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Molecular Oncology - Science topic

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I need the most common methods and procedures to screen a phytochemical having anticancer activity both in vivo (animal model) in vitro and in computational systems. 
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Does anyone have experience with DSS colitis model?
I want to discuss about the scoring system of DAI, for example, to score the bleeding: I want to score as follow (no bleeding=0, mild-moderate blood pellet = 1, dark red pellet=3, gross bleeding =4 ). However, I couldn't find paper using such system. so is it ok to use my own scoring system or any one have reference for such scoring system? 
Thanks in advance.
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Hi Doaa, 
Our lab regularly uses DAI when using the DSS model and published on this a few years ago. 
In it, we make reference to how we evaluate DAI that includes bleeding (In this case, bleeding: 0 (no blood), 1 (Hemoccult positive), 2 (Hemoccult positive and visual pellet bleeding), and 4 (gross bleeding)). 
Hope this helps!
-Janice 
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I
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You could consider using p40. A diffuse (full layered) expression coupled with malignant features on histology favours a SCC cell from a normal keratinocyte.
I think only the basal cells shows p40 positivity in normal skin.
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Where can I find out all the oncogenes and suppressor genes so far?
Thanks!
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See a list in the link below. However, there may be additional genes and the criteria to include a gene in the list may not be stringent. Therefore, if a gene is not well-characterized with respect to an oncogene or tumor suppressor, additional studies may be needed before a gene can be included in the list.
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I have calculated dct as ctref-ctgoi and then calculated ddct as untreated -treated, but I am confused as to whether I should calculate fold change as 2^ddct or 2^-ddct, can someone clarify for me please?  
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Hi Lisa.
OK. In qRT-PCR, increased levels of GOI are indicated by a lower Delta-Ct between the GOI and the housekeeping gene (assuming of course that the treatment doesn't change the expression of the housekeeping gene - do you know this for sure?)
So - let's say that the DCt for IL-2 in T-cells is 10 in the absence of PHA stimulation and 6 when PHA stimulation is applied. Since 6<10, we know immediately that IL-2 mRNA levels are rising as a result of PHA stimulation. There is a difference of 4 Ct units, ~16x increase.
How do we get this from the DCt values?
DDCt = DCt(GOI) - DCt(REF)
           = 6 - 10
           =  -4
So, fold-change must be 2^-DDCt
here are a couple of links to look at:
and
Good Luck!
G
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Hi!I'm currently using BT474 as HER2+ cancer cells model and I would like to know if these cells are oftenly multinucleated or if it's a rare event?
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Certain number of cells in a given culture at a given time contain more than one nucleus (2-4). Therefore, determine the number and see if a particular culture condition(s) increases the number. As noted by Go above, the presence of cells with more than one nucleus is a characteristic of certain tumor cell lines and senescent cells (cells that have exited the cell cycle permanently). This is seen in tumor cells after a genotoxic insult.
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Hello everybody,
can somebody explain me, why there is a borderline in many studies that patients in neoadjuvant BRCA1-cohorts have to be younger than 50 years of age?  Is there some literature which explains it?
Thank you...!!!
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Eerola H, Heikkilä P, Tamminen A, Aittomäki K, Blomqvist C, Nevanlinna H. Relationship of patients’ age to histopathological features of breast tumours in BRCA1 and BRCA2 and mutation-negative breast cancer families. Breast Cancer Research. 2005;7(4):R465-R469. doi:10.1186/bcr1025
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The clonal dynamics of primary tumor cells.
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May be the attached articles could be of help.
Best regards
Robert
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i have treated a tumor cell line using a plant extract and terminated the treatment at different times (eg: 1 hour, 2 hours, 4 hrs and so on) and estimated some enzyme activities and observed that the enzymes decreased up to a certain time, increased again and then decreased again....  how do i interpret this and what exactly is happening??
thank you
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Hi Lairinzuali,
Well, the funny point is that your plant extract makes the enzyme activity you follow versus time to decrease then to increase, then to decrease again at a longer time of incubation.
A possible explanation is that, as suggested by Robert, a first component in your plant extract "quickly" inhibit the enzyme whom activity you look at. But this component does not act for long (why's that ... its stability??? do you heat the incubation mixture?). Then, another component, acting much less "quickly" begins to act at a longer time and, this time, being more stable, decrease largely yhe atcivity of the enzyme you look at.
A possible further explanation is that the second decrease, that appearing after the inetrmediate re-incrase of the enzyme you follow, is due to a component that is produced during your incubation by some enzyme of the tumor cells transforming a compound of your plant extract to a derivative that is toxic to the enzyme activity you look at. This is OF COURSE very interesting, this hypothesis paths the way to inetresting experments and results.
Best regards
Philippe
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I am looking for information regarding extravasation of chemotherapeutic agents from capillaries to tissues. If you could share your information, that would be very helpful.
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I do not know at all wether the attached article can be of help.
Best regards
Robert
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In the majority of studies, it is written that compound X exhibited cytotoxic activity or antiproliferative activity, which sometimes becomes confusing to get across. Therefore, a clear cut picture outlining the major difference between two terminologies will be acknowledged.
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Dear Gaurav,
You are perfectly right!
"Antiproliferative" and "cytotoxic" are used as synonymas while they are actually not!
When using a colorimetric assay (MTT, SRB, XTT, etx...) you cannot speak about "cytotoxicity" by only about "growth inhibitory effects" because a concentration that reduces by 50% the growth of your cell population of interest with your compounds of interest does not mean that 50% of the cells were killed. The possibility remains that indeed 50% of the cells were killed (cytotoxic effects), but also that 50% of the cells faced growth arrest (during the time of the test; cytostatic effects) or that 50% of the cells detached from the bottom of the flask (anti-adhesive (anti-metastatic?) effects), or a mix of these three biological processes.
You have to use the GI50, the LC50 and the TGI indices as validated by the US NCI (see their publicly available website) to make the difference between a cytotoxic (induced cell death) and a cytostatic (inducing "antiproliferative effects".
If you are using a colorimetric assay, simple observations with phase-contrast microscopy (that you are routinely used when you perform cell cultures) can more or less easily inform you about cytotoxic versus cytostatic effects.
You can also use vital dyes in addition to the colorimetric assay.
Hoping that it can be of help.
Robert
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I am studying novel immuno therapeutic strategies in cancer and have had trouble in establishing a reliable system to study combination therapy with PD-1 blockade. I am wondering if anyone has had success with such a model. I have tried B16 tumors and EL4 tumors. Thank you.
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I realise this is an old thread - I'm having trouble getting hold of anti-mouse PD-1 (clone G4 ideally), would any one have access to this (and be willing to ship to Belfast, expenses paid!) or recommend a commercial alternative?
Thanks in advance!
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I am working with c-Myc and cancer. Which cancer cell lines over-express c-Myc? I would be grateful for suggestions.
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Daudi cell line is a Burkitt lymphoma cell line that overxpresses c-Myc.
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Does anyone know or read the paper about the gene, which has opposite effects on tumor growth in vitro and in vivo? I want to get some clue. If you know some or have related paper, please let me know. Thank you in advance.
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 Thanks for the answers. The phenomenon is that it can inhibits the growth of tomor cells in vitro, however, it promotes tumor growth in vivo. I am wondering if there is any good methods to check the differences and mechanisms.
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miRNAs are epigentic regulators and altered expression is reported in cancer. How to find out mutations in miRNA genes and their relevance in cancer? or are the mutaions in miRNA genes or its altered expression relevant in cancer?
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Thank you Charitha. This is an interesting question.
I do not think their altered expression would cause cancer, but contribute to cancer potentiation, according to the evidences in colitis-associated colorectal cancer models that I have found.
It is hard to say whether their mutations were really relevant, but their regulators. However, as fas as they are very important metabolic modulators, it is very interesting to find out ways to detect promptly their alterations in any kind of cancer.
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There is a Co(III) mustard based prodrug which reduced in hypoxia environment and toxic to the cancer cells. if this complex  reduced in cancer cell environment then why not other Co(III) complexes reduced to co(II)? if so what is criteria ? which type of coordinating ligand will facilitate the dissociation of inert Co(III) to labile Co(II)?
what are all the simple method to determine the stability cobalt(III) in biological environment? kindly give some relevant article.
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May be i might not have completely understood your question i would like to answer half portion of your question regarding ligand field that can allow reduction of Co (III) to Co(II) Cobalt(III) low spin t2g6 which is inert however high spin Co(III) with t2g4 eg2 configuration is not inert i suppose ligands which can build up high spin complexes with Co(III) should allow reduction of Co(III) to Co(II) moreover Co(III) is a hard metal ion while Co(II) is borderline hence ligands with softer donor site should allow reduction of Co(III) to Co(II).
Hope it half answers the question.  
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I'm growing 4T1 cells in mice. I'm implanting two contralateral tumors per mouse. I'm having a hard time getting the tumors to grow symmetrically. I understand they won't all be perfect, but I'm getting a lot of shapes that are difficult to caliper, or I'll have tumors with small satellite tumors right next to them.  With 2 tumors on 1 mouse, its hard to get enough mice to enroll in study.
I'm implanting 1 x 10^5 cells in 100 uL volumes. I draw the cells up into the syringe in an 18 g needle, and I implant the cells using a 25 g needle. I slowly inject the tumors on the flank and slowly remove the syringe. The cells are being implanted using serum free media. 
Should I use a smaller gauge (27g) needle to implant? Should I move my implant site up to the shoulder? Should I switch to PBS instead of media?
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Hi,
You can inject 4T1 cells from 5x103 to 1x105 in the up or low fat pad with volume 30ul to 50ul in Balb/c mice.  Then you can have lung metastasis and larger spleen ( 3-4 time weight (g) than normal mouse''s spleen.
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The Polycomb Repressor Complexes (PRC1 and PRC2) are crucial to keep  stem cells in a pluripotent state, by silencing all genes that would be involved in premature differentiation or cell fate determination. PRC2 is involved in H3 trimethylation and PRC1 in methylation of CpG islands. Regulation of both PRC1 and PRC2 is mainly on the level of post-translational modification of the PRC components (such as EZH1/2, PCL1-3, RING1A-B ...) and target specifity is speculated to be governed by non-coding RNAs. There are also many observations that suggest illegitimate PRC2 activation plays a role in carcinogenesis, tumor progression and development of therapy resistant sub-clones. I am wondering if there is a (or a set of) reliable gene-expression markers which represent a good indicator for the activity of PRC1 or PRC2.
I would be grateful for any suggestions, Michael
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Hi Michael,
It is a interesting topic Michael. PRC1 leads to monoubiquitination of H2AK119 not methylation in CpG islands. There have been many groups who have knocked out or Knocked Down specific PcGs (both PRC1 and PRC2) to identify the target most affected, but there isn't a particular gene that's affected. Different groups have got different protein owing to different starting materials (mES, hES, MSCs). It can be said that some key transcription factors can be used as read out of PRC1 or PRC2 activity, but it will depend on cell type to be used. 
Regards,
Prasad.
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I am working in a oncogene characterization, but I have some issues trying to choose, which is the best metastatic model in vitro?
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 If you would not like to ignore the anti-tumor immune response, I strongly recommend that you should use the autograft experiments, in which murine tumor cells such as 4T1 breast cancer cells or B16 melanoma cancer cells established from mice are injected to B6 WT mice in terms of immune system. We have previously published the work focusing on CD44 variant function in the metastasis against redox stress in the pre-metastatic niche (Nat Commun. 2012 Jun 6;3:883).
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We all have experiences that more and more mutations are found in tumors. A few of them are recurrence (driver mutations) but most of them are not. The problem is how to determine a mutation actually a driver mutation for a specific tumor? What standard we should follow and what should be the rule? Many of the mutations may be merely passenger mutations caused by the genetic instability after carcinogenesis process.
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Ultimately, there has to be functional data showing that a particular mutation can transform cells. But realistically, we will never be able to test all of the potential drivers in all types of tumor in that way.
From a genomics perspective, the key question is whether a particular basepair/gene/locus undergoes somatic changs at a greater rate than chance would predict. If it does, then we can suppose that change confers a selective advantage and is likely a driver.
Current "state of the art" models like MutSig for coding changes:
and GISTIC for copy number changes:
attempt to do just this. These approaches are not perfect but I think they've helped us take a step forward in separating drivers from passengers.
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KRAS,NRAS,BRAF wild type colorectal cancer can response the anti-EGFR therapy using cetuximab or panitumumab. However, in some cases such as Her2 or MET amplification there will be an resistant to anti EGFR therapy although tumor has  KRAS,NRAS and BRAF wild type genotype. If there is a polysomy in chromosome 17(Her2:CEP17 ratio 1, however there is a increasing number of chromosome 17 such as 3:3,4:4), using FOLFIRI+Cetuximab+Herceptin can overcome EGFR resistant in metastatic colorectal cancer?
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Very interesting discussion, I would just like to add besides the discussions above, one may also keep in mind the PI3K, MEK, AKT mutations that may be involved and molecules of other alternative or additional  pathways that may be involved in resistant metastatic colorectal carcnomas. The article below may be of help.
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I need to find an antibody to detect high risk HPV types in one go using western blot. could you kindly let me know if there is any company can provide this antibody?
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Hi Brandon,
Could you kindly explain in more deatails!
Regards.
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Differences between monocytes and macrophages regarding their specific cell marker
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At least in mouse f4/80 antibody recognizes macrophages.
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I need the murine cancer cell line. But the problem i am facing is whether cancer cell lines from C57/BL6 mice can be used to study in Balb/c mice or not. Another problem is that, I found some Balb/c mice cancer cell line but mostly in old articles.
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Hello Christine
Thank you so much for such great information. I will follow as your suggestions.
Good luck.
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I was getting good results before, but all of a sudden when I repeated the procedure with the same cell line, same drug, and same drug concentrations, it went wrong. Please find attached before and after pictures.
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if you are using micrococcal nuclease or another endonuclease, the first thing that one could think observing the second picture is that the enzyme did not work: in the new picture there seem to be only high molecular weight DNA and small fragmented RNA. Next time you should have a control (DNA not digested) to see if there are differences between digested and not digested. Good luck
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I was wondering if anyone could share how to identify osteoblastic niche for quiescent hematopoietic stem cells in bone marrow by doing IHC staining
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Hi again
Yes sure Antonio. You have been very supportive. Thanks
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Although the malignant tumors at the initial stage from the stemness starts as a Monoclonal origin, upon the further proliferation, a secondary clonal population of cancer cells are generated. This further continues to go and change the clonality.
Hence, do the malignant tumors need to be addressed as a monoclonal or polyclonal?
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Some molecular techniques can be used to identify clonality for example in Multiple Myeloma Ig gene rearrangements is used as an indicator. If all cells in a colony have the same rearrangement pattern they should be grown clonally. I think this is important because CSCs should recapitulate the disease on their own, from one cell origin. If a tumor bulk is polyclonal, it could be a mixture of different cells divided a couple times and that does not mean these cells are totally clonogenic, in my opinion.
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This project is in a rare type of lymphoid cancer. Due to this rarity, there are only 3 cell lines available for the disease, which I have in the lab. They are drug-sensitive cell lines (drug disclosed only if you are interested in collaboration) and I also have their 3 drug-resistant clones, which were developed in the lab (so total sample n=6). Unfortunately, I do not have any patient samples. I wish to conduct RNA-seq to examine changes at the mRNA level as well as SNV's in these cells. The goal is to identify changes that characterize drug-resistant cells vs. their drug-sensitive WT counterparts. Please tell me if this type of an analysis is possible with such low sample numbers? If so, please let me know if you are interested in collaborating to analyze the resultant RNA-Seq data?
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Dear Aneel,
First of all, I would like to tell you that it is possible to perform this kind of analysis with such a low no. of samples. Actually you want to measure differential gene expression (DGE) which is a quantitative experimental set-up for RNA-seq. Here biological replicates are important and 3 vs 3 will be enough to perform this kind of statistics which we call Explorative or as discovery setting. However, latter on you need to validate your findings on larger cohort which you already know.
I have to admit the we don't work on Lymphoid cancer, so I can't offer any possibilities of collaboration. But my point is to clear your doubt about sample size for RNA-seq...I would say go for it...
Hope this would help you...good luck for successful collaboration
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I am looking for specific markers for arterioles, capillaries and venues for doing immunohistochemial staining by which I can distinguish them properly when I visualize the section under the microscope.
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CD34 is pan-endothelial marker, CD31 stains mature endothelial cells, CD105 and VEGFR2 are suitable for identification of newly formed blood vessels. However, I think that the only way to differentiate arterioles, capillaries and venules is according to their morphology.
Eventually, you could try double staining with endothelial marker and vascular smooth muscle cell marker, like for example, alpha smooth muscle actin.
Arterioles have 1 to 3 layers of smooth muscle cells and they will be CD34+ and alpha SMA+.
Capillaries, in general, have pericytes that stain with alpha SMA. Nevertheless, sinusoidal capillaries have very few if any pericytes, so they will probably stain CD34+ and alpha SMA-.
Postcapillary venules have pericytes, but their morphology is different than morphology of arteriole.
I would prefer plain morphology. Even if you apply double staining, the hematopoetic cells in bone marrow could be alpha SMA positive and that could cause problem in the interpretation of the results.
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Cytokeratins are generally considered as diagnostic marker for epithelial tissues. In molecular classification different sub-types of cytokeratins are used. CK 5/6 specifically stains the basal epithelial cells, whereas, CK 8/18 stains the luminal epithelial cells. On basis of reactivity of these sub-types of cytokeratins, the human and canine mammary tumours are classified into basal and luminal types and basal subtypes atre associated with poor prognosis as compared to luminal tumours. So, in a way cytokeratins can be used as prognostic markers to access prognosis of mammary tumours.
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Cyytokeratin-specific immuohistochemical stains have been used in histopathology for quite sometime to aid diagnosis, for example to discern if cells are indeed epithelial in origin, or in the case of breast cancer ,whether they are of the luminal or basal-like subtypes. Recently overlap has been discovered between some members with the polar opposite molecular subtypes in breast cancer - luminal and basal-like. However, when compared to the gold standard definition of molecular subtypes using gene expression microarray expression signatures (either Intrinsic gene list or PAM50), they have not been found to be specific enough as luminal cytokeratins are expressed in basal-like breast cancers as well, and not all basal-like breast cancers express basal cytokeratins. Thus cytokeratin expression patterns in practice cannot be considered to be characteristic or pathognomonic of either subtype, but rather can be said to be highly associated with each entity. Basal-like cytokeratins DO possess prognostic significance, but less than more specific biomarkers for basal-like breast cancer such as FOXC1, which have been shown to be superior prognostic markers on the basis of comparing prognostic models using either cytokeratins or FOXC1 [Ann Surg Oncol. 2011 Dec;18(13):3839-47. doi: 10.1245/s10434-011-1657-8. Epub 2011 Mar 18.
Basal-like breast cancer defined by FOXC1 expression offers superior prognostic value: a retrospective immunohistochemical study. Ray PS, Bagaria SP, Wang J, Shamonki JM, Ye X, Sim MS, Steen S, Qu Y, Cui X, Giuliano AE].
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Does a primary tumor contain specific cancer cells that can leave the tumor and cause metastasis? Or are these changes triggered by the tumor microenvironment after the cancer cell has left the tumor?
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There may be specific cell markers to identify metastatic cancer cells and these would be important to identify. Notably, circulating tumor cells have an altered cytoskeleton and microtentacles that protect from deformation caused by shear stress. Interestingly, both carcinogenic and non carcinogenic circulating breast cells have microtentacles but those in tumorigenic cells are extra long and motile compared to those in non-tumorigenic cells (Cancer Res. 68, 5678-88, 2008; Cancer Res. 70, 8127-37, 2010). Microtentacles, which are formed by microtubules and also may contain intermediate filaments, are required for efficient attachment and act in the metastatic spread of cancer. Interestingly the common chemotherapeutic paclitaxel, which acts by stabilizing microtubules, strengthens the microtentacles resulting in increased attachment of circulating tumor cells to secondary sites (Breast Cancer Res Treat. 121, 65-78 (2010) so this type of one highly successful therapy for primary tumors may set the stage for a greatly increased risk of metastasis. The observation that ~90% of all cancer deaths are caused by metastatic spread of the primary tumor underscores the importance of this question: the need to understand circulating tumor cells and how they find favorable attachment sites and what their mechanisms of reattachment may be.
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Could you please explain in detail.
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Warburg effect is one the halmarks of cancer. There are basically 3 facts you should know:
1) Most energy produced by cancerous cells is via glycolysis, followed by lactic acid fermentation; essentially anaerobic respiration as opposed to traditional aerobic respiration in non cancerous cells.
2) the rate at which respiration is occurring is much faster for cancerous cells than non-cancerous cells.
3) Low oxygen content in tumors
This should be a start for you
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Some cells seem to produce cancers more frequently than others. There are > 200 distinct human cell types; do all of these produce cancers under some circumstances? If not what is special about cells that never produce cancer? Why do some cells produce cancer relatively frequently while others do not? How well is this predisposition toward or against cancer development understood?
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The only cells that can't form cancer AFAIK are the ones that can't ever proliferate. Erythrocytes are so differentiated that they loose their nucleus. Therefore, without any genes, cancer can't emerge from them. Their precursors however, which possess a nucleus, can develop cancer.
Some cells form cancer more often than others. Different parts of the body are exposed to different concentrations of various carcinogens. Tissues have different proliferative potential, some cells do not proliferate physiologically (cardiomyocytes), while others proliferate like crazy (epithelium). The more "breaks" are limiting cell's life cycle, the more barriers need to be overcome by mutations in protooncogenes, suppressors, and apoptotic genes to start uncontrolled cell division and eventually lead to cancer.
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In measurement of A549 reversal of phenotype/ differentiation using ATRA, how many A549 cells can you seed to produce the required CEA amounts in the medium?
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Haven't found one on google, most papers just report but do not give details on specifics like the cell numbers etc....I tried on my own but I got very low amounts of CEA on ECLIA. If you can give me one, I would very much appreciate it. Thanks
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I am trying to build a new mathematical model of glioblastoma, starting with the most up to date molecular biology, I cannot find a clear answer to why motile cells invade. Hypothetically they are undergoing haptotaxis toward a gradient of nutrient of extracellular matrix, but I lack the details at this point.
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Submissions are invited for experienced and ambitious International researchers working on aspects related to Molecular Oncology for a thematic issue "ADVANCES IN MOLECULAR ONCOLOGY". Please note that for submission of "review articles" you are requested to submit your proposal and a list of PUBMED indexed publication list. The deadline is 15th of October, 2013.
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Dear All
Please also note that EXPERT OPINIONS are also cordially invited from leaders in molecular Oncology. I have already received 3 Expert Opinions for the Thematic Issue.
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I need advice here. Anyone has any good/detailed protocols on developing drug-resistant cancer cell lines? I am interested in creating such cell lines using sub-toxic drug doses at incremental levels.
Thanks.
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I agree with Francis - the best way is to use a "realistic" concentration of drug based on clinical measurements (if available) and wait for resistant clones to grow out. This is tedious - depending on the combination of cell line and drug you are using it can take months - but from my own experience and from talking to other people who have done this, cell lines generated by selecting with a "lethal" dose may develop different mechanisms of resistance compared to those selected via escalating doses. I would add that some cell lines are so sensitive to certain drugs that you will have no choice but to drop the dose below the max. plasma concentration. Doing a basic GI50 type of analysis (using a cell viability/proliferation assay) will help you find the right concentration of drug, as others have suggested. Good luck.
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Some time ago a got an idea. Most of the modern therapies against cancer are low in effect because many cancer cells skills allow survival by adopting specific escape and survival systems. Now I think this strategy is wrong because there is no drug (carried by a monoclonal antibody or a nano-particle) capable of destroy 'tout court' a cancer mass. So any exogenous pressure we promote will be transformed in a darwinian cell selection . And what about if we use cancer cells against cancer cells? You know, cancer cells have some obscure mechanisms permitting them to recognize other tumor cells: they don't kill each other, they responsed in chorus to a stimulus and even metastasize together. So if we might create a tumor cell clone capable of detect and destroy selectively the other tumor cells it will be highly beneficial. It is using an army against an army of equal power. At the end of the battle the result would be the death of both of them. I know this is just an idea because we still don't know the ways through which cancer cells promote their own survival messages and produced combined attacks to the organism, but I mean the strategy to use cancer cells as weapon is not so bad. I'd like to know your opinions and if my suggestion might be technically applicable.
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I think the cancer cells are clever enough to distinguish each other, enemy or friend, but how we can teach the cancer cells turnover?
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I'd like to know if melanoma patients with the BRAF K601E mutation are sensitive to the vemurafenib/dabrafenib treatment.
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Paolo:
On systematic review, I found the evidence aggregated to date gives us two human clinical trials of dabrafenib. As for vemurafenib, we have only preclinical data but there are some trials in progress. In both cases, BRAF K601E mutation in the advanced melanoma setting as a target was a strict inclusion requirement. My review findings are summarized below:
Dabrafenib (GSK2118436)
In a phase I/II trial [1] of this highly potent and selective ATP competitive BRAF inhibitor, of nine melanoma patients with V600K BRAF mutations, four had objective responses. Note however that four of five patients with BRAFK601E progressed during the first restaging. What this suggests is that only patients with BRAF V600K mutations are likely to respond to dabrafenib treatment.
Similarly, in another dabrafenib study [2], three patients experienced a partial response, but both of the patients with BRAFK601E progressed after first restaging, again suggesting dabrafenib response is restricted to BRAF mutations at the 600 position.
Vemurafenib (PLX4032 OR RG7204; commercially: ZELBORAF)
In a preclinical study [3] of 17 melanoma cell lines, vemurafenib (PLX4032/RG7204) was a potent inhibitor of proliferation in those expressing BRAFV600E but not BRAFWT, but note that it also potently inhibited proliferation of melanoma cell lines expressing other codon 600 BRAF mutations (including V600D, V600K, and V600R), and most importantly, also moderately inhibited proliferation of the WM1789 melanoma cell line expressing BRAFK601E. Should human clinical trial data support this preclinical finding, vemurafenib may show clinically relevant inhibition of BRAFK601E mutation of advanced melanoma.
Lessons Learned
Of these two BRAF inhibitors specifically for inhibition of advanced melanoma BRAFK601E mutation, human clinical data fails to provide sufficient support for dabrafenib, and although vemurafenib currently lacks supporting human clinical data, preclinical cell data is suggestive of potential activity, awaiting trial confirmation.
Review Methodology
Parameterized search was conducted over PUBMED, EMBASE, CAMBASE, AMED, Scirus, CENTRAL, Ovid, and Terrko (University of Helsinki), without language or date restrictions, and updated again current as of date of review [April/2013], with systematic reviews and meta-analyses extracted separately. Search was expanded in parallel to include just-in-time (JIT) medical feed sources as returned from Terkko. A further "broad-spectrum" science search using Scirus (410+ million entry database) was then deployed for resources not included in PUBMED and elsewhere. Unpublished studies were located via contextual search, and relevant dissertations were located via NTLTD (Networked Digital Library of Theses and Dissertations) and OpenThesis. Sources in languages foreign to this reviewer were translated by language translation software.
References
1. Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet. 2012;379:1893–1901.
2. Kefford R, Arkenau H, Brown MP, et al., “Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumors,” Journal of Clinical Oncology, vol. 28, abstract 8503, 2010.
3. Yang H, Higgins B, Kolinsky K, et al. RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res 2010 Jul 1; 70(13):5518-27.
Constantine Kaniklidis
European Association for Cancer Research (EACR)