Synthesis and Biochemical Evaluation of 3-Phenoxy-1,4-diarylazetidin-2-ones as Tubulin-Targeting Antitumor Agents.

Structure-activity relationships for a series of 3-phenoxy-1,4-diarylazetidin-2-ones were investigated, leading to the discovery of a number of potent antiproliferative compounds, including trans-4-(3-hydroxy-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (78b) and trans-4-(3-amino-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (90b). X-ray crystallography studies indicate the potential importance of the torsional angle between the 1-phenyl "A" ring and 4-phenyl "B" ring for potent antiproliferative activity and that a trans configuration between the 3-phenoxy and 4-phenyl rings is generally optimal. These compounds displayed IC50 values of 38 and 19 nM, respectively, in MCF-7 breast cancer cells, inhibited the polymerization of isolated tubulin in vitro, disrupted the microtubular structure in MCF-7 cells as visualized by confocal microscopy, and caused G2/M arrest and apoptosis.

Beyond aggression: Androgen-receptor blockade modulates social interaction in wild meerkats.

In male vertebrates, androgens are inextricably linked to reproduction, social dominance, and aggression, often at the cost of paternal investment or prosociality. Testosterone is invoked to explain rank-related reproductive differences, but its role within a status class, particularly among subordinates, is underappreciated. Recent evidence, especially for monogamous and cooperatively breeding species, suggests broader androgenic mediation of adult social interaction.

Disseminated cutaneous Curvularia infection in an immunocompromised host; diagnostic challenges and experience with voriconazole.

An increasing spectrum and number of opportunistic fungal pathogens have been reported to cause disease in humans over the past decade. Disseminated phaeohyphomycoses caused by rare dematiaceous molds in immunocompromised patients have a high mortality rate and are increasingly reported in the literature. Early diagnosis of disseminated phaehyphomycosis is critical especially in neutropenic patients but can be hindered by the low sensitivity of fungal blood cultures and low clinical suspicion.

The Relationship Between Submental Surface Electromyography and Hyo-Laryngeal Kinematic Measures of Mendelsohn Maneuver Duration.

Purpose: The Mendelsohn Maneuver (MM) is a commonly prescribed technique that is taught to individuals with dysphagia to improve swallowing ability. Due to cost and safety concerns associated with videofluoroscopy (VFS) use, submental surface electromyography (ssEMG) is commonly used in place of VFS to train the MM in clinical and research settings. However, it is unknown whether ssEMG accurately reflects the prolonged hyo-laryngeal movements required for execution of the MM.

A TDO2-AhR signaling axis facilitates anoikis resistance and metastasis in triple-negative breast cancer.

The ability of a cancer cell to develop resistance to anoikis, a programmed cell death process triggered by substratum detachment, is a critical step in the metastatic cascade. Triple-negative breast cancers (TNBC) exhibit higher rates of metastasis after diagnosis, relative to estrogen-positive breast cancers, but while TNBC cells are relatively more resistant to anoikis, the mechanisms involved are unclear. Through gene expression and metabolomic profiling of TNBC cells in forced suspension culture, we identified a molecular pathway critical for anchorage-independent cell survival.

Combretastatins: more than just vascular targeting agents?

Several prodrugs of the naturally occurring combretastatins have undergone extensive clinical evaluation as vascular targeting agents (VTAs). Their increased selectivity toward endothelial cells together with their innate ability to rapidly induce vascular shutdown and inhibit tumor growth at doses up to 10-fold less than the maximum tolerated dose led to the clinical evaluation of combretastatins as VTAs. Tubulin is well established as the molecular target of the combretastatins and the vast majority of its synthetic derivatives.

The clathrin-binding and J-domains of GAK support the uncoating and chaperoning of clathrin by Hsc70 in the brain.

Cyclin-G-associated kinase (GAK), the ubiquitously expressed J-domain protein, is essential for the chaperoning and uncoating of clathrin that is mediated by Hsc70 (also known as HSPA8). Adjacent to the C-terminal J-domain that binds to Hsc70, GAK has a clathrin-binding domain that is linked to an N-terminal kinase domain through a PTEN-like domain. Knocking out GAK in fibroblasts caused inhibition of clathrin-dependent trafficking, which was rescued by expressing a 62-kDa fragment of GAK, comprising just the clathrin-binding and J-domains.

The role of general nuclear medicine in breast cancer.

The rising incidence of breast cancer worldwide has prompted many improvements to current care. Routine nuclear medicine is a major contributor to a full gamut of clinical studies such as early lesion detection and stratification; guiding, monitoring, and predicting response to therapy; and monitoring progression, recurrence or metastases. Developments in instrumentation such as the high-resolution dedicated breast device coupled with the diagnostic versatility of conventional cameras have reinserted nuclear medicine as a valuable tool in the broader clinical setting.

Trib3 Is Elevated in Parkinson's Disease and Mediates Death in Parkinson's Disease Models.

Unlabelled: Parkinson's disease (PD) is characterized by the progressive loss of select neuronal populations, but the prodeath genes mediating the neurodegenerative processes remain to be fully elucidated. Trib3 (tribbles pseudokinase 3) is a stress-induced gene with proapoptotic activity that was previously described as highly activated at the transcriptional level in a 6-hydroxydopamine (6-OHDA) cellular model of PD. Here, we report that Trib3 immunostaining is elevated in dopaminergic neurons of the substantia nigra pars compacta (SNpc) of human PD patients.

Taurine supplementation preserves hypothalamic leptin action in normal and protein-restricted mice fed on a high-fat diet.

Malnutrition programs the neuroendocrine axis by disruption of food-intake control, leading to obesity. Taurine (Tau) is neuroprotective and improves anorexigenic actions in the hypothalamus. We evaluated the hypothalamic gene-expression profile and food-intake control in protein-restricted mice submitted to a high-fat diet (HFD) and Tau supplementation.

Impact of Quality Improvement Educational Interventions on Documented Adherence to Quality Measures for Adults with Crohn's Disease.

Background: In recent years, leading organizations in inflammatory bowel disease (IBD) have developed quality measures for the care of adults with Crohn's disease or ulcerative colitis. We used chart audits to assess the impact of quality improvement educational activities on documented adherence to Physician Quality Reporting System measures for IBD.

Methods: Twenty community-based gastroenterologists were recruited to participate in baseline chart audits (n = 200), a series of 4 accredited educational activities with feedback, and follow-up chart audits (n = 200).

Specific downregulation of hippocampal ATF4 reveals a necessary role in synaptic plasticity and memory.

Prior studies suggested that the transcription factor ATF4 negatively regulates synaptic plastic and memory. By contrast, we provide evidence from direct in vitro and in vivo knockdown of ATF4 in rodent hippocampal neurons and from ATF4-null mice that implicate ATF4 as essential for normal synaptic plasticity and memory. In particular, hippocampal ATF4 downregulation produces deficits in long-term spatial memory and behavioral flexibility without affecting associative memory or anxiety-like behavior.

Two-step fabrication technique of gold tips for use in point-contact spectroscopy.

For a successful point-contact spectroscopy (PCS) measurement, metallic tips of proper shape and smoothness are essential to ensure the ballistic nature of a point-contact junction. Until recently, the fabrication of Au tips suitable for use in point-contact spectroscopy has remained more of an art involving a trial and error method rather than an automated scientific process. To address these issues, we have developed a technique with which one can prepare high quality Au tips reproducibly and systematically.

Access to mental health care among women Veterans: is VA meeting women's needs?

Background: Patient-centered access to mental health describes the fit between patient needs and resources of the system. To date, little data are available to guide implementation of services to women veterans, an underrepresented minority within Department of Veteran Affairs (VA) health care. The current study examines access to mental health care among women veterans, and identifies gender-related indicators of perceived access to mental health care.

Zoon's balanitis.

Zoon's balanitis, is typically found in older, uncircumcised males and can be asymptomatic, pruritic, or cause dysuria. The typical appearance is erythematous, discrete, moist plaques with a "cayenne pepper" speckled appearance and an orange hue on the glans penis and sometimes prepuce, which may display "kissing lesions" on areas that are in direct contact with the lesions.These may eventually erode and leave a "rusty stain".

When push comes to shove: unravelling the mechanism and scope of nonemissive meso-unsaturated BODIPY dyes.

We report herein spectroscopy and computational results that illustrate an efficient intramolecular deactivation pathway for meso-unsaturated boron-dipyrromethene (BODIPY) dyes in their singlet excited state. Our results show that the mechanism hinges on the structural flexibility imparted by the boron atom and on the energetic stabilization conferred by extending the conjugation into the meso substituent, which is otherwise unconjugated in the ground state. Following photoexcitation, rotation along the dihedral angle of the meso-unsaturated group results in its conjugation at the expense of shifting one pyrrole moiety in dipyrrin out of the plane.

The Value of Single-photon Emission Computed Tomography/Computed Tomography in the Evaluation of Herniation Pits.

The potential role of the nuclear medicine diagnostic bone scan in identifying herniation pits of the femoral neck is yet to be adequately described. The following cases show incidental findings of subcortical cavities of the femoral neck detected on bone scans. These findings highlight the potential role of the bone scan as a useful imaging modality in identifying and stratifying herniation pits based on physiology, particularly with the addition of single-photon emission computed tomography/computed tomography to the armamentarium.

The multivesicular body is the major internal site of prion conversion.

The conversion of the properly folded prion protein, PrPc, to its misfolded amyloid form, PrPsc, occurs as the two proteins traffic along the endocytic pathway and PrPc is exposed to PrPsc. To determine the specific site of prion conversion, we knocked down various proteins in the endocytic pathway including Rab7a, Tsg101 and Hrs (also known as HGS). PrPsc was markedly reduced in two chronically infected cell lines by preventing the maturation of the multivesicular body, a process that begins in the early endosome and ends with the sorting of cargo to the lysosome.

Theory of point contact spectroscopy in correlated materials.

We developed a microscopic theory for the point-contact conductance between a metallic electrode and a strongly correlated material using the nonequilibrium Schwinger-Kadanoff-Baym-Keldysh formalism. We explicitly show that, in the classical limit, contact size shorter than the scattering length of the system, the microscopic model can be reduced to an effective model with transfer matrix elements that conserve in-plane momentum. We found that the conductance dI/dV is proportional to the effective density of states, that is, the integrated single-particle spectral function A(ω = eV) over the whole Brillouin zone.

Pyridoxamine dihydrochloride in diabetic nephropathy (PIONEER-CSG-17): lessons learned from a pilot study.

Background/aims: Pyridoxamine dihydrochloride (Pyridorin™) blocks pathogenic oxidative pathways in the progression of diabetic nephropathy. The pyridoxamine pilot study was designed to test entry criteria and outcomes. Subjects had SCr 1.

A Dedicated Breast Positron Emission Tomography Scanner: Proof of Concept.

Purpose: This study developed and tested a novel scanner constructed for dedicated positron emission tomography (PET) of the breast. The breast PET (B-PET) scanner is designed with two opposing detectors using curve plate NaI(Tl) detectors to achieve a combination of high spatial resolution and energy resolution.

Methods: Phantom and clinical studies (n = 20) with F-fluorodeoxyglucose were carried out on the whole-body Philips Allegro scanner and the B-PET scanner.

Novel Radiopharmaceuticals in Cardiovascular Medicine: Present and Future.

Advancements in molecular medicine technology have allowed the development of innovative and better radiopharmaceuticals to augment or replace the existing ones, allowing the acquisition of higher-quality and detailed diagnostic information and accuracy. They build on the strengths of the existing radiotracers or remove their shortcomings, thus bringing them closer to the ideal. Given the discovery of more novel molecules, it is now possible that processes in the human body indicative of predisease stage can be imaged, allowing for appropriate interventions earlier-preventing the development of late stage disease, preventing morbidity and mortality, and reducing the burden on the national health care system.

Internationalization, Mobilization and Social Media in Higher Education.

Although there have been significant advances in instrumentation and technology across the medical radiation sciences that changed practice and outcomes, higher education has also seen advances that challenged service delivery. This article provides an insight into higher education trends and collaborative efforts to afford leadership in those domains. Arguably, the greatest pressure in the current higher education environment is the ability to match student and institutional expectations against sustainable, cost-effective innovation.