ABSTRACT

We document for the first time that sanctuary in an organ which expresses high levels of the enzyme cytidine deaminase (CDA) is a mechanism of cancer cell resistance to cytidine analogues. This mechanism could explain why historically, cytidine analogues have not been successful chemotherapeutics against hepatotropic cancers, despite efficacy in vitro. Importantly, this mechanism of resistance can be readily reversed, without increasing toxicity to sensitive organs, by combining a cytidine analogue with an inhibitor of cytidine deaminase (tetrahydrouridine). Specifically, CDA rapidly metabolizes cytidine analogues into inactive uridine counterparts. Hence, to determine if sheltering/protection of cancer cells in organs which express high levels of CDA (e.g., liver) is a mechanism of resistance, we utilized a murine xenotransplant model of myeloid cancer that is sensitive to epigenetic therapeutic effects of the cytidine analogue decitabine in vitro and hepato-tropic in vivo. Treatment of tumor-bearing mice with decitabine (subcutaneous 0.2mg/kg 2X/week) doubled median survival and significantly decreased extra-hepatic tumor burden, but hepatic tumor burden remained substantial, to which the animals eventually succumbed. Combining a clinically-relevant inhibitor of CDA (tetrahydrouridine) with a lower dose of decitabine (subcutaneous 0.1mg/kg 2X/week) markedly decreased liver tumor burden without blood count or bone marrow evidence of myelotoxicity, and with further improvement in survival. In conclusion, sanctuary in a CDA-rich organ is a mechanism by which otherwise susceptible cancer cells can resist the effects of decitabine epigenetic therapy. This protection can be reversed without increasing myelotoxicity by combining tetrahydrouridine with a lower dose of decitabine.

When people discuss contemporary medicine, precision plays one of the most important roles and people’s lives are directly dependent on it. Likewise, any researches pertaining to medicine are necessary to comply with the top standards. The challenge nowadays is that any conclusions of researches can be published online and used as a reference without being adequately checked and approved. Mikhail (Misha) Blagosklonny of Oncotarget perfectly understood this problem and decided to develop an alternative solution. That’s how a weekly oncology-focused research journal named “Oncotarget” has been founded back in 2010. The major principle of this journal is based on Altmetric scores that are used as a quality measure. That assists both readers and authors to validate publications with Altmetric Article Reports that generate “real-time feedback containing data summary related to a particular publication.” Oncotarget website demonstrates a full publications list with respective scores higher than 100 as well as reports discussed previously. Mikhail (Misha) Blagosklonny glad to share his new approach and hopes it provides the required help to anybody, who has interest in oncology.

“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This paper was released back in 2018 by Oncotarget and written by several experts from Hollywood Private Hospital, Edith Cowan University, Dermatology Specialist Group, St. John of God Hospital and The University of Western Australia. The introduction of the study mentions that “recent data shows that Australians are four times more likely to develop a cancer of the skin than any other type of cancer”, and shares an insight on melanoma that “is curable by surgical excision in the majority of cases, if detected at an early stage.”

The paper has got an Altmetric score of 594. Mikhail (Misha) Blagosklonny realizes that most of readers are aiming to understand the very meaning of it. Based on the Altmetric website, the score indicates “how many people have been exposed to and engaged with a scholarly output.” Hence, the article about melanoma, was used for citations in various news articles 69 times. Moreover, it was mentioned in 2 online blogs, as well as 25 Tweets on Twitter and 1 Facebook post. FOX23 of Tulsa, Oklahoma has headlined their report on July 20, 2018 as “New blood test could detect skin cancer early”, using the main content of Australia study 

Another Oncotarget’s study with a top score of 476, is “Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moon-shot,”. This publication has appeared in 60 news stories, 1 online blog post and 6 Twitter posts. The majority of public may have come across a short overview only, however those who visit Mikhail (Misha) Blagosklonny at Oncotarget, do receive helpful scientific facts. Oncotarget is proud to have the chance to share with online readers this highly appreciated and high-quality information, that is trustworthy and reliable.

 

When people mention modern medicine, accuracy plays one of the most crucial roles and human lives are directly dependent on it. Likewise, any researches pertaining to medicine are required to meet the highest standards. The problem today is that any recommendations of researches can be posted online and used as a reference without being precisely verified and approved. Mikhail (Misha) Blagosklonny of Oncotarget clearly understood this issue and tried to come up with an alternative solution. That’s how a weekly oncology-focused research journal named “Oncotarget” has been founded back in 2010. The main principle of this journal is related to Altmetric scores that are used as a quality measure. That helps both readers and authors to quality-check publications with Altmetric Article Reports that provide “real-time feedback containing data summary related to a particular publication.” Oncotarget website demonstrates a full publications list with corresponding scores above 100 as well as reports mentioned above. Mikhail (Misha) Blagosklonny proud to share his new approach and hopes it provides the required assistance to anyone, who has interest in oncology.

“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This article was published back in 2018 by Oncotarget and written by several experts from Hollywood Private Hospital, Edith Cowan University, Dermatology Specialist Group, St. John of God Hospital and The University of Western Australia. The introduction of the study discusses “recent data shows that Australians are four times more likely to develop a cancer of the skin than any other type of cancer”, and shares an insight on melanoma that “is curable by surgical excision in the majority of cases, if detected at an early stage.”

The publication has got an Altmetric score of 594. Mikhail (Misha) Blagosklonny realizes that majority of readers are willing to comprehend the very meaning of it. Based on the Altmetric website, the score indicates “how many people have been exposed to and engaged with a scholarly output.” Likewise, the publication about melanoma, was utilized for citations in various news articles 69 times. Besides that, it was mentioned in 2 online blogs, as well as 25 Tweets on Twitter and 1 Facebook post. FOX23 of Tulsa, Oklahoma has headlined their news on July 20, 2018 as “New blood test could detect skin cancer early”, using the main content of Australia study 

Another Oncotarget’s research with a top score of 476, is “Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moon-shot,”. This article has appeared in 60 news stories, 1 online blog post and 6 Twitter posts. The majority of public may have come across a short overview only, however those who visit Mikhail (Misha) Blagosklonny at Oncotarget, do get useful scientific facts. Oncotarget is proud to have the chance to share with online readers this highly appreciated and high-quality information, that is trustworthy and reliable.