Metabolic reprogramming of oncogene-addicted cancer cells to OXPHOS as a mechanism of drug resistance

The ability to selectively eradicate oncogene-addicted tumors while reducing systemic toxicity has endeared targeted therapies as a treatment strategy. Nevertheless, development of acquired resistance limits the benefits and durability of such a regime. Here we report evidence of enhanced reliance on mitochondrial oxidative phosphorylation (OXPHOS) in oncogene-addicted cancers manifesting acquired resistance to targeted therapies. To that effect, we describe a novel OXPHOS targeting activity of the small molecule compound, OPB-51602 (OPB). Of note, a priori treatment with OPB restored sensitivity to targeted therapies. Furthermore, cancer cells exhibiting stemness markers also showed selective reliance on OXPHOS and enhanced sensitivity to OPB. Importantly, in a subset of patients who developed secondary resistance to EGFR tyrosine kinase inhibitor (TKI), OPB treatment resulted in decrease in metabolic activity and reduction in tumor size. Collectively, we show here a switch to mitochondrial OXPHOS as a key driver of targeted drug resistance in oncogene-addicted cancers. This metabolic vulnerability is exploited by a novel OXPHOS inhibitor, which also shows promise in the clinical setting

Patient Registries in Idiopathic Pulmonary Fibrosis.

Over the past decade, several large registries of patients with idiopathic pulmonary fibrosis (IPF) have been established. These registries are collecting a wealth of longitudinal data on thousands of patients with this rare disease. The data collected in these registries will be complementary to data collected in clinical trials because the patient populations studied in registries have a broader spectrum of disease severity and comorbidities and can be followed for a longer period of time. Maintaining the quality and completeness of registry databases presents administrative and resourcing challenges, but it is important to ensuring the robustness of the analyses. Data from patient registries have already helped improve understanding of the clinical characteristics of patients with IPF, the impact that the disease has on their quality of life and survival, and current practices in diagnosis and management. In the future, analyses of biospecimens linked to detailed patient profiles will provide the opportunity to identify biomarkers linked to disease progression, facilitating the development of precision medicine approaches for prognosis and therapy in patients with IPF

Dynamic testing and transfer: An examination of children's problem-solving strategies

This study examined the problem-solving behaviour of 104 children (aged 7–8 years) when tackling construction-analogy tasks. Children were allocated to one of two conditions: either a form of unguided practice alone or this in combination with training based on graduated prompt techniques. Children's ability to solve figural open-ended analogy-problems was investigated as well as their ability to construct new analogy problems themselves. We examined children's progression in solving analogy problems and the variability in their strategy-use. Results showed that the group that received training made greater progress in solving analogy problems than children who only received unguided practice opportunities. However, the training appeared to give no additional improvement in performance on the transfer task over that of repeated unguided practice alone. Findings from this study demonstrate that an open construction task can provide additional information about children's cognitive learning potential

Empathy, autistic tendencies, and systemizing tendencies - Relationships between standard self-report measures

The aim of the present study was to investigate associations between four highly used self-report measures assessing empathy (measured as both a unidimensional and multidimensional construct), autistic tendencies, and systemizing tendencies. Participants in this study completed the following self-report measures: The Interpersonal Reactivity Index (IRI) and the Empathy Quotient (EQ) to measure empathy, and the Autism Spectrum Quotient (AQ) and the Systemizing Quotient–Revised (SQ-R) to assess autistic and systemizing tendencies, respectively. The final sample consisted of N = 1,098 participants (304 males) without a diagnosed autism spectrum disorder, most of whom were university students. The IRI scale “Perspective Taking” and the EQ were negatively related to the AQ in male and female participants, while the IRI scale “Empathic Concern” was negatively related to the AQ in females only. Moreover, the AQ was positively related to the SQ-R in females only. Lastly, the SQ-R and a number of the empathy scales were significantly associated: For example and surprisingly, the EQ correlated weakly and positively with the SQ-R in both male and female participants. The results from this study illustrate how standard self-report measures of empathy, autistic tendencies, and systemizing tendencies are associated with each other in a large sample not diagnosed with an autism spectrum disorder. Additionally, some potential gender-specific effects are revealed

Strategies to inhibit tumour associated integrin receptors: rationale for dual and multi-antagonists

YesThe integrins are a family of 24 heterodimeric transmembrane cell surface receptors. Involvement in cell attachment to the extracellular matrix, motility, and proliferation identifies integrins as therapeutic targets in cancer and associated conditions; thrombosis, angiogenesis and osteoporosis. The most reported strategy for drug development is synthesis of an agent that is highly selective for a single integrin receptor. However, the ability of cancer cells to change their integrin repertoire in response to drug treatment renders this approach vulnerable to the development of resistance and paradoxical promotion of tumor growth. Here, we review progress towards development of antagonists targeting two or more members of the RGD-binding integrins, notably αvβ3, αvβ5, αvβ6, αvβ8, α5β1, and αIIbβ3, as anticancer therapeutics

Determinants of the continuity in the demand for external auditing services voluntarily: Evidence for the case of Spain

RESUMEN: En la Unión Europea se está viviendo actualmente un intenso debate en torno a la regulación de la auditoría de cuentas. Uno de los temas más relevantes y controvertidos es la definición del tamaño de las empresas obligadas a auditarse. Este trabajo está centrado en el estudio de la contratación voluntaria del servicio de auditoría. En concreto, se examinan los factores que determinan la continuidad del cliente cuando este deja de estar obligado a auditarse. Como metodología de investigación se realiza una encuesta a 275 pymes en España. Los resultados obtenidos ponen de manifiesto que la percepción de la mejora en la calidad de la información financiera y en el control de los registros contables internos es el principal factor que contribuye a continuar contratando de forma voluntaria el servicio. Además, dicha continuidad es más probable en las empresas que ya se auditan voluntariamente, en las auditadas por firmas internacionales y en las que mantienen una menor relación con las entidades de crédito y otros prestamistas.ABSTRACT: The European Union is currently experiencing an intense debate over the legal regulation of auditing.One of the most important and controversial issues is the definition of the size of the companies that arerequired to audit their annual accounts. This work is focused on studying the voluntary hiring of auditingservices. In particular, it examines the factors that may lead companies to continue hiring an auditorvoluntarily if they were no longer required to do so. The research methodology is based on a surveythat was conducted on 275 SMEs in Spain. The results show that the perception of the improvementin the quality of financial reporting and in the control of internal accounting records is the main factorcontributing to continue hiring the audit service voluntarily. Moreover, such continuity is more likely incompanies that are already audited voluntarily, that are audited by international firms and that maintain a lower relation with credit institutions and other lenders

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

Meeting abstrac

Higher harmonic anisotropic flow measurements of charged particles in Pb-Pb collisions at 2.76 TeV

We report on the first measurement of the triangular $v_3$, quadrangular $v_4$, and pentagonal $v_5$ charged particle flow in Pb-Pb collisions at 2.76 TeV measured with the ALICE detector at the CERN Large Hadron Collider. We show that the triangular flow can be described in terms of the initial spatial anisotropy and its fluctuations, which provides strong constraints on its origin. In the most central events, where the elliptic flow $v_2$ and $v_3$ have similar magnitude, a double peaked structure in the two-particle azimuthal correlations is observed, which is often interpreted as a Mach cone response to fast partons. We show that this structure can be naturally explained from the measured anisotropic flow Fourier coefficients.Comment: 10 pages, 4 figures, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/387