Prediction of outcome in patients with low-grade squamous intraepithelial lesions by fluorescence in situ hybridization analysis of human papillomavirus, TERC, and MYC

BACKGROUND Cytology is an excellent method with which to diagnose preinvasive lesions of the uterine cervix, but it suffers from limited specificity for clinically significant lesions. Supplementary methods might predict the natural course of the detected lesions. The objective of the current study was to test whether a multicolor fluorescence in situ hybridization (FISH) assay might help to stratify abnormal results of Papanicolaou tests. METHODS A total of 219 liquid-based cytology specimens of low-grade squamous intraepithelial lesions (LSIL), 49 atypical squamous cells of undetermined significance (ASCUS) specimens, 52 high-grade squamous intraepithelial lesion (HSIL) specimens, and 50 normal samples were assessed by FISH with probes for the human papillomavirus (HPV), MYC, and telomerase RNA component (TERC). Subtyping of HPV by polymerase chain reaction (PCR) was performed in a subset of cases (n=206). RESULTS There was a significant correlation found between HPV detection by FISH and PCR (P<.0001). In patients with LSILs, the presence of HPV detected by FISH was significantly associated with disease progression (P<.0001). An increased MYC and/or TERC gene copy number (>2 signals in>10% of cells) prevailed in 43% of ASCUS specimens and was more frequent in HSIL (85%) than in LSIL (33%) (HSIL vs LSIL: P<.0001). Increased TERC gene copy number was significantly correlated with progression of LSIL (P<.01; odds ratio, 7.44; area under the receiver operating characteristic curve, 0.73; positive predictive value, 0.30; negative predictive value, 0.94) CONCLUSIONS: The detection of HPV by FISH analysis is feasible in liquid-based cytology and is significantly correlated with HPV analysis by PCR. The analysis of TERC gene copy number may be useful for risk stratification in patients with LSIL.

Symmetric inverse consistent nonlinear registration driven by mutual information.

A nonlinear viscoelastic image registration algorithm based on the demons paradigm and incorporating inverse consistent constraint (ICC) is implemented. An inverse consistent and symmetric cost function using mutual information (MI) as a similarity measure is employed. The cost function also includes regularization of transformation and inverse consistent error (ICE). The uncertainties in balancing various terms in the cost function are avoided by alternatively minimizing the similarity measure, the regularization of the transformation, and the ICE terms. The diffeomorphism of registration for preventing folding and/or tearing in the deformation is achieved by the composition scheme. The quality of image registration is first demonstrated by constructing brain atlas from 20 adult brains (age range 30-60). It is shown that with this registration technique: (1) the Jacobian determinant is positive for all voxels and (2) the average ICE is around 0.004 voxels with a maximum value below 0.1 voxels. Further, the deformation-based segmentation on Internet Brain Segmentation Repository, a publicly available dataset, has yielded high Dice similarity index (DSI) of 94.7% for the cerebellum and 74.7% for the hippocampus, attesting to the quality of our registration method.

Identification and characterization of genes encoding phospholipid biosynthetic enzymes of {\it Saccharomyces cerevisiae\/}

Phospholipids are the major component of cellular membranes. In addition to its structural role, phospholipids play an active and diverse role in cellular processes. The goal of this study is to identify the genes involved in phospholipid biosynthesis in a model eukaryotic system, Saccharomyces cerevisiae. We have focused on the biosynthetic steps localized in the inner mitochondrial membrane; hence, the identification of the genes encoding phosphatidylserine decarboxylase (PSD1), cardiolipin synthase (CLS1), and phosphatidylglycerophosphate synthase (PGS1).^ The PSD1 gene encoding a phosphatidylserine decarboxylase was cloned by complementation of a conditional lethal mutation in the homologous gene in Escherichia coli strain EH150. Overexpression of the PSD1 gene in wild type yeast resulted in 20-fold amplification of phosphatidylserine decarboxylase activity. Disruption of the PSD1 gene resulted in 20-fold reduction of decarboxylase activity, but the PSD1 null mutant exhibited essentially normal phenotype. These results suggest that yeast has a second phosphatidylserine decarboxylation activity.^ Cardiolipin is the major anionic phospholipid of the inner mitochondrial membrane. It is thought to be an essential component of many biochemical functions. In eukaryotic cells, cardiolipin synthase catalyzes the final step in the synthesis of cardiolipin from phosphatidylglycerol and CDP-diacylglycerol. We have cloned the gene CLS1. Overexpression of the CLS1 gene product resulted in significantly elevated cardiolipin synthase activity, and disruption of the CLS1 gene, confirmed by PCR and Southern blot analysis, resulted in a null mutant that was viable and showed no petite phenotype. However, phospholipid analysis showed undetectable cardiolipin level and an accumulation of phosphatidylglycerol. These results support the conclusion that CLS1 encodes the cardiolipin synthase of yeast and that normal levels of cardiolipin are not absolutely essential for survival of the cell.^ Phosphatidylglycerophosphate (PGP) synthase catalyzes the synthesis of PGP from CDP-diacylglycerol and glycerol-3-phosphate and functions as the committal and rate limiting step in the biosynthesis of cardiolipin. We have identified the PGS1 gene as encoding the PGP synthase. Overexpression of the PGS1 gene product resulted in over 15-fold increase in in vitro PGP synthase activity. Disruption of the PGS1 gene in a haploid strain of yeast, confirmed by Southern blot analysis, resulted in a null mutant strain that was viable but had significantly altered phenotypes, i.e. inability to grow on glycerol and at $37\sp\circ$C. These cells showed over a 10-fold decrease in PGP synthase activity and a decrease in both phosphatidylglycerol and cardiolipin levels. These results support the conclusion that PGS1 encodes the PGP synthase of yeast and that neither phosphatidylglycerol nor cardiolipin are absolutely essential for survival of the cell. ^

Dating the Siple Dome (Antarctica) Ice Core By Manual and Computer Interpretation of Annual Layering

The Holocene portion of the Siple Dome (Antarctica) ice core was dated by interpreting the electrical, visual and chemical properties of the core. The data were interpreted manually and with a computer algorithm. The algorithm interpretation was adjusted to be consistent with atmospheric methane stratigraphic ties to the GISP2 (Greenland Ice Sheet Project 2) ice core, (BE)-B-10 stratigraphic ties to the dendrochronology C-14 record and the dated volcanic stratigraphy. The algorithm interpretation is more consistent and better quantified than the tedious and subjective manual interpretation.

Stratification and compartmentalisation of immunoglobulin responses to commensal intestinal microbes

The gastrointestinal tract is heavily colonized with commensal microbes with the concentration of bacteria increasing longitudinally down the length of the intestine. Bacteria are also spatially distributed transversely from the epithelial surface to the intestinal lumen with the inner mucus layer normally void of bacteria. Maintenance of this equilibrium is extremely important for human health and, as the dominant immunoglobulin at mucosal sites, IgA influences mutualism between the host and its normal microbiota. In this review we focus on the links between immune and microbial geography of the mammalian intestinal tract.

Dorsolateral and ventromedial prefrontal cortex orchestrate normative choice.

Humans are noted for their capacity to over-ride self-interest in favor of normatively valued goals. We examined the neural circuitry that is causally involved in normative, fairness-related decisions by generating a temporarily diminished capacity for costly normative behavior, a 'deviant' case, through non-invasive brain stimulation (repetitive transcranial magnetic stimulation) and compared normal subjects' functional magnetic resonance imaging signals with those of the deviant subjects. When fairness and economic self-interest were in conflict, normal subjects (who make costly normative decisions at a much higher frequency) displayed significantly higher activity in, and connectivity between, the right dorsolateral prefrontal cortex (DLPFC) and the posterior ventromedial prefrontal cortex (pVMPFC). In contrast, when there was no conflict between fairness and economic self-interest, both types of subjects displayed identical neural patterns and behaved identically. These findings suggest that a parsimonious prefrontal network, the activation of right DLPFC and pVMPFC, and the connectivity between them, facilitates subjects' willingness to incur the cost of normative decisions.

The effects of doxycycline on nitric oxide and stromelysin production in dogs with cranial cruciate ligament rupture

OBJECTIVE To investigate the potential of doxycycline to reduce stromelysin and inducible nitric oxide synthase (iNOS) activity in dogs with osteoarthritis (OA) secondary to spontaneous cranial cruciate ligament (CCL) rupture. STUDY DESIGN Prospective, clinical study. ANIMALS Eighty-one dogs with OA secondary to CCL rupture and 54 normal dogs. METHODS Dogs with OA secondary to CCL rupture were divided into 2 groups before surgery. The Doxy-CCl group received 3 to 4 mg/kg doxycycline orally every 24 hours for 7 to 10 days (n = 35). The CCL group received no treatment (n = 46). Synovial fluid, articular cartilage, synovial membrane, and CCL samples were collected during surgery (Doxy-CCL group and CCL group) or immediately after euthanasia from healthy dogs (control group). Synovial fluid samples were examined cytologically. Total nitric oxide (NOt) concentrations were measured in the supernatant of explant cultures of all tissue samples, and stromelysin activity was measured in the supernatant of explant cultures of cartilage. RESULTS NOt concentrations measured in cartilage were significantly lower in the Doxy-CCL group than in the CCL group, but were not different from those measured in the control group. Doxycycline treatment did not have a significant effect on cartilage stromelysin levels. CONCLUSION The findings in this study indicate that doxycycline inhibits NO production in cartilage in dogs with CCL rupture. CLINICAL RELEVANCE Doxycycline may have a role in the treatment of canine OA by inhibiting NO production.

Experimental, theoretical and numerical investigation of the nonlinear micromechanical properties of bone

Aging societies suffer from an increasing incidence of bone fractures. Bone strength depends on the amount of mineral measured by clinical densitometry, but also on the micromechanical properties of the bone hierarchical organization. A good understanding has been reached for elastic properties on several length scales, but up to now there is a lack of reliable postyield data on the lower length scales. In order to be able to describe the behavior of bone at the microscale, an anisotropic elastic-viscoplastic damage model was developed using an eccentric generalized Hill criterion and nonlinear isotropic hardening. The model was implemented as a user subroutine in Abaqus and verified using single element tests. A FE simulation of microindentation in lamellar bone was finally performed show-ing that the new constitutive model can capture the main characteristics of the indentation response of bone. As the generalized Hill criterion is limited to elliptical and cylindrical yield surfaces and the correct shape for bone is not known, a new yield surface was developed that takes any convex quadratic shape. The main advantage is that in the case of material identification the shape of the yield surface does not have to be anticipated but a minimization results in the optimal shape among all convex quadrics. The generality of the formulation was demonstrated by showing its degeneration to classical yield surfaces. Also, existing yield criteria for bone at multiple length scales were converted to the quadric formulation. Then, a computational study to determine the influence of yield surface shape and damage on the in-dentation response of bone using spherical and conical tips was performed. The constitutive model was adapted to the quadric criterion and yield surface shape and critical damage were varied. They were shown to have a major impact on the indentation curves. Their influence on indentation modulus, hardness, their ratio as well as the elastic to total work ratio were found to be very well described by multilinear regressions for both tip shapes. For conical tips, indentation depth was not a significant fac-tor, while for spherical tips damage was insignificant. All inverse methods based on microindentation suffer from a lack of uniqueness of the found material properties in the case of nonlinear material behavior. Therefore, monotonic and cyclic micropillar com-pression tests in a scanning electron microscope allowing a straightforward interpretation comple-mented by microindentation and macroscopic uniaxial compression tests were performed on dry ovine bone to identify modulus, yield stress, plastic deformation, damage accumulation and failure mecha-nisms. While the elastic properties were highly consistent, the postyield deformation and failure mech-anisms differed between the two length scales. A majority of the micropillars showed a ductile behavior with strain hardening until failure by localization in a slip plane, while the macroscopic samples failed in a quasi-brittle fashion with microcracks coalescing into macroscopic failure surfaces. In agreement with a proposed rheological model, these experiments illustrate a transition from a ductile mechanical behavior of bone at the microscale to a quasi-brittle response driven by the growth of preexisting cracks along interfaces or in the vicinity of pores at the macroscale. Subsequently, a study was undertaken to quantify the topological variability of indentations in bone and examine its relationship with mechanical properties. Indentations were performed in dry human and ovine bone in axial and transverse directions and their topography measured by AFM. Statistical shape modeling of the residual imprint allowed to define a mean shape and describe the variability with 21 principal components related to imprint depth, surface curvature and roughness. The indentation profile of bone was highly consistent and free of any pile up. A few of the topological parameters, in particular depth, showed significant correlations to variations in mechanical properties, but the cor-relations were not very strong or consistent. We could thus verify that bone is rather homogeneous in its micromechanical properties and that indentation results are not strongly influenced by small de-viations from the ideal case. As the uniaxial properties measured by micropillar compression are in conflict with the current literature on bone indentation, another dissipative mechanism has to be present. The elastic-viscoplastic damage model was therefore extended to viscoelasticity. The viscoelastic properties were identified from macroscopic experiments, while the quasistatic postelastic properties were extracted from micropillar data. It was found that viscoelasticity governed by macroscale properties has very little influence on the indentation curve and results in a clear underestimation of the creep deformation. Adding viscoplasticity leads to increased creep, but hardness is still highly overestimated. It was possible to obtain a reasonable fit with experimental indentation curves for both Berkovich and spherical indenta-tion when abandoning the assumption of shear strength being governed by an isotropy condition. These results remain to be verified by independent tests probing the micromechanical strength prop-erties in tension and shear. In conclusion, in this thesis several tools were developed to describe the complex behavior of bone on the microscale and experiments were performed to identify its material properties. Micropillar com-pression highlighted a size effect in bone due to the presence of preexisting cracks and pores or inter-faces like cement lines. It was possible to get a reasonable fit between experimental indentation curves using different tips and simulations using the constitutive model and uniaxial properties measured by micropillar compression. Additional experimental work is necessary to identify the exact nature of the size effect and the mechanical role of interfaces in bone. Deciphering the micromechanical behavior of lamellar bone and its evolution with age, disease and treatment and its failure mechanisms on several length scales will help preventing fractures in the elderly in the future.

Tree size and fecundity influence ballistic seed dispersal of two dominant mast-fruiting species in a tropical rain forest

Seed production, seed dispersal, and seedling recruitment are integral to forest dynamics, especially in masting species. Often these are studied separately, yet scarcely ever for species with ballistic dispersal even though this mode of dispersal is common in legume trees of tropical African rain forests. Here, we studied two dominant main-canopy tree species, Microberlinia bisulcata and Tetraberlinia bifoliolata (Caesalpinioideae), in 25 ha of primary rain forest at Korup, Cameroon, during two successive masting events (2007/2010). In the vicinity of c. 100 and 130 trees of each species, 476/580 traps caught dispersed seeds and beneath their crowns c. 57,000 pod valves per species were inspected to estimate tree-level fecundity. Seed production of trees increased non-linearly and asymptotically with increasing stem diameters. It was unequal within the two species’ populations, and differed strongly between years to foster both spatial and temporal patchiness in seed rain. The M. bisulcata trees could begin seeding at 42–44 cm diameter: at a much larger size than could T. bifoliolata (25 cm). Nevertheless, per capita life-time reproductive capacity was c. five times greater in M. bisulcata than T. bifoliolata owing to former’s larger adult stature, lower mortality rate (despite a shorter life-time) and smaller seed mass. The two species displayed strong differences in their dispersal capabilities. Inverse modelling (IM) revealed that dispersal of M. bisulcata was best described by a lognormal kernel. Most seeds landed at 10–15 m from stems, with 1% of them going beyond 80 m (<100 m). The direct estimates of fecundity significantly improved the models fitted. The lognormal also described well the seedling recruitment distribution of this species in 121 ground plots. By contrast, the lower intensity of masting and more limited dispersal of the heavier-seeded T. bifoliolata prevented reliable IM. For this species, seed density as function of distance to traps suggested a maximum dispersal distance of 40–50 m, and a correspondingly more aggregated seedling recruitment pattern ensued than for M. bisulcata. From this integrated field study, we conclude that the reproductive traits of M. bisulcata give it a considerable advantage over T. bifoliolata by better dispersing more seeds per capita to reach more suitable establishment sites, and combined with other key traits they explain its local dominance in the forest. Understanding the linkages between size at onset of maturity, individual fecundity, and dispersal capability can better inform the life-history strategies, and hence management, of co-occurring tree species in tropical forests.

Incidence of anatomical variations and disease of the maxillary sinuses as identified by cone beam computed tomography: a systematic review.

PURPOSE To analyze available evidence on the incidence of anatomical variations or disease of the maxillary sinuses as identified by cone beam computed tomography (CBCT) in dentistry. MATERIALS AND METHODS A focused question was developed to search the electronic databases MEDLINE, EMBASE, the Cochrane Oral Health Group Trials Register, and CENTRAL and identify all relevant papers published between 1980 and January 19, 2013. Unpublished literature at ClinicalTrials.gov, in the National Research Register, and in the Pro-Quest Dissertation Abstracts and Thesis database was also included. Studies were included irrespective of language. These results were supplemented by hand and gray literature searches. RESULTS Twenty-two studies were identified. Twenty were retrospective cohort studies, one was a prospective cohort study, and one was a case control study. The main indication for CBCT was dental implant treatment planning, and the majority of studies used a small field of view for imaging. The most common anatomical variations included increased thickness of the sinus membrane, the presence of sinus septa, and pneumatization. Reported sinus disease frequency varied widely, ranging from 14.3% to 82%. There was a wide range in the reported prevalence of mucosal thickening related to apical pathology, the degree of lumenal opacification, features of sinusitis, and the presence of retention cysts and polyps. More pathologic findings in the maxillary sinus were reported in men than in women, and the medial wall and sinus floor were most frequently affected. CONCLUSION CBCT is used primarily to evaluate bony anatomy and to screen for overt pathology of the maxillary sinuses prior to dental implant treatment. Differences in the classification of mucosal findings are problematic in the consistent and valid assessment of health and disease of the maxillary sinus.

MicroRNA profile of poorly differentiated thyroid carcinomas: new diagnostic and prognostic insights.

The diagnosis of conventional and oncocytic poorly differentiated (oPD) thyroid carcinomas is difficult. The aim of this study is to characterise their largely unknown miRNA expression profile and to compare it with well-differentiated thyroid tumours, as well as to identify miRNAs which could potentially serve as diagnostic and prognostic markers. A total of 14 poorly differentiated (PD), 13 oPD, 72 well-differentiated thyroid carcinomas and eight normal thyroid specimens were studied for the expression of 768 miRNAs using PCR-Microarrays. MiRNA expression was different between PD and oPD thyroid carcinomas, demonstrating individual clusters on the clustering analysis. Both tumour types showed upregulation of miR-125a-5p, -15a-3p, -182, -183-3p, -222, -222-5p, and downregulation of miR-130b, -139-5p, -150, -193a-5p, -219-5p, -23b, -451, -455-3p and of miR-886-3p as compared with normal thyroid tissue. In addition, the oPD thyroid carcinomas demonstrated upregulation of miR-221 and miR-885-5p. The difference in expression was also observed between miRNA expression in PD and well-differentiated tumours. The CHAID algorithm allowed the separation of PD from well-differentiated thyroid carcinomas with 73-79% accuracy using miR-23b and miR-150 as a separator. Kaplan-Meier and multivariate analysis showed a significant association with tumour relapses (for miR-23b) and with tumour-specific death (for miR-150) in PD and oPD thyroid carcinomas. MiRNA expression is different in conventional and oPD thyroid carcinomas in comparison with well-differentiated thyroid cancers and can be used for discrimination between these tumour types. The newly identified deregulated miRNAs (miR-150, miR-23b) bear the potential to be used in a clinical setting, delivering prognostic and diagnostic informations.

A stratigraphic framework for abrupt climatic changes during the Last Glacial period based on three synchronized Greenland ice-core records: refining and extending the INTIMATE event stratigraphy

Due to their outstanding resolution and well-constrained chronologies, Greenland ice-core records provide a master record of past climatic changes throughout the Last Interglacial–Glacial cycle in the North Atlantic region. As part of the INTIMATE (INTegration of Ice-core, MArine and TErrestrial records) project, protocols have been proposed to ensure consistent and robust correlation between different records of past climate. A key element of these protocols has been the formal definition and ordinal numbering of the sequence of Greenland Stadials (GS) and Greenland Interstadials (GI) within the most recent glacial period. The GS and GI periods are the Greenland expressions of the characteristic Dansgaard–Oeschger events that represent cold and warm phases of the North Atlantic region, respectively. We present here a more detailed and extended GS/GI template for the whole of the Last Glacial period. It is based on a synchronization of the NGRIP, GRIP, and GISP2 ice-core records that allows the parallel analysis of all three records on a common time scale. The boundaries of the GS and GI periods are defined based on a combination of stable-oxygen isotope ratios of the ice (δ18O, reflecting mainly local temperature) and calcium ion concentrations (reflecting mainly atmospheric dust loading) measured in the ice. The data not only resolve the well-known sequence of Dansgaard–Oeschger events that were first defined and numbered in the ice-core records more than two decades ago, but also better resolve a number of short-lived climatic oscillations, some defined here for the first time. Using this revised scheme, we propose a consistent approach for discriminating and naming all the significant abrupt climatic events of the Last Glacial period that are represented in the Greenland ice records. The final product constitutes an extended and better resolved Greenland stratotype sequence, against which other proxy records can be compared and correlated. It also provides a more secure basis for investigating the dynamics and fundamental causes of these climatic perturbations.

Comparison of morphological and rheological conditions between conventional and eversion carotid endarterectomy using computational fluid dynamics - a pilot study

PURPOSE To compare postoperative morphological and rheological conditions after eversion carotid endarterectomy versus conventional carotid endarterectomy using computational fluid dynamics. BASIC METHODS Hemodynamic metrics (velocity, wall shear stress, time-averaged wall shear stress and temporal gradient wall shear stress) in the carotid arteries were simulated in one patient after conventional carotid endarterectomy and one patient after eversion carotid endarterectomy by computational fluid dynamics analysis based on patient specific data. PRINCIPAL FINDINGS Systolic peak of the eversion carotid endarterectomy model showed a gradually decreased pressure along the stream path, the conventional carotid endarterectomy model revealed high pressure (about 180 Pa) at the carotid bulb. Regions of low wall shear stress in the conventional carotid endarterectomy model were much larger than that in the eversion carotid endarterectomy model and with lower time-averaged wall shear stress values (conventional carotid endarterectomy: 0.03-5.46 Pa vs. eversion carotid endarterectomy: 0.12-5.22 Pa). CONCLUSIONS Computational fluid dynamics after conventional carotid endarterectomy and eversion carotid endarterectomy disclosed differences in hemodynamic patterns. Larger studies are necessary to assess whether these differences are consistent and might explain different rates of restenosis in both techniques.

Ovarian and uterine development and hormonal feedback mechanism in a 46 XX patient with CYP19A1 deficiency under low dose estrogen replacement.

Abstract Background: Aromatase deficiency may result in a complete block of estrogen synthesis because of the failure to convert androgens to estrogens. In females, this results in virilisation at birth, ovarian cysts in prepuberty and lack of pubertal development but virilisation, thereafter. Objective and methods: We studied the impact of oral 17β-estradiol treatment on ovarian and uterine development, and on LH/FSH and inhibin B during the long-term follow-up of a girl harboring compound heterozygote point mutations in the CYP19A1 gene. Results: In early childhood, low doses of oral 17β-estradiol were needed. During prepuberty treatment with slowly increasing doses of E2 resulted in normal uterine and almost normal development of ovarian volume, as well as number and size of follicles. Regarding hormonal feedback mechanisms, inhibin B levels were in the upper normal range during childhood and puberty. Low doses of estradiol did not suffice to achieve physiological gonadotropin levels in late prepuberty and puberty. However, when estradiol doses were further increased in late puberty levels of both FSH and LH declined with estradiol levels within normal range. Conclusion: Complete aromatase deficiency provides an excellent model of how ovarian and uterine development in relation to E2, LH, FSH and inhibin B feedback progresses from infancy to adolescence.

Accumulation of FOXP3+T-cells in the tumor microenvironment is associated with an epithelial-mesenchymal-transition-type tumor budding phenotype and is an independent prognostic factor in surgically resected pancreatic ductal adenocarcinoma.

Here we explore the role of the interplay between host immune response and epithelial-mesenchymal-transition (EMT)-Type tumor-budding on the outcome of pancreatic adenocarcinoma (PDAC).CD4+, CD8+, and FOXP3+T-cells as well as iNOS+ (M1) and CD163+- macrophages (M2) were assessed on multipunch tissue-microarrays containing 120 well-characterized PDACs, precursor lesions (PanINs) and corresponding normal tissue. Counts were normalized for the percentage of tumor/spot and associated with the clinico-pathological features, including peritumoral (PTB) and intratumoral (ITB) EMT-Type tumor-budding and outcome.Increased FOXP3+T-cell-counts and CD163-macrophages and decreased CD8+T-cell-counts were observed in PDACs compared with normal tissues and PanINs (p < 0.0001). Increased peritumoral FOXP3+T-cell-counts correlated significantly with venous invasion, distant metastasis, R1-status, high-grade ITB, PTB and independently with reduced survival. Increased intratumoral FOXP3+T-cells correlated with lymphatic invasion, N1-stage, PTB and marginally with adverse outcome. High peritumoral CD163-counts correlated with venous invasion, PTB and ITB. High intratumoral CD163-counts correlated with higher T-stage and PTB.PDAC-microenvironment displays a tumor-favoring immune-cell composition especially in the immediate environment of the tumor-buds that promotes further growth and indicates a close interaction of the immune response with the EMT-process. Increased peritumoral FOXP3+T-cell density is identified as an independent adverse prognostic factor in PDAC. Patients with phenotypically aggressive PDACs may profit from targeted immunotherapy against FOXP3.