David Davis

Some fellow called Mariah Carey says “butterflies”. I will add other insights to this butterfly nonsense in a later posting, in which I will balefully regard the strategic damage done to humanity by butterflies and  by “butterflyness”. Later. “Health and Safety” have taken the right decision to block her “request for 20 white kittens and 100 white doves” to cavort about while she does something trifling, but for quite the wrong reasons.

I am sure you can see what the right ones are. They are cultural rather than safety-based. Now then, under a libertarian civilisational settlement, it may well turn out that certain people become what are commonly called “celebrities”.  But owing to quite different strategic slants in the sorts of education that most people will then want, and which schools and universities will have to provide or go under, I can imagine quite different sorts of “celebrity” cropping up.

The current lot are largely empty sounding-vessels, that respond in their creation to the LCD, broadcast-media-created “popular culture”: this takes minimal effort to engage with, to understand and to get gratification from. The MSM conjures up these phantasmal but otherwise material creatures, milks them in a sort of real-life docusoap for a couple of years, then ritually slaughters them, in public, on the Aztec-Sacrificial-Altar of “yesterday’s news”.

I am not saying that (in place of these poor ephemeral worthless creatures I talked of above) the service-lives, of  great and useful individuals who have just advanced the Western Classical and Scientific Canon in some notable way, will last any longer as newsworthy stuff. Probably, far from it! Unlike stuff such as the “X factor” whatever that is, the pressure to “perform”, such as being the engineer who designed – and against the efforts of governemts – project-managed the Yemen-Somalia Suspension Bridge for example, or the fellow that designed a practical Belt-Mining-Station (with ore-carrier-feeder-facility) for the asteroid belt, will be enormous.

It will only be sustainable by Individuals of a People that recognises, understands and glorifies in the astonishing degree of order in the Universe, and a People that is not deflected  – except by choice and decision to let its hair down occasionally – by dsplays of pointless self-promotion using massed goose-stepping regiments of white kittens accompanied by camera-wielding doves.

Health and Safety rightly put the kybosh on prattish and childish displays of self-authorised semi-divinity. But when the time comes, “Health and Safety” will go too, into the street, along with the jetsam of a tyrannical state which deliberately connives at the infantilisation of Teh People, for its own ends.

The People will of course decide when, and if, displays of adoring white kittens are suitable adjuncts for  the Man Who worked out how to …Read p-53_ …

Just two stories this week – a cancer pathway and innovative dipsticks…

New Relationship between Tumour Suppressor Genes: Knocking out genes in mice believed to play a tumour inhibiting role would intuitively result in rapid cancer development.  However, it was a surprise to McGill researchers that mice lacking the tumour suppressors 4E-BP1 and 4E-BP2 were refractory to cancer growth.  When they deleted another well known tumour suppressor, p53, then they observed enhanced tumour growth more aggressive than knocking out p53 alone.  These results demonstrate for the first time a cooperative effect between 4E-BPs and p53 and highlight the advantages of indentifying individual molecular profiles to predict responsiveness to therapeutic strategies.  Dr. Nahum Sonenberg, who led the research team at McGill University remarks “this is another fine example how basic research, which intends to provide answers to fundamental questions about molecular mechanisms of cell proliferation, leads to unexpected findings that advance our ability to understand and cure human disease.”  The study appears in this week’s issue of Cancer Cell.

Bioactive Paper Sensors: A simple and rapid method to detect pesticides or toxins in food using innovative test strips was recently developed at McMaster University.  These “dipsticks” can sense the presence of small amounts of pesticides in food and within five minutes, a colour change indicates the level of the contaminant.  Future applications of this technology, with a few tweaks,  include detecting for the presence of food borne bacteria such as E.coli, Listeria, or Salmonella.  The practicality, ease of use without the need for large equipment, and the ability to get almost immediate results are huge advantages of the dipsticks to provide rapid screening and could play a role in curbing future outbreaks.  Dr. John Brennan’s team describes their research in the latest issue of Analytical Chemistry.

Normalnie wzruszyłem się. Wszedłem na blogasa, patrzę, a tu dwa razy więcej odwiedzin niż zazwyczaj, mimo że nic ostatnio nie opublikowałem. Sumienie zaczęło mnie gryźć, więc postanowiłem jednak zrobić wypiski, mimo że w tym tygodniu pewnie i tak będzie dużo do czytania z okazji Nobli i w ogóle

Tak więc w tym tygodniu, z lekkim opóźnieniem przeczytacie o tym, co wykończyło T. Reksia; o próbach wyjaśnienia efektu placebo; o energooszczędnych wegorzach; o tym, jak łatwo i wydajnie transportować próbki w skali nano (czyli trochę autoreklamy); o kolejnym sensorze ratującym życie; i na koniec o p53 – nieśmiertelnym białku i nieśmiertelnym temacie…

1. Na wielu spośród zachowanych skamieniałości Tyrannosaurusa rexa można zaobserwować liczne zmiany patologiczne na dolnej szczęce. Do tej pory często przypisywano to skutkom promienicy – bakteryjnemu zakażeniu kości, bądź też opisywano je jako rany wojenne, pochodzące od ugryzień przez inne osobniki. Jednak według pracy opublikowanej zaledwie kilka dni temu w piśmie PLoS ONE, takie zmiany patologiczne mogą wskazywać na pasożytniczą ptasią infekcję, trychomonadozę (rzęsistkowicę). Objawy są podobne do występujących u współczesnych ptaków chorych na tę chorobę. Uczeni wskazują na kilka ciekawych konsekwencji tego znaleziska. Po pierwsze, tyranozaury nie były przodkami ptaków, co wskazuje na to, ze zakażenie nie tylko było międzygatunkowe, ale i “międzygromadowe”, co bynajmniej nie jest tak częste, jakby się to mogło wydawać (i dlatego też każdy przypadek grypy zwierzęcej atakującej ludzi traktuje się z taką uwagą…). Po drugie, choroba prawdopodobnie stała się szybko endemiczna, a rozprzestrzeniała się w populacji tyranozaurów na skutek albo zjadania ofiar zarażonych przez pierwotniaka albo nawet na skutek przypadków kanibalizmu. Wreszcie, wiele wskazuje na to, że przynajmniej niektóre z badanych osobników, zmarły na skutek tej infekcji, najprawdopodobniej przez zagłodzenie na śmierć. Wniosek z tego taki: nawet bycie dużym i groźnym nie czyni nikogo odpornym na zagrożenia. Słonia powalić może nawet mrówka.

“Common Avian Infection Plagued the Tyrant Dinosaurs”, Ewan D. S. Wolff, Steven W. Salisbury, John R. Horner, David J. Varricchio, PLoS ONE 4(9): e7288; DOI: 10.1371/journal.pone.0007288 (30 Sep 2009)

2. Trzech naukowców amerykańskich rozwodzi się w artykule w ostatnim Clinical Pharmacology & Therapeutics nad tym, jak neuroobrazowanie może pomóc nam zrozumieć działanie substancji placebo. Bo że efekt jest i działa, to wiemy, ale pozostaje nieodkrytą tajemnicą, dlaczego organizm po zażyciu tabletek z cukrem zachowuje się, jakby miały działanie terapeutyczne… Badania przy użyciu PET i funkcjonalnego MRI mogą przybliżyć nas do zrozumienia tego zjawiska. Z drugiej jednak strony może sie też okazać, że na każdą uzyskaną odpowiedź pojawi się pięć nowych pytań…

“Neuroimaging Placebo Effects: New Tools Generate New Questions”, J.M. Jarcho, E.A. Mayer and E.D. London, Clinical Pharmacology & Therapeutics 86(4): 352–4; DOI: 10.1038/clpt.2009.126 (2009)

3. Grupa badaczy z Teksasu opisuje w swojej pracy w PLoS Biology strętwokształtną rybę elektryczną, która wyraźnie jest bardziej efektywna w oszczędzaniu energii niż my. Produkcja sygnału elektrycznego jest oczywiście bardzo energochłonna, dlatego ryby z gatunku Sternopygus macrurus (nie tylko te, ale te akurat zostały opisane) zwiększają moc produkowanego pola elektrycznego nawet o 40% w szczególnych okolicznościach , czyli wtedy, kiedy jest im to naprawdę potrzebne – w nocy oraz aby komunikować się z innymi osobnikami tego gatunku. Czyli nawet ryba potrafi! A ja wciąż nie mogę wychować moich współlokatorów tak, żeby nie zostawiali telewizora na stand-by…

“Circadian and Social Cues Regulate Ion Channel Trafficking”, Michael R. Markham, M. Lynne McAnelly, Philip K. Stoddard, Harold H. Zakon, PLoS Biology 7(9): e1000203; DOI: 10.1371/journal.pbio.1000203 (29 Sep 2009)

4. Prawie zapomniałem, ale na szczęście sobie przypomniałem Otóż opublikowaliśmy zaledwie tydzień temu pracę w Chemical Communications, w której pokazaliśmy w jaki sposób można, wykorzystując nową technologię mikrokropli – tak to się chyba nazywa, chociaż jestem niemal pewien, że nie ma jeszcze adekwatnego polskiego słownictwa – łączyć różne techniki analityczne on-line, off-line, jakbyście sobie tylko nie życzyli, nie martwiąc się o utratę analitu i/lub uzyskanego już rozdziału. Ogólnie powiem tylko, że każdy chemik analityk powinien na to rzucić okiem, bo chociaż na razie jest to tylko publikacja proof-of-principle, to samo rozwiązanie jest niezwykle ekscytujące. Ja sam, jak zobaczyłem po raz pierwszy, że działa, to prawie zawału dostałem, tak mi ciśnienie skoczyło.

“Droplet-based compartmentalization of chemically separated components in two-dimensional separations”, X. Z. Niu, B. Zhang, R. T. Marszalek, O. Ces, J. B. Edel, D. R. Klug and A. J. deMello, Chemm. Commun.; DOI: 10.1039/b918100h (2009)

5. Czujnik wykrywający i oznaczający ilościowo pięć różnych bakteryjnych i roślinnych toksyn jednocześnie został opisany przez grupę państwa Dorner w ostatnich numerze Analyst. Grupa wyprodukowała wysoce specyficzne przeciwciała przeciwko toksynom takim tak rycyna czy botulina, które zostały wykorzystane do stworzenia fluorescencyjnego testu wykrywającego te substancje z olbrzymią czułością.

“Simultaneous quantification of five bacterial and plant toxins from complex matrices using a multiplexed fluorescent magnetic suspension assay”, Diana Pauly, Sebastian Kirchner, Britta Stoermann, Tanja Schreiber, Stefan Kaulfuss, Rüdiger Schade, Reto Zbinden, Marc-André Avondet, Martin B. Dorner and Brigitte G. Dorner, Analyst 134: 2028-39; DOI: 10.1039/b911525k (2009)

6. Z okazji 30-lecia odkrycia p53 – białka pełniącego niesamowicię istotną rolę w zaprogramowanej śmierci komórek (apoptozie), a co za tym idzie także często uwikłanego w ten czy inny sposób w patogenezę raka – pismo Nature Reviews Cancer poświęciło mu w ostatnim czasie wiele uwagi. Miałem polecić jeden z artykułów, ale po przejrzeniu spisu treści, polecam właściwie cały numer, bo wygląda na to, że co artykuł, to ciekawszy. W razie braku dostępu do pisma służę pomocą.

Nature Reviews Cancer 9 (2009)

A Montreal flavour this week…

Critical link between EGFR and Src oncogenes: On the heels of last week’s Friday Science Review post on Stat3 in breast cancer, Dr. William Muller’s research team at McGill University has published another significant find linking well known oncogenes, Src and EGFR/ErbB2.  Among their results, they demonstrated how Src can interact with some mutant EGFR receptors (identified in lung cancers) but not with wild type EGFR.  When a Src inhibitor was applied to cells expressing mutant EGFR, it attenuated the cancer-inducing potential of these EGFR mutants.  This suggests that Src is an important enzyme in the EGFR mutant signaling pathway and may present an alternate pathway to combat cancer cell resistance to EGFR inhibitors.

Details of this study are described in this week’s Molecular and Cellular Biology.

MET oncogene in breast cancer: Next door to the Muller Lab at the new Goodman Cancer Centre in Montreal is Dr. Morag Park and her research team who recently generated a mouse model to mimic and study the Met oncogene in breast cancer.  The results were a complex cancer phenotype where gene expression and histological profiles demonstrated similarities to aggressive human breast cancers expressing Met.  Whereas prior to their study, Met was only correlated with poor outcome in breast cancer patients, this mouse model provides the specific link and identifies clinical cases where anti-Met therapy may be beneficial.

You can read more about it here in Proceedings of the National Academy of Sciences.

Key proteins in Natural Killer Cells: Also this week, Dr. André Veillette’s lab at the Institut de recherches cliniques de Montréal (IRCM) generated new insight into how Natural Killer Cells combat cancers of the blood, such as leukemias and lymphomas, or virus-infected blood cells.  As part of our immune system, the defense function of Natural Killer Cells requires three small proteins named SAP, EAT-2 and ERT that are unique to immune cells.  The proteins relay information from the cell surface SLAM family receptors to direct immune activities.  These data may eventually lead to pharmacological methods to increase the activity of Natural Killer Cells in destroying blood cancer cells or virus-infected cells.

Veillette’s lab generated knock-out mice missing all three proteins, which led to their findings, which are published in the latest edition of Nature Immunology.

p53 is regulated by JNK: p53 is a tumor suppressor protein that plays an important role in regulating cell growth and survival.  Its critical functions in the cell require p53 to be highly regulated through multiple layers of control, both to turn on and to turn off the protein’s activities.  One such method recently described in Proceedings of the National Academy of Sciences is through phosphorylation by the enzyme JNK.  This phosphorylation protects p53 from being targeted for destruction, thereby allowing p53 complexes to form and continue with their gene activating activities.

This research project was a collaboration between the Burnam Institute in San Diego and Dr. Katherine Borden’s team at the Université de Montréal.

Jurassic Park (for real?): Can you convert a chicken embryo to develop into a dinosaur?  No, this is not the makings of a movie but the idea of paleontologist Hans Larsson of McGill University who is proposing to try to make it work.  The theory is that by manipulating or swapping certain “switch” genes during the chicken embryo’s development, he can reproduce some features of a dinosaur.  He does not actually intend to hatch live prehistoric animals – for obvious reasons:

“It’s a demonstration of evolution,” said Larsson, who has studied bird evolution for the last 10 years.

“If I can demonstrate clearly that the potential for dinosaur anatomical development exists in birds, then it again proves that birds are direct descendants of dinosaurs.”

“We’re not going to hatch a T. rex or something,” Larsson chuckles.

The idea came to him after meeting Jack Horner, author of the book “How to Build A Dinosaur” and the technical advisor behind the Hollywood version of Jurassic Park.

Come back to the Friday Science Review (perhaps in a few years) for an update on the “chickensaurus” experiment…

“What the nucleolus says to a tumour pathologist” başlıklı makale nükleolle ilgili sorulara cevap veriyor. Özellikle içindeki bir tabloda p53 ün nükleolle olan ilişkisi güzel anlatılmış. Bu sayede reaktif süreçlerde de niye nükleol belirginliği olduğunun cevabını detaylıca öğrenmiş oldum.

Histopathology. 2009 May;54(6):753-62.

Courtesy : Oxford Journal

Although reports on the efficacy of homeopathic medicines in animal models are limited, there are even fewer reports on the in vitro action of these dynamized preparations. In Amla Cancer Research Centre, Kerala , Ellanzhiyil Surendran Sunila, Ramadasan Kuttan, Korengath Chandran Preethi and Girija Kuttan have evaluated the cytotoxic activity of 30C and 200C potencies of ten dynamized medicines against Dalton’s Lymphoma Ascites, Ehrlich’s Ascites Carcinoma, lung fibroblast (L929) and Chinese Hamster Ovary (CHO) cell lines and compared activity with their mother tinctures during short-term and long-term cell culture. The effect of dynamized medicines to induce apoptosis was also evaluated and they have studied how dynamized medicines affected genes expressed during apoptosis. Mother tinctures as well as some dynamized medicines showed significant cytotoxicity to cells during short and long-term incubation. Potentiated alcohol control did not produce any cytotoxicity at concentrations studied. The dynamized medicines were found to inhibit CHO cell colony formation and thymidine uptake in L929 cells and those of Thuja, Hydrastis and Carcinosinum were found to induce apoptosis in DLA cells. Moreover, dynamized Carcinosinum was found to induce the expression of p53 while dynamized Thuja produced characteristic laddering pattern in agarose gel electrophoresis of DNA. These results indicate that dynamized medicines possess cytotoxic as well as apoptosis-inducing properties.

Recently, limited investigations on the efficacy of dynamized medicines in animal models as well as clinical trials have reported that potentiated Lycopodium clavatum has protective action against CCl₄-induced liver damage in rats (3) and that chelidonium 30C could ameliorate both p-dimethylaminoazobenzene and azodye-induced hepatocarcinogenesis in mice (4,5). Anti-genotoxic effect of different dynamized medicines has also been reported (6,7): Arsenicum album was found to ameliorate arsenic-induced toxicity in mice as well as in clinical studies and could reduce the elevated antinuclear antibody titer and hematological toxicities (8,9). Homeopathic therapy for asymptomatic HIV carriers has also proven beneficial (10) and recently Rajendran (11) reported homeopathy as a supportive therapy in cancer. Pathak et al. (12) investigated Ruta 6 on regression of human glioma brain cancer cell growth clinically and found that Ruta induces severe telomere erosion in MGRI brain cancer cells but has no effect on B-lymphoid cells and normal lymphocytes. Banerji and Banerji (13) reported that Ruta was effective for intracranial cysticercosis.

Very few investigations have explored the action of dynamized medicine in in vitro cell culture systems. Podophyllum has been shown to inhibit adhesion of neutrophils to serum-coated micro plates (14). Traumeen S, a homeopathic formulation used clinically to relieve trauma and inflammation has been shown to inhibit the production of Interleukin-β, TNF- and Interleukin-8 by human T cells and monocytes in culture (15). Many homeopathic drugs at low potencies were found to potentiate oxidative metabolism in cultured cells (16).

Medicines Used :

From होम्योपैथी नई सोच/ नई दिशायें

Results:

Although the healing potential of homeopathic drugs is widely accepted, the exact mechanism of action is still unclear. In paragraphs 63–69 of Organon, Hahneman describes the mechanism of action through the ‘primary action’ of the medicine (dynamized or not) and the ‘secondary and curative reaction’ of the organism: ‘Every agent that acts upon the vitality, every medicine, deranges more or less the vital force, and causes a certain alteration in the health of the individual for a longer or a shorter period. This is termed primary action. Although a product of the medicinal and vital powers conjointly, it is principally due to the former power. To its action our vital force endeavors to oppose its own energy. This resistant action is a property, is indeed an automatic action of our life-preserving power, which goes by the name of secondary action or counteraction’. We have tried to explain the mechanism of action of the dynamized preparations taking into consideration the original proposition by Samuel Hahnemann and have approached this problem by investigating the action of dynamized drugs in various cultured cells in a systematic scientific manner.

Cytotoxic activity of a drug is often considered a first step towards elucidating its possible use against cancer and all of the drugs selected are being used by homeopathic practioners against cancer. They have  found that in short-term cytotoxicity research, some of the dynamized preparations showed significant cytotoxic actions against cancer cell lines and at times the activity was higher than that of the mother tinctures. For example, Conium at 200C potency was more cytotoxic than its mother tincture and that the cytotoxicity induced by Carcinosinum was higher at 200C than at 30C potency indicating that dynamization induces the cytotoxic potential of these medications. Results were more pronounced during MTT assay in which a longer period of incubation was involved. Many dynamized preparations at potency of 200C inhibited the growth of L929 cells. Clonogenic assay using CHO cells is a standard method to determine growth inhibitory activity of the drugs and we found that dynamized preparations of Thuja, Hydrastis, Carcinosinum and Podophyllum at 200C potency almost completely inhibited the CHO colony formation. As in other cases, Conium 200C was more active than 30C. We have confirmed the cytotoxic potential of dynamized preparations by thymidine uptake, for the marker of the inhibition DNA synthesis. As in the case other experiments, DNA synthesis was significantly inhibited by several dynamized preparations.

Cytotoxicity could be produced in cells either by necrosis or by apoptotic induction. Apoptosis, which is known as programmed cell death is highly regulated by events taking place within the cell and is highly relevant with respect to the destruction and removal of transformed cells from the body. The induction of apoptosis could be an external agent and a cascade of reactions taking place within the cell produces an ultimate cell death. Some of the events via occurring during apoptosis include morphological changes in the cell, production of apoptotic bodies, damage to genetic material and finally induction of proteolytic enzymes, which produces cellular destruction. Apoptosis could be visualized by morphology and DNA laddering. In the present study, dynamized preparations induced apoptosis as observed from their morphology and DNA laddering. Moreover, dynamized preparation of Carcinosinum could induce the p53, which is considered to be a proapoptotic protein and involved in signal transduction pathway.

The mechanism of action of some of the homeopathic drugs has been proposed. Potentiated preparation of Ruta possesses protective action on normal B-lymphoid cells against H₂O₂-induced chromosomal damage (13). Moreover, the telomere erosion was enhanced in cancer cells by treatment with Ruta while normal cells showed no change. Thus, the telomeres that protect individual chromosomes of cancer cells are damaged by Ruta, which may be the mechanism of its therapeutic action in brain cancer (13).

The protective effect of Chelidonium against p-DAB-induced hepatic cancer may occur by the modulating effect of the drug on restoration of damage caused to several gene-regulated phenomena like enzyme activities and chromosomal abnormalities. This gives insight into the mechanism of action, which may be by means of interfering with the process of carcinogenesis by actively modifying actions of oncogenes or by activating tumor suppressor genes (5). Another mechanism of actions of homeopathic drugs may occur through immune modification. Benveniste (17) has shown that human basophils undergo degranulation not only at usual anti-IgE antibody doses but also at extremely high dilutions. Bastide (18)has shown the therapeutic effect of high dilution of –β interferon and thymic hormones on cellular immunity and had good therapeutic effect in immunodepressed patients. Similarly Bentwich et al. (19) revealed that small amounts of antigens are capable of specific antibody response. The role of immunity in the therapeutic efficacy of homeopathic medicines has also been reviewed (20).

There  results indicate that the dynamized preparation initially produces a secondary action on cells that is in line with the original proposition by Hahnemann on the mechanism of action of medicines dynamized or not. However, limited knowledge in this area does not fully explain the mechanism of action of all drugs . More scientific analyses are warranted to elucidate these interesting preparations of ultra dilutions.

Download full study report

in pdf : http://ecam.oxfordjournals.org/cgi/reprint/6/2/257

in text : http://ecam.oxfordjournals.org/cgi/content/full/6/2/257

human metastatic breast cancer cells (from abcam.com)

Two recently published cancer studies reveal differences in the severity of cancer (specifically breast and colorectal) between black Americans and other racial or ethnic populations are based in genetic variations.  I think we should pause a moment and recognize that today is National Day, an observance popular in K-12 education to recognize the day that the research scientists at NIH completed sequencing of the human genome.  The knowledge gained from that tremendous endeavor has informed the physicians and scientists is countless labs since and the current findings in the disparities between the burden of illness suffered by blacks with breast or colorectal cancer tumors is no different.

Dr. Carol Rosenberg and her colleges at Boston University School of Medicine have discovered that cancer tumors lacking genetic expression for estrogen receptors, progesterone receptors and HER-2 (human epidermal growth factor), so called “triple-negative” tumors were more common among black women.  Specifically, their study of 415 women (36% non-Hispanic white, 43% black, 10% Hispanic, and 10% other) revealed that black women have a three times greater risk of having triple-negative breast cancer tumors as compared to non-Hispanic whites.  Triple-negative phenotype tumors (which make up 15% of all invasive breast cancers) have been associated with poor prognosis and low 5-year survival rates.  The implications are significant to understanding the prevalence of an increased burden of illness and death suffered by black women developing breast cancer.

“The reasons explaining this finding are not certain, but it is possible that black women may be at intrinsically greater risk of these more aggressive tumors,” observed Dr. Rosenberg.

The proportion of black women suffering from triple-negative breast cancer tumors was the same when comparing women under or exactly fifty years of age to those over fifty, as well as women who were obese to those who we not obese.  The findings of this study were release late last month in the Journal of Breast Cancer Research.

Earlier this month, Upender Manne, PhD and his colleges at University of Alabama at Birmingham released the results of their investigation of colorectal cancer in Clinical Cancer Research.  Scientists have thoroughly documented he p53 gene and its association with colon cancer in the literature.  In the current study, statistically significant differences in colorectal cancer tumors where identified and described.  Dr. Manne and his team reviewed 373 patients (63% non-Hispanic white and 37% black surgically treated between 1985 and 1995 at the anatomical, cellular and genetic level.  The codon 72 of the p53 protein can contain the amino acid (a protein building block) proline (Pro) or arginine (Arg).  As a result, there are three different phenotypes of p53 protein Arg/Arg, Arg/Pro or Pro/Pro.  In previous studies, researchers have found the Arg/Arg phenotype of the p53 protein to have a higher potential for inducing apoptosis (or programmed death of cancer cells).  On the other hand, the Pro/Pro phenotype of the protein has been found to accompany a greater proliferation of cancer cells.  In general, mutations that disrupted or inactivated the p53 protein have been associated with progression of the cancer.

The racial difference in the prevalence of these phenotypes of p53 protein associated with the colon cancer tumors was statistically significant.  Nineteen (19%) percent of colorectal cancer tumors in blacks had the Arg/Arg phenotype protein compared to 36% of the tumors in whites; 64% of tumors in blacks had the Arg/Pro phenotype protein compared to 57% of the tumors in whites; and 17% of tumors in black had the Pro/Pro phenotype protein compared to 7% of whites.  The implication of the numbers is this:

blacks had a higher prevalence of the p53 protein phenotype (Pro/Pro) which is associated with more aggressive tumors and progression of the cancer.

Specifically, this Pro/Pro phenotype was 2.5 times more likely to be associated with death in black patients than those with the other phenotypes.  In stark contrast, these Pro/Pro phenotye p53 proteins were only 1.6 times more likely to be associated with death in white patients than those with the other phenotypes.  As Dr. Manne stated,

“African-Americans, but not Caucasians, with the Pro/Pro phenotype had significantly higher mortality…and risk of death due to [colorectal cancer].”

This particular study, also identified additional, statistically significant

April 2009 issue

differences between tumors in blacks and non-Hispanic whites that create future opportunities to examine and disaggregate what Manne referred to as the “confounding from other lifestyle factors of the aggressiveness of the disease.”

Medscape Oncology contacted an independent physician, Dr. Hemant Roy of the Feinberg School of Medicine at Northwestern University to comment on the clinical significance of colorectal cancer study.  “Risk assessment is complex, and this and other genetic polymorphisms are an important piece of the puzzle…While this observation may not necessarily represent a stand-alone future test, it takes us closer to understanding risk and hence targeting screening.”  I think this observation speaks to the value of the molecular and genetic characterizations that come from health disparities research such as the two studies I discussed here, they decipher a piece of the entire puzzle that determine risk factors and help health care providers target and personalize the screening process.

Sources:

Stead LA, Lash TL, Sobieraj JE, Chi DD, Westrup JL, Charlot M, Blanchard RA, Lee JC, King TC, Rosenberg CL. Triple-negative breast cancers are increased in black women regardless of age or body mass index. Breast Cancer Res. 2009 Mar 25;11(2):R18.

Beals JK. New Polymorphisms Affect Colorectal Cancer Risk, Progression in
Blacks.  In Medscape Medical News.  Cited April 24, 2009.  Available at <http://www.medscape.com/viewarticle/590604>

Katkoori VR, Jia X, Shanmugam C, Wan W, Meleth S, Bumpers H, Grizzle WE, Manne U.  Prognostic significance of p53 codon 72 polymorphism differs with race in colorectal adenocarcinoma. Clin Cancer Res. 2009 Apr 1;15(7):2406-16.

Come fanno i tumori a invadere gli organi vicini? E perchè alcuni tumori non generano metastasi e rimangono confinati nel loro organo di origine? I ricercatori dell’Università di Padova e Modena-Reggio Emilia, con un progetto finanziato da Airc, hanno fatto luce sui meccanismi che rendono il tumore più adatto a dare origine a metastasi

In particolare, il gruppo guidato da Stefano Piccolo, del Dipartimento di Biotecnologie Mediche dell’Università di Padova, ha scoperto che alcune mutazioni genetiche presenti nella maggior parte dei tumori sono in grado di determinare la capacità delle cellule cancerose di dare origine a metastasi fin dai primi stati della malattia. Un tumore con questa caratteristica dovrà essere trattato in maniera più aggressiva dal punto di vista chirurgico o farmacologico.

Tra le mutazioni incriminate ci sono quelle nei geni Ras e p53, o quelle che modificano la catena di segnali trasmessa dal gene TGFbeta. Sono tutte mutazioni già note da tempo per essere coinvolte nei processi di diffusione del tumore mediante metastasi, ma la ricerca coordinata da Piccolo ha dimostrato che tali mutazioni collaborano tra di loro e lavorano per raggiungere un obiettivo comune: indebolire la proteina p63, vero e proprio difensore delle cellule dalla metastasi.

Quando una cellula staminale tumorale (potenzialmente immortale) perde p63, viene infatti recuperata la capacità cellulare di migrare e invadere gli organi circostanti. E si parla di recupero di tale capacità poichè il programma di regolazione di geni che rende la cellula capace di migrare è presente a livello embrionale durante la formazione degli organi. In questa fase infatti le cellule si spostano in base a precisi stimoli, in genere di tipo ormonale. Le cellule metastatiche non creano niente di nuovo, semplicemente risvegliano tale programma. Una combinazione di geni mutati stabilisce dunque se il tumore è pronto per dare metastasi che poi si svilupperanno grazie a precisi segnali che arrivano dal microambiente del tumore.

Dal punto di vista dell’applicazione clinica questa ricerca è importante perchè grazie ad alcune “spie molecolari” – geni in grado di dirci se p63 è presente o meno – si potranno definire le migliori strategie di cura, fino ad arrivare a terapie personalizzate.

Fonte: AIRC

Researchers from City of Hope Medical Center have published the results of analysis of samples from 525 patients submitted for p53 mutation testing, clarifying which classification schemes to use in Li-Fraumeni cancer syndrome diagnosis and prognosis.

The information first described at the last ASCO meeting now appears in detail in the Journal of Clinical Oncology.

The publication includes p53 mutation prevalence tables, and some intriguing correlations.

For instance:

* Cancer of ovary, pancreas, and prostate, not normally associated with Li-Fraumeni, occurred in some people with germline p53 mutations.
* No patients with invasive breast cancer between ages 30 and 49 and no relatives with four classic Li-Fraumeni cancers (sarcoma, adrenocortical carcinoma, breast cancer, brain cancer) had germline p53 mutations. All five patients with breast cancer under age 30 and a history of one of these cancers other than breast cancer in a first- or second-degree relative had these mutations.
* In this study, families without at least one member who had one of these four cancers are highly unlikely to have a p53 mutation.

A recent review in Nature Reviews Cancer discusses polymorphisms in the TP53 locus and their implications for cancer.

Clinical Trials

What new studies are testing adenovirus-based gene therapy for cancer using p53?

Practice Guidelines

Find last year’s update to NCCN’s guideline on genetic assessment for families with high risk of breast and ovarian cancer.

(Please ignore the misleading 2001 publication date on this result listing. We’ll look into the problem.)

Noteworthy recent results in Cancer/Hemic
What are your colleagues looking at?

EpCAM

Transcriptional Repression of Epithelial Cell Adhesion Molecule Contributes to p53 Control of Breast Cancer Invasion
Cancer Research (February 1, 2009)

head squamous cell carcinoma

RESULT: Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study
Lancet (March 2, 2009)

RESULT: Phase I Study of Lapatinib in Combination With Chemoradiation in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck
Journal of Clinical Oncology (March 2, 2009)

CLINICAL QUERY of the week
Lessons from a genuine search result

Someone wrote in to say they appreciated finding this result (or, actually, pair of results) with the search term interleukin. (You’ll need to scroll down to find them.)

RESULT: Managing Toxicities of High-Dose Interleukin-2
Cancer Network

TIP: Notice that this result appears twice in close succession on the same page. This is not a mistake. Some publishers divide long online articles into more than one page, and SearchMedica has discovered two pages from the same article that are relevant to the search term.

The first page of the article will not always be the first of several results on the list.

To locate the first page, after clicking on the article title, scroll to the bottom of the page where you will see a list of consecutive numbers. Click on the number “1″ to read the article from the beginning.

Grattis min allra bästaste bästaste vän!!!!!!!

I förrgår hade min bästa vän Magdalena sin disputation på Karolinska Institutet.

Jag åkte dit med min kära pappa och lyssnade på hennes innehållsrika presentation om det arbete hon gjort under hennes sju år där.

Självklart höll hon allt på Engelska och jag som är så otroligt insatt i hennes ämne när det gäller cancer forskning höll med henne om allt hon kommit fram till

The p53-induced Wig-1 protein: Studies of Interaction Partners and Expression in Tumor Cells

Jaa.. det är vad hon fördjupats sig i.. och jag hade ju såklart stenkoll på vad Wig-1 proteinet var och p53 vet ju alla vad det är så jaa..det var intressant.

Men det viktigaste av allt är ändå att min bästa vän nu har fått sin Doktorsgrad(Ph.D.) 

 Ett viktigt bevis på att hon definitivt är den mest smarta människan jag känner!!!

Så när du Magdalena vinner Nobelpriset och botar all världens Cancer så får du inte glömma att JAG är din bästa vän;) hehe

Så förutom att vara världens bästa vän,en underbart pedagogisk och varmhjärtad mamma,en otroligt allmänbildad kvinna och världens bästa fru om man frågar hennes make Micke.. Så är hon nu också Dr. Magdalena.

Så än en gång… GRATTIS MIN ÄLSKADE VÄN!!!!

EWS-FLI1 Suppresses NOTCH-Activated p53 in Ewing’s Sarcoma.

Ban J, Bennani-Baiti IM, Kauer M, Schaefer KL, Poremba C, Jug G, Schwentner R, Smrzka O, Muehlbacher K, Aryee DN, Kovar H.

Cancer Res. 2008 Sep 1;68(17):7100-9.

Although p53 is the most frequently mutated gene in cancer, half of human tumors retain wild-type p53, whereby it is unknown whether normal p53 function is compromised by other cancer-associated alterations. One example is Ewing’s sarcoma family tumors (ESFT), where 90% express wild-type p53. ESFT are characterized by EWS-FLI1 oncogene fusions. Studying 6 ESFT cell lines, silencing of EWS-FLI1 in a wild-type p53 context resulted in increased p53 and p21(WAF1/CIP1) levels, causing cell cycle arrest. Using a candidate gene approach, HEY1 was linked to p53 induction. HEY1 was rarely expressed in 59 primary tumors, but consistently induced upon EWS-FLI1 knockdown in ESFT cell lines. The NOTCH signaling pathway targets HEY1, and we show NOTCH2 and NOTCH3 to be expressed in ESFT primary tumors and cell lines. Upon EWS-FLI1 silencing, NOTCH3 processing accompanied by nuclear translocation of the activated intracellular domain was observed in all but one p53-mutant cell line. In cell lines with the highest HEY1 induction, NOTCH3 activation was the consequence of JAG1 transcriptional induction. JAG1 modulation by specific siRNA, NOTCH-processing inhibition by either GSI or ectopic NUMB1, and siRNA-mediated HEY1 knockdown all inhibited p53 and p21(WAF1/CIP1) induction. Conversely, forced expression of JAG1, activated NOTCH3, or HEY1 induced p53 and p21(WAF1/CIP1). These results indicate that suppression of EWS-FLI1 reactivates NOTCH signaling in ESFT cells, resulting in p53-dependent cell cycle arrest. Our data link EWS-FLI1 to the NOTCH and p53 pathways and provide a plausible basis both for NOTCH tumor suppressor effects and oncogenesis of cancers that retain wild-type p53.

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