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This chapter tracks the way that major and minor faith groups dynamically energised journalism in the nineteenth century by engaging in print culture. With more than 3,000 titles in circulation the denominational press served both established and dissenting religious communities, helped to secure converts, raise funds and provide its readers with a shared identity based on their faith. This was particularly important for migrants who brought with them their own religious and cultural practices. Schism and debate stimulated the publication of religious newspapers and periodicals such as the Church Times, the Nonconformist, the Jewish Chronicle, and the Catholic Herald. Religious bodies used the press to contend against the major ideological shifts of the age: the evolution debate, evangelical revivalism, the challenge of socialism and the inexorable rise of secularism.

Culture contamination, end-product toxicity, and energy efficient product recovery are long-standing bioprocess challenges. To solve these problems, we propose a high-pressure fermentation strategy, coupled with in situ extraction using the abundant and renewable solvent supercritical carbon dioxide (scCO2), which is also known for its broad microbial lethality. Towards this goal, we report the domestication and engineering of a scCO2-tolerant strain of Bacillus megaterium, previously isolated from formation waters from the McElmo Dome CO2 field, to produce branched alcohols that have potential use as biofuels. After establishing induced-expression under scCO2, isobutanol production from 2-ketoisovalerate is observed with greater than 40% yield with co-produced isopentanol. Finally, we present a process model to compare the energy required for our process to other in situ extraction methods, such as gas stripping, finding scCO2 extraction to be potentially competitive, if not superior., End-product toxicity, culture contamination, and energy efficient product recovery are long-standing issues in bioprocessing. Here, the authors address these problems using a fermentation strategy that combines microbial production of branched alcohols with supercritical carbon dioxide extraction.

The Co-operative Party was formed in 1917, though its obvious links with the Labour Party were not formalised until the 1920s. Whilst this development has often been seen by historians, such as G. D. H. Cole, as an immediate to conditions in the Great War and lacking in any real sense of class consciousness, Joan Allen sees it as a much more as a long-term product of the radicalisation of a membership which was gradually unwinding its links with Liberalism much along the lines suggested by Sidney Pollard. Examining the Co-operative branches in the north east of England, she argues that whilst there might have been some disagreement about establishing a political party for the co-operative movement, and difficulties with the local constitutions of co-operatives which were not geared to providing money for political activities, it is clear that was, for a long time, the direction that co-operative societies in the north east were drifting towards in a region where working-class solidarity always counted. There was not the diffidence towards political action and class consciousness in the co-operative movement which some writers have suggested.

Although the Chartist movement generated a vast array of newspapers and journals, the Northern Star has received the most scholarly attention, not least because its dwindling subscription base and chaotic editorial arrangements after 1850 seem to be a corollary to the movement's decline. Yet it was other journals - sponsored and edited by enterprising individuals - which sustained the Chartist cause and helped to foster political solidarities between British and European radicals at the mid-century. This article throws the spotlight on George Julian Harney's monthly Democratic Review of British and Foreign Politics, History and Literature (1849-50). It is noteworthy that Harney edited both the Northern Star and the Democratic Review until September 1850, and from 22 June 1850 to 30 November 1850 he also published a third journal, the weekly Red Republican. Whilst the Red Republican has attracted a good deal of interest from Marxist scholars, who view the first English translation of the Communist Manifest...

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.

Background Preclinical studies show that mitomycin-C (MMC) followed by irinotecan (CPT-11) is synergistic. Therefore, we evaluated the toxicity and efficacy of sequentially administered low-dose MMC and CPT-11 in patients (pts) with pretreated metastatic breast cancer (MBC). Secondary objective was to evaluate the correlation between MMC-induced topoisomerase I (TOPO I) expression and NAD(P)H:quinone oxireductase 1 (NQO1) genotypes in peripheral blood mononuclear cells (PBMC) and efficacy or toxicity of the regimen. Design Thirty-two pts received MMC i.v. 6 mg/m2 day 1 and CPT-11 i.v. 125 mg/m2 days 2 and 8 every 28 days for maximum of six cycles. TOPO I expression and NQO1 reductase genotyping in 23 of 32 (72%) pts were assayed by PCR. Results The median time to progression (TTP) was 4.7 months (95% confidence interval 4.0–5.4 months). TOPO I expression was increased 5- to 10-fold and 20- to 30-fold in PBMC at 24 and 168 h, respectively. There was no relationship between these markers and efficacy or toxicity of the regimen. Conclusions Sequential low-dose MMC and CPT-11 was active and tolerable by pretreated MBC pts. Future trials should focus on less pretreated MBC pts and sequential tumor biopsies to test the hypothesis that increased intratumoral expression of TOPO I is related to efficacy.

The Brassica rapa L. silique is a self-contained environment that maintains hypoxia around the developing seeds, and in which carbon dioxide accumulates to very high concentrations (>30,000 ppm). How the silique microenvironment modulates the composition and amount of storage reserves in the seeds is of interest because of the important agricultural role played by canola ( B. rapa and Brassica napus ) as an oilseed. Because of the small volume and dynamic nature of this microenvironment in Brassica , a standardized system was needed to study the environmental role played in storage reserve deposition. For this purpose we have developed a silique culture system that permits maturation of seed in vitro . Siliques excised from plants just 11 days after pollination complete the ripening of their seeds after 20 days of culture in light (200 μmol/m 2 /s) on MS medium containing 30 g/l sucrose, 0.25 mg/l BAP, and 0.025 mg/l NAA. Cytochemical localization and biochemical analyses revealed that storage reserves were affected by the in vitro maturation system. Although following a comparable ripening timeline to that occurring on the plant, and producing fully germinable seeds, in vitro maturation resulted in a 40% reduction in seed weight and the mature seeds contained decreased lipid, but increased protein, starch and soluble carbohydrates. To study the internal atmosphere surrounding the seeds, we developed a method to capture silique gases in helium with subsequent quantification of O 2 and CO 2 in the sample by gas chromatography. Analysis of the internal silique atmosphere showed that in vitro siliques provided seeds with a less oxygenated environment than they experience attached to the plant. Carbon dioxide concentrations remained high later into the maturation sequence in vitro than on the plant. When sampling gases from siliques attached to plants, we found multiple samples from the same plant resulted in higher variance than when only a single silique was sampled, suggesting that connection to the plant directly influences internal silique gases. Lower O 2 in the in vitro siliques was correlated with depressed lipid content in their mature seeds, supporting the conclusion that oxygen availability limits lipid accumulation. Previous studies showed how environmental factors influence Brassica embryos grown in tissue culture. These systems fail to preserve the component of metabolic regulation that is enforced by the silique wall tissues. Our in vitro maturation system provides a useful tool for specialized investigations since both the gaseous and hormonal environments can be readily manipulated.

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/m 2 of docetaxel on days 1, 8, and 15 in combination with capecitabine 800 mg/m 2 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.

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.

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.

The last decade or so has seen a marked revival of interest in Mazzini’s role in the Risorgimento and a far greater recognition of his contribution to the intellectual currents of the time, those which coalesced around ideas of nation building, self-determination, human rights and democracy.2 To some extent this revisionism has been prompted by the Mazzini and Garibaldi bicentenaries, and the recent 150th anniversary of Italian unification.3 It is also refracted by the turn to transnationalism, an approach which does not diminish the centrality of an Italian focus for Risorgimento studies but rather one which locates it within an international framework — as part of a wider ‘transcontinental, transatlantic and progressive nineteenth-century movement’.4 This work has had an impact on British studies too, expanding on Margot Finn’s groundbreaking critique of post-Chartist politics to flesh out the complex milieu of London emigre society in which Mazzini’s republican ideas were variously debated, contested and embraced.5 Some of these studies have revisited Mazzini’s own writings and there is much to be said for deepening that critique.6 As a natural corollary to this reappraisal, this chapter seeks to explore more fully the world of radical print culture which enabled him to develop and disseminate a vision of democracy that transcended national boundaries.

Background: Mycophenolic acid kinetics have been reported to vary after renal transplantation, and mycophenolic acid area under the concentration-time curve (AUC) is the best predictor of suppression of graft rejection. Methods: To determine whether mycophenolic acid kinetics vary after renal transplantation and to examine the potential role of enterohepatic recirculation, we investigated the kinetics of mycophenolic acid and mycophenolic acid glucuronide on days 2, 5, and 28 after transplantation in 10 kidney transplant recipients (male/female ratio, 1.5; mean age, 41.7 +/- 5.0 years) given 1 g mycophenolate mofetil twice a day. To facilitate therapeutic drug monitoring, we examined a limited sampling strategy for estimating 12-hour mycophenolic acid [AUC(0-12)]. Results: The mean +/- SE AUC(0-12) for mycophenolic acid on day 28 was 38.5 +/- 1.6 mg . h/L, with a secondary peak 4 to 8 hours after dosing that was attributable to enterohepatic recirculation. Marked variability was shown in the kinetic profile of mycophenolic acid among patients across the three sampling days. Mycophenolic acid AUC(0-12) was positively predicted by both serum creatinine (P = .01) and serum albumin (P = .03) but not by time after transplantation, body weight, or trough concentration. Limited sampling (at 0, 1, 3, and 6 hours) accounted for 84.1% of the variability in the mycophenolic acid AUC(0-12) data and predicted the AUC(0-12) closely (r(2) = 0.954) when evaluated in 10 different kidney transplant recipients. Conclusions: Mycophenolic acid AUC(0-12) is predicted by serum albumin and creatinine after kidney transplantation, and the AUC(0-12) may be determined during the early posttransplant period while the patient remains hospitalized with use of a limited sampling strategy to facilitate therapeutic drug monitoring.

Previous experiments had shown that microgravity adversely affected seed development in Brassica rapa L. We tested the hypothesis that gravity controls seed development via modulation of gases around the developing seeds, by studying how hypergravity affects the silique microenvironment and seed development. Using an in vitro silique maturation system, we sampled internal silique gases for 16 d late in the seed maturation sequence at 4 g or 1 g. The carbon dioxide level was significantly higher inside the 4-g siliques, and the immature seeds became heavier than those maturing at 1 g. Pollination and early embryo development were also studied by growing whole plants at 2 g or 4 g for 16 d inside chambers mounted on a large-diameter centrifuge. Each day the rotor was briefly stopped to permit manual pollination of flowers, thereby producing cohorts of same-aged siliques for comparison with stationary control material. The loss of starch and soluble carbohydrates during seed development was accelerated in hypergravity, with seeds developing at 4 g more advanced by 2 d than those at 1 g. Seeds produced at 4 g contained more lipid than those at 1 g. Taken together, these results indicate that hypergravity enhances gas availability to the developing embryos. Gravity's role in seed development is of importance to the space programme because of the plan to use plants for food production and habitat regeneration in extraterrestrial settings. These results are significant because they underscore the tight co-regulation of Brassica seed development and the atmosphere maintained inside the siliques.

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.

Background: We conducted a phase I trial to determine the safety and maximum tolerated dose (MTD) of non-pegylated liposome-encapsulated doxorubicin (Myocete; D-99) administered with weekly docetaxel in metastatic breast cancer (MBC) patients. Patients and methods: Twenty-one patients with no prior chemotherapy for MBC received D-99 (60 or 50 mg/m 2 ) intravenously (i.v.) on day 1 and escalating doses of docetaxel (25, 30 and 35 mg/m 2 ) i.v. on days 1 and 8 in cohorts of three to six patients. Treatment cycles were repeated every 21 days for a maximum of six cycles. Results: The maximum tolerated dose (MTD) was 50 mg/m 2 of D-99 in combination with 25 mg/m 2 of weekly docetaxel. The most common grade 4 toxicity was neutropenia that occurred in 42 (41%) of treatment cycles, with 10 hospitalizations for febrile neutropenia. Serious protocol-defined cardiac events occurred in three (14%) patients, with two (10%; 95% confidence interval [CI] 1% to 30%) developing congestive heart failure (CHF) after a total cumulative anthracycline dose (adjuvant doxorubicin + D-99) of 540 mg/m 2 . Conclusions: D-99 in combination with weekly docetaxel, at the doses and schedule as administered in this trial, is not recommended for phase II testing. Additional trials, using different doses and schedules, are required to evaluate the potential side-effects and efficacy of D-99 and docetaxel.

10542 Background: MMC and CPT-11 are synergistic in preclinical studies, as MMC increases expression of Topoisomerase I (Topo I), the target of CPT-11. Three out of 5 heavily pretreated MBC pts benefited from MMC and CPT-11 in a phase I trial. We designed a phase II trial of this combination in MBC pts and hypothesized that increased Topo I expression in peripheral blood mononuclear cells (PBMC) would correlate with longer time to progression (TTP). Methods: Pt eligibility: ECOG PS 2 or less; no more than 2 prior chemotherapy regimens for MBC; adequate organ function; measurable and non-measurable disease were permitted. Treatment: intravenous (IV) MMC-6 mg/m2 on day 1 and IV CPT-11–125 mg/m2 on days 2 and 8 every 28 days. Genotyping of NQ01 (enzyme that activates MMC) was evaluated by pyrosequencing; Topo I gene expression by reverse transcriptase-polymerase chain reaction (RT-PCR) was evaluated in PBMC pretreatment, 24 hrs, 48 hrs, and 8 days after MMC. Results: Thirty-two pts enrolled with the following characteristics: median age 50 years (range 29–73); median PS 0 (range 0–2); postmenopausal 29 (91%) pts; estrogen receptor (ER) negative 14 (44%) pts; HER-2/neu 3+ by IHC 7 (22%) pts, and 10 (31%) pts were ER(−), PR(−) and HER-2/neu (−). Six (19%) pts had no prior chemotherapy; 7 (22%)-1 prior regimen; and 19 (59%)-2 prior regimens. Pts received a median of 4 cycles (range 1–12). Four (12%) pts experienced grade 4 toxicity (1-neutropenia without fever, 1-abdominal pain, 1-pulmonary embolism, and 1-diarrhea). The most common grade 3 toxicities were neutropenia in 13(41%) pts, nausea in 7 (22%) pts, diarrhea in 6 (19%) pts, fatigue in 5 (16%) pts, and thrombocytopenia in 2 (6%) pts. Median TTP was 4.7 months (95% CI, 4.0 to 5.4 months). For 10 triple negative pts the median TTP of 5.4 months was not different. Baseline and induced Topo I gene expression was greatest in NQ01 wild-type genotype, however, increased Topo I expression in PBMC was associated with shorter TTP. Conclusions: Sequential administration of MMC and CPT-11 had acceptable toxicities and antitumor activity. Our hypothesis that increased Topo I expression in PBMC correlates with longer TTP was incorrect. No significant financial relationships to disclose.