Hypergravity prevents seed production in Arabidopsis by disrupting pollen tube growth.

How tightly land plants are adapted to the gravitational force (g) prevailing on Earth has been of interest because unlike many other environmental factors, g presents as a constant force. Ontogeny of mature angiosperms begins with an embryo that is formed after tip growth by a pollen tube delivers the sperm nucleus to the egg. Because of the importance to plant fitness, we have investigated how gravity affects these early stages of reproductive development. Arabidopsis thaliana (L.) Heynh. plants were grown for 13 days prior to being transferred to growth chambers attached to a large diameter rotor, where they were continuously exposed to 2-g or 4-g for the subsequent 11 days. Plants began flowering 1 day after start of the treatments, producing hundreds of flowers for analysis of reproductive development. At 4-g, Arabidopsis flowers self-pollinated normally but did not produce seeds, thus derailing the entire life cycle. Pollen viability and stigma esterase activity were not compromised by hypergravity; however, the growth of pollen tubes into the stigmas was curtailed at 4-g. In vitro pollen germination assays showed that 4-g average tube length was less than half that for 1-g controls. Closely related Brassica rapa L., which produces seeds at 4-g, required forces in excess of 6-g to slow in vitro tube growth to half that at 1-g. The results explain why seed production is absent in Arabidopsis at 4-g and point to species differences with regard to the g-sensitivity of pollen tube growth.

Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients.

PURPOSE: To evaluate the safety and efficacy of bevacizumab and weekly docetaxel as first- or second-line therapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Twenty-seven MBC patients received i.v. bevacizumab at 10 mg/kg on days 1 and 15 in combination with i.v. docetaxel 35 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Primary end points were to assess toxicity, overall response rate, and progression-free survival. A secondary end point was to assess the relationship between plasma endothelial and cell adhesion markers and clinical outcomes. RESULTS: One-hundred fifty-eight treatment cycles were administered with a median of six cycles (range 1-15 cycles) per patient. The most common grade 4 toxicities per patient were as follows: 2 (7%)-pulmonary embolus, 1 (4%)-febrile neutropenia, and 1 (4%)-infection; grade 3 toxicities were 4 (15%)-neutropenia, 4 (15%)-fatigue, 2 (7%)-neuropathy, 2 (7%)-athralgias, 2 (7%)-stomatitis, 1 (7%)-pleural effusion, and 1 (4%)-hypertension. The overall response rate was 52% [95% confidence interval (95% CI), 32-71%], median response duration was 6.0 months (95% CI, 4.6-6.5 months), and the median progression-free survival was 7.5 months (95% CI, 6.2-8.3 months). In hypothesis-generating univariate and limited multivariate analyses, E-selectin was statistically significantly associated with response to the combination. CONCLUSION: Bevazicumab in combination with weekly docetaxel is active with acceptable toxicities in MBC. Additional studies evaluating E-selectin as a marker of response to bevacizumab-containing chemotherapy are warranted.

Phase II study of weekly docetaxel and capecitabine in patients with metastatic breast cancer.

PURPOSE: This phase II study evaluated the safety and efficacy of weekly docetaxel and capecitabine in patients with metastatic breast cancer. PATIENTS AND METHODS: Thirty-nine patients with metastatic breast cancer received 30 mg/m2 of docetaxel on days 1, 8, and 15 in combination with capecitabine 800 mg/m2 twice daily on days 1-21, repeated every 28 days. RESULTS: The median number of treatment cycles was 4 (range, 1-20 cycles). Grade 3 toxicities per patient were asthenia (n = 7; 18%), diarrhea (n = 7; 18%), nausea/vomiting (n = 5; 13%), stomatitis (n = 5; 13%), neutropenia (n = 5; 13%), and hand-foot syndrome (n = 4; 10%). There were only 2 grade 4 toxicities, febrile neutropenia and pulmonary embolism. The overall response rate was 44% (95% confidence interval (CI), 28%-60%), median duration of response was 9.1 months (95% CI, 6.2-12 months), and median time to progression was 5.5 months (95% CI, 3.7-7.3 months). CONCLUSION: Weekly docetaxel with capecitabine was active with acceptable toxicities. Additional trials to define the optimal schedule of docetaxel and capecitabine are justified.

Gravity control of growth form in Brassica rapa and Arabidopsis thaliana (Brassicaceae): Consequences for secondary metabolism.

How gravity influences the growth form and flavor components of plants is of interest to the space program because plants could be used for food and life support during prolonged missions away from the planet, where that constant feature of Earth's environment does not prevail. We used plant growth hardware from prior experiments on the space shuttle to grow Brassica rapa and Arabidopsis thaliana plants during 16-d or 11-d hypergravity treatments on large-diameter centrifuge rotors. Both species showed radical changes in growth form, becoming more prostrate with increasing g-loads (2-g and 4-g). In Brassica, height decreased and stems thickened in a linear relationship with increasing g-load. Glucosinolates, secondary compounds that contribute flavor to Brassica, decreased by 140% over the range of micro to 4-g, while the structural secondary compound, lignin, remained constant at ∼15% (w/w) cell wall dry mass. Stem thickening at 4-g was associated with substantial increases in cell size (47%, 226%, and 33% for pith, cortex, and vascular tissue), rather than any change in cell number. The results, which demonstrate the profound effect of gravity on plant growth form and secondary metabolism, are discussed in the context of similar thigmostresses such as touch and wind.

Phase II trial of neoadjuvant chemotherapy with docetaxel followed by epirubicin in stage II/III breast cancer.

PURPOSE: In most neoadjuvant chemotherapy regimens, the taxane is administered either in combination with an anthracycline or after an anthracycline-containing regimen. We sought to test the feasibility, safety, and determine the pathological complete response (pCR) rate of administering docetaxel first followed by epirubicin as neoadjuvant chemotherapy in women with clinical stage II, III breast cancer. PATIENTS AND METHODS: Twenty-five women with newly diagnosed clinical stage IIB (n = 10), IIIA (n = 5), or IIIB (n = 10) received 3 cycles of docetaxel 100 mg/M2 intravenously (IV) every 3 weeks followed by 3 cycles of epirubicin 100 mg/M2 IV every 3 weeks. pCR was defined as the absence of invasive cancer in the breast at definitive surgery. RESULTS: The median primary tumor size was 6 cm (range 1-12 cm), and 13 (52%) women had clinically palpable axillary lymph nodes. Patients received 149 of the 150 planned cycles of docetaxel and epirubicin without treatment delays, and only 3 (12%) patients had a dose reduction of docetaxel. Seven (28%) patients experienced febrile neutropenia, and 9 (36%) patients had grade 3 non-hematological toxicities with diarrhea being the most frequent in 3 (12%) patients. Six (24%) patients had pCR in the breast. Analysis of pre- and post-docetaxel biopsies from a subset of patients documented taxane-induced activation of mitogen-activated and stress-activated protein kinase pathways. CONCLUSION: Neoadjuvant docetaxel followed by epirubicin is well tolerated and active in breast cancer. To our knowledge, this is first description of docetaxel-induced activation of mitogen-activated and stress-activated protein kinase pathways in human breast cancer.

Effect of atorvastatin on cyclosporine pharmacokinetics in liver transplant recipients.

BACKGROUND: The development of hyperlipidemia after liver transplant is frequently treated with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) such as atorvastatin. As atorvastatin and the primary immunosuppressant drug, cyclosporine, are metabolized by the same pathway, there is the potential for an interaction. OBJECTIVE: To determine the effect of atorvastatin on cyclosporine pharmacokinetics in liver transplant recipients. METHODS: Six stable, long-term adult liver transplant recipients from a single center who developed posttransplant dyslipidemia were recruited to participate in a 14-day, open-label study of atorvastatin 10 mg/d coadministered with standard posttransplant immunosuppression using constant oral doses of cyclosporine and corticosteroids. A 10-point pharmacokinetic profile was performed prior to and on day 14 after commencement of atorvastatin therapy. Cyclosporine concentrations were measured by HPLC-electrospray-tandem mass spectrometry. The AUC was calculated by the linear trapezoidal rule, with other parameters determined by visual inspection. RESULTS: Atorvastatin coadministration increased the cyclosporine AUC by 9% (range 0-20.6%; 3018 vs 3290 ng.h/mL; p = 0.04). No significant change was evident for other cyclosporine pharmacokinetic parameters. Total cholesterol and low-density lipoprotein cholesterol levels were significantly lower on day 14 than at baseline (p < 0.02). One patient developed a twofold increase in transaminases after 2 weeks of atorvastatin therapy, but no other clinical or biochemical adverse events were recorded. CONCLUSIONS: Atorvastatin coadministration increases the cyclosporine AUC by approximately 10% in stable liver transplant recipients. This change in systemic exposure to cyclosporine is of questionable clinical significance. Atorvastatin is effective in reducing cholesterol levels in liver transplant recipients.