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Montmorillonite is the main crystalline mineral present in bentonite. It is an absorbent, swelling material; the physical chemistry underlying its ability to absorb water and swell occurs at the nanoscale, governed by electrical double-layer interactions. In turn, absorption and swelling lead to important changes in the macroscopic transport properties of the clay. Mesoscale models can help us establish a link between these nanoscale processes and macroscale properties, notably by providing a detailed description of its pore network. Models on the scale of hundreds to thousands of nanometers are required, which cannot realistically be handled using traditional all-atom molecular dynamics simulations. This work presents a coarse-grained (CG) mesoscale model of sodium montmorillonite. In our model, montmorillonite platelets are represented by two types of particles: central nonhydrogen-bonded particles and edge hydrogen-bonding particles. The particle interactions are described by two-body potentials, which were optimized based on all-atom molecular dynamics simulations. Specifically, several potential mean force calculations involving dry and hydrated montmorillonite were performed, using the ClayFF potential to calculate interatomic forces. The CG model was validated by testing the scalability of the model, testing its ability to reproduce potentials of mean force reported elsewhere in the literature, and by comparing the calculated elastic properties of a system containing 1000 Na montmorillonite platelets to experimentally measured elastic properties of bentonite. The simulated elastic properties obtained using our mesoscale model agree with these experimental values.

Rising breakthrough infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in previously immunized individuals have raised concerns for the need for a booster vaccine dose to combat waning antibody levels and new variants. Here we report the results of the open-label, non-randomized part B of a phase 2 trial in which we evaluated the safety and immunogenicity of a booster injection of 50 µg of the coronavirus disease 2019 (COVID-19) vaccine mRNA-1273 in 344 adult participants immunized 6-8 months earlier with a primary series of two doses of 50 µg or 100 µg of mRNA-1273 ( NCT04405076 ). Neutralizing antibody (nAb) titers against wild-type SARS-CoV-2 at 1 month after the booster were 1.7-fold (95% confidence interval (CI): 1.5, 1.9) higher than those at 28 days after the second injection of the primary series, which met the pre-specified non-inferiority criterion (primary immunogenicity objective) and might indicate a memory B cell response. The nAb titers against the Delta variant (B.1.617.2) (exploratory objective) at 1 month after the booster were 2.1-fold (95% CI: 1.8, 2.4) higher than those at 28 days after the second injection of the primary series. The seroresponse rate (95% CI (four-fold rise from baseline)) was 100% (98.7, 100.0) at 28 days after the booster compared to 98.3% (96.0, 99.4) after the primary series. The higher antibody titers at 28 days after the booster dose compared to 28 days after the second dose in the phase 3 COVE study were also observed in two assays for anti-spike IgG antibody measured by ELISA and by Meso Scale Discovery (MSD) Multiplex. The frequency of solicited local and systemic adverse reactions after the booster dose was similar to that after the second dose in the primary two-dose series of mRNA-1273 (50 µg or 100 µg); no new signals were observed in the unsolicited adverse events; and no serious adverse events were reported in the 1-month follow-up period. These results show that a booster injection of mRNA-1273 more than 6 months after completing the primary two-dose series is safe and elicited nAb titers that were statistically significantly higher than the peak titers detected after the primary vaccination series, suggesting that a booster dose of mRNA-1273 might result in increased vaccine effectiveness against infection and disease caused by SARS-CoV-2., (© 2022. The Author(s).)

Purpose: The overall goal was to restore a normal and synchronous blink in unilateral lagophthalmos. We describe the biocompatibility profiling of a novel ferromagnetic implant used for electromagnetic eyelid force generation., Methods: A non-contact blink detection system and an electromagnetic stimulation system were designed and tested. A modified Lester-Burch speculum equipped with strain gauge technology was used in blinking force measurement. Samarium-cobalt magnets were prototyped and coated with parylene-C. Biocompatibility testing was performed using NIH/3T3 mouse fibroblast cells with MTT colorimetric assay cytotoxic quantification., Outcome Measures: Cellular viability and interleukin concentrations., Results: Our system was capable of detecting 95.5 ± 3.6% of blinks in various lighting conditions. Using our force measuring device, the difference between non-paralyzed and paralyzed orbicularis oculi (OO) for normal and forceful blinking closure was 40.4 g and 101.9 g, respectively. A 16.6 × 5.0 × 1.5 mm curved shaped samarium cobalt eyelid implant was successfully developed and showed a reproducible blink at 100 ms with full corneal coverage with external eyelid taping. Compared to gold weights, parylene-C coated samarium cobalt implants showed not only excellent cell viability (82.0 ± 4.9% vs. 88.4 ± 0.9%, respectively, p >  .05), but also below detection threshold for pro-inflammatory marker concentrations (interleukin-6 < 2 pg/mL and interleukin-10 < 3 pg/mL)., Conclusions: We demonstrated excellent in-vitro biocompatibility of our parylene-C coated samarium cobalt implants. We believe that our novel approach can improve the quality-of-life of affected individuals and provides new understanding of blinking biomechanics.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has led to growing concerns over increased transmissibility and the ability of some variants to partially escape immunity. Sera from participants immunized on a prime-boost schedule with the mRNA-1273 COVID-19 vaccine were tested for neutralizing activity against several SARS-CoV-2 variants, including variants of concern (VOCs) and variants of interest (VOIs), compared to neutralization of the wild-type SARS-CoV-2 virus (designated D614G). Results showed minimal, statistically nonsignificant effects on neutralization titers against the B.1.1.7 (Alpha) variant (1.2-fold reduction compared with D614G); other VOCs, such as B.1.351 (Beta, including B.1.351-v1, B.1.351-v2, and B.1.351-v3), P.1 (Gamma), and B.1.617.2 (Delta), showed significantly decreased neutralization titers ranging from 2.1-fold to 8.4-fold reductions compared with D614G, although all remained susceptible to mRNA-1273-elicited serum neutralization. IMPORTANCE In light of multiple variants of SARS-CoV-2 that have been documented globally during the COVID-19 pandemic, it remains important to continually assess the ability of currently available vaccines to confer protection against newly emerging variants. Data presented herein indicate that immunization with the mRNA-1273 COVID-19 vaccine produces neutralizing antibodies against key emerging variants tested, including variants of concern and variants of interest. While the serum neutralization elicited by mRNA-1273 against most variants tested was reduced compared with that against the wild-type virus, the level of neutralization is still expected to be protective. Such data are crucial to inform ongoing and future vaccination strategies to combat COVID-19.

The emergence of SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs) with decreased susceptibility to neutralization has generated interest in assessments of booster doses and variant-specific vaccines. Clinical trial participants who received a two-dose primary series of the COVID-19 vaccine mRNA-1273 approximately 6 months earlier entered an open-label phase 2a study ( NCT04405076 ) to evaluate the primary objectives of safety and immunogenicity of a single booster dose of mRNA-1273 or variant-modified mRNAs, including multivalent mRNA-1273.211. As the trial is currently ongoing, this exploratory interim analysis includes preliminary descriptive results only of four booster groups (n = 20 per group). Immediately before the booster dose, neutralizing antibodies against wild-type D614G virus had waned (P < 0.0001) relative to peak titers against wild-type D614G measured 1 month after the primary series, and neutralization titers against B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) VOCs were either low or undetectable. Both the mRNA-1273 booster and variant-modified boosters were safe and well-tolerated. All boosters, including mRNA-1273, numerically increased neutralization titers against the wild-type D614G virus compared to peak titers against wild-type D614G measured 1 month after the primary series; significant increases were observed for mRNA-1273 and mRNA-1273.211 (P < 0.0001). In addition, all boosters increased neutralization titers against key VOCs and VOIs, including B.1.351, P.1. and B.1.617.2, that were statistically equivalent to peak titers measured after the primary vaccine series against wild-type D614G virus, with superior titers against some VOIs. This trial is ongoing., (© 2021. The Author(s).)

Hydrogen peroxide (H2O2) is recognized as an important signaling molecule in plants. We sought to establish a genetically encoded, fluorescent H2O2 sensor that allows H2O2 monitoring in all major subcompartments of a Chlamydomonas cell. To this end, we used the Chlamydomonas Modular Cloning toolbox to target the hypersensitive H2O2 sensor reduction-oxidation sensitive green fluorescent protein2-Tsa2ΔCR to the cytosol, nucleus, mitochondrial matrix, chloroplast stroma, thylakoid lumen, and endoplasmic reticulum (ER). The sensor was functional in all compartments, except for the ER where it was fully oxidized. Employing our novel sensors, we show that H2O2 produced by photosynthetic linear electron transport (PET) in the stroma leaks into the cytosol but only reaches other subcellular compartments if produced under nonphysiological conditions. Furthermore, in heat-stressed cells, we show that cytosolic H2O2 levels closely mirror temperature up- and downshifts and are independent from PET. Heat stress led to similar up- and downshifts of H2O2 levels in the nucleus and, more mildly, in mitochondria but not in the chloroplast. Our results thus suggest the establishment of steep intracellular H2O2 gradients under normal physiological conditions with limited diffusion into other compartments. We anticipate that these sensors will greatly facilitate future investigations of H2O2 biology in plant cells., (© The Author(s) 2021. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

The thioredoxin fold superfamily is highly diverse and contains many enzymatically active glutathione-dependent thiol-disulfide oxidoreductases, for example glutaredoxins and protein disulfide isomerases. However, many thioredoxin fold proteins remain completely uncharacterized, their cellular function is unknown, and it is unclear if they have a redox-dependent enzymatic activity with glutathione or not. Investigation of enzymatic activity traditionally involved time-consuming in vitro characterization of recombinant proteins, limiting the capacity to study novel mechanisms and structure-function relationships. To accelerate our investigation of glutathione-dependent oxidoreductases, we have developed a high-throughput and semi-quantitative assay in yeast. We combined overexpression of the glutathione transporter OPT1 with genetic fusion constructs between glutathione-dependent oxidoreductases and redox-sensitive green fluorescent protein 2 (roGFP2) to allow the rapid characterization of enzymatic activity with physiological substrates. We show that the kinetics of roGFP2 oxidation by glutathione disulfide correlate well with the in vitro-determined activity of the genetically fused glutaredoxins or mutants thereof. Our assay thus allows direct screening of glutaredoxin activity and rapid investigation of structure-function relationships. We also demonstrate that our assay can be used to monitor roGFP2 oxidation by S-nitrosoglutathione (GSNO). We show that glutaredoxins efficiently catalyze oxidation of roGFP2 by GSNO in both live yeast cells and in vitro. In summary, we have established a novel assay for activity screening and characterization of glutathione-dependent oxidoreductases., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Glutaredoxins are small proteins of the thioredoxin superfamily that are present throughout life. Most glutaredoxins fall into two major subfamilies. Class I glutaredoxins are glutathione-dependent thiol-disulfide oxidoreductases whilst class II glutaredoxins coordinate Fe-S clusters. Class I glutaredoxins are typically dithiol enzymes with two active-site cysteine residues, however, some enzymatically active monothiol glutaredoxins are also known. Whilst both monothiol and dithiol class I glutaredoxins mediate protein deglutathionylation, it is widely claimed that only dithiol glutaredoxins are competent to reduce protein disulfide bonds. In this study, using a combination of yeast 'viability rescue', growth, and redox-sensitive GFP-based assays, we show that two different monothiol class I glutaredoxins can each facilitate the reduction of protein disulfide bonds in ribonucleotide reductase, methionine sulfoxide reductase and roGFP2. Our observations thus challenge the generalization of the dithiol mechanism for glutaredoxin catalysis and raise the question of why most class I glutaredoxins have two active-site cysteine residues., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: The management of advanced basal cell carcinoma (BCC) in the periocular region remains a clinical challenge. Vismodegib (Erivedge TM ) has been approved in 2013 by Health Canada for adult patients with "histologically confirmed metastatic BCC or locally advanced BCC inappropriate for surgery or radiation." An expert consensus was sought to create a standardised approach in the use of this novel treatment., Methods: Fourteen practicing oculoplastic surgeons across Canada were involved in formulating and reviewing guidelines until consensus was reached. A consultancy meeting was followed by further ratification of guidelines over email. Two voting surveys were performed of the group to objectively assess agreement over each statement within the guidelines. Ratification continued until at least two-thirds of the group agreed on every guideline statement., Results: The guidelines summarize 21 statements in a major and minor criteria format. A multidisciplinary team review is suggested for each patient with the involvement of recommended specialists. The internal survey revealed 100% agreement over 9 statements, 91.7% agreement over 8 statements, 83.3% agreement over 4 statements, and 2 statements had 66.7% and 58.7% agreement each. All statements with less than 91.7% agreement were surveyed again, and they were kept, modified, or removed on the basis of a consensus of over 66.7%., Conclusions: These guidelines serve to act as a framework for physicians considering vismodegib for the medical management of patients with advanced or metastatic periocular BCC. Future applications, including neoadjuvant uses of the drug, may become apparent through further research., (Copyright © 2019 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Computer-assisted surgery (CAS) plays a prominent role in certain surgical disciplines. We investigated the current perceptions and use of this technology for orbital surgery. An online survey was emailed to members of the American Society of Ophthalmic Plastic and Reconstructive Surgery, Canadian Society of Oculoplastic Surgery, and British Oculoplastic Surgery Society. Respondents were asked to describe their practice type and seniority, their frequency of orbital surgery, experience, use, and accessibility of CAS, and their opinion on the technology. There were a total of 151 responses across the societies. 105 respondents (69.5%) had been in attending/consultant practice for over 10 years, with over half (54.7%) working in academic/teaching hospitals. The majority (66.7%) had superficial or no experience with CAS. In total, 84.8% of respondents rarely or never use CAS for orbital surgery (n = 128). Posterior orbital surgery (64.2%) and orbital decompression (49.0%) were the two most useful reasons to implement CAS. Longer operating time (58.3%) and cost (54.8%) were the two most selected weaknesses for CAS, whereas improved accuracy in attaining surgical end point(s) (80.8%) and patient safety (63.6%) were the principal advantages. Type of practice was significantly associated with CAS availability/accessibility ( p < 0.05). Proportion of orbital surgery performed in practice was significantly associated with both CAS experience and use ( p < 0.05). Our study confirms an expected variation in the perception and use of CAS for orbital surgery. Demonstrated patient benefit and integration of refined and cost-effective CAS systems into operating room environments may influence its future role.

Glutathione (γ-l-glutamyl-l-cysteinylglycine) is a small tripeptide found at millimolar concentrations in nearly all eukaryotes as well as many prokaryotic cells. Glutathione synthesis is restricted to the cytosol in animals and fungi and to the cytosol and plastids in plants. Nonetheless, glutathione is found in virtually all subcellular compartments. This implies that transporters must exist that facilitate glutathione transport into and out of the various subcellular compartments. Glutathione may also be exported and imported across the plasma membrane in many cells. However, in most cases, the molecular identity of these transporters remains unclear. Whilst glutathione transport is essential for the supply and replenishment of subcellular glutathione pools, recent evidence supports a more active role for glutathione transport in the regulation of subcellular glutathione redox homeostasis. However, our knowledge of glutathione redox homeostasis at the level of specific subcellular compartments remains remarkably limited and the role of glutathione transport remains largely unclear. In this review, we discuss how new tools and techniques have begun to yield insights into subcellular glutathione distribution and glutathione redox homeostasis. In particular, we discuss the known and putative glutathione transporters and examine their contribution to the regulation of subcellular glutathione redox homeostasis.

There is no uniformly accepted standard of care for medical clearance of pediatric patients with psychiatric complaints. Emerging data argue for a thorough history and physical examination and against routine laboratory testing. The differential diagnosis of patients presenting with psychiatric health complaints is extensive and includes both medical and psychiatric disorders. Providers should remain mindful of anchoring or diagnosis momentum bias when caring for these patients, especially patients with a psychiatric history., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Diagnostic errors have a significant impact on health care outcomes and patient care. The underlying causes and development of diagnostic error are complex with flaws in health care systems, as well as human error, playing a role. Cognitive biases and a failure of decision-making shortcuts (heuristics) are human factors that can compromise the diagnostic process. We describe these mechanisms, their role with the clinician, and provide clinical scenarios to highlight the various points at which biases may emerge. We discuss strategies to modify the development and influence of these processes and the vulnerability of heuristics to provide insight and improve clinical outcomes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Pancreatic cancer, the fourth leading cause of cancer death in the United States, has a negative prognosis because metastasis occurs before symptoms manifest. Leiodermatolide, a polyketide macrolide with antimitotic activity isolated from a deep water sponge of the genus Leiodermatium, exhibits potent and selective cytotoxicity toward the pancreatic cancer cell lines AsPC-1, PANC-1, BxPC-3, and MIA PaCa-2, and potent cytotoxicity against skin, breast and colon cancer cell lines. Induction of apoptosis by leiodermatolide was confirmed in the AsPC-1, BxPC-3 and MIA PaCa-2 cells. Leiodermatolide induces cell cycle arrest but has no effects on in vitro polymerization or depolymerization of tubulin alone, while it enhances polymerization of tubulin containing microtubule associated proteins (MAPs). Observations through confocal microscopy show that leiodermatolide, at low concentrations, causes minimal effects on polymerization or depolymerization of the microtubule network in interphase cells, but disruption of spindle formation in mitotic cells. At higher concentrations, depolymerization of the microtubule network is observed. Visualization of the growing microtubule in HeLa cells expressing GFP-tagged plus end binding protein EB-1 showed that leiodermatolide stopped the polymerization of tubulin. These results suggest that leiodermatolide may affect tubulin dynamics without directly interacting with tubulin and hint at a unique mechanism of action. In a mouse model of metastatic pancreatic cancer, leiodermatolide exhibited significant tumor reduction when compared to gemcitabine and controls. The antitumor activities of leiodermatolide, as well as the proven utility of antimitotic compounds against cancer, make leiodermatolide an interesting compound with potential chemotherapeutic effects that may merit further research., Competing Interests: ◆ Conflict of Interest Disclosure: Guzmán, Pitts, Linley, Winder, Baker and Wright have no conflicts of interest to disclose. Xu, Tendyke, Oestreicher, Mitsuhashi and Suh are either current or former employees of Eisai, Inc., (© 2016 UICC.)

Objectives: Eribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B. Eribulin is a mechanistically unique inhibitor of microtubule dynamics. In this study, we investigated whether selective signal pathways were associated with eribulin activity compared to paclitaxel, which stabilizes microtubules, based on gene expression profiling of cell line panels of breast, endometrial, and ovarian cancer in vitro., Results: We determined the sets of genes that were differentially altered between eribulin and paclitaxel treatment in breast, endometrial, and ovarian cancer cell line panels. Our unsupervised clustering analyses revealed that expression profiles of gene sets altered with treatments were correlated with the in vitro antiproliferative activities of the drugs. Several tubulin isotypes had significantly lower expression in cell lines treated with eribulin compared to paclitaxel. Pathway enrichment analyses of gene sets revealed that the common pathways altered between treatments in the 3 cancer panels were related to cytoskeleton remodeling and cell cycle regulation. The epithelial-mesenchymal transition (EMT) pathway was enriched in genes with significantly altered expression between the two drugs for breast and endometrial cancers, but not for ovarian cancer. Expression of genes from the EMT pathway correlated with eribulin sensitivity in breast cancer and with paclitaxel sensitivity in endometrial cancer. Alteration of expression profiles of EMT genes between sensitive and resistant cell lines allowed us to predict drug sensitivity for breast and endometrial cancers., Conclusion: Gene expression analysis showed that gene sets that were altered between eribulin and paclitaxel correlated with drug in vitro antiproliferative activities in breast and endometrial cancer cell line panels. Among the panels, breast cancer provided the strongest differentiation between eribulin and paclitaxel sensitivities based on gene expression. In addition, EMT genes were predictive of eribulin sensitivity in the breast and endometrial cancer panels.

Purpose: Graves' ophthalmopathy (GO) is an autoimmune condition primarily managed with prolonged courses of glucocorticoids, which can be associated with significant side effects. Orbital radiation therapy (RT) is an alternative treatment that has shown variable efficacy in improving orbital and visual symptoms. In this study, the therapeutic benefit of RT was evaluated in terms of patient's ability to taper their corticosteroid requirements, which may better reflect the proposed mechanism of RT and provide a clinically relevant response endpoint., Methods and Materials: This is a retrospective review of consecutive patients treated with orbital RT for GO between 2000 and 2010 at a single tertiary hospital with a dedicated ocular radiation therapy clinic. The primary measure of treatment response was defined as the ability to taper glucocorticoids following RT without any further exacerbation of orbitopathy symptoms. Additional endpoints including ocular symptoms (diplopia, proptosis, visual acuity, extraocular movement) and need for surgical intervention were reported., Results: Of 86 eligible patients, with a mean follow-up of 9.3 months, 81 (94%) patients responded to RT. Of patients taking corticosteroids at baseline, 91% were able to taper off corticosteroids completely and the remaining patients had decreased their doses by 83%. Diplopia, visual acuity, and extraocular movements improved in 29%, 81%, and 58% of patients, respectively. The median reduction in proptosis was 2.5 mm and 2 mm in the left and right eyes, respectively (range, -18 mm to 23 mm)., Conclusions: Orbital RT is a generally well-tolerated treatment that helps minimize the dose and duration of corticosteroid therapy for patients with GO while improving ocular symptoms, including proptosis and diplopia. Prospective research should consider using corticosteroid requirement as a measure of response to orbital RT for GO., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Lupus is an autoimmune disease with a poorly understood etiology that manifests with a diverse pathology. This heterogeneity has been a challenge to clinical drug development efforts. A related difficulty is the uncertain translational power of animal models used for evaluating potential drug targets and candidate therapeutics, because it is unlikely that any 1 preclinical model will recapitulate the spectrum of human disease. Therefore, multiple models, along with an understanding of the immune mechanisms that drive them, are necessary if we are to use them to identify valid drug targets and evaluate candidate therapies successfully. To this end, we have characterized several different mouse lupus models and report their differences with respect to biomarkers and symptoms that are representative of the human disease. We compared the pristane-induced mouse lupus disease model using 3 different strains (DBA/1, SJL, BALB/c), and the spontaneous NZB x NZW F1(NZB/W) mouse model. We show that the models differ significantly in their autoantibody profiles, disease manifestations such as nephritis and arthritis, and expression of type I interferon-regulated genes. Similar to the NZB/W model, pristane-induced disease in SJL mice manifests with nephritis and proteinuria, whereas the pristane-treated DBA/1 mice develop arthritis and an interferon-driven gene signature that closely resembles that in human patients. The elucidation of each model's strengths and the identification of translatable biomarkers yields insight for basic lupus research and drug development, and should assist in the proper selection of models for evaluating candidate targets and therapeutic strategies., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Background: Eribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B. Eribulin is a tubulin-binding drug and approved in many countries worldwide for treatment of certain patients with advanced breast cancer. Here we investigated antiproliferative and antiangiogenic effects of eribulin on vascular cells, human umbilical vein endothelial cells (HUVECs) and human brain vascular pericytes (HBVPs), in vitro in comparison with another tubulin-binding drug, paclitaxel., Methods: HUVECs and HBVPs were treated with either eribulin or paclitaxel and their antiproliferative effects were evaluated. Global gene expression profiling changes caused by drug treatments were studied using Affymetrix microarray platform and custom TaqMan Low Density Cards. To examine effects of the drugs on pericyte-driven in vitro angiogenesis, we compared lengths of capillary networks in co-cultures of HUVECs with HBVPs., Results: Both eribulin and paclitaxel showed potent activities in in vitro proliferation of HUVECs and HBVPs, with the half-maximal inhibitory concentrations (IC50) in low- to sub-nmol/L concentrations. When gene expression changes were assessed in HUVECs, the majority of affected genes overlapped for both treatments (59%), while in HBVPs, altered gene signatures were drug-dependent and the overlap was limited to just 12%. In HBVPs, eribulin selectively affected 11 pathways (p < 0.01) such as Cell Cycle Control of Chromosomal Replication. In contrast, paclitaxel was tended to regulate 27 pathways such as PI3K/AKT. Only 5 pathways were commonly affected by both treatments. In in vitro pericyte-driven angiogenesis model, paclitaxel showed limited activity while eribulin shortened the formed capillary networks of HUVECs driven by HBVPs at low nmol/L concentrations starting at day 3 after treatments., Conclusions: Our findings suggest that pericytes, but not endothelial cells, responded differently, to two mechanistically-distinct tubulin-binding drugs, eribulin and paclitaxel. While eribulin and paclitaxel induced similar changes in gene expression in endothelial cells, in pericytes their altered gene expression was unique and drug-specific. In the functional endothelial-pericyte co-culture assay, eribulin, but not paclitaxel showed strong efficacy not only as a cytotoxic drug but also as a potent antivascular agent that affected pericyte-driven in vitro angiogenesis.

A minimally invasive diagnostic assay for early detection of Alzheimer's disease (AD) is required to select optimal patient groups in clinical trials, monitor disease progression and response to treatment, and to better plan patient clinical care. Blood is an attractive source for biomarkers due to minimal discomfort to the patient, encouraging greater compliance in clinical trials and frequent testing. MiRNAs belong to the class of non-coding regulatory RNA molecules of ∼22 nt length and are now recognized to regulate ∼60% of all known genes through post-transcriptional gene silencing (RNAi). They have potential as useful biomarkers for clinical use because of their stability and ease of detection in many tissues, especially blood. Circulating profiles of miRNAs have been shown to discriminate different tumor types, indicate staging and progression of the disease and to be useful as prognostic markers. Recently their role in neurodegenerative diseases, both as diagnostic biomarkers as well as explaining basic disease etiology has come into focus. Here we report the discovery and validation of a unique circulating 7-miRNA signature (hsa-let-7d-5p, hsa-let-7g-5p, hsa-miR-15b-5p, hsa-miR-142-3p, hsa-miR-191-5p, hsa-miR-301a-3p and hsa-miR-545-3p) in plasma, which could distinguish AD patients from normal controls (NC) with >95% accuracy (AUC of 0.953). There was a >2 fold difference for all signature miRNAs between the AD and NC samples, with p-values<0.05. Pathway analysis, taking into account enriched target mRNAs for these signature miRNAs was also carried out, suggesting that the disturbance of multiple enzymatic pathways including lipid metabolism could play a role in AD etiology.

Blepharoplasty is an operation to modify the contour and configuration of the eyelids in order to restore a more youthful appearance. The surgery involves removing redundant skin, fat, and muscle. In addition, supporting structures such as canthal tendons are tightened. Other conditions such as ptosis, brow ptosis, entropion, ectropion, or eyelid retraction may also need to be corrected at the time a blepharoplasty is performed to ensure the best functional and aesthetic result. Due to the complexity and intricate nature of eyelid anatomy, complications do exist. In addition to a thorough pre operative assessment and meticulous surgical planning, understanding the etiology of complications is key to prevention. Finally, management of complications is just as important as surgical technique.

We present an unusual variant of necrobiotic xanthogranuloma with periorbital involvement. Our patient had an unusually complicated course due to initial misdiagnosis and patient refusal to undergo treatment. We present her clinical course and review the literature on this rare lesion.

INTRODUCTION. The cause of primary acquired nasolacrimal duct obstruction (NLDO) has not been fully elucidated. In an attempt to determine the role of an inflammatory etiology, the pathology of nasolacrimal sac and bone specimens was assessed and correlated with clinical lacrimal variables. MATERIALS AND METHODS. Lacrimal sac and bone tissues from patients with known NLDO were sampled at the time of external dacryocystorhinostomy (DCR). Histopathological analysis was carried out to determine the presence and degree of inflammatory changes present in the tissues, and to correlate them with the clinical presentation. RESULTS. Of 104 cases analyzed, bony inflammatory changes were seen in 14% and lacrimal sac inflammatory changes in 94%. All cases of bony inflammation had accompanying lacrimal sac inflammation. The inflammatory changes were independent of the following variables: gender, duration of symptoms, a history of dacryocystitis, the presence of a lacrimal sac mucocele, the location of obstruction, and the presence of lacrimal sac calculi. CONCLUSIONS. Inflammatory changes are almost invariably present in all patients with NLDO. Its occurrence in bone is probably secondary to lacrimal sac inflammation. Although attempts are made to perform DCR surgery only in the absence of lacrimal sac inflammation, almost all cases exhibit subclinical inflammation. This may suggest that bypassing this 'critical area' of the sac-duct junction, as in a dacryocystorhinostomy, would be more reasonable than to re-canalize through an inflammatory obstruction.

Purpose: To describe the histologic features of the caruncle and to determine its anatomic relationship to the common canaliculus., Methods: Specimens from preserved and fresh-frozen cadavers were studied histopathologically., Results: The average distance between the external surface of the caruncle and the common canaliculus was 0.85 mm, whereas the shortest distance measured was 0.50 mm. Several histologic abnormalities (oncocytic change, apocrine metaplasia, and microscopic stones) were identified in specimens that appeared clinically normal., Conclusion: Caution should be exercised when operations are performed on or near the caruncle to avoid inadvertent damage to the canalicular system.

Objective: The authors describe the first case report of a fungal abscess within a hydroxyapatite orbital implant in a patient who had undergone straightforward secondary hydroxyapatite implant surgery., Design: Case report and literature review., Intervention: Four months postoperatively after pegging and 17 months after original implant placement, chronic discharge and socket irritation became evident. Recurrent pyogenic granulomas were a problem, but no obvious area of dehiscence was present over the implant. The peg and sleeve were removed 31 months after pegging (44 months after original placement of the implant). The pain and discharge did not resolve, and the entire hydroxyapatite orbital implant was removed 45 months after sleeve placement and 58 months after initial implant placement. The pain and discharge settled rapidly., Main Outcome Measures: Cultures and histopathology., Results: Results of bacterial cultures were negative. Results of histopathologic examination of the implant disclosed intertrabecular spaces with multiple clusters of organisms consistent with Aspergillus., Conclusions: Persistent orbital discomfort, discharge, and pyogenic granulomas after hydroxyapatite implantation should cause concern regarding potential implant infection. The authors have now shown that this implant infection could be bacterial or fungal in nature. This is essentially a new form of orbital Aspergillus, that of a chronic infection limited to a hydroxyapatite implant.

Purpose: To identify adrenergic receptor subtypes and their relative distribution in the retractor muscles of the upper eyelid, the levator palpebrae superioris, and the Müller muscle. The pattern of distribution of these receptors in the Müller muscle was further compared in patients with dysthyroid eyelid retraction and in normal subjects., Methods: Müller muscle specimens were collected from 19 patients undergoing ptosis correction and from 8 patients undergoing repair of dysthyroid eyelid retraction. Immunohistochemical staining for alpha 1-, alpha 2-, beta 1-, and beta 2-adrenergic receptors was performed using antihuman rabbit polyclonal antibodies., Results: alpha 2-Adrenergic receptors were the predominant subtype in the Müller muscle, and beta 1-adrenergic receptors were the predominant subtype in the levator muscle. There was no significant difference in the staining pattern between specimens collected from patients with dysthyroid eyelid retraction and those from normal subjects., Conclusions: The interaction between the alpha 2 and beta 1 receptors in the upper eyelid retractor muscles may be important in the control of the upper eyelid position and may contribute to the development of dysthyroid eyelid retraction. Specific alpha 2 antagonists could be developed and may be effective pharmacologic agents for the treatment of eyelid retraction.

Background: A few studies have assessed the sensitivity of ophthalmologists in diagnosing periocular lesions. However, no study has assessed their diagnostic specificity or the degree to which they overdiagnose various lesions. We performed a study to determine the sensitivity and specificity of oculoplastic surgeons' preoperative diagnoses of common and uncommon periocular lesions., Methods: Using the patient records of four oculoplastic ophthalmologists, we reviewed all charts documenting periocular surgery in which lesions were excised and sent for biopsy. For each of 358 cases we recorded the preoperative diagnosis as listed by the surgeon and the postoperative diagnosis as reported by the pathologist. Each preoperative diagnosis was then scored as correct or incorrect. The relative number of each type of lesion was determined, and the ophthalmologists' sensitivity and specificity were calculated., Results: The sensitivity and specificity for the eight most frequently lesions were (in order of frequency) basal cell carcinoma 92.1% and 81.6% respectively, papilloma 81.6% and 66.0%, cyst 66.7% and 69.7%, nevus 53.6% and 75.0%, seborrheic keratosis 27.8% and 71.4%, chalazion 93.3% and 100.0%, squamous cell carcinoma 33.3% and 55.6%, and xanthelasma 100.0% and 76.9%. The values for melanoma were 50.0% and 28.6%, for sebaceous gland carcinoma 0.0% and 100.0%, and for uncommon lesions (nonspecific inflammation, actinic keratosis, granuloma, cavernous hemangioma, folliculitis, benign sweat gland tumour, eccrine hidrocystoma and collagenous tissue) 27.8% and 57.1%. The overall accuracy in lesion identification was 70.0%., Interpretation: Although ophthalmologists have excellent diagnostic sensitivity and specificity for some types of lesion, such as basal cell carcinoma and chalazion, the identification of other lesion types, such as cyst, squamous cell carcinoma and possibly melanoma and sebaceous gland carcinoma, is less optimal.

Purpose: The authors analyzed all the complications associates with the first 100 hydroxyapatite orbital implants performed by one surgeon, and compare scleral wrapping versus Dexon mesh (polyglycolic acid, Davis & Geck, Manati, Puerto Rico) wrapping in light of these complications., Background: Prior studies have not included the full range of complications that can occur with hydroxyapatite orbital implants. Dexon mesh implant wrapping is a promising substitute for sclera and avoids the risks involved in using donor tissue., Methods: A retrospective analysis of 100 consecutive cases was performed., Results: Many minor complications occurred, but the rate of exposure was low (3%) and no implant was lost. Dexon mesh wrapping was similar to scleral wrapping with respect to complications, although more posterior implant placement was necessary to avoid exposure in the Dexon-wrapped group., Conclusions: Surgeons and patients must be prepared for many minor complications when using hydroxyapatite orbital implants, but these can be readily overcome. Dexon mesh wrapping of the implant is recommended to avoid using donor tissue.

Objective: To ascertain if cases of radial keratotomy wound rupture were occurring and whether the globes ruptured through the corneal incisions., Design: Cases of traumatic ruptured globe after incisional corneal refractive surgery were collected from ophthalmologists and from peer-reviewed and other ophthalmic literature., Results: Twenty-eight human eyes (eight previously unreported) are known to have ruptured through refractive corneal incisions in activities of daily living (n = 12), assault (n = 7), motor vehicle accidents (n = 5), and sports (n = 4). Two patients died of their injuries. Of the remaining 26 ruptured eyes, eight (31%) recovered 20/40 or better visual acuity. Six eyes (23%) were totally blinded, six (23%) were legally blinded, and six (23%) had best corrected visual acuity of 20/40 to 20/100 despite multiple surgical procedures., Conclusions: As radial keratotomy becomes more popular the pool of patients who may experience traumatic ruptured globe will grow. Every patient who has had radial keratotomy should be aware that the surgery has weakened the eye(s).

We encountered two patients referred for treatment of Graves' eye disease who had atypical features and were found to have carotid-cavernous fistulae. The relevant clinical findings and investigations used to make this important distinction are described, and the factors involved in the initial diagnostic confusion are analyzed. A correct diagnosis leading to proper treatment was made once atypical features were taken note of and alternative diagnoses considered, despite the context of presumed Graves' eye disease. We conclude that these two entities are quite different but have enough similarities to overlap in certain clinical contexts.

We built an experimental apparatus to investigate the passive elastic characteristics of orbicularis oculi muscle and examined specimens from normal humans, humans with stable Graves' eye disease, and cynomolgus monkeys. Stress-strain curves were determined and found to be exponential. The elastic modulus (Young's modulus), analogous to the stiffness of the material, was calculated as a function of strain. Elastic modulus as a function of instantaneous stress was linear. Monkey elastic modulus values were determined, but did not allow meaningful interspecies comparison because of the small sample size. No significant difference was found between normal humans and humans with Graves' eye disease with respect to elastic modulus values.

We describe the two oldest individuals with nodular granuloma annulare (pseudorheumatoid nodules) in the ophthalmologic literature and propose a unified classification scheme that recognizes pseudorheumatoid nodules to be granuloma annulare, nodular type. All lesions in both cases revealed so-called necrobiotic granulomas, characterized by an acellular central area containing mucin (hyaluronic acid) surrounded by palisading histiocytes (macrophages), diagnostic of granuloma annulare. These features are identical to those reported in the ophthalmologic and older general pathology literature as pseudorheumatoid nodules and the contemporary general and dermatologic pathology literature as granuloma annulare. We believe the diagnosis of nodular granuloma annulare should be employed for necrobiotic lesions displaying distinctive clinicopathologic features to unite the ophthalmologic, general, and dermatologic pathology literature. Granuloma annulare, nodular type, must also be considered in the differential diagnosis of ocular and periocular lesions at any age.