Learning from Anal cancer

One of the cancer that exemplifies the importance of trauma and Viral or infectious influences, is surely the Anal cancer!  Globally decreasing, it remains increasing in those who continue to practice anal sex.   It is also associated with the irritation of infections (HIV, Herpes 16, Chlamydia Trachomatis, and Gonorrhea).  Occurrence of warts remains an intriguing aspect that need further examination as they most likely represent a disruption at Wnt (global disruption of adhesion molecule and sens of polarity) and the notch.  (proof of concept).  Most importantly, This disease seems to involve a strong disruption of the NF-kB and down the stream epigenetic disturbances and associated increase growth hormones (TGFs).  This perception is reenforced by the very low or rare Mutations of KRAS found in this disease, and the effectiveness or exclusive efficacy of Mitomycin, a drug which easily lead to Fibrosis of the lung (which is associated to cyclines/growth factor effect).  Stopping or reducing the infection intensity has proven effective in reducing per-cancerous (Intraepithelial Neoplasia) lesions by at least  half, leading to the recommendation of giving Quadrivalent HPV vaccine  to males at 11-12 years of age by the Advisory Committee on Immunization.

Let's quantify now the NF-kB and the Cytokines in this disease...It could be good for the patients!

?Role of Histone de-actylators?
?miRNA
Interferon and Etoposide better than Cisplatin-5FU alone?

10 RESEARCH QUESTIONS IN ORAL CANCERS AND MEDICINE!

1.Early detection of Oral cancer leads to 90% cure rates whereas lymph node involvement drops that rate to 50% and require combination therapy to be achieved"

Can MDM2 Mutation, decrease E-Cadherin depression, and c_MYC amplification be detected in Sample from Saliva, blood of heavy smoker?

Is RHOC gene mutation predict Node involvement, is WISP3 involved?

2.Can BMPR Mutation and avB3 Integrin (+ associated Metalloprotease) predict for Osteoporosis of the Jaw in patients on Biphosphonate

3.Can Asporidin bound to Nuclear Agent helps detect Metastatic disease In Oral cancers?   (Change in Asporidin increases its Binding of TGF to Increase destruction in Osteoarthritis, and TGF is the autocrine growth hormone in Metastatic disease

4.Using new Biomarkers in Autoimmune diseases, can we develop a Kit to detect Oral Ulcerations that will benefit for a short course of Prednisone?

5.Levels of Interferon-1 in Hairy Leukoplaquia? Why Immunodeficiency is linked to hairy Leukoplaquia Interferon-1 is linked to Immune dysregulation...

6.Cevimeline role in post Radiation "Sicca"

7. can Injection of Lubricin improve Temporo-Mandibular Arthritis

8.Genetic basis of Oral Ulcerations in Beta- blocker users?

9.Role of Androgen Receptors in the deposition of Melanin during the Use of hydroxychloroquin, Minocycline, Methyl dopa, Ketoconazole, and Cytoxan

10.Role of Syndecans in Gingival Hyperplasia (Syndecans bind Growth factor FGF) (Why Gingival Hyperplasia  in patient taking Phenytoins, Cyclosporin, Calcium channel blockers, disruption of genes involved in cellular polarity?)

AT CRBCM, RESEARCH IS OUR PRIORITY!

SPECULATIVE NOTES ABOUT MANTLE CELL LYMPHOMA

In Mantle Cell lymphoma, its most dreadful aspect is the fact that it is an incurable disease
which to most Oncologist means that there is an entrenched genetic driver that is not silenced by current therapy, and will go on to revive the disease.
The elevation of Cyclin-D1 is a patent suspect.
Our speculation however is that it is not that is present that gives a clue to this recalcitrant disease.  It is what is missing.   Why is it that a disease that look like CLL or small lymphocytic Lymphoma, would not have the CD-23 marker?
CD 23 expression seems to be linked to the protective Interleukin 4.
CD23 as commented here by several authors seems to not only be involved in Allergens presentation
but to overall presentation of Antigenes, and to DIFFERENTIATION AND DEDIFFERENTIATION.
ITS EXPRESSION SEEMS LINKED TO IL4.  INDEED INCREASE OF IL4 HAS BEEN LINKED TO AN HYPERSENSITIVITY REACTION.  Differentiation of white cell seems to be linked to favorable outcome through leading to Apoptosis, whereas dedifferentiation seems to be linked to cellular immortality.  Also as it can be apparent, CD23 help with Antigen presentation and activation of class II Major Histocompatibility defense.   The lack of CD23 therefore lead to a global tolerance of involved neoplastic cells and may contibute to tolerance of these cells as they penetrate tissues including the Central Nervous system.
One now wonder what would be the clinical consequence of Giving IL-4 to patient with mantle cell,  Will it increase CD23 expression?  will it have a role in Maintenance setting,  Adding it to Interferon gamma could boost its effectiveness
Can infusion of CD23 molecule makes a difference in this disease?
was the disappearance of CD23 driven by CD21 as one can speculate based of french researchers notes listed below?

Read for your self!
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THESE NOTES ARE FROM THE INTERNET! WE THANK RESEARCHERS MENTIONED HERE!
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Our study shows that grade 3 FLs are more often CD23- than lower grade FLs and that FLs in inguinal LNs are more frequently CD23+ than in LNs from other sites. Furthermore, our findings also indicate that survival is significantly better in CD23+ FLs.(OLTEANU H ET AL)

 Expression of CD23 was more frequently detected in grade 1 FLs than in other grades (grade 1, 37%; grade 2, 18%; grade 3, 23%; transformed, 6%). (THORNS ET AL)


There are two forms of CD23: CD23a and CD23b. CD23a is present on follicular B cells, whereas CD23b requires IL-4 to be expressed on T-cells, monocytes, Langerhans cells, eosinophils, and macrophages.^{[1] (WIKIPEDIA)}

Human lymphocytes shed a soluble form of CD21 (the C3dg/Epstein-Barr virus receptor, CR2) that binds iC3b and CD23

Véronique Frémeaux-Bacchi ET AL...

It has many biological roles, including the stimulation of activated B-cell and T-cell proliferation, and the differentiation B cells into plasma cells.
It is a key regulator in humoral and adaptive immunity.
IL-4 induces B-cell class switching to IgE, and up-regulates MHC class II production. IL-4 decreases the production of Th1 cells, macrophages, IFN-gamma, and dendritic cell IL-12.
Overproduction of IL-4 is associated with allergies.^[2]


The regions of CD23 responsible for interaction with many of its known ligands, including IgE, CD21, major histocompatibility complex (MHC) class II and integrins, have been identified and help to explain the structure–function relationships within the CD23 protein. Translational studies of CD23 underline its credibility as a target for therapeutic intervention strategies and illustrate its involvement in mediating therapeutic effects of antibodies directed at other targets. (M. ACHARYA ET AL)

 The metalloprotease responsible for CD23 release from cells is ADAM10 [24,25],

 Affinity-based approaches demonstrated that αvβ3 was also a functional receptor for CD23 in monocytic cells [38], again leading to cytokine release, and that αvβ5 is a sCD23 receptor linked to growth and survival of human B cell precursors [51]. The αv integrins recognize a short tripeptide motif of arg–lys–cys (RKC) in CD23 in a carbohydrate-independent interaction [51] and the affinity of the αvβ5–derCD23 interaction is approximately micromolar [51], which is broadly equivalent to that found for the derCD23–CD21 interaction [44]. It is not known whether the β2 integrins also recognize the same RKC sequence bound by αv integrins. The binding sites for CD23 on the αv and β2 integrins remain to be elucidated, but available data suggest that this is distinct from the site on the integrin

Clinical and Experimental Immunology

Blackwell Science Inc

CD23/FcεRII: molecular multi-tasking

M Acharya, G Borland, [...], and W Cushley

Additional article information

Abstract

CD23 is the low-affinity receptor for immunoglobulin (Ig)E and plays important roles in the regulation of IgE responses. CD23 can be cleaved from cell surfaces to yield a range of soluble CD23 (sCD23) proteins that have pleiotropic cytokine-like activities. The regions of CD23 responsible for interaction with many of its known ligands, including IgE, CD21, major histocompatibility complex (MHC) class II and integrins, have been identified and help to explain the structure–function relationships within the CD23 protein. Translational studies of CD23 underline its credibility as a target for therapeutic intervention strategies and illustrate its involvement in mediating therapeutic effects of antibodies directed at other targets.

Keywords: CD23, cytokines, IgE, immunoregulation, integrins

Introduction

Immune responses are subject to regulation at many levels, including the influence of different groups of cytokines, cell–cell contact via adhesion interactions and receptor-mediated positive and negative feedback circuits. The low-affinity receptor for immunoglobulin (Ig)E, also known as FcεRII or CD23, participates in all these regulatory processes, either as a membrane-bound glycoprotein or as a freely soluble protein. Structural biology approaches have revealed the fine molecular details of the soluble CD23 (sCD23) protein and the interaction surfaces used by sCD23 to bind its various ligands, and molecular biological and mutagenesis studies have defined critical residues involved in performance of biological functions. CD23 has been suggested to have utility as a diagnostic marker in a range of diseases and to be implicated in the cellular and molecular processes associated with a variety of pathological states; the latter feature has made CD23 a target for therapeutic intervention.

General features of CD23

CD23 was defined initially as the low-affinity receptor for IgE [1,2]. As a membrane protein, CD23 is a type II transmembrane glycoprotein of approximately 45 kDa molecular weight comprising a large C-terminal globular extracellular domain that is strikingly similar to C-type lectins, followed by a stalk region bearing several repeats that serve as a putative leucine zipper that are important in CD23 oligomerization; the stalk region is followed by a short extracellular sequence (in human CD23), a single hydrophobic membrane-spanning region and a short N-terminal cytoplasmic domain [3–7] (Fig. 1). CD23 is expressed in T and B lymphocytes [8], polymorphonuclear leucocytes [9–11], monocytes [10,12], follicular dendritic cells [13], intestinal epithelial cells [14] and bone marrow stromal cells [15], and its expression to subject to regulation by a number of stimuli. In humans, CD23 is encoded by an 11-exon gene, FCER2, located at chromosome 19p13.3 [16], in a cluster with the DC-SIGN and DC-SIGNR genes [17]; the murine equivalent is located on chromosome 8 [18]. CD23 differs dramatically from the high affinity receptor in terms of structure. FcεRI has multiple subunits [5,6,19], whereas FcεRII is comprised solely of a CD23 polypeptide. As the names suggest, their affinities for IgE differ (FcεRI binds IgE with a K_D∼ 1 nM while monomeric CD23 interacts with IgE with a K_D∼ 0·1–1 µM), although the membrane-bound form of CD23 is trimeric [20] and the contribution of the avidity of the trimer for ligand yields a net affinity closer to that of the high-affinity receptor and comparable to that of FcγRI for IgG monomers [21]). Signalling pathways and functional consequences of ligand binding to the receptors are also different [22,23]; for example, cross-linking of FcεRI leads to degranulation of mast cells and release of a number of potent pharmacologically active mediators, while engagement of membrane-bound CD23 suppresses the production of IgE by B lymphocytes.

Fig. 1

Primary structural features of human CD23. (a) The 321 amino acids that comprise the primary structure of human CD23a [1,2,55]. Individual contact residues or binding regions for CD23 ligands are shown in green (major histocompatibility complex class ...

In addition to its role as a low-affinity receptor for IgE, CD23 can also be released from cell surfaces as a range of freely soluble CD23 (sCD23) proteins of 37 kDa, 33 kDa, 25 kDa and 16 kDa, all of which bind IgE and have cytokine-like activities. The metalloprotease responsible for CD23 release from cells is ADAM10 [24,25], which cleaves at the C-terminal side of either ala⁸⁰ to generate the 37 kDa sCD23 molecule or arg¹⁰¹ to yield the 33 kDa species [25]. Mice lacking ADAM10 expression in B cells display defective release of CD23, confirming that ADAM10 is necessary for CD23 cleavage and release in vivo[26]. A further naturally occurring sCD23 fragment is derCD23, produced by action of the der p1 protease found in the faeces of the house dust mite Dermatophagoides pterronysinus; der p1 cleaves between ser¹⁵⁵/ser¹⁵⁶ and glu²⁹⁸/ser²⁹⁹ in CD23 to yield the 16 kDa derCD23 fragment [27,28]. The kinetics and affinity of the interaction of sCD23 with IgE and the ability of sCD23 to diminish or enhance IgE synthesis in stimulated B cells is linked to its oligomerization state. Thus, monomeric sCD23 species, such as derCD23, show monophasic kinetics of interaction with a Cε2–4 domain construct of the IgE Fc region that is of low (micromolar) affinity, and inhibit IgE synthesis in activated B cells [29]. By contrast, trimeric sCD23 molecules display a biphasic interaction with IgE Fc fragments, including a higher affinity component (10–100 nM), and enhance IgE synthesis by activated B cells [29]. The other cytokine activities of sCD23 species have been best studied in human models, and it is clear that sCD23 is highly pleiotropic (Fig. 2). Thus, in the B cell compartment, sCD23 sustains the growth of activated mature B lymphocytes, possibly via an autocrine mechanism [30–32], promotes differentiation of germinal centre centroblasts towards the plasma cell pool [in association with interleukin (IL)-1α][33], and allows B cell precursors to evade apoptosis [34]. In other lineages, sCD23 promotes differentiation of myeloid precursors [35], thymocytes [36] and bone marrow CD4⁺ T cells [37], again in association with IL-1α, and also drives cytokine release by monocytic cells [38]. Given its roles in lymphocyte survival and cytokine release by monocytes, it is no surprise that sCD23 has been linked to the pathophysiology of neoplastic and autoimmune inflammatory conditions (see below).

Fig. 2

Pleiotropy of human sCD23. The effects of sCD23 on B cells, T cells and myeloid cells are illustrated showing biological responses and, where appropriate, signalling responses. An asterisk (*) indicates that the observed effect required the presence of ...

CD23 ligands and signalling

CD23 has multiple ligands, including IgE, CD21 and members of two families of integrins. The principal ligand is IgE, which is bound by both membrane-bound and soluble trimeric CD23 species. The site recognized by CD23 resides in the Cε3 domain of IgE protein and CD23 sterically hinders IgE binding to FcεRI; binding of IgE to CD23 is carbohydrate-independent (i.e. does not require any lectin-like activity of the head domain). The next best characterized ligand for CD23 is CD21 [39]. The interaction with CD21 depends on short consensus repeats in CD21 [40] and occurs when the proteins are freely soluble in solution (sCD21–sCD23 complexes are readily detected in plasma [41]), or are membrane proteins. In the case of membrane proteins, activation of human B cells promotes homotypic adhesion, and the cell clusters are disrupted by anti-CD21 or anti-CD23 antibodies [42], indicating that these two membrane proteins can interact functionally in trans. There is no equivalent homotypic adhesion in murine B cells [43]. The interaction of CD23 with CD21 involves both carbohydrate-dependent and independent interactions [40], and the interaction of derCD23 with CD21 is approximately micromolar (K_D∼ 8·7 × 10⁻⁷ M) [44]. CD23 can also interact in cis and trans with major histocompatibility complex (MHC) class II proteins, in a carbohydrate-independent manner, using structures in the CD23 protein that are located in the stalk region of the molecule [45]. This interaction is believed to facilitate antigen processing and presentation by antigen–IgE complexes captured by CD23 [46].

The first CD23-binding integrins to be identified were the αMβ2 [47,48] and αXβ2 [47] members of the leucocyte integrin family. The ability of anti-integrin antibodies to inhibit binding of CD23 to monocytes or to mimic the effects of CD23 on the cells indicated that these integrins bound CD23 and were linked functionally to monocyte responses to CD23 [47–50]. Affinity-based approaches demonstrated that αvβ3 was also a functional receptor for CD23 in monocytic cells [38], again leading to cytokine release, and that αvβ5 is a sCD23 receptor linked to growth and survival of human B cell precursors [51]. The αv integrins recognize a short tripeptide motif of arg–lys–cys (RKC) in CD23 in a carbohydrate-independent interaction [51] and the affinity of the αvβ5–derCD23 interaction is approximately micromolar [51], which is broadly equivalent to that found for the derCD23–CD21 interaction [44]. It is not known whether the β2 integrins also recognize the same RKC sequence bound by αv integrins. The binding sites for CD23 on the αv and β2 integrins remain to be elucidated, but available data suggest that this is distinct from the site on the integrin that binds matrix proteins by recognition of arg–gly–asp (RGD)-type sequences [51].

Because CD23 exists in membrane-bound and soluble forms, it can both deliver and receive signals. Thus, sCD23 has been demonstrated to drive nitric oxide (NO) production, cyclic adenosine-5′-monophosphate (cAMP) synthesis and cytokine release from monocytic cells [50] and, in this case, integrins appear to act as the receptors for the sCD23 protein. It is clear in human monocytic cells that stimulation of the αMβ2 and αXβ2 integrins with specific monoclonal antibodies (mAbs) both mimics the effect of sCD23 on the cells and triggers the mitogen-activated protein (MAP) kinase cascade [49] and activates nuclear factor (NF)-κB [50]. Similarly, sCD23 activates extracellular regulated kinase (ERK) phosphorylation and, to a much lesser extent, the phosphatidyl insitol 3 (PI-3) kinase pathway in human B cell precursors; the extent and kinetics of ERK phosphorylation are modified by inputs from both G-protein-coupled receptors (CXCR4) and receptors with intrinsic tyrosine kinase activity [platelet-derived growth factor receptor (PDGFR)][52].

  In broad terms, CD23a is expressed constitutively in B cells while transcription of the CD23b isoform is subject to up-regulation following Epstein–Barr virus (EBV) infection [56], stimulation by IL-4 in B cells [57] or monocytes [12] or by engagement of CD40 on B cells [58]. Elements in the human CD23a and CD23b promoters that are responsive to defined stimuli (e.g. IL-4, CD40L) have been mapped [56,59].

 Transitional immature B cells undergo apoptosis and fail to proliferate in response to BCR cross-linking, thus representing a target for negative selection of potentially autoreactive B cells in vivo. In agreement with recent reports, transitional B cells were divided into developmentally contiguous subsets based on their surface expression of CD23. When transferred, CD23⁺ transitional B cells readily localized to the splenic follicles and the outer PALS. Compared with CD23⁻ transitional B cells, CD23⁺ transitional B cells proliferated more vigorously and were rescued from BCR-induced apoptosis to a greater degree, by T cell help signals. However, both CD23⁻ and CD23⁺ transitional B cells failed to up-regulate CD86 (B7-2) in response to BCR ligation. These findings demonstrate that phenotypically defined subsets within the transitional B cell population are functionally distinct. Specifically, responsiveness to T cell help is a late acquisition corresponding to the stage when the B cells gain access to peripheral compartments enriched in antigen and activated T cells. The failure of transitional B cells to up-regulate CD86 to BCR-mediated stimulation suggests a unique interaction between transitional B cells and T cells with implications for tolerance in the T cell compartment. (chung ET al)

Update on Mantle cell( and speculative thoughts)

Mantle Cell Lymphoma is like Non hodgkin lymphoma with a twist
CD20 and CD 5 positive but no CD23 (CLL) nor CD 10 (follicular)

could be diffusely involving the Bowel (Lymphomatous polyposis)
and 20% CNS infiltrating as a late presentation
Cyclin D1 driven condition leading to incurable disease
with Median survival of 3-4 years

Now Ki-67 has been found to be prognotic

Treatment
1.R-CHOP
can be given
but remember here the Median survival is 20 months
It got to be followed by Maintenance Rituxan or transplant
so no good option, except may be in elderly and desperate
2. Most people would try R- HYPERCVAD, or R-Modified HYPERCVAD to make it palatable !
3. after HYPERCVAD comes
Rituxan-Fludarabine Mitoxantrone-Cytoxan  similar to CLL.

Intereferon has been given in Maintenance setting, but perception is that Rituxan Maintenance is better..

4.Now comes Bendamustin and Rituxan    superior to R-CHOP
                     CR     50%          VS                        27%
       Overall Resp     94%          Vs                        85%
                   Nausea and hypersensitivity             Alopecia,neuropathy, constipation


seems like for older patient R-HYPERCVAD folloed by Transplant
whereas Older patient will get more and more Bendamustine-Rituxan

5.Transplant in first remission beter than later!

6.New Active drug and valid option in refractory disease

-----Velcade RR 33%  (prompting Velcade-Bendamustine trial)
-----Revlimid RR 28%
-----Temsorilimus response but not sustained
-----Ibrutinib is shaking things up now, at 560 mg, RR 65-75%, shaking things up so much that it is now being combined to -CHOP, Threatening to become standard therapy?
------And here come Idelalisib  PI3K oral Inhibitor  ?RR 52%
----------ABT-199 a BCL 2 inhibitor (watch for tumor lysis syndrome)

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THE WORLD OF ONCOLOGY IS BEING MOVED BY TARGET THERAPY

OH! DON'T FORGET REDUCED INTENSITY ALLOGENEIC TRANSPLANT IN THIS DISEASE, SOMEONE REPORTED 60-80% 2 YEARS SURVIVAL "IN SELECTED SERIES"
LOT OF EXCITING STUFF IN THIS DISEASE!

IN THE INTERIM !

Part of becoming Laboratory Director is to complete 20 CME units on laboratory management.
We have been hard at work to complete these CMEs.
Therefore, we have not published any communication for the last few days.
Something of exciting nature happened during this period:  WE HEARD FROM CPRIT!
CPRIT IS ALIVE AND BACK IN BUSINESS, WE WELCOME THE NEWS!

IF YOU HAPPEN TO WONDER WHAT LABORATORY WE WILL BE HEADING,  WONDER NO MORE:   THE EL PASO II GRIFOLS LABORATORY!

ACTIVITIES AT CRBCM

ACTIVITY AT CRBCM.

1. We are waiting for last word of the contract with the laboratory of Professor Jianying Zhang ( agreement between UTEP and the CRBCM and the Greater East Cancer Center. ) about the early lung cancer detection project.

2. We are conducting field work in fort Wayne Indiana (under contract)

3. AND THE LARGER NEWS TONIGHT IS THAT DR KANKONDE HAS BEEN RETAINED DIRECTOR OF AN IMPORTANT HEMATOLOGY LABORATORY IN EL PASO.  HE WILL SOON START FINAL ADAPTED TRAINING.  AND YOU WILL BE UPDATED!

4.WE CONTINUE TO SUBMIT GRANT REQUESTS.

5. WE ATTENDED SUCCESSFULLY THE CONFERENCE ON  HEMATOLOGIC MALIGNANCIES IN MIAMI SATURDAY AUGUST 10TH, 2013

THE CRBCM IS ADVANCING  DAY BY DAY!

Few Clues on Myeloma treatment

Some of the Key points in Myeloma Treatment
1. After the diagnosis of Myeloma, determination of presence of Del 17, and t(4:14) is the first step to treatment.  You may be "liable" if Velcade is not included in the first line treatment in patient with  del 17.
2. CYBORD is a good induction option
3. Use of Triplets always better than Doublets
4.In clinical practice, Bortezomib Sub Q is now adopted widely despite lack of clinical trial showing equivalency to IV route (in up front treatment) because it leads to  somewhat less Neuropathy and thrombocytopenia.
5. Dexamethasone is still a corner stone of Myeloma treatment.  Add it even to the newest drug for their full effect to be unleashed (even Pomalidomide has 3 times the effect when Dexamethasone is added!
6.Almost everybody is treating until progression or maintenance therapy is the alternative.  As if now are assuming that the driver of the disease are continuously present!`
Now for Maintenance therapy, not only Revlimid, but also Velcade can be given with Dex in Maintenance setting.
7."In myeloma, a CR (or complete response) is a CR no matter how you got there" meaning any CR give the same benefit to the patient in terms of progression frr survival.
8. The idea of Maintenance therapy was further re-enforced by the VPMT forwed by Maintenance MT in cases treated without transplant!
9.Remember Carfilzomib and Pomalidomide are 3rd live as approved by FDA.  Meaning 2 treatment have to fail before you can prescribe these meds!
10. With Carfilzomid  (approved in July 2012)watch the kidney and cardiac parameters (concerns here)
less Neuropathy noted.
11. With more drugs available, 2 new combination triplets
  Carfilzomib/Pom/Dex
 Velcade/Pom /Dex meds
12 New drugs to be incorporated "  Daratuzumab, Aratuzumab, ARRY520
new combination Len/Carfil/Dex
13 New salvage TD-PACE,  VTD-PACE
14. one trial Cytoxan/Carfilzomid?Dex, surprising Cytoxan an option in Renal failure patients!

IN MYELOMA ANY OPTION IS GOOD BUT WATCH FOR DEL 17 PRESENCE! (pom AND velcade ARE THEN SOME OF THE OPTIONS)

Questions in Vascular lesions of the liver, and some oustanding associations rising questions at CRBCM.

*Taking Oral Contraceptive is associated with Hepatic Adenoma.
*Association between chronic Hepatitis, Cirrhosis, and Hepatoma
*Association between Ulcerative Colitis with Primary biliary cholangitis and Cholangiocarcinoma
why Spider Angioma
why Palmar Erythema
why LDH is linked to Lymphoma
Does a patient with multiple large unresectable
 Angiosarcoma in the liver candidate for liver transplant if there is no evidence of Metastatsis!

Potential Genes to investigate in liver lesions of Vascular tone/component!

1.VEGF and its corollary the EGFR
yes Avastin works in Angiosarcoma of the liver, and these are vascular lesions. So these genes are in play!
2. VHL, HIF yes these lesions are vascular and hypoxia must be coming in,
3.Estrogen, yes remember the predominance in these lesion in women of child bearing age, and the fact that Oral contraceptive must be discontinued, and avoidance of pregnancy is advised.
4.Androgenic Receptor gene, yes user of Androgenic drugs are at increased risk of Adenoma
5. Wnt (yes the catenin are involved for cellular polarity to be alterated and hypertrophy to occur)
6.Insulin Receptor, There must be in intervention from these genes as most patients with these lesions are obese, with diabetes Mellitus or Glycogen storage disorder particularly type 1A and 3.
7"Irritation/Inflammation such as seen with Hemochromatosis and fibrosis point to hyperactivity of the NF-kB and cyclins (IL 1,6,23)
8. Src gene needs examination because of potential development of sarcomatous lesions.
9. Endothelial involvement gives it DIC propensity (Kasabach-Merritt syndrome) or is-it the ADAMS associated with Cyclines involvedin initiating DIC?

?ROS amplification here give it the Metastatic potentials

(to be continued)

keeping track of CME

CONTINUING MEDICAL EDUCATION CERTIFICATE

certifies that

Mutombo Kankonde, MD
2400 Trawood Drive
Suite 303
El Paso, TX 79936

has participated in the enduring material titled

Secondary Prevention in Patients With ACS and Diabetes: How Can We Optimize Therapy?

August 11, 2013

and is awarded 0.50  AMA PRA Category 1 Credit(s)™.

Medscape, LLC designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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Triple Negative Breast cancer a result of amplification of the JNK and the wnt

Persistent Failure at the receptors leads to a stressful situation that stimulate continuously the JNK/ERK with 2 implications:
1. Through the Caveolin based molecules will affect p66hc, a regulator maintaining ROS phosphorylated and active on the triple molecule Actin-Caherin and Beta-catenin (CBF).   Through the Catenin, PTPRB and ultimately MAGI3 will be affected.  CTNN1 leads to loss of polarity and lumen formation, and will activate Angiopoietin 1 Receptor and VGEF amplification, which in turn further amplification of ROS, the agent of metastasis...
2. JNK/ERK will also have epigenetic increasing TGFBeta and NF-kB  amplification lead to RUNX3 amplification.  Subsequent amplification of PIAS3 and MITF3 will do the rest.

2 main targets!  p66Shc and PIAS3, 2 regulators!

(This information results from speculative interpretation of information readily available on the internet)!

JAK2 at the TGF-Beta receptor, Angiopoitin 1 Receptor Tie2, Receptor, VGEF Receptor 2, IQGAP1, ARF6, ROS and its regulator p66Shc, the cadherin, the RUNX3,   which:

The RUNX3 Tumor Suppressor Upregulates Bim in Gastric Epithelial Cells Undergoing Transforming Growth Factor β-Induced Apoptosis

Takashi Yano,

Are just few of the Targets in the slew of events !

News from Medscape!

*"Hematologist-oncologist Farid Fata, MD, in suburban Detroit, Michigan, was arrested August 6 and charged with Medicare fraud in a federal case that stands out from dozens of others recently brought against healthcare providers.
For one thing, the dollar amount of alleged fraud — $35 million — is higher than most for individual providers charged by the government. The potential physical harm to patients described by prosecutors also is far more substantial. In a criminal complaint filed in a federal district court in Detroit, prosecutors said that the 48-year-old Dr. Fata ordered toxic chemotherapy for patients who did not have cancer or whose cancer was in remission. Doing this "is simply poisoning the patient," prosecutors said in a later court filing."  (go to article"

Physician Gave Chemo to Patients Without Cancer, Feds Say

Robert Lowes

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"Diabetic men with prostate cancer (PC) had a 24% decreased risk for PC-specific death for each additional 6 months of metformin treatment after cancer diagnosis, David Margel, MD, PhD, and colleagues reported online August 5 in the Journal of Clinical Oncology. Cumulative metformin use was also associated with decreased risk for all-cause mortality for the first 6 months after diagnosis. "

Metformin Linked to Fewer Prostate Cancer Deaths in Diabetics

Janis C. Kelly

GO to FULL ARTICLES!

MIAMI CONFERENCE ON HEMATOLOGY MALIGNANCIES

Have completed the conference update here in Miami-Florida. The conference gathered close to 100 Oncologist, In the beautiful Hotel Loews at Corner of 16th Street and Collins avenue.
Subject covered went from Myeloma to Myelofibrosis and will be all make subjects of the upcoming blog this week.  Our approach will not only focus GIVING YOU THE HIGHLIGHTS but also discussing how they fit into our perspectives at CRBCM.  And what associated assumptions can be made based on fundamemtal knowledge discussed in the conference.
From the CRBCM stand point, 2 speaker stood out, Professor Jerry Spivak, Director of the Johns Hopkins Center for the chronic Myeloproliferative disorders who spoke enthusiastically about Myelofibrosis and the new drug Ruxolitinib,  And DR Elias Jabbour, an associate professor in the Leukemia Department at MD Anderson cancer Center.
Once again we will summarize all this week material from this conference starting with Myelodysplasia.  We should confess that some drugs earn significant excitement with Ibrutinib in CHronic Lymphocytic Leukemia.  We predict that this drug in combination Rituxan will soon become the standard of care because of its effect that appears independent of whatever genetic prognosis factors (activity across the board)! and also because of high rates of responses!  Potential Hepatic concerns however call for patient close observation and monitoring.  While Pralatrexate is now more chosen in peripheral T cell Lymphoma. Romidepsin is coming a close 2nd in this disease.
Dasatinib won the war against Nilotinib as the choice in practice for the 2nd generation TKI in CML except for those with lung concern as comorbidity.  In mantle cell lymphoma, the rise in importance of Ibrutinib can not be ignored. Pomalidomide strength is with Dex, emphasizing further once again the importance of DExamethasone in this disease!
In Chronic Myeloid leukemia, the importance of Bone marrow transplantation has shriken until you specifically looking for a cure (Allogeneic transplant) and until the TKI have failed or that the transformation (by high blast) is occuring.  Very exciting to see these new drugs trying to define their places in a filed invaded by Target therapy (Vs conventional chemotherapy which is increasingly pushed-by not forgotten).

COULD PHOSPHATONINS EXPLAIN THE CONCURRENCE OF VITAMIN D DEFICIENCY IN AUTOIMMUNE DISEASES

One thing is certain, autoimmune diseases affect Mesenchymal tisues, the tissues that are full of Fibroblast growth factor 23 or Phosphatonins.  and we know that Phosphatonins "inhibit both renal tubular phosphate reabsorption and 1-alpha-hydroxylation of 25-hydroxycalciferol' (YU).  This fact alone will justify low levels in blood of 1,25-dihydroxycalciferol.  Following this assumption, of course the worse the disease the more likely the vitamin deficiency.  Therefore Vitamin D levels could be a biomarker gauging the severity of the disease (prognostic).

It is clear that disturbance of Phosphorus could also contributes to other electrolytes inbalances, grossly increasing the risk level of arrhythmia and sudden death. Of course too much Vitamin D is not good for you either.
Aging and Autoimmune diseases are characterized by increased levels of cytokines, all of which can affects these Phosphatonins with deleterious impact on our systems!  The levels of Vitamin D receptors could also be directly affected by gene suppression by silencing as a result of epigenetic changes that occurs with the slew of cytokins, and may be the cytokins have a promoter effect on the Phosphatonin gene (s).  Proof of concept needed!

HIDDEN EXCITEMENT ABOUT NANOTECHNOLOGY

One of the thing that stops progress to its full expansion, is some time the secrecy that researchers keep around really exciting things happening today in order to reveal only when things are ripe and ready for a "big" disclosure!  Also, the sense that we own technology and fight hands and teeth to keep findings that can save life for ourselves so we can rip the most profits.  It is just a shame that technology brought about by Taxpayers through NIH is bundle up in a patent.  We are still seeing the unfolding the BRCA fight which is still going on.  We just hope that people will come to their sense and free progress in technology for the good of the world!
One thing excited going on in New York is this development of Nanotechnology, it is my understanding that the State gave money and several biotech companies are now pitching in to possess and develop further this area of science, so that the benefit reach us all in time, at least we hope!  In this world of greed, we still should expect another round of fight over this technology!  Brace for it!

One of the way this technology will make a significant difference is the improved specific delivery of potent chemotherapy drugs to specific area of certain cells!   This is a major problem in Oncology since lack of control where the chemotherapy goes lead to devastating and uncontrolled side effects!  It's like a smart Bomb versus a dumb bomb!  This is target therapy at its best.
Researchers are targeting tough cancers with this technology. (ie melanoma, sarcoma and Pancreatic cancers).
The miRNA-708 story stands out in my mind!  That story reported that there is in triple negative breast cancer this miRNA 708 that inhibit Metastatic lesions from Breast cancer.   And because it is a suppressor "gene" for Metastatic breast cancer, it is its lack or deficiency that leads to promotion of metastasis.  The reports suggested that increasing delivery of synthetic genes could restore the inhibition of Metastasis, and Nanotechnology could come to the rescue as a transport of gene here to help us fight advanced Breast cancer.
The story is even bigger when you think back about the implications of better controlling this technology!
It is increasingly recognized that some if not most, are caused by a gene suppression!  PTEN, E-Cadherin, P53, Rb1 to name just a few...One of the toughest thing is restoring  a gene level!   Creating a inhibitor is the stuff we know how to do.  We have all kinds of inhibitors But gene reamplification and activity restoration is a challenge.  NANOTECHNOLOGY will come to the rescue, that is if we have the gene to restore ready for delivery.  Other way to restore is by regulating the gene promoter, or through Liposomes (lamelle technology and E-coli-mechanistic ways!)  Never mind these, nanotechnology is the new way, and it is hugely promising!  (Lawyers, brace yourselves!)

If you don't take magnesium, take it!

There are so many ways of losing Magnesium, that it is surprising we may still have magnesium in our body any more!  every single thing we do to enjoy life and fight aliment seems to remove magnesium from our body.  You run and sweat, you lose magnesium, you take proton pump inhibitor to reduce acid from our stomach due to stressful life, you lose more magnesium, you take a diuretic to fight high blood pressure, you lose potassium and magnesium, you eat fatty food, well you lose magnesium. you take a stool softner, laxative, you lose magnesium.  Many chemotherapy drug will increase your loss of magnesium (Cetuximab, Tacrolimus, Cisplatin, cyclosporine,Panitumumab)
And the blood test do not reveal the story,you have to be fully depleted of magnesium before your blood level changes.  So by the time your blood level changes, it is too late!  So please just eat your green vegetables, nuts, and whole grain cereals, milk and seafood to keep up.
Now if your DR told you you have renal failure or Irritable Bowel disease, magnesium intake can be dangerous as it may lead to toxicity!  You may be a high absorber man or not lose enough to keep you balanced ...you need your DR help here to monitor this more closely...

DRUG WITH POTENTIAL MARKED EPIGENETIC EFFECTS

There are medications of which role or mechanism of action needs clearly further clarification because they may prevent cancer from occuring. One such medication is:  (from mayo site)   Imiquimod.
"Imiquimod topical is used to treat external warts around the genital and rectal areas called condyloma acuminatum. It is not used on warts inside the vagina, penis, or rectum. Imiquimod is also used to treat a skin condition of the face and scalp called actinic keratosis (AK), which is caused by too much sun exposure. Imiquimod may be used to treat certain types of skin cancer called superficial basal cell carcinoma (sBCC).
Imiquimod works on the immune system to help the body fight viruses that cause warts. It does not destroy the viruses directly. It is not known how imiquimod works for actinic keratosis or skin cancer."

Understanding the mode of action of this drug in better detail appears critical for further development of target therapy that may help prevent certain cancers induced by chronic irritation and viral drive!
(another Medication used for same pathology is Podophyllin)
All they say is  "Podophyllin is a cytotoxic agent that has been used topically in the treatment of genital warts. It arrests mitosis in metaphase, an effect it shares with other cytotoxic agents such as the vinca alkaloids⁽²⁾. The active agent is podophyllotoxin, whose concentration varies with the type of podophyllin used; the American source normally containing one-fourth the amount of podophyllotoxin as the Indian source⁽³⁾."

==========================================================
One thing for sure, viral driven neoplastic diseases can be caused by integral incorporation of the viral genome in that of the host, or induce molecular disturbances changing the course of Metabolism and gene amplification or overexpression of transcription factors by affecting modulator or regulatory genes.  Abnormality of splicing will alter major functional core binding molecules, giving  new patterns to metabolic events, boosting hypertrophy (by loss of sense of cell limits and perturbances at adhesion molecules) and proliferation.   And if the the" foreign" (antigen) sense of the viral presence is not completely suppressed, the cell will be superexcited and the NF-kB on overdrive inducing significant epigenetic events including hyperproduction of Cyclins, Tumor growth factors and disturbances at miRNAs and polymerases (RNA--->DNAs).

All in all significant epigenetic events ensue.  Drugs that will affect epigenetic events must have a role in the control or modulation of these events.  We have to assume that Imiquimod and Podophyllin must have significant tampering effects of epigenetic events.  Indeed Etoposide is known to control these kind of diseases. And it is not because of its topoisomerase II activity and DNA attack, but this drug must have significant epigenetic effects, that is why it can tamper even other epigenetic driven pathologies such as the leukemias.  It is surprising that CPT-11 is not as used as Etoposide.  Pointing to role of heterogeneity in variation of pathologic expression of epigenetic events!

One thing for sure, medications important in control of these epigenetic events have the bad side effects of causing pulmonary fibrosis (Mitomycin). This point to the conclusion that some Cyclins/ TGF (Interleukins in particular) are over expressed leading to fibrosis.  And we still don't screen these Cyclins as biomarkers for detections.  But we know it (pulmonary fibrosis) is dose dependent!  Head in a sand situation again!

(Written on the go at CRBCM...)

New study on older women with early Breast cancer, Role of Radiation...GO TO MEDSCAPE FOR FULL ARTICLE!

Lumpectomy Plus Tamoxifen With or Without Irradiation in Women Age 70 Years or Older With Early Breast Cancer: Long-term Follow-up of CALGB 9343

Hughes KS, Schnaper LA, Bellon JR, et al


"
Women over the age of 70 years with early ER-positive invasive breast cancer (tumor measuring no more than 2 cm) and clinically negative axillae were enrolled between 1994 and 1999. A total of 636 participants with stage I breast cancer who were all treated with lumpectomy (axillary exploration was left to the discretion of the treating surgeon) were randomly assigned to receive tamoxifen plus radiation therapy or tamoxifen alone. Primary endpoints were time to local or regional recurrence, frequency of mastectomy, breast cancer-specific survival, time to distant metastasis, and overall survival.

After a median follow-up of 12.6 years, investigators found no significant differences in time to mastectomy, time to distant recurrence, breast cancer-specific survival, or overall survival. At 10 years, 98% of patients who received dual-modality therapy were free from locoregional recurrence as compared with 90% in the group treated with tamoxifen alone. In the group that received tamoxifen alone, 42 of 319 women relapsed, compared with 23 of 317 in the group that received tamoxifen plus radiation therapy. More women in the tamoxifen group had local and regional relapses and were treated with surgery or radiation at the time of relapse. There was no significant difference in the number of distant relapses between the 2 treatment groups."

YOU BE THE JUDGE!

AND HERE HE COMES FROM BRISTOL MEYERS SQUIBB: CETUXIMAB

CRYSTAL REGIMEN IN FIRST LINE KRAS MUTATION NEGATIVE (WILD TYPE) EGFR EXPRESSING METASTATIC COLORECTAL CANCER...


------------------------------------------------------------------------------------------------
                                                  Crystal regimen       vs     Folfiri alone

Median survival                         23.5 months             Vs    19.5 months

Objective response                           57%                  Vs    39%

Median PFS                                  9.5 months           Vs     8.1 months

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

higher chance to respond to treatment, and higher survival, when you add Cetuximab to FOLFIRI.

Side effects:

Acne-like RASH  86%  Vs 13%
Diarrhea      66%   Vs 60
Neutropenia   31%  Vs  24%

Making Acnee-like-rash the most specific side effect to cetuximab!  Why is a good question for the CRCBM.

Theories in Prostate cancer

The notion that over 70% of Autopsy specimens in male will reveal some form of prostate cancer point to the fact the Neoplastic transformation should be expected in most men, and could be described as part of abnormal aging.  The challenge to Oncologist and geneticists before each cancer is to determine which "prostate cancer" is before them in each specific elderly.
The current understanding is that the difference in aggressive versus "indolent" cancer rests in the patterns of genes or mutations that each cancer displayed.  With the abundance of genes that can go wrong and ultimately start a neoplastic transformation, one is left left with many choices.
It is apparent that a scientific observer needs to control certain parameters and see if a theory can be verified.
One such approach is to assume that certain cancers develop as part of normal senescence and follow where the theory leads us.  We need to inventory senescence mechanism at gene level, and see how they can relate or happen in the context of the Prostate gland, and project how that model could lead to a neoplastic transformation, and compare those projection with prostatic tissue of known random cancers, and autopsy specimens in elderly.  May be variations will give us conclusive remarks that may help sort out things and improve our knowledge a bit.
The development of the increased availability of tissue banks will improve our potential in conducting research work and reducing specimen collection time and reduce the randomness of specimens.  It may help control some variable since you can now specify the race, age, and many other parameter during the observation.  Now you can have the bank offer you fresh frozen specimen, or other types of format, or even just the genes already extracted for your observation!

Earned it!

CONTINUING MEDICAL EDUCATION CERTIFICATE

certifies that

Mutombo Kankonde, MD
2400 Trawood Drive
Suite 303
El Paso, TX 79936

has participated in the enduring material titled

Practical Solutions to Current Clinical Challenges in Relapsed/Refractory Multiple Myeloma

August 5, 2013

and is awarded 0.50  AMA PRA Category 1 Credit(s)™.

Medscape, LLC designates this enduring material for a maximum of 0.50 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: 43827518

Cyndi Grimes Director, Continuing Medical Education Medscape, LLC

 

Plethora of Agents in Refractory Myeloma

There is no hematologic disease with so many new active medications
If you give standard chemotherapy agents in this disease, you will be looked upon with strange eyes in this day in age!

If you treat without knowing Cytogenetic changes in plasma cell, shame on you they say

Patient has to classified as "High Risk (del 17p)"  Vs "standard risk"
                                  (Velcade needed absolutely) Vs  (possible REVLIMID-DEX)


For those with Relapsed or refractory, a plethora of choices

1.  Elotuzumab + Revlimid + DEX
2.  Elotuzumab  + Velcade  + DEX
3.  Carfilzomib + Dex
4.  Pomalidomide + Bortezomib + DEX

Despite this you still have new agents

1. ARRY-520
2.Daratumumab
3.Panobinostat
4.Ixazomib
to try!
(Vorinostat said to "disappointing")

(Medscape) go to talk for a full more reliable discussion!  None of the above should be used unless you recheck the info!

HOW FAST MEMBRANE EVENTS REACH THE NUCLEUS, LIKE LIGHTNING FAST!

"Dancing in and out of the nucleus: p120(ctn) and the transcription factor Kaiso.

Daniel JM.

Source

Department of Biology, LSB-331, McMaster University, 1280 Main St. West, Hamilton, ON, Canada L8S 4K1. danielj@mcmaster.ca

Abstract

The catenin p120 (hereafter p120(ctn)) was first identified as a Src kinase substrate and subsequently characterized as an Armadillo catenin member of the cell-cell adhesion cadherin-catenin complex. In the past decade, many studies have revealed roles for p120(ctn) in regulating Rho family GTPase activity and E-cadherin stability and turnover, events that occur predominantly at the plasma membrane or in the cytoplasm. However, the recent discovery of the nuclear BTB/POZ-ZF transcription factor Kaiso as a p120(ctn) binding partner, coupled with the detection of p120(ctn) in the nucleus of some cell lines and tumor tissues, suggested that like the classical beta-catenin, p120(ctn) undergoes nucleocytoplasmic trafficking and regulates gene expression. Indeed, p120(ctn) has a classic nuclear localization signal and does traffic to the nucleus. Moreover, nuclear p120(ctn) regulates Kaiso DNA-binding and transcriptional activity, similar to beta-catenin's modulation of TCF/LEF transcription activity. However unlike beta-catenin, p120(ctn) does not appear to be a transcriptional activator. Hence it remains to be determined whether the sole role of nuclear p120(ctn) is regulation of Kaiso or whether p120(ctn) binds and regulates other transcription factors or nuclear proteins."
======================================================

This article, easily found on Google, is an important example of how fast events  happening at the membrane reach the the depth of the cell at nuclear level.  Indeed E-cadherin is an adhesion protein which is found at the cellular surface, intervening in the the cell to cell interaction.  YET, its interaction with the Kaiso "as a binding partner", put it center to epigenetic events in the cell making the Kaiso a target to stop nuclear effects of E-Cadherins.
Regulation of the Rho is indeed another very significant point, since the Rho is now well known to heavily contribute to proliferation and metastatic potential of malignant cells.
The Kaiso is known to : (Wipedia)

"ZBTB33 has been shown to interact with HDAC3,^[2] Nuclear receptor co-repressor 1^[2] and CTNND1.^[3]"

<sup>again re-enforcing the notion that membrane events can join the epigenetic ones in a FLASH! 

We thank these researchers for advancing medicine ! 

(careful now if you hit the Ku Antigen, you will affect, the PARP1, G quadruplex, and c-MYC, the amplifier ! and therefore KRAS at the membrane, again!)</sup>

Important clinical questions!

Can lipoxins and IL-4 be used as Biomarkers in Hematologic Malignancy
They point to end of inflammatory process
does their "suppression or absence" points to the severity of leukemic process?

Lipoxins are the most recent addition to the family of bioactive products generated from Arachidonic Acid (AA). They have a number of proinflammatory and anti-inflammatory actions. Lipoxins are short lived endogenously produced nonclassic eicosanoids whose appearance in inflammation signals the resolution of inflammation. They are abbreviated as LX, an acronym for lipoxygenase (LO) interaction products. At present two lipoxins have been identified; lipoxin A₄ (LXA₄) and lipoxin B₄ (LXB₄). (wikipedia)  During inflammation, cells die by apoptosis. As part of resolution, lipoxins signal macrophages to the remains of these cells (phagocytosis).^[6] During the acute inflammatory process, the proinflammatory cytokines such as IFN-γ and IL-1β can induce the expression of anti-inflammatory mediators such as lipoxins and IL-4, which promote the resolution phase of inflammation.<sup>[7]

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

Should Inhibitor  of PARP-1 affect cellular levels of superoxide ? and what would be the effect in patient taking anti-oxide.
Can conceptually use of Inhibitor of PARP-1, inhibit the MTOR inhibitors since it impact Mitochondrial Glycolytic state?

And the answer comes from Chantal Ethier et al</sup>

"Phosphorylation of the mTORC1 target S6 is decreased as well as the phosphorylation of the mTORC2 component Rictor on Thr1135. Finally, Akt phosphorylation on Ser473 is lost and then, cell death by necrosis occurs. Inhibition of PARP-1 with the potent PARP inhibitor AG14361 prevents all of these events. Moreover, the antioxidant N-acetyl-L-cysteine (NAC) can also abrogate all the signaling events caused by MNNG exposure suggesting that reactive oxygen species (ROS) production is involved in PARP-1 activation and modulation of mTOR signaling. In this study, we show that PARP-1 activation and PAR synthesis affect the energetic status of cells, inhibit the mTORC1 signaling pathway and possibly modulate the mTORC2 complex affecting cell fate."

Other interactions?

Histone deacetylase inhibitor potentiated the ability of MTOR inhibitor to induce autophagic cell death in Burkitt leukemia/lymphoma

Li Hua Dong<sup>1†

Go to article!</sup>

IRON DEFICIENCY ANEMIA, added insult to the body

*FROM NEWSmax.health
?Anemia increase risk for dementia in elderly
wonder if it is all anemia or Iron deficiency
breakdown would have been more informative.
*Alentuzumab (Anti-CD52) for the treatment of Hypereosinophilic syndrome led to "brisk elimination of symptoms" . Caveat: Alentuzumab side effect. and questionable effect in clearing the bone marrow. Prophylaxis for CMV and Zoster recommended.
"The makers of Alemtuzumab have reportedly withdraw the medication from the united states to prepare for a relaunch in lower dosage" for treatment of refractory Myeloma"  (Strati et al...)
Use of GLEEVEC IS DISCUSSEDIN THE ARTICLE

CASE IN POINT ABOUT FLIPPASE-FLOPPASE

Conceptually, most proteins of physiologic importance made in the cells are stored at the cellular membrane either as an integral part of the membrane called Integrins or anchored to it and in need of Secretases for secretion.
Most of the Integrins are attached to a Metalloproteinases (ADAMS10)
let say Epo, TNF,TGF  or Cyclin-D are attached to the membrane, with an cytoplasmic stimulation which liberates the TNF from its attachment, The TNF is" flipped" into the cell, and its related Metalloproteinase (2,9) is "Flopped" outside the cell.
The TNF will go on to influence epigenetic events such as increase transcription factors, The metalloprotease will go out to influence extracellular events.  Autoimmunes diseases that are associated with high Cytokines levels intracellularly, are also associated with high Metalloproteinnases extracellularly.  And cellular destruction of joint surfaces is in part due to Metalloproteinases doing their job of modifying the extracellular matrix in excess.
In sepsis for example, controlling the Metalloproteinases by a modified Tetracycline has proved to tamper the cellular attacks in this syndrome.
Remember not all proteins is attached to same Metalloproteinase since there are several class.  And all Metalloproteinases are not equal in what they do.  So it is important to inventory the Metalloproteinase by proteins to which they are attached, and to clearly major in each disease process which Metalloproteinase is increased.
Now because we are bound to secrete Metalloproteinase through the Flippase-Floppase process, our cells need to protect themselves from the Metalloproeinases they produce.  So each cell has anti-metalloproteinase "cover" to shield itself from its own production.  Lack of such protection lead to dangerous clotting events called TTP and HUD, events so dramatic that every Hematologist fear a call each time a patient present with low platelet!  The treatment is known, remove the Metalloproteases and other auto-antibodies through pharesis...
Yet Insurers will fight you if you want to know the level of Cytokines and their related Metalloproteinases.  No wonder that the NCI is calling for new Biomarkers in Autoimmune disease, opening the door for the future in Medicine...!

NEWS FROM OTHER SOURCES

*from MEDCSCAPE
" AP26113 is a second-generation ALK and ROS1 inhibitor that seems in vitro to also have some activity against the activating epidermal growth factor receptor (EGFR) mutations and T790M."..." We are showing the results from the phase 1 dose-escalation study^[1] across a broad dose range.
In the ALK patients, most of whom have not responded to crizotinib, we are seeing fantastic activity: a 75% response rate in patients who had progressed on crizotinib. That is occurring at doses from 60 mg all the way up to 240 mg. They are now taking 180 mg forward as the recommended phase 2 dose. It seems to be very well tolerated. One case of pneumonitis occurred at one of the lower doses, and some other patients with low performance status did relatively badly. But after pausing, tightening up on the inclusion criteria, and adding extra patients to those cohorts, "

*"Other monoclonal antibodies being evaluated for relapse and refractory indolent non Hodgkin Lymphoma include Epratuzumab (Anti-CD22) Galiximab (anti-CD80), Dacetuzumab (anti-CD40) and a number of humanized anti CD20 monoclonal antibodies." (ASCO)

*"High levels of soluble IL-2 Receptors (>5 times normal) are present in the sera of almost all patients with Hairy cell leukemia "  (Hagop Kantargian and Susan Obrien) The disease is characterized by Cytopenia and impaired skin test reactivity. inversion of CD4/CD8.
This the driver force in this disease?  or is-it a consequence of epigenic phenomena? Insurer will fight you if you try to make this a biomarker? And we forgot to measure the METALLOPROTEINASES HERE!
The point is that the response to 2-CDA, Pentostatin, and Interferon suggest the IL-2Ra is most likely causative since these agents have profound epigenetic effects.
BY THE WAY, EPRATUZUMAB IS AN ANTI-CD22, WHICH IS ALSO PRESENT IN HAIRY CELL! (proof of concept)

FAILURE IN CURRENT ONCOLOGY PRACTICE: THE CANCER SURVIVOR STORY

"The American Association for Cancer Research has released its second Annual Report on Cancer Survivorship in the United States. The report, published in the AACR’s journal Cancer Epidemiology, Biomarkers & Prevention, shows that as of January 2012, there were approximately 13.7 million cancer survivors in the United States, a number that is expected to rise by 31 percent to 18 million by 2022."(NCSD)

It is quite apparant that one of the shame in Oncology practice is the poor services that we provide to our cancer survivors. Given the current state of knowledge, it is evident that what we do for survivor is small, fragmented and insufficient!  And the service is more insufficient in patient who had been the more treated.
If one had surgery alone, the moral toll of losing a breast, burden of future relationship, perceived Disfiguration and related psychological detrimental effect is a tremendous burden to cope with...Consequences of true anatomic sequelae of surgeries are countless and a huge burden affecting the lives of survivors.  And there are not enough trained psychologist or internists for that matter to meet the demand imposed by cancer on survivors.

If a survivor had Radiation, an additional toll occurs.  Now on top of thyroid dysfunction, Xerostomia, chronic fatigue, and disfiguration, secondary cancer is added.  Suppression of bone marrow after a localized radiation has always pointed out that although Radiation is localized, it has systemic implications.  That is some altered protein escape the area to induce deleterious effects / stressful events at the distance.  fatigue and sometimes nausea result from Radiation.   Myocardial infarction, loss of hair and salivation are most of the time a result of a direct exposure to Radiation, and Anemia/Myelodysplasia can result from pelvic radiation.

And if chemotherapy was part of the treatment, and particularly if it contained Cisplatin or Alkylating agents, Leukemia and secondary cancers become a real possibility.  Lung, renal and hearing toxicities become real.  Chemotherapy induced encephalopaties of various level are present.  Thyroid and fertility disturbances, Dysplasias or all kinds, and the overall neuro-psychiatric background is disturbed. Globally all senses are disturbed.  Alterations of the immune system are poorly evaluated and understood.

Where we fail is in our correct evaluation of these disturbances and risk of future events in order to make a difference in the life of survivors.  Our biomarkers are not up to what the should be for cancer early detection of secondary cancers,minor but significant side effcts are poorly measured and meaningful preventive or therapeutic measures are often lacking!

The point is that under the satisfaction of response to therapy, we fail to address what  is to come for our survivors who often found themselves alone and unprepared  to what is to come.  The oncologist challenge is compounded by the fact that some of the services needed are  not covered by insurers unless packaged in a certain smart fashion.  Insurers who have paid for the treatment, want to run from the demanding patients!  The lack of evidence based supportive treatment does not help either!

As to secondary cancers:

The point is that we know which cancers develop after chemotherapy
AML (CBF LIKE MOLECULE, GENETIC PROFILE OF BONE MARROW 1 YEAR POST TREATEMT?)
Myelodysplasia (genetic profile of Bone marrow
Colon Cancers( Microsattelite, MUC,
Lung cancers (HIF-1a, MUC...,EGFR)
Breast Cancers (WISP3,BRCA1,2...P53 mutation)
Lymphoma (appropriate gene translocations)
Sarcoma (WT-1, secretases)
and even Melanoma (p16,KIT,PTEN
But No one is delving into preventive detection of of genes!
Renal toxicity (NPHS2 gene, ACTN4
Ototoxicity same as renal (may be!)
scars (Metallopreoteases and their inhibition)

Many studies needed for "PROOF OF CONCEPT"
The skeptical will add "is this going to improve survival"  just be in the shoes of survivors once and you will see the need for this testing!

Estimated Percentage of Cancer Deaths Attributable to Established Risk Factors

TARGETING A SINGLE GENE CAN WORK: EPIZYME

Hi MUTOMBO,  Following the recent news of Epizyme’s first patient enrolled in their clinical trial of  EPZ-6438, an inhibitor of EZH2, we caught up with Executive VP & CSO Bob Copeland  to find out what was going on behind the scenes at this exciting time.  "Our DOT1L inhibitor for use in MLL-r leukemia is in phase I now in a dose escalation  stage and likewise our EZH2 inhibitor, 6438, which just recently started a phase I  trial in non-Hodgkin lymphoma patients. We’re very excited about these because  they represent, to the best of our knowledge, the very first and second HMT inhibitors  to ever go into clinical trials" Download Exclusive Interview with Bob Copeland, Epizyme Bob was asked what’s been going on within Epizyme at the moment and also what  he feels has led to their success so far. "It's been a very exciting time at Epizyme; the discovery and the development  data are all falling into place very nicely and now we're seeing the transition of  that into the clinic." He also goes into much more detail about their company strategy and their  continuing involvement with the EpiCongress series.  “Hearing what other thought-leaders are thinking about, sharing learnings  and experiences with our other industrial colleagues as well as our academic  colleagues - it's been fantastic.” The entire interview has been published as a PDF so that you can download your  own copy here . Bob is one of 19 leaders on the speaker panel of EpiCongress London, 19-21 November 2013. He will expand on the challenges of epigenetic drug development and give you exclusive data on Epizyme’s first clinical candidate molecule. He is joined by speakers from the likes of: AstraZeneca, GSK, UCB Pharma, Eli Lilly, 4SC,  Pfizer, Johnson & Johnson, Astex Pharmaceuticals, Domainex, Novartis & more. Download the brochure to find out much more.  I hope you find the interview interesting and hope to see you in on site at EpiCongress London in November. Best wishes, Zardia Zardia Swift Senior Program Director Hanson Wade

MINIATURE BUSES TO DELIVER CHEMOTHERAPY WHERE WE WANT IT IN A CELL

"Research News: Breakthrough in Nano-Medicine Chemotherapy Drug Delivery in Phase II Trials"

NO KIDDING AROUND ANYMORE, ALL WE NEED TO KNOW IS A SPECIFIC ADDRESS IN A CELL AND THE BUS IS ON ITS WAY WITH WHATEVER THE CHEMOTHERAPY LOAD.  THIS IS PRECISION MEDICINE/ONCOLOGY.

NANO PARTICLE TECHNOLOGY AT WORK FOR IMPROVED MEDICINE! 

GO TO ARTICLE!