We introduce a new high-temperature adsorption calorimeter that approaches the ideal limit of a heat detector whereby the signal at any time is proportional to the heat power being delivered to the ...sample and prove its sensitivity for measuring pulse-to-pulse heats of half-reactions during atomic layer deposition (ALD) at 400 K. The heat dynamics of amorphous Al2O3 growth via sequential self-limiting surface reaction of trimethylaluminum (TMA) and H2O is clearly resolved. Calibration enables quantitation of the exothermic TMA and H2O half-reactions with high precision, −343 kJ/mol TMA and −251 kJ/mol H2O, respectively. A time resolution better than 1 ms is demonstrated, allowing for the deconvolution of at least two distinct surface reactions during TMA microdosing. It is further demonstrated that this method can provide the heat of reaction versus extent of reaction during each precursor’s half-reaction, thus providing even richer mechanistic information on the surface processes involved. The broad applicability of this novel calorimeter is demonstrated through excellent signal-to-noise ratios of less exothermic ALD half-reactions to produce TiO2 and MnO.
We introduce and propose zircon M257 as a future reference material for the determination of zircon U‐Pb ages by means of secondary ion mass spectrometry. This light brownish, flawless, cut gemstone ...specimen from Sri Lanka weighed 5.14 g (25.7 carats). Zircon M257 has TIMS‐determined, mean isotopic ratios (2s uncertainties) of 0.09100 ± 0.00003 for 206pb/238U and 0.7392 ± 0.0003 for 207pb/235U. Its 206pb/238U age is 561.3 ± 0.3 Ma (unweighted mean, uncertainty quoted at the 95% confidence level); the U‐Pb system is concordant within uncertainty of decay constants. Zircon M257 contains ∼ 840 μg g−1 U (Th/U ∼ 0.27). The material exhibits remarkably low heterogeneity, with a virtual absence of any internal textures even in cathodoluminescence images. The uniform, moderate degree of radiation damage (estimated from the expansion of unit‐cell parameters, broadening of Raman spectral parameters and density) corresponds well, within the “Sri Lankan trends”, with actinide concentrations, U‐Pb age, and the calculated alpha fluence of 1.66 × 1018 g−1. This, and a (U+Th)/He age of 419 ± 9 Ma (2s), enables us to exclude any unusual thermal history or heat treatment, which could potentially have affected the retention of radiogenic Pb. The oxygen isotope ratio of this zircon is 13.9%o VSMOW suggesting a metamorphic genesis in a marble or calc‐silicate skarn.
Nous présentons et proposons à la communauté le zircon M257 qui pourrait devenir un matériau de référence pour la détermination des âges U‐Pb sur zircon par spectrométrie de masse à ions secondaires (SIMS). Ce spécimen scié d'une gemme brun clair, sans defauts, provenant du Sri Lanka, pèse 5.14 g (25.7 carats). Les moyennes des rapports isotopiques (et les incertitudes associées 2s) mesurées par TIMS sur ce zircon M257 sont 0.09100 ± 0.00003 en 206pb/238U et 0.7392 ± 0.0003 en 207pb/235U. Son âge 206pb/238U est de 561.3 ± 0.3 Ma (moyenne non pondérée, incertitude: 95% intervalle de confiance); le système U‐Pb y est concordant, aux erreurs sur les constantes de désintégration près. Le zircon M257 contient ∼ 840 μg g−1 U (Th/U ∼ 0.27). Ce matériel montre de très faibles hétérogénéités, avec une quasi absence de textures internes, même a I'examen par cathodoluminescence. Le degrê de dommage lié aux radiations (estimé par I'expansion des paramètres de la cellule unitaire, I'élargissement des paramètres des spectres Raman et la densité) est modéré et uniforme. II se corrèle bien, (sur I'alignement “Sri Lanka”) avec les concentrations en actinides, I'âge U‐Pb et la fluence calculée de 1.66 × 1018 g−1 Ceci, coupléà son âge (U+Th)/He de 419 ± 9 Ma (2s), nous permet d'exclure I'existence d'événement thermique passé, ou de traitement par la chaleur, qui aurait potentiellement pu affecter le processus de rétention de Pb radiogénique. Le rapport isotopique de I'oxygène de ce zircon est 13.9%o VSMOW, suggérant une génèse par métamorphisme, au sein d'un marbre ou d'un skarn calco‐silicaté.
Pediatric brain cancer medulloblastoma (MB) standard-of-care results in numerous comorbidities. MB is comprised of distinct molecular subgroups. Group 3 molecular subgroup patients have the highest ...relapse rates and after standard-of-care have a 20% survival. Group 3 tumors have high expression of GABRA5, which codes for the α5 subunit of the γ-aminobutyric acid type A receptor (GABA
R). We are advancing a therapeutic approach for group 3 based on GABA
R modulation using benzodiazepine-derivatives.
We performed analysis of GABR and MYC expression in MB tumors and used molecular, cell biological, and whole-cell electrophysiology approaches to establish presence of a functional 'druggable' GABA
R in group 3 cells.
Analysis of expression of 763 MB tumors reveals that group 3 tumors share high subgroup-specific and correlative expression of GABR genes, which code for GABA
R subunits α5, β3 and γ2 and 3. There are ~ 1000 functional α5-GABA
Rs per group 3 patient-derived cell that mediate a basal chloride-anion efflux of 2 × 10
ions/s. Benzodiazepines, designed to prefer α5-GABA
R, impair group 3 cell viability by enhancing chloride-anion efflux with subtle changes in their structure having significant impact on potency. A potent, non-toxic benzodiazepine ('KRM-II-08') binds to the α5-GABA
R (0.8 µM EC
) enhancing a chloride-anion efflux that induces mitochondrial membrane depolarization and in response, TP53 upregulation and p53, constitutively phosphorylated at S392, cytoplasmic localization. This correlates with pro-apoptotic Bcl-2-associated death promoter protein localization.
GABRA5 expression can serve as a diagnostic biomarker for group 3 tumors, while α5-GABA
R is a therapeutic target for benzodiazepine binding, enhancing an ion imbalance that induces apoptosis.
Monocytes/macrophages are prominent in atherosclerotic plaques where the vascular remodeling and plaque rupture may be influenced by the lipids and cytokines at these sites. Therefore, we evaluated ...the effects of factors found within the vascular wall, such as cytokines, oxidized low‐density lipoprotein (ox‐LDL), low‐density lipoprotein (LDL), and high‐density lipoprotein (HDL), on monocyte‐derived matrix metalloproteinase‐1 (MMP‐1) and ‐9 (MMP‐9) and tissue inhibitor of metalloproteinases‐1 (TIMP‐1). ox‐LDL, LDL, and HDL alone had no effect on MMP‐1, MMP‐9, or TIMP‐1 production. However, in the presence of tumor necrosis factor (TNF)‐α and GM‐CSF, ox‐LDL enhanced MMP‐1 significantly by two‐ to threefold, increased MMP‐9 slightly, and had no effect on TIMP‐1 production. In contrast, HDL suppressed the induction of MMP‐1 by TNF‐α and GM‐CSF as well as the ox‐LDL‐mediated increase in MMP‐1 production. The enhancement of MMP‐1 production by ox‐LDL occurred through, in part, a prostaglandin E2 (PGE2)‐dependent pathway as indomethacin suppressed and PGE2 restored MMP‐1 production. This conclusion was supported further by ox‐LDL‐mediated increases in PGE2 and cyclooxygenase‐2 (COX‐2) production. These data suggest that the interaction of primary monocytes with ox‐LDL and proinflammatory cytokines may contribute to vascular remodeling and plaque rupture.
Purpose
Pediatric brain cancer medulloblastoma (MB) standard-of-care results in numerous comorbidities. MB is comprised of distinct molecular subgroups. Group 3 molecular subgroup patients have the ...highest relapse rates and after standard-of-care have a 20% survival. Group 3 tumors have high expression of
GABRA5
, which codes for the α5 subunit of the γ-aminobutyric acid type A receptor (GABA
A
R). We are advancing a therapeutic approach for group 3 based on GABA
A
R modulation using benzodiazepine-derivatives.
Methods
We performed analysis of
GABR
and
MYC
expression in MB tumors and used molecular, cell biological, and whole-cell electrophysiology approaches to establish presence of a functional ‘druggable’ GABA
A
R in group 3 cells.
Results
Analysis of expression of 763 MB tumors reveals that group 3 tumors share high subgroup-specific and correlative expression of
GABR
genes, which code for GABA
A
R subunits α5, β3 and γ2 and 3. There are ~ 1000 functional α5-GABA
A
Rs per group 3 patient-derived cell that mediate a basal chloride-anion efflux of 2 × 10
9
ions/s. Benzodiazepines, designed to prefer α5-GABA
A
R, impair group 3 cell viability by enhancing chloride-anion efflux with subtle changes in their structure having significant impact on potency. A potent, non-toxic benzodiazepine (‘KRM-II-08’) binds to the α5-GABA
A
R (0.8 µM EC
50
) enhancing a chloride-anion efflux that induces mitochondrial membrane depolarization and in response,
TP53
upregulation and p53, constitutively phosphorylated at S392, cytoplasmic localization. This correlates with pro-apoptotic Bcl-2-associated death promoter protein localization.
Conclusion
GABRA5
expression can serve as a diagnostic biomarker for group 3 tumors, while α5-GABA
A
R is a therapeutic target for benzodiazepine binding, enhancing an ion imbalance that induces apoptosis.
Abstract
Pediatric brain cancer medulloblastoma standard-of-care results in numerous comorbidities. Medulloblastoma is comprised of four molecular subgroups. Group 3 subgroup patients have the ...highest relapse rates and 20% survival after standard-of-care. Group 3 tumors have high expression of GABRA5, which codes for the α5 subunit of the γ-aminobutyric acid type A receptor (GABAAR). We are advancing a therapeutic approach for group 3 based on GABAAR modulation using benzodiazepine-derivatives. We performed analysis of GABR and MYC expression in medulloblastoma tumors and used molecular, cell biological, and whole-cell electrophysiology approaches to establish presence of a functional ‘druggable’ GABAAR in group 3 cells. Analysis of expression of 763 medulloblastoma tumors reveals that group 3 tumors share high subgroup-specific and correlative expression of GABR genes, which code for GABAAR subunits α5, β3 and γ2 and 3. There are ~1000 functional α5-GABAARs per group 3 patient-derived cell that mediate a basal chloride-anion efflux of 2x109 ions/sec. Benzodiazepines, designed to prefer α5-GABAAR, impair group 3 cell viability by enhancing chloride-anion efflux with subtle changes in their structure having significant impact on potency. A potent, non-toxic benzodiazepine (‘KRM-II-08’) binds to the α5-GABAAR (0.8 μM EC50) enhancing a chloride-anion efflux that induces mitochondrial membrane depolarization and in response, TP53 upregulation and p53, constitutively phosphorylated at S392, cytoplasmic localization. This correlates with pro-apoptotic Bcl-2-associated death promoter (BAD) protein localization. GABR expression can serve as a diagnostic biomarker for group 3 tumors, while α5-GABAAR is a therapeutic target for benzodiazepine binding, enhancing an ion imbalance that induces apoptosis.
Citation Format: Laura Kallay, Havva Keskin, Alexandra Ross, Manali Rupji, Olivia A. Moody, Xin Wang, Guanguan Li, Taukir Ahmed, Farjana Rashid, Michael Rajesh Stephen, Kirsten A. Cottrill, Austin Nuckois, Maxwell Xu, Deborah E. Martinson, Frank Tranghese, Yanxin Pei, James M. Cook, Jeanne Kowalski, Michael D. Taylor, Andrew Jenkins, Daniel Pomeranz Krummel, Soma Sengupta. Modulating native GABAA receptors in medulloblastoma with positive allosteric benzodiazepine-derivatives induces cell death abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2623.
The World Health Organization recommends isoniazid preventive therapy (IPT) for preventing tuberculosis in HIV-infected adults, although few countries have instituted this policy. Both IPT and highly ...active antiretroviral therapy (HAART) used separately result in reductions in tuberculosis risk. There is less information on the combined effect of IPT and HAART. We assessed the effect of IPT, HAART or both IPT and HAART on tuberculosis incidence in HIV-infected adults in South Africa.
Two clinical cohorts of HIV-infected patients were studied. Primary exposures were receipt of IPT and/or HAART and the primary outcome was incident tuberculosis. Crude incident rates and incident rate ratios were calculated and Cox proportional hazards models investigated associations with tuberculosis risk.
Among 2778 HIV-infected patients followed for 4287 person-years, 267 incident tuberculosis cases were diagnosed incidence rate ratio (IRR)=6.2/100 person-years; 95% CI 5.5-7.0. For person-time without IPT or HAART, the IRR was 7.1/100 person-years (95% CI 6.2-8.2); for person-time receiving HAART but without IPT, the IRR was 4.6/100 person-years (95% CI 3.4-6.2); for person-time after IPT but prior to HAART, the IRR was 5.2/100 person-years (95% CI 3.4-7.8); during follow-up in patients treated with HAART after receiving IPT the IRR was 1.1/100 person-years (95% CI 0.02-7.6). Compared to treatment-naive patients, HAART-only patients had a 64% decreased hazard for tuberculosis adjusted hazard ratio (aHR)=0.36; 95% CI 0.25-0.51, and patients receiving HAART after IPT had a 89% reduced hazard (aHR=0.11; 95% CI 0.02-0.78).
Tuberculosis risk is significantly reduced by IPT in HAART-treated adults in a high-incidence operational setting in South Africa. IPT is an inexpensive and cost-effective strategy and our data strengthen calls for the implementation of IPT in conjunction with the roll-out of HAART.
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