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Association between the serotonin transporter gene and alcohol consumption in social drinkers
Relatively few studies have investigated the role of the 5HTT gene in intermediate phenotypes such as alcohol consumption in non-alcohol dependent populations. A recent study reported an association with alcohol consumption in a student population. We attempted to replicate these findings and extend on this work in a representative, ethnically homogenous, non-alcohol dependent sample of social drinkers in the United Kingdom. The short allele of the 5HTT gene was significantly associated with, increased alcohol consumption (P = 0.03). There was suggestive evidence of a genotype-sex interaction (P = 0.04). Post-hoc tests indicated higher alcohol consumption in men with one or more copies of the short allele, while in women consumption was highest among heterozygotes compared to both homozygote groups. Age at time of data collection and cigarette consumption were entered as covariates. These results replicate recent previous findings and suggest a possibility that this association may differ in men and women. © 2005 Wiley-Liss, Inc.
Zyban for smoking cessation in a general practice setting: the response to an invitation to make a quit attempt.
The objective of this study was to assess the feasibility and success of Zyban as part of a moderately supported smoking cessation programme within UK general practice. Treatment was offered to 479 moderately dependent smokers (smoking 15 or more cigarettes per day) who had never used Zyban, and who had taken part in a previous NRT trial (the PATCH study). Main outcome measures were point prevalence and continuous abstinence from smoking at 6 and at 12 months. Two hundred and forty were excluded because of medical reasons or prescribing contraindication. Of the remainder (n=239) only 54 (23%) made an active quit attempt. Thirty percent (16/54) were abstinent at six months, and 22% (12/54) at 12 months (biochemically validated point prevalence rates). Age, socio-economic status, nicotine dependence, and genetic profile appeared to have little impact on success rates, but male quit-attempters were significantly more successful than female (40% vs. 10% at 12 months, p<0.05). In conclusion, a real-world smoking cessation programme using Zyban with moderate support within a general practice setting may achieve satisfactory quit rates without widening existing disparities in cessation.
The dopamine D2 receptor C32806T polymorphism (DRD2 Taq1A RFLP) exhibits no association with smoking behaviour in a healthy UK population.
A single nucleotide polymorphism (SNP) in the Taq1A site near the DRD2 gene has been associated in several studies with smoking behaviour. We genotyped 732 current smokers (241 low, one to nine cigarettes a day, 250 mid, 10-19 cigarettes, 241 high, 20+cigarettes) and 243 never-smokers at this site (C32806T), to test for effects on smoking initiation and amount of tobacco consumed. No significant association between minor allele frequency and smoking status was detected. Multiple regression analysis including DRD2 genotype, sex, age and alcohol consumption as predictors showed that level of cigarette consumption was associated with sex (p=0.003) and age (p=0.002) but not with alcohol consumption (p=0.25) or DRD2 genotype (p=0.76).
Pharmacogenomics of Tobacco Addiction
The precise mechanism of nicotine addiction and the influence of genetics on smoking behavior are beginning to be elucidated. A major challenge for the new science of pharmacogenomics is to utilize recent discoveries in genetics to improve existing smoking cessation therapies. Traditional candidate gene studies show that genetic polymorphisms affecting nicotine metabolism and dopaminergic transmission increase the susceptibility to tobacco dependence. Chromosomal regions in which other relevant genes may be located have recently been identified by genome scans. Combining these techniques may open the door to largescale rationally designed studies to identify new genes that are important in the development of nicotine dependence. Animal models have also been used to unravel genetic influences on the behavioral effects of nicotine and highlight in particular the important role that the acetylcholine receptor plays in nicotine action. This chapter reviews these various approaches to elucidating the genetic basis of nicotine dependence. We explore the potential benefits of classifying smokers according to the molecular etiology of their habit in order to plan individually targeted cessation strategies.
Synthesis, biological evaluation and mechanism study based on network pharmacology of amino acids esters of 20(S)-protopanaxadiol as novel anticancer agents.
As one of the metabolites of ginseng, 20(S)-protopanaxadiol (PPD) is a compound with dammarane-type tetracyclic triterpene, which performs a wide range of anticancer activities. In this study, PPD was used as a lead. A series of compounds were synthesized respectively with 11 amino acids through esterification and were evaluated for their cytotoxicity against several cancer cell lines. One of the synthetic products (PL) exhibited potent inhibitory effect on Huh-7 cells relative to that of PPD in vitro. Subsequently, the Annexin V-FITC /PI staining assay was used to verify that PL induced apoptosis of Huh-7 cells in a dose-dependent manner. A UPLC-Q/TOF-MS analysis method was established and validated for assessing pharmacokinetic properties after the administration of PPD and PL in rats. The results showed that compared with PPD, T1/2of PL in rats was prolonged, and the peak time was delayed, resulting in broader tissue distribution of the compound in the body. In addition, the targets of PL against several cancers were predicted and analyzed via network pharmacology. Molecular docking simulations demonstrated that PL interacted with the active sites of the above targets. In conclusion, this study provided a theoretical basis for the development and clinical application of anti-tumor activity of PPD.
Aberrant P53 expression lacks prognostic or predictive significance in colorectal cancer: results from the VICTOR trial.
AIM: Biomarkers with prognostic and predictive value can help stratify patients with colorectal cancer (CRC) into appropriate treatment groups. We sought to evaluate the clinical utility of P53 protein expression as a biomarker in VICTOR, a large phase III trial of rofecoxib in stage II and III CRC. PATIENTS AND METHODS: Tissue micro arrays were constructed from 884 tumors and the expression of P53 was examined by immunohistochemistry. Tumors were dichotomised as either P53-positive (nuclear expression in >10% of cells or the 'absent' pattern, both representing TP53 mutation) or P53-negative (nuclear expression in <10% of cells). RESULTS: Aberrant P53 expression was found in 65% (482/740) of patients. It was associated with distal location (p<0.001) and stage III disease (p<0.001). No effect was observed on disease-free or overall survival, and there was no interaction with chemotherapy or radiotherapy. CONCLUSION: Analysis of P53 expression in the patients recruited to the VICTOR trial confirmed that P53 expression is associated with site and stage of CRC. However, independently, this biomarker has neither prognostic nor predictive utility in this cohort of patients.
PTEN loss in the continuum of common cancers, rare syndromes and mouse models.
PTEN is among the most frequently inactivated tumour suppressor genes in sporadic cancer. PTEN has dual protein and lipid phosphatase activity, and its tumour suppressor activity is dependent on its lipid phosphatase activity, which negatively regulates the PI3K-AKT-mTOR pathway. Germline mutations in PTEN have been described in a variety of rare syndromes that are collectively known as the PTEN hamartoma tumour syndromes (PHTS). Cowden syndrome is the best-described syndrome within PHTS, with approximately 80% of patients having germline PTEN mutations. Patients with Cowden syndrome have an increased incidence of cancers of the breast, thyroid and endometrium, which correspond to sporadic tumour types that commonly exhibit somatic PTEN inactivation. Pten deletion in mice leads to Cowden syndrome-like phenotypes, and tissue-specific Pten deletion has provided clues to the role of PTEN mutation and loss in specific tumour types. Studying PTEN in the continuum of rare syndromes, common cancers and mouse models provides insight into the role of PTEN in tumorigenesis and will inform targeted drug development.
What is the role and impact of molecular markers on treatment decisions for colorectal cancer in the adjuvant setting?
The new mantra for delivering optimal cancer treatment is "personalized care." This extends beyond the holistic to using germline and somatic tumoral mutations to link a specific therapy to some prognostic or predictive factor which defines a particularly responsive patient subgroup who might benefit most from treatment. Furthermore, inherited polymorphisms have the potential to greatly modulate the side effects of treatment, especially for chemotherapy which has a notoriously narrow therapeutic window.
Smoking cessation, weight gain, and DRD4 −521 genotype
AbstractWe investigated change in body mass index following long‐term smoking cessation in a representative cohort of treatment‐seeking heavy smokers in the United Kingdom, to determine the extent of long‐term weight gain in successful quitters versus continuing smokers. We further investigated whether DRD4 genotype moderated any weight gain in either group. Smoking cessation was associated with an increase in BMI, and persisted up to 8 years after smoking cessation. Ex‐smokers at 8‐year follow‐up weighed over 2.5 kg/m3 more on average than they did at baseline, while participants who were smokers at both baseline and 8‐year follow‐up did not demonstrate any change in BMI. We did not observe an interaction between smoking status and DRD4 genotype. However, independently of the weight gain among those who stopped smoking during the course of the study, DRD4 genotype was significantly associated with BMI, with possession of the −521 C‐allele associated with increased BMI. The magnitude of increase in BMI following smoking cessation, and the persistence of this change at 8‐year follow‐up, suggests that health benefits associated with smoking cessation may to some extent be negated by the detrimental effects on health of associated weight gain. Smoking cessation programmes should therefore consider incorporating follow‐up support to promote weight loss among those who successfully stop smoking. © 2006 Wiley‐Liss, Inc.
Neurophysiological effects of high-frequency spinal cord stimulation on cortico-sensory areas in large ovine animal model.
Spinal Cord Stimulation (SCS) has been a cornerstone in managing chronic pain since the late 1960s. However, traditional SCS is often associated with variable efficacy and side effects, driving the development of advanced techniques like high-frequency SCS (hSCS). Previous studies have demonstrated that the power of high-frequency cerebral oscillations increases as a function of stimulus intensity and plays a critical role in local neural processing of peripheral sensory stimuli. Extending from the current body of literature, we hypothesized that hSCS could selectively influence stimulus-triggered neural oscillations involved in sensory processing and perception. Using electrocorticography (ECoG) in sheep (n = 4), we investigated the effects of 8.2 KHz hSCS on low-frequency (4-30 Hz) and high-frequency (70-150 Hz) oscillations in ovine somatosensory and association cortices. Neural signals were recorded before, and after hSCS application to assess frequency-specific modulation of cortical activity. Our findings reveal that hSCS induces broad suppression of high-frequency oscillations across both cortical regions. In contrast, low-frequency oscillations were selectively suppressed or enhanced in both cortices. Furthermore, a linear mixed model analysis revealed that low-frequency oscillations better predict high-frequency modulation in the association than the somatosensory cortex, highlighting a reciprocal low-/high-frequency relationship between cortices. These distinct effects on cortical oscillations suggest potential supraspinal mechanisms through which hSCS may exert its analgesic effects. Our findings provide new insights for optimizing neuromodulation strategies in pain management, emphasizing the role of frequency-specific modulation in sensory and cognitive pain processing. PERSPECTIVE: This study demonstrates that high-frequency spinal cord stimulation modulates cortical oscillations in a frequency- and region-specific manner, suggesting a supraspinal mechanism of pain. These findings advance our understanding of how neuromodulation influences sensory components of pain, with implications for optimizing stimulation protocols in chronic pain management.
Time to recovery following open and endoscopic carpal tunnel decompression: meta-analysis.
BACKGROUND: Carpal tunnel release (CTR) can be performed using either an open or endoscopic approach. The patient recovery trajectories remain poorly understood. This study aimed to define and compare patient-reported recovery following unilateral open and endoscopic CTR. METHODS: A PRISMA-compliant, preregistered (CRD42023427718) systematic review was conducted, searching PubMed, Embase, and Cochrane databases on 4 July 2023 and 21 August 2024. Studies were included if they reported recovery data (patient-reported outcome measures (PROMs)) at predefined time points for adults undergoing unilateral CTR. Boston Carpal Tunnel Questionnaire and Quick Disabilities of Arm, Shoulder, and Hand scores were extracted. Standardized mean change (SMC) scores from baseline were pooled using random-effects meta-analysis. An innovative modification of the National Institutes of Health quality assessment tools was used to evaluate the risk of bias. RESULTS: In all, 49 studies were included (4546 participants included in the analysis; 3137 open CTR, 1409 endoscopic CTR). Both approaches improved PROM scores over 12 weeks, with early (4-week) outcomes strongly correlating (>0.89) with later (12-week) outcomes. Symptoms continued improving up to 104 weeks. At 1 week, open CTR showed symptomatic deterioration (SMC 10.29; 95% confidence interval (c.i.) 6.35 and 14.21 respectively), comparatively, endoscopic CTR demonstrated an improvement (SMC -2.83; 95% c.i. -7.80 and 2.14 respectively). By 2 weeks, symptom severity remained slightly worse in open CTR, but confidence intervals overlapped from week 3 and thereafter open CTR showed greater symptomatic improvement. Most studies had a high risk of bias and measured outcomes too infrequently for a granular comparison. CONCLUSIONS: Patient-reported recovery trajectories for CTR can inform patient counselling and future research. Endoscopic CTR may result in fewer symptoms in the first 2 weeks, but open CTR may offer comparable or potentially greater improvement thereafter. Future trials with high-frequency PROM capture should prioritize early (first 3 weeks) and long-term (≥24 weeks) outcomes.
Therapeutic strategies targeting inflammation and immunity in atherosclerosis: how to proceed?
Atherosclerosis is a chronic inflammatory disease of the arterial wall, characterized by the formation of plaques containing lipid, connective tissue and immune cells in the intima of large and medium-sized arteries. Over the past three decades, a substantial reduction in cardiovascular mortality has been achieved largely through LDL-cholesterol-lowering regimes and therapies targeting other traditional risk factors for cardiovascular disease, such as hypertension, smoking, diabetes mellitus and obesity. However, the overall benefits of targeting these risk factors have stagnated, and a huge global burden of cardiovascular disease remains. The indispensable role of immunological components in the establishment and chronicity of atherosclerosis has come to the forefront as a clinical target, with proof-of-principle studies demonstrating the benefit and challenges of targeting inflammation and the immune system in cardiovascular disease. In this Review, we provide an overview of the role of the immune system in atherosclerosis by discussing findings from preclinical research and clinical trials. We also identify important challenges that need to be addressed to advance the field and for successful clinical translation, including patient selection, identification of responders and non-responders to immunotherapies, implementation of patient immunophenotyping and potential surrogate end points for vascular inflammation. Finally, we provide strategic guidance for the translation of novel targets of immunotherapy into improvements in patient outcomes.