Two new initiatives from the CSCC

The Cancer Stem Cell Consortium (CSCC) has announced the launch of two new initiatives for 2011-2012. Information about these initiatives is available via the websites of the CSCC and Genome Canada.

The two initiatives are:

1. C4Resource: The Canada-California Collaborative Cancer Stem Cell Resource and Technology Platform Network or C4Resource, which would coordinate cancer stem cell research resources and platform technologies more efficiently and effectively to advance research and discovery and accelerate clinical translation of new findings; and,

2. Partnership with CIRM: A second funding partnership with the California Institute for Regenerative Medicine (CIRM) through the CIRM's Disease Team Therapy Development Research Awards.

Information about the CIRM Disease Team Therapy Development Research Award RFA is available at: http://www.cirm.ca.gov/RFA_10-05

From the Editor

I'll be taking some time away from blogging for the remainder of 2010. My tentative plan is to return with a different approach. For example, it may rely much less on blog posts, and more on short news items that can be found via a search of the real-time feed aggregator FriendFeed (FF) for the hashtag #cancerSC. An advantage of FF is that it permits news items and comments to be added by anyone who joins FriendFeed, and thus fosters a more community-oriented approach.

Trials to target CSCs

U-M stem cell trial shows promise against breast cancer by Kim Kozlowski, The Detroit News, September 30, 2010. Excerpt:

The research will be highlighted next week in Detroit during the World Stem Cell Summit, a gathering of 1,200 prominent stem cell scientists, industry leaders and advocates from 30 countries.

OA Video Protocol from Matsui Lab

Isolation of Stem Cells from Human Pancreatic Cancer Xenografts by Zeshaan Rasheed, Qiuju Wang, William Matsui, J Vis Exp 2010(Sep 26);(43). pii: 2169. OA Video Protocol.

Insights into the stem cells of CML

Insights into the stem cells of chronic myeloid leukemia by I Sloma, X Jiang, A C Eaves and C J Eaves, Leukemia 2010(Sep 23). [Epub ahead of print][PubMed citation]. Abstract:

Chronic myeloid leukemia (CML) has long served as a paradigm for generating new insights into the cellular origin, pathogenesis and improved approaches to treating many types of human cancer. Early studies of the cellular phenotypes and genotypes represented in leukemic populations obtained from CML patients established the concept of an evolving clonal disorder originating in and initially sustained by a rare, multipotent, self-maintaining hematopoietic stem cell (HSC). More recent investigations continue to support this model, while also revealing new insights into the cellular and molecular mechanisms that explain how knowledge of CML stem cells and their early differentiating progeny can predict the differing and variable features of chronic phase and blast crisis. In particular, these emphasize the need for new agents that effectively and specifically target CML stem cells to produce non-toxic, but curative therapies that do not require lifelong treatments.

Critical molecular pathways in CSCs of CML

Critical molecular pathways in cancer stem cells of chronic myeloid leukemia by Y Chen, C Peng, C Sullivan, D Li and S Li, Leukemia 2010(Sep); 24(9): 1545-54. Epub 2010 Jun 24. [Connotea bookmark][PubMed citation][Full text]. The abstract of this OA review:

Inhibition of BCR-ABL with kinase inhibitors in the treatment of Philadelphia-positive (Ph(+)) chronic myeloid leukemia (CML) is highly effective in controlling but not curing the disease. This is largely due to the inability of these kinase inhibitors to kill leukemia stem cells (LSCs) responsible for disease relapse. This stem cell resistance is not associated with the BCR-ABL kinase domain mutations resistant to kinase inhibitors. Development of curative therapies for CML requires the identification of crucial molecular pathways responsible for the survival and self-renewal of LSCs. In this review, we will discuss our current understanding of these crucial molecular pathways in LSCs and the available therapeutic strategies for targeting these stem cells in CML.

Must the last CML cell be killed?

Do we have to kill the last CML cell? DM Ross, TP Hughes and JV Melo, Leukemia 2010(Sep 16) [Epub ahead of print][FriendFeed entry][PubMed citation][Full text]. The abstract of this OA review:

Previous experience in the treatment of chronic myeloid leukaemic (CML) has shown that the achievement of clinical, morphological and cytogenetic remission does not indicate eradication of the disease. A complete molecular response (CMR; no detectable BCR-ABL mRNA) represents a deeper level of response, but even CMR is not a guarantee of elimination of the leukaemic, because the significance of CMR is determined by the detection limit of the assay that is used. Two studies of imatinib cessation in CMR are underway, cumulatively involving over 100 patients. The current estimated rate of stable CMR after stopping imatinib is approximately 40%, but the duration of follow-up is relatively short. The factors that determine relapse risk are yet to be identified. The intrinsic capacity of any residual leukaemic cells to proliferate following the withdrawal of treatment may be important, but there may also be a role for immunological suppression of the leukaemic clone. No currently available test can formally prove that the leukaemic clone is eradicated. Here we discuss the sensitive measurement of minimal residual disease, and speculate on the biology of BCR-ABL-positive cells that may persist after effective therapy of CML.

On the low frequency of tumor-initiating cells

Tumor-Initiating Cells Are Rare in Many Human Tumors by Kota Ishizawa and 16 co-authors, including Benjamin G Neel and William Matsui, Cell Stem Cell 2010(Sep 3); 7(3): 279-282. [FriendFeed entry][PubMed citation]. Abstract:

Tumor-initiating cells (TICs) are defined by their ability to form tumors after xenotransplantation in immunodeficient mice and appear to be relatively rare in most human cancers. Recent data in melanoma indicate that the frequency of TICs increases dramatically via more permissive xenotransplantation conditions, raising the possibility that the true frequency of TICs has been greatly underestimated in most human tumors. We compared the growth of human pancreatic, non-small cell lung, and head and neck carcinomas in NOD/SCID and NSG mice. Although TIC frequency was detected up to 10-fold higher in NSG mice, it remained low (<1 in 2500 cells) in all cases. Moreover, aldehyde dehydrogenase-positive (ALDH(+)) and CD44(+)CD24(+) cells, phenotypically distinct cells enriched in TICs, were equally tumorigenic in NOD/SCID and NSG mice. Our findings demonstrate that TICs are rare in these cancers and that the identification of TICs and their frequency in other human malignancies should be validated via primary tumors and highly permissive xenotransplantation conditions.

Some breast cancer tumors may not originate from stem cells?

Surprise breast cancer source by Jennifer Welsh,TheScientist.com, September 2, 2010. First paragraph:

Some breast cancer tumors may not originate from stem cells as previously believed, according to a study published in the September 3rd issue of Cell Stem Cell. The discovery is an important step in the development of treatments for these cancers.

This news story is based on the publication: BRCA1 Basal-like Breast Cancers Originate from Luminal Epithelial Progenitors and Not from Basal Stem Cells by Gemma Molyneux and 11 co-authors, including Matthew J Smalley, Cell Stem Cell 2010(Sep 3); 7(3): 403-417. OA article [Full text] [PubMed citation].

A commentary: Cancer Cell of Origin: Spotlight on Luminal Progenitors by Christine L Chaffer and Robert A Weinberg, Cell Stem Cell 2010(Sep 3); 7(3): 271-272. [PubMed citation].

Isolation and killing of candidate CML stem cells by antibody targeting

Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein by Marcus Järås and 10 co-authors, including Thoas Fioretos, Proc Natl Acad Sci USA 2010(Aug 30). OA article. [Epub ahead of print][PubMed citation]. Abstract:

Chronic myeloid leukemia (CML) is genetically characterized by the Philadelphia (Ph) chromosome, formed through a reciprocal translocation between chromosomes 9 and 22 and giving rise to the constitutively active tyrosine kinase P210 BCR/ABL1. Therapeutic strategies aiming for a cure of CML will require full eradication of Ph chromosome-positive (Ph(+)) CML stem cells. Here we used gene-expression profiling to identify IL-1 receptor accessory protein (IL1RAP) as up-regulated in CML CD34(+) cells and also in cord blood CD34(+) cells as a consequence of retroviral BCR/ABL1 expression. To test whether IL1RAP expression distinguishes normal (Ph(-)) and leukemic (Ph(+)) cells within the CML CD34(+)CD38(-) cell compartment, we established a unique protocol for conducting FISH on small numbers of sorted cells. By using this method, we sorted cells directly into drops on slides to investigate their Ph-chromosome status. Interestingly, we found that the CML CD34(+)CD38(-)IL1RAP(+) cells were Ph(+), whereas CML CD34(+)CD38(-)IL1RAP(-) cells were almost exclusively Ph(-). By performing long-term culture-initiating cell assays on the two cell populations, we found that Ph(+) and Ph(-) candidate CML stem cells could be prospectively separated. In addition, by generating an anti-IL1RAP antibody, we provide proof of concept that IL1RAP can be used as a target on CML CD34(+)CD38(-) cells to induce antibody-dependent cell-mediated cytotoxicity. This study thus identifies IL1RAP as a unique cell surface biomarker distinguishing Ph(+) from Ph(-) candidate CML stem cells and opens up a previously unexplored avenue for therapy of CML.

Two Open Access reviews

1) Cancer Stem Cells in Pancreatic Cancer by Qi Bao and 6 co-authors, including Karl-Walter Jauch and Christiane J Bruns, Cancers 2010(Aug 19); 2(3): 1629-41. [Full text PDF][Scribd entry][Part of the Special Issue Pancreatic Cancer]. Abstract:

Pancreatic cancer is an aggressive malignant solid tumor well-known by early metastasis, local invasion, resistance to standard chemo- and radiotherapy and poor prognosis. Increasing evidence indicates that pancreatic cancer is initiated and propagated by cancer stem cells (CSCs). Here we review the current research results regarding CSCs in pancreatic cancer and discuss the different markers identifying pancreatic CSCs. This review will focus on metastasis, microRNA regulation and anti-CSC therapy in pancreatic cancer.

2) The Emerging Role of the Phosphatidylinositol 3-Kinase/ Akt/Mammalian Target of Rapamycin Signaling Network in Cancer Stem Cell Biology by Alberto M Martelli and 4 co-authors, including James A McCubrey, Cancers 2010(Aug 18); 2(3): 1576-96. [Part of the Special Issue Cancer Stem Cells].

Comment: Review #2 is the first paper that has been published in the special issue on Cancer Stem Cells. As of August 20, 17 more contributions to this special issue are planned. Review #1, although about CSCs, is a contribution to a separate special issue on Pancreatic Cancer.

Selective targeting of neuroblastoma tumour-initiating cells

Selective targeting of neuroblastoma tumour-initiating cells by compounds identified in stem cell-based small molecule screens by Kristen M Smith and 16 co-authors, including David R Kaplan, EMBO Mol Med 2010(Aug 18) [Epub ahead of print][Full text]. Abstract:

Neuroblastoma (NB) is the most deadly extra-cranial solid tumour in children necessitating an urgent need for effective and less toxic treatments. One reason for the lack of efficacious treatments may be the inability of existing drugs to target the tumour-initiating or cancer stem cell population responsible for sustaining tumour growth, metastases and relapse. Here, we describe a strategy to identify compounds that selectively target patient-derived cancer stem cell-like tumour-initiating cells (TICs) while sparing normal paediatric stem cells (skin-derived precursors, SKPs) and characterize two therapeutic candidates. DECA-14 and rapamycin were identified as NB TIC-selective agents. Both compounds induced TIC death at nanomolar concentrations in vitro, significantly reduced NB xenograft tumour weight in vivo, and dramatically decreased self-renewal or tumour-initiation capacity in treated tumours. These results demonstrate that differential drug sensitivities between TICs and normal paediatric stem cells can be exploited to identify novel, patient-specific and potentially less toxic therapies.

See also: New Twist on Drug Screening to Treat Common Childhood Cancer, ScienceDaily, August 18, 2010. Excerpt:

A study led by scientists at The Hospital for Sick Children (SickKids) reveals a new method of identifying drugs to treat children suffering from fatal cancers for which an effective treatment has not been found. Rather than developing a new drug from scratch, which is a complicated and time-consuming process, they tried a different approach: in the lab, they tested existing drugs on cancer stem cells from young patients with neuroblastoma, one of the common cancers of infants and children.

A related blog post is: High-throughput cancer stem cell-based screening assay for therapeutic compounds by Alexey Bersenev, Stem Cell Assays, August 19, 2010 [FriendFeed entry].

Therapeutic implications of colon CSCs

Therapeutic implications of colon cancer stem cells by Eros Fabrizi and 3 co-authors, including Lucia Ricci-Vitiani, World J Gastroenterol 2010(Aug 21); 16(31): 3871-7. OA review. [FriendFeed entry][PubMed citation]. Abstract:

Colorectal cancer is the second most common cause of cancer-related death in many industrialized countries and is characterized by a heterogenic pool of cells with distinct differentiation patterns. Recently, the concept that cancer might arise from a rare population of cells with stem cell-like properties has received support with regard to several solid tumors, including colorectal cancer. According to the cancer stem cell hypothesis, cancer can be considered a disease in which mutations either convert normal stem cells into aberrant counterparts or cause a more differentiated cell to revert toward a stem cell-like behaviour; either way these cells are thought to be responsible for tumor generation and propagation. The statement that only a subset of cells drives tumor formation has major implications for the development of new targeted therapeutic strategies aimed at eradicating the tumor stem cell population. This review will focus on the biology of normal and malignant colonic stem cells, which might contribute to our understanding of the mechanisms responsible for tumor development and resistance to therapy.

Putative tumor-initiating progenitor cells predict poor lung cancer prognosis

Adult lung stem cells, vital to injury repair, associated with poor cancer prognosis, News release, UCLA Newsroom, August 17, 2010. Excerpts:

Adult stem cells that are vital for airway repair in the lung but that persist in areas where pre-cancerous lesions are found are associated with a poor prognosis in patients who develop cancer, even those with early-stage disease, researchers at UCLA's Jonsson Comprehensive Cancer Center have found.

.....

In this study, Gomperts and her team screened around 900 tumors removed from patients with non-small cell lung cancer at UCLA and the University of Texas' MD Anderson Cancer Center, looking to see whether the adult stem cells could be found in the tumor. In her lab, Gomperts is now studying the pre-cancerous lesions where the adult stem cells persist in an attempt to uncover the cascade of molecular events that may transform these cells into lung cancer stem cells.

The news release is based on this publication: Presence of a Putative Tumor-Initiating Progenitor Cell Population Predicts Poor Prognosis in Smokers with Non–Small Cell Lung Cancer by Aik T Ooi and 19 co-authors, including Brigitte N Gomperts, Cancer Res 2010(Aug 15); 70(16): 6639-48. [PubMed citation][Full text]. Abstract:

Smoking is the most important known risk factor for the development of lung cancer. Tobacco exposure results in chronic inflammation, tissue injury, and repair. A recent hypothesis argues for a stem/progenitor cell involved in airway epithelial repair that may be a tumor-initiating cell in lung cancer and which may be associated with recurrence and metastasis. We used immunostaining, quantitative real-time PCR, Western blots, and lung cancer tissue microarrays to identify subpopulations of airway epithelial stem/progenitor cells under steady-state conditions, normal repair, aberrant repair with premalignant lesions and lung cancer, and their correlation with injury and prognosis. We identified a population of keratin 14 (K14)-expressing progenitor epithelial cells that was involved in repair after injury. Dysregulated repair resulted in the persistence of K14+ cells in the airway epithelium in potentially premalignant lesions. The presence of K14+ progenitor airway epithelial cells in NSCLC predicted a poor prognosis, and this predictive value was strongest in smokers, in which it also correlated with metastasis. This suggests that reparative K14+ progenitor cells may be tumor-initiating cells in this subgroup of smokers with NSCLC.

Partnership Pays Off

Northern Exposure by Emmet Pierce, San Diego Business Journal, August 16, 2010. Excerpt:

An example of San Diegans collaborating with Canadians is the work that has taken place at the UC San Diego Moores Cancer Center in cooperation with research at the University of Toronto. The partnership has enabled San Diego researchers to acquire a $20 million grant to develop drugs to be used against leukemia stem cells, Barr says.Dr. Catriona Jamieson, director of the stem cell research program at the Moores center, said scientists from Toronto and San Diego share "a deep and abiding interest in cancer stem cell biology." The Canadian consulate in San Diego was instrumental in helping to create a relationship in which both institutions would benefit, sharing information and applying for funds to support their research.

"The idea was to establish a Canada-California cancer stem cell initiative and obtain connections with Canadian funding agencies, particularly Genome Canada and the Ministry of Health," she said.

Jamieson added, "The most important thing is it allows people with disparate abilities and backgrounds to work together on the same problem."

Barr said the University of Toronto also was able to secure a $20 million research grant because of the collaboration, "so the team is greater than the sum of its parts."

Oxygen, hypoxia and the stem cell niche

Oxygen in Stem Cell Biology: A Critical Component of the Stem Cell Niche by Ahmed Mohyeldin, Tomás Garzón-Muvdi and Alfredo Quiñones-Hinojosa, Cell Stem Cell 2010(Aug 6); 7(2): 150-61. Review. [PubMed citation][FriendFeed entry]. Via Twitter @CellStemCell: Access [to the full text] is free in August worldwide so readers can try out new enhanced online format.

Abstract:

The defining hallmark of stem cells is their ability to self-renew and maintain multipotency. This capacity depends on the balance of complex signals in their microenvironment. Low oxygen tensions (hypoxia) maintain undifferentiated states of embryonic, hematopoietic, mesenchymal, and neural stem cell phenotypes and also influence proliferation and cell-fate commitment. Recent evidence has identified a broader spectrum of stem cells influenced by hypoxia that includes cancer stem cells and induced pluripotent stem cells. These findings have important implications on our understanding of development, disease, and tissue-engineering practices and furthermore elucidate an added dimension of stem cell control within the niche.

Cell of origin for human prostate cancer

Scientists at UCLA find cell of origin for human prostate cancer by Kim Irwin, UCLA Newsroom, July 29, 2010. Excerpts:

"Certainly, the dominant thought is that human prostate cancer arose from the luminal cells because the cancers had more features resembling luminal cells," said Witte, senior author of the study and a Howard Hughes Medical Institute Investigator. "But we were able to start with a basal cell and induce human prostate cancer, and now, as we go forward, this gives us a place to look in understanding the sequence of genetic events that initiates prostate cancer and defining the cell-signaling pathways that may be at work fueling the malignancy, helping us to potentially uncover new targets for therapy."

.....

The new human-in-mouse model system developed in the study was created by taking healthy human prostate tissue that will induce cancer once it is placed in mice, instead of taking malignant tissue that is already cancerous and implanting it. This model can now be used to evaluate the effectiveness of new types of therapeutics. By using defined genetic events to activate specific signaling pathways, researchers can more easily compare therapeutic efficacy. The new model, by deconstructing tissue and then reconstructing it, also will aid in analyzing how the cells change during cancer progression.

This news release is based on the publication: Identification of a Cell of Origin for Human Prostate Cancer by Andrew S Goldstein and 5 co-authors, including Owen N Witte, Science 2010(Jul 30); 329(5991): 568-71. [PubMed citation][FriendFeed entry][Twitter trackbacks via Topsy].

Disagreement about melanoma CSCs

The Evolving Science of Cancer Stem Cells by Carmen Phillips, NCI Cancer Bulletin 2010(Jul 27); 7(15). Excerpt:

Researchers from Stanford University earlier this month reported in Nature that they had found a marker, CD271, that identified a somewhat unique population of cells that could produce melanoma in highly immunocompromised mice; anywhere from 2.5 percent to 41 percent of cells in their human tumor samples expressed the marker. In additional experiments using similar mice on which human skin was engrafted, only tumor cells with the marker could produce tumors and metastases in the mice. (In his lab, Dr. Morrison noted, the same marker did not differentiate tumor-forming from nontumor-forming cells.)

The publication about CD271 is: Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271 by Alexander D Boiko and 11 colleagues, Nature 2010(Jul 1); 466(7302): 133-7. [PubMed citation].

Comments: The sentence: "In his lab, Dr. Morrison noted, the same marker did not differentiate tumor-forming from nontumor-forming cells" is noteworthy. Why the difference in results for CD271?

The publication by Boiko and co-authors was cited in a previous post to this blog, "Melanoma-initiating cells identified", dated July 1, 2010.

See also an earlier post to this blog, "Tumorigenic cells not rare in human melanoma", dated December 3, 2008.

Researchers Study CSCs as Therapeutic Targets for Mesothelioma

Researchers Study Cancer Stem Cells as Therapeutic Targets for Mesothelioma, Asbestos.com, July 26, 2010. Excerpt:

In a study published in the International Journal of Oncology, Cortes-Dericks and colleagues tested whether cancer stem cells in malignant pleural mesothelioma express resistance to cisplatin and pemetrexed, two chemotherapy drugs commonly used to treat mesothelioma cancer.

This news item is based on the OA publication entitled: Putative cancer stem cells in malignant pleural mesothelioma show resistance to cisplatin and pemetrexed by Lourdes Cortes-Dericks, Giovanni L Carboni, Ralph A Schmid and Golnaz Karoubi, Int J Oncol 2010(Aug); 37(2): 437-44. [PubMed citation].

Prostate CSCs sensitive to gamma-tocotrienol?

Gamma-Tocotrienol Kills Prostate Cancer Stem Cells, PRNewswire, July 25, 2010. Excerpt:

The scientists found that low doses of gamma-tocotrienol cause apoptosis in the prostate cancer stem cells and suppress their colony formation capability. This results in a lower prostate cancer stem cell population (as defined by the protein markers CD133 and CD44). Further tests in mice models were conducted, where mice implanted with hormonal refractory prostate cancer cells were given gamma-tocotrienol orally. The results showed that gamma- tocotrienol not only reduced tumour size formed, but also decreased the incidence rate of tumour formation by 75%, as compared to the control group of mice, which had 100% tumour formation. These results strongly suggest that gamma-tocotrienol could be developed for prostate cancer prevention and treatment.

The news release by Davos Life Science is based on the publication:

Gamma-tocotrienol as an effective agent in targeting prostate cancer stem cell-like population by Sze Ue Luk and 11 co-authors, including Ming-Tat Ling, Int J Cancer 2010(Jul 8) [Epub ahead of print][PubMed citation].

Comment:

See also a relevant patent application: (WO/2010/047663) Use of Tocotrienol Composition for the Prevention of Cancer.
Publication Date: 29.04.2010
Applicants: DAVOS LIFE SCIENCE PTE. LTD. [SG/SG]; 16 Tuas South Street 5 Singapore 637795 (SG) (All Except US).
LING, Ming Tat [CN/AU]; (AU) (US Only).
YAP, Wei Ney [MY/SG]; (SG) (US Only).
WONG, Yong Chuan [MY/CN]; (CN) (US Only).
YAP, Yee Leng, Daniel [MY/SG]; (SG) (US Only).

Irradiating brain's stem cell niche

Irradiating brain's stem cell niche doubles survival time for patients with brain cancers by Kim Irwin, News Release, UCLA Newsroom, July 23, 2010. Excerpt:

Patients with deadly glioblastomas who received high doses of radiation that hit a portion of the brain which harbors neural stem cells had double the progression-free survival time as patients who had lower doses or no radiation targeting the area, a study from the radiation oncology department at UCLA's Jonsson Comprehensive Cancer Center has found.

The news release is based on this OA publication: Irradiation of the Potential Cancer Stem Cell Niches in the Adult Brain Improves Progression-free Survival of Patients with Malignant Glioma by Patrick Evers and 6 co-authors, including Frank Pajonk, BMC Cancer 2010(Jul 21); 10(1):384. [Epub ahead of print][FriendFeed entry].

Comment: On the brain as a model system to study the impact of radiation dose given to stem cell niches. Provides clinical evidence, based on an improvement in progression-free survival, to support the hypothesis that higher radiation doses to neural stem cell (NSC) niches improves patient survival by eradicating CSCs.

More about salinomycin

New mission for salinomycin in cancer by Cord Naujokat, SciTopics, July 15, 2010. Excerpt (in the "continue reading" section):

In addition, a very recent study demonstrates that salinomycin overcomes ATP-binding cassette (ABC) transporter-mediated multidrug and apoptosis resistance in human leukemia stem cell-like cells (3).

Reference #3: Salinomycin overcomes ABC transporter-mediated multidrug and apoptosis resistance in human leukemia stem cell-like KG-1a cells, by Dominik Fuchs and 4 co-authors, including Cord Naujokat, Biochem Biophys Res Commun 2010(Apr 16);394(4): 1098-104 [Epub 2010(Mar 27)][PubMed citation].

Comments: Near the end of this article about salinomycin is the comment that "the investigation of its safety, toxicity, pharmacology and anticancer activity in humans will be a challenge." The author then mentions a preliminary study of "a small cohort of patients with metastatic breast cancer or metastatic head and neck cancers". The results of this preliminary study of the toxicity of salinomycin are summarized. They have not yet been published in the peer-reviewed literature, although a manuscript has been submitted [see reference #4 in the article]. The implication of these preliminary results is that there may be a "therapeutic window" for salinomycin, that is, a drug dosage that yields clinically significant benefits in the absence of excessive toxicity.

For a previous commentary on salinomycin, see: Cancer stem cell breakthrough by Kat Arney, Science Update blog, Cancer Research UK, August 14, 2009. Excerpt:

We need to stress that these were laboratory experiments, and there is no evidence yet that salinomycin can treat cancer in humans. Salinomycin is currently used as an antibiotic for chickens and cows, and it can be toxic or even fatal to humans, causing serious muscle and heart problems.

If there is a "therapeutic window" for salinomycin, it could be a small one, and is likely to vary from one tumor to another.

For a previous post to this blog about salinomycin, see: Identification of selective inhibitors of breast CSCs in mice, August 14, 2009.

Innovative Researcher Vlog

SU2C Innovative Researcher Vlog: Dr. Lawlor (Pt. 3). Video (3:09 min) posted July 13, 2010. Features Elizabeth R Lawlor, University of Michigan, an SU2C Innovative Research Grants Investigator. [About SU2C (Stand Up to Cancer)]. She provides brief comments about her project: "Modeling Ewing Tumor Initiation in Human Neural Crest Stem Cells". How do normal stem cells become cancer stem cells?

An example of a recent (OA) publication from her laboratory: CD133 expression in chemo-resistant Ewing sarcoma cells by
Xiaohua Jiang and 8 co-authors, including Elizabeth R Lawlor,
BMC Cancer 2010(Mar 26); 10: 116. [FriendFeed entry][PubMed citation][Full text via PMC].

Two recent OA articles

Two articles, with Open Access (OA) to the full text (PDF):

Putative cancer stem cells in malignant pleural mesothelioma show resistance to cisplatin and pemetrexed, Int J Oncol 2010(Aug); 37(2): 437-44. [PubMed citation].

Possible involvement of stem-like populations with elevated ALDH1 in sarcomas for chemotherapeutic drug resistance, Oncol Rep 2010(Aug); 24(2): 501-5. [PubMed citation].

Comment about these journals:

Spandidos Publications publishes six journals. Of these six, two are: International Journal of Oncology (2009 Impact Factor: 2.4) and Oncology Reports (2009 Impact Factor: 1.6). This publisher provides a hybrid open access option. The Information for Authors for all six journals includes, at the bottom of the page, this information: "Should authors prefer or require their article to be freely available as soon as it has been published, they may request open access immediately upon publication for a fee of EUR 450."

CSC news update 2010-07-03

For links to recent news items about CSC, visit this [Topsy] page. An example of a news item that has received attention in the past week:

Cancer Stem Cells Are Not 'One Size Fits All,' Lung Cancer Models Show http://bit.ly/bE9F0V & http://bit.ly/amEkFR. Hashtag: #cancerSC. Posted to Twitter on Fri Jul 02 via TweetDeck

Melanoma-initiating cells identified

Melanoma-initiating cells identified by study by Krista Conger, News release, Stanford School of Medicine, June 30, 2010. Excerpt:

Scientists at the School of Medicine have identified a cancer-initiating cell in human melanomas. The finding is significant because the existence of such a cell in the aggressive skin cancer has been a source of debate. It may also explain why current immunotherapies are largely unsuccessful in preventing disease recurrence in human patients.

The news release is about this publication: Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271 by Alexander D Boiko and 11 co-authors, including Irving L. Weissman, Nature 2010(Jul 1); 466(7302): 133-7. [FriendFeed entry].

A blog post about this same publication is: Stanford scientists identify a melanoma-initiating cell by Krista Conger, Scope blog, Stanford School of Medicine, June 20, 2010.

See also a commentary about the publication: Cancer stem cells: Invitation to a second round by Peter Dirks, Nature 2010(Jul 1); 466(7302): 40-1. Excerpt:

Boiko et al. study a type of human skin cancer called melanoma and, in particular, cancer cells enriched in a stem-cell marker called CD271. They find that, unlike other cells from the same tumour, CD271-expressing (CD271+) cells could initiate and maintain tumour growth in vivo — an observation consistent with the existence of a melanoma-cell functional hierarchy.

This finding reflects a view different from that of an earlier study by Quintana et al.[3], which demonstrated that, in some cases, as many as 50% of human melanoma cells have tumorigenic potential. In addition, no marker tested identified a tumorigenic subpopulation. The authors[3] concluded that the frequency of cancer cells that can initiate tumorigenesis depends, in part, on the assessment techniques and assays.

Another news item, based on the same publication, is: New hope in fight against skin cancer as deadly 'master cells' are identified for first time, Mail Online, July 1, 2010. Excerpt:

However Dr Alexander Boiko, who made the discovery at Stanford University, said the newly discovered 'stem cells' in advanced skin cancers were often missed by conventional immunotherapy.

'Without wiping out the cells at the root of the cancer, the treatment will fail,' he said.

Comments: Boiko et al. and Dirks suggest reasons why results different from those of Quintana et al. were obtained. One possibility is that the melanomas that the latter authors studied were at an advanced stage. If, as a cancer progresses, more cells acquire the attributes of cancer stem cells, then advanced melanomas may contain very high frequencies of tumorigenic cells.

As Boiko et al. point out in their publication, "The most crucial test of the tumour stem cell hypothesis is that markers or pathways restricted to tumour stem cells can be targets for curative therapies in the patient, which has not yet been done."

CSC news update 2010-06-26

For links to recent news items about CSC, visit this [Topsy] page. An example of a news item that has received attention in the past week:

Max Wicha: Breast cancer stem cells (4 min video) http://bit.ly/bhoNWn (via @cells_nnm). Hashtag: #cancerSC. Posted to Twitter on Fri Jun 25, 2010 via TweetDeck

On glioma recurrence and CSCs

Decreasing glioma recurrence through adjuvant cancer stem cell inhibition by Josh Neman and Rahul Jandial, Biologics: Targets & Therapy 2010(Jun 19); 4: 157-62 [OA review][FriendFeed entry]. Abstract:

Gliomas remain one of the most challenging solid organ tumors to treat and are marked clinically by invariable recurrence despite multimodal intervention (surgery, chemotherapy, radiation). This recurrence perhaps, is as a consequence of the failure to eradicate a tumor cell subpopulation, termed cancer stem cells. Isolating, characterizing, and understanding these tumor-initiating cells through cellular and molecular markers, along with genetic and epigenetic understanding will allow for selective targeting through therapeutic agents and holds promise for decreasing glioma recurrence.

OncoMed Has 'Wnt' in its Sails

OncoMed Has 'Wnt' in its Sails; Bayer Deal Adds $40M Up Front by Jennifer Boggs, Bioworld, June 18, 2010. Excerpts:

[OncoMed's] latest accomplishment is another early stage deal, this time with Bayer Schering Pharma AG, to develop drugs targeting the Wnt signaling pathway. It's an agreement that brings $40 million up front, with the potential for more than $1 billion in future milestones.

.....

The Wnt pathway is believed to be a key target in halting cancer stem cell activity. But only a few other firms - Avalon Pharmaceuticals Inc. (now part of Clinical Data Inc.) and 2008 start-up Wintherix LLC, for example - have entered that space, largely because Wnt is not an easily druggable target.

News release from Bayer: Bayer Schering Pharma and OncoMed Pharmaceuticals Enter Strategic Alliance to Develop Anti-Cancer Stem Cell Therapeutics, June 17, 2010. Excerpt:

Bayer Schering Pharma AG, Germany, and OncoMed Pharmaceuticals, Inc., today announced a global strategic alliance to discover, develop and commercialize novel anti-cancer stem cell therapeutics targeting the Wnt signaling pathway. Cancer stem cells are a subset of tumor cells believed to play a significant role in the establishment, metastasis and recurrence of cancer and agents targeting the Wnt pathway have the potential to be developed as pan-tumor drugs.

Comment: The Bayer-OncoMed strategic alliance has received attention via the social media. See, for example, the results of this FriendFeed search.

CIRM and Wisconsin sign a Declaration of Cooperation

Wisconsin Governor Jim Doyle and California’s State Stem Cell Agency Sign Declaration Of Cooperation to Advance Stem Cell Research toward Cures, News release, California Institute For Regenerative Medicine (CIRM), June 17, 2010. Excerpts:

The California Institute for Regenerative Medicine (CIRM) and the state of Wisconsin, coordinated through and led by the University of Wisconsin-Madison, expect to identify opportunities to further the advancement, promotion and funding of stem cell research and the development of stem cell therapies.

.....

CIRM currently has similar agreements with the Cancer Stem Cell Consortium of Canada, the State of Victoria in Australia, the JST in Japan, the MICINN in Spain, the MRC in the United Kingdom, the BMBF in Germany, MOST in China and the state of Maryland, and the New York Stem Cell Foundation.

Patent application: Levels of Oct1 as a method of identifying CSCs

(WO2010065400) Cancer Biomarker and Methods of Using Thereof.

Excerpt from PCT Biblio. Data:

International Application No.: PCT/US2009/065742
Publication Date: 10.06.2010

Excerpt from Description:

Described herein are biomarkers which can be used for identifying a subject at risk for or evaluating the progression of cancer. In certain aspects, these biomarkers can be used to identify cancer stem cells. These biomarkers can include Octl or molecular variants thereof and downstream targets of Octl. In addition, described herein are methods for reducing the expression of these biomarkers associated with cancer.

Decitabine may target ovarian CSCs?

Two-Drug Phase I Trial Shows Promise in Treating Late-Stage Ovarian Cancer, ScienceDaily, June 13, 2010. Excerpt:

"Our hypothesis is that decitabine isn't just targeting active ovarian cancer cells, but also cancer stem cells that seem to survive the first treatments," [Kenneth] Nephew said. "By keeping tumor suppression genes from being methylated, carboplatin and other platinum-based treatments for ovarian cancer have a better chance of success in the late stages."

This news release is about the publication entitled: A phase 1 and pharmacodynamic study of decitabine in combination with carboplatin in patients with recurrent, platinum-resistant, epithelial ovarian cancer by Fang Fang, Curt Balch and 9 co-authors, including Kenneth P Nephew and Daniela E Matei, Cancer 2010(Jun 8) [Epub ahead of print].

CSC news update 2010-06-13

For links to recent news items about CSC, visit this [Topsy] page. An example of a news item that has received attention in the past week:

Wellcome Trust - award to PTC Therapeutics, to combat drug-resistant cancers http://bit.ly/cJpUie. Hashtag: #cancerSC. Posted to Twitter on Wed Jun 09, 2010 via TweetDeck

CSCs responsible for metastasis identified

Cancer stem cells responsible for metastasis identified: HK study, Xinhua News Agency, June 4, 2010. Excerpt:

Hong Kong researchers have identified a subset of cancer stem cells responsible for metastasis in human colorectal cancer which can help better predict the prognosis and design a more suitable treatment for patients, according to a study made public by the University of Hong Kong on Friday.

The researchers from the university's medicine school discovered that cancer stem cells with a surface marker CD26, which marks a subset of cancer stem cells with metastatic capacity, are present in all terminal colon cancer cells and all metastatic cancer cells.

This news item is about the publication: A Subpopulation of CD26+ Cancer Stem Cells with Metastatic Capacity in Human Colorectal Cancer by Roberta Pang and 13 co-authors, including Wai Lun Law, Ronnie T Poon and Benjamin CY Wong [photos of authors], Cell Stem Cell 2010(Jun 4); 6(6): 603-15. [Summary][Twitter entry][Commentary][FriendFeed entry][Science Pond entry].

Phase I clinical trial of ICT-107

Immune response correlation with progression-free survival in glioblastoma following dendritic cell immunotherapy (ICT-107) by Surasak Phuphanich and 9 co-authors, including Manish Singh, Keith Black and John Wu, J Clin Oncol 28:7s, 2010 (suppl; abstr 2097). To be presented at the 2010 ASCO Annual Meeting, June 06, 2010.

Related news releases:

ImmunoCellular Therapeutics Ltd. (IMUC) to Present Cancer Vaccine Candidate, International Business Times, June 02, 2010. Excerpt:

Data from the company’s recent clinical trial of ICT-107, the company’s dendritic cell-based cancer vaccine candidate, will be presented at the 46th Annual Meeting of the American Society of Clinical Oncology (ASCO) June 4-8 in Chicago.

See also: Immunocellular brain cancer vaccine shows promise, Reuters, June 02, 2010. Excerpt:

"We are targeting specific antigens that are on cancer stem cells ... the only population of cells that can really propagate a tumor," said Dr. John Yu, director of surgical neuro-oncology at Cedars-Sinai Medical Center in Los Angeles and ImmunoCellular's chief scientific officer.

Another related news release: Immunocellular Therapeutics Enters into Research Agreement with University of Pennsylvania to Support Phase II Clinical Trial of ICT-107, Business Wire, April 21, 2010.

Patent application involving miRNAs and CSCs

Methods and Compositions Involving miRNAs in Cancer Stem Cells, Patent Application WO/2010/056737. [FriendFeed entry].

One of the applicants is Mirna Therapeutics, Inc.

CSC news update 2010-05-24

For links to recent news items about CSC, visit this [Topsy] page. An example of a news item that has received attention in the past week:

Markers on xenograft-initiating cells in estrogen receptor-negative breast cancer http://bit.ly/9Xhzbp. Hashtag: #cancerSC. Posted to Twitter on Fri May 21, 2010 via TweetDeck. [PubMed Citation]

An evolving concept of CSCs in tumor biology

An evolving concept of cancer stem cells in tumor biology: a lecture (34:38 min) by Jeremy N Rich. Webcast of the initial presentation at an Educational Session on Cancer Stem Cells and Treatment Resistance, AACR 101st Annual Meeting, April 17, 2010. [FriendFeed entry].

Comment: Dr. Rich's research has a primary emphasis on Glioma Cancer Stem Cell and Brain Tumors. An example of a recent publication: Integrin Alpha 6 Regulates Glioblastoma Stem Cells by Justin D Lathia and 10 co-authors, including Jeremy N Rich, Cell Stem Cell 2010(May 7); 6(5): 421-32. [PubMed citation][FriendFeed entry].

US Patent: Isolation and use of solid tumor stem cells

Isolation and use of solid tumor stem cells, United States Patent 7,713,710. [FreePatentsOnline][PatentStorm].
Publication Date: May 11, 2010.
Inventors: Clarke; Michael F. (Ann Arbor, MI), Morrison; Sean J. (Ann Arbor, MI), Wicha; Max S. (Ann Arbor, MI), Al-Hajj; Muhammad (Ann Arbor, MI).
Assignee: The Regents of the University of Michigan (Ann Arbor, MI) .
Appl. No.: 11/753,191
Filed: May 24, 2007
Abstract:

A small percentage of cells within an established tumor have the properties of stem cells. These solid tumor stem cells give rise both to more tumor stem cells and to the majority of cells in the tumor that have lost the capacity for extensive proliferation and the ability to give rise to new tumors. The solid tumor heterogeneity reflects the presence of tumor cell progeny arising from a solid tumor stem cell. This discovery is the basis for solid tumor stem cell compositions, methods for distinguishing functionally different populations of tumor cells, methods for using these tumor cell populations for studying the effects of therapeutic agents on tumor growth, and methods for identifying and testing novel anti-cancer therapies directed to solid tumor stem cells.

Parent Case Text:

CLAIM OF PRIORITY
This application is a Continuation of U.S. patent application Ser. No. 11/150,073, filed Jun. 10, 2005, which is a Continuation of U.S. patent application Ser. No. 09/920,517, filed Aug. 1, 2001, now U.S. Pat. No. 6,984,522, which claims priority to U.S. provisional applications Ser. No. 60/222,794, filed Aug. 3, 2000, and Ser. No. 60/240,317, filed Oct. 13, 2000, all of which are herein incorporated by reference in their entireties.

Google patents entry for Application Number 11/753,191 (The application that led to patent 7,713,710. The filing date was 24 May 2007).

Google patents entry for Application Number 11/150,073 (See Parent Case Text above: the filing date was 10 June 2005).

Google patents entry for Patent Number 6,984.522 (See Parent Case Text above: the filing date was 1 August, 2001 and the issue date was 10 Jan 2006). [FreePatentsOnline][PatentStorm].

Comment:

Not mentioned in the Parent Case Text above is United States Patent 7,115,360. [FreePatentsOnline][PatentStorm]. This patent was issued October 3, 2006 and filed on August 2, 2001.

The Parent Case Text for patent 7,115,360:

CLAIM OF PRIORITY
This patent is the United States national stage of PCT patent application PCT/US01/24243, published Feb. 14, 2002 as WO 02/12447, which is a continuation of U.S. Ser. No. 09/920,517, filed Aug. 1, 2001, now U.S. Pat. No. 6,984,522. This patent also claims priority to provisional patent applications U.S. Ser. Nos. 60/222,794, filed Aug. 3, 2000, and 60/240,317, Oct. 13, 2000.

Information about this patent was found via a Google search for "Isolation and use of solid tumor stem cells".

Generic drug a potential treatment for glioblastoma?

DCA research on brain cancer, EurekAlert, May 12, 2010. [FriendFeed entry]. Excerpt: "... the orphan generic drug Dichloroacetate (DCA) may hold promise as potential therapy for ... a form of brain cancer called glioblastoma". Another excerpt:

By extracting glioblastomas from 49 patients over a period of 2 years and studying them within minutes of removal in the operating room, the team showed that tumors respond to DCA by changing their metabolism. Then, the team treated 5 patients with advanced glioblastoma and secured tumor tissues before and after the DCA therapy. By comparing the two, the team showed that DCA works in these tumors exactly as was predicted by test tube experiments. This is very important because often the results in non-human models tested in the lab do not agree with the results in patients. In addition, the team showed that DCA has anti-cancer effects by altering the metabolism of glioblastoma cancer stem cells, the cells thought responsible for the recurrences of cancer.

And,

No conclusions can be made on whether the drug is safe or effective in patients with this form of brain cancer, due to the limited number of patients tested by the study's leads Drs Michelakis and Petruk. Researchers emphasize that use of DCA by patients or physicians, supplied from for-profit sources or without close clinical observation by experienced medical teams in the setting of research trials, is not only inappropriate but may also be dangerous. ...

See also: Generic drug may be potential treatment for deadly brain cancer: U of A medical study by Noreen Remtulla and Julia Necheff, ExpressNews, University of Alberta, May 12, 2010.

And: Potential brain-cancer drug shows promise, CBC News, May 12, 2010. [CBC video].

And: Cancer drug trial raises hopes by Elise Stolte, Edmonton Journal, May 13, 2010.

These news reports are about the publication: Metabolic Modulation of Glioblastoma with Dichloroacetate by Evangelos D Michelakis and 12 co-authors, including Kenneth C Petruk, Sci Transl Med 2010(May 12); 2(31): 31ra34.

See also an editorial: Targeting Cell Metabolism in Cancer Patients by Matthew G Vander Heiden, Sci Transl Med 2010(May 12); 2(31) :31ed1. From the TOC: "Dichloroacetate can safely modify glucose metabolism in aggressive brain tumors when administered to patients". Last sentence of the editorial: "Time will tell whether this strategy constitutes an effective cancer therapy".

Comments: After an initial research publication in January 2007 [PubMed citation], DCA attracted much attention. See, for example, the Wikipedia entry for Dichloroacetic acid. And, Cancer society warns of untested drug, CBC News, March 22, 2007.

The Official University of Alberta DCA Website provides FAQs about DCA. It includes, in the News & Updates section, DCA Research Team publishes results of Clinical Trials (dated May 12, 2010) and an earlier Letter from Dr. Evangelos Michelakis (dated October 2008).

CSC news links 2010-05-08

For links to recent news items about CSC, visit this [Topsy] page. Examples of two news items that have received attention in the past week:

New research links ovarian hormones with breast stem-cell growth - Globe and Mail http://bit.ly/brT71E. Hashtag: #cancerSC. Posted to Twitter on Wed May 06, 2010 via TweetDeck. [PubMed Citation]

Broccoli compound limits breast cancer (about sulforaphane) http://bit.ly/9blnNP & http://bit.ly/aOTSDv. Hashtag: #cancerSC. Posted to Twitter on Wed May 05, 2010 via TweetDeck. [PubMed Citation]

CSC news links 2010-05-01

For links to recent news items, visit these [Twitter] or [FriendFeed] pages. Examples of two news items that have received attention:

• Distinct expression levels and patterns of stem cell marker, aldehyde dehydrogenase isoform 1 (ALDH1), in human epithelial cancers by Shan Deng and 15 co-authors, including George Coukos and Lin Zhang, PLoS ONE, 2010(Apr 21); 5(4): e10277 [Connbotea bookmark][PubMed Citation][OA full text]. Last sentence of the abstract:

  As a novel cancer stem cell marker, ALDH1 can be used for tumors whose corresponding normal tissues express ALDH1 in relatively restricted or limited levels such as breast, lung, ovarian or colon cancer.

• AACR: Are Cancer Stem Cells Vulnerable to Trastuzumab? By Ed Susman, MedPage Today (Apr 19) [FriendFeed entry][AACR10 abstract]. Excerpt:

  Mathematical modeling suggests that even in women whose breast cancer does not overexpress the HER-2 gene, treatment with trastuzumab (Herceptin) in the adjuvant setting could wipe out cancer stem cells, researchers reported here.

  
  

More about presentations at AACR10

Five presentations at the 101th annual meeting of the American Association of Cancer Research were highlighted a news release from Geron Corporation (dated March 3, 2010). One presentation that had an explicit focus on CSC was this poster:

Imetelstat, a telomerase inhibitor in phase I trials in solid tumor and hematological malignancies, has broad activity against multiple types of cancer stem cells [Presentation Abstract].

Also mentioned in the news release was an oral presentation by Jerry W Shay, given as part of the Major Symposium entitled: Role of Telomeres and Telomerase in Chromosomal Stability and Disease [Session Detail]. The presentation was:

Role of telomerase in normal and neoplastic stem cells [Presentation Abstract].

Another poster about the telomerase inhibitor imetelstat (GRN163L) was:

Sensitivity and resistance of non-small cell lung cancer to the telomerase inhibitor imetelstat [Presentation Abstract].

Comments: A search of the ClinicalTrials.gov database for GRN163L revealed 6 trials. Four were ongoing, but not recruiting participants. Two were still recruiting: 1) Safety and Dose Study of GRN163L Administered to Patients With Refractory or Relapsed Solid Tumor Malignancies; 2) A Study of GRN163L With Paclitaxel and Bevacizumab to Treat Patients With Locally Recurrent Or Metastatic Breast Cancer.

An analogous search for imetelstat yielded the same 6 trials. All 6 trials have been sponsored by Geron Corporation.

Sessions on CSC Therapeutics at AACR10

There were two poster sessions on Cancer Stem Cell Therapeutics at the 101st Annual Meeting of the American Association for Cancer Research (AACR). The sessions, Cancer Stem Cell Therapeutics 1 and Cancer Stem Cell Therapeutics 2, took place on the morning and afternoon of April 20, 2010 [FriendFeed entry].

Two posters presented in the 2nd session have been highlighted in a news release. See: Alchemia’s HyACT Technology Enhances the Killing of Cancer Stem Cell Populations in Breast and Colorectal Cancer, Business Wire, April 20, 2010 [FriendFeed entry]. One of these is Poster #4293: Evaluation of activated CD44 as a biological target in the eradication of breast cancer stem cells, by Vera J Evtimov and Tracey J Brown [Presentation Abstract]. The other is Poster #4278: HA-Irinotecan targeting of activated CD44 is an effective therapy for the eradication of putative colon cancer stem cells [Presentation Abstract].

CSC news links 2010-04-18

For links to recent news items, visit these [Twitter] or [FriendFeed] pages. Examples of a few news items that have received attention:

• Split ends in CML: divergent roles of Hes1 by Catriona Jamieson, Blood 2010(Apr 8); 115(14): 2726-7 [FriendFeed entry][Connotea bookmark][PubMed citation][Full text PDF]. A comment on: Hes1 immortalizes committed progenitors and plays a role in blast crisis transition in chronic myelogenous leukemia by Fumio Nakahara and 13 co-authors, Blood 2010(Apr 8); 115(14): 2872-81. [Epub 2009(Oct 27)][PubMed citation].


• Metabolism and the leukemic stem cell by Omar Abdel-Wahab and Ross L Levine, J Exp Med 2010(Apr 12); 207(4): 677-80 [Epub 2010(Apr 5)][FriendFeed entry][ResearchGATE entry][CiteULike entry][Connotea bookmark][PubMed citation][Full text].


• A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2alpha by Sascha Seidel and 13 co-authors, including Till Acker, Brain 2010(Apr); 133(Pt 4): 983-95 [FriendFeed entry][ResearchGATE entry][Connotea bookmark][PubMed citation].