Spatial IMA1 regulation restricts root iron acquisition on MAMP perception.

Iron is critical during host-microorganism interactions1-4. Restriction of available iron by the host during infection is an important defence strategy, described as nutritional immunity5. However, this poses a conundrum for externally facing, absorptive tissues such as the gut epithelium or the plant root epidermis that generate environments that favour iron bioavailability. For example, plant roots acquire iron mostly from the soil and, when iron deficient, increase iron availability through mechanisms that include rhizosphere acidification and secretion of iron chelators6-9. Yet, the elevated iron bioavailability would also be beneficial for the growth of bacteria that threaten plant health. Here we report that microorganism-associated molecular patterns such as flagellin lead to suppression of root iron acquisition through a localized degradation of the systemic iron-deficiency signalling peptide Iron Man 1 (IMA1) in Arabidopsis thaliana. This response is also elicited when bacteria enter root tissues, but not when they dwell on the outer root surface. IMA1 itself has a role in modulating immunity in root and shoot, affecting the levels of root colonization and the resistance to a bacterial foliar pathogen. Our findings reveal an adaptive molecular mechanism of nutritional immunity that affects iron bioavailability and uptake, as well as immune responses.

Multitask deep learning on mammography to predict extensive intraductal component in invasive breast cancer.

OBJECTIVES: To develop a multitask deep learning (DL) algorithm to automatically classify mammography imaging findings and predict the existence of extensive intraductal component (EIC) in invasive breast cancer. METHODS: Mammograms with invasive breast cancers from 2010 to 2019 were downloaded for two radiologists performing image segmentation and imaging findings annotation. Images were randomly split into training, validation, and test datasets. A multitask approach was performed on the EfficientNet-B0 neural network mainly to predict EIC and classify imaging findings. Three more models were trained for comparison, including a single-task model (predicting EIC), a two-task model (predicting EIC and cell receptor status), and a three-task model (combining the abovementioned tasks). Additionally, these models were trained in a subgroup of invasive ductal carcinoma. The DeLong test was used to examine the difference in model performance. RESULTS: This study enrolled 1459 breast cancers on 3076 images. The EIC-positive rate was 29.0%. The three-task model was the best DL model with an area under the curve (AUC) of EIC prediction of 0.758 and 0.775 at the image and breast (patient) levels, respectively. Mass was the most accurately classified imaging finding (AUC = 0.915), followed by calcifications and mass with calcifications (AUC = 0.878 and 0.824, respectively). Cell receptor status prediction was less accurate (AUC = 0.625-0.653). The multitask approach improves the model training compared to the single-task model, but without significant effects. CONCLUSIONS: A mammography-based multitask DL model can perform simultaneous imaging finding classification and EIC prediction. CLINICAL RELEVANCE STATEMENT: The study results demonstrated the potential of deep learning to extract more information from mammography for clinical decision-making. KEY POINTS: • Extensive intraductal component (EIC) is an independent risk factor of local tumor recurrence after breast-conserving surgery. • A mammography-based deep learning model was trained to predict extensive intraductal component close to radiologists' reading. • The developed multitask deep learning model could perform simultaneous imaging finding classification and extensive intraductal component prediction.

Unveiling the heightened susceptibility: Exploring early hypophosphatemia in critically ill trauma patients.

BACKGROUND: Phosphorus is a vital mineral crucial for various physiological functions. Critically ill trauma patients frequently experience hypophosphatemia during the immediate post-traumatic phase, potentially impacting outcomes. This study aims to investigate the incidence of early hypophosphatemia in critically major trauma patients. METHODS: In this prospective observational study, trauma patients admitted to the intensive care unit (ICU) within one day were enrolled. These patients were categorized into Hypo-P groups and Non-hypo groups based on the development of new-onset hypophosphatemia within 72 h after feeding. The primary outcome assessed was the incidence of new-onset hypophosphatemia. The secondary outcomes included ICU and hospital stay, ventilation duration, and mortality. RESULTS: 76.1% of patients developed a new onset of hypophosphatemia within 72 h after feeding. The Hypo-P group had significantly longer ICU stays (8.1 days ± 5.5 vs. 4.4 days ± 3.1; p = 0.0251) and trends towards extended hospital stay, ventilation duration, and higher mortality. Additionally, they demonstrated significantly higher urine fractional excretion of phosphate (FEPO4) on the first ICU day (29.2% ± 14.23 vs. 19.5% ± 8.39; p = 0.0242). CONCLUSION: Critically ill trauma patients exhibited a significantly higher incidence of early hypophosphatemia than typical ICU rates, indicating their heightened vulnerability. The significantly high urine FEPO4 underscores the crucial role of renal loss in disrupting phosphate metabolism in this early acute phase after trauma. A significant correlation was observed between hypophosphatemia and longer ICU stays. Monitoring and managing phosphate levels may influence outcomes, warranting further investigation.

IRONMAN tunes responses to iron deficiency in concert with environmental pH.

Iron (Fe) is an essential mineral element that governs the composition of natural plant communities and limits crop yield in agricultural ecosystems due to its extremely low availability in most soils, particularly at alkaline pH. To extract sufficient Fe from the soil under such conditions, some plants, including Arabidopsis (Arabidopsis thaliana), secrete Fe-mobilizing phenylpropanoids, which mobilize sparingly soluble Fe hydroxides by reduction and chelation. We show here that ectopic expression of the peptides IRONMAN (IMA1) and IMA2 improves growth on calcareous soil by inducing biosynthesis and secretion of the catecholic coumarin 7,8-dihydroxy-6-methoxycoumarin (fraxetin) via increased expression of MYB72 and SCOPOLETIN 8-HYDROXYLASE, a response that is strictly dependent on elevated environmental pH (pHe). By contrast, transcription of the cytochrome P450 family protein CYP82C4, catalyzing the subsequent hydroxylation of fraxetin to sideretin, which forms less stable complexes with iron, was strongly repressed under such conditions. We concluded that IMA peptides regulate processes supporting Fe uptake at both acidic and elevated pH by controlling gene expression upstream of or in concert with a putative pHe signal, adapting the plant to prevailing edaphic conditions. This regulatory pattern confers tolerance to calcareous soils by extending the pH range in which Fe can be efficiently absorbed from the soil. Our results further suggest that pHe calibrates the activities of components of the Fe deficiency response, accentuating processes that are most efficient under the prevailing conditions. Altering the expression of IMA peptides provides a route for generating plants adapted to calcareous soils.

Different impacts of cancer types on cancer screening during COVID-19 pandemic in Taiwan.

BACKGROUND: The COVID-19 pandemic has rapidly become a major challenge for global health care systems and affected other priorities such as the utilization of population-based cancer screening services. We sought to examine to what extent the COVID-19 pandemic has affected cancer screening utilization in Taiwan, even the use of inreach and outreach screening services for different types of cancer screening and different regions. METHODS: Using nationwide cervical, breast, colorectal and oral cancer screening data, the percentage changes in screening participants at inreach and outreach services were calculated and compared between January to April 2020 (COVID-19 pandemic) and January to April 2019. RESULTS: The average percentage change declined from 15% to 40% for cervical, breast, and colorectal cancer screening, with a nearly 50% decline in oral cancer screening. There was a greater preference for breast and colorectal cancer screening outreach services, which had greater accessibility and declined less than inreach services in most regions. The screening utilization varied in different regions, especially in eastern Taiwan where the less convenient transportation and lower risk of COVID-19 transmission had a positive change on four types of cancer screening outreach services. CONCLUSION: The COVID-19 pandemic may have had an effect not only in the utilization of different types of cancer screening but also in the preference between inreach and outreach services, and even in variations in screening services in different regions.

Trilinolein, a Natural Triacylglycerol, Protects Cerebral Ischemia through Inhibition of Neuronal Apoptosis and Ameliorates Intimal Hyperplasia via Attenuation of Migration and Modulation of Matrix Metalloproteinase-2 and RAS/MEK/ERK Signaling Pathway in VSMCs.

Cerebrovascular disease is one of the leading causes of disability and death worldwide, and seeking a potential treatment is essential. Trilinolein (TriL) is a natural triacylglycerol presented in several plants. The effects of TriL on cerebrovascular diseases such as cerebral ischemia and carotid stenosis have never been studied. Accordingly, we investigated the protection of TriL on cerebral ischemia/reperfusion (I/R) and vascular smooth muscle cell (VSMC) migration in vivo and in vitro. The cerebral infarction area, the intima to media area (I/M ratio), and proliferating cell nuclear antigen (PCNA)-staining of the carotid artery were measured. Platelet-derived growth factor (PDGF)-BB-stimulated A7r5 cell migration and potential mechanisms of TriL were investigated by wound healing, transwell, and Western blotting. TriL (50, 100, and 200 mg/kg, p.o.) reduced: the cerebral infarction area; neurological deficit; TUNEL-positive apoptosis; intimal hyperplasia; and PCNA-positive cells in rodents. TriL (5, 10, and 20 µM) significantly inhibited PDGF-BB-stimulated A7r5 cell migration and reduced matrix metalloproteinase-2 (MMP-2), Ras, MEK, and p-ERK protein levels in PDGF-BB-stimulated A7r5 cells. TriL is protective in models of I/R-induced brain injury, carotid artery ligation-induced intimal hyperplasia, and VSMC migration both in vivo and in vitro. TriL could be potentially efficacious in preventing cerebral ischemia and cerebrovascular diseases.

pH-dependent transcriptional profile changes in iron-deficient Arabidopsis roots.

BACKGROUND: Iron is an essential element for plants and abundantly present in most mineral soils. The mobility of iron is, however, dependent on the redox potential and hydrogen activity (pH) of the soil, factors that may limit its availability to plants in particular at alkaline pHs. Iron deficiency triggers pronounced changes in the transcriptional profile of plants, inducing processes that aid in the acquisition, uptake, and translocation of iron. How ambient pH impact the transcriptional iron deficiency response has not yet been elucidated in detail. RESULTS: Here, we provide an RNA-seq data set that catalogs global gene expression changes of iron-deficient plants grown at either optimal (5.5) or high (7.0) pH. A suite of 857 genes changed significantly and more than twofold in expression; only 54 genes of this suite were also differentially expressed between iron-deficient and iron-sufficient plants grown at pH 5.5. Among the high pH-responsive genes, 186 were earlier shown to be responsive to short-term transfer to low pH, 91 genes of this subset were anti-directionally regulated by high and low pH. The latter subset contained genes involved in cell wall organization, auxin homeostasis, and potential hubs of yet undefined signaling circuits. Growing iron-deficient plants at high pH also modulated the transcriptional iron deficiency response observed at pH 5.5 by compromising the enzymatic reduction of ferric chelates and favoring the production of iron-mobilizing coumarins. CONCLUSIONS: It is concluded that ambient pH is an important determinant of global gene expression which tunes iron acquisition to the prevailing edaphic conditions.

Statin use and reduced risk of biliary tract cancers in the UK Clinical Practice Research Datalink.

OBJECTIVE: To evaluate the association between statin use and risk of biliary tract cancers (BTC). DESIGN: This is a nested case-control study conducted in the UK Clinical Practice Research Datalink. We included cases diagnosed with incident primary BTCs, including cancers of the gall bladder, bile duct (ie, both intrahepatic and extrahepatic cholangiocarcinoma), ampulla of Vater and mixed type, between 1990 and 2017. For each case, we selected five controls who did not develop BTCs at the time of case diagnosis, matched by sex, year of birth, calendar time and years of enrolment in the general practice using incidence density sampling. Exposures were defined as two or more prescription records of statins 1 year prior to BTC diagnosis or control selection. ORs and 95% CIs for associations between statins and BTC overall and by subtypes were estimated using conditional logistic regression, adjusted for relevant confounders. RESULTS: We included 3118 BTC cases and 15 519 cancer-free controls. Current statin use versus non-use was associated with a reduced risk of all BTCs combined (adjusted OR=0.88, 95% CI 0.79 to 0.98). The reduced risks were most pronounced among long-term users, as indicated by increasing number of prescriptions (ptrend=0.016) and cumulative dose of statins (ptrend=0.008). The magnitude of association was similar for statin use and risk of individual types of BTCs. The reduced risk of BTCs associated with a record of current statin use versus non-use was more pronounced among persons with diabetes (adjusted OR=0.72, 95% CI 0.57 to 0.91). Among non-diabetics, the adjusted OR for current statin use versus non-use was 0.91 (95% CI 0.81 to 1.03, pheterogeneity=0.007). CONCLUSION: Compared with non-use of statins, current statin use is associated with 12% lower risk of BTCs; no association found with former statin use. If replicated, particularly in countries with a high incidence of BTCs, our findings could pave the way for evaluating the value of statins for BTC chemoprevention.

Scopoletin 8-Hydroxylase-Mediated Fraxetin Production Is Crucial for Iron Mobilization.

Iron (Fe) is an essential mineral nutrient and an important factor for the composition of natural plant communities. Low Fe availability in aerated soils with neutral or alkaline pH has led to the evolution of elaborate mechanisms that extract Fe from the soil solution. In Arabidopsis (Arabidopsis thaliana), Fe is acquired by an orchestrated strategy that comprises mobilization, chelation, and reduction of Fe3+ prior to its uptake. Here, we show that At3g12900, previously annotated as scopoletin 8-hydroxylase (S8H), participates in Fe acquisition by mediating the biosynthesis of fraxetin (7,8-dihydroxy-6-methoxycoumarin), a coumarin derived from the scopoletin pathway. S8H is highly induced in roots of Fe-deficient plants both at the transcript and protein levels. Mutants defective in the expression of S8H showed increased sensitivity to growth on pH 7.0 media supplemented with an immobile source of Fe and reduced secretion of fraxetin. Transgenic lines overexpressing S8H exhibited an opposite phenotype. Homozygous s8h mutants grown on media with immobilized Fe accumulated significantly more scopolin, the storage form of scopoletin, supporting the designated function of S8H in scopoletin hydroxylation. Fraxetin exhibited Fe-reducing properties in vitro with higher rates being observed at neutral relative to acidic pH. Supplementing the media containing immobile Fe with fraxetin partially rescued the s8h mutants. In natural Arabidopsis accessions differing in their performance on media containing immobilized Fe, the amount of secreted fraxetin was highly correlated with growth and Fe and chlorophyll content, indicating that fraxetin secretion is a decisive factor for calcicole-calcifuge behavior (i.e. the ability/inability to thrive on alkaline soils) of plants.

The effect of age on N2 and P3 components: A meta-analysis of Go/Nogo tasks.

Suppressing the neural activities to non-target stimuli becomes problematic with advancing age. Go/Nogo tasks, in which subjects are instructed to respond to a certain type of stimuli (Go) and withhold responses to other types of predefined stimuli (Nogo), have been extensively employed to study the age-related alterations of cognitive inhibition. However, it remains inconclusive whether the N2 and P3 electrophysiological responses to successful inhibition to Nogo stimuli are affected by aging processes. Thus, we performed a meta-analysis of Go/Nogo studies to investigate the age effect on Nogo-N2 and Nogo-P3 activities as well as behavioral performance of commission errors. The potential moderators regarding different probabilities of Nogo trials and levels of task difficulty on the effect sizes were also assessed. There were no significant age-related differences in commission errors. However, compared to the younger group, the elderly demonstrated reduced Nogo-N2 amplitudes, particularly in the condition where Nogo probability was less than 50%. Furthermore, age-related reduction of Nogo-P3 amplitudes and prolongation of Nogo-P3 latencies were observed in the condition where Nogo probability was less than 50%. In conclusion, our data suggest that despite similar behavioral performance in the younger and older adults, neural processing of response inhibition becomes inefficient with advancing age.

Effects of solvent molecules on hemi-bonded (CH3SH)2+: infrared absorption of [(CH3SH)2-X]+ with X = H2O, (CH3)2CO, or NH3 and (CH3SH)n+ (n = 3-6).

Three-electron two-center (3e-2c) hemi-bonds play important roles in the oxidation and electron transport of proteins and are implicated to be involved in some neurodegenerative diseases. Our previous investigations on infrared (IR) spectra of (CH3SH)2+ using vacuum-ultraviolet photoionization, infrared dissociation, and time-of-flight detection have shown that (CH3SH)2+ is (3e-2c)-bonded. To investigate the influence of the solvent molecules on the (3e-2c)-bonded (CH3SH)2+ in a supersonic jet, we added H2O or (CH3)2CO or NH3 or (CH3SH)n (n = 1-4) to (CH3SH)2+ and investigated their IR action spectra. The (3e-2c)-bonded (CH3SH)2+ ion core was maintained when a molecule of H2O or (CH3)2CO or CH3SH binds, indicating that the ion core is more stable than the hydrogen bond, whereas the (3e-2c)-bond became broken by a NH3 molecule because the proton transfer led to a more stable hydrogen-bonded structure. The spectral features of the SH-stretching modes of (CH3SH)n+ (n = 3-6) indicate that the (3e-2c)-bonded (CH3SH)2+ ion core is maintained and the first two additional CH3SH are H-bonded to the free SH groups of the ion core. For larger clusters with n = 5 and 6, the additional solvent molecules likely bind to the first solvation shell. These results show also that the (3e-2c)-bonded S∴S structure is more stable than the S∴O and S∴N structures in [(CH3SH)2-X]+ with X = H2O or (CH3)2CO or CH3SH or NH3.

Cardiovascular disease risk and androgen deprivation therapy in patients with localised prostate cancer: a prospective cohort study.

BACKGROUND: As androgen deprivation therapy (ADT) is increasingly being used in men with localised prostate cancer, our goal was to examine the association between ADT and the risk of cardiovascular disease (CVD). METHODS: We conducted a prospective cohort study using records of a large health-care system in California. The study included men with newly diagnosed localised prostate cancer (1998-2008) who initially underwent active surveillance (N=7637) and were followed through 2010. We examined 10 individual CVD outcomes. Cox proportional hazard models incorporated time-varying treatment variables and controlled for race/ethnicity, age, and tumour characteristics, recurrence risk, CVD medication use, and CVD risk factors. RESULTS: Of the 7637 subjects, nearly 30% were exposed to ADT. In the multivariable analyses, ADT was associated with an increased risk of heart failure (adjusted HR=1.81, 95% CI 1.40-2.32) in men without preexisting CVD. Elevated risks of arrhythmia (adjusted HR=1.44, 95% CI 1.02-2.01), and conduction disorder (adjusted HR=3.11, 95% CI 1.22, 7.91) were only observed among patients with preexisting CVD. CONCLUSIONS: In men with clinically localised prostate cancer who were initially under active surveillance, ADT was associated with a greater risk of heart failure in men without any preexisting CVD. We also found an increased risk of arrhythmia and conduction disorder in men with preexisting CVD. This study provides the basis for identifying high-risk men treated with ADT who might benefit from regular cardiac monitoring and lifestyle modification recommendations.

Risks of Serious Toxicities from Intermittent versus Continuous Androgen Deprivation Therapy for Advanced Prostate Cancer: A Population Based Study.

PURPOSE: Randomized trials have shown that intermittent androgen deprivation therapy for patients with advanced prostate cancer may improve sexual and physical functioning compared to continuous androgen deprivation therapy without compromising survival. To our knowledge it is unknown whether intermittent androgen deprivation therapy alters the risk of serious toxicities associated with continuous androgen deprivation therapy. MATERIALS AND METHODS: We performed a population based cohort study of 9,772 men 66 years old or older who were diagnosed with advanced prostate cancer from 2002 to 2011 and treated with androgen deprivation therapy. Intermittent androgen deprivation therapy was defined as a single 90-day interval between 2 androgen deprivation therapy sessions during which patients visited their physicians or underwent prostate specific antigen testing. Outcomes included acute myocardial infarction, stroke, heart failure, type 2 diabetes and fracture. We used Cox proportional hazard models to estimate the HRs of the comparative risk of serious toxicities between intermittent and continuous androgen deprivation therapy. RESULTS: A total of 2,113 (22%), 769 (9%) and 899 men (9%) had a new cardiovascular event, diabetes or fracture, respectively, within 5 years of starting androgen deprivation therapy. Compared to the continuous androgen deprivation therapy group, the intermittent therapy group was at lower risk for serious cardiovascular events (HR 0.64, 95% CI 0.53-0.77), particularly in reducing the risk of heart failure (HR 0.62, 95% CI 0.49-0.78) and fracture (HR 0.52, 95% CI 0.38-0.70, each p <0.0001). CONCLUSIONS: Intermittent androgen deprivation therapy was associated with a lower risk of heart failure and fracture compared to continuous androgen deprivation therapy. This raises toxicity concerns for continuous relative to intermittent therapy and suggests that intermittent androgen deprivation therapy may represent a safer therapeutic choice in elderly men with advanced prostate cancer.

Mortality and Androgen Deprivation Therapy as Salvage Treatment for Biochemical Recurrence after Primary Therapy for Clinically Localized Prostate Cancer.

PURPOSE: Androgen deprivation therapy is often used as salvage treatment in men with rising prostate specific antigen after initial radical prostatectomy or radiotherapy for clinically localized prostate cancer. Given the lack of evidence from general practice, we examined the association of salvage androgen deprivation therapy with mortality in an observational cohort study. MATERIALS AND METHODS: From 3 managed care organizations we assembled a retrospective cohort of all 5,804 men with newly diagnosed localized prostate cancer from 1995 to 2009 who had a prostate specific antigen increase (biochemical recurrence) after primary radical prostatectomy or radiotherapy. The main outcomes were all-cause and prostate cancer specific mortality. We used Cox proportional hazards models to estimate mortality with salvage androgen deprivation therapy as a time dependent predictor. RESULTS: Overall salvage androgen deprivation therapy was not associated with all-cause or prostate cancer specific mortality in the prostatectomy cohort (HR 0.97, 95% CI 0.70-1.35 or HR 1.18, 95% CI 0.68-2.07) or in the radiotherapy cohort (HR 0.84, 95% CI 0.70-1.01 or HR 1.06, 95% CI 0.80-1.40, respectively). Among men with prostate specific antigen doubling time less than 9 months after the prostate specific antigen rise, salvage androgen deprivation therapy was statistically significantly associated with a decreased risk of all-cause and prostate cancer specific mortality in the prostatectomy cohort (HR 0.35, 95% CI 0.20-0.63 and HR 0.43, 95% CI 0.21-0.91) and in the radiotherapy cohort (HR 0.62, 95% CI 0.48-0.80 and HR 0.65, 95% CI 0.47-0.90, respectively). CONCLUSIONS: We found no association of salvage androgen deprivation therapy with all-cause or cause specific mortality in most men with biochemical recurrence after primary radical prostatectomy or radiotherapy for clinically localized prostate cancer. Men with quickly progressed disease may derive a clinical benefit from salvage androgen deprivation therapy.

One way. Or another? Iron uptake in plants.

Iron (Fe) and phosphorus (P), the latter taken up by plants as phosphate (Pi), are two essential nutrients that determine species distribution and often limit crop yield as a result of their low availability in most soils. Pi-deficient plants improve the interception of Pi by increasing the density of root hairs, thereby expanding the volume of soil to be explored. The increase in root-hair frequency results mainly from attenuated primary root growth, a process that was shown to be dependent on the availability of external Fe. Recent data support a hypothesis in which cell elongation during Pi starvation is tuned by depositing Fe in the apoplast of cortical cells in the root elongation zone. Uptake of Fe under Pi starvation appears to proceed via an alternative, as yet unidentified, route that bypasses the default Fe transporter. Fe deposits acquired through this noncanonical Fe-uptake pathway compromises cell-to-cell communication that is critical for proper morphogenesis of epidermal cells and leads to shorter cells and higher root-hair density. An auxiliary Fe-uptake system might not only be crucial for recalibrating cell elongation in Pi-deficient plants but may also have general importance for growth on Pi- or Fe-poor soils by balancing the Pi and Fe supply.

Initiation of Trastuzumab by Women Younger Than 64 Years for Adjuvant Treatment of Stage I-III Breast Cancer.

Purpose: Studies have reported disparities by age and race in the initiation of adjuvant trastuzumab for the initial treatment of older women with early-stage breast cancer, but less is known about its initiation in younger patients. Therefore, we assessed temporal trends and clinical and demographic factors associated with trastuzumab initiation in a large, population-based cohort of patients aged <64 years in 5 states. Methods: Using a cancer registry and claims-linked data set of 13,398 women with incident invasive breast cancer from 2006 to 2011, we identified 934 patients aged <64 years with HER2-positive stage I-III breast cancer. We assessed trastuzumab initiation within the first 9 months after diagnosis and conducted logistic regression analyses to assess sociodemographic and clinical factors associated with trastuzumab initiation. Results: From 2006 to 2011, trastuzumab initiation steadily increased in patients with node-positive (from 65% to 91%) and node-negative (from 39% to 75%) breast cancers. Several tumor-related factors were associated with trastuzumab initiation, including high histologic grades (adjusted odds ratio [aOR], 6.43; 95% CI, 3.27-12.65; and aOR, 3.25; 95% CI, 1.66-6.36, for grades 3 and 2, respectively), node-positive status (aOR, 1.88; 95% CI, 1.28-2.78; P=.001), tumor size >2 cm (aOR, 1.50; 95% CI, 1.04-2.16; P=.03), and hormone receptor-negative status (aOR, 1.51; 95% CI, 1.01-2.26; P=.04). We found a null effect of race. Conclusions: Adjuvant trastuzumab therapy for early-stage breast cancer has been widely disseminated among women aged <64 years. The initiation of this targeted therapy was associated with higher-risk features, consistent with practice guidelines.

Post-Transcriptional Coordination of the Arabidopsis Iron Deficiency Response is Partially Dependent on the E3 Ligases RING DOMAIN LIGASE1 (RGLG1) and RING DOMAIN LIGASE2 (RGLG2).

Acclimation to changing environmental conditions is mediated by proteins, the abundance of which is carefully tuned by an elaborate interplay of DNA-templated and post-transcriptional processes. To dissect the mechanisms that control and mediate cellular iron homeostasis, we conducted quantitative high-resolution iTRAQ proteomics and microarray-based transcriptomic profiling of iron-deficient Arabidopsis thaliana plants. A total of 13,706 and 12,124 proteins was identified with a quadrupole-Orbitrap hybrid mass spectrometer in roots and leaves, respectively. This deep proteomic coverage allowed accurate estimates of post-transcriptional regulation in response to iron deficiency. Similarly regulated transcripts were detected in only 13% (roots) and 11% (leaves) of the 886 proteins that differentially accumulated between iron-sufficient and iron-deficient plants, indicating that the majority of the iron-responsive proteins was post-transcriptionally regulated. Mutants harboring defects in the RING DOMAIN LIGASE1 (RGLG1)(1) and RING DOMAIN LIGASE2 (RGLG2) showed a pleiotropic phenotype that resembled iron-deficient plants with reduced trichome density and the formation of branched root hairs. Proteomic and transcriptomic profiling of rglg1 rglg2 double mutants revealed that the functional RGLG protein is required for the regulation of a large set of iron-responsive proteins including the coordinated expression of ribosomal proteins. This integrative analysis provides a detailed catalog of post-transcriptionally regulated proteins and allows the concept of a chiefly transcriptionally regulated iron deficiency response to be revisited. Protein data are available via ProteomeXchange with identifier PXD002126.

Cardiovascular toxicity after antiangiogenic therapy in persons older than 65 years with advanced renal cell carcinoma.

BACKGROUND: Sorafenib and sunitinib are oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) approved in 2005 and 2006, respectively, for the treatment of patients with renal cell carcinoma (RCC). A population-based, observational cohort study of the cardiovascular risk of VEGFR TKI therapy in elderly RCC patients was conducted. METHODS: Using the Surveillance, Epidemiology, and End Results-Medicare database, this study analyzed patients who were 66 years old or older and were diagnosed with RCC from 2000 to 2009. The incidence of cardiovascular adverse events, including congestive heart failure and cardiomyopathy (CHF/CM), acute myocardial infarction (AMI), stroke, and cardiovascular deaths, was examined through December 2010. A Cox proportional hazards model was created to calculate the hazard ratio (HR), and adjustments were made for age, sex, comorbidity, and the use of other systemic therapy. RESULTS: A total of 171 of 670 patients who received sunitinib or sorafenib had cardiovascular events. The incidence rates for CHF/CM, AMI, and stroke were 0.87, 0.14, and 0.14 per 1000 person-days, respectively. Sunitinib or sorafenib use was associated with an increased risk of cardiovascular events (HR, 1.38; 95% confidence interval [CI], 1.02-1.87) and especially stroke (HR, 2.84; 95% CI, 1.52-5.31) in comparison with 788 patients diagnosed with advanced RCC from 2007 to 2009 who were eligible for Part D but did not receive either agent. In subgroup analyses, patients who were 66 to 74 years old at diagnosis had the highest increased risk of stroke associated with the use of either or both drugs. CONCLUSIONS: Sunitinib and sorafenib might be associated with an increased risk of cardiovascular events and particularly stroke.

Use of androgen deprivation therapy as salvage treatment after primary therapy for clinically localized prostate cancer.

PURPOSE: The optimal use of androgen deprivation therapy as salvage treatment (sADT) for men after initial prostatectomy or radiotherapy for clinically localized prostate cancer is undefined. We describe patterns of sADT use and investigate clinical and sociodemographic characteristics of insured men who received sADT versus surveillance in managed care settings. METHODS: Using comprehensive electronic health records and cancer registry data from three integrated health plans, we identified all men with newly diagnosed clinically localized prostate cancer between 1995 and 2009 who received either prostatectomy (n = 16,445) or radiotherapy (n = 19,531) as their primary therapy. We defined sADT based on the timing of ADT following primary therapy and stage of cancer. We fit Cox proportional hazard models to identify sociodemographic characteristics and clinical factors associated with sADT. RESULTS: With a median follow-up of 6 years (range 2-15 years), 13 % of men who underwent primary prostatectomy or radiotherapy received sADT. After adjusting for selected covariates, sADT was more likely to be used in men who were older (e.g., HR 1.70, 95 % CI 1.48-1.96 or HR 1.33, 95 % CI 1.17-1.52 for age 70+ relative to age 35-59 for primary prostatectomy or radiotherapy, respectively), were African-American, had a short PSA doubling time, had a higher pre-treatment risk of progression, had more comorbidities, and received adjuvant ADT for initial disease. CONCLUSIONS: In men with localized prostate cancer in community practice initially treated with prostatectomy or radiotherapy, sADT after primary treatment was more frequent for men at greater risk of death from prostate cancer, consistent with practice guidelines.

Paeoniflorin inhibits excitatory amino acid agonist-and high-dose morphine-induced nociceptive behavior in mice via modulation of N-methyl-D-aspartate receptors.

BACKGROUND: Pain, the most common reasons for physician consultation, is a major symptom in many medical conditions that can significantly interfere with a person's life quality and general functioning. Almost all painkillers have its untoward effects. Therefore, seeking for a safe medication for pain relieve is notable nowadays. Paeonia lactiflora is a well-known traditional Chinese medicine. Paeoniflorin is an active component found in Paeonia lactiflora, which has been reported to inhibit formalin-induced nociceptive behavior in mice. Aims of this present study were to investigate effects of paeoniflorin on excitatory amino acid agonist- or high-dose morphine-induced nociceptive behaviors in mice. RESULTS: Paeoniflorin (100, 200, 500 nmol, i.c.v.) alone and combined with glutamatergic antagonists (MK-801 14.8 pmol, or NBQX 5 nmol, i.t.) inhibited nociception. Those agents also inhibited the clonic seizure-like excitation induced by high-dose morphine (250 nmol, i.t) in mice. Antisense oligodeoxynucleotides of NMDA receptor subunits NR1, NR2A, NR2B significantly enhanced the inhibition of paeoniflorin on excitatory amino acid-and high-dose morphine-induced nociception. Docking energy data revealed that paeoniflorin had stronger binding activity in NR2A and NR2B than NR2C of NMDA receptors. CONCLUSIONS: Results of this study indicate that paeoniflorin-induced inhibition of excitatory amino acid agonist- and high-dose morphine-induced nociceptive behaviors might be due to modulation of NMDA receptors, specifically the NR2B subunit.