Does Openness to Trade Make Countries More Vulnerable to Sudden Stops, or Less? Using Gravity to Establish Causality

Openness to trade is one factor that has been identified as determining whether a country is prone to sudden stops in capital inflows, crashes in currencies, or severe recessions. Some believe that openness raises vulnerability to foreign shocks, while others believe that it makes adjustment to crises less painful. Several authors have offered empirical evidence that having a large tradable sector reduces the contraction necessary to adjust to a given cut-off in funding. This would help explain lower vulnerability to crises in Asia than in Latin America. Such studies may, however, be subject to the problem that trade is endogenous. Using the gravity instrument for trade openness, which is constructed from geographical determinants of bilateral trade, this paper finds that openness indeed makes countries less vulnerable, both to severe sudden stops and currency crashes, and that the relationship is even stronger when correcting for the endogeneity of trade.

Autophagy and radiosensitization in cancer

Autophagy is a natural self-degradative process by which cells eliminate misfolded proteins and damaged organelles. Autophagy has been shown to have multiple functions in tumor cells that may be dependent on the tumor type and the treatment conditions. Autophagy can have a cytoprotective role and be thought of as a survival mechanism or be cytotoxic in nature and mediate cell death. Radiation, one of the primary treatments for many different types of cancer, almost uniformly promotes autophagy in tumor cells. While autophagy produced in response to radiation is often considered to be cytoprotective, radiation-induced autophagy has also been shown to mediate susceptibility to radiation. This review addresses the complexity of autophagy in response to radiation treatment in three different cancer models, specifically lung cancer, breast cancer and glioblastoma. A deeper understanding of the different roles played by autophagy in response to radiation should facilitate the development of approaches for enhancing the therapeutic utility of radiation by providing strategies for combination treatment with unique radiosensitizers as well as preventing the initiation of strategies which are likely to attenuate the effectiveness of radiation therapy

Deficiency in 3′-phosphoglycolate processing in human cells with a hereditary mutation in tyrosyl-DNA phosphodiesterase (TDP1)

Tyrosyl-DNA phosphodiesterase (TDP1) is a DNA repair enzyme that removes peptide fragments linked through tyrosine to the 3′ end of DNA, and can also remove 3′-phosphoglycolates (PGs) formed by free radical-mediated DNA cleavage. To assess whether TDP1 is primarily responsible for PG removal during in vitro end joining of DNA double-strand breaks (DSBs), whole-cell extracts were prepared from lymphoblastoid cells derived either from spinocerebellar ataxia with axonal neuropathy (SCAN1) patients, who have an inactivating mutation in the active site of TDP1, or from closely matched normal controls. Whereas extracts from normal cells catalyzed conversion of 3′-PG termini, both on single-strand oligomers and on 3′ overhangs of DSBs, to 3′-phosphate termini, extracts of SCAN1 cells did not process either substrate. Addition of recombinant TDP1 to SCAN1 extracts restored 3′-PG removal, allowing subsequent gap filling on the aligned DSB ends. Two of three SCAN1 lines examined were slightly more radiosensitive than normal cells, but only for fractionated radiation in plateau phase. The results suggest that the TDP1 mutation in SCAN1 abolishes the 3′-PG processing activity of the enzyme, and that there are no other enzymes in cell extracts capable of processing protruding 3′-PG termini. However, the lack of severe radiosensitivity suggests that there must be alternative, TDP1-independent pathways for repair of 3′-PG DSBs

Stress and Radiation-Induced Activation of Multiple Intracellular Signaling Pathways

Exposure of cells to a variety of stresses induces compensatory activations of multiple intracellular signaling pathways. These activations can play critical roles in controlling cell survival and repopulation effects in a stress-specific and cell type-dependent manner. Some stress-induced signaling pathways are those normally activated by mitogens such as the EGFR/RAS/PI3K-MAPK pathway. Other pathways activated by stresses such as ionizing radiation include those downstream of death receptors, including pro-caspases and the transcription factor NFKB. This review will attempt to describe some of the complex network of signals induced by ionizing radiation and other cellular stresses in animal cells, with particular attention to signaling by growth factor and death receptors. This includes radiation-induced signaling via the EGFR and IGFI-R to the PI3K, MAPK, JNK, and p38 pathways as well as FAS-R and TNF-R signaling to pro-caspases and NFKB. The roles of autocrine ligands in the responses of cells and bystander cells to radiation and cellular stresses will also be discussed. Based on the data currently available, it appears that radiation can simultaneously activate multiple signaling pathways in cells. Reactive oxygen and nitrogen species may play an important role in this process by inhibiting protein tyrosine phosphatase activity. The ability of radiation to activate signaling pathways may depend on the expression of growth factor receptors, autocrine factors, RAS mutation, and PTEN expression. In other words, just because pathway X is activated by radiation in one cell type does not mean that pathway X will be activated in a different cell type. Radiation-induced signaling through growth factor receptors such as the EGFR may provide radioprotective signals through multiple downstream pathways. In some cell types, enhanced basal signaling by proto-oncogenes such as RAS may provide a radioprotective signal. In many cell types, this may be through PI3K, in others potentially by NFKB or MAPK. Receptor signaling is often dependent on autocrine factors, and synthesis of autocrine factors will have an impact on the amount of radiation-induced pathway activity. For example, cells expressing TGFalpha and HB-EGF will generate protection primarily through EGFR. Heregulin and neuregulins will generate protective signals through ERBB4/ERBB3. The impact on radiation-induced signaling of other autocrine and paracrine ligands such as TGFbeta and interleukin 6 is likely to be as complicated as described above for the ERBB receptors.Fil: Dent, Paul. Virginia Commonwealth University; Estados UnidosFil: Yacoub, Adly. Virginia Commonwealth University; Estados UnidosFil: Contessa, Joseph. Virginia Commonwealth University; Estados UnidosFil: Caron, Ruben Walter. Virginia Commonwealth University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Amorino, Geroge. Virginia Commonwealth University; Estados UnidosFil: Valerie, Kristoffer. Virginia Commonwealth University; Estados UnidosFil: Hagan, Michael P.. Virginia Commonwealth University; Estados UnidosFil: Grant, Steven. Virginia Commonwealth University; Estados UnidosFil: Schmidt Ullrich, Rupert. Virginia Commonwealth University; Estados Unido

Subcutaneous Administration of D-Luciferin is an Effective Alternative to Intraperitoneal Injection in Bioluminescence Imaging of Xenograft Tumors in Nude Mice

Currently, intraperitoneal (IP) injection of D-luciferin is the preferred method of providing substrate for bioluminescence imaging (BLI); however it has a failure rate of 3–10% due to accidental intestinal injection. The present study evaluates the quality of BLI after subcutaneous (SC) injection of D-luciferin and demonstrates the effectiveness of SC injection in anatomically disparate tumor models. Mice bearing luciferase-expressing tumors underwent BLI after SC or IP injection of D-luciferin. The average time to maximal luminescence was 6 min (range 5–9 min) after SC injection and 8 min (range 5–8 min) after IP injection. Within 7 minutes of injection, SC and IP routes yielded similar luminescence in subcutaneous, intracranial, tongue, and lung xenograft tumor models. In a model of combined subcutaneous and intracranial xenografts, SC injection resulted in proportional luminescence at all sites, confirming that preferential delivery of substrate does not occur. While tumors were occasionally not visualized with IP injection, all tumors were visualized reliably with SC injection. Thus, SC injection of D-luciferin is a convenient and effective alternative to IP injection for BLI in nude mice. It may be a preferable approach, particularly for tumors with weaker signals and/or when greater precision is required

Compensatory ErbB3/c-Src signaling enhances carcinoma cell survival to ionizing radiation

EGFR and ErbB2 are two members of the ErbB family of receptor Tyr Kinases identified as therapeutic targets for treating carcinomas. Breast carcinoma cells express different complements and variable proportions of ErbB receptor Tyr kinases, which activate unique and redundant signaling cascades that are essential for cell survival. Previously it was shown that a COOH-terminal truncation mutant of the EGFR (EGFR-CD533) blocks EGFR dependent signals and radiosensitizes breast carcinoma cells. In this study the effects of EGFR-CD533 and an analogous truncation mutant of ErbB2 (ErbB2-CD572) on ErbB receptor family dimerization and signaling are further investigated. Using adenoviral vectors in breast carcinoma cell lines with variable ErbB expression profiles, we demonstrate different effects for each deletion mutant. EGFR-CD533 blocks ligand stimulation of EGFR, ErbB2, and ErbB4, but is associated with a compensatory Tyr kinase activity resulting in phosphorylation of ErbB3. In contrast, ErbB2-CD572 produces a weaker, non-specific pattern of ErbB receptor family inhibition, based upon the ErbB expression pattern of the cell type. Investigation of the compensatory Tyr kinase activity associated with EGFR-CD533 expression identified an ErbB3/c-Src signaling pathway that regulates expression of anti-apoptotic Bcl family proteins. This signaling is active in the T47D cell line, which inherently over-express ErbB3, absent in MDA-MB231 cells, which have low ErbB3 expression levels, and is restored in a MDA-MB231 cell line engineered to over-express ErbB3. Furthermore we demonstrate that ErbB3/c-Src signaling is radio-protective, and that its elimination through pharmacologic inhibition of c-Src enhances radiation-induced apoptosis. In summary, these studies identify a novel ErbB3/c-Src survival signal and point to ErbB3 expression levels as an important variable in therapeutic targeting of ErbB receptors in breast carcinoma cells.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44234/1/10549_2005_Article_9023.pd

The Influence of Hypoxia and pH on Bioluminescence Imaging of Luciferase-Transfected Tumor Cells and Xenografts

Bioluminescence imaging (BLI) is a relatively new noninvasive technology used for quantitative assessment of tumor growth and therapeutic effect in living animal models. BLI involves the generation of light by luciferase-expressing cells following administration of the substrate luciferin in the presence of oxygen and ATP. In the present study, the effects of hypoxia, hypoperfusion, and pH on BLI signal (BLS) intensity were evaluated in vitro using cultured cells and in vivo using a xenograft model in nude mice. The intensity of the BLS was significantly reduced in the presence of acute and chronic hypoxia. Changes in cell density, viability, and pH also affected BLS. Although BLI is a convenient non-invasive tool for tumor assessment, these factors should be considered when interpreting BLS intensity, especially in solid tumors that could be hypoxic due to rapid growth, inadequate blood supply, and/or treatment

Influence of interdisciplinary frailty screening on perioperative complication rates in elderly ovarian cancer patients : results of a retrospective observational study

Purpose: Frailty is a frequent and underdiagnosed multidimensional age-related syndrome, involving decreased physiological performance reserves and marked vulnerability against major stressors. To standardize the preoperative frailty assessment and identify patients at risk of adverse surgical outcomes, commonly used global health assessment tools were evaluated. We aimed to assess three interdisciplinary preoperative screening assessments to investigate the influence of frailty status with in-hospital complications irrespective of surgical complexity and radicality in older women with ovarian cancer (OC). Methods: Preoperative frailty status was examined by the G8 geriatric screening tool (G8 Score-geriatric screening), Eastern Cooperative Oncology Group performance status (ECOG PS-oncological screening), and American Society of Anesthesiologists Physical Status System (ASA PS-anesthesiologic screening). The main outcome measures were the relationship between perioperative laboratory results, intraoperative surgical parameters and the incidence of immediate postoperative in-hospital complications with the preoperative frailty status. Results: 116 consecutive women 60 years and older (BMI 24.8 ± 5.2 kg/m2) with OC, who underwent elective oncological surgery in University Medical Center Mainz between 2008 and 2019 were preoperatively classified with the selected global health assessment tools as frail or non-frail. The rate of preoperative anemia (hemoglobin ≤ 12 g/dl) and perioperative transfusions were significantly higher in the G8-frail group (65.9% vs. 34.1%; p = 0.006 and 62.7% vs. 41.8%, p = 0.031; respectively). In addition, patients preoperatively classified as G8-frail exhibited significantly more postoperative clinical in-hospital complications (27.8% vs. 12.5%, p = 0.045) independent of chronological age and BMI. In contrast, ECOG PS and ASA PS did not predict the rates of postoperative complications (all p values > 0.05). After propensity score matching, the complication rate in the G8-frail cohort was approximately 1.7 times more common than in the G8-non-frail cohort. Conclusion: Preoperative frailty assessment with the G8 Score identified elderly women with OC recording a significantly higher rate of postoperative in-hospital complications. In G8-frail patients, preoperative anemia and perioperative transfusions were significantly more recorded, regardless of chronological age, abnormal BMI and surgical complexity. Standardized preoperative frailty assessment should be added to clinical routine care to enhance risk stratification in older cancer individuals for surgical patient-centered decision-making