Assessing the conservation status of the freshwater pearl mussel in the North of Ireland - Relevance of growth and age characteristics

In order to conserve the freshwater pearl mussel in Ireland, populations that have a high risk of extinction must he identified and given priority for conservation. Growth of freshwater pearl mussels has been found to vary among populations on a wide geographic scale as well as on a local scale. Populations having a high growth constant (k), because of the small size of individuals and their shorter life-span and thus lower reproductive output, may be more likely to become extinct than those which have a low k and hence larger size and greater reproductive output. This study attempts to estimate the growth constant (k) in rivers in Donegal and Northern Ireland based on measuring lire largest shell in each population. Large differences in values of k were found among rivers and these are discussed in relation to catchment bedrock types and the identification of conservation priorities. Appropriate conservation strategies are recommended for Margaritifera margaritifera populations in the north of Ireland.

Regenerative Medicine and New Labour Life Science Policy: Rhetorics of Success, Narratives of Sustainability and Survival

Advances in stem cell science and tissue engineering are being turned into applications and products through a novel medical paradigm known as regenerative medicine. This paper begins by examining the vulnerabilities and risks encountered by the regenerative medicine industry during a pivotal moment in its scientific infancy: the 2000s. Under the auspices of New Labour, British medical scientists and life science innovation firms associated with regenerative medicine, received demonstrative rhetorical pledges of support, aligned with the publication of a number of government initiated reports presaged by Bioscience 2015: Improving National Health, Increasing National Wealth. The Department of Health and the Department of Trade and Industry (and its successors) held industry consultations to determine the best means by which innovative bioscience cultures might be promoted and sustained in Britain. Bioscience 2015 encapsulates the first chapter of this sustainability narrative. By 2009, the tone of this storyline had changed to one of survivability. In the second part of the paper, we explore the ministerial interpretation of the ‘bioscience discussion cycle’ that embodies this narrative of expectation, using a computer-aided content analysis programme. Our analysis notes that the ministerial interpretation of these reports has continued to place key emphasis upon the distinctive and exceptional characteristics of the life science industries, such as their ability to perpetuate innovations in regenerative medicine and the optimism this portends – even though many of the economic expectations associated with this industry have remained unfulfilled.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in cancer progression and survival: a systematic review

Objective: To investigate the association between angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) and disease progression and survival in cancer patients.

Methods: Using terms for cancer and ACEIs/ARBs, MEDLINE, EMBASE and Web of Science were systematically searched for observational/interventional studies that used clinically relevant outcomes for cancer progression and survival.

Results: Ten studies met the inclusion criteria. Two studies showed a significant improvement in overall survival (OS) with ACEI/ARB use among patients with advanced pancreatic (HR 0.52, 95% CI 0.29–0.88) and non-small cell lung cancer (HR 0.56, 95% CI 0.33–0.95). An improvement in progression-free survival (PFS) was also reported for pancreatic cancer patients (HR 0.58, 95% CI 0.34–0.95) and patients with renal cell carcinoma (HR 0.54, p = 0.02). ACEI/ARB use was protective against breast cancer recurrence (HR 0.60, 95% CI 0.37–0.96), colorectal cancer distant metastasis (OR 0.22, 95% CI 0.08–0.65) and prostate specific antigen (PSA) failure in prostate cancer patients (p = 0.034). One study observed a worse OS (HR 2.01, 95% CI 1.00–4.05) and PFS in ACEI users with multiple myeloma (p = 0.085) while another reported an increased risk of breast cancer recurrence (HR = 1.56, 95% CI 1.02–2.39).

Conclusion: There is some evidence to suggest that ACEI or ARB use may be associated with improved outcomes in cancer patients. Larger, more robust studies are required to explore this relationship further.

Potentiation of Inflammatory CXCL8 Signalling Sustains Cell Survival in PTEN-deficient Prostate Carcinoma

Background: Inflammation and genetic instability are enabling characteristics of prostate carcinoma (PCa). Inactivation of the tumour suppressor gene phosphatase and tensin homolog (PTEN) is prevalent in early PCa. The relationship of PTEN deficiency to inflammatory signalling remains to be characterised.

Objective: To determine how loss of PTEN functionality modulates expression and efficacy of clinically relevant, proinflammatory chemokines in PCa.

Design, setting and participants: Experiments were performed in established cell-based PCa models, supported by pathologic analysis of chemokine expression in prostate tissue harvested from PTEN heterozygous (Pten(+/-)) mice harbouring inactivation of one PTEN allele.

Interventions: Small interfering RNA (siRNA)- or small hairpin RNA (shRNA)-directed strategies were used to repress PTEN expression and resultant interleukin-8 (CXCL8) signalling, determined under normal and hypoxic culture conditions.

Outcome measurements and statistical analysis: Changes in chemokine expression in PCa cells and tissue were analysed by real-time polymerase chain reaction (PCR), immunoblotting, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry; effects of chemokine signalling on cell function were assessed by cell cycle analysis, apoptosis, and survival assays.

Results and limitations: Transient (siRNA) or prolonged (shRNA) PTEN repression increased expression of CXCL8 and its receptors, chemokine (C-X-C motif) receptor (CXCR) 1 and CXCR2, in PCa cells. Hypoxia-induced increases in CXCL8, CXCR1, and CXCR2 expression were greater in magnitude and duration in PTEN-depleted cells. Autocrine CXCL8 signalling was more efficacious in PTEN-depleted cells, inducing hypoxia-inducible factor-1 (HIF-1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) transcription and regulating genes involved in survival and angiogenesis. Increased expression of the orthologous chemokine KC was observed in regions displaying atypical cytologic features in Pten(+/-) murine prostate tissue relative to normal epithelium in wild-type PTEN (Pten(WT)) glands. Attenuation of CXCL8 signalling decreased viability of PCa cells harbouring partial or complete PTEN loss through promotion of G1 cell cycle arrest and apoptosis. The current absence of clinical validation is a limitation of the study.

Conclusions: PTEN loss induces a selective upregulation of CXCL8 signalling that sustains the growth and survival of PTEN-deficient prostate epithelium.

Clinicopathological features of homologous recombination-deficient epithelial ovarian cancers: Sensitivity to PARP inhibitors, platinum, and survival

Up to 50% of epithelial ovarian cancers (EOC) display defects in the homologous recombination (HR) pathway. We sought to determine the ramifications of the homologous recombination-deficient (HRD) status on the clinicopathologic features, chemotherapy response, and survival outcomes of patients with EOCs. HR status was determined in primary cultures from ascitic fluid in 50 chemotherapy-naïve patients by a functional RAD51 immunofluorescence assay and correlated with in vitro sensitivity to the PARP inhibitor (PARPi), rucaparib. All patients went on to receive platinum-based chemotherapy; platinum sensitivity, tumor progression, and overall survival were compared prospectively in HR-competent versus HRD patients. Compared with HR-competent patients, the HRD group was predominantly serous with a higher median CA125 at presentation. HRD was associated with higher ex vivo PARPi sensitivity and clinical platinum sensitivity. Median follow-up duration was 14 months; patients in the HRD group had lower tumor progression rates at 6 months, lower overall/disease-specific death rates at 12 months, and higher median survival. We therefore suggest that HRD as predicted by a functional RAD51 assay correlates with in vitro PARPi sensitivity, clinical platinum sensitivity, and improved survival outcome.

Cathepsin S from both tumour and tumour-associated cells promote cancer growth and neovascularisation

Recent murine studies have demonstrated that tumour-associated macrophages in the tumour microenvironment are a key source of the pro-tumourigenic cysteine protease, cathepsin S. We now show in a syngeneic colorectal carcinoma murine model that both tumour and tumour-associated cells contribute cathepsin S to promote neovascularisation and tumour growth. Cathepsin S depleted and control colorectal MC38 tumour cell lines were propagated in both wild type C57Bl/6 and cathepsin S null mice to provide stratified depletion of the protease from either the tumour, tumour-associated host cells, or both. Parallel analysis of these conditions showed that deletion of cathepsin S inhibited tumour growth and development, and revealed a clear contribution of both tumour and tumour-associated cell derived cathepsin S. The most significant impact on tumour development was obtained when the protease was depleted from both sources. Further characterisation revealed that the loss of cathepsin S led to impaired tumour vascularisation, which was complemented by a reduction in proliferation and increased apoptosis, consistent with reduced tumour growth. Analysis of cell types showed that in addition to the tumour cells, tumour-associated macrophages and endothelial cells can produce cathepsin S within the microenvironment. Taken together, these findings clearly highlight a manner by which tumour-associated cells can positively contribute to developing tumours and highlight cathepsin S as a therapeutic target in cancer.

Growth and adrenal suppression in asthmatic children treated with high-dose fluticasone propionate

Background: Fluticasone propionate was introduced in 1993 in the UK as a potentially safer inhaled corticosteroid than those already in use. The efficacy and safety of fluticasone has been established at recommended doses of 200 µg/day, but not at the higher doses that are often used.

Methods: Growth retardation was observed in six severely asthmatic children after introduction of high-dose fluticasone propionate treatment (dry powder). Assessment of cortisol response was by insulin-induced hypoglycaemia in three cases, by short tetracosactrin test in two, and by low-dose tetracosactrin and 24-hour urinary cortisol/creatinine ratio in one.

Findings: Six children with growth retardation noted after treatment with high-dose fluticasone propionate were found to have adrenal suppression. In one case the growth rate and cortisol response returned to normal 9 months after the fluticasone dose was reduced to 500 µg/day.

Interpretation: When high doses of fluticasone propionate are used, growth may be retarded and adrenal suppression may occur.

Elevated NRD1 metalloprotease expression plays a role in breast cancer growth and proliferation

Understanding the molecular etiology of cancer and increasing the number of drugs and their targets are critical to cancer management. In our attempt to unravel novel breast-cancer associated proteins, we previously conducted protein expression profiling of the MCF10AT model, which comprises a series of isogenic cell lines that mimic different stages of breast cancer progression. NRD1 expression was found to increase during breast cancer progression. Here, we attempted to confirm the relevance of NRD1 in clinical breast cancer and understand the functional role and mechanism of NRD1 in breast cancer cells. Immunohistochemistry data show that NRD1 expression was elevated in ductal carcinoma in situ and invasive ductal carcinomas compared with normal tissues in 30% of the 26 matched cases studied. Examination of NRD1 expression in tissue microarray comprising >100 carcinomas and subsequent correlation with clinical data revealed that NRD1 expression was significantly associated with tumor size, grade, and nodal status (P <0.05). Silencing of NRD1 reduced MCF10CA1h and MDA-MD-231 breast-cancer-cell proliferation and growth. Probing the oncogenic EGF signaling pathways revealed that NRD1 knock down did not affect overall downstream tyrosine phosphorylation cascades including AKT and MAPK activation. Instead, silencing of NRD1 resulted in a reduction of overall cyclin D1 expression, a reduction of EGF-induced increase in cyclin D1 expression and an increase in apoptotic cell population compared with control cells.

Combined genomic and phenotype screening reveals secretory factor SPINK1 as an invasion and survival factor associated with patient prognosis in breast cancer

Secretory factors that drive cancer progression are attractive immunotherapeutic targets. We used a whole-genome data-mining approach on multiple cohorts of breast tumours annotated for clinical outcomes to discover such factors. We identified Serine protease inhibitor Kazal-type 1 (SPINK1) to be associated with poor survival in estrogen receptor-positive (ER+) cases. Immunohistochemistry showed that SPINK1 was absent in normal breast, present in early and advanced tumours, and its expression correlated with poor survival in ER+ tumours. In ER- cases, the prognostic effect did not reach statistical significance. Forced expression and/or exposure to recombinant SPINK1 induced invasiveness without affecting cell proliferation. However, down-regulation of SPINK1 resulted in cell death. Further, SPINK1 overexpressing cells were resistant to drug-induced apoptosis due to reduced caspase-3 levels and high expression of Bcl2 and phospho-Bcl2 proteins. Intriguingly, these anti-apoptotic effects of SPINK1 were abrogated by mutations of its protease inhibition domain. Thus, SPINK1 affects multiple aggressive properties in breast cancer: survival, invasiveness and chemoresistance. Because SPINK1 effects are abrogated by neutralizing antibodies, we suggest that SPINK1 is a viable potential therapeutic target in breast cancer.

Alpha emitter radium-223 and survival in metastatic prostate cancer

Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases.