Generating Highly Specific Spectra and Identifying Thermal Decomposition Products via Gas Chromatography / Vacuum Ultraviolet Spectroscopy (GC/VUV): Application to Nitrate Ester Explosives

Gas chromatography/mass spectrometry (GC/MS) is a "workhorse" instrument for chemical analysis, but it can be limited in its ability to differentiate structurally similar compounds. The coupling of GC to vacuum ultraviolet (VUV) spectroscopy is a recently developed technique with the potential for increased detection specificity. To date, GC/VUV has been demonstrated in the analysis of volatile organic compounds, petroleum products, aroma compounds, pharmaceuticals, illegal drugs, and lipids. This paper is the first to report on the utility of GC/VUV for explosives analysis in general, and the first to report on thermal degradation within the VUV cell and its analytical utility. The general figures of merit and performance of GC/VUV were evaluated with authentic standards of nitrate ester explosives (e.g., nitroglycerine (NG), ethylene glycol dinitrate (EGDN), pentaerythritol tetranitrate (PETN), and erythritol tetranitrate (ETN)). In addition, the explosive analytes were thermally degraded in the VUV cell, yielding reproducible, complex and characteristic mixtures of gas phase products (e.g., nitric oxide, carbon monoxide, and formaldehyde). The relative amounts of the degradation products were estimated via spectral subtraction of library spectra. Lastly, GC/VUV was used to analyze milligram quantities of intact and burned samples of double-base smokeless powders containing nitroglycerine, diphenylamine, ethyl centralite, and dibutylphthalat

Real-Time and Wireless Assessment of Adherence to Antiretroviral Therapy With Co-Encapsulated Ingestion Sensor in HIV-Infected Patients: A Pilot Study.

Adherence with antiretroviral therapy is important for preventing disease progression and HIV transmission. The co-encapsulated pill sensor system sends a signal through a cutaneous patch and allows real-time monitoring of pill ingestion. A 16-week pilot study used a sensor system in 15 HIV-infected individuals with real-time monitoring of pill-taking with a personalized short message system text. System acceptability was assessed by survey at weeks 4, 8, 12, and 16. Follow-up occurred in 80% of subjects through 8 weeks. The system effectively collected measures of pill ingestion, which triggered text message reminders. Only 2 of 14 participants stated that co-encapsulated pills were "unable to take" or "poorly tolerated." At least 75% of respondents stated at each visit that the patch was very or somewhat comfortable. With regard to text message reminders, only 10-15% of the participants at any visit did not find the messages to be helpful. Larger studies will define the utility of this system to assess antiretroviral adherence relative to standard measures

Pediatric collaborative care outcomes in a regional model

BackgroundDespite the movement toward hospital-based medical centers acquiring pediatric primary care offices, many primary care pediatricians still work in small, independent practices. To expand mental healthcare access, service delivery models must consider primary care practice needs and regionally available resources.ObjectiveThis report describes the implementation and evaluation of the Mood, Anxiety, ADHD Collaborative Care (MAACC) program over a 4 years period. MAACC. MAACC engaged 97 pediatric primary care clinicians across 39 practices in mental health training and supported the treatment of referred patients through a collaborative care model. To support psychosocial treatment needs, we built a child community therapy referral network of 213 licensed psychotherapy providers.MethodsData were collected on service delivery patterns (e.g., referrals, treatment use, and attrition) and patient outcomes. Measures included parent and children and adolescents PROMIS anxiety and depression short forms and the Parent NICHQ Vanderbilt.ResultsSix hundred ninety-six children and adolescents aged 6–18 were evaluated and provided treatment recommendations. Anxiety disorders were the most common diagnosis (45.4%), followed by ADHD (30.7%) and mood disorder (17%). For children and adolescents with an anxiety or mood disorder, significant improvement was observed from baseline to any initial follow-up and from baseline to 6, 12-, and 18 weeks on children and adolescents and parent measures of anxiety and depression. For children and adolescents with ADHD, significant improvement was observed from baseline to any initial follow-up measure and at 6 and 18 weeks on parent-reported inattentive symptoms. Significant differences in treatment outcomes were identified for children and adolescents with anxiety receiving psychotherapy alone and medication management and psychotherapy.ConclusionMAACC utilization and patient outcomes suggest that real-world collaborative care can effectively provide high-quality care while cultivating increased primary care treatment capacity and building on existing community resources

Novel protein kinase D inhibitors cause potent arrest in prostate cancer cell growth and motility

<p>Abstract</p> <p>Background</p> <p>Protein kinase D (PKD) has been implicated in a wide range of cellular processes and pathological conditions including cancer. However, targeting PKD therapeutically and dissecting PKD-mediated cellular responses remains difficult due to lack of a potent and selective inhibitor. Previously, we identified a novel pan-PKD inhibitor, CID755673, with potency in the upper nanomolar range and high selectivity for PKD. In an effort to further enhance its selectivity and potency for potential <it>in vivo </it>application, small molecule analogs of CID755673 were generated by modifying both the core structure and side-chains.</p> <p>Results</p> <p>After initial activity screening, five analogs with equal or greater potencies as CID755673 were chosen for further analysis: kb-NB142-70, kb-NB165-09, kb-NB165-31, kb-NB165-92, and kb-NB184-02. Our data showed that modifications to the aromatic core structure in particular significantly increased potency while retaining high specificity for PKD. When tested in prostate cancer cells, all compounds inhibited PMA-induced autophosphorylation of PKD1, with kb-NB142-70 being most active. Importantly, these analogs caused a dramatic arrest in cell proliferation accompanying elevated cytotoxicity when applied to prostate cancer cells. Cell migration and invasion were also inhibited by these analogs with varying potencies that correlated to their cellular activity.</p> <p>Conclusions</p> <p>Throughout the battery of experiments, the compounds kb-NB142-70 and kb-NB165-09 emerged as the most potent and specific analogs <it>in vitro </it>and in cells. These compounds are undergoing further testing for their effectiveness as pharmacological tools for dissecting PKD function and as potential anti-cancer agents in the treatment of prostate cancer.</p

The integrin αvβ8 mediates epithelial homeostasis through MT1-MMP–dependent activation of TGF-β1

Întegrins, matrix metalloproteases (MMPs), and the cytokine TGF-β have each been implicated in homeostatic cell behaviors such as cell growth and matrix remodeling. TGF-β exists mainly in a latent state, and a major point of homeostatic control is the activation of TGF-β. Because the latent domain of TGF-β1 possesses an integrin binding motif (RGD), integrins have the potential to sequester latent TGF-β (SLC) to the cell surface where TGF-β activation could be locally controlled. Here, we show that SLC binds to αvβ8, an integrin expressed by normal epithelial and neuronal cells in vivo. This binding results in the membrane type 1 (MT1)-MMP–dependent release of active TGF-β, which leads to autocrine and paracrine effects on cell growth and matrix production. These data elucidate a novel mechanism of cellular homeostasis achieved through the coordination of the activities of members of three major gene families involved in cell–matrix interactions

Vorinostat Eliminates Multicellular Resistance of Mesothelioma 3D Spheroids via Restoration of Noxa Expression

When grown in 3D cultures as spheroids, mesothelioma cells acquire a multicellular resistance to apoptosis that resembles that of solid tumors. We have previously found that resistance to the proteasome inhibitor bortezomib in 3D can be explained by a lack of upregulation of Noxa, the pro-apoptotic BH3 sensitizer that acts via displacement of the Bak/Bax-activator BH3-only protein, Bim. We hypothesized that the histone deacetylase inhibitor vorinostat might reverse this block to Noxa upregulation in 3D. Indeed, we found that vorinostat effectively restored upregulation of Noxa protein and message and abolished multicellular resistance to bortezomib in the 3D spheroids. The ability of vorinostat to reverse resistance was ablated by knockdown of Noxa or Bim, confirming the essential role of the Noxa/Bim axis in the response to vorinostat. Addition of vorinostat similarly increased the apoptotic response to bortezomib in another 3D model, the tumor fragment spheroid, which is grown from human mesothelioma ex vivo. In addition to its benefit when used with bortezomib, vorinostat also enhanced the response to cisplatin plus pemetrexed, as shown in both 3D models. Our results using clinically relevant 3D models show that the manipulation of the core apoptotic repertoire may improve the chemosensitivity of mesothelioma. Whereas neither vorinostat nor bortezomib alone has been clinically effective in mesothelioma, vorinostat may undermine chemoresistance to bortezomib and to other therapies thereby providing a rationale for combinatorial strategies

An Improved Transit Measurement for a 2.4 R⊕ Planet Orbiting A Bright Mid-M Dwarf K2–28

We present a new Spitzer transit observation of K2–28b, a sub-Neptune (Rp = 2.45 ± 0.28 R⊕) orbiting a relatively bright (V_(mag) = 16.06, K_(mag) = 10.75) metal-rich M4 dwarf (EPIC 206318379). This star is one of only seven with masses less than 0.2 M⊙ known to host transiting planets, and the planet appears to be a slightly smaller analogue of GJ 1214b (2.85 ± 0.20 R⊕). Our new Spitzerobservations were taken two years after the original K2 discovery data and have a significantly higher cadence, allowing us to derive improved estimates for this planet's radius, semimajor axis, and orbital period, which greatly reduce the uncertainty in the prediction of near future transit times for the James Webb Space Telescope (JWST) observations. We also evaluate the system's suitability for atmospheric characterization with JWST and find that it is currently the only small (<3 R⊕) and cool (<600 K) planet aside from GJ 1214b with a potentially detectable secondary eclipse. We also note that this system is a favorable target for near-infrared radial velocity instruments on larger telescopes (e.g., the Habitable Planet Finder on the Hobby–Eberly Telescope), making it one of only a handful of small, cool planets accessible with this technique. Finally, we compare our results with the simulated catalog of the Transiting Exoplanet Survey Satellite (TESS) and find K2–28b to be representative of the kind of mid-M systems that should be detectable in the TESS sample