Sepsis is the major cause of death for critically ill patients. Recent progress in proteomics permits a thorough characterization of the mechanisms associated with critical illness. The purpose of this study was to screen potential biomarkers for early prognostic assessment of patients with sepsis.
For the discovery stage, 30 sepsis patients with different prognoses were selected. Urinary proteins were identified using isobaric tags for relative and absolute quantitation (iTRAQ) coupled with LC-MS/MS. Mass spec instrument analysis were performed with Mascot software and the International Protein Index (IPI); bioinformatic analyses were used by the algorithm of set and the Gene Ontology (GO) Database. For the verification stage, the study involved another 54 sepsis-hospitalized patients, with equal numbers of patients in survivor and non-survivor groups based on 28-day survival. Differentially expressed proteins were verified by Western Blot.
A total of 232 unique proteins were identified. Proteins that were differentially expressed were further analyzed based on the pathophysiology of sepsis and biomathematics. For sepsis prognosis, five proteins were significantly up-regulated: selenium binding protein-1, heparan sulfate proteoglycan-2, alpha-1-B glycoprotein, haptoglobin, and lipocalin; two proteins were significantly down-regulated: lysosome-associated membrane proteins-1 and dipeptidyl peptidase-4. Based on gene ontology clustering, these proteins were associated with the biological processes of lipid homeostasis, cartilage development, iron ion transport, and certain metabolic processes. Urinary LAMP-1 was down-regulated, consistent with the Western Blot validation.
This study provides the proteomic analysis of urine to identify prognostic biomarkers of sepsis. The seven identified proteins provide insight into the mechanism of sepsis. Low urinary LAMP-1 levels may be useful for early prognostic assessment of sepsis.
Breast cancer survivors with lymphedema face a lifetime of stressful physical and emotional symptoms and challenging self-care demands. An in-depth understanding of the perceptions and feelings surrounding life with lymphedema is critical to developing effective supportive care approaches.
To explore perceptions and feelings related to lymphedema in breast cancer survivors.
The expressive writings of 39 individuals were evaluated for this descriptive qualitative study. Data were analyzed using conventional content analysis.
Qualitative analyses produced four major themes: (1) marginalization and minimization; (2) multiplying losses; (3) yearning to return to normal; (4) uplifting resources. Sub-themes for each major theme were also identified.
The lymphedema experiences of breast cancer survivors reveal perceptions of marginalization from healthcare providers who are not well informed about lymphedema management and minimize its impact. Multiple distressing losses confront these patients on a daily basis, including body image disturbances, loss of functionality and control over time, permanent uncertainty, and adverse effects on relationships. The daily challenges of lymphedema often result in cumulative frustration and resentment that contribute to failure to perform self-care. Normalcy has been lost, never to return. These women find solace, encouragement and hope to meet the challenges of lymphedema through support from others and their spiritual beliefs.
Implication for Practice
Healthcare providers need greater awareness of the physical and psychosocial effects of lymphedema in breast cancer survivors. Nurses have unique opportunities to serve as advocates for reducing perceived marginalization and promoting effective self-care and other activities that promote psychological well-being and reduce physical deterioration.
Lymphedema; Breast Cancer; Marginalization; Psychosocial Stress; Cancer Treatment Late-effects; Qualitative Research; Women’s Health
Systemic administration of amphetamine (AMPH) induces phosphorylation of MeCP2 at Ser421 (pMeCP2) in select populations of neurons in the mesolimbocortical brain regions. Because AMPH simultaneously activates multiple monoamine neurotransmitter systems, here we examined the ability of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) to induce pMeCP2. Selective blockade of the DA transporter (DAT) or the 5-HT transporter (SERT), but not the NE transporter (NET), was sufficient to induce pMeCP2 in the CNS. DAT blockade induced pMeCP2 in the prelimbic cortex (PLC) and nucleus accumbens (NAc), whereas SERT blockade induced pMeCP2 only in the NAc. Administration of selective DA and 5-HT receptor agonists was also sufficient to induce pMeCP2; however, the specific combination of DA and 5-HT receptors activated determined the regional- and cell-type specificity of pMeCP2 induction. The D1-class DA receptor agonist SKF81297 induced pMeCP2 widely; however, coadministration of the D2-class agonist quinpirole restricted the induction of pMeCP2 to GABAergic interneurons of the NAc. Intra-striatal injection of the adenylate cyclase activator forskolin was sufficient to induce pMeCP2 in medium-spiny neurons, suggesting that the combinatorial regulation of cAMP by different classes of DA and 5-HT receptors may contribute to the cell-type specificity of pMeCP2 induction. Consistent with the regulation of pMeCP2 by multiple monoamine neurotransmitters, genetic disruption of any single monoamine transporter in DAT-, SERT-, and NET-knockout mice failed to eliminate AMPH-induced pMeCP2 in the NAc. Together, these studies indicate that combinatorial signaling through DA and 5-HT receptors can regulate the brain region- and cell-type specific pMeCP2 in the CNS.
MeCP2; monoamine transporters; signal transduction; dopamine; serotonin; nucleus accumbens; dopamine; serotonin; neuropharmacology; signal transduction; MeCP2; monoamine transporters; nucleus accumbens
Until now there has been scarce evidence regarding an optimal antiplatelet strategy and clinical outcomes for patients who had suffered from stent thrombosis (ST).
Methods and Results
140 patients who suffered from stent thrombosis were prospectively registered. Patients received dual (aspirin and 150 mg clopidogrel, N = 66) or triple (additional cilostazol, N = 74) antiplatelet therapy at the physician’s discretion. Thereafter platelet reactivity and one year clinical outcomes were analyzed. The primary outcome included the composite of cardiac death, non-fatal myocardial infarction (MI) or stroke at one year,which developed in 41 (29.3%) patients, consisting of 31 (22.1%) cardiac death, 9 (6.4%) non-fatal MI and 1 (1.4%) stroke. Recurrent definite and probable ST according to ARC definition was observed in 8 (5.7%) and 14 (10.0%) patients, respectively. Triple therapy was associated with significantly lower platelet reactivities (50.2±17.8, % vs. 59.6±17.2, %, P = 0.002) compared to high dose dual antiplatelet therapy. However, the incidence of primary events (24.3% vs. 34.8%, P = 0.172) did not differ between triple and dual antiplatelet therapies. High on-treatment platelet reactivity (HR: 8.35, 95% CI: 2.234∼30.867, P = 0.002) and diabetes (HR: 3.732, 95% CI: 1.353∼10.298, P = 0.011) were independent predictors of primary events.
Patients who suffered from stent thrombosis have a poor prognosis even after revascularization with intensive antiplatelet therapy. Triple antiplatelet therapy was more effective in reducing on-treatment platelet reactivity, compared to high dose dual antiplatelet therapy.
Maternal deaths occur mostly in developing countries and the majority of them are preventable. This study analyzes changes in maternal mortality and related causes in Henan Province, China, between 1996 and 2009, in an attempt to provide a reliable basis for introducing effective interventions to reduce the maternal mortality ratio (MMR), part of the fifth Millennium Development Goal.
Methods and Findings
This population-based maternal mortality survey in Henan Province was carried out from 1996 to 2009. Basic information was obtained from the health care network for women and children and the vital statistics system, from specially trained monitoring personnel in 25 selected monitoring sites and by household survey in each case of maternal death. This data was subsequently reported to the Henan Provincial Maternal and Child Healthcare Hospital. The total MMR in Henan Province declined by 78.4%, from 80.1 per 100 000 live births in 1996 to 17.3 per 100 000 live births in 2009. The decline was more pronounced in rural than in urban areas. The most common causes of maternal death during this period were obstetric hemorrhage (43.8%), pregnancy-induced hypertension (15.8%), amniotic fluid embolism (13.9%) and heart disease (8.0%). The MMR was higher in rural areas with lower income, less education and poorer health care.
There was a remarkable decrease in the MMR in Henan Province between 1996 and 2009 mainly in the rural areas and MMR due to direct obstetric causes such as obstetric hemorrhage. This study indicates that improving the health care network for women, training of obstetric staff at basic-level units, promoting maternal education, and increasing household income are important interventional strategies to reduce the MMR further.
Here we describe five Shewanella baltica genomes recovered from the same sample, as well as 12 years apart from the same sampling station. These genomes expand the collection of previously sequenced S. baltica strains and represent a valuable resource for assessing the role of environmental settings on genome adaptation.
The purpose of this study was to explore the diagnostic value of soluble triggering receptor expressed on myeloid cells 1 (sTREM-1), procalcitonin (PCT), and C-reactive protein (CRP) serum levels for differentiating sepsis from SIRS, identifying new fever caused by bacteremia, and assessing prognosis when new fever occurred.
We enrolled 144 intensive care unit (ICU) patients: 60 with systemic inflammatory response syndrome (SIRS) and 84 with sepsis complicated by new fever at more than 48 h after ICU admission. Serum sTREM-1, PCT, and CRP levels were measured on the day of admission and at the occurrence of new fever (>38.3°C) during hospitalization. Based on the blood culture results, the patients were divided into a blood culture-positive bacteremia group (33 patients) and blood culture-negative group (51 patients). Based on 28-day survival, all patients, both blood culture-positive and -negative, were further divided into survivor and nonsurvivor groups.
On ICU day 1, the sepsis group had higher serum sTREM-1, PCT, and CRP levels compared with the SIRS group (P <0.05). The areas under the curve (AUC) for these indicators were 0.868 (95% CI, 0.798–0.938), 0.729 (95% CI, 0.637–0.821), and 0.679 (95% CI, 0.578–0.771), respectively. With 108.9 pg/ml as the cut-off point for serum sTREM-1, sensitivity was 0.83 and specificity was 0.81. There was no statistically significant difference in serum sTREM-1 or PCT levels between the blood culture-positive and -negative bacteremia groups with ICU-acquired new fever. However, the nonsurvivors in the blood culture-positive bacteremia group had higher levels of serum sTREM-1 and PCT (P <0.05), with a prognostic AUC for serum sTREM-1 of 0.868 (95% CI, 0.740–0.997).
Serum sTREM-1, PCT, and CRP levels each have a role in the early diagnosis of sepsis. Serum sTREM-1, with the highest sensitivity and specificity of all indicators studied, is especially notable. sTREM-1, PCT, and CRP levels are of no use in determining new fever caused by bacteremia in ICU patients, but sTREM-1 levels reflect the prognosis of bacteremia.
ClinicalTrial.gov identifier NCT01410578
Soluble triggering receptor expressed on myeloid cells 1 (sTREM-1); Fever; Sepsis; Bacteremia; Diagnosis; Prognosis
DNA methylation at the 5-position of cytosine (5mC) in the mammalian genome is a key epigenetic event critical for various cellular processes. The Ten-eleven translocation (Tet) family of 5mC-hydroxylases, which convert 5mC to 5-hydroxymethylcytosine (5hmC), offers a way for dynamic regulation of DNA methylation. Here we report that Tet1 binds unmodified C, 5mC- or 5hmC-modified CpG-rich DNA through its CXXC domain. Genome-wide mapping of Tet1 and 5hmC reveals mechanisms by which Tet1 controls 5hmC and 5mC levels in mouse embryonic stem cells (mESCs). We also uncover a comprehensive gene network influenced by Tet1. Collectively, our data suggest that Tet1 controls DNA methylation both by binding to CpG-rich regions to prevent unwanted DNA methyltransferase activity, and by converting 5mC to 5hmC through hydroxylase activity. This Tet1-mediated antagonism of CpG methylation imparts differential maintenance of DNA methylation status at Tet1 targets, ultimately contributing to mESC differentiation and the onset of embryonic development.
The title compound, C14H19N3O3, was synthesized by the reaction of 3-methoxypropionitrile, tert-butyl bromoacetate and ethoxymethylenemalononitrile. In the crystal, N—H⋯O hydrogen bonds link the molecules into chains propagating along the b axis.
Outbreaks of Hand Foot and Mouth Disease (HFMD) have occurred in many parts of the world especially in China. We aimed to summarize the characteristics of the levels of blood glucose and white blood cell (WBC) counts in cases of HFMD in Mainland China and Taiwan, using meta-analysis based on systematic review of published articles.
We systematically reviewed published studies, from the MEDLINE and WANFANG Data, about the levels of blood glucose and WBC counts in cases of HFMD until 15th June 2011, and quantitatively summarized the characteristics of them using meta-analysis.
In total, 37 studies were included in this review. In Mainland China and Taiwan, generally, the average level of blood glucose, the prevalence of hyperglycemia, WBC counts and the prevalence of leukocytosis increased with the severity of the illness. There was no significant difference in the prevalence of leukocytosis between ANS (autonomic nervous system dysregulation)/PE (pulmonary edema) group and CNS (central nervous system) group, and in the average level of blood glucose between healthy controls and mild cases of HFMD. WBC counts in cases infected by EV71 were less than those in cases infected by CA16.
our analyses indicated that blood glucose and WBC counts increased with the severity of HFMD disease, which would help doctors to manage patients efficiently.
High-throughput sequencing studies during the last decade have uncovered that bacterial genomes are very diverse and dynamic, resulting primarily from the frequent and promiscuous horizontal gene exchange that characterizes the bacterial domain of life. However, a robust understanding of the rates of genetic exchange for most bacterial species under natural conditions and the influence of the ecological settings on the rates remain elusive, severely limiting our view of the microbial world. Here, we analyzed the complete genomic sequences and expressed transcriptomes of several Shewanella baltica isolates recovered from different depths in the Baltic Sea and found that isolates from more similar depths had exchanged a larger fraction of their core and auxiliary genome, up to 20% of the total, compared with isolates from more different depths. The exchanged genes seem to be ecologically important and contribute to the successful adaptation of the isolates to the unique physicochemical conditions of the depth. Importantly, the latter genes were exchanged in very recent past, presumably as an effect of isolate's seasonal migration across the water column, and reflected sexual speciation within the same depth. Therefore, our findings reveal that genetic exchange in response to environmental settings may be surprisingly rapid, which has important broader impacts for understanding bacterial speciation and evolution and for modeling bacterial responses to human-induced environmental impacts.
comparative genomics; genome evolution; speciation; horizontal gene transfer; recombination; Shewanella baltica
The purpose of this study was to conduct a preliminary, post-market, home study of the Flexitouch® system to examine the potential efficacy of the device as a component of self-care in breast cancer survivors with truncal lymphedema.
Methods and Results
A quasi-experimental, pre-treatment, post-treatment design was used. Twelve participants received a total of ten self-administered, consecutive, one hour per day treatments. Treatments one and two were observed by study staff and the remaining eight were unobserved. Assessments were conducted at baseline, after the first two treatments, mid-way through therapy, and at the end-of-study. Logs revealed 100% compliance with the eight prescribed unobserved home treatments. Symptoms were assessed by self-report symptom surveys. Signs, objectively observed physical phenomenon, were assessed by staff-initiated skin examination and circumferential truncal measurements. Statistically significant improvement in truncal symptoms and sleep were found. Changes in function and girth were not statistically significant in this initial study.
Breast cancer survivors with truncal lymphedema may benefit from using an advanced pneumatic compression devices with truncal treatment as part of their self-care program. Participants were highly compliant in device use. Further research of this intervention is warranted. To facilitate future research, clinically meaningful reductions in truncal girth should be defined.
Enterovirus 71 (EV71) and Coxsackievirus A16 (CA16) are two major etiological agents of Hand, Foot and Mouth Disease (HFMD). EV71 is associated with severe cases but not CA16. The mechanisms contributed to the different pathogenesis of these two viruses are unknown. VP1 and VP4 are two major structural proteins of these viruses, and should be paid close attention to.
The sequences of vp1s from 14 EV71 and 14 CA16, and vp4s from 10 EV71 and 1 CA16 isolated in this study during 2007 to 2009 HFMD seasons were analyzed together with the corresponding sequences available in GenBank using DNAStar and MEGA 4.0. Phylogenetic analysis of complete vp1s or vp4s showed that EV71 isolated in Beijing belonged to C4 and CA16 belonged to lineage B2 (lineage C). VP1s and VP4s from 4 strains of viruses expressed in E. coli BL21 cells were used to detect IgM and IgG in human sera by Western Blot. The detection of IgM against VP1s of EV71 and CA16 showed consistent results with current infection, while none of the sera were positive against VP4s of EV71 and CA16. There was significant difference in the positive rates between EV71 VP1 and CA16 VP1 (χ2 = 5.02, P < 0.05) as well as EV71 VP4 and CA16 VP4 (χ2 = 15.30, P < 0.01) in the detection of IgG against recombinant proteins with same batch of serum samples. The sera-positive rate of IgG against VP1 was higher than that against VP4 for both EV71 (χ2 = 26.47, P < 0.01) and CA16 (χ2 = 16.78, P < 0.01), which might be because of different positions of VP1 and VP4 in the capsid of the viruses.
EV71 and CA16 were highly diverse in the nucleotide sequences of vp1s and vp4s. The sera positive rates of VP1 and VP4 of EV71 were lower than those of CA16 respectively, which suggested a less exposure rate to EV71 than CA16 in Beijing population. Human serum antibodies detected by Western blot using VP1s and VP4s as antigen indicated that the immunological reaction to VP1 and VP4 of both EV71 and CA16 was different.
To investigate the feasibility of combining the inner-volume-imaging (IVI) technique with single-shot diffusion-weighted (DW) spin-echo echo-planar imaging (SE-EPI) and DW-SPLICE (split acquisition of fast spin-echo) sequences for renal DW imaging.
Materials and Methods
Renal DW imaging was performed in 10 healthy volunteers using single-shot DW-SE-EPI, DW-SPLICE, targeted-DW-SE-EPI and targeted-DW-SPLICE. We compared the quantitative diffusion measurement accuracy and image quality of these targeted-DW-SE-EPI and targeted DW-SPLICE methods with conventional full FOV DW-SE-EPI and DW-SPLICE measurements in phantoms and normal volunteers.
Compared with full FOV DW-SE-EPI and DW-SPLICE methods, targeted-DW-SE-EPI and targeted-DW-SPLICE approaches produced images of superior overall quality with fewer artifacts, less distortion and reduced spatial blurring in both phantom and volunteer studies. The ADC values measured with each of the four methods were similar and in agreement with previously published data. There were no statistically significant differences between the ADC values and intra-voxel incoherent motion (IVIM) measurements in the kidney cortex and medulla using single-shot DW-SE-EPI, targeted-DW-EPI and targeted-DW-SPLICE (p > 0.05).
Compared with full-FOV DW imaging methods, targeted-DW-SE-EPI and targeted-DW-SPLICE techniques reduced image distortion and artifacts observed in the single-shot DW-SE-EPI images, reduced blurring in DW-SPLICE images and produced comparable quantitative DW and IVIM measurements to those produced with conventional full-FOV approaches.
renal; diffusion; targeted; inner volume imaging; SPLICE; EPI
Brassica rapa is an economically important crop and a model plant for studies concerning polyploidization and the evolution of extreme morphology. The multinational B. rapa Genome Sequencing Project (BrGSP) was launched in 2003. In 2008, next generation sequencing technology was used to sequence the B. rapa genome. Several maps concerning B. rapa pseudochromosome assembly have been published but their coverage of the genome is incomplete, anchoring approximately 73.6% of the scaffolds on to chromosomes. Therefore, a new genetic map to aid pseudochromosome assembly is required.
This study concerns the construction of a reference genetic linkage map for Brassica rapa, forming the backbone for anchoring sequence scaffolds of the B. rapa genome resulting from recent sequencing efforts. One hundred and nineteen doubled haploid (DH) lines derived from microspore cultures of an F1 cross between a Chinese cabbage (B. rapa ssp. pekinensis) DH line (Z16) and a rapid cycling inbred line (L144) were used to construct the linkage map. PCR-based insertion/deletion (InDel) markers were developed by re-sequencing the two parental lines. The map comprises a total of 507 markers including 415 InDels and 92 SSRs. Alignment and orientation using SSR markers in common with existing B. rapa linkage maps allowed ten linkage groups to be identified, designated A01-A10. The total length of the linkage map was 1234.2 cM, with an average distance of 2.43 cM between adjacent marker loci. The lengths of linkage groups ranged from 71.5 cM to 188.5 cM for A08 and A09, respectively. Using the developed linkage map, 152 scaffolds were anchored on to the chromosomes, encompassing more than 82.9% of the B. rapa genome. Taken together with the previously available linkage maps, 183 scaffolds were anchored on to the chromosomes and the total coverage of the genome was 88.9%.
The development of this linkage map is vital for the integration of genome sequences and genetic information, and provides a useful resource for the international Brassica research community.
Biliary tract cancer encompasses tumors of the gallbladder, bile duct and ampulla of Vater. Gallbladder cancer is more common in women, whereas bile duct cancer is more common in men, suggesting that sex hormones may play a role in the etiology of these cancers. The intracellular action of estrogens is regulated by the estrogen receptor (ESR); thus, we examined the role of common genetic variants in ESR genes on the risk of biliary tract cancers and stones in a population-based case–control study in Shanghai, China (411 cancer cases, 895 stone cases and 786 controls). We genotyped six single-nucleotide polymorphisms (SNPs), four in ESR1 (rs2234693, rs3841686, rs2228480 and rs1801132) and two in ESR2 (rs1256049 and rs4986938). In all participants, the ESR1 rs1801132 (P325P) G allele was associated with excess risks of bile duct [odds ratio (OR) = 1.7, 95% confidence interval (CI) 1.1–2.8] and ampulla of Vater cancers (OR = 2.1, 95% CI 0.9–4.9) compared with the CC genotype. The association with bile duct cancer was apparent among men (OR = 2.8, 95% CI 1.4–5.7) but not among women (P-heterogeneity = 0.01). Also, the ESR2 rs4986938 (38 bp 3′ of STP) GG genotype was associated with a higher risk of bile duct cancer (OR = 3.3, 95% CI 1.3–8.7) compared with the AA genotype, although this estimate was based on a small number of subjects. None of the other SNPs examined was associated with biliary tract cancers or stones. False discovery rate-adjusted P-values were not significant (P > 0.1). No association was found for ESR1 haplotype based on four SNPs. These preliminary results suggest that variants in ESR genes could play a role in the etiology of biliary tract cancers, especially bile duct cancer in men.
To develop a quantitative multi-parametric PROPELLER (periodically rotated overlapping parallel lines with enhanced reconstruction) MRI approach and its application in a diethylnitrosamine (DEN) chemically-induced rodent model of hepatocarcinogensis for lesion characterization.
MATERIALS AND METHODS
In nine rabbits with 33 cirrhosis-associated hepatic nodules including regenerative nodule (RN), dysplastic nodule (DN), hepatocellular carcinoma (HCC) and cyst, multi-parametric PROPELLER MRI (diffusion-weighted, T2/M0 (proton density) mapping and T1-weighted) were performed. Apparent diffusion coefficient (ADC) maps, T2 and M0 maps of each tumor were generated. We compared ADC, T2 and M0 measurements for each type of hepatic nodule, confirmed at histopathology.
PROPELLER images and resultant parametric maps were inherently co-registered without image distortion or motion artifacts. All types of hepatic nodules demonstrated complex imaging characteristics within conventional T1- and T2-weighted images. Quantitatively, cysts were distinguished from RN, DN and HCC with significantly higher ADC and T2; however, there was no significant difference of ADC and T2 between HCC, DN and RN. Mean tumor M0 values of HCC were significantly higher than those of DN, RN and cysts.
This study exploited quantitative PROPELLER MRI and multi-dimensional analysis approaches in an attempt to differentiate hepatic nodules in the DEN rodent model of hepatocarcinogensis. This method offers great potential for parallel parameterization during non-invasive interrogation of hepatic tissue properties.
PROPELLER MRI; multi-parametric; hepatocarcinogensis; hepatic nodules
There are currently at least 6 major competing criteria that are used to determine response to 90Y and other liver-directed therapies including: a) RECIST, b) WHO, c) volumetric, d) 2D EASL, e) 3D EASL, f) functional diffusion weighted (DW) MR imaging. Our purpose was to evaluate the agreement between these competing tumor response classification schemes based on quantitative measurements of tumor size, necrosis, and changes in water mobility.
In this retrospective study, 20 HCC patients underwent 90Y radioembolization. The patients’ tumor burden before and 3–6 months after treatment was assessed with MRI. The percent change in size of tumors was used to classify patients into response categories. Kappa and agreement statistics were used to compare the concordance between the different criteria.
Conventional size criteria (RECIST, WHO, and volumetric) all had a substantial level of agreement (kappa statistics from 0.76 to 0.78) when classifying patients into response categories. However, the conventional size criteria in relation to either 2D or 3D EASL had only slight to moderate concurrence with kappa statistics as low as 0.06. 2D EASL criteria and functional DW MR imaging resulted in the highest response rates, 11/20 (55%) and 15/20 (75%) respectively, while conventional size criteria produced lower response rates.
Classification of HCC response to 90Y radioembolization was related to which of the competing criteria are used. We recommend that anatomic imaging criteria be used as the primary method to determine response and functional imaging criteria be used as a complementary secondary method.
MeCP2 is a methyl-DNA binding transcriptional regulator that contributes to the development and function of CNS synapses; however the requirement for MeCP2 in stimulus-regulated behavioral plasticity is not fully understood. Here we show that acute viral manipulation of MeCP2 expression in the Nucleus Accumbens (NAc) bidirectionally modulates amphetamine (AMPH)-induced conditioned place preference. Hypomorphic Mecp2 mutant mice have an increased number of NAc GABAergic synapses and show deficient AMPH-induced structural plasticity of NAc dendritic spines. Furthermore these mice show deficient plasticity of striatal immediate early gene inducibility following repeated AMPH administration. Intriguingly, psychostimulants induce phosphorylation of MeCP2 at Ser421, a site that regulates MeCP2's function as a repressor. Phosphorylation is selectively induced in GABAergic interneurons of the NAc, and its extent strongly predicts the degree of behavioral sensitization. These data reveal novel roles for MeCP2 in both mesolimbocortical circuit development and in the regulation of psychostimulant-induced behaviors.
To test the hypothesis that diffusion-weighted (DW)-PROPELLER (periodically rotated overlapping parallel lines with enhanced reconstruction) MRI provides more accurate liver tumor necrotic fraction (NF) and viable tumor volume (VTV) measurements than conventional DW-SE-EPI (spin echo echo-planar imaging) methods.
Materials and Methods
Our institutional Animal Care and Use Committee approved all experiments. In six rabbits implanted with 10 VX2 liver tumors, DW-PROPELLER and DW-SE-EPI scans were performed at contiguous axial slice positions covering each tumor volume. Apparent diffusion coefficient maps of each tumor were used to generate spatially resolved tumor viability maps for NF and VTV measurements. We compared NF, whole tumor volume (WTV), and VTV measurements to corresponding reference standard histological measurements based on correlation and concordance coefficients and the Bland–Altman analysis.
DW-PROPELLER generally improved image quality with less distortion compared to DW-SE-EPI. DW-PROPELLER NF, WTV, and VTV measurements were strongly correlated and satisfactorily concordant with histological measurements. DW-SE-EPI NF measurements were weakly correlated and poorly concordant with histological measurements. Bland–Altman analysis demonstrated that DWPROPELLER WTV and VTV measurements were less biased from histological measurements than the corresponding DW-SE-EPI measurements.
DW-PROPELLER MRI can provide spatially resolved liver tumor viability maps for accurate NF and VTV measurements, superior to DW-SE-EPI approaches. DWPROPELLER measurements may serve as a noninvasive surrogate for pathology, offering the potential for more accurate assessments of therapy response than conventional anatomic size measurements.
diffusion-weighted imaging; PROPELLER; liver tumor; necrosis; viability
Cancer metastasis is a leading cause of cancer morbidity and mortality. More needs to be learned about mechanisms that control this process. In particular, the role of chemokine receptors in metastasis remains controversial. Here, using a highly metastatic breast cancer (4T1) model, we demonstrate that lung metastasis is a feature of only a proportion of the tumor cells that express CCR4. Moreover, the primary tumor growing in mammary pads activates remotely the expression of TARC/CCL17 and MDC/CCL22 in the lungs. These chemokines acting through CCR4 attract both tumor and immune cells. However, CCR4 mediated chemotaxis was not sufficient to produce metastasis, as tumor cells in the lung were efficiently eliminated by NK cells. Lung metastasis required CCR4+ Tregs which directly killed NK cells utilizing beta-galactoside-binding protein. Thus, strategies that abrogate any part of this process should improve the outcome through activation of effector cells and prevention of tumor cell migration. We confirm this prediction by killing CCR4+ cells through delivery of TARC-fused toxins or depleting Tregs and preventing lung metastasis.
Breast cancer; Tregs; NK cell regulation; CCR4; CCL17; βGBP
AIM: To investigate whether intra-procedural diffusion-weighted magnetic resonance imaging can predict response of hepatocellular carcinoma (HCC) during transcatheter arterial chemoembolization (TACE).
METHODS: Sixteen patients (15 male), aged 59 ± 11 years (range: 42-81 years) underwent a total of 21 separate treatments for unresectable HCC in a hybrid magnetic resonance/interventional radiology suite. Anatomical imaging and diffusion-weighted imaging (b = 0, 500 s/mm2) were performed on a 1.5-T unit. Tumor enhancement and apparent diffusion coefficient (ADC, mm2/s) values were assessed immediately before and at 1 and 3 mo after TACE. We calculated the percent change (PC) in ADC values at all time points. We compared follow-up ADC values to baseline values using a paired t test (α = 0.05).
RESULTS: The intra-procedural sensitivity, specificity, and positive and negative predictive values (%) for detecting a complete or partial 1-mo tumor response using ADC PC thresholds of ±5%, ±10%, and ±15% were 77, 67, 91, and 40; 54, 67, 88, and 25; and 46, 100, 100, and 30, respectively. There was no clear predictive value for the 3-mo follow-up. Compared to baseline, the immediate post-procedure and 1-mo mean ADC values both increased; the latter obtaining statistical significance (1.48 ± 0.29 mm2/s vs 1.65 ± 0.35 × 10-3 mm2/s, P < 0.014).
CONCLUSION: Intra-procedural ADC changes of > 15% predicted 1-mo anatomical HCC response with the greatest accuracy, and can provide valuable feedback at the time of TACE.
Hepatocellular carcinoma; Transcatheter arterial chemoembolization; Diffusion-weighted imaging; Apparent diffusion coefficient; Functional imaging biomarker
Biliary tract cancers, encompassing the gallbladder, extrahepatic bile duct, and ampulla of Vater, are uncommon, yet highly fatal malignancies. Gallstones, the primary risk factor for biliary cancers, are linked with hyperlipidemia. We examined the associations of 12 single nucleotide polymorphisms (SNPs) of five genes in the lipid metabolism pathway with the risks of biliary cancers and stones in a population-based case-control study in Shanghai, China. We included 235 gallbladder, 125 extrahepatic bile duct, and 46 ampulla of Vater cancer cases, 880 biliary stone cases, and 779 population controls. Subjects completed an in-person interview and gave blood. Genotyping was conducted by Taqman assay using DNA from buffy coats. The effects of APOE IVS1+69 (rs440446) and APOB IVS6+360C>T (rs520354) markers were limited to men. Men carrying the G allele of APOE IVS1+69 had a 1.7-fold risk of stones (95% confidence interval (CI) =1.2–2.4), a 1.8–fold risk of gallbladder cancer (95% CI=1.0–3.3), a 3.7–fold risk of bile duct cancer (95% CI=2.0–7.0), and a 4-fold risk of ampullary cancer (95% CI=1.4–12.4). Male carriers of the T allele of APOB IVS6+360C>T had a 2-fold risk of bile duct cancer (95% CI=1.2–3.4). The APOB T-T haplotype (APOB IVS6+360C>T, EX4+56C>T) was associated with a 1.6-fold risk of bile duct cancer (95% CI=1.1–2.3). Male and female carriers of the T allele of LDLR IVS9-30C>T (rs1003723) had 1.5-fold risks of bile duct cancer. Our findings suggest that gene variants in the lipid metabolism pathway contribute to the risk of biliary tract stones and cancers, particularly of the bile duct.
single nucleotide polymorphisms; lipid metabolism; gallstones; biliary tract cancer
To test the feasibility of combining inner-volume imaging (IVI) techniques with conventional multishot periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) techniques for targeted-PROPELLER magnetic resonance imaging.
Materials and Methods
Perpendicular section-selective gradients for spatially selective excitation and refocusing RF pulses were applied to limit the refocused field-of-view (FOV) along the phase-encoding direction for each rectangular blade image. We performed comparison studies in phantoms and normal volunteers by using targeted-PROPELLER methods for a wide range of imaging applications that commonly use turbo-spin-echo (TSE) approaches (brain, abdominal, vessel wall, cardiac).
In these initial studies, we demonstrated the feasibility of using targeted-PROPELLER approaches to limit the imaging FOV thereby reducing the number of blades or permitting increased spatial resolution without commensurate increases in scan time. Both phantom and in vivo motion studies demonstrated the potential for more robust regional self-navigated motion correction compared with conventional full FOV PROPELLER methods.
We demonstrated that the reduced FOV targeted-PROPELLER technique offers the potential for reducing imaging time, increasing spatial resolution, and targeting specific areas for robust regional motion correction.
PROPELLER; targeted; inner-volume-imaging; reduced FOV