Cancer Research

Oncotarget

Oncotarget published this trending research paper on March 30, 2021, entitled, "Inhibition of resistant triple-negative breast cancer cells with low-dose 6-mercaptopurine and 5-azacitidine" by researchers from the University of Texas MD Anderson Cancer Center, Houston, Texas.

Abstract:
Highly adaptable breast cancer cells that can opportunistically switch between proliferation and quiescence are often responsible for disease relapse. We have developed a function-based selection strategy for such resistant cells, exemplified by SUM149-MA and FC-IBC02-MA triple-negative breast cancer cells. We have also reported that a lengthy treatment with low-dose 6-mercaptopurine, a clinically useful anti-inflammatory drug, inhibits such resistant cells. To more rigorously test the clinical suitability of 6-mercaptopurine, here we investigated effects of further lowering its dose and the possibility of overcoming resistance to single-drug treatment by combining the drug with another ribonucleoside analog 5-azacitidine. We found that a lengthy treatment with 1 μM 5-azacitidine, without a significant effect on cell proliferation, sensitized cancer cells to the inhibitory effects of low-dose 6-mercaptopurine. Importantly, treatment for several weeks with low doses of 6-mercaptopurine and/or 5-azacitidine did not render cancer cells resistant to chemotherapeutic drugs doxorubicin or paclitaxel. In fact, the cells became more sensitive to chemotherapeutic drugs upon treatment with 6-mercaptopurine and/or 5-azacitidine. Our analyses of protein markers of epithelial-to-mesenchymal transition indicated that treatments with 6-mercaptopurine and/or 5-azacitidine do not significantly reverse this process in our model. Our results showed that safe drugs such as low-dose 6-mercaptopurine singly or combined with 5-azacitidine, which are suitable for use prior to disease relapse, have a potential of inhibiting highly resistant triple-negative breast cancer cells.
To date, this research paper has generated an Altmetric Attention Score of 49. The Altmetric Attention Score provides an at-a-glance indication of the volume and type of online attention the research has received. 

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DOI - https://doi.org/10.18632/oncotarget.27922

Full text - https://www.oncotarget.com/article/27922/text/

Correspondence to - Anthony Lucci - alucci@mdanderson.org and Balraj Singh - bsingh@mdanderson.org

Keywords - resistant TNBC, minimal residual disease, intratumor heterogeneity, breast cancer relapse, metastasis prevention

About Oncotarget

Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Trending with Impact: Combination Therapeutics Inhibit Breast Cancer Resistance

Aging

Aging published this high-scoring research paper on June 26, 2020, entitled, “Cognitive enhancement of healthy older adults using hyperbaric oxygen: a randomized controlled trial,” by researchers from the Shamir Medical Center, Zerifin, Israel; Tel-Aviv University, Tel-Aviv, Israel; Bar Ilan University, Ramat-Gan, Israel.

Abstract:
More than half of community-dwelling individuals sixty years and older express concern about declining cognitive abilities. The current study’s aim was to evaluate hyperbaric oxygen therapy (HBOT) effect on cognitive functions in healthy aging adults.

A randomized controlled clinical trial randomized 63 healthy adults (>64) either to HBOT(n=33) or control arms(n=30) for three months. Primary endpoint included the general cognitive function measured post intervention/control. Cerebral blood flow (CBF) was evaluated by perfusion magnetic resonance imaging.

There was a significant group-by-time interaction in global cognitive function post-HBOT compared to control (p=0.0017). The most striking improvements were in attention (net effect size=0.745) and information processing speed (net effect size=0.788).

Voxel-based analysis showed significant cerebral blood flow increases in the HBOT group compared to the control group in the right superior medial frontal gyrus (BA10), right and left supplementary motor area (BA6), right middle frontal gyrus (BA6), left middle frontal gyrus (BA9), left superior frontal gyrus (BA8) and the right superior parietal gyrus (BA7).

In this study, HBOT was shown to induce cognitive enhancements in healthy aging adults via mechanisms involving regional changes in CBF. The main improvements include attention, information processing speed and executive functions, which normally decline with aging.

To date, this study has generated an Altmetric Attention Score of 111. The Altmetric Attention Score provides an at-a-glance indication of the volume and type of online attention the research has received. 

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DOI - https://doi.org/10.18632/aging.103571

Full text - https://www.aging-us.com/article/103571/text

Correspondence to: Amir Hadanny email: amir.had@gmail.com and Shai Efrati email: efratishai@outlook.com

Keywords: cognitive, hyperbaric oxygen, perfusion, cerebral blood flow, aging

About Aging

Launched in 2009, Aging publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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Top-Performer: Hyperbaric Oxygen Yields Cognitive Benefits in Healthy Older Adults

Oncotarget published this research paper on August 11, 2020, entitled, “Survival after resection of brain metastases with white light microscopy versus fluorescence-guidance: A matched cohort analysis of the Metastasys study data,” by researchers from the University of Medicine Goettingen, Goettingen, Germany; University Medical Center Leipzig, Leipzig, Germany; University Hospital Muenster, Muenster, Germany.

The cover for issue 32 of Oncotarget features Figure 2, "This figure depicts overall survival and local in-brain recurrence-free survival in the study's subgroups," by Hussein, et al. which reported that the aim of the present study is to assess whether the use of 5-ALA has an impact on local recurrence or survival compared to conventional white light microscopic tumor resection.

Two groups were compared:
In the “white light” group, resection was performed with conventional microscopy.
In the 5-ALA group, fluorescence guided peritumoral resection was additionally performed after standard microscopic resection.
Local in-brain recurrence occurred in 21/175 patients with a rate of 15/119 in the white light and 6/56 in the 5-ALA group.

The use of 5-ALA did not result in lower in-brain recurrence or mortality compared to the use of white light microscopy.

Dr. Bawarjan Schatlo from the Department of Neurosurgery at The University of Medicine Goettingen said, "Metastatic brain disease is more common than primary brain tumors."

Another group made the case for extending tumor resection 5 millimeters into peritumoral tissue to perform a so-called supramarginal resection.

Its aim is to prolong progression-free survival through radical resection and improved local tumor control.

In a series of 52 patients, Kamp and colleagues detected positive fluorescence in 62% of resected cerebral metastases.

Thus, the utility and importance of using methods to improve local control of brain metastases remains an unresolved issue.

The aim of the current study was to compare survival and local recurrence in a cohort of patients who underwent surgery for brain metastases with 5-ALA fluorescence microscopy to one that was operated using microscopic white light only.

The Schatlo Research Team concluded in their Oncotarget research paper, "the present study confirmed that regardless of surgical adjunct, radiotherapy is strongly associated with improved survival."

To date, this research paper has generated an Altmetric Attention Score of 48. The Altmetric Attention Score provides an at-a-glance indication of the volume and type of online attention the research has received. 

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DOI - https://doi.org/10.18632/oncotarget.27688

Full text - https://www.oncotarget.com/article/27688/text/

Correspondence to - Bawarjan Schatlo - bawarjan.schatlo@med.uni-goettingen.de

Keywords - brain tumor, brain metastasis, fluorescence-guided surgery, 5-ALA

About Oncotarget

Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Top-Performer: White Light Versus 5-ALA Fluorescence Guided Resection

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Oncotarget published this trending research paper on February 2, 2021, entitled, "Testosterone deficiency in men receiving immunotherapy for malignant melanoma" by researchers from the University of Iowa.

Abstract:
Immunotherapy has been established as a standard of care for patients with malignant melanoma, however, the long-term side-effects of immunotherapy are still emerging. Studies over the last decade have documented increasing reports of endocrine dysfunction following the initiation of immunotherapy. Our study aimed to detect the proportion of men who have low testosterone before, during, and or/after receiving immunotherapy for malignant melanoma, and to determine the proportion of men who receive testosterone replacement therapy after detection of low testosterone. We performed retrospective chart review of patients with malignant melanoma treated with immunotherapy. Low testosterone was identified in 34 out of 49 patients at some point during their treatment with immunotherapy. Despite low testosterone levels in two-thirds of patients, only three patients were treated with testosterone replacement therapy. In addition to laboratory evidence of low testosterone, patients were also symptomatic as 43 out of 49 patients reported fatigue to their providers. Four patients developed hypophysitis and subsequent hypopituitarism, all of whom were receiving Ipilimumab. We conclude that patients with stage 3 or 4 melanoma treated with immunotherapy appear to be at an increased risk of developing testosterone deficiency during their treatment.

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DOI - https://doi.org/10.18632/oncotarget.27876

Full text - https://www.oncotarget.com/article/27876/text/

Correspondence to - Madeline Peters - madeline-peters@uiowa.edu

Keywords - cancer, melanoma, immunotherapy, testosterone deficiency, androgens, skin cancer

About Oncotarget

Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Oncotarget is published by Impact Journals, LLC please visit https://www.ImpactJournals.com or connect with @ImpactJrnls

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Trending with Impact: Melanoma, Immunotherapy, and Testosterone Deficiency

Aging published this research paper on June 19, 2020, entitled, “Biomarkers of aging and lung function in the normative aging study” by researchers from the Harvard T.H. Chan School of Public Health, Boston, MA; Icahn School of Medicine at Mount Sinai, New York, NY; Harvard T.H. Chan School of Public Health, Boston, MA; Northwestern University, Chicago, IL; VA Boston Healthcare System, Boston, MA; Boston University School of Medicine, Boston, MA; Columbia University, New York, NY.

Abstract:
Elderly individuals who are never smokers but have the same height and chronological age can have substantial differences in lung function. The underlying biological mechanisms are unclear. To evaluate the associations of different biomarkers of aging (BoA) and lung function, we performed a repeated-measures analysis in the Normative Aging Study using linear mixed-effect models. We generated GrimAgeAccel, PhenoAgeAccel, extrinsic and intrinsic epigenetic age acceleration using a publically available online calculator. We calculated Zhang’s DNAmRiskScore based on 10 CpGs. We measured telomere length (TL) and mitochondrial DNA copy number (mtDNA-CN) using quantitative real-time polymerase chain reaction. A pulmonary function test was performed measuring forced expiratory volume in 1 second / forced vital capacity (FEV1/FVC), FEV1, and maximum mid-expiratory flow (MMEF). Epigenetic-based BoA were associated with lower lung function. For example, a one-year increase in GrimAgeAccel was associated with a 13.64 mL [95% confidence interval (CI), 5.11 to 22.16] decline in FEV1; a 0.2 increase in Zhang’s DNAmRiskScore was associated with a 0.009 L/s (0.005 to 0.013) reduction in MMEF. No association was found between TL/mtDNA-CN and lung function. Overall, this paper shows that epigenetics might be a potential mechanism underlying pulmonary dysfunction in the elderly.

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DOI - https://doi.org/10.18632/aging.103363

Full text - https://www.aging-us.com/article/103363/text

Correspondence to: Cuicui Wang email: cuicuiwang@hsph.harvard.edu

Keywords: pulmonary health, DNA methylation, biological clock, aging

About Aging

Launched in 2009, Aging publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

Please visit our website at http://www.Aging-US.com​​ or connect with us on:

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Trending with Impact: Biomarkers of Aging and Lung Function in the Normative Aging Study

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The cover paper for Oncotarget Volume 12, Issue 12 is entitled, "Frame-shift mediated reduction of gain-of-function p53 R273H and deletion of the R273H C-terminus in breast cancer cells result in replication-stress sensitivity," by researchers from the Department of Biological Sciences Hunter College, Belfer Building, City University of New York, NY; The Graduate Center Biology and Biochemistry Programs of City University of New York, NY; Department of Biological Sciences, Columbia University, NY; Department of Cell and Developmental Biology, Weill Cornell Medical College, NY.

Abstract:
We recently documented that gain-of-function (GOF) mutant p53 (mtp53) R273H in triple negative breast cancer (TNBC) cells interacts with replicating DNA and PARP1. The missense R273H GOF mtp53 has a mutated central DNA binding domain that renders it unable to bind specifically to DNA, but maintains the capacity to interact tightly with chromatin. Both the C-terminal domain (CTD) and oligomerization domain (OD) of GOF mtp53 proteins are intact and it is unclear whether these regions of mtp53 are responsible for chromatin-based DNA replication activities. We generated MDA-MB-468 cells with CRISPR-Cas9 edited versions of the CTD and OD regions of mtp53 R273H. These included a frame-shift mtp53 R273Hfs387, which depleted mtp53 protein expression; mtp53 R273HΔ381-388, which had a small deletion within the CTD; and mtp53 R273HΔ347-393, which had both the OD and CTD regions truncated. The mtp53 R273HΔ347-393 existed exclusively as monomers and disrupted the chromatin interaction of mtp53 R273H. The CRISPR variants proliferated more slowly than the parental cells and mt53 R273Hfs387 showed the most extreme phenotype. We uncovered that after thymidine-induced G1/S synchronization, but not hydroxyurea or aphidicholin, R273Hfs387 cells displayed impairment of S-phase progression while both R273HΔ347-393 and R273HΔ381-388 displayed only moderate impairment. Moreover, reduced chromatin interaction of MCM2 and PCNA in mtp53 depleted R273Hfs387 cells post thymidine-synchronization revealed delayed kinetics of replisome assembly underscoring the slow S-phase progression. Taken together our findings show that the CTD and OD domains of mtp53 R273H play critical roles in mutant p53 GOF that pertain to processes associated with DNA replication.

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DOI -  https://doi.org/10.18632/oncotarget.27975

Full text - https://www.oncotarget.com/article/27975/text/

Correspondence to - Jill Bargonetti - bargonetti@genectr.hunter.cuny.edu

Keywords - mutant p53, gain-of-function, oligomerization, DNA replication, frame-shift, breast cancer

About Oncotarget

Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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CRISPR Used in Triple Negative Breast Cancer Research

View the latest oncology-focused research published in this week’s issue of Oncotarget, Volume 12, Issue 12.
https://www.oncotarget.com/archive/v12/i12/

Cover Paper - “Frame-shift mediated reduction of gain-of-function p53 R273H and deletion of the R273H C-terminus in breast cancer cells result in replication-stress sensitivity” 
https://doi.org/10.18632/oncotarget.27975

News - “LY6 gene family presents a novel class of potential biomarkers associated with overall survival outcome of pancreatic ductal adenocarcinoma”
https://doi.org/10.18632/oncotarget.27968 (PDF Download)

Editorial - “Neoantigen evolution in head and neck cancer progression: Where do we go from here?” 
https://doi.org/10.18632/oncotarget.27942 (PDF Download)

Editorial - “Unexpected zinc dependency of ferroptosis – what is in a name?” https://doi.org/10.18632/oncotarget.27951 (PDF Download)

Research Paper - “Role for Fgr and Numb in retinoic acid-induced differentiation and G0 arrest of non-APL AML cells” 
https://doi.org/10.18632/oncotarget.27969

Research Paper - “Dynamic cellular biomechanics in responses to chemotherapeutic drug in hypoxia probed by atomic force spectroscopy” 
https://doi.org/10.18632/oncotarget.27974

Research Paper - “Genomic clustering analysis identifies molecular subtypes of thymic epithelial tumors independent of World Health Organization histologic type” https://doi.org/10.18632/oncotarget.27978

Research Paper - “Deep learning with deep convolutional neural network using FDG-PET/CT for malignant pleural mesothelioma diagnosis” 
https://doi.org/10.18632/oncotarget.27979

Keywords - mutant p53, DNA replication, head and neck cancer, biomarker, ferroptosis, retinoic acid(RA), hypoxia, thymic epithelial tumor, mesothelioma, AML, breast cancer, pancreatic cancer, cancer, science, research, oncology

About Oncotarget

Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. 

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Oncotarget is published by Impact Journals, LLC. Please visit https://www.impactjournals.com/ or connect with @ImpactJrnls

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