Structure-Guided Rescaffolding of Selective Antagonists of BCL-XL

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Coinfection of Fusobacterium nucleatum and Actinomyces israelii in Mastoiditis Diagnosed by Next-Generation DNA Sequencing

Some bacterial infections involve potentially complex mixtures of species that can now be distinguished using next-generation DNA sequencing. We present a case of mastoiditis where Gram stain, culture, and molecular diagnosis were nondiagnostic or discrepant. Next-generation sequencing implicated coinfection of Fusobacterium nucleatum and Actinomyces israelii, resolving these diagnostic discrepancies.     

The specificity of sociotropy-autonomy personality dimensions to depression vs. Anxiety

Previous cognitive vulnerability studies have identified sociotropy/dependency as a personality characteristic related to depression. We evaluated sociotropy in differential prediction of depression vs. anxiety. Participants (70 females, 42 males) were tested on the Beck Depression Inventory (BDI) and the Beck Anxiety Inventory (BAI) at two points in time (T1 and T2), separated by an interval of 4 weeks. The Sociotropy-Autonomy Scale (SAS) was administered at T1. Sociotropy was related moderately to the BDI at T1 and T2, but also to the BAI. Autonomy was related to neither. Hierarchical multiple regression analyses found sociotropy to predict anxiety at T2, but not depression. The issue of cognitive vulnerability marker specificity is discussed.     

Thoracic aortic aneurysm and rupture in giant cell arteritis. a descriptive study of 41 cases

Objective. To determine the features and outcomes of patients with giant cell arteritis (GCA) who have aneurysms or rupture of the thoracic aorta. Methods. Patients with GCA seen over a 40-year period who had aneurysms and/or rupture of the thoracic aorta were identified by assistance of a computerized indexing system. The presence of thoracic aortic aneurysms (TAA), with or without aortic valve insufficiency (AI), was determined by radiographs, computed tomography scans, and ultrasound studies of the thorax, angiograms of the aorta, and postmortem examination. Results. Ten men and 31 women with GCA were found to have TAA and/or rupture. Three developed TAA before GCA was diagnosed, 5 developed aortic findings near the time of the diagnosis, and 33 after the diagnosis of GCA (median of 7 years after diagnosis). Sixteen patients developed acute aortic dissection, which caused death in 8. Nineteen patients also had AI due to aortic root dilation, 15 of whom developed congestive heart failure. Eighteen patients underwent 21 surgical procedures for TAA resection and/or aortic valve replacement or repair. Aortitis was documented histologically in 10 cases. Conclusion. Thoracic aortic complications in GCA are associated with serious outcomes that have been underrecognized and may be fatal. Physicians should be alert to the development of these complications at any time in the course of GCA, even many years after usual symptoms have subsided.     

Cordysinocan,a polysaccharide isolated from cultured Cordyceps, activates immune responses in cultured T-lymphocytes and macrophages: Signaling cascade and induction of cytokines

Cordyceps sinensis, a well-known traditional Chinese medicine, possesses activities in anti-tumor, anti-oxidation and stimulating the immune response; however, the identity of active component(s) is not determined. A strain of Cordyceps sinensis, namely UST 2000, has been isolated. By using activity-guided purification, a novel polysaccharide of molecular weight ∼82 kDa was isolated from the conditioned medium of cultured Cordyceps. The isolated exo-polysaccharide, namely cordysinocan, contains glucose, mannose, galactose in a ratio of 2.4:2:1. In cultured T-lymphocytes, application of cordysinocan induced the cell proliferation and the secretion of interleukin-2, interleukin-6 and interleukin-8. In addition, the phosphorylation of extracellular signal-regulated kinases (ERK) was induced transiently by the treatment of cordysinocan. Moreover, application of cordysinocan in cultured macrophages increased the phagocytosis activity and the enzymatic activity of acid phosphatase. These results therefore verify the important role of Cordyceps polysaccharide in triggering such immune responses.     

LC3-associated phagocytosis in bone marrow macrophages suppresses acute myeloid leukemia progression through STING activation

The bone marrow (BM) microenvironment regulates acute myeloid leukemia (AML) initiation, proliferation, and chemotherapy resistance. Following cancer cell death, a growing body of evidence suggests an important role for remaining apoptotic debris in regulating the immunologic response to and growth of solid tumors. Here, we investigated the role of macrophage LC3–associated phagocytosis (LAP) within the BM microenvironment of AML. Depletion of BM macrophages (BMMs) increased AML growth in vivo. We show that LAP is the predominate method of BMM phagocytosis of dead and dying cells in the AML microenvironment. Targeted inhibition of LAP led to the accumulation of apoptotic cells (ACs) and apoptotic bodies (ABs), resulting in accelerated leukemia growth. Mechanistically, LAP of AML-derived ABs by BMMs resulted in stimulator of IFN genes (STING) pathway activation. We found that AML-derived mitochondrial damage–associated molecular patterns were processed by BMMs via LAP. Moreover, depletion of mitochondrial DNA (mtDNA) in AML-derived ABs showed that it was this mtDNA that was responsible for the induction of STING signaling in BMMs. Phenotypically, we found that STING activation suppressed AML growth through a mechanism related to increased phagocytosis. In summary, we report that macrophage LAP of apoptotic debris in the AML BM microenvironment suppressed tumor growth.     

Outer Breast Quadrants Demonstrate Increased Levels of Genomic Instability

Background: Theory holds that the upper outer quadrant of the breast develops more malignancies because of increased tissue volume. This study evaluated genomic patterns of loss of heterozygosity (LOH) and allelic imbalance (AI) in non-neoplastic tissues from quadrants of diseased breasts following mastectomy to characterize relationships between genomic instability and the propensity for tumor development.Methods: Tissues from breast quadrants were collected from 21 patients with various stages of breast carcinoma. DNA was isolated from non-neoplastic tissues using standard methods and 26 chromosomal regions commonly deleted in breast cancer were examined to assess genomic instability.Results: Genomic instability was observed in breast quadrants from patients with ductal carcinomas in situ and advanced carcinomas. Levels of instability by quadrant were not predictive of primary tumor location (P = .363), but outer quadrants demonstrated significantly higher levels of genomic instability than did inner quadrants (P = .017). Marker D8S511 on chromosome 8p22– 21.3, one of the most frequently altered chromosomal regions in breast cancer, showed a significantly higher level of instability (P = .039) in outer compared with inner quadrants.Conclusions: Non-neoplastic breast tissues often harbor genetic changes that can be important to understanding the local breast environment within which cancer develops. Greater genomic instability in outer quadrants can partially explain the propensity for breast cancers to develop there, rather than simple volume-related concepts. Patterns of field cancerization in the breast appear to be complex and are not a simple function of distance from a developing tumor.     

Perspectives on the future of dissemination and implementation research in oral and craniofacial sciences

Dissemination and implementation science is a field of research that promotes the adoption and maintenance of evidence-based interventions in healthcare delivery and community settings and seeks to understand the processes by which such adoption and maintenance occur. While dissemination and implementation science is an established field in health services research, it is relatively new and making inroads in dental, oral and craniofacial research. This article summarizes the proceedings from a scientific panel on ‘Dissemination and Implementation Science for Oral and Craniofacial Health’ that was held during the international Behavioral and Social Oral Health Sciences Summit. The panelists were four experts on dissemination and implementation science in dental and non-dental academic settings in the United States and Scotland, with affiliations ranging from schools of dentistry and public health to the National Institutes of Health and a healthcare system with integrated dental services. The panel discussion addressed how dissemination and implementation science can be used to further oral health research. The narrative report presented here aims to describe the panelists' reflections and insights on their current initiatives in dissemination and implementation research to inform future research endeavors within the oral and craniofacial sciences. Specifically, this article focuses on six discussion topics: (1) how organizational determinants can serve as facilitators or barriers to the implementation of evidence-based dental practice; (2) how dentistry can ‘de-implement’ practices that are not effective; (3) how implementation science can support the delivery of evidence-based dental practice using adaptation; (4) how to get started in implementation science; (5) how the broader environment can support large-scale implementation efforts; and (6) how oral and craniofacial science is well suited for advancing dissemination and implementation research.