5-Aminolevulinic acid-mediated fluorescence diagnosis of colon cancer: A histopathological comparison of fluorescent and non-fluorescent tumours

Background: 5-Aminolevulinic acid (5-ALA) selectively accumulates in cancer cells and is metabolised in the mitochondria to the fluorophore protoporphyrin IX. The GLiSten trial evaluated 5-ALA as a fluorescent probe for intraoperative detection of colon cancer and lymph node metastases. Only 13 of 40 cases showed fluorescence, suggesting a fundamental difference between fluorescent and non-fluorescent cancers. The aim of this study was to investigate whether differences in fluorescence were due to tumour cellularity, in particular T cell infiltration, which may be of prognostic significance. Method: Primary tumour tissue was available from 30 patients. The density of tumour cells, vascularity and stromal compartment size were quantified using digitally scanned tissue sections stained with haematoxylin and eosin. A set of 300 random points was superimposed onto each tumour image. The structure indicated by each point was then categorised as tumour, stroma, vessel or other. The proportions of tumour and vessel points gave the tumour cell density and vessel density respectively. The relative size of the stromal compartment was given by the tumour to stroma ratio. A tissue section was also stained for the T cell marker CD3 by immunohistochemistry. Percentage staining was quantified in three high-density fields using the Nuance imaging system. Results: We were unable to detect any difference between fluorescent and non-fluorescent cancers in terms of tumour cell density (difference in means 3.7%; P = 0.452), vessel density (difference in means 0.17%; P = 0.684), tumour-stroma ratio (difference in mean ratios 0.12; P = 0.934), or T cell count (difference in means 0.92%; P = 0.726). Furthermore, comparisons of the distributions of each variable demonstrated substantial overlap between the fluorescent and non-fluorescent cohorts. Conclusion: The results suggest that tumour and microenvironment structure do not differ between cancers that fluoresce with 5-ALA and those that do not. We therefore propose that the cellular metabolism of 5-ALA is a more likely explanation for differential fluorescence

Dark Solitons in High Velocity Waveguide Polariton Fluids

We study exciton-polariton nonlinear optical fluids in the high momentum waveguide regime for the first time. We demonstrate the formation of dark solitons with the expected dependence of width on fluid density for both main classes of soliton-forming fluid defects. The results are well described by numerical modeling of the fluid propagation. We deduce a continuous wave nonlinearity more than ten times that on picosecond time scales, arising due to interaction with the exciton reservoir

Flood magnitude-frequency and lithologic control on bedrock river incision in post-orogenic terrain

Mixed bedrock-alluvial rivers - bedrock channels lined with a discontinuous alluvial cover - are key agents in the shaping of mountain belt topography by bedrock fluvial incision. Whereas much research focuses upon the erosional dynamics of such rivers in the context of rapidly uplifting orogenic landscapes, the present study investigates river incision processes in a post-orogenic (cratonic) landscape undergoing extremely low rates of incision (> 5 m/Ma). River incision processes are examined as a function of substrate lithology and the magnitude and frequency of formative flows along Sandy Creek gorge, a mixed bedrock-alluvial stream in arid SE-central Australia. Incision is focused along a bedrock channel with a partial alluvial cover arranged into riffle-pool macrobedforms that reflect interactions between rock structure and large-flood hydraulics. Variations in channel width and gradient determine longitudinal trends in mean shear stress (τb) and therefore also patterns of sediment transport and deposition. A steep and narrow, non-propagating knickzone (with 5% alluvial cover) coincides with a resistant quartzite unit that subdivides the gorge into three reaches according to different rock erodibility and channel morphology. The three reaches also separate distinct erosional styles: bedrock plucking (i.e. detachment-limited erosion) prevails along the knickzone, whereas along the upper and lower gorge rock incision is dependent upon large formative floods exceeding critical erosion thresholds (τc) for coarse boulder deposits that line 70% of the channel thalweg (i.e. transport-limited erosion). The mobility of coarse bed materials (up to 2 m diameter) during late Holocene palaeofloods of known magnitude and age is evaluated using step-backwater flow modelling in conjunction with two selective entrainment equations. A new approach for quantifying the formative flood magnitude in mixed bedrock-alluvial rivers is described here based on the mobility of a key coarse fraction of the bed materials; in this case the d84 size fraction. A 350 m3/s formative flood fully mobilises the coarse alluvial cover with τb200-300 N/m2 across the upper and lower gorge riffles, peaking over 500 N/m2 in the knickzone. Such floods have an annual exceedance probability much less than 10- 2 and possibly as low as 10- 3. The role of coarse alluvial cover in the gorge is discussed at two scales: (1) modulation of bedrock exposure at the reach-scale, coupled with adjustment to channel width and gradient, accommodates uniform incision across rocks of different erodibility in steady-state fashion; and (2) at the sub-reach scale where coarse boulder deposits (corresponding to <i>τ</i><sub>b</sub> minima) cap topographic convexities in the rock floor, thereby restricting bedrock incision to rare large floods. While recent studies postulate that decreasing uplift rates during post-orogenic topographic decay might drive a shift to transport-limited conditions in river networks, observations here and elsewhere in post-orogenic settings suggest, to the contrary, that extremely low erosion rates are maintained with substantial bedrock channel exposure. Although bed material mobility is known to be rate-limiting for bedrock river incision under low sediment flux conditions, exactly how a partial alluvial cover might be spatially distributed to either optimise or impede the rate of bedrock incision is open to speculation. Observations here suggest that the small volume of very stable bed materials lining Sandy Creek gorge is distributed so as to minimise the rate of bedrock fluvial incision over time

Recruitment, augmentation and apoptosis of rat osteoclasts in 1,25-(OH)2D3 response to short-term treatment with 1,25-dihydroxyvitamin D3in vivo

Background Although much is known about the regulation of osteoclast (OC) formation and activity, little is known about OC senescence. In particular, the fate of of OC seen after 1,25-(OH)2D3 administration in vivo is unclear. There is evidence that the normal fate of OC is to undergo apoptosis (programmed cell death). We have investigated the effect of short-term application of high dose 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) on OC apoptosis in an experimental rat model. Methods OC recruitment, augmentation and apoptosis was visualised and quantitated by staining histochemically for tartrate resistant acid phosphatase (TRAP), double staining for TRAP/ED1 or TRAP/DAPI, in situ DNA fragmentation end labelling and histomorphometric analysis. Results Short-term treatment with high-dose 1,25-(OH)2D3 increased the recruitment of OC precursors in the bone marrow resulting in a short-lived increase in OC numbers. This was rapidly followed by an increase in the number of apoptotic OC and their subsequent removal. The response of OC to 1,25-(OH)2D3 treatment was dose and site dependent; higher doses producing stronger, more rapid responses and the response in the tibiae being consistently stronger and more rapid than in the vertebrae. Conclusions This study demonstrates that (1) after recruitment, OC are removed from the resorption site by apoptosis (2) the combined use of TRAP and ED1 can be used to identify OC and their precursors in vivo (3) double staining for TRAP and DAPI or in situ DNA fragmentation end labelling can be used to identify apoptotic OC in vivo

Intra-tumoural stromal morphometry predicts disease recurrence but not response to 5-fluorouracil – results from the QUASAR trial of colorectal cancer

Introduction: The biological importance of tumour-associated stroma is increasingly apparent, yet clinical utility remains ill-defined. In stage-II / Dukes B colorectal cancer (CRC), clinical biomarkers are urgently required to direct therapeutic options. We report here prognostic/predictive analyses, and molecular associations, of stromal morphometric quantification in the Quick and Simple and Reliable (QUASAR) trial of CRC. Materials and methods: Relative proportions of tumour epithelium (PoT) or stroma (PoS) were morphometrically quantified using digitised haematoxylin and eosin sections derived from 1,800 patients enrolled in QUASAR which randomised 3,239 (91% stage II) CRC patients between adjuvant fluorouracil/folinic acid (FUFA) chemotherapy and observation. The prognostic/predictive value of PoT/PoS measures were determined by stratified log-rank analyses. Results: High tumour stroma (≥50%) was associated with increased recurrence risk: 31.3% (143/457) recurrence for ≥50% versus 21.9% (294/1,343) if <50% [Rate ratio (RR)=1.62; 95%CI 1.30-2.02, p<0.0001)]. For stromal proportions of ≥65%, 40% (46/115) of patients had recurrent disease within 10 years. The adverse prognostic effect of high stroma was independent of established prognostic variables, and maintained in stage II / Dukes B patients (RR=1.62; 95%CI=1.26-2.08; p=0.0002). KRAS mutation in the presence of high stroma augmented recurrence risk (RR=2.93; 95%CI=1.87-4.59; p=0.0005). Stromal morphometry did not predict response to FUFA chemotherapy. Discussion: Simple digital morphometry applied to a single representative H&E section identifies CRC patients with over 50% higher risk of disease recurrence. This technique can reliably partition patients into sub-populations with differential risks of tumour recurrence in a simple and cost-effective manner. Further prospective validation is warranted

Constructing Memories of Holmfirth through 'Last of the Summer Wine'

Last of the Summer Wine (BBC, 1973-2010) was filmed in Holmfirth, West Yorkshire, UK for 37 years. Its presence in the town has affected collective memories of the space and place of the region. In examining Summer Wine’s continued presence in Holmfirth even after it has ceased production, we investigate how the series as a text, institution and brand serves to spatially inform Holmfirth and construct, embed and inform cultural memory

Methicillin-Resistant Staphylococcus aureus (MRSA) Strain ST398 Is Present in Midwestern U.S. Swine and Swine Workers

BACKGROUND: Recent research has demonstrated that many swine and swine farmers in the Netherlands and Canada are colonized with MRSA. However, no studies to date have investigated carriage of MRSA among swine and swine farmers in the United States (U.S.). METHODS: We sampled the nares of 299 swine and 20 workers from two different production systems in Iowa and Illinois, comprising approximately 87,000 live animals. MRSA isolates were typed by pulsed field gel electrophoresis (PFGE) using SmaI and EagI restriction enzymes, and by multi locus sequence typing (MLST). PCR was used to determine SCCmec type and presence of the pvl gene. RESULTS: In this pilot study, overall MRSA prevalence in swine was 49% (147/299) and 45% (9/20) in workers. The prevalence of MRSA carriage among production system A's swine varied by age, ranging from 36% (11/30) in adult swine to 100% (60/60) of animals aged 9 and 12 weeks. The prevalence among production system A's workers was 64% (9/14). MRSA was not isolated from production system B's swine or workers. Isolates examined were not typeable by PFGE when SmaI was used, but digestion with EagI revealed that the isolates were clonal and were not related to common human types in Iowa (USA100, USA300, and USA400). MLST documented that the isolates were ST398. CONCLUSIONS: These results show that colonization of swine by MRSA was very common on one swine production system in the midwestern U.S., suggesting that agricultural animals could become an important reservoir for this bacterium. MRSA strain ST398 was the only strain documented on this farm. Further studies are examining carriage rates on additional farms

Black Girls Speak STEM: Counterstories of Informal and Formal Learning Experiences

This study presents the interpretations and perceptions of Black girls who participated in I AM STEM – a community-based informal science, technology, engineering, and mathematics (STEM) program. Using narrative inquiry, participants generated detailed accounts of their informal and formal STEM learning experiences. Critical race methodology informed this research to portray the dynamic and complex experiences of girls of color, whose stories have historically been silenced and misrepresented. The data sources for this qualitative study included individual interviews, student reflection journals, samples of student work, and researcher memos, which were triangulated to produce six robust counterstories. Excerpts of the counterstories are presented in this article. The major findings of this research revealed that I AM STEM ignited an interest in STEM learning through field trips and direct engagement in scientific phenomena that allowed the girls to become agentic in continuing their engagement in STEM activities throughout the year. This call to awaken the voices of Black girls to speak casts light on their experiences and challenges as STEM learners ⎯ from their perspectives. The findings confirm that when credence and counterspaces are given to Black girls, they are poised to reveal their luster toward STEM learning. This study provided a space for Black girls to reflect on their STEM learning experiences, formulate new understandings, and make connections between the informal and formal learning environments within the context of their everyday lives, thus offering a more holistic approach to STEM learning that occurs across settings and over a lifetime