Melanoma is the deadliest form of skin cancer. In the early stages, melanoma can be treated successfully with surgery alone and survival rates are high, but after metastasis survival rates drop significantly. Therefore, early and correct diagnosis is key for ensuring patients have the best possible prognosis. Melanoma misdiagnosis accounts for more pathology and dermatology malpractice claims than any cancer other than breast cancer, as an early misdiagnosis can significantly reduce a patient’s chances of survival. As far as treatment for metastatic melanoma goes, there have been several new drugs developed over the last 10 years that have greatly improved the prognosis of patients with metastatic melanoma, however, a majority of patients do not show a lasting response to these treatments. Thus, new biomarkers and drug targets are needed to improve the accuracy of melanoma diagnosis and treatment. This article will discuss the major advancements of melanoma diagnosis and treatment from antiquity to the present day.
Over-expression of the translesion synthesis polymerase (TLS pol) hpol κ in glioblastomas has been linked to a poor patient prognosis; however, the mechanism promoting higher expression in these tumors remains unknown. We determined that activation of the aryl hydrocarbon receptor (AhR) pathway in glioblastoma cells leads to increased hpol κ mRNA and protein levels. We blocked nuclear translocation and DNA binding by the AhR in glioblastoma cells using a small-molecule and observed decreased hpol κ expression. Pharmacological inhibition of tryptophan-2,3-dioxygenase (TDO), the enzyme largely responsible for activating the AhR in glioblastomas, led to a decrease in the endogenous AhR agonist kynurenine (Kyn) and a corresponding decrease in hpol κ protein levels. Importantly, we discovered that inhibiting TDO activity, AhR signaling, or suppressing hpol κ expression with RNA interference led to decreased chromosomal damage in glioblastoma cells. Epistasis assays further supported the idea that TDO activity, activation of AhR signaling and the resulting over-expression of hpol κ function primarily in the same pathway to increase endogenous DNA damage. These findings indicate that up-regulation of hpol κ through glioblastoma-specific TDO activity and activation of AhR signaling likely contributes to the high levels of replication stress and genomic instability observed in these tumors.
Objective: The aim of this study was to examine the relationship between habit strength and clinical features of anorexia nervosa (AN). Habit strength, separate from intention, relates to the persistence of behavior, and is measured by the Self-Report Habit Index (SRHI). We hypothesized that habit strength would be greater among individuals with AN than healthy controls (HC) and that habit strength would be associated with duration and severity of illness.Method: Participants were 116 women with AN (n = 69) and HC (n = 47) who completed the SRHI, the Eating Disorder Examination-Questionnaire (EDE-Q), and a multi-item laboratory meal. The SRHI assessed four domains and these subscales were averaged for the total score.Results: Individuals with AN demonstrated significantly greater habit strength than HC in the total score (t 114 = 7.00, p < .01), and within each domain (restrictive eating, compensatory behavior, delay of eating, and rituals). Total SRHI score was significantly associated with EDE-Q scores for both AN and HC groups (r AN = .59, p AN = <.001; r HC = .32, p HC = .030). Among patients, there was a significant association between SRHI and duration of illness (r = .38, p = .001). There was no significant association between SRHI and caloric intake (r AN = −.20, p AN = .10; r HC = −.25, p HC = .09).Discussion: Habit strength was related to chronicity and severity of AN, suggesting that habit formation may play an important role in illness. These data suggest avenues for mechanism research and treatment development. K E Y W O R D Sanorexia nervosa, duration of illness, eating disorders, habit, Self-Report Habit Index
Background Restriction of food intake is a central feature of anorexia nervosa (AN) and other eating disorders, yet also occurs in the absence of psychopathology. The neural mechanisms of restrictive eating in health and disease are unclear. Methods This study examined behavioral and neural mechanisms associated with restrictive eating among individuals with and without eating disorders. Dietary restriction was examined in four groups of women (n = 110): healthy controls, dieting healthy controls, patients with subthreshold (non-low weight) AN, and patients with AN. A Food Choice Task was administered during fMRI scanning to examine neural activation associated with food choices, and a laboratory meal was conducted. Results Behavioral findings distinguished between healthy and ill participants. Healthy individuals, both dieting and non-dieting, chose significantly more high-fat foods than patients with AN or subthreshold AN. Among healthy individuals, choice was primarily influenced by tastiness, whereas, among both patient groups, healthiness played a larger role. Dorsal striatal activation associated with choice was most pronounced among individuals with AN and was significantly associated with selecting fewer high-fat choices in the task and lower caloric intake in the meal the following day. Conclusions A continuous spectrum of behavior was suggested by the increasing amount of weight loss across groups. Yet, data from this Food Choice Task with fMRI suggest there is a behavioral distinction between illness and health, and that the neural mechanisms underlying food choice in AN are distinct. These behavioral and neural mechanisms of restrictive eating may be useful targets for treatment development.
Self-enucleation is a severe form of self-injurious behavior which presents as an ophthalmologic and psychiatric emergency. It is usually known to occur with untreated psychosis, however, there have been reports of self-enucleation across various psychopathologies. We review a case documenting self-enucleation in the forensic setting in a patient with an unusual presentation and cluster of psychotic symptoms. Literature was reviewed using PubMed/Medline databases with key terms: "forensic science," "forensic psychiatry," "auto-enucleation," "self-enucleation," "Oedipism," "self-harm." This case is unique as it offers an alternative presentation to those most commonly depicted in current literature, helps highlight the sparsity of literature depicting self-enucleation in the forensic setting, and stimulates discussion around various potential differential diagnoses, management strategies and complications of self-enucleation within the forensic setting. It is prudent to emphasize need for aggressive and collaborative treatment for the forensic population regardless of psychopathology, presentation, or propensity for secondary gain.
Normal cell growth is characterized by a regulated epigenetic program that drives cellular activities such as gene transcription, DNA replication, and DNA damage repair. Perturbation of this epigenetic program can lead to events such as mis-regulation of gene transcription and diseases such as cancer. To begin to understand the epigenetic program correlated to the development of melanoma, we performed a novel quantitative mass spectrometric analysis of histone post-translational modifications mis-regulated in melanoma cell culture as well as patient tumors. Aggressive melanoma cell lines as well as metastatic melanoma were found to have elevated histone H3 Lys 27 trimethylation (H3K27me3) accompanied by overexpressed methyltransferase EZH2 that adds the specific modification. The altered epigenetic program that led to elevated H3K27me3 in melanoma cell culture was found to directly silence transcription of the tumor suppressor genes RUNX3 and E-cadherin. The EZH2-mediated silencing of RUNX3 and E-cadherin transcription was also validated in advanced stage human melanoma tissues. This is the first study focusing on the detailed epigenetic mechanisms leading to EZH2-mediated silencing of RUNX3 and E-cadherin tumor suppressors in melanoma. This study underscores the utility of using high resolution mass spectrometry to identify misregulated epigenetic programs in diseases such as cancer, which could ultimately lead to the identification of biological markers for diagnostic and prognostic applications. Melanoma is a deadly variety of skin cancer, accounting for 75% of skin cancer-related deaths. In 2015, melanoma is expected to be the fifth most common cancer in men and the seventh most common cancer in women. According to the World Health Organization, it is estimated that melanoma will result in the death of around 65,000 people globally and 9940 people in the United States in 2015. The high mortality rate associated with metastatic melanoma suggests a lack of efficient diagnostic and prognostic biomarkers (1). EZH2 1 expression has often been positively correlated to the progression of different types of cancer (2, 3). Increased expression of EZH2 has been identified in melanoma tissues (4) as well as prostate, breast, bladder, and liver cancers and has been recognized as a prognostic marker for aggressive prostate and breast cancer (5, 6). EZH2 is a histone modifier that functions as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) (7,8). It is a lysine methyltransferase and promotes the addition of the repressive marker histone H3K27me2/me3 to target chromatin, thereby inducing chromatin compaction and transcriptional repression. Chromatin condensation/compaction leads to transcriptional repression by restricting access to transcriptional regulators like RNA polymerase II and other transcription-associated factors. Hence, silencing of tumor suppressor genes by H3K27me3 is implicated in the initiation and advancement of different types of cancer (9 -11). H3K27me3-silenced tumor suppressor gene...
Manot Cave radiocarbon dates establish Levantine chronology, which is critical for understanding Upper Paleolithic dispersals.
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