Freeze-thaw cycles are predicted to increase in cold temperate regions. The potential influence of the interactions of freeze-thaw cycles and agrochemicals on the release of Cd into river water is unknown. In this study, the interactions of freeze-thaw cycles and chlorpyrifos (FC) on Cd mobility in soils were analysed. The spatial variability of soil Cd under long-term intensive tillage in a freeze-thaw agro-system was also identified. The temporal variation of sediment Cd was detected based on analysis of the sediment geochemistry. The results showed that FC increased soil Cd mobility, with an increase of approximately 10% in CaCl2-extractable Cd. The increased mobile fractions of water-soluble and exchangeable Cd originated from the decreased fraction of Fe-Mn-oxide-associated Cd and organic matter-bound Cd. The total Cd content in the surface soil followed the zonally decreasing trend of dry land > paddy land > natural land. The Cd concentrations and sedimentation rates of the sediment core generally increased from 1943 to 2013 due to agricultural exploration and farmland irrigation system construction, indicating an increase of the Cd input flux into water. The results provide valuable information about the soil Cd transport response to the influence of climatic and anthropogenic factors in cold intensive agro-systems.
To evaluate the quality of methods used in randomized controlled trials (RCTs) of treatments for management of pain and dysfunction associated with temporomandibular muscle and joint disorders (TMJD) and to discuss the implications for future RCTs.
A systematic review was made of RCTs that were implemented from 1966 through March 2006, to evaluate six types of treatments for TMJD: orthopedic appliances, occlusal therapy, physical medicine modalities, pharmacologic therapy, cognitive-behavioral and psychological therapy, and temporomandibular joint surgery. A quality assessment of 210 published RCTs assessing the internal and external validity of these RCTs was conducted using the Consolidated Standards of Reporting Trials (CONSORT) criteria adapted to the methods of the studies.
Independent assessments by raters demonstrated consistency with a mean intraclass correlation coefficient of 0.63 (95% confidence interval). The mean percent of criteria met was 58%, with only 10% of the RCTs meeting the four most important criteria.
Much of the evidence base for TMJD treatments may be susceptible to systematic bias and most past studies should be interpreted with caution. However, a scatter plot of RCT quality versus year of publication shows improvement in RCT quality over time, suggesting that future studies may continue to improve methods that minimize bias.
quality; randomized clinical trials; temporomandibular; tension type headache; TMD; TMJ
The wetland Argialbolls pedon was chosen to investigate the effects of pedogenic processes and anthropogenic activities on the vertical distribution of As concentrations. Two wetland Argialboll cores (90 cm long) were collected from the Sanjiang Plain in northeastern China and analyzed for pH, soil organic matter (SOM), Fe, Mn, and As. The results indicate that SOM accumulated in the upper horizons, while Fe and Mn were reductively leached from the upper horizons and significantly accumulated in the lower argillic horizons. Atmospheric As deposition and As redistribution during the pedogenic process led to the unique vertical distribution of As concentrations in the wetland Argialbolls. Overall, As was leached from upper horizons and then accumulated in the lower argillic horizons. However, continual atmospheric As deposition maintained a slightly elevated As concentration in the top layer. In detail, As concentration in the upper horizons ranged from 1.1 to 5.3 mg kg−1, while it ranged from 18.2 to 65.7 mg kg−1 in the lower argillic horizons. The high As concentration in the argillic horizons might pose a risk to shallow groundwater in the area.
The wetland Argialbolls pedon was chosen to investigate the effects of pedogenic processes and anthropogenic activities on the vertical distribution of lead and mercury concentration and to assess the potential use of soil as an archive of atmospheric Pb and Hg pollution. The soil was sampled from 5 cm from the surface to a depth of 90 cm at two locations in the Sanjiang Plain in northeastern China. The soil was analyzed for pH, soil organic matter (SOM), Fe, Mn, and Al. The results indicate that the SOM concentration gradually decreased with depth, while Fe and Mn were reductively leached from the upper horizons and accumulated significantly in the lower argillic horizons. Atmospheric Pb and Hg deposition and their redistribution during the pedogenic process led to a unique vertical distribution in the wetland Argialbolls. Overall, Pb was leached from the upper horizons and then accumulated in the lower argillic horizons. However, the Hg concentration decreased with depth, following the SOM distribution. The Pb concentration was significantly correlated to the Fe and Mn concentrations in the Argialbolls profiles, while the Hg concentration was significantly correlated with SOM. Post-depositional mobility along the wetland Argialbolls profile is higher for Pb and low for Hg. Therefore, the Argialbolls profile does not provide an accurate reconstruction of atmospheric Pb deposition, but might provide an accurate reconstruction of net atmospheric Hg deposition.
Auxin response factors (ARFs) are an important family of proteins in auxin-mediated response, with key roles in various physiological and biochemical processes. To date, a genome-wide overview of the ARF gene family in citrus was not available. A systematic analysis of this gene family in citrus was begun by carrying out a genome-wide search for the homologs of ARFs. A total of 19 nonredundant ARF genes (CiARF) were found and validated from the sweet orange. A comprehensive overview of the CiARFs was undertaken, including the gene structures, phylogenetic analysis, chromosome locations, conserved motifs of proteins, and cis-elements in promoters of CiARF. Furthermore, expression profiling using real-time PCR revealed many CiARF genes, albeit with different patterns depending on types of tissues and/or developmental stages. Comprehensive expression analysis of these genes was also performed under two hormone treatments using real-time PCR. Indole-3-acetic acid (IAA) and N-1-napthylphthalamic acid (NPA) treatment experiments revealed differential up-regulation and down-regulation, respectively, of the 19 citrus ARF genes in the callus of sweet orange. Our comprehensive analysis of ARF genes further elucidates the roles of CiARF family members during citrus growth and development process.
ARF gene; auxin; citrus; expression analysis; phylogenetic analysis; sweet orange
Electrospun nanomaterials; microfluidics; circulating tumor cell; whole exome sequencing; prostate cancer
The objective of this study was to evaluate the radiation dose and response in terms of local-regional progression-free survival (LRPFS) and overall survival (OS) of patients with stage IV non-small cell lung cancer (NSCLC) undergoing concurrent chemotherapy and thoracic three-dimensional radiotherapy.
In all, we enrolled 201 patients with stage IV NSCLC in this study and analyzed OS in 159 patients and LRPFS in 120.
The 1-, 2-, 3-, and 5-year OS rates were 46.2%, 19.5%, 11.7%, and 5.8%, respectively, the median survival time being 12 months. The median survival times in differential treatment response of primary tumors were 19 of complete response, 13 of partial response, 8 of stable disease, and 6 months of progressive disease, respectively (P = 0.000). The 1-, 2-, 3-, and 5-year LRPFS rates of patients undergoing four to five cycles with doses ≥63 Gy and <63 Gy were 77.4% and 32.6%, 36.2% and 21.7%, 27.2% and 0, and 15.9% and 0, respectively (P = 0.002). According to multivariate analyses, four to five cycles of chemotherapy, gross tumor volume <175.00 cm3 and post-treatment Karnofsky Performance Status score stable or increased by at least 10 units were independent prognostic factors for better OS (P = 0.035, P = 0.008, and P = 0.000, respectively). Radiation dose to the primary tumor ≥63 Gy resulted in better OS (P = 0.057) and LRPFS (P = 0.051), both findings being of borderline significance.
Treatment of IV NSCLC with joint administration of four to five cycles of chemotherapy and three-dimensional radiotherapy may prolong survival, particularly in patients receiving ≥63 Gy radiotherapy, with gross tumor volume <175.00 cm3 and post-treatment Karnofsky Performance Status score not lower than pretreatment values.
Non-small cell lung cancer; Stage IV; Concurrent chemoradiotherapy; Thoracic three-dimensional radiotherapy; Dose; Response
Understanding the fates of soil hydrological processes and nitrogen (N) is essential for optimizing the water and N in a dryland crop system with the goal of obtaining a maximum yield. Few investigations have addressed the dynamics of dryland N and its association with the soil hydrological process in a freeze-thawing agricultural area. With the daily monitoring of soil water content and acquisition rates at 15, 30, 60 and 90 cm depths, the soil hydrological process with the influence of rainfall was identified. The temporal-vertical soil water storage analysis indicated the local albic soil texture provided a stable soil water condition for maize growth with the rainfall as the only water source. Soil storage water averages at 0–20, 20–40 and 40–60 cm were observed to be 490.2, 593.8, and 358 m3 ha−1, respectively, during the growing season. The evapo-transpiration (ET), rainfall, and water loss analysis demonstrated that these factors increased in same temporal pattern and provided necessary water conditions for maize growth in a short period. The dry weight and N concentration of maize organs (root, leaf, stem, tassel, and grain) demonstrated the N accumulation increased to a peak in the maturity period and that grain had the most N. The maximum N accumulative rate reached about 500 mg m−2d−1 in leaves and grain. Over the entire growing season, the soil nitrate N decreased by amounts ranging from 48.9 kg N ha−1 to 65.3 kg N ha−1 over the 90 cm profile and the loss of ammonia-N ranged from 9.79 to 12.69 kg N ha−1. With soil water loss and N balance calculation, the N usage efficiency (NUE) over the 0–90 cm soil profile was 43%. The soil hydrological process due to special soil texture and the temporal features of rainfall determined the maize growth in the freeze-thawing agricultural area.
To evaluate the efficacy of three-dimensional radiotherapy for non-small cell lung cancer (NSCLC) patients with bone metastases.
Clinical data for 95 NSCLC patients with bone metastases were collected and prognostic factors were analyzed. All patients received radiation to their thoracic primary tumor and ≥2 cycles of chemotherapy.
Of these 95 patients, 47 patients had only bone metastases and 48 had both bone metastases and other organ metastases. Univariate analysis showed that factors that statistically significantly contributed to patients having longer overall survival (OS) included receiving a radiation dose to the primary tumor ≥63 Gy, responding to treatment and receiving ≥4 cycles of chemotherapy (p = 0.001, p = 0.037 and p = 0.009, respectively). A radiation dose to the primary tumor ≥63 Gy remained significant for patients with bone metastases only as well as those with bone and other organ metastases when they were analyzed separately (p = 0.045 and p = 0.012, respectively). For patients with bone metastases only, those with T1-2 tumors had longer OS than those with T3-4 (p = 0.048); and patients who received ≥4 cycles chemotherapy compared with those who received <4 cycles had similar OS (p = 0.385). On multivariate analysis, only a radiation dose ≥63 Gy (p = 0.028) and having only bone metastases (p = 0.006) were independent prognostic factors for better OS.
A radiation dose to the primary tumor ≥63 Gy and having only bone metastases were associated with better OS in NSCLC patients with bone metastases. For patients with bone metastases only, besides radiation dose, T status was also correlated with OS, whereas the number of chemotherapy cycles was not. Therefore, aggressive thoracic radiation may play an important role in improving OS.
Non-small Cell Lung Cancer; Bone Metastases; Thoracic Radiotherapy; Chemotherapy
Cancer Diagnosis; Circulating Tumor Cells; Nanostructured materials; Aptamer; Cell Capture; Cell Release
Circulating Tumor Cells; Single-Cell Analysis; Melanoma; BRAF Mutation; Cancer Diagnostics
Circulating tumor cells (CTCs) are one of the most crucial topics in rare cell biology and have become the focus of a significant and emerging area of cancer research. While CTC enumeration is a valid biomarker in prostate cancer, the current FDA-approved CTC technology is unable to detect CTCs in a large portion of late stage prostate cancer patients. Here we introduce the NanoVelcro CTC Chip, a device composed of a patterned silicon nanowire substrate (SiNW) and an overlaid polydimethylsiloxane (PDMS) chaotic mixer. Validated by two institutions participating in the study, the NanoVelcro Chip assay exhibits very consistent efficiency in CTC-capture from patient samples. The utilized protocol can be easily replicated at different facilities. We demonstrate the clinical utility of the NanoVelcro Chip by performing serial enumerations of CTCs in prostate cancer patients after undergoing systemic therapy. Changes in CTC numbers after 4–10 weeks of therapy were compared with their clinical responses. We observed a statistically significant reduction in CTCs counts in the clinical responders. We performed long-term follow up with serial CTC collection and enumeration in one patient observing variations in counts correlating with treatment response. This study demonstrates the consistency of the NanoVelcro Chip assay over time for CTC enumeration and also shows that continuous monitoring of CTC numbers can be employed to follow responses to different treatments and monitor disease progression.
Nanomaterials; microfluidics; circulating tumor cell; prostate cancer; diagnostics
The role of chemotherapy given concurrently with thoracic three-dimensional radiotherapy for stage IV non-small cell lung cancer (NSCLC) is not well defined. We performed this study to investigate overall survival and toxicity in patients with stage IV NSCLC treated with this modality.
From 2003 to 2010, 201 patients were enrolled in this study. All patients received chemotherapy with concurrent thoracic three-dimensional radiotherapy. The study endpoints were the assessment of overall survival (OS) and acute toxicity.
For all patients, the median survival time (MST) was 10.0 months, and the 1-, 2- and 3-year OS rates were 40.2%, 16.4%, and 9.6%, respectively. The MST was 14.0 months for patients who received a total radiation dose ≥63 Gy to the primary tumor, whereas it was 8.0 months for patients who received a total dose <63 Gy (P = 0.000). On multivariate analysis, a total dose ≥63 Gy, a single site of metastatic disease, and undergoing ≥4 cycles of chemotherapy were independent prognostic factors for better OS (P = 0.007, P = 0.014, and P = 0.038, respectively); radiotherapy involving metastatic sites was a marginally significant prognostic factor (P = 0.063). When the whole group was subdivided into patients with metastasis at a single site and multiple sites, a higher radiation dose to the primary tumor remained a significant prognostic factor for improved OS. For patients who received ≥4 cycles of chemotherapy, high radiation dose remained of benefit for OS (P = 0.001). Moreover, for the subgroup that received <4 chemotherapy cycles, the radiation dose was of marginal statistical significance regarding OS (P = 0.063). Treatment-related toxicity was found to be acceptable.
Radiation dose to primary tumor, the number of metastatic sites, and the number of chemotherapy cycles were independent prognostic factors for OS in stage IV NSCLC patients treated with concurrent chemoradiotherapy. In addition to systemic chemotherapy, aggressive thoracic radiotherapy was shown to play an important role in improving OS.
Registered on (ChiCTR-TNC-10001026)
Non-small cell lung cancer; Stage IV; Concurrent chemoradiotherapy; Thoracic three-dimensional radiotherapy; Overall survival
BACKGROUND AND PURPOSE
Cardiac toxicity is a major concern in drug development and it is imperative that clinical candidates are thoroughly tested for adverse effects earlier in the drug discovery process. In this report, we investigate the utility of an impedance-based microelectronic detection system in conjunction with mouse embryonic stem cell-derived cardiomyocytes for assessment of compound risk in the drug discovery process.
Beating of cardiomyocytes was measured by a recently developed microelectronic-based system using impedance readouts. We used mouse stem cell-derived cardiomyocytes to obtain dose-response profiles for over 60 compounds, including ion channel modulators, chronotropic/ionotropic agents, hERG trafficking inhibitors and drugs known to induce Torsades de Pointes arrhythmias.
This system sensitively and quantitatively detected effects of modulators of cardiac function, including some compounds missed by electrophysiology. Pro-arrhythmic compounds produced characteristic profiles reflecting arrhythmia, which can be used for identification of other pro-arrhythmic compounds. The time series data can be used to identify compounds that induce arrhythmia by complex mechanisms such as inhibition of hERG channels trafficking. Furthermore, the time resolution allows for assessment of compounds that simultaneously affect both beating and viability of cardiomyocytes.
CONCLUSIONS AND IMPLICATIONS
Microelectronic monitoring of stem cell-derived cardiomyocyte beating provides a high throughput, quantitative and predictive assay system that can be used for assessment of cardiac liability earlier in the drug discovery process. The convergence of stem cell technology with microelectronic monitoring should facilitate cardiac safety assessment.
safety pharmacology; cardio-safety; hERG; cardiotoxicity; predictive assay; label-free; mechanistic toxicology; ion channel; stem cell; cardiomyocyte
Fish is rich in nutrients that are favorable to bone health, but limited data are available regarding the relationship between fish intake and hip fractures. Our study examined the association between habitual fish intake and risk of hip fractures.
A case-control study was performed between June 2009 and June 2012 in Guangdong Province, China. Five hundred and eighty-one hip fracture incident cases, aged 55 to 80 years (mean: 71 years), were enrolled from four hospitals. 1∶1 matched controls by gender and age (±3 years) were also recruited from communities and hospitals. Face-to-face interviews were used to obtain habitual dietary intake and information on various covariates.
Univariate conditional logistic regression analyses showed significantly dose-dependent inverse correlations between the risk of hip fractures and the intake of fresh-water fish, sea fish, mollusca, shellfish, and total fish in all of the subjects (p-trend: <0.001–0.016). After adjusting for covariates, the associations were slightly attenuated but remained significant for all (p-trend: <0.001–0.017) except for fresh-water fish (p = 0.553). The ORs (95%CI) of hip fractures for the highest (vs. lowest) quartile were 0.80 (0.48–1.31) for fresh-water fish, 0.31 (0.18–0.52) for sea fish, 0.55 (0.34–0.88) for mollusca and shellfish, and 0.47 (0.28–0.79) for total fish, respectively. Stratified and interaction analyses showed that the association was more significant in males than in females (p-interaction = 0.052).
Higher intake of seafood is independently associated with lower risk of hip fractures in elderly Chinese. Increasing consumption of sea fish may benefit the prevention of hip fractures in this population.
The mature nucleocapsid protein of HIV-1, NCp7, and the NC-domains in gag-precursors are attractive targets for anti-AIDS drug discovery. The stability of the 1:1 complex of NCp7 with a 20mer mimic of stem-loop 3 RNA (SL3, also called psi-RNA, in the packaging domain of genomic RNA) is strongly affected by changes in ionic strength. NC-domains recognize and specifically package genomic HIV-1 RNA, while electrostatic attractions and high concentrations of protein and RNA drive NCp7 to completely coat the RNA in the mature virion. The specific interactions from NCp7-binding to loop bases of SL3 produce 1:1 complexes in solutions that have [NaCl] at or above 0.2 M, while the electrostatic interactions can dominate at and below 0.15 M NaCl, leading to complexes that have mainly 1:2 RNA:protein. Persistent, non-equilibrium mixtures of 1:1 and protein-excess complexes can exist at these lower salt concentrations, where the distribution of complexes depends on the order of addition of RNA and protein. Adding salt causes rapid rearrangement of metastable multi-protein complexes to 1:1. The stability of complexes is also affected by the nature of the added salt, with 0.018 M MgCl2 and 0.200 M added NaCl producing the same Kd (21 ± 2 nM); acetate ion stabilizes the 1:1 complex by more than a factor of two compared to the same concentration of chloride ion. Maintaining a salt concentration of 0.2 M NaCl or 18 mM MgCl2 is sufficient for experiments to distinguish drug candidates that disrupt the specific SL3-NCp7 interactions in the 1:1 complex.
RNA; HIV-1; nucleocapsid protein; fluorescence
Voltage-gated sodium channels (Nav) mediate neuronal action potentials. Tetrodotoxin inhibits all Nav isoforms, but Nav1.8 and Nav1.9 are relatively tetrodotoxin-resistant (TTX-r) compared to other isoforms. Nav1.8 is highly expressed in dorsal root ganglion neurons and is functionally linked to nociception, but the sensitivity of TTX-r isoforms to inhaled anesthetics is unclear.
The sensitivities of heterologously expressed rat TTX-r Nav1.8 and endogenous tetrodotoxin-sensitive (TTX-s) Nav to the prototypic inhaled anesthetic isoflurane were tested in mammalian ND7/23 cells using patch-clamp electrophysiology.
From a holding potential of −70 mV, isoflurane (0.53±0.06 mM, ~1.8 MAC at 24°C) reduced normalized peak Na+ current (INa) of Nav1.8 to 0.55±0.03 and of endogenous TTX-s Nav to 0.56±0.06. Isoflurane minimally inhibited INa from a holding potential of −140 mV. Isoflurane did not affect voltage-dependence of activation, but significantly shifted voltage-dependence of steady-state inactivation by −6 mV for Nav1.8 and by −7 mV for TTX-s Nav. IC50 values for inhibition of peak INa were 0.67±0.06 mM for Nav1.8 and 0.66±0.09 mM for TTX-s Nav; significant inhibition occurred at clinically relevant concentrations as low as 0.58 MAC. Isoflurane produced use-dependent block of Nav1.8; at a stimulation frequency of 10 Hz, 0.56±0.08 mM isoflurane reduced INa to 0.64±0.01 vs. 0.78±0.01 for control.
Isoflurane inhibited the tetrodotoxin-resistant isoform Nav1.8 with potency comparable to that for endogenous tetrodotoxin-sensitive Nav isoforms, indicating that sensitivity to inhaled anesthetics is conserved across diverse Nav family members. Block of Nav1.8 in dorsal root ganglion neurons could contribute to the effects of inhaled anesthetics on peripheral nociceptive mechanisms.
Inhibition of voltage-gated Na+ channels (Nav) is implicated in the synaptic actions of volatile anesthetics. We studied the effects of the major halogenated inhaled anesthetics (halothane, isoflurane, sevoflurane, enflurane and desflurane) on Nav1.4, a well characterized pharmacological model for Nav effects.
Na+ currents (INa) from rat Nav1.4 α-subunits heterologously expressed in Chinese hamster ovary cells were analyzed by whole cell voltage-clamp electrophysiological recording.
Halogenated inhaled anesthetics reversibly inhibited Nav1.4 in a concentration- and voltage-dependent manner at clinical concentrations. At equi-anesthetic concentrations, peak INa was inhibited with a rank order of desflurane > halothane ≈ enflurane > isoflurane ≈ sevoflurane from a physiological holding potential (−80 mV). This suggests that the contribution of Na+ channel block to anesthesia might vary in an agent-specific manner. From a hyperpolarized holding potential that minimizes inactivation (−120 mV), peak INa was inhibited with a rank order of potency for tonic inhibition of peak INa of halothane > isoflurane ≈ sevoflurane > enflurane > desflurane. Desflurane produced the largest negative shift in voltage-dependence of fast inactivation consistent with its more prominent voltage-dependent effects. A comparison between isoflurane and halothane showed that halothane produced greater facilitation of current decay, slowing of recovery from fast inactivation, and use-dependent block than isoflurane.
Five halogenated inhaled anesthetics all inhibit a voltage-gated Na+ channel by voltage- and use-dependent mechanisms. Agent-specific differences in efficacy for Na+ channel inhibition due to differential state-dependent mechanisms creates pharmacologic diversity that could underlie subtle differences in anesthetic and nonanesthetic actions.
Cholesterol is known to be a major risk factor for coronary heart
disease (CHD). Current treatments for elevated blood cholesterol
include dietary management, regular exercise, and drug therapy
with fibrates, bile acid sequestrants, and statins. Such
therapies, however, are often suboptimal and carry a risk for
serious side effects. This study shows that microencapsulated
Lactobacillus plantarum 80 (pCBH1) cells can efficiently
break down and remove bile acids, and establishes a basis for
their use in lowering blood serum cholesterol. Results show that
microencapsulated LP80 (pCBH1) is able to effectively break down
the conjugated bile acids glycodeoxycholic acid (GDCA) and
taurodeoxycholic acid (TDCA) with bile salt hydrolase (BSH)
activities of 0.19 and 0.08 μmol DCA/mg CDW/h
respectively. This article also summarizes the physiological
interrelationship between bile acids and cholesterol and predicts
the oral doses of microencapsulated Lactobacillus
plantarum 80 (pCBH1) cells required for lowering cholesterol.