Anomalous Pacific‐Antarctic Ridge volcanism precedes glacial Termination 2

We present results from a well‐dated sediment core on the Pacific‐Antarctic Ridge (PAR) that document a ∼15 cm thick layer of basaltic ash shards that precedes the penultimate deglaciation (Termination 2). The glasses have MORB composition consistent with an axial source and their morphologies are typical of pyroclastic deposits created by submarine volcanism. The ash layer was deposited ∼7 km from the PAR axis, a distance that implies buoyant plumes lofted debris high into the water column with subsequent fallout to the core location. We infer plume rise height using grain settling velocities, the water depth at the core site, and deep ocean current speeds from ARGO floats. Rise heights of 1.5 km or less require unrealistically large current speeds to transport grains to the core site. Instead, the data are consistent with a plume rise height of at least 2 km, implying that T2 was an interval of anomalous volcanism along this segment of the PAR. The timing and duration of the ash deposit is consistent with glacial‐interglacial modulation of ridge magmatism. Volcaniclastic records from additional locations will be necessary to assess whether the PAR record is a rare find or it is representative of mid‐ocean ridge volcanism during glacial terminations

Anomalous Pacific‐Antarctic Ridge volcanism precedes glacial Termination 2

We present results from a well‐dated sediment core on the Pacific‐Antarctic Ridge (PAR) that document a ∼15 cm thick layer of basaltic ash shards that precedes the penultimate deglaciation (Termination 2). The glasses have MORB composition consistent with an axial source and their morphologies are typical of pyroclastic deposits created by submarine volcanism. The ash layer was deposited ∼7 km from the PAR axis, a distance that implies buoyant plumes lofted debris high into the water column with subsequent fallout to the core location. We infer plume rise height using grain settling velocities, the water depth at the core site, and deep ocean current speeds from ARGO floats. Rise heights of 1.5 km or less require unrealistically large current speeds to transport grains to the core site. Instead, the data are consistent with a plume rise height of at least 2 km, implying that T2 was an interval of anomalous volcanism along this segment of the PAR. The timing and duration of the ash deposit is consistent with glacial‐interglacial modulation of ridge magmatism. Volcaniclastic records from additional locations will be necessary to assess whether the PAR record is a rare find or it is representative of mid‐ocean ridge volcanism during glacial terminations

Hydrothermal scavenging of ^(230)Th on the Southern East Pacific Rise during the last deglaciation

Thorium-230 (^(230)Th) is a fundamental tool for estimating sediment fluxes in the open ocean. Because ^(230)Th is rapidly scavenged by particles falling through the water column, the flux of ^(230)Th to underlying sediments is typically equal to its water column production rate. However, recent surveys suggest hydrothermal plumes are unusually efficient scavengers of ^(230)Th. Here we show that hydrothermal scavenging on the Southern East Pacific Rise (SEPR) resulted in ^(230)Th fluxes several times higher than the water column production rate during the last deglaciation. Elevated fluxes likely require diffusive transport of dissolved ^(230)Th from the ridge flanks towards the ridge crest. Depending on the length-scale of ^(230)Th transport, the resulting deficits in ^(230)Th may yield overestimates of sediment flux to ridge flank sediments. We also show that Fe fluxes at 19°S on the SEPR lag those at 11°S and 6°S by several thousand years, inconsistent with a signal driven by changes in deep water pH and oxygen levels. Instead, variable hydrothermal activity is the simplest explanation of the observed signals in the Pacific, Indian, and Atlantic basins

Gene expression profiling of tumour epithelial and stromal compartments during breast cancer progression

The progression of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) marks a critical step in the evolution of breast cancer. There is some evidence to suggest that dynamic interactions between the neoplastic cells and the tumour microenvironment play an important role. Using the whole-genome cDNA-mediated annealing, selection, extension and ligation assay (WG-DASL, Illumina), we performed gene expression profiling on 87 formalin-fixed paraffin-embedded (FFPE) samples from 17 patients consisting of matched IDC, DCIS and three types of stroma: IDC-S ( 10 mm from IDC or DCIS). Differential gene expression analysis was validated by quantitative real time-PCR, immunohistochemistry and immunofluorescence. The expression of several genes was down-regulated in stroma from cancer patients relative to normal stroma from reduction mammoplasties. In contrast, neoplastic epithelium underwent more gene expression changes during progression, including down regulation of SFRP1. In particular, we observed that molecules related to extracellular matrix (ECM) remodelling (e.g. COL11A1, COL5A2 and MMP13) were differentially expressed between DCIS and IDC. COL11A1 was overexpressed in IDC relative to DCIS and was expressed by both the epithelial and stromal compartments but was enriched in invading neoplastic epithelial cells. The contributions of both the epithelial and stromal compartments to the clinically important scenario of progression from DCIS to IDC. Gene expression profiles, we identified differential expression of genes related to ECM remodelling, and specifically the elevated expression of genes such as COL11A1, COL5A2 and MMP13 in epithelial cells of IDC. We propose that these expression changes could be involved in facilitating the transition from in situ disease to invasive cancer and may thus mark a critical point in disease development

Intratumour heterogeneity in the progression to breast cancer metastasis

Unlike the great advances that have been made in reducing breast cancer mortality through the multidisciplinary treatment of primary disease, much less is understood about the natural history of metastatic disease, despite this being the single most significant predictor of poor outcome for patients. Currently, much of treatment decision-making concerning a patient with metastatic disease is based on the biological characteristics of their primary tumour. There is a growing appreciation, however, that metastases arise from clonal subpopulations of cells from a primary tumour that may be genetically and phenotypically heterogeneous. The metastases may also undergo successive rounds of clonal expansion and adaptation in response to selective pressures endured in the foreign microenvironment of new tissues and treatment. In fact, cancer progression and colonisation is likely to be underpinned by a collective cooperation between cellular, genomic and microenvironmental factors that generate diversity to facilitate treatment resistance and metastatic capability. The extent and overall clinical significance of this diversity in metastatic progression is still unclear, owing to the scarcity of samples of metastases that are available for molecular analysis

Pregnancy does not influence colonic polyp multiplicity but may modulate upper gastrointestinal disease in patients with FAP

BACKGROUND: Reproductive factors have been shown by epidemiology studies to alter colorectal cancer risk in women. Familial adenomatous polyposis (FAP) patients carry a germline adenomatous polyposis coli (APC) mutation predisposing to multiple adenoma formation in the intestine. The Min mouse provides a good model of FAP, and we recently reported a significant increase in intestinal tumour multiplicity in a recombinant line of mice following pregnancy. AIM: We considered whether reproduction modulates intestinal tract disease in a large cohort of female patients with FAP (n = 180). RESULTS: Multiple regression analysis showed that the number of colonic polyps observed was not related to the person's pregnancy status nor the position of their APC germline mutation. The proportion of women attaining a high Spigelman stage (3 or 4) was unrelated to having a pregnancy prior to attaining the maximum Spigelman stage (p = 0.6). On the other hand, having a pregnancy significantly increased the proportion of women that attained the highest Spigelman stage when their APC germline mutation occurred within the mutation cluster region or at or after codon 1020 (50%, 6/12, p = 0.005 and 42%, 13/31, p = 0.006, respectively; multivariable logistic regression). CONCLUSION: Our data suggest that reproduction may influence disease severity in the upper gastrointestinal tract in patients with FAP

Metastatic progression of breast cancer: Insights from 50 years of autopsies

There remain no clear guidelines for the optimal management of patients with metastatic breast cancer. To better understand its natural history, we undertook a detailed examination of 197 autopsies performed on women who died of breast cancer. We reviewed clinical, treatment and pathological aspects of all cases and, additionally, pathological features and biomarker expression (ER, PgR, HER2, EGFR, p53, Ki67, c-Kit, CK AE1/AE3) were assessed in detail for the primary tumour and matched metastases for 55 of the cases. Genomes of the primary tumour and multiple metastases were analysed by array-based comparative genomic hybridization for six cases##. 945 metastatic deposits were identified, with a median of four/patient. The most common organs involved were lung/pleura (80%), bone (74%), liver (71%) and non-axillary lymph nodes (55%). Major findings included: (a) patients with CNS metastases were more likely to have bone metastases (p < 0.013); (b) younger age was associated with metastasis to the liver (≤ 49 years; p < 0.001) and to gynaecological organs (≤ 49 years; p = 0.001); (c) surgical excision of the primary tumour was associated with metastasis to the liver (p = 0.002); and (d) ER and PgR showed down-regulation during progression in a non-random manner, particularly in lung/pleura (ER; p < 0.001), liver and bone metastases. Genomic analysis revealed DNA copy number variation between the primary tumour and metastases (e.g. amplification of 2q11.2-q12.1 and 10q22.2-q22.3) but little variation between metastases from the same patient. In summary, the association of CNS and bone metastases, liver and gynaecological metastases in young women and the risk of liver metastases following surgery have important implications for the management of patients with breast cancer. Clonal heterogeneity of the primary tumour is important in developing metastatic propensity and the change in tumour phenotype during progression/colonization highlights the importance of sampling metastatic disease for optimal treatment strategies

Blood-Derived Extracellular Vesicle-Associated miR-3182 Detects Non-Small Cell Lung Cancer Patients

With five-year survival rates as low as 3%, lung cancer is the most common cause of cancer-related mortality worldwide. The severity of the disease at presentation is accredited to the lack of early detection capacities, resulting in the reliance on low-throughput diagnostic measures, such as tissue biopsy and imaging. Interest in the development and use of liquid biopsies has risen, due to non-invasive sample collection, and the depth of information it can provide on a disease. Small extracellular vesicles (sEVs) as viable liquid biopsies are of particular interest due to their potential as cancer biomarkers. To validate the use of sEVs as cancer biomarkers, we characterised cancer sEVs using miRNA sequencing analysis. We found that miRNA-3182 was highly enriched in sEVs derived from the blood of patients with invasive breast carcinoma and NSCLC. The enrichment of sEV miR-3182 was confirmed in oncogenic, transformed lung cells in comparison to isogenic, untransformed lung cells. Most importantly, miR-3182 can successfully distinguish early-stage NSCLC patients from those with benign lung conditions. Therefore, miR-3182 provides potential to be used for the detection of NSCLC in blood samples, which could result in earlier therapy and thus improved outcomes and survival for patients

Short-term effects of restorative justice conferences on post-traumatic stress symptoms among robbery and burglary victims: a randomized controlled trial

Results: Analyses show that PTSS scores are significantly lower among victims assigned to RJC in addition to criminal justice processing through the courts than to customary criminal justice processing alone. There are overall 49 % fewer victims with clinical levels of PTSS, and possible PTSD (IES-R ≥ 25). Main treatment effects are significant (t = 2.069;