Simple Synthesis of 17-β-O-hemisuccinate of Stanozolol for Immunoanalytical Methods

The use of doping in sports is a global problem that affects athletes around the world. Among the different methods developed to detect doping agents in biological samples, there are antibody-based methods that need an appropriate hapten design. Steroids with a hydroxyl group can be converted to the corresponding hemisuccinates. A novel approach to the synthesis of 17\u3b2-O-hemisuccinate of the common doping agent stanozolol is described here. Acylation of stanozolol with methyl 4-chloro-4-oxobutyrate/4-dimethylaminopyridine, followed by mild alkaline hydrolysis with methanolic sodium hydroxide at room temperature, gave the simultaneous protection and deprotection of pyrazole-nitrogen atoms. The proposed new synthetic method allows the desired hemisuccinate derivative to be obtained in only two steps, and with a good total yield starting from stanozolol

MTOR cross-talk in cancer and potential for combination therapy

The mammalian Target of Rapamycin (mTOR) pathway plays an essential role in sensing and integrating a variety of exogenous cues to regulate cellular growth and metabolism, in both physiological and pathological conditions. mTOR functions through two functionally and structurally distinct multi-component complexes, mTORC1 and mTORC2, which interact with each other and with several elements of other signaling pathways. In the past few years, many new insights into mTOR function and regulation have been gained and extensive genetic and pharmacological studies in mice have enhanced our understanding of how mTOR dysfunction contributes to several diseases, including cancer. Single-agent mTOR targeting, mostly using rapalogs, has so far met limited clinical success; however, due to the extensive cross-talk between mTOR and other pathways, combined approaches are the most promising avenues to improve clinical efficacy of available therapeutics and overcome drug resistance. This review provides a brief and up-to-date narrative on the regulation of mTOR function, the relative contributions of mTORC1 and mTORC2 complexes to cancer development and progression, and prospects for mTOR inhibition as a therapeutic strategy

Effects of cytokinins, cytokinin ribosides and their analogs on the viability of normal and neoplastic human cells

We examined the effects of some cytokinins and cytokinin ribosides including a series of adenosine analogs differently substituted in the N(6) position, along with some hypoxanthine derivatives on the viability of normal and neoplastic human cells. Cytokinins such as trans-zeatin, isopentenyladenine and benzyladenine do not show any effect, while cytokinin ribosides such as trans-zeatin riboside, isopentenyladenosine, and benzylaminopurine riboside impair the viability of normal and neoplastic cells, apart from colon carcinoma LoVo cells

Crystallographic and spectroscopic study on a known orally active progestin

6,17a-dimethyl-4,6-pregnadiene-3,20-dione (medrogestone, 2) is for a long time known steroid endowed with progestational activity. In order to study its crystallographic and NMR spectroscopic properties with the aim to fill the literature gap, we prepared medrogestone following a traditional procedure. A careful NMR study allowed the complete assignement of the 1H and 13C NMR signals not only of medrogestone but also of its synthetic intermediates. The structural and stereochemical characterizations of medrogestone togheter with its precursor 17a-methyl-3-ethoxy-pregna-3,5- dien-20-one were described by means of X-ray analysis, allowing a deepened conformational investigation

Unambiguous Characterization of p-Cresyl Sulfate, a Protein-Bound Uremic Toxin, as Biomarker of Heart and Kidney Disease

p-Cresyl sulfate is one of the bound uremic toxins whose level increases in the sera of patients with the severity of chronic kidney disease and is therefore used as a standard for clinical investigations. Our first attempts to obtain p-cresyl sulfate led exclusively to the product of sulfonation of the aromatic ring instead of sulfation on the OH moiety. Nevertheless, this initial discouraging result allowed us to handle both p-cresyl sulfate and 2-hydroxy-5-methylbenzenesulfonic acid obtained by different synthetic pathways. Interestingly, the comparison between the two isomers pointed out that the two molecules show the same fragmentation pattern and are indistinguishable by mass spectrometry. They cannot be separated on several commercially available columns. The only difference between the two compounds is a 10-fold higher ionization yield under negative ion electrospray ionization. NMR spectral studies definitely confirmed the different molecular structures. We present here an unambiguous biomimetic synthetic route for p-cresyl sulfate and the spectroscopic characterization of both the compounds by nuclear magnetic resonance and mass spectrometry

mTOR Cross-Talk in Cancer and Potential for Combination Therapy.

The mammalian Target of Rapamycin (mTOR) pathway plays an essential role in sensing and integrating a variety of exogenous cues to regulate cellular growth and metabolism, in both physiological and pathological conditions. mTOR functions through two functionally and structurally distinct multi-component complexes, mTORC1 and mTORC2, which interact with each other and with several elements of other signaling pathways. In the past few years, many new insights into mTOR function and regulation have been gained and extensive genetic and pharmacological studies in mice have enhanced our understanding of how mTOR dysfunction contributes to several diseases, including cancer. Single-agent mTOR targeting, mostly using rapalogs, has so far met limited clinical success; however, due to the extensive cross-talk between mTOR and other pathways, combined approaches are the most promising avenues to improve clinical efficacy of available therapeutics and overcome drug resistance. This review provides a brief and up-to-date narrative on the regulation of mTOR function, the relative contributions of mTORC1 and mTORC2 complexes to cancer development and progression, and prospects for mTOR inhibition as a therapeutic strategy

Impact of dental care in the prevention of bisphosphonate-associated osteonecrosis of the jaw: a single-center clinical experience

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Change in convergence and accommodation after two weeks of eye exercises in typical young adults

Abstract: Introduction Although eye exercises appear to help heterophoria, convergence insufficiency and intermittent strabismus, true treatment effects can be confounded by placebo, practice and encouragement factors. This study assessed objective changes in vergence and accommodation responses in typical naïve young adults after two weeks of exercises compared to control conditions to assess the extent of treatment effects occur above other factors. Methods 156 asymptomatic young adults were randomly assigned to 6 exercise groups or 2 no-treatment groups. Treatment targeted i) accommodation, ii)vergence, iii) both, iv) convergence>accommodation, v)accommodation>convergence, or vi) a placebo. All were re-tested under identical conditions, except for the second control group who were additionally encouraged during testing. Objective accommodation and vergence were assessed to a range of targets moving in depth containing combinations of blur, disparity and proximity/looming cues. Results Response gain improved more for less naturalistic targets where more improvement was possible. Convergence exercises improved vergence for near across all targets (P=.035). Mean accommodation changed similarly,but non-significantly. No other treatment group differed significantly from the non-encouraged control group, while encouraging effort produced significantly increased vergence (P=.004) and accommodation (P=.005) gains in the other control group. Conclusions True treatment effects were small, only significantly better after vergence exercises to a non-accommodative target, and were rarely related to response they were designed to improve. Exercising accommodation without convergence made no difference to accommodation to cues containing detail. Additional effort improved objective responses the most, so should be controlled carefully in research, and considered when auditing treatment