FROM MEDSCAPE

Important Safety Information  |   Full Prescribing Information

KADCYLA showed treatment benefit in HER2+ metastatic breast cancer (MBC) in overall survival (OS) and progression-free survival (PFS) vs lapatinib + capecitabine¹

For more details about these and other EMILIA trial endpoints, visit KADCYLA.com.

Indication

KADCYLA^® (ado-trastuzumab emtansine), as a single agent, is indicated for the treatment of patients with HER2-positive (HER2+), metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. Patients should have either:

• Received prior therapy for metastatic disease, or
• Developed disease recurrence during or within six months of completing adjuvant therapy

KADCYLA extended median OS by nearly 6 months¹

50% improvement in median PFS for KADCYLA vs lapatinib + capecitabine¹

• 9.6 months vs 6.4 months; HR=0.650; 95% CI: 0.549, 0.771; P<0.0001

Important Safety Information

Boxed WARNINGS: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY

• Do Not Substitute KADCYLA for or with Trastuzumab
• Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin
• Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function
• Embryo-Fetal Toxicity: Exposure to KADCYLA can result in embryo-fetal death or birth defects. Advise patients of these risks and the need for effective contraception

Additional Important Safety Information

Left Ventricular Dysfunction (LVD)

• Patients treated with KADCYLA are at increased risk of developing LVD. In EMILIA, LVD occurred in 1.8% of patients in the KADCYLA-treated group and in 3.3% in the comparator group. Permanently discontinue KADCYLA if LVEF has not improved or has declined further

Pregnancy Registry

• Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. Encourage women who may be exposed to KADCYLA during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720

Pulmonary Toxicity

• Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratory distress syndrome or fatal outcome have been reported in clinical trials with KADCYLA. In EMILIA, the overall frequency of pneumonitis was 1.2%
• Treatment with KADCYLA should be permanently discontinued in patients diagnosed with ILD or pneumonitis

Infusion-Related Reactions, Hypersensitivity Reactions

• Treatment with KADCYLA has not been studied in patients who had trastuzumab permanently discontinued due to infusion-related reactions (IRR) and/or hypersensitivity reactions; treatment with KADCYLA is not recommended for these patients. In EMILIA, the overall frequency of IRRs in patients treated with KADCYLA was 1.4%
• KADCYLA treatment should be interrupted in patients with severe IRR and permanently discontinued in the event of a life-threatening IRR. Patients should be closely monitored for IRR reactions, especially during the first infusion

Thrombocytopenia

• In EMILIA, the incidence of ≥ Grade 3 thrombocytopenia was 14.5% in the KADCYLA-treated group and 0.4% in the comparator group (overall incidence 31.2% and 3.3%, respectively)
• Monitor platelet counts prior to initiation of KADCYLA and prior to each KADCYLA dose. Institute dose modifications as appropriate

Neurotoxicity

• In EMILIA, the incidence of ≥ Grade 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the comparator group (overall incidence 21.2% and 13.5%, respectively)
• Monitor for signs or symptoms of neurotoxicity. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2

HER2 Testing

• Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA. Perform using FDA approved tests by laboratories with demonstrated proficiency

Extravasation

• In KADCYLA clinical studies, reactions secondary to extravasation have been observed and were generally mild. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration. Specific treatment for KADCYLA extravasation is unknown

Nursing Mothers

• Discontinue nursing or discontinue KADCYLA taking into consideration the importance of the drug to the mother

Adverse Reactions

• The most common ADRs seen with KADCYLA in EMILIA (frequency > 25%) were nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI-CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue

You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.

Click here for full Prescribing Information for additional important safety information, including Boxed WARNINGS.

Reference: 1. KADCYLA Prescribing Information. Genentech, Inc. May 2013.

© 2013 Genentech USA, Inc. All rights reserved. TDM0001957100
Genentech USA, Inc.
1 DNA Way
South San Francisco, CA
94080-4990

FDA PAGE on scleroderma!

"FDA approves Opsumit to treat pulmonary arterial hypertension
The U.S. Food and Drug Administration today approved Opsumit (macitentan), a new drug to treat adults with pulmonary arterial hypertension (PAH), a chronic, progressive and debilitating disease that can lead to death or the need for lung transplantation.
PAH is high blood pressure that occurs in the arteries that connect the heart to the lungs. It causes the right side of the heart to work harder than normal, which can lead to limitations on exercise ability and shortness of breath. Opsumit belongs to a class of drugs called endothelin receptor blockers, which act to relax the pulmonary arteries, decreasing blood pressure in the lungs.

Opsumit’s safety and effectiveness were established in a long-term clinical trial where 742 participants were randomly assigned to take Opsumit or placebo. The average treatment duration was about two years. In the study, Opsumit was effective in delaying disease progression, a finding that included a decline in exercise ability, worsening symptoms of PAH or need for additional PAH medication.
Similar to other members of its drug class, Opsumit carries a Boxed Warning alerting patients and health care professionals that the drug should not be used in pregnant women because it can harm the developing fetus. Female patients can receive the drug only through the Opsumit Risk Evaluation and Mitigation Strategy (REMS) Program. This restricted-distribution program requires prescribers to be certified by enrolling in the program; all female patients to be enrolled in the program and comply with applicable pregnancy testing and contraception requirements before initiating treatment; and pharmacies to be certified and to dispense Opsumit only to patients who are authorized to receive it.
Common side effects observed in those treated with Opsumit include low red blood cell count (anemia), common cold-like symptoms (nasopharyngitis), sore throat, bronchitis, headache, flu and urinary tract infection.
Opsumit is marketed by San Francisco-based Actelion Pharmaceuticals US, Inc."

GO TO FDA PAGE WHERE THIS NEWS COMES FROM!

speculative gene Biomarkers!

Can amplification of FAK gene predicts for higher risk of Bacterial endocarditis in the right scenario patient?
can FAK level be an important biomarker for healing, senescence monitoring as it could be a result of cytokine effect, of general health status?
DOES FAK EXPRESSION INCREASE BACTERIAL ATTACHMENT OR INCREASE THROMBOTIC STATE?

CYTOKINE STORM!

Now comes an interesting observation, a cytokine storm can be observed when an antibody attacks the CD3 receptor such as achieved by OKT3.  There is a massive cytokine release  leading to fevers,nausea,vomiting severe headche chest pain,dyspnea and even pulmonary edema. and this syndrome is triggered by the engagement by OKT3 of TCR.  Go figure, these Cytokine are really the effectors of disease!  The affect immunity deeply, always give CMV prophylaxis if you go with the OKT3 option!
WHAT IS IT ABOUT CD3 THAT MAKES IT SO SPECIAL IN STORM TRIGERRING, THE COMPANY IT KEEPS?

THE WORLD OF CYCLINS HAS ABUNDANT INTEREST!

SOME OF THE MANY IMPLICATIONS, /THE IMPACT AND INTEREST BY RESEARCHERS THAT CAUGHT OUR ATTENTION AT CRBCM!

Actions of the chemotactic cytokines MCP-1, MCP-2, MCP-3, RANTES, MIP-1α and MIP-1β on human monocytes

1. Mariagrazia Uguccioni,
2. Massimo D'Apuzzo,
3. Marcel Loetscher,
4. Beatrice Dewald,
5. Marco Baggiolini^*

The activities of six synthetic CC chemokines, MCP-1, MCP-2, MCP-3, RANTES, MIP-1α and MIP-1β on human blood monocytes were studied. All CC chemokines elicited a bimodal migration response in vitro. Highest numbers of migrating cells were obtained with the monocyte chemotactic proteins (MCP) and RANTES, somewhat lower numbers with MIP-1α, and only weak migration with MIP-1β. The most potent attractants were MCP-1 and MIP-1α which reached maximum efficacy at 0.1 to 1 nM. All CC chemokines also induced the release of N-acetyl-β-D-glucosaminidase from cytochalasin B-pretreated monocytes. The MCP were most effective (MCP-1 > MCP-3 > MCP-2), RANTES and MIP-1α showed moderate (1/3 of MCP-1 activity), and MIP-1β only minimal activity. Cytosolic free Ca²⁺ changes and exocytosis were used to monitor receptor desensitization. Marked cross-desensitization was observed among MCP-1, MCP-2 and MCP-3 on the one hand, and RANTES, MIP-1α and MIP-1β on the other, indicating receptor sharing within these two subgroups of CC chemokines. The responses to RANTES, MIP-1α and MIP-1β were also moderately to markedly desensitized by pretreatment with MCP-1, MCP-2 or MCP-3, while the responses to the MCP were virtually unaffected by pretreatment with RANTES, MIP-1α and MIP-1β. These results suggest that the MCP also interact with receptors recognized by RANTES, MIP-1α and MIP-1β, but not vice versa. Binding studies were performed with radiolabeled MCP-1 or MIP-1α. All MCP competed readily for labeled MCP-1 yielding a concentration-dependent sigmoidal displacement curve. Displacement with RANTES, MIP-1α and MIP-1β was observed at higher concentrations, but was not complete. Radiolabeled MIP-1α was displaced efficiently by MIP-1α or MIP-1β, but only partially by RANTES. Of the MCP, only MC-3 completely displaced MIP-1α, while only partial displacement was observed with MCP-1 and MCP-2.
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Monocyte chemoattractant protein-1-induced CCR2B receptor desensitization mediated by the G protein-coupled receptor kinase 2

A. M. Aragay,^*† M. Mellado,^†‡ J. M. R. Frade,^†‡ A. M. Martin,^‡ M. C. Jimenez-Sainz,^* C. Martinez-A,^‡ and F. Mayor, Jr.^*§

Author information ► Article notes ► Copyright and License information ►

This article has been cited by other articles in PMC.

Go to:

Abstract

Monocyte chemoattractant protein 1 (MCP-1) is a member of the chemokine cytokine family, whose physiological function is mediated by binding to the CCR2 and CCR4 receptors, which are members of the G protein-coupled receptor family. MCP-1 plays a critical role in both activation and migration of leukocytes. Rapid chemokine receptor desensitization is very likely essential for accurate chemotaxis. In this report, we show that MCP-1 binding to the CCR2 receptor in Mono Mac 1 cells promotes the rapid desensitization of MCP-1-induced calcium flux responses. This desensitization correlates with the Ser/Thr phosphorylation of the receptor and with the transient translocation of the G protein-coupled receptor kinase 2 (GRK2, also called β-adrenergic kinase 1 or βARK1) to the membrane. We also demonstrate that GRK2 and the uncoupling protein β-arrestin associate with the receptor, forming a macromolecular complex shortly after MCP-1 binding. Calcium flux responses to MCP-1 in HEK293 cells expressing the CCR2B receptor were also markedly reduced upon cotransfection with GRK2 or the homologous kinase GRK3. Nevertheless, expression of the GRK2 dominant-negative mutant βARK-K220R did not affect the initial calcium response, but favored receptor response to a subsequent challenge by agonists. The modulation of the CCR2B receptor by GRK2 suggests an important role for this kinase in the regulation of monocyte and lymphocyte response to chemokines.

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Proteasomal regulation of betac signaling reveals a novel mechanism for cytokine receptor heterotypic desensitization.

Martinez-Moczygemba M, Huston DP.

Source

Baylor College of Medicine, Departments of Medicine and Immunology, Biology of Inflammation Center, Houston, Texas 77030, USA.

Abstract

IL-5, IL-3, and GM-CSF are hematopoietic cytokines that are key mediators of the allergic inflammatory response. The receptors for these three cytokines consist of a cytokine-specific alpha (Ralpha) chain and a shared common beta (betac) chain. Herein, we demonstrate that agonistic ligation of these receptor subunits rapidly induces proteasomal degradation of the betac, but not the Ralpha, cytoplasmic domain, resulting in termination of signal transduction and yielding a truncated betac isoform ligated to the Ralpha subunit. Proteasomal degradation of the betac cytoplasmic domain was also a prerequisite for endocytosis and lysosomal degradation of the ligated receptor subunits. Moreover, proteasome-dependent termination of signaling induced by one betac-engaging cytokine resulted in cellular desensitization to signal transduction by subsequent stimulation with another betac-engaging cytokine. These data provide the first evidence for ligand-dependent proteasomal degradation of the betac cytoplasmic domain, and they establish a novel mechanism for heterotypic desensitization of shared cytokine receptor signaling.

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Proteasomal regulation of βc signaling reveals a novel mechanism for cytokine receptor heterotypic desensitization

Margarita Martinez-Moczygemba and David P. Huston

Author information ► Article notes ► Copyright and License information ►

This article has been cited by other articles in PMC.

Go to:

Abstract

IL-5, IL-3, and GM-CSF are hematopoietic cytokines that are key mediators of the allergic inflammatory response. The receptors for these three cytokines consist of a cytokine-specific α (Rα) chain and a shared common β (βc) chain. Herein, we demonstrate that agonistic ligation of these receptor subunits rapidly induces proteasomal degradation of the βc, but not the Rα, cytoplasmic domain, resulting in termination of signal transduction and yielding a truncated βc isoform ligated to the Rα subunit. Proteasomal degradation of the βc cytoplasmic domain was also a prerequisite for endocytosis and lysosomal degradation of the ligated receptor subunits. Moreover, proteasome-dependent termination of signaling induced by one βc-engaging cytokine resulted in cellular desensitization to signal transduction by subsequent stimulation with another βc-engaging cytokine. These data provide the first evidence for ligand-dependent proteasomal degradation of the βc cytoplasmic domain, and they establish a novel mechanism for heterotypic desensitization of shared cytokine receptor signaling.

Collaborative role of E2F transcriptional activity and G1 cyclindependent kinase activity in the induction of S phase.

Leone G, DeGregori J, Jakoi L, Cook JG, Nevins JR.

Source

Department of Genetics, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.

Abstract

A considerable body of evidence points to a role for both cyclin E/cyclin-dependent kinase (cdk)2 activity and E2F transcription activity in the induction of S phase. We show that overexpression of cyclin E/cdk2 in quiescent cells induces S phase, that this coincides with an induction of E2F activity, and that coexpression of E2F enhances the cyclin E/cdk2-mediated induction of S phase. Likewise, E2F overexpression can induce S phase and does so in the apparent absence of cyclin E/cdk2 activity. In addition, although the inhibition of cyclin E/cdk2 activity blocks the induction of S phase after growth stimulation of normal mouse embryo fibroblasts, inhibition of cyclin E/cdk2 does not block S phase induction in Rb-/- cells where E2F activity is deregulated. These results point to the important roles for E2F and cyclin E/cdk2 in the induction of S phase. Moreover, the nature of the E2F targets and the suspected targets for cyclin E/cdk2 suggests a potential molecular mechanism for the collaborative action of cyclin E/cdk2 and E2F in the induction of S phase.

STATE OF UNSTABLE HOMEOSTASIS: are your cytokines in a balanced state?

You can be thin, you can be average, you BETTER NOT BE OBESE LIKE SOME OF US!  What is important a question is "are your cytokine in balanced state".  Yesterday I met a man who run 7 miles a day, looks fit like a young marine (he is 68 years old) he showed me a certificate he earned from climbing the Kilimajaro a month ago, (If you go to Kilimanjaro get me an extra certificate!) but he was unhappy!  He indeed has noted that he can't built his muscle up, has been losing weight without dieting, and now has tingling sensations in the fingers bilaterally,  A buff of nutrition, he has been consuming a bunch of Vitamin B (B1,B6, B12 and the so called "complex") to no avail.  His neurologist at a loss. Neck radiology clean and Carpal tunnel syndrome Ruled out, I told him its all about the Cytokines!
How do I know about my cytokine state? he asked...
"If you arrived at that question, you understand the crux of the problem" NOBODY MEASURE THE CYTOKINES IN A CLINICAL USEFUL WAY EVEN THOUGH THEY ARE THE EFFECTOR OF ALL PHYSIOLOGIC STATES!
IF YOU LOOK HEALTHY BUT YOUR CYTOKINES IS HIGH, YOU WILL END UP DYING PREMATURELY BECAUSE OF YOUR HOMEOSTASIS IS BASED ON FOUL STATE OF CYTOKINES!  LET BE ANADID ABOUT THIS!  SOON OR LATER, THE UNRAVELING WILL HAPPEN.  WHY, BECAUSE CYTOKINES STIMULATES MANY OTHER UNINTENDED  RECEPTORS, GENES, PATHWAYS AND MORE CYTOKINES!

Activities at CRBCM
One may have noted the slowing down of blog activiTy
we are are planning to sit one more time for Boards
and it is a time occupying deal
CRBCM is meeting contractual obligation in El Paso, same as it did in Houston,
and Austin and Indiana. Now for the forseeable  6-8 weeks we are anchordown in El Paso.
Business getting stronger.
We are excited about the first about, the 1st Biomed research conference, join us!

	A Message from Medical Center of the Americas: Dear Attendees: We look forward to seeing you at the region’s upcoming BIOMED Symposium on October 26, 2013. Pre-Symposium Networking Mixer We would like to invite you to our Pre-Symposium Networking Mixer on October 25, 2013 from 5:30pm-7:30pm at the El Paso Club located at 201 East Main Drive, Suite 1204 in Downtown El Paso. Network with over 200 of the region’s researchers, clinicians and nurses, future leaders and other healthcare professionals. Symposium Venue & Hotel Accommodations Venue The 1st Annual BIOMED Symposium will be held at Camino Real Hotel located at 101 South El Paso Street in Downtown El Paso. Accommodations We have reserved a block of rooms at the Camino Real Hotel located at 101 South El Paso Street and DoubleTree Hotel located at 600 North El Paso Street in Downtown El Paso at a discounted rate. Please make hotel reservations as soon as possible, as we anticipate the hotels to fill up fast. When you call to make a reservation, please indicate to the hotel clerk that you are making a reservation for the “BIOMED Symposium” so that you receive the discounted rate. Symposium Directions & Parking Directions To Camino Real Hotel from Del Sol Medical Center (Driving) Head southeast on Gateway Blvd E Slight left toward Gateway Blvd W Slight left onto Gateway Blvd W Slight left onto the I-10 W ramp Merge onto I-10 Take exist 22B for US-54 toward Patriot Frwy/Alamogordo/Juarez/Ft Bliss Keep left at the fork, follow sings for Juarez and merge into I-110 S Turn right onto the ramp to US-62 W/E Paisano Dr Keep left at the fork, follow signs for US 62 W and merge onto US-62 W/E Paisano Dr Turn right onto S El Paso St The hotel will be on the left To Camino Real Hotel from Texas Tech University Health Sciences Center (Driving) Head west on Alberta Ave toward Fulton Pl Take the 1st left onto Boll Pl Turn right onto Alameda Ave Turn left onto S Copia St Take the ramp onto E Paisano Dr Turn right onto S El Paso St The hotel will be on the left  To Camino Real Hotel from University of El Paso (Driving) Head southeast on Hawthorne St Turn left onto W Yandell Dr Continue onto N Santa Fe St Turn left onto W San Antonio Ave Turn left onto S El Paso St The hotel will be on the left  To Camino Real Hotel from New Mexico State University (Driving) Head west on N Horseshoe St toward S Espina St Take the 1st right onto NM-138 E/S Espina St Take the 1st right onto E University Ave Merge onto I-25 S via the ramp to El Paso Merge onto I-10 E Take exit 19 toward Downtown/Convention Center/Tourist Information Museums Turn right onto N Santa Fe St Turn left onto W San Antonio Ave Turn left onto S El Paso St The hotel will be on the left  To Camino Real Hotel from New Mexico Institute of Mining and Technology (Driving) Head north on Leroy Pl toward College Ave Take the 2nd right onto Bullock Blvd Turn left onto California St Merge onto I-25 S via the ramp to Las Cruces Merge onto I-10 E Take exit 19 toward Downtown/Convention Center/Tourist Information Museums Turn right onto N Santa Fe St Turn left onto W San Antonio Ave Turn left onto S El Paso St The hotel will be on the left To Camino Real Hotel from Instituto Technologico y de Estudios Superiores de Monterrey, Campus Chihuahua (Driving) Head north on Av Heroico C. Militar toward M. Aguilar Saenz Take the 3rd left onto Calle Mercurio Turn right onto Ave. Tecnologico Continue onto Chihuahua-Miguel/Ahumada/Mexico 45 Continue onto Av 16 de Septiembre Turn right toward Juarez Turn left at Gral Rivas Guillen Turn right onto Juarez Continue onto S El Paso St The hotel will be on the left To Camino Real Hotel from DoubleTree Hotel (Walking) Head southwest on E Franklin Ave toward N Santa Fe St Turn left onto N Santa Fe St Turn left onto Sheldon Ct Turn right onto S El Paso St The hotel will be on the right Parking Parking is available at the Camino Real Hotel parking lot and is first-come first-served basis. The rate for the day is $4. Additional parking is available at nearby garages for a charge and free parking is available on the street. Please contact me at nsehgal@bmiamericas.org if you have any additional questions. We look forward to seeing you at the Symposium. Sincerely, Neyha Sehgal | Assistant Director of Market Analysis BioMedical Institute of the Americas 201 East Main Street, Suite 401 (P): (915) 773-5804 (F): (915) 231-1949       BIOMED - MCA Biomedical Research Symposium Hosted by Medical Center of the Americas Saturday, October 26, 2013 from 7:30 AM to 6:00 PM (PDT) Camino Real Hotel - Downtown El Paso, 101 South El Paso Street, El Paso, TX 79901  |  Directions  Print Registration Summary  Contact the Host Download Mobile Registration

This invitation was sent to drkcancerclinic@gmail.com by Medical Center of the Americas the organizer. To stop receiving invitations from this organizer, you can unsubscribe.
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11 GENES AND RELATED COMPOUND TO INVESTIGATE IN SARCOMA

1. TGF BETA 1
2.SOST GENE
3.LIPOFUSCIN
4.RANKL AND RANK
5.CHLORIDE CHANNEL GENE
6 CTSK GENE
7.PORCN GENE
8. LEMD3
9. GNAS GENE
10. FGFR 3
11, INSULIN

THESE ARE MALFORMATION INDUCING GENES.
THE MOST DANGEROUS ARE THE ONE CONNECTED TO ANGIOGENIC GENES, THEY RAISE THE STAKE! LET'S FIND THEM!

PREDICTING OSTEONECROSIS OF THE JAW? THE CYTOKINE WORLD

CAN LEVEL OF PYRIDINOLINE,  (ALKALINE PHOSPHATSE) AND PRIOR EXPOSURE TO MEASLE (OR PARAMYXOVIRUS) PREDICT FOR OSTEONECROSIS OF THE JAW IN PATIENT RECEIVING BIOPHOSPHONATE?

ARE PATIENT WITH PAGET DISEASE PRONE TO OSTEONECROSIS OF THE JAW?

PAGET DISEASE IS THE BEST EXAMPLE OF CYTOKINE DRIVEN DISEASE IN THE ENTIRE WORLD OF DISEASES! (IL-1,IL-6,TNF, RANKL, OSTEOPROTEGERIN, TGF BETA-1 ETC.)

so you know or don't know!

Important Safety Information Prescribing Information www.fosrenol.com www.fosrenolontrack.com FOSRENOL (lanthanum carbonate) is indicated to reduce serum phosphate in patients with end stage renal disease. IMPORTANT SAFETY INFORMATION • FOSRENOL is contraindicated in patients with bowel obstruction, ileus, and fecal impaction. Click here to read more Important Safety Information This is a promotional message from DoctorDirectory.com on behalf of Shire. This material is intended specifically and exclusively for US Healthcare Professionals. Dear Mutombo Kankonde, MD: Dietary Challenges Associated with the Management of ESRD Struggling with the Renal Diet Ronald is a patient undergoing hemodialysis who has been receiving therapy three times weekly for the last 1.5 years. He is obese with a BMI of 33.0 and readily admits to having difficulty following dietary recommendations. Despite dietary intervention in the past, Ronald’s protein intake is high and his serum phosphorus is trending up. ...Is Ronald Ready for Noncalcium Binder Therapy? Start Noncalcium Binder Therapy with FOSRENOL (lanthanum carbonate) Efficacy in placebo-controlled trial7 aRandomized, double-blind, placebo-controlled, parallel-group trial evaluating the control of serum phosphorus with FOSRENOL (lanthanum carbonate) or placebo. Hemodialysis patients (N=126) with serum phosphorus >5.9 mg/dL after the predosing washout phase entered a 6-week, open-label FOSRENOL dose titration phase (750-mg initial daily dose divided with meals; titration up to 3000 mg in order to achieve phosphorus control [≤5.9 mg/dL]). Patients who entered the randomization phase were randomized to continue FOSRENOL (n=49) or received placebo (n=44) for 4 weeks. Mean serum phosphorus levels at the end of dose titration were 5.49 ± 1.48 mg/dL in patients subsequently randomized to continue FOSRENOL and 5.62 ± 1.61 mg/dL in patients subsequently randomized to placebo. Safety Information – Most common adverse events during randomized treatment were nausea (6.0% vs 4.5% [ FOSRENOL vs placebo]), vomiting (6.0% vs 2.3%), diarrhea (4.0% vs 6.8%), and dialysis graft occlusion (6.0% vs 2.3%) Sustained reduction of serum phosphorus in patients who remained on therapy8–10 Abbreviation: ITT, Intent to Treat aOptional 2-year extension phase of an initial 6-month, randomized, open-label trial comparing FOSRENOL (lanthanum carbonate) to calcium carbonate with a 6-month, open-label extension phase. Data shown are from patients who received FOSRENOL throughout the 3-year study. Dotted line represents the target for controlled serum phosphorus, defined as ≤ 5.6 mg/dL. • Phosphorus reductions maintained for up to 3 years (n=46) 8,9 Safety Information • Adverse events in long-term extension studies 9 – In the initial 6-month extension, 23% of patients discontinued because of adverse events; the most common adverse events included nausea (15%) vomiting (14%), diarrhea (12%), and hypotension (11%) – In the optional 2-year extension, 2.4% of adverse events led to withdrawal; the most common adverse events included diarrhea (4%), abdominal pain (3%), and nausea (3%) the content of this article has been removed.  it was not meant for public consumption! • • • • • • • • • •

The center role of cyclins/ NEED FOR A CYTOKINE UNIVERSTY

It is increasingly recognized that Cyclins are the ultimate effectors of health.  Yes the fascination with the DNA, its replication in cell division, its activities with RNA transcription which translate in protein formation, its very nature of keeping the the code of cellular destiny, all that is nice and dandy.   But beyond the genes, what will determine the state of your health, what makes live long, healthy or sick, what makes it happen, ARE THE STATE OF YOUR CYCLINS!
1.It is the cyclins that make you grow (growth factors)
2.It is the cyclins that control passage of stage to stage during  cell division  (the name CYCLIN-dependent Kinase-Cdk comes to mind..
3.It is the cyclins that makes obesity a disease
4.It is the that kick the kinase gene into motion
5.It is the cyclin that inhibit and promote...makes feminine or masculine...
6.It is the cyclins that kill post synaptic cell in Traumatic Brain Injury or strokes
7.It is the cyclins that call specific inflammatory cells to the theater of infection
8. It is the cyclins that determine the virulence or resistance (persitence of a cancer) of a cancer
9. It is through cyclin control that the NF-kB operates to insure survival and adaptation
10. It is through cyclins that some mutations occur, some genes are amplified or repressed and therefore entire pathways are affected,  and more importantly it is through the cyclins that some Receptors are desensitized!
It is through cyclins that Stem cells are stem cells!
It is through cyclins that old people look frail, their muscle hypotrophic!
when a cancer is uncontrollable such as melanoma and kidney cancer, give a cytokine ! (Interleukin-2 or Interferon!)
FOR MOST DEMENTIA TO DEVELOP! LOOK INTO THE CYTOKINS!

So with all this, it is surprising that we don't hear more about the Cyclins!
some are inhibitory, some are promoters, although they can belong to the same family
you die old or from infection because of the cytokines!
so it is a surprise that these no CYTOKINE UNIVERSITY!

HEAD IN THE SAND AGAIN, OR LOSS OF WHAT IS ESSENTIAL!

IT IS ALL ABOUT THE CYTOKINES!

The discovery of DNA and nuclear material has led to the emphasis on the alteration of Nuclear functions to fight cancer, indeed most of the original chemotherapy drugs had mechanisms of action centered on breaking or somehow impairing DNA.  This focus to a certain extent affected our judgement in the evaluation of certain drugs.  We are now finding out that the strength of certain drug  (and weakness /susceptibility to resistance) is not really due to their main effect on DNA (ie. epigenetic disturbances induced by  Etoposide).  The discovery that BCL-2 has a mechanism of resistance to certain drugs is point in case that nuclear material induced disturbances have significant limitations that occur away from the nucleus (at the Mitochondria).  Anti-proliferative chemotherapies have now shown their limits and scientists have kept this in our panoply of options against cancer.

Scientists have long been fascinated by the laws of nature, these driving forces that drive in certain ways or directions the chains of chemical reactions within the cells.  From Glycogenolysis to the Krebs' cycle, to the cellular pathways, role of enzymes these catalysts of chemical reaction and gene regulators, our focus has been progressively shifting.   The maximal effect of standard chemotherapy having been realized, the shift now has gone to driver Mutations, blocking pathways and modulating reactions etc.   But beyond the mutation, gene alterations and so forth, one thing that make a cancer spread like a wild fire is its stimulation by a growth factor, or its self dependence in achieving survival most of the time at very different levels of energy expenditure!  This role squarely falls into the area of epigenetics which is the critical area of Cytokine production determination.  Now, once produced, Cytokines, to be effective, must connect to their receptors!  This is where the wheels rub the asphalt to speed up the chemical reactions!

One of the mechanisms of increased cytokine production, aside from their gene amplification, is failure at the receptor.  Indeed, when a receptor fails, the normal reaction (law of nature) is to concur the resistance by sending more of the same cytokine.  While this increase could be partially succesful in restoring homeostasis depending on the level of abnormality at the receptor, the relative increase has other side effects due to the non specificity of receptors.  Co-receptors or other receptors susceptible to the same cytokine find themselves super excited and are driving downstream reactions at higher rates.  A SIGNIFICANT PHENOMENON NEEDS TO OCCUR AT THIS POINT, THAT IS THE DESENSITIZATION OF SECONDARY RECEPTORS, A TRAUMATIC PHENOMENON WITH POTENTIALLY NEOPLASTIC CONSEQUENCES   (TO BE CONTINUED)

WE BELIEVE IN THE CURE FOR BREAST CANCER

In this month of re-commitment to fighting Breast cancer, it is imperative to stop a while in a moment of reflection for those who have lost the fight, remind ourselves of who they were, what lives they touched as they made us who we are today in many ways.   I remember  my mother who was afflicted by this disease, a kind loving soul, who despite our number (family of 15) had managed to make all of us feel special.  I grew up truly believing that of all her kids, I was the one.  But talking to my other siblings, each one of us felt that special feeling! In 1974, 3 years before she was diagnosed and treated in Belgium, she added to my name a secret portion, "Muendela yenda" (the one who will walk alone) and here I am today, far from the country of origin, in  El Paso, Texas, the sole American Citizen of my family!  Preaching to a silent choir on this blog.  Breast cancer victims are our mothers, sisters, daughters and friends who have affected our lives in many ways. Survivors continue their paths and work touching our lives everyday, reminding us that our fight is needed and is just because there is a price to fight for.  Reminding us that until the cure happens, there is no stone that should remain unturned, no places we should not go, no politician we should not talk to, no genes,proteins, and other molecules that could make a difference we should not explore, poke and tease.  We could wander to other matters of our lives, but this month of October, we should renew our commitment to the fight for the cure of breast cancer.

Efforts made so far have made a meaningful difference, our eyes have opened to new dimensions of cancer research, and the belief in the cure has hardened because through advances in targeting therapy and genetic works, THE CURE IS MORE POSSIBLE, REACHABLE AND REAL!
All we need is cast off the doubt, stop infighting, keep the eyes open, and bring the cure to the shores of our daily reality! We have the means, we have the science, we are full of justified hope, let's keep on marching until the victory rings, making the CURE REAL, PALPABLE  AND ALIVE!

Another misunderstanding? the TGF story

One of the misunderstanding of common practitioner is related to the lack of appreciation of the extent of the impact of TGF or the extent of its actions!  The Tumor Growth factor effects are not limited to growth of cancer cells.  Their mission is not what their name means, remember the cells' aim is not to "grow" it is to survive.  Globally survival means expansion of life but it also means shutting down by inhibition any or most doors to Apoptosis.   In cancer Medicine, Growth factors are probably one of the biggest challenge to therapy because they are the impetus or one of the many driver for cancer resistance!  TGFs block for the cancer as many roads to programmed cell death as possible,  They also function as desensitizers by not only altering Receptors working against their mission, but epigenetically suppress all mechanisms working against them.  And they do this do this effectively by using the c-JUN and the NF-kB. and through their interactions with the Wnt, the Notch and the FAK.
The power and versatility of TGFs action lay in the fact in there no one TGF, but a family of TGFs with numbers attached to them (TGF1,2,3 etc).  And each member having a different effect,  some being completely opposed to each other but circumstances (including location) in the life of the cell will determine which family member will be at work at a given time.

ie. 

Identification of Novel TGF-β/Smad Gene Targets in Dermal Fibroblasts using a Combined cDNA Microarray/Promoter Transactivation Approach*

Franck Verrecchia‡et al!"Members of the TGF-β¹superfamily (activin, bone morphogenic proteins, TGF-βs, and decapentaplegic) are multifunctional cytokines that control various aspects of cell growth and differentiation and play an essential role in embryonic development, tissue repair, or immune homeostasis (1, 2). In addition, TGF-β is the prototypic fibrogenic cytokine, enhancing extracellular matrix (ECM) gene expression and down-regulating that of matrix-degrading enzymes. Increased expression of TGF-β is often associated with fibrotic states and abnormal accumulation of ECM proteins in affected tissues (3-6). The TGF-βs signal via serine/threonine kinase transmembrane receptors, which phosphorylate cytoplasmic mediators of the Smad family (7-9). The ligand-specific Smad1, Smad2, Smad3, and Smad5 interact directly with, and are phosphorylated by, activated TGF-β receptors type I. Smad1 and Smad5 are specific for bone morphogenic proteins, whereas Smad2 and Smad3 can be activated by both TGF-β and activin receptors. Receptor-activated Smads are kept in the cytoplasm in the basal state bound to the protein SARA (Smad anchor forreceptor activation) (10). Upon phosphorylation at their SSXS carboxyl-terminal motif, they are released from SARA and form heteromeric complexes with Smad4, a common mediator for all Smad pathways. The resulting Smad heterocomplexes are then translocated into the nucleus where they activate target genes, binding DNA either directly or in association with other transcription factors. Members of the third group of Smads, the inhibitory Smads, Smad6 and Smad7, prevent phosphorylation and/or nuclear translocation of receptor-associated Smads (7-9)."
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IE.WATCH "ACTIVIN" BECAUSE

"

The ACVRL1 gene provides instructions for making a protein called activin receptor-like kinase 1. This protein is found on the surface of cells, especially in the lining of developing arteries.
The ACVRL1 protein is a receptor. It acts as a "lock" waiting for a specific protein, called its ligand, to serve as the "key." In the case of the ACVRL1 protein, the ligand is called transforming growth factor beta. The interaction between these proteins plays a role in the development of blood vessels. In particular, this protein interaction is involved in the specialization of new blood vessels into arteries or veins."

 ACVR2A has been shown to interact with INHBA,^[4][5] SYNJ2BP^[6][7] and ACVR1B.<sup>[8][9]

=================================================THROUGH IN SYNJ2BP,</sup> 


SYNJ2BP has been shown to interact with LRP2,^[3] ACVR2B,^[1] ACVR2A^[1][4] and LRP1.<sup>[3]


=========================================================THROUGH  LRP1</sup>

 LRP1 has been shown to interact with Apolipoprotein E,^[11][12] Lipoprotein lipase,^[13][14][15] Urokinase receptor,^[16] MAPK8IP2,^[17] Tissue plasminogen activator,^[18][19] Thrombospondin 1,^[20][21][22] SYNJ2BP,^[17] DLG4,^[17] NOS1AP,^[17] calreticulin,^[23] APBB1,^[24] ITGB1BP1,^[17] MAPK8IP1,^[17] GIPC1^[17] and SHC1.^[25][26]


 SHC-transforming protein 1 is a protein that in humans is encoded by the SHC1 gene.^[1] SHC has been found to be important in the regulation of apoptosis and drug resistance in mammalian cells.
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THAT'S HOW YOU FIND OUT HOW TGF WORKS TO BLOCK APOPTOSIS!
ACTIVIN IS A MALFORMATION INDUCING GENE
IT IS BOUND TO INHIBIN A BAD PROGNOSIS BIOMARKER IN GERM CELL CANCER
IT HAS A LINK TO ANGIOGENESIS (DOES AVASTIN WORKS HERE?)
WANT TO GO AFTER SHC1, BE MY GUEST!
IF WE ARE TREATING CANCER PATIENTS LIKE WE DO TODAY WITHOUT LOOKING AT THE CANCER CYTOKINES, WE ARE MISSING THE BIG PICTURE!

WE THANK THE NIH, MDHONORS, AND WIKIPEDIA FOR THEIR CONTRIBUTION TO SCIENCE AND PROGRESS  TOWARD THE CURE  (WE HOLD OFF ON OTHER FUNDING SOURCES )