Friday, July 12, 2013

CAN'T ESCAPE THIS ONE

Afatinib Approved by the FDA for EGFRm+ Lung Cancer

Zosia Chustecka
DisclosuresJul 12, 2013
"A new targeted therapy, afatinib (Gilotrif, Boehringer Ingelheim), has been approved by the US Food and Drug Administration (FDA) for use in the treatment of metastatic nonsmall-cell lung cancer (NSCLC) that tests positive for epidermal growth-factor receptor mutations (EGFRm+). A companion diagnostic test, the Therascreen EGFR PCR Kit (from Qiagen), has been approved at the same time.
About 10% to 15% of NSCLC is EGFRm+ in Western populations, although the incidence of the mutation is higher in Asian populations."

THIS IS SIGNIFICANT AS IT ADDS TO THE ARMAMENTORIUN IN AN OTHERWISE DIFFICULT DISEASE TO TREAT, WE CLEARLY NEED MORE OF THESE NEWS.  IT ALSO PROVIDE FURTHER REASON TO TEST FOR THESE MUTATIONS PRIOR TO CHOOSING WHICH FINAL OPTION IS APPROPRIATE AND MORE PALATABLE FOR OUR PATIENTS.   IT ALSO PROVIDES FOR A BETTER CHANCE FOR INSURANCE TO COVER THIS PRESCRIPTION...THIS IS A GOOD DAY IN ONCOLOGY!

Thursday, July 11, 2013

SILENCE AT CPRIT

At CRBCM we watch the news trying to see if there is any thing happening with one of the most important organization for Cancer Prevention and Research in Texas (CPRIT). I am afraid to report: SILENCE...
Now I do not know what is worse.  The old CPRIT full of politicians that used to lie to us as it turns out!  Or the new and improved CPRIT that is completely silent.   The old one kept us energized even when it was misleading, filling us with false hope while dealing and diverting funds to friends, but at least we believed to the cost of 7 grant submissions.  This new CPRIT, may be overcautious but what is it doing we wonder!  Is-it still putting things into place?  or is it still planning what to do...Only God and insiders know.  Truly I wonder what is worse.   Even in my office, when I am a little late, I come out and tell people who were involved, waiting, to tell what is going on behind the curtains!  Is it fair to ask that the public be kept abreast!

It's been a month since the legislation was passed refunding CPRIT, even if they are still putting competent people in place, the public should know. There have been complete silence as if the institution is closed, as if nobody works there anymore...what is it about?  Did some dark organization take over?  Are we going to disappear in the darkness of night for asking.  We know where the money will ultimately go so just come out and let us know the new rules of the game!   Going under the dark or under water does not help, just come out and lay things straight!

The beneficiaries are MD Anderson, Baylor and you know the rest of the list, the legislators we know them, few new names at CPRIT but the outcome will be the same! I truly doubt the game will have new steps, but it is nice to observe out as  it will be unveiled.  Whether CPRIT like it or not, CRBCM and others will be watching.  The left behind will be there to play their part, disparity will be go on, unless of course true leaders take over CPRIT...and chance of that is minimal to say the least.  True Visionaries are often hard to come by for as long as the influencial organizations around CPRIT such as Bioalliances remain close by.     My experience with Bioalliances was the worse, but what can I say or do, they keep a hold on CPRIT!

QUI VERRA, VERRA or is it QUI SERA SERA (WHATEVER WILL BE, WILL BE!) !  WE ARE STILL LEAVING AN INTERESTING TIME IN CANCER RESEARCH IN TEXAS!

MIAMI, HERE WE COME

CRBCM WILL BE REPORTING FROM MIAMI, IT'S ALL CONFIRMED!  HEMATOLOGIC MALIGNANCIES, HERE WE COME!  NO MORE SECOND HAND INFORMATION, WE ARE GOING TO THE SOURCE, LIKE SAINT THOMAS TOUCHING INTO THE WOUNDS! WE WILL BE LOOKING INTO THE EYES OF PRESENTATRS/LECTURERS  FOR A DEEPER FEEL OF THE INFO! EXPECT A SUMMARY REPORT!
------------------------------------------------------------------------------------------------

09 AUG 13 - FRIDAY     AMERICAN      862 ECONOMY             NONSTOP   
  LV: EL PASO            910A                                        
  AR: DALLAS/FT WOR     1155A                                 CONFIRMED
  AIR MILEAGE FOR THIS SEGMENT IS-  551
                                              AA -AOEBRZ 
 
                        AMERICAN     2024 ECONOMY             NONSTOP   
  LV: DALLAS/FT WOR     1235P                                        
  AR: MIAMI              440P                                 CONFIRMED
  FOOD TO PURCHASE                                                         
  AIR MILEAGE FOR THIS SEGMENT IS- 1121
                                              AA -AOEBRZ 
 
11 AUG 13 - SUNDAY     AMERICAN     1665 ECONOMY             NONSTOP   
  LV: MIAMI              850A                                         
  AR: DALLAS/FT WOR     1100A                                 CONFIRMED
  FOOD TO PURCHASE                                                        
  AIR MILEAGE FOR THIS SEGMENT IS- 1121
                                              AA -AOEBRZ 
 
                        AMERICAN     1569 ECONOMY             NONSTOP   
  LV: DALLAS/FT WOR     1235P                                        
  AR: EL PASO            115P                                 CONFIRMED
  AIR MILEAGE FOR THIS SEGMENT IS-  551
                                              AA -AOEBRZ 
 
.===================================================

Update in some Hematology Malignancies

We will be in Miami for a full report on this Topic in early August, but in the meantime,
about Ibrutinib " Now, updated data show that progression-free survival in patients with treatment-naïve CLL was 96% at 15 months and in relapsed/refractory patients was 87.7% at 18 months." (McCall )
Response even in CLL Bulky disease. An temporary Upsurge in lymphocytosis  was reported but soon settles down.

*"Ponatinib is approved for use in patients with chronic myeloid leukemia (CML) and also Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (Ph+ ALL) who have relapsed or are refractory to other therapies. Many of these patients, but not all, have developed a T315I mutation, which makes the disease resistant to the standard treatment with tyrosine kinase inhibitors (TKIs) such as imatinib (Gleevec)."
(Medscape)  Watch Amylase and lipase and marrow suppression.  READ ORIGINAL ARTICLE BY Z.CHUSTECKA.

*R. NELSON REPORTED ON NEW FDA APPROVAL OF BOSUTINIB!
" Currently, there are no approved therapies available for CML patients who have failed treatment with imatinib (Gleevec, Novartis) and the second-generation products nilotinib (Tasigna, Novartis Oncology) and dasatinib (Sprycel, Bristol-Myers Squibb).
Bosutinib is an oral, once-daily, second-generation inhibitor of Abl and Src family kinases. It is a potent ATP-competitive inhibitor of the BCR-ABL oncogene, and unlike competitors, it has minimal inhibitory activity against c-KIT and PDGFR."

AT THE END YOU NEED PRACTICAL NEWS THANKS TO MEDSCAPE!

Wednesday, July 10, 2013

More news

*SEERS data suggest Stage I colon cancers are better off totally/ resected (radical Resection) than plucked off (Local excision)!
*Remember there is a Metabolic Pancreatic Panel (Xylitol,Glucitol, Inositol, Histidine) keep checking out against the standard CEA and CA19-9!  Is it really better in detecting early Pancreatic cancers? more validation needed.
*Esophageal Cancer...NO Cetuximab!  (The Oncology Report says so!  Read it for a full story!)

*In Vitro Fertilization not associated with Autism rate but association with Mental Retardation was supported in a study by Sandin et al! (of Sweden!)

*Gradual cessation of smoking Vs Abrupt Cessation, no difference in result suggested Per Lindson-Hawley et al! SO DON'T BITE YOUR NAIL ABOUT THIS JUST DO IT, IT'S ALL THE SAME AND LEAD TO RESULT!

SO YOU ARE KEPT IN THE LOOP!

*There are more ALK positive agents available.  They have ROS-1 Inhibition and  some have ANTI-EGFR activity.   Response in Brain tumor are noted.  It is suggested that SOME of these agents work a little longer (in weeks!).  YES most of these agents have  wonderful response rates but not long lasting.

*In Glioma,  Co-deletion of 1p and 19q announces response to chemotherapy. and Mutation in IDH gene is a good prognosis factor!  (Isocitrate De-Hydrogenase). This Mutation is associated with the MGMT promoter of DNA methylation and G-CIMP,TP53, and ATRX.  IDH1 mutation is mostly associated with Oligodendroglioma.

*Women with breast cancer which is ER positive not only will receive chemotherapy but now 10 years of Tamoxifen.  Some reports suggested only 5% of them have a clear discussion of Fertility preservation issues
and fewer see a Reproductive Endocrinologist.  Come ON  Oncologists, wake-up and smell the coffee, the law is coming after you!

*Oral Topotecan is a good second line in Metastatic small cell lung cancer, could you add Avastin!? read David R Spigel et al!

Tuesday, July 9, 2013

NEWS ABOUT ACTOS (from medscape)

Doctors Concerned as India Suspends Diabetes Drug Pioglitazone

Lisa Nainggolan
Jul 08, 2013
 medscape
Diabetologists in India are up in arms following an unexpected decision by the government there to suspend sales of the diabetes drug pioglitazone. The ruling came seemingly out of the blue, and there is much concern among doctors about their patients with type 2 diabetes who are currently taking this medication.
The government suspended the manufacture, sale, and distribution of pioglitazone at the end of June, citing concerns over adverse effects, particularly bladder cancer, according to a report in BMJ and a number of Indian media outlets.
Vijay Panikar, MD, an endocrinologist from Lilavati Hospital, Bandra, Mumbai, who is also the secretary of the Association for Diabetes Care and Prevention, told Medscape Medical News: "I think it's unfortunate. Pioglitazone should not have been banned. The government could have put some restrictions [on it] but still allowed marketing of the drug because there is no clear-cut indication that it does cause bladder cancer." In fact, he said, "there are new data coming, which are probably in favor of pioglitazone, expected in 2014."
And the secretary general of the Indian Pharmaceutical Alliance, which represents 19 research-based national pharmaceutical companies, Beilib D.G. Shah, said his members are also infuriated by this decision, which he says is wrong on a number of levels.
"First, the due process of law for suspensions was not followed," Shah told Medscape Medical News, adding that normally there is a procedure for this type of legislation, with logical steps, none of which were followed in this case. Second, "the government cites the fact that pioglitazone is banned in France and Germany," but the French ban "was 3 years ago," Shah noted, and in Germany "they have suspended sales to new patients" only, he said.
"This drug has been on the Indian market for 12 years, and there has been no suggestion of a link with bladder cancer. This decision has put 3 million patients on pioglitazone at risk and has come so suddenly. Now they will have to go to their diabetologist or doctor and discuss what therapy to change to. One of their choices now is to move to a new therapy, at 10 times the cost. There is a suspicion that some foreign companies [have pressured for this] to switch patients from safe low-cost treatments to newer therapies such as gliptins," he asserted.
Medscape Medical News tried to speak with a representative of the Indian government. But G.N. Singh, PhD, the drugs controller general of India, was overseas and could not be contacted, and Dr. Arun Panda, of the Ministry of Health and Welfare, could not be reached for comment.
Pioglitazone "Cornerstone of Therapy" in India
The thiazolidinedione drug class, which includes rosiglitazone (Avandia, GlaxoSmithKline) as well as pioglitazone, has never been far from controversy. Rosiglitazone was suspended by the European Union in 2010 and its use severely restricted in the United States because of concerns about a possible increased risk of cardiovascular adverse effects, although this assertion has recently been challenged in the second in a high-profile Food and Drug Administration advisory committee meeting.
Shah told Medscape Medical News that rosiglitazone was removed from the Indian market around the same time as it was suspended in Europe, leaving pioglitazone — originally developed by Takeda Pharmaceuticals and marketed as Actos but now widely available as a generic medication — as the remaining thiazolidinedione. It, too, has been associated with adverse effects, including fractures and fluid retention, but bladder cancer is probably the greatest concern. Although pioglitazone has remained on the market in many countries, some — including France and Germany — have banned it or severely restricted its use.
Indian patients are particularly well suited to pioglitazone, Dr. Panikar told Medscape Medical News, "because they have a lot of insulin resistance, so this drug is ideal for that." In fact, pioglitazone "is the cornerstone of treatment in most patients" in India, he stated.
Most in India are taking pioglitazone in combination with either metformin or a sulfonylurea, with many using fixed-dose combination products. Now that pioglitazone is suddenly unavailable, "the next step is to give gliptins or insulin," he explained. However, gliptins "are probably 10 times the price" of pioglitazone, so "a large number of patients…cannot afford this at all," and they also say, "Why should we take insulin…when all this time we were controlled without insulin?" he observed.
He noted that pioglitazone is used in very low doses in India, 7.5 to 15 mg daily. "If you don't have a contraindication for the use of pioglitazone, it should be used in a low dose," he asserted.
Dr. Panikar and others also stress that pioglitazone remains on the market in the United States, the United Kingdom, and in many other Western nations and that it is endorsed and recommended for diabetes management by many respected organizations, including the American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), and the International Diabetes Federation (IDF).
"We are worried, rather than being angry. We are concerned about our patients. We are making appeals to the government to reconsider the decision. Associations are in the process of putting together appeals, which will be presented, and we are hopeful they will reverse this decision," Dr. Panikar said.
Most Indians Cannot Afford Newer Medications
Pioglitazone has been available generically in India for some time, but newer oral type 2 diabetes medications, such as the gliptins (dipeptidyl peptidase-4 [DPP-4] inhibitors), are available only as branded products from Western companies, said Shah, whose organization represents domestic firms, such as Dr. Reddy's Laboratories and Ranbaxy Laboratories. There is 1 exception to this, with the Indian company Glenmark Pharmaceuticals, selling a cheaper version of one of the gliptins, but this is being legally challenged, he noted.
He said that the Indian government ruling on pioglitazone specifically cites that all "drug formulations containing pioglitazone are likely to involve risk to human beings" and states that "safer alternatives to the said drug are available."
While it is true that alternatives are available, many people simply cannot afford them, he maintained. "Around a third" of existing patients could probably afford to switch to newer diabetes medications, but the remainder cannot, he explained.
The market for pioglitazone in India is estimated to be worth about Rs7 billion ($120 million) a year, but the medication is cheap for individual patients, priced as low as Re1 to Rs4 per tablet, according to Indian reports.
But, "We haven't heard the last word yet," Shah asserted. Following "strong protestations" from a number of quarters, the government has now backtracked a little and agreed to a meeting of "technical experts" to discuss the situation, possibly as early as next week, he told Medscape Medical News.
 

AS I REVIEW MELANOMA, MITF COMES UP

MTIF A REGULATOR OF MELANOCYTE DIFFERENTIATION,

AN OLD STORY ON CRBCM

The LysRS-Ap4A-MITF signaling pathway
The LysRS-Ap4A-MITF signaling pathway was first discovered in mast cells, in which , the MAPK pathway is activated upon allergen stimulation. Lysyl-tRNA synthetase (LysRS), which normally resides in the multisynthetase complex with other tRNA sythetases, is phosphorylated on Serine 207 in a MAPK-dependent manner.[30] This phosphorylation causes LysRS to change its conformation, detach from the complex and translocate into the nucleus, where it associates with the MITF-HINT1 inhibitory complex. The conformational change switches LysRS activity from aminoacylation of Lysine tRNA to diadenosine tetraphosphate (Ap4A) production. Ap4A binds to HINT1, which releases MITF from the inhibitory complex, allowing it to transcribe its target genes.[31] Activation of the LysRS-Ap4A-MITF signaling pathway by isoproterenol has been confirmed in cardiomyocytes, where MITF is a major regulator of cardiac growth and hypertrophy.[32][33](wikipedia)

Not only it gives Hypertrophy but epidermolysis goes through this intergrin, it participates in the ERBB pathways.  Mark my word this is are critical pathways in pancreatic cancers.

MTIF GIVES YOU MOTIVES TO GO AFTER IT!
MAKING THE ERBIN A PLAUSIBLE TARGET.
MAKING ALSO A STRONGER CASE THAT MEMBRANE CYTOSKELETON SHOULD BE A GOOD TARGET BECAUSE OF THE WAY IT DRIVES ITS PATHWAY NOT THROUGH THE CYTOSOL( ALTHOUGH THERE IS A SECONDARY RAS/MAPK STIMULATION,) BUT THE PATHWAY HERE IS THROUGH THE RETICULUM ENDOTHELIUM DIRECTLY TO THE NUCLEUS!  CONCEPTUALLY, AN ANTIBODY TO LAMININ ATTACHED TO A SUBUNIT OF A LIPOLYTIC COMPOUND SHOULD HAVE A THERAPEUTIC OR CHEMICAL EFFECT AT THIS LEVEL.  AN INTERESTING APPROACH.  CHANCES ARE IT MAY ALSO HAVE A STRONG IMPACT ON THE WNT-PATHWAY WHICH TRAVEL CLOSE BY AND IS IMPORTANT IN BREAST CANCER!

MTA-1: THIS IS A REAL OPPORTUNITY
Here the cell stopped fooling around trying to lie to you.  Here the cell says to you this is one of my way to metastatasize.  yes this is my gene to mestastasize and I will work like any CBF like molecule by attaching to DNA and make me protein that will have me spread like wild fire!   And by the way I will use a growth hormone like Estrogen.   no kidding around
 "MTA1 has been shown to interact with HDAC1,[4][5] Histone deacetylase 2,[4][6][5] MTA2,[4] Estrogen receptor alpha[7][5] and MNAT1.[8] MTA1 has also been shown to inhibit SMAD7 at the transcriptional level[9]"  

IT DOES NEED TGF TO WORK, TGF IS FOR LOCAL GROWTH ANYWAY THAT WHY IT BLOCKS THE SMAD.

SPINT2
Mutation at SPINT2 leads to significant Malignant Ascites and peritoneal invasion, SPINT 2 is a suppressor of this phenomena. On the Intestinal membrane deficiency of SPINT2 leads to sodium induced/containing diarrhea.  This is also true in Ovarian cancer or peritoneal based tumors.  Targeting this is better then trying Avastin, a blind approach when it comes to effusions management.

MMP11

A metalloproteiase, aimed at breaking down extracellular matrix and be on the move.  Targeting MMP for cancer has proven futile.  The cell is not stupid, it does not put out things that is going to hunt it!  It first builds a strong inhibitor to metalloproteinases.  In fact lack of inhibitors has been recognized as the main pathogenesis of TTP.   With the ADAMs being the integrins involved!  and next is that Inhibitor which is of course expressed in pancreatic cancer.

TIMP1

TIMP1

From Wikipedia, the free encyclopedia
Jump to: navigation, search
TIMP metallopeptidase inhibitor 1

PDB rendering based on 1d2b.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols TIMP1; CLGI; EPA; EPO; HCI; TIMP
External IDs OMIM305370 MGI98752 HomoloGene36321 GeneCards: TIMP1 Gene
RNA expression pattern
PBB GE TIMP1 201666 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 7076 21857
Ensembl ENSG00000102265 ENSMUSG00000001131
UniProt P01033 P12032
RefSeq (mRNA) NM_003254 NM_001044384
RefSeq (protein) NP_003245 NP_001037849
Location (UCSC) Chr X:
47.44 – 47.45 Mb
Chr X:
20.87 – 20.87 Mb

PubMed search ]


TIMP metallopeptidase inhibitor 1, also known as TIMP1, a tissue inhibitor of metalloproteinases, is a glycoprotein that is expressed from the several tissues of organisms.
This protein a member of the TIMP family. The glycoprotein is a natural inhibitor of the matrix metalloproteinases (MMPs), a group of peptidases involved in degradation of the extracellular matrix. In addition to its inhibitory role against most of the known MMPs, the encoded protein is able to promote cell proliferation in a wide range of cell types, and may also have an anti-apoptotic function.
==============
PRKCA  see PRKCG
Here Phorbol esters, diacylglycerol, and calcium become important for the cell performance of various functions.  Did I mention few targets, I truly believe I did!

CDH1  The Cadherin by excellence, not only important as adhesion molecule and role in metastasis.  Its role is amplified by what else anchors here such as Vinculin, and others molecules such as Plakoglobins, amplifying the role.  Remember even Cytochrome C is anchored at the mitochondrial membrane and its release leads to apoptosis!
The anchors are legitimate targets therefore, and brings to mind NACA1 in the anchoring to Histone deacetyl transferase (SEE OUR LEUKEMIA SECTION)  CDH13 THAT'S ANOTHER BALL GAME ALL TOGETHER.  THE CELL TWEACKS SOMETHING AND IT IS ANOTHER BALL GAME ALL TOGETHER!
==========================

NOW IN MELANOMA THEY ADD
1. THE C-KIT
2. BRAF
3.  NRAS
4. GNAQ/GNA11 FOR UVEAL MELANOMA
5. P16/CDKN2A
6. IF MITF IS THE DRIVER, KNOCK OUT AP4A THEY SAY!

CELEBRATION 30 YEARS AGO 8/8/1983

EXACTLY 30 YEARS AGO, I GRADUATED IN MEDICINE WITH THESE GUYS
AND ITS SEEMS LIKE YESTERDAY!


Date: Tue, 9 Jul 2013 08:56:23 +0100
From: adrienkisi@yahoo.fr
Subject: Re: Du lundi 08 Août 1983 au lundi 08 Août 2013 : 30 ans en tant que docteur en médecine
To: kymrisgey_poy@hotmail.com; gkapuku@yahoo.com; tnemuandjare2003@yahoo.fr; llukuni@yahoo.fr; nkinsi@care.org; lukemnkinsi@yahoo.com; mdiese@iapac.org.za; kasongo@pathcare.co.za; kapikabongo@yahoo.com; mwanatambwe_milanga/patho2@nms.ac.jp; kiantede_p_nzogu@yahoo.com; mbimabiala@yahoo.fr; kayembe.m.kashalala@gmail.com; gaston.k@usa.net; tnemuanandjare2003@yahoo.fr; theonemuandjare@gmail.com; ezechkalund@yahoo.fr; emuembo@yahoo.fr; bertzinga@yahoo.fr; ilungan75@hotmail.com; pietuy@yahoo.com; prosdibikabi@hotmail.com; pietuy@yahoo.fr; pmuwonga@hotmail.com; david_nku@kin.salvationarmy.org; fatakibombil@gmail.com; ghsalu@yahoo.fr; ggombe@yahoo.uk.com; gslugoma@gmail.com; henbalt@yahoo.fr; jeanmarie.bamvita@douglas.mcgill.ca; floribert.kasende@yahoo.fr; mutombo.kankonde@kp.org; kanko1@yahoo.com; krubguss@yahoo.fr; chmavula@hotmail.com

THESE ARE GOOD GUYS SPREAD NOW ACROSS AND AROUND THE WORLD DOING WHAT WE LIKE FROM JAPAN TO SAHEL! FROM SOUTH AFRICA TO CANADA! WORKING HARD! HAPPY ANNIVERSARY TO ALL! FROM ZIMBABWE TO FRANCE!

ASPECTS OF AUTOIMMUNE DISEASES/ FROM MEDSCAPE

Gluten Sensitivity Linked to Autism

Fran Lowry
Jul 05, 2013
A subset of children with autism have increased immune reactivity to gluten, but the mechanism of this increased reactivity appears to be distinct from that involved with celiac disease, new research shows.
The results also indicated an association between elevated antibodies to gluten proteins and the presence of gastrointestinal (GI) symptoms in the affected children.
"There is evidence that immune system abnormalities are associated with symptoms in a substantial number of individuals with autism," senior author Armin Alaedini, PhD, assistant professor of medical sciences in the Department of Medicine and the Institute of Human Nutrition at Columbia University Medical Center, New York City, told Medscape Medical News.
"In addition, several studies have evaluated gastrointestinal symptoms and defects in GI barrier function in affected patients. Some have pointed to higher frequency of celiac disease, family history of celiac disease, or elevated antibody to gluten among autistic children, but these studies have been inconsistent about such associations," Dr. Alaedini said.
The study was published online June 18 in PLoS One.
Growing Popularity of Gluten-Free Diets
Diets that exclude gluten are increasingly popular in the autism community, but their effectiveness has not been proven in controlled and blinded studies.
In the current study, Dr. Alaedini and his team analyzed serologic and genetic markers of celiac disease and gluten sensitivity in 37 children diagnosed with autism according to both the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview, Revised (ADI-R) as well as in 27 of their unaffected siblings and 76 age-matched unrelated healthy control individuals.
The blood samples were tested for antibodies to tissue transglutaminase, a sensitive and specific marker of celiac disease, as well as antibodies to gliadin.
The children with autism were also genotyped for celiac disease associated HLA-DQ2 and HLA-DQ8 alleles.
The analysis showed that the children with autism had significantly higher levels of IgG antibody to gliadin compared with unrelated healthy controls individuals (P < .01). The IgG levels were also higher compared with the unaffected siblings but did not reach statistical significance.
The researchers also found that the IgG antigliadin antibody response was significantly greater in the autistic children with GI symptoms in comparison to those without GI symptoms (P < .01).
There was no difference in IgA response to gliadin among the 3 groups.
Additionally, levels of celiac disease–specific serologic markers, for example, antibodies to deamidated gliadin and TG2, did not differ between patients and control individuals.
Nor was an association between increased antigliadin antibody and presence of HLA-DQ2 and -DQ8 observed.
Little Clinical Relevance Yet
The findings have little relevance to bedside practice at the moment, Dr. Alaedini said.
"It would be too early to talk about medical advice or treatment resulting directly from this study. Also, the findings need to be confirmed in larger cohorts."
He added that the observations from this study point to immunologic or intestinal barrier abnormalities and their association with GI symptoms in autism.
"Having a clearer understanding of the immunologic differences in the affected children can give us novel clues about the mechanism of autism, such as the potential involvement of immune-mediated pathways. These clues, in turn, may lead to new treatments that, for example, target those specific immune pathways," Dr. Alaedini noted.
"In addition, characterization of the target gluten molecules in the observed antibody response may offer biomarkers to identify a subset of patients that would respond to certain treatment strategies."
Another Piece of the Puzzle
Commenting on the study, Dan Coury, MD, medical director of the Autism Speaks Autism Treatment Network and professor of pediatrics and psychiatry in the College of Medicine at the Ohio State University, Columbus, said the findings provide additional information to what is currently known about GI problems in autism.
"The investigators found increased levels of an antibody to gluten, but not the abnormalities that are seen with celiac disease which is caused by gluten. They also found these antibodies increased more in those with autism and GI problems than in those with autism alone. These antibodies were significantly increased compared to healthy controls, but not significantly different from unaffected siblings. While the IgG antibodies were higher, the IgA antibodies were not," he told Medscape Medical News.
"In this case," Dr. Coury continued, "IgA antibodies are a sign of immune function of the gut mucosa, while IgG antibodies are a sign of the body having an overall immune response, for example, they can indicate a person's immunity to something such as chickenpox."
The findings pose additional questions, he added.
"The high IgG suggests that without high IgA, what we are seeing may not be related to current GI gluten problems but some past exposure. This would also fit with the fact that there were no abnormalities typically seen in celiac disease.
Review summaries of articles on clinical issues in Type 1 Gaucher disease and gain understanding of patient concerns.
Information from Industry
"It might also mean that this IgG antigliadin antibody isn't actually an antibody to gliadin. It might be an antibody that reacts with gliadin but actually is produced by the body to react to something else," he said.
Dr. Coury noted that because immune abnormalities have been seen in autism, it may be another part of the puzzle that needs to be solved.
"By themselves, antigliadin antibodies do not mean disease. They are part of the whole puzzle. When they occur with other abnormalities and with symptoms, we begin to get a clearer picture. As the authors note, these findings deserve further study. It may be that this will help identify a subgroup of individuals with autism who might benefit from a specific treatment someday, when we have a better understanding of just what is going on here."
The study was funded by the US Department of Defense. Dr. Alaedini and Dr. Coury report no relevant financial relationships.
PLoS One. Published online June 18, 2013. Full article

Monday, July 8, 2013

PROGNOSTIC INDICATORS IN AUTOIMMUNE DISEASES.
=============================================

We have focused lately on some of the indicators of Autoimmune diseases,  and one may be surprised at this focus but keep in mind there no smoke without a fire.  There is no antibody without a gene abnormality.  And some if not all autoimmune diseases lead to lymphoproliferative disorders.  So it is pertinent to start looking into these factors with a critical look.
Factors in Autoimmune diseases are grouped generally in Diagnostic (leading to specific diagnosis), Acute phase (denoting active disease), chronic (denoting persistent disease), prognosis (inferring persistent destruction of tissue).  Remember Auto-immune diseases target Skin, Lung, Liver, the Heart, Central and peripheral Nervous system, the circulatory system (Vasculitis), the joints, kidney and Muscle skeletal systems or in few words "all the systems".  That is why we call these disease "SYSTEMIC DISEASES".

FIRST THE LIST OF PROGNOSIS FACTORS,
AND COMMENTS WILL FOLLOW!

1.  High level or titer of Rheumatoid Factor
2. Persistent Anti-DNA
3. Presence of Anti-Ribosomal Antibody in lupus- CNS involvement.
4. Anti-CL70 --"Diffuse" Scleroderma
5. Anti-centromere Antibody -CREST, there is suggestion of good prognosis! (unless the kidney, heart and lung fibrosis come into play to change that!)
6. Anti-Jo ---lung involvement
7. Anti-Smith and anti-RNP associated with hign Interferon-1 and diruption of immunity-high rate of infection
8.Anti-phospholipid AB (Cardiolipin) -Thrombosis/including strokes, watch Antibody to Beta 2 -glycoprotein-1 (does the same!)
9.-Anti-M2-directed against nuclear Helicase (Polymyositis)
10- Anti-Synthetase
11. anti-signal recognition
12. Anti-topoisomerase (worse prognosis, poor response to Corticosteroids, )
13. Anti -anti RNA Polymerase III---scleroderma involving the Kidney
14. In Sjogren the change of rheumatoid factor from positive to negative when following polyclonal to oligoclonal cells announces lymphoproliferative transformation-act quick here!

Think of these
Next Acute phase factors.......

Saturday, July 6, 2013

Controversy in Gastric cancer

As one reflect on the epidemiology of Gastric cancer, one ends up with questions that are technically answered in the main stream scientific reporting but lead to the following questions in the scientific researcher mind.
1. It is generally accepted as a fact that there is a 75% decrease of Gastric Cancer in the United states over the last few decades.  The official reason is that there has been a significant improvement in food storage and quality of water.  This conclusion is not really clearly based on gene evolution studies or any hard scientific data, it is based on observational evaluation that  poor people living in poor countries still have Gastric Cancers.  This assertion goes on unchallenged even though statistical evaluation in poor countries are notoriously unreliable or non-existent. The Peculiarity of the incidence of this disease in Japan challenges both the notions that poverty and unhealthy conditions  are the dominant forces leading to the disease.  Until all aspects are scientifically explored statements such as "gastric cancer is strongly influenced by nutritional, socio-economic, and medical factor rather than dominated by genetic" call for a pause!  The mere fact that there are twice as many men with gastric cancer than women partially challenges the statement.  And further more incidence variation is seen among the races (and ages).
2.The gastric cancer treated in Japan appears to have a better prognosis.  This fact has been "attributed to the superiority of surgical techniques".  The non adoption of such techniques elsewhere fly against that perception.  There is a lingering feeling that this cancer in the Japanese population is peculiar somehow.  That this peculiarity is the true reason of the good prognosis.  That is, the surgical technique is not fully the reason.  That feeling leaves western surgeons room to continue their current practice.  Indeed it would have been legally unacceptable to do less surgery when the more extensive "is better".

3.The use of Aspirin and non steroidal is associated lower cancer of the G-E junction.  This is contrary to what one would expect.  A medication causing gastric ulcer is in this case protective!

4.H. Pylori has been clearly demonstrated to lead to gastric cancer.  However its eradication is now only indicated for those with an Ulcer.  Why not eradicate all together, a vaccine campaign for example.  Scientist are not sure because "no definitive evidence shows that mass eradication could reduce the incidence" of this disease.  A mass Chinese study reportedly did not achieve such an objective .

WE HAVE GOT TO STUDY GENES AND THEIR DISPARITIES IN RACES MORE THOROUGHLY BEFORE MAKING DEFINITIVE BETTER CONCLUSION!

Friday, July 5, 2013

keeping you in the festivity of independance day!

 To the Inova family,
 
When I was in high school, one of the most enjoyable experiences I had was playing in the concert band.  I was a saxophone player, or a baritone saxophone player to be more precise.  I wasn’t very good due to lack of practice and presumably talent as well,  but I had the opportunity frequently to travel to the “big city” of Asheville, N.C. to audition for a seat on the all-state band.  You see, there are very few baritone sax players and even if you weren’t very good, you had a chance to be chosen for this highly selective band due to lack of competition.  I always used to get nervous despite my reasonably good prospects and can still remember the tension of those auditions as if it were yesterday.
 
So it struck a chord when someone recently shared with me the story of an aspiring French horn  player who tried out for a highly coveted spot on a prestigious symphony orchestra.  The  player had practiced for endless hours and had worked with a coach to gain all the fine points of style and finesse that mark the truly excellent players of the instrument.  To prevent any unintended bias in the selection process, each hopeful had to play behind a screen  to keep their identity hidden.  The orchestra’s other French horn players served as judges to select their new colleague for the orchestra and they were renowned for having extremely high standards.  Excellence in performance was EVERYTHING to them!  So after hearing over twenty auditioning players, it was a little surprising that they were unanimous in their choice and selected the French horn hopeful who had worked so hard.
 
It struck me in hearing that story that excellence really does matter.  Being good or even very good is nice but it’s really not what we at Inova are striving for.  As many of you may know, the Medicare program administrator (CMS) rates each hospital on the quality of its patient experience.  They ask a sample of patients to rate everything from how clean and quiet their room was  to how well the doctors and nurses answered their questions, managed their pain and helped them understand what they needed to do to actively help with their own recovery.  The interesting thing is that the way scores are calculated, they place the highest emphasis on how EXCELLENT the care was.  In many respects, it is the number of patients that rate our care as EXCELLENT that determines how our scores come out (and, as an aside, how much we get paid!).  I have written often that  our highest priorities are embedded in our “TRUE NORTH” goals of providing the highest quality, the best experience for our patients and their families, and reducing our costs  to make our care affordable for the most people.  Like the orchestra musicians, quality, experience and affordability are EVERYTHING to us!
 
And you know what—nothing but excellent IS acceptable!  Like the French horn player who “made the team”, we must remember “very good” just means on some occasions, our patients had pain, they were anxious or fearful,  they didn’t understand what was going on,  they didn’t understand their medicines, or the room was loud and they couldn’t sleep.  Sadly, on some occasions we did things that led to longer periods of recovery and in some instances, caused real harm! 
 
On July 4, we are reminded that some things count most when they are measured in absolutes—such as giving one’s life for your country, or preventing a terrorist bombing, or being there to treat the victims of a disaster.  You either prevail in your efforts or some people may pay dearly--sometimes people die or lose their freedom.  Today we celebrate our independence and similarly, I would invite you to remember that our patients depend on us absolutely. In short, they depend upon us for excellence and nothing less—their very lives may depend upon it. 
 
When the young French horn player who won the audition walked out from behind the screen, the judges” jaws dropped.  Their new colleague (did I mention that they were all men?) was a 29 year old, Asian woman—let’s face it, she didn’t fit the stereotype of what they were expecting at all.  Not by age, not by gender, not by ethnicity – now they had to face the fact that the old French horn section was going to look and be quite different in the future.  And you know what?  It proved to be the best French horn section that great orchestra ever had.  Because nothing less than EXCELLENT was acceptable to their new colleague.  Their true north was simple excellence, just like it is for our patients and their families.  So as we remember fireworks and cookouts, let’s also remember that freedom isn’t free; that excellence doesn’t come without persistent hard work; and that everyone should be judged on their commitment to true north rather than some outdated stereotype.  Our patients deserve nothing less.  Now that’s something we can all celebrate!!
 
God bless you all,
Knox

FURTHER EXPLORATION INTO THE GENES OF PROSTATE CANCER

Prostate cancer is one of the most interesting cancers from research perspective.  It has high Incidence but only 1 in seven patients diagnosed with it dies.  In 2011, close to 241,000 people were diagnosed with this cancer but only 34,000 died of this disease.  This fact points to the fact that some of the pathology in this disease,  has clearly an indolent course while other cases have a virulent course.  The Challenge remains how to best diagnosed those with the virulent course because they require multi-modality therapy for a cure.  It is believed that the virulence status of the disease can be attributed to a mean and bad genetic profile, but to this date the exact profile is being debated.  What is known or currently accepted is that "there is a loss of function of genes that detoxify carcinogens" leading to hypermethylation and silencing of some critical genes which include that of the "PI class Gluthation-S-transferase." (ASCO).

Then there is the fusion of TMPRSS2 with ERG or ETS.  Mutation at SPINK-1  and the involvement RAF kinase are not small businesses!   The RAF Kinase amplification ensures the survival of the disease because with the MAPK (and a little bit of the MTOR) downstream, this pathways is anti-apoptotic.  Therefore it ensures the survival of Prostatic cancer cells.   The SPINK1 is globally a control gene which represses Catalytic enzymes (such as Trypsin) in order to control their activity and keep their activities within normal range.  With SPINK-1 Mutated, there is an uncontrolled cleavage of gene target substrates by relevant Proteases!   and Guess what?  TMPRSS-2 is just such a PROTEASE.
(wikipedia on TMPRSS2-"The protease domain of this protein is thought to be cleaved and secreted into cell media after autocleavage. The biological function of this gene is unknown.[2]")
The association of TMPRSS2 with ERG amplify the action of TMPRSS2.  Yes ERG give the Multiplication power of Red cell to a protease.  A multiplied TMPRSS2 product, a protease, goes  to work on its targets and the rest is History!  It will amplified IL-2, CDK 10, splicing factors (SF3B4 which acts on TOP2A), CHEK1, BMPR1A,and CDC5L and DNA-PKC, CID and CHUK!  Through ZMYND1 it activates C11orf30 and blocks BRAC2 to remove gene repair function and cellular tolerance of genetic errors.  Basically the neoplastic process is set and through BMP, metastasis to the bone is set to occur!
With this understanding-please go to work!
The CRBCM is on your side!
HOW MUCH THE KU HELPS TEMPRSS2 IN ITS LOCALIZATION AT NUCLEAR LEVEL IS STILL TO BE DEFINED!  IF VERIFIED IT WILL MAKE THE KU A SUBSTANTIAL TARGET IN PROSTATE AND PANCREATIC CANCERS!

SO YOU KNOW THIS HAPPENED!

Phase II study of weekly PM00104 (ZALYPSIS) in patients with pretreated advanced/metastatic endometrial or cervical cancer
Medical Oncology, 06/19/2013  Clinical Article







Martin LP et al. – This open–label, two–arm, phase II clinical trial evaluated the antitumor activity and safety profile of PM00104 (Zalypsis) administered as a 1–h, weekly, intravenous infusion (days 1, 8 and 15; every 4 weeks) at a dose of 2 mg/m2 to patients with advanced and/or metastatic endometrial (EC) or cervical cancer (CC) after one previous line of systemic chemotherapy. Despite PM00104 showing mostly mild, predictable, manageable and reversible toxicity, protocol criteria for further recruitment were not met in EC, a futility analysis was done and recruitment was stopped; a low patient recruitment rate together with no evidence of activity in CC resulted in early study closure.


ALSO ONGOING


Study of Zalypsis® (PM00104) in Patients With Unresectable Locally Advanced and/or Metastatic Ewing Family of Tumors (EFT) Progressing After at Least One Prior Line of Chemotherapy

AND 

 

 

Zalypsis: a novel marine-derived compound with potent antimyeloma activity that reveals high sensitivity of malignant plasma cells to DNA double-strand breaks.

Source

Centro de Investigación del Cáncer, Instituto de Biologia Molecular y Celular del Cancer/Centro de Superior de Investigaciones Cientificas-Universidad de Salamanca, Spain. emocio@usal.es

Erratum in

  • Blood. 2010 Jul 8;116(1):151.

Abstract

Multiple myeloma (MM) remains incurable, and new drugs with novel mechanisms of action are still needed. In this report, we have analyzed the action of Zalypsis, an alkaloid analogous to certain natural marine compounds, in MM. Zalypsis turned out to be the most potent antimyeloma agent we have tested so far, with IC(50) values from picomolar to low nanomolar ranges. It also showed remarkable ex vivo potency in plasma cells from patients and in MM cells in vivo xenografted in mice. Besides the induction of apoptosis and cell cycle arrest, Zalypsis provoked DNA double-strand breaks (DSBs), evidenced by an increase in phospho-histone-H2AX and phospho-CHK2, followed by a striking overexpression of p53 in p53 wild-type cell lines. In addition, in those cell lines in which p53 was mutated, Zalypsis also provoked DSBs and induced cell death, although higher concentrations were required. Immunohistochemical studies in tumors also demonstrated histone-H2AX phosphorylation and p53 overexpression. Gene expression profile studies were concordant with these results, revealing an important deregulation of genes involved in DNA damage response. The potent in vitro and in vivo antimyeloma activity of Zalypsis uncovers the high sensitivity of tumor plasma cells to DSBs and strongly supports the use of this compound in MM patients.

Thursday, July 4, 2013

GENES in Pancreatic cancer

*The gene in pancreatic cancer
1.BRCA1, BRCA2,P16,
2.DPC4,
3.STK11/LKB1 (PART OF THE PEUTZ JEGHERS SYNDROME)
Serine/threonine kinase 11 (STK11) also known as liver kinase B1 (LKB1) or renal carcinoma antigen NY-REN-19 is a protein kinase that in humans is encoded by the STK11 gene.[1]WIKIPEDIA

4.KRAS "WHICH IS INTEGRATED IN THE SIGNALING PATHWAYS OF SEVERAL RECEPTOR KINASE INCLUDING EGFR AND THE INSULIN GROWTH FACTOR RECEPTOR-1
5.ATAXIA TELANGIECTASIA
------------------------------------------------------------------------------------------------
 Testosterone
 ESTROGEN
        !
COMPLEX                      !---------cAMPK------cell polarity and inhibition of abnormal morphology
-LBK1 +      -----------------!
-STRAD                           !----------CDC37 and HSP90 ----NFkB (MAPK)
-MO25                             !-----------SMARCA4-------------BRCA1 and P53

if you use this, please quote wikipedia and CRBCM for your own good!

GANETESPIB AND GENES IN PACREATIC CANCER DUE TO PEUTZ JEGHERS SYNDROME (FROM NCI AND WIKIPEDIA)

DO NOT BELIEVE I NEED FURTHER COMMENTS, JUST THINK ABOUT THIS
RESEARCH HAS BEEN DONE! AND SEE IT THROUGH!
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Testosterone and DHT treatment of murine 3T3-L1 or human SGBS adipocytes for 24 h significantly decreased the mRNA expression of LKB1 via the androgen receptor and consequently reduced the activation of AMPK by phosphorylation. In contrast, 17β-estradiol treatment increased LKB1 mRNA, an effect mediated by oestrogen receptor alpha.[2]
However in ER-positive breast cancer cell line MCF-7, estradiol caused a dose-dependent decrease in LKB1 transcript and protein expression leading to a significant decrease in the phosphorylation of the LKB1 target AMPK. ERα binds to the STK11 promoter in a ligand-independent manner and this interaction is decreased in the presence of estradiol. Moreover, STK11 promoter activity is significantly decreased in the presence of estradiol.[3]WIKIPEDIA

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ganetespib 
A synthetic small-molecule inhibitor of heat shock protein 90 (Hsp90) with potential antineoplastic activity. Ganetespib binds to and inhibits Hsp90, resulting in the proteasomal degradation of oncogenic client proteins, the inhibition of cell proliferation and the elevation of heat shock protein 72 (Hsp72); it may inhibit the activity of multiple kinases, such as c-Kit, EGFR, and Bcr-Abl, which as client proteins depend on functional HsP90 for maintenance. Hsp90, a 90 kDa molecular chaperone upregulated in a variety of tumor cells, plays a key role in the conformational maturation, stability and function of "client" proteins within the cell, many of which are involved in signal transduction, cell cycle regulation and apoptosis, including kinases, transcription factors and hormone receptors. Hsp72 exhibits anti-apoptotic functions; its up-regulation may be used as a surrogate marker for Hsp90 inhibition. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

SOCINSKI "Purpose: Ganetespib is a novel inhibitor of the heat shock protein 90 (Hsp90), a chaperone protein critical to tumor growth and proliferation. In this phase II study, we evaluated the activity and tolerability of ganetespib in previously treated patients with non–small cell lung cancer (NSCLC)."Patients were enrolled into cohort A (mutant EGFR), B (mutant KRAS), or C (no EGFR or KRAS mutations). Patients were treated with 200 mg/m2 ganetespib by intravenous infusion once weekly for 3 weeks followed by 1 week of rest, until disease progression. The primary endpoint was progression-free survival (PFS) at 16 weeks. Secondary endpoints included objective response (ORR), duration of treatment, tolerability, median PFS, overall survival (OS), and correlative studies.
Results: Ninety-nine patients with a median of 2 prior systemic therapies were enrolled; 98 were assigned to cohort A (n = 15), B (n = 17), or C (n = 66), with PFS rates at 16 weeks of 13.3%, 5.9%, and 19.7%, respectively. Four patients (4%) achieved partial response (PR); all had disease that harbored anaplastic lymphoma kinase (ALK) gene rearrangement, retrospectively detected by FISH (n = 1) or PCR-based assays (n = 3), in crizotinib-naïve patients enrolled to cohort C. Eight patients (8.1%) experienced treatment-related serious adverse events (AE); 2 of these (cardiac arrest and renal failure) resulted in death. The most common AEs were diarrhea, fatigue, nausea, and anorexia.
Conclusions: Ganetespib monotherapy showed a manageable side effect profile as well as clinical activity in heavily pretreated patients with advanced NSCLCs, particularly in patients with tumors harboring ALK gene rearrangement. Clin Cancer Res; 19(11); 3068–77. ©2013 AACR.

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Signaling pathway of toll-like receptors. Dashed grey lines represent unknown associations
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 SMARCA4 has been shown to interact with Beta-catenin,[7] SIN3A,[8][9] Myc,[10][11] CBX5,[12] SMARCE1,[13][14] HSP90B1,[15] STAT2,[16] CREB-binding protein,[17][18] Glucocorticoid receptor,[19][20] FANCA,[15][21] STK11,[22] BRCA1,[23][24] ACTL6A,[13][14] POLR2A,[8][13][14] ING1,[9] Cyclin E1,[25][26] P53,[27] Estrogen receptor alpha,[17][28] Prohibitin,[29] SMARCC2,[13][14][15] SMARCC1,[8][13][14][15] SMARCB1,[8][13][14][15][30] ARID1B[31][32] and ARID1A.[13][14]


The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SWI/SNF, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44.[2]
BRG1 works to activate or repress transcription. Having functional BRG1 is important for development past the pre-implantation stage. Without having a functional BRG1, exhibited with knockout research, the embryo will not hatch out of the zona pellucida which will inhibit implantation from occurring on the endometrium (uterine wall). BRG1 is also crucial to the development of sperm. During the first stages of meiosis in spermatogenesis there are high levels of BRG1. When BRG1 is genetically damaged, meiosis is stopped in prophase 1, hindering the development of sperm and would result in infertility. More knockout research has concluded BRG1’s aid in the development of smooth muscle. In a BRG1 knockout, smooth muscle in the gastrointestinal tract lacks contractility, and intestines are incomplete in some cases. Another defect occurring in knocking out BRG1 in smooth muscle development is heart complications such as an open ductus arteriosus after birth.[3][4]

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 Heat shock protein 90kDa alpha (cytosolic), member A1 has been shown to interact with TGF beta receptor 2,[3] FKBP5,[4] TGF beta receptor 1,[3] Glucocorticoid receptor,[5][6][7][8][9][10][11] AKT1,[12][13][14] Hop,[15][16] Peroxisome proliferator-activated receptor alpha,[17] AHSA1,[18] HSF1,[19][20] STK11,[21] C-Raf,[22][23] ERN1,[24] PIM1,[25] GNA12,[26] Endothelial NOS,[27][28][29] Androgen receptor,[30][31] CDC37,[32][33] DAP3,[6] SMYD3,[34] Telomerase reverse transcriptase,[12][13] HER2/neu,[35][36] EPRS,[37] P53,[38][39][40] Estrogen receptor alpha[20][41] and GUCY1B3.[27]