Evaluation of clinician-operated sonography and fine-needle aspiration in the assessment of salivary gland tumours.

OBJECTIVES: To evaluate the combination of ultrasound (US) + fine-needle aspiration (FNA) in the assessment of salivary gland tumours in the hands of the otolaryngologist. DESIGN: A retrospective review of case notes was performed. SETTING: Two university teaching hospitals in Switzerland. PARTICIPANTS: One hundred and three patients with a total of 106 focal masses of the salivary glands were included. Clinician-operated US + FNA were the first line of investigation for these lesions. All patients underwent surgical excision of the lesion, which allowed for confirmation of diagnosis by histopathology in 104 lesions and by laboratory testing in two lesions. MAIN OUTCOME MEASURES: Primary--diagnostic accuracy in identifying true salivary gland neoplasms and detecting malignancy. Secondary--predicting an approximate and specific diagnosis in these tumours. RESULTS: The combination of US + FNA achieved a diagnostic accuracy of 99% in identifying and differentiating true salivary gland neoplasms from tumour-like lesions. In detecting malignancy, this combination permitted an accuracy of 98%. An approximate diagnosis was possible in 89%, and a specific diagnosis in 69% of our patients. CONCLUSIONS: Due to economic factors and a high diagnostic accuracy, the combination of US + FNA represents the investigation method of choice for most salivary gland tumours. We suggest that the otolaryngologist be employed in carrying out these procedures, as is already the rule in other medical specialties, while computed tomography and magnetic resonance imaging should be reserved to those few lesions, which cannot be delineated completely by sonography.

ECIL-3 classical diagnostic procedures for the diagnosis of invasive fungal diseases in patients with leukaemia.

Invasive fungal diseases (IFDs) continue to cause considerable morbidity and mortality in patients with haematological malignancy. Diagnosis of IFD is difficult, with the sensitivity of the gold standard tests (culture and histopathology) often reported to be low, which may at least in part be due to sub-optimal sampling or subsequent handling in the routine microbiological laboratory. Therefore, a working group of the European Conference in Infections in Leukaemia was convened in 2009 with the task of reviewing the classical diagnostic procedures and providing recommendations for their optimal use. The recommendations were presented and approved at the ECIL-3 conference in September 2009. Although new serological and molecular tests are examined in separate papers, this review focuses on sample types, microscopy and culture procedures, antifungal susceptibility testing and imaging. The performance and limitations of these procedures are discussed and recommendations are provided on when and how to use them and how to interpret the results.

Advances in the pharmacological treatment of gastro-oesophageal cancer.

Despite a sharp decline in the incidence of gastric cancer during the second half of the 20th century, this malignancy remains the second leading cause of cancer mortality in the world. The incidence and mortality rate of gastric cancer increase with age; at present, the median ages at diagnosis are 67 years for men and 72 years for women in the US. This article reviews and discusses current medical treatment options for both the general population and elderly gastric cancer patients. Management of localized gastric cancer has changed significantly over recent years. Adjuvant chemoradiation is not generally recommended outside the US. After decades of trials of adjuvant chemotherapy with inconclusive results, a significant survival benefit for perioperative combination chemotherapy - as compared with surgery alone - in patients with resectable or locally advanced gastro-oesophageal cancer was recently demonstrated in the UK MAGIC trial. A further large, randomized trial from Japan demonstrated a significant survival benefit for adjuvant chemotherapy with S-1 after D2 resection for gastric cancer. However, both trials are applicable only to the population in which the trials were conducted. Specific data on elderly patients are missing. For patients with metastatic disease, oral fluoropyrimidines, such as capecitabine, have been developed. In Asian patients, treatment with the oral fluoropyrimidine S-1 is safe and effective. Docetaxel, oxaliplatin and irinotecan have demonstrated activity against gastric cancer in appropriately designed, randomized, phase III trials and have increased the available treatment options significantly. In addition, according to preliminary data, trastuzumab in combination with chemotherapy has significantly improved activity when compared to chemotherapy alone in patients with human epidermal receptor (HER)-2-positive gastric and gastro-oesophageal cancers. Thus, therapeutic decisions in patients with advanced gastric cancer may be adapted to the molecular subtype and co-morbidities of the individual patient. Data from retrospective analyses suggest that oxaliplatin seems to be better tolerated than cisplatin in elderly patients.

Les esthésioneuroblastomes Esthesioneuroblastoma.

Esthesioneuroblastoma is an uncommon malignancy originating from olfactive epithelium. Men are more frequently affected than women. Nasal symptoms are the most common revealing signs. Immunohistochemistry helps diagnosis. There is no randomized trial evaluating treatment due to the low incidence of this tumor. Radiotherapy and surgery are the standard of care. Radiotherapy is benefic even in early stage disease. Chemotherapy is indicated in case of locally advanced or metastatic disease.

No complementation between TP53 or RB-1 and v-src in astrocytomas of GFAP-v-src transgenic mice.

Human low-grade astrocytomas frequently recur and progress to states of higher malignancy. During tumor progression TP53 alterations are among the first genetic changes, while derangement of the p16/p14ARF/RB-1 system occurs later. To probe the pathogenetic significance of TP53 and RB-1 alterations, we introduced a v-src transgene driven by glial fibrillary acidic protein (GFAP) regulatory elements (which causes preneoplastic astrocytic lesions and stochastically astrocytomas of varying degrees of malignancy) into TP53+/- or RB-1+/- mice. Hemizygosity for TP53 or RB-1 did not increase the incidence or shorten the latency of astrocytic tumors in GFAP-v-src mice over a period of up to 76 weeks. Single strand conformation analysis of exons 5 to 8 of non-ablated TP53 alleles revealed altered migration patterns in only 3/16 tumors analyzed. Wild-type RB-1 alleles were retained in all RB-1+/-GFAP-v-src mice-derived astrocytic tumors analyzed, and pRb immunostaining revealed protein expression in all tumors. Conversely, the GFAP-v-src transgene did not influence the development of extraneural tumors related to TP53 or RB-1 hemizygosity. Therefore, the present study indicates that neither loss of RB-1 nor of TP53 confer a growth advantage in vivo to preneoplastic astrocytes expressing v-src, and suggests that RB-1 and TP53 belong to one single complementation group along with v-src in this transgenic model of astrocytoma development. The stochastic development of astrocytic tumors in GFAP-v-src, TP53+/- GFAP-v-src, and RB-1+/- GFAP-v-src transgenic mice indicates that additional hitherto unknown genetic lesions of astrocytes contribute to tumorigenesis, whose elucidation may prove important for our understanding of astrocytoma initiation and progression.

Sexualité des adolescents: epidémiologie, approche clinique et stratégies préventives [Adolescent sexuality: epidemiology, clinical approach and preventive measures].

The interest in sexuality of adolescents in medical practice is often mainly focussed on the onset of sexual intercourse and on the emergence of contraceptive needs, though the beginning of adolescence takes place much earlier with the first signs of puberty followed by the menarche. At the issue of this profound metamorphosis the adolescent needs to adapt herself to a modified, sexual body. Adolescence is also a time of identity development and of changes in relationships, which are influenced by gender role in family and perception related to gender during childhood. This article shows epidemiological data to consider and the main issues of gynaecologic consultation with the adolescent. The different stages of development depend on biological and environmental factors which either favour resilience or weaken the individual due to a lack of affection or to abusive relationships. Medical consultation for a gynaecological problem, questions on puberty and development or on contraception give medical professionals and especially gynaecologists a chance to address sexual issues naturally, to anticipate questions as well as contraceptive needs. The consultation with the adolescent includes also the screening for behaviour related to a lack of information or a personal or relational difficulty.

Tenascin-C is a novel RBPJkappa-induced target gene for Notch signaling in gliomas.

Tenascin-C (TNC) expression is known to correlate with malignancy in glioblastoma (GBM), a highly invasive and aggressive brain tumor that shows limited response to conventional therapies. In these malignant gliomas as well as in GBM cell lines, we found Notch2 protein to be strongly expressed. In a GBM tumor tissue microarray, RBPJk protein, a Notch2 cofactor for transcription, was found to be significantly coexpressed with TNC. We show that the TNC gene is transactivated by Notch2 in an RBPJk-dependent manner mediated by an RBPJk binding element in the TNC promoter. The transactivation is abrogated by a Notch2 mutation, which we detected in the glioma cell line Hs683 that does not express TNC. This L1711M mutation resides in the RAM domain, the site of interaction between Notch2 and RBPJk. In addition, transfection of constructs encoding activated Notch2 or Notch1 increased endogenous TNC expression identifying TNC as a novel Notch target gene. Overexpression of a dominant negative form of the transcriptional coactivator MAML1 or knocking down RBPJk in LN319 cells led to a dramatic decrease in TNC protein levels accompanied by a significant reduction of cell migration. Because addition of purified TNC stimulated glioma cell migration, this represents a mechanism for the invasive properties of glioma cells controlled by Notch signaling and defines a novel oncogenic pathway in gliomagenesis that may be targeted for therapeutic intervention in GBM patients.

Association of early repolarization with risk of cardiac mortality in the general population

Early repolarization, which is characterized by an elevation of the J-point on 12-lead electrocardiography, is a common finding that has been considered as benign for decades. However, in the last years, it has been related with vulnerability to idiopathic ventricular fibrillation and with cardiac mortality in the general population. Recently, 4 potential ECG predictors that could differentiate the benign from the malignant form of early repolarization have been suggested. Any previous study about early repolarization has been done in Spain. Aim. To ascertain whether the presence of early repolarization pattern in a resting electrocardiogram is associated with a major risk of cardiac death in a Spanish general population and to determine whether the presence of potential predictors of malignancy in a resting electrocardiogram increases the risk of cardiac mortality in patients with early repolarization pattern. Methods. We will analyse the presence of early repolarization and the occurrence of cardiac mortality in a retrospective cohort study of 4,279 participants aged 25 to 74 years in the province of Girona. This cohort has been followed during a mean of 9.8 years. Early repolarization will be stratified according to the degree of J-point elevation (≥0.1 mV or ≥0.2 mV), the morphology of the J-wave (slurring, notching or any of these two), the ST-segment pattern (ascending or descending) and the localization (inferior leads, lateral leads, or both). Association of early repolarization with cardiac death will be assessed by adjusted Cox-proportional hazards models

Basal cell carcinoma - molecular biology and potential new therapies.

Basal cell carcinoma (BCC) of the skin, the most common malignancy in individuals of mixed European descent, is increasing in incidence due to an aging population and sun exposure habits. The realization that aberrant activation of Hedgehog signaling is a pathognomonic feature of BCC development has opened the way for exciting progress toward understanding BCC biology and translation of this knowledge to the clinic. Genetic mouse models closely mimicking human BCCs have provided answers about the tumor cell of origin, and inhibition of Hedgehog signaling is emerging as a potentially useful targeted therapy for patients with advanced or multiple BCCs that have hitherto lacked effective treatment.

Immunotherapies for uro-genital cancers

Les cancers du col utérin et de la vessie prennent tous deux leur origine dans les sites muqueux et peuvent évoluer lentement de lésions superficielles (lésions squameuses intra-épithéliales de bas à haut grade (HSIL) et carcinomes in situ du col utérin (CIS); ou tumeurs non musculo-invasives de la vessie (NMIBC)) à des cancers invasifs plus avancés. L'éthiologie de ces deux cancers est néanmoins très différente. Le cancer du col utérin est, à l'échelle mondiale, le deuxième cancer le plus mortel chez la femme. Ce cancer résulte de l'infection des cellules basales de l'épithélium stratifié du col utérin par le papillomavirus humain à haut risque (HPV). Les vaccins prophylactiques récemment développés contre le HPV (Gardasil® et Cervarix®) sont des moyens de prévention efficaces lorsqu'ils sont administrés chez les jeunes filles qui ne sont pas encore sexuellement actives; cependant ces vaccins ne permettent pas la régression des lésions déjà existantes. Malgré un développement actif, les vaccins thérapeutiques ciblant les oncogènes viraux E6/E7 n'ont montré qu'une faible efficacité clinique jusqu'à présent. Nous avons récemment démontré qu'une immunisation sous-cutanée (s.c.) était capable de faire régresser les petites tumeurs génitales chez 90% des souris, mais chez seulement 20% des souris présentant de plus grandes tumeurs. Dans cette étude, nous avons développé une nouvelle stratégie où la vaccination est associée à une application locale (intra-vaginale (IVAG)) d'agonistes de TLR. Celle-ci induit une augmentation des cellules T CD8 totales ainsi que T CD8 spécifiques au vaccin, mais pas des cellules T CD4. L'attraction sélective des cellules T CD8 est permise par leur expression des récepteurs de chemokines CCR5 et CXCR3 ainsi que par les ligants E-selectin. La vaccination, suivie de l'application IVAG de CpG, a conduit, chez 75% des souris, à la régression de grandes tumeurs établies. Le cancer de la vessie est le deuxième cancer urologique le plus fréquente. La plupart des tumeurs sont diagnostiquées comme NMIBC et sont restreintes à la muqueuse de la vessie, avec une forte propension à la récurrence et/ou progression après une résection locale. Afin de développer des vaccins contre les antigènes associés à la tumeur (TAA), il est nécessaire de trouver un moyen d'induire une réponse immunitaire CD8 spécifique dans la vessie. Pour ce faire, nous avons comparé différentes voies d'immunisation, en utilisant un vaccin composé d'adjuvants et de l'oncogène de HPV (E7) comme modèle. Les vaccinations s.c. et IVAG ont toutes deux induit un nombre similaire de cellules T CD8 spécifiques du vaccin dans la vessie, alors que l'immunisation intra-nasale fut inefficace. Les voies s.c. et IVAG ont induit des cellules T CD8 spécifiques du vaccin exprimant principalement aL-, a4- et le ligand d'E-selectin, suggérant que ces intégrines/sélectines sont responsables de la relocalisation des cellules T dans la vessie. Une unique immunisation avec E7 a permis une protection tumorale complète lors d'une étude prophylactique, indépendemment de la voie d'immunisation. Dans une étude thérapeutique, seules les vaccinations s.c. et IVAG ont efficacement conduit, chez environ 50% des souris, à la régression de tumeurs de la vessie établies, alors que l'immunisation intra-nasale n'a eu aucun effet. La régression de la tumeur est correlée avec l'infiltration dans la tumeur des cellules T CD8 spécifiques au vaccin et la diminution des cellules T régulatrices (Tregs). Afin d'augmenter l'efficacité de l'immunisation avec le TAA, nous avons testé une vaccination suivie de l'instillation d'agonistes de TLR3 et TLR9, ou d'un vaccin Salmonella Typhi (Ty21a). Cette stratégie a entraîné une augmentation des cellules T CD8 effectrices spécifiques du vaccin dans la vessie, bien qu'à différentes échelles. Ty21a étant l'immunostimulant le plus efficace, il mérite d'être étudié de manière plus approfondie dans le contexte du NMIBC. - Both cervical and bladder cancer originates in mucosal sites and can slowly progress from superficial lesions (low to high-grade squamous intra-epithelial lesions (HSIL) and carcinoma in situ (CIS) in the cervix; or non-muscle invasive tumors in the bladder (NMIBC)), to more advanced invasive cancers. The etiology of these two cancers is however very different. Cervical cancer is the second most common cause of cancer death in women worldwide. This cancer results from the infection of the basal cells of the stratified epithelium of the cervix by high-risk human papillomavirus (HPV). The recent availability of prophylactic vaccines (Gardasil® and Cervarix®) against HPV is an effective strategy to prevent this cancer when administered to young girls before sexual activity; however, these vaccines do not induce regression of established lesions. Despite active development, therapeutic vaccines targeting viral oncogenes E6/E7 had limited clinical efficacy to date. We recently reported that subcutaneous (s.c.) immunization was able to regress small genital tumors in 90% of the mice, but only 20% of mice had regression of larger tumors. Here, we developed a new strategy where vaccination is combined with the local (intravaginal (IVAG)) application of TLR agonists. This new strategy induced an increase of both total and vaccine-specific CD8 T cells in cervix-vagina, but not CD4 T cells. The selective attraction of CD8 T cells is mediated by the expression of CCR5 and CXCR3 chemokine receptors and E-selectin ligands in these cells. Vaccination followed by IVAG application of CpG resulted in tumor regression of large established tumors in 75% of the mice. Bladder cancer is the second most common urological malignancy. Most tumors are diagnosed as NMIBC, and are restricted to the mucosal bladder with a high propensity to recur and/or progress after local resection. Aiming to develop vaccines against tumor associated antigens (TAA) it is necessary to investigate how to target vaccine-specific T-cell immune responses to the bladder. Here we thus compared using an adjuvanted HPV oncogene (E7) vaccine, as a model, different routes of immunization. Both s.c. and IVAG vaccination induced similar number of vaccine-specific CD8 T-cells in the bladder, whereas intranasal (i.n.) immunization was ineffective. S.c. and IVAG routes induced predominantly aL-, a4- and E-selectin ligand-expressing vaccine-specific CD8 T-cells suggesting that these integrin/selectin are responsible for T-cell homing to the bladder. A single E7 immunization conferred full tumor protection in a prophylactic setting, irrespective of the immunization route. In a therapeutic setting, only ivag and s.c. vaccination efficiently regressed established bladder-tumors in ca. 50 % of mice, whereas i.n. immunization had no effect. Tumor regression correlated with vaccine- specific CD8 T cell tumor-infiltration and decrease of regulatory T cells (Tregs). To increase efficacy of TAA immunization, we tested vaccination followed by the local instillation of TLR3 or TLR9 agonist or of a Salmonella Typhi vaccine (Ty21a). This strategy resulted in an increase of vaccine-specific effector CD8 T cells in the bladder, although at different magnitudes. Ty21a being the most efficient, it deserves further investigation in the context of NMIBC. We further tested another strategy to improve therapies of NMIBC. In the murine MB49 bladder tumor model, we replaced the intravesical (ives) BCG therapy by another vaccine strain the Salmonella Ty21a. Ives Ty21a induced bladder tumor regression at least as efficiently as BCG. Ty21a bacteria did not infect nor survive neither in healthy nor in tumor-bearing bladders, suggesting its safety. Moreover, Ty21a induced a transient inflammatory response in healthy bladders, mainly through infiltration of neutrophils and macrophages that rapidly returned to basal levels, confirming its potential safety. The tumor regression was associated to a robust infiltration of immune cells, and secretion of cytokines in urines. Infection of murine tumor cell lines by Ty21a resulted in cell apoptosis. The infection of both murine and human urothelial cell lines induced secretion of in vitro inflammatory cytokines. Ty21a may be an attractive alternative for the ives treatment of NMIBC after transurethral resection and thus deserves more investigation.

Growth promoting signaling by tenascin-C [corrected].

Tenascin-C is an adhesion-modulating extracellular matrix molecule that is highly expressed in tumor stroma and stimulates tumor cell proliferation. Adhesion of T98G glioblastoma cells to a fibronectin substratum is inhibited by tenascin-C. To address the mechanism of action, we performed a RNA expression analysis of T89G cells grown in the presence or absence of tenascin-C and found that tenascin-C down-regulates tropomyosin-1. Upon overexpression of tropomyosin-1, cell spreading on a fibronectin/tenascin-C substratum was restored, indicating that tenascin-C destabilizes actin stress fibers through down-regulation of tropomyosin-1. Tenascin-C also increased the expression of the endothelin receptor type A and stimulated the corresponding mitogen-activated protein kinase signaling pathway, which triggers extracellular signal-regulated kinase 1/2 phosphorylation and c-Fos expression. Tenascin-C additionally caused down-regulation of the Wnt inhibitor Dickkopf 1. In consequence, Wnt signaling was enhanced through stabilization of beta-catenin and stimulated the expression of the beta-catenin target Id2. Finally, our in vivo data derived from astrocytoma tissue arrays link increased tenascin-C and Id2 expression with high malignancy. Because increased endothelin and Wnt signaling, as well as reduced tropomyosin-1 expression, are closely linked to transformation and tumorigenesis, we suggest that tenascin-C specifically modulates these signaling pathways to enhance proliferation of glioma cells.

Epigenetic alteration of the Wnt inhibitory factor-1 promoter occurs early in the carcinogenesis of Barrett's esophagus.

The role of Wnt antagonists in the carcinogenesis of esophageal adenocarcinoma (EAC) remains unclear. We hypothesized that downregulation of the Wnt inhibitory factor-1 (WIF-1) might be involved in the neoplastic progression of Barrett's esophagus (BE). We analyzed the DNA methylation status of the WIF-1 promoter in normal, preneoplastic, and neoplastic samples from BE patients and in EAC cell lines. We investigated the role of WIF-1 on EAC cell growth and the chemosensitization of the cells to cisplatin. We found that silencing of WIF-1 correlated with promoter hypermethylation. EAC tissue samples showed higher levels of WIF-1 methylation compared to the matched normal epithelium. In addition, we found that WIF-1 hypermethylation was more frequent in BE samples from patients with EAC than in BE samples from patients who had not progressed to EAC. Restoration of WIF-1 in cell lines where WIF-1 was methylation-silenced resulted in growth suppression. Restoration of WIF-1 could sensitize the EAC cells to the chemotherapy drug cisplatin. Our results suggest that silencing of WIF-1 through promoter hypermethylation is an early and common event in the carcinogenesis of BE. Restoring functional WIF-1 might be used as a new targeted therapy for the treatment of this malignancy.

Operative Treatment of Ovarian Cancer and Borderline Tumors in Different Hospital Categories in Finland

Surgery is the cornerstone of ovarian cancer treatment and maximal cytoreduction is important. In the early 1980’s primary surgical treatment of ovarian cancer was performed in over 80 hospitals in Finland. The significance of the operative volume of the hospital, of the training of the surgeons and of centralization of surgical treatment has been widely discussed. The aim of the present study was to evaluate the outcome of surgical treatment of ovarian cancer in different hospital categories retrospectively and prospectively, and to analyze if any differences are reflected in survival. The retrospective study included 3851 ovarian cancer patients operated between 1983 and 1994 in Finland. The data was analyzed according to hospital category (university, central, and other) and by quartiles of the hospital operative volume. The results showed that patients operated in the highest operative volume hospitals had the best relative survival. When stratifying the analysis by the period of diagnosis (1983-1988 and 1989-1994), the university hospitals improved their performance the most. The prospective part of the thesis was initiated in 1999 and included 307 patients with invasive ovarian cancer and 65 patients with an ovarian borderline tumor. The baseline and 5-year surveys used a questionnaire that was filled in by the operating surgeons. For analysis of the 5-year followup data, the hospitals were divided into three categories (<10, 10-20, or >20 patients operated in 1999). The effect of the surgical volume was analyzed also as a continuous variable (1-47 operations per year). In university hospitals, pelvic lymphadenectomy was performed in 88 %, and para-aortic lymphadenectomy in 73 %, of the patients with stage I disease. The corresponding figures ranged from 11 % to 21 % in the other hospitals. For stage III ovarian cancer patients operated by gynecological oncologists, the estimated odds ratio for no macroscopic residual tumor was 3.0 times higher (95 % CI 1.2-7.5) than for those operated by general gynecologists. In the university and other hospitals 82% of the patients received platinum-based chemotherapy. Platinum + taxane combination was given to 63 % of the patients in the university and in 49 % in the other hospitals (p = 0.0763). Only a minority of the patients with tumors of borderline malignancy were staged according to recommendations, most often multiple peritoneal biopsies and omentectomy were neglected. FIGO stage, patient age, and residual tumor were independent prognostic factors of cancer-specific 5-year survival. A higher hospital operative volume was also a significant prognostic factor for better cancer-specific survival (p = 0.036) and disease-free survival (p = 0.048). In conclusion, ovarian cancer patients operated in high-volume university hospitals were more often optimally debulked and had a significantly better cancer-specific survival than patients operated in other hospitals. These results favor centralization of primary surgical treatment of ovarian cancer.

Potential role for peroxisome proliferator activated receptor (PPAR) in preventing colon cancer.

BACKGROUND: Peroxisome proliferator activated receptors (PPARs) are nuclear hormone receptors involved in genetic control of many cellular processes. PPAR and PPAR have been implicated in colonic malignancy. Here we provide three lines of evidence suggesting an inhibitory role for PPAR in colorectal cancer development. METHODS: Levels of PPAR mRNA and protein in human colorectal cancers were compared with matched non-malignant mucosa using RNAse protection and western blotting. APC(Min)/+ mice were randomised to receive the PPAR activator methylclofenapate 25 mg/kg or vehicle for up to 16 weeks, and small and large intestinal polyps were quantified by image analysis. The effect of methylclofenapate on serum stimulated mitogenesis (thymidine incorporation), linear cell growth, and annexin V and propidium iodide staining were assessed in human colonic epithelial cells. RESULTS: PPAR (mRNA and protein) expression levels were significantly depressed in colorectal cancer compared with matched non-malignant tissue. Methylclofenapate reduced polyp area in the small intestine from 18.7 mm(2) (median (interquartile range 11.1, 26.8)) to 9.90 (4.88, 13.21) mm(2) (p=0.003) and in the colon from 9.15 (6.31, 10.5) mm(2) to 3.71 (2.71, 5.99) mm(2) (p=0.009). Methylclofenapate significantly reduced thymidine incorporation and linear cell growth with no effect on annexin V or propidium iodide staining. CONCLUSIONS: PPAR may inhibit colorectal tumour progression, possibly via inhibition of proliferation, and may be an important therapeutic target.

The Lin28/let-7 axis regulates glucose metabolism.

The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promote an insulin-sensitized state that resists high-fat-diet induced diabetes. Conversely, muscle-specific loss of Lin28a or overexpression of let-7 results in insulin resistance and impaired glucose tolerance. These phenomena occur, in part, through the let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. In addition, the mTOR inhibitor, rapamycin, abrogates Lin28a-mediated insulin sensitivity and enhanced glucose uptake. Moreover, let-7 targets are enriched for genes containing SNPs associated with type 2 diabetes and control of fasting glucose in human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism.