Molecular response

Here the ijk coordinate system represents the laboratory reference frame the primed coordinate system i j k corresponds to coordinates in the molecular system. The quantities Tj, are the matrices describing the coordinate transfomiation between the molecular and laboratory systems. In this relationship, we have neglected local-field effects and expressed the in a fomi equivalent to simnning the molecular response over all the molecules in a unit surface area (with surface density N. (For simplicity, we have omitted any contribution to not attributable to the dipolar response of the molecules. In many cases, however, it is important to measure and account for the background nonlinear response not arising from the dipolar contributions from the molecules of interest.) In equation B 1.5.44, we allow for a distribution of molecular orientations and have denoted by () the corresponding ensemble average ... 

The phenomenon under consideration is complicated and the theory developed in the last section is fairly simple-involved, but not really difficult. We have successfully discovered that the transition from Newtonian to pseudoplastic behavior is governed by the product 77, or the relative values of the shear rate and the rate of molecular response. 

The perturbation theory presented in Chapter 2 implies that orientational relaxation is slower than rotational relaxation and considers the angular displacement during a free rotation to be a small parameter. Considering J(t) as a random time-dependent perturbation, it describes the orientational relaxation as a molecular response to it. Frequent and small chaotic turns constitute the rotational diffusion which is shown to be an equivalent representation of the process. The turns may proceed via free paths or via sudden jumps from one orientation to another. The phenomenological picture of rotational diffusion is compatible with both... 

When perturbation is fast enough in comparison with the molecular response to it, the averaging procedure proposed in [91] is justified. After substitution of a formal solution of Eq. (2.20)... 

Physiologic stress evokes a molecular response essential to protecting the human body from cellular injury and death. Over the last two decades, molecular determinants of cellular responses to stress have become better understood, as well as their relationship to human health, development, aging, and disease. Molecular re-... 

Jackson, P.J., Naranjo, C.M., McClure, P.R. Roth, E.J. (1985). The molecular response of cadmium resistant Datura innoxia cells to heavy metal stress. In Cellular and Molecular Biology of Plant Stress, ed. J.L. Key and T. Kosuge, pp. 145-60. New York Alan R. Liss. 

Kang et al. [23] compared the clinical, histologic, and molecular responses of normal human skin to topical retinol with that of retinoic acid. Application of retinol and retinoic acid produced epidermal thickening. However, retinol produced less erythema compared with retinoic acid. The authors suggest that these data are compatible with the idea that retinol may he a pro-hormone of retinoic acid. 

Everaarts, J.M., H.M. Sleiderink, P.J. den Besten, R.S. Halbrook, and L.R. Shugart. 1994. Molecular responses as indicators of marine pollution DNA damage and enzyme induction in Limanda limanda and Asterias rubens. Environ. Health. Perspect. 102, Suppl. 12 37-43. 

Crecchio C, Gelsomino A, Ambrosoli R, Minati J, Ruggiero P (2004) Functional and molecular responses of soil microbial communities under differing soil management practices. Soil Biol Biochem 36 1873-1883... 

An alternative construction, termed fragment of molecular response [24], inserts the atomic partition of unity outside the derivative,... 

In these examples, the condensed Fukui functions were computed using Hirsh-feld population analysis [26], which is unique among the commonly employed population analysis methods, because the same results are obtained from the response of molecular fragment and the fragment of molecular response approaches [24]. There are other arguments in favor of the Hirshfeld scheme too [27,28], many of them based on the tendency for the atom-condensed Hirshfeld Fukui functions to be nonnegative [25,29,30]. Nonetheless, condensed Fukui functions maybe computed using any population analysis method common methods... 

Karentz D, Cleaver JE, Mitchell DL (1991) Cell survival characteristics and molecular responses of Antarctic phytoplankton to ultraviolet-B radiation. J Phycol 27 326-341... 

When Jens Oddershede was elected a Fellow of the American Physical Society in 1993, the citation read For contribution to the theory, computation, and understanding of molecular response properties, especially through the elucidation implementation of the Polarization Propagator formalism. Although written more than a decade ago, it is still true today. The common thread that has run through Jens work for the past score of years is development of theoretical methods for studying the response properties of molecules. His primary interest has been in the development and applications of polarization propagator methods for direct calculation of electronic spectra, radiative lifetime and linear and non-linear response properties such as dynamical dipole polarizabilities and... 

Velders, G. J. M., The Electron Density of Molecules A Tool for Understanding Molecular Response, PhD Thesis, University of Twente, The Netherlands (1992), p. 49. 

Marrot, L., Belaidi, J.P., Jones, C., Perez, P., Riou, L., Sarasin, A. and Meunier, J.R. (2003) Molecular responses to photogenotoxic stress induced by the antibiotic lomefloxacin in human skin... 

The estimated event-free survival was 83%, and an estimated 93% of patients had not shown progression of disease to accelerated or blast phase. Contrary to expectations, there was a declining rate of treatment failure after the start of imatinib, being 3.3% in the first year, 7.5% in the second year, 4.8% in the third, 1.5% in the fourth, and only 0.9% in the fifth year. Patients who achieved a CCR by 12 months or a complete molecular response (CMR) by 18 months had risks of progression to accelerated or blast phase of 3% and 0%, respectively. The estimated overall survival rate at 5 years was 89%. An allogeneic HSCT was carried out in 44 patients, and if these patients were censored, the estimated overall survival rate was 92% (26). 

At the cytogenetic level, resistance can be defined as a loss or lack of MCR or CCR. At the molecular level, a complete molecular response is defined as undetectable BCR-ABLl transcripts by PCR or a > 3-log reduction, a BCR-ABLl transcripts which represents a major molecular remission. Loss of either of these responses would be defined as resistance at the molecular level. However, standardization of measurement of BCR-ABLl transcripts by PCR has not yet been accomplished, and results in one lab may not necessarily be equivalent to those of another lab. Also, a standardized definition of resistance at the molecular level is not well defined, although many experts consider a half log or one-log increase which is confirmed in a second sample as a reasonable benchmark for loss of molecular response (27). 

An international effort is underway to harmonize methodologies for detecting BCR-ABLl transcripts and kinase domain mutations and adjusting the results so they are standardized from one lab to another (28,29). The availability of a reproducible real-time quantitative PCR (RQ-PCR) has shown in one study that patients with a major molecular response do not have evidence of cytogenetic abnormalities in their bone marrow, and therefore a policy of performing bone marrow biopsies only in patients who have not achieved or have lost a major molecular response would allow many patients to forego the discomfort and expense of multiple bone marrow biopsies (30). 

By Sokal or Hasford score. HR = hematologic response ECP = early chronic phase CHR = complete HR CgR = cytogenetic response PCgR = partial CgR (Ph + 1-35%) CCgR = complete CgR (Ph + 0%) MMolR = major molecular response ( 0.10 BCR-ABLl gene ratio) ACA = additional chromosome abnormalities NA, not applicable. 

Only patients with the T3151 mutation were resistant to dasatinib. The most common toxicity was myelosuppression, but this was not dose-limiting (93). Subsequent phase 11 trials in different phases and types of Ph+ disease are being reported. A phase 11 study of 186 patients with IM-resistant or -intolerant chronic phase CML with the standard dose of 70 mg orally BID has been reported. A CHR was achieved in 90% of these patients, and 52% achieved an MCR. Only 2% of patients achieving MCR progressed or died. Molecular responses were also seen with reductions in BCR-ABLl/ABLl transcript ratios declining from 66% at baseline to 2.6% by 9 months of therapy (94). 

Hughes TP, Kaeda J, Branford S et al. Frequeney of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 2003 349 1423-1432. 

Larson RA, Druker B, Guilhot F et al. Correlation of pharmacokinetic data with cytogenetic and molecular response in newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib-An analysis of IRIS study data (Abstract 429). B/oorf 2006 108 131a. 

Kantarjian HM, Cortes JE, O Brien S et al. Long-term survival benefit and improved complete eytogenetie and molecular response rates with imatinib mesylate in Philadelphia chromosomepositive chronic-phase chronic myeloid leukemia after failure of interferon-alpha. Blood 2004 104 1979-1988. 

---