INTERESTING DEBATES

1.NF1 Mutation is upstream from
BRAF
and MTOR
But NF-1 is Mutated in Melanoma
can infusion of protein resulting from NF-1 be used to strengthen effect of MTOR inhibitor and BRAF inhibitor by maintaining these pathways open!

2.  Discriminating Redundancy in cellular language
same gene base corresponding to same Amino Acid
same receptors at membrane being sensitive by different stimuli
but when it comes to the RAS, nature and intensity need to matter and this also a function of tissue involved!
some time however the nature of the stimulus is more important particularly inside the cell where ie HP90 seems to stimulate more the CoN to achieve PTEN suppression. And you know that CoM stimulation raise Bcl2 level...we will say more in our upcoming article of langaue of the cell as it pertains to pathways!

3. PTEN is repressed by low expression of gene or mislocalization (reported PNUTS 'role) at Nuclear level or both?

POLYUBIQUITINATION

The rise of the role of antiproteasome in the treatment of hematologic malignancies such Multiple Myeloma
requires us to stop a bit and reflect on the basic role of proteasomes which is to destroy used proteins.  To be recognized as old proteins ready for destruction, the protein is Ubiquitinated and ready for disposal.  The anti-proteasomes in effect block this plan.  And sure enough, Ubiquitinated proteins stay alive longer and guess what, it is an ubiquitinated proteins that seems to contribute to the negative effect on Modulators of pathways.   Ubiquitinated proteins forms stops transcriptions factors at check points, block the NF-kB, and drives the effects of Antiproteasomes.
Can a simple infusion of ubiquitinated TNF blocks its effects, can we start just ubiquitinating growth factors and infuse them to stop infectious process or cancer growth?  Remember, DRIVER Pathways are driven most of the time by regulators who seems to have a negative feedback from UBIQUITINATED specific pathway proteins in general terms (rare exception will exist)! What do you think?  Can a polyubiquitinated growth factor still stimulate effectively its receptor or will it dampen the stimulation and slow the devastating effect of say, TNF?

 

Study: Beta-Blockers May Help Lung Cancer Patients Live Longer By Anna Azvolinsky, PhD1 | January 11, 2013 1Freelance Science Writer and Cancer Network Contributor. Follow Her on Twitter Lung cancer patients who take beta-adrenergic receptor antagonists (beta-blockers) may survive longer and have a lower rate of tumor spread. This is the result of a retrospective study of 722 non–small-cell lung cancer (NSCLC) patients published in Annals of Oncology. Ball-and-stick model of the beta-blocker propranolol(Drug information on propranolol NSCLC patients who were taking beta-blockers for an independent condition during their radiotherapy cancer treatment had a 22% improved survival compared to patients not taking beta-blockers after adjustment for factors such as age, disease stage, and concurrent chemotherapy. Patients on beta-blockers survived 23.7 months compared to 18.6 months for patients who were not taking the drugs. Beta-blockers target the beta receptors on heart muscles and smooth muscles and are commonly prescribed for hypertension, cardiac arrhythmias, and as secondary prevention after a heart attack. Zhongxing Liao, MD, and Daniel Gomez, MD, both from the department of radiation oncology at the MD Anderson Cancer Center in Houston, and colleagues compared outcomes of those NSCLC patients being treated with radiotherapy as their main line of treatment who were either not taking or regularly taking beta-blockers to treat another unrelated condition. While beta-blockers didn’t influence the locoregional progression-free survival, the 155 patients on beta-blockers at the time of their radiotherapy lung cancer treatment had better distant metastasis-free survival (P < .01) and disease-free survival (P < .01) compared to the 567 patients not taking beta-blockers. When adjusting for other factors including age, performance status, histology, concurrent chemotherapy, total tumor volume, stage of disease, those on beta-blockers did better in terms of distant metastasis-free survival (hazard ratio [HR], 0.67; P = .01), disease-free survival (HR, 0.74; P = .02), and overall survival (HR, 0.78; P = .02). There was no correlation, however, with locoregional progression-free survival (HR, 0.91, P = .63). There is nothing unique about the combination of radiation therapy as a modality and beta-blocker usage, according to Gomez. “It would not be unreasonable to propose that these results may be extrapolated to other modalities, such as chemotherapy or surgery.” This study is the first to show a link between improved survival and beta-blocker usage in lung cancer patients. Similar retrospective results have been shown for breast cancer, including triple-negative breast cancer and melanoma. Previous studies have also shown that beta-blockers may have antitumor activity, including in lung cancer models. One previous retrospective lung cancer study did not show any benefit of beta-blockers on patient outcomes. The authors note that the study did not take into account any other clinical factors other than beta-blocker usage and excluded patients with chronic obstructive pulmonary disease or coronary heart disease, both of which are common among cancer patients. Further studies, including prospective trials are needed to follow up and confirm these results. Weakness of the current study include missing data of other medications the patients may have taken during their cancer, data from only a single institution, and lack of data on beta-blocker usage prior to and post-radiation therapy. How beta-blockers may affect metastasis is not clear but may help to suppress chronic stress conditions that result from stress hormones, which have been shown to facilitate the spread of tumor cells from their primary site of origin. “We hypothesize that the mechanism of this benefit is by blocking the beta-adrenergic signaling pathway,” said Gomez. It has been demonstrated in both tissue culture and animal model experiments that blocking this pathway can affect the spread and growth of tumors. “Future molecular studies will help us to understand if the mechanism that we propose is correct, and thus if beta-blockers are indeed directly affecting the aggressiveness of this malignancy, or if these findings are due to the activation or inhibition of another pathway,” said Gomez.

Managing the loopholes in the cell cycle

Cure to cancer is within reach and is within the management of LOOPHOLES. Cancer cells have within their pathways, redundancy that protects these pathways to maintain life of the malignant cell. You close one door, just to see another one open up to ensure that the life of the cancer cell is maintained. So, unless you hit a critical pathway with no escape routes, the treatment result will be partial and temporary. To succeed we need to hit several targets in total and and sometimes sequentially to impose on the cell to choose the path to its natural death (apoptosis). So most treatments which are limited to one or only a few targets prove partially and temporary effective. This is why building an electronic Cell and being able to put in all the pathways and observe where they lead to, what doors open and which ones are closed or closing, which are critical and which lead to apoptosis (natural cell death) is crucial. Which sequence of shut down leads to sure cell death? Right now we are at the step where we are learning about shutting or opening one door and evaluating the sequence of events that follow. But with our model in hand, we can be more comprehensive in our approach. The model will help determine effects on cancer cells by shutting several doors at once, "closing Loopholes" as Tax people would love to say. This approach with target therapy has led to breaking resistance to certain types of cancers that were notoriously resistant. Today, we are starting to have response rates in Melanoma. We have double or triple longevity in Chronic Myeloid Leukemia, GIST, Myeloma etc...Just wait to see what we will get once we manage to give Multistage Multitarget Therapies (MMT). Cure is within the management of Loopholes!

Clinical Hypothesis in research, prevention and Commercialization Hypothesis in cancer therapeutics

Following our first article of October 14th, we believe it is time to suggest a second hypothesis
in therapeutic  research in Cancer.   The early years of cancer treatment, the objective was to blast the cancer cells with chemotherapy that was in our arsenal. Most of the time this approach was able to kill the cells partially.  The cancer cells quickly however learned to escape the blast, creating wonderful resistance mechanisms.   As we progress in molecular biology, we are increasingly shying away from these blast approaches, leaning more and more in identifying metabolic pathways, and identifying targets in that pathway and aiming our gun and shoot it, and see what happens.  This is called Target Therapy.
One pathway that we have learned a bit about is the P53 ( and down the line the pathway the Rb which lead to cell stopping in the cell cycle to allow genetic repair).  This pathway is mostly triggered by an abnormality in the gene.
Today, we go back to the blast approach when we have no good Target therapy option.  In fact we always try to add the target therapy to the blast chemotherapy to see if we could have the most from our money.
combination of Avastin (a target therapy) to chemotherapy is standard therapy in the United states for stage IV Colon cancer.  We know that chemotherapy mostly affect our gene.  This change in gene should trigger the activation of our P53 system to stop the cancer cell in its track for growth.  The question now is should we give chemotherapy in patient who has an altered P53 system.  What is the benefit the gene with chemotherapy, if the system that should be triggered to clean up is out.

Hypothesis:

Altered P53 pathway predict a failure of chemotherapy which has gene disturbance as main effect.
second hypothesis: preservation of status of the wild type P53 during chemotherapy may predict for a successful chemotherapy treatment (Cisplatin).
 if it is true, commercialization is possible...

Don't be shy, give me your opinion!