Ultrastructural pathology of the upper respiratory tract of rabbits experimentally infected with Pasteurella multocida A:3

Twenty-four 8 to 9 week-old Pasteurella multocida-free rabbits were divided into three equal groups, the first group was pretreated with hydrocortisone and inoculated intranasally with pasteurella multocida serotype A:3. The second group was inoculated intranasally with P. multocida without hydrocortisone treatment. The third group was inoculated with phosphate buffered saline only and used as a control group. Pasteurella multocida was isolated from the nasal cavity of all infected rabbits in group 1 and 2 and from the trachea of seven rabbits in group 1 and five rabbits in group 2. This study was conducted to observe the ultrastructural changes of the upper respiratory tract of hydrocortisone treated and non-treated rabbits infected with P. multocida serotype A:3. The ultrastructural changes detected in infected rabbits were ciliary destruction and deciliation of the ciliated epithelial cells, cellular swelling, goblet cell hyperplasia and endothelial cell damage. Pasteurella multocida was observed attached to the degenerated cilia,microvilli and mucus. Pasteurella multocida infection was associated with inflammatory responses, which may have caused tissue damage. It is possible that hydrocortisone modulates the severity of infection as an immune suppressor and an inhibitor of goblet cell secretion

A role for sorting nexin 27 in AMPA receptor trafficking

10.1038/ncomms4176Nature Communications5

Hepatitis C virus mediated chronic inflammation and tumorigenesis in the humanised immune system and liver mouse model

10.1371/journal.pone.0184127PLoS ONE129e018412

Antisense oligonucleotide-mediated MDM4 exon 6 skipping impairs tumor growth

MDM4 is a promising target for cancer therapy, as it is undetectable in most normal adult tissues but often upregulated in cancer cells to dampen p53 tumor-suppressor function. The mechanisms that underlie MDM4 upregulation in cancer cells are largely unknown. Here, we have shown that this key oncogenic event mainly depends on a specific alternative splicing switch. We determined that while a nonsense-mediated, decay-targeted isoform of MDM4 (MDM4-S) is produced in normal adult tissues as a result of exon 6 skipping, enhanced exon 6 inclusion leads to expression of full-length MDM4 in a large number of human cancers. Although this alternative splicing event is likely regulated by multiple splicing factors, we identified the SRSF3 oncoprotein as a key enhancer of exon 6 inclusion. In multiple human melanoma cell lines and in melanoma patient-derived xenograft (PDX) mouse models, antisense oligonucleotide-mediated (ASO-mediated) skipping of exon 6 decreased MDM4 abundance, inhibited melanoma growth, and enhanced sensitivity to MAPK-targeting therapeutics. Additionally, ASO-based MDM4 targeting reduced diffuse large B cell lymphoma PDX growth. As full-length MDM4 is enhanced in multiple human tumors, our data indicate that this strategy is applicable to a wide range of tumor types. We conclude that enhanced MDM4 exon 6 inclusion is a common oncogenic event and has potential as a clinically compatible therapeutic target.Dewaele, Michael Tabaglio, Tommaso Willekens, Karen Bezzi, Marco Teo, Shun Xie Low, Diana H P Koh, Cheryl M Rambow, Florian Fiers, Mark Rogiers, Aljosja Radaelli, Enrico Al-Haddawi, Muthafar Tan, Soo Yong Hermans, Els Amant, Frederic Yan, Hualong Lakshmanan, Manikandan Koumar, Ratnacaram Chandrahas Lim, Soon Thye Derheimer, Frederick A Campbell, Robert M Bonday, Zahid Tergaonkar, Vinay Shackleton, Mark Blattner, Christine Marine, Jean-Christophe Guccione, Ernesto eng Research Support, Non-U.S. Gov't 2015/11/26 06:00 J Clin Invest. 2016 Jan;126(1):68-84. doi: 10.1172/JCI82534. Epub 2015 Nov 23. MDM4 is a promising target for cancer therapy, as it is undetectable in most normal adult tissues but often upregulated in cancer cells to dampen p53 tumor-suppressor function. The mechanisms that underlie MDM4 upregulation in cancer cells are largely unknown. Here, we have shown that this key oncogenic event mainly depends on a specific alternative splicing switch. We determined that while a nonsense-mediated, decay-targeted isoform of MDM4 (MDM4-S) is produced in normal adult tissues as a result of exon 6 skipping, enhanced exon 6 inclusion leads to expression of full-length MDM4 in a large number of human cancers. Although this alternative splicing event is likely regulated by multiple splicing factors, we identified the SRSF3 oncoprotein as a key enhancer of exon 6 inclusion. In multiple human melanoma cell lines and in melanoma patient-derived xenograft (PDX) mouse models, antisense oligonucleotide-mediated (ASO-mediated) skipping of exon 6 decreased MDM4 abundance, inhibited melanoma growth, and enhanced sensitivity to MAPK-targeting therapeutics. Additionally, ASO-based MDM4 targeting reduced diffuse large B cell lymphoma PDX growth. As full-length MDM4 is enhanced in multiple human tumors, our data indicate that this strategy is applicable to a wide range of tumor types. We conclude that enhanced MDM4 exon 6 inclusion is a common oncogenic event and has potential as a clinically compatible therapeutic target.status: publishe

Highly sensitive and specific novel biomarkers for the diagnosis of transitional bladder carcinoma

10.18632/oncotarget.3841Oncotarget61513539-1354

Antisense oligonucleotide-mediated MDM4 exon 6 skipping impairs tumor growth

MDM4 is a promising target for cancer therapy, as it is undetectable in most normal adult tissues but often upregulated in cancer cells to dampen p53 tumor-suppressor function. The mechanisms that underlie MDM4 upregulation in cancer cells are largely unknown. Here, we have shown that this key oncogenic event mainly depends on a specific alternative splicing switch. We determined that while a nonsense-mediated, decay-targeted isoform of MDM4 (MDM4-S) is produced in normal adult tissues as a result of exon 6 skipping, enhanced exon 6 inclusion leads to expression of full-length MDM4 in a large number of human cancers. Although this alternative splicing event is likely regulated by multiple splicing factors, we identified the SRSF3 oncoprotein as a key enhancer of exon 6 inclusion. In multiple human melanoma cell lines and in melanoma patient-derived xenograft (PDX) mouse models, antisense oligonucleotide-mediated (ASO-mediated) skipping of exon 6 decreased MDM4 abundance, inhibited melanoma growth, and enhanced sensitivity to MAPK-targeting therapeutics. Additionally, ASO-based MDM4 targeting reduced diffuse large B cell lymphoma PDX growth. As full-length MDM4 is enhanced in multiple human tumors, our data indicate that this strategy is applicable to a wide range of tumor types. We conclude that enhanced MDM4 exon 6 inclusion is a common oncogenic event and has potential as a clinically compatible therapeutic target

International Harmonization of Nomenclature and Diagnostic Criteria (INHAND): Nonproliferative and Proliferative Lesions of the Dog

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions) Project (www.toxpath.org/inhand.asp) is a joint initiative of the societies of toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying lesions observed in most tissues and organs from the dog used in nonclinical safety studies. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions, lesions induced by exposure to test materials, and relevant infectious and parasitic lesions. A widely accepted and utilized international harmonization of nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists

Antisense oligonucleotide-mediated MDM4 exon 6 skipping impairs tumor growth

MDM4 is a promising target for cancer therapy, as it is undetectable in most normal adult tissues but often upregulated in cancer cells to dampen p53 tumor-suppressor function. The mechanisms that underlie MDM4 upregulation in cancer cells are largely unknown. Here, we have shown that this key oncogenic event mainly depends on a specific alternative splicing switch. We determined that while a nonsense-mediated, decay-targeted isoform of MDM4 (MDM4-S) is produced in normal adult tissues as a result of exon 6 skipping, enhanced exon 6 inclusion leads to expression of full-length MDM4 in a large number of human cancers. Although this alternative splicing event is likely regulated by multiple splicing factors, we identified the SRSF3 oncoprotein as a key enhancer of exon 6 inclusion. In multiple human melanoma cell lines and in melanoma patient-derived xenograft (PDX) mouse models, antisense oligonucleotide-mediated (ASO-mediated) skipping of exon 6 decreased MDM4 abundance, inhibited melanoma growth, and enhanced sensitivity to MAPK-targeting therapeutics. Additionally, ASO-based MDM4 targeting reduced diffuse large B cell lymphoma PDX growth. As full-length MDM4 is enhanced in multiple human tumors, our data indicate that this strategy is applicable to a wide range of tumor types. We conclude that enhanced MDM4 exon 6 inclusion is a common oncogenic event and has potential as a clinically compatible therapeutic targe

sj-tif-2-tpx-10.1177_01926233241230553 – Supplemental material for Guide for Combining Primary Tumors for Statistical Analysis in Rodent Carcinogenicity Studies

Supplemental material, sj-tif-2-tpx-10.1177_01926233241230553 for Guide for Combining Primary Tumors for Statistical Analysis in Rodent Carcinogenicity Studies by Charlotte Keenan, Muthafar Al-Haddawi, Jean-Guy Bienvenu, Alys Elizabeth Bradley, Paul Brown, Hepei Chen, Karyn Colman, Michael Elwell, Nicholas Gatto, Dawn Goodman, Binod Jacob, Lynda Lanning, LuAnn McKinney, Erin Muhlbradt, Rick Perry, Alessandro Piaia, Daniel Potenta, Karen S. Regan, Benjamin Sefing, Michael Thibodeau, Erin Tibbs-Slone, Jochen Woicke and Craig M. Zwickl in Toxicologic Pathology</p

PRDM15 is a key regulator of metabolism critical to sustain B-cell lymphomagenesis

10.1038/s41467-020-17064-0Nature Communications111352