Recurrence due to neoplastic seeding in head and neck cancer: report of two cases and review of the literature

AIMS AND BACKGROUND Tumor progression due to seeding of tumor cells after definitive treatment for squamous cell carcinomas of the head and neck is an uncommon condition that can considerably worsen the outcome of patients with head and neck cancer. METHODS AND STUDY DESIGN We report two cases of recurrence due to neoplastic seeding from oropharyngeal and oral cancer, respectively. We performed a literature review with MEDLINE as the main search engine. RESULTS Seeding was found to occur most often in tracheotomy scars and gastrostomy sites. The oral cavity, hypopharynx and oropharynx were the primary sites in most cases, and advanced tumor stage seemed to be a risk factor for seeding. Treatment options include salvage surgery, which requires thorough resections, radiotherapy when possible, and palliative management. The prognosis of such events is poor. CONCLUSION Although neoplastic seeding is a well-known phenomenon in cancer surgery, many questions remain unanswered, especially regarding preventive measures and management strategies.

Effects of two traits of the ecological state equation on our understanding of species coexistence and ecosystem services

Species coexistence has been a fundamental issue to understand ecosystem functioning since the beginnings of ecology as a science. The search of a reliable and all-encompassing explanation for this issue has become a complex goal with several apparently opposing trends. On the other side, seemingly unconnected with species coexistence, an ecological state equation based on the inverse correlation between an indicator of dispersal that fits gamma distribution and species diversity has been recently developed. This article explores two factors, whose effects are inconspicuous in such an equation at the first sight, that are used to develop an alternative general theoretical background in order to provide a better understanding of species coexistence. Our main outcomes are: (i) the fit of dispersal and diversity values to gamma distribution is an important factor that promotes species coexistence mainly due to the right-skewed character of gamma distribution; (ii) the opposite correlation between species diversity and dispersal implies that any increase of diversity is equivalent to a route of “ecological cooling” whose maximum limit should be constrained by the influence of the third law of thermodynamics; this is in agreement with the well-known asymptotic trend of diversity values in space and time; (iii) there are plausible empirical and theoretical ways to apply physical principles to explain important ecological processes; (iv) the gap between theoretical and empirical ecology in those cases where species diversity is paradoxically high could be narrowed by a wave model of species coexistence based on the concurrency of local equilibrium states. In such a model, competitive exclusion has a limited but indispensable role in harmonious coexistence with functional redundancy. We analyze several literature references as well as ecological and evolutionary examples that support our approach, reinforcing the meaning equivalence between important physical and ecological principles.

Pelagic molybdenum concentration anomalies and the impact of sediment resuspension on the molybdenum budget in two tidal systems of the North Sea

The seasonal dynamics of molybdenum (Mo) were studied in the water column of two tidal basins of the German Wadden Sea (Sylt-Rømø and Spiekeroog) between 2007 and 2011. In contrast to its conservative behaviour in the open ocean, both, losses of more than 50% of the usual concentration level of Mo in seawater and enrichments up to 20% were observed repeatedly in the water column of the study areas. During early summer, Mo removal by adsorption on algae-derived organic matter (e.g. after Phaeocystis blooms) is postulated to be a possible mechanism. Mo bound to organic aggregates is likely transferred to the surface sediment where microbial decomposition enriches Mo in the pore water. First δ98/95Mo data of the study area disclose residual Mo in the open water column being isotopically heavier than MOMo (Mean Ocean Molybdenum) during a negative Mo concentration anomaly, whereas suspended particulate matter shows distinctly lighter values. Based on field observations a Mo isotope enrichment factor of ε = −0.3‰ has been determined which was used to argue against sorption on metal oxide surfaces. It is suggested here that isotope fractionation is caused by biological activity and association to organic matter. Pelagic Mo concentration anomalies exceeding the theoretical salinity-based concentration level, on the other hand, cannot be explained by replenishment via North Sea waters alone and require a supply of excess Mo. Laboratory experiments with natural anoxic tidal flat sediments and modelled sediment displacement during storm events suggest fast and effective Mo release during the resuspension of anoxic sediments in oxic seawater as an important process for a recycling of sedimentary sulphide bound Mo into the water column.

Upper ocean vertical supply: A neglected primary factor controlling the distribution of neodymium concentrations of open ocean surface waters?

Neodymium (Nd) isotopes are an important geochemical tool to trace the present and past water mass mixing as well as continental inputs. The distribution of Nd concentrations in open ocean surface waters (0�100 m) is generally assumed to be controlled by lateral mixing of Nd from coastal surface currents and by removal through reversible particle scavenging. However, using 228Ra activity as an indicator of coastal water mass influence, surface water Nd concentration data available on key oceanic transects as a whole do not support the above scenario. From a global compilation of available data, we find that more stratified regions are generally associated with low surface Nd concentrations. This implies that upper ocean vertical supply may be an as yet neglected primary factor in determining the basin-scale variations of surface water Nd concentrations. Similar to the mechanism of nutrients supply, it is likely that stratification inhibits vertical supply of Nd from the subsurface thermocline waters and thus the magnitude of Nd flux to the surface layer. Consistently, the estimated required input flux of Nd to the surface layer to maintain the observed concentrations could be nearly two orders of magnitudes larger than riverine/dust flux, and also larger than the model-based estimation on shelf-derived coastal flux. In addition, preliminary results from modeling experiments reveal that the input from shallow boundary sources, riverine input, and release from dust are actually not the primary factors controlling Nd concentrations most notably in the Pacific and Southern Ocean surface waters.

Blocking brain-derived neurotrophic factor inhibits injury-induced hyperexcitability of hippocampal CA3 neurons

Brain trauma can disrupt synaptic connections, and this in turn can prompt axons to sprout and form new connections. If these new axonal connections are aberrant, hyperexcitability can result. It has been shown that ablating tropomyosin-related kinase B (TrkB), a receptor for brain-derived neurotrophic factor (BDNF), can reduce axonal sprouting after hippocampal injury. However, it is unknown whether inhibiting BDNF-mediated axonal sprouting will reduce hyperexcitability. Given this, our purpose here was to determine whether pharmacologically blocking BDNF inhibits hyperexcitability after injury-induced axonal sprouting in the hippocampus. To induce injury, we made Schaffer collateral lesions in organotypic hippocampal slice cultures. As reported by others, we observed a 50% reduction in axonal sprouting in cultures treated with a BDNF blocker (TrkB-Fc) 14 days after injury. Furthermore, lesioned cultures treated with TrkB-Fc were less hyperexcitable than lesioned untreated cultures. Using electrophysiology, we observed a two-fold decrease in the number of CA3 neurons that showed bursting responses after lesion with TrkB-Fc treatment, whereas we found no change in intrinsic neuronal firing properties. Finally, evoked field excitatory postsynaptic potential recordings indicated an increase in network activity within area CA3 after lesion, which was prevented with chronic TrkB-Fc treatment. Taken together, our results demonstrate that blocking BDNF attenuates injury-induced hyperexcitability of hippocampal CA3 neurons. Axonal sprouting has been found in patients with post-traumatic epilepsy. Therefore, our data suggest that blocking the BDNF-TrkB signaling cascade shortly after injury may be a potential therapeutic target for the treatment of post-traumatic epilepsy.

Congenital factor XIII deficiency in Pakistan: characterization of seven families and identification of four novel mutations

Deficiency of coagulation factor XIII (FXIII) belongs to the rare bleeding disorders and its incidence is higher in populations with consanguineous marriages. The aims of this study were to characterize patients and relatives from seven families with suspected FXIII deficiency from Pakistan and to identify the underlying mutations. As a first indicator of FXIII deficiency, a 5M urea clot solubility test was used. Plasma FXIII A- and B-subunit antigen levels were determined by ELISA. FXIII activity was measured with an incorporation assay. Sequencing of all exons and intron/exon boundaries of F13A was performed, and a novel splice site defect was confirmed by RT-PCR analysis. Genetic analysis revealed six different mutations in the F13A gene. Two splice site mutations were detected, a novel c.1460+1G>A mutation in the first nucleotide of intron 11 and a previously reported c.2045G>A mutation in the last nucleotide of exon 14. Neither of them was expressed at protein level. A novel nonsense mutation in exon 4, c.567T>A, p.Cys188X, was identified, leading in homozygous form to severe FXIII deficiency. Two novel missense mutations were found in exons 8 and 9, c.1040C>A, p.Ala346Asp and c.1126T>C, p.Trp375Arg, and a previously reported missense mutation in exon 10, c.1241C>T, p.Ser413Leu. All patients homozygous for these missense mutations presented with severe FXIII deficiency. We have analysed a cohort of 27 individuals and reported four novel mutations leading to congenital FXIII deficiency.

U7 snRNP-specific Lsm11 protein: dual binding contacts with the 100 kDa zinc finger processing factor (ZFP100) and a ZFP100-independent function in histone RNA 3' end processing

The 3' cleavage generating non-polyadenylated animal histone mRNAs depends on the base pairing between U7 snRNA and a conserved histone pre-mRNA downstream element. This interaction is enhanced by a 100 kDa zinc finger protein (ZFP100) that forms a bridge between an RNA hairpin element upstream of the processing site and the U7 small nuclear ribonucleoprotein (snRNP). The N-terminus of Lsm11, a U7-specific Sm-like protein, was shown to be crucial for histone RNA processing and to bind ZFP100. By further analysing these two functions of Lsm11, we find that Lsm11 and ZFP100 can undergo two interactions, i.e. between the Lsm11 N-terminus and the zinc finger repeats of ZFP100, and between the N-terminus of ZFP100 and the Sm domain of Lsm11, respectively. Both interactions are not specific for the two proteins in vitro, but the second interaction is sufficient for a specific recognition of the U7 snRNP by ZFP100 in cell extracts. Furthermore, clustered point mutations in three phylogenetically conserved regions of the Lsm11 N-terminus impair or abolish histone RNA processing. As these mutations have no effect on the two interactions with ZFP100, these protein regions must play other roles in histone RNA processing, e.g. by contacting the pre-mRNA or additional processing factors.

Brain-derived neurotrophic factor protects against multiple forms of brain injury in bacterial meningitis

BACKGROUND Brain-derived neurotrophic factor (BDNF) blocks activation of caspase-3, reduces translocation of apoptosis-inducing factor (AIF), attenuates excitotoxicity of glutamate, and increases antioxidant enzyme activities. The mechanisms of neuroprotection suggest that BDNF may be beneficial in bacterial meningitis. METHODS To assess a potentially beneficial effect of adjuvant treatment with BDNF in bacterial meningitis, 11-day-old infant rats with experimental meningitis due to Streptococcus pneumoniae or group B streptococci (GBS) were randomly assigned to receive intracisternal injections with either BDNF (3 mg/kg) or equal volumes (10 mu L) of saline. Twenty-two hours after infection, brains were analyzed, by histomorphometrical examination, for the extent of cortical and hippocampal neuronal injury. RESULTS Compared with treatment with saline, treatment with BDNF significantly reduced the extent of 3 distinct forms of brain cell injury in this disease model: cortical necrosis in meningitis due to GBS (median, 0.0% [range, 0.0%-33.7%] vs. 21.3% [range, 0.0%-55.3%]; P<.03), caspase-3-dependent cell death in meningitis due to S. pneumoniae (median score, 0.33 [range, 0.0-1.0] vs. 1.10 [0.10-1.56]; P<.05), and caspase-3-independent hippocampal cell death in meningitis due to GBS (median score, 0 [range, 0-2] vs. 0.88 [range, 0-3.25]; P<.02). The last form of injury was associated with nuclear translocation of AIF. CONCLUSION BDNF efficiently reduces multiple forms of neuronal injury in bacterial meningitis and may hold promise as adjunctive therapy for this disease.

Accurate evaluation of hadronic uncertainties in spin-independent WIMP-nucleon scattering: Disentangling two- and three-flavor effects

We show how to avoid unnecessary and uncontrolled assumptions usually made in the literature about soft SU(3) flavor symmetry breaking in determining the two-flavor nucleon matrix elements relevant for direct detection of weakly interacting massive particles (WIMPs). Based on SU(2) chiral perturbation theory, we provide expressions for the proton and neutron scalar couplings fp,nu and fp,nd with the pion-nucleon σ term as the only free parameter, which should be used in the analysis of direct detection experiments. This approach for the first time allows for an accurate assessment of hadronic uncertainties in spin-independent WIMP-nucleon scattering and for a reliable calculation of isospin-violating effects. We find that the traditional determinations of Vfpu−fnu and fpd−fnd are off by a factor of 2.

Evaluating perspectives for PRRS virus elimination from pig dense areas with a risk factor based herd index

Porcine reproductive and respiratory syndrome virus (PRRSV) is wide-spread in pig populations globally. In many regions of Europe with intensive pig production and high herd densities, the virus is endemic and can cause disease and production losses. This fuels discussion about the feasibility and sustainability of virus elimination from larger geographic regions. The implementation of a program aiming at virus elimination for areas with high pig density is unprecedented and its potential success is unknown. The objective of this work was to approach pig population data with a simple method that could support assessing the feasibility of a sustainable regional PRRSV elimination. Based on known risk factors such as pig herd structure and neighborhood conditions, an index characterizing individual herds' potential for endemic virus circulation and reinfection was designed. This index was subsequently used to compare data of all pig herds in two regions with different pig- and herd-densities in Lower Saxony (North-West Germany) where PRRSV is endemic. Distribution of the indexed herds was displayed using GIS. Clusters of high herd index densities forming potential risk hot spots were identified which could represent key target areas for surveillance and biosecurity measures under a control program aimed at virus elimination. In an additional step, for the study region with the higher pig density (2463 pigs/km(2) farmland), the potential distribution of PRRSV-free and non-free herds during the implementation of a national control program aiming at national virus elimination was modeled. Complex herd and trade network structures suggest that PRRSV elimination in regions with intensive pig farming like that of middle Europe would have to involve legal regulation and be accompanied by important trade and animal movement restrictions. The proposed methodology of risk index mapping could be adapted to areas varying in size, herd structure and density. Interpreted in the regional context, this could help to classify the density of risk and to accordingly target resources and measures for elimination.

Chromatin structure and DNase I hypersensitivity in the transcriptionally active and inactive porcine tumor necrosis factor gene locus

We have analyzed the chromatin structure of the porcine tumor necrosis factor gene locus (TNF-alpha and TNF-beta). Nuclei from porcine peripheral blood mononuclear cells were digested with different nucleases. As assessed with micrococcal nuclease, the two TNF genes displayed slightly faster digestion kinetics than bulk DNA. Studies with DNaseI revealed distinct DNaseI hypersensitive sites (DH-sites) within the porcine TNF locus. Four DH-sites could be observed in the promoter and mRNA leader regions of the TNF-beta gene. Two DH-sites could be observed for the TNF-alpha gene, one located in the promoter region close to the TATA-box and the other site in intron 3. This pattern of DH-sites was present independently of the activation state of the cells. Interestingly in a porcine macrophage-like cell line, we found that the TNF-alpha promoter DH-site disappeared and another DH-site appeared in the region of intron 1. Additionally, the DH-site of intron 3 could be enhanced by PMA-stimulation in these cells. TNF-beta sites were not detected in this cell line. However, DH-sites were totally absent in fibroblasts (freshly isolated from testicles) and in porcine kidney cells (PK15 cell line) both of which do not transcribe the TNF genes. Therefore, the pattern of DH-sites corresponds to the transcriptional activity of analyzed cells.

Investigation of IL-23 (p19, p40) and IL-23R identifies nuclear expression of IL-23 p19 as a favorable prognostic factor in colorectal cancer: a retrospective multicenter study of 675 patients.

IL-23 is a heterodimeric cytokine involved in inflammatory diseases; its role in cancer progression is controversial. Here we analyse the expression of IL-23 subunits (p40 and p19) and IL-23R in colorectal cancer with regard to disease progression, clinical-pathological and molecular aspects. Immunohistochemistry for IL-23p19, IL-23p40, IL-23R and CD8 was performed on a multi-punch tissue microarray of 195 colorectal cancers (cohort 1), matched normal tissue, adenoma and lymph node metastases. Results were compared with clinical-pathological features and CD8+ T-cell counts, then validated on two patient cohorts (cohort 2: n=341, cohort 3: n=139). Cytoplasmic/membranous expression of IL-23 (p19 and p40 subunits) and IL-23R, respectively were over-expressed in carcinomas versus adenomas and normal tissues (p<0.0001) but were reduced in lymph node metastases (p<0.0001). Nuclear IL-23p19 expression was observed in 23.1% and was associated with early TNM stage (p=0.0186), absence of venous (p=0.0124) and lymphatic invasion (p=0.01493), favorable survival (p=0.014) and absence of distant metastasis (p=0.0146; specificity: 100%). This unexpected cellular localization was confirmed by cell fractionation. The beneficial effect of nuclear IL-23p19 was restricted to tumours with CD8+ high counts. Results were validated on Cohorts 2/3. This multicenter study underlines the possible CD8(+)--dependency and beneficial effect of nuclear IL-23p19 on overall patient survival.

Epidermal growth factor receptor (EGFR) is an independent adverse prognostic factor in esophageal adenocarcinoma patients treated with cisplatin-based neoadjuvant chemotherapy.

Neoadjuvant platin-based therapy is accepted as a standard therapy for advanced esophageal adenocarcinoma (EAC). Patients who respond have a better survival prognosis, but still a significant number of responder patients die from tumor recurrence. Molecular markers for prognosis in neoadjuvantly treated EAC patients have not been identified yet. We investigated the epidermal growth factor receptor (EGFR) in prognosis and chemotherapy resistance in these patients. Two EAC patient cohorts, either treated by neoadjuvant cisplatin-based chemotherapy followed by surgery (n=86) or by surgical resection (n=46) were analyzed for EGFR protein expression and gene copy number. Data were correlated with clinical and histopathological response, disease-free and overall survival. In case of EGFR overexpression, the prognosis for neoadjuvant chemotherapy responders was poor as in non-responders. Responders had a significantly better disease-free survival than non-responders only if EGFR expression level (p=0.0152) or copy number (p=0.0050) was low. Comparing neoadjuvantly treated patients and primary resection patients, tumors of non-responder patients more frequently exhibited EGFR overexpression, providing evidence that EGFR is a factor for indicating chemotherapy resistance. EGFR overexpression and gene copy number are independent adverse prognostic factors for neoadjuvant chemotherapy-treated EAC patients, particularly for responders. Furthermore, EGFR overexpression is involved in resistance to cisplatin-based neoadjuvant chemotherapy.

In search of the internal structure of the processes underlying interval timing in the sub-second and the second range: A confirmatory factor analysis approach

One of the earliest accounts of duration perception by Karl von Vierordt implied a common process underlying the timing of intervals in the sub-second and the second range. To date, there are two major explanatory approaches for the timing of brief intervals: the Common Timing Hypothesis and the Distinct Timing Hypothesis. While the common timing hypothesis also proceeds from a unitary timing process, the distinct timing hypothesis suggests two dissociable, independent mechanisms for the timing of intervals in the sub-second and the second range, respectively. In the present paper, we introduce confirmatory factor analysis (CFA) to elucidate the internal structure of interval timing in the sub-second and the second range. Our results indicate that the assumption of two mechanisms underlying the processing of intervals in the second and the sub-second range might be more appropriate than the assumption of a unitary timing mechanism. In contrast to the basic assumption of the distinct timing hypothesis, however, these two timing mechanisms are closely associated with each other and share 77% of common variance. This finding suggests either a strong functional relationship between the two timing mechanisms or a hierarchically organized internal structure. Findings are discussed in the light of existing psychophysical and neurophysiological data.

Human NR5A1/SF-1 mutations show decreased activity on BDNF (brain-derived neurotrophic factor), an important regulator of energy balance: testing impact of novel SF-1 mutations beyond steroidogenesis

CONTEXT Human NR5A1/SF-1 mutations cause 46,XY disorder of sex development (DSD) with broad phenotypic variability, and rarely cause adrenal insufficiency although SF-1 is an important transcription factor for many genes involved in steroidogenesis. In addition, the Sf-1 knockout mouse develops obesity with age. Obesity might be mediated through Sf-1 regulating activity of brain-derived neurotrophic factor (BDNF), an important regulator of energy balance in the ventromedial hypothalamus. OBJECTIVE To characterize novel SF-1 gene variants in 4 families, clinical, genetic and functional studies were performed with respect to steroidogenesis and energy balance. PATIENTS 5 patients with 46,XY DSD were found to harbor NR5A1/SF-1 mutations including 2 novel variations. One patient harboring a novel mutation also suffered from adrenal insufficiency. METHODS SF-1 mutations were studied in cell systems (HEK293, JEG3) for impact on transcription of genes involved in steroidogenesis (CYP11A1, CYP17A1, HSD3B2) and in energy balance (BDNF). BDNF regulation by SF-1 was studied by promoter assays (JEG3). RESULTS Two novel NR5A1/SF-1 mutations (Glu7Stop, His408Profs*159) were confirmed. Glu7Stop is the 4th reported SF-1 mutation causing DSD and adrenal insufficiency. In vitro studies revealed that transcription of the BDNF gene is regulated by SF-1, and that mutant SF-1 decreased BDNF promoter activation (similar to steroid enzyme promoters). However, clinical data from 16 subjects carrying SF-1 mutations showed normal birth weight and BMI. CONCLUSIONS Glu7Stop and His408Profs*159 are novel SF-1 mutations identified in patients with 46,XY DSD and adrenal insufficiency (Glu7Stop). In vitro, SF-1 mutations affect not only steroidogenesis but also transcription of BDNF which is involved in energy balance. However, in contrast to mice, consequences on weight were not found in humans with SF-1 mutations.