A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress

Cisplatin and its platinum analogs, carboplatin and oxaliplatin, are some of the most widely used cancer chemotherapeutics. Although cisplatin and carboplatin are used primarily in germ cell, breast and lung malignancies, oxaliplatin is instead used almost exclusively to treat colorectal and other gastrointestinal cancers. Here we utilize a unique, multi-platform genetic approach to study the mechanism of action of these clinically established platinum anti-cancer agents, as well as more recently developed cisplatin analogs. We show that oxaliplatin, unlike cisplatin and carboplatin, does not kill cells through the DNA-damage response. Rather, oxaliplatin kills cells by inducing ribosome biogenesis stress. This difference in drug mechanism explains the distinct clinical implementation of oxaliplatin relative to cisplatin, and it might enable mechanistically informed selection of distinct platinum drugs for distinct malignancies. These data highlight the functional diversity of core components of front-line cancer therapy and the potential benefits of applying a mechanism-based rationale to the use of our current arsenal of anti-cancer drugs

Industry Change and Union Mergers in British Retail Finance

This paper investigates the reasons for and implications of the recent merger between three of the largest unions in the retail finance sector, creating UNIFI. Recent union mergers have been explained by environmental changes adversely affecting membership and finances. These prompt leaders to consider merger as an appropriate organizational solution. Mergers are successfully concluded when leaders are able to overcome internal resistance and develop acceptable outcomes. We examine whether these factors are sufficient to explain how the merger between the national banking union and two large company-based staff unions was concluded, given longstanding institutional rivalry. Copyright Blackwell Publishers Ltd/London School of Economics 2001.

Development of a one-step immunochromatographic strip test for the rapid detection of nevirapine (NVP), a commonly used antiretroviral drug for the treatment of HIV/AIDS

Currently, high-performance liquid chromatographic (HPLC) methods are mainly used to measure anfiretroviral plasma concentrations in HIV-infected patients. Although the utility of routine therapeutic drug monitoring (TDM) as an additional toot to optimize long-term antiretroviral therapy is unclear, if TDM is to be widely used, the availability of simple, cheap and reliable methods for the measurement of antiretroviral drug levels are needed, particularly in resource-limited settings. In this study, an immunochromatograhic (IC) strip test to detect the presence of nevirapine (NVP) in body fluids has been developed. Antiserum to NVP was first raised in rabbits by immunization against NVP chemically conjugated with bovine serum albumin, and subsequently validated by Western immunoblotting and competitive indirect ELISA. The partially purified anti-NVP antibodies were conjugated with colloidal gold particles. The conjugation of the colloidal gold and polyclonal antibodies was monitored by UV-vis spectroscopy, while transmission electron microscopy images were used to characterize the particle size and shape of the conjugates, The resulting colloidal gold conjugates were used for the production of an IC strip test to detect nevirapine in human plasma. Preliminary assessment suggests no-cross reactivity of the NVP polyclonal antibodies but assessment of plasma samples from HIV-infected patients receiving HAART needs to be conducted. This assay could potentially be used for drug monitoring as part of the clinical care of HIV infected patients

How Can We Realize Sustainable Development Goals in Rocky Desertified Regions by Enhancing Crop Yield with Reduction of Environmental Risks?

To meet the sustainable development goals in rocky desertified regions like Guizhou Province in China, we should maximize the crop yield with minimal environmental costs. In this study, we first calculated the yield gap for 6 main crop species in Guizhou Province and evaluated the quantitative relationships between crop yield and influencing variables utilizing ensembled artificial neural networks. We also tested the influence of adjusting the quantity of local fertilization and irrigation on crop production in Guizhou Province. Results showed that the total yield of the selected crops had, on average, reached over 72.5% of the theoretical maximum yield. Increasing irrigation tended to be more consistently effective at increasing crop yield than additional fertilization. Conversely, appropriate reduction of fertilization may even benefit crop yield in some regions, simultaneously resulting in significantly higher fertilization efficiency with lower residuals in the environment. The total positive impact of continuous intensification of irrigation and fertilization on most crop species was limited. Therefore, local stakeholders are advised to consider other agricultural management measures to improve crop yield in this region

Periodic Relations between Terrestrial Vegetation and Climate Factors across the Globe

In this paper, cross-spectrum analysis was used to verify the agreement of periodicity between the global LAI (leaf area index) and climate factors. The results demonstrated that the LAI of deciduous forests and permanent wetlands have high agreement with temperature, rainfall and radiation over annual cycles. A low agreement between the LAI and seasonal climate variables was observed for some of the temperate and tropical vegetation types including shrublands and evergreen broadleaf forests, possibly due to the diversity of vegetation and human activities. Across all vegetation types, the LAI demonstrated a large time lag following variation in radiation (>1 month), whereas relatively short lag periods were observed between the LAI and annual temperature (around 2 weeks)/rainfall patterns (less than 10 days), suggesting that the impact of radiation on global vegetation growth is relatively slow, which is in accord with the results of previous studies. This work can provide a benchmark of the phenological drivers in global vegetation, from the perspective of periodicity, as well as helping to parameterize and refine the DGVMs (Dynamic Global Vegetation Models) for different vegetation types

Low-doses of indinavir boosted with ritonavir in HIV-infected Thai patients: pharmacokinetics, efficacy and tolerability

Objectives: To assess the steady-state pharmacokinetics of two reduced doses of indinavir boosted with ritonavir (indinavir/ritonavir) in HIV-infected Thai patients. Patients and methods: Thirteen immunocompromised antiretroviral-naive patients (6 males, 7 females) initiated 600/100 mg indinavir/ritonavir, zidovudine and lamivudine, every 12 h. After 1 month, blood samples were taken at pre-dose, and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 h after drug intake. Indinavir dosing was then reduced to 400 mg (twice daily) and 1 week later an identical series of samples were drawn. Patients then resumed 600 mg of indinavir. HIV-1 RNA viral load was determined at 8, 24 and 48 weeks. Indinavir plasma levels were determined by HPLC and pharmacokinetic parameters by non-compartmental analysis. Results: Median (range) weight was 58 kg (51-73) for men and 53 kg (46-59) for women. On 600 mg of indinavir, median indinavir AUC, C-max and C-min were 39.3 mg(.)h/L (20.6-50.5), 6.2 mg/L (3.7-9.0) and 0.41 mg/L (0.12-0.77), respectively, and on indinavir 400 mg, 18.3 mg(.)h/L (11.1-33.0), 3.8 mg/L (2.2-7.8) and 0.17 mg/L (0.10-0.39), respectively. No renal complications were observed. At 48 weeks, 6/13 (46%) patients had stopped 600 mg of indinavir due to intolerability (gastrointestinal and cutaneous), and 5/7 (71%) patients had a HIV-1 viral load < 50 copies/mL. Conclusions: Reduced doses of indinavir/ritonavir maintained adequate indinavir plasma levels compared to current guidelines suggesting that these doses are efficacious in this setting. Considering the poor tolerability of 600 mg of indinavir, the 400 mg of indinavir may be preferred due to its lower exposure indices but long-term efficacy data are needed

Tree-ring δ18O identifies similarity in timing but differences in depth of soil water uptake by trees in mesic and arid climates

Water availability and uptake by trees will be important to predict tree growth, especially in regions with increasingly drying climate. Tree-ring δ18O (δ18OTR) can be influenced by moisture, so it may be a useful tool for tracking soil moisture content (SMC) variation with respect to the depth from which water is taken up and the timing of water uptake. Here we analyzed the relationship between δ18OTR of conifers and monthly SMC at different depths (0–10 and 0–100 cm) at three dry and three humid sites in China. We found that SMC outperformed local precipitation amount in terms of strength of correlations with δ18OTR in most months during the growing season. At the dry sites, δ18OTR was significantly correlated with topsoil SMC (0–10 cm) but more weakly related to SMC at 0–100 cm during the main growing season (June-July-August), implying that the trees were primarily utilizing shallow water. Whereas humid sites had similar correlations at both depths, suggesting that these trees utilized water over depth. At both sites, the highest correlation between δ18OTR and SMC occurred in months with the strongest monsoonal precipitation (June for the humid sites and July/August for the dry sites), which may indicate rapid cycling of precipitation into surface soils and then into tree roots. These findings are supported by the root distribution at the dry and humid sites, but are contrary to Walter's tree-grass two-layer model that stressed the uptake of deep soil water by trees in dry regions. In summary, our study suggests similar soil water-use seasonality but different water uptake depths of trees under dry and humid climates. This implies that δ18OTR could be a reliable proxy for SMC variation, which may provide important evidence for understanding tree water-use adaptation to changing climate.National Natural Science Foundation of China24 month embargo; available online 2 August 2021This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Geomorphically mediated carbon dynamics of floodplain soils and Implications for net effect of carbon erosion

The fate of organic carbon deposited in floodplain sediments is an important control on the magnitude and direction of the carbon flux from anthropogenically accelerated erosion and channelization of the riverine network. Globally, rates of deposition and the mean residence time (MRT) of carbon within different geomorphic settings remains poorly constrained. We sampled the soil profile to 0.8 m depth from two geomorphic zones: active channel belt (ACB) and lowland floodplain, under long-term pasture adjacent to the river Culm in SW England, UK. We evaluated sedimentation rates and carbon storage using fallout radionuclide 137Cs, particle size and total carbon analyses. Variation in decomposition was assessed via empirical and numerical techniques, using soil aggregate size and density fractionation combined with natural abundance C analysis. Carbon decomposition was simulated using the RothC model and catchment implications were explored using a floodplain evolution model. Sedimentation and carbon accumulation rates were 5-6 times greater in the ACB than the floodplain. Carbon decomposition rates also varied with geomorphic setting. Soil carbon in floodplain cores had more rapid decomposition rates indicated by greater 13C-enrichment and subsoils dominated by mineral-associated soil organic carbon. The carbon in ACB cores was less processed and 13C-depleted by comparison, with more light fraction and macroaggregate-carbon throughout the cores. Decomposition rates in the ACB were estimated to be 4-fold less than the floodplain, as indicated by the RothC model. Including the ACB in floodplain carbon MRT calculations in the floodplain evolution model increased overall MRT by 10%. The major differences in the balance of sedimentation and decomposition rates between active and inactive floodplains suggest that the relative extent of these contrasting floodplain zones is critical to the overall carbon balance of floodplains. Restoration projects could enhance soil carbon storage by maximising active floodplain areas by increasing river channel complexit

Influence of body weight on achieving indinavir concentrations within its therapeutic window in HIV-infected Thai patients receiving indinavir boosted with ritonavir

Indinavir boosted with ritonavir (IDV/r) dosing with 400/100 mg, twice daily, is preferred in Thai adults, but this dose can lead to concentrations close to the boundaries of its therapeutic window. The objectives of this analysis were to validate a population pharmacokinetic model to describe IDV/r concentrations in HIV-infected Thai patients and to investigate the impact of patient characteristics on achieving adequate IDV concentrations. IDV/r concentration data from 513 plasma samples were available. Population means and variances of pharmacokinetic parameters were estimated using a nonlinear mixed effects regression model (NONMEM Version VI). Monte Carlo simulations were performed to estimate the probability of achieving IDV concentrations within its therapeutic window. IDV/r pharmacokinetics were best described by a one-compartment model coupled with a single transit compartment absorption model. Body weight influenced indinavir apparent oral clearance and volume of distribution and allometric scaling significantly reduced the interindividual variability. Final population estimates (interindividual variability in percentage) of indinavir apparent oral clearance and volume of distribution were 21.3 L/h/70 kg (30%) and 90.7 L/70 kg (22%), respectively. Based on model simulations, the probability of achieving an IDV trough concentration greater than 0.1 mg/L was greater than 99% for 600/100 mg and greater than 98% for 400/100 mg, twice daily, in patients weighing 40 to 80 kg. However, the probability of achieving IDV concentrations associated with an increased risk of drug toxicity (greater than 10.0 mg/L) increased from 1% to 10% with 600/100 mg compared with less than 1% with 400/100 mg when body weight decreased from 80 to 40 kg. The validated model developed predicts that 400/100 mg of IDV/r, twice daily, provides indinavir concentrations within the recommended therapeutic window for the majority of patients. The risk of toxic drug concentrations increases rapidly with IDV/r dose of 600/100 mg for patients less than 50 kg and therapeutic drug monitoring of IDV concentrations would help to reduce the risk of IDV-induced nephrotoxicity

Pharmacokinetics and virologic response of zidovudine/lopinavir/ritonavir initiated during the third trimester of pregnancy

Objective: To evaluate the pharmacokinetics and HIV viral load response following initiation during the third trimester of pregnancy of zidovudine plus standard-dose lopinavir boosted with ritonavir (LPV/r), twice daily, until delivery for the prevention of mother-to-child transmission of HIV. Design: Prospective study nested within a multicenter, three-arm, randomized, phase III prevention of mother-to-child transmission of HIV trial in Thailand (PHPT-5, ClinicalTrials.gov Identifier: NCT00409591). Methods: Women randomized to receive 300 mg zidovudine and 400/100 mg LPV/r twice daily from 28 weeks' gestation, or as soon as possible thereafter, until delivery had intensive steady-state 12-h blood sampling performed. LPV/r pharmacokinetic parameters were calculated using noncompartmental analysis. Rules were defined a priori for a LPV/r dose escalation based on the proportion of women with an LPV area under the concentration–time curve (AUC) below 52 μg h/ml (10th percentile for LPV AUC in nonpregnant adults). HIV-1 RNA response was assessed during the third trimester. Results: Thirty-eight women were evaluable; at entry, median (range) gestational age was 29 (28–36) weeks, weight 59.5 (45.0–91.6) kg, CD4 cells count 442 (260–1327) cells/μl and HIV-1 RNA viral load 7818 (<40–402 015) copies/ml. Geometric mean (90% confidence interval) LPV AUC, Cmax and Cmin were 64.6 (59.7–69.8) μg h/ml, 8.1 (7.5–8.7) μg/ml and 2.7 (2.4–3.0) μg/ml, respectively. Thirty-one of 38 (81%) women had an LPV AUC above the AUC target. All women had a HIV-1 viral load less than 400 copies/ml at the time of delivery. Conclusion: A short course of zidovudine plus standard-dose LPV/r initiated during the third trimester of pregnancy achieved adequate LPV exposure and virologic response