Coalition for the Reversal of Breast Cancer Mortality in African American Women

A blog about research, awareness, prevention, treatment and survivorship of Breast Cancer and all cancers, including targeted scientific research and a grassroots approach to increase screening for cancer, especially in the low income and under-insured population of El Paso, Texas, with a view to expand this new health care model to many other 'minority' populations across the United States and beyond

Tuesday, April 30, 2013

AAPS Sues over Maintenance of Certification

SOMEBODY HAD TO SPEAK UP AS THIS CERTIFICATION PROCESS HAS BECOME ALMOST UN-DO-ABLE with intricacies and often undisclosed PASS MARK LEVELS... !
Who in his healthy mind would want to pay dearly and take a very tough exam for which nobody knows what the requirements are to pass (number or % of questions answered correctly) .As a rule now, the exams take place, then all the individual physician's results of the session get corrected and average is computed, to which they then apply a mysterious and never publicized pass mark and then send out the "Pass" and "Fail" letters. We suspect that the computer program is set to always "Fail" at least 33 % of the candidates to assure repeat cash flow thanks to failed candidates having to re-register for an upcoming session. The hospital's requirement of board certification puts undue pressure on specialist and experts of long and good standing and thus deprives the population of valuable medical knowledge and best treatment options.
----------------------
Blog | April 28, 2013 | Healthcare Careers, Performance, Training
By Martin Merritt
The Association of American Physicians & Surgeons (AAPS) filed suit April 23, 2013, against the American Board of Medical Specialties (ABMS) over their maintenance of certification program. The suit, filed in a New Jersey federal court, alleges that the ABMS is restraining trade and causing a reduction in patient access due to burdensome recertification processes.
Jane Orient, MD, the AAPS' executive director, graciously agreed to discuss the issues with me.
Martin Merritt: I understand maintenance of certification (MOC) is one of the hottest topics in the field of medicine today?
Jane Orient: Yes. Many physicians are outraged, not only by the cost an expense which must be incurred to maintain certification, but also by the fear that MOC  is being advanced as a requirement for hospital privileges, and perhaps even maintenance of licensure (MOL).
MM: The public might think the ABMS is a government entity?
Jane Orient, MD JO: The ABMS is a not-for-profit corporation. According to the lawsuit filed by AAPS, the ABMS seems to exist to enrich its own executives, with little appreciable evidence that the MOC program has an effect on the quality of care.
MM: How does the ABMS MOC program actually work?
JO: I can mostly speak about what the lawsuit contains. ABMS and 24 separate corporations, which make up the 24 recognized board-certified specialties have agreed to impose on physicians a recertification program called the ABMS Maintenance of Certification. At one time, a physician could voluntarily choose to become board certified, and upon completion of the process, he or she was board certified for life. Now, the ABMS has decided to force board certified physicians to purchase its products every 10 years. If a physician cannot afford the time or the expense of recertification, he or she may be designated as "not meeting" the requirements of the ABMS, which tends to imply that a physician is less than qualified to care for patients.
MM: What is the AAPS seeking in the suit?
JO: AAPS’ lawsuit, seeks declaratory and injunctive relief to enjoin ABMS’s continuing violations of antitrust law and misrepresentations about the medical skills of physicians who decline to purchase and spend time on its program. AAPS also seeks a refund of fees paid by its members to ABMS and its 24 other corporations as a result of ABMS’ conduct.
Again, the lawsuit itself is the best source for information about the relief requested, but in a nutshell, what we are worried about is the fact that perfectly capable physicians are being black-balled, or locked out of the ability to treat patients, because they do not have the time, or inclination to purchase a product from a private corporation, which has nothing to do with the physician’s ability to treat patients.
MM. You cite an example in the lawsuit, I believe.
JO: In a case cited in this lawsuit, a first-rate physician in New Jersey was excluded from the medical staff at a hospital in his state simply because he had not paid for and spent time on recertification with one of these private corporations. He runs a charity clinic that has logged more than 30,000 visits, but now none of those patients can see him at the local hospital because of the money-making scheme of recertification.
MM: I would like to thank Dr. Orient for speaking with us. You can follow this lawsuit and other issues of concern at the AAPS website.
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Labels: AAPS, board certification, crbcm, healthcare, hospitals

THE PROOF IS IN!

Docetaxel-cisplatin might be superior to docetaxel-capecitabine in the first-line treatment of metastatic triple-negative breast cancer
ANOTHER CONFIRMATION THAT TRIPLE NEGATIVE  BREAST CANCER IS ANOTHER BEAST ALL TOGETHER.  AS WE HAVE SHOWN, HERE THE RECEPTORS ARE COMPLETELY DESENSITIZED, YOU HAVE TO GO TO MEDICATION DEALING WITH THE FIRST AND SECOND LAWS TO ATTACK THE CELL.  YOU HAVE TO GO "NUCLEAR" BY BREAKING DNA AND INTERFERING WITH MACROTUBULES.
WHAT IS UNCLEAR YET IS HOW THE DISEASE FINALLY ESCAPE.  CISPLATIN RESISTANCE MAY BE THROUGH INCREASING REPAIR OF DNA.

"These data demonstrated that overexpression of c-erbB-2/neu can lead to intrinsic Taxol resistance independent from mdr-1 mechanisms. Funding"  YU ET AL
THIS WAY RATHER!

"AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol"

  • Shubha Anand, 
  •  They suggest that AURORA-A amplification will predict poor responsiveness to Taxol and other agents that target the spindle checkpoint. If so, inhibitors of Aurora-A activity may be a valuable adjunct to these agents in the treatment of cancers that overexpress AURORA-A.

"Defective microtubule-kinetochore attachment and spindle formation

Why should elevated Aurora-A activity result in cell cycle abnormalities and chromosomal instability? The yeast ortholog of mammalian Aurora kinases, IPL1p, has been implicated in the mechanisms that regulate the attachment of chromosomes to the mitotic spindle during the metaphase-anaphase transition during mitosis. Several data suggest that IPL1p may work at a proximal position in these mechanisms to regulate steps in the capture of microtubules by kinetochores Biggins et al. 1999 and Li et al. 2002, and after capture, to stabilize correctly attached kinetochores by sensing the tension exerted via bipolar microtubule attachment (Biggins and Murray, 2001). These functions are apparently dependent upon the kinase activity of IPL1p (Biggins et al., 1999).

ALSO:
.".. Aurora-A overexpression in mammalian cells dysregulates these processes," Function of Aurora kinase A in Taxol-resistant breast cancer and its correlation with P-gp
Authors:
Yan Li,"
-----------------------------------------OTHER CONTINUE TO BELIEVE:
" Resistance to chemotherapeutic drugs generally, and to Taxol in particular, takes many forms. The best understood mechanism of resistance to Taxol involves the multidrug-resistance phenotype, mediated by the P-glycoprotein efflux pump"
" drug-resistant cancer cell lines and human tumor tissues have been shown to harbor tubulin gene mutations, alterations in total tubulin content, altered microtubule polymer levels, altered expression of tubulin isotypes, and altered microtubule-associated protein expression (13–20). All of these modifications in tubulin could, directly or indirectly, influence microtubule dynamics. Because suppression of microtubule dynamic instability is the event most sensitive to the lowest concentrations of Taxol, we have hypothesized that drug-sensitive and -resistant cells might display altered dynamic instability profiles that could ultimately be responsible for the resistance."

Resistance to Taxol in lung cancer cells associated with increased microtubule dynamics

A. Gonçalves*
=============================================================
LAI ET AL BELIEVE
" Taxol (paclitaxel) resistance represents a major challenge in breast cancer treatment. The TAZ (transcriptional co-activator with PDZ-binding motif) oncogene is a major component of the novel Hippo-LATS signaling pathway and a transcriptional coactivator that interacts with and activates multiple transcription factors to regulate various biological processes. Here, we report that elevated levels of TAZ found in human breast cancer cells are responsible for their resistance to Taxol."
" higher level of TAZ in mammary cells may be responsible for their resistance to Taxol."
 AND SAY ALL THIS COULD BE PREDICTED!

Prediction of paclitaxel sensitivity by CDK1 and CDK2 activity in human breast cancer cells

Satoshi Nakayama1
THESE AUTHORS CONTEND:

"We found that changes in CDK1 specific activity after paclitaxel treatment predicted the paclitaxel sensitivity of breast cancer cells and xenograft tumors. Baseline CDK2 specific activity was higher in tumors that were sensitive to paclitaxel than in tumors that were resistant to paclitaxel."
FURTHERMORE
" We found that an increase in CDK1 specific activity after paclitaxel treatment correlates with sensitivity of the xenografts to paclitaxel, and a lack of change in CDK1 specific activity correlates with a lack of sensitivity of the xenografts to paclitaxel. These findings indicate that analysis of CDK1 activity could be a powerful approach for predicting paclitaxel sensitivity."
 ==========================================================
MOST INTRIGUING THOUGH :

"MICRORNA-125B CONFERS THE RESISTANCE
OF BREAST CANCER CELLS TO
PACLITAXEL THROUGH SUPRESSION OF PRO-APOPTOTIC BCL-2 ANTAGONIST
KILLER 1 ( BAK 1) EXPRESSION"
MING ZHOU ET AL
THIS APPEAR TO BE THE STUFF TO BELIEVE IN BECAUSE IT GOES ALONG WITH HYPOXIA
WE KNOW THAT ENDOTHELIAL DISTURBANCE BY CHEMOTHERAPY INDUCES HYPOXIA OR HYPOXIC CONDITION STRESSING THE CELL, AND INDIRECTLY INDUCING THE MTOR FOR SURVIVAL.   THIS IS MY FAVORITE CHOICE AND CREATE AN OPPORTUNITY FOR MTOR INHIBITION AFTER FAILURE OF CHEMOTHERAPY!
MTOR EQUAL SURVIVAL

Expression of the anti-apoptotic gene survivin correlates with taxol resistance in human ovarian cancer

  • N. Zaffaroni,
  • M. Pennati,
========================================================
IF YOU WONDER ABOUT TAXOTERE  :   NO CROSS RESISTANCE!

No cross-resistance of taxotere and taxol to conventional chemotherapeutic agents against gastric cancers as detected by MTT assay.

Maeda S, Saikawa Y,
" both intrinsic and acquired TXT-related drug resistance in these PAC cell lines is mainly mediated by P-gp, but had no relationship to MRP and LRP expressions"  lIU ET AL!
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IN PROSTATE CANCER THIS IS NOT GOOD NEWS HOWEVER GIVEN THE CURRENT PATTERNS OF TREATMENT IN THIS DISEASE

"Abiraterone before Taxotere/Docetaxel chemotherapy may cause resistance to Taxotere/Docetaxel
Started By JimJimJimJim , Jul 13 2012 10:54 AM"  

REPORTEDLY BECAUSE OF COMPETITIVE ACTION OR SIMILARITY OF ACTION ON SAME RECEPTORS.
Posted by Peggy Kankonde at 10:33 AM No comments:
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NEW STUDY from cancer network!
"• Median OS with Avastin plus PC was 12.3 months vs 10.3 months with PC alone (HR=0.80 [95% CI, 0.68–0.94], P=0.013)1
• Patients receiving Avastin plus PC vs PC alone were 16% more likely to be alive at 1 year (51% vs 44%) and 53% more likely to be alive at 2 years (23% vs 15%)2
• Avastin plus PC demonstrated a median progression-free survival of 6.2 months (vs 4.5 months with PC alone, HR=0.66 [95% CI, 0.57-0.77], P<0.001) in Study E4599, based on investigator assessment (not independently verified)1,2
• Avastin plus PC had a response rate of 35% vs 15% with PC alone (P<0.001), based on investigator assessment (not independently verified)2
As shown in Study E4599, Avastin plus PC demonstrated an acceptable safety profile
Most common grade 3–5 adverse events in first-line metastatic non-squamous NSCLC patients (≥2% higher incidence in the Avastin arm)1"
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1.BAZIA
Binker et al!
"Acclimation of cellular metabolism to high salt concentrations involved re-modelling of amino acid and protein biosynthesis and increased expression of molecular chaperones (dehydrins, osmotin). Leaves suffered initially from dehydration which resulted in changes in transcript levels of mitochondrial and photosynthetic genes indicating adjustment of energy metabolism."
AtTIL
AtSIS "
This is the stuff of events at the membrane again!

 2. Inflammatory genes!
14 GALINDO_ACT_UP (Inflammatory and apoptosis signaling) IL1B, CXCL2, ILI8RAP, ILIRN, PTGS2, PDGFB, LILRB4, DUSP1, NFKB1A, IER3, FOSL1, CSF3, ICAM1, CCL3, RREB1, TNFSF9, BCL3, UBC, TNFAIP2, CCL4 2.04 0.008
15 CMV_UV-CMV_COMMON_HCMV_6HRS_UP (IFN and inflammatory signaling) RSAD2, MX1, OASL, NR4A2, IFIT3, ILI1, ZC3HAV1, RIPK1, PMAIP1, POLG2, ATF3, CREM, GCH1, C12ORF22, PSCD1, NR4A3, BTRC, SLC745, NR4A1

3. SMARCA5.
4. Harvesting Meis1 for the cure
" Meis1 to determine whether doing so produced an effect on the generation of new heart cells in mice."
 U.S. National Library of Medicine - The World's Largest Medical Library
(to be continued)

Posted by Peggy Kankonde at 6:08 AM No comments:
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Does malignant transformation established once permanently PTEN is depressed, or is it when c-MYC is amplified? or is it when receptors are permanently desensitized? is glycosylation of receptor protein or lack of,  the permanent trigger  of neoplastic transformation? will discuss further these topics!
Activation of P53 and mutation of mutation of Rb1.
EGFR amplification could be secondary to blockage at its receptors
PDGFRA amplification also
HOX gene
or mutation at the Meis1 and equivalent genes
No matter what cancers, these events may happen.
We will delve on these paths.
Posted by Peggy Kankonde at 3:28 AM No comments:
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Monday, April 29, 2013

THE QUESTION HAS BEEN RAISED: BIOTIN?

GIVEN THE IMPACT OF BIOTIN USE BY PATIENTS ON LEUCIN AND METHIONINE METABOLISMS, CAN BIOTIN USE COMPROMISE THE EFFECTIVENESS OF MTOR INHIBITORS? 
WE ARE GOING TO EXPLORE FURTHER THIS IMPORTANT QUESTION GIVEN THE GROWING IMPORTANCE OF MTOR INHIBITOR IN OUR ARMAMENTARIUM AGAINST CANCER AND THE WIDESPREAD USE OF BIOTIN IN OUR POPULATION!  (OR MULTIVITAMIN). WE ALSO KNOW THAT MOST OF US PRODUCE ENOUGH BIOTIN IN OUR COLON FOR DAILY NEED, BUT IS IT OF IMPORTANCE TO TRY TO SEE LEVELS OF BIOTIN IN PATIENTS WITH RESISTANT DISEASES?  IS DECREASING BIOTIN FROM THE BOWEL TO BE PURSUED IN PATIENTS ON MTOR INHIBITORS?  WILL SEARCH FURTHER THIS QUESTION!
Posted by Peggy Kankonde at 2:32 AM No comments:
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Sunday, April 28, 2013

YOU WANT TO TRY SOMETHING NEW AGAINST SARCOMA AND LEUKEMIA
GO AFTER THESE GENES!

SATB1

From Wikipedia, the free encyclopedia
Jump to: navigation, search
SATB homeobox 1

PDB rendering based on 1yse.
Available structures
PDB Ortholog search: PDBe, RCSB
[show]List of PDB id codes
Identifiers
Symbol SATB1
External IDs OMIM: 602075 MGI: 105084 HomoloGene: 2232 GeneCards: SATB1 Gene
[show]Gene Ontology
RNA expression pattern
PBB GE SATB1 203408 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 6304 20230
Ensembl ENSG00000182568 ENSMUSG00000023927
UniProt Q01826 Q60611
RefSeq (mRNA) NM_001131010 NM_001163630
RefSeq (protein) NP_001124482 NP_001157102
Location (UCSC) Chr 3:
18.39 – 18.49 Mb
Chr 17:
51.74 – 51.83 Mb

PubMed search [1] [2]

SATB1 (special AT-rich sequence-binding protein-1) is a protein which in humans is encoded by the SATB1 gene.[1]

Function

SATB1, the global chromatin organizer and transcription factor, has emerged as a key factor integrating higher-order chromatin architecture with gene regulation.[2] Recent studies have unraveled the role of SATB1 in organization of chromatin 'loopscape' and its dynamic nature in response to physiological stimuli.[3] At genome-wide level, SATB1 seems to play a role in organization of the transcriptionally poised chromatin. SATB1 organizes the MHC class-I locus into distinct chromatin loops by tethering MARs to nuclear matrix at fixed distances. Silencing of SATB1 mimics the effects of IFN-γ treatment on chromatin loop architecture of the MHC class I locus and altered expression of genes within the locus. SATB1 has also been shown to induce breast cancer tumor growth and metastasis through the altered expression of large numbers of genes.

Interactions

SATB1 has been shown to interact with HDAC1,[4] SMARCA5,[4] MTA2,[4] CHD4,[4] CUTL1,[5] POLR2J[6] and BAZ1A.[4]

2. HDAS1
3.SMARCA5
4.MTA2
5.CHD4
6.CUTL1
7.POLR2J
8.BAZIA
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MASTERING OF SOME GENES CONTROLLING RECEPTOR FUNCTIONS!

1.SLIT 2    Slit homolog 2 protein is a protein that in humans is encoded by the SLIT2 gene
                SLIT2 has been shown to interact with Glypican 1
 Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation.[2]  WIKIPEDIA

IF YOU RECALL OUR DISCUSSION  ABOUT RECEPTOR FAILURE, TUMOR GROWTH FACTOR FAILED TO STIMULATE OUR RECEPTOR BECAUSE OF LACK OF DERENGEMENT OF GLYCOSYLATION AND HEPARAN WAS THE FAILURE.  THIS PUT SLIT 2 AT THE RECEPTOR PARTICULARLY IN THE CENTRAL NERVOUS SYSTEM!
                              
2.MIG6:   The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2 (refs 3–5). Crystal structures of complexes between the EGFR kinase domain and a fragment of MIG6 show that a approx25-residue epitope (segment 1) from MIG6 binds to the distal surface of the C lobe of the kinase domain. Biochemical and cell-based analyses confirm that this interaction contributes to EGFR inhibition by blocking the formation of the activating dimer interface.(ZANG ET AL!)
 MIG-6 Negative regulator of EGFR signaling in skin morphogenesis. Acts as a negative regulator for several EGFR family members, including ERBB2, ERBB3 and ERBB4. Inhibits EGFR catalytic activity by interfering with its dimerization. Inhibits autophosphorylation of EGFR, ERBB2 and ERBB4. Important for normal keratinocyte proliferation and differentiation. Plays a role in modulating the response to steroid hormones in the uterus. Required for normal response to progesterone in the uterus and for fertility. Mediates epithelial estrogen responses in the uterus by regulating ESR1 levels and activation. Important for regulation of endometrium cell proliferation. Important for normal prenatal and perinatal lung development. Interacts with ERBB2. Interacts with EGFR. Levels are very low in quiescent cells. Up-regulated by mitogens. Belongs to the MIG6 family. Note: This description may include information from UniProtKB.

3.  SATB1  HERE BECAUSE OF THE CONNECTION WITH NUCLEAR MATERIAL.  interferon gamma act through here!

4.  SMAD6
Another powerful decoy
" Smad6 specifically competes with Smad4 for binding to receptor-activated Smad1, yielding an apparently inactive Smad1-Smad6 complex. Therefore, Smad6 selectively antagonizes BMP-activated Smad1 by acting as a Smad4 decoy."  Hata et al
 -------------------------------------------------------------------------------------------------
LTB4, because of its interactions with

Peroxisome proliferator-activated receptor gamma has been shown to interact with:
  • EDF1[8][9][10]
  • EP300[11][12]
  • HDAC3[13][11]
  • MED1[12]
  • NCOA3[12]
  • NCOA4[14]
  • NCOA2[12]
  • NR0B2[15]
  • PPARGC1A[16][17]
  • RB1.[11]

Clinical relevance

PPAR-gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis, and cancer. PPAR-gamma agonists have been used in the treatment of hyperlipidaemia and hyperglycemia.[18] PPAR-gamma decreases the inflammatory response of many cardiovascular cells, particularly endothelial cells.[19] PPAR-gamma activates the PON1 gene, increasing synthesis and release of paraoxonase 1 from the liver, reducing atherosclerosis.[20]
Many insulin sensitizing drugs (namely, the thiazolidinediones) used in the treatment of diabetes target PPARG as a means to lower serum glucose without increasing pancreatic insulin secretion.
A fusion protein of PPAR-γ1 and the thyroid transcription factor PAX8 is present in approximately one-third of follicular thyroid carcinomas, to be specific those cancers with a chromosomal translocation of t(2;3)(q13;p25), which permits juxtaposition of portions of both genes.[21] [22]
Recently pioglitazone, a PPAR-γ agonist has been shown to be effective in reducing inflammation in Parkinson's Disease models. Levels of MMPs and microglia (and therefore TNF-α and other cytokine levels) were found to be reduced. Thus it has been shown to be neuroprotective in MPTP mouse models.

BMP2
The protein encoded by this gene belongs to the transforming growth factor-beta (TGFB) superfamily. The encoded protein acts as a disulfide-linked homodimer and induces bone and cartilage formation. [provided by RefSeq, Jul 2008]
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Labels: crbcm, EGFR, ERBB2, ERRFI1, glycosyl phosphatidylinositol, glypican 1, MIG6, proteglycans, slit homolog 2 protein, SLIT2
DERLINS, A STRONG MECHANISM OF NEOPLASTIC TRANSFORMATION IN BREAST CANCER BECAUSE IT LEADS TO FAILURE OF RECEPTORS!

We have seen that the cellular membrane is one of the most important part to the cell not only because it gives a limit to the cell, but also because of its content and attachment.  The cell provide a boundary to the cell content, it has flippase and floppase/scramblases to maintain certain molecules in or outside its boundaries at a certain gradient, it is full of integrins of all kind of function, it contains the "nervous system" of the cell,  through its reticulum endothelium, it connects rapidos with the Nucleus, and contains all kind of receptors to various stimulant.

We have also explained how receptors' (part of cellular membrane) failure lead to neoplastic transformation by over-stimulation related co-receptors susceptible to same growth factor!   What we did not elaborate on was how a receptor can fail!   AND HERE COME THE DERLINS and the IRHOMS!
-------------------------------------------------------------------------------------------------
WIKIPEDIA
Derlin-1 also known as degradation in endoplasmic reticulum protein 1 is a protein that in humans is encoded by the DERL1 gene.[1][2][3] It is a member of the rhomboid-like clan of polytopic membrane proteins.

Function

Derlin-1 is part of a complex (that includes VIMP, SEL1, HRD1, and HERP) that mediates endoplasmic-reticulum-associated degradation (ERAD) that detects misfolded proteins in the endoplasmic reticulum and targets them for destruction.[4]

Clinical significance

Derlin 1 (DERL1) is up-regulated in metastatic canine mammary tumors as part of the unfolded protein response.

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

IT is our understanding that growth factors, some of which are integrins, some are anchored to the membrane from which they need to spring into motion and complete their function.  There is of course an enzyme that lyse the anchor.  Enzymatic proteins in charge of freeing the growth factors, the cyclins and second messengers to the receptors belong to the clan of the Rhomboid-like proteins.  The Derlins are part of a complexe as stated.  To better understand the derlins let's go back to the cytosol where Ubiquitination attaches ubiquitin to a molecule tagging it to proteasome degradation, the derlins tag membrane proteins for degration by the ERAD complex in the Endoplasmic Reticulum.  The derlin seems to impose a certain folding to the protein (growth hormone) a certain folding incompatible with their use, and therefore destine them to destruction.
It has been shown that upregulation of derlins completely rob the receptors from having  appropriate stimulation by its corresponding growth factors.  Decoy receptor will also take a portion of the growth receptor.  Just remember they do not have the intracellular portion of the receptor so the second messenger will never be stimulated.
====================================================
The Irhoms are decoy Rhomboid like protein.  They are like the enzyme but missing the catalytic teeth to cut the anchor but can attach to the integrins and change it enough to destine it to destruction by the ERAD.

" ZETTL ET AL.
iRhoms are a conserved subfamily of proteins related to rhomboid intramembrane serine proteases that lack key catalytic residues....iRhoms prevent the cleavage of potential rhomboid substrates by promoting their destabilization by endoplasmic reticulum (ER)-associated degradation;"

RHBDF1

From Wikipedia, the free encyclopedia
Jump to: navigation, search
Rhomboid 5 homolog 1 (Drosophila)
Identifiers
Symbols RHBDF1; C16orf8; Dist1; EGFR-RS; gene-89; gene-90; hDist1
External IDs OMIM: 614403 MGI: 104328 HomoloGene: 32085 GeneCards: RHBDF1 Gene
[show]Gene Ontology
RNA expression pattern
PBB GE RHBDF1 218686 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 64285 13650
Ensembl ENSG00000007384 ENSMUSG00000020282
UniProt Q96CC6 Q6PIX5
RefSeq (mRNA) NM_022450 NM_010117
RefSeq (protein) NP_071895 NP_034247
Location (UCSC) Chr 16:
0.11 – 0.13 Mb
Chr 11:
32.21 – 32.22 Mb

PubMed search [1] [2]
This box:
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  • edit
Inactive rhomboid protein 1 (iRhom1) also known as rhomboid 5 homolog 1 or rhomboid family member 1 (RHBDF1) is a protein that in humans is encoded by the RHBDF1 gene.[1][2][3] The alternative name iRhom1 has been proposed, in order to clarify that it is a catalytically inactive member of the rhomboid family of intramembrane serine proteases.
Posted by Peggy Kankonde at 5:20 PM No comments:
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Friday, April 26, 2013

KNOW THIS: A little bit of good news in the nation !

"Diabetes report card chronicling how the United States is faring in terms of management of the condition in adults, based on data to 2010, shows that there has been improvement, but there are still large gaps in terms of the control of 2 important risk factors, smoking and hypertension." (Medscape)".
Posted by Peggy Kankonde at 1:19 AM No comments:
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Labels: crbcm, diabetes, hypertension, medscape, smoking

CONSIDERATIONS IN RECURRENT OVARIAN CANCER TREATMENT:

Nice discussion by
By Edward Tanner, MD1, Deborah K. Armstrong, MD2 | April 15, 2013

In summary, and I hope I dig this right!

That one thing you look at in recurrent Ovarian cancer:
ASSUMING YOUR FIRST TREATMENT WAS PLATINUM BASED, WHICH IS MOST OF THE TIME THE CASE,  the disease free interval of more than 6 months (not 12 months) determines whether the disease is platinum sensitive. Because re-treatment should include platinum in those with the disease still sensitive! 

The other sensitive notion was the issue of Cytoreduction, according to these authors, Cytoreduction in recurrent disease makes sens only if the Progression free interval was more than 1 year (here "12 months" is needed), and when the lesions could be realistically resected! ("gross resection is achievable")

The discussion on Target therapy was limited to:
1. Adding Avastin to Gemzar +platinum which has shown to increase progression free survival
2. to using PARP inhibitors for those with BRCA Mutation
---------------------------------------------------------------
In other news!
"Similarities Between Ovarian and Basal-Like Breast Cancers:
In a copy number and genomic mutation analysis of all four breast cancer subtypes and ovarian cancer tumor samples, basal-like breast cancer and ovarian cancer were found to be most similar. The authors highlight that the similarities between basal-like breast cancer and serous ovarian cancers indicate that these two difficult-to-treat cancer types may be able to be treated with the same therapies—chemotherapy drugs, anti-angiogenesis agents, and others in development."

No comment was reported about the difference on MUCIN genes!
 " For both ovarian and basal-like breast cancer, TP53 was found mutated in 80% of tumors," pointing to the Receptor failure theory developed here!

"Basal-like breast cancers and ovarian cancers had similar rates of mutation and a similar spectrum of mutations. The basal-like tumors had a high frequency of mutations in the ATM, BRCA1, BRCA2, as well as RB1 loss and cyclin E1 amplification—the same mutations identified for ovarian cancers.
About 20% of basal-like breast tumors had a germline or somatic mutation in either BRCA1 or BRCA2. The authors suggest that these BRCA-mutated patients could potentially respond to Poly (ADP-ribose) polymerase (PARP) inhibitors. The analysis also showed various copy number amplifications and deletions that may be therapeutic targets."

For more, go to:

Study Finds Ovarian and Basal-Like/Triple-Negative Breast Cancers Genetically Similar

By Anna Azvolinsky, PhD1
----------------------------------------------------------------------------------------------------------------------


AND ALSO READ THIS:


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ONCOLOGY. Vol. 27 No. 1

mTOR Inhibitors in the Treatment of Breast Cancer

By Shaveta Vinayak, MD, MS1, Robert W. Carlson, MD1 | January 15, 2013
1Department of Medicine, Stanford University School of Medicine, Stanford, California


ABSTRACT: The phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway is commonly dysregulated in breast cancer. In preclinical studies, hyperactivation of the PI3K pathway has been linked to resistance to both endocrine therapy and trastuzumab(Drug information on trastuzumab) (Herceptin). Rapalogs, agents that primarily inhibit mTOR-raptor complex 1, have been studied in combination with endocrine therapy to overcome endocrine resistance. Trials of combination endocrine therapy and rapalogs in metastatic hormone receptor–positive breast cancer have demonstrated variable results. However, two independent trials have recently shown that combination everolimus (Afinitor) and tamoxifen(Drug information on tamoxifen) or combination everolimus and exemestane(Drug information on exemestane) (Aromasin) is more effective than either endocrine agent alone. These trials selected patients with cancer refractory to endocrine therapy, which may be important in sensitizing tumors to inhibition of this pathway. In human epidermal growth factor receptor 2 (HER2)-positive breast cancer, the early clinical data with combinations of PI3K/mTOR inhibitors and anti-HER2 therapies are encouraging.

Posted by Peggy Kankonde at 1:06 AM No comments:
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Labels: avastin, BRCA mutation, crbcm, crbcm breast cancer mortality paradox, cytoreduction, gemzar, ovarian cancer treatment, PARP, platinum based

Thursday, April 25, 2013

NEW OPTIMISM IN RECURRENT OVARIAN CANCER

" There is reason to be optimistic about the future of therapy for patients with recurrent ovarian cancer. Inhibition of Wee-1 may target the universal p53 aberrations observed in high-grade serous cancers, and Wee-1 inhibitors are being developed. Objective responses to a variety of immune therapies have been observed, such as an antibody against cytotoxic T-lymphocyte protein 4 (CTLA 4) (see reference 66 from Vaughn et al[9]) or BMS-936559, and antiprogrammed death ligand-1 (PDL-1) monoclonal antibody[15] and immune therapies are a promising area for development. Aberrant DNA methylation is a frequent epigenetic event in ovarian cancer, and the use of chemotherapy plus epigenetic modulators such as demethylating agents or histone deacetylase inhibitors is being studied. The ability to analyze complex genomic data is rapidly increasing, and ovarian cancer is fairly readily biopsiable. More than ever, patients with recurrent disease should consider participation in high quality research trials."

"the addition of PARP inhibitors to chemotherapy in women with recurrent disease has so far failed to improve survival.[14] Front-line trials with PARP inhibitors are being planned, and may yield better results"
                      
 FROM: 
Management of Recurrent EOC: The State of the Art
By Gini F. Fleming, MD1 | April 15, 2013
 ---------------------------------------------------------------------------------------
WE ARE GOING TO FURTHER COMMENTS OF THESE NEW OPTIONS AS WE LEARN MORE! 
MAY BE WE SHOULD BE ADDING INHIBITORS OF AURORA (s) INSTEAD  !
Posted by Peggy Kankonde at 4:00 PM No comments:
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Labels: BMS-936559, crbcm, CTLA 2, high grade serous cancer, P53, recurrent ovarian cancer, t-lymphocyte protein 4, Wee-1

SOME FACTS ABOUT LUNG CANCER

It is the leading cause of death in many countries,
in the US almost 160,000 deaths per year now,
80% are non small cell cancer of the lung,
some are derived from the Pneumocyte type II (Broncho alveolar),
some from very heavy smoking (small cell characterized by Keratin Pearls and hypercalcemia),
20% localized at diagnosis while more than 50% are already distant at diagnosis, the rest have regional spread.
Smoking provides over 300 Chemicals of which at least 10% are potent carcinogens susceptible of changing genes and receptors on cellular membranes including MUCIN genes.  The Carcinogens create DNA adducts, some will stimulate the AKT pathway directly. Mutation of P53 can happen during MUCIN gene alterations as described.  c-MYC, the gene proliferation amplifier, is often found secondarily activated.

Currently testing is completed for EGFR, ROS-1, ALK, (and in some cases K-RAS in Adenocarcinomas).
(to be continued)
Posted by Peggy Kankonde at 10:28 AM No comments:
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Labels: broncho-alveolar, c-MYC, carcinogens, crbcm, hypercalcemia, keratin pearls, leading cause of death, lung cancer, mucin gene, non small cell cancer, pneumocyte type II

Wednesday, April 24, 2013

SEXUAL TRANSMITTED DISEASE MONTH!

Dear Provider:
 
April is National STD Awareness month!  STD Awareness month is observed to break the silence about the increasing number of sexually transmitted diseases.  Chlamydia and gonorrhea are the most commonly reported STDs in Indiana.  In 2011, there were 27,801 cases of Chlamydia and 6,569 cases of gonorrhea reported across all Indiana counties with the majority of cases in the 15-24 year old population.  Current Indiana STD data can be found at:  https://secure.in.gov/isdh/files/STD_Morbidity(3).pdf.
 
In August of 2012, because of the development of resistant strains of gonorrhea and the increased likelihood of coinfection with gonorrhea and Chlamydia, the CDC’s treatment recommendation for gonorrhea was revised.  Persons with a positive test for gonorrhea should receive medication for both gonorrhea AND Chlamydia regardless of Chlamydia test results.  The current treatment recommendation is co-treatment with Ceftriaxone 250 mg IM (first line of treatment for uncomplicated gonorrhea) and either 1 g Azithromycin PO in a single dose, or Doxycycline 100 mg bid X 7 days.  For additional information, including alternative regimens, please refer to:  http://www.cdc.gov/std/treatment/2010/ 
 
All patients treated for Chlamydia or gonorrhea should be re-tested for these infections within three months of treatment.  Sex partners of patients should be identified, tested, and treated to reduce the number of re-infections.  Expedited Partner Therapy (EPT) is an evidence-based and approved treatment delivery option that allows physicians to provide treatment to partners of patients who are unlikely to seek medical care without a physical exam.  Your assistance with the following brief survey on EPT is appreciated!  http://www.surveymonkey.com/s/CSLCCGN. 
 
I encourage providers to screen patients for STD risk factors, test annually, and treat appropriately. Indiana Administrative Code requires health care providers to report all cases of gonorrhea and chlamydia to the local STD district office within 72 hours.  Local public health workers specially trained in STD (disease intervention specialists, or DIS) may be contacting your office to answer your questions about the new STD treatment guidelines.    Information about where to report STDs in Indiana, as well as EPT, can be found at http://www.in.gov/isdh/17440.htm.
 
Thank you for your help in reducing the transmission of STDs in Indiana.  Please contact Andrea Allen at aallen1@isdh.in.gov for additional information on STD testing, treatment, or data.
 
Sincerely,
Posted by Peggy Kankonde at 4:08 AM No comments:
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Tuesday, April 23, 2013

THE Wnt PATHWAY

THE Wnt PATHWAY
It is one of the most complex and versatile pathways.  It is a powerful pathway because Mutations here have direct impact on cell totipotentiality, metastasis and cell differentiation and survival. It involves the most genes .
1.The Wnt interacts with E-Cadherin and therefore intervenes in the Cell Adhesion and Metastatic spread of cancers.
2. The Wnt influences Calcium concentration in the cell.
Remenber Calcium have influence on Calmodulin function and in Alzheimer dementia, microtubule entanglement is worsened by influx of Calcium
3.  Interaction with the Frizzled assure membrane polarity
?control of the flippase or calcium channels?
4. It has nuclear effect through activation of beta-Catenin (through activation OCT4) which is normally degraded by Ubiquitination, therefore opening the door to Velcade
5. Totipotentiality of cells comes back through the Wnt (through Nanog derepression by removing TCF3 influence)
6. Activate the MTOR to ensure cell survival (through GSK)
8. It controls Mesodermal differentiation (through FLK1)
9. It attenuates the Sonic HedgeHog (through GSK)
10. It has full control of the Neurologic sytem of the cell, and through is wingless system, determines where the function will be displayed
11. It is a stimulator of the c-JUN through RAC-1
12. It confers the status of Neuroendocrine differentiation, control where nerves go or do not go!
It is why Cisplatin has a role in in Neuroendocrine differentiated tumor
13. It is the master of Embryonal Gastrulation
Watch out: attacking Wnt can activate the cancer because of its c-JUN connection which leads to Tumor Growth factor!
14. Viral penetration involves the Wnt
15. It controls cell morphology, migration, endocytosis and cell cycle progression (through Cdc42)

I have to stop to spare you!  Look, I have not started to talk about how it leads to Metastasis...I just have to stop.  The Wnt, a powerful pathway!
Posted by Peggy Kankonde at 10:12 PM No comments:
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Labels: calcium, calcium channels, calmodulin, cell adhesion, crbcm, e-cadherin, flippase, frizzled, OCT4, totipotentiality, velcade, Wnt pathway
LOVE KIDNEY PHYSIOLOGY
THE BEST WAY TO MAKE SURE YOU WAKE UP IN A HOUR
IS TO DRINK 4 GLASSES OF WATER, YOU WILL RUN IN A HOUR .
THAT ONE I REMEMBER 
Posted by Peggy Kankonde at 5:14 AM No comments:
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WHERE IS THE DOOR TO MESENCHYMAL TRANSFORMATION (where is the MEK gene) ?

In Summary,
Epithelial covers of Mucosa secrete a Mucine to protect it against infection and immune system exactions and depending on localization the MUCINE is made a different family member of MUC -x  gene, this is helpful when you have a carcinoma of unknown primary, look at the MUC gene amplified

MUC-1- lungs, stomach, intestines, eyes and several other organs (breast)

this MUC gene is more wide spread

MUC2,  Intestinal but for Pseudomyxoma (goblet cells)

MUC3A (Columnar cells)  for cancer evolving from Crohn and ulcerative Colitis,  if you are looking for association with Gallbladder Cancer, look into the MUC gene class

MUC 4 Endometrial Adenocarcinoma

MUC 5 back to lung (
Overexpression of MUC5 genes is associated with early post-operative metastasis in non-small-cell lung cancer. Chong-Jen Yu1,; Pan-Chyr ...

MUC 6  Kidney and urogenital Mucosa (you want to know about Metastasis? I'm not Kidding?let's follow this!)

MUC 7
This gene encodes a small salivary mucin, in case you are still looking where the hell came the Adenocarcinoma from?

MUC 8  Lung and airway, but in allergy, asthma  you want to really know that this patient has an allergy, check and it is MUC 8!!!

MUC 9  human oviductin gene (protection of fallopian tube, and the embryo), but also Ulcerative colitis like MUC 3A or is it the same, let's run to the Human genome team for a consult!

MUC 10 a submandibular gland apomucin

This is fun!

MUC 11  on chromosome 7 but no interest yet!  write your paper on this one!

MUC12 
 Ubiquitous, with higher expression in colon. Down-regulated in colorectal cancer as well as in the colon of patients with ulcerative colitis (UC) and Crohn's disease (CD).  
 etc.......
 BUT WAIT, YOU CAN START ADDING LETTERS!

The major secreted airway mucins are MUC5AC and MUC5B, while MUC2 is secreted mostly in the intestine but also in the airway.

AND JUST AS YOU START BELIEVING IT IS ALL SIMPLE!  COMES THE CRUSHING NEWS:
YOU reach the door of MESENCHYMALIZATION when you reach MUC-20, this is where epidermal and endothelial switch, where squamous switch to adenocarcinoma, where the MEK gene is located!
AND REMEMBER WITH THE MEK GENE COME ANGIOGENESIS!  THAT'S WHY ANTI-MEK WORK WHERE AVASTIN STOPS OR I SHOULD SAY ONE LEADS TO THE OTHER'S ACTIVITY!

AND IF YOU CONTINUE THIS DANCE, YOU WILL FIND THAT SOME MUC GENE BECOME SPECIFIC TO SOME OTHER SPECIES, WE DON'T MAKE THEM!

ONCE AGAIN FROM SIMPLE THINGS, IT GET COMPLICATED REALLY FAST!
NATURE...RESPECT IT!

Posted by Peggy Kankonde at 2:35 AM No comments:
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