Accessory gland as a site for prothoracicotropic hormone controlled ecdysone synthesis in adult male insects.

Accessory gland as a site for prothoracicotropic hormone controlled ecdysone synthesis in adult male insects.

PLoS One. 2013;8(2):e55131

Authors: Hentze JL, Moeller ME, J�rgensen AF, Bengtsson MS, Bordoy AM, Warren JT, Gilbert LI, Andersen O, Rewitz KF

Abstract
Insect steroid hormones (ecdysteroids) are important for female reproduction in many insect species and are required for the initiation and coordination of vital developmental processes. Ecdysteroids are also important for adult male physiology and behavior, but their exact function and site of synthesis remains unclear, although previous studies suggest that the reproductive system may be their source. We have examined expression profiles of the ecdysteroidogenic Halloween genes, during development and in adults of the flour beetle Tribolium castaneum. Genes required for the biosynthesis of ecdysone (E), the precursor of the molting hormone 20-hydroxyecdysone (20E), are expressed in the tubular accessory glands (TAGs) of adult males. In contrast, expression of the gene encoding the enzyme mediating 20E synthesis was detected in the ovaries of females. Further, Spookiest (Spot), an enzyme presumably required for endowing tissues with competence to produce ecdysteroids, is male specific and predominantly expressed in the TAGs. We also show that prothoracicotropic hormone (PTTH), a regulator of E synthesis during larval development, regulates ecdysteroid levels in the adult stage in Drosophila melanogaster and the gene for its receptor Torso seems to be expressed specifically in the accessory glands of males. The composite results suggest strongly that the accessory glands of adult male insects are the main source of E, but not 20E. The finding of a possible male-specific source of E raises the possibility that E and 20E have sex-specific roles analogous to the vertebrate sex steroids, where males produce primarily testosterone, the precursor of estradiol. Furthermore this study provides the first evidence that PTTH regulates ecdysteroid synthesis in the adult stage and could explain the original finding that some adult insects are a rich source of PTTH.

PMID: 23383307 [PubMed - in process]

chir-258 dovitinib dna-pk

Tumour burden is an independent prognostic factor in metastatic renal cell carcinoma.

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Tumour burden is an independent prognostic factor in metastatic renal cell carcinoma.

BJU Int. 2012 Dec;110(11):1747-53

Authors: Iacovelli R, Lanoy E, Albiges L, Escudier B

Abstract
UNLABELLED: Study Type--Prognosis (cohort series) Level of Evidence 2b. What's known on the subject? and What does the study add? In the literature, few studies have evaluated the role of tumour burden (TB) in metastatic real cell carcinoma (mRCC), even though it has been considered as important in localized tumours. In metastatic patients the role of TB is uncertain because it was analyzed in chemotherapy treated patients or using a partial evaluation of TB. This study, first reports the independent prognostic and predictive role of TB in mRCC patients treated with targeted agents in prospective clinical trials. TB is able to predict prognosis independently to localization of metastases and prognostic class defined by MSKCC criteria, moreover it is strictly related to patient's performance status.
OBJECTIVE: ? To investigate the possible prognostic role of baseline tumour burden (TB) in terms of progression-free survival (PFS) and overall survival (OS), in patients with metastatic renal cell carcinoma (mRCC).
PATIENTS AND METHODS: ? A homogenous group of patients with mRCC enrolled in second-line trials post-cytokine treatment were selected for the present analysis. ? The Response Evaluation Criteria in Solid Tumors (the sum of the longest unidimensional diameter of each target lesion) were used to assess TB. ? The PFS and OS rates were estimated using the Kaplan-Meier method and compared across the groups using the log-rank test. ? The association between TB and PFS or OS was evaluated using a Cox proportional hazards model. Multivariable analyses were adjusted for other prognostic variables: the Memorial Sloan Kettering Cancer Centre (MSKCC) risk class and treatment.
RESULTS: ? A total of 124 patients were included in the final analysis. Of these, 66% received sorafenib or sunitinib and 34% received placebo. The median follow-up was 80.1 month. ? TB was directly related to PFS and OS and these associations remained significant after adjusting for modified MSKCC risk class and treatment,. ? Each 1-cm increase in TB increased the risk of progression by 4.5% (hazard ratio [HR]: 1.05; 95% confidence interval [CI] 1.02-1.07; P < 0.001) and the risk of death by 5% (HR: 1.05; 95% CI 1.03-1.08; P < 0.001).
CONCLUSIONS: ? TB is easy to calculate from standard computed tomography and significantly relates to OS in patients with mRCC. ? We report for the first time the independent prognostic role of baseline TB in multivariate analysis. ?? We believe that this information could be translated into clinical practice.

PMID: 23106948 [PubMed - indexed for MEDLINE]

chir-258 dovitinib dna-pk

Protein kinase A antagonist inhibits ?-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in Apc(Min/+) mice.

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Protein kinase A antagonist inhibits ?-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in Apc(Min/+) mice.

Mol Cancer. 2011;10:149

Authors: Brudvik KW, Paulsen JE, Aandahl EM, Roald B, Task�n K

Abstract
BACKGROUND: The adenomatous polyposis coli (APC) protein is part of the destruction complex controlling proteosomal degradation of ?-catenin and limiting its nuclear translocation, which is thought to play a gate-keeping role in colorectal cancer. The destruction complex is inhibited by Wnt-Frz and prostaglandin E(2) (PGE(2)) - PI-3 kinase pathways. Recent reports show that PGE(2)-induced phosphorylation of ?-catenin by protein kinase A (PKA) increases nuclear translocation indicating two mechanisms of action of PGE(2) on ?-catenin homeostasis.
FINDINGS: Treatment of Apc(Min/+) mice that spontaneously develop intestinal adenomas with a PKA antagonist (Rp-8-Br-cAMPS) selectively targeting only the latter pathway reduced tumor load, but not the number of adenomas. Immunohistochemical characterization of intestines from treated and control animals revealed that expression of ?-catenin, ?-catenin nuclear translocation and expression of the ?-catenin target genes c-Myc and COX-2 were significantly down-regulated upon Rp-8-Br-cAMPS treatment. Parallel experiments in a human colon cancer cell line (HCT116) revealed that Rp-8-Br-cAMPS blocked PGE(2)-induced ?-catenin phosphorylation and c-Myc upregulation.
CONCLUSION: Based on our findings we suggest that PGE(2) act through PKA to promote ?-catenin nuclear translocation and tumor development in Apc(Min/+) mice in vivo, indicating that the direct regulatory effect of PKA on ?-catenin nuclear translocation is operative in intestinal cancer.

PMID: 22168384 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

Accessory gland as a site for prothoracicotropic hormone controlled ecdysone synthesis in adult male insects.

Accessory gland as a site for prothoracicotropic hormone controlled ecdysone synthesis in adult male insects.

PLoS One. 2013;8(2):e55131

Authors: Hentze JL, Moeller ME, J�rgensen AF, Bengtsson MS, Bordoy AM, Warren JT, Gilbert LI, Andersen O, Rewitz KF

Abstract
Insect steroid hormones (ecdysteroids) are important for female reproduction in many insect species and are required for the initiation and coordination of vital developmental processes. Ecdysteroids are also important for adult male physiology and behavior, but their exact function and site of synthesis remains unclear, although previous studies suggest that the reproductive system may be their source. We have examined expression profiles of the ecdysteroidogenic Halloween genes, during development and in adults of the flour beetle Tribolium castaneum. Genes required for the biosynthesis of ecdysone (E), the precursor of the molting hormone 20-hydroxyecdysone (20E), are expressed in the tubular accessory glands (TAGs) of adult males. In contrast, expression of the gene encoding the enzyme mediating 20E synthesis was detected in the ovaries of females. Further, Spookiest (Spot), an enzyme presumably required for endowing tissues with competence to produce ecdysteroids, is male specific and predominantly expressed in the TAGs. We also show that prothoracicotropic hormone (PTTH), a regulator of E synthesis during larval development, regulates ecdysteroid levels in the adult stage in Drosophila melanogaster and the gene for its receptor Torso seems to be expressed specifically in the accessory glands of males. The composite results suggest strongly that the accessory glands of adult male insects are the main source of E, but not 20E. The finding of a possible male-specific source of E raises the possibility that E and 20E have sex-specific roles analogous to the vertebrate sex steroids, where males produce primarily testosterone, the precursor of estradiol. Furthermore this study provides the first evidence that PTTH regulates ecdysteroid synthesis in the adult stage and could explain the original finding that some adult insects are a rich source of PTTH.

PMID: 23383307 [PubMed - in process]

chir-258 dovitinib dna-pk

Cyclin D1 overexpression perturbs DNA replication and induces replication-associated DNA double-strand breaks in acquired radioresistant cells.

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Cyclin D1 overexpression perturbs DNA replication and induces replication-associated DNA double-strand breaks in acquired radioresistant cells.

Cell Cycle. 2013 Feb 6;12(5)

Authors: Shimura T, Ochiai Y, Noma N, Oikawa T, Sano Y, Fukumoto M

Abstract
Fractionated radiotherapy (RT) is widely used in cancer treatment, because it preserves normal tissues. However, repopulation of radioresistant tumors during fractionated RT limits the efficacy of RT. We recently demonstrated that a moderate level of long-term fractionated radiation confers acquired radioresistance to tumor cells, which is caused by DNA-PK/AKT/GSK3?-mediated cyclin D1 overexpression. The resulting cyclin D1 overexpression leads to forced progression of the cell cycle to S-phase, concomitant with induction of DNA double-strand breaks (DSBs). In this study, we investigated the molecular mechanisms underlying cyclin D1 overexpression-induced DSBs during DNA replication in acquired radioresistant cells. DNA fiber data demonstrated that replication forks progressed slowly in acquired radioresistant cells compared with corresponding parental cells in HepG2 and HeLa cell lines. Slowly progressing replication forks were also observed in HepG2 and HeLa cells that overexpressed a nondegradable cyclin D1 mutant. We also found that knockdown of Mus81endonuclease, which is responsible for resolving aberrant replication forks, suppressed DSB formation in acquired radioresistant cells. Consequently, Mus81 created DSBs to remove aberrant replication forks in response to replication perturbation triggered by cyclin D1 overexpression. After treating cells with a specific inhibitor for DNA-PK or ATM, apoptosis rates increased in acquired radioresistant cells but not in parental cells by inhibiting the DNA damage response to cyclin D1-mediated DSBs. This suggested that these inhibitors might eradicate acquired radioresistant cells and improve fractionated RT outcomes.

PMID: 23388457 [PubMed - as supplied by publisher]

zm-447439 rad001 ecdysone

Tumour burden is an independent prognostic factor in metastatic renal cell carcinoma.

Related Articles

Tumour burden is an independent prognostic factor in metastatic renal cell carcinoma.

BJU Int. 2012 Dec;110(11):1747-53

Authors: Iacovelli R, Lanoy E, Albiges L, Escudier B

Abstract
UNLABELLED: Study Type--Prognosis (cohort series) Level of Evidence 2b. What's known on the subject? and What does the study add? In the literature, few studies have evaluated the role of tumour burden (TB) in metastatic real cell carcinoma (mRCC), even though it has been considered as important in localized tumours. In metastatic patients the role of TB is uncertain because it was analyzed in chemotherapy treated patients or using a partial evaluation of TB. This study, first reports the independent prognostic and predictive role of TB in mRCC patients treated with targeted agents in prospective clinical trials. TB is able to predict prognosis independently to localization of metastases and prognostic class defined by MSKCC criteria, moreover it is strictly related to patient's performance status.
OBJECTIVE: ? To investigate the possible prognostic role of baseline tumour burden (TB) in terms of progression-free survival (PFS) and overall survival (OS), in patients with metastatic renal cell carcinoma (mRCC).
PATIENTS AND METHODS: ? A homogenous group of patients with mRCC enrolled in second-line trials post-cytokine treatment were selected for the present analysis. ? The Response Evaluation Criteria in Solid Tumors (the sum of the longest unidimensional diameter of each target lesion) were used to assess TB. ? The PFS and OS rates were estimated using the Kaplan-Meier method and compared across the groups using the log-rank test. ? The association between TB and PFS or OS was evaluated using a Cox proportional hazards model. Multivariable analyses were adjusted for other prognostic variables: the Memorial Sloan Kettering Cancer Centre (MSKCC) risk class and treatment.
RESULTS: ? A total of 124 patients were included in the final analysis. Of these, 66% received sorafenib or sunitinib and 34% received placebo. The median follow-up was 80.1 month. ? TB was directly related to PFS and OS and these associations remained significant after adjusting for modified MSKCC risk class and treatment,. ? Each 1-cm increase in TB increased the risk of progression by 4.5% (hazard ratio [HR]: 1.05; 95% confidence interval [CI] 1.02-1.07; P < 0.001) and the risk of death by 5% (HR: 1.05; 95% CI 1.03-1.08; P < 0.001).
CONCLUSIONS: ? TB is easy to calculate from standard computed tomography and significantly relates to OS in patients with mRCC. ? We report for the first time the independent prognostic role of baseline TB in multivariate analysis. ?? We believe that this information could be translated into clinical practice.

PMID: 23106948 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

Efficacy of Everolimus in Patients with Metastatic Insulinoma and Refractory Hypoglycemia.

Efficacy of Everolimus in Patients with Metastatic Insulinoma and Refractory Hypoglycemia.

Eur J Endocrinol. 2013 Feb 7;

Authors: Bernard V, Lombard-Bohas C, Taquet MC, Caroli-Bosc FX, Ruszniewski P, Niccoli-Sire P, Guimbaud R, Chougnet CN, Goichot B, Rohmer V, Borson-Chazot F, Baudin E

Abstract
BACKGROUND: Refractory hypoglycemia in patients with metastatic insulinoma is an important cause of morbidity and mortality. Everolimus could be a new therapeutic option. METHODS: Within the French Group, we conducted a retrospective, multicentric study of endocrine tumors to evaluate the time to first recurrence of symptomatic hypoglycemia, after everolimus initiation, in patients with metastatic insulinoma and refractory hypoglycemia. Ongoing hyperglycemic medical options, tumor response, and safety information were recorded. RESULTS: Twelve patients with metastatic insulinoma and refractory hypoglycemia treated with everolimus between May 2007 and June 2011 were reviewed. Everolimus (starting dose, 10 mg/d, except in 1 patient, 5 mg/d) was given after a median of 4 previous therapeutic lines. Clinical benefit was observed in 11 patients, allowing withdrawal of hyperglycemic therapy in 6 patients. After a median duration of 6.5 months (range, 1 to 35+ months), median time to first recurrence of symptomatic hypoglycemia was 6.5 months (range, 0 to 35+ months). Three patients discontinued everolimus because of cardiac and/or pulmonary adverse events at 1, 1.5, and 7 months after initiation, which led to 2 deaths. Three patients discontinued everolimus because of tumor progression at 2, 3, and 10 months after initiation, without recurrence of hypoglycemia. CONCLUSION: Everolimus appears to be a new effective treatment for patients with metastatic insulinoma and refractory hypoglycemia. Tolerance should be carefully monitored.

PMID: 23392213 [PubMed - as supplied by publisher]

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