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Central nervous system (CNS) metastases are frequently diagnosed in patients with non-small cell lung cancer (NSCLC). Only recently, clinical trials are broadening eligibility to include patients with brain metastases, offering the potential for some assessment of CNS efficacy to be made. In this work we aim to review the available information on the activity of small molecule targeted drugs for advanced NSCLC with respect to CNS metastases. We analyze a framework for evaluation assessment regarding trials of systemic agents being conducted in patients with, or at risk from, CNS metastases, and provide examples of NSCLC targeted therapies evaluated in the CNS., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Neuropathic pain is a common chronic condition, which remains poorly understood. Many patients receiving treatment continue to experience severe pain, due to limited diagnostic/treatment management programmes. The development of objective clinical diagnostic/treatment strategies requires identification of robust biomarkers of neuropathic pain. To this end, we looked to identify biomarkers of chronic neuropathic pain by assessing gene expression profiles in an animal model of neuropathic pain, and differential gene expression in patients to determine the potential translatability. We demonstrated cross-species validation of several genes including those identified through bioinformatic analysis by assessing their expression in blood samples from neuropathic pain patients, according to conservative assessments of significance measured using Bonferroni-corrected p-values. These include CASP5 (p = 0.00226), CASP8 (p = 0.00587), CASP9 (p = 2.09 × 10 -9 ), FPR2 (p = 0.00278), SH3BGRL3 (p = 0.00633), and TMEM88 (p = 0.00038). A ROC analysis revealed several combinations of genes to show high levels of discriminatory power in the comparison of neuropathic pain patients and control participants, of which the combination SH3BGRL3, TMEM88, and CASP9 achieved the highest level (AUROC = 0.923). The CASP9 gene was found to be common in five combinations of three genes revealing the highest levels of discriminatory power. In contrast, the gene combination PLAC8, ROMO1, and A3GALT2 showed the highest levels of discriminatory power in the comparison of neuropathic pain and nociceptive pain (AUROC = 0.919), when patients were grouped by S-LANSS scores. Molecules that demonstrate an active role in neuropathic pain have the potential to be developed into a biological measure for objective diagnostic tests, or as novel drug targets for improved pain management., (© 2022. The Author(s).)

While language is expressed in multiple modalities, including sign, writing, or whistles, speech is arguably the most common. The human vocal tract is capable of producing the bewildering diversity of the 7000 or so currently spoken languages, but relatively little is known about its genetic bases, especially in what concerns normal variation. Here, we capitalize on five cohorts totaling 632 Dutch twins with structural magnetic resonance imaging (MRI) data. Two raters placed clearly defined (semi)landmarks on each MRI scan, from which we derived 146 measures capturing the dimensions and shape of various vocal tract structures, but also aspects of the head and face. We used Genetic Covariance Structure Modeling to estimate the additive genetic, common environmental or non-additive genetic, and unique environmental components, while controlling for various confounds and for any systematic differences between the two raters. We found high heritability, h 2 , for aspects of the skull and face, the mandible, the anteroposterior (horizontal) dimension of the vocal tract, and the position of the hyoid bone. These findings extend the existing literature, and open new perspectives for understanding the complex interplay between genetics, environment, and culture that shape our vocal tracts, and which may help explain cross-linguistic differences in phonetics and phonology., (© 2022. The Author(s).)

Long-term inhibition of kappa opioid receptor (KOR) signaling in peripheral pain-sensing neurons is a potential obstacle for development of peripherally-restricted KOR agonists that produce analgesia. Such a long-term inhibitory mechanism is invoked from activation of c-Jun N-terminal kinase (JNK) that follows a single injection of the KOR antagonist norbinaltorphimine (norBNI). This effect requires protein synthesis of an unknown mediator in peripheral pain-sensing neurons. Using 2D difference gel electrophoresis with tandem mass spectrometry, we have identified that the scaffolding protein 14-3-3γ is upregulated in peripheral sensory neurons following activation of JNK with norBNI. Knockdown of 14-3-3γ by siRNA eliminates the long-term reduction in KOR-mediated cAMP signaling by norBNI in peripheral sensory neurons in culture. Similarly, knockdown of 14-3-3γ in the rat hind paw abolished the norBNI-mediated long-term reduction in peripheral KOR-mediated antinociception. Further, overexpression of 14-3-3γ in KOR expressing CHO cells prevented KOR-mediated inhibition of cAMP signaling. These long-term effects are selective for KOR as heterologous regulation of other receptor systems was not observed. These data suggest that 14-3-3γ is both necessary and sufficient for the long-term inhibition of KOR by norBNI in peripheral sensory neurons., Competing Interests: Conflicts of interest Authors report no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Pain and pain management in the elderly population is a significant social and medical problem. Pain sensation is a complex phenomenon that typically involves activation of peripheral pain-sensing neurons (nociceptors) which send signals to the spinal cord and brain that are interpreted as pain, an unpleasant sensory experience. In this work, young (4-5 months) and aged (26-27 months) Fischer 344 x Brown Norway (F344xBN) rats were examined for nociceptor sensitivity to activation by thermal (cold and heat) and mechanical stimulation following treatment with inflammatory mediators and activators of transient receptor potential (TRP) channels. Unlike other senses that decrease in sensitivity with age, sensitivity of hindpaw nociceptors to thermal and mechanical stimulation was not different between young and aged F344xBN rats. Intraplantar injection of bradykinin (BK) produced greater thermal and mechanical allodynia in aged versus young rats, whereas only mechanical allodynia was greater in aged rats following injection of prostaglandin E 2 (PGE 2 ). Intraplantar injection of TRP channel activators, capsaicin (TRPV1), mustard oil (TRPA1) and menthol (TRPM8) each resulted in greater mechanical allodynia in aged versus young rats and capsaicin-induced heat allodynia was also greater in aged rats. A treatment-induced allodynia that was greater in young rats was never observed. The anti-allodynic effects of intraplantar injection of kappa and delta opioid receptor agonists, salvinorin-A and D-Pen 2 ,D-Pen 5 ]enkephalin (DPDPE), respectively, were greater in aged than young rats, whereas mu opioid receptor agonists, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) and morphine, were not effective in aged rats. Consistent with these observations, in primary cultures of peripheral sensory neurons, inhibition of cAMP signaling in response to delta and kappa receptor agonists was greater in cultures derived from aged rats. By contrast, mu receptor agonists did not inhibit cAMP signaling in aged rats. Thus, age-related changes in nociceptors generally favor increased pain signaling in aged versus young rats, suggesting that changes in nociceptor sensitivity may play a role in the increased incidence of pain in the elderly population. These results also suggest that development of peripherally-restricted kappa or delta opioid receptor agonists may provide safer and effective pain relief for the elderly., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Opioid overdose is a leading cause of death in the United States. The only treatment available currently is the competitive antagonist, naloxone (Narcan ® ). Although naloxone is very effective and has saved many lives, as a competitive antagonist it has limitations. Due to the short half-life of naloxone, renarcotization can occur if the ingested opioid agonist remains in the body longer. Moreover, because antagonism by naloxone is surmountable, renarcotization can also occur in the presence of naloxone if a relatively larger dose of opioid agonist is taken. In such circumstances, a long-lasting, non-surmountable antagonist would offer an improvement in overdose treatment. Methocinnamox (MCAM) has been reported to have a long duration of antagonist action at mu opioid receptors in vivo. In HEK cells expressing the human mu opioid receptor, MCAM antagonism of mu agonist-inhibition of cAMP production was time-dependent, non-surmountable and non-reversible, consistent with (pseudo)-irreversible binding. In vivo, MCAM injected locally into the rat hindpaw antagonized mu agonist-mediated inhibition of thermal allodynia for up to 96 h. By contrast, antagonism by MCAM of delta or kappa agonists in HEK cells and in vivo was consistent with simple competitive antagonism. Surprisingly, MCAM also shifted the concentration-response curves of mu agonists in HEK cells in the absence of receptor reserve in a ligand-dependent manner. The shift in the [D-Ala 2 ,N-MePhe 4 ,Gly-ol 5 ]-enkephalin (DAMGO) concentration-response curve by MCAM was insensitive to naloxone, suggesting that in addition to (pseudo)-irreversible orthosteric antagonism, MCAM acts allosterically to alter the affinity and/or intrinsic efficacy of mu agonists., (© 2021 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Receptor heteromers often display distinct pharmacological and functional properties compared to the individual receptor constituents. In this study, we compared the properties of the DOP-KOP heteromer agonist, 6'-guanidinonaltrindole (6'-GNTI), with agonists for DOP ([D-Pen2,5]-enkephalin [DPDPE]) and KOP (U50488) in peripheral sensory neurons in culture and in vivo. In primary cultures, all three agonists inhibited PGE 2 -stimulated cAMP accumulation as well as activated extracellular signal-regulated kinase 1/2 (ERK) with similar efficacy. ERK activation by U50488 was Gi-protein mediated but that by DPDPE or 6'-GNTI was Gi-protein independent (i.e., pertussis toxin insensitive). Brief pretreatment with DPDPE or U50488 resulted in loss of cAMP signaling, however, no desensitization occurred with 6'-GNTI pretreatment. In vivo, following intraplantar injection, all three agonists reduced thermal nociception. The dose-response curves for DPDPE and 6'-GNTI were monotonic whereas the curve for U50488 was an inverted U-shape. Inhibition of ERK blocked the downward phase and shifted the curve for U50488 to the right. Following intraplantar injection of carrageenan, antinociceptive responses to either DPDPE or U50488 were transient but could be prolonged with inhibitors of 12/15-lipoxgenases (LOX). By contrast, responsiveness to 6'-GNTI remained for a prolonged time in the absence of LOX inhibitors. Further, pretreatment with the 12/15-LOX metabolites, 12- and 15- hydroxyeicosatetraenoic acid, abolished responses to U50488 and DPDPE but had no effect on 6'-GNTI-mediated responses either in cultures or in vivo. Overall, these results suggest that DOP-KOP heteromers exhibit unique signaling and functional regulation in peripheral sensory neurons and may be a promising therapeutic target for the treatment of pain., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Chronic neuropathic pain (CNP) is one of the most significant unmet clinical needs in modern medicine. Alongside the lack of effective treatments, there is a great deficit in the availability of objective diagnostic methods to reliably facilitate an accurate diagnosis. We therefore aimed to determine the feasibility of a simple diagnostic test by analysing differentially expressed genes in the blood of patients diagnosed with CNP of the lower back and compared to healthy human controls. Refinement of microarray expression data was performed using correlation analysis with 3900 human 2-colour microarray experiments. Selected genes were analysed in the dorsal horn of Sprague-Dawley rats after L5 spinal nerve ligation (SNL), using qRT-PCR and ddPCR, to determine possible associations with pathophysiological mechanisms underpinning CNP and whether they represent translational biomarkers of CNP. We found that of the 15 potential biomarkers identified, tissue inhibitor of matrix metalloproteinase-1 (TIMP1) gene expression was upregulated in chronic neuropathic lower back pain (CNBP) (p = 0.0049) which positively correlated (R = 0.68, p = ≤0.05) with increased plasma TIMP1 levels in this group (p = 0.0433). Moreover, plasma TIMP1 was also significantly upregulated in CNBP than chronic inflammatory lower back pain (p = 0.0272). In the SNL model, upregulation of the Timp1 gene was also observed (p = 0.0058) alongside a strong trend for the upregulation of melanocortin 1 receptor (p = 0.0847). Our data therefore highlights several genes that warrant further investigation, and of these, TIMP1 shows the greatest potential as an accessible and translational CNP biomarker.

Aims: The aim of this systematic literature review was to assess the consequences of dual antiplatelet therapy discontinuation on clinical outcomes after acute coronary syndromes., Methods and Results: A systematic literature search was conducted in PubMed to identify studies reporting data on patients who discontinued dual antiplatelet therapy (planned or unplanned) following acute coronary syndromes and on the clinical impact of dual antiplatelet therapy discontinuation. To be included, more than 50% of the study population had to have had acute coronary syndrome as their index event or, if less than 50%, outcomes data must have been reported separately for the group with acute coronary syndromes. Thirty publications covering 29 studies were identified for inclusion. There was much heterogeneity across studies regarding the included patient populations, treatment durations and outcome definitions and ascertainments. Dual antiplatelet therapy discontinuation was most commonly based on physician decision. Twenty-six studies reported that clopidogrel was prescribed as part of dual antiplatelet therapy. Dual antiplatelet therapy duration was positively associated with a lower risk of all-cause mortality (seven/eight studies), cardiovascular mortality (two/two studies), non-fatal myocardial infarction (two/three studies) and stent thrombosis (five/five studies) in patients and/or patient subgroups in studies without randomised treatment designs, although such associations were not observed in the one study that randomly assigned patients to treatment (i.e. planned discontinuation)., Conclusions: Results from our systematic literature review generally support the benefit of longer-term dual antiplatelet therapy after acute coronary syndromes; however, further research is needed to determine the optimal length of dual antiplatelet therapy in patients after acute coronary syndrome, ideally using prospective studies.

Aims: To assess the international validity of using hospital record data to compare long-term outcomes in heart attack survivors., Methods and Results: We used samples of national, ongoing, unselected record sources to assess three outcomes: cause death; a composite of myocardial infarction (MI), stroke, and all-cause death; and hospitalized bleeding. Patients aged 65 years and older entered the study 1 year following the most recent discharge for acute MI in 2002-11 [n = 54 841 (Sweden), 53 909 (USA), 4653 (England), and 961 (France)]. Across each of the four countries, we found consistent associations with 12 baseline prognostic factors and each of the three outcomes. In each country, we observed high 3-year crude cumulative risks of all-cause death (from 19.6% [England] to 30.2% [USA]); the composite of MI, stroke, or death [from 26.0% (France) to 36.2% (USA)]; and hospitalized bleeding [from 3.1% (France) to 5.3% (USA)]. After adjustments for baseline risk factors, risks were similar across all countries [relative risks (RRs) compared with Sweden not statistically significant], but higher in the USA for all-cause death [RR USA vs. Sweden, 1.14 (95% confidence interval 1.04-1.26)] and hospitalized bleeding [RR USA vs. Sweden, 1.54 (1.21-1.96)]., Conclusion: The validity of using hospital record data is supported by the consistency of estimates across four countries of a high adjusted risk of death, further MI, and stroke in the chronic phase after MI. The possibility that adjusted risks of mortality and bleeding are higher in the USA warrants further study.

Repeated exposure to a homotypic stressor such as forced swimming enhances nociceptive responding in rats. However, the influence of genetic background on this stress-induced hyperalgesia is poorly understood. The aim of the present study was to compare the effects of repeated forced swim stress on nociceptive responding in Sprague-Dawley (SD) rats versus the Wistar Kyoto (WKY) rat strain, a genetic background that is susceptible to stress, negative affect and hyperalgesia. Given the well-documented role of the endocannabinoid system in stress and pain, we investigated associated alterations in endocannabinoid signalling in the dorsal horn of the spinal cord and amygdala. In SD rats, repeated forced swim stress for 10 days was associated with enhanced late phase formalin-evoked nociceptive behaviour, compared with naive, non-stressed SD controls. In contrast, WKY rats exposed to 10 days of swim stress displayed reduced late phase formalin-evoked nociceptive behaviour. Swim stress increased levels of monoacylglycerol lipase (MAGL) mRNA in the ipsilateral side of the dorsal spinal cord of SD rats, an effect not observed in WKY rats. In the amygdala, swim stress reduced anandamide (AEA) levels in the contralateral amygdala of SD rats, but not WKY rats. Additional within-strain differences in levels of CB1 receptor and fatty acid amide hydrolase (FAAH) mRNA and levels of 2-arachidonylglycerol (2-AG) were observed between the ipsilateral and contralateral sides of the dorsal horn and/or amygdala. These data indicate that the effects of repeated stress on inflammatory pain-related behaviour are different in two rat strains that differ with respect to stress responsivity and affective state and implicate the endocannabinoid system in the spinal cord and amygdala in these differences., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The importance of the modulation of pain by emotion is now widely recognised. In particular, stress and anxiety, depending on their nature, duration and intensity, can exert potent, but complex, modulatory influences typified by either a reduction or exacerbation of the pain state. Exposure to either acute or chronic stress can increase pain responding under experimental conditions and exacerbate clinical pain disorders. There is evidence that exposure to chronic or repeated stress can produce maladaptive neurobiological changes in pathways associated with pain processing, resulting in stress-induced hyperalgesia (SIH). Preclinical studies of SIH are essential for our understanding of the mechanisms underpinning stress-related pain syndromes and for the identification of neural pathways and substrates, and the development of novel therapeutic agents for their clinical management. In this review, we describe clinical and pre-clinical models used to study SIH and discuss the neural substrates, neurotransmitters and neuromodulatory systems involved in this phenomenon., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Primary analysis of case-control studies focuses on the relationship between disease ( D ) and a set of covariates of interest ( Y, X ). A secondary application of the case-control study, often invoked in modern genetic epidemiologic association studies, is to investigate the interrelationship between the covariates themselves. The task is complicated due to the case-control sampling, and to avoid the biased sampling that arises from the design, it is typical to use the control data only. In this paper, we develop penalized regression spline methodology that uses all the data, and improves precision of estimation compared to using only the controls. A simulation study and an empirical example are used to illustrate the methodology.

: We propose methods to integrate data across several genomic platforms using a hierarchical Bayesian analysis framework that incorporates the biological relationships among the platforms to identify genes whose expression is related to clinical outcomes in cancer. This integrated approach combines information across all platforms, leading to increased statistical power in finding these predictive genes, and further provides mechanistic information about the manner in which the gene affects the outcome. We demonstrate the advantages of the shrinkage estimation used by this approach through a simulation, and finally, we apply our method to a Glioblastoma Multiforme dataset and identify several genes potentially associated with the patients' survival. We find 12 positive prognostic markers associated with nine genes and 13 negative prognostic markers associated with nine genes.

Competition between scavengers and microorganisms for the nutrients within carrion is well documented. As a significant contributor to food web energetics, carrion serves not only as a food source for scavengers, but also as a reproductive resource for many insects. One example are the burying beetles of the Nicrophorus genus (Coleoptera: Silphidae) whose reproduction is dependent on locating and successfully sequestering vertebrate carrion. Throughout the cooperative preparation of carrion and feeding of the larval offspring, parental beetles coat the carrion with oral and anal secretions known to attenuate the growth of molds and bacteria in the laboratory. We test the hypotheses that Nicrophorus secretions attenuate the growth of naturally occurring microorganisms likely to be found colonizing the carrion resource, and that the active antimicrobial components of the secretions are small antimicrobial peptides (AMPs) similar to those produced by other insects.

Viewing hedonically negative paintings increased the hedonic ratings of subsequently viewed test paintings (positive hedonic contrast; Experiment 1) and also increased the degree of preference between the test paintings (Experiments 2 and 3). This result differs from the reduction in hedonic preference (hedonic condensation) that accompanies negative hedonic contrast. It also differs from the reduction in perceived differences that usually accompanies expansion of stimulus range and that is predicted by numerous theories.