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.

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.

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.

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.

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 Aβ42 and Aβ40, and maintain (or increase) the levels of total Aβ. Furthermore, representative compounds 1 and 5 demonstrated in vivo efficacy to lower Aβ42 in the brain without altering Notch processing in the peripheral.

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 Aβ42 and Aβ40, and maintain the levels of total Aβ. Furthermore, 25 demonstrated excellent pharmacokinetic parameters as well as good CNS penetration in the rat.

Dynamics of Aβ42 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 Aβ42 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 Aβ production.

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.

TASTPM mice expressing amyloid precursor protein and presenilin-1 mutant transgenes are sensitive to γ-secretase modulation and amyloid-β₄₂ lowering by GSM-10h.

Background: Cleavage of the amyloid precursor protein (APP) by β-site APP-cleaving enzyme and γ-secretase results in the generation of amyloid-β (Aβ) 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 Aβ₄₂ peptide while avoiding deleterious activity on Notch processing.

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.

Small interfering RNA-mediated knockdown of notch ligands in primary CD4+ T cells and dendritic cells enhances cytokine production.

The key interaction in the adaptive immune system's response to pathogenic challenge occurs at the interface between APCs and T cells. Families of costimulatory and coinhibitory molecules function in association with the cytokine microenvironment to orchestrate appropriate T cell activation programs. Recent data have demonstrated that the Notch receptor and its ligands also function at the APC:T interface.

The development of a modified human IFN-alpha2b linked to the Fc portion of human IgG1 as a novel potential therapeutic for the treatment of hepatitis C virus infection.

Interferon-alpha (IFN-alpha), in conjunction with ribavirin, is the current standard for the treatment of chronic hepatitis C virus (HCV) infection. This treatment requires frequent dosing, with a significant risk of the development of anti-IFN-alpha neutralizing antibodies that correlates with lack of efficacy or relapse. We have developed an IFN-alpha linked to the Fc region of human IgG1 for improved half-life and less frequent dosing.

Further characterization of the interaction between the cytoskeletal proteins talin and vinculin.

The cytoskeletal protein talin, which is thought to couple integrins to F-actin, contains three binding sites (VBS1-VBS3) for vinculin, a protein implicated in the negative regulation of cell motility and whose activity is modulated by an intramolecular interaction between the vinculin head (Vh) and vinculin tail (Vt) domains. In the present study we show that recombinant talin polypeptides containing the three VBSs (VBS1, residues 498-636; VBS2, residues 727-965; and VBS3, residues 1943-2157) each bind tightly to the same or overlapping sites within vinculin(1-258). A short synthetic talin VBS3 peptide (residues 1944-1969) was sufficient to inhibit binding of a (125)I-labelled talin VBS3 polypeptide to vinculin(1-258), and NMR spectroscopy confirmed that this peptide forms a 1:1 complex in slow exchange with vinculin(1-258).