Genomic alterations underlie a pan-cancer metabolic shift associated with tumour hypoxia

Altered metabolism is a hallmark of cancer. However, the role of genomic changes in metabolic genes driving the tumour metabolic shift remains to be elucidated. Here, we have investigated the genomic and transcriptomic changes underlying this shift across ten different cancer types.A systematic pan-cancer analysis of 6538 tumour/normal samples covering ten major cancer types identified a core metabolic signature of 44 genes that exhibit high frequency somatic copy number gains/amplifications (>20 % cases) associated with increased mRNA expression (ρ > 0.3, q < 10(-3)). Prognostic classifiers using these genes were confirmed in independent datasets for breast and kidney cancers. Interestingly, this signature is strongly associated with hypoxia, with nine out of ten cancer types showing increased expression and five out of ten cancer types showing increased gain/amplification of these genes in hypoxic tumours (P ≤ 0.01). Further validation in breast and colorectal cancer cell lines highlighted squalene epoxidase, an oxygen-requiring enzyme in cholesterol biosynthesis, as a driver of dysregulated metabolism and a key player in maintaining cell survival under hypoxia.This study reveals somatic genomic alterations underlying a pan-cancer metabolic shift and suggests genomic adaptation of these genes as a survival mechanism in hypoxic tumours

Nomograms to predict survival and the risk for developing local or distant recurrence in patients with rectal cancer treated with optional short-term radiotherapy

Surgical oncolog

Multi-frequency VEMPs improve detection of present otolith responses in bilateral vestibulopathy

ObjectiveTo investigate whether multi-frequency Vestibular Evoked Myogenic Potential (VEMP) testing at 500, 750, 1,000, and 2,000 Hz, would improve the detection of present dynamic otolith responses in patients with bilateral vestibulopathy (BV).MethodsProspective study in a tertiary referral center. BV patients underwent multi-frequency VEMP testing. Cervical VEMPs and ocular VEMPs were recorded with the Neuro-Audio system (v2010, Neurosoft, Ivanovo, Russia). The stimuli included air-conducted tone bursts of 500, 750, 1,000, and 2,000 Hz, at a stimulation rate of 13 Hz. Outcome measures included the percentage of present and absent VEMP responses, and VEMP thresholds. Outcomes were compared between frequencies and type of VEMPs (cVEMPs, oVEMPs). VEMP outcomes obtained with the 500 Hz stimulus, were also compared to normative values obtained in healthy subjects.ResultsForty-nine BV patients completed VEMP testing: 47 patients completed cVEMP testing and 48 patients completed oVEMP testing. Six to 15 % more present VEMP responses were obtained with multifrequency testing, compared to only testing at 500 Hz. The 2,000 Hz stimulus elicited significantly fewer present cVEMP responses (right and left ears) and oVEMP responses (right ears) compared to the other frequencies (p ≤ 0.044). Using multi-frequency testing, 78% of BV patients demonstrated at least one present VEMP response in at least one ear. In 46% a present VEMP response was found bilaterally. BV patients demonstrated a significantly higher percentage of absent VEMP responses and significantly higher VEMP thresholds than healthy subjects, when corrected for age (p ≤ 0.002). Based on these results, a pragmatic VEMP testing paradigm is proposed, taking into account multi-frequency VEMP testing.ConclusionMulti-frequency VEMP testing improves the detection rate of present otolith responses in BV patients. Therefore, multi-frequency VEMPs should be considered when evaluation of (residual) otolith function is indicated

The evolutionary state of Miras with changing pulsation periods

Context: Miras are long-period variables thought to be in the asymptotic giant branch (AGB) phase of evolution. In about one percent of known Miras, the pulsation period is changing. It has been speculated that this changing period is the consequence of a recent thermal pulse in these stars. Aims: We aim to clarify the evolutionary state of these stars, and to determine in particular whether or not they are in the thermally-pulsing (TP-)AGB phase. Methods: One important piece of information that has been neglected so far when determining the evolutionary state is the presence of the radio-active s-process element technetium (Tc). We obtained high-resolution, high signal-to-noise-ratio optical spectra of a dozen prominent Mira variables with changing pulsation period to search for this indicator of TPs and dredge-up. We also use the spectra to measure lithium (Li) abundances. Furthermore, we establish the evolutionary states of our sample stars by means of their present-day periods and luminosities. Results: Among the twelve sample stars observed in this programme, five were found to show absorption lines of Tc. BH Cru is found to be a carbon-star, its period increase in the past decades possibly having stopped by now. We report a possible switch in the pulsation mode of T UMi from Mira-like to semi-regular variability in the past two years. R Nor, on the other hand, is probably a fairly massive AGB star, which could be true for all meandering Miras. Finally, we assign RU Vul to the metal-poor thick disk with properties very similar to the short-period, metal-poor Miras. Conclusions: We conclude that there is no clear correlation between period change class and Tc presence. The stars that are most likely to have experienced a recent TP are BH Cru and R Hya, although their rates of period change are quite different.Comment: 11 pages, 7 figures, 2 tables; accepted for publication in A&

Gemcitabine-induced TIMP1 attenuates therapy response and promotes tumor growth and liver metastasis in pancreatic cancer

Gemcitabine constitutes one of the backbones for chemotherapy treatment in pancreatic ductal adenocarcinoma (PDAC), but patients often respond poorly to this agent. Molecular markers downstream of gemcitabine treatment in preclinical models may provide an insight into resistance mechanisms. Using cytokine arrays, we identified potential secretory biomarkers of gemcitabine resistance (response) in the transgenic KRasG12D; Trp53R172H; Pdx-1 Cre (KPC) mouse model of PDAC. We verified the oncogenic role of the cytokine tissue inhibitor of matrix metalloproteinases 1 (TIMP1) in primary pancreatic tumors and metastases using both in vitro techniques and animal models. We identified potential pathways affected downstream of TIMP1 using the Illumina Human H12 array. Our findings were validated in both primary and metastatic models of pancreatic cancer. Gemcitabine increased inflammatory cytokines including TIMP1 in the KPC mouse model. TIMP1 was upregulated in patients with pancreatic intraepithelial neoplasias grade 3 and PDAC lesions relative to matched normal pancreatic tissue. In addition, TIMP1 played a role in tumor clonogenic survival and vascular density, while TIMP1 inhibition resensitized tumors to gemcitabine and radiotherapy. We observed a linear relationship between TIMP-1 expression, liver metastatic burden, and infiltration by CD11b+Gr1+ myeloid cells and CD4+CD25+FOXP3+ Tregs, whereas the presence of tumor cells was required for immune cell infiltration. Overall, our results identify TIMP1 upregulation as a resistance mechanism to gemcitabine and provide a rationale for combining chemo/radiotherapy with TIMP1 inhibitors in PDAC

Identification of lysyl oxidase as an adipocyte-secreted mediator that promotes a partial mesenchymal-to-epithelial transition in MDA-MB-231 cells

Aim: Breast cancer (BC) is the most common cancer in women worldwide, where adiposity has been linked to BC morbidity. In general, obese premenopausal women diagnosed with triple-negative BC (TNBC) tend to have larger tumours with more metastases, particularly to the bone marrow, and worse prognosis. Previous work using a 3-dimensional (3D) co-culture system consisting of TNBC cells, adipocytes and the laminin-rich extracellular matrix (ECM) trademarked as Matrigel, demonstrated that adipocytes and adipocyte-derived conditioned media (CM) caused a partial mesenchymal-to-epithelial transition (MET). Given that MET has been associated with secondary tumour formation, this study sought to identify molecular mediators responsible for this phenotypic change. Methods: Adipocytes were cultured with and without Matrigel, where semi-quantitative proteomics was used to identify proteins whose presence in the CM was induced or enhanced by Matrigel, which were referred to as adipocyte-secreted ECM-induced proteins (AEPs). The AEPs identified were assessed for association with prognosis in published proteomic datasets and prior literature. Of these, 4 were evaluated by the reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA), followed by a functional and MET marker analysis of 1 AEP on MDA-MB-231 cells grown on Matrigel or as monolayers. Results: The 4 AEPs showed a positive correlation between protein expression and poor prognosis. RT-qPCR analysis reported no significant change in AEPs mRNA expression. However, lysyl oxidase (LOX) was increased in CM of ECM-exposed adipocytes. Recombinant LOX (rLOX) caused the mesenchymal MDA-MB-231 TNBC cells to form less branched 3D structures and reduced the expression of vimentin. Conclusions: The data suggest that adipocyte-secreted LOX changes the mesenchymal phenotype of BC cells in a manner that could promote secondary tumour formation, particularly at sites high in adipocytes such as the bone marrow. Future efforts should focus on determining whether targeting LOX could reduce BC metastasis in obese individuals

Evidence of tetragonal distortion as the origin of the ferromagnetic ground state in γ-Fe nanoparticles

γ-Fe and related alloys are model systems of the coupling between structure and magnetism in solids. Since different electronic states (with different volumes and magnetic ordering states) are closely spaced in energy, small perturbations can alter which one is the actual ground state. Here, we demonstrate that the ferromagnetic state of γ-Fe nanoparticles is associated with a tetragonal distortion of the fcc structure. Combining a wide range of complementary experimental techniques, including low-temperature Mössbauer spectroscopy, advanced transmission electron microscopy, and synchrotron radiation techniques, we unambiguously identify the tetragonally distorted ferromagnetic ground state, with lattice parameters a=3.76(2)Å and c=3.50(2)Å, and a magnetic moment of 2.45(5) μB per Fe atom. Our findings indicate that the ferromagnetic order in nanostructured γ-Fe is generally associated with a tetragonal distortion. This observation motivates a theoretical reassessment of the electronic structure of γ-Fe taking tetragonal distortion into account.The authors thank the Fund for Scientific ResearchFlanders, the Concerted Research Action of the KU Leuven (GOA/14/007), the KU Leuven BOF (STRT/14/002), the Hercules Foundation, the Portuguese Foundation for Science and Technology (CERN/FIS-NUC/0004/2015), and the European Union Seventh Framework through ENSAR2 (European Nuclear Science and Applications Research, Project No. 654002), and SPIRIT (Support of Public and Industrial Research Using Ion Beam Technology, Contract No. 227012). We acknowledge the European Synchrotron Radiation Facility (ESRF) for providing beam time (experiments 26-01-1018, 26-01-1057, 20-02-728, HC-1850, HC-2208), as well as C. Baehtz, N. Boudet, and N. Blancand for support during the experiments. We acknowledge the ISOLDE-CERN facility for providing beam time (experiment IS580) and technical assistance. The authors (L.M.C.P., F.K.) acknowledge the facilities and the scientific and technical assistance of the Australian Microscopy & Microanalysis Research Facility at the Centre for Advanced Microscopy, Australian National University. We also acknowledge the contribution of Prof. Mark Ridgway (Australian National University), who passed away before the work was completed

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac