Baseline heart rate variability predicts placebo hypoalgesia in men, but not women

IntroductionPlacebo hypoalgesic effects vary greatly across individuals, making them challenging to control for in clinical trials and difficult to use in treatment. We investigated the potential of resting vagally-mediated heart rate variability (vmHRV) to help predict the magnitude of placebo responsiveness.MethodsIn two independent studies (total N = 77), we administered a placebo paradigm after measuring baseline HRV. In Study I, we delivered heat pain to the forearm, on skin patches treated with “real” and “control” cream (identical inactive creams). In Study II, electrical pulses to the forearm were modulated by sham transcutaneous electrical nerve stimulation. We combined data from both studies to evaluate the relationship between vagally-mediated HRV (vmHRV) parameters and the placebo response size, while also assessing sex differences in this relationship.Results and DiscussionThis revealed a positive association between vmHRV and the degree of pain relief, and this effect was driven by men. These results not only reveal new insights into the (sex-specific) mechanisms of placebo hypoalgesia, but also suggest that measuring vmHRV may be helpful in predicting placebo responsiveness. Given that placebo hypoalgesic effects contribute substantially to treatment outcomes, such a non-invasive and easily obtained predictor would be valuable in the context of personalized medicine

Optimization of Invasion-Specific Effects of Betulin Derivatives on Prostate Cancer Cells through Lead Development

The anti-invasive and anti-proliferative effects of betulins and abietane derivatives was systematically tested using an organotypic model system of advanced, castration-resistant prostate cancers. A preliminary screen of the initial set of 93 compounds was performed in two-dimensional (2D) growth conditions using non-transformed prostate epithelial cells (EP156T), an androgen-sensitive prostate cancer cell line (LNCaP), and the castration-resistant, highly invasive cell line PC-3. The 25 most promising compounds were all betulin derivatives. These were selected for a focused secondary screen in three-dimensional (3D) growth conditions, with the goal to identify the most effective and specific anti-invasive compounds. Additional sensitivity and cytotoxicity tests were then performed using an extended cell line panel. The effects of these compounds on cell cycle progression, mitosis, proliferation and unspecific cytotoxicity, versus their ability to specifically interfere with cell motility and tumor cell invasion was addressed. To identify potential mechanisms of action and likely compound targets, multiplex profiling of compound effects on a panel of 43 human protein kinases was performed. These target de-convolution studies, combined with the phenotypic analyses of multicellular organoids in 3D models, revealed specific inhibition of AKT signaling linked to effects on the organization of the actin cytoskeleton as the most likely driver of altered cell morphology and motility.Peer reviewe

Distraction from Pain: An fMRI Study on the Role of Age-related Changes in Executive Functions

Even though aging is associated with increased and prolonged episodes of pain, little is known about potential age-related changes in the "top-down" modulation of pain, such as cognitive distraction from pain. The hypoalgesic effect of distraction results from a competition for attentional and executive resources mediated by the prefrontal cortex (PFC). Given that age-related grey matter atrophy is particularly prominent in the PFC, older adults may benefit less from distraction to reduce pain than young adults. The aim of this study was to investigate the influence of aging on task-related hypoalgesia and its neural mechanisms, with a focus on the role of executive functions in distraction from pain. 64 participants (32 young adults: 26.69 ± 4.14 years; 32 older adults: 68.28 ± 7.00 years) first completed a battery of neuropsychological tests. In a second session, we administered a pain distraction paradigm while functional brain images were acquired. In this paradigm, participants completed a low (0-back) and a high (2-back) load condition of a working memory task while receiving either innocuous or painful heat stimuli to their lower arm. To control for age-related differences in sensitivity to pain and perceived task difficulty, stimulus intensity and task speed were individually calibrated. Both age groups showed significantly reduced activity in a network of regions involved in pain processing when performing the high compared to the low load distraction task; however, young adults showed a larger neural distraction effect in several of these regions, including the insula, caudate and midcingulate cortex. Moreover, in older adults, better executive functions – in particular inhibitory control abilities – were associated with a larger neural distraction effect in the insula, thalamus and primary somatosensory cortex, and with more activation in several prefrontal cortex regions during the high load task. These findings clearly demonstrate that the top-down control of pain is altered by age and could explain the higher vulnerability of older adults to developing chronic pain. Moreover, our findings suggest that the assessment of executive functions may be a useful tool for predicting the efficacy of cognitive pain modulation strategies in older adults

Optimization of Invasion-Specific Effects of Betulin Derivatives on Prostate Cancer Cells through Lead Development

The anti-invasive and anti-proliferative effects of betulins and abietane derivatives was systematically tested using an organotypic model system of advanced, castration-resistant prostate cancers. A preliminary screen of the initial set of 93 compounds was performed in two-dimensional (2D) growth conditions using non-transformed prostate epithelial cells (EP156T), an androgen-sensitive prostate cancer cell line (LNCaP), and the castration-resistant, highly invasive cell line PC-3. The 25 most promising compounds were all betulin derivatives. These were selected for a focused secondary screen in three-dimensional (3D) growth conditions, with the goal to identify the most effective and specific anti-invasive compounds. Additional sensitivity and cytotoxicity tests were then performed using an extended cell line panel. The effects of these compounds on cell cycle progression, mitosis, proliferation and unspecific cytotoxicity, versus their ability to specifically interfere with cell motility and tumor cell invasion was addressed. To identify potential mechanisms of action and likely compound targets, multiplex profiling of compound effects on a panel of 43 human protein kinases was performed. These target de-convolution studies, combined with the phenotypic analyses of multicellular organoids in 3D models, revealed specific inhibition of AKT signaling linked to effects on the organization of the actin cytoskeleton as the most likely driver of altered cell morphology and motility.</p

Pyrosequencing of the Camptotheca acuminata transcriptome reveals putative genes involved in camptothecin biosynthesis and transport

Background: Camptotheca acuminata is a Nyssaceae plant, often called the "happy tree", which is indigenous in Southern China. C. acuminata produces the terpenoid indole alkaloid, camptothecin (CPT), which exhibits clinical effects in various cancer treatments. Despite its importance, little is known about the transcriptome of C. acuminata and the mechanism of CPT biosynthesis, as only few nucleotide sequences are included in the GenBank database.Results: From a constructed cDNA library of young C. acuminata leaves, a total of 30,358 unigenes, with an average length of 403 bp, were obtained after assembly of 74,858 high quality reads using GS De Novo assembler software. Through functional annotation, a total of 21,213 unigenes were annotated at least once against the NCBI nucleotide (Nt), non-redundant protein (Nr), Uniprot/SwissProt, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Arabidopsis thaliana proteome (TAIR) databases. Further analysis identified 521 ESTs representing 20 enzyme genes that are involved in the backbone of the CPT biosynthetic pathway in the library. Three putative genes in the upstream pathway, including genes for geraniol-10-hydroxylase (CaPG10H), secologanin synthase (CaPSCS), and strictosidine synthase (CaPSTR) were cloned and analyzed. The expression level of the three genes was also detected using qRT-PCR in C. acuminata. With respect to the branch pathway of CPT synthesis, six cytochrome P450s transcripts were selected as candidate transcripts by detection of transcript expression in different tissues using qRT-PCR. In addition, one glucosidase gene was identified that might participate in CPT biosynthesis. For CPT transport, three of 21 transcripts for multidrug resistance protein (MDR) transporters were also screened from the dataset by their annotation result and gene expression analysis.Conclusion: This study produced a large amount of transcriptome data from C. acuminata by 454 pyrosequencing. According to EST annotation, catalytic features prediction, and expression analysis, novel putative transcripts involved in CPT biosynthesis and transport were discovered in C. acuminata. This study will facilitate further identification of key enzymes and transporter genes in C. acuminata

Metabolic Profiles and cDNA-AFLP Analysis of Salvia miltiorrhiza and Salvia castanea Diel f. tomentosa Stib

Plants of the genus Salvia produce various types of phenolic compounds and tanshinones which are effective for treatment of coronary heart disease. Salvia miltiorrhiza and S. castanea Diels f. tomentosa Stib are two important members of the genus. In this study, metabolic profiles and cDNA-AFLP analysis of four samples were employed to identify novel genes potentially involved in phenolic compounds and tanshinones biosynthesis, including the red roots from the two species and two tanshinone-free roots from S. miltiorrhiza. The results showed that the red roots of S. castanea Diels f. tomentosa Stib produced high contents of rosmarinic acid (21.77 mg/g) and tanshinone IIA (12.60 mg/g), but low content of salvianolic acid B (1.45 mg/g). The red roots of S. miltiorrhiza produced high content of salvianolic acid B (18.69 mg/g), while tanshinones accumulation in this sample was much less than that in S. castanea Diels f. tomentosa Stib. Tanshinones were not detected in the two tanshinone-free samples, which produced high contents of phenolic compounds. A cDNA-AFLP analysis with 128 primer pairs revealed that 2300 transcript derived fragments (TDFs) were differentially expressed among the four samples. About 323 TDFs were sequenced, of which 78 TDFs were annotated with known functions through BLASTX searching the Genbank database and 14 annotated TDFs were assigned into secondary metabolic pathways through searching the KEGGPATHWAY database. The quantitative real-time PCR analysis indicated that the expression of 9 TDFs was positively correlated with accumulation of phenolic compounds and tanshinones. These TDFs additionally showed coordinated transcriptional response with 6 previously-identified genes involved in biosynthesis of tanshinones and phenolic compounds in S. miltiorrhiza hairy roots treated with yeast extract. The sequence data in the present work not only provided us candidate genes involved in phenolic compounds and tanshinones biosynthesis but also gave us further insight into secondary metabolism in Salvia

The c4h, tat, hppr and hppd Genes Prompted Engineering of Rosmarinic Acid Biosynthetic Pathway in Salvia miltiorrhiza Hairy Root Cultures

Rational engineering to produce biologically active plant compounds has been greatly impeded by our poor understanding of the regulatory and metabolic pathways underlying the biosynthesis of these compounds. Here we capitalized on our previously described gene-to-metabolite network in order to engineer rosmarinic acid (RA) biosynthesis pathway for the production of beneficial RA and lithospermic acid B (LAB) in Salvia miltiorrhiza hairy root cultures. Results showed their production was greatly elevated by (1) overexpression of single gene, including cinnamic acid 4-hydroxylase (c4h), tyrosine aminotransferase (tat), and 4-hydroxyphenylpyruvate reductase (hppr), (2) overexpression of both tat and hppr, and (3) suppression of 4-hydroxyphenylpyruvate dioxygenase (hppd). Co-expression of tat/hppr produced the most abundant RA (906 mg/liter) and LAB (992 mg/liter), which were 4.3 and 3.2-fold more than in their wild-type (wt) counterparts respectively. And the value of RA concentration was also higher than that reported before, that produced by means of nutrient medium optimization or elicitor treatment. It is the first report of boosting RA and LAB biosynthesis through genetic manipulation, providing an effective approach for their large-scale commercial production by using hairy root culture systems as bioreactors

Family physicians' perspectives on practice guidelines related to cancer control

BACKGROUND: Family physicians (FPs) play an important role in cancer control. While FPs' attitudes towards, and use of guidelines in general have been explored, no study has looked at the needs of FPs with respect to guidelines for the continuum of cancer control. The objective of this study was to understand which guideline topics FPs consider important. METHODS: Five group interviews were conducted by telephone with FPs from across Ontario, Canada. Transcripts were analyzed inductively. Content analysis identified emergent themes. Themes are illustrated by representative quotes taken from the transcripts. RESULTS: The main areas where FPs felt guidelines were needed most included screening – a traditional area of responsibility for FPs – and treatment and follow-up – areas where they felt they lacked the knowledge to best support patients. Confusion over best practice when faced with conflicting guidelines varied according to disease site. FPs defined good guideline formats; the most often cited forms of presentation were tear-off sheets to use interactively with patients, or a binder. Computer-based dissemination was acknowledged as the best way of widely distributing material that needs frequent updates. However, until computer use is a common aspect of practice, mail was considered the most viable method of dissemination. Guidelines designed for use by patients were supported by FPs. CONCLUSIONS: Preferred guideline topics, format, dissemination methods and role of patient guidelines identified by FPs in this study reflect the nature of their practice situations. Guideline developers and those supporting use of evidence-based guidelines (e.g., Canadian Strategy for Cancer Control) have a responsibility to ensure that FPs are provided with the resources they identify as important, and to provide them in a format that will best support their use

Metabolic alterations and distribution of five-carbon precursors in jasmonic acid-elicited Catharanthus roseus cell suspension cultures

Plant science