Complex Systems Analysis of Cell Cycling Models in Carcinogenesis--论文代写范文精选

临床试验表明,通过重建和合理治疗癌症细胞循环可以抑制转移性癌细胞。细胞采用CDK4/6细胞周期，包含CDK2灵活滴定p27的复合体,从而控制扩散。然而,细胞周期蛋白之间相互依赖过程中还有一些未知的因素。因此,p27不仅会导致损失无限制的扩大。下面的paper代写范文进行探讨。

Abstract 
A new approach to the modular, complex systems analysis of nonlinear dynamics in cell cycling network transformations involved in carcinogenesis is proposed. Carcinogenesis is a complex process that involves dynamically inter-connected biomolecules in the intercellular, membrane, cytosolic, nuclear and nucleolar compartments that form numerous inter-related pathways referred to as networks. One such family of pathways contains the cell cyclins. Cyclins are proteins that link several critical pro-apoptotic and other cell cycling/division components, including the tumor suppressor gene TP53 and its product, the Thomsen-Friedenreich antigen (T antigen), Rb, mdm2, c-Myc, p21, p27, Bax, Bad and Bcl-2, which all play major roles in carcinogenesis of many cancers. This novel theoretical analysis based on recently published studies of cyclin signaling, with special emphasis placed on the roles of cyclins D1 and E, suggests novel clinical trials and rational therapies of cancer through reestablishment of cell cycling inhibition in metastatic cancer cells.

The Dual Role of D-type Cyclins and p27 in Proliferation and Differentiation 
Cells employ CDK4/6– cyclin D complexes to flexibly titrate p27 from the complexes containing CDK2, and thereby they control their proliferation. However, mutual dependency between cyclin D and p27 serves also some yet unidentified function in differentiation-related processes. Thus, loss of p27 not only causes unrestricted growth due to inefficient inhibition of CDK2–cyclin E/A, but may also elicit a decrease in levels of D-type cyclins, resulting in differentiation defects. Upon ablation of cyclin D, cells lose their ability to titrate p27 from CDK2–cyclin A/E complexes and proliferation is suppressed. However, defects in differentiation caused by the absence of D-cyclin are reminiscent to defects produced by the absence of p27 (Bryja et al., 2004). When the changes in levels of p27 and/or D-type cyclins occur, an equilibrium alteration could result between proliferation/differentiation processes that may in the end result in tumorigenesis (Bryja et al., 2004).

Conclusions 
Specific Results on the use of Signal Transduction Modulators as Novel Anticancer Drugs 
1. Gleevec, Herceptin (Trastuzumab) and CCI-779 have been approved by FDA for treatments of several types of cancer. 
2. Preclinical studies with C225 showed that ‘Cetuximab’ results in cell cycle arrest, as well as apoptosis in several types of tumors, and it had synergistic effects with cytotoxic chemotherapy; Cetuximab (C225) was reported to be tested further in Phase II and III clinical trials. 
3. Flavopiridol : The goal would be to develop new STKAs that would be similar to flavopyridol, or HMR 1275. Some STKAs act as blockers of Cyclin D1, therefore causing cycle arrest by direct transcription repression of cyclin D1 mRNA (79), and in mantle cell lymphoma, flavopyridol delayed significantly progression of disease in 84% of patients (80).Cytostasis effects are significant and were observed with the flavopyridol to colorectal and prostate carcinoma xenograft models. 

Evaluation of Results and Related Developments The results obtained so far in clinical trials convey the promise as well as the challenges encountered in developing signal transduction inhibitors (STIs) for significant improvements of cancer treatment efficacy with such new anticancer drugs. These STI molecules represent a marked departure from prior chemotherapeutic approaches that have been, and still are, mostly based on cytotoxic anticancer drugs. The fact that encouraging responses with a number of novel STIs have been seen in cancer patients-- as expected from mechanistic in vitro experiments-- reaffirms the relevance of Integrated Cancer Biology research in charting the future course of cancer developmental therapeutics, and especially the importance of understanding signaling transduction functions and the underlying biodynamics in signaling pathways of cancer cells. On the other hand, the initial results obtained raise a number of issues that should be considered before the field can advance towards the eradication of cancer. One such major issue is the lower response observed clinically in cancer patients with some of the new STIs compared to the expected value. Whereas some anticancer agents have entered initial clinical trials with extensive efforts to document target-based effects in conjunction with pharmacology and clinical toxicity evaluations, other agents have not done so, and in those instances the phase I study has no depth, and does not provide valuable information. 

Therefore, lacking clear evidence of definite clinical response, one cannot confidently move forward to the next trail phase. Effective, rational design of combinations with standard cytotoxic agents also remains a challenge in the absence of basic information on anticancer drug interactions. Preclinical models of synergistic effects with signaling agents often proceeds from empiricism rather than understanding on a mechanistic basis, which is what should guide clinical implementation. Another important aspect that must be considered is the need for accurate means of diagnosing the dependence of a tumor on a particular signaling pathway, or target, for novel therapeutic strategies. All of problems and drawbacks considered here call for renewed efforts to define improved assays of target effects in the preclinical phase of a drug's development that can also be translated to the clinical arena. Microarray, proteomic and interactomic, approaches offer the promise of providing such means (Mohr, S. et al., 2002) but these must also be integrated into the clinical trials process. 

The vast amounts of data becoming available from such high throughput measurements with microarrays on human tumors and tissues also require the employment of powerful computers, effective algorithms for data computational analysis, as well as major advances in our understanding of the complex systems dynamics of cancer cells, malignant tumors and tumorimmune interactions in human subjects. Furthermore, higher sensitivity, faster and less expensive diagnostic means must be developed and tested in the clinic to establish their applicability to different types of cancer, and also for the early detection of cancer. Molecular profiling and selective molecular imaging of cancer in human subjects are two such closely related diagnostic means that would make possible individualized cancer therapy, as well as provide the ability to proceed with economically feasible screening of human populations that are considered to be at risk for specific types of cancer by utilizing relatively inexpensive and non-invasive means for early detection of cancer. NIR and fluorescence microspectroscopy based techniques are two such very promising means for the early detection of cancer, as well as for the effective monitoring of the cancer therapy effects in patients, thus also providing the accurate means for diagnosing the dependence of a tumor on a particular signaling pathway, or target, for novel therapeutic strategies.

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