Human CTR1 is a high-affinity copper transporter that also mediates the uptake of the anticancer drug cisplatin by largely unknown transport mechanisms. Here we report the 6-Å projection structure ...obtained for human CTR1 by using electron crystallography of 2D protein crystals in a native phospholipid bilayer. The projection of CTR1 reveals a symmetrical trimer that is >40 Å wide. Notably, the center threefold axis of each trimer forms a region of very low electron density likely to be involved in copper translocation. The formation of a putative pore for metal ions at the interface of three identical subunits deviates from the structural design of typical primary and secondary active transporters and reveals that copper uptake transporters have a novel architecture that is structurally more closely related to channel proteins.
Rituximab-hyper-CVAD alternating with rituximab-high-dose methotrexate and cytarabine is a commonly utilized regimen in the United States for mantle cell lymphoma (MCL) based on phase II single ...institutional data. To confirm the clinical efficacy of this regimen and determine its feasibility in a multicenter study that includes both academic and community-based practices, a phase II study of this regimen was conducted by SWOG.
Forty-nine patients with advanced stage, previously untreated MCL were eligible. The median age was 57.4 years (35–69.8 years).
Nineteen patients (39%) did not complete the full scheduled course of treatment due to toxicity. There was one treatment-related death and two cases of secondary myelodysplastic syndrome (MDS). There were 10 episodes of grade 3 febrile neutropenia, 19 episodes of grade 3 and 1 episode of grade 4 infection. With a median follow-up of 4.8 years, the median progression-free survival was 4.8 years (5.5 years for those ≤65 years) and the median overall survival (OS) was 6.8 years.
Although this regimen is toxic, it is active for patients ≤65 years of age and can be given both at academic centers and in experienced community centers.
Flooding effects on soil microbial communities Unger, Irene M.; Kennedy, Ann C.; Muzika, Rose-Marie
Applied soil ecology : a section of Agriculture, ecosystems & environment,
05/2009, Letnik:
42, Številka:
1
Journal Article
Recenzirano
Flooding affects both above- and below-ground ecosystem processes. While the below-ground changes may be less obvious, they are as important as the above-ground changes. Soil microorganisms are ...sensitive to disturbance, and shifts in soil microbial community structure are expected when anaerobic conditions develop from flooding. The primary objective of these studies was to determine the effect of flooding on soil microbial communities. Simulated floods were established under greenhouse and field conditions. Flood treatments of flowing, intermittent (greenhouse only) or stagnant conditions were compared to a control with no flooding. In addition, residue treatments (incorporation of grass, legume or tree residue) were evaluated under greenhouse conditions. Soil samples from these experiments were examined using phospholipid fatty acid (PLFA) analysis and total N (TN), total organic carbon (TOC) and C:N ratio. Stagnant flood conditions in the greenhouse decreased microbial biomass and markers for aerobic bacteria, Gram-negative bacteria, Gram-positive bacteria, and mycorrhizal fungi. However, residue treatment, in general, did not affect microbial community structure. Effects of flood treatments in the field varied with depth and flood
×
depth interaction. The B:F ratio and microbial biomass decreased with stagnant flooding while other measures were not affected by flooding. Microbial biomass and microbial markers decreased with depth. We found some changes in the soil microbial community due to flooding; however, the 5-week time period of our study may not have been long enough to develop measureable changes. Further changes in the microbial community may occur as flood waters remain in a given area.
Soft lithography is an alternative to silicon-based micromachining that uses replica molding of nontraditional elastomeric materials to fabricate stamps and microfluidic channels. We describe here an ...extension to the soft lithography paradigm, multilayer soft lithography, with which devices consisting of multiple layers may be fabricated from soft materials. We used this technique to build active microfluidic systems containing on-off valves, switching valves, and pumps entirely out of elastomer. The softness of these materials allows the device areas to be reduced by more than two orders of magnitude compared with silicon-based devices. The other advantages of soft lithography, such as rapid prototyping, ease of fabrication, and biocompatibility, are retained.
Key cellular processes are frequently accompanied by protein-facilitated shape changes in the plasma membrane. N-BAR-domain protein modules generate curvature by means of complex interactions with ...the membrane surface. The way they assemble and the mechanism by which they operate are largely dependent on their binding density. Although the mechanism at lower densities has recently begun to emerge, how membrane scaffolds form at high densities remains unclear. By combining electron microscopy and multiscale simulations, we show that N-BAR proteins at high densities can transform a lipid vesicle into a 3D tubular network. We show that this process is a consequence of excess adhesive energy combined with the local stiffening of the membrane, which occurs in a narrow range of mechanical properties of both the membrane and the protein. We show that lipid diffusion is significantly reduced by protein binding at this density regime and even more in areas of high Gaussian curvature, indicating a potential effect on molecular transport in cells. Finally, we reveal that the breaking of the bilayer topology is accompanied by the nematic arrangement of the protein on the surface, a structural motif that likely drives the formation of reticular structures in living cells.
Chemotherapy-induced peripheral neuropathy (CIPN) is common and leads to suboptimal treatment. Acetyl-L-carnitine (ALC) is a natural compound involved in neuronal protection. Studies have suggested ...ALC may be effective for the prevention and treatment of CIPN.
A 24-week randomized double-blind trial comparing ALC (3,000 mg per day) with placebo in women undergoing adjuvant taxane-based chemotherapy was conducted. The primary objective was to determine if ALC prevents CIPN as measured by the 11-item neurotoxicity (NTX) component of the Functional Assessment of Cancer Therapy (FACT) -Taxane scale at 12 weeks. Secondary objectives included changes in 24-week end points, functional status (FACT-Trial Outcome Index TOI), fatigue (Functional Assessment of Chronic Illness Therapy FACIT -Fatigue), and NTX grade.
A total of 409 patients were evaluable (208 received ALC; 201, placebo). In a multivariate linear regression, week-12 scores were 0.9 points lower (more CIPN) with ALC than placebo (95% CI, -2.2 to 0.4; P = .17), whereas week-24 scores were 1.8 points lower with ALC (95% CI, -3.2 to -0.4; P = .01). Patients receiving ALC were more likely to have a > 5-point decrease in FACT-NTX scores (38% v 28%; P = .05), and FACT-TOI scores were 3.5 points lower with ALC (P = .03). Grade 3 to 4 neurotoxicity was more frequent in the ALC arm (eight v one). No differences between arms were observed for FACIT-Fatigue or other toxicities. Serum carnitine level increased with ALC but remained stable with placebo.
There was no evidence that ALC affected CIPN at 12 weeks; however, ALC significantly increased CIPN by 24 weeks. This is the first study to our knowledge showing that a nutritional supplement increased CIPN. Patients should be discouraged from using supplements without proven efficacy.
AMI and stroke are the leading causes of premature mortality and hospitalizations in China. Incidence data at the population level for the two diseases is limited and the reliability and completeness ...of the existing incidence registry have not been investigated. We aim to assess if the completeness of case ascertainment of AMI and stroke incidence has improved since the implementation of electronic reporting and to estimate the incidence of AMI and stroke in Tianjin, China.
We applied the DisMod II program to model the incidence of AMI and stroke from other epidemiological indicators. Inputs include mortality rates from Tianjin's mortality surveillance system, and the point prevalence, remission rates and relative risks taken from IHME's Global Burden of Disease studies. The completeness of AMI and stroke incidence reporting was assessed by comparing the sex and age-specific incidence rates derived from the incidence surveillance system with the modeled incidence rates.
The age and sex standardized modeled incidence per 100,000 person-year decreased (p < 0.0001) from 138 in 2007 to 119 in 2015 for AMI and increased (p < 0.0001) from 520 in 2007 to 534 in 2015 for stroke. The overall completeness of incidence report was 36% (95% CI 35-38%) for AMI and 54% (95% CI 53-55%) for stroke. The completeness was higher in men than in women for both AMI (42% vs 30%, p < 0.0001) and stroke (55% vs 53%, p < 0.0001) and was higher in residents aged 30-59 than those aged 60 or older for AMI (57% vs 38%, p < 0.0001). The completeness of reporting increased by 7.2 (95% CI 4.6-9.7) and 15.7 (95% CI 14.4-16.9) percentage points for AMI and stroke, respectively, from 2007 to 2015 among those aged 30 or above. The increases were observed in both men and women (p < 0.0001) and were more profound (p < 0.0001) among those aged between 30 and 59 and occurred primarily during the 2010 and 2015 period.
Completeness of AMI and stroke incidence surveillance was low in Tianjin but has improved in recent years primarily owing to the incorporation of an automatic reporting component into the information systems of health facilities.
The natural history of follicular lymphoma is believed not to have changed over the last 30 years. Median survivals have ranged from 7 to 10 years, and the disease is considered incurable. However, ...multiple new treatment options have been developed in the last decade, and their impact on survival of follicular lymphoma remains unknown.
In the current analysis, we identified all previously untreated, advanced-stage, follicular lymphoma patients treated with the following three sequential treatment approaches: cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy +/- nonspecific immunostimulants (Southwest Oncology Group SWOG 7426 and 7713: 1974 to 1983); prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide (ProMACE) plus mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) +/- interferon (SWOG 8809: 1988 to 1994); and CHOP followed by monoclonal antibody (MoAb) therapy (SWOG 9800 and 9911: 1998 to 2000). We assessed the patients' progression-free survival (PFS) and overall survival (OS). The MoAb trials included CHOP followed by rituximab (SWOG 9800) and CHOP followed by (131)I-tositumomab (SWOG 9911).
The PFS curves for the CHOP and ProMACE-MOPP studies are overlapping, with 4-year PFS estimates of 46% and 48%, respectively. However, the PFS rate of the CHOP + MoAb studies is significantly improved at 61% (P = .005). The OS curves show improvement with each succeeding study. The 4-year estimate of OS is 69% for the CHOP regimens, 79% for the ProMACE-MOPP study, and 91% for the CHOP + MoAb regimens (P < .001). These conclusions were retained after adjusting for differences in prognostic factors between the study groups.
The results of this study suggest that OS for patients with follicular lymphoma has improved over time and that the choice of initial therapy may matter.
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