Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy.

The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state, resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor volume, and a 57% increase in survival compared to chemotherapy alone. This work describes a molecular strategy through which transcriptional reprogramming of tumor stroma enables chemotherapeutic response and suggests vitamin D priming as an adjunct in PDA therapy. PAPERFLICK:

Proteomic profiling of small extracellular vesicles derived from mouse pancreatic cancer and stellate cells: Role in pancreatic cancer.

Small extracellular vesicles (sEVs) are cell-derived vesicles evolving as important elements involved in all stages of cancers. sEVs bear unique protein signatures that may serve as biomarkers. Pancreatic cancer (PC) records a very poor survival rate owing to its late diagnosis and several cancer cell-derived proteins have been reported as candidate biomarkers. However, given the pivotal role played by stellate cells (PSCs, which produce the collagenous stroma in PC), it is essential to also assess PSC-sEV cargo in biomarker discovery. Thus, this study aimed to isolate and characterise sEVs from mouse PC cells and PSCs cultured alone or as co-cultures and performed proteomic profiling and pathway analysis. Proteomics confirmed the enrichment of specific markers in the sEVs compared to their cells of origin as well as the proteins that are known to express in each of the culture types. Most importantly, for the first time it was revealed that PSC-sEVs are enriched in proteins (including G6PI, PGAM1, ENO1, ENO3, and LDHA) that mediate pathways related to development of diabetes, such as glucose metabolism and gluconeogenesis revealing a potential role of PSCs in pancreatic cancer-related diabetes (PCRD). PCRD is now considered a harbinger of PC and further research will enable to identify the role of these components in PCRD and may develop as novel candidate biomarkers of PC.

The epidemiology of acute pancreatitis in Tasmania over a 12-year period: Is this a disease of disadvantage?

BACKGROUND: The global incidence of acute pancreatitis (AP) is increasing, but little information exists about trends in Australia. This study aimed to describe incidence trends, along with clinical and socio-demographic associations, in the state of Tasmania over a recent 12-year period. METHODS: The study cohort was obtained by linking clinical and administrative datasets encompassing the whole Tasmanian population between 2007 and 2018, inclusive. Pancreatitis case definition was based on relevant ICD-10 hospitalization codes, or elevated serum lipase or amylase in pathology data. Age-standardised incidence rates were estimated, overall and stratified by sex, aetiology, and Index of Relative Socio-economic Disadvantage (IRSD). RESULTS: In the study period, 4905 public hospital AP episodes were identified in 3503 people. The age-standardised person-based incidence rate across the entire period was 54 per 100,000 per year. Incidence was inversely related to IRSD score; 71 per 100,000 per year in the most disadvantaged quartile compared to 32 in the least disadvantaged. Biliary AP incidence was higher than that of alcohol-related AP, although the greatest incidence was in "unspecified" cases. There was an increase in incidence for the whole cohort (average annual percent change 3.23 %), largely driven by the two most disadvantaged IRSD quartiles; the least disadvantaged quartile saw a slight overall decrease. CONCLUSION: This is the first Australian study providing robust evidence that AP incidence is increasing and is at the upper limit of population-based studies worldwide. This increased incidence is greatest in socio-economically disadvantaged areas, meriting further research to develop targeted, holistic management strategies.

The Functional Anatomy and Innervation of the Platysma is Segmental: Implications for Lower Lip Dysfunction, Recurrent Platysmal Bands, and Surgical Rejuvenation.

BACKGROUND: Despite the central role of the platysma in face and neck rejuvenation, much confusion exists regarding its surgical anatomy. OBJECTIVES: This study was undertaken to clarify the regional anatomy of the platysma and its innervation pattern and to explain clinical phenomena, such as the origin of platysmal bands and their recurrence, and the etiology of lower lip dysfunction after neck lift procedures. METHODS: Fifty-five cadaver heads were studied (16 embalmed, 39 fresh, mean age 75 years). Following preliminary dissections and macro-sectioning, a series of standardized layered dissections were performed, complemented by histology and sheet plastination. RESULTS: In addition to its origin and insertion, the platysma is attached to the skin and deep fascia across its entire superficial and deep surfaces. This composite system explains the age-related formation of static platysmal bands, recurrent platysmal bands after complete platysma transection, and recurrent anterior neck laxity after no-release lifting. The facial part of the platysma is primarily innervated by the marginal mandibular branch of the facial nerve, whereas the submandibular platysma is innervated by the "first" cervical branches, which terminate at the mandibular origin of the depressor labii inferioris. This pattern has implications for postoperative dysfunction of the lower lip, including pseudoparalysis, and potential targeted surgical denervation. CONCLUSIONS: This anatomical study, comprised of layered dissections, large histology, and sheet plastination, fully describes the anatomy of the platysma including its bony, fascial, and dermal attachments, as well as its segmental innervation including its nerve danger zones. It provides a sound anatomical basis for the further development of surgical techniques to rejuvenate the neck with prevention of recurrent platysmal banding.

The influence of intraoperative rectal washout on local recurrence of colorectal cancer following curative resection: a systematic review and meta-analysis.

PURPOSE: To determine the effectiveness of rectal washout in preventing local recurrence of distal colorectal cancer following curative resection. METHODS: A systematic review and meta-analysis was performed after a literature search was conducted on MEDLINE, EMBASE, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), ClinicalTrials.gov, and the ISRCTN registry. The study was reported using PRISMA guidelines. The primary endpoint was incidence of local recurrence of cancer after distal colonic and rectal cancer surgery. RESULTS: After screening, 8 studies with a total sample size of 6739 patients were identified. At 5-year follow-up, local recurrence in the washout group (WO) was 6.08% compared to 9.48% in the no-washout group (NWO) group (OR 0.63, 95% CI = 0.51-0.78, Chi2 = 6.76, df = 7, p = 0.45). The relative risk reduction was 36.9%. To exclude a 36.9% relative risk reduction from 9.48 to 6.08% with a 5% significance level and 80% power a randomized control trial would require a total sample size of 1946 participants distributed equally between the two treatment arms. CONCLUSION: It is safe to recommend the use of rectal washout for left sided and rectal tumour resections. It is a simple and safe step during colorectal surgery that appears to improve long-term oncological outcomes and was not reported to be associated with any complications.

A paleodemographic assessment of mortality and fertility rates during the second demographic transition in rural central Indiana.

OBJECTIVES: Since its inception, skeletally based paleodemographic research has emphasized the utility of biocultural models for interpreting the dynamic relationship between the sociocultural and ecological forces accompanying demographic transitions and shaping populations' health and well-being. While the demographic transition associated with the Neolithic Revolution has been a common focus in bioarcheology, the present study analyzes human skeletal remains from a large 19th century cemetery in central Indiana to examine population dynamics during the second demographic transition, a period generally characterized by decreasing fertility rates and improvements in life expectancy. This study demonstrates the potential to methodologically identify regional variations in the timing and interactions between broad-scale socioeconomic changes and technological advancements that characterized the time period through observed changes in survivorship and fertility based on age-at-death distributions. MATERIALS AND METHODS: This study uses three temporally distinct samples (AD 1827-1869; 1870-1889; 1890-1935) from the Bethel Cemetery (n = 503). Kaplan-Meier survival analyses with a log- rank tests are utilized to evaluate survivorship and mortality over time. Next, Cox proportional hazard analyses are employed to examine the interaction between sex and time as covariates. Finally, the D0-14/D ratio is applied to estimate fertility for each of the three temporally bounded cohorts. RESULTS: The Kaplan-Meier survival analyses and Cox proportional hazard modeling revealed statistically significant differences in survivorship between the three time periods. Age-specific mortality rates are reduced among adult female and male age classes in this rural community over the course of the 19th and early 20th centuries, resulting in the increasing life expectancies associated with the second demographic transition. While mortality in early adulthood was common during the first time period and decreases thereafter, sex was not identified as a meaningful covariate. The proportion of juveniles in the three temporal samples indicate that fertility rates were higher than national averages for the better part of the 19th century and subsequently declined around the turn of 20th century for this community. CONCLUSIONS: The results indicate temporal differences between the three periods, demonstrating increased survivorship and decreased mortality and fertility over time. These findings corroborate two key features of the second demographic transition characterized by the move from high rates of both fertility and mortality to reduced rates and a general easing of demographic pressures. The observed trends likely reflect improvements in health, coinciding the industrial advance and economic development within and around Indianapolis. While the socioeconomic factors characterizing the Industrial Revolution drove demographic shifts that parallel an equally important epidemiological transition, potential regional differences are discussed to highlight variability in the timing of demographic transitions. The paleodemographic methods utilized in this study demonstrate improved accuracy and efficacy, which ultimately advances researchers' potential to disentangle population-specific socioeconomic factors that may contribute to asymmetrical experiences of health and mortality.

Diversification of the mygalomorph spider genus Aname (Araneae: Anamidae) across the Australian arid zone: Tracing the evolution and biogeography of a continent-wide radiation.

The assembly of the Australian arid zone biota has long fascinated biogeographers. Covering over two-thirds of the continent, Australia's vast arid zone biome is home to a distinctive fauna and flora, including numerous lineages which have diversified since the Eocene. Tracing the origins and speciation history of these arid zone taxa has been an ongoing endeavour since the advent of molecular phylogenetics, and an increasing number of studies on invertebrate animals are beginning to complement a rich history of research on vertebrate and plant taxa. In this study, we apply continent-wide genetic sampling and one of the largest phylogenetic data matrices yet assembled for a genus of Australian spiders, to reconstruct the phylogeny and biogeographic history of the open-holed trapdoor spider genus Aname L. Koch, 1873. This highly diverse lineage of Australian mygalomorph spiders has a distribution covering the majority of Australia west of the Great Dividing Range, but apparently excluding the high rainfall zones of eastern Australia and Tasmania. Original and legacy sequences were obtained for three mtDNA and four nuDNA markers from 174 taxa in seven genera, including 150 Aname specimen terminals belonging to 102 species-level operational taxonomic units, sampled from 32 bioregions across Australia. Reconstruction of the phylogeny and biogeographic history of Aname revealed three radiations (Tropical, Temperate-Eastern and Continental), which could be further broken into eight major inclusive clades. Ancestral area reconstruction revealed the Pilbara, Monsoon Tropics and Mid-West to be important ancestral areas for the genus Aname and its closest relatives, with the origin of Aname itself inferred in the Pilbara bioregion. From these origins in the arid north-west of Australia, our study found evidence for a series of subsequent biome transitions in separate lineages, with at least eight tertiary incursions back into the arid zone from more mesic tropical, temperate or eastern biomes, and only two major clades which experienced widespread (primary) in situ diversification within the arid zone. Based on our phylogenetic results, and results from independent legacy divergence dating studies, we further reveal the importance of climate-driven biotic change in the Miocene and Pliocene in shaping the distribution and composition of the Australian arid zone biota, and the value of continent-wide studies in revealing potentially complex patterns of arid zone diversification in dispersal-limited invertebrate taxa.

Circulating tumour cells in pancreatic cancer: A systematic review and meta-analysis of clinicopathological implications.

BACKGROUND: The detection and quantification of circulating tumour cells (CTCs) in pancreatic cancer (PC) has the potential to provide prognostic information. The aim of this review was to provide an overview of the literature surrounding CTCs in PC. METHODS: A systematic literature review on CTCs in PC between 2005-2020 was performed. Data based on peripheral vein samples were used to determine the positivity rate of CTCs, their prognostic significance and their relative numbers compared to portal vein (PV) samples. RESULTS: The overall CTC detection rate in forty-four articles was 65% (95%CI: 55-75%). Detection rate for CellSearch was 26% (95%CI: 14-38%), which was lower than for both filtration and microfluidic techniques. In nine studies with >50 patients, overall survival was worse with CTC positivity (HR 1.82; 95%CI: 1.61-2.05). Five of seven studies which described PV CTC collection provided patient-level data. PV CTC yield was 7.7-fold (95%CI 1.35-43.9) that of peripheral blood. CONCLUSIONS: CTCs were detected in the peripheral circulation of most patients with PC and may be related to prognosis and disease stage. PV blood contains more CTCs than peripheral blood sampling. This review points to the maturation of techniques of CTC enrichment, and its evidence base for eventual clinical deployment.

Annual abundance of common Kestrels (Falco tinnunculus) is negatively associated with second generation anticoagulant rodenticides.

Rats and mice can damage food and agricultural products as well as transmit diseases, thereby requiring control of their numbers. Application of Second Generation Anticoagulant Rodenticides (SGARs) often reduces rodent numbers locally. However, predators eating rodents, including non-target species, that have consumed SGARs may be secondarily exposed and potentially lethally poisoned. Here we study whether SGARs may have contributed to the widespread population declines of a rodent-eating raptor, the Common Kestrel (Falco tinnunculus) in the UK. We show that 161 (66.8%) of the 241 Kestrels submitted for ecotoxicology tests between 1997 and 2012 had detectable levels of at least one SGAR in their livers. Adult Kestrels had significantly higher prevalence of SGARs than juveniles, suggesting accumulation of SGARs through time. The prevalence and concentrations of individual SGARs in Kestrels were significantly higher in England than in Scotland. SGAR prevalence in Kestrels were positively associated with some land cover types, primarily arable cereals and broad-leaved woodland, and negatively associated with mainly mean elevation, probably reflecting variation in SGAR usage across land cover types. By using volunteer-collected data on national Kestrel abundance 1997-2012, we show that there is a negative correlation between the Kestrel population index in a specific year and the concentration of bromadialone as well as the total SGAR concentration in the same year. Although correlative, this is the first study to provide evidence for a potential population-limiting effect of SGARs on a raptor.

Targeting the HGF/c-MET pathway in advanced pancreatic cancer: a key element of treatment that limits primary tumour growth and eliminates metastasis.

BACKGROUND: Stromal-tumour interactions facilitate pancreatic cancer (PC) progression. The hepatocyte growth factor (HGF)/c-MET pathway is upregulated in PC and mediates the interaction between cancer cells and stromal pancreatic stellate cells (PSCs). This study assessed the effect of HGF/c-MET inhibition plus gemcitabine (G) on the progression of advanced PC. METHODS: Orthotopic PC was produced by implantation of luciferase-tagged human cancer cells + human PSCs into mouse pancreas. Tumours were allowed to develop without treatment for 4 weeks. Mice were then treated for 6 weeks with one of the following: IgG, G, HGF inhibitor (Hi), c-MET inhibitor (Ci), Hi + Ci, Hi + G, Ci + G, or Hi + Ci + G. RESULTS: Bioluminescence imaging showed similar tumour sizes in all mice at the initiation of treatments. Triple therapy (Hi + Ci + G): (1) completely eliminated metastasis; (2) significantly reduced tumour size as assessed by bioluminescence and at necropsy; (3) significantly reduced proliferating cancer cell density and stem cell marker DCLK1 expression in tumours. In vitro 3D culture studies supported our in vivo findings. CONCLUSION: Even at an advanced disease stage, a two-pronged approach, targeting (a) HGF/c-MET with relevant inhibitors and (b) cancer cells with chemotherapy, completely eliminated metastasis and significantly decreased tumour growth, suggesting that this is a promising treatment approach for PC.

Clinging on to alpine life: Investigating factors driving the uphill range contraction and population decline of a mountain breeding bird.

Climate change and anthropogenic nitrogen deposition are widely regarded as important drivers of environmental change in alpine habitats. However, due to the difficulties working in high-elevation mountain systems, the impacts of these drivers on alpine breeding species have rarely been investigated. The Eurasian dotterel (Charadrius morinellus) is a migratory wader, which has been the subject of uniquely long-term and spatially widespread monitoring effort in Scotland, where it breeds in alpine areas in dwindling numbers. Here we analyse data sets spanning three decades, to investigate whether key potential drivers of environmental change in Scottish mountains (snow lie, elevated summer temperatures and nitrogen deposition) have contributed to the population decline of dotterel. We also consider the role of rainfall on the species' wintering grounds in North Africa. We found that dotterel declines-in both density and site occupancy of breeding males-primarily occurred on low and intermediate elevation sites. High-elevation sites mostly continued to be occupied, but males occurred at lower densities in years following snow-rich winters, suggesting that high-elevation snow cover displaced dotterel to lower sites. Wintering ground rainfall was positively associated with densities of breeding males two springs later. Dotterel densities were reduced at low and intermediate sites where nitrogen deposition was greatest, but not at high-elevation sites. While climatic factors explained variation in breeding density between years, they did not seem to explain the species' uphill retreat and decline. We cannot rule out the possibility that dotterel have increasingly settled on higher sites previously unavailable due to extensive snow cover, while changes associated with nitrogen deposition may also have rendered lower lying sites less suitable for breeding. Causes of population and range changes in mountain-breeding species are thus liable to be complex, involving multiple anthropogenic drivers of environmental change acting widely across annual and migratory life cycles.

Pancreatic stellate cells: Aiding and abetting pancreatic cancer progression.

Tumour-stromal interactions have now been acknowledged to play a major role in pancreatic cancer (PC) progression. The abundant collagenous stroma is produced by a specific cell type in the pancreas-the pancreatic stellate cell (PSC). Pancreatic stellate cells (PSCs) are a unique resident cell type of pancreas and with a critical role in both healthy and diseased pancreas. Accumulating evidence indicates that PSCs interact closely with cancer cells as well as with other cell types of the stroma such as immune cells, endothelial cells and neuronal cells, to set up a growth permissive microenvironment for pancreatic tumours, which facilitates local tumour growth as well as distant metastasis. Consequently, recent work in the field has focused on the development of novel therapeutic approaches targeting the stroma to inhibit PC progression. Such a multi-pronged approach targeting both tumour and stromal elements of PC has been successfully applied in pre-clinical settings. The challenge now is to translate the pre-clinical findings into the clinical setting to achieve better outcomes for pancreatic cancer patients.

Total-evidence analysis of an undescribed fauna: resolving the evolution and classification of Australia's golden trapdoor spiders (Idiopidae: Arbanitinae: Euoplini).

In the trapdoor spider genus Euoplos Rainbow & Pulleine (tribe Euoplini), it was discovered recently that two divergent lineages occur in sympatry in eastern Australia. This challenged the monogeneric classification of the tribe and, in combination with inadequate taxonomic descriptions of some species, precluded comprehensive taxonomic revision. To resolve these issues, we conducted a total-evidence cladistic analysis on a largely undescribed continental fauna-the first such analysis on a group of Australian Mygalomorphae. We combined multilocus molecular data and/or morphological and behavioural data from all known species from eastern Australia (described and undescribed), plus a subset of Western Australian species, to produce a phylogeny for the tribe. We mapped morphological/behavioural characters onto this to identify clade-specific diagnostic characters, and applied these data to a generic reclassification of the tribe. We recovered two sympatric lineages in the Euoplini (the "wafer-door" and "plug-door/palisade" lineages), and revealed the phylogenetic position of all known eastern Australian species within these. Character mapping revealed morphological and behavioural (burrow architecture) features that allow diagnosis of the lineages and clades within them. We erect a new genus, Cryptoforis gen.n., to represent the wafer-door lineage, describe the type species, Cryptoforis hughesae sp.n., and transfer two species from Euoplos to Cryptoforis: C. tasmanica (Hickman, 1928) and C. victoriensis (Main, 1995). This study resolves phylogenetic structure within the Euoplini, and characterizes clades within the tribe to facilitate future taxonomic revisions. It also demonstrates that, whereas male morphology is more informative, female morphological characters relating to genitalia and the scopulation/spination of the anterior legs display phylogenetic signal in the Euoplini, highlighting the subtle nature of informative female characters in mygalomorph spiders.

Inter- and intra-tumoural heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma.

Cancer-associated fibroblasts (CAF) are orchestrators of the pancreatic ductal adenocarcinoma (PDAC) microenvironment. Stromal heterogeneity may explain differential pathophysiological roles of the stroma (pro- versus anti-tumoural) in PDAC. We hypothesised that multiple CAF functional subtypes exist in PDAC, that contribute to stromal heterogeneity through interactions with cancer cells. Using molecular and functional analysis of patient-derived CAF primary cultures, we demonstrated that human PDAC-derived CAFs display a high level of inter- and intra-tumour heterogeneity. We identified at least four subtypes of CAFs based on transcriptomic analysis, and propose a classification for human PDAC-derived CAFs (pCAFassigner). Multiple CAF subtypes co-existed in individual patient samples. The presence of these CAF subtypes in bulk tumours was confirmed using publicly available gene expression profiles, and immunostainings of CAF subtype markers. Each subtype displayed specific phenotypic features (matrix- and immune-related signatures, vimentin and α-smooth muscle actin expression, proliferation rate), and was associated with an assessable prognostic impact. A prolonged exposure of non-tumoural pancreatic stellate cells to conditioned media from cancer cell lines (cancer education experiment) induced a CAF-like phenotype, including loss of capacity to revert to quiescence and an increase in the expression of genes related to CAF subtypes B and C. This classification demonstrates molecular and functional inter- and intra-tumoural heterogeneity of CAFs in human PDAC. Our subtypes overlap with those identified from single-cell analyses in other cancers, and pave the way for the development of therapies targeting specific CAF subpopulations in PDAC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Measuring sarcopenia on pre-operative CT in older adults undergoing emergency laparotomy: a comparison of three different calculations.

INTRODUCTION: Sarcopenia is associated with outcomes in older-adults undergoing emergency surgery. Psoas major measurement is a surrogate marker of sarcopenia with multiple calculations existing normalising to body size and no consensus as to which is optimal. We compared three different psoas-major calculations to predict outcomes in older adults undergoing emergency laparotomy. METHODS: Consecutive over 65s were identified from the National Emergency Laparotomy Audit(NELA) database at a single centre between 2014 and 2018. Psoas major was measured at the L3 level and normalised to height (psoas muscle index, PMI), L3 vertebral body (psoas muscle:L3 ratio, PML3) or body surface area (psoas:body surface area, PBSA) and each correlated to outcomes. Outcome measures included inpatient, 30-day and 90-day mortality. A comparison of the three calculations was performed using the Mann-Whitney U, chi-squared, receiver operating characteristic curves (ROC) and binary logistic regression. RESULTS: Two hundred and sixty-four older adults underwent emergency laparotomy (median age, 75 years ((IQR, 70-81 years), 50% female)). Inpatient mortality was 19.6%, 30-day mortality was 15.1% and 90-day mortality was 18.5%. A total of 31.1% of males and 30% of females were sarcopenic (30.6% overall). A multivariate analysis confirmed each method of psoas major calculation (p < 0.0001) to be associated with mortality, as was ASA-grade (p < 0.0001). Area under the curve (AUC) was greatest for PML3 in predicting mortality (inpatient: PML3, 0.76; PMI, 0.71; PBSA, 0.70; 30-day: PML3, 0.74; PMI, 0.68; PBSA, 0.68; and 90-day: PML3, 0.78; PMI, 0.71; PBSA, 0.70). ASA-grade, P-POSSUM and PML3 were independently associated with mortality on multivariate analysis. ROC analysis of predictions from logistic regression models demonstrated PML3 to be more closely aligned to mortality than ASA or P-POSSUM (inpatient: AUC:PML3, 0.807; ASA, 0.783; P-POSSUM, 0.762; 30-day:AUC: PML3, 0.799; ASA, 0.784; P-POSSUM, 0.787; and 90-day: AUC:PML3, 0.805; ASA, 0.781; P-POSSUM, 0.756). CONCLUSIONS: Sarcopenia was present in 30.6% of older adults undergoing emergency surgery and is associated with a significantly increased mortality. PML3 is superior to PMI or PBSA and should be considered the method of calculation of choice. Additionally, PML3 compares favourably to ASA and P-POSSUM.

Targeting HGF/c-MET Axis in Pancreatic Cancer.

Pancreatic cancer (pancreatic ductal adenocarcinoma (PDAC/PC)) has been an aggressive disease that is associated with early metastases. It is characterized by dense and collagenous desmoplasia/stroma, predominantly produced by pancreatic stellate cells (PSCs). PSCs interact with cancer cells as well as other stromal cells, facilitating disease progression. A candidate growth factor pathway that may mediate this interaction is the hepatocyte growth factor (HGF)/c-MET pathway. HGF is produced by PSCs and its receptor c-MET is expressed on pancreatic cancer cells and endothelial cells. The current review discusses the role of the MET/HGF axis in tumour progression and dissemination of pancreatic cancer. Therapeutic approaches that were developed targeting either the ligand (HGF) or the receptor (c-MET) have not been shown to translate well into clinical settings. We discuss a two-pronged approach of targeting both the components of this pathway to interrupt the stromal-tumour interactions, which may represent a potential therapeutic strategy to improve outcomes in PC.

Dental microwear texture analysis of Homo sapiens sapiens: Foragers, farmers, and pastoralists.

OBJECTIVES: The current study seeks to determine if a sample of foragers, farmers, and pastoralists are distinguishable based on their dental microwear texture signatures. MATERIALS AND METHODS: The study included a sample of 719 individuals from 51 archeological sites (450 farmers, 192 foragers, 77 pastoralists). All were over age 12 and sexes were pooled. Using a Sensofar® white-light confocal profiler we collected dental microwear texture analysis (DMTA) data from a single first or second molar from each individual. We leveled and cleaned data clouds following standard procedures and analyzed the data with Sfrax® and Toothfrax® software. The DMTA variables were complexity and anisotropy. Statistics included ANOVA with partial eta squared and Hedges's g. We also performed a follow-up K-means cluster analysis. RESULTS: We found significant differences between foragers and farmers and pastoralists for complexity and anisotropy, with foragers having greater complexity than either the farmers or the pastoralists. The farmers and pastoralists had greater anisotropy than the foragers. The Old World foragers had significantly higher anisotropy values than New World foragers. Old and New World farmers did not differ. Among the Old World farmers, those dating from the Neolithic through the Late Bronze Age had higher complexity values than those from the Iron Age through the medieval period. The cluster analysis discerned foragers and farmers but also indicated similarity between hard food foragers and hard food farmers. DISCUSSION: Our findings reaffirm that DMTA is capable of distinguishing human diets. We found that foragers and farmers, in particular, differ in their microwear signatures across the globe. There are some exceptions, but nothing that would be unexpected given the range of human diets and food preparation techniques. This study indicates that in general DMTA is an efficacious means of paleodietary reconstruction in humans.

The Combination of Alcohol and Cigarette Smoke Induces Endoplasmic Reticulum Stress and Cell Death in Pancreatic Acinar Cells.

BACKGROUND & AIMS: Smoking, an independent risk factor for pancreatitis, accelerates the development of alcoholic pancreatitis. Alcohol feeding of mice induces up-regulation of spliced X-box binding protein 1 (XBP1s), which regulates the endoplasmic reticulum (ER) unfolded protein response and promotes cell survival upon ER stress. We examined whether smoking affects the adaptive mechanisms induced by alcohol and accelerates disorders of the ER in pancreatic acinar cells. METHODS: We studied the combined effects of ethanol (EtOH) and cigarette smoke extract (CSE) on ER stress and cell death responses in mouse and human primary acini and the acinar cell line AR42J. Cells were incubated with EtOH (50 mmol/L), CSE (20-40 µg/mL), or both (CSE+EtOH), and analyzed by immunoblotting, quantitative reverse-transcription polymerase chain reaction, and cell death assays. Some cells were incubated with MKC-3946, an inhibitor of endoplasmic reticulum to nucleus signaling 1 (ERN1, also called IRE1) that blocks XBP1s formation. Male Sprague-Dawley rats were fed isocaloric amounts of an EtOH-containing (Lieber-DeCarli) or control diet for 11 weeks and exposed to cigarette smoke or room air in an exposure chamber for 2 hours each day. During the last 3 weeks, a subset of rats received intravenous injections of lipopolysaccharide (LPS, 3 mg/kg per week) to induce pancreatitis or saline (control). Pancreatic tissues were collected and analyzed by histology and immunostaining techniques. RESULTS: In AR42J and primary acini, CSE+EtOH induced cell death (necrosis and apoptosis), but neither agent alone had this effect. Cell death was associated with a significant decrease in expression of XBP1s. CSE+EtOH, but neither agent alone, slightly decreased adenosine triphosphate levels in AR42J cells, but induced oxidative stress and sustained activation (phosphorylation) of eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, also called PERK) and increased protein levels of DNA damage inducible transcript 3 (DDIT3, also called CHOP). CHOP regulates transcription to promote apoptosis. Incubation of AR42J or primary mouse or human acinar cells with MKC-3946 reduced expression of XBP1s, increased levels of CHOP, and induced cell death. In rats fed an EtOH diet, exposure to cigarette smoke increased ER stress in acinar cells and sensitized the pancreas to LPS-induced pathology. CONCLUSIONS: Cigarette smoke promotes cell death and features of pancreatitis in EtOH-sensitized acinar cells by suppressing the adaptive unfolded protein response signaling pathway. It also activates ER stress pathways that promote acinar cell death.

Spiny trapdoor spiders (Euoplos) of eastern Australia: Broadly sympatric clades are differentiated by burrow architecture and male morphology.

Spiders of the infraorder Mygalomorphae are fast becoming model organisms for the study of biogeography and speciation. However, these spiders can be difficult to study in the absence of fundamental life history information. In particular, their cryptic nature hinders comprehensive sampling, and linking males with conspecific females can be challenging. Recently discovered differences in burrow entrance architecture and male morphology indicated that these challenges may have impeded our understanding of the trapdoor spider genus Euoplos in Australia's eastern mesic zone. We investigated the evolutionary significance of these discoveries using a multi-locus phylogenetic approach. Our results revealed the existence of a second, previously undocumented, lineage of Euoplos in the eastern mesic zone. This new lineage occurs in sympatry with a lineage previously known from the region, and the two are consistently divergent in their burrow entrance architecture and male morphology, revealing the suitability of these characters for use in phylogenetic studies. Divergent burrow entrance architecture and observed differences in microhabitat preferences are suggested to facilitate sympatry and syntopy between the lineages. Finally, by investigating male morphology and plotting it onto the phylogeny, we revealed that the majority of Euoplos species remain undescribed, and that males of an unnamed species from the newly discovered lineage had historically been linked, erroneously, to a described species from the opposite lineage. This paper clarifies the evolutionary relationships underlying life history diversity in the Euoplos of eastern Australia, and provides a foundation for urgently needed taxonomic revision of this genus.