Preoperative imatinib for patients with primary unresectable or metastatic/recurrent gastrointestinal stromal tumor

OBJECTIVES: Despite its rising popularity, reports on the use of preoperative imatinib mesylate (IM) in patients with advanced gastrointestinal stromal tumor (GIST) are limited. This study aims to explore the clinical efficacy of preoperative IM in patients with primarily unresectable or metastatic/recurrent GIST. METHODS: Between September 2009 and February 2014, patients with primarily unresectable or metastatic/recurrent GIST treated by a single medical team were recruited and considered for preoperative IM therapy. Re-examination was conducted regularly and abdominal enhanced CT data, blood biochemistry and responses to IM were recorded. RESULTS: A total of 18 patients were enrolled, including 13 with a primary tumor (7 stomach, 3 small bowel, 2 rectal and 1 pelvic tumor) and 5 with recurrent or metastatic GIST (2 with liver metastasis, 2 with anastomotic recurrence and 1 with pelvic GIST). The median follow-up time was 9.5 months (range of 3-63). The median tumor sizes before and after initiation of IM treatment were 9.1 cm and 6.0 cm (p = 0.003) based on the CT findings, respectively. All patients showed a decrease in tumor burden and the median tumor size reduction was 35%. Sixteen of the 18 patients showed a partial response to IM and two possessed stable disease. Nine of the 18 patients (50%) underwent surgical resection of primary or metastatic/recurrent tumors, with a median of 7 months of IM therapy. One case each of multivisceral resection and tumor recurrence were noted. CONCLUSIONS: IM as a preoperative therapy is feasible and safe for unresectable or metastatic/recurrent GIST that can effectively decrease tumor size, facilitating resection

A Megavoltage CT Image Enhancement Method for Image-Guided and Adaptive Helical TomoTherapy

Purpose: To propose a novel method to improve the mega-voltage CT (MVCT) image quality for helical TomoTherapy while maintaining the stability on dose calculation.Materials and Methods: The Block-Matching 3D-transform (BM3D) and Discriminative Feature Representation (DFR) methods were combined into a novel BM3D + DFR method for their respective advantages. A phantom (Catphan504) and three serials of clinical (head & neck, chest, and pelvis) MVCT images from 30 patients were acquired using the helical TomoTherapy system. The contrast-to-noise ratio (CNR) and edge detection algorithm (canny) was employed for image quality comparisons between the original and BM3D + DFR enhanced MVCT. A simulated rectangular field of 6 MV X-ray beams were vertically delivered on the original and post-processed MVCT serials of the same CT density phantom, and the dose curves on both serials were compared to test the effects of image enhancement on dose calculation accuracy.Results: In total, 466 transversal MVCT slices were acquired and processed by both BM3D and the proposed BM3D + DFR methods. Compared to the original MVCT image, the BM3D + DFR method presented a remarkable improvement in terms of the soft tissue contrast and noise reduction. For the phantom image, the CNR of the region of interest (ROI) was improved from 1.70 to 4.03. The average CNR of ROIs for 10 patients from each anatomical group, were increased significantly from 1.45 ± 1.51 to 2.09 ± 1.68 for the head & neck (p < 0.001), from 0.92 ± 0.78 to 1.36 ± 0.85 for the chest (p < 0.001), and from 1.12 ± 1.22 to 1.76 ± 1.31 for the pelvis (p < 0.001), respectively. The canny edge detection operator showed that BM3D + DFR provided clearer organ boundaries with less chaos. The root-mean-square of the dosimetry difference on the iso-center passed horizontal dose profile curves and vertical percentage depth dose curves were only 0.09% and 0.06%, respectively.Conclusions: The proposed BM3D + DFR method is feasible to improve the soft tissue contrast for the original MVCT images with coincidence in dose calculation and without compromising resolution. After integration in clinical workflow, the post-processed MVCT may be better applied on image-guided and adaptive helical TomoTherapy

Statistical modeling of spatially stratified heterogeneous data

Spatial statistics is an important methodology for geospatial data analysis. It has evolved to handle spatially autocorrelated data and spatially (locally) heterogeneous data, which aim to capture the first and second laws of geography, respectively. Examples of spatially stratified heterogeneity (SSH) include climatic zones and land-use types. Methods for such data are relatively underdeveloped compared to the first two properties. The presence of SSH is evidence that nature is lawful and structured rather than purely random. This induces another “layer” of causality underlying variations observed in geographical data. In this article, we go beyond traditional cluster-based approaches and propose a unified approach for SSH in which we provide an equation for SSH, display how SSH is a source of bias in spatial sampling and confounding in spatial modeling, detect nonlinear stochastic causality inherited in SSH distribution, quantify general interaction identified by overlaying two SSH distributions, perform spatial prediction based on SSH, develop a new measure for spatial goodness of fit, and enhance global modeling by integrating them with an SSH q statistic. The research advances statistical theory and methods for dealing with SSH data, thereby offering a new toolbox for spatial data analysis

The FilZ protein contains a single PilZ domain and facilitates the swarming motility of pseudoalteromonas sp. SM9913

Swarming regulation is complicated in flagellated bacteria, especially those possessing dual flagellar systems. It remains unclear whether and how the movement of the constitutive polar flagellum is regulated during swarming motility of these bacteria. Here, we report the downregulation of polar flagellar motility by the c-di-GMP effector FilZ in the marine sedimentary bacterium Pseudoalteromonas sp. SM9913. Strain SM9913 possesses two flagellar systems, and filZ is located in the lateral flagellar gene cluster. The function of FilZ is negatively controlled by intracellular c-di-GMP. Swarming in strain SM9913 consists of three periods. Deletion and overexpression of filZ revealed that, during the period when strain SM9913 expands quickly, FilZ facilitates swarming. In vitro pull-down and bacterial two-hybrid assays suggested that, in the absence of c-di-GMP, FilZ interacts with the CheW homolog A2230, which may be involved in the chemotactic signal transduction pathway to the polar flagellar motor protein FliMp, to interfere with polar flagellar motility. When bound to c-di-GMP, FilZ loses its ability to interact with A2230. Bioinformatic investigation indicated that filZ-like genes are present in many bacteria with dual flagellar systems. Our findings demonstrate a novel mode of regulation of bacterial swarming motility

Decreased level of recent thymic emigrants in CD4+ and CD8+T cells from CML patients

<p>Abstract</p> <p>Background</p> <p>T-cell immunodeficiency is a common feature in cancer patients, which may relate to initiation and development of tumor. Based on our previous finding, to further characterize the immune status, T cell proliferative history was analyzed in CD4+ and CD8+ T cells from chronic myeloid leukemia (CML) patients.</p> <p>Methods</p> <p>Quantitative analysis of δRec-ψJα signal joint T cell receptor excision circles (sjTRECs) was performed in PBMCs, CD3+, CD4+ and CD8+T cells by real-time PCR, and the analysis of 23 <it>TRBV-D1 </it>sjTRECs was performed by semi-nested PCR. Forty eight CML cases in chronic phase (CML-CP) were selected for this study and 17 healthy individuals served as controls.</p> <p>Results</p> <p>The levels of δRec-ψJα sjTRECs in PBMCs, CD3+, CD4+, and CD8+ T cells were significantly decreased in CML patients, compared with control groups. Moreover, the numbers of detectable <it>TRBV </it>subfamily sjTRECs, as well as the frequency of particular <it>TRBV-BD</it>1 sjTRECs in patients with CML were significantly lower than those from healthy individuals.</p> <p>Conclusions</p> <p>We observed decreased levels of recent thymic emigrants in CD4+ and CD8+ T cells that may underlay the persistent immunodeficiency in CML patients.</p

Drosophila IAP antagonists form multimeric complexes to promote cell death

Self- and hetero-association of the pro-apoptotic proteins Reaper, Hid, and Grim is required for efficient induction of the cell death program

Tamoxifen mechanically deactivates hepatic stellate cells via the G protein-coupled estrogen receptor

Tamoxifen has been used for many years to target estrogen receptor signalling in breast cancer cells. Tamoxifen is also an agonist of the G protein-coupled estrogen receptor (GPER), a GPCR ubiquitously expressed in tissues that mediates the acute response to estrogens. Here we report that tamoxifen promotes mechanical quiescence in hepatic stellate cells (HSCs), stromal fibroblast-like cells whose activation triggers and perpetuates liver fibrosis in hepatocellular carcinomas. This mechanical deactivation is mediated by the GPER/RhoA/myosin axis and induces YAP deactivation. We report that tamoxifen decreases the levels of hypoxia-inducible factor-1 alpha (HIF-1α) and the synthesis of extracellular matrix proteins through a mechanical mechanism that involves actomyosin-dependent contractility and mechanosensing of tissue stiffness. Our results implicate GPER-mediated estrogen signalling in the mechanosensory-driven activation of HSCs and put forward estrogenic signalling as an option for mechanical reprogramming of myofibroblast-like cells in the tumour microenvironment. Tamoxifen, with half a century of safe clinical use, might lead this strategy of drug repositioning.Peer reviewe