Combined low initial DNA damage and high radiation-induced apoptosis confers clinical resistance to long-term toxicity in breast cancer patients treated with high-dose radiotherapy

Journal Article; Research Support, Non-U.S. Gov't;BACKGROUND. Either higher levels of initial DNA damage or lower levels of radiation-induced apoptosis in peripheral blood lymphocytes have been associated to increased risk for develop late radiation-induced toxicity. It has been recently published that these two predictive tests are inversely related. The aim of the present study was to investigate the combined role of both tests in relation to clinical radiation-induced toxicity in a set of breast cancer patients treated with high dose hyperfractionated radical radiotherapy. METHODS. Peripheral blood lymphocytes were taken from 26 consecutive patients with locally advanced breast carcinoma treated with high-dose hyperfractioned radical radiotherapy. Acute and late cutaneous and subcutaneous toxicity was evaluated using the Radiation Therapy Oncology Group morbidity scoring schema. The mean follow-up of survivors (n = 13) was 197.23 months. Radiosensitivity of lymphocytes was quantified as the initial number of DNA double-strand breaks induced per Gy and per DNA unit (200 Mbp). Radiation-induced apoptosis (RIA) at 1, 2 and 8 Gy was measured by flow cytometry using annexin V/propidium iodide. RESULTS. Mean DSB/Gy/DNA unit obtained was 1.70 ± 0.83 (range 0.63-4.08; median, 1.46). Radiation-induced apoptosis increased with radiation dose (median 12.36, 17.79 and 24.83 for 1, 2, and 8 Gy respectively). We observed that those "expected resistant patients" (DSB values lower than 1.78 DSB/Gy per 200 Mbp and RIA values over 9.58, 14.40 or 24.83 for 1, 2 and 8 Gy respectively) were at low risk of suffer severe subcutaneous late toxicity (HR 0.223, 95%CI 0.073-0.678, P = 0.008; HR 0.206, 95%CI 0.063-0.677, P = 0.009; HR 0.239, 95%CI 0.062-0.929, P = 0.039, for RIA at 1, 2 and 8 Gy respectively) in multivariate analysis. CONCLUSIONS. A radiation-resistant profile is proposed, where those patients who presented lower levels of initial DNA damage and higher levels of radiation induced apoptosis were at low risk of suffer severe subcutaneous late toxicity after clinical treatment at high radiation doses in our series. However, due to the small sample size, other prospective studies with higher number of patients are needed to validate these results.This work was subsidized by a grant from the Ministerio de Educación y Ciencia (CICYT: SAF 2004-00889) and Fundación del Instituto Canario de Investigación del Cáncer (FICIC).Yes2011-0

Single-cell analysis tools for drug discovery and development

The genetic, functional or compositional heterogeneity of healthy and diseased tissues presents major challenges in drug discovery and development. Such heterogeneity hinders the design of accurate disease models and can confound the interpretation of biomarker levels and of patient responses to specific therapies. The complex nature of virtually all tissues has motivated the development of tools for single-cell genomic, transcriptomic and multiplex proteomic analyses. Here, we review these tools and assess their advantages and limitations. Emerging applications of single cell analysis tools in drug discovery and development, particularly in the field of oncology, are discussed

Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer

The IL-6 family of cytokines consists of IL-6, IL-11, IL-27, IL-31, oncostatin M (OSM), leukaemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin 1 (CT-1) and cardiotrophin-like cytokine factor 1 (CLCF1). Membership of this cytokine family is defined by usage of common β-receptor signalling subunits, which activate various intracellular signalling pathways. Each IL-6 family member elicits responses essential to the physiological control of immune homeostasis, haematopoiesis, inflammation, development and metabolism. Accordingly, distortion of these cytokine activities often promotes chronic disease and cancer; the pathological importance of this is exemplified by the successful treatment of certain autoimmune conditions with drugs that target the IL-6 pathway. Here, we discuss the emerging roles for IL-6 family members in infection, chronic inflammation, autoimmunity and cancer and review therapeutic strategies designed to manipulate these cytokines in disease

Global liquidity and commodity prices-a cointegrated VAR approach for OECD countries

This article examines the interactions between money, consumer prices and commodity prices at a global level from 1970 to 2008. Using aggregated data for major Organization for Economic Cooperation and Development (OECD) countries and a Cointegrating Vector Autoregression (CVAR) framework, we are able to establish long-run and short-run relationships among these variables while the process is mainly driven by global liquidity. According to our empirical findings, different price elasticities in commodity and consumer goods markets can explain the recently observed overshooting of commodity over consumer prices. Although the sample period is rather long, recursive tests corroborate that our CVAR fits the data very well.

A high-resolution Late Glacial to Holocene record of environmental change in the Mediterranean from Lake Ohrid (Macedonia/Albania)

Lake Ohrid (Macedonia/Albania) is the oldest extant lake in Europe and exhibits an outstanding degree of endemic biodiversity. Here, we provide new high-resolution stable isotope and geochemical data from a 10 m core (Co1262) through the Late Glacial to Holocene and discuss past climate and lake hydrology (TIC, δ13Ccalcite, δ18Ocalcite) as well as the terrestrial and aquatic vegetation response to climate (TOC, TOC/N, δ13Corganic, Rock Eval pyrolysis). The data identifies 3 main zones: (1) the Late Glacial–Holocene transition represented by low TIC and TOC contents, (2) the early to mid-Holocene characterised by high TOC and increasing TOC/N and (3) the Late Holocene–Present which shows a marked decrease in TIC and TOC. In general, an overall trend of increasing δ18Ocalcite from 9 ka to present suggests progressive aridification through the Holocene, consistent with previous records from Lake Ohrid and the wider Mediterranean region. Several proxies show commensurate excursions that imply the impact of short-term climate oscillations, such as the 8.2 ka event and the Little Ice Age. This is the best-dated and highest resolution archive of past Late Glacial and Holocene climate from Lake Ohrid and confirms the overriding influence of the North Atlantic in the north-eastern Mediterranean. The data presented set the context for the International Continental scientific Drilling Program Scientific Collaboration On Past Speciation Conditions in Lake Ohrid project cores recovered in spring–summer 2013, potentially dating back into the Lower Pleistocene, and will act as a recent calibration to reconstruct climate and hydrology over the entire lake history