Surface Rearrangement and Sublimation Kinetics of Supported Gold Nanoparticle Catalysts.

Heterogeneous catalysts consisting of supported metallic nanoparticles typically derive exceptional catalytic activity from their large proportion of undercoordinated surface sites which promote adsorption of reactant molecules. Simultaneously, these high energy surface configurations are unstable, leading to nanoparticle growth or degradation and eventually a loss of catalytic activity. Surface morphology of catalytic nanoparticles is paramount to catalytic activity, selectivity, and degradation rates, however it is well-known that harsh reaction conditions can cause the surface structure to change. Still, limited research has focused on understanding the link between nanoparticle surface facets and degradation rates or mechanisms. Here, we study a model Au supported catalyst system over a range of temperatures using a combination of in situ transmission electron microscopy, kinetic Monte Carlo simulations, and density functional theory calculations to establish an atomistic picture of how variations in surface structures and atomic coordination environments lead to shifting evolution mechanisms as a function of temperature. By combining experimental results, which yield direct observation of dynamic shape changes and particle sublimation rates, with computational techniques, which enable understanding the fundamental thermodynamics and kinetics of nanoparticle evolution, we illustrate a two-step evolution mechanism in which mobile adatoms form through desorption from low-coordination facets and subsequently sublimate off the particle surface. By understanding the role of temperature in the competition between surface diffusion and sublimation, we are able to show how individual atomic movements lead to particle scale morphological changes and rationalize why sublimation rates vary between particles in a system of nearly identical nanoparticles.

Sonographic Assessment of Hand Injuries: Diagnostic Accuracy and Review of Pathology.

Background: The high soft-tissue contrast of magnetic resonance imaging (MRI) makes it useful for evaluation of hand injuries, but its limitations include cost, imaging artifacts, and patient claustrophobia. Ultrasound is readily available, fast, noninvasive, and radiation free, but its utility for the evaluation of hand soft-tissue injury and pathology is less well known. Purpose: We sought to examine the accuracy of ultrasound for the evaluation of hand injury at a single institution. Methods: We queried a radiology information system for ultrasound cases between 2014 and 2020 at a tertiary care institution using the keyword "hand" and injury terms. We performed a retrospective chart review of cases found according to the type of injury detected on ultrasound. To evaluate the diagnostic accuracy of ultrasound in hand injury and pathology, we recorded postimaging clinical diagnoses and surgical findings. Results: We found 154 patients who underwent ultrasound for hand injuries and had confirmed surgical diagnosis and/or robust clinical follow-up. Tendon injury was the most commonly diagnosed condition on ultrasound (70/154); others detected were retained foreign body (31), mass (21), ligamentous injury (9), pulley injury (8), nerve injury (11), and traumatic arthropathy (4). Ultrasound correctly characterized hand injury in 150/154 cases (97.4%) based on surgical and/or clinical follow-up. Ultrasound failed to diagnose 3 cases of partial tendon tear and 1 case of digital nerve injury. Conclusion: In this retrospective, single-institution review, ultrasound was found to be highly accurate in the detection of soft tissue hand injury and pathology, demonstrating a high concordance rate with surgical and clinical findings. Further study is warranted.

Preclinical Characterization of XL092, a Novel Receptor Tyrosine Kinase Inhibitor of MET, VEGFR2, AXL, and MER.

The multi-receptor tyrosine kinase inhibitor XL092 has been developed to inhibit the activity of oncogenic targets, including MET, VEGFR2, and the TAM family of kinases TYRO3, AXL and MER. Presented here is a preclinical evaluation of XL092. XL092 causes a significant decrease in tumor MET and AXL phosphorylation (P < 0.01) in murine Hs 746T xenograft models relative to vehicle, and a 96% inhibition of VEGFR2 phosphorylation in murine lungs. Dose-dependent tumor growth inhibition with XL092 was observed in various murine xenograft models, with dose-dependent tumor regression seen in the NCI-H441 model. Tumor growth inhibition was enhanced with the combination of XL092 with anti-PD-1, anti-programmed death ligand-1 (PD-L1), or anti-CTLA-4 compared with any of these agents alone in the MC38 murine syngeneic model and with anti-PD-1 in the CT26 colorectal cancer survival model. In vivo, XL092 promoted a decrease in the tumor microvasculature and significant increases of peripheral CD4+ T cells and B cells and decreases in myeloid cells versus vehicle. Significant increases in CD8+ T cells were also observed with XL092 plus anti-PD-1 or anti-PD-L1 versus vehicle. In addition, XL092 promoted M2 to M1 repolarization of macrophages in vitro and inhibited primary human macrophage efferocytosis in a dose-dependent manner. In summary, XL092 was shown to have significant antitumor and immunomodulatory activity in animal models both alone and in combination with immune checkpoint inhibitors, supporting its evaluation in clinical trials.

Discovery of Non-Nucleotide Small-Molecule STING Agonists via Chemotype Hybridization.

The identification of agonists of the stimulator of interferon genes (STING) pathway has been an area of intense research due to their potential to enhance innate immune response and tumor immunogenicity in the context of immuno-oncology therapy. Initial efforts to identify STING agonists focused on the modification of 2',3'-cGAMP (1) (an endogenous STING activator ligand) and other closely related cyclic dinucleotides (CDNs). While these efforts have successfully identified novel CDNs that have progressed into the clinic, their utility is currently limited to patients with solid tumors that STING agonists can be delivered to intratumorally. Herein, we report the discovery of a unique class of non-nucleotide small-molecule STING agonists that demonstrate antitumor activity when dosed intratumorally in a syngeneic mouse model.

Synthesis and Biological Evaluation of a Carbamate-Containing Tubulysin Antibody-Drug Conjugate.

Antibody-drug conjugates (ADCs) use antibodies to deliver cytotoxic payloads directly into tumor cells via specifically binding to the target cell surface antigens. ADCs can enhance the anti-tumor effects of antibodies, and increase the delivery of cytotoxic payloads to cancer cells with a better therapeutic index. An ADC was prepared with a potent carbamate-containing tubulysin analogue attached to an anti-mesothelin antibody via a Cit-Val dipeptide linker. An aniline functionality in the tubulysin analogue was created to provide a site of linker attachment via an amide bond that would be stable in systemic circulation. Upon ADC internalization into antigen-positive cancer cells, the Cit-Val dipeptide linker was cleaved by lysosomal proteases, and the drug was released inside the tumor cells. The naturally occurring acetate of tubulysin was modified to a carbamate to reduce acetate hydrolysis of the ADC in circulation and to increase the hydrophilicity of the drug. The ADC bearing the monoclonal anti-mesothelin antibody and the carbamate-containing tubulysin was highly potent and immunologically specific to H226 human lung carcinoma cells in vitro, and efficacious at well-tolerated doses in a mesothelin-positive OVCAR3 ovarian cancer xenograft mouse model.

BMS-936564/MDX-1338: a fully human anti-CXCR4 antibody induces apoptosis in vitro and shows antitumor activity in vivo in hematologic malignancies.

PURPOSE: CXCR4 has been identified as a prognostic marker for acute myeloid leukemia (AML) and other malignancies. We describe the development and characterization of a fully human antibody to CXCR4 and its application for therapy of AML, non-Hodgkin lymphoma (NHL), chronic lymphoid leukemia (CLL), and multiple myeloma. EXPERIMENTAL DESIGN: Human transgenic mice were immunized with CXCR4-expressing cells, and antibodies reactive with CXCR4 were analyzed for apoptosis induction and ability to interfere with CXCL12-induced migration and calcium flux. In vivo efficacy was determined in multiple AML, NHL, and multiple myeloma xenograft tumors in severe combined immunodeficient mice. RESULTS: BMS-936564/MDX-1338 is a fully human IgG(4) monoclonal antibody that specifically recognizes human CXCR4. In vitro studies show that MDX-1338 binds to CXCR4-expressing cells with low nanomolar affinity, blocks CXCL12 binding to CXCR4-expressing cells, and inhibits CXCL12-induced migration and calcium flux with low nanomolar EC(50) values. When given as monotherapy, MDX-1338 exhibits antitumor activity in established tumors including AML, NHL, and multiple myeloma xenograft models. In addition, we show that MDX-1338 induced apoptosis on a panel of cell lines and propose that antibody-induced apoptosis is one of the mechanisms of tumor growth inhibition. CONCLUSIONS: BMS-936564/MDX-1338 is a potent CXCR4 antagonist which is efficacious as monotherapy in tumor-bearing mice and is currently in phase I for the treatment of relapsed/refractory AML, NHL, CLL, and multiple myeloma.

Subdural haematomas complicating insertion of the low-pressure Novus hydrocephalus valve: a simple method for intra-operative testing of the anti-siphon device.

We previously reported 52 patients with hydrocephalus who were followed up after insertion of low-pressure Novus valves. These valves have a normally open anti-siphon device (ASD) incorporated. There were no cases of subdural haematomas (SDH). Subsequently, three new patients suffered SDH after insertion of these valves. We investigated a simple method for intra-operative testing of the ASD. These new patients had their valves replaced. In the laboratory, flow rates through five valves were recorded as a function of proximal positive pressure and distal negative pressures (siphoning). The flow rates were influenced by both proximal positive and distal negative pressures. The ASD stopped flow at distal negative pressures between -40 and -60 cm H(2)O. Proximal positive pressures increased this threshold. The flow can be measured by counting drops per minute. Three valves removed from patients were functioning as expected, one had unexpectedly slow flow at very high siphoning pressure and one had unexpectedly slow flow rates. In three patients with SDH complicating low-pressure Novus valves, the valves and anti-siphon devices were functioning adequately. Using a simple device, measuring flow rates in drops per minute was reliable and reproducible.

Patterns of practice in the management of prostate cancer: results from multidisciplinary surveys of clinicians in Australia and New Zealand in 1995 and 2000.

OBJECTIVE: To investigate and compare patterns of practice in prostate cancer management in Australia and New Zealand from 1995 to 2000, as there are insufficient randomized trials to guide clinicians in the management of prostate cancer. SUBJECTS AND METHODS: This study represents the two largest published surveys of Australian and New Zealand clinicians dealing with prostate cancer. We sent structured questionnaires on the management of prostate cancer patients to 804 urologists, radiation oncologists and medical oncologists in Australia and New Zealand in December 2000. We compared responses to a similar survey of 579 specialist clinicians in 1995. RESULTS: The response rates were 56% in 1995 and 62% in 2000. In the management of clinically localized disease, the proportion recommending surgery or radiotherapy remained relatively constant between 1995 and 2000, although there was an increase in the use of brachytherapy and adjuvant hormonal therapy, and a reduced tendency to treat pelvic nodes. In the treatment of locally advanced disease, there was an increased use of hormonal treatment and local radiotherapy, with a reduction in the use of total androgen blockade and orchidectomy. In managing positive margins after prostatectomy, there was a clear lack of consensus, with a wide variety of treatment options proposed. CONCLUSIONS: Practice has changed in several areas in 2000 compared to 1995, but not all changes were influenced by the publication of randomized trials or evidence-based guidelines.

Traumatic optic nerve avulsion and central retinal artery occlusion following rugby injury.

Optic nerve avulsion (ONA) secondary to finger gouging is a rare complication. A case is reported of a 14-year-old boy who had an acute loss of vision after being poked in his left eye during a game of rugby union. He was later diagnosed with ONA, and this was associated with central retinal artery occlusion, which was rarely reported in the literature. His progress was complicated by a delayed onset of neovascular glaucoma. This is the first report of ONA secondary to a rugby injury and highlights the need for clinicians to be aware of the potential for loss of sight from gouging.

A profile of the caring attributes of Hong Kong and Thailand psychiatric nurses.

Despite the unique cultural characteristics of psychiatric nurses in Hong Kong and Thailand little has been written about them or their caring practices. This study set out to examine the caring practices and demographic features of nurses working in these two countries where the development of the nursing education system has distinct similarities, yet where culture, career paths and qualifications differ. The Caring Attributes Questionnaire (CAQ), previously used in general nursing samples, was modified and validated for the study and administered to 275 and 227 psychiatric nurses in Hong Kong and Thailand, respectively. The results showed that more of the Hong Kong nurses were educated at the degree level and they tended to be younger, while both had around the same number of years of experience. The CAQ scores increase significantly with position, age and years of experience in the Hong Kong sample yet not for qualifications, while there were no significant differences detected in the Thai sample. The Thai sample had significantly lower CAQ scores and the results suggest that neither education nor experience modify these qualities of a psychiatric nurse, and it may be that nurses are still learning "on the job" rather than in the school. These findings are discussed in the light of findings from other international studies and recommendations for future studies are made.

Clinical experience with the low pressure Novus valve in the treatment of adult hydrocephalus.

PURPOSE: The low pressure Novus valve is a pressure differential valve with a normally open siphon control mechanism. This study evaluates our experience with this valve in adult hydrocephalus and is the first published clinical review of the Novus valve. PATIENTS AND METHODS: From June 1999, we prospectively inserted low pressure Novus valves in all patients requiring new ventriculoperitoneal and ventriculoatrial shunts and requiring shunt valve revision. In December 2000, 52 patients were retrospectively reviewed. RESULTS: The major causes of hydrocephalus were intracranial haemorrhage (18), tumour (10), normal pressure hydrocephalus (10) and trauma (9). Forty one procedures were first shunts and eleven were revisions. The Novus valve was revised once. Complications include one infection and one sudden death from cerebral haemorrhage. No patients developed overdrainage symptoms or subdural haematomas. There were large improvements in symptoms. Ninety-three percent of the patients reported an improvement in daily function and quality of life. The remaining 7% reported no change, despite improvements in symptoms. CONCLUSIONS: The Novus low pressure valve is an effective first choice of valve for adult hydrocephalus.