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)".

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, PhD<sup>1
----------------------------------------------------------------------------------------------------------------------


AND ALSO READ THIS:</sup>

Powered by SearchMedica

 

CME SUPPLEMENTS

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.

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  !

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)

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,

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!

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 

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!

GENES INVOLVED IN APOPTOSIS (THE FIRST LAW AT WORK)

THE FIRST LAW AT WORK:
THIS IS A COMPILATION OF EXCERPTS OF RELEVANT SCIENTIFIC WORK SUPPORTING THE FACTS COVERING THE FIRST LAW
NONE OF THE WORK DETAILED HERE COME FROM CRBCM
THIS BLOG IS NOT A SCIENTIFIC SOURCE BUT HELP READER UNDERSTAND THE FUNDAMENTAL BASIS OF THE FIRST LAW  "CELL INTEND TO PROTECT INTEGRITY OF DNA AND CELL DIVISION PROCESS".  WHEN THAT PROTECTION CAN NOT BE ASSURED, CELL DEATH SHOULD ENSUE.  ONE OF THE FIRST THING THAT CANCEROUS CELLS DO IS TO FIGHT THIS LAW AND ALLOW MISTAKE TO BE TOLERATED, HERE ARE THE GENES INVOLVED IN THE FIRST LAW!  WE THANK ALL RESEARCHERS CITED BELOW FOR THEIR CONTRIBUTION TO SCIENTIFIC ADVANCE!
=======================================================================
1.NOXA

 Noxa (Latin for damage) is a pro-apoptotic member of the Bcl-2 protein family.^[4] Bcl-2 family members can form hetero- or homodimers, and they act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. The expression of Noxa is regulated by the tumor suppressor p53, and Noxa has been shown to be involved in p53-mediated apoptosis.

Sun et al
 Noxa is a BH3-containing mitochondrial protein that contributes to apoptosis by disrupting mitochondrial outer membrane integrity.

Proteasome inhibitor PS-341, the representative of a new class of chemotherapeutic drugs, was capable of inducing apoptosis in cisplatin-resistant SCC cells via the endoplasmic reticulum stress. PS-341 stimulated the phosphorylation of PERK and the unfolded protein response, resulting in the induction of the transcription factor ATF-4. Importantly, the Bcl-2 homology domain 3-only (BH3-only) protein Noxa was found to be strongly induced in cisplatin-resistant SCC cells by PS-341 but not by cisplatin. The knock-down of Noxa using small interference RNA significantly abolished PS-341-mediated apoptosis in SCC cells. Using eIF2α mutant mouse embryonic fibroblasts, we found that functional eIF2α played an essential role in PS-341-induced Noxa expression. Taken together, our novel findings reveal a direct link between PS-341-induced endoplasmic reticulum stress and the mitochondria-dependent apoptotic pathway and suggest that PS-341 may be utilized for overcoming cisplatin-resistance in human SCC.
---------------------------------------------------------------------------------------------------------
2.PUMA:
The p53 upregulated modulator of apoptosis (PUMA) also known as Bcl-2-binding component 3 (BBC3), is a pro-apoptotic protein, member of the Bcl-2 protein family.[
Fribley et al
Biochemical studies have shown that PUMA interacts with antiapoptotic Bcl-2 family members such as Bcl-xL, Bcl-2, Mcl-1, Bcl-w, and A1, inhibiting their interaction with the proapoptotic molecules, Bax and Bak. When the inhibition of these is lifted, they result in the translocation of Bax and activation of mitochondrial dysfunction resulting in release of mitochondrial apoptogenic proteins cytochrome c, SMAC, and apoptosis-inducing factor (AIF) leading to caspase activation and cell death.^[1]
Because PUMA has high affinity for binding to Bcl-2 family members, another hypothesis is that PUMA directly activates Bax and/or Bak and through Bax multimerization triggers mitochondrial translocation and with it induces apoptosis.^[6][7] Various studies have shown though, that PUMA does not rely on direct interaction with Bax/Bak to induce apoptosis.^[8][9]
PUMA function is affected or absent in cancer cells
  it does not appear that genetic inactivation of PUMA is a direct target of cancer.[3  (wikipedia) Resveratrol acts to inhibit and decrease expression of antiapoptotic Bcl-2 family members while also increasing p53 expression. The combination of these two mechanisms leads to apoptosis via activation of PUMA, Noxa and other proapoptotic proteins, resulting in mitochondrial dysfunction.^[48]

3.BAK
willis at al 

 "Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins"

BAX
 The p53 tumor suppressor gene product can induce apoptotic cell death through an unknown mechanism..deficiency in p53 exhibit increases in Bcl-2 and decreases in Bax protein levels in several tissues this can be determined by immunohistochemical and immunoblot methods. (Miyashita et al)
Disruption of the DNA mismatch repair system, characterized by microsatellite instability (MI), plays an important role in the course of human carcinogenesis by increasing the rate of mutations of genes associated with cancers.
mutations of BAX play an important role in the course of carcinogenesis in the stomach, colorectum, and endometrium.Ouyang et al,

 Bax and Bcl-2 modulate Cdk2 activation during thymocyte apoptosis. Gil-Gomez G, Berns A, Brady HJ.

• Up-regulation of p21WAF1 and Bax and down-regulation of Bcl-2 may be the molecular mechanism through which auristatin-PE inhibits cell growth and induces apoptosis. Li Y, Singh B, AliN,SarkarFH.
  
•   pBax expression may be beneficial in predicting the effects of ACT on patients with IDC. Nio Y, Iguchi C, Yamasawa K, Sasaki S, Takamura M, Toga T, Dong M, Itakura M, Tamura K.
  
  
  
  
  Inactivation of the TGFR Beta11 appears to precede BAX Mutation which not only to block Apoptosis
  but also to  provide selective advantage for growth. (remember at this point the exasperated tumor growth factor is amplified through the stress NF-kB/c-FOS route, and act in a autocrine faction on other susceptible receptor  (Lonov et al)

-------------------------------------------------------------------------------------
4.BID
 This gene encodes a death agonist that heterodimerizes with either agonist BAX or antagonist BCL2. The encoded protein is a member of the BCL-2 family of cell death regulators. It is a mediator of mitochondrial damage induced by caspase-8 (CASP8); CASP8 cleaves this encoded protein, and the COOH-terminal part translocates to mitochondria where it triggers cytochrome c release. Multiple alternatively spliced transcript variants have been found, but the full-length nature of some variants has not been defined. [provided by RefSeq, Jul 2008]

Lee et al!
  BID, a pro-apoptotic member of the Bcl-2 family, interconnects the extrinsic apoptosis pathway initiated by death receptors to the intrinsic apoptosis pathway.

=========================================================================
5.APAF-1

This gene encodes a cytoplasmic protein that forms one of the central hubs in the apoptosis regulatory network. This protein contains (from the N terminal) a caspase recruitment domain (CARD), an ATPase domain (NB-ARC), few short helical domains and then several copies of the WD40 repeat domain. Upon binding cytochrome c and dATP, this protein forms an oligomeric apoptosome. The apoptosome binds and cleaves caspase 9 preproprotein, releasing its mature, activated form. The precise mechanism for this reaction is still debated though work published by Guy Salvesen suggests that the apoptosome may induce caspase 9 dimerization and subsequent autocatalysis.^[5] Activated caspase 9 stimulates the subsequent caspase cascade that commits the cell to apoptosis.
Alternative splicing results in several transcript variants encoding different isoforms.^[2]wikipedia

 APAF1 has been shown to interact with NLRP1,^[7] Caspase-9,^{[7][8][9][10][11]} APIP,^[8] BCL2-like 1^[10][11] and HSPA4.^[12]  
Oligomeric Apaf-1 mediates the cytochrome c-dependent autocatalytic activation of pro-caspase-9 (Apaf-3), leading to the activation of caspase-3 and apoptosis. This activation requires ATP. Isoform 6 is less effective in inducing apoptosis
APOPTOSOME
BCL-2
BCL-2 like
BCLX
MCL-1
CASPASE 3 AND 7
CASPASE 9
P53
c-MYC

ONE IMPORTANT MECHANISM OF NEOPLASTIC TRANSFORMATION COMING OUT OF OUR OBSERVATION:

ONE IMPORTANT MECHANISM OF NEOPLASTIC TRANSFORMATION COMING OUT
OF OUR OBSERVATION: THE FAILURE OF RECEPTORS

LET US TAKE THIS EXAMPLE!
---------------------------------------------------------------------------------------------

Tumor necrosis factor-alpha induces mucin hypersecretion and MUC-2 gene expression by human airway epithelial cells.

Levine SJ, Larivée P, Logun C, Angus CW, Ognibene FP, Shelhamer JH.

Source

Critical Care Medicine Department, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland 20892-1662.

Abstract

Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional, pro-inflammatory cytokine that is capable of activating a diverse number of target genes within multiple cell types. Little information is known regarding the role of TNF-alpha in the regulation of human airway mucin hypersecretion and MUC-2 gene expression.

------------------------------------------------------------------------------------------

LET'S ASSUME
THAT A GROWTH FACTOR HAS 2 PRINCIPAL RECEPTORS AND 2 SECONDARY RECEPTORS
(IN THIS EXAMPLE TNF- alpha IS SAID TO HAVE  A "NUMBER OF TARGET GENES")
IF FOR SOME REASONS THE GROWTH FACTOR FAILED TO ACTIVATE ITS PRINCIPAL RECEPTORS,  2 THINGS HAPPEN:

1. THE PRINCIPAL RECEPTOR
initiates a stress like response which will involve the HP90, exacerbating the NF- kB
resulting in further activation of promoter genes and formation of MORE TNF- alpha

2. MORE TNF-alpha will exacerbate the effect on SECONDARY receptors still sensitive, leading to the activation/amplification of unwanted genes,

- Amplification of MUC-1 leads to an Adenoma and eventually Adenocarcinoma.
- Amplification of MUC-2 leads to a pseudomyxoma.
- May be MUC-7 will be lung and bladder Cancer?

Neutrophil elastase induces MUC5AC gene expression in airway epithelium via a pathway involving reactive oxygen species.

Fischer BM, Voynow JA.

Source

Division of Pediatric Pulmonary Diseases, Duke University Medical Center, Durham, North Carolina 27710, USA.

Abstract

Neutrophil-predominant airway inflammation and mucus obstruction of the airways are major pathologic features of chronic airway diseases, including cystic fibrosis and chronic bronchitis. Neutrophils release elastase, a serine protease that impairs mucociliary clearance and stimulates goblet cell metaplasia and mucin production. We previously reported that neutrophil elastase increases expression of a major respiratory mucin gene, MUC5AC, by enhancing mRNA stability. However, the molecular mechanisms of elastase-regulated MUC5AC expression are not known. We hypothesized that reactive oxygen species, generated by elastase treatment, mediate MUC5AC gene expression.

MUC4 gene polymorphisms associate with endometriosis development and endometriosis-related infertility.

Chang CY, Chang HW, Chen CM, Lin CY, Chen CP, Lai CH, Lin WY, Liu HP, Sheu JJ, Tsai FJ.

Source

Human Genetic Center, China Medical University Hospital, Taichung, Taiwan.

Abstract

BACKGROUND:

Mucin 4 (MUC4) plays an important role in protecting and lubricating the epithelial surface of reproductive tracts, but its role in the pathogenesis of endometriosis is largely unknown.

MUC3 human intestinal mucin. Analysis of gene structure, the carboxyl terminus, and a novel upstream repetitive region.

Gum JR Jr, Ho JJ, Pratt WS, Hicks JW, Hill AS, Vinall LE, Roberton AM, Swallow DM, Kim YS.

Source

Gastrointestinal Research Laboratory (151M2), Department of Veterans Affairs Medical Center, University of California, San Francisco, California 94121, USA.

Abstract

MUC3 is a large mucin glycoprotein expressed by the human intestine and gall bladder.

MUC6 - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/MUC6

Reid CJ, Harris A (1999). "Expression of the MUC 6 mucin gene in development of the human kidney and male genital ducts.".

PICK A NUMBER AND YOU WILL FIND WHERE THE CANCER WILL BE. THIS IS THE POWER OF RECEPTORS AND THE POWER OF GENE POLYMORPHISM! 

Let's play:
Full Name mucin 10, submandibular gland salivary mucin

MUC12 »  Mucin-12  (MUC-12)

Protein also known as:  Mucin-11 (MUC-11).

Gene name:  MUC12

This protein has been shown to exist at protein level

Expression

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).  

• CuratedUniProtKB

Ubiquitous cytoplasmic expression in all tissues at variable levels. Highest expression in gastrointestinal tract. ‹silver HPA027769; HPA023835

THIS EXERCISE CAN BE DONE WITH ALL ADENOCARCINOMAS!

DO YOU SEE PORTRAYED HERE A TARGET FOR THERAPY OR DIAGNOSIS?  
LET'S GO TO WORK!


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

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!

Aspirin, colorectal cancer and intreperitoneal chemotherapy

*THE NURSE HEALTH STUDY WHICH FOLLOWED CLOSE TO 200,000 INDIVIDUALS REPORTED OR SUGGESTED ASPIRIN  (325 MG ) REDUCED BY AT LEAST 23% THE RISK OF DEVELOPING COLORECTAL CANCER.  AND THIS WAS IN ADDITION TO CARDIOVASCULAR PREVENTION BENEFITS. APPARENTLY, THE INHIBITION OF CYCLO-OXYGENASE (COX 1 AND 2 ) HAS AN IMPACT ON CELL DIVISION, APOPTOSIS AND ANGIOGENESIS!

*In Colorectal cancer
BRAF mutation is of poor prognosis (10 months Vs 34.7 months for wild type BRAF), tumor is diploid with Microsatellite instability!  Give Vemurafenib!

*Intraperitoneal chemotherapy continues to show survival advantage in Ovarian cancers, despite the fact that the majority of Ovarian cancers with the relevant stage do not receive it!

CPRIT: A former congressman joined its board

PETE GEREN  a well known  former Democratic congressman from the Fort Worth counties, has been named to the CPRIT governing board.  He will bring much needed dynamism and fortitude to CPRIT.

He was nominated by the Speaker of the House of Representative Joe Straus to replace TOM LUCE who is now the new chief operating officer of the O’Donnell Foundation since April 1st, 2013.  The Dallas foundation of philanthropist Peter O’Donnell and his wife Edith, is reported to have contributed more than $600 million over the past 30 years to support scientific research and education.  Their link to CPRIT has been controversial at best!
In other related news, Jay Maguire, a lobbyist with long ties to Tobacco companies, was hired 3 months ago by the CPRIT Foundation, now called the Texas Cancer Coalition.
Observers have been proud of changes and the new direction that CPRIT has taken overall. We wish this important organization for Texas well!

DOES HAIR COLOR CHANGE COMES FROM METHIONINE MALABSORPTION ???

DOES HAIR COLOR CHANGE COMES FROM METHIONINE MALABSORPTION ???

"The following Votrient side effects are common (occurring in greater than 30%) for patients taking Votrient:

• Diarrhea
• Hypertension
• Hair color changes
• Low blood counts (low white blood cells, low platelets)
• Elevated liver function tests (AST, ALT)
• Elevated bilirubin level
• Blood test abnormalities (low phosphorus, low sodium, increased glucose) 

These are less common side effects (occurring in 10-29%) for patients receiving Votrient:

• Nausea
• Vomiting
• Poor appetite
• Fatigue
• Weakness
• Abdominal pain
• Headache
• Blood test abnormalities
• Low Magnesium
• Low Glucose - Low Blood Sugar

This list includes common and less common side effects for those taking Votrient. Votrient's side effects that are very rare -- occurring in less than about 10 percent of patients -- are not listed here. Always inform your health care provider if you experience any unusual symptoms."

(SCOTT HAMILTON CARES )

Error of metabolism points to interesting targets to be used in T cell rearrangement strategy

Error of metabolism points to interesting targets to be used in T cell rearrangement strategy

Glut 2 ----To be looked at in Pancreatic Cancer  (No CNS involvement)
Glut 4
Gs alpha----(To be looked at in Sarcoma)
IRS 1
Biopterin Synthesis
FMR1
GNB
Adenyl Cyclase
===================================================
GENES INVOLVED IN SURVIVAL (ADAPTATION)

RAG 1
RAG 2
(TRANSPOSASE)
DNA -PK
XRCC4
XLF
ARTEMIS
CERNUNNOS
LAMBDA AND MU
VDJ
----------------------------------------------------------
RECEPTOR FOR ALPHA AND BETA CHAIN
CDR, 1-4
TCR
-------------------------------
 MGAT2
--------------------------

GENES INVOLVED IN GLYCOSYLATION

Neu5Ac
Neu 5GC
CMAH
MGAT
FUT8
CHO-STGAL
CHOK1
TRANSFERRIN

LYSOZOMAL LEVEL
GDP MANNOSE
----------------------------
PMM2
MPI
----------------------------
GENES OF MUSCLE DYSTROPHY
POMT1
POMGNT1
DYSTROGLYCAN
FKRP
------------------------------------
GALNT3 MODIFIES FGF23
COSMC FOLDING OF GLYCAN

ROLE OF TRANSFERRIN IN CANCER TREATMENT AND A MEANINGFUL POT POURRI. WE THANK ALL RESEARCHERS CITED FOR THEIR CONTRIBUTION TO SCIENCE!

"Transferrin imbalance can have serious health effects for those with low or high serum transferrin levels. A patient with an increased serum transferrin level often suffers from iron deficiency anemia.^[5] A patient with decreased plasma transferrin can suffer from iron overload diseases and protein malnutrition. An absence of transferrin results from a rare genetic disorder known as atransferrinemia; a condition characterized by anemia and hemosiderosis in the heart and liver that leads to many complications, including heart failure. Most recently, transferrin and its receptor have been shown to diminish tumour cells by using the receptor to attract antibodies.^{[5]" WIKIPEDIA}


Transferrin is also associated with the innate immune system. It is found in the mucosa and binds iron, thus creating an environment low in free iron that impedes bacterial survival in a process called iron withholding. The level of transferrin decreases in inflammation.["

Many conditions including infection and malignancy can depress transferrin levels. The transferrin is abnormally high in iron deficiency anemia.

David Goodsell
" several molecules called lactoferrin and ovotransferrin are similar to transferrin. These molecules, found in milk and egg whites respectively, also have strong binding sites for iron. However, their main function is not delivery. Instead, they serve to protect cells from bacteria. Since they mop up any free iron ions, they starve bacteria of a vital resource, slowing the growth of an infection."

Ponka et al.
" Cellular iron uptake and storage are coordinately regulated through a feedback control mechanism mediated at the post-transcriptional level by cytoplasmic factors know as iron-regulatory proteins 1 and 2. These proteins "sense" levels of iron in the transit pool and, when iron in this pool is scarce, they bind to stem-loop structures known as iron-responsive elements on the 5' untranslated region of the ferritin mRNA and 3' untranslated region of the transferrin mRNA. Such a binding inhibits translation of ferritin mRNA and stabilizes the mRNA for transferrin receptors. The opposite scenario develops when iron in the transit pool is plentiful. This remarkable regulatory mechanism prevents the expansion of a catalytically active intracellular iron pool, while maintaining sufficient concentrations of the metal for metabolic needs.
" 

using transferrin and iron chelators are extremely complex. Improperly managed iron storage and delivery in cell culture systems is a major contributor to oxidative stress and protein damage. For a more complete discussion of transferrin and iron chelators as a cell culture components go to Sigma's Media Expert.

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Primary Functions of Transferrin in Cell Culture Systems:

• Transferrins facilitate extracellular iron storage, and transport.
• Transferrins are important extracellular antioxidants. They bind iron so tightly under physiological conditions that virtually no free iron exists to catalyze the production of free radicals.
• The delivery of iron to cells by transferrins is a receptor-mediated and controlled process. Cells regulate the amount of iron they receive from the extracellular environment by varying transferrin receptor expression 
•  Ceruloplasmin mediated oxidation of iron is accompanied by the conversion of di-oxygen into water. Ceruloplasmin is the only circulating molecule that provides controlled and rapid oxidation of ferrous to ferric iron.

Inoue et al
" We previously found that transferrin (Tf) differentially stimulated the growth of highly metastatic variant lines of murine melanoma and that these highly metastatic cells also had greater numbers of Tf receptors on their cell surfaces. In the present study we found that highly metastatic rat mammary adenocarcinoma cell lines also responded differentially to Tf in proliferation assays,"

Breast Cancer Res Treat. 1999 Aug;56(3):203-17.

Transferrin receptor overexpression enhances transferrin responsiveness and the metastatic growth of a rat mammary adenocarcinoma cell line.

Cavanaugh PG, Jia L, Zou Y, Nicolson GL.

Source

Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.

Abstract

"We previously found that breast cancer cell transferrin receptor expression and proliferative response to transferrin often correlated with metastatic capability.
 We previously found that transferrin (Tf) differentially stimulated the growth of highly metastatic variant lines of murine melanoma and that these highly metastatic cells also had greater numbers of Tf receptors on their cell surfaces. In the present study we found that highly metastatic rat mammary adenocarcinoma cell lines also responded differentially to Tf in proliferation assays,

" Nochoson et al.
The growth of brain-metastasizing melanoma cells appears to be stimulated by other paracrine growth factors, such as paracrine transferrin. Melanoma cells metastatic to brain express higher numbers of transferrin receptors and respond and proliferate at lower concentrations of transferrin than do melanoma cells metastatic to other sites or poorly metastatic melanoma cells. The results suggest that degradation and invasion of brain basement membrane and responses to paracrine neurotrophins and paracrine transferrins are important properties in brain metastasis of murine and human malignant melanoma cells."

" A major organ-derived (paracrine) growth factor has been isolated that differentially stimulates the growth of cells metastatic to the brain. Characterization of this mitogen demonstrated that it is a transferrin-like glycoprotein; cells that are metastatic to brain express greater numbers of transferrin receptors on their surfaces than cells that are poorly metastatic or metastatic to other sites. Transferrin-like factors are expressed in fetal brain and could represent the transferrin-like factors that stimulate growth of brain-"metastatic melanoma and breast cancer cells. These and other factors are probably important in determining whether metastatic cells can successfully invade, colonize, and grow in the CNS."

Reversal by Transferrin of Growth-Inhibitory Effect of Suramin on Hormone-Refractory Human Prostate Cancer Cells

1. S.Machele Donat,
2. C.Thomas Powel,
3. Ron S. Israeli,
4. William R. Fair and
5. Warren D. W. Heston^*

+ Author Affiliations

1. W. D. W. Heston (Urologic Oncology Research Laboratory, Molecular Pharmacology and Therapeutics Section, Sloan-Kettering Institute for Cancer Research; and Urology Service, Department of Surgery, Memorial Hospital, Memorial Sloan-Kettering Cancer Center), R. S. Israeli (Urologic Oncology Research Laboratory, Molecular Pharmacology and Therapeutics Section, Sloan-Kettering Institute for Cancer Research), W. R. Fair (Urology Service, Department of Surgery, Memorial Hospital, Memorial Sloan-Kettering Cancer Center), New York, N. Y.

1. ^*Correspondence to: Waren D. W. Heston, Ph.D., Memorial Sloan-Kettering Cancer Center, 1275 York Ave., Box 334, New York, NY 10021. 

" Transferrin is abundant in bone stroma and has been found to stimulate models of hormone-refractory metastatic prostate cancer. Suramin, a compound that has been used to treat metastatic prostate cancer, has been demonstrated to antagonize the binding of transferrin to the transferrin receptor and to suppress uptake of iron by hematopoietic cells. Purpose: The purpose of our study was to determine whether transferrin may"

Antisense oligonucleotide targeted to the transferrin receptor gene suppresses tumor growth and lung metastases in 4T1 mammary adenocarcinoma mouse model

X. Jiang, A. Israyeeyan, E. Boykin, L. Lomax, J. F. Head and R. L. Elliott Mastology Research Institute, Baton Rouge, LA; School of Veterinary Medical, LSU, Baton Rouge, LA
10616
Iron is required for the activity of ribonucleotide reductase and synthesis of DNA. Cellular surface transferrin receptors (TfR) are the principal transport protein for iron into cells. It has been reported that inhibition of TfR gene expression leads to the suppression of tumor cell growth in cell culture. In the present study, an antisense oligonucleotide targeted to the transferrin receptor gene was used to treat 4T1 mammary adenocarinoma in cell culture and a mouse model. The cytotoxicity of a 24-mer TfR antisense oligonucleotide was determined by ³[H]-thymidine incorporation in vitro. The sense and random sequence

BASALOID TRIPLE NEGATIVE BREAST CANCER RESULT FROM A DEFECT IN GLYCOSYLATION OF RECEPTOR PROTEIN OR A FORM OF CONGENITAL EXOSTOSIS.

We know that the disease is rare like 1/5000 women
that it occurs at age 20-40 like in Polycystic kidney disease when these things develop
it changes the morphology of the cell like dysfunction of molecular membrane would
the receptor lacking post translational  modification by glycosylation will impact their binding of any growth factor  This stresses the cell which will increase further growth factor chronically to justify SECONDARY amplification PIK/MAPK.  The stress will involve particularly the TNF receptor (exostin 1) /TRAP1.
TRAP1 (Heat stroke protein) at cellular is a stimulator of c-JUN/FOS/STAT which further increase growth factor which can effectively act on their receptors.  This persistent vicious cycle leads to the neoplastic process.
Remember when c-FOS is stimulated, c-MYC is not far away to insure proliferation is rapidly started and maintained. 
The defect however start in the Golgi apparatus where Glycosylation should have occurred
and the Wnt is involved since it influences Reticulum Endothelial contact with the Golgi Apparatus!

Yes it becomes imperative to look into EXT 1,2, Retinoblastoma 1 (Rb1), and TRAP1 gene in this disease
because genetic intervention will clearly impact thousands of women. 


This analogy at Estrogen receptor, will affect other ER negative Breast cancer
It is evident that we underestimate the importance of post translational Glycosylation of Receptors in Breast cancers. BUT IT PUT HEPARAN SULFATE METABOLIC DEFICIENCY CENTER TO THIS DISEASE!

REMEMBER THE RULE THAT WHAT CAN CHANGE THE SHAPE AND DEVELOPMENT OF A MEMBRANE OR A HUMAN EXTREMITY (OR STATURE) CAN CAUSE CANCER IF DISTORTED GENETICALLY.   AND ALWAYS REMEMBER THAT A PERSONALITY CHANGE WILL BE ASSOCIATED IN MANY CASES.   CLINICIANS TREATING POLYCYSTIC KIDNEY FORGET TO INVOLVE A PSYCHIATRIST LEAVING THEIR PATIENTS GO THROUGH BROKEN MARRIAGES, PROBLEM AT WORK AND CASES OF SUICIDES!  BE UP IN THE KNOW, GIVING ACE INHIBITORS IS NOT ENOUGH!

WHAT WALKS LIKE A DUCK, QUACKS LIKE A DUCK, LOOKS LIKE A DUCK, IS PROBABLY A DUCK, I WAS TAUGHT IN MY RESIDENCY PROGRAM !

INTRODUCTION TO THE 8TH LAW OF NATURE

THE 8TH LAW INVOLVES OF THE CELL
It is the ultimate purpose of the cell.  All cell live to survive and the cell will escape death by all costs until evidences impose a programed death as the ultimate door to escape stress.  But before its death the cell will unveil an infinite number of adaptative strategies which include resistance to new infection, autophagy, escaping immune system detection, autocrine growth factor compensation and self advantage, Activating variable genes for antibody production and T-cell receptor function, decreasing adhesion molecule, metastasizing  for cancer cells, exostosis of toxic material.  All these function are controlled by genes.  The cell has adaptation potential to even foreign threats never seen by its parents before!

The genes involved start from Transposases (RAG 1, 2) to Artemis, Cernunnos,XRCC4, XLF, VDJ, to FUT8, MGAT, CHOK1 and PMM2, MGAT2
They also include some Genes of differentiation, rearragment genes, glycosylation genes and adaptation genes, plicing and linkage genes.

full groups by class of genes and Nomenclature will follow!

TRIPLE NEGATIVE BREAST CANCER WITH BASAL CELL LIKE CANCER CELLS

Are you kidding me or just fooling me?
Could patients having this disease also have a Glycosylation problem?
Are they suffering from a form of Hereditary Multiple exostosis?
Do they have EXT gene Mutation?
 By claiming the following:
"The mechanism of HME pathology is likely rooted in a disruption of the normal distribution of HS-binding growth factors, which include FGF and morphogens such as hedgehog, Wnt, and members of the TGF-β family. The loss of HS disrupts these pathways"

Hudson Freeze et al are reporting all the mechanisms involved in Basal cell  breast cancer in one sentence and pin it down to Heparan surface.  He is putting the disruption square and round in the Golgy Apparatus.

It makes perfect sense though, these diseases are triple negative pointing to an insensitive receptor
and sure enough we know that receptors are proteins, but in order to work, proteins need Glycosylation and Heparan Sulfate is  :

"Heparan sulfate /hep·a·ran sul·fate/ (hep´ah-ran) is a glycosaminoglycan occurring in the cell membrane of most cells, consisting of a repeating disaccharide unit of glucosamine and uronic acid residues, which may be acetylated and sulfated; it accumulates in several mucopolysaccharidoses."(wikipedia)

Lack of Glycosylation will render receptor insensitive!

THIS IS THE FULL TEXT OF THEIR CLAIM:
Congenital Exostosis

Defects in the formation of heparan sulfate (HS) cause hereditary multiple exostosis (HME), an autosomal dominant disease with a prevalence of about 1:50,000. It is caused by mutations in two genes EXT1 and EXT2, which are involved in HS synthesis. HME patients have bony outgrowths, usually at the growth plates of the long bones. Normally, the growth plate contains chondrocytes in various stages of development, which are enmeshed in an ordered matrix composed of collagen-chondroitin sulfate. In HME, however, the outgrowths are often capped by disorganized cartilagenous masses with chrondrocytes in different stages of development. About 1–2% of patients also develop osteosarcoma.
HME mutations occur in EXT1 (60–70%) and EXT2 (30–40%). The proteins encoded by these genes are thought to exist as a complex in the Golgi and both are required for polymerizing GlcNAcα1–4 and GlcAβ1–3 into HS. However, the partial loss of one allele of either gene appears sufficient to cause HME. This means that haploinsufficiency decreases the amount of HS and that EXT activity is rate limiting for HS biosynthesis. This is unusual because most glycan biosynthetic enzymes are in substantial excess.
The mechanism of HME pathology is likely rooted in a disruption of the normal distribution of HS-binding growth factors, which include FGF and morphogens such as hedgehog, Wnt, and members of the TGF-β family. The loss of HS disrupts these pathways in Drosophila. Mice that are null for either Ext gene are embryonic lethal and fail to gastrulate; however, Ext heterozygous animals are viable and about one third develop a visible exostoses on the ribs. No exostoses develop on the long bones of these animals (in contrast to patients with HME), but subtle chondrocyte growth abnormalities were seen in the growth plates of these bones. Further studies are needed to understand how truncation of the HS chains leads to ectopic growth plate formation and the phenotype abnormalities.

It becomes urgent to test EXT gene in these patients the TRAP1 gene

TRAP1,
Retinoblastoma protein.^[5]

EXT1

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Exostosin 1
Identifiers
Symbols	EXT1; EXT; LGCR; LGS; TRPS2; TTV
External IDs	OMIM: 608177 MGI: 894663 HomoloGene: 30957 GeneCards: EXT1 Gene
EC number	2.4.1.225 2.4.1.224, 2.4.1.225
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2131	14042
Ensembl	ENSG00000182197	ENSMUSG00000061731
UniProt	Q16394	P97464
RefSeq (mRNA)	NM_000127	NM_010162
RefSeq (protein)	NP_000118	NP_034292
Location (UCSC)	Chr 8: 118.81 – 119.12 Mb	Chr 15: 53.06 – 53.35 Mb
PubMed search	[1]	[2]

Exostosin-1 is a protein that in humans is encoded by the EXT1 gene.^[1]
This gene encodes an endoplasmic reticulum-resident type II transmembrane glycosyltransferase involved in the chain elongation step of heparan sulfate biosynthesis. Mutations in this gene cause the type I form of Multiple Exostoses.^[1]

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TNF receptor-associated protein 1
Identifiers
Symbols	TRAP1; HSP 75; HSP75; HSP90L; TRAP-1
External IDs	OMIM: 606219 MGI: 1915265 HomoloGene: 9457 ChEMBL: 1075132 GeneCards: TRAP1 Gene
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	10131	68015
Ensembl	ENSG00000126602	ENSMUSG00000005981
UniProt	Q12931	Q9CQN1
RefSeq (mRNA)	NM_001272049	NM_026508
RefSeq (protein)	NP_001258978	NP_080784
Location (UCSC)	Chr 16: 3.7 – 3.77 Mb	Chr 16: 4.04 – 4.08 Mb
PubMed search	[1]	[2]

Heat shock protein 75 kDa, mitochondrial is a protein that in humans is encoded by the TRAP1 gene.^[1][2][3]

THESE 4 GENES NEEDS TO BE LOOKED AT ASAP IN TRIPLE NEGATIVE BREAST CANCER WITH BASALOID MORPHOLOGY!