HOXA1 drives melanoma tumor growth and metastasis and elicits an invasion gene expression signature that prognosticates clinical outcome.

Melanoma is a highly lethal malignancy notorious for its aggressive clinical course and eventual resistance to existing therapies. Currently, we possess a limited understanding of the genetic events driving melanoma progression, and much effort is focused on identifying pro-metastatic aberrations or perturbed signaling networks that constitute new therapeutic targets. In this study, we validate and assess the mechanism by which homeobox transcription factor A1 (HOXA1), a pro-invasion oncogene previously identified in a metastasis screen by our group, contributes to melanoma progression. Transcriptome and pathway profiling analyses of cells expressing HOXA1 reveals upregulation of factors involved in diverse cytokine pathways that include the transforming growth factor beta (TGFß) signaling axis, which we further demonstrate to be required for HOXA1-mediated cell invasion in melanoma cells. Transcriptome profiling also shows HOXA1's ability to potently downregulate expression of microphthalmia-associated transcription factor (MITF) and other genes required for melanocyte differentiation, suggesting a mechanism by which HOXA1 expression de-differentiates cells into a pro-invasive cell state concomitant with TGFß activation. Our analysis of publicly available data sets indicate that the HOXA1-induced gene signature successfully categorizes melanoma specimens based on their metastatic potential and, importantly, is capable of stratifying melanoma patient risk for metastasis based on expression in primary tumors. Together, these validation data and mechanistic insights suggest that patients whose primary tumors express HOXA1 are among a high-risk metastasis subgroup that should be considered for anti-TGFß therapy in adjuvant settings. Moreover, further analysis of HOXA1 target genes in melanoma may reveal new pathways or targets amenable to therapeutic intervention.

Smoking impedes executive function and related prospective memory.

OBJECTIVE: This study assessed both executive function (EF) and prospective memory (PM) in a group of current smokers (CS) to observe whether deficits in both sets of memory processes co-existed in smokers, comparing this group with a group who had never smoked (NS). METHOD: An existing-groups design was used to compare smokers with the NS group on a Reserve Digit Span Task (RDST) that measured EF and the Cambridge Prospective Memory Test (CAMPROMPT) measuring PM. Age, mood, other drug use and IQ were also measured and controlled for in the study. RESULTS: After omitting anyone using an illegal substance and observing no between-group differences in age, gender, anxiety, depression, alcohol use and IQ, the CS group performed significantly worse on the RDST and recalled significantly fewer time-based and event-based tasks on CAMPROMPT, compared with the NS group. CONCLUSIONS: Both EF and PM deficits were evident in the same cohort of CS when compared with a NS group, a finding which is novel in the current literature. Since both EF and PM are interrelated in that they share common resources in the brain, the finding that both sets of deficits co-existed in smokers suggests that persistent cigarette smoking impedes these underlying resources.

Smoking-related prospective memory deficits observed on naturalistic everyday memory task.

OBJECTIVE: This study assessed self-reported and objective prospective memory (PM) processes in smokers and a never-smoked comparison group. If persistent smoking does impair PM, then one would expect smokers recall being lower on a study that requires them to remember everyday activities when compared with a never-smoked group. METHOD: An existing-groups design was used to compare a group of smokers with a never-smoked group on the self-report Prospective Memory Questionnaire (PMQ) and the Prospective Remembering Video Procedure (PRVP) measuring objective PM. An example of the location-action combination from the PRVP is 'At Thornton's shop' (location), 'Buy a bag of sweets' (action). Participants who reported using an illegal substance (e.g. ecstasy, cannabis), who drank excessively or were 'binge drinkers', or who reported suffering from a clinical condition, such as depression, were excluded from the study. Age, weekly 'safe levels' alcohol use, and strategy use were also measured and controlled for in the study. Each person was tested individually in a quiet laboratory setting on a university campus. RESULTS: After controlling for variations in age, weekly alcohol use, and strategy use, smokers recalled significantly fewer location-action combinations on the PRVP when compared with a never-smoked group, with no between-group differences on self-reported PM as measured by the PMQ. CONCLUSIONS: The findings suggest objective PM deficits are associated with persistent smoking - a relatively unexplored area of research. This cannot be attributed to other drug use, mood, or strategy use. The findings also suggest smokers lack self-awareness of such PM deficits. This study extends the area by utilising a more naturalistic object measure of PM and incorporating strict controls into the study.

Smoking-related prospective memory deficits in a real-world task.

BACKGROUND: Smokers, previous smokers and a never smoked group were compared on self-reported and real world prospective memory (PM - the cognitive ability of remembering to carry out particular actions at some future point in time). METHODS: Twenty-seven current smokers, 24 people who had never smoked and 18 previous smokers were compared using an existing groups design. Scores on the long and short term PM subscales of the Prospective and Retrospective Memory Questionnaire (PRMQ) and scores on a Real World Prospective Memory Task (RWPMT) constituted the dependent measures. Smoking and other drug use were assessed by a Recreational Drug Use Questionnaire. The Hospital Anxiety and Depression Scale gauged levels of anxiety and depression. The National Adult Reading Test measured IQ, and retrospective memory was measured using the PRMQ. Gender, age, anxiety and depression, IQ, alcohol use and the retrospective memory scores, were measured as covariates and controlled for in the analysis. RESULTS: A series of univariate ANCOVAs were applied to the main PM data across the three groups, controlling for variations in age, gender, mood, IQ, alcohol use and retrospective memory scores. These revealed no significant between-group differences on self-reported PM; however smokers recalled significantly fewer action-location combinations than the never smoked and previous smoker groups on the objective RWPMT. CONCLUSIONS: Existing smokers showed reduced performance on RWPMT when compared to the never smoked group and previous smokers. Real-world PM impairments should be added to a growing list of neuropsychological sequelae associated with persistent smoking.

Hair MDMA samples are consistent with reported ecstasy use: findings from a study investigating effects of ecstasy on mood and memory.

AIMS: Our group has conducted several Internet investigations into the biobehavioural effects of self-reported recreational use of MDMA (3,4-methylenedioxymethamphetamine or Ecstasy) and other psychosocial drugs. Here we report a new study examining the relationship between self-reported Ecstasy use and traces of MDMA found in hair samples. METHODS: In a laboratory setting, 49 undergraduate volunteers performed an Internet-based assessment which included mood scales and the University of East London Drug Use Questionnaire, which asks for history and current drug use. They also provided a hair sample for determination of exposure to MDMA over the previous month. RESULTS: Self-report of Ecstasy use and presence in hair samples were consistent (p < 0.00001). Both subjective and objective measures predicted lower self-reported ratings of happiness and higher self-reported stress. Self-reported Ecstasy use, but not presence in hair, was also associated with decreased tension. CONCLUSION: Different psychoactive drugs can influence long-term mood and cognition in complex and dynamically interactive ways. Here we have shown a good correspondence between self-report and objective assessment of exposure to MDMA. These data suggest that the Internet has potentially high utility as a useful medium to complement traditional laboratory studies into the sequelae of recreational drug use.

Does binge drinking in teenagers affect their everyday prospective memory?

AIMS: To examine whether teenage binge drinking has an adverse effect upon everyday prospective memory (PM). DESIGN: The study utilised an existing-groups design, with alcohol group: binge drinkers vs non-binge drinkers as the independent factor, and scores on the two PM memory subscales of the Prospective and Retrospective Memory Questionnaire (PRMQ) and the score on the Prospective Remembering Video Procedure (PRVP) as the dependent factors. Age, anxiety and depression scores, last alcohol use (in hours) and how many years spent drinking, were measured and analysed between the groups. SETTING: Each participant was tested in a laboratory setting. PARTICIPANTS: An opportunity sample of 21 'binge drinkers' (those drinking above 6 units for females and 8 units for males on 2 or more occasions per week) and 29 non-bingers were compared. MEASUREMENTS: Self-reported everyday PM lapses were measured using the PRMQ. The PRVP was used as an objective measure of PM. Alcohol and other drug use were assessed by the University of East London Recreational Drug Use Questionnaire. The Hospital Anxiety and Depression Scale gauged self-reported levels of anxiety and depression. FINDINGS: After controlling for age, anxiety and depression scores, last alcohol use and how many years spent drinking, there were no significant between-group differences on either the self-reported long-term or short-term PM lapses. However, binge drinkers recalled significantly fewer location-action combinations on the PRVP than non-binge drinkers. CONCLUSIONS: The results of the present study suggest that binge drinking in the teenage years leads to impairments in everyday PM.

Dancing hot on Ecstasy: physical activity and thermal comfort ratings are associated with the memory and other psychobiological problems reported by recreational MDMA users.

BACKGROUND: Non-drug factors such as ambient temperature can heighten the adverse effects of MDMA (3,4-methylendioxymethamphetamine) in animals. We assessed whether dancing and feeling hot on Ecstasy would be associated with more psychobiological problems in recreational users. METHODS: In an internet study, 206 unpaid participants (modal age 16-24) reported that they had used recreational Ecstasy/MDMA. They completed a drug use questionnaire, the Prospective Memory Questionnaire (PMQ), questions about dancing and feeling hot when on Ecstasy, and psychobiological problems afterwards. RESULTS: Those who danced 'all the time' when on Ecstasy, reported significantly more PMQ memory problems than the less intensive dancers. Prolonged dancing was also associated with more complaints of depression, memory problems, concentration and organizational difficulties afterwards. Feeling hot when on Ecstasy was associated with poor concentration in the comedown period, and with mood fluctuation and impulsivity off-drug. PMQ long-term problems demonstrated a significant curvilinear relationship with thermal self-ratings; more memory problems were noted by those who felt very hot, and by those who did not feel hot when on Ecstasy. CONCLUSIONS: Non-drug factors such as dancing and feeling hot are associated with the incidence of psychobiological problems reported by recreational Ecstasy/MDMA users.

Self-rated everyday and prospective memory abilities of cigarette smokers and non-smokers: a web-based study.

The present study examined self-ratings of two aspects of everyday memory performance: long-term prospective memory-measured by the prospective memory questionnaire (PMQ), and everyday memory-measured by the everyday memory questionnaire (EMQ). Use of other substances was also measured and used as covariates in the study. To ensure confidentiality and to expand the numbers used in previous studies, an Internet study was carried out and data from 763 participants was gathered. After controlling for other drug use and strategy use, the data from the PMQ revealed that smokers reported a greater number of long-term prospective memory errors than non-smokers. There were also differences between light and heavier smokers in long-term prospective memory, suggesting that nicotine may have a dose-dependent impact upon long-term prospective memory performance. There was also a significant ANOVA group effect on the EMQ, although the trend for more memory errors amongst the heavier smokers was statistically only borderline (p=.057). These findings suggest there are selective memory deficits associated with smoking and that long-term prospective memory deficits should be added to the growing list of problems associated with cigarette use.

Effects of alcohol on subjective ratings of prospective and everyday memory deficits.

BACKGROUND: Research has shown that heavy alcohol use has a detrimental effect on retrospective memory. Less is known about the effect of alcohol on everyday memory. METHODS: This study examined self-ratings of two aspects of memory performance: prospective memory (for example, forgetting to pass on a message) and everyday memory (measured by cognitive failures, such as telling someone a joke that you have told them before). To ensure anonymity and expand on the numbers of participants used in previous studies, data were collected by using the Internet. Data from 763 participants remained after data screening. RESULTS: After controlling for other drug and strategy use, there was clear evidence that differential use of alcohol was associated with impairments in the long-term aspect of prospective memory and with an increased number of cognitive failures. CONCLUSIONS: These results support and extend the findings of previous research: our findings are consistent with the idea that heavy use of alcohol does have a significant and negative effect on everyday cognitive performance. Possible causes of these impairments are discussed.

Patterns of drug use and the influence of gender on self-reports of memory ability in ecstasy users: a web-based study.

Research indicates that the use of recreational drugs, including MDMA ('ecstasy') can result in impairments in cognitive functioning. Recent evidence, based on accounts of 'on drug' effects and cortical binding ratios suggests that women may be more susceptible to the effects of MDMA; however, no research has explored whether there are differences in the long-term behavioural sequelae of the drug between men and women. In addition, little is known about the profile of functioning of the 'typical' user. The present investigation accessed a large sample of recreational drug users, using the Internet, to obtain self-reports of memory functioning with a view to exploring any differences in self-reported ability amongst male and female users, and the level of difficulty reported by the 'typical' ecstasy user. A web site (www.drugresearch.org.uk) was developed and used for data collection. Prospective memory ability was assessed using the Prospective Memory Questionnaire. Self-report of day-to-day memory performance was investigated using the Everyday Memory Questionnaire. The UEL Drug Questionnaire assessed the use of other substances. The number of mistakes made while completing the questionnaires was also taken as an objective measure of performance errors. Findings, based on datasets submitted from 763 respondents, indicate no differences in self-reports of functioning between male and female participants. An overall dissociation between the effects of cannabis and ecstasy on self-reported memory functioning and on the likelihood of making an error during the completion of the questionnaire was found. Typical ecstasy users were found to report significantly more difficulties in long-term prospective memory and to make more completion errors than users of other substances and drug naive controls. Whilst taking into account the fact that participants were recruited via the World Wide Web and that a number of stringent exclusion criteria were applied to the data, a number of conclusions can be drawn. Recreational drug users perceive their memory ability to be impaired compared to non-users. The type of memory difficulties reported varies depending upon the drug of choice. These difficulties are exacerbated in ecstasy users. Individuals reporting average levels of use of ecstasy are more likely to report memory problems than non-ecstasy drug users or drug free individuals. The deleterious effects of ecstasy are therefore not restricted to heavy or chronic users. No gender differences were detected, suggesting that there may be a dissociation between cognitive impairment and cortical binding worthy of further exploration.

Ecstasy/MDMA attributed problems reported by novice, moderate and heavy recreational users.

RATIONALE: The recreational use of MDMA/Ecstasy (3,4-methylenedioxymethamphetamine) is associated with many psychobiological problems, but there is a paucity of data on how these relate to the level of past use. OBJECTIVES: to assess the incidence of Ecstasy-attributed problems as reported by novice, moderate and heavy users. METHODS: 763 unpaid volunteers took part in a WWW study of recreational drug use. This report is based on the 282 Ecstasy users from that sample, who comprised 109 novice users (1-9 occasions), 136 moderate users (10-99 occasions), and 36 heavy users (+100 occasions). Yes/no responses were automatically recorded to a series of questions covering psychobiological problems experienced when drug-free, which were attributed by the respondents to their Ecstasy use. RESULTS: Depression, memory problems, anxiety, mood fluctuation, poor concentration, infections, tremors/twitches and weight loss, were all significantly associated with the extent of Ecstasy use. Thus memory problems attributed to Ecstasy were reported by 19% of novice users, 52% of heavy users and 73% of heavy users (chi-square 42.74, df=2, p<0.001); many of the other variables showed similar trends. CONCLUSIONS: The incidence of problems attributed to Ecstasy use, is directly related to the number of occasions it has been used.

Radical vaginal hysterectomy: classic and modified.

RVH offers significant advantages to the corresponding abdominal procedure, including: the possibility for regional anesthesia, particularly in patients with poor medical conditions; reduced surgical trauma because of the absence of an abdominal incision; applicability in obese patients; shorter surgical time when performed by an experienced surgeon; decreased need for blood transfusions; lower risk for complications; faster postoperative recovery period; shorter hospitalization. The primary drawback to the use of RVH for early stage cervical cancer has always been the lack of lymph node dissection. This has now been modified by the widespread use of laparoscopic lymphadenectomy. The increasing reliability of noninvasive radiologic techniques has provided and will continue to provide greater possibilities for preoperative staging to best determine the needs of the patient. The authors believe that an oncologic surgeon familiar with advanced laparoscopic techniques and RVH is able to take advantage of the benefits of both routes. Furthermore, a surgeon skilled in these techniques and RAH has the tools to ideally care for the specific needs, of each patient. The authors encourage individualization of surgical management, with special emphasis on the revision of the role of RVH in gynecologic oncology.

The impact of Eysenck's extraversion-introversion personality dimension on prospective memory.

Prospective memory (PM) is memory for future events. PM is a developing area of research (e.g., Brandimonte, Einstein & McDaniel, 1996) with recent work linking personality types and their utilisation of PM (Goschke & Kuhl, 1996; Searleman, 1996). The present study compared 28 extraverts and 28 introverts on their short- and long-term prospective memory using the Prospective Memory Scale developed by Hannon, Adams, Harrington, Fries-Dias & Gibson (1995). The main finding was that extraverts reported significantly fewer errors on short- and long-term PM than introverts, and this difference could not be explained in terms of the number of strategies used to support prospective remembering. These findings are discussed in relation to differences between the personality types.

Solubility of airborne uranium compounds at the Fernald Environmental Management Project.

The in vitro solubility of airborne uranium dusts collected at a former uranium processing facility now undergoing safe shutdown, decontamination, and dismantling was evaluated by immersing air filters from high volume samplers in simulated lung fluid and measuring the 238U in sequential dissolution fractions using specific radiochemical analysis for uranium. X rays and photons from the decay of uranium and thorium remaining on the filter after each dissolution period were also directly measured using a planar germanium detector as a means for rapidly evaluating the solubility of the uranium-bearing dusts. Results of these analyses demonstrate that two distinct types of uranium-bearing dusts were collected on the filters depending upon the location of the air samplers. The first material exhibited a dissolution half-time much less than 1 d and was most likely UO3. The dissolution rate of the second material, which was most likely U3O8, exhibited two components. Approximately one-third of this material dissolved with a half time much less than 1 d. The remaining two-thirds of the material dissolved with half times between 230 +/- 16 d and 1,350 +/- 202 d. The dissolution rates for uranium determined by radiochemical analysis and by gamma spectrometry were similar. However, gamma spectrometry analysis suggested a difference between the half times of 238U and its initial decay product 234Th, which may have important implications for in vivo monitoring of uranium.

Prospective memory, everyday cognitive failure and central executive function in recreational users of Ecstasy.

Chronic use of MDMA (3,4-methylenedioxymethamphetamine), or Ecstasy, is believed to lead to impaired psychological performance, including well-documented decrements in laboratory and field tests of retrospective memory. Less is known about the impact of Ecstasy on aspects of 'everyday' memory, despite obvious concerns about such effects. The three studies reported here focused on the impact of chronic Ecstasy use on prospective memory (PM), associated central executive function and other aspects of day-to-day cognition. In study 1 46 regular Ecstasy users were compared with 46 Ecstasy-free controls using the Prospective Memory Questionnaire (PMQ). Ecstasy users reported significantly more errors in PM (remembering to do something in the future); these findings persisted after controlling for other drug use and the number of strategies used to aid memory. No difference was found between representative subgroups on the Lies Scale of the Eysenck Personality Questionnaire. In study 2 a different group of 30 regular Ecstasy users and 37 Ecstasy-free controls was assessed on the PMQ and on a central executive task comprising verbal fluency measures. The results confirmed the significant impairments in long- and short-term PM and revealed corresponding impairments in verbal fluency. In study 3 15 Ecstasy users, 15 cannabis users and 15 non-drug users were assessed using the Cognitive Failures Questionnaire, which requires participants to provide ratings of the frequency of various day-to-day cognitive slips. The results indicate that the Ecstasy users did not perceive their general cognitive performance to be worse than that of controls. Taken together, these results suggest that Ecstasy users have impaired PM that cannot be explained by an increased propensity to exaggerate cognitive failures. These may be attributable, in part, to central executive deficits that are due to frontal lobe damage associated with Ecstasy use. Copyright 2001 John Wiley & Sons, Ltd.

Differential effects of Ecstasy and cannabis on self-reports of memory ability: a web-based study.

Given the legal status of MDMA (3,4-methylenedioxymethamphetamine), or Ecstasy, face-to-face access to participants is sometimes difficult. The number of participants in studies of cognitive performance amongst Ecstasy users is variable, with the average being around 30. Access to a larger number of participants is clearly desirable. The present investigation accessed a larger sample size using a web-based design. A website was developed and used for data collection. Prospective memory ability was assessed using the Prospective Memory Questionnaire. Self-report of day-to-day memory performance was investigated using the Everyday Memory Questionnaire. The Drug Questionnaire assessed the use of other substances as well as Ecstasy, allowing a regression design to isolate the contribution of each substance to any variance on the cognitive measures. Preliminary findings (N = 488) indicate that there is a clear double dissociation between the impact of Ecstasy and cannabis. We found that cannabis was associated with reports of 'here-and-now' cognitive problems in short-term and internally cued prospective memory. In contrast, Ecstasy was associated with reports of long-term memory problems, which were more related to storage and retrieval difficulties. Copyright 2001 John Wiley & Sons, Ltd.

Partial IFN-alpha/beta and IFN-gamma receptor knockout trisomy 16 mouse fetuses show improved growth and cultured neuron viability.

The trisomy 16 mouse fetus is a well-studied model for Down syndrome (trisomy 21), the leading genetic cause of mental retardation in the newborn population. Human chromosome 21 and mouse chromosome 16 each carry a large cluster of genes that code for components of the interferon (IFN)-alpha/beta and IFN-gamma receptors, and Down syndrome cells display significantly increased sensitivity to IFN action. We have previously reported that in utero anti-IFN IgG treatment of mice pregnant with trisomy 16 fetuses results in a significant improvement in trisomy 16 fetus growth and morphology and that anti-IFN-gamma IgG treatment can prevent the premature death of trisomy 16 fetal mouse cortical neurons in culture. We have now used IFN receptor subunit knockout mice to produce mouse fetuses that carry three No. 16 chromosomes and one copy each of disabled IFN-gamma receptor (IFNGR) and IFN-alpha/beta receptor (IFNAR-2) component genes. We report here that this partial IFN receptor knockout trisomy (PIRKOT) mouse fetus has significantly improved growth and yields cortical neurons whose viability is the equivalent of that seen in their euploid counterparts.

Speech, "inner speech," and the development of short-term memory: effects of picture labeling on recall.

Three experiments explored the effect of overt speech on children's use of "inner speech' in short-term memory (STM). Experiments 1 and 2 compared recall of a series of pictured objects when 5- and 11-year-olds either labeled stimuli at presentation or remained silent. Use of inner speech was assessed by manipulating word length of the picture names (Experiment 1) or phonemic similarity (Experiment 2). Word length and phonemic similarity had greater effects in the older children and when pictures were labeled at presentation. These tendencies were such that 5-year-olds were sensitive to word length and phonemic similarity only with labeling. Experiment 3 compared labeling by the child with labeling by the experimenter in 5-year-olds. There were no significant differences with respect to overall performance or effects of word length and phonemic similarity. It is suggested that speaking or listening to speech activates and internal "articulatory loop,' and that such activation is especially important when the child's ability to use inner speech in STM has not fully developed.