Feasibility and efficacy of molecular analysis-directed individualized therapy in advanced non-small-cell lung cancer.

Purpose: The treatment of patients with advanced non-small-cell lung cancer (NSCLC) is based on clinical trials experience. Molecular characteristics that impact metabolism and efficacy of chemotherapeutic agents are not used for decision making. Ribonucleotide reductase subunit 1 (RRM1) is crucial for nucleotide metabolism, and it is the dominant molecular determinant of gemcitabine efficacy.

Nuclear excision repair-based personalized therapy for non-small cell lung cancer: from hypothesis to reality.

The crucial 'flaw' in the existing treatment paradigm for non-small cell lung cancer (NSCLC) is the 'one size fits all approach'. Consequently, adjuvant chemotherapy is given to all patients to benefit a minority and, in the metastatic setting doublet chemotherapy only provides modest improvements in response rates and survival. A personalized approach of treatment selection is therefore desperately needed.

The cardiorespiratory, anthropometric, and performance characteristics of an international/national touring ballet company.

This study examined the cardiorespiratory and anthropometric indices of professional classical ballet dancers in relation to company seniority, gender, and supplemental training. Forty-nine participants from an international touring company carried out a peak Vo(2) test and vertical jump test. Anthropometric measurements and supplemental training activities were also recorded for each participant.

Phase I trial of histone deacetylase inhibition by valproic acid followed by the topoisomerase II inhibitor epirubicin in advanced solid tumors: a clinical and translational study.

Purpose: To determine the safety, toxicity, and maximum-tolerated dose of a sequence-specific combination of the histone deacetylase inhibitor (HDACi), valproic acid (VPA), and epirubicin in solid tumor malignancies and to define the clinical feasibility of VPA as an HDACi.

Patients And Methods: Patients were treated with increasing doses of VPA (days 1 through 3) followed by epirubicin (day 3) in 3-week cycles. The study evaluated pharmacokinetic and pharmacodynamic end points, toxicities, and tumor response.

Determining the extent of biodegradation of fuels using the diastereomers of acyclic isoprenoids.

Improved testing and remediation procedures for sites contaminated with petroleum hydrocarbons are a priority in remote cold regions such as Antarctica, where costs are higher and remediation times are longer. Isoprenoid/n-alkane ratios are commonly used to determine the extent of biodegradation at low levels but are not useful once the n-alkanes have been removed. This study demonstrates how the diastereomers of the acyclic isoprenoids can be used to determine the extent of biodegradation in moderately biodegraded fuel in soils from a bioremediation trial at Casey Station, Antarctica.

Molecular predictors of chemotherapy response in non-small-cell lung cancer.

Lung cancer is the number one cause of cancer-related mortality. In order to improve the outcome of patients, advances in the understanding of cancer biology and the development of therapeutic modalities that target key proliferation and survival mechanisms are needed. In vitro data have demonstrated that the genes RRM1 and ERCC1 are important components of these mechanisms.

Phase I study of carboplatin in combination with gemcitabine and irinotecan in patients with solid tumors: preliminary evidence of activity in small cell and neuroendocrine carcinomas.

Background: The objective of this study was to determine the maximum tolerated dose and dose-limiting toxicity (DLT) of carboplatin in combination with gemcitabine and irinotecan in patients with solid tumors.

Methods: Patients with solid tumors who were not candidates for standard chemotherapy received escalating doses of carboplatin, gemcitabine, and irinotecan.

Results: Twenty-eight patients were enrolled.

A phase 1 escalating single-dose and weekly fixed-dose study of cetuximab: pharmacokinetic and pharmacodynamic rationale for dosing.

Purpose: This phase 1 study evaluated the pharmacokinetic and pharmacodynamic effects of cetuximab on patients with epithelial malignancies.

Experimental Design: Following a skin and tumor biopsy, patients with advanced epithelial malignancies were randomized to receive a single dose of cetuximab at 50, 100, 250, 400, or 500 mg/m2 i.v.

Malignant pleural mesothelioma: a comprehensive review.

Background: The incidence of malignant mesothelioma continues to increase, but the disease remains difficult to detect early and treat effectively.

Methods: The authors review the pathogenesis, incidence, clinical presentation, diagnosis, pathology, and both standard and experimental treatments for mesothelioma.

Results: When possible, surgery (video-assisted thoracoscopy, pleurectomy/decortication, or extrapleural pneumonectomy) is utilized.

A phase I/randomized phase II, non-comparative, multicenter, open label trial of CP-547,632 in combination with paclitaxel and carboplatin or paclitaxel and carboplatin alone as first-line treatment for advanced non-small cell lung cancer (NSCLC).

Purpose: To evaluate the toxicity profile and pharmacological properties of oral CP-547,632 alone and in combination with paclitaxel and carboplatin administered every 3 weeks, and to assess efficacy as measured by the objective response and progressive disease rates of oral CP-547,632 administered in combination with paclitaxel and carboplatin.

Patients And Methods: Patients with stage IIIB/IV or recurrent non-small cell lung cancer receiving first-line chemotherapy were treated with oral daily CP-547,632 in combination with paclitaxel 225 mg/m(2) and carboplatin AUC = 6 every 3 weeks. Pharmacokinetics parameters for CP-547,632 and paclitaxel were determined independently and during co-administration.

Spectroscopic and computational studies of reduction of the metal versus the tetrapyrrole ring of coenzyme F430 from methyl-coenzyme M reductase.

Methyl-coenzyme M reductase (MCR) catalyzes the final step in methane biosynthesis by methanogenic archaea and contains a redox-active nickel tetrahydrocorphin, coenzyme F430, at its active site. Spectroscopic and computational methods have been used to study a novel form of the coenzyme, called F330, which is obtained by reducing F430 with sodium borohydride (NaBH4). F330 exhibits a prominent absorption peak at 330 nm, which is blue shifted by 100 nm relative to F430.

The heart of the matter: a proposal for placing the self of the therapist at the center of family therapy research and training.

As it faces the transition marked by the death or retirement of most of its first-generation founders, the field of family therapy finds itself still unable to answer the critical question of what it is that makes family therapy work. The two dominant approaches to answering this question, the common-factors perspective and the model-specific factors perspective, remain divided at this juncture by a fundamental difference of emphasis between the two. This article proposes a way of integrating the two perspectives via the hypothesis that therapists achieve maximum effectiveness by committing themselves to a family therapy model of proven efficacy whose underlying worldview closely matches their own personal worldview.

RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer.

Purpose: RRM1 encodes the regulatory subunit of ribonucleotide reductase and is a molecular target of gemcitabine. Previous studies showed increased RRM1 expression on continuous exposure of cell lines to gemcitabine and suggested improved survival for patients with low as opposed to high tumoral RRM1 expression when treated with gemcitabine-containing chemotherapy. However, the principal hypothesis that intratumoral levels of gene expression are associated with disease response has not been addressed.

Sequential oral 9-nitrocamptothecin and etoposide: a pharmacodynamic- and pharmacokinetic-based phase I trial.

Purpose: Resistance to topoisomerase (topo) I inhibitors has been related to down-regulation of nuclear target enzyme, whereas sensitization to topo II inhibitors may result from induction of topo II by topo I inhibitors. Here, we evaluated a sequence-specific administration of a topo I inhibitor followed by a topo II inhibitor.

Experimental Design: Twenty-five patients with advanced or metastatic malignancies were treated with increasing doses (0.

Increased bioavailability of intravenous versus oral CI-1033, a pan erbB tyrosine kinase inhibitor: results of a phase I pharmacokinetic study.

Purpose: In phase I studies with oral CI-1033, dose-limiting toxicities were primarily gastrointestinal, supporting the exploration of i.v. dosing to achieve optimal drug exposures by increasing bioavailability.

How nitrogenase shakes--initial information about P-cluster and FeMo-cofactor normal modes from nuclear resonance vibrational spectroscopy (NRVS).

Nitrogenase catalyzes a reaction critical for life, the reduction of N(2) to 2NH(3), yet we still know relatively little about its catalytic mechanism. We have used the synchrotron technique of (57)Fe nuclear resonance vibrational spectroscopy (NRVS) to study the dynamics of the Fe-S clusters in this enzyme. The catalytic site FeMo-cofactor exhibits a strong signal near 190 cm(-)(1), where conventional Fe-S clusters have weak NRVS.

Combination of p53 cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancer.

Purpose: The initial goal of this study was to test the immunologic and clinical effects of a new cancer vaccine consisting of dendritic cells (DC) transduced with the full-length wild-type p53 gene delivered via an adenoviral vector in patients with extensive stage small cell lung cancer.

Experimental Design: Twenty-nine patients with extensive stage small cell lung cancer were vaccinated repeatedly at 2-week intervals. Most of the patients received three immunizations.

Phase I study of the taxane BMS-188797 in combination with carboplatin administered every 3 weeks in patients with solid malignancies.

Rationale: BMS-188797 is one of several novel taxanes in ongoing clinical development. It has superior activity in experimental tumor models when compared with paclitaxel. BMS-188797 has a single C-4 modification, a 4-desacetyl-4-methylcarbonate, compared with paclitaxel.

Adjuvant chemotherapy for non-small cell lung cancer.

Studies of adjuvant chemotherapy for non-small cell lung cancer (NSCLC) did not provide a consistent disease-free survival or overall survival benefit in the 1980s and early 1990s. However, recently reported studies have changed the practice of NSCLC treatment, for which adjuvant chemotherapy is now considered the standard of care. This review outlines the issues that may have limited the detection of beneficial effects of adjuvant chemotherapy in early trials and provides detailed analysis of the results of recently published trials of adjuvant chemotherapy for NSCLC.

Reductive activation of nitrate reductases.

Protein film voltammetry of Paracoccus pantotrophus respiratory nitrate reductase (NarGH) and Synechococcus elongatus assimilatory nitrate reductase (NarB) shows that reductive activation of these enzymes may be required before steady state catalysis is observed. For NarGH complementary spectroscopic studies suggest a structural context for the activation. Catalytic protein film voltammetry at a range of temperatures has allowed quantitation of the activation energies for nitrate reduction.

Normal mode analysis of Pyrococcus furiosus rubredoxin via nuclear resonance vibrational spectroscopy (NRVS) and resonance raman spectroscopy.

We have used (57)Fe nuclear resonance vibrational spectroscopy (NRVS) to study the Fe(S(cys))(4) site in reduced and oxidized rubredoxin (Rd) from Pyrococcus furiosus (Pf). The oxidized form has also been investigated by resonance Raman spectroscopy. In the oxidized Rd NRVS, strong asymmetric Fe-S stretching modes are observed between 355 and 375 cm(-1); upon reduction these modes shift to 300-320 cm(-1).

Stopped-flow Fourier transform infrared spectroscopy of nitromethane oxidation by the diiron(IV) intermediate of methane monooxygenase.

The hydroxylase component (MMOH) of soluble methane monooxygenase from Methylococcus capsulatus (Bath) was reduced to the diiron(II) form and then allowed to react with dioxygen to generate the diiron(IV) intermediate Q in the first phase of a double-mixing stopped-flow experiment. CD3NO2 was then introduced in the second phase of the experiment, which was carried out in D2O at 25 degrees C. The kinetics of the reaction of the substrate with Q were monitored by stopped-flow Fourier transform infrared spectroscopy, observing the disappearance of the asymmetric NO2 bending vibration at 1548 cm-1.

EPR and infrared spectroscopic evidence that a kinetically competent paramagnetic intermediate is formed when acetyl-coenzyme A synthase reacts with CO.

Carbon monoxide dehydrogenase/acetyl-CoA synthase (CODH/ACS) is a bifunctional enzyme which enables archaea and bacteria to grow autotrophically on CO and hydrogen/carbon dioxide using the Wood-Ljundahl pathway. CO produced from reduction of carbon dioxide by CODH is transferred to the active site of ACS through an intramolecular tunnel, where it combines with Coenzyme A and a methyl cation to produce acetyl-CoA. The active site of ACS contains a single [4Fe-4S] cluster bridged by a cysteine sulfur atom to a binuclear center.

Normal-mode analysis of FeCl4- and Fe2S2Cl42- via vibrational mössbauer, resonance Raman, and FT-IR spectroscopies.

[NEt(4)][FeCl(4)], [P(C(6)H(5))(4)][FeCl(4)], and [NEt(4)](2)[Fe(2)S(2)Cl(4)] have been examined using (57)Fe nuclear resonance vibrational spectroscopy (NRVS). These complexes serve as simple models for Fe-S clusters in metalloproteins. The (57)Fe partial vibrational density of states (PVDOS) spectra were interpreted by computation of the normal modes assuming Urey-Bradley force fields, using additional information from infrared and Raman spectra.