FGFR2, HER2 and cMet in gastric adenocarcinoma: detection,prognostic significance and assessment of downstream pathway activation

Receptor tyrosine kinase pathways are potential therapeutic targets in gastric adenocarcinoma patients. We evaluated HER2 and cMet protein expression, and FGFR2 gene amplification to assess their prognostic significance, and downstream mediators pS6 and pERK for their potential utility as pharmacodynamic biomarkers in patients with gastric adenocarcinoma. Tissue microarrays were constructed from resection samples of 184 patients who underwent surgery for gastric/gastro-oesophageal junction adenocarcinoma. Tissue cores were obtained from the tumour body (TB), luminal surface (LS) and invasive edge (IE), and immunohistochemical and fluorescence in situ hybridisation (FGFR2) analysis was performed. FGFR2 amplification was identified in 2 % of cases and associated with worse survival (P?=?0.005). HER2 overexpression was observed in 10 % of cases and associated with increased survival (P?=?0.041). cMet overexpression was observed in 4 % of cases and associated with worse survival (P?<?0.001). On multivariate analysis, only cMet retained significance (P?=?0.006). pS6 and pERK expression were observed in 73 % and 30 % of tumours, respectively, with no association with survival. HER2 (P?=?0.004) and pERK (P?=?0.001) expression differed between tumour regions with HER2 expression increased in the LS compared with the TB and IE. These findings confirm subpopulations in gastric adenocarcinoma with poor outcome that may benefit from specific therapeutic strategies. However, we found heterogeneous HER2, pS6 and pERK overexpression, which presents challenges for their use as predictive biomarkers in gastric biopsies. The potential downstream pharmacodynamic markers pS6 and pERK were expressed across tumour regions, providing evidence that resections and biopsies would yield comparative results in clinical trials.     

Design of donecopride,a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment

RS67333 is a partial serotonin subtype 4 receptor (5-HT₄R) agonist that has been widely studied for its procognitive effect. More recently, it has been shown that its ability to promote the nonamyloidogenic cleavage of the precursor of the neurotoxic amyloid-β peptide leads to the secretion of the neurotrophic protein sAPPα. This effect has generated great interest in RS67333 as a potential treatment for Alzheimer’s disease (AD). We show herein that RS67333 is also a submicromolar acetylcholinesterase (AChE) inhibitor and therefore, could contribute, through this effect, to the restoration of the cholinergic neurotransmission that becomes altered in AD. We planned to pharmacomodulate RS67333 to enhance its AChE inhibitory activity to take advantage of this pleiotropic pharmacological profile in the design of a novel multitarget-directed ligand that is able to exert not only a symptomatic but also, a disease-modifying effect against AD. These efforts allowed us to select donecopride as a valuable dual (h)5-HT₄R partial agonist (K_i = 10.4 nM; 48.3% of control agonist response)/(h)AChEI (IC₅₀ = 16 nM) that further promotes sAPPα release (EC₅₀ = 11.3 nM). Donecopride, as a druggable lead, was assessed for its in vivo procognitive effects (0.1, 0.3, 1, and 3 mg/kg) with an improvement of memory performances observed at 0.3 and 1 mg/kg on the object recognition test. On the basis of these in vitro and in vivo activities, donecopride seems to be a promising drug candidate for AD treatment.Among the large family of serotonin receptors (5-HTR), some of them, such as the subtype 4 (5-HT₄R), are of particular interest in improving memory performance and therefore, decreasing memory deficits, such as those that occur in Alzheimer''s disease (AD). In the CNS, they are located in structures that are primarily involved in cognitive functions, like the olfactory tubercles, basal ganglia, septum, substantia nigra, superior colliculi, hippocampus, and cortex. Several compounds act as agonists to 5-HT₄R (BIMU1, BIMU8, RS17017, SL65.0155, VRX-03011, prucalopride, RS67333, and RS67506). One of the most affine (pK_i = 7.88) and selective vs. other receptors is RS67333, which acts as a partial agonist (1). With respect to the potential therapeutic modulation of 5-HT₄R with RS67333 and excluding its putative antidepressant-like activity (2–4), most studies focused on the promnesic or antiamnesic actions of this compound. These effects on cognitive functions that concern learning and memory are probably, in part, because of the fact that the pharmacological stimulation of these receptors increases the release of ACh in the hippocampus and cortex, and it also increases serotonin, dopamine, and GABA release (5–13). Concerning the selective aspects of memory functions, RS67333 has been shown to improve object recognition in adult (14, 15) and aged animals (16, 17) and place recognition (10) in rodents. It also increases spatial learning on the Morris water maze task in rodents, and it even reverses the deleterious effect of atropine (18) or scopolamine during this same task.Based on the structural analogy existing between RS67333 and donepezil (Fig. 1), we postulated that RS67333 could improve learning and memory by not only activating 5-HT₄R but also, inhibiting acetylcholinesterase (AChE) activity. Indeed, several early studies reported that the inhibition of AChE improved cognition and that this effect is the main reason for the initial use of donepezil, galantamine, and rivastigmine as cognitive enhancers in AD (19, 20). AChE inhibition has also been reported to improve performances in healthy rodents or animal models of memory deficiency (21). The hypothesis of an involvement of AChE inhibition by RS67333 in memory improvement is an issue that has never been tested.Open in a separate windowFig. 1.RS67333 and donepezil are chemically close.Furthermore, such a pharmacological profile could be also exploited to lead to pleiotropic compounds that are theoretically useful in AD treatment. Indeed, today, it is well-established that 5-HT₄R activation not only favors ACh release but also, is involved in the nonamyloidogenic cleavage of amyloid precursor protein (APP) in the neurotrophic sAPPα fragment, with secretion that is detrimental to amyloid-β peptide (Aβ) production (22–24). However, inhibiting the catalytic activity of AChE is widely used to restore cholinergic neurotransmission in AD, and interacting with the peripheral anionic site (PAS) of this enzyme could also reduce amyloid aggregation, for which AChE would be responsible (25). These activities seem to be synergistic when they are associated in an AD animal model, which we have recently shown in mice (26). A second pharmacological approach based on the fact that a single compound may be able to hit multiple targets is now emerging. This concept, called multitarget-directed ligands (MTDLs) (27, 28), would have inherent advantages over a combination of drugs called multiple medication therapy. It would specially obviate the problems linked to the complexity of the pharmacokinetic profile of the combined drugs and the risk of drug–drug interactions. Moreover, MTDL could also alleviate compliance difficulties associated with multiple medication therapy. It has also been shown that MTDLs generally show a higher synergistic effect than that observed with a combination of drugs. Numerous examples of MTDL against AD have been recently described (27). Most of them associate an AChE inhibitory effect with another activity hitting another molecular target of AD, such as antioxidant effect, monoamine oxidase inhibition, calcium channel blocking effect, metal chelating activity, etc. However, no MTDLs associating an inhibition of AChE and 5-HT₄R agonist effect have been hitherto described. Among the different ways to synthesize such MTDLs, one of them is to merge the frameworks of two selective starting compounds, each one exerting an activity toward a sole target (28). This goal is even more easily reached if the starting compounds are structurally close, and it is the reason why we considered the structural analogy between donepezil and RS67333 as a good starting point to design MTDLs displaying both activities (AChE inhibition and 5-HT₄R agonist activities). We will, thus, provide proof of this concept with the synthesis and biological evaluation of MR31147 (donecopride) as conceived from the pharmacomodulation of RS67333.     

Solvent-induced selectivity of Williamson etherification in the pursuit of amides resistant against oxidative degradation

This article reports two discoveries. (1) 2-Methoxyethanol induces unprecedented selectivity for etherification of 5-hydroxy-2-nitrobenzic acids without forming undesired esters. (2) Such compounds are precursors for amides showing unusual robustness against oxidative degradation, essential for molecular electrets that transfer strongly oxidizing holes at about −6.4 eV vs. vacuum.

Selective etherification produces precursors for amides resistant to oxidative degradation, i.e., showing reversible oxidation at 1.5 to 1.7 V vs. SCE.     

Use of antibiotic prophylaxis in elective inguinal hernia repair in adults in London and south-east England: a cross-sectional survey

Purpose

Evidence regarding whether or not antibiotic prophylaxis is beneficial in preventing post-operative surgical site infection in adult inguinal hernia repair is conflicting. A recent Cochrane review based on 17 randomised trials did not reach a conclusion on this subject. This study aimed to describe the current practice and determine whether clinical equipoise is prevalent.

Methods

Surgeons in training were recruited to administer the Survey of Hernia Antibiotic Prophylaxis usE survey to consultant-level general surgeons in London and the south-east of England on their practices and beliefs regarding antibiotic prophylaxis in adult elective inguinal hernia repair. Local prophylaxis guidelines for the participating hospital sites were also determined.

Results

The study was conducted at 34 different sites and received completed surveys from 229 out of a possible 245 surgeons, a 93 % response rate. Overall, a large majority of hospital guidelines (22/28) and surgeons’ personal beliefs (192/229, 84 %) supported the use of single-dose pre-operative intravenous antibiotic prophylaxis in inguinal hernia repair, although there was considerable variation in the regimens in use. The most widely used regimen was intravenous co-amoxiclav (1.2 g). Less than half of surgeons were adherent to their own hospital antibiotic guidelines for this procedure, although many incorrectly believed that they were following these.

Conclusion

In the south-east of England, there is a strong majority of surgical opinion in favour of the use of antibiotic prophylaxis in this procedure. It is therefore likely to be extremely difficult to conduct further randomised studies in the UK to support or refute the effectiveness of prophylaxis in this commonly performed procedure.     

Prevalence and correlates of face recognition impairments after acquired brain injury

Impairments of face recognition after acquired brain injury (ABI) are not restricted to prosopagnosia but commonly arise in association with other cognitive deficits and can be psychosocially debilitating. Despite this, the prevalence and cognitive concomitants of such impairments after ABI have not been systematically investigated. We tested 91 adults with ABI on a range of cognitive measures including several indices of face recognition and learning. The proportion of patients who show impaired performance varied across face learning/recognition tests between 21% and 80%. Principal components analyses indicated orthogonality between impairments of “directed facial processing”, associated with memory and visuoperceptual deficits and manifest in slow learning and matching of previously unfamiliar faces, and of “face identification”, associated with deficits on verbal tests and manifest in difficulty in naming famous faces. Theoretical and rehabilitative implications are considered.     

Stress Mediates the Relationship Between Past Drug Addiction and Current Risky Sexual Behaviour Among Low‐income Women

This study examined the role of stress as a mediator of the relationship between prior drug addiction and current high‐risk sexual behaviour. Eight hundred twenty women aged 18 to 30 years, who received care at community‐based family planning clinics, were interviewed using the Composite International Diagnostic Interview and the Sexual Risk Behavior Assessment Schedule. They also completed the brief version of the Self‐Control Scale as a measure of problem‐solving strategies and measures of recent stressful events, daily hassles and ongoing chronic stress. Regardless of addiction history, stress exposure during the previous 12 months was associated with risky sexual behaviour during the previous 12 months. Structural equation modelling revealed that 12‐month stress levels mediated the relationship between past drug addiction and 12‐month high‐risk sexual behaviours, as well as the negative relationship between problem‐solving strategies and high‐risk sexual behaviours. Problem‐solving strategies did not moderate the relationship between drug addiction and high‐risk sexual behaviours. These findings suggest that stress management training may help reduce risky behaviour among young, low‐income women Copyright © 2014 John Wiley & Sons, Ltd.     

"For the good of the patient," survey of the physicians of the National Medical Association regarding perceptions of DTC advertising, Part II, 2006

BACKGROUND: Since the advent of direct-to-consumer (DTC) advertising in the 1980s, there have been numerous studies and surveys on the topic, addressing issues as varied as its impact on patient understanding of health conditions to its repercussions for drug spending. However, until 2001, there was a dearth of research on DTC advertising's impact on minority populations, specifically the African-American community. The National Medical Association (NMA) remedied that in 2001 by undertaking a landmark study that gauged African-American physicians' perceptions of DTC advertising, its impact on the doctor-patient relationship and, perhaps most importantly, its role in educating underserved populations about critical health issues and potential treatments. In 2006, the NMA decided to once again poll its members on this critical issue to gauge not only current perceptions but how the community's understanding of DTC advertising has changed since 2001. RESULTS: The 2006 survey revealed several clear trends: NMA physicians are more positive toward DTC advertising now than they were in 2001; African-American physicians see DTC advertising as providing substantial educational benefits; physicians believe that DTC advertising helps rather than hurts the doctor-patient relationship; and African-American physicians see the benefits of DTC advertising outweighing its drawbacks. It must be noted that NMA physicians also had clear concerns about DTC advertising that point to potential areas of improvement for pharmaceutical companies.