Obesity and Breast Cancer Risk in Men: A National Case-Control Study in England and Wales.

Background: Breast cancer is rare in men, and information on its causes is very limited from studies that have generally been small. Adult obesity has been shown as a risk factor, but more detailed anthropometric relations have not been investigated. Methods: We conducted an interview population-based case-control study of breast cancer in men in England and Wales including 1998 cases incident during 2005-2017 at ages younger than 80 years and 1597 male controls, with questions asked about a range of anthropometric variables at several ages. All tests of statistical significance were 2-sided. Results: Risk of breast cancer statistically significantly increased with increasing body mass index (BMI) at ages 20 (odds ratio [OR] = 1.07, 95% confidence interval [CI] = 1.02 to 1.12 per 2-unit change in BMI), 40 (OR = 1.11, 95% CI = 1.07 to 1.16), and 60 (OR = 1.14, 95% CI = 1.09 to 1.19) years, but there was also an indication of raised risk for the lowest BMIs. Large waist circumference 5 years before interview was more strongly associated than was BMI with risk, and each showed independent associations. Associations were similar for invasive and in situ tumors separately and stronger for HER2-positive than HER2-negative tumors. Of the tumors, 99% were estrogen receptor positive. Conclusions: Obesity at all adult ages, particularly recent abdominal obesity, is associated with raised risk of breast cancer in men, probably because of the conversion of testosterone to estrogen by aromatase in adipose tissue. The association is particularly strong for HER2-expressing tumors.

Dysphagia in a Palliative Care Setting--A Coordinated Overview of Caregivers' Responses to Dietary Changes: The DysCORD qualitative study.

Primary caregivers (PCGs) are closely involved in preparing meals and feeding patients who are at the end of life, yet their responses to patients' swallowing difficulties have not been extensively analyzed. This study aimed to reach an understanding of PCGs' beliefs, values, and responses to dysphagia and dietary modifications in the palliative care setting. A total of 14 PCGs were interviewed and asked to share their thoughts and feelings about patients' dysphagia symptoms and the diet changes resulting from these symptoms. Qualitative descriptive analysis revealed four emerging themes: caregivers' knowledge, the symbolic role of food, emotional responses to dysphagia, and discordance with dietary recommendations. Our study found that PCGs appear to have a strong desire to continue feeding patients. The findings suggest that providing PCGs with knowledge and emotional support could help them to deal with this issue.

Extinction of care-induced vocalizations by a desensitization routine on a palliative care unit.

Vocalizations during care occur frequently in patients with dementia, and are not uncommon in the palliative setting. Underlying trigger factors may include pain during movement, fear of being turned, startle reflex, attempts at verbal communication, environmental factors such as cold water, and other possible etiologies. A case of a 92 year old female who screamed and called out during bathing is presented. This patient with comorbid dementia and brain lesions did not respond to pre-event pain medication, and became somnolent due to opioid administration for presumed incident pain. A non-pharmacological approach, with a patient-centered focus rather than task orientation, succeeded in extinguishing the vocalizations after a period of six weeks.

Pyridine-derived γ-secretase modulators.

SAR of a novel series of pyridine-derived γ-secretase modulators is described. Compound 5 was found to be a potent modulator in vitro, which on further profiling, was found to decrease Aß42 and Aß40, and maintain (or increase) the levels of total Aß. Furthermore, representative compounds 1 and 5 demonstrated in vivo efficacy to lower Aß42 in the brain without altering Notch processing in the peripheral.

Cardiac resynchronization therapy optimization using noninvasive cardiac output measurement.

AIMS: Noninvasive cardiac output (CO) measurement (NICOM) is a novel method to assess ventricular function and offers a potential alternative for optimization of cardiac resynchronization therapy (CRT) devices. We compared the effect of NICOM-based optimization to no optimization (empiric settings) on CRT outcomes. METHODS: Two hundred and three patients undergoing CRT were assessed in two consecutive nonrandomized groups; an empiric group (n = 54) was programmed to "out of the box" settings with a fixed AV delay of 120 ms and a VV delay of 0 ms; and the optimization group (n = 149) underwent adjustments of both the AV and VV delays according to the greatest improvement in resting CO. The primary endpoints were improvements in left ventricular (LV) volumes and function from baseline at 6 months. Secondary endpoints were change in New York Heart Association (NYHA) class, quality of life score, and 6-minute walk test (6 MWT) performance. RESULTS: After 6 months of CRT, the optimization group had a better clinical response with lower NYHA class (2.1 ± 0.8 vs 2.4 ± 0.8, P = 0.048) and quality of life scores (35 ± 18 vs 42 ± 20, P = 0.045) but no differences in 6-MWT performance (269 ± 110 vs 277 ± 114 m, P = 0.81). Echocardiographic response was also better in the optimization group with lower LV end systolic volume (108 ± 51 vs 126 ± 60 mL, P = 0.048) and higher ejection fraction (30 ± 7 vs 27 ± 8, P = 0.01) compared to empiric settings. CONCLUSION: Device optimization using noninvasive measures of CO is associated with better clinical and echocardiographic response compared to empiric settings.

Pyridazine-derived γ-secretase modulators.

SAR of a novel series of pyridazine-derived γ-secretase modulators is described. Compound 25 was found to be a potent modulator in vitro, which on further profiling, was found to decrease Aß42 and Aß40, and maintain the levels of total Aß. Furthermore, 25 demonstrated excellent pharmacokinetic parameters as well as good CNS penetration in the rat.

Dynamics of Aß42 reduction in plasma, CSF and brain of rats treated with the γ-secretase modulator, GSM-10h.

BACKGROUND: Allosteric modulation of γ-secretase is an attractive therapeutic approach for the treatment of Alzheimer's disease. We recently identified a novel γ-secretase modulator, GSM-10h, which effectively lowers Aß42 production in cells and in amyloid precursor protein transgenic mice. OBJECTIVE: Here, we describe the in vivo characterization of GSM-10h in a model of endogenous Aß production. METHODS: Rats were administered orally with GSM-10h, and the effect on Aß levels in peripheral and central compartments was determined. In addition, the effect of GSM-10h on Notch processing was assessed. RESULTS: Acute administration of GSM-10h to rats causes a dose-dependent decrease in the level of Aß42 in plasma, CSF and brain, with little effect on the level of Aß40 in these compartments. The magnitude of Aß42 lowering in the CSF and brain was further enhanced upon sub-chronic administration of GSM-10h. No deleterious effect on Notch processing was evident in either of these studies. To further explore the dynamics of Aß42 reduction in peripheral and CNS compartments, a time course study was conducted. In all compartments, the decrease in Aß42 was greatest at 6 h after administration of GSM-10h. This decrease in Aß42 was maintained for 9-15 h, after which time Aß42 levels returned to baseline levels. Encouragingly, no rebound in Aß42 levels beyond baseline levels was observed. CONCLUSIONS: These findings support the γ-secretase modulator profile of GSM-10h, and highlight the utility of the rat for assessing the pre-clinical efficacy of γ-secretase modulators.

TASTPM mice expressing amyloid precursor protein and presenilin-1 mutant transgenes are sensitive to γ-secretase modulation and amyloid-ß42 lowering by GSM-10h.

BACKGROUND: Cleavage of the amyloid precursor protein (APP) by ß-site APP-cleaving enzyme and γ-secretase results in the generation of amyloid-ß (Aß) peptides that aggregate and deposit as senile plaques in brains of Alzheimer disease patients. Due to the fundamental role γ-secretase plays in the proteolysis of a number of proteins including Notch, pharmacological inhibition of γ-secretase has been associated with mechanism-based toxicities. Therefore, efforts have focussed on the modulation of γ-secretase activity to selectively decrease levels of Aß42 peptide while avoiding deleterious activity on Notch processing. OBJECTIVE: Here, we describe the in vitro and in vivo characterisation of a novel γ-secretase modulator, GSM-10h, and investigate the potential for shorter Aß peptides to induce neurotoxicity in rat primary cortical neurons. METHODS: The effect of GSM-10h on Aß levels was investigated in SH-SY5Y cells expressing mutant APP and in TASTPM mice expressing APP and presenilin-1 mutant transgenes. The effect of GSM-10h on Notch processing was also determined. RESULTS: In cells, GSM-10h decreased levels of Aß42 while concomitantly increasing levels of Aß38 in the absence of effects on Aß40 levels. In TASTPM mice, GSM-10h effectively lowered brain Aß42 and increased brain Aß38, with no effect on Notch signalling. Unlike Aß42, which causes neuronal cell death, neither Aß37 nor Aß38 were neurotoxic. CONCLUSIONS: These findings confirm GSM-10h exhibits the profile of a γ-secretase modulator. In addition, TASTPM mice are shown to be responsive to treatment with a γ-secretase modulator, thereby highlighting the utility of this bitransgenic mouse model in drug discovery efforts focussed on the development of γ-secretase modulators.

Identification of 2-oxo-N-(phenylmethyl)-4-imidazolidinecarboxamide antagonists of the P2X(7) receptor.

A backup molecule to compound 2 was sought by targeting the most likely metabolically vulnerable site in this molecule. Compound 18 was subsequently identified as a potent P2X(7) antagonist with very low in vivo clearance and high oral bioavailability in all species examined. Some evidence to support the role of P2X(7) in the etiology of pain is also presented.

Piperidine-derived gamma-secretase modulators.

This Letter details the SAR of a novel series of piperidine-derived gamma-secretase modulators. Compound 10h was found to be a potent modulator in vitro, which on further profiling, was found to decrease Abeta42, increase Abeta38 and have no effect on Abeta40 levels. Furthermore, 10h demonstrated excellent pharmacokinetic parameters in the mouse, rat and dog in addition to good CNS penetration in the mouse.

Discovery of N-(3-fluorophenyl)-1-[(4-([(3S)-3-methyl-1-piperazinyl]methyl)phenyl)acetyl]-4-piperidinamine (GSK962040), the first small molecule motilin receptor agonist clinical candidate.

N-(3-fluorophenyl)-1-[(4-([(3S)-3-methyl-1-piperazinyl]methyl)phenyl)acetyl]-4-piperidinamine 12 (GSK962040) is a novel small molecule motilin receptor agonist. It possesses excellent activity at the recombinant human motilin receptor and also at the native rabbit motilin receptor where its agonist activity results in potentiation of the amplitude of neuronal-mediated contractions of isolated gastric antrum tissue. Compound 12 also possesses highly promising pharmacokinetic profiles in both rat and dog, and these results, in combination with further profiling in human native tissue and an in vivo model of gastrointestinal transit in the rabbit, have led to its selection as a candidate for further development.

The identification of potent, selective and CNS penetrant furan-based inhibitors of B-Raf kinase.

Modification of the potent imidazole-based B-Raf inhibitor SB-590885 resulted in the identification of a series of furan-based derivatives with enhanced CNS penetration. One such compound, SB-699393 (17), was examined in vivo to challenge the hypothesis that selective B-Raf inhibitors may be of value in the treatment of stroke.