long-acting aqueous colloidal polydisperse iodinated blood-pool contrast agent, eXIA 160XL, we optimized image acquisition parameters and volume-rendering techniques for finding blood vessels in live animals. Our findings suggest that, to achieve a superior contrast between bone and soft tissue from vessel, multiple-frames (at least 5-8/ frames per view), and 360-720 views (for a full 360&deg; rotation) acquisitions were mandatory. We have also demonstrated the use of a two-dimensional transfer function (where voxel color and opacity was assigned in proportion to CT value and gradient magnitude), in visualizing the anatomy and highlighting the structure of interest, the blood vessel network. This promising work lays a foundation for the qualitative and quantitative assessment of anti-angiogenesis preclinical studies using transgenic or xenograft tumor-bearing mice.

Contrast enhanced small animal vessel imaging by microCT is a rapid, cost-effective and high-throughput technique for serial in situ examination for tumor development, for analyzing the network of blood vessels that nourish them, and for following the response of tumors to preclinical therapeutic intervention(s).

Kontrast Geliştirilmiş Gemi Görüntüleme MicroCT kullanarak

Microscopic computed tomography (microCT) offers high-resolution volumetric imaging of the anatomy of living small animals. However, the contrast between ...

Tıp

An Orthotopic Model of Murine Bladder Cancer

In this straightforward procedure, bladder tumors are established in female C57 mice through the use of catheterization, local cauterization, and subsequent cell adhesion. After their bladders are transurethrally catheterized and drained, animals are again catheterized to permit insertion of a platinum wire into bladders without damaging the urethra or bladder. The catheters are made of Teflon to serve as an insulator for the wire, which will conduct electrical current into the bladder to create a burn injury. An electrocautery unit is used to deliver 2.5W to the exposed end of the wire, burning away extracellular layers and providing attachment sites for carcinoma cells that are delivered in suspension to the bladder through a subsequent catheterization. Cells remain in the bladder for 90 minutes, after which the catheters are removed and the bladders allowed to drain naturally. The development of tumor is monitored via ultrasound. Specific attention is paid to the catheterization technique in the accompanying video.

Bladder tumors are established in female mice in a minimally invasive fashion through catheterization, local cauterization, and subsequent adhesion of carcinoma cells to the burn sites.

Murin Mesane Kanseri bir Ortotopik Model

In this straightforward procedure, bladder tumors are established in female C57 mice through the use of catheterization, local cauterization, and ...

Multi-photon Imaging of Tumor Cell Invasion in an Orthotopic Mouse Model of Oral Squamous Cell Carcinoma

Loco-regional invasion of head and neck cancer is linked to metastatic risk and presents a difficult challenge in designing and implementing patient management strategies. Orthotopic mouse models of oral cancer have been developed to facilitate the study of factors that impact invasion and serve as model system for evaluating anti-tumor therapeutics. In these systems, visualization of disseminated tumor cells within oral cavity tissues has typically been conducted by either conventional histology or with in vivo bioluminescent methods. A primary drawback of these techniques is the inherent inability to accurately visualize and quantify early tumor cell invasion arising from the primary site in three dimensions. Here we describe a protocol that combines an established model for squamous cell carcinoma of the tongue (SCOT) with two-photon imaging to allow multi-vectorial visualization of lingual tumor spread. The OSC-19 head and neck tumor cell line was stably engineered to express the F-actin binding peptide LifeAct fused to the mCherry fluorescent protein (LifeAct-mCherry). Fox1nu/nu mice injected with these cells reliably form tumors that allow the tongue to be visualized by ex-vivo application of two-photon microscopy. This technique allows for the orthotopic visualization of the tumor mass and locally invading cells in excised tongues without disruption of the regional tumor microenvironment. In addition, this system allows for the quantification of tumor cell invasion by calculating distances that invaded cells move from the primary tumor site. Overall this procedure provides an enhanced model system for analyzing factors that contribute to SCOT invasion and therapeutic treatments tailored to prevent local invasion and distant metastatic spread. This method also has the potential to be ultimately combined with other imaging modalities in an in vivo setting.

A comprehensive overview of the techniques involved in generating a mouse model of oral cancer and quantitative monitoring of tumor invasion within the tongue through multi-photon microscopy of labeled cells is presented. This system can serve as a useful platform for the molecular assessment and drug efficacy of anti-invasive compounds.

Oral Skuamöz Hücre Karsinomu Ortotopik Fare Modeli Tümör Hücre Invasion Multi-foton Görüntüleme

Loco-regional invasion of head and neck cancer is linked to metastatic risk and presents a difficult challenge in designing and implementing patient ...

Combination Radiotherapy in an Orthotopic Mouse Brain Tumor Model

Glioblastoma multiforme (GBM) are the most common and aggressive adult primary brain tumors1. In recent years there has been substantial progress in the understanding of the mechanics of tumor invasion, and direct intracerebral inoculation of tumor provides the opportunity of observing the invasive process in a physiologically appropriate environment2. As far as human brain tumors are concerned, the orthotopic models currently available are established either by stereotaxic injection of cell suspensions or implantation of a solid piece of tumor through a complicated craniotomy procedure3. In our technique we harvest cells from tissue culture to create a cell suspension used to implant directly into the brain. The duration of the surgery is approximately 30 minutes, and as the mouse needs to be in a constant surgical plane, an injectable anesthetic is used. The mouse is placed in a stereotaxic jig made by Stoetling (figure 1). After the surgical area is cleaned and prepared, an incision is made; and the bregma is located to determine the location of the craniotomy. The location of the craniotomy is 2 mm to the right and 1 mm rostral to the bregma. The depth is 3 mm from the surface of the skull, and cells are injected at a rate of 2 &mu;l every 2 minutes. The skin is sutured with 5-0 PDS, and the mouse is allowed to wake up on a heating pad. From our experience, depending on the cell line, treatment can take place from 7-10 days after surgery. Drug delivery is dependent on the drug composition. For radiation treatment the mice are anesthetized, and put into a custom made jig. Lead covers the mouse's body and exposes only the brain of the mouse. The study of tumorigenesis and the evaluation of new therapies for GBM require accurate and reproducible brain tumor animal models. Thus we use this orthotopic brain model to study the interaction of the microenvironment of the brain and the tumor, to test the effectiveness of different therapeutic agents with and without radiation.

The purpose of this article is to describe the use of an orthotopic glioblastoma model for chemoradiation studies. This article will go though cell processing, implanting, and radiotherapy of the mouse using an intracranial model.

Bir Ortotopik Fare Beyin Tümörü Modelinde Kombinasyon Radyoterapi

Glioblastoma multiforme (GBM) are the most common and aggressive adult primary brain tumors1. In recent years there has been substantial progress in the ...

Multi-modal Imaging of Angiogenesis in a Nude Rat Model of Breast Cancer Bone Metastasis Using Magnetic Resonance Imaging, Volumetric Computed Tomography and Ultrasound

Angiogenesis is an essential feature of cancer growth and metastasis formation. In bone metastasis, angiogenic factors are pivotal for tumor cell proliferation in the bone marrow cavity as well as for interaction of tumor and bone cells resulting in local bone destruction. Our aim was to develop a model of experimental bone metastasis that allows in vivo assessment of angiogenesis in skeletal lesions using non-invasive imaging techniques.
For this purpose, we injected 105 MDA-MB-231 human breast cancer cells into the superficial epigastric artery, which precludes the growth of metastases in body areas other than the respective hind leg1. Following 25-30 days after tumor cell inoculation, site-specific bone metastases develop, restricted to the distal femur, proximal tibia and proximal fibula1. Morphological and functional aspects of angiogenesis can be investigated longitudinally in bone metastases using magnetic resonance imaging (MRI), volumetric computed tomography (VCT) and ultrasound (US).
MRI displays morphologic information on the soft tissue part of bone metastases that is initially confined to the bone marrow cavity and subsequently exceeds cortical bone while progressing. Using dynamic contrast-enhanced MRI (DCE-MRI) functional data including regional blood volume, perfusion and vessel permeability can be obtained and quantified2-4. Bone destruction is captured in high resolution using morphological VCT imaging. Complementary to MRI findings, osteolytic lesions can be located adjacent to sites of intramedullary tumor growth. After contrast agent application, VCT angiography reveals the macrovessel architecture in bone metastases in high resolution, and DCE-VCT enables insight in the microcirculation of these lesions5,6. US is applicable to assess morphological and functional features from skeletal lesions due to local osteolysis of cortical bone. Using B-mode and Doppler techniques, structure and perfusion of the soft tissue metastases can be evaluated, respectively. DCE-US allows for real-time imaging of vascularization in bone metastases after injection of microbubbles7.
In conclusion, in a model of site-specific breast cancer bone metastases multi-modal imaging techniques including MRI, VCT and US offer complementary information on morphology and functional parameters of angiogenesis in these skeletal lesions.

In the pathogenesis of bone metastasis, angiogenesis is a crucial process and therefore represents a target for imaging and therapy. Here, we present a rat model of site-specific breast cancer bone metastasis and describe strategies to non-invasively image angiogenesis in vivo using magnetic resonance imaging, volumetric computed tomography and ultrasound.

Manyetik Rezonans Görüntüleme, Volumetrik Bilgisayarlı Tomografi ve Ultrason Kullanımı Meme Kanseri Kemik metastazı bir Nude Rat Model Angiogenezis Multi-modal Görüntüleme

Angiogenesis is an essential feature of cancer growth and metastasis formation. In bone metastasis, angiogenic factors are pivotal for tumor cell ...

An Orthotopic Mouse Model of Anaplastic Thyroid Carcinoma

Several types of animal models of human thyroid carcinomas have been established, including subcutaneous xenograft and orthotopic implantation of cancer cells into immunodeficient mice. Subcutaneous xenograft models have been valuable for preclinical screening and evaluation of new therapeutic treatments. There are a number of advantages to using a subcutaneous model; 1) rapid, 2) reproducible, and 3) tumor establishment, growth, and response to therapeutic agents may be monitored by visual inspection. However, substantial evidence has shed light on the short-comings of subcutaneous xenograft models1-3. For instance, medicinal treatments demonstrating curative properties in subcutaneous xenograft models often have no notable impact on the human disease. The microenvironment of the site of xenographic transplantation or injection lies at the heart of this dissimilarity.
Orthotopic tumor xenograft models provide a more biologically relevant context in which to study the disease. The advantages of implanting diseased cells or tissue into their anatomical origin equivalent within a host animal includes a suitable site for tumor-host interactions, development of disease-related metastases and the ability to examine site-specific influence on investigational therapeutic remedies. Therefore, orthotopic xenograft models harbor far more clinical value because they closely reproduce human disease. For these reasons, a number of groups have taken advantage of an orthotopic thyroid cancer model as a research tool4-7.
Here, we describe an approach that establishes an orthotopic model for the study of anaplastic thyroid carcinoma (ATC), which is highly invasive, resists treatment, and is virtually fatal in all diagnosed patients. Cultured ATC cells are prepared as a dissociated cellular suspension in a solution containing a basement membrane matrix. A small volume is slowly injected into the right thyroid gland. Overall appearance and health of the mice are monitored to ensure minimal post-operative complications and to gauge pathological penetrance of the cancer. Mice are sacrificed at 4 weeks, and tissue is collected for histological analysis. Animals may be taken at later time-points to examine more advance progression of the disease. Production of this orthotopic mouse model establishes a platform that accomplishes two objectives: 1) further our understanding of ATC pathology, and 2) screen current and future therapeutic agents for efficacy in combating ATC.

Generation of an orthotopic mouse model of anaplastic thyroid carcinoma is described here. This technique employs surgical placement of human anaplastic thyroid cancer cells into the thyroid of immunodeficient mice, thus creating a more clinically relevant setting to study disease progression as well as screen innovative therapeutic interventions.

Anaplastik Tiroid Kanseri Ortotopik Fare Modeli

Several types of animal models of human thyroid carcinomas have been established, including subcutaneous xenograft and orthotopic implantation of cancer ...

An Orthotopic Bladder Cancer Model for Gene Delivery Studies

Bladder cancer is the second most common cancer of the urogenital tract and novel therapeutic approaches that can reduce recurrence and progression are needed. The tumor microenvironment can significantly influence tumor development and therapy response. It is therefore often desirable to grow tumor cells in the organ from which they originated. This protocol describes an orthotopic model of bladder cancer, in which MB49 murine bladder carcinoma cells are instilled into the bladder via catheterization. Successful tumor cell implantation in this model requires disruption of the protective glycosaminoglycan layer, which can be accomplished by physical or chemical means. In our protocol the bladder is treated with trypsin prior to cell instillation. Catheterization of the bladder can also be used to deliver therapeutics once the tumors are established. This protocol describes the delivery of an adenoviral construct that expresses a luciferase reporter gene. While our protocol has been optimized for short-term studies and focuses on gene delivery, the methodology of mouse bladder catheterization has broad applications.

Implantation of cancer cells into the organ of origin can serve as a useful preclinical model to evaluate novel therapies. MB49 bladder carcinoma cells can be grown within the bladder following intravesical instillation. This protocol demonstrates catheterization of the mouse bladder for the purpose of tumor implantation and adenoviral delivery.

Gene Teslim Çalışmaları Ortotopik Mesane Kanseri Modeli

Bladder cancer is the second most common cancer of the urogenital tract and novel therapeutic approaches that can reduce recurrence and progression are ...

Bioluminescent Orthotopic Model of Pancreatic Cancer Progression

Pancreatic cancer has an extremely poor five-year survival rate of 4-6%. New therapeutic options are critically needed and depend on improved understanding of pancreatic cancer biology. To better understand the interaction of cancer cells with the pancreatic microenvironment, we demonstrate an orthotopic model of pancreatic cancer that permits non-invasive monitoring of cancer progression. Luciferase-tagged pancreatic cancer cells are resuspended in Matrigel and delivered into the pancreatic tail during laparotomy. Matrigel solidifies at body temperature to prevent leakage of cancer cells during injection. Primary tumor growth and metastasis to distant organs are monitored following injection of the luciferase substrate luciferin, using in vivo imaging of bioluminescence emission from the cancer cells. In vivo imaging also may be used to track primary tumor recurrence after resection. This orthotopic model is suited to both syngeneic and xenograft models and may be used in pre-clinical trials to investigate the impact of novel anti-cancer therapeutics on the growth of the primary pancreatic tumor and metastasis.

Improved understanding of pancreatic cancer biology is critically needed to enable the development of better therapeutic options to treat pancreatic cancer. To address this need, we demonstrate an orthotopic model of pancreatic cancer that permits non-invasive monitoring of cancer progression using in vivo bioluminescence imaging.

Pankreas Kanseri İlerleme Bioluminescent Ortotopik Model

Pancreatic cancer has an extremely poor five-year survival rate of 4-6%.  New therapeutic options are critically needed and depend on improved ...

An Orthotopic Murine Model of Human Prostate Cancer Metastasis

Our laboratory has developed a novel orthotopic implantation model of human prostate cancer (PCa). As PCa death is not due to the primary tumor, but rather the formation of distinct metastasis, the ability to effectively model this progression pre-clinically is of high value. In this model, cells are directly implanted into the ventral lobe of the prostate in Balb/c athymic mice, and allowed to progress for 4-6 weeks. At experiment termination, several distinct endpoints can be measured, such as size and molecular characterization of the primary tumor, the presence and quantification of circulating tumor cells in the blood and bone marrow, and formation of metastasis to the lung. In addition to a variety of endpoints, this model provides a picture of a cells ability to invade and escape the primary organ, enter and survive in the circulatory system, and implant and grow in a secondary site. This model has been used effectively to measure metastatic response to both changes in protein expression as well as to response to small molecule therapeutics, in a short turnaround time.

This orthotopic model of human prostate cancer allows for quantification of tumor size, circulating tumor cells, and formation of distinct metastasis to the lung. As cells must escape the primary organ, enter the blood stream, and implant into a secondary site, this model effectively recapitulates the scenario in humans.

İnsan Prostat Kanser metastaz Ortotopik fare modeli

Our laboratory has developed a novel orthotopic implantation model of  human prostate cancer (PCa). As PCa death is not due to the primary tumor, but  ...

Simultaneous PET/MRI Imaging During Mouse Cerebral Hypoxia-ischemia

Dynamic changes in tissue water diffusion and glucose metabolism occur during and after hypoxia in cerebral hypoxia-ischemia reflecting a bioenergetics disturbance in affected cells. Diffusion weighted magnetic resonance imaging (MRI) identifies regions that are damaged, potentially irreversibly, by hypoxia-ischemia. Alterations in glucose utilization in the affected tissue may be detectable by positron emission tomography (PET) imaging of 2-deoxy-2-(18F)fluoro-&#7429;-glucose ([18F]FDG) uptake. Due to the rapid and variable nature of injury in this animal model, acquisition of both modes of data must be performed simultaneously in order to meaningfully correlate PET and MRI data. In addition, inter-animal variability in the hypoxic-ischemic injury due to vascular differences limits the ability to analyze multi-modal data and observe changes to a group-wise approach if data is not acquired simultaneously in individual subjects. The method presented here allows one to acquire both diffusion-weighted MRI and [18F]FDG uptake data in the same animal before, during, and after the hypoxic challenge in order to interrogate immediate physiological changes.

The method presented here uses simultaneous positron emission tomography and magnetic resonance imaging. In the cerebral hypoxia-ischemia model, dynamic changes in diffusion and glucose metabolism occur during and after injury. The evolving and irreproducible damage in this model necessitates simultaneous acquisition if meaningful multi-modal imaging data are to be acquired.

Fare Serebral Hipoksi-iskemi sırasında Eşzamanlı PET / MR Görüntüleme

Dynamic changes in tissue water diffusion and glucose metabolism occur during and after hypoxia in cerebral hypoxia-ischemia reflecting a bioenergetics ...