The reason melanoma is the deadliest form of skin cancer stems from the curious ability of all of its cells to swap fates, according to a study publishing in Cell this week.

 

The-Scientist.com, May 13, 2010, by Edyta Zielinska  –  “This is an important study,” David Fisher, a researcher and dermatologist at Massachusetts General Hospital and Harvard Medical School, said in an email. “The work [helps] to explain several key features of melanoma — which may well occur in other cancers as well.”

One of the defining characteristics of tumor cells is that they divide more rapidly than most tissues in the body. Chemotherapy and radiation are effective treatments for some cancers for that very reason: they target rapidly dividing cells. But recently researchers have found a second population of cells in the tumor, called cancer stem cells, which divide more slowly, are resistant to treatment, and quickly replenish the tumor mass after therapy — causing the cancer to recur in patients.

Meenhard Herlyn from the Wistar Institute and colleagues found that melanoma doesn’t necessarily harbor stem cells, per se. Rather, in this cancer, every tumor cell carries the potential to be both stem-like (slowly dividing) and cancerous (rapidly dividing). This is not the case in other types of cancer, Herlyn explained, since other cancers contain cells that are not tumorigenic — in other words, when those cells are removed from a tumor, they do not have the potential to initiate tumor growth in a new context. In contrast, every cell in a melanoma tumor has that potential, possibly explaining the aggressiveness of this cancer, which is the cause of 75 percent of all deaths from skin cancer.

The researchers were able to distinguish the slowly dividing cells from quickly dividing cells using a marker for the enzyme JARID1B, only expressed by slow growing melanoma cells.

Finding JARID1B was a stroke of luck, said Herlyn. When Alexander Roesch, a visiting clinician from the Regensburg University Medical Center in Germany, told Herlyn that he had a tumor-suppressor gene he wanted to work on named JARID1B, Herlyn told Roesch that the gene was outside the scope of the laboratory. “We told him ‘you have to give up your project,'” Herlyn recalled. But when Roesch found a paper that indicated the JARID1B enzyme was expressed in stem cells, Herlyn agreed to work on it. His laboratory had been focused on trying to characterize melanoma stem cells, so this protein fit the bill. It was a fortuitous decision. “Two and a half years later, we came to the conclusion that there are no stem cells in melanoma,” said Herlyn.

When they took these JARID1B cells out of the tumor environment, these slow-growing cells “literally explode,” said Herlyn. “They have an incredibly high proliferation potential.” But the same fast-growing cells can return to a slow-growing state when re-implanted into an animal.

Not much is know about how JARID1B functions in the cell. It is clearly linked to the cell’s metabolism, and responsible for slowing growth, said Herlyn, “but how it is being turned on,” and its other functions in the cell, “we do not know,” said Herlyn.

The results suggest that therapies for melanoma will have to target both the slow and fast growing populations in order to be effective, the researchers said. To test the therapeutic potential of JARID1B as a target for anti-tumor therapy, Herlyn’s group used a short hairpin RNA to temporarily knock down the JARID1B enzyme. Although they observed an initial increase in tumor growth, over time, the tumor growth slowed. “The tumor cannot be maintained if this gene is knocked down,” said Herlyn.

“The work identifies a potentially important new drug target worthy of clinical investigation,” agreed Fisher.

A. Roesch, et al., “A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth,” Cell, 141:583-94, 2010.

Read more: Fate-swapping cells drive deadly tumor – The Scientist – Magazine of the Life Sciences http://www.the-scientist.com/blog/display/57402/#ixzz0nqzz68Na

WorldHealth.net, May 13, 2010  –  Whereas elevated Prostate Specific Antigen (PSA) levels can be a sign of prostate cancer spread in men with early cancer, the PSA test does not distinguish between slow-growing and aggressive cancers.  As a result, there are suggestions that prostate cancer may be overdiagnosed and overtreated.  Robert W. Veltri, from Johns Hopkins University (Maryland, USA), and colleagues have developed a new blood test, known as the Prostate Health Index (PHI). It measures three forms of PSA, including pro-PSA, a shortened molecule that is missing a few of the amino acids that make up the PSA protein, and suggested to be a highly accurate form of PSA.  The team studied 71 men who were diagnosed with small, low-grade, and low-stage prostate cancer based on their PSA results. Approximately four years later, 39 had unfavorable biopsy results that signaled a need for treatment. The PHI test was performed on blood samples, banked at the time of biopsy, from all 71 men. When the researchers combined the biopsy results with the PHI data, they were able to predict 7 in 10 men that might progress, leading them to conclude that: “Measurement of the serum PHI and tissue DNA content at the time of diagnosis are able to predict which men enrolled in an [active surveillance] cohort will ultimately require treatment for [prostate cancer].”

Read the abstract below…………..

Serum prostate health index and biopsy tissue DNA content at the time of diagnosis predicts the need for treatment in men enrolled in an active surveillance program

Authors

Sumit Isharwal1, Danil Makarov2, Lori J. Sokoll1, Patricia Landis1, Cameron Marlow3, Jonathan I. Epstein1, Alan W. Partin1, H. Ballentine Carter1, Robert W. Veltri1. 1Johns Hopkins University School of Medicine, Baltimore, MD; 2Yale University School of Medicine, New Haven, CT; 3Science Applications International Corporation-Frederick, National Cancer Institute, Frederick, MD

Abstract Body:

Introduction and Objective: We assessed a novel application of the Prostate Health Index [Phi = (proPSA / free PSA) x (square root of PSA)] developed by Beckman-Coulter Inc. and DNA content measurements in benign-adjacent and cancer tissue areas to predict which patients would eventually require treatment for prostate cancer (PCa) in an active surveillance (AS) cohort.
Methods: We identified 71 men at the Johns Hopkins Hospital AS program which had banked serum from the time of diagnosis available for the study. 39 developed an unfavorable biopsy (Gleason score >6, Gleason pattern 4/5, >2 cores positive for cancer, >50% of any core involved with cancer), while 32 have maintained favorable biopsies (median follow-up: 3.7 years). Serum total PSA, free PSA and [-2] proPSA were measured by the Beckman Coulter immunoassay. DNA content measurements of Feulgen-stained biopsy sections were performed with the AutoCyteTM imaging system. Cox proportional hazard regression and Kaplan-Meier plots were used to identify significant prognosticators for unfavorable biopsy conversion-free survival.
Results: The ratio of Phi in serum was significantly higher (37.23 ± 15.76 vs. 30.60 ± 12.70 p=0.03) in men ultimately developing unfavorable biopsies. Serum Phi [HR(95%CI): 2.39 (1.26-4.52), p=0.007], BA excess of optical density (OD) [HR (95%CI): 2.58 (1.17-5.68), p=0.019] and CA standard deviation of OD [HR (95%CI): 5.36 (1.89-15.24), p=0.002] were significant predictors of an unfavorable biopsy conversion in both Kaplan-Meier and Cox regression analysis. Patients with Phi >34.2 and CA standard deviation of OD >4.0 showed the highest risk for unfavorable biopsy conversion (p<0.0001).
Conclusions: Measurement of the serum Phi and tissue DNA content at the time of diagnosis are able to predict which men enrolled in an AS cohort will ultimately require treatment for PCa.

Pregnancy, Chromosomes, and Receptors

By Elliot S. Gershon MD

The-Scientist.com, May 13, 2010  –  The search for potential genetic and environmental causes of schizophrenia began not long after Eugen Bleuler coined the name of the disease in 1908. In the first decades of the 20th century, twin and adoption studies began to consistently point to an inherited component in the susceptibility to the disease. In the decades before the molecular era, the twin data implied that it was a multigenic disease, with multiple genes of modest or small effect.

That general sense of a multifactorial etiology became apparent at a time during which evidence for an environmental component came with surprising difficulty. That evidence emerged slowly from careful epidemiologic studies of second-trimester influenza infections, and from the consequences of deliberate starvation of the Dutch population by the Nazis during the winter of 1944. After both events, women who endured these conditions during their second trimesters had more babies who grew up to have schizophrenia. Researchers have also observed that obstetric and perinatal problems are associated with the disease, and they now generally accept that physical problems during pregnancy can increase the likelihood of schizophrenia.

As the molecular era began in the middle of the 20th century, researchers confirmed the likely multigenic nature of schizophrenia’s etiology. Reseachers began applying the first human molecular genetic maps to schizophrenia soon after such maps became available in the 1980s. They have since linked certain chromosomal regions more or less consistently to schizophrenia in different studies, and some genes in those regions appear to be associated with susceptibility.

Norton, Williams, and Owen, in a 2006 review, concluded that “the strongest evidence for putative schizophrenia susceptibility loci relates to the genes encoding dysbindin (DTNBP1) and neuregulin (NRG1). For other genes, disrupted in schizophrenia (DISC1), D-amino acid oxidase activator (DAOA), regulator of G-protein signaling 4 (RGS4) and V-AKT murine thymoma viral oncogene homolog 1 (AKT1), the data are promising but not yet compelling. In the most convincing cases, the risk haplotypes appear to be associated with small effect sizes and do not fully explain the linkage findings that prompted each study.”1 However, a systematic statistical meta-analytic approach indicates less evidence for DISC1 and RGS4 (see Table 2) and supports other associations. (For a database of all published studies on gene associations with schizophrenia, see www.schizophreniaforum.org/res/sczgene/default.asp).

The data suggest that treatments might be tailored to the susceptibility variants.

It is not clear if a gene-environment interaction exists, or if the environmental events act independently. One recent report indicates a specific gene-environment interaction in schizophrenia, in which traumatic brain injury was more likely to be associated with schizophrenia in patients with a family history of that disorder.2 In the past the interpersonal environment of the family was thought to play a role in susceptibility, but this does not appear to be the case. Nonetheless, some differences in expressed emotion within families are associated with differences in severity of illness in the patients.

The second half of the 20th century also saw the development of biochemical hypotheses for schizophrenia. The most prominent was the dopamine hypothesis that Carlsson and Lindqvist originally put forth in 1963; it was based on the biochemical effects of treatment with the first antipsychotic drugs, which had been introduced only in 1952. Animal studies lent support to what became a building block of antipsychotic drug discovery – the search for dopamine receptor blockers – and treatment, and Carlsson shared a Nobel Prize for this and other research in 2002.

At this time multiple classes of dopamine receptors are known. Genetic mutations in dopamine receptors have also been discovered and have been applied to comparisons of patients and controls for decades. At first there appeared to be no association between these genetic changes and susceptibility to schizophrenia, but as evidence accumulated from studies of thousands of normal controls and patients with schizophrenia, a pattern emerged. Examination and reanalysis of meta-analyses has implicated three dopamine receptors that have genetic variants consistently associated with schizophrenia: DRD1, DRD2, and DRD4 (dopamine receptors 1, 2, and 4). Other evidence also implicates DRD3. Other specific genes, based on biochemical hypotheses, also have strong evidence for association with schizophrenia.

The overall picture for schizophrenia is now quite promising. The genes associated with schizophrenia vulnerability are also related to treatment in the case of dopamine receptors. This suggests that treatments might be tailored to the susceptibility variants, and that the tailored treatments would be more effective in patients who had the specific variants. It also suggests that new treatment approaches might be developed from translational research based on the more recently developed gene-disease associations. Finally, it invites research on prevention based on precautionary care of women through deterrence of viral infections during pregnancy, and improvements in obstetric delivery.

Elliot S. Gershon is Foundations Fund Professor of Psychiatry and Human Genetics at the University of Chicago. 

Table 1. Environmental traumas associated with schizophrenia

Event Age at event
Influenza infection In utero second trimester of pregnancy
Starvation In utero second trimester of pregnancy
Traumatic brain injury Throughout life

Table 2. Genes statistically associated with schizophrenia susceptibility

Symbol Full Name Chromosome
MTHFR 5,10-methylenetetrahydrofolate reductase 1
DRD4 Dopamine D4 receptor 11
DRD2 dopamine receptor D2 11
DRD1 dopamine receptor D1 5
DAO D-amino-acid oxidase 2
IL1B interleukin 1, beta proprotein 2
TPH1 Tryptophan hydroxylase 1 11
TP53 Tumor protein p53 17
HP Haptoglobin 16
DAOA D-Aminoacid Activator 13
DTNBP1 Dystrophin binding protein 1 (Dystrobrevin) 6
COMT Catechol O-methyltransferase 22

 

References

1. N. Norton, H.J. Williams, M.J. Owen, “An update on the genetics of schizophrenia,” Curr Opin Psychiat, 19:158-64, 2006.

2. D. Malaspina et al., “Traumatic brain injury and schizophrenia in members of schizophrenia and bipolar disorder pedigrees,” Am J Psychiat, 158:440-6, 2001.

 

About the author……………..                                              

Elliot S. Gershon, MD

Professor of Psychiatry and Human Genetics

Department of Psychiatry

Adult Psychiatry

 

 

 

Clinical Interests

  • Bipolar Disorders
  • Major Depression
  • Genetic Counseling in Psych.

Practice Location

University of Chicago Medical Center
5841 S. Maryland Avenue
Chicago, IL 60637

Year Started Practice

1969

Board Certification

Psychiatry & Neurology

Specialties

Psychiatry

Medical School 

Harvard Medical School

Internship

Mt. Sinai Hospital, New York, NY,

Residency

Massachusetts Mental Health Center-Harvard Medical School, Boston, Massachusetts

Languages Spoken

English
Hebrew

Email

egershon@yoda.bsd.uchicago.edu

Office Phone

(773) 834-2660 begin_of_the_skype_highlighting              (773) 834-2660      end_of_the_skype_highlighting

Office Fax

(773) 834-3562

Office Postal Address

Elliot S. Gershon, MD
5841 S. Maryland Ave.
MC 3077

Posted on 2010-05-04 06:00:00 in Functional Foods | Inflammation |

WorldHealth.net, May 14, 2010  –  Spanish researchers identify 98  genes whose inflammatory activity is dampened by consumption of olive oil, suggesting the underlying mechanism by which it exerts beneficial effects on chronic conditions from arthritis to heart disease. Francisco Perez-Jimenez, from University of Cordoba (Spain),and colleagues studied 20 patients with metabolic syndrome, who ate breakfast foods covered in two types of olive oil, either extra virgin olive oil (high in phenol compounds), or a low-phenol oil.   Those subjects who ate the breakfast containing olive oil rich in phenolic compounds were found to have a reduced expression of pro-inflammatory genes associated with cardiovascular disease and diabetes, as compared to those who ate the low-phenolic olive oil breakfast.  Concluding that: “This study shows that intake of a breakfast based in virgin olive oil rich in phenol compounds is able to repress the in vivo

expression of several pro-inflammatory genes, thereby switching the activity of peripheral blood mononuclear cells to a less deleterious inflammatory profile,” the researchers submit that: “These results provide at least a partial molecular basis for the reduced risk of cardiovascular disease observed in Mediterranean countries, where virgin olive oil represents the main source of dietary fat.”

Read more at…………   BioMedCentral.com

Gene expression changes in mononuclear cells from patients with metabolic syndrome after acute intake of phenol-rich virgin olive oil

Antonio Camargo, Juan Ruano, Juan M Fernandez,  Laurence D Parnell, Anabel Jimenez, Monica Santos-Gonzalez, Carmen Marin, Pablo Perez-Martinez, Marino Uceda, Jose Lopez-Miranda, and Francisco Perez-Jimenez

BMC Genomics 2010, 11:253doi:10.1186/1471-2164-11-253

Published: 20 April 2010

Abstract (provisional)


Background

Previous studies have shown that acute intake of high-phenol virgin olive oil reduces pro-inflammatory, pro-oxidant and pro-thrombotic markers compared with low phenols virgin olive oil, but it remains unclear if the effects attributed to its phenolic fraction are exerted at the transcriptional level in vivo. To achieve this goal, we aimed at identifying in humans those genes which undergo expression changes mediated by virgin olive oil phenolic compounds.

Results

Postprandial gene expression microarray analysis was performed on peripheral blood mononuclear cells at the postprandial period. Two virgin olive oil-based breakfasts with high (398 ppm) and low (70 ppm) content of phenolic compounds were administered to 20 patients with metabolic syndrome following a double-blinded random crossover design. To eliminate the potential effect that might exist in their usual dietary habits, all subjects followed a similar low-fat, carbohydrate rich diet during the study period. Microarray analysis identified 98 differentially expressed genes (79 underexpressed and 19 overexpressed) when comparing the intake of phenol-rich olive oil with the low-phenol olive oil. Many of those genes are linked to obesity, dyslipemia and type 2 diabetes mellitus. Among these, several genes are involved in inflammatory processes mediated by transcription factor NF-kappa B, activator protein-1 transcription factor complex AP-1, cytokines, mitogen-activated protein kinases MAPKs or arachidonic acid pathways.

Conclusion

This study shows that intake of a breakfast based in virgin olive oil rich in phenol compounds is able to repress the in vivo expression of several pro-inflammatory genes, thereby switching the activity of peripheral blood mononuclear cells to a less deleterious inflammatory profile. These results provide at least a partial molecular basis for the reduced risk of cardiovascular disease observed in Mediterranean countries, where virgin olive oil represents the main source of dietary fat. Admittedly, other lifestyle factors are also likely to contribute to lowered risk of cardiovascular disease in this region.

Summary

Cell.com, May 13, 2010  –  It is now well established that postlearning sleep is beneficial for human memory performance [1,2,3,4,5]. Meanwhile, human and animal studies have demonstrated that learning-related neural activity is re-expressed during posttraining nonrapid eye movement (NREM) sleep [6,7,8,9]. NREM sleep processes appear to be particularly beneficial for hippocampus-dependent forms of memory [1,2,3,10]. These observations suggest that learning triggers the reactivation and reorganization of memory traces during sleep, a systems-level process that in turn enhances behavioral performance. Here, we hypothesized that dreaming about a learning experience during NREM sleep would be associated with improved performance on a hippocampus-dependent spatial memory task. Subjects were trained on a virtual navigation task and then retested on the same task 5 hr after initial training. Improved performance at retest was strongly associated with task-related dream imagery during an intervening afternoon nap. Task-related thoughts during wakefulness, in contrast, did not predict improved performance. These observations suggest that sleep-dependent memory consolidation in humans is facilitated by the offline reactivation of recently formed memories, and furthermore that dream experiences reflect this memory processing. That similar effects were not observed during wakefulness suggests that these mnemonic processes are specific to the sleep state.

Current Biology, Volume 20, Issue 9, 850-855, 22 April 2010

Posted on 2010-05-05 06:00:00 in Stroke

WorldHealth.net, May 13, 2010  –  In that previous studies have determined an association between mild-to-moderate red wine consumption to a reduced incidence of cardiovascular, cerebrovascular, and peripheral vascular risk, Johns Hopkins University School of Medicine (Maryland, USA) researchers investigated the mechanism by which resveratrol, a compound found in the skins and seeds of red grapes, may protect against stroke.  Two hours after feeding mice a single modest dose of resveratrol, the researchers induced an ischemic stroke.  Those animals that had preventively ingested the resveratrol suffered significantly less brain damage, as compared to ones that had not been given the compound.  Sylvain Dore, lead researchers of the study, posits that resveratrol increases levels of an enzyme (heme oxygenase) already known to shield nerve cells in the brain from damage. When the stroke hits, the brain is ready to protect itself because of elevated enzyme levels. In mice that lacked the enzyme, the study found, resveratrol had no significant protective effect and their brain cells died after a stroke. The team concludes that: “The data suggest a potential intracellular pathway by which resveratrol can provide cell/organ resistance against neuropathological conditions.”

Read the abstract below………….on    ScienceDirect.com

Resveratrol protects against experimental stroke: Putative neuroprotective role of heme oxygenase 1

Yoshihito Sakataa, Hean Zhuanga, Herman Kwansaa, Raymond C. Koehlera and Sylvain Doré

Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA

Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, USA

Received 24 September 2009; 

revised 12 March 2010; 

accepted 30 March 2010. 

Available online 8 April 2010.

Abstract

Epidemiological and experimental reports have linked mild-to-moderate wine and/or grape consumption to a lowered incidence of cardiovascular, cerebrovascular, and peripheral vascular risk. This study revealed that resveratrol, an enriched bioactive polyphenol in red wine, selectively induces heme oxygenase 1 (HO1) in a dose- and time-dependent manner in cultured mouse cortical neuronal cells and provides neuroprotection from free-radical or excitotoxicity damage. This protection was lost when cells were treated with a protein synthesis or heme oxygenase inhibitor, suggesting that HO1 induction is at least partially required for resveratrol’s prophylactic properties. Furthermore, resveratrol pretreatment dose-dependently protected mice subjected to an optimized ischemic–reperfusion stroke model. Mice in which HO1 was selectively deleted lost most, if not all, of the beneficial effects. Together, the data suggest a potential intracellular pathway by which resveratrol can provide cell/organ resistance against neuropathological conditions.

Posted on 2010-05-03 06:00:00 in Lifestyle | Musculoskeletal |

WorldHealth.net, May 13, 2010  –  A loss of balance and diminished gait are major fall risk factors in older persons; some previous studies suggest that physical activity based on dance may improve balance and gait.   Jean Krampe, from the University of Missouri’s Sinclair School of Nursing (Missouri, USA), and colleagues studied 11 seniors who participated in regular dance therapy sessions utilizing The Lebed Method, which includes a combination of low-impact dance steps choreographed to music. The researchers found that: “Dance therapy results in positive functional trends, suggesting that further study using dance-based therapy will be useful to decrease fall risks in older persons.”

Read more at the………Nursing Administration Quarterly:

April/June 2010 – Volume 34 – Issue 2 – p 156–161

doi: 10.1097/NAQ.0b013e3181d91851

Article
Dance-Based Therapy in a Program of All-inclusive Care for the Elderly: An Integrative Approach to Decrease Fall Risk
Krampe, Jean MSN, RN; Rantz, Marilyn J. PhD, RN, FAAN; Dowell, Laura PT; Schamp, Richard MD; Skubic, Marjorie PhD; Abbott, Carmen PT
 
Abstract
Background: Loss of balance and diminished gait are major fall risk factors in older persons. Literature suggests that physical activity based on dance may improve balance and gait. The aim of this pilot study was to determine whether dance-based therapy affects the balance/gait of community-based frail seniors.

Conceptual Framework: The Roy Adaptation Model and Environmental Press Theory were used as joint frameworks.

Participants: Eleven participants were recruited from a Program of All-inclusive Care for the Elderly (PACE). Inclusion criteria were (1) Mini-Mental State Examination score of 23 or more, (2) attending PACE on Monday, Wednesday, and Friday, and (3) able to stand with or without assistance.

Methods: A Lebed Method dance intervention was conducted using a longitudinal design 3 times a week for 6 weeks. Functional Reach and Timed Get Up and Go were measured at baseline, 6 weeks after the start of the intervention, and 6 weeks postintervention and repeated to estimate the persistence of the effect.

Conclusions: Graphs were compared looking for functional trends; postintervention interviews were conducted with each subject.

Implications: Dance therapy results in positive functional trends, suggesting that further study using dance-based therapy will be useful to decrease fall risks in older persons.