Selective inhibitors of mTORC1 activate 4EBP1 and suppress tumor growth.

The clinical benefits of pan-mTOR active-site inhibitors are limited by toxicity and relief of feedback inhibition of receptor expression. To address these limitations, we designed a series of compounds that selectively inhibit mTORC1 and not mTORC2. These 'bi-steric inhibitors' comprise a rapamycin-like core moiety covalently linked to an mTOR active-site inhibitor. Structural modification of these components modulated their affinities for their binding sites on mTOR and the selectivity of the bi-steric compound. mTORC1-selective compounds potently inhibited 4EBP1 phosphorylation and caused regressions of breast cancer xenografts. Inhibition of 4EBP1 phosphorylation was sufficient to block cancer cell growth and was necessary for maximal antitumor activity. At mTORC1-selective doses, these compounds do not alter glucose tolerance, nor do they relieve AKT-dependent feedback inhibition of HER3. Thus, in preclinical models, selective inhibitors of mTORC1 potently inhibit tumor growth while causing less toxicity and receptor reactivation as compared to pan-mTOR inhibitors.

Chemoselective Radical Dehalogenation and C-C Bond Formation on Aryl Halide Substrates Using Organic Photoredox Catalysts.

Despite the number of methods available for dehalogenation and carbon-carbon bond formation using aryl halides, strategies that provide chemoselectivity for systems bearing multiple carbon-halogen bonds are still needed. Herein, we report the ability to tune the reduction potential of metal-free phenothiazine-based photoredox catalysts and demonstrate the application of these catalysts for chemoselective carbon-halogen bond activation to achieve C-C cross-coupling reactions as well as reductive dehalogenations. This procedure works both for conjugated polyhalides as well as unconjugated substrates. We further illustrate the usefulness of this protocol by intramolecular cyclization of a pyrrole substrate, an advanced building block for a family of natural products known to exhibit biological activity.

Simulation as a set-up for technical proficiency: can a virtual warm-up improve live fibre-optic intubation?

BACKGROUND: Fibre-optic intubation (FOI) is an advanced technical skill, which anaesthesia residents must frequently perform under pressure. In surgical subspecialties, a virtual 'warm-up' has been used to prime a practitioner's skill set immediately before performance of challenging procedures. This study examined whether a virtual warm-up improved the performance of elective live patient FOI by anaesthesia residents. METHODS: Clinical anaesthesia yr 1 and 2 (CA1 and CA2) residents were recruited to perform elective asleep oral FOI. Residents either underwent a 5 min, guided warm-up (using a bronchoscopy simulator) immediately before live FOI on patients with predicted normal airways or performed live FOI on similar patients without the warm-up. Subjects were timed performing FOI (from scope passing teeth to viewing the carina) and were graded on a 45-point skill scale by attending anaesthetists. After a washout period, all subjects were resampled as members of the opposite cohort. Multivariate analysis was performed to control for variations in previous FOI experience of the residents. RESULTS: Thirty-three anaesthesia residents were recruited, of whom 22 were CA1 and 11 were CA2. Virtual warm-up conferred a 37% reduction in time for CA1s (mean 35.8 (SD 3.2) s vs. 57 (SD 3.2) s, P<0.0002) and a 26% decrease for CA2s (mean 23 (SD 1.7) s vs. 31 (SD 1.7) s, P=0.0118). Global skill score increased with warm-up by 4.8 points for CA1s (mean 32.8 (SD 1.2) vs. 37.6 (SD 1.2), P=0.0079) and 5.1 points for CA2s (37.7 (SD 1.1) vs. 42.8 (SD 1.1), P=0.0125). Crossover period and sequence did not show a statistically significant association with performance. CONCLUSIONS: Virtual warm-up significantly improved performance by residents of FOI in live patients with normal airway anatomy, as measured both by speed and by a scaled evaluation of skills.

Synthesis of Hindered α-Amino Carbonyls: Copper-Catalyzed Radical Addition with Nitroso Compounds.

The synthesis of sterically hindered anilines has been a significant challenge in organic chemistry. Here we report a Cu-catalyzed radical addition with in situ-generated nitroso compounds to prepare sterically hindered amines directly from readily available materials. The transformation is conducted at room temperature, uses abundant copper salts, and is tolerant of a range of functional groups.

Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors.

Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or by crosstalk with other mutant cancer drivers, such as RAS, is a feature of many tumors. Multiple allosteric inhibitors of mTORC1 and orthosteric dual inhibitors of mTORC1 and mTORC2 have been developed as anticancer drugs, but their clinical utility has been limited. To address these limitations, we have developed a novel class of "bi-steric inhibitors" that interact with both the orthosteric and the allosteric binding sites in order to deepen the inhibition of mTORC1 while also preserving selectivity for mTORC1 over mTORC2. In this report, we describe the discovery and preclinical profile of the development candidate RMC-5552 and the in vivo preclinical tool compound RMC-6272. We also present evidence that selective inhibition of mTORC1 in combination with covalent inhibition of KRASG12C shows increased antitumor activity in a preclinical model of KRASG12C mutant NSCLC that exhibits resistance to KRASG12C inhibitor monotherapy.

New strategies for natural products containing chroman spiroketals.

Two cycloaddition strategies are described that lead to various chroman spiroketals from assorted exocyclic enol ethers. Unlike conventional thermodynamic ketalization strategies, the stereochemical outcome for this approach is determined by a kinetic cycloaddition reaction. Thus, the stereochemical outcome reflects the olefin geometry of the starting materials along with the orientation of the associated transition state. However, the initial kinetic product can also be equilibrated by acid catalysis and reconstituted into a thermodynamic stereochemical arrangement. Thus, these strategies uniquely enable synthetic access to either the thermodynamic or kinetic conformation of the spiroketal stereocenter itself. Applications of these strategies in the syntheses of berkelic acid, ß-rubromycin, and paecilospirone are presented along with the use of a chroman spiroketal for the construction of heliespirones A and C.

Reducing the variability between constant-depth film fermenter experiments when modelling oral biofilm.

AIMS: The inherent instabilities associated with the development of multispecies biofilm communities within the constant-depth film fermenter (CDFF) and other microcosm systems can yield unacceptable variability between experiments, which could limit their potential applications in oral microbiology. The extent of this variability needs to be determined and a protocol developed which minimizes it. METHODS AND RESULTS: Two custom-made CDFFs were supplied concurrently with the same inoculation culture, begat from an aliquot of a saliva pool and artificial saliva growth medium via a dual-channel pump. Transformed log(10) data of the viable counts at fixed time points were analysed using the Bland-Altman approach to test for the levels of agreement between two CDFFs running concurrently and those CDFFs run in series. The coefficients(95%) of agreement were lower (i.e. less variable) in the concurrent model than when run in series for total counts of bacteria (1.238 vs 2.124), Lactobacillus spp. (0.517 vs 1.431) and Mutans streptococci (2.817 vs 3.864). Other measures of variability showed a similar trend. CONCLUSIONS: Operating CDFFs concurrently minimizes the degree of difference and variability between them. SIGNIFICANCE AND IMPACT OF THE STUDY: Operating CDFFs concurrently will improve the sensitivity for experiments that seek to determine the effects of a variable, such as a nutritional supplement or antimicrobial agent, and a control.

A strategy for the late-stage divergent syntheses of scyphostatin analogues.

This account details the synthesis of two scyphostatin analogues exhibiting a reactive polar epoxycyclohexenone core and various amide side chains outfitted for late-stage chemical derivatization into the desirable lipophilic tails. Our efforts highlight a key ipso-dearomatization process and provide new insights regarding the incompatibility and orthogonal reactivity of scyphostatin's functional groups. We further showcase the utility of resorcinol derived 2,5-cyclohexadienones as synthetic platforms capable of participating in selective chemical reactivity, and we further demonstrate their potential for rapid elaboration into complex structural motifs.

Controlled drug release to cancer cells from modular one-photon visible light-responsive micellar system.

We present a one-photon visible light-responsive micellar system for efficient, on-demand delivery of small molecules. Release is mediated by a novel class of photochromic material - donor-acceptor Stenhouse adducts (DASAs). We demonstrate controlled delivery of small molecules such as the chemotherapeutic agent (paclitaxel) to human breast cancer cells triggered by micellar switching with low intensity, visible light.

The dexamethasone suppression test in the clinical setting.

The authors administered the dexamethasone suppression test (DST) to 47 inpatients on a clinical, nonresearch psychiatric unit who had been diagnosed according to DSM-III. Of the 30 patients with major depression, 23 (77%) exhibited nonsuppression (serum cortisol concentrations greater than 5 micrograms/dl); only 1 of the 17 patients with other diagnoses and depressive symptoms exhibited nonsuppression. There was no difference in the rate of nonsuppression between the patients with subgroups of major depression, but those with major depression and psychosis had significantly higher postdexamethasone cortisol levels than those with major depression with and without melancholia and those with diagnoses other than major depression.

Appearance of mania in drug-resistant bipolar depressed patients after treatment with L-triiodothyronine.

L-Triiodothyronine (T3) has been reported to potentiate the antidepressant effects of tricyclic antidepressants (TCAs) in patients who do not respond to these drugs, while thyroxine (T4) has been used to treat rapid-cycling bipolar disorder patients. The development of mania in antidepressant-resistant bipolar depressed patients after T3 was added to their antidepressant treatment is reported. It is speculated that thyroid hormone-catecholamine receptor interaction might underlie these T3-associated clinical manifestations. It is concluded that T3 did not prevent the switch to mania in the bipolar depressed patients reported here. Further study is necessary to determine if T3 plays a role in promoting the switch to mania in depressed patients treated with T3 in conjunction with TCAs, and if bipolar depressed patients are particularly vulnerable to mania from the combined effects of TCAs and T3.

Food preference following acute or chronic chlordiazepoxide administration: tolerance to an antineophobic action.

Chlordiazepoxide (CDP) at 15 mg/kg produced two distinct actions in a food preference test, firstly a general appetite-enhancing effect, and secondly an anti-neophobic effect. Following acute injection of CDP the rats changed from eating predominantly familiar food to a novel food. This may signify an anti-neophobic effect of CDP. However, following 10 days of treatment with CDP, the anti-neophobic effect was abolished and the choice of familiar food was enhanced. This could be an indication of a more general appetite-enhancing effect. Hence some form of tolerance may develop to CDP's effects over 10 days of treatment which selectively abolishes anti-neophobic action whilst leaving the appetite effect further enhanced. There were no indications of tolerance developing to the actions of CDP in animals familiarized with all the test foods before the preference test was run. Hence the presence of food novelty may be critical to the observation of some form of selective tolerance.

Psychosis associated with hypopituitarism.

Psychosis is one of many possible psychiatric disturbances associated with endocrinologic abnormalities. Previous reports linking psychosis with hypopituitarism have been limited. Furthermore, such reports suggested that the psychotic symptoms were more accurately part of a delirium. We report two patients with hypopituitarism who presented with psychotic symptoms, in the absence of an altered sensorium. They were assigned functional psychiatric diagnoses on initial presentation. Their symptoms abated after correction of underlying hormonal abnormalities. The evaluation and treatment of psychiatric disturbances associated with hypopituitarism are discussed.

Longitudinal study of neuropsychological functioning in patients on chronic hemodialysis: a preliminary report.

This study is part of a five-year project to investigate the long term effect of chronic hemodialysis on patients with end-stage renal failure. Previous research has associated hemodialysis with progressive dialysis encephalopathy (PDE), which is characterized by speech disturbances, cognitive impairment, myoclonus and behavioral changes. Little is known about the cause or the course of this syndrome except that it begins 14-36 months after treatment onset and usually culminates in death. The purpose of this study was to investigate neuropsychological (cognitive and behavioral) functioning in dialysis patients over a period of years. To date, 34 patients have been studied for 22 months utilizing a cross-sectional method comparing patients at different stages of treatment combined with a longitudinal method of repeated evaluations over time. Current findings show improved cognitive functioning during at least the first year of treatment and no evidence of cognitive deterioration in patients on dialysis for more than one year (M = 4.3). These findings offer strong evidence that PDE is not necessarily a general phenomenon among patients on chronic hemodialysis.

Research issues in psychological studies of chronic dialysis.

Research examining the psychological and psychosocial effects of chronic dialysis has produced numerous controversial issues, such as the role of denial in emotional adjustment and the relationship of intelligence of vocational rehabilitation in dialysis patients. Inconsistent findings leading to these controversies are attributable in part to variance in research design and to shortcomings in methodology and reporting of data. The present article briefly reviews methodological factors not previously addressed in critiques of dialysis research, focusing on subject selection, subject description, illness measures, assessment procedures, conditions of testing, comparison groups, and data analysis. It is concluded that consideration of these factors in the design and conduct of studies will enhance the quality of research in this area.