Published by Elsevier Ltd on behalf of IBRO “

Published by Elsevier Ltd on behalf of IBRO.”
“Poly-N-acetyl glucosamine (pGlcNAc) nanofiber-derived materials effectively achieve hemostasis during surgical procedures. Treatment of cutaneous

wounds with pGlcNAc in a diabetic mouse animal model causes marked increases in cell proliferation and angiogenesis. We sought to understand the effect of the pGlcNAc fibers on primary endothelial cells (EC) in culture and found that pGlcNAc induces EC motility. Cell motility induced by pGlcNAc fibers is blocked by antibodies directed against alpha V beta(3) and alpha(5)beta(1) integrins, both known to play important roles in the regulation of EC motility, 5-Fluoracil cell line in vitro and in vivo. pGlcNAc treatment activates mitogen-activated protein

kinase and increases Ets1, vascular endothelial growth factor (VEGF) and interleukin 1 (IL-1) expression. pGlcNAc activity is not secondary to its induction of VEGF; inhibition of the VEGF receptor does not inhibit the pGlcNAc-induced expression of Ets1 nor does pGlcNAc cause the activation of VEGF receptor. Selleck LCZ696 Both dominant negative and RNA interference inhibition of Ets1 blocks pGlcNAc-induced EC motility. Antibody blockade of integrin results in the inhibition of pGlcNAc-induced Ets1 expression. These findings support the hypothesis that pGlcNAc fibers induce integrin activation which results in the regulation of EC motility and thus in angiogenesis via a pathway dependent on the Ets1 transcription factor and demonstrate that Ets1 is a downstream mediator of integrin activation. Copyright (C) 2007 S. Karger AG, Basel.”
“Synaptic plasticity in inhibitory interneurons is essential to maintain a proper equilibrium between excitation and inhibition in hippocampal network. Recent studies showed that theta-burst-induced long-term potentiation (LTP) at excitatory synapses of oriens/alveus (O/A) interneurons in CA1 hippocampal check details region required the activation of metabotropic glutamate receptor (mGluR) 1. However these

interneurons also express mGluR5 and the contribution of this receptor subtype in interneuron synaptic plasticity remains unexplored. We combined pharmacological and transgenic approaches to examine the relative contribution of mGluR1/5 in LTP at excitatory synapses on O/A interneurons. Bath-application of the selective mGluR1/5 agonist (s)-3,5-dihydroxyphenylglycine (DHPG) induced LTP of compound excitatory postsynaptic potentials. DHPG-induced LTP was not prevented by application of either mGluR1 or mGluR5 antagonists, was still present in mGluR1 knockout mice, but was blocked by co-application of both antagonists. These results indicate that UP can be induced at O/A interneuron synapses by either mGluR1 or mGluR5 activation. As previously reported for mGluR1-dependent LTP, the mGluR5-dependent UP was independent of N-methyl-D-aspartate receptors.

Our results showed that both Shh and Wnt-7a increased the numbers

Our results showed that both Shh and Wnt-7a increased the numbers of cells expressing neuronal markers; however, quantitative immunocytochemical analysis showed that only Wnt-7a enhanced the outgrowth and the development of processes in these cells. In addition, Wnt-7a markedly

suppressed gliogenesis. The electrophysiological analysis revealed that Wnt-7a increased, while Shh decreased the incidence of cells displaying a neuron-like current pattern, represented by outwardly rectifying K(+) currents and tetrodotoxin-sensitive Na(+) currents. Additionally, Wnt-7a increased cell proliferation only at the early stages of differentiation, while Shh promoted proliferation within the entire course of differentiation. Thus we can conclude that Shh and Wnt-7a interfere differently with the process of neuronal differentiation and that they promote distinct stages of neuronal differentiation in neonatal Go6983 NS/PCs. (C) 2010 IBRO. Published

by Elsevier Ltd. All rights reserved.”
“The activation of the human polyomavirus BK causes polyomavirus-associated nephropathy AG-120 research buy in immuno-compromised humans. Studies of the virus have been restricted since the virus DNA replication is species specific. Cell-based and cell-free DNA replication systems, including the BK virus (BKV) monopolymerase DNA replication system using purified proteins, reproduce the species specificity (28). Therefore, the major host proteins comprising this assay, DNA polymerase alpha-primase (Pol-prim) and replication protein A (RPA), were intensively studied here. We demonstrate that Pol-prim plays a major role in the species specificity of BKV DNA replication. Both large subunits p180 and p68 of the enzyme complex have central functions in modulating the host specificity. Recently, an inhibitory activity of BKV DNA replication Selleckchem AZD9291 was described (C. Mahon, B. Liang, I. Tikhanovich, J. R. Abend, M. J. Imperiale, H. P. Nasheuer, and W. R. Folk, J. Virol. 83:5708-5717, 2009), but neither mouse Pol-prim nor mouse RPA diminishes cell-free BKV DNA replication. However, the inhibition of BKV DNA replication in mouse extracts

depends on sequences flanking the core origin. In the presence of human Pol-prim, the inhibitory effect of mouse cell factors is abolished with plasmid DNAs containing the murine polyomavirus early promoter region, whereas the late enhancer region and the core origin are supplied from BKV. Thus, BKV replication is regulated by both Pol-prim, as a core origin species-specific factor, and inhibitory activities, as origin-flanking sequence-dependent factor(s).”
“The hippocampus is a prominent structure to study mechanisms of learning and memory at the cellular level. Long-term potentiation (LTP) as well as long-term depression (LTD) are the major cellular models which could underlie learning and memory formation.

A variety of demographic, lesion-related and procedure-related va

A variety of demographic, lesion-related and procedure-related variables were evaluated for potential impact of technical success and patency. The follow-up protocol included clinical assessment, and color and spectral Doppler evaluation of the stented vessel(s).

Results: The clinical presentation was chronic mesenteric ischemia in 12 patients, acute mesenteric vascular syndromes in 10 patients, foregut ischemia/ischemic pancreatitis in three patients, and prior to endovascular repair of aortic aneurysm in one this website patient. The treated vessel was SMA in 22 procedures, CA in three, and both SMA and CA in one. Technical success was achieved in 23 of the 27 attempted recanalizations (85%). Three patients

who failed the attempt underwent open bypass, and another one underwent retrograde recanalization and stenting of the SMA. Procedure success was only significantly

related to patient age <70 years or procedure performance after the year 2006. Notably, the presence of a stump, ostial plaque, extensive vascular calcification, recanalization mTOR inhibitor route (intraluminal vs subintimal), occlusion length, and vessel diameter had no significant impact on procedure success. Traditional duplex criteria proved unreliable in predicting restenosis. Life table analysis of freedom from symptom recurrence showed a primary and assisted rates of 58% and 80% at 1 year, and 33% and 60% at 2 years, respectively. Clinical recurrences developed in six patients (four presented with abdominal angina and weight loss, two presented with abdominal catastrophe). There were six access-related complications Adenosine and no procedural deaths. Four delayed deaths occurred during follow-up (two cardiac causes, two due to abdominal sepsis).

Conclusions: Endovascular recanalization of mesenteric artery occlusion is both feasible and successful, provided careful planning is used. (J Vasc Surg 2012;55:1674-81.)”
“Many studies have investigated hypothalamus-pituitary-adrenal (HPA) axis responses to psychosocial stress in adults. In children, much less is known about HPA axis reactivity, and a sizable number of studies has

not detected a significant cortisol response. Moreover, there is a tack of studies comparing adults’ and children’s responses to identical stressors. The aim of the present study was to modify an existing laboratory stressor to serve as a potent stressor in children and to allow for direct comparison between children’s and adults’ stress responses. Thirty children, ages 9-12 (14 female), and 31 young adults, ages 18-25 (17 female), were exposed to the modified protocol (TSST-M). A significant increase in salivary cortisol was observed in response to the TSST-M, F(2.5, 125.4) = 19.65, p <.001, eta(2) = .28, and overall, no differences were found between children’s and adults’ responses, F(2.5, 125.4) = .31, n.s.

formigenes levels Mixed model analysis was used to determine the

formigenes levels. Mixed model analysis was used to determine the effects of colonization status on

these variables.

Results: Urinary calcium and oxalate excretion were significantly altered by the dietary changes in O. formigenes colonized and noncolonized individuals. Mixed model analysis showed significant interaction between colonization status and oxalate excretion on a low calcium (400 mg daily)/moderate oxalate (250 mg daily) diet (p = 0.026). Urinary oxalate excretion was 19.5% lower in O. formigenes colonized subjects than in noncolonized subjects on the low calcium/moderate oxalate diet (mean +/- SE 34.9 +/- 2.6 vs 43.6 +/- 2.6 AZD1480 ic50 mg, p = 0.031).

Conclusions: Results suggest that O. formigenes colonization decreases oxalate excretion during periods of low calcium and moderate oxalate intake.”
“The objective of this study was to determine the role of palmitate-induced stimulation of nitric oxide synthase (NOS) on palmitate-induced cell death, specifically distinguishing the effects of the subtype NOS2 from NOS3, defining the effect of NO on

mitochondria death pathways, and determining whether palmitate induces peroxynitrite formation which may impact cardiomyocyte cell survival. Cardiomyocytes from embryonic chick hearts were treated with palmitate 300-500 mu M. Cell death was assessed by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. The ability of palmitate to induce NO production and its consequences were tested by using the NOS inhibitor 7-nitroindazole selleck inhibitor (7-N) and the peroxynitrite scavenger (5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron (III) chloride) (FeTPPS). The effect of palmitate on the mitochondria was assessed by Western blotting for cytochrome c release into the cytosol, and assessment of mitochondrial transmembrane potential (Delta psi(m)) by 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethyl-benzimidazolyl-carbocyanine iodide staining and immunocytochemistry. The NOS inhibitor 7-N, which is selective for NOS2 and not for NOS3, significantly (p < 0.05) increased palmitate-induced cell death. In contrast, 7-N did not alter

cell death produced by the combination of potassium cyanide and deoxyglucose, which, respectively, inhibit glycolysis Venetoclax clinical trial and oxidative phosphorylation. The mitochondrial actions of palmitate, specifically palmitate-induced translocation of mitochondrial cytochrome e to cytosol and loss of mitochondrial transmembrane potential, were not altered by pretreatment with 7-N. FeTPPS, which isomerizes peroxynitrite to nitrate and thereby reduces the toxic effects of peroxynitrite, produced a significant reduction in palmitate-induced cell death. In summary, these data suggest that palmitate stimulates NO production, which has a dual action to protect against cell death or to induce cell death. Palmitate-induced cell death is mediated, in part, through NO generation, which leads to peroxynitrite formation.

Gap junctional communication is thought to be involved in epilept

Gap junctional communication is thought to be involved in epileptogenesis. This communication can be affected by changes in expression of gap junctional protein subunits called connexins (Cxs). One of the main brain regions involved in epileptogenesis is the hippocampus in which there is a network of gap junctional communication between different cell types.

Method: Cx36 and Cx43 expressions at both mRNA and protein level were measured in rat hippocampus during epileptogenesis in the kindling model

of epilepsy.

Results: Cx36 expression at both mRNA and protein level was upregulated during acquisition of focal seizures but returned to basal level after acquisition of secondarily-generalized seizures. No change in Cx43 gene and protein expression was found during kindling epileptogenesis.

Conclusion: These results further selleck inhibitor point out the significance of Cx36 as a target to modify epileptogenic process and to develop antiepileptogenic treatments. (C) 2010 Elsevier Inc. All rights reserved.”
“Direct Response Analysis is a general computational tool for quantifying direct functional interactions between components in cellular signalling systems from experimental AMG510 purchase perturbations and measurements alone. This paper aims to reveal the biological meaning of the

direct response coefficients obtained upon applying DRA to simple Michaelis-Menten type proteomic and gene regulatory systems. These systems describe dimer formation and dissociation,

protein preduction and decay, and transcription. We derive explicit formulae for the direct Amine dehydrogenase response coefficients in terms of biochemical reaction rates, and clarify the potential and limitations of the DRA method. We find that response coefficients are strongly asymmetric, and that they balance persistent characteristics of reactions (e.g. the ratios of on- and off rates) against the time-scales over which these reactions act; fast reactions give stronger response coefficients. The direct interactions between protein species, caused by dimer formation, are effectively negative. We illustrate our results with numerical simulations. (c) 2012 Elsevier Ltd. All rights reserved.”
“Research on early stages of schizophrenia aims to provide early, objective, and stable markers of vulnerability. In this review, we first briefly describe the notion of such markers, or endophenotypes, notably in terms of stability, specificity and heritability. Among other empirical approaches, event-related potentials (ERPs) have been recently considered as putative endophenotypes. The N400 component is an event-related brain potential classically elicited during semantic processing, as suggested by a growing body of empirical studies with a large variety of paradigms. We provide here a short account of its typical descriptions and the interpretations of its functional significance.

The replication phase consisted of 7053 case and 9007 control sam

The replication phase consisted of 7053 case and 9007 control samples. We identified 11 loci that surpassed the threshold for genome-wide significance (p<5×10(-8)). Six were previously identified loci (MAPT, SNCA, HLA-DRB5, BSTI, GAK and LRRK2) and five were newly identified loci (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). The combined population-attributable risk was 60.3% (95% CI 43.7-69-3). In the risk-profile analysis, the odds ratio in the highest quintile of disease BMS202 risk was 2.51 (95% CI 2.23-2.83)

compared with 1.00 in the lowest quintile of disease risk.

Interpretation These data provide an insight into the genetics of Parkinson’s disease and the molecular cause of the disease and could provide future targets for therapies.”
“Background Daily inhaled corticosteroids are an effective treatment for mild persistent asthma, but some children have exacerbations even with good day-to-day control, and many discontinue treatment after becoming asymptomatic. We assessed the effectiveness of an inhaled corticosteroid (beclomethasone dipropionate) used as rescue treatment.

Methods In this 44-week, randomised, double-blind, placebo-controlled trial we enrolled children and adolescents with mild persistent asthma aged 5-18 years from five clinical centres in the USA. A computer-generated randomisation

sequence, stratified by clinical centre and age group, was used to randomly assign participants to one of four treatment groups: twice daily beclomethasone with beclomethasone plus albuterol as rescue (combined group); twice daily beclomethasone

with placebo plus albuterol as GSK-3 inhibitor rescue (daily bedomethasone group); twice daily placebo with beclomethasone plus albuterol as rescue (rescue beclomethasone group); and twice daily placebo with placebo plus albuterol as rescue (placebo group). Twice daily beclomethasone treatment was one puff of beclomethasone (40 mu g per puff) or placebo given in the morning and evening. Rescue beclomethasone treatment was two puffs of PDK4 beclomethasone or placebo for each two puffs of albuterol (180 mu g) needed for symptom relief. The primary outcome was time to first exacerbation that required oral corticosteroids. A secondary outcome measured linear growth. Analysis was by intention toll-eat. This study is registered with, number NCT00394329.

Results 843 children and adolescents were enrolled into this trial, of whom 288 were assigned to one of four treatment groups; combined (n=71), daily beclomethasone (n=72), rescue beclomethasone (n=71), and placebo (n=74)-555 individuals were excluded during the run-in, according to predefined criteria. Compared with the placebo group (49%, 95% CI 37-61), the frequency of exacerbations was lower in the daily (28%, 18-40, p=0.03), combined (31%, 21-43, p=0.07), and rescue (35%, 24-47, p=0.07) groups.

Moreover, rates of response in the extinction components less pre

Moreover, rates of response in the extinction components less precisely reflected previous training in the mindfulness group, suggesting less resurgence of past behaviors after the mindfulness induction (Experiment 2).”
“Na,K-ATPase, an ion pump, has been shown to interact with other proteins in signaling complexes in cardiac myocytes, renal and glial cells, and several other cell types. Our Mdivi1 cost previous in vivo studies indicated that intrahippocampal administration of ouabain (QUA), an inhibitor of Na,K-ATPase, induces NF kappa B activation, leading to an increase in mRNA levels of target genes

of this transcription factor in the rat hippocampus. The present work investigated whether QUA can regulate NF-kappa B in primary cultured rat cerebellar cells. Cells were treated with different concentrations of QUA (1, 10 or 100 mu M) for different click here periods of time (1, 2 and 4 h). QUA induced

a time- and concentration-dependent activation of NF kappa B (peak of activation: 10 mu M, 2 h), involving both p50/p65 and p50/p50 NF kappa B dimers. QUA (10 mu M, 2 h) induced upregulation of tumor necrosis factor alpha (Tnf-alpha), interleukin-1 beta(Il-1 beta), and brain derived neurotrophic factor (Bdnf) mRNA levels. Both NF kappa B activation and gene expression activation induced by QUA (10 mu M) were abolished when cells were pre-treated for 20 min with MK-801 (N-Methyl-D-Aspartate (NMDA) receptor antagonist), manumycin A (farnesyltransferase inhibitor), PP-1(Src-family tyrosine kinase inhibitor) and PD98059 (mitogen-activated protein kinase (MAPK) inhibitor). QUA (10 mu M) alone or in the presence of MK-801, PP-1, PD98059 did not cause cell death or DNA fragmentation. These findings suggest that QUA activates NF kappa B by NMDA-Src-Ras-like protein through MAPK pathways in cultured cerebellar cells. This pathway may mediate an adaptive response in the central

nervous system. Published by Elsevier Ltd.”
“Discriminating same from different multiitem arrays can be represented most as a discrimination between arrays involving low variability and arrays involving high variability. In the present investigation, we first trained pigeons with the extreme values along the variability continuum (arrays containing 16 identical items vs. 16 nonidentical items), and we later tested the birds with arrays involving intermediate levels of variability; we created these testing arrays either by manipulating the combination of same and different items (mixture testing) or by changing the number of items in the same and different arrays (number testing). According to an entropy account (Young & Wasserman, Journal of Experimental Psychology: Animal Behavior Processes 23:157-170, 1997), the particular means of changing variability should have no effect on same-different discrimination performance: Equivalent variability should yield equivalent performance.

History of early-life stress (ELS) was assessed with the Structur

History of early-life stress (ELS) was assessed with the Structured Trauma Interview.

Results. Salivary cortisol responses after 0.5 mg Dex were lower in CFS patients than in controls (before 100 mu g CRF, p=0.038; after 100 mu g CRF, p=0.015). A secondary analysis revealed an influence of early-life stress and of oestrogen intake. After removal of the 10 participants

who were taking an oral oestrogen, patients without a history of ELS showed lower VX-770 chemical structure cortisol responses than patients with ELS and controls (before CRF, p=0.005; after CRF, p=0.008).

Conclusions. CFS is globally associated with reduced cortisol responses in the combined low-dose Dex/CRF test, but this effect is only clearly present in CFS patients without a history of ELS. This study provides further support for an enhanced glucocorticoid negative feedback and/or a reduced central HPA Nec-1s mouse axis drive in CFS. Furthermore, it demonstrates that ELS is an important variable to consider in CFS research.”
“Purpose: We examined trends in pediatric hospitalization for pyelonephritis from 1985 to 2006 and identified factors associated with admission.

Materials and Methods: We performed a population based analysis of hospital discharges using the Office of Statewide Health Planning and Development database to evaluate trends in California regarding pediatric hospitalizations for pyelonephritis

from 1985 to 2006. Multivariable logistic regression was performed to identify factors associated with admission for pyelonephritis.

Results: A total of 46,300 children were hospitalized for pyelonephritis in California from 1985 to 2006. The overall rate of hospitalization for pyelonephritis increased by greater than 80%, from 17 per 100,000 children in the California population

in 1985 to 31 per 100,000 in 2005. This change was primarily due to the nearly ninefold increase in pyelonephritis hospitalizations observed in children younger than 1 year, from 28 per 100,000 in 1985 to 238 per 100,000 in 2005. Among children younger than 1 year males without private insurance and of nonwhite race had increased odds of hospitalization, while females with private insurance and of Asian race had increased odds of hospitalization, compared with nonprivate insurance and white Ergoloid race, respectively.

Conclusions: A significant increase in hospital admissions for pyelonephritis, primarily in children younger than 1 year, occurred in California between 1985 and 2006. Further studies are needed to establish the cause of this striking increase and to determine why certain pediatric populations are at increased risk for hospitalization.”
“Background. Conduct disorder (CD) prior to age 15 has been associated with an increased risk of aggressive behaviour and crime among men with schizophrenia. The present study aimed to replicate and extend this finding in a clinical sample of severely mentally ill men and women.


Real-time PCR analysis of purified PDC from patients prior to and

Real-time PCR analysis of purified PDC from patients prior to and during treatment interruptions revealed that active HIV-1 replication is associated with upregulation of type I IFN-stimulated gene expression.

Treatment of hepatitis C virus-infected patients with IFN-alpha 2b and ribavirin for hepatitis C virus infection resulted in a profound suppression of de novo IFN-alpha production in response to CpG A or inactivated HIV particles, similar to the response observed in HIV-infected patients. Together, these results suggest that diminished Pifithrin-�� price production of type I interferons in vitro by PDC from HIV-1-infected patients may not represent diminished interferon production in vivo. Rather, diminished function in vitro is likely a consequence of prior activation via type I interferons or HIV virions in vivo.”
“OBJECTIVES: To identify factors influencing the duration of cerebrospinal fluid shunt survival after initial placement and after subsequent revisions.

METHODS: We conducted a retrospective cohort study using the Pediatric Health Information System database, which contains resource use data from 37 tertiary care children’s hospitals. Children younger than 18 years who underwent initial cerebro, fluid placement between January 1, 2000, PRT062607 in vitro and December 31, 2005,

were eligible.

RESULTS: During the study period, 20.2, 7.5, and 6.9% of 7399 patients required one, two, or three or more shunt revisions, respectively. Shunt survival rates were lower with each subsequent shunt revision. In multivariable Cox proportional hazards analysis, children undergoing shunt placement in the Northeast census region had a longer duration of shunt survival between initial placement and both the first (adjusted

hazard ratio, 0.74; 95% confidence interval, 0.55-0.99) and second (adjusted hazard ratio, 0.66; 95% confidence interval, selleck 0.51-0.86) revisions. Young age and a principal diagnosis of obstructive hydrocephalus were also associated with a higher risk of failure after initial placement; age-related variation in shunt survival persisted after the first but not the second revision. Among patients with multiple shunt revisions, those with early revision (i.e., revision < 60 d after placement) had a shorter shunt survival time after subsequent revisions (adjusted hazard ratio for second revision, 1.30; 95% confidence interval, 1.11-1.52).

CONCLUSIONS: Regional variation in the risk of ventricular shunt revision exists, and young infants are at the highest risk for shunt failure. Risk factors for the duration of shunt survival differ between the initial and subsequent revisions.”
“Research over the last few years has demonstrated the increasing role of microRNAs (miRNAs) as major regulators of gene expression in diverse cellular processes and diseases.

Biological behavior in HCT-15 cells both in oxia and in hypoxia w

Biological behavior in HCT-15 cells both in oxia and in hypoxia was assessed. Biodistribution in normal mice and in animals bearing induced 3LL Lewis murine lung carcinoma was also studied.

Results: PU-H71 in vitro Metronidazole derivatives were successfully synthesized. Labeling with high radiochemical purity was achieved for both ligands. Tc-99m complexes were stable in labeling milieu

and human plasma. However, presence of the piperazine linker in M2 resulted in higher lipophilicity and protein binding. Although cell uptake in hypoxic conditions was observed for both radiotracers, Tc-99m-NS(3)M2 biodistribution was considered unsuitable for a potential radiopharmaceutical due to high liver uptake and poor blood clearance. However, Tc-99m-NS(3)M1 demonstrated a very favorable in vivo profile both in normal mice and in mice bearing induced tumors.

Conclusion: Selective

uptake and retention in tumor together with favorable tumor/muscle ratio make Tc-99m-NS(3)M1 a promising candidate for further evaluation as potential hypoxia imaging agent in tumors. (C) 2012 Elsevier Inc. All rights reserved.”
“Objectives: Submucosal esophageal cancers (pT1b) are considered superficial, implying good survival. However, some are advanced, metastasizing to regional lymph nodes. Interplay of cancer characteristics and lymphatic anatomy may create a watershed, demarcating low-risk from high-risk cancers. Therefore, we characterized submucosal cancers according to depth of invasion and identified those with high likelihood of lymph node metastases and poor survival.

Methods: From 1983 to 2010, 120 patients underwent esophagectomy for submucosal cancers at Cleveland Clinic. Correlations were sought among cancer characteristics

(location, dimensions, Amylase histopathologic cell type, histologic grade, and lymphovascular invasion [LVI]), and their associations with lymph node metastasis were identified by logistic regression. Associations with mortality were identified by Cox regression.

Results: As submucosal invasion increased, cancer length (P < .001), width (P < .001), area (P < .001), LVI (P = .007), and grade (P = .05) increased. Invasion of the deep submucosa (P < .001) and LVI (P = .06) predicted lymph node metastases: 45% (23/51) of deep versus 10% (3/29) of middle-third and 7.5% (3/40) of inner-third cancers had lymph node metastases, as did 46% (12/26) with LVI versus 18% (17/94) without. Older age and lymph node metastases predicted worse 5-year survival: 94% for younger pN0 patients, 62% for older pN0 patients, and 36% for pN1-2 patients regardless of age.

Conclusions: Submucosal cancer characteristics and lymphatic anatomy create a watershed for regional lymph node metastases in the deep submucosa. This previously unrecognized divide distinguishes superficial submucosal cancers with good survival from deep submucosal cancers with poor survival. Aggressive therapy of more superficial cancers is critical before submucosal invasion occurs.