Anaplastic thyroid carcinoma: three protocols combining doxorubicin, hyperfractionated radiotherapy and surgery

Patients with anaplastic thyroid carcinoma can rarely be cured, but every effort should be made to prevent death due to suffocation. Between 1984 and 1999, 55 consecutive patients with anaplastic thyroid carcinoma were prospectively treated according to a combined regimen consisting of hyperfractionated radiotherapy, doxorubicin, and when feasible surgery. Radiotherapy was carried out for 5 days a week. The daily fraction until 1988 was 1.0 Gy×2 (A) and 1989–92 1.3 Gy×2 (B) . Thereafter 1.6 Gy×2 (C) was administered. Radiotherapy was administered to a total target dose of 46 Gy; of which 30 Gy was administered preoperatively in the first two protocols (A and B), while the whole dose was given preoperatively in the third protocol (C). The therapy was otherwise identical. Twenty mg doxorubicin was administered intravenously weekly. Surgery was possible in 40 patients. No patient failed to complete the protocol due to toxicity. In only 13 cases (24%) was death attributed to local failure. Five patients (9%) ‘had a survival’ exceeding 2 years. No signs of local recurrence were seen in 33 patients (60%); 5 out of 16 patients in Protocol A, 11 out of 17 patients in Protocol B, 17 out of 22 patients in Protocol C (P=0.017). In the 40 patients undergoing additional surgery, no signs of local recurrence were seen in 5 out of 9 patients, 11 out of 14 patients and 17 out of 17 patients, respectively (P=0.005)

Transgressive phenotypes and generalist pollination in the floral evolution of Nicotiana polyploids

This is the author's proofThe file attached is the Accepted/final draft post-refereeing version of the article. 6 month embargo now lapsed

GSK3β Regulates Differentiation and Growth Arrest in Glioblastoma

Cancers are driven by a population of cells with the stem cell properties of self-renewal and unlimited growth. As a subpopulation within the tumor mass, these cells are believed to constitute a tumor cell reservoir. Pathways controlling the renewal of normal stem cells are deregulated in cancer. The polycomb group gene Bmi1, which is required for neural stem cell self-renewal and also controls anti-oxidant defense in neurons, is upregulated in several cancers, including medulloblastoma. We have found that Bmi1 is consistently and highly expressed in GBM. Downregulation of Bmi1 by shRNAs induced a differentiation phenotype and reduced expression of the stem cell markers Sox2 and Nestin. Interestingly, expression of glycogen synthase kinase 3 beta (GSK3β), which was found to be consistently expressed in primary GBM, also declined. This suggests a functional link between Bmi1 and GSK3β. Interference with GSK3β activity by siRNA, the specific inhibitor SB216763, or lithium chloride (LiCl) induced tumor cell differentiation. In addition, tumor cell apoptosis was enhanced, the formation of neurospheres was impaired, and clonogenicity reduced in a dose-dependent manner. GBM cell lines consist mainly of CD133-negative (CD133-) cells. Interestingly, ex vivo cells from primary tumor biopsies allowed the identification of a CD133- subpopulation of cells that express stem cell markers and are depleted by inactivation of GSK3β. Drugs that inhibit GSK3, including the psychiatric drug LiCl, may deplete the GBM stem cell reservoir independently of CD133 status

Vps34 PI 3-kinase inactivation enhances insulin sensitivity through reprogramming of mitochondrial metabolism

Postdoctoral fellowships were from EU Marie Curie (PIEF-GA-2009–252916) and EMBO (ALTF 753–2010) for SA and EU Marie Curie (PIIF-GA-2009–252846) for C.C. J. M.H. was a recipient of a doctoral fellowship from Eisai UK Ltd. Work in our laboratories was supported as follows: BV: MRC [G0700755], BBSRC (BB/I007806/1 and BB/ M013278/1), CRUK (C23338/A15965), the Ludwig Institute for Cancer Research and the National Institute for Health Research (NIHR) UCL Hospitals Biomedical Research Centre; J.M.B.: NIH AG039632, GM112524. and the Albert Einstein Diabetes Research and Training Center Animal Physiology Core DK020541; E.G.: Barry Reed Cancer Research fund; G.S.: BBSRC (BB/L020874/1) and B.H.F.; S.S.: Anatomical Society of Great Britain (GT) and a Wellcome Trust Career Development Fellowship 074246/Z04/Z (S.S.); R.K.S.: Wellcome Trust (WT098498) and M.R.C. (MRC_MC_UU_12012/5); S.A. T. and L.C.: the Francis Crick Institute, which receives its core funding from CRUK (FC001187), MRC (FC001187), and the Wellcome Trust (FC001187); Y.-L.C.: the CRUK Cancer Imaging Centre in association with the MRC and DoH (England) grant C1060/ A10334, C1060/A16464, NHS funding to the NIHR BRC; B.P.: Inserm and the Fondation pour la recherche médicale

Epithelial cancers in the post-genomic era: should we reconsider our lifestyle?

The age-related epithelial cancers of the breast, colorectum and prostate are the most prevalent and are increasing in our aging populations. Epithelial cells turnover rapidly and mutations naturally accumulate throughout life. Most epithelial cancers arise from this normal mutation rate. All elderly individuals will harbour many cells with the requisite mutations and most will develop occult neoplastic lesions. Although essential for initiation, these mutations are not sufficient for the progression of cancer to a life-threatening disease. This progression appears to be dependent on context: the tissue ecosystem within individuals and lifestyle exposures across populations of individuals. Together, this implies that the seeds may be plentiful but they only germinate in the right soil. The incidence of these cancers is much lower in Eastern countries but is increasing with Westernisation and increases more acutely in migrants to the West. A Western lifestyle is strongly associated with perturbed metabolism, as evidenced by the epidemics of obesity and diabetes: this may also provide the setting enabling the progression of epithelial cancers. Epidemiology has indicated that metabolic biomarkers are prospectively associated with cancer incidence and prognosis. Furthermore, within cancer research, there has been a rediscovery that a switch in cell metabolism is critical for cancer progression but this is set within the metabolic status of the host. The seed may only germinate if the soil is fertile. This perspective brings together the different avenues of investigation implicating the role that metabolism may play within the context of post-genomic concepts of cancer