Thursday, August 14, 2014
Friday, July 25, 2014
Phenotypic screening in oncology drug discovery — Hosein Kouros-Mehr
A recent paper* summarized the history of oncology drug discovery and analyzes the contibutions of phenotypic drug discovery vs traditional target-based drug discovery. The authors analyze the development and mechanisms of all small molecule-based cancer drugs approved by the FDA over the past 15 years and those currently in clinical development.
The authors show that the majority of small molecule inhibitors for oncology originated in target-based discovery. However, a significant number of inhibitors were identified in phenotypic drug screening approaches. The authors suggest that the rate-limiting step in bringing compounds identified in phenotypic screenings into clinical development is the lack of mechanistically defined cellular models for the cancer phenotypes in question and also the reliance on traditional drug effects such as cytotoxicity and mitotic arrest, which are only a component of the hallmarks of cancer.
The authors suggest that mechanistically informed phenotypic models may better enable compounds identified in phenotypic screenings to successfully complete clinical development. These models would enable confirmation that the targeted agents have a molecular mechanism of action, which would enable PD biomarker development and development of diagnostic hypotheses and patient tailoring hypotheses.
Wednesday, July 23, 2014
Cholesterol, Wnt signaling, and Cancer - Hosein Kouros-Mehr
A recent paper* has reported a direct biological link between cholesterol and cancer. The Wnt pathway plays an important role in cancer formation and metastasis, particularly in colorectal cancer in which the Wnt-related gene APC is frequently mutated. In this report, the authors find that cholesterol is enriched around the Wnt-related Frizzled and LRP5/6 receptors in cancer cells. This suggested to the authors that perhaps cholesterol itself could activate Wnt signaling. The authors found that cholesterol directly recruits the Wnt-related Dishevelled (Dvl) scaffold protein to the cell membrane through interaction with its PDZ domain. Dvl then activates the canonical Wnt signaling pathway. In this way, cholesterol may directly regulate activation of canonical Wnt signaling and may regulate balance between canonical and non-canonical signaling. Future studies will be needed to determine effects of anti-cholesterol medicines in silencing Wnt signaling and perhaps inhibiting Wnt-driven cancers.
* Sheng, R., et. al. (2014). Cholesterol selectively activates canonical Wnt signalling over non-canonical Wnt signalling. Nature 5 (4393)
Hosein Kouros-Mehr
Tuesday, July 22, 2014
Friday, June 27, 2014
RUNX1 as a biomarker for triple-negative breast cancer - Hosein Kouros-Mehr
With the advent of microarray expression profiling over a decade ago, many new biomarkers have been identified for ER+ breast cancers, such as the transcription factors GATA-3 and XBP-1. A recent paper* identified a novel biomarker for triple-negative (ER- PR- HER2-) breast cancer. RUNX1 is a transcription factor that is the most frequently mutated gene in human leukemia, and the RUNX family plays essential roles in haematopoiesis, osteogenesis and neurogenesis.
In this report, the authors utilized a tissue microarray continaing biopsies from 483 patients with invasive ductal breast adenocarcinoma. The microarray was stained with antibodies for immunihistochemistry. RUNX1 immunostaining was signficantly asociated with pooere cancer-specific survival in patients with ER-negative and triple-negative breast cancer. However, RUNX1 was associated with progesterone receptor positive tumors as well, which is a bit confounding. Interestinlgly, RUNX1 was associated with more CD4+ and CD8+ T-lymphocyte infiltration and CD68+ macrophage infiltration, which have been observed as markers for poor prognosis in breast cancer patients.
Triple negative breast cancer is an unmet medical need and lacks suitable biomarkers for patient stratification. RUNX1 may be used as a biomarker and prognostic indicator correlating with poor prognosis specifically in the triple negative subtype of human breast cancer.
Hosein Kouros-Mehr
*Citation: Ferrari N, Mohammed ZMA, Nixon C, Mason SM, Mallon E, et al. (2014) Expression of RUNX1 Correlates with Poor Patient Prognosis in Triple Negative Breast Cancer. PLoS ONE 9(6): e100759. doi:10.1371/journal.pone.0100759
Monday, June 9, 2014
Retrospective analysis of a pharmaceutical company's R&D pipeline - Hosein Kouros-Mehr
A major pharmaceutical company has published* a thorough analysis of its R&D pipeline from 2005-2010 and summarized the primary reasons for successes and failures of its small-molecule drug projects. While R&D investment in the industry has reached record high levels and there has been a wealth of new technologies and new drug targets to explore, the rate of new drug launches has been steady and drug development costs have increased substantially. The conclusions of this article can be used to boost productivity of drug development efforts in hopes of increasing the number of successful drug launches.
An interesting point made in the paper is that volume-based metrics to boost portfolio projects and drug candidates have not necessarily yielded better performance. The authors state, "This volume-based approach damaged not only the quality and sustainability of R&D pipelines but, more importantly, also the health of the R&D organizations and their underlying scientific curiosity. This is because the focus of scientists and clinicians moved away from the more demanding goal of thoroughly understanding disease pathophysiology and the therapeutic opportunities, and instead moved towards meeting volume-based goals and identifying an unprecedented level of back-up and 'me too' drug candidates. In such an environment, 'truth-seeking' behaviours to understand disease biology may have been over-ridden by 'progression-driven' behaviours that rewarded scientists for meeting numerical volume-based goals." The authors suggest that volume-based metrics should be substituted with a more in depth understanding of drug targets, biologies, and patient selection metrics.
The company describes a comprehensive review undertaken for 142 drug discovery and development projects from candidate phase to Phase II. Data were gathered from more than 80% of these 142 projects and for 95% of projects in clinical phases. Of the projects analysed, 94 closed during the period assessed; 33 closed before clinical testing and a further 61 closed during clinical testing. The review was performed by submitting structured questionnaires to a cross-functional group of scientists and clinicians drawn from the project teams. The primary cause of failure for projects up to Phase II was unacceptale safety, which accounted for more than half of all project closures. The majority of these failures occurred before clinical testing (primarily during regulatory GLP toxicology testing), with safety issues being the reason for 82% of preclinical project closures. The analysis suggested a crucial need for teams to pay attention to preclinical safety signals.
Based on the analysis, the paper concludes that there 5 variable that predict success for an R&D portfolio:
(1) Right target - Strong link between target and disease; differentiated efficacy; available and predictive biomarkers
(2) Right tissue - Adequate bioavailability and tissue exposure; definition of PD biomarkers; clear understanding of preclinical and clinical PK/PD; understanding of drug-drug interactions
(3) Right safety - DIfferentiated and clear safety margins, understanding of secondary pharmcology risk, understanding of reactive metabolites, genotoxicity, drug-drug interactions, understanding of target liability
(4) Right patients - Identification of patient population for tailoring of molecules, definition of risk-benefit for a given population
(5) Right commercial potential - Differentiated value proposition versus future standard of care, focus on market access (payer, provider), personalized health care strategy (diagnostic, biomarkers)
Monday, June 2, 2014
Gene amplifications in cancer TCGA datasets – Hosein Kouros-Mehr
The Cancer Genome Atlas (TCGA) projects have advanced our understanding of the driver mutations, genetic backgrounds, and key pathways that drive cancer types. We recently published* our efforts to identify genes that are commonly amplified in cancers and display a cancer driver signature. Put in another way, we devised a bioinformatics screening strategy to identify putative cancer driver genes amplified across TCGA datasets
We carried out a GISTIC bioinformatics analysis of TCGA datasets spanning 16 cancer subtypes and identified 486 genes that were amplified in two or more datasets. These cancer types include BLCA – Bladder Urothelial Carcinoma, BRCA – Breast invasive carcinoma, CESC – Cervical squamous cell carcinoma and endocervical adenocarcinoma, CRC – Colorectal Cancer (COAD and READ studies combined together), GBM – Glioblastoma multiforme, HNSC – Head and Neck squamous cell carcinoma, KIRC – Kidney renal clear cell carcinoma, LGG – Brain Lower Grade Glioma, LUAD- Lung adenocarcinoma, LUSC -
Lung squamous cell carcinoma, OV – Ovarian serous cystadenocarcinoma, PAAD – Pancreatic adenocarcinoma, PRAD – Prostate adenocarcinoma, SKCM – Skin Cutaneous Melanoma, STAD – Stomach adenocarcinoma, UCEC – Uterine Corpus Endometrioid Carcinoma.
Lung squamous cell carcinoma, OV – Ovarian serous cystadenocarcinoma, PAAD – Pancreatic adenocarcinoma, PRAD – Prostate adenocarcinoma, SKCM – Skin Cutaneous Melanoma, STAD – Stomach adenocarcinoma, UCEC – Uterine Corpus Endometrioid Carcinoma.
From the 486 genes, we identified 75 cancer-associated genes with potential “druggable” properties. The majority of the genes were localized to 14 amplicons spread across the genome. Genes within an amplicon tended to be amplified in the same cancer subtypes. To further identify potential cancer driver genes, we analyzed gene copy number and mRNA expression data from individual patient samples and identified 42 putative cancer driver genes linked to diverse oncogenic processes. Oncogenic activity was further validated by siRNA/shRNA knockdown and by referencing the Project Achilles datasets.
The amplified cancer driver genes represented a number of gene families, including epigenetic regulators, cell cycle-associated genes, DNA damage response/repair genes, metabolic regulators, and genes linked to the Wnt, Notch, Hedgehog, JAK/STAT, NF-KB and MAPK signaling pathways. Among the 42 putative driver genes were known driver genes, such as EGFR, ERBB2 and PIK3CA. Wild-type KRAS was amplified in several cancer types, and KRAS-amplified cancer cell lines were most sensitive to KRAS shRNA, suggesting that KRAS amplification was an independent oncogenic event. A number of MAP kinase adapters were co-amplified with their receptor tyrosine kinases, such as the FGFR adapter FRS2 and the EGFR family adapters GRB2 and GRB7. The ubiquitin-like ligase DCUN1D1 and the histone methyltransferase NSD3 were also identified as novel putative cancer driver genes.
The data presented can be used for patient tailoring efforts — in other words, to tailor novel therapeutics to the patients whose cancers contain the genetics drivers in question and would benefit most from the targeted therapy. The data can also be used to identify potential novel opportunities for drug discovery efforts.
Hosein Kouros-Mehr
* Chen Y, McGee J, Chen X, Doman TN, Gong X, Zhang Y, Hamm N, Ma X, Higgs RE, Bhagwat SV, Buchanan S, Peng SB, Staschke KA,Yadav V, Yue Y, Kouros-Mehr H. (2014) Identification of Druggable Cancer Driver Genes Amplified across TCGA Datasets. PLoS One. 2014 May 29;9(5):e98293. doi: 10.1371/journal.pone.0098293. eCollection 2014.
Thursday, May 22, 2014
Novel method to treat diabetes - Hosein Kouros-Mehr
A recent report in Nature* describes a potentially new way of treating patients with type-2 diabetes. The approach involves block an enzyme involved in the degradation of insulin, thereby boosting insulin levels. The authors identify inhibitors of the insulin-degrading enzyme IDE. A physiologically active IDE inhibitor was identified using a DNA-templated macrocycle small molecule library. The inhibitor binds to IDE in a binding pocket located distally from the catalytic site. Obese mice treated with the IDE inhibitor showed improved glucose tolerance upon administration of oral glucose. Interestingly, the IDE inhibitor regulated multiple hormone levels in these mice, including glucagon and amylin, in addition to insulin. This study suggests that inhibition of insulin degrading enzyme could be a novel approach for the treatment of diabetes.
- Maianti, et. al. (2014). Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones
- Nature, doi:10.1038/nature13297
.Hosein Kouros-Mehr
Friday, May 16, 2014
Evidence of cancer stem cells in patient tumors - Hosein Kouros-Mehr
May 15, 2014
A recent paper* in Cancer Cell provides evidence of cancer stem cells in patient-derived tumors, which may validate the cancer stem cell hypothesis in a hematopoietic malignancy. The cancer stem cell hypothesis has remained controversial due to experimental confounding variables, such as the strain of mice used for cancer stem cell implantation. This study suggests that a rare population of Lin−CD34+CD38−CD90+CD45RA cells function as the propagating cells in patients with low- to intermediate-risk myelodysplastic syndrome.
Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by inefficient hematopoiesis and frequent progression to AML. The authors of the study obtained MDS cells from patients and compared the relationships between Lineage− (Lin−)CD34+CD38−CD90+CD45RA− candidate MDS-SCs with myeloid-restricted granulocyte-macrophage and megakaryocyte-erythroid progenitors (GMPs and MEPs). They also transplanted the Lin−CD34+CD38−CD90+CD45RA− cells into mice and found that they gave rise to tumors with the same molecular signatures as those isolated directly from the patients. The Lin−CD34+CD38−CD90+ MDS-SCs were molecularly and functionally distinct from clonally involved GMPs and MEPs and the Lin−CD34+CD38−CD90+ cells were able to replenish GMPs and MEPs, establishing their hierarchical relationship.
The authors found that deletion of 5q was among the first genetic lesions in MDS in the cancer stem cell population. The 5q deletion was found to precede the acquisition of recurrent driver mutations in MDS , which served to confer self-renewal properties to MDS progenitors.
* Woll, et. al. (2014). Myelodysplastic Syndromes Are Propagated by Rare and Distinct Human Cancer Stem Cells In Vivo. Cancer Cell, in press
- http://dx.doi.org/10.1016/j.ccr.2014.03.036
- Hosein Kouros-Mehr
Friday, May 9, 2014
Novel immunotherapy approach - Hosein Kouros-Mehr
A recent paper* in Science reports that T cells recognizing a mutant protein found only in cancer cells can elicit an anti-tumor response when injected into a patient with end-stage epithelial cancer.
The authors show that a 43-year old patient with metastatic cholangiocarcinoma carried tumor-infiltrating lymphocytes that recognized a mutant form of erbb2-interacting protein (ERBB2IP). To do this, the authors resected lung metastases from the patient for whole exome sequencing and found 26 nonsynonymous mutations. For each mutation, they created minigene constructs (containing the mutation and 12 flanking amino acids) and transfected constructs into antigen-presenting cells for co-culture with patient-derived tumor-infiltrating lymphocytes. They found that a patient-derived T-cell clone responded to mutant ERBB2IP and elicited a T-cell response with the release of IFN-gamma and activation of OX40 and 4-1BB.
The mutated ERBB2IP-specific T cells from the patient were then expanded and used for adoptive transfer to determine if these cells could elicit an anti-tumor response in the patient. The patient received 42.4 billion tumor-infiltrating lymphocytes containing these T cell clones and also received 4 doses of IL-2 to enhance T-cell proliferation. The patient displayed tumor regression 2 months after therapy, despite showing evidence of progressive disease prior to treatment. The patient showed disease stabilization for 13 months after therapy, after which time she experienced disease progression in lungs but not liver.
Further work will be necessary to validate this approach in cancer therapy. T-cell adoptive transfer was previously shown to be a viable option for cancer patients, and the explosion of cancer mutation data from TCGA and other sources will offer new targets for cancer immunotherapy.
*Tran, et. al. (2014). Cancer Immunotherapy Based on Mutation-Specific CD4+ T Cells in a Patient with Epithelial Cancer. Science Vol. 344 no. 6184 pp. 641-645 DOI: 10.1126/science.1251102
Hosein Kouros-Mehr
The authors show that a 43-year old patient with metastatic cholangiocarcinoma carried tumor-infiltrating lymphocytes that recognized a mutant form of erbb2-interacting protein (ERBB2IP). To do this, the authors resected lung metastases from the patient for whole exome sequencing and found 26 nonsynonymous mutations. For each mutation, they created minigene constructs (containing the mutation and 12 flanking amino acids) and transfected constructs into antigen-presenting cells for co-culture with patient-derived tumor-infiltrating lymphocytes. They found that a patient-derived T-cell clone responded to mutant ERBB2IP and elicited a T-cell response with the release of IFN-gamma and activation of OX40 and 4-1BB.
The mutated ERBB2IP-specific T cells from the patient were then expanded and used for adoptive transfer to determine if these cells could elicit an anti-tumor response in the patient. The patient received 42.4 billion tumor-infiltrating lymphocytes containing these T cell clones and also received 4 doses of IL-2 to enhance T-cell proliferation. The patient displayed tumor regression 2 months after therapy, despite showing evidence of progressive disease prior to treatment. The patient showed disease stabilization for 13 months after therapy, after which time she experienced disease progression in lungs but not liver.
Further work will be necessary to validate this approach in cancer therapy. T-cell adoptive transfer was previously shown to be a viable option for cancer patients, and the explosion of cancer mutation data from TCGA and other sources will offer new targets for cancer immunotherapy.
*Tran, et. al. (2014). Cancer Immunotherapy Based on Mutation-Specific CD4+ T Cells in a Patient with Epithelial Cancer. Science Vol. 344 no. 6184 pp. 641-645 DOI: 10.1126/science.1251102
Hosein Kouros-Mehr
Wednesday, April 23, 2014
Novel mechanism for cancer metastasis - Hosein Kouros-Mehr
Cancer Paper 4/23/14 Hosein Kouros-Mehr
Cancer-Secreted miR-105 Destroys Vascular Endothelial Barriers to Promote Metastasis
Zhou et. a., Cancer Cell, Volume 25, Issue 4, p501–515, 14 April 2014
A recent paper suggests a new mechanism for metastasis of cancer cells to distant organs. Metastasis is a complex process consisting of a series of steps that a cancer cell must achieve to establish de novo cancers in distant organs. One of the rate-limiting steps in metastasis is the extravasation and growth of disseminated cells that have reached the vasculature of the distant organ. Here the disseminated cells face several barriers: (1) extravasation across the microvasculature of the distant site, including migration through the endothelial cell layer and basement membrane; (2) survival in the new microenvironment of the distant organ; (3) evasion of the immune response in the distant organ.
Zhou et al. suggest that tumor cells can secrete microRNAs to assist them in the metastatic process. Namely, they suggest that tumors cells can secrete miR-105 into their microenvironment, which targets the ZO-1 tight junction protein gene in endothelials at sites of tumor dissemination. This allows downregulation of tight junction proteins in endothelial cells, which then allows cancer cells to extravasate into distant organs. Interestingly, circulating miR-105 was found to predict metastasis in early-stage breast cancer patients.
New targets/drugs for oncology have traditionally focused on signaling pathways required for primary tumor cell proliferation and growth. While many new cancer drugs have come to market over the last few decades, the overall survival rate of cancer has not decreased as greatly as expected. Metastasis is the primary cause of mortality and morbidity in cancer and new drugs that block metastasis may help increase cancer survival rates.
Hosein Kouros-Mehr
Thursday, April 10, 2014
Novel mutations discovered in a form of ovarian cancer Hosein Kouros-Mehr
A recent paper* in Nature Genetics discovered mutations in the SMARCA4 gene in a form of ovarian cancer known as small cell carcinoma of the ovary. This cancer is highly aggressive and mostly affects young women. The authors sequenced tumors from 12 patients and discovered loss of function mutations in SMARCA4 in 100% of the patients (probability of that happening by chance is less than 0.0000000000000002). The importance of this finding is that it may lead to targeted therapies that can be tailored for patients with this disease.
The SMARCA4 gene is an ATP-dependent helicase that is part of the SWI/SNF complex. This complex regulates chromatin remodeling and is important for transcriptional activation of genes that may be normally silenced in heterochromatin. SWI/SNF complex is composed of many proteins and its mechanism of action is largely unknown, but it is thought that SWI/SNF can destabilize histone-DNA interaction in an ATP-dependent manner and lead to chromatin remodeling of target genes, thereby altering the accessibility and transcription of the target genes. SMARCA4 is a ATP-dependent helicase, which means it helps separate/unwind the strands of DNA using energy derived from ATP hydrolysis.
The authors found that SMARCA4 mutations in these patients were all loss of function mutations that lead to significantly less SMARCA4 protein in the cells. Interestingly, the overexpression of SMARCA4 in SMARCA4-null cancer cell lines led to suppression of cell growth, suggesting that SMARCA4 is a bona fide tumor suppressor. The depletion of SMACA4 using lentiviral shRNA knockdown led to increase cell growth in cell lines.
SMARCA4 mutations are also found in bladder cance, stomach cancer, lung cancer, and glioma (5-8% frequency). Most of these are missense mutations of uncertain consequence, though lung cancers contained frequent inactivating SMARCA4 mutations. Further work will be necessary to identify candidate targets for drug discovery in SMARCA4 mutant tumors. For example, the SMARCA2 ATPase may be upregulated in SMARCA4 mutant tumors and could be a candidate target in this patient population. Further validation will be necessary to evaluate this potential new target.
Jelinic, P., et. al. (2014). Recurrent SMARCA4 mutations in small cell carcinoma of the ovary.
Nature Genetics 23 March 2014
Hosein Kouros-Mehr
Monday, April 7, 2014
the end of Tech Bubble 2.0? Hosein Kouros-Mehr
Is this the beginning of the end?
We are all familiar with the tech bubble of the late 1990s and crash in the early 2000s. Could the charts be setting up for a similar tech crash this year? While it is too early to tell, there are worrisome developments in technology stocks that could easily trigger a correction is not an outright crash over the next 12 months. While this is a purely technical argument, the Nasdaq has not reached the highs of the 2000s and the animal spirits in today's market do not match those in the earlier bubble. But it could be the memories of the first tech bubble crash that prevents the rise of the 2nd tech bubble today.
Here is the weekly Nasdaq-100 chart from 1998-2001. Beginning in October 1998, the Nasdaq-100 spent 17 months above the 20 day weekly moving average and tested it 4 times during that time. Then came a blow off top with a huge bearish engulfing candle that pierced the 20 day MA in March 2000. It wasn't until 6 months later that it failed at the 50 day MA and began to crash to pre-rally levels. The technical damage occurred swiftly and came as a surprise to many. The wise ones took their money out during the period of consolidation before the crash.
Here is the Nasdaq-100 chart from the last two years. As in the previous chart, the Nasdaq-100 spent 15 months above the 20 day MA and tested it 4 times. Over the last week it broke through the 20 day MA to the downside. To continue the uptrend as it stands, the Nasdaq-100 will need to bounce quickly above the 20 day MA and while Janet Yellen may be the one who can do that, it appears that it's time to test the 50 day MA. While it's too early to say whether "Tech Bubble 2.0" is truly over, caution is warranted in the near term.
Disclaimer: The content of this blog should not be used as recommendation to purchase or sell securities.
$QQQ $SPY $GOOG $AAPL $TSLA $NFLX $FB $TWTR
Hosein Kouros-Mehr
We are all familiar with the tech bubble of the late 1990s and crash in the early 2000s. Could the charts be setting up for a similar tech crash this year? While it is too early to tell, there are worrisome developments in technology stocks that could easily trigger a correction is not an outright crash over the next 12 months. While this is a purely technical argument, the Nasdaq has not reached the highs of the 2000s and the animal spirits in today's market do not match those in the earlier bubble. But it could be the memories of the first tech bubble crash that prevents the rise of the 2nd tech bubble today.
Here is the weekly Nasdaq-100 chart from 1998-2001. Beginning in October 1998, the Nasdaq-100 spent 17 months above the 20 day weekly moving average and tested it 4 times during that time. Then came a blow off top with a huge bearish engulfing candle that pierced the 20 day MA in March 2000. It wasn't until 6 months later that it failed at the 50 day MA and began to crash to pre-rally levels. The technical damage occurred swiftly and came as a surprise to many. The wise ones took their money out during the period of consolidation before the crash.
Here is the Nasdaq-100 chart from the last two years. As in the previous chart, the Nasdaq-100 spent 15 months above the 20 day MA and tested it 4 times. Over the last week it broke through the 20 day MA to the downside. To continue the uptrend as it stands, the Nasdaq-100 will need to bounce quickly above the 20 day MA and while Janet Yellen may be the one who can do that, it appears that it's time to test the 50 day MA. While it's too early to say whether "Tech Bubble 2.0" is truly over, caution is warranted in the near term.
Disclaimer: The content of this blog should not be used as recommendation to purchase or sell securities.
$QQQ $SPY $GOOG $AAPL $TSLA $NFLX $FB $TWTR
Hosein Kouros-Mehr
Sunday, March 23, 2014
Cancer Archeology paper - Hosein Kouros-Mehr
Interesting article in Plos One describing discovery of metastastic carcioma in a young male who lived in Sudan in 1200 BC. While not necessarily shedding light into the mechanisms of cancer metastasis, the paper presents interesting novel archeological data that can be used for future historical analyses. The mechanisms that drive metastasis are likely to be as old as the mechanisms that drive normal development.
RESEARCH ARTICLE
On the Antiquity of Cancer: Evidence for Metastatic Carcinoma in a Young Man from Ancient Nubia (c. 1200BC)
- Published: March 17, 2014
- DOI: 10.1371/journal.pone.0090924
Abstract
Cancer, one of the world’s leading causes of death today, remains almost absent relative to other pathological conditions, in the archaeological record, giving rise to the conclusion that the disease is mainly a product of modern living and increased longevity. This paper presents a male, young-adult individual from the archaeological site of Amara West in northern Sudan (c. 1200BC) displaying multiple, mainly osteolytic, lesions on the vertebrae, ribs, sternum, clavicles, scapulae, pelvis, and humeral and femoral heads. Following radiographic, microscopic and scanning electron microscopic (SEM) imaging of the lesions, and a consideration of differential diagnoses, a diagnosis of metastatic carcinoma secondary to an unknown soft tissue cancer is suggested. This represents the earliest complete example in the world of a human who suffered metastatic cancer to date. The study further draws its strength from modern analytical techniques applied to differential diagnoses and the fact that it is firmly rooted within a well-documented archaeological and historical context, thus providing new insights into the history and antiquity of the disease as well as its underlying causes and progression.
Hosein Kouros-Mehr
Friday, March 21, 2014
Cancer Research Articles of Interest - Hosein Kouros-Mehr
I will be posting one cancer research article per week related to cancer metastasis, immunotherapy, angiogenesis, and pathways related to cell proliferation and apoptosis.
March 21, 2014:
1. RTEL1 -- Interesting novel target that is frequently amplified in cancers according to TCGA database (publicly available information). This paper sheds light on its potential mechanism in cancer.
RTEL1: functions of a disease-associated helicase
Hosein Kouros-Mehr
March 21, 2014:
1. RTEL1 -- Interesting novel target that is frequently amplified in cancers according to TCGA database (publicly available information). This paper sheds light on its potential mechanism in cancer.
RTEL1: functions of a disease-associated helicase
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Trends in Cell Biology, 26 February 2014
Copyright © 2014 Elsevier Ltd All rights reserved.
10.1016/j.tcb.2014.01.004
Copyright © 2014 Elsevier Ltd All rights reserved.
10.1016/j.tcb.2014.01.004
Authors
- Highlights
- RTEL1 is an Fe–S helicase that controls homologous recombination by dismantling D-loop intermediates.
- RTEL1 maintains telomere integrity by disassembling T-loops and counteracting G4-DNA structures.
- RTEL1 variants strongly associate with predisposition to glioma, astrocytoma, and glioblastoma.
- Mutations in RTEL1 give rise to Hoyeraal–Hreidarsson syndrome.
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