The present invention relates to novel 4-pregenen-11β-17-21-triol-3,20-dione derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals, as modulators of glucocorticoid or mineralocorticoid receptors. The invention relates specifically to the use of these compounds and their pharmaceutical compositions to treat disorders associated with glucocorticoid or mineralocorticoid receptor modulation.

The disclosure relates to novel C4 and C6 substituted androst-4-ene diones as well as andros-1,4-diene diones and derivatives thereof, their process of preparation, pharmaceutical compounds containing them, and the use of said compounds for the treatment of hormone-related disorders in mammals. This includes hormone-dependent cancers, particularly those caused by elevated levels of estrogen and its intermediates. These compounds can also be used in the treatment of other hormone-related disorders, including benign prostatic hyperplasia, cardiovascular disease, and neurodegenerative disorders.

A compound of the formula (1) wherein the substituents are as defined in claim 1, are useful as a pesticides.

An azaindenofluorenedione derivative shown by the following formula (I), (IIa) or (IIb):

Read full biography of Celine Dion including latest news, trivia, quotes, filmography/discography, awards and fun stuff.

Wavesfactory has announced the release of an accordion collection of Native Instruments Kontakt. Le Parisien is based on three accordions, with a faithful recreation of the sound and behavior of the real instruments. The library features Rouge, Blanc and Noir accordions, each one of them sampled with all registers, giving different sound characteristics, and mechanical […]

The post Wavesfactory releases Le Parisien virtual accordion library for Kontakt appeared first on rekkerd.org.

Plugin Boutique has launched a sale on the Organetta Kontakt library by AudioThing, featuring the sounds of a small portable reed organ made in the late 50s by the German company Hohner. The sound is generated by an electric fan that blows air into a set of brass reeds hence the sound is reminiscent of […]

The post Save 70% on AudioThing’s Organetta melodica and accordion hybrid appeared first on rekkerd.org.

Will progressives and moderates feud as the country burns? Or will they unite to defeat President Trump and usher in a new era of reform?

American rock and roll icon Dion describes how he, one night, heard the soul and rhythm of Hank Williams drifting out of his family radio and was forever changed. Later, Austinite Amanda Cevallos talks country with Elizabeth (who can talk some country) and they bond over their love of Waylon Jennings and Texas dancehalls.

(United States DC Circuit) - Petition denied. The petition for review of a National Labor Relations Board decision was supported by substantial evidence and contentions that the Board violated due process and improperly imposed a notice-reading remedy were without merit.

musicisart magazine Osunlade Samples Dionne Warwick

Producers Osunlade sampled Dionne Warwick‘s classic R&B original Walk the Way You Talk. Osunlade turned their creation “Dionne” into a powerful message with an addictive, motivating dance beat. Released by Dionne Warwick in 1970, the phrasing sampled plays the words “Just because you say things are gonna change, saying something’s wrong isn’t good enough.” The meaning still […]

The post Osunlade Samples Dionne Warwick appeared first on musicisart magazine.

The Lakers worked out JR Smith and Dion Waiters on Monday as they began the process to fill their final roster spot, according to several sources familiar with the situation.

The Lakers plan to sign Dion Waiters on Friday to a minimum deal for the remainder of the season, according to people familiar with the deal.

Dion Waiters has only played three games this season, but coach Frank Vogel says the veteran guard is "definitely a player that can help us."

Odion Ighalo is keen to extend his stay at Manchester United beyond the summer.

Odion Ighalo scored twice as Manchester United beat Derby to reach the FA Cup quarter-finals and leave their all-time top scorer Wayne Rooney on the losing side.

Odion Ighalo hopes his loan deal at Manchester United is extended until the Premier League season is completed.

Triple negative breast cancer (TNBC) remains the most aggressive subtype of breast cancer leading to the worst prognosis. Because current therapeutic approaches lack efficacy, there is a clinically unmet need for effective treatment alternatives. Herein, we demonstrate a promising strategy utilizing a tumor-targeting alkylphosphocholine (NM600) radiolabeled with ¹⁷⁷Lu for targeted radionuclide therapy (TRT) of TNBC. In two murine syngeneic models of TNBC, we confirmed excellent tumor targeting and rapid normal tissue clearance of the PET imaging analog ⁸⁶Y-NM600. Based on longitudinal PET/CT data acquired with ⁸⁶Y-NM600, we estimated the dosimetry of therapeutic ¹⁷⁷Lu-NM600, which showed larger absorbed doses in the tumor compared to normal tissues. Administration of ¹⁷⁷Lu-NM600 resulted in significant tumor growth inhibition and prolonged overall survival in mice bearing syngeneic 4T07 and 4T1 tumors. Complete response was attained in 60% of 4T07 bearing mice, but animals carrying aggressive 4T1 tumor grafts succumbed to metastatic progression. The injected activities used for treatment (9.25 and 18.5 MBq) were well tolerated, and only mild transient cytopenia was noted. Overall, our results suggest that ¹⁷⁷Lu-NM600 TRT has potential for treatment of TNBC and merits further exploration in a clinical setting.

Peptide receptor radiotherapy using ¹⁷⁷Lu-labeled somatostatin ligand analogs is a well-established treatment for neuroendocrine tumors (NET), with ¹⁷⁷Lu-DOTATATE having acquired marketing authorization in Europe and the USA. The investigation of the pharmacokinetics of those radiopharmaceuticals in vivo in humans is crucial for personalized treatment management and understanding of treatment effects. It requires input data on the in vivo stability of the radiopharmaceuticals in blood and plasma. The work presented here is devoted to the investigation of in vivo stability of ¹⁷⁷Lu-DOTATATE in humans affected by NET. Unexpectedly, fast metabolism of the radiopharmaceutical was observed, with fraction of intact ¹⁷⁷Lu-DOTATATE in plasma decreasing rapidly to 23±5% (mean ± SD) at 24 h and 1.7±0.9% at 96 h after injection.

Objectives: Esthesioneuroblastoma (ENB) is rare with limited therapeutic options when unresectable or metastatic; however, expression of somatostatin receptors qualifies it for peptide receptor radionuclide therapy (PRRT). We report outcomes of PRRT in ENB from two referral centers. Methods: Using PRRT databases at two European Neuroendocrine Tumour Society Centers of Excellence, case finding was undertaken between 2004-2018 for patients who had PRRT with recurrent/metastatic ENB deemed unsuitable for further conventional therapies. Evaluations of response using a composite reference standard and for survival were performed. Results: Of seven patients, four had partial response, two had disease stabilization and one had early progression. Possible side effects include worsening CSF-leaks. Median progression-free survival was 17 months (range, 0-30), and median overall survival was 32 months (range, 4–53). Conclusion: PRRT shows promising efficacy and moderate survival duration in unresectable locally advanced or metastatic ENB warranting larger cohort studies incorporating measures of quality of life.

Background: Prostate-specific antigen (PSA) is widely used to monitor treatment response in patients with metastatic castration-resistant prostate cancer (mCRPC). However, PSA measurements are considered only after 12 wk of treatment. We aimed to evaluate the prognostic value of early PSA changes following ¹⁷⁷Lu-labelled prostate specific membrane antigen (LuPSMA) radionuclide treatment in mCRPC patients. Methods: Men who were treated under a compassionate access program with LuPSMA at our institution and had available PSA values at baseline, at 6 wk after treatment initiation were included in this retrospective analysis. Patients were assigned to three groups based on PSA changes: 1) response: ≥30% decline, 2) progression: ≥25% increase and 3) stable: <30% decline and <25% increase. The co-primary endpoints were overall survival and imaging-based progression-free survival. The secondary end points were PSA changes at 12 wk and PSA flare-up. Results: We identified 124 eligible patients with PSA values at 6 wk. A ≥30% decline in PSA at 6 wk was associated with longer overall survival (median 16.7 mo; 95%CI 14.4–19.0) compared with patients with stable PSA (median: 11.8 mo; 95%CI 8.6–15.1; P = 0.007) and progression (median: 6.5 mo; 95%CI 5.2–7.8; p<0.001). Patients with ≥30% decline in PSA at 6 wk also had a reduced risk of imaging-based progression compared with patients with stable PSA (HR: 0.60; 95%CI 0.38–0.94; P = 0.02), while patients with PSA progression had a higher risk of imaging-based progression compared with those showing stable PSA (HR: 3.18; 95%CI 1.95–5.21; p<0.001). The percentage changes of PSA at 6 wk and 12 wk were highly associated (r=0.90; p<0.001). 29 of 31 (94%) patients who experienced early PSA progression at 6 wk achieved biochemical progression at 12 wk. Overall, only 1 of 36 (3%) patients with PSA progression at 6 wk achieved any PSA decline at 12 wk (1% of the entire cohort). Limitations of the study included its retrospective nature and the single center experience. Conclusion: PSA changes at 6 wk after LuPSMA initiation are an early indicator of long-term clinical outcome. Patients progressing by PSA after 6 wk of treatment could benefit from a very early treatment switch decision. PSA flare-up during LuPSMA treatment is very uncommon. Prospective studies are now warranted to validate our findings and potentially inform clinicians earlier on the effectiveness of LuPSMA.

The objective of this retrospective study was to determine the role of ¹⁸F-FDG PET/CT in a large cohort of 495 patients with metastatic neuroendocrine neoplasms (NENs) who were treated with peptide receptor radionuclide therapy (PRRT) with a long-term follow-up. Methods: The 495 patients were treated with ¹⁷⁷Lu- and/or ⁹⁰Y- DOTATOC/DOTATATE PRRT between 2/2002 and 7/2018. All subjects received both ⁶⁸Ga-DOTATOC/TATE/NOC and ¹⁸F-FDG PET/CT prior to treatment and were followed 3-189 months. Kaplan-Meier analysis, log-rank test (Mantel-Cox), and Cox regression analysis were performed for overall survival (OS) and progression-free survival (PFS). Results: 199 patients (40.2%) presented with pancreatic NEN, 49 with CUP (cancer of unknown primary), 139 with midgut NEN, whereas the primary tumor was present in the rectum in 20, in the lung in 38, in the stomach in 8 and other locations in 42 patients. FDG-PET/CT was positive in 382 (77.2%) patients and 113 (22.8%) were FDG-negative before PRRT, while 100% were ⁶⁸Ga-DOTATOC/TATE/NOC positive. For all patients, the median PFS and OS, defined from start of PRRT, were 19.6 mo and 58.7 mo, respectively. Positive FDG predicted shorter PFS (18.5 mo vs 24.1 mo; P = 0.0015) and OS (53.2 mo vs 83.1 mo; P < 0.001) than negative FDG. Amongst the pancreatic NEN, the median OS was 52.8 mo in FDG positive and 114.3 mo in FDG negative subjects (P = 0.0006). For all patients with positive ¹⁸F-FDG uptake, and a ratio of the highest SUV_max on ⁶⁸Ga-SSTR PET to the most ¹⁸F-FDG-avid tumor lesions >2, the median OS was 53.0 mo, compared to 43.4 mo in those patients with a ratio <2 (P = 0.030). For patients with no ¹⁸F-FDG uptake (complete "mismatch" imaging pattern), the median OS was 108.3 mo vs 76.9 mo for SUV_max >15.0 and ≤15.0 on ⁶⁸Ga-SSTR PET/CT, respectively. Conclusion: The presence of positive lesions on ¹⁸F-FDG PET is an independent prognostic factor in patients with NEN treated with PRRT. Metabolic imaging with ¹⁸F-FDG PET/CT compliments the molecular imaging aspect of ⁶⁸Ga-SSTR PET/CT for the prognosis of survival after PRRT. High SSTR expression combined with negative ¹⁸F-FDG PET/CT imaging is associated with the most favorable long-term prognosis.

Joseph G. Yu
Oct 1, 2002; 51:2968-2974
Obesity Studies

Alan R Saltiel
Dec 1, 1996; 45:1661-1669
Perspectives in Diabetes

BM Spiegelman
Apr 1, 1998; 47:507-514
Articles

Treatment of patients with advanced medullary thyroid carcinoma (MTC) is still a challenge. For more than 2 decades, it has been known that the cholecystokinin 2 receptor is a promising target for the treatment of MTC with radiolabeled minigastrin analogs. Unfortunately, kidney toxicity has precluded their therapeutic application so far. In 6 consecutive patients, we evaluated with advanced 3-dimensional dosimetry whether improved minigastrin analog ¹⁷⁷Lu-DOTA-(d-Glu)₆-Ala-Tyr-Gly-Trp-Nle-Asp-PheNH₂ (¹⁷⁷Lu-PP-F11N) is a suitable agent for the treatment of MTC. Methods: Patients received 2 injections of about 1 GBq (~80 μg) of ¹⁷⁷Lu-PP-F11N with and without a solution of succinylated gelatin (SG, a plasma expander used for nephroprotection) in a random crossover sequence to evaluate biodistribution, pharmacokinetics, and tumor and organ dosimetry. An electrocardiogram was obtained and blood count and blood chemistry were measured up to 12 wk after the administration of ¹⁷⁷Lu-PP-F11N to assess safety. Results: In all patients, ¹⁷⁷Lu-PP-F11N accumulation was visible in tumor tissue, stomach, and kidneys. Altogether, 13 tumors were eligible for dosimetry. The median absorbed doses for tumors, stomach, kidneys, and bone marrow were 0.88 (interquartile range [IQR]: 0.85–1.04), 0.42 (IQR: 0.25–1.01), 0.11 (IQR: 0.07–0.13), and 0.028 (IQR: 0.026–0.034) Gy/GBq, respectively. These doses resulted in median tumor-to-kidney dose ratios of 11.6 (IQR: 8.11–14.4) without SG and 13.0 (IQR: 10.2–18.6) with SG; these values were not significantly different (P = 1.0). The median tumor-to-stomach dose ratio was 3.34 (IQR: 1.14–4.70). Adverse reactions (mainly hypotension, flushing, and hypokalemia) were self-limiting and not higher than grade 1. Conclusion: ¹⁷⁷Lu-PP-F11N accumulates specifically in MTC at a dose that is sufficient for a therapeutic approach. With a low kidney and bone marrow radiation dose, ¹⁷⁷Lu-PP-F11N shows a promising biodistribution. The dose-limiting organ is most likely the stomach. Further clinical studies are necessary to evaluate the maximum tolerated dose and the efficacy of ¹⁷⁷Lu-PP-F11N.

Clarke Island is a windswept place in Eastern Bass Strait. It had no residents and could only be accessed by light plane or boat when weather permitted. Having never seen the place, Dion and his family move there in March of 1984. They arrived with few provisions and few possessions to an old farm house in a poor state of repair. To survive they had to learn to live in harmony with the island by forging a semi self-sufficient life style in which they not only grew a garden and kept milking goats, but learned to live off the bounty of the land and sea.

Manchester United have been warned that Odion Ighalo could be set to land a 'big money move' to one of their major European rivals if they do not sign him permanently this summer.

Manchester United striker Odion Ighalo has heaped praise on fellow January arrival Bruno Fernandes and warned the rest of the Premier League: "We've not seen the best of him yet!"

Odion Ighalo says Manchester United will be "a different team" when Paul Pogba is back fit and firing.

Odion Ighalo believes Victor Osimhen has huge potential, with the Manchester United striker praising his compatriot as the "future of Nigerian football."

Loan sensation Odion Ighalo has revealed he felt the benefits of working under Ole Gunnar Solskjaer instantly upon arriving at Manchester United.

Manchester United want to extend Odion Ighalo's loan deal as they continue to weigh up a permanent move.

Manchester United are only pursuing an extension to Odion Ighalo's loan deal and have no immediate plans to negotiate a permanent move.

Broad and principled opposition to Donald Trump’s presidency has drawn millions of previously disengaged citizens to the public square and to the ballot box. But if progressives and moderates are unable—and unwilling—to overcome their differences, they could not only enable Trump to prevail again but also squander an occasion for launching a new era of…

Inspired by origami and looking a bit like an accordion, this no-tools-required bookshelf sets up in seconds to adapt to any space.

Mansfield have suspended midfielders Dion Donohue and Jacob Mellis following an alleged serious breach of club discipline.Neither player was included in the matchday squad in Saturday's win at Carlisle.

With the popularity of athleisure, it was only a matter of time before the unitard became trendy. Fashionably fearless stars like Celine Dion and Sofia Richie embraced the one-and-done garment.

Odion Ighalo is likely to make his Manchester United debut when they play Chelsea on Monday and Ole Gunnar Solskjaer will be hoping the striker makes as much impact as these loan stars.

Celine Dion continued to up the ante as she arrived in another showstopping ensemble as she stepped out of the Hôtel de Crillon in Paris on Sunday.

Odion Ighalo angered a student football team while he was participating in a solo training session over the winter break, according to The Sun. 

Wolves defender Dion Sanderson is attracting interest from the Molineux side's rival Premier League clubs following an impressive start to his loan at Cardiff City in the Championship.

Perrie Edwards stunned fans with her killer vocals as she performed karaoke ijn her kitchen in a jaw-dropping video on Monday.

Kylie Jenner shared a post where she was in all red in a car while wishing her 162M followers joy. The $1B makeup queen also asked fans to buy her makeup collection.

The trio of musical superstars will be joined by the likes of Jennifer Lopez, Camila Cabello, Alicia Keys and Sam Smith for the One World: Together at Home event this Saturday

Nigeria produced a second-half comeback to beat Cameroon 3-2 and book their place in the quarter-finals of the Africa Cup of Nations. The Super Eagles had taken an early lead.