Sunday, November 30, 2014

Recent Big news!

*Recent trial suggested that Jakafi in combination with Xeloda may be useful in second line therapy against pancreatic cancer particularly those induced or accompanied by strong inflammatory response as suggested by high lebel of CRP (C-reative protein) (Targeted Therapy).
*With over 20% success in patents with NSCL cancers, Nivolumab /Pembrolizumab and other anti PD-1/PD-L1 continue to impress researchers and are bound to change the therapeutic approaches in this disease.  Soon everyone will be screened for these antigens as response rates seem to correlate with their presence.
*Does inhibiting Cytokines inducing cachexia in cancer able to change overall survival rates in cancers.   What is the relationships between these Cytokines and Mitochondrial changes and telomeres?

Tuesday, November 25, 2014

After the Cytokine period in a life cycle

First we have a Conception, birth and growth lasting from birth to 10 to 15 years, this period is full of "growth" but seems dominated by the HLA (Histocompatibility build up) but also organ maturation. Trying to establish what is oneself seems to be the priority.  Fight against infections seem to be the determinant event. Here women are the most "build"up in preparation for receiving the child, a foreign entity.

Then come 15 to 25 years of "Hormone reign"when most of the purpose is turned to reproductive function. The testicular cancer happen at this stage.  And in women, infection driven cancers (cervix) will mark this period.  Autoimmune and metabolic diseases will mark this period.

After the reign of the Hormones, after Menopause, commences the "years of the Cytokines".  This last another 20 years. One important fact during the years of the Cytokines, Hormone receptor desensitization with marked endothelial effect in women and does have profound epigenic and nuclear effects at cellular level.  Most cancers will happen here as Cytokines induce them.  In developing countries, most do not reach this period.  The cytokine period obviously last all life long as cancer can happen any day but during the years of 50 to 70, cancer risks are clearly higher but so are arthritic conditions that fully fall on the lapse of the Cytokines.  Mental disturbances also fall on the Cytokines.  Those who are lucky have a good c-fos, c-jun, Fas, FOXO-1, Daf-1 and the Telomeres (families of genes), will enter the new 10-20 years with still the Cytokine but less intense, like the one that make lose weight and muscle tone, the one that induce dementia and further CNS disturbances....

Saturday, November 22, 2014


 In this world of infections, Ciprofloxacin has gained prominent place and is widely prescribed and many antibiotics have similar effect of immunomodulation on mainly the monocytes and of course the lymphocytes.  Widespread use of these antibiotics call for further discrimination at genetic levels.  Ciprofloxacin has been known to amplify several genes including the NFKB, JUN B, C-Myc, AP-1, NFAT, c-fos, c-JUN, fra-1.   The NFAT amplification has the most of the attention here...This amplification calls for a check on the GSK3B  because a secondary amplification of this gene hits many critical genes in the initiation of cancers!  And in a profoundly obese population, the GSK3B has to be assumed to be profoundly disturbed in terms of level.  A high amplification of this gene not only affect key genes but is associated with marked phosphorylation of other genes particularly when interacting with SGK3.   And phosporylation of genes has been implicated in the expansion neoplastic transformations.  i.e the story of Casein Receptors and their relation with breast cancers.
Concurrent amplification of NFAT and GSK3 may be dangerous
1.when interacting with AR- --(Androgen Receptors) because Prostate Cancer may result
2.MUC 1, because Colon cancer may result
3.P53 and the Catenin, the NOTCH, all implicated in various cancers (Breast,tuberous etc..)

Do we check the status of this gene? no, we are still waiting for clinical trials...can't wait to live in the next century when all this will be done!  don't take my words for them!


GSK3B has been shown to interact with:

Wednesday, November 19, 2014

cancer detection movement is on the rise

It is generally thought that cells undergoing Neoplastic transformation will exhibit mutation, amplification or some form of new pattern in their genes, and based on this new pattern, observer can diagnose or even anticipate the behavior or prognosis of the cancer.   But each time, the question that come to mind is, which genes in which cancer?  And with 25,000 genes , the task is not a slim one.  And to make matter worse, Neoplastic cells do not remain static!  They are in constant flush, trying to survive their environment.
We know for example that prostate cancers grow on Androgen stimulation which has become the focus of most prostate cancer treatment with "abiraterone Acetate which blocks androgen synthesis, and Enzalutamide which block the Androgen Receptor" (Nina Sharifi).  We also know now that In their struggle to survive, the prostate cancer cells will acquire the enzyme 3 Beta-Hydroxysteroid dehydrogenase-isoenzyme to self produce DHEA and ultimately DHT.

While it is important to focus on these important driving mechanisms, it is also important to remember that cells use their potentials to fabricate these important enzymes!  Other supportive genes continue to play important supportive roles that also need to be disturbed.  And that remains a further challenge.  At certain times, the supportive role could be the overwhelming activity and detection may be skewed !
Professor Klein proposed 17 Genomic Prostate Core
1.Androgen signaling:
2.Stromal response
and there are
4.Cellular organization
and 5. Reference  (see article:"Genomics for active surveillance now in Practice")

We, at CRBCM, although reserved on the content as most of these reports may be limited, approve of this model of reporting detection as no single gene could actually reflect cellular activities all the time.   The fact is that the Genomic core does not speak about other genes such as the MED1,RAD51, CHEK1, DAPK, MLH1,TIMP3, PPARGs, TMPRSS, ERG, ETV1, SMADs,NBN or miRNAs  even though we know they are into play!

Despite our reservations, it is clear and exciting  to see the vibrant stand for cancer detection  in the general population and of course in targeted markets!   We are meeting today at UTEP to discuss what will be tested in collected blood samples...our bank has already 25 vials of blood samples the first week since we launched this study.  And more people are coming to donate...
CRBCM, progressing  slowly despite adversity!

Tuesday, November 18, 2014

Progression even in cancer detection

The study of cancer particularly as it comes to genes, gene alterations and their quality and quantity  modifications is one of the most exciting field of scientific research.  The cell, even the neoplastic cell, continue to be alive meaning undergoing constant changes and molecular transformations.  Often times, these transformations seem purposeful and clearly directed.  And often times the direction intends to reach "survival".  Less often though, the ultimate purpose is clear death ie when the Telomeres are shortened or the Caspases are engaged.
It is obvious that cancer detection should follow these transitions because some genes may not be over-expressed all the time, and some are even depressed during the neoplastic transformation.  The shear number of cells may affect secreted membrane proteins (such as the Prostate specific membrane Antigens (PSMA) to influence detection (by antibody) but often the predominant ongoing cellular phenomena can only be detected by studies of gene amplifications.
There seem to be 3-4 phases of cancer progression that require adapted detection:

1. The initial phase
where an amplified gene is inducing changes that will initiate the Neoplastic process,
ie effect of smoking on the MDM-2 gene and resultant effect on the P53.
ie. Viral effect on the Src or CSK genes,  this of course before the FUS gets into the frey! YES1! Rho gene...

2.The period of proliferation, that is when the MYC gene is involved to amplify all the genes
but not only the MYC but NPM1, Cyclin B1, and of course the many genes of proliferation

3.Metastatic phase (initial or during disease recurrence) here comes the Ros gene

4. Cellular death where Telomere and Mitochondrial phenomena come into play

we still have to wonder about the NCOA, the EZH2, ATRX, and MED1, TIMP3, where do these fit?

Saturday, November 15, 2014

Amplification of NCK-2 gene is/could be a strong Bio-marker of cancer recurrence

One thing for sure the return of cancer is physiologically one of an extraordinary undertaking in cancer biology.  Indeed as cell reconstitute, reoganization has to occur at several cancer cell levels including the Cytoskeleton.   One of the little known gene that comes into play is the NCK2 gene, a ligand protein /gene that direct to exacerbation of Actin polymerization and " The protein has no known catalytic function but has been shown to bind and recruit various proteins involved in the regulation of receptor protein tyrosine kinases. It is through these regulatory activities that this protein is believed to be involved in cytoskeletal reorganization" wikipedia.    We suggest, It is strong signal that the cancer is back!



Friday, November 14, 2014


A 54 Year old hispanic male presented with rectal bleed at an area hospital
and was admitted.  A subsequent Colonoscopy reported fragments of Colonic Adenocarcinoma.

The patieent underwent a partial colectomy which revealed an Enteric type Adenocarcinoma Grade 2 (moderatelly differentiated invading the Muscularis  propria and into the pericolic fat without involvement of the Serosa
13 nodes obtained none with Metastatic disease
the liver contains a calcified granuloma

we elected to observe this patient
since chemotherapy will not benefit him by adding more than 5 % survival rates
Only those with poorly differentiated carcinoma..."T4, perforation or Obstruction, and less than 10 nodes removed, and angiolymphatic invasion" ASCO.

Another rising star! BLINATUMOMAB

Should we use this for Burkitt lymphoma?
It is normally reviewed for Philadelphia negative ALL...involving the T-cell...

"Blinatumomab received the FDA's Breakthrough Therapy designation earlier this year (OT 8/10/14 issue), which was enacted as part of the FDA's 2012 Safety and Innovation Act to expedite the development and review time of a potential new drug for serious or life-threatening disease where early clinical evidence suggests the drug may demonstrate substantial improvement compared with existing therapies." From Oncology Times

Wednesday, November 12, 2014

Blood draw for research

Blood draw for our research is advancing at higher pace than expected
every one is eager to participate, It is incredible that patients and family are lining up for donation
everything voluntary and consents signed!  It seems that the idea of participating in an UTEP driven study has energize "the base".  El Paso is energized!  Thank you to the donors!

Tuesday, November 11, 2014

CRBCM, Collecting blood samples from volunteers at large from broader cancer studies

With collaboration from the Biomedical Research At UTEP, (DR Zangh), CRBCM has launched today studies investigating the role of cytokines in the production of cancers.  We are collecting blood samples from Volunteers at large, and our cancer patients are going to participate.  The theory is that when after age 55, or post Menopause in women, people enter the age of the "Cytokines" which seem to play a major role in the Neoplasm occurrence.  Collecting blood samples may give us levels of various Cytokines in patients currently with cancers, or who might develop cancer of the next 5 to 10 years.  Also the samples give us opportunity to have genetic testing for cancer screening.  This is an exciting time in cancer...further discovery awaits!   It is worth mentioning that 80% of our population is of Hispanic origin in El Paso!

Friday, November 7, 2014

On the road again! Back to learning again in Vegas!

Your reservation is booked and confirmed. There is no need to call us to reconfirm this reservation.
Traveler Information
Mutombo Kankonde
No frequent flyer details provided Ticket # 0377493618807
* Seat assignments, special meals, frequent flyer point awards and special assistance requests should be confirmed directly with the airline.
Nov 7, 2014 - Departure 1 stop Total travel time: 3 h 38 m
custom air icon El PasoPhoenix 1 h 24 m
347 mi
ELP  12:30pm PHX  1:54pm    
Economy / Coach (S) | Seat 11D | Confirm or change seats with the airline*
Layover: 1 h 5 m
custom air icon PhoenixLas Vegas 1 h 9 m
255 mi
PHX  2:59pm LAS  3:08pm    
US Airways  1826
Economy / Coach (S) | Seat 24C | Confirm or change seats with the airline*
Nov 10, 2014 - Return 1 stop Total travel time: 3 h 6 m
custom air icon Las VegasPhoenix 1 h 6 m
255 mi
LAS  7:45pm PHX  9:51pm    
US Airways  735
Economy / Coach (S) | Seat 16D | Confirm or change seats with the airline*
Layover: 0 h 54 m
custom air icon PhoenixEl Paso 1 h 6 m
347 mi
PHX  10:45pm ELP  11:51pm    
Economy / Coach (S) | Seat 09C | Confirm or change seats with the airline*
Airline Rules & Regulations
  • We understand that sometimes plans change. We do not charge a cancel or change fee. When the airline charges such fees in accordance with its own policies, the cost will be passed on to you.
  • Tickets are nonrefundable, nontransferable and name changes are not allowed.
  • Please read the complete penalty rules for changes and cancellations applicable to this fare.
  • Please read important information regarding airline liability limitations.
Price Summary
Traveler 1: Adult   $327.20
Flight   $262.32
Taxes & Fees   $64.88
Travelocity Booking Fee   $0.00
Total: $327.20
All prices quoted in US dollars.
Additional Flight Services
  • The airline may charge additional fees for checked baggage or other optional se

Wednesday, November 5, 2014

Here Come CRBCM to Beijing....NOone own science!

CRBCM has been invited to Beijing!
by professor Baofo Yu
 FROM:JN BAOFA CANCER HOSPITAL   DATE:2010-05-22 16:46:50  
            Dr. Baofa Yu
BaoFa Yu, M.D
Home Address:    
4443 Governor Drive
San Diego, CA 92122
Tel: (858)597-0219, 858-336-4363 
Fax: 597-0219, Email:

CRBCM working on Cancer Research using all means!!!!

Tuesday, November 4, 2014

proposed track in Neurofibromatosis: what we know about the FUS?


NF1----Ras---ERK---MAPK----Myc---Let-7---XPO5---ILF3----FUS---/TLS-RELA SPI-1

let-7 affects Exportin 5
This FUS explain the diversity of sarcoma that may result:

According to Atlas of Genetics and Cytogenetics

" t(12;16)(q13;p11) chromosomal translocation. It produces the fusion protein FUS/ATF-1.
Disease Angiomatoid fibrous histiocytoma (AFH).
Hybrid/Mutated Gene FUS was interrupted at codon 175 (exon 5) and fused to codon 110 (exon 5) of ATF-1, resulting in an in-frame junction with a glycine to valine (GGT to GTT) transition.
Entity t(7;16)(q33;p11) chromosomal translocation. It produces the fusion protein FUS/CREB3L2 (also known as BBF2H7).
Disease Low grade fibromyxoid sarcoma (LGFMS).
Hybrid/Mutated Gene The breakpoints in the fusion transcripts are produced between the exons 6 or 7 of FUS and the exon 5 of CREB3L2.
Entity t(12;16)(q13;p11) chromosomal translocation. It produces the fusion protein FUS/DDIT3 (also known as CHOP).
Disease Myxoid liposarcoma (MLS).
Hybrid/Mutated Gene 9 different types of fusions between the genes FUS and DDIT3 have been reported. The most frequent rearragements join the exons 5, 7 or 8 of FUS with the exon 2 of DDIT3.
Oncogenesis The unequivocally relation between FUS/DDIT3 and the MLS was shown by the generation of a transgenic mouse model expressing FUS/DDIT3 from a housekeeping promoter.
Entity t(16;21)(p11;q22) chromosomal translocation. It produces the fusion protein FUS/ERG.
Disease Acute myeloid leukemia (AML).
Hybrid/Mutated Gene The junction of both genes is produced between the exons 6 or 7 of FUS and the exon 9 of ERG,or between the exon 8 of FUS and the exon 7 of ERG."   

Monday, November 3, 2014

Beyond the Myc!

Now as it seems to be suggested the mechanism of Cancer development seems to be multiple but one recognize that stimulation of the Myc or one of its variations seem to still the center piece of many neoplastic transformations.   From Burkitt to Small cell cancer, the most aggressive cancer seem to act through this gene.   Even Watson the DNA man went after the Myc as a potential drive for neoplasm.  Myc can increase proliferation by acting through general proliferation factors (transcription factors) but in specific diseases, it can act specifically on downstream genes to drive the neoplastic transformation by using the Leucine unzipping prong (opening the nuclear machine to proliferation) or by opening the Ribosome to protein production needed in the neoplastic transformation.

Our interest in this area stems from our involvement with one family of 4 members that we suspect have  Neurofibromatosis.  NF1 has not been established yet but all members have development issues and lipomatous lesions and imaging has suggested diffuse Neurofibromas.   One member developed Breast cancer, a BRCA was negative,  One member has gait disturbances and speech impairement, and the member with several lipomatous lesions, came to our attention for cough.  CT chest suggested a new peripheral nerve sheath tumor that we are following.  NF1 is a tumor suppressor of the Ras of which amplification will reach the Myc.  The Myc has interactions with BRCA but also several other genes

Thursday, October 30, 2014

New Interesting case at CRBCM

A 47 Year old young Hispanic woman has been referred to us because a 1 year history of abdominal pain and lately has had Hematochezia.  An EGD and colonoscopy were performed and Biopsy in the stomach and the Colon revealed Burkitt Lymphoma. The patient Bone Marrow biopsy is still pending (it is my understanding that a first attempt by the pathologist failed-it should not happen!?  Now patient is asking for general Anesthesia-always a twist to some cases).  Lumbar tap cytology pending!
questions about this case
1.EBV titer?
3.or just plain old Allopurinol
4.Rituxan-HyperCVAD  Vs standerd ALL protocols
5.And now for intrathecal treatment -she is asking for general Anesthesia
6.How to prepare for transplant in patient with lack of Insurance
7. Echo Vs MUGA

Case unfolding, will update you

Sunday, October 26, 2014


certifies that
Mutombo Kankonde, MD
2400 Trawood Drive
Suite 303
El Paso, TX 79936
has participated in the enduring material titled

An Innovative Platform to Improve Patient Care in Multiple Myeloma

October 26, 2014
and is awarded 2.00  AMA PRA Category 1 Credit(s)™.
Medscape, LLC designates this enduring material for a maximum of 2.00 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board.
Certificate Number: 49513617 Cyndi Grimes
Cyndi Grimes
Director, Continuing Medical Education
Medscape, LLC

Saturday, October 25, 2014

Imput on Non Hodgkin lymphoma

3 distinct groups of lymphoma
1.Germinal center
2.Activated B cell
3.Primary Mediastinal B cell lymphoma  (closer to Hodgkin disease)

when activated B cell, the prognosis is worse

somatic mutation may also influence outcome

Hans model   CD10     BCL-6   and MUM-1/IRF4   model to determine cell of origin

The Germinal Center B cell  lymphoma respond well to R-EPOCH  (CD10+, BCL-6+, MUM-1 -negative)
whereas the Activated B-cell lymphoma may be better of with Ibrutinib based treatment

Germinal Center responds better to Revlimid than Activated B cell lymphoma

Addition of Velcade allows to conquer the the resistance due to Activated B Cell Lymphoma

Those c-MYC positivity are the worse...and may need upfront transplant...or a clinical trial

Certificate for 'Advances in the Management of Lymphoma and Chronic Lymphocytic Leukemia' at OMedLive

Certificate for 'Advances in the Management of Lymphoma and Chronic Lymphocytic Leukemia' at OMedLive

The power on Pembro! don't leave home without it (in head and neck cancers)!

Why not combine Pembrolizumab and Methotrexate in head and Neck cancer
and break them up into HPV positive and negative. There is reason to believe this combination would be just as powerful as any Cisplatin based treatment.

Pembrolizumab (Trade name Keytruda formerly lambrolizumab;[1]also known as MK-3475) is a drug marketed by Merck that targets the programmed cell death 1 (PD-1) receptor. The drug is intended for use in treating metastatic melanoma.[2][3] Pembrolizumab was invented by Gregory Carven, Hans van Eenennaam and John Dulos at Organon Biosciences which later became Schering Plough Research Institute and then Merck & Co. [4]
On September 4, 2014 the US Food and Drug Administration (FDA) approved Pembrolizumab as a breakthrough therapy. It is approved for use following treatment with ipilimumab, or after treatment with ipilimumab and a BRAF inhibitor in patients who carry a BRAF mutation.[5]"   and "Methorexate  acts by inhibiting the metabolism of folic acid.[3] Methotrexate began to replace the more toxic antifolate aminopterin starting in the 1950s. The drug was originally synthesised by the Indian biochemist Yellapragada Subbarow and clinically developed by the American paediatrician Sidney Farber.[6][7]
It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.[8]'

Givem the relative tolerance of these two medications, one must surmise this combination of treatment to be the most tolerable yet effective in disease that seems so virally driven!  We are at the gate of excitement in cancer reaserch and cancer target therapy has just began!
The thing is treatment of locally head and neck cancer has left us hanging,   most people who treat this disease will notice that at the end of radiation  treatment most patient are left with residual mass.  And you keep scratching yourself...should we give additional chemotherapy, watch, of have some form of maintenance therapy?
A lot of patient end up being watched...would maintenance with pembro help survival  ?  How about Pembro+Methotrexate?

Sunday, October 19, 2014


a 39 YEAR old Hispanic woman present to us with T2N1 Breast Cancer, she had a Lumpectomy with sentinel node biopsy, the controlateral breast had a reduction to balance her chest, ER positive PR positive, the immunohistochemical for Her-2 2+ however the FISH did not amplify!  DOES SHE NEED ALND?

This case raises many issues age 39, should we obtain a BRCA gene?
2.frequency of triple positive breast
3.should BRAC be positive should with push for bilateral Mastectomy and Bilateral Oophorectomy
4.should BRCA be positive, what are the proximity genes to look at?
5.what is the frequency of lymphedema post RT
6.Is AC-T the best chemotherapy regimen
7. should T be weekly even though Herceptin is not offered?
8.What is the role of PET in helping decide ALND  Vs RT

but first thing first


For Node-Positive Breast Cancer, Axillary Radiation Is Best

Kate Johnson
June 06, 2013
The AMAROS trial involved patients with cT1-2N0 breast cancer up to 5 cm and clinically node-negative axilla who were undergoing either breast conservation or mastectomy with sentinel lymph node mapping.
Of the patients with positive lymph nodes, 744 went on to receive ALND and 681 received axillary radiotherapy.
Radiotherapy (50 Gy in 25 fractions of 2 Gy, 5 days a week) was started within 12 weeks of surgery, and directed at 3 levels of the axilla and the medial part of the supraclavicular fossa, Dr. Rutgers explained. Levels I and II of the axilla were mandatory and level III was optional.
There were no significant differences in between the radiotherapy and surgery groups at baseline. Median age was 55 to 56 years, and 38% to 42% of the patients were premenopausal. Median tumor size was 17 to 18 mm, and 75% of patients had grade 2 or 3 cancer.
In the cohort, 82% underwent breast conservation and the remainder underwent mastectomy; 90% received systemic treatments. A median of 2 sentinel nodes were removed from each woman.
For patients who received axillary clearance, the sentinel node was the only positive node in 67%; 33% had further node involvement and 8% had 4 or more positive nodes.
After 5 years of follow-up, the axillary recurrence rate was "extremely low" in the surgery and radiotherapy groups (0.54% vs 1.03%), Dr. Rutgers reported.
Because "this was far below what we anticipated, the trial was underpowered for a noninferiority comparison," he explained.
There were no significant differences between the surgery and radiotherapy groups in disease-free survival (86.9% vs 82.7%; P = .1788) or overall survival (93.3% vs 92.5%; P = .3386).
However, 5 years after therapy, the rate of lymphedema in the surgery group was twice that of the radiotherapy group (28% vs 14%).
"The AMAROS trial provides very important evidence that the kind of regional nodal treatment used after a positive sentinel node biopsy will not substantially affect the risk for subsequent regional nodal failure, rates of metastasis-free breast-cancer-specific, or overall survival in most patients," Dr. Recht told Medscape Medical News.
He explained that a more important question than whether to choose radiotherapy is which type to choose.
"Is axillary radiotherapy better at preventing regional nodal failure than just irradiating the breast, which includes the lower portion of the axilla in many individuals?" he asked.
Dr. Recht said that previous studies that compared breast radiotherapy with ALND — such as the"

ASCO recommendation
Kristen Golberg
"The guideline updates three recommendations based on evidence from randomized controlled trials:
• Women without sentinel lymph node (SLN) metastases should not receive axillary lymph node dissection (ALND).
• Most women with 1 to 2 metastatic SLNs planning to receive breast conserving surgery with whole breast radiotherapy should not undergo ALND.
• Women with SLN metastases who will receive mastectomy may be offered ALND.
The guideline updates two groups of recommendations based on cohort studies and/or informal consensus: 
• Women with operable breast cancer and multicentric tumors, and/or DCIS who will have mastectomy, and/or had prior breast and/or axillary surgery, and/or had preoperative/neoadjuvant systemic therapy may be offered sentinel lymph node biopsy (SNB).
• Women who have large or locally advanced invasive breast cancers (tumor size T3/T4), and/or inflammatory breast cancer, and/or DCIS, when breast-conserving surgery is planned, and/or are pregnant should not receive SNB.
The ASCO committee noted that in some cases, evidence was insufficient to update previous recommendations."

Wednesday, October 15, 2014

We have crossed 50,000 reviews!

Graph of Blogger page views

Pageviews today
Pageviews yesterday
Pageviews last month       
Pageviews all time history

Functional proximity of main genes

It is striking to notice that during the daily practice of Medicine, it seems that despite the big number of genes in the cell, there seem that most pathology in human seems to coalesce in just a few abnormalities ultimately.  Disturbances seem to be mostly
1. In Cholesterol or lipid disturbances
2. which are linked to thyroid or endocrine (hormone) disturbances
3.which are linked to Autoimmune diseases
4,linked to vitamins (D) disturbances
5. and linked to neoplastic phenomena, linked to Glucose derangements
6. and to neurologic and psychiatric disturbances...
The only new phenomena that may be separate but linked is Infection because indeed Infection involves a foreign body looking in!  And fight against infection seems to follow cellular pathways which depend of the nature of the infectious agent...with Viral infections involving the mitochondrial process more than bacterial infection...

Yes indeed, we see for example that a patient may have an elevated white blood cell could have an infection, but in most cases, it is an autoimmune disease, usually associated to a thyroid dysfuction and a depressive or anxiety component.

Now this notion that Prostate cancer recurrence may be associated with dyslipidemia...
or that polycystic kidney disease be accompanied by depression.

Disturbances in anexins and other supportive structures are somewhat hidden but their importance remains in full force...Now I can see why so many genes are somewhat or definitively much is left un attended to.   My day to day is globally busy with the few genes that I still have my finger up ready to point!  Even when I see the NF1 gene and many growth gene dancing with the BRAC gene...and that triple negative breast cancer in some race is dancing with autoimmune disease that affect the skin (psoriasis)!

Sunday, October 12, 2014

Where don't we dance enough: managing life span, an independent factor in managing cancer patient, and may increase the cure rate!

Because of limited resources available in research, society falls short in the management of cancer patients.  The notion that cancer patient should be managed by affecting only their driver Mutation has been popular lately and most research has focused on this emphasis.  There is a rush to discovering  the driver mutation in each disease.   The truth is that driver mutation although very effective (ie. BRAF inhibitor) for a short time, are quickly overwhelmed by what we have come to know as "mechanisms of resistance"  The point is that cells are constantly exposed to new environmental stimulants.  And their natural TASK is to die or adapt.  And naturally we try to forget or underestimate the adaptative capability of cells, including neoplastic (cancer) cells.  Cure will remain fleeting until a closer look is taken into these adjustment techniques used by the cancer cells.  and it is within that contest that I bring this statement to your mind:

" that SHC-1 not only opposes IIS but also activates JNK signaling. Loss of shc-1 function results in accelerated aging and enhanced sensitivity to heat, oxidative stress, and heavy metals, whereas expression of human p52Shc rescues the shc-1 mutant phenotype. SHC-1 acts upstream of the insulin/IGF receptor DAF-2 and the PI3 kinase AGE-1 and directly interacts with DAF-2. Moreover, SHC-1 activates JNK signaling by binding to MEK-1 kinase. Both aspects converge on controlling the nuclear translocation and activation of the FOXO transcription factor DAF-16." Elke Neuman-Haeflin et al.

If you are shocked and troubled by the placement of this statement here, you are completely within the norm! but let's go back and recapitulate.   Most cells succumbs to external pressure by cellular environmental stimulations.   Hypoxia, autocrine cytokines, chemicals and minerals end up exciting receptors including VEGFRs  (the MEK is close by).  But really when you speak of the VEGF, you imply SHC1,2 and stimulation of Annexins and from there p52, p42, and the famous p66SHC....then you can understand the above sentence...In Gastric cancer for example,  VEGFR2 is stimulated and therefore the effectiveness of Ramucirumab.  (CYRAMZA.)

Please note that the statement speak about p52 and does not even address the main RAS cofactor p66 which may affect Cyclin D and deplete MCI-1 the main depletor of SHC-1. (through PTPNs)
RAS autophosphorylation driving the cancerous process may be hidden here.

These facts point to the truth that independent of cancer driven mutation, control of these processes must occur concurrently to improve the cure!  cancer deaths are produced by progression of cancer but also involvement of cellular maturation and lifespan determinants that most Oncologist do not measure! (we dance very little away from guidelines (NCCN))...

Saturday, October 11, 2014

Pathogenesis of Neoplastic transformations.

Speculative sources of Neoplastic disease

As we plan Cancer Prevention, it seems logical to target potential mechanisms that likely could initiate the neoplastic process in order to propose logical steps.  And clearly, from a beginner stand of view, and from data screening of various cancer, this task could be daunting.  However major patterns have to be proposed as we examine what works, and what are the main metabolic disturbances in each disease.
*In Kidney cancer for example, Here abnormality in the Von Hippel Lindau gene (gene that promote UBIQUINATION) has supported strongly the involvement of an exaggeration of deficient Hypoxia induced factors (HIF) and related proteins.  This facts lead to the removal of inhibitor forces leading to the expansion of VEGF and PDGF.   It takes blocking the either the the VEGF (Avastin) or blocking the MTOR down the line (Everolimus) to slow down the neoplastic process.   Anything in between may have not been efficient.   Hypoxic conditions often found in patient with obesity (associated with sleep Apnea) may favor the frequency of this disease.   The involvement of VEGF explain the importance of abnormal Angiogenesis in this disease...the tumor is bloody ...Therefore, optimizing Oxygenation (CPAP use in obese patient with sleep Apnea), decreasing or impairing VEGF, could have significant prevention use.   Optimizing Iron level may also have a positive impact should studies initiated here further support that iron deficiency may exacerbate the various cellular metabolites.   Interferon and IL-2 should be consider under this light (as to their effect on the VEGF-MTOR  axe. The involvement of Ubiquination beg the question on whether Velcade and anti-TNF related compound may add to the therapy in Kidney cancer.  One thing is for sure, all cancerous transformation try to escape the immune system, and Pembrolizumab could be discussed further within the contest of this disease!   our knowledge is rapidly expanding.

*In Lung Cancer, the neoplastic transformation is diverse since some non smokers are known to develop the disease.  Here we believe that diet based on high levels of anti-oxidant without sufficient compensatory iron (iron deficiency in women particularly) and HIF gene isoforms may lead to  chronic intoxication triggering once again EGFR/VEGF expansion.   Susceptibility of these cancers to Cetuximab/ERBITUX strongly support this hypothesis. Detoxification may also be influenced by CYP1A1 and GSTM1.

In standard lung cancer however, not only HIF is involved, but there is now increasing suspicion that alterations at the MDM-2 has entered the possibility of initiating the disease process forcing further Ubiquination or intervening at some point, affecting the P53, c-MYC, NPM1 and even prot 14-3-3 ("Phosphorylation of Cdc25C by CDS1 and CHK1 creates a binding site for the 14-3-3 family of phosphoserine binding proteins. Binding of 14-3-3 has little effect on Cdc25C activity, and it is believed that 14-3-3 regulates Cdc25C by sequestering it to the cytoplasm, thereby preventing the interactions with CycB-Cdk1 that are localized to the nucleus at the G2/M transition.[wikipedia) effect on Ubiquitination should be re-emphasized.   With stimulation and amplification of the EGFR/VEGF come the importance of ALK, BRAF, again factors that have enterec lung cancer therapeutics since agents active here have become available (to be continued)

Friday, October 10, 2014

Warsaw Indiana, an interesting case

We are back in Warsaw Indiana completing obligations here for CRBCM.
This exercise also expose us to local pathology and ways they are managed by local Oncologist.
An interesting case encounter here is that of a 22 year young mother who had 2 c-sections and was referred for Menorrhagia, she had a Biopsy of the Uterus, and a Von-Willebrand screen suggested very elevated Factor VIII  (3 times the upper limit).    She is obese and suffers from Hypothyroidism.  Now elevation of Factor VIII has been identified as an independent factor determining an Hypercoagulable state.  We may soon be quantifying related gene.  This Hypercoagulable state is however confusing because it is indeed associated with higher risk of stroke and Coronary events.  However, independent of thrombotic event, does it really require Anti-Coagulation for life?
The patient has been advised Aspirin,  do we  justify Xarelto at preventive dosage?  Should weight loss be a sufficient intervention, should we look for coexisting Hercoagulable factor such as Factor V leyden, or Homocystein for that matter...we are checking TSH level of course...Elimination of this factor is associated with certain Blood Group,  should we type and cross ?  Very puzzling case indeed!  What are the genes proximate to this gene?
familial predisposition has been appreciated by the presence of BRCA1 and BRCA2
but increasingly we find young women with breast cancers who do not carry the mutation expected.  By their age and family history, we know there must be a genetic predisposition for the particular cancer of the breast to occur.
1.Mutation in the genes regulating or acting in the vicinity of the BRCA.
For medicine to advance and allow better use of limited resources and decrease the burden of side effects for our patients, It would be critical that new sets of genes enter the standard detection/category testing in the management of Breast Cancer. There are over 100 Mutations knwon!

2As far as BRCA2 is concerned, interaction with RAD51 has been suggested.   Ween et al:"versican and hyaluronan (HA) which interacts with the HA receptor, CD44, have been shown to play critical roles in ovarian cancer metastasis."  These molecule states (isoforms) have been found to be increasingly affected by interaction with growth factors   TGF and even PDGF.  (early detection of metastatic disease).  They should enter biomarker testing.

3.BRCAs are "wild gene"  first because there are hundred of these Mutations
and also because Wikipidea describes multiple various interactions:

"BRCA1 has been shown to interact with