Collagen-I influences the post-translational regulation, binding partners and role of Annexin A2 in breast cancer progression.

Introduction: The extracellular matrix (ECM) has been heavily implicated in the development and progression of cancer. We have previously shown that Annexin A2 is integral in the migration and invasion of breast cancer cells and in the clinical progression of ER-negative breast cancer, processes which are highly influenced by the surrounding tumor microenvironment and ECM. Methods: We investigated how modulations of the ECM may affect the role of Annexin A2 in MDA-MB-231 breast cancer cells using western blotting, immunofluorescent confocal microscopy and immuno-precipitation mass spectrometry techniques. Results: We have shown that the presence of collagen-I, the main constituent of the ECM, increases the post-translational phosphorylation of Annexin A2 and subsequently causes the translocation of Annexin A2 to the extracellular surface. In the presence of collagen-I, we identified fibronectin as a novel interactor of Annexin A2, using mass spectrometry analysis. We then demonstrated that reducing Annexin A2 expression decreases the degradation of fibronectin by cancer cells and this effect on fibronectin turnover is increased according to collagen-I abundance. Discussion: Our results suggest that Annexin A2's role in promoting cancer progression is mediated by collagen-I and Annexin A2 maybe a therapeutic target in the bi-directional cross-talk between cancer cells and ECM remodeling that supports metastatic cancer progression.

Histone Deacetylase 6 Inhibition Exploits Selective Metabolic Vulnerabilities in LKB1 Mutant, KRAS Driven NSCLC.

INTRODUCTION: In KRAS-mutant NSCLC, co-occurring alterations in LKB1 confer a negative prognosis compared with other mutations such as TP53. LKB1 is a tumor suppressor that coordinates several signaling pathways in response to energetic stress. Our recent work on pharmacologic and genetic inhibition of histone deacetylase 6 (HDAC6) revealed the impaired activity of numerous enzymes involved in glycolysis. On the basis of these previous findings, we explored the therapeutic window for HDAC6 inhibition in metabolically-active KRAS-mutant lung tumors. METHODS: Using cell lines derived from mouse autochthonous tumors bearing the KRAS/LKB1 (KL) and KRAS/TP53 mutant genotypes to control for confounding germline and somatic mutations in human models, we characterize the metabolic phenotypes at baseline and in response to HDAC6 inhibition. The impact of HDAC6 inhibition was measured on cancer cell growth in vitro and on tumor growth in vivo. RESULTS: Surprisingly, KL-mutant cells revealed reduced levels of redox-sensitive cofactors at baseline. This is associated with increased sensitivity to pharmacologic HDAC6 inhibition with ACY-1215 and blunted ability to increase compensatory metabolism and buffer oxidative stress. Seeking synergistic metabolic combination treatments, we found enhanced cell killing and antitumor efficacy with glutaminase inhibition in KL lung cancer models in vitro and in vivo. CONCLUSIONS: Exploring the differential metabolism of KL and KRAS/TP53-mutant NSCLC, we identified decreased metabolic reserve in KL-mutant tumors. HDAC6 inhibition exploited a therapeutic window in KL NSCLC on the basis of a diminished ability to compensate for impaired glycolysis, nominating a novel strategy for the treatment of KRAS-mutant NSCLC with co-occurring LKB1 mutations.

Principles for evaluating knowledge co-production in natural resource management: Incorporating decision-maker values.

A key reason for undertaking transdisciplinary processes such as knowledge co-production in natural resource management is to access and apply different knowledge systems to complex issues. However, the value of co-production is predominantly framed by academics. They have focused on research design and outcomes in the form of 'science informing policy'. In this paper we build a more inclusive and holistic framing of knowledge co-production incorporating values of non-academic participants, and values related to the participatory process. Specifically, we examine how knowledge is communicated and deliberated upon and the requirements for this to be done effectively. We draw upon empirical data from interviews with natural resource managers who participated in two case studies of knowledge co-production in Australia and South Africa. Their perspectives are captured in eight evaluation principles that build upon existing evaluation frameworks for public participation. Critically, decision-makers valued science-based outputs not just as salient knowledge sources, but to give legitimacy to their decisions. This need for legitimacy necessitates transparency, fairness and inclusivity in knowledge selection, participation and dialogue within knowledge co-production processes. The practice-based knowledge of decision-makers was important for contextualizing and applying science to specific decision contexts. Another key finding is that communicative competence is central to the process of knowledge co-production because it enables participants to critically explore and understand the knowledge claims of others.

Genitourinary malformations: an under-recognized feature of ectrodactyly, ectodermal dysplasia and cleft lip/palate syndrome.

The ectodermal dysplasia and cleft lip/palate (EEC) syndrome describes the association of ectrodactyly, ectodermal dysplasia and orofacial clefting. As with many autosomal dominant disorders, there is variability in expression and not all of these three core features are present in every individual with the condition. Moreover, there may be additional associated features, which are under-recognized. One of these is the presence of genitourinary anomalies, some of which cause significant morbidity. This report details a further two patients with EEC syndrome and genitourinary involvement, including flaccid megacystis with detrusor muscle failure, bilateral hydronephrosis and megaureter, requiring significant renal and urological involvement during their childhood. We go on to review the literature on the diagnosis and management of genitourinary malformations in EEC syndrome.

Is discharge home with drains after breast surgery producing satisfactory outcomes?

AIM: To assess whether discharging patients after breast cancer surgery with drains in situ and specialist nurse support is producing satisfactory outcomes. PATIENTS AND METHODS: A retrospective study assessing outcome subjectively and objectively in patients treated at the Breast Unit. The full population of patients (124) operated for breast cancer and discharged with drains in situ, comprising 84 mastectomies and 40 wide local excisions with axillary clearance (WLE). Patients were asked to complete a postal questionnaire, and complication and activity data were analysed. RESULTS: The questionnaire response rate was 60%. Only 10% of patients felt the care received at home was 'worse' than that received in hospital. Over a quarter of locally-conservative surgery patients described not being informed of the plan to discharge them with a drain in situ compared to only 9% of mastectomy patients. Only 6% of patients felt 'confident' going home early from hospital. On their first day at home, two-thirds of patients admitted feeling anxious and this was halved by the second day. Lack of confidence emptying drains was significantly worse in older patients. Complication rates were low and mean bed-days saved per patient was 4.7 days (SD 2.3). CONCLUSIONS: Overall patient satisfaction, hospital bed-days saved and low complication rates showed the efficacy of this early discharge policy. There were specific areas needing improvement. Patients should be more clearly informed of the early discharge plan. Greater attention should be paid to allaying patient anxiety during the first day at home, especially in older patients.