Holistic evaluation of a machine learning-based timing calibration for PET detectors under varying data sparsity.

Modern PET scanners offer precise TOF information, improving the SNR of the reconstructed images. Timing calibrations are performed to reduce the worsening effects of the system components and provide valuable TOF information. Traditional calibration procedures often provide static or linear corrections, with the drawback that higher-order skews or event-to-event corrections are not addressed.

Augmented Whole-Body Scanning via Magnifying PET.

A novel technique, called augmented whole-body scanning via magnifying PET (AWSM-PET), that improves the sensitivity and lesion detectability of a PET scanner for whole-body imaging is proposed and evaluated. A Siemens Biograph Vision PET/CT scanner equipped with one or two high-resolution panel-detectors was simulated to study the effectiveness of AWSM-PET technology. The detector panels are located immediately outside the scanner's axial field-of-view (FOV).

A Putative Bacterial ABC Transporter Circumvents the Essentiality of Signal Peptidase.

Unlabelled: The type I signal peptidase of Staphylococcus aureus, SpsB, is an attractive antibacterial target because it is essential for viability and extracellularly accessible. We synthesized compound 103, a novel arylomycin-derived inhibitor of SpsB with significant potency against various clinical S. aureus strains (MIC of ~1 µg/ml).

Synthesis and evaluation of a series of 4-azaindole-containing p21-activated kinase-1 inhibitors.

A series of 4-azaindole-containing p21-activated kinase-1 (PAK1) inhibitors was prepared with the goal of improving physicochemical properties relative to an indole starting point. Indole 1 represented an attractive, non-basic scaffold with good PAK1 affinity and cellular potency but was compromised by high lipophilicity (clogD=4.4).

Structure-Guided Design of Group I Selective p21-Activated Kinase Inhibitors.

The p21-activated kinases (PAKs) play important roles in cytoskeletal organization, cellular morphogenesis, and survival and have generated significant attention as potential therapeutic targets for cancer. Following a high-throughput screen, we identified an aminopyrazole scaffold-based series that was optimized to yield group I selective PAK inhibitors. A structure-based design effort aimed at targeting the ribose pocket for both potency and selectivity led to much-improved group I vs II selectivity.

Message framing for health: moderation by perceived susceptibility and motivational orientation in a diverse sample of Americans.

Objective: The present study examined how gain- and loss-framed informational videos about oral health influence self-reported flossing behavior over a 6-month period, as well as the roles of perceived susceptibility to oral health problems and approach/avoidance motivational orientation in moderating these effects.

Method: An age and ethnically diverse sample of 855 American adults were randomized to receive no health message, or either a gain-framed or loss-framed video presented on the Internet. Self-reported flossing was assessed longitudinally at 2 and 6 months.

Back pocket flexibility provides group II p21-activated kinase (PAK) selectivity for type I 1/2 kinase inhibitors.

Structure-based methods were used to design a potent and highly selective group II p21-activated kinase (PAK) inhibitor with a novel binding mode, compound 17. Hydrophobic interactions within a lipophilic pocket past the methionine gatekeeper of group II PAKs approached by these type I 1/2 binders were found to be important for improving potency. A structure-based hypothesis and strategy for achieving selectivity over group I PAKs, and the broad kinome, based on unique flexibility of this lipophilic pocket, is presented.

Histone deacetylase (HDAC) inhibitor kinetic rate constants correlate with cellular histone acetylation but not transcription and cell viability.

Histone deacetylases (HDACs) are critical in the control of gene expression, and dysregulation of their activity has been implicated in a broad range of diseases, including cancer, cardiovascular, and neurological diseases. HDAC inhibitors (HDACi) employing different zinc chelating functionalities such as hydroxamic acids and benzamides have shown promising results in cancer therapy. Although it has also been suggested that HDACi with increased isozyme selectivity and potency may broaden their clinical utility and minimize side effects, the translation of this idea to the clinic remains to be investigated.

A whole cell assay to measure caspase-6 activity by detecting cleavage of lamin A/C.

Caspase-6 is a cysteinyl protease implicated in neurodegenerative conditions including Alzheimer's and Huntington's disease making it an attractive target for therapeutic intervention. A greater understanding of the role of caspase-6 in disease has been hampered by a lack of suitable cellular assays capable of specifically detecting caspase-6 activity in an intact cell environment. This is mainly due to the use of commercially available peptide substrates and inhibitors which lack the required specificity to facilitate development of this type of assay.

Case studies of minimizing nonspecific inhibitors in HTS campaigns that use assay-ready plates.

Identifying chemical lead matter by high-throughput screening (HTS) has been a common practice in early stage drug discovery. Evolution of small-molecule library composition to include more drug-like molecules with desirable physical chemical properties combined with improving assay technologies has vastly enhanced the capability of HTS. However, HTS campaigns can still be plagued by false positives arising from nonspecific inhibitors.

Intraoperative gamma imaging of axillary sentinel lymph nodes in breast cancer patients.

Sentinel lymph node (SLN) biopsy is now standard practice in the management of many breast cancer patients. Localization protocols vary in complexity and rates of success. The least complex involve only intraoperative gamma counting of radiotracer uptake or intraoperative visualization of blue-dye uptake; the most complex involve preoperative gamma imaging, intraoperative counting and intraoperative dye visualization.

Tc-99m pyrophosphate imaging of poloxamer-treated electroporated skeletal muscle in an in vivo rat model.

Objective: This study investigates whether (99m)Tc pyrophosphate (PYP) imaging provides a quantitative non-invasive assessment of the extent of electroporation injury, and of the effect of poloxamer in vivo on electroporated skeletal muscle.

Methods: High-voltage electrical shock was used to produce electroporation injury in an anesthetized rat's hind limb. In each experiment, the injured limb was treated intravenously by either poloxamer-188, dextran, or saline, and subsequently imaged with (99m)Tc PYP.

A novel high-throughput screening format to identify inhibitors of secreted acid sphingomyelinase.

Secreted extracellular acid sphingomyelinase (sASM) activity has been suggested to promote atherosclerosis by enhancing subendothelial aggregation and retention of low-density lipoprotein (LDL) with resultant foam cell formation. Compounds that inhibit sASM activity, at neutral pH, may prevent lipid retention and thus would be expected to be anti-atherosclerotic. With the goal of identifying novel compounds that inhibit sASM at pH 7.

A model of the acid sphingomyelinase phosphoesterase domain based on its remote structural homolog purple acid phosphatase.

Sequence profile and fold recognition methods identified mammalian purple acid phosphatase (PAP), a member of a dimetal-containing phosphoesterase (DMP) family, as a remote homolog of human acid sphingomyelinase (ASM). A model of the phosphoesterase domain of ASM was built based on its predicted secondary structure and the metal-coordinating residues of PAP. Due to the low sequence identity between ASM and PAP (approximately 15%), the highest degree of confidence in the model resides in the metal-binding motifs.

A pictorial review of coronary artery anatomy on spiral CT.

Coronary artery calcification quantification (scoring) has been done with electron beam CT (EBCT), but is now being done with spiral or helical CT. Many radiologists and cardiologists who do not have EBCT but do have access to spiral CT will now be able to do coronary artery calcification scoring, and will now need to know the spiral CT appearance of the coronary artery anatomy. This pictorial review will demonstrate the anatomy needed for coronary artery calcium scoring.

Preliminary assessment of extrastriatal dopamine D-2 receptor binding in the rodent and nonhuman primate brains using the high affinity radioligand, 18F-fallypride.

We have identified the value of 18F-fallypride [(S)-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-[18F]fluoropropyl)-2, 3-dimethoxybenzamide], as a dopamine D-2 receptor radiotracer for the study of striatal and extrastriatal receptors. Fallypride exhibits high affinities for D-2 and D-3 subtypes and low affinity for D-4 (3H-spiperone IC50s: D-2 = 0.05 nM [rat striata], D-3 = 0.

Differential effects of IFN-beta1b on the proliferation of human vascular smooth muscle and endothelial cells.

The effect of human interferon (IFN)-beta1b (Betaseron) on the proliferation of cultured human vascular smooth muscle and endothelial cells was tested in vitro. IFN-beta1b inhibited thymidine incorporation and growth of primary cultures of human aortic and coronary artery smooth muscle in a concentration-dependent manner. The same concentrations of IFN-beta1b did not inhibit thymidine incorporation or growth of primary cultures of human aortic or coronary artery endothelial cells.

Human vascular endothelial cells are a rich and regulatable source of secretory sphingomyelinase. Implications for early atherogenesis and ceramide-mediated cell signaling.

We recently reported that macrophages and fibroblasts secrete a Zn2+-dependent sphingomyelinase (S-SMase), which, like lysosomal SMase, is a product of the acid SMase gene. S-SMase may cause subendothelial retention and aggregation of lipoproteins during atherogenesis, and the acid SMase gene has been implicated in ceramide-mediated cell signaling, especially involving apoptosis of endothelial cells. Because of the central importance of the endothelium in each of these processes, we now sought to examine the secretion and regulation of S-SMase by vascular endothelial cells.

The 1995 Lindberg Award. Nonthermally mediated muscle injury and necrosis in electrical trauma.

Joule heating has long been considered the principal component of tissue damage in electrical injury. Recent studies suggest electroporation, a nonthermally mediated mechanism of cell membrane damage, is also a factor. We investigated whether electroporation-mediated muscle necrosis can occur in vivo without significant Joule heating.

A miniature gamma camera.

We have described a mobile miniature-gamma-camera system for use in electrical trauma units and have presented images and imaging characteristics of a prototype system. The system has as its principal component a miniature gamma camera based on a PSPMT. The camera is 92 mm x 92 mm x 190 mm in size, weighs 5 kg, has a 48 mm x 48 mm field of view, and has an intrinsic resolution of approximately 3 mm FWHM and 6 mm FWTM.

Immediate and long-term results of carotid endarterectomy for asymptomatic high-grade stenosis.

We examined the operative risks and long-term results of carotid endarterectomy for asymptomatic patients in terms of stroke, death, and recurrent stenosis. The results of a nonrandomized study with a follow-up of 1 to 104 months (mean 46 months) is reported. A tertiary referral center served as the setting for this report.