bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract SY11-02: Microenvironment matters: TGFβ regulates the response to DNA damage
Authors: Barcellos-Hoff Mary Helen 
Published: August 2012

Abstract
Transforming growth factor β1 (TGFβ) is a central regulator of the microenvironment in both normal tissues and tumors. TGFβ resides in the extracellular matrix as a latent complex that requires activation prior to binding to ubiquitous cell surface receptors to initiate a signaling cascade culminating in nuclear Smad activation of transcription. Most cancer cells are no longer responsive to TGFβ growth suppression, yet maintain a partially intact signaling pathway. Why?
Surprisingly, we found that either Tgfb1 genetic deletion in mouse cells or TGFβ inhibition in human cells compromises the execution of the molecular cascade in response to DNA damage. Irradiated epithelial cells exhibit decreased ATM kinase activity and autophosphorylation, reduced phosphorylation of critical DNA damage transducers, and abrogation of cell cycle blockade and apoptosis, which together result in increased radiosensitivity. The ability of exogenous TGFβ to restore these responses indicates that the effect is both cell intrinsic and distal to TGFβ signaling. Recent studies suggest that TGFβ regulates multiple components of the DNA damage response, supporting the conclusion that extrinsic TGFβ is necessary for efficient execution of the intrinsic DNA damage response.
TGFβ may thus provide a survival advantage in tumors, which are a source of exuberant TGFβ activity, provides an unexpected avenue for in cancer treatment. Both ionizing radiation and chemotherapy actually elicit TGFβ activity via redox- and integrin-mediated activation. We tested the translational potential of the requirement for TGFβ in the genotoxic stress program during radiotherapy using TGFβ neutralizing antibodies and small molecule inhibitors of the TGFβ type I receptor kinase in experimental models of breast, lung and brain cancer in vivo and in vitro. TGFβ inhibition prior to radiation increased the radiosensitivity of 10 of 12 human cancer cell lines as measured by clonogenic assay and decreased γH2AX phosphorylation. Notably, glioma stem cells were preferentially protected from DNA damage by high levels of TGFβ, which also promoted self-renewal, both of which were compromised by TGFβ inhibition. Administration of TGFβ neutralizing antibody in vivo increased tumor growth delay following single or multiple radiation fractions and also reduced metastasis. We anticipate that use of TGFβ inhibitors in the context of radiotherapy will increase radiosensitivity and impair the protective tumor microenvironment, providing both local and systemic benefit.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY11-02. doi:1538-7445.AM2012-SY11-02
Abstract SY13-01: Reporter imaging in cancer biology and therapy
Authors: Piwnica-Worms David 
Published: August 2012

Abstract
The tools of molecular imaging can provide spatially- and temporally-resolved information on biological structures and functions. Because researchers have increasingly recognized the importance of context for understanding gene expression and protein function as well as regulatory mechanisms within cellular micro-environments, they have turned to non-invasive imaging technologies to advance research on human health and disease. These non-invasive imaging data can interrogate protein processing, protein-protein interactions, gene expression and flux through metabolic pathways in real-time in cells and live animals, and are increasingly useful in understanding signal transduction and the pathobiology of cancer, which can facilitate development of effective therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY13-01. doi:1538-7445.AM2012-SY13-01
Abstract SY20-02: Role of Polycomb repressors in stem cells, cancer, DNA repair and iPS cell reprogramming
Authors: van Lohuizen Maarten 
Published: August 2012

Abstract
Repressive Polycomb-group (Pc-G) protein complexes and the counteracting Trithorax-group (Trx-G) of nucleosome remodeling factors are involved in the dynamic maintenance of proper gene expression patterns during development, acting at the level of chromatin structure. As such, they are important controllers of cell fate. When deregulated, these master switches of gene expression are strongly implicated in formation of a diverse set of cancers, including leukemia, breast cancer, prostate cancer and glioblastoma. To identify critical Polycomb targets and pathways implicated in brain cancer we performed comprehensive Bmi1-ChIP-seq profiling of mouse and human glioma ‘stem-like’ cells followed by in vivo shRNAi-library screening. These studies revealed a critical cross-talk between the BMP/TGFβ signaling pathways and Bmi1 and also provided new candidate tumor suppressors and non-coding RNAs associated with gliomagenesis. Furthermore, we have characterized in detail an essential E3-ubiquitin ligase activity in the PRC1 Polycomb complex that consists of a functional Ring1B-Bmi1 heterodimer. This E3 ligase activity is required for maintenance of Polycomb repression in normal- and cancer stem cells and hence offers potential novel ways to target cancer stem cells or tumor reforming cells in which the activity of this E3 ligase is hyperactivated. This is further substantiated by dynamic regulation of the Ring1B.Bmi1 E3 ligase activity which also has implications for a novel link between Polycomb silencing and control of Double-Strand DNA repair. Lastly, our recent studies revealed an unanticipated important role for Polycomb repression in the process of cellular ‘iPS’ cell reprogramming. The implications of these findings for stem cell biology, development, and possibilities for new translational approaches to cancer will be discussed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY20-02. doi:1538-7445.AM2012-SY20-02
Abstract SY21-02: DNA methylation and epigenetic instability in human cancer
Authors: Feinberg Andrew P. 
Published: August 2012

Abstract
Alterations in DNA methylation in human cancer were identified 30 years ago but a comprehensive view has emerged with the advent of whole genome bisulfite sequencing. While cancer can be viewed as over 200 distinct diseases that are organ-specific in their pathology, and mutation-specific in their molecular mechanism, recent discoveries in cancer epigenetics suggest a different but complementary view. Epigenetically, cancer may approach a single disorder with certain common features underlying the major reasons for cancer morbidity and mortality. Specifically, several common solid tumor types show increased epigenetic instability in DNA methylation at specific loci but involving the same loci in many different tumor types, and these loci appear to be critical for unregulated cell growth and tissue invasion and metastasis, and they involve the boundaries between CpG islands and shores, as well as large hypomethylated genomic blocks. These blocks correspond to large organized chromatin lysine (K) -modified domains (LOCKs) that are normally modulated during cellular reprogramming in development and epithelial-mesenchymal transition. We suggest a unifying model for the epigenetic basis of cancer in which increased instability in gene expression is mediated by loss in cancer of nuclear structures that control variance during normal development, such as LOCKs and CpG island boundaries. By this view, stochastic noise is a necessary part of cell fate determination leading to Waddingtonian canalization, and cancer is a disease, at least epigenetically, in which these canals are shallower, with increasing noise and the probability of cell type transitions that should not appear in differentiated tissues. At the same time, this increased noise increases the fitness of cancer cells and their resistance to any given therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY21-02. doi:1538-7445.AM2012-SY21-02
Abstract SY29-02: The TSC-mTOR pathway and control of anabolic tumor cell metabolism
Authors: Manning Brendan D. 
Published: August 2012

Abstract
The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) plays an evolutionarily conserved role as a molecular link between cellular growth conditions and the anabolic processes promoting cell growth. This protein kinase complex has the ability to sense and integrate signals emanating from pathways that monitor cellular growth conditions, including the availability of intracellular nutrients and energy, the presence of specific growth factors and cytokines, and a variety of cellular stresses. Importantly, the integrated control over mTORC1 activity and cell growth is corrupted in most human tumors. mTORC1 senses many of these upstream signals through a small G protein switch involving the tuberous sclerosis complex (TSC) tumor suppressors, TSC1 and TSC2, and the Ras-related small G protein Rheb, an essential activator of mTORC1. The TSC1-TSC2 complex functions as a GTPase-activating protein (GAP) for Rheb, thereby stimulating its conversion to the inactive GDP-bound form and inhibiting its activation of mTORC1. Multi-site phosphorylation of the TSC1-TSC2 complex downstream of distinct signaling pathways accounts for much of the signal-integrating capacity of mTORC1. Importantly, both the oncogenic PI3K-Akt and Ras-Erk pathways phosphorylate and inhibit TSC2 to activate mTORC1. Aberrant regulation of the TSC1-TSC2 complex leading to constitutive activation of mTORC1 is a common molecular event in a large variety of pathological settings, including the majority of genetic tumor syndromes and sporadic cancers. However, the molecular mechanisms by which the TSC1-TSC2 complex is regulated and functions to properly control Rheb and mTORC1 are not well understood. Furthermore, the downstream consequences of dysregulated mTORC1 signaling in tumors remain poorly defined. This lecture will focus on recent studies in our laboratory to 1) characterize a third stoichiometric component of the TSC1-TSC2 complex and its role in mTOR regulation, and 2) the role of mTORC1 in the metabolic reprogramming of tumor cells induced by common oncogenic events.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY29-02. doi:1538-7445.AM2012-SY29-02
Adjoint Sensitivity and Predictability of Tropical Cyclogenesis
Authors: Doyle James D. , Reynolds Carolyn A. , Amerault Clark , Moskaitis Jonathan 
Published: August 2012

Abstract
The sensitivity of tropical cyclogenesis and subsequent intensification is explored by applying small perturbations to the initial state in the presence of organized mesoscale convection and synoptic-scale forcing using the adjoint and tangent linear models for the Coupled Ocean–Atmosphere Mesoscale Prediction System (COAMPS). The forward, adjoint, and tangent linear models are used to compare and contrast predictability characteristics for the disturbance that became Typhoon Nuri and a nondeveloping organized convective cluster in the western Pacific during The Observing System Research and Predictability Experiment (THORPEX) Pacific Asian Regional Campaign (T-PARC) and the Tropical Cyclone Structure-2008 (TCS-08) experiments.
The adjoint diagnostics indicate that the intensity (e.g., maximum surface wind speed, minimum surface pressure) of a tropical disturbance is very sensitive to perturbations in the moisture and temperature fields and to a lesser degree the wind fields. The highest-resolution adjoint simulations (grid increment of 13 km) indicate that the most efficient intensification is through moistening in the lower and middle levels and heating in banded regions that are coincident with vorticity maxima in the initial state. Optimal adjoint perturbations exhibit rapid growth for the Nuri case and only modest growth for the nondeveloping system. The adjoint results suggest that Nuri was near the threshold for development, indicative of low predictability. The low-level sensitivity maximum and tendency for optimal perturbation growth to extend vertically through the troposphere are consistent with a “bottom up” development process of TC genesis, although a secondary midlevel sensitivity maximum is present as well. Growth originates at small scales and projects onto the scale of the vortex, a manifestation of perturbations that project onto organized convection embedded in regions of cyclonic vorticity.
On the Rapid Intensification of Hurricane Wilma (2005). Part II: Convective Bursts and the Upper-Level Warm Core
Authors: Chen Hua , Zhang Da-Lin 
Published: August 2012

Abstract
Previous studies have focused mostly on the roles of environmental factors in the rapid intensification (RI) of tropical cyclones (TCs) because of the lack of high-resolution data in inner-core regions. In this study, the RI of TCs is examined by analyzing the relationship between an upper-level warm core, convective bursts (CBs), sea surface temperature (SST), and surface pressure falls from 72-h cloud-permitting predictions of Hurricane Wilma (2005) with the finest grid size of 1 km. Results show that both the upper-level inertial stability increases and static stability decreases sharply 2–3 h prior to RI, and that the formation of an upper-level warm core, from the subsidence of stratospheric air associated with the detrainment of CBs, coincides with the onset of RI. It is found that the development of CBs precedes RI, but most subsidence warming radiates away by gravity waves and storm-relative flows. In contrast, many fewer CBs occur during RI, but more subsidence warming contributes to the balanced upper-level cyclonic circulation in the warm-core (as intense as 20°C) region. Furthermore, considerable CB activity can still take place in the outer eyewall as the storm weakens during its eyewall replacement. A sensitivity simulation, in which SSTs are reduced by 1°C, shows pronounced reductions in the upper-level warm-core intensity and CB activity. It is concluded that significant CB activity in the inner-core regions is an important ingredient in generating the upper-level warm core that is hydrostatically more efficient for the RI of TCs, given all of the other favorable environmental conditions.
A New Type of the Indian Ocean Dipole since the Mid-1970s
Authors: Du Yan , Cai Wenju , Wu Yanling 
Published: August 2012

AbstractThe tropical Indian Ocean dipole/zonal mode (IOD) is phase locked with the austral winter and spring seasons. This study describes three types of the IOD in terms of their peak time and duration. In particular, the authors focus on a new type that develops in May–June and matures in July–August, which is distinctively different from the canonical IOD, which may develop later and peak in September–November or persist from June to November. Such “unseasonable” IOD events are only observed since the mid-1970s, a period after which the tropical Indian Ocean has a closer relationship with the Pacific Ocean. The unseasonable IOD is an intrinsic mode of the Indian Ocean and occurs without an ensuing El Niño. A change in winds along the equator is identified as a major forcing. The wind change is in turn related to a weakening Walker circulation in the Indian Ocean sector in austral winter, which is in part forced by the rapid Indian Ocean warming. Thus, although the occurrence of the unseasonable IOD may be partially influenced by oceanic variability, the authors’ results suggest an influence from the Indian Ocean warming. This suggestion, however, awaits further investigation using fully coupled climate models.
Examining the support needs of ageing family carers in developing future plans for a relative with an intellectual disability
Authors: Taggart Laurence , Truesdale-Kennedy Maria , Ryan Assumpta , McConkey Roy 
Published: August 2012

Background: Planning for the future care of adults with an intellectual disability after the main family carer ceases their care, continues to be a sensitive and difficult time posing challenges for service providers internationally. Limited research has been undertaken on this topic because until recently, people with intellectual disability usually pre-deceased their parents. This study examined ageing carers’ preferences for future care and the support systems required to make such future plans. Methods: The study was conducted in one region of the United Kingdom with a high proportion of family carers. A mixed methods design was employed. In Stage 1, a structured questionnaire was used to collate information on the health, caregiving demands and future planning preferences of 112 parent and sibling carers; aged 60–94 years. In Stage 2, 19 in-depth semistructured interviews were undertaken with a sample of carers to explore a range of issues around future planning. Findings: Over half of the carers were lone carers, mainly female, with many reporting a wide range of health problems. A third of these carers reported that their caregiving resulted in high levels of anxiety. The main preference of the carers was for the person to remain in the family home, with either the family and/or paid staff to support them. A minority of parent carers preferred the person to move into the home of a sibling, although some favoured the person moving to a residential facility with other people with intellectual disabilities. The majority of carers did not want their relative to move into an older people’s residential/nursing facility. In the qualitative data, four main themes were identified around future planning: unremitting apprehension, the extent of planning, obstacles encountered and solutions for future planning. Avoidance, lack of guidance and a lack of appropriate residential provision were cited as obstacles to making future plans compounded by the emotional upset experienced by carers in thinking about the future. Conclusion: Findings of this study clearly identify the emotional, informational and practical supports required by these ageing family carers. These findings have national and international relevance in influencing how governments and service providers support parent and sibling carers to proactively plan for the future, and in the development of both in-home and out-of-home options when a family carer can no longer provide care. This is more urgent than ever given the growing numbers of older persons with intellectual disabilities in future decades.
A humanized single-chain antibody against beta 3 integrin inhibits pulmonary metastasis by preferentially fragmenting activated platelets in the tumor microenvironment
Authors: Zhang Wei , Dang Suying , Hong Tao , Tang Jian , Fan Jing , Bu Dawei , Sun Yanjie , Wang Zhugang , Wisniewski Thomas 
Published: August 2012

AbstractPlatelets play a supportive role in tumor metastasis. Impairment of platelet function within the tumor microenvironment may provide a clinically useful approach to inhibit metastasis. We developed a novel humanized single-chain antibody (scFv Ab) against integrin GPIIIa49-66 (named A11) capable of lysing activated platelets. In this study, we investigate the effect of A11 on the development of pulmonary metastases. In the Lewis lung carcinoma (LLC) metastatic model, A11 decreases the mean number of surface nodules and mean volume of pulmonary nodules. It protects against lung metastases in a time window that extended 4 hours before and 4 hours after the IV injection of LLCs. Coinjection of GPIIIa49-66 albumin reverses the antimetastatic activity of A11 in the B16 melanoma model, consistent with the pathophysiologic relevance of the platelet GPIIIa49-66 epitope. Significantly, A11 had no effect on angiogenesis using both in vitro and in vivo assays. The underlying molecular mechanisms are a combination of inhibition of each of the following interactions: between activated platelets and tumor cells, platelets and endothelial cells, and platelets and monocytes, as well as disaggregation of an existing platelet/tumor thrombus. Our observations may provide a novel antimetastatic strategy through lysing activated platelets in the tumor microenvironment using humanized anti–GPIIIa49-66 scFv Ab.
Effect of muscle load tasks with maximal isometric contractions on oxygenation of the trapezius muscle and sympathetic nervous activity in females with chronic neck and shoulder pain
Authors: Shiro Yukiko , Arai Young-Chang P , Matsubara Takako , Isogai Shunsuke , Ushida Takahiro 
Published: August 2012

Abstract

Background
Sympathetic nervous activity contributes to the maintenance of muscle oxygenation. However, patients with chronic pain may suffer from autonomic dysfunction. Furthermore, insufficient muscle oxygenation is observed among workers with chronic neck and shoulder pain. The aim of our study was to investigate how muscle load tasks affect sympathetic nervous activity and changes in oxygenation of the trapezius muscles in subjects with chronic neck and shoulder pain.

Methods
Thirty females were assigned to two groups: a pain group consisting of subjects with chronic neck and shoulder pain and a control group consisting of asymptomatic subjects. The participants performed three sets of isometric exercise in an upright position; they contracted their trapezius muscles with maximum effort and let the muscles relax (Relax). Autonomic nervous activity and oxygenation of the trapezius muscles were measured by heart rate variability (HRV) and Near-Infrared Spectroscopy.

Results
Oxyhemoglobin and total hemoglobin of the trapezius muscles in the pain group were lower during the Relax period compared with the control group. In addition, the low frequency / high frequency (LF/HF) ratio of HRV significantly increased during isometric exercise in the control group, whereas there were no significant changes in the pain group.

Conclusions
Subjects with neck and shoulder pain showed lower oxygenation and blood flow of the trapezius muscles responding to isometric exercise, compared with asymptomatic subjects. Subjects with neck and shoulder pain also showed no significant changes in the LF/HF ratio of HRV responding to isometric exercise, which would imply a reduction in sympathetic nervous activity.