WHEN IT WORKS, GIVE IT FOR 3 YEARS!

Developed under the direction and sponsorship of Novartis Pharmaceuticals Corporation. 3 years of adjuvant therapy with GLEEVEC reduced the risk of recurrence by 54% vs 1 year of therapy in KIT+ GIST patients (median follow-up of 42 months)1 Orchestrate continued success by extending adjuvant treatment in KIT+ GIST1 View Indication and Important Safety Information The results from the Scandinavian Sarcoma Group (SSG) XVIII/AIO Phase 3 trial showed a significant improvement in recurrence-free survival (RFS) when adjuvant treatment with GLEEVEC® (imatinib mesylate) was extended to 3 years vs 1 year of therapy (median follow-up of 42 months). In addition to improving RFS, trial results demonstrated an overall survival (OS) benefit, with mortality reduced by half in the 3-year arm vs the 1-year arm (12 vs 25 deaths, respectively; median follow-up of 48 months). These findings have prompted updates to the FDA-approved Prescribing Information for GLEEVEC and the NCCN guidelines supporting 3 years of adjuvant treatment for appropriate resected patients with KIT+ GIST.1,2 Please consider this information when making clinical decisions and recommendations for your KIT+ GIST patients. Important Safety Information Serious adverse reactions may occur, including edema, cytopenias, severe congestive heart failure, left ventricular dysfunction, hepatotoxicity, hemorrhage, GI disorders, hypereosinophilic toxicity, dermatologic toxicities, hypothyroidism, toxicities from long-term use, fetal harm, and tumor lysis syndrome. Caution should be recommended when driving a car or operating machinery.1 Download latest Prescribing Information In the SSG trial, risk of tumor recurrence was reduced by half with 3 years vs 1 year of adjuvant GLEEVEC therapy (median 42-month follow-up)1 Recurrence events were 68% higher in the 1-year arm vs the 3-year arm (84 vs 50 events) aSSG XVIII/AIO study was a multicenter, open-label, Phase 3 trial conducted to determine the clinical benefits of 3 years (n=198) vs 1 year (n=199) of adjuvant therapy with GLEEVEC 400 mg/day. Inclusion criteria were tumor diameter >5 cm and mitotic count >5/50 high-power fields (HPFs), or tumor diameter >10 cm and any mitotic count, or tumor of any size with mitotic count >10/50 HPFs, or tumor rupture. The primary end point was RFS defined as the time from date of randomization to the date of recurrence or death from any cause. OS was a secondary end point. Median time of follow-up was 42 and 48 months, respectively.1 GIST=gastrointestinal stromal tumor; NCCN=National Comprehensive Cancer Network; RFS=recurrence-free survival; OS=overall survival. In the SSG trial, no new adverse reactions were reported with longer duration of therapy (3-year arm vs 1-year arm)1 •  As in previous trials, the most frequently reported adverse reactions in this clinical trial were diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain —  14% of patients in the 3-year arm vs 8% of patients in the 1-year arm discontinued treatment due to adverse events (AEs) —  The incidence of serious AEs (Grade ≥3) was 33% in the 3-year arm vs 20% in the 1-year arm Indications and Important Safety Information GLEEVEC® (imatinib mesylate) tablets are indicated for: •  Patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST) •  Adjuvant treatment of adult patients following complete gross resection of KIT (CD117)-positive GIST Important Safety Information •  GLEEVEC is often associated with edema and, occasionally, serious fluid retention. Severe fluid retention was reported in 9% to 13.1% of patients taking GLEEVEC for GIST. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention, which can be serious or life threatening, and be advised to report any rapid, unexpected weight gain. The probability of edema tended to be increased among older patients (>65 years) or those taking higher doses of GLEEVEC. Severe edema was observed in 182 patients (11.1%). If severe fluid retention occurs, manage with diuretic therapy and withhold GLEEVEC until the event has resolved, and then resume, depending on the initial severity of the event •  Cytopenias have been reported. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (eg, every 2 to 3 months). Dose reduction, treatment interruption, or in rare cases discontinuation of treatment may be required for severe neutropenia or thrombocytopenia (see full Prescribing Information for dose adjustment recommendations) •  Severe congestive heart failure and left ventricular dysfunction have been reported. Most of the patients with reported cardiac events have had other comorbidities and risk factors, including advanced age and previous medical history of cardiac disease. Patients with cardiac disease or risk factors for cardiac disease or history of renal failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac or renal failure should be evaluated and treated •  Hepatotoxicity, occasionally severe, may occur. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of GLEEVEC. Assess liver function before initiation of treatment and monthly thereafter, or as clinically indicated. A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment. If severe hepatotoxicity occurs, GLEEVEC should be withheld until the event has resolved and then resumed, depending on the initial severity of the event •  When GLEEVEC is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended •  In the Phase 3 unresectable or metastatic GIST studies, 13% of patients reported hemorrhage (NCI Grades 3/4) at any site. In the Phase 2 unresectable or metastatic GIST study, 5% of patients were reported to have severe gastrointestinal (GI) bleeds and/or intratumoral bleeds. GI tumor sites may have been the source of GI bleeds; therefore, GI symptoms should be monitored at the start of therapy •  In patients with hypereosinophilic syndrome with occult infiltration of HES cells within the myocardium, cardiogenic shock and left ventricular dysfunction have been associated with HES cell degranulation upon initiation of GLEEVEC. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures, and temporarily withholding GLEEVEC •  Bullous dermatologic reactions (eg, erythema multiforme and Stevens-Johnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing reports describe patients able to tolerate the reintroduction of GLEEVEC at a lower dose, with or without concomitant corticosteroids or antihistamines following resolution or improvement of the bullous reaction •  Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with GLEEVEC. TSH levels should be closely monitored in such patients •  Consider potential toxicities—specifically liver, kidney, and cardiac toxicity—and immunosuppression from long-term use •  Fetal harm can occur when administered to a pregnant woman. Therefore, women of reproductive potential should be advised not to become pregnant while taking GLEEVEC tablets and to avoid breastfeeding while taking GLEEVEC because of the potential for serious adverse reactions in nursing infants. Sexually active female patients taking GLEEVEC should use highly effective contraception. If the patient does become pregnant while taking GLEEVEC, the patient should be advised of the potential hazard to the fetus •  Growth retardation has been reported in children and preadolescents receiving GLEEVEC. The long-term effects of prolonged treatment with GLEEVEC on growth in children are unknown; therefore, monitoring of growth in children taking GLEEVEC is recommended •  Cases of tumor lysis syndrome (TLS), including fatal cases, have been reported. The patients at risk for TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of GLEEVEC •  Motor vehicle accidents involving patients receiving GLEEVEC have been reported. Patients should be advised that they may experience undesirable effects such as dizziness, blurred vision, or somnolence during treatment with GLEEVEC. Caution should be recommended when driving a car or operating machinery •  In the Phase 2 unresectable or metastatic GIST trial (400 mg/day; 600 mg/day), severe (NCI Grades 3/4) lab abnormalities—including anemia (3%; 9%) and neutropenia (10%; 11%)—were reported among patients receiving GLEEVEC. In Phase 3 unresectable or metastatic GIST trials (400 mg/day; 800 mg/day), the most frequently reported adverse reactions included abdominal pain (14%; 12%), edema (9%; 13%), fatigue (12%; 12%), nausea (9%; 8%), vomiting (9%; 8%), diarrhea (8%; 9%), rash (8%; 9%), myalgia (6%; 4%), anemia (5%; 6%), and anorexia (7%; 5%). The percentages listed represent NCI Grades 3 and above •  In the adjuvant GIST study comparing 12 months of GLEEVEC vs placebo treatment (GLEEVEC; placebo), severe (NCI Grades 3 and above) lab abnormalities included increase in liver enzymes (ALT) (3%; 0%), (AST) (2%; 0%), decreased neutrophil count (3%; 1%), and decrease in hemoglobin (1%; 0%); severe (NCI Grades 3 and above reported at rates >1%) adverse reactions included abdominal pain (3%; 1%), diarrhea (3%; 1%), rash (3%; 0%), fatigue (2%; 1%), nausea (2%; 1%), vomiting (2%; 1%), decreased white blood cell count (1%; 0%), and periorbital edema (1%; 0%). The frequencies of these reported lab abnormalities and severe adverse reactions were similar in a study comparing 12 vs 36 months of GLEEVEC treatment (12 mo; 36 mo), except for liver enzyme AST (2%; 3%), decreased neutrophil count (5%; 5%), decreased white blood cell count (2%; 3%), pain (1%; 3%), infection (2%; 3%), and blurred vision (1%; 1%), which were higher among patients receiving 36 months of adjuvant treatment with GLEEVEC* •  There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, acute respiratory failure, and GI perforation •  GLEEVEC is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Significant reductions in imatinib concentrations may occur when GLEEVEC is administered concomitantly with agents that are strong CYP3A4 inducers such as rifampin, St. John's wort, and enzyme-inducing antiepileptic drugs, eg, phenytoin. The concomitant use of strong CYP3A4 inducers should be avoided. If patients must be administered a strong CYP3A4 inducer, the dosage of GLEEVEC should be increased by at least 50%, and clinical response should be carefully monitored. Caution is recommended when GLEEVEC is administered with CYP3A4 inhibitors such as ketoconazole, with CYP2D6 substrates that have a narrow therapeutic window, or with CYP3A4 substrates that have a narrow therapeutic window. Other examples of commonly used drugs that may significantly interact with GLEEVEC include acetaminophen, warfarin, erythromycin, and metoprolol. Grapefruit juice should also be avoided in patients taking GLEEVEC. (Please see full Prescribing Information for other potential drug interactions) •  Patients with moderate renal impairment (CrCL=20-39 mL/min) should receive a 50% decrease in the recommended starting dose; future doses can be increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL=40-59 mL/min). For patients with moderate renal impairment, doses greater than 400 mg are not recommended. GLEEVEC should be used with caution in patients with severe renal impairment Common Side Effects of GLEEVEC Tablets •  Almost all patients who received GLEEVEC in the Phase 3 unresectable or metastatic GIST studies experienced adverse reactions at some time. Overall, the incidence of all grades of adverse reactions and the incidence of severe (CTC Grades 3 and above) adverse reactions were similar between the 2 treatment arms, except for edema and rash/related terms, which were reported more frequently in the 800-mg group. The most frequently reported adverse reactions (400 mg/day; 800 mg/day) (all grades) were edema (77%; 86%), fatigue (69%; 75%), nausea (58%; 65%), abdominal pain (57%; 55%), diarrhea (56%; 58%), rash and related terms (56%; 70%), vomiting (37%; 41%), myalgia (32%; 30%), anemia (32%; 35%), anorexia (31%; 36%), and arthralgia (14%; 12%). Therapy with GLEEVEC was discontinued for adverse reactions in 5% of patients studied* •  In the adjuvant treatment of GIST studies, almost all GLEEVEC- and placebo-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations. In Study 1, comparing 12 months of GLEEVEC treatment vs placebo (all grades), these included (GLEEVEC; placebo) diarrhea (59%; 29%), fatigue (57%; 41%), nausea (53%; 28%), periorbital edema (47%; 15%), decreased hemoglobin (47%; 27%), peripheral edema (27%; 15%), rash (26%; 13%), vomiting (26%; 14%), abdominal pain (21%; 22%), anorexia (17%; 9%), muscle spasms (16%; 3%), white blood cell count decreased (15%; 4%), arthralgia (15%; 15%), and myalgia (12%; 12%).* The frequencies of these reported adverse reactions were similar in Study 2, comparing 12 vs 36 months of GLEEVEC treatment (12 mo; 36 mo), except for decreased hemoglobin (72%; 80%), periorbital edema (59%; 74%), muscle spasms (31%; 49%), decreased white blood cell count (35%; 47%), pain (26%; 46%), peripheral edema (33%; 41%), rash (29%; 39%), arthralgia (9%; 17%), and myalgia (9%; 15%), which were higher among patients receiving 36 months of adjuvant treatment with GLEEVEC. Adverse reactions listed represent the most frequently reported for Study 1 with the addition of adverse reactions with higher rates in Study 2* •  In the adjuvant GIST study comparing GLEEVEC vs placebo, drug was discontinued for adverse events in 17% of GLEEVEC- and 3% of placebo-treated patients. Edema, GI disturbances (nausea, vomiting, abdominal distension, and diarrhea), fatigue, low hemoglobin, and rash were the most frequently reported adverse reactions at the time of discontinuation. In the adjuvant study comparing 12 vs 36 months of GLEEVEC treatment, drug was discontinued for adverse events in 8% of patients treated for 12 months and 14% of patients treated for 36 months* •  Supportive care may help reduce the severity of some mild to moderate adverse reactions. However, in some cases, either a dose reduction or interruption of treatment with GLEEVEC may be necessary •  Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered at 400 mg twice a day. For daily dosing of 800 mg and above, dosing should be accomplished using the 400-mg tablet to reduce exposure to iron •  GLEEVEC tablets should be taken with food and a large glass of water to minimize GI irritation •  Patients should be instructed to take GLEEVEC exactly as prescribed and not to change their dose or stop taking GLEEVEC unless they are told to do so by their doctor. If patients miss a dose, they should be advised to take their dose as soon as possible unless it is almost time for their next dose, in which case the missed dose should not be taken. A double dose should not be taken to make up for any missed dose *For more detailed study information, please see full Prescribing Information. References 1.  GLEEVEC® [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2013. 2.  The NCCN Soft Tissue Sarcoma Clinical Practice Guidelines in Oncology (Version 3.2012) ©2012 National Comprehensive Cancer Network, Inc. http://www.nccn.org. Accessed May 24, 2012. To view the most recent and complete version of the guidelines, go online to www.nccn.org. Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080 © 2013 Novartis 4/13 GLI-1062742

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GENES IN LUPUS

TREX1" the major 3'->5' DNA exonuclease in human cells. The protein is a non-processive exonuclease that may serve a proofreading function for a human DNA polymerase. It is also a component of the SET complex, and acts to rapidly degrade 3' ends of nicked DNA during granzyme A-mediated cell death. Mutations in this gene result in Aicardi-Goutieres syndrome, chilblain lupus, RVCL (Retinal Vasculopathy with Cerebral Leukodystrophy), and Cree encephalitis. Multiple transcript variants encoding different isoforms have been found for this gene.<sup>[4]wikipedia"

This explanation have 3 fundamental points that underlie auto-immune disease  
deficiency is 
1. genetic based
2. Involve degradation and disposing of debris
3. Heterogeneity is a strong variable
but it also points to 2 additional facts pattern of Methylation which by now we know to be strongly influenced Estrogen will mark significant difference in expression of this disease in the 2 sexes!</sup>

-------"
BANK1
It is involved in B-cell receptor induced Ca2+ mobilization from intracellular stores and promotes Lyn-mediated phosphorylation of IP3 receptors 1 and 2.. Lyn has emerged as a key enzyme involved in the regulation of cell activation. In these cells, a small amount of LYN is associated with cell surface receptor proteins, including the B cell antigen receptor (BCR),^[5][6] CD40,^[7] or CD19.^[8]..
Lyn has been described to have an inhibitory role in myeloid lineage proliferation.^[9] Following engagement of the B cell receptors, Lyn undergoes rapid phosphorylation and activation. LYN activation triggers a cascade of signaling events mediated by Lyn phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the receptor proteins, and subsequent recruitment and activation of other kinases including Syk, phosholipase Cγ2 (PLCγ2) and phosphatidyl inositol-3 kinase.^[8][10] These kinases provide activation signals, which play critical roles in proliferation, Ca²⁺ mobilization and cell differentiation. Lyn plays an essential role in the transmission of inhibitory signals through phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based inhibitory motifs (ITIM) in regulatory proteins such as CD22, PIR-B and FCγRIIb1. Their ITIM phosphorylation subsequently leads to recruitment and activation of phosphatases such as SHIP-1 and SHP-1,^{[11][12][13][14][15]} which further downmodulate signaling pathways, attenuate cell activation and can mediate tolerance. In B cells, Lyn sets the threshold of cell signaling and maintains the balance between activation and inhibition. Lyn thus functions as a rheostat that modulates signaling rather than as a binary on-off switch.^[16][17][18]
Lyn has also been implicated to have a role in the insulin signaling pathway. Activated Lyn phosphorylates insulin receptor substrate 1 (IRS1). This phosphorylation of IRS1 leads to an increase in translocation of Glut-4 to the cell membrane and increased glucose utilization.^[19] In turn, activation of the insulin receptor has been shown to increase autophosphorylation of Lyn suggesting a possible feedback loop.^[20] The insulin secretagogue, glimepiride (Amaryl®) activates Lyn in adipocytes via the disruption of lipid rafts.^[21] This indirect Lyn activation may modulate the extrapancreatic glycemic control activity of glimepiride.^{[21][22]wikipedia} "

TNFSF4, a member of the dangerous Tumor Necrosis Factor family,  TNF is bad because its devastating effect escape mitigation by steroids and Interferon gamma at certain thresholds!
direct involvement with Death receptors are to be feared!

BLK
TNFAIP3
C2
C1QA
STAT4
PTPN22
LYN
IRAK1
ITGAM
IRFS
C4A,B
CRP
DRB1 1501
 DRB1 0301
FCGR2A, 3A

Evolution of the Role of the Oncologist!

The evolution of the role of the Oncologist has remarkably evolved from the one who had to manage chemotherapy, hormone therapy and immunotherapy to the one who detect and advise carriers of genetic predisposition to cancer when it comes to heritable neoplasms, determination of needed and actionable driver mutations, selecting appropriate referrals for genetic counseling, advising as to recommended Maintenance therapy for survivors and helping them survive with sequellae of various therapies in the management of cancers!
In Prostate Cancer, hormone therapy has been so successful and is relatively benign, that Urologist have encroached and taken over this role that used to be mainly performed by Oncologists.  With the advent of target therapy which now comes in pill form, there will be an increasing shrinkage of the roll of the Oncologist as more physician continue to familiarize themselves with these pills.  To survive, the oncologist needs to further master cell biology to keep a noticeable edge.  And doing so He will find himself encroaching in other specialties of which Immunology/Rheumatology will be more likely the area given the fact that it too is a cell biology based science, and chemotherapy drug have been used here mostly at low doses!
 

INTERESTING ASPECTS OF GERM CELL TUMORS

*In the retroperitoneum, involvement is always associated with Testicular involvement (even non palpable)
whereas Mediastinal involvement could be primary.
*no matter the stage, the objective of the treatment is cure.
*Cryptorchidism needs to be corrected before Puberty to monitor the testicle and reduce the risk of Neoplastic transformation.
*men with HIV, are more likely to have a Seminoma
*klinefelter syndrome is associated with Mediastinal involvement
*In situ presence marks a 50%risk of cancer development within 5 years
*with a Seminoma in 1 Testicule, there is a 2 % concurrent chances of presence in the other testicle!
*Deletion of short arm of  Xsome 12 is present in 80%, the rest have some form of hyperpliody involving 12p.

Genes involved

1.KRAS, " normal tissue signaling, and the mutation of a KRAS gene is an essential step in the development of many cancers.^[3] Like other members of the Ras family, the KRAS protein is a GTPase and is an early player in many signal transduction pathways. KRAS is usually tethered to cell membranes because of the presence of an isoprenyl group on its C-terminus." wikipedia
It is interesting to know that with KRAS activation follow the activation of RALGDS which through the Arrestins wake up the DVL (devil) preparing the cell to early proliferation and metastasis through the Wnt.

2.SOX5
a member of a Core Binding protein /Homebox that direct toward male differentiation, blockage here by Mutation returns some of the totipotentiality to the cell by blocking differentiation (which include Male Brain transformation).
It is believed or speculated that Older Man will have methylation issue at this gene leading to autistic children since this gene is definitely involved with Brain formation/Autistic transformation!

3.CCND2:  BELONGS TO THE CYCLINS!
" This protein has been shown to interact with and be involved in the phosphorylation of tumor suppressor protein Rb. Knockout studies of the homologous gene in mouse suggest the essential roles of this gene in ovarian granulosa and germ cell proliferation. High level expression of this gene was observed in ovarian and testicular tumors.^[2]WIKIPEDIA


 4.JAW1
re-enforcing the notion that membrane perturbances are critical in Testicular cancer
as this gene allow the eluding from Class I molecule detection and disturb anti-proliferative and pro-apoptotic function!

" JAW-1 affects
Calcium release from the endoplasmic reticulum controls a number of cellular processes, including proliferation and contraction of smooth muscle and other cells and contributes to the antiproliferative and proapoptotic effects of nitric oxide and cGMP. (from LocusLink and OMIM)".   WHAT IS IN COMMON TO THESE 4 GENES TO SHOW THAT THEY POTENT GENES, DEFICIENCY OF THESE GENES LEADS TO MALFORMATION (FACIAL OR OTHERWISE!)

ASCO NEWS!
Anti-PD1, a misnomer, yes I believe!
isn't it longer true that if you block programmed cell death, you worsen a cancer?
well don't believe what make sense, "Antibody mediated blockade of the programmed cell death protein-1 and its ligand PD-L1 resulted in a potent and durable tumor regression and prolonged stabilization of disease in patients with solid tumors"...Nivolumad in combination with Ipilumumab yielded a 40% response rate in advanced Melanoma, this is impressive!  "The Synergie between Anti-PD-1 and an Anti-CTLA-4 has been confirmed".

*pomalidomide has been approved for Multiple Myeloma after failure of 2 regimens which contained Velcade and Revlimid. Officially approval was not based on increased survival! 

*Now enroling Trial "A Phase 3 trial for Newly diagnosed EGFRvIII-positive Glioblastoma :Rindopepimut and Temodar Vs Blinded KLH control and Temodar" NCT01480479

TRANSGENDER?

CNN PRESENTED LAST NIGHT: FROM CHRIST TO CHRISTIN, THE STORY OF A MAN WHO HAS GONE TROUGH A "NAVY SEAL" TO A TRANSGENDER WOMAN CURRENTLY ESTROGEN TREATMENT, AND WANTING TO LIVE AS "JUST ANOTHER WOMAN AROUND THE CORNER". THE STORY WAS FASCINATING, AND SOMEWHAT DIFFICULT FOR THE REPORTER WHO COULD NOT LOOK AT "CHRISTINE" IN THE EYE AS MUCH AS CHRISTINE DID!
THIS STORY DID BRING TO MIND ALSO A WEIRD QUESTION THAT POPPED UP ONE DAY BEFORE A CONFERENCE: A TRANSGENDER WOMAN HARD AT WORK ON ESTROGEN TREATMENT, SHOW-UP WITH AN ADVANCED PROSTATE CANCER, QUESTION WAS HOW TO TREAT?
BUT LET GO BACK TO THE GENETIC BASIS OF "TRANS-SEXUALITY" 
THIS FIELD IS CONTROVERSIAL, WITH PSYCHOLOGISTS FIGHTING TO CONSIDER THIS A STRICTLY BEHAVIORAL WHEN GENETICISTS MAINTAIN IT IS STRICTLY A GENETIC DISTURBANCE.
MY FAVORITE THINKING IS THAT IT IS A FAILURE OF METHYLATION OF CRITICAL HORMONAL GENES, BUT OTHER MAINTAIN IT IS AN ABERRATION OF A GENES WHICH IS CHARACTERIZED BY AN ATTACHMENT OF A PROLONGED REPEAT OF MOLECULES.
THERE IS NO FUMES OR SMOKE (IF YOU WANT A LIGHTER OPTION) WITHOUT A FIRE I WANT TO MAINTAIN, SO I LEAN FOR A GENETIC BASIS TO THIS ARGUMENT.
WIKIPEDIA:
"

Genetics

The androgen receptor (AR), also known as NR3C4, is activated by the binding of testosterone or dihydrotestosterone, where it plays a critical role in the forming of primary and secondary male sex characteristics. Hare et al. found that male-to-female transsexuals were found to have longer repeat lengths on the gene, which reduced its effectiveness at binding testosterone.^[18]
A variant genotype for a gene called CYP17, which acts on the sex hormones pregnenolone and progesterone, has been found to be linked to female-to-male transsexualism but not MTF transsexualism. Most notably, the FTM subjects not only had the variant genotype more frequently, but had an allele distribution equivalent to male controls, unlike the female controls. The paper concluded that the loss of a female-specific CYP17 T -34C allele distribution pattern is associated with FtM transsexualism.^[19]"
  Currently, there are numerous scientific explanations of the cause of transsexualism, linking the cause to genetics, brain structure, brain function and prenatal androgen exposure; in addition, other theories have proposed linking the cause to psychological and behavioral reasons. These theories are not necessarily mutually exclusive."

STC1 gene, role in Alzheimer disease?

wikipedia, Stanniocalcin-1 is a " glycoprotein that is expressed in a wide variety of tissues and may have autocrine or paracrine functions. Human Stanniocalcin-1 is a putative molecular biomarker of leukemic microenvironment and the only molecular function known up to date is a SUMO E3 ligase activity in the SUMOylation cycle. STC1 interacts with lots of proteins in the cytoplasm, mithocondria, endoplasmatic reticulum and and dot-like fashion in the nucleus. The N-terminal region of STC1 is the function region which is responsible to establish the interaction with its partners, including SUMO1.[3"
Researchers" found a dramatically upregulated expression of STC during induced neural differentiation in a human neural crest-derived cell line", Paju.(Zhang et al)
"Overexpression of human stanniocalcin 1 in mice produces high serum phosphate levels, dwarfism, and increased metabolic rate. This gene has altered expression in hepatocellular, ovarian, and breast cancers.<sup>[2]wikipedia".

Tamura "</sup>
"The relative expression levels of the STC1 gene were higher in the cancer tissue than in the normal adjacent mucosa and high expression of STC1 correlated with poor postoperative survival.

CONCLUSION:

High expression of the STC1 gene might be a useful predictor of poor postoperative outcome in patients with colorectal cancer."

GUO: " Here, we found that STC1 is down-regulated in Clinical tissues of cervical cancer compared to the adjacent normal cervical tissues (15 cases). Subsequently, the expression of STC1 was knocked down by RNA interference in cervical cancer CaSki cells and the low expression promoted cell growth, migration and invasion."

ASIDE FROM IT BEING A CLEAR TARGET FOR INTERVENTION IN CANCER, THIS GENE SEEMS  TO AFFECT AN IMPORTANT COMPONENT OF MICROFIBRILLARY TANGLES THAT CHARACTERIZE ALZHEIMER DEMENCIA, WHICH IS SHIFT IN CALCIUM PHOSPHATE RATIOS.  IT BEGS A QUESTION : WHAT IS THE ROLE OF STC1 IN ALZHEIMER DISEASE?

GET A LITTLE DIRTY MAY BE GOOD FOR YOU!

I know coming from a health professional it is somewhat surprising or even shocking, but take a moment and read about this statement!

ALLERGIES ARE ON THE RISE!

"The increase in allergic diseases noted in the last 2 decades is thought to result from better hygiene conditions, decreases in infant and childhood infections,and an increasingly sedentary and indoor lifestyles." (Wasserman)
yes the less you have been exposed to antigen the more likely you could become allergic.  You have not challenged your innate immune system enough.  The author suggest that this fact somehow "alters the protective maturation of the acquired immune system".  Now this statement is heavy in implications!  It implies that the development of class II Major Histocompatibility (MHC) is some what influenced in their development by class I Antigen? or am I over-reaching?
Innate immune system is Tolerance of self Antigens?  Acquired Immunity is the stuff mostly class II antigens deal with!
Challenging this statement, will need to read more about this!  At CRBCM, we like this form of challenge! keeps one with sharp mind!
This is germaine to genetics because its throws you next into methylation of genes involved in immunity!
Indeed the "Hygiene Hypothesis" suggested switch off of T2H was not fully completed in favor of T1H...Methylation could have been the silencing mechanism!? check this out!

IN OTHER SAD NEWS AND REMINDER!

"Grand jury hearing evidence on CPRIT grant to Dallas company"-GO TO ARTICLE IN THE DALLAS NEWS!

BAYAN RAJI REPORTED
"
A state audit in January revealed that three grants totaling nearly $60 million were awarded without going through proper review channels. The audit stated Bill Gimson, the executive director of CPRIT at the time, recommended the three grants for approval even though the peer review councils did not recommend them for approval.
Gimson resigned in December."

THE HOUSTON CHRONICLE

CPRIT reform bill heads to governor's desk

By Todd Ackerman, Eric Berger | May 24, 2013 | Updated: May 25, 2013 2:59pm

-----------------------------------------------------------------------------------------------------AND IT'S STILL THERE LAST WE HEARD CAUGHT UP IN A DRINKING INCIDENT

" The news that Gov. Rick Perry is pressuring Travis County District Attorney Rosemary Lehmberg to resign in the wake of her DWI conviction has some Texas liberals seeing a hidden agenda: that the governor wants to short circuit a criminal investigation into the Cancer Prevention and Research Institute of Texas."(THE CHRONICLE)

AND I HAVE TOLD YOU THAT THE CURE IS WITHIN REACH BUT THE HUMAN COMPONENT MAKES IT HARDER TO REACH BEACAUSE HUMANS ARE BEING HUMANS!

THANKS TO MEDSCAPE

"In an highly anticipated decision, the Supreme Court has effectively invalidated the patents held by Myriad Genetics for the BRCA1 and BRCA2 genes.
However, the ruling is not all bad news for Myriad.
The Court unanimously ruled that although naturally isolated DNA is not patentable, synthetically created exon-only strands of nucleotides — complementary (c)DNA — is patentable.
In essence, the Court ruled that 5 of Myriad's claims covering isolated DNA are not eligible for patents. But according to Myriad, the company holds more than "500 valid and enforceable claims in 24 different patents conferring strong patent protection for its BRACAnalysis test."
The ruling was written by Justice Thomas, who was joined by Chief Justice Roberts and Justices Kennedy, Ginsberg, Breyer, Alito, Sotomayor, and Kagan; Justice Scalia concurred in part. The Court held that "a naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated, but cDNA is patent eligible because it is not naturally occurring."
It notes that "Myriad's principal contribution was uncovering the precise location and genetic sequence of the BRCA1 and BRCA2 genes." Although this was an important contribution, "Myriad did not create or alter either the genetic information encoded in the BCRA1 and BCRA2 genes or the genetic structure of the DNA."
In the decision, Justice Thomas notes that Myriad's claims were not "saved by the fact that isolating DNA from the human genome severs chemical bonds and thereby creates a non-naturally occurring molecule." This is because the claims are "simply not expressed in terms of chemical composition, nor do they rely in any way on the chemical changes that result from the isolation of a particular section of DNA."
However, the decision leaves the door somewhat open on gene patenting because it distinguishes natural from synthetic DNA. The Court noted that "cDNA does not present the same obstacles to patentability as naturally occurring, isolated DNA segments."
More specifically, Justice Thomas points out that "cDNA retains the naturally occurring exons of DNA, but it is distinct from the DNA from which it was derived." Thus, this form of DNA is "not a 'product of nature' and is patent eligible under §101."
Long and Convoluted Journey
Today's decision puts an end to what has been a long and protracted case. Myriad acquired patents on the 2 genes in the mid-1990s. Since that time, it has become the sole commercial provider of testing services for BRCA1 and BRCA2 in the United States.
On May 12, 2009, the American Civil Liberties Union and the Public Patent Foundation filed a lawsuit against the US Patent and Trademark Office, Myriad Genetics, and the University of Utah Research Foundation, which hold the patents on the BRCA1 and BRCA2 genes. It charged that patents on human genes violate the First Amendment and patent law because genes are "products of nature," and therefore cannot be patented.
The coplaintiffs in the case, including several medical organizations, physicians, academic researchers, cancer survivors, and patient advocates, represented 150,000 geneticists, pathologists, and laboratory professionals.
On March 29, 2010, a New York federal court ruled against Myriad, finding that patents on the BRCA1 and BRCA2 genes were invalid. Myriad appealed the case, and it was heard by the US Court of Appeals for the Federal Circuit in April 2011. Three months later, the appeals court ruled in Myriad's favor, finding that companies can obtain patents on specific genes.
In March 2012, the US Supreme Court instructed the appeals court to reconsider the case after a unanimous ruling invalidated 2 patents on a blood test that determines drug dosages, which had been licensed to Prometheus Laboratories.
In August 2012, a divided federal appeals court (2 to 1) ruled in favor of Myriad and gene patents in general. However, the Court invalidated patents on methods used to compare gene sequences. A month later, the plaintiffs once again asked the Supreme Court to hear the challenge to Myriad's patents. In November 2012, the Supreme Court agreed to hear it.
Today's decision is likely to have far-reaching implications for the biotechnology industry, and will undoubtedly raise questions about the validity of thousands of other patents that are currently in force.
Victory for Both Sides?
Both sides of the court battle see the ruling as a victory. The American Society for Clinical Pathology (ASCP) and Breast Cancer Action, both plaintiffs in the case, have expressed satisfaction with the ruling in press releases.
"Isolated DNA is a product and law of nature, not an invention, so it is not open to patent protection," said Steve Kroft, MD, FASCP, president-elect of the ASCP, in a statement. "Gene patents hinder advances in patient care and make the process slower and more expensive for women to find out if they have certain gene mutations that could adversely affect their health."
According to the ASCP, the cost of BRCA testing will be considerably lower without patent protection, and laboratories nationwide will be able to conduct the tests. In addition, patients will be able to obtain a second opinion, which Myriad Genetics has not allowed.

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Breast Cancer Action, a nonprofit advocacy group, called the decision a "tremendous win for women's health — and for all our health!" They echoed the sentiments of the ASCP, in that "Myriad's monopoly is broken and other labs can conduct testing, perform vital research, and develop treatments using the human BRCA1 and 2 genes."
Myriad also claimed victory because the Court upheld its claims on cDNA, and pointed out that the Court noted that many of Myriad's unchallenged claims are method claims applying knowledge about the BRCA1 and BRCA2 genes.
"We believe the Court appropriately upheld our claims on cDNA, and underscored the patent eligibility of our method claims, ensuring strong intellectual property protection for our BRACAnalysis test moving forward," said Peter D. Meldrum, president and CEO of Myriad. "More than 250,000 patients rely on our BRACAnalysis test annually, and we remain focused on saving and improving peoples' lives and lowering overall healthcare costs.

 "

A NICE EXAMPLE OF TARGETING THERAPY,

While one will quickly think of CML and the Gleevec story as a hit and run case (I really meant Home Run case) of successful targeting therapy, there is a forgotten case.   Secretly  but concretly established is the case of the GIANT CELL TUMOR OF THE BONE.  The condition is rare but can be a pain in the neck if you pardon my french!  In one percent of cases, it can even Metastasize!  Go figure! for what is described a "benign" disease
It is cause by the RANKL, those receptor that call the Osteoclast like cells to come in the theater and destroy the bone!  well we found DENOSUMAB, and it gave us 80% response rate. nothing to be ashamed about.   DENOSUMAB A GOOD TARGET THERAPY!


AND LIKE IN GOOD COMMERCIAL, THEY GIVE YOU IN SMALL PRINTS (yes but watch for headache,nausea,,hypocalcemia, hypophosphatemia and osteonecrosis of the jaw) AND HOPE YOU DID NOT SEE IT!

GENES IN SARCOMA (CONTINUE)

GNAS-1
This is the perfect example that intermediaries in a pathways can be critical
when a receptor is linked to its ligand, the chemical reaction goes nowhere without some G-protein taking the flash and transmitting this spark to Adenylate Cyclase.   When you see danger, you stand to fight back or run to safety because of GNAS gene.  Believe Me Adrenaline rush will no do you a thing without GNAS, the Gene is so important they gave a Nobel Prize to the guy who found it.
" . A Nobel Prize was awarded to Earl Sutherland in 1971 for discovering the key role of AC-III in human liver, where adrenaline indirectly stimulates AC to mobilize stored energy in the "fight or flight" response. The effect of adrenaline is via a G protein signaling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell (cytoplasm). The outside signal (in this case, adrenaline) binds to a receptor, which transmits a signal to the G protein, which transmits a signal to adenylate cyclase, which transmits a signal by converting adenosine triphosphate to cyclic adenosine monophosphate (cAMP). cAMP is known as a second messenger.^{[1]wikipedia"}
-----------------------------
And I have mentioned that any important gene give a deformity if missing,  this one does.  The name of the deformity

Polyostotic fibrous dysplasia, look it up!

In the brain GNAS-1 dances with important people such as RIC8 which has a nice name to fool you Synembryn-A,

mess with Synembryn A and brace yourself to deal with DGK-1, and EGL-30

to know more ask Klattenhoff!

Klattenhoff C, Montecino M, Soto X, et al. (2003). "Human brain synembryn interacts with Gsalpha and Gqalpha and is translocated to the plasma membrane in response to isoproterenol and carbachol.". J. Cell. Physiol. 195 (2): 151–7.

That is the pattern of cellular events, "start small and keep amplifying"

----------------------------------------another intermediary we spoke about was GNA12

there we discussed already the role of anti-CD44 and anti-P110 alpha

and its link to HSP90.  

Puzzled? go to article-blog! 

PONDERING ABOUT SARCOMA

GENETIC SYNDROMES ASSOCIATED WITH SARCOMA
1.  LI FREUMANI    ASSOCIATED WITH    P 53
2.  RETINOBLASTOMA  ASSOCIATED WITH Rb 1 DELETION
3. NEUROFIBROMATOSIS TYPE 1, WELL EASY   NF-1 MUTATION
4. GARDNER  SNDROME ASSOCIATED WITH APC MUTATION
5. McCUNE ALBRIGHT SYNDROME ASSOCIATED WITH GNAS-1 MUTATION
6. BLOOM, ROTHMUND THOMPSON &WERNER ASSOCIATED WITH LOSS OF HELICASE FUNCTION

ALSO

WELL DIFFERENTIATED LIPOSARCOMA IS LINKED TO AMPLIFICATION OF  MDM2, MUTATION IN CDK4  (AMPLIFICATION MEANS A CLEAR DRIVER GENE, REPRESSING THIS MAY HAVE AN EFFECT AS A THERAPEUTIC INTERVENTION, TRY IT!)

DID YOU KNOW THAT IN OSTEOSARCOMA, METASTASIS TO LYMPH NODES IS SO RARE THE DISEASE IS STAGE IV WHEN THIS HAPPEN?  CONVERSELY, LUNG METS CAN BE REMOVED AND SOME PEOPLE BELIEVE IT IS NOT STAGE IV (THAT'S WHAT HAPPEN WHEN POLITICIANS GETS INVOLVED IN SCIENCE!)  BUT THIS IS TRUE BELIEVE ME, CHECK IT OUT!


WITH THE HELICASE!  YOU'RE TALKING THE HELIX OF DNA
THERE IS THE SCIENCE IN DEPTH !
"Many cellular processes, such as DNA replication, transcription, translation, recombination, DNA repair, and ribosome biogenesis involve the separation of nucleic acid strands that necessitates the use of helicases."WIKIPEDIA

WHEN SOMEONE IS TALIKNG HELICASE, DROP EVERYTHING AND LOOK AT HIM
HE IS TALKING DNA SCIENCE! AND THIS IS SERIOUS BECAUSE SO MANY GENES ARE INVOLVED, BRAIN MALFORMATION AND MALFUNCTION ARE INVOLVED, AND MORE IMPORTANTLY APOPTOSIS (THE CURE) IS NOT FAR AWAY!
" These functions assist in prevention of apoptosis, resulting in cortical size regulation, as well as a contribution to the survival of hippocampal and cortical structures, affecting memory and learning.^[26] This helicase is located on the X chromosome (Xq13.1-q21.1)"  GENES ?  A SLEW INVOLVED!

Dear Colleagues:

 

On May 7, 2013, Governor Pence signed Senate Bill 415 mandating that on July 1, 2015, a provider that is licensed under Indiana Code 25 and who is authorized within the provider’s scope of practice to administer immunizations shall electronically provide immunization data to the immunization data registry for all immunizations administered to individuals who are less than nineteen (19) years of age.  This important legislative mandate will move Indiana closer to the Healthy People 2020 goal of properly immunizing children by creating a comprehensive immunization record of all administered vaccines. 

 

Please see the attached memo for additional information. 

 

William C. VanNess II, MD

State Health Commissioner

 HINTS OF TARGET THERAPY!  JUST DO IT AND THANK ME LATER!

Proposed cytosine cycle.

" Five-hydromethylcytosine (hmC) is generated from 5-methylcytosine (mC) through oxidation catalyzed by the TET family of oxygenases. HmC may then be deaminated by members of the AID/APOBEC family and the resulting 5-hydroxymethyluracyl (hmU) is excised by thymine–DNA glycosylase (TDG), or another DNA glycosylase. This initiates the base excision repair process (BER), leading to replacement of hmU by an unmethylated cytosine. Further oxidation of hmC by TET enzymes may lead to 5-formylcytosine (fC) or 5-carboxylcytosine (caC). These modified cytosines may be specifically recognized and excised by TDG, leading to subsequent BER activity. CaC may also be converted to cytosine by a not yet identified decarboxylase. Oxidation of mC may also impair their recognition by maintenance methyltransferase DNMT1 and allow replication-dependent demethylation. A: abasic (apurinic/apyrimidinic) site."(Mercher et al)
-----------------------------------------------------------------------------
Disruptive antibody

PDZK1 is a scaffold protein that connects plasma membrane proteins and regulatory components, regulating their surface expression in epithelial cells apical domains. It may be involved in the coordination of a diverse range of regulatory processes for ion transport and second messenger cascades. In complex with SLC9A3R1, it may cluster proteins that are functionally dependent in a mutual fashion and modulate the trafficking and the activity of the associated membrane proteins. It may also play a role in the cellular mechanisms associated with multidrug resistance through its interaction with ABCC2 and PDZK1IP1. May potentiate the CFTR chloride channel activity. PDZK1 functions to connect SCARB1 with the cellular machineries for intracellular cholesterol transport and/or metabolism and may be involved in the regulation of proximal tubular Na(+)-dependent inorganic phosphate cotransport therefore playing an important role in tubule function (life science research)
-------------------------------------------------------------------------------------------
IDAX gene blocks the devil (Dvl) and therefore the Wnt, and through Caspase 3, regulate the TET2.
Block the PDZ locus on the Devil and you can get Leukemia under control!

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

FOR ANGIOSARCOMA ,  GO TO YOUNG'S NOTE

II

Abstract

Background:

Angiogenesis is the process of new blood vessel formation

,

and is regulated by angiogenic growth factors

including vascular endothelial growth factor (VEGF)

.

Angiosarcomas are rare, aggressive vascular tumours

.

Studies were performed to investigate the expression of angiogenicgrowth factors in angiosarcoma

,

and to assess vascular targeted agents for the treatment of angiosarcoma

.

Methods:

In vitro studies compared

two human cutaneous angiosarcoma cell lines (ASM and ISO-HAS) with human dermal microvascular endothelial cells (HuD MECs).

The cell lines were compared in functional assays

,

including cell viability, cell differentiaiton and cell migration assays, and protein expression profiled using antibody arrays. Cell responses to vascular targeted agents were compared including response to bevacizumab an anti-VEGF antibody, axitinib a VEGFreceptor (VEGFR) tyrosine

kinase inhibitor

,

selumetinib a MEK inhibitor and DMXAA a vascular disrupting agent.'

 

CXCR4, THE CRBCM IS LOOKING INTO THIS!JUST GO AHEAD AND BRUSH UP WITH ME!

WIKIPEDIA!

'CXCR-4 is an alpha-chemokine receptor specific for stromal-derived-factor-1 (SDF-1 also called CXCL12), a molecule endowed with potent chemotactic activity for lymphocytes. This receptor is one of several chemokine receptors that HIV can use to infect CD4+ T cells. HIV isolates that use CXCR4 are traditionally known as T-cell tropic isolates. Typically, these viruses are found late in infection. It is unclear as to whether the emergence of CXCR4-using HIV is a consequence or a cause of immunodeficiency.
CXCR4 is upregulated during the implantation window in natural and hormone replacement therapy cycles in the endometrium, producing, in presence of a human blastocyst, a surface polarization of the CXCR4 receptors suggesting that this receptor is implicated in the adhesion phase of human implantation.
CXCR4's ligand SDF-1 is known to be important in hematopoietic stem cell homing to the bone marrow and in hematopoietic stem cell quiescence. Until recently, SDF-1 and CXCR4 were believed to be a relatively "monogamous" ligand-receptor pair (other chemokines tend to use several different chemokine receptors in a fairly "promiscuous" manner). Recent evidence demonstrates ubiquitin is also a natural ligand of CXCR4.^[3] Ubiquitin is a small (76-amino acid) protein highly conserved among eukaryotic cells. It is best known for its intracellular role in targeting ubiquitylated proteins for degradation via the ubiquitin proteasome system. Evidence in numerous animal models suggests ubiquitin is anti-inflammatory immune modulator and endogenous opponent of proinflammatory damage associated molecular pattern molecules.^[4] It is speculated this interaction may be through CXCR4 mediated signalling pathways.

Clinical significance

Drugs that block the CXCR4 receptor appear to be capable of "mobilizing" hematopoietic stem cells into the bloodstream as peripheral blood stem cells. Peripheral blood stem cell mobilization is very important in hematopoietic stem cell transplantation (as a recent alternative to transplantation of surgically harvested bone marrow) and is currently performed using drugs such as G-CSF. G-CSF is a growth factor for neutrophils (a common type of white blood cells), and may act by increasing the activity of neutrophil-derived proteases such as neutrophil elastase in the bone marrow leading to proteolytic degradation of SDF-1. Plerixafor (AMD3100) is a drug, recently approved for routine clinical use,^[5] which directly blocks the CXCR4 receptor. It is a very efficient inducer of hematopoietic stem cell mobilization in animal and human studies.
It has been associated with WHIM syndrome.^[6]
While CXCR4’s expression is low or absent in many healthy tissues, it was demonstrated to be expressed in over 23 types of cancer, including breast cancer, ovarian cancer, melanoma, and prostate cancer. Expression of this receptor in cancer cells has been linked to metastasis to tissues containing a high concentration of CXCL12, such as lungs, liver and bone marrow.^[7][8] However, in breast cancer where SDF1/CXCL12 is also expressed by the cancer cells themselves along with CXCR4, CXCL12 expression is positively correlated with disease free (metastasis free) survival. CXCL12 (over-)expressing cancers might not sense the CXCL12 gradient released form the metastasis target tissues since the receptor, CXCR4, is saturated with the ligand produced in an autocrine manner.^[9] Another explanation of this observation is provided by a study that shows the ability of CXCL12 (and CCL2) producing tumors to entrain neutrophils that inhibit seeding of tumor cells in the lung.^[10]

Drug response

Chronic exposure to THC increased T lymphocyte CXCR4 expression on both CD4+ and CD8+ T lymphocytes. ^[11]

Interactions

CXCR4 has been shown to interact with USP14.^[12]"
===========================================================
AND WHY?  READ THIS

IS THERE A RELATION WITH TRIPLE NEGATIVE BREAST CANCER?
HOW DOES STIMULATION OF CXR4 LINKED TO INTERFERON?
IS THERE CORRELATION WITH PSORIASIS? (PRSOS1?)  THESE ARE THE QUESTIONS WE ARE STRUGGLING WITH?

PATIENTS WITH EARLY STAGE BREAST CANCER RECEIVE AC FOLLOWED BY TAXOL ON AN EVERY 2 WEEKS BASES.  NOW IT IS REPORTED THAT THE TAXOL PORTION CAN BE GIVEN WEEKLY WITH LESS TOXICITY AND WITHOUT NEED FOR GROWTH FACTOR AND FOR SAME EFFICACY...TRY IT!

READ:""ONLINE FIRST: Early Breast Cancer: Less Toxicity, Similar Efficacy with Weekly Paclitaxel vs. Every-Two Week Regimen

BY RABIYA S. TUMA, PHD"(ONCOLOGY TIMES)

*FDA HAS APPROVED LENALINOMIDE FOR REFRACTORY MANTLE CELL LUMPHOMA
"Out of 133 patients who were evaluable for efficacy: 26% had an overall response; 7% achieved a complete response or an unconfirmed complete response; and 19% achieved a partial response. Median duration of response for the patients who achieved a complete, an unconfirmed complete, or a partial response was 16.6 months." PER ONCOLOGY TIME.

*AS THE INCIDENCE OF MELANOMA IS INCREASING, IT IS WELCOME NEWS THAT THERE IS PROGRESS IN THE MANAGEMENT OF THIS DISEASE, AND THE INTRODUCTION OF IPILIMUMAB AND VEMURAFENIB HAVE CHANGED NCCN GUIDELINES.
YET THE REPORTED 20 YEAR SURVIVAL IS STILL REPORTED AS

STAGE I        90%      WITH 10% OF PEOPLE DYING WITH THIS DISEASE
STAGE II        50%      WITH HALF OF THESE PATIENTS DYING OF MELANOMA
STAGE III       40%       WITH 60% DYING OF THE DISEASE
STAGE IV       5-10%    WITH 90-95 % DYING.

FOR A WHILE THERE, THERE WAS NO CHANGE OF SURVIVAL IN STAGE IV UNTIL THE ARRIVAL OF IPILIMUMAB, A T CELL ACTIVITY MODULATOR.
AND FOR THOSE BRAF POSITIVE, VEMURAFENIB IS AN OPTION.  REISTANCE TO BRAF CAN BE EXPECTED IF GENES DOWN STREAM ARE OVEREXPRESS. THIS IS WHERE MEK IS LOCATED, AND ADDING ANTI MEK (TRAMETINIB) TO ANTI-BRAF (DABRAFENIB) HAS BEEN SHOWN TO INCREASE RESPONSE RATE.   NOTABLY THE COMBINATION HAS LESS SKIN TOXICITY. BUT GET READY TO FIGHT PYREXIA IF YOU GO THIS WAY!

CONSIDER SENTINEL NODE DISSECTION IN PATIENT WHO'S LESION THICKNESS IS GREATER THAN 0.75mm.

MORE ABOUT 5-AZACITIDINE

Be careful though, when you give an hypomethylating agent, do not expect that the agent is de-methylating everywhere, some molecule end up being methylated, this is called Reverse Methylation.  There seem to me a random (or not) reorganization of the methylation.

Moreau
"Exposure of cells to histone deacetylase inhibitors, or to the demethylating agent 5-aza-2′-deoxycytidine, revealed that HLA-G gene transcription is inhibited by DNA methylation. Reversal of methylation-mediated repression may directly induce HLA-G cell-surface expression, supporting the idea that HLA-G might be activated by such a mechanism during malignancy, inflammation, and allogenic reactions"

what is the meaning of this
is this point to limitation of this drug activity
should we be checking for HLA-G
more work is ahead I guess!

HEIGHTS OF SPECULATIONS

It is generally said that infiltration of Lymphocytes in the tumor points to an immune response against the tumor and therefore imparts a good prognosis, and we did mention this earlier.  But now comes the mitigation to this message, when those lymphocytes are TREG cells the picture is not so clear any more...
"In cancer such as Breast Cancer, there are data that intratumoral Treg cells confer poorer prognosis, in colorectal cancer, Treg cells convey a better prognosis."(Clurman)  Just take a note of this!

Remember Treg are T cell regulators that "maintain tolerance by suppressing expansion of effector cells directed against self Antigen".  If tumors comes from you, than they can have "self Antigen" and will get away with it! and attack you, protected by these Treg cells!  Looking under these perspectives, it now becomes critical to know what Lymphocyte is in the tumor.  A Treg T cell or a true Activated T cell.   let's work at discerning these things before we comment on prognosis!

This point is very emphasized in clinical practice by the example of Ipilimumab.  It is said that its effect resides in the removal of (check point) inhibitory effects of a T cell Regulator (such as the Treg discussed here) CTLA4.  Removing these inhibitory influences unleashes the full might of the Activated T cell against the cancer.  But the side effect to this is that tolerance of normal tissue is low leading to immune attack of even normal tissue.  Cases of Colitis,dermatitis hepatitis, thyroid dysfunction and Stevens Johnson syndrome have been reported, so help you God, Colonic perforation even have been reported.   But yes it is one of the only drug which in recent years or decades, has improved survival in Melanoma, and that is a big first.