Utilising Sentinel-1's Orbital Stability for Efficient Pre-Processing of Radiometric Terrain Corrected Gamma Nought Backscatter.

Radiometric Terrain Corrected (RTC) gamma nought backscatter, which was introduced around a decade ago, has evolved into the standard for analysis-ready Synthetic Aperture Radar (SAR) data. While working with RTC backscatter data is particularly advantageous over undulated terrain, it requires substantial computing resources given that the terrain flattening is more computationally demanding than simple orthorectification. The extra computation may become problematic when working with large SAR datasets such as the one provided by the Sentinel-1 mission. In this study, we examine existing Sentinel-1 RTC pre-processing workflows and assess ways to reduce processing and storage overheads by considering the satellite's high orbital stability. By propagating Sentinel-1's orbital deviations through the complete pre-processing chain, we show that the local contributing area and the shadow mask can be assumed to be static for each relative orbit. Providing them as a combined external static layer to the pre-processing workflow, and streamlining the transformations between ground and orbit geometry, reduces the overall processing times by half. We conducted our experiments with our in-house developed toolbox named wizsard, which allowed us to analyse various aspects of RTC, specifically run time performance, oversampling, and radiometric quality. Compared to the Sentinel Application Platform (SNAP) this implementation allowed speeding up processing by factors of 10-50. The findings of this study are not just relevant for Sentinel-1 but for all SAR missions with high spatio-temporal coverage and orbital stability.

[3 + 2] Cycloadditions and Retrocycloadditions of Niobium Imido Complexes: An Experimental and Computational Mechanistic Study.

We demonstrate reactivity between a ß-diketiminate-supported niobium(III) imido complex and alkyl azides to form niobatetrazene complexes (BDI)Nb(NtBu)(RNNNNR) (BDI = N,N-bis(2,6-diisopropylphenyl)-3,5-dimethyl-ß-diketiminate; R = cyclohexyl (1), benzyl (2)). Intriguingly, niobatetrazene complexes 1 and 2 can be interconverted via addition of an appropriate alkyl azide, likely through a series of concerted [3 + 2] cycloaddition and retrocycloaddition reactions in which π-loaded bis(imido) intermediates are formed. The bis(imido) intermediates were trapped upon addition of alkyl isocyanides to yield five-coordinate bis(imido) complexes (BDI)Nb(NtBu)(NCy)(CNR) (R = tert-butyl (4a), cyclohexyl (4b)). Two computational methods─density functional theory and density functional tight binding (DFTB)─were employed to calculate the lowest energy pathway across the potential energy surface for this multistep transformation. Reaction path calculations for individual cycloaddition or retrocycloaddition processes along the multistep reaction pathway showed that these transformations occur via a concerted, yet highly asynchronous mechanism, in which the two bond-breaking or -making events do not occur simultaneously. The use of the DFTB method in this work highlights its advantages and utility for studying transition metal systems.

A codevelopment process to advance methods for the use of patient-reported outcome measures and patient-reported experience measures with people who are homeless and experience chronic illness.

INTRODUCTION: People who experience social disadvantage including homelessness suffer from numerous ill health effects when compared to the general public. Use of patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs) enables collection of information from the point of view of the person receiving care. Involvement in research and health care decision-making, a process that can be facilitated by the use of PROMs and PREMs, is one way to promote equity in care. METHODS: This article reports on a codevelopment and consultation study investigating the use of PROMs and PREMs with people who experience homelessness and chronic illness. Data were analysed according to interpretative phenomenological analysis. RESULTS: Committee members with lived experience identified three themes for the role of PROMs and PREMs in health care measurement: trust and relationship-building; health and quality of life; and equity, alongside specific recommendations for the design and administration of PROMs and PREMs. The codevelopment process is reported to demonstrate the meaningful investment in time, infrastructure and relationship-building required for successful partnership between researchers and people with lived experience of homelessness. CONCLUSION: PROMs and PREMs can be meaningful measurement tools for people who experience social disadvantage, but can be alienating or reproduce inequity if they fail to capture complexity or rely on hidden assumptions of key concepts. PATIENT OR PUBLIC CONTRIBUTION: This study was conducted in active partnership between researchers and people with experience of homelessness and chronic illness, including priority setting for study design, data construction, analysis and coauthorship on this article.

Characterization of a Molecule Partially Confined at the Pore Mouth of a Zeotype.

We investigate the interaction between a molecule and a pore mouth-a critical step in adsorption processes-by characterizing the conformation of a macrocyclic calix[4]arene-TiIV complex, which is grafted on the external surface of a zeotype (*-SVY). X-ray absorption and 13 C{1 H} CPMAS NMR spectroscopies independently detect a unique conformation of this complex when it is grafted at crystallographically equivalent locations that lie at the interface of 7 Šhemispherical microporous cavities and the external surface. Electronic structure calculations support the presence of this unique conformation, and suggest that it is brought about by a specific orientation of the macrocycle that maximizes non-covalent interactions between calix[4]arene upper-rim tert-butyl substituents and the microporous-cavity walls. Our comparative study provides a rare "snapshot" of a molecule partially confined at a pore mouth, an essential intermediate for adsorption into micropores, and demonstrates how surrounding environment controls this confinement in a sensitive fashion.

Electronic Structures of Rhenium(II) ß-Diketiminates Probed by EPR Spectroscopy: Direct Comparison of an Acceptor-Free Complex to Its Dinitrogen, Isocyanide, and Carbon Monoxide Adducts.

Electron paramagnetic resonance (EPR) studies of the rhenium(II) complex Re(η5-Cp)(BDI) (1; BDI = N,N'-bis(2,6-diisopropylphenyl)-3,5-dimethyl-ß-diketiminate) have revealed that this species reversibly binds N2 in solution: flash frozen toluene solutions of 1 disclose entirely different EPR spectra at 10 K when prepared under N2 versus Ar atmospheres. This observation was additionally verified by the synthesis of stable CO and 2,6-xylylisocyanide (XylNC) adducts of 1, which display EPR features akin to those observed in the putative N2 complex. While we found that 1 displays an extremely large gmax value of 3.99, the binding of an additional ligand leads to substantial decreases in this value, displaying gmax values of ca. 2.4. Following the generation of isotopically enriched 15N2 and 13CO adducts of 1, HYSCORE experiments allowed for the measurement of the corresponding hyperfine couplings associated with spin delocalization onto the electron-accepting ligands in these species, which proved to be small. A cumulative assessment of the EPR data, when combined with insights provided by near-infrared (NIR) spectroscopy and time-dependent density functional theory (TDDFT) calculations, indicated that while the binding of electron acceptors to 1 does lead to decreases in gmax in relative accord with the field strength (i.e., π-acidity) of the variable ligand, the magnitude of these decreases is primarily due to the changes in electronic structure at the Re center.

Sociodemographic Characteristics and Clinical Outcomes of People Receiving Inadequate Prenatal Care: A Retrospective Cohort Study.

OBJECTIVE: This study sought to describe the incidence inadequate prenatal care (IPNC) at an urban level II hospital in Hamilton, Ontario, and to compare the characteristics and outcomes of mothers who received IPNC and their newborns with those who received adequate prenatal care (APNC). This study is the first part of a mixed-methods research program aimed at informing the development of an interdisciplinary, patient-centred, prenatal care program for people who struggle to access conventional modes of care. METHODS: This retrospective cohort study compared mothers and neonates born at St. Joseph's Health Care Hamilton in 2016 with IPNC (fewer than or equal to four antenatal visits, or first visit in third trimester) with those born with APNC (five or more prenatal visits and initial visit before the third trimester). Cases and controls matched 3:1 for age and parity were identified through a retrospective chart review. RESULTS: In total 3235 charts were reviewed, and 69 cases of IPNC were identified (2.1%). The IPNC group had lower education and higher unemployment levels, as well as higher rates of smoking and drug use. Our primary and secondary outcomes of newborn custody loss, neonatal intensive care unit admission, and neonatal length of stay were significantly higher in the IPNC group. CONCLUSION: Patients delivering with IPNC represent a high-risk group with increased rates of adverse neonatal outcomes and newborn custody loss. This quantitative study will inform future research and innovative interdisciplinary program development aimed at increasing access to prenatal care in an effort to improve maternal and neonatal outcomes.

Dynamic Reorganization and Confinement of TiIV Active Sites Controls Olefin Epoxidation Catalysis on Two-Dimensional Zeotypes.

The effect of dynamic reorganization and confinement of isolated TiIV catalytic centers supported on silicates is investigated for olefin epoxidation. Active sites consist of grafted single-site calix[4]arene-TiIV centers or their calcined counterparts. Their location is synthetically controlled to be either unconfined at terminal T-atom positions (denoted as type-(i)) or within confining 12-MR pockets (denoted as type-(ii); diameter ∼7 Å, volume ∼185 Å3) composed of hemispherical cavities on the external surface of zeotypes with *-SVY topology. Electronic structure calculations (density functional theory) indicate that active sites consist of cooperative assemblies of TiIV centers and silanols. When active sites are located at unconfined type-(i) environments, the rate constants for cyclohexene epoxidation (323 K, 0.05 mM TiIV, 160 mM cyclohexene, 24 mM tert-butyl hydroperoxide) are 9 ± 2 M-2 s-1; whereas within confining type-(ii) 12-MR pockets, there is a ∼5-fold enhancement to 48 ± 8 M-2 s-1. When a mixture of both environments is initially present in the catalyst resting state, the rate constants reflect confining environments exclusively (40 ± 11 M-2 s-1), indicating that dynamic reorganization processes lead to the preferential location of active sites within 12-MR pockets. While activation enthalpies are Δ H‡app = 43 ± 1 kJ mol-1 irrespective of active site location, confining environments exhibit diminished entropic barriers (Δ S‡app = -68 J mol-1 K-1 for unconfined type-(i) vs -56 J mol-1 K-1 for confining type-(ii)), indicating that confinement leads to more facile association of reactants at active sites to form transition state structures (volume ∼ 225 Å3). These results open new opportunities for controlling reactivity on surfaces through partial confinement on shallow external-surface pockets, which are accessible to molecules that are too bulky to benefit from traditional confinement within micropores.

Kohn-Sham Density Functional Theory with Complex, Spin-Restricted Orbitals: Accessing a New Class of Densities without the Symmetry Dilemma.

We show that using complex, spin-restricted orbitals in Kohn-Sham (KS) density functional theory allows one to access a new class of densities that is not accessible by either spin-restricted (RKS) or spin-unrestricted (UKS) orbitals. We further show that the real part of a complex RKS (CRKS) density matrix can be nonidempotent when the imaginary part of the density matrix is not zero. Using CRKS orbitals shows significant improvements in the triplet-singlet gaps of a benchmark set, called TS12, for well-established, widely used density functionals. Moreover, it was shown that RKS and UKS yield qualitatively wrong charge densities and spin densities, respectively, leading to worse energetics. We demonstrate that representative modern density functionals show surprisingly no improvement even with a qualitatively more accurate density from CRKS orbitals. To this end, our work not only provides a way to escape the symmetry dilemma whenever there exists a CRKS solution, but also suggests a new route to design better approximate density functionals.

Knockout of Amyloid ß Protein Precursor (APP) Expression Alters Synaptogenesis, Neurite Branching and Axonal Morphology of Hippocampal Neurons.

The function of the ß-A4 amyloid protein precursor (APP) of Alzheimer's disease (AD) remains unclear. APP has a number of putative roles in neuronal differentiation, survival, synaptogenesis and cell adhesion. In this study, we examined the development of axons, dendrites and synapses in cultures of hippocampus neutrons derived from APP knockout (KO) mice. We report that loss of APP function reduces the branching of cultured hippocampal neurons, resulting in reduced synapse formation. Using a compartmentalised culture approach, we found reduced axonal outgrowth in cultured hippocampal neurons and we also identified abnormal growth characteristics of isolated hippocampal neuron axons. Although APP has previously been suggested to play an important role in promoting cell adhesion, we surprisingly found that APPKO hippocampal neurons adhered more strongly to a poly-L-lysine substrate and their neurites displayed an increased density of focal adhesion puncta. The findings suggest that the function of APP has an important role in both dendritic and axonal growth and that endogenous APP may regulate substrate adhesion of hippocampal neurons. The results may explain neuronal and synaptic morphological abnormalities in APPKO mice and the presence of abnormal APP expression in dystrophic neurites around amyloid deposits in AD.

Pharmacokinetics and safety of tadalafil in a paediatric population with pulmonary arterial hypertension: A multiple ascending-dose study.

AIMS: To evaluate the pharmacokinetics and safety of once-daily (QD) tadalafil in paediatric patients with pulmonary arterial hypertension (PAH) to establish an appropriate dose range for further research. METHODS: This was an open-label, multicentre, international, multiple-ascending-dose study. Patients aged ≥2 years were enrolled into 1 of 3 cohorts based on body weight: heavy-weight (≥40 kg), middle-weight (25 to <40 kg), and light-weight (<25 kg). Each patient received tadalafil QD for 10 weeks: 5 weeks at a low dose, then 5 weeks at a high dose. The doses for each cohort were intended to produce plasma tadalafil concentrations within the range produced by 5-10 mg (for the low dose) or 20-40 mg (for the high dose) of tadalafil in adults with PAH. Area under the plasma concentration-time curve during 1 dosing interval (AUCτ ), maximum concentration, and apparent clearance were assessed throughout the trial, as were safety and tolerability. RESULTS: The study enrolled 19 patients aged 2-17 years, weighing 9.9-76.0 kg. Tadalafil's median (range) steady-state AUCτ at the high dose was 7243 (3131-13 088) ng•h/mL across all patients. Concentrations were higher in no bosentan-treated patients than in bosentan-treated patients, but both populations were within the range of respective adult patients taking 20-40 mg QD. Tadalafil had an acceptable safety profile consistent with the known safety profile of tadalafil in adults. CONCLUSIONS: Tadalafil 40 mg QD for patients ≥40 kg, and 20 mg QD for patients <40 kg and aged ≥2 years, are suitable for further research in paediatric patients with PAH.

Excited states via coupled cluster theory without equation-of-motion methods: Seeking higher roots with application to doubly excited states and double core hole states.

In this work, we revisited the idea of using the coupled-cluster (CC) ground state formalism to target excited states. Our main focus was targeting doubly excited states and double core hole states. Typical equation-of-motion (EOM) approaches for obtaining these states struggle without higher-order excitations than doubles. We showed that by using a non-Aufbau determinant optimized via the maximum overlap method, the CC ground state solver can target higher energy states. Furthermore, just with singles and doubles (i.e., CCSD), we demonstrated that the accuracy of ΔCCSD and ΔCCSD(T) (triples) far surpasses that of EOM-CCSD for doubly excited states. The accuracy of ΔCCSD(T) is nearly exact for doubly excited states considered in this work. For double core hole states, we used an improved ansatz for greater numerical stability by freezing core hole orbitals. The improved methods, core valence separation (CVS)-ΔCCSD and CVS-ΔCCSD(T), were applied to the calculation of the double ionization potential of small molecules. Even without relativistic corrections, we observed qualitatively accurate results with CVS-ΔCCSD and CVS-ΔCCSD(T). Remaining challenges in ΔCC include the description of open-shell singlet excited states with the single-reference CC ground state formalism as well as excited states with genuine multireference character. The tools and intuition developed in this work may serve as a stepping stone toward directly targeting arbitrary excited states using ground state CC methods.

N-acetyl-cysteine increases cellular dysfunction in progressive chronic kidney damage after acute kidney injury by dampening endogenous antioxidant responses.

Oxidative stress and mitochondrial dysfunction exacerbate acute kidney injury (AKI), but their role in any associated progress to chronic kidney disease (CKD) remains unclear. Antioxidant therapies often benefit AKI, but their benefits in CKD are controversial since clinical and preclinical investigations often conflict. Here we examined the influence of the antioxidant N-acetyl-cysteine (NAC) on oxidative stress and mitochondrial function during AKI (20-min bilateral renal ischemia plus reperfusion/IR) and progression to chronic kidney pathologies in mice. NAC (5% in diet) was given to mice 7 days prior and up to 21 days post-IR (21d-IR). NAC treatment resulted in the following: prevented proximal tubular epithelial cell apoptosis at early IR (40-min postischemia), yet enhanced interstitial cell proliferation at 21d-IR; increased transforming growth factor-ß1 expression independent of IR time; and significantly dampened nuclear factor-like 2-initiated cytoprotective signaling at early IR. In the long term, NAC enhanced cellular metabolic impairment demonstrated by increased peroxisome proliferator activator-γ serine-112 phosphorylation at 21d-IR. Intravital multiphoton microscopy revealed increased endogenous fluorescence of nicotinamide adenine dinucleotide (NADH) in cortical tubular epithelial cells during ischemia, and at 21d-IR that was not attenuated with NAC. Fluorescence lifetime imaging microscopy demonstrated persistent metabolic impairment by increased free/bound NADH in the cortex at 21d-IR that was enhanced by NAC. Increased mitochondrial dysfunction in remnant tubular cells was demonstrated at 21d-IR by tetramethylrhodamine methyl ester fluorimetry. In summary, NAC enhanced progression to CKD following AKI not only by dampening endogenous cellular antioxidant responses at time of injury but also by enhancing persistent kidney mitochondrial and metabolic dysfunction.

A case of severe Pembrolizumab-induced neutropenia.

Immune checkpoint inhibitors have revolutionized cancer therapy. Given their mechanism of action, immune-related adverse events have been associated with their use. We present the first documented case of pembrolizumab-induced grade IV neutropenia. A 73-year-old women known for myositis, Crohn's disease, and hypothyroidism and diagnosed with PD-L1 positive stage IV pulmonary adenocarcinoma is treated with Pembrolizumab. She develops grade IV neutropenia 2 weeks after her second infusion. She is therefore hospitalized and treated initially with corticosteroids, granulocyte colony-stimulating factor, and intravenous immunoglobulins. Given the persistent neutropenia, cyclosporine was added, but quickly stopped owing to fever. The patient recovered her neutrophils 6.5 weeks after her initial Pembrolizumab infusion and 12 days after admission. She has been subsequently successfully tapered off steroids with no recurrence after 3 months of follow-up. This is the first case of grade IV neutropenia secondary to Pembrolizumab. This case is of particular interest given the patient's pre-existing autoimmune history. Treatment of severe neutropenia due to other PD1 inhibitors has generally consisted of steroids, granulocyte colony-stimulating factor, intravenous immunoglobulins, mycophenolate mofetil, cyclosporine A, and anti-thymocyte globulins - though the benefits of immunosuppression are not clear and may be harmful given the infectious risks. Large studies are required to clarify the spectrum and optimal management of immune-related adverse events and overall risk/benefits of immune checkpoint inhibitors in patients with pre-existing autoimmunity.

Indoxyl Sulfate Induces Apoptosis and Hypertrophy in Human Kidney Proximal Tubular Cells.

Indoxyl sulfate (IS) is a protein-bound uremic toxin that accumulates in patients with declining kidney function. Although generally thought of as a consequence of declining kidney function, emerging evidence demonstrates direct cytotoxic role of IS on endothelial cells and cardiomyocytes, largely through the expression of pro-inflammatory and pro-fibrotic factors. The direct toxicity of IS on human kidney proximal tubular epithelial cells (PTECs) remains a matter of debate. The current study explored the effect of IS on primary cultures of human PTECs and HK-2, an immortalized human PTEC line. Pathologically relevant concentrations of IS induced apoptosis and increased the expression of the proapoptotic molecule Bax in both cell types. IS impaired mitochondrial metabolic activity and induced cellular hypertrophy. Furthermore, statistically significant upregulation of pro-fibrotic (transforming growth factor-ß, fibronectin) and pro-inflammatory molecules (interleukin-6, interleukin-8, and tumor necrosis factor-α) in response to IS was observed. Albumin had no influence on the toxicity of IS. The results of this study suggest that IS directly induced a pro-inflammatory and pro-fibrotic phenotype in proximal tubular cells. In light of the associated apoptosis, hypertrophy, and metabolic dysfunction, this study demonstrates that IS may play a role in the progression of chronic kidney disease.

Independent amplitude approximations in coupled cluster valence bond theory: Incorporation of 3-electron-pair correlation and application to spin frustration in the low-lying excited states of a ferredoxin-type tetrametallic iron-sulfur cluster.

Coupled cluster valence bond (CCVB) is a simple electronic structure method based on a perfect pairing (PP) reference with 2-pair recouplings for strong electron correlation problems. CCVB is spin-pure, size-consistent, and can exactly (in its active space) separate any molecule into atoms for which unrestricted Hartree-Fock (UHF) at dissociation is the sum of the ground state UHF energies of the atoms. However CCVB is far from a complete description of strong correlations. Its first failure to exactly describe spin-recouplings arises at the level of 3 electron pairs, such as the recoupling of 3 triplet oxygen atoms in the dissociation of singlet ozone. Such situations are often associated with spin frustration. To address this limitation, an extension of CCVB, termed CCVB+i3, is reported here that includes an independent (i) amplitude approximation to the 3-pair recouplings. CCVB+i3 thereby has the same basic computational requirements as those of CCVB, which has previously been shown to be an efficient method. CCVB+i3 correctly separates molecules that CCVB cannot. As a by-product, an independent 2-pair amplitude approximation to CCVB, called PP+i2, is also defined. Remarkably, PP+i2 can also correctly separate systems that CCVB cannot. CCVB+i3 is validated on the symmetric dissociation of D3h ozone. CCVB+i3 is then used to explore the role of 3-pair recouplings in an [Fe4S4(SCH3)4]2- cluster that has been used to model the iron-sulfur core of [Fe4S4] ferredoxins. Using localized PP orbitals, such recouplings are demonstrated to be large in some low-lying singlet excited states of the cluster. Significant 3 pair recoupling amplitudes include the usual triangular motif associated with spin frustration and other geometric arrangements of the 3 entangled pairs across the 4 iron centers.

Open-shell coupled-cluster valence-bond theory augmented with an independent amplitude approximation for three-pair correlations: Application to a model oxygen-evolving complex and single molecular magnet.

We report the failure of coupled-cluster valence-bond (CCVB) theory with two-pair configurations [D. W. Small and M. Head-Gordon, J. Chem. Phys. 130, 084103 (2009)] for open-shell (OS) spin-frustrated systems where including three-pair configurations is necessary to properly describe strong spin-correlations. We extend OS-CCVB by augmenting the model with three-pair configurations within the independent amplitude approximation. The resulting new electronic structure model, OS-CCVB+i3, involves only a quadratic number of independent wavefunction parameters. It includes the recently reported closed-shell CCVB+i3 as a special case. Its cost is dominated by integral transformations, and it is capable of breaking multiple bonds exactly for all systems examined so far. The strength of OS-CCVB+i3 is highlighted in realistic systems including the [CaMn3O4] cubane subunit of the oxygen-evolving complex and a molecular magnet with the [Cr9] core unit as well as model systems such as N3, V3O3, and P5. We show that OS-CCVB+i3 is only slightly dependent on the underlying perfect-pairing reference, while OS-CCVB shows a stronger dependence. We also emphasize the compactness of the OS-CCVB+i3 wavefunction compared to the heat-bath configuration interaction wavefunction, a recently introduced soft exponential-scaling approach.

Peripheral treatment with enoxaparin exacerbates amyloid plaque pathology in Tg2576 mice.

Alzheimer's disease (AD) is a complex, progressive neurological disorder characterized by the formation of extracellular amyloid plaques composed of ß-amyloid protein (Aß), the key component in pathogenesis of AD. Peripheral administration of enoxaparin (ENO) reportedly reduces the level of Aß and the amyloid plaques in the cortex of amyloid precursor protein (APP) transgenic mice. However, the exact mechanism of these effects is unclear. Our previous studies indicated that ENO can inhibit APP processing to Aß in primary cortical cells from Tg2576 mice by downregulating BACE1 levels. This study examines whether ENO-induced reduction of amyloid load is due to the decreased APP processing to Aß in Tg2576 mice. Surprisingly, our results indicated that ENO significantly increases the Aß42/Aß40 ratio in cortex and enhances the amyloid plaque load in both cortex and hippocampus, although overall APP processing was not influenced by ENO. Moreover, ENO stimulated the aggregation of both Aß40 and Aß42 in vitro. Although ENO has been reported to improve cognition in vivo and has potential as a therapeutic agent for AD, the results from our study suggest that ENO can exacerbate the amyloid pathology, and the strategy of using ENO for the treatment of AD may require further assessment. © 2016 Wiley Periodicals, Inc.

Coupled cluster valence bond theory for open-shell systems with application to very long range strong correlation in a polycarbene dimer.

The Coupled Cluster Valence Bond (CCVB) method, previously presented for closed-shell (CS) systems, is extended to open-shell (OS) systems. The theoretical development is based on embedding the basic OS CCVB wavefunction in a fictitious singlet super-system. This approach reveals that the OS CCVB amplitude equations are quite similar to those of CS CCVB, and thus that OS CCVB requires the same level of computational effort as CS CCVB, which is an inexpensive method. We present qualitatively correct CCVB potential energy curves for all low-lying spin states of P2 and Mn2+. CCVB is successfully applied to the low-lying spin states of some model linear polycarbenes, systems that appear to be a hindrance to standard density functionals. We examine an octa-carbene dimer in a side-by-side orientation, which, in the monomer dissociation limit, exhibits maximal strong correlation over the length of the polycarbene.

Decreased apoptosis repressor with caspase recruitment domain confers resistance to sunitinib in renal cell carcinoma through alternate angiogenesis pathways.

Apoptosis repressor with caspase recruitment domain (ARC), an endogenous inhibitor of apoptosis, is upregulated in a number of human cancers, thereby conferring drug resistance and giving a rationale for the inhibition of ARC to overcome drug resistance. Our hypothesis was that ARC would be similarly upregulated and targetable for therapy in renal cell carcinoma (RCC). Expression of ARC was assessed in 85 human RCC samples and paired non-neoplastic kidney by qPCR and immunohistochemistry, as well as in four RCC cell lines by qPCR, Western immunoblot and confocal microscopy. Contrary to expectations, ARC was significantly decreased in the majority of clear cell RCC and in three (ACHN, Caki-1 and 786-0) of the four RCC cell lines compared with the HK-2 non-cancerous human proximal tubular epithelial cell line. Inhibition of ARC with shRNA in the RCC cell line (SN12K1) that had shown increased ARC expression conferred resistance to Sunitinib, and upregulated interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF). We therefore propose that decreased ARC, particularly in clear cell RCC, confers resistance to targeted therapy through restoration of tyrosine kinase-independent alternate angiogenesis pathways. Although the results are contrary to expectations from other cancer studies, they were confirmed here with multiple analytical methods. We believe the highly heterogeneous nature of cancers like RCC predicate that expression patterns of molecules must be interpreted in relation to respective matched non-neoplastic regions. In the current study, this procedure indicated that ARC is decreased in RCC.

Amount of Testosterone on Laundered Clothing After Use of Testosterone Topical 2% Solution by Healthy Male Volunteers.

INTRODUCTION: Testosterone 2% solution (Axiron) applied to armpit(s) is used for replacement therapy in men with a deficiency of endogenous testosterone. AIM: To determine the amount of testosterone on subjects' T-shirts 12 hours after applying testosterone solution, the residual testosterone on subjects' T-shirts after laundering, and the testosterone transferred to unworn textile items during laundering with worn T-shirts. METHODS: Healthy males ≥18 years old applied 2 × 1.5 mL of testosterone 2% solution to both axillae (total testosterone dose: 120 mg) and dressed in cotton long-sleeved T-shirts after a ≥3-minute waiting period. T-shirts were worn 12 hours before being removed and cut into halves, after which a 10 × 10 cm sample of each armpit area was excised for testosterone quantification before or after laundering with samples of unworn textiles. MAIN OUTCOME MEASURES: Testosterone on worn T-shirts before and after laundering, and on unworn textiles laundered with the worn T-shirts. RESULTS: Twelve subjects enrolled and completed, with only minor adverse events. Mean testosterone in unwashed worn T-shirts was 7603 µg, with high between-subject variability (3359 µg to 13,069 µg), representing 13% of the dose to 1 armpit. Mean testosterone in worn, laundered T-shirts was 260 µg (7.55 µg to 1343 µg), representing 3% of the dose to 1 armpit. Mean transferred testosterone to other textiles during laundering ranged from 69 µg on texturized Dacron 56T Double to 10,402 µg on 87/13 nylon/Lycra knit, representing 0.0382% to 5.78% of the dose to 1 armpit. CONCLUSION: Thirteen percent of the testosterone applied to axillae was transferred to T-shirts during wear. Ninety-seven percent of the transferred testosterone was removed from the T-shirts during washing, some of which was then absorbed to various degrees by other textiles. Clinical implications of these findings and biological activity of the remaining/transferred testosterone are unknown.