Sunday, March 24, 2013

INTERESTING FACTS

Most Oncologists get more practice changing information from the JCO and the New England Journal of Medicine than from BLOOD which has turned "Molecular" on them!  Blood has become more of a research tool than of impact on day to day Oncology/Hematology practice.  A balance is needed guys over there!  Even the Lancet is now better perceived by "practitioners"!
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*Researchers keeps ahead of Oncology practice, and that is good.
While we are still coming or waking to the reality of the existence of Crizotinib.

Crizotinib

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Crizotinib
Systematic (IUPAC) name
3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine
Clinical data
Trade names Xalkori
MedlinePlus a612018
Licence data US FDA:link
Pregnancy cat. D (US)
Legal status -only (US)
Routes Oral
Pharmacokinetic data
Half-life 46 hours
Identifiers
CAS number 877399-52-5 
ATC code L01XE16
PubChem CID 11626560
DrugBank DB08700
ChemSpider 9801307 Yes
UNII 53AH36668S Yes
KEGG D09731 Yes
ChEMBL CHEMBL601719 Yes
Synonyms PF-02341066
1066
Chemical data
Formula C21H22Cl2FN5O 
Mol. mass 450.337 g/mol
  (what is this?)  (verify)
Crizotinib (trade name Xalkori,[1] Pfizer), is an anti-cancer drug acting as an ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor, approved for treatment of some non-small cell lung carcinoma (NSCLC) in the US and some other countries, and undergoing clinical trials testing its safety and efficacy in anaplastic large cell lymphoma, neuroblastoma, and other advanced solid tumors in both adults and children.[2]
 -------------------------------

RESEARCHERS ARE MOVING FORWARD
LOOKING NOW IN COMBINATION OF
1.  FIG-ROS1
2.  SLC34a2-ROS1
3.  COEXISTENCE  OF EGFR AND ROS1

THIS IS A GOOD SIGN.
IT IS ONCE AGAIN A SIGN OF HOW A CELLULAR PROCESS GETS COMPLICATED QUICKLY JUST AS YOU START UNDERSTANDING.

LESS THAN 0.5% OF ONCOLOGIST HAVE USED CRIZOTINIB TO DATE!

NOMENCLATURE OF GENES IN SMALL CELL LUNG CANCER

Before we start this discussion, a few comments !

1. It is generally accepted that small cell cancer is found in those patients with higher smoking exposure and, indeed, genetic alterations in small cell cancers are deeper (more nuclear) than those in non small cell cancer.  Mutation in Kras and p16 are not a characteristic of small cell lung cancers, whereas nuclear phenomena abound.  p53 mutation which is driven by DNA alteration is found altered in 90% of small cell lung cancer.

Rb gene mutations which affect resumption of DNA duplication is also altered in 90% of small cell lung cancer (SCLC).

c-MYC amplification, which is located down stream cytoplasmic pathways, at the Histone level, is more observed in SCLC.

By going nuclear, SCLC will not respond effectively to superficial (membrane/ cytoplasmic ) interventions such as EGFR blockade. However, there is a secondary angiogenic amplification usually marked by amplification at FGF2 (target and biomarker) which open the door to anti-angiogenic agents in small cell cancer.  Here researcher have to select between an anti-MEK or an anti-FGF2 or both, if cost is not an issue.  Remember that an anti-MEK will also affect secondary amplification of HiF which exacerbates angiogenesis  (and metastasis indirectly) in this disease! Remember: Digoxin inhibit HIF, and HIF amplify angiogenesis through activation of PDGF-B.

2. p16 effect which is occurring in cytoplasmic pathway will not be a major driving target in SCLC, however there is evidence that secondary cytoplasmic phenomena do occur.

see the work of Pederson et al.

==================================

Transcriptional Gene Expression Profiling of Small Cell Lung Cancer Cells 1

  1. Hans Skovgaard Poulsen3
"In the CPH 54 cluster there is also high expression of extracellular matrix proteins, such as a large variety of collagens, fibronectin, and laminin, which are not expressed to the same level by the rest of the SCLC cell lines. This indicates that the cell lines may be of fibroblastoid origin rather than SCLC, although the xenografted tumors from the CPH 54A cell line preserved the pathologically determined features of SCLC (4) . In addition, these are the only cell lines that do not have mutated p53 5 or loss or mutated pRB, two of the characteristics of SCLC (19, 20, 21, 22) . "
"
However, this is the case for another tumor suppressor, CDKN2A (p16INK4), which is a negative regulator of cell proliferation by stabilizing the tumor suppressor pRB. Deletions, reduced expression, or mutations of p16INK4 are observed frequently in a variety of tumors. However, the microarray analyses showed high expression by most SCLC lines and tumors, which is consistent with previous observations of high expression in SCLC tumors (60 , 61) and cell lines (62) . p16INK4 leads to cell cycle arrest in the presence of functional pRB. pRB has been found to be absent or mutated in the majority of SCLC tumors and cell lines (20 , 22 , 63 , 64) . In fact, absence of p16INK4 has been found to be restricted to lung cancer cell lines that retain wild-type pRB (65) . There are two major forms of CDKN2A, p16INK4 and p14ARF, derived by alternative splicing. p14ARF is likewise regarded a tumor suppressor by stabilizing p53, but also has p53-independent cell cycle regulatory functions (66) . The probe sequences on the microarray will recognize both forms. RT-PCR using a p14ARF specific primer set showed expression levels similar to the array analysis (Fig. 4B) demonstrating the presence of this mRNA. p14ARF transcription is stimulated by E2F transcriptions factors (67) , and the analysis shows high expression of E2F1 and E2F3 in all of the SCLC cell lines, as has been found previously for most SCLC tumors by immunohistochemistry (68)  "

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SO E2F1 IS A STRONG TARGET.  THIS COMES UP REPEATEDLY IN OUR BLOG! CHECK IT OUT!  IF YOU FIND IT YOU WILL KNOW WHY.

3.By going nuclear, small cell cancer is closer to Leukemia in their pathogenesis, and DNA alteration is a prominent treatment intervention explaining the superiority of Cisplatin Etoposide in this disease.  (watch for DNA repair potential and the Bcl-2 which are ready to fight back!)

4. Hypermethylation is one of the major means used by the cancer cells to suppress some of the genes that could distract the involved cell from a neoplastic differentiation.  It open the door to an added therapy to the Cisplatin and Etoposide back bone.

5. c-MYC and FGF2  amplification can be driven by PTTG1 (securin), a novel target in SCLC.

6. The growth factors in this disease are
-Bombesin/Gastrin releasing Peptide
-Chromogranin B
-Nicotinic Acethylcholine
-securin

QUESTION FOR YOU: DO YOU THINK AMPLIFICATION OF RET PREDICTS HYPERCALCEMIA?  WE ARE STILL WORKING HARD AT CRBCM !

(GENES IN LUNG CANCERS WILL FOLLOW)

Wishing our friends a relaxed week-end with this rhythmical song: Come on, come on Jay! (standard) by Clement Albert on Ubetoo - Listen to Clement Albert songs for free

Come on, come on Jay! (standard) by Clement Albert on Ubetoo - Listen to Clement Albert songs for free

Saturday, March 23, 2013

CPRIT, a flawed organization?

CPRIT, a great organization in principle, but fundamentally flawed or skewed. By now we know it is a university funding organization.  The idea that CPRIT will ever become what it was imagined to be has been irreversibly given a blow to the cheek.  It still is to be known that it will ever recover. Its funding shackled by politicians who now own this dream-like organization!
And this is very unfortunate because there is increasing evidence that cancer is curable as target therapy has opened a new round of successful therapies. The CPRIT debacle has left deep wounds and critics see in the remnant a living organization bent on continuing the same dance!  The abrupt closure of a few fictitious companies is a tell-tale sign of what is to come unless an uninvolved  visionary leader takes control. Political appointees are unfortunately what we see.  And the objectivity and look from the outside is lost, new wind is not coming and CPRIT's old culture stays the same!  All we will see is a tighter dance, but globally the same dance. Cancer Cure will escape the people one more time!

New researchers are coming to CPRIT backed Universities, but every university has a culture and pressures that shape these researchers.  And the old CPRIT failed to control the events happening after money had been given. Nothing tells the observer that those changes have been put in place.  We know by now that CPRIT is an exclusive university funding source by design (reviewers have strong university ties and see the world in this light and prism) and that the private medical and research sector is excluded.  We should not mention our organization, we have been technically banned given our criticism...CPRIT only wants to hear good things!  But the truth is that it is refusing to hear what would and could make it a grand organization. CPRIT's responsibilities should not stop with the granting of funds, but making sure the implemented projects match CPRIT's objectives and policies even deep into the course of the projects' implementation. That fix has not occurred.  The risk is to end up with disparate and  futile findings (probably commercial). When you look around, there are antibodies commercially available everywhere, however no one is using them in a cohesive plan, and without its own plan for the cure, CPRIT is at the mercy of Universities. And these politicians at the head of CPRIT WILL NOT SEE THE DANGER OF BEING PULLED ONE WAY OR THE OTHER BY POWERFUL UNIVERSITIES.  CPRIT needs to pull away from this cosyness with Universities to achieve its goal quicker. It is playing safe by relying on Universities, but it is loosing its own perspective and is positioning  itself further as being only a university instrument ripe for another round of "cleaner" abuses.

GENES IN PROSTATE CANCERS

In a man, there is a 1/3 chances that if found with cancer, it will be prostate cancer.  But only in 10 percent of those who are dying and who have prostate cancer is it this cancer that causes death.  Meaning a number of patients with prostate cancer will die of another cause.   Over 186,000 men were diagnosed with Prostate Cancer and close to 29,000 died of this disease yearly. A 6.5 to 1 ratio.  This point to a heterogeneous disease, and we will fail by not stating (infamous statement) that autopsy showed that in men over 80 years of age, over 70% will be found with Prostate Cancer.  As if it was part of aging.   By aging, you implicate Telomeres and most likely the MTOR.
Before jumping to the MTOR which is cool lately, there is one overwhelming phenomena, that is the Prostatic cell development is significantly dependent on Testosterone for its growth.  And we have in our armamentarium many agents to stop Testosterone.  As we will suggest and as achieved for many hormones, Testosterone blockage can be completed at the cell level, in the testicles, in the Adrenal gland as well as by blocking it in the Pituitary stalk. It is not until one develops refractoriness to Androgen that one may die of Prostate cancer as the principal cause of death.  So the physician's task is to keep coming up with new strategies to block the Androgens.  There lies the key to treating Prostate Cancers.

THE REVERSAL OF FORTUNES
=========================
It is widely accepted that a small numbers of cells in the prostatic cancer mass (may be less than one percent at onset) will be mutated or spontaneously refractory to Androgen.  As time goes by, more mutations related or not to treatment, will occur, while hormone sensitive cancer cells are being starved from stimulation.  Over time, the refractory cells will grow in importance and drive the life of the tumor and metastasize everywhere replacing the hormone sensitive one. The disease will therefore become non responsive to Hormone and here comes patient rapid deterioration as the malignant tumor now adopts a new pattern of behavior including new locations of metastasis.  Liver lesions, lung lesions and Brain invasion becomes more likely to occur.   Chemotherapy with Taxane and Cabazitaxel, a derivative of natural Taxoids, become the mainstay of treatment.  ( Particularly now that Sipuleucel-T  is advanced to before chemotherapy) Keeping in mind that the reversal of fortune is change of proportions, there is still a portion of hormone responsive cells and Lupron needs to continue while chemotherapy is given!

PSA, Prostate Specific Antigen
======================
Prostate cancer is actually one of the rare diseases that can be screened effectively, and found early by a blood test.  That is until we realize that finding a disease that may not kill early leads to unnecessary treatment and patient futile mental disturbance in many cases.  We are now retracting, pulling back on our toes and people are growing reluctant to be tested. That is until we clarify what it is we should be looking for to make sure we discern who needs therapy! We needs to know who needs an early intervention.  For this the tumor needs to tell us I am bad, and we need to catch the message.  And most researchers believe Genetic profiling is one of the critical approaches  to tell the difference. The challenge is that Adenocarcinoma seems to follow a progression in their deterioration to a full blown cancer.  And some genes are present in prostatitis, Benign Prostatic hypertrophy, Low Gleason prostatic cancer and high gleason cancers.   Now which one makes it a bad cancer.  This is the current challenge but it will clearly open the door to Target therapy!

Molecular basis of Prostatic cancer Pathogenesis.

While dealing with Intraepithelial Atypical lesion, the presence of Alpha-Methylacyl-Coenzyme Aracemase is considered a signature of Adenocarcinoma presence!   In our discussion on Choriocarcinoma, we suggested that Hypermethylation is a major Knockdown way for E2.  It plays a role here too!   And gene fusion is the other abnormality that is a prominent phenomenon TMPRSS2 and ETS fusion (or TMPRSS2-ERG), and things" degenerate" from there !

Also note that the Androgen receptor gene is located on Xq11-13, (note the "q")

GENES in Prostate Cancers! (TO BE DEFINITELY CONTINUED)

GENES IN CHORIOCARCINOMA (AN UPDATE AND TARGET THERAPY)

The major interest here at the CRBCM is of course obtaining a cure.  There is therefore a strong interest in knowing more about cancers that are deemed curable today.  Studying the genes known in these diseases could provide some clues to their susceptibility to chemotherapy drugs available today. Below are some of the genes for CHORIOCARCINOMA:

1. NECC1 on 4q11  (notice the "q" as this may be bad news)

This is a gene of differentiation.  And from what we have gathered, it is a gene that codes for a Core Binding Factor like Molecule, these complexes of major proteins with various functions put together to direct cellular functions in directions.  The proteins globally function as regulators of other cellular functions. These proteins are sequentially positioned in the CBF to drive into some directions.  Most of the times, the CBF has a portion that attaches to the DNA.  The attachment could silence the DNA.  The silenced DNA here seems to block Cardiac differentiation and forces the direction of activity toward syncytial trophoblastic differentiation.  This is why this gene is expressed in normal placenta.  In choricarcinoma, dedifferentiation occurs and NECC1 is mutated and silenced.  This is called a suppressor gene as it relates to Cardiac muscle differentiation, but clearly not for the tumor from what we gathered.  The Mutation will have to occur at the "q" location.  We will look further to establish if the "p" of this gene is located on chromosome 7.
Desactivation of NECC1 leads to cardiac hypertrophy.  Being a CBF like molecule, it may solicit Histone deacetyl transferases as part of its nuclear activity.  We still are unclear whether it is at the center of the pathogenesis of choriocarcinoma or not!
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2.CSH1
The protein encoded by this gene is a member of the somatotropin/prolactin family of hormones and plays an important role in growth control. The gene is located at the growth hormone locus on chromosome 17 along with four other related genes in the same transcriptional orientation; an arrangement which is thought to have evolved by a series of gene duplications. Although the five genes share a remarkably high degree of sequence identity, they are expressed selectively in different tissues. Alternative splicing generates additional isoforms of each of the five growth hormones, leading to further diversity and potential for specialization. This particular family member is expressed mainly in the placenta and utilizes multiple transcription initiation sites. Expression of the identical mature proteins for chorionic somatomammotropin hormones 1 and 2 is up-regulated during development, although the ratio of 1 to 2 increases by term. Mutations in this gene result in placental lactogen deficiency and Silver-Russell syndrome. [provided by RefSeq, Jul 2008]"
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3. IGFR1
"Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a protein that in humans is encoded by the IGF1 gene.[1][2] IGF-1 has also been referred to as a "sulfation factor"[3] and its effects were termed "nonsuppressible insulin-like activity" (NSILA) in the 1970s.
IGF-1 is a hormone similar in molecular structure to insulin. It plays an important role in childhood growth and continues to have anabolic effects in adults.
 IGF-1 is produced throughout life. The highest rates of IGF-1 production occur during the pubertal growth spurt. The lowest levels occur in infancy and old age.
Other IGFBPs are inhibitory. For example, both IGFBP-2 and IGFBP-5 bind IGF-1 at a higher affinity than it binds its receptor. Therefore, increases in serum levels of these two IGFBPs result in a decrease in IGF-1 activity."(Wikipedia)

IGFR1  amplification is used in autocrine faction to drive cancer growth, it acts here a as a TGF.
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4. CHFR
E3 ubiquitin-protein ligase CHFR is an enzyme that in humans is encoded by the CHFR gene.[1][2][3]
(wikipedia)

"One protein that has been suggested to be part of the antephase checkpoint is Chfr (checkpoint protein with an FHA domain and ring finger; Scolnick and Halazonetis, 2000), a ubiquitin ligase that is down-regulated in several cell lines through methylation of its promoter (Mizuno et al., 2002). Chfr was originally reported to delay progress to prometaphase in the presence of colcemid (Scolnick and Halazonetis, 2000), and cells were surprisingly described as delaying with high cyclin B1-Cdk1 activity (Scolnick and Halazonetis, 2000), which conflicted with a role as part of the antephase checkpoint because cyclin B1-Cdk1 is fully activated only in late prophase. However, in Xenopus laevis extracts, Chfr is able to delay the activation of cyclin B-Cdk1, apparently by targeting the Polo-like kinase, Plx, for degradation by the proteasome (Kang et al., 2002), thereby preventing the activation of the Cdc25 phosphatase that activates Cdk1. Chfr has also been reported to affect Polo-like kinase levels in human cells in response to DNA damage (Shtivelman, 2003). But whether Chfr does target Polo for degradation or not is debatable because Chfr has been shown to conjugate ubiquitin via its lysine 63 residue (Bothos et al., 2003) that normally acts in signal transduction, especially for stress signals (Deng et al., 2000; Ulrich and Jentsch, 2000; Hofmann and Pickart, 2001; Pickart, 2001; Wang et al., 2001), rather than to target proteins to the proteasome."
Matsusaka and Pines suggested.

CERTAINLY DOWN REGULATION HERE OPEN THE DOOR TO USE OF VELCADE OR THE PROTEASOME INHIBITORS.
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5. MUC3A"Associations of distinct variants of the intestinal mucin gene MUC3A with ulcerative colitis and Crohn's disease [1]." (WIKI) Its gene is located at 7q22  (notice the q) it has a prognosis value
But we also know that MUC1 will be more important in this cancer and shield by its mucinous product cell from cancer watching cells.

James Gum et al "Mucinous cancers are generally more extensive at diagnosis. Membrane mucins are an important class of glycoproteins with diverse structures and functions. These molecules contain extracellular domains that serve as a scaffold for O-glycosylation. The O-glycans associated with membrane mucins are thought to function in cytoprotection and have been demonstrated to confer anti-adhesion properties upon cells (1). This latter characteristic may play a role in the dissemination and spread of cancer cells. In addition to conferring these electrostatic/physical properties upon cells, membrane mucins can anchor carbohydrate moieties with specific functions. Selectin ligands associated with membrane mucin glycans, for example, play a role in cancer cell extravasation during metastases (2). Certain membrane mucins function in signal transduction as well (35). Several membrane mucins also serve as clinically important tumor antigens (6, 7)."

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6. TAF7

TAF7

From Wikipedia, the free encyclopedia
Jump to: navigation, search
TAF7 RNA polymerase II, TATA box binding protein (TBP)-associated factor, 55kDa
Identifiers
Symbols TAF7; TAF2F; TAFII55
External IDs OMIM600573 MGI1346348 HomoloGene11768 GeneCards: TAF7 Gene
RNA expression pattern
PBB GE TAF7 201023 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 6879 24074
Ensembl ENSG00000178913 ENSMUSG00000051316
UniProt Q15545 Q9R1C0
RefSeq (mRNA) NM_005642 NM_175770
RefSeq (protein) NP_005633 NP_786964
Location (UCSC) Chr 5:
140.7 – 140.7 Mb
Chr 18:
37.64 – 37.64 Mb

PubMed search [1] [2]

Transcription initiation factor TFIID subunit 7 also known as TAFII55 is a protein that in humans is encoded by the TAF7 gene.[1]
The intronless gene for this transcription coactivator is located between the protocadherin beta and gamma gene clusters on chromosome 5. The protein encoded by this gene is a component of the TFIID protein complex, a complex which binds to the TATA box in class II promoters and recruits RNA polymerase II and other factors. This particular subunit interacts with the largest TFIID subunit, as well as multiple transcription activators. The protein is required for transcription by promoters targeted by RNA polymerase II.[2]
TAFII55_N
Identifiers
Symbol TAFII55_N
Pfam PF04658
InterPro IPR006751
The general transcription factor, TFIID, consists of the TATA-binding protein (TBP) associated with a series of TBP-associated factors (TAFs) that together participate in the assembly of the transcription preinitiation complex. TAFII55 binds to TAFII250 and inhibits its acetyltransferase activity. The exact role of TAFII55 is currently unknown but studies have shown that it interacts with the C-jun pathway.[3] The conserved region is situated towards the N-terminal of the protein.[4] This entry talks about the N-terminal domain.
TAF7 interacts with TATA which

The TATA-binding protein (TBP) is a general transcription factor that binds specifically to a DNA sequence called the TATA box. This DNA sequence is found about 30 base pairs upstream of the transcription start site in some eukaryotic gene promoters.[1] TBP, along with a variety of TBP-associated factors, make up the TFIID, a general transcription factor that in turn makes up part of the RNA polymerase II preinitiation complex.[2] As one of the few proteins in the preinitiation complex that binds DNA in a sequence-specific manner, it helps position RNA polymerase II over the transcription start site of the gene. However, it is estimated that only 10-20% of human promoters have TATA boxes. Therefore, TBP is probably not the only protein involved in positioning RNA polymerase II.
TBP is involved in DNA melting (double strand separation) by bending the DNA by 80° (the AT-rich sequence to which it binds facilitates easy melting). The TBP is an unusual protein in that it binds the minor groove using a β sheet.
Another distinctive feature of TBP is a long string of glutamines in the N-terminus of the protein. This region modulates the DNA binding activity of the C-terminus, and modulation of DNA-binding affects the rate of transcription complex formation and initiation of transcription. Mutations that expand the number of CAG repeats encoding this polyglutamine tract, and thus increase the length of the polyglutamine string, are associated with spinocerebellar ataxia 17, a neurodegenerative disorder classified as a polyglutamine disease.[3]

BASICALLY INITIATE OR PARTICIPATE IN THE INITIATION OF OF TRANSCRIPTION/TRANSLATION
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8. CDC123
9. PSMD
10. HAS2
11. CD44  a member of the EZRIN/S100P/ Villin -Complex
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12. S100P 

S100P

From Wikipedia, the free encyclopedia
Jump to: navigation, search
S100 calcium binding protein P

PDB rendering based on 1j55.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols S100P; MIG9
External IDs OMIM600614 HomoloGene81743 GeneCards: S100P Gene
RNA expression pattern
PBB GE S100P 204351 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 6286 n/a
Ensembl ENSG00000163993 n/a
UniProt P25815 n/a
RefSeq (mRNA) NM_005980 n/a
RefSeq (protein) NP_005971 n/a
Location (UCSC) Chr 4:
6.69 – 6.7 Mb
n/a
PubMed search [1] n/a

Protein S100-P is a protein that in humans is encoded by the S100P gene.[1][2][3]
The protein encoded by this gene is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21; however, this gene is located at 4p16. This protein, in addition to binding Ca2+, also binds Zn2+ and Mg2+. This protein may play a role in the etiology of prostate cancer.[3]

Interactions

S100P has been shown to interact with EZR.[4] which this protein serves as an intermediate between the plasma membrane and the actin cytoskeleton. It plays a key role in cell surface structure adhesion, migration, and organization.[2]

Interactions

VIL2 has been shown to interact with Sodium-hydrogen exchange regulatory cofactor 2,[3][4] Merlin,[5] SDC2,[6] CD43,[7] Fas ligand,[8][9] VCAM-1,[10] S100P,[11] ICAM3,[12][13] ICAM-1,[12] Sodium-hydrogen antiporter 3 regulator 1,[14][15] ICAM2,[12] Moesin,[8][16][17] PALLD[18] and PIK3R1.[19]

Given the multitude of interactions the EZERIN appears a critical molecules for signal propagation intra and extra-cellularly.  EZRIN the Villin (Vilain) comes into everything.  In the endothelium,  This complex of molecules is " involved in the generation and maintenance of the anchoring structure. These results provide the first characterization of an endothelial docking structure that plays a key role in the firm adhesion of leukocytes to the endothelium during inflammation." 
This is a basis for novel anti-inflammatory strategy.
It also interact with the so called Peripheral proteins of which  "some are water-soluble proteins and associate with lipid bilayers irreversibly and can form transmembrane alpha-helical or beta-barrel channels. Such transformations occur in pore forming toxins such as colicin A, alpha-hemolysin, and others. They may also occur in BcL-2 like protein , in some amphiphilic antimicrobial peptides , and in certain annexins . These proteins are usually described as peripheral as one of their conformational states is water-soluble or only loosely associated with a membrane.[11]"
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13. delta-like1
14. STOX1
15. JAK/STAT1
16. GCM1
Chorion-specific transcription factor GCMa is a protein that in humans is encoded by the GCM1 gene.[1][2]
This gene encodes a DNA-binding protein with a gcm-motif (glial cell missing motif). The encoded protein is a homolog of the Drosophila glial cells missing gene (gcm). This protein binds to the GCM-motif (A/G)CCCGCAT, a novel sequence among known targets of DNA-binding proteins. The N-terminal DNA-binding domain confers the unique DNA-binding activity of this protein.[2]WIKIPEDIA

Chou et al "the activity of GCMa can be post-translationally regulated by protein phosphorylation, ubiquitination, and acetylation, it is unknown whether GCMa activity can be regulated by sumoylation. In this report, we investigated the role of sumoylation in the regulation of GCMa activity. We demonstrated that Ubc9, the E2 component of the sumoylation machinery...Our study demonstrates that GCMa is a new sumoylation substrate and its activity is down-regulated by sumoylation."
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18. Cx31: Connexin, important in cell adhesion and embryogenesis.  In adult Mutation at Cx31 lead to sensory neural deafness as it contribute to synaptic integrity and Monocyte.  A legitimate secondary target in blood disease.
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also we will include
19. Endoglin
20. Syncitin
21. HCG
22. Connexin 31
23. E-Cadherin

Lets go to work!

Another thing to look at is the propensity in these diseases to develop thrombosis on BEP treatment!
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Basically we see an emphasis on
1. Trophoblastic differentiation
2. a drive to dupplication and genetic amplification
3. Use of IGF as autocrine growth hormone
4. use of invasive and adhesion molecule to metastasize a prominent feature of Choriocarcinoma
5. NF2 could be the indicator of prominent tendency to brain metastasis, we will look for it in Breast and small cell lung cancer
6. E2 Methylation introduces Velcade an the anti-proteasome in refractory disease
7 Anti-EZRIN/Villin as a strategy
8. somewhere, where is the WNT pathways in all this?
Chemotherapy cures here because of rapid DNA multiplication!

Friday, March 22, 2013

Cervical Screening Guidelines Updated

Cervical Screening Guidelines Updated

Laurie Barclay, MD
Mar 21, 2013
Guidelines posted online March 21 by the American Society for Colposcopy and Cervical Pathology (ASCCP) now address management of discordant co-tests, in which results of either Papanicolaou (Pap) smear or human papillomavirus (HPV) testing are positive, but not both. The new algorithms update the 2006 recommendations, based on risk analysis of new data from nearly 1.4 million women in a National Cancer Institute–Kaiser Permanente Northern California cohort.
"The primary focus of the revised recommendations [is] the obsolescence of the 2006 guidelines and the fact that guidelines on management of women with Pap tests read as unsatisfactory or missing endocervical cells were never ratified by a consensus conference," lead author L. Stewart Massad Jr, MD, professor of obstetrics and gynecology at Washington University in St. Louis, Missouri, and ASCCP board of directors member, told Medscape Medical News by email.
According to the 2012 consensus guidelines from the American Cancer Society, ASCCP, and the American Society of Clinical Pathologists, women aged 21 to 65 years should have Pap tests every 3 years. Further screening is not recommended for women with test results negative for precancerous lesions.
"Women ages 21-24 have a very low risk of cancer," Dr. Massad said. "Many lesions identified by Pap testing in this group are HPV-related changes that will resolve without treatment as the body's immune system recognizes and reacts to the HPV; they are not precancer. Treatment of these lesions with usual destructive therapies for precancer can predispose to preterm delivery if these young women later conceive."
For women aged 30 to 64 years, the Pap test and HPV test are preferred for screening. Although previous guidelines had recommended return to "routine screening" after evaluation, it was unknown whether that was still acceptable given the longer screening intervals.
Algorithms in the updated guidelines include the following:
  • Management of discordant co-tests, in which results of either Pap smear or HPV testing are positive, but not both, with integration of co-testing into follow-up. Colposcopy and/or HPV DNA typing may be indicated.
  • Return to "routine" screening in women treated for cervical cancer.
  • Extension of management guidelines for adolescents under 21 years of age to women under 25 years of age. Workup varies according to findings of atypical squamous cells of undetermined significance, or low-grade or high-grade squamous intraepithelial lesion, and may include colposcopy.
  • Consideration of whether cervical intraepithelial neoplasia grade 1 (CIN1) on endocervical canal curettage (ECC) should be treated as positive ECC or CIN1.
  • Management of women with unsatisfactory cytologic findings and specimens that are missing endocervical or transformation zone components. Colposcopy may be required for women with positive HPV results or with repeated unsatisfactory cytologic findings.
The ASCCP funded development of these guidelines. The guidelines authors have disclosed no relevant financial relationships.

News: Hodgkin's disease; Mammograms

News
*German researchers have suggested that in elderly patients with early stage Hodgkin's disease, the 4 cycles of ABVD normally planned before radiation were too toxic and not as effective.  They suggested up to 20% of patients were unable to complete planned therapy.

They also suggested truncated (AVD) combinations with Revlimid or Brentuximab Vedotin  as alternative options.

*Danish researchers have reported that over 400 cases of false alarm mammograms in a screening of 1300 women.  They further suggested that in some cases the false alarm rates could reach up to 60% of cases as reported by Medscape.  This is very remarkable with possibility to further evaluations including invasive surgical procedures.  And a lot of women could end up with an unnecessary Biopsy.  And this is bad news because hx of Biopsy increases Breast cancer risk!

Meat consumption and mortality - results from the European Prospective Investigation into Cancer and Nutrition



Results
As of June 2009, 26,344 deaths were observed. After multivariate adjustment, a high consumption of red meat was related to higher all-cause mortality (hazard ratio (HR) = 1.14, 95% confidence interval (CI) 1.01 to 1.28, 160+ versus 10 to 19.9 g/day), and the association was stronger for processed meat (HR = 1.44, 95% CI 1.24 to 1.66, 160+ versus 10 to 19.9 g/day). After correction for measurement error, higher all-cause mortality remained significant only for processed meat (HR = 1.18, 95% CI 1.11 to 1.25, per 50 g/d). We estimated that 3.3% (95% CI 1.5% to 5.0%) of deaths could be prevented if all participants had a processed meat consumption of less than 20 g/day. Significant associations with processed meat intake were observed for cardiovascular diseases, cancer, and 'other causes of death'. The consumption of poultry was not related to all-cause mortality.
Conclusions
The results of our analysis support a moderate positive association between processed meat consumption and mortality, in particular due to cardiovascular diseases, but also to cancer.
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